"Science, Faculty of"@en . "Chemistry, Department of"@en . "DSpace"@en . "UBCV"@en . "Boulet, Serge L."@en . "2009-06-18T19:13:24Z"@en . "1998"@en . "Doctor of Philosophy - PhD"@en . "University of British Columbia"@en . "The total syntheses of four structurally related, naturally occurring compounds, (\u00C2\u00B1)\u00C2\u00ADverrucosan-2\u00CE\u00B2-ol (61), (\u00C2\u00B1)-neoverrucosan-5\u00CE\u00B2-ol (62), (\u00C2\u00B1)-homoverrucosan-5\u00CE\u00B2,-ol (63), and (\u00C2\u00B1)-(3R, 4R, 5R, 6S, 9#)-cyatha-12,18-diene (64) are discussed in the first part of this thesis. In connection with the total syntheses of the natural products 61-64, a new bifunctional reagent mediated cyclohexenone annulation sequence was developed, but attempted application of this sequence to the natural product syntheses was not successful. The generality, scope and synthetic utility of this new annulation method are described in the second part of this thesis. \r\nThe syntheses of the natural products 61-64 started with the conversion of 3 \u00C2\u00ADmethylcyclohex-2-en-l-one (140) into the known bicyclic enone 179. Recently developed methodology from our laboratory was used as a key step and involved the stereoselective conjugate addition reaction of the cuprate reagent 192 to the enone 179 with control of the 5,6 ring-juncture stereochemistry to afford the ketone 60. A double alkylation of 60, first with the bifunctional reagent 281, and then with methyl iodide, provided the ketone 287. Functional group manipulations were used to convert 287 into 273, which underwent an aldol cyclization-dehydration sequence to provide the corresponding enone 72. Dissolving metal reduction of the latter material afforded the tricyclic ketone 171. From compound 171, diverging synthetic routes gave the cyathane natural product 64 and the three verrucosane\u00C2\u00ADtype natural products 61-63. Ring expansion of 171 and functional group manipulations led to 64. Conversion of 171 into the tricyclic enone 174 involved a series of functional group transformations. Separate synthetic routes from compound 174 led to (\u00C2\u00B1)-neoverrucosan-5\u00CE\u00B2\u00C2\u00ADol (62) or (\u00C2\u00B1)-verrucosan-2\u00CE\u00B2-ol (61), both of which reacted with acid to produce (\u00C2\u00B1)\u00C2\u00AD\r\nhomoverrucosan-5 (5\u00CE\u00B2-ol (63). The four racemic natural products were tested against the P388 \r\nmurine leukemia cell line and possessed cytotoxicity with ED\u00E2\u0082\u0085\u00E2\u0082\u0080's in the range of 1.7\u00C2\u00AD\r\n21 \u00C2\u00B5g/mL. \r\nThe newly developed cyclohexenone annulation sequence involved alkylation of N,N\u00C2\u00ADdimethylhydrazones of general structure 32 with the Afunctional reagent 253 to provide 354. Conversion of 354 into the keto alkenyl iodide 356, followed by n-BuLi-mediated cyclization of 356 and oxidative rearrangement of the resultant allylic alcohol 358 provided the cyclohexenone 359. Each step is experimentally simple, tolerates a variety of ring sizes and functionality, and proceeds in very good yield. [Formula]"@en . "https://circle.library.ubc.ca/rest/handle/2429/9454?expand=metadata"@en . "12358183 bytes"@en . "application/pdf"@en . "TOTAL SYNTHESES OF (\u00C2\u00B1)-NEOVERRUCOSAN-5R-OL, (\u00C2\u00B1)-HOMOVERRUCOSAN-5 R-OL, (+)-VERRUCOSAN-2 (3-OL, AND (\u00C2\u00B1H3R, AR, 5R, 65,9/?)-CYATHA-12,18-DIENE. A NEW CYCLOHEXENONE ANNULATION SEQUENCE. by SERGE L. BOULET B.Sc. (Hons.), University of Manitoba, 1992 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNFVERSITY OF BRITISH COLUMBIA July, 1998 \u00C2\u00A9 Serge L. Boulet, 1998 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of /\? WKK'r^'Ty The University of British Columbia Vancouver, Canada Date DE-6 (2/88) ABSTRACT T h e t o t a l s y n t h e s e s o f f o u r s t r u c t u r a l l y r e l a t e d , n a t u r a l l y o c c u r r i n g c o m p o u n d s , (\u00C2\u00B1) -v e r r u c o s a n - 2 f i - o l (61), (\u00C2\u00B1)-neoverrucosan-5p-ol (62), (\u00C2\u00B1)-homoverrucosan-5p , -ol (63), a n d (\u00C2\u00B1)-(3R, 4R, 5R, 6S, 9 # ) - c y a t h a - 1 2 , 1 8 - d i e n e (64) a re d i s c u s s e d i n t h e f i r s t p a r t o f t h i s t h e s i s . I n c o n n e c t i o n w i t h t h e t o t a l s y n t h e s e s o f t h e n a t u r a l p r o d u c t s 61-64, a n e w b i f u n c t i o n a l r e a g e n t m e d i a t e d c y c l o h e x e n o n e a n n u l a t i o n s e q u e n c e w a s d e v e l o p e d , b u t a t t e m p t e d a p p l i c a t i o n o f t h i s s e q u e n c e t o t h e n a t u r a l p r o d u c t s y n t h e s e s w a s n o t s u c c e s s f u l . T h e g e n e r a l i t y , s c o p e a n d s y n t h e t i c u t i l i t y o f t h i s n e w a n n u l a t i o n m e t h o d a r e d e s c r i b e d i n t h e s e c o n d p a r t o f t h i s t h e s i s . T h e s y n t h e s e s o f t h e n a t u r a l p r o d u c t s 61-64 s t a r t e d w i t h t h e c o n v e r s i o n o f 3 -m e t h y l c y c l o h e x - 2 - e n - l - o n e (140) i n t o t h e k n o w n b i c y c l i c e n o n e 179. R e c e n t l y d e v e l o p e d m e t h o d o l o g y f r o m o u r l a b o r a t o r y w a s u s e d as a k e y s t e p a n d i n v o l v e d t h e s t e r e o s e l e c t i v e c o n j u g a t e a d d i t i o n r e a c t i o n o f the c u p r a t e r e a g e n t 192 to t h e e n o n e 179 w i t h c o n t r o l o f t h e 5 , 6 r i n g - j u n c t u r e s t e r e o c h e m i s t r y to a f f o r d t h e k e t o n e 60. A d o u b l e a l k y l a t i o n o f 60, f i r s t w i t h t h e b i f u n c t i o n a l r e a g e n t 281, a n d t h e n w i t h m e t h y l i o d i d e , p r o v i d e d t h e k e t o n e 287. F u n c t i o n a l g r o u p m a n i p u l a t i o n s w e r e u s e d t o c o n v e r t 287 i n t o 273, w h i c h u n d e r w e n t a n a l d o l c y c l i z a t i o n - d e h y d r a t i o n s e q u e n c e t o p r o v i d e t h e c o r r e s p o n d i n g e n o n e 72. D i s s o l v i n g m e t a l r e d u c t i o n o f t h e l a t t e r m a t e r i a l a f f o r d e d t h e t r i c y c l i c k e t o n e 171. F r o m c o m p o u n d 171, d i v e r g i n g s y n t h e t i c r o u t e s g a v e t h e c y a t h a n e n a t u r a l p r o d u c t 64 a n d t h e t h r e e v e r r u c o s a n e -t y p e n a t u r a l p r o d u c t s 61-63. R i n g e x p a n s i o n o f 171 a n d f u n c t i o n a l g r o u p m a n i p u l a t i o n s l e d to 64. C o n v e r s i o n o f 171 i n t o the t r i c y c l i c e n o n e 174 i n v o l v e d a s e r i e s o f f u n c t i o n a l g r o u p t r a n s f o r m a t i o n s . S e p a r a t e s y n t h e t i c r o u t e s f r o m c o m p o u n d 174 l e d t o (\u00C2\u00B1)-neoverrucosan-5p-o l (62) o r (\u00C2\u00B1)-verrucosan-2p-ol (61), b o t h o f w h i c h r e a c t e d w i t h a c i d t o p r o d u c e (\u00C2\u00B1 ) -h o m o v e r r u c o s a n - 5 (5-ol (63). T h e f o u r r a c e m i c n a t u r a l p r o d u c t s w e r e t e s t e d a g a i n s t t h e P 3 8 8 m u r i n e l e u k e m i a c e l l l i n e a n d p o s s e s s e d c y t o t o x i c i t y w i t h EDso's i n t h e r a n g e o f 1 .7 -21 n g /mL. T h e n e w l y d e v e l o p e d c y c l o h e x e n o n e a n n u l a t i o n s e q u e n c e i n v o l v e d a l k y l a t i o n o f N,N-d i m e t h y l h y d r a z o n e s o f g e n e r a l s t r u c t u r e 32 w i t h t h e A f u n c t i o n a l r e a g e n t 253 to p r o v i d e 354. C o n v e r s i o n o f 354 i n t o t h e k e t o a l k e n y l i o d i d e 356, f o l l o w e d b y n - B u L i - m e d i a t e d c y c l i z a t i o n o f 356 a n d o x i d a t i v e r e a r r a n g e m e n t o f t h e r e s u l t a n t a l l y l i c a l c o h o l 358 p r o v i d e d t h e c y c l o h e x e n o n e 359. E a c h s tep i s e x p e r i m e n t a l l y s i m p l e , t o l e r a t e s a v a r i e t y o f r i n g s i z e s a n d f u n c t i o n a l i t y , a n d p r o c e e d s i n v e r y g o o d y i e l d . 64 140 179 192 O 60 354 356 358 359 TABLE OF CONTENTS ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i i LIST OF FIGURES i x LIST OF GENERAL PROCEDURES x LIST OF ABBREVIATIONS x i ACKNOWLEDGEMENTS xv L INTRODUCTION 1 1.1. G E N E R A L . . . 1 1.2. B A C H G R O U N D 4 1.3. PROPOSALS 13 II. DISCUSSION 16 2.1. T O T A L SYNTHESIS O F T H E DITERPENOIDS (\u00C2\u00B1)-VERRUCOSAN-2p-OL,(+)-NEOVERRUCOSAN -5f3 -OL, (\u00C2\u00B1) -HOMOVERRUCOSAN -5B -OL, AND (\u00C2\u00B1H3R, 4R, 5R, 6S, 9/?)-CYATHA-12,18-DIENE 16 2.1.1. Introductory Remarks 16 2.1.2. Biogenetic Pathway and Synthetic Implications 19 2.1.3. Previous Cyathane Synthetic Studies 2 2 2 . 1 . 3 . 1 . A p p r o a c h b y A y e r a n d W a r d 2 3 2 . 1 . 3 . 2 . A p p r o a c h b y P a q u e t t e 2 6 2 . 1 . 3 . 3 . S u c c e s s f u l A p p r o a c h b y S n i d e r 2 9 2 . 1 . 3 . 4 . S u c c e s s f u l A p p r o a c h b y T o r i 3 2 2 . 1 . 3 . 5 . A l t e r n a t i v e A p p r o a c h b y P i e r s 3 5 2.1.4. Retrosynthetic Analysis 3 7 2.1.5. Towards the Total Synthesis of (\u00C2\u00B1)-Verrucosan-2p-ol, (\u00C2\u00B1)-Neoverrucosan-5P-ol, (\u00C2\u00B1)Homoverrucosan-5(3-01, and (\u00C2\u00B1)-(3R, 4R, 5R, 65,9/f)-Cyatha-12,18-diene 4 0 2 . 1 . 5 . 1 . P r e p a r a t i o n o f the B i c y c l i c K e t o n e 60 4 0 2 . 1 . 5 . 2 . D e v e l o p m e n t o f a N e w C y c l o h e x e n o n e A n n u l a t i o n S e q u e n c e 5 2 2 . 1 . 5 . 3 . P r e p a r a t i o n o f the T r i c y c l i c K e t o n e 171 8 4 2 . 1 . 5 . 4 . P r e p a r a t i o n o f t h e T r i c y c l i c E n o n e 174 1 0 0 2 . 1 . 5 . 5 . C o m p l e t i o n o f t h e S y n t h e s i s o f (\u00C2\u00B1)-Neoverrucosan-5 p - o l (62) a n d (\u00C2\u00B1)-Homoverrucosan-5-ol (63) 116 2 . 1 . 5 . 6 . C o m p l e t i o n o f t h e S y n t h e s i s o f (\u00C2\u00B1)-Verrucosan-5 p - o l (61) 1 2 9 2 . 1 . 5 . 7 . C o m p l e t i o n o f the S y n t h e s i s o f (\u00C2\u00B1 ) -(3R, AR, 5R, 6 5 , 9 t f ) - c y a t h a - 1 2 , 1 8 - d i e n e (64) 137 2.1.6. Biological Activity Studies 146 2.1.7. Conclusions 148 2.2. B I F U N C T I O N A L R E A G E N T M E D I A T E D C Y C L O H E X E N O N E A N N U L A T I O N M E T H O D O L O G Y . 151 2.2.1. Introductory Remarks 151 2.2.2. Preparation of the A^A^-Dimethylhydrazones Substrates 153 2.2.3. Preparation of the Bifunctional Reagent (Z)-4-Iodo-l-(tributylstannyl)but-l-ene (253) 154 2.2.4. Preparation of the Keto Alkenyl Iodide Cyclization Substrates 155 2.2.5. Cyclization of the Keto Alkenyl Iodides to Provide the Tertiary Allylic Alcohols 1 6 2 2.2.6. Oxidative Rearrangement of the Tertiary Allylic Alcohols to the Cyclohexenones 1 7 3 2.2.7. Conclusions 1 7 6 III. EXPERIMENTAL 177 3.1. G E N E R A L 177 3.1.1. Data Acquisition, Presentation, and Experimental Techniques 177 3.1.2. Solvents and Reagents 1 8 0 vi 3.2. T O T A L SYNTHESIS O F T H E DITERPENOIDS (\u00C2\u00B1) -VERRUCOSAN -2B -OL, (\u00C2\u00B1 ) -NEOVERRUCOSAN -5 B -OL, ( \u00C2\u00B1 ) - H O M O V E R R U C O S A N - 5 B - O L , AND (\u00C2\u00B1)-(3R, 4R, 5R, 65 ,9fl ) -CYATHA -12 ,18 -DIENE 183 3.3. B I F U N C T I O N A L R E A G E N T M E D I A T E D C Y C L O H E X E N O N E A N N U L A T I O N M E T H O D O L O G Y 2 5 4 3.3.1. Preparation of tyN-Dimethylhydrazone Substrates 2 6 4 3.3.2. General Procedure 1: P r e p a r a t i o n o f t h e K e t o A l k e n y l I o d i d e s f r o m t h e C o r r e s p o n d i n g 7 Y , / V - D i m e t h y l h y d r a z o n e s a n d ( Z ) - 4 - I o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) 2 6 9 3.3.3. General Procedure 2 : C y c l i z a t i o n o f t h e K e t o A l k e n y l I o d i d e s V i a M e t a l - H a l o g e n E x c h a n g e 2 8 9 3.3.4. General Procedure 3: O x i d a t i v e R e a r r a n g e m e n t o f t h e T e r t i a r y A l l y l i e A l c o h o l s to t h e a , B - U n s a t u r a t e d K e t o n e s 3 0 4 IV. REFERENCES AND FOOTNOTES 3 1 6 v i i LIST OF TABLES Table 1 . A t t e m p t s to C y c l i z e the K e t o A c e t a l 1 8 5 to F o r m t h e B i c y c l i c E n o n e 1 8 6 4 3 Table 2 . C u p r a t e C o n j u g a t e A d d i t i o n s to B i c y c l o [ 4 . 3 . 0 ] n o n - 9 - e n - 2 - o n e s a n d T h e r m o d y n a m i c a l l y C o n t r o l l e d E q u i l i b r a t i o n o f t h e 1 , 4 - A d d u c t s 4 5 Table 3 . T h e T h e r m o d y n a m i c a l l y C o n t r o l l e d E q u i l i b r a t i o n o f s e l e c t e d cis- a n d trans- F u s e d S y s t e m s 4 7 Table 4 . I o d o d e g e r m y l a t i o n R e a c t i o n s U s i n g I o d i n e 61 Table 5 . B r o m o d e g e r m y l a t i o n R e a c t i o n s U s i n g B r o m i n e 6 4 Table 6 . B r o m o d e g e r m y l a t i o n R e a c t i o n s U s i n g N - B r o m o s u c c i n i m i d e ( N B S ) 6 6 Table 7 . I o d o d e g e r m y l a t i o n R e a c t i o n s o f A l k y l a t e d G ' s - A l k e n y l g e r m a n e s 6 7 Table 8 . C h e m i c a l S h i f t a n d P e a k W i d t h at H a l f - H e i g h t f o r S e l e c t e d C - 5 H y d r o x y l a t e d C o m p o u n d s 118 Table 9 . C o m p a r i s o n o f t h e M e l t i n g P o i n t , a n d the I R a n d * H n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( - ) - N e o v e r r u c o s a n - 5 | } - o l ( 62 ) a n d the S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5p-ol ( 6 2 ) 1 2 0 Table 1 0 . C o m p a r i s o n o f 1 3 C n m r S p e c t r a l D a t a f o r the N a t u r a l ( - ) - N e o v e r r u c o s a n - 5 p - o l ( 62 ) a n d the S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5p-ol ( 6 2 ) 121 Table 1 1 . C o m p a r i s o n o f the M e l t i n g P o i n t , a n d the I R a n d * H n m r S p e c t r a l D a t a f o r the N a t u r a l ( + ) - H o m o v e r r u c o s a n - 5 P - o l (63) a n d the S y n t h e t i c ( + ) - H o m o v e r r u c o s a n - 5 P - o l (63 ) 125 Table 1 2 . C o m p a r i s o n o f the 1 3 C n m r S p e c t r a l D a t a f o r the N a t u r a l ( + ) - H o m o v e r r u c o s a n - 5 p - o l ( 6 3 ) a n d the S y n t h e t i c (\u00C2\u00B1)-Homoverrucosan-5P-ol ( 6 3 ) 126 Table 1 3 . C o m p a r i s o n o f the M e l t i n g P o i n t , a n d the I R a n d ^ H n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( - ) - V e r r u c o s a n - 2 p - o l ( 61 ) a n d t h e S y n t h e t i c (\u00C2\u00B1)-Verrucosan-2p-ol (61 ) 1 3 4 v i i i Table 14. C o m p a r i s o n o f the 1 3 C n m r S p e c t r a l D a t a f o r the N a t u r a l ( - ) - V e r r u c o s a n -2 p - o l (61) a n d t h e S y n t h e t i c (\u00C2\u00B1)-Verrucosan-2B-ol (61) 135 Table 15. C o m p a r i s o n o f the TR a n d lH n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( - ) - C y a t h a n e (64) a n d t h e S y n t h e t i c ( i ) - C y a t h a n e (64) 1 4 4 Table 16. In vitro C y t o t o x i c i t y o f t h e S y n t h e t i c R a c e m i c C y a t h a n e a n d V e r r u c o s a n e - t y p e N a t u r a l P r o d u c t s A g a i n s t t h e P 3 8 8 M u r i n e L e u k e m i a C e l l L i n e 147 Table 17. P r e p a r a t i o n o f the K e t o A l k e n y l I o d i d e s f r o m t h e / V , N - D i m e t h y l h y d r a z o n e s 158 Table 18. B u t y l l i t h i u m - M e d i a t e d C y c l i z a t i o n o f the K e t o A l k e n y l I o d i d e s 165 Table 19. O x i d a t i o n o f t h e T e r t i a r y A l l y l i c A l c o h o l s to the C y c l o h e x e n o n e s 175 Table 20. lU n m r ( 4 0 0 M H z , C D C 1 3 ) D a t a f o r the C w - F u s e d B i c y c l i c K e t o n e 194: C O S Y a n d N O E E x p e r i m e n t s 191 Table 21. lH n m r ( 4 0 0 M H z , CDCI3) D a t a f o r the 7 r a n s - F u s e d B i c y c l i c K e t o n e 60: N O E E x p e r i m e n t s 1 9 3 Table 22. lU n m r ( 4 0 0 M H z , CDCI3) D a t a f o r t h e B i c y c l i c H y d r a z o n e 210: C O S Y E x p e r i m e n t 198 Table 23. lU n m r ( 4 0 0 M H z , CDCI3) D a t a f o r the B i c v c l i c D i k e t o n e 273: C O S Y a n d N O E E x p e r i m e n t s 2 1 0 Table 24. ! H n m r ( 4 0 0 M H z , CDCI3) D a t a f o r the T r i c y c l i c K e t o n e 171: C O S Y a n d N O E E x p e r i m e n t s 2 1 5 Table 25. ! H n m r ( 4 0 0 M H z , CDCI3) D a t a f o r the a - H y d r o x y K e t o n e 311: N O E E x p e r i m e n t s 2 2 0 Table 26. * H n m r ( 4 0 0 M H z , C D C I 3 ) D a t a f o r the K e t o E t h e r 317: H o m o n u c l e a r D e c o u p l i n g E x p e r i m e n t s 2 2 3 Table 27. lH n m r ( 4 0 0 M H z , C D C 1 3 ) D a t a f o r ( Z ) - 4 - ( T r i m e t h y l g e r m y l ) b u t -3 - e n - l - o l (207): N O E E x p e r i m e n t s 2 5 8 LIST OF FIGURES Figure 1 . P r o p o s e d T r a n s i t i o n S t a t e f o r I o d o d e m e t a l a t i o n w i t h R e t e n t i o n o f C o n f i g u r a t i o n 6 2 Figure 2 . S t a b i l i z a t i o n o f a C a r b o n i u m I o n b y a P - S i l y l S u b s t i t u e n t 6 3 Figure 3 . T h e lH n m r S p e c t r u m ( 4 0 0 M H z , CDCI3) o f S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5p-ol ( 6 2 ) 1 2 2 Figure 4 . C o m p a r i s o n B e t w e e n the * H n m r S p e c t r a ( 4 0 0 M H z , CDCI3) o f S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5p-ol ( A ) a n d N a t u r a l (\u00C2\u00B1)-Neoverrucosan-5p-ol ( 6 2 ) 123 Figure 5 . T h e ! H n m r S p e c t r u m ( 4 0 0 M H z , CDCI3) o f S y n t h e t i c (\u00C2\u00B1)-Homoverrucosan-5p-ol ( B ) ( 6 3 ) 127 Figure 6 . C o m p a r i s o n B e t w e e n the * H n m r S p e c t r a ( 4 0 0 M H z , CDCI3) o f S y n t h e t i c (\u00C2\u00B1)-Homoverrucosan-5 P - o l ( A ) a n d N a t u r a l ( + ) - H o m o v e r r u c o s a n - 5 p - o l ( B ) ( 6 3 ) 128 Figure 7 . T h e lU n m r S p e c t r u m ( 4 0 0 M H z , CD2CI2) o f S y n t h e t i c (\u00C2\u00B1)-Verrucosan-2p-ol (61 ) 1 3 6 Figure 8 . T h e lH n m r S p e c t r u m ( 4 0 0 M H z , CDCI3) o f S y n t h e t i c (\u00C2\u00B1)-(3R, 4R, 5R, 6S, 9 / ? ) - C y a t h a - 1 2 , 1 8 - d i e n e ( 6 4 ) 145 1 X LIST OF GENERAL PROCEDURES General Procedure 1: P r e p a r a t i o n o f t h e K e t o A l k e n y l I o d i d e s f r o m t h e C o r r e s p o n d i n g 7 V , / Y - D i m e t h y l h y d r a z o n e s a n d ( Z ) - 4 - I o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) 2 6 9 General Procedure 2: C y c l i z a t i o n o f t h e K e t o A l k e n y l I o d i d e s V i a M e t a l - H a l o g e n E x c h a n g e 2 8 9 General Procedure 3: O x i d a t i v e R e a r r a n g e m e n t o f the T e r t i a r y A l l y l i c A l c o h o l s to the a , P - U n s a t u r a t e d K e t o n e s 3 0 4 x i LIST OF ABBREVIATIONS A - a n g s t r o m a - b e l o w the p l a n e o f a r i n g o r 1 , 2 - r e l a t i v e p o s i t i o n A c - a c e t y l a m u - a t o m i c m a s s u n i t s a n a l . - a n a l y s i s A P T - a t t a c h e d p r o t o n test a x - a x i a l ft - a b o v e the p l a n e o f a r i n g o r 1 , 3 - r e l a t i v e p o s i t i o n 9 - B B N - 9 - b o r a b i c y c l o [ 3 . 3 . 1 ] n o n a n e B n - b e n z y l b p - b o i l i n g p o i n t br - b r o a d B u - b u t y l B z - b e n z o y l \u00C2\u00B0C - d e g r e e s C e l s i u s c a l c d . - c a l c u l a t e d c m - c e n t i m e t e r C O S Y - ( 1 H - 1 H ) - h o m o n u c l e a r c o r r e l a t i o n s p e c t r o s c o p y C p - c y c l o p e n t a d i e n y l 1 8 - c r - 6 - 1 8 - c r o w n - 6 ( 1 , 4 , 7 , 10 , 1 3 , 1 6 - h e x a o x a c y c l o o c t a d e c a n e ) C S A - c a m p h o r s u l p h o n i c a c i d C - x - c a r b o n n u m b e r x d - d o u b l e t 8 - c h e m i c a l s h i f t i n pa r t s p e r m i l l i o n f r o m t e t r a m e t h y l s i l a n e A - heat D B U - 1 , 8 - d i a z a b i c y c l o [ 5 . 4 . 0 ] u n d e c - 7 - e n e D E A D - d i e t h y l a z o d i c a r b o x y l a t e D I B A L - H - d i i s o b u t y l a l u m i n u m h y d r i d e D M A P - 4 - d i m e t h y l a m i n o p y r i d i n e D M S - d i m e t h y l s u l f i d e D M S O - d i m e t h y l s u l f o x i d e D N A - d e o x y r i b o n u c l e i c a c i d e\" \" e l e c t r o n x i i E - e n t g e g e n ( c o n f i g u r a t i o n ) e d . - e d i t i o n E d . , E d s . - e d i t o r , e d i t o r s E D 50 - e f f e c t i v e d o s e (to k i l l 5 0 % o f a b i o l o g i c a l s a m p l e ) e .g . - exempli gratia ( f o r e x a m p l e ) epi - e p i m e r i c e q - e q u a t o r i a l e q u i v . - e q u i v a l e n t ( s ) E t - e t h y l g - g r a m G G P P - g e r a n y l g e r a n y l p y r o p h o s p h a t e g l c - g a s - l i q u i d c h r o m a t o g r a p h y h - h o u r ( s ) H M D S - 1 , 1 , 1 , 3 , 3 , 3 - h e x a m e t h y l d i s i l a z a n e H M P A - h e x a m e t h y l p h o s p h o r a m i d e H O M O - h i g h e s t o c c u p i e d m o l e c u l a r o r b i t a l H P L C - h i g h p e r f o r m a n c e l i q u i d c h r o m a t o g r a p h y H - x - h y d r o g e n n u m b e r x H z - he r t z / - i s o I C 50 - i n h i b i t o r y c o n c e n t r a t i o n ( f o r 5 0 % o f a b i o l o g i c a l s a m p l e ) / - P r D M S - w o - p r o p y l d i m e t h y l s i l y l I R - i n f r a r e d J - c o u p l i n g c o n s t a n t i n h e r t z n^Sn-H - n b o n d c o u p l i n g f o r t i n a n d p r o t o n n u c l e i ( i n h e r t z ) K D A - p o t a s s i u m d i i s o p r o p y l a m i d e K H M D S - p o t a s s i u m 1 , 1 , 1 , 3 , 3 , 3 - h e x a m e t h y l d i s i l a z i d e L D A - l i t h i u m d i i s o p r o p y l a m i d e L i H M D S - l i t h i u m 1 , 1 , 1 , 3 , 3 , 3 - h e x a m e t h y l d i s i l a z i d e L i T M P - l i t h i u m 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i n e L U M O - l o w e s t o c c u p i e d m o l e c u l a r o r b i t a l m - m u l t i p l e t m - m e t a M - m o l a r ra-CPBA - m e t a - c h l o r o p e r b e n z o i c a c i d M e - m e t h y l Xlll m g m i l l i g r a m ( s ) m i c r o g r a m ( s ) M H z m e g a h e r t z m i n m i n u t e ( s ) m L m i l l i l i t e r ( s ) u L m i c r o l i t e r ( s ) m m m i l l i m e t e r ( s ) u r n m i c r o m e t e r ( s ) m m o l m i l l i m o l e ( s ) m o l . m o l e c u l a r m p m e l t i n g p o i n t M s m e t h a n e s u l f o n y l n n o r m a l N B S A ^ - b r o m o s u c c i n i m i d e M S N - i o d o s u c c i n i m i d e N M O A ^ - m e t h y l m o r p h o l i n e / V - o x i d e n m r n u c l e a r m a g n e t i c r e s o n a n c e N O E n u c l e a r O v e r h a u s e r e f f e c t P p a g e P p a r a P C C p y r i d i n i u m c h l o r o c h r o m a t e p H - l o g i o [ H + ] P h p h e n y l P P p a g e s P P p y r o p h o s p h a t e p p m par ts p e r m i l h o n P P T S p y r i d i n i u m / ? - t o l u e n e s u l f o n a t e P r p r o p y l p y p y r i d i n e q q u a r t e t R r e c t u s ( c o n f i g u r a t i o n ) rt r o o m t e m p e r a t u r e s s i n g l e t S s i n i s t e r ( c o n f i g u r a t i o n ) sec s e c o n d a r y S E M ( t r i m e t h y l s i l y l ) e t h o x y m e t h y l C t triplet t tertiary T B A F tetrabutylammonium fluoride T B D P S terf-butyldiphenylsilyl T B S tert -butyldimethylsilyl tert tertiary T f trifluoromethanesulfonyl T H F tetrahydrofuran tic thin layer chromatography T M S trimethylsilyl T P A P tetrapropylammonium perruthenate UV ultraviolet -ve negative v/v volume-to-volume ratio mri peak width at half height w/v weight-to-volume ratio Z zusammen (configuration) \u00E2\u0080\u00A2 coordination or complex \u00C2\u00B1 racemic ACKNOWLEDGMENTS X V First and foremost, I would like to acknowledge my research supervisor and mentor Dr. Edward Piers, for having given me the opportunity to join his group, for his support and guidance, and for teaching me an uncompromising commitment to excellence in research. Thanks to all members of the Piers' group, past and present, that I have had the pleasure to know and for having provided a stimulating work and learning environment. Many friends were made and many memories will remain. A special thanks goes out to Patricia Gladstone and Dr. Larry Weiler for proof-reading my thesis. The assistance from the nmr and technical support staff in the chemistry department at UBC is gratefully acknowledged. I would like to dedicate this thesis to my parents whose support and encouragement throughout all theses years were felt in so many ways. Finally, my deepest thanks and appreciation goes to my wife Suzin for having embarked on this journey with me from the beginning, for helping me put it all in perspective, and giving it meaning and purpose. I. INTRODUCTION 1.1. General T h e e v o l u t i o n o f the c h e m i c a l s c i e n c e s i n t h e l a s t c e n t u r y h a s b e e n g r e a t l y i n f l u e n c e d b y t h e p a r a l l e l g r o w t h o f t h e t e c h n o l o g i c a l s e c t o r . O r g a n i c c h e m i s t r y i n p a r t i c u l a r h a s b e e n s t r o n g l y a f f e c t e d b y t h e i n c r e a s e d a v a i l a b i l i t y o f a w i d e v a r i e t y o f u s e f u l s t a r t i n g m a t e r i a l s a n d b y t h e a d v e n t o f i m p r o v e d m e t h o d s f o r t h e s e p a r a t i o n ( c h r o m a t o g r a p h y ) a n d i d e n t i f i c a t i o n ( s p e c t r o s c o p y ) o f o r g a n i c c o m p o u n d s . 1 T h e s e i m p r o v e m e n t s h a v e c a u s e d a s h i f t i n e m p h a s i s f r o m t h e i n v e s t i g a t i o n o f s i m p l e t r a n s f o r m a t i o n s t o i s s u e s o f i n c r e a s e d c o n t r o l a n d s e l e c t i v i t y . S y n t h e t i c o r g a n i c c h e m i s t r y i s g e n e r a l l y d i v i d e d i n t o t w o s u b d i s c i p l i n e s . T h e f i r s t i s m e t h o d o l o g i c a l a n d c o n c e r n s i t s e l f w i t h t h e d e v e l o p m e n t a n d d i s c o v e r y o f n e w c h e m i c a l r e a c t i o n s , a n d a s s e s s i n g t h e i r s c o p e , l i m i t a t i o n s , a n d g e n e r a l i t y . M o s t o f t e n , t h i s m e t h o d -b a s e d r e s e a r c h i s s t i m u l a t e d b y a s p e c i f i c p r o b l e m e n c o u n t e r e d i n t h e s e c o n d b r a n c h o f s y n t h e t i c o r g a n i c c h e m i s t r y , w h i c h i s t a r g e t - b a s e d . I n t h i s a r e a , c h e m i s t s s e l e c t a p a r t i c u l a r s u b s t a n c e , o f t e n a n a t u r a l l y o c c u r r i n g c o m p o u n d ( o r a n a l o g t h e r e o f ) , a n d s e t t h e t o t a l s y n t h e s i s o f t h i s m a t e r i a l as t h e i r g o a l . S p e c i f i c a l l y t a i l o r e d o r g a n i c m o l e c u l e s a r e o f t e n the p r o b e s w h i c h o t h e r b r a n c h e s o f s c i e n c e u s e t o f u l f i l l t h e i r r e s e a r c h n e e d s . T h e p h a r m a c e u t i c a l s c i e n c e s a n d m e d i c i n a l c h e m i s t r y e m p l o y s t r u c t u r e a c t i v i t y r e l a t i o n s h i p s , m a d e p o s s i b l e b y t h e p r e p a r a t i o n o f o r g a n i c m a t e r i a l s , i n d r u g d e s i g n . T h e a b i l i t y t o p r e p a r e s y n t h e t i c f r a g m e n t s o f D N A h a s r e v o l u t i o n i z e d t h e b i o t e c h n o l o g y f i e l d . T h e b i o l o g i c a l s c i e n c e s u s e p r e p a r e d m a t e r i a l s i n m a n y w a y s , i n c l u d i n g e n z y m e b i n d i n g s t u d i e s a n d k i n e t i c s . P o l y m e r c h e m i s t s m u s t s y n t h e s i z e t h e s m a l l e r m o n o m e r u n i t s t ha t c o n f e r to t h e p o l y m e r i t s u n i q u e p r o p e r t i e s . O r g a n i c c h e m i s t r y h a s g r e a t l y b e n e f i t e d f r o m the d e v e l o p m e n t s i n o t h e r f i e l d s (e .g . b i o l o g y , a n a l y t i c a l c h e m i s t r y ) b u t i t s a b i l i t y t o t o u c h s o m a n y o t h e r d i s c i p l i n e s h a s c o n t r i b u t e d to c h e m i s t r y b e i n g d u b b e d the c e n t r a l s c i e n c e . 1 I f o n e o f t h e s t r e n g t h s o f o r g a n i c c h e m i s t r y i s i n i t s a b i l i t y t o p r o v i d e a c c e s s to a w i d e v a r i e t y o f u s e f u l s y n t h e t i c s u b s t a n c e s , t h e n t h e b e n e f i t s o f m e t h o d o l o g y b a s e d r e s e a r c h i s o b v i o u s . T h e i n c r e a s i n g n u m b e r o f c h e m i c a l t r a n s f o r m a t i o n s a v a i l a b l e t o t h e o r g a n i c c h e m i s t a n d t h e a u g m e n t e d s e l e c t i v i t y o f t h e s e p r o c e s s e s , i n c r e a s e s t h e n u m b e r o f d i f f e r e n t m a t e r i a l s a v a i l a b l e , a n d f a c i l i t a t e s t h e i r p r e p a r a t i o n . W h a t t h e n i s t h e p u r p o s e o f t o t a l s y n t h e s i s ? T o t a l s y n t h e s i s i s t h e t e s t i n g g r o u n d f o r n e w m e t h o d o l o g i e s . W i t h i n t h e c o n t e x t o f m o r e c o m p l e x s y s t e m s , t h e l i m i t a t i o n s o f the m e t h o d o l o g y a r e r e v e a l e d t h a t m a y n o t h a v e b e e n e v i d e n t i n s i m p l e r m o d e l s y s t e m s . W h i l e a c h i e v i n g t h e s y n t h e s i s o f t h e t a r g e t is i m p o r t a n t , i t i s t h e i n f o r m a t i o n g a i n e d a l o n g t h e w a y tha t o f t e n i s t h e m o s t r e l e v a n t a n d r e w a r d i n g . T a r g e t - b a s e d r e s e a r c h p l a c e s t h e o r g a n i c c h e m i s t i n a u n i q u e s i t u a t i o n . W i t h a s i n g u l a r g o a l i n m i n d , a n d w h e n f a c e d w i t h a n u n a n t i c i p a t e d p r o b l e m , t h e s y n t h e t i c c h e m i s t i s s t i m u l a t e d to d e v i s e e l e g a n t a n d i n g e n i o u s s o l u t i o n s . A s i d e f r o m d e v e l o p i n g a n d t e s t i n g m e t h o d o l o g i e s , t a r g e t s m a y b e s e l e c t e d b e c a u s e o f t h e i r i n t e r e s t i n g b i o l o g i c a l a c t i v i t y , to c o n f i r m o r i g i n a l s t r u c t u r a l a s s i g n m e n t s , o r e v e n f o r e s t h e t i c r e a s o n s a n d s c i e n t i f i c c u r i o s i t y . T h e d e s i g n o f a f e a s i b l e s y n t h e t i c r o u t e i n v o l v e s b r e a k i n g d o w n t h e t a r g e t m o l e c u l e i n t o a s e q u e n c e o f p r o g r e s s i v e l y s i m p l e r s t r u c t u r e s , w h i c h u l t i m a t e l y l e a d s to c o m m e r c i a l l y a v a i l a b l e s t a r t i n g m a t e r i a l s . T h i s p r o c e s s h a s b e e n c o i n e d r e t r o s y n t h e t i c a n a l y s i s 2 a n d i s the f o u n d a t i o n f o r v i r t u a l l y a l l s y n t h e t i c p l a n n i n g . M u c h e f f o r t h a s b e e n d i r e c t e d t o w a r d t h e d e v e l o p m e n t o f n e w m e t h o d s f o r t h e c o n s t r u c t i o n o f f u n c t i o n a l i z e d c a r b o c y c l i c r i n g s y s t e m s . A n a t t r a c t i v e s t r a t e g y i n v o l v e s the u s e o f A f u n c t i o n a l c o n j u n c t i v e r e a g e n t s w h i c h a re b u i l d i n g b l o c k s that c o n t a i n t w o r e a c t i v e s i t e s , a n d tha t a re i n c o r p o r a t e d i n w h o l e , o r i n pa r t , i n t o a m o r e c o m p l e x s y s t e m . 3 T h e t w o r e a c t i v e s i t e s c a n b e e i t h e r e l e c t r o p h i l i c o r n u c l e o p h i l i c a n d h a v e b e e n t e r m e d \" a c c e p t o r \" (a) o r \" d o n o r \" (d),4 r e s p e c t i v e l y , a n d c a n b e d e p l o y e d s e q u e n t i a l l y o r s i m u l t a n e o u s l y . O f t e n o n e ( o r b o t h ) o f t h e r e a c t i v e s i t e s m u s t b e m a s k e d , to b e u n v e i l e d a t a n o p p o r t u n e m o m e n t . T h e f o l l o w i n g e x a m p l e i s i l l u s t r a t i v e o f t h e u s e o f a b i f u n c t i o n a l r e a g e n t i n a n a n n u l a t i o n s e q u e n c e (Scheme l ) . 5 T h e b i f u n c t i o n a l G r i g n a r d r e a g e n t 1 s e r v e s as t h e s y n t h e t i c e q u i v a l e n t o f t h e b u t a n e - d x , a 3 s y n t h o n 2 . 6 T h e a c c e p t o r s i t e i n t h i s r e a g e n t i s m a s k e d as a k e t a l , a l l o w i n g t h e d o n o r s i t e to b e d e p l o y e d i n the c o p p e r ( I ) - c a t a l y z e d c o n j u g a t e a d d i t i o n o f 1 to 5 , 5 - d i m e t h y l c y c l o p e n t - 2 - e n o n e (3) , to a f f o r d the 1 , 4 - a d d u c t 4. A c i d h y d r o l y s i s o f t h e k e t a l m o i e t y i n 4 g i v e s the d i k e t o n e 5 , w h i c h , w h e n t rea ted u n d e r b a s i c c o n d i t i o n s , u n d e r g o e s a n i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n to a f f o r d t h e t h e r m o d y n a m i c a l l y f a v o r e d a n n u l a t i o n p r o d u c t 6 . 5 - 7 H Scheme 1 1.2 . B a c k g r o u n d I n r e c e n t y e a r s , t h e P i e r s g r o u p h a s i n v e s t e d c o n s i d e r a b l e e f f o r t i n t o t h e d e v e l o p m e n t o f n e w a n n u l a t i o n s e q u e n c e s e m p l o y i n g b i f u n c t i o n a l c o n j u n c t i v e r e a g e n t s . W h i l e t h e m e t h o d s d i f f e r i n t e r m s o f t h e t y p e s o f s u b s t r a t e s u s e d a n d p r o d u c t s g e n e r a t e d , m o s t o f the s e q u e n c e s s h a r e a c o m m o n t h e m e . T h e a n n u l a t i o n s t r a t e g y u s i n g b i f u n c t i o n a l r e a g e n t s o f t e n i n v o l v e s ( a l t h o u g h n o t n e c e s s a r i l y i n t h i s o r d e r ) (1 ) i n t e r m o l e c u l a r c o u p l i n g , (2 ) u n m a s k i n g o f a r e a c t i v e f u n c t i o n , a n d (3) c y c l i z a t i o n . A s e r i e s o f e x a m p l e s w i l l i l l u s t r a t e t h i s . T h e f i r s t t h ree c a s e s i n v o l v e t h e r e a c t i o n o f a , B - u n s a t u r a t e d k e t o n e s w i t h t h e s y n t h e t i c e q u i v a l e n t o f a b u t - l - e n e s y n t h o n . I n t h e f i r s t e x a m p l e , a m e t h y l e n e c y c l o p e n t a n e a n n u l a t i o n s e q u e n c e e m p l o y s the b i f u n c t i o n a l c o n j u n c t i v e r e a g e n t 4 - i o d o - 2 - t r i m e t h y l g e r m y l b u t - l - e n e ( 7 ) , w h i c h s e r v e s as t h e s y n t h e t i c e q u i v a l e n t o f t h e b u t - l - e n e a 2 , d 4 - s y n t h o n (8 ) . T r e a t m e n t o f 7 w i t h terr-butyllithium at l o w t e m p e r a t u r e e f f e c t s a l i t h i u m - i o d i n e e x c h a n g e , a n d t h e a d d i t i o n o f c o p p e r ( I ) c y a n i d e g e n e r a t e s the c u p r a t e r e a g e n t 9 ( e q u a t i o n 1) . GeMe-, \u00E2\u0080\u009E G e M e 3 \u00E2\u0080\u00A2 6 3 1)f-BuLi,THF,-78\u00C2\u00B0C \u00C2\u00B1 ^ d 1 2) C u C N , -78 \u00C2\u00B0C to -35 \u00C2\u00B0C Cu(CN)L A s i l l u s t r a t e d i n S c h e m e 2 , the d o n o r s i t e i n r e a g e n t 9 a d d s i n a c o n j u g a t e s e n s e to the a c c e p t o r s i t e o f c y c l i c e n o n e s o f g e n e r a l s t r u c t u r e 1 0 t o a f f o r d t h e 1 , 4 - a d d u c t s 11 (s tep 1). T h e l a t e n t a c c e p t o r a c t i v i t y i s u n m a s k e d b y c o n v e r t i n g t h e a l k e n y l g e r m a n e 1 1 i n t o t h e c o r r e s p o n d i n g v i n y l i o d i d e 1 2 (s tep 2 ) . T h e a n n u l a t i o n s t e p e m p l o y s a P d ( 0 ) - c a t a l y z e d c o u p l i n g b e t w e e n t h e v i n y l i o d i d e m o i e t y a n d t h e e n o l a t e c a r b o n t o a f f o r d b i c y c l i c c o m p o u n d s o f g e n e r a l s t r u c t u r e 1 3 (step 3 ) . 8 Scheme 2 A c o m p l e m e n t a r y , r e g i o i s o m e r i c m e t h y l e n e c y c l o p e n t a n e a n n u l a t i o n s e q u e n c e h a s a l s o b e e n d e v e l o p e d . T h e b i f u n c t i o n a l c o n j u n c t i v e r e a g e n t u s e d i n t h i s s e q u e n c e i s 4 - c h l o r o -2 - t r i m e t h y l s t a n n y l b u t - l - e n e ( 1 4 ) , w h i c h s e r v e s as t h e s y n t h e t i c e q u i v a l e n t o f t h e b u t - l - e n e d 2 , a 4 - s y n t h o n ( 1 5 ) ( e q u a t i o n 2 ) . T h e l o n g e r a n d t h e r e f o r e w e a k e r c a r b o n - t i n b o n d i n 1 4 i s m o r e l a b i l e t h a n t h e c o r r e s p o n d i n g c a r b o n - g e r m a n i u m b o n d i n 7 . 9 T h e l a t e n t d o n o r a c t i v i t y o f the a l k e n y l s t a n n a n e s i t e i n 1 4 c a n b e c h e m o s e l e c t i v e l y u n m a s k e d i n t h e p r e s e n c e o f the p r i m a r y c h l o r i d e b y t r e a t m e n t w i t h M e L i . A d d i t i o n o f a copper(I) s a l t g e n e r a t e s t h e c u p r a t e r e a g e n t 1 6 ( e q u a t i o n 2) . ? n M e 3 1)MeUTHF,-78\u00C2\u00B0C ^ U ( C N ) L i C l 2) CuCN C l 1 6 6 R e a g e n t 16 a d d s i n a c o n j u g a t e s e n s e to e n o n e s o f g e n e r a l s t r u c t u r e 10 t o a f f o r d t h e a d d u c t 17 (Scheme 3). T h e a n n u l a t i o n s e q u e n c e i s c o m p l e t e d b y i n t r a m o l e c u l a r a l k y l a t i o n o f 17 u s i n g p o t a s s i u m h y d r i d e a f f o r d i n g t h e b i c y c l i c p r o d u c t 18. 1 0 10 17 18 Scheme 3 A t h i r d , r e c e n t e x a m p l e i l l u s t r a t i n g t h e a n n u l a t i o n p r o t o c o l u s i n g a , P - u n s a t u r a t e d k e t o n e s i s s h o w n i n Scheme 4. 4 - I o d o - 2 - t r i m e t h y l g e r m y l b u t - l - e n e (7), t h e s a m e b i f u n c t i o n a l r e a g e n t u s e d i n the s e q u e n c e d e p i c t e d i n Scheme 2, i s e m p l o y e d , b u t i n t h i s c a s e the r e a g e n t i s s e r v i n g as the s y n t h e t i c e q u i v a l e n t o f the b u t - l - e n e d 2 , d 4 - s y n t h o n (19). 19 C o n j u g a t e a d d i t i o n o f the c u p r a t e r e a g e n t 9 to b i c y c l i c e n o n e s o f g e n e r a l s t r u c t u r e 20 a f f o r d s t h e a d d u c t 21 (Scheme 4).11 T h e a l k e n y l g e r m a n e 21 i s c o n v e r t e d to t h e v i n y l i o d i d e 22 b y t r e a t m e n t w i t h i o d i n e . F i n a l l y , r e a c t i o n o f 22 w i t h n - B u L i at - 7 8 \u00C2\u00B0C, r e s u l t s i n l i t h i u m -i o d i n e e x c h a n g e t o g i v e t h e v i n y l l i t h i u m s p e c i e s 23, t h e r e b y u n m a s k i n g t h e l a t e n t d o n o r a c t i v i t y a t t h i s s i t e . T h i s r e s u l t s i n i n t r a m o l e c u l a r a n i o n i c c y c l i z a t i o n o n t o t h e c a r b o n y l c a r b o n , p r o d u c i n g t h e a n n u l a t e d t r i c y c l i c p r o d u c t 24, w h i c h c o n t a i n s a t e r t i a r y a l l y l i c a l c o h o l f u n c t i o n . 1 2 24 23 22 Scheme 4 D u r i n g t h e c o u r s e o f t h e a n n u l a t i o n s t u d y d e p i c t e d i n Scheme 4, i t w a s n e c e s s a r y to p r e p a r e t h e 1 , 4 - a d d u c t s 21. I n t e r e s t i n g l y , p r i o r t o t h i s w o r k , a s y s t e m a t i c s t u d y o f t h e s t e r e o c h e m i c a l o u t c o m e o f c o n j u g a t e a d d i t i o n r e a c t i o n s to b i c y c l o [ 4 . 3 . 0 ] n o n - 9 - e n - 2 - o n e s o f g e n e r a l s t r u c t u r e 20 h a d n e v e r b e e n m a d e . T h i s s t u d y r e v e a l e d that t h e a d d i t i o n o f c u p r a t e r e a g e n t s t o b i c y c l i c a , B - u n s a t u r a t e d k e t o n e s s u c h a s 25 (Scheme 5) r e s u l t s i n p r o d u c t s o f g e n e r a l s t r u c t u r e 26 a n d 27, i n w h i c h t h e n e w l y i n t r o d u c e d g r o u p R 2 i s trans to R 1 . F u r t h e r m o r e , i t w a s d i s c o v e r e d tha t u p o n q u e n c h i n g , the d s - f u s e d p r o d u c t 26 p r e d o m i n a t e d , a n d that t h e t h e r m o d y n a m i c a l l y m o r e s t a b l e trans - f u s e d e p i m e r 27 c o u l d b e o b t a i n e d as t h e m a j o r i s o m e r b y e q u i l i b r a t i o n u s i n g s o d i u m m e t h o x i d e i n m e t h a n o l . 1 1 m i n o r NaOMe, m a J o r MeOH Scheme 5 T h e h i g h d e g r e e o f s t e r e o s e l e c t i v i t y a f f o r d e d b y t h e c o n j u g a t e a d d i t i o n r e a c t i o n s o f c u p r a t e r e a g e n t s t o b i c y c l i c [ 4 . 3 . 0 ] n o n - 9 - e n - 2 - o n e s s u c h as 25, c o u p l e d w i t h t h e a b i l i t y to c o n t r o l t h e 5 , 6 - r i n g f u s i o n s t e r e o c h e m i s t r y (Scheme 5), p l a y e d a p i v o t a l r o l e i n t h e d e s i g n a n d i m p l e m e n t a t i o n o f the p r o p o s e d r e s e a r c h p r o j e c t (vide infra). C y c l i c k e t o n e s h a v e a l s o p r o v e n to b e v a l u a b l e s u b s t r a t e s f o r t h e b i f u n c t i o n a l r e a g e n t m e d i a t e d a n n u l a t i o n p r o t o c o l . I n t h e f o l l o w i n g e x a m p l e , t h e b i f u n c t i o n a l r e a g e n t 28 a n d i ts h o m o l o g u e 29 a r e u s e d i n a m e t h y l e n e c y c l o p e n t a n e a n d a m e t h y l e n e c y c l o h e x a n e a n n u l a t i o n s e q u e n c e , r e s p e c t i v e l y . T h e f i r s t r e a g e n t s e r v e s as t h e b u t - l - e n e d 2 , a 4 - s y n t h o n (15), w h i l e the l a t te r ac ts as t h e p e n t - l - e n e d 2 , a 5 - s y n t h o n (30). 28 15 29 30 D e p l o y m e n t o f t h e d o n o r s i t e o f t h e / V , / V - d i m e t h y l h y d r a z o n e s 32 o f t h e c o r r e s p o n d i n g c y c l i c k e t o n e s o f g e n e r a l s t r u c t u r e 31 b y a l k y l a t i o n , a f f o r d s t h e a l k e n y l s t a n n a n e s 33a a n d 33b. O x i d a t i v e h y d r o l y s i s o f t h e h y d r a z o n e f u n c t i o n y i e l d s t h e k e t o a l k e n y l s t a n n a n e s 34a a n d 34b (Scheme 6). T i n - i o d i n e e x c h a n g e s m o o t h l y c o n v e r t s 34a a n d 34b i n t o t h e c o r r e s p o n d i n g v i n y l i o d i d e s 35a a n d 35b. T r e a t m e n t o f 35a a n d 35b w i t h n - B u L i g i v e s t h e v i n y l l i t h i u m s p e c i e s , w h i c h c y c l i z e o n t o t h e c a r b o n y l c a r b o n a n d t h u s c o m p l e t e s t h e a n n u l a t i o n s e q u e n c e b y p r o d u c i n g t h e t e r t i a r y a l l y l i c a l c o h o l s 36 a n d 37. 1 3 O 31 N H p N M e 2 , EtOH, AcOH reflux N N(Me)j 32 1) LP A, THF 0\u00C2\u00B0C 2) 28 or 29 N N(Me), n S n M e 3 33a n=1 33b n=2 N a l 0 4 , THF, H 2 0 pH 7, rt n-BuLi, THF -78 \u00C2\u00B0C 36 n=1 37 n=2 35a n=1 35b n=2 34a n=1 34b n=2 n S n M e 3 Scheme 6 U s i n g t h e b i f u n c t i o n a l r e a g e n t s 38 a n d 39, a n n u l a t i o n s e q u e n c e s s i m i l a r to t h a t d e s c r i b e d a b o v e a re d e p i c t e d i n Scheme 7 f o r the s y n t h e s i s o f f i v e - 1 4 a n d s e v e n - m e m b e r e d 1 5 c y c l o a l k e n o n e s , r e s p e c t i v e l y . A m a j o r d i f f e r e n c e f r o m the e x a m p l e s s h o w n i n Scheme 6 i s i n t h e p o s i t i o n o f t h e v i n y l i o d i d e m o i e t i e s i n 41a a n d 41b (Scheme 7). S i n c e t h e i o d i n e i s at t h e t e r m i n u s o f t h e d o u b l e b o n d a n d i n a cis o r i e n t a t i o n , t h e c y c l i z a t i o n s t e p y i e l d s the a n n u l a t e d p r o d u c t s 42 a n d 43, i n w h i c h the d o u b l e b o n d l i e s i n s i d e t h e n e w l y f o r m e d r i n g . T h e t e r t i a r y a l l y l i c a l c o h o l s 42 a n d 43 a r e o x i d a t i v e l y r e a r r a n g e d i n t h e p r e s e n c e o f p y r i d i n i u m c h l o r o c h r o m a t e t o a f f o r d t h e c y c l o p e n t e n o n e 44 a n d t h e c y c l o h e p t e n o n e 45, r e s p e c t i v e l y . 10 o 31 N H 2 N M e 2 m C 6 H 6 , reflux O * - 4 N' I a 1) LDA, THF, 0\u00C2\u00B0C I N(Me) 2 B r ^ y = x N(Me) 2 38 or 32 S n B u 3 39 H M P A ; 4\u00C2\u00ABa n=1 then l 2 . C H 2 C I 2 , rt n ~ NaOAc A c O H THF, H 2 0 44 n=1 45 n=3 42 n=1 43 n=3 n 41a n=1 41b n=3 Scheme 7 C l e a r l y , t h e u s e o f b i f u n c t i o n a l r e a g e n t s i n a n n u l a t i o n s e q u e n c e s i s a v a l u a b l e t o o l f o r the s y n t h e t i c c h e m i s t s i n c e t h e s e r e a g e n t s a l l o w f o r the e f f i c i e n t c o n v e r s i o n o f s i m p l e s t a r t i n g m a t e r i a l s i n t o s i g n i f i c a n t l y m o r e c o m p l e x , u s e f u l l y f u n c t i o n a l i z e d p r o d u c t s . T h e a n n u l a t i o n p r o t o c o l s d e s c r i b e d a b o v e h a v e b e e n u s e d s u c c e s s f u l l y i n the t o t a l s y n t h e s i s o f a n u m b e r o f n a t u r a l p r o d u c t s , i n c l u d i n g ( i ) - p e n t a l e n e n e (46),10 (\u00C2\u00B1) -A 9 ( 1 2 ) -capnel lene (47),16 (\u00C2\u00B1)-ambliol B (48),17 (\u00C2\u00B1)-palauolide (49),18 (\u00C2\u00B1)-crinipellin B (50), 1 9 a n d (\u00C2\u00B1)-methyl e p o x y c a n t a b r o n a t e (51).2 0 I n t h e t o t a l s y n t h e s i s o f (\u00C2\u00B1)-crinipellin B (50), e a c h c y c l i z a t i o n w a s e f f e c t e d u s i n g a n a n n u l a t i o n p r o t o c o l e m p l o y i n g a b i f u n c t i o n a l r e a g e n t . T w o o f t h e s e s e q u e n c e s a r e h i g h l i g h t e d i n Scheme 8. I n the t r a n s f o r m a t i o n o f the b i c y c l i c e n o n e 52 i n t o t h e t r i c y c l e 55, the a n n u l a t i o n s e q u e n c e d e s c r i b e d i n Scheme 2 w a s u s e d . C o n j u g a t e a d d i t i o n o f t h e c u p r a t e r e a g e n t 9 t o t h e e n o n e 52 g a v e t h e 1 , 4 - a d d u c t 53 (Scheme 8). T h e a c c e p t o r a c t i v i t y w a s d e p l o y e d b y c o n v e r t i n g t h e a l k e n y l g e r m a n e 53 i n t o t h e v i n y l i o d i d e 54. P a l l a d i u m ( O ) c a t a l y z e d c y c l i z a t i o n o f 54 a f f o r d e d t h e k e t o n e 55. A s e r i e s o f f u n c t i o n a l g r o u p i n t e r c o n v e r s i o n s l e d t o t h e t r i c y c l i c k e t o n e 56, w h i c h u n d e r w e n t t h e c y c l o p e n t e n o n e a n n u l a t i o n s e q u e n c e d e s c r i b e d i n Scheme 7. T h u s , a l k y l a t i o n o f 56 u s i n g ( Z ) - 3 - b r o m o - l -i o d o p r o p e n e (38) g a v e t h e a d d u c t 57. T h e v i n y l i o d i d e m o i e t y o f 57 u n d e r w e n t a l o w t e m p e r a t u r e l i t h i u m - i o d i n e e x c h a n g e u s i n g n - B u L i to g i v e a v i n y l l i t h i u m s p e c i e s , w h i c h c y c l i z e d o n t o t h e c a r b o n y l c a r b o n , a f f o r d i n g t h e t e r t i a r y a l l y l i c a l c o h o l 58. O x i d a t i v e r e a r r a n g e m e n t o f 58 u s i n g p y r i d i n i u m c h l o r o c h r o m a t e g a v e t h e c y c l o p e n t e n o n e 59. F u r t h e r f u n c t i o n a l g r o u p m a n i p u l a t i o n s l e d to t h e s y n t h e s i s o f t h e t a r g e t c o m p o u n d (\u00C2\u00B1)-crinipellin B ( 5 0 ) . 1 9 several steps 1) 9, TMSBr, THF -78 \u00C2\u00B0C to -48 \u00C2\u00B0C R 2) l 2 , C H 2 C I 2 , rt 5 3 R = G e M e 3 5 4 R = l P d ( P P h 3 ) 4 f-BuOK, THF f-BuOH, rt \u00E2\u0080\u00A2,IXV 1) LDA, THF -78 \u00C2\u00B0C 2) 3 8 , rt O T B S 5 7 n-BuLi, THF -78 \u00C2\u00B0C P C C . Cel i te. H C H 2 C I 2 , rt O T B S O H several steps O o ^ ^ \" ' 0 ' O H (\u00C2\u00B1)-crinipellin B 5 0 1.3. Proposals T h e d e v e l o p m e n t o f n e w s y n t h e t i c p r o t o c o l s , i n p a r t i c u l a r a n n u l a t i o n s e q u e n c e s , a n d t h e a p p l i c a t i o n o f t h e s e m e t h o d s t o e f f i c i e n t t o t a l s y n t h e s e s o f n a t u r a l p r o d u c t s h a v e b e e n a m a j o r f o c u s o f t h e P i e r s g r o u p f o r m a n y y e a r s . A n e x p e d i e n t m e t h o d f o r t h e c o n t r o l o f t h e r e l a t i v e c o n f i g u r a t i o n o f t h r e e s t e r e o g e n i c c e n t e r s i n o n e r e a c t i o n s e q u e n c e w a s r e c e n t l y d e v e l o p e d i n t h e c o n j u g a t e a d d i t i o n s o f c u p r a t e r e a g e n t s to bicyclo[4.3.0 ]non-9-en-2-ones 25 ( S c h e m e 5).11 A n u m b e r o f n a t u r a l p r o d u c t s c o n t a i n i n g t h e s u b s t i t u t i o n p a t t e r n a n d s t e r e o c h e m i c a l a r r a n g e m e n t p r e s e n t i n t h e 5 , 6 - b i c y c l i c c o m p o u n d 60 h a v e b e e n d i s c o v e r e d , a n d t h u s , t h e m e t h o d o l o g y r e f e r r e d to a b o v e c o u l d b e e m p l o y e d i n t h e i r s y n t h e s i s . P r o m i s i n g c a n d i d a t e s that c o n t a i n s u c h a s u b u n i t i n c l u d e m e m b e r s o f the v e r r u c o s a n e - t y p e f a m i l y o f d i t e r p e n o i d n a t u r a l p r o d u c t s e x e m p l i f i e d b y v e r r u c o s a n - 2 S - o l (61),21 n e o v e r r u c o s a n - 5 | 3 - o l (62),22 a n d h o m o v e r r u c o s a n - 5 B - o l (63).22b-c O t h e r s t r u c t u r a l l y s i m i l a r n a t u r a l p r o d u c t s i n c l u d e c o m p o u n d 64,23 a m e m b e r o f the c y a t h a n e f a m i l y o f n a t u r a l p r o d u c t s , a n d v a r i e c o l i n (65),24 a h y b r i d o f the o p h i o b o l i n a n d c e r e f e r e n e c l a s s e s o f s e s t e r t e r p e n o i d s . T h e m e t h o d o l o g y d e s c r i b e d i n Scheme 5 ( p a g e 8) w o u l d p r o v i d e r e a d y a c c e s s to the f u n c t i o n a l i z e d 5 ,6 -ring p o r t i o n , w h i c h i s p r e s e n t i n t h e n a t u r a l p r o d u c t s 6 1 - 6 5 . U s i n g t h i s m e t h o d o l o g y , c o m p o u n d 6 0 w o u l d b e r e a d i l y a t t a i n a b l e . 1 1 E f f o r t s d i r e c t e d t o w a r d s t h e t o t a l s y n t h e s i s o f t h e s e n a t u r a l p r o d u c t s w o u l d n e c e s s i t a t e a p p e n d i n g (at l e a s t ) a t h i r d r i n g o n t o c o m p o u n d 6 0 . T h i s w o u l d p r o v i d e t h e o p p o r t u n i t y t o d e v e l o p a n d i m p l e m e n t a n e w b i f u n c t i o n a l r e a g e n t m e d i a t e d a n n u l a t i o n p r o t o c o l . B a s e d o n t h e m e t h o d o l o g y d e s c r i b e d i n Scheme 7 ( p a g e 9), a c y c l o h e x e n o n e a n n u l a t i o n s e q u e n c e (n = 2) c o u l d b e e n v i s a g e d . T h i s c o n v e r s i o n , i n d i c a t e d b y t h e g e n e r a l i z e d t r a n s f o r m a t i o n o f 6 6 i n t o 6 7 , i s b a s e d o n t h e t h e o r e t i c a l c o m b i n a t i o n o f t h e t w o d o n o r - a c c e p t o r s y n t h o n s 6 8 a n d 6 9 (Scheme 9 ) . T h e k e t o n e 6 6 s e r v e s as the s y n t h e t i c e q u i v a l e n t o f 6 8 , w h i l e the p r e p a r a t i o n o f a c o m p o u n d that w o u l d s e r v e as t h e s y n t h e t i c e q u i v a l e n t o f t h e b u t - l - e n e d ^ a ^ s y n t h o n 6 9 , s u c h as 7 0 , w o u l d b e r e q u i r e d . O x i d a t i v e r e a r r a n g e m e n t o f t h e t e r t i a r y a l l y l i c a l c o h o l 7 1 w o u l d p r o v i d e t h e d e s i r e d c y c l o h e x e n o n e 6 7 . T h e f e a s i b i l i t y , s c o p e , a n d u t i l i t y o f the p r o p o s e d a n n u l a t i o n p r o t o c o l w o u l d b e p r o b e d . 6 8 6 9 7 1 III R 3 M N \u00E2\u0080\u0094 / M = Ge or Sn 7 0 Scheme 9 T h e p r e p a r a t i o n o f t h e t r i c y c l i c k e t o n e 72 f r o m c o m p o u n d 60 (Scheme 10) w o u l d ( i n t h e o r y ) b e p o s s i b l e b y i m p l e m e n t a t i o n o f t h i s p r o p o s e d m e t h o d o l o g y . C o m p o u n d 72 w o u l d s e r v e as a k e y , a d v a n c e d i n t e r m e d i a t e , a n d a b r a n c h i n g p o i n t f r o m w h i c h t h e n a t u r a l p r o d u c t s 61-65 c o u l d b e d e r i v e d . 65 Scheme 10 16 II. DISCUSSION 2.1. Total Synthesis of the Diterpenoids (\u00C2\u00B1)-Verrucosan-2B-ol, (\u00C2\u00B1)-Neoverrucosan-5B-ol, (\u00C2\u00B1)-Homoverrucosan-5B-ol, and (\u00C2\u00B1)-(3R, AR, 5R, 6S, 9/?)-Cyatha-12,18-diene. 2.1.1. Introductory Remarks. T h e v e r r u c o s a n e - t y p e f a m i l y o f d i t e r p e n o i d s i s a c l a s s o f n a t u r a l p r o d u c t s , t h e f i r s t m e m b e r o f w h i c h w a s o r i g i n a l l y i s o l a t e d f r o m t h e l i v e r w o r t Mylia verrucosa L i n d b . 2 5 S i n c e t h e i r d i s c o v e r y i n 1 9 7 8 , c o m p o u n d s b e l o n g i n g t o t h i s r e l a t i v e l y s m a l l f a m i l y , c o n s i s t i n g o f a p p r o x i m a t e l y t w e n t y m e m b e r s , h a v e a l s o b e e n i s o l a t e d f r o m m a r i n e s p o n g e s a n d p r o k a r y o t i c b a c t e r i a . 2 6 T h i s g r o u p o f n a t u r a l p r o d u c t s i s d i v i d e d i n t o t h r e e s t r u c t u r a l s u b c l a s s e s : t h e v e r r u c o s a n e s , t h e n e o v e r r u c o s a n e s , a n d t h e h o m o v e r r u c o s a n e s , w h i c h p o s s e s s t h e c a r b o n s k e l e t o n s s h o w n i n 73, 74, a n d 75, r e s p e c t i v e l y . T h e v e r r u c o s a n e s (73) a n d t h e n e o v e r r u c o s a n e s (74) p o s s e s s a n o v e l 3 , 6 , 6 , 5 - t e t r a c y c l i c r i n g s y s t e m a n d d i f f e r o n l y i n t h e p o s i t i o n o f a t t a c h m e n t o f the c y c l o p r o p a n e r i n g . T h e h o m o v e r r u c o s a n e s (75) p o s s e s s a 7 , 6 , 5 -t r i c y c l i c r i n g s y s t e m , a n d c a n b e e n v i s a g e d as b e i n g d e r i v e d f r o m t h e v e r r u c o s a n e s (73) b y r i n g e x p a n s i o n , a n d c l e a v a g e o f the C 3 - C 5 c y c l o p r o p y l b o n d . M o r e h i g h l y o x y g e n a t e d c o m p o u n d s o f e a c h s t r u c t u r a l s u b c l a s s e x i s t , b u t ( - ) -v e r r u c o s a n - 2 B - o l (61),21 ( - ) - n e o v e r r u c o s a n - 5 B - o l (62),22 a n d ( + ) - h o m o v e r r u c o s a n - 5 B - o l M o s t o f t h e n a t u r a l p r o d u c t s b e l o n g i n g to t h e v e r r u c o s a n e - t y p e f a m i l y o f c o m p o u n d s p o s s e s s t h e s a m e r e l a t i v e s t e r e o c h e m i s t r y o n t h e f u n c t i o n a l i z e d 5 , 6 - r i n g p o r t i o n o f t h e i r s t r u c t u r e s , as d e p i c t e d i n 61-63. T h e n e o v e r r u c o s a n e a n d t h e h o m o v e r r u c o s a n e s u b c l a s s e s , h o w e v e r , a l s o i n c l u d e 1 3 - e / n - n e o v e r r u c o s a n e s a n d 1 3 - e p / - h o m o v e r r u c o s a n e s s i n c e s o m e n a t u r a l p r o d u c t s p o s s e s s t h e e p i m e r i c c o n f i g u r a t i o n f o r t h e i s o p r o p y l u n i t at C - 1 3 ( v e r r u c o s a n e n u m b e r i n g ) . F o r e x a m p l e , 1 3 - e / ? / - n e o v e r r u c o s a n - 5 { 3 - o l (76) 2 7 a n d 13-epi-h o m o v e r r u c o s a n - 5 3 - o l (77) 2 7 b- 2 8 a r e i d e n t i c a l w i t h c o m p o u n d s 62 a n d 63, r e s p e c t i v e l y , e x c e p t f o r t h e c o n f i g u r a t i o n at C - 1 3 . 76 77 F r o m a b i o s y n t h e t i c p o i n t o f v i e w t h e e x i s t e n c e o f c o m p o u n d s tha t a r e e p i m e r i c at the p o i n t o f a t t a c h m e n t o f t h e i s o p r o p y l u n i t i s n o t u n u s u a l f o r n a t u r a l p r o d u c t s , s i n c e t h i s s t e r e o c h e m i s t r y r e l i e s u p o n t h e c o n f o r m a t i o n a d o p t e d b y g e r a n y l g e r a n y l p y r o p h o s p h a t e ( G G P P ) o n c y c l i z a t i o n (vide infra).26* 18 T h e c y a t h a n e f a m i l y o f n a t u r a l p r o d u c t s , w h o s e c a r b o n s k e l e t o n i s d e p i c t e d i n s t r u c t u r e 78, a l s o p o s s e s s e s a 7 , 6 , 5 - t r i c y c l i c r i n g s y s t e m . S t r u c t u r a l l y , t h e c y a t h a n e s d i f f e r f r o m t h e h o m o v e r r u c o s a n e s o n l y i n the p o s i t i o n o f a t t a c h m e n t o f t h e m e t h y l g r o u p o n t h e 7 -m e m b e r e d r i n g . T h e c y a t h a n e s w e r e f i r s t d i s c o v e r e d as m e t a b o l i t e s o f t h e b i r d ' s n e s t f u n g u s Cyathus helenae B r o d i e a n d w e r e i s o l a t e d b y A y e r o v e r 2 5 y e a r s a g o . 2 9 81 64 M o s t o f t h e c y a t h a n e s a r e s p 2 h y b r i d i z e d at C - 3 ( c y a t h a n e n u m b e r i n g ) a n d , t h e r e f o r e , t h e i s o p r o p y l u n i t at t h i s p o s i t i o n h a s n o s t e r e o c h e m i c a l d e s i g n a t i o n . H o w e v e r , a f e w c o m p o u n d s h a v e b e e n d i s c o v e r e d i n w h i c h t h e d o u b l e b o n d , w h i c h i s o f t e n ( b u t n o t a l w a y s ) p r e s e n t b e t w e e n C - 4 a n d C - 3 , i s f o u n d i n t h e th ree c a r b o n s i d e c h a i n . T h i s r e s u l t s i n a n oc-i s o p r o p e n y l s u b s t i t u e n t at C - 3 , a n d t h e 5 , 6 - r i n g s y s t e m i s trans-fused, as i s s h o w n i n 6 4 . T h e s u b s t i t u t i o n a n d s t e r e o c h e m i s t r y o f t h i s c y a t h a n e a r e r e m i n i s c e n t o f t h o s e f o u n d i n t h e v e r r u c o s a n e - t y p e f a m i l y {vide supra). 2 . 1 . 2 . Biogenetic Pathway and Synthetic Implications. T h e s t r u c t u r a l s i m i l a r i t i e s b e t w e e n the c y a t h a n e a n d t h e v e r r u c o s a n e - t y p e f a m i l i e s o f n a t u r a l p r o d u c t s p r o m p t e d A s a k a w a to p r o p o s e a b i o g e n e t i c p a t h w a y t h a t a c c o u n t s f o r the f o r m a t i o n o f b o t h c l a s s e s (Scheme 1 1 ) . 2 6 8 1 T h e p r o p o s e d s e q u e n c e i s c o n s i s t e n t w i t h the 1 3 C -a c e t a t e l a b e l i n g s t u d i e s c o n d u c t e d b y A y e r , 3 4 a n d b e g i n s w i t h G G P P ( 8 2 ) , w h i c h i s r e g a r d e d as the n a t u r a l p r e c u r s o r o f t h e d i t e r p e n o i d s . 3 5 T h e c y c l i z a t i o n o f 8 3 to p r o d u c e 8 4 r e a d i l y a c c o u n t s f o r t h e o c c u r r e n c e o f the e p i m e r i c h o m o - a n d n e o v e r r u c o s a n e s at C - 1 3 ( v e r r u c o s a n e n u m b e r i n g ) . T h e o r i e n t a t i o n o f G G P P d u r i n g t h i s c y c l i z a t i o n d e t e r m i n e s t h e s t e r e o c h e m i s t r y at C - 1 3 . S t r u c t u r e 8 4 i s t h e b r a n c h p o i n t b e t w e e n t h e c y a t h a n e s ( 8 5 ) ( p a t h B ) a n d t h e v e r r u c o s a n e - t y p e n a t u r a l p r o d u c t s ( p a t h A ) i n t h e p r o p o s e d b i o s y n t h e t i c r o u t e . I n p a t h A , c y c l o p r o p a n e r i n g f o r m a t i o n a f f o r d s t h e n e o v e r r u c o s a n e s ( 6 2 ) a n d t h e e / ? / - n e o v e r r u c o s a n e s ( 7 6 ) . A c y c l o p r o p y l g r o u p s h i f t , as d e p i c t e d i n 6 2 , r e s u l t s i n t h e f o r m a t i o n o f t h e v e r r u c o s a n e s ( 6 1 ) . R i n g e x p a n s i o n b y c l e a v a g e o f t h e c y c l o p r o p a n e r i n g , r e s u l t s i n the f o r m a t i o n o f t h e h o m o v e r r u c o s a n e s ( 6 3 ) a n d the epi-homoverrucosanes (77 ) . 61 verrucosane 63 R = pH (homverrucosane) 77 R = aH (ep/-homoverrucosane) Scheme 11 T h e p r o p o s e d b i o s y n t h e t i c p a t h w a y (Scheme 11) s u g g e s t s a c o n n e c t i o n b e t w e e n t h e n e o v e r r u c o s a n e , v e r r u c o s a n e , a n d h o m o v e r r u c o s a n e s u b c l a s s e s t h a t m a y h a v e s y n t h e t i c i m p l i c a t i o n s . M u c h o f t h e o r i g i n a l s t r u c t u r a l e l u c i d a t i o n Of t h e s e s u b c l a s s e s of n a t u r a l p r o d u c t s w a s a c h i e v e d b y s p e c t r o s c o p i c m e a n s , a s w e l l a s b y e x t e n s i v e c h e m i c a l t r a n s f o r m a t i o n s . I n f a c t , b e f o r e t h e d i s c o v e r y o f ( + ) - h o m o v e r r u c o s a n - 5 B - o l ( 6 3 ) f r o m a n a t u r a l s o u r c e , i t h a d b e e n s y n t h e s i z e d b y a k n o w n , s t e r e o s e l e c t i v e a c i d c a t a l y z e d r i n g e x p a n s i o n o f a n a t u r a l p r o d u c t p r e c u r s o r . T h e c o n v e r s i o n s o f ( - ) - v e r r u c o s a n - 2 B - o l (61 ) a n d ( - ) - n e o v e r r u c o s a n - 5 B - o l ( 6 2 ) i n t o ( + ) - h o m o v e r r u c o s a n - 5 B - o l ( 6 3 ) w e r e a c c o m p l i s h e d b y t r e a t i n g t h e s t a r t i n g m a t e r i a l s w i t h s u l f u r i c a c i d i n r e f l u x i n g a c e t o n e . T h e s e r e s u l t s p r o v i d e d s u p p o r t i n g e v i d e n c e f o r t h e s t r u c t u r e s o f 6 1 2 1 a a n d 6 2 , 2 2 a b a s e d o n t h e e x p e c t e d s t e r e o c h e m i c a l o u t c o m e o f t h i s r i n g e x p a n s i o n (Scheme 1 2 ) . 3 6 Scheme 1 2 A m e c h a n i s m that a c c o u n t s f o r t h e c o n v e r s i o n o f 6 1 a n d 6 2 i n t o 6 3 a n d w h i c h p a s s e s t h r o u g h a c o m m o n i n t e r m e d i a t e c a n b e p o s t u l a t e d (Scheme 1 3 ) . I n t h e p r e s e n c e o f a q u e o u s a c i d , a n c h i m e r i c a l l y a s s i s t e d i o n i z a t i o n o f t h e h y d r o x y l m o e i t y i n s t r u c t u r e s 8 6 a n d 8 7 , r e p r e s e n t i n g a n e o v e r r u c o s a n e a n d a v e r r u c o s a n e , r e s p e c t i v e l y , l e a d s to r e s o n a n c e s t a b i l i z e d c a t i o n s . R e s o n a n c e c o n t r i b u t o r 8 8 is r e l a t e d to 8 9 b y a 1 , 3 - a l k y l s h i f t . R e a c t i o n o f 9 0 (o r s e e 9 1 ) w i t h w a t e r i s s t e r e o e l e c t r o n i c a l l y p r e d i c t e d to o c c u r s u c h tha t t h e s t e r e o c h e m i s t r y o f t h e n e w l y f o r m e d a l c o h o l i n t h e r i n g e x p a n d e d p r o d u c t 9 2 i s t h e s a m e as t h a t o f t h e o r i g i n a l a l c o h o l ( 8 6 or 8 7 ) . 3 6 T h i s s t e r e o e l e c t r o n i c r e q u i r e m e n t i s l i k e l y t h e r e a s o n that a l l n a t u r a l l y o c c u r r i n g h o m o v e r r u c o s a n e s p o s s e s s t h e s t e r e o c h e m i s t r y f o r t h e a l c o h o l f u n c t i o n at C - 5 ( h o m o v e r r u c o s a n e n u m b e r i n g ) as s h o w n i n 9 2 . A s y n t h e t i c r o u t e l e a d i n g t o e i t h e r neoverrucosan-5p-ol (61) or verrucosan-2p-ol (62), would allow the synthesis of homoverrucosan-5 P-ol (63) by this ring expansion (see Scheme 12). 2 2 H + / H 5 0 88 H o O : 87 H + / H 2 0 90 1,3 alkyl shift H \" 89 92 \u00E2\u0080\u00A2 H + H o O : 91 Scheme 13 2.1.3. Previous Cyathane Synthetic Studies. D e s p i t e t h e i r n o v e l a n d c h a l l e n g i n g s t r u c t u r e s , n o m e m b e r s o f t h e v e r r u c o s a n e - t y p e f a m i l y o f n a t u r a l p r o d u c t s h a v e b e e n s y n t h e s i z e d to date . T h i s m a y b e , i n p a r t , d u e to a l a c k o f i n f o r m a t i o n c o n c e r n i n g t h e i r b i o l o g i c a l a c t i v i t y . T h i s i s s u e c o u l d b e a d d r e s s e d i f c o m p o u n d s f r o m t h i s f a m i l y w e r e s u c c e s s f u l l y s y n t h e s i z e d . H o w e v e r , c e r t a i n m e m b e r s o f t h e s t r u c t u r a l l y s i m i l a r c y a t h a n e s h a v e b e e n r e p o r t e d to e x h i b i t a n t i m i c r o b i a l a n d a n t i f u n g a l a c t i v i t y 3 7 a n d c y t o t o x i c i t y a g a i n s t b o t h t h e P 3 8 8 m u r i n e l e u k e m i a c e l l l i n e a n d t h e A 5 4 9 h u m a n l u n g c a n c e r t u m o r l i n e . 3 8 S o m e c y a t h a n e s h a v e b e e n s h o w n to b e s t r o n g s t i m u l a t o r s o f n e r v e g r o w t h f a c t o r ( N G F ) - s y n t h e s i s . 3 9 A s a r e s u l t , the s y n t h e s i s o f t h e c y a t h a n e s h a s b e e n a t t e m p t e d b y s e v e r a l g r o u p s . A y e r , W a r d , a n d P a q u e t t e h a v e a l l r e p o r t e d u n s u c c e s s f u l r o u t e s to t h i s f a m i l y o f n a t u r a l p r o d u c t s . D u r i n g t h e c o u r s e o f o u r s y n t h e t i c e f f o r t s , t h e f i r s t s u c c e s s f u l t o t a l s y n t h e s e s o f t w o m e m b e r s o f t h e c y a t h a n e s w e r e r e p o r t e d b y S n i d e r . A f t e r the p u b l i c a t i o n o f the r e s u l t s d e s c r i b e d i n t h i s t h e s i s , T o r i r e p o r t e d a n a l t e r n a t i v e s y n t h e s i s to o n e o f t h e c y a t h a n e s p r e p a r e d b y S n i d e r . A p a r t f r o m t h e s y n t h e t i c e f f o r t s d e s c r i b e d h e r e i n , t h e P i e r s g r o u p h a s a l s o d e v e l o p e d a n a p p r o a c h t o t h e s y n t h e s i s o f t h e C - 1 9 ( c y a t h a n e n u m b e r i n g ) o x y g e n a t e d c y a t h a n e s . A b r i e f r e v i e w o f t h e o t h e r s y n t h e t i c a p p r o a c h e s is d e s c r i b e d b e l o w . 2.1.3.1. A p p r o a c h b y A y e r a n d W a r d . T h i s a t t e m p t to s y n t h e s i z e c y a t h i n A 3 (79) w a s s t a r t e d b y A y e r 4 0 a n d w a s l a t e r c o n t i n u e d b y W a r d . 4 1 T h e trans r e l a t i o n s h i p b e t w e e n t h e m e t h y l g r o u p s at C - 6 a n d C - 9 ( c y a t h a n e n u m b e r i n g ) w a s e s t a b l i s h e d as t h e r e s u l t o f t w o s e q u e n t i a l e l e c t r o c y c l i c r e a c t i o n s , the f i r s t b e i n g a [4+2 ] c y c l o a d d i t i o n a n d t h e s e c o n d a [2+2] c y c l o a d d i t i o n ( S c h e m e 14). D i e l s - A l d e r r e a c t i o n o f 2 , 5 - d i m e t h y l - p - b e n z o q u i n o n e (93) a n d 2 , 4 - b i s t r i m e t h y I s i l o x y - l , 3 -p e n t a d i e n e (94) i n r e f l u x i n g x y l e n e g a v e t h e d e c a l i n s y s t e m 95. E n e d i o n e 95 w a s i r r a d i a t e d i n t h e p r e s e n c e o f e x c e s s a l l e n e to g i v e a m i x t u r e o f the r e g i o i s o m e r i c p h o t o a d d u c t s , a n d e s t a b l i s h e d t h e trans r e l a t i o n s h i p b e t w e e n t h e t w o q u a t e r n a r y m e t h y l g r o u p s . T h i s m i x t u r e o f e n o l s i l y l e the rs w a s h y d r o l y z e d to g i v e t h e t r i o n e s 96 a n d 97 (4 :1 i n f a v o r o f 96 as a r e s u l t o f the p h o t o c y c l o a d d i t i o n ) . E p o x i d a t i o n o f t h e e x o c y c l i c m e t h y l e n e g r o u p s i n 96 a n d 97 w i t h 2 4 raeta-chloroperoxybenzoic a c i d , f o l l o w e d b y r e d u c t i o n o f t h e e n o n e c a r b o n y l g r o u p s i n the r e s u l t a n t p r o d u c t s , a f f o r d e d c o m p o u n d s 98 a n d 99, r e s p e c t i v e l y . OH OBz 107 108 (a) x y l e n e , r e f l u x ; (b ) a l l e n e ( e x c e s s ) , T H F , hv, - 4 0 \u00C2\u00B0C; (c ) R e x y n 1 0 1 , M e O H , T H F , r t ; (d) m - C P B A , C H 2 C 1 2 , r t ; (e) 9 - B B N , T H F , 15 \u00C2\u00B0C to r t ; ( f ) P h S H , N a O H , M e O H , T H F , 0 \u00C2\u00B0C to r e f l u x ; (g) P h C O O H , P h 3 P , D E A D , T H F , 15 \u00C2\u00B0C; (h ) N a B E U , M e O H , C H 2 C 1 2 , - 7 8 \u00C2\u00B0C; H O A c , - 7 8 \u00C2\u00B0C to r t ; ( i ) N a O H , M e O H , H 2 0 , 5 0 \u00C2\u00B0C ; ( j ) R a n e y n i c k e l , M e O H , r t ; ( k ) N a O H , M e O H , r e f l u x ; (1) P h C O C l , E t 3 N , D M A P , C H 2 C 1 2 , 3 \u00C2\u00B0C; ( m ) M s C l , p y r i d i n e , 5 0 \u00C2\u00B0C; (n ) D B U , t o l u e n e , r e f l u x ; (0) H 2 , ( P h 3 P ) 3 R h C l , b e n z e n e ; (p ) O3, S u d a n I I I , C H 2 C 1 2 , - 7 8 \u00C2\u00B0C, D M S , p y r i d i n e ; (q) p - T s O H , b e n z e n e , rt. S c h e m e 14 98 100 Scheme 15 E p o x i d e 98 s e r v e s as a l a t e n t 1 , 4 - d i k e t o n e b y n u c l e o p h i l i c r i n g o p e n i n g o f t h e e p o x i d e , f o l l o w e d b y f r a g m e n t a t i o n , as d e p i c t e d i n Scheme 15. S u b s e q u e n t a l d o l c o n d e n s a t i o n o f c o m p o u n d 100 l e d to the a n n u l a t i o n p r o d u c t 101. T h e s e t w o p r o c e s s e s o c c u r i n o n e r e a c t i o n v e s s e l b y t r e a t i n g c o m p o u n d 98 w i t h e t h a n o l i c b e n z e n e t h i o l c o n t a i n i n g N a O H to a f f o r d the t r i c y c l i c e n o n e 101. M i t s o n o b u i n v e r s i o n o f t h e a l l y l i c a l c o h o l f u n c t i o n i n 101 g a v e t h e c o r r e s p o n d i n g b e n z o a t e , w h i c h w a s r e d u c e d w i t h s o d i u m b o r o h y d r i d e to p r o v i d e c o m p o u n d 102. T h e 6 , 6 - r i n g s y s t e m i n 102 i s c w - f u s e d w h e r e a s i n t h e c y a t h a n e s , t h e B C r i n g j u n c t i o n i s f r a n s - f u s e d . T h e r e f o r e , e p i m e r i z a t i o n a t C - 5 w a s n e c e s s a r y . U n f o r t u n a t e l y , t h e 6 , 6 - a ' s - f u s e d s y s t e m i n 102 w a s f o u n d to b e t h e m o r e s t a b l e t h a n the c o r r e s p o n d i n g 6,6-trans-fused s y s t e m . T h i s w a s a t t r i b u t e d t o a s t r o n g n o n - b o n d e d i n t e r a c t i o n b e t w e e n t h e p h e n y l t h i o g r o u p at C - 3 a n d t h e C - 1 0 m e t h y l e n e g r o u p ( c y a t h a n e n u m b e r i n g ) , w h i c h o c c u r s i n t h e trans-fused e p i m e r o f 102. R e m o v a l o f t h e p h e n y l t h i o g r o u p a l l e v i a t e s t h i s p r o b l e m . T h u s , h y d r o l y s i s o f t h e b e n z o a t e g r o u p u n d e r b a s i c c o n d i t i o n s , f o l l o w e d b y r e d u c t i v e d e s u l f u r i z a t i o n u s i n g R a n e y n i c k e l , a n d e p i m e r i z a t i o n w i t h s o d i u m h y d r o x i d e i n m e t h a n o l , l e d to a 9 5 : 5 m i x t u r e i n f a v o r o f the d e s i r e d f r a n s - f u s e d p r o d u c t 103. R e p r o t e c t i o n o f t h e s t e r i c a l l y l e s s h i n d e r e d h y d r o x y l g r o u p as t h e b e n z o a t e , f o l l o w e d b y m e s y l a t i o n o f t h e r e m a i n i n g h y d r o x y l g r o u p a n d s u b s e q u e n t e l i m i n a t i o n w i t h D B U , p r o v i d e d t h e t r i e n e 104. S e l e c t i v e r e d u c t i o n o f t h e d i s u b s t i t u t e d o l e f i n m o i e t y i n 104 w a s a c c o m p l i s h e d u s i n g W i l k i n s o n ' s c a t a l y s t t o a f f o r d 105. C a r e f u l l y c o n t r o l l e d o z o n o l y s i s c l e a v e d t h e 6 - m e m b e r e d r i n g i n 105 to p r o v i d e t h e 1,6 d i k e t o n e 106, w h i c h t h e n u n d e r w e n t a l d o l c o n d e n s a t i o n to g e n e r a t e t h e 5 , 6 , 7 - r i n g s y s t e m p a r t i c u l a r t o t h e c y a t h a n e s . T h u s , t r e a t m e n t o f 106 w i t h d r y p - T s O H i n b e n z e n e g a v e a 3 :1 m i x t u r e o f c o m p o u n d s 107 a n d 108, r e s p e c t i v e l y . T h e l a b i l e b e n z o a t e g r o u p i n 106 w a s p a r t i a l l y h y d r o l y z e d a n d r e s u l t e d i n i n t e r n a l a c e t a l f o r m a t i o n t o p r o v i d e 107. W h e n a l d o l c y c l i z a t i o n d i d o c c u r , s u b s e q u e n t i n t r a m o l e c u l a r b e n z o y l t r a n s f e r w a s o b s e r v e d to g i v e 108. T h e d r i v i n g f o r c e f o r t h i s b e n z o y l m i g r a t i o n w a s p r o p o s e d to b e t h e f o r m a t i o n o f t h e s t a b l e , i n t e r n a l h e m i a c e t a l . T h i s i s the m o s t a d v a n c e d i n t e r m e d i a t e o b t a i n e d b y W a r d , a n d i t c o n t a i n s t h e r i n g s y s t e m w i t h t h e c o r r e c t s t e r e o c h e m i s t r y f o r t h e c y a t h a n e s . T h e d i f f i c u l t y t ha t w o u l d b e e n c o u n t e r e d i n t h e i n t r o d u c t i o n o f t h e i s o p r o p y l g r o u p at C - 3 w a s a s h o r t c o m i n g a n d r e s u l t e d i n t h i s a p p r o a c h b e i n g a b a n d o n e d . 2.1.3.2. Approach by Paquette. P a q u e t t e ' s 4 2 a p p r o a c h to t h e t o t a l s y n t h e s i s o f m e m b e r s o f t h e c y a t h a n e s w a s c h a r a c t e r i z e d b y a n e x p e d i e n t a s s e m b l y o f t h e c o r e s k e l e t o n o f t h i s f a m i l y o f n a t u r a l p r o d u c t s . T h e 7 , 6 , 5 - r i n g s y s t e m c o n t a i n i n g the C - 3 ( c y a t h a n e n u m b e r i n g ) i s o p r o p y l u n i t w a s q u i c k l y a s s e m b l e d , b u t t h e i n a b i l i t y to p r o p e r l y f u n c t i o n a l i z e t h e r i n g s r e s u l t e d i n t h e f a i l u r e o f th i s rou te . C o m b i n a t i o n o f t h e t w o e n a n t i o p u r e f r a g m e n t s 109 a n d 110 b y r e a c t i o n o f t h e c o r r e s p o n d i n g v i n y l l i t h i u m s p e c i e s o f 109 w i t h t h e c a r b o n y l c a r b o n o f 110 a f f o r d e d t h e 1 , 5 -d i e n - 3 - o l 111 (Scheme 16). C o m p o u n d 111 u n d e r w e n t a n a n i o n a c c e l e r a t e d o x y - C o p e r e a r r a n g e m e n t b y t r e a t m e n t w i t h p o t a s s i u m h y d r i d e a n d 1 8 - c r o w n - 6 , a f f o r d i n g c o m p o u n d 112 w h i c h p o s s e s s e s t h e t r i c y c l o [ 7 . 5 . 0 . 0 2 ' 6 ] t e t r a d e c a n e f r a m e w o r k . M e t h y l a t i o n o f 112 o c c u r r e d s t e r e o s e l e c t i v e l y to p r o v i d e 113. T h e i n s t a l l a t i o n o f the s e c o n d m e t h y l g r o u p at C -6 , w h i c h m u s t o c c u r i n a n anti f a s h i o n w i t h r e s p e c t to the e x i s t i n g m e t h y l a t C - 9 , p r o v e d to b e p r o b l e m a t i c . A s t e r e o c o n t r o l l e d [ 2 , 3 ] - W i t t i g r e a r r a n g e m e n t w a s v i e w e d as a p o t e n t i a l s o l u t i o n t o t h i s p r o b l e m . T o w a r d t h i s a t t e m p t e d r e a r r a n g e m e n t , t h e c o n v e r s i o n o f 113 i n t o 114 w a s a c c o m p l i s h e d v i a a n a - ( p h e n y l s e l e n o ) k e t o n e . no reaction Scheme 16 T h e a t t e m p t e d r e d u c t i o n o f t h e c a r b o n y l g r o u p i n 114 r e s u l t e d i n d i s a p p o i n t i n g l y l o w d i a s t e r e o f a c i a l s e l e c t i v i t y to p r o v i d e 115 ( a : B = 1:2) . D i e n o n e 114 w a s u n e x p e c t e d l y a i r -s e n s i t i v e a n d o n s t a n d i n g i n c o n t a c t w i t h t h e a t m o s p h e r e t h e c o n v e r s i o n o f 114 i n t o 116 o c c u r r e d , w h i c h p r o v i d e d a s e r e n d i p i t o u s r o u t e to t h e r e q u i r e d o x y g e n a t i o n at C - l l . T h e s t e r i c a l l y l e s s c o n g e s t e d c a r b o n y l g r o u p i n 116 w a s r e d u c e d w i t h L - S e l e c t r i d e , a n d t h e r e s u l t a n t h y d r o x y l f u n c t i o n w a s p r o t e c t e d as i ts tert-butyldimethylsilyl e t h e r . R e d u c t i o n o f t h e e n o n e c a r b o n y l f u n c t i o n u n d e r t h e L u c h e c o n d i t i o n s p r o v i d e d 117. B o t h r e d u c t i o n s o c c u r r e d s t e r e o s e l e c t i v e l y a n d p r o c e e d e d w i t h t h e d e s i r e d s t e r e o c h e m i s t r y . C o n v e r s i o n o f 117 i n t o t h e s t a n n a n e 118 p r o c e e d e d w i t h o u t i n c i d e n t . H o w e v e r , t h e S t i l l - M i t r a [ 2 , 3 ] -s i g m a t r o p i c r e a r r a n g e m e n t w a s u n s u c c e s s f u l , e v e n u n d e r f o r c i n g c o n d i t i o n s . T h i s w a s a t t r i b u t e d to s u b s t a n t i a l s t e r i c c o n g e s t i o n i n the r e g i o n o f t h e s t a n n y l e ther . A n a l t e r n a t i v e r o u t e to i n t r o d u c e the m e t h y l g r o u p at C - 6 w a s p u r s u e d . T h e m a s k e d k e t o n e at C - 1 4 w a s h o p e d to p r o v i d e a h a n d l e f o r i t s i n s t a l l a t i o n (Scheme 17). R e m o v a l o f t h e e x t r a n e o u s c a r b o n y l g r o u p at C - 8 i n 113 p r o c e e d e d b y the c o n v e r s i o n o f 113 i n t o t h e e n o l p h o s p h a t e 119. T h e d o u b l e b o n d i n t h e s e v e n - m e m b e r e d r i n g w a s t h e n h y d r o g e n a t e d i n o r d e r to a v o i d s i d e r e a c t i o n s a n d the e n o l p h o s p h a t e w a s r e d u c e d to g i v e 120. H y d r o l y s i s o f t h e k e t a l f u n c t i o n i n 120 u n d e r a c i d i c c o n d i t i o n s a f f o r d e d the k e t o n e 121. U n f o r t u n a t e l y , a l k y l a t i o n o f t h e c o r r e s p o n d i n g e n o l a t e r e s u l t e d i n t h e m e t h y l g r o u p h a v i n g t h e w r o n g c o n f i g u r a t i o n i n 122. M a n y o t h e r p i t f a l l s , n o t o u t l i n e d h e r e , b u t d e l i n e a t e d i n t h e f u l l a c c o u n t o f t h i s w o r k , 4 2 p l a g u e d t h i s a p p r o a c h a n d i t w a s u l t i m a t e l y a b a n d o n e d . 29 M e 1 2 2 S c h e m e 1 7 2 . 1 . 3 . 3 . S u c c e s s f u l A p p r o a c h b y S n i d e r . S n i d e r a n d c o w o r k e r s r e c e n t l y p u b l i s h e d a n a c c o u n t o f t h e t o t a l s y n t h e s i s o f (\u00C2\u00B1 ) -a l l o c y a t h i n B2 ( 8 0 ) , a n d ( + ) - e r i n a c i n e A ( 1 2 3 ) , t h e 1 - B - D - x y l o s i d e o f ( + ) - 8 0 . 4 3 T h e s e e f f o r t s r e p r e s e n t t h e f i r s t r e p o r t e d s y n t h e s i s o f m e m b e r s o f the c y a t h a n e f a m i l y . 3 0 O H C R Q 123 R = 80R = H V O H ,OH O H T h e s e q u e n c e b e g a n w i t h a n e n a m i n e R o b i n s o n a n n u l a t i o n r e a c t i o n o f t h e c o m m e r c i a l l y a v a i l a b l e 2 , 6 - d i m e t h y l - 5 - h e p t a n a l (124) t o p r o v i d e t h e c y c l o h e x e n o n e 125 (Scheme 18). L e w i s a c i d i n d u c e d i n t r a m o l e c u l a r c o n j u g a t e a d d i t i o n o f t h e a l k e n e m o i e t y to t h e a , ( 3 - u n s a t u r a t e d k e t o n e a f f o r d e d t h e k n o w n b i c y c l i c a d d u c t 126. C o n v e r s i o n o f 126 i n t o t h e e n o l t r i f l a t e 127, f o l l o w e d b y p a l l a d i u m - c a t a l y z e d m e t h o x y c a r b o n y l a t i o n , g a v e t h e d i e n o a t e 128. R e d u c t i o n o f 128 w i t h D I B A L - H a n d O x i d a t i o n o f t h e a l l y l i c a l c o h o l 129 w i t h M n 0 2 p r o v i d e d d i e n a l 130. C o p p e r - c a t a l y z e d c o n j u g a t e a d d i t i o n o f i s o p e n t e n y l m a g n e s i u m b r o m i d e to 130 p r o v i d e d 131 as a 2 : 3 m i x t u r e o f e p i m e r i c a l d e h y d e s . M e t h y l a t i o n o f 131 a f f o r d e d a 15 :1 m i x t u r e o f the a - a l k y l a t e d a l d e h y d e s . T h e n e w l y i n t r o d u c e d m e t h y l g r o u p i n t h e m a j o r p r o d u c t 132 w a s a n t i t o the a n g u l a r m e t h y l g r o u p at C - 9 , as d e s i r e d . T h e s e v e n -m e m b e r e d r i n g w a s f o r m e d b y a n i n t r a m o l e c u l a r c a r b o n y l e n e r e a c t i o n to a f f o r d t h e a l c o h o l 133, w h i c h w a s p r o t e c t e d as i t s i s o p r o p y l d i m e t h y l s i l y l e t h e r 134. U n f o r t u n a t e l y , t h e s t e r e o c h e m i c a l o u t c o m e o f t h e c o n j u g a t e a d d i t i o n r e a c t i o n w h i c h c o n v e r t e d 130 i n t o 131 r e s u l t e d i n t h e a s - f u s e d 6 - 7 s y s t e m b e i n g p r o d u c e d . T h i s r i n g f u s i o n i s trans i n a l l t h e c y a t h a n e s w h e r e t h e s t e r e o c h e m i s t r y at t h e r i n g j u n c t u r e i s d e f i n e d . A l l o c y a t h i n B2 (80) a n d i ts d e r i v a t i v e e r i n a c i n e (123) a re t w o o f t h e c y a t h a n e s w h e r e C - 5 ( c y a t h a n e n u m b e r i n g ) i s s p 2 h y b r i d i z e d . T h e r e f o r e , t h e s e n a t u r a l p r o d u c t s w e r e s u i t a b l e ta rge ts f o r t h i s a p p r o a c h , s i n c e t h e i n c o r r e c t s t e r e o c h e m i s t r y at t h i s c e n t e r i s e v e n t u a l l y d e s t r o y e d . T o w a r d t h i s e n d , t h e e x o c y c l i c a l k e n e o f 134 w a s o x i d a t i v e l y c l e a v e d a n d the r e s u l t a n t k e t o n e w a s c o n v e r t e d i n t o t h e e n o n e 135. 31 TfO 136 H,C. g.h H,CL 127 R = OTf 128 R = C 0 2 M e 129 R = CH 2 OH 130 R = CHO 135 R = Si(/-Pr)Me2 133 R = H 134 R = Si(/-Pr)Me2 131 R = H 132 R = a-Me C 0 2 M e 137 C 0 2 M e 138 CHO HO CHO 139 R = Ac 123 R = H (a) C4H9N, C 6 H 6 ; C H 3 C O C H = C H 2 ; N a O A c , a q A c O H ; (b ) E t A l C l 2 , C H 2 C 1 2 ; (c ) P r o t o n Sponge\u00C2\u00AE, T f 2 0 ; (d ) P d ( O A c ) 2 , P h 3 P , C O , i - P r 2 E t N , M e O H ; (e) D I B A L - H ; ( f ) M n 0 2 ; ( g ) H 2 C = C ( C H 3 ) C H 2 C H 2 M g B r , C u B r \u00C2\u00AB M e 2 S , T M S C 1 , H M P A ; ( h ) f - B u O K , M e l ; ( i ) M e 2 A l C l ; ( j ) / - P r D M S C l , i m i d a z o l e ; ( k ) O s 0 4 , KIO4; (1) L i H M D S , P h S e C l ; H 2 0 2 ; ( m ) A c O H , H 2 0 , T H F ; (n) D e s s - M a r t i n p e r i o d i n a n e ; (o) K H M D S , P h N T f 2 ; (p ) P d ( O A c ) 2 , P h 3 P , C O , u \u00C2\u00B0 r 2 E t N , M e O H ; ( q ) E t 3 N , M e O H ; ( r ) L i A l H 4 ; ( s ) M n 0 2 ; ( t ) t r i a c e t y l - a - D -x y l o p y r a n o s y l b r o m i d e , H g ( C N ) 2 ; (u) K 2 C 0 3 . S c h e m e 1 8 D e s i l y l a t i o n o f 135, f o l l o w e d b y o x i d a t i o n , g a v e t h e c o r r e s p o n d i n g d i o n e , w h i c h w a s t r e a t e d w i t h K H M D S a n d P h N T f 2 , to a f f o r d e x c l u s i v e l y t h e e n o l t r i f l a t e 136. P a l l a d i u m -c a t a l y z e d m e t h o x y c a r b o n y l a t i o n o f 136 a f f o r d e d t h e k e t o es te r 137, w h i c h i s o m e r i z e d to 138 w h e n t r e a t e d w i t h E t 3 N . R e d u c t i o n o f 138 w i t h l i t h i u m a l u m i n u m h y d r i d e , f o l l o w e d b y o x i d a t i o n w i t h MnC\u00C2\u00BB2, g a v e (\u00C2\u00B1)-allocyathin B2 (80). G l y c o s i d a t i o n o f ( \u00C2\u00B1 ) - 8 0 w i t h e n a n t i o m e r i c a l l y p u r e 2 ,3 ,4 - t r i -C> - a c e t y l - a - D - x y l o p y r a n o s y l b r o m i d e p r o v i d e d a s e p a r a b l e 1:1 m i x t u r e o f ( + ) - e r i n a c i n e A t r i a c e t a t e (139) a n d i ts d i a s t e r e o m e r . H y d r o l y s i s o f the aceta te g r o u p s i n 139 w i t h p o t a s s i u m c a r b o n a t e i n M e O H p r o v i d e d ( + ) - e r i n a c i n e (123). 2.1.3.4. Successful Approach by Tori. A f t e r t h e p u b l i c a t i o n o f the r e s u l t s d e s c r i b e d i n t h i s t h e s i s , d i r e c t e d t o w a r d t h e t o t a l s y n t h e s i s o f t h e v e r r u c o s a n e - t y p e f a m i l y o f n a t u r a l p r o d u c t s , 4 4 t h e s e c o n d t o t a l s y n t h e s i s o f a l l o c y a t h i n B 2 (80) w a s d e s c r i b e d b y T o r i . 4 5 T h e s y n t h e t i c a p p r o a c h e m p l o y e d a s t r a t e g y s o m e w h a t s i m i l a r t o tha t d e s c r i b e d i n t h i s t h e s i s (Scheme 19). T h e 6 - m e m b e r e d B - r i n g w a s d e r i v e d f r o m 3 - m e t h y l c y c l o h e x - 2 - e n - l - o n e (140) a n d a l d o l c h e m i s t r y w a s e x p l o i t e d to c y c l i z e t h e 5 - m e m b e r e d A - r i n g i n 141 a n d t h e 7 - m e m b e r e d C - r i n g i n 80. T h e c o n f i g u r a t i o n o f C - l 1 ( c y a t h a n e n u m b e r i n g ) w a s c o n t r o l l e d b y a d o u b l e a l k y l a t i o n s e q u e n c e f r o m 141. 140 141 Scheme 19 T h e f i r s t s t e p i n t h e s e q u e n c e w a s the c o p p e r ( I ) - c a t a l y z e d c o n j u g a t e a d d i t i o n o f the G r i g n a r d r e a g e n t d e r i v e d f r o m 4 - b r o m o b u t - l - e n e to 3 - m e t h y l - 2 - c y c l o h e x e n - l - o n e (140). K e t a l i z a t i o n o f t h e r e s u l t a n t p r o d u c t a f f o r d e d 143 (Scheme 20). O z o n o l y s i s o f 143 a n d a d d i t i o n o f i s o p r o p y l m a g n e s i u m b r o m i d e to t h e r e s u l t a n t a l d e h y d e a f f o r d e d t h e a l c o h o l 144. J o n e s o x i d a t i o n p r o v i d e d t h e d i k e t o n e 145, w h i c h p r o c e e d e d w i t h c o n c o m i t a n t h y d r o l y s i s o f t h e k e t a l m o i e t y . B a s e - c a t a l y z e d a l d o l c y c l i z a t i o n g a v e the d e s i r e d b i c y c l i c e n o n e 141 a n d a c y l a t i o n o f 141 w i t h t h e a c i d c h l o r i d e 146 p r o v i d e d a l o w y i e l d o f t h e d e s i r e d C - a c y l a t e d c o m p o u n d 147, a l o n g w i t h the O - a c y l a t e d m a t e r i a l . T h e p r o d u c t m i x t u r e w a s i m m e d i a t e l y h y d r o l y z e d , w i t h o u t s e p a r a t i o n , t o g i v e t h e C - a c y l a t e d c o m p o u n d 147 i n 37% y i e l d a n d r e c o v e r e d s t a r t i n g m a t e r i a l (141) i n 6 0 % y i e l d . T h e d i k e t o n e w a s m e t h y l a t e d t o g i v e e x c l u s i v e l y 148. I n i t i a l l y , t h e o r d e r o f t h e s e r e a c t i o n s w a s r e v e r s e d a n d t h e i n c o r r e c t s t e r e o c h e m i s t r y at C - l l ( c y a t h a n e n u m b e r i n g ) w a s o b t a i n e d . R e g i o - a n d s t e r e o s e l e c t i v e , c h e l a t i o n - c o n t r o l l e d r e d u c t i o n o f t h e d i k e t o n e 148 w i t h z i n c b o r o h y d r i d e a f f o r d e d a m i x t u r e o f d i a s t e r e o m e r i c a l c o h o l s i n a r a t i o o f 1 5 : 1 , i n w h i c h the m a j o r c o m p o u n d h a d the c o n f i g u r a t i o n s h o w n i n 149. T h e e x t r e m e l y h i n d e r e d n a t u r e o f t h e c a r b o n y l g r o u p at C - 5 p r e c l u d e d t h e u s e o f W i t t i g c h e m i s t r y to i n t r o d u c e t h e r e q u i s i t e t w o c a r b o n u n i t at t h i s p o s i t i o n . A k i n e t i c a l l y c o n t r o l l e d i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n , f o l l o w e d b y r e d u c t i o n o f t h e l a c t o n e , p r o v i d e d a n m e t h o d f o r h o m o l o g a t i o n a t C - 5 . T h u s , t h e a l c o h o l 149 w a s c o n v e r t e d i n t o the a c e t a t e 150 w h i c h w a s t r e a t e d w i t h L H M D S to y i e l d the h y d r o x y l a c t o n e 151. D e h y d r a t i o n o f 151 w a s a c c o m p l i s h e d w i t h SOCI2 a n d p y r i d i n e to a f f o r d t h e a , B - u n s a t u r a t e d l a c t o n e 152, a l o n g w i t h t h e i s o m e r i c l a c t o n e 153. T h e l a t t e r c o m p o u n d c o u l d b e t r a n s f o r m e d i n t o 152 b y t r e a t m e n t w i t h p o t a s s i u m c a r b o n a t e i n M e O H . R e d u c t i o n o f t h e l a c t o n e 152 w i t h L i A l F L i i n T H F a t r e f l u x p r o v i d e d t h e t r i o l 154 i n l o w y i e l d (37%). T h e t w o p r i m a r y h y d r o x y l f u n c t i o n s w e r e p r o t e c t e d as t h e i r tert-b u t y l d i m e t h y l s i l y l e t h e r s y i e l d i n g 155. C o n v e r s i o n o f t h e r e m a i n i n g s e c o n d a r y a l c o h o l i n t o i t s a c e t a t e , f o l l o w e d b y c l e a v a g e o f t h e s i l y l e t h e r s g a v e t h e d i o l 157. S w e r n o x i d a t i o n o f 157 a f f o r d e d t h e d i a l 158 a n d b a s e - m e d i a t e d i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n r e s u l t e d i n t h e 3 4 f o r m a t i o n o f t h e 7 - m e m b e r e d C - r i n g a n d p r o c e e d e d w i t h c o n c o m i t a n t d e p r o t e c t i o n o f t h e a c e t a t e to a f f o r d a l l o c y a t h i n B2 (80) . 80 S c h e m e 2 0 (a) C H 2 = C H C H 2 C H 2 B r , M g , C u B r M e 2 S , T H F ; (b) H O C H 2 C H 2 O H , T s O H , C 6 H 6 ; (c ) O 3 ; Z n , A c O H ; (d ) C H 3 C H ( B r ) C H 3 , M g , E t 2 0 ; (e) J o n e s o x i d a t i o n ; ( f ) 5 % K O H - M e O H ; (g) L D A , T B D P S O ( C H 2 ) 3 C O C l ( 1 4 6 ) ; (h ) 5 % K O H - M e O H ; ( i ) tert-BuOK, M e l , T H F ; (j) Z n ( B H 4 ) 2 , M e O H ; ( k ) A c 2 0 , D M A P , P y , (1) L H M D S , T H F ; ( m ) S O C l 2 , P y , C H 2 C 1 2 ; (n ) K 2 C 0 3 , M e O H ; ( 0 ) U A I H 4 , T H F ; (p ) T B S C 1 , N E t 3 , C H 2 C 1 2 ; (q) A c 2 0 , D M A P , P y ; (r) P P T S , M e O H ; (s) ( C O C l ) 2 , D M S O , N E t 3 , C H 2 C 1 2 ; (t) 5% K O H - M e O H . 2.1.3.5. Alternative Approach by Piers. O n g o i n g e f f o r t s i n t h e P i e r s g r o u p a re d i r e c t e d t o w a r d s t h e s y n t h e s i s o f s a r c a d o n i n G (81).46 T h i s m e m b e r o f t h e c y a t h a n e f a m i l y d i s t i n g u i s h e s i t s e l f f r o m m o s t o f t h e o t h e r c y a t h a n e s b y t h e p r e s e n c e o f a C - 1 9 ( c y a t h a n e n u m b e r i n g ) h y d r o x y l g r o u p . F r o m a s y n t h e t i c v i e w p o i n t , t h e p r e s e n c e o f t h e C - 1 8 s t e r e o g e n i c c e n t e r t r a n s l a t e s i n t o a c o m p l e x i t y n o t p r e s e n t i n m o s t c y a t h a n e s . A s e q u e n t i a l r i n g c l o s u r e , [ 2 , 3 ] - s i g m a t r o p i c r e a r r a n g e m e n t s t r a t e g y a l l o w e d t h e s y n t h e s i s o f the p r o p e r l y f u n c t i o n a l i z e d A - r i n g . 4 7 O H C T h e s y n t h e t i c s e q u e n c e b e g a n b y e m p l o y i n g a m e t h y l e n e c y c l o h e x a n e a n n u l a t i o n s e q u e n c e a n a l o g o u s t o t h e o n e d e s c r i b e d i n Scheme 3 ( p a g e 6 ) . T h u s , c o p p e r ( I ) - c a t a l y z e d c o n j u g a t e a d d i t i o n o f t h e b i f u n c t i o n a l G r i g n a r d r e a g e n t 159 t o 3 - m e t h y l c y c l o h e x - 2 - e n - l - o n e (140) a f f o r d e d the 1 , 4 - a d d u c t 160 (Scheme 21). I n t r a m o l e c u l a r a l k y l a t i o n r e s u l t i n g f r o m the t r e a t m e n t o f 160 w i t h p o t a s s i u m h y d r i d e g a v e a m i x t u r e o f t h e trans- a n d c i s - f u s e d c o m p o u n d s 161 a n d 162, i n a r a t i o o f 7 8 : 2 2 , r e s p e c t i v e l y . T h e m i x t u r e o f b i c y c l i c k e t o n e s w a s c o n v e r t e d i n t o t h e c o r r e s p o n d i n g / V , A f - d i m e t h y l h y d r a z o n e s 163 a n d 164. A l k y l a t i o n o f the trans-fused e p i m e r 163 w i t h t h e b i f u n c t i o n a l r e a g e n t 165, f o l l o w e d b y o x i d a t i v e r e m o v a l o f t h e h y d r a z o n e f u n c t i o n , p r o v i d e d t h e k e t o n e 166. E p i m e r i z a t i o n o f t h e a x i a l l y o r i e n t e d s i d e c h a i n i n 166, f o l l o w e d b y m e t h y l a t i o n , w h i c h o c c u r r e d w i t h t h e d e s i r e d s t e r e o c h e m i s t r y , g a v e t h e b i c y c l i c k e t o n e 167. I o d o d e g e r m y l a t i o n a f f o r d e d t h e v i n y l i o d i d e , w h i c h w a s t reated w i t h n - B u L i . T h e r e s u l t a n t v i n y l l i t h i o s p e c i e s c y c l i z e d to g i v e the t r i c y c l e 168. C u B r . M e 2 S , THF B F 3 . O E t 2 140 *GeMe 166 1K-BuOK f-BuOH 2) Et 2 NLi, THF 3) Mel 3 1) KDA, H M P A THF I 165 G e M e 3 3) N a l 0 4 , THF H 2 0 , pH 7 G e M e 3 1) NIS C H 2 C I 2 2) n-BuLi 162 M e 2 N N H 2 C S A PhH, reflux N N M e N N M e ; 163 164 O H 167 168 Scheme 21 1) KH, THF 18-cr-6 2) B u 3 S n C H 2 l 3) />BuLi 169 T h e c o n f i g u r a t i o n o f the h y d r o x y l m o i e t y i n 168 i s t r a n s f e r r e d to t h e s i d e c h a i n i n the e n s u i n g S t i l l - M i t r a [ 2 , 3 ] - s i g m a t r o p i c r e a r r a n g e m e n t . T h u s , t h e a l c o h o l 168 w a s c o n v e r t e d i n t o t h e t r i b u t y l s t a n n y l m e t h y l e t h e r i n t e r m e d i a t e , w h i c h r e a r r a n g e d u p o n t r e a t m e n t w i t h n-B u L i . T h e r e a r r a n g e d a l c o h o l 169 p o s s e s s e s the r e q u i r e d r e l a t i v e c o n f i g u r a t i o n at the n e w s t e r e o g e n i c c e n t e r . C o m p o u n d 169 c o n t a i n s t h e c o r r e c t c o n f i g u r a t i o n at a l l s t e r e o g e n i c 3 7 c e n t e r s f o r s a r c a d o n i n G (81). P r e s e n t e f f o r t s i n t h i s a r e a a r e a i m e d a t e l a b o r a t i n g t h e a p p r o p r i a t e l y f u n c t i o n a l i z e d s e v e n - m e m b e r e d C - r i n g . 2.1.4. Retrosynthetic Analysis. O u r p r o p o s e d s y n t h e t i c p l a n f o r the c o n s t r u c t i o n o f t h e th ree v e r r u c o s a n e - t y p e n a t u r a l p r o d u c t s , h o m o v e r r u c o s a n - 5 B - o l (63), v e r r u c o s a n - 2 B - o l (61), a n d n e o v e r r u c o s a n - 5 B - o l (62), a n d f o r t h e c y a t h a n e 64, i s o u t l i n e i n Scheme 22. T h e s t r u c t u r a l a n d s t e r e o c h e m i c a l s i m i l a r i t i e s o f t h e s e ( a n d o t h e r ) n a t u r a l p r o d u c t s , p a r t i c u l a r l y t h e f i v e c o n t i g u o u s s t e r e o c e n t e r s d e p i c t e d i n t h e p a r t s t r u c t u r e 170, l e n d t h e m s e l v e s t o a c e n t r a l i z e d a n d d i v e r g e n t s y n t h e t i c a p p r o a c h . T h e s y n t h e s i s o f a u s e f u l l y f u n c t i o n a l i z e d , a d v a n c e d i n t e r m e d i a t e c o n t a i n i n g t h e f e a t u r e s p r e s e n t i n 170, w o u l d p r o v i d e a c o m p o u n d tha t c o u l d s e r v e as a b r a n c h i n g p o i n t f r o m w h i c h t h e n a t u r a l c o m p o u n d s 61-64 c o u l d b e d e r i v e d . C o m p o u n d 171 w o u l d s e r v e i n t h i s c a p a c i t y . A s s e e n i n S e c t i o n 2 . 1 . 2 ( p a g e 2 1 ) , h o m o v e r r u c o s a n - 5 B - o l (63) c a n b e o b t a i n e d b y r i n g e x p a n s i o n o f e i t h e r v e r r u c o s a n - 2 B - o l (61) o r n e o v e r r u c o s a n - 5 B - o l (62). A h y d r o x y l -d i r e c t e d c y c l o p r o p a n a t i o n o f the a l l y l i c a l c o h o l s 172 a n d 173 w a s e n v i s a g e d as t h e l a s t s tep i n t h e s y n t h e s i s o f t h e n a t u r a l p r o d u c t s 61 a n d 62, r e s p e c t i v e l y . T h e a l c o h o l 172 c a n b e d e r i v e d f r o m 174 v i a a n e n o n e t r a n s p o s i t i o n p r o t o c o l , w h i c h p a s s e s t h r o u g h t h e i n t e r m e d i a c y o f t h e e p o x y k e t o n e 175. C o m p o u n d 173, t h e p e n u l t i m a t e p r e c u r s o r to n e o v e r r u c o s a n - 5 B - o l O 170 171 ( 6 2 ) , i s r e l a t e d t o e n o n e t h e 1 7 4 b y a n o x i d a t i o n . T h e a l l y l i c a l c o h o l 1 7 3 c a n b e d e r i v e d f r o m i t s d o u b l e b o n d c o n g e n e r 1 7 6 b y i s o m e r i z a t i o n o f t h e e x o c y c l i c m e t h y l e n e i n t o t h e s i x -m e m b e r e d r i n g . C o m p o u n d 1 7 6 c a n b e o b t a i n e d f r o m the a d v a n c e d i n t e r m e d i a t e 1 7 1 b y a s e r i e s o f t r a n s f o r m a t i o n s i n c l u d i n g h y d r o g e n a t i o n o f t h e i s o p r o p e n y l d o u b l e b o n d , oc-h y d r o x y l a t i o n , a n d c o n v e r s i o n o f t h e k e t o n e m o i e t y to a m e t h y l e n e g r o u p . T h e c o n n e c t i o n b e t w e e n 1 7 1 a n d t h e c y a t h a n e n a t u r a l p r o d u c t 6 4 , i n v o l v e s a r i n g e x p a n s i o n o f 1 7 1 to p r o v i d e t h e h o m o l o g a t e d k e t o n e 1 7 7 . C o m p o u n d 1 7 1 c a n , i n t h e o r y , b e o b t a i n e d b y e m p l o y i n g a b i f u n c t i o n a l r e a g e n t m e d i a t e d a n n u l a t i o n p r o t o c o l , b y t h e c o m b i n a t i o n o f the s y n t h o n 6 9 w i t h t h e b i c y c l i c k e t o n e 6 0 , as d e s c r i b e d i n S e c t i o n 1.3 ( p a g e 14). A c o m p o u n d that w o u l d s e r v e as t h e s y n t h e t i c e q u i v a l e n t o f t h e s y n t h o n 6 9 i s t h e b i f u n c t i o n a l r e a g e n t 7 0 . A n a d d i t i o n a l a l k y l a t i o n s t e p w o u l d b e r e q u i r e d to i n s t a l l a n a n g u l a r m e t h y l g r o u p at C - 7 ( v e r r u c o s a n e n u m b e r i n g ) . T h e o r d e r o f t h e a l k y l a t i o n r e a c t i o n s w o u l d h a v e to b e s e l e c t e d to e n s u r e t h a t t h e c o r r e c t s t e r e o c h e m i s t r y i s o b t a i n e d at t h i s c e n t e r . T h e k e t o n e 6 0 c a n b e o b t a i n e d u s i n g the m e t h o d o l o g y d e s c r i b e d f o r t h e c o n j u g a t e a d d i t i o n r e a c t i o n s o f c u p r a t e s to b i c y c l o [ 4 . 3 . 0 ] n o n - 9 - e n - 2 - o n e (vide supra). A c u p r a t e r e a g e n t d e r i v e d f r o m i s o p r o p e n y l b r o m i d e ( 1 7 8 ) s h o u l d p r o v i d e a c c e s s to 6 0 b y c o n j u g a t e a d d i t i o n to t h e k n o w n b i c y c l i c k e t o n e 1 7 9 . T h e p r e p a r a t i o n o f 1 7 9 h a s b e e n d e s c r i b e d u s i n g t h e t w o c o m m e r c i a l l y a v a i l a b l e r e a g e n t s , 3 - m e t h y l c y c l o h e x - 2 - e n - l - o n e ( 1 4 0 ) a n d t h e b i f u n c t i o n a l r e a g e n t 2 - ( 2 - b r o m o e t h y l ) -1 , 3 - d i o x a n e ( 1 8 0 ) . T h e s e q u e n c e i n v o l v e s c o n j u g a t e a d d i t i o n f o l l o w e d b y a n i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n . S c h e m e 22 40 2.1.5. Towards the Total Synthesis of (\u00C2\u00B1)-Verrucosan-2B-ol, (\u00C2\u00B1)-Neoverrucosan-5B-ol , (\u00C2\u00B1)-Homoverrucosan-5B-ol, and (\u00C2\u00B1)-(3R, 4R, SR, 6S, 9/?)-Cyatha-12,18-diene. 2.1.5.1. Preparation of the Bicyclic Ketone 60. H e l q u i s t 4 8 h a s d e s c r i b e d a t w o - s t e p s y n t h e s i s o f t h e b i c y c l i c e n o n e 179. T h e f i r s t s tep e m p l o y e d a b i f u n c t i o n a l r e a g e n t m e d i a t e d a n n u l a t i o n p r o t o c o l , i n v o l v i n g t h e c o p p e r ( I ) -c a t a l y z e d c o n j u g a t e a d d i t i o n o f t h e G r i g n a r d r e a g e n t 183b t o 3 - m e t h y l c y c l o h e x - 2 - e n - l - o n e (140). T h e s e c o n d s t e p w a s a n a c i d c a t a l y z e d i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n (Scheme 23). 140 : uB r -Me 2 S, THF, M e 2 S -78 \u00C2\u00B0C, 10 h; warm to 0 \u00C2\u00B0C over 6 h; 0 \u00C2\u00B0C, 2 h HCI, THF O H 2 C \ it 72 h F o r t h e i n i t i a l s t e p s o f o u r w o r k , a s i m i l a r s t r a t e g y w a s u s e d f o r t h e p r e p a r a t i o n o f 179, b u t a n u m b e r o f m o d i f i c a t i o n s w e r e i m p l e m e n t e d w h i c h i n c r e a s e d t h e o v e r a l l e f f i c i e n c y o f t h e s e q u e n c e . T h e f i r s t m o d i f i c a t i o n i n v o l v e d t h e u s e o f a s l i g h t l y d i f f e r e n t b i f u n c t i o n a l r e a g e n t . S t o w e l l 4 9 f o u n d tha t t h e G r i g n a r d r e a g e n t 182, d e r i v e d f r o m t h e b r o m o a c e t a l 180 a n d c o n t a i n i n g a s i x - m e m b e r e d 1 , 3 - d i o x a n e u n i t as t h e p r o t e c t i n g g r o u p f o r t h e m a s k e d a l d e h y d e f u n c t i o n , w a s m o r e s t a b l e , e a s i e r to p r e p a r e , a n d w a s p r o d u c e d i n h i g h e r y i e l d t h a n the G r i g n a r d d e r i v e d f r o m t h e b r o m i d e 183 (Scheme 24). 183b Scheme 24 T h e s e c o n d m o d i f i c a t i o n i n v o l v e d u s i n g K u w a j i m a ' s p r o c e d u r e 5 0 f o r c o n j u g a t e a d d i t i o n o f t h e G r i g n a r d r e a g e n t 182 to the e n o n e 140. K u w a j i m a f o u n d t h a t t h e u s e o f H M P A a n d T M S C 1 as a d d i t i v e s r e d u c e d t h e r e a c t i o n t i m e o f c o p p e r ( I ) - c a t a l y z e d c o n j u g a t e a d d i t i o n r e a c t i o n s a n d i n c r e a s e d the y i e l d , p a r t i c u l a r l y w h e n u n r e a c t i v e e n o n e s w e r e u s e d . T h u s , t r e a t m e n t o f 3 - m e t h y l - 2 - c y c l o h e x e n - l - o n e (140) w i t h the G r i g n a r d r e a g e n t 182 i n t h e p r e s e n c e o f a c a t a l y t i c a m o u n t o f CuBr\u00C2\u00ABMe2S ( - 1 5 m o l % ) , H M P A (3 e q u i v . ) , a n d T M S C 1 (3 e q u i v . ) , a f f o r d e d , a f t e r a n a p p r o p r i a t e w o r k u p p r o c e d u r e , t h e k e t o a c e t a l 184 i n 9 5 % y i e l d ( e q u a t i o n 3). T h e s p e c t r a l p r o p e r t i e s o f c o m p o u n d 184 a r e i d e n t i c a l w i t h t h o s e r e p o r t e d . 5 1 U n d e r t h e s e c o n d i t i o n s , t h e r e a c t i o n w a s c o m p l e t e i n a p p r o x i m a t e l y 2 h , w h e r e a s H e l q u i s t r e p o r t e d a r e a c t i o n t i m e o f 18 h . O 140 1) BrMg 182 C u B r . M e 2 S , THF, HMPA, TMSCI, - 78\u00C2\u00B0C 2) NH 4 CI, H 2 0 (3) T h e l a s t m o d i f i c a t i o n t o t h e p u b l i s h e d p r o c e d u r e i n v o l v e d t h e a c i d c a t a l y z e d a l d o l c o n d e n s a t i o n to g e n e r a t e t h e b i c y c l i c e n o n e 1 7 9 ( S c h e m e 2 5 ) . 5 2 H e l q u i s t p e r f o r m e d t h e a l d o l c o n d e n s a t i o n o f the k e t o a c e t a l 1 8 1 u s i n g a q u e o u s H C l i n T H F at r o o m t e m p e r a t u r e f o r 7 2 h . 1 8 1 n = 0 1 8 4 n = 1 S c h e m e 2 5 I n a n a t t e m p t to r e d u c e t h e l o n g r e a c t i o n t i m e s , the k e t o a c e t a l 1 8 4 w a s h e a t e d at r e f l u x i n the p r e s e n c e o f a q u e o u s H C l (0.1 M ) i n T H F . U n d e r t h e s e c o n d i t i o n s , t h e r e a c t i o n w a s c o m p l e t e a f t e r 2 3 h , b u t the y i e l d o f p r o d u c t w a s s l i g h t l y l o w e r ( 6 6 % ) t h a n tha t r e p o r t e d b y H e l q u i s t ( 7 7 % ) . C o n s i d e r a b l y l o w e r y i e l d s w e r e o b t a i n e d i f t h e r e a c t i o n m i x t u r e w a s h e a t e d f o r l o n g e r t i m e s . C o m p o u n d 1 7 9 h a d to b e d i s t i l l e d i m m e d i a t e l y a n d s t o r e d u n d e r a r g o n , i n a f r e e z e r , t o a v o i d d e c o m p o s i t i o n o v e r t i m e . A s o l u t i o n t o t h i s p r o b l e m w a s i n s p i r e d b y a n a c c o u n t f r o m P i e r s a n d O b a l l a , 5 3 t ha t d e s c r i b e d t h e t o t a l s y n t h e s i s o f ( - ) -h o m a l o m e n o l A a n d ( - ) - h o m a l o m e n o l B . D u r i n g t h e s y n t h e s i s , t h e c o n v e r s i o n o f t h e e n a n t i o m e r i c a l l y p u r e k e t o a c e t a l 1 8 5 i n t o the b i c y c l i c e n o n e 1 8 6 w a s n e c e s s a r y ( T a b l e 1). T h e s e n s i t i v i t y o f t h e T B D P S p r o t e c t i n g g r o u p to the a c i d i c c o n d i t i o n s d e s c r i b e d b y H e l q u i s t ( H C I - H 2 O - T H F ) f o r the a l d o l c o n d e n s a t i o n r e q u i r e d f i n d i n g a n a l t e r n a t i v e w a y o f c a r r y i n g o u t the d e s i r e d t r a n s f o r m a t i o n . A s u m m a r y o f the v a r i o u s a t t e m p t s a re s h o w n i n T a b l e l . 5 4 4 3 Table 1: A t t e m p t s to C y c l i z e t h e K e t o A c e t a l 185 to F o r m t h e B i c y c l i c E n o n e 186. 1 r > Conditions r O T B D P S T B D P S O 185 186 E n t r y C o n d i t i o n s R e s u l t s 1* P P T S , a q u e o u s a c e t o n e , A , o v e r n i g h t . M o s t l y s t a r t i n g m a t e r i a l , a t r a c e a m o u n t o f 186. 2b 8 0 % a q u e o u s a c e t i c a c i d , T H F , r t , 4 h . M o s t l y s t a r t i n g m a t e r i a l . 3 C / > T s O H , C H 2 C 1 2 , A , 5 h. S t a r t i n g m a t e r i a l : P r o d u c t 186 ( - 1 : 1 ) + u n i d e n t i f i a b l e b y p r o d u c t . 4 d 5 0 % a q u e o u s C F 3 C O O H / d i o x a n e r t , 4 h . M o s t l y s t a r t i n g m a t e r i a l . 5 8 0 % a q u e o u s C F 3 C O O H / d i o x a n e ( 1 : 2 ) , 7 0 \u00C2\u00B0C, 16 h . 8 2 % y i e l d o f 186. a- The conditions utilized were reported by Hagiwara and Uda 5 5 for the hydrolysis of 1,3-dioxolanes (i.e. 5-membered ring acetals). b- The condition utilized were reported by Babler et al.56 for the hydrolysis of 1,3-dioxolanes. c- The condition utilized were reported by Baudin et al.57 for the hydrolysis of 1,3-dioxolanes. d- The condition utilized were reported by Lavallee and Hanessian58 for the hydrolysis of 1,3-dioxolanes. T h e c o n d i t i o n s o u t l i n e d i n e n t r i e s 1 -4 i n T a b l e 1 ( e n t r i e s 1 -4 ) a r e l i t e r a t u r e m e t h o d s f o r t h e h y d r o l y s i s o f 1 , 3 - d i o x o l a n e s f u n c t i o n s ( f i v e - m e m b e r e d c y c l i c a c e t a l s ) , b u t w e r e i n e f f e c t i v e i n h y d r o l y z i n g t h e 1 , 3 - d i o x a n e f u n c t i o n ( s i x - m e m b e r e d c y c l i c a c e t a l ) p r e s e n t i n 185. N o t e w o r t h y i s t h e r e a c t i o n s u m m a r i z e d i n e n t r y 5 , i n w h i c h t h e r e a c t i o n p r o c e e d e d i n 8 2 % y i e l d a n d i n v o l v e d t r e a t i n g c o m p o u n d 185 w i t h 8 0 % C F 3 C O O H / d i o x a n e ( 1 :2 ) at 7 0 \u00C2\u00B0C f o r 16 h . T h e s e r e a c t i o n c o n d i t i o n s c o n v e r t e d 184 i n t o 179 i n 3 h 3 0 m i n (Scheme 25), b u t t h e d i f f i c u l t y e n c o u n t e r e d i n r e m o v i n g t h e r e l a t i v e l y h i g h b o i l i n g 1 , 4 - d i o x a n e s o l v e n t w a s p r o b l e m a t i c a n d t h e d i f f i c u l t i e s w o u l d h a v e b e e n m a g n i f i e d o n l a r g e r s c a l e . B y c h a n g i n g the s o l v e n t to T H F , t h e r e a c t i o n w a s c o m p l e t e i n 2 h 3 0 m i n at 7 0 \u00C2\u00B0C a n d t h e y i e l d w a s 9 1 % . 4 4 A f e w a d d i t i o n a l c o m m e n t s a b o u t t h i s a l d o l c o n d e n s a t i o n a r e n e c e s s a r y . T h e r e a c t i o n m i x t u r e w a s h e a t e d at 7 0 \u00C2\u00B0C i n 8 0 % a q u e o u s C F 3 C O O H / T H F (1 :2 ) f o r 2 h 3 0 m i n a n d , a f te r a n a p p r o p r i a t e w o r k u p p r o c e d u r e , f l a s h c h r o m a t o g r a p h y , a n d d i s t i l l a t i o n , t h e e n o n e 179 w a s i s o l a t e d i n 8 2 % y i e l d . T h e c h r o m a t o g r a p h y c o l u m n w a s f l u s h e d w i t h d i e t h y l e t h e r a n d , a f t e r c o n c e n t r a t i o n o f t h e e l u a t e , the r e s i d u a l m a t e r i a l w a s r e s u b j e c t e d t o a c i d i c c o n d i t i o n s ( 1 0 0 % C F 3 C O O H / T H F ( 1 : 2 ) , 7 0 \u00C2\u00B0C) f o r 16 h . A s i m i l a r w o r k u p a n d p u r i f i c a t i o n p r o c e d u r e y i e l d e d a n a d d i t i o n a l 9 % o f t h e e n o n e 179, r e s u l t i n g i n a t o t a l y i e l d o f 9 1 % (Scheme 25a). A n a n a l o g o u s p r o c e d u r e w a s u s e d i n t h e s y n t h e s i s o f c o m p o u n d 186.5 3 P r e s u m a b l y , t h e m o r e p o l a r c o m p o u n d s e l u t e d w i t h d i e t h y l e t h e r a r e i n t e r m e d i a t e s i n t h e c y c l i z a t i o n s e q u e n c e . L o n g e r r e a c t i o n t i m e s t o d r i v e the r e a c t i o n to c o m p l e t i o n ( - 1 7 h ) r e s u l t e d i n a l o w e r y i e l d o f 179 ( 7 4 % ) , a n d p r o d u c e d a n u m b e r o f b y - p r o d u c t s tha t w e r e d i f f i c u l t to s e p a r a t e f r o m the d e s i r e d e n o n e b y c o l u m n c h r o m a t o g r a p h y . 80% C F 3 C O O H THF, 70 \u00C2\u00B0C 184 6o + more polar products 179 100% C F 3 C O O H THF, 70 \u00C2\u00B0C 91% overall Scheme 25a T h e n e x t s t e p i n t h e s y n t h e s i s i n v o l v e d t h e i n t r o d u c t i o n o f a n i s o p r o p e n y l g r o u p v i a c o n j u g a t e a d d i t i o n o f a s u i t a b l y f u n c t i o n a l i z e d c u p r a t e r e a g e n t t o t h e b i c y c l i c e n o n e 179. V e r y l i t t l e i n f o r m a t i o n a b o u t t h e s t e r e o c h e m i c a l o u t c o m e o f c o n j u g a t e a d d i t i o n r e a c t i o n s t o b i c y c l o [ 4 . 3 . 0 ] n o n - 9 - e n - 2 - o n e s w a s k n o w n 5 9 p r i o r to r e c e n t s t u d i e s b y P i e r s a n d O b a l l a . 1 1 I n c o n n e c t i o n w i t h a b i f u n c t i o n a l r e a g e n t a n n u l a t i o n s t u d y (vide supra, p a g e s 6 - 8 ) , t h e 4 5 p r e p a r a t i o n o f t h e b i c y c l i c a d d u c t s 188 a n d 189 f r o m e n o n e s o f g e n e r a l s t r u c t u r e 20 w a s r e q u i r e d . T h e r e s u l t s o f t h e s e e f f o r t s a re s u m m a r i z e d i n Table 2. Table 2: C u p r a t e C o n j u g a t e A d d i t i o n s to B i c y c l o [ 4 . 3 . 0 ] n o n - 9 - e n - 2 - o n e s a n d T h e r m o d y n a m i c a l l y C o n t r o l l e d E q u i l i b r a t i o n o f the 1 , 4 - A d d u c t s ( f r o m r e f e r e n c e 11) . 0 X v. R 2 X ' 1 G e M e 3 \ + G e M e 3 ? H ? /-A JC = X-.xo M ) 20 Ft 1 11 R 1 iS R 1 189 E n t r y | R i 1 R2 | O v e r a l l Y i e l d ( I s o l a t e d ) ris-Fused trans - F u s e d 1 H M e 8 9 % 9 : [1 : 1 3 ] b 2 M e M e 8 6 % 2 0 : [ > 9 9 : 1 l i b 3 H H 8 8 % 5 : [1 : 1 3 0 ] b 4 M e H 9 8 % 6 : n : 1 5 1 b a- Reagent 9 (see page 4), TMSBr, (~5equiv.), THF, -78 \u00C2\u00B0C; H 2 0, NH4C1 - N H 4 O H . b- This ratio was obtained upon equilibraUon (NaOMe/MeOH/rt) of the cis- and trans-fused epimers. T h e c o n j u g a t e a d d i t i o n r e a c t i o n s p r o c e e d e d c o m p l e t e l y s t e r e o s e l e c t i v e l y i n e a c h c a s e , s u c h that t h e 3 - t r i m e t h y l g e r m y l - 3 - b u t e n y l g r o u p w a s i n t r o d u c e d trans t o t h e a n g u l a r g r o u p R 1 . F o r e a c h s u b s t r a t e , h y d r o l y s i s o f t h e r e s u l t a n t e n o l s i l y l e t h e r , a f f o r d e d a m i x t u r e o f the cis a n d trans e p i m e r s at C - l , w i t h t h e c w - f u s e d p r o d u c t p r e d o m i n a t i n g . E a c h o f t h e a d d u c t s i n Table 2 w a s s u b j e c t e d t o b a s e - p r o m o t e d e p i m e r i z a t i o n a n d t h e e q u i l i b r i u m r a t i o o f e a c h p a i r o f i s o m e r s w a s d e t e r m i n e d . I n e a c h c a s e , e x c e p t f o r e n t r y 2 ( R 1 , R 2 = M e ) , t h e trans-fused i s o m e r w a s f o u n d t o b e t h e t h e r m o d y n a m i c a l l y m o r e s t a b l e o f t h e t w o e p i m e r s . E x a m i n a t i o n o f m o l e c u l a r m o d e l s r e v e a l e d tha t t h e ris-fused i s o m e r i n e n t r y 2 i s t h e m o s t s t a b l e d u e to a d e s t a b i l i z i n g p s e u d o 1 , 3 - d i a x i a l i n t e r a c t i o n b e t w e e n t h e t w o m e t h y l g r o u p s w h i c h is p r e s e n t i n t h e trans - f u s e d e p i m e r (see b e l o w ) . T h e e q u i l i b r a t i o n r e s u l t s i n T a b l e 2 a re c o n s i s t e n t w i t h t h o s e r e p o r t e d f o r s t r u c t u r a l l y s i m i l a r c o m p o u n d s . D a n a a n d c o - w o r k e r s 6 0 a l s o d e t e r m i n e d tha t t h e f r a n s - f u s e d e p i m e r s w e r e f a v o r e d w h e n R 1 a n d R 2 w e r e i n a n anti r e l a t i o n s h i p ( T a b l e 3 , e n t r i e s 1 , 2 ) . A m o r e f u n c t i o n a l i z e d e x a m p l e i s p r o v i d e d b y P a q u e t t e 6 1 ( e n t r y 3 ) , i n w h i c h e p i m e r i z a t i o n o f 1 9 0 f u r n i s h e d the t h e r m o d y n a m i c a l l y m o r e s t a b l e trans i s o m e r 1 9 1 . S i m i l a r s t e r e o c o n t r o l t o t ha t d e s c r i b e d a b o v e w a s a n t i c i p a t e d f o r t h e c o n j u g a t e a d d i t i o n o f a n i s o p r o p e n y l g r o u p to the b i c y c l i c e n o n e 1 7 9 a n d f o r t h e e n s u i n g e p i m e r i z a t i o n o f the r i n g j u n c t i o n . T a b l e 3 : T h e T h e r m o d y n a m i c a l l y C o n t r o l l e d E q u i l i b r a t i o n o f s e l e c t e d cis- a n d trans-F u s e d S y s t e m s ( f r o m r e f e r e n c e s 6 0 a n d 61 ) . E n t r y c i s - F u s e d trans - F u s e d 1 ? H M E ip> \u00E2\u0080\u0094 H 1 : 0 H Me H 1 5 . 7 2 Me 1 Me 2 . 2 3 \u00E2\u0080\u00A2. I I I . \ KOCOQ f iT\"\ * \ / r l . A / H MeO W MeO \ = / 1 9 0 1 9 1 I n i t i a l a t t e m p t s d i r e c t e d t o w a r d the p r e p a r a t i o n o f t h e h i g h e r o r d e r c y a n o c u p r a t e 1 9 2 w e r e c a r r i e d o u t b y t r e a t i n g a T H F s o l u t i o n o f 2 - b r o m o p r o p e n e 1 7 8 w i t h n - B u L i , f o l l o w e d b y the a d d i t i o n o f c o p p e r ( I ) c y a n i d e . H o w e v e r , c o n j u g a t e a d d i t i o n p r o d u c t s r e s u l t i n g f r o m t h e a d d i t i o n o f a n n - b u t y l g r o u p to the e n o n e s u b s t r a t e a l w a y s c o n t a m i n a t e d t h e p r o d u c t s . T h i s m a y h a v e b e e n d u e to a n i n c o m p l e t e l i t h i u m - b r o m i n e e x c h a n g e , l e a d i n g to a s l i g h t e x c e s s o f n - B u L i i n s o l u t i o n a n d s u b s e q u e n t f o r m a t i o n o f a n n - b u t y l c u p r a t e r e a g e n t . T h e n-b u t y l a d d i t i o n p r o d u c t s t h a t w e r e f o r m e d w e r e v e r y d i f f i c u l t t o s e p a r a t e f r o m t h e d e s i r e d i s o p r o p e n y l a d d i t i o n a d d u c t s . A m e t h o d that i n v o l v e d the g e n e r a t i o n o f i s o p r o p e n y l l i t h i u m w i t h o u t t h e u s e o f a s e p a r a t e o r g a n o l i t h i u m r e a g e n t r e m e d i e d t h e p r o b l e m . T h u s , s o n i c a t i o n o f a n e t h e r e a l s o l u t i o n o f 2 - b r o m o p r o p e n e ( 1 7 8 ) i n t h e p r e s e n c e o f l i t h i u m m e t a l ( S c h e m e 2 6 ) , f o l l o w e d b y f i l t r a t i o n o f t h e r e a c t i o n m i x t u r e t h r o u g h d r y C e l i t e a n d u n d e r a r g o n , g a v e a 4 8 y e l l o w s o l u t i o n o f i s o p r o p e n y l l i t h i u m (193) i n d i e t h y l e t h e r . 6 2 T h e r e a g e n t p r e p a r e d i n t h i s m a n n e r w a s s t o r e d i n a S u r e Seal\u00C2\u00AE b o t t l e i n t h e r e f r i g e r a t o r a n d w a s t i t r a t e d a n d u s e d w i t h i n 2 4 h . A d d i t i o n o f 2 . 0 e q u i v a l e n t s o f i s o p r o p e n y l l i t h i u m (193) i n d i e t h y l e t h e r t o a s u s p e n s i o n o f 1 .0 e q u i v a l e n t o f c o p p e r ( I ) c y a n i d e i n T H F ( - 7 8 \u00C2\u00B0C, w i t h b r i e f w a r m i n g t o - 4 8 \u00C2\u00B0C, i f n e c e s s a r y ) p r o v i d e d a h o m o g e n e o u s s o l u t i o n o f the h i g h e r o r d e r c u p r a t e 192 (Scheme 26). 6 3 X UEt:\u00C2\u00B0 X ( > T c u < c N > u 2 ^ sonication -78 u y' J2 178 193 192 Scheme 26 A d d i t i o n o f t h e e n o n e 179 to a s o l u t i o n o f the c u p r a t e 192 i n t h e p r e s e n c e o f T M S C 1 6 4 a f f o r d e d a m i x t u r e o f t h e 1 , 4 - a d d u c t s 194 a n d 60 i n a r a t i o o f 1 1 : 1 , 6 5 r e s p e c t i v e l y , i n 8 6 % y i e l d ( e q u a t i o n 4). A s e x p e c t e d , t h e i s o p r o p e n y l g r o u p w a s i n t r o d u c e d s t e r e o s e l e c t i v e l y trans to the a n g u l a r m e t h y l g r o u p a n d t h e c w - f u s e d i s o m e r p r e d o m i n a t e d (vide supra). I t w a s e v i d e n t t h a t t h e s e t w o c o m p o u n d s w e r e e p i m e r i c w h e n , u n d e r e p i m e r i z i n g c o n d i t i o n s ( N a O M e / M e O H , vide infra), the m i x t u r e o f 194 a n d 60 e q u i l i b r a t e d to a m i x t u r e o f the s a m e t w o c o m p o u n d s b u t i n a d i f f e r e n t r a t i o . 17 2) NH 4 CI, H 2 0 8 6 o / o 179 194 60 C o m p o u n d s 194 a n d 60 w e r e d i f f i c u l t t o s e p a r a t e b y c h r o m a t o g r a p h y u s i n g s i l i c a g e l , b u t a s m a l l p u r e s a m p l e o f e a c h w a s o b t a i n e d . T h e c o n f i g u r a t i o n at C - 1 3 ( v e r r u c o s a n e n u m b e r i n g ) a n d o f t h e r i n g j u n c t u r e ( C - 1 0 a n d C - 1 4 ) , w e r e d e t e r m i n e d b y lH n m r N O E 4 9 e x p e r i m e n t s . T h e lH n m r s p e c t r u m o f the m a j o r a s - f u s e d c o m p o u n d 194 r e v e a l e d a s i n g l e t f o r the a n g u l a r m e t h y l ( M e - 2 0 ) at 8 1 .11 , a s i n g l e t f o r t h e v i n y l m e t h y l ( M e - 1 7 ) at 8 1 .71 , a d o u b l e t f o r t h e a n g u l a r p r o t o n H - 1 4 at 8 2 . 5 6 ( 7 = 1 0 . 0 H z ) , a s i g n a l f o r H - l 3 at 8 2 . 8 6 ( d d d , J = 1 0 . 0 , 1 0 . 1 , 10 .1 H z ) , a n d t w o v i n y l p r o t o n s i g n a l s at 8 4 . 7 8 a n d 8 4 . 8 3 f o r H - 1 6 a n d H -16'. N O E d i f f e r e n c e e x p e r i m e n t s o n c o m p o u n d 194 w e r e c o n s i s t e n t w i t h t h e a s s i g n m e n t o f t h e r e l a t i v e c o n f i g u r a t i o n a t e a c h o f t h e c a r b o n s 1 3 , 1 4 , a n d 10 . I r r a d i a t i o n o f t h e s i g n a l at 8 1.11 ( M e - 2 0 ) c a u s e d a n e n h a n c e m e n t o f the s i g n a l at 8 2 . 5 6 ( H - 1 4 ) a n d o f t h e s i g n a l at 82.86 ( H - 1 3 ) . I r r a d i a t i o n o f the s i g n a l a 6 2 . 5 6 ( H - 1 4 ) c a u s e d a n e n h a n c e m e n t o f t h e s i g n a l at 8 1.11 ( M e - 2 0 ) a n d o f t h e s i g n a l at 8 2 . 8 6 ( H - 1 3 ) . F i n a l l y , i r r a d i a t i o n o f t h e s i g n a l at 82.86 ( H - 1 3 ) r e s u l t e d i n e n h a n c e m e n t o f t h e s i g n a l at 81 .11 ( M e - 2 0 ) a n d o f t h e s i g n a l at 8 0 2 . 5 6 ( H - 1 4 ) . T h e s e r e s u l t s a re c o n s i s t e n t w i t h M e - 2 0 , H - 1 4 , a n d H - 1 3 b e i n g o n the s a m e f a c e o f t h e m o l e c u l e . T h a t i s , the c u p r a t e r e a g e n t d e l i v e r e d t h e i s o p r o p e n y l g r o u p trans to the a n g u l a r m e t h y l a n d t h e ring f u s i o n i s cis. T h e * H n m r s p e c t r u m o f the m i n o r trans - f u s e d i s o m e r 60 r e v e a l e d a s i n g l e t f o r the a n g u l a r m e t h y l g r o u p ( M e - 2 0 ) at 8 0 . 7 6 , a s i n g l e t f o r t h e v i n y l m e t h y l ( M e - 1 7 ) at 8 1 .70, a d o u b l e t f o r t h e a n g u l a r p r o t o n H - 1 4 at 8 2 . 4 7 (J = 11.1 H z ) , a s i g n a l f o r H - 1 3 at 8 2 . 8 4 ( d d d , 7 = 1 1 . 1 , 1 1 . 1 , 6 . 6 H z ) , a n d t w o v i n y l p r o t o n s i g n a l s at 8 4 . 6 2 a n d 8 4 . 6 6 f o r H - 1 6 a n d H - 1 6 ' . I n N O E d i f f e r e n c e e x p e r i m e n t s o n c o m p o u n d 60, i r r a d i a t i o n o f t h e s i g n a l at 8 0 . 7 6 ( M e - 2 0 ) c a u s e d a n e n h a n c e m e n t o f t h e s i g n a l at 8 2 . 8 4 ( H - 1 3 ) , a n d v i c e v e r s a , t h e r e b y c o n f i r m i n g tha t t h e c o n j u g a t e a d d i t i o n r e a c t i o n d e l i v e r e d t h e i s o p r o p e n y l m o i e t y trans to the 17 194 5 0 a n g u l a r m e t h y l g r o u p . I r r a d i a t i o n o f the s i g n a l s at 8 1 .70 ( M e - 1 7 ) a n d 8 4 . 6 2 ( H - 1 6 ) c a u s e d a n e n h a n c e m e n t o f t h e s i g n a l at 8 2 . 4 7 ( H - 1 4 ) . I r r a d i a t i o n o f the a n g u l a r h y d r o g e n ( H - 1 4 ) at 8 2 . 4 7 c a u s e d a n e n h a n c e m e n t o f t h e s i g n a l at 8 4 . 6 2 ( H - 1 6 ) . T h e o b s e r v e d e n h a n c e m e n t s b e t w e e n t h e h y d r o g e n s f r o m t h e i s o p r o p e n y l g r o u p ( H - 1 6 a n d M e - 1 7 ) a n d t h e a n g u l a r h y d r o g e n ( H - 1 4 ) a r e c o n s i s t e n t w i t h a trans r i n g j u n c t i o n , s i n c e i t w a s s h o w n t h a t t h e i s o p r o p e n y l g r o u p a n d t h e a n g u l a r m e t h y l ( M e - 2 0 ) a re anti. T h e r e w a s a d d e d e m p i r i c a l e v i d e n c e to h e l p d i s t i n g u i s h b e t w e e n t h e cis- a n d t h e trans-fused e p i m e r s . O b a l l a 6 6 f o u n d that e x a m i n a t i o n o f t h e I R s p e c t r a o f e a c h p a i r o f e p i m e r i c c o m p o u n d s s h o w n i n Table 2 r e v e a l e d t h a t t h e p o s i t i o n s o f t h e c a r b o n y l a b s o r p t i o n s f o r the trans-fused e p i m e r s a r e c o n s i s t e n t l y 11 to 2 2 c m \" 1 h i g h e r t h a n t h o s e f o r t h e c o r r e s p o n d i n g d s - f u s e d e p i m e r s . T h e c a r b o n y l a b s o r p t i o n s f o r c o m p o u n d s 194 a n d 60 w e r e c o n s i s t e n t w i t h t h i s o b s e r v a t i o n . T h e c a r b o n y l s t r e t c h i n g f r e q u e n c y f o r the trans - f u s e d e p i m e r 60 i s 1 7 1 7 c m - 1 , w h e r e a s f o r t h e d s - f u s e d e p i m e r 194 i t i s 1 6 9 8 c m 1 . M o r e o v e r , i n t h e * H s p e c t r a f o r e a c h p a i r o f c o m p o u n d s i n Table 2, O b a l l a f o u n d t h a t t h e a n g u l a r p r o t o n s H - 1 4 i n t h e d s - f u s e d a d d u c t s a r e c o n s i s t e n t l y m o r e d e s h i e l d e d b y t h e a d j a c e n t c a r b o n y l m o i e t y t h a n t h e H - 1 4 p r o t o n s i n t h e c o r r e s p o n d i n g trans-fused a d d u c t s . 6 6 A g a i n , t h i s o b s e r v a t i o n w a s c o n s i s t e n t w i t h c o m p o u n d s 194 a n d 60, s i n c e t h e c h e m i c a l s h i f t o f t h e a n g u l a r p r o t o n s ( H - 1 4 ) a re 8 2 . 5 6 a n d 2 . 4 7 , r e s p e c t i v e l y . E q u i l i b r a t i o n o f t h e 11 :1 m i x t u r e o f e p i m e r s 194 a n d 60, r e s p e c t i v e l y , p r o v i d e d t h e s a m e t w o c o m p o u n d s , i n 9 5 % y i e l d , i n a r a t i o o f 1 :14 ( e q u a t i o n 5). S e p a r a t i o n o f t h e s e 17 60 5 1 s u b s t a n c e s b y c h r o m a t o g r a p h y o n s i l i c a g e l p r o v i d e d p u r e 60 i n - 6 5 % y i e l d . S i n c e t h e c h r o m a t o g r a p h i c s e p a r a t i o n o f 194 a n d 60 w a s q u i t e d i f f i c u l t , t h e y i e l d o f p u r e 60 v a r i e d s o m e w h a t f r o m e x p e r i m e n t to e x p e r i m e n t . H o w e v e r , m i x e d f r a c t i o n s c o u l d e a s i l y be r e c y c l e d . T h u s , i n t e r m e d i a t e 60 w i t h t h e c o r r e c t r e l a t i v e c o n f i g u r a t i o n a t t h r e e o f t h e s t e r e o g e n i c c e n t e r s p r e s e n t i n t h e n a t u r a l p r o d u c t s 61-64 w a s r e a d i l y s y n t h e s i z e d . 2.1.5.2. Development of a New Cyclohexenone Annulation Sequence. T h e n e x t s tep i n t h e s y n t h e t i c s e q u e n c e i n v o l v e d a p p e n d i n g a s i x - m e m b e r e d ring o n t o the b i c y c l i c k e t o n e 60 as i l l u s t r a t e d b y the c o n v e r s i o n o f 60 i n t o 171. T h e s t r a t e g y r e q u i r e d t h e u s e o f m e t h o d s t h a t a l l o w e d f o r c o n t r o l o f t h e s t e r e o c h e m i s t r y a t C - l a n d C - 7 ( v e r r u c o s a n e n u m b e r i n g ) . T h a t i s , a trans 6 , 6 - r i n g f u s i o n , w h e r e t h e n e w l y i n t r o d u c e d m e t h y l g r o u p at C - 7 i s anti t o t h e e x i s t i n g m e t h y l g r o u p at C - 1 0 w a s n e e d e d (Scheme 27). B i r c h r e d u c t i o n s o f 6 , 6 - f u s e d e n o n e s , s u c h as 72, a r e k n o w n t o a f f o r d c o m p o u n d s c o n t a i n i n g a trans-fused ring j u n c t i o n . 6 7 T h u s , p r e p a r a t i o n o f the t r i c y c l i c e n o n e 72 s h o u l d e n s u r e the d e s i r e d s t e r e o c h e m i s t r y at C - l , as s h o w n i n 171. O Q Scheme 27 A n u m b e r o f m e t h o d s a r e k n o w n f o r t h e c o n v e r s i o n o f k e t o n e s i n t o a n n u l a t e d c y c l o h e x e n o n e s . 6 8 H o w e v e r , the d e v e l o p m e n t o f a n e w c y c l o h e x e n o n e a n n u l a t i o n s e q u e n c e w a s u n d e r t a k e n . T h i s s t r a t e g y w a s d e s c r i b e d i n S e c t i o n 1.3 ( p a g e 14 ) a n d i s a n a l o g o u s to t h e m e t h o d o l o g y o u t l i n e d i n Scheme 7 ( p a g e 10) . A l k y l a t i o n o f t h e b i c y c l i c k e t o n e 60 w i t h a s u i t a b l e b i f u n c t i o n a l r e a g e n t , s u c h as 70, f o l l o w e d b y a s e c o n d a l k y l a t i o n w i t h m e t h y l i o d i d e , w a s e x p e c t e d t o p r o v i d e t h e a d d u c t 195 (Scheme 28). T h e m e t h y l a t i o n w a s p r e d i c t e d to o c c u r a x i a l l y , 6 9 t h e r e b y i n s t a l l i n g t h e c o r r e c t c o n f i g u r a t i o n at C - 7 ( v e r r u c o s a n e n u m b e r i n g ) . T h e o r d e r o f t h e a l k y l a t i o n s c o u l d b e r e v e r s e d i f t h e w r o n g c o n f i g u r a t i o n at C - 7 w a s o b t a i n e d . T h e r e m a i n d e r o f t h e s e q u e n c e w a s p r e v i o u s l y d e s c r i b e d i n Scheme 9 ( p a g e 14) . 5 3 G e r m a n i u m - o r t i n - i o d i n e e x c h a n g e w o u l d p r o v i d e t h e c o r r e s p o n d i n g ( Z ) - a l k e n y l i o d i d e , w h i c h w o u l d u n d e r g o a n n - B u L i m e d i a t e d a n i o n i c c y c l i z a t i o n . O x i d a t i v e r e a r r a n g e m e n t o f the r e s u l t a n t t e r t i a r y a l l y l i c a l c o h o l w i t h P C C w o u l d a f f o r d 72. Scheme 28 T h e b i f u n c t i o n a l e l e c t r o p h i l e 70, c o n t a i n i n g e i t h e r a n a l k e n y l g e r m a n e ( M = G e ) o r a n a l k e n y l s t a n n a n e ( M = S n ) m o i e t y , c o u l d s e r v e as t h e s y n t h e t i c e q u i v a l e n t o f a b u t - l - e n e d ] , a 4 - s y n t h o n . I n i t i a l l y , a t t e m p t s w e r e d i r e c t e d t o w a r d s the u s e o f c o m p o u n d 70 w h e r e M = G e , d u e t o t h e g r e a t e r s t r e n g t h o f t h e a l k e n y l g e r m a n e - c a r b o n b o n d v e r s u s t h e a l k e n y l s t a n n a n e - c a r b o n b o n d . 9 T h e c h e m i c a l l i t e r a t u r e c o n t a i n s f e w r e p o r t s r e g a r d i n g t h e p r e p a r a t i o n o f a l k e n y l g e r m a n e s . 1 7 ' 7 0 O f t h e s e , the p r e p a r a t i o n o f 2 - t r i a l k y l g e r m y l a l k - l - e n e s 196 o r (E)-l-t r i a l k y l g e r m y l a l k - l - e n e s 197 a re t h e m o s t c o m m o n . F e w e r g e n e r a l m e t h o d s 7 0 a c f o r t h e f o r m a t i o n o f ( Z ) - l - t r i a l k y l g e r m y l a l k - l - e n e s 198 h a v e b e e n r e p o r t e d . 7 1 T w o s u c h p r o t o c o l s a re d e s c r i b e d b e l o w . Me3Ge GeMe3 R R R GeMe3 196 197 198 54 H y d r o a l u m i n a t i o n ( o r h y d r o b o r a t i o n ) o f g e r r a y l a c e t y l e n e s , f o l l o w e d b y h y d r o l y s i s , p r o v i d e s the ( Z ) - a l k e n y l g e r m a n e s 1 9 8 7 0 a < b T h u s , t r e a t m e n t o f g e r m y l a c e t y l e n e s 1 9 9 w i t h d i i s o b u t y l a l u m i n u m h y d r i d e i n p e n t a n e o r h e x a n e i n t h e p r e s e n c e o f A T - m e t h y l p y r r o l i d i n e 7 0 3 o r w i t h d i i s o b u t y l a l u m i n u m h y d r i d e i n h e x a n e - d i e t h y l e t h e r ( 2 : l ) 7 0 b a f f o r d s , a f t e r h y d r o l y s i s , t h e r e d u c t i o n p r o d u c t s 1 9 8 (Scheme 2 9 ) . R-1 9 9 G e R , ABu 2AIH, pentane or hexane, or ABu 2AIH, Et 2 0-hexane N - C H 3 R GeRc 1 9 8 Scheme 2 9 A n o t h e r m e t h o d f o r the p r e p a r a t i o n o f ( Z ) - l - t r i p h e n y l g e r m y l a l k - l - e n e s 2 0 0 i n v o l v e s a t r i e t h y l b o r a n e i n d u c e d r a d i c a l a d d i t i o n o f t r i p h e n y l g e r m a n e to t h e a c e t y l e n e s 2 0 1 at l o w t e m p e r a t u r e ( e q u a t i o n 6 ) . 7 0 c H i g h e r t e m p e r a t u r e s c a u s e i s o m e r i z a t i o n o f t h e o l e f i n v i a a r a d i c a l m e c h a n i s m . ^ E t 3 B, P h 3 G e H , v R C = C H 3 3 / = s ^ ( 6 ) hexane-toluene R G e P h 3 K a i U 1 v ' -78 \u00C2\u00B0C 2 0 1 2 0 0 T h e f o r m e r m e t h o d w a s s e l e c t e d f o r t h e p r e p a r a t i o n o f t h e ( Z ) -a l k e n y l t r i m e t h y l g e r m a n i u m b i f u n c t i o n a l r e a g e n t 2 0 2 . T h e a l c o h o l m o i e t y o f c o m m e r c i a l l y a v a i l a b l e b u t - 3 - y n e - l - o l ( 2 0 3 ) w a s p r o t e c t e d as t h e t r i m e t h y l s i l y l e t h e r g i v i n g 2 0 4 . T h e v o l a t i l e p r o d u c t 2 0 4 w a s i m m e d i a t e l y t r e a t e d s e q u e n t i a l l y w i t h m e t h y l l i t h i u m a n d t r i m e t h y l g e r m a n i u m b r o m i d e to p r o v i d e t w o p r o d u c t s (Scheme 3 0 ) . T h e m a j o r p r o d u c t w a s t h e p r o t e c t e d g e r m y l a c e t y l e n e 2 0 5 a n d w a s i s o l a t e d i n 5 7 % y i e l d . C o m p o u n d 2 0 5 l a c k s a h y d r o x y l s t r e t c h i n i t s ER s p e c t r u m b u t p o s s e s s e s a n a c e t y l e n e a b s o r p t i o n a t 2 1 6 7 c m \" 1 . T h e 55 * H n m r s p e c t r u m o f 2 0 5 c o n t a i n s t w o n i n e p r o t o n s i n g l e t s at 8 0 . 1 1 a n d at 8 0 . 3 0 f o r t h e t r i m e t h y l s i l y l a n d t r i m e t h y l g e r m y l g r o u p s , r e s p e c t i v e l y . T h e s e c o n d p r o d u c t , i s o l a t e d i n 2 6 % y i e l d , w a s the g e r m y l a t e d c o m p o u n d 2 0 6 , w h i c h l a c k e d the t r i m e t h y l s i l y l f u n c t i o n . A b r o a d h y d r o x y l s t r e t c h at 3 3 3 9 c m - 1 a n d a n a c e t y l e n i c a b s o r p t i o n at 2 1 7 4 c m - 1 a re p r e s e n t i n t h e I R s p e c t r u m o f 2 0 6 . T h e * H n m r s p e c t r u m o f 2 0 6 c o n t a i n s a s i n g l e n i n e p r o t o n s i n g l e t at 8 0 . 3 1 f o r t h e t r i m e t h y l g e r m y l g r o u p a n d a s i g n a l f o r t h e h y d r o x y l p r o t o n a t 8 1 . 8 0 ( d d , J = 6 . 3 , 6 . 3 H z ) . C o m p o u n d 2 0 6 c o u l d b e r e a d i l y c o n v e r t e d i n t o 2 0 5 b y r e p r o t e c t i n g t h e a l c o h o l m o i e t y as the t r i m e t h y l s i l y l e ther . H O T M S C I THF, Et 3 N T M S O ' 0 \u00C2\u00B0C to rt 2 0 3 2 0 4 1) MeLi, THF - 7 8 \u00C2\u00B0C 2 ) M e 3 G e B r THF, - 7 8 \u00C2\u00B0C t o 0 \u00C2\u00B0 C T M S O ,GeMe 3 G e M e 3 2 0 5 5 7 % S c h e m e 3 0 T r e a t m e n t o f t h e g e r m y l a c e t y l e n e 2 0 5 w i t h d i i s o b u t y l a l u m i n u m h y d r i d e i n h e x a n e -d i e t h y l e t h e r ( 2 : 1 ) p r o v i d e d , a f t e r w o r k u p , t h e ( Z ) - a l k e n y l g e r m a n e 2 0 7 . 7 0 a ' b C o n c o m i t a n t l o s s o f the t r i m e t h y l s i l y l e t h e r f u n c t i o n w a s o b s e r v e d , 7 2 t h u s a c c o m p l i s h i n g t w o o p e r a t i o n s i n a s i n g l e s t e p to a f f o r d 2 0 7 i n 8 9 % y i e l d ( e q u a t i o n 7 ) . T h e I R s p e c t r u m o f 2 0 7 c o n t a i n s a h y d r o x y l s t r e t c h at 3 3 3 8 c m - 1 a n d a n o l e f i n i c s t r e t c h at 1 6 1 0 c m - 1 . T h e * H n m r s p e c t r u m o f 2 0 7 e x h i b i t s a s i n g l e n i n e p r o t o n s i n g l e t at 8 0 . 3 8 ( G e M e V h a s i g n a l f o r t h e h y d r o x y l p r o t o n at 8 1 .32 ( d d , J = 6 , 6 H z ) , a n d t w o a l k e n i c s i g n a l s at 8 5 . 2 8 ( d d d , J = 1 2 . 9 , 1 , 1 H z ) a n d at 8 6 . 2 6 ( d d d , J = 1 2 . 9 , 7 , 7 H z ) . T h e c o u p l i n g c o n s t a n t b e t w e e n t h e a l k e n i c p r o t o n s (J = 12.9 H z ) 7 0 a ' c ' e i s c o n s i s t e n t w i t h a ( Z ) - a l k e n y l g e r m a n e . T h e s t e r e o c h e m i s t r y o f t h e d o u b l e 5 6 b o n d w a s a l s o c o n f i r m e d b y N O E d i f f e r e n c e e x p e r i m e n t s i n w h i c h i r r a d i a t i o n o f o n e a l k e n i c s i g n a l c a u s e d a n e n h a n c e m e n t o f t h e o t h e r a l k e n i c s i g n a l , a n d v i c e v e r s a . G e M e 3 /-Bu 2AIH , x /' - - / \ / = \ (7) T M S O v Et 2 0-hexane, rt H O v G e M e 3 89% 205 207 T h e s y n t h e s i s o f t h e b i f u n c t i o n a l r e a g e n t 202 w a s c o m p l e t e d b y d i s p l a c e m e n t o f t h e h y d r o x y l g r o u p i n 207 b y a n i o d i d e . T r e a t m e n t o f 207 w i t h Ph3P\u00C2\u00BBl2 a n d i m i d a z o l e i n d i e t h y l e t h e r - a c e t o n i t r i l e ( 3 : 1 ) p r o v i d e d 202 i n 7 4 % y i e l d ( e q u a t i o n 8).73 T h e s p e c t r a l d a t a f o r 202 f u l l y s u p p o r t the s t r u c t u r a l a s s i g n m e n t . T h e I R s p e c t r u m o f 202 s h o w s a n o l e f i n i c a b s o r p t i o n a t 1 6 0 9 c m - 1 . T h e 1 H n m r s p e c t r u m o f 202 p o s s e s s e s a n i n e p r o t o n s i n g l e t f o r t h e t r i m e t h y l g e r m y l g r o u p at 8 0 . 3 5 a n d s i g n a l s f o r t h e a l k e n y l p r o t o n s at 8 5 . 8 2 ( d d d , J = 1 2 . 8 , 1 .1 , 1.1 H z ) a n d at 8 6 . 1 8 ( d d d , J = 1 2 . 8 , 7 . 3 7 . 3 H z ) . T h e c o u p l i n g c o n s t a n t b e t w e e n the a l k e n i c p r o t o n s (7 = 1 2 . 8 H z ) r e v e a l e d tha t t h e c o n f i g u r a t i o n o f t h e d o u b l e b o n d h a d n o t c h a n g e d . / \ / = \ Ph3P\u00C2\u00BBl2, imidazole / = \ H O V G e M e 3 C H 3 C N - E t 2 0 1 G e M e 3 ( 8 ) n 7 4 % 0 \u00C2\u00B0C to rt 207 202 W i t h t h e b i f u n c t i o n a l e l e c t r o p h i l e 202 i n h a n d , t h e f i r s t s t e p i n t h e a n n u l a t i o n s e q u e n c e i n v o l v e d a l k y l a t i o n o f the b i c y c l i c k e t o n e 60. H o w e v e r , t r e a t m e n t o f 60 w i t h b a s e f o l l o w e d b y t h e h o m o a l l y l i c i o d i d e 202, r e s u l t e d i n t h e c o n v e r s i o n o f 202 i n t o t h e d i e n e 208 v i a e l i m i n a t i o n o f H I ( e q u a t i o n 9). T h e k e t o n e 60 r e m a i n e d u n c h a n g e d . E v i d e n t l y , t h e e n o l a t e o f 60 a c t e d a s a b a s e r a t h e r t h a n as a n u c l e o p h i l e , r e s u l t i n g i n t h e f o r m a t i o n o f the d i e n e 208. 57 II H ? 1 ) base starting material 2>/v\u00E2\u0080\u0094 ,^ + G e M e 3 (9) G e M e 3 60 202 60 208 T h i s r e s u l t w a s d i s a p p o i n t i n g , b u t n o t e n t i r e l y u n e x p e c t e d . T h e p r o b l e m w a s c i r c u m v e n t e d b y t h e u s e o f t h e N , N - d i m e t h y l h y d r a z o n e d e r i v a t i v e o f 60 7 4 s i n c e a l k y l a t i o n o f h y d r a z o n e s w i t h h o m o a l l y l i c i o d i d e s h a v e b e e n p e r f o r m e d s u c c e s s f u l l y . 4 7 - 7 5 T h e p r e p a r a t i o n o f t h e 7 V , / V - d i m e t h y l h y d r a z o n e 209 f r o m t h e b i c y c l i c k e t o n e 60 r e q u i r e d f o r c i n g c o n d i t i o n s . R e f l u x i n g the b i c y c l i c e n o n e 60 f o r s e v e r a l d a y s i n t o l u e n e -d i m e t h y l h y d r a z i n e (1 :1 ) i n t h e p r e s e n c e o f a c a t a l y t i c a m o u n t o f p - t o l u e n e s u l f o n i c a c i d w i t h a z e o t r o p i c r e m o v a l o f w a t e r p r o v i d e d t h e b i c y c l i c h y d r a z o n e 209 i n 6 4 % y i e l d ( e q u a t i o n 10). P e r f o r m i n g t h e r e a c t i o n i n b e n z e n e , u s i n g l e s s d i m e t h y l h y d r a z i n e , i n t h e a b s e n c e o f a n a c i d c a t a l y s t , o r i n t h e p r e s e n c e o f m o l e c u l a r s i e v e s , d i d n o t a f f o r d 209 s a t i s f a c t o r i l y . T h e s u p p o r t i n g s p e c t r a l e v i d e n c e f o r 209 w a s p r o v i d e d b y a h y d r a z o n e s t r e t c h at 1 6 4 5 c n r 1 i n the I R s p e c t r u m a n d b y a s i x p r o t o n s i n g l e t at 8 2 . 3 9 ( -N=N(Me . 2 ) ) i n the * H n m r s p e c t r u m . T h e s i g n a l f o r t h e a n g u l a r m e t h y l g r o u p i s s i t u a t e d at 8 0 . 7 1 , the v i n y l m e t h y l g r o u p i s at 8 1 .72, a n d the a l k e n i c p r o t o n s a p p e a r as a b r o a d t w o p r o t o n s i n g l e t at 8 4 . 6 4 . 5 8 0 \u00E2\u0080\u009E W II H ? M e 2 N N N H 2 N M e 2 , toluene, TsOH azeotropic distillation (10) 60 64% 209 A t t e m p t e d a l k y l a t i o n o f t h e h y d r a z o n e 209 w i t h t h e b i f u n c t i o n a l r e a g e n t 202 u s i n g L D A , n - B u L i , o r K H M D S as t h e b a s e d i d n o t p r o v i d e the a l k y l a t e d m a t e r i a l . H o w e v e r , t h e u s e o f K D A as t h e b a s e , w h i c h h a s b e e n a d v o c a t e d as a s u p e r i o r a l t e r n a t i v e f o r h y d r a z o n e d e p r o t o n a t i o n s , 7 6 i n t h e p r e s e n c e o f H M P A , a f f o r d e d the d e s i r e d a l k y l a t e d m a t e r i a l 210, as a s i n g l e i s o m e r i n 8 0 % y i e l d ( e q u a t i o n 11). E v i d e n c e o b t a i n e d f r o m * H n m r s p e c t r o s c o p y w a s u s e d to a s s i g n the s t r u c t u r e o f 210. T h e p r e s e n c e o f t h e t r i m e t h y l g e r m y l g r o u p w a s i n d i c a t e d b y a h i g h f i e l d n i n e p r o t o n s i n g l e t at 8 0 . 2 2 . T h e a n g u l a r , v i n y l , a n d h y d r a z o n e m e t h y l g r o u p s a p p e a r as s i n g l e t s a t 8 0 . 6 9 , 8 1 . 7 1 , a n d 8 2 . 3 3 , r e s p e c t i v e l y . T h e r e m a i n i n g ( e q u a t o r i a l ) p r o t o n at t h e s i t e o f a l k y l a t i o n ( C - 7 , v e r r u c o s a n e n u m b e r i n g ) w a s f o u n d t o b e s i g n i f i c a n t l y d e s h i e l d e d b y the a d j a c e n t h y d r a z o n e f u n c t i o n a n d i s l o c a t e d at 8 3 . 4 8 (b r d d d , J = 6 . 4 , 6 . 4 , 6 . 4 H z ) . T h e a b s e n c e o f a l a r g e c o u p l i n g c o n s t a n t f o r t h i s p r o t o n i n d i c a t e d that i t i s i n a n e q u a t o r i a l o r i e n t a t i o n , w h i c h i s c o n s i s t e n t w i t h the e x p e c t e d a x i a l a l k y l a t i o n . 6 9 T h e o l e f i n i c s i g n a l s f o r t h e i s o p r o p e n y l g r o u p a p p e a r as a b r o a d t w o p r o t o n s i n g l e t at 8 4 . 6 2 , w h i l e t h e s i g n a l s a t t r i b u t e d to t h e a l k e n y l p r o t o n s o f the g e r m a n i u m s u b s t i t u t e d d o u b l e b o n d are at 8 5 . 6 0 (d , J = 12 .7 H z ) a n d 8 6 . 27 ( d d d , J = 12 .7 , 7 . 3 , 7 . 3 H z ) . 1) KDA, THF , -78 \u00C2\u00B0C 2) r V G e M e 3 202 HMPA, -78 \u00C2\u00B0C - M e 3 G e ' / = V / N di) 209 80% 210 59 After the alkylation of 209 with 202, the hydrazone moiety in 210 was no longer required. Several methods are available for the hydrolysis of hydrazones to the corresponding carbonyl compounds.74b The removal of the hydrazone moiety proved to be more difficult than its installation. The methods that were utilized, which were compatible with existing functionality and would have been practical on larger scale, provided either no reaction or very low yields. These conditions included: excess NaI04, phosphate buffer (pH 7) and water in THF at 40 \u00C2\u00B0C; 7 7 CuCl 2, phosphate buffer (pH 7), and water in THF at 40 \u00C2\u00B0C; 7 8 aqueous HC1 in THF at room temperature;79 NaBC>3, phosphate buffer (pH 7), and ten-BuOH at 60 \u00C2\u00B0C; 8 0 BF3\u00C2\u00ABOEt2, Et20, 0 \u00C2\u00B0C;81 Amberlite YR 120 (acidic ion exchange resin) and water in THF at reflux;82 and AcOH, NaOAc and water in THF at room temperature.83 Eventually, the hydrazone function was sluggishly removed with AcOH and NaOAc in refluxing aqueous THF and provided the corresponding crude ketone in 78% yield. Confident that an adequate method for the removal of the hydrazone function had been found, attention was directed towards the development of the new cyclohexenone annulation sequence. The A r^V-dimethylhydrazone of cycloheptanone 211 was a readily available substrate to test the proposed methodology. Treatment of 211 with LDA, followed by reaction of the resultant anion with the bifunctional electrophile 202 in the presence of HMPA, provided the alkylated hydrazone 212 in 90% yield (equation 12). The *H nmr spectrum for 212 displays singlets for the trimethylgermyl group at 8 0.21 and for the hydrazone methyl groups at 8 2.36. The two olefinic signals in the side chain appear at 8 5.60 (d, 7=13 Hz) and 8 6.25 (ddd, 7 = 13, 7, 7 Hz). N(Me) 2 N 6 2) I 1) LDA, THF, 0\u00C2\u00B0C GeMe 3 G e M e 3 (12) 202 HMPA, -78 \u00C2\u00B0C 90% 212 211 Acid hydrolysis (AcOH, NaOAc, THF, H2O, rt) of the hydrazone 212 gave the keto alkenylgermane 213 in 8 8 % yield (equation 13). Evidence supporting the formation of 213 included the lack of signals attributable to the hydrazone methyl groups in the ! H nmr spectrum. The alkenylgermanium unit was unaffected as shown by a nine proton singlet at 8 0.22 (GeMe3) and two olefinic signals at 8 5.60 (d, 7=13 Hz) and at 8 6.20 (ddd, J = 13,7, 7 Hz). 88% 212 213 The next step in the annulation sequence was a germanium-halogen exchange reaction which was based on work published by Oshima. 7 0 b He investigated the transformation of alkenylgermanes into alkenyl halides employing various halonium sources (I+ and Br+) and the results of this study are summarized in Tables 4-6. The alkenylgermanium compounds 214-217 were treated with iodine in methylene chloride at room temperature (Table 4) to provide the corresponding alkenyl iodides 218-221. Retention of configuration was observed for all cases. Table 4: I o d o d e g e r m y l a t i o n R e a c t i o n s U s i n g I o d i n e ( f r o m r e f e r e n c e 7 0 b ) . l 2 dequ iv . ) J ' \ w / U G e R 3 C H 2 C I 2 , rt ^ / , E n t r y A l k e n y l g e r m a n e A l k e n y l I o d i d e Y i e l d 1 n-Hex G e E t 3 H ( Z ) H 214 n-Hex 1 W H H >97%(Z) 218 8 8 % 2 n-Hex GeEto >=< H Me (Z) 215 n-Hex 1 W H M e >95%(Z) 219 1 0 0 % 3 n-Hex Me X H ( E ) G e R 3 216 n-Hex M e ) = < H 1 > 9 5 % ( \u00C2\u00A3 ) 220 9 8 % 4 n-Dec H >=< H ( E ) G e P r 3 217 n-Dec H X H 1 > 9 7 % ( \u00C2\u00A3 ) 221 8 0 % T h e r e s u l t s o f t h e i o d o d e g e r m y l a t i o n r e a c t i o n s o u t l i n e d i n Table 4 w e r e e n c o u r a g i n g a n d s o i d e n t i c a l c o n d i t i o n s w e r e u s e d to a t t e m p t the c o n v e r s i o n o f 202 i n t o t h e c o r r e s p o n d i n g a l k e n y l i o d i d e . T r e a t m e n t o f t h e b i f u n c t i o n a l e l e c t r o p h i l e 202 w i t h i o d i n e i n m e t h y l e n e c h l o r i d e p r o v i d e d a s i n g l e a l k e n y l i o d i d e p r o d u c t 222. T h e c o u p l i n g c o n s t a n t b e t w e e n t h e t w o o l e f i n i c p r o t o n s w a s c o n s i s t e n t w i t h a c w - a l k e n y l i o d i d e ( 7 = 7 . 4 H z ) . T h u s , the r e a c t i o n h a d p r o c e e d e d w i t h r e t e n t i o n o f c o n f i g u r a t i o n ( e q u a t i o n 14). I n t e r e s t i n g l y , w h e n t h e r e a c t i o n w a s c a r r i e d o u t i n d i e t h y l e the r , o n l y t r a c e a m o u n t o f the a l k e n y l i o d i d e w a s d e t e c t e d . 6 2 l2(1.1 equiv.) (\"~^ J = 7 . 4 H z H H ^ G e M e 3 CH 2 CI 2 , 0 \u00C2\u00B0C | 202 (14) 222 A t r a n s i t i o n s t a t e tha t a c c o u n t s f o r t h e c o n v e r s i o n o f a n a l k e n y l t r i a l k y l t i n i n t o a n a l k e n y l i o d i d e i n t h e p r e s e n c e o f a n i o d o n i u m s p e c i e s h a s b e e n p o s t u l a t e d b y N a s i e l s k i a n d c o w o r k e r s ( F i g u r e 1, M = S n ) . 8 4 T h i s c y c l i c t r a n s i t i o n s t a t e r a t i o n a l i z e s t h e p r e f e r e n t i a l c l e a v a g e o f t h e s p 2 c a r b o n - t i n b o n d b y i n v o l v i n g t h e TC e l e c t r o n s o f t h e d o u b l e b o n d . T h e t r a n s i t i o n s ta te a l s o r a t i o n a l i z e s w h y t h e c o n f i g u r a t i o n o f t h e d o u b l e b o n d o f t h e s t a r t i n g m a t e r i a l i s r e t a i n e d i n t h e p r o d u c t . A s i m i l a r m e c h a n i s m c a n b e p r o p o s e d f o r t h e c o n v e r s i o n o f a n a l k e n y l g e r m a n e i n t o a n a l k e n y l i o d i d e . F i g u r e 1: P r o p o s e d T r a n s i t i o n S t a t e f o r I o d o d e m e t a l a t i o n w i t h R e t e n t i o n o f C o n f i g u r a t i o n ( f r o m r e f e r e n c e 84 ) . A n o t h e r e x p l a n a t i o n f o r t h e o b s e r v e d r e t e n t i o n o f c o n f i g u r a t i o n o f t h e d o u b l e b o n d c a n b e p o s t u l a t e d b a s e d o n t h e p r o p o s e d m e c h a n i s m f o r the r e a c t i o n o f a l k e n y l s i l a n e s w i t h e l e c t r o p h i l e s . It i s w e l l k n o w n tha t c a r b o n i u m i o n s that a r e P t o s i l i c o n a r e s t a b i l i z e d b y h y p e r c o n j u g a t i o n w h i c h i n v o l v e s i n t e r a c t i o n o f the G o r b i t a l o f a c a r b o n - s i l i c o n a b o n d w i t h t h e v a c a n t p o r b i t a l o f t h e a d j a c e n t c a r b o c a t i o n 8 5 ( i .e . t h e P e f f e c t ) ( F i g u r e 2). 6 3 F i g u r e 2: S t a b i l i z a t i o n o f a C a r b o n i u m I o n b y a P - S i l y l S u b s t i t u e n t . R 3 S J p- Effect ( a \u00E2\u0080\u0094 p) A d d i t i o n o f e l e c t r o p h i l e s to a l k e n y l s i l a n e s u s u a l l y o c c u r s s t e r e o s p e c i f i c a l l y w i t h r e t e n t i o n o f c o n f i g u r a t i o n as i l l u s t r a t e d b y t h e c o n v e r s i o n o f 223 to 226.86 T h e e l e c t r o p h i l e a d d s to the a l k e n y l s i l a n e 223 at the c a r b o n b e a r i n g the s i l i c o n a t o m to p r o v i d e the m a x i m a l l y s t a b i l i z e d fi-silyl c a t i o n 225, w h e r e t h e c a r b o n - s i l i c o n o b o n d i s c o - p l a n a r w i t h t h e a d j a c e n t v a c a n t p o r b i t a l (Scheme 31). I s o m e r i z a t i o n o f t h e d o u b l e b o n d r e q u i r e s tha t t h e i n i t i a l l y f o r m e d c a t i o n 224 r o t a t e i n the o p p o s i t e d i r e c t i o n t o tha t s h o w n i n Scheme 31, w h i c h w o u l d r e s u l t i n t h e c a r b o n - s i l i c o n b o n d p a s s i n g t h r o u g h a u n f a v o r a b l e c o n f o r m a t i o n i n w h i c h the c a r b o n - s i l i c o n b o n d i n g a o r b i t a l a n d t h e v a c a n t p o r b i t a l a r e o r t h o g o n a l . T h i s b a r r i e r to r o t a t i o n i s r e s p o n s i b l e f o r the o b s e r v e d s t e r e o s e l e c t i v i t y . T h e s u b s e q u e n t , f a c i l e c l e a v a g e o f the c a r b o n - s i l i c o n b o n d i s p r o m o t e d b y t h e c\u00E2\u0080\u0094>p c o n j u g a t i o n s h o w n i n 225, a n d r e s u l t s i n the a l k e n e p r o d u c t 226 w i t h n e t r e t e n t i o n o f c o n f i g u r a t i o n . S i M e 3 223 224 225 226 Scheme 31 T h e i o d o d e g e r m y l a t i o n r e a c t i o n s i n Table 4 a n d e q u a t i o n 14 s u p p o r t e i t h e r o f the t w o m e c h a n i s m s d e p i c t e d i n F i g u r e 1 a n d Scheme 31. H o w e v e r , t h e l a t t e r m e c h a n i s m m a y b e 6 4 s u c c e s s f u l i n e x p l a i n i n g the u n e x p e c t e d s t e r e o c h e m i c a l o u t c o m e o f c e r t a i n g e r m a n i u m - i o d i n e e x c h a n g e r e a c t i o n s (vide infra). T h e a l k e n y l g e r m a n i u m c o m p o u n d s 214-217 w e r e a l s o t r e a t e d w i t h b r o m i n e i n m e t h y l e n e c h l o r i d e a t - 7 8 \u00C2\u00B0C to g i v e t h e c o r r e s p o n d i n g a l k e n y l b r o m i d e s 227-232, as s h o w n i n Table 5. 7 0 b I n t h e s e c a s e s , i n v e r s i o n o f t h e d o u b l e b o n d c o n f i g u r a t i o n w a s o b s e r v e d a n d o n l y t h e r e a c t i o n s i n e n t r i e s 3 a n d 4 s h o w e d s m a l l a m o u n t s o f t h e p r o d u c t s r e s u l t i n g f r o m r e t e n t i o n o f c o n f i g u r a t i o n . Table 5: B r o m o d e g e r m y l a t i o n R e a c t i o n s U s i n g B r o m i n e ( f r o m r e f e r e n c e 7 0 b ) . < > < Br W Br 2 , CH 2 CI 2 X^/ \u00E2\u0080\u00A2 < GeR 3 -78 \u00C2\u00B0C ^ > E n t r y A l k e n y l g e r m a n e A l k e n y l B r o m i d e Y i e l d 1 n-Hex GeEt 3 ) = ( (2) H H 214 n-Hex H )==( >95%(E) H Br 227 9 1 % 2 n-Hex GeEt 3 H Me 215 n-Hex Me )==< >95%(\u00C2\u00A3) H Br 228 1 0 0 % 3 n-Hex Me >=< ==< 1 0 % ( \u00C2\u00A3 ) H Br 230 9 5 % 4 n-Dec H y={ to H GePr 3 217 n-Dec Br >=< 72%(Z) H H 231 n-Dec H )==< 28%(E) H Br 232 8 0 % C l e a r l y , a n a l t e r n a t i v e m e c h a n i s m t o t h o s e p r o p o s e d f o r t h e i o d o d e g e r m y l a t i o n r e a c t i o n s w i t h i o d i n e m u s t b e i n o p e r a t i o n f o r t h e b r o m o d e g e r m y l a t i o n r e a c t i o n s o f a l k e n y l g e r m a n e s w i t h b r o m i n e . O s h i m a w a s a b l e to i s o l a t e the i n t e r m e d i a t e d i b r o m i d e 2 3 3 f r o m t h e r e a c t i o n o f 2 1 4 w i t h b r o m i n e . T r e a t m e n t o f 2 3 3 w i t h s i l i c a g e l i n h e x a n e f o r 1 h r e s u l t e d i n t h e f o r m a t i o n o f t h e ( E ) - a l k e n y l b r o m i d e 2 2 7 . T h e i n v e r s i o n o f s t e r e o c h e m i s t r y w a s a t t r i b u t e d t o a n r i ' - a d d i t i o n o f b r o m i n e to t h e o l e f i n , f o l l o w e d b y a n r i - e l i m i n a t i o n o f t r i e t h y l g e r m a n i u m b r o m i d e ( S c h e m e 3 2 ) . I o d i n a t i o n i n t h i s m a n n e r i s m u c h s l o w e r a n d t h e v / c - d i i o d i d e s are g e n e r a l l y u n s t a b l e a n d t e n d to r e v e r t b a c k to i o d i n e a n d t h e o l e f i n . 8 7 2 2 7 2 3 3 S c h e m e 3 2 B r o m o d e g e r m y l a t i o n s w e r e a l s o a t t e m p t e d u s i n g T V - b r o m o s u c c i n i m i d e ( N B S ) i n m e t h y l e n e c h l o r i d e at r o o m t e m p e r a t u r e . T h e r e a c t i o n s p r o c e e d e d m a i n l y w i t h r e t e n t i o n o f t h e d o u b l e b o n d c o n f i g u r a t i o n , b u t t h e s t e r e o s e l e c t i v i t y d e p e n d e d o n t h e n a t u r e o f t h e subs t ra te (Table6). 7 0 b Table 6: B r o m o d e g e r m y l a t i o n R e a c t i o n s U s i n g A ^ B r o m o s u c c i n i m i d e ( N B S ) ( f r o m r e f e r e n c e 7 0 b ) . \ J 2 equiv. NBS \ \u00E2\u0080\u0094 / G e E t 3 CH 2CI 2 ,25\u00C2\u00B0C ^ B r E n t r v I A l k e n y l g e r m a n e | A l k e n y l B r o m i d e I Y i e l d 1 n-Hex G e E t 3 H H 214 n-Hex Br )==< 97%(Z) H H 234 1 0 0 % 2 n-Hex G e E t 3 H M e 215 n-Hex Br ) = < 68%(Z) H M e 235 n-Hex M e ) = { 32%(\u00C2\u00A3) H Br 228 9 8 % 3 n-Hex M e H G e E t 3 216 n-Hex M e )==< 81%(E) H Br 230 n-Hex Br )==< 19%(Z) H M e 229 1 0 0 % T h e r e s u l t s o f t h e b r o m o d e g e r m y l a t i o n r e a c t i o n s w i t h N B S m o r e c l o s e l y r e s e m b l e t h o s e f r o m t h e i o d o d e g e r m y l a t i o n s , s i n c e t h e m a j o r p r o d u c t r e s u l t e d f r o m r e t e n t i o n o f c o n f i g u r a t i o n o f t h e d o u b l e b o n d . A m e c h a n i s m s i m i l a r t o t h o s e d e p i c t e d i n F i g u r e 1 a n d Scheme 31 i s l i k e l y i n o p e r a t i o n . T h e a d d i t i o n - e l i m i n a t i o n s e q u e n c e d e s c r i b e d i n Scheme 32, w h i c h w a s u s e d to r a t i o n a l i z e t h e i n v e r s i o n o f c o n f i g u r a t i o n f o r t h e r e a c t i o n o f b r o m i n e w i t h a l k e n y l g e r m a n e s , i s l e s s l i k e l y i n t h e c a s e o f N B S d u e to t h e l o w n u c l e o p h i l i c i t y o f t h e s u c c i n i m i d e c o u n t e r a n i o n . 67 D e s p i t e o b s e r v i n g c o m p l e t e r e t e n t i o n o f t h e c o n f i g u r a t i o n o f t h e d o u b l e b o n d w h e n t h e b i f u n c t i o n a l r e a g e n t 202 w a s t r e a t e d w i t h i o d i n e ( e q u a t i o n 1 4 ) , t h e d e s i r e d i o d o d e g e r m y l a t i o n r e a c t i o n s o f the a l k y l a t e d m a t e r i a l s d i d n o t p r o c e e d as p l a n n e d . W h e n the a l k y l a t e d a d d u c t s c o n t a i n i n g a d s - a l k e n y l g e r m a n i u m m o i e t y w e r e t r e a t e d w i t h a n i o d o n i u m s o u r c e , a m i x t u r e o f t h e cis- a n d the trans-alkenyl i o d i d e s w a s o b t a i n e d . M o r e o v e r , i n m o s t c a s e s , t h e m a j o r p r o d u c t s w e r e t h o s e r e s u l t i n g f r o m i n v e r s i o n o f c o n f i g u r a t i o n (Table 7). Table 7: I o d o d e g e r m y l a t i o n R e a c t i o n s o f A l k y l a t e d C w - A l k e n y l g e r m a n e s . Me 3Ge^ 1^ 1 X | X 1 X 1 O G * Q E n t r y X C o n d i t i o n s a Trans- A l k e n y l I o d i d e b Cis- A l k e n y l I o d i d e b 1 O l 2 , r t 1.7 1 2 o I2..0 \u00C2\u00B0C 2.6 1 3 0 I 2 , -78 \u00C2\u00B0Cc 11 1 4 0 I ( P y ) 2 B F 4 , 0 \u00C2\u00B0 C 2.5 1 5 0 I ( P y ) 2 B F 4 , -78 \u00C2\u00B0C 10 1 6 0 N I S , r t 1 1.3 7 N - N ( M e ) 2 1-2, r t 5 1 a- All the reactions were carried out in CH2CI2 in aluminum foil wrapped flasks using 1.1-1.5 equiv. of the iodonium reagent. b- The ratio of cis to trans isomers was determined by glc and/or nmr spectroscopy, c- The reaction was very slow and was stopped after 4 h before completion. 6 8 A n o t h e r e x a m p l e t h a t i l l u s t r a t e d t h e t e n d e n c y f o r i n v e r s i o n o v e r r e t e n t i o n o f c o n f i g u r a t i o n i n v o l v e d t h e i o d o d e g e r m y l a t i o n o f t h e a l k y l a t e d b i c y c l i c h y d r a z o n e 2 1 0 . T r e a t m e n t o f 2 1 0 w i t h i o d i n e i n m e t h y l e n e c h l o r i d e at r o o m t e m p e r a t u r e p r o v i d e d t h e cis a n d i r o n s - a l k e n y l i o d i d e s 2 3 6 i n a r a t i o o f 1 :14 , r e s p e c t i v e l y ( e q u a t i o n 15 ) . 1 : 1 4 cis: trans 2 1 0 2 3 6 I n a l l c a s e s , t h e t w o i s o m e r i c a l k e n y l i o d i d e s w e r e i n s e p a r a b l e b y c o l u m n c h r o m a t o g r a p h y u s i n g s i l i c a g e l . H o w e v e r , the r a t i o o f the t w o c o m p o u n d s w a s d e t e r m i n e d b y * H n m r s p e c t r o s c o p y s i n c e t h e s i g n a l s d e r i v e d f r o m t h e a l k e n i c p r o t o n s a t t a c h e d to t h e s a m e c a r b o n as t h e i o d i n e a t o m w e r e r e s o l v e d i n t h e * H n m r s p e c t r a o f t h e m i x t u r e s a n d c o u l d b e a s s i g n e d b y the m a g n i t u d e o f t h e i r c o u p l i n g c o n s t a n t s . T h e c o u p l i n g c o n s t a n t s f o r t h i s p r o t o n f o r t h e cis- a n d f r a / w - a l k e n y l i o d i d e s w e r e a p p r o x i m a t e l y 7 H z a n d 1 4 H z , r e s p e c t i v e l y (cf. a l k e n y l i o d i d e 2 2 2 , e q u a t i o n 1 4 , p a g e 62 ) . T h e r e s u l t s o u t l i n e d i n Table 7 a n d e q u a t i o n 1 5 s h o w t h a t t h e o u t c o m e o f t h i s r e a c t i o n i s t e m p e r a t u r e d e p e n d e n t (en t r i es 1 -3 a n d 4 - 5 ) . A d e c r e a s e i n t e m p e r a t u r e i n c r e a s e s t h e a m o u n t o f i n v e r s i o n o f t h e d o u b l e b o n d c o n f i g u r a t i o n . A s e c o n d o b s e r v a t i o n i s that the m e c h a n i s m o f t h e r e a c t i o n s e e m s to b e u n a f f e c t e d b y t h e s o u r c e o f I + . A t a g i v e n t e m p e r a t u r e , i o d i n e o r b i s ( p y r i d i n e ) i o d i n e ( I ) t e t r a f l u o r o b o r a t e ( I ( P y ) 2 B F 4 ) 8 8 g i v e r o u g h l y the s a m e r a t i o o f a l k e n y l i o d i d e s ( e n t r i e s 2 a n d 4 , 3 a n d 5) . E n t r y 6 i s a n e x c e p t i o n , s i n c e t h e u s e o f A M o d o s u c c i n i m i d e ( N I S ) as t h e s o u r c e o f I + f o r t h e i o d o d e g e r m y l a t i o n 8 9 p r o v i d e s t h e d e -f u s e d i s o m e r as t h e m a j o r c o m p o u n d . F i n a l l y , w h e n the k e t o n e c a r b o n y l i s r e p l a c e d w i t h a 6 9 h y d r a z o n e m o i e t y , t h e p r o d u c t r e s u l t i n g f r o m i n v e r s i o n o f c o n f i g u r a t i o n p r e d o m i n a t e s ( see e q u a t i o n 15 a n d c o m p a r e e n t r i e s 1 a n d 7 ) . T h e i s o m e r i z a t i o n o f c i ' s - a l k e n y l t r i p h e n y l g e r m a n e s ( e . g . 237) t o trans-a l k e n y l t r i p h e n y l g e r m a n e s ( e .g . 238) h a s b e e n r a t i o n a l i z e d b y t h e a d d i t i o n - e l i m i n a t i o n o f a t r i p h e n y l g e r m y l r a d i c a l (Scheme 33). 7 0 c n-Dec G e P h 3 n-Dec G e P h 3 n-Dec H ) = ( E t 3 B, P h 3 G e H V - f G e P h 3 rotation ) = { H H toluene, 60 \u00C2\u00B0C H H -Ph3Ge\u00C2\u00BB H G e P h 3 237 239 238 Scheme 33 F r e e r o t a t i o n o f t h e i n t e r m e d i a t e r a d i c a l 239 s c r a m b l e s t h e d o u b l e b o n d s t e r e o c h e m i s t r y . F o r t h e e x a m p l e s i n Table 7 a n d e q u a t i o n 15, i t i s u n l i k e l y t h a t i s o m e r i z a t i o n v i a r a d i c a l s p r i o r t o i o d o d e g e r m y l a t i o n i s r e s p o n s i b l e f o r t h e p o o r s e l e c t i v i t y . I o d i n e c a n b e a s o u r c e o f i o d i n e r a d i c a l s , b u t p r e c a u t i o n s w e r e t a k e n to p e r f o r m t h e r e a c t i o n s i n a l u m i n u m f o i l w r a p p e d f l a s k s , to d i s c o u r a g e p h o t o c h e m i c a l l y i n d u c e d h o m o l y t i c c l e a v a g e o f the i o d i n e b o n d . T h e r e a c t i o n i n Scheme 33 a l s o r e q u i r e s a t e m p e r a t u r e o f a t l e a s t 6 0 \u00C2\u00B0C a n d t h e r e a c t i o n s i n Table 7 w e r e p e r f o r m e d i n a t e m p e r a t u r e r a n g e o f - 7 8 \u00C2\u00B0C to r o o m t e m p e r a t u r e . A d d i t i o n a l e v i d e n c e e x c l u d i n g a r a d i c a l m e c h a n i s m i s the f a c t t ha t I (Py )2BF4 a n d N I S g a v e r e s u l t s s i m i l a r to t h o s e o b s e r v e d w i t h i o d i n e . T h e s e r e a g e n t s a r e n o t p r o n e to r a d i c a l f o r m a t i o n . F i n a l l y , i f r a d i c a l s a r e i n v o l v e d , t h e n i t i s u n l i k e l y t h a t t h e i o d o d e g e r m y l a t i o n o f t h e e l e c t r o p h i l e 202 w i t h i o d i n e i n m e t h y l e n e c h l o r i d e ( e q u a t i o n 14) w o u l d h a v e p r o d u c e d t h e m - a l k e n y l i o d i d e e x c l u s i v e l y . I t a p p e a r s that t h e p r e s e n c e o f a h e t e r o a t o m w i t h l o n e p a i r e l e c t r o n s i n t h e p r o x i m i t y o f the a l k e n y l g e r m a n i u m m o i e t y a f f e c t s t h e o u t c o m e o f t h e i o d o d e g e r m y l a t i o n r e a c t i o n s . A l l the s t a r t i n g m a t e r i a l s i n Table 4 a r e h y d r o c a r b o n - b a s e d a n d d o n o t c o n t a i n a n y h e t e r o a t o m s . H o w e v e r , w h e n t h e r e a c t i o n o f 202 w i t h i o d i n e ( e q u a t i o n 14) w a s c a r r i e d o u t i n a d o n o r s o l v e n t s u c h as d i e t h y l e t h e r i n s t e a d o f m e t h y l e n e c h l o r i d e , v i r t u a l l y n o a l k e n y l i o d i d e w a s d e t e c t e d . A p o s s i b l e e x p l a n a t i o n o f t h e s e r e s u l t s f o l l o w s . A m e c h a n i s m t h a t r a t i o n a l i z e s t h e r e s u l t s o f t h e g e r m a n i u m - i o d i n e e x c h a n g e i s s i m i l a r t o t h a t f o r t h e r e a c t i o n o f e l e c t r o p h i l e s w i t h a l k e n y l s i l a n e s , as d e p i c t e d i n Scheme 31. I n t h i s p r o p o s e d m e c h a n i s m , t h e r e t e n t i o n o f t h e d o u b l e b o n d c o n f i g u r a t i o n i s r a t i o n a l i z e d b y t h e m a x i m u m s t a b i l i z a t i o n a f f o r d e d b y the f a v o r a b l e ( a n d r e q u i r e d ) c o - p l a n a r i t y b e t w e e n the c a r b o n - s i l i c o n c b o n d a n d t h e v a c a n t p o r b i t a l o f t h e c a r b o n i u m i o n . 9 0 T h e r e l u c t a n c e t o r o t a t e a n d i s o m e r i z e t h e d o u b l e b o n d i s d u e to t h e u n f a v o r a b l e o r t h o g o n a l i t y that t h e o r b i t a l s w o u l d e n c o u n t e r u p o n r o t a t i o n . B o t h s i l i c o n a n d t i n c a n s t a b i l i z e (3 c a t i o n s a n d t h e r e f o r e , i t i s n o t u n r e a s o n a b l e to s u g g e s t that g e r m a n i u m , the g r o u p I V m e t a l l o i d s i t u a t e d b e t w e e n s i l i c o n a n d t i n i n t h e p e r i o d i c t a b l e , i s c a p a b l e o f a s i m i l a r s t a b i l i z a t i o n . I f c o o r d i n a t i o n b e t w e e n the h e t e r o a t o m o n t h e r i n g a n d t h e g e r m a n i u m i s i n v o k e d as i n 240 (Scheme 34), t h e n e l e c t r o p h i l i c a t t a c k o f t h e i o d o n i u m i o n o n t h e d o u b l e b o n d i n i t i a l l y p r o v i d e s t h e (3 c a r b o n i u m i o n 241. I n a r e a c t i o n p a t h w a y t h a t i s a n a l o g o u s to that d e s c r i b e d f o r a l k e n y l s i l a n e s ( pa th A ) , a 30\u00C2\u00B0 r o t a t i o n r e s u l t s i n t h e c a r b o n - g e r m a n i u m c b o n d b e i n g p a r a l l e l to t h e v a c a n t p o r b i t a l 242, w h i c h i s r e q u i r e d f o r m a x i m u m s t a b i l i z a t i o n . T h e c o o r d i n a t i o n b e t w e e n t h e h e t e r o a t o m a n d the g e r m a n i u m i s m a i n t a i n e d , a n d t h e s u b s e q u e n t l o s s o f t h e g e r m a n i u m m o i e t y r e s u l t s i n t h e a l k e n e p r o d u c t 243 w i t h r e t e n t i o n o f c o n f i g u r a t i o n . H o w e v e r , d u r i n g r o t a t i o n , as a r e s u l t o f t h e h e t e r o a t o m - g e r m a n i u m c o o r d i n a t i o n , t h e b u l k y i o d i n e a t o m m a y e n c o u n t e r s e v e r e n o n - b o n d e d i n t e r a c t i o n s w i t h the h e t e r o a t o m a n d t h e r e m a i n d e r o f t h e r i n g to w h i c h i t i s a t t a c h e d 242. A l t e r n a t i v e l y , i f t h e g e r m a n i u m r o t a t e s i n t h e o t h e r d i r e c t i o n ( p a t h B ) , the i o d i n e a t o m i s p o i n t i n g a w a y f r o m r i n g as i n 244. D u r i n g t h e r o t a t i o n , the m o l e c u l e w o u l d p a s s t h r o u g h a c o n f o r m a t i o n i n w h i c h the c a r b o n - g e r m a n i u m b o n d w o u l d b e o r t h o g o n a l to t h e p o r b i t a l o f t h e c a r b o c a t i o n , r e s u l t i n g i n a l o s s o f s t a b i l i z a t i o n . T h e l e s s c o n g e s t e d s t e r i c e n v i r o n m e n t f o r t h e i o d i n e a t o m i n 244 m a y o u t w e i g h t h e t e m p o r a r y l o s s o f h y p e r c o n j u g a t i v e s t a b i l i z a t i o n . A c o n f o r m a t i o n a l f l i p f r o m 244 t o 245 r e e s t a b l i s h e s t h e h e t e r o a t o m - g e r m a n i u m c o o r d i n a t i o n w h i l e m a i n t a i n i n g the 71 s t e r e o e l e c t r o n i c r e q u i r e m e n t f o r c a r b o n i u m i o n s t a b i l i z a t i o n . D e g e r m y l a t i o n f r o m t h e m o s t f a v o r a b l e c o n f o r m a t i o n 2 4 5 r e s u l t s i n t h e ( E ) - a l k e n y l i o d i d e 2 4 6 w i t h i n v e r s i o n o f c o n f i g u r a t i o n . inversion 2 4 6 S c h e m e 3 4 T h e r e s u l t s i n Table 7 a n d e q u a t i o n 15 m a y b e r a t i o n a l i z e d u s i n g t h e e x p l a n a t i o n i n Scheme 34. T h e o b s e r v e d t e m p e r a t u r e d e p e n d e n c e i n w h i c h a d e c r e a s e i n t e m p e r a t u r e r e s u l t e d i n m o r e o f t h e trans - i s o m e r b e i n g f o r m e d m a y b e d u e to t h e f a c t t h a t g e r m a n i u m -h e t e r o a t o m c o o r d i n a t e d i n t e r m e d i a t e s s u c h as 242 a n d 245 c o n t r i b u t e m o r e s i g n i f i c a n t l y at l o w t e m p e r a t u r e , t h u s f a v o r i n g p a t h B o v e r p a t h A . S e c o n d l y , t h e p r e f e r e n c e f o r i n v e r s i o n that w a s o b s e r v e d w i t h t h e M N - d i m e t h y l h y d r a z o n e c o u l d b e t h e r e s u l t o f t h e g r e a t e r b u l k o f t h e h y d r a z o n e c o m p a r e d t o a k e t o n e w h i c h i n c r e a s e s t h e s t e r i c i n t e r a c t i o n b e t w e e n t h i s f u n c t i o n a n d t h e i o d i n e a t o m a n d f a v o r s i n t e r m e d i a t e 245 o v e r 242. F i n a l l y , t h e s o u r c e o f the i o d o n i u m i o n ( I + ) (I2 o r ( I ( P y ) 2 B F 4 ) m a y b e i n c o n s e q u e n t i a l s i n c e i n t h e p r o p o s e d m e c h a n i s m , t h e i n t e r m e d i a t e s a r e i d e n t i c a l o n c e t h e i n i t i a l e l e c t r o p h i l i c a t t a c k o f t h e i o d o n i u m i o n h a s o c c u r r e d . T h e u s e o f / V - i o d o s u c c i n i m i d e as t h e s o u r c e o f I + , h o w e v e r , w a s the o n l y c a s e w h e r e t h e d s - f u s e d i s o m e r p r e d o m i n a t e d (Table 7, e n t r y 6 ) . O n c e t h i s r e a g e n t h a s d e l i v e r e d t h e i o d o n i u m i o n , t h e s u c c i n i m i d e c o u n t e r i o n , w h i c h c o n t a i n s a r e s o n a n c e s t a b i l i z e d a n i o n , c o u l d e f f e c t i v e l y c o m p e t e w i t h t h e h e t e r o a t o m o n t h e r i n g f o r g e r m a n i u m c o o r d i n a t i o n . W i t h o u t c o o r d i n a t i o n b e t w e e n g e r m a n i u m a n d t h e h e t e r o a t o m , t h e s t e r i c i n t e r a c t i o n b e t w e e n t h e i o d i n e a n d the r i n g , as i n 242, i s r e m o v e d a n d t h e r e a c t i o n m a y f o l l o w p a t h A , r e s u l t i n g i n r e t e n t i o n o f c o n f i g u r a t i o n . T h e u s e o f N I S f o r i o d o d e g e r m y l a t i o n r e a c t i o n s a n d the s u b s e q u e n t c o o r d i n a t i o n o f s u c c i n i m i d e a n i o n to the g e r m a n i u m h a s p r e v i o u s l y b e e n p r o p o s e d b y P i e r s a n d K a l l e r . 8 9 - 9 1 I n a n a t t e m p t to p e r f o r m a g e r m a n i u m - i o d i n e e x c h a n g e r e a c t i o n o n 247 u s i n g I2, the e x p e c t e d p r o d u c t 248 w a s n o t f o r m e d (Scheme 35). I n s t e a d , t h e p r o d u c t r e s u l t i n g f r o m t r a n s k e t a l i z a t i o n (249) w a s i s o l a t e d i n 7 3 % y i e l d . T h e t r i m e t h y l g e r m a n i u m i o d i d e (Me3GeI), w h i c h i s a b y - p r o d u c t o f t h e r e a c t i o n , w a s p o s t u l a t e d to h a v e c a t a l y z e d t h i s u n w a n t e d k e t a l m i g r a t i o n b y c o o r d i n a t i o n o f t h e g e r m a n i u m w i t h t h e k e t a l o x y g e n s . H o w e v e r , t h e u s e o f N I S p r o v i d e d t h e i o d o d e g e r m y l a t i o n p r o d u c t 248 i n 84% y i e l d . I t w a s p r o p o s e d tha t t h e p r e f e r e n t i a l c o o r d i n a t i o n o f t h e g e r m a n i u m b y - p r o d u c t s w i t h t h e r e s o n a n c e s t a b i l i z e d 7 3 s u c c i n i m i d e a n i o n d e c o m p l e x e d t h e o x o p h i l i c g e r m a n i u m f r o m t h e k e t a l o x y g e n s , a n d t r a n s k e t a l i z a t i o n w a s e f f e c t i v e l y s u p p r e s s e d . S c h e m e 3 5 T h e r e a c t i o n o f the b i f u n c t i o n a l e l e c t r o p h i l e 2 0 2 w i t h i o d i n e i n m e t h y l e n e c h l o r i d e i n t h e a b s e n c e o f h e t e r o a t o m s p r o c e e d e d w i t h r e t e n t i o n o f c o n f i g u r a t i o n ( e q u a t i o n 1 4 ) . W h e n t h e r e a c t i o n w a s c a r r i e d o u t i n d i e t h y l e t h e r , v i r t u a l l y n o r e a c t i o n w a s o b s e r v e d . T h e l o n e p a i r e l e c t r o n s o n t h e o x y g e n o f t h e s o l v e n t m u s t c o o r d i n a t e w i t h t h e g e r m a n i u m a n d s u p p r e s s t h e i o d o d e g e r m y l a t i o n r e a c t i o n . T h e u s e o f b r o m i n e o r N B S f o r b r o m o d e g e r m y l a t i o n r e a c t i o n s d i d n o t o f f e r a s y n t h e t i c a l l y u s e f u l a l t e r n a t i v e to t h e e x a m p l e s i n T a b l e 7 . C o m p l e x m i x t u r e s o f p r o d u c t s w e r e i s o l a t e d i n e a c h c a s e a n d t h e * H n m r s p e c t r a o f t h e c r u d e r e a c t i o n m i x t u r e s i n d i c a t e d that t h e p r o d u c t s r e s u l t i n g f r o m b o t h r e t e n t i o n a n d i n v e r s i o n o f d o u b l e b o n d g e o m e t r y w e r e p r o d u c e d . 7 4 C l e a r l y , t h e u s e o f a b i f u n c t i o n a l e l e c t r o p h i l e c o n t a i n i n g a a l k e n y l g e r m a n i u m m o i e t y f o r t h e d e s i r e d a n n u l a t i o n s e q u e n c e w a s n o t f e a s i b l e d u e t o t h e l o s s o f d o u b l e b o n d s t e r e o c h e m i s t r y . I t w a s p o s s i b l e , h o w e v e r , that a b u l k i e r t r i a l k y l s t a n n a n e g r o u p i n the p l a c e o f t h e t r i m e t h y l g e r m y l m o i e t y w o u l d n o t c o o r d i n a t e as e f f e c t i v e l y w i t h t h e p r o x i m a l h e t e r o a t o m s a n d w o u l d a l l o w i o d o d e s t a n n y l a t i o n t o o c c u r w i t h r e t e n t i o n o f c o n f i g u r a t i o n . T h e p o s t u l a t e d m e c h a n i s m f o r i o d o d e s t a n n y l a t i o n r e a c t i o n s ( F i g u r e 1) d i f f e r s f r o m that o f t h e r e a c t i o n o f a l k e n y l s i l a n e s w i t h e l e c t r o p h i l e s (Scheme 31) a n d t h e g e r m a n i u m - i o d i n e e x c h a n g e (Scheme 34).84 A l s o , t h e c a r b o n - t i n b o n d i s w e a k e r t h a n t h e c a r b o n - g e r m a n i u m b o n d a n d i o d o d e s t a n n y l a t i o n i s a f a s t e r p r o c e s s t h a n i o d o d e g e r m y l a t i o n . 9 T h e s e f a c t o r s c o u l d t r a n s l a t e i n t o t i n - i o d i n e e x c h a n g e p r o c e e d i n g w i t h r e t e n t i o n o f c o n f i g u r a t i o n . T h e p r e p a r a t i o n o f the b i f u n c t i o n a l r e a g e n t c o n t a i n i n g a t r i a l k y l t i n g r o u p i s d e s c r i b e d b e l o w . R e a c t i o n o f a c e t y l e n e gas w i t h the h i g h e r o r d e r m i x e d c y a n o c u p r a t e 250, f o l l o w e d b y t r e a t m e n t o f t h e i n t e r m e d i a t e a l k e n y l c o p p e r s p e c i e s 251 w i t h e t h y l e n e o x i d e , p r o v i d e d t h e k n o w n ( Z ) - a l k e n y l s t a n n a n e 252 i n 8 5 % y i e l d (Scheme 36). 9 2 C o n v e r s i o n o f 252 i n t o the i o d i d e 253 p r o c e e d e d i n 9 3 % y i e l d . 7 3 D = Bu 3 Sn(Bu)Cu(CN)L i 2 T H F C u -78 \u00C2\u00B0C L 250 S n B u 3 J -78 \u00C2\u00B0C 3) H 2 0 H O S n B u 3 251 252 85% P h 3 P - l 2 imidazole C H 3 C N - E t 2 0 0 \u00C2\u00B0C S n B u 3 253 93% Scheme 36 7 5 N o t s u r p r i s i n g l y , a l k y l a t i o n s u s i n g t h e h o m o a l l y l i c i o d i d e 2 5 3 a l s o r e q u i r e d t h e u s e o f / V - d i m e t h y l h y d r a z o n e s i n s t e a d o f k e t o n e s s u b s t r a t e s . O t h e r w i s e , e l i m i n a t i o n o f H I to g i v e t h e d i e n e 2 5 4 w a s o b s e r v e d ( e q u a t i o n 1 6 ) . C o m p o u n d 2 5 4 w a s i s o l a t e d b y c o l u m n c h r o m a t o g r a p h y u s i n g s i l i c a g e l a n d t h e X H n m r s p e c t r u m s h o w e d t h e h i g h f i e l d s i g n a l s a t t r i b u t e d to t h e t r i b u t y l t i n g r o u p a n d a c o m p l e x set o f f i v e a l k e n y l s i g n a l s . I n a d d i t i o n , t h e 1 3 C n m r s p e c t r u m o f 2 5 4 s h o w e d f o u r o l e f i n i c c a r b o n s at 6 1 1 8 . 5 , 1 3 5 . 1 , 1 3 9 . 6 , a n d 1 4 7 . 0 . Ketone enolates S n B u 3 > Ketones + = / ^ ^ S n B u 3 ( i 6 ) 2 5 3 2 5 4 T h e u s e o f a n a l k e n y l s t a n n a n e m o i e t y i n t h e e l e c t r o p h i l e i n s t e a d o f a a l k e n y l g e r m a n e w o u l d r e q u i r e t h e u s e o f m i l d e r , n o n - a c i d i c c o n d i t i o n s f o r the h y d r a z o n e h y d r o l y s i s . U n d e r f o r c i n g a c i d i c c o n d i t i o n s , t h e m o r e l a b i l e a l k e n y l s t a n n a n e m o i e t y w o u l d l i k e l y p r o t i o d e s t a n n y l a t e . A l t e r n a t i v e l y , f o r t h e m o d e l s t u d i e s , t h e t i n - i o d i n e e x c h a n g e r e a c t i o n c o u l d b e c a r r i e d o u t b e f o r e the a c i d i c h y d r a z o n e h y d r o l y s i s , s i n c e t h e a l k e n y l i o d i d e f u n c t i o n l i k e l y w o u l d b e u n a f f e c t e d u n d e r t h e s e c o n d i t i o n s . T h e l a t t e r a p p r o a c h w a s u s e d s i n c e the r e m o v a l o f t h e h y d r a z o n e w i t h N a O A c a n d A c O H i n a q u e o u s T H F w a s v e r y e f f i c i e n t . T h e d i m e t h y l h y d r a z o n e o f c y c l o h e p t a n o n e 2 1 1 w a s a l k y l a t e d w i t h t h e b i f u n c t i o n a l e l e c t r o p h i l e 2 5 3 i n t h e p r e s e n c e o f H M P A to p r o v i d e t h e a d d u c t 2 5 5 , w i t h n o e v i d e n c e o f e l i m i n a t i o n (Scheme 3 7 ) . T i n - i o d i n e e x c h a n g e w a s p e r f o r m e d o n t h e c r u d e r e a c t i o n p r o d u c t w i t h i o d i n e i n CH2CI2 at 0 \u00C2\u00B0C a n d w a s f o l l o w e d b y i m m e d i a t e a c i d i c h y d r o l y s i s o f t h e h y d r a z o n e f u n c t i o n . T h e t h r e e s t e p s e q u e n c e p r o c e e d e d i n 8 6 % y i e l d . I t w a s g r a t i f y i n g to d i s c o v e r t ha t t h e a l k e n y l i o d i d e 2 5 6 w a s f o r m e d w i t h c o m p l e t e r e t e n t i o n o f t h e d o u b l e b o n d c o n f i g u r a t i o n as i n d i c a t e d b y the * H n m r s p e c t r u m . T h e t w o a l k e n y l s i g n a l s a p p e a r at 8 6 .11 ( d d d , J = 1,1,1 H z ) a n d 8 6 . 1 8 ( b r d , J = 1 H z ) . T h e I R s p e c t r u m o f 2 5 6 i n d i c a t e d the p r e s e n c e o f a n a l k e n e a n d a c a r b o n y l m o i e t y b y a b s o r p t i o n s at 1 6 1 6 c m - 1 a n d 1 7 0 3 c m \" 1 , r e s p e c t i v e l y . 7 6 (Me) 2 Nk N 1) LDA, THF, 0\u00C2\u00B0C 2) 253 HMPA, -78 \u00C2\u00B0C S n B u 3 B u 3 S n 211 255 1) l 2 , CH 2CI 2 ,0\u00C2\u00B0C 2) NaOAc, AcOH THF, H 2 0 , rt 256 86% from 211 S c h e m e 37 T h e r a p i d t i n - i o d i n e e x c h a n g e r e a c t i o n c o u l d b e f o l l o w e d v i s u a l l y . A s o l u t i o n o f i o d i n e i n m e t h y l e n e c h l o r i d e w a s a d d e d d r o p w i s e to a s o l u t i o n o f t h e c r u d e a l k e n y l s t a n n a n e 255 i n m e t h y l e n e c h l o r i d e . T h e r e d d i s h - b r o w n c o l o r o f t h e i o d i n e i m m e d i a t e l y d i s a p p e a r e d u n t i l o n e e q u i v a l e n t o f i o d i n e h a d b e e n a d d e d , a n d t h e n t h e c o l o r p e r s i s t e d . T h e r e f o r e , t h e p r o c e d u r e c o u l d b e p e r f o r m e d i n a t i t r i m e t r i c f a s h i o n . T h e u s e o f a t r i b u t y l t i n g r o u p r e s u l t e d i n c o m p l e t e r e t e n t i o n o f t h e d o u b l e b o n d g e o m e t r y u p o n e x c h a n g e w i t h i o d i n e . I n t e r e s t i n g l y , w h e n a t r i m e t h y l t i n g r o u p w a s u s e d i n s t e a d , t r a c e a m o u n t s o f t h e trans-alkenyl i o d i d e r e s u l t i n g f r o m i n v e r s i o n w e r e d e t e c t e d i n the ! H n m r s p e c t r u m . T h e b u l k i e r t r i b u t y l t i n g r o u p m a y b e u n a b l e t o c o o r d i n a t e w i t h the o x y g e n o n t h e r i n g , t h e r e b y e l i m i n a t i n g t h e e f f e c t s s u g g e s t e d t o b e r e s p o n s i b l e r e s p o n s i b l e f o r i n v e r s i o n o f c o n f i g u r a t i o n , as d e s c r i b e d f o r the t r i m e t h y l g e r m a n i u m s u b s t r a t e s ( S c h e m e 34, p a g e 7 1 ) . T h e t r i m e t h y l t i n g r o u p m a y b e s m a l l e n o u g h f o r t h e c o o r d i n a t i o n p a t h w a y to o p e r a t e to a s m a l l e x t e n t . 7 7 T h e r e m a i n d e r o f t h e s e q u e n c e f o r t h e p r o p o s e d a n n u l a t i o n p r o t o c o l p r o c e e d e d as p l a n n e d (Scheme 38). T h u s , a d d i t i o n o f t h e k e t o a l k e n y l i o d i d e 256 t o a c o l d ( - 7 8 \u00C2\u00B0C) s o l u t i o n o f n - B u L i ( 2 . 5 e q u i v a l e n t s ) i n T H F a f f o r d e d a 2 . 5 : 1 m i x t u r e o f t h e a l l y l i c a l c o h o l s 257 i n 8 0 % y i e l d . T h e m i x t u r e o f d i a s t e r e o m e r s w a s s e p a r a b l e b y c o l u m n c h r o m a t o g r a p h y u s i n g s i l i c a g e l , a n d t h e t w o i s o m e r s e x h i b i t e d s i m i l a r s p e c t r a l p r o p e r t i e s . I n t h e TR s p e c t r u m o f t h e m a j o r d i a s t e r e o m e r , a h y d r o x y l s t r e t c h i n g a b s o r p t i o n a p p e a r e d at 3 4 6 9 c m 1 . T h e * H n m r s p e c t r u m s h o w e d t h e p r e s e n c e o f t w o a l k e n y l s i g n a l s at 8 5 . 5 7 ( b r d , J = 9 . 8 H z ) a n d at 8 5 . 7 3 ( d d d , J = 9 . 8 , 5 . 0 , 2 . 4 H z ) . I n a d d i t i o n to the c y c l i z e d c o m p o u n d s , a s m a l l a m o u n t o f the u n c y c l i z e d m a t e r i a l 258 w a s i s o l a t e d ( 6 % y i e l d ) i n w h i c h the i o d i n e h a d b e e n r e p l a c e d b y a h y d r o g e n . T h e s p e c t r a l d a t a f o r c o m p o u n d 258 w a s i n f u l l a c c o r d w i t h t h e s t r u c t u r a l a s s i g n m e n t . T h e I R s p e c t r u m s h o w e d t h e p r e s e n c e o f a c a r b o n y l a b s o r p t i o n at 1 7 0 3 c m - 1 , w h i l e the lH n m r s p e c t r u m c o n t a i n e d a f a i r l y c o m p l e x set o f a l k e n i c s i g n a l s i n t e g r a t i n g f o r th ree p r o t o n s . O x i d a t i v e r e a r r a n g e m e n t o f a m i x t u r e o f the d i a s t e r e o m e r s o f 257 u s i n g PCC-a l u m i n a i n C H 2 C I 2 at r o o m t e m p e r a t u r e a f f o r d e d the e n o n e 259 i n 8 5 % y i e l d . n-BuLi, THF -78 \u00C2\u00B0C 257 2.5: 1 80 % 258 6% PCC-Alumina C H 2 C I 2 , rt 259 85% Scheme 38 78 W i t h i n t h e c o n t e x t o f t h e p l a n n e d t o t a l s y n t h e s i s , o n e d r a w b a c k i n u s i n g a n a l k e n y l s t a n n a n e m o i e t y i n s t e a d o f a n a l k e n y l g e r m a n e w a s the i n c r e a s e d l a b i l i t y o f t h e f o r m e r g r o u p . T h e o n l y c o n d i t i o n s tha t w e r e s u i t a b l e f o r r e m o v i n g t h e h y d r a z o n e f u n c t i o n i n the a l k e n y l g e r m a n e e q u i v a l e n t o f 2 6 0 w e r e s t r o n g l y a c i d i c ( A c O H , N a O A c , T H F , H2O, r e f l u x ) . T h e s e c o n d i t i o n s w o u l d n o t b e c o m p a t i b l e w i t h t h e a l k e n y l s t a n n a n e g r o u p i n 2 6 0 . T h i s p r o b l e m c o u l d b e a l l e v i a t e d b y p e r f o r m i n g t h e s e c o n d a l k y l a t i o n o f t h e h y d r a z o n e 2 6 0 w i t h m e t h y l i o d i d e to p r o v i d e t h e d i a l k y l a t e d c o m p o u n d 2 6 1 . T i n - i o d i n e e x c h a n g e w o u l d t h e n p r o v i d e t h e a l k e n y l i o d i d e , w h i c h w o u l d be s t a b l e to the s t r o n g l y a c i d i c c o n d i t i o n s r e q u i r e d f o r r e m o v a l o f the h y d r a z o n e f u n c t i o n to p r o v i d e the k e t o n e 2 6 2 ( S c h e m e 3 9 ) . B u 3 S n 2 6 2 S c h e m e 3 9 U n f o r t u n a t e l y , a t t h i s p o i n t i n t h e s y n t h e s i s , a l l t h e a v a i l a b l e m a t e r i a l h a d b e e n c o n v e r t e d i n t o t h e b i c y c l i c h y d r a z o n e 2 1 0 c o n t a i n i n g a n a l k e n y l g e r m a n i u m m o i e t y . R a t h e r t h a n g o b a c k to t h e b e g i n n i n g o f t h e s y n t h e t i c s e q u e n c e , i t w a s f e l t t ha t c o m p o u n d 2 1 0 c o u l d s e r v e as a s u i t a b l e m o d e l c o m p o u n d to p r o b e t h e f e a s i b i l i t y o f p e r f o r m i n g t h e s e c o n d a l k y l a t i o n w i t h m e t h y l i o d i d e . 7 9 T h e a t t e m p t e d m e t h y l a t i o n o f 2 1 0 p r o d u c e d a n u n e x p e c t e d r e s u l t . D u e to t h e d i f f i c u l t y e n c o u n t e r e d i n d e p r o t o n a t i n g t h e b i c y c l i c h y d r a z o n e 2 0 9 w i t h a n y b a s e o t h e r t h a n K D A , t h i s r e a g e n t w a s a l s o s e l e c t e d f o r t h e s e c o n d a l k y l a t i o n . H o w e v e r , t r e a t m e n t o f 2 1 0 w i t h K D A i n T H F at - 7 8 \u00C2\u00B0C r e s u l t e d i n a l l y l i c d e p r o t o n a t i o n i n s t e a d o f a b s t r a c t i o n o f t h e p r o t o n a l p h a to t h e h y d r a z o n e ( S c h e m e 4 0 ) . A d d i t i o n o f m e t h y l i o d i d e to t h e a l l y l i c a n i o n 2 6 3 r e s u l t e d i n t h e f o r m a t i o n o f t w o p r o d u c t s (as w e l l as r e c o v e r e d s t a r t i n g m a t e r i a l ) , w h i c h w e r e i n s e p a r a b l e b y s i l i c a g e l c h r o m a t o g r a p h y . S c h e m e 4 0 I n t h e * H n m r s p e c t r u m o f t h e i s o l a t e d m i x t u r e o f c o m p o u n d s , t h e s i g n a l s d u e to m e t h y l g r o u p s w e r e e i t h e r s i g n i f i c a n t l y b r o a d e n e d o r s p l i t i n t o t w o s i g n a l s d u e to t h e m i x t u r e o f d i a s t e r e o m e r s . F o r e x a m p l e , t h e t r i m e t h y l g e r m a n i u m s i g n a l a p p e a r s as t w o s i n g l e t s o f e q u a l i n t e n s i t y at 8 0 . 0 5 0 a n d 8 0 . 0 5 4 . T h e s i g n a l s f o r M e - 1 0 a n d M e - 1 3 ( I U P A C n u m b e r i n g ) w e r e b r o a d e n e d a n d a p p e a r at 8 0 . 7 0 a n d 8 1 . 7 1 , r e s p e c t i v e l y . T h e a n g u l a r h y d r o g e n H - l g i v e s r i s e to t w o d o u b l e t s at 8 2 . 2 6 ( 7 = 11 H z ) a n d 8 2 . 2 7 ( 7 = 11 H z ) , w h e r e a s t h e m e t h y l g r o u p s f r o m the h y d r a z o n e f u n c t i o n a p p e a r as t w o s i n g l e t s at 8 2 . 3 4 8 a n d 8 2 . 3 5 4 . M e t h y l a t i o n c o u l d o c c u r at e i t h e r C - l 5 o r C - 1 7 o f t h e r e s o n a n c e s t a b i l i z e d a l l y l i c a n i o n 263 t o g i v e 265 o r 264, r e s p e c t i v e l y . n m r s p e c t r o s c o p i c a n a l y s i s s u g g e s t e d tha t m e t h y l a t i o n o c c u r r e d at C - 1 7 to p r o v i d e 264. T h e e v i d e n c e f o r a l k y l a t i o n a t C - 1 7 to p r o v i d e 264 w a s d e r i v e d f r o m the * H n m r s p e c t r u m o f t h e m i x t u r e a n d b y h o m o n u c l e a r (^H-^H) d e c o u p l i n g e x p e r i m e n t s . T h e n e w l y i n t r o d u c e d m e t h y l g r o u p a p p e a r s as t w o d o u b l e t s at 8 1 .04 (7 = 4 . 8 H z ) a n d 8 1 .06 ( 7 = 4 . 8 H z ) c o n f i r m i n g tha t t h e m e t h y l g r o u p i s a t t a c h e d to a m e t h i n e c a r b o n ( C - 1 7 ) a n d n o t at C - 3 as d e s i r e d . F u r t h e r e v i d e n c e tha t a l k y l a t i o n d i d n o t o c c u r a l p h a to t h e h y d r a z o n e f u n c t i o n w a s s u p p o r t e d b y t h e p r e s e n c e o f t h e d e s h i e l d e d h y d r o g e n H - 3 as a m u l t i p l e t at 8 3 . 2 6 - 3 . 4 5 . E v i d e n c e that t h e d o u b l e b o n d h a d s h i f t e d d u r i n g a l k y l a t i o n , as s h o w n i n 264, w a s i n d i c a t e d b y t h e c h e m i c a l s h i f t a n d s p l i t t i n g p a t t e r n f o r the a l k e n y l p r o t o n s . T h e a l k e n i c s i g n a l s n o w a p p e a r e d as a m u l t i p l e t at 8 5 . 0 6 - 5 . 1 7 ( H - 1 5 ) a n d as t w o d o u b l e t o f d o u b l e t s at 8 5 . 4 6 ( 7 = 1 5 , 7 H z ) a n d 8 5 . 5 3 ( 7 = 1 5 , 7 H z , H - 1 6 ) . T h e u p f i e l d s h i f t o f the a l k e n y l h y d r o g e n s s u g g e s t e d that t h e g e r m a n i u m m o i e t y w a s n o l o n g e r a t t a c h e d to t h e d o u b l e b o n d , p r e c l u d i n g the f o r m a t i o n o f c o m p o u n d 265. I n o t h e r a l k y l a t e d c o m p o u n d s w h e r e a n a l k e n y l g e r m a n i u m g r o u p i s p r e s e n t , t h e o l e f i n i c s i g n a l s a r e at l o w e r f i e l d . T h e m a g n i t u d e o f t h e c o u p l i n g c o n s t a n t ( 7 = 1 5 H z ) i s i n d i c a t i v e o f a trans d o u b l e b o n d . I n h o m o n u c l e a r d e c o u p l i n g e x p e r i m e n t s , i r r a d i a t i o n o f t h e m u l t i p l e t at 8 5 . 0 6 - 5 . 1 7 ( H -15) r e s u l t e d i n t h e c o l l a p s e o f t h e s i g n a l s a t 8 5 . 4 6 ( d d , 7 = 1 5 , 7 H z ) a n d 8 5 . 5 3 ( d d , 7 = 1 5 , 7 H z , H - 1 6 ) t o t w o d o u b l e t s (7 = 7 H z a n d 7 H z ) . S i m u l t a n e o u s i r r a d i a t i o n o f b o t h t h e d o u b l e t o f d o u b l e t s at 8 5 . 4 6 a n d 8 5 . 5 3 ( H - 1 6 ) r e s u l t e d i n t h e c o l l a p s e o f t h e m u l t i p l e t at 5 5 . 0 6 - 5 . 1 7 ( H - 1 5 ) i n t o a b r o a d t r i p l e t (7 = 8 H z ) . T h e * H n m r s p e c t r o s c o p i c d a t a a n d t h e r e s u l t s o f t h e d e c o u p l i n g e x p e r i m e n t s s t r o n g l y s u p p o r t t h e a s s i g n m e n t o f 264. T h e a l l y l i c d e p r o t o n a t i o n m a y h a v e o c c u r r e d i n p r e f e r e n c e to e n o l a t e a n i o n f o r m a t i o n b e c a u s e t h e p r o t o n at H - 3 i s i n a n e q u a t o r i a l o r i e n t a t i o n . C o r e y 9 3 h a s p r o p o s e d tha t a x i a l p r o t o n s a r e m o r e r e a d i l y a b s t r a c t e d t h a n e q u a t o r i a l o n e s s i n c e t h e e n e r g y o f t h e t r a n s i t i o n state i s l o w e r w h e n t h e r e i s m a x i m u m o r b i t a l o v e r l a p b e t w e e n t h e s p 3 o r b i t a l m a d e a v a i l a b l e b y t h e l e a v i n g a x i a l h y d r o g e n a n d t h e p - o r b i t a l o f t h e c a r b o n y l c a r b o n . F o r e x a m p l e , i n t h e c a s e o f a c y c l o h e x a n o n e (Scheme 41), t h i s i m p l i e s that d u r i n g e n o l a t e f o r m a t i o n t h e a - a x i a l h y d r o g e n H 2 i s a b s t r a c t e d p r e f e r e n t i a l l y to t h e o c - e q u a t o r i a l h y d r o g e n H i . F o r t h e s a m e s t e r e o e l e c t r o n i c r e a s o n s , t h e r e v e r s e r e a c t i o n o f a n e n o l a t e w i t h a p r o t o n o r e l e c t r o p h i l e s h o u l d p r o c e e d s t e r e o s e l e c t i v e l y a x i a l l y . 6 9 Scheme 41 E p i m e r i z a t i o n o f t h e s i d e c h a i n i n 210 f r o m a n a x i a l to a n e q u a t o r i a l o r i e n t a t i o n as i n 266 s h o u l d , i n t h e o r y , b e p o s s i b l e . H o w e v e r , a t t e m p t e d e p i m e r i z a t i o n o f 210 g a v e e x c l u s i v e l y r e c o v e r e d s t a r t i n g m a t e r i a l ( e q u a t i o n 17) w i t h n o e v i d e n c e f o r t h e f o r m a t i o n o f 266. E x a m i n a t i o n o f m o l e c u l a r m o d e l s s u g g e s t e d t h a t e p i m e r 266 e x p e r i e n c e s c o n s i d e r a b l e 1 , 3 - a l l ' y l i c s t r a i n ( A 1 > 3 - s t r a i n ) b e t w e e n t h e s i d e c h a i n a n d t h e b u l k y d i m e t h y l a m i n o m o i e t y ( e q u a t i o n 17). E p i m e r 210 d o e s n o t h a v e t h i s i n t e r a c t i o n a n d i s t h e r e f o r e t h e m o r e s t a b l e o f the t w o i s o m e r s . C l e a r l y , t h i s s t r a t e g y f o r a p p e n d i n g a s i x - m e m b e r e d r i n g o n t o t h e b i c y c l i c k e t o n e 60 h a d to b e r e v i s e d . I n m o d e l s t u d i e s , a f t e r a f e w m o d i f i c a t i o n s t o t h e e l e c t r o p h i l e , t h e n e w l y d e v e l o p e d a n n u l a t i o n p r o t o c o l w o r k e d as e x p e c t e d b u t i t f a i l e d w h e n a p p l i e d to t h e s y n t h e t i c s e q u e n c e . T h e u s e o f d i m e t h y l h y d r a z o n e s i n t h e a l k y l a t i o n s t e p w a s r e s p o n s i b l e f o r t h e e n c o u n t e r e d d i f f i c u l t i e s . T h e h y d r a z o n e w a s n e c e s s a r y to p r e v e n t e l i m i n a t i o n o f H I f r o m the h o m o a l l y l i c i o d i d e d u r i n g a l k y l a t i o n (vide supra) b u t the a c i d i c r e a c t i o n c o n d i t i o n s r e q u i r e d to r e m o v e t h e g r o u p w e r e n o t c o m p a t i b l e w i t h a n a l k e n y l s t a n n a n e m o i e t y . C o n v e r t i n g t h e ( Z ) - a l k e n y l t r i b u t y l s t a n n a n e i n t o t h e ( Z ) - a l k e n y l i o d i d e b e f o r e t h e s e c o n d a l k y l a t i o n w i t h m e t h y l i o d i d e w a s n o t a n o p t i o n s i n c e a n a l k e n y l i o d i d e m o i e t y i s n o t c o m p a t i b l e w i t h the c o n d i t i o n s r e q u i r e d f o r a l k y l a t i o n . A l k y l a t i o n o f s u b s t r a t e s c o n t a i n i n g a n a l k e n y l i o d i d e m o i e t y h a v e b e e n s h o w n to p r o v i d e m a i n l y e l i m i n a t i o n o f H I t o a f f o r d t h e t e r m i n a l a c e t y l e n e . 4 7 T h e n e e d f o r d i m e t h y l h y d r a z o n e s d u r i n g t h e a l k y l a t i o n s t e p w a s f o u n d to b e u n n e c e s s a r y i n a l a t e r r e l a t e d s t u d y b y P i e r s a n d W a l k e r , 1 5 d i r e c t e d t o w a r d s t h e s y n t h e s i s o f c y c l o h e p t e n o n e s . I n t h e i r b i f u n c t i o n a l r e a g e n t a n n u l a t i o n s t u d y , the e l e c t r o p h i l e 39 w a s o n e m e t h y l e n e u n i t l o n g e r t h a n the h o m o a l l y l i c r e a g e n t 253. T h e t e n d e n c y o f t h e e l e c t r o p h i l e 39 to e l i m i n a t e d u r i n g t h e a l k y l a t i o n s t e p w a s r e m o v e d . T h e r e f o r e , t h e b i c y c l i c k e t o n e 60, r a t h e r t h a n t h e c o r r e s p o n d i n g d i m e t h y l h y d r a z o n e , w a s u s e d f o r t h e a l k y l a t i o n s t e p t o p r o v i d e the a d d u c t 267 (Scheme 42). T h e s e c o n d m e t h y l a t i o n p r o c e e d e d as d e s i r e d to p r o v i d e 268. T h e r e m a i n d e r o f t h e a n n u l a t i o n s e q u e n c e p r o c e e d e d as e x p e c t e d . T h u s , t i n - i o d i n e e x c h a n g e o c c u r r e d w i t h r e t e n t i o n o f c o n f i g u r a t i o n to p r o v i d e t h e ( Z ) - a l k e n y l i o d i d e 269. C y c l i z a t i o n u s i n g n - B u L i w a s f o l l o w e d b y o x i d a t i v e r e a r r a n g e m e n t o f t h e r e s u l t a n t a l l y l i c a l c o h o l to p r o v i d e t h e c y c l o h e p t e n o n e 270. 8 3 1) KDA, THF -78 \u00C2\u00B0C 2) H M P A S n B u 3 S n B u 3 -78 \u00C2\u00B0C to -48 \u00C2\u00B0C to rt 1) n-BuLi, THF 0\u00C2\u00B0Ctort(71%) 2) PCC-alumina 3 A mol. sieves C H 2 C I 2 , reflux (72%) 1) LDA, THF -78 \u00C2\u00B0C l 2 , C H 2 C I 2 , rt | ' (94%) 268, X = S n B u 3 , (86%) 269, X = I S c h e m e 42 84 2.1.5.3. Preparation of the Tricyclic Ketone 171. T h e i n a b i l i t y o f t h e n e w l y d e v e l o p e d c y c l o h e x e n o n e a n n u l a t i o n p r o t o c o l to a p p e n d t h e d e s i r e d s i x - m e m b e r e d r i n g i n t h e n a t u r a l p r o d u c t s y n t h e s i s r e s u l t e d i n a d i f f e r e n t s e q u e n c e b e i n g p u r s u e d . A m o r e c l a s s i c a l a p p r o a c h t o w a r d t h e s y n t h e s i s o f t h e c y c l o h e x e n o n e r i n g o f 271 i s t h e b a s e - c a t a l y z e d i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n o f t h e s u i t a b l y f u n c t i o n a l i z e d 1 , 5 - d i k e t o n e 272. A p o t e n t i a l p r o b l e m w i t h t h i s a p p r o a c h i s t h e e x t r e m e l y h i n d e r e d n a t u r e o f t h e c a r b o n y l f u n c t i o n at C - l ( v e r r u c o s a n e n u m b e r i n g ) i n t h e d i k e t o n e p r e c u r s o r 273. T h i s c a r b o n y l i s f l a n k e d b y a q u a t e r n a r y c a r b o n a n d a t e r t i a r y c a r b o n . D u r i n g t h e a l d o l c o n d e n s a t i o n , C - l b e c o m e s s p 3 h y b r i d i z e d a n d the t e r t i a r y a l c o h o l t h u s f o r m e d 274 w o u l d b e i n a v e r y s t e r i c a l l y h i n d e r e d e n v i r o n m e n t (pa th A , Scheme 43). D u e to t h i s s t e r i c c o n g e s t i o n , a n a l t e r n a t i v e r e a c t i o n p a t h w a y c a n b e e n v i s a g e d ( p a t h B ) . A r e t r o - M i c h a e l r e a c t i o n w o u l d b e e n t r o p i c a l l y f a v o r e d a n d w o u l d r e s u l t i n the l o s s o f m e t h y l v i n y l k e t o n e (275) t o p r o v i d e the k e t o n e 276. 272 271 Scheme 43 C o m p o u n d 277, a n i n t e r m e d i a t e s i m i l a r to c o m p o u n d 273, w a s u s e d b y T o r i d u r i n g the t o t a l s y n t h e s i s o f a l l o c y a t h i n B 2 . 4 5 A t t e m p t e d W i t t i g r e a c t i o n s w i t h t h e c a r b o n y l c a r b o n ( C - l ) o f 277 w e r e u n s u c c e s s f u l . T h e i n a b i l i t y t o h o m o l o g a t e at C - l w a s a t t r i b u t e d to t h e h i n d e r e d n a t u r e o f that c a r b o n . T B D P S O 277 8 6 T h e p o t e n t i a l d i f f i c u l t y a s s o c i a t e d w i t h a p o s s i b l e c y c l i z a t i o n p r o c e e d i n g v i a a n a l d o l c o n d e n s a t i o n w a s a r e a s o n that p r o m p t e d t h e d e v e l o p m e n t o f a n e w a n n u l a t i o n s e q u e n c e that w o u l d f o r m t h e s i x - m e m b e r e d r i n g u n d e r k i n e t i c c o n d i t i o n s . D e s p i t e t h e s e c o n c e r n s a n a l d o l c y c l i z a t i o n a p p r o a c h w a s a t t e m p t e d . I n o r d e r t o i n v e s t i g a t e t h e i n t r a m o l e c u l a r a l d o l c o n d e n s a t i o n , a n e w f o u r - c a r b o n e l e c t r o p h i l e w a s n e e d e d . T h e r e q u i r e d r e a g e n t n e e d e d a m a s k e d k e t o n e f u n c t i o n w h i c h c o u l d b e r e a d i l y d e p l o y e d a f t e r t h e s e c o n d a l k y l a t i o n w i t h m e t h y l i o d i d e . T h e p r e p a r a t i o n o f t h e m e t h y l v i n y l k e t o n e e q u i v a l e n t s 278 9 4 a n d 279 9 5 h a v e b e e n d e s c r i b e d . T h e f i r s t e l e c t r o p h i l e u s e d w a s c o m p o u n d 279, w h o s e s y n t h e s i s i s d e s c r i b e d b e l o w . 2 - M e t h y l - 2 - ( 2 - i o d o e t h y l ) - l , 3 - d i o x o l a n e (279) w a s p r e p a r e d a c c o r d i n g to the m e t h o d o f S t o w e l l . 9 5 A q u e o u s h y d r i o d i c a c i d ( H I ) w a s a d d e d to m e t h y l v i n y l k e t o n e i n b e n z e n e a n d the r e s u l t a n t p r o d u c t w a s k e t a l i z e d w i t h e t h y l e n e g l y c o l i n t h e p r e s e n c e o f p - t o l u e n e s u l f o n i c a c i d a n d w i t h a z e o t r o p i c r e m o v a l o f w a t e r ( e q u a t i o n 18). 278 X = Br 279 X = I O 2) H O C H 2 C H 2 O H , p-TsOH, azeotropic distillation (18) 275 279 A t t e m p t e d a l k y l a t i o n s o f t h e b i c y c l i c k e t o n e 60 w i t h t h e i o d o k e t a l 279 d i d n o t p r o v i d e s i g n i f i c a n t a m o u n t s o f a l k y l a t e d a d d u c t s . T h e u s e o f t h e s l i g h t l y m o d i f i e d e l e c t r o p h i l e 280 w a s e q u a l l y u n s u c c e s s f u l ( e q u a t i o n 19). 87 o u V H ? 1) base 2) 60 or starting + trace alkylated material products (19) H o w e v e r , a l k y l a t i o n o f 60 w a s p o s s i b l e u s i n g t h e b i f u n c t i o n a l r e a g e n t 281. C o m p o u n d 281, w h i c h c o n t a i n s a l a t e n t c a r b o n y l g r o u p i n t h e f o r m o f a tert-b u t y l d i m e t h y l s i l y l e t h e r , w a s p r e p a r e d b y a n e f f i c i e n t t h r e e s t e p s e q u e n c e s t a r t i n g f r o m m e t h y l v i n y l k e t o n e (275). T r e a t m e n t o f m e t h y l v i n y l k e t o n e w i t h h y d r i o d i c a c i d i n b e n z e n e , f o l l o w e d b y i m m e d i a t e r e d u c t i o n o f the c r u d e p r o d u c t w i t h d i i s o b u t y l a l u m i n u m h y d r i d e i n b e n z e n e at 0 \u00C2\u00B0C g a v e 4 - i o d o b u t a n - 2 - o l (282). T r e a t m e n t o f t h e c r u d e a l c o h o l 282 w i t h tert-b u t y l d i m e t h y l s i l y l c h l o r i d e i n m e t h y l e n e c h l o r i d e i n t h e p r e s e n c e o f i m i d a z o l e p r o v i d e d the r e q u i r e d i o d i d e 281 i n 7 8 % y i e l d f r o m m e t h y l v i n y l k e t o n e (Scheme 44). O O H 1) HI, benzene, rt 2) DIBAL-H, 0 \u00C2\u00B0C TBSCI. imidazole C H 2 C I 2 , rt 275 282 Scheme 44 O T B S 2 3 1 78% 281 T h e * H n m r s p e c t r u m o f 281 i n d i c a t e d t h e p r e s e n c e o f a terf-butyldimethylsilyl e t h e r b y the p r e s e n c e o f t w o t h r e e p r o t o n s i n g l e t s at 8 0 . 0 6 a n d 8 0 . 0 7 f o r t h e d i a s t e r e o t o p i c m e t h y l g r o u p s a n d a n i n e p r o t o n s i n g l e t at 8 0 . 8 7 f o r the terf-butyl g r o u p . A d o u b l e t f o r t h e m e t h y l g r o u p at C - l i s p r e s e n t at 8 1 .13 (J = 6 . 6 H z ) a n d t h e m e t h y l e n e g r o u p a t C - 4 a p p e a r s as a m u l t i p l e t at 8 3 . 8 2 - 3 . 9 2 . T r e a t m e n t o f t h e b i c y c l i c k e t o n e 60 w i t h p o t a s s i u m 1 , 1 , 1 , 3 , 3 , 3 -h e x a m e t h y l d i s i l a z i d e 9 6 i n T H F , f o l l o w e d b y a d d i t i o n o f t h e b i f u n c t i o n a l r e a g e n t 281 a n d H M P A , g a v e a m i x t u r e o f p r o d u c t s ( e q u a t i o n 20). M o n i t o r i n g the p r o g r e s s o f t h e r e a c t i o n b y t i c i n d i c a t e d t h e a p p e a r a n c e o f o n e m a j o r p r o d u c t i n t h e e a r l y s t a g e s o f t h e r e a c t i o n . O v e r t i m e , t h e a m o u n t o f t h i s p r o d u c t d e c r e a s e s w i t h c o n c o m i t a n t f o r m a t i o n o f a c o n s i d e r a b l y l e s s p o l a r s p o t o n t h e t h i n l a y e r c h r o m a t o g r a m . T h e i n i t i a l l y f o r m e d m a t e r i a l w a s a n i n s e p a r a b l e d i a s t e r e o m e r i c m i x t u r e o f a l k y l a t e d c o m p o u n d s i n w h i c h t h e s i d e c h a i n w a s i n a n a x i a l o r i e n t a t i o n 283. A s t h e r e a c t i o n p r o c e e d e d , c o m p o u n d s 283 i s o m e r i z e d to t h e t h e r m o d y n a m i c a l l y m o r e s t a b l e m i x t u r e o f d i a s t e r e o m e r s 284, w i t h t h e s i d e c h a i n i n t h e e q u a t o r i a l p o s i t i o n . C o m p o u n d s 283 a n d 284 w e r e i s o l a t e d i n 1 4 % a n d 6 6 % y i e l d , r e s p e c t i v e l y . 9 7 A s m a l l a m o u n t o f s t a r t i n g m a t e r i a l 60 ( 1 2 % ) w a s a l s o r e c o v e r e d . T h u s , t h e a l k y l a t i o n p r o c e e d e d i n 8 0 % o v e r a l l y i e l d ( 9 0 % b a s e d o n r e a c t e d k e t o n e 60). T r a c e a m o u n t s o f d i a l k y l a t e d p r o d u c t s 285 w e r e a l s o o b s e r v e d . T h e u s e o f H M P A as a n a d d i t i v e a n d g r a d u a l w a r m i n g o f the r e a c t i o n m i x t u r e m i n i m i z e d the a m o u n t o f 285. I n t e r e s t i n g l y , t h e t w o d i a s t e r e o m e r s o f 283 a n d 284 w e r e n o t f o r m e d i n e q u a l a m o u n t s . I n e a c h c a s e , t h e m a j o r a n d m i n o r d i a s t e r e o m e r s w e r e p r e s e n t i n r a t i o s o f - 2 - 4 : 1 . T h i s r e s u l t i s n o t u n e x p e c t e d s i n c e t h e t w o t r a n s i t i o n s ta tes l e a d i n g to c o m p o u n d 283 a r e d i a s t e r e o m e r i c . D e s p i t e t h e p a i r s o f d i a s t e r e o m e r s o f 283 a n d 284 e a c h b e i n g i n s e p a r a b l e b y s i l i c a g e l c h r o m a t o g r a p h y , t h e lH n m r s p e c t r a w e r e r e a d i l y i n t e r p r e t e d . T h e s p e c t r a s u p p o r t e d the s t r u c t u r a l a s s i g n m e n t s , a n d e x h i b i t e d o n l y s l i g h t b r o a d e n i n g o f m o s t o f t h e s i g n a l s . A s e p a r a t e s i g n a l f o r e a c h o f t h e d i a s t e r e o m e r s w a s s e e n o n l y f o r c e r t a i n r e s o n a n c e s . T h e * H n m r s p e c t r u m o f c o m p o u n d 283 d i s p l a y s s i g n a l s f o r t h e m e t h y l g r o u p s o f t h e tert-b u t y l d i m e t h y l s i l y l f u n c t i o n at 8 0 . 0 1 a n d 0 . 0 2 a n d a n i n e p r o t o n s i n g l e t at 8 0 . 8 6 f o r t h e tert-b u t y l m o i e t y . T h e r e s o n a n c e f o r t h e a n g u l a r m e t h y l g r o u p s ( M e - 2 0 ) i s p r e s e n t at 8 0 .74 , w h i l e t h e m e t h y l g r o u p s a d j a c e n t to t h e T B S - p r o t e c t e d a l c o h o l ( C - 2 ) a p p e a r as t w o d o u b l e t s at 8 1.06 a n d 1.08 (7 = 6 .2 H z i n e a c h c a s e ) . T h e v i n y l m e t h y l g r o u p s ( M e - 1 7 ) a p p e a r as a b r o a d s i n g l e t at 8 1 .69 . T h e a n g u l a r p r o t o n s ( H - 1 4 ) a re a t t r i b u t e d to t w o d o u b l e t s at 8 2 . 6 5 a n d 2 . 6 8 w i t h i d e n t i c a l c o u p l i n g c o n s t a n t s ( 7 = 1 1 . 1 H z ) . T h e d i a s t e r e o m e r s o f 284 e x h i b i t e d v e r y s i m i l a r r e s o n a n c e s . T h e p r e s e n c e o f a terr-butyl g r o u p w a s i n d i c a t e d b y r e s o n a n c e s at 8 0 . 0 2 a n d 0 . 8 6 . T h e r e s o n a n c e s f o r t h e a n g u l a r m e t h y l g r o u p s ( M e - 2 0 ) a p p e a r at 8 0 . 7 0 . T h e m e t h y l g r o u p s n e x t to t h e s i l y l e t h e r m o i e t y ( C - 2 ) a p p e a r as a d o u b l e t at 8 1 .09 ( 7 = 6.1 H z ) , w h i l e t h e v i n y l m e t h y l g r o u p s ( M e - 1 7 ) a re at 8 1 .69. T h e 1 3 C n m r s p e c t r a o f 283 a n d 284 c l e a r l y i n d i c a t e d the p r e s e n c e o f d i a s t e r e o m e r i c p a i r s o f c o m p o u n d s , s i n c e m a n y o f the s i g n a l s a re d o u b l e d . C o m p o u n d s 283 a n d 284 w e r e s h o w n to b e e p i m e r i c at C - 7 ( v e r r u c o s a n e n u m b e r i n g ) b y t w o e x p e r i m e n t s t h a t i n v e r t e d t h e c o n f i g u r a t i o n at t h i s s i t e . T r e a t m e n t o f 283 w i t h N a O M e / M e O H at r e f l u x p r o v i d e d 284, i n d i c a t i n g tha t t h e m o s t s t a b l e c o m p o u n d w a s , as e x p e c t e d , t h e a d d u c t w i t h t h e s i d e c h a i n i n a n e q u a t o r i a l o r i e n t a t i o n (Scheme 45). I n a s e c o n d e x p e r i m e n t , t r e a t m e n t o f 283 w i t h L D A i n T H F at - 7 8 \u00C2\u00B0C, f o l l o w e d b y q u e n c h i n g the e n o l a t e 2 8 6 w i t h w a t e r at l o w t e m p e r a t u r e ( - 7 8 \u00C2\u00B0C) , p r o v i d e d e x c l u s i v e l y c o m p o u n d 2 8 4 (Scheme 45 ) . 2 8 6 Scheme 4 5 T h e l a t t e r e x p e r i m e n t i n d i c a t e d t h a t p r o t o n a t i o n o f t h e e n o l a t e 2 8 6 o c c u r r e d s t e r e o s e l e c t i v e l y a n d d e l i v e r e d the p r o t o n a x i a l l y . T h i s r e s u l t w a s i m p o r t a n t i n t w o r e s p e c t s . F i r s t l y , i t i n d i c a t e d that t h e e q u a t o r i a l p r o t o n at C - 7 i n 2 8 3 c o u l d b e a b s t r a c t e d w i t h a s t r o n g b a s e t o p r o v i d e t h e e n o l a t e 2 8 6 . T h e f o l l o w i n g s tep i n t h e s y n t h e t i c s e q u e n c e i n v o l v e d a l k y l a t i o n w i t h m e t h y l i o d i d e a n d t h e f o u r d i a s t e r e o m e r s , 2 8 3 a n d 2 8 4 , c o u l d b e c o m b i n e d s i n c e t h e y w o u l d a f f o r d the s a m e e n o l a t e a n i o n 2 8 6 . D u r i n g the a t t e m p t e d a l k y l a t i o n o f t h e h y d r a z o n e 2 1 0 at C - 7 , a n a l l y l i c p r o t o n i n t h e s i d e c h a i n w a s a b s t r a c t e d i n p r e f e r e n c e to t h e e q u a t o r i a l p r o t o n (vide supra, Scheme 4 0 , p a g e 7 9 ) . S e c o n d l y , p r o t o n a t i o n o f t h e e n o l a t e a n i o n 2 8 6 o c c u r r e d s t e r e o s e l e c t i v e l y f r o m the a - f a c e a n d i t w a s e x p e c t e d tha t m e t h y l a t i o n o f 2 8 6 w o u l d o c c u r f r o m t h e s a m e f a c e . T h u s , a l l f o u r d i a s t e r e o m e r s , 2 8 3 a n d 2 8 4 , c o u l d b e c o m b i n e d s i n c e t h e y w o u l d e v e n t u a l l y c o n v e r g e to a s i n g l e p r o d u c t . W h e n a m i x t u r e o f 2 8 3 a n d 2 8 4 w a s t r e a t e d w i t h L D A i n T H F a n d m e t h y l i o d i d e w a s a d d e d t o t h e r e s u l t a n t s o l u t i o n , a m i x t u r e o f t w o d i a s t e r e o m e r s 2 8 7 w a s o b t a i n e d i n 9 6 % y i e l d ( e q u a t i o n 2 1 ) . T h e f a c t t ha t 287 c o n s i s t e d o f o n l y t w o d i a s t e r e o m e r s i n d i c a t e d that t h e m e t h y l a t i o n s t e p h a d o c c u r r e d w i t h v e r y h i g h s t e r e o s e l e c t i v i t y . T h e m e t h y l g r o u p ' s a x i a l o r i e n t a t i o n (see Scheme 41) w a s v e r i f i e d b y * H n m r N O E d i f f e r e n c e e x p e r i m e n t s o n a l a t e r c o m p o u n d d e r i v e d f r o m 287, b u t w h i c h e x i s t e d as a s i n g l e d i a s t e r e o m e r (vide infra). T h e t w o d i a s t e r e o m e r s i n 287 w e r e n o t s e p a r a b l e b y s i l i c a g e l c h r o m a t o g r a p h y a n d w e r e t h e r e f o r e c h a r a c t e r i z e d as a m i x t u r e . T h e * H n m r s p e c t r u m o f 287 i n d i c a t e d tha t m e t h y l a t i o n h a d o c c u r r e d a t C - 7 . T h e terf-butyldimethyl s i l y l g r o u p r e m a i n e d i n t a c t as i n d i c a t e d b y s i n g l e t s at 8 0 . 0 2 a n d 0 . 8 6 . T h e a n g u l a r m e t h y l g r o u p ( M e - 2 0 ) a p p e a r e d as t w o s i n g l e t s at 8 0 . 6 9 a n d 0 . 7 0 , w h e r e a s t h e m e t h y l g r o u p a d j a c e n t to t h e T B S O g r o u p ( C - 2 ) a p p e a r s as a d o u b l e t at 8 1.11 (J = 5 .9 H z ) . T h e n e w l y i n t r o d u c e d m e t h y l g r o u p ( M e - 1 9 ) i s a t t r i b u t e d to a s i n g l e t at 8 1.17 a n d the v i n y l m e t h y l ( M e - 1 7 ) to a s i n g l e t at 8 1 .70. T h e s i g n a l f o r H - 1 4 ( v e r r u c o s a n e n u m b e r i n g ) i s p a r t o f a l o w f i e l d t w o p r o t o n m u l t i p l e t at 8 2 . 7 3 - 2 . 8 7 . T h e terf-butyldimethylsilyl g r o u p i n 287 w a s r e m o v e d u s i n g t e t r a - n - b u t y l a m m o n i u m f l u o r i d e i n T H F a n d p r o v i d e d 288 i n 9 8 % y i e l d ( e q u a t i o n 22). A g a i n , t h e m i x t u r e o f d i a s t e r e o m e r s o f 288 w a s i n s e p a r a b l e b y s i l i c a g e l c h r o m a t o g r a p h y . T h e p r e s e n c e o f t h e h y d r o x y l f u n c t i o n w a s i n d i c a t e d b y a b r o a d a b s o r p t i o n at 3 4 2 5 c m - 1 i n t h e IR s p e c t r u m o f 288. T i c a n a l y s i s s u g g e s t e d that t he re w a s a n e q u i l i b r i u m b e t w e e n the h e m i k e t a l 289 a n d t h e o p e n c h a i n h y d r o x y k e t o n e 288. S a m p l e s o f c h r o m a t o g r a p h i c a l l y p u r e 288 a l w a y s s h o w e d the p r e s e n c e o f a s m a l l a m o u n t o f a c o n s i d e r a b l y l e s s p o l a r s p o t o n t h e c h r o m a t o g r a m , w h i c h c o r r e s p o n d e d to 289. C o n v e r s e l y , w h e n t h e n o n - p o l a r c o m p o u n d 289 w a s i s o l a t e d b y 9 2 c o l u m n c h r o m a t o g r a p h y , the m o r e p o l a r s p o t c o r r e s p o n d i n g to t h e h y d r o x y k e t o n e 288 w o u l d a l s o a p p e a r o n t h e c h r o m a t o g r a m . (22) 289 T h e d i a s t e r e o m e r i c m i x t u r e o f a l c o h o l s 288 w a s o x i d i z e d w i t h p y r i d i n i u m c h l o r o c h r o m a t e i n m e t h y l e n e c h l o r i d e i n t h e p r e s e n c e o f Cel ite\u00C2\u00AE. T h e d i k e t o n e 273 w a s i s o l a t e d as a s i n g l e , c r y s t a l l i n e d i a s t e r e o m e r ( m p 7 0 . 0 - 7 0 . 5 \u00C2\u00B0C) i n 9 3 % y i e l d ( e q u a t i o n 23). 93% 288 273 9 3 T h e s p e c t r a l d a t a f o r c o m p o u n d 273 f u l l y s u p p o r t t h e s t r u c t u r a l a s s i g n m e n t . T h e TR s p e c t r u m o f 273 s h o w s a s t r o n g k e t o n e c a r b o n y l a b s o r p t i o n at 1 7 0 8 c m - 1 . T h e 1 3 C n m r s p e c t r u m s h o w e d t h e p r e s e n c e o f t w o k e t o n e c a r b o n y l f u n c t i o n s w i t h s i g n a l s at 8 2 0 9 . 1 a n d 2 1 3 . 6 . F o u r s h a r p m e t h y l s i n g l e t s a re e v i d e n t i n the * H n m r s p e c t r u m o f 273 at 8 0 . 6 9 , 1 . 1 9 , 1 .68 , a n d 2 . 1 1 c o r r e s p o n d i n g to M e - 2 0 , M e - 1 9 , M e - 1 7 a n d M e - 2 , r e s p e c t i v e l y . C O S Y c o r r e l a t i o n s d e t e r m i n e d u n a m b i g u o u s l y tha t t h e t w o o v e r l a p p i n g s i g n a l s a t 8 2 . 7 3 - 2 . 8 5 a r e d u e to t h e p r o t o n s H - 1 3 a n d H - 1 4 . T h e s i g n a l a t t r i b u t e d to H - 1 4 i s a d o u b l e t ( 7 = 11 H z ) s u p e r i m p o s e d o n a m u l t i p l e t . T h e C O S Y s p e c t r u m o f 273 s h o w s c o u p l i n g b e t w e e n H - 1 4 a n d H - 1 3 as w e l l as a s m a l l w - c o u p l i n g b e t w e e n H - 1 4 a n d M e - 2 0 . W i t h a s i n g l e d i a s t e r e o m e r i n h a n d , N O E d i f f e r e n c e e x p e r i m e n t s w e r e p e r f o r m e d o n c o m p o u n d 273 to d e t e r m i n e t h e c o n f i g u r a t i o n at C - 7 . I r r a d i a t i o n o f t h e s i g n a l at 8 1 .19 ( M e -19) c a u s e d a n e n h a n c e m e n t o f the s i g n a l o f H - 1 4 . I r r a d i a t i o n o f t h e m u l t i p l e t at 8 2 . 7 3 - 2 . 8 5 , w h i c h c o n t a i n s H - 1 3 a n d H - 1 4 , c a u s e d a n e n h a n c e m e n t o f t h e s i g n a l at 8 1 .19 ( M e - 1 9 ) . T h e s e N O E d i f f e r e n c e e x p e r i m e n t s i n d i c a t e that M e - 1 9 a n d H - 1 4 a r e o n t h e s a m e f a c e o f the m o l e c u l e . S i n c e H - 1 4 h a s a l r e a d y b e e n s h o w n to b e o n t h e a - s i d e o f t h e m o l e c u l e , t h e n M e -19 m u s t h a v e the d e s i r e d o r i e n t a t i o n i n 273 as s h o w n b e l o w . H H 273 H a v i n g s u c c e s s f u l l y s y n t h e s i z e d t h e d i o n e 273, t h e f e a s i b i l i t y o f t h e i n t r a m o l e c u l a r b a s e - c a t a l y z e d a l d o l r e a c t i o n to c y c l i z e the d e s i r e d c y c l o h e x e n o n e ring w a s t e s t e d . I t w a s 9 4 g r a t i f y i n g t o d i s c o v e r t h a t t r e a t m e n t o f 273 w i t h s o d i u m e t h o x i d e i n r e f l u x i n g e t h a n o l p r o v i d e d t h e d e s i r e d t r i c y c l i c e n o n e 72 i n 8 9 % y i e l d ( e q u a t i o n 24). T h e s t e r i c a l l y c r o w d e d e n v i r o n m e n t i n t h e v i c i n i t y o f t h e c a r b o n y l g r o u p at C - l ( v e r r u c o s a n e n u m b e r i n g ) i n 273 w a s n o t d e t r i m e n t a l t o t h e r e a c t i o n . T h e b i c y c l i c c o m p o u n d 276, w h i c h i s t h e r e s u l t o f a r e t r o - M i c h a e l r e a c t i o n ( p a t h B, Scheme 43, p a g e 8 5 ) , h a d b e e n p r e v i o u s l y s y n t h e s i z e d . 9 8 O n l y t r a c e a m o u n t s (<1%) o f c o m p o u n d 276 w e r e d e t e c t e d b y g a s -l i q u i d c h r o m a t o g r a p h y . T h e s p e c t r o s c o p i c d a t a f o r t h e t r i c y c l i c e n o n e 72 f u l l y s u p p o r t e d i t s s t r u c t u r a l a s s i g n m e n t . T h e I R s p e c t r u m o f 72 c o n t a i n s a n a b s o r p t i o n at 1 6 7 4 c m \" 1 i n d i c a t i n g t h e p r e s e n c e o f a n a , f 3 - u n s a t u r a t e d k e t o n e f u n c t i o n . I n a d d i t i o n , t h e 1 3 C n m r s p e c t r u m s h o w s a s i n g l e c a r b o n y l s i g n a l at 8 1 9 9 . 6 a n d o l e f i n i c s i g n a l s at 8 1 6 9 . 7 a n d 1 2 3 . 5 f o r C - l a n d C - 2 , r e s p e c t i v e l y . T h e *H n m r s p e c t r u m o f 72 e x h i b i t s a l o w f i e l d s i n g l e t f o r H -2 at 8 5 . 6 5 . T h e p r e p a r a t i o n o f the a d v a n c e d i n t e r m e d i a t e 171, w h i c h i s t h e b r a n c h i n g p o i n t o f the s y n t h e t i c r o u t e s d i r e c t e d t o w a r d s the c y a t h a n e 64 a n d v e r r u c o s a n e - t y p e f a m i l y n o w r e q u i r e d a d i s s o l v i n g m e t a l r e d u c t i o n o f t h e e n o n e f u n c t i o n o f 72 t o a f f o r d t h e trans-anti-trans a r r a n g e m e n t p r e s e n t i n the 6 - 6 - 5 t r i c y c l i c p o r t i o n o f t h e n a t u r a l p r o d u c t s 61-64. T h e p a t h w a y f o r t h e c o n j u g a t e r e d u c t i o n o f oc , P - unsaturated c a r b o n y l c o m p o u n d s w i t h m e t a l s ( L i , N a , e t c . ) i n l i q u i d a m m o n i a i s d e p i c t e d i n Scheme 46. A n e n o n e s u b s t r a t e , s u c h as 290, r e c e i v e s t w o e l e c t r o n s f r o m t h e m e t a l t o g i v e the d i a n i o n i n t e r m e d i a t e 291. T h i s i n t e r m e d i a t e i s p r o t o n a t e d to a f f o r d t h e e n o l a t e s a l t 292, w h i c h r e a c t s w i t h a n a p p r o p r i a t e 9 5 p r o t o n d o n o r , u s u a l l y a n a l c o h o l t ha t i s a d d e d to the r e d u c t i o n m i x t u r e , t o g i v e t h e k e t o n e 293. T h e s t e r e o c h e m i s t r y o f t h e c o n j u g a t e r e d u c t i o n i s e s t a b l i s h e d d u r i n g t h e p r o t o n t r a n s f e r to t h e f 3 - carbon . 6 7 T h i s t o p i c h a s b e e n r e v i e w e d b y C a i n e \" b u t o n l y t h e s a l i e n t f e a t u r e s w i l l be d i s c u s s e d h e r e . 1 0 0 T h e s t e r e o c h e m i c a l r e s u l t s o f t h e s e r e d u c t i o n s u s u a l l y r e f l e c t t w o b a s i c r e q u i r e m e n t s . T h e f i r s t i s a s t e r e o e l e c t r o n i c p r e f e r e n c e f o r p r o t o n a t i o n p e r p e n d i c u l a r to the e n o l a t e T C - s y s t e m s i n c e a s t a b i l i z i n g i n t e r a c t i o n w i t h t h e p - c a r b o n o r b i t a l i s m a i n t a i n e d . G i v e n tha t t h i s r e q u i r e m e n t i s m e t , the s t e r e o c h e m i s t r y n o r m a l l y c o r r e s p o n d s to p r o t o n a t i o n o f the m o s t s t a b l e c o n f o r m a t i o n o f t h e d i a n i o n i n t e r m e d i a t e . I n t h e c a s e o f A 1 ' 9 - 2 - o c t a l o n e s 290, t h e r i n g j u n c t i o n o f t h e r e d u c t i o n p r o d u c t i s u s u a l l y trans (Scheme 47).67 I n the r e d u c t i o n o f 290, t h e i n t e r m e d i a t e e n o l a t e d i a n i o n c a n a d o p t the t h r e e d i f f e r e n t h a l f - c h a i r c o n f o r m a t i o n s 294, 295, a n d 296. O f t h e s e , o n l y 294 a n d 295 h a v e the l o n e p a i r e l e c t r o n s at the P - c a r b o n p a r a l l e l to t h e T C - o r b i t a l o f t h e e n o l a t e s y s t e m , a l l o w i n g f o r d e r e a l i z a t i o n . P r o t o n a t i o n o f 294 y i e l d s t h e trans a d d u c t 297, w h e r e a s p r o t o n a t i o n o f c o n f o r m e r 295 g i v e s t h e cis b i c y c l i c k e t o n e 298. I n s i m p l e c a s e s , c o n f o r m e r 96 294 i s m o r e s t a b l e t h a n 295 d u e t o f e w e r s t e r i c i n t e r a c t i o n s , a n d a x i a l p r o t o n a t i o n p r e d o m i n a t e s to a f f o r d t h e trans p r o d u c t 297. 290 294 297 9 0 D O O 296 E x c e p t i o n s to t h e p r e f e r e n c e f o r t h e f o r m a t i o n o f t h e trans r i n g f u s i o n a re u s u a l l y t h e r e s u l t o f u n f a v o r a b l e s t e r i c i n t e r a c t i o n s i n t h e c h a i r - c h a i r c o n f o r m a t i o n o f t h e d i a n i o n i n t e r m e d i a t e . I n Scheme 48, the m a j o r p r o d u c t h a s t h e cis r i n g f u s i o n b e c a u s e t h e c h a i r - c h a i r c o n f o r m e r 299 e x p e r i e n c e s a s e v e r e s t e r i c i n t e r a c t i o n b e t w e e n t h e b u l k y tert-butyl g r o u p a n d t h e m e t h y l g r o u p w h i c h a r e b o t h i n a x i a l p o s i t i o n s . T h i s u n f a v o r a b l e i n t e r a c t i o n i s n o t p resen t i n 300. frans-product c/s-product (minor) (major) Scheme 48 I n t h e c a s e o f t h e t r i c y c l i c e n o n e 72, o n l y t w o c o n f o r m e r s o f t h e d i a n i o n a r e p o s s i b l e w h e r e t h e l o n e p a i r o f e l e c t r o n s at the B - c a r b o n i s p a r a l l e l t o the 7 t -system o f the e n o l a t e (301 a n d 302). C o n f o r m e r 302 e x p e r i e n c e s a 1 , 3 - d i a x i a l i n t e r a c t i o n b e t w e e n M e - 2 0 a n d t h e C - l to C - 2 c a r b o n b o n d (Scheme 49), m a k i n g 301 t h e m o r e s t a b l e d i a n i o n c o n f o r m e r . A x i a l p r o t o n a t i o n o f 301 w o u l d p r o v i d e 171 w i t h t h e d e s i r e d trans r i n g f u s i o n . Scheme 49 T r e a t m e n t o f 72 w i t h l i t h i u m m e t a l i n l i q u i d a m m o n i a a n d T H F i n t h e p r e s e n c e o f tert-butanol a f f o r d e d t h e trans-fused t r i c y c l i c k e t o n e 171 i n 9 8 % y i e l d ( e q u a t i o n 25). S p e c t r o s c o p i c d a t a i n d i c a t e d that t h e e n o n e f u n c t i o n w a s r e d u c e d to t h e k e t o n e . T h e I R s p e c t r u m o f 171 d i s p l a y s a s t r e t c h at 1 7 1 3 c m - 1 , W h i c h i s i n d i c a t i v e o f a s a t u r a t e d k e t o n e c a r b o n y l . T h e c a r b o n y l c a r b o n s i g n a l a p p e a r s at 8 2 1 2 . 5 i n t h e 1 3 C n m r s p e c t r u m o f 171, w h i c h i s i n t h e e x p e c t e d r a n g e 1 0 1 f o r a s a t u r a t e d k e t o n e . T h e m e t h y l s i n g l e t s i n t h e * H n m r s p e c t r u m o f 171 a p p e a r at 8 0 . 7 9 , 1 .07 , a n d 1.65 f o r M e - 2 0 , M e - 1 9 , a n d M e - 1 7 ( v e r r u c o s a n e n u m b e r i n g ) , r e s p e c t i v e l y . C O S Y c o r r e l a t i o n s a l l o w e d f o r t h e a s s i g n m e n t o f a l l t h e p r o t o n s o f 171 i n the * H n m r s p e c t r u m . A m u l t i p l e t at 8 1 . 6 0 - 1 . 7 5 c o n t a i n s H - 1 , H - 6 e q , a n d the v i n y l m e t h y l g r o u p ( M e - 1 7 ) . S p e c t r o s c o p i c d a t a s u p p o r t i n g a trans r i n g f u s i o n w a s p r o v i d e d b y t h e s i g n a l f o r H - 2 a x w h i c h a p p e a r s as a d o u b l e t o f d o u b l e t s ( 7 = 1 4 . 2 , 1 4 . 2 H z ) at 8 2 . 0 6 . T h e t w o l a r g e c o u p l i n g c o n s t a n t s i n d i c a t e a g e m i n a l c o u p l i n g b e t w e e n H - 2 a x a n d H - 2 e q a n d , m o r e i m p o r t a n t l y , a n a x i a l - a x i a l c o u p l i n g b e t w e e n H - 2 a x a n d H - 1 w h i c h i s p o s s i b l e o n l y i f the r i n g f u s i o n i s trans. A d d i t i o n a l e v i d e n c e f o r t h e trans r i n g j u n c t i o n w a s s h o w n b y N O E d i f f e r e n c e e x p e r i m e n t s . I r r a d i a t i o n o f the s i g n a l at 8 0 . 7 9 ( M e - 2 0 ) s h o w e d a n e n h a n c e m e n t o f the s i g n a l f o r H - 1 , w h i c h e m e r g e d c l e a n l y f r o m the m u l t i p l e t at 8 1 . 6 0 - 1 . 7 5 as a d o u b l e t o f d o u b l e t o f d o u b l e t s at 8 1.65 (7 = 1 4 . 2 , 1 2 , 5 H z ) . T h i s i s p o s s i b l e o n l y i f M e - 2 0 a n d H - 1 are o n the s a m e f a c e o f t h e m o l e c u l e , t h u s i n d i c a t i n g a trans r i n g j u n c t i o n b e t w e e n t h e t w o s i x -m e m b e r e d r i n g s . I n a J H n m r N O E d i f f e r e n c e e x p e r i m e n t , i r r a d i a t i o n o f t h e m u l t i p l e t at 8 1 . 6 0 - 1 . 7 5 ( H - 1 , H - 6 e q , M e - 1 7 ) s h o w e d a n e n h a n c e m e n t f o r t h e m e t h y l g r o u p at 8 0 . 7 9 99 ( M e - 2 0 ) . O f t h e p r o t o n s i n t h e i r r a d i a t e d m u l t i p l e t ( H - l , H - 6 e q , a n d M e - 1 7 ) , o n l y H - l i s i n c l o s e e n o u g h p r o x i m i t y to M e - 2 0 to a f f e c t a n e n h a n c e m e n t o f t h e s i g n a l d u e to t h e l a t t e r m e t h y l g r o u p . T h i s r e s u l t f u r t h e r s u p p o r t s t h e s t e r e o c h e m i c a l a s s i g n m e n t o f a trans r i n g f u s i o n . T h e s y n t h e s i s o f t h e a d v a n c e d t r i c y c l i c i n t e r m e d i a t e 1 7 1 , c o n t a i n i n g t h e f i v e c o n t i g u o u s s t e r e o c e n t e r s w i t h t h e c o r r e c t r e l a t i v e s t e r e o c h e m i s t r y , w a s c o m p l e t e . F r o m t h i s c o m p o u n d , d i v e r g i n g s y n t h e t i c r o u t e s c o u l d l e a d t o t h e s y n t h e s i s o f t h e v e r r u c o s a n e - t y p e f a m i l y o f n a t u r a l p r o d u c t s o r the s y n t h e s i s o f t h e c y a t h a n e 64 . T h e s y n t h e s i s o f m e m b e r s o f t h e v e r r u c o s a n e - t y p e f a m i l y w a s i n v e s t i g a t e d f i r s t . '19 171 1 0 0 2 . 1 . 5 . 4 . Preparation of the Tricyclic Enone 1 7 4 . A l l m e m b e r s o f t h e v e r r u c o s a n e - t y p e f a m i l y o f n a t u r a l p r o d u c t s c o n t a i n a s a t u r a t e d t h r e e c a r b o n u n i t at C - 1 3 ( v e r r u c o s a n e n u m b e r i n g ) . T h e r e f o r e , t h e s y n t h e s i s o f 6 1 - 6 3 f r o m c o m p o u n d 1 7 1 r e q u i r e d h y d r o g e n a t i o n o f t h e i s o p r o p e n y l g r o u p a t C - 1 3 t o g i v e a n i s o p r o p y l m o i e t y . A t t e m p t e d h y d r o g e n a t i o n o f 1 7 1 w i t h 1 0 % p a l l a d i u m o n c h a r c o a l i n m e t h a n o l at r o o m t e m p e r a t u r e a f f o r d e d a m i x t u r e o f f o u r m a j o r c o m p o u n d s ( e q u a t i o n 2 6 ) . T w o o f t h e s e w e r e t h e r e c o v e r e d s t a r t i n g m a t e r i a l 1 7 1 a n d t h e e x p e c t e d r e d u c e d p r o d u c t 3 0 3 . T h e r e m a i n i n g t w o p r o d u c t s p o s s e s s e d n m r s p e c t r a that w e r e v i r t u a l l y i d e n t i c a l w i t h t h o s e o f 1 7 1 a n d 3 0 3 , r e s p e c t i v e l y , s u g g e s t i n g tha t t h e y m a y h a v e s t r u c t u r e s 3 0 4 a n d 3 0 5 w h i c h a re e p i m e r i c w i t h 3 0 3 a n d 1 7 1 at C - 1 3 . O O 3 0 4 3 0 5 P a l l a d i u m i s k n o w n to c a t a l y z e the i s o m e r i z a t i o n o f d o u b l e b o n d s . 6 1 * > 1 0 2 M i g r a t i o n o f the d o u b l e b o n d i n 1 7 1 f r o m C - 1 5 - C - 1 6 to C - 1 5 - C - 1 3 w o u l d r e s u l t i n e l i m i n a t i o n o f the s t e r e o g e n i c c e n t e r at C - 1 3 . T h e v e r r u c o s a n e - t y p e f a m i l y o f n a t u r a l p r o d u c t s c o n t a i n s s u b c l a s s e s o f c o m p o u n d s i n w h i c h t h e s i d e c h a i n at C - 1 3 h a s a (3 o r i e n t a t i o n ( see \3-epi-n e o v e r r u c o s a n - 5 B - o l (76) a n d 1 3 - e / n ' - h o m o v e r r u c o s a n - 5 B - o l (77), p a g e 17 ) . H o w e v e r , f o r t h e s y n t h e s i s o f 61-63 a s o l u t i o n t o the p r o b l e m o f d o u b l e b o n d i s o m e r i z a t i o n w a s n e c e s s a r y . P l a t i n u m c a t a l y s t s a r e g e n e r a l l y n o t e f f e c t i v e f o r t h e i s o m e r i z a t i o n o f o l e f i n s . 1 0 2 H y d r o g e n a t i o n o f 171 w i t h 5 % p l a t i n u m o n a l u m i n a i n m e t h a n o l at r o o m t e m p e r a t u r e p r o c e e d e d s l o w l y a n d a f f o r d e d k e t o n e 303 a n d t h e o v e r - r e d u c e d a l c o h o l 306. B y c h a n g i n g t h e h y d r o g e n a t i o n c o n d i t i o n s t o p l a t i n u m o x i d e (PtC\u00C2\u00AB2) i n e t h y l a c e t a t e , t h e r e a c t i o n p r o c e e d e d q u i c k l y a n d c l e a n l y p r o v i d e d c o m p o u n d s 303 a n d 306 i n 5 5 % a n d 4 1 % y i e l d , r e s p e c t i v e l y (Scheme 50). C o m p o u n d 306 c o n s i s t e d o f a m i x t u r e o f e p i m e r i c a l c o h o l s i n a r a t i o o f a p p r o x i m a t e l y 1 5 : 1 , w h i c h w a s s e p a r a t e d f r o m c o m p o u n d 303 b y c h r o m a t o g r a p h y w i t h s i l i c a g e l . T h e m i x t u r e o f a l c o h o l s 306 w a s i m m e d i a t e l y o x i d i z e d to 171 w i t h p y r i d i n i u m c h l o r o c h r o m a t e i n t h e p r e s e n c e o f Celite\u00C2\u00AE i n m e t h y l e n e c h l o r i d e . T h i s t w o s tep p r o c e s s a f f o r d e d the k e t o n e 303 i n 9 5 % o v e r a l l y i e l d f r o m 171. O O H O 171 306 303 I P C C , Celite t C H 2 C I 2 , rt 95% overall yield Scheme 50 T w o d o u b l e t s i n t h e ! H n m r s p e c t r u m o f 303 at 8 0 . 7 4 a n d 0 . 8 2 ( 7 = 6 . 8 H z e a c h ) i n d i c a t e that t h e i s o p r o p e n y l g r o u p has b e e n r e d u c e d to a n i s o p r o p y l m o i e t y . T h e n e x t s t e p i n t h e s y n t h e t i c s e q u e n c e i n v o l v e d the i n t r o d u c t i o n o f a h y d r o x y l g r o u p at C - 5 ( v e r r u c o s a n e n u m b e r i n g ) . A n u m b e r o f m e t h o d s a re k n o w n f o r t h e p r e p a r a t i o n o f a -1 0 2 h y d r o x y c a r b o n y l c o m p o u n d s , 1 0 3 t h e m o s t p r a c t i c a l a n d s i m p l e s t o f t h e s e b e i n g d i r e c t o x i d a t i o n o f a n e n o l a t e a n i o n . M o l e c u l a r m o d e l s r e v e a l e d tha t t h e i s o p r o p y l g r o u p at C - 1 3 i n 303 h i n d e r s t h e m e t h y l e n e g r o u p at C - 2 r e l a t i v e t o C - 5 a n d t h u s , t r e a t m e n t o f 303 w i t h a s t r o n g h i n d e r e d b a s e w o u l d l i k e l y r e s u l t i n a b s t r a c t i o n o f a p r o t o n f r o m C - 5 . O x y g e n t r a n s f e r a g e n t s that h a v e b e e n s u c c e s s f u l l y u s e d f o r t h e d i r e c t o x i d a t i o n o f e n o l a t e s i n c l u d e 3 - p h e n y l -2 - p h e n y l s u l f o n y l o x a z i r i d i n e (307), 1 0 4 t h e m o l y b d e n u m p e r o x i d e r e a g e n t M o 0 5 \u00C2\u00BB p y r i d i n e \u00C2\u00BB H M P A ( M o O P H ) (308),105 b i s ( t r i m e t h y l s i l y l ) p e r o x i d e (309),106 d i m e t h y l d i o x i r a n e (310),107 a n d m o l e c u l a r o x y g e n (O2) . 1 0 8 S 0 2 Ph M \u00C2\u00B0^ Ph H 307 0 ^ 9 / 0 Mo / = N O M e 3 S i O - O S i M e 3 / = i \ o P ( N M e 2 ) 3 308 309 0-0 310 D a v i s ' s u l f o n y l o x a z i r i d i n e 307 w a s the f i r s t r e a g e n t i n v e s t i g a t e d . 1 0 9 T r e a t m e n t o f 303 w i t h K H M D S , 9 6 f o l l o w e d b y a d d i t i o n o f 307, a f f o r d e d t h e a l c o h o l 311 as a s i n g l e d i a s t e r e o m e r i n 4 5 % y i e l d (Scheme 51). O K + H O H 307, THF H or 310, acetone (inverse addition) 312 Scheme 51 103 T h e p r e s e n c e o f a h y d r o x y l m o i e t y i s i n d i c a t e d b y a b r o a d - O H a b s o r p t i o n i n t h e I R s p e c t r u m o f 311 at 3 4 8 9 c m \" 1 a n d b y t h e s i g n a l at 8 3 . 4 9 i n t h e n m r s p e c t r u m tha t e x c h a n g e s u p o n t r e a t m e n t w i t h D2O. T h e s i g n a l d u e to t h e c a r b i n o l p r o t o n ( H - 5 ) i n 311 i s l o c a t e d at 8 4 . 2 5 ( b r d d , 7 = 12 , 7 . 2 H z ) . T h e m a g n i t u d e o f t h e c o u p l i n g c o n s t a n t s f o r H - 5 s u g g e s t e d t h a t i t i s i n t h e a o r i e n t a t i o n s i n c e i t e x h i b i t s o n e l a r g e a x i a l - a x i a l c o u p l i n g ( 7 = 12 H z ) a n d o n e s m a l l e r a x i a l - e q u a t o r i a l c o u p l i n g ( 7 = 7 . 2 H z ) ( s e e d i a g r a m b e l o w ) . T h e c o u p l i n g c o n s t a n t s f o r t h e s i g n a l a t t r i b u t e d to H - 6 e q at 8 2 . 1 9 (7 = 1 2 , 7 . 2 H z ) r e f l e c t a l a r g e g e m i n a l c o u p l i n g w i t h H - 6 a x ( 7 = 1 2 H z ) a n d a s m a l l e r e q u a t o r i a l - a x i a l c o u p l i n g w i t h H - 5 (7 = 7 . 2 H z ) . T h e H - 2 p r o t o n s a r e d e s h i e l d e d b y t h e a d j a c e n t c a r b o n y l g r o u p a n d a p p e a r at 8 2 .31 ( d d d , 7 = 1 4 . 0 , 1 4 . 0 , 1.1 H z ) a n d 8 2 . 5 5 ( d d , 7 = 1 4 . 0 , 3 . 9 H z ) f o r H - 2 a x a n d H - 2 e q , r e s p e c t i v e l y . T h e o b s e r v e d m u l t i p l i c i t y a n d the c o u p l i n g c o n s t a n t s f o r b o t h H - 2 p r o t o n s a re c o n s i s t e n t w i t h h y d r o x y l a t i o n at C - 5 . F i n a l l y , N O E e x p e r i m e n t s u n e q u i v o c a l l y c o n f i r m e d the c o n f i g u r a t i o n at C - 5 . I r r a d i a t i o n o f t h e s i g n a l at 8 4 . 2 5 ( H - 5 ) c a u s e d a n e n h a n c e m e n t o f t h e s i g n a l at 8 1 .13 ( M e - 1 9 ) a n d v i c e v e r s a , i n d i c a t i n g tha t t h e s e t w o g r o u p s a r e i n a 1 , 3 -d i a x i a l r e l a t i o n s h i p . T r e a t m e n t o f t h e p o t a s s i u m e n o l a t e 312 w i t h 307 p r o v i d e d t h e r e g i o - a n d s t e r e o c h e m i c a l l y d e s i r e d a - h y d r o x y l a t e d p r o d u c t 311, b u t i n l o w y i e l d ( 4 5 % ) . I n a d d i t i o n , t h e 3 - p h e n y l - 2 - p h e n y l s u l f o n y l o x a z i r i d i n e b y - p r o d u c t s w e r e d i f f i c u l t to s e p a r a t e f r o m 311 b y c o l u m n c h r o m a t o g r a p h y . T h e u s e o f d i m e t h y l d i o x i r a n e as t h e e l e c t r o p h i l i c o x i d a n t O 311 a m e l i o r a t e d t h e s e p r o b l e m s . T h u s , a d d i t i o n o f a s o l u t i o n o f 312 i n T H F to a s o l u t i o n o f d i m e t h y l d i o x i r a n e 310 i n a c e t o n e 1 1 0 at - 7 8 \u00C2\u00B0C p r o v i d e d 311 i n 8 1 % y i e l d , as w e l l as 4 % r e c o v e r y o f s t a r t i n g m a t e r i a l (Scheme 51). T h e s m a l l a m o u n t o f r e c o v e r e d s t a r t i n g m a t e r i a l 303 w a s l i k e l y d u e to a c o m p e t i n g p r o t o n t r a n s f e r r e a c t i o n b e t w e e n the k e t o n e e n o l a t e 312 a n d a c e t o n e . I t w a s g r a t i f y i n g to f i n d that the s m a l l e r o x i d a n t 310 a f f o r d e d t h e s a m e h i g h l e v e l o f d i a s t e r e o s e l e c t i v i t y as t h e b u l k i e r s u l f o n y l o x a z i r i d i n e 307. B o t h s t e r i c a n d s t e r e o e l e c t r o n i c r e a s o n s a r e l i k e l y r e s p o n s i b l e f o r t h e o b s e r v e d s t e r e o c h e m i c a l p r e f e r e n c e . A d a m h a s s h o w n that t h e d i a s t e r e o s e l e c t i v i t y o f the o x i d a t i o n o f m e t a l e n o l a t e s i s h i g h l y d e p e n d e n t o n t h e s t e r i c d e m a n d o f t h e c a t i o n a s s o c i a t e d w i t h the e n o l a t e . 1 0 7 3 - 1 1 1 I n h i s s t u d i e s , i n c r e a s e d d i a s t e r e o m e r i c e x c e s s e s w e r e o b s e r v e d i n t h e o r d e r T i > S i > N a , L i f o r the e n o l a t e c o u n t e r i o n s . T h e h i g h s e l e c t i v i t y i n the o x i d a t i o n o f 312 m a y h a v e b e e n d u e i n p a r t to the r e l a t i v e l y b u l k y p o t a s s i u m c o u n t e r i o n . T h e p r e s e n c e o f M e - 1 9 o n t h e a - f a c e i s a l s o l i k e l y r e s p o n s i b l e f o r t h e o b s e r v e d B - f a c e h y d r o x y l a t i o n , s i n c e r e a c t i o n o f 307 o r 310 o n t h e a - f a c e o f t h e e n o l a t e 312 w o u l d r e s u l t i n a 1 , 3 -d iax ia l i n t e r a c t i o n b e t w e e n t h e o x i d a n t a n d M e - 1 9 . S t e r e o e l e c t r o n i c f a c t o r s m a y a l s o r a t i o n a l i z e the o b s e r v e d d i a s t e r e o s e l e c t i v i t y . A d a m h a s p r o p o s e d tha t the r e p u l s i o n b e t w e e n t h e L U M O o f t h e e l e c t r o p h i l e a n d t h e H O M O o f t h e e n o l a t e o x y g e n i s e x p e c t e d t o p r o m o t e a n o n -p e r p e n d i c u l a r o r i e n t a t i o n o f t h e a p p r o a c h i n g r e a c t i o n p a r t n e r s . 1 1 l b T h e r e f o r e , a n e l e c t r o p h i l i c o x i d a n t s h o u l d p r e f e r e n t i a l l y a t t a c k t h e C - 2 c a r b o n o f the e n o l a t e d o u b l e b o n d at a n a n g l e g r e a t e r t h a n 90\u00C2\u00B0. T h e n e x t s t e p i n t h e s y n t h e s i s w a s e n v i s a g e d to b e p r o t e c t i o n o f t h e h y d r o x y l m o i e t y i n 311 to p r o v i d e 313 (Scheme 52). T h e r e m a i n d e r o f the s y n t h e s i s o f (\u00C2\u00B1)-neoverrucosan-5 B - o l (62) w a s to i n v o l v e t h e c o n v e r s i o n o f t h e k e t o n e 313 i n t o 315, f o l l o w e d b y h y d r o x y l -d i r e c t e d c y c l o p r o p a n a t i o n o f t h e l a t t e r s u b s t a n c e . C o m p o u n d 314 c o u l d , i n t h e o r y , b e s y n t h e s i z e d b y r e a c t i o n o f l i t h i u m d i m e t h y l c u p r a t e ( M e 2 C u L i ) w i t h t h e a l k e n y l t r i f l a t e 316 d e r i v e d f r o m k e t o n e 313. T h e p r e s e n c e o f t h e s u b s t i t u e n t at C - 5 ( v e r r u c o s a n e n u m b e r i n g ) w a s a n t i c i p a t e d t o r e s u l t i n p r e f e r e n t i a l p r o t o n a b s t r a c t i o n f r o m C - 2 w h e n 313 w a s t r e a t e d w i t h a s t r o n g b a s e . 105 311 R' = H 316 R' = protecting group 62 313 R- = protecting R = OTf group 314 R' = protecting group R = Me 315 R' = H, R = Me S c h e m e 52 T h e ( 2 - t r i m e t h y l s i l y l e t h o x y ) m e t h y l ( S E M ) p r o t e c t i n g g r o u p 1 1 2 i s c o m p a t i b l e w i t h the p r o p o s e d t r a n s f o r m a t i o n s . T h i s p r o t e c t i n g g r o u p c a n b e r e a d i l y r e m o v e d u n d e r m i l d c o n d i t i o n s ( f l u o r i d e i o n ) . A t r i a l k y l s i l y l p r o t e c t i n g g r o u p m a y b e p r o n e t o s i l y l m i g r a t i o n f r o m the h y d r o x y l o x y g e n to the e n o l a t e o x y g e n u p o n e n o l i z a t i o n . C o m p o u n d 311 w a s c o n v e r t e d i n t o t h e S E M e t h e r 317 i n 8 5 % y i e l d ( e q u a t i o n 27) . 1 1 3 E v i d e n c e f o r t h e s u c c e s s f u l i n s t a l l a t i o n o f t h e p r o t e c t i n g g r o u p w a s i n d i c a t e d b y t h e a p p e a r a n c e o f a n i n e p r o t o n s i n g l e t f o r the T M S f u n c t i o n at 6 0 . 0 1 i n the n m r s p e c t r u m . 0 O 106 W i t h t h e h y d r o x y l g r o u p p r o t e c t e d , the n e x t s tep i n v o l v e d p r o t o n a b s t r a c t i o n f r o m C -2 , f o l l o w e d b y r e a c t i o n o f t h e c o r r e s p o n d i n g e n o l a t e w i t h a t r i f l a t i n g a g e n t to p r o v i d e the e n o l t r i f l a t e . T h i s t r a n s f o r m a t i o n d i d n o t p r o c e e d as p l a n n e d . T r e a t m e n t o f 317 w i t h L D A p r o v i d e d t h e t w o m a j o r c o m p o u n d s 318 a n d 319 i n a p p r o x i m a t e l y e q u a l a m o u n t s a l o n g w i t h r e c o v e r e d s t a r t i n g m a t e r i a l (Scheme 53). T h e C - 5 t r i f l a t e d m a t e r i a l 318 c o n t a i n s a c a r b o n y l a b s o r p t i o n at 1 7 4 2 c n r 1 i n the I R s p e c t r u m . T h e * H n m r s p e c t r u m o f 318 i n d i c a t e d that the S E M g r o u p r e m a i n e d i n t a c t , b u t the s p e c t r u m l a c k s t h e s i g n a l f o r t h e c a r b i n o l p r o t o n at C - 5 . T h e a l c o h o l 319 w a s f o r m e d as a s i n g l e d i a s t e r e o m e r w h i c h w a s r e - o x i d i z e d w i t h P C C to p r o v i d e the k e t o n e 317. O O H O 317 319 318 P C C , Celite C H 2 C I 2 , rt Scheme 53 T h e f o r m a t i o n o f 319 i s p r e s u m a b l y d u e to t h e f a c t that t h e C - 2 p o s i t i o n o f 317 i s v e r y h i n d e r e d , d u e l a r g e l y to t h e i s o p r o p y l u n i t at C - 1 3 . R a t h e r t h a n a b s t r a c t i n g a p r o t o n f r o m C - 2 , i t a p p e a r s tha t the l i t h i u m d i i s o p r o p y l a m i d e ( L D A ) a c t e d as a h y d r i d e r e d u c i n g a g e n t to p r o v i d e t h e a l c o h o l 319 ( e q u a t i o n 28). T h e u s e o f l i t h i u m d i e t h y l a m i d e ( L i N E t 2 ) as the b a s e e l i m i n a t e d t h e f o r m a t i o n o f 319, b u t 318 w a s the s o l e p r o d u c t . 107 317 319 A n a l t e r n a t i v e m e t h o d f o r i n t r o d u c i n g the m e t h y l g r o u p a n d t h e C - 2 - C - 3 d o u b l e b o n d i s d e p i c t e d i n Scheme 54. A d d i t i o n o f a m e t h y l G r i g n a r d r e a g e n t to t h e k e t o n e c a r b o n y l at C - 3 i n 317 f o l l o w e d b y d e h y d r a t i o n o f the r e s u l t a n t t e r t i a r y a l c o h o l w o u l d p r o v i d e a n a l k e n e . T h u s , m e t h y l m a g n e s i u m b r o m i d e w a s a d d e d to 317 a n d p r o v i d e d a 9 . 4 : 1 r a t i o o f d i a s t e r e o m e r i c a l c o h o l s 320 i n 9 4 % y i e l d . D e h y d r a t i o n o f 320 c o u l d p r o v i d e th ree p o s s i b l e a l k e n e p r o d u c t s , 321, 322, a n d 323 (Scheme 54). I t s h o u l d b e p o s s i b l e to i s o m e r i z e t h e e x o c y c l i c d o u b l e b o n d o f 322 t o a n e n d o c y c l i c p o s i t i o n to p r o v i d e 323. T r e a t m e n t o f 320 w i t h a n h y d r o u s c a m p h o r s u l f o n i c a c i d i n r e f l u x i n g b e n z e n e o r s u b j e c t i n g a s o l u t i o n o f 320 i n D M S O to r e f l u x w i t h o u t a c i d , d i d n o t a f f o r d c o m p o u n d s 321-323. I n s t e a d , the m a j o r c o m p o u n d i n e a c h c a s e w a s t h e t e t r a c y c l i c e t h e r 324. T h e f o r m a t i o n o f 324 m a y b e r a t i o n a l i z e d b y i o n i z a t i o n o f 320 ( o r p r o t o n a t e d 320) to f o r m t h e t e r t i a r y c a r b o c a t i o n 325, f o l l o w e d b y i n t r a m o l e c u l a r a t t a c k o f t h e o x y g e n o f t h e S E M p r o t e c t i n g g r o u p o n t h e e l e c t r o n - d e f i c i e n t c a r b o n (Scheme 55). T h e s t r u c t u r e o f c o m p o u n d 324 w a s a s s i g n e d as f o l l o w s . T h e I R s p e c t r u m o f 324 d o e s n o t c o n t a i n a h y d r o x y l n o r a c a r b o n y l a b s o r p t i o n , y e t t h e h i g h r e s o l u t i o n m a s s s p e c t r u m i n d i c a t e s t h e p r e s e n c e o f t w o o x y g e n s . T h e * H n m r s p e c t r u m s h o w s a s i g n a l f o r t h e c a r b i n o l p r o t o n H - 5 a t 8 3 .91 ( d d , 7 = 1 0 . 4 , 6 . 9 H z ) a n d t w o s i g n a l s a t 8 5 . 0 2 a n d 5 . 0 8 f o r the h y d r o g e n s o n C * . T h e * H n m r s p e c t r u m i n d i c a t e s t h e p r e s e n c e o f t h r e e t e r t i a r y m e t h y l g r o u p s , w h i c h g i v e r i s e to s i n g l e t s at 8 0 . 7 7 , 8 0 . 7 8 , a n d 8 1.19. T h e 1 3 C n m r s p e c t r u m c o n t a i n s the s i g n a l s f o r C - 5 , C - 3 , a n d C * at 8 7 6 . 1 , 8 7 9 . 0 , a n d 8 9 2 . 2 , r e s p e c t i v e l y . 324 Scheme 55 A m i n o r p r o d u c t i s o l a t e d i n t h e a t t e m p t e d d e h y d r a t i o n r e a c t i o n s o f 320 w a s t h e k e t o n e 326. T h e I R s p e c t r u m o f 326 c o n t a i n s a c a r b o n y l a b s o r p t i o n at 1 7 1 4 c m \" 1 w h i l e the n m r s p e c t r u m h a s a d o u b l e t at 8 1.00 ( 7 = 7 H z ) f o r M e - 1 8 . T h i s p r o d u c t c o u l d a r i s e f r o m l o s s o f w a t e r f r o m 320 to p r o v i d e t h e v i n y l e t h e r 321. S u b s e q u e n t l o s s o f t h e S E M p r o t e c t i n g g r o u p f r o m 321 a n d t a u t o m e r i z a t i o n o f t h e r e s u l t a n t e n o l w o u l d p r o v i d e 326 ( e q u a t i o n 29). N e i t h e r o f the p r o d u c t s 322 n o r 323 (Scheme 54) w e r e d e t e c t e d . 1 1 0 C l e a r l y , a n a l t e r n a t i v e a p p r o a c h f o r i n t r o d u c i n g the m e t h y l g r o u p a n d t h e C - 2 - C - 3 d o u b l e b o n d w a s r e q u i r e d . O n e s t r a t e g y i n v o l v e d c o n v e r t i n g t h e k e t o n e f u n c t i o n o f 313 i n t o a m e t h y l e n e g r o u p to p r o v i d e 176, f o l l o w e d b y i s o m e r i z a t i o n o f t h e e x o c y c l i c d o u b l e b o n d i n t o a n e n d o c y c l i c p o s i t i o n , a f f o r d i n g 314 (Scheme 56). 313 176 314 Scheme 56 A p o s s i b l e m e t h o d f o r i s o m e r i z i n g the d o u b l e b o n d o f 176 to g i v e 314 i s o u t l i n e d i n Scheme 57. T r e a t m e n t o f t h e a l l y l i c a l c o h o l 327 w i t h t w o e q u i v a l e n t s o f p o t a s s i u m tert-b u t o x i d e / n - b u t y l l i f h i u m c o m p l e x ( a s u p e r b a s e 1 1 4 ) c o u l d p r o v i d e t h e a l k a l i m e t a l d i a n i o n 328.115 Q u e n c h i n g 328 w i t h a b u l k y p r o t o n s o u r c e s h o u l d o c c u r at t h e m o r e a c c e s s i b l e C - l 8 p o s i t i o n to p r o v i d e 173. 3 2 7 3 2 8 1 7 3 S c h e m e 5 7 T h e p r e p a r a t i o n o f 3 2 7 w a s a c c o m p l i s h e d b y a n e f f i c i e n t t h ree s tep s e q u e n c e f r o m the h y d r o x y k e t o n e 3 1 1 a n d i s o u t l i n e d b e l o w ( S c h e m e 58 ) . T h e a l c o h o l 3 1 1 w a s c o n v e r t e d i n t o the c o r r e s p o n d i n g tert-butyldimethylsilyl e t h e r 1 1 6 3 2 9 i n q u a n t i t a t i v e y i e l d . T h e p r e s e n c e o f the p r o t e c t i n g g r o u p w a s i n d i c a t e d b y t h r e e m e t h y l s i n g l e t s i n the * H n m r s p e c t r u m o f 3 2 9 at 8 0 . 0 0 , 8 0 . 0 1 , a n d 8 0 . 8 8 . O l e f i n a t i o n o f 3 2 9 w a s a c c o m p l i s h e d i n 9 5 % y i e l d u s i n g t h e T e b b e r e a g e n t 3 3 0 1 1 7 to a f f o r d t h e a l k e n e 3 3 1 . 1 1 8 T h e a l k e n i c p r o t o n s i g n a l s i n t h e * H n m r s p e c t r u m o f 3 3 1 a r e p r e s e n t at 8 4 . 7 1 ( b r d , J = 2 . 3 H z ) a n d 8 4 . 9 5 ( b r d d d , J = 2 . 3 , 2 . 3 , 2 . 3 H z ) . R e m o v a l o f t h e tert-butyldimethylsilyl f u n c t i o n w i t h t e t r a - n - b u t y l a m m o n i u m f l u o r i d e p r o v i d e d the a l c o h o l 3 2 7 i n 9 9 % y i e l d . T h e I R s p e c t r u m o f 3 2 7 s h o w s t h e p r e s e n c e o f a b r o a d h y d r o x y l a b s o r p t i o n at 3 2 2 9 c m \" 1 . S c h e m e 5 8 U n f o r t u n a t e l y , t r e a t m e n t o f 3 2 7 w i t h g r e a t e r t h a n t w o e q u i v a l e n t s o f p o t a s s i u m tert-b u t o x i d e / n - b u t y l l i t h i u m c o m p l e x i n h e x a n e f o l l o w e d b y q u e n c h i n g w i t h i s o p r o p a n o l d i d n o t p r o v i d e t h e i s o m e r i z e d m a t e r i a l 1 7 3 . S t i r r i n g a t 0 \u00C2\u00B0C p r o v i d e d o n l y r e c o v e r e d s t a r t i n g m a t e r i a l w h e r e a s p r o l o n g e d r e a c t i o n at r o o m t e m p e r a t u r e a f f o r d e d u n i d e n t i f i a b l e p r o d u c t s . T h e s t e r i c a l l y h i n d e r e d e n v i r o n m e n t at C - 2 w a s l i k e l y t h e r e a s o n that the d i a n i o n 3 2 8 w a s n o t f o r m e d (vide supra). A t t e m p t e d i s o m e r i z a t i o n o f t h e o l e f i n 3 3 1 u n d e r a v a r i e t y o f a c i d i c , b a s i c , a n d t r a n s i t i o n m e t a l c a t a l y z e d c o n d i t i o n s r e s u l t e d i n e i t h e r n o r e a c t i o n , c o m p l e x r e a c t i o n m i x t u r e s , o r l o s s o f the terf-butyldimethylsilyl g r o u p . A n a l t e r n a t i v e m e t h o d f o r m i g r a t i n g t h e a l k e n i c b o n d i n t o a n e n d o c y c l i c p o s i t i o n i n v o l v e d o x i d a t i o n o f t h e a l l y l i c a l c o h o l 3 2 7 to t h e e n o n e 3 3 2 a n d s u b s e q u e n t i s o m e r i z a t i o n o f the d o u b l e b o n d 1 1 9 t o p r o v i d e 1 7 4 (Scheme 5 9 ) . H o w e v e r , t h i s r o u t e w a s l e s s a t t r a c t i v e b e c a u s e i t r e s u l t s i n t h e d e s t r u c t i o n o f the s t e r e o c h e m i s t r y at C - 5 . 3 2 7 3 3 2 1 7 4 Scheme 5 9 O x i d a t i o n o f 3 2 7 w i t h p y r i d i n i u m c h l o r o c h r o m a t e ( P C C ) o r t e t r a - A L p r o p y l a m m o n i u m p e r r u t h e n a t e ( T P A P ) a p p e a r e d to p r o c e e d s m o o t h l y b y t i c a n a l y s i s to p r o v i d e a s i n g l e l e s s p o l a r u v a c t i v e c o m p o u n d c o r r e s p o n d i n g to 3 3 2 . H o w e v e r , a f t e r a n a p p r o p r i a t e w o r k u p p r o c e d u r e a n d c o n c e n t r a t i o n o f the r e s u l t a n t s o l u t i o n , a s e c o n d e v e n l e s s p o l a r n o n u v a c t i v e c o m p o u n d a p p e a r e d . T h e t w o c o m p o u n d s w e r e s e p a r a t e d b y c o l u m n c h r o m a t o g r a p h y w i t h s i l i c a g e l , b u t c o n c e n t r a t i o n o f s o l u t i o n s c o n t a i n i n g the u v a c t i v e c o m p o n e n t 3 3 2 s h o w e d the a p p e a r a n c e o f t h e s e c o n d l e s s p o l a r c o m p o u n d . T h e i d e n t i f i c a t i o n o f t h e s e c o n d c o m p o n e n t e x p l a i n e d t h i s o b s e r v e d p h e n o m e n o n . T h e e n o n e 3 3 2 i s h i g h l y r e a c t i v e a n d c o n c e n t r a t i o n o f s o l u t i o n s c o n t a i n i n g 3 3 2 r e s u l t e d i n a [4 + 2] c y c l o a d d i t i o n r e a c t i o n o f 3 3 2 w i t h i t s e l f t o p r o v i d e the d i m e r 3 3 3 (Scheme 6 0 ) . 114 O 332 dimerization O Heq Hax 1 H 332 333 Scheme 6 0 A v a r i e t y o f s p e c t r o s c o p i c m e t h o d s c o n f i r m e d t h e s t r u c t u r e o f 333. T h e l o w r e s o l u t i o n m a s s s p e c t r u m o f 333 c o n t a i n s a m o l e c u l a r i o n p e a k ( M + ) o f 5 4 9 a m u , w h i c h i s d o u b l e the m a s s o f 332, a n d the I R s p e c t r u m p o s s e s s e s a c a r b o n y l a b s o r p t i o n at 1 7 1 9 c m \" 1 . T h e l o w e s t f i e l d s i g n a l i n t h e * H n m r s p e c t r u m o f 333 i s a d o u b l e t at 5 2 . 8 1 ( 7 = 11 H z ) c o r r e s p o n d i n g t o H - a (eq) . T h e o n l y o t h e r r e s o l v e d m u l t i p l e t i n t h e * H n m r s p e c t r u m i s a s i g n a l at 8 2 . 2 8 ( d d d , 7 = 1 3 , 1 3 , 4 H z ) w h i c h i s a t t r i b u t e d to H - d ( ax ) . T h e i n t e g r a t i o n o f a l l t h e m e t h y l g r o u p s i g n a l s i n d i c a t e d t h a t e i g h t a r e p r e s e n t , w h i c h i s c o n s i s t e n t w i t h t h e s t r u c t u r e o f 333. T h e 1 3 C n m r s p e c t r u m o f 333 c o n t a i n s s i g n a l s at 8 8 0 , 1 0 5 , 1 4 3 , a n d 2 1 2 , c o r r e s p o n d i n g t o C - c , C - e , C - f , a n d C - b , r e s p e c t i v e l y . T h e c o n f i g u r a t i o n at C - c i n 333 w a s n o t u n a m b i g u o u s l y d e t e r m i n e d b u t c a n b e p r e d i c t e d b a s e d o n the l e a s t s t e r i c a l l y h i n d e r e d a p p r o a c h o f t h e t w o m o l e c u l e s o f 332 as s h o w n i n Scheme 6 0 . F o r m a t i o n o f 333 o c c u r r e d o n l y w h e n s o l u t i o n s o f 332 w e r e c o n c e n t r a t e d a n d s o t h e d e s i r e d i s o m e r i z a t i o n w a s p e r f o r m e d o n d i l u t e s o l u t i o n s o f 332 o b t a i n e d a f t e r w o r k u p o f t h e o x i d a t i o n r e a c t i o n . T h u s , the a l l y l i c a l c o h o l 327 w a s t rea ted w i t h T R A P i n the p r e s e n c e o f N-m e t h y l m o r p h o l i n e - N - o x i d e a n d 4 A m o l e c u l a r s i e v e s i n m e t h y l e n e c h l o r i d e at r o o m t e m p e r a t u r e (Scheme 6 1 ) . T h e o x i d a t i o n r e a c t i o n m i x t u r e w a s p a s s e d t h r o u g h a s h o r t 115 c o l u m n o f s i l i c a g e l a n d t h e c o l u m n w a s e l u t e d w i t h d i e t h y l e t h e r . T h e f i l t r a t e w a s d i l u t e d w i t h e t h a n o l , the d i e t h y l e t h e r a n d m e t h y l e n e c h l o r i d e w e r e r e m o v e d u n d e r r e d u c e d p r e s s u r e , a n d R h C l 3 \u00C2\u00AB 3 H 2 0 1 1 9 w a s a d d e d to t h e r e s u l t a n t e t h a n o l s o l u t i o n o f 332 a n d t h e m i x t u r e w a s h e a t e d at r e f l u x . W h e n t h e s e p r e c a u t i o n s w e r e t a k e n , t h e i s o m e r i z e d e n o n e 174 w a s i s o l a t e d i n 6 1 % y i e l d f r o m t h e a l c o h o l 327. 327 332 174 Scheme 61 S p e c t r o s c o p i c d a t a c o n f i r m e d that t h e d e s i r e d i s o m e r i z a t i o n h a d o c c u r r e d . T h e I R s p e c t r u m o f 174 s h o w s a n e n o n e c a r b o n y l a b s o r p t i o n at 1 6 7 6 c m \" 1 , w h i l e t h e * H n m r s p e c t r u m i n c l u d e s a v i n y l m e t h y l s i n g l e t ( M e - 1 8 ) at 8 1.53 a n d a d e s h i e l d e d b r o a d s i n g l e t f o r H - 2 at 8 6 . 7 5 . F r o m c o m p o u n d 174, d i v e r g i n g s y n t h e t i c r o u t e s c a n l e a d t o e i t h e r (\u00C2\u00B1)-neoverrucosan-5 (3 -o l (62) o r (\u00C2\u00B1)-verrucosan-2p ,-ol (61) (Scheme 62) a n d b o t h 62 a n d 61 c a n b e c o n v e r t e d t o (\u00C2\u00B1)-homoverrucosan-5f5-ol (63). T h e r o u t e l e a d i n g to (\u00C2\u00B1)-neoverrucosan-5p%ol (62) w i l l b e c o n s i d e r e d f i r s t . 63 Scheme 62 2.1.5.5. Completion of the Synthesis of (\u00C2\u00B1 ) -Neoverrucosan-5 B-ol (62) and (\u00C2\u00B1 ) -Homoverrucosan-5 B-ol (63). A s m e n t i o n e d p r e v i o u s l y , t h e s y n t h e s i s o f 174 r e s u l t e d i n t h e s t e r e o c h e m i s t r y at C - 5 b e i n g s a c r i f i c e d . R e d u c t i o n o f t h e c a r b o n y l g r o u p o f 174 w i t h s o d i u m b o r o h y d r i d e i n the p r e s e n c e o f c e r i u m t r i c h l o r i d e i n m e t h a n o l 1 2 0 p r o v i d e d a m i x t u r e o f e p i m e r i c a l l y l i c a l c o h o l s 173 a n d 334, w h i c h w e r e i s o l a t e d i n y i e l d s o f 7 1 % a n d 2 6 % , r e s p e c t i v e l y ( e q u a t i o n 30). 71% 26% 174 173 334 117 T h e m a j o r p r o d u c t w a s t h e a l c o h o l w i t h t h e d e s i r e d c o n f i g u r a t i o n at C - 5 (173). T h i s r e s u l t i s c o n s i s t e n t w i t h L u c h e ' s 1 2 0 o b s e r v a t i o n that a x i a l h y d r i d e a t t a c k i s e n h a n c e d b y t h e p r e s e n c e o f l a n t h a n i d e s a l t s . E v i d e n c e f o r the f o r m a t i o n o f a h y d r o x y l m o i e t y w a s p r o v i d e d b y a n a b s o r p t i o n at 3 3 3 8 c m - 1 i n the I R s p e c t r u m o f 173. A c a r b i n o l p r o t o n i s p r e s e n t i n t h e ! H n m r s p e c t r a o f e a c h o f c o m p o u n d s 173 a n d 334, b u t t h e s i g n a l s a r e s i g n i f i c a n t l y b r o a d that a n a c c u r a t e d e t e r m i n a t i o n o f t h e c o u p l i n g c o n s t a n t s f o r t h e s e s i g n a l s w a s n o t p o s s i b l e . T h e c o n f i g u r a t i o n at C - 5 f o r the' m a j o r a n d m i n o r p r o d u c t s 173 a n d 334 w a s d e t e r m i n e d u s i n g e m p i r i c a l e v i d e n c e a n d b y N O E d i f f e r e n c e e x p e r i m e n t s . T h e w i d t h o f t h e c a r b i n o l p r o t o n p e a k at h a l f - h e i g h t ( w i / 2 ) g i v e s s o m e i n f o r m a t i o n a b o u t t h e m a g n i t u d e o f t h e c o u p l i n g c o n s t a n t s f o r tha t s i g n a l a n d t h e r e f o r e t h e c o n f i g u r a t i o n at tha t c e n t e r . C o m p a r i s o n o f the c h e m i c a l s h i f t a n d t h e p e a k w i d t h at h a l f - h e i g h t f o r H - 5 o f t h e t w o e p i m e r i c a l c o h o l s 173 a n d 334 w i t h p r e v i o u s l y s y n t h e s i z e d c o m p o u n d s s u p p o r t e d t h e a s s i g n e d c o n f i g u r a t i o n s at C - 5 (Table 8). E n t r i e s 1-5 i n Table 8 h a v e a c h e m i c a l s h i f t s g r e a t e r t h a n 4 p p m f o r H - 5 a n d t h e w i d t h at h a l f - h e i g h t i s c o n s i s t e n t l y 2 2 H z . T h i s s t r o n g l y s u g g e s t s that t h e m a j o r p r o d u c t 173, i n w h i c h t h e s i g n a l a t t r i b u t e d to H - 5 i s at 6 4 . 1 0 - 4 . 1 8 a n d the w i d t h at h a l f - h e i g h t i s 2 2 H z , i s the ( 3 - a l c o h o l . I n the m i n o r p r o d u c t 334, t h i s p r o t o n a p p e a r s at 8 3 . 9 5 a n d h a s a w i d t h at h a l f -h e i g h t o f 12 H z . lH n m r N O E d i f f e r e n c e e x p e r i m e n t s a l s o c o n f i r m e d t h e c o n f i g u r a t i o n at C -5 f o r 173. I r r a d i a t i o n o f the s i g n a l at 8 4 . 1 0 - 4 . 1 8 ( H - 5 ) r e s u l t e d i n a n e n h a n c e m e n t o f the s i g n a l at 8 0 . 8 4 ( M e - 1 9 ) a n d v i c e v e r s a . T h i s i s o n l y p o s s i b l e i f H - 5 a n d M e - 1 9 a re o n t h e s a m e f a c e o f t h e m o l e c u l e , as s h o w n b e l o w . H Q H 173 T a b l e 8 : C h e m i c a l S h i f t a n d P e a k W i d t h at H a l f - H e i g h t f o r S e l e c t e d C - 5 H y d r o x y l a t e d C o m p o u n d s E n t r y C o m p o u n d C h e m i c a l S h i f t o f H - 5 P e a k W i d t h o f H - 5 at H a l f - H e i g h t 1 0 H O S ^ S \ 311 4 . 2 5 p p m 2 2 H z 2 0 S E M O ^ J L v 317 4 . 3 3 p p m 2 2 H z 3 o T B S O ^ J L \ 329 4 . 2 8 p p m 2 2 H z 4 T B S O ^ J L v 331 4 . 1 7 - 4 . 2 7 p p m 2 2 H z 5 N I H IT/ 327 4 . 1 9 - 4 . 2 7 p p m 2 2 H z 6 sxx\H xT/ 173 4 . 1 0 - 4 . 1 8 p p m 2 2 H z 7 H O ^ ^ H \"V\" 334 3 . 9 5 p p m 12 H z A W i t t i g - F u r u k a w a h y d r o x y l d i r e c t e d c y c l o p r o p a n a t i o n o f t h e a l l y l i c a l c o h o l 1 7 3 , w h i c h i n c l u d e d t h e m o d i f i c a t i o n s p r o p o s e d b y D e n m a r k , 1 2 1 w a s t h e l a s t s t e p i n t h e s y n t h e s i s o f (\u00C2\u00B1)-neoverrucosan-5(3-ol (62). B i s ( c h l o r o m e t h y l ) z i n c , ( C l C H 2 ) 2 Z n , w a s p r e p a r e d b y t h e a d d i t i o n o f t w o e q u i v a l e n t s o f c h l o r o i o d o m e t h a n e to d i e t h y l z i n c i n d i c h l o r o e t h a n e at 0 \u00C2\u00B0C. R e a c t i o n o f t h e a l l y l i c a l c o h o l 1 7 3 w i t h t h e c y c l o p r o p a n a t i n g r e a g e n t p r o v i d e d ( \u00C2\u00B1 ) -n e o v e r r u c o s a n - 5 P - o l (62) i n 9 2 % y i e l d ( e q u a t i o n 3 1 ) . 92% 1 7 3 62 T h e r a c e m i c s y n t h e t i c n a t u r a l p r o d u c t 62 e x h i b i t e d s p e c t r a l d a t a i d e n t i c a l w i t h t h o s e o f t h e n a t u r a l l y o c c u r r i n g ( - ) - n e o v e r r u c o s a n - 5 p - o l (62) ( T a b l e s 9 a n d IO) . 2 2 8 ' 1 2 2 T h e lH n m r s p e c t r u m ( 4 0 0 M H z , C D C I 3 ) o f s y n t h e t i c (\u00C2\u00B1)-neoverrucosan-5 P-ol (62) i s s h o w n o n p a g e 1 2 2 ( F i g u r e 3 ) . A c o m p a r i s o n o f t h i s s p e c t r u m w i t h t h e *H n m r s p e c t r u m r u n o n a n a u t h e n t i c s a m p l e i s d e p i c t e d o n p a g e 123 ( F i g u r e 4). 1 2 0 T a b l e 9 : C o m p a r i s o n o f t h e M e l t i n g P o i n t , a n d t h e I R a n d ! H n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( - ) - N e o v e r r u c o s a n - 5 | 3 - o l (62) a n d t h e S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5fi-ol (62). D a t a S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5P-ol 62 N a t u r a l ( - ) - N e o v e r r u c o s a n - 5 pVol 62 m e l t i n g p o i n t a 150-152\u00C2\u00B0C 174-175\u00C2\u00B0C a 3 2 6 3 3 2 7 0 T R ( K B r ) a 3 0 5 6 3 0 6 0 ( c m - 1 ) 1 3 8 7 1 3 8 0 1 3 7 9 1 3 7 3 0 . 2 6 (dd , 7 = 4 . 7 , 4 . 7 H z ) 0 . 2 6 ( d d , 7 = 4 . 7 , 4 . 7 H z ) 0 . 5 4 (dd , 7 = 8 . 1 , 4 . 4 H z ) 0 . 5 4 ( d d , 7 = 8 . 2 , 4 . 4 H z ) 0 . 7 2 (s) 0 . 7 2 (s) i H n m r ( C D C 1 3 ; 4 0 0 M H z ) b > c 0 . 8 0 (d , 7 = 6 .7 H z ) 0 . 8 0 (d , 7 = 6 . 9 H z ) (5) 0 .81 (s) 0 .81 (s) 0 . 8 9 (d , 7 = 6.7 H z ) 0 . 8 9 (d , 7 = 6 .9 H z ) 1.16 (s) 1.16 (s) 4 . 0 0 (dd , 7 = 1 0 . 4 , 7 . 5 H z ) 4 . 0 0 ( d d , 7 = 1 0 . 7 , 7 . 3 H z ) a- Reference 22a. b- Only selected 1 H nmr signals are reported. c- The reported 1 H nmr data for the natural (-)-neoverrucosan-5P -ol was obtained from an authentic sample generously provided by John Faulkner (Scripps Institution of Oceanography). Table 10 : C o m p a r i s o n o f 1 3 C n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( - ) - N e o v e r r u c o s a n - 5 f i - o l (62) a n d t h e S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5|3-ol (62). C h e m i c a l S h i f t O b s e r v e d f o r S y n t h e t i c (\u00C2\u00B1)-Neoverrucosan-5 p - o l (62) ( C D C 1 3 , 7 5 . 3 M H z ) ( p p m ) C h e m i c a l S h i f t O b s e r v e d f o r N a t u r a l ( - ) - N e o v e r r u c o s a n - 5 P-ol (62)a ( C D C I 3 , 7 5 . 3 M H z ) ( p p m ) 1 4 . 9 0 1 4 . 9 0 1 7 . 1 8 1 7 . 1 8 1 8 . 5 8 1 8 . 5 8 1 9 . 6 0 1 9 . 6 0 2 1 . 5 5 2 1 . 5 4 2 1 . 9 7 2 1 . 9 7 2 2 . 7 5 2 2 . 7 5 2 5 . 5 4 2 5 . 5 5 2 5 . 8 4 2 5 . 8 4 2 8 . 6 3 2 8 . 6 4 3 4 . 6 1 3 4 . 6 1 3 5 . 2 2 3 5 . 2 2 3 7 . 1 0 3 7 . 1 0 3 9 . 1 2 3 9 . 1 3 4 4 . 0 0 4 4 . 0 1 4 5 . 1 6 4 5 . 1 6 4 6 . 8 6 4 6 . 8 6 4 7 . 1 6 4 7 . 1 6 4 7 . 5 7 4 7 . 5 7 7 1 . 1 7 7 1 . 1 9 a- The 1 3 C nmr spectrum of the naturally occurring (-)-neoverrucosan-5 P-ol was generously provided by Chia-Li Wu (Tamkang University). 122 124 T h e p r e p a r a t i o n o f ( + ) - h o m o v e r r u c o s a n - 5 B - o l (63) f r o m ( - ) - n e o v e r r u c o s a n - 5 B - o l (62) b y a n a c i d c a t a l y z e d r i n g e x p a n s i o n w a s p r e v i o u s l y r e p o r t e d . 2 2 3 F o l l o w i n g t h e p u b l i s h e d p r o c e d u r e , 2 1 3 t r e a t m e n t o f (\u00C2\u00B1)-neoverrucosan-5B-ol (62) w i t h 0 . 5 M s u l f u r i c a c i d i n r e f l u x i n g a c e t o n e p r o v i d e d t h e r i n g e x p a n d e d n a t u r a l p r o d u c t (\u00C2\u00B1) -homoverrucosan-5B-ol (63) i n q u a n t i t a t i v e y i e l d ( e q u a t i o n 32). 1 0 0 % 62 63 T h e r a c e m i c s y n t h e t i c 63 e x h i b i t e d s p e c t r a l d a t a i d e n t i c a l w i t h t h o s e o f t h e n a t u r a l l y o c c u r r i n g ( + ) - h o m o v e r r u c o s a n - 5 B - o l (Tables 11 a n d 12).21a-123 T h e * H n m r s p e c t r u m (400 M H z , C D C I 3 ) o f t h e s y n t h e t i c (\u00C2\u00B1)-homoverrucosan-5B-ol (63) i s s h o w n o n p a g e 127 (Figure 5). A c o m p a r i s o n o f t h i s s p e c t r u m w i t h t h e ! H n m r s p e c t r u m r u n o n a n a u t h e n t i c s a m p l e i s d e p i c t e d o n p a g e 128 (Figure 6). 125 Table 11 : C o m p a r i s o n o f t h e M e l t i n g P o i n t , a n d the I R a n d lH n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( + ) - H o m o v e r r u c o s a n - 5 f i - o l (63) a n d t h e S y n t h e t i c (\u00C2\u00B1)-Homoverrucosan-5 p - o l (63). 63 D a t a S y n t h e t i c ( ) - H o m o v e r r u c o s a n - 5 P - o l (63) N a t u r a l ( + ) - H o m o v e r r u c o s a n - 5 P - o l (63) m e l t i n g p o i n t a 1 4 1 - 1 4 2 ' C 153-154\u00C2\u00B0C a I R a ( K B r ) ( c m - 1 ) 3 2 4 1 3 2 5 0 1 3 8 7 1 3 9 6 1 3 7 8 1 3 8 7 1 0 2 7 1 0 3 3 9 7 2 9 8 0 J H n m r b ,c ( C D C I 3 , 4 0 0 M H z ) (5) 0 . 7 6 (s) 0 . 7 6 (s) 0 .81 (d , 7 = 6 . 7 H z ) 0 .81 (d , 7 = 6 .7 H z ) 0 . 8 3 5 ( d , 7 = 6 .7 H z ) 0 . 8 3 6 (d , 7 = 6 .7 H z ) 0 . 8 4 3 (s) 0 . 8 4 4 (s) 1.74 (s) 1.74 (s) 2 . 1 8 ( d d , 7 = 1 2 , 4 . 5 H z ) 2 . 1 8 ( d d , 7 = 1 2 , 5 . 5 H z ) 2 . 5 3 ( d d d , 7 = 12 .2 , 12 , 1.8 H z ) 2 . 5 3 ( d d d , 7 = 1 2 , 1 2 , 1 . 7 H z ) 3 .57 ( d d d d , 7 = 1 2 . 2 , 1 1 . 0 , 4 . 5 , 2 . 2 H z ) 3 . 57 ( b r d d , 7 = 1 1 , 1 1 H z ) 5 . 2 7 ( b r d , 7 = 6 . 0 H z ) 5 . 2 7 ( b r d , 7 = 5 .8 H z ) a- Reference 21a. b- Only selected 1 H nmr signals are reported. c- The reported 1 H nmr data for the natural (+)-homoverrucosan-5 P-ol was obtained from an authentic sample generously provided by John Faulkner (Scripps Institution of Oceanography). 126 Table 12 : C o m p a r i s o n o f t h e 1 3 C n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( + ) - H o m o v e r r u c o s a n -5 | 3 - o l (63) a n d t h e S y n t h e t i c (\u00C2\u00B1)-Homoverrucosan-5 |3 -o l (63). C h e m i c a l S h i f t O b s e r v e d f o r S y n t h e t i c (\u00C2\u00B1)-Homoverrucosan-5 P-ol (63) ( C D C I 3 , 7 5 . 3 M H z ) ( p p m ) C h e m i c a l S h i f t O b s e r v e d f o r N a t u r a l ( + ) - H o m o v e r r u c o s a n - 5 B - o l (63)a (CDCI3, 1 2 5 . 5 M H z ) ( p p m ) 1 4 . 8 8 1 4 . 8 9 1 7 . 9 9 1 8 . 0 2 2 0 . 0 6 2 0 . 0 7 2 1 . 3 5 2 1 . 3 4 2 2 . 8 3 2 2 . 8 4 2 5 . 7 1 2 5 . 7 0 2 7 . 9 4 2 7 . 9 7 3 5 . 0 6 3 5 . 0 9 3 7 . 9 7 3 7 . 9 9 3 8 . 7 3 3 8 . 7 7 3 8 . 9 1 3 8 . 9 5 4 2 . 5 3 1 2 4 4 2 . 5 8 4 3 . 7 6 4 3 . 8 1 4 6 . 7 5 4 6 . 7 9 4 7 . 6 9 4 7 . 7 5 5 8 . 8 2 5 8 . 8 8 6 5 . 5 7 6 5 . 5 8 1 3 1 . 2 0 1 3 1 . 2 5 1 3 1 . 6 1 1 3 1 . 6 3 a- The 1 3 C nmr spectrum of the naturally occurring (+)-homoverrucosan-5(3-ol was generously provided by John Faulkner (Scripps Institution of Oceanography). 127 129 2 . 1 . 5 . 6 . Completion of the Synthesis of (\u00C2\u00B1)-Verrucosan -5fi -ol ( 6 1 ) . T h e s y n t h e s i s o f (\u00C2\u00B1)-verrucosan-2p >-ol ( 6 1 ) w a s a c c o m p l i s h e d s t a r t i n g f r o m t h e t r i c y c l i c e n o n e 1 7 4 , a n a d v a n c e d i n t e r m e d i a t e i n t h e s y n t h e s i s o f n e o v e r r u c o s a n - 5 pVol (Scheme 6 3 ) . A h y d r o x y l - d i r e c t e d c y c l o p r o p a n a t i o n o f t h e a l l y l i c a l c o h o l 1 7 2 w a s e n v i s a g e d as the f i n a l s tep . steps^ ^ 1 7 4 H i . J cyclopropanation^ 1 7 2 Scheme 6 3 P r e p a r a t i o n o f t h e a l l y l i c a l c o h o l 1 7 2 f r o m 1 7 4 r e q u i r e d a n a b b r e v i a t e d e n o n e t r a n s p o s i t i o n p r o t o c o l . T h e k e y s t e p w a s t h e W h a r t o n r e a c t i o n 1 2 5 w h i c h i n v o l v e s t h e f r a g m e n t a t i o n o f a , P - e p o x y k e t o n e s to g e n e r a t e a l l y l i c a l c o h o l s as d e p i c t e d i n Scheme 6 4 . E p o x i d a t i o n o f t h e a , P - u n s a t u r a t e d k e t o n e 3 3 5 , f o l l o w e d b y r e d u c t i o n o f t h e r e s u l t a n t a , R -e p o x y k e t o n e 3 3 6 w i t h h y d r a z i n e , p r o v i d e s the a l l y l i c a l c o h o l 3 3 7 . T h e c o n f i g u r a t i o n o f the e p o x i d e 3 3 6 s e t s t h e s t e r e o c h e m i s t r y o f t h e h y d r o x y l m o i e t y i n 3 3 7 . O x i d a t i o n o f 3 3 7 a f f o r d s the t r a n s p o s e d e n o n e 3 3 8 . O \u00C2\u00AB/WWvW 3 3 5 epoxidation ] hydrazine * / v \ / w \ / w > reduction - ~ w w w 3 3 6 3 3 7 oxidation O 3 3 8 Scheme 6 4 I n o r d e r t o g e n e r a t e t h e a l l y l i c a l c o h o l w i t h t h e d e s i r e d c o n f i g u r a t i o n f o r the h y d r o x y g r o u p , t h e P - e p o x y k e t o n e w a s r e q u i r e d . E x a m i n a t i o n o f m o l e c u l a r m o d e l s r e v e a l e d that the 1 3 0 a - f a c e o f t h e e n o n e 174 i s s t e r i c a l l y m o r e h i n d e r e d t h a n t h e B - f a c e d u e t o M e - 1 9 ( v e r r u c o s a n e n u m b e r i n g ) . T h u s , e p o x i d a t i o n o f 174 w i t h e x c e s s d i m e t h y l d i o x i r a n e 1 1 0 a p r o v i d e d e x c l u s i v e l y t h e a , B - e p o x y k e t o n e 175 i n 7 2 % y i e l d ( e q u a t i o n 3 3 ) . E p o x i d a t i o n w i t h a l k a l i n e h y d r o g e n p e r o x i d e a f f o r d e d o n l y t r a c e a m o u n t s o f 175, w h i l e t r e a t m e n t o f t h e e n o n e 174 w i t h tert-butyl h y d r o p e r o x i d e i n T H F c o n t a i n i n g t r i t o n B 1 2 6 g a v e 175 i n 6 3 - 6 9 % y i e l d . 72% 174 175 T h e s p e c t r o s c o p i c d a t a f o r c o m p o u n d 175 f u l l y s u p p o r t s t h e s t r u c t u r a l a s s i g n m e n t . T h e ] H n m r s p e c t r u m o f 175 c o n t a i n s a s i n g l e t at 8 1 .36 f o r M e - 1 8 a n d a s i n g l e t at 8 3 . 3 3 f o r H - 2 . T h e c o n f i g u r a t i o n o f t h e e p o x i d e m o i e t y w a s c o n f i r m e d b y * H n m r N O E d i f f e r e n c e e x p e r i m e n t s . I r r a d i a t i o n o f t h e s i g n a l at 8 1 .36 ( M e - 1 8 ) c a u s e d a n e n h a n c e m e n t o f t h e s i g n a l at 8 3 . 3 3 ( H - 2 ) a n d o f the s i g n a l at 8 0 . 8 4 ( M e - 1 9 ) . 175 T h e W h a r t o n r e a c t i o n w a s c a r r i e d o u t b y t r e a t i n g 175 w i t h h y d r a z i n e i n m e t h a n o l i n t h e p r e s e n c e o f a c e t i c a c i d , b u t p r o v i d e d o n l y t r a c e a m o u n t s o f t h e a l l y l i c a l c o h o l 172. T h e m a j o r p r o d u c t w a s a n i n t r a c t a b l e h i g h l y p o l a r c o m p o u n d 1 2 7 t ha t t h e c r u d e ! H n m r s p e c t r u m s u g g e s t e d w a s t h e h y d r o x y h y d r a z o n e 339. T h e l o w e s t f i e l d s i g n a l i n t h e * H n m r s p e c t r u m o f 339 i s a c a r b i n o l p r o t o n ( H - 2 , v e r r u c o s a n e n u m b e r i n g ) at 5 3 . 1 9 ( d d , 7 = 9 . 5 , 9 . 5 H z ) , w h i l e a d o u b l e t c o r r e s p o n d i n g t o H - 6 e q a p p e a r s at 8 2 . 5 7 ( 7 = 13 H z ) . A t h r e e p r o t o n d o u b l e t at 8 1 . 2 0 ( 7 = 7 H z ) w a s a s s i g n e d to M e - 1 8 . A n e x p l a n a t i o n f o r t h e f o r m a t i o n o f c o m p o u n d s s u c h a s 339 i n t h i s r e a c t i o n w a s p r o p o s e d b y S l e s s o r a n d c o w o r k e r s 1 2 8 (Scheme 65). T h e n o r m a l r e a c t i o n p a t h w a y f o r the W h a r t o n r e a c t i o n i s s h o w n i n p a t h A a n d i n v o l v e s c o n v e r s i o n o f t h e k e t o n e f u n c t i o n i n 175 t o the h y d r a z o n e 340 i n t h e p r e s e n c e o f h y d r a z i n e . O p e n i n g o f t h e e p o x i d e r i n g p r o v i d e s t h e a l k e n y l d i a z e n e 341, w h i c h l o s e s n i t r o g e n ( N 2 ) to g i v e t h e a l l y l i c a l c o h o l 172. H o w e v e r , d i i m i d e r e d u c t i o n o f 341 a f f o r d s c o m p o u n d 342, w h i c h p r o v i d e s t h e h y d r o x y h y d r a z o n e 339 ( pa th B ) . 1 3 2 175 340 341 339 Scheme 65 P r o d u c t s r e s u l t i n g f r o m d i i m i d e r e d u c t i o n a r e o f t e n f o r m e d i n t h e W h a r t o n r e a c t i o n . T h e a d d i t i o n o f a n a l k e n e to r e a c t w i t h t h e d i i m i d e i s a s o l u t i o n to t h i s p r o b l e m . 1 2 9 T h u s , p e r f o r m i n g t h e r e a c t i o n i n m e t h a n o l w i t h u s i n g 1 - h e x e n e as a c o - s o l v e n t p r o v i d e d the a l l y l i c a l c o h o l 172 i n 6 8 % y i e l d a n d o n l y t r a c e a m o u n t s o f 339 w e r e o b s e r v e d ( e q u a t i o n 34). T h e s p e c t r a l d a t a f o r c o m p o u n d 172 f u l l y s u p p o r t s t h e s t r u c t u r a l a s s i g n m e n t . T h e I R s p e c t r u m c o n t a i n s a b r o a d a b s o r p t i o n at 3 4 8 0 c m - 1 f o r the h y d r o x y l m o i e t y . T h e * H n m r s p e c t r u m 133 p o s s e s s e s a b r o a d d o u b l e t at 8 1 .72 ( 7 = 1 . 9 H z ) f o r M e - 1 8 ( v e r r u c o s a n e n u m b e r i n g ) , a n d a b r o a d d o u b l e t o f d o u b l e t s at 8 3 . 7 0 ( 7 = 7 . 3 , 7 . 3 H z ) f o r t h e c a r b i n o l p r o t o n H - 2 , w h i c h s i m p l i f i e s to a b r o a d d o u b l e t ( 7 = 7 . 3 H z ) u p o n t r e a t m e n t w i t h D2O. T h e a l k e n i c s i g n a l ( H - 5 ) i n the * H n m r s p e c t r u m a p p e a r s as a b r o a d d o u b l e t at 8 5 . 4 2 ( 7 = 5 . 4 H z ) . 1 7 5 1 7 2 T h e l a s t s tep i n t h e s y n t h e s i s o f (\u00C2\u00B1)-verrucosan-2B-ol ( 6 1 ) w a s a c y c l o p r o p a n a t i o n r e a c t i o n as i n t h e s y n t h e s i s o f (\u00C2\u00B1)-neoverrucosan-5B-ol. T r e a t m e n t o f 1 7 2 w i t h t h e c y c l o p r o p a n a t i n g r e a g e n t b i s ( c h l o r o m e t h y l ) z i n c ((CTCH2)2Zn) i n d i c h l o r o e t h a n e a t 0 \u00C2\u00B0 C 1 2 1 p r o v i d e d ( 6 1 ) i n 9 8 % y i e l d ( e q u a t i o n 3 5 ) . T h e r a c e m i c s y n t h e t i c n a t u r a l p r o d u c t 6 1 e x h i b i t e d s p e c t r a l d a t a i d e n t i c a l w i t h t h o s e o f t h e n a t u r a l l y o c c u r r i n g ( - ) - v e r r u c o s a n - 2 B - o l ( T a b l e 1 3 a n d 1 4 ) . 2 1 - 1 3 0 > 1 3 1 T h e * H n m r s p e c t r u m ( 4 0 0 M H z , C D 2 C 1 2 ) o f s y n t h e t i c (\u00C2\u00B1)-verrucosan-2B-ol i s s h o w n o n p a g e 1 3 6 ( F i g u r e 7 ) . Table 13 : C o m p a r i s o n o f t h e M e l t i n g P o i n t , a n d t h e I R a n d * H n m r S p e c t r a l D a t a f o r the N a t u r a l ( - ) - V e r r u c o s a n - 2 B - o l (61) a n d the S y n t h e t i c (\u00C2\u00B1)-Verrucosan-2B-ol (61). 61 D a t a S y n t h e t i c N a t u r a l (\u00C2\u00B1)-Verrucosan-2B-ol (61) ( - ) - V e r r u c o s a n - 2 B - o l (61) m e l t i n g p o i n t a 90-92\u00C2\u00B0C 76.5-78\u00C2\u00B0C 3 5 0 6 3 6 1 0 I R ( K B r ) a 3 0 5 6 3 0 5 0 ( c m \" 1 ) 1 3 8 4 1 3 8 0 1 0 3 2 1 0 3 5 0 .17 ( dd , 7 = 4 . 6 , 4 . 6 H z ) 0 .17 ( d d , 7 = 4 . 5 , 4 . 5 H z ) 0 . 4 2 ( d d , 7 = 8 . 4 , 4 . 6 H z ) 0 . 4 2 ( dd , 7 = 8 . 5 , 4 . 5 H z ) 0 . 7 2 8 (s) 0 . 7 2 3 ( 4 7 = 1.0, 0 . 5 H z ) 0 . 8 1 2 (d , 7 = 6 .9 H z ) 0 . 8 1 3 (d , 7 = 6 .9 H z ) 0 . 8 5 7 (b r s) 0 . 8 5 7 ( 4 7 = 1 . 0 , 0 . 5 H z ) * H n m r ( C D 2 C 1 2 > 4 0 0 M H z ) b > c 0 . 8 6 8 (d , 7 = 6 . 9 H z ) 0 . 8 6 9 (d , 7 = 6 .9 H z ) (5) 1 .168 (s) 1 .169 ( 4 7 = 0 . 5 H z ) 1.77 ( d d , 7 = 1 3 . 8 , 9 . 3 H z ) 1.77 ( dd , 7 = 1 4 . 0 , 9 . 5 H z ) 2 .01 ( d d d d , 7 = 1 0 . 6 , 10 .6 , 2 . 0 0 ( d d d d , 7 = 1 0 . 5 , 1 0 . 5 , 3 . 8 , 2 . 7 H z 4 . 0 , 2 .5 H z 2 . 1 4 ( d d d d d d d , 7 = 6 x 6 . 9 , 2 . 1 4 ( d d d d d d d , 7 = 6 x 6 . 9 , 2 .7 H z ) 2 .5 H z ) 3 .55 ( dd , 7 = 8 . 9 , 7 . 6 H z ) 3 . 5 5 ( d d , 7 = 9 . 5 , 6 . 5 H z ) a- References 21a and 130. b- Only selected 1 H nmr signals are reported. c-Reference 21b. Table 14 : C o m p a r i s o n o f the 1 3 C n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( - ) - V e r r u c o s a n - 2 p - o l (61) a n d t h e S y n t h e t i c (\u00C2\u00B1)-Verrucosan-2p ,-ol (61). A s s i g n m e n t C h e m i c a l S h i f t O b s e r v e d f o r S y n t h e t i c (\u00C2\u00B1)-Verrucosan-2fJ-ol (61) ( C D C I 3 , 7 5 . 3 M H z ) ( p p m ) C h e m i c a l S h i f t O b s e r v e d f o r N a t u r a l ( - ) - V e r r u c o s a n - 2 | 3 - o l (61)a ( C D C I 3 , 1 0 0 M H z ) ( p p m ) C - 1 7 1 5 . 3 0 1 5 . 2 2 C - 2 0 1 8 . 0 4 1 7 . 9 7 C - 4 1 8 . 7 3 1 8 . 7 0 C - 1 9 1 9 . 5 0 1 9 . 4 2 C - 5 2 1 . 8 3 2 1 . 8 2 C - 1 2 2 2 . 7 2 2 2 . 6 8 C - 1 6 2 3 . 6 5 1 3 2 2 3 . 5 6 C - 3 absent 2 3 . 6 0 C - 1 8 2 5 . 6 2 2 5 . 5 4 C - 1 5 2 8 . 8 7 2 8 . 8 4 C - 9 3 5 . 7 1 3 5 . 7 2 C - 7 3 7 . 3 4 3 7 . 3 2 C - 8 3 7 . 9 3 3 7 . 9 3 C - l l 4 1 . 0 1 4 1 . 0 0 C - 6 4 2 . 8 3 4 2 . 8 3 C - 1 3 4 4 . 3 5 4 4 . 3 5 C - 1 0 4 4 . 6 2 4 4 . 6 1 C - l 4 6 . 8 8 4 6 . 8 9 C - 1 4 4 8 . 3 6 4 8 . 3 7 C - 2 7 3 . 8 0 7 3 . 7 6 a- Reference 21b. 1 3 6 137 T h e s y n t h e s i s o f (\u00C2\u00B1)-homoverrucosan-5 B - o l ( 6 3 ) f r o m (\u00C2\u00B1)-verrucosan-2B-ol ( 61 ) p a r a l l e l e d t h e c o n v e r s i o n o f (\u00C2\u00B1)-neoverrucosan-5 B - o l ( 62 ) t o 6 3 ( e q u a t i o n 3 2 , p a g e 1 2 4 ) . T h u s , t r e a t m e n t o f 6 1 w i t h 0 . 5 M s u l f u r i c a c i d i n r e f l u x i n g a c e t o n e p r o v i d e d ( \u00C2\u00B1 ) -h o m o v e r r u c o s a n - 5 B - o l ( 63 ) i n 5 9 % y i e l d ( e q u a t i o n 3 6 ) . 59% 61 63 2.1.5.7. Completion of the Synthesis of (\u00C2\u00B1)-(3R, 4R, 5R, 65,9fl)-cyatha-12,18-diene (64). A f t e r t h e t o t a l s y n t h e s e s o f t h r e e m e m b e r s o f the v e r r u c o s a n e - t y p e f a m i l y o f n a t u r a l p r o d u c t s w a s a c c o m p l i s h e d , the s y n t h e s i s o f the s t r u c t u r a l l y r e l a t e d c o m p o u n d (\u00C2\u00B1)-(3R, 4R, 5R, 6 5 , 9 i ? ) - c y a t h a - 1 2 , 1 8 - d i e n e ( 64 ) w a s a t t e m p t e d . T h e c y a t h a n e d i t e r p e n o i d 6 4 c o n t a i n s a n i s o p r o p e n y l u n i t a t C - 3 ( c y a t h a n e n u m b e r i n g ) . T h e t r i c y c l i c k e t o n e 171 a l s o h a s a n i s o p r o p e n y l g r o u p at C - 3 a n d p o s s e s s e s t h e c o r r e c t r e l a t i v e c o n f i g u r a t i o n a t a l l t h e s t e r e o c e n t e r s p r e s e n t i n (\u00C2\u00B1 ) -64 . T h e s y n t h e s i s o f (\u00C2\u00B1 ) -64 f r o m c o m p o u n d 171 v i a a o n e -c a r b o n r i n g e x p a n s i o n o f t h e C - r i n g to a f f o r d a c y c l o h e p t e n e w i t h t h e d o u b l e b o n d a n d a m e t h y l g r o u p at C - l 2 w a s u n d e r t a k e n . 171 6 4 S e v e r a l m e t h o d s f o r t h e h o m o l o g a t i o n o f c a r b o c y c l i c r i n g s a r e a v a i l a b l e . 1 3 3 T h e m o s t s u c c e s s f u l o n e c a r b o n r i n g e x p a n s i o n p r o t o c o l t h a t w a s a t t e m p t e d w a s t h e L e w i s a c i d c a t a l y z e d h o m o l o g a t i o n o f k e t o n e s w i t h d i a z o a c e t i c e s t e r s . 1 3 4 T h i s m e t h o d i s k n o w n to b e p a r t i c u l a r l y e f f e c t i v e f o r t h e c o n v e r s i o n o f s i x - m e m b e r e d r i n g k e t o n e s i n t o s e v e n - m e m b e r e d r i n g s . T r e a t m e n t o f t h e k e t o n e 171 w i t h e t h y l d i a z o a c e t a t e i n t h e p r e s e n c e o f B F 3 \u00C2\u00BB E t 2 0 at 0 \u00C2\u00B0C, f o l l o w e d b y w a r m i n g o f t h e r e a c t i o n m i x t u r e t o r o o m t e m p e r a t u r e , a f f o r d e d a n i n s e p a r a b l e m i x t u r e o f t h e p - k e t o e s t e r s 343 a n d 344 w h i c h w e r e i n e q u i l i b r i u m w i t h t h e i r c o r r e s p o n d i n g e n o l f o r m s 345 a n d 346. D e c a r b o x y l a t i o n o f 343 a n d 344 u n d e r K r a p c h o 1 3 5 c o n d i t i o n s ( D M S O , H2O, N a C l , r e f l u x ) p r o v i d e d k e t o n e s 347 a n d 177 w h i c h w e r e s e p a r a b l e b y s i l i c a g e l c h r o m a t o g r a p h y . T h e k e t o n e s 177 a n d 347 w e r e f o r m e d i n a r a t i o o f 1.3:1, r e s p e c t i v e l y , i n a n o v e r a l l y i e l d o f 9 8 % f r o m 171 (Scheme 66). T h e m i n o r c y c l o h e p t a n o n e 347 w a s d i s t i n g u i s h e d f r o m i ts d i a s t e r e o m e r 177 b y i ts * H n m r s p e c t r u m . T h e s p e c t r u m o f 347 c o n t a i n s t w o d i s t i n c t sets o f l o w f i e l d s i g n a l s f o r the p r o t o n s at C-10. T h e t w o d o u b l e t o f d o u b l e t s at 8 2.20 (7 = 1 6 . 5 , 11.7 H z ) a n d 2.68 (7 = 1 6 . 5 , 3 .3 H z ) w e r e a s s i g n e d to H - l O o c a n d H-10P, r e s p e c t i v e l y . 139 EtOoC P 0 p 0 2 B BF3\u00C2\u00ABOEt2 N 2 C H C 0 2 E t *** E t 2 0 , 0 \u00C2\u00B0C to rt 171 343 E t 0 9 C O H 344 H O C 0 2 E t D M S O , H 2 0 NaCl, reflux 347 177 1 1.3 98% yield from 171 Scheme 66 W h e n t h e ring e x p a n s i o n w a s c a r r i e d o u t at - 7 8 \u00C2\u00B0C u s i n g e t h y l d i a z o a c e t a t e a n d a n t i m o n y p e n t a c h l o r i d e (SbCls) 1 3 4 b a n d t h e r e s u l t a n t m i x t u r e w a s s u b j e c t e d t o K r a p c h o d e c a r b o x y l a t i o n , t h e p r o d u c t r a t i o w a s 1.9:1 i n f a v o r o f 177, b u t t h e y i e l d w a s c o n s i d e r a b l y l o w e r (64% o v e r t w o s t e p s ) . T h e l a c k o f s e l e c t i v i t y i n t h e r i n g e x p a n s i o n w a s d i s a p p o i n t i n g , e s p e c i a l l y d u e to t h e w i d e l y d i f f e r e n t r e a c t i v i t i e s o f t h e m e t h y l e n e g r o u p s tha t f l a n k t h e c a r b o n y l m o i e t y i n t h e k e t o n e 171 (vide supra). W h i l e p l a u s i b l e s y n t h e t i c r o u t e s l e a d i n g to 1 4 0 t h e c y a t h a n e 64 c a n b e e n v i s a g e d s t a r t i n g f r o m e i t h e r k e t o n e 347 o r 177, o n l y t h o s e b e g i n n i n g f r o m t h e t r i c y c l i c k e t o n e 177 a re d e s c r i b e d . T h e s i m p l e s t a n d m o s t d i r e c t r o u t e f o r t h e s y n t h e s i s o f 64 f r o m 171 i n v o l v e d 1 , 2 -a d d i t i o n o f a m e t h y l G r i g n a r d r e a g e n t t o t h e c a r b o n y l g r o u p f o l l o w e d b y d e h y d r a t i o n o f t h e r e s u l t a n t t e r t i a r y a l c o h o l . A d d i t i o n o f m e t h y l m a g n e s i u m b r o m i d e to 171 i n d i e t h y l e t h e r at - 7 8 \u00C2\u00B0C w i t h w a r m i n g to 0 \u00C2\u00B0C g a v e a n a p p r o x i m a t e l y 1:1 m i x t u r e o f d i a s t e r e o m e r i c a l c o h o l s 348 i n 8 9 % y i e l d (Scheme 67). A c i d - p r o m o t e d d e h y d r a t i o n o f 348 w i t h c a m p h o r s u l p h o n i c a c i d i n r e f l u x i n g b e n z e n e p r o v i d e d t h e c y a t h a n e n a t u r a l p r o d u c t 64 a n d i t s d o u b l e b o n d i s o m e r 349 i n a r a t i o o f 1 . 8 : 1 , r e s p e c t i v e l y . T h e n o n - p o l a r m i x t u r e o f c o m p o u n d s w a s i n s e p a r a b l e b y s i l i c a g e l c h r o m a t o g r a p h y a n d b y r e v e r s e p h a s e H P L C . O H O . MeMgBr, E t 2 Q -78 \u00C2\u00B0C to 0 \u00C2\u00B0C 177 348 -1:1 89% C S A , benzene reflux 64 1.8 349 1 Scheme 67 D u e to t h e l a c k o f s e l e c t i v i t y i n t h e s y n t h e s i s o f t h e c y a t h a n e 64 b y t h e m e t h o d o u t l i n e d i n S c h e m e 67, a d i f f e r e n t a p p r o a c h w a s i n v e s t i g a t e d w h i c h i n v o l v e d c o u p l i n g o f a n e n o l t r i f l a t e w i t h l i t h i u m d i m e t h y l c u p r a t e . 1 3 6 T r e a t m e n t o f t h e t r i c y c l i c k e t o n e 171 w i t h l i t h i u m d i i s o p r o p y l a m i d e ( L D A ) i n T H F , f o l l o w e d b y t h e a d d i t i o n o f N-p h e n y l t r i f l u o r o m e t h a n e s u l f o n i m i d e ((CFsSC^hNCeHe)137 i n t h e p r e s e n c e o f H M P A , p r o v i d e d a m i x t u r e o f n o n - p o l a r e n o l t r i f l a t e s i n 6 9 % y i e l d ( e q u a t i o n 37). O, TfO TfO * H n m r a n a l y s i s o f t h e c r u d e r e a c t i o n m i x t u r e i n d i c a t e d a 3 .6 :1 r a t i o o f 350 t o 351, r e s p e c t i v e l y . T h e c o m p o u n d s w e r e e x t r e m e l y d i f f i c u l t t o s e p a r a t e b y s i l i c a g e l c h r o m a t o g r a p h y , b u t a s a m p l e o f t h e m a j o r p r o d u c t 350 w a s i s o l a t e d . T h e * H n m r s p e c t r u m o f 350 a n d i H - i H h o m o n u c l e a r d e c o u p l i n g e x p e r i m e n t s c o n f i r m e d that t h e d o u b l e b o n d i s b e t w e e n C - l 2 a n d C - 1 3 ( c y a t h a n e n u m b e r i n g ) . A o n e p r o t o n a l k e n i c s i g n a l a p p e a r s at 8 5 . 6 4 - 5 . 7 0 i n t h e : H n m r s p e c t r u m o f 350 w h i c h i s a t t r i b u t e d to H - 1 3 . O n e o f t h e a l l y l i c p r o t o n s at C - 1 4 a p p e a r s at 8 1.86 ( d d , 7 = 1 4 . 5 , 1 0 . 0 H z ) . I n 1 H - * H h o m o n u c l e a r d e c o u p l i n g e x p e r i m e n t s , i r r a d i a t i o n o f the m u l t i p l e t at 8 5 . 6 4 - 5 . 7 0 ( H - 1 3 ) c a u s e d t h e d o u b l e t o f d o u b l e t s at 8 1 .86 (7 = 1 4 . 5 , 1 0 . 0 H z , H - 1 4 ) t o c o l l a p s e i n t o a d o u b l e t ( 7 = 1 4 . 5 H z ) , as w e l l as r e s o l v e d the s i g n a l f o r t h e s e c o n d C - 14 p r o t o n as a b r o a d d o u b l e t ( 7 = 14 .5 H z ) at 8 2 . 0 5 ( H -14'). T h i s r e s u l t i s o n l y p o s s i b l e f o r c o m p o u n d 350. I n a n a t t e m p t to i m p r o v e t h e r e g i o s e l e c t i v i t y o f the e n o l i z a t i o n r e a c t i o n t h e b u l k i e r b a s e l i t h i u m 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i n e ( L i T M P ) w a s e m p l o y e d . H o w e v e r , t h e s a m e r a t i o ( 3 . 6 : 1 ) o f e n o l t r i f l a t e s w a s o b t a i n e d as w i t h L D A a n d i n a p p r o x i m a t e l y t h e s a m e y i e l d ( 7 3 % ) . W h e n K H M D S w a s u s e d as the b a s e , f o l l o w e d b y t h e a d d i t i o n o f Tf2NPh, a s e c o n d s l i g h t l y m o r e p o l a r s p o t a p p e a r e d o n t h e t i c c h r o m a t o g r a m a l o n g w i t h t h a t o f t h e e n o l t r i f l a t e s . A f t e r s i l i c a g e l c h r o m a t o g r a p h y , e v e r y f r a c t i o n c o n t a i n i n g t h i s c o m p o u n d a l s o s h o w e d e v i d e n c e o f t h e s t a r t i n g m a t e r i a l 1 7 1 . M o r e o v e r , i f the c r u d e r e a c t i o n m i x t u r e w a s a l l o w e d to s t a n d at r o o m t e m p e r a t u r e f o r s e v e r a l d a y s , t h e n e w c o m p o u n d d i s a p p e a r e d a n d s t a r t i n g m a t e r i a l 1 7 1 a p p e a r e d w h e n n o n e h a d b e e n v i s i b l e b e f o r e . T h e c r u d e * H n m r s p e c t r u m s h o w s n e w o l e f i n i c s i g n a l s b e s i d e s t h o s e a t t r i b u t e d t o t h e e n o l t r i f l a t e s . T h i s e v i d e n c e s u g g e s t e d that a m i x t u r e o f the m o r e l a b i l e e n o l s i l y l e the rs 3 5 2 a n d 3 5 3 w e r e a l s o b e i n g p r o d u c e d i n t h e r e a c t i o n ( e q u a t i o n 3 8 ) . E n c o u r a g i n g l y , w h e n t h e e n o l t r i f l a t e s w e r e i s o l a t e d , the r a t i o w a s 11 :1 i n f a v o r o f t h e d e s i r e d d i a s t e r e o m e r 3 5 0 . T h e h i g h e r r e g i o s e l e c t i v i t y o b s e r v e d w i t h K H M D S as c o m p a r e d to L D A o r L i T M P w a s n o t a n t i c i p a t e d . T h e l a r g e r p o t a s s i u m c o u n t e r c a t i o n m a y c o n f e r to the b a s e i n c r e a s e d b u l k m a k i n g i t m o r e s e l e c t i v e . T h e c o n c o m i t a n t f o r m a t i o n o f t h e e n o l s i l y l e thers w a s c i r c u m v e n t e d b y q u e n c h i n g t h e e n o l a t e s w i t h a l a r g e e x c e s s o f t h e t r i f l a t i n g agen t . T h u s , w h e n 2 0 e q u i v a l e n t s o f T f 2 N P h w e r e u s e d , t h e e n o l t r i f l a t e s 3 5 0 a n d 3 5 1 w e r e i s o l a t e d e x c l u s i v e l y i n a r a t i o o f 1 1 : 1 , r e s p e c t i v e l y , i n 7 4 % y i e l d . T h e t r i f l a t e 3 5 0 w a s s e p a r a t e d f r o m i ts d i a s t e r e o m e r 3 5 1 b y s i l i c a g e l c h r o m a t o g r a p h y a f f o r d i n g p u r e 3 5 0 i n 5 2 % y i e l d . T h e l a s t s t e p i n t h e s y n t h e s i s i n v o l v e d t r e a t m e n t o f 3 5 0 w i t h l i t h i u m d i m e t h y l c u p r a t e 1 3 8 i n d i e t h y l e t h e r at 0 \u00C2\u00B0C a n d p r o v i d e d (3R*, AR*, 5R*, 6 5 * , 9 / ? * ) - c y a t h a - 1 2 , 1 8 -d i e n e 6 4 i n 9 8 % y i e l d ( e q u a t i o n 39 ) . 98% 3 5 0 6 4 T h e r a c e m i c s y n t h e t i c p r o d u c t e x h i b i t e d i n f r a r e d a n d * H n m r s p e c t r a l d a t a i d e n t i c a l 1 3 9 w i t h t h o s e d e r i v e d f r o m t h e n a t u r a l l y o c c u r r i n g (-)-(3R, AR, 5R, 6 5 , 9 i ? ) - c y a t h a -1 2 , 1 8 - d i e n e (see T a b l e 1 5 , p a g e 1 4 4 ) . 2 3 - 1 4 0 T h e lU n m r s p e c t r u m o f t h e s y n t h e t i c (\u00C2\u00B1)-64 i s s h o w n o n p a g e 145 ( F i g u r e 8 ) . I n h o m o n u c l e a r ( 1 H - 1 H ) d e c o u p l i n g e x p e r i m e n t s , i r r a d i a t i o n o f t h e m u l t i p l e t at 8 5 . 2 9 - 5 . 3 6 ( H - 1 3 ) r e v e a l e d i t is c o u p l e d to t h e m u l t i p l e t at 8 1 . 6 7 - 1 . 7 3 ( H - 1 4 ) a n d to a s i g n a l that i s p a r t o f the m u l t i p l e t at 8 1 . 9 1 - 2 . 0 5 ( H - 1 4 ' ) . 1 4 1 I r r a d i a t i o n o f t h e s i g n a l at 8 5 . 2 9 - 5 . 3 6 ( H - 1 3 ) a l s o r e s u l t e d i n the s i m p l i f i c a t i o n o f the d o u b l e t o f d o u b l e t o f d o u b l e t o f d o u b l e t s at 8 1.86 (7 = 1 4 . 5 , 6 . 7 , 1.5, 1.5 H z , H - l 1) i n t o a d o u b l e t o f d o u b l e t o f d o u b l e t s ( 7 = 1 4 . 5 , 6 . 7 , 1.5 H z ) . 1 4 4 Table 15 : C o m p a r i s o n o f the TR a n d ! H n m r S p e c t r a l D a t a f o r t h e N a t u r a l ( - ) - C y a t h a n e (64) a n d S y n t h e t i c (\u00C2\u00B1)-Cyathane (64). 64 D a t a S y n t h e t i c N a t u r a l (\u00C2\u00B1)-Cyathane 64 ( - ) - C y a t h a n e 64* 3 0 7 1 3 0 7 5 I R b 2 9 2 1 2 9 1 5 ( c m - 1 ) 1 6 4 1 1 6 4 0 0 . 7 7 (s) 0 . 7 9 (s) 0 . 8 3 (s) 0 . 8 5 (s) lH n m r ( C H C l 3 ) c > d 1.66 ( s ) e 1.52 ( s ) e (8) 1.68 ( s ) e 1.68 ( s ) e 4 . 5 4 - 4 . 5 7 4 . 5 6 ( b r d 7 = 2 H z ) 4 . 6 5 ( b r d d , 7 = 1 . 4 , 0 . 5 H z ) 4 . 6 6 ( b r d , 7 = 2 H z ) 5 . 2 9 - 5 . 3 6 ( m ) 5 . 3 3 ( b r t 7 = 6 H z ) a- Reference 23. b- The IR spectra of synthetic (\u00C2\u00B1)-cyathane 64 and natural (-)-cyathane 64 were obtained as a thin film between NaCl plates and as a solution in carbon tetrachloride, respectively, c- Only selected 1 H nmr signals are reported. d- The J H nmr spectra of the synthetic (\u00C2\u00B1)-cyafhane 64 and the natural (-)-cyathane 64 were acquired at 400 MHz and 80 MHz, respectively, e- See reference 139. 145 146 2.1.6. Biological Activity Studies. V e r y l i t t l e i n f o r m a t i o n i s k n o w n a b o u t t h e b i o l o g i c a l a c t i v i t y o f t h e v e r r u c o s a n e - t y p e f a m i l y o f n a t u r a l p r o d u c t s . H o w e v e r , c e r t a i n m e m b e r s o f t h e s t r u c t u r a l l y s i m i l a r c y a t h a n e s h a v e b e e n r e p o r t e d to e x h i b i t a w i d e r a n g e o f a c t i v i t y . 3 7 - 3 9 T h e f o u r r a c e m i c s y n t h e t i c n a t u r a l p r o d u c t s 61-64 w e r e t e s t e d f o r a n t i m i c r o b i a l a n d a n t i f u n g a l a c t i v i t y 1 4 2 a n d f o r in vitro c y t o t o x i c i t y a g a i n s t t h e P 3 8 8 m u r i n e l e u k e m i a c e l l l i n e . 1 4 3 T h e a n t i m i c r o b i a l a n d a n t i f u n g a l a c t i v i t y tests w e r e t h e K i r b y B a u e r d i s k d i f f u s i o n a s s a y . A k n o w n a m o u n t o f c o m p o u n d i s a b s o r b e d o n t o a d i s k w h i c h i s p l a c e d o n t o a p e t r i d i s h c u l t u r e o f a s e l e c t e d o r g a n i s m . T h e c u l t u r e i s i n c u b a t e d a n d t h e a c t i v i t y o f t h e c h e m o t h e r a p e u t i c a g e n t i s d e t e r m i n e d b y t h e s i z e o f t h e z o n e o f i n h i b i t i o n o f t h e o r g a n i s m o n t h e g r o w t h m e d i u m . T h e f o l l o w i n g f i v e c o m m o n s t a n d a r d p a t h o g e n s w e r e c h o s e n f o r t h e test : m e t h a c i l l i n r e s i s t a n t Staphylococcus aureus ( M R S A ) , Pseudomonas aeruginosa (P. a u r . ) , Echerichia coli ( E . c o l i ) , Candida albicans (C. a l b . ) , a n d Enterobacter species ( E n t . sp . ) . N o n e o f t h e s y n t h e t i c s a m p l e s 61-64 e x h i b i t e d a n t i m i c r o b i a l o r a n t i f u n g a l a c t i v i t y . T h e in vitro c y t o t o x i c i t y s t u d i e s w e r e c o n d u c t e d a g a i n s t t h e c o m m o n s c r e e n i n g a g e n t P 3 8 8 m u r i n e l e u k e m i a c e l l l i n e . T h e r e s u l t s f o r the s y n t h e t i c r a c e m i c n a t u r a l p r o d u c t s 61-64 are s h o w n i n Table 16 a n d a re a p p r o x i m a t e l y w i t h i n t h e s a m e o r d e r o f m a g n i t u d e . O t h e r c y a t h a n e n a t u r a l p r o d u c t s h a v e r e p o r t e d s i m i l a r in vitro c y t o t o x i c i t y ICso's (2.5-11.2 u . g / m L ) a g a i n s t the P 3 8 8 m u r i n e l e u k e m i a c e l l l i n e . 3 8 147 T a b l e 1 6 : In vitro C y t o t o x i c i t y o f t h e S y n t h e t i c R a c e m i c C y a t h a n e a n d V e r r u c o s a n e - t y p e N a t u r a l P r o d u c t s A g a i n s t t h e P 3 8 8 M u r i n e L e u k e m i a C e l l L i n e . S y n t h e t i c R a c e m i c N a t u r a l P r o d u c t EDsoCpig/mL) H*T H ? 6 2 2.1 \u00C2\u00B1 0 . 5 H O , \u00E2\u0080\u0094 / H V H ~? .*^ r H T\" y 6 3 1.7 \u00C2\u00B1 0 . 4 K | O H ^ ^ ' T H T > 6 1 2.1 \u00C2\u00B1 0 . 4 * I H H / 6 4 21 \u00C2\u00B1 3 148 2 . 1 . 7 . Conclusion. T h e w o r k d e s c r i b e d i n t h i s p a r t o f t h e t h e s i s c u l m i n a t e d i n t h e f i r s t r e p o r t e d t o t a l s y n t h e s e s o f t h e f o u r d i t e r p e n o i d n a t u r a l p r o d u c t s , (\u00C2\u00B1)-neoverrucosan-5fi-ol ( 6 2 ) , (\u00C2\u00B1 ) -h o m o v e r r u c o s a n - 5 p - o l ( 6 3 ) , (\u00C2\u00B1)-verrucosan-2p-ol ( 6 1 ) , a n d (\u00C2\u00B1)-(3R, 4R, 5R, 6S, 9 f l ) - c y a t h a -1 2 , 1 8 - d i e n e ( 6 4 ) . T h e s y n t h e s e s o f t h e s e s t e r e o c h e m i c a l l y a n d s t r u c t u r a l l y s i m i l a r n a t u r a l p r o d u c t s f o l l o w e d a c e n t r a l i z e d a n d d i v e r g e n t s y n t h e t i c p l a n . U s e f u l l y f u n c t i o n a l i z e d a d v a n c e d i n t e r m e d i a t e s s e r v e d as b r a n c h i n g p o i n t s f r o m w h i c h t h e n a t u r a l p r o d u c t s w e r e d e r i v e d . O n e o f t h e k e y s t e p s i n v o l v e d a s t e r e o s e l e c t i v e c o n j u g a t e a d d i t i o n r e a c t i o n w h i c h h a d b e e n p r e v i o u s l y d e v e l o p e d i n o u r l a b o r a t o r y . C o n j u g a t e a d d i t i o n o f the c u p r a t e r e a g e n t 1 9 2 to the b i c y c l i c e n o n e 1 7 9 a n d c o n t r o l o f t h e 5 , 6 r i n g - j u n c t u r e s t e r e o c h e m i s t r y g a v e the k e t o n e 6 0 , w h i c h h a s t h e c o r r e c t r e l a t i v e c o n f i g u r a t i o n at t h r e e o f the s t e r e o g e n i c c e n t e r s p r e s e n t i n 6 1 - 6 4 . A n e w b i f u n c t i o n a l r e a g e n t m e d i a t e d c y c l o h e x e n o n e a n n u l a t i o n p r o t o c o l w a s d e v e l o p e d b u t the m e t h o d w a s n o t e f f e c t i v e i n the n a t u r a l p r o d u c t s y n t h e s e s . T h e g e n e r a l i t y o f the n e w a n n u l a t i o n s e q u e n c e i s i n v e s t i g a t e d i n the s e c o n d p a r t o f t h i s t h e s i s . A l t e r n a t i v e l y , a n a l d o l c o n d e n s a t i o n w a s u s e d to a p p e n d the r e q u i r e d s i x - m e m b e r e d r i n g , w h i c h l e d to t h e s y n t h e s i s o f t h e t r i c y c l i c k e t o n e 1 7 1 . F r o m c o m p o u n d 1 7 1 , d i v e r g i n g s y n t h e t i c r o u t e s g a v e the c y a t h a n e n a t u r a l p r o d u c t 6 4 o r t h e th ree v e r r u c o s a n e - t y p e n a t u r a l p r o d u c t s 6 1 - 6 3 . R i n g e x p a n s i o n o f 1 7 1 a n d f u n c t i o n a l g r o u p m a n i p u l a t i o n s l e d to 6 4 . C o n v e r s i o n o f 1 7 1 i n t o t h e t r i c y c l i c e n o n e 1 7 4 i n v o l v e d a s e r i e s o f f u n c t i o n a l g r o u p t r a n s f o r m a t i o n s . S e p a r a t e s y n t h e t i c r o u t e s f r o m c o m p o u n d 1 7 4 l e d to (\u00C2\u00B1)-neoverrucosan-5p-ol ( 6 2 ) a n d (\u00C2\u00B1)-verrucosan-2p-ol (61 ) , b o t h o f w h i c h r e a c t e d w i t h a c i d to p r o d u c e ( + ) - h o m o v e r r u c o s a n - 5 P - o l (63 ) . T h e f o u r s y n t h e t i c r a c e m i c n a t u r a l p r o d u c t s 6 1 - 6 4 w e r e t e s t e d f o r a n t i m i c r o b i a l a n d a n t i f u n g a l a c t i v i t y a n d in vitro c y t o t o x i c i t y a g a i n s t the P 3 8 8 m u r i n e l e u k e m i a c e l l l i n e . N o n e o f t h e s e c o m p o u n d s e x h i b i t e d a n t i m i c r o b i a l o r a n t i f u n g a l a c t i v i t y b u t a l l p o s s e s s e d c y t o t o x i c i t y w i t h EDso's i n t h e r a n g e o f 1 .7 -21 u . g / m L . A s u m m a r y o f t h e s y n t h e s e s o f 61-64 are o u t l i n e d i n Scheme 68. 1 4 9 \ ^ O N V = OTBS O u\== H r II H ? k n y ? OTBS O Scheme 68 (a) BrMg(CH 2 ) 2 C H (0 ( C H 2 ) 3 0) , CuBr\u00C2\u00ABMe 2 S , T M S C 1 , H M P A , T H F , - 7 8 \u00C2\u00B0C to r t , 95%; (b) C F 3 C O O H , T H F , 7 0 \u00C2\u00B0C, 9 1 % ; (c ) r e a g e n t 192, T M S C 1 , T H F - E t 2 0 ; N H 4 C I , H 2 0 , 8 6 % ; (d) M e O N a , M e O H , 4 0 \u00C2\u00B0C, 95%; (e) K H M D S , T H F , - 7 8 \u00C2\u00B0C; r e a g e n t 281, H M P A , - 7 8 \u00C2\u00B0C to - 4 8 \u00C2\u00B0C to rt , 8 0 % ; (f) L D A , T H F , - 7 8 \u00C2\u00B0C to 0 \u00C2\u00B0C; M e l ( e x c e s s ) , - 7 8 \u00C2\u00B0C to rt , 9 6 % ; (g) B114NF, T H F , rt , 9 8 % ; (h ) P C C , C e l i t e , C H 2 C 1 2 , r t , 93%; ( i ) E t O N a , E t O H , r e f l u x , 8 9 % ; ( j ) L i , N H 3 , f - B u O H , T H F , - 7 8 \u00C2\u00B0C ; N H 4 C I ( s o l i d ) , 9 8 % ; ( k ) H 2 (1 a t m o s p h e r e ) , P t 0 2 , E t O A c , r t ; c h r o m a t o g r a p h y ; P C C , C e l i t e , C H 2 C 1 2 , r t , 95%; (1) K H M D S , T H F , - 7 8 \u00C2\u00B0C to 0 \u00C2\u00B0C; d i m e t h y l d i o x i r a n e , a c e t o n e , - 7 8 \u00C2\u00B0C, 8 1 % ; ( m ) T B S C 1 , i m i d a z o l e , CH2CI2, r t , 1 0 0 % ; (n) C p 2 T i C H 2 A l C l M e 2 ( T e b b e r e a g e n t ) , C 6 H 6 , T H F , r t , 95%; (o ) B U 4 N F , T H F , r t , 99%; (p ) T P A P , N M O , 4A m o l e c u l a r s i e v e s , C H 2 C 1 2 , r t ; (q) R h C l 3 \u00C2\u00AB 3 H 2 0 , E t O H , r e f l u x , 6 1 % f r o m 327; ( r ) N 2 C H C 0 2 E t , B F 3 ' E t 2 0 , E t 2 0 , 0 \u00C2\u00B0C to r t ; (s ) D M S O , N a C l , H 2 0 , r e f l u x ; c h r o m a t o g r a p h y , 55% f r o m 171; (t) K H M D S , T H F , - 7 8 \u00C2\u00B0C to 0 \u00C2\u00B0C; P h N ( S 0 2 C F 3 ) 2 , H M P A , 0 \u00C2\u00B0C to r t ; c h r o m a t o g r a p h y , 5 2 % ; M e 2 C u L i , E t 2 0 , - 1 0 \u00C2\u00B0C, 9 8 % . S c h e m e 6 8 ( c o n t i n u e d ) (v ) N a B H 4 , C e C l 3 \u00C2\u00BB 3 H 2 0 , M e O H , r t , 7 1 % ; ( w ) E t 2 Z n , I C H 2 C 1 , C 1 C H 2 C H 2 C 1 , 0 \u00C2\u00B0C, 9 2 % f r o m 1 7 3 ; 9 8 % f r o m 1 7 2 ; ( x ) H 2 S 0 4 , H 2 0 , a c e t o n e , r e f l u x , 9 9 % f r o m 6 2 ; 5 9 % f r o m 6 1 ; ( y ) d i m e t h y l d i o x i r a n e , a c e t o n e , C H 2 C 1 2 , r t , 7 2 % ; (z) H 2 N N H 2 , h e x - l - e n e , M e O H , H O A c , 0 \u00C2\u00B0C, 6 8 % . 2.2. Bifunctional Reagent Mediated Cyclohexenone Annulation Methodology. 2.2.1. Introductory Remarks. F u n c t i o n a l i z e d s i x - m e m b e r e d c a r b o c y c l i c r i n g s a r e c o m m o n s t r u c t u r a l f e a t u r e s i n m a n y c l a s s e s o f n a t u r a l p r o d u c t s . A s a r e s u l t , a n u m b e r o f m e t h o d s h a v e b e e n d e v e l o p e d f o r t h e c o n v e r s i o n o f k e t o n e s i n t o a n n u l a t e d c y c l o h e x e n o n e s . 6 8 I n c o n n e c t i o n w i t h t h e t o t a l s y n t h e s i s o f t h e n a t u r a l p r o d u c t s 61-64 d e s c r i b e d i n t h e f i r s t p a r t o f t h i s t h e s i s , a n e w b i f u n c t i o n a l r e a g e n t m e d i a t e d c y c l o h e x e n o n e a n n u l a t i o n p r o t o c o l w a s d e v e l o p e d . T h e s t r a t e g y f o r t h e n e w s e q u e n c e w a s d e s c r i b e d i n S e c t i o n 1.3 ( p a g e 14) a n d i s a n a l o g o u s to t h e m e t h o d o l o g y o u t l i n e d i n Scheme 7 ( p a g e 10) . T h e d e v e l o p m e n t a n d l i m i t a t i o n s o f t h e n e w m e t h o d w e r e d e s c r i b e d i n d e t a i l i n S e c t i o n 2 . 1 . 5 . 2 ( p a g e s 5 2 - 8 3 ) . T h e m e t h o d o l o g y w a s s u c c e s s f u l i n a p p e n d i n g a c y c l o h e x e n o n e r i n g o n s i m p l e m o d e l c o m p o u n d s b u t f o r r e a s o n s d e l i n e a t e d i n t h e a f o r e m e n t i o n e d s e c t i o n , the m e t h o d w a s u n s u c c e s s f u l w i t h i n the c o n t e x t o f the n a t u r a l p r o d u c t s y n t h e s i s . A s u m m a r y o f t h e s e q u e n c e that w i l l b e e x a m i n e d i s o u t l i n e d i n Scheme 69. 152 N H 2 N M e 2 r C 6 H 6 , reflux 31 H Q 358 P C C , C H 2 C I 2 , rt O 359 N\" ,N(Me) 2 N(Me) 32 357 1) LDA, THF, 0\u00C2\u00B0C 2) i x ^ v / \" 5 ^ S n B u 3 H M P A 253 l 2 ) C H 2 C . 2 , r t ^ 5 4 X = S n B u 3 n-BuLi, THF -78 \u00C2\u00B0C S c h e m e 69 NaOAc A c O H THF, H 2 Q 356 T h e f i r s t s tep i n v o l v e s a l k y l a t i o n o f a n A ^ N - d i m e t h y l h y d r a z o n e d e r i v a t i v e o f g e n e r a l s t r u c t u r e 32 w i t h t h e b i f u n c t i o n a l r e a g e n t ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) to p r o v i d e 354. T i n - i o d i n e e x c h a n g e p r o c e e d s w i t h r e t e n t i o n o f c o n f i g u r a t i o n t o a f f o r d t h e Z -a l k e n y l i o d i d e 355 a n d a c i d h y d r o l y s i s o f t h e h y d r a z o n e f u n c t i o n i n 355 p r o d u c e s t h e k e t o a l k e n y l i o d i d e 356. T r e a t m e n t o f 356 w i t h n - B u L i a t - 7 8 \u00C2\u00B0C p r o v i d e s t h e a l k e n y l l i t h i u m s p e c i e s 357, w h i c h c y c l i z e s o n t o t h e c a r b o n y l t o a f f o r d t h e t e r t i a r y a l l y l i c a l c o h o l 358. O x i d a t i v e r e a r r a n g e m e n t o f 358 w i t h P C C g i v e s the c y c l o h e x e n o n e 359. T h e s e c o n d p a r t o f t h i s t h e s i s i s d e v o t e d to e x p l o r i n g t h e g e n e r a l s y n t h e t i c u t i l i t y o f t h i s n e w l y d e v e l o p e d m e t h o d b y a p p l y i n g i t to a v a r i e t y o f d i f f e r e n t s u b s t r a t e s . 153 2.2.2. Preparation of the A^N-Dimethylhydrazones Substrates. T h e a l k y l a t i o n s tep r e q u i r e d the u s e o f / V , A f - d i m e t h y l h y d r a z o n e s 7 4 i n o r d e r to a v o i d e l i m i n a t i o n o f H I f r o m t h e h o m o a l l y l i c i o d i d e 253 a n d f o r m i n g t h e d i e n e 254, w h i c h w a s o b s e r v e d w i t h k e t o n e e n o l a t e s ( e q u a t i o n 16, p a g e 7 5 ) . A l k y l a t i o n s o f d i m e t h y l h y d r a z o n e s w i t h h o m o a l l y l i c h a l i d e s h a v e b e e n p e r f o r m e d s u c c e s s f u l l y . 4 7 ' 7 5 T h e h y d r a z o n e s 211 a n d 360-364 u s e d i n t h i s s t u d y w e r e p r e p a r e d f r o m t h e c o r r e s p o n d i n g c o m m e r c i a l l y a v a i l a b l e k e t o n e s b y r e f l u x i n g t h e k e t o n e i n n e a t d i m e t h y l h y d r a z i n e o r b y t r e a t i n g t h e k e t o n e w i t h d i m e t h y l h y d r a z i n e i n r e f l u x i n g d r y b e n z e n e w i t h a z e o t r o p i c r e m o v a l o f w a t e r . I n t h i s m a n n e r , t h e h y d r a z o n e s 211, 361, 363, a n d 364 w e r e i s o l a t e d i n y i e l d s o f 9 8 % , 9 4 % , 1 0 0 % , a n d 9 9 % , r e s p e c t i v e l y . T h e p r e p a r a t i o n o f t h e h y d r a z o n e s 360 1 4 4 a n d 362 1 4 5 h a s b e e n p r e v i o u s l y d e s c r i b e d . ,N(Me) 2 N(Me) 2 N N S p e c t r o s c o p i c d a t a w a s u s e d t o c o n f i r m t h e f o r m a t i o n o f e a c h N,N-d i m e t h y l h y d r a z o n e s u b s t r a t e s . F o r e x a m p l e , t h e J H n m r s p e c t r u m o f t h e h y d r a z o n e 364 c o n t a i n s a s i x p r o t o n s i n g l e t at 8 2 . 3 8 f o r t h e t w o m e t h y l g r o u p s o n n i t r o g e n a n d t h e 1 3 C n m r s p e c t r u m e x h i b i t s s i g n a l s at 8 4 7 . 6 a n d 1 7 0 . 7 f o r t h e h y d r a z o n e m e t h y l g r o u p s a n d t h e h y d r a z o n e c a r b o n , r e s p e c t i v e l y . T h e r e m a i n i n g h y d r a z o n e s u b s t r a t e s p r o v i d e d s i m i l a r s p e c t r o s c o p i c d a t a . 1 5 4 2.2.3. Preparation of the Bifunctional Reagent (Z)-4-Iodo-l-(tributylstannyl)but-l-ene (253). T h e r e a g e n t s 70 p o s s e s s i n g a t r i a l k y l g e r m a n i u m o r a t r i a l k y l s t a n n a n e m o i e t y a r e r e a g e n t s that c a n s e r v e as t h e s y n t h e t i c e q u i v a l e n t o f t h e b u t - l - e n e d 1 , a 4 - s y n t h o n (69). M = Ge or Sn 69 70 H o w e v e r , i t w a s d i s c o v e r e d tha t t h e g e r m a n i u m h a l o g e n e x c h a n g e r e a c t i o n s o f s u b s t r a t e s s u c h as 354a d i d n o t p r o c e e d w i t h r e t e n t i o n o f t h e d o u b l e b o n d c o n f i g u r a t i o n ( e q u a t i o n 40). F o r t u n a t e l y , t h e c o r r e s p o n d i n g i o d o d e s t a n n y l a t i o n r e a c t i o n o f a l k e n y l t r i - n -b u t y l s t a n n a n e s d i d o c c u r w i t h r e t e n t i o n . A p o s s i b l e r a t i o n a l i z a t i o n o f t h e s e o b s e r v a t i o n s w a s d i s c u s s e d o n p a g e s 6 0 - 7 6 . R R R R = 0 or N-N(Me) 2 354a T h e b i f u n c t i o n a l r e a g e n t ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) w a s p r e p a r e d b y a n e f f i c i e n t t w o s tep p r o c e d u r e as o u t l i n e d i n Scheme 36 ( p a g e 74). B u 3 S n ^ / 253 155 2.2.4. Preparation of the Keto Alkenyl Iodide Cyclization Substrates. T h e h y d r a z o n e s 211 a n d 360-364 w e r e a l k y l a t e d e f f i c i e n t l y b y t r e a t i n g t h e c o r r e s p o n d i n g a n i o n s w i t h t h e b i f u n c t i o n a l e l e c t r o p h i l e 253 i n t h e p r e s e n c e o f H M P A . U n d e r t h e s e c o n d i t i o n s , e l i m i n a t i o n o f H I f r o m t h e e l e c t r o p h i l e 253 to g i v e the c o r r e s p o n d i n g d i e n e w a s r a r e l y o b s e r v e d . H o w e v e r , p u r i f i c a t i o n o f t h e a l k y l a t e d h y d r a z o n e s b y s i l i c a g e l c h r o m a t o g r a p h y w a s d i f f i c u l t s i n c e t h e a d d u c t s w e r e o f t e n v e r y p o l a r a n d p a r t i a l h y d r o l y s i s o f t h e h y d r a z o n e m o i e t y o n t h e c h r o m a t o g r a p h i c c o l u m n w a s o f t e n o b s e r v e d . A s a r e s u l t , t h e i o d o d e s t a n n y l a t i o n r e a c t i o n s 1 4 6 w e r e c a r r i e d o u t o n the c r u d e a l k y l a t i o n r e a c t i o n p r o d u c t s b y t h e a d d i t i o n o f a s o l u t i o n o f i o d i n e i n m e t h y l e n e c h l o r i d e at 0 \u00C2\u00B0 C . 1 4 7 A f t e r a n a p p r o p r i a t e w o r k u p p r o c e d u r e , t h e c r u d e r e a c t i o n p r o d u c t m i x t u r e w a s i m m e d i a t e l y t r e a t e d w i t h b u f f e r e d a c e t i c a c i d i n a q u e o u s T H F 8 3 to h y d r o l y z e the h y d r a z o n e f u n c t i o n . A n e x a m p l e o f t h i s t h ree s tep s e q u e n c e s t a r t i n g f r o m the h y d r a z o n e 362 i s s h o w n i n Scheme 70. N(Me)2 N(Me)2 N N 367 366 92% from 362 Scheme 70 T h e c o n v e r s i o n o f 362 i n t o 367, w h i c h w a s a c c o m p l i s h e d w i t h o u t i s o l a t i o n o r f u l l c h a r a c t e r i z a t i o n o f t h e i n t e r m e d i a t e s 365 a n d 366, p r o c e e d e d i n 9 2 % o v e r a l l y i e l d . T h e I R s p e c t r u m o f 367 e x h i b i t s a n a b s o r p t i o n at 1 7 1 3 c m - 1 a n d t h e 1 3 C n m r s p e c t r u m p o s s e s s e s a s i g n a l at 8 2 1 1 . 3 i n d i c a t i n g t h e p r e s e n c e o f a k e t o n e f u n c t i o n . T h e p r e s e n c e o f t h e k e t a l m o i e t y w a s i n d i c a t e d b y t w o t h r e e p r o t o n s i n g l e t s at 8 0 . 9 7 a n d 8 1 .00 i n a d d i t i o n to a f o u r p r o t o n m u l t i p l e t at 8 3 . 4 9 - 3 . 5 9 i n t h e lH n m r s p e c t r u m . T h e i o d o d e s t a n n y l a t i o n r e a c t i o n o c c u r r e d w i t h r e t e n t i o n o f c o n f i g u r a t i o n o f t h e d o u b l e b o n d as i n d i c a t e d b y t h e m a g n i t u d e o f t h e c o u p l i n g c o n s t a n t b e t w e e n H - 1 6 ( I U P A C n u m b e r i n g ) a n d H - 1 7 ( 7 = 7 H z ) . T h e r e s u l t s o f t h e p r e p a r a t i o n o f t h e k e t o a l k e n y l i o d i d e s 256 a n d 367-371 f r o m t h e c o r r e s p o n d i n g h y d r a z o n e s a re p r e s e n t e d i n Table 17. T h e t h r e e - s t e p p r o t o c o l p r o v e d to b e q u i t e e f f i c i e n t , p r o c e e d i n g i n y i e l d s r a n g i n g f r o m 5 4 - 9 2 % . E n t r y 4 , h o w e v e r , i n c l u d e s a n a d d i t i o n a l s t e p . T h e k e t o n e o b t a i n e d f r o m t h e h y d r a z o n e 364 c o n s i s t e d o f a m i x t u r e o f e p i m e r s at the p o i n t o f a t t a c h m e n t o f t h e n e w l y i n t r o d u c e d s i d e c h a i n . E q u i l i b r a t i o n o f t h i s m i x t u r e w i t h N a O M e i n M e O H at r o o m t e m p e r a t u r e p r o v i d e d a s i n g l e c o m p o u n d 370 w i t h t h e s i d e c h a i n i n a n e q u a t o r i a l o r i e n t a t i o n . A l t e r n a t i v e l y , a l k y l a t i o n o f t h e a n i o n d e r i v e d f r o m 361 ( e n t r y 2 ) i s e x p e c t e d to o c c u r r e d s t e r e o s e l e c t i v e l y f r o m the c o n v e x f a c e o f t h e b i c y c l i c s y s t e m a f f o r d i n g 369.1 4 T h e o v e r a l l y i e l d s f o r t h e p r e p a r a t i o n o f the i o d o k e t o n e s 256 a n d 367-371 a r e g o o d , as t h e y e n c o m p a s s t h r e e - s t e p s e q u e n c e s ( f o u r s t e p s f o r c o m p o u n d 370). T h e s l i g h t l y l o w e r y i e l d f o r t h e c o n v e r s i o n o f 361 i n t o 369 i s l i k e l y d u e to t h e f a c t that a s m a l l a m o u n t o f t h e d i e n e r e s u l t i n g f r o m t h e e l e c t r o p h i l e u n d e r g o i n g a n e l i m i n a t i o n r e a c t i o n w a s o b s e r v e d i n th i s case . Table 17: P r e p a r a t i o n o f t h e K e t o A l k e n y l I o d i d e s f r o m t h e M N - D i m e t h y l h y d r a z o n e s . NNMe 2 D LDA. THF Q ll 2 ) \ / = \ , HMPA 1 ^ H , 3) l 2 , C H 2 C I 2 1 4) NaOAc, AcOH, THF, H 2 0 E n t r y | H y d r a z o n e | K e t o I o d i d e | Y i e l d 1 NNMe 2 6 360 1 368 73% 2 NNMe 2 w 361 o w 369 54% 3 NNMe 2 ft 362 o ^ o bx! 367 9 2 % 4 NNMe 2 H 364 H 370 57% a 5 NNMe 2 06 363 371 73% 6 NNMe 2 6 211 256 86% a- Includes an additional equilibration step (NaOMe, MeOH, room temperature). 158 A s u b s t r a t e n o t i n c l u d e d i n Table 17 i s t h e B - k e t o e s t e r 372 s i n c e d i f f i c u l t i e s w e r e e n c o u n t e r e d i n i ts a l k y l a t i o n w i t h 253 ( e q u a t i o n 41). 7 5 a T h e s t a b i l i t y o f t h e e n o l a t e a n i o n s o f B - k e t o esters r e s u l t i n m o r e f o r c i n g c o n d i t i o n s b e i n g r e q u i r e d f o r t h e i r a l k y l a t i o n . A t t e m p t e d r e a c t i o n o f t h e p o t a s s i u m e n o l a t e o f 372 w i t h 253 at r o o m t e m p e r a t u r e i n T H F p r o c e e d e d s l u g g i s h l y a n d p r o v i d e l i t t l e o f t h e a l k y l a t e d a d d u c t 373. M o r e o v e r , f o r m a t i o n o f t h e d i e n e 254 w a s o b s e r v e d , t h e a m o u n t o f w h i c h i n c r e a s e d w h e n the a l k y l a t i o n r e a c t i o n m i x t u r e w a s h e a t e d to r e f l u x . T h e d i f f i c u l t i e s e n c o u n t e r e d d u r i n g t h e a l k y l a t i o n o f 372 r e s u l t e d i n t h i s s u b s t r a t e b e i n g a b a n d o n e d . O u / JL C 0 2 E t 1) KH, THF, rt X L c 0 2 E t S n B u 3 372 2 ) B u 3 S n / = V ^ ' 253 Bu 3 Sn (41) 373 254 I n o r d e r to f u r t h e r v a r y t h e t y p e s o f s u b s t r a t e s i n v e s t i g a t e d i n t h e n e w a n n u l a t i o n p r o t o c o l , t h e h y d r a z o n e 362 w a s a l k y l a t e d w i t h 253 as d i s c u s s e d p r e v i o u s l y a n d t h e n t h e h y d r a z o n e m o i e t y w a s h y d r o l y z e d b y t r e a t i n g t h e c r u d e r e a c t i o n m i x t u r e w i t h b u f f e r e d a c e t i c a c i d i n a q u e o u s T H F ( e q u a t i o n 42). I n t h i s m a n n e r , t h e k e t o a l k e n y l s t a n n a n e 374 w a s o b t a i n e d i n 9 0 % y i e l d f r o m 362. T h e c l e a v a g e o f t h e h y d r a z o n e f u n c t i o n w a s f o r t u n a t e l y q u i t e r a p i d (15 m i n u t e s ) . P r o l o n g e d e x p o s u r e to a c i d i c c o n d i t i o n s l i k e l y w o u l d h a v e r e s u l t e d i n p r o t i o d e s t a n n y l a t i o n a n d d e k e t a l i z a t i o n . 1 5 9 N(Me) 2 N 1) LDA, THF, 0\u00C2\u00B0C O SnBu3 (42) THF-HMPA, -78 \u00C2\u00B0C 3) NaOAc, AcOH THF, H 2 0 , rt 90% 362 E v i d e n c e f o r the s t r u c t u r a l a s s i g n m e n t o f 374 i n c l u d e d a n a b s o r p t i o n at 1 7 1 8 c m - 1 i n t h e I R s p e c t r u m a n d a s i g n a l i n d i c a t i n g t h e p r e s e n c e o f a k e t o n e g r o u p i n 374 at 8 2 1 1 . 1 i n the 1 3 C n m r s p e c t r u m . T h e * H n m r s p e c t r u m i n d i c a t e d that 374 c o n t a i n s a n a l k e n y l s t a n n a n e m o i e t y b y t h e s a t e l l i t e p e a k s o f the o l e f i n i c s i g n a l s d u e to t i n - p r o t o n c o u p l i n g . S p e c i f i c a l l y , the s i g n a l a t t r i b u t e d to H - l 7 i s a b r o a d d o u b l e t at 8 5 . 7 9 ( 7 = 12 H z , 2 7sn-H = 7 0 H z ) w h i l e t h e r e s o n a n c e a s s i g n e d to H - 1 6 i s a d o u b l e t o f d o u b l e t s o f d o u b l e t s at 8 6 . 4 7 (7 = 12 , 6 . 5 , 6 .5 H z , 3 7sn-H = 1 4 0 H z ) . T h e c h a r a c t e r i s t i c k e t a l r e s o n a n c e s a re a l s o p r e s e n t i n t h e * H n m r s p e c t r u m . A l k y l a t i o n s o f s u b s t r a t e s s i m i l a r to 374 w i t h m e t h y l i o d i d e h a v e b e e n r e p o r t e d . 1 3 - 47> 7 5 a W h e n 374 w a s a l l o w e d to r e a c t w i t h p o t a s s i u m tert-butoxide at 6 0 \u00C2\u00B0C a n d t h e r e s u l t a n t s o l u t i o n w a s t r e a t e d w i t h e x c e s s m e t h y l i o d i d e , a n u m b e r o f m e t h y l a t e d p r o d u c t s w e r e f o r m e d ( e q u a t i o n 43) i n a d d i t i o n to the m a j o r c o m p o u n d , k e t o n e 375, w h i c h w a s i s o l a t e d i n 3 4 % y i e l d . T h e * H n m r s p e c t r u m o f 375 c o n t a i n s th ree m e t h y l s i n g l e t s , t h e t w o at 8 0 . 9 5 a n d 0 . 9 9 b e i n g a t t r i b u t e d to t h e d i a s t e r e o t o p i c k e t a l m e t h y l g r o u p s , w h i l e t h e t h i r d at 8 1 .09 i s a s s i g n e d to t h e n e w l y i n t r o d u c e d m e t h y l g r o u p at C - 8 . T h e d i m e t h y l a t e d k e t o n e 376 w a s i s o l a t e d i n 2 1 % y i e l d as a n i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , i n a n a p p r o x i m a t e r a t i o o f 6 . 7 : 1 , w h i c h w e r e e p i m e r i c at t h e C - 1 0 p o s i t i o n . T h e r e l a t i v e c o n f i g u r a t i o n at C - 8 a n d C - 1 0 f o r t h e m a j o r d i a s t e r e o m e r i n 376 w a s n o t d e f i n i t e l y e s t a b l i s h e d . B a s e d o n t h e m a g n i t u d e o f t h e c o u p l i n g c o n s t a n t s f o r H - 1 0 i n t h e * H n m r s p e c t r u m o f 376 a n d ^H-lU d e c o u p l i n g e x p e r i m e n t s c a r r i e d o u t o n t h e c o r r e s p o n d i n g a l k e n y l i o d i d e (vide infra), t h e m e t h y l g r o u p at C - 1 0 o c c u p i e s a n e q u a t o r i a l o r i e n t a t i o n . T h e s i g n a l a t t r i b u t e d to H - 1 0 a p p e a r s at 8 2 . 7 3 ( d d q , J = 1 2 . 5 , 6 . 9 , 6 . 9 H z ) a n d t h e 1 2 . 5 H z c o u p l i n g c o n s t a n t i s d u e to a n a x i a l - a x i a l c o u p l i n g b e t w e e n H - 1 0 a n d t h e H - 1 l a x . T h r e e m e t h y l s i n g l e t s a p p e a r i n t h e j H n m r s p e c t r u m o f c o m p o u n d 376 at 8 0 . 7 6 9 , 0 . 8 3 , a n d 0 . 9 3 , w h i l e the m e t h y l g r o u p at C - 1 0 g i v e s rise to a th ree p r o t o n d o u b l e t at 8 0 . 7 7 3 (J =6.9 H z ) . O 376 T h e r e m a i n i n g m i n o r p r o d u c t s w e r e n o t f u l l y c h a r a c t e r i z e d . T h e y i e l d o f c o m p o u n d 375 c o u l d b e i n c r e a s e d to 7 0 % w i t h a c o n c o m i t a n t d e c r e a s e i n the a m o u n t o f c o m p o u n d 376 a n d the o t h e r d i a l k y l a t e d m a t e r i a l o r the t r i - m e t h y l a t e d c o m p o u n d , b y c o o l i n g t h e a l k y l a t i o n r e a c t i o n m i x t u r e to - 7 8 \u00C2\u00B0C b e f o r e a d d i n g m e t h y l i o d i d e . A s o l u t i o n o f e a c h o f the k e t o a l k e n y l s t a n n a n e s 375 a n d 376 i n m e t h y l e n e c h l o r i d e at 0 \u00C2\u00B0C w a s t r e a t e d w i t h a s o l u t i o n o f i o d i n e i n m e t h y l e n e c h l o r i d e to p r o v i d e t h e i o d o k e t o n e s 377 a n d 378 i n 9 7 % a n d 9 1 % y i e l d , r e s p e c t i v e l y . 161 O O R H S n B u 3 | 2 , C H 2 C I 2 , 0 \u00C2\u00B0C c r 375 R 1 = H 376 R 1 = Me 377 R 1 = H (97%) 378 R 1 = M e 1 9 (91%) Scheme 71 I n t h e * H n m r s p e c t r a o f 377 a n d 378 t h e a l k e n y l p r o t o n s i g n a l s d i s p l a y e d n o s a t e l l i t e p e a k s d u e to t i n - p r o t o n c o u p l i n g a n d a p p e a r e d as m u l t i p l e t s a t 8 6 . 0 6 - 6 . 2 2 a n d 6 . 0 4 - 6 . 2 1 , r e s p e c t i v e l y . T h e h i g h r e s o l u t i o n m a s s s p e c t r a o f 377 a n d 378 i n d i c a t e d tha t t h e t r i - n -b u t y l t i n f u n c t i o n s h a d b e e n r e p l a c e d b y a n i o d i n e . T h e n m r s p e c t r u m o f 378 c o n f i r m e d that the o r i e n t a t i o n o f t h e m e t h y l g r o u p w a s s t i l l e q u a t o r i a l s i n c e H - 1 0 s t i l l d i s p l a y s a l a r g e a x i a l - a x i a l c o u p l i n g (8 2 . 8 8 , d d q , 7 = 1 3 . 9 , 5 . 2 , 6 . 6 H z ) . I n h o m o n u c l e a r ^ H - i H ) d e c o u p l i n g e x p e r i m e n t s , i r r a d i a t i o n o f the s i g n a l at 8 2 . 8 8 ( H - 1 0 ) c a u s e d t h e d o u b l e t a t 8 1 .02 (7 = 6 .6 H z , M e - 1 9 ) to c o l l a p s e i n t o a s i n g l e t , w h i l e i r r a d i a t i o n o f t h e d o u b l e t at 8 1 .02 ( M e - 1 9 ) r e s u l t e d i n t h e s i g n a l at 8 2 . 8 8 ( d d q , 7 = 1 3 . 9 , 5 . 2 , 6 . 6 H z , H - 1 0 ) s i m p l i f y i n g to a d o u b l e t o f d o u b l e t s (7 = 1 3 . 9 , 5 . 2 H z , H - 1 0 ) . 2.2.5. Cyclization of the Keto Alkenyl Iodides to Provide the Tertiary Allylic Alcohols. T h e n e x t s t e p i n t h e a n n u l a t i o n s e q u e n c e i n v o l v e d a l o w t e m p e r a t u r e l i t h i u m - i o d i n e e x c h a n g e to g e n e r a t e a n a l k e n y l l i t h i u m s p e c i e s , w h i c h c y c l i z e s o n t o t h e c a r b o n y l c a r b o n to p r o v i d e a t e r t i a r y a l l y l i c a l c o h o l (Scheme 69, p a g e 1 5 2 ) . S i m i l a r c y c l i z a t i o n s h a v e b e e n i n v e s t i g a t e d 1 3 - 14> 1 4 8 ( s e e Scheme 6, p a g e 9 a n d Scheme 7, p a g e 1 0 ) a n d h a v e b e e n e m p l o y e d i n t h e s y n t h e s i s o f n a t u r a l p r o d u c t s (see Scheme 8, p a g e 12) . 1 7 > 1 9 - 4 7 H o w e v e r , t h e i n t r a m o l e c u l a r a d d i t i o n o f a l k e n y l a n i o n s o n t o c a r b o n y l g r o u p s to f o r m s i x - m e m b e r e d r i n g s i n w h i c h t h e d o u b l e b o n d i s e n d o c y c l i c h a s n o t b e e n r e p o r t e d . T h i s 6-exo-trig c y c l i z a t i o n i s s t e r e o e l e c t r o n i c a l l y f a v o r a b l e a c c o r d i n g to B a l d w i n ' s r u l e s . 1 4 9 F o r t h e m e t h o d to b e s u c c e s s f u l , i t i s n e c e s s a r y that t h e l i t h i u m - i o d i n e e x c h a n g e a n d t h e c y c l i z a t i o n s t e p b e r a p i d i n o r d e r to p r e v e n t t h e c o m p e t i n g i n t e r m o l e c u l a r a d d i t i o n o f n - B u L i t o t h e c a r b o n y l g r o u p . P r e v i o u s c y c l i z a t i o n s t u d i e s h a v e s h o w n tha t t h i s r e q u i r e m e n t i s s a t i s f i e d b y u s i n g a l k e n y l i o d i d e s . A n o t h e r r e q u i r e m e n t f o r t h e s u c c e s s f u l c y c l i z a t i o n r e a c t i o n i s t h e u s e o f a n e x c e s s o f a l k y l l i t h i u m r e a g e n t ( 2 . 2 - 2 . 5 e q u i v a l e n t s ) s i n c e l e s s t h a n t h i s a m o u n t o f t e n r e s u l t s i n i n c o m p l e t e l i t h i u m - h a l o g e n e x c h a n g e . T h e r e a c t i o n o f / i - B u L i w i t h a n a l k e n y l i o d i d e g i v e s t h e c o r r e s p o n d i n g a l k e n y l l i t h i u m s p e c i e s a n d n - B u I . T h e r e a c t i o n o f n - B u L i w i t h n - B u I to a f f o r d o c t a n e i s c o m p e t i t i v e w i t h t h e i n i t i a l l i t h i u m - i o d i n e e x c h a n g e , m a k i n g at l e a s t 2 e q u i v a l e n t s o f the a l k y l l i t h i u m n e c e s s a r y . 1 3 T h e i o d o k e t o n e s 256 a n d 367-371 w e r e a d d e d to a c o l d ( - 7 8 \u00C2\u00B0C) , d i l u t e ( 0 . 0 5 M ) s o l u t i o n o f n - B u L i ( 2 . 5 e q u i v a l e n t s ) i n T H F , i n o r d e r to a v o i d i n t e r m o l e c u l a r r e a c t i o n s a n d t o e n s u r e tha t a n e x c e s s o f n - B u L i w a s p r e s e n t to r e a c t w i t h the f o r m i n g rc-BuI. T h e c y c l i z a t i o n i s l i k e l y v e r y f a s t b u t a l l t h e r e a c t i o n m i x t u r e s w e r e s t i r r e d f o r 1 h o u r a n d w e r e t h e n q u e n c h e d at - 7 8 \u00C2\u00B0C w i t h a q u e o u s b a s e , s i n c e t h e t e r t i a r y a l l y l i c a l c o h o l s t h u s f o r m e d are a c i d - s e n s i t i v e . A n e x a m p l e o f t h e n - B u L i - m e d i a t e d r i n g c l o s u r e i n s h o w n i n e q u a t i o n 44. A d d i t i o n o f t h e i o d o k e t o n e 367 to a s o l u t i o n o f n - B u L i i n T H F at - 7 8 \u00C2\u00B0C p r o v i d e d , a f t e r a b a s i c w o r k -u p p r o c e d u r e , a 1:1 m i x t u r e o f t h e d i a s t e r e o m e r i c a l l y l i c a l c o h o l s 379 i n 9 6 % y i e l d . T h e a l c o h o l s c o u l d b e s e p a r a t e d b y s i l i c a g e l c h r o m a t o g r a p h y a n d e a c h d i a s t e r e o m e r w a s c h a r a c t e r i z e d i n d i v i d u a l l y . T h e I R s p e c t r u m o f the l e s s p o l a r a l l y l i c a l c o h o l e x h i b i t s a b s o r p t i o n s f o r t h e h y d r o x y l m o i e t y a n d t h e a l k e n e f u n c t i o n at 3 4 9 6 c m - 1 a n d 1 6 4 4 c m ' 1 , r e s p e c t i v e l y . T h e 1 3 C n m r s p e c t r u m c o n f i r m e d t h e a b s e n c e o f a c a r b o n y l f u n c t i o n a n d t h e p r e s e n c e o f a c a r b i n o l c a r b o n at 8 6 6 . 9 ( C - 4 a ' ) . T h e * H n m r s p e c t r u m c o n t a i n s s i g n a l s a t t r i b u t a b l e to t h e k e t a l f u n c t i o n as w e l l as a l k e n i c p r o t o n s at 8 5 . 6 6 (b r d , 7 = 9 . 8 H z , H - 5 ' ) a n d 8 5 . 7 3 ( d d d , 7 = 9 . 8 , 3 . 1 , 3.1 H z , H - 6 ' ) . T h e m o r e p o l a r a l l y l i c a l c o h o l p r o v i d e d s i m i l a r s p e c t r a l d a t a , as d i d m a n y o f t h e c y c l i z e d s u b s t r a t e s s h o w n i n Table 18. T h e y i e l d f o r m o s t o f the c y c l i z a t i o n s w e r e g o o d a n d the c o n v e r s i o n s o f 367 to 379 (ent ry 3 ) , 377 to 382 ( en t ry 4 ) , 378 t o 383 ( en t ry 5 ) , a n d 370 to 384 ( e n t r y 6 ) w e r e v e r y c l e a n w i t h n o d e t e c t a b l e b y - p r o d u c t s . C o m p o u n d 383 w a s p r o d u c e d as a n i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s ( - 6 - 7 : 1 ) w h i c h w e r e e p i m e r i c a t C - 1 0 d u e to t h e s t a r t i n g m a t e r i a l 378b b e i n g a m i x t u r e o f e p i m e r s (vide infra). T h e a l l y l i c a l c o h o l s 380 ( e n t r y 1) , 381 ( e n t r y 2 ) , 385 ( e n t r y 7 ) , a n d 257 ( e n t r y 8 ) w e r e a c c o m p a n i e d b y m i n o r a m o u n t s ( 8 % , 1 7 % , 1 4 % , a n d 6 % , r e s p e c t i v e l y ) o f t h e c o r r e s p o n d i n g u n c y c l i z e d r e d u c e d m a t e r i a l s i n w h i c h t h e i o d i n e i n t h e s t a r t i n g m a t e r i a l w a s r e p l a c e d b y a h y d r o g e n . F o r t u n a t e l y , t h e s e s u b s t a n c e s w e r e s e p a r a b l e f r o m the a l l y l i c a l c o h o l s b y s i l i c a g e l c h r o m a t o g r a p h y a n d t h e i r s t r u c t u r e s w e r e d e t e r m i n e d u s i n g s p e c t r o s c o p i c d a t a . 164 Table 18: B u t y l l i t h i u m - M e d i a t e d C y c l i z a t i o n o f the K e t o A l k e n y l I o d i d e s . ^4 n-BuLi, THF, -78 \u00C2\u00B0C inverse addition HO \1 E n t r y \ K e t o I o d i d e C y c l i z a t i o n P r o d u c t s ( y i e l d ) O \ 368 \ 380 ( 6 9 % ) 386 ( 8 % ) 369 381 ( 5 5 % ) 387 ( 1 7 % ) 3 4 5 367 R 1 = H , R 2 = H 377 R 1 = M e , R 2 = H 378 R 1 = M e , R 2 = M e 379 R 1 = H , R 2 = H ( 1 : 1 , 9 6 % ) 382 R 1 = M e , R 2 = H ( 9 2 % ) 383 R 1 = M e , R 2 = M e ( 9 0 % ) 370 384 ( 8 9 % ) 371 385 ( 8 6 % ) 388 ( 1 4 % ) 256 257 ( 2 . 5 : 1 , 8 0 % ) 258 ( 6 % ) F o r e x a m p l e , t h e * H n m r s p e c t r u m o f c o m p o u n d 388 c o n t a i n s s e v e n l o w f i e l d sets o f s i g n a l s , f o u r o f w h i c h a r e a t t r i b u t e d to t h e a r o m a t i c p r o t o n s . T h e r e m a i n i n g s i g n a l s i n the o l e f i n i c r e g i o n d i s p l a y e d c o m p l e x c o u p l i n g a n d i n t e g r a t e to a t o t a l o f t h r e e p r o t o n s . A c a r b o n y l a b s o r p t i o n i s p r e s e n t at 1 6 8 5 c m - 1 i n the I R s p e c t r u m o f 388 a n d t h e h i g h r e s o l u t i o n m a s s s p e c t r u m s u p p o r t s t h e r e p l a c e m e n t o f a n i o d i n e w i t h a h y d r o g e n . C o m p o u n d s 389 a n d 390 r e s u l t i n g f r o m d e h y d r o h a l o g e n a t i o n o f t h e s t a r t i n g m a t e r i a l 371 o r n u c l e o p h i l i c a t t a c k o f t h e n - B u L i o n t h e c a r b o n y l f u n c t i o n o f 371 f o l l o w e d b y l i t h i u m - h a l o g e n e x c h a n g e a n d p r o t o n a t i o n w e r e n o t o b s e r v e d . 388 389 390 T h e f o r m a t i o n o f t h e r e d u c e d u n c y c l i z e d b y - p r o d u c t s i s l i k e l y t h e r e s u l t o f i n t r a m o l e c u l a r p r o t o n a b s t r a c t i o n o f the a c i d i c p r o t o n a l p h a to the c a r b o n y l g r o u p a n d ipso to t h e s i d e - c h a i n b y t h e a l k e n y l l i t h i u m s p e c i e s a n d p r o t o n a t i o n o f t h e r e s u l t a n t e n o l a t e o n w o r k u p . T h e l i t h i u m - i o d i n e e x c h a n g e a n d c y c l i z a t i o n p r o c e s s e s a r e v e r y f a s t a n d t h e r e a c t i o n m i x t u r e s w e r e s t i r r e d at - 7 8 \u00C2\u00B0C f o r o n e h o u r t h u s m a k i n g t h e p o s s i b i l i t y that the b y -p r o d u c t s w e r e f o r m e d b y p r o t o n a t i o n o f a n u n r e a c t e d a l k e n y l l i t h i u m s p e c i e s o n w o r k u p v e r y u n l i k e l y . T h e r e a c t i o n s w e r e r u n u n d e r f a i r l y d i l u t e c o n d i t i o n s i n o r d e r to d e c r e a s e t h e p o s s i b i l i t y o f i n t e r m o l e c u l a r p r o t o n a t i o n . T h e u n i m p o r t a n c e o f s t e r i c h i n d r a n c e i n t h e v i c i n i t y o f t h e c a r b o n y l m o i e t y i s i l l u s t r a t e d b y c y c l i z a t i o n o f t h e s u b s t r a t e s 367, 377 a n d 378 (Table 18, e n t r i e s 3-5). T h e y i e l d s a r e a l l h i g h s u g g e s t i n g that the r e a c t i o n s e e m s to b e r e a s o n a b l y t o l e r a n t o f h i g h s t e r i c c o n g e s t i o n . M o s t o f t h e a l l y l i c a l c o h o l s f o r m e d u p o n c y c l i z a t i o n p r o v e d t o b e o n l y o n e d i a s t e r e o m e r . B e s i d e s 379, o n l y t h e b i c y c l o [ 5 . 4 . 0 ] u n d e c e n o l 257 w a s f o r m e d as a m i x t u r e o f d i a s t e r e o m e r s i n a r a t i o o f 2 . 5 : 1 . 1 5 0 T h e c o n f i g u r a t i o n o f t h e c a r b i n o l s t e r e o g e n i c c e n t e r i n e a c h o f the a l l y l i c a l c o h o l s 257 a n d 379-385 i s d e s t r o y e d i n t h e n e x t s t e p a n d t h e r e f o r e t h e r e l a t i v e c o n f i g u r a t i o n o f t h i s c e n t e r w a s n o t d e f i n i t e l y e s t a b l i s h e d . H o w e v e r , e x a m i n a t i o n o f m o l e c u l a r m o d e l s m a y p r o v i d e s o m e i n s i g h t i n t o the s t e r e o c h e m i c a l o u t c o m e o f t h e r e a c t i o n s . T h e c y c l i z a t i o n o f c o m p o u n d 367 p r o v i d e d a 1:1 m i x t u r e o f t h e cis a n d trans a l l y l i c a l c o h o l s 379. U p o n t r e a t m e n t w i t h n - B u L i , c o m p o u n d 367 g i v e s r i s e to a n a l k e n y l l i t h i u m s p e c i e s , t w o c o n f o r m e r s o f w h i c h c a n b e r e p r e s e n t e d as s h o w n i n 391a a n d 391b (Scheme 72). O f t h e s e t w o c o n f o r m e r s , 391a i s t h e m o r e s t a b l e , s i n c e t h e s i d e c h a i n i s i n a n e q u a t o r i a l o r i e n t a t i o n . T w o r e a c t i o n p a t h w a y s p r o c e e d i n g f r o m c o n f o r m e r 391a c a n b e e n v i s a g e d . E q u a t o r i a l a t t a c k ( p a t h w a y i ) p a s s e s t h r o u g h a h a l f - c h a i r - l i k e t r a n s i t i o n s t a t e w h i c h s h o u l d r e s e m b l e s t r u c t u r e X i n Scheme 72. T h i s r e a c t i o n p a t h w a y p r o v i d e s t h e trans - f u s e d c o m p o u n d 379a. A x i a l a t t a c k ( p a t h w a y i i ) , w h i c h a l s o p a s s e s t h r o u g h a h a l f - c h a i r - l i k e t r a n s i t i o n s t a t e t h a t s h o u l d r e s e m b l e s t r u c t u r e Y i n Scheme 72, l e a d s t o t h e cis - f u s e d c o m p o u n d 379b. A x i a l a t t a c k i s p r o b a b l y s l i g h t l y d i s f a v o r e d d u e to t h e d e s t a b i l i z i n g 1,3 s t e r i c i n t e r a c t i o n s w i t h t h e a x i a l h y d r o g e n s . A t h i r d r e a c t i o n p a t h w a y , w h i c h p a s s e s t h r o u g h c o n f o r m e r 391b, l i k e l y a c c o u n t s f o r the f o r m a t i o n o f s o m e o f t h e d s - f u s e d c o m p o u n d ( see f o r m u l a 379c). D u e to g e o m e t r i c c o n s t r a i n t s , c o n f o r m e r 391b c a n o n l y r e a c t v i a p a t h w a y i i i ( e q u a t o r i a l a t t a c k ) t o g i v e 379c. It i s u n c l e a r to w h a t e x t e n t p a t h w a y s i i a n d i i i i n d i v i d u a l l y c o n t r i b u t e to t h e f o r m a t i o n o f the cis - f u s e d c o m p o u n d 379b ( a n d 379c), b u t c o l l e c t i v e l y t h e y a c c o u n t f o r h a l f o f t h e p r o d u c t f o r m e d . H o w e v e r , a n a l y s i s o f t h e p o s s i b l e c y c l i z a t i o n p a t h w a y s f o r c o m p o u n d 370 (vide infra) s u g g e s t s that p a t h w a y i i i i n Scheme 72 m a y b e the p r e f e r r e d r o u t e f o r t h e f o r m a t i o n o f t h e cis - f u s e d p r o d u c t . Scheme 72 T h e a d d i t i o n o f a m e t h y l g r o u p to t h e s a m e c a r b o n as t h e s i d e c h a i n h a d a d r a m a t i c e f f e c t o n t h e s t e r e o c h e m i c a l o u t c o m e o f c y c l i z a t i o n . T h u s , s u b s t r a t e 377 p r o v i d e d a s i n g l e t e r t i a r y a l l y l i c a l c o h o l . E x a m i n a t i o n o f t h e p o s s i b l e r e a c t i o n p a t h w a y s s t r o n g l y s u p p o r t s t h e f o r m a t i o n o f t h e cis i s o m e r (Scheme 73). B o t h c o n f o r m e r s 392a a n d 392b h a v e t w o a x i a l a n d t w o e q u a t o r i a l s u b s t i t u e n t s a n d a re l i k e l y o f s i m i l a r e n e r g y . C o n f o r m e r 392a c a n p a s s 168 t h r o u g h t w o p o s s i b l e r e a c t i o n p a t h w a y s ( i a n d i i ) , b o t h o f w h i c h i n v o l v e h a l f - c h a i r - l i k e t r a n s i t i o n states . 2 p i 377 R 1 , R 2 = H 378' R 1 = Me, R 2 = H 378\" R 1 = H, R 2 = Me n-BuLi, THF, -78 \u00C2\u00B0C ii axial attack QY^^J ' equatorial attack ,0 R 2 Li 392a R 1 , R 2 = H 393a' R 1 = Me, R 2 = H 393a\" R 1 = H, R 2 = Me iii equatorial attack R 1 half-chair-like transition state half-chair-like transition state 392b R 1 , R 2 = H 393b' R 1 = Me, R 2 = H 393b\" R 1 = H, R 2 = Me half-chair-like transition state 382a R 1 , R 2 = H 383a' R 1 = Me, R 2 = H 383a\" R 1 = H, R 2 = Me 382b R 1 , R 2 = H 383b' R 1 = Me, R 2 = H 383b\" R 1 = H, R 2 = Me O H 382c R 1 , R 2 = H 383c' R 1 = Me, R 2 = H 383c\" R 1 = H, R 2 = Me Scheme 73 E q u a t o r i a l a t t a c k ( p a t h w a y i ) i s d i s f a v o r e d d u e to t h e i n c o m i n g a l k e n y l a n i o n a p p r o a c h i n g the c a r b o n y l c a r b o n f r o m t h e s a m e s i d e o f the ring as t h e a x i a l m e t h y l g r o u p . I f t h e a n g l e o f a p p r o a c h o f t h e n u c l e o p h i l i c c e n t e r to t h e p l a n e o f t h e C - 0 d o u b l e b o n d f o l l o w s t h e B u r g i -D u n i t z t r a j e c t o r y ( - 1 0 9 \u00C2\u00B0 ) , 1 5 1 t h e n a n e a r l y e c l i p s e d i n t e r a c t i o n b e t w e e n t h e a l k e n y l g r o u p a n d the a x i a l m e t h y l g r o u p i s e n c o u n t e r e d . A x i a l a t t a c k o n t h e s i d e o p p o s i t e t o t h e m e t h y l g r o u p ( p a t h w a y i i ) a l l e v i a t e s t h i s i n t e r a c t i o n a n d t h e d s - p r o d u c t 382b i s f o r m e d . G e o m e t r i c c o n s t r a i n t s r e q u i r e c o n f o r m e r 392b to p r o c e e d t h r o u g h a h a l f - c h a i r - l i k e t r a n s i t i o n state w h i c h c a n o n l y a f f o r d t h e d s - p r o d u c t (see c o n f o r m e r 382c). I t i s v e r y d i f f i c u l t t o p r e d i c t w h i c h r e a c t i o n p a t h w a y i s f a v o r e d ( i i o r i i i ) s i n c e t h e y w o u l d p r o b a b l y p r o c e e d t h r o u g h t r a n s i t i o n states o f s i m i l a r e n e r g y . T h e i o d o k e t o n e 378 c o n s i s t e d o f a m i x t u r e o f d i a s t e r e o m e r s 378' a n d 378\" i n a r a t i o o f - 6 - 7 : 1 w h i c h a r e e p i m e r i c at C - 1 0 . C y c l i z a t i o n o f a m i x t u r e o f b o t h d i a s t e r e o m e r s p r o v i d e d a n i n s e p a r a b l e m i x t u r e o f a l l y l i c a l c o h o l s i n a r a t i o o f - 6 - 7 : 1 i n d i c a t i n g that o n l y o n e a p p r o a c h o f t h e a l k e n y l a n i o n t o t h e c a r b o n y l w a s f o l l o w e d f o r e a c h d i a s t e r e o m e r . A r g u m e n t s s i m i l a r to t h o s e p r o p o s e d f o r c o m p o u n d 377 c a n b e u s e d t o r a t i o n a l i z e that t h e p r o d u c t s f o r m e d i n the c y c l i z a t i o n o f b o t h d i a s t e r e o m e r s i n 378 a re l i k e l y d s - f u s e d (Scheme 73). T r e a t m e n t d i a s t e r e o m e r 378' w i t h n - B u L i g i v e rise to a n a l k e n y l l i t h i u m s p e c i e s , t w o c o n f o r m e r s o f w h i c h c a n b e r e p r e s e n t e d as s h o w n i n 393a' a n d 293b' (Scheme 73). P a t h w a y i e n c o u n t e r s a n e c l i p s i n g i n t e r a c t i n g b e t w e e n the i n c o m i n g n u c l e o p h i l i c c e n t e r a n d t h e a x i a l m e t h y l g r o u p o n t h e s a m e c a r b o n as the s i d e c h a i n . B o t h p a t h w a y s i i a n d i i i g i v e rise t o the d s - f u s e d p r o d u c t . H o w e v e r , p a t h w a y i i i s l i k e l y f a v o r e d o v e r p a t h w a y i i i s i n c e p a t h w a y i i i i n v o l v e s a c o n f o r m e r i n w h i c h t h e r e a re t h r e e a x i a l a n d t w o e q u a t o r i a l s u b s t i t u e n t s , w h i l e i n p a t h w a y i i t h e c o n f o r m e r i n v o l v e d h a s t w o a x i a l a n d t h r e e e q u a t o r i a l s u b s t i t u e n t s . C o m p o u n d 378\" p r o v i d e s a n a l k e n y l l i t h i u m s p e c i e s o n t r e a t m e n t w i t h n - B u L i , t w o p o s s i b l e c o n f o r m e r s o f w h i c h a re 393a\" a n d 393b\" (Scheme 73). F o r r e a s o n s v e r y s i m i l a r to t h o s e o u t l i n e d a b o v e f o r c o m p o u n d s 377 a n d 378', p a t h w a y i i s d i s f a v o r e d . I n t h i s c a s e , the d s - f u s e d p r o d u c t w h i c h i s f o r m e d i s l i k e l y p r o d u c e d v i a p a t h w a y i i i s i n c e p a t h w a y i i i i n v o l v e s a c o n f o r m e r p o s s e s s i n g t h r e e e q u a t o r i a l a n d t w o a x i a l s u b s t i t u e n t s , w h i l e i n p a t h w a y i i the c o n f o r m e r h a s th ree a x i a l a n d t w o e q u a t o r i a l s u b s t i t u e n t s . A n a n a l y s i s o f t h e c y c l i z a t i o n r e a c t i o n o f t h e k e t o a l k e n y l i o d i d e 370 i s s h o w n i n Scheme 74 a n d s u g g e s t s tha t t h e s i n g l e p r o d u c t f o r m e d i s t h e trans-fused c o m p o u n d . C o n f o r m e r 394a c a n r e a c t b y e q u a t o r i a l a t t a c k ( p a t h w a y i ) t o p r o v i d e t h e trans - f u s e d a d d u c t 384a o r b y a x i a l a t t a c k ( p a t h w a y i i ) t o a f f o r d t h e cis - f u s e d i s o m e r 384b. T h e h a l f - c h a i r - l i k e t r a n s i t i o n s t a t e r e s u l t i n g f r o m e q u a t o r i a l a t t a c k , w h i c h s h o u l d r e s e m b l e s t r u c t u r e X i n Scheme 74, e n c o u n t e r s l i t t l e s t e r i c o r t o r t i o n a l s t r a i n . O n t h e o t h e r h a n d , t h e h a l f - c h a i r - l i k e t r a n s i t i o n s ta te r e s e m b l i n g s t r u c t u r e Y i n Scheme 74 e x p e r i e n c e s a n u m b e r o f 1 , 3 - d i a x i a l s t e r i c i n t e r a c t i o n s w i t h t h e h y d r o g e n s H * m a k i n g t h i s r o u t e l e s s l i k e l y . A c o n f o r m a t i o n a l f l i p o f 394a p r o v i d e s 394b, w h i c h s h o u l d b e c o n s i d e r a b l y h i g h e r i n e n e r g y s i n c e the s i d e c h a i n i s i n a n a x i a l o r i e n t a t i o n a n d t h e r i n g t o w h i c h i t i s a t t a c h e d a d o p t s a b o a t c o n f o r m a t i o n . R e a c t i o n o f c o n f o r m e r 394b t h r o u g h a h a l f - c h a i r - l i k e t r a n s i t i o n s t a t e c a n o n l y p r o v i d e t h e c / s - f u s e d c o m p o u n d 384c. P a t h w a y i i i w o u l d , t h e r e f o r e , b e h i g h e r i n e n e r g y , f u r t h e r s u p p o r t i n g the f o r m a t i o n o f t h e trans-product. I n l i g h t o f t h i s e x p l a n a t i o n , the f o r m a t i o n o f the - f u s e d p r o d u c t i n Scheme 72 ( p a g e 167 ) i s m o r e l i k e l y to h a v e a r i s e n f r o m p a t h w a y i i i s i n c e t h e e x a m p l e i n Scheme 74 s h o w s t h e i m p o r t a n c e o f 1 , 3 - d i a x i a l s t e r i c i n t e r a c t i o n s e n c o u n t e r e d b y the i n c o m i n g n u c l e o p h i l i c c e n t e r . 384a 384b 384c Scheme 74 T h e c y c l i z a t i o n o f the t e t r a l o n e 371 i s c o n s i d e r e d i n Scheme 75. T h i s m o l e c u l e i s n o t as c o n f o r m a t i o n a l l y m o b i l e as t h o s e c o n s i d e r e d p r e v i o u s l y d u e to t h e c o - p l a n a r i t y o f t h e c a r b o n y l g r o u p a n d t h e a r o m a t i c r i n g . T h e o n l y p r o d u c t w h i c h i s o b t a i n e d i n t h i s c y c l i z a t i o n i s p r e d i c t e d to b e t h e trans - f u s e d i s o m e r . C o n f o r m e r 395a i s e x p e c t e d to b e l o w e r i n e n e r g y t h a n 395b s i n c e t h e s i d e c h a i n i n 395a i s i n a n e q u a t o r i a l p o s i t i o n . T h e s i d e c h a i n i n c o n f o r m e r 395a c a n a p p r o a c h the c a r b o n y l g r o u p f r o m the R - f a c e ( p a t h w a y i ) o r f r o m t h e a -1 7 2 f a c e ( p a t h w a y i i ) . B - A t t a c k i s r e l a t i v e l y f r e e o f s t e r i c o r t o r t i o n a l s t r a i n a n d w o u l d p a s s t h r o u g h a h a l f - c h a i r - l i k e t r a n s i t i o n s ta te r e s e m b l i n g s t r u c t u r e X i n Scheme 75 t o p r o v i d e t h e trans-fused i s o m e r 385a. T h e h a l f - c h a i r - l i k e t r a n s i t i o n state f o r a - a t t a c k r e s e m b l e s s t r u c t u r e Y i n Scheme 75 a n d e x p e r i e n c e s a s t e r i c h i n d r a n c e b e t w e e n t h e i n d i c a t e d a l k e n i c a n d a r o m a t i c p r o t o n s ( H * ) m a k i n g t h i s p a t h w a y l e s s l i k e l y . C y c l i z a t i o n t h r o u g h a h a l f - c h a i r - l i k e t r a n s i t i o n s ta te f r o m c o n f o r m e r 395b ( p a t h w a y i i i ) c a n o n l y a f f o r d t h e cis - f u s e d p r o d u c t 385c, b u t i t s u f f e r s f r o m a s i m i l a r s t e r i c i n t e r a c t i o n b e t w e e n t h e a l k e n i c a n d a r o m a t i c p r o t o n s ( H * ) . i beta attack O ii alpha attack 395a 385b Scheme 75 S i m i l a r a r g u m e n t s c a n b e u s e d to r a t i o n a l i z e t h e o u t c o m e o f t h e c y c l i z a t i o n f o r t h e f i v e - m e m b e r e d r i n g s u b s t r a t e s 368 a n d 369. I n b o t h c a s e s a s i n g l e d i a s t e r e o m e r w a s f o r m e d w h i c h i s p r e d i c t e d t o b e ris-fused c o m p o u n d . I n t h e s e c a s e s , h a l f - c h a i r - l i k e t r a n s i t i o n states c a n b e e n v i s a g e d t o a c c o u n t f o r t h e f o r m a t i o n o f e i t h e r t h e cis- o r trans - f u s e d p r o d u c t s . H o w e v e r , i f t h e n u c l e o p h i l i c c e n t e r a p p r o a c h e s the p l a n e o f t h e d o u b l e b o n d at a n a n g l e o f - 1 0 9 \u00C2\u00B0 , 1 5 1 t h e n f o r m a t i o n o f the trans-fused p r o d u c t p r o c e e d s t h r o u g h a t r a n s i t i o n s t r u c t u r e w h i c h e x p e r i e n c e s c o n s i d e r a b l e r i n g s t r a i n . T h i s s t r a i n i s n o t e n c o u n t e r e d w h e n t h e a l k e n y l a n i o n a t t a c k s the c a r b o n y l g r o u p to a f f o r d t h e c w - f u s e d p r o d u c t . I t i s d i f f i c u l t to p r e d i c t w h i c h d i a s t e r e o m e r i s f a v o r e d i n t h e 2 . 5 : 1 m i x t u r e o f p r o d u c t s o b t a i n e d f r o m the c y c l i z a t i o n o f the c y c l o h e p t a n o n e 256. S i m i l a r r e s u l t s h a v e b e e n o b s e r v e d f o r f i v e - m e m b e r e d r i n g a n n u l a t i o n s i n v o l v i n g s e v e n - m e m b e r e d r i n g s u b s t r a t e s . 1 5 0 T h e c o n f o r m a t i o n a l f l e x i b i l i t y o f t h e s e v e n - m e m b e r e d r i n g , h o w e v e r , m a k e s t h e f o r m a t i o n o f e i t h e r the cis or trans - f u s e d p r o d u c t s t h r o u g h a h a l f - c h a i r - l i k e t r a n s i t i o n s ta te e q u a l l y l i k e l y . A r a t i o o f 2 . 5 : 1 r e f l e c t s a v e r y s m a l l d i f f e r e n c e i n e n e r g y o f t h e t r a n s i t i o n s ta tes a n d t h e m a j o r p r o d u c t c a n n o t b e p r e d i c t e d w i t h c o n f i d e n c e . 2.2.6. Oxidative Rearrangement of the Tertiary Allylic Alcohols to the Cyclohexenones. T h e l a s t s t e p i n e a c h o f t h e a n n u l a t i o n s e q u e n c e s w a s t h e o x i d a t i o n o f t h e a l l y l i c a l c o h o l t o p r o v i d e t h e c o r r e s p o n d i n g e n o n e . 1 5 2 P y r i d i n i u m c h l o r o c h r o m a t e 1 5 3 o n b a s i c a l u m i n a 1 5 4 i s u s e d f o r t h i s t r a n s f o r m a t i o n d u e t o i t s e a s e o f p r e p a r a t i o n , h a n d l i n g , w o r k u p , a n d i ts m i l d l y b a s i c n a t u r e , w h i c h i s c o m p a t i b l e w i t h the a c i d - s e n s i t i v e t e r t i a r y a l l y l i c a l c o h o l f u n c t i o n . T h e o x i d a t i o n o f the s u b s t r a t e s 257 a n d 379-385 w a s p e r f o r m e d b y a d d i n g P C C o n a l u m i n a to t h e a l l y l i c a l c o h o l s u b s t r a t e i n m e t h y l e n e c h l o r i d e at r o o m t e m p e r a t u r e . A f t e r a n a p p r o p r i a t e w o r k u p p r o c e d u r e , t h e e n o n e s w e r e p u r i f i e d b y s i l i c a g e l c h r o m a t o g r a p h y a n d c h a r a c t e r i z e d . F o r e x a m p l e , the 1:1 m i x t u r e o f a l l y l i c a l c o h o l s 379 w a s o x i d i z e d t o p r o v i d e t h e e n o n e 396 i n 8 9 % y i e l d ( e q u a t i o n 45) a n d s p e c t r o s c o p i c d a t a s u p p o r t e d tha t t h e d e s i r e d o x i d a t i o n h a d o c c u r r e d . T h e I R s p e c t r u m o f 396 e x h i b i t s a c a r b o n y l a b s o r p t i o n a t 1 6 6 9 c m - 1 a n d t w o a l k e n i c a n d o n e c a r b o n y l c a r b o n s i g n a l s a r e p r e s e n t i n t h e 1 3 C n m r s p e c t r u m at 8 1 2 4 . 6 , 1 6 4 . 9 , 1 9 9 . 5 f o r C - 5 , C - 4 a ' , a n d C - 6 , r e s p e c t i v e l y . T h e lH n m r s p e c t r u m o f 396 c o n t a i n s the e x p e c t e d s i g n a l s f o r t h e k e t a l f u n c t i o n a n d a o n e p r o t o n s i n g l e t at 8 5 . 8 3 f o r H - 5 ' . O 89% 379 396 T h e r e s u l t s f o r t h e r e m a i n i n g s u b s t r a t e s a p p e a r i n Table 19 a n d i l l u s t r a t e tha t t h e o x i d a t i v e r e a r r a n g e m e n t p r o v i d e s t h e c y c l o h e x e n o n e s i n m o d e r a t e t o e x c e l l e n t y i e l d . T h e v o l a t i l i t y o f 397 ( e n t r y 1) p r o b a b l y a c c o u n t s f o r t h e l o w e r y i e l d i n t h i s c a s e . T h e h y d r o x y l m o i e t y i n c o m p o u n d 383 i s q u i t e s t e r i c a l l y h i n d e r e d , w h i c h l i k e l y a c c o u n t s f o r t h e l o w e r y i e l d f o r t h i s s u b s t r a t e a n d t h e f a c t that the r e a c t i o n w a s v e r y s l u g g i s h i n t h i s c a s e . T y p i c a l l y , w i t h i n a m i n u t e a f t e r the a d d i t i o n o f the b r i g h t o r a n g e c o l o r e d P C C o n a l u m i n a , t h e r e a c t i o n m i x t u r e t u r n e d d a r k b r o w n i n d i c a t i n g that t h e o x i d a t i o n w a s p r o c e e d i n g w h i l e t h e e x p e c t e d c o l o u r c h a n g e f o r 383 o c c u r r e d o n l y a f t e r s e v e r a l m i n u t e s . A f t e r 23 h at r o o m t e m p e r a t u r e , t h e r e a c t i o n w a s s t i l l n o t c o m p l e t e , a n d t h e r e f o r e 3 A m o l e c u l a r s i e v e s 1 5 5 w e r e a d d e d f o l l o w e d b y m o r e P C C o n a l u m i n a . E v e n t u a l l y , t h e r e a c t i o n w a s d r i v e n to c o m p l e t i o n b y h e a t i n g at r e f l u x . T h e f o r m a t i o n o f the i n t e r m e d i a t e c h r o m a t e e s t e r i s l i k e l y d i f f i c u l t i n s u c h a s t e r i c a l l y h i n d e r e d e n v i r o n m e n t . 1 5 2 175 Table 19: O x i d a t i o n o f t h e T e r t i a r y A l l y l i c A l c o h o l s to t h e C y c l o h e x e n o n e s . E n t r y | A l l y l i c A l c o h o l c o n d i t i o n s ^ C y c l o h e x e n o n e | Y i e l d 1 380 0 397 6 3 % 2 H4\u00E2\u0080\u0094LH y 381 0 c r o 398 8 8 % 3 4 5 \" 379 R 1 = H , R2 = H ( 1 : 1 ) 382 R 1 = M e , R 2 = H 383 R 1 = M e , R 2 = M e 0 ^ 0 y 396 R 1 = H , R 2 = H 399 R 1 = M e , R 2 = H 400 R 1 = M e , R 2 = M e 8 9 % 8 6 % 4 7 % 6 H 384 H 401 9 4 % 7 69 385 402 4 8 % 8 257 0 $ 259 8 5 % a-PCC on alumina (2.5 equivalents), C H 2 C I 2 , room temperature. b-After 23 h under the conditions outlined in (a), 3 A molecular sieves and PCC on alumina (2.5 equivalents) were added and the reaction mixture was heated at reflux. C o m p o u n d 4 0 0 w a s f o r m e d a n d c h a r a c t e r i z e d as a n i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s ( - 6 - 7 : 1 ) e p i m e r i c at C - 1 0 . T h e r e a c t i o n i n v o l v i n g 3 8 5 p r o d u c e d a n u m b e r o f m i n o r b y - p r o d u c t s . T h i s o b s e r v a t i o n w a s n o t s u r p r i s i n g , s i n c e t h e t e r t i a r y a l c o h o l m o i e t y i n 3 8 5 i s b o t h a l l y l i c a n d b e n z y l i c a n d as s u c h i s q u i t e s u s c e p t i b l e t o i o n i z a t i o n to p r o v i d e a h i g h l y s t a b i l i z e d c a r b o c a t i o n . T h e o b s e r v e d o c c u r r e n c e s o f m i n o r p r o c e s s e s i n c o m p e t i t i o n w i t h t h e d e s i r e d o x i d a t i o n r e a c t i o n i s , t h e r e f o r e , n o t u n e x p e c t e d . 2 . 2 . 7 . C o n c l u s i o n s . T h e w o r k d e s c r i b e d i n t h e s e c o n d p a r t o f t h i s t h e s i s i n v o l v e d t h e d e v e l o p m e n t a n d i m p l e m e n t a t i o n o f a n e w c y c l o h e x e n o n e a n n u l a t i o n s e q u e n c e . T h e b i f u n c t i o n a l c o n j u n c t i v e r e a g e n t ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e ( 2 5 3 ) w a s p r e p a r e d a n d a c t e d as t h e s y n t h e t i c e q u i v a l e n t o f a b u t - l - e n e d 1 , a 4 - s y n t h o n ( 6 9 ) i n t h e n e w a n n u l a t i o n p r o t o c o l . A l k y l a t i o n o f J V . N - d i m e t h y l h y d r a z o n e s d e r i v a t i v e s w i t h 2 5 3 w a s r e q u i r e d to a v o i d e l i m i n a t i o n o f t h e h o m o a l l y l i c i o d i d e to g i v e the c o r r e s p o n d i n g d i e n e , a p r o b l e m e n c o u n t e r e d w i t h k e t o n e o r fi-k e t o es te rs e n o l a t e s . T h e u s e o f a t r i - n - b u t y l s t a n n y l m o i e t y i n t h e e l e c t r o p h i l e w a s n e c e s s a r y to e n s u r e a s t e r e o s e l e c t i v e t i n - i o d i n e e x c h a n g e r e a c t i o n s i n c e i o d o d e g e r m y l a t i o n s d i d n o t o c c u r w i t h r e t e n t i o n o f d o u b l e b o n d c o n f i g u r a t i o n . A c i d h y d r o l y s i s o f t h e h y d r a z o n e m o i e t i e s t o t h e c o r r e s p o n d i n g k e t o n e s w a s f o l l o w e d b y a n e f f i c i e n t , l o w t e m p e r a t u r e , k i n e t i c a l l y c o n t r o l l e d , n - B u L i - m e d i a t e d c y c l i z a t i o n s t e p . T h e b y - p r o d u c t s i n s o m e o f t h e c y c l i z a t i o n r e a c t i o n s w e r e s m a l l a m o u n t s o f the c o r r e s p o n d i n g u n c y c l i z e d m a t e r i a l s i n w h i c h t h e i o d i n e w a s r e p l a c e d b y a h y d r o g e n . O x i d a t i v e - r e a r r a n g e m e n t o f t h e r e s u l t a n t t e r t i a r y a l l y l i c a l c o h o l s p r o v i d e d t h e c y c l o h e x e n o n e s w i t h b e n z y l i c o r v e r y s t e r i c a l l y h i n d e r e d a l c o h o l s a f f o r d i n g l o w e r y i e l d s o f t h e e n o n e s . A s u m m a r y o f t h e n e w a n n u l a t i o n s e q u e n c e i s s h o w n i n S c h e m e 6 9 ( p a g e 1 5 2 ) . E a c h s tep i s e x p e r i m e n t a l l y s i m p l e , t o l e r a t e s a v a r i e t y o f r i n g s i z e s a n d f u n c t i o n a l i t y , a n d p r o c e e d s i n v e r y g o o d y i e l d . III. EXPERIMENTAL 3.1. General. 3.1.1. Data Acquisition, Presentation, and Experimental Techniques. M e l t i n g p o i n t s w e r e m e a s u r e d o n a F i s h e r - J o h n s m e l t i n g p o i n t a p p a r a t u s a n d a r e u n c o r r e c t e d . D i s t i l l a t i o n t e m p e r a t u r e s r e f e r t o a i r - b a t h t e m p e r a t u r e s o f K u g e l r o h r ( b u l b - t o -b u l b ) d i s t i l l a t i o n s a n d a r e u n c o r r e c t e d . T h e r e m o v a l o f r e s i d u a l t r a c e s o f s o l v e n t s a n d / o r m o i s t u r e u n d e r r e d u c e d p r e s s u r e ( v a c u u m p u m p ) , f o r v i s c o u s a n d / o r h i g h m o l e c u l a r w e i g h t c o m p o u n d s , r e f e r s t o s u b m i t t i n g a s a m p l e to a p r e s s u r e o f - 0 . 1 0 T o r r , at r o o m t e m p e r a t u r e , f o r a p e r i o d o f 3 0 - 6 0 m i n . I n f r a r e d ( I R ) s p e c t r a w e r e r e c o r d e d o n a P e r k i n - E l m e r 1 7 1 0 F o u r i e r t r a n s f o r m s p e c t r o p h o t o m e t e r w i t h i n t e r n a l c a l i b r a t i o n , u s i n g e i t h e r f i l m s o f n e a t c o m p o u n d s b e t w e e n s o d i u m c h l o r i d e p l a t e s ( f o r l i q u i d s a m p l e s ) o r p o t a s s i u m b r o m i d e p e l l e t s ( f o r s o l i d s a m p l e s ) . P r o t o n n u c l e a r m a g n e t i c r e s o n a n c e ( * H n m r ) s p e c t r a w e r e r e c o r d e d o n a B r u k e r m o d e l W H - 4 0 0 ( 4 0 0 M H z ) s p e c t r o m e t e r u s i n g d e u t e r i o c h l o r o f o r m (CDCI3) o r d i d e u t e r i o m e t h y l e n e c h l o r i d e (CD2CI2), as i n d i c a t e d . S i g n a l p o s i t i o n s (8 v a l u e s ) a re g i v e n i n par ts p e r m i l l i o n ( p p m ) f r o m t e t r a m e t h y l s i l a n e (8 0 ) a n d w e r e m e a s u r e d r e l a t i v e t o t h e s i g n a l s f o r c h l o r o f o r m ( 8 7 . 2 4 ) o r m e t h y l e n e c h l o r i d e (8 5 . 3 2 ) . C o u p l i n g c o n s t a n t s (J v a l u e s ) a r e g i v e n i n H e r t z ( H z ) . T h e t i n - p r o t o n c o u p l i n g c o n s t a n t s ( / sn -H . ) a re g i v e n as a n a v e r a g e o f the 1 1 7 S n a n d 1 1 9 S n v a l u e s . T h e s p e c t r a l d a t a a r e r e p o r t e d i n t h e f o l l o w i n g f o r m a t : c h e m i c a l s h i f t ( p p m ) , ( m u l t i p l i c i t y , n u m b e r o f p r o t o n s , c o u p l i n g c o n s t a n t ( s ) , a n d a s s i g n m e n t s ( w h e n k n o w n ) ) . T h e a b b r e v i a t i o n s u s e d f o r t h e m u l t i p l i c i t i e s a r e : s f o r s i n g l e t , d f o r d o u b l e t , t f o r t r i p l e t , q f o r q u a r t e t , m f o r m u l t i p l e t , a n d b r f o r b r o a d . I n t h e * H n m r s p e c t r a l a s s i g n m e n t s , f o r n o n - b i c y c l i c c o m p o u n d s c o n t a i n i n g a s p i r o c e n t e r , H - x a n d H - x ' i n d i c a t e p r o t o n s a t t a c h e d to t h e c a r b o n s l a b e l e d C - x o r C - x ' , r e s p e c t i v e l y , a n d t h e n u m b e r i n g h a s b e e n d e s i g n a t e d a c c o r d i n g to t h e I n t e r n a t i o n a l U n i o n o f P u r e a n d A p p l i e d C h e m i s t r y ( I U P A C ) r u l e s f o r t h e n o m e n c l a t u r e o f o r g a n i c c o m p o u n d s . F o r a l l o t h e r t y p e s o f c o m p o u n d s , H - x a n d H - x ' h a v e b e e n u s e d t o d e s i g n a t e p r o t o n s o n t h e s a m e c a r b o n , w i t h H - x ' b e i n g t h e p r o t o n r e s o n a t i n g at l o w e r f i e l d . I n s o m e c a s e s , t h e p r o t o n a s s i g n m e n t s a re s u p p o r t e d b y h o m o n u c l e a r (lH-l\u00C2\u00A5\u00C2\u00A3) s p i n d e c o u p l i n g , C O S Y ( i H ^ H h o m o n u c l e a r c o r r e l a t i o n s p e c t r o s c o p y ) a n d / o r N O E ( n u c l e a r O v e r h a u s e r e n h a n c e m e n t ) d i f f e r e n c e e x p e r i m e n t s . C a r b o n n u c l e a r m a g n e t i c r e s o n a n c e ( 1 3 C n m r ) s p e c t r a w e r e r e c o r d e d o n a V a r i a n m o d e l X L - 3 0 0 ( 7 5 . 3 M H z ) s p e c t r o m e t e r o r o n a B r u k e r m o d e l A C - 2 0 0 E ( 5 0 . 3 M H z ) s p e c t r o m e t e r u s i n g d e u t e r i o c h l o r o f o r m (CDCI3) o r d i d e u t e r i o m e t h y l e n e c h l o r i d e (CD2CI2), as i n d i c a t e d . S i g n a l p o s i t i o n s ( 5 v a l u e s ) a r e g i v e n i n p a r t s p e r m i l l i o n ( p p m ) f r o m t e t r a m e t h y l s i l a n e a n d w e r e m e a s u r e d r e l a t i v e to t h e s i g n a l s o f c h l o r o f o r m - d ( 8 7 7 . 0 ) o r m e t h y l e n e c h l o r i d e - d 2 ( 8 5 3 . 8 ) . A t t a c h e d p r o t o n tests ( A P T s ) , u s e d t o d i f f e r e n t i a t e m e t h y l (CH3) a n d m e t h i n e c a r b o n s ( C H ) ( n e g a t i v e p h a s e s i g n a l s ) f r o m m e t h y l e n e ( C H 2 ) a n d q u a t e r n a r y c a r b o n s ( p o s i t i v e p h a s e s i g n a l s ) , w e r e r e c o r d e d o n a V a r i a n X L - 3 0 0 o r a B r u k e r A C - 2 0 0 E s p e c t r o m e t e r . W h e n A P T d a t a i s g i v e n , s i g n a l s w i t h n e g a t i v e p h a s e s a r e s o i n d i c a t e d i n b r a c k e t s ( - ve ) f o l l o w i n g t h e 1 3 C n m r c h e m i c a l s h i f t . T h e c a r b o n a s s i g n m e n t i s i n d i c a t e d i n p a r e n t h e s e s a f te r the c h e m i c a l s h i f t ( w h e n k n o w n ) . L o w a n d h i g h r e s o l u t i o n m a s s s p e c t r a w e r e r e c o r d e d o n a K r a t o s M S 8 0 o r o n a K r a t o s C o n c e p t I I H Q m a s s s p e c t r o m e t e r . T h e m o l e c u l a r i o n ( M + ) m a s s e s a r e g i v e n u n l e s s o t h e r w i s e n o t e d . F o r s o m e c o m p o u n d s c o n t a i n i n g t h e t r i b u t y l s t a n n y l ( S n B u 3 ) , t r i m e t h y l g e r m y l ( G e M e 3 ) , ( 2 - t r i m e t h y l s i l y l e t h o x y ) m e t h y l ( M e 3 S i C H 2 C H 2 0 C H 2 ) o r tert-b u t y l d i m e t h y l s i l y l (tert-BuMe2Si) g r o u p s , t h e h i g h r e s o l u t i o n s p e c t r o m e t r y m o l e c u l a r m a s s 4 d e t e r m i n a t i o n s w e r e m a d e o n t h e ( M - B u ) + , ( M - M e ) + , ( M - O C H 2 C H 2 T M S ) + , o r t h e ( M -tert-Bu)+ p e a k s , r e s p e c t i v e l y . A l l c o m p o u n d s s u b j e c t e d t o h i g h r e s o l u t i o n m a s s m e a s u r e m e n t w e r e h o m o g e n e o u s b y g l c a n d / o r t i c a n a l y s e s . E l e m e n t a l a n a l y s e s w e r e p e r f o r m e d o n a C a r l o E r b a C H N m o d e l 1 1 0 6 o r o n a F i s o n s E A m o d e l 1 1 0 8 e l e m e n t a l a n a l y z e r , b y t h e U B C M i c r o a n a l y t i c a l L a b o r a t o r y . G a s - l i q u i d c h r o m a t o g r a p h y ( g l c ) w a s p e r f o r m e d o n H e w l e t t - P a c k a r d m o d e l s 5 8 8 0 A a n d 5 8 9 0 gas c h r o m a t o g r a p h s , b o t h e q u i p p e d w i t h f l a m e i o n i z a t i o n d e t e c t o r s a n d f u s e d s i l i c a c o l u m n s . T h e f o r m e r i n s t r u m e n t c o n t a i n e d a - 2 5 m x 0 . 2 1 m m c a p i l l a r y c o l u m n ( H P - 5 , c r o s s - l i n k e d w i t h 5 % p h e n y l m e t h y l s i l i c o n e ) , w h i l e t h e l a t te r c h r o m a t o g r a p h u t i l i z e d a - 2 5 m x 0 . 2 0 m m c a p i l l a r y c o l u m n ( H P - 5 , c r o s s - l i n k e d w i t h 5 % p h e n y l m e t h y l s i l i c o n e ) . T h i n l a y e r c h r o m a t o g r a p h y ( t i c ) w a s c a r r i e d o u t o n c o m m e r c i a l l y a v a i l a b l e a l u m i n u m - b a c k e d s i l i c a g e l 6 0 F254 p l a t e s ( E . M e r c k , t y p e 5 5 5 4 , t h i c k n e s s 0 . 2 m m ) . V i s u a l i z a t i o n w a s a c c o m p l i s h e d b y u s i n g u v a n d / o r i o d i n e a b s o r b e d o n t o s i l i c a g e l , f o l l o w e d b y h e a t i n g t h e c h r o m a t o g r a m a f t e r s t a i n i n g w i t h o n e o f t h e f o l l o w i n g s o l u t i o n s : (a) v a n i l l i n ( 3 - m e t h o x y s a l i c y l a l d e h y d e ) i n a s u l f u r i c a c i d - E t O H m i x t u r e ( 6 % v a n i l l i n w / v , 4 % s u l f u r i c a c i d v / v , a n d 1 0 % w a t e r v / v i n E t O H ) , ( b ) p h o s p h o m o l y b d i c a c i d i n E t O H ( 2 0 % p h o s p h o m o l y b d i c a c i d w / v , A l d r i c h C h e m i c a l C o . , c a t # 3 1 , 9 2 7 - 9 ) , (c ) a n i s a l d e h y d e i n a s u l f u r i c a c i d - E t O H m i x t u r e ( 5 % a n i s a l d e h y d e v / v a n d 5 % s u l f u r i c a c i d v / v i n E t O H ) . F l a s h c h r o m a t o g r a p h y w a s p e r f o r m e d w i t h 2 3 0 - 4 0 0 m e s h s i l i c a g e l ( E . M e r c k , S i l i c a G e l 6 0 ) u s i n g t h e t e c h n i q u e d e s c r i b e b y S t i l l . 1 5 6 T i c g r a d e s i l i c a c h r o m a t o g r a p h y w a s p e r f o r m e d w i t h S i g m a t y p e H s i l i c a g e l 1 0 - 4 0 u r n , n o b i n d e r , u s i n g t h e t e c h n i q u e d e s c r i b e d b y T a b e r . 1 5 7 R a d i a l c h r o m a t o g r a p h y 1 5 8 w a s c a r r i e d o u t w i t h a Chromatotron\u00C2\u00AE M o d e l 7 9 2 4 , u t i l i z i n g 1, 2 , o r 4 m m t h i c k r a d i a l p l a t e s c o a t e d w i t h s i l i c a g e l ( E . M e r c k , s i l i c a g e l 6 0 , PF254, w i t h g y p s u m as b i n d e r ) . C o n c e n t r a t i o n , e v a p o r a t i o n , o r r e m o v a l o f s o l v e n t u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t p r ) r e f e r s t o s o l v e n t r e m o v a l v i a a B i i c h i r o t a r y e v a p o r a t o r at - 1 5 T o r r . U n l e s s o t h e r w i s e s t a t e d , a l l r e a c t i o n w e r e c a r r i e d o u t u n d e r a n a t m o s p h e r e o f d r y a r g o n u s i n g g l a s s w a r e tha t h a d b e e n o v e n ( - 1 4 0 \u00C2\u00B0C) a n d / o r f l a m e d r i e d a n d c o o l e d u n d e r a s t r e a m o f d r y a r g o n . T h e g l a s s s y r i n g e s , s t a i n l e s s s t e e l n e e d l e s , a n d Teflon\u00C2\u00AE c a n n u l a e u s e d to h a n d l e a n h y d r o u s s o l v e n t a n d r e a g e n t s w e r e o v e n d r i e d , c o o l e d i n a d e s i c c a t o r , a n d f l u s h e d w i t h d r y a r g o n p r i o r to u s e . T h e p l a s t i c s y r i n g e s w e r e f l u s h e d w i t h d r y a r g o n b e f o r e u s e . T h e s m a l l a n d l a r g e Teflon\u00C2\u00AE c a n n u l a e w e r e p u r c h a s e d f r o m C a n l a b a n d h a v e t h e f o l l o w i n g d i m e n s i o n s : t h e s m a l l c a n n u l a e h a v e a n i n n e r d i a m e t e r o f 0 . 3 8 m m a n d a w a l l t h i c k n e s s o f 0 . 2 3 m m , a n d t h e l a r g e c a n n u l a e h a v e a n i n n e r d i a m e t e r o f 0 . 9 7 m m a n d a w a l l t h i c k n e s s o f 0 . 3 0 m m . C o l d t e m p e r a t u r e s w e r e m a i n t a i n e d b y the u s e o f t h e f o l l o w i n g c o l d b a t h s : 0 \u00C2\u00B0C, i c e -w a t e r ; - 1 0 \u00C2\u00B0C, - 2 0 \u00C2\u00B0C, - 3 0 \u00C2\u00B0C, - 4 8 \u00C2\u00B0C, a q u e o u s c a l c i u m c h l o r i d e - d r y i c e ( 1 6 . 4 , 2 7 , 3 5 , a n d 4 7 g C a C l 2 / 100 m L H2O, r e s p e c t i v e l y . ) ; 1 5 9 - 7 8 \u00C2\u00B0C, a c e t o n e - d r y i c e . 3 . 1 . 2 . S o l v e n t s a n d R e a g e n t s . A l l s o l v e n t a n d r e a g e n t s w e r e p u r i f i e d a n d d r i e d u s i n g k n o w n p r o c e d u r e s . 1 6 0 B e n z e n e a n d d i c h l o r o m e t h a n e w e r e d i s t i l l e d f r o m c a l c i u m h y d r i d e , w h i l e d i e t h y l e t h e r a n d t e t r a h y d r o f u r a n w e r e d i s t i l l e d f r o m s o d i u m b e n z o p h e n o n e k e t y l . T h e s e f o u r s o l v e n t s w e r e d i s t i l l e d u n d e r a n a t m o s p h e r e o f d r y a r g o n a n d u s e d i m m e d i a t e l y . A c e t o n i t r i l e , 1 , 2 - d i c h l o r o e t h a n e , A ^ N - d i i s o p r o p y l e t h y l a m i n e , M N - d i i s o p r o p y l a m i n e , 1 , 1 , 1 , 3 , 3 , 3 - h e x a m e t h y l d i s i l a z a n e ( H M D S ) , h e x a m e t h y l p h o s p h o r a m i d e ( H M P A ) , n - h e x a n e , 1 - h e x e n e , 2 - m e t h y l - 2 - p r o p a n o l (tert-BuOH), t o l u e n e , a n d t r i e t h y l a m i n e w e r e d i s t i l l e d u n d e r a n a t m o s p h e r e o f d r y a r g o n , f r o m c a l c i u m h y d r i d e . M a g n e s i u m w a s a d d e d to m e t h a n o l a n d , a f t e r r e f l u x i n g t h e m i x t u r e , t h e m e t h a n o l w a s d i s t i l l e d f r o m t h e r e s u l t i n g m a g n e s i u m m e t h o x i d e s o l u t i o n u n d e r a n a t m o s p h e r e o f d r y a r g o n . A b s o l u t e e t h a n o l w a s o b t a i n e d b y d o u b l y d i s t i l l i n g c o m m e r c i a l l y a v a i l a b l e e t h a n o l ( 9 5 % ) , f i r s t f r o m c a l c i u m o x i d e ( C a O ) , a n d t h e n f r o m m a g n e s i u m e t h o x i d e i n a n a n a l o g o u s m a n n e r to t h e p r e v i o u s l y d e s c r i b e d m e t h o d f o r d r y i n g m e t h a n o l . T h e a f o r e m e n t i o n e d r e a g e n t s w e r e s t o r e d u n d e r a n a t m o s p h e r e o f d r y a r g o n i n b o t t l e s s e a l e d w i t h a Sure/Seal\u00C2\u00AE ( A l d r i c h C h e m i c a l C o . , I n c . ) . A l l o t h e r s o l v e n t s w e r e o b t a i n e d c o m m e r c i a l l y a n d u s e d w i t h o u t f u r t h e r p u r i f i c a t i o n . P e t r o l e u m e t h e r r e f e r s t o a h y d r o c a r b o n m i x t u r e w i t h a b o i l i n g p o i n t r a n g e o f 3 0 -6 0 \" C . S o l u t i o n s o f m e t h y l l i t h i u m i n d i e t h y l e t h e r o r n - b u t y l l i t h i u m i n h e x a n e s w e r e o b t a i n e d f r o m t h e A l d r i c h C h e m i c a l C o . a n d w e r e s t a n d a r d i z e d a c c o r d i n g t o t h e m e t h o d s o f K o f r o n a n d B a c l a w s k i 1 6 1 o r C h o n g . 1 6 2 P o t a s s i u m h y d r i d e w a s o b t a i n e d as a 3 5 % s u s p e n s i o n i n m i n e r a l o i l f r o m t h e A l d r i c h C h e m i c a l C o . a n d w a s r i n s e d f r e e o f the o i l w i t h d r y p e n t a n e o r d r y d i e t h y l e t h e r u n d e r a n a t m o s p h e r e o f d r y a r g o n . T h e r e s i d u a l s o l v e n t w a s r e m o v e d f r o m t h e p o t a s s i u m h y d r i d e u n d e r r e d u c e d p r e s s u r e ( v a c u u m p u m p ) . S o l u t i o n s o f p o t a s s i u m 1 , 1 , 1 , 3 , 3 , 3 - h e x a m e t h y l d i s i l a z i d e ( K H M D S ) i n T H F w e r e e i t h e r o b t a i n e d f r o m p o t a s s i u m h y d r i d e a n d 1 , 1 , 1 , 3 , 3 , 3 - h e x a m e t h y l d i s i l a z a n e ( H M D S ) a c c o r d i n g to the p r o c e d u r e o f B r o w n , 9 6 o r t h e c o m m e r c i a l l y a v a i l a b l e ( s o l i d ) m a t e r i a l w a s d i s s o l v e d i n d r y T H F . T h e s o l u t i o n s w e r e s t a n d a r d i z e d a c c o r d i n g t o t h e m e t h o d s o f K o n f r o n a n d B a c l a w s k i . 1 6 1 L i t h i u m d i i s o p r o p y l a m i d e ( L D A ) w a s p r e p a r e d b y a d d i n g a s o l u t i o n o f m e t h y l l i t h i u m ( l . O e q u i v . ) i n d i e t h y l e t h e r o r n - b u t y l l i t h i u m ( l . O e q u i v . ) i n h e x a n e s t o a s o l u t i o n o f d i i s o p r o p y l a m i n e ( - 1 . 1 e q u i v . ) i n d r y T H F at 0 \u00C2\u00B0C. T h e r e s u l t i n g s o l u t i o n w a s s t i r r e d at 0 \u00C2\u00B0C f o r 1 5 - 2 0 m i n p r i o r to u s e . A s o l u t i o n o f N a O M e i n d r y m e t h a n o l w a s p r e p a r e d i n t h e f o l l o w i n g m a n n e r . T o a c o l d ( - 78 \u00C2\u00B0C) f l a s k c o n t a i n i n g e i t h e r s o d i u m h y d r i d e ( N a H ) o r s o d i u m m e t a l w a s a d d e d t h e a p p r o p r i a t e a m o u n t o f d r y M e O H . T h e f l a s k w a s w a n n e d to r o o m t e m p e r a t u r e a n d t h e r e s u l t a n t s o l u t i o n w a s s t o r e d u n d e r a n a t m o s p h e r e o f d r y a r g o n i n b o t t l e s s e a l e d w i t h a Sure/Seal\u00C2\u00AE ( A l d r i c h C h e m i c a l C o . , I nc . ) . A q u e o u s a m m o n i u m c h l o r i d e - a m m o n i u m h y d r o x i d e ( N H 4 C I - N H 4 O H ) ( p H 8 ) s o l u t i o n w a s p r e p a r e d b y t h e a d d i t i o n o f - 5 0 m L o f c o n c e n t r a t e d ( 2 8 - 3 0 % ) a q u e o u s a m m o n i a to - 9 5 0 m L o f s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e s o l u t i o n . A r g o n w a s d r i e d b y b u b b l i n g i t t h r o u g h c o n c e n t r a t e d s u l f u r i c a c i d a n d t h e n b y p a s s i n g i t t h r o u g h a Drierite\u00C2\u00AE a n d p o t a s s i u m h y d r o x i d e ( K O H ) f i l l e d d r y i n g t u b e . B o r o n t r i f l u o r i d e - e t h e r a t e w a s p u r i f i e d b y d i s t i l l a t i o n f r o m c a l c i u m h y d r i d e u n d e r r e d u c e d p r e s s u r e ( 6 0 \" C / 2 0 T o r r ) . C o p p e r b r o m i d e - d i m e t h y l s u l f i d e w a s p r e p a r e d a c c o r d i n g to t h e p r o c e d u r e d e s c r i b e d b y W u t s 1 6 3 a n d w a s s t o r e d i n a d e s i c c a t o r u n d e r a n a t m o s p h e r e o f a r g o n . S o l u t i o n s o f d i m e t h y l d i o x i r a n e i n a c e t o n e w e r e p r e p a r e d a c c o r d i n g to t h e p r o t o c o l s o f S i n g h 1 1 0 b o r A d a m 1 1 0 a a n d w e r e s t a n d a r d i z e d b y i o d o m e t r i c t i t r a t i o n . 1 6 4 I o d i n e w a s p u r i f i e d v i a s u b l i m a t i o n b y w a r m i n g ( ~ 6 0 \u00C2\u00B0C) t h e i o d i n e u n d e r r e d u c e d p r e s s u r e ( - 1 5 T o r r ) . M e t h y l i o d i d e a n d c h l o r o i o d o m e t h a n e w e r e p a s s e d t h r o u g h a s h o r t c o l u m n o f b a s i c a l u m i n a a c t i v i t y I w h i c h h a d b e e n d r i e d i n a n o v e n ( - 1 4 0 \u00C2\u00B0C) a n d a l l o w e d t o c o o l i n a d e s i c c a t o r p r i o r t o u s e . P y r i d i n i u m c h l o r o c h r o m a t e a b s o r b e d o n b a s i c a l u m i n a w a s p r e p a r e d a c c o r d i n g t o t h e m e t h o d o f C h e n g . 1 5 4 T r i m e t h y l s i l y l c h l o r i d e ( T M S C 1 ) a n d t r i m e t h y l g e r m a n i u m b r o m i d e ( M e 3 G e B r ) ( o b t a i n e d f o r m O r g a n o m e t a l l i c s I n c . ) w e r e d i s t i l l e d f r o m c a l c i u m h y d r i d e u n d e r a n a t m o s p h e r e o f d r y a r g o n a n d w e r e u s e d i m m e d i a t e l y . T h e T e b b e r e a g e n t , ( u . - c h l o r o ) ( u - m e t h y l e n e ) b i s ( c y c l o p e n t a d i e n y l ) ( d i m e t h y l a l u m i n u m ) t i t a n i u m , w a s p r e p a r e d v i a t h e e x p e r i m e n t a l p r o c e d u r e d e s c r i b e d b y G r u b b s , 1 6 5 a n d w a s s t o r e d i n a g l o v e b o x u n d e r a n a t m o s p h e r e o f a r g o n . A l l o t h e r r e a g e n t s w e r e c o m m e r c i a l l y a v a i l a b l e a n d w e r e u s e d w i t h o u t f u r t h e r p u r i f i c a t i o n . 183 3.2. Total Synthesis of the Diterpenoids (\u00C2\u00B1)-Verrucosan-2B-ol, (\u00C2\u00B1)-Neoverrucosan-58-ol, (\u00C2\u00B1)-Homoverrucosan-5B-ol, and (\u00C2\u00B1)-(3R, 4R, 5R, 6S, 91?)-Cyatha-12,18-diene. Preparation of 3-[2-(l,3-Dioxan-2-yl)eth-l-yl]-3-methylcyclohexanone (184). O 1) BrMg' CuBr.Me 2S, THF, HMPA, TMSCI, - 78\u00C2\u00B0C 2) NH 4CI, H 2 0 140 184 T o a s t i r r e d s u s p e n s i o n o f f r e s h l y g r o u n d m a g n e s i u m t u r n i n g s ( 3 . 4 8 g , 1 4 3 m m o l , 3 . 0 e q u i v . ) a n d i o d i n e (a f e w c r y s t a l s ) i n d r y T H F ( 3 3 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d d r o p w i s e ( v i a a l a r g e Tef lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f 2 - ( 2 - b r o m o e t h y l ) - l , 3 - d i o x a n e ( 2 3 . 0 g , 118 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 1 0 m L ) . T h e b r o m i d e s o l u t i o n w a s a d d e d at s u c h a ra te that r e f l u x o f t h e r e a c t i o n m i x t u r e w a s m a i n t a i n e d . A f t e r t h e a d d i t i o n w a s c o m p l e t e , the m i x t u r e w a s h e a t e d at r e f l u x f o r 3 0 m i n . T h e m i x t u r e w a s c o o l e d t o r o o m t e m p e r a t u r e , d i l u t e d w i t h d r y T H F ( 1 6 7 m L ) , a n d t h e n w a s c o o l e d t o - 7 8 \u00C2\u00B0C. S o l i d CuBr\u00C2\u00BBMe2S ( 3 . 6 4 g , 17 .7 m m o l , 15 m o l % w i t h r e s p e c t to t h e G r i g n a r d r e a g e n t ) w a s a d d e d i n o n e p o r t i o n . T h e c l o u d y m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 1 h . D r y H M P A ( 2 4 . 7 m L , 1 4 2 m m o l , 3 . 0 e q u i v . ) w a s a d d e d d r o p w i s e a n d t h e m i x t u r e w a s s t i r r e d f o r 10 m i n . A s o l u t i o n o f 3 - m e t h y l - 2 -c y c l o h e x e n - l - o n e (140) ( 5 . 2 4 g , 4 7 . 6 m m o l , 1.0 e q u i v . ) a n d t r i m e t h y l s i l y l c h l o r i d e ( 1 8 . 0 m L , 1 4 2 m m o l , 3 . 0 e q u i v . ) i n d r y T H F (7 m L ) w a s a d d e d d r o p w i s e ( v i a Te f lon\u00C2\u00AE c a n n u l a ) . T h e r e s u l t a n t p a l e y e l l o w m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 2 h 15 m i n , a n d t h e n w a s a l l o w e d to w a r m to r o o m t e m p e r a t u r e . W a t e r ( 3 0 m L ) w a s a d d e d a n d t h e m i x t u r e w a s s t i r r e d f o r 5 m i n b e f o r e a d d i n g a q u e o u s N H 4 C I - N H 4 O H ( p H 8 - 9 , 1 0 0 m L ) a n d d i e t h y l e t h e r ( 1 0 0 m L ) . T h e mixture and was opened to the atmosphere and was stirred vigorously overnight, at which point the aqueous layer was a deep blue. The layers were separated and the aqueous phase was extracted with diethyl ether (3 x 70 mL). The combined organic extracts were washed successively with water (2 x 100 mL), brine (2 x 100 mL), 10% aqueous CuSC\u00C2\u00BB4 solution (1 x 100 mL), brine (1 x 100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (336 g flash silica gel, 1.9:1 petroleum ether - ethyl acetate, 7 cm column). The appropriate fractions were concentrated and the oil thus obtained was distilled (air-bath temperature 132-136 \u00C2\u00B0C/0.15 Torr) to afford the keto acetal 18451(10.2 g, 95%) as a colourless oil. 185 Preparation of 6-Methylbicyclo[4.3.0]non-9-en-2-one (179). O O C F 3 C O O H , THF 70 \u00C2\u00B0C 10 184 179 T o a s t i r r e d s o l u t i o n o f t h e k e t o a c e t a l 184 ( 5 5 8 m g , 2 . 4 6 m m o l , 1 .0 e q u i v . ) i n T H F ( 1 6 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d 8 0 % a q u e o u s t r i f l u o r o a c e t i c a c i d (8 m L : 1.6 m L H2O + 6 . 4 m L o f 1 0 0 % CF3COOH). T h e r e a c t i o n m i x t u r e w a s h e a t e d at 7 0 \u00C2\u00B0C a n d s t i r r e d f o r 2 h 3 0 m i n , a n d t h e n w a s a l l o w e d t o c o o l t o r o o m t e m p e r a t u r e . T h e m i x t u r e w a s n e u t r a l i z e d b y t h e a d d i t i o n o f s a t u r a t e d a q u e o u s NaHCC\u00C2\u00BB 3 ( 15 m L ) , f o l l o w e d b y t h e c a r e f u l a d d i t i o n o f s o l i d N a H C 0 3 . T h e m i x t u r e w a s d i l u t e d w i t h d i e t h y l e t h e r ( 2 0 m L ) , t h e a q u e o u s p h a s e w a s s e p a r a t e d a n d w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 2 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (2 x 4 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 3 0 g t i c s i l i c a g e l , 1.9:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 3 . 5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d the o i l thus o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 9 0 - 1 0 0 \u00C2\u00B0C/0.15 T o r r ) to a f f o r d t h e e n o n e 179 4 8 ( 3 0 5 m g , 8 2 % ) as a c o l o u r l e s s o i l . A f t e r r e c o v e r y o f the e n o n e 179, t h e c o l u m n w a s f l u s h e d w i t h d i e t h y l e t h e r ( 5 0 0 m L ) . T h e e l u a t e w a s c o n c e n t r a t e d , t h e r e s i d u e w a s d i s s o l v e d i n a m i x t u r e o f T H F (8 m L ) a n d 8 0 % t r i f l u o r o a c e t i c a c i d (4 m L : 0 .8 m L H2O + 3 . 2 m L o f 1 0 0 % C F 3 C O O H ) , a n d the m i x t u r e w a s h e a t e d at 7 0 \u00C2\u00B0C f o r 16 h . T h e r e a c t i o n m i x t u r e w a s c o o l e d t o r o o m t e m p e r a t u r e , d i l u t e d w i t h w a t e r (8 m L ) , a n d w a s c a r e f u l l y n e u t r a l i z e d w i t h s o l i d N a H C C \u00C2\u00BB 3 . T h e m i x t u r e w a s d i l u t e d w i t h d i e t h y l e t h e r ( 1 5 m L ) , the l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 1 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e d r i e d o v e r a n h y d r o u s 186 m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e r e s i d u a l m a t e r i a l w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 g t i c s i l i c a g e l , 1 .9:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d (as a b o v e ) t o y i e l d a f u r t h e r 3 4 m g ( 9 % ) o f c o m p o u n d 179. T h e t o t a l y i e l d o f t h e e n o n e 179 1 6 6 w a s 3 3 9 m g ( 9 1 % ) . Preparation of Isopropenyllithium (193). T o a c o l d ( 0 \u00C2\u00B0C) m i x t u r e o f o i l - f r e e 1 6 7 U t h i u m 1 6 8 ( 3 . 9 g , 5 6 0 m m o l , 2 . 0 e q u i v . ) a n d l i t h i u m w i r e 1 6 9 ( 3 . 7 g , 5 3 0 m m o l , 1.9 e q u i v . ) i n d r y E t 2 0 ( 3 2 0 m L ) , i m m e r s e d i n a n i c e -w a t e r f i l l e d s o n i c a t o r , w a s a d d e d d r o p w i s e ( v i a d r o p p i n g f u n n e l ) a s o l u t i o n o f 2 -b r o m o p r o p e n e (178) ( 2 5 . 0 m L , 2 8 1 m m o l , l . O e q u i v . ) i n d r y d i e t h y l e t h e r ( 3 0 m L ) . T h e m i x t u r e w a s s o n i c a t e d d u r i n g t h e a d d i t i o n o f 2 - b r o m o p r o p e n e a n d w a s s o n i c a t e d f o r a n a d d i t i o n a l 4 h , a l l o w i n g t h e m i x t u r e t o w a r m to r o o m t e m p e r a t u r e . T h e r e a c t i o n m i x t u r e w a s a l l o w e d t o s e t t l e f o r 3 0 m i n . T h e m i x t u r e w a s f i l t e r e d u n d e r a r g o n t h r o u g h a p a d o f d r y Celite\u00C2\u00AE (~ 2 0 g ) p r e s o a k e d w i t h d r y d i e t h y l e t h e r (~ 3 0 m L ) . T h e r e s i d u e f r o m t h e r e a c t i o n m i x t u r e w a s r i n s e d w i t h d r y d i e t h y l e t h e r ( 2 0 m L ) t o g i v e , a f t e r f i l t r a t i o n , a y e l l o w s o l u t i o n o f i s o p r o p e n y l l i t h i u m (193) i n a t o t a l o f 2 5 0 m L o f d i e t h y l e t h e r . T h e s o l u t i o n o f i s o p r o p e n y l l i t h i u m w a s t i t r a t e d 1 6 1 t o g i v e a c o n c e n t r a t i o n o f 0 . 9 5 M ( 8 4 % ) . T h e s o l u t i o n o f t h e r e a g e n t w a s s t o r e d i n a S u r e Seal\u00C2\u00AE b o t d e i n the r e f r i g e r a t o r a n d w a s u s e d w i t h i n 2 4 h . sonication 178 193 187 Preparation of Dilithio(diisopropenyl)(cyano)cuprate (192). .A* Li CuCN, THF -78 \u00C2\u00B0C Cu(CN)Li 2 193 192 T o a c o l d ( - 7 8 \u00C2\u00B0C), s t i r r e d s u s p e n s i o n o f C u C N ( 1 0 . 6 g , 1 1 8 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 5 3 5 m L ) w a s a d d e d ( v i a d o u b l e t i p p e d m e t a l c a n n u l a ) a d i e t h y l e t h e r s o l u t i o n o f i s o p r o p e n y l l i t h i u m (193) ( 2 4 8 m L , 0 . 9 5 M , 2 3 6 m m o l , 2 . 0 e q u i v . ) , p r e p a r e d as d e s c r i b e d a b o v e . T h e m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 5 - 1 0 m i n t o g i v e a c l e a r y e l l o w - o r a n g e s o l u t i o n a n d w a s u s e d i m m e d i a t e l y . I n o r d e r to e n s u r e a h o m o g e n e o u s s o l u t i o n , b r i e f w a r m i n g ( 2 -3 m i n ) o f t h e c u p r a t e m i x t u r e to - 4 8 \u00C2\u00B0C w a s s o m e t i m e s n e c e s s a r y , a n d t h e m i x t u r e w a s t h e n r e c o o l e d to - 7 8 \u00C2\u00B0C p r i o r to u s e . 188 Preparation of (IR*, 6S*, 9/?*)-9-Isopropenyl-6-methylbicyclo[4.3.0]nonan-2-one (194) and (IS*, 6S*, 9/f*)-9-IsopropenyI-6-methylbicyclo[4.3.0]nonan-2-one (60). A s o l u t i o n o f t h e c u p r a t e 192 ( 1 . 4 2 m m o l , 1.3 e q u i v . ) w a s p r e p a r e d as d e s c r i b e d a b o v e u s i n g t h e f o l l o w i n g a m o u n t s o f r e a g e n t s : C u C N ( 1 2 7 m g , 1 .42 m m o l , 1.3 e q u i v . ) a n d i s o p r o p e n y l l i t h i u m ( 1 9 3 ) ( 2 .7 m L , 1 .02 M i n E t 2 0 , 2 . 7 5 m m o l , 2 . 6 e q u i v . ) i n d r y T H F (6 m L ) . T o t h i s c o l d ( - 7 8 \u00C2\u00B0C), s t i r r e d c u p r a t e s o l u t i o n w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f t h e e n o n e 179 ( 1 6 0 m g , 1 .07 m m o l , 1.0 e q u i v . ) a n d t r i m e t h y l s i l y l c h l o r i d e ( 0 . 5 4 m L , 4 . 3 m m o l , 4 . 0 e q u i v . ) i n d r y T H F (3 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 3 5 m i n . W a t e r (5 m L ) w a s a d d e d a n d the m i x t u r e w a s a l l o w e d to w a r m to r o o m t e m p e r a t u r e o v e r 1 h 15 m i n . A q u e o u s N H 4 C I - N H 4 O H ( p H 8 - 9 , 15 m L ) a n d d i e t h y l e t h e r ( 1 5 m L ) w e r e a d d e d . T h e m i x t u r e w a s o p e n e d to the a t m o s p h e r e a n d w a s s t i r r e d v i g o r o u s l y o v e r n i g h t , at w h i c h p o i n t t h e a q u e o u s l a y e r w a s a d e e p b l u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 2 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h w a t e r (1 x 2 0 m L ) , a n d b r i n e (2 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s s u b j e c t e d to r a d i a l c h r o m a t o g r a p h y (1 m m p l a t e , 9 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 7 0 - 9 0 \u00C2\u00B0C/0.20 T o r r ) to a f f o r d a m i x t u r e o f t h e k e t o n e 19411 a n d t h e k e t o n e 60 1 1 ( 1 7 6 m g , 8 6 % ) i n a r a t i o o f 1 1 : 1 , r e s p e c t i v e l y , as d e t e r m i n e d b y t h e i n t e g r a t i o n o f t h e i r v i n y l s i g n a l s i n the ! H n m r s p e c t r u m o f the m i x t u r e . T o a s t i r r e d s o l u t i o n o f a m i x t u r e o f t h e k e t o n e s 194 a n d 60 ( 4 8 7 m g , 2 . 5 3 m m o l , 1.0 e q u i v . , r a t i o 1 1 : 1 ) i n d r y M e O H ( 2 0 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d a s o l u t i o n o f N a O M e i n d r y M e O H (4 .8 m L , 0 . 5 0 M , 2 . 4 m m o l , 0 . 9 5 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 4 0 \u00C2\u00B0C f o r 7 4 h . T h e M e O H w a s r e m o v e d b y r o t a r y e v a p o r a t i o n a n d b r i n e ( 1 5 m L ) a n d d i e t h y l e t h e r ( 2 5 m L ) w e r e a d d e d to t h e r e s i d u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e o r g a n i c p h a s e w a s w a s h e d w i t h b r i n e ( 2 x 1 5 m L ) . T h e a q u e o u s p h a s e s w e r e b a c k e x t r a c t e d w i t h d i e t h y l e t h e r ( 2 x 1 5 m L ) a n d the c o m b i n e d o r g a n i c e x t r a c t s w e r e d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e * H n m r s p e c t r o s c o p i c a n a l y s i s o f t h e o i l t h u s o b t a i n e d i n d i c a t e d a . 1 :14 r a t i o o f t h e cis- a n d trans-fused c o m p o u n d s , 194 a n d 60, r e s p e c t i v e l y . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 39 g t i c s i l i c a g e l , 9 :1 p e t r o l e u m e t h e r - d i e t h y l e the r , 4 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l s t h u s o b t a i n e d w e r e d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 7 0 -9 0 \" C / 0 . 2 0 T o r r ) to a f f o r d m i x e d f r a c t i o n s c o n t a i n i n g c o m p o u n d s 194 a n d 60 ( 1 3 6 m g , 2 8 % ) , a n d p u r e trans - f u s e d k e t o n e 60 ( 3 2 5 m g , 6 7 % ) . 1 7 0 T h e t o t a l y i e l d o f c o m p o u n d s 194 a n d 60 w a s 4 6 1 m g ( 9 5 % ) . T h e f i r s t c o m p o u n d that e l u t e d w a s the d s - f u s e d p r o d u c t 194 a n d r e -s u b j e c t i n g t h e m i x e d f r a c t i o n s to f l a s h c h r o m a t o g r a p h y a l l o w e d f o r t h e s e p a r a t i o n o f a p u r e s a m p l e o f t h e k e t o n e 60. 1 9 0 C o m p o u n d 194. I R (neat ) : 3 0 8 3 , 1 6 9 8 , 1 6 4 6 , 1 4 5 6 , 8 8 8 c m \" l . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 1.11 (s, 3 H , Me-10), 1 . 4 1 - 1 . 5 1 ( m , 2 H , H - 5 , H - 7 B ) , 1 . 6 1 - 1 . 7 3 ( m , I H , H - 7 c t ) , 1.71 ( b r s , 3 H , M e - 1 3 ) , 1 . 7 3 - 1 . 9 1 ( m , 4 H , H - 4 , H - 4 ' , H - 5 ' , H - 8 ) , 1 . 9 1 - 2 . 0 3 ( m , I H , H - 8 ' ) , 2 . 1 3 - 2 . 3 0 ( m , 2 H , H - 3 , H - 3 ' ) , 2 . 5 6 (b r d , I H , J = 1 0 . 0 H z , H - l ) , 2 . 8 6 (b r d d d , I H , J = 1 0 . 1 , 1 0 . 1 , 1 0 . 0 H z , H - 9 ) , 4 . 7 8 ( b r s , I H , H - 1 2 ) , 4 . 8 3 ( b r d d d , I H , J = 1.4, 1.4, 1.4 H z , H - 1 2 ' ) . D e t a i l e d * H n m r d a t a ( C D C I 3 ) , d e r i v e d f r o m C O S Y a n d N O E e x p e r i m e n t s , a r e g i v e n i n Table 20. 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 2 1 . 7 , 2 4 . 0 ( - v e ) , 2 8 . 7 , 2 9 . 5 ( - v e ) , 3 5 . 1 , 3 8 . 9 , 4 1 . 1 , 4 6 . 6 , 4 9 . 0 ( - ve ) , 6 2 . 7 ( - v e , C - 9 ) , 1 0 9 . 8 ( C - 1 2 ) , 1 4 6 . 4 ( C - l l ) , 2 1 4 . 0 ( C - 2 ) . E x a c t M a s s c a l c d . f o r C13H20O: 1 9 2 . 1 5 1 4 ; f o u n d : 1 9 2 . 1 5 2 0 . A n a l , c a l c d . f o r C13H20O: C 8 1 . 2 0 , H 1 0 . 4 8 ; f o u n d : C 8 1 . 1 7 , H 1 0 . 4 2 . 191 Table 20: lH n m r ( 4 0 0 M H z , C D C 1 3 ) D a t a f o r t h e C w - F u s e d B i c y c l i c K e t o n e 194: C O S Y a n d N O E E x p e r i m e n t s . A s s i g n m e n t H - x a i H n m r ( 4 0 0 M H z ) 8 ( m u l t i p l i c i t y , 7 ( H z ) ) C O S Y C o r r e l a t i o n s N O E C o r r e l a t i o n s 0 H - 1 2 . 5 6 ( b r d , 7 = 1 0 . 0 ) H - 3 e q , H - 9 H - 9 , M e - 1 0 , M e - 1 3 H - 3 a x p a r t o f t h e m at 2 . 1 3 - 2 . 3 0 H - 3 e q , H - 4 , H - 4 ' H - 3 e q p a r t o f t h e m a t 2 . 1 3 - 2 . 3 0 H - l , H - 3 a x , H - 4 , H - 4 ' H - 4 p a r t o f t h e m at 1 . 7 3 - 1 . 9 1 H - 3 a x , H - 3 e q , H - 4 , H - 5 , H - 5 ' H - 4 ' p a r t o f t h e m at 1 . 7 3 - 1 . 9 1 H - 3 a x , H - 3 e q , H - 4 , H - 5 , H - 5 ' H - 5 p a r t o f t h e m at 1 . 4 1 - 1 . 5 1 H - 4 , H - 4 ' , H - 5 ' H - 5 ' p a r t o f t h e m at 1 . 7 3 - 1 . 9 1 H - 4 , H - 4 ' , H - 5 H-1 a 1 . 6 1 - 1 . 7 3 ( m ) H - 7 R , H - 8 , H - 8 ' , M e - 1 0 H - 7 R p a r t o f t h e m at 1 . 4 1 - 1 . 5 1 H - 7 c t , H - 8 , H - 8 ' H - 8 p a r t o f t h e m at 1 . 7 3 - 1 . 9 1 H - 7 c c , H - 7 R , H - 8 ' , H - 9 H - 9 H - 8 ' 1 . 9 1 - 2 . 0 3 ( m ) H - 7 a , H - 7 R , H - 8 , H - 9 H - 9 2 . 8 6 ( b r d d d , 7 = 1 0 . 1 , 1 0 . 1 , 10.0) H - 1 , H - 8 , H - 8 ' , H - 1 2 , H - 1 2 ' , M e - 1 3 H - 1 , H - 8 , M e -10, M e - 1 3 M e - 1 0 1.11 (s) H - 7 a H - 1 , H - 9 H - 1 2 4 . 7 8 ( b r s) H - 9 , H - 1 2 ' , M e - 1 3 H - 1 2 ' 4 . 8 3 (b r d d d , 7 = 1 . 4 , 1 . 4 , 1 . 4 ) H - 9 , H - 1 2 , M e - 1 3 M e - 1 3 1.71 (s) H - 1 , H - 9 H - 1 , H - 9 a-H' indicates the hydrogen of a pair which is more downfield (H-4' is more downfield than H-4). b-Only the NOE data that could be unambiguously assigned are recorded. 1 9 2 C o m p o u n d 60. I R (neat ) : 3 0 7 8 , 1 7 1 7 , 1 6 4 6 , 8 8 6 c n r * . * H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 7 6 (s , 3 H , M e -10) , 1 . 4 0 - 1 . 7 8 ( m , 4 H ) , 1 .70 (s, 3 H , M e - 1 3 ) , I. 7 8 - 2 . 0 8 ( m , 4 H ) , 2 . 2 2 - 2 . 3 0 ( m , 2 H ) , 2 . 4 7 ( d , I H , J = 11 .1 H z , H - l ) , 2 . 8 4 ( d d d , I H , J = I I . 1, 1 1 . 1 , 6 . 6 H z , H - 9 ) , 4 . 6 2 ( b r s , 1 H , H - 1 2 ) , 4 . 6 6 ( b r s , I H , H - 1 2 ' ) . D e t a i l e d * H n m r d a t a (CDCI3), d e r i v e d f r o m N O E e x p e r i m e n t s , a re g i v e n i n Table 21. 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 18 .6 ( - v e ) , 2 1 . 1 ( - ve ) , 2 4 . 4 , 2 7 . 3 , 3 8 . 5 , 3 9 . 8 , 4 1 . 3 ( - v e ) , 4 1 . 5 , 4 9 . 4 , 6 3 . 3 ( - v e , C - 9 ) , 1 0 8 . 8 ( C - 1 2 ) , 1 4 7 . 5 ( C - 1 3 ) , 2 1 0 . 6 ( C - 2 ) . E x a c t M a s s c a l c d . f o r C13H20O: 1 9 2 . 1 5 1 4 ; f o u n d : 1 9 2 . 1 5 1 7 . A n a l , c a l c d . f o r C 1 3 H 2 0 O : C 8 1 . 2 0 , H 1 0 . 4 8 ; f o u n d : C 8 0 . 9 8 , H 1 0 . 6 8 . 193 Table 21: * H n m r ( 4 0 0 M H z , C D C I 3 ) D a t a f o r t h e Trans-Fused B i c y c l i c K e t o n e 60: N O E E x p e r i m e n t s . I r r a d i a t e d S i g n a l N O E A s s i g n m e n t H - X a lU n m r ( 4 0 0 M H z ) 8 ( m u l t i p l i c i t y , J ( H z ) ) C o r r e l a t i o n s 0 H - l 2 . 4 7 (d , J= 11.1) H - 1 2 , M e - 1 3 H - 9 2 . 8 4 ( d d d , / = 1 1 . 1 , 1 1 . 1 , 6 . 6 ) M e - 1 0 , H - 1 2 , M e - 1 3 M e - 1 0 0 . 7 6 (s) H - 9 H - 1 2 4 . 6 2 (br s) H - l , H - 9 , H - 1 2 ' H - 1 2 ' 4 . 6 6 (br s) H - 1 2 , M e - 1 3 M e - 1 3 1.70 (s) H - l , H - 9 , H - 1 2 a-H' indicates the hydrogen of a pair which is more downfield (H-12' is more downfield than H-12). b-Only the N O E data that could be unambiguously assigned are recorded. 1 9 4 Preparation of (IS*, 6S*, 9/?*)-9-Isopropenyl-6-methylbicyclo[4.3.0]nonan-2-one N,N-dimethylhydrazone (209). Me 9 N NH 2 NMe 2 , toluene, TsOH azeotropic distillation 209 T o a s t i r r e d s o l u t i o n o f t h e b i c y c l i c k e t o n e 60 ( 3 8 5 m g , 2 . 0 0 m m o l , 1.0 e q u i v . ) i n d r y t o l u e n e ( 6 . 7 m L ) w a s a d d e d p - t o l u e n e s u l f o n i c a c i d m o n o h y d r a t e ( 3 8 m g , 0 . 2 0 m m o l , 10 m o l % ) a n d d i m e t h y l h y d r a z i n e ( 6 . 7 m L ) . T h e r e a c t i o n m i x t u r e w a s r e f l u x e d w i t h a z e o t r o p i c r e m o v a l o f w a t e r f o r 5 3 h . T h e m i x t u r e w a s c o o l e d to r o o m t e m p e r a t u r e a n d w a s s t i r r e d f o r a n a d d i t i o n a l 1 4 h . T h e s o l v e n t s w e r e r e m o v e d u n d e r r e d u c e d p r e s s u r e a n d the c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 2 4 g f l a s h s i l i c a g e l , 5 . 7 : 1 p e t r o l e u m e the r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 6 5 - 7 5 \" C / 0 . 2 0 T o r r ) t o a f f o r d t h e h y d r a z o n e 209 ( 2 9 8 m g , 6 4 % ) as a p a l e y e l l o w o i l . I R (neat ) : 3 0 7 7 , 2 8 1 4 , 2 8 5 4 , 1 6 4 5 , 1 4 5 5 , 1 3 7 9 , 1 2 0 4 , 1 0 2 1 , 9 7 3 , 8 8 0 c m - 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 .71 (s, 3 H , M e - 1 0 ) , 1 . 3 4 - 1 . 8 5 ( m , 8 H ) , 1 .72 (s , 3 H , M e - 1 3 ) , 1 . 9 4 - 2 . 0 3 ( m , I H ) , 2 . 0 4 ( d , I H , 7 = 1 1 . 1 H z , H - l ) , 2 . 3 9 (s, 6 H , - N = N ( M e 2 ) , 2 . 9 3 ( d d d , I H , J = 1 1 . 1 , 1 1 . 0 , 6 . 3 H z , H - 9 ) , 3 . 1 4 - 3 . 2 3 ( m , I H ) , 4 . 6 4 (b r s , 2 H , H - 1 2 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 1 8 . 0 ( - v e ) , 2 1 . 6 ( - v e ) , 2 3 . 3 , 2 8 . 3 , 2 8 . 6 , 3 9 . 2 , 3 9 . 7 , 4 1 . 7 ( - v e ) , 4 6 . 9 , 4 7 . 9 ( - v e , 2 C , - N = N ( M e 2 ) , 5 8 . 2 ( - v e ) , 1 0 8 . 4 ( C - 1 2 ) , 1 4 8 . 9 ( C - l l ) , 1 6 7 . 0 ( C - 2 ) . E x a c t M a s s c a l c d . f o r C 1 5 H 2 6 N 2 : 2 3 4 . 2 0 9 6 ; f o u n d : 2 3 4 . 2 1 0 1 . A n a l , c a l c d . f o r C i 5 H 2 6 N 2 : C 7 6 . 8 5 , H 1 1 . 1 9 , N 1 1 . 9 6 ; f o u n d : C 7 7 . 0 0 , H 1 1 . 0 8 , N 1 1 . 7 3 . 196 Preparat ion of (IS *, 3S * , 6R*, 9fl*)-9-Isopropenyl-6-methyl-3-[(Z)-4-(trimethyIgermyl)but-3-en-l-yl]bicyclo[4.3.0]nonan-2-one A^A^-dimethylhydrazone (210). MeoN 2<* v M e 2 N s 13 1) KDA, THF, -78 \u00C2\u00B0C 2) / V ^ \ M e 3 G e N t i W12 ll H ? \u00C2\u00AB 15 I v G e M e 3 202 HMPA, -78 \u00C2\u00B0 C 209 210 T o a s t i r r e d s o l u t i o n o f f - B u O K ( 2 3 m g , 0 .21 m m o l , 2 . 0 e q u i v . ) i n d r y T H F (0 .4 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d d r y d i i s o p r o p y l a m i n e ( 2 9 U.L, 0 .21 m m o l , 2 . 0 e q u i v . ) . T h e m i x t u r e w a s c o o l e d t o - 7 8 \u00C2\u00B0C b e f o r e a d d i n g n - B u L i ( 1 2 5 u L , 1 .41 M i n h e x a n e s , 0 . 1 7 6 m m o l , 1.7 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 2 0 m i n . A s o l u t i o n o f the f r e s h l y d i s t i l l e d h y d r a z o n e 209 ( 2 4 . 5 m g , 0 . 1 0 5 m m o l , 1.0 e q u i v . ) i n d r y T H F (0 .3 m L ) w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 1 h . D r y H M P A ( 3 6 | i L , 0 . 2 1 m m o l , 2 . 0 e q u i v . ) w a s a d d e d a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r a n a d d i t i o n a l 15 m i n . A s o l u t i o n o f f r e s h l y d i s t i l l e d ( o v e r c o p p e r w i r e ) ( Z ) - 4 - i o d o -l - ( t r i m e t h y l g e r m y l ) b u t - l - e n e (202) ( 5 9 m g , 0 . 2 0 m m o l , 1.9 e q u i v . ) i n d r y T H F ( 0 . 3 m L ) w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a n d s t i r r i n g w a s c o n t i n u e d f o r 1 h 10 m i n . D i e t h y l e t h e r (2 m L ) a n d s a t u r a t e d a q u e o u s N a H C 0 3 (2 m L ) w e r e a d d e d a n d t h e m i x t u r e w a s w a r m e d t o r o o m t e m p e r a t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 4 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e ( 3 x 8 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (5.1 g f l a s h s i l i c a g e l , 1 3 . 3 : 1 p e t r o l e u m e t h e r -d i e t h y l e the r , 1.5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l thus 197 o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 3 5 - 1 6 5 \" C / 0 . 2 T o r r ) to a f f o r d t h e h y d r a z o n e 210 ( 3 4 m g , 8 0 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 0 7 7 , 1 6 4 0 , 1 6 0 9 , 1 0 2 1 , 1 2 3 6 , 8 2 6 , 5 9 9 c m \" 1 . ! H n m r ( C D C I 3 , 4 0 0 M H z ) 6 : 0 . 2 2 (s , 9 H , G e M \u00C2\u00A3 3 _ ) , 0 . 6 9 (s , 3 H , M e - 1 0 ) , 1 . 3 3 - 1 . 6 7 ( m , 8 H , H - 4 , H - 5 , H - 5 ' , H - 7 , H - 7 ' , H - 8 , H - 1 4 , H - 1 4 ' ) , 1 . 6 8 - 1 . 8 3 ( m , I H , H - 4 ' ) , 1.71 (s, 3 H , M e - 1 3 ) , 1 . 9 1 - 2 . 0 5 ( m , 2 H , H - 8 ' , H - 1 5 ) , 2 . 0 6 - 2 . 1 8 ( m , I H , H - 1 5 ' ) , 2 . 2 5 ( d , I H , J = 10 .9 H z , H - l ) , 2 . 3 3 (s, 6 H , - N = N - ( M f i 2 ) ) , 2 . 9 3 ( d d d , I H , J = 1 0 . 9 , 1 0 . 9 , 6 . 4 H z , H - 9 ) , 3 . 4 8 ( b r d d d , I H , 7 = 6 .4 , 6 . 4 , 6 . 4 H z , H - 3 ) , 4 . 6 2 ( b r s , 2 H , H - 1 2 ) , 5 . 6 0 ( d , I H , J = 12 .7 H z , H - 1 7 ) , 6 . 2 7 ( d d d , I H , J = 1 2 . 7 , 7 . 3 , 7 . 3 H z , H - 1 6 ) . D e t a i l e d * H n m r d a t a ( C D C I 3 ) , d e r i v e d f r o m a C O S Y e x p e r i m e n t , a re g i v e n i n Table 22. 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 6 : - 0 . 3 ( - v e , G e M e ^ ) , 17 .7 ( - v e ) , 2 1 . 7 ( - v e ) , 2 7 . 3 , 2 8 . 4 , 3 1 . 8 , 3 2 . 4 , 3 5 . 1 , 3 5 . 5 ( - v e ) , 3 9 . 8 , 4 1 . 3 ( - v e ) , 4 7 . 3 ( C - 6 ) , 4 7 . 9 ( - v e , - N = N - ( M e 2 ) . 5 3 . 2 ( - v e ) , 1 0 8 . 3 ( C - 1 2 ) , 1 3 0 . 6 ( - v e , C - 1 7 ) , 1 4 6 . 4 ( - v e , C - 1 6 ) , 1 4 8 . 8 ( C - l l ) , 1 7 0 . 9 ( C - 2 ) . E x a c t M a s s c a l c d . f o r C 2 2 H 4 o 7 4 G e N 2 : 4 0 6 . 2 4 0 3 ; f o u n d : 4 0 6 . 2 3 9 8 . Table 22: lH n m r ( 4 0 0 M H z , CDCI3) D a t a f o r t h e B i c y c l i c H y d r a z o n e 210: C O S Y E x p e r i m e n t . A s s i g n m e n t lH n m r ( 4 0 0 M H z ) C O S Y C o r r e l a t i o n s H - x a 8 ( m u l t i p l i c i t y , 7 ( H z ) ) H - l 2 . 2 5 ( d , 7 = 1 0 . 9 ) H - 9 , M e - 1 0 H - 3 3 .48 (b r d d d 7 = 6 . 4 , 6 .4 , 6 .4 ) H - 4 , H - 4 ' , H - 1 4 , H - 1 4 ' H - 4 p a r t o f the m at 1 . 3 3 - 1 . 6 7 H - 3 , H - 4 ' , H - 5 a x , H - 5 e q H - 4 ' 1 . 6 8 - 1 . 8 3 ( m ) H - 3 , H - 4 , H - 5 a x , H - 5 e q H - 5 a x p a r t o f t h e m at 1 . 3 3 - 1 . 6 7 H - 4 , H - 4 ' , H - 5 e q , M e - 1 0 H - 5 e q p a r t o f the m at 1 . 3 3 - 1 . 6 7 H - 4 , H - 4 ' , H - 5 a x H - 7 a p a r t o f the m at 1 . 3 3 - 1 . 6 7 H - 7 B , H - 8 , H - 8 ' , M e - 1 0 H - 7 B p a r t o f t h e m at 1 . 3 3 - 1 . 6 7 H - 7 a, H - 8 , H - 8 ' H - 8 p a r t o f the m at 1 . 3 3 - 1 . 6 7 H - 7 a, H - 7 B , H - 8 ' , H - 9 H - 8 ' p a r t o f the m at 1 . 9 1 - 2 . 0 5 H - 7 a, H - 7 B , H - 8 , H - 9 H - 9 2 . 9 3 ( d d d 7 = 10 .9 , 10 .9 , 6 .4) H - l , H - 8 , H - 8 ' M e - 1 0 0 . 6 9 (s) H - l , H - 5 a x , H - 7 a H - 1 2 4 . 6 2 (br s) H - 9 , M e - 1 3 H - 1 2 ' 4 . 6 2 (b r s) H - 9 , M e - 1 3 M e - 1 3 1.71 (s) H - 1 2 , H - 1 2 ' H - 1 4 p a r t o f t h e m at 1 . 3 3 - 1 . 6 7 H - 3 , H - 1 4 ' , H - 1 5 , H - 1 5 ' H - 1 4 ' p a r t o f t h e m at 1 . 3 3 - 1 . 6 7 H - 3 , H - 1 4 , H - 1 5 , H - 1 5 ' H - 1 5 p a r t o f t h e m at 1 . 9 1 - 2 . 0 5 H - 1 4 , H - 1 4 ' , H - 1 5 ' , H - 1 6 H - 1 5 ' 2 . 0 6 - 2 . 1 8 ( m ) H - 1 4 , H - 1 4 ' , H - 1 5 , H - 1 6 H - 1 6 6 .27 ( d d d 7 = 1 2 . 7 , 7 . 3 , 7 . 3 ) H - 1 5 , H - 1 5 ' , H - 1 7 H - 1 7 5 . 6 0 ( d , 7 = 1 2 . 7 ) H - 1 6 GeMe . 3 0 . 2 2 (s) N - N ( M e ? ) 2 . 3 3 (s) a-H' indicates the hydrogen of a pair which is more downfield (H-4' is more downfield than H-4). 1 9 9 Preparation of 2-(ter/-Butyldimethylsilyloxy)-4-iodobutane (281). O O T B S A 2 3 1 1) HI, benzene, rt 2) DIBAL-H, 0 \u00C2\u00B0C 1 3) TBSCI, imidazole ; C H 2 C I 2 , rt 275 281 T o a s t i r r e d s o l u t i o n o f h y d r i o d i c a c i d ( 1 2 5 m L , 4 7 % , 4 4 0 m m o l , 1.9 e q u i v ) i n d r y b e n z e n e ( 1 6 4 m L ) , a t r o o m t e m p e r a t u r e , w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f d i s t i l l e d b u t - 3 - e n - 2 - o n e (275) (16 .1 g , 2 2 9 m m o l , 1.0 e q u i v . ) i n d r y b e n z e n e ( 6 5 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 2 h a n d t h e n w a s n e u t r a l i z e d b y t h e c a r e f u l a d d i t i o n o f s o l i d N a H C C \u00C2\u00BB 3 . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h b e n z e n e (1 x 1 0 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e s u c c e s s i v e l y w a s h e d w i t h s a t u r a t e d a q u e o u s N a H C 0 3 (1 x 2 0 0 m L ) , s a t u r a t e d a q u e o u s N a 2 S 2 C > 3 (1 x 2 0 0 m L ) , a n d b r i n e (1 x 2 0 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d f i l t e r e d . T h e a b o v e s t i r r e d s o l u t i o n w a s c o o l e d t o 0 \u00C2\u00B0C a n d w a s p u r g e d w i t h a r g o n . D i i s o b u t y l a l u m i n u m h y d r i d e ( 2 3 0 m L , 1.0 M i n h e x a n e s , 2 3 0 m m o l , 1.0 e q u i v ) w a s a d d e d ( v i a d o u b l e t i p p e d m e t a l c a n n u l a ) a n d t h e m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 3 0 m i n . T h e r e a c t i o n m i x t u r e w a s p o u r e d i n t o a 2 L e r l e n m e y e r f l a s k u s i n g d i e t h y l e t h e r t o r i n s e the r e a c t i o n v e s s e l . T o t h i s m i x t u r e w a s a d d e d l ^ ^ S O ^ l O r ^ O ( 7 4 g , 2 3 0 m m o l , 1.0 e q u i v . ) a n d t h e m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 1 h . T h e t h i c k s l u r r y w a s f i l t e r e d t h r o u g h Celite\u00C2\u00AE (8 x 8 c m c o l u m n ) , t h e c o l l e c t e d m a t e r i a l w a s w a s h e d w i t h d i e t h y l e t h e r ( 1 0 0 0 m L ) , a n d t h e c o m b i n e d f i l t r a t e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e t o g i v e 4 0 . 5 g ( 1 8 7 m m o l , 1.0 e q u i v . ) o f c r u d e l - i o d o b u t a n - 3 - o l . T o t h e c r u d e i o d o a l c o h o l w a s a d d e d d r y CH2CI2 ( 3 7 5 m L ) , f o l l o w e d b y i m i d a z o l e ( 2 8 . 1 g , 4 1 3 m m o l , 2 . 2 e q u i v . ) a n d f e r f - b u t y l d i m e t h y l s i l y l c h l o r i d e ( 3 1 . 1 g , 2 0 6 m m o l , 1.1 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 16 h a n d w a s t h e n f i l t e r e d to r e m o v e s o m e o f t h e s o l i d s . T h e f i l t r a t e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e s o l i d r e s i d u e w a s t r i t u r a t e d w i t h p e t r o l e u m e t h e r a n d t h e r e s u l t a n t m i x t u r e w a s c o n c e n t r a t e d b y r o t a r y e v a p o r a t i o n . T h e r e s i d u e w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 3 0 x 5 .5 c m c o l u m n , f l a s h s i l i c a g e l , 9 :1 p e t r o l e u m e t h e r - d i e t h y l e ther ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 6 5 -7 5 \u00C2\u00B0C/0.20 T o r r ) t o a f f o r d 3 - ( r e r f - b u t y l d i m e t h y l s i l y l o x y ) - l - i o d o b u t a n e ( 2 8 1 ) ( 5 6 . 3 g , 7 8 % b a s e d o n b u t - 3 - e n - 2 - o n e ( 2 7 5 ) ) as a c l e a r c o l o u r l e s s o i l . I R (neat ) : 2 8 8 8 , 1 3 7 6 , 1 2 5 6 , 1 1 2 7 , 1 1 4 8 , 1 0 6 3 , 1 0 8 9 c m \" 1 . ! H n m r ( C D C I 3 , 4 0 0 M H z ) 5 : 0 . 0 6 , 0 . 0 7 (s , s , 3 H e a c h , SiMea'Bu), 0 . 8 7 (s , 9 H , S i M e 2 < B u ) , 1 .13 (d , 3 H , J = 6 . 6 H z , H - 1 ) 1 . 8 2 - 1 . 9 7 ( m , 2 H , H - 3 ) , 3 . 1 5 - 3 . 2 6 ( m , 2 H , H - 4 ) , 3 . 8 2 - 3 . 9 2 ( m , 1 H , H - 2 ) . 1 3 C n m r ( C D C 1 3 ; 7 5 . 3 M H z ) 8 : - 4 . 6 , - 4 . 2 ( - v e , - v e , S i M _ e . 2 r B u ) , 3.5 ( C - 3 ) , 1 8 . 0 ( S i M e 2 C M e 3 ) , 2 3 . 5 ( - ve , C - l ) , 2 5 . 8 ( - ve , S i M e 2 C M e 3 _ ) , 4 3 . 2 ( C - 4 ) , 6 8 . 2 ( - v e , C - 2 ) . E x a c t M a s s c a l c d . f o r C i 0 H 2 2 l O S i ( M - H ) + : 3 1 3 . 0 4 8 5 ; f o u n d : 3 1 3 . 0 4 8 8 . A n a l , c a l c d . f o r C i 0 H 2 3 l O S i : C 3 8 . 2 2 , H 7 . 3 8 ; f o u n d : C 3 8 . 5 5 , H 7 . 5 3 . 201 Preparation of (15*, 3S *, 6R*, 9/?*)-3-[3-(te/t-ButyIdimethylsiloxy)but-l-yl]-9-isopropenyl-6-methylbicyclo[4.3.0]nonan-2-one (284) and (IS*, 3/?*, 6R*, 9fl*)-3-[3-(tert -Butyldimethylsiloxy)but-l-yl]-9-isopropenyI-6-methylbicyclo[4.3.0]nonan-2-one (283). O W 0TBS I! H ? 1) KHMDS, T H F -78\u00C2\u00B0CtoO\u00C2\u00B0C , 1 ? 1 5 2) 281, HMPA -78 \u00C2\u00B0C to -48 \u00C2\u00B0C tort 60 13 O \ ^ 1 2 O T B S H 284 283 T o a c o l d ( - 78 \u00C2\u00B0C), s t i r r e d s o l u t i o n o f K H M D S 9 6 ( 3 . 9 2 m m o l , 1.5 e q u i v . ) i n d r y T H F ( 3 9 m L ) w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f t h e f r e s h l y d i s t i l l e d k e t o n e 60 (501 m g , 2 . 6 1 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 2 . 0 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 5 m i n a n d t h e n w a s w a r m e d t o 0 \u00C2\u00B0C f o r 1 h 3 0 m i n . D r y H M P A ( 1 . 3 m L , 7 . 5 m m o l , 2 . 9 e q u i v . ) w a s a d d e d at a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 10 m i n b e f o r e b e i n g c o o l e d to - 7 8 \u00C2\u00B0C. A s o l u t i o n o f f r e s h l y d i s t i l l e d ( o v e r C u w i r e ) 3-(tert-b u t y l d i m e t h y l s i l y l o x y ) - l - i o d o b u t a n e (281) ( 2 . 5 3 g , 7 . 6 8 m m o l , 3 . 0 e q u i v ) i n d r y T H F (2 m L ) w a s a d d e d ( v i a Te f lon\u00C2\u00AE c a n n u l a ) to the r e a c t i o n m i x t u r e . T h e m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 10 m i n a n d t h e n w a s w a r m e d to a n d m a i n t a i n e d at - 4 8 \u00C2\u00B0C f o r 5 h r . T h e c o l d b a t h ( - 48 \u00C2\u00B0C) w a s a l l o w e d t o s l o w l y w a r m to r o o m t e m p e r a t u r e o v e r n i g h t ( 1 5 h ) . W a t e r ( 1 5 m L ) a n d d i e t h y l e t h e r ( 1 5 m L ) w e r e a d d e d . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 3 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (3 x 6 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 1 5 0 g t i c s i l i c a g e l , 1 3 . 3 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 7 c m c o l u m n ) t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t s ( v a c u u m p u m p ) , t w o f r a c t i o n s a l o n g w i t h r e c o v e r e d s t a r t i n g m a t e r i a l . T h e c o m p o u n d s that e l u t e d f i r s t w e r e the d i a s t e r e o m e r i c m i x t u r e o f t h e k e t o n e s 284 ( 6 5 3 m g , 6 6 % ) a s a s l i g h t l y y e l l o w , v i s c o u s o i l . A n a p p r o x i m a t e r a t i o f o r t h e s e d i a s t e r e o m e r s w a s 2 - 4 : 1 . T h e d a t a b e l o w f o r t h e c o m p o u n d s 284 r e f e r s t o t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s ta ted . I R (neat ) : 3 0 7 9 , 1 7 1 8 , 1 6 4 7 , 1 2 5 5 , 1 0 0 6 , 1 0 8 3 , 8 3 7 c m - 1 . lH n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 0 2 (s , 6 H , S i M e 2 * B u ) , 0 . 7 0 (s , 3 H , M e - 1 0 ) , 0 . 8 6 (s , 9 H , SiMe 2 \u00C2\u00ABBu), 1.09 (d , 3 H , 7 = 6.1 H z , M e - 1 7 ) , 1 . 2 1 - 1 . 1 0 ( m , I H ) , 1 . 3 2 - 1 . 4 5 ( m , 2 H ) , 1 . 4 5 - 1 . 8 6 ( m , 7 H ) , 1 .69 (s , 3 H , M e - 1 3 ) , 1 . 9 6 - 2 . 2 7 ( m , 3 H ) , 2 . 4 7 ( b r d , I H , 7 = 11 .1 H z , H - l ) , 2 . 8 8 ( b r d d d , I H , 7 = 1 1 . 1 , 6 . 1 , 6.1 H z , H - 9 ) , 3 . 7 6 ( d d d d d , I H , 7 = 6 . 1 , 6 . 1 , 6 . 1 , 6 . 1 , 6.1 H z , H - 1 6 ) , 4 . 6 0 ( b r s, I H , H - 1 2 ) , 4 . 6 5 ( b r s , I H , H - 1 2 ' ) . 13C n m r (CDC13, 7 5 . 3 M H z ) 8 : ( m a j o r d i a s t e r e o m e r o n l y ) - 4 . 7 , - 4 . 5 ( - v e , - v e , S i M e 2 * B u ) , 1 8 . 1 , 18 .7 ( - v e ) , 2 1 . 0 ( - v e ) , 2 3 . 5 ( - v e ) , 2 4 . 8 , 2 5 . 9 ( - v e , SiMe 2 C M e a ) , 2 7 . 7 , 3 1 . 8 , 3 7 . 1 , 3 8 . 6 , 3 9 . 7 , 4 1 . 3 ( - v e ) , 5 0 . 0 , 5 0 . 3 ( - v e ) , 6 3 . 5 ( - v e ) , 6 8 . 8 ( - v e , C - 16 ) , 1 0 8 . 8 (C-12), 1 4 7 . 5 (C-ll), 2 1 0 . 7 (C-2). E x a c t M a s s c a l c d . f o r C 2 3 H 4 2 0 2 S i : 3 7 8 . 2 9 5 4 ; f o u n d : 3 7 8 . 2 9 5 7 . A n a l , c a l c d . f o r C 2 3 H 4 2 0 2 S i : C 7 2 . 9 5 , H 1 1 . 1 8 ; f o u n d : C 7 3 . 0 2 , H 1 1 . 3 7 . T h e c o m p o u n d s tha t e l u t e d s e c o n d w e r e t h e d i a s t e r e o m e r i c m i x t u r e o f t h e k e t o n e s 283 ( 1 3 5 m g , 1 4 % ) as a s l i g h t l y y e l l o w , v i s c o u s o i l . A n a p p r o x i m a t e r a t i o f o r t h e s e d i a s t e r e o m e r s w a s 2 - 4 : 1 . T h e d a t a b e l o w f o r t h e c o m p o u n d s 2 8 3 r e f e r s to t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s ta ted . IR (neat ) : 3 0 7 9 , 1 7 1 4 , 1 6 4 7 , 1 3 8 1 , 1 2 5 5 , 1 0 0 6 , 1 0 8 4 , 8 3 7 c m - 1 . lU n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 0 1 , 0 . 0 2 (s, s , 3 H e a c h , S i M e ^ u ) , 0 . 7 4 (s , 3 H , M e - 1 0 ) , 0 . 8 6 (s , 9 H , S i M e ^ ^ B u ) . 1 .06 ( m i n o r d i a s t e r e o m e r ) , 1 .08 ( m a j o r d i a s t e r e o m e r ) ( d , d , 3 H , 7 = 6 . 2 H z ( m i n o r d i a s t e r e o m e r ) , 7 = 6.1 H z ( m a j o r d i a s t e r e o m e r ) , M e - 1 7 ) , 1 . 1 7 - 1 . 2 8 ( m , I H ) I. 3 2 - 1 . 8 2 ( m , 9 H ) , 1 .69 (s , 3 H , M e - 1 3 ) , 1 . 9 4 - 2 . 1 1 ( m , 2 H ) , 2 . 2 0 - 2 . 3 0 ( m , I H ) , 2 . 6 5 ( m a j o r d i a s t e r e o m e r ) , 2 . 6 8 ( m i n o r d i a s t e r e o m e r ) ( d , d , I H , 7 = 11.1 H z ( m a j o r d i a s t e r e o m e r ) , 7 = I I . 1 H z ( m i n o r d i a s t e r e o m e r ) , H - l ) , 2 . 8 3 ( b r d d d , 1 H , 7 = 1 1 . 1 , 1 1 . 1 , 6 . 7 H z , H - 9 ) , 3 . 7 3 ( b r d d d d d , I H , 7 = 6 . 1 , 6 . 1 , 6 . 1 , 6 . 1 , 6 . 1 H z , H - 1 6 ) , 4 . 5 6 - 4 . 6 9 ( m , 2 H , H - 1 2 ) . n m r ( C D C 1 3 , 7 5 . 3 M H z ) 8 : ( m a j o r d i a s t e r e o m e r o n l y ) - 4 . 8 , - 4 . 4 ( - v e , - v e , S i M e j ' B u ) , 1 8 . 0 , 18 .7 ( - v e ) , 2 1 . 2 ( - v e ) , 2 3 . 8 ( - v e ) , 2 5 . 8 ( - v e , S i M e 2 C M e 3 _ ) , 2 7 . 5 , 2 8 . 5 , 2 9 . 0 , 3 5 . 0 , 3 7 . 6 , 3 9 . 8 , 4 0 . 8 ( - v e ) , 4 9 . 4 , 5 0 . 5 ( - v e ) , 5 9 . 0 ( - v e ) , 6 8 . 2 ( - v e , C - 1 6 ) , 1 0 8 . 5 ( C - 1 2 ) , 1 4 7 . 5 ( C - l l ) , 2 1 3 . 6 ( C - 2 ) . E x a c t M a s s c a l c d . f o r C 2 3 H 4 2 0 2 S i : 3 7 8 . 2 9 5 4 ; f o u n d : 3 7 8 . 2 9 5 7 . A n a l , c a l c d . f o r C 2 3 H 4 2 0 2 S i : C 7 2 . 9 5 , H 1 1 . 1 8 ; f o u n d : C 7 3 . 0 8 , H 1 1 . 2 6 . T h e c o m p o u n d that e l u t e d l a s t w a s r e c o v e r e d s t a r t i n g m a t e r i a l 6 0 ( 5 9 m g , 1 2 % ) . T h e t o t a l a m o u n t o f t h e k e t o n e s 2 8 3 a n d 2 8 4 w a s 7 8 8 m g ( 8 0 % , 9 0 % b a s e d o n r e c o v e r e d s t a r t i n g m a t e r i a l ) . 2 0 4 Preparation of ( I S * , 3S *, 6R*, 9\u00C2\u00AB*)-3-[3-(teri-Butyldimethylsiloxy)but-l-yl]-9-isopropenyl-3,6-dimethylbicyclo[4.3.0]nonan-2-one (287). 2) Mel -78\u00C2\u00B0C to 0 \u00C2\u00B0C 284 283 T o a c o l d ( 0 \u00C2\u00B0C), s t i r r e d s o l u t i o n o f d i i s o p r o p y l a m i n e ( 27 m L , 1 9 3 m m o l , 2 . 4 e q u i v . ) i n d r y T H F ( 3 2 0 m L ) w a s a d d e d ( v i a d o u b l e t i p p e d m e t a l c a n n u l a ) n - B u L i ( 1 0 0 m L , 1.6 M i n h e x a n e s , 1 6 0 m m o l , 2 . 0 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 15 m i n a n d t h e n w a s c o o l e d t o - 7 8 \u00C2\u00B0C. T o t h e a b o v e m i x t u r e w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f the k e t o n e s 283 a n d 284 ( 3 0 . 0 g c o m b i n e d , 7 9 . 2 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 6 0 m L ) . T h e r e s u l t a n t m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 1 0 m i n a n d t h e n w a s w a r m e d t o 0 \u00C2\u00B0C f o r 1 h 3 0 m i n to a f f o r d a p a l e y e l l o w m i x t u r e . T h e r e a c t i o n m i x t u r e w a s r e c o o l e d to - 7 8 \u00C2\u00B0C a n d m e t h y l i o d i d e 1 7 1 ( 5 6 . 3 g , 3 9 6 m m o l , 5 . 0 e q u i v . ) w a s a d d e d n e a t ( v i a Te f lon\u00C2\u00AE c a n n u l a ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 3 0 m i n , w a r m e d to 0 \u00C2\u00B0C f o r 3 0 m i n , a n d t h e n w a s w a r m e d t o r o o m t e m p e r a t u r e f o r 3 0 m i n . D i e t h y l e t h e r ( 2 0 0 m L ) a n d s a t u r a t e d a q u e o u s N a H C 0 3 ( 2 0 0 m L ) w e r e a d d e d . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 2 5 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (3 x 2 5 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 3 0 c m x 5 . 5 c m c o l u m n , f l a s h s i l i c a g e l , 1 5 . 7 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t s ( v a c u u m p u m p ) , a n i n s e p a r a b l e m i x t u r e o f t h e d i a s t e r e o m e r i c k e t o n e s 287 ( 2 9 . 8 g , 9 6 % ) as a s l i g h t l y y e l l o w v i s c o u s o i l . A n a p p r o x i m a t e r a t i o f o r t h e s e d i a s t e r e o m e r s w a s 3 - 4 : 1 . T h e d a t a b e l o w f o r t h e c o m p o u n d s 287 re fe rs to t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s t a t e d . 2 0 5 I R (neat ) : 3 0 8 0 , 1 7 1 3 , 1 6 4 7 , 1 3 8 3 , 1 2 5 5 , 1 0 5 8 , 1 0 0 5 , 8 3 6 c m ' 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8: 0 . 0 2 (s , 6 H , S i M ^ u ) , 0 . 6 9 ( m i n o r d i a s t e r e o m e r ) , 0 . 7 0 ( m a j o r d i a s t e r e o m e r ) (s , s , 3 H , M e - 1 0 ) , 0 . 8 6 (s , 9 H , S i M e 2 * B u ) , 1.11 ( d , 3 H , J = 5 . 9 H z , H -18 ) , 1.17 (s , 3 H , H - 1 4 ) , 1 . 3 2 - 1 . 5 8 ( m , 7 H ) , 1 . 6 0 - 1 . 9 0 ( m , 4 H ) , 1 .70 (s , 3 H , H - 1 3 ) , 1 . 9 7 - 2 . 1 0 ( m , I H ) , 2 . 7 3 - 2 . 8 7 ( m , 2 H , o n e o f w h i c h i s H - 9 , t h e o t h e r H - l ) , 3 . 7 5 ( d d d d d , I H , J = 5 . 9 , 5 .9 , 5 . 9 , 5 . 9 , 5 . 9 H z , H - 1 7 ) , 4 . 5 8 ( b r s , I H , H - 1 2 ) , 4 . 6 3 - 4 . 6 8 ( m , I H , H - 1 2 ' ) . 1 3 C n m r ( C D C ^ ^ 7 5 . 3 M H z ) 8: ( m a j o r d i a s t e r e o m e r o n l y ) - 4 . 7 , - 4 . 5 ( - v e , - v e , S i M e 2 * B u ) , 1 8 . 1 , 1 8 . 4 ( - v e ) , 2 1 . 0 ( - v e ) , 2 3 . 9 ( - v e ) , 2 4 . 5 ( - v e ) , 2 5 . 9 ( - v e , S i M e 2 C M e i ) , 2 7 . 9 , 3 3 . 8 , 3 4 . 1 , 3 5 . 7 , 3 6 . 4 , 3 9 . 5 , 4 1 . 3 ( - v e ) , 4 7 . 6 , 4 9 . 2 , 5 8 . 6 ( - v e ) , 6 9 . 2 ( - v e , C - 1 7 ) , 1 0 8 . 4 ( C - 1 2 ) , 1 4 7 . 5 ( C -11) , 2 1 3 . 9 ( C - 2 ) . E x a c t M a s s c a l c d . f o r C 2 o H 3 5 0 2 S i ( M - tert-Bu)+: 3 3 5 . 2 4 0 6 ; f o u n d : 3 3 5 . 2 3 9 7 . A n a l , c a l c d . f o r C ^ H ^ C ^ S i : C 7 3 . 4 1 , H 1 1 . 2 9 ; f o u n d : C 7 3 . 3 8 , H 1 1 . 4 0 . Preparation of ( I S * , 3 S * , 6R *, 9U*)-3-(3-Hydroxybut-l-yl)-9-isopropenyl-3,6-dimethylbicyclo[4.3.0]nonan-2-one ( 2 8 8 ) . O T B S o W Bu 4 NF, THF, rt 2 8 7 2 8 8 T o a s t i r r e d s o l u t i o n o f t h e T B S - p r o t e c t e d k e t o a l c o h o l 2 8 7 ( 9 1 0 m g , 2 . 3 2 m m o l , 1.0 e q u i v . ) i n d r y T H F (7 .7 m L ) , a t r o o m t e m p e r a t u r e , w a s a d d e d t e t r a b u t y l a m m o n i u m f l u o r i d e ( 1 4 m L , 1.0 M i n T H F , 1 4 m m o l , 6 . 0 e q u i v . ) . T h e m i x t u r e w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r 21 h . D i e t h y l e t h e r (15 m L ) a n d s a t u r a t e d a q u e o u s N a H C C \u00C2\u00BB 3 ( 1 5 m L ) w e r e a d d e d . T h e l a y e r s w e r e s e p a r a t e d a n d the a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 3 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (2 x 6 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 6 5 g t i c s i l i c a g e l , 1 .5 :1 h e x a n e s - e t h y l a c e t a t e , 4 . 5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e > 2 0 0 \" C / 0 . 2 T o r r ) t o a f f o r d a n i n s e p a r a b l e m i x t u r e o f t h e d i a s t e r e o m e r i c b i c y c l i c k e t o a l c o h o l s 2 8 8 ( 6 3 6 m g , 9 8 % ) as a s l i g h t l y y e l l o w , v e r y v i s c o u s o i l . A n a p p r o x i m a t e r a t i o f o r t h e s e d i a s t e r e o m e r s w a s 3 - 4 : 1 . T h e d a t a b e l o w f o r t h e c o m p o u n d s 2 8 8 r e f e r s to t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s ta ted . I R (neat ) : 3 4 2 5 (br ) , 3 0 7 5 , 1 7 0 8 , 1 6 4 6 , 1 4 5 6 , 1 1 2 2 , 8 8 2 c m \" 1 . lH n m r ( C D C I 3 , 4 0 0 M H z ) 6: 0 . 7 1 (s , 3 H , M e - 1 0 ) , 1 .15 ( m i n o r d i a s t e r e o m e r ) , 1 .16 ( m a j o r d i a s t e r e o m e r ) ( d , d , 3 H , J = 6 . 2 H z ( m i n o r d i a s t e r e o m e r ) , J = 6 . 2 H z ( m a j o r d i a s t e r e o m e r ) , H - 1 8 ) , 1 .18 (s, 3 H , H - 1 4 ) , 1 . 3 0 - 1 . 9 3 ( m , 1 2 H ) , 1.68 (s, 3 H , H - 1 3 ) , 1 . 9 6 - 2 . 0 8 ( m , 1 H ) , 2 . 7 3 -2 0 7 2 . 8 5 ( m , 2 H , o n e o f w h i c h i s H - 9 ) , 3 . 7 4 ( d d d d d , 1 H , J = 6 . 2 , 6 . 2 , 6 . 2 , 6 . 2 , 6 . 2 H z , H - 1 7 ) , 4 . 5 5 (br s , 1 H , H - 1 2 ) , 4 . 6 2 - 4 . 6 5 ( m , 1 H , H - 1 2 ' ) . 1 3 C n m r ( C D C 1 3 , 7 5 . 3 M H z ) 8 : ( m a j o r d i a s t e r e o m e r o n l y ) 1 8 . 4 ( - v e ) , 2 1 . 0 ( - v e ) , 2 3 . 2 ( - v e ) , 2 4 . 4 ( - v e ) , 2 7 . 7 , 3 3 . 4 , 3 3 . 6 , 3 5 . 5 , 3 5 . 9 , 3 9 . 4 , 4 1 . 1 ( - v e ) , 4 7 . 6 , 4 9 . 4 , 5 8 . 5 ( - v e ) , 6 8 . 3 ( - v e , C -17) , 1 0 8 . 3 ( C - 1 2 ) , 1 4 7 . 4 ( C - l l ) , 2 1 4 . 2 ( C - 2 ) . E x a c t M a s s c a l c d . f o r C18H30O2: 2 7 8 . 2 2 4 6 ; f o u n d : 2 7 8 . 2 2 4 6 . A n a l , c a l c d . f o r C18H30O2: C 7 7 . 6 5 , H 1 0 . 8 6 ; f o u n d : C 7 7 . 7 8 , H 1 0 . 8 3 . Preparation of (IS*, 3S *, 6R*, 9fl*)-3-(3-Oxobut-l-yl)-9-isopropenyI-3,6-dimethylbicyclo[4.3.0]nonan-2-one (273). 2 0 8 T o a s t i r r e d s o l u t i o n o f t h e k e t o a l c o h o l s 288 ( 5 7 0 m g , 2 . 0 5 m m o l , 1.0 e q u i v . ) i n d r y CH2CI2 ( 1 0 . 2 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d o v e n d r i e d , d e s i c c a t o r c o o l e d Celite\u00C2\u00AE ( 8 8 4 m g ) , f o l l o w e d b y p y r i d i n i u m c h l o r o c h r o m a t e ( 8 8 4 m g , 4 .1 m m o l , 2 . 0 e q u i v . ) . T h e d a r k b r o w n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 3 h 3 0 m i n . D r y d i e t h y l e t h e r ( 4 0 m L ) w a s a d d e d a n d t h e m i x t u r e w a s s t i r r e d u n d e r a r g o n , at r o o m t e m p e r a t u r e , f o r 1 h . T h e r e a c t i o n m i x t u r e w a s f i l t e r e d t h r o u g h a c o l u m n (2 .5 c m ) o f Florisi l\u00C2\u00AE ( 2 8 g ) a n d t h e c o l u m n w a s e l u t e d w i t h d i e t h y l e t h e r ( 3 0 0 0 m L ) . T h e f i l t r a t e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e a n d the c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 1:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t s ( v a c u u m p u m p ) , t h e d i k e t o n e 273 ( 5 2 4 m g , 9 3 % ) as a w h i t e s o l i d . R e c r y s t a l l i z a t i o n o f a s m a l l s a m p l e f r o m h e x a n e s a f f o r d e d c o l o u r l e s s c r y s t a l s that e x h i b i t e d m p 7 0 . 0 - 7 0 . 5 \u00C2\u00B0C. I R ( K B r ) : 3 0 7 7 , 1 7 0 8 , 1 6 4 6 , 1 4 5 5 , 1 3 8 4 , 8 8 2 c m \" l . l H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 6 9 (s, 3 H , M e - 1 0 ) , 1 .19 (s , 3 H , M e - 1 8 ) , 1 . 4 2 - 1 . 6 3 ( m , 4 H , H - 5 e q , H - 7 a , H - 7 B , H - 8 ) , 1 . 6 3 - 1 . 7 7 ( m , 3 H , H - 4 e q , H - 1 5 , H - 1 5 ' ) , 1 .68 (s , 3 H , M e - 1 3 ) , 1 . 7 8 -1.88 ( m , 2 H , H - 4 a x , H - 5 a x ) , 1 . 9 5 - 2 . 0 9 ( m , I H , H - 8 ' ) , 2 . 1 1 (s , 3 H , M e - 1 8 ) , 2 . 4 1 - 2 . 6 2 ( m , 2 H , 2 0 9 H - 1 6 ) , 2 . 7 3 - 2 . 8 5 ( m , 2 H , H - l ( d , 7= 11 H z ) , H - 9 ) , 4 . 5 5 ( b r s , I H , H - 1 2 ) , 4 . 6 3 - 4 . 6 7 ( rn , I H , H - 1 2 ' ) . D e t a i l e d lH n m r d a t a ( C D C I 3 ) , d e r i v e d f r o m C O S Y a n d N O E e x p e r i m e n t s , a r e g i v e n i n T a b l e 2 3 . 1 3 C n m r ( C D C 1 3 ) 7 5 . 3 M H z ) 8 : 1 8 . 4 ( - ve ) , 2 1 . 0 ( - v e ) , 24 .1 ( - v e ) , 2 7 . 8 , 2 9 . 8 ( - v e ) , 3 1 . 7 , 3 5 . 4 , 3 6 . 5 , 3 8 . 9 , 3 9 . 4 , 4 1 . 1 ( - v e ) , 4 7 . 3 , 4 9 . 6 , 5 8 . 6 t - v e ) , 1 0 8 . 4 ( C - 1 2 ) , 1 4 7 . 4 ( C - l l ) , 2 0 9 . 1 , 2 1 3 . 6 . E x a c t M a s s c a l c d . f o r C i 8 H 2 8 0 2 : 2 7 6 . 2 0 8 9 ; f o u n d : 2 7 6 . 2 0 8 8 . A n a l , c a l c d . f o r C18H28O2: C 7 8 . 2 1 , H 1 0 . 2 1 ; f o u n d : C 7 8 . 1 8 , H 1 0 . 3 7 . T a b l e 2 3 : * H n m r ( 4 0 0 M H z , C D C I 3 ) D a t a f o r t h e B i c y c l i c D i k e t o n e 2 7 3 : C O S Y a n d N O E E x p e r i m e n t s . A s s i g n m e n t H - x a l H n m r ( 4 0 0 M H z ) 8 ( m u l t i p l i c i t y , J ( H z ) ) C O S Y C o r r e l a t i o n s N O E C o r r e l a t i o n s 0 H - 1 p a r t o f t h e m at 2 . 7 3 - 2 . 8 5 H - 9 , M e - 1 0 H - 5 a x , M e - 1 4 H - 4 e q p a r t o f t h e m at 1 . 6 3 - 1 . 7 7 H - 4 a x , H - 5 a x , H - 5 e q H - 4 a x p a r t o f t h e m at 1 . 7 8 - 1 . 8 8 H - 4 e q , H - 5 a x , H - 5 e q , M e - 1 4 H - 5 a x p a r t o f t h e m a t 1 . 7 8 - 1 . 8 8 H - 4 a x , H - 4 e q , H - 5 e q , M e - 1 0 M e - 1 4 , H - 1 H - 5 e q p a r t o f t h e m at 1 . 4 2 - 1 . 6 3 H - 4 a x , H - 4 e q , H - 5 a x H - 7 a p a r t o f t h e m at 1 . 4 2 - 1 . 6 3 H - 7 p \ H - 8 , H - 8 ' , M e - 1 0 H - 7 R p a r t o f t h e m at 1 . 4 2 - 1 . 6 3 H - 7 a , H - 8 , H - 8 ' H - 8 p a r t o f t h e m at 1 . 4 2 - 1 . 6 3 H - 7 a , H - 7 p \ H - 8 ' , H - 9 H - 8 ' 1 . 9 5 - 2 . 0 9 ( m ) H - 7 a , H - 7 R , H - 8 ' , H - 9 H - 9 p a r t o f t h e m at 2 . 7 3 - 2 . 8 5 (d, J= 11 H z ) H - 1 , H - 8 , H - 8 ' H - 1 2 , M e - 1 3 , M e -1 0 M e - 1 0 0 . 6 9 (s) H - l , H - 5 a x , H - 7 a H - 9 H - 1 2 4 . 5 5 ( b r s ) H - 1 2 ' , M e - 1 3 H - 9 H - 1 2 ' 4 . 6 3 - 4 . 6 7 ( m ) H - 1 2 , M e - 1 3 M e - 1 3 1.68 (s) H - 1 2 , H - 1 2 ' H - 9 M e - 1 4 1.19 (s) H - 4 a x H - l , H - 5 a x , H - 1 5 , H - 1 5 ' , H - 1 6 , H - 1 6 ' H - 1 5 p a r t o f t h e m at 1 . 6 3 - 1 . 7 7 H - 1 5 ' , H - 1 6 , H - 1 6 ' M e - 1 4 H - 1 5 ' p a r t o f t h e m at 1 . 6 3 - 1 . 7 7 H - 1 5 , H - 1 6 , H - 1 6 ' M e - 1 4 H - 1 6 p a r t o f t h e m at 2 . 4 1 - 2 . 6 2 H - 1 5 , H - 1 5 ' , H - 1 6 ' , M e - 1 8 M e - 1 4 H - 1 6 ' p a r t o f t h e m at 2 . 4 1 - 2 . 6 2 H - 1 5 , H - 1 5 ' , H - 1 6 , M e - 1 8 M e - 1 4 M e - 1 8 2 .11 (s) H - 1 6 , H - 1 6 ' a-H' indicates the hydrogen of a pair which is more downfield (H-8' is more downfield than H-8). b-Only the NOE data that could be unambiguously assigned are recorded. 2 1 1 Preparation of (1 a, 3a/J,5a a, 9ba)-l-Isopropenyl-3a,5a-dimethyl-2,3,3a,4,5,5a,6,7,8,9b-decahydro-1 //-cyclopenta[a]naphtha!en-8-one (72). O 273 72 T o c o l d (0 \u00C2\u00B0C) a b s o l u t e E t O H w a s a d d e d s o d i u m m e t a l ( 0 . 7 5 g , 3 3 m m o l , 4 . 4 e q u i v ) a n d the m i x t u r e w a s a l l o w e d to w a r m to r o o m t e m p e r a t u r e . T h e m i x t u r e w a s m a i n t a i n e d at r o o m t e m p e r a t u r e u n t i l a l l t h e s o d i u m w a s c o n s u m e d . T h i s m i x t u r e w a s a d d e d ( v i a Teflon\u00C2\u00AE c a n n u l a ) to a s t i r r e d s o l u t i o n o f the d i k e t o n e 273 ( 2 . 0 3 g , 7 . 3 6 m m o l , 1.0 e q u i v . ) i n a b s o l u t e E t O H ( 7 4 m L ) , at r o o m t e m p e r a t u r e . T h e p a l e y e l l o w m i x t u r e w a s h e a t e d at r e f l u x f o r 18 h . T h e E t O H w a s r e m o v e d u n d e r r e d u c e d p r e s s u r e . W a t e r (75 m L ) , b r i n e (75 m L ) , a n d d i e t h y l e t h e r (75 m L ) w e r e a d d e d t o t h e r e s i d u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 7 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 1 5 0 m L ) a n d the c o m b i n e d a q u e o u s p h a s e s w e r e b a c k e x t r a c t e d w i t h d i e t h y l e t h e r (1 x 1 0 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 3 0 x 5 . 5 c m c o l u m n , f l a s h s i l i c a g e l , 3:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e e n o n e 72 ( 1 . 7 0 g , 8 9 % ) as a p a l e y e l l o w o i l . U p o n s t a n d i n g i n t h e f r e e z e r , t h e o i l s o l i d i f i e d t o p r o v i d e a l o w m e l t i n g ( l e s s t h a n r o o m t e m p e r a t u r e ) , y e l l o w , w a x y s o l i d . 2 1 2 I R (neat ) : 3 0 7 6 , 1 6 7 4 , 1 6 1 9 , 1 4 5 5 , 1 3 8 1 , 8 8 5 c m - 1 . * H n m r ( C D C h , 4 0 0 M H z ) 8 : 0 . 7 0 (s, 3 H , M e - 1 0 ) , 1.27 (s , 3 H , Me-14), 1 . 3 6 - 1 . 7 3 ( m , 7 H ) , 1 .62 (s, 3 H , M e - 1 3 ) , 1 . 7 7 - 1 . 9 2 ( m , 2 H ) , 2 . 0 2 - 2 . 1 3 ( m , 1 H ) , 2 . 2 7 - 2 . 3 7 ( m , 2 H ) , 2 . 4 2 - 2 . 5 4 ( m , 1 H ) , 2 . 6 1 ( d d d , 1 H , J = 1 0 . 7 , 1 0 . 7 , 6 . 4 H z , H - 1 ) , 4 . 6 1 - 4 . 6 3 ( m , 1 H , H - 1 2 ) , 4 . 6 5 - 4 . 6 8 ( m , 1 H , H - 1 2 ' ) , 5 . 6 5 (s, 1 H , H - 9 ) . 1 3 C n m r ( C D C 1 3 , 7 5 . 3 M H z ) 8 : 1 8 . 3 ( - v e ) , 1 9 . 9 ( - v e ) , 2 3 . 8 ( - v e ) , 2 8 . 5 , 3 4 . 0 , 3 5 . 9 8 , 3 6 . 0 3 , 3 8 . 4 , 3 8 . 6 , 3 8 . 9 , 4 3 . 8 ( - v e ) , 4 5 . 8 , 5 1 . 9 ( - v e ) , 1 1 0 . 1 ( C - l 2 ) , 1 2 3 . 5 ( - v e , C - 9 ) , 1 4 6 . 4 ( C - l l ) , 169 .7 ( C - 9 a ) , 1 9 9 . 6 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C i 8 H 2 6 0 : 2 5 8 . 1 9 8 4 ; f o u n d : 2 5 8 . 1 9 8 6 . A n a l , c a l c d . f o r C i 8 H 2 6 0 : C 8 3 . 6 7 , H 1 0 . 1 4 ; f o u n d : C 8 3 . 6 8 , H 1 0 . 1 7 . 2 1 3 Preparation of ( l a , 3a/J, 5aa, 9a/3, 9ba)-l-Isopropenyl-3a,5a-dimethyl-perhydrocyclopenta[a]naphthalen-8-one (171). A c o l d ( - 7 8 \u00C2\u00B0C) , s t i r r e d m i x t u r e o f l i q u i d a m m o n i a ( 1 5 m L , d i s t i l l e d f r o m N a N H 2 ) 1 7 2 a n d l i t h i u m w i r e 1 7 0 ( 1 1 8 m g , 17 m m o l , 8 . 8 e q u i v . ) w a s s t i r r e d a t - 7 8 \u00C2\u00B0C f o r 3 0 m i n , d u r i n g w h i c h t i m e t h e l i t h i u m d i s s o l v e d . A s o l u t i o n o f t h e e n o n e 72 ( 4 9 9 m g , 1 .93 m m o l , 1.0 e q u i v . ) a n d d r y tert-butyl a l c o h o l ( 0 . 7 5 m L , 7 . 8 m m o l , 4 .1 e q u i v . ) i n d r y T H F ( 1 0 . 7 m L ) w a s a d d e d ( v i a Te f lon\u00C2\u00AE c a n n u l a ) . T h e b l u e , b i - p h a s i c m i x t u r e w a s v i g o r o u s l y s t i r r e d at - 7 8 \u00C2\u00B0C f o r 2 0 m i n . E x c e s s l i t h i u m m e t a l w a s d e s t r o y e d b y t h e a d d i t i o n o f i s o p r e n e ( 2 . 0 m L , 2 0 m m o l , 1 0 e q u i v . ) . A f t e r s t i r r i n g at - 7 8 \u00C2\u00B0C f o r 5 m i n , s o l i d N H 4 C I ( ~5 g ) w a s a d d e d a n d a f t e r a f u r t h e r 1 0 m i n , the m i x t u r e w a s o p e n e d to t h e a t m o s p h e r e v i a a n a i r - c o o l e d c o n d e n s e r a n d w a s w a r m e d t o r o o m t e m p e r a t u r e t o a l l o w t h e a m m o n i a t o e v a p o r a t e . D i e t h y l e t h e r ( 2 0 m L ) w a s a d d e d a n d the f l a s k w a s g e n t l y w a r m e d i n a w a t e r b a t h t o r e m o v e a n y r e s i d u a l a m m o n i a . W a t e r ( 2 0 m L ) w a s a d d e d , the l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 4 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (2 x 6 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 3 .5 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t s ( v a c u u m p u m p ) , t h e k e t o a l k e n e 171 ( 4 9 2 m g , 9 8 % ) as a c l e a r c o l o u r l e s s o i l . 2 1 4 I R (neat ) : 3 0 7 2 , 1 7 1 3 , 1 6 4 3 , 1 4 5 9 , 1 3 8 3 , 8 8 5 c m \" 1 . * H n m r ( C D C 1 3 , 4 0 0 M H z ) 6 : 0 . 7 9 (s, 3 H , M e - 1 0 ) , 1 .07 (s , 3 H , M e - 1 4 ) , 1 . 1 8 - 1 . 3 1 ( m , 1 H , H - 3 a ) , 1 . 3 2 - 1 . 5 7 ( m , 8 H , H - 2 , H - 3 p \ H - 4 a x , H - 4 e q , H - 5 a x , H - 5 e q , H - 6 a x , H - 9 b ( 5 1.50, d d , J = 1 2 , 11 H z , o b s e r v e d as a r e s u l t o f a n N O E e x p e r i m e n t , s e e T a b l e 24)), 1 . 6 0 - 1 . 7 5 ( m , 2 H , H - 6 e q , H - 9 a (5 1 .65 , d d d , J = 1 4 . 2 , 12 , 5 H z , o b s e r v e d as a r e s u l t o f N O E e x p e r i m e n t s , s e e T a b l e 24)), 1 .65 (s , 3 H , M e - 1 3 ) , 1 . 8 8 - 2 . 0 1 ( m , 1 H , H - 2 ' ) , 2 . 0 6 ( d d , 1 H , J = 1 4 . 2 , 14 .2 H z , H -9 a x ) , 2 . 2 2 - 2 . 3 1 ( d m , 1 H , J f o r d = 1 5 . 4 H z , H - 7 a x ) , 2 . 3 2 - 2 . 4 6 ( m , 3 H , H - 1 ( 5 2 . 3 5 , d d d , J = 1 1 , 1 1 , 6 H z , o b s e r v e d as a r e s u l t o f a n N O E e x p e r i m e n t , see T a b l e 24), H - 7 e q , H - 9 e q ) , 4 . 5 9 -4 . 6 2 ( m , 1 H , H - 1 2 ) , 4 . 7 0 - 4 . 7 3 ( m , 1 H , H - 1 2 ' ) . D e t a i l e d * H n m r d a t a (CDCI3), d e r i v e d f r o m C O S Y a n d N O E e x p e r i m e n t s , a r e g i v e n i n Table 24. 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 5 : 1 6 . 3 ( - v e ) , 1 8 . 0 ( - v e ) , 1 9 . 4 ( - v e ) , 2 9 . 5 , 3 4 . 7 , 3 4 . 9 , 3 6 . 1 , 3 8 . 1 , 3 9 . 7 , 4 0 . 9 , 4 1 . 4 , 4 3 . 2 , 4 4 . 0 ( - ve ) , 4 6 . 8 ( - ve ) , 4 8 . 3 ( - ve ) , 1 1 0 . 5 ( C - 1 2 ) , 149 .1 ( C - l l ) , 2 1 2 . 5 ( C -8). E x a c t M a s s c a l c d . f o r C i s H i g O : 2 6 0 . 2 1 4 0 ; f o u n d : 2 6 0 . 2 1 3 8 . A n a l , c a l c d . f o r C i 8 H 2 8 0 : C 8 3 . 0 2 , H 1 0 . 8 4 ; f o u n d : C 8 3 . 1 9 , H 1 0 . 6 8 . 2 1 5 T a b l e 2 4 : * H n m r ( 4 0 0 M H z , C D C 1 3 ) D a t a f o r t h e T r i c y c l i c K e t o n e 1 7 1 : C O S Y a n d N O E E x p e r i m e n t s . O A s s i g n -m e n t H x a ! H n m r ( 4 0 0 M H z ) 8 ( m u l t i p l i c i t y , 7 ( H z ) ) C O S Y C o r r e l a t i o n s N O E C o r r e l a t i o n s 0 H - l 2 . 3 5 ( d d d , 7 = 1 1 , 1 1 , 6 ) H - 2 a , H - 2 B , H - 9 b M e - 1 0 , H - 1 2 ' H - 2 a p a r t o f t h e m at 1 . 3 2 - 1 . 5 7 H - l , H - 2 B , H - 3 a , H - 3 B H - 2 B 1 . 8 8 - 2 . 0 1 ( m ) H - l , H - 2 a , H - 3 a , H - 3 B M e - 1 0 H - 3 a 1 . 1 8 - 1 . 3 1 ( m ) H - 2 a , H - 2 B , H - 3 B , M e - 1 0 H - 3 B p a r t o f t h e m at 1 . 3 2 - 1 . 5 7 H - 2 a , H - 2 B , H - 3 a H - 4 a x p a r t o f t h e m at 1 . 3 2 - 1 . 5 7 H - 4 e q , H - 5 a x , H - 5 e q , M e - 1 0 H - 4 e q p a r t o f t h e m at 1 . 3 2 - 1 . 5 7 H - 4 a x , H - 5 a x , H - 5 e q H - 5 a x p a r t o f t h e m at 1 . 3 2 - 1 . 5 7 H - 4 a x , H - 4 e q , H - 5 e q , M e - 1 0 H - 5 e q p a r t o f t h e m at 1 . 3 2 - 1 . 5 7 H - 4 a x , H - 4 e q , H - 5 a x H - 6 a x p a r t o f t h e m at 1 . 3 2 - 1 . 5 7 H - 6 e q , H - 7 a x , H - 7 e q , M e - 1 4 H - 6 e q H - 6 e q p a r t o f t h e m at 1 . 6 0 - 1 . 7 5 H - 6 a x , H - 7 a x , H - 7 e q H - 6 a x , H - 7 e q , M e - 1 4 H - 7 a x 2 . 2 2 - 2 . 3 1 ( d m , 7 f o r d = 15.4) H - 6 a x , H - 6 e q , H - 7 e q H - 7 e q H - 7 e q p a r t o f t h e m at 2 . 3 2 - 2 . 4 6 H - 6 a x , H - 6 e q , H - 7 a x H - 6 e q , H - 7 a x H - 9 a x 2 . 0 6 ( d d , 7 = 1 4 . 2 , 1 4 . 2 ) H - 9 a , H - 9 e q H - 9 e q H - 9 e q p a r t o f t h e m at 2 . 3 2 - 2 . 4 6 H - 9 a , H - 9 a x H - 9 a x H - 9 a 1.65 ( d d d , 7 = 1 4 . 2 , 1 2 , 5 ) H - 9 a x , H - 9 e q , H - 9 b M e - 1 0 H - 9 b 1.50 ( d d , 7 = 1 2 , 1 1 ) H - l , H - 9 a , M e - 1 0 H - 1 2 ' M e - 1 0 0 . 7 9 (s) H - 3 a , H - 4 a x , H - 9 b H - l , H - 9 a , H - 2 B H - 1 2 4 . 5 9 - 4 . 6 2 ( m ) H - 1 2 * , M e - 1 3 M e - 1 3 H - 1 2 ' 4 . 7 0 - 4 . 7 3 ( m ) H - 1 2 , M e - 1 3 H - l , H - 9 b M e - 1 3 1.65 (s) H - 1 2 , H - 1 2 ' H - 1 2 M e - 1 4 1.07 (s) H - 5 a x , H - 6 a x H - 6 e q a-H' indicates the hydrogen of a pair which is more downfield (H-12' is more downfield than H-12). b-Only the NOE data that could be unambiguously assigned are recorded. 2 1 6 Preparation of ( l a , 3a/J, 5aa, 9a/5, 9ba)-l-Isopropyl-3a,5a-dimethyl-perhydrocydopenta[a]naphthalen-8-one (303). Q O H 0 P C C , Celite C H 2 C I 2 , rt 171 306 303 T o a s t i r r e d s o l u t i o n o f the k e t o a l k e n e 171 ( 1 . 9 8 g , 7 .61 m m o l , 1.0 e q u i v . ) i n E t O A c ( 7 6 m L , H P L C g r a d e ) , at r o o m t e m p e r a t u r e , w a s a d d e d PtC\u00C2\u00BB2 ( 1 7 5 m g , 0 . 7 7 1 m m o l , 10 m o l % ) . T h e f l a s k w a s p u r g e d w i t h h y d r o g e n gas a n d the m i x t u r e w a s v i g o r o u s l y s t i r r e d u n d e r a h y d r o g e n a t m o s p h e r e ( u s i n g a b a l l o o n ) f o r 2 5 m i n . T h e r e a c t i o n m i x t u r e w a s f i l t e r e d t h r o u g h a p a d o f Celite\u00C2\u00AE ( 2 0 g ) , t h e c o l l e c t e d m a t e r i a l w a s w a s h e d w i t h d i e t h y l e t h e r ( 1 0 0 0 m L ) , a n d t h e c o m b i n e d f i l t r a t e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 1 2 5 g t i c s i l i c a g e l , 4 : 1 p e t r o l e u m e t h e r -d i e t h y l e t h e r , 5 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t s ( v a c u u m p u m p ) , a m i x t u r e o f t h r e e p r o d u c t s . T h e f i r s t c o m p o u n d that e l u t e d w a s t h e d e s i r e d s a t u r a t e d k e t o n e 303 ( 1 . 0 9 g , 5 5 % ) . T h e s e c o n d a n d t h i r d c o m p o u n d s that e l u t e d w e r e a m i x t u r e o f the o v e r - r e d u c e d a l c o h o l s 306 ( 8 3 5 m g , 4 1 % ) . T h e m o r e p o l a r o f t h e t w o a l c o h o l s w a s the m a j o r d i a s t e r e o m e r a n d w a s f a v o r e d i n a r a t i o o f a p p r o x i m a t e l y 1 5 : 1 . T o a s t i r r e d s o l u t i o n o f t h e a b o v e a l c o h o l s 306 i n d r y CH2CI2 ( 2 6 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d o v e n d r i e d , d e s i c c a t o r c o o l e d Cel i te\u00C2\u00AE ( 1 . 2 g ) , f o l l o w e d b y p y r i d i n i u m c h l o r o c h r o m a t e ( 1 . 1 5 g , 5 . 3 4 m m o l , 1.7 e q u i v . ) . T h e d a r k b r o w n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 2 h 3 0 m i n . D r y d i e t h y l e t h e r ( 1 6 8 m L ) w a s a d d e d a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d u n d e r a r g o n , at r o o m t e m p e r a t u r e , f o r 1 h . T h e m i x t u r e w a s f i l t e r e d t h r o u g h a c o l u m n (3 c m ) o f Florisi l\u00C2\u00AE ( 3 5 g ) a n d t h e c o l u m n w a s e l u t e d w i t h d i e t h y l e t h e r ( 2 0 0 0 m L ) . T h e s o l v e n t w a s r e m o v e d u n d e r r e d u c e d p r e s s u r e a n d t h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 4 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o m b i n e d w i t h t h e p r e v i o u s l y o b t a i n e d k e t o n e 3 0 3 a n d t h e s o l v e n t w a s r e m o v e d u n d e r r e d u c e d p r e s s u r e , to a f f o r d , a f t e r r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o n e 3 0 3 ( 1 . 9 0 g , 9 5 % ) as w h i t e s o l i d , m p 8 6 - 8 7 \"C. I R ( K B r ) : 3 0 5 4 , 1 7 0 9 , 1 4 6 1 , 1 3 8 6 , 1 2 6 6 , 1 1 9 4 , 7 4 1 , 7 0 0 c m \" 1 . J H n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 7 4 (d , 3 H , J = 6 . 8 H z , M e - 1 2 ) , 0 . 7 5 (s , 3 H , M e - 1 0 ) , 0 . 8 2 ( d , 3 H , J = 6 . 8 H z , M e - 1 3 ) , 1 .05 (s, 3 H , M e - 1 4 ) , 1 . 2 0 - 1 . 8 2 ( m , 1 4 H ) , 2 . 1 8 ( d d , 1 H , J = 1 4 . 0 , 14 .0 H z ) , 2 . 2 4 - 2 . 4 9 ( m , 3 H ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 14 .8 ( - v e ) , 16 .3 ( - ve ) , 17 .9 ( - v e ) , 2 1 . 6 , 2 2 . 7 ( - v e ) , 2 8 . 8 ( - ve ) , 3 4 . 7 1 7 3 , 3 6 . 3 , 3 7 . 9 , 3 9 . 9 , 4 0 . 9 , 4 2 . 7 , 4 3 . 3 , 4 3 . 5 ( - v e ) , 4 3 . 7 ( - v e ) , 4 7 . 7 ( - v e ) , 2 1 2 . 2 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C18H30O: 2 6 2 . 2 2 9 7 ; f o u n d : 2 6 2 . 2 2 8 8 . A n a l , c a l c d . f o r C i 8 H 3 0 O : C 8 2 . 3 8 , H 1 1 . 5 2 ; f o u n d : C 8 2 . 0 8 , H 1 1 . 4 3 . 2 1 8 Preparation of ( l a , 3a/J, 5 a a , 7j3, 9a/3, 9ba )-l-Isopropyl-3a,5a-dimethyl-perhydrocyclopenta[a]naphthalen-7-ol-8-one (311). H Q 1) KHMDS, THF, -78 \u00C2\u00B0C to 0 \u00C2\u00B0C H 2) dimethyldioxirane, acetone -78 \u00C2\u00B0C 303 311 T o a c o l d ( - 7 8 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f t h e t r i c y c l i c k e t o n e 303 i n d r y T H F ( 2 2 m L ) w a s a d d e d a s o l u t i o n o f K H M D S ( 1 3 m L , 0 . 3 5 M i n T H F , 4 . 6 m m o l , 1.3 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 15 m i n , w a r m e d t o 0 \u00C2\u00B0C f o r 1 h , a n d t h e n w a s c o o l e d to - 7 8 \u00C2\u00B0C f o r 15 m i n . T h i s m i x t u r e w a s a d d e d q u i c k l y ( v i a l a r g e Tef lon\u00C2\u00AE c a n n u l a , the f l a s k w a s r i n s e d w i t h 2 x 1 0 m L d r y T H F ) t o a c o l d ( - 7 8 \u00C2\u00B0C ) , s t i r r e d s o l u t i o n o f d i m e t h y l d i o x i r a n e 1 1 0 b ( 5 . 3 m m o l , - 0 . 0 8 M , 1.5 e q u i v . ) i n a c e t o n e ( 6 6 m L ) . T h e d i m e t h y l d i o x i r a n e s o l u t i o n h a d b e e n s t i r r e d o v e r d r y N a 2 C 0 3 , at - 7 8 \u00C2\u00B0C, f o r 2 0 m i n , p r i o r to the a d d i t i o n o f t h e e n o l a t e m i x t u r e . 1 0 7 b T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 15 m i n . A q u e o u s N H 4 C I - N H 4 O H ( p H 8 - 9 , 3 5 m L ) w a s a d d e d a n d t h e m i x t u r e w a s w a r m e d to r o o m t e m p e r a t u r e . T h e o r g a n i c s o l v e n t s w e r e r e m o v e d b y r o t a r y e v a p o r a t i o n . D i e t h y l e t h e r ( 5 0 m L ) a n d b r i n e ( 5 0 m L ) w e r e a d d e d to t h e r e s i d u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 7 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e ( 2 x 1 3 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 1.9:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t w o c o m p o u n d s . T h e f i r s t c o m p o u n d tha t e l u t e d w a s r e c o v e r e d s t a r t i n g m a t e r i a l 303 ( 3 3 m g , 4 % ) . T h e s e c o n d c o m p o u n d tha t e l u t e d w a s t h e d e s i r e d a - h y d r o x y 2 1 9 k e t o n e 3 1 1 ( 7 7 1 m g , 8 1 % , 8 4 % b a s e d o n r e c o v e r e d s t a r t i n g m a t e r i a l ) as a w h i t e s o l i d , m p 9 3 - 9 5 \u00C2\u00B0C. I R ( K B r ) : 3 4 8 9 ( b r ) , 1 7 1 3 , 1 4 6 6 , 1 3 8 6 , 1 3 6 0 , 1 2 1 4 , 1 1 7 0 , 1 0 7 2 , 7 3 7 c m \" 1 . * H n m r (CDC13, 4 0 0 M H z ) 6 : 0 . 7 5 (s , 3 H , M e - 1 0 ) , 0 . 7 5 (d , 3 H , 7 = 6 . 6 H z , M e - 1 2 ) , 0 . 8 4 ( d , 3 H , 7 = 6 .7 H z , M e - 1 3 ) , 1 . 0 0 - 1 . 1 0 ( m , 2 H ) , 1 .13 (s, 3 H , M e - 1 4 ) , 1 . 2 3 - 1 . 4 9 ( m , 7 H , o n e o f w h i c h i s H - 6 a x ( 5 1 . 3 2 , d d , 7 = 1 2 , 12 H z , o b s e r v e d a s a r e s u l t o f N O E e x p e r i m e n t s , s e e T a b l e 25)), 1 . 5 3 - 1 . 7 7 ( m , 4 H ) , 2 . 1 9 ( d d , I H , 7 = 1 2 , 7 . 2 H z , H - 6 e q ) , 2 .31 ( d d d , I H , 7 = 1 4 . 0 , 1 4 . 0 , 1.1 H z , H - 9 a x ) , 2 . 5 5 ( d d , I H , 7 = 1 4 . 0 , 3 . 9 H z , H - 9 e q ) , 3 . 4 9 ( b r d , I H , 7 = 2 . 4 H z , - O H , e x c h a n g e s u p o n t r e a t m e n t w i t h D2O), 4 . 2 5 (b r d d , I H , 7 = 1 2 , 7 . 2 H z , wi / 2 = 2 2 H z , H - 7 , s i g n a l b e c o m e s s h a r p e r u p o n t r e a t m e n t w i t h D2O). D e t a i l e d * H n m r d a t a (CDCI3), d e r i v e d f r o m N O E e x p e r i m e n t s , a re g i v e n i n T a b l e 2 5 . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 5 : 1 4 . 9 ( - v e ) , 1 7 . 4 ( - v e ) , 1 8 . 0 ( - v e ) , 2 1 . 5 , 2 2 . 7 ( - v e ) , 2 8 . 9 ( - v e ) , 3 4 . 0 , 3 6 . 0 , 3 6 . 3 , 3 9 . 9 , 4 0 . 5 , 4 3 . 3 , 4 3 . 5 ( - v e ) , 4 5 . 3 ( - v e ) , 4 7 . 6 ( - v e ) , 5 0 . 6 , 7 2 . 3 ( - v e , C - 7 ) , 2 1 1 . 4 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C18H30O2: 2 7 8 . 2 2 4 6 ; f o u n d : 2 7 8 . 2 2 4 5 . A n a l , c a l c d . f o r C18H30O2: C 7 7 . 6 5 , H 1 0 . 8 6 ; f o u n d : C 7 7 . 8 4 , H 1 0 . 8 9 . T a b l e 2 5 : lH n m r ( 4 0 0 M H z , C D C I 3 ) D a t a f o r t h e a - H y d r o x y K e t o n e 3 1 1 : N O E E x p e r i m e n t s . O 3 1 1 I r r a d i a t e d S i g n a l N O E A s s i g n m e n t H - x ! H n m r ( 4 0 0 M H z ) 8 ( m u l t i p l i c i t y , 7 ( H z ) ) C o r r e l a t i o n s a M e - 1 4 1.13 (s) H - 6 e q , H - 7 , H - 9 a x H - 6 e q H - 9 a x 2 . 1 9 ( d d , 7 = 12 , 7 .2 ) 2 .31 ( d d d , 7 = 1 4 . 0 , 14 .0 , 1.1) H - 6 a x , H - 7 , M e - 1 4 H - 9 e q H - 9 e q 2 . 5 5 (dd , 7 = 1 4 . 0 , 3 . 9 ) H - 9 a x H - 7 4 . 2 5 ( b r d d 7 = 1 2 , 7 . 2 ) H - 6 e q , H - 9 a x , M e - 1 4 a-Only the NOE data that could be unambiguously assigned are recorded. 221 Preparation of ( l a , 3a/3, 5 a a , 7/3, 9a/J, 9ba)-l-Isopropyl-3a,5a-dimethyl-7-[2-(trimethylsilyl)ethoxymethoxy]perhydrocyclopenta[a]naphmalen-8-one (317). SEM-CI , Bu 4NI Diisopropylethylamine C H 2 C I 2 , 40 \u00C2\u00B0C S E M Q H 311 T o a s t i r r e d s o l u t i o n o f the o c - h y d r o x y k e t o n e 311 ( 1 8 6 m g , 0 . 6 6 7 m m o l , 1.0 e q u i v ) i n d r y CH2CI2 ( 0 . 3 3 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d s e q u e n t i a l l y d i i s o p r o p y l e t h y l a m i n e ( 0 . 5 8 m L , 3 . 3 m m o l , 5 . 0 e q u i v . ) , t e t r a b u t y l a m m o n i u m i o d i d e ( 2 9 2 m g , 0 . 7 2 1 m m o l , 1.2 e q u i v . ) , a n d 2 - ( t r i m e t h y l s i l y l ) e t h o x y m e t h y l c h l o r i d e ( 0 . 3 6 m L , 2 . 0 m m o l , 3 .1 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s h e a t e d at 4 0 \u00C2\u00B0C f o r 1 h a n d t h e n w a s c o o l e d t o r o o m t e m p e r a t u r e . D i e t h y l e t h e r ( 2 0 m L ) a n d b r i n e ( 2 0 m L ) w e r e a d d e d t o the o r a n g e m i x t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 2 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (2 x 4 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 3 0 g t i c s i l i c a g e l , 3 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 3 .5 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o e t h e r 317 ( 231 m g , 8 5 % ) as a c o l o u r l e s s , v i s c o u s o i l . I R (neat ) : 1 7 2 5 , 1 4 6 7 , 1 3 8 6 , 1 3 6 0 , 1 2 4 9 , 1 1 2 8 , 9 2 1 , 8 3 6 c m \" 1 . ! H n m r (CDCI3,400 M H z ) 8 : 0 . 0 1 (s, 9 H , S i M e j ) , 0 . 7 3 ( d , 3 H , J = 6 .7 H z , M e - 1 2 ) , 0 . 7 4 (s, 3 H , M e - 1 0 ) , 0 . 8 2 ( d , 3 H , J = 6 .7 H z , M e - 1 3 ) , 0 . 8 6 - 0 . 9 3 ( m , 1 H ) , 0 . 9 5 - 1 . 1 8 ( m , 1 H ) , 1 .13 (s, 3 H , M e - 1 4 ) , 1 .23 ( d d , 1 H , 7 = 1 1 . 4 , 1 1 . 4 H z ) , 1 . 3 2 - 1 . 7 8 ( m , 1 2 H ) , 2 . 0 4 ( b r d d , I H , J= 12 .6 , 6 .6 H z , H - 6 e q ) , 2 . 2 6 ( b r d d , I H , J = 1 3 . 5 , 13 .5 H z , H - 9 a x ) , 2 . 4 6 ( d d , I H , J = 1 3 . 5 , 3 .8 H z , H -9 e q ) , 3 . 5 6 - 3 . 7 2 ( m , 2 H , -O-CH2-OCH2), 4 . 3 3 ( d d , I H , J = 1 2 . 8 , 6 . 6 H z , w i / 2 = 2 2 H z , H - 7 ) , 4 . 7 3 (d , I H , J = 8 .5 H z , o n e o f O -CH2 -O), 4 . 7 8 (d , I H , J = 8.5 H z , o n e o f O -CH2 -O). D e t a i l e d * H n m r d a t a ( C D C I 3 ) , d e r i v e d f r o m h o m o n u c l e a r ( 1 H - 1 H ) d e c o u p l i n g e x p e r i m e n t s , a r e g i v e n i n T a b l e 2 6 . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : - 1 . 5 ( - v e , S iMe.3_) , 1 4 . 9 ( - v e ) , 1 7 . 6 ( - v e ) , 1 7 . 9 7 , 1 8 . 0 2 ( - v e ) , 2 1 . 6 , 2 2 . 7 ( - v e ) , 2 8 . 9 ( - v e ) , 3 4 . 2 , 3 6 . 1 , 3 6 . 5 , 3 9 . 9 , 4 2 . 1 , 4 3 . 3 , 4 3 . 5 ( - v e ) , 4 4 . 9 ( - v e ) , 4 7 . 6 ( ve ) , 4 8 . 8 , 6 5 . 3 (-O-CH2-OCH2), 7 6 . 0 ( - v e , C - 7 ) , 9 3 . 7 (O -CH2 -O), 2 0 8 . 8 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C i 9 H 3 i 0 2 ( M - O C H 2 C H 2 T M S ) + : 2 9 1 . 2 3 2 4 ; f o u n d : 2 9 1 . 2 3 2 8 . A n a l , c a l c d . f o r C24H4403Si: C 7 0 . 5 3 , H 1 0 . 8 5 ; f o u n d : C 7 0 . 6 9 , H 1 0 . 6 7 . 2 2 3 T a b l e 2 6 : lH n m r ( 4 0 0 M H z , CDCI3) D a t a f o r the K e t o E t h e r 3 1 7 : H o m o n u c l e a r D e c o u p l i n g E x p e r i m e n t s . I r r a d i a t e d S i g n a l S i g n a l B e i n g O b s e r v e d A s s i g n m e n t H - x * H n m r ( 4 0 0 M H z ) 8 ( m u l t i p l i c i t y , 7 ( H z ) ) 8 p p m ( i n i t i a l m u l t i p l e t , 7 ( H z ) , H - x ) t o r e s u l t i n g m u l t i p l e t a f t e r i r r a d i a t i o n , 7 ( H z ) a H - 6 e q 2 . 0 4 (b r d d , 7 = 12 .6 , 6 .6) 4 . 3 3 ( dd , 7 = 12 .8 , 6 . 6 , H - 7 ) t o d , 7 = 12.8 . H - 7 4 . 3 3 ( d d , 7 = 1 2 . 8 , 6 . 6 ) 2 . 0 4 ( b r d d , 7 = 1 2 . 6 , 6 . 6 , H - 6 e q ) t o d , 7 = 12 .6 . H - 9 a x 2 . 2 6 ( b r d d , 7 = 1 3 . 5 , 1 3 . 5 ) 1 . 6 0 - 1 . 8 0 ( m , i n c l u d e s H - 9 a ) t o a m o d i f i e d , u n r e s o l v e d m . 2 . 4 6 ( d d , 7 = 1 3 . 5 , 3 . 8 , H - 9 e q ) t o a s h a r p e r s i g n a l H - 9 e q 2 . 4 6 ( d d , 7 = 1 3 . 5 , 3 . 8 ) 1 . 6 0 - 1 . 8 0 ( m , i n c l u d e s H - 9 a ) t o a m o d i f i e d , u n r e s o l v e d m . 2 . 2 6 (br d d , 7 = 1 3 . 5 , 1 3 . 5 , H - 9 a x ) t o d , 7 = 13 .5 . a- Only the hydrogens for which changes in their signals could be unambiguously seen are recorded. Preparation of ( l a , 3aj3, 5aa, 7/3, 9a/3, 9b a)-7-(tert-ButyIdtimethylsiloxy)-l-isopropyl-3a,5a-dimethylperhydrocyclopenta[a]naphthalen-8-one (329). 311 329 T o a s t i r r e d s o l u t i o n o f the a - h y d r o x y k e t o n e 311 ( 3 2 6 m g , 1.17 m m o l , 1.0 e q u i v ) i n d r y CH2CI2 ( 4 . 6 m L ) , a t r o o m t e m p e r a t u r e , w a s a d d e d s e q u e n t i a l l y i m i d a z o l e ( 3 1 9 m g , 4 . 6 9 m g , 4 . 0 e q u i v . ) a n d T B S C 1 ( 3 5 4 m g , 2 . 3 5 m m o l , 2 . 0 e q u i v . ) . A w h i t e p r e c i p i t a t e f o r m e d a n d t h e m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 2 1 h . T h e s o l v e n t w a s r e m o v e d b y r o t a r y e v a p o r a t i o n . T h e r e s i d u e w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 19 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o e t h e r 329 ( 4 5 9 m g , q u a n t i t a t i v e y i e l d ) as a c o l o u r l e s s , v i s c o u s o i l . I R (neat ) : 1 7 2 4 , 1 4 7 2 , 1 3 6 7 , 1 3 8 6 , 1 2 1 4 , 1 1 5 0 , 8 3 9 , 7 8 0 c m \" 1 . n m r ( C D C I 3 , 4 0 0 M H z ) 8: 0 . 0 0 , 0 . 1 1 (s, s , 3 H e a c h , S i M e . 2 / B u ) , 0 . 7 3 (s , 3 H , M e - 1 0 ) , 0 . 7 4 (d , 3 H , J = 6 .7 H z , M e - 1 2 ) , 0 . 8 3 (d , 3 H , J = 6 .7 H z , M e - 1 3 ) , 0 . 8 8 (s , 9 H , S i M e 2 / B u ) , 0 . 9 9 -1.09 ( m , 1 H ) , 1 .10 (s , 3 H , M e - 1 4 ) , 1 . 1 8 - 1 . 7 8 ( m , 1 2 H ) , 1 .96 ( d d , 1 H , J = 1 3 . 2 , 6 .7 H z , H -9 a x ) , 2 . 2 2 (br d d , 1 H , J= 1 3 . 7 , 1 2 . 3 H z , H - 6 a x ) , 2 . 4 3 ( d d , 1 H , J= 1 3 . 2 , 3 .9 H z , H - 9 e q ) , 4 . 2 8 ( d d , 1 H , J = 1 2 . 3 , 6 .7 H z , w i / 2 = 2 2 H z , H - 7 ) . 2 2 5 !3.C n m r (CDCI3, 7 5 . 3 M H z ) 5 : - 5 . 5 , - 4 . 6 ( - v e , - v e , S i M e . z ' B u ) , 14.9 ( - v e ) , 1 7 . 6 ( - v e ) , 1 8 . 0 (-v e ) , 1 8 . 5 , 2 1 . 6 , 2 2 . 7 ( - v e ) , 2 5 . 8 ( - v e , S i M e 2 C M \u00C2\u00A3 3 _ ) , 2 8 . 9 ( - v e ) , 3 4 . 3 , 3 6 . 2 , 3 6 . 5 , 4 0 . 0 , 4 1 . 8 , 4 3 . 4 , 4 3 . 5 ( - v e ) , 4 4 . 7 ( - v e ) , 4 7 . 6 ( - v e ) , 5 1 . 6 , 7 4 . 0 ( - ve , C - 7 ) , 2 0 9 . 2 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C 2 4 H 4 4 O 2 S 1 : 3 9 2 . 3 1 1 1 ; f o u n d : 3 9 2 . 3 1 0 4 . A n a l , c a l c d . f o r C 2 4 H 4 4 O 2 S 1 : C 7 3 . 4 1 , H 1 1 . 2 9 ; f o u n d : C 7 3 . 2 1 , H 1 1 . 3 2 . 2 2 6 Preparation of ( l a , 3a/J, 5aa, 7/3, 9a/3, 9ba)-7-(terf-Butyldimethylsiloxy)-l-isopropyl-3a,5a-dimethyl-8-methyleneperhydrocyclopenta[a]naphthalene (331). 329 331 T o a c o l d ( 0 \u00C2\u00B0C), s t i r r e d s o l u t i o n o f t h e k e t o n e 329 ( 1 0 9 m g , 0 . 2 7 9 m m o l , 1.0 e q u i v . ) i n d r y T H F (1 .0 m L ) w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f t h e T e b b e r e a g e n t 1 1 7 330 ( 1 7 0 m g , 0 . 5 9 8 m m o l , 2 . 2 e q u i v . ) i n d r y b e n z e n e (2 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 3 0 m i n a n d t h e n w a s w a r m e d t o r o o m t e m p e r a t u r e f o r 1 h . A q u e o u s s o d i u m h y d r o x i d e ( 1 . 0 M ) w a s a d d e d d r o p w i s e u n t i l g a s e v o l u t i o n ( C H 4 ) c e a s e d . T h e m i x t u r e w a s d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e . T h e r e a c t i o n m i x t u r e w a s f i l t e r e d t h r o u g h a s h o r t p l u g o f Celite\u00C2\u00AE ( - 1 5 g) a n d the c o l l e c t e d m a t e r i a l w a s w a s h e d w i t h d i e t h y l e t h e r ( 1 0 0 m L ) . T h e c o m b i n e d f i l t r a t e w a s d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( l O g f l a s h s i l i c a g e l , 9 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 c m c o l u m n ) a n d t h e s o l v e n t f r o m t h e a p p r o p r i a t e f r a c t i o n s w a s r e m o v e d u n d e r r e d u c e d p r e s s u r e . T h e r e s i d u e w a s r e c h r o m a t o g r a p h e d ( 1 0 g t i c s i l i c a g e l , 9 9 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 .5 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t races o f s o l v e n t ( v a c u u m p u m p ) , the a l k e n e 331 ( 1 0 4 m g , 9 5 % ) as a w h i t e s o l i d , m p 5 0 - 5 1 *C. I R ( K B r ) : 3 0 9 3 , 1 6 5 2 , 1 4 6 2 , 1 3 5 1 , 1 2 5 1 , 1 1 7 3 , 1 0 9 3 , 8 9 6 , 8 3 9 , 7 7 5 , 6 7 6 c m \" 1 . ! H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 0 4 , 0 . 0 5 (s, s , 3 H e a c h , S i M e . 2 * B u ) , 0 . 7 4 (s , 3 H , M e - 1 0 ) , 0 . 7 5 (d , 3 H , 7= 6 .8 H z , M e - 1 2 ) , 0 . 8 6 ( d , 3 H , 7= 6 .8 H z , M e - 1 3 ) , 0 . 9 0 (s, 9 H , S i M e 2 * B u . ) , 0 . 9 4 (s, 3 H , M e - 1 4 ) , 0 . 9 6 - 1 . 4 3 ( m , 1 0 H ) , 1 . 4 9 - 1 . 6 4 ( m , 1 H ) , 1 .70 ( d d , 1 H , 7 = 1 2 . 2 , 5 . 2 H z , H - 6 e q ) , 1 . 7 0 - 1 . 8 0 ( m , 1 H ) , 1 .86 ( d d d d d , 1 H , 7 = 6 . 8 , 6 . 8 , 6 . 8 , 6 . 8 , 3 . 2 H z ) , 1 .96 ( b r d d , 1 H , 7= 1 3 . 2 , 1 3 . 2 H z , H - 9 a x ) , 2 . 3 0 ( d d , 1 H , 7 = 1 3 . 2 , 3 .8 H z , H - 9 e q ) , 4 . 1 7 - 4 . 2 4 ( m , 1 H , w\/2 = 2 2 H z , H -7 ) , 4 . 7 1 (b r d , 1 H , 7 = 2 . 3 H z , H - 1 5 ) , 4 . 9 5 ( b r d d d , 1 H , 7 = 2 . 3 , 2 . 3 , 2 . 3 H z , H - 1 5 ' ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : - 4 . 9 ( - ve , S i M e 2 * B u ) , 15 .1 ( - v e ) , 1 7 . 9 ( - v e ) , 1 8 . 3 ( - v e ) , 1 8 . 4 , 2 1 . 7 , 2 2 . 9 ( - v e ) , 2 5 . 9 ( - ve , S i M e 2 C M e 3 _ ) , 2 9 . 1 ( - v e ) , 3 4 . 6 , 3 5 . 2 , 3 7 . 0 7 , 3 7 . 1 1 , 4 0 . 3 , 4 3 . 7 , 4 3 . 8 ( - ve ) , 4 5 . 4 ( - v e ) , 4 7 . 2 ( - v e ) , 5 2 . 6 , 6 9 . 7 ( C - 7 ) , 1 0 5 . 2 ( C - 1 5 ) , 1 5 1 . 5 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C 2 5 H 4 6 0 S i : 3 9 0 . 3 3 1 8 ; f o u n d : 3 9 0 . 3 3 1 9 . A n a l , c a l c d . f o r C 2 5 H 4 6 0 S i : C 7 6 . 8 5 , H 1 1 . 8 7 ; f o u n d : C 7 6 . 8 5 , H 1 1 . 8 6 . 2 2 8 Preparation of ( l a , 3a[5, 5aa, 7p, 9a/J, 9ba)-l-Isopropyl-8-methylene-3a,5a-dimethyl-perhydrocydopenta[a]naphthalen-7-oI (327). 331 327 T o a s t i r r e d s o l u t i o n o f t h e a l k e n e 331 ( 5 8 m g , 0 . 1 5 m m o l , 1.0 e q u i v . ) i n d r y T H F (1 .5 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d t e t r a b u t y l a m m o n i u m f l u o r i d e ( 0 . 3 m L , 1.0 M i n T H F , 0 . 3 m m o l , 2 . 0 e q u i v . ) a n d t h e m i x t u r e w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r 17 h . D i e t h y l e t h e r ( 2 m L ) a n d s a t u r a t e d a q u e o u s N a H C O - 3 (2 m L ) w e r e a d d e d to t h e r e a c t i o n m i x t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d the a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 10 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e ( 2 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (5 g t i c s i l i c a g e l , 2 .3 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 c m c o l u m n ) , to a f f o r d , a f te r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t races o f s o l v e n t ( v a c u u m p u m p ) , the a l c o h o l 327 (41 m g , 9 9 % ) as a w h i t e s o l i d , m p 1 2 9 - 1 3 0 \u00C2\u00B0C. I R ( K B r ) : 3 2 2 9 (br ) , 1 6 5 0 , 1 4 6 0 , 1 3 6 6 , 1 3 8 2 , 1 0 7 0 , 8 9 8 , 7 4 0 , 6 7 5 c m ' l . * H n m r (CDCI3,400 M H z ) 8: 0 . 7 5 (d , 3 H , J = 6 . 9 H z , M e - 1 2 ) , 0 . 7 6 (s , 3 H , M e - 1 0 ) , 0 . 8 6 (d , 3 H , 7 = 6 . 9 H z , M e - 1 3 ) , 0 . 9 5 (s , 3 H , M e - 1 4 ) , 0 . 9 8 - 1 . 5 0 ( m , 1 1 H ) , 1 . 5 2 - 1 . 6 5 ( m , I H ) , 1 . 7 2 -1 .80 ( m , I H ) , 1 . 8 2 - 1 . 9 3 ( m , I H ) , 1 .86 ( d d , I H , J= 1 3 . 4 , 5 . 3 H z , H - 6 e q ) , 1 .99 ( b r d d , 1 H , 7 = 1 3 . 3 , 1 3 . 3 H z , H - 9 a x ) , 2 . 3 2 ( d d , I H , J = 1 3 . 3 , 3 . 8 H z , H - 9 e q ) , 4 . 1 9 - 4 . 2 7 ( m , I H , w i / 2 = 2 2 H z , H - 7 ) , 4 . 7 6 (d , 1 H , 7 = 1.7 H z , H - 1 5 ) , 4 . 9 0 (d , 1 H , 7 = 1.7 H z , H - 1 5 ' ) . 2 2 9 1 3 C n m r ( C D C I 3 ,75.3 M H z ) 5 : 1 5 . 0 ( - v e ) , 17 .8 ( - ve ) , 1 8 . 3 ( - v e ) , 2 1 . 7 , 2 2 . 9 ( - v e ) , 2 9 . 1 ( - v e ) , 3 4 . 5 , 3 5 . 2 , 3 7 . 0 , 3 7 . 2 , 4 0 . 3 , 4 3 . 7 , 4 3 . 8 ( - v e ) , 4 5 . 4 ( - v e ) , 4 7 . 1 ( - v e ) , 5 2 . 2 , 6 9 . 1 ( - v e , C - 7 ) , 1 0 4 . 2 ( C - 1 5 ) , 1 5 2 . 2 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C 1 9 H 3 2 O : 2 7 6 . 2 4 5 2 ; f o u n d : 2 7 6 . 2 4 4 9 . A n a l , c a l c d . f o r C 1 9 H 3 2 O : C 8 2 . 5 5 , H 1 1 . 6 7 ; f o u n d : C 8 2 . 2 6 , H 1 1 . 8 9 . 2 3 0 Preparation of ( l a , 3a/3, 5aa, 9af3, 9ba)-l-Isopropyl-3a,5a,8-trimethyl. 2,3,3a,4,5,5a,6,7,9a,9b-decahydro-lir7-cyclopenta[a]naphthalen-7.one (174). 327 332 174 T o a s t i r r e d s o l u t i o n o f t h e a l l y l i c a l c o h o l 327 ( 4 2 m g , 0 . 1 5 m m o l , 1.0 e q u i v . ) i n d r y CH2CI2 (1 .5 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d s e q u e n t i a l l y c r u s h e d , d r i e d , 4A m o l e c u l a r s i e v e s ( 7 6 m g ) , T V - m e t h y l m o r p h o l i n e - / / - o x i d e ( 4 5 m g , 0 . 3 8 m m o l , 2 . 6 e q u i v . ) , a n d tetra-TV-p r o p y l a m m o n i u m p e r r u t h e n a t e (6 .4 m g , 0 . 0 1 8 m m o l , 1 2 m o l % ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 15 m i n . T h e m i x t u r e w a s f i l t e r e d t h r o u g h a s h o r t p l u g o f s i l i c a g e l ( 6 0 - 2 3 0 m e s h ) a n d t h e c o l l e c t e d m a t e r i a l w a s w a s h e d w i t h d i e t h y l e t h e r ( 1 0 0 m L ) . T h e c o m b i n e d e l u a t e w a s d i l u t e d w i t h a b s o l u t e E t O H (4 .5 m L ) a n d t h e m e t h y l e n e c h l o r i d e a n d d i e t h y l e t h e r w e r e r e m o v e d b y r o t a r y e v a p o r a t i o n , t a k i n g c a r e t o l e a v e t h e h i g h l y r e a c t i v e e n o n e 332 as a s o l u t i o n i n E t O H . T o the s t i r r e d e t h a n o l s o l u t i o n o f t h e e n o n e 332, at r o o m t e m p e r a t u r e , w a s a d d e d PvhCl3\u00C2\u00AB3H20 (5.1 m g , 0 . 0 2 4 m m o l , 16 m o l % ) . T h e m i x t u r e w a s h e a t e d at r e f l u x f o r 1 h 4 5 m i n a n d t h e n w a s c o o l e d t o r o o m t e m p e r a t u r e . D i e t h y l e t h e r ( 1 0 m L ) a n d b r i n e ( 1 0 m L ) w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 10 m L ) a n d the c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 2 . 5 g t i c s i l i c a g e l , 9 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 1.5 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e e n o n e 174 ( 25 m g , 6 1 % f r o m t h e a l l y l i c a l c o h o l 327) as a w h i t e s o l i d , m p 7 6 - 7 8 \u00C2\u00B0C. 2 3 1 I R ( K B r ) : 3 0 4 0 , 1 6 7 6 , 1 4 5 6 , 1 3 6 8 , 1 3 8 6 , 1 1 7 3 c n r l l H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 8 0 (d , 3 H , J = 6 .8 H z , M e - 1 2 ) , 0 . 8 5 (s, 3 H , M e - 1 0 o r M e -14) , 0 . 8 9 (s, 3 H , M e - 1 0 o r M e - 1 4 ) , 0 . 9 3 ( d , 3 H , J = 6 . 8 H z , M e - 1 3 ) , 1 .09 ( d d d , 1 H , J = 10 .6 , 1 0 . 6 , 1 0 . 6 H z ) , 1 . 2 2 - 1 . 7 7 ( m , 8 H ) , 1 .53 (s, 3 H , M e - 1 5 ) , 1 . 8 7 - 2 . 0 4 ( m , 2 H ) , 2 . 2 3 ( d d , 1 H , J = 1 5 . 9 , 0 . 7 H z , H - 6 e q ) , 2 . 3 2 ( d , 1 H , J= 15 .9 H z , H - 6 a x ) , 2 . 4 8 ( d d d , 1 H , 7 = 1 1 . 5 , 2 . 5 , 2 . 5 H z ) , 6 . 7 5 (br s , 1 H , H - 9 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 15.1 ( - v e ) , 15 .9 ( - v e ) , 1 7 . 6 ( - v e ) , 1 8 . 3 ( - v e ) , 2 1 . 9 , 2 2 . 8 ( - ve ) , 30 .1 ( - v e ) , 3 4 . 5 , 3 5 . 8 , 3 9 . 8 , 4 0 . 3 , 4 3 . 8 ( - ve ) , 4 4 . 2 , 4 5 . 5 ( - v e ) , 4 5 . 7 ( - v e ) , 5 5 . 2 , 1 3 5 . 0 ( - v e , C -8 ) , 1 4 6 . 9 ( - v e , C - 9 ) , 1 9 9 . 8 ( C - 7 ) . E x a c t M a s s c a l c d . f o r C19H30O: 2 7 4 . 2 2 9 7 ; f o u n d : 2 7 4 . 2 3 0 0 . A n a l , c a l c d . f o r C i 9 H 3 o O : C 8 3 . 1 5 , H 1 1 . 0 2 ; f o u n d : C 8 2 . 8 8 , H 1 0 . 8 0 . Preparation of ( l a , 3a/J, 5aa , 7(5, 9a/J, 9ba)-l-Isopropyl-3a,5a,8-trimethyl-2,3,3a,4,5,5a,6,7,9a,9b-decahydro-lH-cyclopenta[a]naphthalen-7-ol (173) and (la,3a/3, 5aa, 7a, 9a/3,9ba)-l-Isopropyl-3a,5a,8-trimethyl-2,3,3a,4,5,5a,6,7,9a,9b-decahydro-lff-cyclopenta[a]naphthalen-7-ol (334). 174 173 334 T o a s t i r r e d s o l u t i o n o f t h e e n o n e 174 ( 2 9 m g , 0 .11 m m o l , 1.0 e q u i v . ) i n d r y M e O H (1 .1 m L ) , a t r o o m t e m p e r a t u r e , w a s a d d e d s e q u e n t i a l l y CeCl3\u00C2\u00BB6H20 ( 7 6 m g , 0 . 2 1 m m o l , 2 . 0 e q u i v . ) , a n d N a B H 4 ( 1 8 m g , 0 . 4 8 m m o l , 4 . 6 e q u i v . ) . T h e m i x t u r e b u b b l e d v i g o r o u s l y a n d the s i d e s o f t h e f l a s k w e r e w a s h e d d o w n w i t h d r y M e O H (0 .3 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 15 m i n a n d t h e n 0.1 M a q u e o u s H C 1 ( 2 - 3 m L ) w a s a d d e d d r o p w i s e . D i e t h y l e t h e r ( 1 0 m L ) w a s a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 1 0 m L ) a n d the c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (2 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (3 g t i c s i l i c a g e l , 2 .3 :1 p e t r o l e u m e t h e r - d i e t h y l e the r , 1.5 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , a m i x t u r e o f the t w o e p i m e r i c a l l y l i c a l c o h o l s 334 a n d 173. T h e f i r s t c o m p o u n d that e l u t e d w a s the a l l y l i c a l c o h o l 334 ( 7 .8 m g , 2 6 % ) as a w h i t e s o l i d , m p 8 9 - 9 0 \u00C2\u00B0C. 2 3 3 I R ( K B r ) : 3 3 9 8 (b r ) , 1 7 1 5 , 1 4 5 6 , 1 3 8 5 , 1 2 6 5 , 1 1 7 3 , 1 0 7 8 , 1 0 3 1 , 8 7 4 , 7 4 1 c m - 1 . lH n m r ( C D C 1 3 , 4 0 0 M H z ) 8: 0 . 7 6 (s, 3 H , M e - 1 0 ) , 0 . 7 7 (d , 3 H , J = 6 . 8 H z , M e - 1 2 ) , 0 . 9 0 (d , 3 H , J = 6 .8 H z , M e - 1 3 ) , 0 . 9 5 (s , 3 H , M e - 1 4 ) , 1 .05 ( d d d , 1 H , J = 1 0 . 7 , 1 0 . 7 , 10 .7 H z ) , 1 . 2 0 -1.68 ( m , 1 0 H ) , 1 . 7 4 - 1 . 8 8 ( m , 2 H ) , 1.78 (s, 3 H , M e - 1 5 ) , 1 . 9 0 - 2 . 0 5 ( m , 2 H ) , 3 . 9 5 (b r d , 1 H , J = 5 .4 H z , H - 7 , w i / 2 = 12 H z ) , 5 .61 (b r s , 1 H , H - 9 ) . 1 3 C n m r ( C D C 1 3 ; 7 5 . 3 M H z ) 8: 15 .1 ( - v e ) , 18 .2 ( - v e ) , 1 8 . 4 ( - v e ) , 2 0 . 7 ( - v e ) , 2 2 . 0 , 2 2 . 9 ( - ve ) , 2 9 . 9 ( - v e ) , 3 3 . 5 , 3 4 . 4 , 3 5 . 7 , 4 0 . 1 , 4 3 . 7 ( - v e ) , 4 4 . 1 , 4 4 . 4 ( - v e ) , 4 6 . 0 ( - v e ) , 4 7 . 9 , 6 8 . 4 ( - v e , C -7 ) , 1 2 6 . 8 ( - v e , C - 9 ) , 1 3 3 . 7 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C19H32O: 2 7 6 . 2 4 5 3 ; f o u n d : 2 7 6 . 2 4 4 9 . T h e s e c o n d c o m p o u n d that e l u t e d w a s t h e d e s i r e d a l l y l i c a l c o h o l 1 7 3 ( 2 0 . 6 m g , 7 1 % ) as a w h i t e s o l i d , m p 9 6 - 9 8 \u00C2\u00B0C. I R ( K B r ) : 3 3 3 8 (br ) , 1 4 5 6 , 1 3 7 8 , 1 3 6 6 , 1 0 6 6 , 1 0 3 5 , 1 0 1 8 , 9 9 6 , 8 2 8 c m ' 1 . 2 H n m r ( C D C I 3 , 4 0 0 M H z ) 8: 0 . 7 5 (d , 3 H , J = 6 .8 H z , M e - 1 2 ) , 0 . 7 7 (s , 3 H , M e - 1 0 ) , 0 . 8 4 (s, 3 H , M e - 1 4 ) , 0 . 8 9 ( d , 3 H , J = 6 .8 H z , M e - 1 3 ) , 1 .03 ( d d d , 1 H , J = 1 0 . 7 , 1 0 . 7 , 10 .7 H z ) , 1 . 1 5 -1 .50 ( m , 8 H ) , 1 . 5 1 - 1 . 6 8 ( m , 2 H ) , 1 .72 (b r d d , 3 H , J = 1.2. 1.2 H z , M e - 1 5 ) , 1 . 7 7 - 1 . 8 7 ( m , 1 H ) , 1.92 ( d d , 1 H , J= 1 2 . 2 , 6 .7 H z ) , 1 . 9 2 - 2 . 0 2 ( m , 1 H ) , 2 . 1 0 - 2 . 1 6 ( m , 1 H ) , 4 . 1 0 - 4 . 1 8 ( m , 1 H , H - 7 , w i / 2 = 2 2 H z ) , 5 . 5 7 (b r s , 1 H , H - 9 ) . I n N O E e x p e r i m e n t s , i r r a d i a t i o n o f t h e s i g n a l at 8 4 . 1 0 - 4 . 1 8 ( H - 7 ) s h o w e d a n e n h a n c e m e n t f o r the s i g n a l a t 8 0 . 8 4 ( M e - 1 4 ) . S i m i l a r l y , i r r a d i a t i o n o f t h e s i g n a l at 8 0 . 8 4 ( M e - 1 4 ) s h o w e d a n e n h a n c e m e n t f o r t h e s i g n a l at 8 4 . 1 0 - 4 . 1 8 ( H - 7 ) . 2 3 4 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 15 .1 ( - v e ) , 17 .3 ( - v e ) , 1 8 . 4 ( - v e ) , 1 9 . 4 ( - v e ) , 2 2 . 0 , 2 2 . 9 ( - v e ) , 2 9 . 9 ( - v e ) , 3 4 . 4 , 3 5 . 6 , 3 7 . 9 , 4 0 . 1 , 4 3 . 7 ( - v e ) , 4 4 . 1 , 4 4 . 2 ( - v e ) , 4 5 . 5 ( - v e ) , 4 9 . 2 , 6 9 . 6 ( - v e , C - 7 ) , 126 .8 ( - v e , C - 9 ) , 1 3 4 . 3 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C19H32O: 2 7 6 . 2 4 5 3 ; f o u n d : 2 7 6 . 2 4 5 1 . A n a l , c a l c d . f o r C 1 9 H 3 2 O : C 8 2 . 5 5 , H 1 1 . 6 7 ; f o u n d : C 8 2 . 3 9 , H 1 1 . 6 5 . 2 3 5 Preparation of (\u00C2\u00B1)-Neoverrucosan-5B-ol (62). H Q H CICH 2 CH 2 C 1 , 0 \u00C2\u00B0C ZnEt 2 , ICH 2CI H Q 173 62 T o a c o l d ( 0 \u00C2\u00B0C), s t i r r e d s o l u t i o n o f d i e t h y l z i n c ( 4 3 U.L, 0 . 4 2 m m o l , 4 . 0 e q u i v . ) i n d r y 1 , 2 - d i c h l o r o e t h a n e (2 .1 m L ) w a s a d d e d c h l o r o i o d o m e t h a n e (61 u L , 0 . 8 4 m m o l , 8.1 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 10 m i n , p r o g r e s s i n g f r o m a c l e a r s o l u t i o n t o a n o p a q u e , w h i t e m i x t u r e . A s o l u t i o n o f the a l l y l i c a l c o h o l 173 ( 2 9 m g , 0 . 1 0 m m o l , 1.0 e q u i v . ) i n d r y 1 , 2 - d i c h l o r o e t h a n e ( 1 . 3 m L ) w a s a d d e d ( v i a d o u b l e t i p p e d m e t a l c a n n u l a ) a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 15 m i n . S a t u r a t e d a q u e o u s N a 2 S 2 C < 3 (1 m L ) a n d s a t u r a t e d a q u e o u s N H 4 C I ( 2 m L ) w e r e a d d e d a n d t h e m i x t u r e w a s w a r m e d t o r o o m t e m p e r a t u r e . D i e t h y l e t h e r (5 m L ) w a s a d d e d a n d the l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 15 m L ) a n d the c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 3 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 2 .5 g t i c s i l i c a g e l , 1.9:1 p e t r o l e u m e t h e r - d i e t h y l e ther , 1.5 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , ( \u00C2\u00B1 ) -n e o v e r r u c o s a n - 5 B - o l (62) ( 2 8 m g , 9 2 % ) as a w h i t e s o l i d , m p 1 5 0 - 1 5 2 \u00C2\u00B0C. T h e r e p o r t e d m e l t i n g p o i n t f o r the n a t u r a l l y o c c u r r i n g ( - ) - n e o v e r r u c o s a n - 5 B - o l i s 1 7 4 - 1 7 5 \u00C2\u00B0 C . 2 2 a I R ( K B r ) : 3 2 6 3 (b r ) , 3 0 5 6 , 1 4 5 2 , 1 3 8 7 , 1 3 7 9 , 1 0 8 1 , 1 0 4 2 , 1 0 2 0 , 9 9 7 c n r * . lU n m r ( C D C h , 4 0 0 M H z ) 8 : 0 . 2 6 ( d d , 1 H , 7 = 4 . 7 , 4 . 7 H z , H - 3 f 3 ) , 0 . 5 4 ( d d , 1 H , 7 = 8 . 1 , 4 .7 H z , H - 3 a ) , 0 . 6 6 ( d d , 1 H , 7 = 1 2 . 2 , 1 2 . 2 H z ) , 0 . 7 2 (s, 3 H , M e - 2 0 ) , 0 . 7 6 - 0 . 8 6 ( m , 1 H ) , 0 . 8 0 (d , 3 H , 7 = 6 .7 H z , M e - 1 6 ) , 0 . 8 1 (s , 3 H , M e - 1 9 ) , 0 . 8 9 (d , 3 H , 7 = 6 .7 H z , M e - 1 7 ) , 0 . 9 7 - 1 . 4 5 ( m , 10 H ) , 1 .16 (s , 3 H , M e - 1 8 ) , 1 . 5 2 - 1 . 6 4 ( m , 1 H ) , 1.67 ( d d , 1 H , 7 = 1 3 . 4 , 7 . 3 H z ) , 1 . 8 3 - 1 . 9 3 ( m , 1 H ) , 2 . 0 8 - 2 . 1 8 ( m , 1 H ) , 4 . 0 0 ( d d , 1 H , 7 = 10 .4 , 7 .5 H z , H - 5 ) . 1 3 C n m r (CDC13, 7 5 . 3 M H z ) 8 : 1 4 . 9 0 ( - v e , C - 1 7 ) , 1 7 . 1 8 ( - v e ) , 1 8 . 5 8 ( - v e ) , 1 9 . 6 0 , 2 1 . 5 5 , 2 1 . 9 7 ( C - 4 ) , 2 2 . 7 5 ( - v e ) , 2 5 . 5 4 ( - v e ) , 2 5 . 8 4 ( - v e ) , 2 8 . 6 3 ( - v e , C - 1 5 ) , 3 4 . 6 1 , 3 5 . 2 2 , 3 7 . 1 0 , 3 9 . 1 2 , 4 4 . 0 0 ( C - 1 0 ) , 4 5 . 1 6 ( - v e , C - 1 3 ) , 4 6 . 8 6 ( - v e , C - l ) , 4 7 . 1 6 , 4 7 . 5 7 ( - v e , C - 1 4 ) , 7 1 . 1 7 ( - v e , C - 5 ) . E x a c t M a s s c a l c d . f o r C 2 0 H 3 4 O : 2 9 0 . 2 6 1 0 ; f o u n d : 2 9 0 . 2 6 1 0 . A n a l , c a l c d . f o r C20H34O: C 8 2 . 6 9 , H 1 1 . 8 0 ; f o u n d : C 8 2 . 8 4 , H 1 1 . 9 1 . T h e r a c e m i c s y n t h e t i c n a t u r a l p r o d u c t 6 2 e x h i b i t e d s p e c t r a l d a t a i d e n t i c a l w i t h t h o s e o f t h e n a t u r a l l y o c c u r r i n g ( - ) - n e o v e r r u c o s a n - 5 R - o l ( 6 2 ) ( T a b l e s 9 a n d 1 0 , p a g e s 120 a n d 121). 22a, 1 2 2 T h e ! H n m r s p e c t r u m ( 4 0 0 M H z , CDCI3) o f s y n t h e t i c (\u00C2\u00B1)-neoverrucosan-5 p-ol ( 6 2 ) i s s h o w n o n p a g e 1 2 2 ( F i g u r e 3 ) . A c o m p a r i s o n o f t h i s s p e c t r u m w i t h t h e * H n m r s p e c t r u m r u n o n a n a u t h e n t i c s a m p l e i s d e p i c t e d o n p a g e 123 ( F i g u r e 4). T o a s t i r r e d s o l u t i o n o f (\u00C2\u00B1 ) -neoverrucosan - 5 p -o l ( 6 2 ) ( 5 . 4 m g , 0 . 0 1 9 m m o l , 1.0 e q u i v . ) i n a c e t o n e ( 1 . 2 5 m L ) w a s a d d e d a q u e o u s s u l f u r i c a c i d ( 0 . 2 5 m L , 0 . 5 M ) . T h e r e a c t i o n m i x t u r e w a s h e a t e d at r e f l u x f o r 4 h a n d t h e n w a s c o o l e d t o r o o m t e m p e r a t u r e . D i e t h y l e t h e r ( 1 0 m L ) a n d w a t e r ( 1 0 m L ) w e r e a d d e d . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h s a t u r a t e d a q u e o u s N a H C 0 3 (1 x 10 m L ) a n d b r i n e (1 x 1 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 2 .5 g t i c s i l i c a g e l , 2 . 3 : 1 p e t r o l e u m e t h e r - d i e t h y l e the r , 1.5 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , (\u00C2\u00B1)-homoverrucosan-5 P -ol ( 6 3 ) ( 5 . 4 m g , q u a n t i t a t i v e y i e l d ) as a w h i t e s o l i d , m p 1 4 1 - 1 4 2 \u00C2\u00B0C. T h e r e p o r t e d m e l t i n g p o i n t f o r t h e n a t u r a l l y o c c u r r i n g ( + ) - h o m o v e r r u c o s a n - 5 P-ol i s 1 5 3 - 1 5 4 \u00C2\u00B0 C . 2 I a > 2 2 I R ( K B r ) : 3 2 4 1 (b r ) , 1 6 7 2 , 1 4 5 5 , 1 3 8 7 , 1 3 7 8 , 1 0 8 6 , 1 0 2 7 , 9 7 2 , 8 6 8 c m \" 1 . * H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 7 6 (s, 3 H , M e - 2 0 ) , 0 .81 ( d , 3 H , J= 6 .7 H z , M e - 1 6 ) , 0 . 8 3 5 (d , 3 H , J = 6 .7 H z , M e - 1 7 ) , 0 . 8 4 3 (s, 3 H , M e - 1 9 ) , 1 .00 ( d d d , 1 H , J = 9 . 9 , 9 . 9 , 9 . 9 H z ) , 1 .14 ( d d , 1 H , J= 11 .4 , 1 1 . 4 H z ) , 1 . 1 7 - 1 . 7 3 ( m , 1 0 H ) , 1 .74 (s, 3 H , M e - 1 8 ) , 1.87 ( d d d , 1 H , 7 = 13 .0 , 3 . 2 , 2 . 6 H z ) , 1 . 9 6 - 2 . 0 5 ( m , 2 H ) , 2 . 1 8 ( d d , 1 H , J = 1 2 , 4 . 5 H z , H - 4 a ) , 2 . 5 3 ( d d d , 1 H , J= 1 2 . 2 , 12 , 1.8 H z , H - 4 B ) , 3.57 ( d d d d , I H , J = 12.2, 11.0, 4 .5, 2.2 H z , H - 5 ) , 5.27 ( b r d , I H , J = 6.0 H z , H-2) . 1 3 C n m r ( C D C 1 3 , 75.3 M H z ) 8 : 14.88 ( - v e ) , 17.99 ( - v e ) , 20.06 ( - v e ) , 21 .35 , 22.83 ( - v e ) , 25.71 ( v e ) , 27.94 ( - ve ) , 35.06, 37.97, 38.73, 3 8 . 9 1 , 4 2 . 5 3 1 2 4 , 43.76 ( - v e ) , 46.75 ( - v e ) , 47.69 (-v e ) , 58.82, 65.57 ( - v e , C - 5 ) , 131.20 (C-3) , 131.61 ( - v e , C - 2 ) . E x a c t M a s s c a l c d . f o r C 2 0 H 3 4 O : 290.2610; f o u n d : 290.2602. A n a l , c a l c d . f o r C 2 o H 3 4 0 : C 82.69, H 11.80; f o u n d : C 82.43, H 11.72. T h e r a c e m i c s y n t h e t i c 6 3 e x h i b i t e d s p e c t r a l d a t a i d e n t i c a l w i t h t h o s e o f the n a t u r a l l y o c c u r r i n g ( + ) - h o m o v e r r u c o s a n - 5 B - o l ( T a b l e s 11 a n d 1 2 , p a g e s 125 a n d 1 2 6 ) . 2 1 a - 1 2 3 T h e * H n m r s p e c t r u m (400 M H z , CDCI3) o f the s y n t h e t i c (\u00C2\u00B1)-homoverrucosan -5B -ol ( 6 3 ) i s s h o w n o n p a g e 127 ( F i g u r e 5 ) . A c o m p a r i s o n o f t h i s s p e c t r u m w i t h t h e * H n m r s p e c t r u m r u n o n a n a u t h e n t i c s a m p l e i s d e p i c t e d o n p a g e 128 ( F i g u r e 6 ) . 2 3 9 Preparation of ( l a , 3aj3, 5aa, 9aj3, 9ba)-8,9 j8-Epoxy-l-isopropyI-3a,5a,8-trimethyl-perhydrocyclopenta[a]naphtha!en-7-one (175). 174 175 T o a s t i r r e d s o l u t i o n o f t h e e n o n e 174 ( 1 5 . 8 m g , 0 . 0 5 7 6 m m o l , 1.0 e q u i v . ) i n d r y CH2CI2 ( 0 . 5 7 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d a s o l u t i o n o f d i m e t h y l d i o x i r a n e 1 1 0 b ( 0 . 3 m m o l , 0 . 0 8 M , 5 . 0 e q u i v . ) i n a c e t o n e ( 3 . 6 m L ) . T h e m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e w h i l e t h r e e a d d i t i o n a l a l i q u o t s o f d i m e t h y l d i o x i r a n e s o l u t i o n ( e a c h a d d i t i o n a l a l i q u o t : 3 . 6 m L , 0 . 0 8 M i n a c e t o n e , 0 . 3 m m o l , 5 . 0 e q u i v ) w e r e a d d e d o n e a l i q u o t at a t i m e at 9 h , 2 4 h , a n d 3 3 h . A f t e r 51 h at r o o m t e m p e r a t u r e , t h e r e a c t i o n m i x t u r e w a s d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 2 . 5 g t i c s i l i c a g e l , 13 :1 p e t r o l e u m e t h e r - d i e t h y l e the r , 2 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t races o f s o l v e n t ( v a c u u m p u m p ) , the e p o x y k e t o n e 175 ( 1 2 . 0 m g , 7 2 % ) as a w h i t e s o l i d , m p 6 4 - 6 5 \u00C2\u00B0C. I R ( K B r ) : 1 7 1 3 , 1 4 6 7 , 1 3 8 8 , 1 2 1 3 , 1 0 9 7 , 8 5 7 , 8 3 9 , 8 0 3 , 7 7 9 c m \" 1 . ! H n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 8 2 ( d , 3 H , J = 6 . 7 H z , M e - 1 2 ) , 0 . 8 4 ( b r s , 6 H , M e - 1 0 a n d M e - 1 4 ) , 0 . 9 2 ( d , 3 H , J = 6 .6 H z , M e - 1 3 ) , 1 . 0 5 - 1 . 1 6 ( m , 2 H ) , 1 . 3 1 - 1 . 5 8 ( m , 6 H ) , 1 .36 (s , 3 H , M e - 1 5 ) , 1 . 6 2 - 1 . 7 4 ( m , I H ) , 1 . 9 6 - 2 . 0 8 ( m , 3 H ) , 1 .99 ( d , I H , J = 1 4 . 6 H z , H - 6 a x ) , 2 . 4 4 ( d d , I H , J= 1 4 . 6 , 0 . 6 H z , H - 6 e q ) , 3 . 3 3 (s, I H , H - 9 ) . 2 4 0 I n N O E e x p e r i m e n t s , i r r a d i a t i o n o f the s i g n a l at 8 3 . 3 3 ( H - 9 ) s h o w e d a n e n h a n c e m e n t f o r the s i g n a l at 8 1.36 ( M e - 1 5 ) . S i m i l a r l y , i r r a d i a t i o n o f the s i g n a l at 8 1 .36 ( M e - 1 5 ) s h o w e d a n e n h a n c e m e n t f o r the s i g n a l at 8 0 . 8 4 ( M e - 1 4 ) a n d f o r the s i g n a l at 8 3 . 3 3 ( H - 9 ) . 1 3 C n m r ( C D C 1 3 , 7 5 . 3 M H z ) 8 : 14 .8 ( - v e ) , 15 .6 ( - ve ) , 1 8 . 4 ( - v e ) , 19.1 ( - v e ) , 2 1 . 8 , 2 2 . 6 ( - ve ) , 2 9 . 7 ( - v e ) , 3 4 . 3 , 3 5 . 0 , 3 9 . 3 , 4 1 . 5 , 4 4 . 2 , 4 4 . 3 ( - v e ) , 4 5 . 0 ( - v e ) , 4 6 . 4 ( - v e ) , 5 2 . 1 , 5 9 . 1 ( C - 8 ) , 6 5 . 4 ( - ve , C - 9 ) , 2 0 6 . 9 ( C - 7 ) . E x a c t M a s s c a l c d . f o r C19H30O2: 2 9 0 . 2 2 4 6 ; f o u n d : 2 9 0 . 2 2 5 0 . A n a l , c a l c d . f o r C19H30O2: C 7 8 . 5 7 , H 1 0 . 4 1 ; f o u n d : C 7 8 . 7 6 , H 1 0 . 3 3 . 2 4 1 Preparation of ( l a , 3a/3, 5 a a , 9/3, 9a/3, 9ba)-l-Isopropyl-3a,5a,8-trimethyl-2,3,3a,4,5,5a,6,9,9a,9b-decahydro-lH-cydopenta[a]naphthalen-9-oI (172). H ? N H 2 N H 2 , MeOH, 1-hexene AcOH, 0 \u00C2\u00B0C to rt O H 03 H VJS 175 T o a c o l d ( 0 \u00C2\u00B0C ) , s t i r r e d s o l u t i o n o f t h e k e t o e p o x i d e 175 ( 3 4 m g , 0 . 1 2 m m o l , 1.0 e q u i v . ) i n d r y M e O H ( 1 .2 m L ) a n d d r y 1 - h e x e n e ( 1 . 2 m L ) w a s a d d e d a c e t i c a c i d ( 3 -4 d r o p s ) . T h e s t i r r e d m i x t u r e w a s p u r g e d w i t h d r y a r g o n . H y d r a z i n e ( 7 4 U.L, 2 . 4 m m o l , 21 e q u i v . ) w a s a d d e d a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 3 0 m i n a n d t h e n w a s w a r m e d t o r o o m t e m p e r a t u r e f o r 1 h . D i e t h y l e t h e r (3 m L ) a n d w a t e r ( 3 m L ) w e r e a d d e d t o the r e a c t i o n m i x t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d the a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 1 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (5 g t i c s i l i c a g e l , 1 1 . 5 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 c m c o l u m n ) , t o a f f o r d , a f te r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , the a l l y l i c a l c o h o l 172 ( 2 2 . 0 m g , 6 8 % ) as a w h i t e s o l i d , m p 8 6 - 8 7 \u00C2\u00B0C. I R ( K B r ) : 3 4 8 0 (b r ) , 1 4 5 6 , 1 3 8 4 , 1 0 3 2 , 1 0 1 5 , 9 9 5 , 8 7 7 c m \" 1 . l H n m r ( C D C 1 3 , 4 0 0 M H z ) 5: 0 . 7 8 (s , 3 H , M e - 1 0 o r M e - 1 4 ) , 0 . 8 1 ( d , 3 H , J = 6 .8 H z , M e -12) , 0 . 8 3 (s , 3 H , M e - 1 0 o r M e - 1 4 ) , 0 . 8 9 ( d , 3 H , J = 6 .7 H z , M e - 1 3 ) , 1.01 ( b r d d d , 1 H , J = 1 1 . 3 , 1 1 . 3 , 1 1 . 3 H z ) , 1 . 0 7 - 1 . 7 8 ( m , 1 0 H ) , 1 .72 ( b r d , 3 H , J = 1.9 H z , M e - 1 5 ) , 1 . 7 9 - 1 . 8 0 ( m , 242 IH), 1.86-2.09 ( m , 3H), 3.70 ( b r d d , IH, J = 7.3,7.3 Hz, H-9, w h e n t r e a t e d w i t h D 2 0 g i v e s a b r d , J = 7.3 Hz, wi/ 2 = 15 Hz), 5.42 (b r d , IH, J = 5.4 Hz, H-7). 1 3 C n m r ( C D C 1 3 , 75.3 M H z ) 8 : 15.1 ( - v e ) , 17.8 ( - v e ) , 18.5 ( - v e ) , 19.6 ( - v e ) , 22 .2 , 23.4 ( - ve ) , 28.5 ( - v e ) , 35 .3 , 36 .7 , 37 .3 , 40.4 , 42 .3 , 44 .0 ( - v e ) , 44 .1 , 47.4 ( - v e ) , 49.5 ( - v e ) , 72 .0 ( - v e , C - 9 ) , 123.0 ( - ve , C - 7 ) , 134.9 (C-8 ) . E x a c t M a s s c a l c d . f o r C I Q H 3 2 0 : 276 .2453; f o u n d : 276.2454. A n a l , c a l c d . f o r C i 9 H 3 2 0 : C 82.55 , H 11.67; f o u n d : C 82.65, H 11.61. 2 4 3 P r e p a r a t i o n o f (\u00C2\u00B1) -Verrucosan-2B-ol ( 61 ) . C I C H 2 C H 2 C I , 0 \u00C2\u00B0C ZnEt 2 , ICH 2CI 1 7 2 6 1 T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f d i e t h y l z i n c ( 1 5 U.L, 0 . 1 5 m m o l , 6 .7 e q u i v . ) i n d r y 1 , 2 - d i c h l o r o e t h a n e ( 0 . 4 3 m L ) w a s a d d e d c h l o r o i o d o m e t h a n e ( 2 0 u L , 0 . 2 8 m m o l , 1 3 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 10 m i n , p r o g r e s s i n g f r o m a c l e a r s o l u t i o n to a n o p a q u e , w h i t e m i x t u r e . A s o l u t i o n o f t h e a l l y l i c a l c o h o l 1 7 2 ( 6 . 0 m g , 0 . 0 2 2 m m o l , 1.0 e q u i v . ) i n d r y 1 , 2 - d i c h l o r o e t h a n e ( 0 . 7 5 m L ) w a s a d d e d ( v i a d o u b l e t i p p e d m e t a l c a n n u l a ) a n d the r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 3 0 m i n . S a t u r a t e d a q u e o u s N a 2 S 2 0 3 (1 m L ) a n d s a t u r a t e d a q u e o u s NH4CI ( 2 m L ) w e r e a d d e d a n d t h e m i x t u r e w a s w a r m e d to r o o m t e m p e r a t u r e . D i e t h y l e t h e r (5 m L ) a n d w a t e r (5 m L ) w e r e a d d e d . T h e l a y e r s w e r e s e p a r a t e d a n d the a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 15 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (0 .5 g t i c s i l i c a g e l , 11 .5 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 1 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , (\u00C2\u00B1)-verrucosan-28-ol ( 6 1 ) ( 6 . 2 m g , 9 8 % ) a s a w h i t e s o l i d , m p 9 0 - 9 2 \u00C2\u00B0C. T h e r e p o r t e d m e l t i n g p o i n t f o r the n a t u r a l l y o c c u r r i n g ( - ) - v e r r u c o s a n - 2 B - o l i s 7 6 . 5 - 7 8 \u00C2\u00B0 C . 2 1 a I R ( K B r ) : 3 5 0 6 (b r ) , 3 0 5 6 , 1 4 6 5 , 1 3 8 4 , 1 2 1 7 , 1 0 3 2 , 9 9 5 , 9 4 0 , 7 4 0 c m \" 1 . ! H n m r ( C D 2 C 1 2 , 4 0 0 M H z ) 5 : 0 . 1 7 ( d d , I H , J = 4 . 6 , 4 . 6 H z , H - 4 B ) , 0 . 4 2 ( d d , I H , J = 8 . 4 , 4 . 6 H z , H - 4 o c ) , 0 . 7 2 8 (s, 3 H , M e - 2 0 ) , 0 . 7 0 - 0 . 7 8 ( m , I H , H - l ) , 0 . 8 1 2 ( d , 3 H , J = 6 . 9 H z , M e -17) , 0 . 8 5 7 (b r s , 3 H , M e - 1 9 ) , 0 . 8 6 8 ( d , 3 H , J = 6 .9 H z , M e - 1 6 ) , 0 . 8 9 - 1 . 4 8 ( m , 1 1 H ) , 1 .168 (s, 3 H , M e - 1 8 ) , 1 . 5 3 - 1 . 6 7 ( m , I H , H - 1 2 B ) , 1 .77 ( d d , I H , J= 1 3 . 8 , 9 . 3 H z , H - 6 e q ) , 2 . 0 1 ( d d d d , I H , J = 1 0 . 6 , 1 0 . 6 , 3 . 8 , 2 . 7 H z , H - 1 3 ) , 2 . 1 4 ( d d d d d d d , I H , J = 6 . 9 , 6 . 9 , 6 . 9 , 6 . 9 , 6 . 9 , 6 . 9 , 2 .7 H z , H - 1 5 ) , 3 . 5 5 ( d d , I H , J = 8 .9 , 7 .6 H z , H - 2 ) . 1 3 C n m r ( C D 2 C 1 2 , 7 5 . 3 M H z ) 8 : 1 5 . 3 0 ( - ve , C - 1 7 ) , 1 8 . 0 4 ( - v e , C - 2 0 ) , 1 8 . 7 3 ( C - 4 ) , 1 9 . 5 0 ( v e , C - 1 9 ) , 2 1 . 8 3 ( - v e , C - 5 ) , 2 2 . 7 2 ( C - 1 2 ) , 2 3 . 6 5 1 3 2 ( - v e , C - 1 6 ) , 2 5 . 6 2 , ( - v e , C - 1 8 ) , 2 8 . 8 7 ( - v e , C -15 ) , 3 5 . 7 1 ( C - 9 ) , 3 7 . 3 4 ( C - 7 ) , 3 7 . 9 3 ( C - 8 ) , 4 1 . 0 1 ( C - l l ) , 4 2 . 8 3 ( C - 6 ) , 4 4 . 3 5 ( - v e , C - 1 3 ) , 4 4 . 6 2 ( C - 1 0 ) , 4 6 . 8 8 ( - ve , C - l ) , 4 8 . 3 6 ( - ve , C - 1 4 ) , 7 3 . 8 0 ( - v e , C - 2 ) . T h e a b o v e * H a n d 1 3 C n m r s p e c t r a l a s s i g n m e n t s w e r e m a d e w i t h t h e h e l p o f t h e r e p o r t e d d a t a f o r the n a t u r a l l y o c c u r r i n g ( - ) - v e r r u c o s a n - 2 B - o l . 2 1 b E x a c t M a s s c a l c d . f o r C 2 0 H 3 4 O : 2 9 0 . 2 6 1 0 ; f o u n d : 2 9 0 . 2 6 1 2 . A n a l , c a l c d . f o r C 2 0 H 3 4 O : C 8 2 . 6 9 , H 1 1 . 8 0 ; f o u n d : C 8 2 . 3 8 , H 1 1 . 7 5 . T h e r a c e m i c s y n t h e t i c n a t u r a l p r o d u c t 6 1 e x h i b i t e d s p e c t r a l d a t a i d e n t i c a l w i t h t h o s e o f the n a t u r a l l y o c c u r r i n g ( - ) - v e r r u c o s a n - 2 B - o l ( T a b l e 1 3 a n d 1 4 , p a g e s 1 3 4 a n d 135) . 2 1 > 1 3 \u00C2\u00B0 -1 3 1 T h e * H n m r s p e c t r u m ( 4 0 0 M H z , C D 2 C 1 2 ) o f s y n t h e t i c (\u00C2\u00B1)-verrucosan-2B-ol i s s h o w n o n p a g e 1 3 6 ( F i g u r e 7 ) . Preparation of (\u00C2\u00B1)-Homoverrucosan-5R-ol (63) from (\u00C2\u00B1)-Verrucosan-2R-ol (61). T o a s t i r r e d s o l u t i o n o f (\u00C2\u00B1)-verrucosan-2R-ol (61) ( 4 .4 rag, 0 . 0 1 5 m m o l , 1.0 e q u i v . ) i n a c e t o n e ( 1 . 2 5 m L ) w a s a d d e d a q u e o u s s u l f u r i c a c i d ( 0 . 2 5 m L , 0 . 5 M ) . T h e r e a c t i o n m i x t u r e w a s h e a t e d at r e f l u x f o r 4 h a n d t h e n w a s c o o l e d to r o o m t e m p e r a t u r e . D i e t h y l e t h e r ( 1 0 m L ) , w a t e r ( 1 0 m L ) , a n d s a t u r a t e d a q u e o u s N a H C 0 3 ( 1 0 m L ) w e r e a d d e d to t h e r e a c t i o n m i x t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 10 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (1 g t i c s i l i c a g e l , 1 .2:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 1.5 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , (\u00C2\u00B1)-homoverrucosan-5R-ol (63) ( 2 . 6 m g , 5 9 % ) as a w h i t e s o l i d , w h i c h w a s i d e n t i c a l , i n a l l r e s p e c t s , w i t h t h e p r e v i o u s l y p r e p a r e d s a m p l e that w a s s y n t h e s i z e d f r o m (\u00C2\u00B1)-neoverrucosan-5 R - o l (62) (see p a g e s 2 3 7 - 2 3 8 ) . Preparation of ( l a , 3aj3, 5aa, 10a/3, 10ba)-l-Isopropenyl-3a,5a-dimethyl-perhydrocyclohepta[g]inden-9-one (347) and ( la , 3a/?, 5aa, 10a/3,10b a)-1-Isopropenyl-3a,5a-dimethylperhydrocyclohepta[g]inden-8-one (177). O O o. \ ^ 1) BF 3 .E t 2 0 ? N 2 C H C 0 2 E t \ Et 2Q, 0 \u00C2\u00B0C to rt 2) DMSO, NaCl H 2 0, reflux 15 171 347 177 T o a c o l d ( 0 \u00C2\u00B0C), s t i r r e d s o l u t i o n o f t h e k e t o n e 171 ( 1 . 1 2 g , 4 . 2 9 m m o l , 1.0 e q u i v . ) i n d r y E t 2 0 ( 4 3 m L ) w a s a d d e d d r y B F 3 * E t 2 0 ( 0 . 7 9 m L , 6 . 4 4 m m o l , 1.5 e q u i v . ) , f o l l o w e d b y t h e d r o p w i s e a d d i t i o n o f e t h y l d i a z o a c e t a t e ( 0 . 6 8 m L , 6 . 4 7 m m o l , 1.5 e q u i v . ) , a l l o w i n g f o r the s a f e v e n t i n g o f t h e n i t r o g e n gas b e i n g f o r m e d . T h e m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 15 m i n a n d t h e n w a s w a r m e d to r o o m t e m p e r a t u r e a n d s t i r r e d f o r 3 5 m i n . T h e m i x t u r e w a s c o o l e d to 0 \u00C2\u00B0C a n d s a t u r a t e d a q u e o u s N a H C 0 3 ( 2 0 m L ) w a s c a r e f u l l y a d d e d . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 2 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 5 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T o t h e r e s u l t a n t r e s i d u e w a s a d d e d s o d i u m c h l o r i d e ( 5 0 9 m g , 8 .71 m m o l , 2 . 0 e q u i v . ) , d i m e t h y l s u l f o x i d e ( 3 0 m L ) , a n d w a t e r ( - 0 . 5 m L ) . T h e s t i r r e d r e a c t i o n m i x t u r e w a s h e a t e d at 1 5 0 \u00C2\u00B0C f o r 6 h . T h e m i x t u r e w a s c o o l e d to r o o m t e m p e r a t u r e a n d d i e t h y l e t h e r ( 1 0 0 m L ) a n d b r i n e ( 5 0 m L ) w e r e a d d e d . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 5 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (4 x 1 0 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e *H n m r s p e c t r o s c o p i c a n a l y s i s o f t h e c r u d e o i l t h u s o b t a i n e d i n d i c a t e d a m i x t u r e o f t h e k e t o n e s 347 a n d 177 i n a r a t i o o f 1 :1 .3 , r e s p e c t i v e l y . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 5 . 7 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , a m i x t u r e o f t h e k e t o n e 347 a n d the k e t o n e 177 ( 1 . 1 6 g , 9 8 % ) . W h i l e t h e s e p a r a t i o n o f 347 a n d 177 w a s d i f f i c u l t , t h e t w o i s o m e r s c o u l d b e s e p a r a t e d b y f l a s h c h r o m a t o g r a p h y o f the m i x t u r e ( t ic s i l i c a g e l , 5 . 7 : 1 p e t r o l e u m e t h e r - d i e t h y l e ther ) . A s a m p l e c h r o m a t o g r a p h i c r u n s h o w e d t h a t a 1 :1 .4 r a t i o o f a m i x t u r e o f the k e t o n e 347 a n d t h e k e t o n e 177 ( 1 . 0 0 2 g , c o m b i n e d ) a f f o r d e d , a f t e r r e p e a t e d c h r o m a t o g r a p h y o f the m i x e d f r a c t i o n s f o l l o w e d b y c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o n e 347 ( 3 6 8 m g , 3 7 % ) as a s l i g h t l y y e l l o w v i s c o u s o i l a n d t h e s l i g h t l y m o r e p o l a r k e t o n e 177 ( 5 5 6 m g , 5 6 % ) as a n o f f - w h i t e s o l i d , m p 5 5 - 5 7 \u00C2\u00B0C. T h e f i r s t c o m p o u n d that e l u t e d w a s the k e t o n e 347. I R (neat ) : 3 0 7 1 , 1 6 9 9 , 1 6 4 1 , 1 4 5 6 , 1 4 0 7 , 8 8 4 c m - * . ! H n m r ( C D C I 3 , 4 0 0 M H z ) 5 : 0 . 8 2 (s, 3 H , M e - 1 4 o r M e - 1 5 ) , 0 . 8 5 (s , 3 H , M e - 1 4 o r M e - 1 5 ) , 1 . 1 5 - 1 . 2 8 ( m , 2 H ) , 1 . 2 9 - 1 . 4 9 ( m , 5 H ) , 1 . 5 1 - 1 . 7 4 ( m , 5 H ) , 1.67 (s , 3 H , M e - 1 3 ) , 1.78 ( d d d , I H , 7 = 1 1 . 7 , 1 1 . 7 , 3 . 3 H z , H - l O a ) , 1 . 9 1 - 2 . 0 4 ( m , I H ) , 2 . 2 0 ( d d , I H , 7 = 1 6 . 5 , 11 .7 H z , H - 1 0 c c ) , 2 . 3 4 - 2 . 5 2 ( m , 3 H ) , 2 . 6 8 ( d d , I H , 7 = 1 6 . 5 , 3 . 3 H z , H - 1 0 6 ) , 4 . 5 9 - 4 . 6 3 ( m , I H , H - 1 2 ) , 4 . 7 1 -4 . 7 4 ( m , I H , H - 1 2 ' ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8: 17 .5 ( - v e ) , 17 .7 ( - v e ) , 1 9 . 0 ( - ve ) , 1 9 . 7 , 2 9 . 8 , 3 5 . 3 , 3 8 . 0 , 3 9 . 1 , 3 9 . 8 , 4 1 . 6 ( - v e ) , 4 3 . 1 , 4 3 . 4 , 4 4 . 3 , 4 6 . 2 , 4 8 . 3 ( - v e ) , 4 9 . 1 ( - v e ) , 1 1 0 . 6 ( C - 1 2 ) , 1 5 0 . 1 ( C - l l ) , 2 1 4 . 9 ( C - 9 ) . E x a c t M a s s c a l c d . f o r C 1 9 H 3 0 O : 2 7 4 . 2 2 9 7 ; f o u n d : 2 7 4 . 2 2 9 4 . 2 4 8 A n a l , c a l c d . f o r C 1 9 H 3 0 O : C 8 3 . 1 5 , H 1 1 . 0 2 ; f o u n d : C 8 3 . 2 4 , H 1 1 . 1 3 . T h e s e c o n d c o m p o u n d that e l u t e d w a s t h e k e t o n e 177. I R ( K B r ) : 3 0 7 1 , 1 7 0 3 , 1 6 4 1 , 1 4 5 5 , 1 3 8 2 , 8 8 3 c m \" 1 . * H n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 8 3 (s, 3 H , M e - 1 4 o r M e - 1 5 ) , 0 . 8 5 (s , 3 H , M e l 4 o r M e - 1 5 ) , 1 . 1 3 - 1 . 7 7 ( m , 1 2 H ) , 1 .64 (s , 3 H , M e - 1 3 ) , 1 . 9 1 - 2 . 0 4 ( m , 2 H ) , 2 . 2 6 - 2 . 5 5 ( m , 5 H ) , 4 . 5 8 - 4 . 6 0 ( m , I H , H - 1 2 ) , 4 . 6 7 - 4 . 6 7 ( m , I H , H - 1 2 ' ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 1 5 . 9 ( - v e ) , 1 7 . 9 ( - v e ) , 1 9 . 3 ( - v e ) , 2 3 . 7 , 3 0 . 1 , 3 5 . 4 , 3 8 . 0 , 3 8 . 3 , 3 8 . 9 , 3 9 . 4 , 4 0 . 0 , 4 3 . 4 , 4 3 . 5 , 4 7 . 5 ( - v e ) , 4 8 . 5 ( - v e ) , 4 9 . 1 ( - v e ) , 1 0 9 . 7 ( C - 1 2 ) , 1 5 0 . 5 ( C - l l ) , 2 1 5 . 6 ( C - 8 ) . E x a c t M a s s c a l c d . f o r C19H30O: 2 7 4 . 2 2 9 7 ; f o u n d : 2 7 4 . 2 2 9 0 . A n a l , c a l c d . f o r C 1 9 H 3 0 O : C 8 3 . 1 5 , H 1 1 . 0 2 ; f o u n d : C 8 3 . 2 5 , H 1 1 . 1 1 . 2 4 9 Preparation of ( l a , 3a/?, 5 a a , 10a/3, 10ba)-l-Isopropenyl-3a,5a-dimethyl-8-trifluoromethylsulphonyloxy-2,3,3a,4,5,5a,9,10,10a,10b-decahydro-l,6A-cyclohepta[g]indene (350) and ( l a , 3a/3, 5aa, 10a/?, 10ba)-l-Isopropenyl-3a,5a-dimethyl-8-trifluoromethylsuIphonyloxy-2,3^3a,4,5,5a,6,7,10a,10b-decahydro-l,10H-cyclohepta[g]indene (351). TfO H ? 1) KHMDS, THF -78 \u00C2\u00B0C to 0 \u00C2\u00B0C 2) HMPA, PhN(S0 2 CF 3 ) 2 0 \u00C2\u00B0C to rt 177 T o a c o l d ( - 78 \u00C2\u00B0C), s t i r r e d s o l u t i o n o f K H M D S 9 6 ( 0 . 8 3 m m o l , 1.3 e q u i v . ) i n d r y T H F ( 8 . 3 m L ) w a s a d d e d ( v i a T e f l o n \u00C2\u00AE c a n n u l a ) a s o l u t i o n o f t h e k e t o n e 177 ( 1 7 6 rag, 0 . 6 4 0 m m o l , 1.0 e q u i v . ) i n d r y T H F (3 m L ) . T h e m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 15 m i n a n d t h e n w a s w a r m e d t o 0 \u00C2\u00B0C f o r 2 h 15 m i n . S o l i d 7 V - p h e n y l t r i f l u o r o m e t h a n e s u l f o n i m i d e (4 .57 g , 12 .8 m m o l , 2 0 e q u i v . ) w a s a d d e d a n d t h e n t h e r e a c t i o n m i x t u r e w a s w a r m e d to r o o m t e m p e r a t u r e a n d s t i r r e d f o r 3 h 3 0 m i n . D i e t h y l e t h e r ( 1 0 m L ) a n d s a t u r a t e d a q u e o u s N a H C 0 3 (5 m L ) w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 1 5 m L ) a n d the c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 3 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e s o l i d r e s i d u e w a s t r i t u r a t e d w i t h p e t r o l e u m e t h e r a n d t h e r e s u l t a n t m i x t u r e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 3 0 g t i c s i l i c a g e l , 5 .7 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 3 . 5 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e n o n - p o l a r f r a c t i o n s , a s o l i d m i x t u r e . T h i s m a t e r i a l w a s r e s u b j e c t e d t o f l a s h c h r o m a t o g r a p h y ( 2 0 g t i c s i l i c a g e l , 1 9 9 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , a m i x t u r e o f t h e v i n y l t r i f l a t e 350 a n d t h e v i n y l t r i f l a t e 351 as a c o l o u r l e s s o i l ( 1 9 2 m g , 7 4 % ) . T h e * H n m r s p e c t r o s c o p i c a n a l y s i s o f t h i s o i l i n d i c a t e d a m i x t u r e o f t h e v i n y l t r i f l a t e 350 a n d t h e v i n y l t r i f l a t e 351 i n a r a t i o o f 1 1 : 1 , r e s p e c t i v e l y . W h i l e s e p a r a t i o n o f c o m p o u n d s 350 a n d 351 w a s e x t r e m e l y d i f f i c u l t , a s m a l l a m o u n t o f t h e d e s i r e d v i n y l t r i f l a t e 350, w h i c h e l u t e d f i r s t , c o u l d b e s e p a r a t e d b y f l a s h c h r o m a t o g r a p h y ( t i c s i l i c a g e l , n - p e n t a n e ) . A s a m p l e c h r o m a t o g r a p h i c r u n s h o w e d tha t a 1 1 : 1 r a t i o o f a m i x t u r e o f t h e v i n y l t r i f l a t e 350 a n d t h e v i n y l t r i f l a t e 351 ( 2 1 4 m g , c o m b i n e d ) a f f o r d e d , a f t e r r e p e a t e d c h r o m a t o g r a p h y o f t h e m i x e d f r a c t i o n s , c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e v i n y l t r i f l a t e 350 ( 1 5 0 m g , 7 0 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 0 7 4 , 1 6 8 9 , 1 6 4 1 , 1 4 5 6 , 1 3 8 5 , 1 2 4 4 , 1 2 0 7 , 1 1 4 3 , 1 0 6 4 , 1 0 4 2 , 9 5 0 , 9 1 0 , 8 1 1 , 6 1 7 , 5 8 4 c m \" 1 . ! H n m r (CDCI3, 4 0 0 M H z ) 5 : 0 . 8 3 (s, 3 H , M e - 1 4 o r M e - 1 5 ) , 0 . 8 8 (s , 3 H , M e - 1 4 o r M e - 1 5 ) , 1 . 1 3 - 1 . 6 2 ( m , 1 0 H ) , 1.65 (s, 3 H , M e - 1 3 ) , 1 . 6 9 - 1 . 8 0 ( m , I H ) , 1.86 ( d d , I H , 7 = 1 4 . 5 , 1 0 . 0 H z , H - 6 ) , 1 . 9 2 - 2 . 0 9 ( m , 2 H , o n e o f w h i c h i s H - 6 ' ) , 2 . 2 2 - 2 . 3 0 ( d m , I H , 7 f o r d = 16.1 H z ) , 2 . 3 8 (br d d d , I H , 7= 1 0 . 4 , 1 0 . 4 , 5 .1 H z , H - l ) , 2 . 5 6 ( d d o f m , I H , 7 f o r d d = 1 4 . 4 , 1 4 . 5 H z ) , 4 . 5 6 - 4 . 5 9 ( m , I H , H - 1 2 ) , 4 . 6 5 - 4 . 6 7 ( m , I H , H - 1 2 ' ) , 5 . 6 4 - 5 . 7 0 ( m , I H , H - 7 ) . I n h o m o n u c l e a r ( i H ^ H ) d e c o u p l i n g e x p e r i m e n t s , i r r a d i a t i o n o f the m u l t i p l e t at 8 5 . 6 4 - 5 . 7 0 ( H - 7 ) , c a u s e d t h e d d at 8 1 .86 (7 = 1 4 . 5 , 1 0 . 0 H z , H - 6 ) t o c o l l a p s e i n t o a d o u b l e t (7 = 14 .5 H z ) , a n d r e s u l t e d i n t h e a p p e a r a n c e o f t h e s i g n a l f o r t h e c o u p l i n g p a r t n e r o f H - 6 , as a b r o a d d o u b l e t (7 = 14 .5 H z ) , at 8 2 . 0 5 ( H - 6 ' ) . 2 5 1 ! 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 5 : 17 .1 ( - v e ) , 1 7 . 9 ( - v e ) , 1 9 . 4 ( - v e ) , 2 2 . 5 , 3 0 . 3 , 3 3 . 2 , 3 5 . 5 , 3 6 . 2 , 3 8 . 7 , 4 0 . 0 , 4 0 . 3 , 4 3 . 4 , 4 7 . 5 ( - v e ) , 4 9 . 0 ( - v e ) , 5 0 . 2 ( - v e ) , 1 0 9 . 5 ( C - 1 2 ) , 1 1 8 . 5 ( d d d , \u00C2\u00A3 F 3 , J = 3 2 0 , 3 2 0 , 3 2 0 H z ) , 1 1 9 . 6 ( - v e , C - 7 ) , 1 5 0 . 7 ( C - 8 o r C - l 1) , 1 5 2 . 8 ( C - 8 o r C - l 1). E x a c t M a s s c a l c d . f o r C20H29F3O3S: 4 0 6 . 1 7 9 0 ; f o u n d : 4 0 6 . 1 7 9 6 . A n a l , c a l c d . f o r C20H29F3O3S: C 5 9 . 0 9 , H 7 . 1 9 ; f o u n d : C 5 9 . 4 4 , H 7 . 2 3 . 2 5 2 Preparation of (3R*, 4R*, 5R*, 65*, 9/?*)-cyatha-12,18-diene (64). T f O 15 Me 2 CuL i , Et 2 0 -10 \u00C2\u00B0C 350 64 T o a c o l d ( - 1 0 \u00C2\u00B0C) , s t i r r e d s u s p e n s i o n o f CuBr\u00C2\u00BBMe2S ( 1 9 0 m g , 0 . 9 2 3 m m o l , 2 0 e q u i v . ) i n d r y d i e t h y l e t h e r (3 .1 m L ) w a s a d d e d M e L i ( - 1 . 6 M i n d i e t h y l e the r ) d r o p w i s e u n t i l t h e y e l l o w c o l o u r d i s a p p e a r e d , g i v i n g a c l e a r c o l o u r l e s s s o l u t i o n . A s o l u t i o n o f the v i n y l t r i f l a t e 350 ( 1 9 . 2 m g , 0 . 4 5 8 m m o l , 1.0 e q u i v . ) i n d r y d i e t h y l e t h e r (2 m L ) w a s a d d e d ( v i a Te f lon\u00C2\u00AE c a n n u l a ) a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 1 0 \u00C2\u00B0C f o r 1 h . A q u e o u s N H 4 C I - N H 4 O H ( p H 8 , 5 m L ) w a s a d d e d , t h e m i x t u r e w a s o p e n e d to t h e a t m o s p h e r e , a n d w a s s t i r r e d u n t i l t h e a q u e o u s l a y e r w a s a d e e p b l u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 1 2 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 2 5 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (1 .5 g t i c s i l i c a g e l , 9 9 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 1.5 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , (3R*, 4R*, 5R*, 6 5 * , 9 / ? * ) - c y a t h a - 1 2 , 1 8 - d i e n e (64) ( 1 2 . 6 m g , 9 8 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 0 7 1 , 2 9 2 1 , 1 7 7 1 , 1 6 4 1 , 1 4 5 5 , 1 3 8 0 , 8 8 3 , 8 3 4 c m \" 1 . ] H n m r (CDCI3,400 M H z ) 5: 0 . 7 7 (s , 3 H , M e - 1 6 o r M e - 1 7 ) , 0 . 8 3 ( s , 3 H , M e - 1 6 o r M e - 1 7 ) , 0 . 8 6 - 1 . 0 4 ( m , 2 H ) , 1 .09 ( d d d , 1 H , J = 1 3 . 1 , 3 . 3 , 3 . 3 H z ) , 1 . 1 3 - 1 . 6 3 ( m , 8 H ) , 1 .66 (d , 3 H , J = 0 . 5 H z , M e - 1 5 o r M e - 2 0 ) , 1 .68 ( b r s , 3 H , M e - 1 5 o r M e - 2 0 ) , 1 . 6 7 - 1 . 7 3 ( m , 1 H , H - 1 4 ) , 1 .86 ( d d d d , I H , 7= 1 4 . 5 , 6 . 7 , 1 .5, 1.5 H z , H - l l ) , 1 . 9 1 - 2 . 0 5 ( m , 2 H , o n e o f w h i c h i s H - 1 4 ' ) , 2 . 1 3 (b r d d , I H , 7 = 13 .4 . 1 3 . 4 H z ) , 2 . 3 8 ( d d d , I H , 7 = 1 0 . 9 , 1 0 . 9 , 5 . 4 H z , H - 3 ) , 4 . 5 4 - 4 . 5 7 ( m , I H , H - 1 9 ) , 4 . 6 5 ( b r d d , I H , 7 = 1.4, 0 . 5 H z , H - 1 9 ' ) , 5 . 2 9 - 5 . 3 6 ( m , I H , H - 1 3 ) . I n h o m o n u c l e a r ( 1 H - 1 H ) d e c o u p l i n g e x p e r i m e n t s , i r r a d i a t i o n o f t h e m u l t i p l e t at 8 5 . 2 9 - 5 . 3 6 ( H - 1 3 ) s h o w e d i t t o b e c o u p l e d to the m u l t i p l e t at 8 1 . 6 7 - 1 . 7 3 ( H - 1 4 ) a n d to a s i g n a l that w a s p a r t o f t h e m u l t i p l e t at 8 1 . 9 1 - 2 . 0 5 ( H - 1 4 ' ) b y s i m p l i f i c a t i o n a n d s h a r p e n i n g o f t h e i r m u l t i p l e t s t r u c t u r e s . 1 4 1 I r r a d i a t i o n o f the s i g n a l at 8 5 . 2 9 - 5 . 3 6 ( H - 1 3 ) a l s o r e s u l t e d i n t h e s i m p l i f i c a t i o n o f the d d d d at 8 1.86 (7 = 1 4 . 5 , 6 . 7 , 1.5, 1.5 H z , H - l l ) i n t o a d d d (7= 1 4 . 5 , 6 . 7 , 1 . 5 H z ) . 1 3 C n m r ( C D C 1 3 , 7 5 . 3 M H z ) 8: 1 7 . 2 ( - ve ) , 18.1 ( - ve ) , 19 .7 ( - v e ) , 2 4 . 1 , 2 5 . 4 ( - v e ) , 2 9 . 7 , 3 0 . 5 , 3 4 . 3 , 3 5 . 8 , 3 6 . 4 , 3 8 . 7 , 4 0 . 3 , 4 3 . 5 , 4 7 . 3 ( - v e ) , 4 9 . 1 ( - v e ) , 5 1 . 5 ( - v e ) , 1 0 8 . 9 ( C - 1 9 ) , 122 .7 ( - ve , C - 1 3 ) , 1 4 0 . 7 ( C - 1 2 ) , 1 5 1 . 4 ( C - 1 8 ) . E x a c t M a s s c a l c d . f o r C20H32: 2 7 2 . 2 5 0 4 ; f o u n d : 2 7 2 . 2 5 0 3 . A n a l , c a l c d . f o r C20H32: C 8 8 . 1 6 , H 1 1 . 8 4 ; f o u n d : C 8 8 . 1 4 , H 1 2 . 0 0 . T h e r a c e m i c s y n t h e t i c p r o d u c t e x h i b i t e d i n f r a r e d a n d * H n m r s p e c t r a l d a t a i d e n t i c a l 3 9 w i t h t h o s e d e r i v e d f r o m the n a t u r a l l y o c c u r r i n g ( - ) - ( 3 / ? , 4R, 5R, 6 5 , 9 / ? ) - c y a t h a - 1 2 , 1 8 - d i e n e ( see T a b l e 1 5 , p a g e 1 4 4 ) . 2 3 < 1 4 0 T h e * H n m r s p e c t r u m o f t h e s y n t h e t i c (\u00C2\u00B1) -64 i s s h o w n o n p a g e 145 ( F i g u r e 8 ) . 3.3. Bifunctional Reagent Mediated Cyclohexenone Annulation Methodology. 2 5 4 Preparation of 4-(Trimethylgermyl)but-3-yn-l-ol (206) and l-(Trimethylgermyl)-4-(trimethylsiloxy)but-l-yne (205). H O 203 T M S C I THF, E t 3 N T M S O 0 \u00C2\u00B0C to rt 204 1) MeLi, THF H Q -78 \u00C2\u00B0C 2) M e 3 G e B r THF, -78 \u00C2\u00B0C toO\u00C2\u00B0C T M S O , G e M e 3 206 G e M e 3 205 T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f f r e s h l y d i s t i l l e d b u t - 3 - y n - l - o l (203) (2 .08 g , 2 9 . 6 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 9 9 m L ) w a s a d d e d d r y t r i e t h y l a m i n e ( 4 .9 m L , 3 9 m m o l , 1.3 e q u i v . ) a n d d r y t r i m e t h y l s i l y l c h l o r i d e ( 5 . 4 m L , 3 9 m m o l , 1.3 e q u i v . ) , w h i c h g a v e a t h i c k w h i t e m i x t u r e . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 1 h 2 0 m i n , w a r m e d t o r o o m t e m p e r a t u r e f o r 4 0 m i n , a n d t h e n w a s c o o l e d t o 0 \u00C2\u00B0C. S a t u r a t e d a q u e o u s N a H C 0 3 ( 2 5 m L ) a n d d i e t h y l e t h e r ( 2 5 m L ) w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h i c e - c o l d d i e t h y l e t h e r (3 x 2 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h i c e - c o l d b r i n e (3 x 4 0 m L , 1 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e v o l a t i l e , c r u d e p r o d u c t w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 3 0 - 6 0 \" C / 1 5 T o r r ) t o a f f o r d 4 - ( t r i m e t h y l s i l o x y ) b u t - l - y n e (204) as a c o l o u r l e s s o i l . T o a c o l d ( - 78 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f the 4 - ( t r i m e t h y l s i l o x y ) b u t - l - y n e (204) p r e p a r e d as d e s c r i b e d a b o v e , i n d r y T H F (99 m L ) w a s a d d e d M e L i ( 2 5 m L , 3 5 m m o l , 1.2 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 2 h a n d t h e n f r e s h l y d i s t i l l e d t r i m e t h y l g e r m a n i u m b r o m i d e ( 7 . 8 8 g , 3 9 . 9 m m o l , 1.3 e q u i v . ) w a s a d d e d n e a t ( v i a Tef lon\u00C2\u00AE c a n n u l a ) . T h e m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 1 h a n d t h e n w a s w a r m e d to 0 \u00C2\u00B0C f o r 5 0 m i n . S a t u r a t e d a q u e o u s N a H C C \" 3 ( 4 0 m L ) a n d d i e t h y l e t h e r ( 4 0 m L ) w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 4 0 m L ) a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (2 x 8 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 2 0 0 g t i c s i l i c a g e l , 2 . 3 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 7 c m c o l u m n ) a f f o r d e d t w o f r a c t i o n s . T h e f i r s t c o m p o u n d that e l u t e d w a s t h e d e s i r e d 1 - ( t r i m e t h y l g e r m y l ) -4 - ( t r i m e t h y l s i l o x y ) b u t - l - y n e (205). C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s , f o l l o w e d b y d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 1 2 0 - 1 2 5 \u00C2\u00B0C/12 T o r r ) o f the o i l t h u s o b t a i n e d , a f f o r d e d the a c e t y l e n e 205 ( 4 . 38 g , 5 7 % ) as a c o l o u r l e s s o i l . I R (neat ) : 2 1 7 6 , 1 2 5 2 , 1 1 0 3 , 9 1 7 , 8 7 8 , 8 4 4 , 6 0 9 c m \" 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 11 (s , 9 H , SiMe.3_) , 0 . 3 0 (s, 9 H , G e M e 3 _ ) , 2 . 4 3 ( d d , 2 H , J = 7 . 2 , 7 .2 H z , H - 3 ) , 3 . 6 7 ( d d , 2 H , J = 7 . 2 , 7 .2 H z , H - 4 ) . 13C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : - 0 . 4 ( - v e ) , - 0 .1 ( - v e ) , 2 4 . 1 ( C - 3 ) , 6 1 . 5 ( C - 4 ) , 8 5 . 4 , 1 0 2 . 4 . E x a c t M a s s c a l c d . f o r C i o H 2 2 7 4 G e O S i : 2 6 0 . 0 6 5 2 ; f o u n d : 2 6 0 . 0 6 5 8 . A n a l , c a l c d . f o r C i 0 H 2 2 G e O S i : C 4 6 . 3 8 , H 8 . 5 6 ; f o u n d : C 4 6 . 5 3 , H 8 . 6 1 . T h e s e c o n d c o m p o u n d t h a t e l u t e d w a s 4 - ( t r i m e t h y l g e r m y l ) b u t - 3 - y n - l - o l ( 2 0 6 ) . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s , f o l l o w e d b y d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 1 0 5 -1 1 5 \u00C2\u00B0 C / 1 2 T o r r ) o f t h e o i l t h u s o b t a i n e d , a f f o r d e d t h e a c e t y l e n e 206 ( 1 . 4 3 g , 2 6 % ) as a c o l o u r l e s s o i l . 2 5 6 I R (neat ) : 3 3 3 9 (br ) , 2 1 7 4 , 1 2 4 1 , 1 0 5 0 , 1 0 2 4 , 8 3 4 , 7 6 9 , 6 0 9 c m \" ! . * H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 .31 (s, 9 H , GeMe_3_), 1 -80 ( d d , I H , J = 6 . 3 , 6 . 3 H z , - O H ) , 2 . 4 9 (dd , 2 H , J = 6 . 3 , 6 . 3 H z , H - 2 ) , 3 . 6 8 ( d d d , 2 H , J = 6 . 3 , 6 . 3 , 6 .3 H z , H - l ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 0 .1 ( - ve , GeM \u00C2\u00A3 3 _ ) , 2 4 . 2 ( C - 2 ) , 6 1 . 0 ( C - l ) , 8 6 . 7 , 1 0 1 . 8 . E x a c t M a s s c a l c d . f o r C 7 H i 4 7 4 G e O : 1 8 8 . 0 2 5 7 ; f o u n d : 1 8 8 . 0 2 6 0 . A n a l , c a l c d . f o r C 7 H i 4 G e O : C 4 5 . 0 1 , H 7 . 5 6 ; f o u n d : C 4 5 . 2 1 , H 7 . 5 4 . Preparation of (Z)-4-(Trimethylgermyl)but-3-en-l-oI (207). G e M e 3 T M S O ' Et 20-hexane, rt H O G e M e 3 205 207 T o a s t i r r e d s o l u t i o n o f l - ( t r i m e t h y l g e r m y l ) - 4 - ( t r i m e t h y l s i l o x y ) b u t - l - y n e (205) ( 4 . 6 3 g , 1 7 . 9 m m o l , 1.0 e q u i v . ) i n d r y d i e t h y l e t h e r ( 3 0 m L ) a n d d r y n - h e x a n e ( 6 0 m L ) , i m m e r s e d i n a r o o m t e m p e r a t u r e w a t e r b a t h , w a s a d d e d d i i s o b u t y l a l u m i n u m h y d r i d e ( 9 0 m L , 1.0 M i n h e x a n e , 9 0 m m o l , 5 . 0 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 1 h 15 m i n a n d t h e n w a s c o o l e d t o 0 \u00C2\u00B0C b e f o r e a d d i n g a q u e o u s NH4CI - N t i i O H ( p H 8 , 7 m L ) . T h e m i x t u r e w a s w a r m e d to r o o m t e m p e r a t u r e a n d w a s s t i r r e d f o r 3 0 m i n to g i v e a g e l a t i n o u s p r e c i p i t a t e . T h e m i x t u r e w a s t r a n s f e r r e d t o a 5 0 0 m L e r l e n m e y e r f l a s k w i t h d i e t h y l e t h e r . A f t e r f u r t h e r s t i r r i n g ( - 3 0 m i n ) , t h e m i x t u r e w a s d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d f i l t e r e d t h r o u g h Celite\u00C2\u00AE (5 g ) . T h e c o l l e c t e d m a t e r i a l w a s w a s h e d 2 5 7 w i t h d i e t h y l e t h e r ( 9 0 0 m L ) a n d t h e f i l t r a t e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 1 0 8 g t i c s i l i c a g e l , 1 .5 :1 p e t r o l e u m e t h e r - d i e t h y l e the r , 5 .5 c m c o l u m n ) to a f f o r d , a f t e r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e a l c o h o l 207 ( 3 . 0 0 m g , 8 9 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 3 3 8 (br ) , 1 6 1 0 , 1 2 3 7 , 1 0 4 8 , 8 2 8 c m \" 1 . * H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 3 8 (s, 9 H , G e M e ^ ) , 1 .32 ( b r d d , I H , 7 = 6 , 6 H z , - O H ) , 2 . 3 6 ( d d d d , 2 H , 7 = 7 , 6 , 6 , 1 H z , H - 2 ) , 3 . 6 7 ( b r d d d , 2 H , 7 = 6 , 6 , 6 H z , H - l ) , 5 . 8 2 ( d d d , I H , 7 = 1 2 . 9 , 1, 1 H z , H - 4 ) , 6 . 2 6 ( d d d , I H , 7 = 1 2 . 9 , 7 , 7 H z , H - 3 ) . D e t a i l e d * H n m r d a t a (CDCI3), d e r i v e d f r o m N O E e x p e r i m e n t s , a re g i v e n i n Table 27. 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 0 . 3 ( - v e , G e M e ^ ) , 3 6 . 7 ( C - 2 ) , 6 2 . 1 ( C - l ) , 1 3 4 . 4 ( - v e ) , 1 4 1 . 9 ( -ve) . E x a c t M a s s c a l c d . f o r C 6 H i 3 7 4 G e O ( M - M e ) + : 1 7 5 . 0 1 7 8 ; f o u n d : 1 7 5 . 0 1 7 3 . A n a l , c a l c d . f o r C 7 H i 6 G e O : C 4 4 . 5 3 , H 8 . 5 4 ; f o u n d : C 4 4 . 3 8 , H 8 . 4 6 . 2 5 8 Table 27: lH n m r ( 4 0 0 M H z , C D C 1 3 ) D a t a f o r ( Z ) - 4 - ( T r i m e t h y l g e r m y l ) b u t - 3 - e n - l - o l (207): N O E E x p e r i m e n t s . G e M e 3 207 I r r a d i a t e d S i g n a l N O E A s s i g n m e n t i H n m r ( 4 0 0 M H z ) 8 ( m u l t i p l i c i t y , 7 ( H z ) ) C o r r e l a t i o n s a G e M e 3 0 . 3 8 (s) H - 4 H - 3 6 . 2 6 ( d d d , 7 = 1 2 . 9 , 7 , 7 ) H - 2 , H - 4 H - 4 5 . 8 2 ( d d d , 7 = 1 2 . 9 , 1 , 1 ) G e M e 3 , H - 3 a-Only the NOE data that could be unambiguously assigned are recorded. Preparation of (Z)-4-Iodo-l-(trimethylgermyl)but-l-ene (202). / \ / = \ Ph3P\u00C2\u00BBl2, imidazole <*. J = \ H O V G e M e 3 C H 3 C N - E t 2 0 1 ^ G e M e 3 0 \u00C2\u00B0C to rt 207 202 T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f t r i p h e n y l p h o s p h i n e ( 8 1 6 m g , 3 . 1 1 m m o l , 4 . 0 e q u i v . ) a n d i m i d a z o l e ( 2 1 1 m g , 3 . 0 9 m m o l , 4 . 0 e q u i v . ) i n d r y d i e t h y l e t h e r ( 5 .8 m L ) a n d d r y a c e t o n i t r i l e ( 1 . 9 m L ) w a s a d d e d i o d i n e ( 3 9 8 m g , 3 . 1 3 m m o l , 4 . 0 e q u i v . ) , w h i c h w a s d i v i d e d a n d a d d e d i n a p p r o x i m a t e l y f o u r e q u a l p o r t i o n s . T h e r e a c t i o n m i x t u r e w a s v i g o r o u s l y s t i r r e d a f te r e a c h a d d i t i o n o f i o d i n e to e n s u r e that a l l the i o d i n e h a d r e a c t e d . T h e m i x t u r e w a s w a r m e d to r o o m t e m p e r a t u r e a n d s t i r r e d f o r 15 m i n b e f o r e c o o l i n g to 0 \u00C2\u00B0C. A s o l u t i o n o f ( Z ) -4 - ( t r i m e t h y l g e r m y l ) b u t - 3 - e n - l - o l (207) i n d r y E t 2 0 ( 0 . 5 m L ) w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a n d the r e a c t i o n m i x t u r e w a s a l l o w e d to w a r m s l o w l y to r o o m t e m p e r a t u r e o v e r 2 h 2 5 m i n . S a t u r a t e d a q u e o u s Na2S2C\u00C2\u00BB3 (5 m L ) a n d p e t r o l e u m e t h e r (5 m L ) w e r e a d d e d , the l a y e r s w e r e s e p a r a t e d , a n d the a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 1 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (2 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e o i l - s o l i d m i x t u r e t h u s o b t a i n e d w a s d i s s o l v e d i n a m i n i m a l a m o u n t o f CH2CI2, a n d p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 9 g f l a s h s i l i c a g e l , p e t r o l e u m e t h e r , 1.5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d , a n d t h e a c q u i r e d o i l w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 8 0 -9 0 \" C / 1 2 T o r r ) t o a f f o r d the a l k e n y l g e r m a n e 202 ( 171 m g , 7 4 % ) as a c o l o u r l e s s o i l . I R (neat ) : 1 6 0 9 , 1 2 3 7 , 1 1 6 8 , 8 2 8 , 6 0 0 , 5 7 1 c m \" 1 . ! H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 3 5 (s, 9 H , G e M e ^ ) , 2 . 6 4 ( d d d d , 2 H , J = 7 . 3 , 7 . 3 , 7 . 3 , 1.1 H z , H - 3 ) , 3 . 1 2 ( d d , 2 H , J = 7 . 3 , 7 . 3 H z , H - 4 ) , 5 . 8 2 ( d d d , 1 H , J = 1 2 . 8 , 1 . 1 , 1.1 H z , H - 1 ) , 6 . 1 8 ( d d d , 1 H , J = 1 2 . 8 , 7 . 3 , 7 .3 H z , H - 2 ) . n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 0 . 3 ( - ve , G e M e 3 _ ) , 4 . 7 ( C - 3 ) , 3 7 . 2 ( C - 4 ) , 1 3 4 . 0 ( - ve ) , 144 .1 ( -ve ) . E x a c t M a s s c a l c d . f o r C 6 H i 2 7 4 G e I ( M - M e ) + : 2 8 4 . 9 1 9 6 ; f o u n d : 2 8 4 . 9 1 9 0 . A n a l , c a l c d . f o r C 7 H i 5 G e I : C 2 8 . 1 5 , H 5 . 0 6 ; f o u n d : C 2 8 . 2 7 , H 4 . 9 0 . Preparation of DiIithio(tributylstannyI)(butyl)(cyano)cuprate (250). 2 6 0 C u C N A > B U U \u00E2\u0080\u00A2 B u 2 C u ( C N ) L i 2 H S n B U 3 \u00E2\u0080\u00A2 Bu 3 Sn(Bu)Cu(CN)L i 2 THF, -78 \u00C2\u00B0C 403 250 T o a c o l d ( - 78 \u00C2\u00B0C), s t i r r e d s u s p e n s i o n o f C u C N ( 1 . 7 4 g , 1 9 . 4 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 6 5 m L ) w a s a d d e d , s l o w l y , n - B u L i ( 2 6 . 5 m L , 1 . 4 9 M i n h e x a n e s , 3 7 . 5 m m o l , 2 . 0 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 2 - 3 m i n t o g i v e a c l e a r , p a l e y e l l o w s o l u t i o n o f t h e i n t e r m e d i a t e c u p r a t e 403. F r e s h l y d i s t i l l e d B u 3 S n H ( 1 1 . 4 g , 3 9 . 2 m m o l , 2 . 0 e q u i v . ) w a s a d d e d n e a t ( v i a Tef lon\u00C2\u00AE c a n n u l a ) , a l l o w i n g f o r t h e s a f e v e n t i n g o f t h e h y d r o g e n g a s b e i n g f o r m e d . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 15 m i n to g i v e a c l e a r , b r i g h t y e l l o w s o l u t i o n o f t h e c u p r a t e r e a g e n t 250 a n d w a s u s e d i m m e d i a t e l y . Preparation of (Z)-4-(Tri-\u00C2\u00AB-butylstannyI)but-3-en-l-ol (252).92 1 3__4 Bu 3 Sn(Bu)Cu(CN)L i 2 1 ) ~ ~ . THF , -78 \u00C2\u00B0 C \u00E2\u0080\u0094 ^ H 0 ^ / KSnBu3 2) A \u00E2\u0080\u00A2 -78 \u00C2\u00B0C 3) N H 4 C I - N H 4 O H , H 2 0 250 252 A s t i r r e d s o l u t i o n o f t h e c u p r a t e r e a g e n t 250 ( 1 9 . 4 m m o l , 1 .0 e q u i v . ) , p r e p a r e d as d e s c r i b e d a b o v e , w a s a l l o w e d to a b s o r b d r y a c e t y l e n e 1 7 5 ( 5 5 0 m L , 2 3 . 1 m m o l , 1.2 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 3 0 m i n . E t h y l e n e o x i d e ( e x c e s s ) , w h i c h w a s d r i e d b y p a s s i n g i t t h r o u g h a c a l c i u m c h l o r i d e d r y i n g t u b e , w a s b u b b l e d t h r o u g h t h e r e a c t i o n m i x t u r e . T h e m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 3 5 m i n a n d t h e n w a s w a r m e d to 0 \u00C2\u00B0C f o r 1 h 15 m i n b e f o r e a d d i n g a q u e o u s N H 4 C I - N H 4 O H ( p H 8 - 9 , 5 0 m L ) a n d d i e t h y l e t h e r ( 5 0 m L ) . T h e m i x t u r e w a s o p e n e d to the a t m o s p h e r e a n d w a s s t i r r e d v i g o r o u s l y f o r 1 h , a t 2 6 1 w h i c h p o i n t t h e a q u e o u s l a y e r w a s a d e e p b l u e . T h e m i x t u r e w a s f i l t e r e d t h r o u g h l o o s e l y p a c k e d g l a s s w o o l i n o r d e r to r e m o v e the s o l i d r e s i d u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 1 5 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 2 0 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 2 0 0 g f l a s h s i l i c a g e l , 4 .6 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 5 . 5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d , a n d the o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 6 0 - 1 7 0 \" C / 0 . 1 T o r r ) t o a f f o r d t h e a l k e n y l s t a n n a n e 252 ( 5 . 9 7 g , 8 5 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 3 1 1 ( b r ) , 1 5 9 9 , 1 4 6 4 , 1 0 4 7 , 8 7 5 , 7 6 9 , 6 5 4 c m \" 1 . lU n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 8 1 - 0 . 9 5 ( m , 1 5 H ) , 1 . 2 4 - 1 . 3 5 ( m , 6 H ) , 1 . 4 3 - 1 . 5 6 ( m , 7 H ) , 2 . 3 0 ( d d d d , 2 H , J = 6 . 8 , 6 . 3 , 6 . 3 , 1.0 H z , H - 2 ) , 3 . 6 6 ( d d d , 2 H , J = 6 . 3 , 6 . 3 , 6 . 3 H z ; u p o n t r e a t m e n t w i t h D2O, t h i s s i g n a l c o l l a p s e s to a d d , J = 6 . 3 , 6 . 3 H z , H - l ) , 5 . 9 8 ( d d , I H , J = 12 .6 , 1.0 H z , 2 J S n - H = 6 8 H z , H - 4 ) , 6 . 4 9 ( d d d , I H , J = 12 .6 , 6 . 8 , 6 .8 H z , 3 j S n . H = 1 3 6 H z , H - 3 ) . 1 3 C n m r (CDCI3, 5 0 . 3 M H z ) 8 : 10 .2 , 13 .6 ( - v e , CH3 f r o m b u t y l g r o u p s ) , 2 7 . 3 , 2 9 . 4 , 4 0 . 1 ( C - 3 ) , 6 2 . 1 ( C - 4 ) , 132 .1 ( - v e , C - l ) , 1 4 4 . 5 ( - v e , C - 2 ) . E x a c t M a s s c a l c d . f o r C i 2 H 2 5 O 1 2 0 S n ( M - B u ) + : 3 0 5 . 0 9 2 6 ; f o u n d : 3 0 5 . 0 9 2 7 . A n a l , c a l c d . f o r C i 6 H 3 4 O S n : C 5 3 . 2 1 , H 9 . 4 9 ; f o u n d : C 5 3 . 1 0 , H 9 . 5 7 . 2 6 2 Preparation of (Z)-4-Iodo-l-(tributyIstannyl)but-l-ene (253). H O SnBu3 Ph3P\u00C2\u00BBl2, imidazole C H 3 C N - E t 2 0 0\u00C2\u00B0C SnBu3 252 253 T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f t r i p h e n y l p h o s p h i n e ( 1 . 3 7 g , 5 . 2 1 m m o l , 1.3 e q u i v . ) a n d i m i d a z o l e ( 7 1 0 m g , 1 0 . 4 m m o l , 2 . 6 e q u i v . ) i n d r y d i e t h y l e t h e r ( 3 0 m L ) a n d d r y a c e t o n i t r i l e ( 1 5 m L ) w a s a d d e d i o d i n e ( 1 . 3 0 g , 5 . 1 4 m m o l , 1.3 e q u i v . ) , w h i c h w a s d i v i d e d a n d a d d e d i n a p p r o x i m a t e l y f o u r e q u a l p o r t i o n s . T h e r e a c t i o n m i x t u r e w a s v i g o r o u s l y s t i r r e d a f te r e a c h a d d i t i o n o f i o d i n e to e n s u r e that a l l t h e i o d i n e h a d r e a c t e d . A s o l u t i o n o f ( Z ) - 4 - ( t r i - n - b u t y l s t a n n y l ) b u t - 3 - e n - l - o l (252) ( 1 . 4 5 g , 4 . 0 1 m m o l , 1 .0 e q u i v . ) i n d r y d i e t h y l e t h e r (5 m L ) w a s a d d e d ( v i a Te f lon\u00C2\u00AE c a n n u l a ) a n d t h e m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 1 h 3 0 m i n . T h e r e a c t i o n m i x t u r e w a s t r e a t e d w i t h s a t u r a t e d a q u e o u s N a H C 0 3 , w a r m e d to r o o m t e m p e r a t u r e , a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r ( 3 x 5 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 1 0 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e o i l - s o l i d m i x t u r e t h u s o b t a i n e d w a s d i s s o l v e d i n a m i n i m a l a m o u n t o f CH2CI2, a n d p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 1 2 0 g f l a s h s i l i c a g e l , p e t r o l e u m e t h e r , 5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e a c q u i r e d o i l w a s r e - c h r o m a t o g r a p h e d ( 6 0 g f l a s h s i l i c a g e l , p e t r o l e u m e t h e r , 4 c m c o l u m n ) . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) a f f o r d e d ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t -1 -ene (253) ( 1 . 7 5 g , 9 3 % ) as a c o l o u r l e s s o i l . I R (neat ) : 1 5 9 6 , 1 4 6 3 , 1 2 4 6 , 1 1 6 6 , 1 0 7 2 , 5 9 8 c n r * . 2 6 3 lH n m r ( C D C I 3 , 4 0 0 M H z ) 5 : 0 . 8 0 - 1 . 0 0 ( m , 1 5 H ) , 1 . 2 3 - 1 . 3 5 ( m , 6 H ) , 1 . 4 3 - 1 . 5 5 ( m , 6 H ) , 2 . 5 7 ( d d d d , 2 H , J = 7 . 4 , 7 . 4 , 6 . 9 , 1.0 H z , H - 3 ) , 3 . 1 2 ( d d , 2 H , J = 7 . 4 , 7 . 4 H z , H - 4 ) , 6 . 0 0 ( d d , I H , J = 1 2 . 5 , 1.0 H z , 2 J s n - H = 6 6 H z , H - l ) , 6 . 41 ( d d d , I H , J = 1 2 . 5 , 6 . 9 , 6 .9 H z , 3 7 S n - H = 1 3 3 H z , H - 2 ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 4 . 5 , 1 0 . 2 , 13 .7 ( - v e , \u00C2\u00A3 H 3 f r o m b u t y l g r o u p s ) , 2 7 . 3 , 2 9 . 1 , 4 0 . 6 , 1 3 1 . 9 ( - v e , C - l ) , 1 4 6 . 5 ( - ve , C - 2 ) . E x a c t M a s s c a l c d . f o r C i 2 H 2 4 l 1 2 0 S n ( M - B u ) + : 4 1 4 . 9 9 4 5 ; f o u n d : 4 1 4 . 9 9 4 3 . A n a l , c a l c d . f o r C i 6 H 3 3 l S n : C 4 0 . 8 0 , H 7 . 0 6 ; f o u n d : C 4 0 . 6 3 , H 7 . 0 9 . 2 6 4 3.3.1. Preparation of N,N-Dirnethylhydrazone Substrates. N(Me)2 N N N(Me)2 362 360 T h e p r e p a r a t i o n o f 3 , 3 - d i m e t h y l - l , 5 - d i o x a s p i r o [ 5 . 5 ] u n d e c a n - 9 - o n e N,N-d i m e t h y l h y d r a z o n e (362),145 a n d c y c l o p e n t a n o n e 7 Y , r V - d i m e t h y l h y d r a z o n e (360)144 h a v e b e e n p r e v i o u s l y r e p o r t e d . Preparation of Cycloheptanone A^-dimethylhydrazone (211).176 A s t i r r e d m i x t u r e o f c y c l o h e p t a n o n e (404) ( 4 . 0 m L , 3 4 m m o l , 1.0 e q u i v . ) a n d N,N-d i m e t h y l h y d r a z i n e ( 4 . 0 m L , 5 3 m m o l , 1.6 e q u i v . ) w a s h e a t e d at r e f l u x f o r 4 8 h . T h e r e a c t i o n m i x t u r e w a s c o o l e d to r o o m t e m p e r a t u r e a n d the e x c e s s A ^ / Y - d i m e t h y l h y d r a z i n e w a s r e m o v e d u n d e r r e d u c e d p r e s s u r e ( v a c u u m p u m p ) . T h e r e s i d u e w a s d i l u t e d w i t h d i e t h y l e t h e r a n d w a t e r , t h e l a y e r s w e r e s e p a r a t e d , a n d the a q u e o u s l a y e r w a s e x t r a c t e d t h r e e t i m e s w i t h d i e t h y l e the r . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d N(Me)2 O N 404 211 2 6 5 c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 5 0 - 6 0 \" C / 0 . 0 5 T o r r ) t o a f f o r d t h e 7 V , / Y - d i m e t h y l h y d r a z o n e 2 1 1 ( 5 . 2 g , 9 8 % ) as a c o l o u r l e s s o i l . I R (neat ) : 2 9 2 8 , 2 8 5 2 , 2 8 1 8 , 2 7 7 0 , 1 6 2 0 c m \" 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 1 . 5 3 - 1 . 6 6 ( m , 8 H ) , 2 . 3 7 - 2 . 5 5 ( m , 2 H ) , 2 . 4 0 (s , 6 H , - N = N ( M S 2 ) ) , 2 . 5 8 - 2 . 6 1 ( m , 2 H ) . 1 3 C n m r (CDCI3, 5 0 . 3 M H z ) 8 : 2 5 . 0 , 2 7 . 2 , 2 9 . 9 , 3 0 . 4 , 3 0 . 8 , 3 7 . 0 , 4 7 . 0 ( - v e , 2 s i g n a l s , -N=N(Me . 2 ) ) , 1 7 4 . 2 ( C - l ) . E x a c t M a s s c a l c d . f o r C9H18N2: 1 5 4 . 1 4 7 1 ; f o u n d : 1 5 4 . 1 4 7 3 . Preparation of (4aa, 8aR)-Perhydronaphthalen-l-one iV,/V-dimethyIhydrazone (364). N(Me)2 405 364 T o a s t i r r e d s o l u t i o n o f trans-decalont (405) ( 4 . 0 g , 2 6 m m o l , 1 .0 e q u i v . ) i n d r y b e n z e n e ( 4 0 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d A ^ ^ V - d i m e t h y l h y d r a z i n e ( 4 . 0 m L , 5 3 m m o l , 2 . 0 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s h e a t e d a t r e f l u x w i t h a z e o t r o p i c r e m o v a l o f w a t e r f o r 15 h , w a s c o o l e d t o r o o m t e m p e r a t u r e , a n d w a s d r i e d o v e r a n h y d r o u s m a g n e s i u m 2 6 6 s u l f a t e . T h e r e a c t i o n m i x t u r e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e a n d t h e r e s u l t i n g y e l l o w m a t e r i a l w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 6 0 - 1 8 0 \u00C2\u00B0C/8 T o r r ) t o a f f o r d t h e N,N-d i m e t h y l h y d r a z o n e 364 ( 5 . 0 5 g , 9 9 % ) as a p a l e y e l l o w o i l . I R (neat ) : 2 8 1 4 , 2 7 6 9 , 1 6 3 5 , 1 4 4 7 , 9 7 5 , 9 5 2 c m \" 1 . * H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 1 . 1 0 - 1 . 5 0 ( m , 7 H ) , 1 . 5 6 - 1 . 8 0 ( m , 6 H ) , 1 . 8 1 - 1 . 9 8 ( m , 2 H ) , 2 . 3 8 (s, 6 H , - N = N ( C H 2 ) 2 ) , 3 . 2 8 - 3 . 3 5 ( d m , I H , . / f o r d = 14 .8 H z ) . 1 3 C n m r (CDCI3, 5 0 . 3 M H z ) 8 : 2 5 . 9 6 , 2 6 . 0 1 , 2 6 . 2 , 2 7 . 2 , 2 8 . 7 , 3 3 . 8 , 3 4 . 6 , 4 4 . 5 ( - v e ) , 4 7 . 6 ( - ve , 2 s i g n a l s , - N = N ( C H 3 h ) , 4 9 . 4 ( - ve ) , 1 7 0 . 7 ( C - l ) . E x a c t M a s s c a l c d . f o r C i 2 H 2 2 N 2 : 1 9 4 . 1 7 8 2 ; f o u n d : 1 9 4 . 1 7 8 5 . A n a l , c a l c d . f o r C i 2 H 2 2 N 2 : C 7 4 . 1 7 , H 1 1 . 4 1 , N 1 4 . 4 2 ; f o u n d : C 7 4 . 1 7 , H 1 1 . 4 3 , N 14 .58 . Preparation of 1,2,3,4-Tetrahydronaphthalen-l-one A^-dimethylhydrazone (363).178 T o a s t i r r e d s o l u t i o n o f a - t e t r a l o n e (406) ( 1 0 g , 6 8 m m o l , 1.0 e q u i v . ) i n d r y b e n z e n e ( 3 0 0 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d A f N - d i m e t h y l h y d r a z i n e ( 5 2 m L , 6 8 0 m m o l , 10 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s h e a t e d at r e f l u x w i t h a z e o t r o p i c r e m o v a l o f w a t e r f o r 2 6 7 4 8 h , w a s c o o l e d to r o o m t e m p e r a t u r e , a n d d r y 4A m o l e c u l a r s i e v e s w e r e a d d e d . T h e m i x t u r e w a s h e a t e d at r e f l u x (as a b o v e ) f o r a n a d d i t i o n a l 4 h , w a s c o o l e d t o r o o m t e m p e r a t u r e , a n d w a s d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e . T h e r e a c t i o n m i x t u r e w a s c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e a n d t h e r e s u l t i n g d a r k b r o w n m a t e r i a l w a s d i s t i l l e d ( a i r -b a t h t e m p e r a t u r e 2 1 5 - 2 2 0 \" C / 3 . 5 T o r r ) t o a f f o r d t h e M / V - d i m e t h y l h y d r a z o n e 3 6 3 ( 1 2 . 8 5 g , q u a n t i t a t i v e y i e l d ) as a p a l e y e l l o w o i l . I R (neat ) : 2 8 1 8 , 2 7 7 3 , 1 6 8 6 , 1 6 1 2 , 1 4 6 7 , 1 4 5 2 , 9 8 0 , 7 6 3 , 7 3 2 c m \" 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 1 . 8 7 - 1 . 9 6 ( m , 2 H , H - 3 ) , 2 . 5 7 (s, 6 H , - N = N ( \u00C2\u00A3 H 2 ) 2 ) , 2 . 7 6 - 2 . 8 5 ( m , 4 H , H - 2 , H - 4 ) , 7 . 0 9 (b r d , I H , J = 7 .5 H z , H - 5 ) , 7 . 1 6 (b r d d , I H , J = 7 . 5 , 7 . 5 H z ) , 7 . 2 3 (br d d , I H , J = 7 . 5 , 7 . 5 H z ) , 8 . 1 4 ( b r d , 1 H , 7 = 7 . 5 H z , H - 8 ) . 1 3 C n m r (CDCI3, 5 0 . 3 M H z ) 5 : 2 2 . 7 , 2 7 . 3 , 2 9 . 9 , 4 7 . 3 ( - v e , 2 s i g n a l s , - N = N ( C H 3 _ h ) , 125 .1 ( - ve ) , 1 2 6 . 2 ( - v e ) , 1 2 8 . 6 ( - ve ) , 1 2 9 . 3 ( - ve ) , 1 3 3 . 1 , 1 3 9 . 7 , 1 6 1 . 0 ( C - l ) . E x a c t M a s s c a l c d . f o r C 1 2 H K 3 N 2 : 1 8 8 . 1 3 1 4 ; f o u n d : 1 8 8 . 1 3 1 2 . A n a l , c a l c d . f o r C i 2 H i 6 N 2 : C 7 6 . 5 6 , H 8 . 5 7 ; f o u n d : C 7 6 . 4 2 , H 8 . 5 2 . 2 6 8 Preparation of ( I S * , 5/?*)-5,,5,-dimethylspiro[(bicyclo[3.3.0]octan-3-one 7V,A^ -dimethylhydrazone)-7^'-(l ,^'-dioxane)](361).179 ,N(Me)s 407 361 T o a s t i r r e d s o l u t i o n o f t h e k e t o n e 407 ( 0 . 5 4 g , 2 . 0 m m o l , 1.0 e q u i v . ) i n d r y b e n z e n e ( 1 0 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d M / V - d i m e t h y l h y d r a z i n e ( 1 . 6 m L , 2 1 m m o l , 11 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s h e a t e d at r e f l u x f o r 12 h a n d t h e n w a s c o o l e d t o r o o m t e m p e r a t u r e . T h e b e n z e n e a n d e x c e s s N , N - d i m e t h y l h y d r a z i n e w e r e r e m o v e d u n d e r r e d u c e d p r e s s u r e ( v a c u u m p u m p ) . T h e c r u d e p r o d u c t w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 2 0 -1 3 0 \u00C2\u00B0C/0.03 T o r r ) to a f f o r d t h e / V , / V \" - d i m e t h y l h y d r a z o n e 361 ( 5 0 3 g , 9 4 % ) as a y e l l o w o i l , w h i c h c r y s t a l l i z e d o n s t a n d i n g . I R ( K B r ) : 2 9 5 2 , 2 8 5 5 , 2 7 7 2 , 1 6 5 6 c m \" 1 . ! H n m r (CDCI3, 4 0 0 M H z ) 8: 0 . 9 0 (s , 3 H , M e - 7 ' ) , 0 . 9 2 (s , 3 H , M e - 8 ' ) , 1 .64 ( d d d , 2 H , 7 = 1 3 . 7 , 6 . 2 , 6 . 2 H z ) , 2 . 2 1 - 2 . 3 4 ( m , 4 H ) , 2 . 4 2 (s , 6 H , - N = N ( M e 2 \u00C2\u00BB . 2 . 5 5 - 2 . 6 2 ( m , 4 H ) , 3 . 4 0 - 3 . 4 8 ( m , 4 H , H - 4 ' , H - 6 ' ) . 1 3 C n m r (CDCI3, 5 0 . 3 M H z ) 8: 2 2 . 4 , 2 2 . 4 , 3 0 . 0 , 3 5 . 0 , 3 7 . 5 , 3 9 . 0 , 3 9 . 5 , 4 0 . 4 , 4 1 . 3 , 4 7 . 1 ( 2 s i g n a l s , -N=N(Me_2), 7 1 . 7 ( C - 4 ' ) , 7 2 . 4 ( C - 6 ' ) , 1 0 9 . 8 ( C - 2 ' , 7 ) , 1 7 4 . 8 ( C - 3 ) . 2 6 9 E x a c t M a s s c a l c d . f o r C 1 5 H 2 6 N 2 O 2 : 2 6 6 . 1 9 9 6 ; f o u n d : 2 6 6 . 1 9 9 5 . 3.3.2. G e n e r a l P r o c e d u r e 1: P r e p a r a t i o n o f t h e K e t o A l k e n y l I o d i d e s f r o m t h e C o r r e s p o n d i n g M N - D i m e t h y l h y d r a z o n e s a n d ( Z ) - 4 - I o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253). N(Me) 2 1) LDA ,THF I 0\u00C2\u00B0C_ N 2) HMPA, ^SnBua 9 s \ -78 \u00C2\u00B0C 253 \ T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d , - 0 . 3 M s o l u t i o n o f L D A ( 2 . 0 e q u i v . ) i n d r y T H F w a s a d d e d ( v i a T e f l o n \u00C2\u00AE c a n n u l a ) a s o l u t i o n o f t h e h y d r a z o n e 32 ( 2 . 2 e q u i v . ) i n d r y T H F ( 1 -1.5 m L / m m o l h y d r a z o n e ) , a n d the r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 2 h . D r y H M P A (4 .0 e q u i v . ) w a s a d d e d a n d t h e m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 5 m i n , a n d t h e n w a s c o o l e d t o - 7 8 \u00C2\u00B0C. A s o l u t i o n o f ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 1 . 0 e q u i v . ) i n d r y T H F ( 1 . 5 - 2 m L / m m o l i o d i d e ) w a s a d d e d d r o p w i s e ( v i a Te f lon\u00C2\u00AE c a n n u l a ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \" C f o r 2 h a n d t h e n w a s w a r m e d to r o o m t e m p e r a t u r e . T h e m i x t u r e w a s t r e a t e d w i t h s a t u r a t e d a q u e o u s N a H C 0 3 ( o n e h a l f o f the t o t a l v o l u m e o f t h e s o l u t i o n ) , d i l u t e d w i t h d i e t h y l e t h e r a n d w a t e r ( the s a m e v o l u m e as t h e a m o u n t o f N a H C 0 3 s o l u t i o n f o r d i e t h y l e t h e r a n d w a t e r ) , a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h r e e t i m e s w i t h d i e t h y l e t h e r . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d f o u r t i m e s w i t h b r i n e , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f the a b o v e r e s i d u e i n d r y CH2CI2 ( 2 m L / m m o l i o d i d e ) w a s a d d e d a 0 . 1 0 M s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 1 . 1 - 1 . 2 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 15 m i n , a n d t h e n w a s t r e a t e d w i t h s a t u r a t e d a q u e o u s N a 2 S 2 0 3 3) l 2, C H 2 C I 2 , 0 \u00C2\u00B0C 4 ) AcOH, NaOAc, THF, H 2 0 , rt 32 356 ( o n e h a l f o f t h e t o t a l v o l u m e o f the s o l u t i o n ) a n d t h e m i x t u r e w a s a l l o w e d to w a r m to r o o m t e m p e r a t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d t h r e e t i m e s w i t h CH2CI2. T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d o n c e w i t h b r i n e , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T o t h e a b o v e r e s i d u e w a s a d d e d , s e q u e n t i a l l y , T H F ( 2 . 5 - 3 m L / m m o l i o d i d e ) , H2O ( 3 . 5 - 4 . 5 m L / m m o l i o d i d e ) , N a O A c (~1 g / m m o l i o d i d e ) , a n d A c O H ( 6 - 8 m L / m m o l i o d i d e ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r t h e s p e c i f i e d a m o u n t o f t i m e , at w h i c h p o i n t t i c a n a l y s i s i n d i c a t e d c o m p l e t e c o n s u m p t i o n o f t h e s t a r t i n g m a t e r i a l . T h e m i x t u r e w a s c a r e f u l l y n e u t r a l i z e d b y a d d i n g s o l i d N a H C 0 3 . D i e t h y l e t h e r a n d w a t e r w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h r e e t i m e s w i t h d i e t h y l e t h e r . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d o n c e w i t h b r i n e , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( t i c s i l i c a g e l ) , a n d the o i l t h u s o b t a i n e d w a s e i t h e r d i s t i l l e d o r t r a c e s o f s o l v e n t w e r e r e m o v e d ( v a c u u m p u m p ) , t o a f f o r d t h e k e t o a l k e n y l i o d i d e 356. 2 7 1 Preparation of 2-[(Z)-4-Iodobut-3-en-l-yl]cycIoheptanone (256). N(Me) 2 N O 10 11 211 256 F o l l o w i n g g e n e r a l p r o c e d u r e 1, a s o l u t i o n o f L D A ( 0 . 9 0 0 m m o l , 2 . 0 e q u i v . ) i n d r y T H F (3 .3 m L ) w a s t r e a t e d w i t h a s o l u t i o n o f c y c l o h e p t a n o n e A f , A 7 - d i m e t h y l h y d r a z o n e (211) ( 1 5 2 m g , 0 . 9 8 8 m m o l , 2 . 2 e q u i v . ) i n d r y T H F (0 .4 m L ) , f o l l o w e d b y t h e s e q u e n t i a l a d d i t i o n o f d r y H M P A ( 0 . 3 1 m L , 1 .8 m m o l , 4 . 0 e q u i v . ) a n d a s o l u t i o n o f ( Z ) - 4 - i o d o - l -( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 2 1 0 m g , 0 . 4 4 7 m m o l , 1.0 e q u i v . ) i n d r y T H F (0 .8 m L ) . T o a s o l u t i o n o f t h e p r o d u c t d e r i v e d f r o m t h e a l k y l a t i o n r e a c t i o n i n d r y CH2CI2 ( 0 . 9 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2C12 ( 4 . 9 m L , 0 . 1 0 M , 0 . 4 9 m m o l , 1.1 e q u i v . ) . T h e m a t e r i a l o b t a i n e d f r o m t h e t i n - i o d i n e e x c h a n g e r e a c t i o n w a s t r e a t e d s e q u e n t i a l l y w i t h T H F (1.1 m L ) , H2O ( 1 .6 m L ) , N a O A c ( 0 . 4 3 g ) , a n d A c O H (3.1 m L ) , a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 2 2 h . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 2 0 g t i c s i l i c a g e l , 5 . 7 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 3 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d , a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 4 5 -1 6 0 \" C / 0 . 1 5 T o r r ) to a f f o r d the k e t o a l k e n y l i o d i d e 256 ( 1 1 2 m g , 8 6 % ) as a c o l o u r l e s s o i l . I R (neat ) : 1 7 0 3 , 1 6 1 0 , 1 4 5 5 , 1 2 8 4 , 9 3 5 , 6 9 4 c m - 1 . * H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 1 . 2 1 - 1 . 4 7 ( m , 4 H ) , 1 . 5 5 - 1 . 6 7 ( m , 2 H ) , 1 . 7 7 - 1 . 9 2 ( m , 4 H ) , 2 . 1 1 (b r d d d , 2 H , J = 1,1,1 H z ) , 2 . 4 3 - 2 . 5 4 ( m , 3 H ) , 6 . 11 ( d d d , 1 H , J = 1,1,1 H z , H - 1 0 ) , 6 . 1 8 ( b r d , 1 H , 7 = 7 H z , H - l l ) . 2 7 2 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 4 . 1 , 2 8 . 6 , 2 9 . 2 , 3 0 . 0 , 3 1 . 3 , 3 2 . 4 , 4 2 . 9 , 5 0 . 9 ( - v e , C - 2 ) , 8 2 . 8 ( - v e , C - 1 0 ) , 1 4 0 . 6 ( - v e , C - l 1), 2 1 5 . 4 ( C - l ) . E x a c t M a s s c a l c d . f o r C i 1H17IO: 2 9 2 . 0 3 2 4 ; f o u n d : 2 9 2 . 0 3 2 1 . A n a l , c a l c d . f o r C11H17IO: C 4 5 . 2 2 , H 5 . 8 7 ; f o u n d : C 4 5 . 2 2 , H 5 . 9 9 . Preparation of 8-[(Z)-4-Iodobut-3-en-l-yl]-3,3-dimethyl-l,5-dioxaspiro[5.5]undecan-9-one (367). 362 367 F o l l o w i n g g e n e r a l p r o c e d u r e 1, a s o l u t i o n o f L D A ( 3 . 4 9 m m o l , 2 . 0 e q u i v . ) i n d r y T H F ( 1 1 . 6 m L ) w a s t r e a t e d w i t h a s o l u t i o n o f 3 , 3 - d i m e t h y l - l , 5 - d i o x a s p i r o [ 5 . 5 ] u n d e c a n - 9 -o n e / V . / V - d i m e t h y l h y d r a z o n e (362)180 ( 9 2 2 m g , 3 . 8 4 m m o l , 2 . 2 e q u i v . ) i n d r y T H F ( 4 m L ) , f o l l o w e d b y t h e s e q u e n t i a l a d d i t i o n o f d r y H M P A ( 1 . 2 1 m L , 6 . 9 5 m m o l , 4 . 0 e q u i v . ) a n d a s o l u t i o n o f ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 8 2 0 m g , 1 .74 m m o l , l . O e q u i v . ) i n d r y T H F (3 m L ) . T o a s o l u t i o n o f the p r o d u c t d e r i v e d f r o m t h e a l k y l a t i o n r e a c t i o n i n d r y CH2CI2 ( 3 . 5 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 2 0 m L , 0 . 1 0 M , 2 . 0 m m o l , 1.1 e q u i v . ) . T h e m a t e r i a l o b t a i n e d f r o m t h e t i n - i o d i n e e x c h a n g e r e a c t i o n w a s t r e a t e d s e q u e n t i a l l y w i t h T H F ( 5 . 4 m L ) , H2O ( 7 .6 m L ) , N a O A c ( 2 . 0 4 g ) , a n d A c O H ( 1 4 . 5 m L ) , a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 2 0 m i n . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 2 . 3 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d , a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 8 5 - 2 0 5 \" C / 0 . 1 5 T o r r ) t o a f f o r d t h e k e t o a l k e n y l i o d i d e 3 6 7 ( 6 0 3 m g , 9 2 % ) as a p a l e y e l l o w o i l . I R (neat ) : 1 7 1 3 , 1 6 1 0 , 1 2 8 0 , 1 1 2 2 , 1 0 2 0 , 9 1 9 , 6 9 2 c m \" l . * H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 9 7 (s, 3 H , Me-12), 1 .00 (s , 3 H , M e - 1 3 ) , 1 . 2 2 - 1 . 3 8 ( m , 2 H ) , 1.47 ( d d , I H , 7 = 1 3 . 1 , 13.1 H z , H - 7 a x ) , 1 . 7 0 - 1 . 8 0 ( m , I H ) , 1 . 8 8 - 2 . 0 0 ( m , I H ) , 2 . 1 6 ( b r d d d , I H , 7 = 7 , 7 , 7 H z ) , 2 . 2 3 - 2 . 3 2 ( m , I H ) , 2 . 4 5 - 2 . 6 4 ( m , 4 H ) , 3 . 4 9 - 3 . 5 9 ( m , 4 H , H - 2 , H - 4 ) , 6 . 1 2 (b r d d d , I H , 7 = 7 , 7 , 7 H z , H - 1 6 ) , 6 . 1 8 - 6 . 2 2 ( d m , I H , 7 f o r d = 7 H z , H - 1 7 ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 2 2 . 5 ( - ve , 2 s i g n a l s , C - 1 2 , C - 1 3 ) , 2 6 . 7 , 3 0 . 2 , 3 1 . 8 , 3 2 . 0 , 3 7 . 0 , 3 7 . 6 , 4 3 . 9 ( - v e , C - 8 ) , 7 0 . 3 ( C - 2 ) , 7 0 . 6 ( C - 4 ) , 8 2 . 9 ( - v e , C - 1 6 ) , 9 6 . 2 ( C - 6 ) , 1 4 0 . 7 ( - v e , C - 1 7 ) , 2 1 1 . 3 ( C - 9 ) . E x a c t M a s s c a l c d . f o r C15H23IO3: 3 7 8 . 0 6 9 2 ; f o u n d : 3 7 8 . 0 6 8 5 . A n a l , c a l c d . f o r C 1 5 H 2 3 I O 3 : C 4 7 . 6 3 , H 6 . 1 3 ; f o u n d : C 4 7 . 7 9 , H 6 . 1 4 . 2 7 4 Preparation of (2a, 4aa, 8aR)-2-[(Z)-4-Iodobut-3-en-l-yl]perhydronaphthaIen-l-one (370). N(Me) 2 364 370 F o l l o w i n g g e n e r a l p r o c e d u r e 1, a s o l u t i o n o f L D A ( 4 . 4 1 m m o l , 2 . 0 e q u i v . ) i n d r y T H F ( 1 5 m L ) w a s t r e a t e d w i t h a s o l u t i o n o f (4aoc, 8 a ( 3 ) - p e r h y d r o n a p h t h a l e n - l - o n e N , N -d i m e t h y l h y d r a z o n e (364)181 ( 9 5 1 m g , 4 . 9 0 m m o l , 2 . 2 e q u i v . ) i n d r y T H F (5 m L ) , f o l l o w e d b y t h e s e q u e n t i a l a d d i t i o n o f d r y H M P A ( 1 . 5 0 m L , 8 . 6 7 m m o l , 3 .9 e q u i v . ) a n d a s o l u t i o n o f ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 1 . 0 4 m g , 2 . 2 1 m m o l , 1.0 e q u i v . ) i n d r y T H F (5 m L ) . T o a s o l u t i o n o f t h e p r o d u c t d e r i v e d f r o m t h e a l k y l a t i o n r e a c t i o n i n d r y CH2CI2 ( 4 . 4 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 2 6 m L , 0 . 1 0 M , 2 . 6 m m o l , 1.2 e q u i v . ) . T h e m a t e r i a l o b t a i n e d f r o m t h e t i n - i o d i n e e x c h a n g e r e a c t i o n w a s t r e a t e d s e q u e n t i a l l y w i t h T H F (6 .3 m L ) , H 2 0 (8 .9 m L ) , N a O A c ( 2 . 3 8 g ) , a n d A c O H ( 1 7 m L ) , a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 17 h . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 4 5 g t i c s i l i c a g e l , 4 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 3 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d , a n d t h e o i l t h u s o b t a i n e d w a s d i s s o l v e d i n d r y M e O H ( 2 2 m L ) . T o t h e s t i r r e d m i x t u r e , at r o o m t e m p e r a t u r e , w a s a d d e d a s o l u t i o n o f N a O M e i n d r y M e O H ( 9 . 0 m L , 0 . 5 0 M , 4 . 5 m m o l , 2 . 0 e q u i v . ) a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 2 0 h . T h e M e O H w a s r e m o v e d b y r o t a r y e v a p o r a t i o n a n d b r i n e ( 2 0 m L ) a n d d i e t h y l e t h e r ( 2 0 m L ) w e r e a d d e d to t h e r e s i d u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 2 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 4 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d 2 7 5 u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 1 1 . 5 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o a l k e n y l i o d i d e 3 7 0 ( 4 2 0 m g , 5 7 % f r o m 3 6 4 ) as a c o l o u r l e s s o i l . I R (neat ) : 1 7 1 3 , 1 6 1 0 , 1 2 7 9 , 1 1 7 1 , 6 9 9 c m \" 1 . i H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 1 . 1 0 - 1 . 5 5 ( m , 8 H ) , 1 . 6 4 - 1 . 8 7 ( m , 5 H ) , 1 . 8 8 - 1 . 9 9 ( m , 2 H ) , 2 . 1 0 - 2 . 1 9 ( m , 3 H ) , 2 . 2 7 ( d d d d , I H , 7 = 1 3 , 6 .6 , 6 . 5 , 6 . 5 H z , H - 2 ) , 6 . 1 2 ( d d d , I H , 7 = 7 , 6 . 2 , 6 .2 H z , H - l l ) , 6 . 1 7 ( d m , I H , 7 f o r d = 7 H z , H - 1 2 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 4 . 9 , 2 5 . 0 , 2 5 . 4 , 2 7 . 1 , 3 2 . 1 , 3 2 . 8 , 3 3 . 5 , 3 4 . 0 , 4 5 . 6 ( - v e ) , 4 9 . 0 ( - v e ) , 5 4 . 8 ( - v e ) , 8 2 . 5 ( - v e , C - l l ) , 1 4 0 . 9 ( - v e , C - 1 2 ) , 2 1 2 . 7 ( C - l ) . E x a c t M a s s c a l c d . f o r C 1 4 H 2 1 I O : 3 3 2 . 0 6 3 7 ; f o u n d : 3 3 2 . 0 6 3 7 . A n a l , c a l c d . f o r C14H21IO: C 5 0 . 6 1 , H 6 . 3 7 ; f o u n d : C 5 0 . 6 6 , H 6 . 2 0 . 2 7 6 Preparation of 2-[(Z)-4-Iodobut-3-en-l-yI]-l,2,3,4-tetrahydronaphthalen-l-one (371). N(Me)2 363 371 F o l l o w i n g g e n e r a l p r o c e d u r e 1, a s o l u t i o n o f L D A ( 3 . 4 5 m m o l , 2 . 0 e q u i v . ) i n d r y T H F ( 1 1 . 8 m L ) w a s t r e a t e d w i t h a s o l u t i o n o f 1 , 2 , 3 , 4 - t e t r a h y d r o n a p h t h a l e n - l - o n e N,N-d i m e t h y l h y d r a z o n e (363)182 ( 7 3 5 m g , 3 .91 m m o l , 2 . 2 e q u i v . ) i n d r y T H F (3 m L ) , f o l l o w e d b y the s e q u e n t i a l a d d i t i o n o f d r y H M P A ( 1 . 2 3 m L , 7 . 0 7 m m o l , 4 . 0 e q u i v . ) a n d a s o l u t i o n o f ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 8 3 2 m g , 1 .77 m m o l , l . O e q u i v . ) i n d r y T H F (3 m L ) . T o a s o l u t i o n o f t h e p r o d u c t d e r i v e d f r o m t h e a l k y l a t i o n r e a c t i o n i n d r y CH2CI2 ( 3 .5 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 2 0 . 4 m L , 0 . 1 0 M , 2 . 0 m m o l , 1.2 e q u i v . ) . T h e m a t e r i a l o b t a i n e d f r o m t h e t i n - i o d i n e e x c h a n g e r e a c t i o n w a s t r e a t e d s e q u e n t i a l l y w i t h T H F ( 5 . 0 m L ) , H 2 0 (7.1 m L ) , N a O A c ( 1 . 8 9 g ) , a n d A c O H ( 1 3 . 5 m L ) , a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 15 h . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 4 0 g t i c s i l i c a g e l , 19:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d , a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 6 5 - 1 8 5 \" C / 0 . 1 5 T o r r ) to a f f o r d t h e k e t o a l k e n y l i o d i d e 371 ( 4 2 2 m g , 7 3 % ) as a p a l e y e l l o w o i l . I R (neat ) : 3 0 6 6 , 3 0 2 3 , 1 6 8 2 , 1 6 0 1 , 1 2 9 4 , 1 2 3 1 , 6 9 9 c m \" 1 . * H n m r ( C D C I 3 , 4 0 0 M H z ) 8: 1 . 1 6 - 1 . 4 1 ( m , I H ) , 1 . 5 3 - 1 . 6 6 ( m , I H ) , 1 . 8 3 - 1 . 9 5 ( m , I H ) , 2 . 0 8 - 2 . 1 8 ( m , I H ) , 2 . 2 3 - 2 . 3 3 ( m , 2 H ) , 2 . 4 2 - 2 . 5 1 ( m , I H ) , 3 . 0 0 ( b r d d , 2 H , J = 7 . 4 , 7 . 4 H z ) , 2 7 7 6 . 1 5 - 6 . 3 0 ( m , 2 H , H - l l , H - 1 2 ) , 7 . 21 ( d , 1 H , J = 7 . 5 H z ) , 7 . 2 8 ( d d , 1 H , J= 7 . 5 , 7 . 5 H z ) , 7 . 4 4 ( d d , 1 H , J = 7 . 5 , 7 . 5 H z ) , 7 . 8 6 (d , 1 H , J = 7 .5 H z ) . 1 3 c n m r ( C D C h , 7 5 . 3 M H z ) 8 : 2 7 . 4 , 2 8 . 2 , 2 8 . 4 , 3 2 . 0 , 4 6 . 5 ( - ve , C - 2 ) , 8 3 . 0 ( - v e , C - l l ) , 1 2 6 . 3 ( - ve ) , 1 2 7 . 2 ( - v e ) , 1 2 8 . 5 ( - v e ) , 1 3 2 . 2 , 1 3 3 . 0 ( - v e ) , 1 4 0 . 6 ( - v e , C - 1 2 ) , 1 4 3 . 6 , 1 9 9 . 4 ( C - l ) . E x a c t M a s s c a l c d . f o r C14H15IO: 3 2 6 . 0 1 6 8 ; f o u n d : 3 2 6 . 0 1 6 0 . A n a l , c a l c d . f o r C 1 4 H 1 5 I O : C 5 1 . 5 5 , H 4 . 6 4 ; f o u n d : C 5 1 . 6 9 , H 4 . 6 6 . Preparation of 2-[(Z)-4-Iodobut-3-en-l-yI]cyclopentanone (368). N ( M e ) 2 N O 6 360 368 F o l l o w i n g g e n e r a l p r o c e d u r e 1, a s o l u t i o n o f L D A ( 3 . 5 3 m m o l , 2 . 0 e q u i v . ) i n d r y T H F ( 1 2 m L ) w a s t r e a t e d w i t h a s o l u t i o n o f c y c l o p e n t a n o n e M N - d i m e t h y l h y d r a z o n e (360)1 8 3 ( 4 9 6 m g , 3 . 9 3 m m o l , 2 . 2 e q u i v . ) i n d r y T H F (2 .5 m L ) , f o l l o w e d b y t h e s e q u e n t i a l a d d i t i o n o f d r y H M P A ( 1 . 2 3 m L , 7 . 0 7 m m o l , 4 . 0 e q u i v . ) a n d a s o l u t i o n o f ( Z ) - 4 - i o d o - l -( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 8 3 1 m g , 1 .76 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 2 . 5 m L ) . T o a s o l u t i o n o f t h e p r o d u c t d e r i v e d f r o m t h e a l k y l a t i o n r e a c t i o n i n d r y CH2CI2 ( 3 .5 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 2 0 . 5 m L , 0 . 1 0 M , 2 . 0 m m o l , 1 .2 e q u i v . ) . T h e m a t e r i a l o b t a i n e d f r o m t h e t i n - i o d i n e e x c h a n g e r e a c t i o n w a s t r e a t e d s e q u e n t i a l l y w i t h T H F ( 4 . 4 m L ) , H2O ( 6 . 2 m L ) , N a O A c ( 1 . 6 6 g ) , a n d A c O H ( 1 1 . 9 m L ) , a n d t h e r e a c t i o n m i x t u r e 2 7 8 w a s s t i r r e d f o r 15 h . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 5 . 7 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d , a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 0 0 -1 1 0 \u00C2\u00B0C/0.15 T o r r ) t o a f f o r d t h e k e t o a l k e n y l i o d i d e 368 ( 3 4 2 m g , 7 3 % ) as a p a l e y e l l o w o i l . I R (neat ) : 1 7 3 5 , 1 6 0 9 , 1 1 5 5 , 1 0 5 0 , 6 9 3 c m \" 1 . lH n m r ( C D C 1 3 , 4 0 0 M H z ) 5 : 1 . 2 2 - 1 . 4 2 ( m , I H ) , 1 . 4 7 - 1 . 6 6 ( m , I H ) , 1 . 6 9 - 1 . 8 2 ( m , I H ) , 1 . 8 4 - 1 . 9 4 ( m , I H ) , 1 . 9 5 - 2 . 3 5 ( m , 7 H ) , 6 . 1 2 ( d d d , I H , 7 = 7 . 2 , 6 . 7 , 6 .7 H z , H - 8 ) , 6 . 2 0 ( d d d , I H , 7 = 7 . 2 , 1, 1 H z , H - 9 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 0 . 6 , 2 7 . 7 , 2 9 . 6 , 3 2 . 6 , 3 7 . 9 , 4 8 . 4 ( - v e , C - 2 ) , 8 3 . 0 ( - v e , C - 8 ) , 1 4 0 . 4 ( - ve , C - 9 ) , 2 2 0 . 6 ( C - l ) . E x a c t M a s s c a l c d . f o r C o H i s I O : 1 3 7 . 0 9 6 6 ; f o u n d : 1 3 7 . 0 9 6 4 . A n a l , c a l c d . f o r C9H13IO: C 4 0 . 9 3 , H 4 . 9 6 ; f o u n d : C 4 1 . 1 1 , H 5 . 0 5 . 2 7 9 P r e p a r a t i o n of (IR *, 2S *, 5R * ) - 2 - [ (Z)-4-Iodobut-3-en-l-yl]-5^5 ,. dimethylspiro[(bicyclo[3.3.0]octan-3-one)-7,2'-(l,v3,-dioxane)] (369). 369 T o a c o l d (0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f L D A (1.4 e q u i v . ) i n d r y T H F ( 5 . 3 m L ) w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f t h e h y d r a z o n e 361 ( 5 4 7 m g , 1.72 m m o l , 1.5 e q u i v . ) i n d r y T H F ( 1 . 5 m L ) , a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 2 h . D r y H M P A (0.56 m L , 3 . 2 m m o l , 2 . 8 e q u i v . ) w a s a d d e d a n d t h e m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 10 m i n , a n d t h e n w a s c o o l e d t o - 7 8 \u00C2\u00B0C. A s o l u t i o n o f ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 5 4 0 m g , 1.15 m m o l , 1.0 e q u i v . ) i n d r y T H F (1.5 m L ) w a s a d d e d d r o p w i s e ( v i a Tef lon\u00C2\u00AE c a n n u l a ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 2 h a n d t h e n w a s w a r m e d t o r o o m t e m p e r a t u r e . T h e m i x t u r e w a s t r e a t e d w i t h s a t u r a t e d a q u e o u s NaHCC\u00C2\u00BB3 (2 .5 m L ) , d i l u t e d w i t h d i e t h y l e t h e r ( 2 .5 m L ) a n d w a t e r ( 2 .5 m L ) , a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h r e e t i m e s w i t h d i e t h y l e t h e r (3 x 15 m L ) a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (4 x 15 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T o a c o l d (0 \u00C2\u00B0C), s t i r r e d s o l u t i o n o f the p r o d u c t d e r i v e d f r o m t h e a l k y l a t i o n r e a c t i o n i n d r y C H 2 C 1 2 ( 2 . 8 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 1 3 . 2 m L , 0.10 M , 1.3 m m o l , 1.1 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 15 m i n , w a s t r e a t e d w i t h s a t u r a t e d a q u e o u s Na2S2C\u00C2\u00BB3 (8 m L ) , a n d t h e n w a s a l l o w e d to w a r m to r o o m t e m p e r a t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h CH2CI2 ( 3 x 15 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 3 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T o t h e m a t e r i a l o b t a i n e d f r o m t h e t i n - i o d i n e e x c h a n g e r e a c t i o n w a s a d d e d s e q u e n t i a l l y T H F ( 3 . 7 m L ) , H 2 0 ( 5 . 2 m L ) , N a O A c ( 1 . 4 0 g ) , a n d A c O H ( 1 0 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 8 h . T h e m i x t u r e w a s c a r e f u l l y n e u t r a l i z e d b y a d d i n g s o l i d N a H C 0 3 . D i e t h y l e t h e r a n d w a t e r w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 2 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e ( 2 x 2 5 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 1.9:1 p e t r o l e u m e t h e r - d i e t h y l e the r , 4 c m c o l u m n ) , t o a f f o r d , a f te r c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t races o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o a l k e n y l i o d i d e 3 6 9 ( 2 5 1 m g , 5 4 % ) as a p a l e y e l l o w o i l . A t t e m p t e d d i s t i l l a t i o n r e s u l t e d i n s o m e d e c o m p o s i t i o n o f t h e p r o d u c t . I R (neat ) : 1 7 3 5 , 1 6 1 0 , 1 4 7 2 , 1 1 1 4 , 6 9 3 c m \" 1 . * H n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 9 4 (s , 3 H , M e - 7 ' ) , 0 . 9 5 (s , 3 H , M e - 8 ' ) , 1 . 3 9 - 1 . 4 9 ( m , I H ) , 1.72 ( d d , I H , 7 = 14 , 7 . 9 H z ) , 1 . 7 6 - 1 . 8 6 ( m , I H ) , 1 .92 ( d d , I H , 7 = 1 3 , 4 H z ) , 2 . 1 0 ( b r d d d , I H , 7 = 7 . 3 , 7 . 3 , 7 . 3 H z ) , 2 . 1 6 - 2 . 2 8 ( m , 3 H ) , 2 . 2 9 - 2 . 3 9 ( m , 2 H ) , 2 . 4 1 - 2 . 5 2 ( m , I H ) , 2 . 4 2 ( d d , I H , 7 = 1 3 , 7 . 1 H z ) , 2 . 7 0 - 2 . 8 0 ( m , I H ) , 3 . 3 9 - 3 . 5 2 ( m , 4 H , H - 4 ' , H - 6 ' ) , 6 . 1 4 ( d d d , 1 H , 7 = 7 . 3 , 6 .6 , 6 .6 H z , H - l l ) , 6 . 1 8 - 6 . 2 5 ( d m , I H , 7 f o r d = 7 .3 H z , H - 1 2 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 2 . 4 ( - v e , 2 s i g n a l s , C - 7 ' , C - 8 ' ) , 2 8 . 7 , 3 0 . 0 , 3 2 . 4 , 3 4 . 6 ( - v e ) , 4 0 . 7 , 4 1 . 3 , 4 3 . 3 ( - v e ) , 4 3 . 8 , 5 3 . 6 ( - v e ) , 7 1 . 9 ( C - 4 1 ) , 7 2 . 1 ( C - 6 1 ) , 8 3 . 2 ( - v e , C - l l ) , 1 0 9 . 5 ( C - 2 1 ) , 1 4 0 . 3 ( - ve , C - 1 2 ) , 2 2 0 . 6 ( C - 3 ) . 2 8 1 E x a c t M a s s c a l c d . f o r C17H25IO3: 4 0 4 . 0 8 4 8 ; f o u n d : 4 0 4 . 0 8 4 1 . A n a l , c a l c d . f o r C 1 7 H 2 5 I O 3 : C 5 0 . 5 1 , H 6 . 2 3 ; f o u n d : C 5 0 . 6 9 , H 6 . 6 3 . Preparat ion of 3,3 -Dimethyl- l ,5 -dioxa -8 - [ (Z )-4-(tributylstannyl)but-3-en-l-yl]spiro[5.5]undecan-9-one (374). 362 374 T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f L D A ( 2 .0 e q u i v . ) i n d r y T H F ( 6 . 4 m L ) w a s a d d e d ( v i a Te f lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f 3 , 3 - d i m e t h y l - l , 5 - d i o x a s p i r o [ 5 . 5 ] u n d e c a n - 9 - o n e N,N-d i m e t h y l h y d r a z o n e (362) ( 4 8 4 m g , 2 . 0 1 m m o l , 2 . 2 e q u i v . ) i n d r y T H F ( 2 . 0 m L ) , a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 2 h . D r y H M P A ( 0 . 6 4 m L , 3 .7 m m o l , 4 . 0 e q u i v . ) w a s a d d e d a n d t h e m i x t u r e w a s s t i r r e d a t 0 \u00C2\u00B0C f o r 10 m i n , a n d t h e n w a s c o o l e d t o - 7 8 \u00C2\u00B0C. A s o l u t i o n o f ( Z ) - 4 - i o d o - l - ( t r i b u t y l s t a n n y l ) b u t - l - e n e (253) ( 431 m g , 0 . 9 1 4 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 2 . 0 m L ) w a s a d d e d d r o p w i s e ( v i a Tef lon\u00C2\u00AE c a n n u l a ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 2 h a n d t h e n w a s w a r m e d to r o o m t e m p e r a t u r e . T h e m i x t u r e w a s t r e a t e d w i t h s a t u r a t e d a q u e o u s NaHCC\u00C2\u00BB3 (6 m L ) , d i l u t e d w i t h d i e t h y l e t h e r ( 6 m L ) a n d w a t e r (6 m L ) , a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d th ree t i m e s w i t h d i e t h y l e t h e r (3 x 10 m L ) a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (4 x 2 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T o t h e m a t e r i a l o b t a i n e d f r o m t h e a l k y l a t i o n r e a c t i o n w a s a d d e d s e q u e n t i a l l y T H F (3 .7 m L ) , H2O ( 5 . 2 m L ) , N a O A c ( 1 . 4 0 g ) , a n d A c O H ( 1 0 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e f o r 15 m i n . T h e m i x t u r e w a s c a r e f u l l y n e u t r a l i z e d b y a d d i n g s o l i d N a H C 0 3 . D i e t h y l e t h e r a n d w a t e r w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 2 0 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 4 0 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 5 0 g t i c s i l i c a g e l , 4 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 c m c o l u m n ) , to a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , the k e t o a l k e n y l s t a n n a n e 3 7 4 ( 4 4 4 m g , 9 0 % ) as a c o l o u r l e s s o i l . I R (neat ) : 1 7 1 8 , 1 5 9 8 , 1 4 5 6 , 1 3 7 6 , 1 1 2 2 , 6 9 3 c m \" 1 . ! H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 8 0 - 0 . 9 7 ( m , 1 5 H ) , 0 . 9 8 (s, 3 H , M e - 1 2 ) , 0 . 9 9 (s, 3 H , M e - 1 3 ) , 1 . 2 2 - 1 . 3 3 ( m , 7 H ) , 1 . 4 2 - 1 . 5 3 ( m , 7 H ) , 1 . 6 9 - 1 . 8 0 ( m , I H ) , 1 . 8 5 - 2 . 1 1 ( m , 3 H ) , 2 . 2 3 - 2 . 3 2 ( m , I H ) , 2 . 4 5 - 2 . 5 9 ( m , 4 H ) , 3 . 5 2 , 3 . 5 4 ( b r s, b r s , 2 H e a c h , H - 2 , H - 4 ) , 5 . 7 9 ( b r d , I H , 7 = 1 2 H z , 2^Sn-H = 7 0 H z , H - 1 7 ) , 6 . 4 7 ( d d d , I H , J= 12 , 6 . 5 , 6 .5 H z , 3/Sn-H = 1 4 0 H z , H - 1 6 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 1 0 . 1 , 1 3 . 6 ( - ve , C H 3 f r o m b u t y l g r o u p s ) , 2 2 . 5 ( - v e , 2 s i g n a l s , C - l 2 , C - 1 3 ) , 2 7 . 2 , 2 8 . 8 , 2 9 . 1 , 3 0 . 1 , 3 1 . 7 , 3 4 . 4 , 3 7 . 0 , 3 8 . 1 , 4 4 . 4 ( - v e , C - 8 ) , 7 0 . 2 ( C - 2 ) , 7 0 . 4 ( C - 4 ) , 9 6 . 3 ( C - 6 ) , 1 2 8 . 2 ( - v e , C - 1 6 ) , 1 4 8 . 2 ( - ve , C - 1 5 ) , 2 1 1 . 1 ( C - 9 ) . E x a c t M a s s c a l c d . f o r C 2 3 H 4 i O 3 1 2 0 S n ( M - B u ) + : 4 8 5 . 2 0 7 5 ; f o u n d : 4 8 5 . 2 0 7 8 . A n a l , c a l c d . f o r C 2 7 H 5 0 O 3 S n : C 5 9 . 9 0 , H 9 . 3 1 ; f o u n d : C 6 0 . 0 0 , H 9 . 3 9 . Preparation of 3,3,8-TrimethyI-l,5-dioxa-8-[(Z)-4-(tributylstannyl)but-3-en-l-yl]spiro[5.5]undecan-9-one (375), (SS*, 10/c*)-3,3,8,10-Tetramethyl-l,5-dioxa-8-[(Z)-4-(tributy!stannyI)but-3-en-l-yl]spiro[5.5]undecan-9-one (376', one diastereomer) and (8S*, 10 S *)-3,3,8,10-Tetramethyl-l,5-dioxa-8-[(Z)-4-(tributyIstannyl)but-3-en-l -yl]spiro[5.5]imdecan-9-one (376\", other diastereomer). T o p o t a s s i u m terf-butoxide ( 38 m g , 0 . 3 4 m m o l , 1.5 e q u i v . ) , at r o o m t e m p e r a t u r e , w a s a d d e d ( v i a Te f lon\u00C2\u00AE c a n n u l a ) a s o l u t i o n o f t h e k e t o n e 374 i n d r y T H F (2 .3 m L ) . T h e s t i r r e d r e a c t i o n m i x t u r e w a s h e a t e d at 6 0 \u00C2\u00B0C f o r 3 h a n d t h e n w a s c o o l e d to - 7 8 \u00C2\u00B0C. M e t h y l i o d i d e ( e x c e s s ) w a s a d d e d b y f i l t e r i n g i t t h r o u g h a d r y b a s i c a l u m i n a f i l l e d p i p e t t e tha t h a d b e e n p u s h e d t h r o u g h a s e p t u m o n t h e r e a c t i o n flask. T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 1 h , t r e a t e d w i t h s a t u r a t e d a q u e o u s NaHCC\u00C2\u00BB3 (3 m L ) , a n d t h e n w a s w a r m e d t o r o o m t e m p e r a t u r e . D i e t h y l e t h e r ( 3 m L ) a n d w a t e r ( 3 m L ) w e r e a d d e d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h d i e t h y l e t h e r (3 x 12 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 2 5 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 11 .5 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) , a f f o r d i n g , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o a l k e n y l s t a n n a n e 375 (88 m g , 7 0 % ) as a c o l o u r l e s s o i l . 2 8 4 I R (neat ) : 1 7 1 3 , 1 5 9 8 , 1 4 6 4 , 1 1 1 0 , 1 0 8 9 , 6 9 3 c m \" 1 . * H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 7 9 - 0 . 9 3 ( m , 1 5 H ) , 0 . 9 5 (s, 3 H , M e -12) , 0 . 9 9 (s , 3 H , M e -13) , 1 .09 (s , 3 H , M e - 1 8 ) , 1 . 2 2 - 1 . 3 4 ( m , 6 H ) , 1 . 4 0 - 1 . 5 8 ( m , 7 H ) , 1 . 7 3 - 1 . 8 5 (ra, 2 H ) , 1 . 8 7 - 2 . 0 8 ( m , 3 H ) , 2 . 1 1 - 2 . 2 3 ( m , 2 H ) , 2 . 3 8 - 2 . 5 7 ( m , 2 H ) , 3 . 4 5 - 3 . 6 8 ( m , 4 H , C - 2 , C - 4 ) , 5 . 7 5 ( d , I H , J = 1 2 . 4 H z , 2 7 s n - H = 7 1 H z , H - 1 7 ) , 6 . 4 0 ( d d d , I H , J = 1 2 . 5 , 6 . 9 , 6 . 9 H z , 3 y S n . H = 1 3 9 H z , H -16). n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 1 0 . 2 , 13 .7 ( - v e , C H 3 f r o m b u t y l g r o u p s ) , 2 2 . 5 ( - v e , C - 1 2 ) , 2 2 . 6 ( - ve , C - 1 3 ) , 2 3 . 8 ( - v e , C - 1 8 ) , 2 7 . 3 , 2 9 . 2 , 3 0 . 1 , 3 1 . 6 , 3 2 . 6 , 3 4 . 7 , 3 8 . 4 , 4 2 . 0 , 4 6 . 9 , 7 0 . 3 ( C -2 ) , 7 0 . 4 ( C - 4 ) , 9 6 . 6 ( C - 6 ) , 1 2 8 . 2 ( - v e , C - 1 7 ) , 1 4 8 . 3 ( - v e , C - 1 6 ) , 2 1 4 . 3 ( C - 9 ) . E x a c t M a s s c a l c d . f o r C 2 4 H 4 3 O 3 1 2 0 S n ( M - B u ) + : 4 9 9 . 2 2 3 4 ; f o u n d : 4 9 9 . 2 2 3 5 . A n a l , c a l c d . f o r C 2 8 H 5 2 0 3 S n : C 6 0 . 5 5 , H 9 . 4 4 ; f o u n d : C 6 0 . 7 9 , H 9 . 6 8 . D u r i n g t h e o p t i m i z a t i o n o f t h i s a l k y l a t i o n r e a c t i o n , t h e m a j o r s i d e - p r o d u c t s w e r e l e s s p o l a r m a t e r i a l , w h i c h w a s d e t e r m i n e d t o b e t h e d i m e t h y l a t e d k e t o a l k e n y l s t a n n a n e s 376. T h i s m a t e r i a l w a s i s o l a t e d as a n i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s i n a n a p p r o x i m a t e r a t i o o f 6 .7 :1 w h i c h w e r e e p i m e r i c at t h e C - 1 0 p o s i t i o n . T h e r e l a t i v e c o n f i g u r a t i o n at C - 8 a n d C -10 f o r t h e m a j o r d i a s t e r e o m e r i n 376 w a s n o t d e f i n i t e l y e s t a b l i s h e d . T h e y i e l d o f c o m p o u n d s 376 v a r i e d d e p e n d i n g o n t h e r e a c t i o n c o n d i t i o n s b u t w h e n t h e y i e l d w a s d e t e r m i n e d , t h e s e d i a s t e r e o m e r s w e r e t y p i c a l l y i s o l a t e d i n - 2 0 % y i e l d . T h e d a t a b e l o w f o r t h e d i m e t h y l a t e d k e t o n e s 376 r e f e r s t o t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s ta ted . I R (neat ) : 1 7 1 2 , 1 5 9 9 , 1 4 6 2 , 1 1 3 0 , 1 0 9 6 , 6 9 2 c m - l . 2 8 5 ! H n m r ( C D C I 3 , 4 0 0 M H z ) 8: 0 . 6 7 - 0 . 8 2 ( m , 1 5 H ) , 0 . 7 6 9 (s, 3 H , M e - 1 2 ) , 0 . 7 7 3 ( d , 3 H , 7 =6 .9 H z , M e - 1 9 ) , 0 . 8 3 (s, 3 H , M e - 1 8 ) , 0 . 9 3 (s , 3 H , M e - 1 3 ) , 1 . 1 2 - 1 . 2 3 ( m , 6 H ) , 1 . 2 8 - 1 . 5 4 ( m , 1 0 H ) , 1 . 8 0 - 1 . 9 3 ( m , 1 H ) , 2 . 0 0 ( d d d , 1 H , 7= 1 3 , 1 3 , 4 . 4 H z , H - 1 4 ) , 2 . 3 0 - 2 . 5 7 ( m , 1 H ) , 2 . 4 0 ( d d , 1 H , 7 = 1 3 , 3 .5 H z , H - 1 4 ' ) , 2 . 7 3 ( d d q , 1 H , 7 = 1 2 . 5 , 6 . 9 , 6 . 9 , 6 . 9 , 6 . 9 H z , H - 1 0 ) , 3 . 3 2 -3 . 5 2 ( m , 4 H , H - 2 , H - 4 ) , 5 . 6 5 ( d , 1 H , 7 = 1 2 . 4 H z , 27sn-H = 7 0 H z , H - 1 7 ) , 6 . 2 5 ( d d d , 1 H , 7 = 12 .4 , 6 . 8 , 6 .8 H z , 37Sn-H = 1 2 0 H z , H - 1 6 ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8: ( m a j o r d i a s t e r e o m e r o n l y ) 1 0 . 2 , 13 .7 ( - v e , C H 3 f r o m b u t y l g r o u p s ) , 1 4 . 3 ( - v e ) , 2 2 . 5 ( - v e ) , 2 2 . 7 ( - v e ) , 2 3 . 0 ( - v e ) , 2 7 . 3 , 2 9 . 2 , 3 0 . 1 , 3 1 . 8 , 3 7 . 0 ( - v e , C - 1 0 ) , 3 8 . 5 , 4 2 . 1 , 4 3 . 2 , 4 7 . 1 , 7 0 . 2 ( C - 2 ) , 7 0 . 6 ( C - 4 ) , 9 6 . 6 ( C - 6 ) , 1 2 8 . 4 ( - v e , C - 1 7 ) , 1 4 8 . 1 ( - v e , C -16) , 2 1 5 . 6 ( C - 9 ) . E x a c t M a s s c a l c d . f o r C 2 5 H 4 5 C > 3 1 2 0 S n ( M - B u ) + : 5 1 3 . 2 3 9 1 ; f o u n d : 5 1 3 . 2 4 0 0 . A n a l , c a l c d . f o r C 2 9 H 5 4 0 3 S n : C 6 1 . 1 7 , H 9 . 5 6 ; f o u n d : C 6 1 . 5 7 , H 9 . 7 0 . 2 8 6 Preparation of 8-[(Z)-4-Iodobut-3-en-l-yl]-3^,8-trimethyl-l,5-dioxaspiro[5.5]undecan-9-one (377). T o a c o l d ( 0 \u00C2\u00B0C ) , s t i r r e d s o l u t i o n o f t h e k e t o a l k e n y l s t a n n a n e 375 ( 1 2 1 m g , 0 . 2 1 8 m m o l , l . O e q u i v . ) i n d r y CH2CI2 ( 0 . 4 5 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 2 .5 m L , 0 . 1 0 M , 0 . 2 5 m m o l , 1.1 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 15 m i n , a n d t h e n s a t u r a t e d a q u e o u s Na2S20*3 ( 2 .5 m L ) w a s a d d e d , a n d t h e m i x t u r e w a s w a r m e d t o r o o m t e m p e r a t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h CH2CI2 (3 x 5 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e (1 x 10 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (5 g t i c s i l i c a g e l , 4 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o a l k e n y l i o d i d e 377 ( 83 m g , 9 7 % ) as a c o l o u r l e s s o i l . I R ( n e a t ) : 1 7 1 3 , 1 6 1 8 , 1 4 6 5 , 1 1 1 0 , 7 0 2 c m - 1 . lH n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 9 6 (s, 3 H , M e - 1 2 ) , 0 . 9 7 (s , 3 H , M e - 1 3 ) , 1 .13 (s , 3 H , M e - 1 8 ) , 1 . 5 5 - 1 . 6 4 ( m , I H ) , 1 .73 ( d d d , I H , J = 1 3 . 6 , 1 1 . 8 , 5 .1 H z ) , 1 . 9 0 - 2 . 0 1 ( m , 2 H ) , 2 . 0 2 - 2 . 2 2 ( m , 4 H ) , 2 . 4 1 - 2 . 5 5 ( m , 2 H ) , 3 . 4 5 - 3 . 5 8 ( m , 4 H , H - 2 , H - 4 ) , 6 . 0 6 - 6 . 2 2 ( m , 2 H , H - 1 6 , H - 1 7 ) . 2 8 7 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 5 : 2 2 . 5 ( - v e , 2 s i g n a l s , C - 1 2 , C - 1 3 ) , 2 3 . 9 ( - v e , C - 1 8 ) , 2 9 . 7 , 3 0 . 1 , 3 2 . 1 , 3 4 . 7 , 3 6 . 2 , 4 1 . 8 , 4 6 . 7 , 7 0 . 3 ( 2 s i g n a l s , C - 2 , C - 4 ) , 8 2 . 6 ( - v e , C - 1 6 ) , 9 6 . 6 ( C - 6 ) , 1 4 0 . 6 ( v e , C - 1 7 ) , 2 1 4 . 3 ( C - 9 ) . E x a c t M a s s c a l c d . f o r C16H25IO3: 3 9 2 . 0 8 4 8 ; f o u n d : 3 9 2 . 0 8 5 2 . A n a l , c a l c d . f o r C i 6 H 2 5 l 0 3 : C 4 8 . 9 9 , H 6 . 4 2 ; f o u n d : C 4 9 . 1 9 , H 6 . 4 1 . Preparation of (85 *, 10^*)-8-[(Z)-4-Iodobut-3-en-l-yl]-3,3,8,10-tetramethyl-l,5-dioxaspiro[5.5]undecan-9-one (378*, one diastereomer) and (85*, 10S*)-8-[(Z)-4-lodobut-3-en-l-yl]-3,3,8,10-tetramethyl-l,5-dioxaspiro[5.5]undecan-9-one (378\", other T o a c o l d ( 0 \u00C2\u00B0C) , s t i r r e d s o l u t i o n o f t h e k e t o a l k e n y l s t a n n a n e s 376 ( 1 7 2 m g , 0 . 3 0 2 m m o l , 1 .0 e q u i v . ) i n d r y CH2CI2 ( 0 . 6 0 m L ) w a s a d d e d a s o l u t i o n o f i o d i n e i n d r y CH2CI2 ( 3 .5 m L , 0 . 1 0 M , 0 . 3 5 m m o l , 1.2 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at 0 \u00C2\u00B0C f o r 15 m i n , a n d t h e n s a t u r a t e d a q u e o u s Na2S2C\u00C2\u00BB3 ( 4 m L ) w a s a d d e d , a n d t h e m i x t u r e w a s w a r m e d t o r o o m t e m p e r a t u r e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d w i t h CH2CI2 ( 3 x 1 2 m L ) . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e diastereomer). 376 378 (1 x 2 5 m L ) , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (20 g t i c s i l i c a g e l , 5.7:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 3 c m c o l u m n ) , t o a f f o r d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e k e t o a l k e n y l i o d i d e s 378 (111 m g , 9 1 % ) as a c o l o u r l e s s o i l . A n a p p r o x i m a t e r a t i o f o r t h e s e d i a s t e r e o m e r s i s 6-7:1 i n f a v o r o f c o m p o u n d 378. T h e s p e c t r o s c o p i c d a t a b e l o w f o r t h e k e t o a l k e n y l i o d i d e s 378 r e f e r s to t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s t a t e d . I R (neat ) : 1 7 1 3 , 1 6 0 9 , 1 4 5 6 , 1 0 9 9 , 6 8 8 c m \" 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 5 : 0 .96 (s , 3H, Me - 1 2 ) , 0 .99 (s , 3H, M e - 1 3 ) , 1.02 ( d , 3H, 7 = 6 .6 H z , M e - 1 9 ) , 1.07 (s , 3H, M e - 1 8 ) , 1.22-1.65 ( m , 3H), 1.73-1.86 ( m , 1H), 1.91-2.21 ( m , 2H), 2.43-2.70 ( m , 2H), 2 .88 ( d d q , 1H, 7 = 1 3 . 9 , 6 . 6 , 6 . 6 , 6 . 6 , 5.2 H z , H -10) , 3 .42 - 3 .64 ( m , 4H, C - 2 , C -4 ) , 6.04-6 . 21 ( m , 2H, H - 1 6 , H - 1 7 ) . I n h o m o n u c l e a r ( ^ H ^ H ) d e c o u p l i n g e x p e r i m e n t s , i r r a d i a t i o n o f the d d q at 8 2 .88 ( 7 = 1 3 . 9 , 6 .6 , 6 .6 , 6 . 6 , 5.2 H z , H-10) c a u s e d the d o u b l e t at 6 1.02 ( 7 = 6 .6 H z , M e - 1 9 ) to c o l l a p s e i n t o a s i n g l e t . I r r a d i a t i o n o f t h e d o u b l e t at 5 1.02 ( 7 = 6 . 6 H z , M e - 1 9 ) c a u s e d t h e d d q at 8 2.88 (7 = 1 3 . 9 , 6 . 6 , 6 . 6 , 6 . 6 , 5.2 H z , H-10) to c o l l a p s e i n t o a d d (7 = 1 3 . 9 , 5.2 H z , H-10). 1 3 C n m r (CDCI3, 75.3 M H z ) 8 : ( m a j o r d i a s t e r e o m e r o n l y ) 14 .3 ( - v e , C - 1 4 ) , 22.55 ( - v e , C -12), 22.63 ( - v e , C - 1 3 ) , 22.8 ( - v e , C - 1 8 ) , 30 . 0 , 30 . 1 , 36 . 3 , 37.0 ( - v e , C -10) , 4 1 . 6 , 43.2, 47.0, 70 . 4 (C -2 ) , 7 0 . 6 (C4), 8 2 . 9 ( - v e , C - 1 6 ) , 96 . 5 ( C - 6 ) , 140 . 3 ( - v e , C - 1 7 ) , 215 . 7 ( C - 9 ) . E x a c t M a s s c a l c d . f o r C17H27IO3: 4 0 6 . 1 0 0 5 ; f o u n d : 4 0 6 . 1 0 0 8 . A n a l , c a l c d . f o r C17H27IO3: C 5 0 . 2 5 , H 6 . 7 0 ; f o u n d : C 5 0 . 5 8 , H 6 . 4 7 . 2 8 9 3.3.3. General Procedure 2: C y c l i z a t i o n o f t h e K e t o A l k e n y l I o d i d e s V i a M e t a l - H a l o g e n E x c h a n g e . n-BuLi, -78 \u00C2\u00B0C H 0 > inverse addition 356 358 T o a c o l d ( - 7 8 \u00C2\u00B0C), s t i r r e d , 0 . 0 5 M s o l u t i o n o f n - B u L i (2 .5 e q u i v . ) i n d r y T H F w a s a d d e d ( v i a Tef lon\u00C2\u00AE c a n n u l a ) , s l o w l y a n d d r o p w i s e , a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e 356 i n d r y T H F (~5 m L / m m o l k e t o a l k e n y l i o d i d e ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d at - 7 8 \u00C2\u00B0C f o r 1 h a n d t h e n w a s t r e a t e d w i t h s a t u r a t e d a q u e o u s NaHCC\u00C2\u00AB3 ( o n e h a l f o f t h e t o t a l v o l u m e o f T H F u s e d ) . T h e m i x t u r e w a s w a r m e d t o r o o m t e m p e r a t u r e , d i l u t e d w i t h d i e t h y l e t h e r a n d w a t e r ( the s a m e v o l u m e as the a m o u n t o f NaHCC\u00C2\u00BB3 s o l u t i o n f o r d i e t h y l e t h e r a n d w a t e r ) , a n d the l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h r e e t i m e s w i t h d i e t h y l e ther . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d o n c e w i t h b r i n e , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e , a n d c o n c e n t r a t e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e m a t e r i a l w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( t i c s i l i c a g e l ) a n d the p r o d u c t w a s e i t h e r d i s t i l l e d o r t r a c e s o f s o l v e n t w e r e r e m o v e d ( v a c u u m p u m p ) a f f o r d i n g the a l l y l i c a l c o h o l 358. 2 9 0 Preparation of Bicyclo[5.4.0]undec-10-en-l-ol (257) and 2-[But-3-en-l-yl]cycloheptanone (258). F o l l o w i n g g e n e r a l p r o c e d u r e 2 , t h e a l l y l i c a l c o h o l 257 w a s p r e p a r e d b y a d d i n g a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e 256 ( 1 5 0 m g , 0 . 5 1 4 m m o l , l . O e q u i v . ) i n d r y T H F (1 .5 m L ) to a s o l u t i o n o f n - B u L i ( 0 . 8 3 m L , 1.55 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 2 5 m L ) . T h e * H n m r s p e c t r o s c o p i c a n a l y s i s o f t h e c r u d e o i l i n d i c a t e d a 2 . 5 : 1 m i x t u r e o f t h e e p i m e r i c a l c o h o l s 257, as d e t e r m i n e d b y the i n t e g r a t i o n o f t h e a l k e n i c s i g n a l s f o r e a c h d i a s t e r e o m e r . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 4 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d t w o f r a c t i o n s . T h e f i r s t c o m p o u n d that e l u t e d w a s t h e a l k e n e 258. C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) a f f o r d e d t h e a l k e n e 258 (5 m g , 6 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 0 7 7 , 1 7 0 3 , 1 6 4 1 , 9 1 1 c m \" 1 . l H n m r ( C D C I 3 , 4 0 0 M H z ) 5: 0 . 7 8 - 0 . 9 5 ( m , 2 H ) , 1 . 1 5 - 1 . 7 0 ( m , 7 H ) , 1 . 7 2 - 1 . 9 0 ( m , 3 H ) , 1 . 9 8 - 2 . 0 7 ( m , I H ) , 2 . 3 7 - 2 . 5 4 ( m , 2 H ) , 4 . 9 0 - 5 . 0 2 ( m , 2 H ) , 5 . 6 8 - 5 . 8 1 ( m , I H ) . E x a c t M a s s c a l c d . f o r C n H i g O : 1 6 6 . 1 3 5 8 ; f o u n d : 1 6 6 . 1 3 6 4 . A m i x t u r e o f t h e a l l y l i c a l c o h o l s 257 w a s t h e n e l u t e d . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d d i s t i l l a t i o n o f t h e o i l t h u s o b t a i n e d ( a i r - b a t h t e m p e r a t u r e 9 0 -256 257 258 2 9 1 9 5 \u00C2\u00B0 C / 0 . 1 5 T o r r ) a f f o r d e d t h e a l l y l i c a l c o h o l s 257 ( 6 9 m g , 8 0 % ) as a c o l o u r l e s s o i l . S e p a r a t i o n o f t h e m i x t u r e o f t h e a l l y l i c a l c o h o l s 257 b y f l a s h c h r o m a t o g r a p h y ( t i c s i l i c a g e l , 4 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r ) , a l l o w e d f o r a s m a l l s a m p l e o f e a c h d i a s t e r e o m e r t o b e i s o l a t e d . T h e c o m p o u n d tha t e l u t e d f i r s t f r o m t h e m i x t u r e o f t h e a l c o h o l s 257 w a s t h e m a j o r p r o d u c t . I R (neat ) : 3 4 6 9 (br ) , 3 0 1 6 , 1 6 5 3 , 9 6 3 , 9 1 2 , 7 4 0 c m \" 1 . * H n m r (CDCI3, 4 0 0 M H z ) 8 : 1 . 2 0 - 1 . 5 1 ( m , 7 H ) , 1 . 5 2 - 1 . 8 8 ( m , 7 H ) , 1 . 9 0 - 2 . 0 8 ( m , 2 H ) , 5 . 5 7 (br d , IH, J = 9 . 8 H z , H - l l ) , 5 . 7 3 ( d d d , I H , J = 9 . 8 , 5 .0 , 2 . 4 H z , H - 1 0 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 2 . 6 , 2 6 . 0 , 2 6 . 3 , 2 6 . 5 , 2 7 . 5 , 2 9 . 6 , 4 2 . 8 ( - v e , C -7) , 4 3 . 5 , 7 0 . 7 (C-l), 1 2 8 . 7 ( - v e ) , 135 .7 ( - ve ) . E x a c t M a s s c a l c d . f o r CnHigO: 1 6 6 . 1 3 5 8 ; f o u n d : 1 6 6 . 1 3 5 7 . A n a l , c a l c d . f o r CnHigO: C 7 9 . 4 6 , H 1 0 . 9 1 ; f o u n d : C 7 9 . 2 8 , H 1 1 . 0 1 . ( D e t e r m i n e d f o r t h e m i x t u r e o f t h e a l c o h o l s 257.) T h e c o m p o u n d that e l u t e d s e c o n d f r o m the m i x t u r e o f t h e a l l y l i c a l c o h o l s 257 w a s the m i n o r p r o d u c t . I R (neat ) : 3 3 6 6 (br ) , 3 0 1 5 , 1 6 5 1 , 1 0 0 4 , 7 2 9 c m \" 1 . * H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 1 . 1 7 - 1 . 6 8 ( m , 9 H ) , 1 . 7 1 - 2 . 0 3 ( m , 7 H ) , 5 . 4 5 ( b r d , I H , J = 9.9 H z , H - l l ) , 5 . 7 1 - 5 . 7 9 ( d m , I H , 7 f o r d = 9 . 9 H z , H - 1 0 ) . 292 1 3 C n m r (CDCI3 ,75.3 M H z ) 8: 21.1, 21.8, 26.9, 28.9, 29.1, 30.0, 41.2, 44.8 ( - v e , C-7), 72.4 ( C - l ) , 128.4 ( - v e ) , 133.3 ( - ve ) . E x a c t M a s s c a l c d . f o r C n H i g O : 166.1358; f o u n d : 166.1355. A n a l , c a l c d . f o r C n H i g O : C 79.46, H 10.91; f o u n d : C 79.28, H 11.01. ( D e t e r m i n e d f o r the m i x t u r e o f t h e a l c o h o l s 257.) Preparation of l',2 ,,3 ,,4 ,,4a ,,7',8 ,,8a'-Octahydro-5,5-dimethyIspiro[(l,3-dioxane).2,2'-naphthalen-4a'-ol] (379). F o l l o w i n g g e n e r a l p r o c e d u r e 2, t h e a l l y l i c a l c o h o l s 379 w e r e p r e p a r e d b y a d d i n g a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e 367 (217 m g , 0.574 m m o l , 1.0 e q u i v . ) i n d r y T H F (2 m L ) to a s o l u t i o n o f n - B u L i (0.93 m L , 1.55 M , 1.4 m m o l , 2.5 e q u i v . ) i n d r y T H F (28 m L ) . T h e * H n m r s p e c t r o s c o p i c a n a l y s i s o f t h e c r u d e o i l i n d i c a t e d a 1:1 m i x t u r e o f e p i m e r i c a l c o h o l s 379, as d e t e r m i n e d b y t h e i n t e g r a t i o n o f t h e a l k e n i c s i g n a l s f o r e a c h d i a s t e r e o m e r . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y (10 g t i c s i l i c a g e l , 1:1.5 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2.5 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e a l l y l i c a l c o h o l s 367 379 379 ( 1 4 0 rag, 9 6 % ) , as a v i s c o u s s e m i - s o l i d o i l . S e p a r a t i o n o f t h e m i x t u r e o f t h e a l l y l i c a l c o h o l s 379 b y f l a s h c h r o m a t o g r a p h y ( t i c s i l i c a g e l , 1 :1 .5 p e t r o l e u m e t h e r - d i e t h y l e the r ) a l l o w e d f o r a s m a l l s a m p l e o f e a c h d i a s t e r e o m e r s t o b e i s o l a t e d . T h e c o m p o u n d that e l u t e d f i r s t w a s a n o f f - w h i t e s o l i d , m p 1 2 3 - 1 2 5 \u00C2\u00B0C. I R ( K B r ) : 3 4 9 6 (br ) , 3 0 1 7 , 1 6 4 4 , 1 1 0 0 , 6 9 2 c m - 1 . i H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 9 1 (s , 3 H , M e - 7 ) , 0 . 9 8 (s , 3 H , M e - 8 ) , 1 . 1 5 - 1 . 2 1 ( m , I H ) , 1 . 3 7 - 1 . 7 0 ( m , 6 H ) , 1 .75 ( d d d , I H , J = 1 3 . 5 , 1 3 . 5 , 4 . 4 H z ) , 1 . 8 8 - 1 . 9 3 ( d m , I H , J f o r d = 9 .7 H z ) , 2 . 0 3 - 2 . 1 1 ( m , 2 H ) , 2 . 1 6 - 2 . 2 4 ( d m , I H , J f o r d = 13 .5 H z ) , 3 . 4 2 - 3 . 5 8 ( m , 4 H , H - 4 , H -6 ) , 5 . 6 6 ( b r d , I H , J = 9 .8 H z , H - 5 ' ) , 5 . 7 3 ( d d d , I H , J = 9 . 8 , 3 . 1 , 3.1 H z , H - 6 ' ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 2 . 5 ( - v e , C - 7 ) , 2 2 . 7 ( - v e , C - 8 ) , 2 3 . 7 , 2 5 . 7 , 2 6 . 9 , 3 0 . 0 , 3 4 . 0 , 3 4 . 6 , 3 7 . 8 ( - v e , C - 8 a ' ) , 6 6 . 9 ( C - 4 a ' ) , 6 9 . 8 (2 s i g n a l s , C - 4 , C - 6 ) , 9 8 . 0 ( C - 2 , 2 ' ) , 1 3 0 . 1 ( - v e ) , 1 3 3 . 0 ( - ve ) . E x a c t M a s s c a l c d . f o r C 1 5 H 2 4 O 3 : 2 5 2 . 1 7 2 6 ; f o u n d : 2 5 2 . 1 7 2 4 . A n a l , c a l c d . f o r C 1 5 H 2 4 O 3 : C 7 1 . 3 9 , H 9 . 5 9 ; f o u n d : C 7 1 . 4 7 , H 9 . 6 1 . ( D e t e r m i n e d f o r t h e m i x t u r e o f t h e a l c o h o l s 379.) T h e c o m p o u n d that e l u t e d s e c o n d w a s a n o f f - w h i t e s o l i d , m p 9 4 - 9 5 \u00C2\u00B0C. I R ( K B r ) : 3 4 3 5 (b r ) , 3 0 1 5 , 1 6 5 0 , 1 1 0 2 , 7 3 2 c m - 1 . lH n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 9 2 (s , 3 H , M e - 7 ) , 0 . 9 8 (s , 3 H , M e - 8 ) , 1 . 1 5 - 1 . 2 7 ( m , I H ) , 1.32 ( d d d , I H , 7 = 1 3 . 3 , 1 3 . 3 , 4 .1 H z ) , 1 . 4 0 - 1 . 5 7 ( m , 2 H ) , 1 . 6 3 - 1 . 7 9 ( m , 2 H ) , 1 . 8 8 - 2 . 0 8 ( m , 2 9 4 5 H ) , 2 . 1 2 - 2 . 2 0 ( d m , 1 H , J f o r d = 1 3 . 3 H z ) , 3 . 4 3 - 3 . 5 3 ( m , 4 H , H - 4 , H - 6 ) , 5 . 5 2 ( d d , 1 H , J = 1 0 . 1 , 1.1 H z , H - 5 ' ) , 5 . 8 3 ( d d d , 1 H , J = 1 0 . 1 , 2 . 9 , 2 . 9 H z , H - 6 ' ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 2 1 . 6 , 2 2 . 5 ( - v e , C - 7 ) , 2 2 . 6 ( - v e , C - 8 ) , 2 2 . 7 , 2 8 . 5 , 3 0 . 0 , 3 3 . 4 , 3 4 . 6 , 3 7 . 2 ( - v e , C - 8 a \" ) , 6 8 . 8 ( C - 4 a ' ) , 6 9 . 7 ( C - 4 ) , 7 0 . 1 ( C - 6 ) , 9 7 . 5 ( C - 2 , 2 ' ) , 1 3 0 . 9 ( - v e ) , 1 3 1 . 3 ( -ve ) . E x a c t M a s s c a l c d . f o r C 1 5 H 2 4 O 3 : 2 5 2 . 1 7 2 6 ; f o u n d : 2 5 2 . 1 7 1 7 . A n a l , c a l c d . f o r C 1 5 H 2 4 O 3 : C 7 1 . 3 9 , H 9 . 5 9 ; f o u n d : C 7 1 . 4 7 , H 9 . 6 1 . ( D e t e r m i n e d f o r t h e m i x t u r e o f t h e a l c o h o l s 379.) Preparation of l',2 ,,3',4 ,,4a ,,7',8',8a ,-Octahydro-5,5,8a ,-trimethyIspiro[(l,3-dioxane)-2,2,-naphthalen-4a'-ol] (382). 377 382 F o l l o w i n g g e n e r a l p r o c e d u r e 2 , t h e a l l y l i c a l c o h o l 382 w a s p r e p a r e d b y a d d i n g a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e 377 ( 1 1 7 m g , 0 . 2 9 8 m m o l , 1.0 e q u i v . ) i n d r y T H F (3 m L ) to a s o l u t i o n o f n - B u L i ( 0 . 5 0 m L , 1 .49 M , 0 . 7 5 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 1 4 . 5 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 1:1 p e t r o l e u m 2 9 5 e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e a l l y l i c a l c o h o l 3 8 2 ( 7 3 m g , 9 2 % ) as a w h i t e s o l i d , m p 8 9 - 9 1 \u00C2\u00B0C. I R ( K B r ) : 3 4 7 1 (b r ) , 3 0 1 5 , 1 6 5 2 , 1 0 9 4 , 7 1 8 c m \" 1 . ! H n m r ( C D C I 3 , 4 0 0 M H z ) 8 : 0 . 8 7 (s , 3 H , M e - 7 ) , 0 . 9 9 (s , 3 H , M e - 8 ) , 1 .03 (s, 3 H , M e - 9 ) , 1 . 2 0 - 1 . 7 0 ( m , 6 H ) , 1 . 8 9 - 2 . 0 9 ( m , 5 H ) , 3 . 4 6 - 3 . 5 9 ( m , 4 H , H - 4 , H - 6 ) , 5 . 4 7 ( d d d , 1 H , 7 = 9 . 9 , 1 . 9 , 1 . 9 H z , H - 5 ' ) , 5 . 7 2 ( d d d , 1 H , J = 9 . 9 , 3 . 3 , 3 .3 H z , H - 6 ' ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 2 . 4 9 ( - v e , 2 s i g n a l s , C - 7 , C - 8 ) , 2 2 . 5 4 , 2 2 . 8 ( - v e , C - 9 ) , 3 0 . 0 , 3 0 . 9 , 3 1 . 6 , 3 2 . 4 , 3 6 . 5 , 3 7 . 2 , 6 9 . 8 ( C - 4 ) , 7 0 . 2 ( C - 6 ) , 7 1 . 4 ( C - 4 a ' ) , 9 7 . 8 ( C - 2 , 2 ' ) , 1 2 9 . 0 ( - v e ) , 133 .1 ( - ve ) . E x a c t M a s s c a l c d . f o r C 1 6 H 2 6 O 3 : 2 6 6 . 1 8 8 2 ; f o u n d : 2 2 6 . 1 8 8 7 . A n a l , c a l c d . f o r C i 6 H 2 6 0 3 : C 7 2 . 1 4 , H 9 . 8 4 ; f o u n d : C 7 1 . 9 6 , H 9 . 9 6 . 2 9 6 P r e p a r a t i o n of (4'p* , 8 a ' a )-l ,,2 ,,3\4\4a^7\8^8a^Octahydro-4\5,5,8a ,-tetramethylspiro[(l,3-dioxane)-2,2'-naphthaIen-4a'-ol] (383, one diastereomer) and (4'a, 8a,a)-l,,2,,3,,4,,4a,,7,,8,,8a,-Octahydro-4,,5,5,8a,-tetramethylspiro[(13-dioxane)-2,2,-naphthalen-4a'-ol] (383, other diastereomer). 378 383 F o l l o w i n g g e n e r a l p r o c e d u r e 2 , t h e a l l y l i c a l c o h o l s 383 w e r e p r e p a r e d b y a d d i n g a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e s 378 ( 1 0 8 m g , 0 . 2 6 6 m m o l , 1.0 e q u i v . ) i n d r y T H F (3 m L ) to a s o l u t i o n o f \u00C2\u00AB - B u L i ( 0 . 4 3 m L , 1 .56 M , 0 . 6 7 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 1 3 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 2 . 3 : 1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e a l l y l i c a l c o h o l s 383 ( 6 7 m g , 9 0 % ) as a c l e a r s o l i d , m p 8 3 - 8 5 \u00C2\u00B0C. A n a p p r o x i m a t e r a t i o f o r t h e s e d i a s t e r e o m e r s w a s 6 - 7 : 1 i n f a v o r o f c o m p o u n d 383. T h e s p e c t r o s c o p i c d a t a b e l o w f o r t h e a l c o h o l s 383 r e f e r s t o t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s t a t e d . I R ( K B r ) : 3 5 0 0 (b r ) , 3 0 2 2 , 1 6 5 2 , 1 1 2 7 , 7 0 4 c m \" 1 . l H n m r ( C D C 1 3 , 4 0 0 M H z ) 6 : 0 . 8 6 (s , 3 H , M e - 7 ) , 0 . 9 3 9 (s , 3 H , M e - 8 ) , 0 . 9 4 1 ( d , 3 H , J = 6.8 H z , M e - 1 0 ) , 1.01 (s , 3 H , M e - 9 ) , 1 . 1 7 - 1 . 3 3 ( m , 2 H ) , 1 . 5 0 - 1 . 6 7 ( m , 2 H ) , 1 .79 ( d d d , 1 H , J = 1 3 . 4 , 3 . 3 , 3 . 3 H z ) , 1 . 9 0 - 2 . 1 2 ( m , 4 H ) , 2 . 3 2 - 2 . 4 2 ( m , I H , H - 4 ' ) , 3 . 4 5 - 3 . 6 2 ( m , 4 H , H - 4 , H - 6 ) , 5 . 5 0 - 5 . 6 4 ( m , 2 H , H - 5 ' , H - 6 ' ) . 1 3 C n m r ( C D C 1 3 , 7 5 . 3 M H z ) 8 : ( m a j o r d i a s t e r e o m e r o n l y ) 1 5 . 0 ( - v e , C - 1 0 ) , 2 2 . 4 ( - v e , C - 7 ) , 2 2 . 5 ( - v e , C - 8 ) , 2 2 . 9 ( - v e , C - 9 ) , 2 3 . 0 , 3 0 . 1 , 3 1 . 1 , 3 5 . 7 ( - v e , C - 4 ' ) , 3 8 . 0 , 3 8 . 4 , 3 9 . 5 , 6 9 . 9 8 ( C -4 ) , 7 0 . 0 2 ( C - 6 ) , 7 4 . 1 ( C - 4 a ' ) , 9 7 . 7 ( C - 2 , 2 ' ) , 1 2 6 . 8 ( - v e ) , 1 3 2 . 9 ( - ve ) . E x a c t M a s s c a l c d . f o r C 1 7 H 2 8 O 3 : 2 8 0 . 2 0 3 8 ; f o u n d : 2 8 0 . 2 0 4 3 . A n a l , c a l c d . f o r C 1 7 H 2 8 O 3 : C 7 2 . 8 2 , H 1 0 . 0 6 ; f o u n d : C 7 3 . 0 5 , H 1 0 . 1 3 . Preparation of (4bB, 8aoc, 10aB)-l,2,4a,4b,5,6,7,8,8a,9,10,10a-Dodecahydrophenanthren-4a-ol (384). H H 9 370 384 F o l l o w i n g g e n e r a l p r o c e d u r e 2 , t h e a l l y l i c a l c o h o l 384 w a s p r e p a r e d b y a d d i n g a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e 370 ( 2 4 4 m g , 0 . 7 3 4 m m o l , 1.0 e q u i v . ) i n d r y T H F ( 4 m L ) to a s o l u t i o n o f n - B u L i ( 1 . 3 m L , 1.4 M , 1.8 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 3 5 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 2 0 g t i c s i l i c a g e l , 7 . 3 : 1 p e t r o l e u m e t h e r - d i e t h y l e the r , 3 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 1 2 0 - 1 4 0 \" C / 0 . 1 5 T o r r ) , t h e a l l y l i c a l c o h o l 384 2 9 8 ( 1 3 8 m g , 8 9 % ) as a c o l o u r l e s s o i l , w h i c h s o l i d i f i e d o n s t a n d i n g t o g i v e a c l e a r s o l i d t h a t e x h i b i t e d m p 2 4 . 5 - 2 5 \u00C2\u00B0C. I R ( K B r ) : 3 4 9 5 (b r ) , 3 0 2 8 , 1 6 4 5 , 1 4 4 9 , 7 2 9 , 7 1 5 c m \" 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 8 5 - 1 . 0 9 ( m , 4 H ) , 1 . 1 1 - 1 . 6 9 ( m , 1 2 H ) , 1 . 7 6 - 1 . 8 2 ( m , I H ) , 1 . 8 6 - 1 . 9 4 ( m , I H ) , 2 . 0 0 - 2 . 1 0 ( m , 2 H ) , 5 . 7 6 ( d d d , I H , J = 1 0 . 0 , 3 . 2 , 3 . 2 H z , H - 3 ) , 5 . 9 8 (b r d , I H , 7 = 1 0 . 0 H z , H - 4 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 4 . 3 , 2 4 . 5 , 2 6 . 0 , 2 6 . 1 , 2 6 . 5 , 2 7 . 7 , 3 4 . 0 , 3 4 . 6 , 3 7 . 0 ( - v e ) , 4 3 . 5 ( - v e ) , 4 9 . 4 ( - v e ) , 6 8 . 9 ( C - 4 a ) , 1 3 0 . 0 ( - v e ) , 1 3 0 . 6 ( - ve ) . E x a c t M a s s c a l c d . f o r C14H22O: 2 0 6 . 1 6 7 1 ; f o u n d : 2 0 6 . 1 6 6 6 . A n a l , c a l c d . f o r C14H22O: C 8 1 . 5 0 , H 1 0 . 7 5 ; f o u n d : C 8 1 . 7 9 , H 1 0 . 8 8 . Preparation of l,2,4a,9,10,10a-Hexahydrophenanthren-4a-ol (385) and 2-[But-3-en-l-yl]-l,2,3,4-tetrahydronaphthalen-l-one (388). 371 385 388 F o l l o w i n g g e n e r a l p r o c e d u r e 2 , t h e a l l y l i c a l c o h o l 385 w a s p r e p a r e d b y a d d i n g a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e 371 ( 2 0 9 m g , 0 . 6 4 1 m m o l , l . O e q u i v . ) i n d r y T H F ( 2 . 5 m L ) t o a s o l u t i o n o f n - B u L i ( 1 . 0 2 m L , 1 .57 M , 1 .60 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 3 2 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 2 .3 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d t w o f r a c t i o n s . T h e f i r s t c o m p o u n d tha t e l u t e d w a s t h e a l k e n e 388 C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , a f f o r d e d t h e a l k e n e 388 ( 1 8 m g , 1 4 % ) , as a c o l o u r l e s s o i l . I R (neat ) : 3 0 7 3 , 3 0 2 5 , 1 6 8 5 , 1 6 4 1 , 1 6 0 2 , 9 9 7 , 9 1 1 , 7 4 1 c m \" 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 1 . 1 4 - 1 . 4 7 ( m , 1 H ) , 1 . 5 4 - 1 . 6 1 ( m , 1 H ) , 1 . 8 2 - 1 . 9 3 ( m , 1 H ) , 2 . 0 3 - 2 . 2 7 ( m , 3 H ) , 2 . 4 4 - 2 . 5 3 ( m , 1 H ) , 2 . 9 5 - 3 . 0 2 ( m , 2 H ) , 4 . 9 4 - 5 . 0 8 ( m , 2 H ) , 5 . 7 7 - 5 . 8 9 ( m , 1 H ) , 7 . 21 ( d , 1 H , 7 = 7 . 6 H z , H - 5 ) , 7 . 2 8 ( d d , 1 H , 7 = 7 . 6 , 7 . 6 H z ) , 7 . 4 3 ( d d , 1 H , 7 = 7 . 6 , 7 .6 H z ) , 8 .01 ( d , 1 H , 7 = 7 .6 H z , H - 8 ) . E x a c t M a s s c a l c d . f o r C i 4 H i 6 0 : 2 0 0 . 1 2 0 1 ; f o u n d : 2 0 0 . 1 1 9 8 . T h e s e c o n d c o m p o u n d that e l u t e d w a s the a l l y l i c a l c o h o l 385. C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) a f f o r d e d t h e a l l y l i c a l c o h o l 385 ( 1 1 0 m g , 8 6 % ) as a w h i t e s o l i d , m p 6 5 - 6 6 \u00C2\u00B0C. I R ( K B r ) : 3 3 3 8 (br ) , 1 9 4 6 , 1 7 2 9 , 1 7 0 7 , 1 6 4 7 , 7 5 3 c m \" 1 . * H n m r (CDCI3, 4 0 0 M H z ) 8 : 1 . 4 8 - 1 . 6 8 ( m , 1 H ) , 1 . 7 0 - 1 . 8 5 ( m , 1 H ) , 1 . 8 8 - 2 . 3 5 ( m , 6 H ) , 2 . 7 3 - 2 . 9 1 ( m , 2 H ) , 5 . 7 7 ( d d d , 1 H , 7 = 9 . 9 , 3 . 3 , 3 . 3 H z , H - 3 ) , 5 . 9 2 ( b r d , 1 H , 7 = 9 . 9 H z , H - 4 ) , 7 . 0 5 (b r d , 1 H , 7 = 7 . 6 H z ) , 7 . 1 5 ( b r d d , 1 H , 7 = 7 . 6 , 7 . 6 H z ) , 7 . 2 2 ( b r d d , 1 H , 7 = 7 . 6 , 7 .6 H z ) , 7 . 6 2 ( b r d , 1 H , 7 = 7 . 6 H z ) . ! 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 2 . 2 , 2 3 . 9 , 2 4 . 8 , 2 8 . 0 , 4 0 . 3 ( - v e , C - l O a ) , 7 0 . 1 ( C - 4 a ) , 1 2 6 . 4 3 0 0 ( - v e ) , 1 2 6 . 9 ( - ve ) , 1 2 7 . 5 ( - v e ) , 1 2 8 . 0 ( - v e ) , 1 2 8 . 4 ( - ve ) , 1 3 2 . 8 ( - v e ) , 1 3 6 . 0 , 1 4 1 . 8 . E x a c t M a s s c a l c d . f o r C14H16O: 2 0 0 . 1 2 0 1 ; f o u n d : 2 0 0 . 1 2 0 2 . A n a l , c a l c d . f o r C i 4 H i 6 0 : C 8 3 . 9 6 , H 8 . 0 5 ; f o u n d : C 8 4 . 0 4 , H 8 . 0 7 . Preparation of Bicyclo[4.3.0]non-2-en-l-ol (380) and 2-[But-3-en-l-yl]-cyclopentanone (386). 368 380 386 F o l l o w i n g g e n e r a l p r o c e d u r e 2 , t h e a l l y l i c a l c o h o l 380 w a s p r e p a r e d b y a d d i n g a s o l u t i o n o f the k e t o a l k e n y l i o d i d e 368 ( 3 2 7 m g , 1 .24 m m o l , 1.0 e q u i v . ) i n d r y T H F (3 m L ) to a s o l u t i o n o f n - B u L i ( 2 . 0 m L , 1 .57 M , 3 .1 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 6 2 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 2 0 g t i c s i l i c a g e l , 4 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 3 c m c o l u m n ) a f f o r d e d t w o f r a c t i o n s . T h e f i r s t c o m p o u n d tha t e l u t e d w a s t h e a l k e n e 386. C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) a f f o r d e d t h e a l k e n e 386 ( 1 4 m g , 8 % ) as a c o l o u r l e s s o i l . I R (neat ) : 1 7 6 6 , 1 6 4 6 , 1 6 1 5 , 9 4 6 , 7 0 0 c m \" 1 . ! H n m r ( C D C 1 3 , 4 0 0 M H z ) 5 : 0 . 8 0 - 0 . 9 5 ( m , I H ) , 1 . 1 7 - 1 . 9 3 ( m , 2 H ) , 1 . 9 5 - 1 . 6 9 ( m , 2 H ) , 1 . 7 0 - 2 . 3 8 ( m , 6 H ) , 4 . 9 0 - 5 . 1 0 ( m , 2 H ) , 5 . 7 1 - 5 . 8 5 ( m , I H ) . 3 0 1 T h e s e c o n d c o m p o u n d that e l u t e d w a s the a l l y l i c a l c o h o l 3 8 0 . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) a f f o r d e d t h e a l l y l i c a l c o h o l 3 8 0 ( 1 1 8 m g , 6 9 % ) as a w h i t e s o l i d , m p 4 0 - 4 1 \u00C2\u00B0C. I R ( K B r ) : 3 2 9 0 (b r ) , 3 0 1 7 , 1 6 5 0 , 9 7 1 , 7 0 6 c m - 1 . * H n m r ( C D C h , 4 0 0 M H z ) 6 : 1 . 3 6 - 1 . 5 2 ( m , 3 H ) , 1 . 5 3 - 1 . 8 3 ( m , 5 H ) , 1 . 8 8 - 2 . 0 5 ( m , 4 H ) , 5 . 6 6 ( d d d , 1 H , J = 1 0 . 0 , 1.7, 1.7 H z , H - 2 ) , 5 . 7 3 ( d d d , 1 H , J = 1 0 . 0 , 3 . 6 , 3 . 6 H z , H - 3 ) . 1 3 C n m r ( C D C h , 7 5 . 3 M H z ) 8 : 2 1 . 6 , 2 2 . 7 , 2 5 . 6 , 2 8 . 6 , 3 9 . 1 , 4 5 . 1 ( - v e , C - 6 ) , 7 8 . 6 ( C - l ) , 1 2 8 . 2 ( - ve ) , 1 3 2 . 2 ( - ve ) . E x a c t M a s s c a l c d . f o r C 9 H 1 4 O : 1 3 9 . 1 0 7 8 ; f o u n d : 1 3 9 . 1 0 7 0 . A n a l , c a l c d . f o r C9H14O: C 7 8 . 2 1 , H 1 0 . 2 1 ; f o u n d : C 7 8 . 0 1 , H 1 0 . 2 2 . Preparat ion of (3aB , 8aoc, 8b B)-l,2,3,3a,4,4a,7,8,8a,8b-Decahydro-5',5'-dimethylspiroICcyclopentatalinden^a-oO-l^'-d'^'-dioxane)] (381) and (IR*, 25*, 5S*)-2-[But-3-en-l-yI]-5',5,-dimethylspiro[(bicyclo[3.3.0]octan-3-one)-7^,-(l',3,-dioxane)] (387). 369 381 387 F o l l o w i n g g e n e r a l p r o c e d u r e 2 , t h e a l l y l i c a l c o h o l 381 w a s p r e p a r e d b y a d d i n g a s o l u t i o n o f t h e k e t o a l k e n y l i o d i d e 369 ( 121 m g , 0 . 3 0 0 m m o l , 1.0 e q u i v . ) i n d r y T H F (4 m L ) to a s o l u t i o n o f n - B u L i ( 0 . 4 8 m L , 1 .56 M , 0 . 7 5 m m o l , 2 . 5 e q u i v . ) i n d r y T H F ( 1 5 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 1 .5 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d t w o f r a c t i o n s . T h e f i r s t c o m p o u n d that e l u t e d w a s t h e a l k e n e 387. C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) a f f o r d e d t h e a l k e n e 387 ( 1 4 m g , 1 7 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 0 7 7 , 1 7 3 6 , 1 6 4 1 , 1 0 0 7 , 9 1 0 c m \" 1 . lH n m r ( C D C 1 3 , 4 0 0 M H z ) 5 : 0 . 9 3 7 (s, 3 H , M e - 7 ' ) , 0 . 9 4 5 (s , 3 H , M e - 8 ' ) , 1 . 2 0 - 1 . 3 3 ( m , I H ) , 1 . 3 5 - 1 . 4 7 ( m , I H ) , 1 .69 ( d d , I H , 7 = 1 3 . 3 , 5 . 9 H z ) , 1 . 7 2 - 1 . 8 2 ( m , I H ) , 1 . 8 4 - 1 . 9 5 ( m , I H ) , 2 . 0 7 - 2 . 3 8 ( m , 6 H ) , 2 . 3 9 - 2 . 4 8 ( m , I H ) , 2 . 6 2 - 2 . 8 0 ( m , I H ) , 3 . 3 9 - 3 . 4 8 ( m , 4 H , H - 4 ' , H - 6 ' ) , 4 . 9 1 - 5 . 0 8 ( m , 2 H ) , 5 . 7 1 - 5 . 8 3 ( m , I H ) . 3 0 3 E x a c t M a s s c a l c d . f o r C 1 7 H 2 6 O 3 : 2 7 8 . 1 8 8 2 ; f o u n d : 2 7 8 . 1 8 8 2 . T h e s e c o n d c o m p o u n d that e l u t e d w a s t h e a l l y l i c a l c o h o l 3 8 1 . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) a f f o r d e d t h e a l l y l i c a l c o h o l 3 8 1 ( 4 6 m g , 5 5 % ) as a w h i t e s o l i d , m p 9 7 . 5 - 9 8 . 5 \u00C2\u00B0C. I R ( K B r ) : 3 4 3 6 (b r ) , 3 0 1 5 , 1 6 4 7 , 1 1 1 4 , 7 3 6 c n r 1 . ! H n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 9 2 (s , 3 H , M e - 7 ) , 0 . 9 6 (s , 3 H , M e - 8 ) , 1 . 4 9 - 1 . 6 1 ( m , 2 H ) , 1 . 6 5 - 2 . 1 0 ( m , 8 H ) , 2 . 1 2 - 2 . 4 0 ( m , 4 H ) , 3 . 4 2 - 3 . 5 1 ( m , 4 H , H - 4 ' , H - 6 ' ) , 5 . 5 7 ( d d , 1 H , J = 10 .0 , 0 .8 H z , H - 5 ) , 5 . 7 5 ( d d d , 1 H , J = 1 0 . 0 , 3 . 6 , 3 .6 H z , H - 6 ) . 1 3 C n m r (CDCI3, 7 5 . 3 M H z ) 8 : 2 1 . 4 , 2 1 . 8 , 2 2 . 4 ( - v e , C - 7 ' ) , 2 2 . 5 ( - v e , C - 8 ' ) , 3 0 . 0 , 3 6 . 5 ( - ve ) , 3 9 . 8 , 4 0 . 2 , 4 1 . 5 ( - v e ) , 4 5 . 9 , 5 0 . 8 ( - v e ) , 7 1 . 8 ( C - 4 ) , 7 2 . 2 ( C - 6 ) , 7 8 . 4 ( C - 4 a ' ) , 1 1 0 . 4 ( C - 2 , 2 ' ) , 1 2 9 . 7 ( - v e ) , 1 3 1 . 6 ( - v e ) . E x a c t M a s s c a l c d . f o r C17H26O3: 2 7 8 . 1 8 8 2 ; f o u n d : 2 7 8 . 1 8 7 8 . A n a l , c a l c d . f o r C17H26O3: C 7 3 . 3 5 , H 9 . 4 1 ; f o u n d : C 7 3 . 1 4 , H 9 . 3 5 . 3 0 4 3.3.4. General Procedure 3: O x i d a t i v e R e a r r a n g e m e n t o f t h e T e r t i a r y A l l y l i c A l c o h o l s to the c t , B - U n s a t u r a t e d K e t o n e s . 358 359 T o a s t i r r e d s o l u t i o n o f t h e a l l y l i c a l c o h o l 358 i n d r y CH2CI2 ( 1 0 m L / m m o l a l c o h o l ) , at r o o m t e m p e r a t u r e , w a s a d d e d p y r i d i n i u m c h l o r o c h r o m a t e o n b a s i c a l u m i n a (2 .5 e q u i v . , 2 1 . 5 w t . % P C C o n b a s i c a l u m i n a ) . T h e d a r k b r o w n m i x t u r e w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r the s p e c i f i e d a m o u n t o f t i m e , at w h i c h p o i n t t i c a n a l y s i s i n d i c a t e d c o m p l e t e c o n s u m p t i o n o f the s t a r t i n g m a t e r i a l . D r y d i e t h y l e t h e r ( f i v e t i m e s t h e v o l u m e o f CH2CI2) w a s a d d e d a n d the m i x t u r e w a s s t i r r e d u n d e r a r g o n , at r o o m t e m p e r a t u r e , f o r 1 h . T h e m i x t u r e w a s f i l t e r e d t h r o u g h a c o l u m n o f Florisi l\u00C2\u00AE ( - 1 0 0 t i m e s t h e w e i g h t o f t h e a l l y l i c a l c o h o l ) a n d t h e c o l u m n w a s e l u t e d w i t h d i e t h y l e t h e r a n d t h e n e t h y l a c e t a t e u n t i l n o u v a c t i v e p r o d u c t c o u l d b e d e t e c t e d i n t h e e l u a t e . T h e s o l v e n t w a s r e m o v e d u n d e r r e d u c e d p r e s s u r e . T h e c r u d e m a t e r i a l thus o b t a i n e d w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( t ic s i l i c a g e l ) a n d t h e p r o d u c t w a s e i t h e r d i s t i l l e d o r t r a c e s o f s o l v e n t w e r e r e m o v e d ( v a c u u m p u m p ) , a f f o r d i n g t h e o c , B - u n s a t u r a t e d k e t o n e 359. 3 0 5 Preparation of Bicyclo[5.4.0]undec-l(ll)-en-10-one (259). O 257 259 F o l l o w i n g g e n e r a l p r o c e d u r e 3 , t h e a , R - u n s a t u r a t e d k e t o n e 259 w a s p r e p a r e d b y a d d i n g P C C o n b a s i c a l u m i n a ( 1 . 3 8 g , 1 .35 m m o l , 2 . 5 e q u i v . ) to a s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l 257 ( 8 9 m g , 0 . 5 4 m m o l , 1 .0 e q u i v . ) i n d r y CH2CI2 ( 5 . 4 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 1 h 3 0 m i n , b e f o r e a d d i n g d r y d i e t h y l e t h e r ( 2 7 m L ) . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 1:1 p e t r o l e u m e t h e r -d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 9 0 - 1 0 0 \u00C2\u00B0C/0.15 T o r r ) t o a f f o r d t h e a , R -u n s a t u r a t e d k e t o n e 259 ( 75 m g , 8 5 % ) as a c o l o u r l e s s o i l . I R (neat ) : 3 0 2 2 , 1 6 6 9 , 1 6 1 0 , 8 8 4 c m - 1 . ! H n m r (CDCI3, 4 0 0 M H z ) 8 : 1 . 4 7 - 1 . 6 7 ( m , 6 H ) , 1 . 6 8 - 1 . 8 8 ( m , 3 H ) , 1 .97 ( d d d d , 1 H , J = 1 3 . 1 , 5 . 1 , 5 . 1 , 5 .1 H z ) , 2 . 2 6 - 2 . 5 6 ( m , 5 H ) , 5 . 8 3 (s, 1 H , H - l l ) . 1 3 C n m r (CDCI3,75.3 M H z ) 8 : 2 7 . 0 , 2 7 . 9 , 2 9 . 7 , 3 1 . 0 , 3 3 . 0 , 3 6 . 4 , 3 6 . 9 , 3 9 . 7 ( - v e , C - 7 ) , 1 2 6 . 4 ( - ve , C - l l ) , 1 7 1 . 5 ( C - l ) , 1 9 9 . 5 ( C - 1 0 ) . E x a c t M a s s c a l c d . f o r C n H i 6 0 : 1 6 4 . 1 2 0 1 ; f o u n d : 1 6 4 . 1 2 0 1 . 306 A n a l , c a l c d . f o r C n H i 6 0 : C 80.44, H 9.82; f o u n d : C 80.25, H 9.81. Preparation of lSl'^'^'^STSSSSa'-Octahydro-S^-dimethylspiroKl^-dioxane)-!,!'-(naphthalen-6'-one)] (396). O 379 396 F o l l o w i n g g e n e r a l p r o c e d u r e 3, t h e a , B - u n s a t u r a t e d k e t o n e 396 w a s p r e p a r e d b y a d d i n g PCC o n b a s i c a l u m i n a (1.06 g , 1.04 m m o l , 2.5 e q u i v . ) to a s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l s 379 (105 m g , 0.42 m m o l , -1:1 m i x t u r e o f a l c o h o l s , 1.0 e q u i v . ) i n d r y CH2CI2 (4.0 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 3 h 30 m i n , b e f o r e a d d i n g d r y d i e t h y l e t h e r (20 m L ) . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (10 g t i c s i l i c a g e l , 2.3:1 p e t r o l e u m e t h e r - d i e t h y l e the r , 2.5 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 175-185 \"C/0.15 T o r r ) t o a f f o r d the o c , B - u n s a t u r a t e d k e t o n e 396 (92 m g , 89%) as a c o l o u r l e s s , v e r y v i s c o u s o i l . IR (neat ) : 3027, 1669, 1622,1122,797 c m \" 1 . 3 0 7 ! H n m r ( C D C h , 4 0 0 M H z ) 8 : 0 . 9 4 (s, 3 H , M e - 7 ) , 1 .00 (s, 3 H , M e - 8 ) , 1 .24 ( d d , 1 H , 7 = 1 2 . 9 , 1 2 . 9 H z ) , 1 . 4 0 - 1 . 5 0 ( m , 1 H ) , 1 . 5 6 - 1 . 6 8 ( m , 1 H ) , 2 . 0 3 - 2 . 1 1 ( m , 1 H ) , 2 . 2 3 - 2 . 6 3 ( m , 7 H ) , 3 . 4 6 -3 . 5 8 ( m , 4 H , H - 4 , H - 6 ) , 5 . 8 3 (s, 1 H , H - 5 ' ) . !3C n m r ( C D C h , 7 5 . 3 M H z ) 8 : 2 2 . 4 ( - v e , C - 7 ) , 2 2 . 6 ( - v e , C - 8 ) , 2 9 . 0 , 3 0 . 1 ( C - 5 ) , 3 0 . 8 , 3 0 . 9 , 3 3 . 8 ( - v e , C - 8 a ' ) , 3 6 . 5 , 3 9 . 5 , 7 0 . 1 (2 s i g n a l s , C - 4 , C - 6 ) , 9 6 . 8 ( C - 2 , 2 ' ) , 1 2 4 . 6 ( - v e , C - 5 ' ) , 1 6 4 . 9 ( C - 4 a ' ) ( 1 9 9 . 5 ( C - 6 ' ) . E x a c t M a s s c a l c d . f o r C15H22O3: 2 5 0 . 1 5 6 9 ; f o u n d : 2 5 0 . 1 5 6 3 . A n a l , c a l c d . f o r C15H22O3: C 7 1 . 9 7 , H 8 . 8 6 ; f o u n d : C 7 1 . 8 3 , H 9 . 0 1 . Preparation of 1 '^SS'^'^'^'^SSa'-Octahydro-S^^a'-trimethylspirottl^-dioxane)-2,2-(naphthalen-6,-one)] (400). O 382 400 F o l l o w i n g g e n e r a l p r o c e d u r e 3 , t h e a , R - u n s a t u r a t e d k e t o n e 400 w a s p r e p a r e d b y a d d i n g P C C o n b a s i c a l u m i n a ( 9 6 0 m g , 0 . 9 3 8 m m o l , 2 . 5 e q u i v . ) t o a s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l 382 ( 1 0 0 m g , . 0 3 7 4 m m o l , 1.0 e q u i v . ) i n d r y C H 2 C I 2 (3 .7 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 5 h 3 0 m i n , b e f o r e a d d i n g d r y d i e t h y l e t h e r ( 1 9 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 1:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e a , B - u n s a t u r a t e d k e t o n e 400 ( 8 5 m g , 8 6 % ) as a c o l o u r l e s s o i l . I R (neat ) : 2 8 6 9 , 1 6 7 4 , 1 6 2 1 , 1 3 9 6 , 1 0 9 3 , 1 1 1 3 , 8 6 6 c m \" 1 . ! H n m r (CDCI3, 4 0 0 M H z ) 8 : 0 . 9 1 (s , 3 H , M e - 7 ) , 1 .02 (s , 3 H , M e - 8 ) , 1 . 1 3 - 1 . 4 2 ( m , I H ) , 1 .32 (s, 3 H , M e - 9 ) , 1 .50 ( d d d , I H , J = 1 3 . 9 , 1 3 . 9 , 4 . 2 H z ) , 1 . 7 2 - 1 . 8 8 ( m , 2 H ) , 2 . 1 2 ( b r d d d , I H , J = 1 4 . 6 , 4 . 2 , 4 . 2 H z ) , 2 . 2 7 - 2 . 5 5 ( m , 4 H ) , 2 . 6 4 ( d d d d , I H , J = 1 4 . 6 , 1 4 . 6 , 4 . 8 , 1.9 H z ) , 3 . 4 2 - 3 . 5 8 ( m , 4 H , H - 4 , H - 6 ) , 5 . 7 3 (s, I H , H - 5 ' ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 2 . 4 ( - ve ) , 2 2 . 7 ( - ve ) , 2 2 . 9 ( - ve ) , 2 9 . 2 , 3 0 . 1 ( C - 5 ) , 3 3 . 4 , 3 4 . 1 , 3 6 . 0 ( C - 8 a ' ) , 3 8 . 6 , 4 3 . 8 , 7 0 . 1 5 ( C - 4 ) , 7 0 . 2 3 ( C - 6 ) , 9 7 . 0 ( C - 2 , 2 ' ) , 1 2 4 . 1 ( - v e , C - 5 ' ) , 1 6 8 . 9 ( C -4a ' ) , 1 9 9 . 2 ( C - 6 ' ) . E x a c t M a s s c a l c d . f o r C16H24O3: 2 6 4 . 1 7 2 6 ; f o u n d : 2 6 4 . 1 7 2 3 . A n a l , c a l c d . f o r C16H24O3: C 7 2 . 6 9 , H 9 . 1 5 ; f o u n d : C 7 2 . 7 3 , H 9 . 1 6 . 3 0 9 P r e p a r a t i o n of (4'B , 8 a ' a V l ' ^ ' ^ ' ^ ' ^ ' ^ ' ^ ' ^ a ' - O c t a h y d r o ^ ' ^ ^ a ' -tetramethylspiro[(l,3-dioxane)-2,2'-naphthaIen-6'-one] (400', one diastereomer) and (4a, 8a ,a)-l ,,2',3 ,,4 ,,4a ,,7 ,,8',8a ,-Octahydro-4',5,5,8a ,-tetramethylspiro[(l,3-dioxane)-2,2'-naphthalen-6'-one] (400\", other diastereomer). O 383 400 T o a s t i r r e d s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l s 383 ( 5 5 m g , 0 . 1 9 m m o l , 1.0 e q u i v . ) i n d r y CH2CI2 ( 1 .9 m L ) , at r o o m t e m p e r a t u r e , w a s a d d e d P C C o n b a s i c a l u m i n a ( 0 . 5 0 g , 0 . 4 9 m m o l , 2 . 5 e q u i v . ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 2 3 h a n d t h e n c r u s h e d , d r i e d , 4A m o l e c u l a r s i e v e s ( 1 6 5 m g ) w e r e a d d e d . 1 5 5 T h e m i x t u r e w a s s t i r r e d f o r a n a d d i t i o n a l 3 h a n d t h e n m o r e P C C o n b a s i c a l u m i n a ( 0 . 5 0 g , 0 . 4 9 m m o l , 2 . 5 e q u i v . ) w a s a d d e d . T h e r e a c t i o n m i x t u r e w a s h e a t e d a t r e f l u x f o r 5 h a n d t h e n w a s c o o l e d t o r o o m t e m p e r a t u r e . D r y d i e t h y l e t h e r ( 1 0 m L ) w a s a d d e d a n d t h e m i x t u r e w a s s t i r r e d at r o o m t e m p e r a t u r e , u n d e r a r g o n , f o r 1 h . T h e m i x t u r e w a s f i l t e r e d t h r o u g h a c o l u m n ( 2 c m ) o f Florisil\u00C2\u00AE (7 g ) a n d t h e c o l u m n w a s e l u t e d w i t h d i e t h y l e t h e r u n t i l n o u v a c t i v e m a t e r i a l c o u l d b e d e t e c t e d i n t h e e l u a n t . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y (5 g t i c s i l i c a g e l , 1.5:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e a,B-u n s a t u r a t e d k e t o n e s 400 ( 25 m g , 4 7 % ) as w h i t e s o l i d , m p 9 5 - 9 7 \u00C2\u00B0C. A n a p p r o x i m a t e r a t i o f o r t h e s e d i a s t e r e o m e r s w a s 6 - 7 : 1 i n f a v o r o f c o m p o u n d 400. T h e s p e c t r o s c o p i c d a t a g i v e n 3 1 0 b e l o w f o r t h e k e t o n e s 4 0 0 r e f e r s t o t h e i n s e p a r a b l e m i x t u r e o f d i a s t e r e o m e r s , u n l e s s o t h e r w i s e s t a t e d . I R ( K B r ) : 2 8 6 9 , 1 6 7 3 , 1 6 1 1 , 1 4 7 1 , 1 0 9 9 , 8 2 2 c m - 1 . ! H n m r ( C D C h , 4 0 0 M H z ) 8 : 0 . 9 5 (s , 3 H , M e - 7 ) , 0 . 9 7 (s , 3 H , M e - 8 ) , 1 .25 (d , 3 H , J = 7 . 3 H z , M e - 1 0 ) , 1 .34 (s, 3 H , M e - 9 ) , 1 .74 ( d d d , 1 H , 7 = 1 3 . 1 , 5 .4 , 2.1 H z ) , 1 . 8 1 - 2 . 1 5 ( m , 3 H ) , 2 . 1 8 (d , 1 H , J = 14 H z ) , 2 . 2 3 - 2 . 4 6 ( m , 2 H ) , 2 . 4 8 - 2 . 7 3 ( m , 2 H ) , 3 . 4 5 - 3 . 5 4 ( m , 4 H , H - 4 , H - 6 ) , 5 . 8 2 (s, 1 H , H - 5 ' ) . 1 3 C n m r ( C D C 1 3 , 7 5 . 3 M H z ) 8 : ( m a j o r d i a s t e r e o m e r o n l y ) 2 1 . 4 ( - v e , C - 9 ) , 2 2 . 6 8 ( - v e , C - 7 ) , 2 2 . 7 3 ( - v e , C - 8 ) , 2 5 . 5 ( - v e , C - 1 0 ) , 3 0 . 1 ( C - 5 ) , 3 3 . 7 , 3 5 . 1 ( - ve , C - 4 ' ) , 3 5 . 8 ( C - 8 a ' ) , 3 6 . 6 , 3 9 . 8 , 4 5 . 0 , 7 0 . 1 ( C - 4 ) , 7 0 . 3 ( C - 6 ) , 9 8 . 2 ( C - 2 , 2 ' ) , 1 2 4 . 3 ( - v e , C - 5 ' ) , 1 7 4 . 4 ( C - 4 a ' ) , 1 9 9 . 7 ( C - 6 ' ) . E x a c t M a s s c a l c d . f o r C17H26O3: 2 7 8 . 1 8 8 2 ; f o u n d : 2 7 8 . 1 8 8 4 . A n a l , c a l c d . f o r C17H26O3: C 7 3 . 3 5 , H 9 . 4 1 ; f o u n d : C 7 3 . 4 4 , H 9 . 5 5 . 3 1 1 Preparation of (4b R, 8 aa, 10aR)-l,2,3,4b,5,6,7,8,8a,9,10,10a-Dodecahydrophenanthren-3-one (401). H H 384 401 F o l l o w i n g g e n e r a l p r o c e d u r e 3 , t h e o c , R - u n s a t u r a t e d k e t o n e 401 w a s p r e p a r e d b y a d d i n g P C C o n b a s i c a l u m i n a ( 1 . 3 8 g , 1 .34 m m o l , 2 . 5 e q u i v . ) t o a s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l 384 ( 111 m g , 0 . 5 3 7 m m o l , 1.0 e q u i v . ) i n d r y C H 2 C I 2 ( 5 . 4 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 5 h 15 m i n , b e f o r e a d d i n g d r y d i e t h y l e t h e r ( 2 6 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 3 :1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e a , R - u n s a t u r a t e d k e t o n e 401 ( 1 0 3 m g , 9 4 % ) as a y e l l o w s o l i d , m p 5 4 - 5 4 . 5 \u00C2\u00B0C. I R ( K B r ) : 3 0 5 4 , 1 6 7 2 , 1 6 1 0 , 8 3 8 c n r * . * H n m r (CDCI3, 4 0 0 M H z ) 8 : 1 . 0 1 - 1 . 4 2 ( m , 7 H ) , 1 . 5 7 - 1 . 7 6 ( m , 5 H ) , 1 . 7 8 - 1 . 9 3 ( m , 3 H ) , 2 . 0 5 - 2 . 1 4 ( m , 1 H ) , 2 . 2 1 - 2 . 3 9 ( m , 3 H ) , 5 . 7 8 (s , 1 H , H - 4 ) . 1 3 C n m r (CDCI3,75.3 M H z ) 8 : 2 5 . 6 , 2 5 . 8 , 2 7 . 7 , 2 8 . 4 , 3 3 . 2 , 3 3 . 9 , 3 4 . 3 , 3 5 . 3 , 3.8.3 ( - ve ) , 4 4 . 1 ( - v e ) , 4 7 . 6 ( - v e ) , 1 2 0 . 7 ( - v e , C - 4 ) , 1 6 9 . 8 ( C - 4 a ) , 2 0 0 . 0 ( C - 3 ) . 3 1 2 E x a c t M a s s c a l c d . f o r C14H20O: 2 0 4 . 1 5 1 4 ; f o u n d : 2 0 4 . 1 5 1 1 . A n a l , c a l c d . f o r C14H20O: C 8 2 . 3 0 , H 9 . 8 7 ; f o u n d : C 8 2 . 2 9 , H 9 . 9 5 . Preparation of l,2,3,9,10,10a-Hexahydrophenanthren-3-one (402). O 384 402 F o l l o w i n g g e n e r a l p r o c e d u r e 3 , t h e a , B - u n s a t u r a t e d k e t o n e 402 w a s p r e p a r e d b y a d d i n g P C C o n b a s i c a l u m i n a ( 1 . 3 5 g , 1 .32 m m o l , 2 . 5 e q u i v . ) to a s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l 384 ( 1 0 6 m g , 0 . 5 2 8 m m o l , 1.0 e q u i v . ) i n d r y C H 2 C l 2 ( 5 . 3 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 2 h , b e f o r e a d d i n g d r y d i e t h y l e t h e r ( 2 6 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 2 . 3 : 1 p e t r o l e u m e t h e r - d i e t h y l e the r , 2 .5 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e o c , B - u n s a t u r a t e d k e t o n e 402 ( 5 0 m g , 4 8 % ) as a w h i t e s o l i d , m p 6 9 - 7 0 \u00C2\u00B0C. I R ( K B r ) : 3 0 6 4 , 1 6 6 1 , 1 5 8 7 , 8 7 8 , 7 6 3 c n r 1 . * H n m r ( C D C I 3 , 4 0 0 M H z ) 5 : 1 .60 ( d d d d , I H , J = 1 3 , 1 3 , 1 3 , 5 . 3 H z ) , 1 . 7 4 - 1 . 8 8 ( m , I H ) , 2 . 0 5 ( d d d d , I H , J = 1 3 , 4 , 4 , 4 H z ) , 2 . 1 4 - 2 . 2 4 ( m , I H ) , 2 . 3 8 - 2 . 6 9 ( m , 3 H ) , 2 . 8 6 - 3 . 0 4 ( m , 2 H ) , 3 1 3 6 . 6 3 (d , 1 H , J = 2 . 2 H z , H - 4 ) , 7 . 1 7 (d , 1 H , J = 7 .5 H z , H - 8 ) , 7 . 2 2 ( d d , 1 H , J = 7 . 5 , 7 .5 H z , H -6 o r H - 7 ) , 7 . 3 0 ( d d , 1 H , J = 7 . 5 , 7 . 5 H z , H - 6 o r H - 7 ) , 7 . 7 6 (d , 1 H , J = 7 . 5 H z , H - 5 ) . n m r ( C D C h , 7 5 . 3 M H z ) 5 : 3 0 . 0 , 3 0 . 3 , 3 0 . 5 , 3 7 . 1 ( - v e , C - l O a ) , 3 7 . 4 , 1 2 0 . 3 ( - v e ) , 125 .1 ( - v e ) , 1 2 6 . 5 ( - v e ) , 1 2 9 . 6 ( - v e ) , 1 3 0 . 5 ( - ve ) , 1 3 1 . 2 ( C - 4 b o r C - 8 a ) , 1 3 9 . 8 ( C - 4 b o r C - 8 a ) , 1 5 8 . 2 ( C - 4 a ) , 2 0 0 . 2 ( C - 3 ) . \u00E2\u0080\u00A2Exact M a s s c a l c d . f o r C 1 4 H 1 4 O : 1 9 8 . 1 0 4 5 ; f o u n d : 1 9 8 . 1 0 4 2 . A n a l , c a l c d . f o r C14H14O: C 8 4 . 8 1 , H 7 . 1 2 ; f o u n d : C 8 4 . 8 3 , H 7 . 0 0 . Preparation of Bicyclo[4.3.0]non-l-en-3-one (397). O 380 397 F o l l o w i n g g e n e r a l p r o c e d u r e 3 , t h e a , f i - u n s a t u r a t e d k e t o n e 397 w a s p r e p a r e d b y a d d i n g P C C o n b a s i c a l u m i n a ( 9 2 4 m g , 0 . 9 0 2 m m o l , 2 . 5 e q u i v . ) t o a s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l 380 ( 5 0 m g , 0 . 3 6 m m o l , 1 .0 e q u i v . ) i n d r y CH2CI2 ( 3 . 6 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 4 h , b e f o r e a d d i n g d r y d i e t h y l e t h e r ( 1 8 m L ) . T h e c r u d e p r o d u c t w a s p u r i f i e d b y f l a s h c h r o m a t o g r a p h y (5 g t i c s i l i c a g e l , 1.5:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 c m c o l u m n ) . T h e a p p r o p r i a t e f r a c t i o n s w e r e c o n c e n t r a t e d a n d t h e o i l t h u s o b t a i n e d w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 7 5 - 8 5 \" C / 0 . 1 5 T o r r ) to a f f o r d t h e a , R - u n s a t u r a t e d k e t o n e 397 (31 m g , 6 3 % ) as a c o l o u r l e s s o i l . 3 1 4 I R (neat ) : 3 0 3 3 , 1 6 6 4 , 8 6 9 , 7 4 5 c m \" 1 . l H n m r ( C D C 1 3 , 4 0 0 M H z ) 8: 1 . 2 7 - 1 . 3 1 ( m , I H ) , 1 . 5 3 - 1 . 7 7 ( m , 2 H ) , 1 . 8 4 - 1 . 9 5 ( m , I H ) , 2 . 0 6 ( d d d , I H , J = 1 2 . 7 , 6 . 8 , 6 .8 H z ) , 2 . 1 7 - 2 . 3 4 ( m , 2 H ) , 2 . 3 9 - 2 . 6 7 (ra, 4 H ) , 5 . 8 7 (b r s , I H , H - 2 ) . 1 3 c n m r (CDCI3, 7 5 . 3 M H z ) 8: 2 3 . 8 , 2 9 . 1 , 3 1 . 7 , 3 2 . 7 , 3 7 . 4 , 4 3 . 0 ( - v e , C - 6 ) , 1 2 2 . 1 ( - v e , C - 2 ) , 1 7 5 . 5 ( C - l ) , 1 9 9 . 8 ( C - 3 ) . E x a c t M a s s c a l c d . f o r C 9 H 1 2 0 : 1 3 6 . 0 8 8 8 ; f o u n d : 1 3 6 . 0 8 9 0 . A n a l , c a l c d . f o r C 9 H i 2 0 : C 7 9 . 3 7 , H 8 . 8 8 ; f o u n d : C 7 9 . 1 0 , H 9 . 0 1 . P r e p a r a t i o n of ( 3 aB , 8 a a , 8b B )-l,2^,3a,4,6,7,8,8a,8b-Decahydro-5,,5'-dimethylspiro[(cyclopenta[a]inden-6-one)-2,2'-(r,3'-dioxane)] (398). O 381 398 F o l l o w i n g g e n e r a l p r o c e d u r e 3 , t h e a . B - u n s a t u r a t e d k e t o n e 3 9 8 w a s p r e p a r e d b y a d d i n g P C C o n b a s i c a l u m i n a ( 6 0 2 m g , 0 . 5 8 8 m m o l , 2 . 5 e q u i v . ) t o a s o l u t i o n o f t h e t e r t i a r y a l l y l i c a l c o h o l 3 8 1 ( 6 5 m g , 0 . 2 4 m m o l , 1.0 e q u i v . ) i n d r y C H 2 C 1 2 ( 2 . 4 m L ) . T h e r e a c t i o n m i x t u r e w a s s t i r r e d f o r 2 h 3 0 m i n , b e f o r e a d d i n g d r y d i e t h y l e t h e r ( 1 2 . 5 m L ) . P u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y f l a s h c h r o m a t o g r a p h y ( 1 0 g t i c s i l i c a g e l , 1:1 p e t r o l e u m e t h e r - d i e t h y l e t h e r , 2 . 5 c m c o l u m n ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d r e m o v a l o f t r a c e s o f s o l v e n t ( v a c u u m p u m p ) , t h e o c , B - u n s a t u r a t e d k e t o n e 3 9 8 ( 5 7 m g , 8 8 % ) as a w h i t e s o l i d , m p 1 0 3 -1 0 4 \u00C2\u00B0C. I R ( K B r ) : 3 0 2 8 , 1 6 6 8 , 1 3 2 0 , 1 1 1 2 , 8 7 6 c m \" 1 . lH n m r ( C D C 1 3 , 4 0 0 M H z ) 8 : 0 . 9 2 (s , 3 H , M e - 7 ' ) , 0 . 9 7 (s, 3 H , M e - 8 ' ) , 1 . 4 9 - 1 . 6 5 ( m , I H ) , 1.78 ( d d , I H , J = 1 3 . 7 , 6 . 5 H z ) . 1 . 9 4 - 2 . 0 5 ( m , I H ) , 2 . 1 1 - 2 . 3 3 ( m , 5 H ) , 2 . 3 8 - 2 . 6 2 ( m , 3 H ) , 2 . 6 3 - 2 . 7 7 ( m , 2 H ) , 3 . 4 0 - 3 . 5 5 ( m , 4 H , H - 4 ' , H - 6 ' ) , 5 . 8 0 (s , I H , H - 5 ) . 1 3 C n m r ( C D C I 3 , 7 5 . 3 M H z ) 8 : 2 2 . 3 5 ( - ve , C - 7 \" ) , 2 2 . 4 4 ( - v e , C - 8 ' ) , 2 9 . 2 , 3 0 . 0 ( C - 5 ' ) , 3 7 . 3 , 3 8 . 5 , 3 8 . 9 ( - ve ) , 3 9 . 6 , 4 0 . 4 , 4 7 . 2 ( - v e ) , 4 7 . 3 ( - v e ) , 7 2 . 0 0 ( C - 4 ' ) , 7 2 . 0 5 ( C - 6 ' ) , 1 1 0 . 4 ( C - 2 , 2 * ) , 1 2 1 . 6 ( - ve , C - 5 ) , 175 .1 ( C - 4 a ) , 1 9 9 . 7 ( C - 6 ) . E x a c t M a s s c a l c d . f o r C 1 7 H 2 4 O 3 : 2 7 6 . 1 7 2 6 ; f o u n d : 2 7 6 . 1 7 2 9 . 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T h i s r e s o n a n c e l i k e l y c o n t a i n s b o t h v i n y l m e t h y l s i g n a l s s i n c e t h e * H n m r s p e c t r u m ( 4 0 0 M H z , C D C I 3 ) o f the s y n t h e t i c (\u00C2\u00B1)-64, s h o w s t w o r e s o l v e d s i n g l e t s at 5 1 .66 a n d 1.68. T h e r e p o r t e d s i n g l e t at 8 1.52 f o r the n a t u r a l c y a t h a n e (-)-64 a l s o a p p e a r s i n t h e s u p p l i e d * H n m r s p e c t r u m a n d i s l i k e l y t h e s i g n a l f o r H 2 O . 140 . W e a re v e r y g r a t e f u l to P r o f e s s o r E m i l i o G h i s a l b e r t i ( U n i v e r s i t y o f W e s t e r n A u s t r a l i a ) f o r c o p i e s o f the i n f r a r e d a n d 1 H n m r s p e c t r a o f (-)-(3R, AR, 5R, 6S, 9 7 ? ) - c y a t h a - 1 2 , 1 8 - d i e n e . 1 4 1 . I n h o m o n u c l e a r d e c o u p l i n g e x p e r i m e n t s d e s c r i b e d i n t h e i s o l a t i o n p a p e r f o r the c y a t h a n e n a t u r a l p r o d u c t 64 ( see r e f e r e n c e 2 3 ) , c o u p l i n g w a s a l s o o b s e r v e d b e t w e e n t h e r e s o n a n c e at 6 5 . 3 3 ( H - 1 3 ) a n d the r e s o n a n c e s c e n t e r e d at 8 1.7 ( H - 1 4 ) a n d 8 2 . 0 ( H - 1 4 ' ) w h e n the s i g n a l at 6 5 . 3 3 w a s i r r a d i a t e d . 142 . T h e m i c r o b i a l a c t i v i t y s t u d i e s w e r e c o n d u c t e d b y P a u l H a y d e n f r o m t h e B i o l o g i c a l S e r v i c e s D e p a r t m e n t at the U n i v e r s i t y o f B r i t i s h C o l u m b i a . 1 4 3 . T h e c y t o t o x i c i t y s t u d i e s w e r e c o n d u c t e d b y D r . T h e r e s a M . A l l e n ' s l a b o r a t o r y at the U n i v e r s i t y o f A l b e r t a . 144 . M i t r a , R . B . ; R e d d y , G . B . Synthesis 1989, 6 9 4 . 1 4 5 . P i e r s , E . ; F r i e s e n , R . W . Can. J. Chem. 1992, 70, 1 2 0 4 . 146 . P i e r s , E . ; C o i s h , P . D . Synthesis 1995, 4 7 , a n d c i t a t i o n s t h e r e i n . 1 4 7 . P e p e y r e , M . ; Q u i n t a r d , J . P . ; R a h m , A . Tin in Organic Synthesis; B u t t e r w o r t h s : L o n d o n , 1 9 8 7 . 1 4 8 . C o o k e , M . P . J r . ; H o u p i s , I. N . Tetrahedron Lett. 1985,26,4987. 3 2 7 149 . B a l d w i n , J . E . J. Chem. Soc, Chem. Commun. 1976, 7 3 4 . 1 5 0 . A s i m i l a r c y c l i z a t i o n o f a s e v e n - m e m b e r e d r i n g k e t o v i n y l i o d i d e to p r o v i d e a f i v e m e m b e r e d - r i n g a f f o r d e d a 2:1 m i x t u r e o f d i a s t e r e o m e r i c a l l y l i c a l c o h o l s (see r e f e r e n c e 14) . 1 5 1 . B i i r g i , H . B . ; D u n i t z , J . D . ; S h e f t e r , E . J. Am. Chem. Soc 1973, 95, 5 0 6 5 . 1 5 2 . D a u b e n , W . G . ; M i c h n o , D . M . J. Org. Chem 1977,42, 6 8 2 . 1 5 3 . 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Organomet. Chem 1997, 542, 2 8 1 . 1 6 3 . W u t s , P . G . M . Synth. Commun. 1981, 7 7 , 1 3 9 . 164 . A d a m , W . ; C h a n , Y . - Y . ; C r e m e r , D . ; G a u s s , J . ; S c h e u t z o w , D . ; S c h i n d l e r , M . J. Org. Chem 1987, 52, 2 8 0 0 . 1 6 5 . L e e , J . B . ; O t t , K . C ; G r u b b s , R . H . J. Am. Chem. Soc. 1982,104,7491. 3 2 8 166 . T h e s p e c t r a l d a t a f o r t h e e n o n e 179 a r e i d e n t i c a l t o t h o s e r e p o r t e d i n r e f e r e n c e 4 8 . 1 6 7 . T h e l i t h i u m m e t a l w a s w a s h e d w i t h p e n t a n e s e v e r a l t i m e s p r i o r t o u s e i n o r d e r to r e m o v e the o i l . 168 . T h e l i t h i u m d i s p e r s i o n u s e d w a s o b t a i n e d f r o m the A l d r i c h C h e m i c a l C o m p a n y , c a t a l o g n u m b e r 2 4 , 8 8 2 - 7 ( s o d i u m c o n t e n t < 0 . 0 5 % ) . 1 6 9 . T h e l i t h i u m w i r e u s e d w a s o b t a i n e d f r o m t h e A l d r i c h C h e m i c a l C o m p a n y , c a t a l o g n u m b e r 2 7 , 8 3 2 - 7 ( 3 . 2 m m i n d i a m e t e r , s o d i u m c o n t e n t - 0 . 5 - 1 % ) . T h e w i r e w a s c u t i n t o - 5 m m p i e c e s b e f o r e w a s h i n g a w a y t h e o i l . 1 6 8 1 7 0 . S i n c e t h e c h r o m a t o g r a p h i c s e p a r a t i o n o f the c o m p o u n d s 194 a n d 60 w a s q u i t e d i f f i c u l t , t h e y i e l d o f p u r e 60 v a r i e d s o m e w h a t f r o m e x p e r i m e n t to e x p e r i m e n t . H o w e v e r , m i x e d f r a c t i o n s c o u l d e a s i l y b e r e c y c l e d . 1 7 1 . T h e m e t h y l i o d i d e w a s p u r i f i e d b y p a s s i n g i t t h r o u g h o v e n d r i e d b a s i c a l u m i n a ( 1 5 x 2 c m c o l u m n ) . 1 7 2 . C r a b t r e e , S . R . ; M a n d e r L . N . ; S e t h i , S . P . Org. Synth. 1991, 70, 2 5 6 . 173 . T h i s s i g n a l i n the 1 3 C n m r s p e c t r u m o f the k e t o n e 303 l i k e l y c o n t a i n s the m i s s i n g q u a t e r n a r y c a r b o n f o r th i s c o m p o u n d b a s e d o n the c h e m i c a l s h i f t o f t h i s r e s o n a n c e . T h i s s i g n a l i s a l s o i n c r e a s e d i n i n t e n s i t y r e l a t i v e to t h e o t h e r m e t h y l e n e s i g n a l s i n t h i s s p e c t r u m . 174 F l e m i n g , I. Organocopper Reagents. A Practical Approach; T a y l o r , R . J . K . ; E d s . ; O x f o r d U n i v e r s i t y P r e s s : O x f o r d , 1 9 9 4 ; p 2 7 9 . 1 7 5 . T h e a c e t y l e n e g a s w a s p a s s e d t h r o u g h t w o c o l d ( - 78 \u00C2\u00B0C) t r a p s , t h r o u g h a g a s o m e t e r , a n d t h e n t h r o u g h a c a l c i u m c h l o r i d e d r y i n g t u b e b e f o r e b e i n g a l l o w e d to a b s o r b i n t o t h e r e a c t i o n m i x t u r e . F o r a s c h e m a t i c o f a s i m i l a r a p p a r a t u s u s e d to d e l i v e r p r e c i s e v o l u m e s o f a c e t y l e n e g a s , s e e F u r b e r , M . ; T a y l o r , R . J . K . ; B u r f o r d , S . C . J. Chem. Soc, Perkin Trans. 1 1986,1809. 176 . D r . C h r i s t i n e R o g e r s ( o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) i s g r a t e f u l l y a c k n o w l e d g e d f o r the c h a r a c t e r i z a t i o n d a t a a n d the e x p e r i m e n t a l p r o c e d u r e u s e d to p r e p a r e M / V - d i m e t h y l h y d r a z o n e 211. 177 . M r . S h a w n D . W a l k e r ( o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) i s g r a t e f u l l y a c k n o w l e d g e d f o r t h e e x p e r i m e n t a l p r o c e d u r e u s e d to p r e p a r e N,N-d i m e t h y l h y d r a z o n e 364. 1 7 8 . M r . S h a w n D . W a l k e r ( o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) i s g r a t e f u l l y a c k n o w l e d g e d f o r t h e e x p e r i m e n t a l p r o c e d u r e u s e d to p r e p a r e N,N-d i m e t h y l h y d r a z o n e 363. 3 2 9 1 7 9 . D r . C h r i s t i n e R o g e r s ( o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) i s g r a t e f u l l y a c k n o w l e d g e d f o r t h e c h a r a c t e r i z a t i o n d a t a a n d the e x p e r i m e n t a l p r o c e d u r e u s e d to p r e p a r e / Y ^ - d i m e t h y l h y d r a z o n e 361. 1 8 0 . / V , / V - D i m e t h y l h y d r a z o n e 362 w a s g e n e r o u s l y p r o v i d e d b y M s . K a t h e r i n e C o o k (o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) . F o r t h e e x p e r i m e n t a l p r o c e d u r e u s e d to p r e p a r e d c o m p o u n d 362, see r e f e r e n c e 1 4 5 . 1 8 1 . N , i V - D i m e t h y l h y d r a z o n e 364 w a s g e n e r o u s l y p r o v i d e d b y M r . S h a w n D . W a l k e r ( o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) . 1 8 2 . / V - D i m e t h y l h y d r a z o n e 363 w a s g e n e r o u s l y p r o v i d e d b y M r . S h a w n D . W a l k e r ( o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) . 1 8 3 . A ^ / V - D i m e t h y l h y d r a z o n e 360 w a s g e n e r o u s l y p r o v i d e d b y M r . S h a w n D . W a l k e r ( o f D r . P i e r s ' r e s e a r c h g r o u p at U B C ) . F o r t h e e x p e r i m e n t a l p r o c e d u r e u s e d t o p r e p a r e d c o m p o u n d 360, s e e r e f e r e n c e 144 . "@en . "Thesis/Dissertation"@en . "1998-11"@en . "10.14288/1.0061501"@en . "eng"@en . "Chemistry"@en . "Vancouver : University of British Columbia Library"@en . "University of British Columbia"@en . "For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use."@en . "Graduate"@en . "Total synthesis of (+-) neoverrucosan-5B-ol, (+-)-homoverrucosan-5B-ol, (+-)-verrucosan-2B-ol, and (+-)-(3R,4R,5R,6S,9R)-cyatha-12,18-diene : a new cyclohexenone annulation sequence"@en . "Text"@en . "http://hdl.handle.net/2429/9454"@en .