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The use of camphor in sesquiterpenoid synthesis Kuo, David Liang 1987

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THE USE OF CAMPHOR IN SESQUITERPENOID SYNTHESIS By DAVID LIANG KUO B . S c , The U n i v e r s i t y of B r i t i s h Columbia, 1983 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 t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA December 1987 © David L i a n g Kuo, 1987 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 C h e m i s t r y The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date December 30, 1987 DE-6(3/81) T h i s t h e s i s i s d e d i c a t e d to my dearest parents, Dr. and Mrs. Y. C. Kuo with love ABSTRACT T h i s t h e s i s , e n t i t l e d "The use of camphor i n s e s q u i t e r -peno id s y n t h e s i s " , c o n s i s t s of three c h a p t e r s . Chapter One d e s c r i b e s the c o n v e r s i o n of (+)-8-bromocamphor (42) i n t o a c h i r a l d i m e t h y l - a c e t a l e n o l s i l y l e ther (105) t h a t undergoes f a c i l e T i C l ^ - p r o m o t e d i n t r a m o l e c u l a r c y c l i s a t i o n to p r o v i d e t r i c y c l i c i n t e r m e d i a t e s ( 1 9 5 a , b ) , which a f t e r a s e r i e s of f u n c t i o n a l group i n t e r c o n v e r s i o n s and the i n t r o d u c t i o n of the gem-dimethyl g r o u p , l eads to the f i r s t e n a n t i o s p e c i f i c t o t a l s y n t h e s i s of ( + ) - l o n g i b o r n e o l (59) ( c a . 13% i n 21 s teps from ( + )-camphor ( 2 6 ) ) . O x i d a t i o n of ( + ) - l o n g i b o r n e o l (59) p r o v i d e s (+ ) - long icamphor (83 ) , which was conver ted i n t o ( + ) - l o n g i -i s o b o r n e o l (89) by r e d u c t i o n . Subsequent treatment w i t h of ( + ) - l o n g i i s o b o r n e o l (89) w i t h M s C l , 4-DMAP, and p y r i d i n e , r e v e a l s ( + ) - l o n g i f o l e n e (61) ( c a . 52% i n 3 s t eps from ( 5 9 ) ) . Two o ther major at tempts were a l s o c a r r i e d out p r i o r to the s u c c e s s f u l s y n t h e s i s of (59) and ( 6 1 ) . T r i e n e a c e t a t e s (103a ,b) were s y n t h e s i s e d ( c a . 8% i n 10 s t eps from (+)-camphor ( 2 6 ) ) , but f a i l e d to undergo the i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n . In a d d i t i o n , (+)-campherenone (151) was a l s o prepared ( c a . 28% i n 9 s t eps from (+)-camphor ( 2 6 ) ) , and both (151) and i t s d e r i -v a t i v e s (170) , and (104) undergo SnCl^-promoted i n t e r m o l e c u l a r t e r t i a r y p t - a l k y l a t i o n r e a c t i o n to p r o v i d e d imers ( 1 6 9 a , b ) . Chapter Two d e s c r i b e s two s y n t h e t i c approaches to a lbene (221) which i n v o l v e s an i n t r a m o l e c u l a r ene r e a c t i o n , or i an i n t r a m o l e c u l a r f r e e r a d i c a l c y c l i s a t i o n r e a c t i o n . A new e n a n t i o s p e c i f i c s y n t h e s i s route to (+)-(3-santalene (259) ( c a . 78% i n 2 s t e p s from (+)-campherenone (151)) i s i l l u s -t r a t e d , however, ( + ) - ( £ - s a n t a l e n e f a i l e d to undergo the i n t r a -m o l e c u l a r ene r e a c t i o n to p r o v i d e o l e f i n (261) . In a d d i t i o n , b r o m o - o l e f i n (260) i s a l s o p r e p a r e d ( c a . 59% i n 14 s t eps from ( + )-camphor ( 2 6 ) ) , but c y c l i s e s i n a 6-£XD_- tr ig mode i n the i n t r a m o l e c u l a r f r e e r a d i c a l c y c l i s a t i o n r e a c t i o n to p r o v i d e methyl e ther (331) . Chapter Three d e s c r i b e s an e v a l u a t i o n of the p o t e n t i a l use of (+)-5 ,6-dehydrocamphor (323) as a c h i r a l synthon i n the s y n t h e s i s of the A , B r i n g system ( c f . 329) of s e v e r a l c l a s s e s of t e r p e n o i d . ( + )-5 ,6-dehydrocamphor (323) was p r e p a r e d from ( - ) -endo-3-bromocamphor (41) i n two s t e p s , and which i s then c o n v e r t e d to b i c y c l i c enones ( 3 6 8 a , b , 369a ,b , 3 7 6 a ,b) by a sequence i n which the key r e a c t i o n was an a n i o n i c oxy-Cope rearrangement . B i c y c l i c enones ( 3 6 8 a , b) were c o n v e r t e d to t r i c y c l i c k e t a l s ( 3 8 5 a , b ) , but at tempts to c o n v e r t t h i s compound to an a n g u l a r l y methy la ted i n t e r m e d i a t e (434) were u n s u c c e s s f u l . F u r t h e r m o r e , 1 , 5 - d i e n o l s ( 4 0 9 a , b ) , s y n t h e s i s e d from (323) i n c a . 50% y i e l d , f a i l e d to undergo an a n i o n i c oxy-Cope rearrangement to p r o v i d e b i c y c l i c ketones ( 4 1 0 a , b ) . A l -t e r n a t i v e ways of c o n s t r u c t i n g an a n g u l a r methyl group i n t o the C(10) p o s i t i o n i n b i c y c l i c enones ( 3 6 9 a , b , or 3 7 6 a ,b) are c u r r e n t l y b e i n g i n v e s t i g a t e d i n our l a b o r a t o r y . In a d d i t i o n , b i c y c l i c ketones ( 3 7 3 a , b) c o u l d serve as key i n t e r m e d i a t e s i i i n an e n a n t i o s p e c i f i c s y n t h e s i s of s p i r o d y s i n (421) , and i n d i r e c t l y to the s y n t h e s i s of f u r o d y s i n (422) , and f u r o d y s i n i n (423) . i i i TABLE OF CONTENTS ABSTRACT i TABLE OF CONTENTS i v LIST OF TABLES v i SPECTRA APPENDIX v i i LIST OF ABBREVIATIONS AND TERMINOLOGY i x ACKNOWLEDGEMENTS x i i i GENERAL INTRODUCTION 1 Chapter 1: An E n a n t i o s p e c i f i c S y n t h e s i s o f ( + ) - L o n g i b o r n e o l and ( + ) - L o n g i f o l e n e . 24 1 . 1 . 0 . INTRODUCTION 25 1 . 2 . 0 . DISCUSSION 35 1 . 3 . 0 . EESLLLXS. 42 1 . 3 . 1 . INTRAMOLECULAR DIELS-ALDER REACTION APPROACH 42 1 . 3 . 2 . INTROMOLECULAR LEWIS ACID INDUCED oC-TERTIARY  ALKYLATION APPROACH 61 1 . 3 . 3 . INTRAMOLECULAR MUKAIYAMA REACTION APPROACH 68 1 . 4 . 0 . EXPERIMENTAL 88 Chapter 2: S y n t h e t i c Approaches To Albene 160 2 . 1 . 0 . INTRODUCTION 161 2 . 2 . 0 . DTSCUSSION AND RESULTS 171 2 . 2 . 1 . INTRAMOLECULAR ENE REACTION APPROACH 171 i v 2.2.2. INTRAMOLECULAR FREE RADICAL CYCI.TSATTON APPROACH 178 2.3.0. EXPERIMENTAL 192 Chapter 3: A Synthetic Approach to the A,B Ring System of Terpenoids 211 3.1.0. INTRODUCTION 212 3.2.0. DISCUSSION AND RESULTS 217 3.3.0. EXPERIMENTAL 242 SPECTRA APPENDIX: 269 REFERENCES: " 293 v L I S T OF TABLES Page Table 1: Attempts i n the I n t r a m o l e c u l a r D i e l s - A l d e r R e a c t i o n 60 Table 2: [ot] D Of ( + ) , And ( - ) - L o n g i b o r n e o l s 80 Table 3: [oG D Of ( + ) , And (- ) - L o n g i f o l enes 82 v i SPECTRA APPENDIX Compounds page D i e n o l s (142b) and (142a) [*H-n .m.r . (400MHz) ] 270 1 Dienone (136a,b) [ H - n . m . r . ( 4 0 0 M H z ) ] 271 T r i e n e - a c e t a t e s (103a,b) [ 1 H - n . m . r . ( 4 0 0 M H z ) ] 271 C y a n o k e t a l s (167a,b) [ *H-n . m. r . (400MHz ) ] 272 Dimers (169a,b) [Low R e s o l u t i o n Mass Spectrum] 272 Dimers (169a,b) [ *H-n .m.r . (400MHz) ] 273 p-bromobenzoate (186) [ X - r a y c r y s t a l l o g r a p h i c s t e r e o v i e w s ] 273 Hydroxye thoxy-ke tones (192b) and (192a) [ 1 H - n . m . r . ( 4 0 0 M H z ) ] 274 Hydroxye thoxy-ke tones (192a ,b) [ I n f r a - r e d spectrum] 275 (R)-methoxy-ketone (195a) and (s ) -methoxy-ketone (195b) [ H - n . m . r . ( 4 0 0 M H z ) ] 276 (R) -methoxy-ketone (195a) [ X - r a y c r y s t a l l o g r a p h i c s t e r e o v i e w s ] 277 (+)-Camphor (26) [ I n f r a - r e d spectrum] 275 (+ ) - l o n g i b o r n e o l (59) [ I n f r a - r e d spectrum] 277 ( + ) - l o n g i b o r n e o l (59) [ 1 H - n . m . r . ( 4 0 0 M H z ) ] : Money and K u o ' s 278 A n d e r s o n ' s ( N a t u r a l s o u r c e ) 278 Welch ' s ( ( i ) - l o n g i b o r n e o l ) ) 279 L o n g i b o r n e o l MTPA E s t e r (211) [ 1 H - n . m . r . ( 2 7 0 M H z ) ] 279 19 L o n g i b o r n e o l MTPA E s t e r (211) [ F - n . m . r . ( 2 5 4 M H z ) ] 2 8 0 13 L o n g i b o r n e o l MTPA E s t e r (211) [ C - n . m . r . ] 281 ( + ) - L o n g i f o l e n e (61) [ I n f r a - r e d spectrum] 282 ( + ) - L o n g i f o l e n e (61) [ 1 H - n . m . r . ( 4 0 0 M H z ) ] 282 v i i (+)-Longifolene (61) [Low reso lut ion mass spectrum] 283 Hydroxy-ester (324) [Infra-red spectrum] 283 Hydroxy-ester (324) [ *H-n.m.r.(400MHz)] 284 Hydroxy-ester (323) [^-n.m.r.(400MHz)] 284 Methyl ether (331) [*H-n.m.r.(400MHz)] 285 B i c y c l i c a lcohols (365a,b) [ *H-n . m. r . (400MHz) ] ( L - s e l e c t r i d e ) 285 B i c y c l i c acetates (366a,b) [ *H-n . m . r . (400MHz ) ] 286 B i c y c l i c enones (368a,b) [ *H-n . m . r . ( 400MHz ) ] 286 Enone (392) [X-ray crys ta l lographic stereoviews] 287 Dimer (411) [X-ray crys ta l lographic stereoviews] 287 ( + ) -Longi isoborneol (89) [ *H-n.m.r.(400MHz)] 288 (+)-Longicamphor (83) [ *H-n . m . r . (400MHz ) ] 288 ( + )-Campherenone (151) [*H-n.m.r.(400MHz ) ] 289 < + )-oC-Santalene (259) [ *H-n . m •. r . ( 400MHz ) ] 289 B i c y c l i c enones (368a,b) [ \-r\. m . r . ( 400MHz ) ] 290 B i c y c l i c enones (369a,b) [ 1 H-n.m.r.(400MHz)] 290 Dienols (409a,b) [ : H-n.m.r.(400MHz)] 291 B i c y c l i c a lcohols (365a,b) [ X H-n.m.r.(300MHz)] (LiAlH ) 291 (+)-8-Bromocamphor (42) [ X H-n.m.r.(400MHz)] 292 v i i i L I S T OF ABBREVIATIONS AND TERMINOLOGY (a) Terminology S i n c e many of the compounds r e f e r r e d to i n t h i s t h e s i s are o p t i c a l l y a c t i v e , i n order to d i f f e r e n t i a t e between enant iomers the term *ent' i s u sed . ' E n t ' r e f e r s to the enant iomer of the compound g i v e n , eg . ( + )-camphor 1D_ has the s t r u c t u r e : (-0-CAMPHOR 10 ( - ) -camphor i s thus denoted as ent10. (b) Abbrev i a t i o n s The f o l l o w i n g a b b r e v i a t i o n s are used i n t h i s t h e s i s : A - A c t i v a t i n g group Ac - A c e t y l AIBN - 2 , 2 ' - A z o b i s - ( i s o b u t y r o n i t r i l e ) APT - A t t a c h e d P r o t o n T e s t ax - A x i a l BB - Broad Band Decouple bp - B o i l i n g p o i n t ix br - Broad ( i r and i H - n . m . r . ) Bu - tertiary-Butyl Bu - B u t y l Cone. - C o n c e n t r a t e d c - C o n c e n t r a t i o n i n g/100 mL of s o l v e n t CD - C i r c u l a r D i c h r o i s m d - Double t ( ^ - n . m . r . ) DHP - D i h y d r o p y r a n e DIBAL - 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 DIS - D i s c o n n e c t i o n DMAP - 4 - D i m e t h y l a m i n o p y r i d i n e DMF - N ,N-Dimethyl formamide DMS - D i m e t h y l s u l p h i d e DMSO - D i m e t h y l s u l p h o x i d e E - E l e c t r o p h i l e EG - E t h y l e n e G l y c o l eq - E q u a t o r i a l E t - E t h y l FGI - F u n c t i o n a l Group I n t e r c o n v e r s i o n g l e - G a s - l i q u i d Chromatography HMPA - Hexamethylphosphoramide i r - I n f r a r e d LDA - 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 t . - L i t e r a t u r e m - M u l t i p l e t ( H i - n . m . r . ) or Medium ( i r ) M - Molar x Me - Methyl mmol - M i l l i m o l e m/e - Mass to charge r a t i o MHz - Mega hertz MOM - Methoxymethyl mp - M e l t i n g p o i n t Ms - Methanesulphonyl MTPA - oL-Methoxy-oC-( t r i f luoromethyl )pheny l a c e t y 1 N - Normal(concentration) NBS - N-Bromosuccinimide n.m.r. - Nuclear Magnetic Resonance NOE - Nuclear Overhauser E f f e c t PCC - P y r i d i n i u m Chlorochrornate PDC - P y r i d i n i u m Dichromate ph - Phenyl ppm - P a r t s per M i l l i o n py - P y r i d i n e q - Quartet (^H-n.m.r.) s - S i n g l e t (^-n.m.r.) or Strong ( i r ) t - T r i p l e t ( 1H-n.m.r.) TBAF - Tetrabutylammonium F l u o r i d e TBDMS - t e r t i a r v - B u t v l d i m e t h y l s i l y l t - t e r t i a r y THF - Te t r a h y d r o f u r a n t i c - Thin Layer Chromatography TMS - T r i m e t h y l s i l y l x i t r i f l a t e - Trifluoromethanesulphonate UV - U l t r a V i o l e t w/v - Weight to volume r a t i o w - Weak ( i r ) WM - Wagner Meerwein Rearrangement Wt. - Weight [ot] - S p e c i f i c R otation at 589 nm 2,3 exo Me - 2 , 3-gxo_-Methy 1 s h i f t 2,6 H - 2,6-Hydride s h i f t £ - Chemical s h i f t i n ppm from the t e t r a m e t h y l s i l a n e s i g n a l V - Wavenumbers ( c m - 1 ) x i i ACKNOWLEDGEMENTS T h i s t h e s i s could not be w r i t t e n without e x t e n s i v e helps from the f i n e group of people at U.B.C. F i r s t , I wish to acknowledge my r e s e a r c h s u p e r v i s o r , P r o f e s s o r Thomas Money, f o r h i s s t i m u l a t i n g ideas, p a t i e n t enlightenment, and continuous support i n many ways throughout the course of t h i s work. I a l s o wish to thank the former members of P r o f e s s o r Money's re s e a r c h group, Dr. S. P i p e r , Dr. J . Hutchinson and Mr. G. Roberts f o r t h e i r t e c h n i c a l a s s i s t a n c e at the very beginning of my r e s e a r c h . A s p e c i a l thanks goes to Mr. A. Cl a s e f o r p r o o f r e a d i n g my t h e s i s . My s i s t e r Miss Feng-ni Kuo's on-going help d u r i n g the p r e p a r a t i o n of t h i s t h e s i s i s a p p r e c i a t e d . In a d d i t i o n , the expert m i c r o a n a l y t i c a l work of Mr. P. Borda, the e x c e l l e n t X-ray c r y s t a l l o g r a p h i c a n a l y s i s of Dr. J . T r o t t e r and Dr. S. R e t t i g , together with the s k i l l e d t e c h n i c i a n s i n n.m.r. and mass spectrometry l a b o r a t o r i e s i n the department are g r a t e f u l l y acknowledged. F i n a l l y , I wish to thank the Department of Chemistry, U.B.C. and N.S.E.R.C., Canada f o r t h e i r f i n a n c i a l support over the past four y e a r s . x i i i "The s y n t h e s i s of subs tances o c c u r r i n g i n N a t u r e , perhaps i n g r e a t e r measure than in any other area of o r g a n i c c h e m i s t r y , p r o v i d e s a measure of the c o n d i t i o n and powers of the s c i e n c e " R. B. Woodward i n P e r s p e c t i v e s i n O r g a n i c C h e m i s t r y (1956) GENERAL INTRODUCTION The s t r u c t u r a l d i v e r s i t y of n a t u r a l products has presented a c o n s i d e r a b l e c h a l l e n g e to the org a n i c chemists who are concerned with t h e i r l a b o r a t o r y s y n t h e s i s , and indeed t h i s c h a l l e n g e has pro v i d e d impetus f o r g r e a t advances i n s y n t h e t i c methodology. The problems a s s o c i a t e d with s y n t h e t i c methodology i n v o l v e c o n s t r u c t i o n of the carbon framework, f u n c t i o n a l group t r a n s f o r m a t i o n , and c o n t r o l of ab s o l u t e s t e r e o c h e m i s t r y . In g e n e r a l , however, the c o n t r o l of absolute s t e r e o c h e m i s t r y remains the most complicated i s s u e i n de v e l o p i n g a s y n t h e t i c s t r a t e g y to a p a r t i c u l a r n a t u r a l product. Most n a t u r a l products e x i s t i n nature as e n a n t i o m e r i c a l l y pure compounds and u s u a l l y only one enantiomer i s r e s p o n s i b l e f o r the p a r t i c u l a r b i o l o g i c a l a c t i v i t y , while the other one i s e i t h e r i n a c t i v e or capable of causing s e r i o u s s i d e e f f e c t s [1] . Stimulated by the enantiomeric p u r i t y of most n a t u r a l products and by the complete asymmetric i n d u c t i o n of enzymic r e a c t i o n s o c c u r r i n g i n b i o l o g i c a l systems, o r g a n i c chemists have developed ways of p r e p a r i n g e n a n t i o m e r i c a l l y pure forms of n a t u r a l products by ( i ) r e s o l v i n g some convenient i n t e r m e d i a t e or f i n a l product; ( i i ) c o n s t r u c t i n g the t a r g e t molecule from a c h i r a l i n t e r m e d i a t e s by means of asymmetric i n d u c t i o n [2]; and ( i i i ) the u t i l i s a t i o n of inexpensive, and r e a d i l y a v a i l a b l e c h i r a l s t a r t i n g m a t e r i a l s [3]. A b r i e f d i s c u s s i o n of each of these approaches w i l l be provided below. 1 ( i ) F i r s t , the conventional method of obtaining enantio-merically pure target molecules has been the employment of r e s o l u t i o n of r a c e m a t e s . To separate enantiomers at the end of a synthesis, e s p e c i a l l y of multi-step ones results in the loss of at least half of the product. The resolution of racemates at the beginning of a synthesis i s p a r t i c u l a r l y useful in those cases where both enantiomers can either be used in the synthesis or transformed into s y n t h e t i c a l l y useful building blocks. For example, in the synthesis of the macrolide, erythrynolide B ( 1 ) [ 4 ] , the racemic ketal ( 2 ) was resolved by separating the co-rresponding mandelate esters ( 3 ) and ( 4 ) . Subsequent hydrolysis 0 (1) (2) (3) of these esters provided enantiomerically pure ketals ( 5 ) and ( 6 ) which were then used as the c h i r a l s t a r t i n g materials in the construction of upper l e f t half and lower right half of the target molecule ( 1 ) respectively. ( i i ) An alternative approach to the synthesis of natural products which avoids wasteful and often time consuming resolution steps, involves asymmetric i n d u c t i o n . Generally, 2 the f i r s t r e a c t i o n of an a c h i r a l s t a r t i n g molecu le to generate a c h i r a l c e n t e r w i l l i n e v i t a b l y p r o v i d e racemates as shown i n Scheme 1. F u r t h e r m o r e , any subsequent r e a c t i o n to generate B (R)-AB + (S)-AB e n a n t i o m e r i c p r o d u c t s ( R . R ) - A B C + (S.S)-ABC + • (R.S)-ABC + (S.R)-ABC enantiomeric and diastereomeric products Scheme 1 a d d i t i o n a l c h i r a l c e n t e r s w i l l produce both d i a s t e r e o m e r s and enant iomers i n which the d i a s t e r e o m e r s c o u l d be p o s s i b l y s e p a r a t e d , whereas the enant iomers must be r e s o l v e d . Thus i t i s d e s i r a b l e tha t the f i r s t s tep i n the r e a c t i o n sequence s h ou l d 3 generate p r e f e r e n t i a l l y one enantiomer over the o t h e r . T h i s asymmetric i n d u c t i o n , which c o n v e r t s an a c h i r a l u n i t i n t o a c h i r a l u n i t i n which the enant iomers ( R ) - C and ( S ) - C are pro^ duced i n unequal amounts, u s u a l l y r e q u i r e s a c h i r a l a u x i l a r y . I t i s t h i s aspec t of asymmetric i n d u c t i o n which p l a y s a c e n t r a l r o l e i n the r e a c t i o n p r o c e s s and d i c t a t e s which r e a c t i o n p r o d -uc t ( R ) - C or ( S ) - C w i l l predominate , as i l l u s t r a t e d i n Scheme 2 A* ( c h i r a l molecule) [A*••«B(R)] 7.S. [A* * • 'B(S)] T.S. (R)-c , ( c h i r a l product) ( S ) - C ( c h i r a l product) Scheme 2 The r a t i o of ( R ) - C / ( S ) - C produced i s dependent on the r e l a t i v e r a t e c o n s t a n t s K(R) and K(S) l e a d i n g to the r e s p e c t i v e d i a s t e r e o m e r i c t r a n s i t i o n s t a t e s ( T . S . ) . The magnitude of the d i f f e r e n c e i n f r e e energy ( A A G * ) w i l l de termine the r a t i o of e n a n t i o m e r i c p r o d u c t s ( R ) - C / ( S ) - C s i n c e these two compet ing p r o c e s s e s are a f u n c t i o n of the r e s p e c t i v e f r e e e n e r g i e s of 4 4 o a c t i v a t i o n ( A G ). A p p r o x i m a t e l y , a A A G of 2 k c a l / m o l e at 0 C can produce e s s e n t i a l l y one of the enant iomers i n at l e a s t 80% 4 e n a n t i o m e r i c excess [ 5 ] and t h i s r a t i o may be deemed as s y n t h e t i c a l l y u s e f u l . Hence i t i s d e s i r a b l e to maximise A A G * which would i n c r e a s e the e n a n t i o m e r i c excess of the p r o d u c t . Four examples of the asymmetric i n d u c t i o n approach i n v o l v i n g the use o f c h i r a l a u x i l a r i e s are p r o v i d e d below. {1} Asymmetric D i e l a - A l d e r Reaction O p p o l z e r ' s and Helmchen's r e s e a r c h groups [6] have demo-n s t r a t e d the use of a wide v a r i e t y of f u n c t i o n a l i s e d a l c o h o l s of e n a n t i o m e r i c camphor d e r i v a t i v e s as c h i r a l a u x i l a r i e s i n a s -ymmetric s y n t h e s i s . T h i s methodology i n g e n e r a l has three adv-antages which i n c l u d e the h igh degree of asymmetric i n d u c t i v e s e l e c t i v i t y , r e a d i l y a v a i l a b l e and i n e x p e n s i v e p r e c u r s o r s of the c h i r a l a u x i l a r i e s i n both e n a n t i o m e r i c forms, and easy r e -moval of the c h i r a l a u x i l a r i e s a f t e r i n t r o d u c t i o n of new c h i r a -l i t y has been a c h i e v e d . Scheme 3 shows t i t a n i u m t e t r a c h l o r i d e promoted a d d i t i o n of c y c l o p e n t a d i e n e to both enant iomers of the c o n f o r m a t i o n a l l y r i g i d c i s - d i p h e n y l m e t h y l b o r n y l a c r y l a t e , which e x h i b i t s a h i g h degree o f asymmetric i n d u c t i o n , where (7) gave ( R ) - c y c l o a d d u c t (8) and (9) produced ( S ) - c y c l o a d d u c t ( 1 0 ) . {2} Asymmetric 1,4-Addition O p p o l z e r and co -workers [7] have r e p o r t e d boron t r i f l u r o r i d e mediated 1 , 4 - a d d i t i o n of organocopper reagent s to c h i r a l d e r i v a t i v e s of oC,/3-unsaturated c a r b o n y l compounds which a l s o r e s u l t e d i n a h i g h degree o f asymmetric i n d u c t i o n , as i l l u s t r a t e d i n Scheme 4. Here , 1 , 4 - a d d i t i o n of organocopper reagent to (11) produced e s t e r (12) w i t h a h i g h degree of 5 s e l e c t i v i t y , which was subsequently hydrolysed to a c i d (13) {3} Asymmetric H v d r o b o r a t i o n Brown and Z w e i f e l [8] have deve loped the p r e p a r a t i o n of the h i g h l y o p t i c a l l y pure d i i s o p i n o c a m p h e n y l b o r a n e ( I P C 2 B H ) (14) from the r e a c t i o n of ( + ) - or (-)-o(_-pinene (15) and b o r a n e - t e t r a h y d r o f u r a n . T h i s organoborane reagent was u t i l i s e d i n the asymmetric h y d r o b o r a t i o n of d i e n e (16) to p r o v i d e (17) by Corey and N o y o r i i n the s y n t h e s i s of P G F 0 , (18) [ 9 ] , as shown i n Scheme 5. BH, • SMej ( + ) - ( 1 5 ) (14) HO ^CHjCOjMe ^ ^ ^,(CH 2) 3COOH n-C sH u (16) (17) Scheme 5 {4} Asymmetric A l k y l a t i o n Meyers and co -workers have demonstrated the use of c h i r a l o x a z o l i n e (19) [10] i n the asymmetric a l k y l a t i o n r e a c t i o n , in which ( S ) - a c i d (20) was o b t a i n e d w i t h h i g h e n a n t i o m e r i c exces s , and the methoxyamino a l c o h o l (21) , as expec ted , was u t i l i s e d to r e g e n e r a t e the c h i r a l o x a z o l i n e as i l l u s t r a t e d i n Scheme 6. In s p i t e of these developements i n the asymmetric s y n t h e -s i s , the c o n t r o l of a b s o l u t e s t e r e o c h e m i s t r y and the r e g i o s p e c i -f i c i n t r o d u c t i o n of f u n c t i o n a l i t y at prede termined s i t e s remain 7 L i X (21) (20) Scheme 6 c r u c i a l problems i n the c o n s t r u c t i o n of even moderately f u n c t i o n a l i s e d c h i r a l compounds, that i s , i n most cases the minor, undesired, enantiomer i s a l s o formed. To minimise t h i s drawback i n asymmetric s y n t h e s i s , an a l t e r n a t i v e approach would i n v o l v e the use of an e n a n t i o m e r i c a l l y pure s t a r t i n g m a t e r i a l . In essence, t h i s approach i n v o l v e s s c r u t i n i s i n g the molecular s t r u c t u r e of the t a r g e t molecule to i d e n t i f y hidden elements, decode the s t e r e o c h e m i c a l i n f o r m a t i o n , and transpose the t a r g e t molecule e i t h e r p a r t i a l l y or t o t a l l y , i n t o the carbon framework of a s u i t a b l e c h i r a l s t a r t i n g m a t e r i a l [ 1 1 ] . The c h o i c e of a c h i r a l s t a r t i n g m a t e r i a l i s l e f t to the imagination and c r e a t i v i t y of the o r g a n i c chemist and g e n e r a l l y conforms to the f o l l o w i n g g u i d e l i n e s . F i r s t , 8 the c h i r a l s t a r t i n g m a t e r i a l must be r e a d i l y a v a i l a b l e at a reasonable c o s t . Second, i t should be a v a i l a b l e i n both en-antiomeric forms so t h a t e i t h e r enantiomer of the t a r g e t mo-l e c u l e could be s y n t h e s i s e d . T h i r d , i t must possess v e r s a t i l e chemical r e a c t i v i t y so that i t can be used to c o n s t r u c t a wide v a r i e t y of l a r g e molecules. The pace of u t i l i s i n g c h i r a l s t a r t i n g m a t e r i a l s i n n a t u r a l product s y n t h e s i s has been e x c e p t i o n a l l y r a p i d d u r i n g the past s e v e r a l years. By now the l i t e r a t u r e has witnessed a l a r g e number of s u c c e s s f u l t o t a l syntheses employing c h i r a l s t a r t i n g m a t e r i a l s , and Schemes 7-10 i l l u s t r a t e the s p e c i f i c use of ( R ) - l , 2 - i s o p r o p y l i d e n e g l y c e -raldehyde (22) [12], (-)- or ( + ) - t a r t a r i c a c i d (23) [13], (-)-or (+)-carvone (24) [14], and D-glucose (25) [15] r e s p e c t i v e l y . Camphor i s another r e a d i l y a v a i l a b l e c h i r a l s t a r t i n g m a t e r i a l which has been widely u t i l i s e d i n the s y n t h e s i s of n a t u r a l products. Camphor e x i s t s i n nature in three forms (+), (-), and racemic. (+)-Camphor (26) i s the most abundant enan-tiomer, and can be i s o l a t e d from the wood of the camphor l a u -r e l (Cinnamomum camphora). On the other hand, (-)-camphor (27) (26) (27) (28) 9 PROSTAGLANDIN E [12a] 1 (22) (•*•) -DIHYDROANTIRHINE [12e] IPSDIENOL [12b] 0 H " ' 0. H BREFELDIN A [12c] > H OH •( + ) . f 6 R . V T O - P E S T A L 0 T I N [12d] Scheme 7 IONOPHORE ANTIBIOTIC X-145^7A [1 3 a ] I , Scheme 8 11 1 .25-DIHYDROXYCHOLECALCIFEROL [14b] Scheme 9 12 AVERMECTTN B l a AGLYCONE [ 1 5 a ] I [ 1 5 c ] ERYTHRONOLIDE A [15b] Scheme 10 1 3 which i s much l e s s common, occurs i n the o i l of the sagebrush (Artemesia t r i c l e n t a t a ) . Although (-)-camphor i s not as r e a d i a v a i l a b l e as and more expensive than (+)-camphor, i t can be e a s i l y prepared by the o x i d a t i o n of the more abundant and r e l a t i v e l y inexpensive (-)-borneol (28). At f i r s t g l ance, the molecular s t r u c t u r e of camphor seems to i n d i c a t e that t h i s compound w i l l not have the v a r i e d chemical r e a c t i v i t y normally r e q u i r e d f o r a c h i r a l s t a r t i n g m a t e r i a l i n n a t u r a l product s y n t h e s i s . However, the v e r s a t i -l i t y of camphor as a c h i r a l s t a r t i n g m a t e r i a l i s a s s o c i a t e d with i t s tendency to undergo molecular rearrangements which pr o v i d e an o p p o r t u n i t y f o r the i n t r o d u c t i o n of f u n c t i o n a l i t y at C(3), C(4), C(5), C(6), C(8), C(9) and C(10) p o s i t i o n s (Scheme 11). In a d d i t i o n , r i n g cleavage (Scheme 12) of C ( l ) -G(2), C(2)-C(3) and C ( l ) - C ( 7 ) bonds can produce many u s e f u l s y n t h e t i c i n t e r m e d i a t e s . Camphor chemistry has been r e c e n t l y reviewed [16], and t h e r e f o r e only a b r i e f d e s c r i p t i o n of the methods to func-t i o n a l i s e camphor and the a p p l i c a t i o n of these d e r i v a t i v e s i n the e n a n t i o s p e c i f i c s y n t h e s i s of n a t u r a l products w i l l be p r ovided below. <1> C(41 S u b s t i t u t i o n (Scheme 13) (-)-4-Methylcamphor (29) has r e c e n t l y prepared from (+)-camphor (26) i n 4 steps [17]. I t has the p o t e n t i a l of being transformed i n t o the r i n g D and p a r t of r i n g C (30) of t r i t e r p e n o i d s such as lanostane (31) and d e r i v a t i v e s while 14 ( +)-4-methylcamphor ( e n t - 2 9 ) c o u l d l ead to d i a s t e r e o m e r i c t r i t e r p e n o i d s such as euphane ( 3 2 ) . T h i s s y n t h e t i c p o t e n -t i a l i s based on the assumption tha t 4-methylcamphor c o u l d be conver ted to 9 ,10-d ibromo-4-methy lcamphor (33) and t h a t 15 <a) C I e a v a £ e of C ( l ) - C ( 2 ) Bond (b) Cleavage of C (2 ) -C(3 ) Bond (c) Cleavage of C( 1 )-C(7) Bond Scheme 12 16 (30) (33) Scheme 13 subsequent r i n g cleavage between C ( l ) and C(2) carbon-carbon bond would r e v e a l an intermediate (30) which could be conve-r t e d to the C,D r i n g system of lanostane (31). E f f o r t s towards 17 t h i s o b j e c t i v e are c u r r e n t l y b e i n g made i n our l a b o r a t o r y [17 ] . <2> C ( 5 1 S u b s t i t u t i o n (Scheme 14) Scheme 14 shows the p r e p a r a t i o n of 5-bromocamphor (34) from 3 , 5 - c y c l o c a m p h o r (35) [18 ] . Other r o u t e s to C(5) f u n c -f u n c t i o n a l i s e d camphors can be c a r r i e d out e i t h e r m i c r o b i o -l o g i c a l l y [19] or c h e m i c a l l y [19] through remote o x i d a t i o n of b o r n y l a c e t a t e (36) to a f f o r d 5 - k e t o b o r n y l a c e t a t e (37) and 6 - k e t o b o r n y l a c e t a t e (38) as the major and minor p r o d u c t s r e s p e c t i v e l y . Both (37) and (38) have been u t i l i s e d i n the s y n t h e s i s of ( + ) - n o j i g i k u a l c o h o l (39) by Money et a l . [20 ] . (39) Scheme 14 18 <3> 0(6^ S u b s t i t u t i o n (-)-6-fincia-BroiDocamphor (40) can be prepared from the rearrangement of ( + )-3-£Djip_-bromocamphor (41) with chlorosul fonic acid [21]. An evaluation of the use of (40) in the enan-t i o s p e c i f i c synthesis of terpenoids i s provided in chapter 3 <4> C f f n S n h s t . i t . u t i o n (Scheme 15) (+) or (-)-8-Bromocamphor (42) or (43) can be e a s i l y prepared from (+) or (-)-camphor (26) or (27) in 3 steps [22]. Its usefulness as a c h i r a l intermediate in natural product synthesis i s c l e a r l y r e f l e c t e d in Scheme 15 [23], and chapters 1 and 2 of thi s thesis. <5> C(9"> S u b s t i t u t i o n (Scheme 16) (+)-9-Bromocamphor (44) prepared from (41) in 2 steps [22] has been used in the synthesis of ( +)-o(.-santalene (45) [24], ( + )-c(-santalol (46) [25], ( +)-isoepicampherenol (47) [23], ( + )-epi-(3-santalene (48) [23], and the steroid i n t e r -mediate (49) [26] (cf. Scheme 16). <6> C(\C\) S u b s t i t u t i o n (Scheme 17) (+)-10-Gamphorsulfonic acid (50) i s derived from the treatment of (+)-camphor (26) with acetic anhydride and concentrated s u l f u r i c acid [27]. Its enantiomeric ammonium (41) (40) 19 OH I . 49S ' OH | (•)-longlborneot W-c . -phor ( • ) - l o n g l c a . p h o r « _ ' t (26) (42) \ V : 3 steps sH^J rT^f0 m. »» rTr° (-O-lonnIcyelene r ^ (O-copaborneol^v^ J (•O-ylanj.oborneol (-) -camphor (27) (43) /K^ £^ • / S r — - i ? b f (-)-eopaeanphene* ^ (^)-copacanphor* ^ ( - ) -c»»pherenonc (+)-ylanBocaaphor* (-)-aatlvene r OH W f (-)-cyclocopacaaphene'* (4)-a -sant«lene (-)-camph*renol (-)-B-aantalene (-)-cycloeat lvene •f enant loner also known * unknown ln nature Scheme 15 (.)-!M«picanT*»r«r«l ( 4 7 ) <0-Epi-|*-»ontaUr* (48) Scheme 16 21 s a l t (51) has been a p p l i e d i n the s y n t h e s i s of (-)-khusimone (52a) and ( + ) - z i z a n o i c a c i d (52b) [28] as shown i n Scheme 17. <7> C ( 9 1 . ' C ( l t n S u b s t i t u t i o n (Scheme 18) (+)-9,10-Dibromocamphor (53), prepared from (41) i n 3 ste p s [29] has been widely u t i l i s e d as an important c h i r a l i n t e r m e d i a t e i n the s y n t h e s i s of (-)-estrone (54) [30], the C a l i f o r n i a red s c a l e pheromone (55) [31], p r e c u r s o r of the C,D (51) (52a) (5.2b) Scheme 17 r i n g system of v i t a m i n (56) [32], C,D r i n g system of 11-o x y - s t e r o i d s (57) [33], and the h e l e n a n o l i d e intermediate (58) [34] ( c f . Scheme 18). One of the main aims of the r e s e a r c h d e s c r i b e d i n t h i s t h e s i s was to i n v e s t i g a t e the f u r t h e r use of C(8) f u n c t i o n -a l i s e d camphor d e r i v a t i v e s (Chapter 1 and Chapter 2), and C(6) f u n c t i o n a l i s e d camphor d e r i v a t i v e s (Chapter 3) i n the e n a n t i o s p e c i f i c s y n t h e s i s of t e r p e n o i d s . 22 PRECURSOR OF THE C,D RING SYSTEM OF VITAMIN D 0 ( 5 6 ) Scheme 18 23 C h a p t e r 1 An E n a n t i o s p e c i f i c S y n t h e s i s of (+)-Longiborneol And ( + ) - L o n g i f o l e n e 24 1 .1 .0 . INTRODUCTION L o n g i b o r n e o l ( 5 9 ) , l o n g i c y c l e n e ( 6 0 ) , and l o n g i f o l e n e (61) c o - o c c u r i n P i n u s l o n g i f o l i a Roxb. [35 ] , and t h e i r t o t a l s y n t h e s i s has a t t r a c t e d c o n s i d e r a b l e a t t e n t i o n over the pas t two decades . An obv ious s t r u c t u r a l f e a t u r e of these compounds i s the presence of the t r i c y c l i c carbon s k e l e t o n i n which the b i c y c -l o [ 2 . 2 . l ] h e p t a n e u n i t i s fused w i t h a seven-membered r i n g . At l e a s t 6 r e s e a r c h groups have d e v i s e d ingen ious methods to c o n -s t r u c t t h i s s t r u c t u r a l s u b - u n i t , and t h e i r s u c c e s s f u l s y n t h e a e B p r o v i d e racemic l o n g i f o l e n e , l o n g i b o r n e o l , and l o n g i c y c l e n e , or one of t h e i r enant iomers by u s i n g a r e s o l u t i o n s t e p , or employing a c h i r a l a u x i l i a r y . An e n a n t i o s p e c i f i c s y n t h e s i s * of these s e s q u i t e r p e n o i d s has not been r e a l i s e d p r i o r to the r e s e a r c h d e s c r i b e d i n t h i s t h e s i s , and to p l a c e our s y n t h e t i c endeavours i n p e r s p e c t i v e , a b r i e f account and schemat ic r e p r e s e n t a t i o n of p r e v i o u s s y n t h e t i c r o u t e s to l o n g i f o l e n e , l o n g i b o r n e o l , and l o n g i c y c l e n e are p r o v i d e d below. * We d e f i n e e n a n t i o s p e c i f i c s y n t h e s i s as one i n which r e a d i l y a v a i l a b l e e n a n t i o m e r i c s t a r t i n g m a t e r i a l s p r o v i d e e n a n t i o m e r i c p r o d u c t s [36 ] . (60) (61) 25 The i n i t i a l breakthrough was made by E . J . Corey and co-workers [37] (Scheme 19) in 1964 by using the Wieland-Miescher ketone (62) to synthesise the diketone intermediate (63). Subsequent intramolecular Michael c y c l i s a t i o n of (63) provided the t r i c y c l i c diketone (64), which establ ished the t r i c y c l i c carbon skeleton that was necessary for the completion of the f i r s t t o t a l synthesis of ( • ) - l ong i fo l ene . In add i t ion , the preparation of the o p t i c a l l y act ive natural product was also accomplished by reso lut ion of the L-(+)-2 ,3 -butanedi th io l ketal (65). (65) A la ter synthes is , completed by J . E . McMurry and S. J . Isser [38] (Scheme 20), also s tarted with Wieland-Miescher ketone (62) and used keto-epoxide (66) as a precursor of the t r i c y c l i c keto-a lcohol (67). Ring expansion followed by fragmentation and several funct iona l group interconversions resulted in a second t o t a l synthesis of ( l ) - l o n g i f o l e n e . A t h i r d longifolene synthesis was described by H. S. Johnson et a l . [39] in 1975. In th i s approach (Scheme 21) the t r i c y c l i c carb ino l intermediate (68) was constructed by an 26 (_+) - L o n g i f o l e n e R e a g e n t s and c o n d i t i o n s ; ( i ) H O C H 2 C H 2 O H - £ - T o l u e n e s u l p h o n i c a c i d ; ( i i ) CH 3CH=PPh 3; ( i i i ) OsO^; ( i v ) £ - T o l u e n e s u l p h o n y l c h l o r i d e ; ( v ) L i C 1 0 4 ; ( v i ) 6N HCI; ( v i i ) E t 3 N - H O C H 2 C H 2 O H - 2 2 5 ° C; ( v i i i ) P r g C N a , C H 3 I ; ( i x ) HSCH 2CH 2SH-BF 3; (x) LAH; ( x i ) H^NH^Na-HOCH 2CH 2OH; ( x i i ) CrC^-HOAc; ( x i i i ) M e L i ; ( x i v ) S0C1 - P y r i d i n e . Scheme 19 27 | (x) , ( x i ) ( i ) - L o n g i f o l e n e R e a g e n t s and c o n d i t i o n s ; ( i ) H O C H 2 C H 2 O H - £ - T o l u e n e s u l p h o n i c a c i d ; ( i i ) H 2 < P d ; ( i i i ) M e M g l ; ( i v ) H * ; ( v ) m - C l - C 6 H 4 C 0 3 H ; ( v i ) N a C H ^ O C H j , - ( v i i ) H + ; ( v i i i ) K O ^ B u / C H B r 3 ; ( i x ) A g C 1 0 4 ; (x ) N a / l i q . N H 3 ; . ( x i ) C o l l i n s r e a g e n t ; ( x i i ) M e 2 C u L i ; ( x i i i ) N a B H ^ ; ( x i v ) M s C l ; ( x v ) K O f c B u ; ( x v i ) T r i s t r i p h e n y l p h o s p h i n e r o d i u t t i c h l o r i d e / H 2 ; ( x v i i ) M e L i ; ( x v i i i ) S O C l j - P y r i d i n e . Scheme 20 28 (+ )-Long i f o l ene R e a g e n t s and c o n d i t i o n s : ( i ) C u L i ( ( C H 2 ) 3 C = C C H 3 ) 2 ; ( i i ) C l ^ C O C l ; ( i i i ) M e L i - E t 0 ; ( i v ) B r 2 - C H 2 C 1 2 > -(v ) 2 / 4 , 6 - ( C H , ) o C , H - C 0 . N ( C H . ) / , ; ( v i ) L A H ; ( v i i ) CF,Cr> H; ( v i i i ) Z n B r - , / N a B H C N ; ( i x ) p _ - T o l u e n e s u l p h o n i c a c i d ; (x ) R u O 2 / 5 0 % H 2 0 i n B u O H / H 5 I 0 6 - N a I 0 4 ; ( x i ) L i N ( U P r ) 2 - M e I ; ( x i i ) M e L i ; ( x i i i ) S O C l 2 - P y r i d i n e . Scheme 21 29 a c i d - c a t a l y s e d c y c l i s a t i o n of enynol (69) d e r i v e d from 2-i s o p r o p y l i d e n e c y c l o p e n t a n o n e (70). T h i s i n t e r m e d i a t e (68) was then converted to ( I ) - l o n g i f o l e n e , as d e s c r i b e d i n Scheme 21. An a l t e r n a t i v e s y n t h e t i c route (Scheme 22) to ( i ) -l o n g i f o l e n e was d e s c r i b e d by W. Oppolzer and T. Godel [40] i n 1977 and 1984. A key f e a t u r e of t h i s route was the use of an i n t r a m o l e c u l a r p h o t o a d d i t i o n / r e t r o - a l d o l i s a t i o n process ( I n t r a m o l e c u l a r de Mayo Reaction) to c o n s t r u c t the t r i c y c l i c i n t e r m e diate (71). By r e s o l v i n g intermediate (72) Oppolzer and T. Godel [41] used t h i s route to s y n t h e s i s e ( + ) - l o n g i f o l e n e (61). Recently, A. G. S c h u l t z and S. Puig [42] i n 1985 a l s o r e p o r t e d the s y n t h e s i s of both racemic and ( - ) - l o n g i f o l e n e (78) (Scheme 23), i n which the t r i c y c l i c carbon s k e l e t o n was c o n s t r u c t e d by the combination of an i n t r a m o l e c u l a r 1,3-d i p o l a r r e a c t i o n (73 - 74) and e l e c t r o c y c l i c r e a c t i o n (75 - 76). By u s i n g o p t i c a l l y pure benzoxazepenone (77) as the s t a r t i n g m a t e r i a l [43] A. G. S c h u l t z and S. Puig were able to use t h i s procedure to s y n t h e s i s e ( - ) - l o n g i f o l e n e (78). The only s y n t h e s i s of l o n g i b o r n e o l and l o n g i c y c l e n e was p u b l i s h e d by S. C. Welch and R. L. Walters [44] i n 1973 and i n v o l v e d the use of (-)-carvone (79) as a c h i r a l s t a r t i n g m a t e r i a l . The route (Scheme 24) f e a t u r e d a r e d u c t i v e c y c l -i s a t i o n step to c o n s t r u c t the i n t e r m e d i a t e b i c y c l i c k e t o l (80). T h i s compound, (80), was then converted to t e t r a c y c l i c 30 ketone (81) v i a an intramolecular carbene i n s e r t i o n , and f i n a l l y by a ser ies of simple react ions to ( i ) - l o n g i c y c l e n e . Furthermore, c y c l i s a t i o n of b i c y c l i c keto-mesylate (82) (Scheme 24) resulted in the synthesis of ( i )-longicamphor and subsequent s tereose lec t ive reduction provided ( • ) -longiborneol . 0 (77) (78) 31 Scheme 2 2 32 R e a g e n t s and c o n d i t i o n s : ( i ) B i r c h r e d u c t i o n , ( i i ) LDA, 2.2-dimethyl-5-iodopentanal, ( i i i ) N-bromoacetamide, Methanol, ( i v ) DBN, (v) Acetone, p - t o l u e n e s u l f o n i c a c i d , a f t e r s i l i c a gel chromatography, ( v i ) l - a i r , i n o - t r a n s - 2 , 3 - d i p h e n y l a z i r i d i n e , heat, ( v i i ) hv, heat, xylene, ( v i i i ) H a , Pd/C,(ix) KOH, Methanol-vater, (x) tol u e n e , reflux, ( x i ) M e L i , THF, ( x i i ) SOCl a , P y r i d i n e . Scheme 23 33 (79) ( j f ) - L o n g i b o r n e o l (+_)-Long i camphor R e a g e n t s and- c o n d i t i o n s ; ( i ) H B r - H O A c ; ( i i ) KOH, MeOH; ( i i i ) H 2 - P d / C ; ( i v ) N a H , C H 3 C H B r C H = C H C H 3 ; ( v ) R u O ^ , 0 s 0 4 , H 2 0 , t B u O H , N a I 0 4 ; ( v i ) N a O A c , A c ^ O ; ( v i i ) D I B A L - H ; ( v i i i ) H + ; ( i x ) M s C l ; (x ) C o l l i d i n e ; ( x i ) P P h 3 = C H O C H 3 ; ( x i i ) H C 1 0 4 ; ( x i i i ) K 2 C 0 3 , C H 3 O H ; ( x i v ) C r 0 3 , H 2 S 0 4 ; (xv.) (C0C1 ) 2 > ( x v i J C H ^ ; ( x v i i ) C u ; ( x v i i i ) D I B A L - H ; ( x i x ) M s C l ; ( x x ) L A H ; ( x x i ) P P h 3 = C H 2 ; ( X x i i ) B H j - T H F ; ( x x i i i ) H 2 0 2 , _0H; ( x x i v ) M s C l ; ( x x v ) C r 0 3 ~ P y r i d i n e ; ( x x v i ) N a N ( S i M e 3 ) 2 , DME; ( x x v i i ) C a , N H 3 , n - P r O H . Scheme 24 34 1 .2 .0 . DISCUSSION A d e s i r a b l e f e a t u r e of a s y n t h e t i c s t r a t e g y i s t h a t i t be a p p l i c a b l e to more than one compound w i t h i n any c l a s s of 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 products. T h i s was the g o a l of the s t r a t e g y we adopted f o r the s y n t h e s i s of ( + ) - l o n g i b o r n e o l (59), ( + ) - l o n g i c y c l e n e (60), and ( + ) - l o n g i f o l e n e (61). The key f e a t u r e of our s y n t h e t i c plan was to c o n s t r u c t the l o n g i f o l e n e s t r u c t u r e by a route based on i t s proposed b i o s y n t h e s i s [45] (Scheme 25) . Thus, we considered that the B i o s y n t h e s i s of l o n g i f o l e n e Scheme 2 5 35 l o n g i f o l e n e s t r u c t u r e c o u l d be produced by Wagner-Meerwein rearrangement of the s y n t h e t i c e q u i v a l e n t of the t r i c y c l i c secondary c a r b o c a t i o n ( 8 4 ) . L a b o r a t o r y analogy f o r t h i s a p p r o -ach i s p r o v i d e d by the s y n t h e s i s of (+)-camphene (85 ) , a mono-t e r p e n o i d analogue o f ( + ) - l o n g i f o l e n e (61 ) , by Wagner-Meerwein rearrangement of ( - ) - i s o b o r n e o l (86) d e r i v e d from (+)-camphor (26) (Scheme 26) . Prompted by t h i s a n a l o g y , we p o s t u l a t e d tha t ( + ) - l o n g i f o l e n e (61) c o u l d be s y n t h e s i s e d from ( + ) - l o n g i c a m p h -or (83) by a s i m i l a r r e a c t i o n sequence, tha t i s , r e d u c t i o n of (87) (88) Scheme 26 (+ ) - long icamphor (83) f o l l o w e d by the Wagner-Meerwein r e a r r a n g -ement of the r e s u l t i n g ( + ) - l o n g i i s o b o r n e o l (89) as d e p i c t e d i n Scheme 27. I t i s c l e a r t h e r e f o r e , t h a t the s y n t h e s i s o f (+)-longicamphor .(83) i s of s y n t h e t i c importance s i n c e there i s a 36 p o t e n t i a l s y n t h e t i c r e l a t i o n s h i p among (+)-longicamphor (83), ( + ) - l o n g i b o r n e o l (59), ( + ) - l o n g i i s o b o r n e o l (89), (+)-l o n g i c y c l e n e (60) and ( + ) - l o n g i f o l e n e (61). In f a c t , the r e c o g n i t i o n of (+)-longicamphor (83) as a key in t e r m e d i a t e was an i n t e g r a l p a r t of pr e v i o u s s t u d i e s i n our l a b o r a t o r y on the development of s t e r e o s e l e c t i v e s y n t h e t i c approaches OH (59) Scheme 27 from camphor to a wide v a r i e t y of s e s q u i t e r p e n o i d s (Scheme 28). These s e s q u i t e r p e n o i d s were grouped together i n s t r u c -t u r a l q u a r t e t s and the parent ketones i n each set were i d e n t i f i e d as (+)-epicampherenone (90), (+)-copacamphor (91), (-)-campherenone (92), (+)-ylangocamphor (93), and (+)-longicamphor (83). Furthermore, the t r a n s f o r m a t i o n of each of the parent ketones to other members of the q u a r t e t i n v o l v e d r e d u c t i o n , dehydration-rearrangement, and intramo-l e c u l a r c y c l o p r o p a n a t i o n processes s i m i l a r to those used i n 37 (+) -Isoep Icampherenol (47) (48) (+)-eplca«pherenone* (+)-epi-B-M«t»lene yT (90) CO co (+)-a-santalen« (45) OH I , (•O-copaborneol^ (94) (-)-copacamphene* y (+)-copacanphor* (95) ^ ' (91) (-)-cyclocopacanphene^ * (96) (+)-a-aantalene (45) OH , (+) -long lborneol (59) (+)-camphor (26) (-)-camphor (27) <SS ( +) - long Ic aaphor * (83) V (-O-longlfolene' _J61) (+)-longicyclene (60) OH r (+)-ylangoborneol (101) (-)-campherenone ( 92 ) (-)-campherenol (-)-B-santalene (97) (98) (+)-ylangoca«phor* (-)-satlvene (93) (100) r (-)-eyeloaatlvene (99) ] enantiomer a l s o known * unknown l n nature Scheme 28 the c o n v e r s i o n of (+)-camphor (26 ) , to ( + ) - b o r n e o l (87 ) , (+)-camphene ( 8 5 ) , and t r i c y c l e n e (88) (Scheme 26) . The succes s of our e a r l i e r s t u d i e s came from the development of s y n t h e t i c r o u t e s from camphor to most of the p a r e n t ketones l i s t e d above. T h i s succes s was based on a new t h r e e - s t e p p r o c e d u r e , deve loped i n our l a b o r a t o r y [22] , to brominate camphor r e g i o s p e c i f i c a l l y at the C(8) p o s i t i o n . As a r e s u l t , the e n a n t i o s p e c i f i c s y n t h e s i s of ( + ) - i s o e p i c a m p h e r e n o l (47 ) , ( + ) - e p i - {3-santalene (48 ) , ( +)-oC-santalene (45 ) , ( + ) - c o p a b o r -n e o l (94 ) , ( - ) -copacamphene (95 ) , ( - ) - cyc locopacamphene (96 ) , ( - ) -campherenol (97 ) , ( - ) - /J - santa lene (98 ) , ( - ) - c y c l o s a t i v e n e ( 9 9 ) , ( - ) - s a t i v e n e (100) , and ( + ) - y l a n g o b o r n e o l (101) [23] were comple ted . However, these e a r l i e r e f f o r t s f a i l e d to complete the s y n t h e t i c c o n n e c t i o n between (+)-camphor (26) and ( + ) - long icamphor (83 ) , and hence ( + ) - l o n g i b o r n e o l (59 ) , ( + ) - l o n g i c y c l e n e (60 ) , and ( + ) - l o n g i f o l e n e (61) (Scheme 28) . In o r d e r to c o n s t r u c t the (+) - long icamphor (83) s k e l e t o n u s i n g (+)-camphor (26) as the c h i r a l s t a r t i n g m o l e c u l e , two c a r b o n - c a r b o n bond f o r m a t i o n s , t h a t i s , "Bond 1" and "Bond 2" *Bond 1 " Bond 2" 39 of (102) must be achieved. A l l p r e v i o u s attempts i n our l a b o r -a t o r y to s y n t h e s i s e (+)-longicamphor (83) i n t h i s way were un-s u c c e s s f u l [46]. Ne v e r t h e l e s s , the la c k of an e n a n t i o s p e c i f i c s y n t h e s i s of ( + ) - l o n g i b o r n e o l (59) and ( + ) - l o n g i f o l e n e (61) i n the l i t e r a t u r e prompted us to undertake t h i s c h a l l e n g e again. L i k e a lengthy journey, the management of a s u c c e s s f u l s y n t h e s i s from i t s s t a r t i n g p o i n t to i t s d e s t i n a t i o n r e q u i -res a c a r e f u l l y planned o u t l i n e , the f l e x i b i l i t y to accomo-date d i v e r s i o n s along the way, and the endurance to see the journey through to a s a t i s f a c t o r y c o n c l u s i o n . The enantiospe-c i f i c s y n t h e s i s of ( + ) - l o n g i b o r n e o l ( 59 ) , and ( + ) - l o n g i f o l e n e (61) r e p r e s e n t s f a i r l y a c c u r a t e l y a s y n t h e s i s that i s b u i l t around a r a t h e r s p e c i f i c approach. S y n t h e t i c approaches that we i n v e s t i g a t e d to c o n s t r u c t the t r i c y c l i c s k e l e t o n of longicam-phor (83) i n c l u d e d (1 .3 .1.) INTRAMOLECULAR DIELS-ALDER REACTION  APPROACH of t r i e n e a c e t a t e (103b) , ( 1 . 3 . 2 0 INTRAMOLECULAR LEWIS  ACID-INDUCED TERTIARY ALKYLATION of campherenone h y d r o c h l o r i d e e n o l - t r i m e t h y l s i l y l ether (104) , and ( 1 . 3 . 3 ^ INTRAMOLECULAR  MUKAIYAMA CYCLISATION of an d i m e t h y l - a c e t a l e n o l s i l y l ether (105) . These approaches w i l l be d i s c u s s e d c h r o n o l o g i c a l l y . 40 (105) 41 1.3.0. RESULTS 1.3.1. INTRAMOLECULAR DIELS-ALDER REACTION APPROACH The s t r i k i n g u t i l i t y of the intramolecular D i e l s - A l d e r react ion in the construction of carbocycles of a wide var ie ty of natura l products [47] led us to consider the app l i ca t ion of th i s react ion to the construct ion of the t r i c y c l i c skeleton of (+)-longicamphor (83). This react ion involves the in terac t ion between a conjugated diene and a monoene to form two bonds generating a six-membered r ing (Scheme 29). Scheme 29 Several general i sat ions concerning th i s react ion can be categorised in terms of r e a c t i v i t y , r e g i o s e l e c t i v i t y , and s t e r e o s e l e c t i v i t y . F i r s t , the dienophi le r e a c t i v i t y i s incre -ased by electron-withdrawing groups, whereas the diene react -i v i t y i s increased by e lectron-donating groups. For example, in the cyclopentadiene (106), replacement of the hydrogen by a carbomethoxy group (107) reduces the c y c l i s a t i o n temperature o o from 250 to 110 C [48]. Furthermore, p lac ing ac t iva t ing groups 42 (CH3)3SiO, R *H ( 1 0 6 ) R S C H 3 O z C <107) on both the t e r m i n a l and non-terminal carbon atoms of the d i e n o p h i l e of compound (108) r e s u l t s i n g r e a t l y enhanced r e a c t i v i t y as shown by the c y c l i s a t i o n temperatures [49]. Regiochemically, the i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n can g i v e e i t h e r fused or bridged products as shown i n Scheme 30. In g e n e r a l , most i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n s g i v e the fused products (109) and (110) [50]. The bridged products (111) and (112) can a l s o be produced f o r a t r a n s - d i e n e having at l e a s t a f i v e carbon chain with a reasonable u n s t r a i n e d R X ( 1 0 8 ) 0 R = H; X « H 2 ( 1 4 0 ° ) *> R= H; X = 0 (110°) C R* C 2H 50 2C;X=0{<25 0) 43 £ > - CO FUSED BRIDGED Scheme 30 t r a n s i t i o n s t a t e (Scheme 31). In the case of c i s - d i e n e (113), a (423) (111) (112) CH 30 2C 0 ( 1 0 9 ) (53%) (110) Scheme 31 44 p o s s i b l e s i t u a t i o n f o r the formation of bridged product (114) [51] i s only when a n t i - a d d i t i o n occurs perhaps due to a l e s s s t r a i n e d t r a n s i t i o n s t a t e . S t e r e o c h e m i c a l l y , the i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n may g i v e r i s e to c i s or trans fused products depending on the o r i e n t a t i o n of the diene r e l a t i v e to the d i e n o p h i l e i n the t r a n s i t i o n s t a t e . G e n e r a l l y , t r a n s dienes g i v e t r a n s - f u s e d products v i a an a n t i - t r a n s i t i o n s t a t e , and c i s - f u s e d products v i a a s y n - t r a n s i t i o n s t a t e . On the c o n t r a r y , c i s - d i e n e s g i v e c i s - f u s e d products v i a an a n t i - t r a n s i t i o n s t a t e and t r a n s -fused products v i a a s y n - t r a n s i t i o n s t a t e as shown i n Scheme 32. F a c t o r s such as chain length, s u b s t i t u e n t s on the c h a i n , type of diene, type of d i e n o p h i l e , and c a t a l y s t s may l i m i t the number of above p o s s i b i l i t i e s . For example, the e s t e r (115) and i t s geometric isomer (116) c y c l i s e f a v o r a b l y v i a an a n t i - t r a n s i t i o n s t a t e to pr o v i d e the t r a n s - f u s e d products (117) and (118) as the major products, as shown i n Scheme 33 [52]. A p o s s i b l e e x p l a n a t i o n f o r 45 trans DIENE trans -FUSED trans DIENE cis- FUSED as DIENE c/s-FUSED cis DIENE trons-FUSED Scheme 3 2 46 CH302C-NS, (115) o 150° (39%) b MENTHOXY AlCU, (72%) 23° C0 2 CH 3 cb H (26%) (116) C0 2CH, H 1 H (118) 0 180° (49%) b C2H5AIC12, (14%) 2 3 ° (26%) (13%) Scheme 33 t h i s r e s u l t i s the f a c t t h a t d u r i n g the f o r m a t i o n of the f ive-membered r i n g , the two s u b s t i t u e n t s on the c y c l o p e n t a n e r i n g are e c l i p s e d i n the s y n - t r a n s i t i o n s t a t e (119) which i s thus e n e r g e t i c a l l y l e s s f a v o r e d than the a n t i - t r a n s i t i o n s t a t e (120) w i t h s taggered s u b s t i t u e n t s . F u r t h e r m o r e , non-bonded i n t e r a c t i o n s w i t h i n the c h a i n between the hydrogen atoms on carbon 4 and carbon 8 appear to be more severe in the 47 s y n - t r a n s i t i o n s t a t e . Notice that i n the presence of a Lewis 5 (119) (120) a c i d , e s t e r (115) g i v e s more t r a n s - f u s e d product because of the enhanced £njio_-select i v i t y . However, the Lewis a c i d f a i l e d to a f f e c t e s t e r (116), probably due to the in c r e a s e d secondary o r b i t a l i n t e r a c t i o n which i s not able to overcome the p r e f e r -ence f o r the a n t i - t r a n s i t i o n s t a t e . To use an i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n i n the c o n s t r u c t i o n of the t r i c y c l i c s k e l e t o n of longicamphor (83), a p o s s i b l e i n t e r m e d i a t e molecule such as t r i e n e a c e t a t e (103), which possesses a c i s - d i e n e with e l e c t r o n - d o n a t i n g methyl groups attached and a d i e n o p h i l e with an acetoxy group attached, was c o n s i d e r e d . In t h i s approach, i t was hoped that on t h e r m o l y s i s , t r i e n e a c e t a t e (103) would c y c l i s e to a f f o r d t e t r a c y c l i c a c e t a t e (124). Subsequent h y d r o l y s i s of (124) f o l l o w e d by hydrogenation of (125) could p r o v i d e (+)-longicamphor (83) as i l l u s t r a t e d i n Scheme 34. Once the 48 (83) (125) Scheme 34 p o s s i b l e f e a s i b i l i t y of employing the i n t r a m o l e c u l a r D i e l s -A l d e r r e a c t i o n had been recognised, the main c h a l l e n g e became the p r e p a r a t i o n the in t e r m e d i a t e , t r i e n e a c e t a t e (103). I t was envisaged that the c i s - d i e n e moiety i n t r i e n e a c e t a t e (103) could be i n c o r p o r a t e d v i a a W i t t i g r e a c t i o n between a n o n - s t a b i l i s e d W i t t i g reagent (126) and an aldehyde (127) to produce d i e n e - k e t a l (128) as shown i n Scheme 35. Furthermore, (126) could be d e r i v e d from a C(8) f u n c t i o n -a l i s e d (+)-camphor d e r i v a t i v e (42). 4 9 ( 1 2 6 ) ( 1 28) Scheme 35 A s y n t h e t i c p l a n f o r the p r e p a r a t i o n of the W i t t i g reagent (126) i s o u t l i n e d i n Scheme 36. T h u s , t reatment of (+)-camphor ( 1 2 6 ) ( 1 3 1 ) ( 4 2 ) R e a g e n t s and c o n d i t i o n s : ( i ) B r 2 , HBr, HOAc, 110°C; ( i i ) B r ^ CISC^H; ( i i i ) Z n , HOAc, E t 2 0 , 0°C; ( i v ) Me S i C l , HOCH 2CH 2OH. Scheme 36 50 (26) w i t h bromine , c a t a l y s e d by HBr gas at h i g h temperature a f f o r d e d (+) -3 ,3-d ibromocamphor (129) i n 99% y i e l d . At room temperature t h i s b r o m i n a t i o n r e a c t i o n does not proceed to any s i g n i f i c a n t e x t e n t . Wagner-Meerwein rearrangement and bromina-t i o n of (129) i n bromine and c h l o r o s u l f o n i c a c i d p r o v i d e d 3 , 3 , 6 - tr ibromocamphor (130) i n about 50-60% y i e l d . The mechanism of t h i s r e a r r a n g e m e n t - b r o m i n a t i o n r e a c t i o n was proposed as shown i n Scheme 37, which f e a t u r e s an unusua l 2,3[e_ndo] methyl s h i f t i n i n t e r m e d i a t e (132) f o l l o w e d by b r o m i n a t i o n r e g i o s p e c i f i c -a l l y at the C(8) p o s i t i o n of compound (129) . E f f o r t s have been made to improve the y i e l d of (130) w i t h o ther a c i d s such as t r i f l u r o a c e t i c a c i d and c o n c e n t r a t e d h y d r o c h l o r i c a c i d , but c h l o r o s u l f o n i c a c i d remains the best c h o i c e f o r t h i s r e a r r a n -gement -brominat ion s t e p . Debrominat ion of (130) i n the p r e s -ence of z i n c dust and a c e t i c a c i d produced (+)-8-bromocamphor (42) in about 45-50% y i e l d over these three s t e p s . K e t a l i s -a t i o n of (42) w i t h c h l o r o t r i m e t h y l s i l a n e and e t h y l e n e g l y c o l [53] produced (+)-8-bromocamphor e t h y l e n e k e t a l (131) , b u t , u n -f o r t u n a t e l y treatment of (131) w i t h t r i p h e n y l p h o s p h i n e f a i l e d to produce the d e s i r e d W i t t i g reagent (126) . L i k e w i s e , there was no r e a c t i o n when (+) -8- iodocamphor e thy lene k e t a l (133) was X=I X=Br (133) (131) 51 Scheme 37 t r e a t e d with t r i p h e n y l p h o s p h i n e . I t seems l i k e l y that the f a i l u r e of these r e a c t i o n s i s due to severe s t e r i c hindrance at C(8) by the k e t a l group of (131) or (133). As a r e s u l t , we decided to i n t r o d u c e an aldehyde or e q i v a l e n t f u n c t i o n a l i t y at the C(8) p o s i t i o n of camphor, and then couple t h i s compound (134) with a p r e n y l W i t t i g reagent (135) to o b t a i n dienone (136). I t was a n t i c i p a t e d , however, t h a t t h i s W i t t i g r e a c t i o n would r e s u l t i n the trans-isomer (136a) as the major product s i n c e a s t a b i l i s e d W i t t i g reagent would be used. I t was our hope t h a t by v a r y i n g r e a c t i o n c o n d i t i o n s [54] i t might be p o s s i b l e to o b t a i n the c i s - i s o m e r (136b) as the major product. I t occurred to us then that l a c t o l (137) p r e s e n t s a good OH O (137) (138) 53 candidate f o r t h i s W i t t i g r e a c t i o n , s i n c e i t i s i n e q u i l i -brium with hydroxy-aldehyde (138). The s y n t h e t i c route to the l a c t o l (137), o u t l i n e d i n Scheme 38, i n v o l v e d treatment (137) ( 1 41) R e a g e n t s and c o n d i t i o n s : ( i ) KOAc, DMSO, 110°C; ( i i ) LAH, THF; ( i i i ) A g 2 C 0 3 , PhH; ( i v ) DIBAL-H, P h C H 3 , -78°C. Scheme 38 of (+)-8-bromocamphor (42) with potassium a c e t a t e and dimethyl s u l f o x i d e at high temperature to a f f o r d (+)-8-acetoxy-camphor (139) i n 93% y i e l d . Hydride r e d u c t i o n of (139) at 0°C provided epimeric d i o l s (140) i n 75% y i e l d . The epimeric r a t i o (4:1, ej^:ejid_Q.) of d i o l s was determined from 1H-n.m.r. i n t e g r a t i o n s of the C(2) proton s i g n a l s . O x i d a t i o n of d i o l s (140) with s i l v e r carbonate on c e l i t e i n r e f l u x i n g benzene [55] gave 54 l a c t o n e (141) in 77% y i e l d . DIBAL r e d u c t i o n [129] of (141) then p r o v i d e d a mixture of e p i m e r i c l a c t o l s (137) (93% y i e l d ) which was condensed w i t h the W i t t i g reagent (135) [56] d e r i v e d from p r e n y l bromide to p r o v i d e a mix ture o f d i e n o l s (142a ,b) i n 82% y i e l d . S u r p r i s i n g l y , the r a t i o of c i s to t r a n s isomers of d i e n o l s (142b:142a) was i n d i c a t e d by ^ - n . m . r . i n t e g r a t i o n (page 270 ) to be 7 :1 . The assignment of the s t e r e o s e l e c t i v i t y of t h i s W i t t i g r e a c t i o n i s s i m i l a r to t h a t r e p o r t e d by G . Pat tenden and co-workers f o r the s y n t h e s i s of ( E ) - 2 , 2 , 6 - t r i m e t h y l h e p t a - 3 , 5 - d i e n o i c a c i d (143) [ 5 7 ] . T h i s unusua l o b s e r v a t i o n i n which a s t a b i l i s e d W i t t i g reagent such as (135) r e s u l t e d i n the c i s - i s o m e r as the major p r o d u c t i s an i n t e r e s t i n g one. We are not sure of the a c t u a l course of t h i s r e a c t i o n , however a p o s s i b l e s u g g e s t i o n (Scheme 40) i s c o o r d i n a t i o n of the phosphorous of the y l i d e (145) w i t h the a l k o x i d e an ion of l a c t o l (144) f o l l o w e d by n u c l e o p h i l i c a t t a c k of the y l i d e on the a ldehyde f u n c t i o n a l i t y of (144) to g i v e (146) . Subsequent r o t a t i o n around the newly formed c a r b o n -carbon bond to form an oxaphosphetane i n t e r m e d i a t e (147) f o -l lowed by d e c o m p o s i t i o n in the u s u a l way would produce the c i s -(143) 55 d i e n o l (142b) and t r i p h e n y l p h o s p h i n e o x i d e . The p-bromobenzoate Scheme 40 56 d e r i v a t i v e (148) of (142b) was a c o l o r l e s s o i l and thus p r e v e -nted us c o n f i r m i n g the s t e r e o c h e m i s t r y of t h i s compound by X -j j - B r o m o b e n z o y l -c h l o r i d e , p y r i d i n e ( 1 42b) (148) ray c r y s t a l l o g r a p h i c a n a l y s i s . O x i d a t i o n [69] o f d i e n o l s (142a,b) p r o v i d e d (136a,b) which , on treatment 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 i n t e t r a h y d -r o f u r a n f o l l o w e d by a c e t i c a n h y d r i d e p r o v i d e d t r i e n e a c e t a t e s (103a,b). The r a t i o of c i s to t r a n s isomers i n both d ienones <136b:136a) (page 271) and t r i e n e a c e t a t e s (103b:103a) (page 271) was i n d i c a t e d by ^ H - n . m . r . i n t e g r a t i o n to be about 7:1. OH + (130) ( 1 4 2 a ) (142b) + ( 1 3 6 a ) ( 1 0 3 a ) + (103b) Scheme 54 57 U n f o r t u n a t e l y , a l l at tempts to induce t h i s compound to undergo i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n were u n s u c c e s s f u l ( T a b l e 1 ) . A v a r i e t y of r e a c t i o n c o n d i t i o n s were examined such as v a r y i n g s o l v e n t s , t e m p e r a t u r e s , and r e a c t i o n t imes [58 ] . In a d d i t i o n , c a t a l y s t s such as d i e t h y l a l u m i n u m c h l o r i d e [52] and cuprous t r i f l a t e - b e n z e n e complex [59] which were reputed to a i d the c y c l o a d d i t i o n p r o c e s s by c h e l a t i n g aluminum (150a) or copper (150b) wi th the d i ene and d i e n o p h i l e , had no e f f e c t on t h i s r e a c t i o n (Scheme 4 1 ) . Scheme 41 To account f o r the f a i l u r e of the i n t r a m o l e c u l a r D i e l s -A l d e r r e a c t i o n , i t was thought t h a t f o r s t e r i c reasons the c i s - t r i e n e a c e t a t e (103b) would e x i s t i n the s - t r a n s c o n f -58 ormat ion (149) . As a r e s u l t , the geometry of the d i e n e and d i e n o p h i l e c o u l d not be p r o p e r l y a l i g n e d f o r c y c l o a d d i t i o n . (103b) < 1 4 9 ) Scheme 55 I t i s a l s o p o s s i b l e t h a t the e l e c t r o n - r i c h n a t u r e of the d i e n o p h i l e made the r e a c t i o n e n e r g e t i c a l l y u n f a v o r a b l e . 59 ATTEMPTS IN THE INTRAMOLECULAR DIELS-ALDER REACTION ENTRY CONDITIONS SOLVENTS TEMPT .CO TIME RESULTS 1 REFLUX 0-XYLENE 150 23 hrs. -2 SEALED TUBE TOLUENE DILUTE 180 3 days -3 SEALED TUBE TOLUENE CONC. 190 64 hrs. -4 SEALED TUBE NEAT 150 16 hrs. -5 Et 2 A l C l CH2C12 25 2.5 days -6 SEALED N.M.R. TUBE (i) 85 ( i i ) 106 ( i i i ) 120 (iv) 140 (v) 160 (vi) 180 (vii) 190 ( v i i i ) 205 50 hrs. 41 hrs. 24 hrs. 40 hrs. 16 hrs. 16 hrs. 13 hrs. 6 days -7 REFLUX 0-DICHLO-BENZENE 180 16 hrs -8 SEALED TUBE 0-DI-CHLORO-BENZENE 180 3 days T a b l e 1 60 1 . 3 . 2 . INTRAMOLECULAR LEWIS ACID INDUCED d-TERTIARY ALKYLATION A r e t r o - s y n t h e t i c a n a l y s i s (Scheme 42) of ( + ) - l o n g i -camphor (83) shows a p o s s i b l e d i s c o n n e c t i o n at the C ( 6 ) - C ( 7 ) c a r b o n - c a r b o n bond to p r o v i d e (+)-campherenone (151) . As shown i n the p r e v i o u s s t u d i e s [23] ( - ) -campherenone (92) can be s y n -t h e s i s e d by p r e n y l a t i o n of a C(8 ) f u n c t i o n a l i s e d ( - ) - camphor and t h e r e f o r e , (+)-camphor (26) was chosen as the c h i r a l s t a r -t i n g m a t e r i a l . Our immediate r e s e a r c h o b j e c t i v e was t h e r e f o r e (26) Scheme 42 61 the f o r m a t i o n of the c a r b o n - c a r b o n bond between C(3) and C(13) i n (151) . T h i s s y n t h e t i c s t r a t e g y has been p r e v i o u s l y examined i n our l a b o r a t o r y u s i n g a v a r i e t y of methods [46 ] , but no s u c -cess was a c h i e v e d . R e c e n t l y , however, a new method of i n t r a -m o l e c u l a r a l k y l a t i o n of a ketone w i t h a d i - s u b s t i t u t e d a l k e n e , c a t a l y s e d by S n C l ^ has been r e p o r t e d by Reetz and co-workers [ 6 0 ] , and examples c i t e d from the l i t e r a t u r e i n c l u d e d the SnCl^-media ted c y c l i s a t i o n s of (153) , (154) ,and (155) which l e d to the f o r m a t i o n of (156) , (157) , and (158) r e s p e c t i v e l y as d e p i c t e d i n Scheme 44. The mechanism of these f a v o r e d 6-and 7 - e n d o - t r i g o n a l c y c l i s a t i o n s was proposed by Reetz to be 0 - s t a n n y l a t i o n of the e n o l i s e d form (159) to generate (160) and HCI . P r o t o n a t i o n of the a lkene r e s u l t s i n c y c l i s a t i o n of the t e r t i a r y c a t i o n (161) to g i v e (162) as shown i n Scheme 43. (160) (161) (162) Scheme 43 62 o o O J C H J o o ( C H 2 ) - , - < (156) (c). R = CHjO, n (b), R e CH,0. n (e). R = CH, , n 1 . 9 6 % 2. 62% 1 , 80% (154) CO,CH, 61% (157) (155) HftCjO (158) 63% Scheme 44 63 Motivated by these a n a l o g i e s , we decided to t e s t the v a l i d i t y of t h i s i n t r a m o l e c u l a r o(.-tertiary a l k y l a t i o n on ( + )-campherenone (151). The s y n t h e t i c route to the longicamphor sk-e l e t o n from (+)-campherenone (151) was an exte n s i o n of pre v i o u s s t u d i e s i n our l a b o r a t o r y on the development of s t e r e o s e l e c t i v e s y n t h e t i c approaches from camphor to a v a r i e t y of complex ses-q u i t e r p e n o i d s u s i n g (-)-campherenone (92) as a key intermediate (Scheme 28). To evaluate t h i s i n t r a m o l e c u l a r a l k y l a t i o n approach, our f i r s t p reoccupation was to s y n t h e s i s e (+)-campherenone (151) by the route o u t l i n e d i n Scheme 46. T h i s new route i s r e l a t i v e l y Scheme 45 l e s s hazardous than the pr e v i o u s one (Scheme 45) which i n v o l v e d r e a c t i o n of (-)-8-iodocamphor ethylene k e t a l (163) with a p r e n y l complex (164) to pro v i d e (-)-campherenone (92). In t h i s amended route to ( +)-campherenone (151), (+ )-8-cyanocamphor ethylene k e t a l (166) was s y n t h e s i s e d from (+)-camphor (26) i n 48% overa-l l y i e l d by the sequence p r e v i o u s l y developed i n our l a b o r a t o r y [61]. A l k y l a t i o n of (166) with l i t h i u m d i i s o p r o p y l a m i d e and p r -en y l bromide i n t e t r a h y d r o f u r a n at -78°C a f f o r d e d a mixture of 64 (26) (42) (165) (v) (167a,b) (166) (133) ( v i i i ) (168) (151) Re a g e n t s and c o n d i t i o n s : ( i ) B r 2 , HBr, HOAc, 110°C; ( i i ) B r 2 , HS0 3C1; ( i i i ) Zn, HOAc, E t 2 0 , 0°C; ( i v ) K l , DMSO, 110°C, 3 d a y s ; (v) Me S i C l , H O C H ^ H ^ OH; ( v i ) NaCN, DMSO, 70°C, 2 d a y s ; ( v i i ) LDA, THF, -78°C; P r e n y l Bromide; ( v i i i ) K, HMPA, E t 2 0 , fcBuOH, 0°C; ( i x ) HCI, Me 2CO. Scheme 46 C ( 8 ) epimers ( 1 6 7 a , b ) of the d e s i r e d products i n 9 5 % y i e l d (6:1 r a t i o , determined by 1H-n.m.r.) (page 2 7 2 ) . Since the new c h i r a l center c r e a t e d would be destroyed i n the f o l l o w i n g step, the s t e r e o s e l e c t i v i t y i n t h i s a l k y l a t i o n r e a c t i o n [62] i s not s i g n i f i c a n t (page 69 ). Decyanation of ( 1 6 7 a , b ) u s i n g potassium 6 5 meta l i n hexamethylphosphoramide [63] f o l l o w e d by h y d r o l y s i s of (168) f u r n i s h e d (+)-campherenone (151) i n 75% o v e r a l l y i e l d from ( 1 6 7 a , b ) . Having (+)-campherenone (151) a v a i l a b l e , we proceeded to examine the i n t r a m o l e c u l a r ^ - t e r t i a r y a l k y l a t i o n s t ep w i t h the hope t h a t the c y c l i s a t i o n would take p l a c e to form the c a r b o n - c a r b o n bond between C(3) and C(13) and thus p r o -v i d e the longicamphor s k e l e t o n . When (+)-campherenone (151) was r e a c t e d wi th SnCl^ a mix ture o f epimers of d i m e r i c compounds (169a ,b) was i s o l a t e d . The ev idence f o r t h i s s t r u c t u r a l a s s i -gnment of the p r o d u c t s of t h i s r e a c t i o n i n c l u d e d the o c c u r r e n c e of a s i g n a l at 440(M ) in the mass spectrum (page 2 7 2 ) . The r a t i o of epimers was determined to be about 2 .3 :1 from the i n t e g r a t i o n in the ^ H - n . m . r . spectrum (page 2 7 3 ) . Thus i n t e r -m o l e c u l a r c o u p l i n g r a t h e r than i n t r a m o l e c u l a r c o u p l i n g between C(3 ) and C(13) of (+)-campherenone (151) had o c c u r r e d . As an e x t e n s i o n of these i n v e s t i g a t i o n s , campherenone h y d r o c h l o r i d e e n o l t r i m e t h y l s i l y l e ther (104) , and campherenone h y d r o c h l o r i d e e n o l a c e t a t e (170) were prepared from (151) . When (104) and (170) were s e p a r a t e l y t r e a t e d w i t h S n C l 4 under h i g h d i l u t i o n to attempt to promote i n t r a m o l e c u l a r r a t h e r than i n t e r m o l e c u -l a r a l k y l a t i o n , d imers (169) (Scheme 47) were aga in the o n l y p r o d u c t s i s o l a t e d . 66 (170) R e a g e n t s and c o n d i t i o n s : (i) HCI, E t 2 0 ; ( i i ) LDA, THF, -78°C; Me 3SiCl; ( i i i ) LDA, THF, -78°C; A c 2 0 ; (iv) SnCl 4, CH 2Cl2»0°C.• Scheme 47 67 1.3.3. INTRAMOLECULAR MUKAIYAHA REACTION APPROACH In view of the f a i l u r e of the i n t r a m o l e c u l a r o t - t e r t i a r y a l k y l a t i o n approach, we decided to i n v e s t i g a t e the intramole-c u l a r v a r i a n t of a method of c y c l i s a t i o n developed i n i t i a l l y by Mukaiyama and co-workers [64]. The few examples of i t s a p p l i c a t i o n to n a t u r a l product s y n t h e s i s i n c l u d e the synthe-s i s of hydroazulenone ( 1 7 2 ) [65], jatrophone ( 1 7 4 ) [66], and i s o c l o v e n e ( 1 7 7 ) [67] as shown i n Schemes 48, 49, and 50 r e s p e c t i v e l y . In essence t h i s r e a c t i o n i n v o l v e s T i C l . - d i r e c t e d ( 1 7 1 ) (172) Scheme 48 i n t r a m o l e c u l a r condensation between a c e t a l s and enol s i l y l e t h e r s and, as i l l u s t r a t e d above, has been used f o r the ( 1 7 3 a ) (173b) (174) Scheme 49 68 (175) (176) (177) Scheme .50 s y n t h e s i s of seven- and eleven-membered r i n g s . Thus, our i n i t i a l g oal was to c o n s t r u c t t r i m e t h y l s i l y l e n o l ether (178) with the ex p e c t a t i o n that c y c l i s a t i o n mediated by T i C l ^ would r e s u l t i n the formation of the b a s i c t r i c y c l i c longicamphor s k e l e t o n . The s y n t h e t i c route to (178) i s o u t l i n e d i n Scheme 51, and i n v o l v e s a l k y l a t i o n of (+)-8-cyanocamphor ethylene k e t a l (166) with l i t h i u m d i i s o p r o p y l a m i d e and l- t e r t - b u t y l d i m e t h y l s i l y l o x y - 3 - b r o m o p r o p a n e (179) i n t e t r a -o hydrofuran at -78 C. A mixture of C(8) epimers (about 7:1 r a t i o ) of the d e s i r e d products (180a,b) were produced and the major epimer (180a) was i s o l a t e d by column chromatography and converted to the c r y s t a l l i n e p-bromobenzoate d e r i v a t i v e (186) (Scheme 52). Subsequent X-ray c r y s t a l l o g r a p h i c a n a l y s i s [68] showed t h a t the c h i r a l c e n t e r at C(8) i n t h i s compound (186) had the ( R ) - c o n f i g u r a t i o n ( p a g e 273 ). Although the c h i r a l center w i l l be destroyed i n the f o l l o w i n g step, the 69 < 1 6 6 ) R 1=H, R 2=CN (180a ) ( 181) R =CN, R =H (180b) ( i i i ) (184) (183) (182) ( v i ) R e a g e n t s and c o n d i t i o n s : ( i ) LDA, THF, -78°C; ^ B u M e ^ i O C H ^ H CH^Br; ( i i ) K, H e x a -m e t h y l p h o s p h o r a m i d e , E t 2 0 , ^BuOH, O^C; ( i i i ) H C I , Me 2C0; ( i v ) PDC, C H 2 C 1 2 ; ( v ) p - T o l u e n e s u l f o n i c a c i d , EG, PhH; ( v i ) LDA, THF, -78°C; M e g S i C l ; ( v i i ) T i C l ^ C H 2 C 1 2 , -78°C; ( v i i i ) p - B r o m o b e n z o y l C h l o r i d e , P y r i d i n e . Scheme 51 70 R e a g e n t s and c o n d i t i o n s : ( i ) TBAF; ( i i ) p - B r o m o b e n z o y l c h l o r i d e , P y r i d i n e Scheme 52 s t e r e o s e l e c t i v i t y r e s u l t i n g from t h i s a l k y l a t i o n [ 6 2 ] i s i n t e r e s t i n g . I t i s probable that a l k y l a t i o n from the " r e " face of the enolate (187) to g i v e the (R)-product (180a) i s due to the s t e r i c e f f e c t imposed by both C ( 9 ) and C ( 1 0 ) methyl groups as d e p i c t e d i n Scheme 53. Presumably a (187) (180a) Scheme 5 3 s i m i l a r s t e r e o s e l e c t i v i t y occurs d u r i n g the p r e v i o u s l y noted a l k y l a t i o n of (167) (page 65). Decyanation of (180a,b) with 71 potass ium metal i n t e r t - b u t a n o l and hexamethylphosphoramide a l s o r e s u l t e d i n d e s i l y l a t i o n to a f f o r d h y d r o x y - k e t a l (181) [63] i n 82% y i e l d as w e l l as s m a l l amounts of s i l y l e ther (188) and h y d r o x y - n i t r i l e s (185a,b) (Scheme 56). (185a,b) (188) H y d r o l y s i s of (181), f o l l o w e d by o x i d a t i o n [69] of the r e s u l t i n g hydroxy-ketone (182) p r o v i d e d k e t o - a l d e h y d e (183) i n 96% y i e l d . F u r t h e r q u a n t i t i e s of (183) were prepared from s i l y l -e ther (188) (Scheme 54) , and n i t r i l e s (185a,b) (Scheme 55) . Se-l e c t i v e a c e t a l i s a t i o n of the a ldehyde over the ketone f u n c t i o -n a l i t y in (183) w i t h e t h y l e n e g l y c o l and c a t a l y t i c p - t o l u e n e -s u l f o n i c a c i d i n r e f l u x i n g benzene p r o v i d e d k e t o - a c e t a l (184) (Scheme 51) which was then c o n v e r t e d to the c o r r e s p o n d i n g e n o l -s i l y l e ther a c e t a l (178) i n about 88% o v e r a l l y i e l d . C y c l i s a t -ion of (178) w i t h T i C l 4 i n methylene c h l o r i d e at - 7 8 ° C p r o v i d e d two d i a s t e r e o m e r i c p r o d u c t s (192a,b) i n 78% y i e l d . The 2:1 r a -t i o of epimers was i n d i c a t e d from ^ - n . m . r . (page 2 7 4 ) - I t w a s 72 Reagents and c o n d i t i o n s : ( i ) TBAF; ( i i ) HCI, Me2CO; ( i i i ) PDC, CH C l . Scheme 54 CN CN CN (185a,b) (189) (190) ( i i i ) (183) (191) Reagents and c o n d i t i o n s : ( i ) PCC, CH 2C1 2; ( i i ) p - T o l u e n e s u l f o n i c a c i d , EG, PhH; ( i i i ) K, HMPA, E t 2 0 , tBuOH, 0°C; ( i v ) HCI, Me 2C0. Scheme 55 73 p a r t i c u l a r l y i n t e r e s t i n g to note the d i s a p p e a r a n c e of the C-H bending band (CH 2 "CO) at about 1413 c m - 1 (page 2 7 5 ) s i n c e t h i s i s a u s e f u l d i a g n o s t i c t e s t f o r c a r b o n - c a r b o n bond f o r -mation at the C(3 ) p o s i t i o n of (+)-camphor (26) [70] (page 275 )-Attempts to prepare a c r y s t a l l i n e p-bromobenzoate d e r i v a t i v e (193a ,b) of hydroxy-ke tones (192a ,b ) f a i l e d . In order to make subsequent f u n c t i o n a l group t r a n s f o r -mations e a s i e r , we d e c i d e d to attempt the c y c l i s a t i o n r e a c t i o n on the d i m e t h y l a c e t a l e n o l s i l y l e ther (105) (Scheme 56) T h i s compound was s y n t h e s i s e d from k e t o - a l d e h y d e (183) i n 83% o v e r -a l l y i e l d and on treatment w i t h T i C l ^ i n methylene c h l o r i d e o at -78 C , (105) p r o v i d e d two d i a s t e r e o m e r i c p r o d u c t s (195a ,b) R =H, R 2=0Me (195b) ( 1 05) R =0Me, R 2=H (1 9 5 a ) R e a g e n t s and c o n d i t i o n s : ( i ) H C ( 0 M e ) 3 , C e C l 3 , MeOH; ( i i ) LDA, THF, -78°C; M e ^ i C l ; ( i i i ) T i C l , CH C l . 4 1 Scheme 56 74 (Scheme 56) i n a r a t i o of 3:1 determined from the H - n . m . r . spectrum (page 276). The major d i a s t e r e o m e r , (R)-methoxy-ketone (195a) , proved to be c r y s t a l l i n e and i t s s t r u c t u r e and a b s o l u t e c o n f i g u r a t i o n were conf irmed by X - r a y c r y s t a l l o -g r a p h i c a n a l y s i s (page 277) [68 ] , A l t h o u g h the mechanism of t h i s Lewis a c i d d i r e c t e d a l d o l r e a c t i o n has not been s t u d i e d i n d e t a i l , K o c i e n s k i et a l . [71] r e c e n t l y suggested tha t r i n g c l o s u r e i n v o l v e d n u c l e o p h i l i c a d d i t i o n to an e l e c t r o p h i l i c oxonium ion i n the c o n v e r s i o n of (196) i n t o the c*.-alkoxy-benzocyclooctanone (199) as shown i n Scheme 57. We are not sure the a c t u a l course of the r e a c -t i o n i n our c a s e , but i t seems l i k e l y t h a t the i n t r a m o l e c u l a r n u c l e o p h i l i c a d d i t i o n which r e s u l t s i n r i n g c l o s u r e c o u l d take p l a c e e i t h e r at the " s i face" (200) or the "re face" (201) of the oxonium ion (Scheme 58) . Thus , (R)-methoxy-ketone OTMS OTMS (196) (197) OTMS cr • 0 0T.CI 3 (199) (198) Scheme 57 75 (195a) would r e s u l t from a d d i t i o n to the " s i face" of the oxonium ion and (S) -methoxy-ketone (195b) , from a d d i t i o n to the "re face" . The s t e r e o s e l e c t i v i t y ( ( R ) : ( S ) , 3 : 1 ) observed i s p r o b a b l y due to the more f a v o r a b l e c o n f o r m a t i o n of the n u c l e o p h i l i c a d d i t i o n at the " s i face" of the oxonium ion Scheme 58 Having c o n s t r u c t e d the t r i c y c l i c s k e l e t o n of the ( + ) - l o n -gicamphor framework, we now c o n s i d e r e d the problem of i n t r o d u -c i n g gem-dimethyl groups at the C(6) p o s i t i o n . To a v o i d a p o s s -i b l e r e t r o - a l d o l p r o c e s s o c c u r r i n g d u r i n g the d e m e t h y l a t i o n of the methoxy group i n (195a,b) , we d e c i d e d to reduce the ketone group of (195a,b) f i r s t and then p r o t e c t the a l c o h o l s r e s u l t e d . L i t h i u m aluminum h y d r i d e r e d u c t i o n of methoxy-ketones (195a,b) was s t r a i g h t f o r w a r d but we found t h a t a c e t y l a t i o n of the epime-r i c a l c o h o l s (202a,b) a f f o r d e d a c e t a t e (203) and r e c o v e r e d a l c -o h o l (202a) . The r e s i s t a n c e of the ( R ) - m e t h o x y a l c o h o l (202a) 76 to a c e t y l a t i o n i s due to the p r o x i m i t y of the oxygen of the axo_-alcohol and the (R)-methoxy group (Scheme 59) . S i n c e (202a) (202a) R e a g e n t s and c o n d i t i o n s : ( i ) LAH, THF; ( i i ) A C 2 0 , 4-DMAP, P y r i d i n e . Scheme 59 was the major p r o d u c t , we d e c i d e d to amend our s y n t h e t i c route by r e d u c i n g (195a ,b) w i t h c a l c i u m metal i n l i q u i d ammonia [23, 72] to p r o v i d e enolo_-alcohols (204a, b) i n 98% y i e l d . Subsequent a c e t y l a t i o n p r o v i d e d methoxy-ace ta tes (205a ,b) i n 89% y i e l d , y i e l d . D e m e t h y l a t i o n w i t h boron t r i b r o m i d e / s o d i u m i o d i d e / 1 5 -crown-5 i n methylene c h l o r i d e [73] f o l l o w e d by o x i d a t i o n [69] p r o v i d e d k e t o - a c e t a t e (207) i n 85% o v e r a l l y i e l d (Scheme 60) . To i n t r o d u c e the gem-dimethyl mo ie ty , we f i r s t i n v e s t i -gated d i r e c t gemina l d i m e t h y l a t i o n of k e t o - a c e t a t e (207) u s i n g M e 2 T i C l 2 , a reagent deve loped by Reetz et a l . [74 ] . T h i s was 77 (i) (ii) ( 1 9 5 a , b ) OH ( 2 0 4 a , b ) (iii) O CAC (iv) (207) (206) R e a g e n t s and c o n d i t i o n s : ( i ) Ca/NH 3, E t 0 ; ( i i ) A c 2 0 , 4-DMAP, P y r i d i n e ; ( i i i ) B B r ^ (15 - C r o w n - 5 , N a l , CH 0C1 , ( i v ) PDC, CH C l . 1 u n s u c c e s s f u l , however, and t h e r e f o r e we r e s o r t e d to the t r a d i t i o n a l three s t e p - p r o c e d u r e of c o n v e r t i n g a ketone group to a gem-dimethyl moie ty , t h a t i s , m e t h y l e n a t i o n , c y c l o p r o p a -n a t i o n , and h y d r o g e n o l y s i s (Scheme 61) . W i t t i g o l e f i n a t i o n of (207) w i t h m e t h y l e n e t r i p h e n y l p h -osphorane i n t e t r a h y d r o f u r a n a f f o r d e d a lkene a c e t a t e (208), which was reduced w i t h l i t h i u m aluminum h y d r i d e to p r o v i d e h y d r o x y - o l e f i n (209) i n 85% o v e r a l l y i e l d . C y c l o p r o p a n a t i o n of the e x o c y c l i c double bond of (209) u s i n g the m o d i f i e d Simmons-Smith reagent ( E t ^ n / C H 2 I 2 ) C 7 5 l » a f f o r d e d the t e t r a c y c l i c a l -c o h o l (210) i n 99% y i e l d . F i n a l l y , h y d r o g e n o l y s i s of the c y c l o -propane r i n g i n (210) u s i n g Adam's c a t a l y s t ( P t 0 2 ) [76] i n ace -t i c a c i d at 40 p . s . i . o c c u r r e d q u a n t i t a t i v e l y , to complete the f i r s t e n a n t i o s p e c i f i c t o t a l s y n t h e s i s of ( + ) - l o n g i b o r n e o l (59). 78 Scheme 60 (207) ( 2 08) (209) ( i i i ) (59) ( 2 10) R e a g e n t s and c o n d i t i o n s : ( i ) P h 3 M e P B r , B u L i , -78°C-20°C; ( i i ) LAH, THF; ( i i i ) E t 2 Z n , C H 2 I 2 , PhMe; ( i v ) H 2 / P t 0 2 , HOAc, 2.5 A t m o s p h e r e . Scheme 61 25 o The s p e c i f i c r o t a t i o n ( [o<.] +15.83 ) of our s y n t h e t i c D ( + ) - l o n g i b o r n e o l (59) compares f a v o r a b l y w i t h those r e p o r t e d in the l i t e r a t u r e [77] ( c f . T a b l e 2 ) . In a d d i t i o n , our s y n t h e t i c ( + ) - l o n g i b o r n e o l (59) has v e r y s i m i l a r i n f r a r e d spectrum (page 277 )» 1 H - n . m . r . spectrum (page 278)» and gas -l i q u i d chromotographic r e t e n t i o n time as t h a t of racemic l o n g i b o r n e o l [78] and n a t u r a l l y o c c u r r i n g l o n g i b o r n e o l [79] . The c o r r e s p o n d i n g "Mosher e s t er" d e r i v a t i v e (211) [80] of our s y n t h e t i c ( + ) - l o n g i b o r n e o l (59) was prepared and the 1 19 1 ? H - n . m . r . (page 2 7 9 ) , F - n . m . r . (page 2 8 0 ) , and C - n . m . r . (page 281) s p e c t r a of t h i s compound conf irmed the e n a n t i o m e r i c p u r i t y of our s y n t h e t i c m a t e r i a l . 79 GROUPS LONGIBORNEOL [0C] D REFERENCES Money and Kuo ( + ) o 15.83 [84] Doi and c o - v o r k e rs ( + ) o 18 . 50 [ 7 7 a ] A k i y o s h i and co - v o r k e r s ( + ) 18.40° [ 7 7 b ] Matsuo and co - v o r k e r s (-) o 16. 30 [ 7 7 c ] T a b l e 2 80 To complete the s y n t h e s i s of ( + ) - l o n g i f o l e n e (61), ( + ) - l o n g i b o r n e o l (59) was o x i d i s e d [69] to (+)-longicamphor (83) which was then reduced with l i t h i u m aluminum hydride to p r o v i d e ( + ) - l o n g i i s o b o r n e o l (89) (Scheme 62). Treatment (61) R e a g e n t s and c o n d i t i o n s : ( i ) PCC, C H 2 C 1 2 ; ( i i ) LAH, THF; ( i i i ) M e S C ^ C l , P y r i d i n e , . 4-DMAP, 100°C, 16 h o u r s . Scheme 62 of ( + ) - l o n g i i s o b o r n e o l (89) with methanesulfony1 c h l o r i d e i n 4-dimethylaminopyridine and p y r i d i n e at high temperature, f o l l o w e d by column chromatography of the product, a f f o r d e d a c o l o r l e s s o i l . The i n f r a r e d spectrum (page 282) of t h i s product showed bands at 1661 cm * and 871 cm * which i n d i c a t e d the presence of an e x o c y c l i c double bond. T h i s , together with '''H-n.m.r. spectrum (page 282). mass spectrum (page 283 ). and elemental m i c r o a n a l y s i s prompted us to conclude that the Wagner-Meerwein rearrangement had occurred s u c c e s s f u l l y to 81 p r o v i d e ( + ) - l o n g i f o l e n e ( 6 1 ) . In a d d i t i o n , the s p e c i f i c 25 o r o t a t i o n ([od] +51.77 ) of our s y n t h e t i c ( + ) - l o n g i f o l e n e ( 6 1 ) D was v e r y s i m i l a r to the l i t e r a t u r e v a l u e s [81] ( c f . T a b l e 3 ) . GROUPS LONGIFOLENE REFERENCES Oppolzer and co-vorkers ( + ) o 51 . 5 [81a] G. Ourisson and co-vorkers (-) o 51.0 [81b] Money and Kuo ( + ) o 51.7 [84] T a b l e 3 Scheme 25 (page 35) p r o v i d e s an o u t l i n e of l o n g i f o l e n e ( 6 1 ) b i o s y n t h e s i s and shows t h a t the f i n a l s t ep i n the c o n s t r -u c t i o n of t h i s n a t u r a l product i s p r o b a b l y a Wagner-Meerwein rearrangement of the t r i c y c l i c secondary c a r b o c a t i o n (84) f o l l o w e d by d e p r o t o n a t i o n . S i m i l a r l y , the key s tep i n our 82 s y n t h e t i c route to ( + ) - l o n g i f o l e n e (61) i s the Wagner-Meerwein rearrangement of ( + ) - l o n g i i s o b o r n e o l (89) and t h e r e f o r e , the f i n a l s tep i n our s y n t h e s i s of ( + ) - l o n g i f o l e n e (61) i s analogous to i t s p o s t u l a t e d b i o s y n t h e t i c p r o c e s s . "If there is one way better than another, i t i s the way of nature" F i n a l l y , we hoped to s y n t h e s i s e d ( + ) - l o n g i c y c l e n e (60) from the hydrazone d e r i v a t i v e (212) of (+) - long icamphor (83) by a r e a c t i o n analogous to tha t used i n the s y n t h e s i s of t r i c y c l e n e (88) [82 ] , and ot-santalene (45) [24] ( c f . Scheme 63 ) . However, a l l our attempts to p r e p a r e the r e q u i r e d hydrazone (212) f a i l e d . An examinat ion of the m o l e c u l a r model r e v e a l s t h a t s t e r i c h i n d r a n c e around the c a r b o n y l group of (+ ) - long icamphor (83) i s q u i t e severe ( c f . Scheme 64) . A r i s t o t l e (213) (88) (214) (45) Scheme 63 83 ( 8 3 ) (212) (60) Scheme 64 Although t h i s d i r e c t approach to s y n t h e s i s e ( + ) - l o n g i c -y c l e n e (60) from (+) - long icamphor (83) was not s u c c e s s f u l , i t i s i n t e r e s t i n g to note tha t in 1964 Dev and co -workers [83] demonstrated the rearrangement of ( + ) - l o n g i f o l e n e (61) to (+)-l o n g i c y c l e n e (60 ) , i s o l o n g i f o l e n e (215) , and ( J ) - l o n g i f o l e n e as shown in Scheme 65. (61) ( 6 0 ) (215) (_+) - L o n g i f o l e n e Scheme 65 84 In summary, at tempts to s y n t h e s i s e (+) - longicamphor (83) by an i n t r a m o l e c u l a r D i e l s - A l d e r r e a c t i o n or by i n t r a m o l e c u -l a r Lewis a c i d induced o t - t e r t i a r y a l k y l a t i o n were u n s u c c e s s f u l . However, the i n t r a m o l e c u l a r Mukaiyama r e a c t i o n p r o v i d e d a t r i -c y c l i c i n t e r m e d i a t e (195a,b) which was used i n the e n a n t i o s p e -c i f i c t o t a l s y n t h e s i s of ( + ) - l o n g i b o r n e o l (59), and ( + ) - l o n g i -f o l e n e (61). S i n c e (+)-camphor (26) can l ead to ( + ^ l o n g i b o r n e -o l (59), (+ ) - long icamphor (82), and ( + ) - l o n g i f o l e n e (61), ( - ) -camphor (27) shou ld p r o v i d e the n a t u r a l l y o c c u r r i n g ( - ^ l o n g i -b o r n e o l (216), and ( - ) - l o n g i f o l e n e (78) as shown i n Scheme 66. In c o n c l u s i o n , Scheme 67 i l l u s t r a t e s a s e r i e s of 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 p r o d u c t s t h a t have been s y n t h e s i s e d i n our l a b o r a t o r y from e i t h e r (+)-8-bromocamphor (42) or ( - ) -8-bromocamphor (43), and i n c l u d e s the more r e c e n t i n v e s t i g a -t i o n s d e s c r i b e d above [84 ] . 85 H (•) - tsoepteamphertnol (4)-ep1-B-aantalene CO (•)-a-aantalene OH • , (•f) -copa borneol (+)-eplcampherenone* (-)-copacamphene* y (+)-copacamphor* (-) -eye loeopacaaphene (-0-camphor (-)-camphor ( -)-campherenone (•)-longicamphor* r -$9S ' OH j *(•*•)-long Ihorneol (4)-longlfoleneT (+)-longicyclene OH r (4)-y langobomeol (+)-ylangoca«phor* (-)-satlvene (+)-a-aantatene (-)-campherenol (-)-fl-santatene r (-)-cycloaatlvene t ] enantIomer also known * unknown In nature Scheme 67 1.4.0. EXPERT MENTAL General M e l t i n g p o i n t s (mp) were determined on a K o f l e r micro h e a t i n g stage and are unc o r r e c t e d . I n f r a r e d ( i r ) s p e c t r a were recorded on a Perkin-Elmer model 710 B spectrophotometer and were c a l i b r a t e d u s i n g the 1601 cm" 1 band of p o l y s t y r e n e . Absorption p o s i t i o n s ( V m a x ) are given i n cm - 1. O p t i c a l r o t a t i o n s ( £ , ) were measured on a Perkin-Elmer 141 p o l a r i m e t e r at a ambient temperature. The proton n u c l e a r magnetic resonance (*H n.m.r.) s p e c t r a were taken i n deuterochloroform and recorded at 80 MHz on a Bruker WP-80 spectrometer, at 300 MHz on a Varia n XL-300 spectrometer, at 400 MHz on a Bruker WH-400, 100 MHz on a Var i a n XL-100 spectrometer or at 270 MHz on a u n i t c o n s i s t i n g of an Oxford instrument 63.4 KG superconducting magnet, a N i c o l e t 32K computer and Bruker TT-23 console. S i g n a l p o s i t i o n s are given i n p a r t s per m i l l i o n downfield from t e t r a m e t h y l s i l a n e u s i n g the s c a l e . In the case of compounds c o n t a i n i n g t r i a l -k y l s i l y l groups the chemical s h i f t s were determined r e l a t i v e to chloroform s i g n a l ($7.25). S i g n a l m u l t i p l i c i t y , c o u p l i n g cons-t a n t s and assignments of s e l e c t e d s i g n a l s are i n d i c a t e d i n 13 parentheses. C n.m.r. s p e c t r a were made i n deuterochloroform and determined on a Bruket WP-400 insturment at 100.6 MHz with s i g n a l p o s t i o n s given i n p a r t s per m i l l i o n downfield from t e t r a -19 m e t h y l s i l a n e (used as an e x t e r n a l s t a ndard). F n.m.r. s p e c t r a were obtained i n deuterochloroform u s i n g e i t h e r a V a r i a n XL-100 88 ins trument o p e r a t i n g at 94.1 MHz or a Bruker HXS-270 s p e c t r o -meter at 254 MHz. The s i g n a l s are quoted in p a r t s per m i l l i o n d o w n f i e l d from t r i f l u o r o a c e t i c a c i d (used as an e x t e r n a l r e f e r -e r c e ) . Low r e s o l u t i o n mass s p e c t r a were obta ined u s i n g a V a r i a n MAT CH-4B spec trometer and exact masses were o b t a i n e d by h i g h r e s o l u t i o n mass s p e c t r o s c o p y on a K r a t o s MS-50 mass s p e c t r o -meter . A l l compounds c h a r a c t e r i s e d by h igh r e s o l u t i o n mass s p e c t r o m e t r y e x h i b i t e d 1 spot on t i c . Low r e s o l u t i o n gas l i q u i d chromatography/mass s p e c t r a (gc/ms) were o b t a i n e d on a C a r l o E r b a 41 6 0 / K r a t o s MS80 RFA ins trument u s i n g a 0.25 mm x 15 m column w i t h he l ium as the c a r r i e r gas . G a s - l i q u i d chromatography was performed on e i t h e r a Hewlett Packard model 5830A gas chromatograph w i t h a 6 f t x 1/8 i n . column of 3% 0V-17 or a Hewlet t Packard model 5880A gas chromatograph u s i n g a 50 m or 12 m x 0.2 mm column of Carbowax 10 M or a 12 m x 0.2 mm column of 0V-101 . The c a r r i e r gas was n i t r o g e n f o r the 5830A and he l ium f o r the 5880A. In a l l cases a flame i o n i s a t i o n d e t e c t o r was used . X-Ray c r y s t a l l o g r a p h i c a n a l y s e s were c a r r i e d out by D r . S. R e t t i g and m i c r o a n a l y s e s were performed by Mr. P. B o r d a , 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 , U n i v e r s i t y of B r i t i s h C o l u m b i a , Vancouver . A l l r e a c t i o n s i n v o l v i n g moi s ture s e n s i t i v e reagents were performed under an atmosphere of d r y argon u s i n g e i t h e r oven or f lame d r i e d g l a s s w a r e . A l l r e a c t i o n p r o d u c t s were d r i e d by a l -lowing the s o l u t i o n s to s tand over anhydrous magnesium s u l p h a t e . The s o l v e n t s and reagents used were p u r i f i e d as f o l l o w s : t e t r a -89 hydrofuran and dimethoxyethane were d i s t i l l e d from calcium hydride and then from l i t h i u m aluminum hydride (LAH). D i e t h y l ether was d i s t i l l e d from LAH and hexamethylphosphoramide (HMPA), Benzene, methylene c h l o r i d e , d i i s o p r o p y l a m i n e , t r i e t h y l a m i n e , d i m e t h y l s u l p h o x i d e (DMSO), and p y r i d i n e were d i s t i l l e d from calcium hydride. Methanol was obtained by d i s t i l l a t i o n from magnesium methoxide. Petroleum ether (the hydrocarbon f r a c t i o n of b o i l i n g range 30-60°C) was d i s t i l l e d p r i o r to use. F l a s h chromatography was performed u s i n g Merck s i l i c a g e l 60, 230-400 mesh and t h i n l a y e r chromatography ( t i c ) u s i n g B a k e r f l e x s i l i c a g e l 1B2-F sheets. A l l chemicals were s u p p l i e d by A l d r i c h Chemical Company unl e s s otherwise s t a t e d . 90 f - W s o b o r n e o l (86>> L i t h i u m t r i b u t o x y aluminum h y d r i d e (3 .8 g , 15 mmol) was suspended i n d r y t e t r a h y d r o f u r a n (40 mL) at 0 ° C , and a s o l u t i o n of (+)-camphor (26) (1 .5 g , 9.8 mmol) in d r y t e t r a h y d r o f u r a n (10 mL) was s l o w l y added. The r e a c t i o n mixture was s t i r r e d at 0 C under an argon atmosphere f o r 3 hours . A f t e r d i l u t i o n w i t h water (10 mL), c a r e f u l l y f o l l o w e d by e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d ( M g S O ^ . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatograph ( s i l i c a g e l , p e t . e t h e r ) to a f f o r d ( - ) - i s o b o r n e o l (86) (1 .5 g, 99%) as a white s o l i d , which was r e c r y s t a l l i s e d from pentane ( 2 5 ° C ) as c o l o r l e s s p r i s m s ; mp 212°C ( s e a l e d t u b e ) ; ( l i t . * mp 2 1 4 ° C ( s e a l e d t u b e ) ) ; M I ° - 1 9 . S ° ( C 2 .04 , CHC1 3), [oC]g ° - 3 4 . 4 ° (c 1.80, C 2 H 50H): ( l i t . * [et]D - 3 4 . 6 ° (c 0 .50 , a l ) ) ; S (80 MHz, CDCI3): 0.83 ( s , 3H, C H 3 ) , 0.93 ( s , 3H, C H 3 ) , 1 .0 ( s , 3H, C H 3 ) , 3.6 ( d d , 1H, RH.0H, J = 2 Hz , 7 H z ) . * CRC Handbook of C h e m i s t r y and P h y s i c s , 56th ed . 1975-1976, C-345 . 91 f+^-Camphene (851 (86) (85) ( - ) - I s o b o r n e o l (86) (3 .2 g , 21 mmol) was t r e a t e d w i t h methanesulphony1 c h l o r i d e (3 .2 mL, 41 mmol) and 4 -d imethy lam-i n o p y r i d i n e (0 .10 mg) i n dry p y r i d i n e (15 mL) at 1 0 5 ° C under an argon atmosphere f o r 16 hours . A f t e r d i l u t i o n w i t h water (10 mL) and e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were was-hed w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and water , and d r i e d (MgSO^). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromato-graphy ( s i l i c a g e l , p e t . e t h e r ) to o b t a i n (+)-camphene (85) ( 1 . 9 g , 67%) as a c o l o r l e s s o i l ; toO^ + l O B 0 < c 1-87, C 2 H 5 O H ) , [oOJ5 5 +118 0 (c 1.77, C 6 H 6 ) ( l i t . * [oU D + 1 0 4 ° (c 0 .40 , C 2 H s 0 H ) ) ; S (80 MHz, C D C 1 3 ) : 1.05 ( s , 3H, C H 3 ) , 1.07 ( s , 3H, C H 3 ) , 4 .50 ( s , 1H, RC:CHH), 4 .70 ( s , 1H, RC:CHR) . * CRC Handbook of C h e m i s t r y and P h y s i c s , 56th ed. 1975-1976, C-228 92 ( + 1-3.3-Dibromr>camDhor (129) °*c5 (26) (129) Bromine (292 mL, 5.70 mol) was added to (+)-camphor (26) (102 g , 0.670 mmol; A l d r i c h Chemica l C o . ) d i s s o l v e d in g l a c i a l a c e t i c a c i d (326 mL, 5.70 mol) and hydrogen bromide gas was bubbled through the r e a c t i o n mixture f o r 1 hour at 1 1 0 ° C . S t i r r i n g was c o n t i n u e d at 1 1 0 ° C f o r 16 hours i n the dark and the r e a c t i o n mix ture was then poured i n t o water and excess bromine d e s t r o y e d w i t h sodium b i s u l p h i t e . The aqueous l a y e r was e x t r a c t e d w i t h e ther and the combined o r g a n i c e x t r a c t s were washed w i t h water , s a t u r a t e d sodium b i c a r b o n a t e , s a t u r a t e d b r i n e , and d r i e d over MgS0 4 . Removal of s o l v e n t gave a p a l e y e l l o w o i l which s o l i d i f i e d upon c o o l i n g i n i c e - b a t h . C r y s t a l -l i s a t i o n from pe tro l eum ether p r o v i d e d ( + ) -3 ,3 -d ibromocamphor (129) (205 g , 99.0%); mp 6 0 ° C ; [oC]^5 + 3 7 . 1 ° (c 1.67, C 2 H 5 0 H ) ; ^ m a x ( C C 1 4 ) : 2950, 1770 c m " 1 ; & (CDCI3, 80 MHz): 1.05 ( s , 3H, C H 3 ) , 1.15 ( s , 3H, C H 3 ) , 1.27 ( s , 3H, C H 3 ) , 2.82 ( d , 1H; J=4 Hz, C 4 H ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 3 0 8 / 3 1 0 / 3 1 2 ( 0 . 5 9 / 1 . 1 5 / 0 . 6 6 , M>M + 2/M++4 ) , 284 ( 1 . 4 3 ) , 282 ( 2 . 9 2 ) , 280 ( 1 . 0 9 ) , 232 ( 8 . 2 8 ) , 230 ( 7 . 9 7 ) , 203 ( 1 1 . 3 ) , 201 ( 1 1 . 7 ) , 123 ( 6 6 . 8 ) , 107 ( 4 4 . 1 ) , 95 .0 ( 2 8 . 0 ) , 91^0 (32.01- 83.0 (100): Exact, mass c a l c d . f o r C 1 0 H 1 4 O B r 2 : 93 307.9411/309.9391/311.9370; found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 307 .9418/309.9397/311.9375. A n a l , c a l c d . f o r C 1 0 H 1 4 0 B r 2 : C 38 .74 , H 4 .55; found: C 38 .63 , H 4 .58 . <'+'>-8-Bromocamphor (A?A 122*1 (129) (130) (42) A s o l u t i o n of ( +) -3 ,3-dibromocamphor (129) (19 .7 g , 63.5 mmol) i n bromine (3 .30 mL, 63.5 mmol) was coo led i n an i c e - w a t e r bath w h i l e c h l o r o s u l p h o n i c a c i d (25 .0 mL, 372 mmol) was added d r o p w i s e . The i c e bath was then removed and s t i r r i n g was c o n -t i n u e d f o r 3 .5 hours be fore the r e a c t i o n mix ture was c a r e f u l l y poured onto i c e . Excess bromine was d e s t r o y e d w i t h sodium b i -s u l p h i t e and the aqueous s o l u t i o n was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and d r i e d ( M g S O ^ . Upon removal of s o l v e n t , crude 3 , 3 , 8 - t r i b r o m o c a m p h o r (130) (24 .2 g) was o b t a i n e d as a v i s c o u s brown o i l which was used i n the next s tep wi thout f u r t h e r p u r i f i c a t i o n . Crude 3 , 3 , 8 - t r i b r o m o c a m p h o r (130) (300 g , 0.771 mol) was d i s s o l v e d i n g l a c i a l a c e t i c a c i d (450 mL) and coo led by an i c e -94 water b a t h . Z i n c dus t (75.0 g , 1.15 m o l ) , was s l o w l y added w i t h v i g o r o u s s t i r r i n g . The i c e - w a t e r bath was then removed and s t i r -r i n g was c o n t i n u e d f o r 4 .5 hours at room temperature . The r e -a c t i o n mixture was poured i n t o i c e - w a t e r c o n t a i n i n g sodium b i c a r -bonate , and e x t r a c t e d wi th e t h e r . The combined o r g a n i c e x t r a c t was washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and then d r i e d ( M g S 0 4 ) . Removal of s o l v e n t gave a brown o i l (190 g) which upon f r a c t i o n a l d i s t i l l a t i o n p r o v i d e d ( + ) - 8 - b r o -mocamphor (42) (107 g , 60.0%) as a c o l o r l e s s c r y s t a l l i n e s o l i d ; bp ( range , 0.05 mmHg) 7 0 - 1 1 0 ° C . S u b l i m a t i o n f o l l o w e d by c r y -o s t a l l i s a t i o n from petro leum e ther (30-60 C) p r o v i d e d c o l o r l e s s c r y s t a l s ; mp 8 3 - 8 5 ° C ; [oC]^5 + 73 . 1 ° (c 1.17, C 2 H 5 0 H ) ; [ot]^5+76 . 7° (c 1.24, C H C 1 3 ) ; R f 0.39 (pe tro leum e t h e r : e t h e r , 9 :1 ) ; Vmax (CHCI3): 2975, 1751 c m - 1 ; £ (CDCI3, 400 MHz): 0.93 ( s , 3H, C H 3 ) , 1.15 ( s , 3H, C H 3 ) , 3 .10 , 3.17 (AB q u a r t e t , 2H, J A B = 1 0 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 2 3 0 / 2 3 2 ( 3 . 5 7 / 2 . 7 9 , M/M++2), 205 ( 1 . 1 8 ) , 188 ( 1 . 9 3 ) , 186 ( 2 . 0 5 ) , 175 ( 1 . 0 7 ) , 159 ( 1 . 4 5 ) , 151 ( 5 . 3 6 ) , 149 ( 1 5 . 1 ) , 109 ( 2 8 . 4 ) , 108 ( 4 2 . 7 ) , 107 ( 4 6 . 6 ) , 95.0 ( 1 0 . 0 ) ; Exac t mass c a l c d . f o r C 1 0 H 1 5 0 B r : 230.0306/232.0286; found: 230.0308/232.0290; An&L. c a l c d . f o r C 1 0 H 1 5 0 B r : C 38 .74 , H 4 .550; found: C 38 .63 , H 4 .580 . 95 (+1-8-Bromocamphor e t h y l e n e k e t a l (1311 (42) (131) To a s o l u t i o n of (+)-8-bromocamphor (42) (9 .8 g , 4 .3 mmol) i n d r y e t h y l e n e g l y c o l (140 mL, 354 mmol) under an argon atmo-sphere was added c h l o r o t r i m e t h y l s i l a n e (31 .0 mL, 244 mmol) and the r e a c t i o n mix ture s t i r r e d f o r 6 hours at room temperature . Water (50 mL) was then added and worked up by e x t r a c t i o n w i t h e h t e r , and the combined o r g a n i c l a y e r s were washed wi th sodium b i c a r b o n a t e s o l u t i o n (10%) and b r i n e , and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography on s i l i c a g e l ( p e t . e t h e r : e t h e r , 15:1) to a f f o r d the (+)-8-bromocamphor e t h y l e n e k e t a l (131) (10 g , 88%) as a c o l o r l e s s o i l ; [oC]^5 + 1 2 . 1 ° (c 1.02, C H C 1 3 ) ; V m a x ( f i l m ) : 2981 c m " 1 ; S ( C D C 1 3 , 400 MHz): 0.82 ( s , 3H, CH3 ), 1.06 ( s , 3H, C H 3 ) , 3 . 70 -4 .00 (m, 4H, R0CH. 2CH. 20R), 3 .24 , 4.22 (AB q u a r t e t , 2H; J A B = 1 0 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 274/276 ( 0 . 2 0 0 / 0 . 1 6 0 , M + / M + + 2 ) , 273 ( 1 . 7 2 ) , 197 ( 1 . 2 7 ) , 196 ( 1 3 . 5 ) , 195 (1001: Exac t mass c a l c d . f o r c i 2 H i g ° 2 B r ( M + + l ) : 275.0568; found: 275.0468: A n a l . c a l c d . f o r C 1 2 H i g 0 2 B r : C 52 .38 , H 6 .96; found: C 52 .60 , H 6 .93 . 96 f+l-B-Iodocamphor (1651 I (42) (165) Dry potass ium i o d i d e (31 .2 g , 188 mmol) was added to a s t i r r e d s o l u t i o n of ( + )-8-bromocamphor (42) (14.4 g , 63.0 mmol) in dry d i m e t h y l s u l f o x i d e (60 mL) and s t i r r i n g was c o n t i n u e d at 1 1 0 ° C under an argon atmosphere f o r 40 hours . The c o o l e d r e -a c t i o n mixture was added to water (200 mL), e x t r a c t e d w i t h e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h b r i n e , and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 15:1) to a f f o r d ( +) -8- iodocamphor (165) (17 g , 95%) as a c o l o r l e s s o i l ; R F 0.30 ( p e t . e t h e r : e t h e r , 9 :1 ) ; [oL] £ 5 + 7 2 . 1 ° (c 14.5; CHCI3) ; Vmay. ( f i l m ) : 2981, 1741 c m - 1 ; h (CDCI3, 270 MHz): 0.94 ( s , 3H, CH3 ) , 1.12 ( s , 3H, C H 3 ) , 2 .91 , 3.00 (AB q u a r t e t , 2H, RCH. 2 I , J A B = 1 0 H z ) ; m/e ( r e l a t i v e i n t e n -s i t y ) : 278 ( 2 3 . 1 , M + ) , 277 ( 1 . 9 0 ) , 223 ( 1 . 9 0 ) , 182 ( 3 . 3 0 ) , 1.52 ( 7 . 3 0 ) , 151 ( 5 0 . 0 ) , 123 ( 2 8 . 0 ) , 109 ( 6 9 . 4 ) , 107 (100); E X J U L L Biaaa c a l c d . f o r C 1 0 H 1 5 0 I : 278.0167; found: 278.0169; AaaJ.. c a l c d . f o r C 1 0 H 1 5 O I : C 43 .18 , H 5 .440, I 45 .63; found C 43 .30 , H 5 .430, I 45 .45 . 97 ( + 1-8-Iodocamphor e thy lene k e t a l (1331 1 I (165) (133) C h l o r o t r i m e t h y l s i l a n e (31 .0 mL, 242 mmol) was added to a s o l u t i o n of ( +) -8- iodocamphor (165) (16 .8 g , 60.4 mmol) in dry e t h y l e n e g l y c o l (80 mL) under an argon atmosphere and the r e -a c t i o n mixture s t i r r e d f o r 6 hours at room tempera ture . Water (50 mL) was added and the mix ture was e x t r a c t e d w i t h e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h sodium b i c a r b o n a t e s o l u t i o n (10%), b r i n e , and d r i e d (MgSO^). The s o l v e n t was r e -moved under vacuo and the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 15:1 ) , to p r o v i d e (+) -8- iodocamphor e t h y l e n e k e t a l (133) (18 g, 94%) as a c o l o r l e s s o i l : R f 0.63 ( p e t . e t h e r : e t h e r , 9 :1 ) ; [oC]^ 5 + 3 4 . 3 ° (c 0 .70 , C H C 1 3 ) ; Z ^ m a x ( f i l m ) : 2973 c m " 1 ; & (CDCI3, 400 MHz): 0.82 ( s , 3H, C H 3 ) , 1.05 ( s , 3H, C H 3 ) , 3 .04 , 4 .07 (AB q u a r t e t , 2H, ICtL 2 R, J A B = 1 0 H z ) , 3 . 74 -3 .98 (m, 4H, R0CH. 2CH. 20R); m/e ( r e l a t i v e i n t e n s i t y ) : 321 (0 .270 , M + - l ) , 304 ( 0 . 2 2 0 ) , 262 ( 0 . 2 9 0 ) , 221 ( 0 . 5 9 0 ) , 197 ( 1 . 3 8 ) , 196 ( 1 3 . 4 ) , 195 (100); Exact mass c a l c d . f o r C 1 2 H 1 9 I 0 2 ( M + - l ) : 321.0350; found: 321.0350; Anal, c a l c d . f o r C 1 2 H i g I 0 2 : C 44 .74 , H 5.940; found: C 45 .03 , H 6 . 100 . 98 ( + 1-8-CvanooamDhor et.hvlsnft k e t a l ( 1661 T22a1 X X=Br (131) (166) X=I (133) (a) Dry sodium cyan ide (9 .00 g , 184 mmol) was added to a s t i r r e d s o l u t i o n of ( +)-8-bromocamphor e t h y l e n e k e t a l (131) (10 .3 g , 37.6 mmol) i n dry d i m e t h y l s u l p h o x i d e (150 mL) and s t i r r i n g c o n t i n u e d at 6 0 ° C under an argon atmosphere f o r 7 d ays . A f t e r c o o l i n g , the r e a c t i o n mix ture was added to water (200 mL), e x t r a c t e d wi th e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h b r i n e , and d r i e d (MgSO^). The s o l v e n t was removed under vacuo , and the crude product was p u r i f i e d by column c h r o -matography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 6:1) to p r o v i d e (+)-8-cyanocamphor e t h y l e n e k e t a l (166) (4 .5 g , 54%) as a c o l o r l e s s o i l ; R f 0.48 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; [ o C ] p 5 + 5 . 0 6 ° (c 2 .35 , C 2 H 5 0 H ) ; Vmax ( f i l m ) : 2950, 2250 c m - 1 ; £ ( C D C 1 3 , 400 MHz): 0.85 ( s , 3H, C H 3 ) , 1.09 ( s , 3H, C H 3 ) , 2 .30 , 2.98 (AB q u a r t e t , 2H, NCCH 2 R, J A B = 1 6 H z ) , 3 .70 -4 .00 (m, 4H, R0CtL2CH.20R>'» m / e ( r e l a t i v e i n t e n s i t y ) : 221 ( 1 . 0 7 , M + ) , 182 ( 3 . 1 4 ) , 181 ( 2 4 . 8 ) , 166 ( 1 . 9 4 ) , 140 ( 1 . 3 0 ) , 133 ( 1 . 0 1 ) , 127 ( 1 . 7 6 ) , 125 ( 3 . 8 7 ) , 113 ( 1 1 . 7 ) , 95 .0 (100); Exact mass c a l c d . f o r C 1 3 H i g 0 2 N : 221.1416; found: 221.1416; Anal, c a l c d . f o r C 1 3 H i g 0 2 N : C 70 .56 , H 8.650, N 6 .330; found: C 70 .72 , H 8.800, N 6.220. 99 (b) Dry sodium cyan ide (1 .46 g , 29.8 mmol) was added to a s t i r r e d s o l u t i o n of (+ ) -8- iodocamphor e t h y l e n e k e t a l (133) (2 .4 g , 7 .5 mmol) i n d r y d i m e t h y l s u l p h o x i d e (35 mL) and s t i r -r i n g c o n t i n u e d at 6 0 ° C under an argon atmosphere f o r 3 d ays . A f t e r c o o l i n g , the r e a c t i o n mixture was poured onto water (50 mL), e x t r a c t e d w i t h e ther and worked up i n the u s u a l way. Column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 6:1) of the crude p r o d u c t gave (+)-8-cyanocamphor e thy lene k e t a l (166) (1 .5 g , 92%) as a c o l o r l e s s o i l . C v a n o k e t a l s (167a rb'> NC (166) (167a,b) n - B u t y l l i t h i u m (1 .6 M; hexane) (3 .6 mL, 5 .7 mmol) was added to a s t i r r i n g s o l u t i o n of d i i s o p r o p y l a m i n e (0 .80 mL, 5.7 mmol) i n d r y t e t r a h y d r o f u r a n (8 .0 mL) and s t i r r i n g c o n t i n u e d under an argon atmosphere at 0 ° C f o r 30 minutes . The s o l u t i o n was then c o o l e d to - 7 8 ° C and (+)-8-cyanocamphor e t h y l e n e k e t a l (166) (1 .0 g , 4 .7 mmol) i n d r y t e t r a h y d r o f u r a n (23 mL) was added to t h i s c o o l e d s o l u t i o n at - 7 8 ° C . S t i r r i n g was c o n t i n u e d f o r 2 hours b e f o r e p r e n y l bromide (0 .8 mL, 7.1 mmol) was i n t r o d u c e d 100 at -78 C . The r e a c t i o n mixture was s t i r r e d f o r 10 hours whi l e warming to room temperature , and worked up by adding water (10 mL) and e x t r a c t i n g w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d ammonium c h l o r i d e s o l u t i o n and b r i n e s o l u t i o n , and d r i e d (MgSO,^). Removal of s o l v e n t f o l l o w e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) p r o v i d e d a mix ture of epimers of c y a n o k e t a l s (167a ,b) (1 .3 g , 95%) as a c o l o r l e s s o i l ; the r a t i o (6 :1) of epimers was de termined from the pro ton i n t e g r a t i o n s in the n . m . r . spectrum; R f 0.22 ( p e t . e t h e r : e t h e r , 9 :1 ) ; ^ m a x ( f i l m ) : 2975, 2250 c m - 1 ; S (CDCI3, 400 MHz): '^H-n.m.r . ass ignments of major d i a s t e r e o m e r : 1.03 ( s , 3H, C H 3 ) , 1.10 ( s , 3H, CH3 ) , 1.65 ( s , 3H, CH3 ) , 1.75 ( s , 3H, C H 3 ) , 3.38 (dd , 1H, R 2 C a C N , J=4 Hz, 12 H z ) , 3 .70 -4 .00 (m, 4H, ROC2&4OR), 5.24 ( t , 1H, ( C H 3 ) 2 C : CH.R, J = 8 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 289 ( 4 . 6 2 , M + ) , 181 ( 1 7 . 8 ) , 125 ( 1 5 . 6 ) , 107 ( 1 . 1 0 ) , 99 .0 ( 1 . 3 0 ) , 96.0 ( 7 . 5 0 ) , 95 (100); Exact mass c a l c d . f o r C 1 8 H 2 7 0 2 N : 289.2024; found: 289.2045; A n a l , c a l c d . f o r C H ,0 N : f o r C 74.70, H 9.400, N 4.840; f o u n d : C 74.3 9 , 18 27 2 H 9.550, N 4.900. 101 (•O-Campherenone e t h y l e n e k e t a l (168) (167a,b) (168) To a s o l u t i o n of potass ium (0 .36 g , 92.0 mmol) i n d r y hexamethylphosphoramide (7.0 mL) under an argon atmosphere at 2 5 ° C was added a s o l u t i o n of c y a n o k e t a l epimers (167a,b) (1 . 3 g , 4 . 6 mmol) i n anhydrous e ther (7.0 mL), f o l l owed by t e r t - b u t a n o l (0 . 6 5 mL, 6.9 mmol). S t i r r i n g was cont inued f o r 12 hours and worked up by adding b r i n e s o l u t i o n (10 mL) and e x t r a c t i n g wi th e t h e r . The combined o r g a n i c l a y e r s were washed w i t h b r i n e s o l u t i o n and d r i e d ( M g S O ^ . The s o l v e n t was removed and the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r r e t h e r , 10:1) to p r o v i d e ( - ) -campherenone e t h y l e n e k e t a l (168) (0 .72 g , 78%) as a c o l o r l e s s o i l ; Rf 0 .89 ( p e t . e t h e r : e t h e r , 9:1); [oC] l5-14 • 5 ° (c 0 .58, C H C l 3 ) ; ^ m a x ( f i l m ) : 2776, 1661 cm" 1 (w); £ (CDC13, 400 MHz): 0 .80 ( s , 3H, C H 3 ) , 0 .88 ( s , 3H, C H 3 ) , 1.62 ( s , 3H, C H 3 ) , 1.69 ( s , 3H, C H 3 ) , 3.7-4.0 (m, 4H, ROC2H4OR), 5 . 1 5 ( t , 1H, H.a, J = 8 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 264 (10 . 9 , M + ) , 221 ( 2 . 6 7 ) , 195 ( 2 . 1 6 ) , 187 ( 2 . 7 4 ) , 180 ( 6 . 8 2 ) , 165 ( 4 . 4 4 ) , 159 (2.10), 155 ( 2 . 2 9 ) , 153 ( 7 . 4 9 ) , 149 (2.00), 140 ( 3 . 5 7 ) , 135 ( 6 . 6 6 ) , 133 (4.02), 125 (100); E x a c t mass c a l c d . f o r C 1 7 H 2 s 0 2 : 264.2089; found: 102 264.2086; A n a l , c a l c d . f o r C 1 7 H 2 8 0 2 : c 77 .22 , H 10.67; found: C 77 .50 , H 10.70. (+1-Campherenone (1511 ( 1 6 8 ) ( 1 5 1 ) ( - ) -Campherenone e t h y l e n e k e t a l (168) (0 .51 g , 2 .0 mmol) was d i s s o l v e d i n acetone (5 .0 mL) and t r e a t e d w i t h h y d r o c h l o r i c a c i d (1 .0 N, 3 .0 mL) f o r 3 hours at 2 5 ° C . A f t e r work-up by e x t r a -c t i n g wi th e t h e r , the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and d r i e d (MgS0 4 ) to p r o v i d e a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to p r o v i d e (+)-campherenone (151) (0 .42 g , 96%) as a c o l o r l e s s o i l ; R f 0.50 ( p e t . e t h e r : e t h e r , 9 :1 ) ; [oC] g 5 + 3 0 . 8 ° (c 2 .78 , CHCI3 ) ( l i t . [23] f o r ( - ) -campherenone; [<*] J 3 - 3 0 . 6 ° (c 10 .7 , C H C I 3 ) ) ; Vmax ( f i l m ) : 2979, 1748 c m - 1 ; $ (CDCI3, 400 MHz): 0.90 ( s , 3H, C H 3 ) , 0.98 ( s , 3H, C H 3 ) , 1.59 ( s , 3H, CH3) , 1.67 ( s , 3H, CH3 ) , 5.05 ( t , 1H, ( C H 3 ) 2 C : C E R , J=8 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 220 ( 1 9 . 0 , M + ) , 163 ( 3 . 9 8 ) , 137 ( 6 . 8 3 ) , 135 ( 1 2 . 7 ) , 121 ( 1 2 . 7 ) , 109 ( 3 4 . 2 ) , 95.0 ( 2 9 . 0 ) , 69.0 ( 4 5 . 0 ) ; Exac t mass c a l c d . f o r C 1 C - H 0: 220.1827; 1 0 3 found: 220.1827; A n a l , c a l c d . f o r C 1 5 H 2 4 0 : C 81 .76 , H 10.98; found: C 82 .00 , H 11.00. ( +^-Campherenone h y d r o c h l o r i d e (4261 (151) - (426) (+)-Campherenone (151) (0 .28 g, 1.3 mmol) was d i s s o l v e d in anhydrous e ther (8 .0 mL) and c o n c e n t r a t e d h y d r o c h l o r i c a c i d (3 .0 mL, 13 mmol) was added s l o w l y at 2 5 ° C . S t i r r i n g was c o n -t i n u e d f o r 8 hours b e f o r e water (10 mL) was added and the r e -a c t i o n mixture was e x t r a c t e d w i t h e ther and the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , b r i n e , and d r i e d (MgSO^). Removal of s o l v e n t f o l l o w e d by column chromatography of the crude p r o d u c t on s i l i c a g e l ( p e t . e t h e r : e t h e r , 10:1) a f f o r d e d ( +)-campherenone h y d r o c h l o r i d e (426) (0 .32 g , 96%) as a c o l o r l e s s o i l ; R f 0 .38 ( p e t . e t h e r : e t h e r , 9 :1 ) ; [og 2 5 + 3 7 . 9 ° (c 0.47 , CHC1 3 >; t>max ( f i l m ) : 1741, 2964 c m - 1 ; S ( C D C 1 3 , 400 MHz): 0 .9 ( s , 3H, C H 3 ) : 0.93 ( s , 3H, C H 3 ) , 1.55 ( s , 6H, R ' R C : C ( C R 3 ) 2 ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 256 ( 9 . 9 2 , M + ) , 221 ( 1 0 . 0 ) , 220 ( 2 3 . 3 ) , 177 ( 8 . 3 8 ) , 163 ( 1 7 . 6 ) , 151 ( 1 0 . 8 ) , 137 ( 1 5 . 1 ) , 135 ( 1 9 . 6 ) , 123 ( 1 5 . 1 ) , 111 ( 3 9 . 5 ) , 109 104 ( 8 4 . 2 ) , 108 ( 2 6 . 9 ) , 95.0 ( 6 9 . 0 ) , 81.0 (100); Exact mass c a l c d . f o r C 1 5 H 2 5 0 C 1 : 256.1594; found: 256.1596; Anal, c a l c d . f o r C 1 5 H 2 5 0 C 1 : C 70 .15 , H 9.810; found: C 69 .90 , H 10 .09 . Campherenone h y d r o c h l o r i d e eno l t r i m e t h v l s i l v 1 e ther (104) L i t h i u m d i i s o p r o p y l a m i d e was generated by r e a c t i n g n - b u -t y l l i t h i u m (1 .6 M; hexane) (0 .29 mL, 0.43 mmol) w i t h d i i s o p r o -pylamine (0 .06 mL, 0.43 mmol) i n d r y t e t r a h y d r o f u r a n (4 .0 mL) at 0 C under an argon atmosphere f o r 30 minutes . T h i s was coo led to -78 C and a s o l u t i o n of (+)-campherenone h y d r o c h l o r i d e (426) (91 mg, 0.35 mmol) in d r y t e t r a h y d r o f u r a n (2 .0 mL) was added to the r e a c t i o n m i x t u r e . A f t e r 2 h o u r s , f r e s h l y d i s t i l l e d c h l o r o -t r i m e t h y s i l a n e (0 .07 mL, 0.53 mmol) was added and s t i r r i n g was c o n t i n u e d f o r 1 hour at room tempera ture . The s o l v e n t was f i l -t e r e d through a column of c e l i t e and evaporated to p r o v i d e cam-pherenone h y d r o c h l o r i d e e n o l t r i m e t h y l s i l y l e ther (104) (112 mg, 97%) as a c o l o r l e s s o i l . ( f i l m ) : 2977, 1618 c m - 1 ; S ( C D C 1 3 , 80 MHz): 0.2 ( s , 9H, R S i ( C H _ 3 ) 3 ) , 0 .7 ( s , 3H, C H 3 ) , 0.85 ( s , 3H, C H 3 ) , 1.55 ( s , 6H, ( C H . 3 ) 2 C C 1 R ) , 4 .58 ( d , 1H (TMS0 )RC: CRR' , Cl (426) (104) 105 J=4 H z ) . Campherenone h y d r o c h l o r i d e e n o l a c e t a t e ( 1 7 0 ) Cl (426) (170) A s o l u t i o n of ( +)-campherenone h y d r o c h l o r i d e (426) (89 mg, 0 . 30 mmol) i n d r y t e t r a h y d r o f u r a n (5 .0 mL) was t r e a t e d at 2 5 ° C wi th n - b u t y 1 1 i t h i u m (1 .6 M; hexane) (0 .3 mL, 0.4 mmol) f o r 15 minutes . The e n o l a t e anion thus generated was coo l ed to - 5 0 ° C and t r e a t e d wi th d r y a c e t i c anhydr ide (0 .06 mL, 0.60 mmol). A f t e r 15 minutes , the r e a c t i o n mixture was warmed to 2 5 ° C and s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (5 mL) was added to quench excess a c e t i c a n h y d r i d e . The mix ture was then e x t r a c t e d wi th p e t . e ther and the combined o r g a n i c l a y e r s were washed w i t h b r i n e s o l u t i o n and d r i e d (MgS04). A f t e r removal of s o l v e n t , the crude p r o d u c t was p r u i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 6:1) to p r o v i d e campherenone h y d r o c h l o r i d e e n o l -a c e t a t e (170) (92 mg, 95%) as a c o l o r l e s s o i l . R f 0.65 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; Vmax ( f i l m ) : 2980, 1760 c m " 1 ; % (CDCI3, 400 MHz): 0.78 ( s , 3H, C H 3 ) , 0.92 ( s , 3H, C H 3 ) , 1.56 ( s , 3H, C H 3 ) , 1.57 ( s , 3H, C H 3 ) , 2.15 ( s , 3H, CH. CO R ) , 5.53 ( d , 1H, 106 (AcO)RC:CH_R', J=4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 298 (3 .20 , M + ) , 258 ( 1 8 . 2 ) , 256 ( 5 4 . 6 ) , 220 ( 7 2 , 2 ) , 192 ( 1 6 . 5 ) , 179 ( 5 5 . 8 ) , 177 ( 2 1 . 5 ) , 161 ( 2 0 . 6 ) , 149 ( 1 6 . 1 ) , 137 ( 7 7 . 1 ) , 135 ( 7 5 . 2 ) , 123 ( 2 5 . 5 ) , 110 (100); E x a c t mass c a l c d . f o r C 1 7 H 2 7 0 C l : 298.1699; found: 298.1700. Attempted C y c l i s a t i o n of Campherenone D e r i v a t i v e s (a) To a c o o l e d (0 C ) , w e l l s t i r r e d s o l u t i o n of (+)-camph-erenone (151) (25 mg, 0.10 mmol) i n d r y methylene c h l o r i d e (2 mL ) under an argon atmosphere was added dropwise s t a n n i c c h l o r i d e (0 .003 mL, 0.020 mmol). A f t e r 24 hours the r e a c t i o n m i x t u r e was d i l u t e d w i t h water (10 mL) and e x t r a c t e d w i t h e t h e r . The com-b i n e d o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r -bonate s o l u t i o n and water , and d r i e d ( M g S O ^ . A f t e r removal of 107 s o l v e n t , the crude product was p r u i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to g i v e campherenone dimers (169a ,b) (13 mg) as a c o l o r l e s s o i l ; Rf 0.1 ( p e t . e t h e r : e t h e r , 9 :1 ) ; Vmax ( f i l m ) : 2986, 1736 c m " 1 ; £ ( C D C 1 3 , 400 MHz): 1 H -n . m . r . of major d i a s t e r e o m e r : 0.81 ( s , 6H, ( 0 0 3 ) 2 ) , 0-90 ( s , 6H, ( C E 3 ) 2 ) , 0 .93 , 0.98 ( s , s, 6H, ( C H . 3 ) 2 ) , 1.62 ( s , 3H, CH 3 ) , 1.86 ( s , 3H, C H 3 ) , 5.00 ( t , 1H, ( C H 3 ) 2 C: CH.R, J= 8 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 440 ( 8 . 4 5 , M 4 ) , 277 ( 5 . 9 4 ) , 262 ( 3 . 4 5 ) , 233 ( 3 . 1 6 ) , 222 ( 1 3 . 3 ) , 220 ( 1 6 , 7 ) , 177 ( 8 . 1 1 ) , 149 ( 1 1 . 7 ) , 138 ( 1 0 . 6 ) , 135 ( 1 3 . 1 ) , 121 ( 1 2 . 9 ) , 109 ( 4 1 . 2 ) , 95 .0 ( 5 1 . 0 ) ; E X A C J L mass, c a l c d . f o r C 3 0 H 4 8 0 2 : 440.3654; found: 440.3650. (b) T i t a n i u m t e t r a c h l o r i d e (0 .055 mL, 0.500 mmol) was o added dropwise to a coo led (-78 C ) , w e l l - s t i r r e d s o l u t i o n of cam-pherenone h y d r o c h l o r i d e eno l t r i m e t h y l s i l y l e ther (104) (0 .13 g , 0.42 mmol) in d r y methylene c h l o r i d e (26 mL) under an argon atmosphere. A f t e r 12 hours , the r e a c t i o n mixture was d i l u t e d w i t h water (10 mL) and e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed wi th s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and water , and d r i e d ( M g S O ^ . A f t e r removal of s o l v e n t , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to g i v e a mixture of epimers of campherenone d imers (169a ,b) (47 mg). ( c ) To a c o o l e d ( 0 ° C ) , w e l l - s t i r r e d s o l u t i o n of d r y s t a n -_ 3 _2 n i c c h l o r i d e (6x10 mL, 5.4x10 mmol) i n d r y methylene c h l o r i d e (6 .0 mL) was added a s o l u t i o n of (+)-campherenone h y d r o c h l o r i d e (426) (68 mg, 0.27 mmol) in methylene c h l o r i d e (8 .0 mL) dropwise , 108 under an argon atmosphere. A f t e r 2 days , the r e a c t i o n mixture was d i l u t e d w i t h water (10 mL) and e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i -carbonate s o l u t i o n and water , and d r i e d (MgS04). A f t e r removal of s o l v e n t , the crude p r o d u c t was p u r i f i e d by column chromato-graphy ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to g i v e a mixture ( 3 . 5 : 1 . 0 by n . m . r . ) of epimers of campherenone d imers (169a,b) (57 mg) as a c o l o r l e s s o i l . (d) To a coo l ed ( 0 ° C ) , w e l l - s t i r r e d s o l u t i o n of camphere-none h y d r o c h l o r i d e e n o l a c e t a t e (170) (76 mg, 0.27 mmol) in d r y methylene c h l o r i d e (5 mL) under an argon atmosphere was added - 3 - 2 s t a n n i c c h l o r i d e (6 .4x10 mL, 5.4x10 mmol). A f t e r 16 hours , the r e a c t i o n mix ture was d i l u t e d w i t h water (10 mL) and e x t r a -c ted w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and water , and d r i e d (MgS04). A f t e r removal of s o l v e n t , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to g i v e campherenone d imers (169a ,b) (20 mg) as a c o l o r l e s s o i l . 109 t e r t - B u t v l d i m e t h v l s i l v l t r i f l u o r o m e t h a n e s u l f o n a t e (TBDMS t r i f l a t e ) . \ 1 I / CF3SO3H + 7>-Si-CI • » CF3S03-Si-<-T r i f l u o r o m e t h a n e s u l p h o n i c a c i d (20 .5 mL, 232 mmol) was added dropwise to f r e s h l y subl imed t e r t - 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 (35 .0 g, 232 mmol) at room temperature and the o r e s u l t i n g mixture heated at 60 C f o r 16 hours . The p r o d u c t was then d i s t i l l e d from the r e a c t i o n f l a s k to a f f o r d TBDMS t r i f l a t e 56.0 g, 91.0%) as a c o l o r l e s s o i l (bp 6 5 - 6 7 ° C ; 12 mmHg). 3 - B r o m o - l - t e r t - b u t v l d i m e t h v l s i l v l o x y p r o p a n e (179) B r ^ ^ x ^ Q H + CF3S03-Si-<£ (179). F r e s h l y d i s t i l l e d TBDMS t r i f l a t e (13 g , 49 mmol) was added dropwise to a s o l u t i o n of 3 - b r o m o - l - p r o p a n o l (6 .8 g, 49 mmol) and 2 , 6 - l u t i d i n e (5 .3 g , 49 mmol) in d r y methylene 110 c h l o r i d e (35 mL) at 0 C and s t i r r e d under an argon atmosphere f o r 4 hours . The r e a c t i o n mix ture was added to water (51 mL) and e x t r a c t e d w i t h methylene c h l o r i d e . The combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , s a t u r a t e d ammonium c h l o r i d e s o l u t i o n and water , and d r i e d (MgS04). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 9:1) to a f f o r d the 3 - b r o m o - t e r t - b u t y l d i m e t h y l s i l y l o x y p r o p a n e (179) (10 .1 g , 85.0%) as a c o l o r l e s s o i l ; R f 0 .95 ( p e t . e t h e r : e t h e r , 9 :1 ) ; ^ m a x ( f i l m ) : 2940 c m " 1 ; S ( C D C 1 3 , 270 MHz): 0.08 ( s , 6H, R S i ( C H . 3 ) 2 ) , 0.91 ( s , 9H, (CH.3 ) 2 C - S i R ) , 1 .96-2 .08 (m, 2H, R0CH 2 CR 2 CH B r ) , 3.72 ( t , 2H, RCH. 2 0Si , J = 6 H z ) , 3.50 ( t , 2H, RCH_ 2Br, J = 6 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 2 5 3 / 2 5 5 ( 7 . 0 4 / 6 . 6 9 , M + +l /M + +3) 213 ( 1 . 3 8 ) , 207 ( 1 . 0 4 ) , 205 ( 1 . 0 2 ) , 197 ( 5 2 . 1 ) , 195 ( 5 3 . 4 ) , 169 ( 6 3 . 5 ) , 167 ( 6 6 . 1 ) , 139 ( 9 0 . 3 ) , 137 ( 8 9 . 7 ) , 115 (100) . I l l K p r . a l - n i t r i I R S f l B O n . r O (166) R 1=H,R 2=CN (180a) R =CN,R =H (180b) n - B u t y l l i t h i u m (1 .60 M; hexane) (31 mL, 31 mmol) was added to a s t i r r e d s o l u t i o n of d i i s o p r o p y l a m i n e (4 .4 mL, 31 mmol) in d r y t e t r a h y d r o f u r a n (50 mL) under an argon atmosphere o at 0 C , and s t i r r e d f o r 30 minutes . (+)-8-Cyanocamphor e t h y l e n e k e t a l (166) (5 .7 g , 26 mmol) i n d r y t e t r a h y d r o f u r a n (20 mL) was added to t h i s coo l ed s o l u t i o n at - 7 8 ° C and s t i r r i n g was c o n t i n u e d f o r 2 hours be fore a s o l u t i o n of 3 - b r o m o - l - t e r t - b u t y -l d i m e t h y l s i l y l o x y p r o p a n e (179) (9 .3 g , 39 mmol) i n t e t r a h y -o d r o f u r a n (20 mL) was i n t r o d u c e d at -78 C . The r e a c t i o n mixture was s t i r r e d f o r 10 hours whi l e warming to room temperature and worked up by adding water (10 mL) and e x t r a c t i n g w i t h e t h e r . The combined o r g a n i c e x t r a c t s were washed w i t h s a t u r a t e d ammonium c h l o r i d e s o l u t i o n and b r i n e , and d r i e d (MgSO^). A f t e r removal of s o l v e n t and column chromatography ( s i l i c a g e l , p e t . e h t e r : e t h e r , 5:1) a mix ture of ( R ) - k e t a l - n i t r i l e (180a) and i t s epimer (180b) ( 9 . 5 g , 94%) was o b t a i n e d as a c o l o r l e s s o i l . The r a t i o (6:1) of epimers (180a:180b) was determined by pro ton i n t e g r a t i o n s i n the n . m . r . ; Rf 0.85 ( p e t . e t h e r : e t h e r , 1:1); V ( f i l m ) : 1 N r max 2980, 2257 c m " 1 ; & ( C D C 1 3 , 400 MHz): 0.55 ( s , 6H, R S i ( C H . 3 ) 2 > , 112 0.89 ( s , 9H, (CH.3 ) 3 C S i R ) , 1.25 ( s , 3H, CH 3 ) , 1.75 ( s , 3H, CH 3 ) , 3 . 40 -3 .50 (m, 1H, R , C H C N R 2 ) , 3 . 58 -3 .98 (m, 6H, ROCtfeClfcOR, and R C E . 2 0 S i ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 393 (0 .410 , M + ) , 378 (1 .14) 338 ( 1 . 6 4 ) , 226 ( 2 6 . 3 ) , 293 ( 2 . 1 0 ) , 292 ( 9 . 1 4 ) , 274 ( 2 . 6 3 ) , 265 ( 1 . 3 5 ) , 181 ( 3 9 . 7 ) , 113 ( 1 5 . 1 ) , 95 (100); E x a c t mass c a l c d . f o r C22H3g0 3 SiN: 393.2699; found 393.2707; Anal, c a l c d . f o r C 2 2 H 3 g 0 3 S i N : C 67 .13 , H 10.00, N 3.560; found: C 67 .10 , H 10.12, N 3 .780 . ( - ) - H v d r Q x y - k e t a l (181) (185a,b) Potass ium (0 .14 g , 3 .6 mmol) was added to d r y hexamethyl -o phosphoramide (6 .0 mL) under an argon atmosphere at 25 C and to the dark b lue s o l u t i o n was added a s o l u t i o n of n i t r i l e s (180a ,b) (0 .71 g , 1.8 mmol) i n anhydrous e ther (5 .0 mL) and t e r t - b u t a n o l (0 .25 mL, 2 .7 mmol). S t i r r i n g was c o n t i n u e d f o r 10 hours and 113 the r e a c t i o n was worked up i n the u s u a l way. The curde p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e h t e r : e t h e r , 5:1) to a f f o r d ( - ) - h y d r o x y - k e t a l (181) (0 .36 g , 83%) as a c o l o r l e s s o i l ; R f 0.32 ( p e t . e t h e r : e t h e r , 1:1); [©Op 5-14 . 7 ° (c 0 .45 , C H C 1 3 ) ; fc>max ( f i l m ) ; 2964, 3407 c m " 1 ; $ ( C D C 1 3 , 400 MHz): 0.80 ( s , 3H, CH3 ) , 0 .85 ( s , 3H, CH3 ) , 3 . 70 -4 .00 (m, 4H, R0CH. 2CH. 20R), 3 . 6 6 ( t , 2H, RCtt 2 0H, J= 6 H z ) ; m/e ( r e l a t i v e i n t e n -s i t y ) : 254 ( 6 . 4 8 , M + ) , 224 ( 1 . 7 9 ) , 223 ( 1 . 7 3 ) , 199 ( 2 . 2 6 ) , 195 ( 1 .19) , 181 ( 1 1 . 7 ) , 143 ( 3 6 . 5 ) , 135 ( 1 3 . 4 ) , 125 ( 9 9 . 9 ) , 99 .0 (41. 0 ) , 95.0 (100); E x a c t mass c a l c d . f o r C 1 5 H 2 6 0 3 : 254.1882; found: 254.1879; Anal, c a l c d . f o r C 1 5 H 2 5 0 3 : C 70 .83 , H 10.30; found: C 70 .56 , H 10.41 . A l a t e r f r a c t i o n p r o v i d e d s i l y l e ther (188) (11 mg) as a c o l o r l e s s o i l ; R f 0.81 ( p e t . e t h e r : e t h e r , 1:1); [ o C ] p 5 - 6 . 9 ° (c 0 .77 , CHCI3) ; Vmax ( f i l m ) : 2886 c m - 1 ; S (CDCI3 , 400 MHz): 0.60 ( s , 6H, R S i ( C H . 3 ) 2 ) , 0.79 ( s , 3H, CH3 ) , 0.84 ( s , 3H, CH3 ) , 0.91 ( s , 9H, RSiC(CtL 3 ) 3 ) , 3.62 ( t , 2H, RCH^OSi, J= 6 H z ) , 3 . 71 -3 .96 (m, 4H, R0Ca. 2 CtL 2 0R); m/e ( r e l a t i v e i n t e n s i t y ) : 368 ( 4 . 4 3 , M + ) , 353 ( 2 . 3 1 ) , 311 ( 2 0 . 7 ) , 268 ( 1 1 . 8 ) , 267 ( 5 4 . 6 ) , 257 ( 2 4 . 8 ) , 193 ( 5 3 . 7 ) , 181 ( 1 4 . 9 ) , 175 ( 2 9 . 4 ) , 125 ( 7 4 . 9 ) , 119 ( 3 3 . 9 ) , 95 .0 (100); Exac t mass c a l c d . f o r C 2 1 H 4 0 0 3 S i : 368.2746; found: 368.2737; Anal, c a l c d . f o r C 2 1 H 4 0 0 3 S i : C 68 .42 , H 10.94; found: C 68 .71 , H 10.88. A f i n a l f r a c t i o n p r o v i d e d a m i x t u r e of epimers of n i t r i l e s (185a,b) (89 mg) as a c o l o r l e s s o i l ; R f 0.26 ( p e t . e t h e r : e t h e r , 2 :3 ) ; Vmax ( f i l m ) : 3420, 2970, 2248 c m " 1 ; S (CDCI3, 400 MHz): 1.03 ( s , 3H, C H 3 ) , 1.08 ( s , 3H, C H 3 ) , 3 .45 , 3.46 (dd , 114 1H, RjR2C0.CN, J= 10 Hz, 4 H z ) , 3 . 70 -4 .00 (m, 6H, R O C Q .2C O2O R , and R C R 2 0 H ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 279 (0 .480 , M + ) , 239 ( 0 . 7 9 0 ) , 182 ( 4 . 4 7 ) , 181 ( 3 5 . 8 ) , 144 ( 2 . 0 2 ) , 113 ( 1 1 . 6 ) , 95 .0 (100); E x a c t mass c a l c d . f o r C 1 6 H 2 5 0 3 N : 279.1834; found: 279.1819; A n a l , c a l c d . C 1 6 H 2 5 0 3 N : C 68 .79 , H 9 .020, N 5 .010; found: C 68 .70 , H 9 .000, N 4 .900 . A f u r t h e r q u a n t i t y of h y d r o x y - k e t a l ( 1 8 1 ) was o b t a i n e d when t e t r a - n - b u t y l ammonium f l u o r i d e (0 .10 L , 1.0 M s o l u t i o n i n t e t r a h y d r o f u r a n ) was added to ( - ) - s i l y l - e t h e r ( 1 8 8 ) (10 .5 g , 0 28.5 mmol) at 25 C under an argon atmosphere. S t i r r i n g was c o n -t i n u e d f o r 6 hours b e f o r e water (50 mL) was added. The r e a c t i o n mix ture was e x t r a c t e d w i t h e ther and the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , b r i n e , and d r i e d (MgSO^). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to g i v e the ( - ) - h y d r o x y - k e t a l ( 1 8 1 ) (7 .0 g , 97%) as a c o l o r l e s s o i l . 115 ( + ) -Hvdroxv-ke tone (1821 HO HO (181) (182) H y d r o x y k e t a l (181) (1 .0 g , 3 .9 mmol) was d i s s o l v e d in acetone (20 mL), h y d r o c h l o r i d e s o l u t i o n (1 .0 N, 12 mL) was added o dropwise and the r e a c t i o n mixture s t i r r e d at 25 C f o r 2 hours . The r e a c t i o n mix ture was added to water (20 mL) and worked up i n the u s u a l way to p r o v i d e a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to a f f o r d (+ ) -hydroxy-ke tone (182) (0 .81 g , 99%) as a c o l o r l e s s o i l ; R f 0.30 ( p e t . e t h e r : e t h e r , 7 :2 ) ; [<*] J 5 +41. 9 ° (c 0 .16 , C H C 1 3 ) ; Vmax ( f i l m ) : 3340, 2980, 1745 c m " 1 ; S (CDCI3, 400 MHz): 0.91 ( s , 3H, C H 3 ) , 0.97 ( s , 3H, CH3) , 3.64 ( t , 2H, RCR 2 0H, J=6 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 210 (22 .9 M + ) , 192 ( 1 . 5 9 ) , 177 ( 1 . 6 3 ) , 168 ( 1 . 3 1 ) , 167 ( 2 . 0 8 ) , 153 ( 3 . 8 5 ) , 151 ( 9 . 9 9 ) , 149 ( 5 . 3 2 ) , 138 ( 1 8 . 5 ) , 137 ( 2 5 . 1 ) , 135 ( 1 7 . 7 ) , 111 ( 1 4 . 2 ) , 110 ( 1 5 . 1 ) , 109 (100); Exac t mass c a l c d . f o r C 1 3 H 2 2 0 2 : 210.1620; found: 210.1615; A n a l , c a l c d . f o r C 1 3 H 2 2 0 2 : C 74 .24 , H 10.54; found: C 73 .96 , H 10.80. 116 (+1-Keto-a ldehvde (1831 (182) (183) A s o l u t i o n of (+ ) -hydroxy-ke tone (182) (0 .76 g , 3 .6 mmol) and p y r i d i n i u m d ichromate (2 .7 g, 7.2 mmol) in dry methylene o c h l o r i d e (25 mL) was s t i r r e d at 25 C under an argon atmosphere f o r 10 hours . The r e a c t i o n mixture was then d i l u t e d wi th e ther and f i l t e r e d through a pad of s i l i c a g e l . removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromato-graphy ( s i l i c a g e l , p e t . e t h e r : e t h e r , 4:1) to p r o v i d e (+ ) -ke to -aldehyde (183) (0 .72 g, 96%) as a c o l o r l e s s o i l . R f 0.49 ( p e t . e t h e r : e t h e r , 2 :7 ) ; [ot] g5+27 . 5 ° (c 1.18, CHCI3) ; # m a x ( f i l m ) : 2735 c m - 1 ; & (CDCI3, 400 MHz): 0.91 ( s , 3H, CH3) , 0.98 ( s , 3H, C H 3 ) , 9 .76 ( t , 1H, RCRO, J=1.5 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 208 ( 1 4 . 1 , M + ) , 180 ( 6 . 0 3 ) , 175 ( 9 . 9 5 ) , 162 ( 6 . 5 6 ) , 147 ( 1 4 . 4 ) , 137 ( 2 4 . 9 ) , 136 ( 1 4 . 7 ) , 135 ( 2 4 . 9 ) , 133 ( 2 1 . 9 ) , 109 ( 5 7 . 1 ) , 95 .0 ( 8 1 . 0 ) ; Exac t mass c a l c d . f o r C 1 3 H 2 0 0 2 : 208.1463; found: 208,1467; A n a l , c a l c d . f o r C 1 3 H 2 o ° 2 : c ? 4 . 9 6 , H 9.680; found: C 74 .89 , H 9 .730. 117 K e t n - a c e t a l (1841 (183) (184) A s o l u t i o n of ( + ) - k e t o - a l d e h y d e (183) (38 mg, 0.18 mmol), e t h y l e n e g l y c o l (0 .01 mL, 0.23 mmol) and p - t o l u e n e s u I f o n i c a c i d ( c a t a l y t i c amount) in benzene (5 .0 mL) was r e f l u x e d i n a Dean-S t a r k apparatus f o r 1.25 hours . Water (20 mL) was added and the r e a c t i o n mixture was e x t r a c t e d w i t h e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h sodium hydrox ide s o l u t i o n (5%), and b r i n e , and d r i e d (MgS04). Removal of s o l v e n t gave a crude product which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to p r o v i d e k e t o - a c e t a l (184) (40 mg, 89%) as a c o l o r l e s s o i l ; Rf 0.41 ( p e t . e t h e r : e t h e r , 1:1); ^max ( f i l m ) : 1740, 2979 c m " 1 ; % (CDCI3 , 400 MHz): 0.91 ( s , 3H, CH3 ) , 0.97 ( s , 3H, C H 3 ) , 3 . 8 0 - 4 . 0 0 (m, 4H, R0CH. 2CtL 20R), 4.84 ( t , 1H R C E ( 0 R 1 ) 2 , J=4.5 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 252 (4 .52 M + ) , 238 ( 1 . 2 4 ) , 191 ( 2 . 9 0 ) , 190 ( 6 . 8 9 ) , 95.0 ( 1 5 . 0 ) , 73.0 (100); Exac t mass c a l c d . f o r C 1 5 H 2 4 0 3 : 252.1725; found: 252.1722; A n a l . c a l c d . f o r C 1 5 H 2 4 0 3 : C 71 .39 , H 9.590; found: C 71 .12 , H 9 .550. 118 E n n l s i l v l e t h e r a c e t a l M 7 8 1 L i t h i u m d i i s o p r o p y l a m i d e was generated by r e a c t i n g n - b u t -y l l i t h i u m (1 .6 M; hexane) (1 .3 mL, 2.0 mmol) w i t h d i i s o p r o p y l a m -o ine (0 .28 mL, 2.0 mmol) i n dry t e t r a h y d r o f u r a n (5 .0 mL) at 0 C under an argon atmosphere f o r 30 minutes . A s o l u t i o n of k e t o -a c e t a l (184) (0 .41 g , 1.7 mmol) in dry t e t r a h y d r o f u r a n (5 .0 mL) o was then added to t h i s coo l ed r e a c t i o n mixture at -78 C and, a f t e r 2 hours , d r y c h l o r o t r i m e t h y l s i l a n e (0 .37 mL, 2.6 mmol) was i n t r o d u c e d . S t i r r i n g was c o n t i n u e d f o r 1 hour and the temp-o e r a t u r e i n c r e a s e d to 25 C . The s o l v e n t was removed under vacuo and a s o l u t i o n of the r e s i d u e in e ther was f i l t e r e d through a pad of c e l i t e and sand. Removal of e ther under vacuo p r o v i d e d e n o l s i l y l e ther a c e t a l (178) (0 .54 g , 98%) as a c o l o r l e s s o i l ; Vmax ( f i l m ) : 2951, 1616 c m " 1 ; $ ( C D C 1 3 , 80 MHz): 0.13 ( s , 9H, R S i ( C H . 3 ) 3 ) , 0.67 ( s , 3H, C H 3 ) , 0.81 ( s , 3H, C H 3 ) , 3 . 50 -4 .00 (m, 4H, R0CH. 2 CE 2 0R) , 4.54 ( d , 1H, RCH.:C0RR, J=4 H z ) , 4 .79 ( t , 1H, RCH.(0R) 2 , J=4.5 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 324 ( 4 . 5 7 , M + ) , 281 ( 1 . 2 2 ) , 253 ( 3 . 1 1 ) , 252 ( 5 . 2 9 ) , 251 ( 1 6 . 0 ) , 209 ( 8 . 9 6 ) , 183 ( 1 5 . 6 ) , 99.0 ( 9 . 5 1 ) , 95.0 ( 7 . 1 9 ) , 73.0 (100); A n a l , c a l c d . f o r C 1 8 H 3 2 0 3 S i : C 66 .62 , H 9.940; found: C 66 .68 , H 9 .880. 119 Hvdroxvethoxv-ketones ( 1 9 2 a r b ) 0 0 I I ( 1 7 8 ) (192a,b) To a s o l u t i o n of t r i m e t h y l s i l y l eno l e ther (178) (0 .13 g, 0.40 mmol) in d r y methylene c h l o r i d e (25 mL) under an argon atm-osphere was added t i t a n i u m t e t r a c h l o r i d e (0 .05 mL, 0.48 mmol), and the r e a c t i o n was s t i r r e d at - 7 8 ° C f o r 20 minutes . S a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (10 mL) was added at - 7 8 ° C and a f t e r warming, the r e a c t i o n mixture was e x t r a c t e d w i t h e ther and the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i -carbonate s o l u t i o n , b r i n e and water , and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t gave a crude product which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 4:1) to a f f o r d a m i x t u r e of epimers of hydroxye thoxy-ke tones (192a ,b) (78 mg, 78%) as a c o l o r l e s s o i l . The r a t i o ( 1 . 2 : 1 . 0 ) of epimers (192a: 192b) was determined from p r o t o n i n t e g r a t i o n i n the n . m . r . spec trum. 192a: R f 0.22 ( p e t . e t h e r : e t h e r , 3 : 7 ) , V m a x ( f i l m ) : 3457, 1734, 2950 c m " 1 ; & ( C D C 1 3 , 270 MHz): 0.92 ( s , 3H, C H 3 ) , 0.97 ( s , 3H, C H 3 ) , 2 .48 ( d , 1H, H.7, J=6 H z ) , 3 . 6 0 - 3 . 7 0 (m, 4H, R0CH. 2 CR. 2 0R), 3 . 70 -3 .80 (m, 1H, R 2CH.0R); m/e ( r e l a t i v e i n t e n s i t y ) : 252 ( 2 . 8 3 , M + ) , 234 ( 1 . 1 6 ) , 222 ( 3 . 1 8 ) , 209 ( 2 . 2 7 ) , 207 ( 3 . 4 4 ) , 192 ( 3 . 3 8 ) , 191 ( 6 . 9 2 ) , 190 ( 9 . 9 1 ) , 179 ( 1 . 9 9 ) , 177 ( 1 . 3 6 ) , 175 120 ( 6 . 7 0 ) , 173 ( 6 . 0 7 ) , 164 ( 3 . 6 0 ) , 163 ( 1 8 . 3 ) , 147 ( 5 9 . 0 ) , 137 ( 1 0 . 7 ) , 135 ( 2 9 . 8 ) , 134 ( 2 6 . 6 ) , 132 ( 2 3 . 2 ) , 107 ( 2 2 . 4 ) , 9 5 . 0 ( 2 7 . 1 ) ; Exact, mass c a l c d . f o r C 1 5 H 2 4 0 3 : 2 5 2 . 1 7 2 5 ; found: 2 5 2 . 1 7 2 5 . 192b: R f 0 . 2 8 ( p e t . e t h e r : e t h e r , 3 : 7 ) ; Vmax ( f i l m ) : 3457, 2950 , 1734 cm"1 ; 6 (CDCI3, 270 M H z ) : 0 . 9 2 ( s , 3H , C H 3 ) , 2 . 3 0 -2 . 4 0 (m, 2H, C(3)H\, C(4 )H, ) . 3 . 5 0 - 3 . 7 5 (m, 4 H , R0CR 2 CH-2 O R ) , 3 . 7 6 -3 .86 (m, 1H, R 2 CH.0R); m/e ( r e l a t i v e i n t e n s i t y ) : 252 ( 3 5 . 1 , M + ) , 234 ( 3 . 9 2 ) , 224 ( 1 . 1 8 ) , 222 ( 6 . 0 4 ) , 209 ( 4 . 4 6 ) , 208 ( 5 . 9 7 ) , 107 ( 3 1 . 6 ) , 191 ( 2 2 . 4 ) , 190 ( 7 0 . 9 ) , 175 ( 4 0 . 2 ) , 163 ( 4 7 . 3 ) , 162 ( 4 1 . 7 ) , 161 ( 1 9 . 9 ) , 149 ( 1 3 . 8 ) , 148 ( 2 7 . 4 ) , 147 ( 1 0 0 ) ; E X J L C J L mass, c a l c d . f o r C 1 5 H 2 4 0 3 : 2 5 2 . 1 7 2 5 ; found: 2 5 2 . 1 7 2 1 . p-Bromobenzoate (193a,b) p-Bromobenzoy1 c h l o r i d e ( 0 . 1 5 g , 0 .70 mmol) was added to a s o l u t i o n of the major epimer of hydroxyethoxy-ketones (192a,b) 121 (20 mg, 0.08 mmol) in d r y p y r i d i n e (5 .0 mL) at 25 C under an argon atmosphere. The r e a c t i o n mix ture was s t i r r e d f o r 3 hours and h y d r o c h l o r i c a c i d (1 .0 N, 10 mL) was added and then e x t r a c -ted w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h hy-d r o c h l o r i c a c i d (1 .0 N) , potass ium hydrox ide (1 .0 N ) , b r i n e and water and d r i e d (MgS04). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was t r i t u r a t e d w i t h e t h a n o l and the mother l i q u o r was c o n c e n t r a t e d down under reduced p r e s s u r e and the r e s i d u e was then p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to p r o v i d e (+)-p-bromobenzoate (193a ,b) (34 mg, 97%) as a c o l o r l e s s o i l ; R f 0.97 ( p e t . e t h e r : e t h e r , 3 :7 ) ; [ o C ] ^ 5 + 6 2 . 1 ° (c 0 .35 , CHCI3) ; Vmax ( f i l m ) : 2960, 1725 c m - 1 ; $ (CDC1 3 , 400 MHz): 0.92 ( s , 3H, C H 3 ) , 0.96 ( s , 3H, C H 3 ) , 2.04 ( d , 1H, C ( 4 ) H , J=4 H z ) , 2.44 ( d , 1H, C ( 3 ) H , J = 6 H z ) , 3.86 (dd , 1H, R 2CH.0R, J = 12 Hz , 5 H z ) , 3 . 7 0 - 3 . 8 0 , 2 . 9 8 - 4 . 1 0 , 4 . 40 -4 .58 (m, m, m, 1H, 1H, 2H, ROC2H4OH), 7.58 ( d , 2H, B r C 6 H 2 H 2 R , J = 8 H z ) , 7.93 ( d , 2H, B r C 6 H 2 H _ 2 R ' J = 8 H z > » m / e ( r e l a t i v e i n t e n s i t y ) : 434/436 ( 3 . 0 3 / 2 .87 , M + / M + + 2 ) , 251 ( 1 . 1 9 ) , 247 ( 1 . 4 7 ) , 245 ( 1 . 3 7 ) , 234 ( 2 . 2 7 ) , 231 ( 1 . 1 1 ) , 230 (12 .3 ) , 229 ( 9 7 . 7 ) , 228 ( 1 2 . 9 ) , 227 (100); Exact mass c a l c d . f o r C 2 2 H 2 7 0 4 B r : 434.1102/436.1090; found: 434.1Q94/436. 1082; A n a l , c a l c d f o r C 2 2 H 2 7 0 4 B r ; C 6 0 . 7 0 , H 6.250, Br 18.35; found: C 60 .62 , H 6 .400, Br 18.16. 122 ( + ) -Dimethoxvketone (194) (183) (194) ( + ) - K e t o - a l d e h y d e (183) (0 .64 g , 3.1 mmol) was t r e a t e d w i t h a m e t h a n o l i c s o l u t i o n of cer ium t r i c h l o r i d e heptahydrate (0 . 4 M, 6.7 mL) and t r i m e t h y l or tho formate (2 .3 mL, 21 mmol). S t i r -r i n g was c o n t i n u e d at 2 5 ° C for 2 hours b e f o r e sodium b i c a r b o n a t e s o l u t i o n (5.0%, 20 mL) was added and the r e a t i o n mix ture was ex-t r a c t e d wi th e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h b r i n e and d r i e d (MgS04). The crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 1:1) to p r o v i d e (+)-dimethoxyketone (194) (0 .63 g , 83%) as a c o l o r l e s s o i l ; R f 0.72 ( p e t . e t h e r : e t h e r , 2 :7 ) ; [oC]p5 + 32. 1 ° (c 0 .98 , C H C 1 3 ) ; Vmax ( f i l m ) : 2960, 1742, 1121 c m " 1 ; 8 (CDCI3 , 270 MHz): 0.90 ( s , 3H, C H 3 ) , 0.95 ( s , 3H, C H 3 ) , 3.30 ( s , 6H, RCH(0CH.3 ) 2 ) , 4 .33 ( t , 1H, RCH(0CH. 3 ) 2 » J=4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 254 ( 0 . 9 8 , M + ) , 224 ( 2 . 2 8 ) , 223 ( 1 3 . 7 ) , 222 ( 1 9 . 4 ) , 207 ( 3 . 8 8 ) , 191 ( 1 5 . 2 ) , 190 ( 2 2 . 6 ) , 175 ( 1 4 . 9 ) , 162 ( 1 0 . 4 ) , 149 ( 1 1 . 3 ) , 148 ( 1 6 . 5 ) , 147 ( 1 8 . 4 ) , 75.0 (100); Exac t mass c a l c d . f o r C 1 5 H 2 6 0 3 : 254.188; found: 254.188; A n a l , c a l c d . f o r C i 5 H 2 6 0 3 : C 70 .83 , H 10.30; found: C 71 .12 , H 10.26. 123 f+1-Dimethvl a c e t a l e n o l s i l v l e ther (105) (194) (105) L i t h i u m d i i s o p r o p y l a m i d e was generated by adding n - b u t -y l l i t h i u m (1 .6 M; hexane) (2 .4 mL, 3.6 mmol) w i t h d i i s o p r o p y l -amine (0 .50 mL, 3 .6 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL) at o 0 C under an argon atmosphere f o r 30 minutes . A s o l u t i o n of (+) -dimethoxyketone (194) (0 .74 g , 2 .9 mmol) i n dry t e t r a h y -d r o f u r a n (10 mL) was then i n t r o d u c e d to t h i s coo l ed r e a c t i o n o mixture at -78 C . A f t e r 2 hours , f r e s h l y d i s t i l l e d c h l o r l t r i -m e t h y l s i l a n e (0 .56 mL, 4.4 mmol) was added and s t i r r i n g was c o n t i n u e d f o r 1 hour w h i l e the temperature warmed s l o w l y to o 25 C . The s o l v e n t was removed and a pentane s o l u t i o n of the crude p r o d u c t was f i l t e r e d through a column of c e l i t e and sand . Removal of s o l v e n t p r o v i d e d ( + ) - d i m e t h y l a c e t a l e n o l s i l y l e ther (105) (0 .960 g , 100%) as a c o l o r l e s s o i l ; [otO^ + l • 6 ° (c 0 .61 , C H C 1 3 ) ; ^ m a x ( f i l m ) : 1620, 2975 c m " 1 ; £ (CDCI3, 270 MHz): 0.18 ( s , 9H, R S i ( C H 3 ) 3 ) , 0 .69 ( s , 3H, CH3 ) , 0,84 ( s , 3H C H 3 ) , 3 .28 ( d , 6H, RHC(OCH. 3) 2> J = 2.0 H z ) , 4 .31 ( t , 1H, RCfcL(0CH 3) 2 , J=4 H z ) , 4 .51 ( d , 1H, R 3 C H _ : C R 1 R 2 , J = 3 .5 H z ) ; m/e ( r e l a t i v e i n t e n -s i t y ) : 326 ( 1 . 3 5 , M + ) , 312 ( 1 . 5 7 ) , 311 ( 6 . 7 8 ) , 296 ( 2 . 1 8 ) , 295 ( 7 . 6 8 ) , 294 ( 1 5 . 9 ) , 251 ( 8 . 9 3 ) , 209 ( 1 8 . 9 ) , 208 ( 1 7 . 1 ) , 182 124 ( 2 8 . 5 ) , 75.0 (100); Exact mass c a l c d . f o r C 1 8 H 3 4 0 3 S i : 326.2277; found: 326.2271; A n a l , c a l c d . f o r C 1 8 H 3 4 0 3 S i : C 66 .21 , H 10.50, found: C 66 .32 , H 10.63. ( R l - a n d (S ) -Methoxv-ke tones M f l 5 » . h 1 (105) (0 .57 g , 1.8 mmol) in d r y methylene c h l o r i d e (40 mL) under an argon atmosphere was added t i t a n i u m t e t r a c h l o r i d e (0 .23 mL, o 2 .1 mmol) at -78 C and the r e a c t i o n mixture was s t i r r e d f o r 45 minutes . S a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (10 mL) was o added at -78 C and the r e a c t i o n mixture was worked up i n the u s u a l way. The crude p r o d u c t was p u r i f i e d by column chromato-graphy ( s i l i c a g e l , p e t . e t h e r : e t h e r , 1:1) to p r o v i d e ( S ) - m e t h -oxy-ketone (195b) (83 mg, 21%) as a c o l o r l e s s o i l , f o l l o w e d by (R) -methoxy-ketone (195a) (261 mg, 66%) as a white s o l i d . Rery -s t a l l i s a t i o n from pentane p r o v i d e d (195a) as c o l o r l e s s p r i s m s : mp 40 C ; R f 0.64 ( p e t . e t h e r : e t h e r , 2 :7 ) ; [ci3p 5 + 9 1 . 5 ° (c 0 .34, C H C 1 3 ) ; l/max ( C H C 1 3 ) : 2951, 1741, 1100 c m - 1 ; S (CDC1 3 , 400 MHz): 0.91 ( s , 3H, C H 3 ) , 0.97 ( s , 3H, C H 3 ) , 2.45 ( d , 1H, H_, J = 6 H z ) , (105) To a s o l u t i o n of ( + ) - d i m e t h y l a c e t a l e n o l s i l y l e ther 125 3.42 ( s , 3H, ROCH3), 3 - 6 5 ( d d ' 1 H ' R 2 C H - 0 M e ' J = 6 H z ' 4 H z ) ' m / e ( r e l a t i v e i n t e n s i t y ) : 222 ( 1 7 . 9 , M + ) , 207 ( 3 . 5 5 ) , 193 ( 4 . 9 2 ) , 192 ( 2 6 . 4 ) , 191 ( 3 . 3 6 ) , 190 ( 1 5 . 4 ) , 179 ( 5 . 0 0 ) , 177 ( 1 0 . 9 ) , 175 ( 1 8 . 4 ) , 163 ( 3 2 . 4 ) , 162 ( 2 0 . 5 ) , 148 ( 2 0 . 0 ) , 147 ( 5 9 . 5 ) , 135 ( 1 8 . 8 ) , 134 ( 3 5 . 9 ) , 107 ( 6 7 . 7 ) , 95 .0 ( 8 8 . 0 ) , 71.0 (100); Exact  mass c a l c d . f o r Ci 4H22C>2 : 222.1619; found: 222.1619; A n a l , c a l c d . f o r C 1 4 H 2 2 0 2 : C 75 .63 , H 9.970; found: C 75 .43 , H 9 .870. Methoxy-ketone (195b): R f 0.87 ( p e t . e t h e r : e t h e r , 2 : 7 ) ; [OC ] D 5 + 7 2 . 7 ° (C 1 .7, CHCI3) ; Vmax ( f i l m ) : 2951, 1741, 1100 c m " 1 ; £ (CDCI3, 400 MHz): 0.92 ( s , 3H, C H 3 ) , 0.94 ( s , 3H, C H 3 ) , 2 .38 ( d , 1H, C H_, J = 2 H z ) , 3 .35 ( s , 3H, ROCU3 ) , 3.68 (ddd , 1H, R 2 CHPMe, J = l l Hz , 7 Hz , 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 222 ( 2 1 . 1 , M + ) , 211 ( 1 5 . 1 ) , 190 ( 2 6 . 3 ) , 175 ( 2 3 . 8 ) , 162 ( 2 2 . 1 ) , 149 (43 .8 ) , 147 ( 5 9 . 0 ) , 135 ( 3 1 . 4 ) , 121 ( 3 3 . 1 ) , 109 ( 5 7 . 2 ) , 107 (61 .9 ) , 105 ( 4 7 . 2 ) , 95.0 (100); Exact mass c a l c d . f o r C 1 4 H 2 2 0 2 : 222.1620; found: 222.1635; A n a l , c a l c d . f o r C 1 4 H 2 2 0 2 : C 75 .63 , H 9.970; found: C 75 .80 , H 9 .990. 126 Mfi thoxv-a lcoho l s ( 2 0 2 a . b i (195a,b) (202a,b) To a c o l d (0 C ) , s t i r r e d s o l u t i o n of l i t h i u m aluminum h y d r i d e (73 mg, 1.9 mmol) in d r y t e t r a h y d r o f u r a n (20 mL) under an argon atmosphere was added a s o l u t i o n of a m i x t u r e of epimers of methoxy-ketones ( 1 9 5 a , b ) (0 .43 g , 1.9 mmol) i n d r y t e t r a h y -d r o f u r a n (5 . 0 mL). S t i r r i n g was c o n t i n u e d f o r 2 hours and, a f t e r d i l u t i o n w i t h water (10 mL), the r e a c t i o n mix ture was worked up by e x t r a c t i o n w i t h e ther and the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d ( 1 .0 N) and b r i n e , and d r i e d (Mg-SO^). The s o l v e n t was removed under vacuo and the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10 :1) to g i v e a mix ture of m e t h o x y - a l c o h o l s ( 2 0 2 a , b ) (0 .4 g , 91%) as a c o l o r l e s s o i l ; Vmax ( f i l m ) : 3500, 2950, 1080 c m - 1 ; & (CDCI3, 80 MHz): 1 H - n . m . r . ass ignments of major d i a s t e r e o m e r : 0 .83 ( s , 3H, C H 3 ) , 0 .99 ( s , 3H, C H 3 ) , 3.41 ( s , 3H, Rj R 2CH0CH_ 3), 3 .50 -3 .70 (m, 1H, R 1 R 2 CR0Me) , 3.94 ( d , 1H, R 2 CR0H, J=8 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 223 ( 0 . 4 2 ) , 222 ( 3 . 6 4 ) , 207 ( 1 . 4 9 ) , 206 ( 6 . 6 1 ) , 192 ( 1 7 . 1 ) , 177 ( 1 5 . 9 ) , 174 ( 1 9 . 0 ) , 161 ( 1 9 . 8 ) , 159 ( 3 5 . 0 ) , 149 ( 2 4 . 7 ) , 147 ( 2 1 . 1 ) , 133 ( 2 3 . 8 ) , 131 ( 2 9 . 3 ) , 121 ( 3 2 . 3 ) , 119 ( 3 5 . 4 ) , 105 ( 5 4 . 7 ) , 109 ( 6 7 . 0 ) , 95 .0 (100) ; F . x » c t 127 n&s_s. c a l c d . C 1 4 H 2 4 0 2 : 224.1776; found: 224.1775; Anal, c a l c d . f o r C 1 4 H 2 4 0 2 : C 74 .95 , H 10.78; found: C 74 .89 , H 10.72. (S)-Methpxy-acetate (2Q3) ( 2 0 2 a ) Dry a c e t i c anhydr ide (0 .12 g , 1.2 mmol) was added to a s o l u t i o n of a mix ture of e p i m e r i c methoxya lcoho l s (202a,b) (0 .13 g , 0.59 mmol) and 4 - d i m e t h y l a m i n o p y r i d i n e (15 mg, 0.12 mmol) in d r y p y r i d i n e (5 .0 mL) at 2 5 ° C under an argon atmosphere. S t i r r i n g was c o n t i n u e d f o r 12 hours and the r e a c t i n mixture was d i l u t e d w i t h water (10 mL) and e x t r a c t e d wi th e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d s o -l u t i o n (1 .0 N) and b r i n e , and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f i e d by column chromato-graphy ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to a f f o r d ( S ) - m e t h -128 oxyace ta te (203) (29 mg) and ( R ) - m e t h o x y a l c o h o l (202a) (89 mg), r e s p e c t i v e l y , as c o l o r l e s s o i l s . A c e t a t e (203): Rf 0 .70 ( p e t . e t h e r : e t h e r , 3:2); ^ m a x ( f i l m ) : 2975, 1740 c m " 1 ; & (CDCI3, 80 MHz): 0 .85 ( s , 3H, C H 3 ) , 0 .88 ( s , 3H, CH3), 2.12 ( s , 3H, ROCOCH.3), 3.10-3.25 (m, 1H, R 1 R 2CE0Me) J 3 .30 ( s , 3H, ROCH3), 4.95 ( d , 1H, R 2CE0Ac, J=9 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 251 (0 . 3 9 ) , 224 (1 . 0 3 ) , 219 (1 . 8 7 ) , 207 (10.2), 206 ( 3 6 . 7 ) , 191 (12 . 8 ) , 175 (17.2), 174 (53.0), 163 ( 1 5 . 7 ) , 161 (10.2), 160 ( 1 6 . 5 ) , 159 (100); Exact mass c a l c d . f o r C 1 6 H 2 6 0 3 : 266.1882; found: 266.1873; Anal, c a l c d . f o r C 1 6 H 2 6 0 3 : C 72 .14 , H 9.840; found: C 72.20, H 9 .840. M e t h o x y - e n d o - a l c o h o l s ( 204a r b1 C a l c i u m (0 .84 g , 21 mmol) was t r e a t e d wi th d r y l i q u i d o ammonia (80 mL) at -78 C f o r 5 minutes under an argon atmo-sphere and a s o l u t i o n of methoxyketone (195a ,b) (0 .72 g , 3.2 mmol) i n d r y e ther (6 .0 mL) was then added. The r e a c t i o n mixture was s t i r r e d at r e f l u x f o r 30 minutes and d r y 1 -propano l (3 .0 mL) was added. Care was taken at a l l t imes to exc lude water from (195a,b) OH (204a,b) 129 the system. When the b lue c o l o r was d i s c h a r g e d the r e a c t i o n mix ture was d i l u t e d w i t h water and e x t r a c t e d w i t h e ther and the r g a n i c l a y e r s were washed wi th h y d r o c h l o r i c a c i d ( 1 . 0 N) and b r i n e , and d r i e d (MgS0 4 ) .Removal of s o l v e n t gave a crude product which was p r u i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to g i v e a mixture of e p i m e r i c methoxy-endo.-a l c o h o l s (204a,b) (0 .71 g , 98%) as a c o l o r l e s s o i l ; R f 0.30 ( p e t . e t h e r : e t h e r , 1:1); J/ v ( f i l m ) : 3492, 2967 c m - 1 ; & (CDC1 3 , 400 MHz): ^ M - n . m . r . ass ignments of major d i a s t e r -eomer: 0.80 ( s , 3H, C H 3 ) , 0.97 ( s , 3H, C H 3 ) , 3.38 ( s , 3H, R 0 C H 3 ) , 3 . 5 0 - 3 . 6 0 (m, ,1H, R 2CH.0Me), 3.92 ( d , 1H, R2CH_0H, J = 8 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 224 ( 0 . 8 8 , M + ) , 206 ( 2 . 6 7 ) , 193 ( 2 . 6 2 ) , 192 ( 2 0 . 3 ) , 191 ( 2 . 0 8 ) , 177 ( 2 3 . 8 ) , 174 ( 1 5 . 0 ) , 161 ( 2 5 . 5 ) , 159 ( 2 3 . 9 ) , 108 ( 3 2 . 7 ) , 107 ( 7 6 . 4 ) , 95.0 (100); E*ac_t mas_s. c a l c d . f o r C 1 4 H 2 4 0 2 : 224.1776; found: 224.1776; A n a l , c a l c d . f o r C 1 4 H 2 4 0 2 : C 74 .95 , H 10.78; found: C 74 .73 , H 10.68. Methoxy-endo-ace ta te s (205a P b) (204a,b ) (205a,b ) Dry a c e t i c anhydr ide (7 .3 mL, 77 mmol) was added to a 130 s o l u t i o n of e p i m e r i c m e t h o x y - e n d o - a l c o h o l s (204a ,b) (5 .7 g , 26 mmol) and 4 - d i m e t h y l a m i n o p y r i d i n e (9 .4 g , 77 mmol) i n d r y p y r i d i n e (0 .15 L ) at 2 5 ° C under an argon atmosphere. S t i r r i n g was c o n t i n u e d f o r 5 hours b e f o r e water (50 mL) was added and the r e a c t i o n m i x t u r e worked up i n the u s u a l way. Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column c h r o -matography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to p r o v i d e a mixture of e p i m e r i c methoxy-e_njlQ_-acetates (205a ,b) (6 .08 g , 89%) as a c o l o r l e s s o i l ; Rf 0.58 ( p e t . e t h e r : e t h e r , 1:1); ^ m a x ( f i l m ) : 2947, 1741 c m - 1 ; S ( C D C 1 3 , 400 MHz): 1 H - n . m . r . a s s i g n -ments of major d i a s t e r e o m e r : 0.82 ( s , 3H, CH3 ) , 0.85 ( s , 3H, C H 3 ) , 2 .06 ( s , 3H, ROCOCH3), 3 .25 ( s , 3H, ROCH3), 3 .25-3 .34 (m, 1H, RCHOMe), 5.30 ( d d , 1H, RCHjOAc, J=5 Hz, 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 251 ( 1 . 2 8 ) , 236 ( 7 . 5 3 ) , 224 ( 1 7 . 3 ) , 207 ( 3 4 . 0 ) , 206 ( 4 4 . 0 ) , 174 ( 8 2 . 1 ) , 159 ( 6 6 . 3 ) , 119 ( 5 5 . 7 ) , 107 ( 7 9 . 0 ) , 105 ( 6 4 . 9 ) , 95.0 ( 9 1 . 5 ) , 91.0 ( 7 7 . 3 ) , 83,0 ( 7 1 . 5 ) , 79.0 ( 8 2 . 8 ) , 71.0 (100); E x a c t mass c a l c d . f o r C 1 6 H 2 6 0 3 : 266.1881; found: 266.1873; A n a l , c a l c d . f o r C 1 6 H 2 6 0 3 : C 72 .14 , H 9.840; found: C 72 .11 , H 9 .900. 131 H v d r o x v - a c e t a t e s (206a P b) To a w e l l s t i r r e d s o l u t i o n of a mixture of e p i m e r i c me-thoxy-e_odo_-acetates (205a ,b) ( 2 .0 g, 7.5 mmol) in d r y methylene o c h l o r i d e (10 mL) at -30 C under an argon atmosphere was added 15-crown-5 (0 .30 M, 8.9 mL) s a t u r a t e d w i t h dry sodium i o d i d e in dry methylene c h l o r i d e f o l l o w e d by boron t r i b r o m i d e ( 1 . 3 M, 1 .5 mL) in d r y methylene c h l o r i d e . S t i r r i n g was c o n t i n u e d f o r 4 hou-r s and the r e a c t i o n worked up by d i l u t i o n wi th s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (20 mL) f o l l o w e d by e x t r a c t i o n w i t h methy-lene c h l o r i d e . The combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , h y d r o c h l o r i c a c i d ( 1 .0 N ) , s a t u r a t e d sodium b i s u l p h i t e s o l u t i o n and water , and d r i e d ( M g S O ^ . Removal of s o l v e n t gave a crude product which was p u r i -f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5 : 1 ) to y i e l d a mix ture of e p i m e r i c h y d r o x y a c e t a t e s (206a ,b) (1 . 7 g , 89%) as a c o l o r l e s s o i l ; Rf 0 .29 ( p e t . e t h e r : e t h e r , 1 : 1 > J ^max < f i l « n > : 3467, 2967, 1717 c m - 1 ; & ( C D C 1 3 , 400 MHz): "^H-n.m.r. ass ignments of major d i a s t e r e o m e r : 0 .88 ( s , 3H, CH3) , 0 .89 ( s , 3H, C H 3 ) , 2.01 ( s , 3H, ROCOCH3), 3.33 ( d , 1H, R2CH0fcL, J = 12 Hz , exchangeable w i t h D 2 0 ) , 3 . 53 -3 .60 (m, 1H, R 2CH£>H), 4.74 132 ( d d , 1H, R 2CtLOAc, J=4.5 Hz , 1.5 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 252 ( 0 . 5 9 , M + ) , 250 ( 1 . 3 8 ) , 210 ( 1 . 8 7 ) , 209 ( 1 . 2 3 ) , 208 ( 7 . 0 9 ) , 207 ( 3 . 8 5 ) , 206 ( 1 . 9 5 ) , 193 ( 1 0 . 5 ) , 192 ( 4 9 . 2 ) , 190 ( 1 2 . 6 ) , 174 ( 5 3 . 7 ) , 159 ( 6 3 . 1 ) , 121 (100); Exac t mass c a l c d . f o r C 1 5 H 2 4 0 3 : 252.1725; found: 252.1731; A n a l , c a l c d . f o r C 1 5 H 2 4 0 3 : C 71 .39 , H 9 .590; found: C 71 .62 , H 9 .600. A s o l u t i o n of e p i m e r i c h y d r o x y - a c e t a t e s (206a,b) (90 mg, 0.35 mmol) and p y r i d i n i u m d ichromate (0 .40 g , 1.1 mmol) i n d r y methylene c h l o r i d e (10 mL) was s t i r r e d at 6 0 ° C under an argon atmosphere f o r 10 hours . The r e a c t i o n mixture was then d i l u t e d wi th e ther and f i l t e r e d through a pad of s i l i c a g e l . Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column c h r o -matography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:0) to g i v e (+) -ke-t o - a c e t a t e (207) (85 mg, 95%) as a white s o l i d , which was r e c r y -o s t a l l i s e d from pentane as c o l o r l e s s p r i s m s ; mp 77-79 C ; R f 0.48 ( p e t . e t h e r : e t h e r , 1:1); [ o C ] p 5 + 1 0 1 ° (c 0 .65 , CHCI3) ; Vmax (CHCI3) : 2969, 1717, 1699 c m " 1 ; g (CDCI3, 400 MHz): 0.94 ( s , 3H, C H 3 ) , 0.98 ( s , 3H, C H 3 ) , 2.07 ( s , 3H, ROCOCR3), 5.05 (dd , 133 1H, R2CfcLOAc, J=4.5 Hz, 1.5 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 250 ( 2 3 . 9 , M * ) , 208 ( 3 2 . 6 ) , 207 ( 5 4 . 5 ) , 191 ( 1 8 . 7 ) , 190 (100); E x a c t mass c a l c d . f o r C 1 5 H 2 2 0 3 : 250.1569; found: 250.1572; A n a l , c a l c d . f o r C 1 5 H 2 2 0 3 : C 71 .97 , H 8.860; found: C 72 .06 , H 8 .850. ( + ) - A l k e n e - a c e t a t e (208) (207) (208) M e t h y l t r i p h e n y l p h o s p h o n i u m bromide (1 .5 g , 4 .2 mmol) was suspended in d r y t e t r a h y d r o f u r a n (20 mL) under an argon atmo-o sphere and coo led to -78 C . n - B u t y l l i t h i u m (1 .3 M; hexane) (3 .2 mL, 4.2 mmol) was added and a f t e r 10 minutes the c o l d bath was removeed and the r e a c t i o n mix ture was s t i r r e d f o r 1 hour . D u r i n g t h i s t ime a l l the s o l i d d i s a p p e a r e d and the s o l u t i o n became dark orange . A s o l u t i o n of ( + ) - k e t o - a c e t a t e (207) (0 .70 g , 2 .8 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL) was then i n t r o d u c e d . S t i r r i n g was c o n t i n u e d f o r 1 hour and the r e a c t i o n mix ture was then d i l u t e d w i t h water (10 mL) and e x t r a c t e d w i t h pe tro l eum e t h e r . Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 15:1) to p r o v i d e ( + ) - a l k e n e - a c e t a t e (208) (0 .59 g , 85%) as a c o l o r l e s s 134 o i l ; R f 0.94 ( p e t . e t h e r : e t h e r , 1:1); CoC]§5 + 1 8 . 3 ° (c 0 .16 , C H C 1 3 ) ; Vmax ( f i l m ) : 2960, 1738, 1640, 885 c m - 1 ; h ( C D C I 3 , 270 MHz): 0.82 ( s , 3H, C H 3 ) , 0.88 ( s , 3H, C H 3 ) , 2 .05 ( s , 3H, R0C0CH\ 3 ), 4 .55 ( s , 1H, R 2 R 1 C : C R H ) , 4 .57 ( s , 1H, R 1 R 2 C : C H H . ) , 5.12 ( d d , 1H, R 2 C E 0 A c , J= 4 . 5 H Z , 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 247 ( 0 . 1 0 ) , 239 ( 2 . 3 7 ) , 207 ( 2 . 4 1 ) , 206 ( 7 . 1 5 ) , 205 ( 4 . 2 2 ) , 191 ( 1 2 . 7 ) , 188 ( 6 7 . 7 ) , 173 ( 4 8 . 6 ) , 160 ( 4 4 . 5 ) , 145 ( 4 3 . 1 ) , 131 ( 5 0 . 6 ) , 121 ( 4 0 . 2 ) , 108 ( 4 2 . 2 ) , 107 ( 6 4 . 4 ) , 95.0 ( 6 7 . 8 ) , 93.0 ( 8 2 . 4 ) , 91.0 (100); A n a l , c a l c d . f o r C 1 6 H 2 4 0 2 : C 77 .38 , H 9 .740 , found: C 77 .56 , H 9 .690. ( + ) - H v d r o x v - o I e f i n (2091 OAc OH (208) (209) To a c o l d (0 C) s t i r r e d s o l u t i o n of l i t h i u m aluminum h y d r i d e (10 mg, 0.28 mmol) i n d r y t e t r a h y d r o f u r a n (1 .0 mL) under an argon atmosphere was added a s o l u t i o n of ( + ) - a l k e n e - a c e t a t e ( 208) (68 mg, 0.28 mmol) i n d r y t e t r a h y d r o f u r a n (3 .0 mL). S t i r r i n g was c o n t i n u e d f o r 2 hours and the r e a c t i o n mix ture worked up i n the u s u a l way. Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 135 10:1) to g i v e ( + ) - h y d r o x y - o l e f i n (209) (56 .0 mg, 99.6%) as a c o l o r l e s s o i l ; R f 0.67 ( p e t . e t h e r : e t h e r , 1:1); [ec]p 5 + 6 4 ° (c 0 . 5 , C H C U ) ; V , ( f i l m ) : 3375, 2950, 1640, 885 c m - 1 ; % ( C D C 1 , , 270 MHz): 0.89 ( s , 3H, C H 3 ) , 0.90 ( s , 3H C H 3 ) , 3.91 ( d d , 1H, RCH.0H, J=4.5 Hz , 2 H z ) , 4.62 ( s , 1H, R ^ C i C H J i ) , 4 .67 ( s , 1H, R 2 R i C : C H E ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 206 ( 9 . 4 9 , M + ) , 204 ( 2 . 3 3 ) , 191 ( 3 8 . 8 ) , 188 ( 3 1 . 1 ) , 173 ( 3 0 . 3 ) , 163 ( 2 2 . 2 ) , 161 ( 2 3 . 2 ) , 146 ( 3 9 . 6 ) , 136 ( 6 9 . 6 ) , 132 ( 2 9 . 0 ) , 123 ( 2 5 . 0 ) , 121 ( 8 5 . 7 ) , 109 ( 4 0 . 5 ) , 108 ( 6 6 . 9 ) , 107 (100); E x a c t mass c a l c d . f o r C 1 4 H 2 2 0 : 206.1672; found: 206.1671; A n a l , c a l c d . f o r C 1 4 H 2 2 0 : C 81 .49 , H 10.75; found: C 81 .27 , H 10.60. ( + 1 - T e t r a c v c l i c a l c o h o l (2101 OH OH (209) (210) To a w e l l s t i r r e d heated (60 C) s o l u t i o n of ( + ) - h y d r o x y -o l e f i n (209) (0 .42 g , 2 .0 mmol) i n d r y to luene (5 .0 mL) was added s u c c e s s i v e l y a s o l u t i o n of d i e t h y l z i n c (1 .4 mL, 2.8 mmol, 25% w/v) i n to luene and methylene i o d i d e (0 .23 m l , 2.8 mmol). A stream of d r y a i r was passed through the r e a c t i o n mixture f o r 3 .5 h o u r s . A f t e r a c i d i f i c a t i o n w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , the 136 r e a c t i o n mixture was e x t r a c t e d w i t h e t h e r , and the o r g a n i c l a y e r s were washed w i t h b r i n e and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromato-graphy ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to a f f o r d ^ ^ t e t r a -c y c l i c a l c o h o l ( 2 1 0 ) (0 .45 g , 99%) as a white s o l i d , which was r e c r y s t a l l i s e d from pentane as c o l o r l e s s p r i s m s ; mp 1 0 9 - 1 1 1 ° C ; [c*: iJ5 5 +31.6 0 (c 0 .31 , C H C 1 3 ) ; R f 0.21 ( p e t . e t h e r : e t h e r , 8 :2) ; V m a x (CHCI3) : 3643, 3010, 2965 c m - 1 ; g ( C D C 1 3 , 400 MHz): 0 .20-0.28 (m, 2H, c y c l o p r o p y l ( H - ) ) , 0 . 40 -0 .53 (m, 2H, c y c l o p r o p y l ( R ) ) , 0.88 ( s , 6H, M e 2 ) , 4 .03 (dd , 1H, R ^ C R O H , J=4 Hz , 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 220 ( 2 . 8 9 , M + ) , 205 ( 8 . 4 2 ) , 203 ( 1 . 5 3 ) , 202 ( 5 . 9 1 ) , 189 ( 1 5 . 1 ) , 187 ( 1 8 , 8 ) , 177 ( 1 1 . 0 ) , 161 ( 1 0 . 2 ) , 159 ( 1 3 . 4 ) , 149 ( 1 9 . 2 ) , 147 ( 1 6 . 0 ) , 146 ( 1 2 . 2 ) , 145 ( 1 8 . 7 ) , 135 ( 2 9 . 8 ) , 121 ( 4 5 . 1 ) , 119 ( 3 3 . 7 ) , 107 ( 8 1 . 3 ) , 105 ( 5 4 . 8 ) , 95.0 ( 8 1 . 6 ) , 93.0 ( 9 1 . 2 ) , 91.0 ( 9 6 . 6 ) , 79.0 (100); Exact mass c a l c d . f o r C 1 5 H 2 4 0 : 220.1827; found: 220.1821; A n a l , c a l c d . f o r C 1 C : H 7 4 0 : C 81 .76 , H 10.98; found: C 81 .89 , H 10.88. 137 ( + 1 - L o n g i b o r n e o l (591 (210) ( 5 9 > To a s o l u t i o n of ( + ) - t e t r a c y c l i c a l c o h o l (210) (0 .38 g, 1.7 mmol) in g l a c i a l a c e t i c a c i d (3 .0 mL) was added p l a t i n u m oxide (16 mg, 0.07 mmol). The r e s u l t a n t suspens ion was s t i r r e d under 2 .7 atm of hydrogen at room temperature f o r 12 hours . S a -t u r a t e d sodium b i c a r b o n a t e s o l u t i o n was added u n t i l the mix ture was n e u t r a l and the aqueous s l u r r y was e x t r a c t e d wi th e t h e r . The combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d ( M g S O ^ . Removal of s o l v e n t y i e l d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i -ca g e l , p e t . e t h e r : e t h e r , 5:1) to p r o v i d e ( + ) - l o n g i b o r n e o l (59) (0 .38 g , 100%) which c r y s t a l l i s e d from pentane as c o l o r l e s s p r i s m s ; mp 1 0 5 - 1 0 7 ° C ( l i t . [77] mp f o r ( - ) - l o n g i b o r n e o l , 106-1 0 7 ° C ) ; R f 0.41 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; [oL]^ 5 + 1 5 . 8 ° (c 0.54 , CHC1 3 ) ( l i t . [77] f o r ( - ) - l o n g i b o r n e o l , [ OU D 5 - 1 6 . 3 ° (c 0 .66 , C H C I 3 ) ) ; Vmax (CHCI3 ) : 3643, 2943 c m " 1 ; £ (CDCI3, 400 MHz): 0.84 ( s , 3H, C H 3 ) , 0 .87 ( s , 3H, CH3) , 0.94 ( s , 6H, CH3 , C H 3 ) , 3 .77 ( d d , 1H, R 2 CH0H, J=5 Hz , 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 222 ( 7 . 3 6 , M + ) , 208 ( 4 . 5 2 ) , 207 ( 2 8 . 4 ) , 204 ( 5 0 . 5 ) , 189 ( 5 9 . 9 ) , 161 ( 2 5 . 9 ) , 133 ( 2 6 . 5 ) , 121 ( 2 6 . 3 ) , 1 1 9 ( 8 1 . 1 ) , 138 109 ( 5 8 . 5 ) , 95.0 (100); E x a c t mass c a l c d . f o r C 1 5 H 2 6 0 : 222.1983; found: 222.1979; A n a l , c a l c d . C 1 5 H 2 6 0 : C 81 .02 , H 11.79; found: C 81 .16 , H 11 .69 . L o n g i b o r n e o l MTPA E s t e r (2111 OH 0 (59) (211) To a s t i r r e d s o l u t i o n of ( + ) - l o n g i b o r n e o l (59) (15 .0 mg, 0.067 mmol) in d r y carbon t e t r a c h l o r i d e (0 .5 mL) and p y r i d i n e (2 .0 mL) was added R-(+ ) - e *w -methoxy-o ( - tr i f luoromethy lpheny lace ty 1 c h l o r i d e ( ( + ) - M T P A - c h l o r i d e ; 26 mg, 0.10 mmol) at 2 5 ° C under an argon atmosphere. A f t e r 20 h o u r s , the s o l u t i o n was d i l u t e d w i t h water (10 mL) and e x t r a c t e d w i t h e ther and the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d (MgSO^). Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to y i e l d pure l o n g i b o r n e o l MTPA e s t e r (211) (28 mg, 95%) as a white s o l i d . C r y s t a l l i s a t i o n from pentane a f f o r d e d (211) as 139 c o r l e s s p r i s m s ; mp 89-91 C; R f 0.88 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; ^ m a x ( C H C l 3 ) : 1750 c m " 1 ; § ( C D C 1 3 , 270 MHz): 0.80 ( s , 3H, C H 3 ) , 0.81 ( s , 3H, C H 3 ) , 0.83 ( s , 3H, C H 3 ) , 0.94 ( s , 3H, CH3>, 3.57 ( q , 3H, R 0 C H 3 , J = 1.2 H z ) , 5.41 ( d d , 1H, R^  R^CfcLOR^ , J=4 Hz , 2 Hz ) , 7 . 3 6 - 7 . 4 4 , 7 .58 -7 .66 (m, m, 3H, 2H, R C 6 H 5 ) ; 1 3 C - n . m . r . ( C D C 1 3 , 100.6 MHz): 22 .237 , 26 .979, 30 .035 , 33 .297, 35 .201 , 40 .685 , 50 .626, 52 .000, 60 .597 , ( q u a r t e r n a r y and methylene c a r b o n s ) ; 13.210, 22 .279, 28 .798, 29 .402, 44 .019 , 55 .463, 60 .597 , 23.990 (methyl and methine c a r b o n s ) , 83.772 (RCLF 3 ) , 125.383, 127.456, 128.215, 129.450 ( a r o m a t i c c a r b o n s ) , 166.000 ( c a r b o n y l c a r b o n ) . 1 9 F - n . m . r . ( C D C 1 3 , 254 MHz): s i n g l e t at 5.08 i n the r e s o l u t i o n enhanced p r o t o n decoupled spectrum; m/e ( r e l a t i v e i n t e n s i t y ) : 220 ( 1 . 2 0 ) , 205 ( 4 9 . 1 ) , 189 ( 5 8 . 4 ) , 95.0 (100); E x a c t mass c a l c d . f o r C 2 5 H 3 3 0 3 F 3 : 438.2381; found: 438.2377; A n a l c a l c d . f o r C 2 5 H 3 3 0 3 F 3 , C 68 .47 , H 7 .590; found: C 68 .44 , H 7 .690. 140 ( + ) -Longicamphor (83) ( 5 9 ) (83) P y r i d i n i u m ch lorochromate (0 .51 g , 2.4 mmol) was suspended in d r y methylene c h l o r i d e (2 .0 mL), and a s o l u t i o n ( + ) - l o n g i b o r -n e o l (59) (0 .35 I , 1.6 mmol) i n d r y methylene c h l o r i d e (4 .0 mL) was added r a p i d l y at room temperature . A f t e r "3 hours under argon the b l a c k r e a c t i o n mixture was d i l u t e d w i t h e ther and f i l t e r e d through a pad of s i l i c a g e l . Removal of the s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r ) to a f f o r d (+) - longicamphor (83) (0 .29 g , 85%) as a c o l o r l e s s o i l ; R f 0.87 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; C o ^ ] p 5 + 1 8 . 9 ° (c 0 .74 , C 2 H 5 0 H ) ; Vmax ( f i l m ) : 2971, 1739 c m " 1 ; i ( C D C 1 3 , 400 MHz), 0.89 ( s , 3H, C H 3 ) , 0.92 ( s , 3H, C H 3 ) , 1.00 ( s , 3H, C H 3 ) , 1.07 ( s , 3H, C H 3 ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 220 (100, M + ) , 206 ( 7 . 0 0 ) , 205 ( 2 8 . 4 ) , 178 ( 1 2 . 6 ) , 177 ( 8 6 . 7 ) , 163 ( 1 9 . 9 ) , 150 ( 2 0 . 1 ) , 149 ( 2 5 . 7 ) , 137 ( 3 4 . 7 ) , 136 ( 4 3 . 5 ) , 135 ( 3 4 . 8 ) , 124 ( 5 2 . 9 ) , 95 .0 ( 9 5 . 4 ) ; Exac t mass c a l c d . f o r C 1 5 H 2 4 0 : 272.1827; found: 220.1826; A n a l , c a l c d . f o r C 1 5 H 2 4 0 : C 81 .76 , H 10.98; found: C 81 .67 , H 11.00. 141 ( + 1 - L o n g i i s o b o r n e o l (891 H (83) (89) L i t h i u m aluminum h y d r i d e (22 mg, 0.59 mmol) was suspended in d r y t e t r a h y d r o f u r a n (2 .0 mL) at 0 ° C , and a s o l u t i o n of ( + ) - l o -ngicamphor (83) (0 .13 g , 0.59 mmol) i n dry t e t r a h y d r o f u r a n ( 1 . 5 o mL) was added s l o w l y . The r e a c t i o n mix ture was s t i r r e d at 0 C u n -der an argon atmosphere f o r 3 h o u r s , and then d i l u t e d w i t h water (10 mL) and e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) , b r i n e and water , and d r i e d ( M g S 0 4 ) . A f t e r removal of s o l v e n t the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r ) to y i e l d ( + ) - l o n g i i s o b o r n e o l (89) (0 .12 g, 92%) as a c o l o r l e s s o i l ; R f 0.94 ( p e t . e t h e r : e t h e r , 9 :1 ) ; Lot] £ 5+4 5 . 8 ° (c 0 .69 , C H C 1 3 ) ; 1 / m a x ( f i l m ) : 3436, 2965 c m - 1 ; S (CDCI3 , 400 MHz): 0.80 ( s , 3H, C H 3 ) , 0.94 ( s , 3H, C H 3 ) , 0.98 ( s , 3H, C H 3 ) , 1.12 ( s , 3H, C H 3 ) , 3.84 ( d d , 1H, R 2 CR0H, J=8 Hz , 4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 222 ( 4 . 5 0 , M) , 221 ( 1 . 8 0 ) , 220 ( 5 . 3 0 ) , 219 ( 2 . 2 0 ) , 208 ( 3 . 8 0 ) , 207 ( 1 7 . 1 ) , 205 ( 1 1 . 3 ) , 204 ( 4 8 . 1 ) , 189 ( 3 4 . 4 ) , 161 ( 2 4 . 7 ) , 137 ( 3 1 . 1 ) , 133 ( 3 5 . 9 ) , 119 (100); Exac t mass c a l c d . f o r C 1 5 H 2 6 0 : 22.1984; found: 222.1987; AJQJELI. c a l c d . f o r C 2 5 H 2 6 0 : C 81 .02 , H 11.79; found: C 81 .28 , H 11.80. 142 < - + W . o r » g i f o l e n R (R11 ( 8 9 ) ( 6 1 ) ( + ) - L o n g i i s o b o r n e o l (89) (0 .12 g , 0.54 mmol) was t r e a t e d w i t h methanesulphony1 c h l o r i d e (0 .08 mL, 1.1 mmol) and 4 - d i -o m e t h y l a m i n o p y r i d i n e (30 mg) in d r y p y r i d i n e (1 .0 mL) at 105 C under an argon atmosphere f o r 16 hours . A f t e r d i l u t i o n w i t h water (10 mL) and e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , s a t u r a t e d so -dium b i c a r b o n a t e s o l u t i o n and water , and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r ) to g i v e ( + ) - l o n g i f o l e n e (61) (73 mg, 66%) as a c o l o r l e s s o i l ; R f 0.91 ( p e t . e t h e r : e t h e r , 10:0); [ o L ] J 5 + 5 1 . 8 ° (c 1.07, C H C 1 3 ) ( l i t . [81] [ O U D 9 + 5 1 . 7 ° ( C 0 . 3 5 ) ; Vmax ( f i l m ) : 2964, 1661, 871 c m " 1 ; 6 (CDCI3 , 400 MHz): 0.90 ( s , 3H, C H 3 ) , 0.95 ( s , 3H, C H 3 ) , 1.00 ( s , 3H, CH3 ) , 4 .50 ( s , 1H, R 1 R 2 C : C t t H ) , 4 .75 ( s , 1H, R 1 R 2 C : C H H . ) ; m/e ( r e l a t i v e i n -t e n s i t y ) : 204 ( 4 7 . 6 , M + ) , 203 ( 1 5 . 4 ) , 190 ( 1 1 . 8 ) , 189 ( 6 3 . 2 ) , 175 ( 2 7 . 2 ) , 163 ( 1 9 . 6 ) , 162 ( 1 8 . 4 ) , 161 ( 7 6 . 0 ) , 133 ( 5 6 . 7 ) , 121 ( 5 9 . 0 ) , 119 ( 6 6 . 2 ) , 109 ( 6 5 . 2 ) , 108 ( 5 5 . 0 ) , 107 ( 8 6 . 5 ) , 95.0 ( 9 6 . 6 ) , 91.0 (100); Exact mass c a l c d . f o r C 1 5 H 1 4 : 204.1878; found: 204.1877; A n a l - c a l c d . f o r C 1 5 H 2 4 : C 88 .16 , H 11.84; 143 found: C 87 .94 , H 11.72. p-Brpmobenzoate (186) p-Bromobenzoyl c h l o r i d e (0 .63 g , 2 .9 mmol) was added to a s o l u t i o n of n i t r i l e (185a) (0 .10 g , 0.36 mmol) i n d r y p y r i d i n e o (10 mL) at 25 C under an argon atmosphere. The mix ture was s t i r -red f o r 2.5 hours and h y d r o c h l o r i c a c i d (1 .0 N, 20 mL) was added and then e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , potass ium hydrox ide s o l u -t i o n and b r i n e , and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was t r i t u r a t e d w i t h e t h a n o l and the mother l i q u o r was c o n c e n t r a t e d down under vacuo and the r e s i d u e was p u r i f i e d by column chromatography to p r o v i d e the p-bromo-benzoate (186) (0 .16 g , 99%) as a white s o l i d . R e c r y s t a l l i s a t i o n from a mix ture of p e t . e t h e r : e t h e r (4 :1) a f f o r d e d c o l o r l e s s p r i s m s ; mp 1 0 0 - 1 0 2 ° C ; R f 0.89 ( p e t . e t h e r : e t h e r , 3 : 2 ) ; Vmax ( C C 1 4 ) : 2972, 2240, 1592 c m " 1 ; £ ( C D C 1 3 , 270 MHz); 103 ( s , 3H, C H 3 ) , 1.09 ( s , 3H, C H 3 ) , 3.53 ( d d , 1H, R ^ C R C N , J = 12 Hz , 4 H z ) , 3 .80 (m, 4H R00R), 4 .37 ( t , 2H, RC^OCORj , J = 8 H z ) , 7 .58-8 .00 144 (m, 4H, R C 6 H . 4 B r ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 461 (0 .200 , M + ) , 421 ( 0 . 2 1 0 ) , 181 ( 5 6 . 2 ) , 95.0 (100); E x a c t mass c a l c d . f o r C 2 3 H 2 8 N 0 4 B r : 461.1177; found: 461.1177; A n a l , c a l c d . f o r C 2 3 H 2 8 N 0 4 B r : C 59 .75 , H 6 .100, N 3 .030 , Br 17.28; found: C 59 .59 , H 6 .150, N 2 .930 , Br 17 .35 . Aldehydes (189) (185a,b ) ( 1 8 9 ) A s o l u t i o n of mix ture of epimers of n i t r i l e s (185a ,b) (3 .6 g , 13 mmol) and p y r i d i n i u m ch lorochromate ( 6 . 9 g , 32 mmol) i n d r y methylene c h l o r i d e (20 mL) was s t i r r e d at room temperature under an argon atmosphere f o r 4 hours . The r e a c t i o n mix ture was then d i l u t e d w i t h e ther and f i l t e r e d through a pad of s i l i c a g e l . A f t e r washing the s i l i c a g e l w i t h more e t h e r , the s o l v e n t was removed under vacuo and the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 2 : 1 ) . T h i s a f f o r d e d a mix ture of epimers of a ldehydes (189) ( 3 . 0 g , 84%) as a c o l o r l e s s o i l ; Rf 0.28 ( p e t . e t h e r : e t h e r , 1:1); v ( f i l m ) : 2975, 2750, 2250, 1730 c m - 1 ; § ( C D C 1 3 , 80 MHz): 1 H - n . m . r . ass ignments of major 145 d i a s t e r e o m e r : 1.05 ( s , 3H, C H 3 ) , 1.10 ( s , 3H C H 3 ) , 2.78 ( t , 2H, RCH. 2CH0, J = 7 H z ) , 3 .49 ( d d , 1H, R ^ C R C N , J = 12 Hz , 6 H z ) , 3 . 7 0 - 4 . 0 0 (m, 4H, R0(CH_2 ) 2 0 R ) , 9.87 ( s , 1H, CEO); m/e ( r e l a t i v e i n t e n s i t y ) : 277 (0 .030 , M + ) , 181 ( 2 0 . 0 ) , 113 ( 1 9 . 1 ) , 96.0 ( 1 2 . 0 ) , 95 .0 (100); E x a c t mass c a l c d . f o r C 1 6 H 2 3 N 0 3 : 277.1677; found: 277.1672. A c e t a l - n i t r i l e s (190) CN CN (189) ( 1 9 0 ) A s o l u t i o n of a ldehydes ( 1 8 9 ) (2 .2 g , 7 .8 mmol), e t h y -lene g l y c o l (0 .86 mL, 16 mmol) and p - t o l u e n e s u I f o n i c a c i d ( c a t a l y t i c amount) i n benzene (50 mL) was r e f l u x e d i n a Dean-S t a r k apparatus f o r 3 h o u r s . The r e a c t i o n mix ture was d i l u t e d w i t h water (20 mL) and then e x t r a c t e d w i t h e ther and the com-b i n e d o r g a n i c l a y e r s were washed w i t h sodium hydrox ide s o l u t i o n (5%) and b r i n e , and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to g i v e a mix ture of epimers of a c e t a l n i t r i l e s ( 1 9 0 ) ( 2 . 3 g , 92%) as a c o l o r l e s s o i l ; R f 0.30 ( p e t . e t h e r : e t h e r , 1:1); D „ , v ( f i l m ) : 2980, 2255 c m - 1 ; o (CDC1-,,-146 400 MHz): H - n . m . r . ass ignments of major d i a s t e r e o m e r : 1.04 ( s , 3H, C H 3 ) , 1.08 ( s , 3H, C H 3 ) , 3.48 (dd , 1H, R ^ C H - C N , J = 12 Hz, 4 H z ) , 3 . 80 -4 .00 (m, 4H, R0C 2 H_ 4 0R), 4 .92 ( t , 1H, ( R 1 0 ) 2 C H . R 2 , J=4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 321 (0 .260 , M + ) , 181 ( 3 8 . 6 ) , 113 ( 1 2 . 3 ) , 95 .0 (100); E x a c t mass c a l c d . f o r C 1 8 H 2 7 N 0 4 : 321.1939; found: 321.1932; A n a l . c a l c d . f o r C 1 8 H 2 7 N 0 4 : C 67 .26 , H 8 .470, N 4 .360; found: C 67 .49 , H 8 .430, N 4 .470 . A c e t a l - k e t a l (191) CN ylphosphoramide (15 mL) was added m e t a l l i c potass ium (0 .61 g , o 16 mmol) under an argon atmosphere at 0 C . To the r e s u l t a n t navy b l u e s o l u t i o n was i n t r o d u c e d a s o l u t i o n of a mixture of epimers of a c e t a l - n i t r i l e s (190) ( 2 . 5 g , 7.8 mmol) i n d r y e ther (15 mL) f o l l o w e d by t e r t - b u t a n o l (1 .5 mL, 16 mmol). S t i r r i n g was c o n t i n u e d f o r 10 h o u r s , worked up by add ing b r i n e (50 mL), and then the r e a c t i o n mixture was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed wi th b r i n e and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude product (190) (191) To a 100 mL round-bottom f l a s k c o n t a i n i n g d r y hexameth-147 was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e h t e r : e t h e r , 5:1) to p r o v i d e a c e t a l - k e t a l (191) (1 .8 g , 80%) as a c o l o r l e s s o i l ; Rf 0.52 ( p e t . e t h e r : e t h e r , 1:1); "V m a x ( f i l m ) : 2970 c m - 1 ; $ ( C D C 1 3 , 400 MHz): 0.80 ( s , 3H, C H 3 ) , 0.86 ( s , 3H, C H 3 ) , 4 .87 ( t , 1H, ( R 1 0 ) 2 C H . R 2 , J=4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 296 ( 5 . 1 0 , M + ) , 224 ( 6 . 1 4 ) , 185 ( 2 5 . 3 ) , 126 ( 1 4 . 3 ) , 125 (100); Exac t mass c a l c d . f o r C 1 7 H 2 8 0 4 : C 68 .89 , H 9.520; found: C 69 .05 , H 9 .510. ( - n - K e t o - a l d e h v d e (1831 A c e t a l - k e t a l (191) (1 .4 g , 4 .7 mmol) was d i s s o l v e d i n acetone (40 mL), h y d r o c h l o r i c a c i d (1 .0 N, 20 mL) was added s l -owly and the r e a c t i o n mixture was s t i r r e d at 25 C f o r 2 hours . The r e a c t i o n mix ture was added to water (20 mL) and worked up i n the u s u a l way to p r o v i d e a curde p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to a f f o r d ( + ) - k e t o - a l d e h y d e (183) (0 .95 g , 56%). ( S p e c t r a l d a t a c f . page 112) 148 (+1-8-Acetoxvcamphor (1391 Br 0 (42) (139) Dry potass ium a c e t a t e (31 .9 g, 325 mmol) was added to a w e l l - s t i r r e d s o l u t i o n of (+)-8-bromocamphor (42) (25 .0 g , 108 o mmol) in dry d i m e t h y l s u l p h o x i d e (100 mL) at 110 C under an argon atmosphere f o r 5 days . A f t e r c o o l i n g , water (100 mL) was added and the r e a c t i o n mix ture was e x t r a c t e d w i t h e t h e r , and the combined o r g a n i c l a y e r was washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , b r i n e and d r i e d (MgS04). A f t e r removal of s o l v e n t , the crude p r o d u c t was column chromato-graphed ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to g i v e (+)-8-acetoxycamphor (139) (21 .1 g , 93.0%) as a c o l o r l e s s o i l ; Rf 0.59 ( p e t . e t h e r : e t h e r , 1:1); O-]g 5 + 1 0 . 0 ° (c 2 .49 , C H C l 3 ) ; I > m a x ( f i l m ) : 2996, 1746, 1234 c m - 1 ; & (CDCI3, 400 MHz): 0.92 ( s , 3H, C H 3 ) , 1.02 ( s , 3H, C H 3 ) , 2.03 ( s , 3H, R 0 C 0 C R 3 ) , 3 . 8 1 , 3.85 (AB q u a r t e t , 2H, RCH. 20Ac, J A B = 1 6 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 210 ( 8 . 8 2 , M + ) , 192 ( 3 . 0 5 ) , 182 ( 5 . 2 7 ) , 168 ( 8 . 3 9 ) , 167 ( 2 0 . 1 ) , 153 ( 3 . 9 1 ) , 152 ( 3 . 0 3 ) , 151 ( 3 . 5 3 ) , 150 ( 1 9 . 5 ) , 149 ( 4 . 0 2 ) , 135 ( 5 . 7 4 ) , 125 ( 3 . 3 9 ) , 122 ( 1 7 . 4 ) , 109 ( 2 6 . 3 ) , 108 (100); EjjacJL mass, c a l c d . f o r C 1 2 H 1 8 0 3 : 210.1256; found: 210.1249; Anal, f o r C 1 2 H 1 8 0 3 : C 68 .54 , H 8.630; found: C 68 .44 , H 8 .560. 149 D i o l s (14Q) A s o l u t i o n of ( + ) -8-acetoxycamphor (139) (11 .6 g , 55.4 mmol) in d r y t e t r a h y d r o f u r a n (80 mL) was i n t r o d u c e d s l o w l y to suspens ion of l i t h i u m aluminum h y d r i d e (3 .78 g , 100 mmol) in o d r y t e t r a h y d r o f u r a n (100 mL) at 0 C under an argon atmosphere. A f t e r 4 hours , water (20 mL) was c a r e f u l l y added and the r e -a c t i o n mixture was e x t r a c t e d w i t h e t h e r , and the combined o r g -a n i c l a y e r s were washed wi th h y d r o c h l o r i c a c i d (1 .0 N ) , s a t u -r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and d r i e d ( M g S O ^ A f t e r removal of s o l v e n t , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 2:1) to y i e l d d i o l s (140) (7 .0 g , 75%) as a white s o l i d , which r e c r y -s t a l l i s e d from e t h y l a c e t a t e as c o l o r l e s s p r i s m s . The r a t i o of e_xji- to aado.- d i o l s was determined from p r o t o n i n t e g r a t i o n s o i n the n . m . r . to be 4 : 1 , r e s p e c t i v e l y ; mp 275 C ; R f 0 .048, 0.072 ( p e t . e t h e r : e t h e r , 1:1); f m a x ( C H C 1 3 ) : 3326, 2936 c m - 1 ; o (CDCI3, 400 MHz): 1 H - n . m . r . ass ignments of major d ias tereome 0.92 ( s , 3H, C H 3 ) , 0.97 ( s , 3H, C H 3 ) , 3 .64 , 3.94 (AB q u a r t e t , 2H, RCH. 20H, J A B = 1 2 H z ) , 3.68 ( d , 1H, R 1 R 2 Co.0H, J=4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 170 ( 0 . 0 4 , M + ) , 168 ( 0 . 1 9 ) , 152 ( 2 . 5 5 ) , 150 140 ( 7 . 6 8 ) , 139 ( 1 3 . 6 ) , 138 ( 2 . 2 0 ) , 137 ( 1 0 . 2 ) , 121 ( 1 7 . 8 ) , 108 ( 9 0 . 7 ) , 105 ( 1 0 . 0 ) , 95.0 (100); Exac t mass c a l c d . f o r C 1 0 H 1 8 0 2 : 170.1307; found: not observed; A n a l . c a l c d . f o r C 1 0 H 1 8 0 2 : C 70 .55 , H 10.66; found: C 70 .58 , H 10.72. (-)-Lactone (141) 0 (140) (141) A mixture of d i o l s (140) (0 .49 g , 2 .9 mmol) and s i l v e r carbonate on c e l i t e (16 g , 29 mmol) i n dry benzene (40 mL) was r e f l u x e d in a D e a n - S t a r k apparatus f o r 1.5 days . The mixture was f i l t e r e d and, a f t e r removal of benzene, the crude product was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 4:1) to p r o v i d e ( - ) - l a c t o n e (141) (0 .37 g , 77%) as a white s o l i d which r e c r y s t a l l i s e d from pentane as c o l o r l e s s p r i s m s ; mp 199-2 0 0 ° C ; [ o L ] J 0 - 6 0 . 7 ° (c 2 .22 , C 2 H 5 0 H ) ; R f 0.47 ( p e t . e t h e r : e t h e r , 1:1); Vmax ( C H C 1 3 ) : 2960, 1760 c m " 1 ; S (CDCI3, 400 MHz): 1.05 ( s , 3H, C H 3 ) , 1.10 ( s , 3H, CH3 ) , 4 .25 ( d , 1H, R2CHX>R, J=4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 166 ( 5 . 7 8 , M + ) , 151 ( 4 . 9 9 ) , 139 ( 5 . 6 5 ) , 138 ( 4 8 . 4 ) , 137 ( 1 0 . 9 ) , 124 ( 9 . 1 5 ) , 123 ( 4 2 . 3 ) , 109 ( 2 1 . 2 ) , 95.0 (100); Exac t mass c a l c d . f o r C 1 0 H 1 4 0 2 : 166.0994; found: 151 166.1002; A n a l , c a l c d . f o r C 1 0 H 1 4 0 2 : C 72 .26 , H 8.490; found: C 72 .16 , H 8 .600. L a o t o l s (1371 (141) (137) To a s o l u t i o n of ( - ) - l a c t o n e (141) (1 .1 g , 6.6 mmol) i n o d r y t o l u e n e (20 mL) c o o l e d to -78 C under an argon atmosphere was added 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 (1 .0 M, hexane) (16 mL, 16 mmol). A f t e r 45 minutes , the r e a c t i o n was c a u t i o u s l y o quenched at -78 C wi th methanol (10 mL) u n t i l e v o l u t i o n of gas ceased . The r e a c t i o n mixture was e x t r a c t e d wi th e t h e r , and s e v e r a l drops of sodium b i s u l p h a t e s o l u t i o n (2 .0 N) were added to break up the g e l a t i n o u s p r e c i p i t a t e . A f t e r removal of s o l -v e n t , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 1:1) to produce a mixture of epimers of l a c t o l s (137) (1 .1 g , 97%) as a white s o l i d ; the r a t i o of epimers was determined from p r o t o n i n t e g r a t i o n s i n the n . m . r . to be 2 :1 ; R f 0.30 ( p e t . e t h e r : e t h e r , 1:1); ^ m a x ( C H C 1 3 ) : 3421, 2988 c m - 1 ; $ (CDCI3 , 400 MHz): 1 H - n . m . r . ass ignments of major d i a s t e r e o m e r : 0.96 ( s , 3 H , ' C H 3 ) , 1.00 ( s , 3H, CH3 ) , 2.83 152 ( d , 1H, R 1 R 2 C H O E , J=4 H z ) , 3.74 ( d , 1H, Rl R2CH.0R, J=4 H z ) ; 5.16 ( d , 1H, R C H ( O R ) 2 , J=4 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 168 ( 0 . 7 8,M +), 156.0 ( 2 3 . 3 2 ) , 150 ( 2 . 1 5 ) , 139 ( 2 . 5 7 ) , 135 ( 3 . 5 3 ) , 125 ( 1 1 . 3 ) , 124 ( 1 6 . 8 ) , 106 ( 2 0 . 0 ) , 95.0 (100); Exact mass c a l c d . f o r C 1 0 H 1 6 0 2 : 168.1150; found: 168.1138; A n a l , c a l c d . f o r C10H16O2: C 71 .39 , H 9.590; found: C 71 .20 , H 9 .800. P r e n y l Tr iphenv lphosphon ium Bromide (135) T r i p h e n y l p h o s p h i n e (13 g , 48 mmol) was d i s s o l v e d in d r y benzene (20 mL) under an argon atmosphere and p r e n y l bromide (7 .1 g , 48 mmol) was added. S t i r r i n g was c o n t i n u e d at 25 C f o r 12 hours and worked up by f i l t e r i n g and washing the p r e c i p i t a t e w i t h benzene and pentane . A f t e r d r y i n g , the crude p r o d u c t was r e c r y s t a l l i s e d from methylene c h l o r i d e to p r o v i d e p r e n y l t r i -phenylphosphonium bromide ( 1 3 5 ) (19 .6 g , 100%) as c o l o r l e s s p r i s m s ; mp 2 3 4 - 2 3 5 ° C ( l i t . [56b] mp 2 4 2 ° C ) ; 8 (CDCI3, 400 MHz): 1.18 ( d , 3H, C H 3 , J=4 H z ) , 1.55 ( d , 3H, CH3 , J=6 H z ) , 4 . 4 0 , 4 .50 ( d d , 2H, R C t t 2 P P h 3 B r , J=14 Hz , 40 H z ) , 4 . 7 5 - 5 . 2 5 (m, 1H, Me 2 C:CH_R), 7 . 50 -8 .00 (m, 15H, RPtCgB^ ) 3 B r ) . 153 D-ifinols (142a .b) OH (130) (142a) (142b) An a l i q u o t of sodium m e t h y l s u l f i n y l m e t h i d e (28 mL, 31 mmol), prepared from sodium h y d r i d e (3 .4 g) in d r y d i m e t h y l s u l p h o x i d e (0 .10 L ) , was t r e a t e d w i t h p r e n y l t r i p h e n y l p h o s p h -onium bromide (135) (5 .1 g, 12 mmol) at 80 C under an argon atmosphere f o r 20 minutes . A s o l u t i o n of l a c t o l (137) (1 .0 g, 6.2 mmol) in d r y d i m e t h y l s u l p h o x i d e (30 mL) was then added and a f t e r 3 .5 h o u r s , the r e a c t i o n mixture was c o o l e d , water (30 mL) was added, and e x t r a c t e d w i t h pe tro leum e t h e r . The combined o r g a n i c e x t r a c t was evaporated to p r o v i d e a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to y i e l d a mix ture of isomers of d i e n o l s (142a ,b) ( 1 .1 g , 82%) as a c o l o r l e s s o i l ; the r a t i o (1 :7) of i somers (142a ,b) was determined from p r o t o n i n t e g r a -t i o n s i n the n . m . r . ; (142b): Rf 0.27 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; Vmax ( f i l m ) : 3426, 2991, 1641 c m " 1 ; 8 ( C D C 1 3 , 400 MHz): 0.96 ( s , 3H, C H 3 ) , 1.03 ( s , 3H, C H 3 ) , 1.73 ( s , 3H, C H 3 ) 1.82 ( s , 3H, C H 3 ) , 3.45 ( d d , 1H, R 2 CR0H, J = 8 Hz , 4 H z ) , 5.55 ( d , 1H, H a , J = 12 H z ) , 6.20 ( d , 1H, He, J = 12 H z ) , 6.14 (dd , 1H, Hb, J = 12 Hz, 24 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 220 ( 6 1 . 5 , M + ) , 218 ( 9 . 3 3 ) , o 154 202 ( 2 1 . 6 ) , 176 ( 4 2 . 1 ) , 161 ( 2 1 . 0 ) , 159 ( 3 8 . 2 ) , 133 ( 7 7 . 4 ) , 131 ( 2 2 . 3 ) , 125 ( 6 7 . 7 ) , 121 ( 3 5 . 5 ) , 119 ( 3 9 . 9 ) , 110 ( 1 4 . 8 ) , 109 (100); (142a): R f 0.34 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; 1>max ( f i l m ) : 3426, 2991, 1641 c m " 1 ; 6 ( C D C 1 3 , 400 MHz): 0.92 ( s , 3H, CH3) , 1.01 ( s , 3H, C H 3 ) , 3.74 ( s , 3H, C H 3 ) , 3 .75 ( s , 3H, CH3 ) , 3.48 ( t , 1H, R 2 CK0H, J=6 H z ) , 5.8 ( d , 1H, H a , J=16 H z ) , 5.81 ( d , 1H, He, J=10 H z ) , 6.27 ( d d , 1H, Hb, H=16 Hz , 10 H z ) : m/e ( r e l a t i v e i n t e n s i t y ) : see b e f o r e . Exact mass c a l c d . f o r C15H24O: 220.1827; found: 220.1829; Anal c a l c d . f o r C 1 5 H 2 4 0 : C 81 .76 , H 10.89; found: C 81 .46 , H 11.00. p-Bromobenzovl E s t e r (148) p-Bromobenzoyl c h l o r i d e (0 .14 g , 0.64 mmol) was added to a s o l u t i o n of d i e n o l (142a,b) (17 mg, 0.08 mmol) i n d r y p y r i n e ( 3 .0 mL) at 25 C under an argon atmosphere. The mix ture was s t i r r -ed f o r 22 hours and i n h y d r o c h l o r i c a c i d (1 .0 N, 10 mL) was added and e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) , potass ium hydrox ide (1 .0 N ) , b r i n e and water , and d r i e d (MgS04). A f t e r removal of s o l v e n t , the (142b) (148) 155 crude p r o d u c t was p u r i f i e d by column chromatography to g i v e p - b r -omobenzoyl e s t e r (148) (25 mg, 78%) as a c o l o r l e s s o i l . Rf 0.92 ( p e t . e t h e r : e t h e r , 1:1); ^ m a x ( f i l m ) : 2985, 1710, 1592 c m - 1 ; S ( C D C 1 3 , 270 MHz): 0.98 ( s , 3H, C H 3 ) , 0 .99 ( s , 3H, C H 3 ) , 1.67 ( s , 3H, C H 3 ) , 1.75 ( s , 3H, C H 3 ) , 4 .78 ( d d , 1H, R 1 R 2 CH.0R, J=4 Hz , 8 H z ) , 5.65 ( d , 1H, Ha, J=12 H z ) , 6.05 ( d d , 1H, Hb, J=24 Hz, 12 H z ) , 6.12 ( d , 1H, He, J=12 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 402 (7 .18 , M + ) , 219 ( 3 9 . 8 ) , 202 ( 8 7 . 1 ) , 187 ( 5 5 . 9 ) , 185 ( 8 4 . 5 ) , 183 ( 8 3 . 6 ) , 174 ( 3 7 . 6 ) , 159 ( 7 6 . 6 ) , 147 ( 4 2 . 4 ) , 133 ( 7 1 . 1 ) , 122 ( 5 0 . 6 ) , 119 ( 5 0 . 9 ) , 107 ( 8 0 . 4 ) , 91.0 ( 6 5 . 5 ) , 55.0 ( 5 8 . 1 ) , 41 .0 (100); Exac t mass c a l c d . f o r C 2 2 H 2 7 0 2 B r : 402.1193; found: 402.1189. A n a l , c a l c d . f o r C 2 2 H 2 7 0 2 B r : C 65 .51 , H 6.750; found: C 65 .30 , H 6 .950. Dienones (136a .b ) (136a) (142a) + (136b) (142b) A s o l u t i o n of d i e n o l s (142a,b) (1 .1 g , 5.1 mmol) and p y r i d i n i u m d ichromate ( 9 . 5 g , 25 mmol) i n d r y methylene 156 c h l o r i d e (35 mL) was s t i r r e d at room temperature under an argon atmosphere f o r 12 hours . The r e a c t i o n m i x t u r e was then d i l u t e d w i t h e ther and f i l t e r e d through a pad of s i l i c a g e l . A f t e r removal of s o l v e n t , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 15:1) to y i e l d a mix ture of d i enones (136a,b) (0 .68 g, 62%) as a c o l o r -l e s s o i l ; the r a t i o (1 :7) of i somers (136a:136b) was determined from proton i n t e g r a t i o n i n the n . m . r . ; (136b): R f 0 .56 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; ^ m a x ( f i l m ) : 2991, 1744 c m " 1 ; S (CDCI3 , 400 MHz): 1.01 ( s , 3H, C H 3 ) , 1.14 ( s , 3H, C H 3 ) , 1.73 ( s , 3H, C H 3 ) , 1.84 ( s , 3H, C H 3 ) , 5.13 ( d , 1H, H a , J=8 H z ) , 6.15 ( d , 1H, H e , J=10 H z ) , 6.16 ( d d , 1H, Hb, J=24 Hz, 12 H z ) ; (136b): 0.99 ( s , 3H, C H 3 ) , 1.09 ( s , 3H, C H 3 ) , 1.76 ( s , 3H, C H 3 ) , 1.81 ( s , 3H, C H 3 ) , 5.41 ( d , 1H, H a , J=16 H z ) , 5.73 ( d , 1H, He, J=10 H z ) , 6.28 (dd , 1H, Hb, J=16 Hz , 10 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 218 ( 2 7 . 3 , M ) , 203 ( 1 2 . 3 ) , 175 ( 1 6 . 6 ) , 161 ( 1 4 . 4 ) , 149 ( 3 4 . 7 ) , 147 ( 1 4 . 8 ) , 135 ( 1 3 . 2 ) , 107 (100); E x a c t mass c a l c d . f o r C 1 5 H 2 2 0 : 218.1671; found: 218.1672; A n a l , c a l c d . f o r C 1 C . H 9 0 0 : C 82 .51 , H 10.15; found: C 82 .18 , H 10.04. 157 T r i e n e - a c e t a t e s ( 1 0 3 a r b 1 A s o l u t i o n of d ienones (136a ,b) (0 .18 g , 0.83 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL) was t r e a t e d at 25 C w i t h n - b u t y l l i -thium (1 .6 M, hexane) (0 .700 mL, 1.06 mmol) f o r 15 minutes . The e n o l a t e an ion thus generated was c o o l e d to - 5 0 ° C and t r e a t e d w i t h d r y a c e t i c anhydr ide (0 .16 mL, 1.7 mmol). A f t e r 15 minutes , the r e a c t i o n mix ture was warmed to room temperature and s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n (5 .0 mL) was added to quench excess a c e t i c a n h y d r i d e . The mix ture was then e x t r a c t e d w i t h p e t . e ther and the combined o r g a n i c l a y e r s were washed w i t h b r i n e and d r i e d ( M g S O ^ . A f t e r removal of s o l v e n t , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 20:1) to a f f o r d a m i x t u r e of i somers of t r i e n e - a c e t a t e s (103a:b) (0 .14 g, 64%) as a c o l o r l e s s o i l ; the r a t i o (1:7) of i somers (103 a:103b) was determined from pro ton i n t e g r a t i o n s i n the n . m . r . ; 158 (103b): R f 0.81 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; V m a x ( f i l m ) : 2925, 1759, 1620 c m " 1 ; S ( C D C 1 3 , 400 MHz): 0.94 ( s , 3H, C H 3 ) , 1.06 ( s , 3H, C H 3 ) , 1.71 ( s , 3H, CH3) , 1.81 ( s , 3H, CH3 ) , 2.13 ( s , 3H, ROCOCH3), 5.49 ( d , 1H, H a , J=10 H z ) , 5.59 ( d , 1H, Hd, J=4 H z ) , 6.10 ( d , 1H, He, J=10 H z ) , 6 .10 ( d d , 1H, Hb, J=24 Hz , 12 H z ) ; (103a): 0.90 ( s , 3H, C H 3 ) , 0 .95 ( s , 3H, C H 3 ) , 1.73 ( s , 6H, R 2 ( C H 3 ) 2 ) , 2 .17 ( s , 3H, ROCOCH3), 5.63 ( d , 1H, H d , J=4 H z ) , 5.80 ( d , 1H, Ha, J=10 H z ) , 5.19 ( d , 1H, He, J=16 H z ) , 6.19 (dd , 1H, Hb, J = 16 Hz , 10 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 260 ( 2 . 9 2 , M + ) , 219 ( 1 . 4 7 ) , 218 ( 8 . 3 2 ) , 217 ( 3 . 4 4 ) , 203 ( 3 . 1 5 ) , 185 ( 4 . 0 6 ) , 175 ( 8 . 8 4 ) , 162 ( 8 . 9 1 ) , 161 ( 4 . 2 3 ) , 147 ( 1 8 . 2 ) , 109 ( 1 7 . 3 ) , 91.0 ( 2 3 . 8 ) , 78.0 ( 1 5 . 7 ) ; Exact mass c a l c d . f o r C 1 7 H 2 4 0 2 : 260.1776; found: 260.1775; A n a l , c a l c d . f o r C 1 7 H 2 4 0 2 : C 78 .42 , H 9.290; found: C 78 .36 , H 9 .180. 159 CHAPTER 2 S y n t h e t i c Approaches to Albene 1 6 0 2 . 1 . 0 . INTRODUCTION ( - ) - A l b e n e (221) , a t r i c y c l i c C i 2 H i e [85] t r i s n o r s e s q u i t e r p e n o i d , was f i r s t i s o l a t e d from P e t a s i t e s  a l b u s i n 1962. D e s p i t e e x t e n s i v e e f f o r t s i n v o l v i n g a v a r i e t y of d e g r a d a t i v e and s y n t h e t i c s t u d i e s , the c o r r e c t s t r u c t u r e and a b s o l u t e c o n f i g u r a t i o n of t h i s e l u s i v e molecu le has been a s u b j e c t of c o n t r o v e r s y f o r n e a r l y two decades . (221) The f i r s t t e n t a t i v e s t r u c t u r a l p r o p o s a l (222) was made by L . Novotny and V . Herout in 1964 [86 ] . L a t e r , F . Sorm and co -workers [87] , on the b a s i s of s p e c t r o s c o p i c ev idence and c h e m i c a l c o r r e l a t i o n between " ( - ) - a l b e n e " (223) and (+)-camphene (224) , proposed a new s t r u c t u r e (223) f o r ( - ) - a l b e n e . ch8 ckf (222) (223) (224) S t r u c t u r e (223) was supported i n 1973 by P . T . Lansbury and R. M. Boden [88] who s y n t h e s i s e d albanone (228) from cam-p h e n i l o n e (225) as shown i n Scheme 68. The key s tep i n t h i s 161 Scheme 68 s y n t h e t i c r o u t e was the f o r m i c a c i d c a t a l y s e d c y c l i s a t i o n of the b i c y c l i c c h l o r o - a l k e n e (226) . The wel l -known p r e f e r e n c e of e x o - 2 . 3 - m e t h y l s h i f t s over the c o r r e s p o n d i n g endo s h i f t s i n n o r b o r n y l c a t i o n s (Scheme 69) prompted Lansbury to conc lude t h a t t h i s c y c l i s a t i o n s t ep would p r o v i d e (227) r a t h e r than (232) . In 1979, however, W. K r e i s e r and co -workers repeated L a n s b u r y ' s exper iments (Scheme 70) , and r e p o r t e d t h a t X - r a y c r y s t a l l o g r a p h i c a n a l y s i s of the 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e d e r i v a t i v e of a lbanone (234) [89] c l e a r l y showed t h a t t h i s compound, a lbanone , had the exji c o n f i g u r a t i o n (235) . Hence 162 they proposed t h a t the f o r m i c a c i d c a t a l y s e d c y c l i s a t i o n Scheme 69 163 ct N02 R e a g e n t s and c o n d i t i o n s : ( i ) ( C F 2 C O ) 2 0 , H O ( 8 0 % ) , H 2 S 0 4 ( c a t . ) / H O A c ; ( i i ) S a po-n i f i c a t i o n ; ( i i i ) C r 0 _ , P y r i d i n e ; ( i v ) 2,4-(NO ) C H NHNH , 5 2. Z o 4 H + ; ( v ) P b ( 0 A c ) 4 -Scheme 70 164 of (233) i n v o l v e d an e n d o - 2 . 3 - m e t h y l s h i f t as shown i n Scheme 69. With e x p e r i e n c e g a i n e d from s t u d i e s of the rearrangement o f the b i c y c l o [ 2 . 2 . l ] h e p t a n e s k e l e t o n , T . Money p o i n t e d out i n 1979 [90] t h a t the 2,3-fixo_-methyl s h i f t r e p o r t e d by Lansbury and R. M. Boden e a r l i e r was p r o b a b l y c o r r e c t , but suggested t h a t t h i s was f o l l o w e d by Wagner-Meerwein rearrangement , 2 ,6 h y d r i d e s h i f t , Wagner-Meerwein rearrangement and c y c l i s a t i o n r e a c t i o n sequences (Scheme 71) to p r o v i d e s t r u c t u r e (243) as a c y c l i s a t i o n p r o d u c t . Thus i t was suggested t h a t ( - ) - a l b e n e had the e n a n t i o m e r i c s t r u c t u r e (221) . T h i s c o n c l u s i o n was i n d e p e n d e n t l y made by J . E . Baldwin and T . C . Barden who went on to c o n f i r m the s t r u c t u r e of ( - ) - a l b e n e (221) by e l e g a n t m e c h a n i s t i c and s y n t h e t i c s t u d i e s [91 ] . The c h a l l e n g e p r e s e n t e d by the s t r u c t u r e of a lbene has has l ed to the s u c c e s s f u l comple t ion of four t o t a l s y n t h e s e s . A b r i e f account of these s y n t h e t i c approaches i s p r o v i d e d below. L a n s b u r y ' s i n i t i a l s y n t h e s i s i n 1973 (Scheme 68) was repeated by W. K r e i s e r and L . J a n i t s c h k e i n 1978 and the t r i c y c l i c p r o d u c t was r e a s s i g n e d as the e x o - f i v e membered r i n g s t r u c t u r e (232) . In 1981, J . E . Baldwin and T . C . Barden [91] r e p o r t e d a s y n t h e s i s of ( l ) - a l b e n e t h a t f e a t u r e d the c o n v e r s i o n of h e m i a c e t a l (246) i n t o cyc lopentenone (247) (Scheme 72) . In 1982, B . M. T r o s t and P. Renaut [92] (Scheme 73) u t i l i s e d the p a l l a d i u m c a t a l y s e d c y c l o a d d i t i o n of 165 2,3 Me fc£0 — ££fl-2,3-methyl shift WM =Wogner-Meerwein rearrangement 2.6Hr2.6-hydride shift Scheme 71 166 ( + ) - A l b e n e ( 2 4 7 ) R e a g e n t s and c o n d i t i o n s : ( i ) M e L i ; ( i i ) DHP, TsOH; ( i i i ) ^ B u K A l H ; ( i v ) KOH; ( v ) ( tBu)„AlH; ( v i ) Ac O, NaOAc; ( v i i ) L i / E t N H . 2 ^ ^ Scheme 72 167 R e a g e n t s and c o n d i t i o n s : ( i ) ( i - C 3 H 7 0 ) 3 P , P d ( O A c ) 2 , THF, R e f l u x ; ( i i ) LAH, E t h e r , 0°C; ( i i i ) 0 3 , C H 2 C 1 2 , CH 3OH, -78°C; ( C H 3) ( i v ) KN(M'e 3Si) , DME, HMPA, [(CH ) 2 N ] P ( 0 ) C 1 , 0° C (v) L i , C 0H_NH_, THF, tC-H^OH, -5°C. Scheme 73 168 2 - [ ( t r i m e t h y l s i l y l ) m e t h y l ] - 3 - i o d o - l - p r o p a n e (249) w i t h d i e B t e r (248) as the key r e a c t i o n and produced the d e s i r e d c y c l o a d d u c t (250) which a f t e r r e d u c t i o n and o z o n o l y s i s p r o v i d e d the b a s i c t r i c y c l i c s k e l e t o n (252) of a l b e n e . Red-u c t i o n of the c o r r e s p o n d i n g t r i p h o s p h a t e (253) then p r o v i d e d ( l ) - a l b e n e . In 1983, A . S. D r e i d i n g et a l . [93] completed another s y n t h e s i s of ( • ) - a l b e n e (Scheme 74) i n which t e r m i n a l c y c l i s a t i o n of a lkynone (258) r e s u l t e d i n s u c c e s s f u l ann-u l a t i o n to p r o v i d e cyc lopentenone (247) . The r e q u i r e d o l e f i n f u n c t i o n a l i t y was then i n t r o d u c e d v i a the S h a p i r o r e a c t i o n to produce ( i ) - a l b e n e . S y n t h e t i c r o u t e s to a lbene have been c o n s i d e r e d i n our l a b o r a t o r y [94] s i n c e the p r o p o s a l f o r the a b s o l u t e c o n f i g u r a t i o n of a lbene was made [90 ] . The main o b j e c t of t h i s work was to deve lop an e n a n t i o s p e c i f i c s y n t h e s i s of (+) -a lbene (221) . Two s y n t h e t i c approaches , i n c l u d i n g an i n t r a m o l e c u l a r ene r e a c t i o n of (+) - f t - santa lene (259) , and an i n t r a m o l e c u l a r f r e e r a d i c a l c y c l i s a t i o n r e a c t i o n of b r o m o - o l e f i n (260) r e s p e c t i v e l y w i l l be d e s c r i b e d . (260) 169 ( 2 4 5 ) (255) ( i i ) < 2 4 7) (+ )-Albene R e a g e n t s and c o n d i t i o n s : ( i ) H e a t ; ( i i ) C H 3 S i C = C S i C H 3 , A1C1 ; ( i i i ) Na B 0 ; ( i v ) 580°C; ( v ) H , Pd/C; ( v i ) TsNHNH ; ( v i i ) M e L i . Scheme 74 170 2 . 2 . 0 . DISCUSSION AND RESULTS 2 . 2 . 1 . INTRAMOLECULAR ENE REACTION From a b i o s y n t h e t i c s t a n d p o i n t [90] , ( - ) - a l b e n e (221) c o u l d be produced i n na ture by c y c l i s a t i o n of ( +) - |5-santalene (259) f o l l o w e d by e l i m i n a t i o n of the i s o p r e n y l group . P r e v i o u s at tempts i n our l a b o r a t o r y to s y n t h e s i s e a lbene v i a a c i d c a t a -l y s e d c y c l i s a t i o n of (+ ) - (3-santalene (259) and (+ ) - e p i - £ - s a n t -a l ene (48) were u n s u c c e s s f u l [ 7 0 , 9 4 ] . A c l o s e examinat ion of m o l e c u l a r model of ( + ) - £ - s a n t a l e n e (259) r e v e a l e d tha t the ene and e n o p h i l e p o r t i o n s of t h i s molecule c o u l d a l i g n f a v o r a b l y in the t r a n s i t i o n s t a t e (263) (Scheme 75) . I t was hoped that Scheme 75 171 thermal c y c l i s a t i o n of ( + )-/3-santalene (259) would take p l a c e smoothly to produce the d e s i r e d o l e f i n (261). Ozono-l y s i s of o l e f i n (261) followed by B a e y e r - V i l l i g e r o x i d a t i o n and e l i m i n a t i o n of the corresponding a c e t a t e (264) could then p r o v i d e (-)-albene (221) as shown i n Scheme 76. Scheme 76 Before d e s c r i b i n g the s y n t h e s i s of ( + ) - (3-santalene (259), the s u b s t r a t e f o r the p r o j e c t e d i n t r a m o l e c u l a r ene r e a c t i o n , a b r i e f g e n e r a l d e s c r i p t i o n of the i n t r a m o l e c u l a r ene r e a c t i o n i s provided below. The i n t r a m o l e c u l a r ene r e a c t i o n [95] u s u a l l y i n v o l v e s t h e r m o l y s i s of an o l e f i n with an a l l y l i c 172 hydrogen a t tached (ene) and an e n o p h i l e (an e l e c t r o n -d e f i c i e n t m u l t i p l e bond) ( 2 6 5 ) i n t r a m o l e c u l a r l y w i t h e i t h e r exo- or e n d o - t r a n s i t i o n s t a t e to g i v e a c y c l i c o l e f i n ( 2 6 6 ) . Z = C R 2 , O Three d i f f e r e n t c y c l i s a t i o n modes are p o s s i b l e and these are o u t l i n e d in Scheme 77. In Baldwin t e r m i n o l o g y [96] , r e a c t i o n types 1-3 r e p r e s e n t axo_-e_xo_, exo-endo and endo-endo c y c l i s a t i o n s r e s p e c t i v e l y . For our own purpose , o n l y i n t r a m o l e c u l a r ene r e a c t i o n of type 1 w i l l be d i s c u s s e d h e r e . Type 1 c y c l i s a t i o n i s m a i n l y a s s o c i a t e d w i t h the t h e r m o l y s i s of a 1 ,6 d i e n e such as compound ( 2 6 7 ) which p r o -v i d e s compound ( 2 6 8 ) as the major p r o d u c t and compound ( 2 6 9 ) as the minor p r o d u c t [97 ] . E x a m i n a t i o n of t r a n s i t i o n s t a t e s i l l u s t r a t e s t h a t the e x a - t r a n s i t i o n s t a t e ( 2 7 0 ) , which g i v e s the t r a n s - s u b s t i t u t e d p r o d u c t ( 2 6 9 ) , appears to be h i g h l y s t r a i n e d , thus f a v o r i n g the almost e x c l u s i v e f o r m a t i o n of the 173 Type 1 Type 2 Type 3 Scheme 77 c i s - s u b s t i t u t e d p r o d u c t (268) v i a the r e l a t i v e l y u n s t r a i n e d e n d o - t r a n s i t i o n s t a t e (271) (Scheme 78).' ( 2 7 0 ) (269) (271 ) (268) Scheme 7 8 174 Use has been made of t h i s g e n e r a l p r i n c i p l e i n a r e c e n t s t e r e o s e l e c t i v e s y n t h e s i s of a s p i r o - s e s q u i t e r p e n o i d , (+)-(3-acorenol (274) [98 ] . The s p i r o c y c l i c s k e l e t o n (273) of t h i s compound was c o n s t r u c t e d by an i n t r a m o l e c u l a r ene r e a c t i o n of d i e n e (272) , and i t s s t e r e o c h e m i s t r y r e s u l t s from the a n o l a - t r a n s i t i o n s t a t e (275) r a t h e r than the l e s s f a v o r e d exo-t r a n s i t i o n s t a t e (276) which shows a non-bonded i n t e r a c t i o n between the b r i d g e C(4) and the cyc lohexene u n i t C ( 6 ) , as shown i n Scheme 79. (272) (273) O H (274) C O O E l (275) (273) C O O E l (277) (276) Scheme 79 175 P r e v i o u s i n v e s t i g a t i o n s [23] i n our l a b o r a t o r y have e s t a b l i s h e d t h a t ( - ) - / 3 - santa l ene (98) can be s y n t h e s i s e d from ( - ) -campherenone (92) wh ich , i n t u r n , was d e r i v e d from ( - ) -camphor (27). ( +)-(S-santalene (259) was s y n t h e s i s e d i n a s i m i l a r f a s h i o n w i t h the e x c e p t i o n t h a t a l e s s hazardous sequence (Scheme 80) was used to c o n v e r t (+)-camphor (26) to (+)-campherenone (151) ( c f . page 66) [61 ] . Subsequent h y d r i d e r e d u c t i o n of (151) f o l l o w e d by Wagner-Meerwein rearrangement of ( + ) -campherenol (278) p r o v i d e d ( + )-/3>-santalene (259) i n 74% y i e l d from (+ )-campherenone (151). With (+)- /3-santalene (259) a v a i l a b l e , at tempts were made to c a r r y out the i n t r a m o l e c u l a r ene r e a c t i o n to form the d e s i r e d o l e f i n (261). T h i s r e a c t i o n was c a r r i e d out at d i f f e r e -o o nt temperatures r a n g i n g from 200 C-550 C in s e a l e d tubes . Howe-v e r , a f t e r s e v e r a l attempts we were f o r c e d to conc lude tha t the d e s i r e d compound (261) was not produced under these c o n d i t i o n s . Subsequent to t h i s a t tempt , we noted tha t J . E . Baldwin et a l . have p r e v i o u s l y r e p o r t e d t h a t t h e r m o l y s i s of o l e f i n (262) p r o v i d e d ( - ) - (3 - santa lene (98) v i a a r e t r o - e n e p r o c e s s [ 91c ] . T h i s i s a p o s s i b l e e x p l a n a t i o n f o r our f a i l u r e i n the attempt of an i n t r a m o l e c u l a r ene r e a c t i o n on (+ ) - (?-santalene (259). 176 ( 2 6 ) (42) (165) (1 6 7 a , b ) (166) (133) ( v i i i ) (168) (151) (278) (xi ) R e a g e n t s and c o n d i t i o n s : ( i ) B r 2 , HBr, HOAc, 110°C; ( i i ) B r 2 , HSO C l ; ( i i i ) Zn, HOAc, E t 2 0 , 0°C; ( i v ) K l , DMSO, 110°C, 3 d a y s ; ( v ) Me S i C l , HOCH 2-CH 2OH; ( v i ) NaCN, DMSO, 70°C, 2 d a y s ; ( v i i ) LDA, THF, -78°C; P r e n y l B r o m i d e ; ( v i i i ) K, HMPA, E t j O , t B u 0 H , 0°C; ( i x ) H CI, Me 2C0; ( x ) LAH, THF; ( x i ) M e S O ^ l , P y r i d i n e , 4-DMAP, 100 C, 16 h o u r s . Scheme 80 177 2 . 2 . 2 . INTRAMOLECULAR FREE RADICAL CYCI.TSATTO APPROACH Our second s y n t h e t i c approach to the s y n t h e s i s of a lbene a lbene i n v o l v e d an i n t r a m o l e c u l a r f r e e r a d i c a l c y c l i s a t i o n r e a -c t i o n . R e c e n t l y , t h e r e has been an i n c r e a s e i n the use of f r e e r a d i c a l r e a c t i o n s f o r the s y n t h e s i s of c y c l i c compounds. These c y c l i s a t i o n r e a c t i o n s e x h i b i t i n t e r e s t i n g r e g i o s e l e c t i v i t i e s and s t e r e o s e l e c t i v i t i e s . For example, A . L . J . Beckwi th and C . H . S c h i e s s e r [99] have shown t h a t the 5 -hexeny l r a d i c a l (279) c y c l i s e d r e g i o s e l e c t i v e l y to produce the s m a l l e r r i n g (281) , t h a t i s , the l e s s s t a b l e p r i m a r y r a d i c a l (280) was formed f a s t e r than the more s t a b l e secondary r a d i c a l (282) . The p r e f e r e n t i a l f o r m a t i o n of (261) i s c o n s i s t e n t w i t h B a l d w i n ' s (282) (283) (284) Scheme 81 178 r u l e s [96] which s t a t e t h a t 5-e_xo_-trigonal c y c l i s a t i o n s are more f a v o r a b l e than 6-ejid_Q.-trigonal c y c l i s a t i o n p r o c e s s e s . Beckwi th e x p l a i n e d the r e g i o s e l e c t i v e f o r m a t i o n of (281) v i a the most f a v o r e d t r a n s i t i o n s t a t e (284) (Scheme 81 ) . The s t e r e o s e l e c t i v i t y of f r e e r a d i c a l c y c l i s a t i o n has a l s o been r e p o r t e d by Beckwi th [99 ] , and two u s e f u l g u i -d e l i n e s g o v e r n i n g the r i n g c l o s u r e of s u b s t i t u t e d hexenyl r a d i c a l s were f o r m u l a t e d . The f i r s t g u i d e l i n e i s t h a t 1- or 3 - s u b s t i t u t e d r a d i c a l s p r e f e r e n t i a l l y g i v e c i s - d i s u b s t i t u t e d c y c l o p e n t y l p r o d u c t s , and the second one i s t h a t 2- or 4-s u b s t i t u t e d r a d i c a l s g i v e main ly t r a n s - d i s u b s t i t u t e d c y c l o -p e n t y l p r o d u c t s . For example, c y c l i s a t i o n of 3 - m e t h y l - 5 -hexenyl r a d i c a l (285) g i v e s more c i s - i s o m e r (287) . On the o ther hand, c y c l i s a t i o n of 2-methy1-5-hexeny1 r a d i c a l (288) g i v e s more t r a n s - i s o m e r (289) than c i s - i s o m e r (290) . S i m i l -a r l y , c y c l i s a t i o n of 4-methy1-5-hexeny1 r a d i c a l (291) a l s o produced more t r a n s isomer (292) (Scheme 82) . Beckwith e x p l a -ined these r e s u l t s on the b a s i s of the t r a n s i t i o n s t a t e s t r u c -t u r e (294) of these r a d i c a l s i n which the more f a v o r a b l e c o n f -ormer s h o u l d bear the s u b s t i t u e n t s i n the e q u a t o r i a l p o s i t i o n . 179 ( 285) ( 288) (291) (286) (287) (25%) (75%) - Yr • (289) (65%) Y Y (290) (35%) . r i * 0 v ^  (292) ((293) (83%) (17%) Scheme 8 2 180 Many a p p l i c a t i o n s of f r e e r a d i c a l c y c l i s a t i o n i n n a t u r a l p r o d u c t s y n t h e s i s have been p u b l i s h e d d u r i n g the pas t decade . Examples , i n c l u d e the s y n t h e s i s of (1)-copacamphene (296) and ( i ) - s a t i v e n e (297) by P. B a k u z i s et a l . i n 1976 [100] (Scheme 83 ) , d i h y d r o a g a r o f u r a n (299) by B u c h i and H. Wuest i n 1979 [101] (Scheme 84) , and n o r s e y c h e l l a n o n e (301) by G . S t o r k and N. H . Ba ine in 1985 [102] (Scheme 85 ) . (300) (301) Scheme 85 181 In the key r e a c t i o n s l e a d i n g to these compounds, a l k y l r a d i c a l s produced from a l k y l h a l i d e s (295) , (298) , and (300) r e a c t i n t r a m o l e c u l a r l y w i t h an a lkene f u n c t i o n a l i t y to form the c y c l i s e d p r o d u c t s . An e x t e n s i o n of t h i s methodology i n v o l v e s double r a d i c a l c y c l i s a t i o n to form two r i n g s , and an e l egant example of t h i s t e c h n i q u e i s p r o v i d e d by the r e c e n t s y n t h e s i s o f b u t e n o l i d e (304) (Scheme 86) d e s c r i b e d by S t o r k and R. Hook [103] . S u c c e s s i v e r a d i c a l c y c l i s a t i o n has a l s o been used in the recen t s y n t h e s i s of h i r s u t e n e (306a) [104] (Scheme 88) , s i l p h i p e r f o l - 6 - e n e (305b) and 9 - e p i s i l p r i p e r f o l - 6 - e n e (305d) ( 302 ) Scheme 86 (304) < (305a) (305b) ( 305) (305d) Scheme 87 182 (306a) (306b) Scheme 88 [105] (Scheme 87) . The s u c c e s s f u l syntheses d e s c r i b e d above prompted us to c o n s i d e r t h a t the c o n s t r u c t i o n of the c y c l o p e n t a n e r i n g of ( - ) - a l b e n e (221) c o u l d be accompl i shed by a f r e e r a d i c a l c y c l i s a t i o n r e a c t i o n . The proposed s y n t h e t i c p l a n o u t l i n e d in Scheme 89 env i sages i n t r a m o l e c u l a r f r e e r a d i c a l c y c l i s a t i o n of the bromo o l e f i n (307) . I t was hoped tha t the r a d i c a l i n t e r m e d i a t e (308) would add to the double bond in a 5-e_xo_-t r i g f a s h i o n to produce the a lbene framework (310) and dehy-d r a t i o n would then p r o v i d e (+) -a lbene (311) . R e t r o - s y n t h e t i c a n a l y s i s (Scheme 90) r e v e a l s tha t bromo o l e f i n (307) c o u l d be c o n s t r u c t e d , in t h e o r y , from a lkene a ldehyde (312) and an a p p r o p r i a t e u n i t (313) . F i n a l l y , a lkene a ldehyde (312) c o u l d be d e r i v e d from compound (314) , which c o u l d be formed by Wagner-Meerwein rearrangement of a C(8) f u n c t i o n a l i s e d camphor d e r i v a t i v e (315) [94] . In the proposed e n a n t i o s p e c i f i c s y n t h e s i s of a l b e n e , (+)-camphor (26) was t h e r e f o r e chosen as the c h i r a l s t a r t i n g m a t e r i a l (Scheme 91) . Treatment of (+)-8-bromocamphor (42) d e r i v e d from (+)-camphor (26) i n 3 s t eps as d e s c r i b e d e a r l i e r (page 50) w i t h potass ium 183 (307) (308) Scheme 89 a c e t a t e i n d i m e t h y l s u l f o x i d e at h i g h temperature (Scheme 91) gave (+) -8-acetoxycamphor (139) , which underwent s e l e c t i v e r e d u c t i o n w i t h sodium b o r o h y d r i d e i n ammonium c h l o r i d e and e t h a n o l to p r o v i d e h y d r o x y - a c e t a t e (316) . Subsequent r e a c t i o n of (316) w i t h methanesulfony1 c h l o r i d e , 4 - d i m e t h y l a m i n o p y r i d -ine and p y r i d i n e r e s u l t e d in Wagner-Meerwein rearrangement and 184 (26) Scheme 90 f o r m a t i o n of a lkene a c e t a t e (317) . H y d r i d e r e d u c t i o n of a lkene a c e t a t e (317) f o l l o w e d by o x i d a t i o n w i t h p y r i d i n i u m ch lorochromate [69] a f f o r d e d a lkene a ldehyde (312) which was t r e a t e d w i t h methyl a c e t a t e (313) and l i t h i u m d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n to a f f o r d (319) i n over 33% y i e l d from (+)-8-bromocamphor (42 ) . H y d r i d e r e d u c t i o n of h y d r o x y - e s t e r (319) p r o v i d e d the d i o l s (320) i n 89% y i e l d . The p r i m a r y 185 (318) (317) • (316) ( v i i i ) R e a g e n t s and c o n d i t i o n s : ( i ) B r 2 , H B r ' HOAc, 110°C; ( i i ) B r 2 , CISO3H; ( i i i ) Zn, HOAc, E t 2 0 , 0°C; ( i v ) KOAc, DMSO, 110°C; ( v ) NaBH 4, NH 4 EtOH; ( v i ) M e S 0 2 C l , P y r i d i n e , 4-DMAP, 100°C, 16 h o u r s ; ( v i i ) LAH, THF; ( v i i i ) PCC, C H 2 C 1 2 ; ( i x ) LDA, THF, -78° CH 3C0 2Me; ( x ) LAH, THF. Scheme 91 186 a l c o h o l i n t h i s compound (320) was s e l e c t i v e l y p r o t e c t e d as the b u l k y t e r t - b u t y I d i p h e n y l s i l y 1 e ther (321) [106] (Scheme 92) . A c e t y l a t i o n of (321) p r o v i d e d s i l y l e ther e s t e r (322) which was t r e a t e d w i t h tetrabutylammonium f l u o r i d e i n t e t r a h y d r o f u r a n to g i v e the d e s i r e d h y d r o x y - a c e t a t e (323) , and a b y - p r o d u c t . The i n f r a r e d spectrum ( c f . page 283 ) ° f t h i s b y - p r o d u c t showed a b s o r p t i o n s at 3460 cm * , and 1740 cm which i n d i c a t e d the presence of a l c o h o l and e s t e r f u n c t i o n -n a l i t i e s . When i t s ^ H - n . m . r , spectrum (page 284) was compared wi th t h a t of h y d r o x y - e s t e r (323) (page 284)» we conc luded tha t t h i s b y - p r o d u c t was the i s o m e r i c h y d r o x y - e s t e r (324) (Scheme 92) . To account f o r the f o r m a t i o n of (324) i n t h e d e s i l y l a t i o n r e a c t i o n of (322) , we proposed tha t a 1 , 3 - a c y l t r a n s f e r r e a c t i o n (Scheme 93) had taken p l a c e d u r i n g the d e s i l y l a t i o n r e a c t i o n . 1 , 3 - A c y l t r a n s f e r s of t h i s type have r e p o r t e d i n the l i t e r a t u r e [107] . S ince d e s i l y l a t i o n of (322) p r o v i d e d a mix ture of i s o -mer ic h y d r o x y - e s t e r s (323) and (324) , we d e c i d e d to r e p l a c e the a c e t a t e group i n (324) w i t h a methyl e ther (Scheme 94) . Treatment of s i l y l e ther (321) w i t h potass ium h y d r i d e and (322) (324) Scheme 93 187 ( 3 2 0 ) ( i ) (321) I J ( i i ) ( 3 2 6) (325) ( i v ) ( 260) R e a g e n t s and c o n d i t i o n s : ( i ) t B u t y l d i p h e n y l s i l y l C h l o r i d e , I m i d a z o l e , DMF; ( i i ) NaH, THF, M e l ; ( i i i ) TBAF; ( i v ) P P h ^ &r2' C H 2 C 1 2 * Scheme 94 188 Ph + R e a g e n t s and c o n d i t i o n s : ( i ) t B u t y l d i p h e n y l s i l y l C h l o r i d e , I m i d a z o l e , DMF; ( i i ) A c 2 0 , 4-DMAP, P y r i d i n e ; ( i i i ) TBAF. Scheme 9 2 methyl i o d i d e i n t e t r a h y d r o f u r a n a f f o r d e d the m e t h o x y - s i l y l ether (325) which was d e s i l y l a t e d to pr o v i d e methyl ether a l c o h o l (326) as the only product. With the p r o t e c t i n g group problem s o l v e d , we then proceeded with the s y n t h e s i s of bromo-o l e f i n (260) by bromonating methyl ether a l c o h o l (326) with bromine and t r i p h e n y l p h o s p h i n e i n methylene c h l o r i d e [108]. 189 The s y n t h e s i s of b r o m o - o l e f i n (260) a l lowed us to i n v e -s t i g a t e the c r u c i a l i n t r a m o l e c u l a r f r e e r a d i c a l c y c l i s a t i o n r e a c t i o n . Treatment of b r o m o - o l e f i n (260) w i t h a z o b i s - ( i s o b u -o t y r o n i t r i l e ) and t r i b u t y l t i n h y d r i d e i n benzene at 60 C [109] p r o v i d e d a s i n g l e p r o d u c t . The 1 H - n . m . r . spectrum (page 285) of t h i s p r o d u c t i n d i c a t e d the presence of o n l y one methyl group and was c l e a r l y i n c o n s i s t e n t w i t h the spectrum expected f o r the d e s i r e d p r o d u c t (329). Indeed, the 1 H - n . m . r . spectrum led us to conc lude tha t the r e a c t i o n product was the t r i c y c l i c methyl e ther (331) (Scheme 95) . The c y c l i s a t i o n of the i n t e r m e -d i a t e r a d i c a l (327) c o u l d occur by e i t h e r a 5 - e j £ o _ - t r i g or a 6-© j a d j i - t r i g mode. A l though the 5-e_xo_-trig mode would u s u a l l y be p r e f e r r e d f o r geometr i c r e a s o n s , t h i s c y c l i s a t i o n i n v o l v e s s t -e r i c i n t e r a c t i o n and t o r s i o n a l s t r a i n between the C H 3 and CH2 groups a t t a c h e d to a d j a c e n t carbon atoms of the i n t e r m e d i a t e framework (328). In c o n t r a s t , the g e o m e t r i c a l l y l e s s f a v o r e d 6-end_Q_-trig c y c l i s a t i o n i n v o l v e s a secondary f r e e r a d i c a l i n t -ermediate (330) and i s not accompanied by s e r i o u s s t e r i c i n t e -r a c t i o n . T h e r e f o r e , due to s t e r i c e f f e c t s , the f o r m a t i o n of c y c l o a l k y l r a d i c a l (330) was p r e f e r r e d over c y c l o a l k y l methyl r a d i c a l (328), and we o b t a i n e d the u n d e s i r e d p r o d u c t (331) as the f a v o r e d one. In summary, s y n t h e t i c approaches to c o n s t r u c t the b a s i c t r i c y c l i c carbon framework of (+)- or ( - ) - a l b e n e (221) i n c l u d e the i n t r a m o l e c u l a r ene r e a c t i o n and the i n t r a m o l e c u l a r f r e e r a d i c a l c y c l i s a t i o n r e a c t i o n . A new e n a n t i o s p e c i f i c s y n t h e t i c 190 r o u t e to ( + ) - ( i - santa lene (259) from ( + )-camphor (26) was d e s c r i b e d , but t h i s compound u n f o r t u n a t e l y f a i l e d to undergo an i n t r a m o l e c u l a r ene r e a c t i o n to p r o v i d e (261) . In a d d i t i o n , b r o m o - o l e f i n (260) , was a l s o s y n t h e s i s e d from (+)-camphor (26) but c y c l i s e d i n a 6-exja.-tr i g mode i n the i n t r a m o l e c u l a r f r e e r a d i c a l r e a c t i o n approach to p r o v i d e a six-membered r i n g p r o d u c t (331) . Scheme 95 191 2.3.0. EXPERIMENTAL ( c f . page 88) 192 ( - ) - I s o c a m p h e r e n o l (278^ (151) (278) L i t h i u m aluminum h y d r i d e (0 .26 g , 6.8 mmol) was s u s -o pended i n dry t e t r a h y d r o f u r a n (30 mL) at 0 C , and a s o l u t i o n of (+)-campherenone (151) (1 .0 g , 4 .5 mmol) in d r y t e t r a h y d r o -f u r a n (15 mL) was s l o w l y i n t r o d u c e d . The r e a c t i o n mix ture was o s t i r r e d at 0 C under an argon atmosphere f o r 3 hours . A f t e r d i l u t i o n w i t h water (20 mL) c a r e f u l l y f o l l o w e d by e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h h y d r o -c h l o r i c a c i d (1 .0 N ) , b r i n e and water , and d r i e d ( M g S O ^ . Upon removal of s o l v e n t under vacuo, the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r ) to y i e l d ( - ) - i s o c a m p h e r e n o l (278) (0 .99 g , 98%) as a c o l o r l e s s o i l ; R f 0.20 ( p e t . e t h e r : e t h e r , 9 :1 ) ; [ o C ] § 5 - 2 4 . 7 ° (c 0 .90 , CHCI3); V ( f i l m ) : 3420, 2970 c m - 1 ; S ( C D C 1 , , 400 MHz): 0.85 ( s , 'max 3 3H, C H 3 ) , 0.91 ( s , 3H, C H 3 ) , 1.62 ( s , 3H, R1R2C :CCH.3CH 3 ) , 1.68 ( s , 3H, R 1 R 2 C : C C H 3 C E 3 ) , 3.64 ( d d , 1H, R ^ C R O H , J = 12 Hz , 4 H z ) , 5.14 (m, 1H, R 1 R 2 C : C H . R 3 ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 222 (0 .110 , M + ) , 220 ( 1 . 8 6 ) , 204 ( 2 . 2 2 ) , 1.59 ( 4 . 3 4 ) , 135 ( 4 . 3 8 ) , 122 ( 7 2 . 1 ) , 109 (14 .5 ) 107 ( 1 2 . 6 ) , 94.0 ( 2 5 . 2 ) , 94.0 (100); Exac t mass c a l c d . f o r C 1 5 H 2 6 0 : 222.1984; found: 222.1987; A n a l , c a l c d . f o r Cx5H 2 6 0: 193 C 81 .02 , H 11.79; found: C 81 .00 , H 11 .91 . ( + V - S a n t a l e n e (259^ ( - ) - I s o c a m p h e r e n o l (278) (1 .0 g 4 .5 mmol) was t r e a t e d w i t h methanesulphony1 c h l o r i d e (1 .0 g, 9.0 mmol) and 4 - d i m e t h y -o l a m i n o p y r i d i n e (0 .15 g) in dry p y r i d i n e (10 mL) at 100 C under an argon atmosphere f o r 16 hours . A f t e r d i l u t i o n w i t h water (10 mL), f o l l o w e d by e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y -ers were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) , s a t u r a t e d sodium b i c a r b o n a t e d s o l u t i o n and water , and d r i e d (MgS04). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r ) to a c c o m p l i s h ( + ) - p - s a n -t a l e n e (259) (0 .73 g , 80%) as a c o l o r l e s s o i l ; R f 0.93 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; [oC] g 5 + 1 1 2 . 6 ° (c 1.60, CHCI3) ( l i t . [23] f o r ( - ) - p - s a n t a l e n e [oC ]g 8 -112° (c 5 .01 , CHCI3)); 1> m a x ( f i l m ) : 2979, 1658, 878 c m - 1 ; o (CDCI3, 400 MHz): 1.05 ( s , 3H, C H 3 ) , 1.61 ( s , 3H, R 1 R 2 C : C C t L 3 C H 3 ) , 1.68 ( s , 3H, R x R 2 C : CCH3CH.3), 4 .46 ( s , 1H, R ^ C i C H J O , 4 .73 ( s , 1H, R 1 R 2 C : C H t L ) , 5.10 ( t , 1H, R 1 R 2 C:CfcLR 3 , J = 8 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 204 ( 1 . 4 8 , M + ) , 194 189 ( 1 . 3 0 ) , 161 ( 3 . 8 3 ) , 148 ( 1 . 2 4 ) , 147 ( 2 . 1 1 ) , 133 ( 3 . 5 4 ) , 122 ( 3 8 . 7 ) , 94 .0 (100); Exac t mass c a l c d . f o r C 1 5 H 2 4 : 204.1878; found: 204.1878; A n a l , c a l c d . f o r C 1 5 H 2 4 : C 88 .16 , H 11.84; found: C 88 .19 , H 11 .91 . H v d r o x v - a c e t a t e (316) (139) (316) Sod ium b o r o h y d r i d e (0 .77 g , 20 mmol) was added to a s o l u t i o n of ammonium c h l o r i d e (5 .45 g , 101 mmol) i n 95% e t h a n o l (40 mL), f o l l o w e d by the a d d i t i o n of a s o l u t i o n of (+) -8-acetoxycamphor (139) (2 .0 g , 0.52 mmol) i n 95% e t h a n o l o (25 mL). The r e a c t i o n mixture was s t i r r e d at 0 C f o r 30 minutes and at room temperature f o r 15 h o u r s . I t was then c a r e f u l l y poured i n t o h y d r o c h l o r i c a c i d (1 .0 N) in a s e p a r a t o r y f u n n e l and e x t r a c t e d wi th e t h e r . The combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e and b r i n e , and d r i e d (MgSO^). Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , pe tro leum e t h e r : e t h e r , 5:1) to y i e l d pure h y d r o x y - a c e t a t e (316) (1 .7 g, 86%) as a c o l o r -l e s s o i l . R f 0.41 ( p e t . e t h e r : e t h e r , 1:1); ^ m a x ( f i l m ) : 3498, 195 2955, 1730 c m _ i ; & ( C D C 1 3 , 80 MHz): H - n . m . r . ass ignments of major d i a s t e r e o m e r : 0.95 ( s , 3H, CH3 ) , 1.00 ( s , 3H, CH3 ) , 2.10 ( s , 3H, C H 3 ) , 4 .05 ( d , 1H, RCROH, J=4 H z ) ; m/e ( r e l a t i v e i n t e n -s i t y ) : 212 (0 .000 , M + ) , 194 ( 0 . 0 8 0 ) , 152 ( 8 . 4 9 ) , 137 ( 6 . 0 0 ) , 123 ( 6 . 2 0 ) , 121 ( 7 . 5 9 ) , 108 (100); E x a c t mass c a l c d . f o r C 1 2 H 2 0 0 3 : 212.1412; found: (not o b s e r v e d ) ; A n a l . c a l c d . f o r C I 2 H 2 Q 0 3 : C 67 .89 , H 9.500; found: C 68 .10 , H 9 .430. A l k e n e - a c e t a t e (3171 H y d r o x y - a c e t a t e (316) (17 g , 80 mmol) was t r e a t e d wi th methanesulphony1 c h l o r i d e (26 g , 0.23 mmol) and 4 - d i m e t h y l a m i -n o p y r i d i n e (1 .0 g) i n d r y p y r i d i n e (100 mL) was r e f l u x e d under an argon atmosphere f o r 12 hours . A f t e r d i l u t i o n w i t h water (20 mL) and e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , s a t u r a t e d sodium b i -carbonate s o l u t i o n and b r i n e , and d r i e d (MgSO^). Removal of s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to g i v e a l k e n e - a c e t a t e (317) (9 .4 g , 60%) as a c o l o r l e s s o i l . R f 0.93 196 ( p e t . e t h e r r e t h e r , 1:1); ^ a x ( f i l m ) : 2981, 1744, 1664, 891 cm S (CDC13 , 270 MHz): 1.15 ( s , 3H, C H 3 ) , 2.06 ( s , 3H, C H 3 ) , 3 .75 , 3.92 (AB q u a r t e t , 2H, RCR 2 0Ac , J A B = 12 H z ) , 4.58 ( s , 1H, RC:CH.H), 4.82 ( s , 1H, RC:CHH_); m/e ( r e l a t i v e i n t e n s i t y ) : 194 ( 9 . 9 3 , M + ) , 152 ( 3 . 2 8 ) , 134 ( 2 9 . 1 ) , 121 ( 9 4 . 6 ) , 119 ( 1 4 . 4 ) , 106 ( 2 9 . 5 ) , 93.0 (100); E x a c t mass c a l c d . f o r C 1 2 H 1 8 0 2 : 194.1307; found: 194.1314; A n a l . c a l c d . f o r C 1 2 H 1 8 0 2 : C 74 .19 , H 9.340; found: C 74 .00 , H 9 .180. H v d r o x v - o l e f i n (318) ( 3 1 7> (318) o To a c o l d (0 C ) , s t i r r e d s o l u t i o n of l i t h i u m aluminum h y d r i d e (68 mg, 1.8 mmol) i n d r y t e t r a h y d r o f u r a n (5 .0 mL) under an argon atmosphere was added a s o l u t i o n of a l k e n e - a c e t a t e (317) (0 .35 g , 1.8 mmol) i n d r y t e t r a h y d r o f u r a n (5 .0 mL). S t i r r i n g was c o n t i n u e d f o r 3 hours and the r e a c t i o n mixture was worked up i n the u s u a l way. Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to g i v e h y d r o x y - o l e f i n (318) (0 .23 g , 84%) as a c o l o r l e s s o i l . R f 0.36 ( p e t . e t h e r : e t h e r , 1:1); \ a x ( f i l m ) : 3396, 2971, 197 1668, 890 cm ; S ( C D C 1 3 , 270 MHz): 1.12 ( s , 3H, C H 3 ) , 3.28 ( d d , 1H, RCHHOH, J=12 Hz , 4 .5 H z ) , 3.46 ( d d , 1H, RCHHOH, J=12 Hz, 7 .5 H z ) ; 4.52 ( s , 1H, RC:CHH), 4 .83 ( s , 1H, RC:CHH); m/e ( r e l a t i v e i n t e n s i t y ) : 152 ( 6 . 6 3 , M + ) , 134 ( 0 . 7 3 0 ) , 124 ( 2 3 . 4 ) , 121 ( 9 2 . 5 ) , 108 ( 4 . 3 2 ) , 105 ( 9 . 1 0 ) , 93 .0 (100); E x a c t mass c a l c d . f o r C 1 0 H 1 6 0 : 152.1201; found: 152.1204; A n a l , c a l c d . f o r C 1 Q H 1 6 0 : C 78 .90 , H 10.59; found: C 78 .77 , H 10.40. Alkene-aldehvde (312) P y r i d i n i u m ch lorochromate (3 .0 g , 14 mmol) was suspended in d r y methylene c h l o r i d e (15 mL), and a s o l u t i o n of hydroxy-o l e f i n (318) (0 .70 g , 4 .6 mmol) in d r y methylene c h l o r i d e (10 mL) was added r a p i d l y at room temperature . A f t e r 4 hours under an argon atmosphere the b l a c k r e a c t i o n mix ture was d i -l u t e d w i t h e ther and f i l t e r e d through a pad of s i l i c a g e l . Removal of s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to a f f o r d a l k e n e - a l d e h y d e (312) (0 .61 g , 88%) as a c o l o r l e s s o i l . R f 0.89 ( p e t . e t h e r : e t h e r , 1:1); Vmayi ( f i l m ) : 2995, 2850, 198 2749, 1736, 1666, 896 c m - 1 ; $ ( C D C 1 3 , 270 MHz): 1.14 ( s , 3H, C H 3 ) , 4 .58 ( s , 1H, RC:CRH), 4 .98 ( s , 1H, RC:CHR), 9.33 ( s , 1H, RCH.0); m/e ( r e l a t i v e i n t e n s i t y ) : 150 ( 4 . 1 8 , M + ) , 121 ( 5 8 . 9 ) , 105 ( 1 7 . 5 ) , 93.0 (100); Exac t mass c a l c d . f o r C 1 0 H 1 4 0 : 150.1045: found: 150.1044. H v d r o x v - e s t e r s (319) n - B u t y 1 1 i t h i u m (1 .6 M; hexane) (3 .0 mL, 4 .6 mmol) was a d -ded to a s t i r r e d s o l u t i o n of d i i s o p r o p y l a m i n e (0 .47 g , 4 .6 mmol) in dry t e t r a h y d r o f u r a n (10 mL) under an argon atmosphere at 0 ° C and s t i r r e d f o r 30 minutes . Methy l a c e t a t e (313) (0 .31 g , 4.2 mmol) i n d r y t e t r a h y d r o f u r a n (5 .0 mL) was added to t h i s coo led s o l u t i o n at - 7 8 ° C . S t i r r i n g was c o n t i n u e d f o r 2 hours b e f o r e a l -kene-a ldehyde (312) (0 .57 g , 3 .8 mmol) was i n t r o d u c e d at - 7 8 ° C . The r e a c t i o n mix ture was s t i r r e d f o r 5 minutes , worked up by adding water (5 .0 mL) and e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d ammonium c h l o r i d e s o l u t i o n and b r i n e , and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t under vacuo and subsequent column chromatography ( s i l i c a g e l , p e t . 199 e t h e r : e t h e r , 15:1) a f f o r d e d a mixture of h y d r o x y - e s t e r s (319) (0 .72 g , 93%) as a c o l o r l e s s o i l . The r a t i o of the e p i m e r i c h y d r o x y - e s t e r s was determined by ^ H - n . m . r . i n t e g r a t i o n to be about 1:1. R f 0 .17 ( p e t . e t h e r : e t h e r , 1:1); ^ m a x ( f i l m ) : 3541, 2981, 1733, 1651, 889 c m " 1 : 8 (CDCI3, 400 MHz): 1 H - n . m . r . of one of the d i a s t e r e o m e r s : 1.03 ( s , 3H, C H 3 ) , 3.71 ( s , 3H, CH3), 3.96 ( d d , 1H, RCfcLOH, J=10 Hz , 4 H z ) , 4 .70 ( s , 1H, RC:CHH), 4 .89 ( s , 1H, RC:CHK); m/e ( r e l a t i v e i n t e n s i t y ) : 224 (0 .000 , M + ) , 206 ( 7 . 5 8 ) , 178 ( 7 . 8 8 ) , 167 ( 1 . 9 3 ) , 149 ( 6 . 5 7 ) , 121 ( 1 8 . 6 ) , 105 ( 1 4 . 1 ) , 103 ( 4 7 . 4 ) , 94 .0 (100); Exac t mass c a l c d . f o r C 1 3 H 2 0 O 3 : 224.1412; found: 206.1312; Anjal. c a l c d . f o r C 1 3 H 2 Q 0 3 : c 69 .61 , H 8.990; found: C 69 .65 , H 9 .100. D i o l s (320) (319) (320) To a c o l d (0 C ) , s t i r r e d s o l u t i o n of l i t h i u m aluminum h y d r i d e (64 mg, 1.7 mmol) i n d r y t e t r a h y d r o f u r a n ( 5 . 0 mL) u n -der an argon atmosphere was added a s o l u t i o n of a mix ture of hy-o x y - e s t e r s (319) (0 .19 g , 0.85 mmol) i n d r y t e t r a h y d r o f u r a n (5 mL). S t i r r i n g was c o n t i n u e d f o r 4 hours and the r e a c t i o n mixture 200 was worked up in the u s u a l way. Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 4:1) to g i v e d i o l s (320) (0 .15 g , 89%) as a c o l o r l e s s o i l . Rf 0.37 ( p e t . e t h e r : e t h e r , 9 : l ) ; 1 > n i a x ( f i lm) ' -3350, 2955, 1645, 870 c m - 1 ; 6 ( C D C 1 3 , 400 MHz): : H - n . m . r . of one of the d i a s t e r e o m e r s : 1.05 ( s , 3H, C H 3 ) , 3.64 ( d d , 1H, RCH.0H, J=4 Hz , 8.5 H z ) , 3 . 7 9 - 3 . 8 9 (m, 2H, RCH. 2 0H), 4 .63 ( s , 1H, RC:CH_H), 4 .93 ( s , 1H, RC:CHHJ; m/e ( r e l a t i v e i n t e n s i t y ) : 196 ( 0 . 3 0 , M + ) , 178 ( 2 . 8 3 ) , 168 ( 1 . 2 3 ) , 160 ( 0 . 2 8 0 ) , 133 ( 2 . 6 2 ) , 122 ( 2 7 . 9 ) , 105 ( 1 1 . 7 ) , 94.0 (.100); Exact mass c a l c d . f o r C 1 2 H 2 0 0 2 : 196.1463; found: 196.1459; A n a l , c a l c d . f o r C 1 2 H 2 0 0 2 : C 73 .43 , H 10.27; found: C 73 .20 , H 10.16. S i l v l e t h e r s (321) Dry t e r t - b u t y l d i p h e n y l s i l y l c h l o r i d e (0 .94 mL, 3 .6 mmol) was added to a s t i r r i n g mixture of d i o l s (320) (0 .65 g , 3 .3 mmol) and i m i d a z o l e (0 .49 g , 7 .3 mmol) i n d r y dimethyIformamide (5 .0 mL) at 2 5 ° C under an argon atmosphere. S t i r r i n g was c o n t i -nued f o r 2 hours b e f o r e water (10 mL) was added and the r e a c t i o n 201 mixture was e x t r a c t e d wi th e ther and the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , b r i n e , and d r i e d (Mg-SO4). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to g i v e s i l y l e t h e r s (321) (1 .4 g , 99%). R f 0.77 ( p e t . e t h e r : e t h e r , 1:1) ; " V m a x . ( f i l m ) : 3450, 3070, 2950, 1652, 1598, 896 c m - 1 ; & (CDCI3, 400 MHz): ^ - n . m . r . of one of the d i a s t e r e -omers: 1.09 ( s , 9H, ^ u ) , 3.71 ( d , b r o a d , 1H, RCH.0H, J = 10 H z ) , 3 .80-3 .94 (m, 2H, R C R 2 0 S i ) , 4 .68 ( s , 1H, RC:CRH), 4 .92 ( s , 1H, RC:CHH_), 7 . 34 -7 .47 (m, 5H, R C 6 R 5 ) , 7 .65-7 .74 (m, 5H, RC 6 H_ 5 ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 434 (0 .000 , M + ) , 377 ( 2 3 . 7 ) , 360 ( 4 . 6 8 ) , 313 ( 6 . 2 7 ) , 289 ( 2 8 . 1 ) , 255 (100); Exac t mass c a l c d . f o r C 28^ 38^ 2 ^ i : 434.2641; found: (not o b s e r v e d ) ; A n a l . c a l c d . f o r C 2 8 H 3 8 ° 2 S i : C 77 .37 , H 8.810; found: C 77 .14 , H 8 .930. 202 S i l v l ether esters (322) Dry a c e t i c anhydr ide (0 .59 mL, 5.9 mmol) was added to a s t i r r e d s o l u t i o n of s i l y l e t h e r s (321) (0 .85 g , 2.0 mmol) and 4 - d i m e t h y l a m i n o p y r i d i n e (0 .12 g , 0.98 mmol) i n d r y p y r i d i n e (15 mL) at 2 5 ° C under an argon atmosphere. S t i r r i n g was c o n -t i n u e d f o r 2 .5 hours b e f o r e water (15 mL) was added. The r e a c -t i o n mix ture was e x t r a c t e d wi th e t h e r , and the combined o r g a n i c l a y e r was washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d (MgS04). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by a column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 15:1) to o b t a i n s i l y l e ther e s t e r s (322) (0 .87 g , 93%) as a c o l o r l e s s o i l . R f 0.67 ( p e t . e t h e r : e t h e r , 9 :1 ) ; 1/ v ( f i l m ) : 3078, 2966, 1736, 1651, 1591, 891 c m - 1 ; III ci X S ( C D C 1 3 , 400 MHz); 1 H - n . m . r . o f one of the d i a s t e r e o m e r s : 1.06, ( s , 3H, C H 3 ) , 1.94 ( s , 3H, C H 3 ) , 3 . 5 8 - 3 . 6 7 (m, 2H, R C K . 2 0 S i ) , 4 .49 ( s , 1H, RC:CHH), 4 .77 ( s , 1H, R C : C H E ) , 5 . 10 -5 .19 (m, 1H, RCROAc), 7 . 3 4 - 7 . 4 6 , 7 .64 -7 .76 (m, m, 5H, 5H, R O - S K C g H ^ ) 2 t Bu) ; m/e ( r e l a t i v e i n t e n s i t y ) : 476 ( 0 . 0 0 , M + ) , 419 ( 2 . 9 2 ) , 360 ( 3 . 0 7 ) , 359 ( 9 . 9 0 ) , 289 ( 4 4 . 1 ) , 259 ( 2 0 . 2 ) , 241 ( 2 1 . 7 ) , 211 203 ( 2 2 . 2 ) , 199 ( 8 5 . 2 ) , 183 ( 3 4 . 7 ) , 167 ( 1 7 . 9 ) , 161 (100); H v r i r Q x v - a c e t a t s s (323 r 324) n-Tetrabutylamraonium f l u o r i d e (17 .6 mL, 1.0 M s o l u t i o n in t e t r a h y d r o f u r a n ) was added to s i l y l e ther e s t e r s (322) o 0.84 g , 1.7 mmol) at 25 C under an argon atmosphere. S t i r r i n g was c o n t i n u e d f o r 3 hours be fore water (10 mL) was added. The r e a c t i o n mix ture was e x t r a c t e d w i t h e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and d r i e d ( M g S O ^ . Upon removal of s o l v e n t under vacuo , the crude product was p u r i f i e d by column chroma-tography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to p r o v i d e a mix-t u r e of h y d r o x y - a c e t a t e s (324) (0 .21 g , 52%) and hydroxy-a c e t a t e s (323) (0 .12 g , 30%) as c o l o r l e s s o i l s (324) R f 0.32 ( p e t . e t h e r : e t h e r , 1:1); V ( f i l m ) : 3460, 2974, 1740, 1660, 204 899 c m - 1 ; £ (CDCI3, 400 MHz): 1 H - n . m . r . of one of the d i a s t e r -eomers: 1.01 (s, 3H, C H 3 ) , 2.06 ( s , 3H, C H 3 ) , 3.61 ( d , 1H, RCH_-0H, J = 12 H z ) , 4 .25 ( d d , 2H, RCH. 20Ac, J = 8 Hz, 4 H z ) , 4 .57 (s, 1H, RC:CHH), 4 .96 ( s , 1H, RC:CHH_); m/e ( r e l a t i v e i n t e n s i t y ) : 238 ( 0 . 0 0 , M + ) , 220 ( 0 . 2 0 0 ) , 178 ( 0 . 8 0 0 ) , 151 ( 0 . 9 0 0 ) , 136 ( 2 . 1 0 ) , 122 ( 1 7 . 2 ) , 117 ( 2 2 . 5 ) , 105 ( 7 . 0 0 ) , 99.0 ( 1 2 . 4 ) , 94 .0 (100); (323) R f 0.13 ( p e t . e t h e r : e t h e r , 1:1); V m a x ( f i l m ) : 3445, 2951, 1728, 1655, 890 c m " 1 ; & (CDCI3, 400 MHz): 1 H - n . m . r . of one of the d i a s t e r e o m e r s : 1.11 ( s , 3H, CH3 ) , 2 .09 ( s , 3H, C H 3 ) , 3 . 40 -3 .49 , 3 .59 -3 .69 (m, m, 1H, 1H, RCH_20H), 4 .56 ( s , 1H, RC:CHJ1), 5.00 ( s , 1H, RC:CHH.), 5.10 (dd , 1H, RCH-OAc, J = 12 Hz , 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 238 (0 .100 , M + ) , 220 ( 0 . 1 0 0 ) , 205 ( 0 . 2 0 0 ) , 178 ( 1 3 . 8 ) , 164 ( 6 . 1 0 ) , 136 ( 5 0 . 5 ) , 133 ( 1 5 . 7 ) , 121 ( 2 6 . 5 ) , 105 ( 1 2 . 6 ) , 93.0 ( 8 9 . 1 ) ; Exac t mass c a l c d . f o r C 1 4 H 2 2 0 3 : 238.1569; found: 238.1550. M e t h o x v l - s i l v l e t h e r s (325) At 0 C , a s o l u t i o n of h y d r o x y - s i l y 1 e t h e r s (321) (0 .68 g , 1.6 mmol) in d r y t e t r a h y d r o f u r a n (10 mL) under an argon atmosph-205 ere was added to a suspens ion of sodium h y d r i d e (38 mg, 1.6 mmol ) i n d r y t e t r a h y d r o f u r a n (10 mL) f o l l o w e d by methyl i o d i d e (0 .22 g, 1.6 mmol). The r e s u l t i n g r e a c t i o n mixture was then r e f l u x e d f o r 12 hours b e f o r e water (10 mL) was c a r e f u l l y added. E x t r a c -t i o n w i t h e ther was f o l l o w e d by washing w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d (MgS04). Upon removal of s o l v e n t the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) and p r o v i d e d m e t h o x y l - s i l y l e t h e r s (325) (0 .68 g , 96%) as a c o l o r l e s s o i l ; ^ m a x ( f i l m ) : 3155, 2950, 1650, 1590, 890 c m - 1 ; $ ( C D C 1 3 , 400 MHz): 1 H - n . m . r . of one of the d i a s t e r e o m e r s : 1.06 ( s , 3H, C H 3 ) , 3.36 ( s , 3H, C H 3 ) , 3 .30 -3.43 (m, 1H, RCHOMe), 3 .89 -4 .07 (m, 2H, RCH. 2 0S i ) , 4 .82 ( s , 1H, RC:CB_H), 4.84 ( s , 1H, RC:CHH), 7 . 4 0 - 7 . 5 2 , 4 . 7 0 - 4 . 7 9 (m, m, 5H, 5H, R 0 S i ( C 6 H 5 ) 2 t B u ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 448 (0 .000 , M + ) , 416 ( 0 . 3 0 0 ) , 391 ( 2 . 5 0 ) , 359 ( 2 9 . 0 ) , 269 ( 5 . 5 0 ) , 255 ( 7 . 7 0 ) , 225 ( 1 8 . 9 ) , 213 ( 4 6 . 7 ) , 197 ( 2 7 . 5 ) , 183 ( 6 2 . 3 ) , 165 ( 1 5 . 7 ) , 161 ( 5 8 . 1 ) , 135 ( 7 8 . 3 ) , 119 ( 3 8 . 4 ) , 105 ( 9 3 . 0 ) ; Exac t mass c a l c d . f o r C 2 g H 4 o 0 2 S i : 448.2797; found: (not o b s e r v e d ) ; A n a l , c a l c d . f o r C 2 g H 4 o 0 2 S i : C 77 .62 , H 8.990; found: C 77 .88 , H 8 .900. 206 M e t h y l e t h e r a l c o h o l s (326) n-Tetrabutylammonium f l u o r i d e (5 .7 mL, 1.0 M s o l u t i o n in t e t r a h y d r o f u r a n ) was added to m e t h o x y l - s i l y l e t h e r s (325) (0.64 g , 1.4 mmol) at 2 5 ° C under an argon atmosphere. S t i r -r i n g was c o n t i n u e d f o r 1.5 hours be fore water (10 mL) was added. The r e a c t i o n mix ture was e x t r a c t e d w i t h e ther and the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i -carbonate s o l u t i o n and b r i n e , and d r i e d (MgS04). Upon removal of s o l v e n t under vacuo , the crude product was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to a f f o r d methyl e ther a l c o h o l s (326) (0 .24 g , 93%: based on r e -covered s t a r t i n g m a t e r i a l ) . R f 0.15 ( p e t . e t h e r : e t h e r , 3 :2 ) ; Vmax ( f i l m ) : 3368, 2950, 1643, 888 c m " 1 ; 8 ( C D C 1 3 , 400 MHz): 1 H - n . m . r . of one of the d i a s t e r e o m e r s : 1.07 ( s , 3H, C H 3 ) , 3.22 ( d d , 1H, RCHOMe, J=10 Hz , 3 H z ) , 3 .41 ( s , 3H, C H 3 ) , 3 . 70 -3 .89 (m, 2H, RCHHOH), 4 .81 ( s , 1H, RC:CHH). 4.84 ( s , 1H, RC:CHR); m/e ( r e l a t i v e i n t e n s i t y ) : 180 ( 1 . 4 0 ) , 179 ( 0 . 7 0 0 ) , 178 ( 7 . 0 0 ) , 93.0 ( 1 8 . 2 ) , 92 .0 ( 2 3 . 0 ) , 89.0 (100); Exact mass c a l c d . f o r C 1 3 H 2 2 ° 2 : 210.1619; found: (not o b s e r v e d ) ; A n a l . c a l c d . f o r C 1 3 H 2 2 ° 2 : c 74 .24 , H 10.54; found: C 74 .33 , H 10 .69 . 207 R r n m o - o l e f i n (260) Bromine (0 .30 mL) was added dropwise to a s o l u t i o n of t r i p h e n y l p h o s p h i n e (0 .15 g , 0.57 mmol) i n dry methylene c h l o r -o ide (7 .0 mL) at 0 C under an argon atmosphere. To t h i s p a l e y e l l o w i s h r e a c t i o n mix ture was then added a s o l u t i o n of methyl e t h -er a l c o h o l s (326) (90 mg, 0.38 mmol) i n d r y methylene c h l o r i d e ( 5.0 mL) and s t i r r i n g was c o n t i n u e d f o r 15 minutes . A f t e r removal of s o l v e n t , the r e a c t i o n mixture was e x t r a c t e d w i t h p e t . e ther and the combined o r g a n i c l a y e r s were then washed w i t h sodium b i s u l f i t e s o l u t i o n and b r i n e , and d r i e d (MgSO,^). Upon removal of s o l v e n t the crude p r o d u c t was p u r i f i e d by column chromato-graphy ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) to a f f o r d bromo-o l e f i n (260) (0 .22 g , 95%: based upon 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 c o l o r l e s s o i l . R f 0.91 ( p e t . e t h e r : e t h e r , 1:1); Vmax ( f i l m ) : 2950, 1655, 900 c m " 1 ; J ( C D C 1 3 , 400 MHz): n . m . r . of one of the d i a s t e r e o m e r s : 1.04 ( s , 3H, CH3 ) , 3.24 ( d d , 1H, RCfcLOMe, J=5 Hz , 7 H z ) , 3.44 ( s , 3H, CH ) , 3 . 4 5 - 3 . 6 5 (m, 2H, R C E 2 B r ) , 4 .80 ( s , 1H, RC:CHH), 4 .85 ( s , 1H, RC:CHR); m/e ( r e l a t i v e i n t e n s i t y ) : 272/274 ( 1 . 5 0 / 1 . 3 0 , M + / M + + 2 ) , 246 ( 6 . 2 0 ) , 244 ( 7 . 4 0 ) , 193 ( 0 . 7 0 ) , 153 ( 9 4 . 3 ) , 151 (100); E_x_ac_t 208 mass, c a l c d . f o r C 1 3 H 2 1 O B r , 274.0755/272.0775; found: 274.0752/ 272.0775; A n a l , c a l c d . f o r C 1 3 H 2 1 0 B r : C 57 .15 , H 7 .750, Br 29 .25; found: C 57 .22 , H 7 .740, Br 29 .10 . Methvl ether (331) A mix ture of b r o m o - o l e f i n (260) (0 .12 g , 0.44 mmol, 0.05 M) a z o b i s - ( i s o b u t y r o n i t r i l e ) (0 .02 mmol, 0.05 M), and t r i b u t y l -t i n h y d r i d e (0 .14 mL, 0.53 mmol, 0.05 M) as a benzene s o l u t i o n of a p p r o p r i a t e m o l a r i t y was r e f l u x e d under an argon atmosphere f o r 3 hours . Work-up was c a r r i e d out by removal of benzene and the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 10:1) a f f o r d e d methyl e ther ( 3 3 1 ) (35 .6 mg, 53%: based on 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 ) . R f 0.89 ( p e t . e t h e r : e t h e r , 10:1) ; Vmax ( f i l m ) : 2936, 1382, 1102 c m " 1 ; £ ( C D C 1 3 , 400 MHz): 1 H - n . m . r . of one of the d i a s t e r e o m e r s : 0.92 ( s , 3H, C H 3 ) , 2 .93 ( t , 1H, RCROMe, J=4 H z ) , 3 .29 ( s , 3H, C H 3 ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 194 ( 1 8 . 0 , M + ) , 179 ( 5 . 6 0 ) , 209 166 (18.6), 165 (5.30), 162 (10.6), 134 (100); Exac t mass c a l c d . f o r C,nH„0: 194.1670; found: 194.1667. 210 C h a p t e r 3 A S y n t h e t i c Approach to the A,B Ring Systen of Terpenoids 211 3 . 1 . 0 . INTRODUCTION While s e v e r a l r e s e a r c h groups have r e p o r t e d s y n t h e t i c approaches to the A , B s t r u c t u r a l sub-u n i t (322) [110] of some s p e c i f i c t e r p e n o i d s , a g e n e r a l e n a n t i o s p e c i f i c s y n t h e t i c route has not ye t been r e p o r t e d . (322 ) A g e n e r a l s y n t h e t i c r o u t e to t e r p e n o i d s c o n t a i n i n g t h i s A , B s t r u c t u r a l s u b - u n i t (322) must have the p o t e n t i a l to produce compounds i n which the R i and R2 groups c o u l d be e l a b o r a t e d to the remainder of a s p e c i f i c t e r p e n o i d . In a d d i t i o n , a g e n e r a l s y n t h e t i c r o u t e should be capab le of p r o d u c i n g compounds w i t h oxygen f u n c t i o n a l i t y at the C ( l ) , C(3 ) and (7) p o s i t i o n s . T h i s chapter d e s c r i b e s an e v a l u -a t i o n of the p o t e n t i a l use of (+) -5 ,6 -dehydrocamphor (323) as a c h i r a l synthon i n the e n a n t i o s p e c i f i c s y n t h e s i s o f s e l e c t e d s e s q u i t e r p e n o i d s , d i t e r p e n o i d s , s e s t e r t e r p e n o i d s , and t r i t e r p e n o i d s (Scheme 96) . The b a s i c f e a t u r e of our g e n e r a l s y n t h e t i c approach i s the i n i t i a l c o n v e r s i o n of (+) -5 ,6 -dehydrocamphor (323) to v a r i o u s t e r t i a r y a l c o h o l s (325) by treatment w i t h 212 S e s q u i t e r p e n o i d s OAc P o l y q o d i a l W a r b u r q a n a l C i n n a m o d i a l N o r d r i m e n o n e D r i m e n o l D i t e r p e n o i d s C a s s a i c a c i d M a n o o l OH F o r s k o l i n S e s t e r t e r p e n o i d Scheme 96 213 a p p r o p r i a t e a l k e n y l G r i g n a r d reagents (324) . The a l k o x i d e s (326) d e r i v e d from these t e r t i a r y a l c o h o l s (325) would be exp-ec ted to undergo a n i o n i c oxy-Cope rearrangement , the p r o d u c t s of which c o u l d be subsequent ly t rans formed to the conjugated enones (328) . F i n a l l y , s t e r e o s e l e c t i v e i n t r o d u c t i o n of an angu lar methyl group at the C(10) p o s i t i o n c o u l d p r o v i d e (329) (Scheme 97) which c o u l d then serve as a key i n t e r m e d i a t e i n the s y n t h e s i s of s p e c i f i c compounds b e l o n g i n g to the v a r i o u s c l a s s e s of t e r p e n o i d s shown above ( c f . Scheme 96) . The s y n t h e s i s of a l k e n y l h a l i d e s and a l k e n y l G r i g n a r d reagent s has r e c e i v e d c o n s i d e r a b l e a t t e n t i o n and a v a r i e t y of these compounds (Scheme 98) [111] c o u l d be used s y n t h e t i c a l l y to g a i n access to a v a r i e t y of i n t e r m e d i a t e s , r e p r e s e n t e d by s t r u c t u r e (329) . 214 Scheme 97 215 (335) Scheme 98 216 3 . 2 . 0 . DISCUSSION AMD RESULTS The a n i o n i c oxy-Cope rearrangement has become f i r m l y e s t a b l i s h e d [112] as an important r e a c t i o n i n s y n t h e t i c meth-odo logy . A l k o x i d e s d e r i v e d from norbonenone d e r i v a t i v e s (336), (338), (340), and (342) undergo t h i s rearrangement and p r o v i d e compounds (337) [113] , (339) [114] , (341) [115] , and (343) [116] which have been used as key i n t e r m e d i a t e s i n n a t u r a l p r o d u c t s y n t h e s i s (Scheme 99 ) . The development i n our l a b o -r a t o r y of a s imple s y n t h e s i s of e i t h e r ( - ) or ( + ) - 5 , 6 -dehydrocamphor (323) l ed us to c o n s i d e r t h a t a n i o n i c oxy-Cope rearrangement of a l k o x i d e s d e r i v e d from t h i s compound would p r o v i d e b i c y c l i c ketone (327) ( c f . Scheme 97) , which c o u l d s erve as a c h i r a l i n t e r m e d i a t e i n a g e n e r a l e n a n t i o s p e c i f i c s y n t h e t i c approach to a wide v a r i e t y of t e r p e n o i d s . L i t e r a t u r e route s to 5 ,6-dehydrocamphor i n v o l v e f i v e to n i n e s t eps [117] , and t h e r e f o r e we d e v i s e d an a l t e r n a t i v e two s tep procedure [21] which i n v o l v e s a c i d - c a t a l y s e d rearrangement of ( +)-anjio_-3-bromocamphor (41) to ( - ) -endo-6-bromocamphor (40), f o l l o w e d by d e h y d r o h a l o g e n a t i o n . The remarkable rearrangement of ( + )-fijidji-3-bromocamphor (41) to ( - ) - e n j ± o _ - 6 - b r o m o c a m p h o r (40) i s based on an e a r l i e r r e p o r t by Nish ikawa and co -workers [118] who d e s c r i b e d the rearrangement of (+) -3 ,9-d ibromocamphor (344) to ( - ) - 6 , 9 - d i b r o m o c a m p h o r (345), but noted t h a t the c o r r e s p o n d i n g r e a c t i o n w i t h (+) -3-endja.-brocamphor (41) i n fuming s u l f u r i c a c i d r e s u l t e d o n l y in C ( 9 ) - s u l f o n a t i o n (Scheme 100). In c o n t r a s t , we d i s c o v e r e d t h a t 217 (342) (343) Scheme 99 218 Scheme 100 treatment of ( + )-£DjiQ.-3-bromocamphor ( 4 1 ) w i t h c h l o r o s u l f o n i c a c i d f o r 15 minutes at 2 0 ° C p r o v i d e d (- )-ejado_-6-bromocamphor ( 4 0 ) i n about 50% y i e l d (Scheme 101). I t seems r e a s o n a b l e to assume t h a t the mechanism of t h i s remarkable rearrangement (Scheme 102), which c o n v e r t s ( +)-ejnjio_-3-bromocamphor ( 4 1 ) to (-)-enjio_-6-bromocamphor ( 4 0 ) or ( + ) -and j i - 3 , 9 - d i b r o m o c a m p h o r ( 3 4 4 ) to ( - ) - e n d o - 6 f 9-dibromocamphor ( 3 4 5 ) i s analogous to t h a t proposed f o r the a c i d - c a t a l y s e d r a c e m i s a t i o n of (+)-camphor ( 2 6 ) ( c f . Scheme 102). Support f o r t h i s view i s p r o v -ided by our o b s e r v a t i o n t h a t ( + )-ej id_Q.-3-bromo-10-deuterio-2 camphor ( 3 4 6 ; *= H , Scheme 106) r e a r r a n g e s to ( - )-enjio_-bromo-2 8 -deuter iocamphor ( 3 4 7 ; *= H, Scheme 102). The s t r u c t u r e of 219 0 ( i ) 0 Br (4i) Br (40) ( 323) • H 0 2 C / (360) R e a g e n t s and c o n d i t i o n s : ( i ) HS0,C1; ( i i ) KOH, DMSO, H»0, 100°C. Scheme 101 1 t h i s l a t t e r compound (347) was conf irmed by H - n . m . r . (400 MHz), and by i t s c o n v e r s i o n to ( - ) - 8 - d e u t e r i o c a m p h o r (348, * = 2 H , Scheme 102) [ 2 1 , 1 1 9 ] . Dehydrobrominat ion of ( - )-endji-6-bromocamphor (40) w i t h potass ium h y d r o x i d e / d i m e t h y l s u l f o x i d e / w a t e r p r o v i d e d (+) -5 ,6 -dehydrocamphor (323) , and t h e r e f o r e an o p p o r t u n i t y to p r e p a r e a s e r i e s of c h i r a l a l k o x i d e s which c o u l d undergo the a n i o n i c oxy-Cope rearrangement . ct -Campholenic a c i d (360) was a l s o produced i n t h i s r e a c t i o n , by c l eavage of the /3-bromo-ketone f u n c t i o n a l i t y i n (-)-end_o_-6-bromocamphor (40). In our i n i t i a l i n v e s t i g a t i o n we d i s c o v e r e d t h a t , i n c o n -t r a s t w i t h (+)-camphor (26) [120] , a d d i t i o n of v inylmagnes ium bromide to (+) -5 ,6-dehydrocamphor (323) occurs i n e x c e l l e n t y i e l d (99%) to p r o v i d e 2 - v i n y 1 - 5 , 6 - d e h y d r o i s o b o r n e o l (361) 220 WM X=Y=H ( 2 6 ) X=Br, Y=H ( 3 4 6 ) X=Y=Br ( 3 4 9 ) WM X=Y=H ( 3 4 8 ) X=Br, Y=H ( 3 4 7 ) X=Y=Br ( 3 5 0 ) Y * 2,3-Me 2,3-Me Scheme 102 (323 ) 0 ( i ) R=H (361) R= e (370) R=H (362) R=Me (371) R 1=H,R 2=OH,R=H(365a) R 1=OH,R 2=H,R=H(365b) R 1=OH,R 2=H,R=Me(374b) R 1=H,R 2=OH,R=Me(374a) R=H (364) R=Me ( 3 7 3 a , b ) R=H (363) R=Me (372) R1=H,R 2=OAc,R=H R 1=OAc,R 2=H,R=H R 1=H,R 2=OAc,R=H (3 6 8 a ) (366b) R 1=OAc,R 2=H,R=H (36 8 b ) R 1=H,R 2=OMe,R= Me (375a)R 1=OMe,R 2=H,R=Me (376b) R^=OMeTR 2=H,R=Me (375b)^ l=H,R 2=OMe,R=Me ( 3 7 6 a ) R 1=H,R 2=0Me,R=H ( 3 6 7 a ) Rj=H,R 2=0Me,R=H " N'~ v R =OMe,R =H,R=H (36 7 b ) R,=0Me,R„=H,R=H 1 ( 3 6 9 a ) (369b) R e a g e n t s and c o n d i t i o n s ( i ) V i n y l M a g n e s i u m Bromide,* THF, ( o r 2 - B r o m o - p r o p e n y l -M agnesium B r o m i d e , T H F ) ; ( i i ) KH, THF; ( i i i ) LAH, THF, ( o r L - S e l e c t r i d e , THF, -78°C); ( i v ) A c ^ , ( o r KH, M e l , T H F ) ; ( v ) 0 3 , C H ^ l ^ C H ^ H ; PhH, p - T o l u e n e s u l f o n i c a c i d . 4-DMAP, P y r i d i n e , ( v i ) P P h 3 ; ( v i i ) Scheme 103 222 (Scheme 103). Treatment of (361) w i t h potass ium h y d r i d e [130] i n t e t r a h y d r o f u r a n at room temperature f o r about 10 minutes promoted the a n i o n i c oxy-Cope rearrangement of a l k o x i d e (362) and l e d to the f o r m a t i o n of c i s - b i c y c l i c ketone (364) i n about 95% y i e l d . S t e r e o s e l e c t i v e r e d u c t i o n of (364) w i t h L - s e l e c t r i d e i n t e t r a h y d r o f u r a n at - 7 8 ° C a f f o r d e d a mix ture of e p i m e r i c a l c o h o l s (365a:365b; r a t i o 6:1) (page 285 ) which were then t r e a t e d w i t h a c e t i c anhydr ide and d i m e t h y l a m i n o p y r i d i n e [121] i n p y r i d i n e to p r o v i d e the c o r r e s p o n d i n g a c e t a t e s (366a: 366b; r a t i o 6:1) ( c f . page 2 8 6 ) . The s t e r e o c h e m i s t r y of the a c e t a t e groups i n (366a ,b) was deduced from the s p l i t t i n g p a t -t e r n of the s i g n a l ( 1 H - n l m . r . ) a s s o c i a t e d w i t h the CHOAc group in each compound (page 2 8 6 ) . The s t e r e o s e l e c t i v i t y of the r e d u c t i o n l e a d i n g to e p i m e r i c a l c o h o l s ( 3 6 5 a ,b) i s governed by the f a c t tha t a d d i t i o n of L - s e l e c t r i d e to the c a r b o n y l group i s s t e r i c a l l y h i n d e r e d by oC-axial hydrogen atoms. In c o n t r a s t , a d d i t i o n of a l e s s b u l k y h y d r i d e r e d u c i n g agent ( l i t h i u m aluminum h y d r i d e ) , o c c u r s w i t h the o p p o s i t e s t e r e o s e l e c t i v i t y to p r o v i d e (365a:365b; r a t i o 1:3) . In t h i s case the s t e r i c f a c t o r i s l e s s important and a d d i t i o n i s presumably governed by t o r s i o n a l s t r a i n (Scheme 104). O z o n o l y s i s of ( 3 6 6 a , b) i n methanol and methylene c h l o r i d e ( 1 : 1 ) , f o l l o w e d by r e d u c t i v e work-up w i t h t r i p h e n y l p h o s p h i n e [28] p r o v i d e d crude k e t o - a l d e h y d e s ( 3 7 7 a , b) which were then t r e a t e d w i t h a c a t a l y t i c amount of p - t o l u e n e s u I f o n i c a c i d i n r e f l u x i n g benzene to p r o v i d e b i c y c l i c enones ( 3 6 8 a , b) i n 223 OH Scheme 104 224 1*2= OMe, R.j=H, R=H, (37&a) R 2 = H , R^OMe, R=H, (378b) R^OMe, R^  = H , R=Me, (379a) R2= H , R<| =OMe, R=Me, ( 379b) R2=OAc, R^H, R=H, (377a) R2=H, R.,=OAc, R=H, (377b) about 60% ov e r a l l y i e l d from (366a,b). When ( +)-5,6-dehydrocamphor (323) was treated with 2-propenylmagnesium bromide in refluxing tetrahydrofuran for 2.5 hours, anionic oxy-Cope rearrangement occurred in s i t u and diastereomeric b i c y c l i c ketones (373a,b) were obta-ined d i r e c t l y in about 80% y i e l d . At room temperature, how-ever, the product (ca. 80% y i e l d ) was a mixture ( r a t i o ca. 2:1) of b i c y c l i c ketones (373a,b) and the expected t e r t i a r y alcohol (370). Treatment of compound (370) with potassium hy-o dride in tetrahydrofuran at 20 C for f i v e minutes provided the b i c y c l i c ketones (373a,b) ( r a t i o ca. 2:1) in about 90% y i e l d . Although the stereochemistry of the methyl group at C(8) i s not unique, our synthetic plan envisages subsequent control at t h i s center ( c f . page 240). Hydride reduction of (373a,b) followed by treatment with potassium hydride and methyl iodide in tetrahydrofuran provided (375a,b). Subsequent 225 c o n v e r s i o n of (375a ,b) to b i c y c l i c enones (376a ,b) was accompl i shed by r i n g c l eavage and 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 as d e s c r i b e d above (Scheme 103). The s t e r e o c h e m i s t r y at C(10) i n b i c y c l i c enones (368a ,b) and ( 3 7 6 a , b ) , and (369a ,b) was not e s t a b l i s h e d at t h i s s tage of our s y n t h e t i c r o u t e , and at tempts to p r e p a r e a s u i t a b l e c r y s t a -l l i n e d e r i v a t i v e of e i t h e r compound (381) [122] or (383) ( S c h -eme 105) f o r x - r a y a n a l y s i s are c o n t i n u i n g i n the l a b o r a t o r y . Reagents and c o n d i t i o n s : 2 , 4 - D i n i t r o p h e n y l h y d r a z i n e , E t h a n o l . Scheme 105 I n d i r e c t ev idence has been o b t a i n e d (page 235) to suppor t the t r a n s s t e r e o c h e m i s t r y at the r i n g j u n c t i o n i n enones ( 3 6 8 a , b ) , ( 3 6 9 a , b ) , and ( 3 7 6 a , b ) . 226 With the enones a v a i l a b l e , both a c y c l o p r o p a n a t i o n approach and an a n i o n i c oxy-Cope rearrangement approach were c a r r i e d out i n the attempt to i n t r o d u c e the r e q u i r e d angu lar methyl group at the C(10) p o s i t i o n of the A , B s t r -u c t u r a l s u b - u n i t (322). 227 The next o b j e c t i v e i n our s y n t h e t i c route was the i n t r o -d u c t i o n of an a n g u l a r methyl group at the C(10) p o s i t i o n . In our i n i t i a l approach (Scheme 106), Simmons-Smith c y c l o p r o p a -H (434) (385a, b ) R e a g e n t s and c o n d i t i o n s : ( i ) H + , EG, PhH; ( i i ) C H ^ , E t ^ n , P h C H ^ ( i i i ) P t 0 2 , H 2 . Scheme 106 n a t i o n ( E t 2 Z n / C H 2 l 2 / T o l u e n e ) [75] of the deconjugated k e t a l (384a,b) d e r i v e d from enones (368a,b) [123,112e] p r o v i d e d the c y c l o p r o p a n e d e r i v a t i v e s (385a,b) i n 85% y i e l d . In t h i s r e a c -t i o n , methylene carbene can add e i t h e r from /3 or oC face of the double bond to p r o v i d e (£-385a) and (o(-385b) r e s p e c t i v e l y (Scheme 107). One approach to c o n t r o l the s t e r e o c h e m i s t r y of t h i s c y c l o p r o p a n a t i o n r e a c t i o n would be to use i n t e r m e d i a t e 228 (<*-385b) Scheme 107 (387) (Scheme 108), d e r i v e d from an a p p r o p r i a t e a l k e n y l G r i g -nard reagent . T h i s would p r e s e n t the o p p o r t u n i t y to c a r r y out a h y d r o x y 1 - d i r e c t e d c y c l o p r o p a n a t i o n r e a c t i o n . (389) (388) Scheme 108 229 H y d r o g e n o l y s i s of (385a ,b) i n the presence of PtO^ i n e t h a n o l at 2 .5 atmosphere was u n s u c c e s s f u l . I n c r e a s i n g the hydrogen p r e s s u r e was a l s o found i n e f f e c t i v e , a l t h o u g h f u r t h e r i n v e s t -i g a t i o n s i n t h i s a r e a are a n t i c i p a t e d . A c i d - c a t a l y s e d r i n g opening of c y c l o p r o p a n e d e r i v a t i v e s has p r e v i o u s l y been r e p o -r t e d . For example, G r i e c o et a l . [124] have shown t h a t t r e a t -ment of c y c l o p r o p y l k e t a l (390) w i t h p e r c h l o r i c a c i d , r i n g c l e a v e d p r o d u c t (391) was o b t a i n e d (Scheme 109). When (385a ,b) was t r e a t e d w i t h p e r c h l o r i c a c i d i n methylene c h l o r i d e , enone (392) was i s o l a t e d i n 82% y i e l d Scheme 110). The s t r u c t u r e and a b s o l u t e c o n f i g u r a t i o n of t h i s p r o d u c t were deduced from 1 H - n . m . r . spectrum (page 286) and conf irmed by X - r a y c r y s t a l l o g r a p h i c a n a l y s i s (page 287) [ 68 ] . MeO MeO Scheme 109 (385a) (392) Scheme 110 2 30 The f o r m a t i o n of (392) presumably i n v o l v e s p r o t o n a t i o n of the c y c l o p r o p a n e r i n g of (385a ,b), f o l l o w e d by r i n g opening to p r o v i d e the t e r t i a r y c a r b o c a t i o n (393) r a t h e r than the s e c -ondary c a r b o c a t i o n (395) . Independent h y d r o l y s i s of the k e t a l f u n c t i o n a l i t y (393) then p r o v i d e d enone (392) (Scheme 111). (385) (393) (394) 1 (395) (392) Scheme 111 In f u t u r e i n v e s t i g a t i o n s at tempts w i l l be made to c l e a v e the d ibromocyc lopropane r i n g (397) under b a s i c c o n d i t i o n s (Scheme 112). Another p o s s i b l e approach i s o u t l i n e d i n Scheme 113, which f e a t u r e s a Wharton r e a c t i o n [125] of hydrazone (402) f o l l o w e d by a s i l y l o x y c y c l o p r o p a n a t i o n r e a c t i o n [126] . 231 Br (399) (398) Scheme 112 I t i s expected t h a t b a s i c h y d r o l y s i s of (404) would then r e v e a l the A , B s t r u c t u r a l s u b - u n i t w i t h the a n g u l a r methyl group i n t r o d u c e d . 232 Scheme 113 2 3 3 An a l t e r n a t i v e means of i n t r o d u c i n g the a n g u l a r methyl group at the C(10) p o s i t i o n i s to s y n t h e s i s e the 1 , 5 - d i e n o l s (409a ,b) w i t h the e x p e c t a t i o n t h a t i t would undergo a n i o n i c oxy-Cope rearrangement to p r o v i d e ketones (410a ,b) (Scheme H ( 4 1 0 a , b ) ( 4 0 9 a , b ) R e a g e n t s and c o n d i t i o n s : ( i ) LDA, THF-HMPA, -78°C; AcOH, E t 2 0 , -78°C; ( i i ) V i n y l Mag-Magnesium B r o m i d e , THF; ( i i i ) ( a ) KH, THF, 25°C; (b) KH, THF-HMPA, R e f l u x ; ( c ) KH, THF, 15-Cro-wn-5, R e f l u x ; (d) KH, KH, HMPA, 200°C. Scheme 114 118). The p r e p a r a t i o n of 1 , 5 - d i e n o l s (409a ,b) were c a r r i e d out by f i r s t d e c o n j u g a t i n g the b i c y c l i c enones (369a ,b) 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 i n t e t r a h y d r o f u r a n f o l l o w e d by k i n e t -i c quenching w i t h g l a c i a l a c e t i c a c i d [123] to p r o v i d e ketones ( 4 0 8 a , b ) . I t i s i n t e r e s t i n g to note t h a t an attempt to decon-234 j u g a t e b i c y c l i c enones (368a ,b) i n t h i s way l ed to the forma-t i o n of a dimer (411) (Scheme 115) whose s t r u c t u r e and a b s o l -ute c o n f i g u r a t i o n were e s t a b l i s h e d by X - r a y c r y s t a l l o g r a p h i c a n a l y s i s [68] (page 2 8 7 ) - I n c i d e n t l y , t h i s r e s u l t p r o v i d e s i n d i r e c t ev idence f o r the t r a n s s t e r e o c h e m i s t r y of the enones ( 3 6 8 a , b ) , ( 3 6 9 a , b ) , and ( 3 7 6 a , b) ( c f . page 2 2 6 ) -H (411) Scheme 115 In order to a v o i d t h i s c o m p l i c a t i o n , the methyl e ther p r o t e c t i n g group was used i n s t e a d of the a c e t a t e s . Enone methyl e t h e r s ( 3 6 9 a , b) were deconjugated to p r o v i d e the enones ( 4 0 8 a , b ) , which r e a c t e d w i t h v inylmagnes ium bromide i n t e t r a h -y d r o f u r a n to p r o v i d e 1 , 5 - d i e n o l s ( 4 0 9 a , b) i n 80% y i e l d . T h i s was then t r e a t e d w i t h potass ium h y d r i d e i n t e t r a h y d r o f u r a n at 2 5 ° C , but s t a r t i n g m a t e r i a l was r e c o v e r e d c o m p l e t e l y . More v i g o r o u s r e a c t i o n c o n d i t i o n s (KH/15-crown-5 e ther /HMPA/heat or K H / H M P A / 2 0 0 ° C ) a l s o f a i l e d to promote c o n v e r s i o n of ( 4 0 9 a ,b) to b i c y c l i c ketones ( 4 1 0 a , b ) . At t h i s s tage we c o n s i d e r t h a t the f a i l u r e of ( 4 0 9 a , b) to undergo a n i o n i c oxy-Cope r e a r r a n g e -ment i s due to 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 between a methyl 235 THPO (412) T H P O (414) THPO i T (416) (415) Scheme 117 236 group and the d e v e l o p i n g v i n y l group in the t r a n s i t i o n s t a t e (Scheme 116). That a n i o n i c oxy-Cope rearrangements can be (410a ) Scheme 116 i n h i b i t e d by s t e r i c f a c t o r s has been c l e a r l y e s t a b l i s h e d by p r e v i o u s i n v e s t i g a t i o n s . For example, the s t e r o i d i n t e r -mediate (412) hav ing the ( E ) - c o n f i g u r a t i o n underwent a n i o n i c oxy-Cope rearrangement to p r o v i d e (414), wh i l e the c o r r e s -ponding ( Z ) - i s o m e r (416), f a i l e d to produce any r e a r r a n g e d p r o d u c t s . I t has been suggested t h a t t h i s i s due to the " q u a s i - 1 , 3 - d i a x i a l i n t e r a c t i o n " between C ( 1 6 ) - 0 - K * and C ( 2 0 ) -CHa (Scheme 121) [117] . I t has a l s o been shown t h a t treatment of (417) w i t h po tas s ium h y d r i d e in t e t r a h y d r o f u r a n p r o v i d e d (418) i n 79% y i e l d (Scheme 118). In c o n t r a s t , s i m i l a r t r e a t -ment of (419) p r o v i d e d (420) i n o n l y 11% y i e l d [112b] . In the 237 (419a) Scheme 118 l a t t e r case , 1 , 3 - d i a x i a l i n t e r a c t i o n s between methyl group i n i n the t r a n s i t i o n s t a t e (419a) can be invoked to e x p l a i n the poor y i e l d . In a d d i t i o n to these i n v e s t i g a t i o n s c o n c e r n i n g the s t e r -e o s e l e c t i v e i n t r o d u c t i o n of angu lar methyl s u b s t i t u e n t s i n t o i n t e r m e d i a t e s (368a,b) , (369a,b) and (376a,b) , i t i s worth n o -t i n g t h a t b i c y c l i c ketones (373a,b) have c o n s i d e r a b l e p o t e n t i a l as c h i r a l i n t e r m e d i a t e s i n the s y n t h e s i s of s p i r o d y s i n (421) , 238 a marine n a t u r a l p r o d u c t . Scheme 119 i l l u s t r a t e s a p o s s i b l e s y n t h e t i c route from (373a,b) to an i n t e r m e d i a t e e s t e r (428) by a l l y l i c o x i d a t i o n of the v i n y l i c methyl group of (424). I t i s expected t h a t t h i s compound c o u l d then be c h e m i c a l l y t r a n -sformed to s p i r o d y s i n (421). The scheme would a l s o r e p r e s -ents a f o r m a l s y n t h e s i s of the marine n a t u r a l p r o d u c t s , f u r o -d y s i n (422) and f u r o d y s i n i n (423) s i n c e R. J . W e l l s and c o -workers [128] have p r e v i o u s l y demonstrated tha t s p i r o d y s i n (421) can be conver ted to f u r o d y s i n (422) and f u r o d y s i n i n (423) (1 :1 ) i n the presence of B F o - e t h e r a t e in benzene (Scheme 120). Scheme 120 In c o n c l u s i o n , we have i n v e s t i g a t e d the p o t e n t i a l use of (+)-5,6 -dehydrocamphor (323) as a c h i r a l synthon i n t e r p e n o i d s y n t h e s i s , and, as a r e s u l t , have deve loped a s y n t h e t i c r o u t e to b i c y c l i c ketones (373a,b) and b i c y c l i c enones (368a,b), (369a,b) and (376a,b). Attempts have been made to i n t r o d u c e a n g u l a r f u c t i o n a l i t y i n t o the C(10) p o s i t i o n of b i c y c l i c 239 » Scheme 119 240 enones (368a ,b) , ( 369a ,b) , and (376a ,b) , but so f a r these have been u n s u c c e s s f u l . However, a l t e r n a t i v e s y n t h e t i c r o u t e s to t h i s r e s e a r c h o b j e c t i v e are b e i n g i n v e s t i g a t e d . In a d d i t i o n , b i c y c l i c ketones (373a,b) are b e i n g e v a l u a t e d as i n t e r m e d i a t e s i n the e n a n t i o s p e c i f i c s y n t h e s i s of s p i r o d y s i n (421) , and, i n d i r e c t l y to the s y n t h e s i s of f u r o d y s i n (422) and f u r o d y s i n i n (423) . 241 3 . 3 . 0 . EXPERIMENTAL ( c f . page 88) 242 ( - ) -6-endo-Bromocamphor (40) 0 0 Br <41> (O-3-gndja.-Brpmocamphor (41) (55 .0 g , 238 mmol) ( A l d r i -ch C h e m i c a l C o . ) i n c h l o r o s u l f o n i c a c i d (180 mL) was s t i r r e d o at 55 C f o r 15 minutes and then poured onto i c e . A f t e r e x t r a -c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and d r i e d (MgSO^). Removal of the s o l v e n t under vacuo p r o v i d e d a crude s o l i d which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e ther : e ther , 15 : 1) to p r o v i d e ( - )-6-endjQ_-bromocamphor (40) (27 g , 50%) as a white c r y s t a l l i n e s o l i d . R f 0.53 ( p e t . e ther : e ther , 4 : 1) ; mp 5 6 ° C ( s e a l e d t u b e ) ; [ o C ] § 5 - 5 1 . 8 ° (c 4 .96 , C H 2 C 1 2 ) ; Vmax ( f i l m ) : 1745 cm - 1 , g (CDC1 3 , 400MHz): 0.92 ( s , 3H, C H 3 ) , 0.98 ( s , 3H, C H 3 ) , 1.00 ( s , 3H, C H 3 ) , 4 .22 ( d d , 1H, RCHJBr, J = 3 .5 Hz , 10 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 230/232 (1 .8 0 /1 -20 , M + / M + + 2 ) , 167 ( 1 1 . 0 ) , 151 ( 3 9 . 0 ) , 149 ( 3 0 . 0 ) , 109(100); Exac t mass c a l c d . f o r CifjHisOBr: 230.0306/232.0286; found ( h i g h r e s o l u t i o n mass s p e c t r o m e t r y ) : 230.0303/232.0274; A n a l , c a l c d . f o r C 1 0 H 1 5 0 B r : C 51 .97 , H 6 .54 , Br 34 .57; found: C 51 .93 , H 6 .45 , Br 34 .68 . 243 (+) -5 .6-Dehvdrocamphor ( 3 2 3 ) 0 0 Br (40) ( - ) -6-endo-Bromocamphor (40) (7 .0 g , 30 mmol), po tass ium hydrox ide (8 .33 g , 143 mmol), d i m e t h y l s u l f o x i d e (250 mL) and water (50 mL) were s t i r r e d t o g e t h e r at 1 0 0 ° C f o r 16 h o u r s . Upon c o o l i n g , the r e a c t i o n mixture was d i l u t e d wi th water , e x t r a c t e d w i t h e ther and the combined o r g a n i c l a y e r s were washed w i t h b r i n e and d r i e d (MgS04). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 15:1) to a f f o r d ( + ) -5 ,6 -dehydrocam-phor (323) (2 .4 g , 50%) as a white s o l i d ; mp 1 4 9 - 1 5 1 ° C ( s e a l e d tube) ( l i t . [117] mp 1 4 8 ° C f o r e n a n t i o m e r ) ; R f 0.68 (pe tro leum e t h e r : e t h e r , 4 : l ) ; [ot] J 5 + 7 5 6 ° (c 0 .500, C H 2 C 1 2 ) , ( l i t . foL]D - 7 3 5 ° (c 1 .00, EtOH) f o r enantiomer [117] ) ; Vmax ( C H C 1 3 ) : 1735 c m - 1 ; 6 (CDC13 , 400 MHz): 0.91 ( s , 3H, C H 3 ) , 1.01 ( s , 3H, C H 3 ) , 1.07 ( s , 3H, C H 3 ) , 5.58 ( d , 1H, C(6,)li , J=6 H z ) , 6.45 ( d d , 1H, C ( 5 ) H , J=6 Hz , 3 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 150 ( 1 2 . 0 , M + ) , 93 .0 ( 5 8 . 0 ) , 85.0 ( 5 9 . 0 ) , 71.0 ( 9 2 . 0 ) , 69 .0 (100); E x a c t mass c a l c d . f o r C 1 0 H 1 4 0 : 150.1045; found: 150.1049; 244 Dieno] (361) To a s t i r r e d s o l u t i o n of (+) -5 ,6 -dehydrocamphor (323) ( 9.2 g , 61 mmol) in d r y t e t r a h y d r o f u r a n (50 mL) at 0 ° C under an argon atmosphere was added v i n y l magnesium bromide s o l u t i o n ( 1 . 0 M i n THF, A l d r i c h Chemica l C o . ) (184 mL 184 mmol) d r o p w i s e . A f t e r the comple t ion of the a d d i t i o n , the i c e bath was removed and s t i r r i n g was c o n t i n u e d at 2 5 ° C f o r 2 .5 hours be fore s a t u r -ated aqueous ammonium c h l o r i d e (50 mL) was v e r y c a r e f u l l y add ed . F o l l o w i n g e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d ( 0 . 5 N ) , b r i n e , and d r i e d (MgSO^). Removal of s o l v e n t under vacuo p r o v i d e d the d i e n o l (361) (11 g , 99%) as a p a l e y e l l o w o i l which was used d i r e c t l y f o r the a n i o n i c oxy-Cope rearrangement wi thout f u r t h e r p u r i f i c a t i o n . Rf 0.44 ( p e t . e ther : e ther , 4 :1) . * m a x ( f i l m ) : 349, 2975, 1637, 1584 c m " 1 ; & ( C D C 1 3 , 400MHz): 0.93 ( s , 3H, C H 3 ) , 0 .95 ( s , 3H, C H 3 ) , 1.20 ( s , 3H, C H 3 ) , 5.01 ( d d , 1H, fcLb, J=10 Hz , 2 H z ) , 5.16 ( d d , 1H, Ha, J=18 Hz , 2 H z ) , 5.62 ( d , 1H, R., J=6 H z ) , 5.85 ( d d , 1H, Ho, J=10 Hz , 18 H z ) , 6.01 ( d d , 1H, fcU, J=4 Hz , 6 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 245 178 (0 .990 , M + ) , 163 ( 2 . 7 0 ) , 161 ( 0 . 5 0 0 ) , 145 ( 2 . 5 1 ) , 135 ( 2 . 2 8 ) , 108 ( 9 8 . 5 ) , 93 .0 (100); E x a c t mass c a l c d . f o r C 1 2 H 1 8 0 : 178.2762; found: 178.1362; A a a l . c a l c d . f o r C 1 2 H 1 8 0 : C 80 .85 , H 10.18; found: C 81 .00 , H 10 .23 . B i c v c l i c ketone (364) To a s t i r r e d mix ture of potass ium h y d r i d e (0 .71 g, 18 mmol) i n d r y t e t r a h y d r o f u r a n (20 mL) at 2 5 ° C under an argon a t -mosphere was i n t r o d u c e d a s o l u t i o n of d i e n o l (361) (2 .1 g , 12 mmol). S t i r r i n g was c o n t i n u e d f o r 10 minutes b e f o r e p r o p a n o l (5 .0 mL) was v e r y c a r e f u l l y added. A f t e r d i l u t i o n w i t h water (25 mL) f o l l o w e d by e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d ( M g S O ^ . Removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 1 0 : 1 ) to p r o v i d e b i c y c l i c ketone (364) (2 .0 g , 95%) as a c o l o r l e s s o i l . R^  0 .6 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; [ O C ] D 5 - H 9 ° ( C 0 .550, C H C 1 3 ) ; Vmax ( f i l m ) : 2990, 1715, 1662 c m - 1 ; & ( C D C 1 3 , 400MHz): 0.93 ( s , 3H, C H 3 ) , 1.03 ( 3 2 1 ) (364) 246 ( s , 3H, C H 3 ) , 1.62 ( t , 3H, C H 3 , J=2.0 H z ) , 5.16 ( t , 1H, RfcLC:CR, J=2.0 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 178 ( 3 5 . 8 , M + ) , 164 ( 1 2 . 2 ) , 163 (100); E x a c t mass c a l c d . f o r C 1 2 H 1 8 0 : 178.2762; found: 178.2759; B i c v c l i o A l c o h o l s ( 3 6 5 a r b ) (364) R 1=H,R 2=0H (3 6 5 a ) R 1=0H,R 2=H (365b) At -78 C , under an argon atmosphere, L - s e l e c t r i d e (27 mL, 19 mmol; 1.0 M i n THF, A l d r i c h Chemica l C o . ) was s l o w l y added to a s t i r r e d s o l u t i o n of b i c y c l i c ketone (364) (1 .1 g , 6.2 mmol) i n THF (20 mL). A f t e r 1.5 h o u r s , the r e a c t i o n was quenched at - 7 8 ° C w i t h H 2 0 (5 .0 mL) c a r e f u l l y . H 2 0 2 (30 Wt.% s o l u t i o n in H 2 0 ( 2 .0 mL) was added and the mix ture was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d ( 1 . 0 N ) , and b r i n e and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromato-graphy ( s i l i c a g e l ; p e t . e t h e r : e t h e r , 8:1) to p r o v i d e a mixture of e p i m e r i c b i c y c l i c a l c o h o l s (365a, b ) ( 1 . 0 g , 90%) as a c o l o r l e s s o i l . The r a t i o of the e p i m e r i c a l c o h o l s was determined from ^ H - n . m . r . p r o t o n i n t e g r a t i o n to be 6 :1 . Rf 247 0.34 ( p e t . e t h e r : e t h e r , 1:1); Vmax ( f i l m ) : 3375, 2943, 1650 c m - 1 ; & (CDCI3, 400MHz): ^ H - n . m . r . of major d i a s t e r e o m e r : 0.94 ( s , 3H, C H 3 ) , 0 .97 ( s , 3H, C H 3 ) , 1.63 ( t , 3H, CH3 . J= 2 .0 H z ) , 3 . 80 -3 .90 (m, 1H, RCH.0H ) , 5.25 ( s , 1H, RH.C:CR); m/e ( r e l a t i v e i n t e n s i t y ) : 180 ( 6 3 . 8 ) , 179 ( 1 1 . 2 ) , 165 ( 1 6 . 9 ) , 162 ( 1 2 . 1 ) , 147 (100); Exac t mass c a l c d . f o r C12H20O: 180,2922; found: 180.1510. B i c v c l i c A c e t a t e s (366a .b) H H R l " H , R 2 = 0 H ( 3 6 5 a > R =H,R =0Ac ( 3 6 6 a ) R 1 =0H,R 2=H (365b) R ^ O A c R =H (366b) Dry a c e t i c anhydr ide (0 .69 mL, 7.3 mmol) was added to a s t i r r e d s o l u t i o n of e p i m e r i c b i c y c l i c a l c h o l s ( 3 6 5 a , b ) (0 .44 g , 2.4 mmol) and 4 - d i m e t h y l a m i n o p y r i d i n e (0 .15 g , 1.2 mmol) i n d r y p y r i d i n e (15 mL) at 2 5 ° C under an argon atmosphere. S t i r r i n g was c o n t i n u e d f o r 3 hours b e f o r e water (20 mL) was The r e a c t i o n m i x t u r e was e x t r a c t e d w i t h e t h e r , and the combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chroma-tography ( s i l i c a g e l , p e t . e t h e r : e ther , 10:1) to g i v e a 248 mixture of e p i m e r i c b i c y c l i c a c e t a t e s (366a ,b) (0 .53 g , 98%) as a c o l o r l e s s o i l . R f 0.55 ( p e t . e t h e r : e t h e r , 4 : 1 ) . V m a x ( f i l m ) : 2957, 1735 c m * 1 ; & ( C D C 1 3 , 400MHz): lH n . m . r . of major d i a s t e r e o m e r : 0.97 ( s , 3H, C H 3 ) , 0.98 ( s , 3H, C H 3 ) , 1.60 ( t , 3H, C H 3 , J=2.0 H z ) , 2.04 ( s , 3H, C H 3 ) , 4 . 8 8 - 4 . 9 7 (m, 1H, RHCOAc), 5.22 ( s , 1H, RH.C:CR); m/e ( r e l a t i v e i n t e n s i t y ) : 222 ( 1 . 0 8 , M + ) , 217 ( 3 . 2 3 ) , 162 ( 4 0 . 4 ) , 147 ( 6 1 . 1 ) , 145 ( 2 0 . 8 ) , 121 (100); Exac t mass c a l c d . f o r C 1 4 H 2 2 0 2 : 222.1619; found: 222.1607; A n a l . c a l c d . f o r C 1 4 H 1 2 0 2 : C 75 .63 , H 9 .97; found: C 75 .57 , H 10 .07 . B i c y c l i c enones (368a .b) R I = H , R 2 = 0 A C ( 3 6 6 a ) R 1 = H , R 2 = 0 A c ( 3 6 8 a ) R = 0 A c , R =H (366b) R ^ O A c R ^ H (368b) At - 7 8 C C , ozone ( c o n d i t i o n : E= 80 V , a i r i n l e t = 8.0 p s i , ozone o u t l e t = 0.06 p s i ) was a l lowed to pass through a s t i r r e d s o l u t i o n of b i c y c l i c a c e t a t e s ( 3 6 6 a , b ) (0 .95 g , 4 .3 mmol) i n d r y d i c h l o r o m e t h a n e (20 mL) and methanol (20 mL) u n t i l p e r s i s -t e n t b lue c o l o r was o b t a i n e d . The mix ture was g r a d u a l l y warm-ed to about - 2 5 ° C under an argon atmosphere and t r i p h e n y l p h o s -phine ( 1 . 1 g , 4 .3 mmol) was added. S t i r r i n g was c o n t i n u e d at 249 - 2 5 ° C f o r 2 .5 hours and at 2 5 ° C f o r 0.5 hour . F o l l o w i n g rem-o v a l of s o l v e n t under vacuo , the crude k e t o - a l d e h y d e s (377a,b) ( T'.max 2820, 1730 cm 1 ) were d i s s o l v e d i n d r y benzene (40 mL). p - T o l u e n e s u l f o n i c a c i d (100 mg) was added, and the r e s u l t i n g mix ture was r e f l u x e d f o r 4 hours i n a D e a n - S t a r k a p p a r a t u s . A f t e r c o o l i n g and e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , and b r i n e , and d r i e d (MgS0 4). Upon removal of s o l v e n t under under vacuo , the crude p r o d u c t was p u r i f i e d by column chroma-tography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 1 0 : 1 ) to p r o v i d e b i c y c l i c enones (368a,b) ( 0 . 5 4 g , 60%) as a c o l o r l e s s o i l . R f 0.68 ( p e t . e t h e r : e t h e r , 1 : 1 ) ; Vmax ( f i l m ) : 2950, 1735, 1678, 1380, 1368 c m - 1 ; & (CDC1 3 , 400MHz): ^ - n . m . r . of major d i a s t e r e o m e r : 1.05 ( s . 3H, C H 3 ) , 1.21 ( s , 3H, C H 3 ) , 2.07 ( s , 3H, C H 3 ) , 5.05 ( t , 1H, R 2CH0Ac, J = 3 H z ) , 5.96 ( d d , 1H, 0 : C -RCH.:CHR', J = 10 Hz , 3 H z ) , 6.57 ( d , 1H, 0: CRCH,: CHR' , J = 10 H z ) : m/e ( r e l a t i v e i n t e n s i t y ) : 236 ( 2 4 . 1 , M +), 198 ( 1 . 9 0 ) , 194 ( 1 0 . 2 ) , 193 ( 2 . 9 0 ) , 176 (100); Exact mass c a l c d . f o r C 1 4 H 2 0 ° 3 : 236.1535; found: 236.1416; Anal, c a l c d . f o r C 1 4 H 2 0 0 3 : C 71 .16 , H 8 .53; found: C 71 .30 , H 8 .66 . 250 B i c v c l i c k e t a l s ( 3 8 4 a r b ) H (368a,b) (384a,b) (427a,b) p - T o l u e n e s u l f o n i c a c i d ( 5 . 0 mg) was added to a s t i r r e d s o l u t i o n of b i c y c l i c enones (368a,b) (0 .10 g , 0.50 mmol) in f r e s h l l e d d i s t i l l e d e t h y l e n e g l y c o l (0 .30 mL, 50 mmol) and d r y benzene (20 mL) under an argon atmosphere. The r e s u l t i n g mixture was r e f l u x e d f o r 20 hours in a D e a n - S t a r k a p p a r a t u s . A f t e r c o o l i n g and e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n , and b r i n e and d r i e d ( M g S O ^ . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 1 5 : 1 ) to p r o v i d e a m i x t u r e of b i c y c l i c k e t a l s (384a,b) (96 mg, 70%) and b i c y c l i c k e t a l a l c o h o l s (427a ,b) (24 mg) as a c o l o r l e s s o i l . (384a ,b) : R f 0 .63 ( p e t . e t h e r : e t h e r , 1 : 1 ) ; ^ m a x ( f i l m ) : 2950, 1735, 1382 c m - 1 ; 6 (CDC1 3 , 400MHz): 1 H - n . m . r . o f major d i a s t e r e o m e r : 0.88 ( s , 3H, C H 3 ) , 0 .93 (s, 3H, C H 3 ) , 2.06 ( s , 3H, C H 3 ) , 3 . 85 -4 .00 (m, 4H, R 0 C H . 2 - C & 2 - 0 - R ) , 5.18 ( t , 1H, RC&OAc, J = 3 H z ) , 5.29 ( d d , 1H, RH_C:CR 2, J = 5 Hz , 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 280 ( 2 . 5 0 , M + ) , 239 ( 3 . 2 0 ) , 220 ( 6 . 9 0 ) , 205 ( 2 . 3 0 ) , 251 177 ( 5 2 . 5 ) , 114 (100); Exact, mass c a l c d . f o r C 1 6 H 2 4 0 4 -280.1674; found: 280.1668; Anal, c a l c d . f o r C 1 6 . H 2 4 0 4 : C 68 .55 , H 8 .63 , found: C 68 .28 , H 8 ,86 . ( 4 2 7 a , b ) : R f 0.14 ( p e t . e t h e r : e t h e r , 1 : 1 ) ; Vmax ( f i l m ) : 3408, 2943, 1384 c m " 1 ; 8 (CDCI3, 400 MHz): 1 H - n . m . r . of major d i a s t e r e o m e r : 0.87 ( s , 3H, C H 3 ) , 0.94 ( s , 3H, C H 3 ) , 3 . 8 7 - 4 . 0 0 (m, 4H, ROCH^CH^OR), 4 .21 ( t , 1H, R 2CH.0H, J = 3 H z ) , 5.26 ( s , 1H, R 'UC :CR"R" ' ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 238 ( 4 . 3 0 , M + ) , 220 ( 0 . 5 0 ) , 195 ( 3 5 . 0 0 ) , 151 ( 1 5 . 1 ) , 114 (100) : E x a c t mass c a l c d . f o r C 1 4 H 2 2 0 3 : 238.1568; found: 238.1563. B i c v c l i c k e t a l s (384a .b) (427a,b) (384a,b) Dry a c e t i c anhydr ide (0 .09 mL, 0.97 mmol) was added to a m i x t u r e of b i c y c l i c k e t a l a l c o h o l s (427a ,b) (0 .12 g , 0.48 mmol)and 4 - d i m e t h y l a m i n o p y r i d i n e (30 mg, 0.24 mmol) i n d r y p y -r i d i n e (10 mL) at 2 5 ° C under an argon atmosphere. S t i r r i n g was c o n t i n u e d f o r 3 hours b e f o r e water (20 mL) was added. The r e -a c t i o n mixture was e x t r a c t e d w i t h e ther and the combined o r g a n -252 i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (1 .0 N) and b r i n e , and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t under vacuo f o l l o w e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 1 0 : 1 ) a f f o r d e d b i c y c l i c k e t a l s ( 384a ,b) (0 .13 g , 97%) as a c o l o r l e s s o i l . C y c l o p r p p y l - k e t a l s (385a .b) (384a,b) (385a,b) To a w e l l s t i r r e d , heated ( 6 0 ° C ) s o l u t i o n of b i c y c l i c k e t a l s (384a ,b) (0 .07 g , 0.27 mmol) i n d r y to luene (5 .0 mL) was added s u c c e s s i v e l y a s o l u t i o n of d i e t h y l z i n c (0 .38 mL, 0.38 mmol, 25% w/v) and methylene i o d i d e (0 .03 mL, 0.38 mmol). S t i r r i n g was c o n t i n u e d at 6 0 ° C under an argon atmosphere f o r 6 h o u r s . A f t e r c o o l i n g , h y d r o c h l o r i c a c i d (0 .5 N) was c a r e f u l l y added and the mix ture was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h h y d r o c h l o r i c a c i d (0 .5 N) and b r i n e , and d r i e d (MgS04). Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 2 0 : 1 ) to p r o v i d e c y c l o p r o p y l k e t a l s (385a ,b) (65 mg, 94%; based on the r e c o -253 vered s t a r t i n g m a t e r i a l ) ; as a c o l o r l e s s o i l . Rf 0.71 ( p e t . e t h e r : e t h e r , 1:1); J > m a x ( f i l m ) : 3050, 2950, 1730, 1380 c m - 1 ; S ( C D C 1 3 , 400MHz): 1 H - n . m . r . of major d i a s t e r e o m e r : 0 .33-0 .54 (m, 3H, R 2 C R C E R ' ) , 0.76 ( s , 3H, C H 3 ) , 1.01 ( s , 3H, C H 3 ) , 2.05 ( s , 3H, C H 3 ) , 3 . 6 8 - 3 . 9 8 (m, 4H, R0CR.2CH_20R ) , 5 .20 -5 .26 (m, 1H, RCROAc ) . To a s t i r r e d s o l u t i o n of c y c l o p r o p y l - k e t a l s (385a ,b) (60 mg, 0.20 mmol) i n d r y d i ch loromethane (10 mL) at 0 ° C under an argon atmosphere was added p e r c h l o r i c a c i d (1 .0 mL) d r o p w i s e . S t i r r i n g was c o n t i n u e d f o r 4 hours b e f o r e water (10 mL) was a d -ded. F o l l o w i n g e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y -ers were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo , the crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i -ca g e l , p e t . e t h e r : e t h e r , 10:1) to p r o v i d e enone (392) (41 mg, 82%) as a white s o l i d . R e c r y s t a l l i s a t i o n from p e t . e t h e r : e t h e r , 10:1) a f f o r d e d c o l o r l e s s p r i s m s , mp 1 5 0 - 1 5 2 ° C . Rf 254 0.49 ( p e t . e ther . -e ther ,1 :1 ) ; Vmax ( C H C 1 3 ) : 2986, 1726, 1662, 1387, 1371 c m - 1 ; 8 ( C D C 1 3 , 400MHz): 0.94 ( s , 3H, CH3 ) , 1.07 ( s , 3H, C H 3 ) , 2.05 ( s , 3H, C H 3 ) , 5.19 ( t , 1H, RC&OAc, J=3 H z ) , 5-83 C.s. 1H- H R ' C : C R C H 3 ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 250 ( 2 0 . 3 , M + ) , 190 ( 5 2 . 1 ) , 175 ( 3 4 . 5 ) , 162 ( 2 6 . 5 ) , 147 ( 5 1 . 0 ) , 121 ( 5 4 . 0 ) , 108 ( 6 8 . 2 ) , 93 ( 6 9 . 5 ) ; Exact mass c a l c d . f o r C 1 5 H 2 2 ° 3 : 2 5 0 - 1 5 6 8 ; found: 250.1571; A n a l . c a l c d . f o r C15H22O3: C 71 .97 , H 8.860; found: C 71 .69 , H 8 .700. B i c y c l i c ketones ( 3 7 3 a r b ) A 3-neck f l a s k f i t t e d w i t h a condenser was charged w i t h f r e s h l y crushed magnesium t u r n i n g s (1 .73 g , 70 .9 mmol) i n d r y t e t r a h y d r o f u r a n (35 mL) and a c r y s t a l of i o d i n e . The r e a c t i o n mix ture was s t i r r e d v i g o r o u s l y under an argon atmosphere at room t e m p e r a t u r e , and a s o l u t i o n of 2-bromopropene i n d r y t e t r a h y d r o f u r a n (10 mL) was then i n t r o d u c e d . The mix ture was r e f l u x e d f o r 20 minute s , a f t e r which t ime a s o l u t i o n of (+)-5 ,6-dehydrocamphor (323) (1 .53 g , 2.30 mmol) i n d r y t e t r a -hydrofuran (25 mL) was s l o w l y added. The mix ture was s t i r r e d ( 323) (373a ,b ) 255 v i g o r o u s l y at room temperature f o r 20 minutes and then r e f l u x e d f o r 1.5 hours . S a t u r a t e d ammonium c h l o r i d e (50 mL) was added and the mixture was e x t r a c t e d wi th e t h e r . The combined o r g a n i c l a y e r s were washed w i t h water and b r i n e , and d r i e d (MgS04). Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e ther : e t h e r , 9 : l ) to y i e l d pure b i c y c l i c ketones (373a ,b) (1 .74 g , 89%) as a c o l o r l e s s o i l . Rf 0.41 ( p e t . e t h e r : e t h e r , 4 : 1 ) . The r a t i o ( c a . 2:1) of the epimers of (373a ,b) was determined by ^ - n . m . r . i n t e g r a t i o n , y ( f i l m ) : 2950, 1715, 1643 c m - 1 ; max S ( C D C 1 3 , 400 MHz): 1 H - n . m . r . of major d i a s t e r e o m e r : 0.91 ( s , 3H, C H 3 ) , 1.01 ( s , 3H, C H 3 ) , 1.04 ( d , 3H, C H 3 , J = 8 H z ) , 1.32 ( q , 1H, RCH.CH 3 ) , 1 .60-1 .61 (m, 3H, C H 3 ) , 5.21 ( s , 1H, H 3 C C R : C H . R ' ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 192 ( 4 6 . 4 , M + ) , 177 (100); E x a c t mass c a l c d . f o r C 1 3 H 2 0 0 : 192.1514; found: 192. 1514; found: 192.1506; A n a l , c a l c d . f o r C 1 3 H 2 0 0 : c 81 .20 , H 10.48; found: C 80 .90 , H 10.47. 256 To a c o l d (0 C ) , s t i r r e d s o l u t i o n of l i t h i u m aluminum h y d r i d e (0 .56 g , 15 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL) under an argon atmosphere was added a s o l u t i o n of b i c y c l i c ketones (373a ,b) (1 .2 g , 5 .9 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL). S t i r r i n g was c o n t i n u e d f o r 1 hour and the r e a c t i o n mixture was quenched by c a r e f u l a d d i t i o n of water (10 mL) f o l l o w e d by d i l u t i o n w i t h h y d r o c h l o r i c a c i d (1 .0 N ) , and e x t r a c t i o n w i t h e t h e r . The combined o r g a n i c l a y e r s were then washed w i t h water , b r i n e and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , pe tro leum e t h e r : e t h e r , 4:1) to p r o v i d e mix ture of d i a s t e r e o m e r i c b i c y c l i c a l c o h o l s (374) (1 .1 g , 98%) as a c o l o r l e s s o i l . R f 0.37 ( p e t . e t h e r : e t h e r , 1:1); 2/m a x ( f i l m ) : 3350, 1645 c m - 1 ; 5 (CDCI3 , 400MHz): 1 H - n . ' n . r . of major a i a s t e r e o m e r : 0 .91-1 .01 (m, 9H, C H 3 , C H 3 , C H 3 ) , 1 .56-1.57 (m, 3H, C H 3 ) , 3 . 7 2 - 3 . 7 5 (m, 1H, RR'CHOH), 5.11 ( s , 1H, H 3 C C R : C H . R ' ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 194 ( 1 8 . 5 , M + ) , 179 ( 1 6 . 3 ) , 176 ( 1 3 . 0 ) , 161 (100); E x a c t mass c a l c d . f o r C 1 3 H 2 2 0 : 194.1671; found: 194.1675. 257 B i c v c l i c methvl e t h e r s (375) (374) (375) A s o l u t i o n of b i c y c l i c a l c o h o l s (374) (0 .90 g , 4 .6 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL) was added to a suspens ion of po-ta s s ium h y d r i d e (0 .28 g , 7.0 mmol) and methyl i o d i d e (0 .49 mL, 7.9 mmol) in d r y t e t r a h y d r o f u r a n (10 mL). S t i r r i n g was c o n t i -nued f o r 15 minutes and the r e a c t i o n was then c a r e f u l l y quen-ched w i t h water (10 mL) and e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h water and b r i n e , and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 9 : 1 ) to p r o v i d e mixture of d i a s t e r e o m e r i c b i c y c l i c methyl e t h e r s (375) (85 mg, 99%) as a c o l o r l e s s o i l . R f : 0.61 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; V m a x ( f i l m ) : 1643 c m - 1 ; g ( C D C 1 3 , 400MHz): 1 H - n . m . r . of major d i a s t e r e o m e r : 0 .86 -1 .00 (m, 9H, CH3, CH3, C H 3 ) , 1 .54-1 .55 (m, 3H, C H 3 ) , 3 .30 ( s , 3H, R-OCH.3 ) , 3 . 1 5 -3.21 (m, 1H, RR'CH.0CH 3 ) , 5.11 ( s , 1H, H3CCR: CH.R' ); m/e ( r e l a -t i v e i n t e n s i t y ) : 208 ( 1 4 . 1 , M + ) , 193 ( 9 . 5 0 ) , 176 ( 1 8 . 7 ) , 161 (100); E x a c t mass c a l c d . f o r C 1 4 H 2 4 0 : 208.1827; found: 208.1826. 258 B i c v o l i c enones (376) (375) (376) At - 7 8 ° C , ozone ( c o n d i t i o n : E=80 V, a i r i n l e t = 8 . 0 p s i , ozone o u t l e t = 0 . 0 6 p s i ) was a l lowed to pass through a s t i r r e d s o l u t i o n of b i c y c l i c methyl e t h e r s (375) (0 .72 g , 3.4 mmol) i n d r y d i c h l o r o m e t h a n e (15 mL) and methanol (15 mL) u n t i l a p e r s i -s t e n t b lue c o l o r was o b t a i n e d . The mix ture was g r a d u a l l y warmed to about - 2 5 ° C under an argon atmosphere and t r i p h e n y l p h o s p h i n e (0 .90 g, 3.4 mmol) was added. S t i r r i n g was c o n t i n u e d at - 2 5 ° C f o r an hour and at 2 5 ° C f o r 30 minutes . A f t e r removal of s o l v e n t under vacuo , the crude k e t o - a l d e h y d e s (479a ,b) ( V m a X i 2820, 1730 c m - 1 ) were d i s s o l v e d in d r y benzene (30 mL). p - T o l u e n e s u l f o n i c a c i d (0 .10 g) was added and the mix ture was r e f l u x e d f o r 5 hours i n a D e a n - S t a r k a p p a r a t u s . A f t e r c o o l i n g and e x t r a c t i o n w i t h e t h e r , the combined o r g a i n c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b r o n a t e s o l u t i o n and b r i n e , and d r i e d ( M g S O ^ . Removal of s o l v e n t a f f o r d e d a crude p r o d u c t was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 9 : 1 ) to p r o v i d e mix ture of d i a s t e r e o m e r i c b i c y c l i c enones (376) (0 .55 g , 74%) as a p a l e y e l l o w o i l . Rf : 0.43 ( p e t . e t h e r : e ther , 1:1); V m a x ( f i l m ) : 1675, 1616 c m " 1 ; § (CDC1 3 , 400MHz): 259 1 H - n . m . r of major d i a s t e r e o m e r : 0 .78 -1 .22 (m, 9H, (CH3 )2 and C H 3 ) , 3 . 1 7 - 3 . 4 5 (m, 1H, R 2 CH.0CH 3 ) , 3 . 17 -3 .45 (m, 3H, R-0CH3) , 5.97 (dd , 1H, RRC:C(C0)HR, J=10 Hz , 4 H z ) , 6 .55 , 6.58 ( d t , 1H, RH_(C0)C :CHR, J = 10 Hz , 2 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 222 ( 1 9 . 5 , M + ) , 190 ( 2 8 . 6 ) , 175 ( 1 4 . 7 ) , 120 ( 4 8 . 1 ) , 93 .0 ( 6 3 . 7 ) , 81 .0 (100) . Methy l e t h e r s (367a .b) A s o l u t i o n of b i c y c l i c a l c o h o l s (365a ,b) (0 .78 g , 4.36 mmol) i n d r y t e t r a h y d r o f u r a n (15 mL) was added to a suspens ion of potass ium h y d r i d e (0 .22 g , 5.4 mmol) and methyl i o d i d e (0 . 41 mL, 6.5 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL). S t i r r i n g was c o n t i n u e d f o r 25 minutes and then c a r e f u l l y quenched w i t h water (10 mL) and e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h water and s a t u r a t e d b r i n e and d r i e d (MgS04>. Removal of s o l v e n t p r o v i d e d a crude p r o d u c t which was p u r i f -i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r / 9 : 1) to g i v e methyl e t h e r s (367a ,b) (0 .85 g , 99%) as a p a l e y e l l o w o i l . R f : 0.45 ( p e t . e t h e r : e t h e r , 4 : 1 ) ; H H R 1=H,R 2=0H ( 3 6 5 a ) R =0H,R =H (365b) 260 V m a x ( f i l m ) : 1641 c m ; & ( C D C 1 3 , 400MHz): H - n . m . r . of major d i a s t e r e o m e r : 0.91 ( s , 3H, C H 3 ) , 0.98 ( s , 3H, CH3) , 1.54-1 .56 (m, 3H, C H 3 ) , 2 . 97 -3 .08 (m, 1H, RR'CH_0CH3 ) , 3.32 ( s , 3H, C H 3 ) , 5.01 ( s , 1H, H 3 C C R : C H R ' ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 194 ( 1 1 . 6 , M + ) , 162 ( 1 4 . 5 ) , 147 ( 5 5 . 1 ) , 119 (100); Exac t mass c a l c d . f o r C 1 3 H 2 2 0 : 194.1670; found: 194.1668. B i c y c l i c Enones (369a .b) R 1=H,R 2=0Me ( 3 6 9 a ) R^ =H,R =0Me (369a ) R 1=0Me,R 2=H (369b) R ^ O M e ^ =H (369b) At -78 C , ozone ( c o n d i t i o n : E=80 V, a i r i n l e t = 8 p s i , ozone o u t l e t = 0 . 0 6 p s i ) was a l lowed to pass through a s t i r r e d s o l u t i o n of methyl e t h e r s (367a ,b) ( 1 . 5 g , 7.5 mmol) i n d r y d i c h l o -romethane (20 mL) and methanol (20 mL) u n t i l a p e r s i s t e n t b lue c o l o r was o b t a i n e d . The mix ture was g r a d u r a l l y warmed to about - 2 5 ° C under an argon atmosphere and t r i p h e n y l p h o s p h i n e ( 2 . 0 g , 7 .5 mmol) was added. S t i r r i n g was c o n t i n u e d at - 2 5 ° C f o r 30 minutes and 2 5 ° C f o r 30 minutes . A f t e r removal of s o l v e n t under vacuo , the crude k e t o - a l d e h y d e s (378a ,b) ( ^ m a x : 2820, 1730 cm 1 ) was d i s s o l v e d i n d r y benzene (20 mL). p - T o l u e n e s u l f o n i c a c i d (20 mg) was added and 261 the r e s u l t i n g mix ture was r e f l u x e d f o r 4 .5 hours i n a Dean-S t a r k a p p a r a t u s . A f t e r c o o l i n g and e x t r a c t i o n w i t h e t h e r , the combined o r g a n i c l a y e r s were washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and d r i e d (MgSC^). Removal of s o l v e n t under vacuo a f f o r d e d a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 5:1) to a f f o r d b i c y c l i c enones (369a ,b) (1 .4 g , 89%) as a c o l o r l e s s o i l . R f 0.29 ( p e t . e t h e r : e t h e r , 2 : 1 ) ; Vmax ( f i l m ) : 1673, 1633 cm 1 ; & (CDCI3, 400 MHz): ^ H - n . m . r . of major i somer: 1.10 ( s , 3H, C H 3 ) , 1.21 ( s , 3H, C H 3 ) , 3 . 05 -3 .12 (m, 1H, RR'CH.0CH 3 ) , 3.32 ( s , 3H, C H 3 ) , 5.95 (dd , 1H, RC(0 )CH: CH.R' , J=4 Hz , 10 H z ) , 6.56 ( d t , 1H, RC(0)CR:CHR' , J=10 Hz, 2Hz); m/e ( r e l a t i v e i n t e n -s i t y ) : 208 ( 2 3 . 7 , M + ) , 176 ( 2 3 . 4 ) , 161 ( 1 7 . 0 ) , 81 (100); Exac_L Haas, c a l c d . f o r C 1 3 H 2 o ° 2 : 208.1463; found: 208.1459. K f i t n n R S (40Ba.h) (369a,b) (408a,b) L i t h i u m d i i s o p r o p y l a m i d e was generated by s t i r r i n g n -b u t y l l i t h i u m (1 .6 M; hexane) (2 .0 mL, 3.2 mmol) w i th d i i s o -propy lamine (0 .45 mL, 3.2 mmol) at 0 ° C under an argon atmos-262 phere in d r y t e t r a h y d r o f u r a n (10 mL) and hexamethylphosphor-amide (0 .37 mL, 2 .3 mmol) f o r 30 minutes . T h i s s o l u t i o n was then coo l ed to - 7 8 ° C and a s o l u t i o n of b i c y c l i c enones (369a ,b) (0 .46 g , 2.2 mmol) i n d r y t e t r a h y d r o f u r a n (10 mL) was added. The r e s u l t i n g mix ture was s t i r r e d a t - 7 8 ° C f o r 1 h o u r , a f t e r which t ime i t was t r a n s f e r r e d v i a a c a n n u l a to a c o l d ( - 7 8 ° C ) s o l u t i o n of a c e t i c a c i d (0 .62 mL, 11 mmol) i n anhydrous e ther (15 mL). T h i s s o l u t i o n was a l lowed to warm to room temperature , e x t r a c t e d w i t h e ther and washed w i t h s a t u r a t e d sodium b i c a r b -onate s o l u t i o n and b r i n e , and d r i e d (MgSO^). Removal of s o l v e n t p r o v i d e d a crude ketones (408a ,b) (0.41 g , 87%). % : 0.33 ( p e t . e t h e r : e t h e r , 1 : 1 ) ; V m a x ( f i l m ) : 1707 c m - 1 ; S ( C D C 1 3 , 400MHz): ^ H - n . m . r . of major d i a s t e r e o m e r : 1.06 ( s , 3H, CH3) , 1.18 ( s , 3H, C H 3 ) , 3 . 1 8 - 3 . 3 8 (m, 1H, RR'CHOMe), 3.37 ( s , 3H, R 0 C H 3 ) , 5 .35-5 .42 (m, 1H, H a ) . To a s o l u t i o n of ketones (408a ,b) (0 .4 g , 1.9 mmol) i n d r y t e t r a h y d r o f u r a n (15 mL) was added v inylmagnes ium b r o -263 mide ( 1 . 0 M, THF) ( 1 . 9 mL, 1 .9 mmol) at 0°C under an argon a t -mosphere. S t i r r i n g was c o n t i n u e d at 2 5 ° C f o r 2 .5 hours and then r e f l u x e d f o r 0 .5 hour . A f t e r c o o l i n g , the r e a c t i o n mix ture was quenched c a r e f u l l y w i t h s a t u r a t e d ammonium c h l o r i d e s o l u t i o n (50 mL) f o l l o w e d by e x t r a c t i o n w i t h e t h e r . The combined o r g a n i c l a y e r s were washed w i t h water and b r i n e , and d r i e d (MgSO^). Removal of s o l v e n t gave a crude p r o d u c t which was p u r i f i e d by column chromatography ( s i l i c a g e l , p e t . e t h e r : e t h e r , 9 :1 ) to a f f o r d d i e n o l s (409a ,b) (0 .34 g , 76%) as a c o l o r l e s s o i l . Rf : 0 .65 ( p e t . e t h e r : e t h e r , 1 : 1 ) ; ^ m a x ( f i l m ) : 3440, 1640 c m - 1 ; & (CDCI3, 400 MHz): 1 H - n . m . r . of major d i a s t e r e o m e r : 0 .91 ( s , 3H, C H 3 ) , 0 .92 ( s , 3H, C H 3 ) , 3 .17 -3 .26 (m, 1H, R R ' C R 0 C H 3 ) , 3.37 ( s , 3H, R 0 C H 3 ) , 5 .11 (dd , 1H, Hb, J = l l Hz , 1 .5 H z ) , 5.30 (dd , 1H, H o , J=17.5 Hz , 1 .5 H z ) , 5 .31 -5 .33 (m, 1H, H d ) , 6.45 ( d d , 1H, H * , J = l l Hz, 17.5 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 236 ( 1 7 . 2 , M + ) , 218 ( 3 . 9 0 ) , 204 ( 6 . 1 0 ) , 186 ( 4 . 0 0 ) , 98 .0 E x a c t mass c a l c d . f o r C 1 5 H 2 4 0 2 : 236.1776; found: 236.1774; A n & l . c a l c d . f o r C 1 5 H 2 4 0 2 : C 76 .23 , H 10 .23; found: C 75 .99 , H 10 .29 . 264 p-Bromobenzoates ( 3 8 1 a . b ) 0' Me (369a ,b ) (428a ,b ) (381a ,b ) At - 7 8 ° C , NaBH 4 (23 mg, 0.60 mmol) was added to a s t i r r e d s o l u t i o n of enones ( 3 6 9 a , b ) (0 .12 g , 0.60 mmol) and C e C l 3 - 7 H 2 0 (0 .22 g , 0.60 mmol) i n methanol (10 mL). S t i r r i n g was c o n t i n u e d at - 7 8 ° C f o r 10 minutes and at 2 5 ° C f o r 1 hour , b e f o r e water (2 .0 mL) was added. E x t r a c t i o n w i t h e ther was f o l l o w e d by washing w i t h h y d r o c h l o r i d e a c i d (0 .5 N) and b r i n e , and d r i e d ( M g S 0 4 ) . Removal of s o l v e n t under vacuo p r o v i d e d a l l y l i c a l c o h o l s ( 4 2 8 a , b ) (0 .13 g , 99%) as a y e l l o w i s h o i l . V m a x ( f i l m ) : 3410 cm 1 . T h i s crude product was d i r e c t l y used i n the next s tep wi thout f u r t h e r p u r i f i c a t i o n . p-Bromobenzoyl c h l o r i d e (0 .42 g , 1.9 mmol) was added to a s o l u t i o n of a l l y l i c a l c o h o l s ( 4 2 8 a , b ) (0 .13 g , 0.59 mol) in d r y p y r i d i n e (10 mL) at 2 5 ° C under an argon atmosphere. The mix ture was s t i r r e d f o r 2 hours and h y d r o c h l o r i d e a c i d (1 .0 N, 10 mL) was then added and the m i x t u r e e x t r a c t e d w i t h e t h e r . The combined o r g a n i c l a y e r s were washed wi th h y d r o c h l o r i d e a c i d (1 .0 N ) , po tass ium hydrox ide s o l u t i o n (1 .0 N) and b r i n e , and d r i e d ( M g S 0 4 ) . Upon removal of s o l v e n t under vacuo the 265 crude product was t r i t u r a t e d wi th e t h a n o l , and the mother l i q u o r was c o n c e n t r a t e d . The r e s i d u e was p u r i f i e d by column chromatography ( p e t . e t h e r : e t h e r , 5 : 1 ) to g i v e p-bromobenzoates (381a ,b) (0 .16 g , 66%), as a c o l o r l e s s o i l . R f : 0.56 ( p e t . e t h e r : e t h e r , 1 : 1 ) ; \ a x ( f i l m ) : 1720 c m " 1 ; S ( C D C 1 3 , 300MHz): ^ - n . m . r . of major d i a s t e r e o m e r : 1.05 ( s , 3H, C H 3 ) , 1.14 ( s , 3H, C H 3 ) , 3.36 ( s , 3H, R 0 C H 3 ) , 3 .10 (m, 1H, R C E 0 C H 3 ) , 5 . 4 - 5 . 7 (m, 2H, RCH_:CH.R'), 7.58 ( d , 2H, aromat i c H s ' , J=7.5 H z ) , 7.92 ( d , 2H, aromat i c H s ' , J=7.5 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 392/394 ( 0 . 2 0 0 / 0 . 2 0 0 , M + / M + + 2 ) , 360 ( 1 0 . 0 ) , 185 ( 9 8 . 0 ) . Hydrazones (383a ,b) Enones (376a ,b) (95 mg, 0.42 mmol), and P d / C (10 mg) i n hexane (2 mL) was t r e a t e d w i t h hydrogen at 50 p s i at 2 5 ° C f o r 2 hours . A f t e r f i l t e r i n g o f f the c a t a l y s t , the f i l t r a t e was c o n c e n t r a t e d to p r o v i d e ketones (429a ,b) (85 mg, 89%) as 266 a c o l o r l e s s o i l . Vmax ( f i l m ) : 1705 c m " 1 . H2SO4 ( c o n c e n t r a t e d , 1 mL) was s l o w l y added to a s t i r r e d s o l u t i o n of ketones (429a ,b) (85 mg, 0 .37 mmol), and 2 , 4 -d i n i t r o p h e n y l h y d r a z i n e (0 .15 g , 0.76 mmol) i n e t h a n o l (5 mL). The r e a c t i o n mix ture was r e f l u x e d f o r 5 minutes , c o o l e d , and f i l t e r e d . The f i l t r a t e was c o n c e n t r a t e d and p u r i f i e d by column chromatography ( p e t . e t h e r : e t h e r , 1 0 : 1 ) to p r o v i d e hydrazones hydrazones (383a ,b) (0 .14 g , 91%) as a y e l l o w s o l i d , 6 ( C D C I 3 , 300MHz): 1 H - n . m . r . of major d i a s t e r e o m e r : 0 . 9 - 1 . 4 (m, 9H , gem-d i m e t h y l and C H 3 ) , 3 .36 ( s , 3H, R 0 C H 3 ) , 3 . 2 - 3 . 4 (m, 1H, RCROMe), 7.96 ( d , 1H, Ha , J=9 H z ) , 8.30 ( d , 1H, Hb, J=9 H z ) , 9 .15 ( s , 1H, H o ) , 11 .2 ( d , 1H, R'NRR", J=9 H z ) ; m/e ( r e l a t i v e i n t e n s i t y ) : 404 ( 2 5 . 1 , M + ) , 85 .0 ( 8 8 . 2 ) , 41 .0 (100) . L i t h i u m d i i s o p r o p y l a m i d e was generated by s t i r r i n g n - b u t y l l i t h i u m (1 .6 M, hexane) (0 .63 mL, 1.0 mmol) w i t h 267 d i i s o p r o p y l a m i d e (0 .1 mL, 1.0 mmol) at 0 C under an argon atmosphere i n d r y t e t r a h y d r o f u r a n (10 mL) f o r 30 minutes . The r e a c t i o n mix ture was then c o o l e d to -78 C and a s o l u t i o n of b i c y c l i c enone (368a) (0 .24 g , 1.0 mmol) i n d r y t e t r a -h y d r o f u r a n (10 mL) was added. The r e s u l t i n g mix ture was s t i r -red at - 7 8 ° C f o r one hour , a f t e r which time i t was c a n u l a t e d i n t o a c o l d ( - 7 8 ° C ) s o l u t i o n of a c e t i c a c i d ( 1 . 7 mL, 30 mmol) i n anhydrous e ther (10 mL). T h i s s o l u t i o n was a l lowed to warm to room temperature , e x t r a c t e d w i t h e t h e r , and washed w i t h s a t u r a t e d sodium b i c a r b o n a t e s o l u t i o n and b r i n e , and d r i e d (MgSO^j). A f t e r removal of s o l v e n t , the crude p r o d u c t was p u r i f i e d by column chromotography ( p e t . e t h e r : e t h e r , 5:1) to p r o v i d e dimer (411) as c o l o r l e s s pr i sms (0 .22 g , 91%). mp 2 1 8 ° C ; Vmax ( C D C 1 3 ) : 3496(w), 1715 c m - 1 ; S (CDCI3 , 300MHz): 0.84 ( s , 3H, C H 3 ) , 0.93 ( s , 3H, CH 3) , 4 .59 ( s , 1H, ROE), 5 .38-5.53 (m, 3H, RCR:CHR' , and R"CH.0Ac); m/e ( r e l a t i v e i n t e n s i t y ) : 472 ( 4 . 9 0 , M + ) , 454 ( 7 5 . 3 ) , 236 ( 5 1 . 3 ) , 176 ( 2 8 . 9 ) , 159 (100) . 258 PPKCTRA APPENDIX 271 ( 1 6 7 a , b ) 0 ppm 'H-n.m.r.(400MHz) * i t* >• <i i> 10 0 D i m e r s ( 1 6 9 a , b ) i i i i i I—i i i i I ' P T - I I i 1 i I'I'I i i i i r-r-H • 'n'f"' ' I I I ' I I I I | I I 1 l - l T t - I T-t'-pt-l | | | | | I I | T - | I I I «»» 44* i t * 4l-.TT--1 3 T W p V f t ' - r r r t t l | ' l i V i ' M r - f r f r t > i » t | ' |W-T T-t-t-r-r 'f,V fVr-r i i i i i I j i i i i i >** 1U 1 ( 7 i t * 'I i i ' I ' i i - r i -Low R e s o l u t i o n Mass S p e c t r u m 272 273 274 I n f r a - r e d spectrum of compounds (192a,b) FMiGUtMCr (CM 'I I n f r a - r e d spectrum of compound (26) 275 276 S t e r e o v i e w s o f compound ( 1 9 5 a ) , a n a l y s e d by X - r a y c r y s t a l l o g r a p h y . I n f r a - r e d s p e c t r u m o f (59) 277 278 279 (5.08 ppm) F-n.m.r.(254MHz) : s i n g l e t a t 5 .08 i n t h e r e s o l u t i o n e n h a n c e d p r o t o n d e c o u p l e d s p e c t r u m . C 1 3 B 0 I | I I I I | I I I I | I I I I | I I I I | I I I I | 1 I T I [ 6 0 4 0 10 PPM 0 i I i i i i | I I i t | i i I i | i i i i | 1 1 1 1 I ' 1 1 1 1 1 1 1 1 I 1 1 1 1 1 1 1 I 1 1 1 ' 1 160 140 120 100 8 0 A P T C - n . m . r . of compound (211) 4ooo 3 *00 iioo • ' •oo ?40o ?ooo i«oo i*>oo 1400 1 7 0 0 iooo • o o * 0 0 " 400 f R F O u f N C Y (CM ') I n f r a - r e d s p e c t r u m of ( + ) - L o n g i f o l e n e (61) 2 8 2 71 M M It 21 I f I* • III ' ] i ' i l l I ' l i | i i i i i i i l t | i i l i l l l i l [ i i i i i i tit til I M t i l III (I II _ II 11 tl II I'l'i ,111111M, ,I, ' i i iii'rh'. Ji l| I'l'lUl 1! , I , Low r e s o l u t i o n mass s p e c t r u m of compound (61) MtCROMCTEM Un> I n f r a - r e d spectrum of compound (324) 283 284 285 5 4 3 2 1 0 ppm H-n . m.r. (400MHz) 286 S t e r e o v i e w s o f compound (392) , a n a l y s e d by X- r a y c r y s t a l l o g r a p h y . S t e r e o v i e w s o f compound (411) ' a n a l y s e d by X- r a y c r y s t a l l o g r a p h y . 287 289 5 4 3 2 1 0 ppm 1 H - n . m . r . ( 4 0 0 M H z ) 290 291 292 REFERENCES 293 [1] G. B l a s c h k e , Arr.neim. - F o r s c h . 1979, 2 £ , 1640. [2] (a) G. Q u i n k e r t , H . S t a r k , Angew. Chem. I n t . E d . E n g l . . 1983. ?.?.. 637. (b) B . F r a s e r - R e i d , R. C . Anderson , F n r t s c h t . Chem. Org. Naturst., 1980, 29., 1. [3] (a ) S. H a n e s s i a n , A c c . Chem. Res. . 1979, 12., 159. (b) W. A. Szabo, and H . T . L e e , A l d r i c h i m i c a A c t a . . 1980, 13., 13. [4] B. M. 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