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Thermal rearrangement of functionalized 6-exo-(1-alkenyl)bicyclo\3.1.0]hex-2-enes application to the… Jung, Grace Lorena 1985

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THERMAL REARRANGEMENT OF FUNCTIONAL]!ZED 6-EXO-(1-ALKENYL)BICYCLO[3.1.0]HEX-2-ENES APPLICATION TO THE TOTAL SYNTHESIS OF (+)-SINULARENE by GRACE LORENA JUNG B.Sc, University of B r i t i s h Columbia, 1 9 8 0 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (DEPARTMENT OF CHEMISTRY) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA June 198 5 (c) Grace Lorena Jung In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date Aug )E-6 n / s n ABSTRACT This thesis describes f i r s t l y , a study involving the thermal rearrangement of substituted 6-exo-r (1-alkenyl) b i c y c l o -[3.1.0]hexenes, and secondly, the application of t h i s type of transformation to a t o t a l synthesis of (+)-sinularene (125). The 6-exo-(1-alkenyl)bicyclo[3.1.0]hexenes (187, 189, 192, 19 4, 240, 27 4 and 340) were prepared and thermolyzed i n sealed tubes to afford the corresponding bicyclo[3.2.1]octa-2,6-dienes (188, 190, 193, 195, 241, 276 and 341) i n generally excellent y i e l d s . With the exception of 190, the thermolysis products were subjected to acid-catalyzed hydrolysis to give the respective bicyclo[3.2.1]octenones. From t h i s study, i t i s clear that a) the Cope rearrangement of substrates, such as 274 and 340, containing even s t e r i c a l l y bulky substituents on the 6-alkenyl side chain presents a viable means of gener-ating f unctionalized bicyclo [ 3 . 2 .1] octa-2 , 6^-dienes, b) th i s methodology provides for the placement of s y n t h e t i c a l l y useful f u n c t i o n a l i t i e s on any of the carbon bridges of the b i c y c l o -[3.2.1]octane skeleton, and c) the transformations 24 0+2 41 and 274->276 provide strong evidence for the s t e r e o s p e c i f i c i t y of the rearrangement process. In the t o t a l synthesis of (+)-sinularene (125), the key step involved the thermal rearrangement of 322 to afford the bicyclo[3.2.1]octadiene 321. The compound 322 was readi l y prepared as follows. l-Lithio-3-methyl-l-butyne was treated with methacrolein to furnish the a l l y l i c alcohol 331, which was transformed into the ester 332 v i a an orthoester Claisen rearrangement (hot t r i e t h y l .orthoacetate, propionic a c i d ) . Hydrolysis of the ester 332, followed by reaction of the re-sultant acid with oxalyl chloride i n refluxing hexane gave the corresponding acid chloride 334. Treatment of 334 with a cold, ethereal solution of diazomethane afforded the diazo ketone 335, which i n the presence of copper (II) acetoacetonate i n re f l u x i n g benzene, underwent an intramolecular carbenoid c y c l i -zation to furnish the b i c y c l i c ketone 336. Semihydrogenation of 336 using L i n d l a r 1 s catalyst gave stereoselectively the c i s -alkenyl ketone 337. The enone 33 8 was obtained by oxidizing the t r i m e t h y l s i l y l enol ether of 337 using palladium (II) ace-tate i n a c e t o n i t r i l e . When the enone 338 was treated with lithium divinylcuprate, the two epimeric products 339 and 346 were obtained i n a r a t i o of 9:1, respectively, and were sus-sequently separated by column chromatography. Trapping the lithium enolate of 339 with t - b u t y l d i m e t h y l s i l y l chloride led to the required enol ether 322. Thermolysis (220°C, sealed tube) of 322 i n benzene produced exclusively i n 86% y i e l d the desired b i c y c l i c triene 321. Subjection of 321 to hydrobor-ation using disiamylborane gave, aft e r oxidative workup, the alcohol 347, which on treatment with p-toluenesulfonyl chloride i n the presence of 4-dimethylaminopyridine, afforded the ketone 349. Successive hydrogenation of 349 and Wittig o l e f i n a t i o n of the resultant ketone 280 completed the t o t a l synthesis of (+)-sinularene (125). i v •>-SiQ 187 192 194 240 274 340 R_—R.—R r —R /-—H 2. 3 4 b b R-,=R .—Rr=R,—H, R„ =CH=CH„ 3 4 5 6 2 2 R3=R4=R5=R6=H, R 2=CH 2C0 2Et R 3 — R 5 — ^ ' R 4 = C 0 2 M e ' R 6 = - P r R =R =R =R =H, R =iPr 2 3 4 6 5 — R2=R4=R6=H, R 5=iPr, R^ =Me 188  193  195  241  276 341 0 189 190 331 OH FT ^ O ^ 332: R=OEt 334: R=C1 335: R=CHN, 0 336 337 b r 7 338 339 322 280 125 V TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS V LIST OF TABLES v i i LIST OF FIGURES v i i i ACKNOWLEDGEMENTS x ABBREVIATIONS x i CHAPTER I: THERMAL REARRANGEMENTS OF 6-ALKENYL-BICYCLO[3.1.0]HEX-2-ENES 1 1.1 Introduction 1 1.1.1 Previous Work on the Cope Rearrange-ments of cis-1,2-Divinylcyclopropanes . . . 1 1.1.2 The Application of Di v i n y l c y c l o -propane Rearrangements i n Synthesis . . . . 15 1.1.3 Previous Work on the Cope Rearrange-ments of 6-Alkenylbicyclo[3.1.0]- 26 hex-2-enes 1.1.4 The Problem 34 1.1.5 Methods for the Assembly of Bicyclo[3.1.0]hexanones 36 1.2 Discussion 50 1.2.1 The Synthesis and Rearrangement of 2-(tert-Butyldimethylsiloxy)-6-exo-vinylbicyclo[3.1.0]hex-2-ene TT87) 50 1.2.2 The Synthesis and Rearrangement of 6-exo-Vinylbicyclo[3.1.0]hex-3-en-2-one (189) and C-4 Function-a l i z e d 6-exo-Vinylbicyclo[3.1.0]-hex-2-enes 192 and 194 60 v i Page 1.2.3 The Synthesis and Rearrangement of 6-exo- [ (E) •- and (Z)-1-alkenyl]-bicyclo[3.1.0]hex-2-enes (240) and (274) 95 1.2.4 Conclusion 138 CHAPTER I I : THE TOTAL SYNTHESIS OF (+)-SINULARENE 139 2.1 Introduction 139 2.1.1 The Iso l a t i o n and Characterization of (-)-Sinularene 139 2.1.2 Previous Syntheses of Sinularene 141 2.2 Discussion 150 2.2.1 The Synthetic Plan 150 CHAPTER I I I : EXPERIMENTAL 196 3.1 General 196 3.2 Solvents and Reagents 198 3.3 Model Studies 201 3.4 The Total Synthesis of (+)-Sinularene . . . . 258 BIBLIOGRAPHY 286 v i i L I S T O F T A B L E S Page TABLE I: "^H nmr Spectral Data for Compounds 278 and 279 . 134 TABLE I I . '''H nmr Spectral Data for Compounds 276 and 341 168 TABLE I I I . Drying Agents Used for Solvents and Reagents 199 v i i i LIST OF FIGURES Page FIGURE 1. "^H nmr spectrum assignments for the vinylcyclopropane moiety of ketone 179 52 FIGURE 2. The homonuclear spin decoupling experiment with 189 69 FIGURE 3. The 400 MHz 1H nmr spectrum of 190 71 FIGURE 4. The homonuclear spin decoupling experiment with 190 73 FIGURE 5. The 400 MHz 1H nmr spectrum of 237 . . . 78 FIGURE 6. The homonuclear spin decoupling experiment with 237 8 0 FIGURE 7. The 400 MHz 1H nmr spectrum of 192 . . . 82 FIGURE 8. The 400 MHz 1H nmr spectrum of 194 . . . 85 FIGURE 9. The homonuclear spin decoupling experiment with 194 87 FIGURE 10. The 400 MHz 1H nmr spectrum of 193 . . . 89 FIGURE 11. The 400 MHz 1H nmr spectrum of 238 . . . 91 FIGURE 12. The homonuclear spin decoupling experiment for 238 9 3 FIGURE 13. The 400 MHz 1H nmr spectrum of 258 . . . 102 FIGURE 14. The expanded region 6 5.6-6.3 of the -*-H nmr spectrum of 259 . 104 FIGURE 15. The 400 MHz 1H nmr spectrum of 274 . . . 121 FIGURE 16. The homonuclear spin decoupling experiment with 241 126 FIGURE 17. The 400 MHz 1H nmr spectrum of 276 . . . 128 8  homonuclear spin decoupling experiment with 276 130 i x L I S T O F F I G U R E S ( C O N T . ' D ) Page F I G U R E 1 9 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f 2 7 8 . . . 1 3 2 F I G U R E 2 0 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f 2 7 9 . . . 1 3 3 F I G U R E 2 1 . T h e h o m o n u c l e a r s p i n d e c o u p l i n g e x p e r i m e n t w i t h 2 7 8 1 3 6 F I G U R E 2 2 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f 3 3 6 . . . 1 5 9 F I G U R E 2 3 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f 3 4 0 . . . 1 6 3 F I G U R E 2 4 . T h e 4 0 0 M H z n m r s p e c t r u m o f 3 4 1 . . . 1 6 5 F I G U R E 2 5 . T h e h o m o n u c l e a r s p i n d e c o u p l i n g e x p e r i m e n t w i t h 3 4 1 1 6 7 F I G U R E 2 6 . T h e h o m o n u c l e a r s p i n d e c o u p l i n g e x p e r i m e n t w i t h 3 4 3 1 7 0 F I G U R E 2 7 . T h e 4 0 0 M H z AH n m r s p e c t r u m o f 3 3 9 . . . 1 7 6 F I G U R E 2 8 . T h e n u c l e a r O v e r h a u s e r e n h a n c e m e n t e x p e r i m e n t w i t h 3 3 9 . . . 1 7 8 F I G U R E 2 9 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f 3 4 6 . . . 1 8 0 F I G U R E 3 0 . T h e 4 0 0 M H z XH n m r s p e c t r u m o f 3 2 2 . . . 1 8 2 F I G U R E 3 1 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f 3 2 1 . . . 1 8 4 F I G U R E 3 2 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f 1 9 0 . . . 1 9 0 F I G U R E 3 3 . T h e 4 0 0 M H z 1H n m r s p e c t r u m o f (+) - s i n u l a r e n e 192.a" 1 3 F I G U R E 3 4 . T h e 1 0 0 . 6 M H z C n m r s p e c t r u m o f ( + ) - s i n u l a r e n e . 192-b X ACKNOWLEDGEMENTS I wish to express my gratitude to Professor Ed Piers for the opportunity to have learned and worked under his excellent guidance. The p a r t i c u l a r combination of his humour, patience and professionalism i n chemistry c r a f t has made i t a pleasure to work with him. Thanks must go to present and past members of Dr. Piers' group for sharing i n both the agonies and ecstasies of research. Their cooperation, ideas and friendship have seen me through many an obstacle. For t h e i r technical expertise and cooperation, thanks must go to members of the departmental mass spectral a n a l y t i c a l and nmr labs. My thanks and best wishes are extended to Dr. Brian Keay for many enlightening discussions, h e l p f u l suggestions and c r i t i c i s m s , and the care taken i n proof reading t h i s thesis. I am indebted to Kevin Holme, not only for meticulously proof reading t h i s thesis, but for his steady patience and encouragement ( p a r t i c u l a r l y on those days when nothing seemed to go r i g h t ) . F i n a n c i a l support i n the form of a University Graduate Fellowship (1980-81) and scholarships from the Natural Sciences and Engineering Research Council of Canada (1981-84) are g r a t e f u l l y acknowledged. x i ABBREVIATIONS The f o l l o w i n g a b b r e v i a t i o n s have been used t h r o u g h o u t t h i s t h e s i s : Ac = a c e t y l acac = a c e t y l a c e t o n a t e 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 Bu = b u t y l mCPBA = m e t a - c h l o r o p e r b e n z o i c a c i d d = d o u b l e t DBU = l , 8 - d i a z a b i c y c l o [ 5 . 4 . 0 ] u n d e c - 7 - e n e 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 DMAP = 4 - d i m e t h y l a m i n o p y r i d i n e DME = 1,2-dimethoxyethane DMSO = d i m e t h y l s u l f o x i d e e q u i v = e q u i v a l e n t ( s ) E t = e t h y l g l c = 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 m = m u l t i p l e t Me = m e t h y l mp = m e l t i n g p o i n t nmr = n u c l e a r m agnetic resonance PCC = p y r i d i n i u m c h l o r o c h r o m a t e PDC = p y r i d i n i u m d i c h r o m a t e Ph = p h e n y l P r = p r o p y l q = q u a r t e t r . t . = room t e m p e r a t u r e s = s i n g l e t s i a = s i a m y l t = t r i p l e t THF = t e t r a h y d r o f u r a n t r i m e t h y l s i l y l t h i n - l a y e r c h r o m a t o g r a p h y p a r a - t o l u e n e s u l f o n y l x i i i TO MY PARENTS, with a f f e c t i o n , gratitude and respect ... 1 Chapter I THERMAL REARRANGEMENTS OF 6-ALKENYLBICYCLO[3.1.0]HEX-2-ENES 1.1 Introduction 1.1.1 Previous Work on the Cope Rearrangements of cis-1,2-Divinylcyclopropanes A well-documented reaction of c i s _ - l , 2-divinylcyclo-propane systems i s the [3,3]-sigmatropic s h i f t (Cope rearrange-ment) , the f a c i l i t y of which i s attributed to the accompanying 2 * I t i s not the intention nor i s i t within the scope of this thesis to provide an exhaustive review of the Cope rearrange-ment of cis-1,2-divinylcyclopropane systems. For review a r t i c l e s on the subject, the reader i s referred to r e f s . 1-6. For a th e o r e t i c a l treatment of the Cope rearrangement, see r e f s . 7 and 8. 2 r e l i e f of s t r a i n i n the cyclopropane ring and the favorable o r b i t a l overlap between the double bonds i n the t r a n s i t i o n 6 9 state. F i r s t reported about 25 years ago, c i s - 1 , 2 - d i v i n y l -cyclopropane (1_) was noted for i t s extreme l a b i l i t y , as Vogel's attempts to synthesize and i s o l a t e this compound were thwarted. Under the conditions of the Hoffmann degradation of the quaternary ammonium hydroxide 3_5'''"^  and the elimination of the amine oxide 4_,"'"0 only 1,4-cycloheptadiene (2) was i s o l a t e d . Doering and Roth"*"1 obtained s i m i l a r r e s u l t s ; copper (I) chloride catalyzed cyclopropanation of cis-1,3,5-hexatriene at -45°C (eq. [1]) furnished 1,4-cycloheptadiene rather than cis-1,2-divinylcyclopropane, presumably v i a intermediate formation of cis-1,2-divinylcyclopropane. Indeed, cis-1,2-divinylcyclopropane eluded i s o l a t i o n and character^-12 i z a t i o n u n t i l 1973, when Brown and coworkers found that i t rearranged quickly to 1,4-cycloheptadiene at temperatures above -20°C, with a h a l f - l i f e of 90 seconds at 35°C. Since then, i t has been characterized also, i n the form of a complex 5_, which 13 i s stable at ambient temperatures. There are a number of compounds incorporating a cis-1,2-[1] •1 3 Rhacac-f6 - 2 0 ° C R h a c a c - f 6 [ 2 ] d i v i n y l c y c l o p r o p a n e s y s t e m w h i c h e x h i b i t f a c i l e d e g e n e r a t e C o p e r e a r r a n g e m e n t s . T h i s p h e n o m e n o n g i v e s r i s e t o s o m e i n t e r e s t i n g f e a t u r e s i n t h e t e m p e r a t u r e - d e p e n d e n t n m r s p e c t r a 1 4 1 4 c 1 5 o f s y s t e m s s u c h a s b u l l v a l e n e (6_) , b a r b a r a l a n e (7) ' 1 6 a n d s e m i b u l l v a l e n e (8_) . W h i l e t h e n m r s p e c t r a r e c o r d e d a t l o w t e m p e r a t u r e s a r e c o n s i s t e n t w i t h t h e s t r u c t u r e s s h o w n T A B L E 1 : R a t e C o n s t a n t s f o r t h e V a l e n c e T a u t o m e r i z a t i o n o f B u l l v a l e n e , B a r b a r a l a n e a n d S e m i b u l l v a l e n e C o m p o u n d 6 7_ 8 F i r s t - O r d e r R a t e  C o n s t a n t ( / s e c ) 3 4 4 0 1 . 7 3 X 1 0 2 . 2 X 1 0 ' T e m p e r a t u r e (°C) 2 5 2 5 1 0 3 T h i s t y p e o f r e a r r a n g e m e n t a f f o r d s a p r o d u c t w h i c h i s e q u i v a l e n t t o t h e s t a r t i n g m a t e r i a l . 4 ( T a b l e 1 ) , t h o s e r e c o r d e d a t h i g h e r t e m p e r a t u r e s r e v e a l t h e c o a l e s c e n c e o f s i g n a l s , i n d i c a t i v e o f a r a p i d e q u i l i b r i u m b e t w e e n t h e t a u t o m e r i c f o r m s . I n t h e c a s e o f s e m i b u l l v a l e n e , t h i s i n t e r c h a n g e i s o b s e r v e d e v e n a t - 1 1 0 ° C , f a s t e r t h a n a n y 1 fie o t h e r s y s t e m k n o w n t o u n d e r g o t h e C o p e r e a r r a n g e m e n t . S i m p l e r , b i c y c l i c d e r i v a t i v e s o f c i s - 1 , 2 - d i v i n y l c y c l o -p r o p a n e s , s u c h a s n o r c a r a d i e n e (9_) , h o m o t r o p i l i d e n e (10_) a n d 1 1 , h a v e b e e n f o u n d t o u n d e r g o t h e r m a l i s o m e r i z a t i o n s a l s o 1 7 w i t h r e m a r k a b l e e a s e . D o e r i n g a n d K n o x r e p o r t e d t h a t c a r b e n e a d d i t i o n t o b e n z e n e ( e q . [ 3 ] ) l e d t o t h e e x c l u s i v e 1 1 1 2 5 i s o l a t i o n of 1 , 3 , 5-cycloheptatriene, rather than norcaradiene. In fact, there i s no evidence for the existence of norcaradiene 18 even at - 1 5 0°C, although cer t a i n substituted norcaradienes 19 4 12 have been i s o l a t e d . Homotropilidene ( 1 £ ) , ' another example of a compound which undergoes the degenerate Cope rearrangement (eq. [ 4 ] ) , exhibits the rapid e q u i l i b r a t i o n c h a r a c t e r i s t i c of bullvalene (6_) . Perhaps the simplest known example of a stable cis - 1 , 2-divinylcyclopropane, 1 1 was 20 i s o l a t e d and characterized by Baird and Reese, after i t s 2 1 existence was speculated by Roth over 20 years ago. Roth 2 1 i s o l a t e d only the b i c y c l i c nonadiene 12_ a f t e r subjection of 1 , 3 , 5-cyclooctatriene to carbene addition (eq. [ 5 ] ) , and postulated that the Cope rearrangement of 11. to 12_ had occurred 20 rapidly at room temperature. However, Baird and Reese reported that 1JL, having a h a l f - l i f e of ca. 1 day at 25 °C, isomerized to give 12^ when heated for 1 hour at 6 0 °C. r A l k y l substitution at the terminal s i t e s of the v i n y l groups, p a r t i c u l a r l y when this substitution i s of c i s orient-ation, has been shown to have quite a dramatic influence on the rate of rearrangement of cis - 1 , 2-divinylcyclopropanes. For example, the c i s , trans derivative 1_3 rearranges at 1 5 °C to give the cycloheptadiene 1_5 whereas the c i s , c i s isomer 14 o 22 requires heating at 75°C to achieve the same transformation. Just as s t r i k i n g are the r e l a t i v e rate differences found i n the thermal isomerizations for the cis - 1 , 2-divinylcyclopropanes 23 shown i n Table 2 . I t i s noteworthy that 18 with a single 6 n B u 1 3 1 5 1 4 c i s m e t h y l g r o u p s u b s t i t u t i o n o n t h e v i n y l m o i e t y r e a r r a n g e s c o n s i d e r a b l y s l o w e r t h a n 17_, w h i c h h a s t w o m e t h y l s u b s t i t u e n t s b o t h o f t r a n s o r i e n t a t i o n o n t h e v i n y l g r o u p s . A g a i n , t h e m a r k e d c o n t r a s t i n r a t e o f r e a r r a n g e m e n t i s o b s e r v e d b e t w e e n c i s - a n d t r a n s - m e t h y l s u b s t i t u t i o n o n a v i n y l m o i e t y i n 18_ a n d 1_6, r e s p e c t i v e l y . I n a d d i t i o n , t h e r e a r r a n g e m e n t r a t e o f t h e s e s y s t e m s a p p e a r s t o b e a f f e c t e d i n a v e r y s i m i l a r f a s h i o n b y t h e p r e s e n c e o f a l k y l s u b s t i t u e n t s o f s y n o r i e n t a t i o n ( r e l a t i v e t o v i n y l m o i e t i e s ) o n t h e c y c l o p r o p a n e r i n g . W h i l e t h e a n t i - 9 - m e t h y 1 d e r i v a t i v e l j ^ r e a d i l y r e a r r a n g e s t o 2_1 a t ~ 21 r o o m t e m p e r a t u r e , t h e s y n - 9 - m e t h y l i s o m e r 20_ r e q u i r e s T A B L E 2 : R e l a t i v e R a t e s o f t h e C o p e R e a r r a n g e m e n t o f c i s - 1 , 2 - D i a l k e n y l c y c l o p r o p a n e s Me Me 7 heating at 150°C for i t s transformation into the epimeric product 22.^ 19 21 R=Me, R'=H 20 22 R=H, R'=Me These variations i n reaction rates may be ra t i o n a l i z e d by examination of the t r a n s i t i o n state through which the c i s -1,2-dialkenylcyclopropanes undergo the Cope rearrangement. Although two possible t r a n s i t i o n states can be envisaged as shown i n Scheme 1, i t i s believed that these transformations proceed through a t r a n s i t i o n state having boat-like geometry 25-27 (23b) during the course of a [3,3]-sigmatropic s h i f t . A~ Cope rearrangement proceeding v i a a c h a i r - l i k e t r a n s i t i o n state (23a) would furnish the highly unstable trans,trans-cyclohepta-diene 2_4, whereas the rearrangement involving a boat-like t r a n s i t i o n state (23b) would afford the r e l a t i v e l y more stable cis,cis-cycloheptadiene 25. A comparison of the boat-like t r a n s i t i o n states 2_6 and 2_7 (eqs. [6] and [7]) to 23b reveals the d e s t a b i l i z i n g s t e r i c interactions which would account for the rearrangement rate differences between 1^ 6, 18_ and cis-1,2-divinylcyclopropane. The [3,3]-sigmatropic rearrangement of 16 would proceed through a t r a n s i t i o n state (26), which suffers 8 SCHEME 1 11 U 24 25 mainly from a methyl-hydrogen i n t e r a c t i o n . In addition to this s t e r i c i n t e r a c t i o n , 27_ i s further destabilized ( r e l a t i v e to 23b) by a s t e r i c repulsion of greater severity between the propenyl methyl and cis-cyclopropyl proton ('methyl-ring i n t e r -* action'), as r e f l e c t e d by the r e l a t i v e l y slower transformation of 1_8 to 3_2. Intermediate to these two types of s t e r i c * The deactivation energies (AAG^) of the methyl-ring and methyl-hydrogen interactions have been approximated as 4.55 and 0.84 kcal/mol, r e s p e c t i v e l y . ^ 9 10 * r e p u l s i o n s i s the m e t h y l - m e t h y l i n t e r a c t i o n d e s t a b i l i z i n g 28_ i n the Cope rearrangement o f Y]_ t o 3_3 (eq. [ 8 ] ) . The r e l a t i v e ease o f the c o n v e r s i o n o f 19 i n t o 2_1 (eq. [ 9 ] ) , i n c o n t r a s t t o the t r a n s f o r m a t i o n o f 20_ i n t o 22_ (eq. [10]) may be r a t i o n -a l i z e d by a s i m i l a r argument. That i s , one can e n v i s a g e t h a t the d e s t a b i l i z a t i o n o f 3_0 by t h e s t e r i c r e p u l s i o n between the cis_-eye l o p ropy 1 m e t h y l and r i n g r e s i d u e (-CI^CH,^-) would n e c e s s i t a t e h a r s h e r c o n d i t i o n s f o r the rearrangement o f 2_0 t o 22. [11] [12] [13] The AAG v a l u e e s t i m a t e d f o r a m e t h y l - m e t h y l i n t e r a c t i o n i s 1.03 k c a l / m o l . 2 3 11 There are cases where such s t e r i c interactions present i n the t r a n s i t i o n state of the Cope rearrangement may be so severe that the cis-1,2-dialkenylcyclopropanes f a i l to under-go [3,3]-sigmatropic s h i f t s and only e q u i l i b r a t i o n between the c i s and trans isomers (34 % 35, 36 t 37, 38 t 39) i s observed 26 27 even at elevated temperatures. ' Generally, the trans-1,2-divinylcyclopropanes exhibit greater thermal s t a b i l i t y than t h e i r c i s counterparts. Certainly th i s i s the case with trans-1,2-divinylcyclopropane since i t was i s o l a t e d and characterized 13 years before i t s elusive c i s 9 isomer. However, the trans compound i s known to rearrange at SCHEME 2 40 elevated temperatures (ca. 190°C) to afford 1,4-cycloheptadiene, either by epimerizing to the c i s isomer (path a), which then suffers a rapid Cope rearrangement, or by way of a b i r a d i c a l species 40_ which closes d i r e c t l y (path b) to give the cyclo-heptadiene (Scheme 2). While there i s evidence that the pathway 12 leading to the transient formation of c i s - 1 , 2 - d i v i n y l c y c l o -25 27—29 30—32 propane may involve one- ' or two-centre epimer-* 34 i z a t i o n s , the role of b i r a d i c a l s mechanistically i s s t i l l 25 35-39 a matter of discussion. Under thermolytic ' and photo-40-42 l y t i c conditions, there are indications that a b i r a d i c a l species i s manifested i n the intermediate formation of c i s - 1 , 2 -divinylcyclopropane (path a), which then spontaneously under-goes the Cope rearrangement. However, there seems to be l i t t l e evidence supporting the d i r e c t closure of a b i r a d i c a l intermediate (path b) to furnish cycloheptadiene. The rearrangements of a number of tran s - 1 , 2 - d i a l k e n y l -cyclopropane systems have been studied. For example, 4_1 and 27 42 have been shown to isomerize cleanly to 3_3 and 43, respectively, upon subjection to a temperature of 178°C for 4.2 hours (eq. [ 14 ] ) . S i m i l a r l y , the rearrangement products 43 44 46 and 47_ were obtained ' by heating 4_4 and 4_5, respectively, at 200°C fo r 5 hours. I t has been p r o p o s e d 2 5 ' 2 7 that these transformations involve a one-centre epimerization to the corresponding cis-dialkenylcyclopropanes i n the i n i t i a l and rate-determining step, followed by a rapid [ 3 , 3 ]-sigmatropic rearrangement of the c i s isomers to the observed cyclohepta-dienes. P a r t i c u l a r l y noteworthy i s the highly s t e r e o s p e c i f i c nature of these thermal rearrangements, i n which geometrically isomeric trans-dialkenylcyclopropanes afford exclusively the 33 * Garin has shown that both modes of epimerization may be competing processes. 13 42 R=H, R'=Me 47 R'=R"=C02Me,-R=H 44 R=R"=C02Me, R'=H 45 R'=R"=C02Me, R=H epimeric cycloheptadienes. In fact, the f i r s t hint of the s t e r e o s p e c i f i c i t y exhibited by the Cope rearrangement of these systems, appeared i n the work connected to the i s o l a t i o n and study of naturally occurring * trans-1,2-dialkenyIcyclopropanes (5£ and 52) and cyclohepta-dienes (5_1 and 5_3) found i n the brown algaes D i c t y o p t e r i s ^ ^ 52 49 and Ectocarpus s i l i c u l o s u s . Pettus and Moore investigated the p o s s i b i l i t y of dictyopterene A (50) and dictyopterene B (52) being the biogenetic precursors of dictyopterene C (51) 1 4 a n d d i c t y o p t e r e n e D1 (5_3) r e s p e c t i v e l y ( e q s . [ 1 6 ] a n d [ 1 7 ] ) . I n t e r e s t i n g l y , t h e y d i s c o v e r e d t h a t s u b j e c t i o n o f 50_ a n d 5_2_ t o e l e v a t e d t e m p e r a t u r e s l e d t o t h e e x c l u s i v e i s o l a t i o n o f c y c l o h e p t a d i e n e s w h i c h w e r e e n a n t i o m e r i c t o 5_1 a n d 53.. F r o m t h e s e f i n d i n g s , t h e y c o n c l u d e d t h a t t h e f o r m a t i o n o f 5_1 a n d 5 3 v i a t h e r m a l i n v i v o r e a r r a n g e m e n t f r o m t r a n s - 1 , 2 - d i a l k e n y l -c y c l o p r o p a n e s 5_0 a n d 52_, r e s p e c t i v e l y , w a s i m p r o b a b l e . A n o t h e r c o n s i d e r a t i o n w h i c h s u p p o r t e d t h i s c o n c l u s i o n i s t h e h i g h a c t i v a t i o n e n e r g y p a r a m e t e r s o f a t h e r m a l p a t h w a y . S i n c e t h e n , t h e p l a u s i b i l i t y o f p h o t o c h e m i c a l i n v i v o r e a r r a n g e m e n t s 5 3 o f 5JD a n d 5_2 h a s b e e n d e m o n s t r a t e d a n d h a s t h u s l e n t s u p p o r t 4 1 4 2 t o t h e r o l e o f b i r a d i c a l s ' i n s u c h t r a n s f o r m a t i o n s . F e w e x a m p l e s o f n a t u r a l p r o d u c t s i n c o r p o r a t i n g t h e t r a n s -1 , 2 - d i a l k e n y l c y c l o p r o p a n e s y s t e m a r e k n o w n . A m b r u c i t i n ( 4 8 ) , f o u n d i n a s o i l - i n h a b i t i n g b a c t e r i a P o l y a n g i u m  c e l l u l o s u m v a r . f u l v u m h a s b e e n s h o w n t o e x h i b i t b o t h a n t i -f u n g a l a n d a n t i b i o t i c a c t i v i t y . ^ 5 ' ^ 6 A s w e l l , E p s t e i n e t a _ l . h a v e r e p o r t e d t h e i s o l a t i o n o f r o t h r o c k e n e (4_9) f r o m a s p e c i e s o f s a g e b r u s h A . t r i d e n t a r o t h r o c k i i . 4 7 15 in vivo (?) H [ 1 6 ] 5 0 5 1 in vivo (?) H [ 1 7 ] E t 5 2 5 3 T h e s t u d i e s o n t h e s e m a r i n e n a t u r a l p r o d u c t s s o o n s p u r r e d t h e i n t e r e s t o f s y n t h e t i c o r g a n i c c h e m i s t s a n d t h e C o p e r e a r r a n g e m e n t o f 1 , 2 - d i v i n y l c y c l o p r o p a n e s g r a d u a l l y a t t r a c t e d r a t t e n t i o n i n s y n t h e t i c a p p l i c a t i o n s . 1 . 1 . 2 T h e A p p l i c a t i o n o f D i v i n y l c y c l o p r o p a n e R e a r r a n g e m e n t s A l t h o u g h t h e C o p e r e a r r a n g e m e n t o f d i v i n y l c y c l o p r o p a n e s y s t e m s h a s m u c h l i t e r a t u r e p r e c e d e n t , i t s a w o n l y s p o r a d i c u s e i n t h e s y n t h e s e s o f n a t u r a l p r o d u c t s i n t h e f i r s t f i f t e e n y e a r s o r s o a f t e r i t s d i s c o v e r y . G e n e r a l l y , s u c h s y n t h e s e s 5 4 w e r e d i r e c t e d a t b r i d g e d a r a c h i d o n i c a c i d a n a l o g u e s a n d s i m p l e m o n o c y c l i c c y c l o h e p t a d i e n e s i s o l a t e d f r o m m a r i n e 4 1 4 2 5 5 s o u r c e s . ' ' H o w e v e r , a s t h e s y n t h e t i c p o t e n t i a l o f d i -v i n y l c y c l o p r o p a n e r e a r r a n g e m e n t s r e c e i v e d m o r e r e c o g n i t i o n , i n S y n t h e s i s 1 6 s y n t h e t i c o r g a n i c c h e m i s t s b e g a n u s i n g t h i s i n t e r e s t i n g t r a n s -f o r m a t i o n w i t h i n c r e a s i n g f r e q u e n c y . I n s t u d i e s a i m e d a t t h e s y n t h e s i s o f t h e d i t e r p e n e p l a n t -5 6 5 7 g r o w t h r e g u l a t o r , p o r t u l a l (5_4) , M a r i n o a n d F e r r o s h o w e d t h a t t h e r e a r r a n g e m e n t o f t h e 3 - c y c l o p r o p y l u n s a t u r a t e d e s t e r " 5 5 t o t h e f u n c t i o n a l i z e d c y c l o h e p t a d i e n e 56_ p r o c e e d e d s m o o t h l y a t 2 1 0 ° C a n d i n e x c e l l e n t y i e l d ( 9 2 % ) . H a v i n g p r o v e n t h e f e a s i b i l i t y o f t h i s r e a r r a n g e m e n t i n s y n t h e s i s , i n v e s t i g a t o r s t h e n s o u g h t t o d e m o n s t r a t e t h e v e r s a t i l i t y o f t h e t h e r m a l i s o m e r i z a t i o n o f i n c r e a s i n g l y c o m p l e x d i v i n y l c y c l o p r o p a n e s . I n d e v e l o p i n g s y n t h e t i c a p p r o a c h e s t o h y d r o a z u l e n e s y s t e m s , 5 8 M a r i n o a n d K a n e k o s t u d i e d t h e r e a r r a n g e m e n t o f t h e 6 - c y c l o -p r o p y l e n o n e 5 7 a t o t h e c y c l o h e p t a d i e n e 5 8 a ( S c h e m e 3 ) . U n d e r t h e c o n d i t i o n s o f t h e t h e r m o l y s i s , 5 8 a w a s n o t a c t u a l l y i s o l a t e d , b u t i s o m e r i z e d t o t h e m o r e s t a b l e e n o n e 5 9 v i a a 1 7 S C H E M E 3 5 9 5 8 [ 1 , 3 ] - h y d r o g e n s h i f t . S i m i l a r l y , t h e c y c l o p r o p y l e n o n e 5 7 b 5 9 w a s f o u n d t o r e a r r a n g e t o t h e b i c y c l o [ 5 . 3 . 0 ] d e c a d i e n e 5 8 b a t e l e v a t e d t e m p e r a t u r e s . H o w e v e r , t h i s m e t h o d o l o g y w a s n o t . o n l y l a c k i n g i n s t e r e o s e l e c t i v i t y i n t h e p r e p a r a t i o n o f t h e k e y i n t e r m e d i a t e s 5_7, b u t d e m o n s t r a t e d l i m i t e d f l e x i b i l i t y i n s u b s t i t u t i o n p a t t e r n s o n t h e c y c l o p r o p a n e r i n g . F o r e x a m p l e , r e a c t i o n o f t h e e n o n e s u l f o x o n i u m m e t h y l i d e 6 0 a w i t h a c r o l e i n l e d t o a m i x t u r e o f c y c l o p r o p y l a l d e h y d e s 6 1 a . S u b -s e q u e n t s u b j e c t i o n o f 6 1 a t o c a r b o e t h o x y m e t h y l e n e t r i p h e n y l -p h o s p h o r a n e (6_2) f u r n i s h e d t h e m i x t u r e o f d i a l k e n y l c y c l o -p r o p a n e s 5 7 a . L a t e r s t u d i e s d o n e i n d e p e n d e n t l y b y b o t h M a r i n o ^ a n d W e n d e r ^ d e m o n s t r a t e d t h e u s e o f l - l i t h i o - 2 - v i n y l c y c l o p r o p a n e 6 3 i n t h e a s s e m b l y o f 3 - c y c l o p r o p y l e n o n e s 6 4 a n d t h e t h e r m a l 1 8 i s o m e r i z a t i o n o f t h e l a t t e r s u b s t a n c e s t o t h e b i c y c l o [ 5 . 3 . 0 ] -d e c a d i e n o n e 6_5 ( S c h e m e 4 ) . E x t e n s i o n o f t h e s e s t u d i e s t o t h e SCHEME 4 6 3 6 5 p r e p a r a t i o n o f f u n c t i o n a l i z e d c y c l o h e p t a n e s w a s e x e m p l i f i e d b y 6 1 W e n d e r ' s s y n t h e s i s ( S c h e m e 5 ) o f ( + ) - k a r a h a n a e n o n e ( 6 6 ) . T h e k e y i n t e r m e d i a t e 6_7 w a s p r e p a r e d i n t h r e e s t e p s f r o m i s o -b u t y r a l d e h y d e a n d a m i x t u r e o f l - l i t h i o - 2 - m e t h y l - 2 - v i n y l c y c l o -p r o p a n e s 6_8, a n d r e a r r a n g e d o n h e a t i n g ( c a . 1 6 5 - 1 7 5 ° C ) t o a f f o r d 6_9. S u b s e q u e n t d e p r o t e c t i o n o f 6_9 p r o v i d e d ( + ) - k a r a h a n a e n o n e (6_6) i n a n o v e r a l l y i e l d o f 5 4 % . 6 2 C o n c u r r e n t s t u d i e s b y P i e r s a n d N a g a k u r a i n v e s t i g a t e d t h e u t i l i z a t i o n o f l i t h i u m p h e n y l t h i o ( 2 - v i n y l c y c l o p r o p y l ) c u p r a t e 7 0 i n t h e p r e p a r a t i o n o f 0 - ( 2 - v i n y l c y c l o p r o p y l ) e n o n e s 71^ a n d d i e n o n e s 7_2 f r o m 3 - i o d o e n o n e s 7 3 ( e q . [ 1 8 ] ) . T h e s e s t u d i e s 1 9 S C H E M E 5 2 0 l e d e v e n t u a l l y t o t h e h i g h l y s t e r e o s e l e c t i v e p r e p a r a t i o n ' o f l i t h i u m p h e n y l t h i o [ 2 , 2 - d i m e t h y l - c i s - ( a n d t r a n s - ) - 3 - v i n y l c y c l o p r o p y l ) c u p r a t e s (7_4 a n d 75_, r e s p e c t i v e l y ) , w h i c h w e r e 2 1 e m p l o y e d t o p r e p a r e t h e g - c y c l o p r o p y l e n o n e s 76_ a n d 77_ ( S c h e m e 6 ) . W h e r e R = H , b o t h 7 6 . a n d 7_7 r e a r r a n g e d s m o o t h l y t o g i v e t h e b i c y c l i c e n o n e 7_9. H o w e v e r , w h e r e R = M e , 76_ a n d 7 7 i s o m e r i z e d t o g i v e n o t o n l y t h e e x p e c t e d C o p e r e a r r a n g e m e n t p r o d u c t 8_0, b u t a l s o t h e p r o d u c t 7 7 b r e s u l t i n g f r o m e p i m e r -i z a t i o n a n d 8 1 , o b t a i n e d t h r o u g h a [ 1 , 5 ] - h y d r o g e n s h i f t . S C H E M E 7 0 C^ 1 7 0 a 8 2 a : n = 0 b : n = l 7 0 a Li H CuSPh H OSiMe, 8 3 [ a ] ( i ) L D A , T H F , - 7 8 ° C ( i i ) M e ^ S i C l , E t ^ N [ b ] 1 0 0 - 1 1 0 ° C R e a c t i o n o f a s i m i l a r r e a g e n t , l i t h i u m p h e n y l t h i o ( 2 - c i s -v i n y l c y c l o p r o p y l ) c u p r a t e ( 7 0 a ) w i t h v a r i o u s c y c l i c a c y l c h l o r i d e s 8_2 p r o v i d e d a n e n t r y i n t o s p i r o s y s t e m s s u c h a s 8 3 a a n d 83_b ( S c h e m e 7 ) ,6 5 T h e c o m p l e x c y c l o p r o p y l c u p r a t e r e a g e n t s 8 4 a a n d 8 4 b , 6 6 s t e r e o s e l e c t i v e l y p r e p a r e d f r o m t h e c o r r e s p o n d i n g c y c l o p r o p y l b r o m i d e s , f o u n d a p p l i c a t i o n i n t h e s y n t h e s i s o f p o l y c y c l i c s y s t e m s . T h u s , t r e a t m e n t o f t h e 3 - i o d o e n o n e 7 3 a w i t h t h e S C H E M E 8 c u p r a t e 8_4 l e d t o t h e i s o l a t i o n o f t h e 3 / Y ~u n s a tu r a t e d k e t o n e 8 5 , p r e s u m a b l y f o r m e d f r o m t h e t h e r m a l i s o m e r i z a t i o n o f t h e c i s - d i v i n y l c y c l o p r o p a n e 8 6 u n d e r t h e r e a c t i o n c o n d i t i o n s 6 6 ( S c h e m e 8 ) . I n t e r e s t i n g l y , a d e g r e e o f s t e r e o s p e c i f i c i t y w a s o b s e r v e d i n t h e t h e r m a l ( 2 4 0 ° C ) r e a r r a n g e m e n t o f a 1:1 2 3 m i x t u r e o f 8 7 b a n d 8 7 c ( p r e p a r e d f r o m 8_9 a n d l i t h i u m p r o p i o n a t e ) , w h i c h a f f o r d e d a 1:1 m i x t u r e o f t h e b i c y c l i c e n o l e t h e r s 8 8 b a n d 8 8 c ( S c h e m e 9 ) ,6 7 SCHEME 10 f T h e C o p e r e a r r a n g e m e n t o f d i v i n y l c y c l o p r o p a n e s c o n t i n u e d t o f i n d a p p l i c a t i o n i n t h e s y n t h e s e s o f n a t u r a l l y - o c c u r r i n g s u b s t a n c e s , a s e x e m p l i f i e d b y t h e u s e o f t h i s m e t h o d o l o g y b y 6 8 W e n d e r a n d c o w o r k e r s i n t h e s y n t h e s i s o f t h e p s e u d o g u a i a n e s ( + ) - d a m s i n i c a c i d ( 9 0 ) a n d ( + ) - c o n f e r t i n ( 9 1 ) a s i n d i c a t e d i n S c h e m e 1 0 . I n i t i a l l y , e f f o r t s t o c o n v e r t t h e g - c y c l o p r o p y l e n o n e 9 2 a i n t o t h e c o r r e s p o n d i n g r i n g - f u s e d c y c l o h e p t a d i e n e 9 3 u n d e r t h e r m a l c o n d i t i o n s e n c o u n t e r e d d i f f i c u l t i e s s i n c e 24 the d e s i r e d 93_ was o b t a i n e d o n l y as a minor p r o d u c t . A t e l e v a t e d t e m p e r a t u r e s a p p r o x i m a t i n g 140°C, 92a was found t o i s o m e r i z e p r e d o m i n a n t l y v i a a [ 1 , 5 ] - s i g m a t r o p i c hydrogen s h i f t t o a f f o r d t h e t r i e n o n e 9_4. T h i s o b s t a c l e was n e a t l y overcome by s i m u l t a n e o u s i r r a d i a t i o n (>290 nm) and t h e r m o l y s i s ( c a . 98°C) o f 92a, r e s u l t i n g i n a p h o t o - i n d u c e d e q u i l i b r a t i o n between 92a and 92b, and the i r r e v e r s i b l e Cope rearrangement o f the l a t t e r s u b s t a n c e t o the key i n t e r m e d i a t e 93_. Sub-sequent e l a b o r a t i o n o f 93_ f u r n i s h e d b o t h o f t h e p h a r m o c o l o g i c a l l y i n t e r e s t i n g n a t u r a l p r o d u c t s 9_0 and 91. SCHEME 11 95 98 25 C o n c u r r e n t i n v e s t i g a t i o n s b y P i e r s a n d R u e d i g e r ^ ^ ' ^ d e m o n s t r a t e d a g a i n t h e v e r s a t i l i t y o f a s y n t h e t i c s t r a t e g y i n c o r p o r a t i n g t h e t h e r m a l r e a r r a n g e m e n t o f d i v i n y l c y c l o p r o p a n e s i n t h e s y n t h e s i s o f r a c e m i c g - h i m a c h a l e n e (9_5) a s s h o w n i n S c h e m e 1 1 . T h e l i t h i u m p h e n y l t h i o ( v i n y l c y c l o p r o p y l ) c u p r a t e 9 6 , s y n t h e s i z e d f r o m a c r o l e i n i n s i x s t e p s , w a s a l l o w e d t o r e a c t w i t h 3 - i o d o - 2 - c y c l o h e x e n - l - o n e t o a f f o r d t h e 0 - c y c l o -p r o p y l e n o n e 9_7. S u b j e c t i o n o f t h e i n t e r m e d i a t e 9_7 t o t h e r m o l y s i s i n r e f l u x i n g x y l e n e p r o v i d e d t h e d e s i r e d b i c y c l o -[ 5 . 4 . 0 ] u n d e c a d i e n o n e 9_8 e x c l u s i v e l y , a n d s u b s e q u e n t a p p r o p r i a t e s y n t h e t i c m a n i p u l a t i o n o f 98_ l e d s m o o t h l y t o ( + ) - g - h i m a c h a l e n e ( 9 5 ) . M o r e r e c e n t l y , W e n d e r a n d c o w o r k e r s , ^ w h i l e d e v e l o p i n g a v i a b l e s y n t h e t i c a p p r o a c h t o h i g h l y f u n c t i o n a l i z e d t r i - a n d t e t r a c y c l i c d i t e r p e n e s , h a v e p r e p a r e d a n d r e a r r a n g e d a c o m p l e x OMe H + OMe r . t , [ 1 9 ] OMe TOO d i v i n y l c y c l o p r o p a n e 9_9. T r e a t m e n t o f 9_9 w i t h d i l u t e a c i d a t r o o m t e m p e r a t u r e p r o v i d e d t h e t r i c y c l i c m e t h o x y k e t o n e 1 0 0 , w h i c h c o n s t i t u t e s t h e b a s i c b a c k b o n e o f t h e t i g l i a n e , d a p h n a n e a n d i n g e n a n e f a m i l i e s o f n a t u r a l p r o d u c t s . 26 G i v e n t h e v a r i o u s e x a m p l e s o f s y n t h e t i c s t r a t e g i e s i n c o r p o r a t i n g t h e C o p e r e a r r a n g e m e n t o f d i v i n y l c y c l o p r o p a n e s y s t e m s , i t w o u l d s e e m t h a t t h e s y n t h e t i c p o t e n t i a l o f t h i s i n t e r e s t i n g t r a n s f o r m a t i o n h a s b e e n w e l l d e m o n s t r a t e d . I n c o n t r a s t , t h e t h e r m a l r e a r r a n g e m e n t o f t h e 6 - a l k e n y l b i c y c l o -[ 3 . 1 . 0 ] h e x - 2 - e n e s 1 0 1 , a t y p e o f c o m p l e x d i v i n y l c y c l o p r o p a n e , h a s a t t r a c t e d r e l a t i v e l y l i t t l e a t t e n t i o n f r o m a s y n t h e t i c p o i n t o f v i e w , a n d w i l l b e d i s c u s s e d i n t h e n e x t s e c t i o n . 1 . 1 . 3 P r e v i o u s W o r k o n t h e C o p e R e a r r a n g e m e n t s o f 6 - A l k e n y l -b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e s I n v i e w o f t h e c o n s i d e r a b l e d o c u m e n t a t i o n a v a i l a b l e o n t h e C o p e r e a r r a n g e m e n t o f d i v i n y l c y c l o p r o p a n e s , i t i s s o m e w h a t s u r p r i s i n g t o d i s c o v e r t h e r e l a t i v e p a u c i t y o f l i t e r a t u r e p r e c e d e n t s f o r t h e r m a l r e a r r a n g e m e n t s o f 6 - a l k e n y l b i c y c l o [ 3 . 1 . 0 ] -h e x e n e s t o t h e c o r r e s p o n d i n g b i c y c l o [ 3 . 2 . 1 ] o c t a d i e n e s y s t e m s . G e n e r a l l y , t h e f e w s t u d i e s d o n e h a v e b e e n l i m i t e d t o s y s t e m s w h i c h h a v e v e r y l i t t l e s u b s t i t u t i o n , a n d t h e s i m p l e s t o f t h e s e , 1 0 2 1 0 1 a 1 0 4 6 - e n d o - v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e ( 1 0 1 a ) w a s f i r s t r e p o r t e d 7 2 b y C u p a s e t a l . T h e s e i n v e s t i g a t o r s f o u n d t h a t t r e a t m e n t o f t h e b i c y c l i c a l d e h y d e 1 0 2 w i t h m e t h y l e n e t r i p h e n y l p h o s p h o r a n e 27 (103) i n refl u x i n g THF did not allow i s o l a t i o n of the presumed intermediate 101a, but cleanly provided bicyclo[3.2.1]octa-2,6-diene (104). Milder conditions for the preparation of 101a were sought and i n 1965, Brown is o l a t e d t h i s dialkenylcyclo-propane 101a from low temperature (ca. -15° to 0°C) Wittig 73 conditions and reported i t s h a l f - l i f e of 1 day at 25°C. In contrast, 6-exo-vinylbicyclo[3.1.0]hex-2-ene (101b) displays the s t a b i l i t y t y p i c a l of trans-divinylcyclopropanes at ambient temperatures and rearranges at 195°C to furnish the same SCHEME 12 (-)-106 (-)-101b compound 104. Baldwin and G i l b e r t ' s investigations have 2 8 shown that t h i s process proceeds by way of a one-centre epimerization at C-6, presumably to afford the intermediate 101a, which i s rapidly transformed into 104 v i a a Cope 28 * rearrangement. Thus, both o p t i c a l l y active 101a and 101b were thermally isomerized at d i f f e r e n t temperatures to give the same o p t i c a l l y active compound 104, as outlined i n Scheme 12. Had a two-centre (C-l and C-5) epimerization process occurred exclusively, the enantiomer (+)-104 would have been expected. As i n the cases of simple divinylcyclopropanes, substitution seems to impart greater s t a b i l i t y to the 6-alkenyl-bicyclo[3.1.0]hexenes. For example, the b i c y c l i c diene 110, which could be stored at room temperature for months without 75 . . any apparent change, exhibits a s t a b i l i t y attributed to the repulsive s t e r i c interactions of the gem-dimethyl group and 74 * Klumpp and Schakel have recently shown that subjection of 105 to a temperature of 325°C resulted i n the i s o l a t i o n of the Cope rearrangement product 107 and a trace of 109. However, the thermolysis of 107 at 500°C afforded exclusively 109, presumably v i a the b i r a d i c a l 108. 108 109 29 [21] 110 111 112 •the c y c l o p r o p a n e r i n g i n the b o a t - l i k e t r a n s i t i o n s t a t e 111 (eq. [ 2 1 ] ) . However, a t 350°C, 110 undergoes a [ 3 , 3 ] -s i g m a t r o p i c i s o m e r i z a t i o n t o a f f o r d 112 e x c l u s i v e l y . As w e l l , b o t h m e t h y l e n o l e t h e r s 113 and 114 r e q u i r e e l e v a t e d temper-a t u r e s ( c a . 220°C) t o r e a r r a n g e i n t o t h e b i c y c l i c e t h e r 115 SCHEME 13 116 117 118 30 7 6 (Scheme 13) . I n f a c t , 113 does n ot r e a r r a n g e t o 115 a t a lower t e m p e r a t u r e , b u t i n s t e a d undergoes a g e o m e t r i c a l isomer-i z a t i o n t o y i e l d 114. T h i s b e h a v i o u r , c o n t r a s t e d w i t h the r e l a t i v e l y f a c i l e r earrangement o f 6-endo-(2-trans-methoxy-v i n y l ) b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e (116) t o 117, i s a s c r i b e d t o the s e v e r e s t e r i c i n t e r a c t i o n between the ci s - m e t h o x y group and the r i n g methylene i n the t r a n s i t i o n s t a t e 118. N o t a b l y , t h e s e t r a n s f o r m a t i o n s (113 -»• 115 and 116 + 117) a l s o c o n s t i t u t e an example o f t h e s t e r e o s p e c i f i c i t y w i t h w h i c h t h e 6 - a l k e n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e s undergo [ 3 , 3 ] - s i g m a t r o p i c i s o m e r i z a t i o n s . SCHEME 14 CHO 120 119 R 1=R 2=H, R 3 = C 0 2 M e R 1=R 3=H, R 2=C0 2Me R-j^OBu-, R 2=C0 2H, R 3=H 121 77 R^OBu-, R 2=H, R 3=C0 2H A l a t e r s t u d y conducted by C a n t e l l o and co w o r k e r s ' ' g i v e s f u r t h e r t e s t i m o n y t o the h i g h l y s t e r e o s p e c i f i c n a t u r e o f t h e s e t r a n s f o r m a t i o n s . Thus, b o t h 119a and 119b, p r e p a r e d from 120 under W i t t i g c o n d i t i o n s , r e a r r a n g e d smoothly t o t h e b i c y c l o - . [3.2.1]octadienes 121a and 121b, respectively (Scheme 14). Interestingly, investigations regarding the Cope rearrange-ment of substituted 6-alkenylbicyclo[3.1.0]hex-2-enes have been conspicuously lacking, and the study conducted by 7 8 Klumpp et a l . constitutes one of the few i n this area. Thus, the preparation and rearrangement of systems such as 119c and 119d provide an entry into bicyclo[3.2.1]octadienes substituted at C-4 and C-8. Unfortunately, this case presents a poor example of the s t e r e o s p e c i f i c i t y of these thermal isomerizations since a mixture of the trans and c i s carboxylic acids 119c and 119d, respectively, obtained from a Knoevenagal condensation of the b i c y c l i c aldehyde 120 and malonic acid, was rearranged to afford a mixture of 121c and 12Id. Our own i n t e r e s t i n the [3,3]-sigmatropic rearrangement of 6-alkenylbicyclo[3.1.0]hex-2-enes stems from the f a c t that a number of s t r u c t u r a l l y i n t r i g u i n g natural products incorp-orate the bicyclo[3.2.1]octane carbon skeleton into t h e i r structures. That naturally occurring substances such as 9-79 80 isocyanopupukeanane (122), quadrone (123), prezizaene 81 82 (124) and sinularene (125) have recently piqued the i n t e r e s t of many organic synthetic chemists, i s p l a i n l y 8 3 indicated by the abundance of independent syntheses of quadrone (123). Since substituted bicyclo[3.2.1]octadienes are p o t e n t i a l l y excellent intermediates for the t o t a l syntheses of prezizaene (124), quadrone (123) and sinularene (125), we embarked on a 32 H 125 123 study directed at the syntheses of functionalized b i c y c l o -[3.2.1]octadienes through the Cope rearrangement of the corresponding precursor 6-alkenylbicyclo[3.1.0]hex-2-enes. In this connection, recent investigations by Piers and R u e d i g e r ^ ' ^ have focussed on the preparation and rearrange-~ ment of systems 126-129, which possess a variety of substitution patterns, p a r t i c u l a r l y at C - l , C-2, C-3 and C-5. The synthetic strategy employed to assemble these divinylcyclopropane analogues i s outlined i n Scheme 15. The b i c y c l i c ketones 130a-c were prepared from the a l l y l i c bromides 131a-c and the dianion of methyl acetoacetate (139) i n three steps. Using standard conditions, the ketones 130a-c and 132 were converted into the desired bicyclo[3.1.0]hexenes 126-129. Subjection of 126-129 to refluxing xylene afforded the corresponding b i -cyclo [ 3 . 2 . 1] octadienes 133-135 i n quantitative y i e l d s while 136 was obtained i n an o v e r a l l y i e l d of 57% from 132. Also 33 SCHEME 15 133: R=R 1=R 2=H 134: R=R2=H, R±=Me 135: R 2 = H / R=R-L=Me 136: R=R1=H, R2=Me [ a l ( i ) LDA, THF, -78°C ( i i ) M el [b] ( i ) LDA, THF, -78°C ( i i ) t - B u M e , S i C l , THF-HMPA 130a 137 138 34 described was the preparation and thermal isomerization of a compound with a substitution pattern quite d i f f e r e n t from that of 126. Trapping the enolate anion of 130a with phenyl-selenenyl chloride followed by an oxidation-elimination procedure yielded 137. Subsequent thermolysis of 137 produced the i n t e r e s t i n g bicyclo[3.2.1]octadienone 138 i n modest y i e l d . C learly, t h i s methodology would appear to hold considerable promise, allowing for the convenient preparation of b i c y c l o -[3.2.1]octane compounds possessing substituents at either bridgehead p o s i t i o n and with s y n t h e t i c a l l y useful functional-i t i e s on two or a l l three bridges. 1.1.4 The Problem The Cope rearrangement of substituted 6-alkenylbi-cyclo[3.1.0]hex-2-enes presents a synthetic entry into functionalized bicyclo[3.2.1]octadienes. In view of the sc a r c i t y with which this methodology has seen exploitation s y n t h e t i c a l l y , i t became desirable to demonstrate the versat-i l i t y of t h i s i n t e r e s t i n g transformation by i t s application to the syntheses of naturally occurring substances, namely * quadrone (123) and sinularene (125). Hence, with the eventual goal of synthesizing (+)-sinularene (125), we extended the investigation i n i t i a t e d * At the present time, the investigation of this methodology i n the syntheses of (+)-quadrone i s ongoing i n our laboratory. 35 0 i n our laboratory ' to accommodate a number of features pertinent to the assembly of this natural product: 1. Since these previous studies i n our laboratory were made on the rearrangement of substrates with a carbomethoxy group at C - l (see Scheme 15, 126-129), we wished to investigate the rearrangement of substrates which lack a C - l substituent. 2. I t would be necessary to provide a synthetic "handle" r on the one-carbon bridge (C-8) of the bicyclo-octadiene product 141 thereby requiring the preparation and rearrange-ment of a 6-alkenylbicyclo[3.1.0]hex-2-ene 140 with a suitable f u n c t i o n a l i t y at C-4. [22] 140 141 36 3. I t was important to determine whether the rearrangement of these systems was st e r e o s p e c i f i c with respect to the substituents on the 6-alkenyl side chain i n 140. That i s , would rearrangement of geometrically isomeric sub-strates [R group (E) or (Z) on the 6-alkenyl side chain] afford products (c_f. 141) epimeric at C-4? Indeed, where R^ i s a s t e r i c a l l y bulky group (e.g. isopropyl), the v i a b i l i t y of the Cope rearrangement of 140 i s i n * question. This thesis w i l l discuss the preparation and rearrange-ment of various substituted 6-(l-alkenyl)bicyclo[3.1.0]hex-2-enes to the corresponding functionalized bicyclo[3.2.1]octadienes, and the application of this methodology to the t o t a l synthesis of (+)-sinularene (125) w i l l be discussed. 1.1.5 Methods for the Assembly of Bicyclo[3.1.0]hexanones Although the [3,3]-sigmatropic rearrangement of 6-alkenyl-bicyclo[3.1.0]hex-2-enes provides a p o t e n t i a l l y useful synthetic entry into bicyclo[3.2.1]octadienes, i t i s clear that a viable method for the preparation of the substrate systems i s r e q u i s i t e to the application of this transformation i n synthesis. In p r i n c i p l e , t h i s methodology should not only u t i l i z e established synthetic routes but just as importantly, For a discussion concerning s t e r i c factors involved i n divinylcyclopropane rearrangements, see r e f . 64 and references c i t e d therein. 3 7 d e m o n s t r a t e v e r s a t i l i t y i n t e r m s o f s u b s t i t u t i o n p a t t e r n s i n t h e d e s i r e d b i c y c l o [ 3 . 1 . 0 ] h e x e n e s . [ 2 3 ] F o r t u n a t e l y , t h e m e t h o d s t o a s s e m b l e b i c y c l o [ 3 . 1 . 0 ] h e x a n -2 - o n e s 1 4 2 , w h i c h c a n b e c o n v e r t e d e a s i l y t o t h e c o r r e s p o n d i n g b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e s 1 4 0 ( e q . [ 2 3 ] ) , h a v e b e e n w e l l i n v e s t i g a t e d . A p r o v e n r o u t e u s e d f o r t h e s y n t h e s i s o f p o l y -c y c l e s i n c o r p o r a t i n g t h e b i c y c l o [ x . 1 . 0 ] m o i e t y i s t h e i n t r a -* m o l e c u l a r r e a c t i o n o f o l e f i n i c d i a z o c a r b o n y l c o m p o u n d s , a s 8 6 f i r s t d e m o n s t r a t e d b y S t o r k a n d F i c i n i ( e q . [ 2 4 ] ) . T h u s , _ i n t h e p r e s e n c e o f c o p p e r - b r o n z e i n r e f l u x i n g c y c l o h e x a n e , t h e d i a z o k e t o n e 1 4 3 w a s c o n v e r t e d i n t o b i c y c l o [ 4 . 1 . 0 ] h e p t a n -2 - o n e ( 1 4 4 ) . I n a s i m i l a r f a s h i o n , t h e b i c y c l o [ 3 . 1 . 0 ] h e x a n -2 - o n e 1 4 5 w a s p r e p a r e d b y m e a n s o f a c o p p e r ( I I ) m e d i a t e d 0 Q [ 2 4 ] 1 4 3 1 4 4 A s u r v e y o f i n t r a m o l e c u l a r c y c l i z a t i o n s o f d i a z o c a r b o n y l c o m p o u n d s h a s b e e n c o m p i l e d b y B u r k e a n d G r i e c o . 8 5 3 8 [ 2 5 ] 1 4 6 1 4 5 c y c l i z a t i o n o f t h e d i a z o k e t o n e 1 4 6 ( e q . [ 2 5 ] ) . I n d e e d , t h e 8 8 - 9 1 n u m e r o u s e x a m p l e s ( e q s . [ 2 6 ] - [ 2 8 ] ) o f b i c y c l o [ 3 . 1 . 0 ] -h e x a n o n e s s u c h a s 1 4 9 - 1 5 3 , s y n t h e s i z e d e x p l o i t i n g t h e c a r b e n o i d [ 2 6 ] [ 2 7 ] [ 2 8 ] c y c l i z a t i o n o f d i a z o c a r b o n y l p r e c u r s o r s g i v e s t e s t i m o n y t o t h e f l e x i b i l i t y o f t h i s m e t h o d o l o g y t o s u b s t i t u t i o n p a t t e r n s . P a r t i c u l a r l y n o t e w o r t h y i s t h e s t e r e o s p e c i f i c i t y o f t h i s 9 1 p r o c e s s a s e x e m p l i f i e d b y e q s . [ 2 7 ] a n d [ 2 8 ] . 39 I n v e s t i g a t i o n s c o n n e c t e d t o t h e s t e r e o c o n t r o l l e d g e n e r -a t i o n o f a c y c l i c s i d e c h a i n s o f s o m e n a t u r a l p r o d u c t s l e d 9 2 T r o s t a n d c o w o r k e r s t o t h e p r e p a r a t i o n a n d c o p p e r - i n d u c e d c y c l i z a t i o n o f t h e d i a z o k e t o e s t e r 1 5 4 t o f u r n i s h t h e m o r e c o m p l e x b i c y c l i c k e t o e s t e r 1 5 5 a s s h o w n i n S c h e m e 1 6 . C a r b e n o i d c y c l i z a t i o n o f 1 5 4 p r o v i d e d s t e r e o s e l e c t i v e l y 1 5 5 , S C H E M E 1 6 [ a ] c o p p e r - b r o n z e , r e f l u x i n g M e Cf iH _ ( 7 3 - 8 0 % ) [ b ] L i M e » C u , E t20 , 0°C ( 8 6 % ) 2 w h i c h , u p o n s u b j e c t i o n t o l i t h i u m d i m e t h y l c u p r a t e , w a s t r a n s -f o r m e d i n t o t h e k e t o n e 1 5 6 w i t h t h e d e s i r e d s t e r e o c h e m i s t r y f o r t h e a c y c l i c s i d e c h a i n o f t h e s t e r o i d a l D r i n g ( s e e 1 5 7 ) a n d v i t a m i n D m e t a b o l i t e s 1 5 8 . I n a p a r t i c u l a r l y i n t r i g u i n g e x a m p l e o f t h e s e c a r b e n o i d 9 3 c y c l i z a t i o n s , N o z a k i e t a l . e m p l o y e d a n o p t i c a l l y a c t i v e 40 * [29] 159 Ph copper ( I I ) complex 159 t o i n d u c e asymmetry i n the p r o d u c t 160 o b t a i n e d from the d i a z o ketone 161. T h i s case c o n s t i t u t e s s t r o n g e v i d e n c e f o r a c a r b e n e - c o p p e r - o l e f i n complex as an r i n t e r m e d i a t e d e s p i t e t h e s l i g h t l y d i f f e r i n g i n t e r p r e t a t i o n s on t h e e x a c t n a t u r e o f t h e s e i n t e r m e d i a t e complexes. Of c a r b e n o i d a d d i t i o n s t o c o n j u g a t e d o l e f i n s , t h e r e seem t o be fewer examples, but o f a s u f f i c i e n t number t o demonstrate the e x p e d i e n c e o f t h i s s y n t h e t i c r o u t e t o 6 - a l k e n y l b i c y c l o -[3.1.0]hexan-2-ones. Such systems drew p a r t i c u l a r a t t e n t i o n as t h e key i n t e r m e d i a t e s i n s y n t h e s e s d i r e c t e d a t the b i o -l o g i c a l l y i m p o r t a n t p r o s t a g l a n d i n s . C o n c u r r e n t b u t independent 94 95 96 s t u d i e s by Taber and Kondo e t a l _ . ' y i e l d e d a means of g e n e r a t i n g w i t h h i g h s t e r e o s e l e c t i v i t y t h e 6 - e x o - ( E - l - a l k e n y l ) -b i c y c l o [ 3 . 1 . 0 ] h e x a n o n e s 162 from th e t r a n s , t r a n s d i e n i c d i a z o 4 1 nC*H 5 n l l CO2R C u ( a c a c ) 1 6 3 nC5H,| [ 3 0 ] 1 6 2 e s t e r s 1 6 3 ( e q . [ 3 0 ] . T h i s t r a n s f o r m a t i o n w a s p u t t o p r o m p t 9 7 u s e b y K o n d o e t a _ l . i n a s y n t h e s i s o f ( + ) - p r o s t a g l a n d i n F2 a ( 1 6 4 ) a s s h o w n i n S c h e m e 1 7 . 0 C02Me N 2 1 6 5 : R= N r " ° H 1 HO S C H E M E 1 7 s e v e r a l s t e p s [ a ] C u ( a c a c ): >, r e f l u x i n g b e n z e n e ( 6 1 % ) [ b ] i - P r O H - H20 , p _ - M e C6H4S 03H ( 8 6 % ) " ~ . 9 8 9 9 M o r e r e c e n t l y , H u d l i c k y a n d c o w o r k e r s ' c o m p l e t e d a t o t a l s y n t h e s i s o f ( + ) - h i r s u t e n e ( 1 6 8 ) , s t a r t i n g f r o m t h e c y c l i c a l d e h y d e 1 6 9 . T h u s , t h e d i e n i c d i a z o k e t o n e 1 7 0 w a s p r e p a r e d v i a a f i v e s t e p s e q u e n c e f r o m 1 6 9 a n d t h e i n t r a -m o l e c u l a r c y c l o p r o p a n a t i o n o f t h e f o r m e r p r o d u c e d 4 2 S C H E M E 1 8 1 6 9 1 6 8 [ a ] C u ( a c a c )2, r e f l u x i n g b e n z e n e , 8 h ( 9 4 % ) [ b ] V y c o r ( p r e -t r e a t e d w i t h P b C O , ) , 5 8 0 ° C ( 6 8 % ) [ c ] R h C l , , H _ 0 - E t O H , r e f l u x " , 3 0 m i n ( ? % ) [ d ] P t 02, H2, 4 0 p s i , 8 h [ e f P h p = C H2, DMSO ( ? % ) s t e r e o s e l e c t i v e l y t h e k e y i n t e r m e d i a t e 1 7 1 . T h e r m a l b o n d r e -o r g a n i z a t i o n o f 1 7 1 p r o v i d e d t h e c y c l o p e n t e n e a n n u l a t i o n p r o d u c t 1 7 2 , w h i c h w a s c o n v e r t e d i n t o t h e n a t u r a l l y o c c u r r i n g s u b s t a n c e 1 6 8 a f t e r t h r e e s t e p s . H u d l i c k y e t a l . ^ " ^ h a v e a p p l i e d t h i s i n t r a m o l e c u l a r c a r b e n o i d c y c l i z a t i o n t o g e n e r a t e t h e t r i c y c l i c s k e l e t o n s o f a n u m b e r o f n a t u r a l p r o d u c t s s u c h a s c o r i o l i n , t h e i s o c o m e n e s a n d p e n t a l e n i c a c i d . 4 3 p e n t a l e n i c a c i d I t i s c l e a r t h a t t h e t h e r m a l r e a r r a n g e m e n t s e x h i b i t e d b y s e v e r a l b i c y c l o [ 3 . 1 . 0 ] h e x a n o n e s ( e . g . 1 7 1 -> 1 7 2 ) m u s t b e c o n -s i d e r e d p o t e n t i a l l y c o m p e t i n g p r o c e s s e s i n t h e C o p e r e a r r a n g e -m e n t s o f t h e s t r u c t u r a l l y s i m i l a r 6 - a l k e n y l b i c y c l o [ 3 . 1 . 0 ] h e x -2 - e n e s . I n d e e d , a t e l e v a t e d t e m p e r a t u r e s , t h e r e a r e a n u m b e r o f a v e n u e s a v a i l a b l e t o b i c y c l o [ 3 . 1 . 0 ] h e x a n o n e s . F o r e x a m p l e , 1 0 3 T r o s t a n d V l a d u c h i c k d i s c o v e r e d t h a t t h e r m o l y s i s ( 3 5 0 ° C ) o f t h e b i c y c l i c k e t o n e 1 7 3 p r o c e e d e d v i a a c o n c e r t e d p r o t o n 4 4 1 7 4 m i g r a t i o n a n d c o n c o m i t a n t c y c l o p r o p a n e r i n g c l e a v a g e t o y i e l d s m o o t h l y t h e g - k e t o e s t e r 1 7 4 . 9 8 1 0 4 E l s e w h e r e , H u d l i c k y a n d c o w o r k e r s ' f o u n d t h a t f l a s h t h e r m o l y s i s o f t h e v i n y l c y c l o p r o p a n e 1 7 5 t h r o u g h a P y r e x S C H E M E 1 9 " 1 7 7 1 7 8 45 column heated at 400°C gave exclusively the 1,4-diene 176 * through a [1,5]-hydrogen s h i f t (Scheme 19). However, when the thermolysis of 175 was done at 600°C using a Vycor column pretreated with lead carbonate, a 3:1 mixture of 177 and 178 was obtained. I t i s inte r e s t i n g to note that subjection of 176 to a temperature of 600°C also afforded a mixture of 177 and 178 i n s i m i l a r proportions. I t was proposed"*"^ that the l a t t e r reaction entailed the reformation of the ketone 175, which subsequently underwent bond reorganization to give 177 and 17 8. [31] 179 180 Both C o r e y 1 0 6 and H u d l i c k y 9 8 ' 1 0 7 ' 1 0 8 found that the simpler 6-exo-vinylbicyclo[3.1.0]hexan-2-one (179) rearranged smoothly at elevated temperatures (ca. 500°-600°C) to furnish the bicyclo[3.3.0]octenone 180. In fact, t h i s transformation was p i v o t a l i n a synthesis of 11-deoxyprostaglandin (181) 104 by Corey and Wollenberg as outlined i n Scheme 20. I t i s noteworthy that the application of the organotin reagent 182 to the preparation of the key intermediate 179 constitutes yet * For a review on [1,5]-sigmatropic hydrogen s h i f t s , see Ref. 105, and the references c i t e d therein. 46 S C H E M E 2 0 OTHP M = n B u3S n M = L i M = C u - C s C - C3H7 OH 1 8 6 g , h OHC 1 8 5 1 8 0 s e v e r a l OMe • s t e p s OS0 2 Me 1 7 9 (CH^COJJH (CH2)4CH3 1 8 1 [ a ] ( i ) n B u L i , T H F , - 7 8 ° C , 1 h ( i i ) 1 - p e n t y n y l c o p p e r , T H F , - 7 8 ° C , 1 h ( i i i ) - 5 0 ° C , 1 0 m i n ( i v ) 2 - c y c l o p e n t e n o n e , -78°± - 5 0 ° C , 2 h ( 8 0 % ) [ b ] h y d r o l y s i s [ c ] m e s y l a t i o n [ d ] K O B u - , T H F , 0 ° C , 5 m i n ( q u a n t . ) [ e ] 6 0 0 ° C [ f ] N a B H . , M e O H , - 4 0 ° C [ g ] O s 04, N a I 04 [ h ] B F3- E t20 , M e O H ( 6 5 % f r o m 1 8 6 ) a n o t h e r m e a n s o f a s s e m b l i n g a b i c y c l o [ 3 . 1 . 0 ] h e x a n o n e s y s t e m . T h u s , t h e ( t r i - n - b u t y l s t a n n y l ) a l k e n e 1 8 2 w a s t r a n s f o r m e d i n t o t h e m i x e d G i l m a n ( c u p r a t e ) r e a g e n t 1 8 4 , w h i c h a d d e d c o n j u g a t e l y 47 to 2-cyclopentenone to provide 185. Subsequent hydrolysis of the tetrahydropyranyl ether and mesylation of the resultant alcohol, followed by base-mediated ring closure afforded the vinylcyclopropane 179. Flash thermolysis of t h i s l a t t e r material at 600°C furnished the bicyclo[3.3.0]octenone 180, which, upon suitable elaboration, led to the b i o l o g i c a l l y i n t e r e s t i n g prostaglandin 181. Although these thermal rearrangements generally require 28 72—78 higher temperatures than those reported ' for the Cope rearrangement of 6-alkenylbicyclo[3.1.0]hex-2-enes, such processes may warrant consideration es p e c i a l l y i n those cases where the t r a n s i t i o n state for the Cope rearrangement suffers from d e s t a b i l i z a t i o n . I t seemed appropriate to extend the previously i n i t i a t e d i n v e s t i g a t i o n s ^ ' ^ regarding the Cope rearrangements of these b i c y c l i c divinylcyclopropane systems by f i r s t turning to 6-exo-vinylbicyclo[3.1.0]hexan-2-one (179), the synthesis of which has been described by Corey^ 0^ and Hudlicky . ^  ' 1^ > 7 ' ^ u** In p r i n c i p l e , 179 could serve as a cornerstone from which a number of the desired substituted 6-vinylbicyclo[3.1.0]hexene systems (cf. 187, 189, 192 and 194) can be derived. Such systems embody a 1,2-trans-divinylcyclopropane moiety and should be capable of undergoing Cope rearrangement to the corresponding bicyclo[3.2.1]octadienes (cf. 188, 190, 193 84 and 195) . In l i g h t of the reported rearrangement of 126 to 133 (eq. [32]), i t became desirable to prepare and rearrange 4 8 195 the analogue 187 for the sake of a comparison, i . e . to determine the e f f e c t ( i f any) of the carbomethoxy moiety at C - l (cf. 126) on the thermal bond reorganization. 4 9 ->-SiO 133 50 1.2 D i s c u s s i o n 1.2.1 T h e S y n t h e s i s a n d R e a r r a n g e m e n t o f 2 - t e r t - B u t y l d i m e t h y l -s i l o x y - 6 - e x o - v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e (187) T h e f i r s t t a s k a t h a n d w a s t h e p r e p a r a t i o n o f 6 - e x o - v i n y l -b i c y c l o [ 3 . 1 . 0 ] h e x a n - 2 - o n e ( 1 7 9 ) . T h i s w a s a c c o m p l i s h e d i n a n o v e r a l l y i e l d o f 3 2 % , s t a r t i n g f r o m d i v i n y l c a r b i n o l ( 1 9 6 ) a n d 9 8 1 0 7 - 1 0 8 u s i n g a s y n t h e t i c r o u t e d e s c r i b e d b y H u d l i c k y e t a l . ' ( S c h e m e 2 1 ; i n o u r h a n d s , t h e i n t e r m e d i a t e s w e r e o b t a i n e d i n t h e y i e l d s s h o w n ) . D i v i n y l c a r b i n o l ( 1 9 6 ) ^ -n^ ~ l ^ -Q w a s r e a d i l y S C H E M E 21 1 9 7 19_8 9 9 R = O E t R = O H R = C 1 0 5 8 % 1 7 9 2 0 0 [ a ] M e C ( O E t )v p r o p i o n i c a c i d ( c a t . ) , 1 3 0 - 1 3 5 ° C , 2 0 h [ b ] ( i ) K O H , M e O H , H ^ O , r e f l u x , 5 h ( i i ) H-.0+ ( n e u t . , 7 3 % f r o m 1 9 6 ) [ c ] ( C 0 C 1 )2, r e f l u x i n g h e x a n e , 2 . 5 h ( 8 9 % ) [ d ] C H ^ , E t20 , 0°C ( > 9 5 % ) [ e ] C u ( a c a c )2, r e f l u x i n g b e n z e n e , 1 h p r e p a r e d b y r e a c t i o n o f a c r o l e i n w i t h v i n y l m a g n e s i u m b r o m i d e i n T H F ( 2 7 % ) . T r e a t m e n t o f 1 9 6 w i t h t r i e t h y l o r t h o a c e t a t e a n d 51 a c a t a l y t i c amount of acid provided the trans-dienoate 197  v i a an orthoester Claisen rearrangement. The high s t e r e o s e l e c t i v i t y of t h i s rearrangement i s well documented"'"11 and can be r a t i o n a l i z e d by a comparison of the non-covalent interactions present i n the two possible chair-l i k e t r a n s i t i o n states (represented by 201 and 202) for the Claisen rearrangement (Scheme 22). I t i s clear that of the SCHEME 22 197 202 two t r a n s i t i o n states, 201 i s more de s t a b i l i z e d owing to the 1,3-diaxial i n t e r a c t i o n between the v i n y l and ethoxy substituents. Consequently, the reaction proceeds by way of the thermo-dynamically preferred t r a n s i t i o n state 202, which affords the ester 197 with a trans-disubstituted y / <$-olefinic bond. The ester 197 was transformed smoothly into the desired b i c y c l i c ketone 179 v i a a sequence of standard reactions. Thus, 5 2 t h e a c i d 1 9 8 o b t a i n e d f r o m 1 9 7 , w a s c o n v e r t e d i n t o t h e c o r r e s p o n d i n g a c y l c h l o r i d e 1 9 9 , w h i c h p r o v i d e d , u p o n t r e a t -m e n t w i t h e t h e r e a l d i a z o m e t h a n e , t h e d i a z o k e t o n e 2 0 0 i n e x c e l l e n t y i e l d . S u b s e q u e n t i n t r a m o l e c u l a r c y c l o p r o p a n a t i o n o f t h e l a t t e r m a t e r i a l i n t h e p r e s e n c e o f C u C a c a c ^ f u r n i s h e d t h e k e t o n e 1 7 9 , w h i c h e x h i b i t e d a c a r b o n y l a b s o r p t i o n ( vm a x —1 9 8 —1 1 7 2 5 c m ; l i t . v 1 7 2 3 c m ) a n d a b s o r p t i o n s e x p e c t e d m a x c c f o r a v i n y l g r o u p ( vm a x 3 0 8 5 , 1 6 4 0 , 9 9 0 , 9 1 0 c m- 1) i n t h e i r s p e c t r u m . A l t h o u g h i t r e v e a l e d m o r e f i n e s t r u c t u r e , t h e 4 0 0 M H z ^H n m r s p e c t r u m o f t h i s m a t e r i a l c o m p a r e d f a v o u r a b l y w i t h 9 8 t h a t r e p o r t e d b y H u d l i c k y e t a l . , a n d d i s p l a y e d t h e v i n y l g r o u p c l e a r l y a s a n A M X s y s t e m ( F i g . 1 ) . T h e a s s i g n m e n t o f J B C = 1 . 5 H z — B D = 1 7 H Z . u ^ C D = 1 0 H Z « x i Q-3 -<•/.. I C 6 4 . 9 9 J _ _ = 8 . 5 H z F 6 J : 8 3 7"H F | D D -DE d d V U _ — E G " ^ E F 6 5 . 3 5 = 2 , 5 H z d d d J _ _ = 5 H z —•i G F i g . 1 . ^H n m r s p e c t r u m a s s i g n m e n t s f o r t h e v i n y l c y c l o -p r o p a n e m o i e t y o f k e t o n e 1 7 9 t h e s i g n a l a t 6 1 . 9 3 t o t h e c y c l o p r o p y l p r o t o n H ^ w a s b a s e d o n a d e c o u p l i n g s t u d y , i n w h i c h i r r a d i a t i o n a t 6 5 . 3 5 ( HD) c a u s e d n o t o n l y t h e e x p e c t e d s i g n a l s i m p l i f i c a t i o n s a t 6 5 . 1 4 ( H _ ) a n d 6 5 . 3 5 ( H ^ ) , b u t t h e c o l l a p s e o f t h e r e s o n a n c e a t 6 1 . 9 3 t o a n o v e r l a p p i n g d o u b l e t o f d o u b l e t s (J„,- - J ™ = 2 . 5 H z ) . 53 With the b i c y c l i c ketone 179 i n hand, attention was directed to the preparation of the 6-vinylbicyclo[3.1.0]hexene systems 187 and 189. Thus, treatment of the ketone 179 with 1.1 equivalents of lithium ^ diisopropylamide at -78°C, followed by trapping of the resultant enolate anion * with t e r t - b u t y l d i m e t h y l s i l y l chloride i n 189 the presence of hexamethylphosphoramide provided the s i l y l enol ether 187 i n 95% y i e l d . 187 I n i t i a l l y , t r i m e t h y l s i l y l chloride was employed to trap the lithium enolates. However, the resultant s i l y l enol ethers proved to be unstable, unlike t h e i r t e r t - b u t y l d i m e t h y l s i l y l counterparts, which posed few problems to handling and p u r i f i c a t i o n . 54 The i r spectrum of this compound lacked a carbonyl absorption and exhibited the absorptions (v 3060, 3020, 1622, 840 cm 1) t y p i c a l of the o l e f i n i c moieties i n the assigned structure. On the other hand, the "*"H nmr spectrum of 187, i n which there were few overlapping signals, provided a r e l a t i v e wealth of information. As expected, the proton resonances, attributed to the t-butyl and methyl groups bonded to s i l i c o n , were found at 6 0 . 9 3 and 0 . 1 5 , respectively. Markedly u p f i e l d from the set of signals due to the v i n y l group, the broad s i n g l e t at 6 4 . 3 0 was i n d i c a t i v e of the o l e f i n i c proton H^ . adjacent to the siloxy substituent. The neighbouring methylene protons (H T and H„) gave r i s e to two J ii sets of overlapping doublet of doublet of doublets (6 2 .29 and 2 .52 ) i n which the t e l l t a l e large coupling ( J = 17 Hz) c h a r a c t e r i s t i c of geminal protons, was quite obvious. From models, i t appeared that the H^-Hj dihedral angle approximated 90° whereas that of H -H_ was =20°. In accordance with the O ii 112 Karplus equation, one would expect a stronger coupling between H_ and H„ than that between H_, and H_, and the resen-ts ii ( j j ances at 6 2 . 2 9 (JQJ - 0) and 2 . 5 2 ( J ^ = 8 Hz) were consequently assigned to H and H , respectively. Both of these protons 0 ii exhibited a small coupling to the v i n y l proton H T ( J T T = 3 Hz, J T „ = 2 Hz). The cyclopropyl protons H„, H^ and H_ appeared —-Lii ti Jt ta as complex multiplets at 6 1 . 1 4 , 1 . 5 7 - 1 . 6 3 and 1 . 6 7 - 1 . 7 2 . How-ever, the resonance at 6 1 .14 displayed a large coupling ( J _ D E = 9 Hz) and was consequently attributed to H^. 5 5 [34] 187 188 The stage was now set for the Cope rearrangement of the 6-vinylbicyclo[3.1.0]hex-2-ene 187. Thus, the s i l y l enol ether 187 was sealed i n vacuo i n a s i l y l a t e d pyrolysis tube and subjected to a temperature of 200°C for 2 hours, a f t e r which time g l c analysis indicated the presence of a new single component. This material, i d e n t i f i e d as the bicyclo[3.2.1]-octadiene 188, was obtained i n almost quantitative y i e l d (eq. [34]) . 188 Although the i r spectrum (v 3040, 3000, 1615 cm - 1) of 3 c max thi s compound did not d i f f e r dramatically from that of i t s pre-cursor 187, the nmr spectrum was quite complicated i n comparison, and did not lend i t s e l f r e a d i l y to analysis. 56 However, the signals at 6 0.14, 0.16, 0.93 and 5.11 indicated that the t e r t - b u t y l d i m e t h y l s i l y l enol ether moiety had remained i n t a c t , and more s i g n i f i c a n t l y , the signals due to a v i n y l substituent were c l e a r l y absent, being supplanted by resonances attr i b u t a b l e to environmentally d i f f e r e n t o l e f i n i c protons (6 5.11, 5.27-5.32 and 6.16-6.22). By means of decoupling studies, i t was possible to show that the methylene proton H T exhibits a long-range coupling to H T. These two protons are i n an orientation approaching the planar zig-zag or W arrangement which maximizes long-range interactions of t h i s 113 type Interestingly, this proton (Hj) couples with neither bridgehead protons (H„ and H ) since both H -H and H_ —H d i -r J\ r ± ± is. hedral angles approximate 90°. Therefore, H^ appears as a broad doublet with the geminal coupling (J = 9.5 Hz) to H„, and Li weak long-range coupling to H . C02Me 126 Me02C 133 ,84 [32] Compared with the reported rearrangement of 126 to 133 (eq. [32]) under the conditions of r e f l u x i n g xylene (b.p. 138°C) for 2.5 hours, the Cope rearrangement of 187 to the b i c y c l o -[3.2.1]octadiene 188 (eq. [34]) necessitated a higher thermolysis temperature (200°C, 2 hours) for the reaction to complete i n 57 a reasonable length of time. Indeed, i n an early attempt, a solution of 187 i n xylene was heated under reflux to y i e l d , after 17.5 hours, mainly the s t a r t i n g material. This observed difference i n reaction rates of 126 and 187, although i t i s by no means quantified, may be r a t i o n a l i z e d i n terms of the r e l a t i v e s t a b i l i z a t i o n imparted by the C - l carbomethoxy moiety i n 126 to the t r a n s i t i o n state involved i n the rate-determining epimerization step (126 -»- 205) as outlined i n Scheme 23. P r i o r to Cope rearrangement, the 6-exo-vinylbicyclo[3.1.0]-hex-2-ene 187 i s believed to undergo a one-center thermal 2 8 epimerization at C-6 to furnish the endo isomer 206, pre-sumably v i a formation of an intermediary b i r a d i c a l 25 35-39 species. ' By a s i m i l a r mechanism, the carbomethoxy analogue 126 epimerizes to 205, but at a rate faster than that involving the conversion of 187 into 206. The f a c i l i t a t i o n of the epimerization process (126 -*• 205) may be attributed to the s t a b i l i z a t i o n of the b i r a d i c a l intermediate a r i s i n g from -126 by means of d e l o c a l i z a t i o n involving the carbomethoxy sub-st i t u e n t . On the other hand, the b i r a d i c a l intermediate a r i s i n g from 187 c l e a r l y lacks t h i s extra s t a b i l i z a t i o n and i s thus formed from 187 at a much slower rate. Nevertheless, once the epimerization has occurred, both 205 and 206 undergo Cope rearrangement quite r e a d i l y , owing to the concomitant r e l i e f of s t r a i n i n the cyclopropane r i n g as well as the favourable ir-orbi t a l overlap between the double bonds i n the quasi-boat 5 8 \ t ->-SiO Me02C SCHEME 23 \ 59 t r a n s i t i o n state. [35] 188 Hydrolysis of the enol ether 188 was accomplished smoothly i n THF at room temperature by treatment of th i s substance with aqueous hydrochloric acid. Bicyclo[3.2.1]oct-2-en-6-one (207) was thus obtained i n 88% y i e l d (eq. [35]), and exhibited an i r spectrum which indicated the presence of a ketone (v 1730 c ^ max cm 1) and a c i s - d i s u b s t i t u t e d alkene (v 3025, 1640, 735 max cm ^ ) . Examination of the H^ nmr spectrum of 207 showed that 207 the resonance of the enol ether o l e f i n i c proton was absent. The u p f i e l d region was complicated by the presence of three pairs of methylene protons, two of these pairs appearing as AB systems. While Hj and H z appeared at 6 2.03 and 2.08, respectively with a geminal coupling of 11 Hz, H T and H 6 0 r e s o n a t e d a t 6 2 . 3 4 a n d 2 . 2 9 , r e s p e c t i v e l y w i t h a g e m i n a l c o u p l i n g o f 1 7 . 5 H z . L a s t l y , t h e m e t h y l e n e p r o t o n s H_, a n d H , c o n s t i t u t i n g a n A X s y s t e m , w e r e a l s o c o u p l e d s t r o n g l y ( J „v = 1 8 H z ) t o e a c h o t h e r a n d a p p e a r e d a t 6 2 . 4 3 a n d 2 . 2 0 , r e s p e c t -i v e l y . H a v i n g d e m o n s t r a t e d t h a t t h e C o p e r e a r r a n g e m e n t o f 2 - t e r t -b u t y l d i m e t h y l s i l o x y - 6 - e x o - v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e ( 1 8 7 ) o c c u r s v e r y e f f i c i e n t l y , w e w e r e e n c o u r a g e d t o i n v e s t i g a t e s i m i l a r r e a r r a n g e m e n t s o f m o r e h i g h l y s u b s t i t u t e d s u b s t r a t e s . 1.2.2 T h e S y n t h e s i s a n d R e a r r a n g e m e n t o f 6 - e x o - V i n y l b i c y c l o -[ 3 . 1 . 0 ] h e x - 3 - e n - 2 - o n e ( 1 8 9 ) a n d C - 4 F u n c t i o n a l i z e d 6 - e x o - V i n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e s 1 9 2 a n d 1 9 4 S c h e m e 2 4 2 0 8 2 0 9 O n t h e b a s i s o f t h e r e a c t i o n s s h o w n i n g e n e r a l t e r m s i n S c h e m e 2 4 , o n e c a n e n v i s a g e t h a t a n e n o n e s u c h a s 1 8 9 c o u l d s e r v e a s a s u i t a b l e p r e c u r s o r f o r t h e s y n t h e s i s o f bicyclo[3.2.1]octadienes substituted at C-8. That i s , nucleo-p h i l i c attack at C-4 of 189 should occur predominantly from the convex side of the molecule, giving an intermediate enolate anion with the newly introduced substituent i n an exo orient-ation. The intermediate, upon trapping with a suitable electro-p h i l e , would provide the enol ether 208, which should, upon thermolysis, rearrange to the b i c y c l i c diene 209. 1. "CH2=CH 2. base; t-BuMe 2SiCl [36] 189 192 210 Et02C / 4 [37] 189 194 For the placement of a two-carbon "handle" with exo orientation at C-8 of the bicyclo[3.2.1]octane skeleton, i t was f e l t that the stereoselective preparation (with respect to C-4) and rearrangement of the systems 192 and 194 would be i n s t r u c t i v e . Conceivably, the f u n c t i o n a l i z a t i o n at C-4 i n these systems could be accomplished v i a known methods, i . e . the conjugate addition to the enone 189 using either v i n y l cuprate or Grignard reagents (eq. [36]) or a s i l y l ketene 62 =< OSi^f OEt \ 210 179 [38] 189 190 acetal 210 (eq. [37]). Moreover, the enone 189 i s i t s e l f a vinylbicyclo[3.1.0]-hexene and successful Cope rearrangement of this compound would provide a bicyclo[3.2.1]octadiene 190 functionalized at C-8, as shown i n equation [38]. The ct, g-unsaturated ketone 189 may be derived from the b i c y c l i c ketone 179, the synthesis of which was discussed e a r l i e r (vide supra). For the preparation of a,g-enones from the parent saturated ketones, a number of methods are known. For example, b i c y c l o -[3.1.0]hex-3-en-2-one (211) was generated from the ketone 145 using a three-step sequence involving i n i t i a l l y the synthesis of the a-bromoacetal 212, which subsequently was dehydro-114 halogenated and deprotected (Scheme 25). However, for the conversion of the ketone 179 into the desired enone 189 (eq. 6 3 S C H E M E 2 5 0 HO t>H B r , 1 4 5 Br N a O M e 2 1 2 0 H 3 0 + 2 1 1 [ 3 9 ] ) , t h i s m e t h o d w a s n o t c o n s i d e r e d s u i t a b l e s i n c e t h e u s e o f b r o m i n e c o u l d p r e s e n t t h e p r o b l e m o f c o m p e t i n g s i d e r e a c t i o n s , Q [ 3 9 ] 1 7 9 1 8 9 0SiMe3 0 [ 4 0 ] 2 1 3 64 A l t e r n a t i v e l y , t h e r e h a v e b e e n r e c e n t r e p o r t s o f o x i d i z i n g t r i m e t h y l s i l y l e n o l e t h e r s t o a , B - e n o n e s . F l e m i n g a n d P a t t e r s o n1 1 5 d e s c r i b e d t h e u s e o f d i c h l o r o d i c y a n o b e n z o q u i n o n e ( D D Q ) t o o x i d i z e t h e e n o l e t h e r 2 1 3 t o 2 - c y c l o p e n t e n - l - o n e ( e q . [ 4 0 ] ) i n a y i e l d o f 2 0 % . I n a n e a r l i e r p a p e r , S a e g u s a e t a l .1 1 r e p o r t e d t h a t p a l l a d i u m ( I I ) a c e t a t e s u p p l e m e n t e d b y p _ - b e n z o -q u i n o n e c o n s t i t u t e d a n e f f i c i e n t o x i d a n t s y s t e m t o e f f e c t t h e s a m e t r a n s f o r m a t i o n i n a y i e l d o f 9 8 % ( e q . [ 4 0 ] ) . I n d e e d , t h e p a l l a d i u m ( I I ) c a t a l y z e d d e h y d r o s i l y l a t i o n o f s i l y l e n o l e t h e r s h a s b e e n a p p l i e d t o a n u m b e r o f n a t u r a l p r o d u c t s y n t h e s e s i n t h e p a s t s i x y e a r s , a s e x e m p l i f i e d i n S c h l e s s i n g e r ' s 1 1 7 s y n t h e s i s ( S c h e m e 2 6 ) o f t h e p s e u d o g u a i a n o l i d e h e l e n a l i n ( 2 1 4 ) , a n d v e r y r e c e n t l y , i n a s y n t h e s i s o f t h e s e s q u i t e r p e n o i d S C H E M E 2 6 [ a ] ( i ) L i N ( S i M e - , ) ( i i ) M e ^ S i C l [ b ] P d ( O A c ) - , M e C N ( 7 3 % f r o m 2 1 5 ) 3 2 3 2 65 SCHEME 2 7 217 Me^SiO 216 [a] M e - S i l , E t -N, CH,C1_, -78°C 217) J z z [b] P d ( O A c ) 2 , MeCN (74% from 218 c a p n e l l e n e (216) by P i e r s and 118 K a r u n a r a t n e (Scheme 2 7 ) . D e s p i t e the o f f e r o f good y i e l d s , t h i s method was n o t p a r t i c u l a r l y a p p e a l i n g as a means t o pr e p a r e t h e b i c y c l i c enone 189 i n vi e w o f t h e i n s t a b i l i t y o b s e r v e d i n our p r e v i o u s e x p e r i e n c e w i t h 2 - t r i m e t h y l s i l o x y - 6 - e x o - v i h y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e (218). However, we found ( v i d e i n f r a ) t h a t t h i s method was a good a l t e r n a t i v e t o the w e l l e s t a b l i s h e d s e l e n o x i d e f r a g m e n t a t i o n t o g e n e r a t e ct,g-enones from t h e s a t u r a t e d k e t o n e s . U n d e n i a b l y , t h e r e e x i s t s a c o n s i d e r a b l e volume o f document-a t i o n d e d i c a t e d t o the p r o c e d u r e f o r the c o n v e r s i o n o f ketones t o t h e i r a , 3 - u n s a t u r a t e d d e r i v a t i v e s v i a the sequence o f 66 SCHEME 28 0 i t SeR 219 [o] 0 t j f S e R 220 * reactions shown i n Scheme 28. This conversion i s implemented formally i n three steps: (a) introduction of a seleno group alpha to the carbonyl, (b) oxidation of the resultant selenide 219 to the selenoxide l e v e l , and (c) fragmentation of the selenoxide 220 to give the ct,g-enone. However, from a p r a c t i c a l point of view, th i s procedure i s usually a "two-pot" process, since the selenoxide normally fragments under the conditions 121 of i t s formation. For example, Reich et al_. have reported the preparation of the cyclopentenone 221 from the ketone 222. The intermediary c t-phenylselenenyl ketone 223 was obtained by treating the lithium enolate of ketone 222 with phenylselenenyl * For reviews on the use of organoselenium reagents i n organic synthesis, the reader i s referred to Refs. 119 and 120, and the references c i t e d therein. 67 0 0 0 179 224 189 bromide. Oxidation of 223 with hydrogen peroxide, followed by * elimination, gave 221 i n an o v e r a l l y i e l d of 66%. In a si m i l a r manner, the lithium enolate of the b i c y c l i c ketone 17 9 was formed using 1.1 equivalents of lithium d i i s o -propylamide i n THF at -7 8°C, and was subsequently quenched by the addition of a solution of phenylseleneny1 chloride i n HMPA. The resultant selenides 224, which were obtained i n 79% yield,-were subjected to oxidative elimination using hydrogen peroxide and pyridine i n dichloromethane at room temperature to furnish the enone 189 i n a mediocre o v e r a l l y i e l d of 50%. I n i t i a l attempts to improve the y i e l d of the oxidation by using sodium metaperiodate i n methanol led to much lower y i e l d s , but our e f f o r t s were rewarded when the entire sequence of reactions 123 was performed i n "one-pot" as described by Reich et a l . 122 * Toshimitsu et a l . have recently reported that c t-pyridyl-seleno derivatives undergo oxidative elimination more readily than a-phenylseleneny1 ketones. 68 Thus, the l i t h i u m e n o l a t e o f ketone 179 g e n e r a t e d by the method d e s c r i b e d above, was quenched by t h e a d d i t i o n o f a s o l u t i o n o f p h e n y l s e l e n e n y l c h l o r i d e i n THF. O x i d a t i o n o f the c t - p h e n y l s e l e n i d e s t o the s e l e n o x i d e s was i n d u c e d by t h e i n t r o d u c t i o n o f a c e t i c a c i d and hydrogen p e r o x i d e t o the r e s u l t a n t r e a c t i o n m i x t u r e a t 0°C. Under t h e s e c o n d i t i o n s , s e l e n o x i d e f r a g m e n t a t i o n ensued and t h e b i c y c l i c enone 189 was i s o l a t e d i n 88% y i e l d . The i r spectrum o f 189 e x h i b i t e d t h e e x p e c t e d a b s o r p t i o n s (v 3050, 1690, 1640 cm 1 ) f o r an a , ^ - u n s a t u r a t e d k e t o n e . I n max ' ' ' the ^H nmr spectrum, the v i n y l p r o t o n s o f the c o n j u g a t e d system were c l e a r l y v i s i b l e . W h i l e t h e a - p r o t o n (Hj) r e s o n a t e d as a d o u b l e t a t S 5.70, the B - p r o t o n (Hj) appeared c h a r a c t e r i s t i c a l l y d o w n f i e l d a t 6 7.64 as a d o u b l e t o f d o u b l e t o f d o u b l e t s . The s p l i t t i n g p a t t e r n shown by H T a r o s e from d i s s i m i l a r c o u p l i n g t o Hj ( J J J = 5.5 H z ) , H G ( J ^ j = 2.5 Hz) and H F ( J _ F J = 1 Hz) . That t h e v i n y l group had r e t a i n e d i t s i n t e g r i t y was e v i d e n c e d by the AMX p a t t e r n i n the o l e f i n i c r e g i o n . I n t h e h i g h e r f i e l d p o r t i o n o f t h e spectrum, t h e resonances o f the t h r e e c y c l o p r o p y l p r o t o n s were w e l l r e s o l v e d and were a s s i g n e d on t h e b a s i s o f a d e c o u p l i n g e x p e r i m e n t ( F i g . 2 ) . By i r r a d i a t i n g a t 6 7.64 nmr spectrum, and (b) the spectrum with i r r a d i a t i o n at 6 7 .64 (H^) . 70 (H ) , the signal at 6 2.59 collapsed to a doublet of doublets u (J_„ = 4 Hz, J__ = 3 Hz) and was attributed to H . The — r o —hiij Ca assignment of the complex resonance at 6 2.17 to H„ was made E without d i f f i c u l t y since the strong coupling between H D and H £ (J = 9 Hz) was quite evident. Furthermore, the similar coupling between H and the other cyclopropyl protons (J™ -J_ E G = 3.0 Hz) were apparent. By the process of elimination, the multiplet at 6 2.27-2.32 was attributed to the remaining cyclopropyl proton H„. r 0 0 189 190 [38] For the rearrangement of the b i c y c l i c enone 189 to the ketone 190 (eq. [38.]) , the conditions were chosen to minimize -the decomposition of the substrate 189, which darkened on standing at 4°C under argon and i n the absence of l i g h t . Thus, 189 was thermolyzed i n solution (dry benzene) at 160°C for 4 hours (sealed tube) to give, af t e r d i s t i l l a t i o n , a material which was shown to be the bicyclo[3.2.1]octa-2,6-dien-8-one (190). In l i g h t of the i n s t a b i l i t y exhibited by the substrate 189, i t was perhaps not e n t i r e l y surprising to i s o l a t e the product 190 i n a modest y i e l d of 68% while the remaining balance of mass was recovered i n the form of a t a r . Hj 190 Nevertheless, spectral analysis of the d i s t i l l e d product v e r i f i e d that the desired compound 190 had been obtained. Examination of the i r spectrum of this material indicated the presence of a saturated ketone (v 1755 cm "*") as well as the ^ max o l e f i n i c moieties (v 3050, 1622, 680 cm ). Close scrutiny max t i i 2 of the nmr spectrum of 190 (Fig. 3) revealed the presence of four o l e f i n i c protons, which were environmentally d i f f e r e n t (<5 5.46-5.53, 6.04, 6.21 and 6.69) from those i n 189. I t was possible to d i s t i n g u i s h between H and H by decoupling H_ (6 6. 69), which c l e a r l y revealed J_ K E (7 Hz) while the multiplet at 6 2.73-2.82, attributed i n part to H„ and H „ , s i m p l i f i e d (Fig. 4) . Et0 2 C-^ 1 9 2 1 9 4 W i t h t h e d e s i r e d a , g - e n o n e 1 8 9 i n h a n d a n d t h e s u c c e s s f u l F i g . 4 . T h e h o m o n u c l e a r s p i n d e c o u p l i n g e x p e r i m e n t w i t h 1 9 0 : ( a ) t h e n o r m a l 4 0 0 M H z H n m r s p e c t r u m e x p a n d e d f o r t h e r e g i o n b e t w e e n 6 2 . 4 - 6 . 7 , a n d ( b ) t h e s p e c t r u m w i t h i r r a d i a t i o n a t 6 6 . 6 9 ( HT) . 7 4 d e m o n s t r a t i o n o f a r o u t e f o r t h e p r e p a r a t i o n o f b i c y c l o [ 3 . 2 . 1 ] -o c t a d i e n e s f u n c t i o n a l i z e d a t C - 8 , a t t e n t i o n w a s d i r e c t e d t o t h e t a s k o f s y n t h e s i z i n g a n d r e a r r a n g i n g t h e s i l y l e n o l e t h e r s 1 9 2 a n d 1 9 4 s u b s t i t u t e d a t C - 4 w i t h e x o g e o m e t r y . 1 8 9 * 1 9 2 I n p r i n c i p l e , t h e d e s i r e d e n o l e t h e r 1 9 2 c o u l d b e o b t a i n e d f r o m t h e c o p p e r ( I ) - c a t a l y z e d c o n j u g a t e a d d i t i o n o f v i n y l m a g n e s i u m b r o m i d e t o t h e e n o n e 1 8 9 , f o l l o w e d b y d e r i v a t i z a t i o n u s i n g 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 . H o w e v e r , u n d e r t h e c o n d i t i o n s o f c o n j u g a t e a d d i t i o n , t h e r e a r e i n d i c a t i o n s t h a t c y c l o p r o p a n e r i n g c l e a v a g e c o u l d b e a c o m p e t i n g p r o c e s s . F o r 1 2 5 i n s t a n c e , M a r s h a l l a n d R u d e n o b s e r v e d t h a t r e a c t i o n o f t h e -c o n j u g a t e d c y c l o p r o p y l e n o n e 2 2 5 w i t h l i t h i u m d i m e t h y l c u p r a t e y i e l d e d t h e 1 , 4 - a d d u c t 2 2 6 ( 4 3 % ) a n d c y c l o p r o p a n e r i n g c l e a v e d a d d u c t 2 2 7 ( 4 9 % ) a s s h o w n i n e q . [ 4 1 ] , R e a c t i o n o f t h e s a m e Et 2 2 5 2 2 7 2 2 6 7 5 Me 2 2 8 2 3 1 0 Me 2 3 2 2 2 9 Ph 2 3 3 Ph [ 4 2 ] 2 3 0 0 ^ ^ Y ^ M e XJ  [43] 2 3 4 c u p r a t e r e a g e n t w i t h t h e a , $ - e n o n e 2 2 8 f u r n i s h e d a 4 8 : 5 2 m i x t u r e o f t h e n o r m a l c o n j u g a t e a d d i t i o n p r o d u c t 2 2 9 a n d 1 2 6 t h e c y c l o p r o p a n e r i n g o p e n e d p r o d u c t 2 3 0 ( e q . [ 4 2 ] ) . A n e x a m p l e w h i c h p e r h a p s r e s e m b l e s t h e b i c y c l i c k e t o n e 1 8 9 m o r e c l o s e l y i s s h o w n i n e q . [ 4 3 ] . T r e a t m e n t o f t h e b i c y c l o [ 3 . 1 . 0 ] h e x e r i o n e 2 3 1 w i t h l i t h i u m d i m e t h y l c u p r a t e g a v e a m i x t u r e o f t h e 1 , 4 - a d d u c t 2 3 2 ( 9 2 % ) , a n d t h e r i n g - c l e a v e d p r o d u c t s 23_3 ( 2 % ) a n d 23_4 ( 6 % ) .1 2 7 A l t h o u g h t h e e x a m p l e s c i t e d a b o v e b e a r s o m e r e s e m b l a n c e t o t h e b i c y c l i c e n o n e 1 8 9 o f i n t e r e s t , t h e y m a y n o t s e r v e a p p r o p r i a t e l y a s m o d e l s f o r t h e b e h a v i o u r o f 1 8 9 u n d e r s i m i l a r r e a c t i o n c o n d i t i o n s . D u e t o t h e p r e s e n c e o f t h e C - 6 v i n y l s u b -1 2 8 s t i t u e n t , t h e r e d u c t i o n p o t e n t i a l a n d t h e r e f o r e t h e r e a c t i v i t y p a t t e r n o f 1 8 9 m a y b e q u i t e d i f f e r e n t f r o m t h o s e o f t h e c y c l o -p r o p y l k e t o n e s s h o w n i n e q s . [ 4 1 ] - [ 4 3 ] . H o w e v e r , c y c l o p r o p a n e r i n g - c l e a v a g e s h o u l d n o t b e e n t i r e l y d i s m i s s e d a s a p o s s i b l e 76 side reaction i n the conjugate addition of a Grignard reagent to the cyclopropyl enone 189. M + 0 Assuming that the addition of v i n y l magnesium bromide to the enone 189 proceeds i n a conjugate sense, the s i l y l enol ether 192 could conceivably be obtained by the d i r e c t trapping of the resultant metalated enolate 235 with tert-butyldimethyl-s i l y l chloride i n a "one-pot" procedure. However, i n practice, * only t r i m e t h y l s i l y l enol ethers have been prepared i n this manner. In an i n i t i a l attempt to prepare the t r i m e t h y l s i l y l enol ether 236 using this method, the procedure described by House 133 et a l . was employed to form the metalated enolate 235 by the addition of v i n y l magnesium bromide to the enone 189 i n the For more information concerning the preparation of s i l y l enol ethers from enolates, the reader should consult r e f s . 116, 129 and 130. The trapping of enolates generated from copper (I)-catalyzed Grignard additions to enones, using t r i m e t h y l s i l y l chloride, has been described.80e,131,132 7 7 p r e s e n c e o f a c a t a l y t i c a m o u n t o f c u p r o u s b r o m i d e - d i m e t h y l * 8 Oe 1 3 2 s u l f i d e c o m p l e x . D i r e c t q u e n c h i n g ' o f t h e e n o l a t e 2 3 5 w i t h a m i x t u r e o f t r i m e t h y l s i l y l c h l o r i d e , t r i e t h y l a m i n e a n d h e x a m e t h y l p h o s p h o r a m d e g a v e a 7 : 1 m i x t u r e o f t h e d i v i n y l k e t o n e 2 3 7 a n d t h e e n o l e t h e r 2 3 6 i n a n u n e n v i a b l e y i e l d o f 4 8 % . B e c a u s e 2 3 6 w a s q u i t e s u s c e p t i b l e t o h y d r o l y s i s a n d c o n s e q u e n t l y d i d n o t l e n d i t s e l f r e a d i l y t o h a n d l i n g o r p u r i f i c a t i o n , t h e a l t e r n a t i v e " t w o - p o t " m e t h o d o f p r e p a r i n g t h e t e r t - b u t y l d i m e t h y l s i l y l e n o l e t h e r 1 9 2 w a s i n v e s t i g a t e d a n d p r o v e d t o b e m o r e s u c c e s s f u l . T h u s , u s i n g t h e p r o c e d u r e 1 3 3 o f H o u s e e_t a l . t h e e n o n e 1 8 9 w a s a d d e d t o a m i x t u r e o f v i n y l m a g n e s i u m b r o m i d e " * " ^ ' a n d a c a t a l y t i c a m o u n t o f c u p r o u s b r o m i d e - d i m e t h y l s u l f i d e c o m p l e x i n T H F t o g i v e , a f t e r q u e n c h i n g w i t h a q u e o u s a m m o n i u m c h l o r i d e , t h e k e t o n e 2 3 7 i n a n i s o l a t e d y i e l d o f 8 0 % . S i n c e n o n e o f t h e p r o d u c t s r e s u l t i n g f r o m c y c l o p r o p a n e c l e a v a g e w e r e d e t e c t e d , o u r i n i t i a l m i s g i v i n g s a b o u t s u c h c o m p e t i n g p r o c e s s e s p r o v e d , i n f a c t , t o b e u n f o u n d e d . N o t s u r p r i s i n g l y , t h e i r s p e c t r u m o f 2 3 7 r e s e m b l e d t h a t o f t h e s i m p l e b i c y c l i c k e t o n e 1 7 9 a n d i n d i c a t e d t h e p r e s e n c e o f a k e t o n e c a r b o n y l ( v 1 7 1 8 c m "*") a n d t h e v i n y l m o i e t i e s ( v J m a x J m a x 3 0 5 0 , 1 6 3 5 , 9 9 0 , 9 1 5 c m- 1) . D u e t o t h e p r e s e n c e o f t h e v i n y l s u b s t i t u e n t o n t h e c y c l o p e n t a n e r i n g , t h e "^H n m r s p e c t r u m o f 2 3 7 n o t o n l y d i f f e r e d f r o m t h a t e x h i b i t e d b y 1 7 9 , b u t d i s p l a y e d C u p r o u s b r o m i d e - d i m e t h y l s u l f i d e c o m p l e x w a s p r e p a r e d a n d p u r i f i e d i n a c c o r d a n c e w i t h r e f s . 1 3 4 - 1 3 6 . 79 well resolved signals, which offered themselves r e a d i l y to analysis (Fig. 5). The presence of two v i n y l groups was quite apparent i n the o l e f i n i c portion of the spectrum. Upfield from th i s area was the resonance at 6 3.02 attributed to H T, whose overlapping doublet of doublets arose from si m i l a r couplings to H and the v i n y l proton H„ (J T„ = J T T = 8 Hz). Most i n t e r e s t i n g l y , H appears to couple neither with H,_ nor the bridgehead proton H^, thereby suggesting that both H -H„ and H.-HT dihedral angles approximate 90°. Indeed, a model of 237 e a s i l y assumes a conformation which accommodates these observations, as did subsequent decoupling experiments. Thus," i r r a d i a t i o n at 6 3.02 (H_) led to no change at the resonances at <5 1.87-1.94 (H„) and 2.04 (H_), while the anticipated i> C J signal s i m p l i f i c a t i o n s occurred at 6 2.36 (HT) and 5.84 (H„) as shown i n F i g . 6. More importantly, t h i s decoupling study provided grounds for the stereochemical assignment of H T i n the form of a 22% signal i n t e n s i t y increase or nuclear 137 Overhauser enhancement (n.O.e.) at 6 2.36 (Hj). If the orientation of H T was exo, the resonance due to H„ rather than J ii Hj would be expected to shown a n.O.e. To dismiss t h i s 8 0 g . 6 . T h e h o m o n u c l e a r s p i n d e c o u p l i n g e x p e r i m e n t w i t h 2 3 7 : ( a ) t h e n o r m a l 4 0 0 M H z 1H n m r s p e c t r u m e x p a n d e d f o r t h e r e g i o n b e t w e e n 6 1 . 5 - 3 . 3 , a n d ( b ) t h e s p e c t r u m w i t h i r r a d i a t i o n a t 6 3 . 0 2 ( H ) . 81 p o s s i b i l i t y and to confirm the endo stereochemistry of H , an J experiment wherein was decoupled might have proven useful. However, such an experiment was not possible since the signal of i n t e r e s t was obscured by that of H at <5 1.87-1.94. [44] With the stereochemistry of the C-4 v i n y l substituent established, the d i v i n y l ketone 237 was smoothly converted into the r e q u i s i t e s i l y l enol ether 192 i n >97% y i e l d (eq. [44] ) . As expected, a carbonyl absorption was absent i n the i r spectrum of 192, but the o l e f i n i c absorptions ( v m a x 3060, 3015, 1618 cm "*") were c l e a r l y v i s i b l e . The uncomplicated "*"H nmr spectrum of th i s material as shown i n F i g . 7 presented i t s e l f r e a d i l y to analysis. Immediately evident were the singlets at 6 0.18 and 0.95 due to the tert-butyIdimethy1siloxy substituent 83 and the broad s i n g l e t at 6 4.31, which was attributed to the v i n y l proton adjacent to the sil o x y substituent. With the 2 introduction of another sp centre i n the cyclopentane r i n g , the H-H dihedral angle apparently approaches 90°. Con-sequently, H appeared as an unresolved doublet at <S 3.13 with the largest coupling to HT, (J_ T, = 7.5 Hz) . The other s i l y l enol ether 194 of i n t e r e s t could be prepared from the b i c y c l i c enone 189 v i a Michael addition of t e r t - b u t y l d i m e t h y l s i l y l ketene acetal 210 with concomitant trapping of the resultant enolate (eq. [37]). To date, con-jugate additions of 210 to a,g-unsaturated carbonyl systems 13 8 have been effected using Lewis acids (e.g. T i C l 4 ) i n 0Si-<-210 [3 E t 0 2 C ^ / 194 dichloromethane and a (rather exotic) Lewis base [ i . e . t r i s -139 (dimethylamino)sulfonium d i f l u o r o t r i m e t h y l s i l i c o n a t e ] i n 140 141 THF, under high pressure (10-15 kbar) ' and thermally i n 142 a c e t o n i t r i l e . However, the s i l y l enol ethers cannot be i s o l a t e d using Lewis acid catalysts, and only the trimethyl-s i l y l derivatives have been prepared v i a Lewis base c a t a l y s i s The high pressure method seems to be e f f e c t i v e i n inducing ketene acetal additions to enones having s t e r i c and conform-ation a l constraints, and has been used to prepare both 84 t r i a l k y l - and ter t- b u t y l d i m e t h y I s i l y l enol ethers. Due purely to technical reasons, this method was not attempted i n our e f f o r t s to transform 189 into 194. Instead, the alt e r n a t i v e thermally-induced addition, which i s conducted i n a c e t o n i t r i l e , was investigated. Thus, i n accordance with the procedure described by 142 Tamura et a l . , a mixture of the enone 189 and 1.5 equivalents * of the s i l y l ketene acetal 210 i n a c e t o n i t r i l e was warmed at 55°C. Small amounts of 210 were added every 30 minutes for 12 hours, after which time the s i l y l enol ether 194 was obtained i n only 33% y i e l d . The remaining unreacted enone 189 was recovered almost qu a n t i t a t i v e l y , thereby indicating that 194 was i s o l a t e d i n >95% y i e l d based on unrecovered enone 189. These re s u l t s were not e n t i r e l y discouraging since y i e l d s as high as 60% were obtained but after long reaction times. 142 Considering the reaction times of 12 hours reported by Tamura for the addition of 210 to the r e l a t i v e l y unhindered 2-cyclo-hexen-l-one, the sluggish nature of the reaction using the enone 189 as substrate was not unexpected. Et02C The s i l y l ketene acetal 210 was prepared from ethyl acetate. 143 ( C H3)2S i 6 4 * S 5 F i g . 8 . T h e 4 0 0 M H z H n m r s p e c t r u m o f 1 9 4 . 86 Nevertheless, spectral analysis of the product indicated that these e f f o r t s were f r u i t f u l i n providing the desired 194 . The i r spectrum of t h i s material was consistent with the pro-posed structure and exhibited the expected absorptions of an ester ( v _ 1730, 1255 cm as well as those of the o l e f i n i c max residues (v 3050, 787 cm ^ ) . Immediately evident i n the max 1 nmr spectrum (Fig. 8) were the presence of the t e r t - b u t y l -dimethylsiloxy group (singlets at <5 0.16 and 0.94), the ethyl ester and the v i n y l moiety. Interestingly, decoupling of H_, (Fig. 9) revealed a small coupling (J = 3 Hz) between H_. and — Ca H despite the approximation of the H -HT dihedral angle to J CJ u 90°. I t i s pertinent to point out that the s i m i l a r i t y between the coupling ( J _ T = 3 Hz) and the corresponding J _ T (2.5 Hz) in 192, provided the basis on which the endo stereochemistry of H T i n 194 was assigned. u Et02C 194 [45] [46] With the two desired vinylbicyclo[3.1.0]hex-2-enes 192 and 194 i n hand, attention was directed to t h e i r thermal 8 7 (b) - J ll Et02C-x H. 194 Et02C-CH_20-(a) CH_3CH20-H, H, H20 Fi g . 9. The homonuclear spin decoupling experiment with 194; (a) the normal 400 MHz 1H nmr spectrum expanded for the region 6 1.2-3.0, and (b) the spectrum with i r r a d i a t i o n at 6. 1.73 (H_) . G 88 rearrangement. I t was g r a t i f y i n g to discover that heating the s i l y l enol ethers i n sealed tubes at 200°C afforded cleanly i n each case a new single product, as indicated by glc analysis (eqs. [45] and [46]). The rearranged s i l y l enol ethers 193 and 195 were is o l a t e d i n y i e l d s of 89% and 98% respectively. O l e f i n i c absorptions were c l e a r l y v i s i b l e i n the i r spectra of 193 (v 3050, 3010, 1624 cm - 1) and 195 (v ^ max ' ' max 3050, 3010, 1620 cm ) i n addition to the ester carbonyl stretch (v 1725 cm ^) i n the l a t t e r compound. In the ^ "H max * nmr spectra, the resonances of the t e r t - b u t y l group (6 0.92), the s i l y l methyls (6 0.14-0.16) and the H T v i n y l proton (193: <5 4.95-5.01; 195: 6 4.97) bore testimony to the fa c t that the s i l y l enol ether moieties had survived the thermolyses. Also evident were the now-familiar s p l i t t i n g patterns of the v i n y l protons and H , each occurring at almost i d e n t i c a l chemical s h i f t s i n the spectra of 193 and 195. In the H nmr spectrum of 193 (Fig. 10), the proton H appeared as a doublet at <5 2.65, due to coupling only with the v i n y l proton H (J = 7.5 Hz). Indeed, the apparent lack of z coupling implies that both Hp-H-j. and Hj-H^ dihedral angles must be close to 90°, thereby v e r i f y i n g the endo stereochemistry 193 1 9 0 o f . I t w a s p o s s i b l e t o d i s t i n g u i s h b e t w e e n t h e t w o b r i d g e -h e a d p r o t o n s HF a n d HR b y d e c o u p l i n g H ^ , w h i c h l e d t o t h e c o l l a p s e o f t h e r e s o n a n c e a t 6 2 . 3 8 (H ) t o a n u n r e s o l v e d K d o u b l e t ( J _ - _ = 2 . 5 H z ) . — J is. T h e l o w f i e l d r e g i o n o f t h e "''H n m r s p e c t r u m o f 1 9 5 w a s , i n c o n t r a s t , m u c h s i m p l e r o w i n g t o t h e l a c k o f a C - 8 v i n y l s u b s t i t u e n t , w h i l e t h e h i g h e r f i e l d p o r t i o n c o n s i s t i n g o f o v e r l a p p i n g r e s o n a n c e s w a s q u i t e d i f f i c u l t t o i n t e r p r e t e v e n w i t h t h e a i d o f d e c o u p l i n g s t u d i e s . D i s a p p o i n t i n g l y , n o t a c l u e r e g a r d i n g t h e s t e r e o c h e m i s t r y a t C - 8 c o u l d b e g l e a n e d f r o m t h i s s p e c t r u m . I t w a s t h e r e f o r e g r a t i f y i n g t o f i n d t h a t a n a l y s i s o f t h e ^H n m r s p e c t r u m o f t h e h y d r o l y z e d p r o d u c t 2 3 9 p r o v i d e d g r o u n d s f o r t h e s t e r e o c h e m i c a l a s s i g n m e n t a t C - 8 . [ 4 7 ] [ 4 8 ] A c i d - c a t a l y z e d h y d r o l y s i s ( T H F - 5 % H C l , r . t . ) o f t h e r e -a r r a n g e d s i l y l e n o l e t h e r s 1 9 3 a n d 1 9 5 t o t h e c o r r e s p o n d i n g b i c y c l o [ 3 . 2 . 1 ] o c t e n o n e s 2 3 8 a n d 2 3 9 p r o c e e d e d s m o o t h l y i n y i e l d s o f 9 3 % a n d 9 4 % , r e s p e c t i v e l y ( e q s . [ 4 7 ] a n d [ 4 8 ] ) . 91 92 The a n t i c i p a t e d ketone a b s o r p t i o n s (v 1730 cm-"*") were in 3.x c l e a r l y v i s i b l e i n t h e i r s p e c t r a o f 238 and 239 and i n the l a t t e r , t h e e s t e r c a r b o n y l a b s o r p t i o n appeared a t 1740 cm~\ These s p e c t r a a l s o e x h i b i t e d t h e a b s o r p t i o n s t y p i c a l o f a l k e n e s (238: v m a v 3052, 3010, 1630 c m - 1 ; 239: v 3000, 1625 - l , cm ) . A c u r s o r y e x a m i n a t i o n o f t h e "^H nmr spectrum o f t h e ketone 238 ( F i g . 11) showed t h a t t h e s i l y l e n o l e t h e r m o i e t y was a b s e n t . Due t o t h e p r e s e n c e o f two p a i r s o f methylene p r o t o n s , the h i g h - f i e l d r e g i o n p r e s e n t e d a c h a l l e n g i n g e x e r c i s e f o r a d e t a i l e d a n a l y s i s . The resonance a t 6 2.91, w h i c h was th e f u r t h e s t d o w n f i e l d i n t h i s r e g i o n , was a s s i g n e d t o w i t h the a i d o f an e x p e r i m e n t i n w h i c h H z was d e c o u p l e d . Hj i s c o u p l e d n o t o n l y t o H z ( J = 5.5 H z ) , b u t a l s o q u i t e w e a k l y t o th e b r i d g e h e a d p r o t o n s H„ (6 2.59-2.63) and H v (6 2.66), whose r is. r e s o n a n c e s sharpened when H^ was d e c o u p l e d ( F i g . 1 2 ) . T h i s same d e c o u p l i n g e x p e r i m e n t r e v e a l e d t h e l o n g - r a n g e c o u p l i n g ( J = 2 Hz) between and H J f w h i c h a r e o r i e n t e d i n a p l a n a r 113 z i g - z a g o r W arrangement. T h i s f i n d i n g p r o v i d e d f u r t h e r s u b s t a n t i a t i o n o f t h e s t e r e o c h e m i s t r y a t C-8. The e x p e r i m e n t i n w h i c h H D was d e c o u p l e d p r o v e d v e r y i n f o r m a t i v e f o r the 93 2.9 2.7 2.5 2. 3 TP)Y\ F i g . 12. The homonuclear spin decoupling experiment for 238: (a) the normal 4 00 MHz H nmr spectrum expanded for 6 2.2-3.0, and (b) the spectrum with i r r a d i a t i o n at 6 2.91 (Hj). 94 assignment of the complex resonances at 6 2.52 and 6 2.30 to H c and H^, respectively. Other than coupling geminally to H x (J = 18 Hz), H c couples to H p (J = 5.5 Hz), and s i m i l a r l y to H D and H E ( J ^ = = 2 Hz!). Compared to H c, H x d i f f e r s i n i t s coupling to H p (J = 2 Hz) and H D (J = 3.5 Hz). The other methylene protons H_ and H„ appeared at 6 2.20 and 2.43 respectively, the former of which forms a dihedral angle of =90° with the bridgehead proton H . Consequently, H T apparently couples with Hj (J = 2 Hz) and H y (J = 17.5 Hz), but not with H R. In contrast, H y exhibits a strong coupling to H R (J = 6 Hz) . 239 I t was obvious from the H nmr spectrum of 239 that the s i l y l enol ether moiety was absent. The complexity of the high f i e l d portion of the spectrum was undoubtedly attributed to the presence of three pairs of methylene protons. Neverthe-le s s , Hj resonated as an overlapping doublet of doublets at 6 2.70 due to si m i l a r couplings to the protons alpha to the ester group. H^ was coupled weakly tb one bridgehead proton H , the resonance (6 2.60) of which sharpened when the signal at 6 2.70 was i r r a d i a t e d . These data seemed to be consistent with the endo stereochemical assignment of H T i n 239. 95 Although the "compression" of resonances i n the region of 6 2.22-2.45 did not permit a detailed interpretation, the a v a i l -able data indicated the successful preparation of the desired keto ester 239. Even though the reactions described to this point provide access to bicyclo[3.2.1]octa-2,6-dienes which bear substituents on the one- and two-carbon bridges, examples of these systems which are substituted on the three-carbon bridge were scarce. I t was thought that t h i s problem could be approached i n con-junction with a study regarding the s t e r e o s p e c i f i c i t y with which 6-(1-alkenyl)bicyclo[3.1.0]hex-2-ene systems undergo [3,3]-sigmatropic rearrangements. 1.2.3 The Synthesis and Rearrangement of 6-exo-[(E)- and (Z)-1-alkenyl]bicyclo[3.1.0]hex-2-enes (240) and (274) An unquestionably appealing feature of the Cope rearrange-ment as the key step i n a synthesis of sinularene (125) using th i s methodology would be i t s capacity to situate stereo-s p e c i f i c a l l y the s t e r i c a l l y bulky isopropyl substituent with exo geometry at C-4 of the bicyclo[3.2.1]octane skeleton. This feature would be suitably demonstrated by the stereo-s p e c i f i c rearrangement of the geometric isomers 240 and 242 [49] 240 241 96 [50] to the 4-endo- and 4-exo-isopropylbicyclo[3.2.1]octadienes 241 and 243, respectively (eqs. [49] and [50]). In p r i n c i p l e , the preparation of the trans isomer 240 84 could be patterned after the reported syntheses of sim i l a r compounds (cf. Scheme 15) and could therefore be accessed by u t i l i z i n g the a l l y l i c bromide 244 to alkylate the dianion of methyl acetoacetate. This synthetic sequence i s shown i n Scheme 29. SCHEME 29 246 97 The i n i t i a l t a s k a t hand then e n t a i l e d the p r e p a r a t i o n o f the a l l y l i c bromide 244, i n wh i c h the two t r a n s double bonds c o u l d be g e n e r a t e d by means o f W i t t i g - t y p e o l e f i n a t i o n 144 p r o c e s s e s (Scheme 3 0 ) . A r e p o r t by I s l e r and coworkers SCHEME 30 258 257 d e s c r i b e d the use o f t h e W i t t i g r e a c t i o n between the a,$-u n s a t u r a t e d aldehyde 24 8 and the s t a b i l i z e d phosphorane 249 i n t h e s y n t h e s i s o f the c a r o t e n o i d 250 (eq. [ 5 1 ] ) . The h i g h s t e r e o s e l e c t i v i t y o f t h i s o l e f i n a t i o n was e x e m p l i f i e d a g a i n when a c e t a l d e h y d e was t r e a t e d w i t h t h e s t a b i l i z e d phosphorane 251 t o g i v e an e s t e r m i x t u r e composed o f 96.5% m e t h y l t i g l a t e 146 252 and 3.5% o f the g e o m e t r i c i s o m e r 253. A r e v i e w a r t i c l e on the W i t t i g r e a c t i o n i s a v a i l a b l e and p r o v i d e s a s u r v e y o f s t a b i l i z e d phosphoranes which have been p r e p a r e d . 98 255 In a s i m i l a r manner, carbethoxymethylenetriphenylphosphor-ane (254) , prepared from triphenylphosphine and ethyl bromo-147 acetate according to the procedure of Denney and Ross, was allowed to react with isobutyraldehyde i n refluxing dichloro-methane to give the a,g-unsaturated ester 255 i n 92% y i e l d (eq. [53]). Quite evident i n the i r spectrum of this material 9 9 w e r e t h e a b s o r p t i o n s t y p i c a l o f a n a , g - u n s a t u r a t e d e s t e r ( v 1 7 1 5 , 1 6 4 8 c m ^) . T h e ''"H n m r s p e c t r u m c l e a r l y i n d i c a t e d t h e p r e s e n c e o f t h e e s t e r a n d i s o p r o p y l g r o u p s a n d , a s e x p e c t e d f o r a c o n j u g a t e d s y s t e m , t h e a - a n d g - p r o t o n s r e s o n -a t e d a t 6 5 . 7 6 a n d 6 . 9 5 , r e s p e c t i v e l y . I m p o r t a n t l y , t h e s e o l e f i n i c s i g n a l s e x h i b i t e d t h e l a r g e ( J = 1 6 H z ) c o u p l i n g t y p i c a l o f p r o t o n s h a v i n g a t r a n s r e l a t i o n s h i p . T h e p o s s i b i l i t y o f r e d u c i n g t h e e s t e r 2 5 5 d i r e c t l y t o t h e a , g - u n s a t u r a t e d a l d e h y d e a t l o w t e m p e r a t u r e s ( c _ a . - 1 2 7 ° C ) u s i n g o n e e q u i v a l e n t o f d i i s o b u t y l a l u m i n u m h y d r i d e ( D I B A L ) * i n p e n t a n e w a s i n v e s t i g a t e d . T h i s r e a c t i o n w a s a b a n d o n e d C02Et D I B A L p e n t a n e [ 5 4 ] 2 5 5 2 5 6 a f t e r s e v e r a l t r i a l s l e d t o m i x t u r e s o f t h e d e s i r e d <x,g-un-s a t u r a t e d a l d e h y d e 2 5 7 a n d t h e a l l y l i c a l c o h o l 2 5 6 . C o n -s e q u e n t l y , a t w o - s t e p s e q u e n c e w a s u s e d t o e f f e c t t h e s a m e t r a n s f o r m a t i o n . U s i n g a s l i g h t e x c e s s o v e r t h e r e q u i r e d 2 e q u i v a l e n t s o f d i i s o b u t y l a l u m i n u m h y d r i d e i n p e n t a n e , t h e u n s a t u r a t e d e s t e r A r e v i e w o n t h e a p p l i c a t i o n s o f D I B A L a s a r e d u c i n g a g e n t h a s b e e n p u b l i s h e d . 1 4 8 F o r e x a m p l e s o f r e d u c t i o n s o f e s t e r s t o a l d e h y d e s u s i n g D I B A L , t h e r e a d e r s h o u l d c o n s u l t r e f . 1 4 8 a n d t h e r e f e r e n c e s c i t e d t h e r e i n . 1 0 0 2 5 5 w a s r e d u c e d s m o o t h l y t o t h e a l l y l i c a l c o h o l 2 5 6 ( v J J m a x 3 3 0 0 , 1 6 6 0 c m- 1) i n a y i e l d o f 9 5 % ( e q . [ 5 4 ] ) . I n t h e 1H n m r s p e c t r u m o f 2 5 6 , t h e r e s o n a n c e s a t 6 5 . 3 8 - 5 . 8 7 , w h i c h i n t e g r a t e d f o r t w o p r o t o n s , t e s t i f i e d t o t h e f a c t t h a t t h e d o u b l e b o n d h a d r e m a i n e d i n t a c t t h r o u g h o u t t h e r e d u c t i o n , a n d t h e t w o - p r o t o n m u l t i p l e t a t 6 4 . 0 4 - 4 . 1 7 w e r e u n d o u b t e d l y d u e t o t h e p r o t o n s w h i c h w e r e a d j a c e n t t o t h e O H g r o u p . A n u m b e r o f m e t h o d s t o o x i d i z e t h e a l l y l i c a l c o h o l 2 5 6 t o t h e a , g - u n s a t u r a t e d a l d e h y d e 2 5 7 w e r e a t t e m p t e d . T h e s e 1 4 9 a t t e m p t s i n c l u d e d t h e u s e o f p y r i d i n i u m c h l o r o c h r o m a t e ( P C C ) i n d i c h l o r o m e t h a n e a n d t h e o x i d a t i v e c o m b i n a t i o n o f d i m e t h y l s u l f o x i d e - o x a l y l c h l o r i d e - t r i m e t h y l a m i n e i n d i c h l o r o m e t h a n e ( S w e r n o x i d a t i o n ) .1 5 0 H o w e v e r , t h e b e s t y i e l d s w e r e o b t a i n e d u s i n g p y r i d i n i u m c h l o r o c h r o m a t e a d s o r b e d o n a l u m i n a ,1 5 1 a n d w e r e l i k e l y d u e , i n p a r t , t o t h e e a s e o f w o r k u p . P C C - o n - _ _ CHO >. [ 5 5 ] a l u m i n a , C H C l 2 5 6 2 5 7 T h u s , r e a c t i o n o f t h e a l l y l i c a l c o h o l 2 5 6 w i t h a n e x c e s s o f p y r i d i n i u m c h l o r o c h r o m a t e a d s o r b e d o n a l u m i n a i n d i c h l o r o -m e t h a n e g a v e , a f t e r 3 h o u r s a t a m b i e n t t e m p e r a t u r e s , t h e d e s i r e d a l d e h y d e 2 5 7 i n a q u a n t i t a t i v e y i e l d ( e q . [ 5 5 ] ) . I n t h e i r s p e c t r u m o f t h i s m a t e r i a l , t h e r e w a s n o s i g n o f a n O-H 1 0 1 a b s o r p t i o n , b u t t h e p r e s e n c e o f a n a , 3 - u n s a t u r a t e d a l d e h y d e f u n c t i o n ( v 2 7 8 0 , 2 7 0 0 , 1 6 7 5 , 1 6 2 2 c m "1) w a s e v i d e n t . I n m a x t h e n m r s p e c t r u m o f 2 5 7 , t h e a l d e h y d e p r o t o n a p p e a r e d a t 6 9 . 5 5 a s a d o u b l e t w i t h a c o u p l i n g o f 8 H z t o t h e a d j a c e n t o l e f i n i c p r o t o n . CHO P h3P = C H C 02E t 2 5 9 COzEt [ 5 6 ] 2 5 7 2 5 8 1 5 2 T o o b t a i n t h e d o u b l y u n s a t u r a t e d e s t e r 2 5 8 ( e q . [ 5 6 ] ) , t h e a l d e h y d e 2 5 7 w a s s u b j e c t e d t o t h e s a m e W i t t i g o l e f i n a t i o n 1 4 4 1 4 5 c o n d i t i o n s a s d e s c r i b e d e a r l i e r f o r t h e t r a n s f o r m a t i o n ' o f i s o b u t y r a l d e h y d e t o 2 5 5 . U n f o r t u n a t e l y , t h e y i e l d o f t h i s r e a c t i o n w a s d i s a p p o i n t i n g l y a n d i n e x p l i c a b l y l o w ( 4 4 % ) . H o w -e v e r , d u e t o t i m e c o n s t r a i n t s , t h e i n v e s t i g a t i o n o f a l t e r n a t i v e r e a g e n t s w h i c h m a y h a v e p r o v i d e d b e t t e r r e s u l t s w a s n o t p u r -s u e d . COpEt 2 5 8 N e v e r t h e l e s s , t h e i r s p e c t r u m o f 2 5 8 w a s c o n s i s t e n t w i t h ( C H3) 2C H 103 the shown structure (v 3010, 1700, 1635, 1612 cm ), and in the "^H nmr spectrum of th i s material, the isopropyl and ethyl ester groups were evident (Fig. 13). The trans stereo-chemistry of the a,g-unsaturation was c l e a r l y v i s i b l e i n the form of a 14 Hz coupling exhibited by H„ (doublet at 6 5.80). r Appearing t y p i c a l l y downfield at 6 7.26 was a doublet of doub-l e t s due to Hp. The remaining o l e f i n i c protons, H c and H^ resonated as a p a i r of doublet of doublets at 6 6.09 and 6.13, respectively, with AB symmetry. By decoupling H„, the large trans coupling of 15 Hz (J_£D) was observed i n the collapsed doublet at 6 6.13 (H n). CO2ET DIBAL >< "OH [57] pentane 258 259 Again using diisobutylaluminum hydride i n pentane, the doubly unsaturated ester 258 was reduced cleanly to the a l l y l i c alcohol 259 (v 3300, 1650 cm "*") as shown i n eq. [57]. In *—~ max the nmr spectrum of 259, the two protons adjacent to the OH moiety appeared as a doublet (J = 6 Hz) at 6 4.15. A de-t a i l e d analysis of the o l e f i n i c region of the "^H nmr spectrum of 259 i s provided i n F i g . 14. I n i t i a l e f f o r t s to convert the alcohol 259 into the cor-153 responding a l l y l i c bromide using triphenylphosphine dibromide 1 0 4 JCD =15 Hz J D E =10 J B C = 7Hz -i u 6.2 6.0 5.8 5.6 TPrv F i g . 1 4 . T h e e x p a n d e d r e g i o n 6 5 . 6 - 6 . 3 o f t h e H n m r s p e c t r u m o f 2 5 9 . 105 in a c e t o n i t r i l e containing an equivalent of triethylamine did not prove f r u i t f u l . An alternative method which was described 154 by M i l l e r fortunately met with more success. Thus, treat-ment of 259 with phosphorus tribromide i n the presence of PBr pyridine, ether [ 5 8 ] 2 5 9 2 4 4 pyridine furnished, af t e r 4 hours at 0°C, the a l l y l i c bromide 244 as a v o l a t i l e l i q u i d i n a y i e l d of 78% (eq. [58]). Be-cause th i s material had a tendency to darken on standing even at 0°C, i t was d i s t i l l e d immediately p r i o r to use. The i r spectrum of 244 showed no O-H absorption and i n the nmr spectrum, the resonances of the protons adjacent to the bromine appeared as a doublet (J = 8 Hz) at 6 4.04. The isopropyl group and the four o l e f i n i c protons were c l e a r l y v i s i b l e , as was the almost 1:1 r a t i o of bromine-isotopic molecular ions i n the mass spectrum. With the desired a l k y l a t i n g material 244 i n hand, the assembly of the bicyclo[3.1.0]hexane skeleton was i n i t i a t e d according to Scheme 29 (vide supra). The dianion of methyl acetoacetate, which was generated 155 in the manner reported by Huckin and Weiler, reacted with the a l l y l i c bromide 244 at 0°C i n THF to afford the desired 106 0 0 THF, 0°C 2 4 4 ^ — [59] 3-keto ester 245 i n a modest y i e l d of 53% (eq. [59]). I t i s possible that the mediocre y i e l d r e f l e c t e d the i n s t a b i l i t y of the a l k y l a t i n g material 244 and perhaps, the e f f i c i e n c y of the reaction could be improved by shortening the reaction times. 1 5 5'"'" 5 6 However, this was not investigated further. The i r spectrum of the alkylated product 245 exhibited the anticipated absorptions of an unsaturated keto ester ( v m a v 1740, 1710, 1650, 1620 cm" 1). In the 1H nmr spectrum of t h i s compound, the resonances which were attributed to the isopropyl and methyl ester groups were quite v i s i b l e . The two protons alpha to both the ketone and ester moieties appeared as a s i n g l e t at <5 3.46 while the two which were alpha to only the ketone function resonated at 6 2.65 as a t r i p l e t (J = 7 Hz). Although the o l e f i n i c signals were p a r t i a l l y overlapped, i t was possible to discern the two large couplings of 14.5 and 15 Hz which indicated the trans,trans geometry of the two conjugated double bonds. Treatment of the 3-keto ester 245 with p_-toluenesulfonyl * 162 azide i n a c e t o n i t r i l e containing triethylamine led to the 107 [ 6 0 ] 245 246 e s s e n t i a l l y quantitative formation of a yellow viscous o i l , which was i d e n t i f i e d as the diazo keto ester 246 (eq. [60]). The strong c h a r a c t e r i s t i c absorption (v 2120 cm""'") of 3 r max diazo-containing compounds was c l e a r l y i n evidence i n the i r spectrum of 246, as were the carbonyl bands at v m a x 1710 and 1650 cm "*". With the exception of the missing s i n g l e t (6 3.46) which was due to the a-methylene protons of 245, the "^H nmr spectrum of the diazo ester 246 resembled that of the pre-cursor 245. Tosyl azide (p_-toluenesulfonyl azide) was prepared i n accordance with Doering and DePuy. 1" A comparison of a number of diazo transfer agents has been reported.158 Diazo transfer has been effected from t o s y l azide and phase-transfer conditons,159 as well as from 2,4,6-tri-isopropylphenylsulfonyl azide and p_-carboxybenzene-su l f o n y l azide.1^1 1 0 8 T h e i n t r a m o l e c u l a r c a r b e n o i d c y c l i z a t i o n o f t h e d i a z o e s t e r 2 4 6 w a s i n d u c e d b y a c a t a l y t i c a m o u n t o f c o p p e r ( I I ) * 9 8 a c e t o a c e t o n a t e i n r e f l u x i n g b e n z e n e a n d f u r n i s h e d t h e 6 - v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x a n o n e 2 4 7 i n 7 8 % y i e l d ( e q . [ 6 1 ] ) . I n v i e w o f t h e s t e r e o s p e c i f i c i t y w i t h w h i c h c o p p e r - i n d u c e d 9 1 9 2 c a r b e n o i d a d d i t o n s h a v e b e e n k n o w n t o o c c u r , ' t h e a s s i g n -m e n t o f e x o s t e r e o c h e m i s t r y t o t h e C - 6 a l k e n y l s i d e c h a i n d i d n o t s e e m p r e s u m p t u o u s . S p e c t r a l c o n f i r m a t i o n o f t h i s s t e r e o c h e m i c a l a s s i g n m e n t w a s n o t a v a i l a b l e u n t i l a f t e r t h e n e x t s t e p . T h e c a r b o n y l g r o u p s i n c o m p o u n d 2 4 7 g a v e r i s e t o i r a b s o r p t i o n s a t ^m a K 1 7 5 0 a n d 1 7 2 0 c m I n t h e h i g h f i e l d r e g i o n o f t h e 1H n m r s p e c t r u m o f t h i s m a t e r i a l , t h e o n l y d i s -c e r n i b l e r e s o n a n c e s w e r e t h e p a i r o f d o u b l e t s a t <S 0 . 9 5 a n d 0 . 9 6 , w h i c h w e r e a s s i g n e d t o t h e i s o p r o p y l m e t h y l g r o u p s , a n d t h e o v e r l a p p i n g d o u b l e t o f d o u b l e t s a t 6 2 . 6 7 , w h i c h w e r e d u e t o t h e C - 5 c y c l o p r o p y l p r o t o n . T h i s p r o t o n i s a p p a r e n t l y c o u p l e d s i m i l a r l y t o t h e o t h e r c y c l o p r o p y l p r o t o n a t C - 6 ( J = 5 . 5 H z ) a n d t o t h e C - 4 e x o p r o t o n . T h e C - 5 a n d C - 4 e n d o p r o t o n s f o r m a d i h e d r a l a n g l e w h i c h i s n e a r t o 9 0 ° a n d t h e s e p r o t o n s w o u l d t h e r e f o r e b e e x p e c t e d t o c o u p l e w e a k l y ( i f a t a l l ) w i t h e a c h o t h e r . F u r t h e r d o w n f i e l d , t h e t h r e e - p r o t o n s i n g l e t a t <5 3 . 7 6 e a s i l y e s t a b l i s h e d t h e p r e s e n c e o f t h e m e t h y l e s t e r . M o r e i m p o r t a n t l y , t h e l a r g e c o u p l i n g ( J = 1 5 . 5 H z ) C o p p e r ( I I ) a c e t o a c e t o n a t e [ C u f a c a c ^ ] w a s p r e p a r e d f r o m a c e t y l a c e t o n e a n d c u p r i c a c e t a t e i n a c c o r d a n c e w i t h r e f . 1 6 3 . 1 0 9 w h i c h w a s o b s e r v e d i n t h e o l e f i n i c r e s o n a n c e s a t 6 5 . 2 1 a n d 5 . 7 1 , a t t e s t e d t o t h e E s t e r e o c h e m i s t r y o f t h e 3 - m e t h y l - l -b u t e n y l s i d e c h a i n . [ 6 2 ] 2 4 7 2 4 0 C o n v e r s i o n o f t h e b i c y c l i c k e t o e s t e r 2 4 7 t o t h e d e s i r e d s i l y l e n o l e t h e r 2 4 0 w a s r o u t i n e l y a c c o m p l i s h e d i n 8 7 % y i e l d . N o t s u r p r i s i n g l y , t h e i r s p e c t r u m o f 2 4 0 s h o w e d a s t r o n g o l e f i n i c b a n d a t 1 6 2 0 c m A n e x a m i n a t i o n o f t h e n m r s p e c t r u m o f 2 4 0 c l e a r l y r e v e a l e d t h e p r e s e n c e o f t h e t e r t -b u t y l a n d s i l y l m e t h y l g r o u p s b y t h e s i n g l e t s a t 6 0 . 9 5 a n d 0 . 1 6 , r e s p e c t i v e l y . T h e d i a g n o s t i c a l l y i m p o r t a n t b r o a d s i n g l e t a t 6 4 . 3 8 w a s a s s i g n e d t o t h e s h i e l d e d v i n y l p r o t o n w h i c h i s a d j a c e n t t o t h e s i l o x y s u b s t i t u e n t . T h e c y c l o p r o p y l p r o t o n H£ r e s o n a t e d a t 6 1 . 7 3 , a t s l i g h t l y h i g h e r f i e l d t h a n t h e c o r r e s p o n d i n g p r o t o n i n t h e p r e c u r s o r k e t o n e 2 4 7 (6 2 . 0 0 -110 2.34). This phenomenon was observed also i n the cases of other analogous s i l y l enol ethers (vide supra) and i s probably due to the position of H £ within the shielding cone of the cyclopentene double bond. I t i s pertinent to point out that H„ must necessarily be endo to experience t h i s shielding e f f e c t , but the most convincing grounds for the stereochemical assignment of H £ l i e s i n the observed thermal s t a b i l i t y of 240. If the butenyl side chain was endo, 240 would probably be quite susceptible to Cope rearrangement at ambient temper-72,73,76 atures. Two sets of signals which exhibited the conspicuously large geminal coupling of 16 Hz, were situated at 6 2.58 and 2.23. The former was assigned to H z, which coupled to the bridgehead proton H_ (J = 7 Hz) and to the v i n y l proton H T (J = 2 Hz), while the l a t t e r was attributed to H . Again, the H -H dihedral angle appears to be almost 90° and consequently no coupling was observed between these two protons. H , how- -ever, exhibited a coupling of 3 Hz to H^. The o l e f i n i c protons H., and H , both of which occurred as doublet of doublets at a v 6 5.59 and 5.48, respectively, exhibited t h e i r trans r e l a t i o n -ship i n the form of a 15 Hz coupling. Having successfully prepared the r e q u i s i t e s i l y l enol ether 240 with the (E)-3-methyl-l-butenyl substituent, we directed our e f f o r t s at the synthesis of the corresponding (Z) isomer 242. Scheme 31 shows a possible means of preparing 242 from the b i c y c l i c keto ester 130a. That i s , one can envisage I l l SCHEME 31 2 4 2 2 6 1 a n o x i d a t i v e c l e a v a g e o f t h e a l k e n e m o i e t y i n 1 3 0 a t o f u r n i s h t h e c y c l o p r o p y l a l d e h y d e 2 6 0 w h i c h , u p o n s u i t a b l e o l e f i n a t i o n a n d a p p r o p r i a t e d e r i v a t i z a t i z a t i o n , w o u l d g i v e t h e d e s i r e d c o m p o u n d 2 4 2 . * T h e s t a r t i n g m a t e r i a l 1 3 0 a w a s s y n t h e s i z e d i n a c c o r d a n c e 81 w i t h t h e r o u t e d e s c r i b e d b y P i e r s a n d R u e d i g e r ( S c h e m e 3 2 ) . We are thankful to Pam Murch who prepared a s u f f i c i e n t quantity of 130a as part of a summer project i n our laboratory. 1 1 2 S C H E M E 3 2 1 3 0 a 2 6 3 [ a ] 1 3 1 a , T H F - H M P A , 0°C ( 7 0 % ) [ b ] p_-MeC g ^ S O N'3, E t ^ N , M e C N [ c ] C u - b r o n z e , r e f l u x i n g t o l u e n e ( 5 0 % f r o m 2 6 2 ) O z o n o l y s i s ( 03, M e O H , C H2C 12, - 7 8 ° C ) o f t h e k e t o e s t e r 1 3 0 a f o l l o w e d b y r e d u c t i v e w o r k u p w i t h d i m e t h y l s u l f i d e p r o -* c e e d e d s m o o t h l y t o a f f o r d t h e c y c l o p r o p y l a l d e h y d e 2 6 0 i n 8 7 % y i e l d ( e q . [ 6 3 ] ) . [ 6 4 ] T h i s m a t e r i a l e x h i b i t e d s p e c t r a i n a c c o r d w i t h s t r u c t u r a l a s s i g n m e n t s a n d g a v e s a t i s f a c t o r y h i g h r e s o l u t i o n m a s s s p e c t r o m e t r i c m e a s u r e m e n t s . 1 1 3 1 6 4 U n f o r t u n a t e l y , t r e a t m e n t o f t h e a l d e h y d e 2 6 0 w i t h t h e 1 6 5 p h o s p h o r a n e 2 6 4 , w h i c h w a s p r e p a r e d f r o m t r i p h e n y l p h o s p h i n e a n d i s o b u t y l b r o m i d e , y i e l d e d l i t t l e i f a n y o f t h e d e s i r e d a l k e n e 2 6 1 ( e q . [ 6 4 ] ) . T h i s f a i l u r e m i g h t b e a t t r i b u t e d a t l e a s t p a r t l y t o t h e s t e r i c c o n g e s t i o n p r o v i d e d b y t h e e s t e r g r o u p , t h e r e b y r e n d e r i n g t h e a l d e h y d e l e s s a c c e s s i b l e t o n u c l e o p h i l i c a t t a c k . T o r e m e d y t h i s p r o b l e m , a n o t h e r a l d e h y d e * s u c h a s 2 6 5 , w h i c h w a s d e e m e d s u i t a b l e f o r t h e i n v e s t i g a t i o n a t h a n d , w a s s o u g h t . a ) 03 b ) M e2S 0 - < ^ y ^ ™ ° [ 6 5 ] 1 7 9 2 6 5 S u b j e c t i o n o f t h e b i c y c l i c k e t o n e 1 7 9 t o o z o n o l y t i c c o n d i t i o n s ( O ^ , M e O H , C H2C T2, - 7 8 ° C ) g a v e , a f t e r w o r k u p w i t h d i m e t h y l s u l f i d e , t h e a l d e h y d e 2 6 5 i n 8 6 % y i e l d ( e q . [ 6 5 ] ) . U s i n g i n v e r s e a d d i t i o n o f t h e p h o s p h o r a n e 2 6 4 t o t h e a l d e h y d e 2 6 5 , t h e W i t t i g o l e f i n a t i o n g a v e t h e a l k e n e 2 6 6 a n d i t s t r a n s i s o m e r i n a n u n e n v i a b l e y i e l d o f 3 5 % ( e q . [ 6 6 ] ) . * I t w a s a s s u m e d t h a t t h e l a c k o f a C - l c a r b o m e t h o x y g r o u p w o u l d b e o f n o c o n s e q u e n c e t o t h e s t e r e o s p e c i f i c i t y o f t h e C o p e r e a r r a n g e m e n t o f t h e s e v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x e n e s . * * T h i s m a t e r i a l e x h i b i t e d s p e c t r a i n a c c o r d w i t h s t r u c t u r a l a s s i g n m e n t s a n d g a v e s a t i s f a c t o r y h i g h r e s o l u t i o n m a s s s p e c t r o m e t r i c d e t e r m i n a t i o n s . 1 1 4 CHO 2 6 4 [ 6 6 ] 2 6 5 2 6 6 M o r e o v e r , t h e c i s a n d t r a n s i s o m e r s w e r e o b t a i n e d i n a r a t i o o f n o h i g h e r t h a n 7 : 2 ( a s j u d g e d b y g l c a n a l y s i s ) . E f f o r t s t o s e p a r a t e t h e s e g e o m e t r i c i s o m e r s b y c o l u m n a n d g a s - l i q u i d c h r o m a t o g r a p h y p r o v e d f r u i t l e s s . D u e t o t h e u n a c c e p t a b l y l o w y i e l d s a n d p o o r s t e r e o s e l e c t i v i t y o f t h i s r e a c t i o n , t h i s s y n -t h e t i c a p p r o a c h t o p r e p a r e a b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e w i t h a C - 6 ( Z _ ) - 3 - m e t h y l - l - b u t e n y l s u b s t i t u e n t w a s a b a n d o n e d . A n a l t e r n a t i v e m e a n s o f g e n e r a t i n g c i s - o l e f i n s i s p r o v i d e d b y t h e p a r t i a l h y d r o g e n a t i o n o f a c e t y l e n i c b o n d s , a n d b y u s i n g t h i s s t r a t e g y i t s h o u l d b e p o s s i b l e t o o b t a i n 2 6 6 f r o m t h e a c e t y l e n i c c o m p o u n d 2 6 7 ( e q . [ 6 7 ] ) . T h e t a s k a t h a n d t h e n w a s t o p r e p a r e 2 6 7 a n d t h i s c o u l d b e a c c o m p l i s h e d e m p l o y i n g a [ 6 7 ] 2 6 7 2 6 6 1 1 5 S C H E M E 33 s y n t h e t i c a p p r o a c h w h i c h i s a n a l o g o u s t o t h a t u s e d i n t h e p r e p a r a t i o n o f t h e s i m p l e b i c y c l i c k e t o n e 1 7 9 . S c h e m e 3 3 o u t l i n e s t h e s e q u e n c e f o r t h e p r e p a r a t i o n o f 2 6 7 , s t a r t i n g f r o m t h e a c e t y l e n i c a l c o h o l 2 6 8 . T h e a c e t y l e n i c a l c o h o l 2 6 8 w a s r e a d i l y p r e p a r e d f r o m 3 - m e t h y l - l - b u t y n e a n d a c r o l e i n i n o n e s t e p ( e q . [ 6 8 ] ) . T h u s , 3 - m e t h y l - 1 - b u t y n e w a s t r e a t e d w i t h 1.1 e q u i v a l e n t s o f n - b u t y l -l i t h i u m i n T H F a t - 7 8 ° C a n d t h e r e s u l t a n t l i t h i u m a c e t y l i d e w a s t r e a t e d w i t h a c r o l e i n t o a f f o r d t h e a l c o h o l 2 6 8 ( v m a x 3 3 5 0 c m ) a s a v o l a t i l e o i l i n 8 6 % y i e l d . T h e i r s p e c t r u m o f t h i s m a t e r i a l f e a t u r e d b a n d s w h i c h a r e c h a r a c t e r i s t i c o f t r i p l e ( v 2 2 1 5 c m "*") a n d d o u b l e ( v 1 6 3 0 c m "*") b o n d s . ^ m a x m a x T h e H n m r s p e c t r u m o f t h e a l c o h o l 2 6 8 c l e a r l y i n d i c a t e d t h e p r e s e n c e o f t h e i s o p r o p y l a n d v i n y l g r o u p s a n d w a s c o n s i s t e n t w i t h t h e g i v e n s t r u c t u r e 2 6 8 . [ 6 9 ] 2 7 3 T h e t r a n s f o r m a t i o n o f t h e a l c o h o l 2 6 8 t o t h e y,S-un-1 1 s a t u r a t e d e s t e r 2 6 9 v i a a n o r t h o e s t e r C l a i s e n r e a r r a n g e m e n t , p r e s u m a b l y i n v o l v i n g t h e t r a n s i t i o n s t a t e 2 7 3 , p r o c e e d e d s m o o t h l y a n d w i t h h i g h s t e r e o s e l e c t i v i t y . T h u s , r e a c t i o n o f 2 6 8 w i t h h o t t r i e t h y l o r t h o a c e t a t e i n t h e p r e s e n c e o f a c a t a l y t i c a m o u n t o f p r o p i o n i c a c i d a f f o r d e d t h e t r a n s - o l e f i n 2 6 9 i n a y i e l d o f 6 6 % . T h e i r s p e c t r u m o f 2 6 9 c l e a r l y s h o w e d t h e c a r b o n y l b a n d ( v 1 7 3 0 c m o f t h e e s t e r f u n c t i o n a l o n g 1 m a x ^ w i t h t h e a c e t y l e n i c a b s o r p t i o n ( v 2 1 9 0 c m ^ ) , w h i l e t h e 117 nmr spectrum confirmed the trans stereochemistry of the double bond. That i s , a large trans coupling of 15.5 Hz was discern-i b l e i n the o l e f i n i c resonances at 6 5.49 and 6.00. [70] 269 270 Routine hydrolysis (KOH, H20-MeOH) of the ethyl ester 269 furnished the corresponding acid 270 as colourless c r y s t a l s , which were p u r i f i e d by low-temperature r e c r y s t a l -l i z a t i o n from heptane (eq. [70]). Obtained i n 78% y i e l d , the acid 270 (v a 3200-2500, 1701 cm - 1) exhibited a 1H nmr max spectrum which lacked the ethoxy resonances, but otherwise resembled that of the s t a r t i n g material 269. [71] 270 271 In accordance with a procedure described by Hudlicky et 9 8 a l . , the acid 270 was refluxed with o x a l y l chloride i n hexane to provide, a f t e r one hour, the acid chloride 271 i n 83% y i e l d (eq. [71]). The i r spectrum of t h i s material exhibited the 1 1 8 c a r b o n y l a b s o r p t i o n t y p i c a l o f a c y l c h l o r i d e s ( v 1 7 9 0 c m ) a n d t h e w e a k b u t u n m i s t a k a b l e a c e t y l e n i c b a n d ( vm a x 2 1 9 0 c m . T h e "^H n m r s p e c t r u m w a s c o n s i s t e n t w i t h t h e s t r u c t u r e 2 7 1 . [ 7 2 ] 2 7 1 2 7 2 T r e a t m e n t o f t h e a c y l c h l o r i d e 2 7 1 w i t h e t h e r e a l d i a z o -* m e t h a n e a t 0°C l e d s m o o t h l y t o t h e a l m o s t q u a n t a t i v e f o r m a t i o n o f t h e d i a z o k e t o n e 2 7 2 ( e q . [ 7 2 ] ) . I n t h e i r s p e c t r u m o f 2 7 2 , t h e s t r o n g b a n d s a t v 2 0 8 5 a n d 1 6 3 4 c m 1, w h i c h a r e r m a x ' 1 6 7 c h a r a c t e r i s t i c o f c t - d i a z o k e t o n e s , w e r e c l e a r l y v i s i b l e . W i t h t h e e x c e p t i o n o f t h e s i n g l e t a t 6 5 . 2 1 w h i c h w a s a s s i g n e d t o t h e p r o t o n a d j a c e n t t o t h e d i a z o m o i e t y , t h e "*"H n m r s p e c t r u m w a s q u i t e s i m i l a r t o t h o s e o f t h e a c i d 2 7 0 a n d t h e a c y l c h l o r i d e 2 7 1 . I n t h e p r e s e n c e o f a c a t a l y t i c a m o u n t o f c o p p e r ( I I ) a c e t o a c e t o n a t e , t h e d i a z o k e t o n e 2 7 2 u n d e r w e n t a c a r b e n o i d c y c l i z a t i o n i n r e f l u x i n g b e n z e n e t o a f f o r d s t e r e o s e l e c t i v e l y i n 7 7 % y i e l d , t h e d e s i r e d b i c y c l o [ 3 . 1 . 0 ] h e x a n o n e 2 6 7 ( e q . * S c o t t a n d M i n t o n h a v e c i r c u m v e n t e d t h e p r o b l e m o f u s i n g a n e x c e s s o f d i a z o m e t h a n e t o s c a v e n g e H C 1 b y d e v e l o p i n g a p r o c e d u r e w h i c h c a l l s f o r 1 e q u i v a l e n t o f d i a z o m e t h a n e i n t h e p r e s e n c e o f t r i e t h y l a m i n e . 1 1 9 [ 7 3 ] 2 7 2 2 6 [ 7 3 ] ) . A s i n t h e c a s e o f 2 4 7 , t h e s t e r e o c h e m i s t r y o f t h e C - 6 a l k e n y l s u b s t i t u e n t w a s a s s i g n e d a s e x o i n l i g h t o f t h e w e l l d o c u m e n t e d s t e r e o s p e c i f i c i t y o f t h e c a r b e n o i d 9 1 9 2 c y c l i z a t i o n . ' I n t h e i r s p e c t r u m o f t h i s c o m p o u n d , t h e c a r b o n y l b a n d a p p e a r e d a t v 1 7 2 5 c m 1. N o o l e f i n i c r e s o n -m a x a n c e s w e r e o b s e r v e d i n t h e n m r s p e c t r u m o f 2 6 7 , w h i c h p r o -v i d e d l i t t l e i n f o r m a t i o n o t h e r t h a n e v i d e n c e f o r a n i s o p r o p y l g r o u p . [ 6 7 ] q u i n o l i n e 2 6 7 2 6 6 T o g e n e r a t e t h e c i s - a l k e n e , t h e a c e t y l e n i c k e t o n e 2 6 7 w a s p a r t i a l l y h y d r o g e n a t e d u s i n g L i n d l a r ' s c a t a l y s t ( 5 % P d / * C a C O - ) a n d a t r a c e o f q u i n o l i n e t o t e m p e r t h e a c t i v i t y o f t h e * M a r v e l l a n d L i h a v e m a d e a s u r v e y o f v a r i o u s c a t a l y s t s u s e d f o r t h e s e m i h y d r o g e n a t i o n o f t r i p l e b o n d s . L i n d l a r ' s c a t a l y s t w a s p r e p a r e d a n d u s e d i n a c c o r d a n c e w i t h p r o c e d u r e s g i v e n i n r e f . 1 6 9 . 120 catalyst (eq. [67]). No further hydrogenation of the r e s u l t -ant alkene was observed since the reaction simply stopped afte r the uptake of one equivalent of hydrogen. A 95:2 mix-ture (judged by glc analysis) of the cis-alkene 266 and i t s trans isomer were obtained and these substances were readi l y separated by column chromatography. In this manner, 266 was i s o l a t e d i n 94% y i e l d . 266 L i t t l e information was gleaned from the i r spectrum of 266, which was similar to that of the s t a r t i n g material 267. The nmr spectrum of t h i s material was more h e l p f u l , and indicated the presence of two o l e f i n i c protons i n the form of -a pair of overlapping doublet of doublets, one at 6 4.65 and the other at 6 5.24. Both sets of resonances revealed a coupling of 10.5 Hz, which i s t y p i c a l of c i s disubstituted double bonds. Other than the isopropyl resonances, the doublet of doublets at 6 1.75 which was assigned to H p was c l e a r l y v i s i b l e . This cyclopropyl proton couples to H^ (J = 5 Hz) and \J — t o H p ( J = 2 . 5 H z ) . Transformation of the ketone 266 into the s i l y l enol ether 274 was effected smoothly i n the usual way and -in 98% 122 [ 7 4 ] 2 6 6 2 7 4 y i e l d (eq. [74]) . As expected, the i r spectrum of 274 exhibited a strong o l e f i n i c band at v 1625 cm The "^H nmr spectrum of this max ^ compound (Fig. 15), having well resolved signals which were revealing i n fine structure, presented a ver i t a b l e challenge to spectral i n t e r p r e t a t i o n . As i n the spectrum of the ketone 266, the c i s geometry of the (Z^)-3-methyl-l-butenyl double bond was shown by a coupling constant of 10.5 Hz i n the o l e f i n i c resonances at 6 4.64 and 5.14. By decoupling H 0, i t was possible to assign the overlapping doublet of doublets at 6 4.64 to H D and the signal at 6 5.14 (similar s p l i t t i n g pat-tern) to Er. Expectedly, H_ appeared as a broad s i n g l e t at 123 6 4.31 and i s t h e most s h i e l d e d o f t h e o l e f i n i c p r o t o n s owing t o t h e e l e c t r o n - r i c h n a t u r e o f t h e e n o l e t h e r d o u b l e bond. By d e c o u p l i n g E^, w h i c h e l i m i n a t e d a s m a l l a l l y l i c c o u p l i n g , t h e m u l t i p l e t a t 6 1.60 sharpened and was c o n s e q u e n t l y a s s i g n e d t o Hp. To d i s t i n g u i s h between t h e o t h e r c y c l o p r o p y l p r o t o n s , Hp was d e c o u p l e d . As a r e s u l t , the u n r e s o l v e d d o u b l e t a t 6 1.28 c o l l a p s e d t o a broad s i n g l e t and was t h e r e f o r e a s s i g n e d t o H E, w h i c h c o u p l e s q u i t e s t r o n g l y t o H D ( J = 10 H z ) . By a p r o c e s s o f e l i m i n a t i o n , t h e f i n a l c y c l o p r o p y l p r o t o n H^ , was Ca a s s i g n e d t o t h e m u l t i p l e t a t 6 1.50-1.55. As i n s i m i l a r s ystems, H j r e s o n a t e d a t h i g h e r f i e l d (6 2.30) t h a n H z (6 2.52), and e x h i b i t e d a v e r y s m a l l c o u p l i n g t o t h e b r i d g e h e a d p r o t o n H_, ( J < 1 Hz) , presumably due t o t h e f a c t t h a t the H„-H T d i -la — la J h e d r a l a n g l e i s c l o s e t o 90°. As r e f l e c t e d by t h e o v e r l a p p i n g d o u b l e t o f d o u b l e t o f d o u b l e t s , H_ i s c o u p l e d t o H T ( J = 3 H z ) , g e m i n a l l y t o H„ ( J = 16.5 Hz) and s u r p r i s i n g l y t o H_ ( J = 3 H z ! ) . Indeed, when H j was d e c o u p l e d , the s i g n a l a t 6 1.60 (H_) c o l l a p s e d t o a d o u b l e t o f d o u b l e t s (J„_ = 6.Hz, J„_, = 2 r — r Ca —h,r H z ) . The p r o t o n H z, w h i c h r e s o n a t e d as a d o u b l e t o f d o u b l e t o f d o u b l e t s a t 6 2.52, c o u p l e s t o H_ ( J = 16.5 H z ) , t o H^ , J — Ca ( J = 7 Hz) and t o Hj ( J = 2 H z ) . H a v i n g s u c c e s s f u l l y s y n t h e s i z e d the E and Z o l e f i n s 240 and 274, we t u r n e d our a t t e n t i o n t o t h e t h e r m a l r e a r r a n g e -ment o f t h e s e systems. A p o t e n t i a l problem a t t e n d s t h e Cope rearrangement o f 274, w h i c h p o s s e s s e s a Z_ i s o p r o p y l group on t h e 6 - a l k e n y l s i d e c h a i n . Bond r e o r g a n i z a t i o n o f 274 i n a 124 275 Cope sense would be presumed to proceed v i a the t r a n s i t i o n state 275. However, th i s t r a n s i t i o n state suffers from a notable s t e r i c i n t e r a c t i o n between the isopropyl group and the cyclopentenyl ring residue. I t i s possible that t h i s s t e r i c s t r a i n could so d e s t a b i l i z e the t r a n s i t i o n state that, upon thermolysis, an al t e r n a t i v e lower energy rearrangement takes place. [49] [75] 274 276 125 Compounds 240 and 274 were dissolved i n benzene and the solutions were heated i n sealed pyrolysis tubes. Thus, thermolysis of 240 at 200°C for 2 hours afforded, i n 95% y i e l d , the bicyclo[3.2.1]octadiene 241 with an endo isopropyl substituent at C-4 (eq. [49]). On the other hand, 274 re-arranged smoothly at 240°C to provide, after 4.5 hours, a single product i n 93% y i e l d . I t was g r a t i f y i n g to i d e n t i f y this thermolysis product as the desired bicyclo[3.2.1]octa-diene 276 with an exo C-4 isopropyl group (eq. [75]), and to find that our misgivings concerning the v i a b i l i t y of this transformation (274 -»• 276) were i n fact unfounded. Me02C 241 The i r spectrum of the enol ether 241 was much l i k e that of the s t a r t i n g material 240 i n general appearance. However, the ester carbonyl band occurred at v 1700 cm 1 as expected 2 max c for an ex, 3-unsaturated ester, and an o l e f i n i c absorption was found at 1610 cm In the "'"H nmr spectrum of 241, the doublet displaying a geminal coupling ( J X 1 7 = 9.5 Hz) at 6 1.78 was assigned to H T. In view of both H T-H„ and H —H dihedral 3 I I F I K angles being =^90°, i t was not surprising to f i n d that H^ couples with neither bridgehead protons. Decoupling E^ led Me02C ° f y M i H D H K 11 6.3 5.44 3 0 V (b) H_ ,H, 2.8 2.2 2 P P M F i g . 16. The homonuclear spin decoupling experiment with 241: (a) the normal 400 MHz H nmr spectrum for the region 6 2.0-6.4, and (b) the spectrum with i r r a d i a t i o n at 6 5. 44 (H ) . 127 to the assignment of the complex resonance at 6 2.20 to H„, which couples to the two bridgehead protons (J„_ = 4 Hz, 3 v r r = 5 Hz) and long-range to H^ , ( J = 1 Hz) . To v e r i f y the assignment of H^, H„ was decoupled, leading to the collapse of the s p l i t t i n g pattern at 6 2.92 (H,J to a doublet ( J ^ _ = J\ —KZ 5 Hz) . The 5 Hz coupling between H_, and H„ i s of diagnostic importance i n the endo stereochemical assignment of the C-4 isopropyl substituent. Had this substituent been exo, a smaller coupling between H c and H p would be anticipated i n view of the H^ -H^ , dihedral angle being, i n such a case, almost 90°. By decoupling Hp, the collapsed signal due to H c at 6 2.06 c l e a r l y exhibited the 5 Hz coupling (J™) as shown i n —Cr d e t a i l by F i g . 16b. 276 The i r spectrum o f the s i l y l e n o l e t h e r 276, o t h e r t h a n d i s p l a y i n g an o l e f i n i c band a t v 1620 cm o f f e r e d l i t t l e max i n f o r m a t i o n o f d i a g n o s t i c v a l u e . The "*"H nmr spectrum o f 276 ( F i g . 17) i n many ways resembled t h a t o f the endo isomer 241, but on c l o s e r e x a m i n a t i o n the s u b t l e d i f f e r e n c e s p r o v e d en-l i g h t e n i n g . A t 6 5.11, the d o u b l e t e x h i b i t i n g a 3 Hz c o u p l i n g ( J T T . ) , was a s s i g n e d t o H T, whic h i s r e l a t i v e l y s h i e l d e d by the 129 ele c t r o n - r i c h enol ether double bond. The proton Hj, being coupled only to H„ (J = 9.5 Hz), appeared as a doublet at 6 1.75. This geminal coupling (J = 9.5 Hz) was found i n the complex signal assigned to H z at 6 1.97. I t was possible to di s t i n g u i s h between the bridgehead protons H and H by de-coupling H . Apparently H_ exhibits a 5 Hz coupling with H_ as shown by the collapse of the complex signal (H ) at 6 1.97 to a doublet of doublets ( J T ( 7 = 9.5 Hz, J v„ = 3 Hz) when H^ — J . L —is. Z r was decoupled (Fig. 18). S i g n i f i c a n t l y , t h i s decoupling experiment caused only a s l i g h t sharpening of the signal assigned to H c at 6 1.88-1.94. That i s , the coupling between H c and H p i s < 1 H z , as would be anticipated i f H c was endo, an orientation i n which H forms, with H , a dihedral angle approximating 90°. . r a f f . t o r Me02C \ Me02C 241 277 278 The 3-siloxy a,3-unsaturated ester 241 was converted to a mixture of the B-keto esters 277 v i a fluoride-mediated cleavage of the s i l y l enol ether moiety. T i c analysis c l e a r l y indicated the presence of two components. Subsequent d e - V carboxylation was accomplished by re f l u x i n g the mixture 277 in THF i n the presence of hydrochloric acid. A single 130 F i g . 18. The homonuclear spin decoupling experiment with 276: (a) the normal 4 00 MHz XH nmr spectrum expanded for the region 6 1.6-2.0, and (b) the spectrum with i r r a d i a t i o n at 6 2.38 (H^). 131 compound was obtained i n 50% y i e l d over the two steps, and was shown to have the structure 278. [ 7 6 ] Acid-catalyzed hydrolysis (THF-5% HCl, r.t.) of the s i l y l enol ether 276 provided the ketone 279 i n 57% y i e l d . Ketones 278 and 279 were shown to be two d i s t i n c t l y d i f f e r e n t compounds by glc analysis. The i r spectra of these epimeric ketones were expectedly s i m i l a r . In the spectrum of 278, the carbonyl absorption occurred at v 1730 cm ^, J ^ max ' whereas i n the spectrum of 279, the corresponding band was at 1735 cm - 1. In contrast, the "*"H nmr spectra of 27 8 and 279 as shown in Figs. 19 and 20, are remarkably d i f f e r e n t , p a r t i c u l a r l y i n the high f i e l d region. In f a c t , the only s i m i l a r i t y l i e s i n the s p l i t t i n g patterns and chemical s h i f t s of the o l e f i n i c protons i n 278 and 279. Table I shows a comparison of the "^H nmr spectral data for the ketones 278 and 279. I t i s in t e r e s t i n g to note that the resonances of the non-equivalent isopropyl methyl groups i n the ^ H nmr spectrum of 278 appeared almost 0.1 ppm apart, at 6 0.95 and 1.06. In the high f i e l d region of the normal spectrum, the only signal 1 "k ic T A B L E I . H n m r D a t a f o r C o m p o u n d s 2 7 8 a n d 2 7 9 . C o m p o u n d 6 H c 6 H D 6 H E - F 6 Ex 6 H J 6 H K 6 H y 6 H z 278 2.12 O L d d d d ^ C F ^ C D ~ ^ C E = 2.5 5.63 d d d J n F = 1 ° ^ D= 2'5 J*" =1.5 6.05 d d d d 2.69- ; 2.77 m ' 2.00 d d J T 7=11.5 2.22 d d J =17.5 2.69-2.77 m 2.28 d d J T =17.5 2.09 d d d d J T =11.5 279 1.85-1.93 m 5.55 d d d ^ D E= 9-5 ^ D= 3-5 s= 1-5 6.07 O L d d d d 2.59 d J F Z = 5 . 5 2.06 d J I Z=11.5 2 .28 O L d d d J^ Y=16.5 JI*=2.5 2.73-2.79 m 2.23 d d J-,v=16.5 £ K Y ~ 5 1.85-1.93 * * * O L = o v e r l a p p i n g A l l c o u p l i n g c o n s t a n t s g i v e n i n H e r t z ( H z ) Hv 2 7 8 which was well resolved was a doublet of doublets at 6 2.00, assigned to H^ .. This proton exhibits a 11.5 Hz geminal coupling with H„ and a long-range coupling of 3 Hz with H . Protons H and H v appeared as a pair of doublet of doublets U JL with AB symmetry at 5 2.22 and 2.28, respectively. Other than coupling geminally with H (J = 17.5 Hz), H couples only with ft. . Upon consideration of the dihedral angles i n -volved, i t i s not surprising that the bridgehead proton H couples with H (J = 5.5 Hz), but not with H T. Without the X — J aid of decoupling experiments, i t was not possible to make any further assignments due to the complexity of the remaining resonances i n the region 6 2.05-2.15. However, the elimination of small couplings i n th i s region by decoupling H revealed H i a number of d e t a i l s which proved he l p f u l i n completing the assignments (Fig. 21b). That i s , the 11.5 Hz geminal coupling between H and H was di s c e r n i b l e i n the collapsed s p l i t t i n g pattern at 6 2.09 which was consequently assigned to H z. The proton H z also exhibits 5.5 and 4 Hz couplings with the neigh-bouring bridgehead protons H^ , and H v. The other signal p a r t i a l l y uncovered by decoupling H„ was attributed to H . As C O F i g . 21. The homonuclear spin decoupling experiment with 278: (a) the normal 400 MHz H nmr spectrum expanded for the region 5 1.9-2.8, and (b) the spectrum with i r r a d i a t i o n at 6 6.05 (H ). 137 i n the precursor s i l y l enol ether 241, displays a 5 Hz coupling with H„, reaffirming the endo stereochemistry of the r isopropyl substituent at C-4. Hj 279 In contrast with that of 278, the H nmr spectrum of 279 exhibited fewer overlapping resonances i n the high f i e l d region. The resonances of the isopropyl methyl groups, unlike those of 278, occurred as an almost overlapping pair of doub-l e t s . Decoupling the isopropyl methine proton showed that the signal due to H c was obscured by the multiplet at ,6 1.85-1.93. The protons Hj and H Y appeared as an AB system, and were assigned with the aid of an experiment i n which H^ was decoupled. The long-range coupling ( J J J = 2.5 Hz) constant was eliminated from the s p l i t t i n g pattern of H T. The proton Ev appeared as a complex multiplet at 6 2.73-2.79, while H„ resonated as an unresolved doublet at 6 2.59, exhibiting a 5.5 Hz coupling with E^. As i n the precursor s i l y l enol ether 276, the coupling between H c and H p was < 1 Hz, thereby supporting the exo stereochemical assignment of the isopropyl substituent at C-4. C l e a r l y , compounds 278 and 279 are epimeric at C-4. 1 3 8 T h u s , f o r b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e s w h i c h c o n t a i n b u l k y s u b -s t i t u e n t s o n t h e 6 - ( 1 - a l k e n y l ) s i d e c h a i n , t h i s s t u d y n o t o n l y d e m o n s t r a t e s t h e v i a b i l i t y o f t h e C o p e r e a r r a n g e m e n t , b u t a l s o p r o v i d e s s t r o n g e v i d e n c e f o r t h e s t e r e o s p e c i f i c i t y * o f t h i s p r o c e s s . 1 . 2 . 4 C o n c l u s i o n I t i s c l e a r f r o m t h e s y n t h e t i c s t u d i e s d e s c r i b e d t h u s f a r i n t h i s t h e s i s t h a t t h e C o p e r e a r r a n g e m e n t o f 6 - ( l -a l k e n y l ) b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e s c o n t a i n i n g e v e n s t e r i c a l l y b u l k y s u b s t i t u e n t s o n t h e 6 - a l k e n y l s i d e c h a i n p r e s e n t s a v i a b l e m e a n s o f g e n e r a t i n g f u n c t i o n a l i z e d b i c y c l o [ 3 . 2 . 1 ] -o c t a - 2 , 6 - d i e n e s . M o r e o v e r , t h i s m e t h o d o l o g y p r o v i d e s f o r t h e p l a c e m e n t o f s y n t h e t i c a l l y u s e f u l f u n c t i o n a l i t i e s o n a n y o f t h e c a r b o n b r i d g e s o f t h e b i c y c l o [ 3 . 2 . 1 ] o c t a n e s k e l e t o n . F i n a l l y , t h e s t e r e o s p e c i f i c i t y o f t h e r e a r r a n g e m e n t p r o c e s s w o u l d l e n d a m e a s u r e o f e l e g a n c e t o a n a t u r a l p r o d u c t s y n -t h e s i s u s i n g t h i s m e t h o d o l o g y t o a c c e s s t h e k e y i n t e r m e d i a t e . F o r a n y n e w l y d e v e l o p e d s y n t h e t i c a p p r o a c h , t h e u l t i m a t e t e s t o f i t s p o t e n t i a l l i e s i n i t s a p p l i c a t i o n t o t h e s y n t h e s i o f t a r g e t m o l e c u l e s , a n d i n o u r w o r k , t h e n a t u r a l l y o c c u r r i n g s e s q u i t e r p e n o i d s i n u l a r e n e ( 1 2 5 ) w a s s u c h a t a r g e t m o l e c u l e . T h e s e r e s u l t s w e r e r e c e n t l y r e p o r t e d i n a c o m m u n i c a t i o n . 139 Chapter II THE TOTAL SYNTHESIS OF (+)-SINULARENE 2.1 Introduction 2.1.1 The I s o l a t i o n and Characterization of (-)-Sinularene 8 2 In 1977, Djerassi and coworkers isol a t e d a new sesqui-terpene hydrocarbon, named sinularene, as a major component from the hexane extract of dried colonies of a sof t coral S i n u l a r i a mayi (Coelenterata, Anthozoa, Alcyonaria, Alcyonacea). Obtained i n 0.01% y i e l d (based on dried animal material), sinularene was deduced to possess a t r i c y c l i c skeleton and empirical formula C^^H2^. From the infrared, "*"H and "^C nmr s p e c t r a 8 2 1 3 of sinularene, a number of s t r u c t u r a l features were immediately apparent. F i r s t , bands (v 3076, 1660, 870 cm"1) i n the infrared ' max ' ' spectrum, as well as the resonances of two v i n y l i c protons ("''H nmr) , an o l e f i n i c methylene carbon and an o l e f i n i c 13 quaternary carbon ( C nmr) indicated the presence of an exo-c y c l i c methylene. Second, both infrared (v 1382, 1365 cm "*") 2 2 max ' and 1H nmr [6 0.90, 0.92 (d, d, 3H each, J=6.4 Hz)] spectra supported the presence of an isopropyl group. And t h i r d , based on the "'"H nmr spectrum, sinularene also contained a t e r t i a r y methyl group. Ozonolysis of sinularene provided a compound (later 140 assigned as 280), which was found to have an empirical formula C],4 H22° a n d displayed an infrared band at 1740 cm 1 (v ), i n d i c a t i v e of a cyclopentanone. Subjection of max J sinularene to osmium tetroxide oxidation afforded a d i o l ( l ater assigned as 281) with empirical formula ci5 H26°2 a n d which exhibited resonances ["*"H nmr 6 3.68, 3.91 (d, d, IH each, J=11.0 Hz)] attributed to two is o l a t e d methylene protons adjacent to the hydroxyl moiety. In addition, sinularene was subjected to hydroboration-oxidation conditions to y i e l d 284 285 1 4 1 t h e p r i m a r y a l c o h o l 2 8 2 1 a n d r e a c t i o n o f 2 8 1 w i t h p _ - b r o m o -b e n z o y l c h l o r i d e l e d t o t h e c r y s t a l l i n e b e n z o a t e 2 8 3 , b u t t h e s p e c t r a o f 2 8 2 a n d 2 8 3 p r o v i d e d f e w s t r u c t u r a l c l u e s o f u s e . O n t h e b a s i s o f t h e s e e x p e r i m e n t a l a n d s p e c t r a l d a t a , i t w a s d e t e r m i n e d t h a t t h e e x o c y c l i c m e t h y l e n e w a s o n a f i v e -m e m b e r e d r i n g i n s i n u l a r e n e . I n f a c t , t h e e x a c t s t r u c t u r e o f s i n u l a r e n e w a s n o t e s t a b l i s h e d u n t i l a n x - r a y d e t e r m i n a t i o n o f 2 8 3 w a s m a d e . C o n s e q u e n t l y , a p u r i f i e d s a m p l e o f 2 0 s i n u l a r e n e { [cx]D - 1 4 2 ° ( c 0 . 5 5 i n C C 14) } w a s a c c o r d e d t h e s t r u c t u r e 1 2 5 . T w o s e s q u i t e r p e n e s , 1 2 - a c e t o x y s i n u l a r e n e ( 2 8 4 ) a n d 1 2 - a c e t o x y c y c l o s i n u l a r e n e ( 2 8 5 ) , w h i c h a r e r e l a t e d t o s i n u l a r e n e s t r u c t u r a l l y , h a v e b e e n i s o l a t e d r e c e n t l y f r o m t h e d i c h l o r o m e t h a n e e x t r a c t o f a c o r a l C l a v u l a r i a i n f l a t a a n d c h a r a c t e r i z e d . 2 . 1 . 2 P r e v i o u s S y n t h e s e s o f S i n u l a r e n e U p u n t i l t h e p r e s e n t t i m e , t h r e e t o t a l s y n t h e s e s o f ( + ) - s i n u l a r e n e h a v e b e e n r e p o r t e d , a n d i t s e e m s r e l e v a n t t o b r i e f l y o u t l i n e t h e m h e r e . 1 7 1 C o l l i n s a n d W e g e c o m p l e t e d t h e t o t a l s y n t h e s i s o f s i n u l a r e n e ( 1 2 5 ) i n a f i f t e e n s t e p s e q u e n c e s t a r t i n g w i t h t h e l a c t o n e 2 8 61 7 2 ( S c h e m e 3 4 ) . T h u s , t r e a t m e n t o f 2_86 w i t h l i t h i u m a l u m i n u m h y d r i d e f o l l o w e d b y c o n v e r s i o n o f t h e r e s u l t -a n t m a t e r i a l t o a n i n t e r m e d i a t e h y d r o x y t o s y l a t e a n d o x i d a t i o n p r o v i d e d t h e b i c y c l i c k e t o n e 2 8 7 • T r a n s f o r m a t i o n o f t h e l a t t e r m a t e r i a l t o t h e i o d i d e a n d p r o t e c t i o n o f t h e k e t o n e m o i e t y 1 4 2 S C H E M E 3 4 2 9 4 2 9 8 [ 3 8 % f r o m 2 8 0 ] [ a ] L i A l H4, E t20 , r e f l u x , 1 h ( 8 8 % ) [ b ] £ - M e C6H4S 02C l , p y r -i d i n e , 0 ° C , 5 h [ c ] P C C , C H2C 12, r . t . , 2 h ( 4 5 % o v e r t w o s t e p s ) [ d ] N a l , D M F , 8 0 ° C , 4 . 5 h ( 7 4 % ) [ e ] H O C H2C H2O H , H+ ( 7 5 % ) [ f ] 2 8 9 , D M F , 5 5 ° C , 2 0 h ( 7 7 % ) [ g ] H-.0+ [ h ] n t - C l C . . H . C O - H , t t ~ 6 b e n z e n e , 0 ° C , 2 h ( 9 1 % ) [ i ] K O B u - , H O B u - , r e f l u x , 4 h ( 2 9 2 : 2 2 % ; 2 9 6 : 3 1 % ) [ j ] A c C l , M e2N P h [ k ] 4 5 0 ° C [ 1 ] H2, P t , 0 ° C , 2 0 m i n [m] M e L i , E t90 , r e f l u x , 2 h ; H , 0 143 gave the iodo acetal 288, which, when treated with the n - a l l y l n i c k e l complex 289 , was converted into 290. Acetal 290 was hydrolyzed to the corresponding ketone, which was subsequently treated with m-chloroperbenzoic acid to give a diastereomeric mixture of the epoxy ketones 291. When 291 was subjected to basic conditions, a mixture of the alcohols 292 and 296 was obtained i n a 1:1 r a t i o (as judged by g l c a n a l y s i s ) . These epimeric alcohols 292 and 296 were separated by column chromatography, and each were transformed into the corresponding acetates and thermolyzed. Thus, from 296 was obtained a mixture of 294 and 297 i n a r a t i o of 4:6 respectively, while from 292, a mixture of 293 and 294 was recovered i n a r a t i o of 95:5, respectively. Hydrogenation of the terminal alkene 293 furnished the intermediate b i c y c l i c ketone 280 / which exhibited a ''"H nmr spectrum quite d i f f e r e n t from that of the epimer 298, obtained v i a hydrogenation of 294. Subsequent treatment of the ketone 280 with methyllithium gave the alcohol 295 / which, upon acetylation followed by p y r o l y t i c elimination of acetic acid, was transformed into racemic sinularene (125) . Unfortunately, t h i s t o t a l synthesis of (+)-sinularene was marred by the lack of s t e r e o s e l e c t i v i t y i n the epoxidation leading to the formation of 291. In the key step of t h e i r reported synthesis of 17 3 (+)-sinularene (125) , Oppolzer and coworkers demonstrated 144 the use of a highly regio- and stereoselective intramolecular "magnesium-ene" reaction (Scheme 35). Thus, the b i c y c l i c tosylate 299 was converted into the corresponding iodide 300, which was treated with the dianion 301 of t i g l i c acid to provide, with high r e g i o s e l e c t i v i t y , the y-alkylated acid 302. Reduction of the acid 302 followed by to s y l a t i o n and sub-ject i o n of the resultant tosylate to nucleophilic displacement by chloride ion 301 furnished 303. In the c r i t i c a l c y c l i z a t i o n step, the Grignard reagent formed from 303 was heated to give the c y c l i z e d alkenylmagnesium chloride, which was subsequently carboxylated to afford the b i c y c l i c acid 304 regio- and stereo-s e l e c t i v e l y . The r e l a t i v e stereochemistry re s u l t i n g from th i s reaction was evidenced by the smooth iodolactonization of 304 as well as by trapping the c y c l i z e d Grignard species with 0 2 followed by Jones' oxidation to afford the ketone 298, the "*"H . nmr and infrared spectra of which was i d e n t i c a l to those of an authentic sample of 298. Subsequently, reduction of 304 led to the intermediate alcohol 305, from which both sinularene (125) and 5-epi-sinularene (308) were obtained v i a d i f f e r e n t synthetic paths. Thus, hydrogenation of 305 followed by acetylation and p y r o l y t i c elimination of acetic acid afforded (+)-5-epi-sinularene (308). To obtain the desired exo con-fi g u r a t i o n of the isopropenyl moiety, 305 was subjected to a sequence of synthetic transformations which had the o v e r a l l e f f e c t of epimerizing the isopropenyl group to the 1 4 5 S C H E M E 3 5 1 2 5 3 0 7 2 9 8 [ a ] N a l , a c e t o n e , r e f l u x , 9 h ( 8 7 % ) [ b ] 3 0 1 , H M P A , -78°-»-0oC-*-r . t . , 1 6 h ( 7 8 % ) [ c ] L i A l H ^ [ d ] M e S 02C l , p y r i d i n e , 0 ° C , 3 h [ e ] I N a q . H C l , 0 ° C , 1 0 m i n ( 5 5 % f r o m 3 0 2 ) [ f ] ( i ) a c t . M g , T H F , - 7 8° C - » - r . t . , 2 h ( i i ) 5 0 ° C , 1 6 h ( i i i ) C 02, - 1 0 ° C ( i v ) 8 0 ° C , 2 h ( 4 7 % f r o m 3 0 3 ) [ g ] H2, P t , M e O H ( 9 9 % ) [ h ] A c C l , N E t3, D M A P , C H2C 12, 0 ° C , 2 h [ i ] 5 0 0 ° C [ j ] ( i ) N a H , D M F , r . t . ( i i ) H M P A , M e l , r . t . , 1 6 h ( 8 9 % ) [ k ] ( i ) 03, M e O H , - 7 8 ° C ( i i ) M e2S , - 7 8 ° C + r . t . , 2 h ( q u a n t . ) [ 1 ] K O H , E t O H , H20 , r e f l u x , 7 h ( 9 0 % ) [m] P h3P = C H2, T H F , r . t . , 1 6 h ( 6 9 % ) [ n ] M e3S i I , N a l , M e C N , r . t . , 2 h ( 7 8 % ) 146 thermodynamically preferred orientation. Hence, ozonolysis of the methyl ether 306 followed by base-mediated epimerization and Wittig o l e f i n a t i o n of the resultant ketone afforded the exo-isopropenyl isomer 307. Subsequently, 307 was hydrogenated and deprotection of the methyl ether gave an intermediate alcohol, which, when subjected to acetylation and then f l a s h p y r o l y s i s , was converted to (+)-sinularene (125). In l i g h t of the stereochemistry obtained as a r e s u l t of the key c y c l i z a t i o n step, t h i s work constitutes an i n t e r e s t i n g a p p l i c a t i o n of the unusual "magnesium-ene" reaction, but more so with respect to the synthesis of 5-epi-sinularene (308) than to that of sinularene (125). OAc 284 309 This same methodology was recently applied to the t o t a l 174 syntheses of (+)-12-acetoxysinularene (284) and (+)-5-epi-12-acetoxysinularene (309) . 1 *7 5 1V 6 The synthetic approach ' developed by F a l l i s and 177 coworkers, to the t o t a l synthesis of (+)-sinularene (125) was quite d i f f e r e n t from those used i n the two previously reported syntheses of sinularene. Central to t h i s fourteen step synthesis (Scheme 36), was an intramolecular Diels-Alder 147 SCHEME 36 * OBz 319: R=Ac [a] Mn02 (83%) [b] LDA, THF, -78°C, 312 (93%) [c] NaH, PhCH 2Br, DME (80%) [d] LiAlH^ (95%) [e] PDC (65%) [f] Ph3P=CHC02Me, THF, r e f l u x (72%) [gl H 2, Pd/C (85%) [h] Ph 3P, CC1 4, MeCN (97%) [i] H 2, Pd/C, MeOH (99%) [j] LiAlH (99%) [k] Ac 20, pyridine (99%) [1] 550°C (77%) 148 reaction, which, i n addition to generating the required t r i c y c l i c skeleton of sinularene, provides for incorporation of the t e r t i a r y methyl group. Thus, oxidation of the b i c y c l i c alcohol 310 provided the corresponding aldehyde 311, which was treated with the anion of methyl 3-methylbutyrate 312 to give a 2:14:30:47 mixture of diastereomeric 3-hydroxy esters. Sub-sequently t h i s mixture was separated and the major diastereomer was protected as a benzyl ether and reduced to the alcohol 313. Oxidation of the alcohol 313 and Wittig o l e f i n a t i o n furnished the intermediate a,3-unsaturated ester 314, which underwent cycloaddition under the conditions of the l a t t e r reaction to give the t e t r a c y c l i c ester 315. Under the conditions f o r hydrogenolytic deprotection of the benzyl ether i n 315, cyclo-propane ring cleavage and hydrogenation of the double bond occurred concomitantly. Treatment of the resultant hydroxy ester 316 with triphenylphosphine and carbon tetrachloride i n a c e t o n i t r i l e led to the formation of the o l e f i n 317, which, when hydrogenated and reduced, was converted to the alcohol 318. Acetylation of 318 followed by p y r o l y t i c elimination afforded (+)-sinularene (125). Although t h i s work embodies a novel means of assembling the bicyclo[3.2.1]octane framework of sinularene and was executed generally with good y i e l d s , i t i s unfortunate that there was a lapse i n s t e r e o s e l e c t i v i t y i n the preparation of the Diels-Alder cycloaddition substrate. With respect to these previous syntheses, the novelty and s t e r e o s e l e c t i v i t y featured by our synthetic methodology 1 4 9 ( v i d e i n f r a ) s e e m e d t o w a r r a n t t h e a p p l i c a t i o n o f t h i s m e t h o d -o l o g y t o a n e w t o t a l s y n t h e s i s o f ( + ) - s i n u l a r e n e . 150 2.2 Discussion 2.2.1 The Synthetic Plan In p r i n c i p l e , any complex organic molecule (target molecule) may be broken down by a series of (bond-breaking) disconnections and/or functional group interconversions (FGI) to generate successively simpler intermediates u n t i l * an e a s i l y accessible s t a r t i n g material i s obtained. Using 179 this "retro-synthetic analysis", one can envisage sinularene (125) being derived from the b i c y c l i c ketone 280  v i a a possible f i r s t disconnection which corresponds to a Wittig-type o l e f i n a t i o n . The two-carbon bridge indicated as the s i t e of the second disconnection could be put into place by the formation of a bond between C-7 and the terminal SCHEME 37 \ 321 An excellent introduction to the strategy and t a c t i c s of designing organic syntheses i s provided by r e f . 178. 1 5 1 c a r b o n o f t h e v i n y l g r o u p a t C - 8 . T h i s c o u l d b e a c c o m p l i s h e d b y a n i n t r a m o l e c u l a r r e a c t i o n b e t w e e n t h e k e t o n e e n o l a t e a n d a p r i m a r y h a l i d e o r t o s y l a t e e l a b o r a t e d f r o m t h e v i n y l " h a n d l e " i n 3 2 0 . A t t h i s s t a g e , i t i s c l e a r t h a t t h e b i c y c l o [ 3 . 1 . 0 ] -h e x - 2 - e n e 3 2 2 a n d t h e b i c y c l o [ 3 . 2 . 1 ] o c t a d i e n e 3 2 1 w o u l d c o n -s t i t u t e p o t e n t i a l l y e x c e l l e n t k e y i n t e r m e d i a t e s i n t h i s r e t r o -s y n t h e t i c s e q u e n c e . T h e C o p e r e a r r a n g e m e n t o f t h e s i l y l e n o l e t h e r 3 2 2 m i g h t b e e x p e c t e d t o o c c u r u n d e r c o n d i t i o n s w h i c h a r e s i m i l a r t o t h o s e r e q u i r e d f o r t h e t r a n s f o r m a t i o n ( 2 7 4 2 7 6 ) . [ 7 5 ] 2 7 4 2 7 6 H o w e v e r , t h e r e i s a p o t e n t i a l p r o b l e m a t t e n d i n g t h e t h e r m a l r e a r r a n g e m e n t o f 3 2 2 . T h e p r e s e n c e o f a m e t h y l s u b -s t i t u e n t a t C - 5 i n t h i s s u b s t a n c e p r o v i d e s f o r t h e p o s s i b i l i t y o f a [ 1 , 5 ] - s i g m a t r o p i c h y d r o g e n s h i f t ,1 0 5 w h i c h w o u l d a f f o r d , a t l e a s t i n i t i a l l y , t h e t e t r a e n e 3 2 3 ( e q . [ 7 7 ] ) . F o r t r a n s - d i v i n y l c y c l o p r o p a n e s y s t e m s , t h e r e a r e n o t o n l y e x a m p l e s i n w h i c h t h e [ 1 , 5 ] - h y d r o g e n s h i f t w a s a c o m p e t i n g t h e r m a l p r o c e s s , b u t c a s e s i n w h i c h t h i s r e a c t i o n w a s t h e o n l y o n e o b s e r v e d . U p o n t h e r m o l y s i s a t 2 2 0 ° C , t h e g - c y c l o p r o p y l 152 80 77 81 enone 7_7 afforded a 1:4 mixture of 8_0 and 8_1, respectively, the l a t t e r compound ar i s i n g from a [1,5]-hydrogen s h i f t (eq. [ 7 8 ] ) , 6 3 Indeed, the sigmatropic hydrogen migration has been observed at reaction temperatures as low as 100°C. Sarel et 18 0 a l . have found that subjection of the divinylcyclopropane 324 to a temperature of 130°C gave, aft e r 6 hours, the triene 325 i n 83% y i e l d (eq. [79]). Under similar conditions, 326 was obtained i n 81% y i e l d from 327. 1 8 (^ Both Marino*^ and 6 8 Wender showed that thermolysis of 92a produces almost exclusively the trienone 94_ (eq. [80]). For the trans-divinylcyclopropane of i n t e r e s t (322), thermal bond reorganization proceeding v i a the Cope rearrange-ment would presumably involve isomerization of 322 to i t s 153 9 ] 92a 94 epimer 328 which would undergo the [3,3]-sigmatropic rearrange-ment to give the bicyclo[3.2.1]octadiene 321 as shown i n Scheme 38. In the anticipated t r a n s i t i o n state 330 for th i s process, there i s a severe s t e r i c repulsion between the isopropyl group and H . On the other hand, a s i m i l a r s t e r i c i n t e r a c t i o n involving the isopropyl substituent and H^ , would d e s t a b i l i z e the presumed t r a n s i t i o n state 329 for the [1,5]-sigmatropic hydrogen s h i f t . I t was therefore d i f f i c u l t to predict the preferred mode of rearrangement i n the case of the vinylbicyclo[3.1.0]hex-2-ene 322. Indeed, i t seemed the answer would be provided only upon thermolysis of th i s material. The preparation of the s i l y l enol ether 322 could be accomplished employing a synthetic route s i m i l a r to that 1 5 4 1 5 5 d e s c r i b e d p r e v i o u s l y f o r t h e s y n t h e s i s o f c o m p o u n d 2 7 4 . T h i s e n t i r e s e q u e n c e i s o u t l i n e d i n S c h e m e 3 9 , s t a r t i n g w i t h t h e a c e t y l e n i c a l c o h o l 3 3 1 . T h e a c e t y l e n i c a l c o h o l 3 3 1 w a s c o n v e n i e n t l y p r e p a r e d f r o m 3 - m e t h y l - l - b u t y n e a n d m e t h a c r o l e i n . T h u s , 1.1 e q u i v a l e n t s o f m e t h a c r o l e i n w e r e a d d e d t o a T H F s o l u t i o n o f l - l i t h i o - 3 - m e t h y l -1 - b u t y n e , w h i c h w a s g e n e r a t e d b y t r e a t i n g 3 - m e t h y l - l - b u t y n e SCHEME 3 9 3 3 8 ' ' 3 3 9 * 3 2 2 156 [81] 331 with n-butyllithium (eq. [81]). A single compound was obtained i n quantitative y i e l d and was i d e n t i f i e d as the desired alcohol 331 (v 3350, 2220, 1650 cm - 1). max ' ' ' An examination of the "^"H nmr spectrum of th i s material showed c l e a r l y the presence of the isopropyl group, the two o l e f i n i c protons and the carbinol proton. The v i n y l methyl group appeared as a broad s i n g l e t at 6 1.85 while the carb-i n o l (adjacent to the hydroxyl group) resonated as a broad s i n g l e t at 6 4.77. [82] 331 332 This alcohol 331, when treated with t r i e t h y l orthoacetate i n the presence of propionic acid, provided stereoselectively the Y , <5-unsaturated ester 332 (v 1730 cm ^) i n 58% y i e l d ' ' max 1 157 v i a the orthoester Claisen rearrangement (eq. [82]). The nmr spectrum of the ester 332 was not complex and the resonances of the isopropyl, ethoxy and v i n y l methyl groups were e a s i l y i d e n t i f i e d . The sole o l e f i n i c proton occurred as'a broad s i n g l e t at 6 5.29. Although spectral substantiation of the trans geometry of the t r i s u b s t i t u t e d o l e f i n was not available, i t did not seem presumptuous to assign the given structure to the ester i n l i g h t of the l i t e r -ature documentation on the predominance of trans-substituted o l e f i n s generated by the Claisen rearrangement.1''""'' [83] 332 333 The ester 332 was routinely hydrolyzed (KOH, MeOH-H20) to furnish the corresponding acid 333 i n a moderate y i e l d of 68%. In the i r spectrum of this compound, the broad 0-H (v c max 3300-2500 cm - 1) and carbonyl ( v m a x 1705 cm - 1) absorptions t y p i c a l of a saturated carboxylic acid were evident, while i n the 1H nmr spectrum of 333, a very broad s i n g l e t at 6 10.85 was attributed to the carboxyl proton. 9 8 In the manner described by Hudlicky and coworkers, treatment of the acid 333 with oxalyl chloride i n refluxing 158 HO ^ o ( C O C l ) c r 0 % [ 8 4 ] 3 3 3 3 3 4 h e x a n e s m o o t h l y a f f o r d e d i n q u a n t i t a t i v e y i e l d t h e a c y l c h l o r i d e 3 3 4 ( e q . [ 8 4 ] ) . T h e c h a r a c t e r i s t i c c a r b o n y l a b s o r p -t i o n o f a n a c i d c h l o r i d e a t h i g h w a v e n u m b e r s ( v 1 7 9 0 c m ^) ^ m a x w a s c l e a r l y v i s i b l e i n t h e i r s p e c t r u m , a s w e r e t h e u n s a t -u r a t e d b a n d s a t v 2 2 0 0 a n d 1 6 2 3 c m 1. T h e "'"H n m r s p e c t r u m m a x o f t h i s c o m p o u n d w a s c o n s i s t e n t w i t h t h e a s s i g n e d s t r u c t u r e . [ 8 5 ] 3 3 4 3 3 5 U p o n r e a c t i o n o f t h e a c y l c h l o r i d e 3 3 4 w i t h e t h e r e a l d i a z o m e t h a n e , t h e d i a z o k e t o n e 3 3 5 w a s r e a d i l y a n d q u a n t -i t a t i v e l y o b t a i n e d a s a v i s c o u s y e l l o w o i l ( e q . [ 8 5 ] ) . T h i s m a t e r i a l , w h i c h t e n d e d t o d a r k e n o n s t a n d i n g e v e n a t 5°C a n d i n t h e a b s e n c e o f l i g h t , w a s u s e d s h o r t l y a f t e r i t s p r e p a r a t i o n . 159 1 6 0 T h e d i a z o k e t o n e 3 3 5 w a s i d e n t i f i e d b y t h e s t r o n g d i a z o a b s o r p t i o n a t v 2 0 8 5 c m 1 a n d t h e c a r b o n y l b a n d a t 1 6 3 3 ^ m a x J c m i n t h e i r s p e c t r u m . A l s o i n e v i d e n c e w a s t h e w e a k e r , b u t d i s t i n c t a c e t y l e n i c a b s o r p t i o n a t 2 2 0 0 c m T h e ''"H n m r s p e c t r u m o f 3 3 5 r e s e m b l e d t h a t o f i t s p r e c u r s o r a c i d 3 3 3 w i t h t h e e x c e p t i o n o f a s i n g l e t a t 6 5 . 2 1 d u e t o t h e p r o t o n f l a n k e d b y t h e k e t o n e a n d d i a z o m o i e t i e s . 0 [ 8 6 ] 3 3 5 3 3 6 C o p p e r - c a t a l y z e d i n t r a m o l e c u l a r c y c l i z a t i o n o f t h e d i a z o k e t o n e 3 3 5 p r o c e e d e d s m o o t h l y a n d s t e r e o s e l e c t i v e l y i n r e f l u x -i n g b e n z e n e t o f u r n i s h t h e b i c y c l i c k e t o n e 3 3 6 i n 8 1 % y i e l d . A c u r s o r y e x a m i n a t i o n o f t h e i r s p e c t r u m o f t h i s m a t e r i a l s h o w e d t h e p r e s e n c e o f a k e t o n e c a r b o n y l g r o u p ( vm a x 1 7 2 5 - 1 , c m ) . A s s h o w n i n F i g . 2 2 , t h e i s o p r o p y l m e t h y l r e s o n a n c e s w e r e c l e a r l y v i s i b l e i n t h e n m r s p e c t r u m o f 3 3 6 , a s w a s t h e s i n g l e t d u e t o t h e b r i d g e h e a d m e t h y l g r o u p a t 6 1 . 4 4 . W h e r e a s m o s t o f t h e r e m a i n i n g p r o t o n s o c c u r r e d a s a c l u s t e r o f r e s o n a n c e s a t 6 1 . 9 4 - 2 . 1 4 , t h e t w o c y c l o p r o p y l p r o t o n s a p p e a r e d a s w e l l i s o l a t e d s i g n a l s a t 6 1 . 6 9 a n d 1 . 8 7 . T h e d o u b l e t a t 6 1 . 6 9 w a s e a s i l y a s s i g n e d t o t h e c y c l o p r o p y l 161 p r o t o n a l p h a t o the k e t o n e . A p p a r e n t l y , t h i s p r o t o n c o u p l e s (J = 3 Hz) o n l y w i t h the o t h e r c y c l o p r o p y l p r o t o n . < b c v 336 S e m i h y d r o g e n a t i o n o f the a l k y n e 336 u s i n g L i n d l a r ' s c a t a l y s t (Pd/CaCO^) and a t r a c e o f q u i n o l i n e i n pentane gave s t e r e o s e l e c t i v e l y , a f t e r 3 h o u r s , the d e s i r e d c i s - a l k e n e 337 i n a y i e l d o f 91% (eq. [ 8 7 ] ) . B e s i d e s the appearance o f the o l e f i n i c a b s o r p t i o n (v ^ ^ max 1650 cm "*") as a s h o u l d e r on the c a r b o n y l a b s o r p t i o n ( v m a x 1719 cm ^ ) , the i r spectrum o f t h i s compound d i d not seem much d i f f e r e n t from t h a t o f t h e s t a r t i n g m a t e r i a l 336. On t h e o t h e r hand, the "*"H nmr spectrum was more i n f o r m a t i v e and c l e a r l y e x h i b i t e d two o l e f i n i c s i g n a l s a t 6 4.91 and 5.36, b o t h o f w h i c h d i s p l a y e d t h e 11.5 Hz c o u p l i n g c o n s i s t e n t w i t h a c i s - d i s u b s t i t u t e d o l e f i n i c bond. Compared w i t h t h a t o f the p r e c u r s o r a l k y n e 336, the a l l y l i c c y c l o p r o p y l p r o t o n appeared f u r t h e r d o w n f i e l d as p a r t o f a m u l t i p l e t w h i c h i n t e g r a t e d f o r 5 p r o t o n s a t 6 1.90-2.25. The b r i d g e h e a d p r o t o n o c c u r r e d as an u n r e s o l v e d d o u b l e t a t «$ 1.57, e x h i b i t i n g a 2 Hz c o u p l i n g t o the n e i g h b o r i n g c y c l o p r o p y l p r o t o n . W i t h the c i s - o l e f i n i c k etone 337 i n hand, we f e l t t h a t 162 the thermal rearrangement of i t s s i l y l enol ether 340 would prove a worthy exercise to provide some insight into the rearrangement of the key intermediate 322. That i s , would the Cope rearrangement of 322 be plagued by a competing [1,5] hydrogen s h i f t ? Using standard conditions, the ketone 337 was smoothly and almost quantitatively transformed into the s i l y l enol ether 340 (eq. [88]) . [88] 337 340 The i r spectrum of this compound exhibited a strong o l e f i n i c absorption at v 1627 cm 1 . The presence of the max c bridgehead methyl group rendered the "*"H nmr spectrum of 340 (Fig. 23} somewhat less complex than that of the analogue 274, which lacked a methyl substituent at C-5. In the F i g . 23. The 400 MHz H nmr spectrum of 340. 164 o l e f i n i c region of the spectrum, appeared as a broad s i n g l e t at 6 4.27 and exhibited small couplings to the neighbouring methylene protons (J T„ = J T T = 2.5 Hz). Indeed, when H was —X L —X J X decoupled, the signals at 6 2.37 and 2.30 collapsed to a doublet of doublets (J_„ = 16.5 Hz, J = 2.5 Hz) and a doublet — J L — (J_„ = 16.5 Hz) respectively. Unfortunately, i t was not — J ii possible to make unequivocal assignments for Hj and H z« De-coupling the isopropyl methine proton provided a means to dis t i n g u i s h between the o l e f i n i c protons. In the event, the signal at 6 5.27 collapsed to a doublet (J^ -j-, = 11 Hz) and was assigned to H^, while the overlapping doublet of doublet of doublets at 6 4 .92 was accorded to H^ (J™ = 11 Hz, = 9 U —CD —Dti Hz, J_ B D = 1 Hz) . In turn, the decoupling of H D was used to assign the doublet of doublets at 6 1.34 to H„ (J^r. = 9 Hz, ti —Uti = 2.5 Hz) and the signal at 6 1.32 to H . —tit t ->-SiO / \ 340 4.5 h 240°C [89] 341 \ ^ - S i O / \ 342 166 With a measure of a n t i c i p a t i o n , a benzene solution of the s i l y l enol ether 340 was sealed i n a pyroly s i s tube and heated at 240°C for 4.5 hours. G r a t i f y i n g l y , the sole product is o l a t e d i n 86% y i e l d was i d e n t i f i e d as the bicyclo[3.2.1]-octa-2,6-diene 341 (eq. [89]), and no sign of the triene 342 anticipated from a [1,5]-hydrogen migration was observed. As expected, the i r spectrum of compound 341 was not very h e l p f u l from a diagnostic point of view. On the other hand, the nmr spectrum of 341 (Fig. 24) indicated that the s i l y l enol ether moiety was i n t a c t . A c i s coupling of 10 Hz CJpg) can be detected i n the o l e f i n i c resonances at 6 5.29 and 5.96 (H D and H , r e s p e c t i v e l y ) . Decoupling H D (Fig. 25b) showed that H^ , (<S 2.46) coupled strongly with H z ( J _ F Z = 5 Hz) but only weakly with H c ( J ^ <_ 1 Hz) . This l a t t e r observation i s noteworthy since i t supports the exo assignment of the i s o -propyl group at C-4. When H was decoupled (Fig. 25c), the complex pattern due to H c s i m p l i f i e d and exhibited a 7 Hz coupling between H c and the isppropyl methine proton, as well as two s i m i l a r couplings (vT™ - J,™ - 3 Hz) . Decoupling H 167 zie *J iB ' iT" TPW F i g . 25. The homonuclear spin decoupling experiment with 341: (a) the normal 4 00 MHz nmr spectrum ex-panded for region 6 1.6-2.5, (b) the spectrum with i r r a d i a t i o n at 6 5.29 (H ), and (c) the spectrum with i r r a d i a t i o n at s 2.46 (H ). 1 "k * T A B L E I I . H n m r D a t a f o r C o m p o u n d s 2 7 6 a n d 3 4 1 . 6 H c 8 HD 6 H E 6 H F 6 H. 6 H J 6 H K 6 H K 2 7 6 1 . 8 8 -1 . 9 4 m 5 . 3 3 OL ddd 7fD-2 —DF 6 . 2 1 OL dddd J ^ E - 1 ^EZ 1 2 . 3 8 d ^FZ = 5 1 . 7 5 d ^ i z = 9 - 5 5 . 1 1 d 2 . 5 2 -2 . 5 7 m 1 . 9 7 OL*dddd ^ E Z _ 1 3 4 1 1 . 8 3 -1 . 8 8 m 5 . 2 9 ddd ^E- 3 ° ^DF 2 5 . 9 6 ddd J n F = 1 ° 2 . 4 6 d ^FZ = 5 1 . 6 2 -1 . 7 2 m 4 . 8 7 s 1 . 7 5 ddd ^EZ" 1 * ** O L = o v e r l a p p i n g A l l c o u p l i n g c o n s t a n t s g i v e n i n H e r t z (Hz) 169 also made i t possible to assign the complex signal at <$ 1.75 to H , which i s coupled geminally to H T (J T„ = 9 Hz). This large 9 Hz coupling was also d i s c e r n i b l e i n the multiplet at 6 1.62-1.72, which was consequently attributed to E^ and the isopropyl methine proton. Table II compares the "*"H nmr spectral data of compounds 276 and 341. These compounds d i f f e r only i n the presence of a bridgehead methyl substituent at C - l of 341 but the i r spectra show subtle differences i n chemical s h i f t s , p a r t i c u l a r l y for H £ and E^, which are i n closer proximity to thi s substituent. [90] 341 343 Hydrolysis of the s i l y l enol ether was accomplished e f f i c i e n t l y by treating 341 with 5% aqueous hydrochloric acid i n THF. The bicyclo[3.2.1]octenone 343 (v 1735 cm was _____ i n 9 . x thus obtained i n 93% y i e l d . In the •'"H nmr spectrum of the b i c y c l i c ketone 343, a 9.5 Hz c i s coupling can be seen i n the resonances assigned to H^ and H„ at 6 5.51 and 5.75, respectively. As i n compound 341, H„, which resonated as an unresolved doublet at 6 2.60, 170 1.8 IB TPM F i g . 26. The homonuclear spin decoupling experiment with 343: (a) the normal 400 MHz -*-H nmr spectrum expanded for the region <5 1.5-2.3, and (b) the spectrum with i r -radiation at 6 2.60 (H^). 171 Hz Me He X H D Hx 343 couples strongly to H (J = 5.5 Hz) and weakly to H_, (J < 1 Hz). Indeed, when Hp was decoupled (Fig. 26c), only a very small coupling was eliminated from the s p l i t t i n g pattern of H c at 6 1.77-1.84. Again, the lack of coupling between Hp and Hj was not sur p r i s i n g , considering the dihedral angle involved ( = 90°) . Consequently i n the same decoupling exper-iment, the doublet of doublet accorded to Hj at 6 1.86 showed no change whereas the signal of the geminal proton H z at 1.69 collapsed to a doublet (J. I Z = 11.5 Hz) . The assignments of the doublet of doublets at 6 2.24 to H_ and the doublet (J T„ J — J X = 17 Hz) at 6 1.95 to H were made without d i f f i c u l t y . Of these two protons, only H_ exhibits a long-range coupling of 3.5 Hz with Hj. Presumably, t h i s arises from the planar z i g -113 zag o r i e n t a t i o n of Hj and Hj. Certainly the successful Cope rearrangement of 340 to 341 seemed to bode well f o r the key step (322 •+ 321) i n assembling the bicyclo[3.2.1]octane frame of sinularene. With-out further ado, e f f o r t s were directed at the placement of an exo v i n y l substituent at C-4, which could be accomplished by 172 the conjugate addition of an appropriate nucleophile to the enone 338. The preparation of the l a t t e r compound proved to be problematic, plagued either by poor y i e l d s or by the production of inseparable mixtures consisting of the desired enone 338 and small amounts of the saturated ketone 337. For example, [91] 337 338 after some experimentation, the best y i e l d for the transform-ation of 337 into 338 v i a selenoxide fragmentation was obtained 121 using Reich's "one-pot" procedure of forming and oxidizing the a-selenide, followed by elimination of the resultant selenoxide. Thus, the lithium enolate of 337 which was gener-ated by treating 337 with 1.5 equivalents of lithium d i i s o -propylamide, was quenched with phenylselenenyl chloride to afford the a-phenylselenides 344. To the resultant reaction mixture was added acetic acid and hydrogen peroxide for the conversion of the selen-ides into selenoxides, which conveniently fragmented under the conditions of the reaction to furnish the b i c y c l i c enone 338 i n an unenviable y i e l d of 50%. In an 173 attempt to better t h i s y i e l d , an alternative method was 142 sought. Using the method of Tamura, the t r i m e t h y l s i l y l enol ether 345 was readily prepared from the reaction of the ketone 337 and t r i m e t h y l s i l y l iodide i n the presence of triethylamine i n dichloro- IV^S methane. Unfortunately, due to the i n -s t a b i l i t y of the product 345, a small amount of the st a r t i n g material 337 was 345 always obtained after workup. Con-sequently, the crude enol ether was not p u r i f i e d but was used immediately i n the subsequent step. Subjection of th i s material to a two-fold excess of palladium (II) acetate i n -variably produced a mixture of the desired enone 338 and the saturated ketone 337, with the best r a t i o obtained under these conditions being 5:1 (as judged by glc ana l y s i s ) , respectively. The o v e r a l l material balance of th i s two-step sequence was 78%. Although e f f o r t s to resolve the mixture by t i c and preparative" glc were f r u i t l e s s , t h i s mixture was used i n the next step since i t was possible to recover and recycle the ketone 337 at that stage. 338 1 7 4 T h e i r s p e c t r u m o f t h e e n o n e 3 3 8 w a s c o n s i s t e n t f o r a n a , B - u n s a t u r a t e d e n o n e ( v 1 6 9 0 c m "*") . I n t h e n m r m a x s p e c t r u m o f 3 3 8 , t h e o l e f i n i c p r o t o n s H a n d HT a p p e a r e d a t 6 5 . 6 6 a n d 7 . 5 2 , r e s p e c t i v e l y . B y d e c o u p l i n g HD, i t w a s p o s s i b l e t o a s s i g n t h e d o u b l e t o f d o u b l e t s a t 6 2 . 3 6 t o H „ . El T h e c y c l o p r o p y l p r o t o n e x h i b i t s a 9 . 5 H z c o u p l i n g w i t h HQ a n d a 3 H z c o u p l i n g t o t h e o t h e r c y c l o p r o p y l p r o t o n H „ . T h i s F l a t t e r p r o t o n r e s o n a t e d a s a u n r e s o l v e d d o u b l e t ( J ™ = 3 H z ) —EF a t 6 1 . 9 9 . 3 3 8 T H F , - 3 0 ° C 3 3 9 9 : 4 3 4 6 [ 9 2 ] A l t h o u g h c o n j u g a t e a d d i t i o n o f a n u c l e o p h i l e a t C - 4 w o u l d b e e x p e c t e d t o o c c u r p r e d o m i n a n t l y f r o m t h e c o n v e x f a c e o f 3 3 8 t o p r o v i d e a v i n y l s u b s t i t u e n t w i t h a n e x o o r i e n t a t i o n , i t w a s p o s s i b l e t h a t t h e p r e s e n c e o f t h e b r i d g e h e a d m e t h y l g r o u p w o u l d r e d u c e t h e s t e r e o s e l e c t i v i t y o f 1 , 4 - a d d i t i o n , a s c o m p a r e d t o t h a t o b s e r v e d f o r t h e e n o n e 1 8 9 . I n a n a t t e m p t t o p r e p a r e t h e k e t o n e 3 3 9 , t h e e n o n e 3 3 8 w a s a d d e d t o a m i x t u r e o f v i n y l m a g n e s i u m b r o m i d e1^9'1 1^ a n d a c a t a l y t i c q u a n t i t y o f 1 8 9 c o p p e r ( I ) b r o m i d e - d i m e t h y l s u l f i d e c o m p l e x 175 i n THF at -30°C i n accordance with a procedure described by 133 House et al_. After workup with aqueous ammonium chloride, a 9:4 mixture consisting of the desired alkylated ketone 339 and i t s epimer 346 was obtained i n an is o l a t e d y i e l d of 63% (eq. [92]). A l t e r n a t i v e l y , conjugate addition to the enone 338 using lithium divinylcuprate was found to provide better stereo-s e l e c t i v i t y than the copper (I)-catalyzed Grignard reaction described above. Thus, using another method reported by 134 House et a l . , lithium divinylcuprate was prepared from 338 339 346 9:1 t e t r a v i n y l t i n ' and added to an 85:15 mixture of the enone 338 and the saturated ketone 337 at -63°C. The product thus obtained consisted of a 9:1:0.8 mixture of the desired ketone 339, the epimer 346 and the ketone 337, respectively (eq. [93]). This mixture was conveniently resolved by column chromatography and the ketone 339 was recovered i n 69% y i e l d . * I t was found that y i e l d s of these copper (I)-catalyzed con-jugate additions were affected dramatically by the purity of the copper (I) cat a l y s t . Hence copper (I) bromide-di-methyl s u l f i d e was p u r i f i e d using the methods indicated i n r e f s . 134-136. The i r spectrum of the ketone 339 exhibited the expected carbonyl (v 1722 cm - 1) and o l e f i n i c (v 3070, 3000, 1635 mdx iricix cm absorptions. F i g . 27 shows the 400 MHz "^H nmr spectrum of 339, i n which the two o l e f i n i c protons H^ and H Q appeared at <5 5.39 and 4.91, respectively, and exhibited a 10.5 Hz coupling t y p i c a l of a c i s - d i s u b s t i t u t e d alkene. Interestingly, H_, which appeared at 6 2.91, couples to H T (J = 8 Hz) but not to H z. These observations were not unexpected upon examination of models, which showed that the HT—H_ dihedral angle approx-u la imated 90° while the H T — H d i h e d r a l angle was -30°. Indeed, decoupling H caused the signal due to H_ at 6 2.55 to collapse to a doublet (J T„ = 18.5 Hz) but caused no change to the doub-l e t (J_ I Z = 18.5 Hz) assigned to H z at 6 1.89. To d i s t i n g u i s h between the cyclopropyl protons, H D was decoupled, eliminating a 8.5 Hz coupling from the signal at 6 2.15, which was con-sequently accorded to H E. Using a nuclear Overhauser enhance-ment experiment i n which the signal at 6 2.15 (HE) was i r -radiated, i t was possible to assign unequivocally the endo configuration to H (Fig. 28). As well, the signal at 6 2.55 178 179 exhibited a n.O.e. e f f e c t , thereby v e r i f y i n g i t s assignment H< 3 4 6 The H nmr spectrum of the epimer 346 as shown i n F i g . 29, i s expectedly s i m i l a r to that of 339, p a r t i c u l a r l y i n the o l e f i n i c region. A comparison of these two spectra brings to l i g h t a number of noteworthy differences i n the high f i e l d area. F i r s t l y , the resonance of the t e r t i a r y methyl sub-st i t u e n t i n 339 i s 0.11 ppm u p f i e l d from the resonance of the same group i n 346. This observation may be r a t i o n a l i z e d by the shielding provided to the methyl substituent by the syn v i n y l group i n 339.. A si m i l a r argument may be applied to explain the second phenomenon: the apparent reversal of shielding experienced by the two methylene protons alpha to the ketone; i n 339, H appeared further u p f i e l d than H , where-as i n 346, the s i t u a t i o n was reversed. That i s to say, the v i n y l group seems to shield the neighbouring syn proton, which happens to be i n 339 but Hj i n 346. Thirdly, other than coupling to Ev, H T couples to both H T and H„ ( J X T = 9.5 Hz, IS. J J. L —-J.J J j Z = 9 Hz) i n 346 as anticipated i f i t s configuration was exo. 181 [ 9 4 ] 3 3 9 3 2 2 In a n t i c i p a t i o n of the c r u c i a l Cope rearrangement, the ketone 339 was transformed routinely into the t r a n s - d i v i n y l -cyclopropane 322 i n 96% y i e l d (eq. [94]). The i r spectrum of 322 exhibited strong o l e f i n i c absorp-tions at v 1635 and 1620 cm Moreover, the singlets at max 3 <5 0.17 and 0.94 i n the 1H nmr spectrum of 322 (Fig. 30) t e s t -i f i e d to the presence of the s i l y l methyl and t-butyl groups. The large (J^g = 9 Hz) coupling e a s i l y q u a l i f i e d the signal at 6 1.40 to be att r i b u t a b l e to H £. The other cyclopropyl proton H„, which resonated at 6 1.34, couples to H„ (J = 2.5 Hz) and a l l y l i c a l l y to H (J = 1 Hz). Being doubly a l l y l i c , H i s quite deshielded and appeared at 6 3.10 as a unresolved doublet (J = 9 Hz) due to the coupling with H . The proton H 183 the most shielded of the o l e f i n i c protons, resonated at 6 4.20 while the remaining o l e f i n i c protons assumed s p l i t t i n g patterns almost i d e n t i c a l with those observed for the ketone 339. [95] With the stereocontrolled synthesis of the key i n t e r -mediate 322 accomplished successfully, the stage was set for i t s thermal rearrangement. Thus, a benzene solution of the s i l y l enol ether 322 was sealed i n a pyrolys i s tube and heated at 220°C f o r 4.5 hours to give a single product, which to our delight was i d e n t i f i e d as the de-s i r e d bicyclo[3.2.1]octa-2,6-diene 321 (eq. [95]). There was no evidence for the formation of the triene 323 from a possible competing [1,5]-hydrogen s h i f t , thereby proving that our i n i t i a l misgivings were (happily) unfounded. Indeed, the successful thermolysis of the analogous vinylbicyclo[3.1.0]hex-2-ene 340 forecasted accurately the outcome for the rearrangement of 322. Produced i n 86% y i e l d , the enol ether 321 exhibited an i r spectrum which predictably resembled that of i t s precursor 322. F i g . 31. The 400 MHz 1 H nmr s p e c t r u m o f 321. 185 321 At a glance, the H nmr spectrum of 321 (Fig. 31) did not seem complicated, i t s s i m p l i c i t y undoubtedly due to the presence of a bridgehead methyl group and a C-8 v i n y l sub-st i t u e n t . The t - b u t y l d i m e t h y l s i l y l enol ether had evidently stayed i n t a c t . The proton , resonating at 6 5.35, displayed a c i s coupling (J = 9.5 Hz) with H„. Decoupling H^ aided i n the assignment of the doublet of doublets at 6 6.00 to H„ and the multiplet at 6 1.92-1.97 to H c. The proton Hj resonated as a doublet at 6 2.4 6 ( J j K = 9 Hz) and did not exhibit any coupling with the neighbouring Hp. Appearing as a broad sing-l e t at <S 2.26, H„ displays only a small coupling with H_, there-in C by a t t e s t i n g to the endo configuration of the l a t t e r . These data would seem to indicate the successful assembly of the r e q u i s i t e bicyclo[3.2.1]octane skeleton with the stereo-s p e c i f i c placement of an exo isopropyl substituent at C-4. At t h i s stage, the remaining synthetic sequence (Scheme 40) required the elaboration of the v i n y l moiety into a primary alcohol which could be converted into i t s tosylate or some other suitable leaving group. Hydroboration of the v i n y l 1 8 6 S C H E M E 4 0 1 2 5 2 8 0 3 4 9 substituent should provide the desired primary alcohol, but the question here concerns chemoselectivity. That i s , would i t be possible to hydroborate the v i n y l moiety s e l e c t i v e l y i n the presence of two other double bonds? The double bond on the three-carbon bridge i s flanked by a quaternary centre on one side and by a s t e r i c a l l y bulky isopropyl substituent on the other, and should therefore be the least l i k e l y of the three s i t e s of unsaturation to be attacked by a hydroborating agent. By s t e r i c argument alone, the v i n y l moiety should be the most reactive alkene. However, i t i s known that polar 1 8 3 a substituents have a d i r e c t i v e e f f e c t on hydroboration and that the rate of th i s reaction i s increased by increasing the electron density of the double bond. 1 8 3* 3 B y considering only el e c t r o n i c factors, the s i l y l enol ether, which consists of an 1 8 7 e l e c t r o n - r i c h d o u b l e b o n d , w o u l d b e t h e m o s t s u s c e p t i b l e t o h y d r o b o r a t i o n . O n t h e o t h e r h a n d , t h i s m o i e t y i s s o m e w h a t s t e r i c a l l y h i n d e r e d . I d e a l l y , t h e h y d r o b o r a t i n g r e a g e n t r e q u i r e d u n d e r t h e c i r c u m s t a n c e s , s h o u l d b e b o t h s t e r i c a l l y d e m a n d i n g a n d l e s s s e n s i t i v e t o e l e c t r o n i c i n f l u e n c e s . A 1 8 4 1 8 5 c a n d i d a t e w h i c h m e e t s t h e s e c r i t e r i a i s d i s i a m y l b o r a n e . ' [ 9 6 ] T h u s , r e a c t i o n o f t h e s i l y l e n o l e t h e r 3 2 1 w i t h s l i g h t l y 1 8 6 1 8 7 o v e r 2 e q u i v a l e n t s o f d i s i a m y l b o r a n e ' a t 0 ° C , f o l l o w e d b y o x i d a t i o n o f t h e r e s u l t a n t t r i a l k y l b o r a n e w i t h a l k a l i n e h y d r o g e n p e r o x i d e g a v e i n 8 6 % y i e l d , t h e a l c o h o l 3 4 7 (vm a x 3 3 0 0 c m- 1, e q . [ 9 6 ] ) . I n t h e ^H n m r s p e c t r u m o f 3 4 7 , a 2 - p r o t o n m u l t i p l e t c o r r e s p o n d i n g t o t h e m e t h y l e n e p r o t o n s a d j a c e n t t o t h e h y d r o x y 1 g r o u p , a p p e a r e d a t 6 3 . 6 3 - 3 . 7 9 . T h e s i n g l e t s a t 6 0 . 1 1 a n d 0 . 1 3 , i n t e g r a t i n g f o r a t o t a l o f 6 p r o t o n s , t h e 9 - p r o t o n s i n g -l e t a t 6 0 . 9 0 a n d t h e s i n g l e t a t 6 4 . 6 9 c o l l e c t i v e l y i n d i c a t e d t h a t t h e s i l y l e n o l e t h e r m o i e t y h a d s u r v i v e d t h e h y d r o b o r a t i o n . A s w e l l , t h e c i s - d i s u b s t i t u t e d a l k e n e h a d r e m a i n e d i n t a c t a s e v i d e n c e d b y t h e s i g n a l s d u e t o a n d a t 6 5 . 3 0 a n d 5 . 9 8 , r e s p e c t i v e l y . T h e 9 . 5 H z c i s c o u p l i n g w a s d i s c e r n i b l e i n b o t h 1 8 8 3 4 7 o f t h e s e o l e f i n i c r e s o n a n c e s . A s e x p e c t e d t h e u p f i e l d r e g i o n o f t h e s p e c t r u m h a d b e c o m e m o r e c o m p l e x a n d m a n y o f t h e s i g -n a l s n o w o c c u r r e d t o g e t h e r a s m u l t i p l e t s . T h e r e s o n a n c e o f H j o c c u r r e d a t 6 1 . 9 4 a n d w a s a d o u b l e t " o f d o u b l e t s d u e t o d i s s i m i l a r c o u p l i n g s t o t h e n e i g h b o u r i n g m e t h y l e n e p r o t o n s ( J = 1 0 H z , J = 3 . 5 H z ) . T o a n t i c i p a t e t h e f o r m a t i o n o f t h e t w o - c a r b o n b r i d g e i n t h e k e t o n e 3 4 9 ( s e e S c h e m e 4 0 ) b y f l u o r i d e - i n d u c e d c l e a v a g e o f t h e s i l y l e n o l e t h e r a n d a c o n c o m i t a n t i n t r a m o l e c u l a r a l k y l a t i o n , i t w a s d e s i r a b l e t o c o n v e r t t h e p r i m a r y a l c o h o l i n t o a l e a v i n g g r o u p s u c h a s a t o s y l a t e . [ 9 7 ] 3 4 7 3 4 9 A f t e r s o m e e x p e r i m e n t a t i o n , i t w a s d i s c o v e r e d t h a t t h e a d d i t i o n o f t h e a l c o h o l 3 4 7 t o a m i x t u r e o f p _ - t o l u e n e s u l f o n y l 1 8 9 chloride and 4-dimethylaminopyridine i n dichloromethane, offered the best r e s u l t s . However, none of the anticipated tosylate was i s o l a t e d . Instead, i t was a pleasant surprise to f i n d that the single product iso l a t e d could be i d e n t i f i e d as the c y c l i z e d ketone 349 (eq. [97]). Thus, under the reaction conditions, the i n i t i a l l y formed tosylate was un-stable and, apparently, underwent an alkene-assisted s o l v o l y t i c ring closure with accompanying cleavage of the s i l y l ether. s i l i c a gel OTs [ 9 8 ] 351 350 A s i m i l a r transformation was observed by Piers and co-18 8 workers i n work leading to the synthesis of (-)-copacamphene (350) as shown i n eq. [98]. Subjection of the tosylate 351 to s i l i c a gel column chromatography gave, i n 89% y i e l d , (-)-copacamphene (350). In our case, t h i s fortuitous transformation (347 349) afforded the ketone 349 i n 79% y i e l d and shortened the remaining synthetic sequence by one step. Examination of the i r spectrum of t h i s material revealed a ketone carbonyl absorption (v J * max 1745 cm - 1) and o l e f i n i c bands (v 3005, 1630 cm - 1). ' max ' ' Figure 32 shows the 1H nmr spectrum of 349, i n which the o l e f i n i c protons H D and H E have converged to an AB system. The 3 4 9 proton H_ appeared as a doublet at 6 5 . 5 9 due to the c i s coupling (J = 1 0 Hz) with Hp. The doublet of doublet of doublets displayed by Hp at 6 5 . 6 3 also exhibits smaller couplings with H_, (J = 3 . 5 Hz) and with H„ (J = 1 . 5 Hz) . Decoupling both H_ and H_ led to the collapse of the signal due to Hp at 6 2 . 2 8 to a doublet, and the complex multip l e t due to H c at 6 1 . 9 0 - 1 . 9 6 to a doublet of doublets. This decoupling experiment uncovered the small coupling (J = 2 . 5 Hz) between H_, and H_ and that (J = 9 . 5 Hz) between H_, and the isopropyl methine proton. 199] 3 4 9 2 8 0 The reduction of the double bond i n 3 4 9 was attempted i n i t i a l l y using diimide. Thus, reaction of the alkene 3 4 9 with diimide generated i n s i t u from p_-toluenesulfonylhydrazide 192 and sodium acetate ' i n a reflu x i n g mixture of THF and water, proceeded sluggishly to give after 54 hours, the ketone 280 i n a y i e l d of 43% (eq. [99]). I t was cl e a r that this y i e l d was unacceptable, and as a consequence, c a t a l y t i c hydro-genation of the bond was attempted. Thus, the alkene 349 was subjected to hydrogenation catalyzed by palladium supported on carbon i n methanol to give after 26.5 hours, a L)3:7 mix-ture consisting of 280 and s t a r t i n g material 349. The reaction became quite sluggish near the end and despite the addition of more ca t a l y s t , would not consume the remaining s t a r t i n g material. Although e f f o r t s to resolve t h i s mixture were f r u i t -l e s s , the mixture was used i n the next step. The major component of th i s mixture was shown by glc analysis to have a retention time i d e n t i c a l with that of the product from the diimide reduction of 349. The i r spectrum of 280 was consistent with a ketone (v 1740 cm - 1), and the max H^ nmr spectrum of this material exhibited no signals due to " o l e f i n i c protons. Not s u r p r i s i n g l y , most of the signals now occurred as overlapping multiplets between 6 1.38-2.11, and the only i n t e l l i g i b l e resonances were those of the isopropyl methyl groups as a 6-proton pair of doublets at 6 0.8 9 and 0.92, and the t e r t i a r y methyl group as a 3-proton s i n g l e t at 6 1.00. The ''"H nmr and i r spectra of the ketone 280, never-theless, were i d e n t i c a l with those of an authentic sample of * ^t)~280. Since t h i s ketone was used as an intermediate i n a * • We are g r a t e f u l to Professor Wege for copies of "'"H nmr and i r spectra of (+)-280. 125 ho a* 193 171 reported synthesis of (+)-sinularene by C o l l i n s and Wege, the work described to th i s point constituted a formal synthesis of (+)-sinularene (125). Previously, the conversion of the ketone 280 into 125 was 171 accomplished i n a three-step sequence (see Scheme 34). We were, however, able to e f f e c t t h i s transformation i n one step by means of a Wittig o l e f i n a t i o n (eq. [100]). Ph 3P=CH 2 THF, A [100] 125 Thus, treatment of a 93:7 mixture consisting of the ketone and 349 with methylenetriphenylphosphorane (generated by treating methyltriphenylphosphonium bromide with n-butyl-lithium) i n re f l u x i n g THF gave, a f t e r p u r i f i c a t i o n (column chromatography) of the crude product, a pure sample of (+)-sinularene i n 78% y i e l d . This material exhibited i r , 1H 13 nmr, C nmr and mass spectra i d e n t i c a l with those of an * authentic sample of (+)-sinularene and the naturally occurring 82 sesquiterpene (-)-sinularene. This constitutes the successful t o t a l synthesis of (+)-sinularene i n a t o t a l of sixteen steps (from methacrolein * We are gr a t e f u l to Professor Oppolzer for ^"H nmr, i r and mass spectra of (+)-sinularene. 194 SCHEME 41 125 280 349 l a ] ( i l n B u L i , THF, -30°C ( i i ) m e t h a c r o l e i n ( i i i ) NH 4C1 [b] MeC.(OEt) 3, E t C 0 2 H , 130°C [c] KOH, HjO, MeOH, r e f l u x [d] ( C O C l ) 2 , hexane, r e f l u x [e] CH 2N 2, E t 2 0 , 0°C [ f ] C u ( a c a c ) 2 , benzene, r e f l u x [g] Pd/CaC0 3, P b ( O A c ) 2 , q u i n o l i n e , pentane [h] M e 3 S i I E t 3 N , C H 2 C 1 2 , -78°C [ i ] P d ( O A c ) 2 , MeCN, r . t . [ j ] ( i ) (CH2=CH) 2 C u L i , E t 2 0 , -63°-*--30°C ( i i ) NH 4C1-H 20 [k] ( i ) LDA, THF, -78°C ( i i ) t - B u M e 2 S i C l , THF-HMPA -78°C-»-r.t. [1] 220°C, benzene, s e a l e d tube [m] ( i ) S i a 2 B H , THF ( i i ) H 2 0 2 , NaOH In] p_-MeC 6H 4S0 2Cl, DMAP, C H 2 C 1 2 , r . t . [o] H 2, Pd/C, MeOH, r . t . Ip] Ph 3P=CH 2, THF, r e f l u x 1 9 5 a n d 3 - m e t h y l - l - b u t y n e ) w i t h a n o v e r a l l y i e l d o f 3 . 9 % ( s e e 1 9 1 S c h e m e 4 1 ) a n d r e p r e s e n t s t h e f i r s t r e p o r t e d a p p l i c a t i o n o f t h e s t e r e o s p e c i f i c C o p e r e a r r a n g e m e n t o f a 6 - e x o - [ ( Z ) - 1 -a l k e n y l ) ] b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e ( i . e . 3 2 2 ->- 3 2 1 ) t o t h e t o t a l s y n t h e s i s o f a n a t u r a l l y o c c u r r i n g s u b s t a n c e . 196 Chapter III EXPERIMENTAL 3.1 General Melting points were determined using a Fisher-Johns melting point apparatus and are corrected. B o i l i n g points are uncorrected and those designated as air-bath temperatures r e f e r to short-path (Kugelrohr) d i s t i l l a t i o n s . Infrared (ir) spectra were recorded on a Perkin-Elmer model 710B in f r a r e d spectrophotometer and were ca l i b r a t e d using the 1601 cm 1 1 13 band of polystyrene f i l m . Proton ( H) and carbon ( C) nuclear magnetic resonance spectra were taken i n deuteriochloroform using tetramethylsilane (TMS) as i n t e r n a l standard. These spectra were recorded using Bruker WP-80 or WH-400 spectro-meters. The 270 MHz spectra were recorded on a unit comprised of an Oxford Instruments 63.4 KG superconducting-magnet and a Ni c o l e t 32K Model 1180 computer attached to a Bruker WP-60 console. Signal positions are given i n parts per m i l l i o n (6) from TMS and the m u l t i p l i c i t y , integrated peak areas, coupling constants (where possible) and proton assignments are indicated i n parentheses. In cases of compounds with t e r t -b u t y l d i m e t h y l s i l y l groups, the resonance positions were de-193 termined r e l a t i v e to the chloroform signal (<5 7.27). Low resolution mass spectra (ms) were recorded with a 1 9 7 V a r i a n / M A T C H 4 B m a s s s p e c t r o m e t e r w h i l e h i g h r e s o l u t i o n m a s s s p e c t r a w e r e r e c o r d e d w i t h a K r a t o s / A E I MS 5 0 m a s s s p e c t r o m e t e r . G l c - m a s s s p e c t r o m e t r i c a n a l y s i s w a s d o n e u s i n g a C a r l o E R B A 4 1 0 0 g a s c h r o m a t o g r a p h e q u i p p e d w i t h a 1 5 m x 0 . 2 6 mm f u s e d s i l i c a c o l u m n c o a t e d w i t h c r o s s l i n k e d a n d b o n d e d D B - 5 [ ( 9 5 % ) - d i m e t h y l - ( 5 % ) - d i p h e n y l p o l y s i l o x a n e ] a n d c o u p l e d w i t h a K r a t o s MS 8 0 R F A m a s s s p e c t r o m e t e r . H i g h r e s o l u t i o n m a s s s p e c t r a w e r e r e c o r d e d w i t h a K r a t o s / A E I MS 5 0 m a s s s p e c t r o m e t e r . M i c r o a n a l y s e s w e r e p e r f o r m e d b y M r . 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 o f B r i t i s h C o l u m b i a . A n a l y t i c a l g a s l i q u i d c h r o m a t o g r a p h y ( g l c ) w a s p e r f o r m e d o n a H e w l e t t - P a c k a r d m o d e l 5 8 3 2 A g a s c h r o m a t o g r a p h u s i n g a 6 f t x 0 . 1 2 5 i n s t a i n l e s s s t e e l c o l u m n p a c k e d w i t h 5 % O V - 1 7 o n 8 0 - 1 0 0 m e s h C h r o m o s o r b W ( H P ) a n d a t h e r m a l c o n d u c t i v i t y d e t e c t o r o r o n a H e w l e t t - P a c k a r d m o d e l 5 8 8 0 g a s c h r o m a t o g r a p h u s i n g a 2 5 m x 0 . 2 1 mm f u s e d s i l i c a c o l u m n c o a t e d w i t h c r o s s -l i n k e d S E - 5 4 [ ( 9 4 % ) - d i m e t h y l - ( 5 % ) - d i p h e n y l - ( 1 % ) - v i n y l p o l y -s i l o x a n e ] a n d a f l a m e - i o n i z a t i o n d e t e c t o r . T h e c o l u m n u s e d a n d t h e i n i t i a l o v e n t e m p e r a t u r e a r e i n d i c a t e d i n p a r e n t h e s e s . A l l a n a l y s e s w e r e d o n e u s i n g a t e m p e r a t u r e p r o g r a m ( 2 0° C p e r m i n , f i n a l t e m p e r a t u r e 2 0 0 ° C ) a f t e r t h e f i r s t 2 m i n a t t h e i n i t i a l t e m p e r a t u r e . P r e p a r a t i v e g l c w a s d o n e u s i n g a V a r i a n A e r o g r a p h 9 0 - F g a s c h r o m a t o g r a p h a n d a 1 0 f t x 0 . 2 5 i n s t a i n l e s s s t e e l c o l u m n p a c k e d w i t h 5 % O V - 1 7 o n S u p e l c o WHP ( 1 0 0 - 1 2 0 m e s h ) . 1 9 8 T h i n l a y e r c h r o m a t o g r a p h y ( t i c ) w a s a c c o m p l i s h e d o n c o m m e r c i a l a l u m i n u m - b a c k e d s i l i c a g e l p l a t e s ( E . M e r c k , T y p e 5 5 3 9 ) . P r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y w a s d o n e o n 2 0 x 2 0 c m g l a s s p l a t e s c o a t e d w i t h 0 . 9 mm o f s i l i c a g e l ( E . M e r c k , S i l i c a g e l 6 0 ) . C o n v e n t i o n a l c o l u m n c h r o m a t o g r a p h y w a s p e r f o r m e d u s i n g 7 0 - 2 3 0 m e s h s i l i c a g e l ( E . M e r c k ) o r 8 0 -2 0 0 m e s h n e u t r a l a l u m i n a ( F i s h e r - S c i e n t i f i c ) , w h i l e f l a s h c o l u m n c h r o m a t o g r a p h y w a s d o n e u s i n g 2 3 0 - 4 0 0 m e s h s i l i c a g e l ( E . M e r c k ) a c c o r d i n g t o t h e p r o c e d u r e d e v e l o p e d b y S t i l l e t a l . A l l r e a c t i o n s r e q u i r i n g a n h y d r o u s c o n d i t i o n s w e r e d o n e u s i n g g l a s s w a r e w h i c h w a s f l a m e - d r i e d u n d e r a n a r g o n f l o w . C o l d t e m p e r a t u r e s w e r e m a i n t a i n e d b y u s e o f t h e 1 9 5 f o l l o w i n g b a t h s : a q u e o u s c a l c i u m c h l o r i d e / C 02 ( - 3 0 ° C ) , c h l o r o f o r m / C 02 ( - 6 3 ° C )1 9 6 a n d a c e t o n e / C 02 ( - 7 8 ° C ) .1 9 6 3 . 2 S o l v e n t s a n d R e a g e n t s S o l v e n t s a n d r e a g e n t s w e r e p u r i f i e d a n d d r i e d u s i n g 1 9 7 — 2 0 1 e s t a b l i s h e d p r o c e d u r e s i n w h i c h t h e d r y i n g a g e n t s u s e d a r e s u m m a r i z e d i n T a b l e I I I . A l l s o l v e n t s w e r e d i s t i l l e d p r i o r t o u s e . T h e p e t r o l e u m e t h e r u s e d w a s t h e f r a c t i o n s w i t h a b o i l i n g r a n g e c a . 3 0 - 6 0 ° C . S o l u t i o n s o f n - b u t y l l i t h i u m a n d p h e n y l l i t h i u m w e r e o b t a i n e d f r o m A l d r i c h C h e m i c a l C o . , I n c . a n d w e r e s t a n d a r d -2 0 i z e d u s i n g t h e p r o c e d u r e s d e s c r i b e d b y G i l m a n a n d C a r t l e d g e , 1 9 9 T A B L E I I I . D R Y I N G A G E N T S U S E D F O R S O L V E N T S & R E A G E N T S M a t e r i a l D r y i n g A g e n t R e f e r e n c e a c e t o n i t r i l e P „ 0 _ 1 9 8 b e n z e n e C a H2 1 9 7 d i c h l o r o m e t h a n e P2 ^ 5 1 9 7 d i e t h y l e t h e r N a / P h2C O 1 9 8 d i i s o p r o p y l a m i n e C a H2 1 9 9 * h e x a m e t h y l p h o s p h o r a m i d e C a H2 h e x a n e C a H2 1 9 7 m e t h a n o l M g ( O M e )2 2 0 1 o x a l y l c h l o r i d e p c l5 1 9 7 p e n t a n e C a H2 1 9 7 p y r i d i n e C a H2 1 9 9 t e t r a h y d r o f u r a n ( T H F ) N a / P h2C O 1 9 8 t i n ( I V ) c h l o r i d e P „ Oc 1 9 7 t r i e t h y l a m i n e C a H 1 9 9 * d i s t i l l e d u n d e r r e d u c e d p r e s s u r e ( 0 . 1 T o r r ) 200 Ronald et a l . or Kofron and Baclawski. Also obtained from A l d r i c h were tetra-n-butylammonium fl u o r i d e (1.0 M) solution i n THF, diisobutylaluminum hydride (DIBAL, 1.0 M) solution i n hexane, and borane-dimethyl s u l f i d e complex. 3-Methyl-l-butyne was purchased from Farchan Labs. p_-Toluenesulfonyl chloride was p u r i f i e d by continuous 197 extraction with petroleum ether, triphenylphosphme was 197 r e c r y s t a l l i z e d from ethyl acetate and methanol and p_-toluenesulfonylhydrazide was r e c r y s t a l l i z e d from THF and petroleum ether. Lithium diisopropylamide (LDA) was prepared by the addition of a hexane solution of n-butyllithium (1.0 equiv) to a solution of diisopropylamine (1.1 equiv) i n dry THF at -78°C under argon. The r e s u l t i n g solution was s t i r r e d at 0°C . 0 „ . . 205 for 20 mm p r i o r to use. Saturated basic aqueous ammonium chloride (pH 8) was prepared by the addition of 50 mL of aqueous ammonium hydroxide (58%) to 1 L of saturated aqueous ammonium chloride. 201 3.3 Model Studies 3.3.1 General Procedure A: The Preparation of 6-exo-(1-Alkenyl)bicyclo[3.1.0]hex-2-enes To a cold (-78°C), s t i r r e d solution of LDA (1.1 equiv) i n anhydrous THF (5 mL/nunol of LDA) , under argon, was added a solut i o n of the parent ketone (1.0 equiv) i n THF. A f t e r the r e s u l t i n g mixture had been s t i r r e d at -78°C fo r 0.5 h, a THF solution of HMPA (2.0 equiv) and freshly sublimed t e r t -b u t y l d i m e t h y l s i l y l chloride (1.5 equiv) was added. The reaction mixture was s t i r r e d at -78°C fo r another 0.5 h and then at room temperature for 2 h. The r e s u l t i n g mixture was poured into saturated aqueous sodium bicarbonate and the layers were separated. A f t e r extraction of the aqueous layer with ether, the organic extracts were combined, washed th r i c e with brine and dried (anhydrous magnesium s u l f a t e ) . Evap-oration of the solvent under reduced pressure (water a s p i r -ator) afforded a yellow residue, which was subjected to chromatography on a short column of neutral alumina (80-200 mesh, e l u t i o n with petroleum ether). Subsequent concentration of the appropriate f r a c t i o n s , followed by d i s t i l l a t i o n of the r e s i d u a l material furnished the s i l y l enol ethers as c l e a r , colourless o i l s . 3.3.2 General Procedure B: Preparation of Bicyclo[3.2.1]-octa-2,6-dienes P r i o r to use, a l l glass p y r o l y s i s tubes (2 mm wall thickness) were s i l y l a t e d i n the following manner. The tubes 202 were washed t h o r o u g h l y w i t h d e t e r g e n t and w a t e r , and were soaked i n 1% aqueous p o t a s s i u m h y d r o x i d e f o r 15 m i n u t e s . They were washed s u c c e s s i v e l y w i t h s p e c t r o g r a d e methanol (4X's) and s p e c t r o g r a d e t o l u e n e ( 2 X ' s ) , and t h e n were soaked i n a 5% s o l u t i o n o f N , N - b i s ( t r i m e t h y l s i l y l ) a c e t a m i d e i n t o l u e n e f o r 15 m i n u t e s . A f t e r s u c c e s s i v e r i n s e s w i t h t o l u e n e and m e t h a n o l , the tubes were o v e n - d r i e d , c o o l e d t o room t e m p e r a t u r e and s t o r e d e i t h e r i n a d e s s i c a t o r o r s e a l e d w i t h a r u b b e r septum. The s o l u t i o n s o f s u b s t r a t e s i l y l e n o l e t h e r s i n d r y benzene were degassed i n the g l a s s p y r o l y s i s tubes by a l t e r n a t e l y f r e e z i n g ( i n l i q u i d n i t r o g e n ) and thawing the s o l u t i o n s t h r i c e . These g l a s s tubes were s e a l e d i n vacuo (0.1 T o r r ) a t -196°C ( l i q u i d n i t r o g e n ) , packed w i t h sand i n a s t e e l c o n t a i n e r and h e a t e d a t t h e a p p r o p r i a t e temperature i n an oven. R e a c t i o n p r o g r e s s was m o n i t o r e d by g l c and t h e t h e r m o l y s e s were t e r m i n a t e d when s t a r t i n g m a t e r i a l was no l o n g e r a p p a r e n t . The tubes were c o o l e d t o room t e m p e r a t u r e and u n s e a l e d . Subsequent s o l v e n t removal gave l i g h t y e l l o w o i l s w h i c h were d i s t i l l e d under reduced p r e s s u r e t o a f f o r d the d e s i r e d s i l y l e n o l e t h e r s g e n e r a l l y i n e x c e l l e n t y i e l d s . A number o f s e a l e d t u b e s c o n t a i n i n g t h e s o l u t i o n s were he a t e d s i m u l t a n e o u s l y , b u t each tube was opened and i t s c o n t e n t s a n a l y z e d by g l c a t d i f f e r e n t t i m e s . The r e a c t i o n was st o p p e d when s t a r t i n g m a t e r i a l was no l o n g e r a p p a r e n t by g l c . 2 0 3 3.3.3 Preparation of 6-exo-Vinylbicyclo[3.1.0]hexan-2-one The b i c y c l i c ketone 179 was prepared i n accordance with 98 the procedures reported by Hudlicky et a_l. In our hands, this material was obtained i n an o v e r a l l y i e l d of 36% from d i v i n y l c a r b i n o l , 1 0 9 ' 1 1 0 and exhibited air-bath d i s t i l l a t i o n temperature 70-75°C/15 Torr; i r (f i l m ) : 3085, 1725, 1640, 1180, 990, 910, 887 cm"1; 1H nmr (400 MHz, CDC13) 6 1.83 (d of d, IH, H , J_ F G = 5 Hz, J E F = 2.5 Hz), 1.93 (overlapping d of d of d, IH, H E, J D E = 8.5 Hz, J_Eg - J E F = 2.5 Hz), 2.03-2.25 (m, 5H) , 4.99 (d of d, IH, H„, J^_. = 10 Hz, J__ = 1.5 Hz), 5.14 (d of d, IH, Hg, J_ B D = 17 Hz, J B C = 1.5 Hz), 5.35 (d of d of d, IH, H D, J B D = 17 Hz, = 10 Hz, J_ D E = 8.5 Hz) . I r r a d i a t i o n at 6 5.35 (HD) caused the signal at 6 1.93 to collapse to an overlapping d of d (J = 2.5 Hz), the signal at 6 4.99 to collapse to a d (J = 1.5 Hz), and the signal at 6 5.14 to collapse to a d (J = 1.5 Hz). Exact mass calcd. for CQH^QO: 122.0732; found: 122.0730. 2 0 4 3 . 3 . 4 P r e p a r a t i o n o f 2 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 6 - e x o -v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e F o l l o w i n g g e n e r a l p r o c e d u r e A , t h e k e t o n e 1 7 9 ( 0 . 1 2 2 g , 1 . 0 m m o l ) w a s c o n v e r t e d i n t o t h e s i l y l e n o l e t h e r 1 8 7 ( 0 . 2 2 4 g , 9 5 % , a i r - b a t h d i s t i l l a t i o n t e m p e r a t u r e 5 0 - 5 4 ° C / 0 . 2 T o r r ) , w h i c h w a s s h o w n b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) t o c o n s i s t o f o n e c o m p o n e n t a n d e x h i b i t e d i r ( f i l m ) : 3 0 6 0 , 3 0 2 0 , 1 6 2 7 , 1 2 5 0 , 1 2 1 0 , 8 4 0 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 5 ( s , 6 H , C H3- S i - C H3) , 0 . 9 3 ( s , 9 H , (CH_3) 3C - S i - 0 - ) , 1 . 1 4 ( o v e r l a p p i n g d o f d o f d , I H , HE, = 9 H z , JE F « JE G « 2 H z ) , 1 . 5 7 - 1 . 6 3 ( m , I H , H_ o r H _ ) , 1 . 6 7 - 1 . 7 2 ( m , I H , H_ o r H _ ) , 2 . 2 9 r CJ r o ( o v e r l a p p i n g d o f d o f d , I H , HT, JT„ = 1 7 H z , J _ _ - J ^ , , - - 3 H z ) , 2 . 5 2 ( d o f d o f d , I H , H „ , JT„ = 1 7 H z , = 8 H z , JT„ = 2 H z ) , 4 . 3 0 ( b r o a d s , I H , H j , w . ^ = 6 H z ) , 4 . 8 6 ( d o f d , I H , Hc, = 1 0 H z , JB C = 2 H z ) , 5 . 0 1 ( d o f d , l H , HR, JB D = 1 6 H z , JB C = 2 H z ) , 5 . 4 1 ( d o f d o f d , I H , H f J _B D = 1 6 H z , J c D = 1 0 H z , = 9 H z ) . E x a c t m a s s c a l c d . f o r C1 4H2 4O S i : 2 3 6 . 1 5 9 6 ; f o u n d : 2 3 6 . 1 5 9 2 . 2 0 5 3 . 3 . 5 P r e p a r a t i o n o f 6 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) b i c y c l o -[ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n e I n a c c o r d a n c e w i t h g e n e r a l p r o c e d u r e B , t h e s i l y l e n o l e t h e r 1 8 7 ( 0 . 1 1 2 g , 0 . 4 7 4 m m o l ) w a s t h e r m o l y z e d a t 2 0 0 ° C f o r 2 h , b u t w i t h o u t s o l v e n t . D i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 7 9 - 8 2 ° C / 0 . 1 T o r r ) o f t h e t h e r m o l y s a t e f u r n i s h e d t h e s i l y l e n o l e t h e r 1 8 8 ( 0 . 1 1 0 g , > 9 7 % ) a s a c o l o u r l e s s o i l , w h i c h c o n s i s t e d o f a s i n g l e p e a k b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 3 0 4 0 , 3 0 0 0 , 1 6 1 5 , 1 2 4 5 , 8 8 0 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 4 , 0 . 1 6 ( s , s , 3 H e a c h , C H _3- S i - C H3) , 0 . 9 3 ( s , 9 H , ( C H3) 3S i - 0 - ) , 1 . 7 7 ( d , I H , H j , J_JZ = 9 . 5 H z ) , 2 . 0 6 -2 . 2 3 ( m , 3 H , Hc, Hx, Hz) , 2 . 4 6 - 2 . 5 4 ( m , 2 H , H ^ , Hp) , 5 . 1 1 ( d , I H , H ^ , J _ = 2 . 5 H z ) , 5 . 2 7 - 5 . 3 2 ( m , I H , H^) , 6 . 1 6 - 6 . 2 2 ( m , J —J J\ u I H , H „ ) . I r r a d i a t i o n a t 6 6 . 1 6 - 6 . 2 2 ( H „ ) c a u s e d t h e s i g n a l s a t 6 1 . 7 7 a n d 6 2 . 4 6 - 2 . 5 4 t o s h a r p e n , t h e s i g n a l s a t 6 2 . 0 6 -2 . 2 3 a n d 6 5 . 2 7 - 5 . 3 2 t o s i m p l i f y ; i r r a d i a t i o n a t 6 5 . 2 7 - 5 . 3 2 ( HD) c a u s e d t h e s i g n a l s a t 6 2 . 4 6 - 2 . 5 4 t o s h a r p e n , a n d t h e s i g n a l s a t 6 2 . 0 6 - 2 . 2 3 a n d 6 6 . 1 6 - 6 . 2 2 t o s i m p l i f y ; a n d i r r a d i a t i o n a t 6 5 . 1 1 ( HT) c a u s e d t h e s i g n a l s a t 6 1 . 7 7 a n d 6 2 . 4 6 - 2 . 5 4 t o s h a r p e n . E x a c t m a s s c a l c d . f o r C . . H . O S i : 2 3 6 . 1 5 9 6 ; f o u n d : 2 0 6 2 3 6 . 1 5 9 5 . 3 . 3 . 6 P r e p a r a t i o n o f B i c y c l o [ 3 . 2 . 1 ] o c t - 2 - e n - 6 - o n e A m i x t u r e o f t h e s i l y l e n o l e t h e r 1 8 8 ( 0 . 1 7 9 g , 0 . 7 5 7 m m o l ) , 5 % a q u e o u s h y d r o c h l o r i c a c i d ( 3 m L ) a n d T H F ( 3 m L ) w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r 6 h . S u b s e q u e n t l y , t h e r e a c t i o n m i x t u r e w a s d i l u t e d w i t h e t h e r a n d p o u r e d c a r e f u l l y i n t o s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e . T h e l a y e r s w e r e s e p a r a t e d , t h e a q u e o u s p h a s e w a s e x t r a c t e d t w i c e w i t h e t h e r , a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . C a r e f u l r e m o v a l o f s o l v e n t u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 4 0 - 4 5 ° C / 0 . 1 T o r r ) o f t h e r e s u l t a n t r e s i d u e a f f o r d e d 0 . 0 8 1 g ( 8 8 % ) o f t h e d e s i r e d k e t o n e 2 0 7 . T h i s m a t e r i a l , c o n s i s t i n g o f o n e c o m p o n e n t b y g l c ( O V - 1 7 , 8 0 ° C ) a n d t i c ( p e t r o l e u m e t h e r -e t h e r , 5 : 1 ) a n a l y s e s , a n d e x h i b i t e d i r ( f i l m ) : 3 0 2 5 , 1 7 3 0 , 1 6 4 0 , 7 3 5 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 2 . 0 3 ( d , I H , H j , JT„ = 1 1 H z ) , 2 . 0 8 ( o v e r l a p p i n g d o f d o f d , I H , H _ , J _ „ = 1 1 H z , Jw l 7 « J « 4 . 5 H z ) , 2 . 2 0 ( u n r e s o l v e d d , I H , Hv, J _v — r a —"KA A ~ C A = 1 8 H z ) , 2 . 2 9 ( d o f d , I H , H , JjY = 1 7 . 5 H z , J _ K Y = 5 H z ) , 2 0 7 2 . 3 4 (overlapping d of d of d, I H , H j , J j Y = 1 7 . 5 H z , J_ZJ = 3 H z , J _ „ = 1 . 5 H z ) , 2 . 4 3 (overlapping d of d of d of d, I H , — J K Hc, = 1 8 H z , ^ = 5 H z , ^ = ^ = 2 . 5 H z ) , 2 . 5 7 - 2 . 6 2 (m, I H , H _ ) , 2 . 7 3 - 2 . 8 0 (m, I H , H . J , 5 . 4 7 (overlapping d of d r J\ of d, I H , HD, = 9 . 5 H z , = J D X « 3 H z ) , 6 . 0 1 - 6 . 0 9 (m, I H , HE) . Exact mass calcd. for C g H j ^ O : 1 2 2 . 0 7 3 2 ; found: 1 2 2 . 0 7 3 2 . 3 . 3 . 7 Preparation of 6-exo-Vinylbicyclo [ 3 . 1 . 0 ]hex - 3-en - 2-one Following the procedure reported by Reich et a l . the b i c y c l i c ketone 1 7 9 was transformed into the enone 1 8 9 v i a a one-pot selenoxide elimination. Thus, to a cold ( - 7 8° C ) , s t i r r e d solution of LDA ( 4 . 9 1 mmol) i n anhydrous THF ( 1 0 mL), under an atmosphere of argon, was added a solution of the ketone 1 7 9 ( 0 . 5 0 0 g, 4 . 0 9 mmol) i n THF ( 7 mL). The resultant mixture was s t i r r e d at - 7 8 ° C for 0 . 5 h, after which time a solution of phenylselenenyl chloride ( 0 . 9 4 1 g, 4 . 9 1 mmol) i n THF ( 6 mL) was added dropwise v i a a syringe. A f t e r the mix-ture had been s t i r r e d at 0°C f o r 0 . 5 h, a solution of acetic acid ( 0 . 4 6 9 mL, 8 . 1 8 mmol) i n water ( 0 . 5 mL) was added. 2 0 8 S u b s e q u e n t l y , 3 0 % a q u e o u s h y d r o g e n p e r o x i d e ( 2 . 3 2 g , 2 0 . 5 m m o l ) w a s a d d e d d r o p w i s e t o t h e c o l d ( 0°C ) r e a c t i o n m i x t u r e a n d t h e m i x t u r e w a s s t i r r e d a t 0°C f o r 1 h . T h e r e a c t i o n m i x t u r e w a s d i l u t e d w i t h p e t r o l e u m e t h e r - e t h e r ( 1 : 1 ) a n d t h e n w a s p o u r e d i n t o s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e . T h e l a y e r s w e r e s e p a r a t e d , t h e a q u e o u s p h a s e w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r , a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . A f t e r s o l v e n t r e m o v a l b y a t m o s p h e r i c d i s t i l l a t i o n a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 7 8 - 8 3 ° C / 0 . 1 T o r r ) o f t h e r e s u l t a n t p a l e y e l l o w r e s i d u e , 0 . 4 3 1 g ( 8 8 % ) o f t h e e n o n e 1 8 9 w a s o b t a i n e d a s a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l t e n d e d t o d e c o m p o s e o n s t a n d i n g e v e n a t 4°C u n d e r a r g o n a n d i n t h e a b s e n c e o f l i g h t , a n d t h e r e f o r e w a s d i s t i l l e d j u s t p r i o r t o u s e . T h e e n o n e 1 8 9 e x h i b i t e d i r ( f i l m ) : 3 0 7 0 , 3 0 5 0 , 1 6 9 0 , 1 6 4 0 c m "1; 1 "H n m r ( 4 0 0 M H z , C D C 13) 6 2 . 1 7 ( o v e r l a p p i n g d o f d o f d , I H , HE, = 9 H z , JE G = JE F « 2 . 5 H z ) , 2 . 2 7 - 2 . 3 2 ( m , I H , Hp) , 2 . 5 9 ( o v e r l a p p i n g d o f d o f d , 1 H , HQ, J _F G = 4 H z , J ^ j = 2 . 5 H z , JE G = 3 H z ) , 5 . 0 6 ( d o f d , I H , Hc, = 1 0 H z , J _B C = 1 H z ) , 5 . 2 0 ( d o f d , I H , H g , J _B D = 1 7 H z , J _B C = 1 H z ) , 5 . 4 5 ( d o f d o f d , I H , HD, JB D = 1 7 H z , = 1 0 H z , = 9 H z ) , 5 . 7 0 ( d , I H , HT f JT T = 5 . 5 H z ) , 7 . 6 4 ( d o f d o f d , I H , H _ , JT T = 5 . 5 H z , J _T = 2 . 5 H z , J _ _ = 1 H z ) . I r r a d i a t i o n a t 6 7 . 6 4 ( HT) c a u s e d t h e s i g n a l a t & 2 . 2 7 - 2 . 3 2 t o s h a r p e n , t h e s i g n a l a t 6 2 . 5 9 t o c o l l a p s e t o a d o f d ( J = 4 H z , J = 3 H z ) a n d t h e s i g n a l a t 6 5 . 7 0 t o c o l l a p s e t o a s ; a n d i r r a d i a t i o n a t 209 6 2 .59 (H.,) c a u s e d t h e s i g n a l a t 6 2.17 t o c o l l a p s e t o a d o f G d ( J = 9 Hz, J = 2.5 H z ) , t h e s i g n a l a t 6 2.27-2.32 t o c o l l a p s e t o a d o f d ( J = 2.5 Hz, J = 1 H z ) , and t h e s i g n a l a t 6 7.64 t o c o l l a p s e t o a d o f d ( J = 5.5 Hz, J = 1 H z ) . E x a c t mass c a l c d . f o r CgHgO: 120.0575; f o u n d : 120.0574. 3.3.8 P r e p a r a t i o n o f B i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n - 8 - o n e A c c o r d i n g t o g e n e r a l p r o c e d u r e B, a s o l u t i o n o f t h e enone 189 (39.7 mg, 0.331 mmol) i n a n h y d r o u s benzene (3 mL) was h e a t e d a t 160°C f o r 4 h t o a f f o r d , a f t e r s o l v e n t r e m o v a l , a p a l e y e l l o w r e s i d u e . D i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 4 7 - 5 1 ° C / 0 . 1 T o r r ) o f t h i s m a t e r i a l p r o v i d e d t h e k e t o n e 190 (27.0 mg, 6 8 % ) , w h i c h e x h i b i t e d a s i n g l e s p o t by t i c ( p e t r o l e u m e t h e r - e t h e r , 1:1) and s i n g l e peak by g l c a n a l y s i s (OV-17, 80°C) ; i r ( f i l m ) : 3050, 1755, 1622, 680 cm" 1; X H nmr (400 MHz, CDC1 3) 6 2.45-2.53 (m, IH, H c o r H x ) , 2.73-2.82 (m, 3H, H_, H__, and H_ o r H v ) , 5.46-5.53 (m, IH, H_), 6.04 ( o v e r -l a p p i n g d o f d o f d o f d, IH, H , J\QE = 9 Hz, J _ K E = 7 Hz, J _ E X ? = 3 Hz, = 2 Hz) , 6.21 (d o f d , IH, H y, = 7 Hz, J p y = 3 H z ) , 6.69 (d o f d , IH, H_, J T V = 7 Hz, J__, = 3 Hz) . I r r a d i a t i o n a t 6 2.45-2.53 (H o r H ) c a u s e d t h e s i g n a l s a t 210 6 2.73-2.82, 6 5.46-5.53 and 6 6.04 to sharpen; and i r r a d i a t i o n at 6 6.69 (H ) caused the s i g n a l at 6 2.73-2.82 to sharpen and the signal at 6 6.21 to collapse to a d (J = 3 Hz). Exact mass calcd. for C gH gO: 120.0575; found: 120.0563. 3.3.9 Preparation of 4-exo-6-exo-Divinylbicyclo[3.1.0]hexan-2-one In accordance with a procedure reported by House et a l . , copper (I) catalyzed addition of v i n y l magnesium bromide to the enone 189 afforded the ketone 191. To a flame-dried, three-necked f l a s k equipped with a pressure-equalizing addition funnel, dry-ice condenser and argon gas i n l e t adaptor, was added magnesium turnings (0.0690 g, 2.84 mmol), anhydrous THF (4 mL) and a few c r y s t a l s of iodine. A solution, of v i n y l bromide (0.212 mL, 3.00 mmol) i n THF (2 mL) was added dropwise u n t i l the reaction had i n i t i a t e d , and thereafter at a rate to maintain mild r e f l u x . The r e s u l t i n g mixture was refluxed for 0.3 h and cooled to room temperature to give a c l e a r , yellow solution of v i n y l magnesium b r o m i d e . 1 0 9 , 1 1 ^ Half of t h i s solution was transferred v i a a syringe to another f l a s k and cooled to -30°C. To the cold (-30°C), e f f i c i e n t l y s t i r r e d s olution of v i n y l magnesium bromide, was added copper (I) 2 1 1 b r o m i d e - d i m e t h y l s u l f i d e c o m p l e x1 3 4 - 1 3 6 ( 3 . 0 m g , 0 . 0 1 3 4 m m o l ) a n d t h e r e s u l t a n t m i x t u r e w a s s t i r r e d a t - 3 0 ° C f o r 1 0 m i n , a f f o r d i n g a g r e e n s u s p e n s i o n . A s o l u t i o n o f t h e e n o n e 1 8 9 ( 0 . 0 9 4 7 g , 0 . 7 8 9 m m o l ) i n T H F ( 3 m L ) w a s a d d e d d r o p w i s e t o t h e r e a c t i o n m i x t u r e o v e r a p e r i o d o f 1 0 m i n . S u b s e q u e n t l y , t h e m i x t u r e w a s a l l o w e d t o w a r m t o 0°C o v e r a p e r i o d o f 4 0 m i n , d i l u t e d w i t h e t h e r a n d p o u r e d i n t o s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e . T h e a q u e o u s p h a s e w a s e x t r a c t e d t h o r -o u g h l y w i t h e t h e r a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d s u c c e s s i v e l y w i t h s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n -a t e , t w i c e w i t h b r i n e a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . C o n c e n t r a t i o n u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e - 8 5 ° C / 0 . 1 T o r r ) o f t h e y e l l o w r e s i d u e t h u s o b t a i n e d f u r n i s h e d t h e d e s i r e d k e t o n e 1 9 1 ( 0 . 0 9 3 2 g , 8 0 % ) a s a c l e a r , c o l o u r l e s s o i l , w h i c h w a s e s s e n t i a l l y p u r e b y g l c ( O V - 1 7 , 8 0 ° C ) a n d t i c ( p e t r o l e u m e t h e r - e t h e r , 5 : 1 ) a n a l y s e s . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) 3 0 5 0 , 1 7 1 8 , 1 6 3 5 , 9 9 0 , 9 1 5 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 1 . 8 7 - 1 . 9 4 ( m , 2 H , H „ , H _ ) , 1 . 9 7 ( o v e r l a p p i n g d o f d o f d , l H , HE, = 8 . 5 H z , J£ F A JE G = 4 H z ) , 2 . 0 4 ( o v e r l a p p i n g d o f d , I H , HG, JF G- = 5 H z , JE G = 4 H z ) , 2 . 3 6 ( d o f d , l H , H j , J _I Z = 1 8 . 5 H z , JT T = 8 H z ) , 3 . 0 2 ( o v e r l a p p i n g d o f d , I H , H _ , JT I, = —JL. J J —•u is. JI : R = 8 H z ) , 5 . 0 1 ( d o f d , I H , Hc, = 1 0 . 5 H z , J _B C = 1 H z ) , 5 . 0 4 ( o v e r l a p p i n g d o f d o f d , I H , H ^ , JR M = 1 0 H z , = ^ = 1 H z ) , 5 . 1 2 ( o v e r l a p p i n g d o f d o f d , I H , H ^ , J _K N = 1 7 . 5 H z , J^JJ = JJJJ = 1 H z ) , 5 . 1 5 ( d o f d o f d , I H , HB, JB D = 1 7 H z , JB C = 1 H z , J _B E < 1 H z ) , 5 . 3 6 ( d o f d o f d , I H , H ^ , J _B D = 1 7 2 1 2 H z , = 1 0 . 5 H z , J _ „ = 8 . 5 H z ) , 5 . 8 4 ( d o f d o f d , I H , —LD —Uti is. JT^T = 1 7 . 5 H z , J__„ = 1 0 H z , JT T, = 8 H z ) . I r r a d i a t i o n a t 6 — K N ' — K M ' — J K 3 . 0 2 ( H ) c a u s e d a s i g n a l i n t e n s i t y i n c r e a s e o f 2 2 % ( n u c l e a r O v e r h a u s e r e n h a n c e m e n t ) a t 6 2 . 3 6 , t h e s i g n a l a t 6 5 . 0 4 t o c o l l a p s e t o a d o f d ( J = 1 0 H z , J = 1 H z ) , t h e s i g n a l a t 6 5 . 1 2 t o c o l l a p s e t o a d o f d ( J = 1 7 . 5 H z , J = 1 H z ) , a n d t h e s i g n a l a t 6 5 . 8 4 t o c o l l a p s e t o a d o f d ( J = 1 7 . 5 H z , J = 1 0 H z ) . ; i r r a d i a t i o n a t 6 5 . 8 4 ( H ^ ) c a u s e d t h e s i g n a l a t 6 3 . 0 2 is. t o c o l l a p s e t o a d (J_ = 8 H z ) , t h e s i g n a l s a t 6 5 . 0 4 a n d 6 5 . 1 2 t o s i m p l i f y ; a n d i r r a d i a t i o n a t <5 5 . 3 6 ( H p ) c a u s e d t h e s i g n a l s a t 6 1 . 9 7 , 6 5 . 0 1 a n d 6 5 . 1 5 t o s i m p l i f y . E x a c t m a s s c a l c d . f o r Ci nH1 20 : 1 4 8 . 0 8 8 8 ; f o u n d : 1 4 8 . 0 8 8 6 . 3 . 3 . 1 0 P r e p a r a t i o n o f 2 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 4 - e x o -6 - e x o - d i v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e I n a c c o r d a n c e w i t h g e n e r a l p r o c e d u r e A , t h e k e t o n e 1 9 1 ( 0 . 1 4 0 g , 0 . 9 4 5 m m o l ) w a s t r a n s f o r m e d i n t o t h e s i l y l e n o l e t h e r 1 9 2 ( 0 . 2 4 0 g , > 9 7 % , a i r - b a t h d i s t i l l a t i o n t e m p e r a t u r e 1 3 0 - 1 3 5 ° C / 0 . 1 T o r r ) . T h i s m a t e r i a l p r o v e d t o b e e s s e n t i a l l y p u r e b y g l c a n a l y s i s ( S E - 5 4 , 8 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 3 0 6 0 , 3 0 1 5 , 1 6 1 8 c m- 1; 2H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 8 ( s , 6 H , 2 1 3 C H3- S i - C H3) , 0 . 9 5 ( s , 9 H , (CH_3) 3C - S i - 0 - ) , 1 . 2 3 ( o v e r l a p p i n g d o f d o f d , I H , H£, JD E = 8 . 5 H z , J£ F = 3 . 5 H z , J_EQ = 2 . 5 H z ) , 1 . 5 1 ( d o f d o f d , I H , HF, Jp G = 6 . 5 H z , J _E F = 3 . 5 H z , J _I p = 1 . 5 H z ) , 1 . 7 5 ( o v e r l a p p i n g d o f d o f d , I H , HQ, Jp G = 6 . 5 H z , J _E G = J^j = 2 . 5 H z ) , 3 . 1 3 ( u n r e s o l v e d d , I H , H j , J jK = 7 . 5 H z ) , 4 . 3 1 ( b r o a d s , I H , H j , = 5 H z ) , 4 . 8 8 ( d o f d , I H , H _ , Jo r, = 1 0 . 5 H z , JD„ = 1 . 5 H z ) , 4 . 9 4 ( d o f d o f d , I H , C —CD —rJC HM ' ^ K M = 1 0 H Z' ^MN = 2 H z' i Z j M = 1 H Z )' 5'0 3 ( d °f d' 1 H' HB, JB D = 1 7 H z , JB C = 1 . 5 H z ) , 5 . 0 5 (d o f d o f d, I H , H ^ , JK N = 1 7 H z , = 2 H z , J jN = 1 H z ) , 5 . 4 1 ( d o f d o f d , I H , HD, JB D = 1 7 H z , J ^ p = 1 0 . 5 H z , JD E = 8 . 5 H z ) , 5 . 7 5 ( d o f d o f d , I H , HR, JR N = 1 7 H z , JK M = 1 0 H z , JjK = 7 . 5 H z ) . I r r a d i a t i o n a t 6 4 . 3 1 ( H ^ ) c a u s e d t h e s i g n a l a t 6 1 . 5 1 t o c o l l a p s e t o a d o f d ( J = 6 . 5 H z , J = 3 . 5 H z ) , t h e s i g n a l a t 6 1 . 7 5 t o s h a r p e n a n d t h e s i g n a l a t 6 3 . 1 3 t o s h a r p e n t o a d o f d ( J = 7 . 5 H z , J = 2 . 5 H z ) ; i r r a d i a t i o n a t 6 3 . 1 3 ( H _ ) — — u c a u s e d t h e s i g n a l a t 6 1 . 5 1 t o s h a r p e n , t h e s i g n a l a t <5 1 . 7 5 t o c o l l a p s e t o a d o f d ( J = 6 . 5 H z , J = 2 . 5 H z ) , t h e s i g n a l a t 6 4 . 9 4 t o c o l l a p s e t o a d o f d ( J = 1 0 H z , J = 2 H z ) , t h e s i g n a l a t 6 5 . 0 5 t o c o l l a p s e t o a d o f d ( J = 1 7 H z , J = 2 H z ) , a n d t h e s i g n a l a t 6 5 . 7 5 t o c o l l a p s e t o a d o f d ( J = 1 7 H z , J = 1 0 H z ) ; a n d i r r a d i a t i o n a t 6 5 . 4 1 ( H p ) c a u s e d t h e s i g n a l a t 6 1 . 2 3 t o c o l l a p s e t o a b r o a d s , a n d t h e s i g n a l s a t 6 4 . 8 8 a n d 6 5 . 0 3 t o s i m p l i f y . E x a c t m a s s c a l c d . f o r C , , H _ , O S i : 2 6 2 . 1 7 5 3 ; f o u n d : 1 6 2 6 2 6 2 . 1 7 5 9 . 2 1 4 3.3.11 P r e p a r a t i o n o f 6 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 8 - e x o -v i n y l b i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n e F o l l o w i n g g e n e r a l p r o c e d u r e B , a s o l u t i o n o f t h e s i l y l e n o l e t h e r 1 9 2 ( 0 . 1 1 8 g , 0 . 4 5 0 m m o l ) i n d r y b e n z e n e ( 2 . 5 m L ) w a s h e a t e d a t 2 0 0 ° C f o r 5 h . A f t e r s o l v e n t r e m o v a l , d i s t i l -l a t i o n ( a i r - b a t h t e m p e r a t u r e 8 0 - 8 5 ° C / 0 . 1 T o r r ) o f t h e r e -s u l t a n t r e s i d u e p r o v i d e d t h e d e s i r e d m a t e r i a l 1 9 3 ( 0 . 1 0 5 g , 8 9 % ) , w h i c h e x h i b i t e d a s i n g l e p e a k b y g l c a n a l y s i s ( S E - 5 4 , 8 0 ° C ) a n d i r ( f i l m ) : 3 0 5 0 , 3 0 1 0 , 1 6 2 4 , 1 2 4 5 , 7 9 0 c m "1; XH n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 4 , 0 . 1 5 ( s , s , 3 H e a c h , C H 3 - S i - C H 3 ) , 0 . 9 2 ( s , 9 H , ( C H3)3C - S i - 0 - ) , 2 . 1 4 - 2 . 2 8 ( m , 2 H , H , H ) , 2 . 3 1 -2 . 3 5 ( m , I H , HF) , 2 . 3 8 ( d o f d , I H , H , J £ K = 6 H z , J ^R = 2 . 5 H z ) , 2 . 6 5 ( d , I H , H _ , JT [ 7 = 7 . 5 H z ) , 4 . 9 5 - 5 . 0 1 ( m , 2 H , H _ , X — X L J HM) , 5 . 0 8 ( d o f d o f d , I H , HN, J^z = 1 7 . 5 H z , = 2 H z , JT„ = 1 H z ) , 5 . 3 3 ( u n r e s o l v e d d , I H , H ^ , = 9 . 5 H z ) , —XJM u —Uti 6 . 0 3 ( d o f d o f d , I H , Hz, = 1 7 . 5 H z , = 1 0 H z , J = 7 . 5 H z ) , 6 . 2 5 ( d o f d o f d o f d , I H , H p , J^E = 9 . 5 H z , _ J p K = 6 H z , J ^ ^ , = = 2 H z ) . I r r a d i a t i o n a t 6 6 . 0 3 ( H „ ) c a u s e d —CE —EX L t h e s i g n a l a t 6 2 . 6 5 t o c o l l a p s e t o a s , t h e s i g n a l s a t 6 4 . 9 5 - 5 . 0 1 a n d 6 5 . 0 8 t o s i m p l i f y ; i r r a d i a t i o n a t 6 6 . 2 5 ( H ^ ) c a u s e d t h e s i g n a l a t 6 2 . 1 4 - 2 . 2 8 t o s i m p l i f y , t h e s i g n a l a t 2 1 5 6 2 . 3 8 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 2 . 5 H z ) , a n d t h e s i g n a l a t 6 5 . 3 3 t o s i m p l i f y ; a n d i r r a d i a t i o n a t 6 5 . 3 3 ( H p ) c a u s e d t h e s i g n a l a t 6 2 . 1 4 - 2 . 2 8 t o s i m p l i f y , t h e s i g n a l a t 6 2 . 3 1 - 2 . 3 5 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 4 . 5 H z ) , t h e s i g n a l a t 6 2 . 3 8 t o s h a r p e n a n d t h e s i g n a l a t 6 6 . 2 5 t o s i m p l i f y . E x a c t m a s s c a l c d . f o r C , - H _ _ O S i : 2 6 2 . 1 7 5 3 ; f o u n d : 1 6 2 6 2 6 2 . 1 7 5 2 . 3 . 3 . 1 2 P r e p a r a t i o n o f 8 - e x o - V i n y l b i c y c l o [ 3 . 2 . 1 ] o c t - 2 - e n - 6 - o n e n j 2 3 8 A m i x t u r e o f t h e s i l y l e n o l e t h e r 1 9 3 ( 0 . 0 9 5 5 g , 0 . 3 6 4 m m o l ) , 5 % a q u e o u s h y d r o c h l o r i c a c i d ( 9 m L ) a n d T H F ( 5 m L ) w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r 5 . 5 h . S u b s e q u e n t l y , t h e r e s u l t a n t m i x t u r e w a s d i l u t e d w i t h p e t r o l e u m e t h e r - e t h e r ( 1 : 1 ) a n d p o u r e d c a r e f u l l y i n t o s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e . T h e a q u e o u s p h a s e w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r , a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d w i t h b r i n e a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . C o n c e n t r a t i o n a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 6 3 - 6 7 ° C / 0 . 1 T o r r ) o f t h e r e s u l t a n t p a l e y e l l o w r e s i d u e a f f o r d e d 5 0 m g ( 9 3 % ) o f a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l , i d e n t i f i e d a s t h e d e s i r e d 216 ketone 238, was e s s e n t i a l l y pure by glc analysis (SE-54, 80°C). An a n a l y t i c a l sample, obtained by preparative glc (OV-17), exhibited i r (film): 3052, 3010, 1730, 1630, 998, 920, 730 cm"1; 1H nmr (400 MHz, CDC13) 6 2.20 (d of d, IH, H J f J ^ Y = 17.5 Hz, J T T = 2 Hz), 2.30 (overlapping d of d of d of d, IH, —x J H x, ^ = 18 Hz, J D X = 3.5 Hz, J £ X = J p x = 2 Hz), 2.43 (d of d, IH, H , J j V = 17.5 Hz, J R Y = 6 Hz), 2.52 (overlapping d of d of d of d, IH, H c, = 18 Hz, J^p = 5.5 Hz, = = 2 Hz), 2.59-2.63 (m, IH, H_), 2.66 (overlapping d of d, IH, H-, JVT, = 6.5 Hz, Jvv = 6 Hz), 2.91 (unresolved d of d, IH, JS. i —t\ti —IN. i H_, J T I 7 = 5.5 Hz, J T T = 2 Hz), 5.08 (overlapping d of d of d, X —xZ — X L J IH, H N, J N Z = 17.5 Hz, = 1.5 Hz, J I N = 1 Hz) , 5.14 (over-lapping d of d of d, IH, H M, Ji/[Z = 10.5 Hz, £ M N = 1.5 Hz, J_m = 1.5 Hz), 5.53 (overlapping d of d of d, IH, H^, J_^E = 9.5 Hz, = 2 Hz, J D X = 3.5 Hz), 5.90 (d of d of d, IH, H z, = 17.5 Hz, = 10.5 Hz, J T _ = 5.5 Hz), 6.14 (d of d of d of d, IH, H E, J D E = 9.5 Hz, J K E = 6.5 Hz, = £ E X = 2 Hz). Ir r a d i a t i o n at 6 5.90 (H„) caused the signal at S 2.91 to collapse to a broad s ( W j ^ = 5 Hz), the signal at 6 5.08 to collapse to an overlapping d of d (J = 1.5 Hz, J = 1 Hz), and the signal at 6 5.14 to collapse to an overlapping d of d (J = 1.5 Hz, J = 1 Hz); i r r a d i a t i o n at 6 2.91 (Hj) caused the s i g -nal at <5 2.6 6 to sharpen, the signal at 6 5.08 to collapse to to a d of d (J = 17.5 Hz, .J = 1.5 Hz), the signal at 6 5.14 to collapse to a d of d (J = 10.5 Hz, J = 1.5 Hz), and the signal at 6 5.90 to collapse to a d of d (J = 17.5 Hz, J = 10.5 Hz); i r r a d i a t i o n at 6 6.14 (H_) caused the signal at 2 1 7 .6' 2 . 3 0 t o c o l l a p s e t o a d o f d o f d ( J = 1 8 H z , J = 3 . 5 H z , J = 2 H z ) , t h e s i g n a l a t 6 2 . 5 2 t o c o l l a p s e t o a d o f d o f d ( J = 1 8 H z , J = 5 . 5 H z , J = 2 H z ) , t h e s i g n a l a t <5 2 . 6 6 t o c o l l a p s e t o a d ( J = 6 H z ) , t h e s i g n a l a t <5 2 . 9 1 t o s h a r p e n a n d t h e s i g n a l a t 6 5 . 5 3 t o c o l l a p s e t o a n o v e r l a p p i n g d o f d ( J = 3 . 5 H z , J = 2 H z ) ; a n d i r r a d i a t i o n a t 6 5 . 5 3 ( H p ) c a u s e d t h e s i g n a l a t 6 2 . 3 0 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 1 8 H z ) , t h e s i g n a l a t 6 2 . 5 2 t o c o l l a p s e t o a d o f d o f d ( J = 1 8 H z , J = 5 . 5 H z , J = 2 H z ) , a n d t h e s i g n a l a t 6 6 . 1 4 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 6 . 5 H z ) . E x a c t m a s s c a l c d . f o r C1 0H1 2 °: 1 4 8«0 8 8 8' ' f o u n d : 1 4 8 . 0 8 8 7 . 3.3.13 P r e p a r a t i o n o f 2 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 4 - e x o -c a r b e t h o x y m e t h y 1 - 6 - e x o - v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e A c c o r d i n g t o a p r o c e d u r e r e p o r t e d b y T a m u r a e_t a l , t h e e n o n e 1 8 9 w a s t r a n s f o r m e d i n t o t h e s i l y l e n o l e t h e r 1 9 4 . T h u s , a m i x t u r e o f t h e e n o n e 1 8 9 ( 0 . 1 5 7 g , 1 . 3 1 m m o l ) , t h e 1 4 3 s i l y l k e t e n e a c e t a l 2 1 0 ( 0 . 3 9 7 g , 1 . 9 6 m m o l ) a n d a n h y d r o u s a c e t o n i t r i l e ( 3 m L ) w a s s t i r r e d a t 5 5° C f o r 1 2 h . T h e r e a c t i o n m i x t u r e w a s c o n c e n t r a t e d a n d t h e r e s u l t a n t r e s i d u e w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 0 3 - 1 0 6 ° C / 0 . 1 T o r r ) t o 2 1 8 f u r n i s h 0 . 1 4 0 g ( 3 3 % ) o f a c l e a r , c o l o u r l e s s o i l w h i c h e x -h i b i t e d i r ( f i l m ) : 3 0 5 0 , 1 7 3 0 , 1 6 2 0 , 1 2 5 5 , 7 8 7 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 6 ( s , 6 H , C H3- S i - C H _3) , 0 . 9 4 ( s , 9 H , (CH_3) 3C - S i - 0 - ) , 1 . 2 1 ( o v e r l a p p i n g d o f d o f d , I H , H£, J _D E = 9 H z , JE F = 3 . 5 H z , JE G = 2 . 5 H z ) , 1 . 2 6 ( t , 3 H , C H _3C H2- 0 - , J = 7 . 5 H z ) , 1 . 4 9 ( o v e r l a p p i n g d o f d o f d , I H , H p , 3_FQ = 6 . 5 H z , J _ _ = 3 . 5 H z , J _ _ = 1 . 5 H z ) , 1 . 7 3 ( o v e r l a p p i n g d o f d o f —tut — r X d , I H , H , Jp G = 6 . 5 H z , JE G = J ^ j = 2 . 5 H z ) , 2 . 2 9 ( d o f d , I H , Hx, JX Y = 1 5 H z , J jX = 8 H z ) , 2 . 3 4 ( d o f d , I H , Hy, J _X Y = 1 5 H z , = 7 H z ) , 2 . 8 8 - 2 . 9 4 ( m , I H , H j ) , 4 . 1 4 ( q , 2 H , C H 3C H2- 0 - , J = 7 H z ) , 4 . 3 5 ( b r o a d s , I H , H j , w ^ = 5 H z ) , 4 . 8 7 ( d o f d , I H , Hc, JQD = 1 0 H z , J _ B C = 1 . 5 H z ) , 5 . 2 0 ( d o f d , I H , H _ , Jn r, = 1 7 H z , Jo r, = 1 . 5 H z ) , 5 . 4 0 ( d o f d o f d , I H , Hn, J - . ^ = 1 7 H z , J_ = 1 0 H z , J _ „ = 9 H z ) . I r r a d i a t i o n a t 6 4 . 3 5 ( H j ) c a u s e d t h e s i g n a l a t 6 1 . 4 9 t o s h a r p e n t o a d o f d ( J = 6 . 5 H z , J = 3 . 5 H z ) , a n d t h e s i g n a l a t 6 2 . 8 8 - 2 . 9 4 t o s h a r p e n t o a n o v e r l a p p i n g d o f d o f d ( J = 8 H z , J = 7 H z , J = 3 H z ) ; i r r a d i a t i o n a t 6 2 . 8 8 - 2 . 9 4 ( HT) c a u s e d t h e s i g n a l a t 6 1 . 7 3 t o c o l l a p s e t o a d o f d ( J = 6 . 5 H z , J = 2 . 5 H z ) , t h e s i g n a l a t 6 2 . 2 9 t o c o l l a p s e t o a d ( J = 1 5 H z ) , t h e s i g n a l a t 6 2 . 3 4 t o c o l l a p s e t o a d ( J = 1 5 H z ) a n d t h e s i g n a l a t 6 4 . 3 5 t o s h a r p e n ; i r r a d i a t i o n a t 6 5 . 4 0 ( HQ) c a u s e d t h e s i g n a l a t 6 1 . 2 1 t o c o l l a p s e t o a b r o a d s (w±/ 2 = 7 H z ) , a n d t h e s i g -n a l s a t 6 4 . 8 7 a n d 6 5 . 2 0 t o s i m p l i f y ; a n d i r r a d i a t i o n a t 6 1 . 7 3 ( H „ ) c a u s e d t h e s i g n a l a t 6 1 . 2 1 t o c o l l a p s e t o a d o f d ( J = 9 H z , J = 3 . 5 H z ) , t h e s i g n a l a t 6 1 . 4 9 t o c o l l a p s e t o a 2 1 9 d o f d ( J = 3 . 5 H z , J = 1 . 5 H z ) , t h e s i g n a l a t 6 2 . 8 8 - 2 . 9 4 t o c o l l a p s e t o a n o v e r l a p p i n g d o f d o f d ( J = 7 H z , J = 8 H z , J = 2 . 5 H z ) , a n d t h e s i g n a l a t 6 4 . 3 5 t o s h a r p e n . E x a c t m a s s c a l c d . f o r C1 8H3 ( )03S i : 3 2 2 . 1 9 6 4 ; f o u n d : 3 2 2 . 1 9 5 7 . 3.3.14 P r e p a r a t i o n o f 6 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 8 - e x o -( c a r b e t h o x y m e t h y l ) b i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n e F o l l o w i n g g e n e r a l p r o c e d u r e B, a s o l u t i o n o f t h e s i l y l e n o l e t h e r 1 9 4 ( 6 8 . 0 m g , 0 . 2 1 1 m m o l ) i n d r y b e n z e n e ( 3 m L ) w a s t h e r m o l y z e d a t 2 0 0 ° C f o r 2 . 5 h . S o l v e n t r e m o v a l a n d d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 1 3 1 - 1 3 5 ° C / 0 . 1 T o r r ) o f t h e r e s i d u e t h u s o b t a i n e d a f f o r d e d t h e d e s i r e d e n o l e t h e r 1 9 5 ( 6 6 . 7 m g , 9 8 % ) , w h i c h e x h i b i t e d a s i n g l e p e a k b y g l c a n a l y s i s ( S E - 5 4 , 8 0 ° C ) a n d i r ( f i l m ) : 3 0 5 0 , 3 0 1 0 , 1 7 2 5 , 1 6 2 0 , 7 9 0 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 4 , 0 . 1 6 ( s , s , 3 H e a c h , C H3- S i - C H3) , 0 . 9 2 ( s , 9 H , (CH_3) 3C - S i - 0 - ) , 1 . 2 6 ( t , 3 H , C H3C H20 - , J = 7 H z ) , 2 . 1 5 ( u n r e s o l v e d d , I H , Hc o r Hx, = 1 7 H z ) , 2 . 2 0 - 2 . 3 1 ( m , 3 H ) , 2 . 3 1 - 2 . 3 5 ( u n r e s o l v e d d o f d , I H , HR, £E K = 5 . 5 H z , = 2 . 5 H z ) , 2 . 4 3 - 2 . 5 2 ( m , 3 H , H „ , H „ ) , 4 . 1 3 ( q , 2 H , —-u i S jyi JM C H . C H „ 0 - , J = 7 H z ) , 4 . 9 7 ( d , I H , H _ , JT T. = 2 . 5 H z ) , 5 . 2 8 - 5 . 3 3 ' ( u n r e s o l v e d d , I H , H ^ , = 1 0 H z ) , 6 . 2 0 - 6 . 2 6 ( m , I H , H_) . 220 Ir r a d i a t i o n at 6 6.20-6.26 (H_) caused the signal at 6 2.15 to collapse to a d of d (J = 17 Hz, J = 3 Hz), the signal at 6 2.20-2.31 to simplify, the signal at 6.2.31-2.35 to collapse to a broad s, and the signal at 6 5.28-5.33 to collapse to a broad s; and i r r a d i a t i o n at 6 5.28-5.33 (H^) caused the signal at 6 2.15 to sharpen to a d (J = 17 Hz), the signal at 6 2.20-2.31 to simplify and the signal at 6 6.20-6.26 to collapse to an unresolved d (J = 5.5 Hz). Exact mass calcd. for C-^H^O^Si: 322.1964; found: 322.1963. 3.3.15 Preparation of 8-exo-Carbethoxymethylbicyclo[3.2.1]-A mixture of the s i l y l enol ether 195 (54.2 mg, 0.168 mmol), 5% aqueous hydrochloric acid (2 mL) and THF (2 mL) was s t i r r e d at room temperature for 5.5 h. Subsequently, the reaction mixture was diluted with ether and poured into satur-ated aqueous sodium bicarbonate. The aqueous layer was ex-tracted t h r i c e with ether, and the combined ethereal extracts were washed twice with brine and dried over anhydrous magnesium sul f a t e . Concentration afforded the desired ketone 239 (33 mg, 94%) as a clear, colourless o i l , which was homogeneous by oct-2-en-6-one 2 2 1 g l c ( O V - 1 7 , 8 0 ° C ) a n d t i c ( p e t r o l e u m e t h e r - e t h e r , 5 : 1 ) a n a l y s e s . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 0 0 , 1 7 4 0 , 1 7 3 0 , 1 6 2 5 c m "1; XH n m r ( 4 0 0 M H z , C D C 13) 6 1 . 2 7 ( t , 3 H , C H3C H20 - , J = 7 H z ) , 2 . 2 2 - 2 . 4 5 ( m , 6 H , Hx, Hj 7 H ^ , H ^ , Hy, Hp) , 2 . 5 4 ( o v e r l a p p i n g d o f d o f d o f d , I H , Hc, = 1 8 H z , J _ _ = 5 . 5 H z , J _ _ = 2 . 5 H z , JY,^ = 2 H z ) , 2 . 6 0 ( o v e r l a p p i n g d —Cr —CU —Cti o f d , I H , HK, JE K = 7 H z , JK Y = 6 H z , = 1 H z ) , 2 . 7 0 ( o v e r -l a p p i n g d o f d , I H , H j , Ji m = 7 . 5 H z , 3_m = 8 H z ) , 4 . 1 5 ( q , 2 H , C H3C H _20 - , J = 7 H z ) , 5 . 5 1 ( o v e r l a p p i n g d o f d o f d , I H , HD, = 9 . 5 H z , = 2 . 5 H z , J _D X = 3 . 5 H z ) , 6 . 1 1 ( o v e r -l a p p i n g d o f d o f d o f d , I H , H£, J _D E = 9 . 5 H z , J _E K = 7 H z , J _ , „ = 0 YV = 2 H z ) . I r r a d i a t i o n a t 6 5 . 5 1 ( H ^ ) c a u s e d t h e s i g -n a l a t <5 2 . 2 2 - 2 . 4 5 t o s i m p l i f y , t h e s i g n a l a t 6 2 . 5 4 t o c o l -l a p s e t o a d o f d o f d ( J = 1 8 H z , J = 5 . 5 H z , J = 2 H z ) a n d t h e s i g n a l a t 6 6 . 1 1 t o c o l l a p s e t o a d o f d ( J = 7 H z , J = 2 H z ) ; i r r a d i a t i o n a t 6 6 . 1 1 ( H ) c a u s e d t h e s i g n a l a t 6 2 . 2 2 -2 . 4 5 t o s i m p l i f y , t h e s i g n a l a t 6 2 . 5 4 t o c o l l a p s e t o a d o f d o f d ( J = 1 8 H z , J = 5 . 5 H z , J = 2 . 5 H z ) , t h e s i g n a l a t 6 2 . 6 0 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 6 H z ) , a n d t h e s i g n a l a t 6 5 . 5 1 t o c o l l a p s e t o a b r o a d s ; a n d i r r a d i a t i o n a t 6 2 . 7 0 ( H ^ ) c a u s e d t h e s i g n a l a t 6 2 . 2 2 - 2 . 4 5 t o s i m p l i f y , a n d t h e s i g n a l s a t 6 2 . 6 0 a n d 6 6 . 1 1 t o s h a r p e n . E x a c t m a s s c a l c d . f o r C , ^ H . ^ O _ : 2 0 8 . 1 0 9 9 ; f o u n d : 1 2 1 6 3 2 0 8 . 1 0 9 6 . 2 2 2 3.3.16 Preparation of Ethyl (E)-4-methyl-2-pentenoate 144 The procedure described by I s l e r et al., and l a t e r by 146 House and Rasmussen was followed. Thus, to a s t i r r e d 147 solution of carbethoxymethylenetriphenylphosphorane (40.0 g, 114.9 mmol) i n anhydrous dichloromethane (100 mL), under an atmosphere pf argon, was added dropwise, v i a a syringe, isobutyraldehyde (10.4 mL, 114.9 mmol), and the resultant mixture was refluxed for 4 h. Most of the solvent was re-moved by d i s t i l l a t i o n at atmospheric pressure leaving a white residue, which was t r i t u r a t e d with pentane and the resultant mixture was f i l t e r e d through a short column of s i l i c a g e l . Careful concentration of the eluate and d i s t i l l a t i o n (air-bath temperature 45-50°C/0.1 Torr) of the yellow residue thus ob-tained, furnished the ester 255 (15.0 g, 92%) as an odoriferous, colourless o i l . This material, which consisted of one compon-ent by glc (OV-17, 80°C) and t i c (petroleum ether-ether, 9:1) analyses, exhibited i r ( f i l m ) : 3050, 1715, 1648, 1308, 995 cm"1; XH nmr (80 MHz, CDC13) 6 1.06 (d, 6H, CH3-CH-CH_3, J = 7 Hz) , 1.30 (t, 3H, CH3CH20-, J = 7 Hz), 2.46 (overlapping d of d of septet, IH, Hfi, J B C = 7 Hz, £ B D = 1 Hz, J = 7 Hz), 4.20 (q, 2H, CH3CH20-, J = 7 Hz), 5.76 (d of d, IH, H^, JQD = 16 Hz, 2 2 3 JB D = 1 H z ) , 6 . 9 5 ( d o f d , 1 H , Hc, = 1 6 H z , J _B C = 7 H z ) . E x a c t m a s s c a l c d . f o r CoHn. 0 „ : 1 4 2 . 0 9 9 4 ; f o u n d : o 14 Z 1 4 2 . 0 9 9 1 . 3 . 3 . 1 7 P r e p a r a t i o n o f ( E ) - 4 - M e t h y l - 2 - p e n t e n - l - o l T o a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f t h e e s t e r 2 5 5 ( 1 . 0 0 g , 7 . 0 4 m m o l ) i n a n h y d r o u s p e n t a n e ( 1 5 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d d r o p w i s e v i a a s y r i n g e , a h e x a n e s o l u t i o n o f 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 7 . 6 m m o l ) . T h e r e s u l t a n t m i x t u r e w a s s t i r r e d a t - 7 8 ° C f o r 1 h a n d t h e n a t 0°C f o r a n a d d i t i o n a l h o u r . S u b s e q u e n t l y , s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e ( 1 m L ) w a s a d d e d t o t h e c o l d ( 0° C ) r e a c t i o n m i x t u r e , w h i c h w a s a l l o w e d t o w a r m t o r o o m t e m p e r -a t u r e a n d t h e n w a s p o u r e d i n t o 5 % a q u e o u s h y d r o c h l o r i c a c i d . T h e a q u e o u s p h a s e w a s w a s h e d t w i c e w i t h 5 % a q u e o u s h y d r o -c h l o r i c a c i d , b r i n e , s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e a n d b r i n e , a n d d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e . S o l v e n t r e m o v a l b y d i s t i l l a t i o n a t a t m o s p h e r i c p r e s s u r e f u r n i s h e d t h e a l l y l i c a l c o h o l 2 5 6 ( 0 . 6 6 8 g , 9 5 % ) a s a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d a s i n g l e p e a k b y g l c a n a l y s i s ( O V - 1 7 , 6 0 ° C ) a n d i r ( f i l m ) : 3 3 0 0 ( b r o a d ) , 3 0 1 0 , 1 6 6 0 , 9 7 0 c m "1; XH n m r ( 8 0 M H z , C D C 13) 6 1 . 0 0 ( d , 6 H , C H _3- C H - C H3, J = 7 H z ) , 2 2 4 1 . 4 7 ( b r o a d s , I H , - O H , D20 e x c h a n g e a b l e ) , 2 . 1 0 - 2 . 6 0 ( m , I H , C H3- C H - C H3) , 4 . 0 4 - 4 . 1 7 ( m , 2 H , -CH_2-OH) , 5 . 3 8 - 5 . 8 7 ( m , 2 H , H - C = C - H ) . E x a c t m a s s c a l c d . f o r C ^ Hn_ 0 : 1 0 0 . 0 8 8 8 ; f o u n d : 1 0 0 . 0 8 8 7 . 6 1 2 3 . 3 . 1 8 P r e p a r a t i o n o f ( E ) - 4 - M e t h y l - 2 - p e n t e n a l T o a n e f f i c i e n t l y s t i r r e d s o l u t i o n o f t h e a l l y l i c a l c o h o l 2 5 6 ( 0 . 2 0 0 g , 2 . 0 0 m m o l ) i n a n h y d r o u s d i c h l o r o m e t h a n e ( 1 0 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d p y r i d i n i u m 1 5 1 c h l o r o c h r o m a t e ( 3 . 2 0 m m o l ) s u p p o r t e d o n a l u m i n a . T h e i n i t i a l l y o r a n g e s u s p e n s i o n b e c a m e b l a c k a l m o s t i m m e d i a t e l y o n a d d i t i o n o f t h e o x i d i z i n g a g e n t . S u b s e q u e n t l y , t h e r e -s u l t a n t m i x t u r e w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r 3 h a n d t h e n w a s f i l t e r e d t h r o u g h a s h o r t c o l u m n o f s i l i c a g e l ( 7 0 -2 3 0 m e s h ) . T h e b r o w n r e s i d u e a t t h e h e a d o f t h e c o l u m n w a s r i n s e d t h o r o u g h l y w i t h a n h y d r o u s e t h e r a n d t h e s o l v e n t w a s r e m o v e d f r o m t h e f i l t r a t e b y d i s t i l l a t i o n a t a t m o s p h e r i c p r e s s u r e , l e a v i n g a b r o w n o i l . T h i s m a t e r i a l w a s s u b j e c t e d t o f l a s h d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e = 3 0 ° C / 0 . 1 T o r r ) , w h i c h a f f o r d e d t h e a l l y l i c a l d e h y d e 2 5 7 ( 0 . 1 9 4 g , > 9 8 % ) a s a c l e a r , c o l o u r l e s s o i l . T h e o i l w a s e s s e n t i a l l y p u r e b y g l c 2 2 5 analysis ( O V - 1 7 , 8 0 ° C ) and exhibited i r (film): 3 0 1 0 , 2 7 8 0 , 2 7 0 0 , 1 6 7 5 , 1 6 2 2 , 9 8 0 cm"1; 1H nmr ( 8 0 M H z , C D C 13) 6 1 . 1 3 (d, 6 H , C H0- C H - C H0, J = 7 H z ) , 2 . 3 7 - 2 . 8 5 (m, I H , H _ ) , 6 . 1 0 (d of —3 — J — a d of d, I H , HD, = 1 6 H z , = 8 H z , Jf i D = 1 H z ) , 6 . 8 6 (d of d, I H , Hc, = 1 6 H z , JB C = 7 H z ) , 9 . 5 5 (d, I H , H£, = 8 H z ) . Exact mass calcd. for C , Hi n0 : 9 8 . 0 7 3 2 ; found: 9 8 . 0 7 3 2 . 6 1 0 3 . 3 . 1 9 P r e p a r a t i o n o f E t h y l ( 2 E ) , ( 4 E ) - 6 - m e t h y l - 2 , 4 - h e p t a -4 . 1 5 2 d i e n o a t e H B 'Me 1 4 4 The procedure by I s l e r et a l . and l a t e r by House and 1 4 6 Rasmussen was followed. Thus, to a s t i r r e d solution of 1 -1 4 7 carbethoxymethylenetriphenylphosphorane ( 6 . 3 2 g, 1 8 . 1 mmol) in anhydrous dichloromethane ( 1 5 mL), under an atmosphere of argon, was added a solution of the a l l y l i c aldehyde 2 5 7 ( 1 . 7 8 g, 1 8 . 1 mmol) i n dichloromethane ( 4 mL), and the resultant mixture was refluxed for 5 h. Subsequently, the solvent was removed by d i s t i l l a t i o n at atmospheric pressure, and the s t i l l -pot residue was t r i t u r a t e d with pentane and then was f i l t e r e d through a layer of s i l i c a gel ( 7 0 - 2 3 0 mesh). After the f i l -t rate was concentrated, Kugelrohr d i s t i l l a t i o n (air-bath 2 2 6 t e m p e r a t u r e 6 8 - 7 5 ° C / 0 . 1 T o r r ) o f t h e y e l l o w o i l t h u s o b t a i n e d , g a v e 1 . 3 4 g ( 4 4 % ) o f a c l e a r , c o l o u r l e s s o i l , w h i c h w a s o f > 9 9 % p u r i t y b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) a n d c o n s i s t e d o f a s i n g l e c o m p o n e n t b y t i c a n a l y s i s ( p e t r o l e u m e t h e r - e t h e r , 1 : 1 ) . T h i s m a t e r i a l , i d e n t i f i e d a s t h e e s t e r 2 5 8 , e x h i b i t e d i r ( f i l m ) : 3 0 1 0 , 1 7 0 0 , 1 6 3 5 , 1 6 1 2 , 1 0 0 5 c m "1; n m r ( 4 0 0 M H z , C D C 13) 6 1 . 0 5 ( d , 6 H , C H3- C H - C H _3, J = 7 H z ) , 1 . 3 0 ( t , 3 H , C H _3C H20 - , J = 7 H z ) , 2 . 4 3 ( o v e r l a p p i n g d o f s e p t e t , I H , H g , JB C = 6 H z , J = 7 H z ) , 4 . 2 2 ( q , 2H-, C H3C H20 - , J = 7 H z ) , 5 . 8 0 ( d , I H , Hp, J _E p = 1 4 H z ) , 6 . 0 9 ( d o f d , I H , Hc, = 1 5 H z , JB C = 6 H z ) , 6 . 1 3 ( d o f d , I H , HD, = 1 5 H z , J _D E = 9 H z ) , 7 . 2 6 ( d o f d , I H , H ^ , J _ _ = 1 4 H z , J _ _ = 9 H z ) . I n t h e f o l l o w i n g d e c o u p l i n g e x p e r i m e n t s , t h e r e g i o n 6 5 . 5 - 7 . 5 w a s o b s e r v e d : i r r a d i a t i o n a t 6 2 . 4 3 ( H ) c a u s e d t h e s i g n a l a t 6 6 . 0 9 t o c o l l a p s e t o a d ( J = 1 5 H z ) ; i r r a d i a t i o n a t <5 7 . 2 6 ( H „ ) c a u s e d t h e s i g n a l a t 6 5 . 8 0 t o c o l l a p s e t o a s , a n d t h e s i g n a l a t 6 6 . 1 3 t o c o l l a p s e t o a d ( J = 1 5 H z ) ; a n d i r r a d i a t i o n a t 6 5 . 8 0 ( H ) c a u s e d t h e s i g n a l a t 6 7 . 2 6 t o c o l l a p s e t o a r d ( J = 9 H z ) . E x a c t m a s s c a l c d . f o r CX UH1 6 ° 2: x 6 8-± l 50 ; f o u n d : 1 6 8 . 1 1 5 1 . 2 2 7 3 . 3 . 2 0 P r e p a r a t i o n o f ( 2 E J , ( 4 E ) - 6 - M e t h y l - 2 , 4 - h e p t a d i e n - l - o l T o a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f t h e e s t e r 2 5 8 ( 0 . 3 8 6 g , 2 . 3 0 m m o l ) i n a n h y d r o u s p e n t a n e ( 7 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d d r o p w i s e v i a a s y r i n g e , a h e x a n e s o l u t i o n o f 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 ( 5 . 0 5 m m o l ) . T h e r e s u l t a n t m i x t u r e w a s s t i r r e d a t - 7 8 ° C f o r 1 h a n d t h e n a t 0°C f o r a n o t h e r 3 h . S u b s e q u e n t l y , s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e ( 1 m L ) w a s a d d e d t o t h e c o l d ( 0° C ) r e a c t i o n m i x t u r e , w h i c h w a s a l l o w e d t o w a r m t o r o o m t e m p e r a t u r e o v e r a p e r i o d o f 0 . 5 h . T h e r e a c t i o n m i x t u r e w a s d i l u t e d w i t h e t h e r , p o u r e d i n t o 5 % a q u e o u s h y d r o c h l o r i c a c i d a n d t h e l a y e r s w e r e s e p a r a t e d . T h e o r g a n i c l a y e r w a s w a s h e d t w i c e w i t h 5 % a q u e o u s h y d r o c h l o r i c a c i d , b r i n e , s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e a n d b r i n e , a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . A f t e r s o l v e n t r e m o v a l b y d i s t i l l a t i o n a t a t m o s p h e r i c p r e s s u r e , K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 6 0 - 6 5aC / 0 . 1 T o r r ) o f t h e r e s i d u a l o i l a f f o r d e d t h e a l c o h o l 2 5 9 ( 0 . 2 8 0 g , > 9 6 % ) a s a c l e a r , c o l o u r l e s s l i q u i d . T h i s m a t e r i a l w a s s h o w n t o c o n s i s t o f o n e c o m p o n e n t b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 3 3 0 0 ( b r o a d ) , 3 0 5 0 , 1 6 5 0 , 9 9 0 c m- 1; 2 2 8 n m r ( 2 7 0 M H z , C D C 13) 6 1 . 0 0 ( d , 6 H , C H _3- C H - C H _3, J = 7 H z ) , 1 . 5 7 ( b r o a d s , I H , - O H ) , 2 . 3 4 ( d o f s e p t e t , I H , H _ , J _ _ = 7 H z , J = 7 H z ) , 4 . 1 5 ( d , 2 H , H _ , J _ _ = 6 H z ) , 5 . 6 8 ( d o f d , — VJ — r o I H , Hc, = 1 5 H z , JB C = 7 H z ) , 5 . 7 4 ( d o f t , I H , Hp, J£ F = 1 5 H z , JF G = 6 H z ) , 6 . 0 2 ( d o f d , I H , H ^ , = 1 5 H z , = 1 0 H z ) , 6 . 2 2 ( d o f d , I H , H „ , J„„ = 1 5 H z , J _ _ = 1 0 H z ) . i l —h,r — U-fci F o r t h e f o l l o w i n g d e c o u p l i n g e x p e r i m e n t , t h e r e g i o n 6 5 . 5 - 6 . 5 w a s o b s e r v e d : i r r a d i a t i o n a t 6 2 . 3 4 (H_.) c a u s e d t h e s i g n a l hi a t 6 5 . 6 8 t o c o l l a p s e t o a d ( J = 1 5 H z ) , a n d t h e s i g n a l a t 6 6 . 0 2 t o s h a r p e n . E x a c t m a s s c a l c d . f o r CoH1 / t0 : 1 2 6 . 1 0 4 5 ; f o u n d : 1 2 6 . 1 0 4 3 . 3 . 3 . 2 1 P r e p a r a t i o n o f ( 2 E ) , ( 4 E ) - l - B r o m o - 6 - m e t h y l - 2 , 4 - h e p t a d i e n e F o l l o w i n g t h e p r o c e d u r e d e s c r i b e d b y M i l l e r , t h e a l l y l i c a l c o h o l 2 5 9 w a s c o n v e r t e d i n t o t h e c o r r e s p o n d i n g a l l y l i c b r o m i d e 2 4 4 . T h u s , t o a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n o f t h e a l c o h o l 2 5 9 ( 1 . 0 0 g , 7 . 9 3 m m o l ) a n d p y r i d i n e ( 3 2 y L , 0 . 4 0 m m o l ) i n a n h y d r o u s e t h e r ( 2 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d d r o p w i s e a s o l u t i o n o f p h o s p h o r u s t r i b r o m i d e ( 0 . 2 3 m L , 3 . 2 m m o l ) i n e t h e r ( 1 m L ) . T h e r e s u l t a n t m i x t u r e w a s s t i r r e d a t 0°C f o r 4 h a n d t h e n w a s p o u r e d i n t o i c e -w a t e r . T h e o r g a n i c p h a s e w a s w a s h e d s u c c e s s i v e l y w i t h b r i n e , 2 2 9 5 % a q u e o u s s o d i u m b i c a r b o n a t e a n d b r i n e , a n d d r i e d o v e r a n -h y d r o u s m a g n e s i u m s u l f a t e . A f t e r c a r e f u l c o n c e n t r a t i o n u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) a n d f l a s h d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e = 3 0 ° C / 0 . 1 T o r r ) , 1 . 1 7 g ( 7 8 % ) o f a p a l e y e l l o w o i l w a s o b t a i n e d . T h i s m a t e r i a l , i d e n t i f i e d a s t h e b r o m i d e 2 4 4 , d a r k e n e d r a p i d l y o n s t a n d i n g a t r o o m t e m p e r a t u r e . I t w a s t h e r e f o r e d i s t i l l e d i m m e d i a t e l y p r i o r t o u s e . A s a m p l e o f t h e b r o m i d e 2 4 4 e x h i b i t e d i r ( f i l m ) : 3 0 1 0 , 1 6 4 3 , 9 9 0 c m "1; 1H n m r ( 8 0 M H z , C D C 13) 6 1 . 0 0 ( d , 6 H , C H3- C H - C H _3, J = 7 H z ) , 2 . 1 0 - 2 . 6 0 ( m , I H , C H3- C H - C H3) , 4 . 0 4 ( d , 2 H , - C H ^ B r , J = 8 H z ) , 5 . 5 5 - 6 . 5 0 ( m , 4 H , v i n y l i c p r o t o n s ) . 7 9 E x a c t m a s s c a l c d . f o r C g H ^ - j B r : 1 8 8 . 0 2 0 0 ; f o u n d : 1 8 8 . 0 2 0 0 . 3 . 3 . 2 2 P r e p a r a t i o n o f M e t h y l ( 6 E ) , ( 8 E ) - 1 0 - m e t h y l d o d e c a - 6 , 8 -d i e n - 3 - o n e 2 4 5 I n a c c o r d a n c e w i t h t h e p r o c e d u r e r e p o r t e d b y H u c k i n a n d W e i l e r ,1 5 5 t h e d i a n i o n o f m e t h y l a c e t o a c e t a t e w a s a l k y l a t e d w i t h t h e a l l y l i c b r o m i d e 2 4 4 . T o a c o l d ( - 7 8 ° C ) , s t i r r e d s u s p e n s i o n o f s o d i u m h y d r i d e ( 0 . 1 5 g , 6 . 8 m m o l ) i n a n h y d r o u s T H F ( 3 0 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d a s o l u t i o n o f m e t h y l a c e t o a c e t a t e ( 0 . 7 1 9 g , 6 . 1 9 m m o l ) i n T H F 2 3 0 ( 2 m L ) . T h e r e s u l t a n t m i x t u r e w a s s t i r r e d a t 0°C f o r 1 0 m i n t o f u r n i s h a p a l e g r e y s u s p e n s i o n , t o w h i c h w a s a d d e d a h e x a n e s o l u t i o n o f n - b u t y l l i t h i u m ( 6 . 8 1 m m o l ) . E f f i c i e n t s t i r r i n g a t 0°C w a s m a i n t a i n e d f o r a n o t h e r 1 5 m i n , a f t e r w h i c h t i m e a g r e e n m i x t u r e w a s o b t a i n e d . S u b s e q u e n t l y , a s o l u t i o n o f t h e a l l y l i c b r o m i d e 2 4 4 ( 1 . 1 7 g , 6 . 1 9 m m o l ) i n T H F ( 3 m L ) w a s a d d e d a n d t h e r e s u l t i n g m i x t u r e w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r 2 h . T h e r e a c t i o n m i x t u r e w a s d i l u t e d w i t h e t h e r a n d t h e n w a s p o u r e d c a r e f u l l y i n t o 5 % a q u e o u s h y d r o c h l o r i c a c i d , m o r e o f w h i c h w a s a d d e d u n t i l t h e a q u e o u s l a y e r w a s n o l o n g e r b a s i c t o l i t m u s p a p e r . A f t e r t h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r , t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d t h r i c e w i t h b r i n e a n d d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e . S o l -v e n t r e m o v a l u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) a n d s u b j e c t i o n o f t h e r e s u l t a n t r e s i d u e t o f l a s h c o l u m n c h r o m a t o -g r a p h y ( 1 0 0 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 4 5 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h y l a c e t a t e , 5 : 1 ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s , t h e g - k e t o e s t e r 2 4 5 ( 0 . 7 4 3 g , 5 3 % ) a s a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 0 0 , 1 7 4 0 , 1 7 1 0 , 1 6 5 0 , 1 6 2 0 , 9 9 3 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 1 . 0 0 ( d , 6 H , C H _3- C H - C H _3, J = 7 H z ) , 2 . 3 1 ( o v e r l a p p i n g d o f s e p t e t , I H , H ' , J = 7 H z , Jn r i = 7 H z ) , 2 . 3 7 ( o v e r l a p p i n g d o f t , 2 H , H„, J„„ — — r 5 l _ Cj — r CJ = 7 H z , J = 7 H z ) , 2 . 6 5 ( t , 2 H , 0 = C - C H _2- C H2- , J = 7 H z ) , 3 . 4 6 ( s , 2 H , 0 = C - C H2- C 02C H3) , 3 . 7 6 ( s , 3 H , - C 02C H _3) , 5 . 5 7 2 3 1 ( o v e r l a p p i n g d o f t , I H , H , J _E F = 1 4 . 5 H z , J_FQ = 7 H z ) , 5 . 6 1 ( d o f d , I H , Hc, = 1 5 H z , JB C = 7 H z ) , 5 . 9 8 ( d o f d , I H , HD, = 1 5 H z , J^E = 1 0 H z ) , 6 . 0 6 ( d o f d , I H , H ^ , J _ E F = 1 4 . 5 H z , = 1 0 H z ) . I r r a d i a t i o n a t 6 2 . 6 5 c a u s e d t h e s i g -—DIJ n a l a t 6 2 . 3 7 t o c o l l a p s e t o a d ( J = 7 H z ) . E x a c t m a s s c a l c d . f o r C13H2 0 ° 3: 2 2 4 . 1 4 1 2 ; f o u n d : 2 2 4 . 1 4 1 1 . 3.3.23 P r e p a r a t i o n o f M e t h y l ( 6 E ) , ( 8 E ) - 2 - d i a z o - 1 0 - m e t h y l -d o d e c a - 6 , 8 - d i e n - 3 - o n e 2 4 6 I n a c c o r d a n c e w i t h t h e p r o c e d u r e r e p o r t e d b y R e g i t z , t h e 8 - k e t o e s t e r 2 4 5 w a s t r a n s f o r m e d i n t o t h e d i a z o k e t o e s t e r 2 4 6 . T o a s t i r r e d s o l u t i o n o f t h e 3 - k e t o e s t e r 2 4 5 ( 0 . 2 0 0 g , 0 . 8 9 2 m m o l ) a n d p _ - t o l u e n e s u l f o n y l a z i d e ( 0 . 1 7 6 g , 0 . 8 9 2 m m o l ) i n a n h y d r o u s a c e t o n i t r i l e ( 4 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d t r i e t h y l a m i n e ( 0 . 1 2 4 m L , 0 . 8 9 2 m m o l ) , a n d t h e r e s u l t a n t m i x t u r e w a s s t i r r e d a t r o o m t e m p e r a t u r e . R e a c t i o n p r o g r e s s w a s m o n i t o r e d b y t i c ( p e n t a n e - e t h e r , 4 : 1 ) , w h i c h i n d i c a t e d t h a t a l l o f t h e s t a r t i n g m a t e r i a l h a d b e e n c o n s u m e d a f t e r 2 4 h . R e m o v a l o f s o l v e n t u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) f u r n i s h e d a y e l l o w r e s i d u e , w h i c h w a s d i s s o l v e d i n a m i n i m u m a m o u n t o f e t h e r . P e n t a n e w a s a d d e d t o t h i s s o l u t i o n 2 3 2 u n t i l n o f u r t h e r s o l i d m a t e r i a l p r e c i p i t a t e d . T h e s l u r r y t h u s o b t a i n e d w a s f i l t e r e d t h r o u g h a l a y e r o f C e l i t e a n d t h e f i l -t r a t e w a s c o n c e n t r a t e d t o g i v e a y e l l o w o i l . D i s s o l u t i o n o f t h e o i l i n p e n t a n e a n d f i l t r a t i o n o f t h e p e n t a n e s o l u t i o n w a s r e p e a t e d u n t i l n o f u r t h e r s o l i d p r e c i p i t a t e d . T h e v i s c o u s , y e l l o w s y r u p o b t a i n e d a f t e r c o n c e n t r a t i o n o f t h e f i l t r a t e , d i s p l a y e d a s i n g l e s p o t b y t i c a n a l y s i s ( p e t r o l e u m e t h e r -e t h e r , 5 : 1 ) a n d w a s i d e n t i f i e d a s t h e d e s i r e d d i a z o k e t o e s t e r 2 4 6 ( 0 . 2 1 6 g , 9 7 % ) . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 0 0 , 2 1 2 0 , 1 7 1 5 , 1 6 5 0 , 1 3 1 0 , 9 9 5 c m "1; XH n m r ( 8 0 M H z , C D C 13) 6 1 . 0 0 ( d , 6 H , C H3- C H - C H3, J = 7 H z ) , 2 . 1 0 - 2 . 6 5 ( m , 3 H , C H3- C H - C H3, - C H2- C = C - ) , 2 . 9 4 ( t , 2 H , 0 = C - C H2~ , J = 7 H z ) , 3 . 8 5 ( s , 3 H , - C O „ C H _ ) , 5 . 3 0 - 6 . 3 0 ( m , 4 H , o l e f i n i c p r o t o n s ) . 3 . 3 . 2 4 P r e p a r a t i o n o f l - C a r b o m e t h o x y - 6 - e x o - [ ( E ) - 3 - m e t h y l - l -b u t e n y l ] b i c y c l o [ 3 . 1 . 0 ] h e x a n - 2 - o n e T h e p r o c e d u r e d e s c r i b e d b y H u d l i c k y e t a _ l . w a s f o l l o w e d f o r t h e c o n v e r s i o n o f t h e d i a z o k e t o e s t e r 2 4 6 t o t h e b i c y c l i c B - k e t o e s t e r . T h u s , t o a s t i r r e d s u s p e n s i o n o f C u ( a c a c ) 2 " H ^1 ( 2 7 m g , 0 . 1 0 m m o l ) i n r e f l u x i n g , a n h y d r o u s b e n z e n e ( 1 6 m L ) , 'Z 2 4 7 9 8 2 3 3 u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d d r o p w i s e a s o l u t i o n o f t h e d i a z o k e t o e s t e r 2 4 6 ( 0 . 1 8 0 g , 0 . 7 2 4 m m o l ) i n b e n z e n e ( 3 m L ) . T h e r e s u l t i n g m i x t u r e w a s r e f l u x e d f o r 6 h , c o o l e d t o r o o m t e m p e r a t u r e a n d f i l t e r e d t h r o u g h a l a y e r o f C e l i t e . C o n c e n t r a t i o n o f t h e c l e a r , g r e e n f i l t r a t e u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) f u r n i s h e d a d a r k y e l l o w o i l , w h i c h w a s s u b j e c t e d t o p r e p a r a t i v e t i c ( s i l i c a g e l , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h y l a c e t a t e , 5 : 1 ) . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 9 0 - 9 5 ° C / 0 . 1 T o r r ) o f t h e y e l l o w r e s i d u e t h u s o b -t a i n e d , a f f o r d e d 0 . 1 2 5 g ( 7 8 % ) o f a c l e a r , c o l o u r l e s s o i l , w h i c h w a s o f > 9 8 % p u r i t y b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) . T h i s m a t e r i a l , i d e n t i f i e d a s t h e b i c y c l i c 3 - k e t o e s t e r 2 4 7 , e x -h i b i t e d i r ( f i l m ) : 3 0 1 0 , 1 7 5 0 , 1 7 2 0 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 9 5 , 0 . 9 6 ( d , d , 3 H e a c h , C H3" C H - C H3, J = 7 H z ) , 2 . 0 0 - 2 . 3 4 ( m , 6 H ) , 2 . 6 7 ( o v e r l a p p i n g d o f d , I H , E„, J _ _ = \j —ki\j « 5 . 5 H z ) , 3 . 7 6 ( s , 3 H , - C O _ C H . , ) , 5 . 2 1 ( d o f d o f d , I H , HD, Jb d = 1 5 . 5 H z , J D E = 8 . 5 H z , = 1 H z ) , 5 . 7 1 ( d o f d , I H , Hf i, JB D = 1 5 . 5 H z , JB C = 7 H z ) . E x a c t m a s s c a l c d . f o r cx3Hi 8 ° 3: 2 2 2 . 1 2 5 6 ; f o u n d : 2 2 2 . 1 2 5 1 . 2 3 4 3 . 3 . 2 5 P r e p a r a t i o n o f 2 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 1 - c a r b o -m e t h o x y - 6 - e x o - [ ( E ) - 3 - m e t h y l - l - b u t e n y l ] b i c y c l o [ 3 . 1 . 0 ] • h e x - 2 - e n e -Aio ^ MB / L J s . MR Hj ^ H G 2 4 0 F o l l o w i n g g e n e r a l p r o c e d u r e A , t h e k e t o e s t e r 2 4 7 ( 0 . 1 0 0 g , 0 . 4 5 0 m m o l ) w a s t r a n s f o r m e d i n t o t h e s i l y l e n o l e t h e r 2 4 0 ( 0 . 1 3 1 g , 8 7 % , a i r - b a t h t e m p e r a t u r e 1 4 9 - 1 5 2 ° C / 0 . 1 T o r r ) . T h i s m a t e r i a l c o n s i s t e d o f a s i n g l e c o m p o n e n t b y g l c a n a l y s i s ( S E - 5 4 , 1 1 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 1 7 2 0 , 1 6 2 0 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 6 ( s , 6 H , C H _3- S i - C H3) , 0 . 9 5 ( s , 9 H , ( C H3) 3- S i - 0 - ) , 0 . 9 7 , 0 . 9 8 ( d , d , 3 H e a c h , C H3- C H - C H _3, J = 7 H z ) , 1 . 7 3 ( d o f d , I H , HE, JD E = 9 H z , J£ G = 5 H z ) , 2 . 1 1 ( o v e r l a p p i n g d o f d , I H , H , J „ , , = 5 H z , J„„ = 7 H z ) , 2 . 2 3 ( d o f d , I H , H.,, J _ _ = 1 6 H z , J _ = 3 H z ) , 2 . 2 2 - 2 . 3 4 ( m , I H , Hc) , 2 . 5 8 ( d o f d o f d , I H , Hz, JjZ = 1 6 H z , ^ 2 = 7 H z , J J Z = 2 H z ) , 3 . 6 9 ( s , 3 H , - C 02C H3) , 4 . 3 8 ( b r o a d s , l H , H ^ , w±/2 = 6 H z ) , 5 . 4 8 ( d o f d , I H , H , JD r, = 1 5 H z , J _ _ = 9 H z ) , 5 . 5 9 ( d . o f d , I H , HB, JB D = 1 5 H z , JB C = 6 H z ) . E x a c t m a s s c a l c d . f o r C ^ g H ^ C ^ S i : 3 3 6 . 2 1 2 1 ; f o u n d : 3 3 6 . 2 1 2 2 . 2 3 5 3.3.26 P r e p a r a t i o n o f 6 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 7 - c a r b o -rne t h o x y - 4 - e n d o - i s o p r o p y l b i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n e % F HC Me Me02C A c c o r d i n g t o g e n e r a l p r o c e d u r e B , a s o l u t i o n o f t h e s i l y l e n o l e t h e r 2 4 0 ( 0 . 1 2 3 g , 0 . 3 6 6 m m o l ) i n b e n z e n e ( 2 . 5 m L ) w a s h e a t e d a t 2 0 0°C f o r 2 h . R e m o v a l o f s o l v e n t a n d s u b s e q u e n t d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 1 3 1 - 1 3 6 ° C / 0 . 1 T o r r ) o f t h e r e s i d u e p r o v i d e d t h e d e s i r e d c o m p o u n d 2 4 1 ( 0 . 1 1 7 g , 9 5 % ) w h i c h c o n s i s t e d o f a s i n g l e c o m p o n e n t b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 1 2 , 1 7 0 0 , 1 6 1 0 , 1 2 1 5 , 8 5 0 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 1 9 , 0 . 2 1 ( s , s , 3 H e a c h , C H3- S i - C H3) , 0 . 9 1 , 1 . 0 0 ( d , d , 3 H e a c h , C H3~ C H - C H3, J = 7 H z ) , 0 . 9 7 ( s , 9 H , ( C H3) 3C - S i - 0 - ) , 1 . 6 4 ( d o f s e p t e t , I H , H g , J _B C = 8 . 5 H z , J = 6 . 5 H z ) , 1 . 7 8 ( d , I H , H _ , JT„ = 9 . 5 H z ) , 2 . 0 6 ( o v e r l a p p i n g d o f d o f d o f d , I H , H^,, J _ _ , = 8 . 5 H z , J „ „ = 5 H z , J _ _ = J _ _ = 2 . 5 H z ) , 2 . 2 0 ( o v e r l a p p i n g d o f d o f d o f d , I H , Hz, JI Z = 9 . 5 H z , JF Z = 4 H z , JR Z = 5 H z , £E Z = 1 H z ) , 2 . 7 3 ( o v e r l a p p i n g d o f d , I H , H ^ , J _F Z = 4 H z , = 5 H z ) , 2 . 9 2 ( o v e r l a p p i n g d o f d , I H , HR, J _E K = 6 H z , JR Z = 5 H z ) , 3 . 6 6 ( s , 3 H , - C 02C H3) , 5 . 4 4 ( u n r e s o l v e d d , I H , H , JL^  = 9 . 5 H z ) , , 6 . 3 0 ( o v e r l a p p i n g d o f d o f d o f d , I H , H , JL^ = 9 . 5 H z , J V , ^ = 6 H z , = 2 . 5 H z , J _ _ = 1 H z ) . I r r a d i a t i o n a t 6 5 . 4 4 — T J K — — t i l l 2 3 6 (HD) caused the signal at 6 2 . 0 6 to collapse to a d of d of d (J = 8 . 5 Hz, J = 5 Hz, J = 2 . 5 Hz), the signal at 6 2 . 7 3 to sharpen, and the signal at 6 6 . 3 0 to collapse to an unresolved d of d (J = 6 Hz, J = 2 . 5 Hz); i r r a d i a t i o n at 6 6 . 3 0 (H„) caused the signal at 6 2 . 0 6 to collapse to a d of d of d (J = 8 . 5 Hz, J = 5 Hz, J = 2 . 5 Hz), the signal at 6 2 . 9 2 to collapse to a d (J = 5 Hz), and the signal at 6 5 . 4 4 to collapse to an overlapping d of d (J * 2 Hz); and i r r a d i a t i o n at <5 1 . 7 8 (Hj) caused the signal at 6 2 . 2 0 to collapse to an overlapping d of d of d (J = 5 Hz, J = 4 Hz, J = 1 Hz). Exact mass calcd. for C ^ H ^ C ^ S i : 3 3 6 . 2 1 2 1 ; found: 3 3 6 . 2 1 2 8 . 3 . 3 . 2 7 Preparation of 4 - e n d o - I s o p r o p y l b i c y c l o [ 3 . 2 . 1 ] o c t - 2 -en-6-one To a s t i r r e d solution of the s i l y l enol ether 2 4 1 ( 0 . 1 5 0 g, 0 . 4 4 6 mmol) i n anhydrous THF ( 5 mL), under an atmosphere of argon, was added a THF solution of tetra-n-butylammonium fl u o r i d e ( 1 . 3 4 mmol). Reaction progress was monitored by glc (SE - 5 4 , 1 1 0 ° C ) , which indicated the absence of s t a r t i n g material after the reaction mixture had been s t i r r e d at room temperature for 1 h. Subsequently, the mixture was d i l u t e d with petroleum 2 3 7 e t h e r - e t h e r ( 1 : 1 ) a n d w a s p o u r e d i n t o s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r , t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d t w i c e w i t h b r i n e a n d d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e . R e -m o v a l o f s o l v e n t f r o m t h e s o l u t i o n t h u s o b t a i n e d y i e l d e d 0 . 1 0 0 g o f a p a l e , y e l l o w o i l , w h i c h e x h i b i t e d t w o s p o t s b y t i c a n a l y s i s ( p e t r o l e u m e t h e r - e t h e r , 2 : 1 ) . A m i x t u r e o f t h e p a l e y e l l o w o i l , 5 % a q u e o u s h y d r o -c h l o r i c a c i d ( 1 1 m L ) a n d T H F ( 7 m L ) w a s r e f l u x e d f o r 2 3 h , a f t e r w h i c h t i m e t h e r e a c t i o n m i x t u r e w a s c o o l e d t o r o o m t e m p e r a t u r e a n d w a s p o u r e d c a r e f u l l y i n t o s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e . T h e a q u e o u s l a y e r w a s e x t r a c t e d t w i c e w i t h e t h e r , t h e o r g a n i c e x t r a c t s w e r e c o m b i n e d , w a s h e d t w i c e w i t h b r i n e a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . C o n c e n -t r a t i o n a n d s u b j e c t i o n o f t h e r e s u l t a n t p a l e y e l l o w o i l t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 1 8 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 1 4 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 1 2 : 1 ) a f f o r d e d t h e b i c y c l i c k e t o n e 2 7 8 ( 3 6 . 8 m g , 5 0 % ) a s a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l , c o n s i s t i n g o f a s i n g l e c o m p o n e n t b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) , e x h i b i t e d i r ( f i l m ) : 3 0 2 0 , 1 7 3 0 , 7 3 5 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 9 5 , 1 . 0 6 ( d , d , 3 H e a c h , C H3~ C H - C H3, J = 7 H z ) , 1 . 4 3 ( d o f s e p t e t , I H , H g , JB C = 1 0 H z , J = 6 . 5 H z ) , 2 . 0 0 ( d o f d , I H , Ejr J_1Z = 1 1 . 5 H z , JT T = 3 H z ) , 2 . 0 9 ( d o f d o f d o f d , I H , H _ , JT„ = 1 1 . 5 H z , J = 5 . 5 H z , J = 4 H z , J _ _ = 1 . 5 H z ) , 2 . 1 2 ( o v e r l a p p i n g d o f d — — — h i i i o f d o f d , I H , Hc, JB C = 1 0 H z , ^ = 5 H z , = = 2 . 5 2 3 8 H z ) , 2 . 2 2 ( d o f d , I H , H j , ^ = 1 7 . 5 H z , = 3 H z ) , 2 . 2 8 ( d o f d , I H , Hv, JT V = 1 7 . 5 H z , J _ _v = 5 . 5 H z ) , 2 . 6 9 - 2 . 7 7 ( m , 1 —U x —xv x 2 H , Hp, HK) , 5 . 6 3 ( d o f d o f d , I H , H p , = 1 0 H z , = 2 . 5 H z , = 1 . 5 H z ) , 6 . 0 5 ( d o f d o f d o f d , I H , HE, J _D E = 1 0 H z , J _ _ _ = 6 H z , jr = 2 . 5 H z , JT?U = 1 . 5 H z ) . I r r a d i a t i o n a t 6 1 . 4 3 ( H _ ) c a u s e d t h e s i g n a l s a t 6 0 . 9 5 a n d 6 1 . 0 6 t o 13 c o l l a p s e t o a s , a n d t h e s i g n a l a t 6 2 . 1 2 t o s i m p l i f y ; i r -r a d i a t i o n a t <5 5 . 6 3 ( H p ) c a u s e d t h e s i g n a l a t 6 2 . 1 2 t o c o l l a p s e t o a d o f d o f d ( J = 1 0 H z , J = 5 H z , J = 2 . 5 H z ) , a n d t h e s i g n a l a t 6 6 . 0 5 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 6 H z ) ; i r r a d i a t i o n a t 6 6 . 0 5 ( H „ ) c a u s e d t h e s i g n a l a t 6 2 . 0 9 t o c o l l a p s e t o a d o f d o f d ( J = 1 1 . 5 H z , J = 5 . 5 H z , J = 4 H z ) , t h e s i g n a l a t 6 2 . 1 2 t o c o l l a p s e t o a d o f d o f d ( J = 1 0 H z , J = 5 H z , J = 2 . 5 H z ) , t h e s i g n a l a t 6 2 . 6 9 - 2 . 7 7 t o s h a r p e n , a n d t h e s i g n a l a t 6 5 . 6 3 t o c o l l a p s e t o a b r o a d s . E x a c t m a s s c a l c d . f o r C ^ H T , 0 : 1 6 4 . 1 2 0 1 ; f o u n d : 1 6 4 . 1 1 9 7 . 3 . 3 . 2 8 P r e p a r a t i o n o f 6 - M e t h y l - l - h e p t e n - 4 - y n - 3 - o l 'A HO He HB 2 6 8 T o a c o l d ( - 7 8° C ) , s t i r r e d s o l u t i o n o f 3 - m e t h y l - l - b u t y n e ( 1 . 5 0 m L , 1 4 . 7 m m o l ) i n a n h y d r o u s T H F ( 2 5 m L ) , u n d e r a n 2 3 9 a t m o s p h e r e o f a r g o n , w a s a d d e d a h e x a n e s o l u t i o n o f n - b u t y l -l i t h i u m ( 1 6 . 1 m m o l ) . T h e r e a c t i o n t e m p e r a t u r e w a s m a i n t a i n e d a t - 3 0 ° C f o r 1 h a n d t h e n a s o l u t i o n o f a c r o l e i n ( 1 . 0 8 m L , 1 6 . 1 m m o l ) i n a n h y d r o u s T H F ( 5 m L ) w a s a d d e d d r o p w i s e t o t h e r e s u l t i n g m i x t u r e . T h e r e a c t i o n m i x t u r e w a s a l l o w e d t o w a r m t o r o o m t e m p e r a t u r e o v e r a p e r i o d o f 1 h w i t h s t i r r i n g , d i l u t e d w i t h e t h e r , a n d w a s p o u r e d i n t o s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e o r g a n i c p h a s e w a s w a s h e d s u c c e s s i v e l y w i t h s a t u r a t e d a q u e o u s s o d i u m b i c a r b -o n a t e , t w i c e w i t h b r i n e a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l -f a t e ) . C a r e f u l s o l v e n t r e m o v a l o n a r o t a r y e v a p o r a t o r a f f o r d e d a p a l e y e l l o w l i q u i d , w h i c h w a s d i s t i l l e d ( a i r -b a t h t e m p e r a t u r e 6 5 - 6 8 ° C / 0 . 1 T o r r ) t o g i v e t h e a l c o h o l 2 6 8 ( 1 . 5 7 g , 8 6 % ) a s a v o l a t i l e , c o l o u r l e s s o i l . T h i s m a t e r i a l w a s > 9 9 % p u r e b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 3 3 5 0 ( b r o a d ) , 3 0 5 0 , 2 2 1 5 , 1 6 3 0 , 9 9 2 , 9 3 0 c m- 1; 1H n m r ( 8 0 M H z , C D C 13) 6 1 . 1 8 ( d , 6 H , C H3- C H - C H _3, J = 7 H z ) , 1 . 9 5 ( b r o a d s , I H , - O H , D20 e x c h a n g e a b l e ) , 2 . 6 2 ( s e p t e t , I H , M e2C - H , J = 7 H z ) , 4 . 8 7 ( b r o a d s , I H , Hc, w ^ = 6 H z ) , 5 . 2 0 ( o v e r l a p p i n g d o f d o f d , I H , H^/ = 1 0 H z , = JA C = 1 . 5 H z ) , 5 . 4 3 ( o v e r l a p p i n g d o f d o f d , I H , H „ , J _ , . _ = 1 7 H z , ^ A B a - B C " 1 , 5 H Z )' 6 , 0 0 ( d °f d °f d' 1 H' HM ' — B M = 1 7 H Z' J , , . . = 1 0 H z , J . , . . = 5 H z ) . — A M ' — C M E x a c t m a s s c a l c d . f o r C g H ^ O : 1 2 4 . 0 8 8 8 ; f o u n d : 1 2 4 . 0 8 8 1 . 2 4 0 3 . 3 . 2 9 P r e p a r a t i o n o f E t h y l ( E ) - 8 - m e t h y l - 4 - n o n e n - 6 - y n o a t e I n a c c o r d a n c e w i t h t h e p r o c e d u r e d e s c r i b e d b y J o h n s o n e t a l .l l l c a nd l a t e r b y P a r k e r a n d K o s l e y ,l l l d t h e a l c o h o l 2 6 8 w a s c o n v e r t e d i n t o t h e e s t e r 2 6 9 . A m i x t u r e o f t h e v i n y l -c a r b i n o l 2 6 8 ( 1 . 8 2 g , 1 4 . 7 m m o l ) , p r o p i o n i c a c i d ( 0 . 0 6 6 m L , 0 . 8 8 1 m m o l ) a n d t r i e t h y l o r t h o a c e t a t e ( 1 3 . 4 m L , 7 3 . 3 m m o l ) w a s s t i r r e d a t 1 3 0 - 1 3 5 ° C . T h e r e a c t i o n p r o g r e s s w a s m o n i t o r e d b y t i c ( p e t r o l e u m e t h e r - e t h e r , 3 : 1 ) , w h i c h i n d i c a t e d t h e a b -s e n c e o f s t a r t i n g m a t e r i a l a f t e r 4 0 . 5 h . S u b s e q u e n t l y , m o s t o f t h e t r i e t h y l o r t h o a c e t a t e w a s r e m o v e d b y f r a c t i o n a l d i s t i l -l a t i o n a t a t m o s p h e r i c p r e s s u r e o f t h e c r u d e r e a c t i o n m i x t u r e a n d t h e s t i l l p o t r e s i d u e w a s s u b j e c t e d t o f l a s h c o l u m n c h r o m a t o -g r a p h y ( 1 2 5 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 4 5 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 9 : 1 ) . A f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a n d K u g e l r o h r d i s t i l l a t i o n ( a i r -b a t h t e m p e r a t u r e 9 1 - 1 0 4 ° C / 0 . 1 T o r r ) o f t h e r e s u l t a n t o i l , t h e e s t e r 2 6 9 ( 1 . 8 8 g , 6 6 % ) w a s o b t a i n e d a s a n o d o r i f e r o u s , c o l o u r -l e s s o i l o f > 9 8 % p u r i t y b y g l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 0 0 , 2 1 9 0 , 1 7 3 0 , 9 6 0 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 1 . 1 7 ( d , 6 H , C H3- C H - C H _3, J = 7 H z ) , 2 4 1 1 . 2 5 ( t , 3 H , C H3C H20 - , J = 7 H z ) , 2 . 3 5 - 2 . 4 4 ( m , 4 H , 0 = C - C H2- C H2- C = ) , 2 . 6 4 ( s e p t e t , I H , M e2C - H , J = 7 H z ) , 4 . 1 2 ( q , 2 H , C H3C H20 - , J = 7 H z ) , 5 . 4 9 ( u n r e s o l v e d d , l H , H g , J = 1 5 . 5 H z ) , 5 . 9 5 - 6 . 0 4 ( m , I H , H ^ ) . E x a c t m a s s c a l c d . f o r CX2H] _ 8 ° 2: 1 9 4 . 1 3 0 7 ; f o u n d : 1 9 4 . 1 3 1 6 . 3 . 3 . 3 0 P r e p a r a t i o n o f ( E ) - 8 - M e t h y l - 4 - n o n e n - 6 - y n o i c a c i d 2 7 0 A m i x t u r e o f p o t a s s i u m h y d r o x i d e ( 0 . 4 0 g , 7 . 1 m m o l ) , t h e e s t e r 2 6 9 ( 1 . 1 5 g , 5 . 9 4 m m o l ) , w a t e r ( 0 . 5 m L ) a n d m e t h a n o l ( 2 0 m L ) w a s r e f l u x e d f o r 3 . 5 h . T h e r e a c t i o n m i x t u r e w a s i n i t i a l l y c h e c k e d f o r b a s i c i t y a n d t h e n w a s e x t r a c t e d w i t h p e t r o l e u m e t h e r t o r e m o v e a n y n o n p o l a r i m p u r i t i e s . T h e a q u e o u s p h a s e w a s s t i r r e d a t 0°C a n d a c i d i f i e d b y d r o p w i s e a d d i t i o n o f a 1 0 % a q u e o u s s o l u t i o n o f h y d r o c h l o r i c a c i d u n t i l t h e s o l u t i o n w a s s t r o n g l y a c i d i c t o l i t m u s p a p e r . T h e r e -s u l t i n g m i x t u r e w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r a n d t h e o r g a n i c e x t r a c t s w e r e c o m b i n e d a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . S o l v e n t r e m o v a l u n d e r r e d u c e d p r e s s u r e p r o v i d e d a v i s c o u s y e l l o w o i l , w h i c h w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 1 3 9 - 1 4 3 ° C / 0 . 1 T o r r ) t o g i v e t h e a c i d 2 7 0 ( 0 . 7 7 0 g , 7 8 % ) a s a 2 4 2 c o l o u r l e s s o i l . O n c o o l i n g t o r o o m t e m p e r a t u r e , t h i s o i l s o l i d i f i e d a n d t h e a c i d w a s r e c r y s t a l l i z e d f r o m h e p t a n e t o a f f o r d a w h i t e s o l i d , w h i c h c o n s i s t e d o f o n e c o m p o n e n t b y g l c a n a l y s i s ( S E - 5 4 , 8 0 ° C ) a n d e x h i b i t e d m . p . 6 5 . 5 - 6 7 . 5 ° C ; i r ( C H C 13) : 3 2 0 0 - 2 5 0 0 , 1 7 0 1 , 9 6 0 c m "1; XH n m r ( 8 0 M H z , C D C 13) 6 : 1 . 1 7 ( d , 6 H , C H3- C H - C H3, J = 7 H z ) , 2 . 3 2 - 2 . 5 2 ( m , 4 H , 0 = C - C H2- C H2- C = ) , 2 . 6 5 ( s e p t e t , I H , M e2C - H , J = 7 H z ) , 5 . 5 3 ( u n r e s o l v e d d , I H , H „ , J _ _ = 1 5 . 5 H z ) , 5 . 8 5 - 6 . 3 0 ( m , I H , H^ ) . E x a c t m a s s c a l c d . f o r c I Q H 1 4 ° 2 : 1 6 6 . 0 9 9 4 ; f o u n d : 1 6 6 . 0 9 8 8 . A n a l . c a l c d . f o r c1 0Hi 4 ° 2: C 7 2-2 5' H 8 . 4 9 ; f o u n d : C 7 2 . 0 9 , H 8 . 4 0 . 3 . 3 . 3 1 P r e p a r a t i o n o f ( E ) - 8 - m e t h y l - 4 - n o n e n - 6 - y n o y l c h l o r i d e 2 7 1 I n a c c o r d a n c e w i t h a p r o c e d u r e r e p o r t e d b y H u d l i c k y e t 9 8 a l . a s o l u t i o n o f t h e a c i d 2 7 0 ( 0 . 6 4 8 g , 3 . 9 0 m m o l ) a n d o x a l y l c h l o r i d e ( 1 . 0 2 m L , 1 1 . 7 m m o l ) i n d r y h e x a n e ( 1 7 m L ) w a s r e f l u x e d f o r 1 h . S o l v e n t a n d e x c e s s o x a l y l c h l o r i d e w e r e r e m o v e d u n d e r r e d u c e d p r e s s u r e t o a f f o r d a d a r k y e l l o w r e s i d u e . K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 7 0 -7 5 ° C / 0 . 1 T o r r ) o f t h i s m a t e r i a l g a v e a p u n g e n t - s m e l l i n g , 2 4 3 c o l o u r l e s s o i l , w h i c h w a s i d e n t i f i e d a s t h e a c i d c h l o r i d e 2 7 1 ( 0 . 6 0 0 g , 8 3 % ) . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 0 0 , 2 1 9 0 , 1 7 9 0 , 9 6 0 c m "1; 1H n m r ( 8 0 M H z , C D C 13) 6 : 1 . 1 7 ( d , 6 H , C H _3- C H - C H3, J = 7 H z ) , 2 . 3 0 - 3 . 0 9 ( m , 5 H ) , 5 . 5 4 ( u n r e s o l v e d d , I H , HB, JA B = 1 6 H z ) , 5 . 9 9 ( d o f t , I H , H ^ , £A B = 1 6 H z , J = 6 . 5 H z ) . 3 5 E x a c t m a s s c a l c d . f o r C ^ Q H ^ O C l : 1 8 4 . 0 6 5 5 ; f o u n d : 1 8 4 . 0 6 6 3 . 3.3.32 P r e p a r a t i o n o f ( E ) - l - D i a z o - 9 - m e t h y l - 5 - d e c e n - 7 - y n - 2 - o n e 2 7 2 A c c o r d i n g t o a p r o c e d u r e r e p o r t e d b y D e B o e r a n d 2 0 6 B a c k e r , a s o l u t i o n o f d i a z o m e t h a n e i n e t h e r w a s p r e p a r e d f r o m D i a z a l d ( N - m e t h y l - N - n i t r o s o - p _ - t o l u e n e s u l f o n a m i d e ) , w h i c h i s a v a i l a b l e f r o m A l d r i c h . T o a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n o f d i a z o m e t h a n e ( 0 . 8 1 1 g , 1 9 . 3 m m o l ) i n e t h e r ( 3 0 m L ) w a s a d d e d d r o p w i s e , v i a a f l a m e - p o l i s h e d p i p e t t e , a s o l u t i o n o f t h e a c y l c h l o r i d e 2 7 1 ( 0 . 6 0 0 g , 3 . 2 5 m m o l ) i n e t h e r ( 4 m L ) . G a s e v o l u t i o n w a s i m m e d i a t e l y e v i d e n t d u r i n g a d d i t i o n . T h e r e s u l t i n g y e l l o w s o l u t i o n w a s m a i n t a i n e d a t 0°C f o r 0 . 5 h a n d t h e n w a r m e d t o r o o m t e m p e r a t u r e o v e r a p e r i o d o f 1 h w i t h s t i r r i n g . E x c e s s 244 diazomethane was removed by b u b b l i n g a r g o n , v i a a f l a m e -p o l i s h e d p i p e t t e , t h r o u g h the s o l u t i o n o v e r a p e r i o d o f 0.5 h. The y e l l o w s o l u t i o n was d r i e d (anhydrous magnesium s u l -f a t e ) and c o n c e n t r a t e d t o a f f o r d the d i a z o k e tone 272 as a v i s c o u s y e l l o w o i l (0.600 g, 9 7 % ) , w h i c h tended t o decompose on s t a n d i n g even a t 4°C and i n t h e absence o f l i g h t . Hence the crude d i a z o k e tone was n o t p u r i f i e d b u t was used immediate-l y i n the n e x t r e a c t i o n . A sample o f 272 e x h i b i t e d i r ( f i l m ) : 3070, 2085, 1634, 960 c m - 1 ; 1 H nmr (80 MHz, CDC1 3) 6: 1.18 (d, 6H, CH3-CH-CH_3, J = 7 Hz) , 2.32-2.52 (m, 4H) , 2.65 (sep-t e t , I H, Me 2C-H, J = 7 H z ) , 5.21 ( s , IH, N 2CH-C=0), 5.50 (un-r e s o l v e d d, IH, H B, J^B = 16 H z ) , 5.85-6.20 (m, IH, H^). ms m/e: 162 ( M - N 2 ) + 3.3.33 P r e p a r a t i o n o f 6 - e x o - ( 3 - M e t h y l - l - b u t y n y l ) b i c y c l o -[3.1.0]hexan-2-one 0 267 F o l l o w i n g a p r o c e d u r e r e p o r t e d by H u d l i c k y e t a l . , the d i a z o k e t o n e 272 was t r a n s f o r m e d i n t o the b i c y c l i c k e t one 267. 163 Thus, t o a r e f l u x i n g s u s p e n s i o n o f Cu (acac) 2 ' H ^ (0.0637 g, 0.226 mmol) i n anhydrous benzene (16 mL), under an atmosphere o f a r g o n , was added v i a a p r e s s u r e - e q u a l i z i n g a d d i t i o n f u n n e l a s o l u t i o n o f t h e y e l l o w d i a z o k e tone 272 (0.618 g, 3.25 mmol) 2 4 5 i n b e n z e n e ( 8 m L ) . A f t e r t h e r e a c t i o n m i x t u r e w a s r e f l u x e d f o r a p e r i o d o f 1 h a n d w a s c o o l e d t o r o o m t e m p e r a t u r e , t h e b e n z e n e w a s r e m o v e d c a r e f u l l y u n d e r r e d u c e d p r e s s u r e . S u b -j e c t i o n o f t h e r e s i d u e t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 7 0 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 3 5 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 5 : 1 ) a f f o r d e d , a f t e r c o n c e n t r a t i o n o f t h e d e s i r e d f r a c t i o n s a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 7 4 - 8 0 ° C / 0 . 1 T o r r ) o f t h e m a t e r i a l t h u s o b t a i n e d , t h e k e t o n e 2 6 7 a s a c l e a r , c o l o u r l e s s o i l ( 0 . 4 0 7 g , 7 7 % ) . G l c a n a l y s i s ( O V - 1 7 , 8 0 ° C ) s h o w e d t h i s m a t e r i a l t o b e p u r e a n d t i c a n a l y s i s ( p e t r o l e u m e t h e r - e t h e r , 5 : 1 ) i n d i c a t e d o n l y o n e s p o t . T h e k e t o n e 2 6 7 e x h i b i t e d i r ( f i l m ) : 3 0 3 0 , 1 7 2 5 , 1 1 8 0 , 8 8 2 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 1 . 1 2 ( d , 6 H , C H3- C H - C H3, J = 6 . 5 H z ) , 1 . 7 0 - 1 . 7 5 ( m , I H ) , 1 . 9 4 - 2 . 1 8 ( m , 5 H ) , 2 . 2 4 ( d o f d , I H , J = 1 0 . 5 H z , J = 4 . 5 H z ) , . 2 . 4 9 ( d o f s e p -t e t , I H , M e2C - H , J = 1 . 5 H z , J = 6 . 5 H z ) . E x a c t m a s s c a l c d . f o r CX XHX40 : 1 6 2 . 1 0 4 5 ; f o u n d : 1 6 4 . 1 0 4 4 . 2 4 6 3 . 3 . 3 4 P r e p a r a t i o n o f 6 - e x o - [ ( Z ) - 3 - M e t h y l - l - b u t e n y l ] b i c y c l o -[ 3 . 1 . 0 ] h e x a n - 2 - o n e 3 5 1 2 6 6 T o a p r e h y d r o g e n a t e d s u s p e n s i o n o f L i n d l a r ' s c a t a l y s t ( 5 % P d / C a C O - j , 1 0 m g ) a n d q u i n o l i n e ( 4 p L , 0 . 0 3 0 9 m m o l ) i n d r y p e n t a n e ( 1 5 m L ) , w a s a d d e d a s o l u t i o n o f t h e a l k y n e 2 6 7 ( 0 . 2 0 0 g , 1 . 2 3 m m o l ) i n p e n t a n e ( 2 m L ) , a n d t h e m i x t u r e w a s s t i r r e d a t r o o m t e m p e r a t u r e u n d e r h y d r o g e n . R e a c t i o n p r o g r e s s w a s m o n i t o r e d b y g l c ( S E - 5 4 , 1 2 0 ° C ) , w h i c h i n d i c a t e d t h e a b s e n c e o f s t a r t i n g m a t e r i a l a f t e r 2 . 5 h . R e m o v a l o f p a l l a d i u m c a t a l y s t b y f i l t r a t i o n t h r o u g h a s h o r t c o l u m n o f C e l i t e a n d c o n c e n t r a t i o n o f t h e e l u a t e a f f o r d e d a p a l e y e l l o w o i l w h i c h w a s s h o w n t o c o n s i s t o f t h e c i s - a n d t r a n s - i s o m e r s i n a r a t i o o f 9 5 : 2 r e s p e c t i v e l y , b y g l c ( S E - 5 4 , 1 2 0 ° C ) . T h e s e i s o m e r s 2 0 7 2 0 8 w e r e s e p a r a t e d o n a A g N O ^ - i m p r e g n a t e d s i l i c a g e l ' ( 2 0 g o f 7 0 - 2 3 0 m e s h i m p r e g n a t e d w i t h 5 g o f A g N O ^ i n a 1 7 x 1 6 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 1 2 : 1 ) c o l u m n . A f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s , a p p r o x i m a t e l y 3 . 5 m g o f t h e t r a n s - i s o m e r 3 5 1 a n d 1 9 5 m g o f t h e c i s - i s o m e r 2 6 6 w e r e r e c o v e r e d . K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 7 5 - 8 0 ° C / 0 . 1 T o r r ) o f t h e c i s - a l k e n e 2 6 6 f u r n i s h e d a c o l o u r l e s s o i l ( 1 9 0 m g , 9 4 % ) w h i c h e x h i b i t e d o n e p e a k b y g l c ( S E - 5 4 , 2 4 7 1 2 0 ° C ) a n d o n e s p o t b y t i c ; i r ( f i l m ) : 3 0 0 0 , 1 7 2 2 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 9 9 , 1 . 0 1 ( d , d , 3 H e a c h , C H3- C H - C H _3, J = 6 . 5 H z ) , 1 . 7 5 ( d o f d , I H , Hp, Jp G = 5 H z , J _E p, = 2 . 5 H z ) , 2 . 0 0 - 2 . 2 1 ( m , 6 H ) , 2 . 7 0 ( d o f d o f s e p t e t , I H , Hf i, g_BQ = 9 H z , J = 6 . 5 H z , J _B D = 1 H z ) , 4 . 6 5 ( o v e r l a p p i n g d o f d o f d , I H , HD, = 1 0 . 5 H z , JD E = 9 . 5 H z , J _B D = 1 H z ) , 5 . 2 4 ( o v e r -l a p p i n g d o f d o f d , I H , Hc, JC D = 1 0 . 5 H z , JB C = 9 H z , < 1 H z ) . E x a c t m a s s c a l c d . f o r C.^H.r0: 1 6 4 . 1 2 0 1 ; f o u n d : 1 6 4 . 1 2 0 3 , 1 1 1 6 3 . 3 . 3 5 P r e p a r a t i o n o f 2 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 6 - e x o -t ( Z ) - 3 - m e t h y l - l - b u t e n y l ] b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e I n a c c o r d a n c e w i t h g e n e r a l p r o c e d u r e A , t h e k e t o n e 2 6 6 ( 0 . 1 6 0 g , 0 . 9 7 5 m m o l ) w a s c o n v e r t e d i n t o t h e s i l y l e n o l e t h e r 2 7 4 ( 0 . 2 6 6 g , 9 8 % , a i r - b a t h d i s t i l l a t i o n t e m p e r a t u r e 1 1 0 -1 1 5 ° C / 0 . 1 T o r r ) , w h i c h w a s s h o w n t o c o n s i s t o f o n e c o m p o n e n t b y g l c a n a l y s i s ( O V - 1 7 , 1 1 0 ° C ) , a n d e x h i b i t e d i r ( f i l m ) : 3 0 3 0 , 1 6 2 5 , 1 2 5 5 , 9 6 0 , 7 8 7 c m "1; ^ n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 1 7 , 0 . 1 8 ( s , s , 3 H e a c h , C H3- S i - C H3) , 0 . 9 4 ( s , 9 H , ( C H3) C - S i - 0 - ) , 0 . 9 9 ( d , 6 H , C H _3- C H - C H _3, J = 6 . 5 H z ) , 1 . 2 8 ( u n r e s o l v e d d , I H , HE ' - D E = 1 0 H z )' i -5 0 - 1-5 5 <m' 1 H' HG)' 1 - 5 9 - 1 . 6 4 ( m , I H , Hp) , 2 . 3 0 ( o v e r l a p p i n g d o f d o f d , I H , HT, J _ „ = 1 6 . 5 H z , JT T = 2 4 8 J p j = 3 Hz) , 2.52 (d of d of d, IH, W^, = 16.5 Hz, = 7 Hz, J I Z = 2 Hz), 2.73 (d of d of septet, IH, Hg, J g C = 9.5 Hz, J = 6.5 Hz, J g D < 1 Hz), 4.31 (broad s, IH, Hj, ^Ly2 = 5.5 Hz), 4.64 (overlapping d of d, IH, H^, = 10.5 Hz, J D E = 10 Hz), 5.14 (overlapping d of d, IH, H c, JQD = 10.5 Hz, J „ = 9.5 Hz). I r r a d i a t i o n at <S 2.73 (H_.) caused the signal at 6 0.99 to collapse to a s, the signal at 6 4.64 to sharpen, and the signal at 6 5.14 to collapse to a d (J = 10.5 Hz); i r r a d i a t i o n at 6 5.14 (Hc) caused the signal at 6 1.28 to sharpen, the signal at 6 2.73 to collapse to an unresolved septet (J = 6.5 Hz), and the signal at 6 4.64 to collapse to a d (J = 10 Hz); i r r a d i a t i o n at 6 4.64 (H^) caused the signal at 6 1.28 to collapse to a broad s, the signal at 6 2.73 to sharpen, and the signal at 6 5.14 to collapse to a d (J = 9.5 Hz); i r r a d i a t i o n at 6 1.28 (H_) caused the signal at 6 1.50-1.55 to collapse to an overlapping d of d (J = 6 Hz, J = 7 Hz), the signal at 6 1.60 to collapse to a d of d (J = 6 Hz, J = 3 Hz), and the signal at <5 4.64 to collapse to a d (J = 10.5 Hz); i r r a d i a t i o n at 6 4.31 (H^ .) caused the signal at 6 1.50-1.55 to collapse to a d of d of d (J = 7 Hz, J = 6 Hz, J = 3.5 Hz), the signal at 6 1.60 to collapse to an overlapping d of d of d (J = 6 Hz, J = 3 Hz), the signal at 6 2.30 to collapse to a d of d (J = 16.5 Hz, J = 3 Hz), and the signal at 6 2.52 to collapse to a d of d (J = 16.5 Hz, J = 7 Hz); and i r r a d i a t i o n at 6 2.30 (HT) caused the sig n a l at 6 1.50-1.55 to sharpen, the signal at 6 1.60 to collapse to a d of d (J = 6 2 4 9 H z , J = 2 H z ) , t h e s i g n a l a t <5 2 . 5 2 t o c o l l a p s e t o a n u n -r e s o l v e d d ( J = 7 H z ) , a n d t h e s i g n a l a t 6 4 . 3 1 t o s h a r p e n , E x a c t m a s s c a l c d . f o r C ^ H ^ C - S i : 2 7 8 . 2 0 6 6 ; f o u n d : 2 7 8 . 2 0 7 3 . 3 . 3 . 3 6 P r e p a r a t i o n o f 6 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 4 - e x o -i s o p r o p y l b i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n e A s o u t l i n e d i n g e n e r a l p r o c e d u r e B , a s o l u t i o n o f s i l y l e n o l e t h e r 2 7 4 ( 0 . 1 0 1 g , 0 . 3 6 3 m m o l ) i n b e n z e n e ( 2 . 5 m L ) w a s h e a t e d a t 2 4 0 ° C f o r 4 . 5 h . T h e c r u d e m a t e r i a l o b t a i n e d a f t e r s o l v e n t r e m o v a l w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 8 9 - 9 3 ° C / 0 . 1 T o r r ) t o a f f o r d t h e i s o m e r i z e d s i l y l e n o l e t h e r 2 7 6 ( 9 4 . 2 m g , 9 3 % ) , w h i c h w a s s h o w n t o c o n s i s t o f o n e c o m p o n e n t b y g l c a n a l y s i s ( S E - 5 4 , 1 1 0 ° C ) . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 5 0 , 3 0 1 0 , 1 6 2 0 , 8 4 1 , 7 8 5 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) <5: 0 . 1 3 , 0 . 1 5 ( s , s , 3 H e a c h , C H _3- S i - C H3) , 0 . 9 2 ( s , 9 H , (CH_3) 3C - S i - 0 - ) , 0 . 9 6 , 0 . 9 9 ( d , d , 3 H e a c h , C H3- C H - C H _3, J = 7 H z ) , 1 . 6 8 ( d o f s e p t e t , I H , H g , J = J _B C = 7 H z ) , 1 . 7 5 ( d , I H , H.T/ J _ _ = 9 . 5 H z ) , 1 . 8 8 - 1 . 9 4 ( m , I H , H . J , 1 . 9 7 ( o v e r -l a p p i n g d o f d o f d o f d , I H , H _ , JT = 9 . 5 H z , J „ „ = 5 H z , JK Z = 3 H z , JE Z = 1 H z ) , 2 . 3 8 ( u n r e s o l v e d d , I H , H , J pZ = 5 H z ) , 2 . 5 2 - 2 . 5 7 ( m , I H , H „ ) , 5 . 1 1 ( d , I H , H _ , JT„ = 3 H z ) , 250 5.33 (overlapping d of d of d, 1H, Hp, = 9.5 Hz, = 3 Hz, Jn„ = 2 Hz), 6.21 (overlapping d of d of d of d, IH, IL, JnT? = 9.5 Hz, JV,^ = 6 Hz, J__ = 2 Hz, = 1 Hz) . I r r a d i a t i o n —Uhi — X J J \ — — t i n at 6 5.11 (HT) caused the signal at 6 2.52-2.57 to collapse to overlapping d of d (J = 6 Hz, J = 3 Hz); i r r a d i a t i o n at 6 2.52-2.57 (H._) caused the signal at 6 1.97 to collapse to a d of d o f d (J = 9.5 Hz, J = 5 Hz, J = 1 Hz), the signal at 6 5.11 to collapse to a s, the signal at 6 5.33 to sharpen, and the signal at 6 6.21 to collapse to an unresolved d of d (J = 9.5 Hz, J = 2 Hz); i r r a d i a t i o n at 6 6.21 (H„) caused the signal JCl at 6 1.88-1.94 to collapse to a d of d (J = 7 Hz, J = 3 Hz), the signal at 6 1.97 to sharpen, the signal at 6 2.52-2.57 to collapse to an overlapping d of d (J = 3 Hz), and the signal at 6 5.33 to collapse to an unresolved d of d (J = 3 Hz, J = 2 Hz); i r r a d i a t i o n at 6 5.33 (Hp) caused the signal at 6 1.88-1.94 to collapse to an unresolved d (J = 7 Hz), the signals at 6 2.38 and 6 2.52-2.57 to sharpen, and the signal at 6 6.21 to collapse to an unresolved d (J = 6 Hz); and i r r a d i a t i o n at 6 2.38 (H_) caused the signal at 6 1.88-1.94 to collapse to an overlapping d of d of d (J = 7 Hz, J = 3 Hz, J = 2 Hz), the signal at 6 1.97 to collapse to a d of d (J = 9.5 Hz, J =3 Hz), the signal at 6 5.33 to collapse to a d of d (J = 9.5 Hz, J = 3 Hz), and the signal at 6 6.21 to sharpen. Exact mass calcd. f o r C-^H^OSi: 278.2066; found: 278.2067. 2 5 1 3 . 3 . 3 7 P r e p a r a t i o n o f 4 - e x o - I s o p r o p y l b i c y c l o [ 3 . 2 . 1 ] o c t - 2 - e n -6 - o n e A m i x t u r e o f t h e s i l y l e n o l e t h e r 2 7 6 ( 0 . 1 5 8 g , 0 . 5 6 8 m m o l ) , 5 % a q u e o u s h y d r o c h l o r i c a c i d ( 1 4 m L ) a n d T H F ( 6 m L ) w a s s t i r r e d u n d e r a n a t m o s p h e r e o f a r g o n f o r 3 h a t r o o m t e m p e r a t u r e . T h e r e s u l t i n g r e a c t i o n m i x t u r e w a s d i l u t e d w i t h e t h e r a n d w a s p o u r e d i n t o s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n -a t e a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r , a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . A f t e r r e m o v a l o f s o l v e n t u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) , t h e r e s u l t i n g p a l e y e l l o w o i l w a s s u b j e c t e d t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 1 8 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 1 4 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 9 : 1 ) . E v a p -o r a t i o n o f s o l v e n t f r o m t h e a p p r o p r i a t e f r a c t i o n s a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 9 8 - 1 0 1 ° C / 0 . 1 T o r r ) o f t h e r e s u l t a n t m a t e r i a l g a v e t h e k e t o n e 2 7 9 ( 5 3 . 0 m g , 5 7 % ) a s a c o l o u r l e s s o i l . G l c a n a l y s i s ( S E - 5 4 , 8 0 ° C ) o f t h i s m a t e r i a l i n d i c a t e d t h e p r e s e n c e o f a s i n g l e c o m p o n e n t a n d t i c a n a l y s i s ( p e t r o l e u m e t h e r - e t h e r , 9 : 1 ) s h o w e d a s i n g l e s p o t . T h e k e t o n e 2 7 9 e x h i b i t e d i r ( f i l m ) : 3 0 1 3 , 1 7 3 5 , 7 4 1 c m- 1; 1H 2 5 2 n m r ( 4 0 0 M H z , C D C ±3) 6 : 0 . 9 7 , 0 . 9 8 ( d , d , 3 H e a c h , C H3- C H - C H _3, J = 6 . 5 H z ) , 1 . 6 8 ( d o f s e p t e t , I H , H g , JB C = 8 H z , J = 6 . 5 H z ) , 1 . 8 5 - 1 . 9 3 ( m , 2 H , Hc, Yi^) , 2 . 0 6 ( u n r e s o l v e d d , I H , H^ , JI Z = 1 1 . 5 H z ) , 2 . 2 3 ( d o f d , I H , Hy, J ^ y = 1 6 . 5 H z , J K y = 5 H z ) , 2 . 2 8 ( o v e r l a p p i n g d o f d o f d , I H , H , = 1 6 . 5 H z , J-r-r = 2 . 5 H z , JT T, = 1 . 5 H z ) , 2 . 5 9 ( u n r e s o l v e d d , I H , H _ , J _ _ —_L J — u Is. r — r ii = 5 . 5 H z ) , 2 . 7 3 - 2 . 7 9 ( m , I H , H ) , 5 . 5 5 ( d o f d o f d , I H , H p , J _ _ = 9 . 5 H z , CT = 3 . 5 H z , cr = 1 . 5 H z ) , 6 . 0 7 ( o v e r l a p p i n g —Dri —CD —JJr d o f d o f d o f d , I H , HE, JD E = 9 . 5 H z , JE R = 6 . 5 H z , = 2 H z , J „ „ = 1 . 5 H z ) . I r r a d i a t i o n a t 6 0 . 9 8 ( i s o p r o p y l m e t h y l — E a p r o t o n s ) c a u s e d t h e s i g n a l a t 6 1 . 6 8 t o c o l l a p s e t o a d ( J = 8 H z ) ; i r r a d i a t i o n a t 6 1 . 6 8 ( H ) c a u s e d t h e s i g n a l a t 6 1 . 8 5 -1 . 9 3 t o s i m p l i f y ; i r r a d i a t i o n a t 6 6 . 0 7 ( H£) c a u s e d t h e s i g n a l s a t 6 1 . 8 5 - 1 . 9 3 a n d 6 2 . 7 3 - 2 . 7 9 t o s h a r p e n , a n d t h e s i g n a l a t 6 5 . 5 5 t o c o l l a p s e t o a d o f d ( J = 3 . 5 H z , J = 1 . 5 H z ) ; i r r a d i a t i o n a t 6 2 . 7 3 - 2 . 7 9 ( Hv) c a u s e d t h e s i g n a l a t 6 1 . 8 5 -J \ 1 . 9 3 t o s i m p l i f y , t h e s i g n a l a t 6 2 . 0 6 t o s h a r p e n , t h e s i g n a l a t 6 2 . 2 3 t o c o l l a p s e t o a d ( J = 1 6 . 5 H z ) , t h e s i g n a l a t 6 2 . 2 8 t o c o l l a p s e t o a d o f d ( J = 1 6 . 5 H z , J = 2 . 5 H z ) , a n d t h e s i g n a l a t 6 6 . 0 7 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 9 . 5 H z ) ; i r r a d i a t i o n a t 6 5 . 5 5 ( H p ) c a u s e d t h e s i g n a l a t 6 1 . 8 5 -1 . 9 3 t o s i m p l i f y , a n d t h e s i g n a l a t 6 6 . 0 7 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 6 . 5 H z ) ; i r r a d i a t i o n a t 6 2 . 5 9 ( H p ) c a u s e d t h e s i g n a l a t 6 1 . 8 5 - 1 . 9 3 t o s i m p l i f y , t h e s i g n a l a t 6 2 . 0 6 t o s h a r p e n , t h e s i g n a l a t 6 5 . 5 5 t o c o l l a p s e t o a d o f d ( J = 9 . 5 H z , J = 3 . 5 H z ) , a n d t h e s i g n a l a t 6 6 . 0 7 t o s h a r p e n ; a n d 2 5 3 i r r a d i a t i o n a t 6 2 . 0 6 ( H j ) c a u s e d t h e s i g n a l a t 6 1 . 8 5 - 1 . 9 3 t o s i m p l i f y , a n d t h e s i g n a l a t 6 2 . 2 8 t o s h a r p e n . E x a c t m a s s c a l c d . f o r C , , H1 C0 : 1 6 4 . 1 2 0 1 ; f o u n d : 1 6 4 . 1 2 0 5 . 1 1 1 6 3 . 3 . 3 8 P r e p a r a t i o n o f 2 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 5 - m e t h y 1 -6 - e x o - [ ( Z ) - 3 - m e t h y l - l - b u t e n y l ] b i c y c l o [ 3 . 1 . 0 ] h e x - 2 - e n e H B -Me F o l l o w i n g g e n e r a l p r o c e d u r e A , t h e k e t o n e 3 3 7 ( 4 2 . 5 m g , 0 . 2 3 9 m m o l ) w a s t r a n s f o r m e d i n t o t h e s i l y l e n o l e t h e r 3 4 0 ( 6 2 . 0 m g , 8 9 % , a i r - b a t h d i s t i l l a t i o n t e m p e r a t u r e 1 1 2 - 1 1 5 ° C / 0 . 1 T o r r ) . T h i s m a t e r i a l p r o v e d t o b e e s s e n t i a l l y p u r e b y g l c a n a l y s i s ( O V - 1 7 , 1 2 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 3 0 6 0 , 3 0 0 0 , 1 6 2 7 , 1 2 5 8 , 9 6 0 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 1 6 ( s , 6 H , C H3~ S i - C H3) , 0 . 9 3 ( s , 9 H , ( C H3)3C - S i - 0 - ) , 0 . 9 8 , 0 . 9 9 ( d , d , 3 H e a c h , C H3~ C H - C H3, J = 7 H z ) , 1 . 2 4 ( s , 3 H , t e r t i a r y - C H _ ) , 1 . 3 2 ( o v e r l a p p i n g d o f d , H _ , J _ _ = J „ „ = 2 . 5 H z ) , 1 . 3 4 ( d o f d , H _ , J _ _ = 9 H z , J _ _ = 2 . 5 H z ) , 2 . 3 0 ( d o f £ i —Uti • —hr d , HT o r H „ , J „ = 1 6 . 5 H z , J = 2 . 5 H z ) , 2 . 3 7 ( d o f d o f d , J is —J is — H o r H „ , JT„ = 1 6 . 5 H z , J = 2 . 5 H z ) , 2 . 7 0 ( m , I H , H ) , 4 . 2 7 o it — u Zi —* JD ( b r o a d s , I H , HI, w^ 2 = 5 H z ) , 4 . 9 2 ( d o f d o f d , I H , H ^ , = 1 1 H z , J _ _ = 9 H z , Jn T^ = 1 H z ) , 5 . 2 7 ( d o f d o f d , I H , H _ , JCD = 1 1 H z , J B C = 9 H z , JCE = 1 H z ) . I n t h e f o l l o w i n g d e -c o u p l i n g e x p e r i m e n t s , t h e r e g i o n 6 1 . 2 0 - 6 . 0 0 w a s o b s e r v e d : 2 5 4 i r r a d i a t i o n a t 6 2 . 7 0 ( H _ ) c a u s e d t h e s i g n a l a t 6 4 . 9 2 t o c o l l a p s e t o a d o f d ( J = 1 1 H z , J = 9 H z ) , a n d t h e s i g n a l a t <S 5 . 2 7 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 1 1 H z ) ; i r r a d i a t i o n a t 6 4 . 2 7 ( H j ) c a u s e d t h e s i g n a l a t 6 1 . 3 2 t o s h a r p e n , t h e s i g n a l a t 6 2 . 3 0 t o c o l l a p s e t o a d ( J = 1 6 . 5 H z ) , a n d t h e s i g n a l a t 6 2 . 3 7 t o c o l l a p s e t o a d o f d ( J = 1 6 . 5 H z , J = 2 . 5 H z ) ; a n d i r r a d i a t i o n a t 6 4 . 9 2 ( H p ) c a u s e d t h e s i g n a l a t 6 1 . 3 4 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 2 . 5 H z ) , t h e s i g -n a l a t 6 2 . 7 0 t o s h a r p e n , a n d t h e s i g n a l a t 6 5 . 2 7 t o c o l l a p s e t o a d ( J = 9 H z ) . E x a c t m a s s c a l c d . f o r C j g H ^ O S i : 2 9 2 . 2 2 2 2 ; f o u n d : 2 9 2 . 2 2 1 9 . 3 . 3 . 3 9 P r e p a r a t i o n o f l - M e t h y l - 4 - e x o - i s o p r o p y l - 6 - ( t e r t - b u t y l -d i m e t h y l s i l o x y ) b i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n e F o l l o w i n g g e n e r a l p r o c e d u r e B , a s o l u t i o n o f t h e s i l y l e n o l e t h e r 3 4 0 ( 4 8 . 3 m g , 0 . 1 6 5 m m o l ) i n b e n z e n e ( 3 m L ) w a s t h e r m o l y z e d a t 2 2 0 ° C f o r 4 . 5 h . R e m o v a l o f s o l v e n t a n d s u b -s e q u e n t d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 9 1 - 9 6 ° C / 0 . 1 T o r r ) f u r n i s h e d t h e d e s i r e d m a t e r i a l 3 4 1 ( 4 1 . 6 m g , 8 6 % ) , w h i c h e x -h i b i t e d a s i n g l e p e a k b y g l c a n a l y s i s ( S E - 5 4 , 1 2 0 ° C ) , a n d i r ( f i l m ) : 3 0 7 0 , 3 0 2 0 , 1 6 2 8 , 1 2 6 5 , 9 4 5 , 7 9 8 c m "1; 1H n m r ( 4 0 0 M H z , 2 5 5 C D C 13) 6 : 0 . 1 2 , 0 . 1 5 ( s , s , 3 H e a c h , C H3- S i - C H _3) , 0 . 9 1 ( s , 9 H , ( C H3) 3C - S i O - ) , 0 . 9 6 , 0 . 9 9 ( d , d , 3 H e a c h , C H _3- C H - C H _3, J = 7 H z ) , 1 . 0 9 ( s , 3 H , t e r t i a r y - C H ) , 1 . 6 2 - 1 . 7 2 ( m , 2 H , H j , H g ) , 1 . 7 5 ( d o f d o f d , Hz, JI Z = 9 H z , Jp z = 5 H z , £E Z = 1 H z ) , 1 . 8 3 - 1 . 8 8 ( m , I H , H _ ) , 2 . 4 6 ( u n r e s o l v e d d , I H , H _ , J _ _ = 5 C r —t L H z ) , 4 . 8 7 ( s , I H , H - C = C - 0 - S i ) , 5 . 2 9 ( d o f d o f d , H _ , J _ „ = — D —Dti 1 0 H z , = 3 H z , = 2 H z ) , 5 . 9 6 ( d o f d o f d , H g , J^E = 1 0 H z , J _ _ = 2 . 5 H z , :r = 1 H z ) . I r r a d i a t i o n a t 6 5 . 2 9 ( H _ ) — ( _ £ l — t l L l D c a u s e d t h e s i g n a l a t 6 1 . 8 3 - 1 . 8 8 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 7 H z ) , t h e s i g n a l a t 6 2 . 4 6 t o s h a r p e n , a n d t h e s i g n a l a t 6 5 . 9 6 t o c o l l a p s e t o a b r o a d s ; a n d i r r a d i a t i o n a t 6 2 . 4 6 ( H _ ) c a u s e d t h e s i g n a l a t 6 1 . 7 5 t o c o l l a p s e t o a d o f d ( J = r — 9 H z , J = 1 H z ) , t h e s i g n a l a t 6 1 . 8 3 - 1 . 8 8 t o c o l l a p s e t o a n o v e r l a p p i n g d o f d o f d ( J = 7 H z , J = 3 H z , J = 2 . 5 H z ) , a n d t h e s i g n a l a t 6 5 . 2 9 t o c o l l a p s e t o a d o f d ( J = 1 0 H z , J = 3 H z ) . E x a c t m a s s c a l c d . f o r C ^ H ^ O S i : 2 9 2 . 2 2 2 2 ; f o u n d : - -2 9 2 . 2 2 1 4 . 3.3.40 P r e p a r a t i o n o f 1 - M e t h y l - 4 - e x o - i s o p r o p y l b i c y c l o [ 3 . 2 . 1 ] -o c t - 2 - e n - 6 - o n e 256 A mixture of the s i l y l enol ether 341 (0.0587 g, 0.201 mmol), 5% aqueous hydrochloric acid (2 mL) and THF (4 mL) was s t i r r e d under an atmosphere of argon at room temperature for 3 h. The r e s u l t i n g reaction mixture was d i l u t e d with ether and was poured into saturated aqueous sodium bicarbonate, and the layers were separated. Subsequently, the aqueous layer was extracted thoroughly with ether, the organic extracts were combined and dried (anhydrous magnesium s u l f a t e ) . After removal of solvent under reduced pressure (water a s p i r a t o r ) , the residue thus obtained was subjected to f l a s h column chromatography (48 g of 230-400 mesh s i l i c a gel i n a 26x150 mm column, e l u t i o n with petroleum ether-ether, 4:1). Concen-t r a t i o n of the desired fract i o n s and Kugelrohr d i s t i l l a t i o n (air-bath temperature 69-73°C/0.1 Torr) of the material thus obtained, afforded the ketone 343 (0.0334 g, 93%) as a c l e a r , colourless l i q u i d . The ketone 343, a single component by glc (SE-54, 120°C) and t i c (petroleum ether-ether, 9:1) analyses exhibited i r ( f i l m ) : 3025, 1735, 1635, 725 cm"1; nmr (400 MHz, CDC13) 6: 0.91, 0.92 (d, d, 3H each, CH^-CH-CIL., J = 7 Hz), 1.19 (s, 3H, t e r t i a r y -CH_3) , 1.53-1.65 (m, IH, Hfi) , 1.69 (d of d, IH, H z, J I Z = 11.5 Hz, J p z = 5.5 Hz), 1.77-1.84 (m, IH, H c), 1.86 (d of d, IH, H^ ., J_JZ = 11.5 Hz, JJ;J = 3.5 Hz), 1.95 (d, IH, H x, J j X = 17 Hz), 2.24 (d of d, 1H, Hj, J j = 17 Hz, J I ( J = 3.5 Hz), 2.60 (unresolved d, IH, H p, = 5.5 Hz), 5.51 (d of d, IH, H n, J = 9.5 Hz, J__ = 3.5 Hz), 5.75 (d, IH, H , J_ = 9.5 Hz). In the following decoupling experiments, 2 5 7 t h e r e g i o n 6 1 . 0 0 - 3 . 0 0 w a s o b s e r v e d : i r r a d i a t i o n a t 6 5 . 5 1 ( H p ) c a u s e d t h e s i g n a l a t 6 1 . 7 7 - 1 . 8 4 t o c o l l a p s e t o a n u n -r e s o l v e d d ( J = 8 H z ) ; a n d i r r a d i a t i o n a t 6 2 . 6 0 ( H _ J c a u s e d — r t h e s i g n a l a t 6 1 . 6 9 t o c o l l a p s e t o a d ( J = 1 1 . 5 H z ) , a n d t h e s i g n a l a t 6 1 . 7 7 - 1 . 8 4 t o s h a r p e n . E x a c t m a s s c a l c d . f o r C , „ Hl o0 : 1 7 8 . 1 3 5 8 ; f o u n d : xZ xo 1 7 8 . 1 3 5 7 . 2 5 8 3 . 4 T h e T o t a l S y n t h e s i s o f ( + ) - S i n u l a r e n e 3 . 4 . 1 P r e p a r a t i o n o f 2 , 6 - D i m e t h y l - l - h e p t e n - 4 - y n - 3 - o l T o a s t i r r e d , c o l d ( - 7 8° C ) s o l u t i o n o f 3 - m e t h y l - l - b u t y n e ( 0 . 3 7 5 m L , 3 . 6 7 m m o l ) i n a n h y d r o u s T H F ( 5 m L ) w a s a d d e d a h e x a n e s o l u t i o n o f n - b u t y l l i t h i u m ( 4 . 0 4 m m o l ) , a n d t h e r e -s u l t i n g m i x t u r e w a s s t i r r e d a t - 3 0 ° C f o r 1 h . S u b s e q u e n t l y , m e t h a c r o l e i n ( 0 . 3 3 4 m L , 4 . 0 4 m m o l ) w a s a d d e d d r o p w i s e t o t h e y e l l o w r e a c t i o n m i x t u r e , w h i c h w a s t h e n s t i r r e d e f f i c i e n t l y a t - 3 0 ° C f o r a n o t h e r h o u r a n d t h e n w a s p o u r e d i n t o s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e . E t h e r w a s a d d e d t o t h e r e s u l t a n t m i x t u r e a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s p h a s e w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r a n d t h e c o m b i n e d e t h e r e x -t r a c t s w e r e w a s h e d s u c c e s s i v e l y w i t h s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e , s a t u r a t e d s o d i u m b i c a r b o n a t e , t w i c e w i t h b r i n e a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . C a r e f u l s o l -v e n t r e m o v a l u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) l e f t a v o l a t i l e , y e l l o w r e s i d u e , w h i c h w a s d i s t i l l e d ( a i r - b a t h t e m p -e r a t u r e 6 7 - 7 2 ° C / 0 . 1 T o r r ) t o f u r n i s h t h e a l l y l i c a l c o h o l 3 3 1 ( 0 . 5 0 6 g , > 9 8 % ) a s a c l e a r , c o l o u r l e s s o i l . A n a l y s i s b y g l c ( S E - 5 4 , 8 0 ° C ) i n d i c a t e d t h a t t h i s m a t e r i a l w a s o f > 9 8 % p u r i t y . 2 5 9 T h e a l c o h o l 3_31 e x h i b i t e d i r ( f i l m ) : 3 3 5 0 ( b r o a d ) , 3 0 6 5 , 2 2 2 0 ( d i s u b s t i t u t e d a l k y n e ) , 1 6 5 0 c m- 1; 1H n m r ( 8 0 M H z , C D C 13) 6 : •1.17 ( d , 6 H , C H3- C H - C H3, J = 7 H z ) , 1 . 7 7 ( b r o a d s , I H , - O H , D20 e x c h a n g e a b l e ) , 1 . 8 5 ( b r o a d s , 3 H , CH_3-C=) , 2 . 6 1 ( d o f s e p -t e t , I H , H , J = 6 . 5 H z , J _ , _ = 2 H z ) , 4 . 7 7 ( b r o a d s , I H , H - C - O H ) , 4 . 9 0 , 5 . 1 5 ( b r o a d s , b r o a d s , I H e a c h , H2C = C ) . E x a c t m a s s c a l c d . f o r C g H ^ O : 1 3 8 . 1 0 4 5 ; f o u n d : 1 3 8 . 1 0 4 4 . 3.4.2 P r e p a r a t i o n o f E t h y l ( E ) - 4 , 8 - d i m e t h y l - 4 - n o n e n - 6 - y n o a t e 3 3 2 1 1 1 c F o l l o w i n g t h e p r o c e d u r e r e p o r t e d b y J o h n s o n e t a l . 1 1 I d a n d l a t e r , b y P a r k e r a n d K o s l e y , t h e a l c o h o l 3 3 1 w a s t r a n s f o r m e d i n t o t h e e s t e r 3 3 2 v i a t h e o r t h o e s t e r C l a i s e n r e a r r a n g e m e n t . T h u s , a m i x t u r e o f t h e a l c o h o l 3 3 1 ( 0 . 4 5 9 g , 3 . 3 2 m m o l ) , t r i e t h y l o r t h o a c e t a t e ( 3 . 0 5 m L , 1 6 . 6 m m o l ) a n d p r o p i o n i c a c i d ( 0 . 0 1 4 9 m L , 0 . 2 0 0 m m o l ) w a s s t i r r e d a t 1 3 0 ° C f o r 2 0 h , b y w h i c h t i m e t i c a n a l y s i s ( p e t r o l e u m e t h e r - e t h e r , 7 : 1 ) i n d i c a t e d t h e a b s e n c e o f s t a r t i n g m a t e r i a l . M o s t o f t h e t r i e t h y l o r t h o a c e t a t e w a s r e m o v e d b y f r a c t i o n a l d i s t i l l a t i o n a t a t m o s p h e r i c p r e s s u r e a n d t h e s t i l l p o t r e s i d u e w a s s u b j e c t e d t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 1 2 5 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 4 5 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 2 6 0 2 5 : 1 ) . A f t e r r e m o v a l o f s o l v e n t f r o m t h e a p p r o p r i a t e f r a c t i o n s a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 8 1 - 8 6 ° C / 0 . 1 T o r r ) o f t h e o i l t h u s o b t a i n e d , t h e e s t e r 3 3 2 ( 0 . 4 0 2 g , 5 8 % ) w a s i s o l a t e d a s a n o d o r i f e r o u s , c o l o u r l e s s l i q u i d , w h i c h w a s s h o w n t o c o n s i s t o f o n e c o m p o n e n t b y g l c ( S E - 5 4 , 8 0 ° C ) a n d t i c a n a l y s e s . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1 7 3 0 c m ^ ; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 1 . 1 9 ( d , 6 H , C H3- C H - C H _3, J = 7 H z ) , 1 . 2 5 ( t , 3 H , C H _3C H2- 0 - , J = 7 H z ) , 1 . 8 7 ( s , 3 H , CH_3-C=) , 2 . 3 6 - 2 . 4 5 ( m , 4 H , 0 = C - C H2- C H _2- C = ) , 2 . 7 0 ( s e p t e t , I H , M e2C - H , J = 7 H z ) , 4 . 1 3 ( q , 2 H , C H3C H2~ 0 - , J = 7 H z ) , 5 . 2 9 ( b r o a d s , I H , H - C = ) . E x a c t m a s s c a l c d . f o r ci 3H2 0 ° 2: 2 0 8 . 1 4 6 3 ; f o u n d : 2 0 8 . 1 4 5 3 . 3 . 4 . 3 P r e p a r a t i o n o f ( E ) - 4 , 8 - D i m e t h y l - 4 - n o n e n - 6 - y n o i c a c i d 0 3 3 3 A m i x t u r e o f t h e e s t e r 3 3 2 ( 0 . 5 0 0 g , 2 . 4 0 m m o l ) , p o t a s s i u m h y d r o x i d e ( 0 . 2 7 6 g , 2 . 8 8 m m o l ) , w a t e r ( 1 m L ) a n d m e t h a n o l ( 1 0 m L ) w a s r e f l u x e d f o r 4 h.. T h e r e a c t i o n m i x t u r e w a s a l l o w e d t o c o o l t o r o o m t e m p e r a t u r e , c h e c k e d f o r b a s i c i t y t o l i t m u s p a p e r , a n d e x t r a c t e d t w i c e w i t h p e t r o l e u m e t h e r t o r e m o v e n o n p o l a r i m p u r i t i e s . T h e a q u e o u s l a y e r w a s f i l t e r e d 2 6 1 t h r o u g h a l a y e r o f C e l i t e a n d c o o l e d t o 0 ° C . T o t h e c o l d , e f f i c i e n t l y s t i r r e d s o l u t i o n , w a s a d d e d 1 0 % a q u e o u s h y d r o -c h l o r i c a c i d u n t i l t h e s o l u t i o n w a s a c i d i c t o l i t m u s p a p e r . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r a n d t h e o r g a n i c e x t r a c t s w e r e c o m b i n e d a n d d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) . E v a p o r a t i o n o f s o l v e n t a n d l o w - t e m p e r -a t u r e ( - 7 8° C ) r e c r y s t a l l i z a t i o n o f t h e r e s i d u a l m a t e r i a l f r o m h e x a n e f u r n i s h e d t h e a c i d 3 3 3 ( 0 . 2 9 4 g , 6 8 % ) a s a c o l o u r l e s s o i l , w h i c h g a v e a s i n g l e p e a k b y g l c ( O V - 1 7 , 1 0 0 ° C ) a n d e x -h i b i t e d i r ( f i l m ) : 3 3 0 0 - 2 5 0 0 , 1 7 0 5 c m- 1; 1H n m r ( 8 0 M H z , C D C 13) 5 : 1 . 2 2 ( d , 6 H , C H3- C H - C H _3, J = 7 H z ) , 1 . 9 0 ( s , 3 H , C H3- C = ) , 2 . 3 0 - 3 . 0 0 ( m , 5 H , M e2C - H , 0 = C - C H2- C H _2- C = ) , 5 . 3 0 ( b r o a d s , I H , H - C = ) , 1 0 . 8 5 ( b r o a d s , I H , H 02C - ) . E x a c t m a s s c a l c d . f o r C.-H-.^O-: 1 8 0 . 1 1 5 0 ; f o u n d : 1 8 0 . 1 1 5 1 . : 11 16 2 3 . 4 . 4 P r e p a r a t i o n o f ( E ) - 4 , 8 - D i m e t h y l - 4 - n o n e n - 6 - y n o y l c h l o r i d e 0 3 3 4 T h e p r o c e d u r e d e s c r i b e d b y H u d l i c k y e t a l . w a s f o l l o w e d t o c o n v e r t t h e a c i d 3 3 3 i n t o t h e c o r r e s p o n d i n g a c y l c h l o r i d e 3 3 4 . A c c o r d i n g l y , a s o l u t i o n o f t h e a c i d 3 3 3 ( 9 . 7 5 g , 5 4 . 1 m m o l ) a n d o x a l y l c h l o r i d e ( 1 4 . 2 m L , 1 6 2 . 4 m m o l ) i n a n h y d r o u s h e x a n e ( 2 3 5 m L ) w a s r e f l u x e d u n d e r a r g o n f o r 1 h . R e m o v a l o f s o l v e n t a n d e x c e s s o x a l y l c h l o r i d e w a s e f f e c t e d u n d e r r e d u c e d 2 6 2 p r e s s u r e ( w a t e r a s p i r a t o r ) . T h e b r o w n , o i l y s t i l l p o t r e s i d u e w a s d i s t i l l e d ( a i r - b a t h t e m p e r a t u r e 9 4 - 9 9 ° C / 0 . 1 T o r r ) t o a f f o r d 1 0 . 3 g ( > 9 8 % ) o f a p a l e y e l l o w l i q u i d . T h i s m a t e r i a l , w h i c h w a s i d e n t i f i e d a s t h e a c y l c h l o r i d e 3 3 4 , e x h i b i t e d i r ( f i l m ) : 2 2 0 0 ( d i s u b s t i t u t e d a l k y n e ) , 1 7 9 0 , 1 6 2 3 c m "1; 1H n m r ( 8 0 M H z , C D C 13) 6 1 . 2 0 ( d , 6 H , C H3- C H - C H _3, J = 7 H z ) , 1 . 8 8 ( s , 3 H , CH_3-C=) , 2 . 3 2 - 3 . 1 3 ( m , 5 H , M e2C - H , 0 = C - C H2- C H _2- C = ) , 5 . 3 1 ( b r o a d s , I H , H - C = ) . 3 7 E x a c t m a s s c a l c d . f o r C , , H1 C0 C l : 2 0 0 . 0 7 8 2 ; f o u n d : ± 1 I D 2 0 0 . 0 7 8 3 . 3 . 4 . 5 P r e p a r a t i o n o f ( E ) - l - D i a z o - 5 , 9 - d i m e t h y l - 5 - d e c e n - 7 - y n - 2 -o n e 0 3 3 5 A n e t h e r e a l s o l u t i o n o f d i a z o m e t h a n e w a s p r e p a r e d a s 2 0 6 d e s c r i b e d b y D e B o e r a n d B a c k e r . T o a c o l d ( 0° C ) , s t i r r e d s o l u t i o n o f d i a z o m e t h a n e ( 0 . 2 4 g , 5 . 6 7 m m o l ) i n e t h e r ( 1 5 m L ) w a s a d d e d d r o p w i s e , v i a a f l a m e - p o l i s h e d p i p e t t e , a s o l u t i o n o f t h e a c y l c h l o r i d e 3 3 4 ( 0 . 2 5 0 g , 1 . 2 6 m m o l ) i n e t h e r ( 3 m L ) . E v o l u t i o n o f n i t r o g e n g a s w a s a p p a r e n t a l m o s t i m m e d i a t e l y . T h e r e s u l t i n g m i x t u r e w a s s t i r r e d a t 0°C f o r 0 . 5 h , a n d a t r o o m t e m p e r a t u r e f o r 1 2 6 3 h . T h e r e s i d u a l d i a z o m e t h a n e w a s d i s p e l l e d b y b u b b l i n g a r g o n t h r o u g h t h e y e l l o w s o l u t i o n v i a a f l a m e - p o l i s h e d p i p e t t e f o r 0 . 5 h . D r y i n g ( a n h y d r o u s m a g n e s i u m s u l f a t e ) a n d c o n c e n t r a t i o n o f t h e y e l l o w e t h e r e a l s o l u t i o n y i e l d e d t h e d i a z o k e t o n e 3 3 5 ( 0 . 2 5 0 g , > 9 7 % ) a s a v i s c o u s y e l l o w s y r u p . T h e c r u d e d i a z o k e t o n e w a s n o t p u r i f i e d b u t w a s u s e d i m m e d i a t e l y i n t h e n e x t r e a c t i o n . A s a m p l e o f t h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3 0 7 0 , 2 2 0 0 , 2 0 8 5 , 1 6 3 3 c m- 1; 1H n m r ( 8 0 M H z , C D C 13) <S: 1 . 1 8 ( d , 6 H , C H3~ C H - C H3, J = 7 H z ) , 1 . 8 8 ( s , 3 H , CH_3-C=) , 2 . 4 0 ( s , 4 H , 0 = C - C H - C H - C = ) , 2 . 7 0 ( s e p t e t , I H , M e2C - H , J = 7 H z ) , 5 . 2 1 ( s , I H , N = N = C - H ) , 5 . 2 8 ( b r o a d s , I H , H - C = ) . m s m / e : 2 0 4 ( M+) , 1 7 6 ( M - N2)+ 3 . 4 . 6 P r e p a r a t i o n o f 5 - M e t h y 1 - 6 - e x o - ( 3 - m e t h y l - l - b u t y n y l ) -b i c y c l o [ 3 . 1 . 0 ] h e x a n - 2 - o n e 3 3 6 I n a c c o r d a n c e w i t h a p r o c e d u r e d e s c r i b e d b y H u d l i c k y e t 9 8 a l . , t h e d i a z o k e t o n e 3 3 5 w a s c o n v e r t e d i n t o t h e b i c y c l i c 1 6 3 k e t o n e 3 3 6 . T o a s t i r r e d s u s p e n s i o n o f C u ( a c a c )2' H20 ( 0 . 0 2 2 g , 0 . 0 8 4 m m o l ) i n r e f l u x i n g a n h y d r o u s b e n z e n e ( 6 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d d r o p w i s e , v i a a n a d d i t i o n f u n -n e l , a s o l u t i o n o f t h e d i a z o k e t o n e 3 3 5 ( 0 . 2 2 8 g , 1 . 1 2 m m o l ) 2 6 4 i n a n h y d r o u s b e n z e n e ( 3 m L ) . W h e n t h e a d d i t i o n w a s c o m p l e t e , t h e r e s u l t i n g d a r k b r o w n m i x t u r e w a s r e f l u x e d f o r a n h o u r a n d t h e n w a s c o o l e d t o r o o m t e m p e r a t u r e . M o s t o f t h e b e n z e n e w a s c a r e f u l l y r e m o v e d u n d e r r e d u c e d p r e s s u r e ( w a t e r a s p i r a t o r ) a n d t h e r e s i d u e w a s s u b j e c t e d t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 7 0 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 3 5 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 3 : 1 ) . T h e d e s i r e d f r a c t i o n s w e r e c o n c e n t r a t e d t o g i v e a y e l l o w o i l , w h i c h w a s d i s t i l l e d ( a i r -b a t h t e m p e r a t u r e 8 5 - 8 8 ° C / 0 . 1 T o r r ) t o a f f o r d 0 . 1 6 g ( 8 1 % ) o f a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l , s h o w n t o b e t h e d e -s i r e d k e t o n e 3 3 6 , c o n s i s t e d o f a s i n g l e c o m p o n e n t b y g l c ( S E -5 4 , 1 2 0 ° C ) a n d t i c ( p e t r o l e u m e t h e r - e t h e r , 3 : 1 ) a n a l y s e s , a n d e x h i b i t e d i r ( f i l m ) : 1 7 2 5 , 1 1 7 2 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 1 . 1 4 ( d , 6 H , C H _3- C H - C H3, J = 7 H z ) , 1 . 4 4 ( s , 3 H , t e r t i a r y - C H - ) , 1 . 6 9 ( d , I H , H _ , J _ _ = 3 H z ) , 1 . 8 7 ( o v e r l a p p i n g d o f — J r —hit d , I H , H£, J£ F = 3 H z , Jf i E = 1 . 7 H z ) , 1 . 9 4 - 2 . 1 4 ( m , 4 H , 0 = C - C H „ - C H - ) , 2 . 5 3 ( d o f s e p t e t , I H , H , J = 7 H z , J _ _ = 1 . 7 — / — z a — — J O J C J H z ) . I r r a d i a t i o n a t 6 1 . 8 7 ( H _ ) c a u s e d t h e s i g n a l a t 6 1 . 6 9 t o c o l l a p s e t o a s , a n d t h e s i g n a l a t 6 2 . 5 3 t o c o l l a p s e t o a s e p t e t ( J = 7 H z ) . E x a c t m a s s c a l c d . f o r C,_H..^O: 1 7 6 . 1 2 0 1 ; f o u n d : 1 7 6 . 1 1 9 6 . 1 z ±b A n a l , c a l c d . f o r C.-H-.^O: C 8 1 . 7 6 , H 9 . 1 6 ; f o u n d : C 8 1 . 6 9 , ±z l b H 9 . 2 0 . 2 6 5 3.4.7 P r e p a r a t i o n o f 5 - M e t h y l - 6 - e x o - [ ( Z ) - 3 - m e t h y l - l - b u t e n y l ] -b i c y c l o [ 3 . 1 . 0 ] h e x a n - 2 - o n e Me 3 3 7 A s u s p e n s i o n o f 5 % p a l l a d i u m s u p p o r t e d o n c a l c i u m c a r b o n -a t e ( 0 . 0 4 8 7 g , p r e p a r e d w i t h l e a d a c e t a t e a s d e s c r i b e d b y 1 6 9 L i n d l a r a n d D u b o i s ) i n a n h y d r o u s p e n t a n e ( 7 m L ) w a s p r e -h y d r o g e n a t e d . T o t h e r e s u l t i n g m i x t u r e w a s a d d e d d r o p w i s e , v i a a s y r i n g e , a s o l u t i o n o f t h e a l k y n e 3 3 6 ( 0 . 9 7 3 g , 5 . 5 3 m m o l ) i n p e n t a n e ( 3 m L ) , a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d e f f i c i e n t l y u n d e r h y d r o g e n . T h e p r o g r e s s o f t h e r e a c t i o n w a s e a s i l y m o n i t o r e d b y g l c ( S E - 5 4 , 1 2 0 ° C ) a n d a f t e r 3 h , a l l b u t a t r a c e o f s t a r t i n g m a t e r i a l h a d b e e n c o n s u m e d . F i l t r a t i o n o f t h e r e a c t i o n m i x t u r e t h r o u g h a l a y e r o f C e l i t e a n d c o n c e n -t r a t i o n o f t h e f i l t r a t e y i e l d e d a c o l o u r l e s s o i l , w h i c h w a s s u b j e c t e d t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 1 2 5 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 4 5 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 5 : 1 ) . A f t e r c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s , K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p e r a t u r e 7 8 -8 0 ° C / 0 . 1 T o r r ) o f t h e r e s u l t a n t o i l f u r n i s h e d t h e a l k e n e 3 3 7 C O . 9 0 0 g , 9 1 % ) a s a c l e a r , c o l o u r l e s s o i l . G l c a n a l y s i s ( S E -5 4 , 1 2 0 ° C ) o f t h i s m a t e r i a l r e v e a l e d t h e p r e s e n c e o f o n l y o n e c o m p o n e n t a n d t i c a n a l y s i s ( p e t r o l e u m e t h e r - e t h e r , 5 : 1 ) s h o w e d 2 6 6 a single spot. The alkene 337 exhibited i r (film): 3001, 1719, -1 1. H nmr (400 MHz, CDC13) 6: 0.98, 1.00 (d, d, 3H 1650 cm each, CH3-CH-CH_3, J = 7 Hz) , 1.32 (s, 3H, t e r t i a r y -CH_3) , 1.57 (unresolved d, IH, H_, J = 2 Hz), 1.90-2.25 (m, 5H, r — 0=C-CH„-CH -, H^) , 2.60-2.73 (m, IH, H,,) , 4.91 (overlapping d of d, IH, H^, J „ = 11.5 Hz, J__ = 10 Hz), 5.36 (overlapping d of d, IH, H c, ^ = 11.5 Hz, J B C = 10 Hz). Exact mass calcd. for C 1 2 H 1 8 0 : 178.1358; found: 178.1357. 3.4.8 Preparation of 5-Methyl-6-exo-[(Z)-3-methyl-l-butenyl]-bicyclo[3.1.0]hex-3-en-2-one Me^SiO 345 a) V ia palladium (II) mediated o x i d a t i o n 1 1 6 of the t r i m e t h y l s i l y l enol ether 345 According to the procedure outlined by Seitz and 209 F e r r e r i a , t r i m e t h y l s i l y l iodide was prepared i n the following manner. A mixture of iodine (3.55 g, 14.0 mmol) and hexamethyl-d i s i l a n e (2.87 mL, 14.0 mmol) was warmed under argon for 0.5 h at 50°C. The t r i m e t h y l s i l y l iodide was cooled to room temper-ature, taken up i n a syringe, and added dropwise to a cold (-78°C), s t i r r e d solution of the ketone 337 (0.713 g, 4.00 mmol) and triethylamine (4.46 mL, 32.0 mmol) i n anhydrous dichloro-methane (40 mL). The r e s u l t i n g dark orange suspension was 2 6 7 s t i r r e d a t - 7 8 ° C . A f t e r 0 . 5 h , g l c a n a l y s i s ( S E - 5 4 , 1 2 0 ° C ) i n d i c a t e d t h a t a l l o f t h e s t a r t i n g m a t e r i a l h a d b e e n c o n s u m e d . T h e r e a c t i o n m i x t u r e w a s d i l u t e d w i t h e t h e r a n d p o u r e d i n t o a 1 : 1 m i x t u r e o f 5 % a q u e o u s s o d i u m t h i o s u l f a t e a n d s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e . T h e l a y e r s w e r e s e p a r a t e d , a n d t h e o r g a n i c l a y e r w a s d r i e d o v e r m a g n e s i u m s u l f a t e a n d c o n c e n -t r a t e d . T h e r e s i d u a l m a t e r i a l , w h i c h w a s s h o w n b y g l c a n a l y s i s t o c o n s i s t o f a 1 2 : 1 m i x t u r e o f t h e s i l y l e n o l e t h e r 3 4 5 a n d t h e s t a r t i n g m a t e r i a l 3 3 7 , w a s o x i d i z e d i m m e d i a t e l y i n t h e n e x t r e a c t i o n . T h e c r u d e e n o l e t h e r w a s t a k e n u p i n a c e t o n i t r i l e ( 3 m L ) a n d t h e s o l u t i o n w a s a d d e d d r o p w i s e , v i a a s y r i n g e , t o a s t i r r e d s u s p e n s i o n o f p a l l a d i u m ( I I ) a c e t a t e ( 1 . 8 0 g , 8 . 0 0 m m o l ) i n a n h y d r o u s a c e t o n i t r i l e ( 3 m L ) . T h e i n i t i a l l y o r a n g e s u s p e n s i o n b e c a m e b l a c k i m m e d i a t e l y o n a d d i t i o n o f t h e e n o l e t h e r s o l u t i o n . S t i r r i n g o f t h e r e s u l t i n g m i x t u r e w a s c o n t i n u e d f o r 1 h . T h e r e a c t i o n m i x t u r e w a s f i l t e r e d , w a s h e d t w i c e w i t h s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e , d r i e d ( a n h y d r o u s m a g -n e s i u m s u l f a t e ) a n d c o n c e n t r a t e d t o g i v e a d a r k b r o w n o i l . S u b j e c t i o n o f t h e r e s i d u e t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 7 0 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 4 5 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 7 : 1 ) a n d c o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a f f o r d e d 0 . 5 5 4 g o f a c l e a r , c o l o u r l e s s o i l . A c c o r d i n g t o g l c a n a l y s i s ( S E - 5 4 , 1 2 0 ° C ) , t h i s m a t e r i a l w a s a 5 : 1 m i x t u r e o f t h e e n o n e 3 3 8 a n d t h e k e t o n e 3 3 7 , r e s p e c t -i v e l y . T h e r e t e n t i o n t i m e o f t h e m a j o r c o m p o n e n t w a s i d e n t i c a l 2 6 8 w i t h t h a t o f t h e e n o n e 3 3 8 p r e p a r e d v i a s e l e n o x i d e e l i m i n a t i o n . A t t e m p t s t o r e s o l v e t h e m i x t u r e o f 3 3 8 a n d 3 3 7 b y g l c o r t i c w e r e n o t s u c c e s s f u l . C o n s e q u e n t l y , t h e m i x t u r e w a s u s e d i n t h e n e x t r e a c t i o n . 1 2 3 b ) V i a s e l e n o x i d e e l i m i n a t i o n T o a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f l i t h i u m d i i s o -p r o p y l a m i d e ( 2 . 3 0 m m o l ) i n a n h y d r o u s T H F ( 1 5 m L ) , u n d e r a n a t m o s p h e r e o f a r g o n , w a s a d d e d d r o p w i s e a s o l u t i o n o f t h e k e t o n e 3 3 7 ( 0 . 2 7 3 g , 1 . 5 3 m m o l ) i n T H F ( 3 m L ) , a n d t h e r e -s u l t i n g m i x t u r e w a s s t i r r e d a t - 7 8 ° C f o r 0 . 5 h . A s o l u t i o n o f p h e n y l s e l e n e n y l c h l o r i d e ( 0 . 4 4 0 g , 2 . 3 0 m m o l ) i n T H F ( 4 m L ) w a s a d d e d d r o p w i s e a n d t h e r e a c t i o n m i x t u r e w a s s t i r r e d a t 0°C f o r 0 . 5 h . S u b s e q u e n t l y , a c e t i c a c i d ( 0 . 1 7 5 m L , 3 . 0 6 m m o l ) a n d a s o l u t i o n o f 3 0 % a q u e o u s h y d r o g e n p e r o x i d e ( 0 . 8 6 8 g ) d i l u t e d w i t h w a t e r ( 2 m L ) w e r e a d d e d , t h e l a t t e r d r o p w i s e . T h e r e a c t i o n m i x t u r e w a s m a i n t a i n e d a t 0°C w i t h e f f i c i e n t s t i r r i n g f o r a n o t h e r 0 . 5 h , d i l u t e d w i t h p e t r o l e u m e t h e r - e t h e r ( 1 : 1 ) a n d p o u r e d i n t o s a t u r a t e d a q u e o u s s o d i u m b i c a r b o n a t e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d t h o r o u g h l y w i t h e t h e r . T h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d t w i c e w i t h b r i n e , d r i e d ( a n h y d r o u s m a g n e s i u m s u l f a t e ) a n d c o n c e n t r a t e d . S u b j e c t i o n o f t h e r e s u l t i n g r e s i d u e t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 7 0 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 3 3 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 7 : 1 ) , c o n c e n t r a t i o n o f t h e d e s i r e d f r a c t i o n s , a n d K u g e l r o h r d i s t i l -l a t i o n ( a i r - b a t h t e m p e r a t u r e 7 6 - 8 0 ° C / 0 . 1 T o r r ) f u r n i s h e d t h e 2 6 9 e n o n e 3 3 8 ( 0 . 1 3 6 g , 5 0 % ) . A n a l y s i s b y t i c ( p e t r o l e u m e t h e r -e t h e r , 7 : 1 ) i n d i c a t e d t h a t t h i s m a t e r i a l c o n s i s t e d o f o n l y o n e c o m p o n e n t . T h e e n o n e 3 3 8 e x h i b i t e d i r ( f i l m ) : 3 0 2 5 , 3 0 0 0 , -1 1 , H n m r ( 4 0 0 M H z , C D C 13) 6 0 . 9 7 , 1 6 9 0 , 1 4 6 0 , 1 1 7 5 , 7 6 7 c m 0 . 9 8 ( d , d , 3 H e a c h , C H3~ C H - C H3, J = 7 H z ) , 1 . 4 5 ( s , 3 H , t e r t i a r y - C H _ ) , 1 . 9 9 ( u n r e s o l v e d d , I H , H „ , J „ „ = 3 H z ) , 2 . 3 6 ( d o f d , I H , H _ , J _ _ = 9 . 5 H z , J _ _ = 3 H z ) , 2 . 6 0 - 2 . 7 3 ( m , I H , hi —Dhi —hit HB) , 4 . 9 1 ( o v e r l a p p i n g d o f d o f d , I H , Hn, J ^n = 1 2 H z , J . —DE = 9 . 5 H z , J _ _ = 1 H z ) , 5 . 4 0 ( o v e r l a p p i n g d o f d o f d , I H , V\„, —13D C = 1 2 H z , JB C = 9 H z , ^ < 1 H z ) , 5 . 6 6 ( d o f d , l H , H J R JT T = 5 . 5 H z , J _ _ = 1 H z ) , 7 . 5 2 ( d o f d , I H , H , J _ _ = 5 . 5 H z , - F l = 1 H z ) . I r r a d i a t i o n a t 6 4 . 9 1 ( H p ) c a u s e d t h e s i g n a l a t 6 2 . 3 6 t o s i m p l i f y , t h e s i g n a l a t 6 2 . 6 0 - 2 . 7 3 t o s h a r p e n , a n d t h e s i g n a l a t 6 5 . 4 0 t o c o l l a p s e t o a d ( J = 9 H z ) ; i r r a d i a t i o n a t 6 7 . 5 2 ( H j ) c a u s e d t h e s i g n a l a t 6 1 . 9 9 t o c o l l a p s e t o a d o f d ( J = 3 H z , ' J = 1 H z ) , a n d t h e s i g n a l a t 6 5 . 6 6 t o c o l l a p s e t o a d ( J = 1 H z ) . E x a c t m a s s c a l c d . f o r C . . H . , 0 : 1 7 6 . 1 2 0 1 ; f o u n d : 1 7 6 . 1 2 0 3 . LA l b 3 . 4 . 9 P r e p a r a t i o n o f 5 - M e t h y l - 6 - e x o - [ ( Z ) - 3 - m e t h y l - l - b u t e n y l ] -4 - e x o - v i n y l b i c y c l o [ 3 . 1 . 0 ] h e x a n - 2 - o n e 270 a) V ia copper-catalyzed Grignard reaction with the enone 338 i j w »„• • • 109,110 . , As previously reported by Miginiac, v i n y l mag-nesium bromide was prepared i n the following manner. To a flame-dried three-necked flask f i t t e d with a dry-ice condenser and argon gas i n l e t adaptor, was added magnesium turnings (0.0203 g, 0.835 mmol), anhydrous THF (3 mL) and a few cry s t a l s of iodine. A solution of v i n y l bromide (0.060 mL, 0.835 mmol) i n THF (1 mL) was added dropwise v i a a syringe u n t i l the reaction had i n i t i a t e d and thereafter, at a rate to maintain mild r e f l u x . After the addition was complete, the mixture was refluxed for 0.3 h to give a clear, yellow solution, half of which was transferred v i a a syringe to another flask and cooled to - 3 0 ° C . To the cold ( - 3 0° C ) , e f f i c i e n t l y s t i r r e d THF solution of v i n y l magnesium bromide, was added copper (I) bromide-dimethyl s u l f i d e complex 1 3^ 1 3 6 (14.3 mg, 0.0696 mmol) and the mixture was s t i r r e d at - 3 0°C for 10 min, affording a green suspension. A solution of the enone 338 (0.0490 g, 0.278 mmol) i n THF (3 mL) was introduced dropwise to the reaction mixture over a period of 10 min, a f t e r which time, a brownish-green mixture was obtained. The r e s u l t i n g mixture was allowed to warm to 0°C over a period of 4 0 min, d i l u t e d with ether and poured into saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted thoroughly with ether. Af t e r the combined organic layers were washed successively 271 with saturated aqueous sodium bicarbonate and twice with brine, dried (anhydrous magn sium sulfate) and concentrated, 36 mg of a pale yellow o i l was obtained. This material displayed two spots by t i c (petroleum ether-ether, 7:1) and was shown by glc analysis (SE-54, 120°C) to consist of a 9:4 mixture of the desired ketone 339 and the epimer 346. 134 b) Via conjugate addition of lithium divinylcuprate to the enone 338 T e t r a v i n y l t i n was prepared from t i n (IV) chloride and 181 182 v i n y l magnesium bromide as outlined by Seyferth et a l . ' To a s t i r r e d solution of t e t r a v i n y l t i n (0.258 g, 1.14 mmol) i n anhydrous ether (5 mL), under an atmosphere of argon, was added dropwise a solution of phenyllithium (4.54 mmol) i n a mixture of cyclohexane and ethyl ether. A white p r e c i p i t a t e formed almost immediately and the r e s u l t i n g reaction mixture was s t i r r e d f o r 0.5 h. The s t i r r i n g was stopped and the white p r e c i p i t a t e was allowed to s e t t l e to the bottom of the fl a s k . Via a syringe, the pale yellow supernatant was transferred to another f l a s k and cooled to -63°C with e f f i c i e n t s t i r r i n g . Cuprous bromide-dimethyl s u l f i d e c o m p l e x 1 3 4 - 1 3 6 (0.467 g, 2.27 mmol) was added and the r e s u l t i n g mixture was s t i r r e d at -63°C for 0.3 h to furnish a dark grey suspension. Subsequently, 0.200 g of a 85:15 (glc analysis: SE-54, 120°C) mixture of the enone 338 and the ketone 337, respectively, was dissolved i n ether (3 mL) and thi s solution was added dropwise v i a a syringe to the cuprate mixture. During addition of the substrate, the 2 7 2 r e a c t i o n m i x t u r e b e c a m e d a r k p u r p l e . T h e r e s u l t i n g m i x t u r e w a s s t i r r e d e f f i c i e n t l y a t - 3 0 ° C f o r 0 . 2 5 h a n d t h e n a t r o o m t e m p e r a t u r e f o r 1 h . S a t u r a t e d a q u e o u s b a s i c ( p H 8 ) a m m o n i u m c h l o r i d e ( 6 m L ) a n d e t h e r ( 5 m L ) w e r e a d d e d a n d t h e r e s u l t i n g m i x t u r e w a s s t i r r e d v i g o r o u s l y u n t i l t h e a q u e o u s l a y e r b e c a m e d e e p b l u e . T h e l a y e r s w e r e s e p a r a t e d a n d t h e a q u e o u s p h a s e w a s e x t r a c t e d t w i c e w i t h e t h e r . T h e e t h e r e a l l a y e r s w e r e c o m b i n e d , w a s h e d s u c c e s s i v e l y w i t h s a t u r a t e d a q u e o u s p H 8 a m m o n i u m c h l o r i d e a n d b r i n e , a n d d r i e d o v e r m a g n e s i u m s u l f a t e . S o l v e n t r e m o v a l y i e l d e d a p a l e y e l l o w o i l w h i c h w a s s u b j e c t e d t o c o l u m n c h r o m a t o g r a p h y ( 5 0 g o f 7 0 - 2 3 0 m e s h s i l i c a g e l i n a 1 9 x 3 8 4 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 5 : 1 ) . C o n c e n t r a t i o n o f t h e a p p r o p r i a t e f r a c t i o n s a f f o r d e d t h e d e -s i r e d p r o d u c t 3 3 9 ( 0 . 1 3 6 g , 6 9 % , a i r - b a t h d i s t i l l a t i o n t e m p -e r a t u r e 9 3 - 9 7 ° C / 0 . 1 T o r r ) , t h e e p i m e r 3 4 6 ( 0 . 0 1 5 g , 8 % , a i r -b a t h d i s t i l l a t i o n t e m p e r a t u r e 9 1 - 9 5 ° C / 0 . 1 T o r r ) a n d t h e k e t o n e 3 3 7 ( 0 . 0 1 1 6 g ) . T h e k e t o n e 3 3 9 e x h i b i t e d i r ( f i l m ) : 3 0 7 0 , 3 0 0 0 , 1 7 2 2 , 1 6 3 5 , 9 2 0 c m- 1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 1 . 0 0 , 1 . 0 1 ( d , d , 3 H , C H3- C H - C H3, J = 6 . 5 H z ) , 1 . 2 0 ( s , 3 H , t e r t i a r y -CH_3) , 1 . 6 3 ( b r o a d s , I H , Hp, w . ^ = 5 . 5 H z ) , 1 . 8 9 ( d , I H , Hz, J T „ = 1 8 . 5 H z ) , 2 . 1 5 ( d o f d o f d , I H , H ^ , J = 8 . 5 H z , J ^ = —x o ti —Dti — E r 3 H z , J Y _ = 1 H z ) , 2 . 5 5 ( d o f d , I H , H , J _ _ = 1 8 . 5 H z , J T _ = —Cr* X — L L —XJ 8 H z ) , 2 . 6 7 ( d o f d o f s e p t e t , I H , HD, J _ , _ = 9 . 5 H z , J = 6 . 5 H z , J _ _ < 1 H z ) , 2 . 9 1 ( o v e r l a p p i n g d o f d , I H , H , J T T , = 1 0 — r J D J — J K H z , J _ _ = 8 H z ) , 4 . 9 1 ( o v e r l a p p i n g d o f d o f d , I H , H _ , J _ , _ = —XJ D - C D 1 0 . 5 H z , J D E = 8 . 5 H z , J B D < 1 H z ) , 5 . 0 4 - 5 . 1 2 ( m , 2 H , H ^ , H ^ ) , 2 7 3 5 . 3 9 ( o v e r l a p p i n g d o f d o f d , I H , H _ , = 1 0 . 5 H z , J _ _ = C — C D —ESC 9 . 5 H z , J _ _ = 1 H z ) , 5 . 7 2 ( o v e r l a p p i n g d o f d o f d , I H , H „ , — C E i J\ J - . .T = 1 7 H z , J = 1 0 H z , J _ _ = 1 0 H z ) . I r r a d i a t i o n a t 6 2 . 1 5 (H ) c a u s e d a n u c l e a r O v e r h a u s e r e n h a n c e m e n t ( n . O . e . ) a t 6 Ei 2 . 5 5 , 6 2 . 6 7 a n d 6 2 . 9 1 ; i r r a d i a t i o n a t <5 5 . 3 9 ( H ) c a u s e d t h e s i g n a l a t 6 2 . 1 5 t o c o l l a p s e t o a d o f d ( J = 8 . 5 H z , J = 3 H z ) , t h e s i g n a l a t 6 2 . 6 7 t o c o l l a p s e t o a n u n r e s o l v e d s e p t e t ( J = 6 . 5 H z ) , a n d t h e s i g n a l a t <S 4 . 9 1 t o c o l l a p s e t o a n u n -r e s o l v e d d ( J = 8 . 5 H z ) ; i r r a d i a t i o n a t 6 4 . 9 1 ( H p ) c a u s e d t h e s i g n a l a t 6 2 . 1 5 t o c o l l a p s e t o a n o v e r l a p p i n g d o f d ( J = 3 H z , J = 1 H z ) , t h e s i g n a l a t 6 2 . 6 7 t o c o l l a p s e t o a d o f s e p -t e t ( J = 9 . 5 H z , J = 6 . 5 H z ) , a n d t h e s i g n a l a t 6 5 . 3 9 t o c o l -l a p s e t o a n u n r e s o l v e d d ( J = 9 . 5 H z ) ; i r r a d i a t i o n a t 6 2 . 1 5 ( H p ) c a u s e d t h e s i g n a l a t 6 1 . 6 3 t o s h a r p e n , t h e s i g n a l a t 6 4 . 9 1 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 1 0 . 5 H z ) , a n d t h e s i g n a l a t 6 5 . 3 9 t o c o l l a p s e t o a d o f d ( J = 1 0 . 5 H z , J = 9 . 5 H z ) ; a n d i r r a d i a t i o n a t 6 2 . 9 1 ( HT) c a u s e d t h e s i g n a l a t 6 2 . 5 5 t o c o l l a p s e t o a d ( J = 1 8 . 5 H z ) , t h e s i g n a l a t 6 5 . 0 4 - 5 . 1 2 t o c o l l a p s e t o a n o v e r l a p p i n g p a i r o f d o f d ( J = 1 7 H z , J = 1 0 H z , ' J = 1 . 5 H z ) , a n d t h e s i g n a l a t 6 5 . 7 2 t o c o l l a p s e t o a d o f d ( J = 1 7 H z , J = 1 0 H z ) . E x a c t m a s s c a l c d . f o r c±4H2 o0 : 2 0 4- 1 5 1 4 ; f o u n d : 2 0 4 . 1 5 1 7 . T h e e p i m e r 3 4 6 e x h i b i t e d 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 1 . 0 0 ( d , 6 H , C H3- C H - C H3, J = 6 . 5 H z ) , 1 . 3 1 ( s , 3 H , t e r t i a r y -CH_3) , 1 . 6 3 ( b r o a d s , I H , Hp, = 5 . 5 H z ) , 2 . 0 8 ( d o f d , I H , H^., 2 7 4 J T R 7 = 1 8 H z , J _ _ = 9 . 5 H z ) , 2 . 2 0 - 2 . 2 9 ( m , 2 H , H _ , H J , 2 . 6 8 — J . ii — J . J Hi il ( d o f d o f s e p t e t , I H , H n , J _ _ = 9 . 5 H z , J = 6 . 5 H z , J „ < 1 H z ) , 2 . 9 1 ( o v e r l a p p i n g d o f d o f d , I H , H j , J = 9 . 5 H z , = 9 H z , = 7 H z ) , 4 . 8 9 ( o v e r l a p p i n g d o f d o f d , I H , H p , J ^ P = 1 0 . 5 H z , J p j . = 9 H z , J B D < 1 H z ) , 5 . 1 0 - 5 . 1 7 ( m , 2 H , H^, H ) , 5 . 3 8 ( o v e r l a p p i n g d o f d o f d , I H , H c , = 1 0 . 5 H z , J^c = 9 . 5 H z , JCJ; = 1 H z ) , 5 . 8 3 ( d o f d o f d , I H , H R , J _ K N = 1 7 . 5 H z , J „ . . = 1 0 H z , J T V = 7 H z ) . I r r a d i a t i o n a t 6 4 . 8 9 —KM ' —JK ( H p ) c a u s e d t h e s i g n a l a t 6 2 . 2 0 - 2 . 2 9 t o s i m p l i f y , t h e s i g n a l a t 6 2 . 6 8 t o c o l l a p s e t o a d o f d ( J = 9 . 5 H z , J = 6 . 5 H z ) , a n d t h e s i g n a l a t 6 5 . 3 8 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 9 . 5 H z ) ; i r r a d i a t i o n a t 6 1 . 6 3 (H,,) c a u s e d t h e s i g n a l a t 6 2 . 2 0 - 2 . 2 9 t o c o l l a p s e t o a p a i r o f d ( J = 1 8 H z , J = 9 H z ) ; i r r a d i a t i o n a t 6 2 . 9 1 (H ) c a u s e d t h e s i g n a l a t 6 2 . 0 8 t o c o l l a p s e t o a d ( J = 1 8 H z ) , t h e s i g n a l a t 6 2 . 2 0 - 2 . 2 9 t o s i m p l i f y , t h e s i g n a l a t 6 5 . 1 0 - 5 . 1 7 t o c o l l a p s e t o a p a i r o f " d o f d ( J = 1 7 . 5 H z , J = 1 0 H z , J = 1 . 5 H z ) , a n d t h e s i g n a l a t 6 5 . 8 3 t o c o l l a p s e t o a d o f d ( J = 1 7 . 5 H z , J = 1 0 H z ) ; a n d i r r a d i a t i o n a t 6 5 . 1 0 - 5 . 1 7 ( H M , H N) c a u s e d t h e s i g n a l a t 6 2 . 9 1 t o s h a r p e n , a n d t h e s i g n a l a t 6 5 . 8 3 t o c o l l a p s e t o a d ( J = 7 H z ) . m s m / e : 2 0 4 ( M+) , 1 8 9 , 1 6 2 ( 1 0 0 % ) 2 7 5 3 . 4 . 1 0 P r e p a r a t i o n o f 2 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 5 - m e t h y 1 -6 - e x o - [ (Z^) - 3 - m e t h y l - l - b u t e n y l I - 4 - e x o - v i n y l b i c y c l o -[ 3 . 1 . 0 ] h e x - 2 - e n e M e\ HB . M e ME I n a c c o r d a n c e w i t h g e n e r a l p r o c e d u r e A , t h e k e t o n e 3 3 9 ( 0 . 6 2 3 g , 3 . 0 5 m m o l ) w a s c o n v e r t e d s m o o t h l y i n t o t h e s i l y l e n o l e t h e r 3 2 2 ( 0 . 9 3 3 g , 9 6 % , a i r - b a t h d i s t i l l a t i o n t e m p e r a -t u r e 1 1 8 - 1 2 3 ° C / 0 . 1 T o r r ) . T h i s m a t e r i a l w a s e s s e n t i a l l y p u r e b y g l c a n a l y s i s ( S E - 5 4 , 1 2 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 3 0 5 5 , 1 6 3 5 , 1 6 2 0 , 9 6 0 , 9 2 0 , 7 9 0 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 1 7 ( s , 6 H , C H3- S i - C H3) , 0 . 9 4 ( s , 9 H , (CH_3) C - S i - O - ) , 0 . 9 9 ( d , 6 H , C H3- C H - C H3, J = 7 H z ) , 1 . 1 3 ( s , 3 H , t e r t i a r y -CH_3) , 1 . 3 4 ( o v e r l a p p i n g d o f d , I H , H _ , J _ _ = 2 . 5 H z , J _ _ = 1 H z ) , h —hit — r J . 1 . 4 0 ( u n r e s o l v e d d o f d , I H , H „ , J _ _ = 9 H z , J _ _ = 2 . 5 H z ) , ti —Li hi —x j r 2 . 7 1 ( d o f d o f s e p t e t , I H , H _ , = 9 H z , J = 7 H z , = hi —r>C — —h\Li 1 H z ) , 3 . 1 0 ( u n r e s o l v e d d , I H , H _ , J-v = 9 H z ) , 4 . 2 0 ( d o f d , J — J IN. I H , H j , J J J = 2 . 5 H z , JF I = 1 H z ) , 4 . 9 2 ( o v e r l a p p i n g d o f d o f d , I H , HD, = 1 1 H z , JD E = 9 H z , JB D = 1 H z ) , 4 . 9 8 ( d o f d , I H , HM, J m = 1 0 H z , = 2 H z ) , 5 . 0 4 ( d o f d o f d , I H , HN ' - K N = 1 7 H z' ^MN = 2 H z' J jN = 1 H z ) , 5 . 2 9 ( o v e r l a p p i n g d o f d o f d , I H , Hc, = 1 1 H z , JB C = 9 H z , JC E = 1 H z ) , 5 . 7 4 id o f d o f d , I H , HK, JK N = 1 7 H z , JK M = 1 0 H z , J jK = 9 H z ) . 2 7 6 E x a c t m a s s c a l c d . f o r C ^ H ^ C - S i : 3 1 8 . 2 3 7 9 ; f o u n d : 3 1 8 . 2 3 7 0 . 3 . 4 . 1 1 P r e p a r a t i o n o f 6 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 1 - m e t h y l -4 - e x o - i s o p r o p y l - 8 - e x o - v i n y l b i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n e Ki Me HB F o l l o w i n g g e n e r a l p r o c e d u r e B , a s o l u t i o n o f t h e s i l y l e n o l e t h e r 3 2 2 ( 0 . 1 7 0 g , 0 . 5 3 4 m m o l ) i n b e n z e n e ( 3 m L ) w a s t h e r m o l y z e d a t 2 2 0 ° C f o r 4 . 5 h t o a f f o r d , a f t e r p u r i f i c a t i o n o f t h e c r u d e p r o d u c t b y c o l u m n c h r o m a t o g r a p h y ( 7 0 - 2 3 0 m e s h n e u t r a l a l u m i n a p r e t r e a t e d w i t h t r i e t h y l a m i n e , e l u t i o n w i t h p e t r o l e u m e t h e r ) a n d K u g e l r o h r d i s t i l l a t i o n ( a i r - b a t h t e m p -e r a t u r e 8 8 - 9 5 ° C / 0 . 1 T o r r ) t h e e n o l e t h e r 3 2 1 ( 0 . 1 4 6 g , 8 6 % ) . T h i s m a t e r i a l w a s > 9 9 % p u r e b y g l c ( S E - 5 4 , 1 2 0 ° C ) a n d e x h i b i t e d i r ( f i l m ) : 3 0 5 0 , 2 9 9 0 , 1 6 3 0 , 1 6 2 0 , 1 4 6 0 , 9 4 0 , 9 1 5 , 7 8 4 c m "1; XH n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 1 3 , 0 . 1 5 ( s , s , 3 H e a c h , C H3- S i - C H3) , 0 . 9 2 ( s , 9 H , (CH_3) 3C - S i - 0 - ) , 0 . 9 5 ( s , 3 H , t e r t i a r y -CH_3) , 0 . 9 7 , 1 . 0 0 ( d , d , 3 H e a c h , C H _3- C H - C H3, J = 7 H z ) , 1 . 6 7 -1 . 7 9 ( m , I H , HD) , 1 . 9 2 - 1 . 9 7 ( m , I H , H _ ) , 2 . 2 6 ( b r o a d s , I H , H _ , hi C F Wl / 2 = 4 H z )' 2 , 4 6 ( d' 1 H / HI ' - I K = 9 H z )' 4 , 7 4 ( S' 1 H' H - C = C - 0 - S i ) , 5 . 0 1 ( d o f d , I H , HM, = 1 0 H z , = 2 . 5 H z ) , 5 . 0 8 ( d o f d o f d , I H , HN, JK N = 1 7 H z , = 2 . 5 H z , < 1 H z ) , 5 . 3 5 ( d o f d o f d , I H , H p , J _D E = 9 . 5 H z , = 3 H z , 2 7 7 = 2 H z ) , 5 . 9 6 ( d o f d o f d , I H , HR, J _K N = 1 7 H z , = 1 0 ' H z , JI K = 9 H z ) , 6 . 0 0 ( d o f d , I H , H g , = 9 . 5 H z , = 2 H z ) . I r r a d i a t i o n a t 6 5 . 3 5 ( H p ) c a u s e d t h e s i g n a l a t 6 1 . 9 7 t o c o l l a p s e t o a n u n r e s o l v e d d ( J = 7 H z ) , t h e s i g n a l a t 6 2 . 2 6 t o s h a r p e n , a n d t h e s i g n a l a t 6 6 . 0 0 t o c o l l a p s e t o a d ( J = 2 H z ) ; i r r a d i a t i o n a t 6 1 . 9 2 - 1 . 9 7 ( H ) c a u s e d t h e s i g -n a l a t 6 1 . 6 7 - 1 . 7 9 t o c o l l a p s e t o a s e p t e t ( J = 7 H z ) , t h e s i g -n a l a t <5 2 . 2 6 t o s h a r p e n , t h e s i g n a l a t 6 5 . 3 5 t o c o l l a p s e t o a d o f d ( J = 9 . 5 H z , J = 2 H z ) , a n d t h e s i g n a l a t <5 6 . 0 0 t o c o l l a p s e t o a d ( J = 9 . 5 H z ) ; a n d i r r a d i a t i o n a t 6 2 . 2 6 ( H _ ) c a u s e d t h e s i g n a l a t 6 1 . 9 2 - 1 . 9 7 t o c o l l a p s e t o a n o v e r l a p p i n g d o f d o f d ( J = 7 H z , J = 3 H z , J = 2 H z ) , a n d t h e s i g n a l a t 6 5 . 3 5 t o c o l l a p s e t o a d o f d ( J = 9 . 5 H z , J = 3 H z ) . E x a c t m a s s c a l c d . f o r C ^ Q H ^ O S I : 3 1 8 . 2 3 7 9 ; f o u n d : 3 1 8 . 2 3 6 5 . 3 . 4 . 1 2 P r e p a r a t i o n o f 6 - ( t e r t - B u t y l d i m e t h y l s i l o x y ) - 8 - e x o - ( 2 -h y d r o x y e t h y l ) - 4 - e x o - i s o p r o p y l - l - m e t h y l b i c y c l o [ 3 . 2 . 1 ] -o c t a - 2 , 6 - d i e n e D i s i a m y l b o r a n e w a s g e n e r a t e d i n s i t u a c c o r d i n g t o B r o w n ' s 1 8 6 1 8 7 p r o c e d u r e ' i n t h e f o l l o w i n g m a n n e r . T o a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n o f b o r a n e - d i m e t h y l s u l f i d e c o m p l e x ( 0 . 3 4 6 278 mmol) i n THF (2 mL), under argon, was added 2-methyl-2-butene (0.110 mL, 1.04 mmol) dropwise v i a a syringe. S t i r r i n g of the mixture was maintained for 2 h at 0°C. A solution of the alkene 321 (0.050 g, 0.157 mmol) i n THF (2 mL) was introduced dropwise to the cold (0°C) disiamyl-borane solution. The r e s u l t i n g mixture was allowed to warm to room temperature over a period of 1.5 h, by which time glc analysis (SE-54, 120°C) indicated the absence of s t a r t i n g material. A solution of sodium hydroxide (0.0138 g, 0.346 mmol) i n water (1 mL) and a 30% aqueous solution of hydrogen peroxide (0.106 mL, 1.04 mmol) were added to the recooled (0°C) reaction mixture. This s t i r r e d mixture was allowed to warm to room temperature over a period of 1 h. The reaction mixture was d i l u t e d with a 1:1 mixture of petroleum ether and ether, and poured into saturated aqueous ammonium chloride. A f t e r the layers had been separated, the aqueous layer was extracted thoroughly with ether, and the organic extracts were combined, washed with brine and dried (anhydrous magnesium s u l f a t e ) . Solvent removal under reduced pressure (water aspir-ator) gave a l i g h t yellow o i l , which was subjected to column chromatography (18 g of 80-200 mesh neutral alumina i n a lOx 225 mm column). E l u t i o n of the column with petroleum ether (30 mL), petroleum ether-ether (5:1, 30 mL), and ether (30 mL), followed by concentration of the appropriate f r a c t i o n s , afforded the alcohol 347 (0.045 g, 86%) as an odoriferous, colourless o i l , shown by glc (SE-54, 120°C) and t i c (petroleum 279 e t h e r - e t h e r , 5:1) a n a l y s e s t o c o n s i s t o f a s i n g l e component. T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3300 ( b r o a d ) , 3000, 1622 c m - 1 ; 1H nmr (400 MHz, CDC1 3) 6: 0.11, 0.13 ( s , s, 3H each, CH 3-Si-CH_ 3) , 0.90 ( s , 9H, (CH_3) C-Si-O-) , 0.95, 0.97 (d, d, 3H, CH 3-CH-CH 3, J = 6.5 H z ) , 0.99 ( s , 3H, t e r t i a r y -CH_3) , 1.49-1.70 (m, 3H, H , H^ o r H„, -OH), 1.73-1.82 (m, IH, H,. o r H z) , 1.85-1.91 (m, IH, H c) , 1.94 (d o f d, IH, H j , J _ I K = 10 Hz, J I Z = 3.5 H z ) , 2.28 (broad s, IH, H p, ^±y2 = 4 , 5 H z ) ' 3.63-3.79 (m, 2H, HO-CH 2~), 4.69 ( s , IH, H-C=C-0-Si), 5.30 (d o f d o f d, IH, H D, = 9.5 Hz, ^ = 3 Hz, J _ D F = 2 Hz) , 5.98 (d o f d, IH, H_, J = 9.5 Hz, J n p = 2 H z ) . I r r a d i a t i o n a t 6 5.30 t, —Dti —Ch (Hp) caused the s i g n a l a t 6 1.85-1.91 t o c o l l a p s e t o an un-r e s o l v e d d ( J = 7 H z ) , t h e s i g n a l a t 6 2.28 t o sh a r p e n , and the s i g n a l a t 6 5.9 8 t o c o l l a p s e t o an u n r e s o l v e d s; i r r a d i a t i o n a t 6 2.28 (H„) caused t h e s i g n a l a t 6 1.85-1.91 r t o c o l l a p s e t o an o v e r l a p p i n g d o f d o f d ( J = 7 Hz, J = 3 Hz, J = 2 H z ) , and the s i g n a l a t 6 5.30 t o c o l l a p s e t o a d o f d ( J = 9.5 Hz, J = 3 H z ) ; and i r r a d i a t i o n a t & 3.63-3.79 (HO-CH2~) caused the s i g n a l s a t 6 1.49-1.70 and 6 1.73-1.82 t o s i m p l i f y . E x a c t mass c a l c d . f o r C__H_^0„Si: 336.2485; found: 20 Jb 2. 336.2486. 280 3 . 4.12 Preparation of 10-exo-1sopropy1-7-methy1tricyclo-3 7 [4.4.0.0 ' ]dec-8-en-2-one A solution of p_-toluenesulfonyl chloride (0.184 g, 0.964 mmol) i n anhydrous dichloromethane (2 mL) was added dropwise to a cold (0°C), s t i r r e d solution of 4-dimethylaminopyridine (0.236 g, 1.93 mmol) i n dichloromethane (5 mL), and the re-su l t i n g mixture was s t i r r e d at room temperature for 20-30 min. To th i s solution was added dropwise a solution of the alcohol 347 (0.216 g, 0.643 mmol) i n dichloromethane (3 mL). After the reaction mixture had been s t i r r e d for 1.3 h at room temp-erature, glc analysis (SE-54, 120°C) indicated the absence of st a r t i n g material and the appearance of a new component. The reaction mixture was d i l u t e d with ether and poured into a sat-urated aqueous solution of sodium bicarbonate. The layers were separated and the aqueous layer was extracted thoroughly with ether. The combined organic extracts were washed successively with brine, 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and dried (anhydrous magnesium s u l f a t e ) . Solvent removal under reduced pressure (water aspirator) afforded a pale, yellow o i l , which was d i s t i l l e d 2 8 1 ( a i r - b a t h t e m p e r a t u r e 8 3 - 8 7 ° C / 0 . 1 T o r r ) t o f u r n i s h 0 . 1 0 3 g ( 7 9 % ) o f a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l w a s i d e n t i f i e d a s t h e k e t o n e 3 4 9 a n d e x h i b i t e d a s i n g l e c o m p o n e n t b y g l c ( S E - 5 4 , 1 2 0 ° C ) a n d t i c ( p e t r o l e u m e t h e r - e t h e r , 9 : 1 ) i r ( f i l m ) : 3 0 0 5 , 1 7 4 3 , 1 6 3 0 , 7 2 7 c m "1; 1H n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 9 5 , 0 . 9 8 ( d , d , 3 H e a c h , C H _3- C H - C H3, J = 7 H z ) , 1 . 0 9 ( s , 3 H , t e r t i a r y - C H _ ) , 1 . 3 5 - 1 . 4 3 ( m , I H ) , 1 . 5 2 - 1 . 6 6 ( m , 2 H , H „ ) , 1 . 9 0 -1 . 9 6 ( m , I H , H „ ) , 1 . 9 8 - 2 . 0 7 ( m , 3 H ) , 2 . 2 8 ( b r o a d s , I H , H ^ , C r Wl / 2 = 5 , 5 H z )' 2 , 3 5 (u n r e s o l v e d d/ 1 H' Hj ' £ = 3 H z) ' 5-5 9 ( d , I H , H E , = 1 0 H z ) , 5 . 6 3 ( d o f d o f d , I H , H p , = 1 0 H z , JY,^ = 3 . 5 H z , J„„ = 1 . 5 H z ) . I r r a d i a t i o n a t 6 5 . 6 1 —LL) —Or ( H ^ , H_) c a u s e d t h e s i g n a l a t 6 1 . 9 0 - 1 . 9 6 t o c o l l a p s e t o a d o f d (J = 9 . 5 H z , J = 2 . 5 H z ) a n d t h e s i g n a l a t 6 2 . 2 8 t o c o l l a p s e t o a d (J = 2 . 5 H z ) . E x a c t m a s s c a l c d . f o r C ^ H ^ O : 2 0 4 . 1 5 1 4 ; f o u n d : 2 0 4 . 1 5 2 6 . 3.4.14 P r e p a r a t i o n o f 1 0 - e x o - I s o p r o p y l - 7 - m e t h y l t r i c y c l o -[ 4 . 4 . 0 . 0 3 / 7 ] d e c a n - 2 - o n e a ) V i a p a l l a d i u m - c a t a l y z e d h y d r o g e n a t i o n o f t h e a l k e n e 349 T o a v i g o r o u s l y s t i r r e d , p r e h y d r o g e n a t e d s u s p e n s i o n o f 2 1 0 1 0 % p a l l a d i u m s u p p o r t e d o n c a r b o n ( 4 m g ) i n m e t h a n o l ( 2 282 mL), under an atmosphere of hydrogen, was added a solution of the unsaturated ketone 349 (43.3 mg, 0.212 mmol),in methanol (2 mL). E f f i c i e n t s t i r r i n g of the r e s u l t i n g mixture at room temperature was maintained and reaction progress was monitored employing glc (SE-54, 120°C). A f t e r 24.5 h, the hydrogenation had become quite sluggish, and another 3 mg of the palladium ca t a l y s t was introduced. The reaction mixture was s t i r r e d for another 2 h, f i l t e r e d through a layer of C e l i t e and con-centrated under reduced pressure (water a s p i r a t o r ) . D i s t i l -l a t i o n (air-bath temperature 93-98°C/0.1 Torr) of the residue gave 43.1 mg of a cl e a r , colourless o i l which was composed of a 93:7 mixture of the desired material (280) and s t a r t i n g material (349), respectively, based on glc analysis. Attempts to resolve the mixture by t i c were f r u i t l e s s . From g l c analysis (SE-54, 120°C), the retention time of the major component proved to be i d e n t i c a l with that of the desired ketone 280 prepared v i a diimide reduction. Subsequently, the ketone mix-ture was subjected to Wi t t i g o l e f i n a t i o n . b) V i a diimide reduction of the alkene 349 In accordance with the procedure described by Magnus et 189 190 a l . , and Hart and Kanai, a solution of sodium acetate (0.247 g, 3.01 mmol) i n water (5 mL) was added dropwise, over a period of 4 h, to a s t i r r e d , r e f l u x i n g mixture of the ketone 349 (30.0 mg, 0.147 mmol), p_-toluenesulfonylhydrazide (340 mg, 1.82 mmol), THF (3 mL) and water (3 mL). The r e s u l t i n g mixture was refluxed and reaction progress was monitored by 2 8 3 g l c ( S E - 5 4 , 1 2 0 ° C ) . A f t e r 1 5 h , t h e r e a c t i o n h a d b e c o m e s l u g g i s h . C o n s e q u e n t l y , m o r e p _ - t o l u e n e s u l f o n y l h y d r a z i d e ( 3 4 0 m g ) a n d a q u e o u s s o d i u m a c e t a t e ( 0 . 2 4 7 g ) w e r e a d d e d , t h e l a t t e r i n a d r o p w i s e m a n n e r v i a a s y r i n g e . T h e s e a d d i t i o n s w e r e r e p e a t e d t w i c e m o r e , a f t e r 2 3 h a n d 3 9 h o f r e a c t i o n t i m e . O n l y a t r a c e o f s t a r t i n g m a t e r i a l r e m a i n e d u n c o n s u m e d a f t e r 5 4 h . T h e r e a c t i o n m i x t u r e w a s d i l u t e d w i t h d i c h l o r o m e t h a n e , p o u r e d i n t o s a t u r a t e d a q u e o u s a m m o n i u m c h l o r i d e a n d t h e l a y e r s w e r e s e p a r a t e d . T h e a q u e o u s l a y e r w a s e x t r a c t e d t h r i c e w i t h d i c h l o r o m e t h a n e a n d t h e c o m b i n e d o r g a n i c e x t r a c t s w e r e w a s h e d t w i c e w i t h 5 % a q u e o u s s o d i u m h y d r o x i d e , t w i c e w i t h b r i n e , d r i e d o v e r a n h y d r o u s m a g n e s i u m s u l f a t e a n d c o n c e n t r a t e d t o f u r n i s h a p a l e y e l l o w , v i s c o u s o i l . S u b j e c t i o n o f t h i s r e s i d u e t o f l a s h c o l u m n c h r o m a t o g r a p h y ( 1 8 g o f 2 3 0 - 4 0 0 m e s h s i l i c a g e l i n a 1 4 x 1 5 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h e r , 3 : 1 ) p r o v i d e d , a f t e r c o n c e n t r a t i o n o f t h e d e s i r e d f r a c t i o n s , t h e k e t o n e 2 8 0 ( 1 3 . 1 m g , 4 3 % ) a s a c l e a r , c o l o u r l e s s o i l . T h i s m a t e r i a l w a s e s s e n t i a l l y p u r e , b a s e d o n g l c a n a l y s i s ( S E - 5 4 , 1 2 0 ° C ) , a n d e x h i b i t e d n m r a n d i r s p e c t r a w h i c h w e r e i d e n t i c a l * w i t h t h o s e o f a n a u t h e n t i c s a m p l e o f ( + ) - 2 8 0 . T h e k e t o n e 2 8 0 e x h i b i t e d i r ( f i l m ) : 1 7 4 0 , 1 4 6 7 , 7 4 0 c m "1; """H n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 8 9 , 0 . 9 2 ( d , d , 3 H e a c h , C H3- C H - C H _3, J = 6 . 5 H z ) , 1 . 0 0 ( s , 3 H , t e r t i a r y -CH_3) , 1 . 3 8 - 1 . 6 4 ( m , 6 H ) , 1 . 6 6 - 1 . 7 7 ( m , 2 H ) , 1 . 9 1 - 2 . 0 0 ( m , 2 H ) , 2 . 0 2 - 2 . 1 1 ( m , 2 H ) , 2 . 1 4 ( u n r e s o l v e d We a r e g r a t e f u l t o P r o f e s s o r W e g e f o r c o p i e s o f H n m r a n d i r s p e c t r a o f ( + ) - 2 8 0 . 2 8 4 d , I H , J = 4 . 5 H z ) . E x a c t m a s s c a l c d . f o r C1 4H2 20 : 2 0 6 . 1 6 7 1 ; f o u n d : 2 0 6 . 1 6 7 1 . 3.4.15 P r e p a r a t i o n o f ( + ) - S i n u l a r e n e 1 2 5 T o a s t i r r e d s u s p e n s i o n o f 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 b r o m i d e ( 0 . 3 7 6 g , 1 . 0 5 m m o l ) i n T H F ( 1 0 m L ) w a s a d d e d d r o p -w i s e , v i a a s y r i n g e , a h e x a n e s o l u t i o n o f n - b u t y l l i t h i u m ( 1 . 0 5 m m o l ) a n d t h e r e s u l t i n g y e l l o w p h o s p h o r a n e s o l u t i o n w a s s t i r r e d a t r o o m t e m p e r a t u r e f o r 2 0 m i n u t e s . T h e k e t o n e 2 8 0 ( 2 1 . 7 m g , 0 . 1 0 5 m m o l ) i n T H F ( 2 m L ) w a s a d d e d , a n d t h e r e -s u l t i n g m i x t u r e w a s r e f l u x e d . R e a c t i o n p r o g r e s s w a s m o n i t o r e d b y g l c ( S E - 5 4 , 1 2 0 ° C ) , w h i c h i n d i c a t e d t h a t a f t e r 4 6 . 5 h o f r e f l u x i n g , s t a r t i n g m a t e r i a l w a s s t i l l p r e s e n t a n d t h e r e a c t i o n h a d b e c o m e q u i t e s l u g g i s h . C o n s e q u e n t l y , m o r e m e t h y l t r i p h e n y l -p h o s p h o r a n e ( 1 . 0 5 m m o l ) w a s p r e p a r e d i n t h e m a n n e r o u t l i n e d a b o v e , a n d a d d e d t o t h e r e a c t i o n m i x t u r e v i a a s y r i n g e . A f t e r t h e r e a c t i o n m i x t u r e h a d b e e n r e f l u x e d f o r a n o t h e r 2 2 . 5 h , g l c r e v e a l e d t h a t a l l o f t h e s t a r t i n g m a t e r i a l h a d b e e n c o n -s u m e d . A d d i t i o n o f a f e w d r o p s o f w a t e r r e s u l t e d i n i m m e d i a t e d e c o l o u r i z a t i o n a n d t h e f o r m a t i o n o f a w h i t e p r e c i p i t a t e . E v a p o r a t i o n o f m o s t o f t h e s o l v e n t u n d e r r e d u c e d p r e s s u r e 2 8 5 ( w a t e r a s p i r a t o r ) l e f t a w h i t e r e s i d u e , w h i c h w a s t a k e n u p i n p e t r o l e u m e t h e r , d r i e d b y t h e a d d i t i o n o f a n h y d r o u s m a g -n e s i u m s u l f a t e a n d f i l t e r e d t h r o u g h a c o l u m n o f s i l i c a g e l ( 2 . 5 g o f 7 0 - 2 3 0 m e s h s i l i c a g e l i n a 6 x 1 6 0 mm c o l u m n , e l u t i o n w i t h p e t r o l e u m e t h e r ) . A f t e r c o n c e n t r a t i o n o f t h e e l u a t e , 1 6 . 8 m g ( 7 8 % ) o f a c l e a r , c o l o u r l e s s o i l w a s o b t a i n e d . T h i s m a t e r i a l , s h o w n t o b e 1 0 0 % p u r e b y g l c ( S E - 5 4 , 1 2 0 ° C ) a n d t o e x h i b i t o n l y o n e s p o t b y t i c ( p e t r o l e u m e t h e r ) , d i s p l a y e d 1 1 3 i r , H n m r , C n m r a n d m a s s s p e c t r a i d e n t i c a l w i t h t h o s e o f * a n a u t h e n t i c s a m p l e o f ( + ) - s i n u l a r e n e a n d t h e n a t u r a l l y 8 2 o c c u r r i n g s e s q u i t e r p e n e ( - ) - s i n u l a r e n e . T h e o i l e x h i b i t e d i r ( f i l m ) : 3 0 6 0 , 1 6 6 1 , 1 4 6 2 , 1 3 8 5 , 1 3 8 2 , 1 3 7 0 , 8 7 8 c m- 1; XH n m r ( 4 0 0 M H z , C D C 13) 6 : 0 . 9 0 , 0 . 9 2 ( d , d , 3 H e a c h , C H _3- C H - C H3, J = 6 . 5 H z ) , 0 . 9 1 ( s , 3 H , t e r t i a r y -CH_3) , 1 . 0 5 - 1 . 3 2 ( m , 5 H ) , 1 . 4 6 - 1 . 5 1 ( m , 2 H ) , 1 . 5 6 - 1 . 8 1 ( m , 3 H ) , 1 . 8 5 - 1 . 9 5 ( m , I H ) , 2 . 1 4 ( u n r e s o l v e d d , I H , H - C - C = C , J = 3 . 5 H z ) , 2 . 2 0 ( b r o a d s , I H , H - C - C = C , Wj^/2 = 7 H z ) , 4 . 5 8 ( b r o a d s , I H , H - C = C , w . ^ = 3 H z ) , 4 . 7 8 ( b r o a d s , I H , H - C = C , w . ^ = 4 H z ) ; 1 3C n m r ( 1 0 0 . 6 M H z , C D C 13) : t h r e e C H3 ( 2 0 . 7 , 2 0 . 8 , 2 1 . 4 ) , f i v e C H2 ( 2 2 . 4 , 2 6 . 0 , 3 0 . 2 , 3 1 . 7 , 1 0 1 . 2 ) , f i v e C H ( 2 9 . 1 , 4 2 . 9 , 4 9 . 2 , 5 0 . 2 , 5 3 . 5 ) , t w o C ( 4 6 . 9 , 1 6 3 . 3 ) . E x a c t m a s s c a l c d . f o r C1 5H2 4: 2 0 4 . 1 8 7 8 ; f o u n d : 2 0 4 . 1 8 8 0 . We a r e g r a t e f u l t o P r o f e s s o r O p p o l z e r f o r H n m r , i r a n d m a s s s p e c t r a o f ( + ) - s i n u l a r e n e . 2 8 6 B I B L I O G R A P H Y E . M . M i l ' v i t s k a y a , A . V . T a r a k a n o v a a n d A . F . P l a t e , R u s s . C h e m . R e v . 4 j > , 4 6 9 ( 1 9 7 6 ) S . J . R h o a d s a n d N . R . R a u l i n s , O r g . R e a c t . 2_2, 5 4 ( 1 9 7 5 ) H .M. F r e y a n d R . W a l s h , C h e m . R e v . 69_, 1 0 3 ( 1 9 6 9 ) W. v o n E . D o e r i n g a n d W.R. R o t h , A n g e w . C h e m . I n t . E d . E n g l . 2 , 1 1 5 ( 1 9 6 3 ) E . V o g e l , A n g e w . C h e m . I n t . E d . E n g l . 2, 1 ( 1 9 6 3 ) S . J . R h o a d s , M o l e c u l a r R e a r r a n g e m e n t s , P a r t 1 , e d . P . d e M a y o , I n t e r s c i e n c e , N . Y . , 1 9 6 3 . p . 6 5 5 M . S i m o n e t t a , G . F a v i n i , C . M a r i a n i a n d P . G r a m a c c i o n i , J . A m e r . C h e m . S o c . 9_0, 1 2 8 0 ( 1 9 6 8 ) Y . O s a m u r a , S . K a t o , K . M o r o k u m a , D . F e l l e r , E . R . D a v i d s o n a n d W.T. B o r d e n , J . A m e r . C h e m . S o c . 1 0 6 , 3 3 6 2 ( 1 9 8 4 ) E . V o g e l , A n g e w . C h e m . 7 2 , 4 ( 1 9 6 0 ) E . V o g e l , K . - H . O t t a n d K . G a j e k , L i e b i g s A n n . 6 4 4 , 1 7 2 ( 1 9 6 1 ) W. v o n E . D o e r i n g a n d W.R. R o t h , T e t r a h e d r o n 1 9 , 7 1 5 ( 1 9 6 3 ) J . M . B r o w n , B . T . G o l d i n g a n d J . J . S t o f k o , J r . , J . C h e m . S o c . C h e m . C o m m u n . 3 1 9 ( 1 9 7 3 ) J . M . B r o w n , B . T . G o l d i n g a n d J . J . S t o f k o , J r . , J . C h e m . S o c . P e r k i n T r a n s . I I , 4 3 6 ( 1 9 7 8 ) a ) G . S c h r o d e r , A n g e w . C h e m . I n t . E d . E n g l . 2_, 4 8 1 ( 1 9 6 3 ) ; C h e m . B e r . 97_, 3 1 4 0 ( 1 9 6 4 ) b ) R . M e r e n y i , J . F . M . O t h a n d G . S c h r o d e r , C h e m . B e r . 9 7 , 3 1 5 0 ( 1 9 6 4 ) c ) W. v o n E . D o e r i n g , B . M . F e r r i e r , E . T . F o s s e l , J . H . H a r t e n s t e i n , M . J o n e s , J r . , G . K l u m p p , R . M . R u b i n a n d M . S a u n d e r s , T e t r a h e d r o n , 2 3 , 3 9 4 3 ( 1 9 6 7 ) d ) G . S c h r o d e r a n d J . F . M . O t h , A n g e w . C h e m . I n t . E d . E n g l . 6 , 4 1 4 ( 1 9 6 7 ) 2 8 7 1 5 . a ) U . B i e t h a n , H . K l u s a c e k , a n d H . M u s s o , A n g e w . C h e m . I n t . E d . E n g l . 6, 1 7 6 ( 1 9 6 7 ) b ) H . T s u r u t a , K . K u r a b a y a s h i a n d T . M u k a i , T e t r a h e d r o n L e t t . 3 7 7 5 ( 1 9 6 7 ) 1 6 . a ) H . E . Z i m m e r m a n a n d G . L . G r u n e w a l d , J . A m e r . C h e m . S o c . 8 8 , 1 8 3 ( 1 9 6 6 ) b ) J . M e i n w a l d a n d D . S c h m i d t , J . A m e r . C h e m . S o c . 9 1 , 5 8 7 7 ( 1 9 6 9 ) c ) H . E . Z i m m e r m a n , J . D . R o b b i n s a n d J . S c h a n t l , J . A m e r . C h e m . S o c . 91, 5 8 7 8 ( 1 9 6 9 ) d ) H . E . Z i m m e r m a n , R.W. B i n k l e y , R . S . G i v e n s , G . L . G r u n e w a l d a n d M . A . S h e r w i n , J . A m e r . C h e m . S o c . 9 1 , 3 3 1 6 ( 1 9 6 9 ) e ) A . K . C h e n g , F . A . L . A n e t , J . M i o d u s k i a n d J . M e i n w a l d , J . A m e r . C h e m . S o c . 96, 2 8 8 7 ( 1 9 7 4 ) 1 7 . W. v o n E . D o e r i n g a n d L . H . K n o x , J . A m e r . C h e m . S o c . 7 2 , 2 3 0 5 ( 1 9 5 0 ) ; i b i d . 7_5, 2 9 7 ( 1 9 5 3 ) 1 8 . a ) F . A . L . A n e t , J . A m e r . C h e m . S o c . 8_6, 4 5 8 ( 1 9 6 4 ) b ) F . R . J e n s e n a n d L . A . S m i t h , J . A m e r . C h e m . S o c . 8 6 , 9 5 6 ( 1 9 6 4 ) c ) G . M a i e r , A n g e w . C h e m . I n t . E d . E n g l . 6 , 4 0 2 ( 1 9 6 7 ) 1 9 . J . M a r c h , A d v a n c e d O r g a n i c C h e m i s t r y , 2 n d e d . , M c G r a w -H i l l , 1 9 7 7 . p . 7 9 2 , a n d t h e r e f e r e n c e s c i t e d t h e r e i n 2 0 . M . S . B a i r d a n d C . B . R e e s e , J . C h e m . S o c . C h e m . C o m m u n . 1 5 1 9 ( 1 9 7 0 ) 2 1 . W.R. R o t h , J u s t u s L i e b i g s A n n . C h e m . 6 7 1 , 1 0 ( 1 9 6 4 ) 2 2 . G . O h l o f f a n d W. P i c k e n h a g e n , H e l v . C h i m . A c t a 5^2, 8 8 0 ( 1 9 6 9 ) 2 3 . M . P . S c h n e i d e r a n d A . R a u , J . A m e r . C h e m . S o c . 1 0 1 , 4 4 2 6 ( 1 9 7 9 ) 2 4 . W. G r i m m e , J . A m e r . C h e m . S o c . 9_5, 2 3 8 1 ( 1 9 7 3 ) 2 5 . C . U l l e n i u s , P.W. F o r d a n d J . E . B a l d w i n , J . A m e r . C h e m . S o c . 9 4 , 5 9 1 0 ( 1 9 7 2 ) 2 6 . T . S a s a k i , S . E g u c h i a n d M . O h n o , J . O r g . C h e m . 3_7, 4 6 6 ( 1 9 7 2 ) 2 7 . J . E . B a l d w i n a n d C . U l l e n i u s , J . A m e r . C h e m . S o c . 9 6 , 1 5 4 2 ( 1 9 7 4 ) 2 8 . J . E . B a l d w i n a n d K . E . G i l b e r t , J . A m e r . C h e m . S o c . 98_, 8 2 8 3 ( 1 9 7 6 ) 2 8 8 2 9 . F . T . S m i t h , J . C h e m . P h y s . 29., 2 3 5 ( 1 9 5 8 ) 3 0 . J . A . B e r s o n , L . D . P e d e r s e n a n d B . K . C a r p e n t e r , J . A m e r . C h e m . S o c . 98_, 1 2 2 ( 1 9 7 6 ) ; i b i d . 9 7 , 2 4 0 ( 1 9 7 5 ) 3 1 . J . A . B e r s o n a n d L . D . P e d e r s e n , J . A m e r . C h e m . S o c . 9 7 , 2 3 8 ( 1 9 7 5 ) 3 2 . J . J . G a j e w s k i , R . J . W e b e r , R . B r a u n , M . L . M a n i o n a n d B . H y m e n , J . A m e r . C h e m . S o c . 9_9, 8 1 6 ( 1 9 7 7 ) 3 3 . D . L . G a r i n , T e t r a h e d r o n L e t t . 3 0 3 5 ( 1 9 7 7 ) 3 4 . R . S . C o o k e a n d U . H . A n d r e w s , J . A m e r . C h e m . S o c . 9 6 , 2 9 7 4 ( 1 9 7 4 ) 3 5 . M . A r a i a n d R . J . C r a w f o r d , C a n . J . C h e m . 5_0, 2 1 5 8 ( 1 9 7 2 ) 3 6 . M . S c h n e i d e r , A n g e w . C h e m . I n t . E d . E n g l . 1_4, 7 0 7 ( 1 9 7 5 ) 3 7 . J . A . B e r s o n , P . B . D e r v a n , R . M a l h e r b e a n d J . A . J e n k i n s , J . A m e r . C h e m . S o c . 9_8, 5 9 3 7 ( 1 9 7 6 ) 3 8 . M . P . S c h n e i d e r a n d B . C s a c s k o , J . C h e m . S o c . C h e m . C o m m u n . 3 3 0 ( 1 9 7 7 ) 3 9 . J . A . B e r s o n , T . M i y a s h i a n d G . J o n e s , J . A m e r . C h e m . S o c . 96_, 3 4 6 8 ( 1 9 7 4 ) 4 0 . M . P . S c h n e i d e r a n d J . R e b e l l , J . C h e m . S o c . C h e m . C o m m u n . 2 8 3 ( 1 9 7 5 ) 4 1 . M . S c h n e i d e r a n d A . E r b e n , A n g e w . C h e m . I n t . E d . E n g l . 1 6 , 1 9 2 ( 1 9 7 7 ) 4 2 . M . P . S c h n e i d e r a n d M . G o l d b a c h , J . A m e r . C h e m . S o c . 1 0 2 , 6 1 1 5 ( 1 9 8 0 ) 4 3 . D . B r u l e , J . - C . C h a l c h a t a n d R . V e s s i e r e , B u l l . S o c . C h i m . F r . 3 8 5 ( 1 9 7 8 ) 4 4 . D . B r u l e , J . - C . C h a l c h a t , R . - P . G a r r y , B . L a c r o i x , A . M i c h e t a n d R . V e s s i e r e , B u l l . S o c . C h i m . F r . 5 7 ( 1 9 8 1 ) 4 5 . D . T . C o n n o r a n d M . v o n S t r a n d t m a n n , J . O r g . C h e m . 4 2 , 3 6 6 4 ( 1 9 7 7 ) ; i b i d . 4 3 , 4 6 0 6 ( 1 9 7 8 ) 4 6 . G . J u s t a n d P . P o t v i n , C a n . J . C h e m . 5_8_, 2 1 7 3 ( 1 9 8 0 ) 4 7 . W.W. E p s t e i n , L . A . G a u d i o s o a n d G . B . B r e w s t e r , J . O r g . C h e m . 4 9 , 2 7 4 8 ( 1 9 8 4 ) 2 8 9 4 8 . R . E . M o o r e , J . A . P e t t u s , J r . a n d M . S . D o t y , T e t r a h e d r o n L e t t . 4 7 8 7 ( 1 9 6 8 ) 4 9 . J . A . P e t t u s , J r . a n d R . E . M o o r e , J . C h e m . S o c . C h e m . C o m m u n . 1 0 9 3 ( 1 9 7 0 ) ; J . A m e r . C h e m . S o c . 9_3, 3 0 8 7 ( 1 9 7 1 ) 5 0 . R . E . M o o r e , J . A . P e t t u s , J r . a n d J . M i s t y s y n , J . O r g . C h e m . 39_, 2 2 0 1 ( 1 9 7 4 ) 5 1 . R . E . M o o r e , A c c . C h e m . R e s . 10_, 4 0 ( 1 9 7 7 ) 5 2 . D . G . M u l l e r , L . J a e n i c k e , M . D o n i k e a n d T . A k i n t o r i , S c i e n c e 1 7 1 , 8 1 5 ( 1 9 7 1 ) 5 3 . W. P i c k e n h a g e n , F . ' N a f , G . O h l o f f , P . M u l l e r a n d J . - C . P e r l b e r g e r , H e l v . C h i m . A c t a 5 6 , 1 8 6 8 ( 1 9 7 3 ) 5 4 . K . C . N i c o l a o u a n d S . W e b b e r , J . C h e m . S o c . C h e m . C o m m . 3 5 0 ( 1 9 8 4 ) 5 5 . a ) L . J a e n i c k e , T . A k i n t o r i a n d D . G . M u l l e r , A n g e w . C h e m . I n t . E d . E n g l . 1 0 , 4 9 2 ( 1 9 7 1 ) b ) M . S c h n e i d e r a n d A . R a u , A n g e w . C h e m . I n t . E d . E n g l . 18_, 2 3 1 ( 1 9 7 9 ) c ) T . A k i n t o r i , L . J a e n i c k e , F . - J . M a r n e r a n d S . W a f f e n s c h m i d t , L i e b i g s A n n . 9 8 6 ( 1 9 7 9 ) 5 6 . a ) S . Y a m a z a k i , S . T a m u r a , F . M a r u m o a n d Y . S a i t o , T e t r a h e d r o n L e t t . 3 5 9 ( 1 9 6 9 ) b ) M . M a t s a h a s h i a n d H . S h i b a o k a , P l a n t C e l l . P h y s i o l . . J p n . 6 , 8 7 ( 1 9 6 5 ) c ) T . T o k o r o y a m a , K . M a t s u o , R . K a n a z a w a , H . K o t s u k i a n d T . K u b o t a , T e t r a h e d r o n L e t t . 3 0 9 3 ( 1 9 7 4 ) d ) R . K a n a z a w a a n d H . K o t s u k i , T e t r a h e d r o n L e t t . 3 6 5 1 ( 1 9 7 5 ) 5 7 . J . P . M a r i n o a n d M . P . F e r r o , J . O r g . C h e m . 46_, 1 9 1 2 ( 1 9 8 1 ) 5 8 . J . P . M a r i n o a n d T . K a n e k o , T e t r a h e d r o n L e t t . 3 9 7 1 , 3 9 7 5 ( 1 9 7 3 ) 5 9 . J . P . M a r i n o a n d T . K a n e k o , J . O r g . C h e m . 3_9, 3 1 7 5 ( 1 9 7 4 ) 6 0 . J . P . M a r i n o a n d L . J . B r o w n e , T e t r a h e d r o n L e t t . 3 2 4 5 ( 1 9 7 6 ) 6 1 . P . A . W e n d e r a n d M . P . F i l o s a , J . O r g . C h e m . 4 1 , 3 4 9 0 ( 1 9 7 6 ) 6 2 . E . P i e r s a n d I . N a g a k u r a , T e t r a h e d r o n L e t t . 3 2 3 7 ( 1 9 7 6 ) 6 3 . E . P i e r s , I . N a g a k u r a a n d H . E . M o r t o n , J . O r g . C h e m . 4 3 , 3 6 3 0 ( 1 9 7 8 ) 2 9 0 6 4 . E . P i e r s , H . E . M o r t o n , I . N a g a k u r a a n d R.W. T h e i s , C a n . J . C h e m . 6 1 , 1 2 2 6 ( 1 9 8 3 ) 6 5 . E . P i e r s a n d H . - U . R e i s s i g , A n g e w . C h e m . I n t . E d . E n g l . 1 8 , 7 9 1 ( 1 9 7 9 ) 6 6 . C K . L a u , P h . D t h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 9 7 8 6 7 . J o h n R . G r i e r s o n , P h . D t h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 9 8 3 6 8 . P . A . W e n d e r , M . A . E i s e n s t a t a n d M . P . F i l o s a , J . A m e r . C h e m . S o c . 1 0 1 , 2 1 9 6 ( 1 9 7 9 ) 6 9 . E . P i e r s a n d E . H . R u e d i g e r , J . C h e m . S o c . C h e m . C o m m u n . 1 6 6 ( 1 9 7 9 ) ; C a n . J . C h e m . 6 1 , 1 2 3 9 ( 1 9 8 3 ) 7 0 . E . H . R u e d i g e r , P h . D t h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a , 1 9 8 0 7 1 . P . A . W e n d e r , C L . H i l l e m a n n a n d M . J . S z y m o n i f k a , T e t r a h e d r o n L e t t . 2 2 0 5 ( 1 9 8 0 ) 7 2 . C . C u p a s , W . E. W a t t s a n d P . v o n R . S c h l e y e r , T e t r a h e d r o n L e t t . 2 5 0 3 ( 1 9 6 4 ) 7 3 . J . M . B r o w n , J . C h e m . S o c . C h e m . C o m m u n . 2 2 6 ( 1 9 6 5 ) 7 4 . G.W. K l u m p p a n d M . S c h a k e l , T e t r a h e d r o n L e t t . 4 5 9 5 ( 1 9 8 3 ) 7 5 . W. A d a m , O . D e . L u c c h i a n d D . S c h e u t z o w , J . O r g . C h e m . 4 6 , 4 1 3 0 ( 1 9 8 1 ) 7 6 . J . M . B r o w n , J . C h e m . S o c . C h e m . C o m m u n . 6 3 8 ( 1 9 6 7 ) 7 7 . B . C . C . C a n t e l l o , J . M . M e l l o r a n d G . S c h o l e s , J . C h e m . S o c . C , 2 9 1 5 ( 1 9 7 1 ) 7 8 . G.W. K l u m p p , J . W . F . K . B a r n i c k , A . H . V e e f k i n d a n d F . B i c k e l h a u p t , R e e l . T r a v . C h i m . P a y s - B a s , 8_8, 7 6 6 ( 1 9 6 9 ) 7 9 . a ) B . J . B u r r e s o n , P . J . S c h e u e r , J . F i n e r a n d J . C l a r d y , J . A m e r . C h e m . S o c . 9_7, 4 7 6 3 ( 1 9 7 5 ) b ) M . R . H a g a d o n e , B . J . B u r r e s o n , P . J . S c h e u e r , J . S . F i n e r a n d J . C l a r d y , H e l v . C h i m . A c t a 62^, 2 4 8 4 ( 1 9 7 9 ) 8 0 . a ) R . L . R a n i e r i a n d G . J . C a l t o n , T e t r a h e d r o n L e t t . 4 9 9 ( 1 9 7 8 ) b ) G . J . C a l t o n , R . L . R a n i e r i a n d M . A . E s p e n s h a d e , J . A n t i b i o t . 3 1 , 3 8 ( 1 9 7 8 ) 2 9 1 8 1 . a ) T . N a k a n i s h i , E . Y a m a g a t a , K . Y o n e d a a n d I . M i u r a , P h y t o c h e m . 2_0, 1 5 9 7 ( 1 9 8 1 ) b ) L . P i o v e t t i , C . F r a n c i s c o , G . P a u l y , 0 . B e n c h a b a n e , C . B e r n a r d - D a g a n a n d A . D i a r a , P h y t o c h e m . 2_0, 1 2 9 9 ( 1 9 8 1 ) c ) R.W. H e f e n d e h l a n d F . L . R o m e r o , L l o y d i a , 4_1, 2 8 3 ( 1 9 7 8 ) d ) R . N . G a n g u l y , G . K . T r i v e d i a n d S . C . B h a t t a c h a r y y a , I n d i a n J . C h e m . B , 1 6 B ( 1 ) , 2 0 - 2 ( 1 9 7 8 ) , i b i d . 2 3 - 6 ( 1 9 7 8 ) e ) J . H u d e c a n d D . N . K i r k , T e t r a h e d r o n 32,, 2 4 7 5 ( 1 9 7 6 ) f ) L . P i o v e t t i a n d A . D i a r a , P h y t o c h e m . 16_, 1 0 3 ( 1 9 7 7 ) g ) N . H . A n d e r s e n , C R . C o s t i n , D . D . S y r d a l a n d D . P . S v e d b e r g , J . A m e r . C h e m . S o c . 9_5, 2 0 4 9 ( 1 9 7 3 ) h ) P . R . V e t t e l a n d R . M . C o a t e s , J . O r g . C h e m . 4_5, 5 4 3 0 ( 1 9 8 0 ) i ) N . H . A n d e r s e n , S . E . S m i t h a n d Y . O h t a , J . C h e m . S o c . C h e m . C o m m u n . 4 4 7 ( 1 9 7 3 ) j ) N . H . A n d e r s e n a n d M . S . F a l c o n e , C h e m . & I n d . 6 2 ( 1 9 7 1 ) k ) P . J . C a r r o l , E . L . G h i s a l b e r t i a n d D . E . R a l p h , P h y t o c h e m . 1 5 , 7 7 7 ( 1 9 7 6 ) 1 ) B . T o m i t a a n d Y . H i r o s e , P h y t o c h e m . 1 2 , 1 4 0 9 ( 1 9 7 3 ) 8 2 . a ) C M . B e e c h a n , C . D j e r a s s i , J . S . F i n e r a n d J . C l a r d y , T e t r a h e d r o n L e t t . 2 3 9 5 ( 1 9 7 7 ) b ) C M . B e e c h a n , C . D j e r a s s i a n d H . E g g e r t , T e t r a h e d r o n 3 4 , 2 5 0 3 ( 1 9 7 8 ) 8 3 . a ) S . D . B u r k e , C.W. M u r t i a s h a w , J . O . S a u n d e r s , J . A . O p l i n g e r a n d M . S . D i k e , J . A m e r . C h e m . S o c . 1 0 6 , 4 5 5 8 ( 1 9 8 4 ) b ) S . D . B u r k e , C.W. M u r t i a s h a w , J . O . S a u n d e r s a n d M . S . D i k e , J . A m e r . C h e m . S o c . 1 0 4 , 8 7 2 ( 1 9 8 2 ) c ) S . D . B u r k e , C.W. M u r t i a s h a w a n d J . A . O p l i n g e r , T e t r a h e d r o n L e t t . 2 9 4 9 ( 1 9 8 3 ) d ) S . D a n i s h e f s k y , K . V a u g h a n , R . C . G a d w o o d , K . T s u z u k e , J . A m e r . C h e m . S o c . 1 0 3 , 4 1 3 6 ( 1 9 8 1 ) e ) W.K. B o r n a c k , S . S . B h a g w a t , J . P o n t o n a n d P . H e l q u i s t , J . A m e r . C h e m . S o c . 1 0 3 , 4 6 4 7 ( 1 9 8 1 ) f ) A . S . K e n d e , B . R o t h , P . J . S a n f i l i p p o a n d T . J . B l a c k l o c k , J . A m e r . C h e m . S o c . 1 0 4 , 5 8 0 8 ( 1 9 8 2 ) g ) K . T a k e d a , Y . S h i m o n o a n d E . Y o s h i i , J . A m e r . C h e m . S o c . 1 0 5 , 5 6 3 ( 1 9 8 3 ) h ) R . H . S c h l e s s i n g e r , J . L . W o o d , A . J . P r e s s , R . A . N u g e n t a n d W.H. P a r s o n s , J . O r g . C h e m . 4_8, 1 1 4 6 ( 1 9 8 3 ) i ) J . M . D e w a n c k e l e , F . Z u t t e r m a n a n d M . V a n d e w a l l e , T e t r a h e d r o n 3_9, 3 2 3 5 ( 1 9 8 3 ) j ) A . B . S m i t h , I I I a n d J . P . K o n o p e l s k i , J . O r g . C h e m . 4 9 , 4 0 9 4 ( 1 9 8 4 ) k ) K . K o n , K . I t o a n d S . I s o e , T e t r a h e d r o n L e t t . 3 7 3 9 ( 1 9 8 4 ) 2 9 2 8 4 . E . P i e r s a n d E . H . R u e d i g e r , J . O r g . C h e m . 4 5 , 1 7 2 5 ( 1 9 8 0 ) 8 5 . S . D . B u r k e a n d P . A . G r i e c o , O r g . R e a c t . 26_, 3 6 1 ( 1 9 7 9 ) 8 6 . G . S t o r k a n d J . F i c i n i , J . A m e r . C h e m . S o c . 83_, 4 6 7 8 ( 1 9 6 1 ) 8 7 . M.M. F a w z i . a n d C D . G u t s c h e , J . O r g . C h e m . 3 1 , 1 3 9 0 ( 1 9 6 6 ) 8 8 . K . K o n d o , E . H i r o a n d D . T u n e m o t o , T e t r a h e d r o n L e t t . 4 4 8 9 ( 1 9 7 6 ) 8 9 . K . M o r i , M . O h k i a n d M . M a t s u i , T e t r a h e d r o n 26_, 2 8 2 1 ( 1 9 7 0 ) 9 0 . S . J u l i a , M . J u l i a a n d G . L i n s t r u m e l l e , B u l l . S o c . C h i m . F r . 3 4 9 0 , 3 4 9 9 ( 1 9 6 6 ) 9 1 . G . A . R u s s e l l , P . R . W h i t t l e a n d J . M c D o n n e l l , J . A m e r . C h e m . S o c . 89_, 5 5 1 5 ( 1 9 6 7 ) 9 2 . B . M . T r o s t , D . F . T a b e r , a n d J . P . A l p e r , T e t r a h e d r o n L e t t . 3 8 5 7 ( 1 9 7 6 ) 9 3 . H . N o z a k i , H . T a k a y a , S . M o r i u t i a n d R . N o y o r i , T e t r a h e d r o n , 2 4 , 3 6 5 5 ( 1 9 6 8 ) 9 4 . D . F . T a b e r , J . A m e r . C h e m . S o c . 9_9, 3 5 1 3 ( 1 9 7 7 ) 9 5 . K . K o n d o , T . U m e n o t o , T . T a k a h a t a k e a n d D . T u n e m o t o , T e t r a h e d r o n L e t t . 1 1 3 ( 1 9 7 7 ) 9 6 . D . T u n e m o t o , N. A r a k i a n d K . K o n d o , T e t r a h e d r o n L e t t . 1 0 9 ( 1 9 7 7 ) 9 7 . K . K o n d o , T . U m e n o t o , K . Y a k o a n d D . T u n e m o t o , T e t r a h e d r o n L e t t . 3 9 2 7 ( 1 9 7 8 ) 9 8 . T . H u d l i c k y , F . J . K o s z y k , T . M . K u t c h a n a n d J . P . S h e t h , J . O r g . C h e m . 4_5, 5 0 2 0 ( 1 9 8 0 ) 9 9 . T . H u d l i c k y , T . K u t c h a n , S . R . W i l s o n a n d D . T . M a o , J . A m e r . C h e m . S o c . 1 0 2 , 6 3 5 1 ( 1 9 8 0 ) 1 0 0 . T . H u d l i c k y , B . C . R a n u , S . M . N a q v i a n d A . S r n a k , J . O r g . C h e m . 5_0, 1 2 3 ( 1 9 8 5 ) 1 0 1 . B . C . R a n u , M . K a v k a , L . A . H i g g s a n d T . H u d l i c k y , T e t r a h e d r o n L e t t . 2 4 4 7 ( 1 9 8 4 ) 1 0 2 . T . H u d l i c k y a n d R . P . S h o r t , J . O r g . C h e m . 4 7 , 1 5 2 2 ( 1 9 8 2 ) 2 9 3 1 Q 3 . B . M . T r o s t a n d W.C. V l a d u c h i c k , J . O r g . C h e m . 4_4, 1 4 8 ( 1 9 7 9 ) 1 0 4 . T . H u d l i c k y a n d F . J . K o s z y k , T e t r a h e d r o n L e t t . 2 4 8 7 ( 1 9 8 0 ) 1 0 5 . C.W. S p a n g l e r , C h e m . R e v . 7_6. 1 8 7 ( 1 9 7 6 ) 1 0 6 . E . J . C o r e y a n d R . H . W o l l e n b e r g , J . O r g . C h e m . 4 j 0 , 2 2 6 5 ( 1 9 7 5 ) 1 0 7 . T . H u d l i c k y a n d J . P . S h e t h , T e t r a h e d r o n L e t t . 2 6 6 7 ( 1 9 7 9 ) 1 0 8 . T . H u d l i c k y , J . P . S h e t h , V . G e e a n d D . B a r n v o s , T e t r a h e d r o n L e t t . 4 8 8 9 ( 1 9 7 9 ) 1 0 9 . C . P r e v o s t , P . M i g i n i a c a n d L . M i g i n i a c - G r o i z e l e a u , B u l l . S o c . C h i m . F r . 2 4 8 5 ( 1 9 6 4 ) 1 1 0 . P . M i g i n i a c , A n n . C h i m . 1_, 4 4 7 ( 1 9 6 2 ) 1 1 1 . a ) C . L . P e r r i n a n d D . J . F a u l k n e r , T e t r a h e d r o n L e t t . 2 7 8 3 ( 1 9 6 9 ) b ) D . J . F a u l k n e r a n d M.R. P e t e r s e n , T e t r a h e d r o n L e t t . 3 2 4 3 ( 1 9 6 9 ) c ) W . S . J o h n s o n , L . W e t h e m a n n , W.R. B a r t l e t t , T . J . B r o c k s o m , T . - t . L i , D . J . F a u l k n e r a n d M . R . S e n , J . A m e r . C h e m . S o c . 9_2, 7 4 1 ( 1 9 7 0 ) d ) K . A . P a r k e r a n d R.W. K o s l e y , J r . , T e t r a h e d r o n L e t t . 6 9 1 ( 1 9 7 5 ) e ) F . E . Z i e g l e r , A c c . C h e m . R e s . 1 0 , 2 2 7 ( 1 9 7 7 ) f ) S . M . W e i n r e b , N . A . K h a t r i a n d J . S h r i n g a r p u r e , J . A m e r . C h e m . S o c . 1 0 1 , 5 0 7 3 ( 1 9 7 9 ) 1 1 2 . H . G u n t h e r , NMR S p e c t r o s c o p y - A n I n t r o d u c t i o n , J o h n W i l e y & S o n s , N e w Y o r k , 1 9 8 0 . p . 1 0 6 1 1 3 . s e e r e f . 1 1 2 , p p . 1 1 5 - 1 1 6 1 1 4 . G . A . R u s s e l l a n d G . R . S t e v e n s o n , J . A m e r . C h e m . S o c . 9 3 , 2 4 3 2 ( 1 9 7 1 ) 1 1 5 . I . F l e m i n g a n d I . P a t t e r s o n , S y n t h e s i s 7 3 6 ( 1 9 7 9 ) 1 1 6 . Y . I t o , T . H i r a o a n d T . S a e g u s a , J . O r g . C h e m . 4_3, 1 0 1 1 ( 1 9 7 8 ) 1 1 7 . M...R. R o b e r t s a n d R . H . S c h l e s s i n g e r , J . A m e r . C h e m . S o c . 1 0 1 , 7 6 2 6 , 7 6 2 7 ( 1 9 7 9 ) 1 1 8 . E . P i e r s a n d V . K a r u n a r a t n e , C a n J . C h e m . 6 2 , 6 2 9 ( 1 9 8 4 ) 2 9 4 1 1 9 . D . L . J . C l i v e , A l d r i c h i m i c a A c t a 1 1 , 4 3 ( 1 9 7 8 ) ; T e t r a h e d r o n 3_4, 1 0 4 9 ( 1 9 7 8 ) 1 2 0 . H . J . R e i c h , A c c . C h e m . R e s . 1_2, 2 2 ( 1 9 7 9 ) 1 2 1 . H . J . R e i c h , J . M . R e n g a a n d I . L . R e i c h , J . A m e r . C h e m . S o c . 9 7 , 5 4 3 4 ( 1 9 7 5 ) 1 2 2 . A . T o s h i m i t s u , H . O w a d a , S . U e m u r a a n d M . O k a n o , T e t r a h e d r o n L e t t . 2 1 0 5 ( 1 9 8 2 ) 1 2 3 . H . J . R e i c h , I . L . R e i c h a n d J . M . R e n g a , J . A m e r . C h e m . S o c . 9 5 , 5 8 1 3 ( 1 9 7 3 ) 1 2 4 . B . I . I o n i n a n d B . A . E r s h o v , NMR S p e c t r o s c o p y i n O r g a n i c C h e m i s t r y , P l e n u m P r e s s , N e w Y o r k , 1 9 7 0 . p . 1 4 0 1 2 5 . J . A . M a r s h a l l a n d R . A . R u d e n , J . O r g . C h e m . 37_, 6 5 9 ( 1 9 7 2 ) 1 2 6 . C P . C a s e y a n d M . C C e s a , J . A m e r . C h e m . S o c . 1 0 1 , 4 2 3 6 ( 1 9 7 9 ) 1 2 7 . C . F r e j a v i l l e , R . J u l l i e n , H . S t a h l - L a r i v i e r e , M . W a n a t a n d D . Z a n n , T e t r a h e d r o n 3 J 3 , 2 6 7 1 ( 1 9 8 2 ) 1 2 8 . H . O . H o u s e , A c c . C h e m . R e s . 9_, 5 9 ( 1 9 7 6 ) 1 2 9 . J . K . R a s m u s s e n , S y n t h e s i s 9 1 ( 1 9 7 7 ) 1 3 0 . P . B r o w n b r i d g e , S y n t h e s i s 1 ( 1 9 8 3 ) 1 3 1 . G . S t o r k a n d P . F . H u d r l i k , J . A m e r . C h e m . S o c . 9_0, 4 4 6 2 ( 1 9 6 8 ) 1 3 2 . C . H . H e a t h c o c k a n d R . D . M o o r e , J . O r g . C h e m . 4 J L , 1 3 9 6 ( 1 9 7 6 ) 1 3 3 . H . O . H o u s e , C . - Y . C h u , W.V. P h i l l i p s , T . S . B . S a y e r a n d C . - C . Y a u , J . O r g . C h e m . 42_, 1 7 0 9 ( 1 9 7 7 ) 1 3 4 . H . O . H o u s e , C . - Y . C h u , J . M . W i l k i n s a n d M . J . U m e n , J . O r g . C h e m . 4 0 , 1 4 6 0 ( 1 9 7 5 ) 1 3 5 . A . B . T h e i s a n d C . A . T o w n s e n d , S y n . C o m m . 1 1 , 1 5 7 ( 1 9 8 1 ) 1 3 6 . P . G . M . W u t s , S y n . C o m m . 1 1 , 1 3 9 ( 1 9 8 1 ) 1 3 7 . s e e r e f . 1 1 2 , p p 2 9 9 - 3 0 4 2 9 5 1 3 8 . K . S a i g o , M , O s a k i a n d T . M u k a i y a m a , C h e m L e t t . 1 6 3 ( 1 9 7 6 ) 1 3 9 . T . V . R a j a B a b u , J . O r g . C h e m . 4 9 , 2 0 8 3 ( 1 9 8 4 ) 1 4 0 . R . A . B u n c e , M . F . S c h l e c h t , W.G. D a u b e n a n d C . H . H e a t h c o c k , T e t r a h e d r o n L e t t . 4 9 4 3 ( 1 9 8 3 ) 1 4 1 . Y . Y a m a m o t o , K . M a r u y a m a a n d K . M a t s u m o t o , T e t r a h e d r o n L e t t . 1 0 7 5 ( 1 9 8 4 ) 1 4 2 . Y . K i t a , J . S e g a w a , J . H a r u t a , T . F u j i i a n d Y . T a m u r a , T e t r a h e d r o n L e t t . 3 7 7 9 ( 1 9 8 0 ) 1 4 3 . M.W. R a t h k e a n d D . F . S u l l i v a n , S y n . C o m m . 3_, 6 7 ( 1 9 7 3 ) 1 4 4 . 0 . I s l e r , H . G u t m a n n , M . M o n t a v o n , R . R u e g g , G . R y s e r a n d P . Z e l l e r , H e l v . C h i m . A c t a 40_, 1 2 4 2 ( 1 9 5 7 ) 1 4 5 . A . M a e r c k e r , O r g . R e a c t . I j 4 , 2 7 0 ( 1 9 6 5 ) 1 4 6 . H . O . H o u s e a n d G . H . R a s m u s s e n , J . O r g . C h e m . 26^, 4 2 7 8 ( 1 9 6 1 ) 1 4 7 . D . B . D e n n e y a n d S . T . R o s s , J . O r g . C h e m . 2_7, 9 9 8 ( 1 9 6 2 ) 1 4 8 . E . W i n t e r f e l d t , S y n t h e s i s 6 1 7 ( 1 9 7 5 ) 1 4 9 . E . J . C o r e y a n d J . W . S u g g s , T e t r a h e d r o n L e t t . 2 6 4 7 ( 1 9 7 5 ) 1 5 0 . a ) A . J . M a n c u s o , S . - L . H u a n g a n d D . S w e r n , J . O r g . C h e m . 4 3 , 2 4 8 0 ( 1 9 7 8 ) b ) A . J . M a n c u s o a n d D . S w e r n , S y n t h e s i s 1 6 5 ( 1 9 8 1 ) c ) K . O m u r a a n d D . S w e r n , T e t r a h e d r o n 34_, 1 6 5 1 ( 1 9 7 8 ) 1 5 1 . Y . - S . C h e n g , W . - L . L i u a n d S . - h . C h e n , S y n t h e s i s 2 2 3 ( 1 9 8 0 ) 1 5 2 . W.R. R o u s h , J . A m e r . C h e m . S o c . 1 0 2 , 1 3 9 0 ( 1 9 8 0 ) 1 5 3 . L . H o r n e r , H . O e d i g e r a n d H . H o f f m a n n , L i e b i g s A n n . 6 2 6 , 2 6 ( 1 9 5 9 ) 1 5 4 . R . B . M i l l e r , S y n . C o m m . 2 6 7 ( 1 9 7 2 ) 1 5 5 . S . N . H u c k i n a n d L . W e i l e r , J . A m e r . C h e m . S o c . 9_6, 1 0 8 2 ( 1 9 7 4 ) 1 5 6 . s e e r e f . - 7 0 , p . 1 0 0 1 5 7 . W. v o n E . D o e r i n g a n d C . H . D e P u y , J . A m e r . C h e m . S o c . 7 5 , 5 9 5 5 ( 1 9 5 3 ) 1 5 8 . G . G . H a z e n , L . M . W e i n s t o c k . R . C o n n e l l a n d F.W. B o l l i n g e r , S y n . C o m m . 9 4 7 ( 1 9 8 1 ) 2 9 6 1 5 9 . R . E . H a r m o n , G . W e l l m a n , S . K . G u p t a , J . O r g . C h e m . 3 8 , 1 1 ( 1 9 7 3 ) 1 6 0 . L . L o m b a r d o a n d L . N . M a n d e r , S y n t h e s i s 3 6 8 ( 1 9 8 0 ) 1 6 1 . J . B . H e n d r i c k s o n a n d W.A. W o l f , J . O r g . C h e m . 3_3, 3 6 1 0 ( 1 9 6 8 ) 1 6 2 . M . R e g i t z , A n g e w . C h e m . I n t . E d . E n g l . 6_, 7 3 3 ( 1 9 6 7 ) 1 6 3 . C E . D e n o o n , J r . , O r g a n i c S y n t h e s e s C o l l . V o l I I I , e d . E . C . H o r n i n g , W i l e y , N e w Y o r k , 1 9 5 5 . p p 1 6 - 1 7 1 6 4 . C F . H a u s e r , T.W. B r o o k s , M . L . M i l e s , M . A . R a y m o n d a n d G . B . B u t l e r , J . O r g . C h e m . 28_, 3 7 2 ( 1 9 6 3 ) 1 6 5 . U . H . M . F a g e r l u n d a n d D . R . I d l e r , J . A m e r . C h e m . S o c . 7 9 , 6 4 7 3 ( 1 9 5 7 ) 1 6 6 . L . T . S c o t t a n d M . A . M i n t o n , J . O r g . C h e m . 4 2 , 3 7 5 7 ( 1 9 7 7 ) 1 6 7 . a ) P . Y a t e s , B . L . S h a p i r o , N . Y o d a a n d J . F u g g e r , J . J . A m e r . C h e m . S o c . 79.' 5 7 5 6 ( 1 9 5 7 ) b ) A . F o f f a n i , C . P e c i l e a n d S . G h e r s e t t i , T e t r a h e d r o n 1 1 , 2 8 5 ( 1 9 6 0 ) 1 6 8 . E . N . M a r v e l l a n d T . L i , S y n t h e s i s 4 5 7 ( 1 9 7 3 ) 1 6 9 . H . L i n d l a r a n d R . D u b o i s , O r g a n i c S y n t h e s e s C o l l . V o l . V , H . E . B a u m g a r t e n , W i l e y , N e w Y o r k , 1 9 7 3 . p p 8 8 0 - 8 8 3 1 7 0 . J . C . B r a e k m a n , D . D a l o z e , A . D u p o n t , B . T u r s c h , J . P . D e c l e r q , G . G e r m a i n a n d M . V a n M e e r s s c h e , T e t r a h e d r o n 3_7, 1 7 9 ( 1 9 8 1 ) 1 7 1 . P . A . C o l l i n s a n d D . W e g e , A u s t . J . C h e m . 3_2, 1 8 1 9 ( 1 9 7 9 ) 1 7 2 . S . B e c k m a n n a n d H . G e i g e r , C h e m . B e r . 9_4, 4 8 ( 1 9 6 1 ) 1 7 3 . W. O p p o l z e r , H . F . S t r a u s s a n d D . P . S i m m o n s , T e t r a h e d r o n L e t t . 4 6 7 3 ( 1 9 8 2 ) 1 7 4 . W. O p p o l z e r , T . B e g l e y a n d A . A s h c r o f t , T e t r a h e d r o n L e t t . 8 2 5 ( 1 9 8 4 ) 1 7 5 . G . G a l l a g h e r , A . S . N g , S . K . A t t a h - P o k u , K . A n t c z a k , S . J . A l w a r d , J . F . K i n g s t o n a n d A . G . F a l l i s , C a n . J . C h e m . 6 2 , 1 7 0 9 ( 1 9 8 4 ) 1 7 6 . S . K . A t t a h - P o k u , K . A n t c z a k , S . J . A l w a r d a n d A . G . F a l l i s , C a n . J . C h e m . 6 2 , 1 7 1 7 ( 1 9 8 4 ) 2 9 7 1 7 7 . K . A n t c z a k , J . F . K i n g s t o n a n d A . G . F a l l i s , C a n . J . C h e m . 6 3 , 9 9 3 ( 1 9 8 5 ) 1 7 8 . a ) S . W a r r e n , O r g a n i c S y n t h e s i s - T h e D i s c o n n e c t i o n A p p r o a c h , W i l e y , C h i c h e s t e r , 1 9 8 2 b ) S . T u r n e r , T h e D e s i g n o f O r g a n i c S y n t h e s e s , E l s e v i e r , A m s t e r d a m , 1 9 7 6 . 1 7 9 . E . J . C o r e y a n d W.T. W i p k e , S c i e n c e 1 6 6 , 1 7 8 ( 1 9 6 9 ) 1 8 0 . S . S a r e l , A . S c h l o s s m a n a n d M . L a n g b e h e i m , T e t r a h e d r o n L e t t . 6 9 1 ( 1 9 8 1 ) 1 8 1 . D . S e y f e r t h , O r g a n i c S y n t h e s e s C o l l . V o l . I V , e d . N . R a b j o h n , W i l e y , N e w Y o r k , 1 9 6 3 . p p 2 5 9 - 2 6 0 1 8 2 . D . S e y f e r t h a n d F . G . A . S t o n e , J . A m e r . C h e m . S o c . 7_9, 5 1 5 ( 1 9 5 7 ) 1 8 3 . a ) W. C a r r u t h e r s , S o m e M o d e r n M e t h o d s o f O r g a n i c S y n t h e s i s , 2 n d e d . , C a m b r i d g e U n i v e r s i t y P r e s s , C a m b r i d g e , 1 9 7 8 . p . 2 7 9 b ) H . O . H o u s e , M o d e r n S y n t h e t i c R e a c t i o n s , 2 n d e d . , B e n j a m i n - C u m m i n g s , M e n l o P a r k , 1 9 7 2 . p . 1 1 2 1 8 4 . H . C . B r o w n , R . L i o t t a a n d C . G . S c o u t e n , J . A m e r . C h e m . S o c . 9_8, 5 2 9 7 ( 1 9 7 6 ) 1 8 5 . H . C . B r o w n , J . C h a n d r a s e k h a r a n a n d D . J . N e l s o n , J . A m e r . C h e m . S o c . 1 0 6 , 3 7 6 8 ( 1 9 8 4 ) 1 8 6 . H . C . B r o w n a n d G . Z w e i f e l , J . A m e r . C h e m . S o c . 8_3, 1 2 4 1 ( 1 9 6 1 ) 1 8 7 . H . C . B r o w n , O r g a n i c S y n t h e s e s v i a B o r a n e s , W i l e y , N e w Y o r k , 1 9 7 5 1 8 8 . E . P i e r s , M . B e r t G e r a g h t y , R . D . S m i l l i e a n d M . S o u c y , C a n . J . C h e m . 53_, 2 8 4 9 ( 1 9 7 5 ) 1 8 9 . P . M a g n u s , T . G a l l a g h e r , P . B r o w n a n d J . C . H u f f m a n , J . A m e r . C h e m . S o c . 1 0 6 . 2 1 0 5 ( 1 9 8 4 ) 1 9 0 . D . J . H a r t a n d K . K a n a i , J . O r g . C h e m . 47_, 1 5 5 5 ( 1 9 8 2 ) 1 9 1 . E . P i e r s a n d G . L . J u n g , C a n . J . C h e m . 63_, 9 9 6 ( 1 9 8 5 ) 1 9 2 . E . P i e r s , G . L . J u n g a n d N . M o s s , T e t r a h e d r o n L e t t . 3 9 5 9 ( 1 9 8 4 ) 1 9 3 . s e e r e f . 1 1 2 , p . 2 3 2 9 8 1 9 4 . W.C. S t i l l , M . K a h n a n d A . M i t r a , J . O r g . C h e m . 4_3, 2 9 2 3 ( 1 9 7 8 ) 1 9 5 . Y . P . B r y a n a n d R . H . B y r n e , J . C h e m . E d . 47, 3 6 1 ( 1 9 7 0 ) 1 9 6 . A . J . G o r d o n a n d R . A . F o r d , T h e C h e m i s t ' s C o m p a n i o n , J o h n W i l e y & S o n s , N e w Y o r k , 1 9 7 2 . p . 4 5 1 1 9 7 . D . D . P e r r i n , W . L . F . A r m a r e g o a n d D . R . P e r r i n , P u r i f i c a t i o n  o f L a b o r a t o r y C h e m i c a l s , 2 n d e d . , P e r g a m o n P r e s s , O x f o r d , 1 9 8 0 1 9 8 . D . R . B u r f i e l d , K . H . L e e a n d R . H . S m i t h e r s , J . O r g . C h e m . 4_2, 3 0 6 0 ( 1 9 7 7 ) 1 9 9 . D . R . B u r f i e l d , R . H . S m i t h e r s a n d A . S . C . T a n , J . O r g . C h e m . 46, 6 2 9 ( 1 9 8 1 ) 2 0 0 . D . R . B u r f i e l d a n d R . H . S m i t h e r s , J . O r g . C h e m . 4_3, 3 9 6 6 ( 1 9 7 8 ) 2 0 1 . D . R . B u r f i e l d a n d R . H . S m i t h e r s , J . O r g . C h e m . 4_8, 2 4 2 0 ( 1 9 8 3 ) 2 0 2 . H . G i l m a n a n d F . K . C a r t l e d g e , J . o f O r g a n o m e t a l . C h e m . 2_, 4 4 7 1 ( 1 9 6 4 ) 2 0 3 . M . R . W i n k l e , J . M . L a n s i n g e r a n d R . C . R o n a l d , J . C h e m . S o c . C h e m . C o m m u n . 8 7 ( 1 9 8 0 ) 2 0 4 . W.G. K o f r o n a n d L . M . B a c l a w s k i , J . O r g . C h e m . 4_1, 1 8 7 9 ( 1 9 7 6 ) 2 0 5 . R . J . C r e g g e , J . L . H e r r m a n n , C S . L e e , J . E . R i c h m a n a n d R . H . S c h l e s s i n g e r , T e t r a h e d r o n L e t t . 2 4 2 5 ( 1 9 7 3 ) 2 0 6 . a ) T h . J . D e B o e r a n d H . J . B a c k e r , R e e l . T r a v . C h i m . 7_3, 2 2 9 ( 1 9 5 4 ) b ) T h . J . D e B o e r a n d H . J . B a c k e r , O r g a n i c S y n t h e s e s C o l l . V o l . I V , e d . N . R a b j o h n , W i l e y , N e w Y o r k , 1 9 6 3 . p p 2 5 0 - 2 5 3 2 0 7 . B . L o e v , P . E . B e n d e r a n d R . S m i t h , S y n t h e s i s 3 6 2 ( 1 9 7 3 ) 2 0 8 . K . C N i c o l a o u , R . L . M a g o l d a , W . J . S i p i o , W . E . B a r n e t t e , Z . L y s e n k o a n d M.M. J o u l l i e , J . A m e r . C h e m . S o c . 1 0 2 , 3 7 8 4 ( 1 9 8 0 ) 2 0 9 . D . E . S e i t z a n d L . F e r r e i r a , S y n . C o m m . 9 , 9 3 1 ( 1 9 7 9 ) 2 1 0 . R . M o z i n g o , O r g a n i c S y n t h e s e s C o l l . V o l . I l l , e d . E . C . H o r n i n g , W i l e y , N e w Y o r k , 1 9 5 5 . p p 6 8 5 - 6 9 0 

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