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Thermal rearrangement of 1,2-divinylcyclopropanes as applied to the total synthesis of (±)-β-himachalene… Ruediger, Edward Herbert 1980

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THERMAL REARRANGEMENT OF 1,2-DIVINYLCYCLOPROPANES AS APPLIED TO THE TOTAL SYNTHESIS OF (±) -|3-HIMACHALENE AND THE SYNTHESIS OF BICYCLO [3 .2. ]~] OCTADIENES by EDWARD HERBERT RUEDIGER B . S c , Brock U n i v e r s i t y , 1974 M . S c , Brock U n i v e r s i t y , 1977 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept th is thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA November 1980 Edward Herbert Ruediger In presenting th is thes is in p a r t i a l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary shal l make it f ree ly ava i lab le for reference and study. I fur ther agree that permission for extensive copying of th is thesis for scho la r ly purposes may be granted by the Head of my Department or by his representat ives . It is understood that copying or pub l ica t ion of th is thes is for f inanc ia l gain sha l l not be allowed without my wri t ten permission. Department of The Univers i ty of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1WS Date J-/4K/UAFLY 7~*c } 498< • ABSTRACT The work d e s c r i b e d i n t h i s t h e s i s i n v o l v e s two separate a p p l i c a t i o n s of the thermal rearrangement of 1 , 2 - d i v i n y l c y c l o -propane systems i n or g a n i c s y n t h e s i s . In the f i r s t case, the thermal rearrangement of the 3 - ( c y c l o p r o p y l ) e n o n e (100) to a f f o r d the seven-membered r i n g annelated product (101) comprised the key step i n the t o t a l s y n t h e s i s of (±)-8-himachalene (3). Compound (100) was r e a d i l y prepared i n s i x steps as f o l l o w s . Treatment of a c r o l e i n with 2 , 2 - d i m e t h y l - l , 3 - p r o p a n e d i o l i n the presence of p - t o l u e n e s u l -f o n i c a c i d a f f o r d e d the a c e t a l (117) which rea c t e d with dibromo-carbene under phase t r a n s f e r c o n d i t i o n s to a f f o r d the c r y s t a l -l i n e dibromocyclopropane (116) . The l a t t e r m a t e r i a l r e a c t e d s t e r e o s e l e c t i v e l y with n - b u t y l l i t h i u m and iodomethane at -95°C to give predominantly the c i s - m e t h y l a t e d cyclopropane (114). A c i d h y d r o l y s i s of (114) a f f o r d e d (E)-2-bromo-2-methylcyclo-propanecarboxaldehyde (113) which underwent a W i t t i g r e a c t i o n with i s o p r o p y l i d e n e t r i p h e n y l p h o s p h o r a n e to y i e l d the o l e f i n (112) . Successive treatment of (112) with t - b u t y l l i t h i u m and phenylthiocopper l e d to the iri s i t u formation of a l i t h i u m p h e n y l t h i o c u p r a t e reagent (111) which rea c t e d with 3-iodo-2-cyclohexen-l-one to give the r e q u i r e d &-(cyclopropyl)enone (100). Thermolysis (138°C) of (100) l e d to the e x c l u s i v e f o r -mation of the b i c y c l i c ketone (101). M e t h y l a t i o n of ketone - i i -(101) f o l l o w e d by s e l e c t i v e c a t a l y t i c hydrogenation of the d i s u b s t i t u t e d double bond gave the ketone (127). P r e p a r a t i o n of the e n o l phosphate (128) of the ketone (127) and r e d u c t i o n of the former with l i t h i u m i n ethylamine completed the success-f u l t o t a l s y n t h e s i s o f (±) -B-himachalene. The thermal rearrangements of a number of 6 - a l k e n y l b i c y c l o -[3.1 . tT]hex-2-enes (221) (^-^4 = Me , H) to a f f o r d the c o r r e s -ponding b i c y c l o [ 3 . 2 . l ] o c t a - 2 , 6 - d i e n e s (222) (R-^-^ = M e > H) are a l s o d e s c r i b e d . The former were r e a d i l y prepared i n four steps ^ from methyl a c e t o a c e t a t e . Thus, the a l k y l a t i o n of the d i a n i o n of methyl ac e t o a c e t a t e with (E)-5-bromo-l,3-pentadiene, (E)-5-bromo-2-methyl-1,3-pentadiene, (2E,4E)- and (2E,4_Z)-1-bromo-2-methyl-2,4-hexadiene l e d to a s e r i e s of B-keto e s t e r s . Diazo group t r a n s f e r r e a c t i o n of these B -keto e s t e r s a f f o r d e d the corresponding a-diazo e s t e r s which underwent a 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 to give the a p p r o p r i a t e 6-exo-(1-a l k e n y l ) b i c y c l o [ 3 . 1 . 0 ] h e x a n - 2 - o n e s . Treatment of these ketones with l i t h i u m d i i s o p r o p y l a m i d e followed by t r a p p i n g of the r e s u l t a n t l i t h i u m e n o l a t e s with 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 l e d to the s i l y l e n o l e t h e r s (221) . Thermolysis (138°C or 165°C) of the l a t t e r l e d c l e a n l y to the d e s i r e d b i c y c l o -[ 3 . 2 . l ] o c t a - 2 , 6 - d i e n e s (222). These rearranged s i l y l e n o l e t h e r s were r e a d i l y d e p r o t e c t e d to give the corresponding B-keto e s t e r s . - i i i -S i m i l a r l y , 1-carbornethoxy-6-exo-vinylbicyclo [3 . 1 . Cf] hex-3-en-2-one (237) rearranged thermally to a f ford 1-carbomethoxy-b i c y c l o [ 3 . 2 . l ] o c t a - 2 , 6 - d i e n - 8 - o n e (240) . - i v -TABLE OF CONTENTS Page TITLE PAGE i ABSTRACT i i TABLE OF CONTENTS V LIST OF TABLES v i LIST OF FIGURES v i i ACKNOWLEDGEMENTS v i i i INTRODUCTION I. The Rationale 1 II. The Cope Rearrangement o f 1 , 2 - D i v i n y l c y c l o -propanes 4 I I I . I so la t ion and S t ruc tura l E luc ida t ion of B-Himachalene 17 IV. Previous Syntheses of (±) -B-Himachalene . . . . 19 V. The Cope Rearrangement of 6 - A l k e n y l b i c y c l o -Q . l . f f ] hex-2-enes 24 VI. Conclusion 28 DISCUSSION I. B-Himachalene: The Synthetic Plan 30 I I . The Tota l Synthesis of (±)-B -Himachalene . . . 39 III. The Synthesis of B i c y c l o Q . 1 . 0 ] h e x a n e s . . . . 78 IV. The Synthesis of the Required A l l y l i c Bromides 88 V. The Synthesis of 1 -Carbornethoxy -6 -exo- (1-alkenyl) b i c y c l o Q . 1.0] hex-2-ene Systems . . . . 98 VI. The Synthesis of B i c y c l o (j . 2 . l] oc ta -2 , 6 -diene Systems I l l VI I . Conclusion 134 EXPERIMENTAL 135 BIBLIOGRAPHY 212 - v -LIST OF TABLES Page TABLE I: Chemical S h i f t Data for some Subst i tuted Cyclopropanes 46 TABLE II: XH nmr Data for Compounds (207) and (213) . . . 93 - v i -LIST OF FIGURES Page FIGURE 1: The 270 MHz *H nmr Spectrum of the Dibromocyclopropane (116) 44 FIGURE 2: The 270 MHz 1E nmr Spectrum of the c i s - M e t h y l a t e d Cyclopropane (114) 50 FIGURE 3: The 270 MHz 1E nmr Spectrum of the trans-Methylated Cyclopropane (136) 52 FIGURE 4: The 100 MHz 1H nmr Spectrum of the 2,4-Dinitrophenylhydrazone (137) 56 FIGURE 5: The 100 MHz JH nmr Spectrum of the 2,4-Dinitrophenylhydrazone (139) 58 FIGURE 6: The Computer Simulated *H nmr Spectra o f ; (A) The Four-proton Spin System (Hg.^) of Compound (137), and; (B) The Four-proton Spin System (H , ,,) of Compound (139) 3 . 60 - v i i -ACKNOWLEDGEMENTS I would l i k e to express my sincere thanks to Professor Edward P ie rs for the opportunity to have learned under h is very capable d i r e c t i o n and for h is continued in te res t during a l l stages of these s t u d i e s . Both h is knowledge and h is sense of humour made i t a pleasure to work with him. Many thanks must a lso go to the members of Dr. P i e r s ' research group (past and present) who shared in both exasper-at ion and i n s p i r a t i o n , not merely as col leagues but as f r i e n d s . F i n a n c i a l assistance in the form of scholarships from the Nat ional Research Counci l of Canada and the Natural Sciences and Engineering Research Counci l of Canada is g r a t e f u l l y acknowledged. I a lso wish to thank P a t r i c i a Grabi for her e f f i c i e n t typing of th is manuscript and to my fel low graduate students who grac ious ly agreed to proofread i t . - v i i i -TO CHERYL -for her patience and for daring to walk among f i e r c e elephants. VISITOR: Herr Pro fessor , I admire you not only for the q u a l i t y but a lso for the quanti ty and d i v e r s i t y of your work, for being so successfu l in everything you attempt. ADOLF VON BAEYER: You should know how many things which I t ry f a i l . You would then rea l i ze that the percentage of success is very sma l l . - quoted in Chem Tech, 10, 341 (1980) - x -- 1 -INTRODUCTION I. The Rationale Nature has provided man with a host of r e l a t i v e l y s imple, as well as extremely complex, organic compounds which d isp lay a wide range of b i o l o g i c a l a c t i v i t y . The majority of these compounds or ig ina te from the plant world and from some lower forms of animal l i f e . Although chemists and biochemists have only f a i r l y recent ly begun to study the role of these mole-cules in p lants themselves''", the pharmacological importance of many of these compounds has been known for cen tur ies . A recent t r e a t i s e deal ing with fo lk and modern herbal medicine states that: "Such use of natura l products - leaves , bark, r o o t s , blossoms, and other parts of herbs and trees - i s almost as o ld as mankind. In f a c t , the botan ica l kingdom was by far the main source of a l l drugs u n t i l synthet ics came of age during the present century ." The names of many important drugs can be traced to the generic names of the plants from which they were f i r s t i s o -l a t e d . D i g i t a l i s , i so la ted from foxglove ( D i g i t a l i s purpurea), atropine from deadly nightshade (Atropa bel ladonna), diosgenin from wild yams (Dioscorea distachya) and v i n c r i s t i n e from Madagascar periwinkle (Vinca rosea)* are but a few examples of potent , na tura l ly occurr ing drugs. * The accepted generic name of th is plant has recent ly been changed to Catharanthus roseus. - 2 -In the pas t , organic chemists were constrained to study-ing the structure of natura l products by chemical degradation to simpler fragments of known s t ruc ture . Synthesis was in most cases r e l a t i v e l y pr imi t ive and used mainly in v e r i f y i n g s t r u c t u r a l assignments. Even today the t o t a l synthesis of natura l products may s t i l l be used as a method of corroborat -ing i n i t i a l s t r u c t u r a l e l u c i d a t i o n s . However, as techniques have become more ref ined and a n a l y t i c a l and s p e c t r a l data more access ib le and informat ive, the synthet ic chemist has become more daring in attempting syntheses of complex organic molecules. In the short period of about 75 years , beginning with W i l l s t a t t e r 1 s t o t a l synthe-3 s i s of tropine (1) , the stage has been reached, as in Corey 's 4 recent synthesis of g i b b e r e l l i c acid (2) , where an inc reas -ing number of s t r u c t u r a l l y and stereochemical ly i n t r i c a t e molecules are being synthesized. - 3 -Synthet ic organic chemistry has evolved to not only a science seeking to emulate the e f f i c i e n c y and s p e c i f i c i t y found in b iosynthet ic pathways, but a lso an ar t in which ingenuity and c r e a t i v i t y are at a premium as the synthet ic 5 - 7 chemist seeks to r i v a l the elegance of Nature's syntheses One c l a s s of natura l products which has received con-s iderable a t ten t ion , from a synthet ic point of view, i s made up of compounds having a C^j. carbon ske le ton . The parent hydrocarbons of th is group have the empir ica l formula C ^ 5 H 2 4 and were named the sesquiterpenes. Due to the i s o l a t i o n of g many examples of th is c l a s s having diverse f u n c t i o n a l i t y , they are now commonly re fer red to as sesqui terpenoids. The i s o l a t i o n and t o t a l synthesis of many sesquiterpenoids have 9 - 1 1 been reviewed , and synthet ic studies of new sesqui terpen-oids continue to be wel l represented in the current l i t e r a t u r e . Since the sesquiterpenoids provide both f a i r l y simple as wel l as stereochemical ly chal lenging ta rge ts , the i r t o t a l synthesis provides a proving ground for newly developed synthet ic methods which have often been i n i t i a l l y studied using c a r e f u l l y chosen substrates containing l i t t l e ( i f any) l a b i l e f u n c t i o n a l i t y . An increas ing number of s t r u c t u r a l l y unique and b i o l o g i -c a l l y ac t ive natura l products have been i d e n t i f i e d which 12 incorporate a seven-membered r ing in the i r carbon skeletons 13 Sesquiterpenoids such as , for example, 3 -hiroachalene (3J , 14 15 helena l in (4) , gnididione (5_) and 4 a , 78-aromadendranediol - 4 -(6) have a t t r a c t e d a g r e a t d e a l o f i n t e r e s t and p r o v i d e a l i k e l y f o c a l p o i n t f o r s y n t h e t i c s t u d i e s d i r e c t e d toward a v e r s a t i l e and p r a c t i c a l method of p r e p a r i n g seven-membered r i n g s . 5 6 I I . The Cope Rearrangement of 1 , 2 - D i v i n y l c y c l o p r o p a n e s 17 The [3,3] s i g m a t r o p i c (Cope) rearrangement o f 1,2-d i v i n y l c y l o p r o p a n e s t o c y c l o h e p t a d i e n e s * i s a f a c i l e p r o c e s s due t o the c o n c o m i t a n t r e l i e f of r i n g s t r a i n . In f a c t , i n i -t i a l a t t e m p t s t o p r e p a r e c i s - 1 , 2 - d i v i n y l c y c l o p r o p a n e were T h i s s e c t i o n i s n o t i n t e n d e d as a comprehensive r e v i e w of the Cope rearrangement of 1 , 2 - d i v i n y l c y c l o p r o p a n e s y s -tems, but r a t h e r as a b r i e f d i s c u s s i o n t o p r o v i d e a c o n t e x t f o r the work d e s c r i b e d i n t h i s t h e s i s . For a more e x h a u s t i v e t r e a t m e n t o f the s u b j e c t the r e a d e r i s r e f e r r e d t o r e f . 17, and r e f e r e n c e s c i t e d t h e r e i n . - 5 -u n s u c c e s s f u l . Both the Hofmann d e g r a d a t i o n of compound ( 7 ) i U and the a d d i t i o n o f methylene onto the c e n t r a l double bond of 19 n c i s - h e x a t r i e n e a t -50 C l e d t o the e x c l u s i v e i s o l a t i o n o f 1 , 4 - c y c l o h e p t a d i e n e . - o R = CH 2 N(CH 3 ) 3 OH O More r e c e n t l y , the i s o l a t i o n and c h a r a c t e r i z a t i o n o f 20 c i s - 1 , 2 - d i v m y l c y c l o p r opane has been d e s c r i b e d . I t was found t o r e a r r a n g e r a p i d l y t o 1 , 4 - c y c l o h e p t a d i e n e above -20°C, w i t h a h a l f - l i f e of 90 seconds a t 35°C. More s u b s t i t u t e d c i s - d i v i n y l c y c l o p r o p a n e s have been shown t o be t h e r m a l l y more s t a b l e . W h i l e the c i s , t r a n s - d i v i n y l c y c l o p r o p a n e (8a) r e a r -ranges s p o n t a n e o u s l y a t room temperature t o g i v e the c y c l o -h e p t a d i e n e (9a) , the ci_s,ci_s-isomer (10a) has been i s o l a t e d and found t o r e a r r a n g e t o g i v e the same p r o d u c t a t 75°C 22 S i m i l a r l y , k i n e t i c s t u d i e s have shown t h a t the r a t e c o n s t a n t (at 40°C) f o r the rearrangement o f (8b) t o (9b) i s 1500 times g r e a t e r than t h a t o f the rearrangement of (10b) t o ( 9 b ) . - 6 -Cr" H «3 a) R=n-Bu b) R= Me The r e l a t i v e r a t e s of these r e a c t i o n s may be u n d e r s t o o d by c o n s i d e r i n g the t r a n s i t i o n s t a t e r e q u i r e d f o r the r e a r -rangement t o o c c u r . A l t h o u g h the Cope rearrangement o f a c y c l i c systems has been shown t o proceed v i a a c h a i r - l i k e 23 t r a n s i t i o n s t a t e (eq. 1 ) , g e o m e t r i c a l c o n s t r a i n t s p r e c l u d e t h i s type o f t r a n s i t i o n s t a t e i n the case o f 1 , 2 - d i v i n y l c y c l o -p r opanes, s i n c e i t would r e s u l t i n the f o r m a t i o n o f h i g h l y s t r a i n e d t r a n s , t r a n s - 1 , 4 - c y c l o h e p t a d i e n e s (eq. 2 ) . A b o a t -l i k e t r a n s i t i o n i s thus r e q u i r e d f o r the rearrangement of (10) t o (9) (eq. 3 ) . When R=H, the rearrangement o c c u r s 20 below room temperature , whereas when R = a l k y l the r e a c t i o n i s r e t a r d e d by d e s t a b l i z a t i o n o f the r e q u i r e d b o a t - l i k e t r a n s -22 s i t i o n s t a t e by a l k y l - r m g s t e r i c i n t e r a c t i o n s In f a c t , some c i s - d i v i n y l c y c l o p r o p a n e d e r i v a t i v e s h a v i n g more pronounced s t e r i c i n t e r a c t i o n s of t h i s type do n o t _ 7 -- 8 -Trans-1 ,2 -d iv iny lcyc lopropane has been iso la ted and i s thermally more stable than the c i s - i s o m e r . However, on heating at 190°C for 2 hours i t rearranges c lean ly to 1,4-25 cycloheptadiene . This may occur by an epimer izat ion* to give c i s - d i v i n y l c y c l o p r o p a n e , which rearranges spontaneously, or v i a a d i r a d i c a l intermediate** which c y c l i z e s d i r e c t l y . h ighly s t e r e o s p e c i f i c nature of these react ions (the products "Epimerizat ion" is used here in a general sense to descr ibe any stereomutation whose net r e s u l t i s a t r a n s - c i s isomer iza t ion . This may, in f a c t , occur by competing one- and two-centre epimer izat ions. In the case of t rans-1-phenylcyclopropane-2-d and t r a n s - c y c l o -propane-1,2-d2, two-centre epimerizat ion has been shown to be the dominant mode of s te reomuta t ion^ . However, the nature of the stereomutations of more subst i tuted cyclopropane systems is s t i l l a matter of d i s c u s s i o n . For c o n f l i c t i n g in terpre ta t ions regarding the p a r t i c i -pation o f - d i r a d i c a l intermediates in the thermal and photochemical rearrangements of 1 ,2 -d iv iny lcyc lopropanes , the reader i s re fer red to r e f . 27 and references c i t e d the re in . - 9 -22 are (18) , (19) and (11.) , r e s p e c t i v e l y ) has been e x p l a i n e d in terms of a one-centre e p i m e r i z a t i o n as the r a t e - d e t e r m i n i n g step, f o l l o w e d (in the f i r s t two examples) by a r a p i d Cope rearrangement. While i n v e s t i g a t i n g the b i o s y n t h e t i c r e l a t i o n s h i p between the marine n a t u r a l products d i c t y o p t e r e n e A (_20) and C (21) and d i c t y o p t e r e n e B (22) and D' (23) f Pickenhagen, 29 e t a l . found t h a t t r a n s - 1 , 2 - d i v i n y l c y c l o p r o p a n e d e r i v a t i v e s underwent low temperature photochemical rearrangement to - 10 -a f ford the corresponding 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 and u l t imate ly the appropriate cycloheptadienes. Although a d i r a d i c a l mechanism was postu la ted , the exact react ion mechan-30 ism could not be defined based on the ava i lab le data A number of other recent s t u d i e s , involv ing attempts to apply the thermal rearrangement of 1 ,2-d iv inylcyclopropane systems to the t o t a l synthesis of several monocycl ic , cycloheptane-31-33 based marine natura l products , have been reported . How-ever, although the Cope rearrangement of d iv inylcyclopropanes to cycloheptadienes is a well-documented process, few other invest iga t ions have appl ied th is react ion in the t o t a l syn-thesis of n a t u r a l l y occurr ing substances. - 11 -In 1973, Marino and Kaneko r e p o r t e d the p r e p a r a t i o n of the r i n g - f u s e d c y c l o h e p t a d i e n e (24a) v i a a thermal rearrange-ment of the 8 - c y c l o p r o p y l enone ( 2 5 a ) 3 4 ' 3 5 . S i m i l a r l y , the thermal rearrangement of compound (25b) a f f o r d e d the c y c l o -3 6 heptadiene (24b) 25 a) n=1,R=H,R=C02Et ?4 b) n=0, R=Me,R=C02Et U n f o r t u n a t e l y , the methodology used to prepare the key i n t e r -mediates (25) s u f f e r e d from a b a s i c l a c k of s t e r e o s p e c i f i c i t y , as w e l l as p r o v i d i n g l i m i t e d f l e x i b i l i t y i n r e s p e c t to the s u b s t i t u t i o n p a t t e r n about the c y c l o p r o p y l r i n g . For example, the r e a c t i o n of the sulfoxonium y l i d (26) 35 with a c r o l e i n a f f o r d e d a mixture of the aldehydes (27) Treatment of t h i s mixture with 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 -phosphorane (28_) l e d to a mixture of (29) and (3_0) , which 3 5 upon h e a t i n g a t 100-140°C gave (3_0) as the s o l e product 37 38 L a t e r , independent s t u d i e s by Wender and Marino used the r e a c t i o n of 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 s (3JL) with 3 - a l k o x y - 2 - c y c l o a l k e n - l - o n e s (3_2) t o prepare the - 12 -B-(v iny lcyc lopropy l ) enones (33_) and u l t imate ly the r i n g -fused cycloheptadienes (3_4) . 39 Concurrent invest iga t ions by P iers and Nagakura , 4 u t i l i z i n g the react ion of 3 - iodo-2 -cyc loa lken - l -ones (35) with l i th ium phenyl th io (2 -v iny lcyc lopropyl )cuprate (36), provided an a l te rnat ive route to compounds l i k e (3_7) and (38) . 41 More recen t l y , P i e r s , Nagakura and Morton reported the s t e r e o s p e c i f i c preparation of c i s - and t r a n s - d i v i n y l -cyclopropane der iva t ives (3_9) and (4_0) v ia react ion of the - 13 -- 14 -appropriate l i th ium phenylthiocuprates (4_1) and (42J with the iodo-enones (4_5) . Thermal rearrangement of these compounds afforded the r ing- fused cycloheptadienes (4_3) and (4_4) , although some other thermal rearrangements were observed as wel l (Scheme 1) H Li i CuS^P H 41 H Li CuS^P SCHEME 1 42 R=H 44 - 15 -C o n s i d e r i n g the s t r u c t u r e of 8-himachalene (3_) , i t appeared that a s u i t a b l y s u b s t i t u t e d ( 2 - v i n y l c y c l o p r o p y l ) c y c l o -hexenone s i m i l a r to (3_9) and (4_0) would be an i d e a l key i n t e r -mediate i n s y n t h e s i z i n g the r e q u i r e d b i c y c l o [ [ 5 . 4 .(Qunde-cadiene carbon s k e l e t o n . P a r t of t h i s t h e s i s w i l l d e s c r i b e the t o t a l s y n t h e s i s of (±)-B-himachalene using t h i s g e n e r a l approach. The v i a b i l i t y of t h i s approach was f u r t h e r demonstrated 42 . . . . ( a f t e r completion of the s y n t h e s i s d e s c r i b e d i n t h i s the-43 s i s ) by a r e c e n t t o t a l s y n t h e s i s of the pseudoguaianes(±)-damsinic a c i d (48_) and (±)-conf er t i n (4_9) , which made use of the Cope rearrangement of the B - c y c l o p r o p y l enones (46) to a f f o r d the d e s i r e d b i c y c l i c intermediate (4_7) • A p p r o p r i -ate e l a b o r a t i o n of t h i s i n t e r mediate a f f o r d e d both of the n a t u r a l products (4_8) and (49_) . 44 Even more r e c e n t l y , Wender and co-workers have rep o r t e d ,the p r e p a r a t i o n and Cope rearrangement of a more complex d i v i n y l c y c l o p r o p y l system ( i . e . 5_0) , to a f f o r d the t r i c y c l i c compound (5_1) which c o n t a i n s the b a s i c carbon s k e l e t o n of a - 16 -number of pharmacological ly in te res t ing t r i - and t e t r a c y c l i c d i terpenes. 50 51 Given the u t i l i t y of the thermal rearrangement of various types of d iv inylcyclopropane systems, further work in th is area would seem imminent. - 17 -III. I so la t ion and S t ruc tura l E luc ida t ion of g-Himachalene In 1952 two new sesqui terpenoids, named a - and B-hima-13 chalene, were iso la ted as the major const i tuents of the e s s e n t i a l o i l of Himalayan cedar (Cedrus deodara Loud . ) . 45 4 6 Both of these compounds were la ter found ' to be b i c y c l i c hydrocarbons with the empir ica l formula C 1 5 H 2 4 ' T ^ e P r e ~ sence of two double bonds was shown by quant i ta t ive c a t a l y t i c hydrogenation and by percamphoric acid epoxidat ion. Further -more, i t was found that they both y ie lded the same d ihydro-ch lor ide on treatment with hydrogen ch lor ide in acet ic acid and the same mixture of products on selenium dehydrogenation. The l a t t e r was i d e n t i f i e d as a mixture of 2-methyl-6- (p-to ly l ) -heptane (5_2) , cadalene (53) and a th i rd f rac t ion recognized as containing a 1 , 2 , 4 - t r i s u b s t i t u t e d benzene moiety The in f rared spectrum of p-himachalene showed the pre-sence of one t r i s u b s t i t u t e d double bond ( v m a x 1665, 857 cm 1 ) while that of a-himachalene indicated the presence of a - 18 -t r i s u b s t i t u t e d double bond (v = 1665, 865 cm x ) as w e l l as max an e x o c y c l i c methylene ( v m a x 3060, 1770, 1625, 885 cm ^ ) . The 1Hnmr s p e c t r a o f both compounds showed the presence o f two t e r t i a r y m e t h y l g r o u p s , w h i l e B-himachalene a l s o c o n t a i n e d two v i n y l i c m e t h y l s and a-himachalene c o n t a i n e d o n l y one v i n y l i c m e t h y l . On the b a s i s o f these e x p e r i m e n t a l d a t a the himachalenes 45 were a s s i g n e d the carbon s k e l e t o n (5_4) Moreover, o x i d a t i v e o z o n o l y s i s o f g-himachalene a f f o r d e d a m i x t u r e o f p r o d u c t s which was c o n s i s t e n t w i t h B-himachalene h a v i n g s t r u c t u r e (3_) , r a t h e r than the o t h e r p o s s i b l e i s o m e r i c s t r u c t u r e (5_5) . E p o x i d a t i o n o f d i h y d r o - a - h i m a c h a l e n e , f o l l o w e d by t r e a t -ment of the r e s u l t a n t e p o x i d e w i t h boron t r i f l u o r i d e e t h e r a t e a f f o r d e d a s i n g l e ketone which was shown t o have s t r u c t u r e (5_6) . T h i s c o n f i r m e d the s t r u c t u r e (5_7) f o r a-himachalene. A p u r i f i e d sample o f a-himachalene (b.p. 93-94°C/2 mm, - 19 -2 5 2 5 n 47 n D 1.5082, [a]D (CHC1 3) -192.3 U) was s u b s e q u e n t l y shown t o have the a b s o l u t e s t e r e o c h e m i s t r y shown i n s t r u c t u r e (57a). S i n c e both a- and B-himachalene r e a c t e d w i t h H C l - a c e t i c a c i d t o form the same d i h y d r o c h l o r i d e d e r i v a t i v e i n which the s t e r e o c h e m i s t r y a t was u n a f f e c t e d , the a b s o l u t e s t e r e o -c h e m i s t r y a t C-^  f o r both a- and B-himachalene i s i d e n t i c a l . T h e r e f o r e , the a b s o l u t e s t e r e o c h e m i s t r y o f a pure sample of n 2 5 2 5 B-himachalene (b.p. 121-122 /4 mm, n D 1.5130, [ a ] D (CHC1 3) n 4 7 +224.7 ) was shown t o be r e p r e s e n t e d by s t r u c t u r e ( 3 a ) . IV. P r e v i o u s Syntheses of (±) -B-Himachalene Two p r e v i o u s s y n t h e s e s o f (±) - B-himachalene have been 48 4 9 r e p o r t e d ' and i t seems a p p r o p r i a t e t o o u t l i n e them 48 b r i e f l y . De Mayo and co-workers , u s i n g the p r o c e s s of p h o t o c y c l o a d d i t i o n t o u l t i m a t e l y g e nerate a seven-membered r i n g system, p r e p a r e d (±) - B-himachalene i n a t e n - s t e p s y n t h e -s i s s t a r t i n g from (5_8) (Scheme 2 ) . Thus, i r r a d i a t i o n o f 2 - m e t h y l - l , 3 - c y c l o p e n t a n e d i o n e e n o l a c e t a t e (58_) i n the - 2 0 -SCHEME 2 AcO AcO 66 67 a )R 1 4 =H,R 2 =Me,R 3 =OH 3_ b) R 1 | 3 =H, R 2=Me,R 4=OH c) R ^ M e ^ ^ H ^ O H presence of the ethylene keta l of cyclohexenone (5_9) afforded the desired ketone (60_) . Reduction of th is mater ia l with sodium borohydride gave the a lcohol (£1) , which upon t rea t -ment with methanesulfonyl ch lor ide and tr iethylamine y ie lded - 21 -the m e s y l a t e (6j2) . H y d r o l y s i s of ((52) w i t h 2% aqueous sodium h y d r o x i d e i n dio x a n e a t 70°C r e s u l t e d i n a f r a g m e n t a t i o n t h a t gave ketone (6_3) . Treatment o f (63_) w i t h methylmagnesium i o d i d e , f o l l o w e d by s u b j e c t i o n o f the r e s u l t a n t p r o d u c t to Simmons-Smith c o n d i t i o n s (diiodomethane, z i n c - c o p p e r c o u p l e ) and m i l d a c i d h y d r o l y s i s , a f f o r d e d the ketone (6_4) . A l k y l a -t i o n o f ( 6 4 ) (iodomethane-potassium t - b u t o x i d e ) gave (65_) , which upon h y d r o g e n a t i o n i n a c e t i c a c i d ( c o n t a i n i n g sodium a c e t a t e ) over a p l a t i n u m - r h o d i u m c a t a l y s t gave (66) . Reduc-\ t i o n o f t h i s ketone w i t h sodium i n t o l u e n e - i s o p r o p y l a l c o h o l gave a m i x t u r e of the d i o l s (6_7a-c) i n y i e l d s of 40, 18 and 26%, r e s p e c t i v e l y . The d i o l s were s u b s e q u e n t l y s e p a r a t e d ( t i c ) and d e h y d r a t e d by the a c t i o n o f phosphorus o x y c h l o r i d e and p y r i d i n e . Under these c o n d i t i o n s the d i o l s (67b) and (6_7c) gave a m i x t u r e o f d i e n e s c o n t a i n i n g (± )-B-himachalene w h i l e d e h y d r a t i o n of ( 6 J a ) a f f o r d e d a m i x t u r e i n which none of the d e s i r e d p r o d u c t was d e t e c t e d . U n f o r t u n a t e l y , t h i s s u c c e s s f u l t o t a l s y n t h e s i s o f racemic B - h i m a c h a l e n e was con-c l u d e d by a f i n a l s t e p i n v o l v i n g a m i x t u r e o f compounds, con-t a i n i n g o n l y about 8% (as judged by g l c a n a l y s i s ) o f the t i t l e compound. F u r t h e r m o r e , the p e n u l t i m a t e s t e p of the s y n t h e s i s l e d t o a m i x t u r e of p r o d u c t s , o f which o n l y the minor com-ponents ( i . e . 6_7b,c) s e r v e d as p r e c u r s o r s f o r the t a r g e t compound. A l t h o u g h the i n t r o d u c t i o n of p r o d u c t m i x t u r e s (and the a t t e n d a n t low y i e l d s ) a t the b e g i n n i n g of any t o t a l - 22 -synthesis may be to lerated (at bes t ) , complex mixtures become object ionable or even d isastrous in the f i n a l stages of a synthes is . 49 Wenkert and Naemura approached the problem d i f f e r e n t l y , u t i l i z i n g the intramolecular D ie ls -A lder react ion of the a c y c l i c intermediate (77.) as the key step in their to ta l syn-thesis of B-himachalene (Scheme 3 ) . The s ta r t ing mate r ia l , 3 , 3 , 6 - t r i m e t h y l - 5 - h e p t e n a l (68_) , was p r e p a r e d 5 0 in three steps from the read i l y ava i lab le dimethyldimedone (6_9) . SCHEME 3 - 23 -A Reformatsky r e a c t i o n ( e t h y l 2 - b r o m o a c e t a t e - z i n c ) o f (68) gave the 3-hydroxy e s t e r (7_0) which was s u b s e q u e n t l y d e h y d r a t e d (phosphorus o x y c h l o r i d e - p y r i d i n e ) t o g i v e the d i e n o i c e s t e r s (7JL) • T h i s m i x t u r e was hydrogenated over 5% p a l l a d i u m - o n - c h a r c o a l t o g i v e the s i n g l e e s t e r (72^) . Photo-. . . 51 s e n s i t i z e d o x y g e n a t i o n o f t h i s m a t e r i a l l e d t o a m i x t u r e of the a l l y l i c a l c o h o l s (73a,b) which were de h y d r a t e d t o a f f o r d the d i e n o i c e s t e r (^4). R e d u c t i o n o f the e s t e r m o i ety ( l i t h i u m aluminum h y d r i d e ) , f o l l o w e d by o x i d a t i o n (chromium t r i o x i d e -p y r i d i n e i n d i c h l o r o m e t h a n e ) gave the aldehyde (25). F i n a l l y , t r e a t m e n t o f the aldehyde (7_5) w i t h vinylmagnesium bromide and subsequent o x i d a t i o n of the r e s u l t i n g a l c o h o l (7_6) com-p l e t e d the p r e p a r a t i o n o f the key i n t e r m e d i a t e (7_7) . The a c i d - c a t a l y z e d c y c l i z a t i o n of (77) r e s u l t e d i n the f o r m a t i o n of the b i c y c l i c ketone (78.) , as was hoped (Scheme 4 ) . The r e a c t i o n o f t h i s m a t e r i a l w i t h m e t h y l l i t h i u m y i e l d e d 7 - i s o h i m a c h a l o l (7_9) w h i c h , on d e h y d r a t i o n w i t h phosphorus o x y c h l o r i d e i n p y r i d i n e , gave a m i x t u r e of a-himachalene (57) and 3-himachalene (3_) c o n t a i n i n g l e s s than 20% o f the l a t t e r . a-Himachalene (5_7) was a l s o p r e p a r e d d i r e c t l y from ketone (78) by t r e a t m e n t of the l a t t e r m a t e r i a l w i t h m e t h y l e n e t r i -phenylphosphorane (J3TJ) . T h i s s y n t h e s i s would be more appro-p r i a t e l y c o n s i d e r e d an e f f i c i e n t r o u t e t o a-himachalene (5_7) , w i t h the p r o d u c t i o n of 3 - h i m a c h a l e n e (3_) b e i n g somewhat i n c i d e n t a l . - 24 -SCHEME U With due c o n s i d e r a t i o n t o these p r e v i o u s s y n t h e s e s , the a p p l i c a t i o n of new s y n t h e t i c methodology t o the t o t a l s y n t h e -s i s o f (±)-B-himachalene d i d n o t seem redundant. V. The Cope Rearrangement of 6 - A l k e n y l b i c y c l o [ 3 .1. Oj hex- 2-enes A s i m p l e b i c y c l i c analogue of c i s - 1 , 2 - d i v i n y l c y c l o p r o -pane i s r e p r e s e n t e d by 6 - e n d o - v i n y l b i c y c l o f"3 .1. 0~1 hex-2-ene (81) . As such, i t i s not s u r p r i s i n g t h a t the Cope r e a r r a n g e -ment of t h i s compound t o g i v e b i c y c l o Q . 2. f] o c t a - 2 , 6 - d i e n e 52 53 (8 2) i s a v e r y f a c i l e p r o c e s s ' . An i n i t i a l attempt t o - 25 -pre p a r e (81) u s i n g the W i t t i g r e a c t i o n o f b i c y c l o [3 .1.6] hex-2-ene-endo-6-carboxaldehyde (83) 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 -phorane (_80) gave o n l y (8_2) . 8 3 81 82 Compound (8_1) was s u b s e q u e n t l y i s o l a t e d u s i n g the same r e a c t i o n a t lower t e m p e r a t u r e s and was found t o have a h a l f -o 5 3 l i f e o f a p p r o x i m a t e l y 1 day a t 25 C . On the o t h e r hand 6 - e x o - v i n y l b i c y c l o [3 .1.0~| hex-2-ene (84 ) ( l i k e o t h e r t r ans-1, 2-d i v i n y l c y c l o p r o p a n e s ) i s s t a b l e a t ambient temperature but o 54 r e a r r a n g e s t o g i v e compound (8_2) a t 195 C . T h i s p r o c e s s 54 . . . . was shown t o proceed v i a a o n e - c e n t r e e p i m e r i z a t i o n a t Cg, presumably t o g i v e the 6-endo isomer which r a p i d l y r e a r r a n g e d t o compound (82) . Thus, both o p t i c a l l y a c t i v e (8_1) and (8 4) r e a r r a n g e d t h e r m a l l y ( a l b e i t a t d i f f e r e n t temperatures) t o 54 a f f o r d the same o p t i c a l l y a c t i v e compound (8^2) (Scheme 5) . A f u r t h e r s t u d y u s i n g the e n o l e t h e r s (8_5) and (86) showed t h a t these compounds r e a r r a n g e d s t e r e o s p e c i f i c a l l y t o 5 5 a f f o r d b i c y c l o [3 .2 . f ] o c t a d i e n e s s u b s t i t u t e d a t C^ (Scheme 6) . Whereas (85_) r e a r r a n g e d r e a d i l y t o a f f o r d the endo-m e t h o x y - b i c y c l o Q . 2 . 1 ] o c t a d i e n e ( 8 2 )» compound (86) was SCHEME 5 CHO 80 fast H-8J 81 base 80 CHO — (-)-83a (-)-84 t h e r m a l l y s t a b l e and, as i n the case of c i s , c i s , c i s - l , 2 -2 2 d i p r o p e n y l - c y c l o p r o p a n e (_11) , a f f o r d e d o n l y the t r a n s -T h i s was e x p l a i n e d i n terms o f the severe s t e r i c i n t e r -a c t i o n s between the c i s - m e t h o x y group and the r i n g methylene 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 r e q u i r e d f o r the Cope rearrangement t o o c c u r . However, on b e i n g heated t o 220°C both (8_6) and (88) r e a r r a n g e d c l e a n l y t o a f f o r d ( 8 9 ) 5 5 . 5 6 S i m i l a r l y , Klumpp and co-workers have used the Knoevenagel c o n d e n s a t i o n of aldehydes (9_0) and m a l o n i c a c i d t o p r e p a r e the b i c y c l o [ 3 .1.0] hexenes (9^1) (Scheme 7 ) . The isomer (88) on b e i n g heated t o 180°C. - 27 -85 R 1=H,R 2=OMe 87 7 86 Ri = OMe,R 2=H 89 88 II ready rearrangement of the l a t t e r t o g i v e the b i c y c l o [ 3 . 2 . T\ -o c t a d i e n e s (9_2) p r o v i d e d an e n t r y i n t o b i c y c l o [3 . 2 . l ] o c t a -d i e n e s s u b s t i t u t e d a t both and Cg. U n f o r t u n a t e l y , these w orkers o b t a i n e d m i x t u r e s o f c i s - and t r a n s - c a r b o x y l i c a c i d s i n p r e p a r i n g (9_1) and s i n c e these m i x t u r e s were r e a r r a n g e d t o g i v e m i x t u r e s o f the endo- and exo- c a r b o x y l i c a c i d s (9_2) no f i r m c o n c l u s i o n s c o u l d be drawn r e g a r d i n g the s t e r e o s p e c i f i -c i t y o f the r e a c t i o n . 57 However, more r e c e n t l y i t has been shown t h a t compounds (91a) and (91b) r e a r r a n g e s t e r e o s p e c i f i c a l l y t o y i e l d the b i c y c l o [3 . 2 . l ] o c t a d i e n e s (92a) and (92b), r e s p e c t i v e l y . In s p i t e - 28 -90a)R-, = H 91 a )R 1 > 2 =H,R 3 =C0 2 H S2 b)Ri = O B u l b) R l f ' 3=H f R 2 =C0 2 H c) R ^ O B u i , R 2 = H , R 3 = C 0 2 H d) R ^ O B u t , R 2 = C 0 2 H , R 3=H of these r e s u l t s , the Cope rearrangement of 8 - a l k e n y l - b i c y c l o -[3 .1.<J]hexenes as an entry to b i c y c l o [ 3 . 2 . Q octanes has not been s y n t h e t i c a l l y e x p l o i t e d . VI . Conclusion The bicycloQ.2.1]octane r ing system i s incorporated into numerous sesquiterpenes possessing unique carbon skeletons and in t r igu ing b i o l o g i c a l a c t i v i t y . The synthet ic in te res t generated by recent ly i so la ted sesquiterpenes, such as for example cycloseychel lene (93J 5 8 , 9-isocyanopupukeanane (94) 5 9 , sinularene (9_5) 6 0 and quadrone ( 9 _ 6 ) 6 1 ' 6 2 , i s perhaps most 6 3 — 6 6 convincingly demonstrated by the host of recent indepen-dent syntheses of (94). - 29 -NC 95 96 In l i g h t of these f a c t s , i t was thought that at tent ion should be turned to the synthesis of more highly funct iona-l i z e d b i c y c l o [3 . 2 . ]~] octanes using the Cope rearrangement of 6 - v i n y l b i c y c l o [3 .1. fT] hex-2-enes . Part of th is thesis w i l l d iscuss the preparation of var ious 6 -a lkeny lb icyc lo [3 .1. fT] -hex-2-enes and the Cope rearrangement of these compounds to af ford f unct iona l i zed b i c y c l o [3 . 2 . TJ octa -2 ,6 -d ienes . - 30 -DISCUSSION I. g-Himachalene; The Synthetic Plan Any complex organic molecule may, in p r i n c i p l e , be syn-thesized from a s impler , more read i ly ava i lab le precursor v ia a f i n i t e number of chemical t ransformat ions* . Thus, a funda-6 7 mental approach to the design of any t o t a l synthesis is the 6 8 " re t ro -synthe t ic ana lys is" of the target molecule. By work-ing backwards from the desired compound using bond-breaking or funct iona l group manipulat ion, success ive ly less complex poten-t i a l intermediates are generated. Idea l l y , these intermediates should then provide a route from a p r a c t i c a l s ta r t ing mate r i a l , through a number of known (or newly developed) chemical reac-t i o n s , to the target compound. The large number of possib le synthet ic pathways to any given target , which are produced using th is type of a n a l y s i s , has s t i r r e d recent in te res t in 69 computer-assisted synthet ic design . More usual ly the syn-thet ic chemist must re ly on h is /her knowledge of ava i lab le synthet ic methods as wel l as h is /her i n t u i t i o n in choosing the most promising synthet ic plan from the number of p o s s i b i l i t i e s provided by a re t ro -syn the t ic a n a l y s i s . A successfu l synthe-t i c planner w i l l try not only to reconci le the chemical reac-t ions used in the proposed synthesis with transformations This i s , of course , a gross o v e r - s i m p l i f i c a t i o n and a lso more e a s i l y said than done! - 31 -h a v i n g p r e c e d e n t i n the l i t e r a t u r e , but w i l l attempt to a n t i -c i p a t e p o s s i b l e b o t t l e n e c k s . T h e r e f o r e , a major c o n s i d e r a t i o n i n c h o o s i n g a s p e c i f i c s y n t h e t i c p l a n i s i t s v e r s a t i l i t y . A number of methods s h o u l d be a v a i l a b l e t o e f f e c t a r e q u i r e d t r a n s f o r m a t i o n ( i n case of an i n i t i a l f a i l u r e ) or t o p r e pare a key i n t e r m e d i a t e and t h e r e s h o u l d be a degree of f l e x i b i l i t y i n the o r d e r i n which the r e a c t i o n s may be performed. The importance of these f e a t u r e s w i l l become more apparent as the s y n t h e t i c a t t e m p t s l e a d i n g t o the t o t a l s y n t h e s i s o f (±)~3~ himachalene are d e s c r i b e d ( v i d e i n f r a ) . The s y n t h e t i c p l a n n i n g f o r the t o t a l s y n t h e s i s of 3-hima-c h a l e n e was s i m p l i f i e d by the f a c t t h a t the t a r g e t had been chosen w i t h a p a r t i c u l a r key s t e p i n mind. S i n c e the t h e r m a l rearrangement of a 3 - ( v i n y l c y c l o p r o p y l ) enone such as (9_7) t o 39 g i v e (98_) would p r o v i d e the b a s i c c a r b o n s k e l e t o n r e q u i r e d , the o n l y o t h e r c o n s i d e r a t i o n was the p o s i t i o n o f the r i n g s u b s t i t u e n t s . On s t u d y i n g 3-himachalene i t became apparent t h a t e i t h e r (9_9) or (100) would 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 key i n t e r m e d i a t e s i n t h i s s y n t h e t i c scheme. The Cope rearrangement of the c i s - d i v i n y l c y c l o p r o p a n e ( 9 9 ) , f o r i n s t a n c e , s h o u l d o ccur a t , or s l i g h t l y above, ambient tem-p e r a t u r e t o g i v e the b i c y c l i c ketone (101). However, a c o m p l i c a t i n g f a c t o r i n t h i s case might be the ease o f i s o -m e r i z a t i o n o f the e x o c y c l i c double bond i n t o c o n j u g a t i o n w i t h - 32 -the ketone. This type of isomerizat ion has been reported in 41 a s imi la r case (cf . 43a -> 4_4) This obviously represents an undesirable complicat ion since the conversion of (102) back to the desired compound (101) would not be a f a c i l e process. The t rans-d iv iny lcyc lopropane (100), on the other hand, would be expected to rearrange only at elevated temperatures and th is would provide a higher degree of con t ro l over the course of the react ion sequence. In th is case , i f necessary, the ketone f u n c t i o n a l i t y could be funct iona l i zed before the Cope rearrangement step in order to preclude the p o s s i b i l i t y of an isomerizat ion of the exocyc l ic double bond (eq. 4) . - 3 3 -- 34 -One c o m p l i c a t i o n which might be a s s o c i a t e d w i t h u s i n g the Cope rearrangement o f (100) t o prepare (101) i s the pos-70 s i b i l i t y o f a competing homo [ 1 , 5 ] s i g m a t r o p i c hydrogen s h i f t , which would l e a d t o the t r i e n o n e (106). T h i s type o f a r e a c t i o n has been r e p o r t e d to occur i n the 41 t h e r m a l rearrangement of the r e l a t e d compounds (4_0) and ( 1 0 7 ) 3 8 ' 4 3 . 107 43 However, Wender and co-wor ker s"*J found t h a t t h i s problem c o u l d be c i r c u m v e n t e d by u s i n g a p h o t o e p i m e r i z a t i o n o f the t r a n s - d i v i n y l c y c l o p r o p a n e (107) to g i v e the c i s - i s o m e r (108). - 35 -As a r e s u l t , simultaneous i r r a d i a t i o n and thermolysis of com-pound (107) produced the desired r ing- fused product (109). This type of approach should a lso be e f f e c t i v e in the case at hand, i f a homo .Qf!T] sigmatropic hydrogen s h i f t should occur on thermolysis of compound (100) . hv 39 71 P iers and Nagakura have shown ' that B - a l k y l - a , B -unsaturated ketones can be conveniently prepared by the reac-t ion of B-halo a,B-unsaturated ketones with a l k y l cuprate reagents. Applying th is methodology to the problem at hand, the B~(vinylcyclopropyl)enone (100) can be v i s u a l i z e d as the product of the react ion of 3 - iodo-2-cyclohexen- l -one (110) and the organocuprate reagent (111). Li i CuS<P 110 111 - 36 -The r e a g e n t (111) c o u l d be p r e p a r e d i n s i t u from the t e r t i a r y bromide (112), which i n t u r n s h o u l d be a v a i l a b l e v i a a W i t t i g . r e a c t i o n o f the a p p r o p r i a t e aldehyde (113). Li I CuS<P 111 112 Br CHO 113 The problem o f the s t e r e o c h e m i s t r y of compound (113) c o u l d be addressed i n the f o l l o w i n g manner. I f the aldehyde were p r o t e c t e d as the a c e t a l (114) t h i s m a t e r i a l might be a v a i l a b l e v i a a l k y l a t i o n of the c a r b e n o i d (115), which c o u l d be ge n e r a t e d by a l i t h i u m - b r o m i n e exchange r e a c t i o n o f the di b r o m o c y c l o p r o p a n e (116). The a c e t a l m o i e t y would thus serve 4> Br Br 4 two p u r p o s e s . As a p r o t e c t i n g group i t would a l l o w the p r e -p a r a t i o n of compound (116) by the a d d i t i o n o f dibromocarbene 72 - 37 -t o the v i n y l d i o x a n e ( 1 1 7 ) * , s i n c e the a d d i t i o n o f d i h a l o c a r -benes t o a , 8 - u n s a t u r a t e d aldehydes i s n o t a f e a s i b l e p r o c e s s 7 3 Br Br 117 H Br H F u r t h e r m o r e , the oxygen atoms of the a c e t a l s h o u l d be i n an i d e a l p o s i t i o n t o s t a b i l i z e the c a r b e n o i d (115) by i n t r a -m o l e c u l a r c h e l a t i o n o f the l i t h i u m ^ 5 . S t e r e o s e l e c t i v e a l k y l a t i o n o f 1 - l i t h i o c y c l o p r o p y l b r o -7 6 mides was f i r s t r e p o r t e d by Hiyama, e t a l . . In the case of the b e n z y l e t h e r (121) the f a c t t h a t c i s - a l k y l a t i o n predomi-n a t e d (to a f f o r d compound 122a) was e x p l a i n e d i n terms o f the M a r i n o and Browne have r e p o r t e d the p r e p a r a t i o n o f 2 , 2 - d i b r o m o c y c l o p r o p a n e c a r b o x a l d e h y d e (118) by the a d d i -t i o n o f dibromocarbene t o a c r o l e i n d i e t h y l a c e t a l (119), f o l l o w e d by a c i d c a t a l y z e d h y d r o l y s i s of the a c e t a l (120). However, no y i e l d s were r e p o r t e d . Br Br Br Br •OEt Bn,C: OEt 119 CHO 120 OEt - 38 -in te rac t ion of the l i th ium ion with the ethereal oxygen (eq. 5 ) 7 6 . S i m i l a r l y , P i e r s , e_t a l . 4 1 have reported that protona-t ion of the carbenoid derived from the tetrahydropyranyl ether (123) provided e x c l u s i v e l y compound (124 ) , presumably again due to the s t a b i l i z a t i o n of the carbenoid intermediate (125) by intramolecular che la t ion of the l i th ium ion (eq. 6 ) . Since i t appeared that compound (100) could be prepared s t e r e o s e l e c t i v e l y in th is manner, i t was chosen as the key intermediate in the synthet ic route to B-himachalene (3J • A possib le route from the b i c y c l i c ketone (101) to B-himachalene (3_) seemed somewhat more obvious. A l k y l a t i o n of the ketone (101) would lead to the mono-methylated ketone (126) in an unambiguous manner. C a t a l y t i c hydrogenation of th is mater ia l should favour reduction of the d isubst i tu ted double bond to af ford the ketone (127 ) . Preparation of the - 39 -e n o l phosphate (128) o f t h i s k e t o n e , f o l l o w e d by r e d u c t i o n 77 o f the former s u b s t a n c e w i t h l i t h i u m i n e t h y l a m m e would complete the s y n t h e s i s o f ( + ) - B - h i m a c h a l e n e (3_) i n a t o t a l of e l e v e n s t e p s . The e n t i r e s y n t h e t i c p l a n i s summarized i n Scheme 8. I I . The T o t a l S y n t h e s i s o f (±)-g-Himachalene 7 S i n c e a c r o l e i n d i e t h y l a c e t a l (115) i s a known compound and has i n f a c t been used t o p r e p a r e 2,2-dibromocyclopropane-74 car b o x a l d e h y d e d i e t h y l a c e t a l (120) , t h i s r e a c t i o n was con-s i d e r e d as a p o s s i b l e s t a r t i n g p o i n t f o r the s y n t h e s i s of the aldehyde (113). U n f o r t u n a t e l y , a l l a t t e m p t s t o p r e p a r e (120) from (119) f a i l e d and t h i s approach was abandoned. The r e p o r t e d s t a b i l i t y and ease o f f o r m a t i o n of c y c l i c 79 six-membered a c e t a l s o f a c r o l e i n l e d t o the attempted p r e -p a r a t i o n of 2 - v i n y l - 5 , 5 - d i m e t h y l - 1 , 3 - d i o x a n e (117) from a c r o l e i n and 2 , 2 - d i m e t h y l - 1 , 3 - p r o p a n e d i o l i n benzene c o n t a i n i n g a c a t a -l y t i c amount of p - t o l u e n e s u l f o n i c a c i d . A z e o t r o p i c (Dean-S t a r k ) removal of water from t h i s r e a c t i o n m i x t u r e l e d t o the f o r m a t i o n o f the a c e t a l (117) i n about 68% y i e l d , as w e l l as a - 41 -v i s c o u s o i l w h i c h , when c r y s t a l l i z e d from pentane, a f f o r d e d c o l o u r l e s s c r y s t a l s w i t h a m e l t i n g p o i n t of 64-66°C. The l a t t e r compound ( i s o l a t e d i n about 13% y i e l d ) was i d e n t i f i e d as the t e t r a h y d r o p y r a n y l e t h e r (129). T h i s compound was a p p a r e n t l y produced by the r e a c t i o n o f the dimer o f a c r o l e i n (130) w i t h two e q u i v a l e n t s o f 2 , 2 - d i m e t h y l - 1 , 3 - p r o p a n e d i o l * . I t was found t h a t the a c e t a l (117) c o u l d be more con-v e n i e n t l y p r e p a r e d by the r e a c t i o n of a c r o l e i n and 2,2-d i m e t h y l - 1 , 3 - p r o p a n e d i o l a t room temperature i n d i c h l o r o m e t h a n e S i m i l a r l y , the l a c t o l (131) has been r e p o r t e d as the p r o d u c t of the r e a c t i o n o f (130) w i t h 2-methyl-2,4-p e n t a n e d i o l under a c i d - c a t a l y z e d c o n d i t i o n s . - 42 -c o n t a i n i n g a t r a c e of p - t o l u e n e s u l f o n i c a c i d . Compound (117) was i s o l a t e d as a l o w - b o i l i n g l i q u i d whose i r spectrum showed no c a r b o n y l a b s o r p t i o n . The 1E nmr showed l o w - f i e l d m u l t i -81 p l e t s c h a r a c t e r i s t i c of the H2C=CH- moiety . An AB p a i r of d o u b l e t s c e n t r e d a t 6 3.60 and a t t r i b u t e d t o the f o u r a c e t a l methylene p r o t o n s , showed a c o u p l i n g c o n s t a n t (J = 11 8 2 Hz) which i s comparable t o t h a t r e p o r t e d f o r the a x i a l -e q u a t o r i a l g e m i n a l c o u p l i n g between the C^ p r o t o n s o f 1,3-d i o x a n e (132). The g e m i n a l m e t h y l groups of the a c e t a l appeared as s i n g l e t s a t 6 1.22 and 0.74. With the s t r u c t u r e o f (117) c o n f i r m e d , a t t e n t i o n was t u r n e d t o i t s p o s s i b l e r e a c t i o n w i t h dibromocarbene t o g i v e the d i b r o m o c y c l o p r o p a n e (116) . G e n e r a t i o n o f dibromocarbene 8 3 was e f f e c t e d by the method of Makosza , i n v o l v i n g t r e a t m e n t o f bromoform w i t h aqueous sodium h y d r o x i d e under p h a s e - t r a n s f e r 84 c o n d i t i o n s . The r e a c t i o n o f a c e t a l (117) under these con-d i t i o n s gave a d a r k , t a r r y m i x t u r e . T h i s i s c o n s i s t e n t w i t h 8 5 the r e c e n t o b s e r v a t i o n t h a t the r e a c t i o n medium of a 132 - 43 -d i h a l o c a r b e n e a d d i t i o n onto a r e a c t i v e o l e f i n remains n e a r l y c o l o u r l e s s , whereas the r e a c t i o n w i t h s t e r i c a l l y or e l e c t r o n i -c a l l y d e a c t i v a t e d o l e f i n s l e a d s t o the e x t e n s i v e f o r m a t i o n of b l a c k polymers from the h a l o f o r m p r e s e n t . The dark r e a c t i o n m i x t u r e c o n t a i n e d a number of p r o d u c t s (as judged by g l c a n a l y s i s ) and s t a r t i n g m a t e r i a l was a l s o p r e s e n t even a f t e r a r e a c t i o n time o f 20 h o u r s . Longer r e a c t i o n times d i d not i n c r e a s e the y i e l d of the d e s i r e d p r o d u c t , a l t h o u g h the amount of r e t u r n e d s t a r t i n g m a t e r i a l d e c r e a s e d . F o r t u n a t e l y , i t was found t h a t the d e s i r e d p r o d u c t (116) c r y s t a l l i z e d from a pen-tane s o l u t i o n o f the crude r e a c t i o n m i x t u r e . R e c r y s t a l l i z a t i o n of t h i s m a t e r i a l from pentane a f f o r d e d (116) as c o l o u r l e s s c r y s t a l s i n 27% y i e l d . The 100 MHz 1E nmr of t h i s m a t e r i a l showed no e v i d e n c e o f the v i n y l i c p r o t o n s i g n a l s of the s t a r t -i n g m a t e r i a l but showed a new h i g h f i e l d m u l t i p l e t a t 6 1.5 t o 2.2 which i n t e g r a t e d f o r t h r e e p r o t o n s . The s i m p l e AB p a i r o f d o u b l e t s found i n the s t a r t i n g m a t e r i a l was s u p p l a n t e d by a more complex m u l t i p l e t which was a t t r i b u t e d t o the f o u r a c e t a l methylene p r o t o n s . S i n c e e x a c t p r o t o n assignments i n the compound (116) would f a c i l i t a t e s t e r e o c h e m i c a l assignments i n the n e x t s t e p , the 270 MHz *H nmr spectrum was o b t a i n e d i n o r d e r t o enhance the r e s o l u t i o n o f o v e r l a p p i n g s i n g l e p r o t o n m u l t i p l e t s . E x a m i n a t i o n of the 270 MHz XH nmr spectrum of the d i b r o m o c y c l o p r o p a n e (116) ( F i g . 1) showed t h r e e d i s t i n c t s i n g l e p r o t o n m u l t i p l e t s a t 6 2.01, 1.84 and 1.61. S i n c e - 45 -s u b s t i t u e n t s c i s t o a c y c l o p r o p y l p r o t o n g e n e r a l l y tend t o 8 6 s h i e l d i t , the h i g h e s t f i e l d o v e r l a p p e d d o u b l e t of d o u b l e t s i s a t t r i b u t e d t o the p r o t o n c i s t o the a c e t a l group ( H c ) . S i n c e i n t h i s case the g e m i n a l c o u p l i n g ( J = 6 Hz) t o H^ i s e q u i v a l e n t t o the v i c i n a l c o u p l i n g t o the t r a n s - p r o t o n H . t h i s m u l t i p l e t appears as a t r i p l e t . S i n c e the v i c i n a l coup-l i n g o f c _ i s - c y c l o p r o p y l p r o t o n s i s always l a r g e r (7.0 - 12.6 Hz) than the c o u p l i n g o f t r a n s p r o t o n s i n the same system 8 7 (4.0 - 9.6 Hz) and u s u a l l y l a r g e r than g e m i n a l c o u p l i n g s (3.1 - 9.1 H z ) , the d o u b l e t o f d o u b l e t s a t 6 1.84 (J = 11, 6 Hz) i s a s s i g n e d t o H^. The resonance o f h i g h e s t m u l t i p l i c i t y (6 2.01) i s a s s i g n e d t o the r e m a i n i n g c y c l o p r o p y l p r o t o n H , s i n c e i t can c o u p l e cl t o t h r e e o t h e r p r o t o n s w h i l e H^ and H c may o n l y c o u p l e t o two o t h e r p r o t o n s . T h i s m u l t i p l e t appears as an o v e r l a p p i n g p a i r of t r i p l e t s s i n c e the a b s o l u t e v a l u e s of the c o u p l i n g con-s t a n t s J a c and J Q d are e q u a l . I t i s i n t e r e s t i n g t o note t h a t the r e l a t i v e c h e m i c a l s h i f t s a s s i g n e d t o these t h r e e c y c l o p r o p y l p r o t o n s are s i m i l a r 8 8 t o those r e p o r t e d f o r the d i c h l o r o c y c l o p r o p a n e s (133) (Table 1) • The somewhat unexpected c o m p l e x i t y o f the m u l t i p l e t a t t r i b u t e d t o the a c e t a l methylenes s h o u l d a l s o be e x p l a i n e d b r i e f l y . I f the two methylenes are assumed t o be n o n - e q u i v a -l e n t then two AB p a i r s of d o u b l e t s would be produced (based - 46 -TABLE I . C h e m i c a l S h i f t Data f o r some S u b s t i t u t e d C y c l o -propanes^° X H a H b H c -OAc 1.58 1.84 4.28 - O C H 3 1.52 1.67 3.62 -Br 1.58 2.08 3.45 -Ph 1.73 1.85 2.80 89 on an e x p e c t e d g e m i n a l c o u p l i n g o f about 11 H z ) . However, the expected e i g h t - l i n e m u l t i p l e t i s c o m p l i c a t e d by an a d d i t i o n a l s p l i t t i n g , i n the low f i e l d h a l f o f the m u l t i p l e t , o f about 2 Hz (see F i g . 1 ) . T h i s may be e x p l a i n e d as a l o n g range "W-ty p e " c o u p l i n g (which i s g e n e r a l l y i n the range of 1 - 2 Hz) between the two e q u a t o r i a l methylene p r o t o n s H and H ,, "si "q s i n c e they s h o u l d be i n the p l a n a r z i g - z a g c o n f i g u r a t i o n 89 r e q u i r e d t o maximize t h i s i n t e r a c t i o n H, b H a x H ° * ' A l t h o u g h the low y i e l d of d i b r o m o c y c l o p r o p a n e (116) o b t a i n e d by the a d d i t i o n of dibromocarbene t o the o l e f i n (117) was d i s a p p o i n t i n g , i t was n o t e n t i r e l y u n a n t i c i p a t e d . S i n c e dibromocarbene behaves l i k e an e l e c t r o p h i l e toward o l e f i n i c - 47 -bonds, the r e a c t i v i t y o f the o l e f i n g e n e r a l l y i n c r e a s e s as the 72 number o f a l k y l s u b s t i t u e n t s on the double bond are i n c r e a s e d .. 2 - V i n y 1 - 5 , 5 - d i m e t h y l - 1 , 3 - d i o x a n e (117) i s d e a c t i v a t e d t o e l e c t r o p h i l i c a t t a c k b oth because i t i s a m o n o - s u b s t i t u t e d o l e f i n and due t o the i n d u c t i v e e l e c t r o n - w i t h d r a w i n g e f f e c t o f the a d j a c e n t oxygens. N a t u r a l l y the y i e l d w i l l s u f f e r s i n c e these d e a c t i v a t i n g e f f e c t s cause s l u g g i s h a d d i t i o n o f dibromocarbene t o the s t a r t i n g m a t e r i a l , thus a l l o w i n g f o r a 9 g r e a t e r p o s s i b i l i t y o f s i d e r e a c t i o n s . For example, S t e i n b e c k has r e p o r t e d t h a t c y c l i c a c e t a l s l i k e (134) may undergo an i n s e r t i o n r e a c t i o n w i t h d i h a l o c a r b e n e s , under phase t r a n s f e r c o n d i t i o n s , t o form the d i h a l o m e t h y l k e t a l s (135). S i d e r e a c -t i o n s o f t h i s t y pe may i n f l u e n c e the e f f i c i e n c y o f the r e a c -t i o n o f (117) t o (116) and a ccount f o r the p r o d u c t m i x t u r e s which were o b s e r v e d . 134 135 B r B r - 48 -However, s i n c e t h i s r e a c t i o n was o n l y the second s t e p i n the s y n t h e s i s and s i n c e the s t a r t i n g m a t e r i a l (117) was r e a d i l y a v a i l a b l e , i t was p o s s i b l e t o work on a s c a l e which p r o v i d e d r e a s o n a b l e q u a n t i t i e s of (116) d e s p i t e the low y i e l d o b t a i n e d . The r e a c t i o n of di b r o m o c y c l o p r o p a n e (116) w i t h 1 e q u i v -a l e n t o f n - b u t y l l i t h i u m i n THF-HMPA (4:1) a t -95°C ( i n the presence of iodomethane) gave a m i x t u r e o f two new compounds ( as judged by g l c a n a l y s i s ) . On s m a l l s c a l e ( c a . 1.0 mmol) the r a t i o o f these p r o d u c t s was about 93:7. By an a l o g y w i t h the r e a c t i o n o f the b e n z y l e t h e r (121) under the same c o n d i -t i o n s , t o a f f o r d (122a) and (122b) i n a comparable r a t i o (97:3) , the p r o d u c t was t e n t a t i v e l y i d e n t i f i e d as a m i x t u r e o f the i s o m e r i c a l k y l a t e d compounds (114) and (136). On s c a l i n g up t h i s r e a c t i o n ( c a . 10-50 mmol) the r a t i o o f these two p r o d u c t s d e c r e a s e d t o 87:13. Column chromatography of t h i s m i x t u r e a f f o r d e d the major component as a l o w - m e l t i n g - 49 -s o l i d (m.p. 24.5-26°C) i n 74% y i e l d . The 270 MHz JH nmr spec-trum o f t h i s m a t e r i a l was q u i t e s i m i l a r t o t h a t of the s t a r t i n g m a t e r i a l w i t h the a d d i t i o n of a s i n g l e t i n t e g r a t i n g f o r thr e e p r o t o n s a t 6 1.84. The t h r e e s i n g l e p r o t o n m u l t i p l e t s a s s i g n e d t o the c y c l o p r o p y l p r o t o n s a l s o r e s o n a t e d a t h i g h e r f i e l d than those o b s e r v e d i n the *H nmr of the s t a r t i n g m a t e r i a l (see F i g . 2 ) . A l t h o u g h the m u l t i p l e t a t 6 1.7-2.0 was p a r t i a l l y obscured by the new m e t h y l s i n g l e t , the o t h e r two m u l t i p l e t s showed s p l i t t i n g p a t t e r n s a l m o s t i d e n t i c a l w i t h those found i n the 270 MHz 1H nmr o f the d i b r o m o c y c l o p r o p a n e (116). I f the r e l a t i v e c h e m i c a l s h i f t s 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 have remained the same as i n the s t a r t i n g m a t e r i a l , then the t r i p l e t ( 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 t r i b u t e d t o H c had undergone the l a r g e s t change i n c h e m i c a l s h i f t on g o i n g from (116) t o (114) . T h i s might be e x p e c t e d s i n c e i t i s the o n l y p r o t o n 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 c i s t o the c y c l o p r o p y l m e t h y l group and thus most s u s c e p t i b l e t o d i r e c t s h i e l d i n g . The l e s s e r changes i n the c h e m i c a l s h i f t s o f the o t h e r two m u l t i p l e t s may be r a t i o n a l i z e d as b e i n g due t o the d e c r e a s e i n i n d u c t i v e e l e c t r o n -w i t h d r a w a l from the c y c l o p r o p y l r i n g on g o i n g from a dibromo-c y c l o p r o p a n e t o a mono-bromocyclopropane system. The n o t a b l e s i m p l i f i c a t i o n o f the a c e t a l methylene s i g -n a l s (as compared t o those o b s e r v e d i n the dib r o m o c y c l o p r o p a n e 116) may be e x p l a i n e d by a f o r t u i t o u s o v e r l a p o f the p a i r o f a x i a l p r o t o n d o u b l e t s t o form one d o u b l e t and a p a r t i a l o v e r l a p FIGURE 2. The 270 MHz JH nmr Spectrum of the c i s - M e t h y l a t e d Cyclopropane (114) - 51 -o f the p a i r o f e q u a t o r i a l p r o t o n d o u b l e t o f d o u b l e t s t o g i v e a " t r i p l e d o u b l e t " ( F i g . 2 ) . These d a t a appeared t o be c o n s i s t e n t w i t h the i d e n t i f i c a -t i o n o f t h i s compound as the c i s - m e t h y l a t e d compound (114). F u r t h e r s u b s t a n t i a t i o n of the s t e r e o c h e m i s t r y was p r o v i d e d by a n a l y s i s o f the *H nmr s p e c t r a o f the p r o d u c t s o f the n e x t s t e p ( v i d e i n f r a ) . The minor component of the r e a c t i o n m i x t u r e was a l s o i s o l a t e d u s i n g column chromatography and was o b t a i n e d as f i n e , c o l o u r l e s s c r y s t a l s (m.p. 52-53°C) i n 11% y i e l d . The 270 MHz 1E nmr spectrum of t h i s m a t e r i a l e x h i b i t e d a t h r e e p r o t o n s i n g l e t a t 6 1.78 a s s i g n e d t o the c y c l o p r o p y l m e t h y l group ( F i g . 3 ) . No s t e r e o c h e m i c a l assignment c o u l d be made based on the s m a l l d i f f e r e n c e between the c h e m i c a l s h i f t s o f the c y c l o p r o p y l m e t h y l groups i n (114) and ( 1 3 6 ) * . However, there are s e v e r a l n o t a b l e d i f f e r e n c e s between the XH nmr o f com-pound (136) and t h a t of the compound i d e n t i f i e d as the c i s -m e t h y l a t e d isomer (114). The c y c l o p r o p y l p r o t o n s which e x h i b -i t e d t h r e e d i s t i n c t s i n g l e p r o t o n m u l t i p l e t s i n (114) c o a l e s c e t o form a complex m u l t i p l e t a t 6 1.04-1.18 i n the minor a l k y l a -t i o n p r o d u c t . I n t e r p r e t a t i o n o f the s p l i t t i n g o f t h i s P r e v i o u s workers ' have based t h e i r s t e r e o c h e m i c a l a s s i g n m e n t s , i n compounds l i k e (114) and (136) , on r e l a -t i v e l y l a r g e d i f f e r e n c e s i n the c h e m i c a l s h i f t s o f c i s and t r a n s m e t h y l s u b s t i t u e n t s . However, these d i f f e r e n c e s were due t o s u b s t a n t i a l s h i e l d i n g by a p h e n y l group and s h i e l d i n g e f f e c t s o f comparable magnitude are not observed i n (114) and (136). FIGURE 3. The 270 MHz *H nmr Spectrum of the trans-Methylated Cyclopropane (136) - 53 -m u l t i p l e t was n o t p o s s i b l e , but a q u a l i t a t i v e assessment c o u l d j u s t i f y the i d e n t i f i c a t i o n of t h i s m a t e r i a l as the t r a n s -m e t h y l a t e d isomer (136). In a g e n e r a l s e n s e , the t r a n s d i s -p o s i t i o n o f the m e t h y l group might cause an a v e r a g i n g o f the s h i e l d i n g e f f e c t s which were thought to cause l a r g e d i f f e r -ences i n c h e m i c a l s h i f t s o f the c y c l o p r o p y l p r o t o n s i g n a l s i n the case of the c i s - i s o m e r (114) ( v i d e s u p r a ) . More p a r t i c u -l a r l y , the d e c r e a s e d s h i e l d i n g o f (as compared t o H c) s h o u l d r e s u l t i n a d o w n f i e l d s h i f t of the a p p r o p r i a t e resonance, w h i l e the i n c r e a s e d s h i e l d i n g of and H g (as compared t o and H ) , caused by the t r a n s - m e t h y l group, would be expected t o cause an u p f i e l d s h i f t o f these r e s o n a n c e s . T h i s might e x p l a i n the o b s e r v e d "compression" of the c y c l o p r o p y l p r o t o n s i g n a l s i n (136) r e l a t i v e t o (114) (see F i g . 2, 3 ) . The s t e r e o c h e m i s -t r y a s s i g n e d t o (136) was s u b s t a n t i a t e d by a more d e t a i l e d a n a l y s i s of the *H nmr o f the p r o d u c t s of the n e x t s t e p (vide  i n f r a ) . H y d r o l y s i s o f the a c e t a l (114) t o g i v e the d e s i r e d p r o -d u c t (E)-2-bromo-2-methylcyclopropanecarboxaldehyde (113) was e x p e c t e d t o proceed r e a d i l y under a c i d i c c o n d i t i o n s . However, the a c e t a l (114) t e n a c i o u s l y r e s i s t e d a c i d - c a t a l y s e d h y d r o l y -s i s . In f a c t , the s t a r t i n g m a t e r i a l was r e c o v e r e d unchanged upon t r e a t m e n t w i t h 1 N HCl i n methanol a t room temperature and even a f t e r attempted h y d r o l y s i s i n r e f l u x i n g g l a c i a l a c e t i c a c i d ! A l t h o u g h the a c e t a l appeared t o be h y d r o l y z e d (as judged - 54 -by g l c and i r a n a l y s i s ) , a t l e a s t p a r t i a l l y , by t r i f l u o r o -a c e t i c a c i d o r by t i t a n i u m t e t r a c h l o r i d e i n d i c h l o r o m e t h a n e , these r e a c t i o n s were not r e p r o d u c i b l e . A p p a r e n t l y , s i n c e c y c l i c six-membered a c e t a l s are s t a b l e and e a s i l y formed (even 8 0 under aqueous c o n d i t i o n s ) , they are not r e a d i l y h y d r o l y z e d However, the h y d r o l y s i s o f the a c e t a l s o f some s e n s i t i v e 92 a c e t y l e n i c a l d e h y d e s u s i n g f o r m i c a c i d has been r e p o r t e d t o proceed r e a d i l y . I t was w i t h a measure o f r e l i e f t h a t the r e a c t i o n o f the a c e t a l (114) w i t h 88% f o r m i c a c i d was found t o g i v e the aldehyde (113), as a v o l a t i l e l i q u i d , i n 72% y i e l d . * The i r spectrum o f t h i s m a t e r i a l e x h i b i t e d a c h a r a c t e r i s t i c C-H (aldehyde) a b s o r p t i o n a t 2780 c m - 1 and a c a r b o n y l absorp-t i o n a t 1710 c m - 1 . Due t o i t s v o l a t i l i t y and i t s tendency t o decompose s l o w l y on s t a n d i n g , the aldehyde (113) was c h a r a c -t e r i z e d f u r t h e r as i t s 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e ( 1 3 7 ) * * . Th * T h i s method has s i n c e been r e p o r t e d ^ " 3 as an e f f e c t i v e means o f h y d r o l y z i n g another c y c l o p r o p a n e c a r b o x a l d e h y d e a c e t a l d e r i v a t i v e , i n c o n n e c t i o n w i t h s t u d i e s r e l a t i n g the s y n t h e s i s o f p r o s t a g l a n d i n s . 94 ** T h i s d e r i v a t i v e was p r e p a r e d i n the u s u a l way and was p u r i f i e d by r e c r y s t a l l i z a t i o n from the a p p r o p r i a t e s o l -v ent (see E x p e r i m e n t a l s e c t i o n ) . 114 H 113 H - 5 5 -mass spectrum of t h i s m a t e r i a l e x h i b i t e d a m o l e c u l a r i o n c l u s -t e r ( B r 8 1 / B r 7 9 ) a t m/e 344/342 and a major fragment (M-Br) a t m/e 263. T h i s , t o g e t h e r w i t h the a n a l y t i c a l d a t a , i s c o n s i s -t e n t w i t h the r e q u i r e d m o l e c u l a r f o r m u l a c n H 2 1 B r N 4 ° 4 * ^ e *H nmr spectrum of (137) i d e n t i f i e d i t q u i t e c l e a r l y as a 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e ( F i g . 4 ) . The m u l t i p l e t which had been obscured by the c y c l o p r o p y l m e t h y l s i n g l e t i n (114) i s now c l e a r l y v i s i b l e . The s p l i t t i n g p a t t e r n s o f a l l t h r e e c y c l o p r o p y l p r o t o n s are d i s t i n c t and q u i t e s i m i l a r t o those observed i n both d i b r o m o c y c l o p r o p a n e (116) and the monobromo-c y c l o p r o p a n e (114). The p r o t o n assignments are based both on c h e m i c a l s h i f t s and c o u p l i n g c o n s t a n t s (see F i g . 4 ) . These appear t o c o r r o b o r a t e the p r e v i o u s i d e n t i f i c a t i o n o f (114) as the c i s - m e t h y l a t e d i s o m e r . F u r t h e r e v i d e n c e t o s u p p o r t the s t e r e o c h e m i c a l assignments of (114) and (136) was p r o v i d e d by h y d r o l y s i s o f the t r a n s - m e t h y l a t e d a c e t a l (136) i n 88% f o r m i c a c i d (as done p r e v i o u s l y i n the case o f 114) which l e d t o (Z)-2-bromo-2-methylcyclopropanecarboxaldehyde (138). The l a t t e r was a l l o w e d t o r e a c t d i r e c t l y w i t h 2 , 4 - d i n i t r o p h e n y l -h y d r a z i n e t o a f f o r d the c o r r e s p o n d i n g hydrazone (139). - 5fc -FIGURE 4. The 100 MHz 1H nmr Spectrum of the 2,4-Dinitrophenylhydrazone (137) . - 57 -The l a t t e r compound had a d i f f e r e n t appearance and m e l t -i n g p o i n t from those o f the d i n i t r o p h e n y l h y d r a z o n e (137). However, the mass spectrum e x h i b i t e d the same m o l e c u l a r i o n (m/e 344/342) and major fragment (M-Br, m/e 263) found i n (137) and was found t o have the r e q u i r e d m o l e c u l a r f o r m u l a , C l l H l l B r N 4 ° 4 ' T h e l o w ~ f i e l d h a l f o f the *H nmr spectrum o f (139) ( F i g . 5) i s a l m o s t i d e n t i c a l t o t h a t o f i t s isomer (137) (see F i g . 4 ) . However, as i n the t r a n s - m e t h y l a t e d a c e t a l (136), t h e r e i s a "compression" o f the m u l t i p l e t s a t h i g h -f i e l d which are a s s i g n e d t o the t h r e e c y c l o p r o p y l p r o t o n s (when compared t o the m u l t i p l e t s e x h i b i t e d by the analogous p r o t o n s i n the i s o m e r i c d i n i t r o p h e n y l h y d r a z o n e 137) . But i n t h i s c a s e , i n c o n t r a s t t o the *H nmr of (136), i n d i v i d u a l p r o t o n assignments are p o s s i b l e . The s h i f t o f the resonances a s s i g n e d t o H a, and H^, t o h i g h e r f i e l d , as compared t o those o f H Q and H ^ , may be e x p l a i n e d i n terms o f the s h i e l d i n g e f f e c t e x e r t e d by the c i s - m e t h y l s u b s t i t u e n t . S i m i l a r l y , the s h i f t o f the resonance a s s i g n e d t o H ., t o lower f i e l d (compared t o H ) may be e x p l a i n e d e i t h e r i n terms of d e s h i e l d i n g by the c i s - b r o m i n e s u b s t i t u e n t or by the removal o f the s h i e l d i n g e f f e c t o f the me t h y l group which i s e x p e r i e n c e d by H c (see F i g . 4 and 5 ) . The n a t u r e o f the m u l t i p l e t a s s i g n e d t o H . was e l u c i -a d a t e d by means o f a d e c o u p l i n g e x p e r i m e n t . Thus, i r r a d i a t i o n o f the d o u b l e t a t 6 7.36 ( H d i ) r e s u l t e d i n a c o l l a p s e o f the m u l t i p l e t a s s i g n e d t o g i v e a d o u b l e t ( J = 10 Hz) c e n t r e d a t FIGURE 5. The 100 MHz lU nmr Spectrum of the 2,4-Dinitrophenylhydrazone (139) . - 59 -6 1.87. The o t h e r m u l t i p l e t s remained unchanged. The l a c k o f a v i s i b l e c o u p l i n g between the t r a n s o r i e n t e d p r o t o n s H , ' a 8 7 and H c, (expected t o be about 4.0 t o 9.6 Hz ) i s not immedi-a t e l y c l e a r . There i s , however, good agreement between the e x p e r i m e n t a l l y o b t a i n e d s p e c t r a ( F i g . 4, 5) and the computer s i m u l a t e d s p e c t r a (Scheme 9) o f two f o u r - p r o t o n s p i n systems, g e n e r a t e d u s i n g the e x p e r i m e n t a l l y o b t a i n e d c h e m i c a l s h i f t s and c o u p l i n g c o n s t a n t s * . W i t h these d a t a i n hand, the s t e r e o -c h e m i c a l a s signments o f the ald e h y d e s (113) and (138) as the ( E ) - and (Z)- i s o m e r s , r e s p e c t i v e l y , seemed a s s u r e d . 95 The W i t t i g r e a c t i o n o f (E)-2-bromo-2-methylcyclopropane-c a r b o x a l d e h y d e (113) w i t h i s o p r o p y l i d e n e t r i p h e n y l p h o s p h o r a n e ( 1 4 0 ) * * proceeded smoothly t o g i v e the o l e f i n (108) i n 70% y i e l d . The i r spectrum of t h i s m a t e r i a l e x h i b i t e d a b s o r p t i o n s (v ~ 1440, 1385, 1150 cm-"*") which are c o n s i s t a n t w i t h the max 96 p resence o f a t r i s u b s t i t u t e d double bond . No c a r b o n y l a b s o r p t i o n was i n e v i d e n c e . The *H nmr spectrum o f (112) was * The computer s i m u l a t e d s p e c t r a were o b t a i n e d u s i n g a Bruke r WP-80 s p e c t r o m e t e r . L i n e b r o a d e n i n g i n the e x p e r i -m e n t a l l y o b t a i n e d spectrum o f (139) ( F i g . 5) i s e x p l a i n e d i n terms o f second o r d e r e f f e c t s r a t h e r than an u n r e s o l v e d c o u p l i n g between H a» and H c 1 • T h i s e x p l a n a t i o n i s sub-s t a n t i a t e d by the f a c t t h a t f i n e s p l i t t i n g s are r e s o l v e d i n the computer g e n e r a t e d spectrum (A) ( l i n e w i d t h = 0.06 Hz) where J a i ^ c i was s e t a t 0 Hz ( F i g . 6 ) . ** The phosphorane (140) was g e n e r a t e d _in s i t u by the r e a c -t i o n o f i s o p r o p y l t r i p h e n y l p h o s p h o n i u m i o d i d e w i t h one e q u i v a l e n t o f m e t h y l l i t h i u m (see E x p e r i m e n t a l ) . ® ~t ® JUL FIGURE 6. The Computer Simulated »H nmr Spectrum o f ; (A) The Four-proton Spin System FIGUKb F f C o m p o u n d { U 1 ) f a n d ; ( B ) T n e F o u r - p r o t o n Spin System ( H g , _ d,) of Compound (139). - 61 -113 H 112 H more d e f i n i t i v e , showing a doublet of septets (J = 7.5, 1.5 Hz) at 6 4.76 which corresponds to the lone v i n y l i c proton. A long-range coupl ing of 1.5 Hz between the v i n y l i c proton and the v i n y l i c methyl groups would a lso account for the broadening of the s i n g l e t s assigned to the l a t t e r (6 1.72 and 1.78). The cyc lopropy l protons showed s p l i t t i n g patterns and r e l a t i v e chemical s h i f t s analogous to those described for the mono-methylated aceta l (114) and the 2,4-dinitrophenylhydrazone (137) (vide supra) . The mass spectrum of the o l e f i n (112) +79 81 showed a molecular ion c lus te r (M B r / Br m/e 190/188) and major fragments (m/e 109 (M-Br), 67 (-C^Hg)) ind ica t ing the molecular formula CgH^Br a n f3 was consis tent with the assigned structure . The react ion of the o l e f i n (112) with t - b u t y l l i t h i u m at -78 °C , followed by treatment of the l i t h i a t e d species with phenyl th iocopper* , gave the desired l i th ium phenylthiocuprate * Although soluble phenylthiocopper has been prepared in s i t u and used i m m e d i a t e l y ^ 7 »99a , large scale and/or repet -i t i v e experiments are most convenient ly done using s o l i d phenylthiocopper^". - 62 -(111) which was 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 -one (110) t o g i v e the s u b s t i t u t e d cyclohexenone (100) i n quan-t i t a t i v e y i e l d * . B The r e a c t i o n was found t o proceed most e f f i c i e n t l y when a m i x t u r e o f THF and e t h e r (1:1) was employed as s o l v e n t , as opposed t o the use of e i t h e r one o f the s o l v e n t s a l o n e * * . * For an e x a m i n a t i o n of the r e l a t i v e m e r i t s o f l i t h i u m phen-y l t h i o c u p r a t e s , o t h e r mixed c u p r a t e s and l i t h i u m d i a l k y l -c u p r a t e s i n s u b s t i t u t i o n r e a c t i o n s , the r e a d e r i s r e f e r r e d t o r e f . 99, and r e f e r e n c e s c i t e d t h e r e i n . ** There have been v a r i o u s r e p o r t s r e g a r d i n g s o l v e n t e f f e c t s on r e a c t i o n s i n v o l v i n g c u p r a t e r e a g e n t s ^ S b . The use o f e t h e r as s o l v e n t has been shownlOOa t o favour c o n j u g a t e a d d i t i o n o f c u p r a t e r e a g e n t s t o a , 8 - u n s a t u r a t e d c a r b o n y l compounds, w h i l e the use of THF as s o l v e n t i n c r e a s e s the r a t e o f r e a c t i o n o f c u p r a t e s w i t h a l k y l h a l i d e s ^ - u ^ a ' ' : > and s u p p r e s s e s c o n j u g a t e a d d i t i o n . - 63 -The 6- (v inylcyclopropyl )enone (100) could be d i s t i l l e d at 110-125°C (0.3 mm). Under these c o n d i t i o n s , i t d id not rear -range to the b i c y c l i c ketone (101) . The i r spectrum of the d i s t i l l e d mater ia l exhibi ted absorptions c h a r a c t e r i s t i c of an a,B-unsaturated ketone ( v m a x 1660, 1600 cm"^) and examination of the 270 MHz *H nmr spec-trum showed that the cyc lopropy l moiety was i n t a c t . The v i n y l i c proton adjacent to the carbonyl group produced a s i n g l e t (6 5.92) while the v i n y l i c proton on the 2-methyl-propenyl group gave a broad doublet (6 4 . 9 2 ) . Moreover, the s ingle proton mul t ip le ts (6 1 .36 , 0.64) assigned to two of the cyc lopropy l protons showed c h a r a c t e r i s t i c chemical s h i f t s and coupl ing constants . A l l the observed resonances could be assigned in accord with structure (100). It was g r a t i f y i n g that the react ion of (110) with (111) had proceeded so wel l to a f ford compound (100). As was hoped, the l a t t e r mater ia l was stable enough to be read i ly i s o l a t e d , as would be expected of a t rans -1 ,2 -d iv iny lcyc lopropane d e r i v a -t i v e . It remained to be seen i f (100) would undergo a smooth Cope rearrangement to give the desired b i c y c l i c ketone (101), or whether th is react ion would be plagued by e i ther a bond migration to lead to the a,B-unsaturated ketone (102) or a homo Q-f5] sigmatropic hydrogen s h i f t to give trienone (106), u J u u j • • • i 4 . 38 ,41 ,43 as had been observed in s imi la r systems ' ' - 64 -The t h e r m a l rearrangement o f the c y c l o h e x e n o n e d e r i v a t i v e (100) was c a r r i e d o u t i n r e f l u x i n g x y l e n e (b.p. 138°C). The p r o g r e s s o f the r e a c t i o n was c o n v e n i e n t l y m o n i t o r e d by g l c a n a l y s i s and was judged t o be complete a f t e r 3 hours. Removal of the s o l v e n t a f f o r d e d the b i c y c l i c ketone (101) q u a n t i t a -t i v e l y and t h i s m a t e r i a l was used d i r e c t l y i n the next s t e p o f the r e a c t i o n sequence w i t h o u t f u r t h e r p u r i f i c a t i o n . The i r spectrum o f (101) 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 (\>max 1700 cm - 1) c h a r a c t e r i s t i c o f a c y c l o h e x a n o n e d e r i v a t i v e . f - 65 -There was, however, no e v i d e n c e f o r the presence o f the a , B - i a n s a t u r a t e d ketone (102) even i n a d i s t i l l e d sample of the ketone (101). The 1H nmr spectrum of (101) c l e a r l y showed a broad s i n g l e t a t <5 3.74 which i s a s s i g n e d t o the r i n g j u n c t i o n p r o t o n . F u r t h e r m o r e , the s i n g l e v i n y l i c m e t h y l group i s d i s -t i n c t from the o t h e r two r i n g m e t h y l s and appears as a broad s i n g l e t a t 5 1.80. The v i n y l i c p r o t o n s H Q and H b form d i s -t i n c t i v e low f i e l d m u l t i p l e t s a t & 5.50 and 5.14, r e s p e c t i v e l y . The former appears as a double d o u b l e t of d o u b l e t s due t o c o u p l i n g between H a and ( J = 12 H z ) , as w e l l as two d i f f e r -e n t c o u p l i n g s (J = 8, 3 Hz) w i t h the i n d i v i d u a l a l l y l i c p r o t o n s H c- P r o t o n H^ appears as a d o u b l e t of d o u b l e t s due t o v i c i n a l c o u p l i n g o f H a and H^ combined w i t h an a l l y l i c c o u p l i n g ( J = 3 Hz) t o o n l y one o f the p r o t o n s H c- The l a r g e d i f f e r e n c e i n c o u p l i n g c o n s t a n t s between H and the two p r o t o n s H_ may be e x p l a i n e d i n terms of l a r g e d i f f e r e n c e s i n the d i h e d r a l a n g l e s between the p r o t o n s i n q u e s t i o n . S i n c e a l l y l i c c o u p l i n g s are a l s o dependent on the d i h e d r a l angle between the p r o t o n s b e i n g considered"'"^"'', t h i s may a l s o e x p l a i n why H b has a v i s i b l e c o u p l i n g t o o n l y one o f the p r o t o n s H c. S i n c e the B ~ ( c y c l o p r o p y l ) e n o n e (100) r e a r r a n g e d c l e a n l y t o g i v e the b i c y c l i c ketone (101) w i t h o u t subsequent bond m i g r a t i o n t o g i v e the a , B - u n s a t u r a t e d ketone (102), e l a b o r a -t i o n o f the b a s i c carbon s k e l e t o n c o u l d be performed a f t e r the t h e r m a l rearrangement of (100), r a t h e r than b e f o r e . - 66 -The a l k y l a t i o n o f ketone (101) proceeded r e a d i l y by the a d d i t i o n of one e q u i v a l e n t of l i t h i u m d i i s o p r o p y l a m i d e (LDA) f o l l o w e d by t r e a t m e n t o f the r e s u l t i n g l i t h i u m e n o l a t e w i t h iodomethane and hexamethylphosphoramide (HMPA). P u r i f i c a t i o n o f the p r o d u c t by d i s t i l l a t i o n a f f o r d e d the m e t h y l a t e d ketone (126) i n a 90% y i e l d (from the 6 - ( c y c l o p r o p y l ) e n o n e (100)),. The 1H nmr o f t h i s m a t e r i a l was a l m o s t i d e n t i c a l w i t h t h a t o f the s t a r t i n g m a t e r i a l , e x c e p t f o r a skewed d o u b l e t (J = 6 Hz) a t 6 1.06 which i n t e g r a t e d f o r t h r e e p r o t o n s and was a s s i g n e d t o the secondary m e t h y l group. 2)MeI-HMPA Glc-mass s p e c t r o m e t r i c a n a l y s i s of the m e t h y l a t e d ketone (126) i n d i c a t e d t h a t i t was a 92:8 m i x t u r e o f the two p o s s i b l e d i a s t e r e o m e r s (M + m/e 218). Attempted e p i m e r i z a t i o n of t h i s m i x t u r e u s i n g sodium methoxide i n methanol l e d t o o n l y a s l i g h t change i n the i s o m e r i c r a t i o (80:20). Treatment o f (126) w i t h sodium methoxide i n d^-methanol a t r e f l u x tempera-t u r e f o r 30 h o u r s , f o l l o w e d by t r e a t m e n t w i t h l e d t o the i n c o r p o r a t i o n o f two d e u t e r i u m s (mass s p e c t r u m ) . S i n c e the *H nmr o f t h i s m a t e r i a l showed the d i s a p p e a r a n c e o f the r i n g j u n c t i o n p r o t o n (6 3.84) and the c o l l a p s e o f the methyl d o u b l e t - 67 -t o a s i n g l e t a t 6 1.06, i t was i d e n t i f i e d as the d 2 - k e t o n e (140) . Me. Me NdOMe D k ^ A ^ / MeOD ^^i^J 126 / ^ 140 / _ U l Me' D There was no e v i d e n c e f o r the presence o f the d2~a:,8-u n s a t u r a t e d ketone (141), which would have r e s u l t e d from y - d e u t e r a t i o n of the e n o l a t e (142). I t appeared t h a t the o r i g i n a l c o n c e r n r e g a r d i n g bond m i g r a t i o n i n ketones l i k e (101) and (126) was unfounded. The reason f o r the r e l a t i v e s t a b i l i t y o f ketone (101) as compared w i t h the p r e v i o u s l y s t u d i e d ketone 41 (43a) i s u n c l e a r . W ith the s u c c e s s f u l s y n t h e s i s of the m e t h y l a t e d ketone (126) , the b a s i c carbon s k e l e t o n o f B-himachalene (3_) i s c l e a r l y v i s i b l e . C o m p l e t i o n o f the s y n t h e s i s would depend on the r e d u c t i o n o f one double bond and use of the ketone f u n c -t i o n a l i t y as a handle t o i n t r o d u c e a double bond. - 68 -0 0 138" H y d r o g e n a t i o n o f the d i s u b s t i t u t e d double bond was approached f i r s t , s i n c e i t was f e l t t h a t t h i s c o u l d b e s t be done i n the presence o f o n l y one o t h e r double bond. The h y d r o g e n a t i o n of a d i s u b s t i t u t e d d o u b l e bond i n the presence of a t e t r a s u b s t i t u t e d double bond c o u l d be attempted i n a number of ways. However, i t was thought t h a t the homo-102 geneous c a t a l y s t t r i s ( t r i p h e n y l p h o s p h i n e ) r h o d i u m c h l o r i d e c o u l d be employed most a d v a n t a g e o u s l y t o e f f e c t t h i s t r a n s f o r -m a t i o n . Not o n l y are the r a t e s of h y d r o g e n a t i o n i n the p r e -sence o f t h i s c a t a l y s t e x t r e m e l y s e n s i t i v e t o s t e r i c c on-s t r a i n t s , but they a l s o d e c r e a s e w i t h i n c r e a s i n g r i n g s i z e " * " 0 3 . In f a c t , t r i - and t e t r a s u b s t i t u t e d double bonds are hydrogen-a t e d i n the presence o f t r i s ( t r i p h e n y l p h o s p h i n e ) r h o d i u m c h l o -r i d e o n l y under f o r c i n g c o n d i t i o n s and even then the r a t e s are r e l a t i v e l y s l o w ^ " 0 3 . A t m o s p h e r i c p r e s s u r e c a t a l y t i c hydrogen-a t i o n o f the m e t h y l a t e d ketone (126) i n benzene, c o n t a i n i n g a - 69 -small amount of t r is( t r iphenylphosphine)rhodium c h l o r i d e , afforded the hydrogenated ketone (127) in a 95% y i e l d (after d i s t i l l a t i o n ) . The react ion proceeded c lean ly and did not lead to any d i s c e r n i b l e over - reduct ion . The i r spectrum of (127) exhib i ted the c h a r a c t e r i s t i c carbonyl absorption ( v m a x 1700 c m - 1 ) , while the mass spectrum showed a molecular ion (m/e 220) corresponding to a product r e s u l t i n g from hydrogen-ation of only one of the double bonds of ketone (126) . The 1E nmr of the product ketone (127) was lack ing in any v i n y l i c proton s igna ls but had retained the v i n y l i c methyl resonance at 6 1 . 7 4 . ( P h 3 P ) 3 R h C l 9 — H 2 Examination of th is mater ia l by glc-mass spectrometric ana lys is indicated that (127) was a c t u a l l y an 85 :15 mixture of the two poss ib le diastereomers. However, s ince the asym-metric centre at (himachalene numbering) was to be l o s t in the next step and since both diastereomers would give the same product , t h i s i s not s y n t h e t i c a l l y important. One method which has been explo i ted in producing o l e f i n s from ketones i s the l i thium-amine reduct ion of the - 70 -77 104 c o r r e s p o n d i n g e n o l phosphates ' . For example/ r e d u c t i o n o f the a , B - u n s a t u r a t e d ketone (143) w i t h two e q u i v a l e n t s o f l i t h i u m i n ammonia, f o l l o w e d by t r a p p i n g o f the r e s u l t a n t l i t h i u m e n o l a t e w i t h d i e t h y l c h l o r o p h o s p h a t e l e d t o the e n o l 7 7 phosphate (144) i n 56% y i e l d . R e d u c t i o n o f t h i s m a t e r i a l was then a c c o m p l i s h e d w i t h l i t h i u m i n e t h y l a m i n e and t e r t -b u t y l a l c o h o l . T h i s gave the d e s i r e d o l e f i n (145) i n 91% y i e l d . U n f o r t u n a t e l y , t r e a t m e n t of the ketone (127) w i t h LDA, f o l l o w e d by attempted t r a p p i n g o f the r e s u l t a n t l i t h i u m e n o l a t e w i t h d i e t h y l c h l o r o p h o s p h a t e , d i d not g i v e any of the d e s i r e d e n o l phosphate (128) . Due t o t h i s unexpected f a i l u r e , an a l t e r n a t i v e method of c o m p l e t i n g the s y n t h e s i s was sought. One p o s s i b i l i t y which was c o n s i d e r e d was the S h a p i r o o l e f i n s y n t h e s i s ^ ^ . T h i s method i s based on the f a c t t h a t the t o s y l h y d r a z o n e s o f - 71 -1) L D A #~ 2) (EtO)2P'Cl ketones r e a c t w i t h e x c e s s a l k y l l i t h i u m t o g i v e v i n y l a n i o n s , which are r e a d i l y p r o t o n a t e d t o a f f o r d o l e f i n s . For i n s t a n c e , when the t o s y l h y d r a z o n e o f 2-octanone (146) i s t r e a t e d w i t h two 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 a t -78°C, the d i a n i o n (14 7) i s g e n e r a t e d . On warming, t h i s s p e c i e s decomposes t o g i v e the v i n y l a n i o n (148), w h i c h , upon a d d i t i o n o f a c i d , i s r a p i d l y 106 p r o t o n a t e d t o a f f o r d 1-octene (149) N II NHS02C6H5Me H3CCC6H13 146 2 RL i NS0 2C 6H 5Me --vll H 2CCCsHi3 U7 H9C=CHC6H13 U9 H2C=CC6H13 148 N * ^ Cl H2C=CC6H13 - 72 -However, a l l a t t e m p t s t o p r e p a r e the t o s y l h y d r a z o n e of ketone (127) were f r u s t r a t e d . Recent r e p o r t s t h a t 2 , 4 , 6 - t r i -i s o p r o p y l b e n z e n e s u l f o n y l h y d r a z i d e " ^ 7 r e a c t s under v e r y m i l d c o n d i t i o n s w i t h even h i n d e r e d ketones t o g i v e 2 , 4 , 6 - t r i i s o -108 p r o p y l b e n z e n e s u l f o n y l h y d r a z o n e s ( t r i s y l h y d r a z o n e s ) l e d t o the attempted p r e p a r a t i o n of the t r i s y l h y d r a z o n e o f the ketone (127). However, even t h i s method f a i l e d t o produce any of the 127 150 The reason f o r the ketone (127) r e s i s t i n g t o s y l - and t r i s y l h y d r a z o n e f o r m a t i o n i s p r o b a b l y a f u n c t i o n of the s t e r i c h i n d r a n c e o f the c a r b o n y l group by the f l a n k i n g m e t h y l sub-s t i t u e n t s . I t i s perhaps i n t e r e s t i n g t o note t h a t p r e v i o u s 4 5 workers were unable t o p r e p a r e e i t h e r the semicarbazone or the 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e of the ketone (5j5) , which i s the f u l l y s a t u r a t e d a n a l o g o f ketone (127). 109 A t about t h i s time Gorecka and co-workers r e p o r t e d the p r e p a r a t i o n o f d i e t h y l bromophosphate, which they found t o be more r e a c t i v e than d i e t h y l c h l o r o p h o s p h a t e i n c o n n e c t i o n w i t h - 73 -p e p t i d e s y n t h e s i s . D i e t h y l bromophosphate was pr e p a r e d as 109 d e s c r i b e d i n the l i t e r a t u r e , by the r e a c t i o n o f t r i e t h y l -p h o s p h i t e w i t h bromine. With a measure of a n t i c i p a t i o n , a s o l u t i o n of the ketone (127) was t r e a t e d w i t h 1.5 e q u i v a l e n t s o f LDA and the r e s u l t i n g l i t h i u m e n o l a t e was a l l o w e d t o r e a c t w i t h 2.0 e q u i v a l e n t s o f d i e t h y l bromophosphate. I t was g r a t i f y i n g t o f i n d t h a t the i r spectrum of the crude p r o d u c t o f t h i s r e a c t i o n showed no c a r -b o n y l a b s o r p t i o n but r a t h e r the a b s o r p t i o n s c h a r a c t e r i s t i c o f a t r i a l k y l p h o s p h a t e ( v m a v 1275, 1040, 975 c m - 1 ) . The mass m ax spectrum of t h i s m a t e r i a l e x h i b i t e d a m o l e c u l a r i o n a t m/e 356, which c o r r e s p o n d s t o the p a r e n t mass o f the e n o l phos-phate (128_) . The *H nmr spectrum o f a d i s t i l l e d sample o f the e n o l phosphate (128) d i s p l a y e d the m u l t i p l e t s c h a r a c t e r i s t i c of an e t h y l phosphate e s t e r (6 4.17, 1.34). The resonance a s s i g n e d t o the r i n g j u n c t i o n p r o t o n (<5 3.39) was s t i l l p r e s e n t and the m e t h y l group a d j a c e n t t o the oxygen f u n c t i o n a l i t y now - 74 -appeared as a broad s i n g l e t w i t h a c h e m i c a l s h i f t a p p r o p r i a t e f o r a v i n y l i c m e t h y l (6 1.78). The e n o l phosphate (128) was o b t a i n e d as a v i s c o u s o i l which was pure by t i c a n a l y s i s and as such was most conven-i e n t l y used d i r e c t l y i n the n e x t r e a c t i o n . 1) L D A 2)(EtO) 2PBr The s u c c e s s f u l c o m p l e t i o n o f the t o t a l s y n t h e s i s o f (±) - 8-himachalene (3_) now depended on the r e d u c t i o n of the e n o l phosphate (128). An e x p l o r a t o r y e x p e r i m e n t , i n v o l v i n g r e d u c t i o n of the e n o l phosphate (151) (prepared from the ketone (126) and d i e t h y l bromophosphate) w i t h l i t h i u m i n e t h y l a m i n e c o n t a i n i n g t e r t - b u t y l a l c o h o l , gave a complex m i x t u r e ( g l c a n a l y s i s ) which was n o t examined f u r t h e r . An a l t e r n a t i v e method f o r r e d u c i n g e n o l phosphates, u s i n g h i g h l y a c t i v a t e d t i t a n i u m m e t a l , has a l s o been reported 1"'' 0. Thus, f i n e l y d i v i d e d t i t a n i u m m e t a l was produced i n s i t u by the r e a c t i o n of anhydrous t i t a n i u m t r i c h l o r i d e w i t h p o t a s s i u m m e t a l i n d r y t e t r a h y d r o f u r a n (THF). To t h i s b l a c k s u s p e n s i o n - 75 -was added the e n o l phosphate (128 ) and the m i x t u r e was heated t o r e f l u x . T i c a n a l y s i s of the r e a c t i o n m i x t u r e a t v a r i o u s times showed t h a t a s m a l l amount o f B-himachalene was b e i n g formed, but t h a t i t was a minor component o f a complex mix-t u r e . T h i s method was t h e r e f o r e abandoned. 0 II (EtO),PO 1) L D A 2 ) (EtO) 2 PBr L ' * E t N H p 2 complex mixture t -BuOH 2 (trace) The reason f o r these f a i l u r e s was not c l e a r . In the case o f the attempted r e d u c t i o n o f (151), the m u l t i p l i c i t y of p r o d u c t s might be r a t i o n a l i z e d i n terms of a base induced i s o m e r i z a t i o n o f one o f the o l e f i n i c bonds t o g i v e a c o n j u g a t e d d i e n e such as (152) , f o l l o w e d by r e d u c t i o n t o a f f o r d the non-c o n j u g a t e d d i e n e (153). R e d u c t i o n s o f c o n j u g a t e d d i e n e s w i t h l i t h i u m - a l k y l a m i n e m i x t u r e s a re w e l l known 1 1 1 and t h i s type - 76 -o f o v e r - r e d u c t i o n may compete w i t h s i m p l e r e d u c t i o n o f the e n o l phosphate m o i e t y . I f t h i s i s the c a s e , t h i s type o f o v e r - r e d u c t i o n s h o u l d not be o p e r a t i v e i n the case of the e n o l phosphate (128) s i n c e n o n-conjugated n o n - t e r m i n a l double bonds are u s u a l l y s t a b l e t o the r e a c t i o n c o n d i t i o n s b e i n g used 151 152 153 C o n s e q u e n t l y , the e n o l phosphate (128) was t r e a t e d w i t h l i t h i u m i n e t h y l a m i n e ( c o n t a i n i n g t e r t - b u t y l a l c o h o l ) a t 0°C f o r 20 m i n u t e s . Aqueous work-up of the r e a c t i o n m i x t u r e , f o l l o w e d by p u r i f i c a t i o n ( p r e p a r a t i v e t i c , d i s t i l l a t i o n ) o f the crude p r o d u c t , a f f o r d e d a pure sample o f (± ) - B-himachalene i n a 38% y i e l d (from ketone 127)*. T h i s m a t e r i a l was i d e n t i c a l i n a l l r e s p e c t s (except o p t i c a l a c t i v i t y ) w i t h an a u t h e n t i c sample of the n a t u r a l p r o d u c t B-himachalene (3_) • T h i s c o n s t i t u t e s the s u c c e s s f u l t o t a l s y n t h e s i s o f ( ± ) - B - h i m a c h a l e n e i n a t o t a l of e l e v e n s t e p s and r e p r e s e n t s T h i s r e a c t i o n worked w e l l and a f f o r d e d ( ± ) - B - h i m a c h a l e n e as the s i n g l e major p r o d u c t . The low y i e l d was p r o b a b l y a f u n c t i o n o f the s c a l e on which the r e a c t i o n was p e r -formed combined w i t h the v o l a t i l i t y o f the p r o d u c t . - 77 -0 the f i r s t r e p o r t e d a p p l i c a t i o n of the Cope rearrangement of a 6 - ( 2 - v i n y l c y c l o p r o p y l ) a,B-unsaturated ketone (e.g. 100 ->• 101) to the t o t a l s y n t h e s i s of a n a t u r a l l y o c c u r r i n g compound. - 78 -III. The Synthesis of B icyc lo [3 .1.0]] hexanes 52-57 Although previous studies have indicated that 6 -a lkeny lb icyc lo Q . 1. (T] hex-2-enes rearrange read i ly to af ford subst i tuted b i c y c l o [1.2 .1] octa-2 , 6 -d ienes , the app l ica t ion of th is react ion to the to ta l synthesis of s p e c i f i c natural products would require a v iable method of preparing su i tab ly subst i tuted b i c y c l o (~3 . 1 . fJ] hexene systems. Since the prepara-t ion of these types of compounds is by no means t r i v i a l , any synthet ic study requi r ing them as key intermediates would i d e a l l y exp lo i t proven routes to re lated substra tes . For tunate ly , keen in te res t in the synthesis of na tura l ly occurr ing prostaglandins and their analogs* has stimulated a number of synthet ic approaches to subst i tuted b i c y c l o [3 . 1 . cT]-hexanes. For example, in connection with the synthesis of a 112 prostaglandin , Corey and Wollenberg prepared the cyclopen-tanone der iva t ive (154) by the conjugate addi t ion of the cuprate reagent (155) to 2 -cyc lopenten- l -one . Conversion of the tetrahydropyranyl ether (154) to the mesylate (156), f o l -lowed by treatment of the la t te r with base, afforded 6-exo-v i n y l b i c y c l o [3 . 1 . (T]hexan-2-one (157) . It can be seen that a der iva t ive of ketone (157) such as the enol ether (158) would represent a t rans-div inylcyclopropane * For a recent d iscuss ion of prostaglandin syntheses, the reader i s re fer red to r e f . 67 (chapt. 10) and references c i ted there in . - 79 -U 6 H + H 7 C 3 -= -OTHP Cu I Li H 155 OTHP 154 1 5 6 O S 0 2 M e u 157 system which should be capable of a Cope rearrangement to a f ford the b i c y c l o J J . 2 . l ] octadiene ( 1 5 9 ) . i 157 158 ^ x O - S i -< 159 Using quite a d i f f e r e n t entry into the prostaglandins, K o n d o 1 1 3 and T a b e r 1 1 4 reported the preparation of the 6 -a lkenyl -b i c y c l o Q . 1 .0 ]hexan-2-one ( 1 6 0 ) v ia the copper-catalyzed i n t r a -molecular c y c l i z a t i o n of the diazo ester ( 1 6 1 ) 1 1 5 The l a t te r - 80 -m a t e r i a l was c o n v e n i e n t l y p r e p a r e d by a l k y l a t i o n of the d i a n i o n 11 ft of m e t h y l a c e t o a c e t a t e w i t h the bromide (162) , f o l l o w e d by r e a c t i o n o f the r e s u l t i n g B-keto e s t e r (163) w i t h p - t o l u e n e -117 s u l f o n y l a z i d e t o e f f e c t a d i a z o group t r a n s f e r (Scheme 9 ) . SCHEME 9 0 0 161 1JP I t i s i n t e r e s t i n g t o note t h a t both workers found t h a t the t r a n s , t r a n s c o n f i g u r a t i o n of the d i a z o e s t e r (161) l e d t o e x c l u s i v e f o r m a t i o n o f the 6 - e x o - a l k e n y l d e r i v a t i v e (160). 118 More r e c e n t l y , Kondo and co-workers have r e p o r t e d u s i n g a s i m i l a r approach t o o b t a i n the more h i g h l y s u b s t i t u t e d b i c y c l i c compound (164) , by u s i n g t r a n s , t r a n s - 2 , 4 - d e c a d i e n a l (165) to a l k y l a t e the d i a n i o n of m e t h y l a c e t o a c e t a t e . 119 In an e a r l i e r r e p o r t , T r o s t e t a_l. found t h a t the d i a z o e s t e r (166) ( c o n t a i n i n g a c i s double bond) underwent an - 81 -0 0 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 t o g i v e the 6 - e n d o - a l k y l s u b s t i -t u t e d b i c y c l i c compound (167). T h i s type o f s t e r e o s p e c i f i c i t y i n the 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 d i a z o c a r b o n y l compounds t o g i v e b i c y c l o [x. 1. fT] a l k a n e systems has been r e p o r t e d i n a i . 115 number o f c a s e s - 82 -The thermal rearrangements of a number of b i c y c l o [3 .1. (TJ -112 120-122 hexan-2-one systems have a l s o been s t u d i e d ' . They must be c o n s i d e r e d as p o s s i b l e competing r e a c t i o n s i f d e r i v -a t i v e s of these compounds are used as key intermediates i n the p r e p a r a t i o n of b i c y c l o Q . 2 . f ] octadienes v i a the Cope rearrange-112 ment. Corey and co-workers found that f l a s h p y r o l y s i s of 6-vinylbicycloQ.l.(Tjhexan-2-one (157) at 600°C a f f o r d e d the b i c y c l i c ketone (168) . 0 1 6 9 0 H 600 ' 157 The p r e p a r a t i o n of (157) by the 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 of the d i a z o ketone (169) and the p y r o l y s i s of the former (at 500°C) to give (168) has a l s o been repo r t e d by H u d l i c k y 120 and co-workers . S i m i l a r l y , the r e l a t e d ketone (170) was 121 prepared from the d i a z o ketone (171) . F l a s h p y r o l y s i s of ketone (170) a t 400°C through a pyrex column l e d to a - 83 -homoQ, 5~] si g m a t r o p i c hydrogen s h i f t ' u to give almost e x c l u -s i v e l y the dienone (172). However, when the p y r o l y s i s was performed at 600°C using a lead carbonate t r e a t e d Vycor column, the b i c y c l i c ketone (173) and the dienone (174) were produced 121 i n a r a t i o of 4:1 (Scheme 10). SCHEME 10 S i m i l a r l y , the p r e p a r a t i o n of the b i c y c l o [3 .1. bj hexan-one (175) by the 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 r e a c t i o n of the 122 d i a z o e s t e r (176) was r e p o r t e d in connection with the syn-t h e s i s of 2 , 3 - d i s u b s t i t u t e d cyclopentanones. The ketone (175) - 84 -was found to rearrange smoothly at 350°C by a concerted proton transfer and cyclopropane r ing cleavage to give the keto ester (177). Although these rearrangements proceed at temperatures higher than those reported for the Cope rearrangement of 52 — 57 6 -a lkeny lb icyc lo [3 . 1 . (T] hex-2-enes , they cannot be d i s -missed e n t i r e l y as processes which may poss ib ly compete with the desired Cope rearrangement. It was thought that the planned synthet ic study could best be i n i t i a t e d using a r e l a t i v e l y simple 6 - v i n y l b i c y c l o [3 .1.0~[ -hexan-2-one l i k e (178). Based on the prev ious ly described approaches to the synthesis of s imi lar compounds (vide supra) , ketone (178) should be access ib le by a l k y l a t i n g the dianion 123 of methyl acetoacetate with (E)-5-bromo-l ,3-pentadiene (179) , followed by a diazo transfer react ion of the resu l t ing B-keto 124 ester (18 0). Copper-catalyzed intramolecular c y c l i z a t i o n of the diazo ester (181) should then lead to the 6 - e x o - v i n y l -b icyclo[3 .1 .0]hexan-2-one (178). The enol ether (182^ ) of th is - 85 -ketone r e p r e s e n t s a t r a n s - 1 , 2 - d i v i n y l c y c l o p r o p a n e system which 54 may undergo a o n e - c e n t r e e p i m e r i z a t i o n t o g i v e the c i s - 1 , 2 -d i v i n y l c y c l o p r o p a n e d e r i v a t i v e (183) . The l a t t e r would be e x p e c t e d t o r e a r r a n g e s p o n t a n e o u s l y t o produce the b i c y c l o -r 3 . 2 . r ] o c t a - 2 , 6 - d i e n e (18 4) . T h i s whole sequence i s o u t l i n e d i n Scheme 11. SCHEME 11 C l e a r l y , a number of more h i g h l y s u b s t i t u t e d d e r i v a t i v e s of (178) would a l s o be r e q u i r e d i n o r d e r t o examine both the - 86 -genera l i ty and the s t e r e o s p e c i f i c i t y of the react ion repre-sented by ( 1 8 2 ) ->- ( 1 8 4 ) . The jud ic ious addi t ion of methyl subst i tuents to the basic structure represented by ( 1 7 8 ) , for example, would pro-vide further ins ight into the v i a b i l i t y of th is react ion where other rearrangements are conceiveable , as wel l as providing access to more h ighly subst i tuted b i c y c l o [3 . 2 . l] octadienes . For instance, the methylated ketone ( 1 8 5 ) would provide the enol ether ( 1 8 6 ) . The l a t t e r mater ia l should undergo a Cope rearrangement to give the b i c y c l o [3 . 2 . l ] octadiene ( 1 8 7 ) subst i tuted at C,-. On the other hand, the ketone ( 1 8 8 ) would y i e l d the enol ether ( 1 8 9 ) . Compound ( 189 ) might rearrange v ia a homo[1,5] sigmatropic hydrogen s h i f t involv ing the r ing junct ion methyl group (to af ford a trienone) in competition with the Cope rearrangement leading to compound ( 1 9 0 ) . The s t e r e o s p e c i f i c i t y of the rearrangement being studied is a v i t a l considerat ion i f th is methodology is to be e f f e c -t ive in preparing s p e c i f i c na tura l l y occurr ing carbon ske le -tons. This problem may be addressed by preparing the 6 - Q E ) -propenyf] b i c y c l o [ 3 . 1 . <T\ hexan-2-one ( 1 9 1 ) and the 6 - Q z ) -propenyf] isomer ( 1 9 2 ) and noting i f thei r s i l y l enol e thers , ( 1 9 3 ) and ( 1 9 4 ) , rearrange c lean ly to provide the 4-endo-m e t h y l b i c y c l o [ 3 . 2 . 1 ] o c t a d i e n e ( 1 9 5 ) and the 4-exo-methyl isomer ( 1 9 6 ) , r e s p e c t i v e l y , without any crossover . - 87 -- 88 -Based on the s y n t h e t i c r o u t e i l l u s t r a t e d i n Scheme 11 (v i d e supra) i t can be seen t h a t the r e q u i s i t e ketones f o r t h i s s t u d y may be p r e p a r e d from the p r o d u c t o f the a l k y l a t i o n of the d i a n i o n of m e t h y l a c e t o a c e t a t e w i t h the a l l y l i c b r o -mides (179) and ( 1 9 7 ) - ( 1 9 9 ) . IV. The S y n t h e s i s of the R e q u i r e d A l l y l i c Bromides The s i m p l e s t a l l y l i c bromide r e q u i r e d as a s t a r t i n g mate-r i a l was (E)-5-bromo-l,3-pen t a d i e n e (179) . T h i s m a t e r i a l was r e a d i l y p r e p a r e d from a c r o l e i n i n two s t e p s , u s i n g a m o d i f i c a -123 t i o n of the l i t e r a t u r e p r e p a r a t i o n . Thus, the r e a c t i o n of a c r o l e i n w i t h v i n y l magnesium bromide i n THF a f f o r d e d 1,3-125 p e n t a d i e n - 3 - o l (200) i n 66% y i e l d . The l r spectrum of t h i s m a t e r i a l e x h i b i t e d a broad h y d r o x y l a b s o r p t i o n ( v m a x 3375 cm" 1) and the 1U nmr spectrum was c o n s i s t e n t w i t h the a s s i g n e d s t r u c t u r e . - 89 -U s i n g a two-phase p r o c e d u r e r e p o r t e d p r e v i o u s l y ' " ' ' " ' i " , a pentane s o l u t i o n o f (200) was t r e a t e d w i t h 48% hydrobromic a c i d a t 0°C f o r 1 hour. T h i s l e d t o the bromide (179) i n 72% y i e l d . The i r spectrum o f t h i s compound was q u i t e s i m p l e and showed no r e m a i n i n g h y d r o x y l group a b s o r p t i o n . The 1E nmr spectrum of (179) c o n t a i n e d complex m u l t i p l e t s i n the v i n y l i c r e g i o n and a d o u b l e t (6 4.03) a s s i g n e d t o the -CI^Br group. The p r e p a r a t i o n o f the o t h e r a l l y l i c bromides (197)-(199) had t o be approached i n q u i t e a d i f f e r e n t manner. House and 128 Rasmusson f o u n d - t h a t s i m p l e a l d e h y d e s r e a c t e d s t e r e o s e l e c -95 t i v e l y w i t h the s t a b i l i z e d phosphorane (201) t o a f f o r d o l e -f i n s w i t h a t r ans c o n f i g u r a t i o n . A c r o l e i n , f o r i n s t a n c e , r e a c t e d w i t h phosphorane (201) t o a f f o r d almost e x c l u s i v e l y 128 the t r a n s - d i e n o i c e s t e r (202) - 90 -In l i g h t o f t h i s r e s u l t , the r e a c t i o n o f a phosphorane l i k e (201) w i t h s u i t a b l e a , 8 - u n s a t u r a t e d aldehydes was deemed an i d e a l way o f p r e p a r i n g d i e n o i c e s t e r s which s h o u l d p r o v i d e the a l l y l i c bromides (197)- (199) i n a s t r a i g h t f o r w a r d manner. C o n s e q u e n t l y , 2 - c a r b e t h o x y e t h y l i d e n e t r i p h e n y l p h o s p h o r a n e 128 129 (203) was p r e p a r e d as d e s c r i b e d i n the l i t e r a t u r e ' T h i s phosphorane r e a c t e d w i t h a c r o l e i n i n d i c h l o r o m e t h a n e t o ] 10 . g i v e e t h y l ( E ) - 2 - m e t h y l - 2 , 4 - p e n t a d l e n o a t e (204) i n 80% y i e l d . The i r spectrum o f t h i s m a t e r i a l e x h i b i t e d a b s o r p t i o n s c h a r a c t e r i s t i c o f an a,8 , y , 6 - u n s a t u r a t e d e s t e r ( v m a x 1715, 1635, 1600 c m " 1 ) . R e d u c t i o n of the a,8-unsaturated e s t e r (204) w i t h l i t h i u m (ethoxy)aluminum h y d r i d e * i n e t h e r a t 0°C, gave the a l l y l i c a l c o h o l (205) i n 99% y i e l d w i t h no a p parent o v e r - r e d u c t i o n . T h i s m a t e r i a l e x h i b i t e d a broad h y d r o x y l a b s o r p t i o n ( v m a x * T h i s r e a g e n t was p r e p a r e d i n s i t u by the a d d i t i o n of one e q u i v a l e n t o f anhydrous e t h a n o l t o a s u s p e n s i o n of l i t h i u m aluminum h y d r i d e i n e t h e r . I t has been used t o reduce a , 8 - u n s a t u r a t e d e s t e r s t o a l l y l i c a l c o h o l s w i t h -out c o n c o m i t a n t r e d u c t i o n of the double bond 1- 3 1. - 91 -3300 cm-"1') i n the i r spectrum and t h e r e was no e v i d e n c e of a c a r b o n y l a b s o r p t i o n . LAH-EtOH C 0 2 E t OH 2 0 4 2 0 5 Treatment o f the a l l y l i c a l c o h o l (205) w i t h t r i p h e n y l -phosphine d i b r o m i d e 132 i n a c e t o n i t r i l e , c o n t a i n i n g one e q u i v -a l e n t of t r i e t h y l a m i n e , a f f o r d e d (E)-5-bromo-4-methyl-1,3-133 p e n t a d i e n e (197) 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 71%. T h i s m a t e r i a l had q u i t e a s i m p l e i r spectrum w i t h no h y d r o x y l a b s o r p t i o n i n e v i d e n c e . The *H nmr spectrum of t h i s m a t e r i a l was c o n s i s t e n t w i t h the a s s i g n e d s t r u c t u r e . P h 3 P . B r 2 2 0 5 U s i n g the same type o f r e a c t i o n sequence,(2E,4E)-1-bromo-2-methyl-2,4-hexadiene (198) was p r e p a r e d i n about 60% o v e r -a l l y i e l d . Thus, the r e a c t i o n of phosphorane (203) w i t h c r o t o n a l d e h y d e (206) i n d i c h l o r o m e t h a n e a f f o r d e d e t h y l (2E,4E)-2-methyl-2,4-hexadienoate ( 2 0 7 ) 1 3 4 ' 1 3 5 i n 85% y i e l d . The i r - 92 -spectrum of t h i s m a t e r i a l d i s p l a y e d the a b s o r p t i o n s e x p e c t e d of an u n s a t u r a t e d e s t e r ( v _ a v 1710, 1640, 1615 c m - 1 ) . The t r a n s , t r a n s c o n f i g u r a t i o n of (207) was r e a d i l y appar-e n t from i t s JH nmr spectrum (Table I I ) . The c o u p l i n g c o n s t a n t between and H c (J = 15 Hz) i s c h a r a c t e r i s t i c of a t r a n s 8 7 v i c i n a l c o u p l i n g a c r o s s a double bond , w h i l e the low f i e l d s h i f t o f H^ (6 7.21) i s e x p l a i n e d i n terms of i t s c i s r e l a -t i o n s h i p t o the c a r b e t h o x y group. A l t h o u g h e t h y l (2E,4E)-2-m e t h y l - 2 , 4 - h e x a d i e n o a t e (207) has been p r e p a r e d p r e v i o u s l y , the e a r l i e s t r e p o r t of i t s s y n t h e s i s from c r o t o n a l d e h y d e (206) 134 and e t h y l 2-bromopropionate i n the presence of z i n c r e c o r d e d o n l y an e l e m e n t a l a n a l y s i s f o r the p r o d u c t o b t a i n e d . The same 135 . . . p r o d u c t was s u b s e q u e n t l y p r e p a r e d i n o n l y t r a c e q u a n t i t i e s i n a dmixture w i t h the (2E, 4 Z )-isomer. R e d u c t i o n of the e s t e r ( L i ( E t O ) A l H ^ - e t h e r ) a f f o r d e d a s i n g l e a l c o h o l ( v m _ v 3325 cm 1.) , which was i d e n t i f i e d as max ( 2 E , 4 E ) - 2 - m e t h y l - 2 , 4 - h e x a d i e n - l - o l (208_)136, i n 98% y i e l d . Treatment of the a l l y l i c a l c o h o l (208) w i t h t r i p h e n y l -phosphine d i b r o m i d e i n a c e t o n i t r i l e c o n t a i n i n g t r i e t h y l a m i n e a f f o r d e d the a l l y l i c bromide (198) i n 71% y i e l d . T h i s m a t e r i a l TABLE I I . *H Nmr Data f o r Compounds (207) and (213) .* aHUC H c 207 Hb H c a H 3 C / \ 3 H d C 0 2 E t 213 Compound 6 H a 6 H b 6 H c 6 H d 6 H e C o u p l i n g C o n s t a n t s (Hz) 207 1.89 d (1.88) 6.10 d of q (6.3 m) 6.40 d of d (6.3 m) 7.21 br d (7.06 d o f q) 1.94 br s (1.88) J a , b = 6 ' J b , c = 1 5 ( 1 6 ) ; J c d = 10 (10.5) ; <Jd,e = 1 ' 9 ) -213 1.89 d (1.82) 5.93 d of q (6.20 d of q) 6.36 d of d of q (6 m) 7.56 d o f q (7.42 d o f q) 1.96 s (1.82) J a , b = 7 ; J b , c = 1 1 ( 1 2 ) ; J c f d = 1 1 ( 1 1 ' 8 ) ;  J d , e = 2 ( 1 ' 8 ) -VD U J * l i t e r a t u r e v a l u e s i n p a r e n t h e s e s . - 94 -LAH-EtOH V - ^ C 0 2 E t V ° H 2 0 7 ? P J darkened r a p i d l y even a t -20°C i n the absence o f l i g h t and was u s u a l l y used i m m e d i a t e l y a f t e r b e i n g d i s t i l l e d . P h 3 P . B r 2 \ = OH - B r 208 1 9 8 The p r e p a r a t i o n o f the i s o m e r i c a l l y l i c bromide (199) was s l i g h t l y more i n v o l v e d , s i n c e the c i s a n a l o g of c r o t o n -aldehyde (206) i s not a v a i l a b l e . S i n c e d i s u b s t i t u t e d a c e t y -l e n e s may be reduced t o c i s - a l k e n e s i n a number of ways*, the s t a r t i n g m a t e r i a l chosen f o r t h i s sequence was 2 - b u t y n a l (209) . T h i s compound has been p r e v i o u s l y p r e p a r e d i n f o u r s t e p s from c r o t o n a l d e h y d e ( 2 0 6 ) 1 4 1 . However, the o v e r a l l y i e l d was o n l y about 5% and a more p r a c t i c a l method was sought. The a l k y l a t i o n of the d i a n i o n of p r o p a r g y l a l c o h o l (210)** w i t h iodomethane proceeded i n a s t r a i g h t f o r w a r d f a s h i o n t o g i v e 1 A? 2 - b u t y n - l - o l (211) i n 30% y i e l d . * For a number of r e c e n t examples, the reader i s r e f e r r e d t o r e f . 137-140 and r e f e r e n c e s c i t e d t h e r e i n . ** The d i a n i o n was g e n e r a t e d by the r e a c t i o n o f p r o p a r g y l a l c o h o l (210) w i t h 2 e q u i v a l e n t s o f l i t h i u m amide i n ammonia. L i t h i u m amide was used s i n c e sodium bases have been shown t o l e a d m a i n l y t o 0 - a l k y l a t i o n l 4 3 . - 95 -H- \ OH 2 LiNH : N H , L i — = Mel M e - = -OLi \ OH 210 211 A l t h o u g h the a l c o h o l (211) c o u l d be o x i d i z e d by u s i n g 144 145 a c t i v a t e d manganese d i o x i d e or p y r i d i n i u m dichromate , the most s a t i s f a c t o r y r e s u l t s i n terms o f r e a c t i o n r a t e and p u r i t y o f the p r o d u c t were o b t a i n e d by u s i n g barium mangan-146 a t e . Thus, t r e a t m e n t o f a l c o h o l (211) w i t h barium mangan-ate i n d i c h l o r o m e t h a n e f o r 65 hours a f f o r d e d 2 - b u t y n a l (209) i n 75% y i e l d . The r e a c t i o n o f t h i s m a t e r i a l w i t h phosphorane (203) i n the u s u a l way gave the d e s i r e d e s t e r (212) i n 60% y i e l d . M e — = • 211 OH M e — = — C H O 2 0 9 Me \ \S Me 212 C 0 2 E t The i r spectrum of t h i s m a t e r i a l e x h i b i t e d a b s o r p t i o n s c h a r a c t e r i s t i c of a d i s u b s t i t u t e d a l k y n e (v 2210 cm ^) and J max of an a , B - u n s a t u r a t e d e s t e r ( v T T , = v 1710, 1615 c m - 1 ) . The 1U nmr spectrum showed the presence of a lo n e v i n y l i c p r o t o n - 96 -(6 6.48) which was coupled (J = 2 Hz) to the terminal methyl group (doublet, 6 2.03). This type of long range coupling is 147 t y p i c a l of methyl alkynes 140 P a r t i a l hydrogenation of the alkyne (212) (5% Pd-BaSC>4, pyr idine) proceeded read i ly and dramat ica l ly slowed down or even stopped after the uptake of 1 equivalent of hydrogen*. This led to the production of a s ingle d ienoic ester ( v m a x 1710, 1635, 1605 c m - 1 ) , which was i d e n t i f i e d as e thy l (2E,4Z)-13S 2-methyl-2,4-hexadienoate (213) , in a y i e l d of 85%. M v 6 H H \ . ^b y H c ^ Me Pd-BaS0 4 V _ / Me ^ \ H , , p y r Me \ C 0 2 E t 2 Y C 0 2 E t 212 2 213 This compound was not the same as the prev iously prepared (2E,4E) - isomer (g lc , 1H nmr) and the 1U nmr data compared well 135 with the reported values (see Table II) . The coupl ing between H^ and H c (J = 11 Hz) i s c h a r a c t e r i s t i c of the c i s conf igura t ion^^ . Although the c a t a l y t i c hydrogenation of alkynes to c i s -alkenes has predominantly been accomplished in the past using L i n d l a r ' s c a t a l y s t l 4 ° , a more convenient method using palladium-on-barium s u l f a t e , poisoned with a trace of q u i n o l i n e , has been r e p o r t e d - ^ . i n the case at hand, the use of 5% pal ladium-on-barium su l fa te combined with pyr id ine as s o l v e n t 1 ^ 0 proved to be superior to the prev ious ly described methods. - 97 -R e d u c t i o n o f the e s t e r (213) w i t h l i t h i u m (ethoxy)aluminum h y d r i d e gave the a l l y l i c a l c o h o l (214) ( v m a x 3375 cm - 1) i n q u a n t i t a t i v e y i e l d . The s t e r e o c h e m i c a l i n t e g r i t y of the d i e n e system would n o t be e x p e c t e d t o be a f f e c t e d d u r i n g the c o u r s e o f t h i s r e a c t i o n . However, c o n v e r s i o n o f the a l l y l i c a l c o h o l (214) (Ph-jP.B^, MeCN, Et^N) t o a bromide produced a m i x t u r e of the d e s i r e d compound, (2E,4_Z)-1-bromo-2-methyl-2,4-hexadiene (199), and the p r e v i o u s l y p r e p a r e d (2E,4E)-isomer (198) i n 87% y i e l d . The *H nmr spectrum o f t h i s m i x t u r e suggested t h a t i t c o n t a i n e d the two isomers i n about e q u a l amounts, based on the i n t e g r a t e d v a l u e s o f t h e i r i n d i v i d u a l methylene s i g n a l s (6 3.97, 4.03). The c o m p l e x i t y o f the v i n y l i c p r o t o n resonances p r e c l u d e d f u r t h e r a n a l y s i s . - 98 -T h i s a p p a r e n t t r a n s , c i s - t r a n s , t r a n s i s o m e r i z a t i o n might be e x p l a i n e d i n terms o f the f o r m a t i o n o f a carbonium i o n a r i s i n g from the i n t e r a c t i o n o f the a l l y l i c a l c o h o l (214) w i t h t r a c e s of HBr g e n e r a t e d d u r i n g the c o u r s e o f the r e a c t i o n . T h i s would be e x p e c t e d t o l e a d t o an e q u i l i b r a t i o n between the (2E,4Z )-isomer and the more s t a b l e (2E,4E) c o n f i g u r a t i o n . 2_U The m i x t u r e was u n s t a b l e even a t -20°C and was used i m m e d i a t e l y a f t e r b e i n g d i s t i l l e d . A l t h o u g h the p r o d u c t i o n of a m i x t u r e i n t h i s s t e p was d i s h e a r t e n i n g , i t w a s thought t h a t i f the i s o m e r i c r a t i o was m a i n t a i n e d i n subsequent s t e p s , v a l i d c o n c l u s i o n s c o u l d s t i l l be made r e g a r d i n g the s t e r e o s p e c i f i c i t y of c e r t a i n r e a c t i o n s i n the proposed r e a c t i o n sequence (v i d e  supra) . V. The S y n t h e s i s of 1 - C a r b o m e t h o x y - 6 - e x o - ( 1 - a l k e n y l ) - b i c y c l o - . 1. Q~[ hex-2-ene Systems With the s y n t h e s i s o f the d e s i r e d a l l y l i c bromides (179), (197)-(199) h a v i n g been completed ( a l b e i t w i t h 199 i n admixture w i t h 198), the s y n t h e s i s o f the r e q u i s i t e b i c y c l i c ketones was i n i t i a t e d a c c o r d i n g t o Scheme 11 ( v i d e s u p r a ) . - 99 -A f t e r some e x p e r i m e n t a t i o n , the a l l y l i c bromides (179) (197) and (198) were found t o r e a c t smoothly w i t h the d i a n i o n o f m e t h y l acetoacetate"''"''^ a t 0°C t o a f f o r d the B-ke'to e s t e r s (180), (215) and (216) i n y i e l d s o f 84, 71 and 60%, r e s p e c -t i v e l y . The lower y i e l d s of (215) and (216) were thought t o be a f u n c t i o n o f the r e l a t i v e i n s t a b i l i t i e s o f the s t a r t i n g m a t e r i a l s (197) and (198). A l t h o u g h the 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 has conven-t i o n a l l y been p r e p a r e d by the r e a c t i o n o f met h y l a c e t o a c e t a t e w i t h 1 e q u i v a l e n t o f sodium h y d r i d e , f o l l o w e d by the a d d i t i o n - 100 -116 o f 1 e q u i v a l e n t o f n - b u t y l l i t h i u m , the use o f 2 e q u i v a l e n t s 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 * (LDA) was found t o be the method of c h o i c e i n the case a t hand. The d i f f e r e n c e s i n the y i e l d s o b t a i n e d were n e g l i g i b l e when l i t h i u m i s o p r o p y l c y c l o h e x y l a m -151 152 ide or l i t h i u m 2 , 2 , 6 , 6 - t e t r a m e t h y l p i p e r i d i d e were sub-s t i t u t e d f o r l i t h i u m d i i s o p r o p y l a m i d e . The optimum r e a c t i o n time f o r these r e a c t i o n s ( a t 0°C) was found t o be about 5 min-u t e s and i t was most advantageous t o quench the r e a c t i o n mix-t u r e s by p o u r i n g them i n t o 1 N HC1. The y i e l d s were not a m e l i o r a t e d by the use o f l o n g e r r e a c t i o n t i m e s and, i n f a c t , b y - p r o d u c t f o r m a t i o n i n c r e a s e d d r a m a t i c a l l y a f t e r about 5 m i n u t e s . The i r s p e c t r a o f compounds (180), (215) and (216) showed a b s o r p t i o n s c h a r a c t e r i s t i c o f a B-keto e s t e r moiety ( v m a x -1750, 1720 c m - 1 ) . The *H nmr s p e c t r a of these compounds were c o n s i s t e n t w i t h the a s s i g n e d s t r u c t u r e s , a l t h o u g h the v i n y l i c m u l t i p l e t s o b s e r v e d i n compound (18 0) c o u l d not be a n a l y z e d . A l l o f these B-keto e s t e r s d i s p l a y e d a s h a r p s i n g l e t (<5 3.46-3.48) a s s i g n e d t o the methylene group l o c a t e d between the c a r b o n y l groups. Treatment of the d i a n i o n of m e t h y l a c e t o a c e t a t e w i t h the m i x t u r e (1:1) o f bromides (198) and (199) l e d t o a m i x t u r e o f the B-keto e s t e r s (216) and (217) i n an i s o l a t e d y i e l d of 28% ( a f t e r chromatography and d i s t i l l a t i o n ) . The reason f o r t h i s low y i e l d i s not c e r t a i n , a l t h o u g h the l a c k o f p u r i t y o f the T h i s v a r i a t i o n has a l s o been r e p o r t e d by Huckin and W e i l e r - 101 -bromide m i x t u r e may c e r t a i n l y have been a c o n t r i b u t i n g f a c t o r . However, no a t t e m p t was made t o o p t i m i z e t h i s y i e l d . The i r spectrum o f the m i x t u r e of (216) and (217) was almost i d e n t i c a l w i t h t h a t of (216) ( v ^ , , 1750, 1720 cm" 1). T h i s s i m i l a r i t y was a l s o n o t e d i n the JH nmr spectrum. How-e v e r , the a-methylene resonance o f the i n d i v i d u a l components of the m i x t u r e were r e s o l v e d (6 3.46, 3.48). The i n t e g r a t e d v a l u e s o f these peaks suggested t h a t the two components were p r e s e n t i n about a 1:1 r a t i o . S i n c e compounds (216) and (217) were i n s e p a r a b l e ( t i c , g l c ) , the m i x t u r e was used i n subse-quent r e a c t i o n s . Br 1 9 8 Br 199 0 0 216 OMe 0 0 OMe 117 The d i a z o t r a n s f e r r e a c t i o n of 8-keto e s t e r s (18 0 ) , (215) and (216) proceeded w e l l a t room temperature u s i n g p - t o l u e n e s u l f o n y l a z i d e i n a c e t o n i t r i l e c o n t a i n i n g 1 e q u i v -a l e n t of t r i e t h y l a m i n e . R e a c t i o n i n t h i s manner a f f o r d e d the d i a z o e s t e r s ( 1 8 1 ) , (218) and (219) i n e s s e n t i a l l y q u a n t i t a t i v e - 102 -y i e l d . S i n c e these compounds were a l l found t o be pure by t i c a n a l y s i s , t h e y were r o u t i n e l y used d i r e c t l y i n the n e x t r e a c -t i o n . The d i a z o e s t e r s (181), (218) and (219) were e a s i l y i d e n -t i f i e d by an a b s o r p t i o n i n t h e i r i r s p e c t r a ( v _ , v 2125 cm 1 ) 9 6 which i s p e c u l i a r t o the d i a z o group . Moreover, the c a r -b o n y l groups e x h i b i t e d a b s o r p t i o n s a t c o n s i s t e n t l y lower wave numbers (v = 1720, 1655 cm""*") than those r e c o r d e d f o r the max c o r r e s p o n d i n g 8 - k e t o e s t e r s (180), (215) and (216). 0 o OMe OMe 0 0 OMe OMe 216 OMe OMe The 1H nmr s p e c t r a of these compounds were i n a l l cases v e r y s i m i l a r t o those o f the s t a r t i n g m a t e r i a l s , w i t h the e x c e p t i o n o f the d i s a p p e a r a n c e o f s i n g l e t s (<S 3.46-3.48) a s s i g n e d t o the a-methylene group i n the B-keto e s t e r s (180), (215) and (216). - 103 -A number o f s o - c a l l e d improved methods have been r e p o r t e d f o r e f f e c t i n g d i a z o t r a n s f e r r e a c t i o n s . These i n c l u d e u s i n g heterogeneous r e a c t i o n m i x t u r e s i n c o m b i n a t i o n w i t h phase 153 t r a n s f e r c a t a l y s i s , the use of p - a c e t a m i d o b e n z e n e s u l f o n y l a z i d e 1 5 4 i n s t e a d o f p - t o l u e n e s u l f o n y l a z i d e and the use o f 2 , 4 , 6 - t r i i s o p r o p y l b e n z e n e s u l f o n y l a z i d e under phase t r a n s f e r 155 c o n d i t i o n s However, the method developed by R e g i t z 1 1 ^ was the most e f f i c a c i o u s i n t h i s i n s t a n c e . The r e a c t i o n of the m i x t u r e o f the B-keto e s t e r s (216) and (217) w i t h p - t o l u e n e s u l f o n y l a z i d e i n the presence of t r i e t h y l a m i n e gave a m i x t u r e of the d i a z o e s t e r s (219) and (220) . 0 0 0 0 The s p e c t r a l d a t a o f the m i x t u r e of (219) and (220) were p r a c t i c a l l y i d e n t i c a l w i t h those e x h i b i t e d by the pure d i a z o e s t e r (219). S i n c e t h i s was once a g a i n an i n s e p a r a b l e m i x t u r e ( t i c ) , i t was used as such i n the f o l l o w i n g r e a c t i o n . - 104 -The 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 the d i a z o e s t e r s (181), (218) and (219) i n r e f l u x i n g t o l u e n e a f f o r d e d the d e s i r e d b i c y c l i c ketones (178) , (188) and (191) (64, 57 and 50% y i e l d , r e s p e c t i v e l y ) . T h i s r e a c t i o n gave u n s a t i s f a c t o r y r e s u l t s when benzene was used as s o l v e n t and the y i e l d s were dependent on the c a t a l y s t used. The most e f f e c t i v e c a t a l y s t f o r t h i s r e a c t i o n was copper ( I I ) a c e t y l -a c e t o n a t e * , a l t h o u g h the y i e l d s o b t a i n e d when copper-bronze was used were o n l y s l i g h t l y l o w e r . The use o f anhydrous cop-per ( I I ) s u l f a t e gave s i g n i f i c a n t l y lower y i e l d s . 0 The i r s p e c t r a o f (178), (188) and (191) showed no remain-i n g d i a z o a b s o r p t i o n and the !H nmr s p e c t r a c o n f i r m e d the p r e -sence of o n l y one double bond i n each c a s e . There have been r e p o r t s of d r a m a t i c a l l y improved y i e l d s when t h i s s o l u b l e c a t a l y s t was used i n s t e a d of o t h e r cop-per s p e c i e s t o e f f e c t i n t r a m o l e c u l a r r e a c t i o n s o f d i a z o compounds . - 105 -S i m i l a r l y , 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 of the m i x t u r e of the d i a z o e s t e r s (219) and (220) l e d t o a m i x t u r e of the b i c y c l i c ketones (191) and (192) i n 46% y i e l d . The i r and 1H nmr s p e c t r a of t h i s m i x t u r e were q u i t e s i m i l a r t o those of a pure sample of (191) . However, w h i l e the *H nmr o f (191) d i s p l a y e d a sharp s i n -g l e t (6 3.79) c o r r e s p o n d i n g t o the e s t e r m e t h y l group and a d o u b l e t (<5 1.75, J = 5 Hz) a s s o c i a t e d w i t h the v i n y l i c m e t h y l group, the m i x t u r e o f (191) and (192) e x h i b i t e d a p a i r o f s i g -n a l s (6 3.77, 3.79) a s s i g n e d t o the i n d i v i d u a l e s t e r methyl groups and a m u l t i p l e t (6 1.68-1.78) a s s i g n e d t o the v i n y l i c m e t h y l groups. The r e l a t i v e peak h e i g h t s of the e s t e r m e t h y l s i g -n a l s s u g g e s t e d t h a t (191) and (192) were p r e s e n t i n a 1:1 r a t i o . The attempted s e p a r a t i o n of t h i s m i x t u r e by f r a c t i o n a l c r y s t a l l i z a t i o n (pentane) gave c o l o u r l e s s c r y s t a l s , m.p. - 106 -40.5-41.5°C*. E x a m i n a t i o n o f t h i s m a t e r i a l by XH nmr i n d i c a t e d t h a t i t was a m i x t u r e of (191) and (192). Thus the m i x t u r e of (191) and (192) c o u l d not be s e p a r a t e d ( g l c , t i c , f r a c t i o n a l c r y s t a l l i z a t i o n ) and was c a r r i e d through t o the n e x t r e a c t i o n i n the sequence. The m e t h y l a t e d ketone (185)** was c o n v e n i e n t l y p r e p a r e d i n 72% y i e l d v i a a l k y l a t i o n (LDA; MeI-HMPA) of the b i c y c l i c ketone (178) . The *H nmr spectrum of (18 5) was s i m i l a r t o t h a t o f (178) but c o n t a i n e d an a d d i t i o n a l d o u b l e t (6 1.10, 6 Hz) a s s i g n e d t o the m e t h y l group a d j a c e n t t o the c a r b o n y l . 0 Me l HMPA ^ C O o M e 2 ) M e I " 178 l£5 W i t h the d e s i r e d b i c y c l o [3 .1.0] hexan-2-ones (178), (185), (188) , (191) and (192) i n hand, a t t e n t i o n c o u l d be t u r n e d t o the p r e p a r a t i o n o f the a c t u a l key i n t e r m e d i a t e s which had been e n v i s a g e d a t the o u t s e t o f t h i s s t u d y . Thus, t r e a t m e n t o f the ketones (178.), (185), (188) and (191) w i t h 1 e q u i v a l e n t 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 a t -78°C, f o l l o w e d by t r a p p i n g the r e s u l t a n t l i t h i u m e n o l a t e s w i t h * C r y s t a l l i z a t i o n o f the pure ketone (191) from pentane a f f o r d e d c o l o u r l e s s c r y s t a l s , m.p. 84-86°C. ** A l t h o u g h t h i s m a t e r i a l was thought t o be a d i a s t e r e o m e r i c m i x t u r e , no s t e r e o c h e m i c a l assignment was attempted s i n c e i t was n o t c r u c i a l t o the outcome o f subsequent r e a c t i o n s - 107 -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 , l e d t o the f o r m a t i o n of the s i l y l e n o l e t h e r s (18 2 ) , (186), (189) and (193), r e s p e c t i v e l y , i n e s s e n t i a l l y q u a n t i t a t i v e y i e l d s . The 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 s were found t o be more s t a b l e than the c o r -r e s p o n d 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 and s i n c e these compounds were t o be used i n subsequent t h e r m o l y s e s , the use o f the f o r -mer was i n d i c a t e d . A l l of these compounds demonstrated s p e c t r a l f e a t u r e s i n a c c o r d w i t h the a s s i g n e d s t r u c t u r e s . For example, the i r spectrum of compound (182) c o n t a i n e d a b s o r p t i o n s c h a r a c t e r i s t i c 0 C0 2Me C0 2Me 178 1 8 2 V S i - 0 ' i i C0 2Me C0 2 Me 1 8 5 1 8 6 V S i - 0 - 108 -of an e s t e r c a r b o n y l ( v m a x 1720 cm" 1) as w e l l as an e n o l e t h e r <w 1 6 3 0 c m _ 1 ) • The 1H nmr o f t h i s m a t e r i a l was perhaps more i l l u m i n a t -i n g . The h i g h f i e l d s h i f t of the t e r t - b u t y l group (6 0.88) and the s i l y l m e t h y l groups (6 0.08) i s e x p e c t e d f o r a l k y l s u b s t i t u e n t s bonded t o s i l i c o n . The v i n y l i c p r o t o n a d j a c e n t to the s i l o x y group appears as a d o u b l e t o f d o u b l e t s ( J = 4.5, 2.5 Hz) a t 6 4.33 due t o d i s s i m i l a r c o u p l i n g t o the d i a s t e r e o -t o p i c methylene p r o t o n s n e x t t o i t . The v i n y l i c r e g i o n a l s o 81 showed the type o f resonances t y p i c a l o f a v i n y l group The 1E nmr spectrum of s i l y l e n o l e t h e r (186), on the ot h e r hand, i n d i c a t e d the presence of a v i n y l i c m e t h y l s u b s t i t -uent (br s, 6 1.47) and two n o n - e q u i v a l e n t s i l y l m e thyl groups (5 0.07, 0.04). As i n the case of compound (182), the s i l y l e n o l e t h e r (189) p r o v i d e d an i n f o r m a t i v e 1E nmr spectrum. Due t o the presence o f the br idgehead m e t h y l group the v i n y l i c r e g i o n was r e a d i l y a n a l y z e d (Scheme 1 2 ) . s, ' u 66.25 C0,MeHd ddd Me J a d = 10Hz J b d = 1 7 H z Jcd=10Hz J b c= 2.5 Hz - 109 -The v i n y l i c p r o t o n n e x t t o the s i l o x y group appeared as a t r i p l e t ( J = 2.5 Hz) a t 6 4.43 w h i l e the v i c i n a l methylene p r o t o n s r e s o n a t e d a t 6 2.43 (d, J = 2.5 H z ) . The c o r r e s p o n d -i n g p r o t o n s i n the e n o l e t h e r (193) e x h i b i t e d a l m o s t the i d e n t i c a l c o u p l i n g and c h e m i c a l s h i f t s . In a d d i t i o n , the t e r m i n a l v i n y l i c m e t h y l group appeared as a d o u b l e t (J = 5 Hz) a t 6 1.68. The m i x t u r e of the b i c y c l i c ketones (191) and (192) r e a c t e d i n the same way as the o t h e r ketones under i n v e s t i g a -t i o n t o g i v e a m i x t u r e of the s i l y l e n o l e t h e r s (193) and (194) i n q u a n t i t a t i v e y i e l d . The i r spectrum o f t h i s m i x t u r e was almost i d e n t i c a l w i t h t h a t r e c o r d e d f o r the i n d i v i d u a l com-pound (193) . A l t h o u g h t h i s m i x t u r e c o u l d not be r e s o l v e d ( t i c , g l c ) the XH nmr began t o g i v e an i n c r e a s i n g amount of i n f o r m a -t i o n on the i n d i v i d u a l components. The v i n y l i c p r o t o n s a d j a -c e n t t o the oxygen f u n c t i o n a l i t y appeared as a p a i r o f t r i p l e t s (J = 2 Hz) a t 6 4.33 and 4.37. The n e i g h b o u r i n g methylene p r o t o n s r e s o n a t e d a t 6 2.31 and 2.35 as a p a i r o f d o u b l e t s (J = 2 H z ) . F i n a l l y , the v i n y l i c m e t h y l groups e x h i b i t e d two o v e r l a p p i n g d o u b l e t s (J = 5 Hz) a t 6 1.62 and 1.67. In each c a s e , one of the p a i r o f resonances c o r r e s p o n d e d c l o s e l y t o the *H nmr of compound (193). The m i x t u r e was judged t o con-t a i n (193) and (194) i n a 1:1 r a t i o , based on the *H nmr d a t a . The s t r u c t u r e o f the s i l y l e n o l e t h e r s seemed a s s u r e d a t t h i s p o i n t . The exo- c o n f i g u r a t i o n of the 6 - a l k e n y l - 110 -s u b s t i t u e n t s was c l e a r , based on the s t e r e o s p e c i f i c i t y of i n t r a m o l e c u l a r carbene additions"'""'"^, and on the s t a b i l i t y o f these d i v i n y l c y c l o p r o p a n e systems even d u r i n g d i s t i l l a t i o n a t about 100°C. The endo-isomers, b e i n g c i s - d i v i n y l c y c l o p r o p a n e systems would have been e x p e c t e d t o r e a r r a n g e a t temperatures w e l l below 100°C. G l c a n a l y s i s of these s i l y l e n o l e t h e r s o f t e n i n d i c a t e d the p resence o f a minor (10-12%) i m p u r i t y which was not observed i n the *H nmr and was a t t r i b u t e d t o rearrangement on the column. T h i s seemed t o p o r t e n d the s u c c e s s of the Cope rearrangement of the b i c y c l o [ 1 . 1 . 0 ] hex-2-ene systems (182) , (186) , (189) , (193) and (194) . - I l l -VI. The Synthesis of B i c y c l o [3 . 2 . T\ octa -2 ,6 -d iene Systems 5 2 — 5 7 Based on the l i t e r a t u r e precedents , b i c y c l o [3 . 1 . fT] -hex-2-ene systems of the general structure (221) would be expected to rearrange thermally v ia a [ 3 f 3 J sigmatropic s h i f t to provide ready access to the b i c y c l o [ 3 . 2.f]o c t a - 2 , 6 - d i e n e s (222) . Since the rearrangement of the s i l y l enol ethers ( 1 8 2 ) , (18 6 ) , (189) and (193) was the key step in the proposed reac-t ion sequence, there was no small in te res t in the outcome of the reac t ion . In the event, heating the s i l y l enol ethers in re f lux ing xylene (b.p. 138°C) or mesitylene (b.p. 165°C) pro-ceeded smoothly in each case to af ford a s ingle product. F o l -lowing the course of each react ion by g lc analys is indicated that the product was i d e n t i c a l with the minor component observed during g lc ana lys is of the s ta r t ing mate r ia l . Since each of the s i l y l enol ethers rearranged thermally to give s ingle compounds in e s s e n t i a l l y quant i ta t ive y i e l d , these - 112 -w e r e i d e n t i f i e d a s t h e d e s i r e d 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 8 4 ) , ( 1 8 7 ) , (190) a n d ( 1 9 5 ) . 184 / | — C0 2 Me 1 8 2 C 0 2 M e 187 / C0 2 Me 189 J. C ° 2 M e — Me • ^ - S i - 0 193 1 C02Me — Me 190 / ~~ C0 2 Me Me 195 / C0 2 Me E x a m i n a t i o n o f t h e i r s p e c t r a o f t h e s e m a t e r i a l s 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 r e q u i s i t e a , B - u n s a t u r a t e d e s t e r m o i e t y (v = 1 7 0 0 , 1600 c m - 1 ) . The *H nmr s p e c t r a o f a l l o f 1 max t h e s e c o m p o u n d s s h o w e d t h e p r e s e n c e o f o n l y two v i n y l i c p r o -t o n s . The p r e s e n c e o f a t e r t - b u t y l s i n g l e t (6 0 . 9 8 - 0 . 8 8 ) and s i l y l m e t h y l s i n g l e t s (6 0 . 2 4 - 0 . 0 6 ) v e r i f i 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 i e s h a d r e m a i n e d i n t a c t d u r i n g t h e t h e r -m o l y s e s . - 113 -The 1E nmr s p e c t r a o f these compounds are a l s o s i m i l a r 5 6 t o those r e p o r t e d f o r s i m i l a r b i c y c l o Q . 2 . TJ o c t a - 2 ,6-dienes C l o s e r s c r u t i n y o f the 1U nmr o f compound (184) shows two complex m u l t i p l e t s i n the v i n y l i c r e g i o n (6 6.27, 5.27) which n o n e t h e l e s s e x h i b i t a d i s c e r n i b l e AB type o f symmetry. The s p l i t t i n g o f these m u l t i p l e t s was no doubt c o m p l i c a t e d by a c o m b i n a t i o n o f v a r i o u s p o s s i b l e v i c i n a l and a l l y l i c c o u p l i n g s of each v i n y l i c p r o t o n . These s p l i t t i n g s were s i m p l i f i e d i n the case o f compound (18 7) s i n c e the p o s i t i o n i n g of the b r i d g e h e a d methyl group e l i m i n a t e d the p o s s i b i l i t y o f one lo n g - r a n g e p r o t o n c o u p l i n g . Thus, w h i l e the v i n y l i c p r o t o n a t C 2 s t i l l appeared as a m u l t i p l e t (6 6.26) the p r o t o n a t C 3 (6 5.33) appeared as a d o u b l e t of t r i p l e t s , due t o a c i s - v i n y l c o u p l i n g of 10 Hz com-bi n e d w i t h a v i c i n a l c o u p l i n g t o the p r o t o n s e q u a l t o 3 Hz, S i m i l a r l y , the v i n y l i c r e g i o n of the lE nmr spectrum of compound (190) was somewhat s i m p l i f i e d by the presence o f the m e t h y l s u t s t i t u e n t a t C-^ . - 114 -190 C 0 2 M The p r o t o n a t C 2 r e s o n a t e d as a broad d o u b l e t ( J = 10 Hz) a t 6 6.13 due t o c i s c o u p l i n g t o the p r o t o n on • The observed l i n e b r o a d e n i n g was e x p l a i n e d i n terms o f u n r e s o l v e d a l l y l i c c o u p l i n g ( s ) w i t h one or both of the p r o t o n s on C^. The o t h e r v i n y l i c p r o t o n appeared as a double t r i p l e t of doub-l e t s due t o v i c i n a l c o u p l i n g s t o one v i n y l i c p r o t o n ( J = 10 Hz) and two a l l y l i c p r o t o n s (J = 4 Hz) combined w i t h a l o n g -range c o u p l i n g t o the b r i d g e h e a d p r o t o n on (J = 2 H z ) . Much the same type of s p l i t t i n g was observed i n the *H nmr spectrum o f the s i l y l e n o l e t h e r (195). The p r o t o n a t C 2 a g a i n appeared as a broad d o u b l e t (6 6.01, J = 10 H z ) . However, i n t h i s case the v i n y l i c p r o t o n - 115 -at r e s o n a t e d as a double d o u b l e t o f d o u b l e t s (J = 10, 3, 2 Hz) due t o the presence of o n l y one a l l y l i c p r o t o n . S i n c e the s t e r e o c h e m i c a l outcome o f t h i s r e a c t i o n was o f major i n t e r e s t , e v e r y attempt was made t o g l e a n any p o s s i b l e s t e r e o c h e m i c a l i n f o r m a t i o n p r o v i d e d by the 1E nmr spectrum o f (195). The r i n g m e t h y l s u b s t i t u e n t a t appeared as a doub-l e t (J = 6 Hz) a t 6 0.92. U n f o r t u n a t e l y , an u n e q u i v o c a l assignment of the m e t h y l b e i n g i n e i t h e r the endo or exo con-f i g u r a t i o n was not p o s s i b l e based on the *H nmr d a t a . How-e v e r , upon c o n s i d e r i n g the s t e r e o s e l e c t i v i t y observed i n the 55 57 rearrangement o f s i m i l a r systems ' and the f a c t t h a t o n l y a s i n g l e p r o d u c t was produced i n the t h e r m o l y s i s o f s i l y l e n o l e t h e r (193), i t d i d n o t seem presumptuous t o a s s i g n the endo c o n f i g u r a t i o n t o the C^-methyl group (see Scheme 13 ) . The t h e r m a l rearrangement o f the m i x t u r e o f s i l y l e n o l e t h e r s (193) and (194) proceeded more s l o w l y (10 h o u r s , 165°C) than the rearrangements o f the o t h e r s i l y l e n o l e t h e r s . The p r o d u c t of the r e a c t i o n was i d e n t i f i e d as a m i x t u r e of the 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 (195) an.d (196) . As i n a l l the p r e v i o u s c a s e s i n t h i s r e a c t i o n s e r i e s , the i n d i v i d u a l com-ponents were i n s e p a r a b l e ( t i c , g l c ) . The s p e c t r a l p r o p e r t i e s of t h i s m a t e r i a l were almost i d e n t i c a l w i t h those p r e v i o u s l y observed f o r the s i n g l e com-ponent (195). The v i n y l i c m u l t i p l e t s i n the 1E nmr spectrum o f the m i x t u r e were complex m u l t i p l e t s which c o u l d not be - 116 -SCHEME 13 Me Me - 117 -a n a l y z e d . However, the i n d i v i d u a l resonances o f the r i n g m e t h y l s u b s t i t u e n t s o f (195) and (196) were d i s c e r n i b l e as a p a i r o f d o u b l e t s a t 6 0 .92 and 1.03, r e s p e c t i v e l y . J u d g i n g by the i n t e g r a t e d v a l u e s o f these m u l t i p l e t s , compounds (195) and (196) were p r e s e n t i n a r a t i o of about 1:1. T h i s i s an i m p o r t a n t c o n c l u s i o n , s i n c e i f i t was pos-s i b l e t o s u b j e c t a 1:1 m i x t u r e o f the s i l y l e n o l e t h e r s (19 3) and (194) t o t h e r m a l rearrangement c o n d i t i o n s and t h e r e b y i s o l a t e ( i n q u a n t i t a t i v e y i e l d , no l e s s ) a 1:1 m i x t u r e of the i s o m e r i c 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 (195 ) and (196) , the s t e r e o s p e c i f i c i t y o f the rearrangement c o u l d not be h e l d i n s e r i o u s doubt. N o n e t h e l e s s , f u r t h e r s t u d i e s were embarked t o a s c e r t a i n more p r e c i s e l y the n a t u r e o f the m i x t u r e i n ques-t i o n ( v i d e i n f r a ) . A t t h i s p o i n t i t would be a p p r o p r i a t e t o touch b r i e f l y on the r e l a t i v e r a t e s observed f o r the rearra n g e m e n t s . A l t h o u g h these were by no means q u a n t i f i e d , t h e r e were s e v e r a l q u a l i -t a t i v e o b s e r v a t i o n s o f i n t e r e s t . As might be e x p e c t e d , the s i l y l e n o l e t h e r s (186) and (193) r e a r r a n g e d more s l o w l y than the u n s u b s t i t u t e d compound (182) . T h i s may be u n d e r s t o o d i n terms o f s t e r i c i n t e r a c t i o n s which would come i n t o p l a y i n the r e q u i r e d b o a t - l i k e t r a n s i -t i o n s t a t e e x e m p l i f i e d by (223) and (224). The case o f the m i x t u r e of the s i l y l e n o l e t h e r s (193) and (194) was, on the o t h e r hand, u n i q u e . As the course o f - 118 -RO C 0 2 M e C0 2 Me Me 223 224 the react ion was followed by g lc a n a l y s i s , i t became apparent that at l eas t a port ion of the s ta r t ing mater ia l was being converted to some species which coincided with neither the s ta r t ing mater ia l nor the f i n a l ( isolated) product. This species was only slowly (t = 10 h) converted to the f i n a l pro-duct even at 165°C. This led to the speculat ion that the c i s -d iv inylcyclopropane system (225) was rap id ly produced v ia a one-centre epimerizat ion of (194). Perhaps s t e r i c in te rac -55 t i o n s , of the type observed prev iously , between the ec l ipsed c is -p ropeny l moiety and the r ing methylenes led to an accumu-la t ion of the endo-isomer (225) . The l a t t e r could then rear -range slowly to a f ford (196) . This would be an in te res t ing hypothesis to pursue using a pure sample of (194), since the Me C0 2 Me Me s l o w M e . j ^ O R C0 2 Me 194 225 196 - 119 -accumulation of c i s -d iv iny lcyc lopropanes during the thermal rearrangement of t rans-d iv iny lcyc lopropanes to cycloheptadienes or b i c y c l o [5 .2.r]octadienes has not been previously observed. However, further study in th is vein was not attempted here. Deprotection of the rearranged s i l y l enol ethers was most conveniently e f fec ted using anhydrous potassium f l u o r i d e . Thus, treatment of compounds (184) , (187) , (190) and (195) with anhydrous potassium f luor ide in methanol at 0°C"'"5^ led to the B-keto esters (226)- (229) (in 82, 63 , 77 and 83% y i e l d , r e s p e c t i v e l y ) . The i r spectra of the l a t t e r compounds displayed the carbonyl absorptions ( v m a x - 1750, 1725 cm )^ c h a r a c t e r i s t i c of B-keto e s t e r s . S i m i l a r l y , examination of the *H nmr spec-tra showed no evidence for the presence of any t e r t - b u t y l d i -m e t h y l s i l y l enol e thers . A l l of the B-keto esters (226)-(229) were found to be mixtures of the two possib le d ias te reo -mers. For example, the *H nmr spectrum of compound (226) exhibi ted a pair of doublets (J = 3 and 6 Hz) at 6 3.26 and 3.34 which were assigned to the proton adjacent to the carbo-methoxy group in the i n d i v i d u a l diastereomers. Upon consider ing the d ihedra l angles invo lved , i t can be seen that an exo proton at th is pos i t ion would couple more strongly with the bridgehead proton than would an endo proton. Thus, the doublet at 6 3.26 (J = 3 Hz) was assigned to the exo-carbornethoxy isomer. The in tegrat ion showed that the - 120 -186 / I C 0 2 M e 2 - ^ - 6 H " v C 0 2 M e M e 187 / C 0 2 M e 22 7 H C 0 2 M e M e 190 / | C 0 2 M e J<5 — 8 H *C02Me Me 1 9 5 / | X C 0 2 M e 2_2_9 H - A r r O C 0 2 M e exo- and endo-carbornethoxy isomers o f (226) were p r e s e n t i n a r a t i o of 3:1. Compound (227) showed q u i t e s i m i l a r s i g n a l s a t 6 3.29 (d, J = 3 Hz) and 3.40 (d, J = 6 Hz) which a g a i n suggested a 3:1 r a t i o o f the exo- and endo-carbornethoxy i s o m e r s , r e s p e c -t i v e l y . - 121 -The 1E nmr s p e c t r a of compounds (228) and (229) were, however, more complex. In the case of (228) , both the c a r b o -methoxy group (<5 3.70, 3.75) and the b r i d g e h e a d m e t h y l group (6 1.20, 1.35) appeared as a p a i r of s i n g l e t s i n a r a t i o of 1:2. The low f i e l d s h i f t (6 1.35) o f the b r i d g e h e a d methyl s u b s t i t u e n t of the major isomer suggested an exo o r i e n t a t i o n of the carbomethoxy group, s i n c e t h i s c o n f i g u r a t i o n appeared t o produce g r e a t e r d e s h i e l d i n g e f f e c t s on the a d j a c e n t b r i d g e -head m e t h y l group than would an e n d o - o r i e n t e d e s t e r m o i e t y . T h i s assignment appears t o be c o n s i s t e n t w i t h the n a t u r e of the s i g n a l s a s s i g n e d t o the p r o t o n s a d j a c e n t t o the e s t e r group. In the major isomer t h i s p r o t o n produced a s i n g l e t (6 3.08), w h i l e the c o r r e s p o n d i n g p r o t o n i n the o t h e r d i a -stereomer l e d t o a d o u b l e t (J = 2 Hz) a t 6 3.18. T h i s may be e x p l a i n e d i n terms of a long-range c o u p l i n g between an exo p r o t o n n e x t t o the e s t e r group and the b r i d g e h e a d p r o t o n a t C,., s i n c e o n l y t h i s o r i e n t a t i o n approaches the r e q u i r e d p l a n a r z i g - z a g c o n f i g u r a t i o n which maximizes long-range i n t e r -89 a c t i o n s of t h i s type On the b a s i s of these o b s e r v a t i o n s compound (228) was i d e n t i f i e d as a 1:2 m i x t u r e o f i t s endo- and exo-carbornethoxy i s o m e r s , r e s p e c t i v e l y . S i m i l a r l y , i n the case o f compound (229) , the c a r b o -methoxy group (6 3.71, 3.73) and the b r i d g e h e a d methyl group (6 1.20, 1.38) l e d t o p a i r s o f s i n g l e t s i n a r a t i o o f about - 122 -7:5. The r i n g m e t h y l s u b s t i t u e n t a l s o appeared as a p a i r of d o u b l e t s (J = 6 Hz) a t 6 1.03 and 1.07. As was observed i n (228), the p r o t o n a d j a c e n t t o the e s t e r m o i e t y gave a s i n g l e t (6 3.04) and a d o u b l e t (6 3.11, J = 2 H z ) , presumably f o r the same reasons suggested i n the p r e v i o u s c a s e . Treatment of the m i x t u r e of s i l y l e n o l e t h e r s (195) and (196) w i t h p o t a s s i u m f l u o r i d e i n methanol gave a m i x t u r e of the 8-keto e s t e r s (229) and (230) ( v m a x 1750, 1730 cm - 1) i n a r a t i o ( g l c ) o f 45:55 (or 55:45) and a y i e l d of 77%. The *H nmr spectrum of t h i s m i x t u r e was c o m p l i c a t e d by the p o s s i b l e p r e -sence o f f o u r d i a s t e r e o m e r s . To r e s o l v e t h i s c o m p l e x i t y , one of the c h i r a l c e n t r e s was e l i m i n a t e d v i a a dec a r b o m e t h o x y l a -t i o n . Thus, the base-promoted h y d r o l y s i s - d e c a r b o x y l a t i o n (methanol - I N KOH) o f the m i x t u r e of (229) and (230) gave a m i x t u r e o f the ketones (231) and (232) i n 63% y i e l d . The i r spectrum of t h i s m i x t u r e showed t h a t o n l y one c a r -b o n y l a b s o r p t i o n remained ( v m a x 1735 cm "*") , w h i l e the *H nmr spectrum c l e a r l y c o r r o b o r a t e d the f a c t t h a t the carbomethoxy group had been removed. The presence of a 1:1 p a i r o f d o u b l e t s (J = 7 Hz) a t 6 1.01 and 1.08, which were a s s i g n e d t o the meth y l s u b s t i t u e n t s , demonstrated t h a t t h i s m a t e r i a l was a m i x t u r e of two d i a s t e r e o m e r s . T h i s was v e r i f i e d by comparing the m i x t u r e o f (231) and (232) w i t h a pure sample of (231) which was p r e p a r e d by the base-promoted d e c a r b o m e t h o x y l a t i o n o f the 8-keto e s t e r (229). - 123 -T h e ' H nmr of (231) was s i m i l a r t o t h a t observed f o r the m i x t u r e o f (231) and (232) . However, the r i n g - m e t h y l s u b s t i t -uent (at C 4) appeared as a d o u b l e t ( J = 8 Hz) a t 6 1.01 and t h i s c o i n c i d e s w i t h one o f the p a i r o f d o u b l e t s found i n the JH nmr o f the m i x t u r e of (231) and (232) . The m i x t u r e of (231) and (232) showed two peaks by g l c and the peak c o r r e s p o n d i n g t o the former was i d e n t i f i e d by c o -i n j e c t i o n o f the m i x t u r e w i t h a pure sample o f (231). In t h i s way, (231) and (232) were found t o be p r e s e n t i n the m i x t u r e i n a r a t i o o f 47:53. T h i s r a t i o c o i n c i d e s w i t h the s t e r e o -i s o m e r i c r a t i o w hich was found t h r o u g h o u t t h i s s e r i e s and - 124 -demonstrates t h a t the Cope rearrangement o f the 6 - ( 1 - p r o p e n y l ) -b i c y c l o [ 3 . 1 . (TJhex-2-enes (193) and (194) i s a s t e r e o s p e c i f i c p r o c e s s . In o r d e r t o assuage any r e m a i n i n g f e a r s as t o the s t r u c -t u r e o f the r e a r r a n g e d g-keto e s t e r s ( 2 2 6 ) - ( 2 2 9 ) , a r e l a t e d compound o f known s t r u c t u r e was sought which c o u l d s e r v e as a s t a n d a r d f o r comp a r i s o n . The compound chosen was b i c y c l e -rs . 2 . !T] o c t - 2 - e n - 6 - o n e (233) , which had been p r e v i o u s l y p r e -157 pared by another method . T h i s m a t e r i a l was o b t a i n e d from a m i x t u r e of the i s o m e r i c e t h y l e n e k e t a l s (235) and ( 2 3 6 ) * . 235 2_36 A c i d - c a t a l y z e d (THF - I N HC1, 0°C) h y d r o y l s i s of the e t h y l e n e k e t a l m i x t u r e , f o l l o w e d by p r e p a r a t i v e g l c * The m i x t u r e of the e t h y l e n e k e t a l s (235) and (236) was k i n d l y p r o v i d e d by Dr. Stephen A. M o n t i . - 125 -s e p a r a t i o n o f the r e s u l t i n g ketone m i x t u r e , a f f o r d e d pure samples o f bicyclo [ 3.2.X ]oct-2-en-6-one (233) and b i c y c l e -rs .2.f] oct-3-en-6-one (234) . These m a t e r i a l s d i s p l a y e d i r and 1 H nmr s p e c t r a which c o r r e s p o n d e d t o those r e p o r t e d i n the l i t e r a t u r e 1 5 ^ . H y d r o l y s i s - d e c a r b o x y l a t i o n o f the g-keto e s t e r (226) (THF -1 N HC1, r e f l u x ) a f f o r d e d b i c y c l o [3 .2.1]oct-2-en-6-one (233) i n 94% y i e l d . T h i s m a t e r i a l was i d e n t i c a l ( g l c , i r , *H nmr) w i t h the 15 7 p r e v i o u s l y p r e p a r e d sample o f the b i c y c l i c ketone (233) . The comparison was unambiguous s i n c e the ketones (233) and (234) d i s p l a y e d q u i t e d i f f e r e n t g l c r e t e n t i o n times and 1H nmr s p e c t r a . A l t h o u g h the r e a c t i o n s used t o t h i s p o i n t p r o v i d e d a c c e s s t o h i g h l y s u b s t i t u t e d b i c y c l o [3 . 2. T\ o c t a - 2 , 6 - d i e n e s , examples of these systems which were s u b s t i t u t e d a t Cg were c o n s p i c u o u s i n t h e i r absence. I t was thought t h a t t h i s problem might be s o l v e d i n a number o f ways. F i r s t of a l l , the b i c y c l i c ketone (178) c o u l d be t r a n s f o r m e d i n t o the a , 8 - u n s a t u r a t e d ketone (237) u s i n g known methods. - 126 -0 0 ( V ^ — -C 0 2 M e C02Me 178 23_7 I t can be seen t h a t c o n j u g a t e a d d i t i o n o f a s u i t a b l e n u c l e o p h i l e t o the enone (237), f o l l o w e d by t r a p p i n g o f the i n t e r m e d i a t e e n o l a t e a n i o n w i t h 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 , would l e a d t o a s i l y l e n o l e t h e r (238) , s i m i l a r t o the p r e v i o u s l y p r e p a r e d examples. The Cope rearrangement of t h i s m a t e r i a l s h o u l d then p r o v i d e the d e s i r e d b i c y c l o |~3 . 2 . f ] -o c t a - 2 , 6 - d i e n e (239) s u b s t i t u t e d a t CR. - 127 -Q u i t e a d i f f e r e n t type of b i c y c l o Q . 2. T\ o c t a d i e n e might a l s o be p r e p a r e d by the d i r e c t t h e r m a l rearrangement of the a , g - u n s a t u r a t e d ketone (237) i t s e l f . T h i s would p r o v i d e the b i c y c l i c system (240) w i t h a c a r b o n y l group a t C g. The p r e p a r a t i o n of the enone (237) was approached as f o l -l ows. A l t h o u g h the s y n t h e s i s o f b i c y c l o [3 .1.0]hex-3-en-2-one 158 (241) from the s a t u r a t e d ketone (242) had been r e p o r t e d , t h i s method was deemed u n s u i t a b l e s i n c e i t i n v o l v e d the use of bromine (Scheme 1 4 ) , which might cause a number of s i d e r e a c -t i o n s i n the case a t hand. SCHEME H 241 - 128 -An a l te rna t ive approach to a,6-unsaturated ketones has recent ly been reported in which the enolates of ketones were quenched with d ipheny ld isu l f ide to af ford a -su l fenyla ted pro-159 ducts . Oxidation of the l a t te r to s u l f o x i d e s , followed by thermolysis , led to the formation of a,6-unsaturated ketones 1 (Scheme 15) . SCHEME 15 Thus, the l i th ium enolate of ketone (178) was generated by the addi t ion of 1 equivalent of l i th ium diisopropylamide (LDA) and was subsequently quenched by addit ion to a so lut ion of d ipheny ld isu l f ide in HMPA. This led to the a -su l feny la ted ketone (243) in 74% y i e l d . Unfortunately , the attempted oxidat ion of the phenyl-s u l f i d e (243) with e i ther m-chloroperbenzoic acid in d i c h l o r o -methane at -78°C or with sodium metaperiodate in methanol at Q O c 1 5 9 g a v e complex mixtures of no synthet ic u t i l i t y . - 129 -R e i c h , e t a l . have a l s o r e p o r t e d the analogous s e l e -nium-based method o f e f f e c t i n g the t r a n s f o r m a t i o n of ketones t o enones by s e l e n y l a t i o n f o l l o w e d by s e l e n o x i d e e l i m i n a t i o n (Scheme 16) . SCHEME 16 T h i s method has been s u c c e s s f u l l y used i n a number o f u J 4 . 160,161 5-membered r i n g systems ' C o n s e q u e n t l y the l i t h i u m e n o l a t e of ketone (178) (gen-e r a t e d i n the u s u a l manner) was t r e a t e d w i t h 1.2 e q u i v a l e n t s of p h e n y l s e l e n i u m c h l o r i d e i n HMPA a t -78°C. P u r i f i c a t i o n o f the r e s u l t i n g p r o d u c t by p r e p a r a t i v e t i c a f f o r d e d the d e s i r e d p h e n y l s e l e n i d e (244) i n 69% y i e l d . The *H nmr spectrum - 130 -of th is mater ia l was quite s imi lar to that of the s ta r t ing ketone (178) with the addi t ion of two l o w - f i e l d mul t ip le ts (8 7.52-7.74 and 7.20-7.45) assigned to the aromatic protons of the a-phenylseleno moiety. C 0 2 M e C 0 2 M e 178 24_4 Oxidation of a so lu t ion of the phenylselenide (244) in dichloromethane with 30% hydrogen p e r o x i d e 1 ^ 0 presumably led to the selenoxide (245) which el iminated at or below room 162 temperature to a f ford the a,B-unsaturated ketone (237) in 47% y i e l d . The i r spectrum of th is mater ia l exhibi ted absorp-t ions ( v m a x 1705, 1575 cm )^ ind ica t ive of the presence of an a,B-unsaturated ketone. The 1E nmr spectrum showed that the vinylcyclopropane moiety had remained in tact and no methylene s igna ls were observed. The v i n y l i c protons of the conjugated double bond were a lso c l e a r l y v i s i b l e . The B-proton resonated at c h a r a c t e r i s t i c a l l y low f i e l d (6 7.66) as a doublet of doub-l e t s (J = 6, 3 Hz) while the a-proton appeared as a doublet (J = 6 Hz) at 6 5.81. Although the y i e l d of th is react ion was less than e n v i -ab le , i t afforded a pure sample of the desired enone (237) while other attempted methods f a i l e d . Diminished y ie lds have been reported to o c c u r ^ " using the e l iminat ion of the - 131 -a - s e l e n o x i d e s o f some o t h e r c y c l i c ketones b e a r i n g an a-hydro-gen. s With the r e q u i s i t e a ,{3-unsaturated ketone (237) i n hand, the p o s s i b l e r e a c t i o n of t h i s compound w i t h a c u p r a t e r e a g e n t was b r i e f l y i n v e s t i g a t e d . The b r e v i t y of the i n v e s t i g a t i o n was p r e c i p i t a t e d by the i s o l a t i o n of a complex m i x t u r e of com-pounds when the enone (237) was a l l o w e d t o r e a c t 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 . The p o s s i b i l i t y o f s i d e r e a c t i o n s o c c u r r i n g i n t h i s p r o c e s s was n o t e n t i r e l y u n a n t i c i p a t e d , s i n c e the n u c l e o p h i l i c r i n g - o p e n i n g o f c y c l o p r o p a n e s w i t h c u p r a t e r e a g e n t s has been shown t o compete w i t h c o n j u g a t e a d d i t i o n i n a number of 8 - c y c l o p r o p y l a ,£-unsaturated k e t o n e s ' ^ 3 ' ^ 4 . Due t o t h i s i n i t i a l f a i l u r e , as w e l l as time l i m i t a t i o n s , t h i s approach was a b o r t e d . F o r t u n a t e l y , the attempted Cope rearrangement of the d i v i n y l c y c l o p r o p a n e (237) i t s e l f met w i t h more s u c c e s s . In the e v e n t , compound (237) was r e f l u x e d i n x y l e n e (b.p. 138°C) f o r 18 h o u r s . G l c a n a l y s i s d u r i n g the c o u r s e o f the r e a c t i o n - 132 -2 3 7 i n d i c a t e d t h a t the d i s a p p e a r a n c e o f the s t a r t i n g m a t e r i a l c o i n -c i d e d w i t h the f o r m a t i o n o f a s i n g l e p r o d u c t . T h i s m a t e r i a l was i d e n t i f i e d as the b i c y c l o [ 3 , 2 . f ] o c t a - 2 f 6-diene (240) which was i s o l a t e d i n 73% y i e l d . The i r spectrum of t h i s compound showed the presence of an e s t e r c a r b o n y l (v„ = v 1770 cm - 1) as w e l l as a 5-membered ITlclX r i n g ketone (v 1730 cm ^ ) . E x a m i n a t i o n of the lU nmr 3 max spectrum o f t h i s compound showed a number o f s i m i l a r i t i e s t o the XH nmr s p e c t r a r e p o r t e d f o r some o t h e r examples o f b i c y c l e -rs . 2.1] o c t a - 2 , 6 - d i e n e s 5 6 . The presence o f o n l y f o u r v i n y l i c p r o t o n s was e a s i l y v i s i b l e . The p r o t o n (H Q) a t appeared as a d o u b l e t ( J = 7 Hz) a t 6 6.71. A m u l t i p l e t a t about - 133 -8 6.2-6.4 was thought t o be due t o the o v e r l a p p i n g s i g n a l s of H b and H c. A l t h o u g h a d o u b l e t o f d o u b l e t s (J = 10, 7 H z ) , thought t o a r i s e from H^, c o u l d be d i s c e r n e d the s i g n a l s due t o H c were o b s c u r e d . Double i r r a d i a t i o n e x p e r i m e n t s h e l p e d t o c l a r i f y the s i t u a t i o n . Thus, i r r a d i a t i o n of the d o u b l e t a t 6 6.71 l e d t o a c o l l a p s e of the double d o u b l e t a s s i g n e d t o H^ t o g i v e a s i m p l e d o u b l e t (J = 3 Hz) a t 6 6.28. S i m i l a r l y , i r r a d i a t i o n of the broad d o u b l e t o f t r i p l e t s ( J = 7, 3 Hz) a t 6 5.58, which was a s s i g n e d t o H^, l e d t o a c o l l a p s e of the o b s c u r e d m u l t i p l e t o r i g i n a t i n g from H c t o a s i n g l e t a t 6 6.30. The appearance o f the m u l t i p l e t a s s i g n e d t o was s i m p l i f i e d on i r r a d i a t i o n o f the m u l t i p l e t s c e n t r e d a t 6 6.3. The d o u b l e t of t r i p l e t s o b s e r v e d c o u l d be e x p l a i n e d i n terms of H^ b e i n g s p l i t by v i c i n a l c o u p l i n g (J = 10 Hz) t o a c i s v i n y l i c p r o t o n and a v i c i n a l c o u p l i n g (J = 3 Hz) t o two a l l y l i c methylene p r o t o n s . The b r o a d e n i n g o f these s i g n a l s may r e s u l t from u n r e -s o l v e d l o n g - r a n g e c o u p l i n g s and second o r d e r s p l i t t i n g s . The f o r m a t i o n of a s i n g l e p r o d u c t d u r i n g the t h e r m o l y s i s of 1-car borne t h o x y - 6 - e x o - v i n y l b i eye l o [3 . 1 . cT] hex-3-en-2-one (237) and the s p e c t r a l p r o p e r t i e s o f t h a t p r o d u c t a l l s u p p o r t i t s i d e n t i f i c a t i o n as 1 - c a r b o m e t h o x y b i c y c l o [ 3 . 2 . l ] o c t a - 2 , 6 -dien-8-one (240). T h i s p r o v i d e s an a d d i t i o n a l example o f the Cope rearrangement of 6 - a l k e n y l b i c y c l o [3.1.0]hexenes as an e n t r y i n t o s u b s t i t u t e d b i c y c l o [ 3 . 2 . l ] o c t a d i e n e systems. - 1 3 4 -VII . Conclusion On the basis of the synthet ic studies described in th is thes is i t would appear that the po ten t ia l of the Cope rearrange-ment of 6 -exo - (1 -a lkeny l ) b i c y c l o p . 1 . 0 ~ | hex-2-ene systems as an entry in to the b i c y c l o [3 . 2 . f ] octane r ing system i s wel l es tab-l i s h e d . This methodology allows convenient access to b i c y c l o -Q j . 2 . l ] octane systems having funct iona l group "handles" which would allow further e laborat ion at any one of the r ing carbons. The app l ica t ion of th is synthet ic method to the t o t a l synthe-s i s of an appropriate natura l product might not only provide an e f f i c i e n t and v e r s a t i l e route to a key intermediate, but a lso add a measure of novelty and elegance to the synthet ic sequence. - 135 -EXPERIMENTAL G e n e r a l I n f o r m a t i o n M e l t i n g p o i n t s were det e r m i n e d u s i n g a F i s h e r - J o h n s m e l t -i n g p o i n t a p p a r a t u s and are u n c o r r e c t e d . B o i l i n g p o i n t s are a l s o u n c o r r e c t e d and those d e s i g n a t e d as a i r - b a t h temperatures r e f e r t o s h o r t - p a t h ( K u g e l r o h r ) d i s t i l l a t i o n s . I n f r a r e d ( i r ) s p e c t r a were r e c o r d e d on P e r k i n - E l m e r model 710 or model 710B i n f r a r e d s p e c t r o p h o t o m e t e r s and were c a l i b r a t e d u s i n g the 1601 c m - 1 band o f p o l y s t y r e n e f i l m . P r o t o n magnetic resonance (*H nmr) s p e c t r a were taken i n d e u t e r o c h l o r o f o r m u s i n g t e f r a -me t h y l s i l a n e (TMS) as i n t e r n a l s t a n d a r d . These s p e c t r a were r e c o r d e d u s i n g V a r i a n A s s o c i a t e s T-60, HA-100 or XL-100 spec-t r o m e t e r s or a B r u k e r WP-80 s p e c t r o m e t e r . The 270 MHz s p e c t r a were r e c o r d e d on a u n i t c o m p r ised o f an O x f o r d I n s t r u m e n t s 63.4 KG s u p e r c o n d u c t i n g magnet and a N i c o l e t 16K computer a t t a c h e d t o a Bruker TT-23 c o n s o l e . A l l *H nmr s p e c t r a were 100 MHz s p e c t r a u n l e s s s t a t e d o t h e r w i s e . S i g n a l p o s i t i o n s a re g i v e n i n p a r t s 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 , c o u p l i n g c o n s t a n t s (where p o s s i b l e ) , i n t e g r a t e d peak areas and p r o t o n assignments are i n d i c a t e d i n p a r e n t h e s e s . Low r e s o l u -t i o n mass s p e c t r a (ms) were r e c o r d e d w i t h a Varian/MAT CH4B mass s p e c t r o m e t e r . Glc-mass s p e c t r o m e t r i c a n a l y s i s was done u s i n g a Pye Unicam S e r i e s 104 gas chromatograph and a VG Micromass 12 mass s p e c t r o m e t e r t o g e t h e r w i t h a Watson-Biemann - 136 -I n t e r f a c e . H i g h r e s o l u t i o n mass s p e c t r a were r e c o r d e d w i t h a K r a t o s / A E I MS 50 or MS 902 mass 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 were performed by Mr. P. B o r d a , M i c r o a n a l y t i c a l L a b o r a t o r y , U n i v e r s i t y of B r i t i s h C olumbia. A n a l y t i c a l gas l i q u i d chromatography ( g l c ) was done u s i n g a H e w l e t t - P a c k a r d HP 5832A gas chromatograph and the f o l l o w i n g columns: i ) 6 f t x 0.125 i n , 5% OV-17 on Chromosorb W (HP) (80-100 mesh); i i ) 6 f t x 0.125 i n , 5% OV-210 on Chromosorb W (HP) (80-100 mesh); i i i ) 10 f t x 0.125 i n , 10% SE-30 on Chromosorb W (HP) (80-100 mesh). The column used and the i n i -t i a l oven temperature are 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 -ses were done u s i n g a temperature program (25°C per min, f i n a l t emperature 200°C) a f t e r the f i r s t 5 min a t the i n i t i a l tem-p e r a t u r e . P r e p a r a t i v e g l c was done u s i n g a V a r i a n Aerograph 90-P gas chromatograph and the f o l l o w i n g columns; i ) 10 f t x 0.25 i n , 10% OV-17 on Chromosorb W (60-80 mesh); i i ) 10 f t x 0.25 i n , 10% SE-54 on Chromosorb W (60-80 mesh). T h i n l a y e r chromatography ( t i c ) was c a r r i e d o ut on 20 x 5 cm g l a s s p l a t e s c o a t e d w i t h 0.3 mm of s i l i c a g e l (E. Merck, S i l i c a G e l 60) or on c o m m e r c i a l s i l i c a g e l p l a t e s (Eastman Chomagram Sheet Type 13181). P r e p a r a t i v e t h i n l a y e r chroma-tography was c a r r i e d o ut on 20 x 20 cm 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. Merck, S i l i c a G e l 6 0 ) . Column chromatography was done u s i n g 70-230 mesh s i l i c a g e l (E. Merck) - 137 -and f l a s h column chromatography was done u s i n g 230-400 mesh s i l i c a g e l (E. Merck) a c c o r d i n g t o the procedure developed by S t i l l 1 6 5 . A l l r e a c t i o n s r e q u i r i n g anhydrous c o n d i t i o n s were done u s i n g g l a s s w a r e which was f l a m e - d r i e d under a n i t r o g e n f l o w . A l l r e a c t i o n s were done under a n i t r o g e n atmosphere, u n l e s s s t a t e d o t h e r w i s e . S o l v e n t s and Reagents S o l u t i o n s o f m e t h y l l i t h i u m , n - b u t y l l i t h i u m and t - b u t y l -l i t h i u m were o b t a i n e d from A l d r i c h C h e m i c a l Company, I n c . and were s t a n d a r d i z e d u s i n g Gilman's p r o c e d u r e 1 6 6 . L i t h i u m d i i s o p r o p y l a m i d e (LDA) was p r e p a r e d by the a d d i -t i o n of a hexane s o l u t i o n of n - b u t y l l i t h i u m (1.0 e q u i v ) t o a s o l u t i o n of d i i s o p r o p y l a m i n e (1.1 e q u i v ) i n d r y t e t r a h y d r o f u r a n (THF) a t -78°C under n i t r o g e n . The r e s u l t i n g s o l u t i o n was then s t i r r e d a t 0°C f o r 20 min b e f o r e b e i n g used. 98 P h e n y l t h i o c o p p e r was p r e p a r e d by r e f l u x m g a m i x t u r e of cuprous o x i d e (43 g, 0.30 mol) and t h i o p h e n o l (75 g, 0.68 mol) i n 1500 ml o f e t h a n o l f o r 5 days. S u c t i o n f i l t r a t i o n o f t h i s m i x t u r e , f o l l o w e d by d r y i n g the r e s u l t i n g y e l l o w s o l i d under h i g h vacuum, gave p h e n y l t h i o c o p p e r i n e s s e n t i a l l y q u a n t i t a t i v e y i e l d . D i e t h y l bromophosphate ( d i e t h y l phosphorobromidate) was 109 p r e p a r e d by the p r o c e d u r e of Gorecka and was p u r i f i e d by - 138 -f l a s h d i s t i l l a t i o n (room temperature/0.1 mm) i n t o a r e c e i v e r cooled to -78°C. Bromoform and iodomethane were passed through a s h o r t column of A c t i v i t y I b a s i c alumina p r i o r to being used. The s o l v e n t s used were d r i e d and p u r i f i e d (when necessary) by the f o l l o w i n g procedures. Tet r a h y d r o f u r a n (THF) and d i e t h y l ether were d i s t i l l e d 167 from sodium benzophenone k e t y l under n i t r o g e n . T r i e t h y l a m i n e and d i i s o p r o p y l a m i n e were d i s t i l l e d from c a l c i u m hydride and s t o r e d over 3A molecular s i e v e s . t e r t -B u t y l a l c o h o l was a l s o d i s t i l l e d from c a l c i u m h y d r i d e . Hexamethylphosphoramide (HMPA) was d i s t i l l e d from barium oxide and s t o r e d over 13x molecular s i e v e s . Dichloromethane and a c e t o n i t r i l e were both d i s t i l l e d from phosphorous pentoxide and a c e t o n i t r i l e was s t o r e d over 4A molecular s i e v e s . Xylene (b.p. 138°) and mesitylene were both d i s t i l l e d from sodium. Anhydrous e t h a n o l was obtained by d i s t i l l i n g a b solute e t h a n o l from magnesium e t h o x i d e . Petroleum ether r e f e r s to the f r a c t i o n b o i l i n g a t 30-60°C. - 139 -P r e p a r a t i o n o f 2 - V i n y l - 5 , 5 - d i m e t h y l - 1 , 3 - d i o x a n e (117) To a s o l u t i o n o f 2 , 2 - d i m e t h y l - 1 , 3 - p r o p a n e d i o l (104 g, 1.0 mol) and p - t o l u e n e s u l f o n i c a c i d (0.2 g) i n 500 ml of d r y d i c h l o r o m e t h a n e was added a c r o l e i n (56.0 g,-1.0 mol) i n one p o r t i o n . To the r e s u l t i n g c l o u d y s o l u t i o n was added anhydrous magnesium s u l f a t e (= 10 g) and s t i r r i n g was m a i n t a i n e d a t room temperature f o r 5 h. The r e a c t i o n m i x t u r e was then f i l t e r e d t h rough a s h o r t column o f A c t i v i t y I b a s i c a l umina (100 g) and the s o l v e n t was c a r e f u l l y removed on a r o t a r y e v a p o r a t o r . F l a s h d i s t i l l a t i o n o f the r e s u l t i n g y e l l o w o i l i n t o a r e c e i v e r c o o l e d t o -78°C gave the a c e t a l (117) (114 g, 80%) as a c o l o u r -l e s s l i q u i d , b.p. 28°C/0.1 mm. A n a l y s i s of t h i s m a t e r i a l by t i c ( p etroleum e t h e r - e t h e r = 10:1) showed one sp o t o n l y and g l c a n a l y s i s (OV-17, 80°C) i n d i c a t e d > 99% p u r i t y ; i r ( f i l m ) : 2975, 2860, 1100 c m - 1 ; *H nmr 6: 5.95 (d of d of d, J = 17 Hz, J ' = 10 Hz, J M = 5 Hz, IH, HC=CH 2), 5.48 (br d, J = 17 Hz, IH, HC=cC^ )f 5.33 (br d, J = 10 Hz, IH, HC=C^ H), 4.86 (d, J = 5 Hz, IH, a c e t a l m e t h i n e ) , 3.68 and 3.52 (AB q u a r t e t , J = 11 Hz, 4H, a c e t a l m e t h y l e n e s ) , 1.22 ( s , 3H, gem-methyl), 0.74 ( s , 3H, gem-methyl). E x a c t mass c a l c d . f o r C 8 H 1 4 0 2 : 142.0994; found: 142.0994. - 140 -P r e p a r a t i o n o f the Dibromocyclopropane (116) To a 3-necked round-bottomed f l a s k f i t t e d w i t h an overhead m e c h a n i c a l s t i r r e r and a s e l f - e q u a l i z i n g d r o p p i n g f u n n e l was added 2 - v i n y l - 5 , 5 - d i m e t h y l - 1 , 3 - d i o x a n e (117) (4.26 g, 30.0 mmol), bromoform (15.2 g, 60.0 mmol), t r i e t h y l b e n z y l a m m o n i u m c h l o r i d e (0.15 g) and a s m a l l amount (0.25 ml) o f e t h a n o l . To t h i s r a p i d l y s t i r r e d m i x t u r e was added dropwise 50% aqueous NaOH (25 ml) and s t i r r i n g was c o n t i n u e d f o r 20 h. The r e s u l t -i n g t a r r y m a t e r i a l was d i l u t e d w i t h c o l d water (250 ml) and e x t r a c t e d w i t h pentane ( 3 x ) . The combined o r g a n i c e x t r a c t s were washed w i t h water u n t i l the aqueous phase remained n e u t r a l The s o l u t i o n was then d r i e d (anhydrous magnesium s u l f a t e ) and the s o l v e n t and e x c e s s bromoform were removed under reduced p r e s s u r e . The r e s u l t i n g dark brown o i l was taken up i n pen-tane and then f i l t e r e d t h r o ugh a s h o r t column o f A c t i v i t y I a l u m i n a . Removal o f the s o l v e n t from the e l u a n t gave a y e l l o w o i l (6.0 g) which was d i s s o l v e d i n pentane. The p r o d u c t c r y s t a l l i z e d from t h i s s o l u t i o n on s t a n d i n g a t -15°C. R e c r y s -t a l l i z a t i o n (pentane) gave the d i b r o m o c y c l o p r o p a n e (116) - 141 -(2.50 g, 27%) as c o l o u r l e s s c r y s t a l s , m.p. 75-77°C; i r (CHC1 3): 2975, 2870, 1100 c m - 1 ; *H nmr 6: 4.19 (d, J = 6 Hz, IH, ace-t a l m e t h i n e ) , 3.3-3.8 (m, 4H, a c e t a l m e t h y l e n e s ) , 1.5-2.2 (m, 3H, c y c l o p r o p y l p r o t o n s ) , 1.22 ( s , 3H, gem-methyl), 0.72 ( s , 3H, gem-methyl); (270 MHz) 6: 4.20 (d, J = 6 Hz, IH, a c e t a l m e t h i n e ) , 3.70 and 3.63 ( p a i r of d of d, J = 10 Hz, J • 2 Hz, 2H, a c e t a l m e t h y l e n e s , H e q U a t o r i a l ^ ' 3*47 a n d 3.41 ( p a i r of d, J = 10 Hz, 2H, a c e t a l m e t h y l e n e s , H . , ) , 2.01 (d o f d o f d, J = 11 Hz, J ' = J " = 6 Hz, IH, H ), 1.84 (d o f d, J = 11 Hz, J ' = 6 Hz, I H , H b ) , 1.61 (d o f d, J = J * = 6 Hz, IH, H c ) , 1.23 ( s , 3H, gem-methyl), 0.73 ( s , 3H, gem-methyl). A n a l , c a l c d . f o r C g H 1 4 B r 2 0 2 : C 34.42, H 4.50; found: C 34.63, H 4.70. P r e p a r a t i o n of the M e t h y l a t e d C y c l o p r o p a n e s (114) and (136) Br Me An 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 d i b r o m o c y c l o p r o p a n e (116) (8.00 g, 25.5 mmol) i n d r y THF (125 ml) c o n t a i n i n g 25 ml of d r y HMPA and iodomethane (7.2 g, 51 mmol) was c o o l e d t o -95°C under n i t r o g e n . To t h i s m i x t u r e was added a hexane s o l u t i o n o f n - b u t y l l i t h i u m (30.6 mmol) and the r e s u l t i n g p a l e - 142 -y e l l o w s o l u t i o n was then a l l o w e d t o s l o w l y warm t o room tem-p e r a t u r e . The r e a c t i o n m i x t u r e was c o n c e n t r a t e d , poured i n t o b r i n e and e x t r a c t e d w i t h pentane ( 3 x ) . The combined o r g a n i c f r a c t i o n s were washed w i t h b r i n e , d r i e d over anhydrous magne-sium s u l f a t e and the s o l v e n t was removed under reduced p r e s s u r e t o g i v e a p a l e y e l l o w o i l (7.1 g ) . G l c a n a l y s i s (OV-17, 100°C) showed a m i x t u r e of two major components i n a r a t i o of 87:13. S e p a r a t i o n of t h i s m i x t u r e by column chromatography (petroleum e t h e r - e t h e r = 10:1) f o l l o w e d by K u g e l r o h r d i s t i l l a t i o n gave two pure f r a c t i o n s . The f i r s t f r a c t i o n was i d e n t i f i e d as the c i s - m e t h y l a t e d p r o d u c t (114) (4.90 g, 7 4 % ) , b.p. ( a i r - b a t h ) 63°C/0.1 mm. C r y s t a l l i z a t i o n o f t h i s m a t e r i a l from pentane a f f o r d e d c o l o u r l e s s c r y s t a l s , m.p. 24.5-26°C. G l c a n a l y s i s (OV-17, 100°C) i n d i c a t e d the presence o f a s i n g l e pure compo-nen t ; i r ( f i l m ) : 2975, 2870, 1100 ( b r ) , 1020 ( b r ) , 785 c m - 1 ; lU nmr (270 MHz) 6: 4.25 (d, J = 6.5 Hz, IH, a c e t a l m e t h i n e ) , 3.65 and 3.68 ( o v e r l a p p i n g p a i r o f d of d, J = 11 Hz, J ' = 2 Hz, 2H, a c e t a l m e t h y l e n e s , H e q U a t o r i a l 5 ' 3 , 4 2 ( d ' J = 1 1 H z ' 2H, a c e t a l m e t h y l e n e s , H a x ^ a ^ ) > 1.84 ( s , 3H, c y c l o p r o p y l m e t h y l ) , 1.7-2.0 (m, IH, H J , 1.36 (d o f d, J = 10 Hz, J ' = 6.5 Hz, IH, Hfa) 1.21 ( s , 3H, gem-methyl), 0.92 (d of d, J = J ' = 6.5 Hz, IH, H ), 0.72 ( s , 3H, gem-methyl); ms m/e 249/247 (M-H), 169 (M-Br). A n a l , c a l c d . f o r C 1 Q H 1 7 B r 0 2 : C 48.21, H 6.88; found: C 48.38, H 6.86. - 143 -The second f r a c t i o n was i d e n t i f i e d as the t r a n s - m e t h y l a t e d p r o d u c t (136) (0.72 g, 11%) which was o b t a i n e d as f i n e c o l o u r -l e s s c r y s t a l s ( p e n t a n e ) , m.p. 52-53°C. G l c a n a l y s i s (OV-17, 100°C) i n d i c a t e d the presence o f a s i n g l e pure component; i r ( f i l m ) : 2970, 2865, 1470, 1170, 1095 c m - 1 ; 'H nmr (270 MHz) 6: 4.29 (d, J = 6.5 Hz, IH, a c e t a l m e t h i n e ) , 3.68 and 3.72 ( o v e r l a p p i n g p a i r o f d of d, J = 11 Hz, J ' = 2 Hz, 2H, a c e t a l m e t h y l e n e s , H e q u a t o r i a x ) ' 3.53 and 3.49 ( o v e r l a p p i n g p a i r of d, J = 11 Hz, 2H, a c e t a l m e t h y l e n e s , H a x ^ a ^ ) > 1.78 ( s , 3H, c y c l o p r o p y l m e t h y l ) , 1.24 ( s , 3H, gem-methyl), 1.04-1.18 (m, 3H, c y c l o p r o p y l p r o t o n s ) , 0.74 ( s , 3H, gem-methyl); ms m/e 249/247 (M-H), 169 (M-Br). A n a l , c a l c d . f o r C 1 ( ) H 1 7 B r 0 2 : C 48.21, H 6.88; found: C 48.16, H 7.00. P r e p a r a t i o n o f (E)-2-Bromo-2-methyl-cyclopropanecarboxaldehyde (113) B r ,CH0 H r The a c e t a l (114) (10.8 g, 0.043 mol) was added t o 100 ml of degassed 88% f o r m i c a c i d and the r e s u l t i n g m i x t u r e was s t i r r e d under n i t r o g e n f o r 1.5 h a t room t e m p e r a t u r e . The m i x t u r e was then poured over i c e and the aqueous m i x t u r e was - 144 -e x t r a c t e d w i t h pentane (2x) . The o r g a n i c e x t r a c t s were washed w i t h s a t u r a t e d aqueous sodium b i c a r b o n a t e u n t i l n e u t r a l , d r i e d over anhydrous magnesium s u l f a t e and the s o l v e n t was c a r e f u l l y removed on a r o t a r y e v a p o r a t o r . T h i s gave 10.4 g o f a s l i g h t l y y e l l o w l i q u i d . F l a s h e v a p o r a t i o n (0.1 mm) o f t h i s m a t e r i a l a t (or s l i g h t l y above) room temperature i n t o a -196°C t r a p ( l i q u i d N 2) gave the aldehyde (113) (5.05 g, 72%) as a c o l o u r -l e s s , v o l a t i l e l i q u i d . G l c a n a l y s i s (OV-17, 100°C) showed t h i s m a t e r i a l t o be p u r e ; i r ( f i l m ) : 2875, 2780, 1710 c m - 1 . The aldehyde (113) was most c o n v e n i e n t l y c h a r a c t e r i z e d as i t s 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e (137); o r a n g e - r e d c r y s t a l s ( e t h a n o l - H 2 0 ) , m.p. 160-161.5°C ( d e c ) ; *H nmr 6: 9.34 (br s, IH, NH), 9.12 (d, J = 3 Hz, IH, H ) , 8.34 (d o f d, J = 10 Hz J ' = 3 Hz, IH, H f ) , 7.93 (d, J = 10 Hz, IH, H ) , 7.38 (d, J = 6.5 Hz, I H , H d ) , 2.50 (d o f d o f d, J = 10 Hz, J ' = J " = 6.5 Hz, IH, H J , 1.88 ( s , 3H, m e t h y l ) , 1.76 (d of d, J = 10 Hz, J ' = 6.5 Hz, I H , H f a), 1.40 (d o f d, J = J ' = 6.5 Hz, IH, H ); ms m/e 344/342 ( M + ) , 263 (M-Br). A n a l , c a l c d . f o r c 1 1 H n B r N 4 0 4 : c 38 .50, H 3.23, N 16.33; found: C 38.58, H 3.11, N 16.25. - 14 5 -S i m i l a r l y , h y d r o l y s i s o f the d i a s t e r e o m e r i c a c e t a l (136), f o l l o w e d by d e r i v a t i z a t i o n , gave the 2 , 4 - d i n i t r o p h e n y l h y d r a z o n e (139) as y e l l o w c r y s t a l s ( e t h a n o l - H 2 0 ) , m.p. 152-154°C; l H n m r 6 : 11.18 (br s, IH, NH) , 9.15 (d, J = 3 Hz, IH, H e,) , 8.35 (d o f d, J = 10 Hz, J ' = 3 Hz, IH, H f , ) , 7.99 (d, J = 10 Hz, IH, H , ) , 7.36 (d, J = 8 Hz, IH, H d , ) , 1.92 ( s , 3H, m e t h y l ) , 1.87 (d o f d, J = 10 Hz, J ' = 8 Hz, IH, H , ) , 1.61 (d, J = 6 Hz, I H , H , ) , 1.45 (d of d, J = 10 Hz, J ' = 6 Hz, IH, H b , ) ; ms m/e 334/342 ( M + ) , 263 (M-Br). A n a l , c a l c d . f o r c 1 1 H i 1 B r N 4 ° 4 : c 38.50, H 3.23, N 16.33; found: C 38.27, H 3.20, N 16.20. P r e p a r a t i o n o f the O l e f i n (112) To a s u s p e n s i o n o f i s o p r o p y l t r i p h e n y l p h o s p h o n i u m i o d i d e (6.20 g, 14.4 mmol) i n 50 ml of d r y THF a t -78°C under n i t r o -gen was added an e t h e r s o l u t i o n of m e t h y l l i t h i u m (14.4 mmol) dro p w i s e w i t h s t i r r i n g . The r e a c t i o n m i x t u r e was then warmed t o room temperature and s t i r r i n g was c o n t i n u e d u n t i l a c l e a r , b l o o d - r e d s o l u t i o n of the phosphorane was o b t a i n e d . The s o l u t i o n was r e c o o l e d t o -78°C, a s o l u t i o n o f the aldehyde (113) (2.00 g, 12.3 mmol) i n 5 ml of THF was added and the - 146 -r e a c t i o n m i x t u r e was s u b s e q u e n t l y s t i r r e d a t room temperature f o r 2 h. The r e s u l t i n g m i x t u r e was then d i l u t e d w i t h pentane and f i l t e r e d t hrough a s h o r t column of s i l i c a g e l ( e l u t i o n w i t h p e n t a n e ) . C a r e f u l removal o f the s o l v e n t from the e l u a n t , f o l l o w e d by f l a s h d i s t i l l a t i o n (=:50oC/0.1 mm) of the p r o d u c t i n t o a -78°C t r a p , gave the o l e f i n (112) (1.60 g, 70%) as a c o l o u r l e s s , v o l a t i l e l i q u i d . G l c a n a l y s i s (OV-17, 100°C) i n d i -c a t e d g r e a t e r than 99% p u r i t y ; i r ( f i l m ) : 3010, 2960, 1440, 1385, 1150 c m - 1 ; *H nmr 6: 4.76 (d of s e p t u p l e t s , J = 7.5 Hz, J ' = 1.5 Hz, IH, v i n y l i c p r o t o n ) , 2.12 (m, IH, H J , 1.78 (br s, 3H, v i n y l i c m e t h y l ) , 1.72 (br s, 3H, v i n y l i c m e t h y l ) , 1.70 ( s , 3H, c y c l o p r o p y l m e t h y l ) , 1.46 (d of d, J = 10 Hz, J ' = 6.5 Hz, IH, H b ) , 0.64 (d o f d, J = J 1 = 6.5 Hz, IH, H c ) ; ms m/e 190/188 ( M + ) , 109 (M-Br), 67 (M-Br-C^Hg). P r e p a r a t i o n o f 3 - I o d o - 2 - c y c l o h e x e n - l - o n e (110) 0 To a s u s p e n s i o n o f f r e s h l y c r y s t a l l i z e d t r i p h e n y l p h o s -p h i n e (7.50 g, 29.0 mmol) i n 100 ml o f d r y a c e t o n i t r i l e was added i o d i n e (7.20 g, 29.0 mmol) and the r e s u l t i n g s l u r r y was s t i r r e d a t room temperature under n i t r o g e n f o r 0.5 h. To the r e s u l t i n g y e l l o w s u s p e n s i o n was added t r i e t h y l a m i n e (4.00 m l , 29.0 mmol) and then 1,3-cyclohexanedione (3.15 g, 28.0 mmol). - 147 -T h i s gave a c l e a r r e d s o l u t i o n which was heated t o r e f l u x f o r 20 h. A f t e r the r e a c t i o n m i x t u r e had c o o l e d t o room tempera-t u r e i t was c o n c e n t r a t e d and the r e s u l t i n g brown o i l was t r i t -u r a t e d w i t h e t h e r (4 x 150 m l ) . The s u p e r n a t a n t e t h e r s o l u -t i o n s were combined and the s o l v e n t was removed under reduced p r e s s u r e . T h i s a f f o r d e d a b r o w n i s h o i l which was d i l u t e d w i t h p e n t a n e - e t h e r ( 1 : 1 ) , f i l t e r e d and then passed through a s h o r t column of F l o r i s i l ( e l u t i o n w i t h p e n t a n e - e t h e r ) . Removal o f the s o l v e n t from the e l u a n t , f o l l o w e d by s h o r t - p a t h d i s t i l l a -t i o n ( a i r - b a t h t emperature 75-85°C/0.1 mm) of the r e s i d u a l o i l gave 3 - i o d o - 2 - c y c l o h e x e n - l - o n e (110) (5.20 g, 84%) as a p a l e y e l l o w o i l which c r y s t a l l i z e d on s t a n d i n g a t -15°C, m.p. 15-17°C; i r ( f i l m ) : 1675, 1595 c m - 1 ; lE nmr <5: 6.72 ( t , J = 2 Hz, IH, v i n y l i c p r o t o n ) , 2.8-3.1 (m, 2H, a l l y l i c m e t h y l e n e ) , 1.7-2.5 (m, 4H). T h i s m a t e r i a l was i d e n t i c a l w i t h samples of (110) t h a t were p r e v i o u s l y p r e p a r e d i n t h i s l a b o r a t o r y . P r e p a r a t i o n of the B ~ ( C y c l o p r o p y l ) e n o n e (100) To a s t i r r e d s o l u t i o n o f o l e f i n (112) (1.03 g, 5.4 mmol) i n 50 ml of d r y THF-ether (1:1) was added dro p w i s e a pentane - 148 -s o l u t i o n o f t - b u t y l l i t h i u m (10.8 mmol) a t -78°C under n i t r o g e n . The r e s u l t i n g p a l e y e l l o w s o l u t i o n was s t i r r e d a t -78°C f o r 98 0.5 h and then p h e n y l t h i o c o p p e r (0.93 g, 5.4 mmol) was added v i a a s o l i d a d d i t i o n tube. The r e s u l t i n g s u s p e n s i o n was warmed t o -20°C f o r 0.5 h t o g i v e a dark reddish-brown s o l u -t i o n . To t h i s s o l u t i o n a t -78°C was added a s o l u t i o n o f 3 - i o d o - 2 - c y c l o h e x e n - l - o n e (110) (0.80 g, 3.6 mmol) i n 5 ml o f THF. The r e a c t i o n m i x t u r e was warmed t o -20°C f o r 15 min and then s t i r r e d a t room temperature f o r a f u r t h e r 2 h. The r e a c -t i o n was quenched by the a d d i t i o n of 2 ml o f methanol f o l l o w e d by d i l u t i o n w i t h e t h e r . T h i s gave an o r a n g e - y e l l o w s u s p e n s i o n which was f i l t e r e d t h r ough a s h o r t column o f F l o r i s i l ( e l u t i o n w i t h e t h e r ) . Removal o f the s o l v e n t from the e l u a n t a f f o r d e d 1.09 g o f a y e l l o w o i l . C a r e f u l s h o r t - p a t h d i s t i l l a t i o n ( a i r -bath temperature 110-125°C/0.3 mm) o f t h i s o i l gave the 8 - ( c y c l o p r o p y l ) e n o n e (100) (0.74 g, 100%) as a p a l e y e l l o w o i l . 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) showed a s i n g l e spot and g l c a n a l y s i s (OV-210, 150°C) showed g r e a t e r than 98% p u r i t y ; i r ( f i l m ) : 1660 ( a , 8 - u n s a t u r a t e d k e t o n e ) , 1600 c m - 1 ; JH nmr (270 MHz) 6: 5.92 ( s , IH, H J , 4.92 (br d, J = 10 Hz, IH, H f a), 2.34 ( t , J = 8 Hz, 2H, H ) , 2.18 (m, 2H, H d ) , 1.96 (d of t , J = J ' = 8 Hz, 2H, H e ) , 1.74 ( s , 3H, v i n y l i c m e t h y l ) , 1.68 ( s , 3H, v i n y l i c m e t h y l ) , 1.6-1.8 (m, IH, H f ) , 1.36 (d of d, J = 10 Hz, J ' = 5 Hz, IH ), 1.18 ( s , 3H, c y c l o p r o p y l m e t h y l ) , 0.64 (d o f d, J = J 1 = 5 Hz, IH, H n ) ; ms m/e 204 ( M + ) . - 149 -A n a l , c a l c d . f o r C 1 4 H 2 Q 0 : C 82.30, H 9.87; found: C 82.06, H 9.90. P r e p a r a t i o n o f the Cope Rearrangement P r o d u c t (101) A s o l u t i o n o f B - ( c y c l o p r o p y l ) e n o n e (100) (274 mg, 1.34 mmol) i n 30 ml of d r y , degassed x y l e n e (b.p. 138°C) was heated t o r e f l u x under n i t r o g e n f o r 3 h. A f t e r the s o l u t i o n had been c o o l e d t o room temperature the s o l v e n t was removed under reduced p r e s s u r e t o g i v e 276 mg o f a pale' y e l l o w o i l . 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) showed a s i n g l e s p o t and g l c a n a l y s i s (OV-210, 150°C) i n d i c a t e d g r e a t e r than 99% p u r i t y . C o n s e q u e n t l y t h i s m a t e r i a l was used d i r e c t l y i n the n e x t s t e p . An a n a l y t i c a l sample of (101) was o b t a i n e d by d i s -t i l l a t i o n , a f f o r d i n g a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 87-100°C/0.1 mm; i r ( f i l m ) : 1700 c m - 1 ; *H nmr 6: 5.50 (d of d of d, J = 12 Hz, J ' = 8 Hz, J " = 3 Hz, IH, H J , 5.14 (d of d, J = 12 Hz, J ' = 3 Hz, IH, H b ) , 3.74 (br s, I H , r i n g j u n c t i o n p r o t o n ) , 2.38 (m, I H , H ), 2.74 (m, IH, H ), 2.54-1.90 (com-p l e x m, 6H, H d ) , 1.80 (br s, 3H, v i n y l i c m e t h y l ) , 1.08 ( s , 3H, gem-methyl), 1.02 ( s , 3H, gem-methyl); ms m/e 204 ( M + ) . - 150 -A n a l , c a l c d . f o r C 1 4 H 2 0 O : C 82.30, H 9.87; found: C 82.29, H 9.80. P r e p a r a t i o n o f the M e t h y l a t e d Ketone (126) To a s o l u t i o n o f LDA (1.76 mmol) i n 20 ml o f d r y THF a t -78°C was added a s o l u t i o n of ketone (101) (276 mg, 1.35 mmol) i n 5 ml o f d r y THF. The r e s u l t i n g y e l l o w s o l u t i o n was s t i r r e d f o r 0.5 h a t -78°C and then f o r 0.5 h a t 0°C. A f t e r adding d r y HMPA (2.70 mmol), the r e s u l t i n g orange s o l u t i o n was c o o l e d t o -78°C, iodomethane (5.40 mmol) was added and s t i r r i n g was c o n t i n u e d a t -78°C f o r 0.5 h and then a t room temperature f o r 0.5 h. The r e a c t i o n m i x t u r e was then d i l u t e d w i t h b r i n e and 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 (2x) . The o r g a n i c e x t r a c t s were washed w i t h b r i n e , d r i e d over anhydrous magnesium s u l f a t e and the s o l v e n t s were removed under reduced p r e s s u r e t o g i v e 295 mg of a y e l l o w o i l . D i s t i l l a t i o n gave the mono-methylated ketone (126) (265 mg, 90% from 100) as a p a l e y e l l o w o i l , b.p. ( a i r - b a t h ) 100-108°C/0.1 mm. T i c a n a l y s i s (petroleum e t h e r - e t h e r = 5:1) showed a s i n g l e s p o t and g l c a n a l y s i s (OV-210, 150°C) showed the presence of two components i n a r a t i o o f 92:8. Subsequent a n a l y s i s by glc-mass s p e c t r o m e t r y - 151 -i n d i c a t e d t h a t t h e s e two components were d i a s t e r e o m e r i c (M' m/e 2 1 8 ) ; i r ( f i l m ) : 1700 c m - 1 ; *H nmr 6: 5.48 (d of d o f d, J = 12 Hz, J 1 = 8 Hz, J " = 3 Hz, IH, H ) , 5.14 (d o f d, J = 12 Hz, J * = 3 Hz, I H , H^), 3.84 (br s, IH, r i n g j u n c t i o n p r o t o n ) , 3.5-3.1 (m, IH, H J , 3.0-2.7 (m, IH, H ) , 2.64-1.90 (m, 5H, H d ) , 1.78 (br s, 3H, v i n y l i c m e t h y l ) , 1.09 ( s , 3H, gem-methyl), 1.06 (skewed d, J = 6 Hz, 3H, se c o n d a r y m e t h y l ) , 0.96 ( s , 3H, gem-methyl). A n a l , c a l c d . f o r C 1 5 H 2 2 0 : C 82.52, H 10.16; found: C 82.17, H 10.80. Attempted I s o m e r i z a t i o n of the M e t h y l a t e d Ketone (12 6) To a s o l u t i o n of ketone (126) (12 mg, 0.055 mmol) i n 2 ml of d^-methanol was added a s m a l l amount of sodium methoxide and the r e s u l t i n g y e l l o w s o l u t i o n was r e f l u x e d under n i t r o g e n f o r 30 h. A f t e r h a v i n g been c o o l e d t o room t e m p e r a t u r e , the r e a c t i o n m i x t u r e was t r e a t e d w i t h D 20 and the aqueous m i x t u r e was s u b s e q u e n t l y 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 ( 2 x ) . The combined e x t r a c t s were washed ( b r i n e ) , d r i e d (MgSO^) and the s o l v e n t was e v a p o r a t e d . D i s t i l l a t i o n ( a i r - b a t h temperature 100-110°C/0.1 mm) o f the r e s i d u a l y e l l o w o i l gave 8 mg of 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 (OV-210, 150°C) showed t h a t t h i s - 152 -m a t e r i a l was a m i x t u r e o f two components i n a r a t i o o f 80:20. Subsequent glc-mass s p e c t r o m e t r i c a n a l y s i s i n d i c a t e d t h a t these were d i a s t e r e o m e r s w i t h a p a r e n t mass o f m/e 220. The major component c o r r e s p o n d e d t o the predominant isomer, o f the s t a r t i n g m i x t u r e . The 1H nmr spectrum showed the d i s a p p e a r -ance o f the broad s i n g l e t (6 3.84) a s s i g n e d t o the r i n g j u n c -t i o n p r o t o n and the c o l l a p s e of the d o u b l e t , a s s i g n e d t o the m e t h y l a d j a c e n t t o the k e t o n e , t o a s i n g l e t (6 1.06). The v i n y l i c m e t h y l s i g n a l (6 1.78) remained unchanged. T h i s i n d i -c a t e d t h a t the e x o c y c l i c double bond had n o t m i g r a t e d i n t o c o n j u g a t i o n w i t h the ketone. Moreover, the i r spectrum showed an a b s o r p t i o n a t 1700 cm 1 (6-membered r i n g ketone) and t h e r e was no e v i d e n c e f o r the p r e s e n c e o f an a , 8 - u n s a t u r a t e d ketone. On the b a s i s o f these d a t a the p r o d u c t was i d e n t i f i e d as the d 2 - k e t o n e (140) . P r e p a r a t i o n o f the Hydrogenated Ketone (127) To a s o l u t i o n of the ketone ( 1 2 6 ) (170 mg, 0.78 mmol) i n 30 ml of degassed benzene was added 35 mg of t r i s ( t r i p h e n y l -102 p h o s p h i n e ) r h o d i u m c h l o r i d e ( W i l k i n s o n ' s c a t a l y s t ) and the r e s u l t i n g o r a n g e - r e d s o l u t i o n was s t i r r e d under hydrogen - 153 -(=1 atm) f o r 22 h. The p r o g r e s s of the r e a c t i o n was most e a s i l y m o n i t o r e d by g l c a n a l y s i s (OV-210, 150°C). The r e a c -t i o n m i x t u r e was then d i l u t e d w i t h p e t r o l e u m e t h e r and f i l -t e r e d through a s h o r t column of s i l i c a g e l . E v a p o r a t i o n of the f i l t r a t e gave 188 mg o f a brown o i l . D i s t i l l a t i o n of t h i s m a t e r i a l gave the hydrogenated ketone (127) (163 mg, 95%) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 98-112°C/0.1 mm. The p r o -d u c t showed one sp o t by t i c (petroleum e t h e r - e t h e r = 5:1) and two components (85:15 r a t i o ) by g l c a n a l y s i s (OV-210, 150°C). Subsequent glc-mass s p e c t r o m e t r i c a n a l y s i s i n d i c a t e d t h a t these two components were d i a s t e r e o m e r i c (M + m/e 220); i r ( f i l m ) : 1700 cm-"''; *H nmr 6: 3.42 (br s, IH, r i n g j u n c t i o n p r o t o n ) , 2.90-1.84 (m, 7H), 1.74 (br s, 3H, v i n y l i c m e t h y l ) , 1.52 (m, 4H), 1.05 (d, J = 6 Hz, 3H, secondary m e t h y l ) , 1.00 ( s , 3H, gem-methyl), 0.86 ( s , 3H, gem-methyl). A n a l . c a l c d . f o r C 1 5 H 2 4 0 : C 81.76, H 10.98; found: C 81.67, H 11.00. P r e p a r a t i o n o f the E n o l Phosphate (128) To a s o l u t i o n o f LDA (0.42 mmol) i n 4 ml of d r y THF, a t -78°C under n i t r o g e n , was added d r o p w i s e a s o l u t i o n o f ketone - 154 -(127) (61 mg, 0.28 mmol) i n 2 ml o f d r y THF. The r e a c t i o n m i x t u r e was s t i r r e d a t -78°C f o r 0.5 h and a t 0°C f o r 15 min. The s o l u t i o n was then r e - c o o l e d t o -78°C and TMEDA (1.5 ml) was added, f o l l o w e d by the dropwise a d d i t i o n of d i e t h y l 109 bromophosphate (200 mg, 0.56 mmol). S t i r r i n g was c o n t i n u e d a t -78°C f o r 0.5 h and then f o r 1 h a t room t e m p e r a t u r e . The r e s u l t i n g s l i g h t l y y e l l o w i s h s u s p e n s i o n was poured i n t o b r i n e and e x t r a c t e d w i t h e t h e r (2x) . The combined e t h e r e a l f r a c -t i o n s were washed w i t h b r i n e ( 3 x ) , d r i e d (MgSO^) and the s o l -v e n t s were removed under reduced p r e s s u r e . T h i s gave 115 mg o f a y e l l o w o i l which showed one major low R.^  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 = 2:1) and no c a r b o n y l a b s o r p t i o n i n the i r spectrum. T h i s u n p u r i f i e d m a t e r i a l was used d i r e c t l y i n the n e x t r e a c t i o n . An a n a l y t i c a l sample was o b t a i n e d by p r e p a r a t i v e t i c ( p e n t a n e - e t h y l a c e t a t e = 4:1) f o l l o w e d by d i s t i l l a t i o n . T h i s a f f o r d e d the e n o l phosphate (128) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 155-165°C/0.1 mm. G l c a n a l y s i s (OV-210, 150-200°C) i n d i c a t e d g r e a t e r than 99% p u r i t y ; i r ( f i l m ) : 1450, 1275, 1040, 975 c m - 1 ; XH nmr 6: 4.17 (d of q, J = J ' = 8 Hz, 4H, - P ( O ) ( O C H 2 C H 3 ) 2 ) , 3.39 (br s, IH, r i n g j u n c t i o n p r o t o n ) , — V I I 1.9-2.6 (m, 4H), 1.78 (br s, 3H, 0-C=C-CH 3), 1.70 (br s, 3H, -C=C-CH 3), 1.1-1.6 (m, 6H), 1.34 (d of t , J = 8Hz, J ' = 2 Hz, 6H, - P ( 0 ) ( O C H 2 C H 3 ) 2 ) , 1.06 ( s , 3H, gem-methyl), 0.80 ( s , 3H, gem-methyl); ms m/e 356 ( M + ) . - 155 -A n a l , c a l c d . f o r C" 1 9H 3 3P0 4: C 64 .02, H 9.33; found: C 64.27, H 9.39. P r e p a r a t i o n o f ( ± ) - B-Himachalene (3) To a s o l u t i o n of l i t h i u m m e t a l (9 mg, 1.3 mgatom) i n e t h y l a m i n e (25 m l , d i s t i l l e d from L i ) a t 0°C under n i t r o g e n was added dropwise a s o l u t i o n o f the e n o l phosphate (128) (4 6 mg, 0.13 mmol) and d r y t e r t - b u t y l a l c o h o l (38.5 mg, 0.5 2 mmol) i n 2 ml o f d r y THF. The r e a c t i o n m i x t u r e was s t i r r e d a t 0°C f o r 20 min and then c a u t i o u s l y quenched w i t h w a t e r . The r e s u l t i n g aqueous m i x t u r e was 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 (2x) and the e t h e r e a l e x t r a c t s were washed ( b r i n e ) , d r i e d (MgSO^) and the s o l v e n t s were removed under reduced p r e s s u r e t o g i v e 18 mg o f a p a l e y e l l o w o i l . P r e p a r a t i v e t i c ( p e t r o l e u m e t h e r - e t h e r = 2:1) f o l l o w e d by d i s t i l l a t i o n ( a i r -b a t h temperature 70-80°C/0.1 mm) gave ( ± ) - B - h i m a c h a l e n e (3) (10 mg, 38% from ketone 127) as a c o l o u r l e s s o i l which was i d e n t i c a l ( t i c , g l c , i r , 1U nmr) w i t h an a u t h e n t i c sample of the n a t u r a l p r o d u c t B-himachalene*; i r ( f i l m ) : 2950, 1450, * Samples of the n a t u r a l p r o d u c t were k i n d l y p r o v i d e d by Dr. V. Lukes ( C z e c h o s l o v a k i a ) and Dr. T. N o r i n (Sweden). - 156 -1380, 1360; JH nmr 6: 5.45 (m, IH, v i n y l i c p r o t o n ) , 2.90 (br s, I H , r i n g j u n c t i o n p r o t o n ) , 2.7-1.2 (m, 10H), 1.74 (br s, 6H, v i n y l i c m e t h y l s ) , 0.98 ( s , 3H, gem-methyl), 0. ( s , 3H, gem-methyl). - 157 -125 Preparation of 1 ,4-Pentadien-3-ol OH To a f lame-dried 3-necked f lask f i t t e d with a dropping funne l , a d r y - i c e condenser and a nitrogen i n l e t was added 50 ml of dry THF, magnesium turnings (4.86 g , 0.20 gatom) and a few c r y s t a l s of iod ine . A so lut ion of v i n y l bromide (14.00 ml, 0.20 mol) in 50 ml of dry THF was then added dropwise so as to i n i t i a t e and maintain a gentle r e f l u x . The react ion mixture was subsequently heated to ref lux for a further 0.5 h. This gave a c lear brown so lut ion of v i n y l magnesium bromide. This so lu t ion was then cooled to -15°C and a solut ion of ac ro le in (12.70 ml . 0^19 mol) in 50 ml of dry THF was added dropwise while e f f i c i e n t s t i r r i n g was maintained. The r e s u l t -ing greenish suspension was warmed to 50°C for 1 h and then cooled (0°C) and c a r e f u l l y quenched by the dropwise addit ion of saturated aqueous ammonium c h l o r i d e . The inorganic sa l t s p rec ip i ta ted to a s o l i d mass and the supernatant was decanted in to a mixture of ammonium ch lor ide and i c e . The residue was washed with ether (2 x 100 ml) and the washings were added to the ice-ammonium ch lor ide mixture. The mixture was extracted wel l with ether (3 x) and the extracts were combined and dr ied (Na 0 S0 4 ) . Care fu l removal of the solvents (rotary evaporator) - 158 -f o l l o w e d by f r a c t i o n a l d i s t i l l a t i o n u s i n g a 15 cm V i g r e u x column gave 1 , 4 - p e n t a d i e n - 3 - o l (10.5 g, 66%) as a c o l o u r l e s s , v o l a t i l e l i q u i d , b.p. 116°C ( l i t . 1 2 5 b.p. 115-116°C); i r ( f i l m ) : 3375 ( b r , -OH), 995, 925 c m - 1 ; *H nmr 6: 5.93 (d of d of d, J = 17 Hz, J ' = 11 Hz, J " = 6 Hz, 2H, H 2C=CH), 5.27 H H (d of d o f d, J = 17 Hz, J 1 = J " = 1 Hz, 2H, H/C=C^ ) , 5.16 (d of d of d, J = 11 Hz, J 1 = J " = 1 Hz, 2H, - ^ C = C ^ ) , 4.62 (t of d of d, J = 6 Hz, J ' = J " = 1 Hz, 1 H, -CH(OH)), 2.72 ( s , IH, D 20 ex c h a n g e a b l e , -OH). 123 P r e p a r a t i o n o f (E)-5-Bromo-l,3-pentadiene Br To a s o l u t i o n of 1 , 4 - p e n t a d i e n - 3 - o l (9.07 g, 0.11 mol) i n 50 ml of pentane, c o o l e d t o 0°C under n i t r o g e n , was added 8.8 N HBr* (13.6 m l , 0.12 mol) which had been p r e - c o o l e d t o 0°C. The r e s u l t i n g heterogeneous m i x t u r e was s t i r r e d v i g o r -o u s l y a t room temperature f o r 1 h. The aqueous l a y e r was then s e p a r a t e d and d i s c a r d e d and the o r g a n i c l a y e r was washed w i t h i c e - c o l d water u n t i l n e u t r a l (4 x ) . A f t e r d r y i n g the o r g a n i c l a y e r (MgS0 4) the s o l v e n t was c a r e f u l l y removed ( r o t a r y * C o n s t a n t b o i l i n g HBr (48%) was p u r i f i e d i f c o l o u r e d , by d i s t i l l i n g from S n C l 2 - T h i s gave a c o l o u r l e s s l i q u i d , b.p. 126°C. - 159 -e v a p o r a t o r ) t o g i v e 12.46 g of a p a l e y e l l o w l i q u i d . F l a s h d i s t i l l a t i o n (room temperature/0.1 mm) of t h i s m a t e r i a l i n t o a -78°C t r a p a f f o r d e d (E)-5-bromo-l,3-pentadiene (11.50 g, 72%) as a p a l e y e l l o w l i q u i d which was a p o t e n t l a c h r y m a t o r ; i r ( f i l m ) : 1600, 1200 ( s t r ) , 1000 ( s t r ) , 915 cm" 1; JH nmr 6: 6.50-6.16 (m, 2H, H 2C=C(H)-C(H)=), 6.06-5.70 (m, IH, I =C(H)CH 2Br), 5.44-5.14 (m, 2H, H 2C=C-), 4.03 (skewed d, J = 7 Hz, 2H, - C H 2 B r ) . P r e p a r a t i o n of the Phosphorane (203) 1 '2.8 House was f o l l o w e d . Thus, t o a s u s p e n s i o n of t r i p h e n y l -phosphine (110 g, 0.42 mol) i n 400 ml o f s p e c t r a l grade ben-zene was added e t h y l 2-bromo-propionate (75.7 g, 0.42 mol) and the r e s u l t i n g m i x t u r e was heated to 70-80°C under n i t r o g e n f o r 40 h. E f f i c i e n t s t i r r i n g was m a i n t a i n e d t h r o u g h o u t . The r e s u l t i n g m i x t u r e was c o o l e d t o room temperature and the s o l v e n t was then removed under reduced p r e s s u r e t o g i v e a p a l e y e l l o w gum. T h i s m a t e r i a l was taken up i n water and the r e s u l t i n g s u s p e n s i o n was f i l t e r e d t o g i v e a c o l o u r l e s s , t r a n s l u c e n t s o l u t i o n o f the phosphonium s a l t . To t h i s r a p i d l y s t i r r e d s o l u t i o n was added dropwise a 4 N sodium h y d r o x i d e s o l u t i o n C0 2Et The g e n e r a l p r o c e d u r e r e p o r t e d by I s l e r 129 and l a t e r by - 160 -u n t i l no 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 . The p r e c i p i t a t e was c o l l e c t e d by s u c t i o n f i l t r a t i o n and washed w i t h water u n t i l the f i l t r a t e was n e u t r a l . The r e s u l t i n g m a t e r i a l was d r i e d under vacuum (0.1 mm) t o g i v e the phosphorane (203) (80 g, 53%) as a c a n a r y y e l l o w s o l i d , m.p. 156-159°C. C r y s t a l l i z a t i o n o f a s m a l l sample of t h i s m a t e r i a l from e t h y l a c e t a t e gave ca n a r y y e l l o w c r y s t a l s , m.p. 161-162°C ( l i t . 1 2 9 m.p. 156-157°C); ms m/e 362 ( M + ) , 333 (M-Et), 317 (M-OEt), 289 (M- C 0 2 E t ) . 130 P r e p a r a t i o n o f E t h y l (£)-2-Methyl-2,4-pentadienoate C 0 2 E t To a s o l u t i o n o f phosphorane (203) (40.0 g, 0.11 mol) i n 150 ml o f d i c h l o r o m e t h a n e under n i t r o g e n was added a c r o l e i n (6.2 g, 0.11 m o l ) , dropwise through the top of a r e f l u x con-d e n s e r . An e x o t h e r m i c r e a c t i o n ensued and the r e a c t i o n mix-t u r e was heated t o m a i n t a i n g e n t l e r e f l u x f o r an a d d i t i o n a l 2 h. The r e s u l t i n g s o l u t i o n was c o n c e n t r a t e d and then d i l u t e d w i t h pentane t o p r e c i p i t a t e t r i p h e n y l p h o s p h i n e o x i d e . The m i x t u r e was f i l t e r e d and the r e s i d u e was washed w i t h an a d d i -t i o n a l p o r t i o n of pentane. The s o l v e n t was removed from the combined o r g a n i c s o l u t i o n s t o g i v e a y e l l o w o i l . F l a s h d i s -t i l l a t i o n (= 50°C/0.1 mm) o f t h i s m a t e r i a l i n t o a -78°C t r a p gave e t h y l ( E ) - 2 - m e t h y l - 2 , 4 - p e n t a d i e n o a t e (12.3 g,80%) as a - 161 -c l e a r , c o l o u r l e s s l i q u i d . G l c a n a l y s i s o f t h i s l i q u i d (OV-17, 60°C) showed one p r o d u c t o n l y ; i r ( f i l m ) : 1715 ( e s t e r c a r -b o n y l ) , 1635, 1600 c m - 1 ; *H nmr 6: 7.19 (d o f q, J = 12 Hz, J ' = 2 Hz, IH, HC=CMe), 6.68 (d of d o f d, J = 17 Hz, J ' = 12 Hz, J " = 10 Hz, IH, H 2C=CH), 5.58 (d o f d, J = 17 Hz, J ' = 2 H H Hz, IH, „/C=C^ ) , 5.46 (d of d, J = 10 Hz, J ' = 2 Hz, IH, n • |^C=C^) , 4.24 (q, J = 7 H z , 2 H , -OCH 2CH 3), 1.97 (d, J = 2 Hz, 3H, v i n y l i c m e t h y l ) , 1.32 ( t , J = 7 Hz, 3H, -OCH 2CH 3). E x a c t mass c a l c d . f o r c 8 H i 2 ° 2 : 140.0837; found 140.0841. P r e p a r a t i o n o f (£)-2-Methyl-2,4-pentadien-l-ol OH To a v i g o r o u s l y s t i r r e d s u s p e n s i o n of 95% L i A l H ^ (2.55 g, 0.067 mol) i n 200 ml o f d r y e t h e r a t 0°C under n i t r o g e n , was added dro p w i s e a s o l u t i o n o f anhydrous EtOH (3.90 m l , 0.067 mol) i n 10 ml of e t h e r . A f t e r about 15 min a s o l u t i o n of the e s t e r (204) (12.30 g, 0.089 mol) i n 30 ml of e t h e r was added and s t i r r i n g was c o n t i n u e d a t 0°C f o r 1 h. The r e a c t i o n was then quenched by the a d d i t i o n o f s o l i d sodium s u l f a t e d e c a -h y d r a t e and s t i r r i n g was m a i n t a i n e d u n t i l a w h i t e g r a n u l a r p r e c i p i t a t e formed. The i n s o l u b l e s a l t s were removed by s u c -t i o n f i l t r a t i o n and washed s e v e r a l times w i t h a d d i t i o n a l p o r -t i o n s of e t h e r . The combined e t h e r e a l s o l u t i o n s were - 162 -c o n c e n t r a t e d under reduced p r e s s u r e and the r e s u l t i n g l i q u i d was f l a s h d i s t i l l e d ( = 60°C/0.1 mm) i n t o a -78°C t r a p . T h i s gave the a l c o h o l (205) (8.60 g, 99%) as a c l e a r , c o l o u r l e s s l i q u i d . G l c a n a l y s i s (OV-17, 60°C) showed the presence o f o n l y one component; i r ( f i l m ) : 3300 ( b r , -OH), 1660, 1600 ( s h ) ; 1H nmr 6: 6.63 (d o f d o f d, J = 16 Hz, J ' = J " = 10 I I Hz, IH, H 9C=CH), 6.09 (br d, J = 10 Hz, IH, HC=CMe), 5.08-6.31 (m, 2H, H 2C=), 4.08 ( s , 2H, -CH 2OH), 1.80 ( s , 3H, v i n y l i c m e t h y l ) , 1.68 ( s , IH, D 20 ex c h a n g e a b l e , -OH). E x a c t mass c a l c d . f o r C,H,~0: 98.0731; found: 98.0730. — ^ — b IU 133 P r e p a r a t i o n o f (E_)-5-Bromo-4-methyl-1, 3-pentadiene Br To a m i x t u r e o f t r i p h e n y l p h o s p h i n e (23.6 g, 0.090 mol) i n 100 ml o f d r y a c e t o n i t r i l e a t 0°C under n i t r o g e n , was added bromine (4.6 m l , 0.090 mol) and the r e s u l t i n g s o l u t i o n was s t i r r e d u n t i l t r i p h e n y l p h o s p h i n e d i b r o m i d e p r e c i p i t a t e d as a f l o c c u l e n t w h i t e s o l i d . To t h i s s u s p e n s i o n was added t r i -e t h y l a m i n e (12.5 m l , 0.090 mol) f o l l o w e d by a s o l u t i o n o f the a l c o h o l (205) (8.00 g, 0.081 mol) i n 15 ml o f a c e t o n i t r i l e . The r e s u l t i n g m i x t u r e was s t i r r e d a t room temperature f o r 0.5 h and then f i l t e r e d . The f i l t e r cake was washed w i t h p e t r o l e u m - 163 -e t h e r and the combined o r g a n i c f i l t r a t e s were c o n c e n t r a t e d a t reduced p r e s s u r e . T h i s a f f o r d e d an o i l y m i x t u r e which was s u b s e q u e n t l y 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 and then r e - f i l t e r e d Removal o f the s o l v e n t from the f i l t r a t e f o l l o w e d by f l a s h d i s t i l l a t i o n (= 40°C/0.1 mm) of the r e s i d u a l o i l i n t o a -78°C t r a p gave the bromide (197) (10.0 g, 71%) as a p a l e y e l l o w , v o l a t i l e l i q u i d . G l c a n a l y s i s (OV-17, 60°C) showed the p r e -sence of o n l y one peak; i r ( f i l m ) : 1210, 995, 920 (br) c m - 1 ; 1H nmr (80 MHz) 6: 6.13-6.68 (m, 2H, v i n y l i c p r o t o n s ) , 5.15-5.43 (m, 2H, v i n y l i c p r o t o n s ) , 4.05 ( s , 2H, - C H 2 B r ) , 1.92 ( s , 3H, v i n y l i c m e t h y l ) . '6 9 7 Q E x a c t mass c a l c d . f o r C^ -H- B r : 159.9888; found 159.9899. * , u t 134,135 Preparation of E thy l (2E_,4E)-2-Methyl-2 ,4-hexadienoate C 0 2 E t To a s o l u t i o n o f the phosphorane (203) (10.86 g, 0.03 mol) i n 30 ml of d i c h l o r o m e t h a n e under n i t r o g e n , was added dropwise f r e s h l y d i s t i l l e d c r o t o n a l d e h y d e (2.10 g, 0.03 m o l ) . The r e s u l t i n g s o l u t i o n was heated t o r e f l u x f o r 20 h and then c o o l e d and c o n c e n t r a t e d t o about one h a l f volume. D i l u t i o n w i t h pentane p r e c i p i t a t e d t r i p h e n y l p h o s p h i n e o x i d e which was - 164 -removed by f i l t r a t i o n . The r e s i d u e was washed w i t h pentane and the o r g a n i c s o l u t i o n s were combined. Removal o f the s o l v e n t s under reduced p r e s s u r e f o l l o w e d by f l a s h d i s t i l l a t i o n (40°C/ 0.1 mm) o f the r e s u l t i n g y e l l o w o i l i n t o a -78°C t r a p a f f o r d e d e t h y l ( 2 E , 4 E ) - 2 - m e t h y l - 2 , 4 - h e x a d i e n o a t e (3.94 g, 85%) as a c l e a r , c o l o u r l e s s l i q u i d . G l c a n a l y s i s o f t h i s m a t e r i a l (OV-17, 60°C) showed the presence of o n l y one component; i r ( f i l m ) : 1710 ( e s t e r c a r b o n y l ) , 1640, 1615 c m - 1 ; *H nmr 6: I I 7.21 (br d, J = 10 Hz, IH, HC=C-C0 2Et), 6.40 (d of d, J = 15 Me^ M Hz, J ' = 10 Hz, IH, H^C=C^) , 6.10 (d o f q, J = 15 Hz, J = Me •H 6 Hz, IH, R^C=C^) , 4.22 (q, J = 8 Hz, 2H, -OCH 2CH 3), 1.94 (br s, 3H, E t ) r 1.89 (d, J = 6 Hz, 3H, ^|>>) , 1.31 ( t , J = 8 Hz, 3H, -OCH 2CH 3); ms m/e 154 ( M + ) , 139 (M-CH 3), 109 (M-OEt). 1 3 fi P r e p a r a t i o n of (2E , 4E)-2-Me t h y l - 2 , 4 - h e x a d i e n - l - o l OH To a s u s p e n s i o n o f 95% L i A l H ^ (708 mg, 17.7 mmol) i n 50 ml o f d r y e t h e r , a t 0°C under n i t r o g e n , was added dro p w i s e a s o l u t i o n o f anhydrous e t h a n o l (1.03 m l , 17.7 mmol) i n 10 ml of e t h e r . T h i s m i x t u r e was s t i r r e d v i g o r o u s l y a t 0°C f o r 15 min and then a s o l u t i o n of e s t e r (207) (3.64 g, 23.6 mmol) i n - 165 -10 ml of ether was added. S t i r r i n g was continued f o r 1 h and the r e a c t i o n was then quenched by the a d d i t i o n of s o l i d sodium s u l f a t e decahydrate. The r e s u l t i n g white granular s o l i d was removed by f i l t r a t i o n and washed w e l l with a d d i t i o n a l e t h e r . C o n c e n t r a t i o n of the e t h e r e a l f i l t r a t e , f o l l o w ed by f l a s h d i s -t i l l a t i o n (K 50°C/0.1 mm) of the r e s i d u a l o i l i n t o a -78°C t r a p , gave the a l c o h o l (208) (2.60 g, 98%) as a c l e a r , c o l o u r -l e s s l i q u i d . T i c a n a l y s i s (pentane-ether =4:1) of t h i s m a t e r i a l showed only one spot; i r ( f i l m ) : 3325 (br, -OH); lE nmr (80 MHz) 6: 6.30 (br d of d, J = 15 Hz, J ' = 10 Hz, Me. I /Me IH, H^C=CH), 6.00 (br d, J = 10 Hz, IH, HC=C^ C H ), 5.70 (d ' Me 2 of q, J = 15 Hz, J ' = 7 Hz, IH, H/C=), 4.05 (s, 2H, -CH 2OH), 1.83 (d, J = 7 Hz, 3H, ^ / C = ), 1.80 (s, 3H, < ^ 0 H> , 1-58 (s, IH, D 20 exchangeable, -OH); ms m/e 112 (M +), 97 (M-CH 3), 79 (M-CH 3-H 20). P r e p a r a t i o n of (2E_,4E_)-l-Bromo-2-methyl-2,4-hexadiene To a suspension of t r i p h e n y l p h o s p h i n e (3.51 g, 13.4 mmol) i n 25 ml of dry a c e t o n i t r i l e was added bromine (0.69 ml, 13.4 mmol) at 0°C under n i t r o g e n . The s o l u t i o n was s t i r r e d u n t i l a f i n e white s o l i d p r e c i p i t a t e d . To t h i s mixture was added - 166 -t r iethylamine (1.86 ml , 13.4 mmol) followed by a so lut ion of the a lcoho l (208) (1.50 g , 13.4 mmol) in 5 ml of a c e t o n i t r i l e . The r e s u l t i n g so lu t ion was then s t i r r e d at room temperature for a further hour. The solvents were then removed under reduced pressure and the res idua l mater ia l was suspended in pentane. S o l i d triphenylphosphine oxide was removed by f i l -t ra t ion and washed with an add i t iona l port ion of pentane. The solvent was c a r e f u l l y evaporated from the combined pentane so lut ions to give a yellow l i q u i d . Flash d i s t i l l a t i o n (0.1 mm) of th is mater ia l at room temperature into a -78°C trap gave the bromide (198) (1.67 g , 71%) as a pale yellow l i q u i d which darkened rap id ly even when stored at -20°C in the dark. It was therefore rout ine ly d i s t i l l e d immediately pr ior to being used; i r ( f i lm) : 1445, 1215, 960 c m - 1 ; *H nmr 6: 6.42-5.70 (m, 3H, v i n y l i c protons) , 4.05 (s, 2H, -CH^Br), 1.87 (s, 3H, Me Me^ = C - C H B r ) r 1 , 8 0 ( d ' J = 6 H Z ' 3 H ' ~ H r C = ) * 2 79 Exact mass c a l c d . for CyH-Q Br: 174.0044; found: 1744.0040. 14 2 Preparation of 2 - B u t y n - l - o l Me— OH To about 1 1 of dry ammonia was added L i wire (14.7 g , 2.1 gatom) and a few c r y s t a l s of Fe (NO )^ ^ • 9 ^ 0 and the - 16 7 -r e s u l t i n g mixture was s t i r r e d u n t i l the i n i t i a l blue colour was replaced by the greyish-white colour of l i th ium amide. To th is suspension was added a so lut ion of propargyl a lcohol (56.0 g , 1.0 mol) in 200 ml of dry THF, over about 20 min. The react ion mixture was then s t i r r e d for an addi t ional 40 min. At th is p o i n t , a so lu t ion of iodomethane (142 g, 1.0 mol) in 100 ml of dry THF was added over about 0.5 h and the react ion mixture was s t i r r e d for an add i t iona l 1 h. The react ion was subsequently quenched by the cautious addi t ion of s o l i d ammo-nium ch lor ide and the ammonia was allowed to evaporate over-n ight . The remaining residue was d isso lved in brine and then extracted with ether (2 x ) . The ether extract was washed (water, b r i n e ) , dr ied (MgSO^), and the solvent was c a r e f u l l y removed under reduced pressure to give a yellow l i q u i d . D i s -t i l l a t i o n (55 -56°C/= 25 mm) of th is mater ia l gave 2 - b u t y n - l - o l (21.0 g , 30%) as a c l e a r , co lour less l i q u i d , b.p. 134-138° ( l i t . 1 4 2 b .p . 141-142°C; 1 4 0 - 1 4 2 ° ) ; i r ( f i lm) : 3300 (br, -OH), 2280, 2210 c m " 1 ; 1U nmr (60 MHz) 6: 4.13 (q, J = 2 Hz, 2H, -CH 2 OH), 2.90 (br s , IH, D 20 exchangeable -CH 2OH), 1.80 (t, J = 2 Hz, 3H, methyl) . 141 Preparation of 2-Butynal M e — = — C H O 146 To a suspension of 300 g of barium manganate in 750 ml of dichloromethane was added 2 - b u t y n - l - o l (17.0 g , 24.3 - 168 -mmol) and the r e s u l t i n g s l u r r y was s t i r r e d a t room temperature under n i t r o g e n f o r 65 h. The m i x t u r e was then s u c t i o n f i l t e r e d t h rough a bed of C e l i t e and the f i l t e r cake was washed w i t h d i c h l o r o m e t h a n e . The s o l v e n t s were c a r e f u l l y removed from the f i l t r a t e ( r o t a r y e v a p o r a t o r ) t o g i v e 2 - b u t y n a l (12.4 g, 75%) as a l i g h t y e l l o w l i q u i d . T h i s m a t e r i a l was used w i t h -o ut f u r t h e r p u r i f i c a t i o n i n the n e x t s t e p ; i r ( f i l m ) : 2860, 2300, 2210 ( s t r ) , 1665 (aldehyde C=0) c m - 1 ; JH nmr (60 MHz) 6: 9.03 ( s , IH, -CHO), 2.05 ( s , 3H, m e t h y l ) . P r e p a r a t i o n of E t h y l ( E ) - 2 - M e t h y l h e x - 2 - e n - 4 - y n o a t e To a s o l u t i o n o f phosphorane (203) (65.9 g, 18.2 mmole) i n 250 ml of d i c h l o r o m e t h a n e was added dropwise 2 - b u t y n a l (12.4 g, 18.2 mmol) and the r e s u l t i n g s o l u t i o n was heated t o r e f l u x under n i t r o g e n f o r 4 h. The s o l u t i o n was then con-c e n t r a t e d and 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 i n orde r t o p r e -c i p i t a t e t r i p h e n y l p h o s p h i n e o x i d e . The p r e c i p i t a t e was removed by f i l t r a t i o n and washed w i t h a d d i t i o n a l p e t r o l e u m e t h e r . Removal o f the s o l v e n t s from the f i l t r a t e gave a y e l l o w o i l which was f l a s h d i s t i l l e d (= 50°C/0.1 mm) i n t o a -78°C t r a p t o g i v e the d e s i r e d e s t e r (212) (16.6 g, 60%) as a c l e a r , Me \ Me C 0 2 E t - 169 -c o l o u r l e s s l i q u i d ; i r ( f i l m ) : 2210 ( d i s u b s t i t u t e d a l k y n e ) , 1710 ( e s t e r C=0) , 1615 cm" 1; lE nmr (60 MHz) 6 : 6.48 (m, 1H, v i n y l i c p r o t o n ) , 4.13 (q, J = 8 Hz, -OCH 2CH 3), 2.03 (d, J = 2 Hz, 3H, t e r m i n a l m e t h y l ) , 2.00 ( s , 3H, v i n y l i c m e t h y l ) , 1.23 ( t , J = 8 Hz, 3H, -OCH 2CH 3); ms m/e 152 ( M + ) , 124 (M-C 2H 4), 107 (M-OC 2H 5). E x a c t mass c a l c d . f o r C 9 H i 2 ° 2 : 152.0837; found: 152.0837. 135 P r e p a r a t i o n of E t h y l (2£, 4£)-2-Me t h y l - 2 , 4-hexadienoate C 0 2 E t To 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 of 5% p a l l a d i u m - o n - b a r i u m s u l f a t e (1.0 g) i n 200 ml of p y r i d i n e under a hydrogen atmos-phere, was added the a c e t y l e n i c e s t e r (212) (15.0 g, 0.099 mol) i n about 20 ml o f p y r i d i n e . E f f i c i e n t s t i r r i n g was m a i n t a i n e d w h i l e the hydrogen uptake was m o n i t o r e d . A f t e r one e q u i v a l e n t o f hydrogen had been consumed the r a t e of uptake d e c r e a s e d s h a r p l y . The r e a c t i o n m i x t u r e was then f i l t e r e d through a bed of C e l i t e and d i l u t e d w i t h water (500 m l ) . The aqueous mix-t u r e was e x t r a c t e d w i t h pentane (3 x) and the combined e x t r a c t s were washed ( b r i n e 3 x, 1 N HC1 5 x, b r i n e 3 x) and then d r i e d over sodium s u l f a t e . Removal of the s o l v e n t s on a r o t a r y e v a p o r a t o r gave 13.5 g o f a f r a g r a n t y e l l o w o i l . F l a s h - 170 -d i s t i l l a t i o n (= 50°C/0.1 mm) o f t h i s m a t e r i a l i n t o a -78°C t r a p gave the d e s i r e d e s t e r (213) (12.9 g, 85%) as a c l e a r , c o l o u r l e s s l i q u i d ; i r ( f i l m ) : 1710 ( e s t e r C=0), 1635, 1605, 725 c m - 1 ; XH nmr (80 MHz) 6: 7.56 (d of q, J = 11 Hz, J 1 = 2 Hz, IH, HC=CC0 2Et), 6.36 (d of d o f q, J = J ' = 11 Hz, J " = 2H, IH, MeC=CH), 5.93 (d of q, J = 11 Hz, J ' = 7 Hz, IH, H \ ' -J^C=), 4.25 (q, J = 8 Hz, 2H, -OCH 2CH 3), 1.96 ( s , 3H, =C(Me)CO„Et), 1.89 ( d , J = 7 Hz, 3H, H^C=), 1.34 ( t , J = 8 — 2 Me-^  Hz, 3H, -OCH 2CH 3); ms m/e 154 ( M + ) , 139 (M-CH 3), 111 (M-CH 3-C 2H 4). P r e p a r a t i o n o f (2E , 4Z.) -2-Me t h y l - 2 , 4 - h e x a d i e n - l - o l • A s u s p e n s i o n o f L i ( E t O ) A l H 3 (0.042 mol) i n 250 ml o f d r y e t h e r was p r e f o r m e d , as d e s c r i b e d p r e v i o u s l y , from 95% L i A l H ^ (1.68 g, 0.042 mol) and anhydrous e t h a n o l (2.44 m l , 0.042 mol) a t 0°C under n i t r o g e n . A s o l u t i o n of the e s t e r (213) (8.6 g, 0.056 mol) i n 20 ml of d r y e t h e r was added and s t i r r i n g was c o n t i n u e d a t 0°C f o r 1 h. The r e a c t i o n was then quenched by the a d d i t i o n o f s o l i d sodium s u l f a t e d e c a h y d r a t e and the r e s u l t -i n g w h i t e g r a n u l a r p r e c i p i t a t e was removed by s u c t i o n f i l t r a -t i o n . The f i l t e r cake was washed w i t h a d d i t i o n a l p o r t i o n s of - 171 -e t h e r and the combined e t h e r e a l f i l t r a t e was washed ( b r i n e ) and d r i e d ( N a 2 S 0 ^ ) . Removal o f the s o l v e n t from t h i s s o l u t i o n , f o l l o w e d by f l a s h d i s t i l l a t i o n (= 50°C/0.1 mm) o f the r e s u l t -i n g p a l e y e l l o w o i l , gave the d e s i r e d a l c o h o l (214) (6.3 g, 100%) as a c o l o u r l e s s l i q u i d ; i r ( f i l m ) : 3375 ( b r , -OH), 720 cm 1 ; lH nmr (60 MHz) 6: 5.2-6.4 (m, 3H, v i n y l i c p r o t o n s ) , 4.00 ( s , 2H, -CH 2OH), 2.13 (br s, IH, D 20 e x c h a n g e a b l e , -CH 20H), 1.73 (d, J = 7 Hz, 3H, Me(H)C = ), 1.73 ( s , 3H, =C(Me)CH 2OH). E x a c t mass c a l c d . f o r C 7H^ 20: 112.0888; found: 112.0903. P r e p a r a t i o n of a M i x t u r e of (2E,4E)- and (2E,4Z)-1-Bromo-2- methy1-2,4-hexad i e n e Br ^ B r 199 1 9 8 A s u s p e n s i o n o f t r i p h e n y l p h o s p h i n e d i b r o m i d e i n 35 ml of dr y a c e t o n i t r i l e was p r e p a r e d , as done p r e v i o u s l y , from t r i -p h e n y l p h o s p h i n e (3.00 g, O . O l l m o l ) and bromine (0.59 m l , 0.011 mol) a t 0°C under n i t r o g e n . To t h i s m i x t u r e was added t r i -e t h y l a m i n e (1.59 m l , 0.011 mol) and a s o l u t i o n o f the a l c o h o l (214) (1.25 g, 0.011 mol) i n 5 ml o f a c e t o n i t r i l e . S t i r r i n g was c o n t i n u e d a t room temperature f o r 1 h and the r e s u l t i n g - 172 -s l u r r y was c o n c e n t r a t e d under reduced p r e s s u r e . The r e s i d u a l m a t e r i a l was suspended i n pentane and the i n s o l u b l e m a t e r i a l was removed by f i l t r a t i o n . Removal of the s o l v e n t from the f i l t r a t e , f o l l o w e d by f l a s h d i s t i l l a t i o n (=50°C/0.1 mm) of the r e s i d u a l o i l i n t o a -78°C t r a p , a f f o r d e d a mixture of the bromides (198) and (199) (1.70 g, 87%) as a pale y e l l o w l i q u i d . T h i s m a t e r i a l darkened q u i c k l y on standing at room temperature and was d i s t i l l e d immediately p r i o r to being used; i r ( f i l m ) : 1240, 1105, 725 cm - 1; 1E nmr (60 MHz) 6: 5.2-6.5 (m, 3H, v i n y l i c p r o t o n s ) , 3.97 and 4.02 (1:1 p a i r of s, 2H, -CH 2Br), 1.87 (d, J = 7 Hz, 3H, t e r m i n a l methyl), 1.83 (br s, 3H, =C(Me)CH 2Br). 79 Exact mass c a l c d . f o r C - y H ^ Br: 174 .0044; found: 174.0033. On the b a s i s of the *H nmr d a t a , t h i s m a t e r i a l was i d e n -t i f i e d as a 1:1 mixture of the (2E,4Z)- and (2E,4E)-isomers. T h i s mixture was used as such i n the subsequent r e a c t i o n . P r e p a r a t i o n of the 8-Keto E s t e r s (180) and (215)- (217) General Procedure To a s o l u t i o n of LDA (2.1 equiv) in dry THF at -5°C under n i t r o g e n , was added methyl a c e t o a c e t a t e (1.0 equiv) and the r e s u l t i n g y e l l o w s o l u t i o n was s t i r r e d at 0°C f o r 20 min. To 1 3 ft t h i s s o l u t i o n of the d i a n i o n was added the a p p r o p r i a t e bromide and s t i r r i n g was continued at 0°C f o r 5 min. The - 173 -r e a c t i o n m i x t u r e was then poured i n t o a m i x t u r e o f 1 N HC1 and e t h e r and the aqueous phase was b a c k - e x t r a c t e d w i t h e t h e r . The combined e t h e r e x t r a c t s were washed once w i t h 1 N HC1 and then w i t h b r i n e (3 x ) . D r y i n g of the o r g a n i c phase (MgS0 4 or Na2SC>4) and removal of the s o l v e n t s under reduced p r e s s u r e gave the crude p r o d u c t . T h i s m a t e r i a l was p u r i f i e d by f l a s h c h r o m a t o g r a p h y 1 ^ 5 and/or d i s t i l l a t i o n . P r e p a r a t i o n o f g-Keto E s t e r (180) As d e s c r i b e d i n the g e n e r a l p r o c e d u r e , m e t h y l a c e t o a c e -t a t e (539 u l , 5.0 mmol) was added t o a s o l u t i o n of LDA (10.5 mmol) i n 25 ml o f d r y THF. A l k y l a t i o n of the r e s u l t i n g d i a n i o n w i t h ( E)-5-bromo-l,3-pentadiene (179) (735 mg, 5.0 mmol) f o l -lowed by r o u t i n e aqueous work-up gave the crude g-keto e s t e r (18 0 ) . D i s t i l l a t i o n of t h i s m a t e r i a l gave pure (180) (766 mg, 8 4 % ) , b.p. ( a i r - b a t h ) 81-85°C/0.1 mm. G l c a n a l y s i s (OV-17, 100°C) of t h i s c o l o u r l e s s o i l showed o n l y one peak and 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 = 4:1) showed a s i n g l e s p o t ; i r ( f i l m ) : 1755 ( e s t e r ) , 1715 ( k e t o n e ) , 1650, 1630, 1600 cm" 1; XH nmr <S: 5.9-6.6 (m, 2H, v i n y l i c p r o t o n s ) , 5.52-5.80 (m, IH, v i n y l i c p r o t o n ) , 4.92-5.20 (m, 2H, v i n y l i c p r o t o n s ) , 3.74 - 174 -( s , 3H, -OCH3) , 3.46 ( s , 2H, -CR~2C02Me) , 2.28-2.74 (m, 4H, — C H 2 C H 2 _ ) • E x a c t mass c a l c d . f o r c i o H 1 4 ° 3 : 182.0943; found: 182.0948. P r e p a r a t i o n o f g-Keto E s t e r (215) F o l l o w i n g the g e n e r a l p r o c e d u r e , the d i a n i o n of meth y l a c e t o a c e t a t e was g e n e r a t e d u s i n g LDA (13.8 mmol) and meth y l a c e t o a c e t a t e (712 y l , 6.6 mmol) i n 35 ml o f d r y THF. The d i a n i o n was a l k y l a t e d w i t h bromide (197) (1.06 g, 6.6 mmol) and the r e a c t i o n m i x t u r e was worked up as d e s c r i b e d p r e v i o u s l y . F l a s h chromatography (pe t r o l e u m e t h e r - e t h e r = 4:1) f o l l o w e d by d i s t i l l a t i o n o f the crude p r o d u c t gave the 8-keto e s t e r (215) (920 mg , 71%) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 88-92°C/0.1 mm. 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 peak by g l c a n a l y s i s (OV-17, 100°C) and a s i n g l e spot by 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 = 4:1); i r ( f i l m ) : 1750 ( e s t e r ) , 1720 ( k e t o n e ) , 1655 (w); XH nmr 6: 6.57 (d of d o f d, J = 17 Hz, I J ' = J " = 10 Hz, I H , H 2C=CH), 5.86 (br d, J = 10 Hz, IH, I I I HC=CMe), 4.90-5.22 (m, 2H, H 2C=C-), 3.75 ( s , 3H, -OCH 3), 3.47 ( s , 2H, -CH 2C0 2Me), 2.62-2.80 (m, 2H, =C-CH 2-), 2.34 (skewed t , J = 8 Hz, 2H, -CH 9-C^°), 1.78 ( s , 3H, v i n y l i c m e t h y l ) . - 175 -E x a c t mass c a l c d . f o r c n H i 6 ° 3 : 196.1099; found: 196.1102. P r e p a r a t i o n o f the g-Keto E s t e r (216) 0 0 OMe The d i a n i o n of m e t h y l a c e t o a c e t a t e was g e n e r a t e d i n the u s u a l manner by the a d d i t i o n of m e t h y l a c e t o a c e t a t e (2.46 m l , 22.8 mmol) t o a s o l u t i o n o f LDA (47.0 mmol) i n 75 ml o f d r y THF, a t 0°C under n i t r o g e n . A l k y l a t i o n of the d i a n i o n w i t h bromide (198) (4.00 g, 22.8 mmol), f o l l o w e d by the p r e s c r i b e d work-up, gave the c r u d e p r o d u c t as a y e l l o w o i l . P u r i f i c a t i o n o f t h i s m a t e r i a l by f l a s h chromatography (pentane-ether = 3:1), f o l l o w e d by d i s t i l l a t i o n , a f f o r d e d the g-keto e s t e r (216) (2.87 g, 60%) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 103-108°C/ 0.1 mm. 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 s p o t by t i c a n a l y s i s ( p e n t a n e - e t h e r = 3:1) and one peak by g l c a n a l y s i s (OV-17, 100°C); i r ( f i l m ) : 1750, 1720, 1650, 1630 cm" 1; *H nmr (80 I MHz) 6: 6.25 (d of d, J = 15 Hz, J 1 = 10 Hz, IH, Me(H)C=CH), I I 5.80 (d, J = 10 Hz, I H , HC=CCH 2-), 5.58 (d o f q, J = 15 Hz, J ' = 6 Hz, IH, Me(H)C=CH), 3.75 ( s , 3H, -C0 2Me), 3.48 ( s , 2H, -CH 2C0 2Me), 2.20-2.80 (m, 4H, -CH 2CH 2-), 1.76 (d, J = 6 Hz, 3H, Me(H)C = ), 1.73 ( s , 3H, =C(Me)CH 2~). E x a c t mass c a l c d . f o r C 1 2 H 1 8 0 3 : 210.1256; found: 210.1256. - 176 -P r e p a r a t i o n o f a M i x t u r e o f the B-Keto E s t e r s (216) and (217) 0 0 o o OMe + - ^ ^ ^ ^ " ^ — ^ O M e F o l l o w i n g the g e n e r a l p r o c e d u r e , m e t h y l a c e t o a c e t a t e (2.75 m l , 25.5 mmol) was added t o a s o l u t i o n o f LDA (53.6 mmol) i n 100 ml o f d r y THF a t 0°C under n i t r o g e n . A l k y l a t i o n of t h i s m i x t u r e w i t h the bromides (198) and (199) (4.90 g, 28.0 mmol) f o l l o w e d by s t a n d a r d work-up of the r e a c t i o n mix-t u r e a f f o r d e d a y e l l o w o i l . P u r i f i c a t i o n o f t h i s m a t e r i a l by f l a s h chromatography (pe t r o l e u m e t h e r - e t h e r = 4:1), f o l l o w e d by d i s t i l l a t i o n , gave a m i x t u r e o f the B - k e t o e s t e r s (216) and (217) (1.52 g, 28 % ) * as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 120-130°C/0.1 mm. T h i s m a t e r i a l was pure by t i c (pentane-e t h e r = 4:1) and g l c a n a l y s i s (OV-17, 100°C); i r ( f i l m ) : 1750, 1720, 720 c m - 1 ; 1E nmr <5: 5.36-6.45 (m, 3H, v i n y l i c p r o t o n s ) , 3.75 ( s , 3H, -C0 2Me), 3.46 and 3.48 (1:1 p a i r o f s, 2H, -CH 2C0 2Me), 2.56-2.82 (m, 2H), 2.24-2.54 (m, 2H), 1.75 (d, J = 6 Hz, 3H, t e r m i n a l m e t h y l ) , 1.74 ( s , 3H, =C(Me)CH 2~). E x a c t mass c a l c d . f o r c i 2 H 1 8 ° 3 : 210.1256; found: 210.1261. The reason f o r t h i s low y i e l d remains u n c l e a r , however, n o a t t e m p t was made t o o p t i m i z e the y i e l d . - 177 -On the b a s i s o f the 1E nmr d a t a , t h i s m a t e r i a l was i d e n -t i f i e d as a 1:1 m i x t u r e of the (E,£)- and ( E , E ) - i s o m e r s . T h i s m i x t u r e was used as such i n the subsequent r e a c t i o n . P r e p a r a t i o n o f the D i a z o E s t e r s (181) and (218)-(220) G e n e r a l P r o c e d u r e To a s o l u t i o n of the a p p r o p r i a t e B - k e t o e s t e r (1.0 e q u i v ) and p - t o l u e n e s u l f o n y l a z i d e * (1.0 e q u i v ) i n a c e t o n i t r i l e was added t r i e t h y l a m i n e (1.0 e q u i v ) and the r e s u l t i n g s o l u t i o n was s t i r r e d a t room temperature under n i t r o g e n f o r 16-24 h. The r e a c t i o n s c o u l d be c o n v e n i e n t l y m o n i t o r e d by t i c (pentane-e t h e r = 4:1). The a c e t o n i t r i l e was then removed under reduced p r e s s u r e and the r e s i d u a l m a t e r i a l was d i s s o l v e d i n a minimum amount of e t h e r . D i l u t i o n w i t h pentane p r e c i p i t a t e d p-toluene-s u l f onamide and any e x c e s s a z i d e . F i l t r a t i o n of the pentane s o l u t i o n f o l l o w e d by removal o f the s o l v e n t gave a y e l l o w o i l . T h i s o i l was d i s s o l v e d i n pentane and r e - f i l t e r e d t o remove any r e s i d u a l i n s o l u b l e m a t e r i a l . The a - d i a z o compounds were thus o b t a i n e d e s s e n t i a l l y pure ( s i n g l e spot by t i c ; pentane-e t h e r = 4:1) and were used w i t h o u t f u r t h e r p u r i f i c a t i o n i n the n e x t s t e p . 168 P r e p a r e d by the method of D o e r i n g and DePuy from p - t o l u e n e s u l f o n y l c h l o r i d e and sodium a z i d e i n e t h a n o l -P water - 178 -P r e p a r a t i o n of the Diazo E s t e r (181) N 2 As d e s c r i b e d i n the g e n e r a l procedure, a mixture of the 6-keto e s t e r (180) (3.03 g, 0.0166 mol), p - t o l u e n e s u l f o n y l azide (3.27 g, 0.0166 mol) and t r i e t h y l a m i n e (2.31 ml, 0.0166 mol) i n 50 ml of a c e t o n i t r i l e was s t i r r e d at room temperature, under n i t r o g e n , f o r 20 h. The a-diazo e s t e r (181) (3.42 g, 99%) was obtained ( a f t e r the p r e s c r i b e d work-up) as a yellow o i l which e x h i b i t e d a s i n g l e peak by g l c a n a l y s i s (OV-17, 100°C) and a s i n g l e spot by t i c (pentane-ether = 4:1). T h i s m a t e r i a l was used d i r e c t l y i n the next step; i r ( f i l m ) : 2125 ( d i a z o ) , 1720, 1655 cm" 1; XH nmr 6: 6.00-6.52 (m, 2H, v i n y l i c p r o t o n s ) , 5.74 (ove r l a p p i n g d of t , J = 14 Hz, J " = 7 Hz, IH, =C(H)CH 2-), 4.96-5.20 (m, 2H, v i n y l i c p r o t o n s ) , 3.86 (s, 3H, -OMe), 2.98 ( t , J = 7 Hz, 2H, - C H 2 C ( 0 ) - ) f 2.44 (ove r l a p p i n g d of t , J = J ' = 7 Hz, 2H, =C-CH 2-). P r e p a r a t i o n of Diazo E s t e r (218) 0 0 A mixture of the g-keto e s t e r (215) (3.315 g, 0.017 mol), p - t o l u e n e s u l f o n y l azide (3.329 g, 0.017 mol) and t r i e t h y l a m i n e - 179 -(2.35 m l , 0.017 mol) i n 75 ml o f a c e t o n i t r i l e was s t i r r e d under n i t r o g e n f o r 21 h. The p r e s c r i b e d work-up a f f o r d e d the a - d i a z o compound (218) (3.792 g, 100%) as a y e l l o w 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 s p o t by t i c a n a l y s i s (petroleum e t h e r - e t h e r = 4:1) and was used d i r e c t l y i n the n e x t r e a c t i o n ; i r ( f i l m ) : 2125 ( d i a z o ) , 1720, 1665 ( s t r ) c m - 1 ; *H nmr (60 MHz) 6: 6.47 (d of d o f d, J = 17 Hz, J ' = J " = 10 Hz, IH, H 2C=CH), 5.78 (br d, J = 10 Hz, IH, HC=CMe), 4.8-5.2 (m, 2H, v i n y l i c p r o -1 I t o n s ) , 3.80 ( s , 3H, -0CH 3), 2.7-3.1 (m, 2H, =C-CH 2"), 2.1-2.6 (m, 2H, -EjC-Cf-0) , 1.77 ( s , 3H, v i n y l i c m e t h y l ) . P r e p a r a t i o n o f D i a z o E s t e r (219) A m i x t u r e of the g-keto e s t e r (216) (530 mg, 2.52 mmol), p - t o l u e n e s u l f o n y l a z i d e (496 mg, 2.52 mmol) and t r i e t h y l a m i n e (351 y l , 2.52 mmol) i n 25 ml of a c e t o n i t r i l e was s t i r r e d a t room temperature under n i t r o g e n f o r 24 h. The r e a c t i o n m i x t u r e was worked up as d e s c r i b e d p r e v i o u s l y t o a f f o r d the a - d i a z o e s t e r (219) (595 mg, 100%) as a y e l l o w 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 s p o t by t i c a n a l y s i s (petroleum e t h e r - e t h e r = 3:1) and was used d i r e c t l y i n the n e x t s t e p ; i r ( f i l m ) : 2125 ( d i a z o ) , 1720, 1655 c m - 1 ; XH nmr (60 MHz) 6: 5.2-6.4 (m, 0 0 - 18 0 -3H, v i n y l i c p r o t o n s ) , 3.80 ( s , 3H, -C0 2Me), 2.1-3.1 (m, 4H, -CH0CH--) , 1.73 (br s, 6H, v i n y l i c m e t h y l s ) . P r e p a r a t i o n of a M i x t u r e o f the D i a z o E s t e r s (219) and (220) 0 0 OMe + OMe A 1:1 m i x t u r e o f the B-keto e s t e r s (216) and (217) (1.439 g, 6.85 mmol), p - t o l u e n e s u l f o n y l a z i d e (1.35 g, 6.85 mmol) and t r i e t h y l a m i n e (953 u l , 6.85 mmol) i n 50 ml of a c e t o n i t r i l e was s t i r r e d a t room temperature under n i t r o g e n f o r 16 h. Stan d a r d work-up o f the r e a c t i o n m i x t u r e a f f o r d e d a m i x t u r e of the d i a z o e s t e r s (219) and (220) (1.622 g, 100%) as a y e l -low 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 s p o t by t i c a n a l y s i s ( p etroleum e t h e r - e t h y l a c e t a t e = 9:1) and was used d i r e c t l y i n the n e x t r e a c t i o n ; i r ( f i l m ) : 2125 ( d i a z o ) , 1720, 1655, 720 c m - 1 ; 1E nmr (60 MHz) 6: 5.1-6.3 (m, 3H, v i n y l i c p r o t o n s ) , 3.80 ( s , 3H, -C0 2Me), 2.77-3.13 (m, 2H, m e t h y l e n e ) , 2.13-2.63 (m, 2H, m e t h y l e n e ) , 1.75 ( s , 3H, =C(Me)CH 2~), 1.68 ( d , J = 6 Hz, 3H, t e r m i n a l m e t h y l ) . - 181 -P r e p a r a t i o n o f the R e q u i r e d B i c y c l o (~3 .1. 0~| hexanones G e n e r a l Procedure To a r e f l u x i n g m i x t u r e o f c a t a l y s t (CuSO^, Cu-bronze or C u ( a c a c ) 2 . H 2 0 * ) i n t o l u e n e was added, dro p w i s e over about 0.5 h, a s o l u t i o n o f the a - d i a z o e s t e r i n t o l u e n e . The r e a c t i o n m i x t u r e was r e f l u x e d under n i t r o g e n f o r an a d d i t i o n a l 2-3 h. The c o u r s e of the r e a c t i o n was c o n v e n i e n t l y f o l l o w e d by t i c (pentane-ether = 3:1). A f t e r the r e a c t i o n was c o m p l e t e , the c o o l e d m i x t u r e was f i l t e r e d t hrough a bed o f C e l i t e and the f i l t e r bed was washed w i t h e t h e r . Removal o f the s o l v e n t s from the f i l t r a t e gave a y e l l o w o i l . T h i s m a t e r i a l was p u r i -f i e d by f l a s h chromatography, f o l l o w e d by d i s t i l l a t i o n , t o a f f o r d the d e s i r e d p r o d u c t as a c o l o u r l e s s o i l . P r e p a r a t i o n of the B i c y c l o [3 .1. CT] hexanone (178 ) 0 C0 2 Me A. As d e s c r i b e d i n the g e n e r a l p r o c e d u r e , a s o l u t i o n o f the a - d i a z o e s t e r (181) (1.345 g, 0.0647 mol) i n 10 ml o f t o l u e n e was added t o a s u s p e n s i o n o f anhydrous copper ( I I ) T h i s compound was p r e p a r e d as done p r e v i o u s l y 1 6 9 from Cu(OAc) 2.H 2° and 2,4-pentanedione i n w a t e r . - 18 2 -s u l f a t e (130 mg) i n 90 ml of r e f l u x i n g t o l u e n e . R e f l u x i n g was c o n t i n u e d f o r an a d d i t i o n a l 3 h. P r e s c r i b e d work-up of the r e a c t i o n m i x t u r e , f o l l o w e d by f l a s h chromatography (petroleum e t h e r - e t h y l a c e t a t e = 4:1) and then d i s t i l l a t i o n of the r e s i d -u a l o i l , a f f o r d e d the b i c y c l o [ 3 . 1 . t f ] h e x a n o n e (178) (528 mg, 45%) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 100-110°C/0.1 mm. G l c a n a l y s i s (OV-17, 100°C) o f t h i s m a t e r i a l showed o n l y one peak; i r ( f i l m ) : 1730 ( b r ) , 1635 c m - 1 ; XH nmr 6: 5.12-5.86 (m, 3H, v i n y l i c p r o t o n s ) , 3.78 ( s , 3H, -OMe), 2.64-2.77 (m, IH, r i n g j u n c t i o n p r o t o n ) , 2.0-2.4 (m, 5H). E x a c t mass c a l c d . f o r C 1 Q H 1 2 0 3 : 180.0787; found: 180 .0787. B. S i m i l a r l y , a s o l u t i o n o f (181) (1.019 g, 0.049 mol) i n 5 ml o f t o l u e n e was added t o a s u s p e n s i o n of Cu-bronze (100 mg) i n 75 ml o f r e f l u x i n g t o l u e n e and r e f l u x i n g was c o n t i n u e d f o r 3 h. S t a n d a r d work-up o f the r e a c t i o n m i x t u r e , f o l l o w e d by p u r i f i c a t i o n as d e s c r i b e d above, a f f o r d e d the b i c y c l i c ketone (178) (527 mg, 60%) as a 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 was i d e n t i c a l ( t i c , g l c , i r , 1U nmr) w i t h the p r e v i o u s l y p r e -pared sample o f (178). C. In the same manner, a s o l u t i o n o f (181) (1.009 g, 0.0485 mol) i n 5 ml o f t o l u e n e was added t o a r e f l u x i n g s o l u t i o n o f C u ( a c a c ) 2 . H 2 0 (64 mg, 0.05 e q u i v ) i n 75 ml of t o l u e n e . The r e a c t i o n was a l l o w e d t o proceed f o r 3 h. R o u t i n e work-up and p u r i f i c a t i o n gave the b i c y c l i c ketone (178) (557 mg, 64%) as - 18 3 -a c o l o u r l e s s o i l which was i d e n t i c a l ( t i c , g l c , i r , *H nmr) with p r e v i o u s l y prepared samples of (178). P r e p a r a t i o n of the Methylated B i c y c l o [3 . l . ( f j hexanone (185) C 0 2 M e To a s o l u t i o n of LDA (1.04 mmol) i n 10 ml of dry THF, at -78°C under n i t r o g e n , was added a s o l u t i o n of the b i c y c l i c ketone (178) (156 mg, 0.87 mmol) i n 2 ml of THF. The s o l u t i o n was s t i r r e d at -78°C f o r 0.5 h and then a mixture of iodomethane (108 u l , 1.74 mmol) and HMPA (302 y l , 1.74 mmol) was added. The r e a c t i o n mixture was allowed to warm s l o w l y to ambient temperature and then s t i r r e d f o r an a d d i t i o n a l 1 h. The mix-ture was then poured i n t o b r i n e and e x t r a c t e d with pentane (3 x ) . The o r g a n i c e x t r a c t s were washed (brine) and d r i e d (MgSO^) and the s o l v e n t was evaporated to give a yellow o i l . D i s t i l l a t i o n of t h i s m a t e r i a l a f f o r d e d the methylated ketone (18 5) (121 mg, 72%) as a c o l o u r l e s s o i l , b.p. (air - b a t h ) 110-115°C/0.1 mm. T i c a n a l y s i s (pentane-ether = 3:1) and g l c a n a l y s i s (OV-17, 100°C) both i n d i c a t e d the presence of a s i n g l e product; i r ( f i l m ) : 1750, 1725, 1640 cm - 1; *H nmr (80 MHz) 6: 5.08-5.85 (m, 3H, v i n y l i c p r o t o n s ) , 3.80 (s, 3H, -C0 2Me), 1.68-2.60 (m, 5H), 1.10 (d, J = 6 Hz, 3H, methyl). Exact mass c a l c d . f o r c 1 1 H i 4 ° 3 : 194.0943; found: 194.0946. - 18 4 -Preparation of the B i c y c l o [3 . 1. C[]hexanone (188) A so lu t ion of the diazo compound (218) (3.752 g , 0.017 mol) in 50 ml of toluene was added to a so lut ion of Cu (acac ) 2 ,H 2 0 (221 rag, 0.05 equiv) in 350 ml of re f lux ing toluene over 1 h. Heating was continued for an add i t iona l 2 h. Standard work-up gave a crude yellow o i l . Flash chroma-tography (petroleum e ther -e thy l acetate = 4:1) and then d i s -t i l l a t i o n of th is mater ia l gave the b i c y c l i c ketone (188) (1.873 g , 57%) as a co lour less o i l , b .p . (air-bath) 8 3 - 8 8 ° C / 0.1 mm. The o i l s o l i d i f i e d on standing at -15°C to give co lour less c r y s t a l s , m.p. 38 -40°C; i r ( f i lm) : 1750, 1720, 1635 c m " 1 ; *H nmr 6: 5.91 (d of d of d , J = 17 Hz, J ' = J " = 10 Hz, IH, HC=CH2) , 5.32 (d of d , J = 17 Hz, J ' = 2 Hz, IH, H H H H ^C=CCE) , 5.24 (d of d , J = 10 Hz, J 1 = 2 Hz , IH, J^C=cC~) > 3.78 (s, 3H, -OCH 3 ) , 1.94-2.40 (m, 5H), 1.48 (s, 3H, r ing junct ion methyl) . Exact mass c a l c d . for c u H i 4 ° 3 : 194 .0943; found: 194.0949. - 185 -Preparation of the Bicyclo|"3 .1.0*1 hexanone (191) A mixture of the diazo compound (219) (595 mg, 2.52 mmol) and Cu-bronze (200 mg) in 25 ml of toluene was heated to ref lux under nitrogen for 2.5 h. Standard work-up of the react ion mixture gave 606 mg of a dark yellow o i l . P u r i f i c a t i o n by preparat ive t i c (pentane-ether = 3:1), followed by d i s t i l l a t i o n of the r e s u l t i n g mater ia l , afforded the b i c y c l i c ketone (191) (259 mg, 50%) as a co lour less o i l , b .p . 1 0 5 - 1 1 2 ° C / 0 . 1 mm. This mater ia l s o l i d i f i e d on standing to give co lour less c r y s -t a l s , m.p. 7 5 - 7 7 ° C . R e c r y s t a l l i z a t i o n of a port ion of th is mater ia l from pentane gave co lour less c r y s t a l s , m.p. 8 4 - 8 6 ° C . Glc ana lys is (OV-17, 100°C) showed a s ingle peak and t i c ana lys is (pentane-ether = 3:1) showed one spot only; i r (CHCl^): 1720 (br) , 970 ( t rans-o le f in ) c m - 1 ; JH nmr (80 MHz) 6: 5.3-6.1 (m, 2H, v i n y l i c protons) , 3.79 (s, 3H, -C0 2 Me), 1.9-2.6 (m, 5H), 1.75 (d, J = 5 Hz, 3H, v i n y l i c methyl) , 1.48 (s, 3H, t e r t i a ry -methy l ) . Exact mass c a l c d . for c i 2 H 1 6 ° 3 : 208.1100; found: 208 .1105 - 186 -P r e p a r a t i o n of a Mixture of the B i c y c l o P . 1.0~| hexanones (191) and (192) A s o l u t i o n of the mixture of the d i a z o compounds (219) and (220) (1.622 g, 6.87 mmol) in 30 ml of toluene was added to a r e f l u x i n g s o l u t i o n of Cu (acac) 2 ' H 2 ° ^ 9 0 m < 3 ' 0 , 0 5 equiv) i n 100 ml of toluene over 45 min. The s o l u t i o n was r e f l u x e d for an a d d i t i o n a l 1.5 h and then worked up i n the u s u a l manner. This gave 1.25 g of a v i s c o u s yellow o i l . P u r i f i c a t i o n of t h i s m a t e r i a l by f l a s h chromatography (petroleum e t h e r - e t h y l acetate = 5:1), followed by d i s t i l l a t i o n , a f f o r d e d a mixture of the ketones (191) and (192) (655 mg, 46%) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 110-115°C/0.1 mm. T h i s m a t e r i a l showed a s i n g l e spot by t i c a n a l y s i s (pentane-ethy1 acetate = 5:1) and a s i n g l e peak by g l c a n a l y s i s (OV-17, 100°C). C r y s t a l l i z a t i o n of a p o r t i o n of t h i s m a t e r i a l from pentane (-15°C) gave c o l o u r -l e s s c r y s t a l s , m.p. 40.5-41.5°C; i r ( f i l m ) : 1720 (br),740 cm - 1; *H nmr 6: 5.34-5.92 (m, 2H, v i n y l i c p r o t o n s ) , 3.77 and 3.79 (1:1 p a i r of s, 3H, -C0 2Me), 2.04-2.52 (m, 5H), 1.68-1.78 (m, 3H, v i n y l i c methyl), 1.46 (s, 3H, r i n g j u n c t i o n methyl) . - 18 7 -Exact mass c a l c d . f o r c i 2 H l 6 ° 3 : 208.1100; found: 208.1103. I On the b a s i s of the H nmr data t h i s m a t e r i a l was id e n -t i f i e d as a 1:1 mixture of the (E)- and (Z)-isomers. The mixture was c a r r i e d through to the next r e a c t i o n . P r e p a r a t i o n of the Required S i l y l Enol E thers  General Procedure To a s o l u t i o n of LDA (1:1 equiv) i n dry THF a t -78°C under n i t r o g e n was added a s o l u t i o n of the parent ketone (1.0 equiv) i n THF. The r e s u l t i n g pale yellow s o l u t i o n of the enol a t e anion was s t i r r e d at -78°C f o r 0.5 h. To t h i s s o l u -t i o n was added, as a s o l i d , f r e s h l y sublimed 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 (1.5 equiv) f o l l o w e d by HMPA (2.0 e q u i v ) . The r e a c t i o n mixture was s t i r r e d a t -78°C f o r 0.5 h and then at room temperature f o r 1.0 h. The s o l v e n t s were then removed under reduced pressure and the r e s i d u a l m a t e r i a l was t r i t u r a t e d with pentane. The combined pentane e x t r a c t s were washed with a s m a l l amount of b r i n e to remove any remaining HMPA and then passed through a s h o r t column of f l o r i s i l ( e l u t e d with pentane-ether = 2:1). Removal of the s o l v e n t s from the e l u a n t gave the s i l y l e n o l e t h e r s as e s s e n t i a l l y pure o i l s ( s i n g l e spot by t i c ; pentane-ether = 2:1). These c o u l d be p u r i f i e d f u r t h e r by d i s -t i l l a t i o n but were more c o n v e n i e n t l y used d i r e c t l y i n the next ste p . - 188 -Preparation of the S i l y l Enol Ether (182) C 0 2 M e To a so lu t ion of LDA (1.87 mmol), in 20 ml of dry THF at -78°C under n i t rogen , was added a so lut ion of the ketone (178) (300 mg, 1.70 mmol) in 2 ml of THF and the resu l t ing yellow so lu t ion was s t i r r e d at -78°C for 0.5 h. To th is reac-t ion mixture was added t e r t - b u t y l d i m e t h y l s i l y l ch lor ide (385 mg, 2.55 mmol) and HMPA (3.4 mmol) and s t i r r i n g was continued at -78°C for 0.5 h and then at room temperature for 1 h. F o l -lowing the prescr ibed work-up procedure, the react ion mixture y ie lded a yellow o i l . Carefu l d i s t i l l a t i o n of th is mater ia l afforded the s i l y l enol ether (182) (476 mg, 97%) as a co lour -less o i l , b .p . (air-bath) 1 1 5 - 1 2 0 ° C / 0 . 1 mm. T ic analys is (pentane-ether = 2:1) showed a s ingle spot . Glc ana lys is (OV-17, 100°C) showed one major component as wel l as a minor component (- 12%) which was shown (vide infra) to be due to rearrangement of the product on the column; i r ( f i lm) : 1720, 1630, 860, 840, 780 c m - 1 ; XH nmr 6: 5.88 (d of d of d , J = I 17 Hz, J ' = J " = 10 Hz, IH, HC=CH 2), 5.12 (d of d , J = 17 Hz, J 1 = 2.5 Hz, IH, H ^C=C^-) , 4.99 (d of d , J = 10 Hz, J ' = 2.5 \ ^H Hz, IH, „ > > r „) , 4.33 (d of d , J = 4.5 Hz, J = 2.5 Hz, IH, n n HC=C-OSiR 3) , 3.64 (s, 3H, -C0 2 Me), 2.55 (d of d of d , J = 17 - 189 -Hz, J 1 = 6.5 Hz, J " = 2.5 Hz, I H , methylene p r o t o n ) , 2.05-2.26 (m, 2H), 1.72 (d of d, J = 10 Hz, J ' = 6 Hz, endo c y c l o -p r o p y l p r o t o n ) , 0.88 (s, 9H, t - b u t y l ) , 0.08 (s, 6H, s i l y l m e t h y l s ) . Exact mass c a l c d . f o r c i 6 H 2 6 S i ° 3 : 294.1652; found: 294.1657. P r e p a r a t i o n of the S i l y l E n o l Ether (18 6) C 0 2 Me F o l l o w i n g the p r e s c r i b e d procedure, a s o l u t i o n of the ketone (185) (98 mg, 0.51 mmole) i n 1 ml of THF was added to a s o l u t i o n of LDA (0.61 mmol) in 10 ml of THF at -78°C under n i t r o g e n . A f t e r 0.5 h, t e r t - b u t y l d i m e t h y I s i l y 1 c h l o r i d e (116 mg, 0.77 mmole) and HMPA (177 y l , 1.02 mmole) were added and the r e a c t i o n mixture was s t i r r e d f o r 0.5 h a t -78°C and f o r 1 h at room temperature. Standard work-up of the r e a c t i o n mix-t u r e , f o l l o w e d by d i s t i l l a t i o n of the r e s i d u a l o i l , gave the s i l y l e n o l ether (186) (102 mg, 65%) as a c o l o u r l e s s o i l , b.p. (air - b a t h ) 105-110°C/0.1 mm. Glc a n a l y s i s (OV-17, 100°C) of t h i s compound showed a s i n g l e major peak, as w e l l as a minor component (= 12%) which was a t t r i b u t e d to thermal rearrange-ment of some of the product on the column; i r :(film): 1725, 1675, 1635 (w), 875, 845, 785 cm - 1; JH nmr 6: 4.90-6.05 - 190 -(m, 3H, v i n y l i c protons) , 3.66 (s, 3H, -C0 2 Me), 1.4-2.8 (m, 4H) , 1.47 (br s , 3H, v i n y l i c methyl) , 0.92 (s, 9H , t - b u t y l ) , 0.07 and 0.04 (pair of s , 3H each, s i l y l methyls) . Exact mass c a l c d . for C ^ l ^ g S i O ^ : 308.1808; found: 308.1792. To a so lut ion of LDA (3.37 mmol) in 30 ml of dry THF was added a so lut ion of the ketone (188) (594 mg, 3.06 mmol) in 5 ml of THF at -78°C under n i t rogen . After 0.5 h, t e r t - b u t y l -d i m e t h y l s i l y l ch lor ide (689 mg, 4.59 mmol) and HMPA (1.06 ml , 612 mmol) were added and s t i r r i n g was continued for 0.5 at -78°C and 1 h at room temperature. Standard work-up y ie lded 961 mg of a pale yellow o i l , which on d i s t i l l a t i o n afforded the s i l y l enol ether (189) (888 mg, 94%) as a co lour less o i l , b .p . (air-bath) 9 4 - 9 8 ° C / 0 . 1 mm. T ic ana lys is (pentane-ether = 2:1) of th is mater ia l showed a s ingle spot . Glc ana lys is (OV-17, 100°C) showed one major component and a minor com-ponent (= 10%) which was due to thermal rearrangement of the product on the column (vide i n f r a ) ; i r ( f i lm) : 1730, 1640, 840, 790 c m - 1 ; lU nmr (80 MHz) 6: 6.25 (d of d of d , J = 17 Preparat ion of the S i l y l Enol Ether (18 9) - 191 -Hz, J ' = J " = 10 Hz, IH, HC=CH 2), 5.23 (d o f d, J = 17 Hz, J ' = 2.5 Hz, IH, H^C=C^~), 5.13 (d of d, J = 10 Hz, J ' = 2.5 Hz, \ yS. I I IH, ^C=C^U) , 4.43 ( t , J = 2.5 Hz, IH, HC=C-0SiR 3), 3.72 ( s , 3H, -C0 2Me), 2.43 (d, J = 2.5 Hz, 2H,•methylene), 1.81 (d, J = 10 Hz, IH, c y c l o p r o p y l p r o t o n ) , 1.33 ( s , 3H, t e r t i a r y m e t h y l ) , 0.89 ( s , 9H, t - b u t y l ) , 0.15 ( s , 6H, s i l y l m e t h y l s ) . E x a c t mass c a l c d . f o r C 1 7H 2gSiC> 3: 308 . 1808 ; found: 308.1826. P r e p a r a t i o n of the S i l y l E n o l E t h e r (193) Me C 0 2 Me Me To a s o l u t i o n o f LDA (2.64 mmol) i n 25 ml o f d r y THF was added a s o l u t i o n of the ketone (191) (500 mg, 2.40 mmol) i n 2 ml of THF, a t -78°C under n i t r o g e n . A f t e r 0.5 h, 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 (540 mg, 3.60 mmol) and HMPA (834 y l , 4.80 mmol) were added and s t i r r i n g was c o n t i n u e d f o r 0.5 h a t -78°C and 1.5 h a t room t e m p e r a t u r e . S t a n d a r d work-up of the r e a c t i o n m i x t u r e a f f o r d e d the s i l y l e n o l e t h e r (193) (717 mg, 93%) as a p a l e y e l l o w o i l . T h i s m a t e r i a l was pure by t i c (petroleum e t h e r - e t h e r = 2:1) and g l c a n a l y s i s (OV-17, 100°C); i r ( f i l m ) : 1730, 1640, 845 c m - 1 ; XH nmr (80 MHz) 6: 5.40-5.97 (m, 2H, t r a n s v i n y l i c p r o t o n s ) , 4.33 ( t , J = 2 Hz, - 192 -1H, HC=C-OSiR 3), 3.63 ( s , 3H, -C0 2Me), 2.33 (d, J = 2 Hz, 2H, m e t h y l e n e ) , 1.68 (d, J = 5 Hz, 3H, v i n y l i c m e t h y l ) , 1.5-1.8 (m, I H ) , 1.23 ( s , 3H, t e r t i a r y m e t h y l ) , 0.84 ( s , 9H, t - b u t y l ) , 0.08 ( s , 6H, s i l y l m e t h y l s ) . E x a c t mass c a l c d . f o r C^gH^QSiO^: 322.1964; found: 322.1985. P r e p a r a t i o n of a M i x t u r e o f the S i l y l E n o l E t h e r s (193) and (194) To a so lu t ion of LDA (1.1 mmol) in 10 ml of dry THF was added a so lu t ion of a mixture of the ketones (191) and (192) (208 mg, 1.0 mmol) in 2 ml of THF at -78°C under n i t rogen. After 20 min, t e r t - b u t y l d i m e t h y l s i l y l ch lor ide (225 mg, 1.5 mmol) and HMPA (348 u l , 2.0 mmol) were added and s t i r r i n g was continued at -78°C for 0.5 h and at room temperature for 1 h. The usual work-up afforded a mixture of the s i l y l enol ethers (193) and (194) (322 mg, 100%) as a pale yellow o i l . This mater ia l exhib i ted a s ingle spot by t i c (pentane-ether = 3:1) and one peak by g lc ana lys is (OV-17, 1 0 0 ° C ) . It was used d i r e c t l y in the next reac t ion ; i r ( f i lm) : 1725, 1640, 845, 790 c m - 1 ; XH nmr 6: 5.44-5.94 (m, 2H, v i n y l i c protons) , 4.33 - 193 -and 4.37 (1:1 p a i r of t , J = 2 Hz, IH, HC=C-OSiR 3), 3.62 ( s , 3H, -C0 2Me), 2.31 and 2.35 (1:1 p a i r of d, J = 2 Hz, 2H, m e t h y l e n e ) , 1.7-2.0 (m, I H ) , 1.62 and 1.67 (1:1 p a i r o f d, J = 5 Hz, 3H, v i n y l i c m e t h y l ) , 1.21 ( s , 3H, r i n g j u n c t i o n m e t h y l ) , 0.84 ( s , 9H, t - b u t y l ) , 0.06 ( s , 6H, s i l y l m e t h y l s ) . E x a c t mass c a l c d . f o r C ^ H ^ S i C ^ : 322.1964; found: 322.1961. Based on the *H nmr, t h i s m a t e r i a l was i d e n t i f i e d as a 1:1 m i x t u r e o f s i l y l e n o l e t h e r (194) and the p r e v i o u s l y p r e -pared s i l y l e n o l e t h e r (193) . T h i s m i x t u r e was used d i r e c t l y i n the rearrangement s t e p . P r e p a r a t i o n o f the Rearranged S i l y l E n o l E t h e r s  G e n e r a l P r o c e d u r e A s o l u t i o n o f each of the p r e v i o u s l y p r e p a r e d s i l y l e n o l e t h e r s i n a s m a l l amount o f s o l v e n t ( x y l e n e or m e s i t y l e n e ) was added t o the same s o l v e n t a t r e f l u x t e m p e r a t u r e . T h i s s o l u t i o n was f u r t h e r r e f l u x e d under n i t r o g e n u n t i l the r e a c -t i o n was judged complete by g l c a n a l y s i s . The s o l u t i o n was then c o o l e d t o room temperature and the s o l v e n t was removed under reduced p r e s s u r e . The r e s u l t i n g o i l was d i s s o l v e d i n pentane and f i l t e r e d through a s h o r t column of F l o r i s i l ( e l u -t i o n w i t h p e n t a n e - e t h e r = 5:1). The s o l v e n t was removed from the e l u a n t t o g i v e the d e s i r e d p r o d u c t as a c o l o u r l e s s o i l . F u r t h e r p u r i f i c a t i o n c o u l d be a c h i e v e d by d i s t i l l a t i o n but the - 194 -p r o d u c t s were s u f f i c i e n t l y pure ( s i n g l e s p o t by t i c ; pentane-e t h e r = 5:1) t o be used d i r e c t l y i n the n e x t s t e p . P r e p a r a t i o n o f the Rearranged S i l y l E n o l E t h e r (184) C0 2 Me A s o l u t i o n o f the s i l y l e n o l e t h e r (18 2) (300 mg, 1.02 mmol) i n 20 ml o f d r y x y l e n e was heated t o r e f l u x under n i t r o -gen f o r 2.5 h. The r e a c t i o n was c o n v e n i e n t l y m o n i t o r e d by g l c a n a l y s i s (OV-17, 100°C), which showed a g r a d u a l i n c r e a s e i n the h e i g h t o f the peak which o c c u r r e d as the minor component i n a g l c a n a l y s i s o f the s t a r t i n g m a t e r i a l , w i t h a c o n c o m i t a n t d e c r e a s e i n the h e i g h t of the peak c o r r e s p o n d i n g t o the major component. Sta n d a r d work-up of the r e a c t i o n m i x t u r e a f f o r d e d the s i l y l e n o l e t h e r (184) (296 mg, 99%) as a p a l e y e l l o w o i l . G l c a n a l y s i s (OV-17, 100°C) of t h i s m a t e r i a l i n d i c a t e d g r e a t e r than 98% p u r i t y and i t was used d i r e c t l y i n the n e x t s t e p ; i r ( f i l m ) : 1710, 1615, 840, 790 c m - 1 ; ]H nmr 6: 6.27 (m, IH, v i n y l i c p r o t o n ) , 5.27 (m, IH, v i n y l i c p r o t o n ) , 3.62 ( s , 3H, -C0 2Me), 2.89 (br t , J = 5 Hz, IH, d i a l l y l i c b r i d g e h e a d p r o t o n ) , 2.5-2.7 (m, I H ) , 1.9-2.3 (m, 3H), 1.5-1.75 (m, I H ) , 0.91 ( s , 9H, t - b u t y l ) , 0.16 ( s , 6H, s i l y l m e t h y l s ) . - 195 -E x a c t mass c a l c d . f o r C 1 5 H 2 3 S i C > 3 [M +-15] : 279.1417; found: 279.1424. P r e p a r a t i o n o f the Rearranged S i l y l E n o l E t h e r (187) Me C0 2 Me As d e s c r i b e d i n the g e n e r a l p r o c e d u r e , a s o l u t i o n o f the s i l y l e n o l e t h e r (186) (79 mg, 0.26 mmole) i n 10 ml o f d r y m e s i t y l e n e was heated t o r e f l u x under n i t r o g e n f o r 1 h. S t a n d -ard work-up of the r e a c t i o n m i x t u r e gave the s i l y l e n o l e t h e r (18 7) (77 mg, 97%) as a p a l e y e l l o w o i l . T h i s m a t e r i a l was pure by g l c a n a l y s i s (OV-17, 100°C) and was used d i r e c t l y i n the n e x t s t e p ; i r ( f i l m ) : 1700, 1600, 840, 790 c m - 1 ; *H nmr 6: 6.26 (m, IH, v i n y l i c p r o t o n a d j a c e n t t o b r i d g e h e a d ) , 5.33 (d o f t , J = 10 Hz, J ' = 3 Hz, IH, v i n y l i c p r o t o n ) , 3.60 ( s , 3H, -C0 2Me), 2.88 (br t , J = 5 Hz, I H , b r i d g e h e a d p r o t o n ) , 1.5-2.8 (m, 4H), 1.07 ( s , 3H, br i d g e h e a d m e t h y l ) , 0.88 ( s , 9H, t - b u t y l ) , 0.24 and 0.06 ( p a i r of s, 3H e a c h , s i l y l m e t h y l s ) . E x a c t mass c a l c d . f o r C 1 6 H 2 5 S i 0 3 [ M + - 1 5 ] : 293.1573; found: 293.1555. - 196 -P r e p a r a t i o n of the Rearranged S i l y l E n o l Ether (190) C 0 2 M e A s o l u t i o n of the s i l y l e n o l ether (18 9) (440 mg, 1.43 mmol) i n 50 ml of dry xylene was heated to r e f l u x under n i t r o -gen f o r 6 h. The r e a c t i o n was c o n v e n i e n t l y monitored by g l c a n a l y s i s (OV-17, 100°C). The product e x h i b i t e d a s i n g l e peak having the same r e t e n t i o n time as that of the minor component observed d u r i n g g l c a n a l y s i s of the s t a r t i n g m a t e r i a l . Stand-ard work-up of the r e a c t i o n mixture, followed by d i s t i l l a t i o n of the r e s i d u a l o i l , a f f o r d e d the s i l y l e n o l ether (190) (410 mg, 93%) as a c o l o u r l e s s o i l , b.p. 100-105°C/0.1 mm; i r ( f i l m ) : 1700, 1600, 850, 790 cm" 1; *H nmr (80 MHz) 6: 6.13 (br d, J = 10 Hz, IH, v i n y l i c proton adjacent to bridgehead), 5.29 (d of t of d, J = 10 Hz, J ' = 4 Hz, J " = 2 Hz, IH, v i n y l i c p r o t o n ) , 3.69 (s, 3H, -C0 2Me), 1.55-2.80 (m, 5H), 1.30 (s, 3H, bridgehead methyl), 0.98 (s, 9H, t - b u t y l ) , 0.21 (s, 6H, s i l y l m e t h y l s ) . Exact mass c a l c d . for C-^H^SiO^: 308.1808 ; found: 308.1801. - 197 -P r e p a r a t i o n o f the Rearranged S i l y l E n o l E t h e r (195) Me ^ -T"~-Me C02Me A s o l u t i o n o f the s i l y l e n o l e t h e r (193) (715 mg, 2.22 mmol) i n 75 ml of d r y m e s i t y l e n e was heated t o r e f l u x under n i t r o g e n f o r 4 h. Stan d a r d work-up of the r e a c t i o n m i x t u r e a f f o r d e d the s i l y l e n o l e t h e r (195) (715 mg, 100%) as a p a l e y e l l o w o i l . T h i s m a t e r i a l was pure by g l c (OV-17, 100°C) and 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 = 3:1) and was used d i r e c t l y i n the n e x t s t e p ; i r ( f i l m ) : 1700, 1600, 840, 785 cm - 1 ; XH nmr 6: 6.01 (br d, J = 10 Hz, IH, v i n y l i c p r o t o n a d j a c e n t t o b r i d g e h e a d ) , 5.07 (d o f d of d, J = 10 Hz, J 1 = 3 Hz, J " = 2 Hz, IH, v i n y l i c p r o t o n ) , 3.60 ( s , 3H, -C0 2Me), 1.50-2.58 (m, 4H), 1.20 ( s , 3H, br i d g e h e a d m e t h y l ) , 0.92 (d, J = 6 Hz, 3H, r i n g m e t h y l ) , 0.88 ( s , 9H, t - b u t y l ) , 0.14 and 0.11 ( p a i r o f s, 3H ea c h , s i l y l m e t h y l s ) . E x a c t mass c a l c d . f o r C 1 7 H 2 ? S i 0 3 [M +-15* : 307.1729; found: 307.1713. - 198 -P r e p a r a t i o n of a M i x t u r e of the Rearranged S i l y l E n o l E t h e r s (195) and (196) M e . — ' M e — C 0 2 M e — C 0 2 M e A s o l u t i o n o f a m i x t u r e o f the s i l y l e n o l e t h e r s (193) and (194) (219 mg, 0.68 mmol) i n 20 ml of d r y m e s i t y l e n e was heated t o r e f l u x under n i t r o g e n f o r 10 h. The r e a c t i o n was most c o n v e n i e n t l y m o n i t o r e d by g l c a n a l y s i s (OV-17, 100°C). The p r e s c r i b e d work-up of the r e a c t i o n m i x t u r e a f f o r d e d a mix-t u r e o f the s i l y l e n o l e t h e r s (195) and (196) (210 mg, 96%) as a 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 s p o t by t i c ( p e ntane-ether = 3:1) and one peak by g l c a n a l y s i s (OV-17, 100°C) and was used d i r e c t l y i n the n e x t s t e p ; i r ( f i l m ) : 1695, 1605, 850, 790 c m - 1 ; *H nmr 6: 6.01 (br d, J = 10 Hz, IH, v i n y l i c p r o t o n a d j a c e n t t o b r i d g e h e a d ) , 4.98-5.22 (m, IH, v i n y l i c p r o t o n ) , 3.61 ( s , 3H, -C0 2Me), 2.2-2.5 (m, 3H), 1.5-1.8 (m, I H ) , 1.20 ( s , 3H, b r i d g e h e a d m e t h y l ) , 0.92 and 1.03 (1:1 p a i r o f d, J = 6 Hz, 3H, r i n g m e t h y l ) , 0.88 ( s , 9H, t - b u t y l ) , 0.12 ( s , 6H, s i l y l m e t h y l s ) . E x a c t mass c a l c d . f o r C 1 7 H 2 7 S i 0 3 [M +-15] : 307.1729; foun d : 307.1713. - 199 -Based on the 1E nmr data, t h i s m a t e r i a l was i d e n t i f i e d as a 1:1 mixture of the s i l y l e n o l ether (196) and the p r e v i o u s l y prepared s i l y l e n o l ether (195) . T h i s mixture was used d i r e c t l y i n the next s t e p . P r e p a r a t i o n of the Rearranged g-Keto E s t e r s  General Procedure 156 Using the method r e p o r t e d by Oppolzer , the a p p r o p r i a t e s i l y l e n o l ether (1.0 equiv) was d i s s o l v e d i n methanol (spec-t r a l grade) and anhydrous potassium f l u o r i d e (3.0 equiv) was added at 0°C. S t i r r i n g was continued f o r 1 h at 0°C under n i t r o g e n and the r e a c t i o n mixture was then concentrated and d i l u t e d with s a t u r a t e d aqueous NH^Cl. The aqueous mixture was e x t r a c t e d with petroleum ether (2 x) and the combined or g a n i c e x t r a c t s were washed (1 N HC1, b r i n e 2 x ) , d r i e d (Na2SO^) and the s o l v e n t was evaporated. The r e s u l t i n g y e l -l owish o i l was d i s t i l l e d under reduced pressure to give the d e s i r e d g-keto e s t e r as a c o l o u r l e s s o i l . - 200 -P r e p a r a t i o n of the Rearranged B-Keto E s t e r (226) H X0 2 Me A c c o r d i n g t o the g e n e r a l p r o c e d u r e , a s o l u t i o n o f the s i l y l e n o l e t h e r (18 4) (111 mg, 0.38 mmol) i n 7 ml of methanol was t r e a t e d w i t h p o t a s s i u m f l u o r i d e (66 mg, 3 e q u i v ) a t 0°C. Stan d a r d work-up of the r e a c t i o n m i x t u r e a f f o r d e d 74 mg of a p a l e y e l l o w o i l . D i s t i l l a t i o n of t h i s m a t e r i a l gave a d i a s -t e r e o m e r i c m i x t u r e o f the B-keto e s t e r (226) (56 mg, 82%) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 85-88°C/0.1 mm. G l c a n a l y s i s (OV-17, 100°C) o f t h i s m a t e r i a l showed a s i n g l e peak; i r ( f i l m ) 1755 ( b r ) , 1735 ( b r ) , 1640 (w) cm" 1; *H nmr 6: 6.08 (m, IH, v i n y l i c p r o t o n a d j a c e n t t o b r i d g e h e a d ) , 5.54 (d o f t , J = 10 Hz, J 1 = 3 Hz, IH, v i n y l i c p r o t o n ) , 3.69 ( s , 3H, -C0 2Me), 3.34 and 3.26 (1:3 p a i r o f d, J = 6 and 3 Hz, r e s p e c t i v e l y , IH, I -CHC0 2Me). E x a c t mass c a l c d . f o r c i o H 1 2 ° 3 : 180.0786; found: 180.0789. - 201 -P r e p a r a t i o n of the Rearranged B-Keto E s t e r (227) Me As d e s c r i b e d i n the g e n e r a l p r o c e d u r e , a m i x t u r e o f the s i l y l e n o l e t h e r (187) (31 mg, 0.10 mmol) and p o t a s s i u m f l u o -r i d e (18 mg, 3.0 e q u i v ) i n 3 ml of methanol was s t i r r e d a t 0°C f o r 1 h under n i t r o g e n . S t a n d a r d work-up of the r e a c t i o n mix-t u r e , f o l l o w e d by d i s t i l l a t i o n of the r e s i d u a l o i l , a f f o r d e d the 8-keto e s t e r (227) (12 mg, 63%) as a d i a s t e r e o m e r i c mix-t u r e , b.p. ( a i r - b a t h ) 80-85°C/0.1 mm. G l c a n a l y s i s (OV-17, 100°C) of t h i s m a t e r i a l showed a s i n g l e peak; i r ( f i l m ) : 1750, 1720, 1640 (w) cm" 1; *H nmr 6: 6.10 (br d of d, J = 9 Hz, J ' = 7 Hz, IH, v i n y l i c p r o t o n a d j a c e n t t o b r i d g e h e a d ) , 5.61 (br d of t , J = 9 Hz, J 1 = 3 Hz, IH, v i n y l i c p r o t o n ) , 3.72 ( s , 3H, -C0 2Me), 3.40 and 3.29 (1:3 p a i r of d, J = 6 and 3 H, r e s p e c t i v e l y , I H , -CHC0 2Me), 2.9-3.2 (m, I H ) , 1.8-2.5 (m, 4H), 1.17 ( s , 3H, b r i d g e h e a d m e t h y l ) . E x a c t mass c a l c d . f o r c n H 1 4 ° 3 : 194 .0943; found: 194.0950. - 202 -P r e p a r a t i o n o f the Rearranged B-Keto E s t e r (228) Me H X 0 2 M e F o l l o w i n g the p r e s c r i b e d p r o c e d u r e , a s o l u t i o n of the s i l y l e n o l e t h e r (190) (380 mg, 1.23 mmol) i n 25 ml o f meth-a n o l was t r e a t e d w i t h p o t a s s i u m f l u o r i d e (215 mg, 3 e q u i v ) a t 0°C. S t a n d a r d work-up of the r e a c t i o n m i x t u r e , f o l l o w e d by d i s t i l l a t i o n o f the r e s i d u a l m a t e r i a l , a f f o r d e d a d i a s t e r e o -m e r i c m i x t u r e of the B-keto e s t e r (228) (184 mg, 77%) as a c o l o u r l e s s l i q u i d , b.p. ( a i r - b a t h ) 85-95°C/0.1 mm. G l c analy-s i s (OV-17, 100°C) o f t h i s m a t e r i a l showed a s i n g l e peak; i r ( f i l m ) : 1750, 1725, 1630 (w) c m - 1 ; *H nmr (80 MHz) 6: 5.80 (br d, J = 10 Hz, v i n y l i c p r o t o n a d j a c e n t t o b r i d g e h e a d ) , 5.53 (d o f t , J = 10 Hz, J ' = 3 Hz, IH, v i n y l i c p r o t o n ) , 3.75 and 3.70 (2:1 p a i r of s, 3H, -C0 2Me), 3.18 and 3.08 (d, J = I 2 Hz and s, r e s p e c t i v e l y , IH, -CHC0 2Me), 2.55-2.88 (m, IH, b r i d g e h e a d p r o t o n ) , 2.20-2.45 (m, 2H, a l l y l i c m e t h y l e n e ) , 1.93 (d, J = 3 Hz, 2H, m e t h y l e n e ) , 1.35 and 1.20 (2:1 p a i r of s, 3H, b r i d g e h e a d m e t h y l ) . E x a c t mass c a l c d . f o r c j i H i 4 ° 3 : 194.0943; found: 194.0938. - 203 -P r e p a r a t i o n o f the Rearranged B-Keto E s t e r (229) As d e s c r i b e d p r e v i o u s l y , a s o l u t i o n o f the s i l y l e n o l e t h e r (195) (652 mg, 2.02 mmol) and p o t a s s i u m f l u o r i d e (354 mg, 3 e q u i v ) i n 50 ml of methanol was s t i r r e d a t 0°C under n i t r o g e n f o r 1 h. S t a n d a r d work-up of the r e a c t i o n m i x t u r e y i e l d e d 437 mg o f a y e l l o w o i l . D i s t i l l a t i o n of t h i s m a t e r i a l gave a d i a s t e r e o m e r i c m i x t u r e o f the B-keto e s t e r (229) (347 mg, 83%) as a c o l o u r l e s s l i q u i d , b.p. ( a i r - b a t h ) 92-96°C/0.1 mm. G l c a n a l y s i s (OV-17, 100°C) of t h i s m a t e r i a l showed a s i n g l e peak; i r ( f i l m ) : 1750, 1725, 1640 cm 1 ; 1H nmr 6: 5.64-5.84 (m, I H , v i n y l i c p r o t o n ) , 5.36-5.54 (m, IH, v i n y l i c p r o t o n ) , 3.73 and 3.71 (5:7 p a i r o f s, 3H, -C0 2Me), 3.11 and t 3.04 (d, J = 2 Hz and s, r e s p e c t i v e l y , I H , -CHC0 2Me), 2.4-2.8 (m, 2H), 1.6-2.0 (m, 2H), 1.38 and 1.20 (5:7 p a i r of s, 3H, b r i d g e h e a d m e t h y l ) , 1.07 and 1.03 (5:7 p a i r of d, J = 6 Hz, m e t h y l ) . E x a c t mass c a l c d . f o r C ^ 2 H 1 6 ° 3 : 208.1100; found: 208.1102. - 204 -P r e p a r a t i o n o f a M i x t u r e o f the Rearranged B-Keto E s t e r s (229) and (230) Me A m i x t u r e o f the s i l y l e n o l e t h e r s (195) and (196) (210 mg, 0.65 mmol), t o g e t h e r w i t h p o t a s s i u m f l u o r i d e (113 mg, 3 e q u i v ) i n 10 ml o f m e t h a n o l , was s t i r r e d a t 0°C under n i t r o g e n f o r 1 h. The r e a c t i o n m i x t u r e was worked up i n the u s u a l man-ner t o a f f o r d 110 mg o f a c o l o u r l e s s o i l . D i s t i l l a t i o n o f t h i s m a t e r i a l gave a d i a s t e r e o m e r i c m i x t u r e o f the f o u r 8 - k e t o e s t e r s (229) and (230) (104 mg, 77%) as a c o l o u r l e s s l i q u i d , b.p. ( a i r -bath) 100-115°C/0.1 mm. G l c a n a l y s i s (OV-17, 100°C) o f the m i x t u r e showed two peaks i n a r a t i o o f about 45:55; i r ( f i l m ) : 1750, 1730 cm" 1; ]H nmr <S: 5.56-5.80 (m, IH, v i n y l i c p r o t o n ) , 5.30-5.50 (m, IH, v i n y l i c p r o t o n ) , 3.64, 3.66 and 3.68 ( t r i o o f s, 3H, -C0 2Me), 2.96-3.10 (m, IH, HC-C0 2Me), 2.3-2.8 (m, 2H), 1.6-2.0 (m, 2H), 1.14, 1.28 and 1.30 ( t r i o o f s, 3H, b r i d g e -head m e t h y l ) , 0.97, 1.01 and 1.04 ( t r i o o f d, J = 6 Hz, 3H, r i n g m e t h y l ) . E x a c t mass c a l c d . f o r C 1 2 H 1 6 0 3 : 208.1100; found: 208.1097. On the b a s i s o f the g l c and *H nmr d a t a t h i s m a t e r i a l was i d e n t i f i e d as a m i x t u r e o f the f o u r p o s s i b l e d i a s t e r e o m e r s of - 205 -B-keto e s t e r (229) and B-keto e s t e r (230) . T h i s m i x t u r e was used i n the subsequent d e c a r b o r n e t h o x y l a t i o n . P r e p a r a t i o n o f B i c y c l o [ 3 . 2 . f ] oct-2-en-6-one (233). 233 234 A s o l u t i o n o f the d i a s t e r e o m e r i c m i x t u r e o f B-keto e s t e r (226) (27 mg, 0.22 mmol) i n a m i x t u r e of 1 N HC1 (3 ml) and THF (1 ml) was h eated t o r e f l u x under n i t r o g e n f o r 4 h. The r e a c -t i o n m i x t u r e was then poured i n t o b r i n e and e x t r a c t e d w i t h pentane. The pentane s o l u t i o n was washed ( b r i n e ) and d r i e d (MgSO^) and the s o l v e n t s were c a r e f u l l y removed t o a f f o r d b i c y c l o [ 3 . 2 . 1 ] o c t - 2 - e n - 6 - o n e (233) (17 mg, 9 4 % ) ; i r ( f i l m ) : 1735 c m - 1 ; *H nmr 6: 5.95-6.22 (m, IH, v i n y l i c p r o t o n ) , 5.39-5.64 (m, IH, v i n y l i c p r o t o n ) , 2.70-2.90 (m, I H ) , 2.51-2.69 (m, I H ) , 2.21-2.47 (m, 4H), 1.98-2.17 (m, 2H). T h i s m a t e r i a l was i d e n t i c a l ( g l c r e t e n t i o n t i m e s on OV-17 15 7 and SE-30, *H nmr) w i t h an i n d e p e n d e n t l y p r e p a r e d sample of b i c y c l o Q . 2 . r ] o c t - 2 - e n - 6 - o n e (233 ) .* * T h i s m a t e r i a l was k i n d l y p r o v i d e d by Dr. S.A. M o n t i as a m i x t u r e o f the e t h y l e n e k e t a l s of b i c y c l o [ 3 . 2 . f l o c t - 2 - e n -6-one (233) and b i c y c l o [ 3 .2 . f j oct-3-en-6-one (234) . The i s o m e r i c m i x t u r e was h y d r o l y z e d i n THF-1 N HC1 a t 0°C t o a f f o r d a m i x t u r e o f the i s o m e r i c ketones which was sub-s e q u e n t l y s e p a r a t e d by p r e p a r a t i v e g l c (SE-54, 140°C) t o g i v e pure samples of the i n d i v i d u a l ketones (233) and (23_4) . - 206 -P r e p a r a t i o n o f 1-M e t h y 1 - 4 - e n d o - m e t h y l b i c y c l o [ 3 . 2 .T \ o c t - 2 - e n - 6-one (231) A m i x t u r e o f the g-keto e s t e r (229) (34 mg, 0.16 mmol), 2 ml o f methanol and 1 ml o f 2 N aqueous p o t a s s i u m h y d r o x i d e was heated t o r e f l u x f o r 5 h. The r e a c t i o n m i x t u r e was poured i n t o aqueous ammonium c h l o r i d e and e x t r a c t e d w i t h e t h e r . The o r g a n i c l a y e r was washed ( b r i n e ) , d r i e d (MgSO^) and the s o l -v e n t s were removed t o g i v e a p a l e y e l l o w o i l . D i s t i l l a t i o n ( a i r - b a t h t emperature 40-50°C/0.1 mm) o f t h i s m a t e r i a l a f f o r d e d 1-me thy 1 - 4 - e n d p - m e t h y l b i c y c l o ["3 . 2 . 3T] oct-2-en-6-one (231) (12 mg, 50%) as a c o l o u r l e s s l i q u i d . G l c a n a l y s i s (OV-17, 100°C) of t h i s compound showed a s i n g l e peak; i r ( f i l m ) : 1730, 745, 700 c m - 1 ; *H nmr <5: 5.77 (d o f d, J = 10 Hz, J ' = 2 Hz, IH, v i n y l i c p r o t o n a d j a c e n t t o b r i d g e h e a d ) , 5.39 (d of d o f d, J = 10 Hz, J ' = J " = 2 Hz, IH, v i n y l i c p r o t o n ) , 2.67 (q o f d o f d, J = 7 Hz, J ' = J " = 2 Hz, I H , a l l y l i c p r o t o n ) , 2.37-2.55 (m, IH, b r i d g e h e a d p r o t o n ) , 2.10-2.25 (m, 2H, - C H 2 C ( 0 ) ) , 1.92-1.98 (m, 2H, m e t h y l e n e ) , 1.24 ( s , 3H, b r i d g e h e a d m e t h y l ) , 1.01 (d, J = 7 Hz, 3H, r i n g m e t h y l ) . E x a c t mass c a l c d . f o r c i n H 1 4 0 : 150.1045; found: 150 .1044 . - 207 -P r e p a r a t i o n o f a M i x t u r e of 1 , 4 - D i m e t h y l b i c y c l o Q ^ T \ o c t - 2 -en-6-ones (231) and (232) Me 232 Me. 231 The d i a s t e r e o m e r i c m i x t u r e o f the 8-keto e s t e r s (229) and (230) (13.4 mg, 0 .064 mmol) i n 0.5 ml of methanol and 1.5 ml o f 1 N aqueous p o t a s s i u m h y d r o x i d e was heated t o r e f l u x under n i t r o g e n f o r 5 h. The r e a c t i o n m i x t u r e was then poured i n t o aqueous ammonium c h l o r i d e and e x t r a c t e d w i t h e t h e r . The e t h e r e a l e x t r a c t was washed ( b r i n e ) and d r i e d (MgSO^) and the s o l v e n t was removed t o g i v e a p a l e y e l l o w l i q u i d . D i s t i l l a -t i o n o f t h i s m a t e r i a l a f f o r d e d a m i x t u r e o f the ketones (231) and (232) (6 mg, 63%) as a c o l o u r l e s s l i q u i d , b.p. ( a i r - b a t h ) 40-50°C/0.1 mm. G l c a n a l y s i s (OV-17, 100°C) showed two peaks i n a r a t i o o f 47:53; i r ( f i l m ) : 1735, 750 c m - 1 ; lH nmr 6: 5.73 (br d, J = 10 Hz, I H , v i n y l i c p r o t o n a d j a c e n t t o b r i d g e -h ead), 5.35 and 5.39 ( p a i r of br d, J = 10 Hz, IH, v i n y l i c p r o t o n ) , 1.7-2.7 (m, 6H), 1.24 ( s , 3H, b r i d g e h e a d m e t h y l ) , 1.01 and 1.08 (= 1:1 p a i r o f d, J = 7 Hz, 3H, r i n g m e t h y l ) . E x a c t mass c a l c d . f o r C 1 Q H 1 4 0 : 150.1045; found: 150.1044. - 208 -Based on g l c and *H nmr d a t a , t h i s m a t e r i a l was i d e n t i -f i e d as a d i a s t e r e o m e r i c mixture of 1-methy1-4-exo-methyl-b i c y c l o [ 3.2. 1 ]oct-2-en-6-one (232) and 1-methy1-4-endo-m e t h y l b i c y c l o [ 3.2 . 1 ]oct-2-en-6-one (231). P r e p a r a t i o n of the P h e n y l s e l e n i d e (244) 0 C 0 2 M e To a s o l u t i o n of LDA (1.2 mmole) i n 10 ml of dry THF was added a s o l u t i o n of the b i c y c l i c ketone (178) (180 mg, 1.0 mmol) i n 2 ml of THF, at -78°C under n i t r o g e n , and s t i r r i n g was continued a t -78°C f o r 0.5 h. To t h i s s o l u t i o n was added a s o l u t i o n of phenylselenium c h l o r i d e (230 mg, 1.2 mmol) and HMPA (348 y l , 2.0 mmol) i n 2 ml of THF. A f t e r s t i r r i n g a t -78°C f o r 5 min the c o l d r e a c t i o n mixture was poured i n t o a mixture of 1 N HC1 and pentane-ether (1:1) and e x t r a c t e d . The or g a n i c e x t r a c t was washed (saturated aqueous sodium b i c a r -bonate, brine) and d r i e d (Na 2SO^) and the s o l v e n t s were removed to g i v e a ye l l o w o i l . T h i s m a t e r i a l was p u r i f i e d by pr e p a r a -t i v e t i c (chloroform) to remove excess phenylselenium c h l o r i d e (high Rj) and b a s e l i n e i m p u r i t i e s . T h i s gave the phenyl-s e l e n i d e (244) (230 mg, 69%) as a v i s c o u s yellow o i l which e x h i b i t e d two spots by t i c a n a l y s i s ( c h l o r o f o r m ) ; i r ( f i l m ) : - 209 -1720 ( b r ) , 745 cm" 1; JH nmr 6: 7.52-7.74 (m, 2H, a r o m a t i c p r o t o n s ) , 7.20-7.45 (m, 3H, a r o m a t i c p r o t o n s ) , 5.9-6.9 (m, 3H, v i n y l i c p r o t o n s ) , 3.76 and 3.78 ( p a i r o f s, -CO^Me), 2.0-3.0 (m, 5H). 8 0 E x a c t mass c a l c d . f o r C-^gH^g S e 0 3 : 336.0264; found: 336.0262. P r e p a r a t i o n o f the Enone (237) H g R = C 0 2 M e A s o l u t i o n o f the p h e n y l s e l e n i d e (244) (428 mg, 1.28 mmol) i n 25 ml o f d i c h l o r o m e t h a n e was c o o l e d t o 0°C under n i t r o g e n and a s o l u t i o n o f 30% hydrogen p e r o x i d e (0.35 ml) i n 2 ml o f water was added. The r e s u l t i n g two-phase system was s t i r r e d v i g o r o u s l y a t room temperature f o r 0.5 h and was then poured i n t o s a t u r a t e d aqueous sodium b i c a r b o n a t e . The o r g a n i c phase was s e p a r a t e d and the aqueous phase was back-e x t r a c t e d w i t h d i c h l o r o m e t h a n e . The combined o r g a n i c phase was washed ( b r i n e , 2 x) and d r i e d (MgSO^) and the s o l v e n t was removed under reduced p r e s s u r e . D i s t i l l a t i o n o f the r e s u l t i n g y e l l o w o i l gave the enone (237) (106 mg, 47%) as a c o l o u r l e s s o i l , b.p. ( a i r - b a t h ) 98-102°C/0.1 mm. T h i s o i l e x h i b i t e d a s i n g l e peak by g l c a n a l y s i s (OV-17, 100°C); i r ( f i l m ) : 1740 - 210 -( s h o u l d e r ) , 1705, 1575 cm~ x; XH nmr 6: 7.66 (d of d, J = 6 Hz, J ' = 3 Hz, IH, H ) , 5.81 (d, J = 6 Hz, I H , Hfa) , 5.86 (d o f d o f d, J = 18 Hz, J 1 = J " = 10 Hz, IH, H ), 5.32 (d o f d, J = 18 Hz, J 1 = 2 Hz, IH, H d ) , 5.22 (d of d, J = 10 Hz, J ' = 2 Hz, IH, H g ) , 3.83 ( s , 3H, -CC^Me), 3.12 (d of d, J = 4 Hz, J ' = 3 Hz, IH, H ) , 2.51 (d of d, J = 10 Hz, J ' = 4 Hz, IH, H f) . E x a c t mass c a l c d . f o r c i n H 1 0 ° 3 : 178.0629; found: 178.0629. P r e p a r a t i o n o f 1 - C a r b o m e t h o x y b i c y c l o [ 3 . 2 . 1 ] o c t a - 2 , 6 - d i e n - 8 - one (240) A s o l u t i o n o f the enone (237) (15 mg, 0.08 mmole) i n 5 ml o f d r y x y l e n e was heated t o r e f l u x under n i t r o g e n f o r 18 h. The r e a c t i o n was c o n v e n i e n t l y m o n i t o r e d by g l c a n a l y s i s (OV-17, 100°C), w i t h one p r o d u c t b e i n g formed which had a s l i g h t l y lower r e t e n t i o n time than t h a t o f the s t a r t i n g m a t e r i a l . The r e a c t i o n m i x t u r e was a l l o w e d t o c o o l and the s o l v e n t was removed under reduced p r e s s u r e . D i s t i l l a t i o n o f the r e s i d u a l m a t e r i a l gave the b i c y c l o [ 3 . 2 . l ] o c t a d i e n o n e (240) (11 mg, 73%) - 211 -as a c o l o u r l e s s l i q u i d , b.p. (ai r - b a t h ) 76-80°C/0.1 mm. This m a t e r i a l e x h i b i t e d a s i n g l e peak by g l c a n a l y s i s (OV-17, 100°C) i r ( f i l m ) : 1770, 1730 cm - 1; 1U nmr 6: 6.71 (d, J = 7 Hz, IH, H J , 6.30 (m, IH, H ), 6.28 (d of d, J = 7 Hz, J ' = 3 Hz, IH, a C H f a), 5.58 (br d of t , J = 10 Hz, J ' = 3 Hz, IH, H d ) , 3.82 (s, 3H, -C0 2Me), 2.9-3.0 (m, IH, H e ) , 2.35-3.05 (m, 2H, H f ) . Exact mass c a l c d . f o r c i o H 1 0 ° 3 : 178.0629; found: 178.0629. - 212 -BIBLIOGRAPHY 1. J.B. Pridham, Ed., "Terpenoids i n P l a n t s " , Academic P r e s s , New York (1967). 2. L. Aikman, "Nature's Healing A r t s : From Folk Medicine to Modern Drugs", N a t i o n a l Geographic S o c i e t y , Washing-ton, D.C. (1977). 3. R. W i l l s t a t t e r , Annalen, 326, 1 (1903). 4. E . J . Corey, R.L. Danheiser, S. Chandrasekaran, P. S i r e t , G.E. Keck and J.-L. Gras, J . Amer. Chem. S o c , 100, 8031 (1978); E . J . Corey, R.L. Danheiser, S. Chandrase-karan, G.E. Keck, B. Gopalan, S.D. Larsen, P. S i r e t and J.-L. Gras, J . Amer. Chem. Soc., 100, 8034 (1978); E . J . Corey and J.G. Smith, J . AmerT Chem. S o c , 101, 1038 (1979). 5. N. Anand, J.S. B i n d r a ; a n d S. Ranganathan, " A r t i n Organic S y n t h e s i s " , Holden-Day, San F r a n c i s c o (1970). 6. J.S. Bindra and R. 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