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An investigation of the effect of organic soil constituents on boron adsorption Gu, Baohua 1986

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INVESTIGATION OF THE EFFECT OF ORGANIC SOIL CONSTITUENTS ON BORON ADSORPTION by BAOHUA GU B. Agr., N a n j i n g A g r i c u l t u r a l U n i v e r s i t y , 1982 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS.FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES Department of S o i l S c i e n c e We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA OCTOBER, 1986 © Baohua Gu, 1986 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an advanced degree a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I agree t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d by t h e head o f my department o r by h i s o r h e r r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f C^\\Qyr\'\£>h The U n i v e r s i t y o f B r i t i s h Columbia 1956 Main Mall • Vancouver, Canada V6T 1Y3 Date DE-6 (3/81) i i A B S T R A C T The preparation and synthetic u t i l i t y of a number of s t r u c t u r a l l y i n t e r e s t i n g donor-acceptor reagents i s described. I t has been found that protonative deconjugations of geometrically isomeric yS-trimethyl-stannyl-a,^-unsaturated esters are highly s t e r e o s p e c i f i c . Thus, treatment of the esters (131) and (137) with l i t h i u m diisopropylamide i n THF or THF-HMPA followed, i n each case, by t r a n s f e r of the resultant s o l u t i o n to a c o l d (-98°C) s o l u t i o n of a c e t i c a c i d i n ether, provided e x c l u s i v e l y the a l k y l 3-trimethylstannyl-3-alkenoates (167) and (173), r e s p e c t i v e l y . Ethyl (Z) and (E)-3-trimethylstannyl-3-pentenoates were converted into the chlorides (99) and (100), r e s p e c t i v e l y . Transmetalation of (99) afforded (204), which was transformed into the Grignard reagent (218) . Both (204) and (218) serve e f f e c t i v e l y as conjunctive reagents which are s y n t h e t i c a l l y equivalent to the (E)-d^,a^-2-pentene synthon (200). For example, copper(I)-catalyzed conjugate a d d i t i o n of (218) to enones and subsequent intramolecular a l k y l a t i o n of the r e s u ltant prod-ucts form the basis of a new (Z)-ethylidenecyclopentane annulation process [(220) -* (222)]. I n t e r e s t i n g l y , although transmetalation of (100) also occurred smoothly, the resultant l i t h i o reagent (207) s e l f - a n n i h i l a t e d r a p i d l y even at low temperatures to give ethylidene-cyclopropane. The annulation method described above played a key r o l e i n short syntheses of (±)-oplopanone (257), (±)-8-epi-oplopanone (323), and i i i (±)-anhydro-oplopanone (258). Thus (Z)-ethylidenecyclopentane annulation of 4-isopropyl-2-cyclohexen-l-one provided the b i c y c l i c ketone (307). Suitable f u n c t i o n a l group manipulations transformed (307) into (±)-(257), (±)-(323), and (±)-(258). Reaction of 1-alkyn-3-ols with Me3SnCu.Me2S-MeOH, [Me3SnZn(t-Bu) 2]Li-CuCN, or [Me3SnZnEt2]Li-CuCN provided, i n varying r a t i o s , the vinylstannanes (109) and (339). Orthoester Cl a i s e n rearrangement of (109) and (339) afforded the esters (357) and (363), r e s p e c t i v e l y . Ethyl (Z)-4-trimethylstannyl-4-hexenoate was transformed into the ch l o r i d e (370). Compound (370) i s a convenient precursor of reagents (371) and (374) which are s y n t h e t i c a l l y equivalent to the (E)-d J,a -2-hexene synthon (379). For instance, the Grignard reagent (374) served as a p i v o t a l species i n the development of a new six-membered annulation method [(101) -* (380)]. 131 167 S n M e 3 137 173 i v 9 9 M = S n M e , 2 0 4 M = L i 2 1 8 M = M g B r 2 0 0 I O O M = S n M e , 2 0 7 M = L i V M e 3 S Q R-1 0 9 R S n M e , \__y 3 :o2Et 3 5 7 H 3 3 9 M©3Sn C02Et 3 6 3 3 7 0 M = S n M e , 3 7 9 3 7 1 M = L i 3 7 4 M = M g B r 0 0 101 3 8 0 vi TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v i LIST OF TABLES i x LIST OF FIGURES x ABBREVIATIONS x i ACKNOWLEDGEMENTS x i i i INTRODUCTION 1 I. General 2 I I . Previous Work 22 I I I . Proposals 26 DISCUSSION 30 I. Protonative Deconjugation of A l k y l 3-Trimethylstannyl-2-alkenoates 31 A. Preparation of a,/9-Acetylenic Esters . . . . 31 B. Preparation of /3-Trimethylstannyl-a,/9-unsaturated Esters 34 C. Stereochemical Investigations of Protonative Deconjugation of y3-Trimethylstannyl-a,/9-unsaturated Esters 41 v i i I I . Synthesis and Transmetalation of (Z)- and (E)-5-Chloro-3-trimethylstannyl-2-pentenes 59 A. Preparation of (Z) - and (E)-5-Chloro-3-trimethylstannyl-2-pentenes 59 B. Transmetalation of (Z)-5-Chloro-3-trimethylstannyl-2-pentene 60 C. Transmetalation of (E)-5-Chloro-3-trimethylstannyl-2-pentene 64 D. Copper(I)-Catalyzed Conjugate Addit i o n of the Grignard Reagent Derived from (204) to C y c l i c Enones: Convenient (Z)-Ethylidene-cyclopentane Annulation Sequences 67 I I I . T o t a l Synthesis of the Oplopanane-type Sesquiterpenoids (±)-0plopanone, (±)-8-epi-Oplopanone, and (±)-Anhydro-oplopanone 84 A. Introduction 84 B. Previous Synthetic Approaches to (±)-Oplopanone 86 C. T o t a l Synthesis of (±)-Anhydro-oplopanone 94 D. To t a l Synthesis of (±)-8-epi-0plopanone and (±)-Oplopanone 109 IV. Hydrostannylation of l-Alkyn-3-ols Via Stannyl-metalation. Preparation of (E)- 6 - C h l o r o - 3 - l i t h i o -2-hexene and the Related Grignard Reagent . . . 118 A. Preparation of l-Alkyn-3-ols 118 B. Addition of the (Trimethylstannyl)copper Reagent to l-Alkyn-3-ols 120 C. Reaction of (Trimethylstannyl)zinc Reagents with l-Alkyn-3-ols 126 D. The Orthoester Claisen Rearrangement of 2-Trimethylstannyl-l-alken-3-ols and ( E ) - l -Trimethylstannyl-l-alken-3-ols 131 v i i i E. P r e p a r a t i o n and Reac t ions o f ( E ) - 6 - C h l o r o -3 - l i t h i o - 2 - h e x e n e . ( Z ) - E t h y l i d e n e c y c l o -hexane A n n u l a t i o n Sequences 135 EXPERIMENTAL 1 4 0 REFERENCES 247 i x LIST OF TABLES Table Page I Preparation of A l k y l (E)-3-Trimethylstannyl 2-alkenoates 36 II Preparation of A l k y l (Z)-3-Trimethylstannyl 2- alkenoates 38 III Preparation of A l k y l (Z)-3-Trimethylstannyl 3- alkenoates 47 IV Preparation of A l k y l (E)-3-Trimethylstannyl 3- alkenoates 49 V Preparation of (Z)-Ethylidenecyclopentane Annulation products 71 VI Preparation of 1-Alkyn-3-ols from Aldehydes . . . . 121 VII Reaction of the (Trimethylstannyl)copper Reagent with l-Alkyn-3-ols 123 VIII Reaction of the (Trimethylstannyl)zinc Reagents with l-Alkyn-3-ols . 130 IX Preparation of Ethyl (Z)-4-Trimethylstannyl-4- alkenoates 132 X Preparation of Ethyl (E)-3-Trimethylstannyl-4-alkenoates 133 X LIST OF FIGURES Figure Page 1 The perspective view of the alcohol (252) 82 2 The 400 MHz *H nmr spectrum of (307) 99 3 The 400 MHz -^H nmr spectrum of (311) 100 4 The 400 MHz % nmr spectrum of (310) 106 5 The 400 MHz XH nmr spectrum of (314) 106 6 The 400 MHz -^H nmr spectrum of (315) 108 7 The 400 MHz XH nmr spectrum of (323) 113 8 The 400 MHz ^H nmr spectrum of (-)-oplopanone . . . . 113 x i ABBREVIATIONS The following abbreviations have been used throughout t h i s t h e s i s : Ac = ace t y l Bu = but y l m-CPBA = meta-chloroperoxybenzoic a c i d d = doublet DMAP = dimethylaminopyridine DME = dimethoxyethane DMF •= N,N-dimethylformamide DMSO = dimethyl sulfoxide equiv = equivalent(s) Et = eth y l glc = g a s - l i q u i d chromatography HMPA — hexamethylphosphoramide i r = i n f r a r e d LAH = l i t h i u m aluminum hydride LDA = l i t h i u m diisopropylamide m - mu l t i p l e t Me = methyl MEM - methoxyethoxymethyl MOM = methoxymethyl mp •= melting point Ms = methanesulfonyl NBS = N-bromosuccinimide x i i nmr = nuclear magnetic resonance PCC = pyridinium chlorochromate Ph = phenyl Pr = propyl PPTS = pyridinium p.-toluenesulfonate Py = pyridine r t = room temperature q = quartet s •= s i n g l e t t = t r i p l e t Tf •= t r i f luoromethanesulfonyl THF = tetrahydrofuran t i c = t h i n layer chromatography TMS = t r i m e t h y l s i l y l x i i i ACKNOWLEDGEMENTS I am indebted to my research supervisor, Professor Edward Piers, f o r h i s guidance and encouragement both i n and out of the laboratory. His advice and continued i n t e r e s t are greatly appreciated. I would l i k e to thank a l l the members of "The Group" for pleasant associations at both the academic and s o c i a l l e v e l . Special thanks are due to Dr. Anderson Maxwell, Peter Marrs, and Rick Friesen for t h e i r d i l i g e n t proofreading. Thanks are also extended to the tec h n i c a l s t a f f at UBC for courteous and r e l i a b l e assistance and to Mrs. Rani Theeparajah for her prompt and e f f i c i e n t typing of t h i s manuscript. F i n a n c i a l support from the U n i v e r s i t y of B r i t i s h Columbia i n the form of a U n i v e r s i t y Graduate Fellowship i s g r a t e f u l l y acknowledged. x i v TO MY PARENTS, with a f f e c t i o n - 1 -INTRODUCTION - 2 -INTRODUCTION I . Genera l The chemica l s y n t h e s i s of o r g a n i c molecules cont inues to occupy an i n c r e a s i n g l y important p l a c e i n the r e p e r t o i r e of the o r g a n i c chemis t . The achievement o f a s y n t h e s i s of a complex o r g a n i c molecule i n v o l v e s the development o f a s y n t h e t i c s t r a t e g y and p l a n , the s e l e c t i o n of s p e c i f i c i n d i v i d u a l s teps and t h e i r o r d e r i n g , and the demanding task of e x p e r i m e n t a l e x e c u t i o n of the s y n t h e s i s . A g e n e r a l approach to the a n a l y s i s o f a complex s y n t h e t i c t a r g e t i s to work the problem backwards. The t a r g e t molecule i s m e t h o d i c a l l y broken apar t i n such a way t h a t the fragments can be reassembled w i t h reasonable assurance o f success . The purpose o f such a r e t r o s y n t h e t i c analys is^- i s to generate a t r e e of s y n t h e t i c i n t e r m e d i a t e s t h a t t e rminates w i t h a number of a c c e s s i b l e s t a r t i n g m a t e r i a l s . The s y n t h e s i s then i n v o l v e s the s tepwise c o n s t r u c -t i o n o f the p lanned i n t e r m e d i a t e s through the a p p l i c a t i o n o f e s t a b l i s h e d ch e mica l r e a c t i o n s . The success o f r e t r o s y n t h e t i c a n a l y s i s depends upon a p e r c e p t i o n of the s t r u c t u r a l f e a t u r e s of the t a r g e t m o l e c u l e . Corey has r e c e n t l y put f o r w a r d f i v e types o f s t r a t e g i e s f o r r e t r o s y n t h e t i c a n a l y s i s . ^ The p l a n n i n g of a s y n t h e s i s i s g r e a t l y f a c i l i t a t e d by r e c o g n i z i n g w i t h i n a t a r g e t molecule c e r t a i n u n i t s which can be s y n t h e s i z e d , modi-f i e d , or j o i n e d by known or c o n c e i v a b l e s y n t h e t i c o p e r a t i o n s . Such u n i t s are r e f e r r e d to as s y n t h o n s . ^ The i d e n t i f i c a t i o n o f synthons - 3 -provides c o n t r o l over tree branching and helps i n carrying out a b i d i r e c t i o n a l a n alysis, that i s , a combined retr o s y n t h e t i c and synthetic search. A reagent i s a compound or intermediate a c t u a l l y used to carry out a synthetic operation.^ The reactions most frequently used i n organic synthesis are polar i n nature, i . e . they involve the use of n u c l e o p h i l i c or donor (d) and e l e c t r o p h i l i c or acceptor (a) reagents.^ In synthetic strategy, c e n t r a l importance i s attached to minimizing the number of steps and u t i l i z i n g p r i m a r i l y construction reactions.-' In a convergent synthesis, i f one plans to combine two previously synthes-ized components A and B i n a key step to form a target molecule, i t i s u s u a l l y necessary to activate A and/or B. However, such a c t i v a t i o n i s not necessary i f a h i g h l y reactive coupling agent i s used to j o i n the non-activated A and B. Since such reagents are designed to couple two or more components, they are c a l l e d multiple coupling reagents (MCR).^ Seebach has o u t l i n e d the following properties^ as being c r u c i a l f or the successful deployment of a multiple coupling reagent: ( i ) I t should f u r n i s h the desired carbon skeleton and f u n c t i o n a l i t y pattern. ( i i ) I t must allow for s e l e c t i v e , sequential (or simultaneous) i n t e r -molecular formation of two or more new bonds to take place. ( i i i ) I f i t has heterotopic s i t e s , they must be w e l l - d i f f e r e n t i a t e d . (iv) I f the r e a c t i v e s i t e s are diastereotopic, no mixtures of dia-stereomers should be formed. B i f u n c t i o n a l conjunctive reagents,^ which are s i m i l a r i n concept and function to multiple coupling reagents, are substances that possess - 4 -two reactive sites (e.g. two donor centers, two acceptor centers, or one donor and one acceptor center) and are incorporated in whole or in part into a substrate molecule. Some bifunctional conjunctive reagents have the ability to undergo cyclizations. Such reagents usually react with a bifunctional substrate by an intermolecular coupling step followed by an intramolecular step. Selected examples of such reagents are given below. Sulfur-containing groups acidify adjacent C-H bonds and are rela-tively easy to remove from organic molecules. These properties allow for the use of 1,3-dithiane8 (d^.d1) and methyl benzenesulfonylacetate9 (d^d 1) as effec tive bifunctional reagents. For example, cyclobutanone 4 This summary is not meant to be exhaustive, but is given to provide the reader with some background regarding the use of bifunctional reagents. 5 (A) has been synthesized by the reaction of 1,3-dithiane (1) with a 1,3-dihalopropane. 8 A f t e r 2-(3-chloro-l-propyl)-1,3-dithiane (2) was produced by the rea c t i o n of l i t h i a t e d 1,3-dithiane with a l-halo-3-chloropropane, the former substance was again treated with n-butyl-lit h i u m . Compound (3) thus obtained was converted into cyclobutanone (4) by mercuric chloride promoted hydrolysis (equation 1). This example i l l u s t r a t e s the u t i l i t y of 1,3-dithiane (1) as a carbonyl d dianion ( C-=0) equivalent, d Trost has used methyl benzenesulfonylacetate as the equivalent of a d key methylene dianion synthon ( CH2) i n the synthesis of (±)-recifeio-d l i d e ( 9 ) . 9 b A l k y l a t ion of the sodium s a l t of methyl benzenesulfonyl-acetate with (5) and reductive h y d r o l y s i s of the r e s u l t a n t product gave the a c i d (6) . Conversion of the a c i d (6) into i t s a c i d chloride and rea c t i o n of the l a t t e r material with the alcohol (7) gave the r e q u i s i t e precursor (8) . Refluxing a s o l u t i o n of the sodium s a l t of (8) with Pd(PPh3)^ produced the corresponding twelve-membered lactone, which was converted into (±)-recifeiolide (9) by decarbomethoxylation, followed by reductive d e s u l f o n y l a t i o n (equation 2). The d i c h l o r i d e (11) was used as the equivalent of a novel a,a synthon i n an elegant synthesis of (±)-/9-vetivone ( 1 3 ) . ^ The f i r s t a l k y l a t i o n was c a r r i e d out by allowing the l i t h i u m enolate of the enol ether of 1,3-cyclohexanedione (10) to react with the d i c h l o r i d e (11). Subsequent a d d i t i o n of two equivalents of l i t h i u m diisopropylamide provided the spiroannulation product (12) (equation 3). The stereo-chemistry of compound (12) was ant i c i p a t e d to be as shown because the f i r s t a l k y l a t i o n step would involve displacement of the a l l y l i c halide. - 6 -13 7 In the second, intramolecular alkylation reaction, the new carbon-carbon bond would be expected to form trans to the pseudo-axially oriented methyl group. The validity of this assumption was checked by conversion of (12) into the natural product (13). Based on the concept of nuclear synthons, Hendrickson has developed a synthesis of dihydrojasmone (18) in which mesyl triflone (14) d d , , was used as an olefin polyanion equivalent ( C-C ) . 1 Methylation of d d the a,a -dianion of (14), followed by the generation of a new a,a ' -di-2 Q-BuLi 2. Mel T f ^ S 0 2 \ 3 . n-BuLl 4 R| T f ^ S Q ^ R i -2n-BuLi 2. H 15 16 D 0 2 / R K MnO, Tf v , S - \ KzCQ. 18 (4) R=n-C 5 H I These are small molecular units capable of initiating multiple constructions in one operation. These units provide a nucleus of reactivity capable of rapidly elaborating around i t a large product skeleton and hence the name nuclear synthons.^ a 8 anion and a l k y l a t i o n of the l a t t e r species with 1-iodopentane, afforded the sulfone (15). Slow addition of a c r o l e i n to the a,a'-dianion of (15) led to the a l l y l i c alcohol (16) . Treatment of (16) with active manganese dioxide gave the c y c l i c keto sulfone (17) v i a oxidation and spontaneous c y c l i z a t i o n . The f i n a l step to generate dihydrojasmone (18) from (17) v i a the Ramberg-Backlund r e a c t i o n - ^ 0 was accomplished by-treatment of the keto sulfone (17) with potassium carbonate (equation 4). l i b Yamamoto and co-workers have reported a new asymmetric annulation protocol v i a d i r e c t coupling of a,w-dihalides (a,a) with dianions derived from d i a l k y l succinates ( d , d ) . 1 2 For example, (-)-dimenthyl cyclopropane - trans-1.2-dicarboxylate (20) was obtained i n 99% enantio-meric excess when the dianion of (-)-dimenthyl succinate (19) was allowed to react with 0.5 equivalent of bromochloromethane at low temperature (equation 5). R 0 2 C XOoR u 2. C H ^ r CI (5) R=L-Menthyl 20 Yamamoto has also developed a new one-pot construction of function-a l i z e d cyclopentanones v i a d i r e c t coupling of ^-halo esters and diester dianions. 13 For example, reaction of the dianion of diisopropyl (E)-3-hexendioate (22) with ethyl 3-bromopropionate (23) led to - 9 -formation of the 2,3-disubstituted cyclopentanone (24) as a mixture of geometric isomers. The latter material was transformed into the ketal (25) in good yield. This reaction sequence was used in a short synthesis of 11-deoxyprostaglandin E 2 (26) (Scheme l ) . 1 3 b 2LDA-HMRAW 22 25 Br(CH2)C(XEt 23 0 ^C0 2 R p- , HO OH, H + 24 R=i-Pr Scheme 1 The diene (27) has been used as a formal equivalent to the a,d-synthon (28) in a multiple annulation sequence developed by Trost.-^ Thus, alkylation of the sodium enolate of the keto sulfone (29) with the diene (27), followed by cyclization of the resultant product (30) with - 10 -tetra-n-butylammonium fluoride or ethylaluminum dichloride, afforded the 2,3-disubstituted-l,3-butadiene (31). Facile Diels-Alder reaction of (31) with dimethyl acetylenedicarboxylate gave mainly the adduct (32) (Scheme 2). Scheme 2 - 1 1 The i d e n t i f i c a t i o n of prostaglandins, polyquinanes, and r e l a t e d natural products as important synthetic targets has sparked an active i n t e r e s t and consequent growth i n the development of new methodologies for the synthesis of five-membered carbocycles. Recently, Danheiser has described one such novel [3+2] approach to cyclopentane d e r i v a t i v e s . ^ ( T r i m e t h y l s i l y l ) a l l e n e s (33) serve as three carbon d,a components (34) i n t h i s r e g i o s e l e c t i v e one-step annulation leading to ( t r i m e t h y l s i l y l ) -cyclopentenes. As shown by means of a s p e c i f i c example i n equation 6, an a,^-unsaturated ketone (35) was treated with the ( t r i m e t h y l s i l y l ) -allene (37) i n the presence of titanium t e t r a c h l o r i d e to provide the annulation product (39). I n i t i a l complexation of the enone (35) and titanium t e t r a c h l o r i d e would generate the alkoxy a l l y l i c carbocation (36). R e g i o s e l e c t i v i t y of e l e c t r o p h i l i c s u b s t i t u t i o n of t h i s cation at C-3 of the allene (37) was a n t i c i p a t e d to be as shown because the r e s u l t a n t v i n y l c a t i o n (38) would be s t a b i l i z e d by i n t e r a c t i o n with the adjacent c a r b o n - s i l i c o n bond. A 1,2-shift of the t r i m e t h y l s i l y l group, followed by i n t e r c e p t i o n of the isomeric v i n y l c a t i o n by the titanium enolate, would then generate the new five-membered r i n g . The scope of t h i s annulation strategy has now been extended to the synthesis of 33 34 12 39 heterocyclic compounds by using aldehydes and N-acyl imine derivatives as allenophiles.^•->c The regioselectivity, stereoselectivity and scope of application associated with the Diels-Alder reaction remains unparalleled for the synthesis of cyclohexane derivatives. Reagents that are equivalent to the a,d-synthon (41), as developed by Trost,* 6 offer the possibility of extending such benefits to the synthesis of five-membered rings. 13 In compounds such as (40) (X •= leaving group, M •= S i or Sn) , the t r i a l k y l s i l y l or t r i a l k y l s t a n n y l groups are removed to provide carbanion equivalents, whereas the X groups (X - OAc, O S O 2 C H 3, h a l i d e , etc.) are removed to provide carbocation equivalents. Thus, rea c t i o n of these conjunctive reagents with palladium(O) complexes gives a j r - a l l y l p a l l a -dium intermediate (42) i n which the C-M bond i s weakened by the proximal p o s i t i v e charge. Attack on the metal center by X® r e s u l t s i n formation of the palladium complex (43) as a reactive intermediate (see equation 7 ) . Equations 8 and 9 provide examples of reactions of the " t r i -methylenemethane" equivalent (45) with e l e c t r o n - d e f i c i e n t o l e f i n s to form new cyclopentane annulated p r o d u c t s . ^ a - 14 X0 2Me + 45 (Ph3P)4Pd n-C 6H 1 3 (9) 02Me 47 48 A different approach, employing 3-iodo-2-(trimethylsilylmethyl)-1-propene (50) as a bifunctional reagent, has been used effectively in the synthesis of the highly functionalized linear triquinane, (± ) -cor iol in 49 50 Scheme 3 (53). 17 The /3-keto s u l f i d e (49) was al k y l a t e d c l e a n l y with the iodide (50) to provide (51). Oxidation of (51) to the disulfone, followed by fluoride-induced c y c l i z a t i o n , produced (52). With t h i s e f f e c t i v e annulation protocol for the /?-keto s u l f i d e (49), the stage was set for completion of the synthesis, which mainly required adjustment of the oxidation pattern (Scheme 3 ) . Boger has recently demonstrated the use of cyclopropenone ketals (54) as equivalents to the b i f u n c t i o n a l d,a-synthon (55).^ 8 For example, treatment of (57) with the cyclopropenone k e t a l (56) resu l t e d i n a r e g i o s e l e c t i v e thermal add i t i o n reaction to provide the adduct (58) 54 55 (10) 56 57 58 (equation 10). As shown i n equation 11, n u c l e o p h i l i c attack of the str a i n e d cyclopropene onto the e l e c t r o n - d e f i c i e n t o l e f i n , rearrangement of the cyclopropyl cation to the a l l y l cation, and subsequent collapse 16 -56 ( i i ) of the dipole have been proposed to explain the formation of the observed products. The carbethoxycyclopropylphosphonium salt (59) provides another example of a reagent that is equivalent to a d,a-synthon [see (60)] and BF 4 P h 3 P ^ C 0 ^ E t 59 P r u P s X 02Et Na 60 is used for cyclopentene annulation.^ For example, the sodium enolate of the hydroxymethylene ketone (61) underwent clean spiroannulation upon treatment with (59) to produce a single crystalline spiro keto ester (62) (equation 12). The latter substance is a pivotal intermediate in 17 (12) the synthesis of spirovetivane sesquiterpenes. 1'" Recent preparations of stereochemically defined organolithium reagents have provided a most useful approach to the s t e r e o s p e c i f i c construction of carbon-carbon bonds. 2^ In l i g h t of the s t e r e o s e l e c t i v e preparation 2-*-" 2^ and f a c i l e transmetalation 2-* of vinylstannanes to the corresponding v i n y l l i t h i u m reagents, i t was decided to make use of substituted t r i a l k y l s t a n n y l alkenes as p o t e n t i a l precursors of novel donor-acceptor reagents. A b r i e f introduction to the use of v i n y l -stannanes as intermediates i n organic synthesis should, therefore, be i n order. The metathesis reaction between an organolithium and an organo-stannane (or an organic de r i v a t i v e of other heavy metals) i s known as transmetalation. Early studies of t h i s r eaction demonstrated that i t is a r e v e r s i b l e process 2^ leading to an equilibrium mixture favoring the - 18 -more s t a b l e o r g a n o l i t h i u m (equat ion 1 3 ) . * - i n - R + R'Li ^ -Sn-R* + RLi (13) I I K i n e t i c s t u d i e s of the l i t h i u m - t i n exchange have g e n e r a l l y been i n t e r p r e t e d i n terms of a f o u r centered t r a n s i t i o n s t a t e (63) . ^ The p o s s i b l e i n t e r m e d i a c y of t r a n s i e n t or s t a b l e " a t e " complexes (64) has a l s o been s u g g e s t e d . ^ .Li. R; R' [R - S r r -R ' ] Li Srv 63 64 S e v e r a l c h a r a c t e r i s t i c s of the t r a n s m e t a l a t i o n o f v i n y l s t a n n a n e s make t h i s r e a c t i o n p a r t i c u l a r l y a t t r a c t i v e : ( i ) the r e a c t i o n u s u a l l y proceeds e f f i c i e n t l y a t low temperatures , ( i i ) the r e a c t i o n i s s t e r e o -s p e c i f i c , and ( i i i ) the b y - p r o d u c t of the r e a c t i o n i s a c o o r d i n a t i v e l y s a t u r a t e d compound ( e . g . t e t r a m e t h y l t i n ) t h a t u s u a l l y does not i n t e r f e r e A l t h o u g h o r g a n o l i t h i u m s are o f t e n r e p r e s e n t e d as monomeric s p e c i e s , they are known to e x i s t as aggregates whose degree of a s s o c i a t i o n may be a f f e c t e d by s o l v e n t , c o n c e n t r a t i o n , and temperature (see r e f . 20) . For the sake of p i c t o r i a l c l a r i t y , monomeric spec ies w i l l be used i n f o r m u l a t i o n s . 19 -with reactions of the l i t h i a t e d product. The following two examples are representative of the use of t h i s type of reaction i n organic synthesis. S t i l l ' s synthesis of the germacranolide eucannabinolide (71) i l l u s t r a t e s an elegant use of a f u n c t i o n a l i z e d v i n y l s t a n n a n e . 2 8 The desired cyclobutenyl t i n reagent (67) was prepared from the k e t a l (65) by a two step sequence ou t l i n e d i n equation 14. Coupling of (67) and •D-Bu-jSnMgCl D-Bu3Sn MsO- ' 0 -Bu 3 Sn -OMe 2. MsCl K 2 C 0 3 , -OMe (14) -OMe OMe 65 0 M & OMe 66 67 the enone (68) proceeded v i a transmetalation of (67) and a d d i t i o n of the enone (68) to the resultant s o l u t i o n of the corresponding cyclobutenyl-l i t h i u m reagent. The a d d i t i o n occurred trans to the bulky isopropenyl substituent to provide a s i n g l e diastereomer (69). Oxy-Cope r i n g expansion of (69) l e d to formation of the enone (70). Appropriate f u n c t i o n a l group manipulations converted (70) into the natural product (71) (equation 15). A t o t a l synthesis of b r e f e l d i n A (78) by Corey i s based on a r e t r o s y n t h e t i c plan in v o l v i n g two v i n y l s t a n n a n e s . 2 9 Both of the organotin compounds (72) and (76) were prepared r e a d i l y by hydrostannyl-a t i o n of the corresponding terminal acetylenes using t r i - n - b u t y l t i n hydride and a z o b i s i s o b u t y r o n i t r i l e as i n i t i a t o r . 20 70 R=PhCH20CHa T r a n s m e t a l a t i on of (72) with, n - b u t y l l i t h i u m , f o l l o w e d by a d d i t i o n o f 1 - p e n t y n y l c o p p e r , gave the c o r r e s p o n d i n g cuprate reagent . The l a t t e r s p e c i e s r e a c t e d s t e r e o s e l e c t i v e l y w i t h enone (73) to produce the conjugate adduct (74) i n good y i e l d ( e q u a t i o n 16) . C o n v e r s i o n of (74) i n t o the aldehyde (75) was c a r r i e d out by a s e r i e s o f s tandard reac-t i o n s . T r a n s m e t a l a t i o n of (76) and r e a c t i o n of the r e s u l t i n g l i t h i o s p e c i e s w i t h the aldehyde (75) r e s u l t e d i n e f f i c i e n t c a r b o n y l a d d i t i o n to p r o v i d e the a l c o h o l (77) , which was conver ted i n t o ( ± ) - b r e f e l d i n A (78) i n seven s teps (equat ion 17) . V i n y l s t a n n a n e s are u s u a l l y prepared by h y d r o s t a n n y l a t i o n of a c e t y l -e n i c compounds. When t h i s type of r e a c t i o n i s c a r r i e d out on a 1-a lkyne as s u b s t r a t e , the major product of the r e a c t i o n i s n o r m a l l y the c o r r e s -- 21 n-BujSn t-BuMe 2SiO 1. n-BuLi 2. n-Pr-CEC-Cu Na X(C0 2Et) 2 3-0 • a 72 73 (17) 78 22 sponding (E)-1-trialkylstannyl-l-alkene. However, the formation of mixtures of products is not unusual.^ Other more regio- and stereo-selective methods for the preparation of vinylstannanes would enhance their usefulness. II. Previous Work Previous work in our laboratories had shown that addition of the elements of Me3Sn-H across the triple bond of a ,£-acetylenic esters (79) by reaction of these substrates with lithium (phenylthio)(trimethyl-stannyl )cupr ate (80)^1 could be controlled experimentally so as to produce, highly stereoselectively, either of the geometrically isomeric 0-trimethylstannyl esters (81) and (82).21 Thus, the conjugate addition of (80) to (79) at low temperature (-78°C) in the presence of methanol produced (>98% stereoselectivity) the (E) ester (81), while the (Z) ester (82) was the major (>96% stereoselectivity) product obtained after hydrolysis when the reaction was performed at higher temperature (-48°C) in the absence of a proton source (Scheme 4). 21 Further work had shown that the (trimethylstannyl)copper reagent (84)22 a (ided regioselectively to w-substituted 1-alkynes (83) (X = leaving group or potential leaving group) at -63°C in the presence of methanol to provide, efficiently, the corresponding 2 -(trimethyl-stannyl)-1-alkenes (85) (equation 18).23 The products (85) potentially represented convenient precursors of bifunctional conjunctive reagents which could be conceived as being 23 -R - C E C - C C X j R ' 7 9 [Me 3 SnCuSPh]L i 8 0 MeOH i.[Me£nCuSPh]Li ,-48°C 8 0 2 .MeOH R M e 3 S n ' 81 M e 3 S r / VogR' 8 2 Scheme 4 Me 3 SnCu- Me 2 S H" C S C - ( C H ^" X M s S - i 3 = T - - H 2 C = < S n M 6 3 as, MGUH, -63 C 2 V ( C H j 8 3 8 5 H 2 C=CT ' (CH 2 ) n . ,CH 2 8 6 24 f o r m a l l y e q u i v a l e n t to the donor -acceptor synthons (86) . T r a n s m e t a l a t i o n o f A - c h l o r o - 2 - ( t r i m e t h y l s t a n n y l ) - 1 - b u t e n e (87) w i t h m e t h y l l i t h i u m at -78°C, f o l l o w e d by a d d i t i o n of p h e n y l t h i o c o p p e r 3 2 0 r cuprous c y a n i d e , p r o v i d e d c l e a r s o l u t i o n s o f the c o r r e s p o n d i n g cuprate r e a g e n t s . These reagents proved to be s u f f i c i e n t l y s t a b l e to a l l o w f o r (19) t h e i r r e a c t i o n w i t h 2 - m e t h y l - 2 - c y c l o p e n t e n - l - o n e (88) to a f f o r d a good y i e l d o f the c o r r e s p o n d i n g conjugate a d d i t i o n p r o d u c t ( 8 9 ) . 3 3 Treatment of (89) w i t h potass ium h y d r i d e p r o v i d e d the b i c y c l i c ketone (90) ( e q u a t i o n 19) . As d e l i n e a t e d i n e q u a t i o n 20, t h i s new five-membered r i n g a n n u l a t i o n method was based on the t h e o r e t i c a l combinat ion of a d 2 , a 3 - s y n t h o n (91) w i t h the d 2 , a 4 - s y n t h o n (92) . The u t i l i t y of t h i s methylenecyclopentane a n n u l a t i o n process was demonstrated by i t s a p p l i c a t i o n to the s y n t h e s i s of the s e s q u i t e r p e n o i d s ( + ) . A 9 ( 1 2 ) - c a p n e l l e n e ( 9 6 ) 3 4 a and ( ± ) - p e n t a l e n e n e . 3 4 b For example, the ketone (90) was t ransformed i n t o the enone (94) v i a a sequence of s t a n d a r d r e a c t i o n s . C o p p e r ( I ) - c a t a l y z e d conjugate a d d i t i o n of the G r i g n a r d reagent prepared from (87) ( M e L i , MgBr 2 ) o c c u r r e d s t e r e o s e l e c -t i v e l y from the convex s i d e of the molecule to produce a s i n g l e a d d i t i o n - 25 (20) 91 92 93 9 5 9 6 (21) p r o d u c t , w h i c h was c o n v e r t e d r e a d i l y i n t o t h e a n n u l a t i o n p r o d u c t (95) R e d u c t i o n o f the k e t o n e , f o l l o w e d b y d e o x y g e n a t i o n , a f f o r d e d ( ± ) - A 9 < 1 2 ) . c a p n e l l e n e (96) ( e q u a t i o n 2 1 ) . 3 4 a - 26 -I I I . P r o p o s a l s I t i s e v i d e n t from the r e s u l t s r e p o r t e d above t h a t the v i n y l -stannane (87) i s r e a d i l y prepared and tha t i t i s a s y n t h e t i c a l l y v i a b l e e q u i v a l e n t t o the 1-butene d 2 , a ^ - s y n t h o n (92) . A p o t e n t i a l l y important e x t e n s i o n to the methodology summarized above i n v o l v e d the p o s s i b i l i t y o f p r e p a r i n g , s t e r e o s e l e c t i v e l y , a n a l -ogous reagents t h a t would be s y n t h e t i c a l l y e q u i v a l e n t to the donor-acceptor synthons (97) and (98) . For example, i t was o f c o n s i d e r a b l e i n t e r e s t to determine whether or not one c o u l d prepare and employ s y n t h e t i c a l l y ( Z ) - and ( E ) - 5 - c h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - p e n t e n e s , (99) and (100) r e s p e c t i v e l y , and the r e l a t e d l i t h i o and G r i g n a r d r e a g e n t s . 97 98 99 1 0 0 C l e a r l y , these m a t e r i a l s c o u l d serve as s y n t h e t i c e q u i v a l e n t s to the ( E ) - and (Z) -2-pentene d 3 , a 5 - s y n t h o n s [(97) and (98) , R - Me] r e s p e c t -i v e l y and, i f the proposed use of these spec ies were to be s u c c e s s f u l , one c o u l d per form s t e r e o s e l e c t i v e e t h y l i d e n e c y c l o p e n t a n e a n n u l a t i o n s shown i n g e n e r a l terms i n e q u a t i o n 22. The new a n n u l a t i o n method, apart from b e i n g i n t e r e s t i n g from a s t r i c t l y m e t h o d o l o g i c a l p o i n t of v i e w , would e x h i b i t c o n s i d e r a b l e promise f o r a p p l i c a t i o n s to o r g a n i c syn-- 27 -(22) 101 102 R=Me,R=H 103 R =H ,R'=Me t h e s i s . For example, the annulation product (105) (see equation 23) could p o t e n t i a l l y serve as a s t e r o i d CD-ring synthon. (23) 104 105 I t was envisaged that compounds (99) and (100) could be prepared from the corresponding (3-trimethylstannyl-a,^-unsaturated esters (81) and (82) (R = Et) by a three step sequence of deconjugation, reduction and conversion of the r e s u l t i n g alcohols to corresponding chlorides (Scheme 5). Although the deconjugation of a l k y l (E)- and (Z)-2-alkenoates had been reported p r e v i o u s l y , 3 ^ the e f f e c t of a C-3 sub s t i -tuent on the stereochemistry of the process had not been investigated p r i o r to our work. Continuing the general study of the preparation and use of struc-t u r a l l y i n t e r e s t i n g b i f u n c t i o n a l reagents, we wished to prepare reagents that might serve as synthetic equivalents to donor-acceptor synthons of - 28 Scheme 5 g e n e r a l s t r u c t u r e (106) . Thus, e x p l i c i t l y , we w i s h e d to prepare v i n y l s t a n n a n e s o f g e n e r a l s t r u c t u r e (107) . The l a t t e r substances were 1 0 6 107 expected to be o b t a i n a b l e from the e s t e r s (110) w h i c h , i n t u r n , would be a c c e s s i b l e from the c o r r e s p o n d i n g a l l y l i c a l c o h o l s (109) by o r t h o -a c e t a t e - b a s e d C l a i s e n rearrangement r e a c t i o n s (Scheme 6 ) . - 29 -H-CEC C02Et 107 108 109 110 Scheme 6 a) b) c) d) In summary, the primary objectives of this study were the follow-ing: to investigate protonative deconjugation of alkyl 3-trimethyl-stannyl-2-alkenoates, to synthesize and study the transmetalation of the geometrically isomeric 5-chloro-3-trimethylstannyl-2-pentenes, i f possible, to develop stereoselective ethylidenecyclopentane annulation sequences and apply the methodology to natural product synthesis, and to prepare and investigate the chemistry of alkyl (Z)-4-trimethyl-stannyl-4-alkenoates with a view to develop a general (Z)-ethyli-denecyclcohexane annulation method. - 30 -DISCUSSION 31 DISCUSSION I . P r o t o n a t l v e D e c o n j u g a t i o n o f A l k y l 3 - T r l m e t h y l s t a n n v l - 2 - a l k e n o a t e s A . P r e p a r a t i o n o f a , / 9 - A c e t y l e n i c E s t e r s E t h y l 2 - p e n t y n o a t e (113)^6 and e t h y l 6 - t e r t - b u t y l d i m e t h y l s i l o x y - 2 -h e x y n o a t e (116) were p r e p a r e d by r e a c t i o n o f t h e c o r r e s p o n d i n g a l k y n y l -l i t h i u m w i t h e t h y l c h l o r o f o r m a t e ( e q u a t i o n 2 4 ) . The r e q u i r e d a l k y n y l -l i t h i u m s p e c i e s were g e n e r a t e d b y d e p r o t o n a t i o n o f t h e c o r r e s p o n d i n g 1 - a l k y n e w i t h m e t h y l l i t h i u m . R C H 2 ^ = C - H - ^ = ^ (24) R = M e III 112 113 R=t-BuMe2SiOCH2CH 2 114 115 ||6 1 , 1 - D i b r o m o o l e f i n s , a v a i l a b l e b y r e a c t i o n o f a l d e h y d e s w i t h a c a r b o n t e t r a b r o m i d e - t r i p h e n y l p h o s p h i n e r e a g e n t , 3 ^ were a l s o u s e d as p r e c u r s o r s t o a . y S - a c e t y l e n i c e s t e r s . F o r e x a m p l e , t r e a t m e n t o f 3 - m e t h y l b u t a n a l (117) w i t h c a r b o n t e t r a b r o m i d e - t r i p h e n y l p h o s p h i n e a f f o r d e d t h e d i b r o m o o l e f i n (118) w h i c h , upon s u c c e s s i v e t r e a t m e n t w i t h m e t h y l l i t h i u m (2 e q u i v ) and e t h y l c h l o r o f o r m a t e , p r o v i d e d e t h y l 5 -meth-y l - 2 - h e x y n o a t e (119) ( e q u a t i o n 2 5 ) . I n an e s s e n t i a l l y i d e n t i c a l manner , - 32 -3-t r i m e t h y l s i l y l p r o p a n a l ( 1 2 0 ) 3 8 was converted into the a,/S-acetylenic ester (122) (equation 26). Br Br U l 0 P h 3 P C B r 4 ' > ^ l 2 M e L i C - C O B (25) H v 2ClC02Et 2 117 118 119 Br Br p 9 P h 3 P C B r 4 R Y i-2MeLi R l A u - — ^ V ^ - c s c - c a E t (26) H 2ClC02Et 2 120 121 122 R = M e 3 S i C H 2 Methyl 4-cyclopropyl-2-butynoate (129) could not be prepared v i a the above-mentioned methods because neither the corresponding terminal alkyne nor cyclopropylacetaldehyde were r e a d i l y a v a i l a b l e . I t has been reported that Li-CteC-CC^Et may be derived r e a d i l y from e t h y l propynoate, and that the former reagent adds to aldehydes and ketones to give ethyl 4-hydroxy-2-alkynoates i n good y i e l d . 3 9 However, no a l k y l a t i o n reactions were reported, presumably because of the normally observed sluggish r e a c t i v i t y of a l k a l i metal acetylides with such elect r o -p h i l e s . ^ Suzuki and coworkers reported a u s e f u l though somewhat cumbersome s o l u t i o n to t h i s problem. These workers described a general synthesis of 2-alkynoates v i a the reaction of iodine with the "ate" complexes obtained from l i t h i u m ethoxycarbonylacetylide and t r i a l k y l -- 33 -b o r a n e s . ^ l Success ive treatment of e t h y l propynoate (123) w i t h LDA (1 equiv) and the r e q u i r e d t r i a l k y l b o r a n e r e s u l t e d i n f o r m a t i o n of the complex (124) , which r e a c t e d w i t h i o d i n e at low temperature to p r o v i d e the c o r r e s p o n d i n g e t h y l 2 - a l k y n o a t e (125) ( e q u a t i o n 27 ) . R e c e n t l y , H-CEC-C0 2Et Li[R3B-C=C-C02Et] -^R-CEC-C0 2 Et (27) 123 124 125 Boland r e p o r t e d a l k y l a t i ons of the copper s a l t o f e t h y l propynoate w i t h a l l y l i c h a l i d e s , but the methodology was not a p p l i c a b l e to o t h e r c l a s s e s of e l e c t r o p h i l e s . 4 2 I n 1974, C a r l s o n r e p o r t e d the p r e p a r a t i o n of the p r o p y n o i c a c i d d i a n i o n (127) and i t s r e g i o s e l e c t i v e a d d i t i o n to unsymmetr ica l epoxides to p r o v i d e the c o r r e s p o n d i n g 6" -hydroxyacetylenic a c i d s (128) i n moderate y i e l d s ( e q u a t i o n 2 8 ) . 4 3 The d i a n i o n (127) was generated a t -45°C w i t h LDA i n a 1:1 THF-HMPA s o l v e n t system and was a l l o w e d to r e a c t w i t h epoxides a t room temperature f o r c a . 2-3 days to form the c o r r e s p o n d i n g h y d r o x y a c e t y l e n i c a c i d s (128) . The r o l e o f HMPA was c r u c i a l , s i n c e the r e a c t i o n s c a r r i e d out w i t h o u t HMPA r e s u l t e d i n the f o r m a t i o n of l i t t l e or no a d d i t i o n p r o d u c t . A H - C E C - C 0 2 H L i - C g C - C Q l i ' . ^ • R C H C H f ^ - C Q H « » 2 OH 126 127 128 34 -A modified version of the procedure reported above was used i n our "one-pot" synthesis of methyl 4-cyclopropyl-2-butynoate (129). Thus, when a s o l u t i o n of the dianion of propynoic a c i d (127) i n THF-HMPA was allowed to react with eyelopropylmethy1 bromide 4 4 (1.05 equiv, room temperature, 24 h) and subsequently with methyl iodide (4 equiv, room temperature, 24 h), the ester (129) was produced d i r e c t l y i n 53% y i e l d (equation 29). The dianion (127) was produced at -10°C i n a 1:2 THF-HMPA solvent system, which was necessary to maintain a s o l u t i o n throughout the dianion generation-addition sequence. L i - C = C - C 0 2 L i ' C H z B t [ > - C H 2 - € = C - C 0 2 M e (29) 2 Mel c 127 129 The g e n e r a l i t y of t h i s reaction was not investigated, but i t i s expected that the re a c t i o n sequence can be c a r r i e d out with other r e a c t i v e h a l i d e s . I f successful, t h i s "one-pot" procedure could represent an a t t r a c t i v e route to the preparation of t h i s c l a s s of compounds. B. Preparation of ^-Trimethylstannyl-a,/5-unsaturated Esters Previous work i n our l a b o r a t o r i e s 2 ^ had already established that l i t h i u m (phenylthio)(trimethylstannyl)cuprate (80)31 smoothly transfers one Me3Sn group to a ,/9-acetylenic esters (79). Furthermore, i t was 35 e s t a b l i s h e d tha t the s t e r e o c h e m i c a l course of t h i s r e a c t i o n can be c o n t r o l l e d e x p e r i m e n t a l l y to p r o v i d e e i t h e r the (E) - or the ( Z ) - / 9 - t r i -m e t h y l s t a n n y l - a , / 9 - u n s a t u r a t e d e s t e r s (81) and (82) , r e s p e c t i v e l y . R - C E C - C C y ? [ Me^nCuSPh] Li 79 8 0 R^ ^COgR' R^ M e 3 S n / r ~ M e 3 S n / r ~ \ o 2 R ' 81 82 The a , / ? - a c e t y l e n i c e s t e r s (130) were c o n v e r t e d i n t o the correspond-i n g (E) e s t e r s (131) v i a a s l i g h t l y m o d i f i e d v e r s i o n of the r e p o r t e d p r o c e d u r e . For example, a d d i t i o n o f a THF s o l u t i o n o f e t h y l 2 -pentyn-oate (113) c o n t a i n i n g 1.7 e q u i v a l e n t s o f methanol to a s o l u t i o n (THF) of 1.4 e q u i v a l e n t s of the cuprate reagent (80)* ( -98°C, 15 m i n ; -78°C, 6 h ) , f o l l o w e d by a workup and chromatography o f the crude p r o d u c t , a f f o r d e d the (E) e s t e r (132) i n 79% y i e l d (Table I ) . The o r i g i n a l procedure 2 ^- r e q u i r e d two e q u i v a l e n t s o f the cuprate reagent (80) . We d i s c o v e r e d t h a t w i t h 1.4 e q u i v a l e n t s of (80) the r e a c t i o n took a l o n g e r time to go to c o m p l e t i o n (6 h i n s t e a d o f 3 h ) , but the s t e r e o s e l e c t i v i t y and o v e r a l l e f f i c i e n c y appeared to be u n a f f e c t e d . I t was a l s o n o t i c e d t h a t a d d i t i o n o f pe t ro leum ether ( i n s t e a d of e ther as i n the o r i g i n a l procedure) i n the workup procedure caused a f a s t e r and more complete A b r i g h t r e d s o l u t i o n of t h i s reagent was prepared by a d d i t i o n of 1 e q u i v o f s o l i d ( p h e n y l t h i o ) c o p p e r 3 2 to a c o l d ( -20 C C) s o l u t i o n of ( t r i m e t h y l s t a n n y l ) l i t h i u m 1 ^ i n THF under an argon atmosphere (see r e f . 31) . Table I: Preparation of A l k y l (E)-3-Trimethylstannyl-2-alkenoates a RCH 2 ^=C-C0 2 tf 130 Entry Substrate 130 R R' Product 131 Y i e l d (%) b 1 113 Me Et 132 79 2 116 t-BuMe 2SiOCH 2CH 2 Et 133 71 3 122 Me 3SiCH 2 Et 134 73 4 129 cyclopropyl Me 135 74 5 119 i-P r Et 136 74 a Reacti THF, -.on conditions 98°C, 15 min; : [Me 3SnCuSPh]Li (1. -78°C, 6 h. 4 equiv), MeOH (1. . 7 equiv), b Y i e l d of p u r i f i e d , d i s t i l l e d product. - 37 -p r e c i p i t a t i o n of (phenylthio)copper. In e s s e n t i a l l y i d e n t i c a l fashion, other a,£-acetylenic esters (130) could be transformed smoothly into the corresponding (E)-/9-trimethyl-stannyl-a,/9-unsaturated esters (131) (see Table I ) . Although the r e s u l t s summarized i n the table require l i t t l e a d d i t i o n a l comment, i t should be emphasized that, i n each case, f l a s h column chromatography 4^ was performed on the crude material to remove hexamethylditin and a small amount (<3% by glc analysis) of the corresponding (Z) isomer (137) that was formed i n the reaction. In accordance with the reported procedure,^1 r e a c t i o n of ethyl 2-pentynoate (113) with 1.3 equiv of the cuprate reagent (80) at -78°C fo r 15 min and at -48°C f o r 4 h, followed by protonation (ethanol), workup, and chromatography of the crude product, provided the (Z) ester (138) i n 76% y i e l d (Table I I ) . In s i m i l a r fashion, other a,/3-acetylenic esters (130) were converted into the corresponding (Z) - f 3 -trimethyl-stannyl-a ,/S-unsaturated esters (137) i n good y i e l d . These r e s u l t s are summarized i n Table I I . The structures assigned to the products shown i n Tables I and II were supported by the s p e c t r a l data derived from these substances. In p a r t i c u l a r , the nmr spectra of these products f u l l y corroborated the stereochemical assignments. For example, the nmr spectrum of the ester (136) exhibited the signals expected for a trimethylstannyl group (a 9-proton s i n g l e t at 6 0.16 with s a t e l l i t e peaks due to Sn-H cou-p l i n g , J •=• 56 Hz), an isopropyl group (a 6-proton doublet at 6 0.89, J = 7 Hz and a 1-proton m u l t i p l e t at 6 1.60-1.72), and an e t h y l ester moiety (a 3-proton t r i p l e t at S 1.27 and a 2-proton quartet at 5 4.13, J = 7 38 -Table I I : P r e p a r a t i o n of A l k y l ( Z ) - 3 - T r i m e t h y l s t a n n y l - 2 - a l k e n o a t e s * RCH 2-<HC-CO 2R' R-130 137 E n t r y S u b s t r a t e 130 R R' Product 137 Y i e l d (%)b 1 113 Me Et 138 76 2 116 t - B u M e 2 S i 0 C H 2 C H 2 Et 139 79 3 122 M e 3 S i C H 2 Et 140 78 4 129 c y c l o p r o p y l Me 141° 67 5 119 i - P r Et 142 76 a R e a c t i o n c o n d i t i o n s : [Me 3 SnCuSPh]Li (1 .3 e q u i v ) , THF, -78°C, 15 min; -48°C, 4 h ; quenched w i t h EtOH. b Y i e l d of p u r i f i e d , d i s t i l l e d p r o d u c t . The r e a c t i o n mixture was quenched w i t h MeOH. 39 H z ) . I n a d d i t i o n , a 2 - p r o t o n double t o f double ts (J - 1, 7 Hz) due to the a l l y l i c methylene protons appeared at 6 2 .80 , w h i l e the o l e f i n i c p r o t o n gave r i s e to a t r i p l e t (J - 1 Hz) a t 6 6.00 ( w i t h s a t e l l i t e peaks due to Sn-H c o u p l i n g , J - 75 H z ) . The ^H nmr spectrum of the geometr i -c a l l y i s o m e r i c e s t e r (142) was v e r y s i m i l a r to t h a t of (136) but d i f f e r e d s i g n i f i c a n t l y i n three important a s p e c t s . The p o s i t i o n of the s i g n a l (6 2.80) due t o the a l l y l i c methylene protons of (136) was c o n s i d e r a b l y d o w n f i e l d from the s i g n a l (6 2.27) due to the c o r r e s p o n d i n g p r o t o n s o f the i s o m e r i c e s t e r (142) . Thus, i t i s reasonable to assume t h a t the 7 - p r o t o n s are c i s to the e s t e r group i n (136) but t r a n s to the e s t e r group i n ( 1 4 2 ) . 4 7 The chemica l s h i f t s of the o l e f i n i c protons observed i n the s p e c t r a of (136) and (142) (fi 6.00 and 6 6 .28 , r e s p e c t -i v e l y ) are i n agreement w i t h the o b s e r v a t i o n t h a t o l e f i n i c protons i n u n s a t u r a t e d o r g a n o t i n compounds are s h i e l d e d by a c i s v i c i n a l t r i a l k y l -s t a n n y l s u b s t i t u t e n t to the ex tent o f about 0.5 p p m . 4 8 I t i s a l s o known t h a t i n compounds i n which a t r i a l k y l s t a n n y l group and a hydrogen atom are v i c i n a l on an o l e f i n i c l i n k a g e , Jgn-H * s m u c n l a r g e r when the two s u b s t i t u e n t s are t r a n s to each o ther than when they are c i s to each o t h e r . 4 8 The v a l u e s of J.sn-H a s s o c i a t e d w i t h the o l e f i n i c protons i n e s t e r s (136) and (142) (75 Hz and 121 H z , r e s p e c t i v e l y ) render f u r t h e r support to the s t e r e o c h e m i c a l ass ignments . S t r u c t u r a l assignments of the o ther products shown i n Tables I and I I were conf i rmed by analogous comparisons . The course of the r e a c t i o n of the cuprate reagent (80) w i t h a , / 3 - a c e t y l e n i c e s t e r s (130) can be r a t i o n a l i z e d as f o l l o w s . 4 9 A d d i t i o n ( c i s s t e r e o c h e m i s t r y ) of (80) to (130) p r o v i d e s i n i t i a l l y the v i n y l -- 40 -cuprate species (143) (the "kinetic intermediate") which may rearrange to the copper allenoate (144) at higher temperatures. When the reaction is carried out at low temperatures in the presence of a proton source, protonation of (143) is faster than its rearrangement to (144) and results in stereoselective formation of the (E) ester (131) . On the other hand, assuming that the stereochemistry of protonation of the allenoate (144) is influenced by the relative stabilities of the products (i .e . the transition state for protonation has product-like character), reaction of (80) with (130) at higher temperatures and subsequent protonation would provide the (Z) ester (137) stereoselec-tively (Scheme 7). The ester (137) would be expected to be more stable than (131) because the trimethylstannyl group (A value - 0.94 kcal/ mol->0) i s less sterically demanding than an alkyl group (for example, the A value for a methyl group is 1.74 kcal/mol->l) . Of course, this is a rather simplistic "explanation" and does not take into consideration various factors which may affect the stability of the i n i t i a l intermedi-ate (143), including the nature of the reaction medium (solvent) and the possible oligomeric structures of the intermediates. Regardless of the mechanistic rationale, i t is important from a strictly synthetic point of view that each of the isomeric esters (131) and (137) can be prepared readily by reaction of the cuprate reagent (80) with a ,/9-acetylenic esters (130) under appropriate experimental conditions. The i n i t i a l reaction of Q,y3-acetylenic esters with (trialkyl-stannyl)cuprates is known to be reversible.^ 2 Scheme 7 C. S t e r e o c h e m i c a l I n v e s t i g a t i o n s of P r o t o n a t i v e Decon jugat ion of £ - T r i m e t h y l s t a n n y l - a , / 9 - u n s a t u r a t e d E s t e r s W i t h s u f f i c i e n t q u a n t i t i e s of (131) and (137) i n hand, we turned our a t t e n t i o n to a s tudy o f the p r o t o n a t i v e d e c o n j u g a t i o n of these g e o m e t r i c a l l y i s o m e r i c / ? - t r i m e t h y l s t a n n y l - a , u n s a t u r a t e d e s t e r s . In 1972, Rathke r e p o r t e d the p r e p a r a t i o n and r e a c t i o n s of d i e n o l a t e anions d e r i v e d from a,f3-unsaturated e s t e r s . ^ 3 I t was w e l l e s t a b l i s h e d by Rathke t h a t treatment of a , /9 -unsaturated e s t e r s w i t h an excess of a s t e r i c a l l y h i n d e r e d amide base r e s u l t e d i n the q u a n t i t a t i v e f o r m a t i o n of 42 -the c o r r e s p o n d i n g d i e n o l a t e a n i o n s . The l a t t e r spec ies were shown to r e a c t w i t h e l e c t r o p h i l e s predominant ly a t the a lpha carbon . Thus, a d d i -t i o n o f e t h y l c ro tonate (145) to a s o l u t i o n of l i t h i u m N - i s o p r o p y l c y c l o -hexylamide i n THF-HMPA produced the extended e n o l a t e a n i o n (146) which c o u l d be quenched w i t h d i l u t e h y d r o c h l o r i c a c i d to p r o v i d e , i n 87% y i e l d , the , 7 - u n s a t u r a t e d e s t e r (147) . A l t e r n a t i v e l y , r e a c t i o n of (146) w i t h methyl i o d i d e f u r n i s h e d the e s t e r (148) i n 87% y i e l d (Scheme 8 ) . Scheme 8 Subsequent ly , i t was shown by S c h l e s s i n g e r t h a t a 1:1 complex of LDA w i t h HMPA r e p r e s e n t e d an e s s e n t i a l l y n o n - n u c l e o p h i l i c base f o r d e p r o t o n a t i o n of a,/8-unsaturated e s t e r s and a l l o w e d f o r the e f f i c i e n t mono- and d i a l k y l a t i o n o f these e s t e r s a t the a l p h a carbon a t o m . ^ 4 The s y n t h e t i c p o t e n t i a l o f t h i s r e a c t i o n was soon r e c o g n i z e d by organic 43 chemists and is well-reflected in the growing number of reports that have appeared on this topic in the past decade. However, most of these reports failed to shed any light on the configurational aspects associ-ated with the double bond migrations in these deconjugative processes. The few examples that did provide some information on the stereochemis-try of the carbon-carbon double bond produced in these reactions indi-cated no clear-cut trend (see citations given in ref. 35). It was f irst noted by Krebs,3->a and later supported by Kende3->b with improved results, that protonation of lithium dienoates derived from (Z)-2-alkenoates (149) provided the corresponding (E)-3-enoate products (150) (equation 30), whereas dienolates obtained from (E)-2-enoates (151) gave mainly the (Z)-3-enoate products (152) (equation 31). In the examples cited, the former transformation was shown to be highly stereoselective regardless of the size of the R g r o u p . I n contrast, however, the stereoselectivity associated with deconjugation of (E)-2-alkenoates (151) was found to decrease significantly with an increase in the size of the R group. For example, although the substrate (153) produced exclusively the ester (154) (equation 32), deconjugation of (155) and (158) provided, in each case, a mixture of the possible isomeric p,7-unsaturated products (equations 33 and 34) . 3 5 b Quite recently, Yamamoto has discovered that the stereoselectivity of protonative deconjugation of (E)-2-alkenoates depends on the size of the ester alkoxy group and on the nature of the base employed for deprotonation. Thus, for example, protonative deconjugation of the (E)-2-dodecenoate (161) using potassium hexamethyldisilazide as the base - 44 -R C0 2Et 1) LDA, T H F - H M P A , -78°C 2) H 2 0, - 7 8 ° C R 1 4 9 (30) 150 C0 2 Et R. C0 2Et 151 R> •C0 2Et 152 (31) C0 2Et 153 C 0 2 E t 154 (32) (33) 156 (81%) 157(13%) CO.Et + C0 2 Et 158 (34) C0 2 Et 159 ( 6 2 % ) 1 6 0 ( 3 5 % ) - 45 R ^ ' -KN(SiMe, ) 2 R v / - C O / R (35) O R " 2 - H 2 0 ' 6 I 162(62^) 163(2%) R = D - C 8 H I 7 R '=CH(i -P r ) 2 produced the (Z)-3-dodecenoate (162) highly s t e r e o s e l e c t i v e l y (equation 35). A more complex case ensues when the s t a r t i n g a,/9-unsaturated esters have another substituent at C-3. I t has been es t a b l i s h e d that the k i n e t i c deprotonation of /9,/3-dialkyl-a,/3-unsaturated esters using LDA i s s i t e - s e l e c t i v e and involves a 7 C-H bond on the a l k y l group that i s c i s to the ester group. However, stereochemical correspondence between the double bond geometry i n the s t a r t i n g 2-alkenoates and i n the products has not been reported. Previous work i n our laboratory had demonstrated the f e a s i b i l i t y of protonative deconjugation of ^-trimethylstannyl-a,^-unsaturated s ft e s t e r s . J O Treatment of compound (164) with two equivalents of LDA at 0°C, followed by inverse quenching of the r e s u l t i n g dienolate anion with g l a c i a l a c e t i c a c i d at -98°C provided a 94:6 mixture of the deconjugated ester (165) and the ester (166) [geometric isomer of the s t a r t i n g material (164)] (equation 36). The conditions used f o r quenching the dienolate anion were important, since quenching with saturated aqueous For examples of s t e r e o s e l e c t i v e transformations of 2,4-alkadienoic esters to the corresponding 3,5-dienoic isomers, see r e f . 56. - 46 -ammonium chloride at -78°C afforded a mixture of the desired product (165) and the ester (166) in a ratio of 2.5:1. The o.^-unsaturated ester (166) was presumed to have been formed via 7-protonation of the extended enolate anion. H C0 2 Et COeEt M e 3 S n \ J \ i.LDA MtjSn^J + M e , S n x J S x H ( 3 6 ) l ^ C ° 2 E t 2-AcOH " ' 1 6 4 165(75%) 166(5%) Protonative deconjugation of the alkyl (E)-3-trimethylstannyl-2-alkenoates (131) was carried out by a procedure very similar to that summarized above. For example, a bright yellow solution of the dieno-late anion of ethyl (E)-3-trimethylstannyl-2-pentenoate (132) was prepared by reaction of (132) with 2.3 equiv of LDA in THF (-78°C, 0.5 h; 0°C, 1 h). The solution was cooled to -78°C and then was transferred by means of a cannula to a cold (-98°C) solution of acetic acid in ether to afford, after workup and subsequent distil lation of the crude product, ethyl (Z)-3-trimethylstannyl-3-pentenoate (168) as the exclusive product in 82% yield (Table 111) . In an analogous manner, the (E) esters (133)-(135) were converted cleanly and efficiently into the corresponding (Z)-p,7-unsaturated esters (169)-(171), respectively. These results are summarized in Table III. Careful analysis of the crude products of these reactions by glc and nmr spectroscopy showed the complete absence of the geometrically isomeric esters (174)-(177). Ethyl (E)-5-methyl-3-trimethylstannyl-2-hexenoate (136) exhibited some anomalous behaviour. Deconjugation of (136) by the normal 47 Table I I I : Preparation of A l k y l ( Z ) - 3-Trimethylstannyl - 3-alkenoates a Entry Substrate 131 R R' Product 167 Y i e l d (%) b 1 132 Me Et 168 82 2 133 t-BuMe 2SiOCH 2CH 2 Et 169 83 3 134 Me 3SiCH 2 Et 170 72 4 135 cyclopropyl Me 171 79 5 136 i - P r Et 172c 63 Reaction conditions: LDA (2.3 equiv), THF, -78°C, 0.5 h; 0°C, 1 h; inverse quench, AcOH (excess), ether, -78°C -» - 98°C. Y i e l d of p u r i f i e d , d i s t i l l e d product. LDA-HMPA (2.3 equiv) was used. - 48 -procedure was not clean and gave, in addition to the desired 0,y-un-saturated ester (172), a mixture of unidentified products. It seemed possible that the formation of the side-products was due to relatively slow removal of one of the (hindered) 7 protons in (136). The sluggish nature of the deprotonation could result in condensation of the dieno-late anion with unreacted a,/9-unsaturated ester (136). Alternatively, LDA could act as a nucleophile and add conjugatively to the unsaturated ester at a rate competitive with proton abstraction. Indeed, formation of such a Michael adduct from a structurally related substrate has been reported by Schlessinger. In any case, the deconjugation of (136) could be accomplished cleanly by deprotonating this substrate with LDA-HMPA complex. When this modification was employed, the crude product was found to be isomerically pure (glc analysis) and, upon distillation, provided the /9,7-unsaturated ester (172) in 63% yield. Protonative deconjugation of the (Z) esters (138)-(142) also occurred with complete stereoselectivity, producing exclusively the alkyl (E)-3-trimethylstannyl-3-alkenoates (174)-(178), respectively, in decent yields. Table IV summarizes these results. As expected, none of the geometrically isomeric deconjugated esters (168)-(172) could be detected in the crude products. The procedure employed for these reactions was very similar to that used for the (E) esters, except that deprotonation was done with 1.5 equiv of LDA in THF containing 1.5 equiv of HMPA. This modification was found to be necessary since deprotona-tion of ethyl (Z)-3-trimethylstannyl-2-pentenoate (138) with LDA alone (2.3 equiv), followed by protonation, provided (glc analysis) a mixture consisting mainly of the starting (Z)-ester (138) (14%) and the 49 -Table IV: Preparation of A l k y l (E)-3-Trimethylstannyl-3-alkenoates a R-Me3Sn CO^' 137 7 3 Entry Substrate 137 R R' Product 173 Y i e l d (%) b 1 138 Me Et 174 87 2 139 t-BuMe2SiOCH2CH2 Et 175 81 3 140 Me 3SiCH 2 Et 176 78 4 141 cyclopropyl Me 177 77 5 142 i-P r Et 178 71 a Reaction conditions: 1 h; inverse quench, IDA-HMPA (1.5 equiv), AcOH (excess), ether, THF, -78°C -78°C, 0. -98°C. .5 h; 0°C, Yield of purified, disti l led product. - 50 -r e q u i r e d 0,7-unsaturated e s t e r (174) (80%). The f a c t t h a t d e p r o t o n a t i o n o f (138) w i t h LDA-HMPA (1.5 equiv) r e s u l t e d i n e x c l u s i v e f o r m a t i o n of (174) a f t e r i n v e r s e quenching, i n d i c a t e s t h a t the presence o f HMPA was e s s e n t i a l f o r r a p i d and complete f o r m a t i o n o f the d i e n o l a t e a n i o n from the (Z) e s t e r (138) . The s p e c t r a l data of the products shown i n Tables I I I and IV are i n complete agreement w i t h the ass igned s t r u c t u r e s . As noted b e f o r e , the ^H nmr s p e c t r a of these compounds were v e r y u s e f u l i n a s c e r t a i n i n g t h e i r s t e r e o c h e m i s t r y . For example, the ^H nmr spectrum o f the e s t e r (168) showed a 9 - p r o t o n s i n g l e t a t S 0.20 ( w i t h s a t e l l i t e peaks due to Sn-H c o u p l i n g , J - 54 H z ) , a 3 - p r o t o n double t a t S 1.76 (J - 6 H z ) , and a 2 - p r o t o n d o u b l e t a t S 3.20 (J - 1 H z ) , i n d i c a t i n g thereby the presence o f a t r i m e t h y l s t a n n y l group, a v i n y l methyl group, and an a l l y l i c methylene m o i e t y , r e s p e c t i v e l y . A 3 - p r o t o n t r i p l e t a t 6 1.26 (J - 7 Hz) and a 2 - p r o t o n q u a r t e t a t 6 4.12 (J - 7 Hz) showed the presence o f an e t h y l e s t e r f u n c t i o n . More i m p o r t a n t l y , the s i g n a l due to the v i n y l p r o t o n i n (168) appeared a t S 6.16 as a t r i p l e t o f q u a r t e t s (J = 1, 6 Hz) w i t h s a t e l l i t e peaks due to t i n - p r o t o n c o u p l i n g (J .s n-H = H z ) . The l a t t e r c o u p l i n g constant i n d i c a t e d a v i c i n a l t r a n s r e l a t i o n s h i p between the t r i m e t h y l s t a n n y l group and the v i n y l p r o t o n 4 8 and hence e s t a b l i s h e d the s t e r e o c h e m i s t r y as ( Z ) . I n the * H nmr spectrum o f the g e o m e t r i c a l l y i s o m e r i c e s t e r (174), the o l e f i n i c p r o t o n s i g n a l appeared a t 6 5.84 (0.32 ppm u p f i e l d from the c o r r e s p o n d i n g s i g n a l i n (168)) and e x h i b i t e d J . s n _H •= 72 H z . These data showed t h a t , i n (174), there i s v i c i n a l c i s r e l a t i o n s h i p between the t r i m e t h y l s t a n n y l group and the v i n y l p r o t o n . 51 The infrared spectra of compounds (168) and (174) corroborated the structural assignments. Thus, absorption bands at 1720 and 1725 cm"1 indicated the non-conjugated nature of the ester carbonyl groups in (168) and (174), respectively. The corresponding conjugated esters (132) and (138) showed carbonyl absorptions at 1705 and 1700 cm"1, respectively. The Sn-Me rocking vibration of the trimethylstannyl moiety gave rise to an absorption band at around 770 cm"1 in the infrared spectra of these compounds. Similar analyses of the spectral data of a l l the other compounds (169)-(172) and (175)-(178) fully supported the structural assignments. In accord with previous o b s e r v a t i o n s , t h e trimethylstannyl compounds did not exhibit molecular ion peaks in their mass spectra. In these cases, the high resolution mass spectrometric measurements were carried out on the m/e - (M+-15) fragments. The results summarized above showed that protonative deconjugation of (Z)- and (E)-3-trimethylstannyl-2-alkenoates Is highly stereospecific and occurs with inversion of precursor double bond geometry. Recently, Baldwin has made the observation that " in a reaction that involves a formal 1,2-olefin shift, inversion of olefin configuration occurs with migration of the double bond".^ j h e stereospecific isomerizations discussed above exemplify this generalization. Krebs found that when the deconjugated esters (150) (R - Me) and (154) [derived from (149) (R - Me) and (153), respectively] were reexposed to deconjugation conditions (LDA-HMPA, -70°C; aq. N H 4 C I ) , the esters (150) (R -= Me) and (154) were recovered unchanged in good yie ld . 3 - * a i t was, therefore, concluded that the observed stereoselec-52 t i v i t i e s a s s o c i a t e d w i t h the double bond m i g r a t i o n s i n the decon jugat ive processes [equat ions 30 (R •» Me) and 32] must have t h e i r o r i g i n i n the d e p r o t o n a t i o n s t e p . Kende and Toder have presented s a t i s f a c t o r y mecha-n i s t i c arguments to e x p l a i n the observed i n v e r s i o n o f s t e r o c h e m i s t r y i n the d e c o n j u g a t i o n o f a,^-unsaturated e s t e r s t h a t possess a d i s u b s t i t u t e d double b o n d . 3 5 b The proposed r a t i o n a l e i s based upon s t e r e o e l e c t r o n i c c o n t r o l ( o r b i t a l o v e r l a p ) i n f o r m a t i o n o f the c o n f o r m a t i o n a l l y s t a b l e i n t e r m e d i a t e carbanions and the r e l a t i v e s t a b i l i t i e s o f these carbanions or the t r a n s i t i o n s t a t e s l e a d i n g to them. A m o d i f i e d v e r s i o n of Kende and T o d e r ' s proposed m e c h a n i s t i c r a t i o n a l e i s p r e s e n t e d below. The b a s i c s t e r e o c h e m i c a l c o n s i d e r a t i o n s * f o r the (E) -» (Z) and * For ana lyses of the t r a n s i t i o n s t a t e s proposed i n the k i n e t i c d e p r o t o n a t i o n o f e s t e r s , ke tones , and a,/3-unsaturated amides, see r e f . 61. - 53 -(Z) -+ (E) deconjugative transformations of the geometrically isomeric 2-alkenoates (149) and (151) are illustrated in Scheme 9. Stereoelec-tronic considerations require that two conformations for each starting ester be considered as possible arrangements that could lead to transi-tion states for deprotonation. These conformations for (149) and (151) are shown in Scheme 9. In these conformations, the base would approach along the axis of the correctly aligned C-H bond being broken so that deprotonation would occur perpendicular to the plane of the conjugated pi system. Assuming that the transition states for deprotonation have some product-like character, the relative stabilities of the stereo-isomeric carbanions obtained from the two conformations of the starting 2-alkenoates would have a significant influence on the preferred transi-tion-state pathway for deprotonation (product development control). In the case of the (Z) substrates (Scheme 9), the incipient anions (182) derived from the conformation (180) would be destabilized by severe A(1>3) strain^ 2 between the R and CC^Et groups. For the alternative route, the intermediate anions (181) [derived from conformation (179)] lack the A ^ ' 3 ) strain present in (182) and are consequently more easily formed from (149). Protonation then occurs at the alpha carbon of (181) to provide the 0,7-unsaturated esters (150) with complete stereoselecti-vity. In the absence of major steric interactions, consideration of two opposing factors becomes essential in order to explain the striking preference for the formation of (Z)-3-alkenoates (152) from the corres-ponding (E)-2-alkenoate precursors (151). The developing anions (186), obtainable from the conformation (184), would be stabilized by the cis - 54 -Scheme 9 a l k y l s u b s t i t u e n t R b u t w o u l d be d e s t a b i l i z e d b y A ^ 1 , 3 ) s t r a i n between R and H . The s t a b i l i z i n g i n f l u e n c e o f an a l k y l group i n a c i s o i d a l l y l i c a n i o n s y s t e m h a s b e e n w e l l - d o c u m e n t e d i n t h e l i t e r a t u r e . 6 3 F o r example , t h e p o t a s s i u m s a l t o f t h e c r o t y l a n i o n shows a f r e e e n e r g y p r e f e r e n c e o f more t h a n 2 k c a l / m o l f o r a c i s geometry (187) o v e r a t r a n s f o r m (188) ( e q u a t i o n 3 7 ) . 6 3 c S e v e r a l e x p l a n a t i o n s , i n c l u d i n g h y p e r c o n j u g a t i v e i n t e r a c t i o n , 6 ^ 2 c y c l i c c o n j u g a t i o n ( " a r o m a t i c i t y " ) , 6 4 b i n t r a m o l e c u l a r (37) h y d r o g e n b o n d i n g , b ^ c a n d i n c r e a s e i n the CCC a n g l e o f t h e a l l y l a n i o n u n i t , 6 ^ have b e e n p r o p o s e d t o r a t i o n a l i z e t h e o b s e r v e d p r e f e r e n c e f o r t h e e n d o - o r ( Z ) - c o n f i g u r a t i o n o f t h e c r o t y l a n i o n s y s t e m . I n e x t r a p o l a t i n g t h e s e o b s e r v a t i o n s and i d e a s t o t h e d e c o n j u g a t i o n o f the ( E ) - 2 - a l k e n o a t e s ( 1 5 1 ) , one c o u l d p r o p o s e t h a t when R i s s m a l l , g r e a t e r s t a b i l i t y i s e x p e c t e d f o r t h e ( Z ) - c a r b a n i o n s (186) t h a n f o r t h e i r s t e r e o i s o m e r s ( 1 8 5 ) . T h i s p o s t u l a t e r a t i o n a l i z e s t h e p r e f e r e n t i a l f o r m a t i o n o f t h e ( Z ) - p r o d u c t s (152) s t a r t i n g f r o m t h e ( £ ) - e s t e r s ( 1 5 1 ) . The above c o n c e p t s a r e r e a d i l y e x t e n d e d t o r a t i o n a l i z e t h e r e s u l t s o b t a i n e d f r o m o u r s t u d y o f the d e c o n j u g a t i o n o f / ? - t r i m e t h y l s t a n n y l - a , / 9 -u n s a t u r a t e d e s t e r s . The h i g h l y s t e r e o s e l e c t i v e t r a n s f o r m a t i o n o f the ( E ) - e s t e r s (131) i n t o the c o r r e s p o n d i n g ( Z ) - e s t e r s (167) c a n be r a t i o n a l i z e d by c o n s i d e r a t i o n o f t h e two c o n f o r m a t i o n s (189) and (190) l e a d i n g t o t h e t r a n s i t i o n s t a t e s (A) and ( B ) , r e s p e c t i v e l y , f o r - 56 -d e p r o t o n a t i o n (Scheme 1 0 ) . The s e v e r e A ^ ' 3 ) s t r a i n p r e s e n t i n (B) e a s i l y o v e r r i d e s the b e n e f i t s o f ( Z ) - s u b s t i t u e n t s t a b i l i z a t i o n . T h u s , d e s p i t e t h e p r e s e n c e o f s t e r i c c o m p r e s s i o n b e t w e e n pJ- and M e 3 S n i n ( A ) , t h i s t r a n s i t i o n s t a t e i s s t i l l l o w e r i n e n e r g y c o n t e n t t h a n (B) and i s Scheme 10 - 57 consequently the preferred t r a n s i t i o n state leading to the exclusive formation of ( 1 6 7 ) . The s t e r e o s e l e c t i v i t y associated with the deconjugation of a l k y l (Z)-3-t rimethylstannyl-2-alkenoates ( 137 ) (see Table I V ) i s more consistent and, i n most cases, much higher than that connected with deconjugation of the corresponding esters ( 1 5 1 ) (see equations 32-34) la c k i n g the Me3Sn group. This difference may be r a t i o n a l i z e d as follows. Deprotonation of these esters occurs v i a one or both of two possible t r a n s i t i o n states, one of which [represented by (D)] would eventually lead to the products ( 1 73 ) and ( 1 5 2 ) , while the other [represented by ( C ) ] would ul t i m a t e l y provide the corresponding geometric isomers (Scheme 1 1 ) . When R^ i s small (e.g. R* - Me) and Y = H, (D) i s of lower energy than (C) because of the s t a b i l i z i n g influence of R! i n the c i s o i d a l l y l i c anion system present i n t h i s t r a n s i t i o n state. Hence, deprotonation occurs s o l e l y v i a t r a n s i t i o n state (D) and r e s u l t s i n the exclusive formation of ( 1 5 2 ) . However, as becomes r e l a t i v e l y more bulky [e.g. R^ = Et, i - P r ] , the non-bonded s t e r i c s t r a i n between R^ and H* [see (D)] becomes in c r e a s i n g l y important and deprotonation v i a t r a n s i t i o n state (C) (Y - H) competes s i g n i f i c a n t l y with deprotonation v i a (D) (Y » H). Therefore, s t e r e o s e l e c t i v i t y of the deconjugative process ( 1 5 1 ) -* ( 1 52 ) i s highly dependent on the size of the a l k y l substituent R^. In contrast, when Y = SnMe3, the A ^ ' 3 ) s t e r i c s t r a i n between and H* i n (D) i s o f f s e t by non-bonded repulsion between R^  and Y (= SnMe3) i n ( C ). Thus, apparently, even when R^ i s r e l a t i v e l y bulky, deprotonation occurs e x c l u s i v e l y by way of t r a n s i t i o n state (D) (Y = - 58 SnMe3) and substrates (137) are converted cleanly into the corresponding ^,7-unsaturated esters (173). 137 Y = S n M e 3 151 Y=H NC i - P r l , R1 X 167 Y = S n M e , I 5 0 Y = H ~ N ( i - P r ) s D II ,Y FT ^-COoR 173 Y - S n M e , I 5 2 Y = H ~ Scheme 11 59 I I . Synthesis and Transmetalation of (Z)- and (E)-5-Chloro-3-trimethyl-stannyl-2-pentenes A. Preparation of (Z)- and (E)-5-Chloro-3-trimethylstannyl-2-pentenes As described i n the previous section, protonative deconjugation of ethy l (E)-3-trimethylstannyl-2-pentenoate (132) and i t s geometric isomer (138) provided an e f f i c i e n t and highly s t e r e o s e l e c t i v e route to the synthesis of eth y l (Z) - and (E)-3-trimethylstannyl-3-pentenoates, (168) and (174), r e s p e c t i v e l y . These esters are, p o t e n t i a l l y , precursors of s t r u c t u r a l l y i n t e r e s t i n g donor-acceptor conjunctive reagents. For example, reduction of the ester (168) proceeded smoothly when i t was allowed to react with l i t h i u m aluminum hydride i n dry ether at -20°C (equation 38). The alcohol (193) thus produced i n 88% y i e l d showed the diagnostic 0-H s t r e t c h i n g absorption i n i t s i r spectrum at 3300 cm"-'-. Treatment of t h i s substance with triphenylphosphine-carbon tetrachlor-- 60 -ide 6^ i n the presence of triethylamine-*8 afforded (Z)-5-chloro-3-tri-methylstannyl -2 -pentene (99) in 83% yield. In similar fashion, the ester (174) was converted, via the alcohol (194), into the chloride (100) in 66% overall yield. The chemical shifts (6 6.20 and 6* 5.83) and the magnitude of the tin-proton coupling constants (135 Hz and 76 Hz) of the olefinic protons in the ^H nmr spectra of the geometrically isomeric chlorides (99) and (100), respectively, were consistent with their assigned structures. B. Transmetalation of (Z)-5-Chloro-3-trimethylstannyl-2-pentene The mere presence of both a carbon-lithium bond and a primary halide function in a reagent may be regarded as antithetical to its deployment in organic reactions. However, i t is occasionally possible to release these thermolabile compounds from the constraint of the fate assigned to them as short-lived intermediates by preparing and using them in situ in appropriate solvents at low temperatures. As mentioned in the Introduction, a series of reports-^ 2 ' 3 3 • 3 ^ from our laboratory has described the successful preparation and synthetic u t i l i ty of the I unusual donor-acceptor reagent 4-chloro-2-lithio-l-butene (195) (equation 39). The feasibility of preparing its homologue (197) by transmetalation of 5-chloro-2-trimethylstannyl-1-pentene (196), and its pivotal role in the development of a methylenecyclohexane annulation method was demonstrated in our laboratory by work done concurrently with that outlined in this thesis . 6 6 It was also shown that reagent (197) 61 8 7 1 9 5 decomposes slowly even at -50°C. Thus, transmetalation (MeLi, THF, -78°C) of (196) afforded (197) and treatment of the latter reagent with cyclohexanone at -78°C, followed by suitable workup, provided the alcohol (198) in 84% yield (equation 40). However, the yield of (198) decreased to 76%, 58%, and 0% when the reaction mixture was allowed to warm to -63, -48, and -20°C, respectively, prior to addition of the ketone. These results indicated that low temperatures were mandatory for successful deployment of this d,a reagent. 0 (40) In light of these results, i t was of interest to study the possi-bi l i ty of the chlorides (99) and (100) serving as precursors of reagents (199) and (201) , which would be synthetically equivalent to the geometrically isomeric d3,a^-2-pentene synthons (200) and (202), respectively. Real ut i l i ty of (199) and (201) as bifunctional conjunc-tive reagents was necessarily contingent upon the successful transmet-alation of (99) and (100), respectively, and upon the stability of the - 62 -a M=Li or MgBr or (CuSPh)Li resulting vinyllithium compounds. There is evidence in the literature to suggest that i f there is an alkyl substituent in a vicinal cis relationship to a trialkylstannyl group, the transmetalation of that vinylstannane is likely to be slower than that of the corresponding geometric isomer.**7 For example, a THF solution of (203) (3:1 mixture of trans and cis isomers, respectively) was treated with one equivalent of n-butyllithium (-70°C, 1 h) and then was quenched with water. Separation of the unreacted vinylstannanes (203) (20%) by chromatography and analysis of this material by 13C nmr spectrum revealed that the trans:cis ratio of (203) had changed to 2:3.^ 7 b On the basis of these observations, transmetalation of the (Z)-chloride (99) was anticipated to be a challenging task. It was, therefore, very gratifying to find that compound (99) underwent transmetalation cleanly upon exposure to 1.1 equiv of methyl-lithium at -78°C for 20 min to produce a light brown solution of the - 63 organolithium reagent (204). When this solution was treated with a slight excess (1.1 equiv) of cyclohexanone and was subsequently quenched with saturated aqueous ammonium chloride at -78°C, a mixture of the chloro alcohol (205) (31%) and the cyclic ether (206) (40%) was produced (equation 41). The 1H nmr spectrum of the chloro alcohol (205) 0 99 204 205 206 exhibited a broad triplet at 6 2.48 (J - 7 Hz) due to the al lyl ic methylene protons while the -CH2CI protons gave rise to a normal triplet at S 3.60 (J = 7 Hz). The one proton triplet of quartets (J - 1, 7 Hz) at 6 5.36 was indicative of the olefinic proton attached to carbon bearing the methyl group. The ir spectrum of (205) showed the 0-H stretching absorption band at 3425 cm"1. In the -^ H nmr spectrum of the spiro ether (206), the signals due to the al lyl ic methylene protons and the -OCH2- protons appeared as a multiplet (5 2.35-2.68) and a triplet (6 3.75, J •= 7 Hz), respectively. The signal at 6 5.36 (t of q, J •= 2, 7 Hz) was assigned to the olefinic proton. The signals due to the vinyl methyl protons could not be located exactly in the ^H nmr spectra of (205) and (206) because of the presence of cyclohexane ring protons in the same region. It has been well established that the stereochemical integrity of double bonds is completely preserved in the transmetalation 64 -of v i n y l s t a n n a n e s and i n r e a c t i o n s of the v i n y l l i t h i u m reagents thus p r o d u c e d . * On t h i s b a s i s , the double bonds i n compounds (205) and (206) have been ass igned the (Z) c o n f i g u r a t i o n . C. T r a n s m e t a l a t i o n o f ( E ) - 5 - C h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - p e n t e n e : Format ion of E t h y l i d e n e c y c l o p r o p a n e Encouraged by the f i n d i n g s summarized above, we embarked on the t r a n s m e t a l a t i o n of the g e o m e t r i c a l l y i s o m e r i c c h l o r o v i n y l s t a n n a n e (100) . Compound (100) was a l l o w e d to r e a c t ( t e t r a h y d r o f u r a n , -78°C, 20 min) w i t h 1.1 e q u i v o f m e t h y l l i t h i u m and the r e s u l t a n t s o l u t i o n was t r e a t e d w i t h cyclohexanone. However, even though a l l o f the s t a r t i n g m a t e r i a l (100) had been consumed, no c a r b o n y l a d d i t i o n p r o d u c t c o u l d be i s o l a t e d . Other attempts to t r a p the expected l i t h i o compound (207) w i t h e l e c t r o p h i l e s ( cyc lopentanone , benzaldehyde) f a i l e d . R a p i d s e l f -a n n i h i l a t i o n to form e t h y l i d e n e c y c l o p r o p a n e (208) seemed a p l a u s i b l e pathway f o r the "d isappearance" of (207) . I n an experiment des igned to determine the f a t e of (207) , the r e a c t i o n mix ture o b t a i n e d by treatment of (100) w i t h m e t h y l l i t h i u m , as o u t l i n e d above, was t r e a t e d w i t h 2 , 4 - d i -n i t r o b e n z e n e s u l f e n y l c h l o r i d e (209) and then was a l l o w e d to warm to room temperature . In accordance w i t h our e x p e c t a t i o n s , the product For example, see r e f . 67 and r e f e r e n c e s c i t e d t h e r e i n . T h i s reagent has been used f o r the c h a r a c t e r i z a t i o n of o l e f i n s (see r e f . 68) . - 65 (42) N0 2 210 obtained upon recrystallization (54% yield) proved to be the substituted cyclopropane (210) (equation 42). The spectral data obtained from this material are in complete agreement with the structural assignment. The mass spectrum of (210) contained prominent peaks corresponding to the molecular ion and (M +- 3-*Cl). The nmr spectrum showed the signals expected for cyclopropyl protons (a 3-proton multiplet and a 1-proton multiplet at 5 1.20-1.40 and S 1.52-1.65, respectively) and a methyl group (a 3-proton doublet at 6 1.66, J -= 7 Hz). The aromatic protons on the 2,4-dinitro-benzenesulfenyl group gave rise to three 1-proton signals at 6 8.40 (d, J - 10 Hz), 8.54 (d of d, J - 2, 10 Hz), and 8.98 (d, J - 2 Hz). More importantly, regiochemistry of the addition product was indicated by a 1-proton quartet at 6 4.38 (J — 7 Hz), assigned to the proton geminal to the chlorine atom. Had the regioisomer been formed, this proton (gemi-nal to the SAr group) would probably have resonated at significantly - 66 -higher f i e l d . * Thus, i t is evident that, even at -78°C, the li thio compound (207) undergoes facile intramolecular displacement of chloride ion to afford ethylidenecyclopropane (208), which reacts with the sulfenyl chloride (209) to produce the addition product (210). The instability of (207) as compared with its geometric isomer (204) is very surprising. Intermediate (207) may possess higher energy than (204) by virtue of the steric interaction between the cis alkyl substituents. This difference in energy of the intermediates (204) and (207) might be responsible for a lower activation-energy barrier for intramolecular cyclization in the case of (207) relative to that of its geometric isomer (204). Regardless of the rationale for the difference in stability, i t is clear that, in sharp contrast to (E)-5-chloro-3-lithio-2-pentene (204), the (Z)-isomer (207) is very unstable even at -78°C and hence is not a viable reagent for organic synthesis. It seems highly likely that i f a substance with structure similar to (207) is to be employed successfully * For example, in the XH nmr spectra of (211) 6 9 a and (212) 6 9 b, the protons H A , Hg, and H c appear at 6 3.05, 4.36, and 3.54, respectively. 211 212 67 as a donor-acceptor reagent, the chlorine atom will have to be sup-planted by a group (e.g., a protected alcohol moiety) which is not easily displaced. D. Copper(I)-Catalyzed Conjugate Addition of the Grignard Reagent Derived from (204) to Cyclic Enones: Convenient (Z)-Ethylidene-cyclopentane Annulation Sequences The facil i ty with which organocuprates and organocopper reagents undergo conjugate addition to a,/5-unsaturated ketones has attracted a great deal of interest and has been utilized very imaginatively in organic synthesis. 7^ An ini t ia l report in 1941 by Kharasch and Tawney described the use of catalytic quantities of CuCl in the presence of MeMgBr for effecting 1,4-addition of a methyl group to isophorone.7^ Much work has been performed since then and a plethora of different types of Cu-based reagents are now available to achieve these important t ransformat ions .However , the precise composition of these reagents or the identification of the reactive species present in the reaction mixtures are usually not known. The mechanistic details are equally unclear. There is evidence for a pathway involving i n i t i a l complexation of organocuprates with enones. 7 3 a The intermediacy of a copper(III) /?-adduct, which can undergo C-C bond formation by reductive elimination, For some recent chemical and spectroscopic studies on the composi-tion of organocuprates, see ref. 72. - 68 -is widely accepted.'-3 An i n i t i a l coordination of the carbonyl oxygen atom to the cuprate cluster, followed by electron transfer from the cuprate to the enone, to form an anion radical and an electron-deficient metal cluster has also been proposed.^ Despite the a b i l i t y of a number of different reagents of this type to serve as Michael donors, i t is often observed that any one combina-tion of cuprous salt and organometallic reagent may not be applicable, in a general sense, to a l l Michael acceptors. Thus, "the nature of R-Metal (Metal - MgX, L i ) , the choice of organocopper vs organocuprate, solvent, and the need for additives a l l contribute to the complexity of determining which reagent is best suited for the substrate in ques-t i o n " . 7 0 1 3 In addition, in order to make our annulation process synthetically viable, we were interested in preparing heterocuprates of the general structure (213) rather than bis-homocuprates (214). In view Li CI 213 214 of the likelihood of decomposition of (204) at higher temperatures, 6 6 i t was important to select a proper auxiliary ligand so that the conjugate addition reactions could be performed at low temperatures (below - 6 3 ° C ) . In making i n i t i a l choices regarding the nature of the copper(I) spec ies to use and general reaction conditions to employ, we were guided by past experience in our laboratory with structurally similar reagents 3 3 - 69 -Thus, a d d i t i o n of s o l i d p h e n y l t h i o c o p p e r (1 equiv) to a c o l d (-78°C) s o l u t i o n of ( E ) - 5 - c h l o r o - 3 - l i t h i o - 2 - p e n t e n e (204) i n THF [obta ined by t r a n s m e t a l a t i o n of (99) w i t h 1.1 equiv of M e L i ] , f o l l o w e d by s t i r r i n g of the m i x t u r e a t -78°C f o r 20 minutes , produced a y e l l o w s o l u t i o n - s u s p e n -s i o n o f the l i t h i u m p h e n y l t h i o c u p r a t e (215) . T h i s s o l u t i o n - s u s p e n s i o n was t r e a t e d s u c c e s s i v e l y w i t h one e q u i v a l e n t o f 2 -cyc lohexen-1 -one (216) ( -78°C, 2 h) and 1.4 equiv of HMPA ( -78°C, 15 min) and then was a l l o w e d to warm to room temperature . S u i t a b l e workup and f l a s h chromatography p r o v i d e d the b i c y c l i c o l e f i n i c ketone (217) i n 30% y i e l d ( e q u a t i o n 4 3 ) . T h i s I n i t i a l r e s u l t i n d i c a t e d the f e a s i b i l i t y o f the d e s i r e d e t h y l i d e n e c y c l o p e n t a n e a n n u l a t i o n but c l e a r l y , the y i e l d l e f t much to be d e s i r e d . T h e r e f o r e , we turned our a t t e n t i o n to c o p p e r ( I ) - c a t a l y z e d conjugate a d d i t i o n s o f the G r i g n a r d reagent (218) . T h i s reagent was prepared i n a s t r a i g h t f o r w a r d manner by treatment o f a THF s o l u t i o n of the c o r r e s p o n d i n g l i t h i o reagent (204) w i t h 1.2 e q u i v a l e n t s o f anhydrous magnesium bromide. Conjugate a d d i t i o n o f (218) to 2 -cyc lohexen-1-one (216) i n the presence o f 0.25 equiv o f cuprous b r o m i d e - d i m e t h y l s u l f i d e complex , 7 - * f o l l o w e d by treatment o f the s o l u t i o n o f the r e s u l t a n t e n o l a t e a n i o n w i t h HMPA as d e s c r i b e d above, and s u i t a b l e workup, p r o -v i d e d a 1:5 m i x t u r e (by g l c a n a l y s i s ) o f the c y c l i z e d p r o d u c t (217) and (43) 215 217 70 the c h l o r o ketone (219) ( equat ion 4 4 ) . The c h o i c e of s o l v e n t s and the nature of l i g a n d s i s known to i n f l u e n c e d r a m a t i c a l l y the outcome of organocopper conjugate a d d i t i o n - e n o l a t e t r a p p i n g r e a c t i o n s . 7 ^ 3 However, i n the o v e r a l l process d e s c r i b e d above, the use o f THF as s o l v e n t was v i t a l to the success of the i n i t i a l t r a n s m e t a l a t i o n r e a c t i o n of (99) and to the s t a b i l i t y of the l i t h i o spec ies (204) thus produced. An B r M 9 I t .2l6£uBr-Me£,THF B 2. HMPA 218 217 219 a l t e r n a t i v e p l o y was to quench the enola te a n i o n w i t h a p r o t o n source and to i s o l a t e the c o r r e s p o n d i n g conjugate a d d i t i o n p r o d u c t . The e n o l a t e c o u l d then be generated from the l a t t e r m a t e r i a l under more f a v o r a b l e c o n d i t i o n s f o r 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 . Thus, the f o l l o w i n g procedure i s r e p r e s e n t a t i v e f o r the e f f e c t i v e use of compound (99) i n c a r r y i n g out ( Z ) - e t h y l i d e n e c y c l o p e n t a n e a n n u l a t i o n r e a c t i o n s [ g e n e r a l i z e d i n (220) -*• (222) , Table V ] . T r a n s m e t a l a t i o n ( M e L i , THF, -78°C, 20 min) o f the v i n y l s t a n n a n e (99) produced the l i t h i o d e r i v a t i v e (204) , w h i c h , upon treatment w i t h 1.2 e q u i v a l e n t s of anhydrous MgBr2, was conver ted i n t o the G r i g n a r d reagent (218) . D i l u t i o n of the s o l u t i o n ( -78°C) w i t h Et20 , f o l l o w e d by s u c c e s s i v e a d d i t i o n of C u B r . f ^ S (0 .3 e q u i v ) , 2 - c y c l o h e x e n - l - o n e (216) (1 e q u i v ) , and B F 3 - E t 2 0 (1.2 e q u i v ) 7 * * gave, a f t e r a r e a c t i o n time of 2 h and s u i t a b l e workup, the conjugate a d d i t i o n p r o d u c t (219) i n 70% y i e l d . 71 -Table V: Preparation of (Z)-Ethylidenecyclopentane Annulation Products3 220 A •Y B 221 222 Entry Enone Conjugate Addition Product (% yield) b Annulation Product (% yield) b 0 216 0 223 224 235 (79) 228 234 (72) 240 (85) Reaction conditions A: 218 ( 1 equiv), CuBr.Me2S (0.3 equiv), B F 3 . E t 2 0 (1 . 2 equiv), THF-Et20, -78°C, 2 h; sat. NH 4C1. B: KH, THF, r . t . , 2.5 h; sat. N H 4 C I . Yield of purified, disti l led product. 73 -Intramolecular alkylation (KH, THF, r .t . ) of the latter material pro-vided the bicyclic olefinic ketone (217) in 78% isolated yield (equation 45). The generality of this interesting annulation sequence was demon-strated by the conversion of the enones (223)-(228) into the annulation products (235)-(240), respectively (see Table V). In each case, a procedure identical with that outlined above was employed. The overall yields were typically about 50%. Interestingly, even the conjugate additions of the relatively hindered Grignard reagent (218) to the 0,/9-disubstituted enones (223), (226), and (228) were quite efficient. Two points regarding the procedure employed are noteworthy. Dilution of the THF solution of the Grignard reagent (218) with ether (approximately two times the original volume of the THF solution) was important especially for the reactions involving the substituted enones. For example, 3-methy'l-2-cyclohexen-l-one (223) was converted into the addition product (229) in 41% yield when ether was not used. However, the same transformation was achieved in 61% yield by employing the aforementioned procedure. Good donor solvents (e.g. THF, DME) are known to retard the rate of conjugate addition and their admixture with less - 74 -p o l a r s o l v e n t s has been employed s u c c e s s f u l l y to o p t i m i z e y i e l d s of the d e s i r e d 1 , 4 - a d d i t i o n r e a c t i o n s . 7 ^ a > 7 7 L i k e w i s e , the s y n t h e t i c u t i l i t y of boron t r i f l u o r i d e - e t h e r a t e i n promoting conjugate a d d i t i o n s of organocopper compounds to enones i s w e l l - d o c u m e n t e d . 7 6 R e c e n t l y , a comparat ive s tudy of the i n f l u e n c e o f v a r i o u s Lewis a c i d s on r e a c t i o n s o f h i g h e r order cuprates 7 0 b w a s c o n d u c t e d . 7 6 3 S p e c i a l mention was made of B F 3 - E t 2 0 f o r i t s ' unique a b i l i t y to compensate f o r reduced mixed cuprate r e a c t i v i t y v i a s u b s t r a t e a c t i v a t i o n . There i s evidence to i n d i c a t e t h a t B F 3 ' E t 2 0 can ac t as a s t r o n g Lewis a c i d even i n the presence o f o r g a n o l i t h i u m s p e c i e s . 7 8 The r e s u l t s o f the s tudy of a number o f ( Z ) - e t h y l i d e n e c y c l o p e n t a n e a n n u l a t i o n sequences are summarized i n Table V . I n a l l cases s t u d i e d , the crude product o b t a i n e d a f t e r the c o p p e r ( I ) - c a t a l y z e d a d d i t i o n of the G r i g n a r d reagent (218) to enones c o n s i s t e d e s s e n t i a l l y of the conjugate a d d i t i o n p r o d u c t ( s ) and a s m a l l amount o f the u n r e a c t e d enone. In each case , the products were r e a d i l y separated from the s t a r t i n g m a t e r i a l by s u b j e c t i o n of the crude mix ture to f l a s h chromatography on s i l i c a g e l . The g l c and t i c ana lyses of the c h l o r o ketones (219) , (229) , (231) , (232) and (234) [see Table V] i n d i c a t e d t h a t they c o n s i s t e d of e s s e n t i a l l y one component. T h e i r s p e c t r a l data are i n agreement 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 (229) showed a c a r b o n y l a b s o r p t i o n a t 1705 c m - 1 . The nmr spectrum of (229) e x h i b i t e d s i g n a l s expected f o r the t e r t i a r y methyl group (a 3 -proton s i n g l e t a t 6 1 .19 ) , the v i n y l methyl group (a 3 - p r o t o n double t at 8 1.79, J - 7 H z ) , and the o l e f i n i c p r o t o n (a 1 - p r o t o n q u a r t e t a t 6 5 . 3 8 , J •= 7 H z ) . A d d i t i o n a l l y , the -CH 2 C1 protons gave r i s e to a m u l t i p l e t at 75 -6 3 .47-3 .57 w h i l e the s i g n a l due to the a l l y l i c methylene protons appeared as a m u l t i p l e t at 6 2 . 3 9 - 2 . 5 3 . The l a t t e r assignments were c o n f i r m e d by a d e c o u p l i n g exper iment . Thus, i r r a d i a t i o n o f the m u l t i p -l e t a t S 3 .47-3 .57 ( - C H 2 C 1 ) s i m p l i f i e d the m u l t i p l e t a t 6 2 .39 -2 . 53 ( - C H 2 - ) t o a p a i r of double ts (J - 14 Hz , i n each c a s e ) . Not s u r p r i s i n g l y , the compounds (230) and (233) were, i n each case, found to c o n s i s t o f a mixture of epimers . I n the ^H nmr spectrum of (230) , the secondary methyl group gave r i s e to a p a i r of d o u b l e t s ( r a t i o - 2 : 1 , J - 7 Hz i n each case) a t 6 1.06 and 0 .90 , r e s p e c t i v e l y . Thus, the r a t i o of the two epimers i n (230) was a p p r o x i m a t e l y 2 : 1 . S i m i l a r l y , compound (233) was found by ^H nmr spec t roscopy to c o n s i s t o f an a p p r o x i m a t e l y equal p r o p o r t i o n of two epimers . 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 s of the c h l o r o ketones (221) to y i e l d the r i n g - a n n u l a t e d products (222) were c l e a n and e f f i c i e n t . In t h e o r y , the products i n i t i a l l y o b t a i n e d , except f o r (236) and (239) , c o u l d have undergone subsequent e p i m e r i z a t i o n a t the b r i d g e h e a d p o s i t i o n ad jacent to the c a r b o n y l group. However, a l l the i n t r a m o l e c u l a r a l k y l a -t i o n p r o d u c t s (222) were found to be i s o m e r i c a l l y p u r e . T h i s observa-t i o n , i n i t i a l l y made on the crude products on the b a s i s o f g l c a n a l y s e s , was l a t e r c o n f i r m e d by analyses of the ^H nmr s p e c t r a o f these r i n g -a n n u l a t e d p r o d u c t s . The s p e c t r a l p r o p e r t i e s o f these compounds agreed w e l l w i t h the proposed s t r u c t u r e s . For example, the i r spectrum of (239) showed an a b s o r p t i o n i n the r e g i o n expected f o r non-conjugated ketone c a r b o n y l groups on a 5-membered r i n g (1725 c m ' ^ ) . In the ^H nmr spectrum of (239) , the s i g n a l s c o r r e s p o n d i n g to the t e r t i a r y methyl group and the v i n y l methyl group appeared a t 8 1.11 ( 3 - p r o t o n s i n g l e t ) 76 -and a t 6 1 .66 ( 3 - p r o t o n b r o a d d o u b l e t , J - 7 H z ) , r e s p e c t i v e l y . The m e t h i n e p r o t o n gave r i s e t o a o n e - p r o t o n m u l t i p l e t a t S 2 .88-2 .94 whereas t h e 1 - p r o t o n b r o a d q u a r t e t a t 6 5 .35 ( J - 7 Hz) was a t t r i b u t e d t o t h e o l e f i n i c p r o t o n . S i n c e t h e a n n u l a t i o n p r o d u c t s (222) a r e p r o d u c e d b y k i n e t i c a l l y c o n t r o l l e d i n t r a m o l e c u l a r a l k y l a t i o n s o f t h e c o r r e s p o n d i n g c h l o r o k e t o n e s (221) , t h e b r i d g e h e a d s t e r e o c h e m i s t r y o f t h e i n i t i a l l y p r o d u c e d b i c y c l i c k e t o n e s w o u l d be e x p e c t e d t o be c i s . 3 3 <3^ > 7 7 b S u b s e q u e n t e p i m e r i z a t i o n i s n o t p o s s i b l e i n c a s e o f compounds (236) and ( 2 3 9 ) . H e n c e , t h e s e two b i c y c l i c k e t o n e s w o u l d p o s s e s s c i s - f u s e d r i n g s y s t e m s . I n t h e ^ H nmr s p e c t r u m o f ( 2 3 6 ) , t h e m e t h i n e p r o t o n s i g n a l a p p e a r s as a d o u b l e t o f d o u b l e t s ( J - 5, 12 Hz) a t S 2 . 6 3 . The c o u p l i n g c o n s t a n t s a g r e e w i t h t h e s p e c u l a t i o n t h a t t h e b r i d g e h e a d p r o t o n w o u l d be a x i a l l y o r i e n t e d ( w i t h r e s p e c t t o t h e s i x - m e m b e r e d r i n g ) i n t h e p r e f e r r e d c o n f o r m a t i o n o f t h i s m o l e c u l e . T r a n s - f u s e d b i c y c l o [ 3 . 3 . 0 ] o c t a n e s y s t e m s a r e v e r y s t r a i n e d a n d e v e n u n d e r e p i m e r i z i n g c o n d i t i o n s , t h e c i s - f u s e d r i n g s y s t e m s w o u l d be p r e f e r r e d . T h e r e f o r e , t h e s t e r e o c h e m i s t r y a t t h e r i n g j u n c t i o n o f e a c h o f t h e compounds ( 2 3 7 ) , (238) and (240) c a n be ( r e a s o n a b l y ) assumed t o be c i s . A s e x p e c t e d on the b a s i s o f k i n e t i c p r e f e r e n c e f o r 5-membered r i n g f o r m a t i o n o v e r 6- o r 7-membered r i n g c l o s u r e s , t h e s i t e - s e l e c t i v i t y w i t h t h e s e i n t r a m o l e c u l a r c y c l i z a t i o n s [ (221) -+ ( 2 2 2 ) , T a b l e V] w a s f o u n d t o be e x c e l l e n t . F o r e x a m p l e , t h e ^ H nmr s p e c t r u m o f t h e p r o d u c t o b t a i n e d u p o n t r e a t m e n t o f t h e c h l o r o k e t o n e (234) w i t h p o t a s s i u m h y d r i d e c o n t a i n e d a 1 - p r o t o n d o u b l e t o f d o u b l e t s ( J - 9 , 18 Hz) a t S 2 . 5 0 . T h i s s i g n a l , a s s i g n e d t o the p r o t o n H A i n ( 2 4 0 ) , e s t a b l i s h e d 77 u n e q u i v o c a l l y the s t r u c t u r e of the annula ted p r o d u c t as (240) . No p r o t o n i n the r e g i o i s o m e r i c product (241) would be expected to g ive r i s e to such a c o u p l i n g p a t t e r n . The f o r m a t i o n of a s i n g l e s tereo isomer upon i n t r a m o l e c u l a r a l k y l a -t i o n o f the c h l o r o ketone (219) was somewhat s u r p r i s i n g . The f r e e energy d i f f e r e n c e between c i s - and t r a n s - h y d r i n d a n e [(242) and (243) , r e s p e c t i v e l y ] has been e s t i m a t e d to be l e s s than 1 k c a l / m o l . 7 9 A l s o , M H H 2 4 2 243 c y c l i z a t i o n o f the c h l o r o ketone (244) u s i n g potass ium h y d r i d e has been r e p o r t e d to produce the two s t e r e o i s o m e r i c products (245) and (246) i n a r a t i o o f 4 . 9 : 1 , r e s p e c t i v e l y ( e q u a t i o n 4 6 ) . ^ M o l e c u l a r mechanics (46) 78 c a l c u l a t i o n s on the two p o s s i b l e products (217) and (247) o b t a i n a b l e from c y c l i z a t i o n of (219) i n d i c a t e d t h a t the energy d i f f e r e n c e between St* these isomers i s q u i t e s m a l l . The r i n g - f u s i o n s t e r e o c h e m i s t r y o f the c y c l i z a t i o n p r o d u c t of (219) was shown to be c i s as f o l l o w s . I n a d d i t i o n to the s i g n a l s due to the o l e f i n i c p r o t o n (8 5 .29 , 1 p r o t o n t r i p l e t o f q u a r t e t s , J = 2, 7 Hz) and the v i n y l methyl group (8 1.64, 3 - p r o t o n t r i p l e t o f d o u b l e t s , J - 1 .5 , 7 H z ) , the ^H nmr spectrum o f the product (217) e x h i b i t e d f o u r i d e n t i f i -ab le resonances a t 8 3 .00-3 .06 ( 1 - p r o t o n m u l t i p l e t ) , 8 2 .62-2 .70 ( 1 - p r o t o n m u l t i p l e t ) , 8 1.72 ( 1 - p r o t o n d o u b l e t o f d o u b l e t o f q u a r t e t s , J - 4 , 5 , 13 H z ) , and 8 1.40 ( 1 - p r o t o n double t o f q u a r t e t s , J - 4 , 13 H z ) . These s i g n a l s were a s s i g n e d to the protons H A , Hg, H ^ , and Hp, r e s p e c t -i v e l y , on the b a s i s of d e c o u p l i n g exper iments . Thus, i r r a d i a t i o n a t 8 217 247 2.66 (Hg) s i m p l i f i e d the s i g n a l a t 5 3 .00-3 .06 (H A ) to a double t o f d o u b l e t s (J - 6, 13 H z ) . On the other hand, s a t u r a t i o n of the s i g n a l at 6 3.03 (H A ) caused the s i g n a l a t 5 2 .62-2 .70 (Hg) and 8 1.40 (H D ) to modify to a d o u b l e t o f double ts (J — 8, 9 Hz) and a d o u b l e t of t r i p l e t s We thank P r o f . L a r r y W e i l e r o f t h i s department f o r p e r f o r m i n g these m o l e c u l a r mechanics c a l c u l a t i o n s . - 79 -( J - 4 , 13 H z ) , r e s p e c t i v e l y . The s i g n a l a t 8 1.72 ( H C ) remained unchanged i n both o f the exper iments . The magnitude o f the c o u p l i n g cons tants a s s o c i a t e d w i t h H A and HJJ, as summarized above, a l o n g w i t h the f a c t t h a t the s i g n a l s due to these protons e x h i b i t w i d t h - a t - h a l f - h e i g h t of 26 and 24 Hz , r e s p e c t i v e l y , enabled us to es t imate the v a l u e of J A g as -7 H z . The l a t t e r v a l u e i n d i c a t e d a c i s r i n g - f u s i o n s t e r e o c h e m i s t r y f o r compound (217) . T h i s c o n c l u s i o n was v e r i f i e d by means o f a n u c l e a r Overhauser enhancement (nOe) d i f f e r e n c e exper iment . Thus, s a t u r a t i o n of the s i g n a l a t 8 3.03 (H A ) caused a n o t i c e a b l e s i g n a l enhancement at 8 2.62-2 .70 (Hg) . I n t e r e s t i n g l y , an a p p r e c i a b l e enhancement was a l s o observed f o r the s i g n a l a t 8 1.64 ( v i n y l methyl g r o u p ) . T h i s r e s u l t i s i n l i n e w i t h the a s s i g n e d ( Z ) - c o n f i g u r a t i o n o f the carbon-carbon double bond i n (217) . Furthermore , the c o u p l i n g p a t t e r n (d of d of d , J •= 6, 7, 13 Hz) o f the br idgehead p r o t o n H A i n the compound (217) suggests t h a t t h i s substance e x i s t s l a r g e l y i n a conformat ion (A) t h a t h o l d s H A i n an a x i a l o r i e n t a t i o n w i t h r e s p e c t to the six-membered r i n g . T h i s p r e f e r -ence i s p r o b a b l y because of the severe A ^ ' 3 ) s t e r i c compression present i n the a l t e r n a t i v e c o n f o r m a t i o n (B) ( e q u a t i o n 4 7 ) . (47) 2 I 7 A 2 I 7 B - 80 -U n f o r t u n a t e l y , the br idgehead p r o t o n c o u l d not be i d e n t i f i e d w i t h conf idence i n case of the compound (235) , which was o b t a i n e d as a s i n g l e s te reo i somer by treatment o f the c h l o r o ketone (229) w i t h potassium h y d r i d e . The c o n s t i t u t i o n and r e l a t i v e s t e r e o c h e m i s t r y o f compound (235) , which i s s t r u c t u r a l l y r e l a t e d to some r e c e n t l y prepared s t e r o i d C D - r i n g synthons , was shown c o n c l u s i v e l y by two independent methods. H y d r o l y s i s ( K 2 C O 3 , MeOH) of the ace ta te ( 2 4 8 ) 8 0 ' * (one enant iomer) , f o l l o w e d by o x i d a t i o n (PCC, NaOAc, C H 2 C I 2 ) 8 1 o f the r e s u l t a n t a l c o h o l (249) , p r o v i d e d the ketone (250) which was s p e c t r a l l y d i f f e r e n t from (235) ( e q u a t i o n 4 8 ) . Thus, the o l e f i n i c p r o t o n ( t r i p l e t of q u a r t e t s , J = 2 , 7 H z ) , and the br idgehead methyl group ( s i n g l e t ) appeared a t 6 5.21 and 6 0 .88 , r e s p e c t i v e l y i n the * H nmr spectrum of (250) w h i l e the c o r r e s p o n d i n g s i g n a l p o s i t i o n s i n the * H nmr spectrum of (235) were 6 5.28 and 6 1 .32 , r e s p e c t i v e l y . A d d i t i o n a l l y , the a x i a l o r i e n t a t i o n of the br idgehead p r o t o n i n (250) was r e f l e c t e d i n the c o u p l i n g p a t t e r n a s s o c i a t e d w i t h i t (5 2 .60 , double t o f d o u b l e t s , J = 6, 12 H z ) . In accordance w i t h our e x p e c t a t i o n s , treatment o f (250) w i t h potass ium h y d r o x i d e i n E t O H - ^ O caused complete i s o m e r i z a t i o n a t the br idgehead p o s i t i o n ad jacent to the c a r b o n y l group and produced a ketone which e x h i b i t e d i r and ^H nmr s p e c t r a i d e n t i c a l w i t h those o f our a n n u l a t i o n p r o d u c t (235) ( e q u a t i o n 48 ) . The a n n u l a t i o n product (235), o b t a i n e d by i n t r a m o l e c u l a r a l k y l a t i o n We w i s h to express our deep a p p r e c i a t i o n to D r . B a g g i o l i n i , Hoffmann-La Roche, I n c . , New J e r s e y , f o r a generous sample of compound (248) . - 81 -: H AcO M e OH K 2 C 0 3 •* H H O P C C , N a O A c H (48) 0 0 2 4 8 249 250 235 of the chloro ketone (229), was reduced with sodium borohydride in methanol to produce, after flash chromatography of the crude product mixture, two epimeric alcohols (251) and (252) in a ratio of 37:63, respectively. Recrystallization from heptane provided needle-shaped constitution and relative stereochemistry of (252) and, in turn, those of compound (235) (Fig. 1). In summation, i t was found that the stability of the 5-chloro-3-lithio-2-pentenes is dramatically dependent on the geometry of the double bond. Thus, the (Z)-isomer (207), formed by transmetalation of We thank Dr. Steven Rettig of this department for performing the X-ray crystallographic analysis. - 82 F i g u r e 1: The p e r s p e c t i v e v i e w of the a l c o h o l (252) compound (100) , was v e r y u n s t a b l e and, even a t -78°C, was conver ted r a p i d l y i n t o e t h y l i d e n e c y c l o p r o p a n e (208) ( e q u a t i o n 4 9 ) . I n c o n t r a s t , ( E ) - 5 - c h l o r o - 3 - l i t h i o - 2 - p e n t e n e (204) and the c o r r e s p o n d i n g G r i g n a r d reagent (218) , r e a d i l y prepared from (99), were s u f f i c i e n t l y s t a b l e to serve as p i v o t a l s p e c i e s i n the development o f a new ( Z ) - e t h y l i d e n e -cyc lopentane a n n u l a t i o n method ( e q u a t i o n 50) . The l a t t e r o p e r a t i o n shows c o n s i d e r a b l e promise f o r a p p l i c a t i o n s i n o r g a n i c s y n t h e s i s . For example, our a n n u l a t i o n method may be u s e f u l f o r the p r e p a r a t i o n of the b i c y c l o [ 4 . 3 . O J n o n a n e (hydrindane) fragment w i d e l y encountered i n nature i n a v a r i e t y of n a t u r a l p r o d u c t s . The ionophore a n t i b i o t i c X-14547A ( 2 5 3 ) ° ^ a n d the p h y s i o l o g i c a l l y a c t i v e v i t a m i n D3 m e t a b o l i t e l a , 2 5 - d i -h y d r o x y c h o l e c a l c i f e r o l ( 2 5 4 ) 8 3 are r e p r e s e n t a t i v e examples of such n a t u r a l p r o d u c t s . Indeed, the e n a n t i o m e r i c a l l y pure b i c y c l i c acetate 83 -253 254 - 84 -(248) was used as a key b u i l d i n g b l o c k i n a t o t a l l y s y n t h e t i c route to o b t a i n l a , 2 5 - d i h y d r o x y c h o l e c a l c i f e r o l ( 2 5 4 ) . 8 0 Thus, ene r e a c t i o n of (248) w i t h e t h y l propynoate a f f o r d e d (255) and c a t a l y t i c h y d r o g e n a t i o n o f the l a t t e r substance proceeded s t e r e o s e l e c t i v e l y from the l e s s h i n d e r e d face t o produce (256) i n e x c e l l e n t y i e l d ( e q u a t i o n 51) . T h i s compound was subsequent ly conver ted i n t o the n a t u r a l product ( 2 5 4 ) . 8 0 248 255 256 The r i n g - f u s i o n s t e r e o c h e m i s t r y o f the hydr indane n u c l e u s present i n n a t u r a l products i s i n v a r i a b l y t r a n s . T h e r e f o r e , s u c c e s s f u l a p p l i c a t i o n o f our methodology demands a p l a n i n v o l v i n g e f f e c t i v e e p i m e r i z a t i o n a t a br idgehead p o s i t i o n a t some l a t e r stage of the s y n t h e s i s . I l l . T o t a l S y n t h e s i s o f the Oplopanane-tvpe S e s q u i t e r p e n o i d s (±)Oplopanone, ( ± ) - 8 - e p i - 0 p l o p a n o n e . and (±)-Anhydro-oplopanone A . I n t r o d u c t i o n Oplopanax i a p o n i c u s . a shrub b e l o n g i n g to A r a l i a c e c e , i s used as an a n t i p y r e t i c and cough cure i n Japan. I n 1965, a new type o f s e s q u i t e r -85 pene ketone , (±)-oplopanone (257), was i s o l a t e d from the e ther e x t r a c t of t h i s p l a n t and i t s s t r u c t u r e and abso lu te c o n f i g u r a t i o n were r e p o r t e d . 8 4 Subsequent ly , i t has been de tec ted i n many d i v e r s e o r g a n i s m s . 8 ^ xhe o l e f i n i c ketones ( - ) -anhydro-oplopanone ( 2 5 8 ) 8 6 and (-)-Qf-oplopenone ( 2 5 9 ) 8 7 are a l s o n a t u r a l p r o d u c t s , h a v i n g been i s o l a t e d from Euryops pedunculatus and S a n t o l i n a o b l o n p i f o l i a . r e s p e c t i v e l y . The substances (257)-(259) are three members o f a s m a l l group o f oplopanane-type s e s q u i t e r p e n o i d s . 2 5 7 2 5 8 2 5 9 I t i s i n t e r e s t i n g to s p e c u l a t e on the b i o g e n e t i c o r i g i n of these sesqui te rpene n a t u r a l p r o d u c t s . D u r i n g t h e i r work on the s t r u c t u r a l e l u c i d a t i o n o f oplopanone (257) , Minato and coworkers c o n v e r t e d (257) i n t o the ketone ( 2 6 0 ) . 8 4 S ince ketone (260) was o b t a i n a b l e from a - c a d i n o l ( 2 6 1 ) , 8 8 the authors suggested t h a t a - c a d i n o l (261) c o u l d be (52) - 86 -a p r e c u r s o r of oplopanone (257) i n the p l a n t body and t h a t the former substance may be conver ted i n t o (257) by r i n g c o n t r a c t i o n . Cocker has proposed the f o l l o w i n g two-stage process f o r the b i o g e n e t i c f o r m a t i o n of the oplopanone carbon s k e l e t o n from a cadinane ( e q u a t i o n 5 3 ) . 8 9 (53) 2 6 2 2 6 3 2 6 4 Bohlmann's s p e c u l a t i o n 8 * ' concern ing the b i o g e n e t i c f o r m a t i o n of anhydro-oplopanone (258) i n v o l v e s o x i d a t i o n of b i s a b o l e n e (265), f o l l o w e d by i n t r a m o l e c u l a r a l d o l condensat ion o f the r e s u l t a n t ke to aldehyde (266) , to p r o v i d e the enone (268) . I n t r a m o l e c u l a r " M i c h a e l " a d d i t i o n and subsequent r e d u c t i o n c o u l d then occur i n a s t e r e o s e l e c t i v e manner to a f f o r d anhydro-oplopanone (258) (Scheme 12) . B. P r e v i o u s S y n t h e t i c Approaches t o (±)-Oplopanone The b i c y c l i c s t r u c t u r e o f oplopanone (257) , i n c o r p o r a t i n g a t rans -fused b i c y c l o [ 4 . 3 . 0 ] n o n a n e r i n g system and f i v e c h i r a l c e n t e r s , o f f e r s an i n t e r e s t i n g s y n t h e t i c c h a l l e n g e . The f i r s t s y n t h e s i s o f (257) was r e p o r t e d by Caine and T u l l e r i n 1 9 7 1 . 9 ^ T h e i r approach was based on an e legant photochemica l rearrangement of the c r o s s - c o n j u g a t e d c y c l o h e x a -- 87 -2 6 8 2 6 9 2 5 8 Scheme 12 dienone (274) i n g l a c i a l a c e t i c a c i d . Thus, t reatment o f 1 ,4 -dimethoxy-2-butanone (271) w i t h the potass ium e n o l a t e o f (270) p r o v i d e d a mix ture o f d i k e t o n e s (272) i n 25% y i e l d . A l d o l condensa t ion o f (272) w i t h a l c o h o l i c potass ium h y d r o x i d e , f o l l o w e d by se lenium d i o x i d e o x i d a t i o n of the r e s u l t a n t enone (273) i n t e r t - b u t y l a l c o h o l , a f f o r d e d the r e q u i r e d dienone (274) as the major p r o d u c t . The p h o t o - i n d u c e d rearrangement of (274) i n a c e t i c a c i d proceeded s t e r e o s e l e c t i v e l y to produce (275) i n good y i e l d . The t r a n s f o r m a t i o n of (275) i n t o the e p i m e r i c m i x t u r e (276) was accompl ished v i a a two-step sequence i n v o l v i n g r e d u c t i o n and a c e t y l a t i o n . Cleavage of the a l l y l i c ace ta te and r e d u c t i o n o f the t e r t i a r y ace ta te grouping were e f f e c t e d by treatment o f (276) w i t h 88 l i t h i u m i n e t h y l a m i n e . Subsequent h y d r o l y s i s of the r e s u l t i n g hydroxy enol e t h e r under e q u i l i b r a t i n g c o n d i t i o n s produced the t r a n s - f u s e d b i c y c l i c hydroxy ketone (277) . Treatment of (277) w i t h sodium a c e t y l i d e gave the e t h y n y l c a r b i n o l (278), which was conver ted i n t o the a -acetoxy ketone (279) by oxymercurat ion of the t r i p l e bond, f o l l o w e d by demercur-a t i o n w i t h hydrogen s u l f i d e . Reduct ive removal of the acetoxy group w i t h c a l c i u m i n l i q u i d ammonia and Jones ' o x i d a t i o n of the d i o l thus o b t a i n e d , completed the f i r s t t o t a l s y n t h e s i s of (±) -oplopanone (257) (Scheme 1 3 ) . 9 0 T a b e r ' s s t r a t e g y f o r the synthes is 9 - 1 - o f (±) -oplopanone (257) was d e v i s e d from a " l o g i c a l " r e t r o s y n t h e t i c a n a l y s i s of the t a r g e t m o l e c u l e . As shown i n Scheme 14, the s y n t h e s i s of (257) was accompl ished i n t e n s teps from 2 - m e t h o x y - 5 - i s o p r o p y l b e n z o i c a c i d (280) . R e d u c t i v e a l k y l a -t i o n of (280) w i t h /3-bromophenetole p r o v i d e d the enone (281) . C o p p e r ( I ) -mediated conjugate a d d i t i o n o f v inylmagnesium bromide o c c u r r e d t r a n s to the i s o p r o p y l group to produce the d e s i r e d t r i s u b s t i t u t e d cyclohexanone (282) . Thus, three c h i r a l centers w i t h the r e q u i r e d c o n f i g u r a t i o n were generated i n the key s tep of t h i s s y n t h e s i s . W i t t i g o l e f i n a t i o n of (282) gave (283) , which was t r e a t e d w i t h boron t r i b r o m i d e to a f f o r d the somewhat u n s t a b l e bromide (284) . Chemoselect ive h y d r o b o r a t i o n was c a r r i e d out w i t h d i s i a m y l b o r a n e and o x i d a t i v e workup produced the bromo a l c o h o l (285) . O x i d a t i o n of (285) , f o l l o w e d by i n t r a m o l e c u l a r a l k y l a t i o n of the r e s u l t a n t bromo aldehyde under e q u i l i b r a t i n g c o n d i -t i o n s , p r o v i d e d the b i c y c l i c aldehyde (286) . T h i s compound was conver ted i n t o (±)-oplopanone (257) by a d d i t i o n o f m e t h y l l i t h i u m to give (287) , s u c c e s s i v e treatment of the l a t t e r substance w i t h aqueous 89 -OMe 2 7 9 2 5 7 Scheme 13 - 90 -OMe ^ Y C C 2 H l L i . N H 3 Lj J 2 . P h O ^ B r 3 H C I - H 2 0 0 0 CuBr-Me 2 S 2 8 0 281 2 8 2 C H f = P P h 3 BBr , •Br »• S i c ^ B H . T H F 2 . a q N a O H , H 2 0 2 2 8 3 2 8 4 3 r , PCC 2 KOt-Bu.t -BuOH O H MeLi 2 8 5 2 8 6 H Q , i H g t O A c ^ . H g O - T H F 2aqNaOH .NcSH 4 Scheme 14 - 91 m e r c u r i c ace ta te and aqueous b a s i c sodium b o r o h y d r i d e , and o x i d a t i o n of the r e s u l t i n g d i o l (288) w i t h PCC. A c l a i m e d s y n t h e s i s of oplopanone (257) by K o s t e r and Wolf 9 2 centered around the a p p l i c a t i o n of a c a t i o n i c 7r - c y c l i z a t i o n of the a , ^ - u n s a t u r a t e d ketone (292), as d e p i c t e d i n Scheme 15. Treatment of 4 - i s o p r o p y l p h e n o l (289) w i t h ( 2 - c h l o r o e t h y l ) d i e t h y l a m i n e gave the c o r r e s p o n d i n g e ther w h i c h , upon B i r c h r e d u c t i o n , p r o v i d e d the d i h y d r o -benzene d e r i v a t i v e (290) . S i t e - s e l e c t i v e m e t a l l a t i o n o f (290) w i t h n - b u t y l l i t h i u m , and treatment of the l i t h i o compound w i t h 5-bromo-2-methyl -2 -pentene produced (291) . H y d r o l y s i s o f the e n o l e ther was accompl ished w i t h h y d r o c h l o r i c a c i d and the r e s u l t i n g ketone i s o m e r i z e d under the r e a c t i o n c o n d i t i o n s to a f f o r d (292) . D i r e c t c a t i o n - o l e f i n c y c l i z a t i o n was c a r r i e d out by treatment of the l a t t e r m a t e r i a l w i t h a m i x t u r e o f a c e t i c anhydride and a c e t i c a c i d c o n t a i n i n g a c a t a l y t i c amount o f p e r c h l o r i c a c i d a t 0°C. The r i n g - c l o s u r e was found to be s t e r e o s e l e c t i v e , o c c u r r i n g t r a n s to the i s o p r o p y l group, and h y d r o l y s i s of the r e s u l t i n g e n o l ace ta te (293) under e q u i l i b r a t i n g c o n d i t i o n s produced a 2 :3 m i x t u r e of (294) and i t s epimer (295) , r e s p e c t i v e l y . The r e l a t i v e s t a b i l i t i e s of (294) and (295) were r a t i o n a l i z e d on the b a s i s o f r e l a t i v e s t e r i c compression between the C-3 and C-5 s u b s t i t u e n t s i n the two epimers . E p o x i d a t i o n of t h i s mixture of epimers w i t h d i m e t h y l -s u l f o n i u m m e t h y l i d e (299) or d i m e t h y l o x o s u l f o n i u m m e t h y l i d e (300) was r e p o r t e d to produce a l l f o u r of the p o s s i b l e s t e r e o i s o m e r i c s p i r o -MeJB-CHj, Me 2 S-CH 2 0 2 9 9 3 0 C 92 2 9 6 2 9 7 2 9 8 2 5 7 Scheme 15 - 93 e p o x i d e s . However, under a p p r o p r i a t e r e a c t i o n c o n d i t i o n s [ (299) , K O ( t - B u ) , DMF, 0 ° C ] , one isomer was found to predominate . The s t r u c t u r e of t h i s isomer was c la imed to be as d e p i c t e d i n (296) . R e d u c t i o n of (296) , o z o n o l y s i s of the r e s u l t a n t o l e f i n i c a l c o h o l (297) , and e q u i l i b r a t i o n of the k e t o l (298) thus o b t a i n e d , was r e p o r t e d to p r o v i d e a 1:4 m i x t u r e of (298) and (±)-oplopanone (257) . However, the mp of t h i s s y n t h e t i c substance " (257)" ( 6 3 - 6 4 ° C ) 9 2 was q u i t e d i f f e r e n t from those r e p o r t e d ( 1 0 1 . 5 - 1 0 2 ° C , 9 0 , 9 7 - 9 8 ° C 9 1 ) p r e v i o u s l y f o r ( ± ) - ( 2 5 7 ) . R e c e n t l y , Yamamura and c o w o r k e r s 9 3 have r e p o r t e d a b i o m i m e t i c s y n t h e s i s o f (±) -oplopanone (257) from (±)-germacrene-D (301) . T r e a t -ment of (301) w i t h N-bromosuccinimide i n 3:2 THF-H2O produced a mixture of seven bromo compounds, from which (302) was i s o l a t e d i n 7% y i e l d . R e d u c t i o n of the a l l y l i c bromide (302) and o x i d a t i o n o f the r e s u l t a n t a - c a d i n o l (261) w i t h excess osmium t e t r o x i d e , a f f o r d e d the t r i o l (303) w h i c h , upon f u r t h e r treatment w i t h methanesu l fonyl c h l o r i d e and DMAP i n p y r i d i n e , p r o v i d e d (±)-oplopanone (257) (Scheme 16) . Thus, t h i s s y n t h e s i s supports the p o s t u l a t e d 8 ^ ' 8 9 i n t e r m e d i a c y o f cadinanes ( a - c a d i n o l , i n p a r t i c u l a r ) i n the b i o s y n t h e s i s o f oplopanane-type s e s q u i t e r p e n o i d s . A t o t a l s y n t h e s i s of (±)-anhydro-oplopanone (258) was not r e p o r t e d p r i o r to p u b l i c a t i o n of our work. However, B a b k i n e _ t _ _ a l . 8 - > a have r e p o r t e d t h a t d e h y d r a t i o n of ( - ) -oplopanone (257) w i t h t h i o n y l c h l o r i d e g i v e s a m i x t u r e of two o l e f i n i c ketones (258) and (304) ( e q u a t i o n 54) . The r e p o r t e d ( p a r t i a l ) s p e c t r a l data ( i r , ^H nmr) of the former sub-stance are i n agreement w i t h those r e p o r t e d f o r ( - ) -anhydro-oplopanone (258) by Bohlmann and Z d e r o . 9 2 - 94 -303 257 Scheme 16 258 304 C. T o t a l S y n t h e s i s o f (±)-Anhydro-oplopanone 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 (±) -anhydro-oplopanone (258) was somewhat 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 one key s tep i n mind. I t was envisaged that the 257 - 95 b i c y c l o [ A . 3 . 0 ] n o n a n e nucleus c o u l d be assembled r e a d i l y by. the genera l s t r a t e g y used f o r the p r e v i o u s l y developed ( Z ) - e t h y l i d e n e c y c l o p e n t a n e a n n u l a t i o n p r o c e s s . The e t h y l i d e n e moiety was contemplated to serve as a convenient p r e c u r s o r f o r the r e q u i r e d a - a c e t y l s i d e c h a i n . Thus, the former u n i t c o u l d e a s i l y be conver ted i n t o the l a t t e r f u n c t i o n by a s imple h y d r o b o r a t i o n - o x i d a t i o n sequence of r e a c t i o n s . The s tereochemis-t r y o f the a c e t y l moiety was not c r i t i c a l , s i n c e the p r e v i o u s syn-t h e s e s 9 ^ " 9 2 0 f (±)-oplopanone (257) had i n d i c a t e d t h a t the r e q u i r e d C - 3 c o n f i g u r a t i o n s h o u l d be thermodynamical ly more s t a b l e than the c o r r e -sponding epimer . Hence, the d e s i r e d substance c o u l d be o b t a i n e d by b a s e - c a t a l y z e d e q u i l i b r a t i o n . The proposed s y n t h e t i c route to ( ± ) - ( 2 5 8 ) i s summarized i n Scheme 17. 3 0 9 3 1 0 2 5 8 Scheme 17 C o p p e r ( I ) - c a t a l y z e d conjugate a d d i t i o n o f the G r i g n a r d reagent (218) to (305) would be expected to take p l a c e predominant ly (or c o m p l e t e l y ) t r a n s to the i s o p r o p y l g r o u p . 9 1 ' 9 4 T h i s would generate the d e s i r e d s t e r e o c h e m i s t r y a t C-4 and C-5 [see (258) , Scheme 1 7 ] . However, the c o n s t r u c t i o n o f the r e q u i r e d t r a n s hydrindane system was a more c h a l l e n g i n g t a s k , s i n c e i n t r a m o l e c u l a r a l k y l a t i o n o f (306) was e n v i -s i o n e d to p r o v i d e (307) w i t h c i s r i n g - f u s i o n s t e r e o c h e m i s t r y . We chose to approach t h i s problem i n the f o l l o w i n g manner. I n s p e c t i o n o f molecu-l a r models l e d to the c o n c l u s i o n t h a t h y d r o b o r a t i o n o f the k e t a l of (307) s h o u l d occur s t e r e o s e l e c t i v e l y from the more open a - f a c e o f the molecule to g i v e (308) . I t was hoped t h a t d e p r o t e c t i o n o f (308) , and base c a t a l y z e d e p i m e r i z a t i o n o f the r e s u l t a n t ke tone , would p r o v i d e (309) as the major p r o d u c t . M o l e c u l a r models appear to i n d i c a t e tha t the v a r i o u s s t e r i c i n t e r a c t i o n s i n the t r a n s isomer (309) a r e , i n t o t a l , l e s s severe than the s t e r i c r e p u l s i o n s i n the c o r r e s p o n d i n g c i s - f u s e d i somer . Once the necessary t r a n s - f u s e d r i n g system was assembled, W i t t i g o l e f i n a t i o n , o x i d a t i o n , and e p i m e r i z a t i o n of the a c e t y l s i d e c h a i n would f u r n i s h (±)-anhydro-oplopanone (258) (Scheme 17) . The s t a r t i n g m a t e r i a l chosen f o r the s y n t h e s i s , 4 - i s o p r o p y l - 2 -cyc lohexen-1-one (305) , i s commerc ia l ly a v a i l a b l e from A l d r i c h Chemical C o . , I n c . I n f r a r e d and ^H nmr s p e c t r a of t h i s m a t e r i a l i n d i c a t e d that i t was e s s e n t i a l l y pure and d e v o i d o f the c o r r e s p o n d i n g 0,7-unsaturated ke tone . The conjugate a d d i t i o n of the G r i g n a r d reagent (218) to the enone (305) proceeded i n a s t r a i g h t f o r w a r d manner to p r o v i d e (306) (equat ion 97 55) . Thus, to a c o l d ( -78°C) s o l u t i o n of ( Z ) - 5 - c h l o r o - 3 - t r i m e t h y l -s t a n n y l -2 -pentene (99) i n THF was added, s u c c e s s i v e l y , m e t h y l l i t h i u m (1 .1 e q u i v ) , anhydrous magnesium bromide (1.2 e q u i v ) , dry e t h e r , copper b r o m i d e - d i m e t h y l s u l f i d e (0 .3 e q u i v ) , 4 - i s o p r o p y l - 2 - c y c l o h e x e n - l - o n e (305) (1 e q u i v ) , and B F 3 • E t 2 0 (1 .2 e q u i v ) . A f t e r the r e s u l t a n t s o l u t i o n had been s t i r r e d f o r 2 h , i t was t r e a t e d w i t h s a t u r a t e d aqueous ammonium c h l o r i d e . F r a c t i o n a l d i s t i l l a t i o n o f the crude p r o d u c t thus ob ta ined p r o v i d e d the c h l o r o ketone (306) i n 70% y i e l d ( e q u a t i o n 55) . Concordant w i t h e x p e c t a t i o n , the M i c h a e l a d d i t i o n r e a c t i o n was h i g h l y s t e r e o s e l e c -t i v e and l e d to e x c l u s i v e f o r m a t i o n o f the d e s i r e d t r a n s - d i s u b s t i t u t e d cyclohexanone ( 3 0 6 ) . 9 4 2 1 8 - CuBr»Me2S. BF 3«Et 20. THF, -78* C 305 306 307 (55) The s p e c t r a l da ta d e r i v e d from (306) are i n complete agreement w i t h the proposed s t r u c t u r e . The % nmr spectrum o f t h i s m a t e r i a l e x h i b i t e d s i g n a l s c o r r e s p o n d i n g to the v i n y l methyl group ( 3 - p r o t o n t r i p l e t of d o u b l e t s a t S 1 .64, J <= 1 .5 , 7 Hz) and the o l e f i n i c p r o t o n ( 1 - p r o t o n q u a r t e t a t 6 5 .36 , J = 7 H z ) . The presence of the i s o p r o p y l group was i n d i c a t e d by a p a i r of 3 - p r o t o n d o u b l e t s a t 6 0.72 and 0.76 (J = 7 Hz i n each c a s e ) . More i m p o r t a n t l y , the s i g n a l due to the methine p r o t o n H A appeared as a double t o f t r i p l e t s (J - 4 . 5 , 12 Hz) a t 6 2.89 w h i l e the 98 -p r o t o n Hg gave r i s e t o a double t of double t s o f double t s (J - 2 . 5 , 4 . 5 , 13 Hz) a t 6 2 .17 . The l a t t e r assignments were conf i rmed when s a t u r a t i o n of the s i g n a l c o r r e s p o n d i n g t o Hg (5 2.17) r e s u l t e d i n s i m p l i f i c a t i o n of the s i g n a l at S 2.89 (H A ) to a s imple t r i p l e t (J - 12 H z ) . These r e s u l t s showed t h a t H A i s a x i a l l y o r i e n t e d on the six-membered r i n g and t h a t the s t e r e o c h e m i s t r y o f the a d d i t i o n product i s as shown i n (306). 306 Upon exposure to potass ium h y d r i d e (2 .5 equiv) i n t e t r a h y d r o f u r a n a t room temperature , compound (306) c y c l i z e d smoothly to p r o v i d e the b i c y c l i c ketone (307) i n 92% y i e l d ( e q u a t i o n 55) . I n t e r e s t i n g l y , compound (307) was the s o l e product o b t a i n e d even when the i n t r a m o l e -c u l a r a l k y l a t i o n o f (306) was c a r r i e d out under e q u i l i b r a t i n g c o n d i t i o n s [ K O ( t - B u ) , t -BuOH, 35-40°C, 15 h ] . Thus, (307) appears to be the k i n e t i c as w e l l as the thermodynamical ly f a v o r e d p r o d u c t o f t h i s c y c l i -z a t i o n r e a c t i o n . The s t e r e o c h e m i s t r y o f the r i n g f u s i o n i n (307) was e s t a b l i s h e d as f o l l o w s . I n the ^H nmr spectrum of (307) , the br idgehead protons H A and Hg gave r i s e to a broad double t o f d o u b l e t s (J - 7, 10 Hz) and a broad q u a r t e t (J - 7 Hz) a t 6 2.88 and 2 .63 , r e s p e c t i v e l y ( F i g . 2 ) . I r r a d i a -t i o n of the s i g n a l a t 6 2.88 (H A ) s i m p l i f i e d the s i g n a l a t 6 2.63 (Hg) to a broad t r i p l e t (J - 7 Hz) whereas s a t u r a t i o n o f the s i g n a l c o r r e -sponding t o Hg (6 2.63) r e s u l t e d i n s i m p l i f i c a t i o n of the s i g n a l at - 99 -F i g u r e 2 : The 400 MHz i H nmr spectrum o f (307) 8 2.88 (H A ) t o a b r o a d double t (J - 10 H z ) . The v i c i n a l c o u p l i n g c o n s t a n t J ^ g i s , t h e r e f o r e , 7 Hz and suggested a c i s - r e l a t i o n s h i p between H A and Hg. A d d i t i o n a l , more concre te evidence was o b t a i n e d by way o f a d i f f e r e n c e n u c l e a r Overhauser enhancement (nOe) exper iment . Thus, i r r a d i a t i o n a t S 2.88 (H A ) caused s i g n a l enhancement a t 6 2.63 (Hg) and a t S 1.63 ( v i n y l methyl g r o u p ) , s u p p o r t i n g thereby the ass igned s t r u c t u r e (307) f o r the c y c l i z a t i o n p r o d u c t . I n order to a l l o w f o r h y d r o b o r a t i o n of the t r i s u b s t i t u t e d double bond o f (307) , the ketone (307) was c o n v e r t e d i n t o the k e t a l (311) by S t e r z y c k i ' s m e t h o d . 9 ^ Thus, a mixture o f the ketone (307) (1 e q u i v ) , e t h a n e d i o l (3 e q u i v ) , and p y r i d i n i u m p . - t o l u e n e s u l f o n a t e 9 6 (0 .3 equiv) i n benzene was r e f l u x e d w i t h water s e p a r a t i o n by a Dean-Stark t rap to 100 p r o v i d e , a f t e r s u i t a b l e workup and d i s t i l l a t i o n , the k e t a l (311) i n 94% y i e l d (equat ion 56) . 307 311 The lH nmr spectrum of the k e t a l (311) ( F i g . 3) was c o n s i s t e n t w i t h the proposed s t r u c t u r e . The s i g n a l s a t 6 2 .61 ( 1 - p r o t o n d o u b l e t of d o u b l e t s , J - 7, 11 H z ) , 2 .00-2 .09 ( 1 - p r o t o n m u l t i p l e t ) , 1.33 ( 1 - p r o t o n d o u b l e t of q u a r t e t s , J - 4 , 11 H z ) , and 1.11 ( 1 - p r o t o n t r i p l e t of F i g u r e 3 : The 400 MHz i H nmr spectrum of (311) 101 t r i p l e t s , J - 3 , 11 H z ) , were ass igned to the protons H A , Hg, H x , and H z , r e s p e c t i v e l y . S a t u r a t i o n o f the s i g n a l a t 6 2 .61 (H A ) s i m p l i f i e d the s i g n a l s c o r r e s p o n d i n g to Hg (6 2 .00-2 .09) and H z (fi 1.11) to a broad t r i p l e t (J - 8 Hz) and t r i p l e t of double t s (J - 3, 11 H z ) , r e s p e c t i v e l y . On the o ther hand, i r r a d i a t i o n a t 6 2.04 (Hg) reduced the resonance due to H A (5 2.61) to a s imple double t (J - 11 Hz) w h i l e the p a t t e r n f o r H z (5 1.11) remained u n a f f e c t e d . The s i g n a l a t 6 1.33 ( H x ) was unchanged under the c o n d i t i o n s o f these d e c o u p l i n g exper iments . The c i s r i n g -f u s i o n of the hydr indane s k e l e t o n i n (311) was thus suppor ted by the v i c i n a l c o u p l i n g cons tant (7 Hz) between H A and Hg. I t was p l e a s i n g to f i n d t h a t compound (311) underwent h y d r o b o r a t i o n h i g h l y s t e r e o s e l e c t i v e l y upon treatment w i t h borane-methyl s u l f i d e complex (1 .5 e q u i v ) to a f f o r d , a f t e r o x i d a t i v e workup (3 M NaOH, 30% H 2 O 2 ) and f l a s h chromatography of the crude p r o d u c t , the a l c o h o l s (308) and (312) i n a r a t i o o f 95 :5 , r e s p e c t i v e l y ( e q u a t i o n 57) . The s p e c t r a l data d e r i v e d from the a l c o h o l s (308) and (312) are c o n s i s t e n t w i t h the expected r e g i o c h e m i s t r y of the h y d r o b o r a t i o n p r o -c e s s . However, no f i r m c o n c l u s i o n s c o u l d be drawn about the proposed s t e r e o c h e m i c a l ass ignments . For example d e c o u p l i n g experiments (see E x p e r i m e n t a l s e c t i o n ) suggested t h a t the br idgehead p r o t o n H A e x h i b i t e d - 102 -d o u b l e t o f d o u b l e t o f d o u b l e t s (J - 7, 8, 11 Hz) a t 8 2.13 i n the 1 H nmr spectrum o f (308). Furthermore , the c o u p l i n g cons tant between H A and Hy appeared to be 8 H z . However, the c o r r e s p o n d i n g protons c o u l d not be i d e n t i f i e d i n the ^H nmr spectrum o f (312). Hence, the s t e r e o -c h e mic a l assignments i n (308) and (312) were made p r i m a r i l y on the b a s i s of p r e d i c t i o n s r e g a r d i n g s t e r i c approach c o n t r o l i n the h y d r o b o r a t i o n r e a c t i o n . The e t h y l e n e d i o x y group, h a v i n g served i t s i n t e n d e d p r o t e c t i n g f u n c t i o n , was removed by r e f l u x i n g a s o l u t i o n o f compound (308) (1 e q u i v ) and p y r i d i n i u m p . - t o l u e n e s u l f o n a t e (0.3 e q u i v ) i n wet acetone f o r 2 h . A n a l y s i s o f the crude p r o d u c t i n d i c a t e d t h a t i t c o n s i s t e d o f a 2 : 1 * m i x t u r e o f the e p i m e r i c k e t o l s (309) and (313), r e s p e c t i v e l y ( e q u a t i o n 58). The f a c t t h a t a mixture was o b t a i n e d showed t h a t f a c i l e e p i m e r i z a t i o n a t the br idgehead p o s i t i o n ad jacent to the c a r b o n y l group had o c c u r r e d under the c o n d i t i o n s f o r d e p r o t e c t i o n . The m i x t u r e o f epimers (309) and (313) was t r e a t e d w i t h a s o l u t i o n o f sodium methoxide (0 .3 equiv) i n methanol a t room temperature and the p r o g r e s s o f f u r t h e r e p i m e r i z a t i o n was moni tored by g l c a n a l y s i s . A f t e r (58) 75:25 3 0 8 3 0 9 3 1 3 T h i s r a t i o v a r i e d s l i g h t l y from experiment to exper iment . 103 the m i x t u r e had been s t i r r e d f o r 3.5 h , the r a t i o of (309) : (313) was found to remain c o n s t a n t . G a s - l i q u i d chromatography as w e l l as nmr s p e c t r a o f the crude m i x t u r e suggested tha t the e q u i l i b r i u m r a t i o of (309) and (313) was 3 : 1 , r e s p e c t i v e l y . The i r spectrum of t h i s mixture showed a b s o r p t i o n s a t 3450 and 1700 c m ~ l , i n d i c a t i n g the presence of an a l c o h o l f u n c t i o n and a c a r b o n y l group, r e s p e c t i v e l y . The s p e c t r a l data d e r i v e d from the m i x t u r e o f (309) and (313) f a i l e d to p r o v i d e any i n f o r m a t i o n r e g a r d i n g the r i n g - f u s i o n s t e r e o -c h e m i s t r y of the two p r o d u c t s . The s t e r e o c h e m i c a l assignments i n (309) and (313) were based on the e q u i l i b r a t i o n s t u d i e s and on c o n f o r m a t i o n a l ana lyses o f these two compounds. The k e t a l (308) was known to have a c i s r i n g j u n c t i o n . T h e r e f o r e , d e p r o t e c t i o n must p r o v i d e i n i t i a l l y the c i s - f u s e d k e t o l . E p i m e r i z a t i o n o f t h i s i n i t i a l l y formed c i s - f u s e d k e t o l would then p r o v i d e the c o r r e s p o n d i n g t r a n s i somer . S ince the percentage o f (309) was found to i n c r e a s e a t the expense o f (313) a f t e r complete disappearance o f the k e t a l (308) (by g l c a n a l y s i s ) , compound (309) was a s s i g n e d the t r a n s r i n g - j u n c t i o n s t e r e o c h e m i s t r y . The preponderance of the t r a n s - f u s e d k e t o l (309) a t e q u i l i b r i u m may be r a t i o n a l i z e d on the b a s i s o f c o n f o r m a t i o n a l analyses as d e p i c t e d i n Scheme 18. Conformer (313B) i s o b v i o u s l y l e s s s t a b l e than (313A) because of a) the s y n - a x i a l i n t e r a c t i o n s between the i s o p r o p y l group and the a x i a l hydrogens at C-7 and C-9 and b) the r a t h e r severe i n t e r a c t i o n s ( 1 , 3 - d i -a x i a l type) o f the C-3 s u b s t i t u t e n t w i t h C-6 and C - 8 . Of the remaining two c o n f i g u r a t i o n a l isomers (309) and (313A), the former may be envisaged to be more s t a b l e because i t appears to possess fewer and l e s s severe i n t e r a c t i o n s than those present i n (313A). For example, the - 104 -3 0 9 Scheme 18 s y n - a x i a l i n t e r a c t i o n s i n v o l v i n g C - l and the a x i a l protons on C-5 and C - 7 , p r e s e n t i n (313A), are absent i n (309) . Furthermore , the s t e r i c i n t e r a c t i o n between the C-3 and C-5 s u b s t i t u e n t s a l s o appears to be l e s s severe i n (309) than i n (313A). However, there i s a p p r e c i a b l e angle 7 9 s t r a i n " i n c o r p o r a t e d i n t o the t r a n s - h y d r i n d o n e (309) r e l a t i v e to i t s c i s epimer (313A). T h e r e f o r e , on b a l a n c e , the energy d i f f e r e n c e between (309) and (313) might be expected to be q u i t e s m a l l , w i t h the t rans isomer (309) b e i n g s l i g h t l y f a v o r e d . T h i s s m a l l energy d i f f e r e n c e i s r e f l e c t e d i n the f o r m a t i o n o f a 3 :1 mixture o f (309) and (313) , r e s p e c t -i v e l y , under e q u i l i b r a t i n g c o n d i t i o n s . I t was g r a t i f y i n g to f i n d tha t the 3:1 mix ture o f (309) and (313) was c o n v e r t e d p r i m a r i l y i n t o the d e s i r e d t r a n s - f u s e d o l e f i n i c a l c o h o l - 105 (310) upon treatment w i t h three e q u i v a l e n t s o f m e t h y l e n e t r i p h e n y l -phosphorane i n d i m e t h y l s u l f o x i d e . 9 7 Thus, the W i t t i g r e a c t i o n a f f o r d e d , a f t e r s u i t a b l e workup and f l a s h chromatography o f the crude p r o d u c t on s i l i c a g e l , the o l e f i n i c a l c o h o l s (310) and (314) i n i s o l a t e d y i e l d s o f 76% and 4%, r e s p e c t i v e l y ( e q u a t i o n 59) . E v i d e n t l y , e q u i l i b r a -t i o n o f (309) and (313) o c c u r r e d under these r e a c t i o n c o n d i t i o n s and the t r a n s isomer (309) p r e f e r e n t i a l l y condensed w i t h m e t h y l e n e t r i p h e n y l -0 309:313 314 310 phosphorane. T h i s r e s u l t may stem from the g r e a t e r s t e r i c h indrance connected w i t h the c a r b o n y l group i n the c i s - v e r s u s t r a n s - h y d r i n d o n e i somers , (313) and (309) , r e s p e c t i v e l y . More e x p l i c i t l y , i n e i t h e r i somer , approach of the W i t t i g reagent from the under s i d e o f the c a r b o n y l group i s d i s f a v o r e d on s t e r i c grounds. However, the p face of the c a r b o n y l i s l e s s s t e r i c a l l y crowded i n (309) than i n (313) . As a r e s u l t , the W i t t i g o l e f i n a t i o n o f (309) would be expected to be f a s t e r than t h a t o f the c i s - i s o m e r (313) . The o b s e r v a t i o n o f p r i o r e p i m e r i z a -t i o n i n the W i t t i g r e a c t i o n i s wel l -documented i n the l i t e r a t u r e . 9 8 The s p e c t r a l data o b t a i n e d from compounds (310) and (314) are i n complete agreement w i t h the s t r u c t u r a l ass ignments . In p a r t i c u l a r , the ^H nmr s p e c t r a o f (310) and (314) ( F i g . 4 and 5, r e s p e c t i v e l y ) were very - 106 -- 107 -u s e f u l i n a s c e r t a i n i n g t h e i r r i n g - f u s i o n s t e r e o c h e m i s t r y . In the nmr spectrum o f (310) , the protons H A and H x gave r i s e to a double t o f t r i p l e t s (J = 8, 11 Hz) and a double t of q u a r t e t s (J - 4 , 11 Hz) a t 6 1.20 and 1.05, r e s p e c t i v e l y . I n a d d i t i o n , the a l l y l i c pro tons Hg and H c e x h i b i t e d a m u l t i p l e t at 6 2 . 3 0 - 2 . 3 9 . S a t u r a t i o n of the s i g n a l s c o r r e s -ponding to H B and H c (5 2 .30-2 .39) m o d i f i e d the s i g n a l s a t 6 1.20 (H A ) and 1.05 (H^) to a double t o f double t s ( J - 8, 11 Hz) and a s imple q u a r t e t ( J = 11 H z ) , r e s p e c t i v e l y . T h i s d e c o u p l i n g experiment i n d i c a t e d t h a t the c o u p l i n g constant between H A and Hg was 11 H z , thus s u g g e s t i n g a t r a n s - r e l a t i o n s h i p between these two p r o t o n s . On the o t h e r hand, i n the * H nmr of (314) , the s i g n a l s due the br idgehead protons H A and Hg appeared a t S 2.06 ( 1 - p r o t o n double t o f d o u b l e t o f d o u b l e t s , J - 7, 8, 10 Hz) and a t 6 2 .65 -2 .71 ( 1 - p r o t o n m u l t i p l e t ) , r e s p e c t i v e l y . F u r t h e r -more, i r r a d i a t i o n a t 6 2.68 (Hg) l e d t o s i m p l i f i c a t i o n o f the s i g n a l a t S 2.06 (H A ) t o a d o u b l e t o f d o u b l e t s ( J - 7, 10 H z ) . Hence, i n the case o f compound (314) , - 8 H z . T h i s v a l u e i s c e r t a i n l y w i t h i n the range expected f o r a c i s r i n g j u n c t i o n . Having d e v i s e d a reasonably e f f i c i e n t route to the o l e f i n i c a l c o h o l (310) , we began w o r k i n g toward the f i r s t o f our chosen s y n t h e t i c o b j e c t i v e s , (±)-anhydro-oplopanone (258) , as o u t l i n e d i n e q u a t i o n 60. O x i d a t i o n of (310) w i t h p y r i d i n i u m c h l o r o c h r o m a t e 8 1 i n methylene c h l o r i d e produced (± ) -3 -epi -anhydro-oplopanone (315) i n 93% y i e l d . The * H nmr spectrum of t h i s m a t e r i a l ( F i g . 6) e s t a b l i s h e d u n e q u i v o c a l l y the s t e r e o c h e m i c a l assignments of a l l the c h i r a l centers i n (315) . Thus, the s i g n a l s due to the protons H ^ , H A , and appeared a t S 0.98 (1 -proton d o u b l e t o f q u a r t e t s , J - 4 , 12 H z ) , 1.27 ( 1 - p r o t o n d o u b l e t o f t r i p l e t s , - 108 -J - 7, 12 H z ) , and 1.81 ( 1 - p r o t o n t r i p l e t o f t r i p l e t s , J - 3 , 12 H z ) , r e s p e c t i v e l y . A d d i t i o n a l l y , the protons H c , Hg, and Hy gave r i s e to s i g n a l s a t 6 2.33 ( 1 - p r o t o n t r i p l e t of d o u b l e t s , J - 4 , 13 H z ) , 2 .46-2.57 ( 1 - p r o t o n m u l t i p l e t ) , and 3.15 ( 1 - p r o t o n d o u b l e t of d o u b l e t s of d o u b l e t s , J - 4 , 7, 9 H z ) , r e s p e c t i v e l y . D e c o u p l i n g experiments c o r r o b o r a t e d these assignments and showed t h a t the magnitude o f bo th of the v i c i n a l c o u p l i n g cons tants J^g and J A Z i s 12 H z . These va lues i n d i c a t e c l e a r l y the a x i a l o r i e n t a t i o n of Hg, H A , and H z on the 6-membered r i n g . I n a d i f f e r e n c e n u c l e a r Overhauser enhancement (nOe) exper iment , s a t u r a t i o n of the s i g n a l a t 5 1.27 (H A ) r e s u l t e d i n s i g n a l i n t e n s i t y enhancement a t S 3.15 (Hy) , s u g g e s t i n g a c i s - r e l a t i o n s h i p between H A and Hy. T h i s experiment e s t a b l i s h e d the c o n f i g u r a t i o n of the - 109 -f o u r t h c h i r a l cen ter i n compound (315) . B a s e - c a t a l y z e d e q u i l i b r a t i o n (NaOMe, MeOH, 60°C) o f compound (315) y i e l d e d a 7:93 m i x t u r e o f (315) and (±)-anhydro-oplopanone (258) ( e q u a t i o n 60 ) . 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 of t h i s m i x t u r e from p e t r o -leum e t h e r p r o v i d e d pure ( ± ) - ( 2 5 8 ) which e x h i b i t e d mp 68°C and gave nmr spectrum (400 MHz) i d e n t i c a l w i t h t h a t o f ( - ) - a n h y d r o - o p l o p a n o n e . * Furthermore , i r , ms, and nmr s p e c t r a d e r i v e d from our s y n t h e t i c substance are i n agreement w i t h those r e p o r t e d f o r ( - ) - a n h y d r o -oplopanone. 8*> I n summary, the t o t a l s y n t h e s i s o f (±)anhydro-oplopanone (258) was a c h i e v e d i n 24% o v e r a l l y i e l d from 4 - i s o p r o p y l - 2 - c y c l o h e x e n - l - o n e (305) . D. T o t a l S y n t h e s i s of (±)-8-ep_i-Oplopanone and (±)-Oplopanone The k e t o l (309) was c o n s i d e r e d as a good 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 (±)-oplopanone (257) . S t e r e o s e l e c t i v e a x i a l a d d i t i o n of a We thank P r o f . Bohlmann f o r a copy o f the -"-H nmr spectrum of ( - ) - ( 2 5 8 ) . 110 -methyl a n i o n e q u i v a l e n t to the c a r b o n y l group would generate the r e q u i r e d C-8 c o n f i g u r a t i o n and a s t r a i g h t f o r w a r d o x i d a t i o n - e p i m e r i z a t i o n sequence s h o u l d then p r o v i d e (±)-oplopanone (257) (Scheme 19) . Scheme 19 The a v a i l a b i l i t y of reagents f o r the a x i a l a d d i t i o n o f a l k y l n u c l e o p h i l e s to s u b s t i t u t e d cyclohexanones i s v e r y l i m i t e d . The a d d i -t i o n of a l k y l l i t h i u m s , G r i g n a r d reagents , or organocuprates tend to f a v o r e q u a t o r i a l a t t a c k to produce the c o r r e s p o n d i n g a x i a l a l c o h o l s . " Under s p e c i f i c r e a c t i o n c o n d i t i o n s , t r i m e t h y l a l u m i n u m i s known to g ive predominant a x i a l a t t a c k , l ° u a but the s t e r e o s e l e c t i v i t y o f t h i s a d d i t i o n i s g r e a t l y reduced when the cyclohexanones have an a - e q u a t o r i a l s u b s t i t u e n t . 1 0 0 b >* An a l t e r n a t i v e approach to t h i s type o f c o n v e r s i o n i n v o l v e s s te reo -Very r e c e n t l y , Yamamoto has r e p o r t e d a s o l u t i o n to t h i s problem i n v o l v i n g the use o f new, b u l k y organoaluminum compounds (see r e f . 100c) . I l l s e l e c t i v e e p o x i d a t i o n o f (309) f o l l o w e d by r e d u c t i o n to p r o d u c t (316) . I t was r e p o r t e d by Corey and Chaykovsky t h a t d i m e t h y l s u l f o n i u m niethyl ide (299) r e a c t s w i t h cyclohexanones to add methylene across the c a r b o n y l p r e f e r e n t i a l l y from the a x i a l s i d e . T h u s , when 4 - t e r t - b u t y l c y c l o -hexanone (317) was a l l o w e d to r e a c t w i t h (299) i n THF, the ox i ranes (318) and (319) were produced i n a r a t i o of 5 : 1 , r e s p e c t i v e l y (equat ion 51) 101 x h i s observed s e l e c t i v i t y has been r a t i o n a l i z e d on the b a s i s of k i n e t i c p r e f e r e n c e f o r a x i a l a d d i t i o n to the c a r b o n y l group, s i n c e the i n i t i a l l y formed s u l f o n i u m b e t a i n e s are known to c o l l a p s e to epoxides f a s t e r than they r e v e r t to s t a r t i n g m a t e r i a l s . ^ 2 M e ? S - C H 2 , 3 1 7 3 1 8 319 Treatment o f the 1:3 mix ture o f the k e t o l s (313) and (309) w i t h 3 e q u i v a l e n t s o f d i m e t h y l s u l f o n i u m m e t h y l i d e (299) i n DMSO-THF gave, a f t e r f l a s h chromatography of the crude product and r e c r y s t a l l i z a t i o n o f the major p r o d u c t from petroleum e t h e r , the epoxide (320) (mp 9 2 . 5 - 9 3 ° C ) i n 69% y i e l d ( e q u a t i o n 62) . The ^H nmr spectrum of (320) e x h i b i t e d a one-p r o t o n double t o f t r i p l e t s (J = 8, 11 Hz) a t S 2 .30 . T h i s s i g n a l , a t t r i b u t e d to H A , e s t a b l i s h e d the f a c t t h a t (320) possesses a t rans r i n g - f u s i o n . I n a d d i t i o n , the AB p a i r of double t s (J = 5 Hz i n each case) a t S 2.57 and 2.66 (IH each) correspond to the epoxide p r o t o n s . However, no c o n c l u s i o n r e g a r d i n g the c o n f i g u r a t i o n o f the epoxide r i n g - 112 c o u l d be drawn from the s p e c t r a l data o f (320) . L i t h i u m aluminum h y d r i d e r e d u c t i o n o f the epoxide (320) y i e l d e d the d i o l (321) ( equat ion 62) . Treatment of (321) w i t h PCC and sodium ace ta te i n methylene c h l o r i d e a f f o r d e d the k e t o l (322) w h i c h , upon e q u i l i b r a t i o n (NaOMe, MeOH, 6 0 ° C ) , p r o v i d e d a 7:93 m i x t u r e o f (322) and ( ± ) - 8 - e p i - o p l o p a n o n e (323) ( e q u a t i o n 63) . Pure (323) was o b t a i n e d from t h i s m i x t u r e by f l a s h chromatography, f o l l o w e d by r e c r y s t a l l i z a t i o n o f the d e s i r e d m a t e r i a l from h e x a n e - e t h e r . The m e l t i n g p o i n t o f (323) (62°C) was q u i t e d i f f e r e n t from those r e p o r t e d ( 1 0 1 . 5 - 1 0 2 6 C , 9 0 9 7 - 9 8 ° C 9 1 ) p r e v i o u s l y f o r (± ) -oplopanone . Furthermore , the 400 MHz -"-H nmr spectrum o f (323) ( F i g . 7) i s v e r y s i m i l a r t o , but c l e a r l y d i f f e r e n t f rom, t h a t o f a u t h e n t i c ( - ) -oplopanone ( 2 5 7 ) 8 4 ( F i g . 8 ) . I n the * H nmr spectrum o f (323), the - 113 -114 br idgehead protons H A and Hg e x h i b i t e d s i g n a l s a t 5 2.02 ( 1 - p r o t o n q u a r t e t , J •= 11 Hz) and 1.94 ( 1 - p r o t o n double t o f double t o f d o u b l e t s , J - 4 , 8, 11 H z ) , r e s p e c t i v e l y , whereas the s i g n a l s due to the protons H Y and H z appeared at 6 2.60 ( 1 - p r o t o n double t of t r i p l e t s , J - 5, 11 Hz) and 1.07 ( 1 - p r o t o n t r i p l e t o f t r i p l e t s , J •= 3 , 11 H z ) , r e s p e c t i v e l y . These assignments were conf i rmed by a p p r o p r i a t e d e c o u p l i n g exper iments . The c o u p l i n g p a t t e r n of H A ( q u a r t e t , J - 11 Hz) c o n f i r m e d the ass igned s t e r e o c h e m i s t r y a t C - 3 , C-4 , C-5 and C-9 i n compound (323) . T h e r e f o r e , the o n l y c h i r a l cen ter i n (323) which has a c o n f i g u r a t i o n d i f f e r e n t from (±)-oplopanone (257) i s C - 8 . A t t h i s p o i n t i t became apparent t h a t , c o n t r a r y to our " w i s h e s " , the a d d i t i o n o f d i m e t h y l s u l f o n i u m m e t h y l i d e (299) to the k e t o l (309) had o c c u r r e d predominant ly from the e q u a t o r i a l s i d e of the cyclohexane r i n g . The p r e f e r e n c e f o r e q u a t o r i a l a t t a c k i n t h i s case may be r a t i o n a l i z e d on the b a s i s of s t e r i c h indrance to a t t a c k from the a ( a x i a l ) face of (309) . There are examples i n the l i t e r a t u r e which suggest t h a t the i n c o r p o r a t i o n o f an a - e q u a t o r i a l methyl group i n s u b s t i t u t e d c y c l o h e x a -nones can r e v e r s e the normal ( a x i a l ) o r i e n t a t i o n o f a t t a c k by d i m e t h y l -s u l f o n i u m m e t h y l i d e (299) on these s u b s t r a t e s . ^ ° 2 b As p o i n t e d out p r e v i o u s l y (see Scheme 15) , K o s t e r and W o l f 9 2 r e p o r t e d r e c e n t l y an e f f i c i e n t p r e p a r a t i o n o f a mix ture of the ketones (294) and (295) . Treatment of t h i s mix ture w i t h d i m e t h y l s u l f o n i u m m e t h y l i d e (299) ( e q u i l i b r a t i n g c o n d i t i o n s ) was r e p o r t e d to g i v e mainly the epoxide (296) w h i c h , upon s u b j e c t i o n to an a p p r o p r i a t e sequence of r e a c t i o n s ( l i t h i u m aluminum h y d r i d e r e d u c t i o n , o z o n o l y s i s , and base-promoted e p i m e r i z a t i o n ) , was c l a i m e d to p r o v i d e (±)-oplopanone (257) 115 -H Q M e 2 S - C H 2 + _ (64) 294 Qts 295 trans 296 257 ( e q u a t i o n 64 ) . The m e l t i n g p o i n t o f t h i s s y n t h e t i c m a t e r i a l ( 6 3 - 6 4 ° C ) 9 ^ i s s i g n i f i c a n t l y d i f f e r e n t from those r e p o r t e d ( 1 0 1 . 5 - 1 0 2 ° C , 9 0 97-9 8 ° C 9 1 ) p r e v i o u s l y f o r ( ± ) - ( 2 5 7 ) . Indeed, the mp o f K o s t e r and W o l f ' s s y n t h e t i c m a t e r i a l i s v e r y c l o s e to t h a t (62°C) o f the compound (323) prepared i n our work. Moreover , the ketones (295) and (309) are s t r u c t u r a l l y q u i t e s i m i l a r . T h e r e f o r e , i t appears h i g h l y l i k e l y tha t the a d d i t i o n of d i m e t h y l s u l f o n i u m m e t h y l i d e (299) to (295) had a l s o o c c u r r e d from the e q u a t o r i a l s i d e of the ketone c a r b o n y l group. I t i s thus e v i d e n t from our work t h a t K o s t e r and Wolf had a c t u a l l y p r e p a r e d , not ( ± ) - ( 2 5 7 ) , but ( ± ) - 8 - e p i - o p l o p a n o n e (323) . A t t h i s j u n c t u r e , we t u r n e d our a t t e n t i o n to e p o x i d a t i o n of the a lkene f u n c t i o n i n compound (310). I t was e n v i s i o n e d t h a t i f the a x i a l approach o f a reagent a t C-8 i s d i s f a v o r e d , as i n d i c a t e d by the r e a c t i o n of d i m e t h y l s u l f o n i u m m e t h y l i d e (299) w i t h (309), then the e p o x i d a t i o n of (310) s h o u l d occur p r e f e r e n t i a l l y from the e q u a t o r i a l s i d e to p r o v i d e the d e s i r e d epoxy a l c o h o l (324) . Treatment o f (310) w i t h m - c h l o r o p e r -b e n z o i c a c i d r e s u l t e d i n f o r m a t i o n of the epoxides (324) and (320) i n a p p r o x i m a t e l y equal p r o p o r t i o n s . However, e p o x i d a t i o n o f (310) v i a the c o r r e s p o n d i n g b r o m o h y d r i n s l ^ 3 proved to be reasonably s t e r e o s e l e c t i v e . 116 Thus, t reatment o f the o l e f i n i c a l c o h o l (310) w i t h N-bromosuccinimide i n DMSO-water ( 3 : 1 ) , f o l l o w e d by immediate treatment o f the r e s u l t i n g crude bromohydrin mix ture w i t h methanol ic potass ium carbonate , p r o v i d e d , a f t e r chromatographic s e p a r a t i o n of the r e s u l t a n t p r o d u c t s , the d e s i r e d epoxide (324) (63%, mp 91°C) a long w i t h a s m a l l amount (12%) of the e p i m e r i c substance (320) ( e q u a t i o n 65) . I n the nmr spectrum of 310 324 (63%) 320(12%) (324) , the s i g n a l s due to the two epoxide protons appeared a t 6 2.48 ( 1 - p r o t o n d o u b l e t , J - 5 H z ) , and 2.86 ( 1 - p r o t o n d o u b l e t o f d o u b l e t s , J - 2 , 5 H z ) . The s m a l l c o u p l i n g constant (2 Hz) a s s o c i a t e d w i t h the l a t t e r resonance was a t t r i b u t e d to a l o n g range W c o u p l i n g 4 7 between one of the o x i r a n e protons and the br idgehead p r o t o n Hg. T h i s o b s e r v a t i o n p r o v i d e d s t r o n g support f o r the a s s i g n e d s t e r e o c h e m i s t r y of the epoxide moiety i n (324) . Examinat ion o f m o l e c u l a r models shows t h a t W c o u p l i n g of one o f the o x i r a n e protons w i t h Hg i s p o s s i b l e o n l y i f the epoxide methylene protons are on the a lpha face of the m o l e c u l e . The s t e r e o s e l e c t i v i t y observed i n the bromohydrin-based e p o x i d a t i o n r e a c t i o n may be r a t i o n a l i z e d as f o l l o w s . S t u d i e s on bromohydrin forma-t i o n i n aqueous DMSO have shown tha t i n the case of an unsymmetr ica l b r i d g e d bromonium i o n , the n u c l e o p h i l e (DMSO) r e a c t s a t the carbon atom w i t h the more pronounced c a r b o n i u m - i o n c h a r a c t e r . 1 0 3 3 However, the 117 r e a c t i o n i s known to e x h i b i t a h i g h degree of s t e r e o s e l e c t i v i t y w i t h predominant a n t i a d d i t i o n , r u l i n g out a d i s c r e t e c a r b o n i u m - i o n i n t e r -mediate . T h e r e f o r e , assuming the f o r m a t i o n o f the b r i d g e d bromonium i o n from the a lkene f u n c t i o n i n compound (310) to be r e v e r s i b l e , p r e f e r e n -t i a l n u c l e o p h i l i c a t t a c k from the more open /9-face of the molecule should p r o v i d e the bromohydrin (325) . Base-promoted i n t r a m o l e c u l a r r i n g c l o -sure would then produce the r e q u i r e d epoxy a l c o h o l (324) ( e q u a t i o n 66) . (66) 310 325 324 R e d u c t i o n o f the compound (324) produced the c o r r e s p o n d i n g d i o l (316) (96%, mp 117-118°C) w h i c h , upon o x i d a t i o n , a f f o r d e d ( ± ) - 3 - e p i -oplopanone (326) (94%, mp 68°C) ( e q u a t i o n 67) . E q u i l i b r a t i o n of the l a t t e r m a t e r i a l w i t h sodium methoxide i n methanol gave a 6:94 m i x t u r e of (326) and (±) -oplopanone (257) . 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 of t h i s mix ture from h exane-ether p r o v i d e d pure ( i ) - ( 2 5 7 ) (mp 99-100°C) i n 84% y i e l d . T h i s m a t e r i a l e x h i b i t e d t i c p r o p e r t i e s and gave nmr spectrum (400 MHz) i d e n t i c a l w i t h those of n a t u r a l ( - ) - o p l o p a n o n e . 8 4 • * We are v e r y g r a t e f u l to D r . M. Matsumoto, S h i o n o g i Research L a b o r a t o r y , f o r a sample of ( - ) - (257) and f o r cop ies o f i t s i r and ^H nmr s p e c t r a and to P r o f e s s o r Taber f o r cop ies o f i r , ^H nmr, and mass s p e c t r a of ( ± ) - ( 2 5 7 ) . - 118 -257 In summation, the t o t a l s y n t h e s i s o f (±) -oplopanone (257) was accompl ished i n 15% o v e r a l l y i e l d from 4 - i s o p r o p y l - 2 - c y c l o h e x e n - l - o n e (305) . The s y n t h e t i c sequence used i n t h i s s y n t h e s i s demonstrated the v i a b i l i t y o f employing the newly developed ( Z ) - e t h y l i d e n e c y c l o p e n t a n e a n n u l a t i o n method i n o r g a n i c s y n t h e s i s . I V . H y d r o s t a n n y l a t i o n of l - A l k y n - 3 - o l s V i a S t a n n y l m e t a l a t i o n . P r e p a r a t i o n of ( E )-6 - C h l o r o - 3 - 1 i t h i o - 2 - h e x e n e and the R e l a t e d G r i g n a r d Reagent A . P r e p a r a t i o n of l - A l k y n - 3 - o l s H a v i n g e s t a b l i s h e d the f e a s i b i l i t y of p r e p a r i n g ( Z ) - 5 - c h l o r o - 3 - t r i -m e t h y l s t a n n y l -2 - p e n t e n e (99) and h a v i n g demonstrated the s y n t h e t i c 119 -M M e , S n R 9 9 M = S n M e 3 2 0 4 M = U 218 M = MgBr 107 u t i l i t y o f the c o r r e s p o n d i n g l i t h i o (204) and G r i g n a r d (218) reagents , we t u r n e d our a t t e n t i o n to the p o s s i b i l i t y o f p r e p a r i n g t r i m e t h y l -stannanes o f g e n e r a l s t r u c t u r e (107). As mentioned i n the I n t r o d u c t i o n , i t was envisaged t h a t the d e s i r e d b i f u n c t i o n a l reagents (107) c o u l d be o b t a i n e d s t e r e o s e l e c t i v e l y v i a o r t h o e s t e r - b a s e d C l a i s e n rearrangement of the c o r r e s p o n d i n g v i n y l s t a n n a n e s (109) (Scheme 6 ) . The e f f i c i e n c y of t h i s route was c o n t i n g e n t upon the r e g i o s e l e c t i v e h y d r o s t a n n y l a t i o n of l - a l k y n - 3 - o l s (108) to p r o v i d e the v i n y l s t a n n a n e s (109). H - C E O C XR C0 2Et 107 108 109 110 Scheme 6 The r e q u i s i t e e t h y n y l c a r b i n o l s (108) were r e a d i l y prepared by r e a c t i o n o f monol i th ium a c e t y l i d e w i t h the a p p r o p r i a t e a ldehydes . 104 3 - B u t y n - 2 - o l (336) was ob ta ined from the A l d i c h Chemical C o . , Inc. 120 The mono-lithium ac e t y l i d e was, i n turn, generated by a d d i t i o n of n-butyl-l i t h i u m to acetylene i n THF at -78°C. A summary of the preparation of a number of l-alkyn-3-ols from the corresponding aldehydes i s given i n Table VI. B. Addition of the (Trimethylstannyl)copper Reagent to l-Alkyn-3-ols I t had be en shown e a r l i e r that r e a c t i o n of the (trimethylstan-nyl)copper reagent (84) 2 2 with various w-substituted 1-alkynes (83) i n the presence of methanol afforded high y i e l d s of the corresponding 2-trimethylstannyl-l-alkenes (85) (equation 18). 2 3 We have investigated Me 3SnCu- Me 2 S 8 4 = / S n M e 3 ^ H - C = C - ( C H 2 ) n X MeOH, - 6 3 ° C " H^ ScH2)nX 8 3 8 5 the r e a c t i o n of reagent (84) with 3-butyn-2-ol (336). The regioselec-t i v i t y of a d d i t i o n was found to be c r i t i c a l l y dependent on various r e a c t i o n parameters. In general, i t was found that the presence of an i n s i t u proton source (MeOH) and low r e a c t i o n temperatures (-63°C to -78°C) favored the formation of the desired product (337) (equation 68). Under optimum conditions, the isomeric vinylstannanes (337) and (338) were produced i n a r a t i o of 3:1, r e s p e c t i v e l y . Thus, reaction of 3-butyn-2-ol (336) with 1.5 equivalents of Me3SnCu-Me2S (84) i n the - 121 -Table V I : P r e p a r a t i o n of l - A l k y n - 3 - o l s from A l d e h y d e s 3 R R-CHO ) - C = C - H OH 3 2 7 108 Entry Aldehyde 327 R Product 108 Yield (%) b 1 328 n-hexyl 332 69 2 329 CH3OCH20(CH2)2 333 75 3 330 H2C-CH(CH2)2 334 74 4 331 cyclopropyl 335 74 a Reaction conditions r . t . , 1 h; H 2 0. : Li-OC-H (1 .1 equiv), THF, -78°C, 30 min; Yield of purified, d i s t i l l e d product. 122 )-C =C-H OH Me,SnCu-Me2S 84 Me 3Sn (68) 336 337 338 presence o f methanol (50 equiv) a t -78 C C f o r 2 .5 h and a t 0°C f o r 1 h a f f o r d e d the t r imethyls tannanes (337) and (338) i n i s o l a t e d y i e l d s of 52% and 17%, r e s p e c t i v e l y . I n s i m i l a r f a s h i o n , o ther a c e t y l e n i c a l c o h o l s (108) were conver ted i n t o m i x t u r e s o f the c o r r e s p o n d i n g v i n y l -stannanes (109) and (339) (see Table V I I ) . In each case , a procedure i d e n t i c a l w i t h t h a t o u t l i n e d above was employed. The i s o m e r i c a l l y l i c a l c o h o l s (109) and (339) were, i n each case , r e a d i l y separable by f l a s h column chromatography on s i l i c a g e l . The r a t i o of (109) and (339) formed i n each r e a c t i o n (Table V I I ) r e f e r s t o i s o l a t e d y i e l d s of p u r i f i e d p r o d u c t s . The r e g i o - and s t e r e o c h e m i c a l assignments o f these products were based p r i m a r i l y on nmr s p e c t r o s c o p y . I n the nmr s p e c t r a of the 2 , 2 - d i s u b s t i t u t e d v i n y l s t a n n a n e s (109), the o l e f i n i c protons produced v e r y s i m i l a r and c h a r a c t e r i s t i c s i g n a l p a t t e r n s . T y p i c a l l y , the protons H A and H x gave r i s e t o s i g n a l s a t around S 5 .2 and 5 . 8 , r e s p e c t i v e l y , w i t h J^x ~ 2 H z . Each resonance was s p l i t f u r t h e r by c o u p l i n g w i t h the a l l y l i c methine p r o t o n (J = 0-3 H z ) . The magnitude o f the t i n - p r o t o n c o u p l i n g cons tants gave an a d d i t i o n a l i n d i c a t i o n t h a t H A was c i s to the t r i m e t h y l s t a n n y l group (J.Sn-H ~ 7 2 Hz) w h i l e H ^ was t r a n s to Me3Sn Sn-H ~ a n c ^ bence the two protons must have been geminal to - 123 -Table V I I : R e a c t i o n of the ( T r i m e t h y l s t a n n y l ) c o p p e r Reagent w i t h l - A l k y n - 3 - o l s a OH 108 109 3 3 9 Entry Substrate R Products Ratio" Combined 109:339 109:339 Y i e l d (%) b 336 Me 337:338 75:25 69 332 n-hexyl 340:344 66 :34 65 333 CH3OCH20(CH2)2 341:345 58:42 71 334 H2C=CH(CH2)2 342:346 60:40 72 335 cyclopropyl 343:347 55:45 64 a Reaction conditions: reagent (84) (1.5 equiv), MeOH (50 equiv), THF, -78°C, 2.5 h , 0°C, 1 h ; sat NH4C1. D Based on i s o l a t e d y i e l d s of p u r i f i e d products. 124 each o t h e r . On the o ther hand, i n the nmr s p e c t r a of the i s o m e r i c ( E ) - v i n y l -stannanes (339) , the o l e f i n i c protons H L and H M t y p i c a l l y e x h i b i t e d an AB p a t t e r n around 6 6.1 w i t h AS ~ 0.15 and J.LM ~ 19 H z . Each l i n e i n t h i s AB p a t t e r n was f u r t h e r s p l i t by c o u p l i n g w i t h the a l l y l i c methine p r o t o n . The u p f i e l d double t (HL) was f u r t h e r s p l i t i n t o two double t s (J = 5 Hz) by v i c i n a l c o u p l i n g whereas the d o w n f i e l d d o u b l e t (H^) was f u r t h e r s p l i t i n t o two double t s by a l l y l i c c o u p l i n g (J = 0-1 H z ) . The magnitude o f J j ^ ( « 19 Hz) i n d i c a t e d t h a t the o l e f i n i c protons were t r a n s and, t h e r e f o r e , t h a t the a lkene (339) possessed the (E) c o n f i g u r a t i o n . I n a d d i t i o n , Jgn-H a s s o c i a t e d w i t h H L and H M were ~ 75 Hz and ~ 80 H z , r e s p e c t i v e l y . These v a l u e s a l s o i n d i c a t e d t h a t H L was c i s to the Me3Sn moiety w h i l e H M was geminal t o i t . 4 8 Thus, i n t e r p r e t a t i o n o f the o l e f i n i c p r o t o n s i g n a l s i n the 1H nmr s p e c t r a of the p r o d u c t s (109) and (339) u n e q u i v o c a l l y a s c e r t a i n e d the r e g i o - and s t e r e o c h e m i c a l ass ignments . The chromatographic b e h a v i o r o f the i s o m e r i c v i n y l s t a n n a n e s (109) and (339) was a l s o q u i t e u s e f u l i n making p r e l i m i n a r y s p e c u l a t i o n s r e g a r d i n g the r e g i o c h e m i c a l outcome o f these h y d r o s t a n n y l a t i o n reac -t i o n s . More e x p l i c i t l y , the d e s i r e d 2 - t r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l s (109) c o n s i s t e n t l y showed g r e a t e r m o b i l i t i e s on t i c ana lyses ( s i l i c a g e l , development w i t h petro leum e t h e r - e t h y l ace ta te m i x t u r e s ) and s h o r t e r r e t e n t i o n times on g l c analyses than the c o r r e s p o n d i n g ( E ) - v i n y l s t a n n a n e s (339) . Thus, one may make reasonably c o n f i d e n t t e n t a t i v e assignments of r e g i o c h e m i s t r y of the i s o m e r i c v i n y l s t a n n a n e s (109) and (339) s i m p l y by g l c or t i c . - 125 -I t i s e v i d e n t t h a t , i n c o n t r a s t to s i m i l a r t r a n s f o r m a t i o n s " i n v o l v i n g 1 -a lkynes t h a t c o n t a i n a p o l a r f u n c t i o n a l group ( e . g . OH, OR) f u r t h e r removed from the t r i p l e bond, r e a c t i o n o f the a c e t y l e n i c a l c o -h o l s (108) w i t h Me3SnCu -Me2S does not e x h i b i t n o t a b l e r e g i o s e l e c t i v i t y . I t i s not immediate ly obvious why a hydroxy group ad jacent to the a lkyne f u n c t i o n s h o u l d n o t i c e a b l y i n f l u e n c e the r e g i o s e l e c t i v i t y o f the t r i -m e t h y l s t a n n y l c u p r a t i o n and r e s u l t i n the p r o d u c t i o n o f r e l a t i v e l y g r e a t e r amounts o f the v i n y l s t a n n a n e s (339) . There i s evidence t h a t suggests t h a t the r e a c t i o n o f Me3SnCu-Me2S w i t h 1 -a lkynes i s r e v e r s i b l e . 2 3 T h e r e f o r e , i t i s p o s s i b l e t h a t the r e l a t i v e thermodynamic s t a b i l i t y o f the i n t e r m e d i a t e v i n y l c o p p e r spec ies (348) and (349) i s , a t l e a s t p a r t i a l l y , r e s p o n s i b l e f o r the f i n a l product d i s t r i b u t i o n . When Y •= H , the i n d u c t i v e e f f e c t of the a l k y l group would d e s t a b i l i z e the i n t e r m e d i a t e s (349) r e l a t i v e to (348) . P r o t o n a t i o n of (348) would then p r o v i d e the 2 - t r i m e t h y l s t a n n y l - l - a l k e n e s r e g i o s e l e c t i v e l y . However, when Y = OH, the 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 oxygen may p r o v i d e a d d i t i o n a l s t a b i l i t y t o (349) r e l a t i v e . t o (348) because o f the p r o x i m i t y o f oxygen to the a n i o n i c center i n the former i n t e r m e d i a t e . Thus, one may r a t i o n a l i z e the observed decrease o f r e g i o s e l e c t i v i t y as a consequence o f comparable s t a b i l i t i e s o f the i n t e r m e d i a t e s (348) and (349) (Y = OH). A l t e r n a t i v e l y , an i n i t i a l c o o r d i n a t i o n of the hydroxy R 348 349 - 126 group w i t h the o r g a n o m e t a l l i c reagent may r e s u l t i n p r e f e r e n t i a l forma-t i o n o f the i n t e r m e d i a t e (349) (Y - OH) v i a i n t e r n a l d e l i v e r y of the reagent . C. R e a c t i o n o f ( T r i m e t h y l s t a n n y l ) z i n c Reagents w i t h l - A l k y n - 3 - o l s I n 1984, Oshima and coworkers r e p o r t e d t h a t the r e a c t i o n of t e r m i -n a l a c e t y l e n e s w i t h ( n - B u 3 S n ) 2 Z n i n the presence of v a r i o u s t r a n s i t i o n - m e t a l c a t a l y s t s p r o v i d e s the c o r r e s p o n d i n g 2 - t r i - n - b u t y l -s t a n n y l - 2 - a l k e n e s p r e f e r e n t i a l l y . * 0 5 Thus, t reatment o f 4 - b e n z y l o x y - l -butyne (350) w i t h ( n - B u 3 S n ) 2 Z n - C u C N and ( n - B u 3 S n ) 2 Z n - P d ( P P h 3 ) 4 gave a m i x t u r e o f the v i n y l s t a n n a n e s (351) and (352) i n r a t i o s o f 26:74 and 14 :86 , r e s p e c t i v e l y ( e q u a t i o n 69) . The organozinc reagent ( n - B u 3 S n ) 2 Z n was p r e p a r e d by m i x i n g t r i - n - b u t y l s t a n n y l l i t h i u m (2 equiv) w i t h z i n c bromide (1 e q u i v ) . ( n - B i u S r ^ Z n , H H R - C E C - H — — - W • > = (69) S n n - B u 3 n - B u 3 S n 350 351 352 R= PhCH2aCH2)2 Subsequent ly , i t was d i s c o v e r e d t h a t the s i l y l z i n c compound [PhMe2SiZnR2]Li , d e r i v e d from d i m e t h y l p h e n y l s i l y l l i t h i u m and the r e q u i r e d d i a l k y l z i n c , r e a d i l y add to a lkynes i n the presence of copper ( I ) cyanide to produce, a f t e r s u i t a b l e workup, the corresponding - 127 -v i n y l s i l a n e s w i t h good c o n t r o l o f r e g i o - and s t e r e o c h e m i s t r y . 1 0 6 The r e g i o s e l e c t i v i t y o f t h i s e f f e c t i v e h y d r o s i l y l a t i o n was found to be c r i t i c a l l y dependent on the nature o f the d i a l k y l z i n c employed. For i n s t a n c e , the r e a c t i o n of [PhMe2SiZnEt2]Li w i t h 4 - b e n z y l o x y - 1 - b u t y n e (350) p r o v i d e d a mix ture o f the ( E ) - a l k e n e (353) and i t s r e g i o i s o m e r (354) i n a r a t i o of 67 :33 , whereas compound (354) was the predominant p r o d u c t (95% r e g i o s e l e c t i v i t y ) o b t a i n e d when [PhMe2SiZn( tBu)2]Li was employed ( e q u a t i o n 70) . Among the v a r i o u s t r a n s i t i o n meta l c a t a l y s t s employed, CuCN was found to be the most e f f e c t i v e i n c a t a l y z i n g these s i l y l z i n c a t i o n r e a c t i o n s . We have prepared the analogous ( t r i m e t h y l s t a n n y l ) z i n c reagents and i n v e s t i g a t e d t h e i r r e a c t i o n s w i t h l - a l k y n - 3 - o l s . The reagents (355)* (PhMe ?SiZnR 2)Li K R\ R - C = C - H V ^ W * > = <70> U U L SiMe2Ph PhMe^Si 350 353 3 5 4 R'=PhCH20(CH2)2 R a t i o 353:354 Et 67:33 i - P r 33:67 t - B u 5:95 * These f o r m u l a t i o n s are not meant to i m p l y a c t u a l s t r u c t u r e s , but are used to show s t o i c h i o m e t r y and f o r convenience . - 128 -and (356) were prepared by r e a c t i o n o f equimolar amounts o f Me3SnLi and the r e q u i r e d d i a l k y l z i n c i n THF a t -20°C f o r 20 min (equat ions 71 and 72) . As w i t h most cuprates and analogous r e a g e n t s , these o r g a n o z i n c a t e s M e 3 S n L i + ( t - B u ) 2 Z n > [ M e 3 S n Z n ( t - B u ) 2 ] L i (71) 355 M e 3 S n L i + E t 2 Z n > [ M e 3 S n Z n E t 2 ] L i (72.) 356 are l i k e l y to be t h e r m a l l y u n s t a b l e and s e n s i t i v e to oxygen. T h e r e f o r e , these reagents were always prepared immediate ly p r i o r to t h e i r use and m a i n t a i n e d under an atmosphere o f dry argon. For the p r e p a r a t i o n of (355) , i t i s b e s t to use r e l a t i v e l y f r e s h (< 2 weeks o l d ) d i - t e r t - b u t y l -z i n c s o l u t i o n . I n n e a r l y a l l the cases s t u d i e d , h i g h e r r e g i o s e l e c t i v i t i e s ( r e l a -t i v e to those p r o v i d e d by r e a c t i o n s i n v o l v i n g Me 3 SnCu-Me 2 S) were o b t a i n e d when the a c e t y l e n i c a l c o h o l s (108) were s u b j e c t e d to CuCN-c a t a l y z e d s t a n n y l z i n c a t i o n r e a c t i o n s . For example, when 3 - b u t y n - 2 - o l (336) was a l l o w e d to r e a c t w i t h 2 e q u i v a l e n t s o f the reagent (355) i n the presence o f a c a t a l y t i c amount o f c o p p e r ( I ) c y a n i d e , the i s o m e r i c v i n y l s t a n n a n e s (337) and (338) were produced i n a r a t i o o f 4 : 1 (Table V I I I , E n t r y 1 ) . I t may be r e c a l l e d t h a t the r e a c t i o n o f 3 - b u t y n - 2 - o l (336) w i t h Me 3 SnCu-Me 2 S had p r o v i d e d a 3 :1 mix ture o f (337) and (338) , r e s p e c t i v e l y (Table V I I , E n t r y 1 ) . S i m i l a r (minor) improvements i n r e g i o s e l e c t i v i t y were o b t a i n e d w i t h the a lkynes (332)-(334) (compare Tables V I I and V I I I ) . However, i n the case o f l - c y c l o p r o p y l - 2 - p r o p y n - o l (335) , d i r e c t s t a n n y l c u p r a t i o n and C u C N - c a t a l y z e d s t a n n y l z i n c a t i o n w i t h - 129 the reagent (355) gave e s s e n t i a l l y i d e n t i c a l p r o p o r t i o n s o f (3A3) and (347) . I n analogy w i t h the f i n d i n g s of Oshima and c o w o r k e r s , ^ 6 w e have found t h a t the r e g i o c h e m i s t r y of these r e a c t i o n s i s governed by the na ture of the d i a l k y l z i n c employed. Thus, when the s t a n n y l z i n c a t i o n s of s u b s t r a t e s (108) were c a r r i e d out w i t h the reagent (356) i n the presence of CuCN, the m i x t u r e s o f r e a c t i o n products c o n s i s t e d l a r g e l y of the (E) -v i n y l s t a n n a n e s (339) (Table V I I I ) . I n each case , a procedure i d e n t i c a l w i t h t h a t o u t l i n e d above f o r reagent (355) was employed. I t i s c l e a r t h a t a r a t h e r s imple change i n the c o n s t i t u t i o n o f the o r g a n o z i n c a t e reagent [Me3SnZnR.2]Li has a p ro found e f f e c t on the r e g i o c h e m i s t r y o f the o v e r a l l t r a n s f o r m a t i o n (compare, f o r example, E n t r i e s 1 and 2, Table V I I I ) . A c l o s e r examinat ion o f the r e s u l t s summarized i n Table V I I I r e v e a l s t h a t h i g h e r , more c o n s i s t e n t r e g i o -s e l e c t i v i t i e s (>85%) were o b t a i n e d i n the r e a c t i o n s o f a c e t y l e n i c a l c o h o l s (108) w i t h reagent (356) . On the o ther hand, i n the r e a c t i o n s of (108) w i t h reagent (355) , the r e g i o s e l e c t i v i t y o f the o v e r a l l t r a n s f o r m a t i o n decreased as the s i z e o f the R group i n c r e a s e d (compare E n t r i e s 1, 3 , 9, Table V I I I ) . F u r t h e r e x p e r i m e n t a t i o n i s needed to unders tand the reasons u n d e r l y i n g these observed r e s u l t s . From a s y n t h e t i c p o i n t of v i e w , i t i s important t h a t the a t t a i n a b l e r e g i o s e l e c t i v i t i e s of the C u C N - c a t a l y z e d s t a n n y l z i n c a t i o n r e a c t i o n s of e t h y n y l c a r b i n o l s (108) made the a c q u i s i t i o n o f reasonable y i e l d s of e i t h e r (109) or (339) q u i t e s t r a i g h t f o r w a r d . - 130 -Table V I I I : R e a c t i o n of the ( T r i m e t h y l s t a n n y l ) z i n c Reagents w i t h l - A l k y n - 3 - o l s R ) - C =C-H OH 108 E n t r y Subs t ra te R C o n d i - Products R a t i o b Combined t i o n s 3 109: : 339 109:339 Y i e l d (%)b 1 336 Me A 337: :338 82:18 67 2 336 Me B 337: :338 11:89 73 3 332 n - h e x y l A 340: :344 75:25 70 4 332 n - h e x y l B 340: :344 2:98 64 5 333 CH 3 OCH 2 0(CH 2 )2 A 341: :345 74:26 69 6 333 C H 3 O C H 2 0 ( C H 2 ) 2 B 341 :345 6:94 67 7 334 H 2 O C H ( C H 2 ) 2 A 342: :346 68:32 63 8 334 H 2 O C H ( C H 2 ) 2 B 342: :346 9:91 70 9 335 c y c l o p r o p y l A 343: :347 53:47 72 10 335 c y c l o p r o p y l B 343: 347 15:85 68 a R e a c t i o n c o n d i t i o n s . A : reagent (355) (2. 0 e q u i v ) , CuCN (0.04 e q u i v ) , THF, -20°C, 1 h ; 0°C, 1 h ; s a t . N H 4 C I . B: reagent (356) (2. 0 e q u i v ) , CuCN (0.04 e q u i v ) , THF, -20°C, 1 h ; 0°C, 1 h ; s a t . N H 4 C 1 . Based on i s o l a t e d y i e l d s o f p u r i f i e d p r o d u c t s . M e 3 S r \ _ ^ H A Hi SnMe, O 3 109 339 - 131 -D. The O r t h o e s t e r C l a i s e n Rearrangement of 2 - T r i m e t h y l s t a n n y l - l -a l k e n - 3 - o l s and ( E ) - l - T r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l s W i t h s u f f i c i e n t q u a n t i t i e s o f the i s o m e r i c a l l y l i c a l c o h o l s (109) and (339) i n hand, we embarked on the o r t h o e s t e r C l a i s e n rear range-m e n t - ^ 7 o f these compounds. When 3 - t r i m e t h y l s t a n n y l - 3 - b u t e n - 2 - o l (337) was heated w i t h 7 e q u i v a l e n t s of t r i e t h y l o r t h o a c e t a t e and 0.06 e q u i -v a l e n t o f p r o p a n o i c a c i d a t 135-138°C f o r 2.5 h under c o n d i t i o n s a l l o w i n g f o r d i s t i l l a t i v e removal of e t h a n o l , the e s t e r (358) was produced c l e a n l y and e f f i c i e n t l y i n 82% y i e l d (Table I X ) . I n s i m i l a r f a s h i o n , the a l c o h o l s (340)-(342) were r e a d i l y t rans formed i n t o the c o r r e s p o n d i n g e s t e r s (359) - (361) , r e s p e c t i v e l y (Table I X ) . I n t e r e s t -i n g l y , o r t h o a c e t a t e - b a s e d C l a i s e n rearrangement o f the i s o m e r i c a l l y l i c a l c o h o l s (338) and (344)-(346) a l s o proceeded c l e a n l y to p r o v i d e , i n good y i e l d s , the s t r u c t u r a l l y i n t e r e s t i n g and p o t e n t i a l l y u s e f u l a l l y l i c t r i m e t h y l s t a n n a n e s (364) - (367) , r e s p e c t i v e l y . These r e s u l t s are summarized i n Table X . Two comments s h o u l d be made r e g a r d i n g the data g i v e n i n Table IX and X . F i r s t l y , t reatment of the crude product m i x t u r e w i t h aqueous potass ium dihydrogen phosphate (5%)-^ 8 h y d r o l y z e d the excess t r i e t h y l o r t h o a c e t a t e and thus made the workup c l e a n e r and more e f f i c i e n t . Even the a l l y l i c v i n y l s t a n n a n e s (363) were found to be s t a b l e under these workup c o n d i t i o n s . Secondly , the r e a c t i o n s o f the c y c l o p r o p y l d e r i v a -t i v e s (343) and (347) were found to be s l u g g i s h and gave r i s e to s e v e r a l b y - p r o d u c t s ( g l c and t i c a n a l y s e s ) . When 15 e q u i v a l e n t s of t r i e t h y l o r t h o a c e t a t e and 0.2 e q u i v a l e n t of propanoic a c i d were employed, the 132 Table I X : P r e p a r a t i o n of E t h y l ( Z ) - 4 - T r i m e t h y l s t a n n y l - 4 - a l k e n o a t e s a E n t r y Subs t ra te R Product Y i e l d (%)b 1 337 Me 358 82 2 340 n - h e x y l 359 80 3 341 CH 3 OCH 2 0(CH 2 )2 3 6 0 7 6 4 342 H 2 C = C H ( C H 2 ) 2 361 79 5 343 c y c l o p r o p y l 362 c 58 R e a c t i o n c o n d i t i o n s : CH3C(OEt>3 (7 e q u i v ) , CH3CH 2 C0 2 H (0.06 e q u i v ) , 135-140°C, 2.5 h ; aqueous K H 2 P 0 4 (5%), r . t . , 30 min . Y i e l d o f p u r i f i e d , d i s t i l l e d p r o d u c t . C H 3 C ( O E t ) 3 (15 equiv) and C H 3 C H 2 C 0 2 H (0.2 equiv) were used . - 133 -Table X : P r e p a r a t i o n of E t h y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 4 - a l k e n o a t e s a 339 363 E n t r y S u b s t r a t e R Product Y i e l d (%)b 1 338 Me 364 75 2 344 n - h e x y l 365 77 3 345 CH 3 OCH 2 0(CH 2 )2 366 79 4 346 H 2 C - C H ( C H 2 ) 2 367 77 5 347 c y c l o p r o p y l 368 c 62 R e a c t i o n c o n d i t i o n s : C H 3 C ( 0 E t ) 3 (7 e q u i v ) , C H 3 C H 2 C 0 2 H (0.06 e q u i v ) , 135-140°C, 2.5 h ; aqueous K H 2 P 0 4 (5%), r . t . , 30 m i n . Y i e l d o f p u r i f i e d , d i s t i l l e d p r o d u c t . C H 3 C ( 0 E t ) 3 (15 equiv) and C H 3 C H 2 C 0 2 H (0.2 equiv) were used . 134 -r e a c t i o n s appeared to be f a s t e r and r e l a t i v e l y c l e a n . S u b j e c t i o n of the crude m i x t u r e s to f l a s h chromatography on s i l i c a g e l a f f o r d e d the d e s i r e d e s t e r s (362) and (368) i n y i e l d s o f 58 and 62%, r e s p e c t i v e l y . Thus, i n accord w i t h the w e l l - e s t a b l i s h e d s t e r e o s e l e c t i v i t y of the o r t h o e s t e r C l a i s e n r e a r r a n g e m e n t , 1 0 7 the secondary a l l y l i c a l c o h o l s u b s t r a t e s (109) and (339) were conver ted s o l e l y i n t o the c o r r e s p o n d i n g 7 , 6 - u n s a t u r a t e d e s t e r s (357) and (363) , r e s p e c t i v e l y . The s p e c t r a l data d e r i v e d from these compounds are i n complete agreement w i t h the ass igned s t r u c t u r e s . For example, the i r spectrum o f (358) c o n t a i n e d the a p p r o p r i a t e bands f o r an e s t e r (1736 cm" 1 ) c o n t a i n i n g an a lkene f u n c t i o n (1624 cm" 1 ) and a t r i m e t h y l s t a n n y l group (770 c m " 1 ) . I n a d d i t i o n , i n the 1 H nmr spectrum o f (358) , the v i n y l methyl group and the o l e f i n i c p r o t o n gave r i s e to s i g n a l s a t 6 1.70 (a 3 - p r o t o n d o u b l e t , J = 6 Hz) and 6.10 (a 1 - p r o t o n q u a r t e t , J - 6 H z , J.sri-H " H z )> r e s p e c t i v e l y . The magnitude o f the t i n - p r o t o n c o u p l i n g constant (140 Hz) a s s o c i a t e d w i t h the v i n y l p r o t o n c l e a r l y i n d i c a t e d i t s t r a n s r e l a t i o n s h i p w i t h the t r i m e t h y l s t a n n y l group and thus c o n f i r m e d the s t e r e o c h e m i c a l a s s i g n -ments . The i r spectrum of the i s o m e r i c t r i m e t h y l s t a n n a n e (364) was a l s o i n d i c a t i v e o f the presence o f an e s t e r moiety (1729 c m " 1 ) , an alkene f u n c t i o n (1654 c m " 1 ) , and a t r i m e t h y l s t a n n y l group (767 c m " 1 ) . F u r t h e r -more, i n the -^ H nmr spectrum of compound (364), the two o l e f i n i c protons gave r i s e to s i g n a l s at 6 5.14 ( 1 - p r o t o n double t of q u a r t e t of doub-l e t s , J •= 1, 6, 16 Hz) and 5.49 ( 1 - p r o t o n q u a r t e t o f double t of d o u b l e t s , J •= 1.5, 8, 16 H z ) . The magnitude of the c o u p l i n g constant between the two v i n y l i c protons (16 Hz) was c l e a r l y i n the range 135 -expected f o r a t r a n s d i s u b s t i t u t e d double bond. Analogous s p e c t r a l ana lyses were made i n a s s i g n i n g the s t r u c t u r e s o f the o ther products shown i n Tables IX and X . E . P r e p a r a t i o n and Reac t ions of ( E ) - 6 - C h l o r o - 3 - l i t h i o - 2 - h e x e n e . ( Z ) - E t h y l i d e n e c y c l o h e x a n e A n n u l a t i o n Sequences Having d e v i s e d a reasonably e f f i c i e n t and s t e r e o s e l e c t i v e route to e t h y l ( Z ) - 4 - t r i m e t h y l s t a n n y l - 4 - h e x e n o a t e (358) , we t u r n e d our a t t e n t i o n to the p r e p a r a t i o n o f the c o r r e s p o n d i n g c h l o r o v i n y l s t a n n a n e (370) . Treatment o f (358) w i t h l i t h i u m aluminum h y d r i d e i n e t h e r a t 0°C produced the o l e f i n i c a l c o h o l (369) i n good y i e l d ( e q u a t i o n 73) . 96% 72% 358 369 370 R e a c t i o n o f the a l c o h o l (369) w i t h t r i p h e n y l p h o s p h i n e - c a r b o n t e t r a -c h l o r i d e i n the presence o f t r i e t h y l a m i n e a f f o r d e d ( Z ) - 6 - c h l o r o - 3 - t r i -m e t h y l s t a n n y l - 2 - h e x e n e (370) ( e q u a t i o n 73) . The s p e c t r a l data of compounds (369) and (370) c o r r o b o r a t e d f u l l y the a s s i g n e d s t r u c t u r e s . S u r p r i s i n g l y , s u c c e s s i v e treatment o f a c o l d ( -78°C) THF s o l u t i o n of compound (370) w i t h m e t h y l l i t h i u m (2 h) and cyclohexanone (1 h ) , 136 f o l l o w e d by aqueous workup, d i d not p r o v i d e any of the expected c h l o r o a l c o h o l (372) and/or the s p i r o e ther (373) . To the c o n t r a r y , t i c and g l c ana lyses of the recovered m a t e r i a l showed the presence o f unconsumed v i n y l s t a n n a n e (370) . I t may be r e c a l l e d t h a t the analogous compound ( Z ) - 5 - c h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - p e n t e n e (99) had undergone complete t r a n s m e t a l a t i o n upon exposure to 1.1 equiv of m e t h y l l i t h i u m i n THF at -78°C f o r 20 m i n . These two r e s u l t s seem to i n d i c a t e t h a t the c h l o r i d e f u n c t i o n i n (99) p l a y s some r o l e i n the t r a n s m e t a l a t i o n r e a c t i o n of that compound. H i g h e r r e a c t i o n temperatures ( e . g . -48°C) and use o f DME as s o l v e n t f a i l e d to p r o v i d e b e t t e r r e s u l t s f o r the d e s i r e d t r a n s m e t a l a t i o n reac-t i o n o f (370) . E v e n t u a l l y , i t was found t h a t compound (370) underwent complete t r a n s m e t a l a t i o n when t r e a t e d w i t h m e t h y l l i t h i u m (1 .1 equiv) and HMPA (1 .1 e q u i v ) i n THF a t -78°C f o r 1 h . The a d d i t i o n o f cyclohexanone to the s o l u t i o n o f ( E ) - 6 - c h l o r o - 3 - l i t h i o - 2 - h e x e n e (371) thus o b t a i n e d , f o l l o w e d by warming o f the r e a c t i o n m i x t u r e to room temperature , p r o -duced the s p i r o e ther (373) i n 68% y i e l d ( e q u a t i o n 74) . T h i s r e s u l t e s t a b l i s h e d c l e a r l y t h a t the v i n y l l i t h i u m s p e c i e s (371) i s s t a b l e at low temperatures and i s a v i a b l e donor -acceptor reagent f o r s y n t h e s i s . I t was g r a t i f y i n g to f i n d tha t the G r i g n a r d reagent (374) , o b t a i n e d by treatment o f (371) w i t h anhydrous MgBr 2 (1 .2 e q u i v ) , r e a c t e d c l e a n l y w i t h 2 - c y c l o p e n t e n - l - o n e (225) and 2 - m e t h y l - 2 - c y c l o h e x e n - l - o n e (224) i n the presence of CuBr -Me2S (0 .3 equiv) and B F 3 - E t 2 0 (1 .2 equiv) to p r o v i d e the conjugate a d d i t i o n products (375) and (376) , r e s p e c t i v e l y , i n good y i e l d s (equat ions 75 and 76) . I n t r a m o l e c u l a r a l k y l a t i o n of the c h l o r o ketones (375) and (376) o c c u r r e d smoothly upon treatment of these - 137 -MejSn MeLi THF-HMPA -78'C,1hr 370 H a] (74) 372 373 substances w i t h potass ium h y d r i d e i n THF. The ( Z ) - e t h y l i d e n e c y c l o h e x a n e a n n u l a t i o n products (377) and (378) , r e s p e c t i v e l y , were formed e x c e l l e n t y i e l d s . i n BrMg 374 , CuBr»Me2S BF3-Et20, -78°C KH THF (75) BrMg 374 , CuBcMe 2S BF3-Et20,_78°C 376 378 (76) Not u n e x p e c t e d l y , the c h l o r o ketone (376) was found to c o n s i s t of a 2:1 m i x t u r e of epimers . A c c o r d i n g l y , i n the lH nmr spectrum of (376), - 138 -the secondary methyl groups of the two epimers gave r i s e to a p a i r of d o u b l e t s ( r a t i o 2 : 1 , J •= 7 Hz i n each case) a t S 0.89 and 1.06, r e s p e c t i v e l y . However, k i n e t i c a l l y c o n t r o l l e d i n t r a m o l e c u l a r a l k y l a t i o n of b o t h the epimers s h o u l d p r o v i d e the same c i s - fused b i c y c l i c ketone ( 3 7 8 ) . 3 3 ' 3 4 > 7 7 b Indeed, g l c a n a l y s i s o f the crude product and the ^H nmr spectrum o f (378) i n d i c a t e d tha t a s i n g l e o l e f i n i c ketone was o b t a i n e d when the e p i m e r i c mix ture (376) was t r e a t e d w i t h potass ium h y d r i d e . The c i s b i c y c l i c ketone (377) , produced by i n t r a m o l e c u l a r a l k y l a t i o n o f ( 3 7 5 ) , 3 3 • 3 4 » 7 7 b c o u l d have undergone subsequent e p i m e r i z a t i o n a t the br idgehead p o s i t i o n ad jacent to the c a r b o n y l group. However, the ^H nmr spectrum o f (377) showed t h a t the c y c l i z a t i o n product o f (375) c o n s i s t e d o f a s i n g l e b i c y c l i c o l e f i n i c ketone p o s s e s s i n g a c i s r i n g - f u s i o n s t e r e o c h e m i s t r y . Thus, the ^H nmr spectrum of (377) c o n t a i n e d a resonance a t S 3.22 ( 1 - p r o t o n broad q u a r t e t , J •= 7 H z ) , a t t r i b u t e d to one of the br idgehead p r o t o n s . T h i s s i g n a l i n d i c a t e d a 7 Hz c o u p l i n g constant between the br idgehead protons and hence a c i s - f u s e d b i c y c l i c hydrindane u n i t i n compound (377) . I n summary, i t was found t h a t a d d i t i o n o f the elements o f Me 3 Sn-H across the t r i p l e bond of a c e t y l e n i c a l c o h o l s (108) by r e a c t i o n of these s u b s t r a t e s w i t h Me 3 SnCu-Me 2 S-MeOH, [ M e 3 S n Z n ( t - B u ) 2 ] L i - C u C N , or [Me 3 SnZnEt2]Li -CuCN p r o v i d e s , i n v a r y i n g r a t i o s , the t r i m e t h y l s t a n n y l a lkenes (109) and (339) . Or thoace ta te -based C l a i s e n rearrangement of compounds (109) and (339) was shown to a f f o r d the e s t e r s (357) and (363) , r e s p e c t i v e l y (equat ions 77 and 78) . These e s t e r s a r e , poten-t i a l l y , p r e c u r s o r s o f s t r u c t u r a l l y i n t e r e s t i n g d o n o r - a c c e p t o r conjunc-- 139 -t i v e r e a g e n t s . For example, the e s t e r (358) was conver ted i n t o the c h l o r i d e (370) , w h i c h , upon t r a n s m e t a l a t i o n ( M e L i , THF-HMPA, -78°C) produced the v i n y l l i t h i u m (371). Compound (371) and the corresponding G r i g n a r d reagent (374) serve as s y n t h e t i c e q u i v a l e n t s to the ( E ) - d 3 , a 5 -2-hexene synthon (379) i n the newly developed ( Z ) - e t h y l i d e n e c y c l o h e x a n e a n n u l a t i o n method [(101) •* (380) ] . The a l l y l i c t r i m e t h y l s t a n n a n e s (363) are a l s o p o t e n t i a l l y u s e f u l reagents and the c h e m i s t r y of these substances i s c u r r e n t l y under i n v e s t i g a t i o n i n our l a b o r a t o r y . 1 0 8 109 357 358 R = M G 1 0 8 339 363 370 M=SnMe. 371 M = Li * 3 7 4 M=MgBr 379 101 380 - 140 -EXPERIMENTAL - 141 -EXPERIMENTAL Genera l M e l t i n g p o i n t s were determined 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 apparatus 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 were r e c o r d e d as a i r - b a t h temperatures r e q u i r e d f o r b u l b - t o - b u l b (Kuge l rohr ) d i s t i l l a t i o n s and are a l s o u n c o r r e c t e d . I n f r a r e d ( i r ) s p e c t r a were o b t a i n e d on l i q u i d f i l m s , KBr p e l l e t s , or c h l o r o f o r m s o l u t i o n s , employing a P e r k i n - E l m e r model 1710 spectrophotometer ( i n t e r n a l c a l i b r a t i o n ) or a P e r k i n - E l m e r model 710B spectrophotometer c a l i b r a t e d u s i n g the 1601 c m " 1 band of a p o l y s t y r e n e f i l m . P r o t o n and carbon-13 n u c l e a r magnetic resonance (% and 1 3 C nmr) s p e c t r a were r e c o r d e d on d e u t e r o c h l o r o f o r m s o l u t i o n s u s i n g Bruker models WP-80, HXS-270 or WH-400 spectrometers or a V a r i a n model XL-300 i n s t r u m e n t . S i g n a l p o s i t i o n s are g i v e n i n 6 u n i t s and were measured r e l a t i v e t o t e t r a m e t h y l s i l a n e (TMS) as the i n t e r n a l s tandard or to the c h l o r o f o r m s i g n a l (5 7 . 2 5 ) . 1 0 9 The m u l t i p l i c i t y , number of p r o t o n s , c o u p l i n g c o n s t a n t s , and assignments (where p o s s i b l e ) are i n d i c a t e d i n p a r e n t h e s i s . The t i n - p r o t o n c o u p l i n g cons tants (J.sn-H^ a r e g i v e n as an average o f the 1 1 7 S n and 1 1 9 S n v a l u e s . Low and h i g h r e s o l u t i o n mass s p e c t r a were recorded w i t h Varian/MAT CH4B and/or K r a t o s / A E l MS 50 mass spec t rometers . I n cases o f compounds w i t h t r i -m e t h y l s t a n n y l groups the m o l e c u l a r weight d e t e r m i n a t i o n s (h igh r e s o l u -t i o n mass spectrometry) were based on 1 2 0 S n and were made on the (M+-CH 3) p e a k . 5 9 - 142 G a s - l i q u i d chromatography ( g l c ) analyses were performed on Hewle t t -Packard models 5880 or 5890 c a p i l l a r y gas chromatographs u s i n g 25 m x 0.21 mm fused s i l i c a columns coated w i t h c r o s s - l i n k e d SE-54 and flame i o n i z a t i o n d e t e c t o r s . T h i n l a y e r chromatography ( t i c ) analyses were done on commercial aluminum-backed s i l i c a g e l p l a t e s (E. Merck, Type 5554). V i s u a l i z a t i o n was accompl ished w i t h u l t r a v i o l e t l i g h t , i o d i n e , and/or by s p r a y i n g the p l a t e w i t h 5% ammonium molybdate - 10% aqueous s u l f u r i c a c i d . Conven-t i o n a l column chromatography was done on 70-230 mesh s i l i c a g e l (E. Merck) w h i l e f l a s h chromatograp hy 4 6 was done on 230-400 mesh s i l i c a g e l (E. M e r c k ) . A l l compounds t h a t were s u b j e c t e d to mass s p e c t r o m e t r i c determina-t i o n s were homogeneous by t i c and g l c a n a l y s e s . U n l e s s o therwise s t a t e d , a l l r e a c t i o n s were c a r r i e d out under an atmosphere o f d r y argon u s i n g glassware t h a t had been t h o r o u g h l y f lame-d r i e d . C o l d temperatures used f o r v a r i o u s r e a c t i o n s were o b t a i n e d as f o l l o w s : i c e - a c e t o n e ( - 1 0 ° C ) , 27 g C a C l 2 / 1 0 0 ml H 2 0 / C 0 2 ( - 2 0 ° C ) , 1 1 0 46 g C a C l 2 / 1 0 0 ml H 2 0 / C 0 2 ( - 4 8 ° C ) , c h l o r o f o r m / C 0 2 ( - 6 3 ° C ) , a c e t o n e / C 0 2 ( -78°C) and m e t h a n o l / N 2 ( - 9 8 ° C ) . S o l v e n t s and reagents were p u r i f i e d and d r i e d u s i n g e s t a b l i s h e d p r o c e d u r e s . 1 1 1 E ther and THF were d i s t i l l e d from sodium benzophenone k e t y l . T r i e t h y l a m i n e , d i i s o p r o p y l a m i n e , HMPA, DMSO and DMF were d i s -t i l l e d from c a l c i u m h y d r i d e . Methylene c h l o r i d e and carbon t e t r a c h l o -r i d e were d i s t i l l e d from P 2 0 5 . 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 between 30-60°C. - 143 -H e x a m e t h y l d i t i n was ob ta ined from O r g a n o m e t a l l i c s , I n c . and was 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 . S o l u t i o n s of m e t h y l l i t h i u m (low h a l i d e ) i n e ther and n - b u t y l l i t h i u m i n hexane were o b t a i n e d from A l d r i c h Chemical C o . , I n c . and were s t a n -d a r d i z e d u s i n g the procedure o f K o f r o n and B a c l a w s k i . H - 2 Cuprous b r o m i d e - d i m e t h y l s u l f i d e complex was prepared by the method o f H o u s e , a f t e r washing the commercial cuprous bromide w i t h metha-nol75b P h e n y l t h i o c o p p e r was prepared by the method of P o s n e r . 3 2 Cuprous cyanide was purchased from A l d r i c h Chemical C o . , I n c . and was 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 . S a t u r a t e d aqueous ammonium c h l o r i d e (pH 8) was prepared by the a d d i t i o n o f =50 ml o f aqueous ammonium h y d r o x i d e (58%) to 1 L of s a t u r a t e d aqueous ammonium c h l o r i d e . 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 prepared by the a d d i t i o n o f a s o l u t i o n o f m e t h y l l i t h i u m i n e ther to 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 equiv) i n d r y THF a t -78°C. The r e s u l t i n g c o l o r l e s s s o l u t i o n was then s t i r r e d a t 0°C f o r 10 min be fore b e i n g used . Anhydrous magnesium bromide was prepared by the dropwise a d d i t i o n o f a s o l u t i o n o f 1 ,2-dibromoethane i n d r y e ther to a suspens ion of magnesium (0 .5 equiv) In dry e t h e r . The e t h e r was removed under h i g h vacuum. A s t o c k s o l u t i o n of anhydrous z i n c c h l o r i d e was prepared by m e l t i n g the s o l i d under vacuum, c r y s t a l l i z i n g from dry THF under argon, and d i s s o l v i n g i n dry T H F . 1 1 3 A s t o c k s o l u t i o n of d i - t e r t - b u t y l z i n c was prepared by the dropwise - 144 -a d d i t i o n o f a s o l u t i o n of anhydrous z i n c c h l o r i d e i n dry THF to t e r t -b u t y l magnesium c h l o r i d e (2 equiv) i n dry THF at 0 ° C . ^ A f t e r the a d d i t i o n was complete the r e a c t i o n mixture was s t i r r e d f o r 24 h a t room temperature and then was s t o r e d under argon. A s o l u t i o n of d i e t h y l z i n c i n to luene was o b t a i n e d from A l d r i c h Chemical C o . , I n c . P r e p a r a t i o n of T r i m e t h y l s t a n n y l l i t h i u n r ° To a c o l d ( - 2 0 ° C ) , s t i r r e d s o l u t i o n o f h e x a m e t h y l d i t i n i n d r y THF (=10 mL per mmol) was added a s o l u t i o n o f m e t h y l l i t h i u m i n e ther (1 e q u i v ) . 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 a t -20°C f o r 20 min to a f f o r d a s o l u t i o n of t r i m e t h y l s t a n n y l l i t h i u m . P r e p a r a t i o n of L i t h i u m ( P h e n y l t h i o ) ( t r i m e t h y l s t a n n y l ) c u p r a t e (80) [Me 3SnCuSPhjLi To a c o l d ( - 2 0 ° C ) , s t i r r e d s o l u t i o n o f t r i m e t h y l s t a n n y l l i t h i u m i n dry THF was added s o l i d p h e n y l t h i o c o p p e r (1 e q u i v ) . The r e s u l t i n g s l u r r y was s t i r r e d at -20°C f o r 20 min to a f f o r d a b r i g h t r e d s o l u t i o n of l i t h i u m ( p h e n y l t h i o ) ( t r i m e t h y l s t a n n y l ) c u p r a t e (80) . 145 P r e p a r a t i o n of the ( T r i m e t h y l s t a n n y l ) c o p p e r R e a g e n t z z (84) Me3SnCu-Me2S To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of t r i m e t h y l s t a n n y l l i t h i u m i n dry THF was added s o l i d cuprous b r o m i d e - d i m e t h y l s u l f i d e (1 e q u i v ) . The r e s u l t i n g s l u r r y was s t i r r e d at -78°C f o r 10 min and a t -63°C f o r 15 min to a f f o r d a dark r e d s o l u t i o n o f (84) . P r e p a r a t i o n o f the ( T r i m e t h y l s t a n n y l ) z i n c Reagent (355) To a c o l d ( - 2 0 ° C ) , s t i r r e d s o l u t i o n of t r i m e t h y l s t a n n y l l i t h i u m i n dry THF was added a s o l u t i o n of d i - t e r t - b u t y l z i n c i n THF (1 e q u i v ) . 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 -20°C f o r 20 min to a f f o r d a p a l e y e l l o w s o l u t i o n of (355) . - 146 -P r e p a r a t i o n of the ( T r i m e t h y l s t a n n y l ) z i n c Reagent (356) [Me 3 SnZnEt 2 ] Li To a c o l d ( - 2 0 ° C ) , s t i r r e d s o l u t i o n of t r i m e t h y l s t a n n y l l i t h i u m i n d r y THF was added a s o l u t i o n of d i e t h y l z i n c i n to luene (1 e q u i v ) . 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 -20°C f o r 20 min to a f f o r d a p a l e y e l l o w s o l u t i o n of (356) . P r e p a r a t i o n of E t h y l 6 - t e r t - B u t y l d i m e t h y l s i l o x y - 2 - h e x y n o a t e (116) t-BuMe 2 S i O C H 2 C H 2 C H 2 - C = C - C 0 2 E t To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f 5 - t e r t - b u t y l d i m e t h y l s i l o x y -1-pentyne ( 1 1 4 ) 1 1 5 (2 .0 g , 10 mmol) i n 35 mL o f d r y THF was added a s o l u t i o n o f m e t h y l l i t h i u m i n e ther (7 .1 mL, 10 mmol). The r e s u l t i n g c l e a r s o l u t i o n was s t i r r e d a t -78°C f o r 15 m i n , warmed to -20°C and s t i r r e d a t t h i s temperature f o r 1 h . E t h y l c h l o r o f o r m a t e (1 .0 mL, 10 mmol) was added and the y e l l o w s o l u t i o n was s t i r r e d a t -20°C f o r 1 h and a t room temperature f o r 1 h . S a t u r a t e d aqueous sodium b i c a r b o n a t e and e t h e r were added. The o r g a n i c l a y e r was s e p a r a t e d , washed (water, b r i n e ) and d r i e d (MgS0 4 ) . S o l v e n t removal ( r o t a r y e v a p o r a t i o n ) , 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 1 0 5 - 1 1 5 ° C / 0 . 3 Torr ) of 147 -the r e s i d u a l o i l , a f f o r d e d 2.43 g (89%) of the e s t e r (116) as a c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 2210, 1705, 1250, 1110, 1060, 840 c m 4 ; X H nmr (80 MHz, CDC1 3) 6: 0.03 ( s , 6H, M e 2 S i - ) , 0.88 ( s , 9H, M e 3 C S i - ) , 1-28 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 1.80 (m, 2H, - C H 2 C H 2 C H 2 - ) , 2.40 ( t , 2H, - C H 2 - O C - , J - 7 H z ) , 3.65 ( t , 2H, - 0 C H 2 - , J - 6 H z ) , 4.18 (q , 2H, - O C H 2 C H 3 , J - 7 H z ) . Exact Mass c a l c d . f o r C 1 3 H 2 3 0 3 S i (M+-CH 3 ) : 255.1417; found: 255.1419. P r e p a r a t i o n o f M e t h y l 4 - C y c l o p r o p y l - 2 - b u t y n o a t e (129) To a c o l d (-20°C), s t i r r e d s o l u t i o n o f d i i s o p r o p y l a m i n e (140 /JL, 1 mmol), and p r o p y n o i c a c i d (616 /xL, 10 mmol) i n 7.5 mL of dry THF was added a s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (14.5 mL, 21 mmol). A f t e r the l i g h t y e l l o w s o l u t i o n had been s t i r r e d at -20°C f o r 10 m i n , 15 mL of HMPA was added and s t i r r i n g was c o n t i n u e d a t -20°C f o r 15 min and at -10°C f o r 1.5 h . C y c l o p r o p y l m e t h y l b r o m i d e 4 4 (1.42 g , 10.5 mmol) was added. The s o l u t i o n was a l l o w e d to warm to room temperature . A f t e r 24 h , methyl i o d i d e (2.5 mL, 40 mmol) was added and s t i r r i n g was c o n t i n u e d f o r a f u r t h e r 24 h a t room temperature . C o l d water and e ther were added. The aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed (water , b r i n e ) and d r i e d (MgSO,^) . S o l v e n t removal a f f o r d e d a y e l l o w o i l which was s u b j e c t e d to f l a s h 148 chromatography on s i l i c a g e l (30 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 2 5 : 1 ) . C o n c e n t r a t i o n of the a p p r o p r i a t e f r a c t i o n s and d i s t i l l a t i o n ( a i r - b a t h temperature 5 0 - 6 5 ° C / 0 . 3 T o r r ) of 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 735 mg (53%) of the e s t e r (129) as a c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3050, 2210, 1710, 1260 c m ' 1 ; lE nmr (80 MHz, CDC1 3) 6: 0 .50-1 .50 (m, 5 H , c y c l o p r o p y l p r o t o n s ) , 2.30 (d , 2H, - C H 2 - C ^ , J. - 7 H z ) , 3.78 ( s , 3 H , - O C H 3 ) . Exact Mass c a l c d . f o r C 8 H 1 0 0 2 : 138.0681; found: 138.0680. Genera l Procedure 1: P r e p a r a t i o n o f 1 , 1 - D i b r o m o o l e f I n s (381) To a reagent- 3 ' prepared by s t i r r i n g a m i x t u r e o f z i n c dust (3 .3 g , 50 mmol), t r i p h e n y l p h o s p h i n e (13.1 g , 50 mmol), carbon te t rabromide (16.6 g , 50 mmol), and 80 mL of d r y dichloromethane a t room temperature f o r 24 h was added the a p p r o p r i a t e aldehyde (25 mmol). The r e s u l t i n g t a n suspens ion was s t i r r e d a t room temperature f o r 2 h . Petroleum ether (400 mL) was added and the supernatant s o l u t i o n was decanted from the o i l . The o i l was taken up i n 80 mL dich loromethane , petro leum ether (400 mL) was added and the supernatant s o l u t i o n was a g a i n decanted. C o n c e n t r a t i o n of the combined supernatant s o l u t i o n s , 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 (0 .1 T o r r , r e c e i v i n g b u l b c o o l e d to - 7 8 ° C ) , a f f o r d e d the c o r r e s p o n d i n g d i b r o m o o l e f i n (381) . H Br - 149 -Genera l Procedure 2 : P r e p a r a t i o n of a . ^ - A c e t y l e n i c E s t e r s (130) R C H 2 - C = C - C 0 2 Et A s o l u t i o n of the a p p r o p r i a t e 1 , 1 - d i b r o m o o l e f i n (381) (20 mmol) i n 50 mL o f d r y THF at -78°C was t r e a t e d w i t h a s o l u t i o n of m e t h y l l i t h i u m i n e t h e r (42 mmol). A f t e r b e i n g s t i r r e d a t -78°C f o r 1 h and at room temperature f o r 1 h , the s o l u t i o n was c o o l e d to -20°C. E t h y l c h l o r o f o r -mate (28 mmol) was added and the s o l u t i o n was s t i r r e d a t -20°C f o r 1 h and a t room temperature f o r 1 h . S a t u r a t e d aqueous sodium b i c a r b o n a t e and e t h e r were added. The o r g a n i c l a y e r was washed (water , b r i n e ) , d r i e d ( M g S O ^ , and c o n c e n t r a t e d . D i s t i l l a t i o n o f the r e s i d u a l o i l a f f o r d e d the c o r r e s p o n d i n g a , / J - a c e t y l e n i c e s t e r (130) . P r e p a r a t i o n o f E t h y l 5 -Methyl -2 -hexynoate (119) Br Br 118 119 F o l l o w i n g g e n e r a l procedure 1 o u t l i n e d above, 3 -methy lbutana l (117) (2.7 mL, 25 mmol) a f f o r d e d 5.68 g (94%) of the d i b r o m o o l e f i n (118) as a c o l o r l e s s o i l ( f l a s h d i s t i l l a t i o n temperature < 5 0 ° C / 0 . 1 T o r r ) . This - 150 -m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1610, 1460, 1380, 1365, 860, 790 c m ' 1 ; X H nmr (80 MHz, C D C 1 3 ) 6": 0.93 ( d , 6H, -CHMe 2 , J - 7 H z ) , 1 .50-1 .85 (m, 1H, - C H M e 2 ) , 2.00 ( t , 2H, -CH 2 CHMe 2 , J - 7 H z ) , 6.41 ( t , 1H, o l e f i n i c p r o t o n , J — 7 H z ) . F o l l o w i n g g e n e r a l procedure 2, 1 , l - d i b r o m o - 4 - m e t h y l - 1 - p e n t e n e (118) (5.57 g , 23 mmol) i n 60 mL of dry THF was t r e a t e d s u c c e s s i v e l y w i t h a s o l u t i o n o f m e t h y l l i t h i u m i n e ther (30.9 mL, 48 mmol) and e t h y l c h l o r o -formate (3 .1 mL, 32.2 mmol). Normal workup, 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 85-100°C/20 T o r r ) , a f f o r d e d 2.622 g (74%) of the e s t e r (119) as a c l e a r , c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 2234, 1713, 1388, 1367, 1251 c m " 1 ; X H nmr (80 MHz, C D C I 3 ) 6: 1.00 (d , 6H, M e 2 C H - , J - 7 H z ) , 1.32 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 1.60-2.10 (m, 1H, M e 2 C H - ) , 2.23 ( d , 2H, - C H 2 - 0 , J - 6 H z ) , 4 .20 (q , 2H, - O C H 2 C H 3 , J - 7 H z ) . Exact Mass c a l c d . f o r C g H ! ^ (M+-CH 3) : 139.0759; f o u n d : 139.0757. P r e p a r a t i o n o f E t h y l 5 - T r i m e t h y l s i l y l - 2 - p e n t y n o a t e (122) Me 3Si Me 3 Si C H 2 C H 2 - C = C - C 0 2 Et 121 | 2 2 F o l l o w i n g g e n e r a l procedure 1, 3 - t r i m e t h y l s i l y l - l - p r o p a n a l (120) 3 * (3.25 g , 25 mmol) a f f o r d e d 6.60 g (92%) of 1 , l - d i b r o m o - 4 - t r i m e t h y l s i l y l -- 151 -1- butene (121) as a c o l o r l e s s o i l ( f l a s h d i s t i l l a t i o n temperature < 5 0 ° C / 0 . 1 T o r r ) . 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 r e a c t i o n . Compound (121) (6 .60 g , 23 mmol) was d i s s o l v e d i n 130 mL o f d r y THF and the s o l u t i o n was t r e a t e d s u c c e s s i v e l y w i t h a s o l u t i o n of m e t h y l l i t h i u m i n e t h e r (34.9 mL, 48 mmol) and e t h y l ch loro formate (2 .7 mL, 28 mmol) as o u t l i n e d i n g e n e r a l procedure 2. Normal workup, 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 70-85°C/19 T o r r ) , a f f o r d e d 3.33 g (73%) o f the e s t e r (122) as a c o l o r l e s s l i q u i d . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 2239, 1713, 1251 c m - 1 ; lE nmr (270 MHz, CDC1 3 ) 6: 0.24 ( s , 9H, M e 3 S i - ) , 1.05 ( t , 2H, M e 3 S i C H 2 - , J = 7 H z ) , 1.48 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 2.53 ( t , 2H, M e 3 S i C H 2 C H 2 - , J = 7 H z ) , 4 .40 ( q , 2H, - O C H 2 C H 3 , J - 7 H z ) . Exact Mass c a l c d . f o r C 9 H 1 5 0 2 S i ( M + - C H 3 ) : 183.0842; found: 183.0848. Genera l Procedure 3 : P r e p a r a t i o n of A l k y l ( E ) - 3 - T r i m e t h y l s t a n n y l -2- a lkenoates (131) To a c o l d ( - 9 8 C C ) , s t i r r e d s o l u t i o n o f l i t h i u m ( p h e n y l t h i o ) ( t r i -m e t h y l s t a n n y l ) cuprate (80) (1 .4 mmol) i n 14 mL o f dry THF was added, d r o p w i s e , a s o l u t i o n o f the a p p r o p r i a t e a , j S - a c e t y l e n i c e s t e r (130) (1 .0 mmol) i n =1.0 mL o f d r y THF c o n t a i n i n g d r y methanol (1 .7 mmol). 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 -98°C f o r 20 m i n , warmed to -78°C, and Me 3 Sn R - 152 -s t i r r e d f o r a f u r t h e r 6 h . A f t e r s u c c e s s i v e a d d i t i o n of methanol or e t h a n o l (-2 mL) and petro leum e ther (-30 mL), the m i x t u r e was a l l o w e d to warm to room temperature w i t h v i g o r o u s s t i r r i n g . The r e s u l t i n g y e l l o w s l u r r y was f i l t e r e d through a s h o r t column o f F l o r i s i l . The column was e l u t e d w i t h a f u r t h e r 30 mL of pe t ro leum e t h e r and the combined e l u a t e was c o n c e n t r a t e d . The r e s i d u e was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , petro leum e t h e r - e t h e r m i x t u r e as e l u a n t ) . C o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s , 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 , a f f o r d e d the c o r r e s p o n d i n g a l k y l ( E ) - 3 - t r i m e t h y l s t a n n y l - 2 - a l k e n o a t e (131) . Genera l Procedure 4: P r e p a r a t i o n of A l k y l ( Z ) - 3 - T r i m e t h y l s t a n n y l - 2 -a lkenoates (137) To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f l i t h i u m ( p h e n y l t h i o ) -( t r i m e t h y l s t a n n y l ) c u p r a t e (80) (1 .3 mmol) i n 13 mL d r y THF was added the a p p r o p r i a t e a , / 3 - a c e t y l e n i c e s t e r (130) (1 .0 mmol) as a s o l u t i o n i n = 1.0 mL o f d r y THF. The r e a c t i o n mix ture was s t i r r e d a t -78°C f o r 15 m i n , warmed t o -48°C, and s t i r r e d a t t h a t temperature f o r 4 h . A f t e r s u c c e s s i v e a d d i t i o n of methanol or e t h a n o l (~ 2 mL) and petro leum ether (-30 mL), the m i x t u r e was a l l o w e d to warm to room temperature w i t h v i g o r o u s s t i r r i n g . Normal workup (as i n g e n e r a l procedure 3 ) , f o l l o w e d M e 3 S n C 0 2 R ' - 153 by d i s t i l l a t i o n of the crude product gave the c o r r e s p o n d i n g a l k y l ( Z ) - 3 -t r i m e t h y l s t a n n y l - 2 - a l k e n o a t e (137) . P r e p a r a t i o n o f E t h y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 2 - p e n t e n o a t e (132) F o l l o w i n g g e n e r a l procedure 3 , e t h y l 2-pentynoate ( 1 1 3 ) J b (126 mg, 1 mmol) was c o n v e r t e d i n t o the / ? - t r i m e t h y l s t a n n y l - a . ^ - u n s a t u r a t e d e s t e r (132) . F l a s h chromatography of the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 200 :3 ) , 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 5 5 - 7 0 ° C / 0 . 2 T o r r ) o f the m a t e r i a l thus o b t a i n e d , a f f o r d e d 229.8 mg (79%) o f the (E)-pentenoate (132) as a c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1705, 1600, 1175, 770 c m ' 1 ; X H nmr (CDC1 3 , 80 MHz) 6: 0.20 ( s , 9H, -SnMe.3, J S n . H - 54 H z ) , 1.05 ( t , 3H, C H 3 C H 2 - , J - 7 H z ) , 1.30 ( t , 3H, C H 3 C H 2 0 - , J - 7 H z ) , 2.90 (broad q , 2H, C H 3 C H 2 C - , J - 7 H z ) , 4 .15 (q , 2H, C H 3 C H 2 0 - , J - 7 H z ) , 5.95 ( t , I H , o l e f i n i c p r o t o n , J - 1 H z , J .s n -H " 7 3 H z ) . Exact Mass c a l c d . f o r C 9 H 1 7 0 2 S n ( M + - C H 3 ) : 277.0250; found: 277.0250. 154 P r e p a r a t i o n of E t h y l ( Z ) - 3 - T r i m e t h y l s t a n n y l - 2 - p e n t e n o a t e (138) C02Et F o l l o w i n g g e n e r a l procedure 4 , e t h y l 2-pentynoate (113)- , b (126 mg, 1 mmol) was conver ted i n t o the e s t e r (138) . F l a s h chromatography of the crude p r o d u c t on s i l i c a g e l (18 g , e l u t i o n w i t h pet ro leum e t h e r - e t h e r , 2 0 0 : 3 ) , 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 5 5 - 6 5 ° C / 0 . 2 Torr ) o f the m a t e r i a l thus o b t a i n e d , a f f o r d e d 220.9 mg (76%) of the (Z) -pentenoate (138) as a c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1700, 1600, 1195, 770 c m " 1 ; X H nmr (CDC1 3 , 80 MHz) 6: 0.18 ( s , 9H, -SnMe 3 , J S n . H - 54 H z ) , 1.02 ( t , 3H, C H 3 C H 2 0 , J - 7 H z ) , 1.28 ( t , 3H, C H 3 C H 2 0 - , J - 7 H z ) , 2.30 (broad q , 2H, C H 3 C H 2 C - , J - 7 H z ) , 4.18 (q , 2H, C H 3 C H 2 0 - , J - 7 H z ) , 6.35 ( t , I H , o l e f i n i c p r o t o n , J - 1 Hz , J_S n-H ~ 1 2 1 H z ) . Exact Mass c a l c d . f o r C 9 H 1 7 0 2 S n (M+-CH;}) : 277.0250; f o u n d : 277.0252. P r e p a r a t i o n of E t h y l ( E ) - 6 - t e r t - B u t v l d i m e t h v l s i l o x v - 3 - t r i m e t h y l s t a n n y l -2-hexenoate (133) 155 F o l l o w i n g g e n e r a l procedure 3 , e t h y l 6 - t e r t - b u t y l d i m e t h y l s i l o x y - 2 -hexynoate (116) (270 mg, 1 mmol) was conver ted i n t o the e s t e r (133) . S u b j e c t i o n o f the crude m i x t u r e t o f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 30:1) p r o v i d e d a c o l o r l e s s l i q u i d which upon d i s t i l l a t i o n ( a i r - b a t h temperature 1 5 0 - 1 6 0 ° C / 0 . 3 Torr ) gave 309.5 mg (71%) o f pure (E)-hexenoate (133) as a c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1695, 1580, 1175, 840, 770 c m - 1 ; X H nmr (400 MHz, CDC1 3) 6: 0.04 ( s , 6H, - S i M e 2 ) , 0.20 ( s , 9H, -SnMe 3 , J S n . H - 56 H z ) , 0.89 ( s , 9H, - S i C M e 3 ) , 1.27 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 1 .60-1 .66 (m, 2H, - C H 2 C H 2 C H 2 - ) , 2 .89-2 .94 (m, 2H, -CH 2C-=), 3.64 ( t , 2H, - S i O C H 2 - , J - 6 H z ) , 4 .15 ( q , 2H, - O C H 2 C H 3 , 1 - 7 H z ) , 5.96 (broad s, 1H, o l e f i n i c p r o t o n , J_sn-H - 73 H z ) . Exact Mass c a l c d . f o r C i g H 3 3 0 3 S i S n (M+-CH 3 ) : 421.1221; found: 421.1208. P r e p a r a t i o n o f E t h y l ( Z ) - 6 - t e r t - B u t v l d i m e t h v l s i l o x y - 3 - t r i m e t h y l s t a n n y l -2-hexenoate (139) F o l l o w i n g g e n e r a l procedure 4 , e t h y l 6 - t e r t - b u t y l d i m e t h y l s i l o x y - 2 -hexynoate (116) (270 mg, 1 mmol) was conver ted i n t o the e s t e r (139) . F l a s h chromatography of the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h pe t ro leum e t h e r - e t h e r , 5 0 : 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 1 4 5 - 1 5 5 ° C / 0 . 3 T o r r ) , p r o v i d e d 344.5 mg (79%) of the - 156 -(Z)-hexenoate (139) as a c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1695, 1585, 1200, 835, 770 c m " 1 ; X H nmr (400 MHz, CDC1 3 ) 6: 0.05 ( s , 6H, - S i M e 2 ) , 0.19 ( s , 9H, -SnMe 3 , J S n . H - 56 H z ) , 0.91 ( s , 9H, - S i C M e 3 ) , 1.29 ( t , 3H, - 0 C H 2 C H 3 , J - 7 H z ) , 1 .57-1 .64 (m, 2H, - C H 2 C H 2 C H 2 - ) , 2 .46 -2 .51 (m, 2H, -CH 2 C=) , 3.61 ( t , 2H, - 0 C H 2 C H 2 - , J - 6 H z ) , 4 .18 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 6.37 (broad s , I H , o l e f i n i c p r o t o n , J_sn-H ~ 1 2 0 H z ) - Exact Mass c a l c d . f o r C i 6 H 3 3 0 3 S i S n ( M + - C H 3 ) : 421.1221; f o u n d : 421.1240. P r e p a r a t i o n of M e t h y l ( E ) - 4 - C y c l o p r o p y l - 3 - t r i m e t h y l s t a n n y l - 2 -butenoate (136) F o l l o w i n g g e n e r a l procedure 3, methyl 4 - c y c l o p r o p y l - 2 - b u t y n o a t e (129) (138 mg, 1. mmol) was conver ted i n t o the e s t e r (136) . F l a s h chromatography o f the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h pet ro leum e t h e r - e t h e r , 5 0 : 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 temper-a ture 6 0 - 7 5 ° C / 0 . 3 T o r r ) o f the m a t e r i a l thus o b t a i n e d , a f f o r d e d 225.0 mg (74%) o f the (E) -butenoate (136) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3050, 1710, 1590, 1170, 770 c m ' 1 ; X H nmr (400 MHz, CDC1 3) S: 0 .23 ( s , 9H, -SnMe 3 , J_sn-H = 5 6 H z ) • 0 .15-0 .20 and 0 .45-0 .50 (m, m, 2H each, c y c l o p r o p y l methylene p r o t o n s ) , 0 .73-0 .82 (m, I H , c y c l o p r o p y l methine p r o t o n ) , 2.83 (d o f d , 2H, -CH 2 C=, J - 1, 7 H z ) , 3.68 ( s , 3H, - 0 C H 3 ) , - 157 5.99 ( t , 1H, o l e f i n i c p r o t o n , J - 1 H z , J-Sn-H = 7 6 H z ) - Exact Mass c a l c d . f o r C 1 0 H 1 7 O 2 S n (M+-CH3): 289.0250; found: 289.0238. P r e p a r a t i o n of M e t h y l ( Z ) - 4 - C y c l o p r o p y l - 3 - t r i m e t h y l s t a n n y l - 2 -butenoate (142) F o l l o w i n g g e n e r a l procedure 4 , methyl 4 - c y c l o p r o p y l - 2 - b u t y n o a t e (129) (138 mg, 1 mmol) was conver ted i n t o the e s t e r (142) . F l a s h chromatography o f the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h pet ro leum e t h e r - e t h e r , 2 0 0 : 3 ) , 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 6 0 - 8 0 ° C / 0 . 3 T o r r ) o f the o i l thus o b t a i n e d , a f f o r d e d 203.7 mg (67%) o f the (Z) -butenoate (142) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3060, 1705, 1600, 1200, 770 c m * 1 ; X H nmr (400 MHz, CDC1 3) 6: 0.19 ( s , 9H, -SnMe 3 , J S n . H - 56 H z ) , 0 .06-0 .12 and 0 .46-0 .53 (m, m, 2H each, c y c l o p r o p y l methylene p r o t o n s ) , 0 .77-0 .85 (m, 1H, c y c l o p r o p y l methine p r o t o n ) , 2.34 (d o f d , 2H, - C H 2 C ~ , 1 - 1 , 7 Hz) , 3.73 ( s , 3H, - O C H 3 ) , 6.53 ( t , 1H, o l e f i n i c p r o t o n , J - 1 H z , J.sn-H ~ 1 2 0 H z ) - Exact Mass c a l c d . f o r C 1 0 H 1 7 ° 2 S n ( M + " C H 3 ) : 289.0250; found: 289.0250. - 158 -P r e p a r a t i o n of E t h y l ( E ) - 5 - M e t h y l - 3 - t r i m e t h y l s t a n n y l - 2 - h e x e n o a t e (134) F o l l o w i n g g e n e r a l procedure 3, e t h y l 5 -methyl -2-hexynoate (119) (154 mg, 1 mmol) was conver ted i n t o the e s t e r (134) . F l a s h chromato-graphy o f the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h petroleum e t h e r - e t h e r , 2 0 0 : 3 ) , 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 8 5 - 9 5 ° C / 0 . 3 T o r r ) o f the r e s u l t a n t o i l , p r o v i d e d 236.7 mg (74%) of the (E)-hexenoate (134) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1719, 1597, 1385, 1367, 1177, 771 c m " 1 ; X H nmr (270 MHz, C D C I 3 ) 6: 0.16 ( s , 9H, -SnMe 3 , J_Sn-H - 56 H z ) , 0.89 ( d , 6H, -CHMe 2 , J - 7 H z ) , 1.27 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 1 .60-1 .72 (m, 1H, - C H M e 2 ) , 2.80 (d o f d , 2H, -CH 2 C=, J -= 1, 7 H z ) , 4 .13 ( q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 6.00 ( t , 1H, o l e f i n i c p r o t o n , J -1 H z , J gn-H ~ 7 5 H z ) - Exact Mass c a l c d . f o r C 1 1 H 2 ^ 0 2 S n ( M + - C H 3 ) : 305.0563; f o u n d : 305.0566. P r e p a r a t i o n o f E t h y l ( Z ) - 5 - M e t h y l - 3 - t r i m e t h y l s t a n n y l - 2 - h e x e n o a t e (140) F o l l o w i n g g e n e r a l procedure 4, e t h y l 5 -methyl -2-hexynoate (119) - 159 -(154 mg, 1 mmol) was conver ted i n t o the e s t e r (140) . F l a s h chromatogra-phy of the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 1 0 0 : 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 7 0 - 8 0 ° C / 0 .3 T o r r ) o f the m a t e r i a l thus o b t a i n e d , a f f o r d e d 243.0 mg (76%) o f the (Z)-hexenoate (140) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1704, 1599, 1385, 1369, 1196, 772 c m - 1 ; 1 H nmr (270 MHz, C D C l 3 ) 6: 0.15 ( s , 9H, -SnMe 3 , J S n - H = 5 6 H z )> ° - 8 7 ( d , 6H, -CHMe 2 . I • 7 H z ) , 1.27 ( t , 3H, - 0 C H 2 C H 3 , J - 7 H z ) , 1 .60-1 .72 (m, I H , - C H M e 2 ) , 2.27 (d o f d , 2H, -CH 2 C=, J = 1, 7 H z ) , 4.16 ( q , 2H, - 0 C H 2 C H 3 , J = 7 H z ) , 6.28 ( t , I H , o l e f i n i c p r o t o n , J •= 1 H z , J s n - H = ^ 1 H z ^ • Exact Mass c a l c d . f o r C 1 1 H 2 1 0 2 S n (M+-CH5): 305.0563; f o u n d : 305.0554. P r e p a r a t i o n of E t h y l ( E ) - 5 - T r i m e t h y l s i l y l - 3 - t r i m e t h y l s t a n n y l - 2 -pentenoate (135) F o l l o w i n g g e n e r a l procedure 3, e t h y l 5 - t r i m e t h y l s i l y l - 2 - p e n t y n o a t e (122) (198 mg, 1 mmol) was conver ted i n t o the e s t e r (135) . F l a s h chromatography o f the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h pe t ro leum e t h e r - e t h e r , 4 0 : 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 temper-a ture 8 5 - 9 5 ° C / 0 . 2 T o r r ) o f the o i l thus o b t a i n e d , p r o v i d e d 265.4 mg (73%) o f the (E) -pentenoate (135) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1710, 1600, 1240, 1180, 840, 760 c m - 1 ; 1 H nmr (400 MHz, CDC1 3) 5 : 0.03 ( s , 9H, 160 -- S i M e 3 ) , 0.20 ( s , 9H, -SnMe 3 , J S n . H - 56 H z ) , 0 .55-0 .60 (m, 2H, M e 3 S i C H 2 - ) , 1.28 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 2 .80-2 .88 (m, 2H, -CH 2 C=), 4 .16 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 5.87 ( t , I H , o l e f i n i c p r o t o n , J = 1 349.0645; found: 349.0634. P r e p a r a t i o n o f E t h y l ( Z ) - 5 - T r i m e t h y l s i l y l - 3 - t r i m e t h y l s t a n n y l - 2 -pentenoate (141) F o l l o w i n g g e n e r a l procedure 4 , e t h y l 5 - t r i m e t h y l s i l y l - 2 - p e n t y n o a t e (122) (198 mg, 1 mmol) was conver ted i n t o the e s t e r (141) . F l a s h chromatography of the crude product on s i l i c a g e l (18 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 5 0 : 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 temper-a ture 7 0 - 8 0 ° C / 0 . 2 T o r r ) o f the m a t e r i a l thus o b t a i n e d , a f f o r d e d 283.6 mg (78%) o f the (Z)-pentenoate (141) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1703, 1600, 1201, 861, 769 c m - 1 ; X H nmr (270 MHz, CDC1 3) 6: 0.01 ( s , 9H, - S i M e 3 ) , 0.16 ( s , 9H, -SnMe 3 , I S n . H = 56 H z ) , 0 .50-0 .58 (m, 2H, - C H 2 S i M e 3 ) , 1.28 ( t , 3H, - 0 C H 2 C H 3 , J - 7 H z ) , 2 .33-2 .40 (m, 2H, -CH 2 C=), 4 .15 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 6.33 ( t , I H , o l e f i n i c p r o t o n , J «* 1 H z> i S n - H " 1 2 0 H z ) - Exact Mass c a l c d . f o r C 1 2 H 2 5 0 2 S i S n ( M + - C H 3 ) : 349.0645; f o u n d : 349.0644. H z , sLsn-H " 7 3 H z ) - Exact Mass c a l c d . f o r C 1 2 H 2 5 0 2 S i S n (M+'CH;}) : - 161 -Genera l Procedure 5: P r e p a r a t i o n of A l k y l ( Z ) - 3 - T r i m e t h y l s t a n n y l - 3 -a lkenoates (167) . P r o t o n a t i v e Deconjugat ion of A l k y l ( E ) - 3 - T r i m e t h y l -s t a n n y l - 2 - a l k e n o a t e s (131) . To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of LDA (1.15 mmol) i n 5 mL of dry THF was added a s o l u t i o n o f the a p p r o p r i a t e a l k y l ( E ) - 3 - t r i m e t h y l -s t a n n y l -2 - a l k e n o a t e (131) (0 .5 mmol) i n 0 .5 mL o f d r y THF. The b r i g h t 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 30 min and a t 0°C f o r 1 h . The s o l u t i o n was c o o l e d to -78°C and t r a n s f e r r e d i n t o a c o l d ( - 9 8 ° C ) , v i g o r o u s l y s t i r r e d s o l u t i o n o f g l a c i a l a c e t i c a c i d (0 .3 mL) i n 5 mL of e t h e r , u s i n g e i t h e r a s y r i n g e or a c a n n u l a . The s o l u t i o n was a l l o w e d to warm t o room temperature and s a t u r a t e d aqueous sodium b i c a r b o n a t e and e ther were added. The o r g a n i c l a y e r was separa ted and the aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e x t r a c t was washed (water , b r i n e ) , d r i e d ( M g S O ^ , and c o n c e n t r a t e d . The r e s i d u a l o i l was d i s t i l l e d to a f f o r d pure deconjugated e s t e r (167) . P r e p a r a t i o n of E t h y l ( Z ) - 3 - T r i m e t h y l s t a n n y l - 3 - p e n t e n o a t e (168) SnMe 3 - 162 -F o l l o w i n g g e n e r a l procedure 5, e t h y l ( E ) - 3 - t r i m e t h y l s t a n n y l - 2 -pentenoate (132) (145.5 mg, 0.5 mmol) was c o n v e r t e d i n t o the e s t e r (168) . A n a l y s i s of the crude product by g l c showed the complete absence o f the g e o m e t r i c a l l y i s o m e r i c e s t e r . D i s t i l l a t i o n ( a i r - b a t h temperature 6 5 - 8 0 ° C / 0 . 2 T o r r ) o f the crude product a f f o r d e d 119 mg (82%) o f the pure j 8 , 7 - u n s a t u r a t e d e s t e r (168) as a c o l o r l e s s o i l ; i r ( f i l m ) 1720, 1160, 770 c m - 1 ; 1 H nmr (400 MHz, CDC1 3) 8: 0.20 ( s , 9H, -SnMe 3 , J S n . H - 54 H z ) , 1.26 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 1.76 ( d , 3H, CH 3 C=, J = 6 H z ) , 3.20 ( d , 2H, - C C H 2 - , J = 1 H z ) , 4 .12 (q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 6.16 ( t o f q , 1H, o l e f i n i c p r o t o n , J •= 1, 6 H z , J_sn_H = 131 H z ) . Exact Mass c a l c d . f o r C 9 H 1 7 0 2 S n ( M + - C H 3 ) : 277.0250; found: 277.0246. P r e p a r a t i o n o f E t h y l ( Z ) - 6 - t e r t - B u t v l d i m e t h v l s i l o x y - 3 - t r i m e t h y l s t a n n y l -3-hexenoate (169) F o l l o w i n g g e n e r a l procedure 5, e t h y l (E ) - 6 - t e r t - b u t y l d i m e t h y l -s i l o x y - 3 - t r i m e t h y l s t a n n y l - 2 - h e x e n o a t e (133) (217.5 mg, 0 .5 mmol) was s u b j e c t e d to p r o t o n a t i v e d e c o n j u g a t i o n . A n a l y s i s o f the crude product by g l c i n d i c a t e d the e x c l u s i v e f o r m a t i o n o f one i somer . D i s t i l l a t i o n ( a i r - b a t h temperature 1 5 5 - 1 6 5 ° C / 0 . 3 T o r r ) o f the crude p r o d u c t p r o v i d e d 180.1 mg (83%) o f the pure / ? ,7 - u n s a t u r a t e d e s t e r (169) as a c o l o r l e s s o i l ; i r ( f i l m ) 1720, 1110, 840, 775 c m " 1 ; ^ nmr (400 MHz, CDC1 3) 8: - 163 0.04 ( s , 6H, - S i M e 2 ) , 0.16 ( s , 9H, -SnMe 3 , J S n - H - 54 H z ) , 0.91 ( s , 9H, - S i C M e 3 ) , 1.20 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 2.24 ( q , 2H, -CH2CH2C«, J = 7 H z ) , 3.17 ( s , 2H, - C H 2 C 0 2 E t ) , 3.51 ( t , 2H, - S i O C H 2 - , J. - 7 H z ) , 4.10 (q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 6.05 ( t , I H , o l e f i n i c p r o t o n , J - 7 H z , J S n _ H - 129 H z ) . Exact Mass c a l c d . f o r C 1 6 H 3 3 0 3 S i S n ( M + ' C H ^ : 421.1221; f o u n d : 421.1204. P r e p a r a t i o n o f M e t h y l ( Z ) - 4 - C y c l o p r o p y l - 3 - t r i m e t h y l s t a n n y l - 3 -butenoate (172) P r o t o n a t i v e d e c o n j u g a t i o n o f methyl ( E ) - 4 - c y c l o p r o p y l - 3 - t r i m e t h y l -s t a n n y l -2 -butenoate (136) (151.5 mg, 0 .5 mmol) was c a r r i e d out as o u t l i n e d i n g e n e r a l procedure 5 . A n a l y s i s o f the crude product by g l c showed the e x c l u s i v e f o r m a t i o n o f one isomer . D i s t i l l a t i o n ( a i r - b a t h temperature 6 0 - 7 5 ° C / 0 . 3 T o r r ) o f t h i s m a t e r i a l gave 119.3 mg (79%) of the pure fl,7-unsaturated e s t e r (172) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3060, 1730, 1615, 1180, 770 c m - 1 ; * H nmr (400 MHz, CDC1 3) 6: 0.22 (s , 9H, -SnMe 3 , J S n - H ~ 5 6 Hz>> 0 .38-0 .44 and 0 .72-0 .78 (m, m, 2H each, c y c l o p r o p y l methylene p r o t o n s ) , 1 .26-1.36 (m, I H , c y c l o p r o p y l methine p r o t o n ) , 3.18 ( s , 2H, - C C H 2 - ) , 3.66 ( s , 3H, - O C H 3 ) , 5.42 (d , IH, o l e f i n i c p r o t o n , J - 8 H z , J.Sn-H " I 2 8 H z ) . Exact Mass c a l c d . f o r C 1 0 H 1 7 0 2 S n ( M + - C H 3 ) : 289.0250; found: 289.0253. 164 P r e p a r a t i o n o f E t h y l ( Z ) - 5 - M e t h y l - 3 - t r i m e t h y l s t a n n y l - 3 - h e x e n o a t e (170) procedure 5. Thus, HMPA (23.6 / i L , 0.14 mmol) was added dropwise to a s o l u t i o n of LDA (0.14 mmol) i n 0.5 mL of dry THF at -78°C. A f t e r the c l e a r s o l u t i o n had been s t i r r e d a t -78°C f o r 15 m i n , a s o l u t i o n of e t h y l ( E ) - 5 - m e t h y l - 3 - t r i m e t h y l s t a n n y l - 2 - h e x e n o a t e (134) (18.9 mg, 0.06 mmol) i n 0.5 mL o f dry THF was added s l o w l y 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 30 min and a t 0°C f o r 1 h . The s o l u t i o n was r e c o o l e d to -78°C and t r a n s f e r r e d ( s y r i n g e ) i n t o a c o l d ( - 9 8 ° C ) , v i g o r o u s l y s t i r r e d s o l u t i o n o f g l a c i a l a c e t i c a c i d (0 .1 mL) i n 1 mL o f d r y e t h e r . Normal workup y i e l d e d a crude y e l l o w product w h i c h , on the b a s i s o f a g l c a n a l y s i s , was i s o m e r i c a l l y p u r e . The crude m a t e r i a l was passed through a s h o r t column o f s i l i c a g e l (3 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 1 0 0 : 1 ) . C o n c e n t r a t i o n of the e l u a t e and d i s t i l l a t i o n ( a i r - b a t h tempera-t u r e 8 5 - 9 5 ° C / 0 . 3 T o r r ) o f the r e s i d u a l o i l gave 11.9 mg (63%) o f the £ , 7 - u n s a t u r a t e d e s t e r (170) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1731, 1584, 1399, 1369, 1180, 760 c m " 1 ; 1 H nmr (400 MHz, CDC1 3 ) 5: 0.20 ( s , 9H, -SnMe 3 , J S n _ H - 56 H z ) , 0.98 (d , 6H, -CHMe 2 , J - 7 H z ) , 1.25 ( t , 3H, - 0 C H 2 C H 3 , J - 7 H z ) , 2 .16-2 .26 (m, I H , - C H M e 2 ) , 3.16 ( s , 2H, - C C H 2 - ) , 4.12 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 5.84 ( d , I H , o l e f i n i c p r o t o n , J = 9 H z> i S n - H " 1 2 8 H z ) - Exact Mass c a l c d . f o r C 1 1 H 2 1 0 2 S n ( M + - C H 3 ) : 305.0563; f o u n d : 305.0559. Compound (170) was prepared v i a a m o d i f i e d v e r s i o n of genera l - 165 P r e p a r a t i o n o f E t h y l ( Z ) - 5 - T r i m e t h y l s i l y l - 3 - t r i m e t h y l s t a n n y l - 3 -pentenoate (171) Me s Si SnMe 3 H •COfeEt F o l l o w i n g g e n e r a l procedure 5, e t h y l ( E ) - 5 - t r i m e t h y l s i l y l - 3 - t r i -m e t h y l s t a n n y l - 2 - p e n t e n o a t e (135) (181.5 mg, 0.5 mmol) was s u b j e c t e d to p r o t o n a t i v e d e c o n j u g a t i o n . A n a l y s i s o f the crude product by g l c showed the complete absence o f the g e o m e t r i c a l l y i s o m e r i c e s t e r . D i s t i l l a t i o n ( a i r - b a t h temperature 8 5 - 9 5 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t p r o v i d e d 129.9 mg (72%) of the pure (},7-unsaturated e s t e r (171) as a c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1730, 1615, 1245, 1170, 845, 760 c m * 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 0.02 ( s , 9H, - S i M e 3 ) , 0.18 ( s , 9H, -SnMe 3 , J S n _ H - 54 H z ) , 1.25 ( t , 3H, -OCH 2 CH. 3 , J - 7 H z ) , 1.54 ( d , 2H, M e 3 S i C H 2 - , J - 8 H z ) , 3.17 ( s , 2H, - C H 2 C 0 2 E t ) , 4 .11 ( q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 6.10 ( t , 1H, o l e f i n i c p r o t o n , J - 8 Hz , J-Sn-H " 1 3 1 H z ) • Exact  Mass c a l c d . f o r C 1 2 H 2 5 0 2 S i S n (M+-CH;}) : 349.0645; f o u n d : 349.0651. 166 Genera l Procedure 6: P r e p a r a t i o n of A l k y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 3 -a lkenoates (173) . P r o t o n a t i v e Deconjugat ion of A l k y l ( Z ) - 3 - T r i m e t h y l -s t a n n y l - 2 - a l k e n o a t e s (137) Hexamethylphosphoramide (130.5 / i L , 0.75 mmol) was added to a s o l u t i o n o f LDA (0.75 mmol) i n 5 mL o f d r y THF a t -78°C. A f t e r the c l e a r s o l u t i o n had been s t i r r e d a t -78°C f o r 15 m i n , a s o l u t i o n of the a p p r o p r i a t e a l k y l ( Z ) - 3 - t r i m e t h y l s t a n n y l - 2 - a l k e n o a t e (137) (0 .5 mmol) i n 0.5 mL o f d r y THF was added dropwise 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 30 min and a t 0°C f o r 30 m i n . The s o l u t i o n was c o o l e d to -78°C and then was t r a n s f e r r e d i n t o a c o l d ( - 9 8 ° C ) , v i g o r o u s l y s t i r r e d s o l u t i o n of g l a c i a l a c e t i c a c i d (0 .3 mL) i n 5 mL o f e t h e r , u s i n g e i t h e r a s y r i n g e or a c a n n u l a . The s o l u t i o n was a l l o w e d to warm to room temperature and s a t u r a t e d aqueous sodium b i c a r b o n a t e and e ther were added. The o r g a n i c l a y e r was separa ted and the aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e x t r a c t was washed (water , b r i n e ) , d r i e d (MgS0 4 ) , and c o n c e n t r a t e d . The r e s i d u a l o i l was d i s t i l l e d to a f f o r d pure decon-j u g a t e d e s t e r (173) . - 167 -P r e p a r a t i o n of E t h y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 3 - p e n t e n o a t e (174) C02Et SnMe 3 F o l l o w i n g genera l procedure 6, e t h y l ( Z ) - 3 - t r i m e t h y l s t a n n y l - 2 -pentenoate (138) (145.5 mg, 0.5 mmol) was s u b j e c t e d t o p r o t o n a t i v e d e c o n j u g a t i o n . A n a l y s i s o f the crude product by g l c showed the e x c l u -s i v e f o r m a t i o n o f one i somer . D i s t i l l a t i o n ( a i r - b a t h temperature 5 0 - 7 0 ° C / 0 . 2 T o r r ) o f t h i s m a t e r i a l a f f o r d e d 125.9 mg (87%) o f the pure deconjugated e s t e r (174) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1725, 1125, 770 c m " 1 ; 1 H nmr (400 MHz, C D C I 3 ) , 6: 0.14 ( s , 9H, -SnMe 3 , J S n - H " 5 4 H z ) , 1.27 ( t , 3H, - 0 C H 2 C H 3 , J - 7 H z ) , 1.75 ( d , 2H, CH 3 C=, J - 7 H z ) , 3.24 ( d , 2H, - C C H 2 , J - 2 H z ) , 4 .13 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 5.84 ( t of q , I H , o l e f i n i c p r o t o n , J - 2, 7 H z , J_sn-H " 7 2 H z ) . Exact Mass c a l c d . f o r C 9 H 1 7 0 2 S n (M+-CH 3 ) : 277.0250; f o u n d : 277.0250. P r e p a r a t i o n o f E t h y l ( E ) - 6 - t e r t - B u t y l d i m e t h y l s i l o x y - 3 - t r i m e t h y l s t a n n y l -3-hexenoate (175) F o l l o w i n g g e n e r a l procedure 6, e t h y l ( Z ) - 6 - t e r t - b u t y l d i m e t h y l -s i l o x y - 3 - t r i m e t h y l s t a n n y l - 2 - h e x e n o a t e (139) (217.5 mg, 0.5 mmol) was - 168 s u b j e c t e d to p r o t o n a t i v e d e c o n j u g a t i o n . A n a l y s i s o f the crude product by g l c i n d i c a t e d the e x c l u s i v e f o r m a t i o n o f one isomer . D i s t i l l a t i o n ( a i r - b a t h temperature 1 5 0 - 1 6 0 ° C / 0 . 3 T o r r ) o f the crude o i l p r o v i d e d 175.8 mg (81%) o f the pure fi,7-unsaturated e s t e r (175) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1720, 1100, 840, 770 c m " 1 ; X H nmr (400 MHz, C D C I 3 ) , 6: 0.05 ( s , 6H, - S i M e 2 ) , 0.12 ( s , 9H, -SnMe 3 , J S n . H - 56 H z ) , 0.89 ( s , 9H, - S i C M e 3 ) , 1.25 ( t , 3H, - O C H 2 C H 3 , J - 7 Hz) , 2.38 (q, 2H, - C H 2 C H 2 0 , J = 7 H z ) , 3.29 ( d , 2H, - C H 2 C 0 2 E t ) , 3.65 ( t , 2H, - S i O C H 2 - , J - 7 H z ) , 4.12 (q, 2H, - O C H 2 C H 3 , J - 7 H z ) , 5.77 ( t o f t , 1H, o l e f i n i c p r o t o n , J - 1 .5 , 7 H z , Js n -H ~ 7 3 H z >- Exact Mass c a l c d . f o r C 1 6 H 3 3 0 3 S i S n ( M " 1 " - ^ ) : 421.1221; f o u n d : 421.1218. P r e p a r a t i o n of M e t h y l ( E ) - 4 - C y c l o p r o p y l - 3 - t r I m e t h y l s t a n n y l - 3 -butenoate (178) P r o t o n a t i v e d e c o n j u g a t i o n of methyl ( Z ) - 4 - c y c l o p r o p y l - 3 - t r i m e t h y l -s t a n n y l - 2 - b u t e n o a t e (142) (151.5 mg, 0 .5 mmol) was c a r r i e d out as o u t l i n e d i n g e n e r a l procedure 6. A n a l y s i s o f the crude product by g l c showed the e x c l u s i v e f o r m a t i o n o f one isomer . D i s t i l l a t i o n ( a i r - b a t h temperature 6 5 - 8 0 ° C / 0 . 3 T o r r ) o f the crude product gave 116.4 mg (77%) of the pure 0,7-unsaturated e s t e r (178) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3060, 1730, 1605, 1170, 770 c m " 1 ; X H nmr (400 MHz, CDC1 3) 5 : 0.11 ( s , - 169 -9H, -SnMe 3 , I s n - H " 5 6 H z ) • 0 .37-0 .45 and 0.75 to 0.83 (m, m, 2H each, c y c l o p r o p y l methylene p r o t o n s ) , 1 .60-1.70 (m, I H , c y c l o p r o p y l methine p r o t o n ) , 3.43 ( d , 2H, - C C H 2 - , J - 2 H z ) , 3.68 ( s , 3H, - O C H 3 ) , 6.04 ( t of d , I H , o l e f i n i c p r o t o n , J - 2, 9 H z , J_s n_H ~ 72 H z ) . Exact Mass c a l c d . f o r C 1 0 H 1 7 O 2 S n ( M + - C H 3 ) : 289.0250; found: 289.0253. P r e p a r a t i o n of E t h y l ( E ) - 5 - M e t h y l - 3 - t r i m e t h y l s t a n n y l - 3 - h e x e n o a t e (176) P r o t o n a t i v e d e c o n j u g a t i o n o f e t h y l ( Z ) - 5 - m e t h y l - 3 - t r i m e t h y l s t a n n y l -2-hexenoate (140) (159.5 mg, 0.5 mmol) was c a r r i e d out as o u t l i n e d i n g e n e r a l procedure 6. A n a l y s i s of the crude product by g l c showed the complete absence o f the g e o m e t r i c a l l y i s o m e r i c e s t e r . The crude product was passed through a s h o r t column of s i l i c a g e l (8 g , e l u t i o n w i t h pe t ro leum e t h e r - e t h e r , 1 0 0 : 1 ) . C o n c e n t r a t i o n o f the e l u a t e and d i s t i l -l a t i o n ( a i r - b a t h temperature 7 0 - 8 0 ° C / 0 . 2 T o r r ) o f the o i l thus o b t a i n e d a f f o r d e d 112.6 mg (71%) o f the y3,7-unsaturated e s t e r (176) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1734, 1369, 1327, 1180, 769 c m " 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 0.10 ( s , 9H, -SnMe 3 , J S n . H " 56 H z ) , 0.95 (d , 6H, -CHMe 2 , J - 7 H z ) , 1.25 ( t , 3H, - 0 C H 2 C H 3 , J » 7 H z ) , 2 .66-2 .74 (m, I H , -CHMe 2 ) , 3.26 ( d , 2H, - C C H 2 - , J «= 1.5 H z ) , 4 .10 (q , 2H, - 0 C H 2 C H 3 , 2 - 7 H z ) , 5.50 ( t o f d , I H , o l e f i n i c p r o t o n , J «= 1 .5 , 9 Hz , J_sn_H ~ 75 H z ) . Exact Mass c a l c d . f o r C 1 1 H 2 1 0 2 S n ( M + ' C ^ ) : 305.0563; f o u n d : 305.0568. - 170 -P r e p a r a t i o n o f E t h y l ( E ) - 5 - T r i m e t h y l s i l y l - 3 - t r i m e t h y l s t a n n y l - 3 -pentenoate (177) F o l l o w i n g g e n e r a l procedure 6, e t h y l ( Z ) - 5 - t r i m e t h y l s i l y l - 3 - t r i -m e t h y l s t a n n y l -2 -pentenoate (141) (181.5 mg, 0.5 mmol) was s u b j e c t e d to p r o t o n a t i v e d e c o n j u g a t i o n . A n a l y s i s of the crude p r o d u c t by g l c showed the complete absence o f the g e o m e t r i c a l l y i s o m e r i c e s t e r . D i s t i l l a t i o n ( a i r - b a t h temperature 8 5 - 9 5 ° C / 0 . 2 T o r r ) o f the crude product a f f o r d e d 140.8 mg (78%) of the pure /S ,7 -unsaturated e s t e r (177) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1733, 1601, 1249, 1178, 855, 766 c m ' 1 ; X H nmr (400 MHz, CDC1 3) 6: 0.02 ( s , 9H, - S i M e 3 ) , 0.12 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 1.22 ( t , 3H, - O C H 2 C H 3 , J - 7 H z ) , 1.67 ( d , 2H, M e 3 S i C H 2 - , J - 8 H z ) , 3.23 ( d , 2H, - C H 2 C 0 2 E t , J - 1.5 H z ) , 4 .12 ( q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 5.77 ( t o f t , 1H, o l e f i n i c p r o t o n , J - 1 .5 , 8 Hz , I s n - H " 7 5 H z ) - Exact  Mass c a l c d . f o r C 1 2 H 2 5 0 2 S i S n (M+-CH 3 ) : 349.0645; f o u n d : 349.0642. Genera l Procedure 7: R e d u c t i o n of E s t e r s t o A l c o h o l s To a c o l d ( - 2 0 ° C ) , s t i r r e d s o l u t i o n - s u s p e n s i o n o f l i t h i u m aluminum h y d r i d e (247 mg, 6.5 mmol) i n 50 mL o f dry e ther was added dropwise a s o l u t i o n of the a p p r o p r i a t e e s t e r (10 mmol) i n 10 mL o f d r y e t h e r . The r e a c t i o n m i x t u r e was s t i r r e d at -20°C f o r 1.5 h . The c o l d bath was - 171 -removed and the r e a c t i o n mix ture was t r e a t e d c a u t i o u s l y w i t h sodium s u l f a t e decahydrate . A f t e r complete p r e c i p i t a t i o n o f the aluminum s a l t s , the r e s u l t i n g s l u r r y was 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 (30 g , e l u t i o n w i t h e t h e r ) . C o n c e n t r a t i o n o f the e l u a t e and G e n e r a l procedure 7 was f o l l o w e d . From 2.91 g (10 mmol) o f e t h y l ( Z ) - 3 - t r i m e t h y l s t a n n y l - 3 - p e n t e n o a t e (168) there was o b t a i n e d , a f t e r d i s t i l l a t i o n ( a i r - b a t h temperature 6 0 - 7 5 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , 2.181 g (88%) of the a l c o h o l (193) as a c o l o r l e s s o i l . This m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3300, 1600, 1040, 770 c m - 1 ; ^-H nmr (80 MHz, CDC1 3) 6: 0.23 ( s , 9 H , -SnMe 3 , J S n . H - 52 H z ) , 1.60 (broad s , 1H, exchanges w i t h D 2 0 , - C H 2 0 H ) , 1.77 (broad d , 3H, C H 3 C - , J - 7 H z ) , 2.48 (broad t , 2H, - C C H 2 - , J - 7 H z ) , 3.56 ( t a f t e r a d d i t i o n o f D 2 0 , 2H, - C H 2 0 H , J - 7 H z ) , 6.20 ( t o f q , 1H, o l e f i n i c p r o t o n , J •= 2 . 5 , 7 Hz, J S n . H - 138 H z ) . Exact Mass c a l c d . f o r C 7 H 1 5 0 S n ( M + - C H 3 ) : 235.0144; f o u n d : 235.0146. 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 c o r r e s p o n d i n g a l c o h o l . P r e p a r a t i o n o f ( Z ) - 3 - T r i m e t h y l s t a n n y l - 3 - p e n t e n - l - o l (193) OH - 172 P r e p a r a t i o n of ( E ) - 3 - T r i m e t h y l s t a n n y l - 3 - p e n t e n - l - o l (194) R e d u c t i o n o f e t h y l ( E ) - 3 - t r i m e t h y l s t a n n y l - 3 - p e n t e n o a t e (174) (2.91 g , 10 mmol) was accomplished v i a g e n e r a l procedure 7. D i s t i l l a t i o n ( a i r - b a t h temperature 7 5 - 9 0 ° C / 0 . 3 T o r r ) o f the crude p r o d u c t a f f o r d e d 2.158 g (87%) o f the a l c o h o l (194) as a c l e a r , c o l o r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 3300, 1600, 1040, 770 c m " 1 ; * H nmr (80 MHz, CDC1 3) 6: 0.13 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 1.45 ( t , 1H, exchanges w i t h D 2 0 , -OH, J - 7 H z ) , 1.75 ( d , 3H, CH 3 C=, J - 7 H z ) , 2.58 ( t , 2H, - C C H 2 - , J - 7 H z ) , 3.62 (q , 2H, - C H 2 0 H , J - 7 H z ) , 5.87 ( t o f q , 1H, o l e f i n i c p r o t o n , J - 2 . 5 , 7 H z , Jsr i -H " 7 7 H z ^ - Exact Mass c a l c d . f o r C 7 H 1 5 O S n (M+-CH;}): 235.0144; found: 235.0156. P r e p a r a t i o n of ( Z ) - 5 - C h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - p e n t e n e (99) Me 3 Sn To a s t i r r e d s o l u t i o n of the a l c o h o l (193) (2.490 g , 10 mmol) i n 50 mL of d r y carbon t e t r a c h l o r i d e was added t r i e t h y l a r a i n e (1 .5 mL, 11 mmol) and t r i p h e n y l p h o s p h i n e (5.25 g , 20 mmol). The r e s u l t a n t s o l u t i o n was r e f l u x e d f o r 24 h . Petroleum e ther (75 mL) was added and the - 173 r e s u l t i n g s l u r r y was f i l t e r e d through a column o f F l o r i s i l (40 g, e l u t i o n w i t h petro leum e t h e r ) . E v a p o r a t i o n of the s o l v e n t from the combined e l u a t 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 e ( a i r - b a t h temperature 4 0 - 5 0 ° C / 0 . 3 T o r r ) , a f f o r d e d 2.207 g (83%) o f the c h l o r i d e (99) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1610, 770, 740 c m - 1 ; X H nmr (80 MHz, CDC1 3) 6: 0.20 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 1.75 (broad d , 3H, CH 3C=, J - 7 H z ) , 2.60 (broad t , 2H, - C C H 2 - , J - 7 H z ) , 3.45 ( t , 2H, - C H 2 C 1 , J = 7 h z ) , 6.20 ( t o f q , I H , o l e f i n i c p r o t o n , J - 2, 7 H z , J S n - H = 1 3 5 H z ) . Exact Mass c a l c d . f o r C 7 H 1 4 3 5 C l S n ( M " 1 " - ^ ) : 252.9806; found: 252.9807. P r e p a r a t i o n o f ( E ) - 5 - C h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - p e n t e n e (100) To a s t i r r e d s o l u t i o n of the a l c o h o l (194) (1.245 g , 5 mmol) i n 30 mL of dry carbon t e t r a c h l o r i d e was added t r i e t h y l a m i n e (765 /iL, 5.5 mmol) and t r i p h e n y l p h o s p h i n e (2.62 g , 10 mmol). The r e s u l t a n t s o l u t i o n was r e f l u x e d f o r 24 h . Petroleum e ther (50 mL) was added and the r e s u l t i n g s l u r r y was f i l t e r e d through a column of F l o r i s i l (25 g, e l u t i o n w i t h petro leum e t h e r ) . E v a p o r a t i o n of the s o l v e n t from the combined e l u a t 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 e ( a i r - b a t h temperature 4 0 - 5 5 ° C / 0 . 3 T o r r ) , a f f o r d e d 1.013 g (76%) o f the c h l o r i d e (100) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1600, 770, 740 c m " 1 ; lE nmr (80 - 174 -MHz, C D C I 3 ) 5 : 0.18 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 1.75 ( d , 3H, CH 3C=, J = 7 H z ) , 2.75 (broad t , 2H, - C C H 2 , J - 7 H z ) , 3.45 ( t , 2H, - C H 2 C l , J - 7 H z ) , 5.83 ( t o f q , I H , o l e f i n i c p r o t o n , J - 2, 7 H z , J_sn-H " 7 6 H z ) -Exact Mass c a l c d . f o r C 7 H 1 4 3 5 C l S n (M+'CH^ : 252.9806; found: 252.9814. T r a n s m e t a l a t i o n of ( E ) - 5 - C h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - p e n t e n e (100) . P r e p a r a t i o n of the C h l o r o S u l f i d e (210) To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f ( E ) - 5 - c h l o r o - 3 - t r i m e t h y l -s t a n n y l -2 -pentene (100) (200 mg, 0.75 mmol) i n 2 mL o f d r y THF was added a s o l u t i o n o f m e t h y l l i t h i u m i n e ther (0.57 mL, 0.82 mmol). A f t e r the l i g h t y e l l o w s o l u t i o n had b een s t i r r e d a t -78°C f o r 20 m i n , a s o l u t i o n of 2 , 4 - d i n i t r o b e n z e n e s u l f e n y l c h l o r i d e (209) (160 mg, 0.91 mmol) i n 4 mL o f d r y methylene c h l o r i d e was added and the r e a c t i o n m i x t u r e was a l l o w e d to warm s l o w l y to room temperature . A f t e r 16 h , the s o l v e n t was evapor-a t e d and the crude p r o d u c t was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h petro leum e t h e r - e t h y l a c e t a t e , 85 :15 ) . The y e l l o w s o l i d thus o b t a i n e d was r e c r y s t a l l i z e d from hexane-acetone. There was o b t a i n e d 111.3 mg (54%) of the c h l o r o s u l f i d e (210) as a y e l l o w s o l i d , which had mp 128-130°C and e x h i b i t e d i r ( K B r ) : 3050, 1570, 1500, 1330, 1040, 910, 830, 730 c m - 1 ; 1 H nmr [80 MHz, ( C D 3 ) 2 C 0 ] 5: H x N 0 2 - 175 -1 .20-1.40 and 1.52-1.65 (m, m, 3H and I H , c y c l o p r o p y l p r o t o n s ) , 1.66 (d , 3H, C H 3 C H - , J - 7 H z ) , 4.38 (q , I H , C H 3 C H - , J - 7 H z ) , 8.40 ( d , I H , H A , J.AB ~ 1 0 H z )> 8 - 5 4 <d o f d - H B - J-BX " 2 H z> i A B " 1 0 H z > . 8 - 9 8 ( d - 1 H -H x , J B X - 2 H z ) . Exact Mass c a l c d . f o r C 1 1 H 1 1 N 2 0 4 3 5 C 1 S : 302.0129; f o u n d : 302.0123. Transmetalation of (Z)-5-Chloro-3-trimethylstannyl-2-pentene (99). Preparation of (Z)-5-Chloro-3-(l-hydroxycyclohexyl)-2-pentene (205) and (Z)-4-Ethylidene-l-oxaspiro[4.5]undecane (206) 205 206 To a c o l d ( - 7 8 6 C ) , s t i r r e d s o l u t i o n o f (Z) - 5 - c h l o r o - 3 - t r i m e t h y l -s t a n n y l - 2 - p e n t e n e (99) (133.6 mg, 0 .5 mmol) i n 2 mL o f dry THF was added a s o l u t i o n o f m e t h y l l i t h i u m i n e ther (0.43 mL, 0.55 mmol). The r e s u l t -i n g l i g h t 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 20 m i n . Cyc lohexa-none (57 / i L , 0.55 mmol) was added and 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 45 m i n . S a t u r a t e d aqueous ammonium c h l o r i d e (0 .5 mL) and e ther (10 mL) were added and the mix ture was a l l o w e d to warm to room temperature . The aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed (water , b r i n e ) , d r i e d (MgS0 4 ) , and concen-t r a t e d . The r e s u l t i n g o i l was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (10 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 9 3 : 7 ) . The l e s s p o l a r product was i s o l a t e d by removal o f the s o l v e n t from 176 the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h tempera-t u r e 4 0 - 5 5 ° C / 0 . 2 Torr ) o f the r e s i d u a l m a t e r i a l . The c o l o r l e s s o i l o b t a i n e d (33.2 mg, 40%) was i d e n t i f i e d as the s p i r o e ther (206) , which e x h i b i t e d i r ( f i l m ) : 1060, 910 c m " 1 ; * H nmr (80 MHz, C D C I 3 ) 6: 1 .18-1.80 (m, 13H), 2 .35-2 .68 (m, 2H, - C C H 2 - ) , 3.75 ( t , 2H, - C H 2 0 - , J - 7 H z ) , 5.36 ( t o f q , 1H, o l e f i n i c p r o t o n , J - 2, 7 H z ) . Exact Mass c a l c d . f o r C 1 1 H 1 8 0 : 1 6 6 . 1 3 5 8 ; found: 166.1359. The more p o l a r product was i s o l a t e d by c o n c e n t r a t i o n o f the appro-p r i a t e column f r a c t i o n s , 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 7 0 - 8 5 ° C / 0 . 2 T o r r ) o f the r e s i d u a l o i l . The c o l o r l e s s o i l o b t a i n e d (31.4 mg, 31%) was i d e n t i f i e d as the a l c o h o l (205) , which e x h i b i t e d i r ( f i l m ) : 3425, 1120, 960 c m " 1 ; X H nmr (80 MHz, C D C I 3 ) 6: 1 .05-2 .20 (m, 14H), 2.48 (broad t , 2H, - C C H 2 - , J - 7 H z ) , 3.60 ( t , 2H, - C H 2 C 1 , J - 7 H z ) , 5.36 (t o f q , 1H, o l e f i n i c p r o t o n , J - 1, 7 H z ) . Exact Mass c a l c d . f o r C 1 1 H 1 9 0 3 5 C 1 : 202.1126; f o u n d : 202.1126. Genera l Procedure 8: T r a n s m e t a l a t i o n of ( Z ) - 5 - C h l o r o - 3 - t r i m e t h y l -s t a n n y l - 2 - p e n t e n e (99) and Conjugate A d d i t i o n of the G r i g n a r d Reagent (218) t o C y c l i c Enones (220) 218 220 221 To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of ( Z ) - 5 - c h l o r o - 3 - t r i m e t h y l -- 177 -s t a n n y l - 2 - p e n t e n e (99) (133.6 mg, 0.5 mmol) i n 2 mL o f d r y THF was added a s o l u t i o n o f m e t h y l l i t h i u m i n e ther (0.45 mL, 0.55 mmol). The c o l o r -l e s s s o l u t i o n was s t i r r e d a t -78°C f o r 20 m i n . Anhydrous magnesium bromide (110.5 mg, 0.6 mmol) was added and the r e s u l t a n t m i l k y s o l u t i o n was s t i r r e d f o r 10 m i n . The s o l u t i o n was then d i l u t e d by dropwise a d d i t i o n o f 4 mL of dry e ther 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 a f u r t h e r 10 m i n . A f t e r s u c c e s s i v e a d d i t i o n o f copper bromide-dimethy1-s u l f i d e complex (30.8 mg, 0.15 mmol), the a p p r o p r i a t e c y c l i c enone (220) (0 .5 mmol), and boron t r i f l u o r i d e - e t h e r a t e (74 / i L , 0.6 mmol), the 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 2 h . S a t u r a t e d aqueous ammonium c h l o r i d e (pH 8) (3 mL) and e ther (10 mL) were added s u c c e s s i v e l y and the m i x t u r e was a l l o w e d to warm to room temperature w i t h v i g o r o u s s t i r r i n g . S t i r r i n g was m a i n t a i n e d u n t i l the aqueous phase became deep b l u e . The l a y e r s were separa ted and the aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined e ther e x t r a c t was washed (water , b r i n e ) , d r i e d (MgS0 4 ) , and c o n c e n t r a t e d . The r e s u l t i n g o i l was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l , i f necessary . D i s t i l l a t i o n o f the o i l thus ob ta ined p r o v i d e d the conjugate a d d i t i o n product (221) . P r e p a r a t i o n of ( Z ) - 3 - [ 3 - ( 5 - C h l o r o - 2 - p e n t e n y l ) ] c y c l o h e x a n o n e (219) 0 - 178 -F o l l o w i n g g e n e r a l procedure 8, 2 -cyc lohexen-1-one (216) (48 mg, 0 .5 mmol) was c o n v e r t e d i n t o the c h l o r o ketone (219) . Normal workup, f o l l o w e d by f l a s h chromatography o f the crude product on s i l i c a g e l (10 g , e l u t i o n w i t h pet ro leum e t h e r - e t h e r , 3:1) and d i s t i l l a t i o n ( a i r - b a t h temperature 7 5 - 9 0 ° C / 0 . 2 T o r r ) o f the o i l thus o b t a i n e d , y i e l d e d 70.5 mg (70%) o f (219) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1710, 1230, 885, 740 c m - 1 ; 1 H nmr (400 MHz, C D C I 3 ) S: 1.63 (broad d , 3H, - C C H 3 , J - 7 H z ) , 1 .67-1 .79 (m, 3H), 2 .10-2 .53 (m, 7H), 2 .88-2 .98 (m, 1H, H A ) , 3 .50-3 .63 (m, 2H, <=CCH2CH2C1), 5.32 (q , 1H, o l e f i n i c p r o t o n , J - 7 H z ) . Exact  Mass c a l c d . f o r C 1 1 H 1 7 0 3 5 C 1 : 200.0969; found: 200.0966. P r e p a r a t i o n of ( Z ) - 3 - [ 3 - ( 5 - C h l o r o - 2 - p e n t e n y l ) ] - 3 - m e t h y l c y c l o -hexanone (229) 0 F o l l o w i n g g e n e r a l procedure 8, 3 - m e t h y l - 2 - c y c l o h e x e n - l - o n e (223) (55 mg, 0 .5 mmol) was conver ted i n t o the c h l o r o ketone (229) . Normal workup, f o l l o w e d by f l a s h chromatography o f the crude p r o d u c t on s i l i c a g e l (10 g , e l u t i o n w i t h pet ro leum e t h e r - e t h e r , 3:1) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 1 0 5 ° C / 0 . 2 T o r r ) o f the crude o i l thus o b t a i n e d , a f f o r d e d 65.1 mg (61%) o f (229) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1705, - 179 -1230, 740 c m " 1 ; 1 H nmr (400 MHz, CDC1 3) 6: 1.19 ( s , 3H, C H 3 C - ) , 1.72-1 .78 (m, I H ) , 1.79 (d , 3H, C H 3 O , J - 7 H z ) , 1 .83-1 .92 (m, 2H) , 2 .07-2 .16 (m, IH) , 2 .26-2 .35 (m, 3H), 2 .39-2 .53 (m, 2 H , - C C H 2 - ) , 2.68 ( d , I H , J - 1 4 H z ) , 3 .47-3 .57 (m, 2H, - C H 2 C 1 ) , 5.38 (q , I H , o l e f i n i c p r o t o n , J - 7 H z ) . I r r a d i a t i o n at 6 3.52 ( -CH 2 C1) s i m p l i f i e d the m u l t i p l e t a t S 2 .39-2 .53 (=CCH 2-) to a p a i r o f d o u b l e t s (J = 14 Hz each) . Exact Mass c a l c d . f o r C 1 2 H 1 9 0 3 5 C 1 : 214.1126; f o u n d : 214.1125. P r e p a r a t i o n o f the C h l o r o Ketone M i x t u r e (230) F o l l o w i n g g e n e r a l procedure 8, 2 - m e t h y l - 2 - c y c l o h e x e n - l - o n e ( 2 2 4 ) 1 1 ° (48 mg, 0.5 mmol) was conver ted i n t o the c h l o r o ketone (230) . Normal workup, f o l l o w e d by f l a s h chromatography o f the crude p r o d u c t on s i l i c a g e l (10 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 3:1) and d i s t i l l a t i o n ( a i r - b a t h temperature 1 0 5 - 1 2 0 ° C / 0 . 3 T o r r ) o f the crude m a t e r i a l thus o b t a i n e d , p r o v i d e d 68.2 mg (64%) o f (230) as a c o l o r l e s s o i l . T h i s m a t e r i a l showed one spot on t i c a n a l y s i s (petroleum e t h e r - e t h e r , 3 : 1 ) . The 1 H nmr spectrum i n d i c a t e d t h a t i t c o n s i s t e d o f a 2 :1 m i x t u r e of two epimers . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1700, 1230, 730 c m " 1 ; 1 H nmr (400 MHz, C D C I 3 ) 6: 0.90 and 1.06 ( d , d , r a t i o 2 : 1 , 3H, C H 3 C H - , J = - 180 7 Hz each) , 1 .55-2.66 (m, 1 2 H ) , 3 . 0 2 - 3 . 1 2 (m, 1 H , H A ) , 3 .49-3 .70 (m, 2H, - C H 2 C I ) , 5 .32-5 .48 (m, 1 H , o l e f i n i c p r o t o n ) . Exact Mass c a l c d . f o r C 1 2 H 1 9 0 3 5 C 1 : 214.1126; found: 214.1127. P r e p a r a t i o n of ( Z ) - 3 - [ 3 - ( 5 - C h l o r o - 2 - p e n t e n y l ) ] c y c l o p e n t a n o n e (231) F o l l o w i n g g e n e r a l procedure 8, 2 - c y c l o p e n t e n - l - o n e (225) (41 mg, 0 .5 mmol) was c o n v e r t e d i n t o the c h l o r o ketone (231) . Normal workup, f o l l o w e d by f l a s h chromatography on s i l i c a g e l (10 g , e l u t i o n w i t h pe t ro leum e t h e r - e t h e r , 3 :1) and d i s t i l l a t i o n ( a i r - b a t h temperature 8 5 - 1 0 0 ° C / 0 . 3 T o r r ) o f the o i l thus o b t a i n e d a f f o r d e d 63.9 mg (69%) of (231) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1730, 1160, 740 c m * 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 1.69 (broad d , 3H, C H 3 C - , J - 7 H z ) , 1 .72-1 .85 (m, 1H), 2 .01-2 .50 (m, 7H), 3 .25-3 .35 (m, 1H, H A ) , 3 .50-3 .59 (m, 2H, - C H 2 C 1 ) , 5.42 (q , 1H, o l e f i n i c p r o t o n , J - 7 H z ) . Exact Mass c a l c d . f o r C 1 0 H 1 5 0 3 5 C 1 : 186.0813; found: 186.0816. - 181 P r e p a r a t i o n o f ( Z ) - 3 - [ 3 - ( 5 - C h l o r o - 2 - p e n t e n y l ) ] - 3 - m e t h y l c y c l o -pentanone (232) 0 F o l l o w i n g g e n e r a l procedure 8, 3 - m e t h y l - 2 - c y c l o p e n t e n - l - o n e (226) (46.6 mg, 0 .5 mmol) was conver ted i n t o the c h l o r o ketone (232) . Normal workup, f o l l o w e d by f l a s h chromatography o f the crude product on s i l i c a g e l (10 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 3:1) and d i s t i l l a t i o n ( a i r - b a t h temperature 8 5 - 9 5 ° C / 0 . 2 T o r r ) o f the o i l thus o b t a i n e d , p r o v i d e d 56.9 mg (57%) o f (232) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1730, 1165, 745 c m " 1 ; X H nmr (400 MHz, C D C 1 3 ) 6: 1.22 ( s , 3H, CH .3C-) , 1.73 (d , 3H, C H 3 O , J - 7 H z ) , 2 .11-2 .18 (m, 2H), 2 .25-2 .33 (m, 2H), 2.45 ( s , 2H, 0 - C - C H 2 - C - ) , 2 .48-2 .55 (m, 2H), 3.57 ( t , 2H, - C H 2 C 1 , J - 7 H z ) , 5.34 (q , 1H, o l e f i n i c p r o t o n , J - 7 H z ) . Exact Mass c a l c d . f o r C i ] H 1 7 0 3 5 C l : 200.0969; f o u n d : 200.0966. P r e p a r a t i o n of the C h l o r o Ketone M i x t u r e (233) - 182 F o l l o w i n g genera l procedure 8, 2 - m e t h y l - 2 - c y c l o p e n t e n - 1 - o n e ( 2 2 7 ) 1 1 7 (46.6 mg, 0.5 mmol) was conver ted i n t o the c h l o r o ketone mix ture (233) . Normal workup, f o l l o w e d by f l a s h chromatography of the crude p r o d u c t on s i l i c a g e l (10 g , e l u t i o n w i t h pe t ro leum e t h e r - e t h e r , 3:1) and d i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 1 0 0 ° C / 0 . 2 T o r r ) of the crude o i l thus o b t a i n e d , a f f o r d e d 56.4 mg (56%) of (233) as a c o l o r l e s s o i l . T h i s m a t e r i a l showed one spot on t i c a n a l y s i s (petroleum e t h e r -e t h e r , 3 : 1 ) . The nmr spectrum i n d i c a t e d t h a t i t c o n s i s t e d o f a 1:1 m i x t u r e of two epimers . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1725, 1155, 735 c m * 1 ; X H nmr (400 MHz, CDC1 3) 6": 0.92 and 1.00 ( d , d , r a t i o 1 : 1 , 3 H , C H 3 C H - , J - 7 Hz each) , 1.65 and 1.68 ( d , d , r a t i o 1 : 1 , 3H, CH 3 C=, J -7 Hz e a c h ) , 1 .70-2.49 (m, 7H), 2.85 and 3.45 (d of t and q , r a t i o 1 :1 , 1H, H A , J - 6, 11 Hz and 8 H z ) , 3 .50-3 .63 (m, 2H, - C H 2 C 1 ) , 5.45 and 5.52 (q , q , r a t i o 1 : 1 , 1H, o l e f i n i c p r o t o n , J - 7 Hz each) . Exact Mass c a l c d . f o r C n H 1 7 0 3 5 C l : 200.0969; found: 200.0963. P r e p a r a t i o n of c i s , ( Z ) - 1 - [ 3 - ( 5 - C h l o r o - 2 - p e n t e n y l ) ] b i c y c l o [ 3 . 3 . 0 ] -octan-3-one (234) F o l l o w i n g g e n e r a l procedure 8, b i c y c l o [ 3 . 3 . 0 ] o c t - 1 - e n - 3 - o n e ( 2 2 8 ) 1 1 8 (61 mg, 0.5 mmol) was conver ted i n t o the c h l o r o ketone (234). 183 -Normal workup, f o l l o w e d by f l a s h chromatography o f the crude product on s i l i c a g e l (10 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 3:1) and d i s t i l l a -t i o n ( a i r - b a t h temperature 1 1 5 - 1 3 0 ° C / 0 . 3 T o r r ) o f the o i l thus o b t a i n e d , p r o v i d e d 81.3 mg (72%) o f (234) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1725, 1170, 745 c m ' 1 ; X H nmr (400 MHz, CDC1 3) 6: 1 .43-1.58 (m, 3H), 1.69 (d, 3H, CH 3 C=, J - 7 H z ) , 1 .65-1.78 (m, I H ) , 1 .92-2 .04 (m, 3H), 2.10 (d of d , I H , J - 5 , 18 H z ) , 2 .46-2 .59 (m, 4H) , 2 .84-2 .91 (m, I H ) , 3 .46-3.57 (m, 2H, - C H 2 C 1 ) , 5.36 (q , I H , o l e f i n i c p r o t o n , J - 7 H z ) . Exact Mass c a l c d . f o r C 1 3 H 1 9 0 3 5 C 1 : 226.1126; found: 226.1121. Genera l Procedure 9: C y c l i z a t i o n o f the C h l o r o Ketones (221) . P r e p a r a t i o n o f the ( Z ) - E t h y l i d e n e c y c l o p e n t a n e A n n u l a t i o n Products 222 To a s t i r r e d suspens ion of potass ium h y d r i d e (30 mg, 0.75 mmol) i n 2 mL o f dry THF was added, dropwise , a s o l u t i o n of the a p p r o p r i a t e c h l o r o ketone (221) (0.30 mmol) i n 1 mL of d r y THF. The r e s u l t a n t y e l l o w m i x t u r e was s t i r r e d a t room temperature f o r 2.5 h . Sa tura ted aqueous ammonium c h l o r i d e (3 mL) and e ther (8 mL) were added and the mixture was s t i r r e d f o r 10 m i n . The l a y e r s were separated and the aqueous l a y e r was e x t r a c t e d thoroughly w i t h e t h e r . The combined ether e x t r a c t was washed (water , b r i n e ) and d r i e d (MgS0 4 ) . S o l v e n t removal - 184 -under reduced p r e s s 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 c o r r e s p o n d i n g annula ted product (222) . P r e p a r a t i o n o f c i s , ( Z ) - 7 - e t h y l i d e n e b i c y c l o [ 4 . 3 . 0 ] n o n a n - 2 - o n e (217) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone (219) (60.2 mg, 0.3 mmol) was conver ted i n t o the b i c y c l i c ketone (217) . Normal workup, 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 4 5 - 6 0 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 38.3 mg (78%) o f (217) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1700, 1230, 890 c m " 1 ; -^H nmr (400 MHz, CDC1 3 ) 8: 1.40 (d of q , I H , 1 - 4 , 13 H z ) , 1.64 ( t o f d , 3H, C H 3 C - , J - 1 .5 , 7 H z ) , 1.72 (d of d of q , I H , J - 4 , 5 , 13 H z ) , 1 .83-2 .05 (m, 4H) , 2 .25-2 .55 (m, 4H), 2 .62-2 .70 (m, I H , H g ) , 3 .00-3 .06 (m, I H , H A ) , 5.29 ( t o f q , I H , o l e f i n i c p r o t o n , J - 2, 7 H z ) . I r r a d i a t i o n a t 6 2.66 (Hg) : s i g n a l a t 8 3.03 (H A ) s i m p l i f i e d to a d o f d (J - 6, 13 H z ) , m u l t i p l e t at 8 1.83-2.05 s i m p l i f i e d . I r r a d i a t i o n at 8 3.03 ( H A ) : s i g n a l a t 8 2.66 (Hg) s i m p l i f i e d to a d o f d (J «= 8, 9 H z ) , s i g n a l at 8 1.40 s i m p l i f i e d to a d o f t (J = 4, 13 H z ) , m u l t i p l e t at 8 1 .83-2.05 s i m p l i f i e d . In a d i f f e r e n c e n u c l e a r Overhauser enhancement (nOe) exper iment , i r r a d i a t i o n a t 8 3.03 (HA) caused s i g n a l enhancement at 8 2.66 (Hg) and a t 8 1.64 ( C H ^ C - ) . Exact  Mass c a l c d . f o r C n H 1 6 0 : 164.1202; found: 164.1196. 185 P r e p a r a t i o n o f c i s , ( Z ) - 6 - M e t h y l - 7 - e t h y l i d e n e b i c y c l o [ 4 . 3 . 0 ] n o n a n - 2 - o n e (235) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone (229) (64.2 mg, 0 .3 mmol) was conver ted i n t o the b i c y c l i c ketone (235). Normal workup, 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 45-60°C/0.2 T o r r ) o f the crude p r o d u c t , p r o v i d e d 41 .9 mg (79%) o f (235) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1700, 1240 c m ' 1 ; ^ nmr (400 MHz, CDC1 3) 6: 1.32 ( s , 3H, C H 3 C - ) , 1.67 ( t o f d , 3H, CH 3CH=, J - 2, 7 H z ) , 1 .70-1.79 (m, 2H), 1 .83-2 .05 (m, 4H) , 2.25-2.32 (m, I H ) , 2.36-2.45 (m, 4H) , 5.28 ( t o f q, I H , o l e f i n i c p r o t o n , J - 2 , 7 H z ) . Exact Mass c a l c d . f o r C 1 2 H i s 0 : 178.1358; found: 178.1358. - 186 P r e p a r a t i o n of c i s . ( Z ) - 6 - M e t h y l - 7 - e t h y l i d e n e b i c y c l o [ 4 . 3 . 0 ] n o n a n - 2 - o n e (235) from the B i c y c l i c A c e t a t e (248) 2 4 8 2 4 9 2 5 0 2 3 5 To a s t i r r e d s o l u t i o n of potass ium carbonate (264 mg, 1.6 mmol) i n 4 mL of aqueous methanol was added a s o l u t i o n of the e n a n t i o m e r i c a l l y pure b i c y c l i c ace ta te ( 2 4 8 ) 8 0 (88.8 mg, 0.4 mmol) i n 2 mL o f methanol . The r e s u l t i n g c l e a r s o l u t i o n was s t i r r e d a t room temperature f o r 24 h . The s o l u t i o n was d i l u t e d w i t h water and e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e x t r a c t was washed (water , b r i n e ) and d r i e d (MgSO,^) . S o l v e n t removal and d i s t i l l a t i o n ( a i r - b a t h temperature 8 0 - 9 0 e C / 0 . 4 T o r r ) of the r e s i d u a l o i l , a f f o r d e d 63.3 mg (88%) o f the a l c o h o l (249) as a c o l o r l e s s o i l ; * H nmr (400 MHz, C D C 1 3 ) S: 0 .90 ( s , 3 H , C H 3 C - ) , 1 .09-1.78 (m, 1 0 H ) , 1.82-1 .90 (m, 1 H ) , 1 .99-2.08 (m, 1 H ) , 2 .13-2 .30 (m, 2 H ) , 2 . 3 8-2 . 4 8 (m, 1 H ) , 3.64 (d of t , 1 H , -CHOH, J - 5 , 11 H z ) , 5.14 ( t o f q , 1 H , o l e f i n i c p r o t o n , J - 2, 7 H z ) . To a s t i r r e d s o l u t i o n - s u s p e n s i o n o f p y r i d i n i u m chlorochromate (PCC) (97 mg, 0.45 mmol) and sodium ace ta te (7 .4 mg, 0.09 mmol) i n 2 mL of dry methylene c h l o r i d e was added a s o l u t i o n o f the b i c y c l i c a l c o h o l (249) (54 187 mg, 0 .3 mmol) i n 0.5 mL o f dry C H 2 C I 2 . The b l a c k r e a c t i o n mixture was s t i r r e d a t room temperature f o r 2 h . Dry e ther (10 mL) was added and the supernatant was decanted from the b l a c k gum. The l a t t e r r e s i d u e was s t i r r e d w i t h a f u r t h e r 5 mL of dry e ther and the o r g a n i c s o l u t i o n was a g a i n decanted. The combined o r g a n i c s o l u t i o n was passed through a s h o r t column o f F l o r i s i l (3 g , e l u t i o n w i t h e t h e r ) . The combined e l u a t e was c o n c e n t r a t e d to a f f o r d a c l e a r p a l e y e l l o w o i l . T h i s o i l was d i s t i l l e d ( a i r - b a t h temperature 5 0 - 6 5 8 C / 0 . 2 T o r r ) to a f f o r d 42.0 mg (79%) of (250) as a c o l o r l e s s o i l ; X H nmr (400 MHz, C D C I 3 ) 6: 0.88 ( s , 3H, C H 3 C - ) , 1 .61-1 .85 (m, 5H), 1 .89-2 .15 (m, 3H), 2 .22-2 .34 (m, 3H), 2 .37-2 .48 (m, 2H), 2.60 (d o f d , I H , H B , J - 6, 12 H z ) , 5.21 ( t o f q , I H , o l e f i n i c p r o t o n , J - 2, 7 H z ) . A m i x t u r e o f 1% aqueous potass ium h y d r o x i d e (1 mL) and e t h a n o l (15 mL) was s t i r r e d f o r 5 m i n . To 5 mL o f t h i s s o l u t i o n was added a s o l u -t i o n o f the b i c y c l i c ketone (250) (25 mg, 0.14 mmol) i n 0 .5 mL of e t h a n o l . The r e s u l t i n g c l e a r s o l u t i o n was s t i r r e d a t room temperature f o r 3 .5 h . The s o l u t i o n was d i l u t e d w i t h water and e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e x t r a c t was washed (water , b r i n e ) and d r i e d (MgS04). S o l v e n t removal and d i s t i l l a t i o n ( a i r - b a t h temperature 5 0 - 6 0 ° C / 0 . 2 T o r r ) o f the r e s i d u a l o i l gave 19.7 mg (79%) o f a c o l o r l e s s o i l . T h i s compound was s p e c t r a l l y i d e n t i c a l w i t h the a n n u l a t i o n product (235) ; i r ( f i l m ) : 1700, 1240 c m - 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 1.32 (s , 3H, C H 3 C - ) , 1.67 ( t o f d , 3H, C H 3 O , J - 2, 7 H z ) , 1 .70-1 .79 (m, 2 H ) , 1.83-2 .05 (m, 4H) , 2 .25-2 .32 (m, I H ) , 2 .36-2 .45 (m, 4H) , 5.28 ( t o f q, I H , o l e f i n i c p r o t o n , J -= 2, 7 H z ) . 188 -P r e p a r a t i o n o f the B i c y c l i c A l c o h o l s (251) and (252) H O 251 252 To a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n of the b i c y c l i c ketone (235) (178 mg, 1 mmol) i n 15 mL of dry methanol was added a s o l u t i o n of sodium b o r o h y d r i d e (45 .5 mg, 1 . 2 mmol) i n 2 mL of d r y methanol . A f t e r the r e s u l t i n g s o l u t i o n had been s t i r r e d at 0°C f o r 15 m i n , g l a c i a l a c e t i c a c i d ( 1 mL) and e t h e r (25 mL) were added. The l a y e r s were separa ted and the aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed (aqueous NaHCO^, w a t e r , b r i n e ) , d r i e d (MgSO^) and c o n c e n t r a t e d under reduced p r e s s u r e . The crude o i l thus o b t a i n e d was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h pet ro leum e t h e r - e t h y l a c e t a t e , 85 :15 ) . The l e s s p o l a r product was i s o l a t e d by removal o f the s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h tempera-t u r e 5 5 - 7 0 ° C / 0 . 2 T o r r ) of the r e s i d u a l m a t e r i a l . There was thus o b t a i n e d 5 4 . 7 mg (30%) o f the a l c o h o l (251) as a c o l o r l e s s o i l which e x h i b i t e d i r ( f i l m ) : 3300, 1 0 2 0 c m " 1 ; 1 H nmr (400 MHz, C D C 1 3 ) 6: 1.20 ( s , 3 H , C H 3 C - ) , 1 . 2 6 - 1 . 5 3 (m, 6H) , 1 . 6 5 ( t o f d , C H 3 O , J - 2 , 7 H z ) , 1 . 6 0 - 1 . 9 0 (m, 3 H ) , 2 . 0 9 - 2 . 1 4 (m, 1 H ) , 2 . 3 8 - 2 . 4 4 (m, 2 H ) , 3 . 4 0 - 2 . 4 8 (m, 1 H , - C H 0 H - ) , 5 . 2 5 ( t of q , 1 H , o l e f i n i c p r o t o n , J - 2 , 7 H z ) . Exact  Mass c a l c d . f o r C 1 2 H 2 0 O : 180.1515; found: 180.1513. The more p o l a r product was i s o l a t e d by c o n c e n t r a t i o n of the appro-- 189 -p r i a t e column f r a c t i o n s , 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 7 5 - 9 0 ° C / 0 . 2 T o r r ) o f the r e s i d u a l o i l . There was o b t a i n e d 92.1 mg (51%) o f compound (252) as a whi te s o l i d . R e 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 heptane p r o v i d e d a c r y s t a l l i n e compound which e x h i b i t e d mp 83.5-84°C; i r ( K B r ) : 3300, 1020 c m " 1 ; 1 H nmr (400 MHz, C D C 1 3 ) 6: 1.32 ( s , 3H, CH3C-), 1 .26-1 .44 (m, 3H), 1 .52-1.75 (m, 9H), 2 .00-2 .06 (m, I H ) , 2 .28-2 .44 (m, 2H), 3 .92-3 .98 (m, I H , -CH0H-) , 5.21 ( t o f q , I H , o l e f i n i c p r o t o n , J - 2, 7 H z ) . I r r a d i a t i o n a t 6 3.95 s i m p l i f i e d the s i g n a l a t 6 2.03 to a d o f d ( J - 6, 12 H z ) ; the m u l t i p l e t s a t 8 1 .26-1 .44 and 6 1.52-1 .75 were a l s o changed. The c o n s t i t u t i o n and r e l a t i v e stereochem-i s t r y o f (252) was conf i rmed by an X - r a y c r y s t a l l o g r a p h i c s t u d y . Exact  Mass c a l c d . f o r C 1 2 H 2 0 O : 180.1515; found: 180.1512. A n a l , c a l c d . f o r c 1 2 H 2 0 O : c - 80 .00 ; H , 11 .11 ; found: C, 79.70; H , 11 .26 . P r e p a r a t i o n of c i s . ( Z ) - l - M e t h y l - 7 - e t h y l i d e n e b i c y c l o [ 4 . 3 . 0 ] n o n a n - 2 - o n e (236) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone mixture (230) (64.2 mg, 0 .3 mmol) was conver ted i n t o the b i c y c l i c ketone (236). Normal workup, 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 4 5 - 6 0 ° C / 0.2 T o r r ) o f the crude p r o d u c t , p r o v i d e d 44.0 mg (83%) o f 236 as a - 190 -c o l o r l e s s o i l ; i r ( f i l m ) : 1710, 1440 c m - 1 ; * H nmr (400 MHz, C D C 1 3 ) 6: 1.06 ( s , 3H, C H 3 C - ) , 1 .40-1.50 (m, 2H), 1.64 ( t o f d , C H 3 C - , J - 2, 7 H z ) , 1.71 ( t o f q , 1H, J - 5 , 12 H z ) , 1 .80-1.88 (m, 1H) , 1 . 9 2 - 2 . 0 0 (m, 1H), 2 .09-2 .17 (m, 1H), 2 .31-2 .42 (m, 2H), 2 .43-2 .54 (m, 2 H ) , 2.63 (d of d , 1H, J - 5, 12 H z ) , 5.29 ( t o f q , 1H, o l e f i n i c p r o t o n , 1 - 2 , 7 H z ) . Exact Mass c a l c d f o r C 1 2 H 1 8 0 : 178.1358; found: 178.1359. Preparation of cis,(Z)-6-Ethylidenebicyclo[3.3.0]octan-2-one (237) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone (231) (56 mg, 0 .3 mmol) was c o n v e r t e d i n t o the b i c y c l i c ketone (237). Normal workup, 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 4 0 - 5 0 8 C / 0 . 2 T o r r ) of the crude p r o d u c t , p r o v i d e d 35.0 mg (78%) o f (237) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1730, 1130 c m " 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 1.68 ( t o f d , 3H, CH 3 C=, J - 1 .5 , 7 H z ) , 1 .75-1.95 (m, 3H), 2 .15-2 .37 (m, 5H), 2 .64-2 .71 (m, 1H), 3 .32-3 .40 (m, 1H), 5.36 ( t o f q , 1H, o l e f i n i c p r o t o n , J - 1 .5 , 7 H z ) . Exact Mass c a l c d f o r C 1 0 H 1 4 0 : 150.1045; f o u n d : 150.1044. 191 P r e p a r a t i o n o f c i s . ( Z ) - 5 - M e t h y l - 6 - e t h y l i d e n e b i c y c l o [ 3 . 3 . 0 ] o c t a n - 2 - o n e (238) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone (232) (60.2 mg, 0.3 mmol) was conver ted i n t o the b i c y c l i c ketone (238) . Normal workup, 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 4 0 - 5 0 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 42.4 mg (86%) of (238) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1730, 1140 c m " 1 ; XE nmr (400 MHz, C D C l 3 ) 6: 1.30 ( s , 3H, C H 3 C - ) , 1.74 ( t o f d , 3H, CH3C-=, J - 2, 7 H z ) , 1 .81-1.88 (m, 2H), 1 .92-2 .01 (m, I H ) , 2 .18-2 .29 (m, 3H), 2 .34-2 .43 (m, 3H), 5.36 (broad q , I H , o l e f i n i c p r o t o n , J - 7 H z ) . Exact Mass c a l c d f o r C ^ H ^ O : 164.1202; found: 164.1202. P r e p a r a t i o n o f c i s , ( Z ) - l - M e t h y l - 6 - e t h y l i d e n e b i c y c l o [ 3 . 3 . 0 ] o c t a n - 2 - o n e (239) 192 -F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone mix ture (233) (60.2 mg, 0 .3 mmol) was conver ted i n t o the b i c y c l i c ketone (239). Normal workup, 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 4 5 - 6 0 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 38.9 mg (79%) o f (239) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1725, 1105 c m " 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 1.11 ( s , 3 H , C H 3 C - ) , 1 . 4 1 - 1 . 4 9 (m, I H ) , 1.66 (broad d , 3 H , C H 3 O , J = 7 H z ) , 1 . 6 9 - 1 . 7 9 (m, I H ) , 1 . 8 7 - 1 . 9 4 (m, I H ) , 2 . 1 4 - 2 . 3 9 (m, 5H), 2 . 8 8 - 2 . 9 4 (m, I H ) , 5 . 3 5 (broad q , I H , o l e f i n i c p r o t o n , J = 7 H z ) . Exact  Mass c a l c d . f o r C n H 1 6 0 : 164.1202; f o u n d : 164.1200. P r e p a r a t i o n o f the T r i c y c l i c Ketone (240) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone (234) (68 mg, 0.3 mmol) was c o n v e r t e d i n t o the t r i c y c l i c ketone (240) . Normal workup, 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 65-80"C/0 .2 T o r r ) of the crude p r o d u c t , a f f o r d e d 48.3 mg (85%) of (240) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1725, 1135 c m " 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 1 .39-1.47 (m, I H ) , 1 .70-1.80 (m, 6H), 1 .89-2.00 (m, 2H), 2 .10-2 .23 (m, 4H) , 2 .28-2 .35 (m, 2H), 2.50 (d of d , I H , H A , J - 9, 18 H z ) , 2 .75-2 .82 (m, I H ) , 5.37 ( t of q , I H , o l e f i n i c p r o t o n , J = 2, 7 H z ) . Exact Mass c a l c d . f o r C 1 3 H 1 8 0 : 190.1358; f o u n d : 190.1358. - 193 -P r e p a r a t i o n o f t r a n s . ( Z ) - 4 - I s o p r o p y l - 3 - [ 3 - ( 5 - c h l o r o - 2 - p e n t e n y l ) ] cyclohexanone (306) F o l l o w i n g g e n e r a l procedure 8, 4 - i s o p r o p y l - 2 - c y c l o h e x e n - l - o n e (305) (690 mg, 5 mmol) was conver ted i n t o the c h l o r o ketone (306) . F r a c t i o n a l d i s t i l l a t i o n of the crude m a t e r i a l o b t a i n e d on workup gave i n i t i a l l y a s m a l l amount o f the s t a r t i n g enone (305) , f o l l o w e d by 845.1 mg (70%) of the c h l o r o ketone (306) ( a i r - b a t h temperature 1 4 0 - 1 5 5 ° C / 0 . 3 T o r r ) , as a c o l o r l e s s o i l ; i r ( f i l m ) : 1710, 1200, 730 c m - 1 ; lU nmr (400 MHz, CDC1 3) 6: 0.72 and 0.96 ( d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1.44 (d of q , 1H, J - 4 . 5 , 13 H z ) , 1.64 ( t o f d , 3H, C H 3 O , J - 1 .5 , 7 H z ) , 1 .67-1.78 (m, 2H), 1 .98-2 .05 (m, 1H), 2.17 (d o f d o f d , 1H, H B , J - 2 . 5 , 4 . 5 , 13 H z ) , 2 .30-2 .49 (m, 5H), 2.89 (d of t , 1H, H A , J - 4 . 5 , 12 H z ) , 3 .55-3 .65 (m, 2H, - C H 2 C 1 ) , 5.36 ( q , 1H, o l e f i n i c p r o t o n , J - 7 H z ) . I r r a d i a t i o n at S 2.17 (H B ) s i m p l i f i e d the s i g n a l a t 6 2.89 (H A ) to a t (J - 12 Hz) and m o d i f i e d the m u l t i p l e t s a t 6 2 .30-2 .49 and 6 1 .98 -2 .05 . E x a c t . Mass c a l c d . f o r C 1 4 H 2 3 0 3 5 C 1 : 242.1449; f o u n d : 242.1444. 194 P r e p a r a t i o n o f the B i c y c l i c Ketone (307) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone (306) (824.5 mg, 3.4 mmol) was conver ted i n t o the b i c y c l i c ketone (307). Normal workup, 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 7 0 - 8 0 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 644.5 mg (92%) of (307) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1705, 1245 c m - 1 ; ^-H nmr (400 MHz, CDC1 3) 6: 0.86 and 0.98 ( d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1 .43-1.53 (m, 2H), 1.63 (q of d , 3H, CH 3 C=, J = 1 .5 , 7 H z ) , 1 .84-2 .01 (m, 4H) , 2 .22-2 .37 (m, 2H), 2 .49-2 .58 (m, 2H), 2.63 (broad q , 1H, H B , J - 7 H z ) , 2.88 (broad d o f d , 1H, H A , J - 7, 10 H z ) , 5.33 ( t o f q , 1H, o l e f i n i c p r o t o n , J - 1 .5 , 7 H z ) . I r r a d i a t i o n a t 8 2.88 ( H A ) : s i g n a l a t 6 2.63 (Hg) s i m p l i f i e d to a broad t ( J - 7 H z ) , m u l t i p l e t s a t 6 2 .49-2 .58 and 6 1 .43-1 .53 a l s o changed. I r r a d i a t i o n a t 8 2.63 (Hg) : 6 2.88 (H A ) s i m p l i f i e d to a broad d (J •= 10 H z ) , m u l t i p l e t s a t 6 2 .22-2 .33 and 8 2 .49-2 .58 a l s o changed. I n a d i f f e r e n c e n u c l e a r Overhauser enhancement (nOe) exper iment , i r r a d i a t i o n a t 6 2.88 (H A ) caused s i g n a l enhancement at 6 2.63 (Hg), 8 1.63 (CH3C=) and a t 8 0.86 ( -CHMe-) . Exact Mass c a l c d . f o r C 1 4 H 2 2 0 : 206.1672; f o u n d : 206.1666. 195 -P r e p a r a t i o n of the K e t a l (311) To a s t i r r e d s o l u t i o n o f the b i c y c l i c ketone (307) (1 .00 g , 4.85 mmol) i n 55 mL o f benzene was added s u c c e s s i v e l y e t h a n e d i o l (903.9 mg, 14.55 mmol) and p y r i d i n i u m p . - to luenesul fonate 9 * * (365.5 mg, 1.46 mmol). The m i x t u r e was r e f l u x e d under a Dean-Stark water t r a p f o r 2 .5 h . Benzene was removed under reduced pressure and 60 mL o f e t h e r was added to the r e s i d u e . The r e s u l t a n t m i x t u r e was washed ( s a t u r a t e d aqueous sodium b i c a r b o n a t e , b r i n e ) and d r i e d (MgS0 4 ) . S o l v e n t removal under reduced p r e s s u r e and d i s t i l l a t i o n ( a i r - b a t h temperature 1 1 5 - 1 2 5 ° C / 0 .3 T o r r ) o f the r e s i d u a l o i l a f f o r d e d 1.140 g (94%) o f (311) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1440, 1145, 1105 c m - 1 ; lE nmr (400 MHz, CDC1 3) 5 : 0.84 and 0.90 ( d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1.11 ( t o f t , I H , H z , J - 3 , 11 H z ) , 1.33 (d o f q , I H , J - 4 , 11 H z ) , 1 .55-1 .85 (m, 9H), 2 .00-2 .09 (m, I H , H g ) , 2 .14-2 .23 (m, I H ) , 2 .41-2 .50 (m, I H ) , 2.61 (d of d , I H , H A , J - 7, 11 H z ) , 3.94 (broad s , 4H, - 0 C H 2 C H 2 0 - ) , 5.24 (q , I H , o l e f i n i c p r o t o n , J = 7 H z ) . I r r a d i a t i o n a t 6 2 .61 ( H A ) : s i g n a l at 6 2 .00-2 .09 (Hg) s i m p l i f i e d to a broad t (J - 8 H z ) , s i g n a l a t 6 1.11 (H z ) s i m p l i f i e d to a t o f d (J - 3 , 11 H z ) . I r r a d i a t i o n a t 5 2.04 (Hg): s i g n a l a t 6 2.61 (H A ) s i m p l i f i e d to a d ( J - 11 H z ) , the m u l t i p l e t a t 5 - 196 -1 .55-1.85 was a l s o s i m p l i f i e d . Exact Mass c a l c d . f o r Cl6**26°2 : 250.1934; f o u n d : 250.1938. P r e p a r a t i o n of the T r i c y c l i c A l c o h o l (308) To a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n o f the k e t a l (311) (500 mg, 2.0 mmol) i n 8 mL o f d r y THF was added, dropwise , borane-methyl s u l f i d e complex (300 / i L , 3 .0 mmol). The r e s u l t i n g c o l o r l e s s s o l u t i o n was s t i r r e d a t 0°C f o r 30 min and a t room temperature f o r 3.5 h . S u f f i c i e n t water was added to quench the excess borane. Aqueous 3M sodium hydro-x i d e (1 .0 mL, 3.0 mmol) was added s l o w l y to t h i s s o l u t i o n . A f t e r the s o l u t i o n had been c o o l e d to 0°C, 30% hydrogen p e r o x i d e (1 .0 mL, 8.8 mmol) was added dropwise and the r e s u l t i n g s o l u t i o n was heated a t 40 -50 c C f o r 1 h . S a t u r a t e d aqueous ammonium c h l o r i d e (4 mL) and ether (10 mL) were added and the l a y e r s were s e p a r a t e d . The aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h pet ro leum e t h e r - e t h e r , 1 : 1 . The combined o r g a n i c e x t r a c t was washed (water , b r i n e ) , d r i e d (MgS0 4 ) , and con-c e n t r a t e d . The r e s u l t i n g o i l was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (28 g , e l u t i o n w i t h petro leum e t h e r - e t h e r 1 1 : 9 ) . 197 The major , l e s s p o l a r product was i s o l a t e d by removal of the s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r -b a t h temperature 1 4 8 - 1 5 8 ° C / 0 . 3 T o r r ) o f the r e s i d u e . The c o l o r l e s s o i l thus o b t a i n e d (444.2 mg, 83%) was i d e n t i f i e d as the t r i c y c l i c a l c o h o l (308) ; i r ( f i l m ) : 3450, 1380, 1 1 2 0 c m - 1 ; X H nmr (400 MHz, C D C 1 3 ) 5 : 0.79 and 0.94 (d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1.20 ( d , 3H, -CH(0H )Me, J - 7 H z ) , 1 .25-1.36 (m, I H ) , 1.49 ( t o f t , I H , H z , J - 3 , 11 Hz), 1.59-1 .85 (m, 8H), 1 .89-1.96 (m, I H , H y ) , 2.13 (d of d of d , H A , J - 7 , 8, 11 H z ) , 2 .24 -2 .31 (m, I H ) , 2.99 (broad s , I H , exchanges w i t h D 2 0 , -OH), 3 .90-3 .99 (m, 4H, - 0 C H 2 C H 2 0 - ) , 3 .99-4 .05 (m, I H , H M ) . I r r a d i a t i o n a t 6 4 .02 ( H M ) : m u l t i p l e t a t 6 1 .89-1.96 (Hy) s i m p l i f i e d to a q (J - 8 H z ) , d a t S 1.20 (-CH(OH)Me) s i m p l i f i e d to a s . I r r a d i a t i o n a t S 1.92 (Hy) : the m u l t i p l e t a t 6 3 .99-4 .05 (HM) s i m p l i f i e d to a q (J - 7 H z ) , the m u l t i p l e t a t 6 2 .24 -2 .31 changed and the s i g n a l a t 6 2.13 (H A ) became a d o f d ( J - 7 , 11 H z ) . I r r a d i a t i o n a t S 2.13 ( H A ) : the m u l t i p l e t a t 6 1 .89-1.96 (Hy) changed and the s i g n a l a t S 1.49 (H z) became a t o f d (J - 3 , 11 H z ) . Exact Mass c a l c d . f o r 0 1 3 ^ 3 0 3 : 268.2039; f o u n d : 268.2033. The m i n o r , more p o l a r product was i s o l a t e d by c o n c e n t r a t i o n o f the a p p r o p r i a t e column f r a c t i o n s , 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 tem-p e r a t u r e 1 5 0 - 1 6 0 ° C / 0 . 3 T o r r ) o f the r e s i d u a l crude m a t e r i a l . The c o l o r l e s s o i l thus o b t a i n e d (20.3 mg, 4%), was i d e n t i f i e d as the t r i c y -c l i c a l c o h o l (312) ; i r ( f i l m ) : 3450, 1370, 1100 c m " 1 ; 1 H nmr (400 MHz, C D C I 3 ) 5 : 0.89 and 0.94 ( d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1.05 (t of t , IH, H z , J - 3, 11 H z ) , 1.18 (d , 3H, -CH(0H)Me, J - 7 H z ) , 1.26-1.38 (m, 2 H ) , 1 .52-1 .64 (m, 5H), 1 .77-1.89 (m, 5H), 1.99 (d o f d , IH, J - 198 - 6, 11 H z ) , 3 .64-3 .71 (m, 1H, H M ) , 3 .88-4 .00 (m, 4H, - O C H 2 C H 2 0 - ) . Exact Mass c a l c d . f o r C 1 6 H 2 g 0 3 : 268.2039; found: 268.2043. P r e p a r a t i o n o f the Hydroxy Ketone M i x t u r e (309) and (313) 3 0 9 313 A s t i r r e d s o l u t i o n o f the k e t a l (308) (402 mg, 1.5 mmol) i n 13.5 mL of acetone c o n t a i n i n g 1.5 mL o f water and p y r i d i n i u m p . - t o l u e n e s u l f o -n a t e 9 6 (113 mg, 0.45 mmol) was r e f l u x e d f o r 2 h . Most o f the s o l v e n t was removed under reduced p r e s s u r e and 45 mL o f e t h e r was added to the r e s i d u e . The r e s u l t a n t mix ture was washed w i t h aqueous sodium b i c a r b o -nate and b r i n e and then was d r i e d (MgS0 4 ) . Removal o f the s o l v e n t under reduced p r e s s u r e gave 311.5 mg (93%) o f a y e l l o w o i l . A n a l y s i s of t h i s m a t e r i a l by g l c i n d i c a t e d t h a t i t c o n s i s t e d o f a 2 : 1 * m i x t u r e of (309) and (313) r e s p e c t i v e l y . A s o l u t i o n of sodium methoxide (0.42 mmol) i n 2 mL of dry methanol was added to a s t i r r e d s o l u t i o n of the crude product i n 3 mL of dry methanol . The y e l l o w s o l u t i o n was s t i r r e d a t room temperature f o r 3.5 h . S a t u r a t e d aqueous ammonium c h l o r i d e (2 mL) and e t h e r (10 mL) were T h i s r a t i o v a r i e d s l i g h t l y from experiment to exper iment . - 199 -added. The aqueous l a y e r was e x t r a c t e d thoroughly w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed ( b r i n e ) , d r i e d (MgS0 4 ) , and concen-t 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 1 4 0 - 1 5 0 ° C / 0 . 3 T o r r ) o f the r e s i d u a l o i l a f f o r d e d 269.8 mg (80%) of a c o l o r l e s s o i l which was a 3:1 m i x t u r e of the hydroxy ketones (309) and (313); i r ( f i l m ) : 3450, 1700, 1370, 1110 c m " 1 ; X H nmr (400 MHz, CDC1 3) 5: 0.79 and 0.92 (d , d , r a t i o 3 : 1 , 3H, -CHMe.2, J - 7 Hz each) , 1.00 and 1.02 ( d , d , r a t i o 1 :3 , 3 H , -CHMe 2 > J - 7 Hz each) , 1.15 and 1.17 ( d , d , r a t i o 1 :3 , 3H, -CH(0H)Me, J - 7 Hz each) , 1 .05-2 .55 (m, 13H), 2 .69-2 .76 and 2 .99-3 .07 (m, m, r a t i o 1 :3 , 1H), 3 .90-3 .97 and 4 .19 -4 .27 (m, m, r a t i o 1 :3 , 1H, -CH(OH)Me). Exact Mass c a l c d . f o r C 1 4 H 2 4 0 2 : 224.1777; f o u n d : 224.1774. P r e p a r a t i o n o f the O l e f i n i c A l c o h o l (310) A s t i r r e d suspens ion o f sodium h y d r i d e (74 mg, 3 mmol) i n 12 mL of dry d i m e t h y l s u l f o x i d e was heated a t 80°C f o r 35 m i n , d u r i n g which time hydrogen e v o l u t i o n ceased. The r e s u l t i n g s o l u t i o n of m e t h y l s u l f i n y l c a r b a n i o n 9 7 was c o o l e d to room temperature and a s o l u t i o n of m e t h y l -t r iphenylphosphonium bromide (1.11 g , 3 .1 mmol) i n 5 mL o f d r y DMSO w a s added by s y r i n g e . The y e l l o w s l u r r y of the y l i d e was s t i r r e d f o r 10 min at room temperature and a s o l u t i o n of the 3:1 m i x t u r e o f k e t o l s (309) - 200 -and (313) , r e s p e c t i v e l y , (224 mg, 1 mmol) i n 5 mL of dry DMSO was added. A f t e r the r e s u l t i n g s o l u t i o n had been s t i r r e d a t room temperature f o r 16 h , i t was poured i n t o i c e - w a t e r and the mixture was e x t r a c t e d thoroughly w i t h pentane. The combined e x t r a c t was washed (1 :1 d i m e t h y l s u l f o x i d e -w a t e r , w a t e r , and b r i n e ) , d r i e d (MgS0 4 ) , and c o n c e n t r a t e d . The r e s i d u a l y e l l o w o i l was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g, e l u t i o n w i t h petro leum e t h e r - e t h e r , 4 : 1 ) . The major , l e s s p o l a r product was i s o l a t e d by removal of the s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r -b a t h temperature 7 5 - 9 0 ° C / 0 . 1 T o r r ) o f the remain ing o i l . The c o l o r l e s s o i l thus o b t a i n e d (167.9 mg, 76%) was i d e n t i f i e d as the o l e f i n i c a l c o h o l (310) , which e x h i b i t e d i r ( f i l m ) : 3350, 1635, 890 c m " 1 ; lH nmr (400 MHz, CDC1 3) 6: 0.76 and 0.97 (d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1.00 ( d , I H , exchanges w i t h D 2 0 , -OH, J - 6 H z ) , 1.05 (d o f q , I H , H x , J - 4 , 11 H z ) , 1.14 ( d , 3H, -CH(0H)CH 3 , J - 7 H z ) , 1.20 (d o f t , I H , H A , J - 8, 11 H z ) , 1.49 (broad t , I H , J - 8 H z ) , 1 .65-2 .03 (m, 8H) , 2 .30-2 .39 (m, 2H, Hg and H c ) , 4 . 15 -4 .22 (m, I H , H M ) , 4 .51 ( d , I H , o l e f i n i c p r o t o n , J - 2 H z ) , 4 .61 ( d , I H , o l e f i n i c p r o t o n , J - 2 H z ) . I r r a d i a t i o n a t S 2.34 (Hg, H c ) : s i g n a l a t 1.05 (H x ) s i m p l i f i e d to a q (J - 11 H z ) , s i g n a l a t S 1.20 (H A ) s i m p l i f i e d to a d o f d (J - 8, 11 H z ) , m u l t i p l e t a t S 1.65-2 .03 was a l s o changed. I r r a d i a t i o n a t 6 4 .19 ( H ^ ) : s i g n a l at S 1.14 (-CH(0H)CH 3 ) s i m p l i f i e d to a s , s i g n a l a t 6 1.00 (-0H) became a s, m u l t i p l e t at 6 1 .65-2 .03 was s i m p l i f i e d . Exact Mass c a l c d . f o r C 1 5 H 2 5 O : 222.1985; f o u n d : 222.1981. The m i n o r , more p o l a r product was i s o l a t e d by c o n c e n t r a t i o n of the a p p r o p r i a t e column f r a c t i o n s , 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 tern-- 201 -p e r a t u r e 8 0 - 9 0 ° C / 0 . 1 T o r r ) o f the remain ing crude m a t e r i a l . The c o l o r l e s s o i l thus o b t a i n e d (9.7 mg, 4%) was i d e n t i f i e d as the o l e f i n i c a l c o h o l (314) ; i r ( f i l m ) : 3350, 1635, 880 c m - 1 ; X H nmr (400 MHz, CDC1 3) 8: 0.79 and 0.93 (d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1 .12-1.19 (m, 1H), 1.20 ( d , 3H, -CH(0H)Me, J - 7 H z ) , 1 .31-1.39 (m, 2H), 1 .63-1.85 (m, 6H), 1 .92-1.99 (m, 1H, H Y ) , 2.06 (d of d of d , 1H, H A , J - 7, 8, 10 H z ) , 2 .14-2 .33 (m, 2H) , 2 .65-2 .71 (m, 1H, H f i ) , 3 .92-4 .00 (m, 1H, H M ) , 4.69 (broad s, 1H, o l e f i n i c p r o t o n ) , 4 .71 (broad s , 1H, o l e f i n i c p r o t o n ) . I r r a d i a t i o n a t 8 3.96 ( H M ) : s i g n a l a t 8 1 .92-1.99 (H Y ) s i m p l i f i e d to a q (J - 8 H z ) , 8 1.20 (-CH(OH)Me) became a s . I r r a d i a t i o n a t 8 2.68 (Hg): s i g n a l a t 8 2.06 (H A ) s i m p l i f i e d to a d o f d (J - 7, 10 H z ) , m u l t i p l e t a t 8 1 .63-1 .85 was a l s o changed. Exact Mass c a l c d . f o r C ^ H ^ O : 222.1985; f o u n d : 222.1983. P r e p a r a t i o n of (±) -3-e£i -Anhydro-oplopanone (315) To a s t i r r e d s o l u t i o n - s u s p e n s i o n o f p y r i d i n i u m chlorochromate (PCC) (233 mg, 1.08 mmol) i n 2 mL of dry methylene c h l o r i d e was added a s o l u t i o n of the o l e f i n i c a l c o h o l (310) (120 mg, 0.54 mmol) i n 2 mL of dry 202 C H 2 C I 2 . The b l a c k r e a c t i o n mixture was s t i r r e d a t room temperature f o r 2 h , 10 mL of d r y e ther was added, and the supernatant was decanted from the b l a c k gum. The l a t t e r m a t e r i a l was s t i r r e d w i t h a f u r t h e r 10 mL of d r y e ther and the e ther s o l u t i o n was aga in decanted. The combined o r g a n i c s o l u t i o n was passed through a s h o r t column of F l o r i s i l (8 g, e l u t i o n w i t h e t h e r ) . The combined e l u a t e was c o n c e n t r a t e d to a f f o r d a c l e a r 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 temperature 100-115°C/0 . 3 T o r r ) o f the crude o i l a f f o r d e d 110.7 mg (93%) o f (315) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3060, 1710, 1645, 885 c m " 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 0.76 and 0.90 ( d , d , 3H each, -CHMe 2 , J_ - 7 Hz e a c h ) , 0.98 (d of q , I H , H x , J - 4 , 12 H z ) , 1.27 (d of t , I H , H A , J - 7 , 12 H z ) , 1 .54-1 .77 (m, 4H) , 1.81 ( t o f t , I H , H z , J - 3 , 12 H z ) , 1 .87-1 .94 (m, I H ) , 1 .98-2.07 0 (m, 2H), 2.17 ( s , 3H, CH 3c'-), 2.33 ( t o f d , I H , H c , J - 4 , 13 H z ) , 2 .46-2 .57 (m, I H , H g ) , 3.15 (d of d of d , I H , Hy, 2 - 4 , 7, 9 H z ) , 4 .53 ( d , I H , o l e f i n i c p r o t o n , J. - 2 H z ) , 4 .63 ( d , I H , o l e f i n i c p r o t o n , J - 2 H z ) . I r r a d i a t i o n a t S 3.15 ( H y ) : s i g n a l a t 6 1.27 (H A ) s i m p l i f i e d to a t (J - 12 Hz) and the m u l t i p l e t a t 6 1 .98-2.07 was changed. I r r a d i a t i o n a t 6 2.52 (Hg) : m u l t i p l e t a t 6 1 .87-1 .94 s i m p l i f i e d to a t (J - 9 Hz) and the s i g n a l a t 6 1.27 (H A ) became a d o f d (J - 7, 12 H z ) . I r r a d i a t i o n a t S 1.27 ( H A ) : 6 3.15 (Hy) s i m p l i f i e d to a d o f d (J - 4 , 9 H z ) , S 2 .46 -2 .57 (Hg) became a broad t (J - 9 H z ) , and 6 1.81 (H z ) changed i n t o a t o f d (J - 3 , 12 H z ) . I r r a d i a t i o n a t 6 0.98 ( H x ) : 6 2.33 ( H c ) s i m p l i f i e d to a d of d (J - 4 , 13 Hz) and 6 1.81 ( H z ) changed i n t o a t o f d (J - 3, 12 H z ) . In a d i f f e r e n c e n u c l e a r Overhauser enhancement (nOe) exper iment , i r r a d i a t i o n at S 1.27 (H A ) caused s i g n a l enhancement a t 6 3.15 ( H y ) , 6 0.98 (H x ) and 6 0.76 ( -CHMe-) . Exact Mass - 203 -c a l c d . f o r C 1 5 H 2 4 0 : 220.1828; found: 220.1826. P r e p a r a t i o n of (±)-Anhydro-oplopanone (258) A s o l u t i o n o f sodium methoxide (0.17 mmol) i n 2 mL o f d r y methanol was added to a s t i r r e d s o l u t i o n o f the o l e f i n i c ketone (315) (98 mg, 0.45 mmol) i n 2 mL o f d r y methanol . The y e l l o w s o l u t i o n was s t i r r e d a t 60°C f o r 24 h . The s o l u t i o n was c o o l e d to room temperature and 2 mL of s a t u r a t e d aqueous ammonium c h l o r i d e and 10 mL o f e t h e r were added. The aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed ( b r i n e ) , d r i e d (MgS0 4) and c o n c e n t r a t e d . A n a l y s i s o f the crude p r o d u c t by g l c i n d i c a t e d t h a t i t c o n s i s t e d of a 93:7 mixture of (±)-anhydro-oplopanone (258) and the s t a r t i n g e p i m e r i c ketone (315) . R e c r y s t a l l i z a t i o n o f t h i s mix ture from petroleum e ther p r o v i d e d 81.4 mg (83%) of pure (258) which e x h i b i t e d mp 68°C; i r ( C H C 1 3 ) : 3060, 1705, 1645, 885 c m - 1 ; 1 H nmr (400 MHz, C D C I 3 ) 6: 0.66 and 0.91 ( d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1.11 (d of q , 1H, H x , J - 4 , 11 H z ) , 1.27 ( t of t , 1H, H z , J - 3, 11 H z ) , 1 .50-1.76 (m, 5H) , 1.81 (d o f d of d , 1H, H B , 0 J - 5, 7, 11 H z ) , 1 .87-2.04 (m, 3H), 2.18 ( s , 3H, C H 3 C - ) , 2.37 (d of d - 204 -o f d , I H , H c > J - 3 , 4 , 13 H z ) , 2.71 (d of t , I H , J - 5 , 11 H z ) , 4.57 ( d , I H , o l e f i n i c p r o t o n , J - 2 H z ) , 4.67 ( d , I H , o l e f i n i c p r o t o n , J = 2 H z ) . I r r a d i a t i o n a t 6 2.71 (Hy) : m u l t i p l e t s a t 6 1 .50-1.76 and 5 1 .87-2 .04 s i m p l i f i e d . I r r a d i a t i o n a t 6 2.37 ( H c ) : the s i g n a l a t 6 1.11 (H x ) s i m p l i f i e d to a q (J - 11 Hz) and m u l t i p l e t at 6 1 .87-2.04 was changed. I r r a d i a t i o n at S 1.27 ( H z ) : the s i g n a l a t 6 1.11 (H x ) became a d o f t (J - 4 , 11 H z ) , and m u l t i p l e t a t 6 1 .50-1.76 s i m p l i f i e d . 1 3 C nmr (75.6 MHz, CDC1 3) 6: 15.7 ( q ) , 22.0 ( q ) , 26.6 ( t ) , 27.4 ( t ) , 28.5 ( t ) , 28.9 ( q ) , 29.6 ( d ) , 35.3 ( t ) , 49 .3 ( d ) , 51.8 ( d ) , 52.1 ( d ) , 56.1 ( d ) , 103.6 ( t ) , 150.9 ( s ) , 211.7 ( s ) . The chemica l s h i f t s and the m u l t i p l i -c i t i e s r e p o r t e d above were d e r i v e d from the p r o t o n n o i s e decoupled and the o f f - r e s o n a n c e decoupled 1 3 C nmr s p e c t r a , r e s p e c t i v e l y . Exact Mass c a l c d . f o r C 1 5 H 2 4 0 : 220.1828; f o u n d : 220.1828. These s p e c t r a l data are i n agreement w i t h those r e p o r t e d f o r ( - ) -anhydro-oplopanone . P r e p a r a t i o n o f t h e Epoxy A l c o h o l (320) A s t i r r e d s o l u t i o n - s u s p e n s i o n o f sodium h y d r i d e (28.8 mg, 1.2 mmol) i n 2 mL o f d r y DMSO was heated a t 80°C f o r 35 m i n , d u r i n g which time 205 hydrogen e v o l u t i o n ceased. The r e s u l t i n g s o l u t i o n o f m e t h y l s u l f i n y l c a r b a n i o n was c o o l e d to room temperature , d i l u t e d w i t h 4 mL o f dry THF, and then was c o o l e d w i t h an i c e - s a l t b a t h . A s o l u t i o n o f t r i m e t h y l s u l -fonium i o d i d e 1 1 9 (244.8 mg, 1.2 mmol) i n 3 mL o f d r y DMSO was added over a p e r i o d o f three minutes . A f t e r the s o l u t i o n had been s t i r r e d f o r an a d d i t i o n a l m i n u t e , a s o l u t i o n of the 3:1 mix ture of the k e t o l s (309) and (313) , r e s p e c t i v e l y , (89.6 mg, 0.4 mmol) i n 3 mL o f d r y DMSO was added i n one s i n g l e p o r t i o n and s t i r r i n g was c o n t i n u e d a t i c e - s a l t temperature f o r 30 min and then f o r 8 h w i t h the b a t h removed. S a t u r a t e d aqueous ammonium c h l o r i d e (3 mL) and pentane (15 mL) were added s u c c e s s i v e l y and the aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined e x t r a c t was washed (water , b r i n e ) , d r i e d (MgS0 4 ) , and c o n c e n t r a t e d . The r e s i d u a l o i l was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (10 g, e l u t i o n w i t h pet ro leum e t h e r - e t h e r , 2 : 1 ) . C o n c e n t r a t i o n o f the appro-p r i a t e column f r a c t i o n s gave a p a l e y e l l o w s o l i d , which was r e c r y s t a l -l i z e d from petro leum e ther to a f f o r d 65.6 mg (69%) o f w h i t e , needle shaped c r y s t a l s (mp 9 2 . 5 - 9 3 ° C ) o f the epoxide (320) ; i r ( C H C 1 3 ) : 3590, 3350, 3000, 1240, 900 c m - 1 ; X H nmr (300 MHz, C D C I 3 ) 6: 0 .81 and 0.97 ( d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1.14 ( d , 3H, -CH(0H)Me, J - 7 H z ) , 1 .10-1 .72 (m, 10 H ) , 1 .80-2 .05 (m, 3H), 2.30 (d of t , I H , H A , J - 8, 11 H z ) , 2.57 and 2.66 ( d , d , IH each, AB p a i r o f d o u b l e t s , epoxide p r o t o n s , J - 5 Hz each) , 4.16 (broad q, I H , H M , J - 7 H z ) . Exact Mass c a l c d . f o r C 1 5 H 2 6 ° 2 : 238.1934; found: 238.1935. 206 -P r e p a r a t i o n of the D i o l (321) To a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n - 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 (6 mg, 0.15 mmol) i n 2 mL o f dry e ther was added a s o l u t i o n of the epoxy a l c o h o l (320) (33.7 mg, 0.14 mmol) i n 2 mL o f d r y e t h e r . 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 room temperature f o r 1 h . Normal workup (as o u t l i n e d i n g e n e r a l procedure 7 ) , 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 9 5 - 1 1 0 ° C / 0 . 3 T o r r ) o f the crude p r o d u c t , a f f o r d e d 30.95 mg (91%) of (321) as a g l a s s y , low m e l t i n g s o l i d . T h i s m a t e r i a l e x h i b i t e d i r ( C H C 1 3 ) : 3600, 3450, 1370, 880 c m - 1 ; X H nmr (300 MHz, C D C I 3 ) 6": 0.81 and 0.93 ( d , d , 3H each, -CHMe 2 , J - 7 H z ) , 1.13 ( d , 3H, -CH(0H)Me, J •= 7 H z ) , 1.18 ( s , 3H, C H 3 C - ) , 1 .20-2 .05 (m, 15H), 4 .11 (broad q , 1 H , -CH(0H)Me, J - 7 H z ) . Exact Mass c a l c d . f o r C 1 A H 2 5 0 2 (M+-CH3) : 225.1856; f o u n d : 225.1859. 207 P r e p a r a t i o n of the Hydroxy Ketone (322) To a s t i r r e d s o l u t i o n - s u s p e n s i o n o f PCC (52.6 mg, 0.24 mmol) and sodium ace ta te (5 .0 mg, 0.06 mmol) In 2 mL o f d r y methylene c h l o r i d e was added a s o l u t i o n of the d i o l (321) (29.3 mg, 0.12 mmol) i n 2 mL of dry C H 2 C I 2 . The b l a c k r e a c t i o n mix ture was s t i r r e d a t room temperature f o r 2 h , 10 mL o f d r y e ther was added, and the supernatant s o l u t i o n was decanted from the b l a c k gum. The l a t t e r m a t e r i a l was s t i r r e d w i t h a f u r t h e r 10 mL o f d r y e t h e r and the o r g a n i c s o l u t i o n was a g a i n decanted. The combined o r g a n i c s o l u t i o n was passed through a s h o r t column of F l o r i s i l (3 g , e l u t i o n w i t h e t h e r ) . The combined e l u a t e was concen-t r a t e d to o b t a i n 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 temperature 9 5 - 1 1 0 ° C / 0 . 3 T o r r ) a f f o r d e d 26.5 mg (91%) o f (322) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3450, 1700, 1360 c m * 1 ; X H nmr (300 MHz, C D C I 3 ) 6: 0.82 and 0.89 ( d , d , 3H each , -CHMe.2. J - 7 Hz each) , 1.08 (broad s , exchanges w i t h D 2 0 , 1H, -OH) , 1.20 ( s , 3H, C H 3 C ( 0 H ) - ) , 1 .16-2 .00 (m, 12H), 2.16 (s , 3H, C H 3 ^ - ) , 3.14 (d o f d of d , 1H, H Y , J - 4 , 7, 9 Hz) . Exact Mass c a l c d . f o r C 1 5 H 2 6 0 2 : 238.1934; found: 238.1922. - 208 -P r e p a r a t i o n of (± ) -8 -ep i -Oplopanone (323) H 0 - , / y B H f=Jr H A s o l u t i o n o f sodium methoxide (0.04 mmol) i n 0 .5 mL o f d r y metha-n o l was added t o a s t i r r e d s o l u t i o n o f the k e t o l (322) (22.5 mg, 0.095 mmol) i n 2 mL o f d r y methanol . The y e l l o w s o l u t i o n was s t i r r e d a t 60°C f o r 24 h . The s o l u t i o n was c o o l e d to room temperature and 1 mL of s a t u r a t e d ammonium c h l o r i d e and 5 mL o f e ther were added. The aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed ( b r i n e ) , d r i e d ( M g S O ^ , and c o n c e n t r a t e d . A n a l y s i s o f the crude product by g l c i n d i c a t e d t h a t i t c o n s i s t e d o f a 93:7 m i x t u r e o f ( ± ) - 8 - e p i -oplopanone (323) and the s t a r t i n g e p i m e r i c k e t o l (322). The y e l l o w o i l was s u b j e c t e d t o f l a s h chromatography on s i l i c a g e l (6 g , e l u t i o n w i t h petro leum e t h e r - e t h e r , 1 1 : 9 ) . Removal o f the s o l v e n t from the a p p r o p r i -ate f r a c t i o n s , f o l l o w e d by r e c r y s t a l l i z a t i o n of the r e s i d u e from hexane-e t h e r , a f f o r d e d 18.8 mg (84%) o f pure (323) which e x h i b i t e d mp 62°C; i r ( C H C 1 3 ) : 3590, 3450, 1705, 1465, 1390, 1375, 1360 c m - 1 ; X H (nmr) (400 MHz, C D C I 3 ) 6: 0.72 and 0.90 (d , d , 3H each, -CHMe 2 . J - 7 Hz each) , 1.07 ( t o f t , I H , H z , J - 3, 11 H z ) , 1.22 ( s , 3H, C H 3 C ( 0 H ) - ) , 1 . 2 9 - 1 . 3 7 (m, 4H) , 1 .43-1 .63 (m, 4H) , 1 .70-1.77 (m, 2H), 1.94 (d of d of d , IH, 0 Hg, J - 4 , 8, 11 H z ) , 2 . 0 2 (q , I H , H A , J - 11 H z ) , 2.19 ( s , 3H, C H 3 C - ) , - 209 -2 . 6 0 (d o f t , I H , H Y , J - 5, 11 H z ) . I r r a d i a t i o n a t 6 2.60 (Hy) : 6 2 . 0 2 (H A ) s i m p l i f i e d to a t ( J = 11 H z ) , m u l t i p l e t a t 5 1 .43-1 .63 was a l s o s i m p l i f i e d . I r r a d i a t i o n a t S 1.07 ( H z ) : 6 2.02 (H A ) s i m p l i f i e d to a t ( J - 11 H z ) , m u l t i p l e t s at S 1 .29-1 .37 , 6 1 .43-1 .63 and 1.70-1.77 were a l s o changed. 1 3 C nmr (75.6 MHz, CDC1 3) 6: 15.8 ( q ) , 20.7 ( t ) , 2 1 . 9 ( q ) , 24.5 ( t ) , 28.2 ( q ) , 28.7 ( t ) , 29.0 ( q ) , 29.7 ( d ) , 40 .0 ( t ) , 44.8 ( d ) , 49.4 ( d ) , 55.7 ( d ) , 56.1 ( d ) , 70.4 ( s ) , 212.1 ( s ) . The chemical s h i f t s and the m u l t i p l i c i t i e s r e p o r t e d above were d e r i v e d from the p r o t o n n o i s e decoupled and the o f f - r e s o n a n c e decoupled 1 3 C nmr s p e c t r a , r e s p e c t i v e l y . Exact Mass c a l c d . f o r Ci5H26°2 : 238.1934; found: 238.1929. P r e p a r a t i o n o f the Epoxy A l c o h o l (324) 324 320 To a s t i r r e d s o l u t i o n of the o l e f i n i c a l c o h o l (310) (53.5 mg, 0 . 2 4 mmol) i n 3 mL of DMSO and 1 mL of water was added N-bromosuccinimide (NBS) (85.8 mg, 0.48 mmol) i n one p o r t i o n . A f t e r 45 m i n , the r e a c t i o n mix ture was t r e a t e d w i t h 2 mL of s a t u r a t e d aqueous sodium b icarbonate and 2 mL o f water . The r e s u l t i n g mixture was e x t r a c t e d thoroughly w i t h - 210 e ther and the combined e ther e x t r a c t was washed (water , b r i n e ) , d r i e d (MgSO^), and c o n c e n t r a t e d to a f f o r d a c l e a r p a l e y e l l o w l i q u i d which was used d i r e c t l y i n the next r e a c t i o n . The above p r o d u c t , a m i x t u r e of bromohydrins , was s t i r r e d v i g o r o u s -l y f o r 1.5 h w i t h a suspens ion of potass ium carbonate (66.6 mg, 0.48 mmol) i n 3 mL o f methanol . The r e a c t i o n mix ture was d i l u t e d w i t h water and e x t r a c t e d w i t h e t h e r . The e ther e x t r a c t was washed (water , b r i n e ) , d r i e d (MgSO^), and c o n c e n t r a t e d to g i v e a p a l e y e l l o w l i q u i d . This l i q u i d was s u b j e c t e d t o f l a s h chromatography on s i l i c a g e l (12 g , e l u t i o n w i t h pet ro leum e t h e r - e t h e r , 7 : 3 ) . The m i n o r , l e s s p o l a r product was i s o l a t e d by removal o f s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by r e c r y s t a l l i z a t i o n o f the r e s i d u e from pet ro leum e t h e r . The l o n g , needle -shaped c r y s t a l s thus o b t a i n e d (6 .6 mg, 12%), e x h i b i t e d s p e c t r a and mp i d e n t i c a l w i t h those of the epoxy a l c o h o l (320) . The major , more p o l a r product was o b t a i n e d by c o n c e n t r a t i o n of the a p p r o p r i a t e column f r a c t i o n s f o l l o w e d by r e c r y s t a l l i z a t i o n o f the r e s i d u e from petro leum e t h e r . The substance thus o b t a i n e d as l o n g , needle -shaped c r y s t a l s (36.1 mg, 63%) was i d e n t i f i e d as the epoxy a l c o h o l (324) which e x h i b i t e d mp 91°C; i r ( C H C 1 3 ) : 3590, 3450, 3040, 840 c m * 1 ; 1 H nmr (300 MHz, C D C I 3 ) 6": 0.79 and 0.98 (d , d , 3H each, -CHMe 2 , 1 - 7 Hz each) , 1.14 ( d , 3H, CH 3 CH(0H)- , J = 7 H z ) , 1 .18-1 .45 (m, 4H), 1 .58-2 .05 (m, 9H), 2.34 (d of t , 1H, H A , J - 7, 11 H z ) , 2.48 ( d , 1H, H G , J - 5 H z ) , 2.86 (d o f d , 1H, Hp, J_ - 2, 5 H z ) , 4.16 (broad q , 1H, H M , J - 7 H z ) . Exact Mass c a l c d . f o r C 1 5 H 2 6 0 2 : 238.1934; f o u n d : 238.1933. 211 -P r e p a r a t i o n of the D i o l (316) To a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n - s u s p e n s i o n o f l i t h i u m aluminum h y d r i d e (6 mg, 0.15 mmol) i n 2 mL of dry e ther was added a s o l u t i o n of the epoxy a l c o h o l (324) (33.3 mg, 0.14 mmol) i n 2 mL of dry e t h e r . 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 room temperature f o r 1 h . Normal workup (as o u t l i n e d i n g e n e r a l procedure 7 ) , f o l l o w e d by r e c r y s t a l l i z a t i o n of the w h i t e s o l i d from petro leum e t h e r - e t h e r , gave 32.2 mg (96%) of (316) i n the form o f needle shaped c r y s t a l s which e x h i b i t e d mp 117-118"C; i r ( C H C 1 3 ) : 3590, 3400, 1370, 1120, 890 c m " 1 ; X H nmr (400 MHz, CDC1 3) 6: 0.78 and 0.94 ( d , d , 3H each, -CHMe 2 , J - 7 Hz e a c h ) , 1.07 (d of q , I H , J - 4 , 11 H z ) , 1.08 ( s , 3H, C H 3 C ( 0 H ) - ) , 1.12 ( d , 3H, C H 3 C H ( 0 H ) - , J - 7 H z ) , 1 .24-1 .41 (m, 4H) , 1.51 ( t o f t , I H , J - 3, 11 H z ) , 1 .60-2 .00 (m, 8H), 4 .11 (d o f q , I H , -CH(0H)Me, J - 1, 7 H z ) . Exact Mass c a l c d . f o r C 1 4 H 2 5 ° 2 (W*"-CH 3 ) : 225.1856; found: 225.1852. - 212 P r e p a r a t i o n of (± ) -3-epi -Oplopanone (326) To a s t i r r e d s o l u t i o n - s u s p e n s i o n of PCC (50.5 mg, 0.23 mmol) i n 2 mL o f d r y methylene c h l o r i d e was added a s o l u t i o n of the d i o l (316) (28.1 mg, 0.12 mmol) i n 2 mL o f d r y C H 2 C I 2 . The b l a c k r e a c t i o n mixture was s t i r r e d a t room temperature f o r 2 h , 10 mL o f dry e ther was added, and the supernatant s o l u t i o n was decanted from the b l a c k gum. The l a t t e r m a t e r i a l was s t i r r e d w i t h a f u r t h e r 10 mL o f d r y e t h e r and the e t h e r l a y e r was a g a i n decanted. The combined o r g a n i c s o l u t i o n was passed through a s h o r t column o f F l o r i s i l (3 g , e l u t i o n w i t h e t h e r ) . The combined e l u a t e was c o n c e n t r a t e d and d i s t i l l e d ( a i r - b a t h temperature 8 5 - 9 5 ° C / 0 . 2 T o r r ) to a f f o r d 26.2 mg (94%) o f (326) as a whi te s o l i d which e x h i b i t e d mp 68°C; i r ( C H C I 3 ) : 3590, 3450, 1700, 1385, 1370, 1360 c m * 1 ; 1 H nmr (400 MHz, C D C I 3 ) 6: 0.79 and 0.89 (d , d , 3H each, -CHMe 2 , J - 7 Hz e a c h ) , 1.01 (d of q , 1H, H x , 1 - 4 , 11 H z ) , 1.09 ( s , 3H, C H 3 C ( 0 H ) - ) , 1 .33-1.49 (m, 4H) , 1 .57-1.73 (m, 4H) , 1.77 ( t o f d , 1H, H c , J - 3, 13 H z ) , 1 .83-2.00 (m, 2H), 2.08 (d of t , 1H, H A , J - 7, 11 H z ) , 0 2.16 ( s , 3H, CH3(i-), 3.13 (d of d of d , 1H, H Y , J - 4 , 7, 9 H z ) . Exact  Mass c a l c d . f o r C 1 5 H 2 6 0 2 : 238.1934; f o u n d : 238.1945. - 213 -P r e p a r a t i o n of (±)-Oplopanone (257) A s o l u t i o n o f sodium methoxide (0.04 mmol) i n 0.5 mL o f d r y metha-n o l was added to a s t i r r e d s o l u t i o n o f the k e t o l (326) (10 mg, 0.042 mmol) i n 2 mL o f dry methanol . The y e l l o w s o l u t i o n was s t i r r e d at 40-45°C f o r 36 h . The s o l u t i o n was c o o l e d to room temperature and 1 mL o f s a t u r a t e d ammonium c h l o r i d e and 3 mL o f e t h e r were added. The aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed ( b r i n e ) , d r i e d ( M g S O ^ , and c o n c e n t r a t e d . A n a l y s i s of the crude s o l i d by g l c i n d i c a t e d t h a t i t c o n s i s t e d o f a 94:6 m i x t u r e of (±) -oplopanone (257) and the s t a r t i n g e p i m e r i c k e t o l (326) . 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 o f the p a l e y e l l o w s o l i d from hexane-ether p r o v i d e d 8.43 mg (84%) o f needle -shaped c r y s t a l s (mp 99-100°C) o f (±)-oplopanone (257) , which e x h i b i t e d i r ( C H C 1 3 ) : 3590, 3450, 1710, 1465, 1385, 1370, 1360 c m " 1 ; -^H nmr (400 MHz, C D C I 3 ) 6: 0.70 and 0.90 ( d , d , 3H each, -CHMe 2 , J - 7 Hz each) , 1 .04-1.17 (m, 2H), 1.20 ( s , 3H, C H 3 C ( 0 H ) - ) , 1 .35-1 .63 (m, 7H), 1 .77-1.87 (m, 3H), 1.96 (broad q, 1H, H A , J - 11 Hz), 0 2.19 ( s , 3H, C H 3 C - ) , 2.66 (d of d of d , 1H, H Y , 1 - 6 , 9, 11 H z ) . 1 3 C nmr (75.6 MHz, C D C I 3 ) 6: 15.6 ( q ) , 20.3 ( q ) , 22.0 ( q ) , 23.0 ( t ) , 25.3 ( t ) , 28.6 ( t ) , 29.6 ( q ) , 29.7 ( d ) , 42 .1 ( t ) , 46.7 ( d ) , 49.5 ( d ) , 55.8 - 214 -( d ) , 57.0 ( d ) , 73.1 ( s ) , 211.5 ( s ) . The chemica l s h i f t s and the m u l t i p l i c i t i e s r e p o r t e d above were d e r i v e d from the p r o t o n no ise decoupled and the o f f - r e s o n a n c e decoupled 1 3 C nmr s p e c t r a , r e s p e c t i v e l y . Exact Mass c a l c d . f o r C 1 5 H 2 6 0 2 : 238.1934; found: 238.1932. Compound (257) e x h i b i t e d t i c p r o p e r t i e s and s p e c t r a [*H nmr (400 MHz), i r ] i n agreement w i t h those r e p o r t e d f o r ( - ) - o p l o p a n o n e . 8 4 A l s o , the mp of our s y n t h e t i c m a t e r i a l was v e r y c l o s e to those r e p o r t e d ( 1 0 1 . 5 - 1 0 2 ° C 9 0 , 9 7 - 9 8 ° C 9 1 ) f o r ( ± ) - ( 2 5 7 ) . Genera l Procedure 10: P r e p a r a t i o n o f l - A l k y n - 3 - o l s (108) To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of a c e t y l e n e (~ 1.6 g , 60 mmol) i n 100 mL o f d r y THF was added a s o l u t i o n o f n - b u t y l l i t h i u m i n hexane (35.3 mL, 55 mmol) over a 10 min p e r i o d . 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 15 min and a s o l u t i o n o f the a p p r o p r i -ate aldehyde (50 mmol) i n 8 mL o f dry THF was added dropwise over a 5 min p e r i o d . 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 30 min and then f o r 1 h w i t h the bath removed. Water (40 mL) was added, f o l l o w e d by anhydrous potass ium carbonate u n t i l the aqueous phase became p a s t y . The organic phase was decanted and the aqueous l a y e r was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined o r g a n i c e x t r a c t was d r i e d (MgSO^) and c o n c e n t r a t e d . The r e m a i n i n g o i l was d i s t i l l e d under reduced p r e s s u r e t o a f f o r d the - 215 -c o r r e s p o n d i n g e t h y n y l c a r b i n o l (108) . P r e p a r a t i o n of l - N o n y n - 3 - o l (332) F o l l o w i n g g e n e r a l procedure 10, h e p t a n a l (328) (5.71 g , 50 mmol) was c o n v e r t e d i n t o l - n o n y n - 3 - o l . Normal workup, 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 85-95°C/17 T o r r ) o f the crude o i l , a f f o r d e d 4.86 g (69%) o f (332) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3312, 2200, 1125, 628 c m " 1 ; lti nmr (300 MHz, CDC1 3) 5: 0.90 ( t , 3H, C H 3 C H 2 - , J - 7 H z ) , 1 .20-1 .50 (m, 8H), 1 .60-1.85 (m, 3H), 2.47 (broad s , I H , sCH), 4.34 (broad s , I H , -CHOH). Exact Mass c a l c d f o r C 9 H 1 6 0 : 140.1202; f o u n d : 140.1194. P r e p a r a t i o n of l - C y c l o p r o p y l - 2 - p r o p y n - l - o l (335) F o l l o w i n g g e n e r a l procedure 10, cyc lopropanecarbaldehyde (331) • L / : u (1 .0 g , 14.3 mmol) was a l l o w e d to r e a c t w i t h a s o l u t i o n of monol i th ium a c e t y l i d e (16 mmol) i n 40 mL of dry THF. D i s t i l l a t i o n 216 ( a i r - b a t h temperature 35-50°C/19 T o r r ) o f the o i l o b t a i n e d a f t e r workup a f f o r d e d 1.014 g (74%) of (335) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3305, 3086, 2116, 1030, 652 c m " 1 ; * H nmr (270 MHz, C D C l 3 ) 5 : 0 .40-0 .63 (m, 4H) , 1 .18-1 .30 (m, 1H, c y c l o p r o p y l methine p r o t o n ) , 2.06 (broad s , 1H, exchanges w i t h D 2 0 , -OH), 2.43 (d , 1H, ^ C H , J = 3 H z ) , 4 .20 (d of d , 1H, -CH(OH), J = 3, 7 H z ) . Exact Mass c a l c d . f o r CgHyO (M+-H): 95.0497; f o u n d : 95.0494. P r e p a r a t i o n of 5 -Methoxymethoxy- l -pentyn-3 -o l (333) F o l l o w i n g g e n e r a l procedure 1 0 , 3-(methoxymethoxy)propanal (329)* (5 .9 g , 50 mmol) was conver ted i n t o 5.371 g (75%) o f the c a r b i n o l ( 3 3 3 ) ( a i r - b a t h d i s t i l l a t i o n temperature 9 0-100 ° C / 1 7 T o r r ) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3290, 2114, 1151, 1039, 667 c m ' 1 ; X H nmr (80 MHz, C D C I 3 ) 5: 2 . 0 0 (q , 2 H , - C H 2 C H 2 0 - , J - 7 H z ) , 2 . 4 8 ( d , 1 H , - C H , J - 2 H z ) , 3 . 0 5 (d , 1 H , exchanges w i t h D 2 0 , -OH, J - 7 H z ) , 3 . 4 0 ( s , 3 H , - O C H 3 ) , 3 . 7 8 (broad t , 2 H , - C H 2 C H 2 0 - , J = 7 H z ) , 4 .45 -4 .60 (m, 1 H , -CH(OH)), 4 .65 ( s , 2 H , - 0 C H 2 0 - ) . Exact Mass c a l c d . f o r C 7 H 1 1 0 3 (M+-H): 143.0708; found: 143.0706. We are g r a t e f u l to Mr . P e t e r Marrs f o r a generous s u p p l y of (329). 217 P r e p a r a t i o n of 6 - H e p t e n - l - y n - 3 - o l (334) H F o l l o w i n g g e n e r a l procedure 10, 4 - p e n t e n a l (330)l^i- (1 .0 g, 12 mmol) was a l l o w e d to r e a c t w i t h a s o l u t i o n o f monol i th ium a c e t y l i d e (18 mmol) i n 40 mL of dry THF. D i s t i l l a t i o n ( a i r - b a t h temperature 4 5 - 6 5 ° C / 19 T o r r ) o f the crude product o b t a i n e d a f t e r workup p r o v i d e d 964.9 mg (74%) of (334) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3304, 3079, 2116, 1642, 1025, 916, 655 c m ' 1 ; X H nmr (80 MHz, CDC1 3) 6: 1 .75-1 .95 (m, 2H, - C H 2 C H ( 0 H ) - ) , 2 .12-2 .32 (m, 3H), 2.48 ( d , I H , - C H , J - 2 H z ) , 4 .40 (d of t , I H , -CH(OH)- , J - 2, 7 H z ) , 5.01 ( t o f d , I H , Hg, J - 1, 10 H z ) , 5.07 ( t o f d , I H , H A , 2 - 1 , 17 H z ) , 5.85 ( t o f d o f d , I H , H x , J - 7 , 10, 17 H z ) . Exact Mass c a l c d . f o r C 7 H 9 0 (M+-H) : 109.0654; f o u n d : 109.0657. Genera l Procedure 11 : A d d i t i o n o f the ( T r i m e t h y l s t a n n y l ) c o p p e r Reagent (84) t o l - A l k y n - 3 - o l s (108) i n the Presence o f M e t h a n o l . P r e p a r a t i o n of 2 - T r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l s (109) and ( E ) - l - T r i m e t h y l s t a n n y l - l -a l k e n - 3 - o l s (339) R - ^ H X Me3SnCu.Me2: 1 0 9 8 4 To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n of the ( t r i m e t h y l s t a n n y l ) c o p p e r - 218 -reagent (84) (3 mmol) i n 24 mL of dry THF was added a THF s o l u t i o n (1 mL) o f the a p p r o p r i a t e l - a l k y n - 3 - o l (108) (2 mmol) f o l l o w e d by anhydrous methanol (4.05 mL, 100 mmol). The dark r e d s o l u t i o n was s t i r r e d at -78°C f o r 2 .5 h and a t 0°C f o r 1 h . S a t u r a t e d aqueous ammonium c h l o r i d e (pH 8) (5 mL) and e ther (20 mL) were added and the m i x t u r e was a l l o w e d to warm to room temperature w i t h v i g o r o u s s t i r r i n g . S t i r r i n g was m a i n t a i n e d u n t i l the aqueous phase became deep b l u e and the o r g a n i c phase became c l e a r . The l a y e r s were separated and the aqueous phase was e x t r a c t e d t h o r o u g h l y w i t h e t h e r . The combined o r g a n i c s o l u t i o n was washed w i t h s a t u r a t e d aqueous ammonium c h l o r i d e (pH 8 ) , d r i e d (MgSO^), and c o n c e n t r a t e d . S u b j e c t i o n o f the r e s i d u e to f l a s h chromatography on s i l i c a g e l , c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s and b u l b - t o - b u l b d i s t i l l a t i o n o f the crude products thus o b t a i n e d a f f o r d e d the c o r r e -sponding 2 - t r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l (109) and ( E ) - 1 - t r i m e t h y l -s t a n n y l - 1 - a l k e n e - 3 - o l (339) . Genera l Procedure 12: A d d i t i o n of the ( T r i m e t h y l s t a n n y l ) z i n c Reagent (355) o r (356) t o l - A l k y n - 3 - o l s i n the Presence of Cuprous Cyanide . P r e p a r a t i o n o f 2 - T r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l s (109) and/or ( E ) - l - T r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l s (339) 355 356 S o l i d cuprous cyanide (3 .6 mg, 0.04 mmol) and a THF (1.5 mL) - 219 s o l u t i o n o f the a p p r o p r i a t e l - a l k y n - 3 - o l (108) (1 mmol) were added s u c c e s s i v e l y to a c o l d ( - 2 0 ° C ) , s t i r r e d s o l u t i o n o f the ( t r i m e t h y l s t a n -n y l ) z i n c reagent (355) or (356) (2 mmol) i n 10 mL o f d r y THF. The r e s u l t i n g orange s o l u t i o n was s t i r r e d a t -20°C f o r 1 h and a t 0°C f o r 1 h . S a t u r a t e d aqueous ammonium c h l o r i d e (pH 8) (4 mL) and e t h y l acetate (15 mL) were added and the mixture was a l l o w e d to warm to room tempera-t u r e w i t h v i g o r o u s s t i r r i n g . S t i r r i n g was m a i n t a i n e d u n t i l the aqueous phase became deep b l u e and the o r g a n i c phase became c l e a r . The l a y e r s were separa ted and the aqueous phase was e x t r a c t e d t h o r o u g h l y w i t h e t h y l a c e t a t e . The combined o r g a n i c e x t r a c t was washed (water , b r i n e ) , d r i e d (MgS04), and c o n c e n t r a t e d . S u b j e c t i o n of the r e s i d u e t o f l a s h chroma-tography on s i l i c a g e l , c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s and d i s t i l l a t i o n o f the crude products thus o b t a i n e d p r o v i d e d the c o r r e -sponding 2 - t r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l (109) and ( E ) - 1 - t r i m e t h y l -s t a n n y l - l - a l k e n e - 3 - o l (339) . P r e p a r a t i o n of 3 - T r i m e t h y l s t a n n y l - 3 - b u t e n - 2 - o l (337) and ( E ) - 4 - T r i m e t h y l s t a n n y l - 3 - b u t e n - 2 - o l (338) a) V i a Genera l Procedure 11 , Reagent (84) (Me3SnCu.Me2S) F o l l o w i n g g e n e r a l procedure 11, 3 - b u t y n - 2 - o l (336) (140 mg, 2 mmol) 3 3 7 3 3 8 - 220 was c o n v e r t e d i n t o a mixture of the v i n y l s t a n n a n e s (337) and (338). The crude m i x t u r e was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h petro leum e t h e r - e t h y l a c e t a t e , 1 9 : 1 ) . The major , l e s s p o l a r p r o d u c t was i s o l a t e d by removal of s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 65-75°C/17 T o r r ) o f the r e s i d u e . The c o l o r l e s s o i l thus o b t a i n e d (244.2 mg, 52%) was i d e n t i f i e d as the o l e f i n i c a l c o h o l (337) ; i r ( f i l m ) : 3353, 3040, 1067, 923, 770 c m ' 1 ; X H nmr (80 MHz, C D C 1 3 ) 6: 0 .20 ( s , 9H, -SnMe 3 , i S n - H - 5 4 H z ) . 1 - 2 5 ( d . 3 H » C H 3 C H - , J - 7 H z ) , 1.62 ( d , I H , exchanges w i t h D 2 0 , -OH, J - 6 H z ) , 4 .30 -4 .55 (m, I H , - C H ( O H ) - ) , 5.20 (d o f d , I H , H A , J - 2 ,3 H z , J S n . H - 72 H z ) , 5.75 (d o f d , I H , H x , J - 2 , 3 H z , J S n . H - 143 H z ) . Exact Mass c a l c d . f o r C 6 H 1 3 O S n (M+-CH3): 220.9989; found: 221.0001. The minor , more p o l a r product was o b t a i n e d by d i s t i l l a t i o n ( a i r -b a t h temperature 80-90 e C/17 T o r r ) o f the o i l d e r i v e d from c o n c e n t r a t i o n of the a p p r o p r i a t e column f r a c t i o n s . T h i s m a t e r i a l (81.4 mg, 17%), a c o l o r l e s s o i l , was i d e n t i f i e d as the a l c o h o l (338) ; i r ( f i l m ) : 3339, 1605, 1059, 989, 769 c m - 1 ; X H nmr (80 MHz, CDC1 3) 5: 0.15 ( s , 9H, -SnMe 3 , J S n _ H = 56 H z ) , 1.25 ( d , 3H, - C H 3 , J - 7 H z ) , 1.83 (broad s , I H , exchanges w i t h D 2 0 , -OH), 4 .10 -4 .35 (m, I H , - C H ( O H ) - ) , 5 .85-6 .37 (m, 2H, o l e f i n i c p r o t o n s , J_sn_H •= 72 and 79 H z ) . Exact Mass c a l c d . f o r C^H^OSn (M+-CH3): 220.9989; found: 220.9990. - 221 b) V i a Genera l Procedure 12, Reagent (355) { [Me3SnZn(t -Bu) 2 ]Li> F o l l o w i n g g e n e r a l procedure 12, 3 - b u t y n - 2 - o l (336) (70 mg, 1 mmol) was a l l o w e d to r e a c t w i t h the ( t r i m e t h y l s t a n n y l ) z i n c reagent (355) (2 mmol) i n the presence o f cuprous cyanide (3.6 mg, 0.04 mmol). Workup, p r o d u c t s e p a r a t i o n , and d i s t i l l a t i o n s as d e s c r i b e d above y i e l d e d 129.3 mg (55%) of (337) and 28.4 mg (12%) o f (338) . These m a t e r i a l s e x h i b i t e d i r and nmr s p e c t r a i d e n t i c a l w i t h those d e s c r i b e d above. c) V i a Genera l Procedure 12, Reagent (356) [ ( M e 3 S n Z n E t 2 ) L i ] Genera l procedure 12 was f o l l o w e d . Thus, t reatment o f 3 - b u t y n - 2 - o l (336) (70 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) z i n c reagent (356) (2 mmol) i n the presence o f cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 18.9 mg (8%) of (337) and 152.9 mg (65%) o f (338) . The i d e n t i t y o f these m a t e r i a l s was c o n f i r m e d by a n a l y s i s ( g l c and t i c ) and s p e c t r a ( i r , * H nmr) . - 222 P r e p a r a t i o n of 2 - T r i m e t h y l s t a n n y l - l - n o n e n - 3 - o l (340) and ( E ) - l - T r i m e t h y l s t a n n y l - l - n o n e n - 3 - o l (344) H-C eH 1 3 n-C6Hi3-' ~ ^ r ? H M H .SnMe 3 340 344 a) V i a G e n e r a l Procedure 11 , Reagent (84) (Me3SnCu.Me 2S) F o l l o w i n g g e n e r a l procedure 11, l - n o n y n - 3 - o l (332) (280 mg, 2 mmol) was c o n v e r t e d i n t o a mix ture of the v i n y l s t a n n a n e s (340) and (344) . The crude m i x t u r e was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h pet ro leum e t h e r - e t h y l a c e t a t e , 1 9 : 1 ) . The major , l e s s p o l a r product was p u r i f i e d by d i s t i l l a t i o n ( a i r -b a t h temperature 7 5 - 9 0 ° C / 0 . 2 T o r r ) o f the r e s i d u a l m a t e r i a l d e r i v e d from c o n c e n t r a t i o n o f the a p p r o p r i a t e column f r a c t i o n s . T h i s m a t e r i a l (262.9 mg, 43%), a c o l o r l e s s o i l , was i d e n t i f i e d as the o l e f i n i c a l c o h o l (340); i r ( f i l m ) : 3373, 1039, 925, 769 c m - 1 ; X H nmr (270 MHz, C D C l 3 ) 6": 0.18 ( s , 9H, -SnMe 3 , J _ S n _ H - 54 H z ) , 0.87 (broad t , 3H, C H 3 C H 2 - , J - 7 H z ) , 1 .23-1 .33 (m, 7H), 1 .38-1.60 (m, 3H), 4 .16 -4 .25 (m, 1H, - C H ( O H ) - ) , 5.23 (d of d , 1H, H A , J - 2 , 2 H z , J S n . H - 71 H z ) , 5.73 (d of d , 1H, H x , J = 2, 2 H z , J S n _ H ~ 1 4 5 H z >- Exact Mass c a l c d . f o r C 1 1 H 2 3 0 S n ( M + - C H 3 ) : 291.0771; f o u n d : 291.0752. The minor , more p o l a r product was o b t a i n e d by removal o f s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 8 0 - 9 5 ° C / 0 . 2 T o r r ) o f the r e s i d u a l m a t e r i a l . The c o l o r l e s s o i l o b t a i n e d (135.6 mg, 22%) was i d e n t i f i e d as the o l e f i n i c a l c o h o l - 223 -(344) ; i r ( f i l m ) : 3338, 990, 769 c m " 1 ; X H nmr (270 MHz, CDC1 3) 6: 0.15 ( s , 9H, -SnMe 3 , J S n . H - 56 H z ) , 0.87 (broad t , 3H, C H 3 C H 2 - , J - 7 H z ) , 1 .25-1 .35 (m, 7H), 1 .47-1.54 (m, 3H), 4 .02-4 .08 (m, I H , - C H ( O H ) - ) , 6.01 (d o f d , I H , H L , J = 5, 19 H z , J S n - H - 73 H z ) , 6.18 (d o f d , I H , H M J - 1, 19 H z , J S n _ H - 81 H z ) . Exact Mass c a l c d . f o r C 1 1 H 2 3 0 S n (M+-CH3): 291.0771; f o u n d : 291.0771. b) V i a Genera l Procedure 12, Reagent (355) { [ M e 3 S n Z n ( t - B u ) 2 ] L i } Genera l procedure 12 was f o l l o w e d . Thus, t reatment of 1 - n o n y n - 3 - o l (332) (140 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) z i n c reagent (355) (2 mmol) i n the presence o f cuprous cyanide (3 .6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 161.5 mg (53%) o f (340) and 53.4 mg (17%) o f (344) . These m a t e r i a l s were i d e n t i f i e d on the b a s i s of t h e i r g l c and t i c p r o p e r t i e s and t h e i r s p e c t r a ( i r and ^H nmr) . c) V i a Genera l Procedure 12, Reagent (356) [ ( M e 3 S n Z n E t 2 ) L i ] Genera l procedure 12 was f o l l o w e d . Thus treatment o f 1 - n o n y n - 3 - o l (332) (140 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) z i n c reagent (356) (2 mmol) i n the presence of cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 3.9 mg (1%) of (340) and 192.7 mg (63%) o f (344) . These - 224 m a t e r i a l s were i d e n t i f i e d on the b a s i s o f t h e i r chromatographic proper -t i e s ( t i c , g l c ) and t h e i r s p e c t r a ( i r , nmr) . P r e p a r a t i o n of l - C y c l o p r o p y l - 2 - t r i m e t h y l s t a n n y l - 2 - p r o p e n - l - o l (343) and ( E ) - l - C y c l o p r o p y l - 3 - t r i m e t h y l s t a n n y l - 2 - p r o p e n - l - o l (347) a) V i a G e n e r a l Procedure 11, Reagent (84) (Me 3SnCu.Me2S) F o l l o w i n g g e n e r a l procedure 11, l - c y c l o p r o p y l - 2 - p r o p y n - l - o l (335) (192 mg, 2 mmol) was conver ted i n t o a m i x t u r e of the v i n y l s t a n n a n e s (343) and (347) . The crude mix ture was s u b j e c t e d to f l a s h chromato-graphy on s i l i c a g e l (18 g , e l u t i o n w i t h petro leum e t h e r - e t h y l a c e t a t e , The major , l e s s p o l a r product was p u r i f i e d by d i s t i l l a t i o n ( a i r -b a t h temperature 4 5 - 5 5 ° C / 0 . 2 T o r r ) o f the r e s i d u a l m a t e r i a l d e r i v e d from c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s . T h i s m a t e r i a l (183.0 mg, 35%), a c o l o r l e s s o i l , was i d e n t i f i e d as the o l e f i n i c a l c o h o l (343); i r ( f i l m ) : 3413, 3080, 3006, 1028, 925, 770 c m " 1 ; X H nmr (400 MHz, CDC1 3) 6: 0 .20 ( s , 9H, -SnMe.3, J S n . H - 52 H z ) , 0 .24-0 .30 (m, IH) , 0 .36-0 .42 (m, I H ) , 0 .52-0 .60 (m, 2H), 0 .92-1 .01 (m, I H ) , 1.68 ( s , I H , exchanges w i t h D 2 0 , -OH) , 3.48 (d of d of d , I H , -CH(OH)- , J - 1, 1, 8 H z ) , 5.26 (d of d , I H , H A , J - 1, 2 H z , J S n . H * 7 1 H z )> 5.83 (d o f d , I H , H x , J - 1, 2 343 347 9 : 1 ) . - 225 -H z> ^ S n - H " 1 4 3 H z >- Exact Mass c a l c d . f o r C g H 1 5 0 S n ( M + - C H 3 ) : 247.0144; found: 247.0147. The minor , more p o l a r product was obta ined by removal of s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 5 5 - 6 5 ° C / 0 . 2 T o r r ) o f the r e s i d u a l m a t e r i a l . The c o l o r l e s s o i l o b t a i n e d (151.6 mg, 29%) was i d e n t i f i e d as the o l e f i n i c a l c o h o l (347) ; i r ( f i l m ) : 3337, 3080, 1024, 990, 764 c m " 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 0 .10 ( s , 9 H , -SnMe 3 , I S n . H - 56 H z ) , 0 .24-0 .38 (m, 2H), 0 .51-0 .60 (m, 2H), 0 .92-1 .03 (m, 1H), 1.65 ( d , 1H, exchanges w i t h D 2 0 , -OH, J - 6 H z ) , 3 .42-3 .50 (m, 1H, - C H ( O H ) - ) , 6.09 (d o f d , 1H, H L , J -5, 19 H z , J _ S n _ H - 72 H z ) , 6.25 (d o f d , 1H, H M , J - 1, 19 H z , J S n . H - 80 H z ) . Exact Mass c a l c d . f o r C 8 H 1 5 O S n ( M + - C H 3 ) : 247.0144; found: 247.0140. b) V i a Genera l Procedure 12, Reagent (355) { [Me3SnZn( t -Bu) 2 ]L I ) G e n e r a l procedure 12 was f o l l o w e d . Thus treatment of 1 - c y c l o -p r o p y l - 2 - p r o p y n - l - o l (335) (96 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) -z i n c reagent (355) (2 mmol) i n the presence o f cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 100.3 mg (38%) o f (343) and 89.1 mg (34%) of (347) . These m a t e r i a l s were i d e n t i f i e d on the b a s i s o f t h e i r chromatographic p r o p e r t i e s ( t i c , g l c ) and t h e i r s p e c t r a ( i r , ^H nmr). - 226 -c) V i a Genera l Procedure 12, Reagent (356) [(Me3SnZnEt£)Li] Genera l procedure 12 was f o l l o w e d . Thus treatment o f 1 - c y c l o -p r o p y l - 2 - p r o p y n - l - o l (335) (96 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) -z i n c reagent (356) (2 mmol) i n the presence of cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 26.9 mg (10%) o f (343) and 151.2 mg (58%) of (347) . These m a t e r i a l s were i d e n t i f i e d on the b a s i s o f t h e i r chromatographic p r o p e r t i e s ( t i c , g l c ) and t h e i r s p e c t r a ( i r , nmr) . P r e p a r a t i o n of 5 - M e t h o x y m e t h o x y - 2 - t r i m e t h y l s t a n n y l - l - p e n t e n - 3 - o l (341) and ( E ) - 5 - M e t h o x y m e t h o x y - l - t r i m e t h y l s t a n n y l - l - p e n t e n - 3 - o l (345) M e ^ S n w H A H ^ S n M e 3 M 0 M 0 C H 2 C H 2 - H ^ H x M O M O C H . C H , - ^ ^ 341 3 4 5 a) V i a Genera l Procedure 11, Reagent (84) (Me3SnCu.Me2S) F o l l o w i n g g e n e r a l procedure 11 , 5 - m e t h o x y m e t h o x y - l - p e n t y n - 3 - o l (333) (288 mg, 2 mmol) was conver ted i n t o a mix ture of the v i n y l -stannanes (341) and (345). The crude mix ture was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h pet ro leum e t h e r - e t h y l a c e t a t e , 4 : 1 ) . The major , l e s s p o l a r product was p u r i f i e d by d i s t i l l a t i o n ( a i r -b a t h temperature 7 5 - 8 5 ° C / 0 . 2 T o r r ) of the r e s i d u a l m a t e r i a l d e r i v e d f r o m 227 c o n c e n t r a t i o n of the a p p r o p r i a t e f r a c t i o n s . T h i s m a t e r i a l (255 .1 mg, 41%), a c o l o r l e s s o i l , was i d e n t i f i e d as the o l e f i n i c a l c o h o l (341); i r ( f i l m ) : 3474, 1150, 1044, 921, 771 c m " 1 ; X H nmr (270 MHz, C D C 1 3 ) 6": 0.13 ( s , 9H, -SnMe 3 , I S n . H - 55 H z ) , 1 .67-1.74 (m, 2H, - C H 2 C H 2 0 - ) , 2.64 (d, 1 H , exchanges w i t h D 2 0 , -OH, J - 6 H z ) , 3.33 ( s , 3H, - O C H 3 ) , 3 .60-3 .73 (m, 2H, - C H 2 C H 2 0 - ) , 4 .36-4 .46 (m, 1H, -CH(OH)- ) , 4 .58 ( s , 2H, - 0 C H 2 0 - ) , 5.22 (broad s, 1H, H A , J S n - H " 7 2 H z >- 5 • 7 4 (broad s , 1H, H x , J S n - H = 146 H z ) . Exact Mass c a l c d . f o r C 9 H 1 9 0 3 S n ( M ^ - C ^ ) : 295.0356; found: 295.0360. The m i n o r , more p o l a r product was o b t a i n e d by removal o f s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 9 0 - 1 0 0 ° C / 0 . 2 T o r r ) o f the r e s i d u a l m a t e r i a l . The c o l o r l e s s o i l o b t a i n e d (186.7 mg, 30%) was i d e n t i f i e d as the o l e f i n i c a l c o h o l (345); i r ( f i l m ) : 3428, 1151, 1044, 990, 921, 769 c m " 1 ; X H nmr (270 MHz, C D C I 3 ) 6: 0.13 ( s , 9H, -SnMe 3 , J S n - H ~ 5 5 H z > . 1 .70-1 .90 (m, 2H, - C H 2 C H 2 0 - ) , 2.46 ( d , 1H, exchanges w i t h D 2 0 , -OH, J - 5 H z ) , 3.35 ( s , 3H, - O C H 3 ) , 3 .60-3 .77 (m, 2H, - C H 2 C H 2 0 - ) , 4 .22-4 .32 (m, 1H, -CH(OH)- ) , 3.60 ( s , 2H, - 0 C H 2 0 - ) , 6.02 (d of d , 1H, H L , J - 5 , 19 H z , J S n . H = 74 H z ) , 6.25 (broad d , 1H, H M , J - 19 H z , J S n - H = 8 0 H z ) • Exact Mass c a l c d . f o r C 9 H 1 9 0 3 S n ( M + - C H 3 ) : 295.0356; found: 295.0353. b) V i a Genera l Procedure 12, Reagent (355) { [ M e 3 S n Z n ( t - B u ) 2 ] L i } Genera l procedure 12 was f o l l o w e d . Thus treatment o f 5-methoxy-m e t h o x y - l - p e n t y n - 3 - o l (333) (144 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) -- 228 -z i n c reagent (355) (2 mmol) i n the presence of cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 157.8 mg (51%) o f (341) and 55.5 mg (18%) o f (345) . These m a t e r i a l s were i d e n t i f i e d on the b a s i s o f t h e i r chromatographic p r o p e r t i e s ( t i c , g l c ) and t h e i r s p e c t r a ( i r , nmr) . c) V i a Genera l Procedure 12, Reagent (356) [ ( M e 3 S n Z n E t 2 ) L i ] Genera l procedure 12 was f o l l o w e d . Thus treatment o f 5-methoxy-m e t h o x y - l - p e n t y n - 3 - o l (333) (144 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) -z i n c reagent (356) (2 mmol) i n the presence of cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 12.5 mg (4%) o f (341) and 195.2 mg (63%) of (345) . These m a t e r i a l s were i d e n t i f i e d on the b a s i s o f t h e i r chromato-g r a p h i c p r o p e r t i e s ( t i c , g l c ) and t h e i r s p e c t r a ( i r , * H nmr) . P r e p a r a t i o n o f 2 - T r i m e t h y l s t a n n y l - l , 6 - h e p t a d i e n - 3 - o l (342) and ( E ) - l - T r i m e t h y l s t a n n y l - l , 6 - h e p t a d i e n - 3 - o l (346) 342 346 - 229 a) V i a Genera l Procedure 11, Reagent (84) (Me 3 SnCu.Me 2 S) F o l l o w i n g g e n e r a l procedure 11, 6 - h e p t e n - l - y n - 3 - o l (334) (220 mg, 2 mmol) was conver ted i n t o a mix ture of the v i n y l s t a n n a n e s (342) and (346) . The crude mix ture was s u b j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h petroleum e t h e r - e t h y l a c e t a t e , 9 : 1 ) . The major , l e s s p o l a r p r o d u c t was p u r i f i e d by d i s t i l l a t i o n ( a i r -b a t h temperature 5 0 - 6 0 ° C / 0 . 2 T o r r ) o f the r e s i d u a l m a t e r i a l d e r i v e d from c o n c e n t r a t i o n of the a p p r o p r i a t e f r a c t i o n s . T h i s m a t e r i a l (238.0 mg, 43%), a c o l o r l e s s o i l , was i d e n t i f i e d as the o l e f i n i c a l c o h o l (342); i r ( f i l m ) : 3387, 3078, 1014, 913, 769 c m - 1 ; X H nmr (300 MHz, CDC1 3) 6: 0.20 ( s , 9H, -SnMe 3 , J S n _ H - 54 H z ) , 1 .50-1.72 (m, 3H), 2 .05-2 .21 (m, 2H, - C H 2 C - ) , 4 .28 (broad t , 1H, -CH(OH)- , J - 7 H z ) , 5.00 (q of d , 1H, H G , J - 2 , 10 H z ) , 5.06 (q o f d , 1H, Hp, J - 2 , 18 H z ) , 5.27 (d o f d , 1H, H A , J - 1, 2 H z , J S n - H " 7 6 H z >- 5 - 7 8 <d o f d . 1H> H X - I " 1. 2 H z . Isn-H " 152 H z ) , 5.86 ( t o f d of d , 1H, H T , J - 7, 10, 18 H z ) . Exact Mass c a l c d . f o r C 9 H 1 7 O S n ( M + ' C H ^ : 261.0301; found: 261.0309. The minor , more p o l a r product was o b t a i n e d by removal o f s o l v e n t from the a p p r o p r i a t e f r a c t i o n s , f o l l o w e d by d i s t i l l a t i o n ( a i r - b a t h temperature 6 5 - 7 5 ° C / 0 . 2 T o r r ) o f the r e s i d u a l m a t e r i a l . The c o l o r l e s s o i l o b t a i n e d (158.9 mg, 29%) was i d e n t i f i e d as the o l e f i n i c a l c o h o l (346) ; i r ( f i l m ) : 3335, 3078, 991, 911, 769 c m " 1 ; X H nmr (300 MHz, CDC1 3) 6: 0.14 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 1 .58-1.69 (m, 3H), 2 .08-2 .23 (m,2H), 4 .05 -4 .17 (m, 1H, - C H ( 0 H ) - ) , 4 .98 (broad d , 1H, H G , J - 10 H z ) , 5.07 (broad d , 1H, Hp, J - 17 H z ) , 5.85 ( t o f d of d , 1H, H T , J - 7, 10, 17 H z ) , 6.02 (d of d , 1H, H L , J - 6, 18 H z , I S n . H - 7 5 H z ) > 230 -6.18 (d , I H , % , J - 18 Hz , J S n _ H " 8 0 H z ) - Exact Mass c a l c d . f o r C 9 H 1 7 O S n (M+-CH3): 261.0301; found: 261.0306. b) V i a Genera l Procedure 12, Reagent (355) { [ M e 3 S n Z n ( t - B u ) 2 ] L i ) Genera l procedure 12 was f o l l o w e d . Thus treatment of 6 - h e p t e n - l -y n - 3 - o l (334) (110 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) z i n c reagent (355) (2 mmol) i n the presence o f cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 118.0 mg (43%) of (342) and 55.7 mg (20%) of (346). These m a t e r i a l s were i d e n t i f i e d on the b a s i s o f t h e i r chromatographic p r o p e r t i e s ( t i c , g l c ) and t h e i r s p e c t r a ( i r , * H nmr) . c) V i a Genera l Procedure 12, Reagent (356) [ ( M e 3 S n Z n E t 2 ) L i ] Genera l procedure 12 was f o l l o w e d . Thus treatment o f 6 - h e p t e n - l -y n - 3 - o l (334) (110 mg, 1 mmol) w i t h the ( t r i m e t h y l s t a n n y l ) z i n c . r e a g e n t (356) (2 mmol) i n the presence o f cuprous cyanide (3.6 mg, 0.04 mmol), f o l l o w e d by workup, f l a s h chromatography, and d i s t i l l a t i o n s as d e s c r i b e d above, a f f o r d e d 17.4 mg (6%) of (342) and 175.8 mg (64%) o f (346). These m a t e r i a l s were i d e n t i f i e d on the b a s i s o f t h e i r chromatographic p r o p e r t i e s ( t i c , g l c ) and t h e i r s p e c t r a ( i r , ^H nmr) . 231 Genera l procedure 13: Orthoacetate -Based C l a i s e n Rearrangements. P r e p a r a t i o n of E t h y l ( Z ) - 4 - T r i m e t h y l s t a n n y l - 4 - a l k e n o a t e s (357) or E t h y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 4 - a l k e n o a t e s (363) 357 363 A m i x t u r e o f the a p p r o p r i a t e 2 - t r i m e t h y l s t a n n y l - l - a l k e n - 3 - o l (109) [or ( E ) - 1 - t r i m e t h y l s t a n n y l - 1 - a l k e n - 3 - o l (339)] (0.5mmol) , t r i e t h y l o r t h o - a c e t a t e (642 fiL, 3.5 mmol) and propanoic a c i d (2 .3 f*L, 0.03 mmol) was heated a t 135-140°C f o r 2.5 h w i t h d i s t i l l a t i v e removal o f e t h a n o l . A f t e r the mix ture had been c o o l e d to room temperature , i t was t r e a t e d w i t h 25 mL o f aqueous potass ium dihydrogen phosphate (5%) and then s t i r r i n g was c o n t i n u e d f o r 30 m i n . The mix ture was e x t r a c t e d thoroughly w i t h e t h e r . The e ther e x t r a c t was washed ( s a t u r a t e d aqueous sodium b i c a r b o n a t e , w a t e r , b r i n e ) and d r i e d (MgS0 4 ) . S o l v e n t removal and d i s t i l l a t i o n of 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 the c o r r e s p o n d i n g C l a i s e n rearrangement p r o d u c t (357) [or (363) ] . P r e p a r a t i o n of E t h y l ( Z ) - 4 - T r i m e t h y l s t a n n y l - 4 - h e x e n o a t e (358) ^ ,SnMe3 :o2Et F o l l o w i n g g e n e r a l procedure 13, 3 - t r i m e t h y l s t a n n y l - 3 - b u t e n - 2 - o l - 232 -(337) (236 mg, 1 mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (1.28 mL, 7 mmol) and propanoic a c i d (4.5 / i L , 0.06 mmol) a t 135-140°C f o r 2.5 h under c o n d i t i o n s f o r d i s t i l l a t i v e removal o f e t h a n o l . Normal workup and d i s t i l l a t i o n ( a i r - b a t h temperature 5 5 - 6 5 ° C / 0 . 2 T o r r ) o f the r e s i d u a l o i l p r o v i d e d 250.0 mg (82%) of a c o l o r l e s s o i l which was i d e n t i f i e d as the e s t e r (358) ; i r ( f i l m ) : 1736, 1624, 1371, 1163, 1044, 770 c m " 1 ; 1 H nmr (80 MHz, CDC1 3) 6: 0.23 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 1.25 ( t , 3H, - C H 2 C H 3 , J = 7 H z ) , 1.70 ( d , 3H, CH 3C=, J = 6 H z ) , 2 .20-2 .55 (m, 4H), 4 .10 (q , 2H, - C H 2 C H 3 , J - 7 H z ) , 6.10 (q , 1H, o l e f i n i c p r o t o n , J - 6 Hz , J.Sn-H " 1 4 0 H z ) - Exact Mass c a l c d . f o r C 1 0 H 1 9 O 2 S n (M+-CH;}) : 291.0407; f o u n d : 291.0416. P r e p a r a t i o n of E t h y l (Z)-4 -Tr imethyls tannyl-4 -undecanoate (359) F o l l o w i n g g e n e r a l procedure 13, 2 - t r i m e t h y l s t a n n y l - l - n o n e n - 3 - o l (340) (306 mg, 1 mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (1.28 mL, 7 mmol) and propanoic a c i d (4 .5 / i L , 0.06 mmol) a t 135-140°C f o r 2 .5 h w i t h d i s t i l l a t i v e removal o f e t h a n o l . Normal workup, 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 9 5 - 1 0 5 ° C / 0 . 2 T o r r ) o f the crude m a t e r i a l , a f f o r d e d 302.3 mg (80%) of (359) as c o l o r l e s s o i l ; i r ( f i l m ) : 1740, 1621, 1371, 1160, 1040, 770 c m - 1 ; X H nmr (270 MHz, CDC1 3) 5 : 0.18 ( s , 9H, -SnMe 3 , J S n . H - 54 H z ) , 0.87 (broad t , 3H, - C H 2 C H 2 C H 3 , J - 7 H z ) , n-c6H13 SnMe - 233 1 .20-1.36 (m, 11H), 1.96 (q , 2H, - C H 2 C H 2 C H 2 0 , J - 7 H z ) , 2.30 ( t , 2H, J - 7 H z ) , 2.43 ( t , 2H, J - 7 H z ) , 4.08 (q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 6.00 ( t , 1H, o l e f i n i c p r o t o n , J - 7 H z , J_sn_H - 143 H z ) . Exact Mass c a l c d . f o r C 1 5 H 2 9 0 2 S n (M+-CH3): 361.1190; found: 361.1196. P r e p a r a t i o n o f E t h y l ( Z ) - 5 - C y c l o p r o p y l - 4 - t r i m e t h y l s t a n n y l - 4 - p e n t e n o a t e Genera l procedure 13 was used w i t h some m o d i f i c a t i o n . A mix ture of l - c y c l o p r o p y l - 2 - t r i m e t h y l s t a n n y l - 2 - p r o p e n - l - o l (343) (131 mg, 0.5 mmol), t r i e t h y l o r t h o a c e t a t e (1.37 mL, 7.5 mmol) and propanoic a c i d (7 .5 / iL , 0 .1 mmol) was heated a t 135-138°C f o r 3 h , as e t h a n o l was removed by d i s t i l l a t i o n . The crude product o b t a i n e d a f t e r normal workup was s u b j e c t e d t o f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h pet ro leum e t h e r - e t h y l a c e t a t e , 1 9 : 1 ) . D i s t i l l a t i o n ( a i r - b a t h tempera-t u r e 7 5 - 8 5 ° C / 0 . 2 t o r r ) o f the r e s i d u a l m a t e r i a l d e r i v e d from concentra -t i o n of the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 96.8 mg (58%) o f (362) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3082, 1737, 1619, 1181, 1043, 770 c m * 1 ; X H nmr (400 MHz, CDC1 3) 6: 0.23 ( s , 9H, -SnMe 3 , J S n - H " 5 2 H z > . 0 .34-0 .38 and 0 .67-0 .73 (m, m, 2H each, c y c l o p r o p y l methylene p r o t o n s ) , 1 .19-1.25 (m, 1H, c y c l o p r o p y l methine p r o t o n ) , 1.23 ( t , 3H, - C H 3 , J - 7 H z ) , 2.29 ( t , (362) 234 2H, J - 8 H z ) , 2.47 ( t , 2H, J - 8 H z ) , 4 .11 (q , 2H, - C H 2 C H 3 , J - 7 H z ) , 5.39 (broad d , I H , o l e f i n i c p r o t o n , J - 8 H z , lsn-U ~ 1 3 5 H z ) - Exact  Mass c a l c d . f o r C 1 2 H 2 1 0 2 S n (M+-CH3): 317.0563; found: 317.0566. P r e p a r a t i o n o f E t h y l ( Z ) - 7 - M e t h o x y m e t h o x y - 4 - t r i m e t h y l s t a n n y l - 4 -heptenoate (360) MOMOCH2CH2 F o l l o w i n g g e n e r a l procedure 13, 5 -methoxymethoxy-2 - t r imethyl -s t a n n y l - l - p e n t e n - 3 - o l (341) (155 mg, 0.5mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (642 pL, 3 .5 mmol) and propanoic a c i d (2 .3 p L , 0.03 mmol) a t 135-138°C, f o r 2.5 h , as e t h a n o l was removed by d i s t i l l a t i o n . Normal workup, 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 1 0 0 - 1 1 0 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 144.5 mg, (76%) o f (360) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1735, 1622, 1152, 1044, 920, 772 c m " 1 ; X H nmr (270 MHz, C D C I 3 ) 5: 0.18 ( s , 9H, -SnMe 3 , J S n - H " 5 5 H z > . 1 - 2 0 ( t , 3H, - C H 2 C H 3 , J - 7 H z ) , 2 .23-2 .30 (m, 4H) , 2 .40-2 .50 ( t , 2H, J - 7 H z ) , 3.30 ( s , 3H, - 0 C H 3 ) , 3.46 ( t , 2H, - 0 C H 2 C H 2 , I - 7 H z ) , 4.06 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 4 .56 ( s , 2H, - 0 C H 2 0 - ) , 5.98 ( t , I H , o l e f i n i c p r o t o n , J - 7 H z , J_sn-H ~ 1 3 7 H z ) - Exact Mass c a l c d . f o r C 1 3 H 2 5 0 4 S n ( M + - C H 3 ) : 365.0774; found: 365.0772. - 235 -P r e p a r a t i o n o f E t h y l ( Z ) - 4 - T r i m e t h y l s t a n n y l - 4 , 8 - n o n a d i e n o a t e (361) F o l l o w i n g g e n e r a l procedure 13, 2 - t r i m e t h y l s t a n n y l - l , 6 - h e p t a d i e n -3 - o l (342) (138 mg, 0.5 mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (642 /JL, 3 .5 mmol) and propanoic a c i d (2 .3 pL, 0.03 mmol) a t 135-140°C f o r 2.5 h , as e t h a n o l was removed by d i s t i l l a t i o n . Normal workup, 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 8 5 - 9 5 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 136.5 mg (79%) o f (361) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3078, 1739, 1641, 1620, 1159, 1040, 913, 770 c m " 1 ; X H nmr (270 MHz, CDC1 3 ) 6: 0 .14 ( s , 9H, -SnMe 3 , J S n - H " 5 6 H z > . ! - 2 3 3 H - - C H 2 C H 3 , J= 7 H z ) , 2 .03-2 .13 (m, 4H) , 2.28 ( t , 2H, J - 7 H z ) , 2.47 ( t , 2H, J - 7 H z ) , 4 .10 (q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 4 .93 (broad d , I H , H A , J - 10 H z ) , 4 .98 (broad d , I H , H B , J - 16 H z ) , 5 .70-5 .84 (m, I H , H c ) , 6.00 (m, I H , H D , Isn-H ~ 1 3 6 H z ) - Exact Mass c a l c d . f o r C 1 3 H 2 3 0 2 S n (M+-CH-}): 331.0720; f o u n d : 331.0716. P r e p a r a t i o n of E t h y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 4 - h e x e n o a t e (364) F o l l o w i n g genera l procedure 13, ( E ) - 4 - t r i m e t h y l s t a n n y l - 3 - b u t e n - 2 - o l - 236 -(338) (236 mg, 1 mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (1.28 mL, 7 mmol) and propanoic a c i d (4 .5 / *L, 0.06 mmol) a t 135-140°C f o r 2.5 h , under c o n d i t i o n s f o r d i s t i l l a t i v e removal o f e t h a n o l . Normal workup and d i s t i l l a t i o n ( a i r - b a t h temperature 5 5 - 6 5 ° C / 0 . 2 T o r r ) 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 228.9 mg (75%) o f a c o l o r l e s s o i l t h a t was i d e n t i f i e d as the e s t e r (364) ; i r ( f i l m ) : 1729, 1654, 1371, 1186, 1035, 967, 767 c m ' 1 ; X H nmr (270 MHz, CDC1 3) 6: 0.04 ( s , 9H, -SnMe 3 , J S n - H *= 56 H z ) , 1.21 ( t , 3H, - C H 2 C H 3 , J= 7 H z ) , 1.61 (d o f d , 3H, CH 3 C=, J - 1 .5 , 6 H z ) , 2 .20 -2 .32 (m, 1H, Me 3 SnCH-) , 2.53 (d o f d , 1H, - C H 2 C 0 2 E t , J - 6, 16 H z ) , 2.55 (d o f d , 1H, - C H 2 C 0 2 E t , J - 8, 16 H z ) , 4.09 (q , 2H, - O C H 2 C H 3 , J - 7 H z ) , 5.14 (d o f q o f d , 1H, H A , 1 - 1 , 6, 16 H z ) , 5.49 (q o f d of d , 1H, H B , J = 1 .5 , 8, 16 H z ) , Exact Mass c a l c d . f o r C 1 1 H 2 2 0 2 S n : 306.0642; f o u n d : 306.0651. P r e p a r a t i o n of E t h y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 4 - u n d e c e n o a t e (365) F o l l o w i n g g e n e r a l procedure 13, ( E ) - l - t r i m e t h y l s t a n n y l - l - n o n e n-3 - o l (344) (153 mg, 0.5 mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (642 p L , 3.5 mmol) and propanoic a c i d (2.3 A»L. 0.03 mmol) a t 135-140°C f o r 2.5 h , as e t h a n o l was removed by d i s t i l l a t i o n . Normal workup, 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 95-105°C/0.2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 144.2 mg (77%) of (365) as a c o l o r l e s s o i l ; i r ( f i l m ) : - 237 -1734, 1650, 1466, 1372, 1186, 1035, 966, 767 c m ' 1 ; X H nmr (400 MHz, CDC1 3) 6: 0.06 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 0.88 (broad t , 3H, - C H 2 C H 2 C H 3 , J - 7 H z ) , 1 .21-1.35 (m, 11H), 1.97 (broad q , 2H, -CH 2 C=, J = 7 H z ) , 2.32 (broad d of t , I H , Me 3 SnCH- , J - 7, 8 H z ) , 2.58 (d of d , I H , - C H 2 C 0 2 E t , J - 7, 16 H z ) , 2.60 (d of d , I H , - C H 2 C 0 2 E t , J - 8, 16 H z ) , 4 .12 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 5.18 (d of t o f d , I H , H A , J - 1, 7, 15 H z ) , 5.51 ( t o f d o f d , I H , H B , J - 1, 8, 15 H z ) . Exact Mass c a l c d . f o r C 1 5 H 2 9 0 2 S n (M+-CH 3) 361.1190; found: 361.1188. P r e p a r a t i o n of E t h y l ( E ) - 5 - C y c l o p r o p y l - 3 - t r i m e t h y l s t a n n y l - 4 - p e n t e n o a t e Genera l procedure 13 was used w i t h some m o d i f i c a t i o n . A m i x t u r e of ( E ) - 1 - c y c l o p r o p y l - 3 - t r i m e t h y l s t a n n y l - 2 - p r o p e n - l - o l (347) (131 mg, 0.5 mmol), t r i e t h y l o r t h o a c e t a t e (1.37 mL, 7.5 mmol) and propanoic a c i d (7 .5 fiL, 0 .1 mmol) was heated at 135-140°C f o r 3 h , as e t h a n o l was removed by d i s t i l l a t i o n . The crude product o b t a i n e d a f t e r normal workup was sub-j e c t e d to f l a s h chromatography on s i l i c a g e l (18 g , e l u t i o n w i t h p e t r o -leum e t h e r - e t h e r , 9 7 : 3 ) . D i s t i l l a t i o n ( a i r - b a t h temperature 7 5 - 8 5 ° C / 0 . 2 T o r r ) o f the m a t e r i a l d e r i v e d from c o n c e n t r a t i o n o f the a p p r o p r i a t e f r a c t i o n s a f f o r d e d 102.3 mg (62%) o f (368) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3080, 1733, 1649, 1371, 1186, 1035, 959, 767 c m " 1 ; LB nmr (400 (368) - 238 MHz, C D C I 3 ) 6: 0.07 ( s , 9H, -SnMe 3 , J S n . H - 56 H z ) , 0 .23-0 .28 and 0. 58-0.65 (m, m, 2H each, c y c l o p r o p y l methylene p r o t o n s ) , 1.25 ( t , 3H, - C H 2 C H 3 , J - 7 H z ) , 1 .26-1.34 (m, 1H, c y c l o p r o p y l methine p r o t o n ) , 2.31 (broad , over lapped d o f d o f d , 1H, Me 3 SnCH-, J - 7, 8, 8 H z ) , 2.56 (d o f d , 1H, - C H 2 C 0 2 E t , J - 7, 16 H z ) , 2.59 (d of d , 1H, - C H 2 C 0 2 E t , J = 8, 16 H z ) , 4 .12 (q , 2H, - C H 2 C H 3 , J - 7 H z ) , 4 .81 (d o f d o f d , 1H, H A , J -2, 8, 15 H z ) , 5.57 (d of d of d , 1H, H B , J - 1, 8, 15 H z ) . I r r a d i a t i o n a t 6 5.57 (Hg) : S 4 .81 (H A ) s i m p l i f i e d to a d of d (J - 2, 8 Hz) and 6 2.31 (Me 3SnCH-) became a broad d o f d o f d (J - 2, 7, 8 H z ) . I r r a d i a -t i o n a t 6 4 .81 ( H A ) : s i g n a l a t S 5.57 (Hg) s i m p l i f i e d to a d o f d (J = 1, 8 Hz) and 6 1 .26-1 .34 ( c y c l o p r o p y l methine pro ton) was changed. Exact Mass c a l c d f o r C 1 2 H 2 1 0 2 S n ( M + ' C H ^ : 317.0563; f o u n d : 317.0564. P r e p a r a t i o n o f E t h y l ( E ) - 7 - M e t h o x y m e t h o x y - 3 - t r i m e t h y l s t a n n y l - 4 -heptenoate (366) MOMOCH 2 CH 2 x Me 3 Sn 'C0 2Et F o l l o w i n g g e n e r a l procedure 13, ( E ) - 5 - m e t h o x y m e t h o x y - 1 - t r i m e t h y l -s t a n n y l -1 -penten- 3- o l (345) (155 mg, 0.5mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (642 / i L , 3.5 mmol) and propanoic a c i d (2 .3 ixL, 0.03 mmol) at 135-138°C, f o r 2.5 h , as e t h a n o l was removed by d i s t i l l a t i o n . Normal workup, 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 100 -110°C/0 .2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 150.0 mg, (79%) of (366) as a - 239 -c o l o r l e s s o i l ; i r ( f i l m ) : 1733, 1650, 1372, 1039, 960, 920, 769 c m " 1 ; X H nmr (400 MHz, C D C l 3 ) 6": 0.06 ( s , 9H, -SnMe 3 , J S n _ H - 55 H z ) , 1.24 ( t , 3H, - 0 C H 2 C H 3 , J - 7 H z ) , 2 .23-2 .27 (m, 3H), 2.57 (d o f d , I H , - C H 2 C 0 2 E t , J - 7, 18 H z ) , 2 .60 (d of d , I H , - C H 2 C 0 2 E t , J - 8, 18 H z ) , 3.34 ( s , 3H, - 0 C H 3 ) , 3.48 ( t , 2H, - 0 C H 2 C H 2 - , J - 7 H z ) , 4 .10 (q , 2H, - 0 C H 2 C H 3 , J - 7 H z ) , 4 .59 ( s , 2H, - 0 C H 2 0 - ) , 5.16 ( t o f d , I H , H A , J - 7 , 15 H z ) , 5.62 (d o f d , I H , Hg, J - 8, 15 H z ) . Exact Mass c a l c d . f o r C 1 4 H 2 g 0 4 S n : 380.1009; f o u n d : 380.1005. P r e p a r a t i o n of E t h y l ( E ) - 3 - T r i m e t h y l s t a n n y l - 4 , 8 - n o n a d i e n o a t e (367) F o l l o w i n g g e n e r a l procedure 13, ( E ) - 1 - t r i m e t h y l s t a n n y l - 1 , 6 - h e p t a -d i e n - 3 - o l (346) (138 mg, 0.5 mmol) was heated w i t h t r i e t h y l o r t h o a c e t a t e (642 n~L, 3 .5 mmol) and propanoic a c i d (2 .3 fiL, 0 .3 mmol) a t 135-140°C f o r 2.5 h , as e t h a n o l was removed by d i s t i l l a t i o n . Normal workup, 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 9 0 - 1 0 0 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 133.6 mg (77%) o f (367) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3077, 1733, 1641, 1186, 1035, 967, 912, 768 c m " 1 ; X H nmr (270 MHz, CDC1 3 ) 6: 0.07 ( s , 9H, -SnMe 3 , J S n . H = 52 H z ) , 1.24 ( t , 3H, - C H 2 C H 3 , J - 7 H z ) , 2 .03-2 .10 (m, 4 H ) , 2.30 (d o f t , I H , Me 3 SnCH- , J = 7, 8 H z ) , 2.56 (d o f d , I H , - C H 2 C 0 2 E t , J - 7 , 16 H z ) , 2.59 (d o f d , I H , - C H 2 C 0 2 E t , J - 8, 16 H z ) , 4 .10 (q , 2H, - 0 C H 2 C H 3 , J = 7 H z ) , 4 .92 (broad - 240 -d , 1H, Hp, J - 10 H z ) , 4.98 (broad d , 1H, H G , J — 16 H z ) , 5 .09-5 .23 (m, 1H, H A ) , 5.53 (broad d o f d , 1H, H B , J - 8, 15 H z ) , 5 .70-5 .84 (m, 1H, H T ) . Exact Mass c a l c d . f o r C j ^ H ^ O ^ n : 346.0955; f o u n d : 346.0961. P r e p a r a t i o n o f ( Z ) - 4 - T r i m e t h y l s t a n n y l - 4 - h e x e n - l - o l (369) Genera l procedure 7 was f o l l o w e d . To a c o l d ( 0 ° C ) , s t i r r e d s o l u t i o n - s u s p e n s i o n o f l i t h i u m aluminum h y d r i d e (85.5 mg, 2.25 mmol) i n 15 mL of d r y e t h e r was added, dropwise , a s o l u t i o n o f e t h y l ( Z ) - 4 - t r i -m e t h y l s t a n n y l - 4 - h e x e n o a t e (358) (918 mg, 3 mmol) i n 8 mL o f d r y e t h e r . 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 1 h . Normal workup, 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 5 5 - 6 5 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , p r o v i d e d 758.7 mg (96%) of the o l e f i n i c a l c o h o l (369) as a c o l o r l e s s o i l ; i r ( f i l m ) : 3333, 1624, 1449 1055, 769 c m * 1 ; lE nmr (80 MHz, CDC1 3 ) 6: 0 .20 ( s , 9H, -SnMe 3 , J S n . H - 52 H z ) , 1.33 ( t , 1H, exchanges w i t h D 2 0 , -OH, J - 7 H z ) , 1 .48-1.78 (m, 5H), 2.28 (broad t , 2H, = C C H 2 - , J - 7 H z ) , 3.60 ( q , 2H, - C H 2 C H 2 O H , J - 7 H z ) , 6.10 ( t o f q , 1H, o l e f i n i c p r o t o n , J - 1 .5 , 7 Hz , J_sn-H ~ H z ) - Exact Mass c a l c d . f o r C 8 H 1 7 O S n ( M + ' C ^ ) : 249.0301; f o u n d : 249.0306. - 241 -P r e p a r a t i o n of ( Z ) - 6 - C h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - h e x e n e (370) CI To a s t i r r e d s o l u t i o n o f the a l c o h o l (369) (660 mg, 2 .5 mmol) i n 20 mL o f d r y carbon t e t r a c h l o r i d e was added t r i e t h y l a m i n e (383 /JL , 2.75 mmol) and t r i p h e n y l p h o s p h i n e (1 .31 g , 5 mmol). The r e s u l t a n t s o l u t i o n was r e f l u x e d f o r 24 h . Petroleum e ther (50 mL) was added and the r e s u l t i n g s l u r r y was f i l t e r e d through a column o f F l o r i s i l (15 g, e l u t i o n w i t h pet ro leum e t h e r ) . E v a p o r a t i o n o f the s o l v e n t from the combined e l u a t e , 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 6 0 - 7 0 ° C / 0 . 2 T o r r ) o f the r e s i d u a l o i l , a f f o r d e d 510.6 mg (72%) of the c h l o r i d e (370) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1623, 981, 769, 720 c m ' 1 ; lH nmr (80 MHz, CDC1 3) 6: 0.23 ( s , 9H, -SnMe 3 , J S n - H " 5 2 H z > ' 1-63-1.95 (m, 5H), 2.33 (broad t , 2H, - C C H 2 - , J - 7 H z ) , 3.50 ( t , 2H, - C H 2 C 1 , J = 7 H z ) , 6.10 ( t o f q , I H , o l e f i n i c p r o t o n , J - 1 .5 , 6 H z , J S n - H = 1 4 2 H z ) . Exact Mass c a l c d . f o r C 8 H 1 6 3 5 C l 1 1 8 S n (M+-CH3): 264.9957; found: 264.9944. - 242 T r a n s m e t a l a t i o n of ( Z ) - 6 - C h l o r o - 3 - t r i m e t h y l s t a n n y l - 2 - h e x e n e (370) . P r e p a r a t i o n of ( Z ) - 5 - E t h y l i d e n e - l - o x a s p i r o [ 5 . 5 ] d o d e c a n e (373) To a c o l d ( - 7 8 " C ) , s t i r r e d s o l u t i o n o f ( Z ) - 6 - c h l o r o - 3 - t r i m e t h y l -s t a n n y l -2 -hexene (370) (141.2 mg, 0.5 mmol) i n 2 mL o f d r y THF was added s u c c e s s i v e l y a s o l u t i o n of m e t h y l l i t h i u m i n e ther (0.33 mL, 0.55 mmol) and HMPA (95.7/ iL, 0.55 mmol). A f t e r the l i g h t y e l l o w s o l u t i o n had been s t i r r e d f o r 1 h , cyclohexanone (57 p L , 0.55 mmol) was added and s t i r r i n g was c o n t i n u e d f o r 1 h at -78°C and f o r 10 h w i t h the c o o l i n g bath removed. S a t u r a t e d aqueous ammonium c h l o r i d e (0.5 mL) and e ther (10 mL) were added and the l a y e r s were s e p a r a t e d . The aqueous l a y e r was e x t r a c t e d w i t h e t h e r . The combined o r g a n i c e x t r a c t was washed (water , b r i n e ) , d r i e d (MgSO^), and c o n c e n t 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 3 0 - 4 0 ° C / 0 . 2 T o r r ) o f the crude product p r o v i d e d 61.5 mg (68%) o f the s p i r o e ther (373) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1659, 1445, 1088, 998 c m - 1 ; X H nmr (80 MHz, CDC1 3) 5: 1 .45-2 .05 (m, 15H), 2.23 (broad t , 2H, - C C H 2 - , 1 - 7 H z ) , 3.70 ( t , 2H, - C H 2 0 - , J - 7 H z ) , 5.18 (t of q , 1H, o l e f i n i c p r o t o n , J - 1 .5 , 7 H z ) . Exact Mass c a l c d . f o r C 1 2 H 2 0 O : 180.1515; found: 180.1514. - 243 -P r e p a r a t i o n of ( Z ) - 3 - f 3 - ( 6 - C h l o r o - 2 - h e x e n y l ) ] c y c l o p e n t a n o n e (375) 371 375 To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f ( Z ) - 6 - c h l o r o - 3 - t r i m e t h y l -s t a n n y l - 2 - h e x e n e (370) (141.2 mg, 0.5 mmol) i n 2 mL o f dry THF was added s u c c e s s i v e l y a s o l u t i o n of m e t h y l l i t h i u m i n e t h e r (0.33 mL, 0.55 mmol) and HMPA (95.7 / i L , 0.55 mmol). The r e s u l t i n g l i g h t 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 1 h to o b t a i n the c o r r e s p o n d i n g v i n y l l i t h i u m i n t e r m e d i a t e (371) . F o l l o w i n g genera l procedure 8, t h i s s o l u t i o n was t r e a t e d w i t h anhydrous magnesium bromide (110.5 mg, 0.6 mmol) and then was d i l u t e d w i t h 4 mL o f d r y e t h e r . Cuprous b r o m i d e - d i m e t h y l s u l f i d e complex (30.8 mg, 0.15 mmol), 2 - c y c l o p e n t e n - l - o n e (225) (41 mg, 0.5 mmol), and boron t r i f l u o r i d e - e t h e r a t e (74 / i L , 0.6 mmol) were added. Genera l c o n d i t i o n s and workup (genera l procedure 8) p r o v i d e d the c h l o r o ketone (375) . F r a c t i o n a l d i s t i l l a t i o n o f the crude m a t e r i a l o b t a i n e d on workup gave i n i t i a l l y a s m a l l amount o f the s t a r t i n g enone, f o l l o w e d by 59.0 mg (59%) of the c h l o r o ketone (375) ( a i r - b a t h temperature 9 0 - 1 0 0 ° C / 0 . 2 T o r r ) , as a c o l o r l e s s o i l ; i r ( f i l m ) : 1743, 1153, 978, 722 c m - 1 ; X H nmr (80 MHz, C D C I 3 ) 6: 1.68 (broad d , 3H, CH 3 C=, J = 7 H z ) , 1 .75-2 .75 (m, 10H), 3 .05-3 .45 (m, I H , H A ) , 3.58 ( t , 2H, - C H 2 C 1 , J = 7 H z ) , 5.35 (broad q , I H , o l e f i n i c p r o t o n , J - 7 H z ) . Exact Mass c a l c d . f o r C 1 1 H 1 7 0 3 5 C 1 : 200.0969; found: 200.0967. - 244 P r e p a r a t i o n of the C h l o r o Ketone M i x t u r e (376) o ci To a c o l d ( - 7 8 ° C ) , s t i r r e d s o l u t i o n o f ( Z ) - 6 - c h l o r o - 3 - t r i m e t h y l -s t a n n y l -2 -hexene (370) (141.2 mg, 0.5 mmol) i n 2 mL o f d r y THF was added s u c c e s s i v e l y a s o l u t i o n o f m e t h y l l i t h i u m i n e ther (0.33 mL, 0.55 mmol) and HMPA (95.7 / i L , 0.55 mmol). The l i g h t y e l l o w s o l u t i o n was s t i r r e d at -78°C f o r 1 h , to o b t a i n the c o r r e s p o n d i n g v i n y l l i t h i u m i n t e r m e d i a t e (371) . F o l l o w i n g g e n e r a l procedure 8, t h i s s o l u t i o n was t r e a t e d w i t h anhydrous magnesium bromide (110.5 mg, 0.6 mmol), and then was d i l u t e d w i t h 4 mL o f dry e t h e r . Cuprous b r o m i d e - d i m e t h y l s u l f i d e complex (30.8 mg, 0.15 mmol) , 2 - m e t h y l - 2 - c y c l o h e x e n - 1 - o n e ( 2 2 4 ) 1 1 6 (48 mg, 0.5 mmol), and boron t r i f l u o r i d e - e t h e r a t e (745 /*L, 0.6 mmol) were added. Genera l c o n d i t i o n s and workup (genera l procedure 8) p r o v i d e d the c h l o r o ketone mix ture (376) . F r a c t i o n d i s t i l l a t i o n o f the crude p r o d u c t o b t a i n e d on workup gave i n i t i a l l y a s m a l l amount of the s t a r t i n g enone, f o l l o w e d by 69.7 mg (61%) of (376) ( a i r - b a t h temperature 1 0 5 - 1 1 5 ° C / 0 . 2 T o r r ) , as a c o l o r l e s s o i l ; i r ( ( f i l m ) : 1709, 1313, 1017, 965, 730 c m " 1 ; X H nmr (400 MHz, CDC1 3) S: 0.89 and 1.06 ( d , d , r a t i o 2 : 1 , 3H, C H 3 C H - , J = 7 Hz each) , 1 .59-2 .85 (m, 14H), 3 .06-3 .11 (m, 1H, H A ) , 3 .53-3 .61 (m, 2 H , - C H 2 C 1 ) , 5 .29-5 .37 (m, 1H, o l e f i n i c p r o t o n ) . Exact Mass c a l c d . f o r C 1 3 H 2 i 0 3 5 C l : 228.1282; found: 228.1282. - 245 -P r e p a r a t i o n of c i s . ( Z ) - 2 - E t h v l i d e n e b i c y c l o f 4 . 3 . 0 1 n o n a n - 7 - o n e (377) F o l l o w i n g g e n e r a l procedure 9, the c h l o r o ketone (375) (60.2 mg, 0.3 mmol) was a l l o w e d to r e a c t w i t h a s t i r r e d suspens ion o f potassium h y d r i d e (30 mg, 0.75 mmol) i n 2 mL of d r y THF. Normal workup, 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 45 -55 D C/0 .2 T o r r ) o f the crude p r o d u c t , p r o v i d e d 39.7 mg (81%) o f the b i c y c l i c ketone (377) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1741, 1133, 877 cm"; ^-H nmr (270 MHz, CDC1 3) 6: 1 .26-1 .35 (m, 2H), 1.64 (d o f d , 3H, CH 3CH=, J - 1 .5 , 7 Hz), 1.66-2 .50 (m, 9H), 3.22 (broad q, I H , J - 7 H z ) , 5.32 (broad q, IH, o l e f i n i c p r o t o n , J - 7 H z ) . Exact Mass c a l c d . f o r C ^ H ^ g O : 164.1202; f o u n d : 164.1203. P r e p a r a t i o n of c i s , ( Z ) - l - M e t h y l - 7 - e t h y l i d e n e b i c y c l o [ 4 . 4 . 0 ] d e c a n - 2 - o n e (378) F o l l o w i n g genera l procedure 9, the c h l o r o ketone mix ture (376) (68.6 mg, 0 .3 mmol) was a l l o w e d t o r e a c t w i t h a s t i r r e d suspens ion o f - 246 -potass ium h y d r i d e (30 mg, 0.75 mmol) i n 2 mL of dry THF. Normal workup, 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 5 0 - 6 0 ° C / 0 . 2 T o r r ) o f the crude p r o d u c t , a f f o r d e d 49.4 mg (86%) of (378) as a c o l o r l e s s o i l ; i r ( f i l m ) : 1703, 1451, 924 c m - 1 ; X H nmr (400 MHz, C D C I 3 ) 6: 1.06 ( s , 3 H , - C - C H 3 ) , 1 .18-1 .20 (m, 2H), 1 .47-1.76 (m, 3H), 1.55 (d o f d , 3H, CH 3CH=, J - 2, 7 H z ) , 2 .00-2 .15 (m, 4H), 2 .25-2 .39 (m, 2H), 2 .60-2 .70 (m, 2 H ) , 5.28 ( t o f q , I H , o l e f i n i c p r o t o n , J - 2 , 7 H z ) . Exact Mass c a l c d . f o r C 1 3 H 2 0 O : 192.1515; found: 192.1513. 247 -REFERENCES 1 - 248 REFERENCES 1. For a d i s c u s s i o n on r e t r o s y n t h e t i c a n a l y s i s , see S. Warren, "Organic S y n t h e s i s : The D i s c o n n e c t i o n A p p r o a c h " , W i l e y , N . Y . (1982) . 2. E . J . Corey , A.K. Long, and S . D . R u b e n s t e i n , S c i e n c e , 228, 408 (1985) . 3. E . J . Corey, Pure A p p l . 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