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Annulations leading to bicyclic dienes : Diels-Alder reactions of (some of) the dienes and dolastane… Friesen, Richard William 1988

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ANNULATIONS LEADING TO BICYCLIC DIENES: DIELS-ALDER REACTIONS OF (SOME OF) THE DIENES AND DOLASTANE DITERPENOID SYNTHESES By RICHARD WILLIAM FRIESEN B.Sc, The U n i v e r s i t y of Waterloo, 1984 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA January 1988 © Richard William Friesen, 1988 .1 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. The University of British 1956 Main Mall Vancouver, Canada Department of V6T 1Y3 DE-6G/81) i i ABSTRACT The preparation of b i c y c l i c dienes of the general structures ( 7 2 ) , ( 8 2 ) , ( 8 3 ) and ( 1 6 2 ) i s described. These materials have been prepared v i a a novel annulation sequence inv o l v i n g (a) the a l k y l a t i o n of various carbonyl containing substances with the donor acceptor reagents ( 4 3 ) , ( 4 4 ) , ( 1 0 8 ) - ( 1 1 4 ) and ( 1 5 4 ) , (b) the conversion of the a l k y l a t i o n products into the enol t r i f l a t e s , and (c) the palladium(O) catalyzed intramolecular coupling of the enol t r i f l a t e - v i n y l s t a n n a n e moieties v i a e i t h e r a "one" or "two pot" process. The Diels-Alder reactions of the "parent" b i c y c l i c diene ( 7 5 ) , the c i s o i d c i s diene ( 1 4 5 ) and the c i s o i d trans diene ( 1 4 6 ) are described. Four basic questions regarding the face s e l e c t i v i t y , r e g i o s e l e c t i v i t y , s t e r e o s e l e c t i v i t y and comparative r e a c t i v i t y of the dienes i n the forma-t i o n of the Diels-Alder adducts of general structure ( 1 7 4 ) are addressed. The annulation sequences described above have been applied to the f i r s t t o t a l syntheses of the dolastane diterpenoids (±)-(14S)-dolasta-1(15),7,9-trien-14-ol ( 2 3 9 ) and (±)-amijitrienol ( 2 4 2 ) . Thus, the substituted cycloheptanone ( 2 6 2 ) , prepared i n seven steps from the commercially a v a i l a b l e material ( 2 6 1 ) , was converted v i a a ser i e s of transformations, i n c l u d i n g the newly developed annulation process, into the b i c y c l i c diene ( 2 6 4 ) . Introduction of the two appendages to ( 2 6 4 ) proceeded s t e r e o s e l e c t i v e l y to provide the keto vinylstannane ( 2 6 5 ) . Ring closure was e f f e c t e d with the desired stereochemistry to y i e l d ( ± ) - ( 2 3 9 ) . i i i A reduction, deprotection sequence afforded the ketone (249) from the diene k e t a l (263). A se r i e s of three steps i n v o l v i n g an a l d o l condensation, Swern oxidation and st e r e o s e l e c t i v e methylation provided the diketone (290). Chemo- and s t e r e o s e l e c t i v e reduction of (290) followed by pr o t e c t i o n of the alcohol moiety y i e l d e d the s i l y l ether (303). C y c l i z a t i o n , according to the methodology described herein, and deprotection of the s i l y l ether moiety produced (±)-(242). 72 m 82 83 162 1 _ M e 3Sn^(CH 2)n^ I 4 3 n = 2 4 4 n = 3 Me3Sn 1 5 4 (108) H (109) C02Me (110) H (111) CH20M0M (112) H (113) Ct^OSiMe^u* (114) CH 2CH 3 R2 C02Me H CH20M0M H CH 2OSiMe 2Bu t H H i v V TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS v LIST OF TABLES v i i LIST OF FIGURES v i i i ABBREVIATIONS x ACKNOWLEDGEMENTS x i i I. INTRODUCTION 1 1.1.0 General Introduction 1 1.2.0 Previous Work and Proposals 11 I I . DISCUSSION 17 2.1.0 Annulations Leading to B i c y c l i c Dienes 17 2.1.1 Annulations Employing w-Iodo-2-trimethyl-stannyl-l-alkenes 17 2.1.2 Annulations Employing Methyl (E)- and (Z)-6-Iodo-3-trimethylstannyl-2-hexenoates, Derivatives Therefrom and (Z)-l-Bromo-4-methyl-3-trimethylstannyl-2-pentene 39 2.2.0 The Diels-Alder Reactions of the B i c y c l i c Dienes (75), (145) and (146) 67 v i 2.2.1 The Diels-Alder Reactions of the Dienes ( 7 5 ) , (145) and (146) with Symmetrical Dienophiles 69 2.2.2 The Diels-Alder Reactions of the Dienes ( 7 5 ) , (145) and (146) with Unsymmetrical Dienophiles 79 2.3.0 The Tot a l Syntheses of the Dolastane Diterpenoids (±)-(14S)-Dolasta-l(15),7,9-tri e n - 1 4 - o l and (±)-Amijitrienol 113 2.3.1 Introduction 113 2.3.2 The Tot a l Synthesis of (±)-(14S)-Dolasta-1(15),7,9-trien-14-ol 117 2.3.3 The T o t a l Synthesis of (±)-Amijitrienol 141 I I I . EXPERIMENTAL 159 3.1.0 General Procedures, Solvents and Reagents . . . . 159 3.2.0 Experimental Procedures 163 3.2.1 Preparation of Donor-Acceptor Reagents 163 3.2.2 Preparation of B i c y c l i c Dienes 191 3.2.3 Diels-Alder Study of the Dienes ( 7 5 ) , (145) and (146) 252 3.2.4 (±)-(14S)-Dolasta-l(15),7,9-trien-14-ol (239) Experimental 284 3.2.5 (±)-Amijitrienol (242) Experimental 304 IV. REFERENCES 316 V. APPENDIX 326 5.0.0 Appendix 1: X-ray Crystallographic Data . . . . 326 v i i LIST OF TABLES Table Page 1 A l k y l a t i o i i of Carbonyl Species with w-Iodo-2-trimethylstannyl-l-alkenes 21 2 Preparation of Enol T r i f l a t e s of General Structure (65) 27 3 Preparation of B i c y c l i c Dienes of General Structure (72) 29 4 C y c l i z a t i o n of Substrate (66) Under Various Reaction Conditions 34 5 Preparation of Primary Iodides from the Corresponding Chlorides 48 6 A l k y l a t i o n of /3-Keto Esters with Methyl (Z)-and (E)-6-Iodo-3-trimethylstannyl-2-hexenoates and Derivatives Therefrom 50 7 Preparation of C i s o i d Cis and C i s o i d Trans B i c y c l i c Dienes from the Al k y l a t e d Compounds (115) i n Ei t h e r a "One Pot" or "Two Pot" Reaction Sequence 52 8 A l k y l a t i o n of Carbonyl Species with (Z)-l-Bromo-4-methyl-3-trimethylstannyl-2-pentene (154) . . . . 61 9 Preparation of B i c y c l i c Dienes Containing Two Endocyclic Double Bonds from the A l k y l a t e d Materials (155) 63 10 The Diels-Alder Reactions of the B i c y c l i c Dienes (75), (145) and (146) with Symmetrical Dienophiles 71 11 The Diels-Alder Reactions of the B i c y c l i c Dienes (75), (145) and (146) with Unsymmetrical Dienophiles 81 v i i i LIST OF FIGURES Figure Page 1 The 400 MHz LH nmr Spectrum of the Diene (75) . . . . 38 2 The 400 MHz % nmr Spectrum of the C i s o i d Cis Diene (142) 55 3 The 400 MHz *H nmr Spectrum of the C i s o i d Trans Diene (142) 55 4 Stereoview of the Benzoate (152) 59 5 The 400 MHz 1H nmr Spectrum of the Diene (167) . . . 66 6 Stereoview of the T r i e s t e r (175) 70 7 Stereoview of the T r i c y c l i c Ester (177) 73 8 Stereoview of the T r i c y c l i c Ester (179) 76 9 Stereoview of the D i o l (198) 83 10 Stereoview of the D i o l (199) 84 11 The 400 MHz ^H nmr Spectra of the Compounds D and M . . 90 12 The 400 MHz *H nmr Spectra of the Compounds G and N . . 91 13 The 400 MHz 1H nmr Spectra of the Compounds H and P . . 92 14 The P a r t i a l 400 MHz ^H nmr Spectra of the Nitro Esters J-L and M, N and P 96 15 Stereoview of the Nitro Ester (195) 100 16 Stereoview of the Benzoate (206) 102 17 The 400 MHz 1H nmr Spectrum of (264) 129 18 The 400 MHz nmr Spectrum of the Ketone (287) . . . 135 19 The 400 MHz XH nmr Spectrum of the Ketone (288) . . . 135 20 The 400 MHz *H nmr Spectrum of the V i n y l Iodide (266) 137 i x 21 The 300 MHz LH nmr Spectrum of Natural (239) i n C 6D 6 140 22 The 400 MHz lH nmr Spectrum of Synthetic (±)-(239) i n C 6D 6 140 23 The 400 MHz 1H nmr Spectrum of the Ketone (249) . . . 145 24 The 400 MHz XH nmr Spectrum of the Diketone (290) . . . 150 25 The 400 MHz 1H nmr Spectrum of the Diketone (301) . . . 150 26 The 400 MHz 1H nmr Spectrum of the Keto S i l y l Ether (303) 153 27 The 400 MHz ^H nmr Spectrum of Natural (+)-Amijitrienol (242) 157 28 The 400 MHz 1H nmr Spectrum of Synthetic (±)-Amijitrienol (242) 157 X LIST OF ABBREVIATIONS Ac - ac e t y l APT - attached proton t e s t Ar - a r y l br - broad Bu - n-butyl Bu^ - is o b u t y l Bu c - t e r t - b u t y l d - doublet DDQ - 2,3-dichloro-5,6-dicyano-l,4-benzoqulnone DIBAL - diisobutylaluminum hydride DMAP - 4-N,N-dimethylaminopyridine DME - 1,2-dimethoxyethane DMF - dimethylformamide DMPU - l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone DMSO - dimethylsulfoxide equiv - equivalent(s) Et - eth y l g - gram(s) gl c - g a s - l i q u i d chromatography h - hour HMPA - hexamethylphosphoramide i r - i n f r a r e d k c a l - k i l o c a l o r i e s IDA - li t h i u m diisopropylamide Me - methyl x i mg - milligram(s) min - minute(s) MOM - methoxymethyl mp - melting point m - m u l t i p l e t mol - mole(s) mmol - millimole(s) nmr - nuclear magnetic resonance nOe - nuclear Overhauser enhancement PCC - pyridinium chlorochromate Ph - phenyl P r 1 - isopropyl Py - pyridine q - quartet r t - room temperature s - s i n g l e t t - t r i p l e t TBDMS - ter t - b u t y l d i m e t h y l s i l o x y TBAF - tetra-n-butylammonium f l u o r i d e TCNE - tetracyanoethylene Tf - trifluoromethanesulfonyl Tf 2NPh - N-phenyltrifluoromethanesulfonimide 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 uv - u l t r a v i o l e t x i i ACKNOWLEDGEMENTS I am indebted to my research supervisor, Professor Edward Piers, f o r h i s guidance and support throughout the course of these studies and for i n s t i l l i n g the at t i t u d e that anything worth doing i s worth doing w e l l . In addition, thanks are extended to the past and present members of the group f o r i n t e r a c t i o n and pleasant associations, both s o c i a l l y and academically. Special thanks go to Dr. Kevin Holme, Dr. Brian Keay and Warren Piers f o r t h e i r friendship and contributions. The able and e f f i c i e n t recording of the majority of my sp e c t r a l data by the te c h n i c a l s t a f f of the nmr, mass spectrometry and elemental analysis l a b o r a t o r i e s i s greatly appreciated as i s the prompt and e f f i c i e n t typing of t h i s manuscript by Mrs. Rani Theeparajah. Thanks are extended to Drs. Peter Marrs and Gordon Bates f o r t h e i r d i l i g e n t proofreading. F i n a n c i a l assistance from the Natural Sciences and Engineering Research Council of Canada, the B.C. P r o v i n c i a l Government and UBC i n the forms of a 1967 Sciences and Engineering Scholarship, a Post-Secondary Scholarship and a Fellowship Supplement, r e s p e c t i v e l y , i s g r a t e f u l l y acknowledged. F i n a l l y , I would l i k e to thank my wife, Rose, f o r her continued patience, encouragement and support during these studies. - 1 -I. INTRODUCTION 1.1.0 General Introduction The past decade of organic chemistry has been witness to an explo-s i o n i n the discovery and development of new synthetic methodology. Two areas which have received considerable a t t e n t i o n are: (1) the prepara-t i o n and use of organic reagents which contain two rea c t i v e s i t e s , and (2) the search f o r new methods of forming carbon-carbon bonds. Organic reagents which contain two reactive s i t e s (often one n u c l e o p h i l i c or donor ( d ) l s i t e and one e l e c t r o p h i l i c or acceptor ( a ) l s i t e ) , have been r e f e r r e d to as conjunctive^ or b i f u n c t i o n a l conjunctive reagents.^ By d e f i n i t i o n , these reagents are incorporated wholly or p a r t i a l l y into a substrate molecule by sequential deployment of t h e i r r e a c t i v e centers. Recently, i t has become evident that these bifunc-t i o n a l conjunctive reagents are p a r t i c u l a r l y s u i t e d f o r annulation processes which r e s u l t i n the formation of carbocycles, f i r s t by an intermolecular coupling r e a c t i o n followed by an intramolecular step.^ A sin g l e example, chosen from the recent l i t e r a t u r e , w i l l serve to i l l u s t r a t e t h i s point. A key s e r i e s of reactions i n the synthesis of (±)-aristolone (1), as reported by Prasad and Chan,^ involved the use of 3- ( p h e n y l t h i o ) - 1 - ( t r i -methylsiloxy)-1-methoxy-l,3-butadiene (2) as the synthetic equivalent of the d^.a^-synthon (3). (Synthons are defined as " s t r u c t u r a l units w i t h i n a molecule which are r e l a t e d to possible synthetic operations".^) - 2 -1 2 3 Lewis a c i d catalyzed conjugate a d d i t i o n of (2) to the a,^-unsat-urated ketone (4) provided the Michael adduct (5). Formation of the s i x -membered r i n g was then r e a l i z e d by treatment of (5) with potassium t e r t -butoxide (equation 1 ) . Compound (6) was converted into (±)-aristolone 6 (1) v i a an eight step s e r i e s of reactions. Thus, t h i s six-membered r i n g annulation was based on the t h e o r e t i c a l combination of a ,a^-synthon (7) with a d^,a 1-synthon (3) (equation 2). The formation of the carbon-carbon bond i s one of the most funda-mental processes i n organic synthesis and poses one of the greatest - 3 -6: 0 \ + (2) d i i H 'SPh 7 3 6 challenges to the synthetic organic chemist. To achieve i t s formation with a degree of s e l e c t i v i t y , under re a c t i o n conditions which allow f o r the presence of a v a r i e t y of f u n c t i o n a l groups elsewhere i n the mole-cule, while at the same time remaining a general procedure, i s an imposing but desirable a s p i r a t i o n . One of the methods developed recently f o r the formation of the carbon-carbon bond involves the cross-coupling of an organometallic species (RM) and an organic e l e c t r o p h i l e (R'X), catalyzed by a Group VIII t r a n s i t i o n metal (equation 3).^ Included i n t h i s e f f o r t has been a search f o r a method f o r the cross-coupling of v i n y l partners (R and R' are both a l k e n y l ) . A s e l e c t i v e , s t e r e o s p e c i f i c preparation of conju-gated dienes v i a t h i s route was desirable since many natural products (e.g. carotenoids, in s e c t pheromones, hormones) contain 1,3-diene substructures, the geometry of which profoundly a f f e c t s p h y s i o l o g i c a l a c t i v i t y . Also, a v a r i e t y of 1,3-dienes are continuously required as substrates f o r D i e l s - A l d e r reactions. The f i r s t general method f o r the formation of conjugated dienes by employing t h i s type of methodology, RM + R'X c a t a l y s t > R _ R , + m (3) - 4 -the cross-coupling of (E)-1-alkenylalanes (8a) with (E)-or ( Z ) - l - i o d o -alkenes (8) catalyzed by Ni (equation 4), was not reported by Negishi and coworkers** u n t i l 1976. In the decade since then, t h i s type of re a c t i o n has been investigated f o r organometallic species which include the a l k a l i and a l k a l i earth metals L i ^ ' ^ 3 and Mg,10"^ re s p e c t i v e l y , the main group metals B, 16-23,28 A l8,24-29 S i27 a n d S n7(d,e),30-34 a n d the t r a n s i t i o n metals T i , 2 7 C u , 3 5 " 3 7 Z n , 2 7 • 2 9 > 3 6 • 3 7 z r > 2 4. 27,38 c d 2 7 Hg, 7(k)i27 and Ce . 2 7 S i m i l a r l y , the organic e l e c t r o p h i l e s which have likewise been studied include v i n y l halides (X - CI, Br, I ) , ^ " 3 ^ v i n y l t r i f l a t e s (X - O S 0 2 C F 3 ) , 3 0 " 3 2 • 3 4 and v i n y l phosphates (X 0P0(0R)2).25.26 Portions of review a r t i c l e s and books have dealt with t h i s type of coupling process. 7 55%, 90% E,Z The g e n e r a l i t y and degree of success achieved i n the cross-coupling of two alkenyl groups i n t h i s manner varies greatly, and i s dependent, - 5 -p r i n c i p a l l y , on the metal i n the organometallic partner. The organome-t a l l i c reagents a v a i l a b l e f o r use i n the cross-coupling r e a c t i o n s u f f e r from several common drawbacks. The majority w i l l not t o l e r a t e reactive f u n c t i o n a l i t y e i t h e r i n the organometallic partner (because of incompa-t i b i l i t y i n the procedure f o r t h e i r preparation) or the organic e l e c t r o -p h i l i c partner. S i m i l a r l y , t h e i r preparation i s often d i f f i c u l t , many are oxygen and moisture s e n s i t i v e , and storage, other than f o r a short time i n s i t u , i s impossible. Organotin compounds s u f f e r from few or none of these drawbacks. V i n y l stannanes containing a wide v a r i e t y of f u n c t i o n a l groups can be prepared v i a a number of well documented procedures (the reader i s r e f e r r e d to reference 39 for leading references). The intermolecular cross-coupling of vinylstannanes and v i n y l t r i f l a t e s was reported by S t i l l e and coworkers i n 1984. 3^ This work was a l o g i c a l extension of e a r l i e r reports by t h i s group on the palladium catalyzed cross-coupling of organostannanes with a r y l h a l i d e s , ^ benzyl halides.^O a c y l h a l i d e s , ^ and a l l y l i c h a l i d e s . ^ ^ The r e a c t i o n was found to be f a i r l y general i f c a r r i e d out i n the presence of l i t h i u m c h l o r i d e . For example, treatment of 4-tert-butylcyclohexenyl t r i f l a t e (10) and v i n y l t r i b u t y l s t a n n a n e (11) with 0.02 equivalents of palladium t e t r a k i s (triphenylphosphine) (Pd(PPh3)4> i n THF at room temperature provided a dark brown s o l u t i o n which contained none of the coupled product (12). However, i n the presence of two equivalents of l i t h i u m c h l o r i d e , t h i s same r e a c t i o n mixture y i e l d e d the desired diene (12) i n 91% y i e l d (equation 5 ) . 3 0 - 6 -Pd(PPh ) f X ^ v Pd(PPh ) 4 ( c a O , , 10 12 The c a t a l y s t of choice f o r t h i s r e a c t i o n i s PdCPPl^)^ although others have been tested with varying degrees of s u c c e s s . 3 2 S i m i l a r l y , THF appears to be the solvent favoured by these workers, although other solvents which can both s o l u b i l i z e l i t h i u m c h l o r i d e and act as c a t a l y s t ligands, such as DME, dioxane, HMPA, DMPU, DMSO, and DMF are as equally a c c e p t a b l e . 3 2 S t e r i c hindrance about the v i n y l t r i f l a t e does not a f f e c t the coupling reaction. For example, coupling of 2,5,5-trimethylcyclopent-l-enyl t r i f l a t e (13) with (14) under the same rea c t i o n conditions as out l i n e d above, afforded the diene (15) i n 80% y i e l d (equation 6). 3^ OTf Pd(PPhJ. (cat.) + B u 3 S n / ^ r / 3 4 » X (6) I L i C l \ — ' 13 14 15 One of the a t t r a c t i v e features of t h i s r e a c t i o n l i e s i n the f a c t that v i n y l t r i f l a t e s can be prepared r e g i o s e l e c t i v e l y from ketones using enolate c h e m i s t r y . 4 3 Thus, coupling of ei t h e r 6-methylcyclohexenyl t r i f l a t e (17) or 2-methylcyclohexenyl t r i f l a t e (18) (both prepared from - 7 -2-methylcyclohexanone (16)) with traris-1-(trimethylstannyl)-2-(trimethyl s i l y l ) e t h y l e n e (19), under the t y p i c a l r e a c t i o n conditions, provided the dienes (20) and (21) i n y i e l d s of 100% and 90%, r e s p e c t i v e l y (equation 7 ) . 3 2 TMS (7) On the basi s of some mechanistic work, S t i l l e and coworkers proposed the following c a t a l y t i c cycle f o r the palladium-catalyzed cross-coupling of v i n y l t r i f l a t e s and vinylstannanes (Scheme 1). Thi s mechanism involves, i n i t i a l l y , the oxidative a d d i t i o n of the v i n y l t r i f l a t e (10) to Pd(PPh3)4, i n the presence of l i t h i u m c h l o r i d e , to y i e l d (22) and l i t h i u m t r i f l a t e . In the absence of l i t h i u m c h l o r i d e , oxidative a d d i t i o n of the v i n y l t r i f l a t e (10) to Pd(PPh 3) 4 y i e l d e d a dark brown powder, presumably (25), which would not p a r t i c i p a t e further Scheme 1 - 9 -i n the c a t a l y t i c cycle (equation 8). T h e o r e t i c a l l y , formation of the intermediate (22) can take place by one of two paths (equations 8 and 9). Oxidative a d d i t i o n of the v i n y l t r i f l a t e (10) to PdLn to form the organopalladium(II) t r i f l a t e (25), followed by r e a c t i o n with l i t h i u m c h l o r i d e , would give (22) (equation 8). A l t e r n a t i v e l y , a r e v e r s i b l e r e a c t i o n of l i t h i u m chloride with PdLjj could form a s a l t such as (26) which could then undergo oxidative a d d i t i o n with the enol t r i f l a t e (10) to provide (22) (equation 9). S t i l l e and coworkers c i t e 3^P nmr data CI L — P d - L P d L 4 PdL, OTf LiCl (8) 10 25 22 L — P d L 4 + LiCl ^ : 10 ±r Li*[PdL nCl]' 26 f o r (26) and (22) to support the l a t t e r mechanism. 3 2 Stang and K o w a l s k i ^ have recently reported that the oxidative a d d i t i o n of cyclohexenyl t r i f l a t e (27) to Pt(PPh3)4 provided a stable Pt(II) complex which could be i s o l a t e d . Characterization of t h i s complex indi c a t e d i t to have the structure (28) (equation 10). Further, t h i s complex which contains a a - v i n y l l i g a n d and a non-coordinating t r i f l a t e anion, underwent r e a c t i o n with tetrabutylammonium bromide to y i e l d the neutral - 10 -OTf-Pt (Ph 3 P) A + OTf 6 R 3 P 27 28 Bu^NBr P R 3 (10) 29 trans square p l a n a r product (29) (equation 10). Although one must take care i n e x t r a p o l a t i n g from Pt to Pd, the r e a c t i o n s shown i n equation 10 would l e n d support to the mechanism o u t l i n e d i n equation 8. Returning to Scheme 1, t r a n s m e t a l l a t i o n of the intermediate (22) w i t h v i n y l t r i b u t y l s t a n n a n e (11) y i pin's the t r a n s - b i s (organo)palladium ( I I ) complex (23). The t r a n s m e t a l l a t i o n step i s i n a l l l i k e l i h o o d the ra t e determining step 4-*- 0 and the order of t r a n s f e r of li g a n d s attached to t i n f o l l o w s : PhC=C > CH2=C > Ph > Me. 4 1 c This r e a c t i v i t y order i s c o n s i s t e n t f o r a r e a c t i o n t r a n s i t i o n s t a t e i n which the e l e c t r o p h i l i c v i n y l p a l l a d i u m ( I I ) c h l o r i d e complex (22) a t t a c k s the more n u c l e o p h i l i c carbon attached to t i n , r e s u l t i n g i n the b u i l d up of negative charge at the "more favourable" carbon atom. This group w i l l become the one which i s t r a n s f e r r e d . F i n a l l y , r a p i d trans to c i s i s o m e r i z a t i o n provides the c i s - b i s ( organo)palladium(II) complex (24) and t h i s intermediate undergoes r a p i d - 11 -reductive e l i m i n a t i o n to provide the diene (12) and i n doing so, regenerates the palladium(O) c a t a l y s t . Subsequent to the work which w i l l be presented i n t h i s t h e s i s , S t i l l e and Tanaka reported the synthesis of l a r g e - r i n g lactones v i a the Intramolecular coupling of v i n y l t r i f l a t e s and v i n y l s t a n n a n e s . 3 4 Very recent l y , S t i l l e and Groh described the cross-coupling of vinylstannanes and v i n y l h a l i d e s . 3 3 F i n a l l y , the cross-coupling of vinylstannanes with v i n y l h a l i d e s 4 ^ or v i n y l t r i f l a t e s 3 * i n the presence of carbon monoxide provides, i n good y i e l d , the unsymmetrical d i v i n y l ketone. 1.2.0 Previous Work and Proposals E a r l i e r i n v e s t i g a t i o n s i n our l a b o r a t o r i e s demonstrated that a v a r i e t y of vinylstannanes were a v a i l a b l e by the o v e r a l l hydrostannyla-t i o n ( a d d i t i o n of the elements of Sn and H) of the t r i p l e bonds of a,0-a c e t y l e n i c esters (30) and w-chloro-l-alkynes (31). With the appropriate choice of experimental conditions i n the use of e i t h e r l i t h i u m (phenylthio)(trimethylstannyl)cuprate (32)4*> or the (trimethylstannyl)copper reagent ( 3 3 ) , 4 7 e i t h e r of the geometrically isomeric $-trimethylstannyl esters (34) or (35) could be obtained h i g h l y s t e r e o s e l e c t i v e l y . 4 7 , 4 8 Thus, the conjugate a d d i t i o n of (33) to (30) at -78°C provided s t e r e o s e l e c t i v e l y (>99% s t e r e o s e l e c t i v i t y ) the (£)-ester (35) a f t e r h y d r o l y s i s , 4 7 while at -48°C, the conjugate a d d i t i o n of (32) to (30) produced the (2)-ester (34) as the major product (98% stereo-s e l e c t i v i t y ) a f t e r h y d r o l y s i s 4 8 (Scheme 2). - 12 -Scheme 2 Further, i t was shown that (33) added r e g i o s e l e c t i v e l y to (31) at - 6 3 ° C i n the presence of methanol to provide the w-chloro-2-(trimethyl-stannyl)-1-alkenes (36) i n good y i e l d (equation l l ) . 4 9 HC-=C-(CH2)nCl h J h J ^ ^ 0 2 N 2 . N H 4 C I (pH 8 ) , H O A C M e 3 S n ^ ( C H 2 ) n C l 31 36 - 13 -The vinylstannaries (36) were recognized to be convenient precursors of b i f u n c t i o n a l conjunctive reagents containing p o t e n t i a l donor (d) and acceptor (a) s i t e s . As such, they could conceivably be viewed as being formally equivalent to the donor-acceptor synthons (37). II Me 3Sn^NCH 2) nCl 36 It ScH2)n.,CH2 37 The u t i l i t y of these reagents was demonstrated by t h e i r a p p l i c a t i o n to novel f i v e a n d six-membered r i n g annulation processes. For example, cuprous bromide-dimethyl s u l f i d e catalyzed conjugate a d d i t i o n of the Grignard reagent obtained from 5-chloro-2-(trimethylstannyl)-1-pentene (38) v i a transmetallation with methyllithium at -78°C, followed by treatment with anhydrous magnesium bromide, to the enone (39) y i e l d e d the a d d i t i o n product (40) (equation 1 2 ) . ^ C y c l i z a t i o n was smoothly e f f e c t e d by intramolecular a l k y l a t i o n , employing potassium hydride, to provide the b i c y c l i c ketone (41) (equation 12). (12) 41 - 14 -The u t i l i t y of t h i s methylenecyclohexane annulation process was demonstrated by i t s a p p l i c a t i o n to the t o t a l synthesis of the sesquit-erpenoid (±)-axisonitrile-1 (42) (equation 13).^ 2 From the above discussion i t i s obvious that the vinylstannane (38) i s conveniently prepared from the corresponding terminal acetylene (31) (n — 3) and i s s y n t h e t i c a l l y equivalent to the 1-pentene d 2 .a-'-synthon 41 (13) 42 38 38a (38a). However, the u t i l i z a t i o n of t h i s compound (and others l i k e i t , i . e . (36), n - 2,4 etc.) as a b i f u n c t i o n a l conjunctive reagent i n annulation processes i s l i m i t e d to the i n i t i a l deployment of the p o t e n t i a l donor s i t e (vinylstannane moiety) followed by the use of the p o t e n t i a l acceptor s i t e ( a l k y l halide) (Scheme 3). A u s e f u l , and p o t e n t i a l l y important extension of t h i s methodology would be to reverse the order of deployment of the r e a c t i v e s i t e s of the - 15 -reagents (36), and In t h i s way develop a novel annulation sequence (Scheme 3). Scheme 3 Based on the intermolecular palladium-catalyzed cross-coupling of vinylstannanes and v i n y l t r i f l a t e s developed by S t i l l e and cowork-e r s , 3 0 " 3 4 we envisaged that i n i t i a l intermolecular a l k y l a t i o n of a carbonyl species A with a s u i t a b l y a c t i v e (X - I rather than CI) donor-acceptor reagent, followed by enol t r i f l a t e formation (to C) (according to McMurry 4 3) and f i n a l l y intramolecular coupling, would provide a novel annulation sequence f o r the preparation of b i c y c l i c dienes D (Scheme 4 ) . Further, i t was hoped that not only simple dienes D (R 2 and R 3 - H) - 16 -• enol t r i f l a t e | formation Scheme 4 would be a v a i l a b l e by employing t h i s methodology but that, by u t i l i z i n g (Z)- and (E)-esters such as (34) and (35) (R contains a w-iodo group), s p e c i f i c a l l y s u bstituted dienes D (R 2 or R 3 - ester or d e r i v a t i v e therefrom) would become a v a i l a b l e . I f t h i s annulation process were f e a s i b l e , the novel b i c y c l i c dienes so produced would provide i n t e r e s t i n g substrates with which to probe the Di e l s - A l d e r r e a c t i o n . F i n a l l y , i f the intramolecular coupling was indeed general, the methodology could, i n theory, be applied to natural product synthesis. I t was with these primary goals i n mind that the work to be pre-sented i n t h i s thesis was i n i t i a t e d . - 17 -II. DISCUSSION 2.1.0 Annulations Leading to Bicyclic Dienes 2.1.1 Annulations Employing w-Iodo-2-trimethylstannyl-l-alkenes I n i t i a l l y , we set out to t e s t the f e a s i b i l i t y of the annulation sequence o u t l i n e d In Scheme 4 using the simple donor-acceptor reagents (43) and (44). These reagents were prepared by a simple F i n k e l s t e i n r e a c t i o n from the known 4 9 w-chloro-l-alkenes (36) which i n turn were prepared using a modified v e r s i o n of the reported methodology 4 9 from the appropriate terminal acetylenes (31). For example, addi t i o n of a THF s o l u t i o n of commercially a v a i l a b l e 5-chloro-l-pentyne (45) to a THF s o l u t i o n of 1.3 equivalents of the (trimethylstannyl)copper reagent ( 3 3 ) 4 7 ( - 7 8 ° C , 6 h), followed by workup and chromatography of the crude product, provided the alkene (38) i n 65% y i e l d (equation 14). In a s i m i l a r manner, 6-chloro-1-hexyne (46) ^ 3 was converted into the alkene (47) i n 7 2 % y i e l d (equation 14). As o r i g i n a l l y d e s c r i b e d , 4 9 i t appeared that i t was necessary to have methanol present i n the reac t i o n mixture i n order for 43 n = 2 44 n = 3 36 HCiC-(CH2)nCH2Cl 31 - 18 -HCiC-(CH 2 ) n CH 2Cl Me3SnCu-SMe2 (33) -78°C 1 Me 3Srr^(CH 2) n" XI 45 n = 2 46 n = 3 38 n = 2 47 n = 3 Nal, Me2CO, ref l u x Me3SrrNCH2)n'' (14) 43 n = 2 44 n = 3 the hydrostannylation to proceed to completion. However, we found that even i n the absence of methanol decent y i e l d s of the desired w-chloro -2 -trimethylstannyl-l-alkenes (38) and (47) could be r e a l i z e d on a 15 mmol scale. Presumably, the p o s t u l a t e d 4 ^ intermediate vinylcopper species (48) i s s u f f i c i e n t l y stable that i n s i t u protonation of t h i s species i s not required and acceptable y i e l d s of (36) can be r e a l i z e d by quenching the r e a c t i o n mixture with a proton source (equation 15). 33 31 Me?S-Cu SnMeo H (CH2)n" XI Me OH HO Ac 36 (15) 48 The r e q u i s i t e w-iodo-l-alkenes (43) and (44) were obtained by F i n k e l s t e i n reactions. For example, r e f l u x i n g an acetone s o l u t i o n containing the ch l o r i d e (38) and sodium iodide (5-10 equivalents) afforded the iodide (43) i n 88% y i e l d (equation 14). S i m i l a r l y , the chl o r i d e (47) was converted into the iodide (44) i n 84% y i e l d (equation 14). - 19 -The structures assigned to (43) and (44) were supported by the s p e c t r a l data, e s p e c i a l l y the nmr spectra, of these compounds. For example, the nmr spectrum of the iodide (43) exhibited a 9-proton s i n g l e t at S 0.20 with s a t e l l i t e peaks due to Sn-H coupling (J - 53 Hz), the si g n a l s expected for a M^Sn group. In ad d i t i o n to the two 2-proton m u l t i p l e t s between S 1.7-2.55 ( a l l y l i c and homo-allylic methylene protons), a s i g n a l f o r the -CH2I protons was observed at S 3.20 (2-proton t r i p l e t , J - 7 Hz). In the corresponding c h l o r i d e (38), t h i s t r i p l e t was observed at 5 3.52. F i n a l l y , signals f o r the v i n y l protons were observed at 6 5.23 (1-proton doublet of t r i p l e t s , J = 2.5, 1.5 Hz, J_Sn-H = 74 Hz) and S 5.73 (1-proton doublet of t r i p l e t s , J = 2.5, 1.3 Hz, Jgn-H - 152 Hz). The chemical s h i f t s of the o l e f i n i c protons observed i n the spectrum of (43) (5 5.23 and 5 5.73) are i n agreement with the observation that o l e f i n i c protons i n unsaturated organostan-nanes are shielded 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 group by about 0.5 ppm.^4 Also, when a hydrogen atom and a t r i a l k y l s t a n n y l substituent are v i c i n a l on an o l e f i n i c bond, 2sn-H * s m u c b la r g e r when these two substituents are trans to each other than when they are s i t u a t e d i n a c i s r e l a t i o n . A n a l o g o u s observations were made f o r the iodide (44). The carbonyl compounds used f o r the annulation sequences are e i t h e r commercially a v a i l a b l e ((50) and (55)) or are known compounds that were prepared using known methodology. The y9-keto esters (52)55 and (54)56 were prepared according to the procedure of Deslongchamps and co-workers. 55 The B-keto esters (51)57 a n d (53)57 w e r e prepared according to the procedure of Reich and coworkers.57 A l k y l a t i o n of the potassium enolates of the B-keto esters of general - 20 -structure (49) (prepared by treatment of the /3-keto esters with potassium hydride) with the w-iodo-2-trimethylstannyl-l-alkene (43) proceeded smoothly i n r e f l u x i n g THF. For example, a d d i t i o n of a THF s o l u t i o n of methyl 2-oxocyclopentanecarboxylate (50) to a suspension of potassium hydride i n THF (1.1 equivalents, room temperature, 45 min), followed by a s o l u t i o n of 5-iodo-2-trimethylstannyl-l-pentene (43) i n THF (1.1 equivalents, r e f l u x , 8 h) provided, a f t e r chromatography and d i s t i l l a t i o n of the crude product, the a l k y l a t e d compound (56) i n 60% y i e l d (Entry 1, Table 1). In an i d e n t i c a l fashion the /9-keto esters (51)-(54) were e f f i c i e n t l y a l k y l a t e d to provide the compounds (57)-(60) r e s p e c t i v e l y , and the substrate (50) was a l k y l a t e d with 6-iodo-2-tri-methylstannyl -1-hexene (44) to a f f o r d compound (61) (Table 1). A l k y l a t i o n of 2-methylcyclohexanone (55) with the iodide (43), v i a the potassium enolate of (55) prepared under e q u i l i b r a t i n g conditions (KOBu1^ Bu^H-THF), gave the a l k y l a t e d compound (62) i n 46% y i e l d (Entry 7, Table 1) . Two points regarding two of the reactions summarized i n Table 1 are noteworthy. A l k y l a t i o n of methyl 5-methyl-2-oxocyclopentanecarboxylate (51) and methyl 6-methyl-2-oxocyclohexanecarboxylate (53) with the iodide (43) provided, i n each case, a mixture of C- and 0-alkylated products (equation 17) i n r a t i o s of 96:4 and 3:1, r e s p e c t i v e l y (Entries 2 and 4, Table 1). The formation of O-alkylation products was not observed i n any of the other examples c i t e d i n Table 1. Secondly, a s i n g l e C-alkylated diastereomer was obtained from the a l k y l a t i o n of each of the /9-keto esters (51) and (53). These s t e r e o s e l e c t i v i t i e s and the formation of O-alkylation products can be r a t i o n a l i z e d by consideration - 21 -Table 1: A l k y l a t i o n of Carbonyl Species with w-Iodo -2-trimethyl-stannyl-1-alkenes 0 0 R1 J££ — - m ( q v - - A Y s n M e 3 49 56a Entry Substrate R2 m Conditions Iodide Product n Y i e l d ( % ) b 1 50 C02Me H 1 A 43 56 2 60 2 51 C02Me Me 1 A 43 57 2 57 c 3 52 C02Me H 2 A 43 58 2 91 4 53 C02Me Me 2 A 43 59 2 5 7 d 5 54 C02Me H 3 A 43 60 2 92 6 50 C02Me H 1 A 44 61 3 63 7 55 Me H 2 B 43 62 2 46 a Reaction Conditions: A: KH (1.1 equiv), THF, r t , 30-45 min; (43) or (44) (1.1 equiv), r e f l u x . B: KOBu*- (1.5 equiv), THF-Bu^H (7:1), r t , 30 min; (43) (1.1 equiv), r t , 3 h; H 20. 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. c A 96:4 mixture of C- and O-alkylated products, r e s p e c t i v e l y (by glc) . ^ A 3:1 mixture of C- and O-alkylated products, r e s p e c t i v e l y (by ^H nmr). - 22 -of the po s s i b l e t r a n s i t i o n states involved i n the reactions. Consider i n i t i a l l y the a l k y l a t i o n of methyl 6-methyl -2-oxocyclo-hexanecarboxylate (53). There e x i s t two possible h a l f - c h a i r conforma-tions f o r the enolate anion generated from (53), (63a) and (63b). In conformer (63a), there i s an A^> 2 i n t e r a c t i o n ^ ^ between the pseudo-eq u a t o r i a l secondary methyl group and the carbomethoxy group. This type of i n t e r a c t i o n i s absent i n conformer (63b). Therefore, the ground state energy of (63b) i s predicted to be lower than that of (63a). Following from t h i s argument, i t i s assumed that the t r a n s i t i o n states derived by e l e c t r o p h i l i c attack on the enolate anion (63b) should be lower i n energy than those derived from the enolate anion (63a). I t i s also assumed that a l k y l a t i o n of the enolate anion (63b) i s under stereo-e l e c t r o n i c c o n t r o l and proceeds v i a a t r a n s i t i o n state that has considerable product-like character and i n which the e l e c t r o p h i l e approaches the enolate i n an a x i a l o r i e n t a t i o n . The possible t r a n s i t i o n states derived from (63b) which we must consider are represented by (63c) and (63d). T r a n s i t i o n state (63c) would be d e s t a b i l i z e d by an - 23 -e c l i p s i n g i n t e r a c t i o n between the a x i a l methyl group and the incoming a l k y l a t i n g agent. I t would also be d e s t a b i l i z e d r e l a t i v e to t r a n s i t i o n state (63d) since the t r a n s i t i o n state depicted i n (63c) has a higher energy b o a t - l i k e conformation. Therefore, one would p r e d i c t (63d) to be the t r a n s i t i o n state of lowest energy, leading to the expected product (59). The formation of O-alkylation products i n t h i s r e a c t i o n can also be explained by examining t r a n s i t i o n state (63d). The developing gauche i n t e r a c t i o n between the a x i a l methyl group and the equa t o r i a l ester moiety i n (63d), which would be absent i f the methyl group were simply a hydrogen atom (as i n the a l k y l a t i o n of 0-keto ester (52); see Entry 3, Table 1), r a i s e s the energy of t h i s t r a n s i t i o n state s u f f i c i e n t l y that O - a l k y l a t i o n i s allowed to compete with C - a l k y l a t i o n . The a l k y l a t i o n of methyl 5-methyl-2-oxocyclopentanecarboxylate (51) proceeds i n much the same manner. The enolate anion (63e) generated from (51) i s r e l a t i v e l y f l a t . E l e c t r o p h i l i c attack can occur perpendic-- 24 -u l a r to e i t h e r face of t h i s anion. However, attack from the /3-face v i a t r a n s i t i o n state (63f) w i l l r e s u l t i n a severe s t e r i c i n t e r a c t i o n between the incoming a l k y l a t i n g agent and the secondary methyl group. Since t h i s type of i n t e r a c t i o n i s absent i n e l e c t r o p h i l i c attack from the a-face of (63e), the t r a n s i t i o n state (63g) derived from an a-face approach would be expected to be lower i n energy than t r a n s i t i o n state (63f). Therefore, the expected product would be (57). 63e 63f 63g Employing an argument s i m i l a r to the one d e t a i l e d previously, O - a l k y l a t i o n would be allowed to compete with C - a l k y l a t i o n which takes place v i a t r a n s i t i o n state (63g) because of the developing s t e r i c i n t e r a c t i o n between the secondary methyl group and the ester moiety. The a l k y l a t e d products l i s t e d i n Table 1 displayed spectra i n accord with the assigned structures. For example, the mass spectrum of com-pound (57) exhibited the c h a r a c t e r i s t i c M+-15 ( 1 2 0 S n ) 5 8 peak at m/e 373 and the i r spectrum of (57) displayed absorptions f o r the carbonyl groups (1750 and 1725 cnT^) and the trimethylstannyl group (770 cm'^). Furthermore, the *H nmr spectrum ex h i b i t e d s i g n a l s consistent with the assigned structure. E s p e c i a l l y d i s t i n c t i v e were the si g n a l s due to the Me^Sn protons (6" 0.09, 9-proton s i n g l e t , Jgn-H ~ ->4 Hz), the secondary methyl group (S 1.10, 3-proton doublet, J - 7.5 Hz), the methyl ester (S - 25 -3.63, 3-proton s i n g l e t ) and the o l e f i n i c protons (6 5.10 and 6 5.61, 1-proton s i n g l e t each, Jsn-H ~ 7 2 **z and 152 Hz, r e s p e c t i v e l y ) . In keeping with the goal of devising an annulation procedure based on the intramolecular cross-coupling of a vinylstannane and an enol t r i f l a t e moiety (Scheme 4) the next task at hand was to convert the ketones (56)-(62) into the corresponding enol t r i f l a t e s . Of the methods a v a i l a b l e f o r the preparation of enol t r i f l a t e s from ketone enolates, the procedure o u t l i n e d by McMurry and S c o t t 4 3 was deemed to be most s u i t a b l e . These researchers demonstrated that treatment of 4-tert-butylcyclohexanone (64) with LDA i n DME at -78°C, followed by trapping of the r e s u l t a n t l i t h i u m enolate with N-phenyltrifluoromethanesulfoni-mide (Tf 2NPh) at 0°C, provided the enol t r i f l a t e (10) i n 82% y i e l d (equation 1 8 ) . 4 3 (18) Successive treatment of a THF s o l u t i o n of LDA (1.1 equivalents) at -48°C with a THF s o l u t i o n of the ketone (56) (1 equivalent, 1 h) and Tf 2NPh (1.17 equivalents), followed by warming of the r e a c t i o n mixture to room temperature, provided a f t e r chromatography of the crude product, the enol t r i f l a t e (66) (equation 19) i n 64% y i e l d . The s p e c t r a l data fo r (66) confirmed the s t r u c t u r a l assignment. The i r spectrum of (66) showed a carbonyl absorption at 1740 crn"^- along with absorptions at 1425 cm~^ and 1145 cm"^ (sulfonate asymmetric and symmetric stretches, - 26 -TfO <?02Me •SnMe3 (19) 56 66 r e s p e c t i v e l y ) . The -"-H nmr spectrum exhibited the expected si g n a l s f o r the a l i p h a t i c protons (6 1.10-2.75, 10 protons), the methyl ester (5 3.75, 3-proton s i n g l e t ) and the trimethylstannyl group (5 0.18, 9-proton s i n g l e t , J_sn-H ~ ^3 Hz). In addition, three o l e f i n i c proton signals were observed at 6 5.15 (1-proton doublet of t r i p l e t s , J - 2.8, 1.3 Hz, J S n . H - 72 Hz), S 5.65 (1-proton doublet of t r i p l e t s , J - 2.8, 1.4 Hz, J_gn_H - 152 Hz) and 6 5.78 (1-proton m u l t i p l e t , v\/2 ~ -> Hz). The preparation of a v a r i e t y of enol t r i f l a t e s of general structure (65) from the corresponding a l k y l a t e d materials (56) using t h i s procedure i s summarized i n Table 2. In a l l cases, the enol t r i f l a t e d e r i v a t i v e was p u r i f i e d by column chromatography on s i l i c a g e l . Decomposition of these products, due to the l a b i l i t y of the enol t r i f l a t e moiety on heating, precluded t h e i r p u r i f i c a t i o n by d i s t i l l a -t i o n . Nonetheless, ^H nmr analysis of the chromatographically p u r i f i e d products i n d i c a t e d that they were of s u f f i c i e n t p u r i t y (>95% pure) to carry through to the next step. The sp e c t r a l properties of the products (67)-(71) were s i m i l a r to those o u t l i n e d f o r (66) and were i n agreement with t h e i r assigned structure. With a v a r i e t y of vinylstannane-enol t r i f l a t e s i n hand, we set out to t e s t the f e a s i b i l i t y of u t i l i z i n g them i n an intramolecular coupling reaction, the type of which S t i l l e and coworkers had demonstrated to be Entry Substrate R m n Product Y i e l d (%) b 1 56 H 1 2 66 64 2 57 Me 1 2 67 62 3 58 H 2 2 68 71 4 59 Me 2 2 69 84 5 60 H 3 2 70 63 6 61 H 1 3 71 63 a Reaction Conditions ( 1 . 1 7 - 1 . 5 7 equiv), : LDA ( 1 -48°C to . 1 - 1 . 5 r t , 30 equiv), min. THF, -48°C, 1 h; Tf 2NPh Y i e l d of chromatographically p u r i f i e d product. - 28 -p o s s i b l e intermolecularly. 30 The r e s u l t s of t h e i r work indi c a t e d that the solvent and c a t a l y s t of choice were THF and palladium t e t r a k i s ( t r i -phenylphosphine) (Pd(PPh 3)4), r e s p e c t i v e l y . Thus, monitoring a r e f l u x i n g THF s o l u t i o n of the vinylstannane-enol t r i f l a t e (66) and 0.05 equivalents of Pd(PPh 3)4 by g l c i n d i c a t e d that (66) was c l e a n l y converted into a single compound i n 11 hours. I s o l a -t i o n and c h a r a c t e r i z a t i o n of t h i s compound showed that the b i c y c l i c diene (73) had been formed i n 82% y i e l d (equation 20). The g e n e r a l i t y of t h i s novel and i n t e r e s t i n g annulation sequence was demonstrated by converting the vinylstannane-enol t r i f l a t e s (67)-(71) into the annulation products (74)-(78), r e s p e c t i v e l y (Table 3). The dienes (74)-(78) were prepared by employing a procedure which was i d e n t i c a l with that o u t l i n e d above for the preparation of (73). The y i e l d s were u s u a l l y greater than 80%. The only v a r i a b l e i n these reactions was the r e a c t i o n time required f o r the complete conversion of the substrate (65) into the diene (72), with no p a r t i c u l a r trend being immediately obvious. The c y c l i z a t i o n of the substrates (66)-(71) i n THF proceeded by the i n i t i a l formation of a deep red s o l u t i o n upon the a d d i t i o n of Pd(PPh 3)4. This was followed during the course of the r e a c t i o n by the deposition of a f i n e black powder (palladium black) as w e l l as a darkening of the r e a c t i o n mixture to a dark brown colour. The (20) 66 C0,Me 73 - 29 -Table 3: The Preparation of B i c y c l i c Dienes of General Structure ( 7 2 ) a 65 7 2 Entry Substrate R m n Time ( h ) a Product Y i e l d (%) b 1 66 H 1 2 11 73 82 2 67 Me 1 2 9 74 82 3 68 H 2 2 3 75 90 4 69 Me 2 2 19 76 86 5 70 H 3 2 3 77 85 c 6 71 H 1 3 23 78 50 a Reaction Conditions: Pd(PPh 3) 4 (5 mol % ) , THF, r e f l u x . 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. This product was a mixture of several diene isomers which, on the ba s i s of g l c a n a l y s i s , contained 85% of the desired diene (77). - 30 -crude product mixture was e s s e n t i a l l y composed of the expected diene and inorganic materials (see Entry 5, Table 3 f o r the lone exception). I s o l a t i o n of the dienes (73)-(78) so produced was e a s i l y accomplished simply by removing the solvent under reduced pressure and subjecting the r e s u l t i n g crude o i l to f l a s h chromatography on s i l i c a g e l . Several points about the coupling r e a c t i o n i t s e l f deserve mention. S t i l l e and coworkers indicated that l i t h i u m c h l o r i d e was a necessary a d d i t i v e f o r the intermolecular cross-coupling of the enol t r i f l a t e (10) and vinylstannane (11) to take place (see equation 5 ) . 3 ^ They postulated that i n the absence of l i t h i u m c h l o r i d e , the palladium c a t a l y s t was e f f e c t i v e l y removed from the c a t a l y t i c c y c l e as the organo palladium(II) t r i f l a t e (25) (equation 21) since transmetallation of t h i s species with the vinylstannane (11) d i d not occur. The reasons for the lack of r e a c t i v i t y i n the absence of l i t h i u m c h l o r i d e were not discussed. A possible explanation may be that the intermolecular rate of transmetallation of (25) with (11) i s slow, allowing other u n i d e n t i f i e d , detrimental side reactions to predominate (equation 21). (21) side reactions - 31 -In our examples, no lithium chloride is required for the successful intramolecular coupling of the vinylstannane and enol triflate moieties. The success of these reactions in the absence of lithium chloride may simply be due to the intramolecular nature of the process. Thus, i t is plausible that the transmetalation of the organopalladium(II) triflate species with the vinylstannane moiety in (79) (step B, Scheme 5) may be sufficiently fast intramolecularly that the rate determining step of the overall coupling process is the in i t i a l oxidative addition reaction (step A, Scheme 5) to form (79). Furthermore, the relatively high rate at which the intramolecular transmetalation occurs apparently precludes the potentially competing decomposition of the organopalladium(II) triflate moiety (such as in (25)). Transmetalation in (79) (step B, Scheme 5) provides necessarily the cis-bis (organo)palladium(II') intermediate (80), since the formation of the corresponding trans isomer would be impossible under the cyclic constraints of the system. Intermediate (80) can then undergo fast reductive elimination to provide the diene (72) (step C, Scheme 5). A single qualitative experiment, designed to test the effect of lithium chloride on the cyclization of the substrate (66), was performed. Compound (66), lithium chloride (10 equivalents) and Pd(PPh3)4 (2 mol %) were allowed to react as described above. The results indicated that the rate of the cyclization decreased (75% conversion after 15 h) and that the isolated yield of the resulting diene (73) likewise decreased (58% yield) (Entry 9, Table 4). Thus, the presence of lithium chloride appeared to decrease the efficiency of the intramolecular coupling reaction. Scheme 5 - 33 -A s e r i e s of reactions were c a r r i e d out to determine i f the solvent and c a t a l y s t of choice f o r the intramolecular coupling r e a c t i o n were THF and Pd(PPh3)4, r e s p e c t i v e l y . The r e s u l t s of the c y c l i z a t i o n of substrate (66) under various r e a c t i o n conditions are summarized i n Table 4. Of the several palladium c a t a l y s t s tested, Pd(PPh3)4 i s c l e a r l y superior to the others. Also, i t appears that THF and CH3CN are equally a t t r a c t i v e as re a c t i o n solvents i f only the y i e l d of the expected diene i s examined. However, the re a c t i o n i n CH3CN appears to be considerably f a s t e r than that i n THF (compare Entries 1 and 7, Table 4). The success of t h i s r e a c t i o n i n CH3CN i s i n contrast to the report of S t i l l e and coworkers. 3 2 They observed that i n CH3CN, the coupling of (10) with (11) proceeded i n 77% y i e l d i n 24 hours while i n THF, the diene (12) was produced i n 95% y i e l d i n the same time peri o d (equation 22). The r a t i o n a l e given was that CH3CN does not s o l u b i l i z e l i t h i u m c h l o r i d e w e l l , leading to the eventual decomposition of the c a t a l y s t under the re a c t i o n c o n d i t i o n s . 3 2 Bu 0SnCHCH 0 (11), L i C l 3 2 r 1^ (22) P d ( P P h 3 ) 4 ( cat . ) THF, 95% CH3CN, 77% In connection with another aspect of t h i s thesis ( r e f e r to the se c t i o n on the synthesis of the dolastane diterpenoids) i t was thought that the e f f i c i e n c y of the o v e r a l l annulation sequence might be improved i f the two steps (enol t r i f l a t e formation and coupling of the v i n y l -- 34 -Table 4: C y c l i z a t i o n of Substrate (66) Under Various Reaction C o n d i t i o n s 3 • C0 2Me 66 73 Entry Solvent Catalyst Time (h) % Conversion^ Y i e l d (%) c 1 THF Pd(PPh 3) 4 8 100 88 2 THF Pd(PhCN) 2Cl 2 17 <5 --3 THF P d ( P E t 3 ) 2 C l 2 17 96 51 4 THF Pd(OAc) 2 21 43 --5 THF P d C l 2 17 0 --6 THF Pd(PPh 3) 2(CH 2Ph)Cl 17 6 7 CH3CN Pd(PPh 3) 4 4 100 90 8 PhH Pd(PPh 3) 4 15 65 9 THF P d ( P P h 3 ) 4 d 15 75 58 e Reaction Conditions: c a t a l y s t (5 mol % ) , solvent, r e f l u x . Amount of substrate consumed based on g l c analysis (assuming that a l l new peaks appearing on the glc or i g i n a t e from the substrate and that a l l new compounds produced can be observed by g l c a n a l y s i s ) . Glc y i e l d of (73) (diene (74) as i n t e r n a l standard). 10 equivalents of L i C l present. Y i e l d of p u r i f i e d , i s o l a t e d product. - 35 -stannane and enol t r i f l a t e moieties) were combined into a "one pot" process (Scheme 6). I t was f e l t that the r e l a t i v e l y low y i e l d of the enol t r i f l a t e s (66)-(71) (Table 2, y i e l d s from 62-83%) was due p r i m a r i l y to t h e i r decomposition on s i l i c a gel i n the chromatographic p u r i f i c a t i o n procedure. Consequently, i t was hoped that i s o l a t i o n of the p o t e n t i a l l y unstable enol t r i f l a t e (65) could be avoided. m R ' ' C0 2Me 72 Scheme 6 In the event, a THF s o l u t i o n of the ketone (58) (1 equivalent) was added to a THF s o l u t i o n of LDA (1.5 equivalents) and HMPA (2 equiva-lents) at -78°C. Treatment of the r e a c t i o n mixture a f t e r 70 minutes (10 minutes at -78°C, 1 h at 0°C) with Tf 2NPh (1.57 equivalents) provided the corresponding enol t r i f l a t e (68) as a s o l u t i o n i n THF. A d d i t i o n of Pd(PPh3)4 (3 mol % ) , followed by r e f l u x i n g the r e a c t i o n mixture f o r 5 h, afforded the diene (75) i n 72% y i e l d (equation 23). In contrast, preparation of the diene (75) v i a a "two pot" procedure was accomplished - 36 -i n a 64% o v e r a l l y i e l d (see Entry 3, Table 2 and Entry 3, Table 3). The dienes prepared i n each of these reactions exhibited i d e n t i c a l spectra (1-H nmr, i r , mass). 62 R=Me 8 1 p=Me (24) In a s i m i l a r manner, the ketone (62) (Entry 7, Table 1) was converted into the diene (81) i n 55% o v e r a l l y i e l d (equation 24). The preparation of the b i c y c l i c dienes (73)-(78) and (81) constit u t e s a novel annulation procedure. The unique, s t r u c t u r a l l y i n t e r e s t i n g b i c y c l i c dienes a l l gave spectra i n accord with the assigned structures. Several points regarding the spectra of these compounds are i n order. In ad d i t i o n to an absorption due to the carbonyl group (-1720 cm~l), the i r spectra exhibited a weak band at -1620 cm'^ and a medium strength band at -890 crn"^-. These absorptions are c h a r a c t e r i s t i c of the conjugated diene u n i t and R]^R2C=CH2 u n i t , r e s p e c t i v e l y . ^ 0 The ^-H nmr spectra were also consistent with the assigned structures. In p a r t i c u -l a r , the three o l e f i n i c proton signals were d i s t i n c t i v e . For example, i n the -^H nmr spectrum of the diene (75) (Figure 1) the three v i n y l protons are observed at 5 4.64 ( t r i p l e t , J a D = J a d - 2.5 Hz), 8 4.92 ( t r i p l e t , J a b - J b d - 2.5 Hz) and S 5.86 ( t r i p l e t , J c f - J^g - 4 Hz). These signals were assigned to the protons H a, H D and H c, resp e c t i v e l y , on the basis of decoupling experiments and a differe n c e nuclear Over-- 37 -hauser enhancement (nOe) experiment. Thus, i r r a d i a t i o n at S 4.64 (H a) s i m p l i f i e d the s i g n a l at S 4.92 (H D) to a broad s i n g l e t while i r r a d i a t i o n at 6 4.92 (H b) s i m p l i f i e d the s i g n a l at 6 4.64 (H a) to a broad s i n g l e t . Neither of these decoupling experiments caused a change i n the s i g n a l at 6 5.86 (H c). However, i r r a d i a t i o n of H c (5 5.86) i n a differ e n c e nOe experiment caused s i g n a l enhancement at S 4.92 (H^) and not at 6* 4.64 (H a) (see Figure 1). A s i m i l a r pattern for the o l e f i n i c proton chemical s h i f t s i s observed f o r a l l of the dienes l i s t e d i n Table 3. In each case, the exo c y c l i c methylene protons give r i s e to signals between 6 4.6 and S 5.2 while the o l e f i n i c r i n g proton resonates between 6 5.6 and 5 6.0. In summary, i t was found that u t i l i z a t i o n of the w-iodo-2-trimethyl-stannyl-l-alkenes (43) and (44) i n annulation sequences f o r the preparation of dienes of general structure (72) i s f e a s i b l e (see Tables 1, 2, and 3). We wished to extend the u t i l i t y of t h i s methodology to Include the preparation of s p e c i f i c a l l y substituted dienes of general structures (82) and (83) as w e l l as b i c y c l i c dienes i n which both double bonds were endocyclic i n nature, such as In (84). Success of t h i s goal would require the preparation and use of donor-acceptor reagents of the - 38 -39 general structures (85), (86) and (87), r e s p e c t i v e l y . The study d i r e c t e d towards the preparation of these dienes i s o u t l i n e d i n the next section. 2.1.2 Annulations Employing Methyl (E)- and (Z)-e-Iodo-S-trimethyl-stannyl^-hexenoates , Derivatives Therefrom and (Z)-l-Bromo-4-me thy1-3-trime thy1stanny1-2-pentene The a,y9-acetylenic esters required f o r t h i s study, methyl 6-chloro-2-hexynoate (91) and methyl 4-methyl-2-pentynoate (92) , were prepared as follows. Deprotonation of the commercially a v a i l a b l e 1-alkynes (45) and (88) with methyllithium, followed by re a c t i o n of the r e s u l t i n g alkynyl-l i t h i u m species (89) and (90) with methyl chloroformate, provided the a c e t y l e n i c esters (91) and (92) i n y i e l d s of 93% and 94%, r e s p e c t i v e l y (equation 25). - 40 -MeLi ClC0 2Me R - C =C-H ^ R-CiC-Li =— R -C5C-C0 2 Me (25) 45 R=C1(CH 2) 3 89 91 88 R=Me2CH 90 92 Previous work i n our l a b o r a t o r i e s 4 ' ' 4 8 had est a b l i s h e d that the Me 3Sn group of e i t h e r l i t h i u m (phenylthio)(trimethylstannyl)cuprate ( 3 2 ) 4 6 or (trimethylstannyl)copper(I) dimethylsulfide ( 3 3 ) 4 7 could be added s t e r e o s e l e c t i v e l y to a./9-acetylenic esters to provide e i t h e r the (Z)- or the (E)-/9-trimethylstannyl-a,/?-unsaturated esters (34) and (35), r e s p e c t i v e l y (Scheme 2). R H Me 3 S n ' F ^ C 0 2 M e 34 32 R-C5C-C0 2 Me 33 R C02Me " M e 3 S n > l 30 35 Thus, the a,/}-acetylenic esters (91) and (92) were converted into the corresponding (Z) esters (93) and (94) v i a the reported procedure. 4 8 For example, a d d i t i o n of a THF s o l u t i o n of methyl 4-methyl-2-pentynoate (92) to a THF s o l u t i o n of 1.3 equivalents of the cuprate reagent (32) (-78°C, 15 min; -48°C, 4 h), followed by a d d i t i o n of methanol, workup, and chromatography of the crude material, produced the (Z) ester (94) i n 83% y i e l d (equation 26). In a s i m i l a r manner, methyl 6-chloro-2-hexy-noate (91) was converted into the (Z) ester (93) i n 87% y i e l d (equation 26). In each case, a d d i t i o n of petroleum ether (instead of d i e t h y l - 41 -[Me 3SnCuSPh]Li, p H R-CEC-C02Me — » Me3Sn>=<C02Me <26> -48°C; Me OH 91 R=C1(CH 2) 3 93 94 92 R=Me2CH ether as o r i g i n a l l y reported) i n the workup procedure caused a more ra p i d and complete p r e c i p i t a t i o n of (phenylthio)copper. In addition, i n each case, f l a s h chromatography of the crude material was required to remove hexamethylditin and a small amount (2-3% by glc) of the isomeric (E) ester that was formed from the reaction. The a,£-acetylenic ester (91) was converted into the corresponding (E) ester (95) v i a the reported procedure. 4 7 Thus, r e a c t i o n of methyl 6-chloro-2-hexynoate (91) with 1.3 equivalents of the (trimethylstan-nyl)copper reagent (33) at -78°C f o r 3 h i n THF, followed by a d d i t i o n of saturated aqueous ammonium chloride (pH 8), workup, and chromatography of the crude r e a c t i o n product, afforded the (E) ester (95) i n 79% y i e l d (equation 27). Me SnCu-SMe , / \ .CO^ Me Cl(CH2)3C?C-C02Me —y • C\-f W (27) -78°C; NH4C1 (pH 8) Me3bn H The structures assigned to the /?-trimethylstannyl-a,^-unsaturated esters (93)-(95) were supported by the spectra exhibited by these compounds. In p a r t i c u l a r , the ^H nmr spectra were u s e f u l f o r confirming - 42 -the stereochemical assignments. For example, i n comparing the nmr spectra of the (Z) ester (93) with the (E) ester (95), three s i g n i f i c a n t d ifferences are observed. The a l l y l i c methylene protons i n (93) and (95) are observed at S 2.59 (2-proton broad t r i p l e t , J = 7 Hz) and S 3.00 (2-proton broad t r i p l e t , J = 7 Hz). I t i s reasonable to assume that the downfield s h i f t experienced by the a l l y l i c methylene protons i n (95) compared to those i n (93) i s due to the c i s d i s p o s i t i o n of the 7-protons and the ester group i n ( 9 5 ) . ^ Secondly, the chemical s h i f t s of the o l e f i n i c protons i n (93) and (95) are 5 6.40 (1-proton t r i p l e t , J = 1.5 Hz, Isn-H = 1 1 7 H z> a n d * 5 - 9 9 (1-proton t r i p l e t , J - 1 Hz, Isn-H = 71 Hz), re s p e c t i v e l y . These chemical s h i f t s are i n agreement with the observation that 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 substituent on an o l e f i n i c bond shields the o l e f i n i c proton by about 0.5 ppm.^4 T h i r d l y , i t has been observed that when a proton and a t r i a l k y l s t a n n y l group are v i c i n a l on an o l e f i n i c bond, the Sn-H coupling constant i s much larger when they are trans than when they are c i s to each o t h e r . ^ 4 In t h i s case, we observe sI_sn-H t o he 117 Hz and 71 Hz f o r the (Z) ester (93) and the (E) ester (95), r e s p e c t i v e l y . The stereochemical outcome of the reaction of the (trimethylstannyl) copper reagent (33) and the cuprate reagent (32) with a,/3-acetylenic esters of general structure (30) can be r a t i o n a l i z e d as f o l l o w s . ^ 2 Cis ad d i t i o n of (32) or (33) to (30) i n i t i a l l y provides the vinylcuprate or vinylcopper species (96) or (97), r e s p e c t i v e l y (the " k i n e t i c " i n t e r -mediate) (Scheme 7). The s t a b i l i t y of (96) or (97) i s contingent upon several f a c t o r s . The main factors i n t h i s case appear to be the c o n s t i t u t i o n of the copper species (96) and (97) and the re a c t i o n - 43 -temperature. Depending on these factors (and p o s s i b l y a d d i t i o n a l considerations such as the reaction solvent, the s i z e of R, the possible oligomeric structure of the copper containing intermediates), (96) or (97) may rearrange to the copper allenoates (98) or ( 9 9 ) . ^ Protonation of (96) or (97) would provide (35), while protonation of (98) or (99) would provide the geometrical isomer (34). Apparently, at lower temperatures (-48° to -78°C) (97) does not rearrange to (99) and, thus, protonation provides s t e r e o s e l e c t i v e l y the (E) ester (35). On the other hand, at -48°C, (96) does rearrange to the allenoate (98) which, upon protonation, provides s t e r e o s e l e c t i v e l y the (Z) ester (34) (Scheme 7). 32 R-CiC -C0 2Me ^ 30 or 33 p p — w h e 3 S n ' v C 0 2 M e CuX R > , C 0 2 M e M e 3 S n > l 96 97 X=(SPh) L i X=SMe„ 35 r r |Me3Sn OMe OCuX 1- Me3S R H n^^CO-jMe 98 X=(SPh)Li 99 X=SMen 34 Scheme 7 - 44 -The s t e r e o s e l e c t i v i t y observed i n the k i n e t i c protonation of (98) can be r a t i o n a l i z e d i n two ways. The ester (34) would be expected to be more stable than (35) because the M^Sn group (A value - 0.94 k c a l / mol*>4) i s le s s s t e r i c a l l y demanding than an a l k y l group (A value f o r the methyl group, f o r example i s 1.74 k c a l / m o l ^ ) . Therefore, assuming that the t r a n s i t i o n state of k i n e t i c protonation of (98) has some product l i k e character, the stereochemistry observed i n (34) i s to be expected. A l t e r n a t i v e l y , k i n e t i c protonation of (98) would be expected to take place by the approach of the protonating species to the l e s s hindered side of the allenoate. Since the MejSn group i s b u l k i e r than the R group, and thus more s t e r i c a l l y hindering to the approach of the protonating species, (34) would be the expected product. Viewed s o l e l y from the p o t e n t i a l u t i l i t y i n synthesis, t h i s metho-dology provides c l e a n l y and e a s i l y e i t h e r of the desired Q,^-unsaturated esters (34) or (35). With qu a n t i t i e s of the (Z) and (E) esters (93) and (95) i n hand, we set out to convert them into the desired donor-acceptor reagents (86) and (85), r e s p e c t i v e l y . H^CO^Me 1 Me 3SrT > _ _ ^ M e 3 S n s i Me3Sn Reduction of the a.^-unsaturated esters (93) and (95) with diisobutylaluminum hydride (DIBAL) was e f f e c t e d without incident to - 45 -provide the corresponding allylic alcohols. For example, addition of a hexane solution of DIBAL (2.5 equivalents) to a solution of the (Z) ester (93) in diethyl ether (-78°C, 1 h; 0°C, 2 h) provided the allylic alcohol (100) in 97% yield after distillation of the crude reaction product (equation 28). Alcohol (100) displayed the expected absorption at 3350 cm"^ - in the i r spectrum as well as a one-proton triplet (exchangeable with D20) in the nmr spectrum at 6 1.41. In a similar manner, the (E) ester (95) was converted into the corresponding allylic alcohol (101) in 89% yield (equation 28). The alcohols (100) and (101) were protected as the corresponding methoxymethoxy (MOM) and tert-butyldimethylsiloxy (TBDMS) ethers (102)-(105). For example, reaction of the (Z) allylic alcohol (100) with chloromethyl methyl ether (MOM-Cl) (1.5 equivalents) in the presence of ethyldiisopropylamine (1.5 equivalents) in methylene chloride at room temperature provided, after distillation of the crude reaction product, the MOM ether (102) in 87% yield (equation 29). The nmr spectrum of (102) displayed the expected signals for the -OCH2OCH3 moiety at S 3.35 (3-proton singlet) and S 4.62 (2-proton singlet). The (E) allylic alcohol (101) was converted in a similar manner into the MOM ether (103) in 94% yield (equation 29). DIBAL, E t 2 0 CI (28) - 46 -CI Me 3Sn y 100 R L=H, R2=CH2OH 101 R^CH OH, R2=H C1CH20CH3, CH 2C1 2 (29) 102 R3=H, R4=CH OMOM 3 4 103 R =CH2OMOM, R =»H Reaction of the (Z) a l l y l i c alcohol (100) with TBDMS-C1 (1.2 equivalents) i n the presence of imidazole (2.5 equivalents) i n DMF (room temperature, 15 h), followed by workup and d i s t i l l a t i o n of the crude product, produced the s i l y l ether (104) i n 89% y i e l d (equation 30). Again, -^H nmr spectroscopy provided evidence f o r the formation of the s i l y l ether (104) (6-proton s i n g l e t at 6 0.06 and a 9-proton s i n g l e t at 6 0.90). S i m i l a r l y , the (E) a l l y l i c alcohol (101) was converted into the corresponding s i l y l ether (105) i n 84% y i e l d (equation 30). CISiMe Bu*. DMF C l M e 3 S r / V C l M e 3 S r / = = V (30) 100 R^H, R2=CH20H 104 R3=H, R 4=CH 20SiMe^u* 101 R1=CH20H, R2=H 105 R^O^OSiMe'^u 1 1, R4=H The (£) a l l y l i c alcohol (101) was also converted i n t o the (E ) - 3 -heptene (107). I n i t i a l l y , the a l l y l i c acetate (106) was prepared by treatment of the alcohol (101) with a c e t i c anhydride (1.5 equivalents), 4-N,N-dimethylaminopyridine (0.1 equivalents) and triethylamine (1.5 equivalents) i n methylene chloride (room temperature, 15 h). The - 47 -a l l y l i c acetate (106) was obtained i n 97% y i e l d (equation 31). The spectra exhibited by (106) confirmed that the acetate group had been incorporated i n t o the molecule (carbonyl absorption at 1741 cm'^ i n the i r spectrum and a 3-proton s i n g l e t at S 2.07 i n the *H nmr spectrum). Displacement of the a l l y l i c acetate moiety was e f f e c t e d by r e a c t i o n of (106) with l i t h i u m dimethylcuprate (2 equivalents) i n d i e t h y l ether (0°C, 15 m i n ) . 6 7 D i s t i l l a t i o n of the crude material provided the (E)-3-heptene (107) i n 87% y i e l d (equation 31). The *H nmr spectrum of (107) displayed the expected signals f o r the e t h y l moiety at 6 0.98 (3-proton t r i p l e t , J - 7 Hz) and 6 2.14 (2-proton quintet, J - 7 Hz). 101 106 Me 0CuLi / V C H o C H - i 1 r\-J \=U L * (3D E t 2 o M e 3 S n ^ > < 107 Each of the primary chlorides (93), (95), (102)-(105) and (107) were e a s i l y and e f f i c i e n t l y converted into the corresponding primary iodides (108)-(114) by employing a F i n k e l s t e i n r e a c t i o n as described previously (Table 5). The s p e c t r a l data derived from each of these iodides f u l l y corroborated the assigned structures. Most informative i n the ^H nmr spectra was the observed chemical s h i f t of the - C H 2 I protons. In going from the ch l o r i d e to the analogous iodide, an expected68 u p f i e l d s h i f t f o r these methylene protons of about 0.35 ppm was observed i n each case. - 48 -Table 5: Preparation of Primary Iodides from the Corresponding C h l o r i d e s 3 Entry Chloride R l R 2 Iodide Y i e l d (%) b 1 93 H C02Me 108 98 2 95 C02Me H 109 94 3 102 H CH20M0M 110 94 4 103 CH20M0M H 111 95 5 104 H CH 2OSiMe 2Bu t 112 86 6 105 CH 2OSiMe 2Bu t H 113 93 7 107 CH 2CH 3 H 114 94 a Reaction Conditions: Nal (5-7 equivalents), Me2C0, r e f l u x . b Y i e l d of p u r i f i e d , d i s t i l l e d products. - 49 -The stage was now set to tes t the f e a s i b i l i t y of the annulation sequence o u t l i n e d i n Scheme 4 using substituted donor-acceptor reagents of general structures (85) and (86 ) . A l k y l a t i o n of the potassium enolates of the /9-keto esters (50) and (52) , as previously described, with the w-iodides (108)-(114) proceeded c l e a n l y i n r e f l u x i n g THF to a f f o r d the corresponding a l k y l a t e d sub-stances (116)-(126) (Table 6). These a l k y l a t e d materials displayed spectra i n accord with the assigned structures. For example, the isomeric compounds (121) and (123) each exhibited the c h a r a c t e r i s t i c M+-15 (^-20sn)^8 peak at m/e 447 i n t h e i r mass spectra and the i r spectra displayed carbonyl absorptions at 1710 and 1715 cm'^ and absorptions due to the Me3Sn groups at 779 and 772 cm'^, re s p e c t i v e l y . The ^H nmr spectra of (121) and (123) exhibited signals consistent with the assigned structures. T y p i c a l were the signals due to the M^Sn protons at 8 0.15 i n (121) (9-proton "singlet, I s n - H = 5 3 H z ) a n d 5 i n (123) (9-proton s i n g l e t , Jg n_H = 53 Hz), the methyl ester at 8 3.70 i n (121) and 6 3.71 i n (123) (3-proton s i n g l e t each), and the o l e f i n i c protons at 8 6.12 i n (121) (1-proton t r i p l e t , J = 6 .3 Hz, I s n - H = 1 3 1 H z ) a n d at 5 5.72 i n (123) (1-proton t r i p l e t , J = 6 Hz, Isn-H = 7 7 H z ) • The a l k y l a t i o n s summarized i n Table 6 were very clean, providing only C-alkylated adducts and none of the corresponding O-alkylated isomers. The a l k y l a t e d materials (116)-(126) were u t i l i z e d i n the c y c l i z a t i o n procedure based on the intramolecular coupling of vinylstannane and enol t r i f l a t e moieties. In procedures i d e n t i c a l with those described previously, b i c y c l i c dienes of general structure (128) were obtained v i a - 50 -Table 6: A l k y l a t i o n of B-Keto Esters with Methyl (Z)- and (E)-6-Iodo-2-trimethylstannyl-2-hexenoates and Derivatives Therefrom 3 m 49 115 Entry Substrate m Iodide R 1 R z Product Y i e l d (%) 1 50 1 108 H C02Me 116 63 2 52 2 108 H C02Me 117 71 3 50 1 109 C02Me H 118 78 4 52 2 109 C02Me H 119 57 5 50 1 110 H CH20M0M 120 68 6 52 2 110 H CH20M0M 121 70 7 50 1 111 CH20M0M H 122 67 8 52 2 111 CH20M0M H 123 74 9 52 2 112 H CH 20SiMe 2Bu t 124 69 10 52 2 113 CH 20SiMe 2Bu t H 125 88 11 52 2 114 CH 2CH 3 H 126 75 Reaction Conditions: KH (1.1 equiv), THF, r t , 30-45 min; (108)-(114) (1.1 equiv), r e f l u x . Y i e l d of p u r i f i e d , d i s t i l l e d product. - 51 -the intermediate enol t r i f l a t e s (127) (Table 7). The diene preparation proceeded by coupling of the vinylstannane - enol t r i f l a t e s i n t r a -molecularly using Pd(PPh3) 4 and was accomplished by means of e i t h e r a "two pot" (Entries 1-5, 7, 8 and 10, Table 7) or "one pot" (Entries, 6, 9, 11-13, Table 7) sequence. Preparation of the i s o l a t e d enol t r i f l a t e s (129)-(136) from the substances (116)-(123), r e s p e c t i v e l y , proceeded v i a a procedure i d e n t i c a l with that described e a r l i e r . The structures of the enol t r i f l a t e s (129)-(136) were f u l l y corroborated by the s p e c t r a l data derived from these compounds. No further comment need be made regarding these reactions other than to point out that deprotonation of those substrates containing an a,/9-unsaturated ester moiety (compounds (116)-(119)) occurred chemoselectively by removal of a proton adjacent to the ketone function. As was observed e a r l i e r , the i n s t a b i l i t y of the derived enol t r i f l a t e s (127) to s i l i c a gel chromatography may account for several of the lower y i e l d s shown i n Table 7. A s i g n i f i c a n t increase i n the o v e r a l l y i e l d of the diene was obtained when a "one pot" r e a c t i o n sequence was c a r r i e d out as opposed to a "two pot" procedure. For example, preparation of the c i s o i d trans diene (143) was accomplished i n an 84% o v e r a l l y i e l d from the substrate (122) i n a "one pot" process while the same conversion was achieved i n 73% o v e r a l l y i e l d v i a a "two pot" sequence (Entries 8 and 9, Table 7). An i n t e r e s t i n g observation can be made regarding the choice of c a t a l y s t i n the "one pot" process. Replacing Pd(PPh.3)4 with Pd(0Ac)2 i n two of the reactions (Entries 11 and 12, Table 7) r e s u l t s i n the formation of the dienes (145) and (146) i n only s l i g h t l y lower y i e l d s . - 52 -Table 7: Preparation of C i s o i d Cis and C i s o i d Trans B i c y c l i c Dienes from the Alkylated Compounds (115) i n Ei t h e r a "One Pot" or "Two Pot" Reaction Sequence a 128 Entry Substrate m R 1 R z Enol Y i e l d Diene Y i e l d T r i f l a t e ( %) b (%) c 1 116 1 H C02Me 129 64 137 75 2 117 2 H C02Me 130 64 138 75 3 118 1 C02Me H 131 57 139 89 4 119 2 C02Me H 132 62 140 90 5 120 1 H CH20M0M 133 84 141 86 6 120 1 H CH20M0M - - 141 73 f 7 121 2 H CH20M0M 134 90 142 87 8 122 1 CH20M0M H 135 88 143 83 9 122 1 CH20M0M H - - 143 84 f 10 123 2 CH20M0M H 136 92 144 11 124 2 H CH 20SiMe 2Bu t - - 145 12 125 2 CH 2OSiMe 2Bu t H - - 146 61 f(50) ' 13 126 2 CH 2CH 3 H - - 147 61 f Reaction Conditions A: LDA (1.1-1.5 equiv), THF, -48°C, 1 h; Tf 2 N P h (1.17-1.57 equiv), -48o:C to r t , 30 min. B: Pd(PPh 3) 4 (5 mol % ) , THF, re f l u x . C: Pd(PPh 3)4 (5 mol % ) , THF, r e f l u x , no i s o l a t i o n of enol t r i f l a t e (127). Y i e l d of chromatographically p u r i f i e d product. Y i e l d of p u r i f i e d , d i s t i l l e d product. Pd(0Ac) 2 used instead of Pd(PPh 3)4. CH3CN used instead of THF. These dienes were prepared using reaction conditions A and C; a l l others were prepared using A and B. - 53 -The reason that a Pd(II) c a t a l y s t i s able to carry out the desired conversion i n these cases i s that an i n s i t u reduction of Pd(II) to Pd(0) occurs. This reduction i s most l i k e l y accomplished by the re a c t i o n of Pd(0Ac>2 with the LDA 6 9 or diisopropylamine present i n the re a c t i o n mixture. The coordi n a t i v e l y unsaturated Pd(0) species so produced can then enter the c a t a l y t i c cycle as before (see Scheme 5). The preparation of the b i c y c l i c dienes (137)-(147) constitutes an extension to the annulation procedure d e t a i l e d previously. The crude r e a c t i o n mixtures were r e l a t i v e l y clean, providing the expected dienes i n y i e l d s of 61-90% a f t e r f l a s h chromatography and d i s t i l l a t i o n of the crude materials. Even the s t e r i c a l l y hindered c i s o i d c i s dienes (137), (138), (141), (142), and (145) (Entries 1, 2, 6, 7 and 11, Table 7) were obtained c l e a n l y and e f f i c i e n t l y . The c y c l i z a t i o n step proved to be s t e r e o s p e c i f i c . Retention of the geometry about the o l e f i n i c bond i n the vinylstannane moiety was not unexpected. S t i l l e and coworkers 3 0 demonstrated that the coupling of tra n s - 1 - ( t r i m e t h y l s t a n n y l ) - 2 - ( t r i m e t h y l s i l y l ) e t h y l e n e (19) and the enol t r i f l a t e (148) proceeded with r e t e n t i o n of the double bond geometry i n (19). The diene (149) was obtained i n 90% i s o l a t e d y i e l d (equation 32). SiMe 3 H Y S i M e 3 P d ( p p h J . , J M e 3 S n ^ H ( c a t . ) , L i C l 148 19 149 Thus, the c i s o i d c i s and c i s o i d trans dienes (142) and (144) were obtained as the sole products from the precursors (134) and (136), r e s p e c t i v e l y , i n y i e l d s of 87% and 84% (equation 33). The nmr - 54 -135 • 144 spectra of these two compounds were of use i n proving the stereochemis-t r y of the substituents about the exocyclic methylene douoble bond (Figures 2 and 3). In the spectrum of the c i s o i d c i s diene (142), resonances f o r the a l l y l i c methylene protons (-OCH2C-) were observed as 1-proton si g n a l s at 6 4.19 and 6 4.21, while i n the spectrum of the c i s o i d trans diene (144), the corresponding protons (-OCH^C-) gave r i s e to 1-proton signals at 6 4.09 and 6 4.14. The observed downfield s h i f t (-0.1 ppm) of these protons i n the c i s o i d c i s diene (142) compared to those i n the c i s o i d trans diene (144) may be r a t i o n a l i z e d by the proximity of the methylene (-OCH.2C-) protons i n (142) to the deshielding cone of the double bond i n the r i n g . 7 ^ A s i m i l a r deshielding e f f e c t i s observed when one compares the chemical s h i f t s of the o l e f i n i c protons H b (S 5.39) and H d (S 5.57) of the c i s o i d c i s and c i s o i d trans dienes (142) and (144), r e s p e c t i v e l y . In t h i s case, the chemical s h i f t d i f f e r e n c e i s about 0.2 ppm. - 55 -5 4 ppm 3 2 1 Figure 2: The 400 MHz XH nmr Spectrum of the C i s o i d Cis Diene (142) 6 5 4 ppm 3 2 1 Figure 3: The 400 MHz AH Spectrum of the C i s o i d Trans Diene (144) - 56 -A s e r i e s of difference nOe experiments was u t i l i z e d to confirm the stereochemical assignments of the exocyclic methylene substituents i n (142) and (144). I r r a d i a t i o n of the o l e f i n i c r i n g proton H a (5 5.59) of the c i s o i d c i s diene (142) caused enhancement of the signals correspond-ing to the a l l y l i c methylene protons (-OCH^C-) at 5 4.19 and S 4.21 and not of the v i n y l proton H D at S 5.39 (Figure 2). On the other hand, i r r a d i a t i o n of the o l e f i n i c r i n g proton H c (6 5.82) of the c i s o i d trans diene (144) caused s i g n a l enhancement of the o l e f i n i c proton H d at 5 5.57 and not of the a l l y l i c methylene protons (-0CH.2C=) at 5 4.09 and S 4.14 (Figure 3). The r e s u l t s of these experiments provide strong support f o r the stereochemical assignments and show c l e a r l y that, as expected, 3 0 the c y c l i z a t i o n reactions are s t e r e o s p e c i f i c . The other dienes l i s t e d i n Table 7 e x h i b i t spectra consistent with the ind i c a t e d structures. P a r t i c u l a r l y c h a r a c t e r i s t i c i n the nmr spectra are the observed chemical s h i f t d ifferences between the exocy-c l i c methylene substituents (both the v i n y l proton and a l l y l i c methylene protons) i n a set of c i s o i d c i s and c i s o i d trans diene isomers. The q u a l i t a t i v e u l t r a v i o l e t (uv) a c t i v i t y of the dienes (116)-(125) i s i n t r i g u i n g and deserves mention. Without exception, the c i s o i d c i s dienes have a much lower uv a c t i v i t y on a t i c chromatogram than t h e i r corresponding c i s o i d trans isomers. This observation may be r a t i o n a l -i z e d on the basis that deviation from coplanarity of the two o l e f i n i c bonds i n the diene u n i t would decrease conjugation between the i n t e r -a c t i n g double bonds. This decrease i n the extent of conjugation would i n turn decrease the i n t e n s i t y of the uv absorption due to the diene system. One can also p r e d i c t that, i n ad d i t i o n to the hypochromic - 57 -e f f e c t mentioned above, a hypsochromic s h i f t ( s h i f t to shorter wave-length) of the uv absorption band should occur i n these c a s e s . 7 ^ The d i f f e r e n c e i n the degree of deviation from p l a n a r i t y i n the diene units of the c i s o i d c i s and c i s o i d trans dienes (141) and (143), re s p e c t i v e l y , was observed by comparing the uv spectra of these two substances. In the uv spectrum (methanol solution) the c i s o i d trans diene (143) the X m a x was observed at 229 nm with a molar a b s o r p t i v i t y (e) of 12,000 M"^  cm"l. The uv spectrum of the c i s o i d c i s diene (141) displayed a A m a x at 216 nm with a molar a b s o r p t i v i t y (e) of 10,000 M"^  cm"-'-. The expected, c a l c u l a t e d v a l u e 7 ^ for the absorption wavelength of dienes such as these i s about 283 nm. Thus, the c i s o i d c i s diene appears to deviate from p l a n a r i t y to a greater extent than the corresponding c i s o i d trans diene. The observations summarized above suggest that the c i s o i d c i s dienes are non-planar with respect to the two o l e f i n i c bonds. The non-p l a n a r i t y can be r a t i o n a l i z e d as follows. A substituent on the " i n s i d e " of t h i s diene u n i t would have a large s t e r i c i n t e r a c t i o n with the o l e f i n i c r i n g proton (see (150)) i f the double bonds were co-planar. As C 0 2 M e 150 a r e s u l t , the energy of a species with t h i s conformation would be expected to be greater than that of a non-planar conformer. The extent to which t h i s type of i n t e r a c t i o n would a f f e c t the p l a n a r i t y of the - 58 -diene u n i t was of some i n t e r e s t to us since i t could dramatically a l t e r the subsequent r e a c t i v i t y of the c i s o i d c i s dienes. In order to e s t a b l i s h the actual deviation from p l a n a r i t y i n the c i s o i d c i s diene u n i t , the following reactions were c a r r i e d out. A s o l u t i o n of the c i s o i d c i s diene (145) i n THF was treated with tetrabutylammonium f l u o r i d e (2 equivalents, room temperature, 20 min). The crude a l c o h o l (151) was allowed to react with p,-nitrobenzoyl c h l o r i d e (1.5 equivalents) i n the presence of triethylamine (2 equiva-lents) and 4-N,N-dimethylaminopyridine (0.1 equivalents) i n methylene c h l o r i d e . Workup and chromatography of the crude mixture provided the benzoate (152) i n 85% o v e r a l l y i e l d from (145) (equation 34). (34) 145 152 R e c r y s t a l l i z a t i o n of (152) from hexane y i e l d e d needle-like c r y s t a l s (mp 131-132°C). Single c r y s t a l X-ray analysis of t h i s compound 7 2 (Appendix 1) i n d i c a t e d that the t o r s i o n a l angle between the C^-C^ and C3-C4 bonds was 54° (Figure 4). I f the above r e s u l t accurately represents the ground state conformation of t h i s molecule i n s o l u t i o n , then the p l a n a r i t y of the diene u n i t i s found to be severely disrupted. Thus, the observations made e a r l i e r regarding the uv a c t i v i t y of the analogous c i s o i d c i s dienes have some basis. - 59 -Extension of the intramolecular cross-coupling re a c t i o n to the preparation of b i c y c l i c dienes such as (84) was attempted as a f i n a l t e s t of the generality of the annulation process developed thus f a r . Formation of dienes such as (84) required the preparation and use of a donor-acceptor reagent such as (87). Ve chose to prepare the reagent 84 87 - 60 -(ZJ-l-bromo-4-methyl-3-trimethylstannyl-2-pentene (154) ( i . e . , X - Br, R.1 - Me2CH i n (87)) f o r reasons which w i l l become obvious l a t e r i n the discussion. With the (Z.) ester (94) i n hand (see equation 26), reduction of the a,/9-unsaturated e s t e r was e f f e c t e d with DIBAL as previously described (equation 35). The r e s u l t a n t (£) a l l y l i c alcohol (153), produced i n 97% y i e l d , was converted into the (£) a l l y l i c bromide (154) i n a y i e l d of 86% by treatment of (153) with triphenylphosphine dibromide (1.2 equivalents, -10°C, 15 min) and triethylamine (1.2 equivalents) i n methylene c h l o r i d e (equation 35). The bromide (154) proved to be quite 94 153 154 unstable, decomposing even upon storage at -4°C i n the dark. Thus, i t was used immediately a f t e r i t s preparation i n the subsequent a l k y l a t i o n reactions and i t was not d i s t i l l e d p r i o r to use. A l k y l a t i o n of the potassium enolates of the /9-keto esters (50), (52) and (54) with the a l l y l i c bromide (154) proceeded smoothly under r e a c t i o n conditions (THF, room temperature or r e f l u x , 1 h) milder than those required f o r a l k y l a t i o n with the a l k y l iodides (108)-(114). The a l k y l a t e d materials (157)-(159) were obtained, a f t e r chromatography and d i s t i l l a t o n of the crude r e a c t i o n products, i n y i e l d s of about 80% (Entries 1-3, Table 8). A l k y l a t i o n of 2-methylcycloheptanone ( 1 5 6 ) 7 3 with the (Z) a l l y l i c bromide (154), v i a the potassium enolate of (156) - 61 -Table 8: A l k y l a t i o n of Carbonyl Species with (Z)-l-Bromo-4-methyl-3-trimethylstannyl-2-pentene (154) 49 155 Entry Substrate R m Reaction Product Y i e l d C o n d i t i o n s 3 (%) b 1 50 C02Me 1 A c 157 78 2 52 C02Me 2 A 158 85 3 54 C02Me 3 A 159 80 4 156 Me 3 B 160 42 Reaction Conditions A: KH (1.1 equiv), THF, r t , 30-45 min; (154) (1.1 equiv), r t , 1-2 h. B: K0Bu c (0.95 equiv), THF-But0H (4:1), r t , 30 min; (154) (1 equiv), r t , 2 h. Y i e l d of p u r i f i e d , d i s t i l l e d product. A l k y l a t i o n done at r e f l u x temperature f o r 1 h. - 62 -prepared under equilibrating conditions (KOBu^ Bu^H-THF), yielded the alkylated compound (160) in 42% yield (Entry 4, Table 8). The alkylated materials (157)-(160) listed in Table 8 displayed spectra in accord with the assigned structures. For example, the mass spectrum of (157) exhibited the characteristic M+-15 ( 1 2 0Sn) 5 8 peak at m/e 373 and the i r spectrum displayed carbonyl absorptions at 1740 and 1720 cm'* and an absorption at 773 cm"* due to the Me3Sn group. The *H nmr spectrum exhibited signals consistent with the assigned structure. Signals corresponding to the Me^ Sn group (5 0.19, 9-proton singlet, J S n . H - 53 Hz), the methyl ester (6 3.69, 3-proton singlet) and the olefinic proton (6* 5.75, 1-proton doublet of triplets, J - 1, 8 Hz, J S n . H - 144 Hz) were typical of those observed in the other alkylated materials (158)-(160) (compound (160) exhibited a signal for the tertiary methyl group protons at S 1.04). The alkylated materials (157)-(160) were converted (LDA, THF; Tf2NPh) into the corresponding enol triflates (163)-(166). Intramole-cular cyclization of the latter substances in the presence of a cata-lytic amount of Pd(PPh3)4 (5 mol %, THF or C H 3 C N ) was effected to provide the bicyclic dienes (167)-(170). A summary of the results of this "two pot" reaction sequence on the substrates (157)-(160) can be found in Table 9. An interesting observation was made in comparing the cyclization reactions of the enol triflate-vinylstannanes (165) and (166) (Entries 3 and 4, Table 9). The only difference between these two compounds is that (165) has a carbomethoxy group situated at what will ultimately become the angular position in the diene (169), while (166) has a simple - 63 -Table 9: Preparation of B i c y c l i c Dienes Containing Two Endocyclic Double Bonds from the Alkylated Materials (155) a Reaction Conditions A: LDA (1.5 equiv), THF, -48°C, 1 h; Tf 2NPh (1.57 equiv), -48°C to r t , 30 min. B: Ph(PPh3),4 (5 mol % ) , CH3CN, re f l u x . Y i e l d of chromatographically p u r i f i e d product. Y i e l d of p u r i f i e d , d i s t i l l e d product. C y c l i z a t i o n Conditions: Pd(PPh 3)4 (5 mol % ) , THF, r t , 5 min. - 64 -methyl substituent at the same p o s i t i o n . However, c y c l i z a t i o n of (165) requires 30 minutes at 82°C ( r e f l u x i n g CH3CN) f o r completion, while (166) i s completely converted into (170) a f t e r only 5 minutes at room temperature (THF solution) (equation 36). A s i m i l a r observation can be (36) 166 R=Me THF, 5 min, r t 170 made i n comparing the formation of the dienes (75) and (81). The r e a c t i o n times required f o r the Pd(O)-catalyzed c y c l i z a t i o n ( r e f l u x i n g THF) of the precursor vinylstannane-enol t r i f l a t e s into the dienes (75) and (81) are 3 hours and 30 minutes, r e s p e c t i v e l y (Entry 3, Table 3 and equation 24). 1 R The observed diff e r e n c e i n r e a c t i v i t y between the c y c l i z a t i o n s r e s u l t i n g i n the formation of the dienes (75) and (169) and the dienes (81) and (170) i s due to the presence of the i n d u c t i v e l y e l e c t r o n with-drawing ester moiety i n (68) and (165). As was pointed out previously, i t i s l i k e l y that the oxidative a d d i t i o n step i s the rate determining step i n the c a t a l y t i c cycle (step A, Scheme 5). Thus, the presence of an ester moiety, which i s i n d u c t i v e l y e l e c t r o n withdrawing, must i n some - 65 -manner r e t a r d the rate of the oxidative a d d i t i o n of the enol t r i f l a t e (65) to the Pd(0) c a t a l y s t (step A, Scheme 5). The exact manner i n which the retardation operates i s not known since the mechanism of the oxidative a d d i t i o n r e a c t i o n i s s t i l l a question of some u n c e r t a i n t y . 7 4 The e f f e c t i s nonetheless dramatic as can be observed by the widely d i f f e r i n g conditions required f o r the c y c l i z a t i o n of (68) and (165). The preparation of the b i c y c l i c dienes (167)-(170) l i s t e d i n Table 9 demonstrates further the v e r s a t i l i t y of the annulation procedure. The dienes (167)-(270) exhibited spectra i n f u l l accord with the assigned structures. The -^H nmr spectra were e s p e c i a l l y u s e f u l i n assigning structure. The spectrum of each of the dienes (167)-(170) displayed, between 8 5.5 and 8 5.8, signals due to two o l e f i n i c protons. One of these signals appeared as a broad unresolved peak (W]y2 = 6 Hz) and was assignable to the v i n y l proton v i c i n a l to the isopropyl group. Speci-f i c a l l y , the diene (167) exhibited i n the 1-H nmr spectrum (Figure 5), i n add i t i o n to signals assigned to the isopropyl group (5 1.10 and 8 1.14, 3-proton doublets each, J = 7 Hz; 8 2.54, 1-proton multiplet) and the methyl ester (8 3.63, 3-proton s i n g l e t ) , eight other completely resolved signals corresponding to the remaining protons. V i a a s e r i e s of decoupling experiments, each s i g n a l could be assigned as indicated i n Figure 5 (see Experimental f o r decoupling experiments). - 66 -Figure 5: The 400 MHz iH nmr Spectrum of the Diene (167) In summation, the previous two sections have o u t l i n e d the prepara-t i o n of b i c y c l i c dienes of the general structures (72), (82), (83) and (162). The annulation sequences that have been employed have been based 72 82 83 162 on the t h e o r e t i c a l combination of the d,a-synthon (171) (derived from a carbonyl containing reagent of general structure (49)) with e i t h e r the d,a-synthon (172) or the d,a-synthon (173) (equation 37). In p r a c t i s e , - 67 -a 172 m • m \ (37) 49 171 a 173 m R the annulations have been achieved by the use of the donor-acceptor reagents (43), (44), (108)-(114) and (154) i n which the order of deployment of the rea c t i v e s i t e s was: (1) acceptor ( a l k y l halide) and (2) donor (vinylstannane). The following s e c t i o n w i l l describe the r e a c t i v i t y of several of these dienes with respect to the Die l s - A l d e r r e a c t i o n . 2.2.0 The Die l s - A l d e r Reactions of the B i c y c l i c Dienes (75), (145) and The four basic questions which were to be addressed i n attempting to explore and compare the Diels-Alder r e a c t i o n s 7 6 " 7 9 of the s t r u c t u r a l l y novel b i c y c l i c dienes (75) (the "parent" diene), (145) and (146) (equation 38) are summarized as follows. (1) what i s the preferred face s e l e c t i v i t y of the add i t i o n of a dienophile to the b i c y c l i c diene (146) with respect to the angular ester f u n c t i o n a l i t y ( i . e . a- or /3-face approach)? (2) For those dienophiles i n which there i s the p o t e n t i a l f o r endo or exo s e l e c t i v i t y i n the c y c l o a d d i t i o n t r a n s i t i o n state, which mode w i l l be favoured upon addi t i o n of the dienophile to each of the a-and /?-faces of the dienes? (3) In the case of unsymmetrical dieno-p h i l e s , what w i l l be the favoured regiochemistry of a d d i t i o n of these reagents to the dienes? (4) What i s the differ e n c e i n the r e a c t i v i t y of the c i s o i d c i s diene (145) and the c i s o i d trans diene (146)? The study d i r e c t e d towards answering these four basic questions Is o u t l i n e d i n the following pages. Throughout t h i s discussion, the a-face r e f e r s to the face of the molecule on which the angular ester group i s s i t u a t e d while the 0-face r e f e r s to the face opposite the angular ester moiety. - 69 -2.2.1 The Di e l s - A l d e r Reactions of the Dienes (75), (145) and (146) with Symmetrical Dienophiles The parent diene (75), upon treatment with dimethyl acetylenedicar-boxylate (2 equivalents, benzene, r e f l u x , 6 h), provided, i n 78% y i e l d , a mixture of two Diels-Alder adducts, (175) and (176), i n a r a t i o of 3:1 (equation 39). Six s i n g l e t s corresponding to the methyl ester proton 75 175 176 resonances were observed between 6 3.67 and S 3.80 i n the 1-H nmr spectrum of the mixture (5 3.67 and 6 3.70, r a t i o 1:3; 6* 3.75 and 6 3.76, r a t i o 1:3; 6 3.78 and 5 3.80, r a t i o 3:1). These two compounds could not be separated by chromatography or f r a c t i o n a l c r y s t a l l i z a t i o n and i t was not possible on the basis of nmr experiments (nOe or decoupling) to determine which isomer was the major product. X-ray c r y s t a l l o g r a p h i c analysis of the m i x t u r e 7 2 (Appendix 1) ind i c a t e d that the major isomer was the t r i e s t e r (175) (Figure 6). Thus, the f i r s t observation i s that the angular ester moiety does d i r e c t the incoming dienophile to the opposite face of the diene, r e s u l t i n g i n a preference f o r B- face approach. - 70 -Figure 6: Stereoview of the Triester (175) The face selectivity of dienophile approach was tested with a sterically more demanding symmetrical dienophile (tetracyanoethylene, TCNE) and a symmetrical dienophile (maleic anhydride) which would be able to display endo or exo selectivity in the cycloaddition reaction. The results of the reactions between these two dienophiles and the bicyclic dienes are summarized in Table 10. Treatment of the parent diene (75) with TCNE (1.05 equivalents; Entry 1, Table 10) afforded two products in a ratio of 96:4 (by glc) in a combined yield of 83% (equation 40). The major isomer, obtained as a pure substance by fractional crystallization of the mixture from diethyl ether-chloroform, exhibited np 146-147"C. Based on the results of the previous reaction, the major isomer was expected to be the tricyclic ester (177), resulting from preferential attack of the dienophile from - 71 -Table 10: The Diels-Alder Reactions of the B i c y c l i c Dienes (75), (145) and (146) with Symmetrical Dienophiles rS Dienophile Product(s) I 1 J \ * 4o2Me Entry Diene D i e n o p h i l e a Reaction Conditions Product(s) ( r a t i o ; b ' c combined y i e l d , d %) 1 75 W THF, r t , 30 min 177, e 180 (96:4; 83) c 2 146 W THF, r t , 30 min 178, 181 (7:1, 7 4 ) b 3 146 W THF, -78°C, 2 h 178 (84) 4 145 W E t 2 0 , r e f l u x , 15 h 179 e (72) 5 146 X PhH, r e f l u x , 18 h 182 (63) 6 145 X PhH, r e f l u x , 3 days 183 (18) Dienophile: W, tetracyanoethylene; X.. maleic anhydride. Ratios were determined by c a r e f u l analysis of the crude product mixture by ^H nmr spectroscopy. Ratios were determined by analysis of the crude product mixture by g l c I s o l a t e d y i e l d of (combined) p u r i f i e d product(s). See Chart 1 (next page) f o r s t r u c t u r a l formulae. The c o n s t i t u t i o n and r e l a t i v e stereochemistry of these compounds was confirmed by si n g l e c r y s t a l X-ray a n a l y s i s . - 72 -Chart 1 the B-£ace of the diene (75). Evidence f o r t h i s assignment was sought by inspecting the nmr spectrum of the major isomer. The s i g n a l corresponding to the angular, a l l y l i c proton i n the nmr spectrum of the major product was observed at S 3.31 as a broad doublet (J - 12.5 Hz). Based on the analysis of molecular models, t h i s angular proton i n (177) (H a) would be pseudo-axial, and thus would be expected to have an a x i a l - a x i a l (H a-H D) coupling of -12 Hz.' 3 However, i n what appears to be the most stable conformation of (180), the angular a l l y l i c proton H c i s trans and d i a x i a l to H^ and, therefore, the coupling constant associated with the a l l y l i c proton cannot be used to d i s t i n g u i s h between (177) and (180). Difference nOe experiments also f a i l e d to provide evidence that the major isomer has the structure shown i n (177). Therefore, a si n g l e c r y s t a l X-ray a n a l y s i s 7 2 (Appendix 1) of the major isomer was undertaken and confirmed that t h i s substance has the c o n s t i t u t i o n and r e l a t i v e sterochemistry depicted i n (177) (Figure 7). The minor component observed i n the r e a c t i o n mixture was not i s o l a t e d but was assumed to be the isomeric product (180) r e s u l t i n g from the approach of TCNE to the a-face of the diene (75). Figure 7: Stereoview of the T r i c y c l i c Ester (177) - 74 -Treatment of the c i s o i d trans diene (146) with TCNE (1.15 equiva-l e n t s ; Entry 2, Table 10) at room temperature provided a mixture of two compounds i n a combined y i e l d of 74%, i n a r a t i o of 7:1 (equation 41). The si g n a l s corresponding to the -OSiCMe.3 protons i n the nmr spectrum of t h i s mixture were observed at S 0.94 and 6 0.97 ( r a t i o 1:7). A s i n g l e isomer was obtained i n 84% y i e l d when the r e a c t i o n was c a r r i e d out at -78°C (Entry 3, Table 10). The product obtained from t h i s l a t t e r r e a c t i o n corresponded to the major product of the r e a c t i o n c a r r i e d out at ambient temperature. Based on the observed r e a c t i v i t y of TCNE with the parent diene (75), TCNE would be expected to favour a 0-face approach to the diene (146). 146 178 181 R=SiMe 2Bu C Thus, the major (or sole) product from t h i s r e a c t i o n was assigned the structure (178). A d d i t i o n a l support f o r the assignment was found by comparing the nmr spectra of (177) and (178). The resonances a t t r i b u t e d to the angular a l l y l i c protons i n the -^H nmr spectra of (177) and (178) were observed as broad doublets (J - 12.5 Hz i n each case) at S 3.31 and 6 3.10, re s p e c t i v e l y . The minor isomer (181) observed i n the crude r e a c t i o n mixture could - 75 -not be i s o l a t e d but was assumed to be the t r i c y c l i c ester r e s u l t i n g from the approach of TCNE to the a-face of diene (146). The r e a c t i o n of the c i s o i d c i s diene (145) with TCNE (8 equivalents; Entry 4, Table 10) d i d not proceed at or below ambient temperature but at 35°C ( r e f l u x i n g d i e t h y l ether) provided a s i n g l e product i n 72% y i e l d (equation 42). The crude substance was r e c r y s t a l l i z e d from hexane-acetonitrile to a f f o r d a c r y s t a l l i n e material that exhibited mp 127-128°C. The *H nmr spectrum of t h i s material d i d not c l e a r l y e x h i b i t (42) C02Me 179 C02Me 145 R = SiMe 2Bu a resonance assignable to the angular a l l y l i c proton. However, a 2-proton m u l t i p l e t was observed at S 3.26, presumably due to the t e r t i a r y a l l y l i c protons H a and H D. Based on the observations made e a r l i e r , the product from t h i s r e a c t i o n was expected to have r e s u l t e d from the approach of TCNE to the /3-face of (145). In order to confirm t h i s assignment, an X-ray analysis of the r e a c t i o n product was under-taken . Single c r y s t a l X-ray a n a l y s i s 7 2 (Appendix 1) confirmed that the product of the above r e a c t i o n was the expected [4+2] cycloadduct (179) (Figure 8). - 76 -Figure 8: Stereoview of the T r i c y c l i c Ester (179) Reaction of the c i s o i d trans diene (146) with maleic anhydride afforded a s i n g l e product which was i s o l a t e d i n 63% y i e l d (equation 43). H Y ^ 0 S i M e 2 B u t Cf5 C02Me 146 C02Me 182 R=SiMe 2Bu t (43) - 77 -The 1H nmr spectrum of t h i s material displayed, i n ad d i t i o n to signals corresponding to the s i l y l ether function (5 0.04 and S 0.07, two 3-proton s i n g l e t s ; S 0.89, 9-proton s i n g l e t ) , the methyl ester group (6 3.66, 3-proton s i n g l e t ) , the -OCH^Si protons (6 3.65 and 6 3.74, 1-proton si g n a l s each) and twelve a l i p h a t i c protons between S 1.21 and S 2.40, a p a i r of mul t i p l e t s at S 2.51-2.64 (H a and H d) and S 3.35 (H b and H c ) . Since the coupling constants between the protons H a-H b and the protons H c-H d could not be determined, i t was not poss i b l e to confirm that the anhydride i s o l a t e d from the reac t i o n mixture has the structure depicted i n (182). I t i s known,B^ however, that maleic anhydride has a strong p r e d i l e c t i o n f o r an endo t r a n s i t i o n state. For example, r e a c t i o n of cyclopentadiene with maleic anhydride provides the endo adduct A with > 98.5% s t e r e o s e l e c t i v i t y (equation 4 4 ) . 8 ^ Preference f o r an endo t r a n s i t i o n state i n the addit i o n of maleic anhydride to dienes r u l e d out the p o s s i b i l i t y that t h i s dienophile had added to the a-face of the diene (146). There would be a s t e r i c i n t e r a c t i o n between the angular ester group and maleic anhydride i n the t r a n s i t i o n state of a reac t i o n which proceeded by way of an a-face, endo o r i e n t a t i o n of these reactants. These f a c t s , taken together with the e a r l i e r observations (44) A - 78 -regarding the directing ability of the angular ester moiety (to the B-£ace of the diene (146)), led to the conclusion that the sole product from the Diels-Alder reaction of (146) with maleic anhydride is the anhydride (182). The reaction between the cisoid cis diene (145) and maleic anhydride required an extended period of time to reach completion (Entry 6, Table 10). A single Diels-Alder adduct was isolated in 18% yield from the crude reaction mixture (equation 45). On the basis of the arguments (45) C0 2Me C0 2Me 145 183 R=SiMe„Bu t presented above for the analogous reaction of the diene (146) with maleic anhydride and taking into account the fact that the reaction of the cisoid cis diene (145) with the reactive dienophile TCNE gave exclusively product (179) (vide supra), the substance isolated from this reaction mixture was assigned the structure (183). The i r spectrum of (183) displayed the expected8^- anhydride absorptions at 1864 cm'^  and 1784 cm'l (asymmetric and symmetric carbonyl stretches, respectively) and the nmr spectrum was consistent with the assigned structure. The major product from the reaction of (145) with maleic anhydride was isolated as a non-crystalline white solid which proved to be impossible to crystallize and was quite insoluble in the common deuter-- 79 -ated solvents (CDCI3, (CT^^CO, CD3OD, CgDg). The i r spectrum of t h i s u n i d e n t i f i e d material (184) included absorptions f o r the anhydride moiety (1849, 1779 cm"1) and the * H nmr spectrum ( i n (CT^^SO) indicated that the t e r t - b u t y l d i m e t h y l s i l o x y group had been l o s t . The peak of highest mass i n the low r e s o l u t i o n mass spectrum of (184) was observed at m/e 414 (022^22^8 hy high r e s o l u t i o n mass spectrometry). I t was not possible on the basis of t h i s evidence to determine the c o n s t i t u t i o n of (184) although i t i s obviously not a simple D i e l s - A l d e r product. Having completed a study of the r e a c t i o n of the dienes (75), (145) and (146) with symmetrical dienophiles, the next course of a c t i o n was to examine t h e i r r e a c t i v i t y with unsymmetrical dienophiles. 2.2.2 The D i e l s - A l d e r Reactions of the B i c y c l i c Dienes (75), (145) and (146) with Unsymmetrical Dienophiles I t i s t h e o r e t i c a l l y possible that eight products can be obtained from the D i e l s - A l d e r reactions of unsymmetrical dienophiles and the dienes (75), (145) and (146). Fortunately, t h i s "worst case" scenario was not r e a l i z e d . Even so, the proof of structure of the products which were i s o l a t e d proved to be quite challenging. Perhaps most disappoint-ing was the lack of information which was obtained from the ^H nmr spectrum of these i s o l a t e d materials. Consequently, t h i s spectroscopic t o o l could not be used for determining the c o n s t i t u t i o n and r e l a t i v e stereochemistry of the new substances. As w i l l be discussed, however, the ^H nmr spectra were useful f o r comparison purposes once the - 80 -structure of several of the Diels-Alder products had been determined. The substituted ethylenes, methyl acrylate and n i t r o e t h y l e n e , 8 2 were the unsymmetrical dienophiles chosen to be reacted with the b i c y c l i c dienes (75), (145) and (146). The r e s u l t s obtained from the Diels-Alder reactions of these substrates are summarized i n Table 11 and are discussed i n greater d e t a i l i n the following paragraphs. Treatment of the parent diene (75) with methyl a c r y l a t e (5 equiva-l e n t s ; Entry 1, Table 11) provided, i n 85% y i e l d , a mixture of three Die l s - A l d e r products, A, B and C, i n a r a t i o of 2.7:1.7:1, r e s p e c t i v e l y (equation 46). The nmr spectrum of t h i s mixture exhibited f i v e (46) 75 s i n g l e t s ( i n a r a t i o of 4.4:1.7:1:1:2.7), corresponding to the methyl ester protons, between 6 3.68 and 6 3.72. The three compounds could not be completely separated by chromatography. However, samples of the major isomer (A) and the isomer next greatest i n abundance (B) could be obtained as pure substances by subjecting the mixture to drip column chromatography on s i l i c a g e l . The f i r s t component to be eluted was compound B. The i r spectrum of t h i s o i l exhibited an absorption due to the ester moieties at 1720 cm'^. The *H nmr spectrum of B_ displayed si g n a l s a t t r i b u t e d to the methyl ester protons at 6 3.67 and S 3.68 (3-proton s i n g l e t s each). The proton adjacent to the ester moiety (-CHC^Me) resonated at 6 2.31 (1-proton - 81 -Table 11: The Diels-Alder Reactions of the Dienes (75), (145) and (146) with Unsymmetrical Dienophiles R 1. R 2 Dienophile Products C0 2Me Entry Diene D i e n o p h i l e 3 Reaction Conditions Product(s) ( r a t i o ; b , c combined y i e l d , d %) 1 75 Y PhH, r e f l u x , 3 days 186, e 187, 188 e (2.7:1:1.7; 8 5 ) b - c 2 146 Y PhH, r e f l u x , 3 days 192, 193, 194 (47:16:35; 8 8 ) f 3 145 Y f f 4 75 Z E t 2 0 , r t , 3 h 189, 190, 191 (3:1:2; 8 3 ) c 5 146 Z E t 2 0 , r t , 3 h 195, e 196, 197 e ( 3 : t r a c e : l ; 8 1 ) b 6 145 Z E t 2 0 , r e f l u x , 7 h 195, e 196, 197 e (2.5:trace:1; 7 8 ) b Dienophiles: Y, methyl acrylate; Z, nitroethylene. Ratios were determined by c a r e f u l analysis of the crude product mixture by ^H nmr spectroscopy. Ratios were determined by analysis of the crude product mixture by g l c . I s olated y i e l d of (combined) p u r i f i e d product(s). See Chart 2 (next page) f o r s t r u c t u r a l formulae. The c o n s t i t u t i o n and r e l a t i v e stereochemistry of these compounds was confirmed by s i n g l e c r y s t a l X-ray analysis of the substance i t s e l f (195) or of a s u i t a b l e d e r i v a t i v e (186, 188, 197). See discussion. - 82 -C0 2 Me C0 2 Me COoMe 186 R^H, R2=C02Me 1 2 189 R =H, R =N02 192 R'=L, R2=C02Me 195 R^L, R2=N0o 187 R^H, R2=C02Me 190 R"=H, R2=N.02 193 Rl=L, R2=C02Me 1 2 196 R =L, R =N02 188 R^H, R2=C02Me 191 R^H, R2=N02 194 Rl=L, R2=C02Me 1 2 197 R =L, R =N0„ L=CH 20SlMe 2Bu Chart 2 doublet of t r i p l e t s , J - 3, 12 Hz). The signals f o r the other protons which may have been useful i n determining the structure of B could not be assigned. Thus, a c r y s t a l l i n e d e r i v a t i v e of B was prepared i n order to e s t a b l i s h i t s c o n s t i t u t i o n and r e l a t i v e stereochemistry v i a X-ray an a l y s i s . Reduction ( r e f l u x i n g d i e t h y l ether, 6.5 h) of the d i e s t e r B with l i t h i u m aluminum hydride (1.5 equivalents) afforded the corresponding d i o l B_a i n 83% y i e l d . The i r spectrum of ]?»a exhibited the expected a l c o h o l absorption at 3310 cm*1. R e c r y s t a l l i z a t i o n of JJa from methanol provided c r y s t a l s (mp 162.5-164°C) which were analyzed by X-ray c r y s t a l l o g r a p h y . 7 2 This analysis (Appendix 1) demonstrated that the c o n s t i t u t i o n and r e l a t i v e stereochemistry of the d i o l Ba i s as shown i n (198) (Figure 9). Thus, the d i e s t e r B i s (188). - 83 -The second component to be eluted from the column was compound A, the major D i e l s - A l d e r isomer. This o i l exhibited an absorption due to the ester groups at 1732 cm'1 i n i t s i r spectrum. Although the *H nmr spectrum of A proved to be of as l i t t l e use as the nmr spectrum of compound (188) i n the assignment of structure, two sig n a l s were d i s t i n c t i v e . They were observed at S 2.35 (1-proton broad doublet, i -13 Hz) and S 2.73 (1-proton doublet of doublet of doublets, 1 - 2 . 8 , 6, - 84 -13 Hz) and were assigned to the angular, allylic proton and the -CHCO^ Me proton, respectively. Diester A. was reduced with lithium aluminum hydride (1.5 equiva-lents, THF, reflux, 1 h) to provide the diol M in 97% yield. X-ray crystallographic analysis 7 2 (Appendix 1) of the material obtained upon recrystallization (mp 182.5-184.5'C) of Afi from ethanol-hexane showed that the diol &a has the structure indicated in (199) (Figure 10). Figure 10: Stereoviev of the Diol (199) Therefore, the diester A. possesses the structure indicated in (186). Aa = 199 A = 186 - 85 -I t remained to determine the structure of the minor isomer (C) observed i n the crude product mixture obtained from the r e a c t i o n of (75) with methyl a c r y l a t e . On the expectation that £ was simply epimeric with e i t h e r (186) or (188), a methanol s o l u t i o n of a 3:1 mixture (by glc) of compounds (186) and C_, r e s p e c t i v e l y , was refluxed i n the presence of sodium methoxide (0.5 equivalents) f o r two weeks. A f t e r t h i s time period, 86% of the o r i g i n a l material was recovered. Glc an a l y s i s of t h i s o i l showed that i t consisted of a mixture of two compounds i n a r a t i o of 1:6.1 and that these substances had the same glc r e t e n t i o n times as the compounds (186) and C, r e s p e c t i v e l y . Thus, the d i e s t e r C i s epimeric with the d i e s t e r (186) and possesses the structure i n d i c a t e d i n (187). A pure sample of (187) could not be C02Me C = 187 obtained from the r e a c t i o n mixture. However, the ^H nmr spectrum of the mixture of (186) and (187) exhibited signals d i s t i n c t i v e to (187) at S 2.49 (1-proton broad t r i p l e t , J. - 11 Hz) and at 6 3.688 and 3.690 (3-proton s i n g l e t s each) as well as signals corresponding to (186) ( s p e c i f i c a l l y the methyl ester proton resonances were observed at S 3.67 and 6 3.71). The r e s u l t s discussed above showed that the r e a c t i o n of the parent diene (75) with methyl acrylate i s completely r e g i o s e l e c t i v e , providing - 86 -the three d i e s t e r s (186)=A, (187)=C and (188)sB i n a r a t i o of 2.7:1:1.7, r e s p e c t i v e l y (see equation 46). I t i s known 8 3 that Lewis acids can dramatically a l t e r the rate, r e g i o s e l e c t i v i t y and s t e r e o s e l e c t i v i t y (endo/exo s e l e c t i v i t y ) of the Die l s - A l d e r r e a c t i o n of unsymmetrical dienes and dienophiles. The p o s s i b i l i t y of achieving greater endo s e l e c t i v i t y i n the r e a c t i o n of the diene (75) with methyl acrylate l e d to an i n v e s t i g a t i o n of the r e a c t i o n of these substances i n the presence of various Lewis acids (BF3 -0Et2, TiCT^, Et2AlCl and SnCl^). Unfortunately, decomposition of the diene (75) was observed i n the presence of these c a t a l y s t s under a v a r i e t y of r e a c t i o n conditions. The c i s o i d trans and c i s o i d c i s dienes (146) and (145), respect-i v e l y , were treated with methyl acrylate (-10 equivalents) i n r e f l u x i n g benzene (Entries 2 and 3, Table 11). In the case of the c i s o i d trans diene (146) (Entry 2, Table 11), the crude r e a c t i o n product was found to be comprised of at l e a s t three components by t i c analysis. Due to the large degree of overlapping of the peaks of i n t e r e s t i n the nmr spectrum of t h i s mixture, neither an i n d i c a t i o n of the number of isomers produced, nor t h e i r r a t i o , could be determined. The crude r e a c t i o n product was subjected to medium pressure chroma-tography and three separate f r a c t i o n s were i s o l a t e d ( i n the order of t h e i r elution) i n a r a t i o of 1:0.06:1.8 ( f r a c t i o n s D, E and F, respect-i v e l y ) i n a combined y i e l d of 88%. Fractions D and E were pure substances while f r a c t i o n F consisted of two compounds, G and H, i n a 3:1 r a t i o , r e s p e c t i v e l y (-0SiMe_2 signals i n the nmr spectrum of F - 87 -observed at S 0.89 and 6 0.91, r a t i o 3:1). A pure sample of compound G was obtained by subjection of f r a c t i o n F to drip column chromatography while a pure sample of compound H was obtained i n the following manner. Based on the r e s u l t s of the Diels-Alder r e a c t i o n of the parent diene (75) with methyl acr y l a t e , i t was f e l t that substances G and H might be epimeric at the CHC02Me center. Accordingly, a methanol s o l u t i o n of G was r e f l u x e d i n the presence of sodium methoxide (0.5 equivalents). nmr an a l y s i s of the crude product a f t e r a r e a c t i o n time of s i x days in d i c a t e d that i t consisted of a 1:9 mixture of the d i e s t e r s G and H, r e s p e c t i v e l y . Drip column chromatography of the mixture provided a pure sample of compound H. Thus, the r e a c t i o n of the c i s o i d trans diene (146) with methyl ac r y l a t e provides, i n 88% y i e l d , a mixture of four isomers, D, E , G and H, i n a r a t i o of 1:0.06:1.35:0.45, r e s p e c t i v e l y (equation 47). I t H Y ^ 0 S i M e 2 B u t CO C0 2 Me » D + E + G + H (47) k J 1 : 0.06 : 1.35 : 0.45 co 2Me 146 was already known that compounds G and H are epimeric. I t was also discovered that D and E could not be interconverted; i n f a c t , neither D nor E underwent epimerization when they were subjected f o r extended periods of time to the e q u i l i b r a t i n g r e a c t i o n conditions described above f o r compound G. - 88 -The assignment of structures to compounds D, G and H. was made on the basis of the analogy of chemical r e a c t i v i t y and by s p e c t r a l (mainly nmr) comparisons with compounds of known structure. I t may be r e c a l l e d that r e a c t i o n of the parent diene (75) with methyl a c r y l a t e provided three compounds ( i n the order of t h e i r chromatographic e l u t i o n ) , B, A. and C, i n a r a t i o of 1.7:2.7:1, re s p e c t i v e l y . I t i s not unreasonable to conclude that the three major compounds i s o l a t e d from the r e a c t i o n of the c i s o i d trans diene (146) with methyl acr y l a t e ( i n the order of t h e i r e l u t i o n ) , D, G and H, obtained i n a r a t i o of 2.2:3:1, r e s p e c t i v e l y , are d i e s t e r s analogous to B, A and C. C 0 2 M e C 0 2 M e C 0 2 M e B =188 A = 186 C = 187 Comparison of the iH nmr spectra of the d i e s t e r s D, G and H with the nmr spectra of the n i t r o esters M., N and P, re s p e c t i v e l y , provided fur t h e r support f o r the s t r u c t u r a l assignments given above. The structures of the n i t r o esters M.» fi> and P_ were determined to be those shown i n (197), (195) and (196), r e s p e c t i v e l y (vide i n f r a ) . The p a r t i a l nmr spectra of the compounds J) and {J, G and N, g and P are i l l u s t r a t e d i n Figures 11, 12, and 13, r e s p e c t i v e l y . In comparing these spectra, several s t r i k i n g s i m i l a r i t i e s within each p a i r may be noted. - 89 -OR OR i C 0 2 M e C 0 2 M e M = 197 N = 195 R = SiMe^Bu 1 1 P = 196 Perhaps most informative and unique (with respect to t h e i r r e l a t i v e chemical s h i f t s and t h e i r observed couplings) are the sig n a l s corres-For example, i n the spectrum of compound D, signals a t t r i b u t e d to these protons are observed at 6" 3.44 ( t r i p l e t , J - 10 Hz) and 6 3.74 (doublet of doublets, J - 3.8, 10 Hz) while i n the spectrum of compound M, the analogous protons resonate at 6 3.50 (doublet of doublets, J - 8, 10 Hz) and 6 3.75 (doublet of doublets, J - 4, 10 Hz) (Figure 11). S i m i l a r l y , i n the spectrum of G these protons resonate at 6 3.63-3.70 (buried under -OCH/j signals) while i n the spectrum of N they resonate at 6 3.66 (doublet of doublet, J - 3, 10 Hz) and 6 3.73 (doublet of doublets, J - 5, 10 Hz) (Figure 12). F i n a l l y , i n the spectrum of H, sign a l s corresponding to these protons are seen at 5 3.47 (doublet of doublets, J - 8.5, 10 Hz) and 6 3.66-3.72 (buried under -OCH3 signals) while those In the spectrum of compound P_ are observed at S 3.59 (doublet of doublets, 2 - 6 . 3 , 10 Hz) and 6 3.68 (doublet of doublets, J - 3.4, 10 Hz) (Figure 13). Other unassignable resonances In the *H nmr spectra of these compounds are also u s e f u l i n making comparisons between the various isomers. The reader i s r e f e r r e d to Figures 11-13 f o r t h i s purpose. ponding to the -CHCH.20SiMe2Buc protons i n the spectrum of each isomer. - 91 -- 93 -Based on the evidence presented above, the d i e s t e r s D, G and H were assigned the structures (194), (192) and (193), r e s p e c t i v e l y . The structure of the minor isomer (E) (-2%) i s o l a t e d from the crude r e a c t i o n mixture was not determined. I t i s possible that E • (200) i s epimeric at the CHCC^Me center with (194), even though no interconversion was observed when (194) and (200) were treated with sodium methoxide i n r e f l u x i n g methanol. D E 194 G = 192 H = 193 R = SiMe„Bu t I t i s also possible that (200) i s one of the possible isomers r e s u l t i n g from the ad d i t i o n of methyl acrylate to the diene (146) with regiochemistry opposite to that observed i n (192)-(194). In s p i t e of t h i s p o s s i b i l i t y , the Diels-Alder r e a c t i o n of the c i s o i d trans diene (146) with the unsymmetrical dienophile methyl ac r y l a t e Is observed to be hi g h l y (>98%) r e g i o s e l e c t i v e . The D i e l s - A l d e r r e a c t i o n of the c i s o i d c i s diene (145) with methyl a c r y l a t e d i d not take place. These reactants were subjected to a v a r i e t y of r e a c t i o n conditons and i n no case were any Diels-Alder adducts i s o l a t e d or even observed (by glc) i n the crude re a c t i o n mixtures. A 92% recovery of the diene (145) was r e a l i z e d a f t e r r e f l u x i n g (145) i n the presence of methyl acrylate i n benzene f o r four days. Heating the diene (145) i n benzene i n the presence of methyl - 94 -a c r y l a t e at 186°C (sealed tube) f o r 42 hours l e d only to the decomposi-t i o n of the diene. S i m i l a r l y , r e a c t i o n of (145) with dimethyl acetylenedicarboxylate under a v a r i e t y of conditions provided no D i e l s - A l d e r adducts. Thus, i t appears that the s t e r i c f a c t o rs which preclude the forma-t i o n of a planar diene moiety i n the c y c l o a d d i t i o n t r a n s i t i o n state of (145) slow down the rate of the Diels-Alder r e a c t i o n to such an extent that no r e a c t i o n i s observed with l e s s reactive dienophiles such as methyl a c r y l a t e , dimethyl acetylenedicarboxylate and nitroethylene (vide i n f r a ) . However, with the more reactive dienophiles, TCNE and maleic anhydride, an a l t e r n a t i v e two-step r e a c t i o n mechanism 7 8 may account f o r the products observed i n the reactions of these dienophiles with the diene (145). I f t h i s mode of r e a c t i o n i s operating, one would have to conclude that the second intramolecular step i s f a s t e r than the p o t e n t i a l bond r o t a t i o n i n a possible intermediate such as (185), since the o v e r a l l a d d i t i o n i s s t e r e o s p e c i f i c , providing only (179). C02Me C02Me C02Me 145 185 179 The next reactions to be investigated involved the dienes (75), (145) and (146) and nitroethylene (prepared from 2-nitroethanol as described In reference 82). - 95 -Reaction of the parent diene (75) with excess nitroethylene (Entry 4, Table 11) was complete i n 3 hours at room temperature and provided a mixture of three compounds, J , K. and J,, i n a r a t i o of 3:2:1 (by g l c ) , r e s p e c t i v e l y (equation 48). The - C H N O 2 proton si g n a l s i n the *H nmr spectrum of t h i s mixture were observed at 6 4.44 and 6 4.70-4.76 i n a r a t i o of about 1:2, re s p e c t i v e l y . The crude product was observed as a si n g l e spot by t i c a n a l y s i s . Subjection of the mixture to d r i p column chromatography provided a pure sample of the n i t r o ester K ( f i r s t (48) C02Me 75 compound to be eluted). Compounds J and L, which could not be obtained as pure substances, were found to be e p i m e r i c . 8 4 Thus, a s o l u t i o n of a mixture of the n i t r o esters J , K and L ( r a t i o 3:2:1 by glc) and potassium tert-butoxide (0.5 equivalents) i n t e r t - b u t y l alcohol was s t i r r e d f o r 16 hours. Workup and chromatography of the crude material provided a mixture of the compounds J_, K and L i n a r a t i o of 0.7:2:3.1, r e s p e c t i v e l y (by g l c ) , i n a y i e l d of 87%. Based on the analogy of the chemical r e a c t i v i t y of the parent diene (75) with methyl acrylate (vide supra) and the observations made above, the substances J , K and L. were assigned the structures (189), (191), and (190), r e s p e c t i v e l y . Further evidence f o r these assignments was obtained by s p e c t r a l comparisons. S p e c i f i c a l l y , the chemical s h i f t and coupling constants of the - C H N O 2 proton i n the nmr spectra of the - 96 -C02Me C02Me C02Me J = 189 K E 191 L = 190 mixture of the compounds J , K and L. are s i m i l a r to those found i n the analogous n i t r o esters N, M. and P, r e s p e c t i v e l y (the structures of which have been unambiguously assigned (vide i n f r a ) ) (Figure 14). 5 4 ppm Figure 14: The P a r t i a l 400 MHz *H nmr Spectra of the N i t r o Esters J-L and M, N and P - 97 -In the '•H nmr spectrum of the n i t r o ester K, the CHNO2 proton s i g n a l i s observed at 5 4.44 (doublet of t r i p l e t s , J - 3.8, 10.5 Hz) while i n the ^H nmr spectrum of the n i t r o ester M, t h i s proton resonates at 6 4.58 (doublet of doublet of doublets, J — 3, 10.5, 12 Hz). S i m i l a r l y , these proton signals are observed i n the nmr spectra of compounds J. and N. at 6 4.74 (multiplet) and 6 4.75 ( m u l t i p l e t ) , r e s p e c t i v e l y . F i n a l l y , the sign a l s corresponding to these protons i n the 1H nmr spectra of compounds L. and P. are found at S 4.71 (multiplet) and 6 4.68 (doublet of doublet of doublets, J - 4, 9, 12 Hz), r e s p e c t i v e l y (Figure U ) . The r e s u l t s summarized above showed that the [4+2] c y c l o a d d i t i o n of nitroethylene to the parent diene (75) i s completely r e g i o s e l e c t i v e . Further evidence f o r the complete r e g i o s e l e c t i v i t y was found by conver-t i n g the n i t r o group i n the Diels-Alder adducts into a ketone moiety as described by McMurry and Melton. 8^ Thus, treatment of a 3:1:2 mixture (by glc) of the n i t r o esters (189)-(191) with sodium methoxide (1 equivalent) i n methanol, followed by addition of an aqueous s o l u t i o n of titanium t r i c h l o r i d e (4 equivalents) and ammonium acetate (25 equiva-lents) to the r e s u l t i n g nitronate anion (3 h, room temperature) provided a s i n g l e ketone (201) i n 90% y i e l d (equation 49). This substance (49) 189-191 201 - 98 -exhi b i t e d spectra consistent with the assigned structure. The ketone C-0 s t r e t c h i n the i r spectrum of (201) was observed at 1710 cm"*. More importantly, the r e l a t i v e stereochemistry of the angular a l l y l i c proton and the angular methyl ester was confirmed by a di f f e r e n c e nOe experi-ment i n which i r r a d i a t i o n of the methyl ester protons at S 3.69 caused a s i g n a l enhancement of the angular proton at S 2.82 (broad doublet, J_ -13 Hz). A d d i t i o n a l l y , MM2 c a l c u l a t i o n s * i n d i c a t e d that the isomeric ketone (202) should be -2.6 kcal/mol l e s s stable than (201). I t i s reasonable to assume that under the r e a c t i o n conditions, compound (202), which would have been present i n the i n i t i a l product mixture, epimerized to the more stable isomer (201). 202 203 Further, treatment of (201) with potassium tert-butoxide ( t e r t - b u t y l a l c o h o l , room temperature) provided the unsaturated ketone (203). The i r spectrum of (203) displayed an enone carbonyl absorption at 1668 cm'l. The nmr spectrum of (203) demonstrated that the conjugated enone moiety was present (6" 133.8, 6 155.3, and S 199.6) and, i n addi t i o n , the ^H nmr spectrum of (203) displayed no sig n a l s which were consistent with the presence of a v i n y l proton. A v i n y l proton s i g n a l * We are g r a t e f u l to Professor L. Weiler f o r c a r r y i n g out these c a l c u l a t i o n s . - 99 -would be expected i n the nmr spectrum of a compound of structure (204). I f nitroethylene had been added to the diene (75) with regiochemistry opposite to that which was observed, the substance (204) would have been expected from the s e r i e s of reactions j u s t described (equation 50). NO-^ N 0 2 C0 2Me (50) The r e a c t i o n of nitroethylene with the c i s o i d trans diene (146) was c a r r i e d out (Entry 5, Table 11) i n d i e t h y l ether at room temperature. The nmr spectrum of the crude r e a c t i o n product ind i c a t e d that there were three compounds, M, N_ and P, present i n a r a t i o of -1 : 3 : trace, r e s p e c t i v e l y , (equation 51). Only compounds M and N_ were i s o l a t e d , i n - X 1 ^ N 0 2 00 M + _N + _P (51) 1 : 3 : trace C0 2Me 146 y i e l d s of 24% and 57%, r e s p e c t i v e l y , a f t e r chromatography of the crude mixture on s i l i c a g e l . Compound P was obtained by e q u i l i b r a t i o n (potassium tert-butoxide. t e r t - b u t y l alcohol, 100°C) of the n i t r o ester N. 8 4 The n i t r o ester P was obtained i n a 92% y i e l d a f t e r chromatography - 1 0 0 -of the crude ma t e r i a l . The spectra derived from compounds H. U a n d £ showed that these substances were Diel s - A l d e r adducts. However, the s p e c t r a l data d i d not provide d e f i n i t i v e information regarding c o n s t i t u -t i o n and r e l a t i v e stereochemistry. Thus, i t became necessary to use X-ray analyses f o r conclusive structure determinations. R e c r y s t a l l i z a t i o n of compound fi from chloroform provided c r y s t a l s (mp 8 9 - 9 0 ' C ) s u i t a b l e f o r an X-ray c r y s t a l l o g r a p h i c a n a l y s i s . This a n a l y s i s 7 2 (Appendix 1 ) showed that the structure of E i s as i n d i c a t e d i n ( 1 9 5 ) (Figure 15). Thus, the structure of the n i t r o ester P must be as shown i n ( 1 9 6 ) since ( 1 9 5 ) and ( 1 9 6 ) are i n t e r c o n v e r t i b l e by epimerization. Figure 1 5 : Stereoview of the N i t r o Ester ( 1 9 5 ) - 101 -Treatment of the s i l y l ether M. with tetra-n,-butylammonium f l u o r i d e (2 equivalents, THF, room temperature) provided the corresponding a l c o h o l (205) which was converted into the p.-nitrobenzoate (206) (66% 0,Nk C 0 2 M e C 0 2 M e 195 196 R = SiMe 2 Bu y i e l d from M) by r e a c t i o n with p_-nitrobenzoyl c h l o r i d e (1.5 equivalents) i n the presence of 4-N,N-dimethylaminopyridine (0.1 equivalents) i n r e f l u x i n g methylene chloride (equation 52). R e c r y s t a l l i z a t i o n of the TBAF _ r M »» 205 - THF cic°-0"N°2 °zN CH 2 C1 2 (52) benzoate (206) from benzene afforded c r y s t a l s (mp 142.5-143.5°C) which were s u i t a b l e f o r X-ray a n a l y s i s . This a n a l y s i s 7 2 (Appendix 1) showed that the structure of the benzoate i s as i n d i c a t e d i n (206) (Figure 16). Therefore, the structure of the n i t r o ester M. i s as shown i n (197). Thus, a completely r e g i o s e l e c t i v e a d d i t i o n of nitroethylene to the c i s o i d trans diene (146) was observed. - 102 -i C0 2Me Next to be considered was the r e a c t i o n between nitroethylene and the c i s o i d c i s diene (145) (Entry 6, Table 11). I t was found that f or the r e a c t i o n to proceed, the substrates had to be r e f l u x e d i n d i e t h y l ether f o r seven hours. The nmr spectrum of the crude product mixture i n d i c a t e d the presence of three components, Q, J and V, present i n a r a t i o of -1:trace:2.5, r e s p e c t i v e l y (equation 53). These compounds could be c l e a n l y separated by column chromatography and they were i s o l a t e d i n y i e l d s of 21% (Q), 3% (T) and 54% (V). The spectra of these - 103 -*• 2. + 1  + 1  ( 5 3 ) 1 : 2.5 : trace compounds were i d e n t i c a l (!) with those of the n i t r o esters obtained from the Diel s - A l d e r r e a c t i o n of the c i s o i d trans diene (146) with nitroethylene ( i . e . , Q • (197), T - (196) and V o (195)). I t appears that i n the presence of nitroethylene (or some other impurity r e s u l t i n g from the preparation of nit r o e t h y l e n e ) , the c i s o i d  c i s diene (145) undergoes an isomerization to the c i s o i d trans diene (146), followed by a normal Diels-Alder transformation. There are two pieces of evidence i n support of t h i s statement. F i r s t , the product mixtures obtained from the reactions of nitroethylene with (145) and (146) are e s s e n t i a l l y i d e n t i c a l (see Entries 5 and 6, Table 11). Secondly, r e f l u x i n g a s o l u t i o n of the c i s o i d c i s diene (145) i n d i e t h y l ether or THF i n the absence of nitroethylene r e s u l t e d i n no observable (glc) isomerization of (145) into (146) even a f t e r extended periods of time. The diene (145) could be recovered unchanged i n high y i e l d . The manner i n which t h i s c i s to trans isomerization occurs was not inv e s t i g a t e d f u r t h e r . I t may be possible that nitroethylene i t s e l f i s promoting the isomerization (electron t r a n s f e r mechanism?) or that some other impurity a r i s i n g from the nitroethylene preparation procedure (such as an a c i d i c species) causes the isomerization. - 104 -With the body of information contained i n Tables 10 and 11, the questions that were r a i s e d at the beginning of t h i s study regarding the D i e l s - A l d e r r e a c t i v i t y of the dienes (75), (145) and (146) can be answered. (1) Tetracyanoethylene (W) and maleic anhydride (X) approach the dienes (75), (145) and (146) predominantly or e x c l u s i v e l y from the side opposite the angular (X^Me moiety (0-attack) (Entries 1-6, Table 10). However, with dimethyl acetylenedicarboxylate, methyl a c r y l a t e (Y) and nitroethylene (Z), the predominance of ^-attack i s much l e s s (1.8-33:1, B- to a-attack) (Entries 1-6, Table 11). These r e s u l t s can be r a t i o n a l i z e d on the basis of the s t e r i c demand of the d i f f e r e n t dieno-p h i l e s i n the Diels-Alder reaction. There i s l i t t l e or no s t e r i c hindrance to approach of any of these dienophiles to the /?-face of the dienes (75), (145) or (146). However, c e r t a i n a-face attack t r a n s i t i o n states are g r e a t l y d e s t a b i l i z e d (see (207)) by a s t e r i c i n t e r a c t i o n between a dienophile substituent and the angular C^Me function. In the case of TCNE, t h i s type of i n t e r a c t i o n cannot be avoided i n an a-face approach and thus TCNE i s r e f e r r e d to as " s t e r i c a l l y demanding". Dienophiles which have a high p r e d i l e c t i o n f o r an endo R' 207 - 105 -t r a n s i t i o n state (e.g. maleic anhydride) can, i n an analogous manner, be considered to be s t e r i c a l l y demanding when approaching (75), (145) and (146) from the a-face. The remainder of the dienophiles employed i n the Diels-Alder reactions of (75), (145) and (146) can react v i a exo t r a n s i t i o n states on the a-face of these dienes and thus, are "less s t e r i c a l l y demanding". (2) We observed that the approach of the dienophiles W-Z from the /9-face of the dienes (75), (145) and (146) i s st e r e o s e l e c t i v e , occurring e x c l u s i v e l y (Entries 3 and 4, Table 10; maleic anhydride, X) or p r i n c i p a l l y (Entries 1-6, Table 11; dienophiles W, Y, Z) (endo:exo. 1.8-2.7:1) v i a endo t r a n s i t i o n states. Conversely, attack of the dienophiles on the a-face of the dienes proceeds e x c l u s i v e l y v i a exo t r a n s i t i o n states (Entries 1-6, Table 11). Presumably t h i s mode of attack occurs because a-face endo t r a n s i t i o n states are gr e a t l y d e s t a b i l i z e d (see (207)) by a s t e r i c i n t e r a c t i o n between a dienophile substituent and the angular C02Me function as described above. (3) The manner i n which unsymmetrical dienophiles react with the dienes (75) and (146) i s completely r e g i o s e l e c t i v e (Entries 1-6, Table 11). These r e s u l t s are i n accord with predictions based on (a) the matching of surfaces representing the a t t r a c t i o n of model e l e c t r o p h i l e s to dienes and the a t t r a c t i o n of model nucleophiles to d i e n o p h i l e s 8 6 ( s i m i l a r to a f r o n t i e r molecular o r b i t a l approach 7 9) or (b) b i r a d i c a l arguments. 8 7 The arguments used i n p r e d i c t i n g the r e g i o s e l e c t i v i t y of the Diels-Alder r e a c t i o n based on b i r a d i c a l arguments 8 7 are applied to the cases studied - 106 -herein. The f i r s t assumption to be made i s that the angular ester moiety plays no r o l e i n determining the regiochemistry of the ad d i t i o n of the unsymmetrical dienophiles to the dienes (75) and (146). This assumption appears to be j u s t i f i e d since i t i s known8^ that substituents at the 2-position of dienes are dominated by substituents (even by r e l a t i v e l y "weak" d i r e c t i n g groups) at the 1-position. For example, treatment of 2-ethoxy-l-methylbutadiene (208) with the unsymmetrical dienophiles (209) (E - el e c t r o n withdrawing group) provides the "ortho" adduct (210) , demonstrating that the weakly d i r e c t i n g methyl group overrides the i n t e r n a l ethoxy substituent (equation 54). Thus, the dienes (75) and (146) can be represented by the s i m p l i f i e d , s ubstituted butadienes (211) and (216), r e s p e c t i v e l y (Scheme 8). A d d i t i o n of methyl acrylate or nitroethylene (E - CX^Me or N0£ i n Scheme 8) to the butadienes (211) and (216) can provide two intermediate b i r a d i c a l s i n each case, (212) and (213) from (211), and (217) and (218) from (216). Consideration of the r e l a t i v e s t a b i l i t i e s of each species allows one to p r e d i c t which regioisomer should predominate 8 7 i n the product mixture. In the f i r s t case (where R - H), the Intermediate a l l y l i c r a d i c a l i s s t a b i l i z e d by more a l k y l s u b s t i t u e n t s 8 9 i n (212) than i n (213) (3 vs. Me Me (54) 208 209 210 - 107 -214 215 219 220 224 225 Scheme 8 2). The regioisomer predicted to be preferred i n t h i s case, (214)^ i s the regioisomer which i s observed (Entries 1 and 4, Table 11). In the second case (where R - CH 20SiMe 2Bu t), one has to consider two b i r a d i c a l intermediates, (217) and (218). The a l l y l i c r a d i c a l i n (217) i s s t a b i l i z e d by three a l k y l substituents. The a l l y l i c r a d i c a l i n (218) - 1 0 8 -i s s t a b i l i z e d b y t w o a l k y l s u b s t i t u e n t s a n d d e s t a b i l i z e d 8 ' " b y t h e p r e s e n c e o f a n i n d u c t i v e l y e l e c t r o n w i t h d r a w i n g , o x y g e n c o n t a i n i n g s u b s t i t u e n t i n t h e t h i r d p o s i t i o n (R - C H ^ O S i M ^ B u * 1 ) . T h u s , t h e r e g i o i s o m e r e x p e c t e d t o b e p r e f e r r e d i n t h i s c a s e , ( 2 1 9 ) , i s t h e r e g i o i s o m e r w h i c h i s o b s e r v e d ( E n t r i e s 2 , 5 a n d 6, T a b l e 1 1 ) . E v e n t h o u g h t h e a n a l y s i s b a s e d o n b i r a d i c a l a r g u m e n t s c o r r e c t l y p r e d i c t s t h e o b s e r v e d r e g i o s e l e c t i v i t y , i t w a s i n t r i g u i n g t o a n a l y z e t h e r o l e p l a y e d b y t h e e t h e r o x y g e n i n t h e d i e n e ( 1 4 6 ) . T h i s e l e c t r o n w i t h d r a w i n g g r o u p i s r e m o v e d f r o m t h e d i e n e u n i t i n ( 1 4 6 ) b y a -CH2-g r o u p a n d y e t i t a p p e a r s t o b e 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 t h e r e g i o s e l e c t i v i t y o b s e r v e d i n t h e D i e l s - A l d e r r e a c t i o n s o f ( 1 4 6 ) . I t w a s r e a s o n e d t h a t i f t h i s s u b s t i t u e n t w e r e r e p l a c e d w i t h a s i m p l e a l k y l g r o u p , s u c h a s i n t h e d i e n e ( 1 4 7 ) (R - CH2CH3 i n S c h e m e 8 ) , t h e s t a b i l i t i e s o f t h e r e s u l t i n g i n t e r m e d i a t e b i r a d i c a l s ( 2 2 2 ) a n d ( 2 2 3 ) s h o u l d b e s i m i l a r . T h u s , b o t h p r o d u c t s ( 2 2 4 ) a n d ( 2 2 5 ) s h o u l d b e o b s e r v e d f r o m t h e D i e l s - A l d e r r e a c t i o n o f t h e d i e n e ( 1 4 7 ) w i t h a n u n s y m m e t r i c a l d i e n o p h i l e . T r e a t m e n t o f t h e d i e n e ( 1 4 7 ) w i t h m e t h y l a c r y l a t e ( 1 0 e q u i v a l e n t s , b e n z e n e , r e f l u x , 3 d a y s ) p r o v i d e d , i n 84% y i e l d , a n o i l ( 2 2 6 ) ( e q u a t i o n 55) w h i c h p r o v e d t o b e a m i x t u r e o f a t l e a s t f i v e i s o m e r i c d i e s t e r s b y Me02C (55) C0,Me C0 2Me 147 226 - 109 -g a s - l i q u i d chromatography-low r e s o l u t i o n mass spectrometry. This d i e s t e r mixture (226) was treated with LDA (2.5 equivalents, THF) and the r e s u l t i n g mixture of enolate anions was allowed to react with phenyl selenenyl c h l o r i d e (2.5 equivalents). The derived selenides were treated, i n THF, with aqueous hydrogen peroxide (10 equivalents) and a c e t i c a c i d and the r e s u l t i n g selenoxides underwent e l i m i n a t i o n to provide a mixture of dienes. This mixture was treated with 2,3-di-chloro-5,6-dicyano-l,4-benzoquinone (DDQ) (1.1 equivalents, benzene). Chromatography of the crude product mixture provided two aromatic compounds, (227) and (228), as an inseparable mixture, i n 82% o v e r a l l y i e l d from (226) (equation 56). The *H nmr spectrum of the mixture 226 227 228 i n d i c a t e d that the di e s t e r s (227) and (228) were present i n a r a t i o of 1.4:1, r e s p e c t i v e l y . In assigning the structures of (227) and (228), the *H nmr sign a l s that were of p a r t i c u l a r importance were those derived from the methylene protons of the e t h y l moiety (-CH.2CH3). The signals due to these protons were observed at 6 2.60 and 6 2.86 (quartet each, r a t i o 1.4:1, J - 7.5 Hz each). The s i g n a l f u r t h e s t downfield at 6 2.86 can be assigned to the -CH2CH3 protons of the d i e s t e r (228) because of the proximity of the ethyl moiety to the deshielding cone of the ester - 110 -carbonyl f u n c t i o n . 7 ^ In summary, the r e g i o s e l e c t i v i t y of the addi t i o n of methyl acrylate to the diene (147) i s low. In contrast, the additions of unsymmetrical dienophiles to the dienes (75) and (146) are h i g h l y r e g i o s e l e c t i v e . These r e s u l t s are i n accord with predictions made on the basis of b i r a d i c a l arguments. 8 7 (4) The f i n a l question to be addressed i s that of diene r e a c t i v i t y . Expectedly, the Diels-Alder r e a c t i v i t y of the c i s o i d c i s diene (145) i s much lower than that of the c i s o i d trans diene (146). Presumably, the dif f e r e n c e i n r e a c t i v i t y i s due to the r e l a t i v e a b i l i t y of the c i s o i d  c i s and c i s o i d trans dienes to a t t a i n a planar diene conformation i n the cy c l o a d d i t i o n t r a n s i t i o n state. D e s t a b i l i z a t i o n of t h i s t r a n s i t i o n state i n the reactions of the c i s o i d c i s diene (145) occurs as a r e s u l t of the s t e r i c i n t e r a c t i o n between the exocyclic methylene substituent with the o l e f i n i c proton i n the r i n g (see structure (150)). Only the rea c t i o n of (145) with very reactive dienophiles ( t e t r a -cyanoethylene, W; maleic anhydride, X) gave "normal Diels-Alder" products (Entries 4 and 6, Table 10). Even then, the y i e l d i n one case was only 18% (Entry 6, Table 10). As discussed previously, i t i s l i k e l y that these products a r i s e v i a a two-step process rather than a concerted c y c l o a d d i t i o n process. With the les s r e a c t i v e dienophiles, e i t h e r no cy c l o a d d i t i o n was observed (methyl a c r y l a t e , Y, Entry 3, Table 11; dimethyl acetylenedicarboxylate) or a l t e r n a t i v e processes occurred (nitroethylene, Z, Entry 6, Table 11). The p o t e n t i a l synthetic u t i l i t y of the Diels-Alder products has been - I l l -demonstrated by the preparation of the ketones (201) (see equation 49) and (203). A d d i t i o n a l l y , exposure of the n i t r o ester (195) to conditions i d e n t i c a l with those described previously f o r the preparation of the ketone (201), provided the ketone (232) i n 83% y i e l d (equation 58). The ketone (232) exhibited the expected carbonyl absorptions at 1740 and 1729 cm'^ i n the i r spectrum. (58) 195 232 The f a c i l e preparation of the aromatic ester (235) was accomplished i n three steps from the parent diene (75) (equation 59). The diene (75) (59) i • C0 2Me C0 2Me 234 235 - 112 -was allowed to react with 1,2-bis(phenylsulfonyl)ethylene (1.2 equiva-lents) i n r e f l u x i n g benzene. A sin g l e product (233) was obtained i n 82% y i e l d . Although the r e l a t i v e stereochemistry of t h i s compound was not determined, i t seems reasonable, on the basis of the previous r e s u l t s , that exclusive /J-face attack has occurred to provide (233). Reductive e l i m i n a t i o n of s u l f o n y l moieties was accomplished by t r e a t i n g the ester (233) with 2% sodium amalgam (6.8 equivalents of sodium) i n methanol. The diene (234) so produced was dehydrogenated with DDQ (1.02 equiva-lents) i n r e f l u x i n g benzene to provide the aromatic ester (235) i n 74% y i e l d from (233). The structure of (235) was f u l l y supported by i t s derived spectra. The ^ 3C nmr spectrum of (235) exhibited only ten signals because of the symmetry present i n (235). In addition, the nmr spectrum of (235) displayed only two signals i n the aromatic region at 6* 6.95 (2-proton broad doublet, J = 7.5 Hz) and 8 7.11 (1-proton t r i p l e t , J - 7.5 Hz). The s t r u c t u r a l s i m i l a r i t y of (some of) the Diels-Alder products reported above to the amphilectane-type d i t e r p e n o i d s 9 0 (e.g. 8,15-di-isocyano-ll(20)-amphilectene (236)) i s obvious. The a p p l i c a t i o n of (some of) the methods reported here to the t o t a l synthesis of diterpe-noids such as (236) i s being a c t i v e l y pursued i n our l a b o r a t o r i e s . NC 236 - 113 -2.3.0 The T o t a l Syntheses of the Dolastane Diterpenoids (±)-(14S)-Dolasta-l(15),7,9-trien-14-ol and (±)-Amijitrienol 2.3.1 Introduction The dolastane-type diterpenoids are a small family of s t r u c t u r a l l y i n t e r e s t i n g marine natural p r o d u c t s . 9 1 The f i r s t member of t h i s family to be discovered i n Nature, d o l a t r i o l (237), was i s o l a t e d from the ethanol extract of the poisonous Indian Ocean seahare St y l o c h e i l u s  l o n g i c a u d a . 9 1 a Since then, over 16 diterpenoids, possessing the unique, l i n e a r l y fused 6-7-5 dolastane c a r b o c y c l i c framework ( 2 3 8 ) 9 1 a have been i s o l a t e d from various marine sources. 1 The absolute stereochemistry of these substances i s known. 9 1 n»*- Although varying degrees of unsatura-t i o n and oxygen f u n c t i o n a l i z a t i o n are found to be present i n the dolastanes, of the members that have been reported to date, only three ( ( 2 3 9 ) 9 1 S , ( 2 4 0 ) 9 1 h and ( 2 4 1 ) 9 1 e ' n ) contain a conjugated, heteroannular diene system incorporating carbons 7-10. In addition, ( 2 4 2 ) 9 1 J i s the only member that includes a conjugated diene function connecting carbons 13, 14, 1 and 15. - 114 -239 R=H 240 R=0H 241 R=OAc The t r i e n o l , (14S)-dolata-l(15),7,9-trien-14-ol (239), was i s o l a t e d as a minor component from the hexane extracts of a mixture of the brown seaweeds Dictvota l i n e a r i s and D. d i v a r i c a t a . c o l l e c t e d from the c o r a l reefs o f f the Hondouras Bay Islands. The t r i e n o l , ( + ) - a m i j i t r i e n o l (242), was i s o l a t e d from the methanol extracts of D. l i n e a r i s of unknown o r i g i n . 9 ^ J The t r i c y c l i c dolastane diterpenoids, which may incorporate a trans-fused 6-7 r i n g junction, various degrees of unsaturation and up to four c h i r a l centers, o f f e r i n t e r e s t i n g synthetic challenges. The t o t a l synthesis of (±)-(239) or (±)-(242) had not been reported p r i o r to the p u b l i c a t i o n of our work. However, Pattenden and Robertson had r e p o r t e d 9 2 a synthesis of the r e l a t e d dolastane diterpenoid (±)-isoami-j i o l (243). Subsequent to our work, Mehta and Krishnamurthy r e p o r t e d 9 3 ' * the synthesis of (+)-(239) and (+)-(243). A d d i t i o n a l l y , Paquette and coworkers have re c e n t l y r e p o r t e d 9 4 the synthesis of the non-naturally occurring dolastane (±)-doladiol acetate (244). The synthetic approaches of Pattenden 9 2 and Mehta 9 3 to the compounds (±)-(243) and (+)-(239) and (+)-(243), r e s p e c t i v e l y , are based on We thank Professor G. Mehta f o r sending us a pr e p r i n t of h i s paper. - 115 -HO, OH OAc 243 244 reactions and key steps quite d i f f e r e n t from those u t i l i z e d i n our syntheses of (±)-(239) and (±)-(242). Pattenden's strategy f o r the synthesis of (±)-(243) 9 2 involved the i n i t i a l formation of the key azulenone intermediate (249) (see Scheme 9). Thus, the s i l y l enol ether (246) was prepared from the enamine (245) i n three standard steps. An intramolecular [2+2] photocyclo-a d d i t i o n of (246) i n hexane provided the cyclobutane (247) which underwent reductive coupling with acetone to a f f o r d the alkene (248) i n 52% y i e l d from (246). In the presence of aqueous HF, the cyclobutane (248) e a s i l y fragmented to f u r n i s h the key 5,7-ring system present i n (249) . A l k y l a t i o n of the l i t h i u m enolate derived from (249) with the Iodo alkyne (250) produced regio- and s t e r e o s e l e c t i v e l y a s i n g l e epimer of the s u b s t i t u t e d azulenone (251). A l k y l a t i o n of the sodium enolate of (251) l e d to formation of the b i s - a l k y l a t e d azulenones (252) and (253) i n a r a t i o of 4:1, r e s p e c t i v e l y . Deprotection of the terminal acetylene moiety i n (252), followed by intramolecular coupling of t h i s function-a l i t y with the ketone moiety i n the presence of sodium naphthalene r a d i c a l anion, gave s t e r e o s e l e c t i v e l y deoxyisoamijiol (254) i n 41% y i e l d . A l l y l i c oxidation of (254) with selenium dioxide and t e r t -butylhydroperoxide completed the f i r s t t o t a l synthesis of a dolastane diterpenoid, (±)-isoamijiol (243) (Scheme 9). - 116 -Scheme 9 - 117 -Mehta's approach to the synthesis of the dolastanes' J also proceeded v i a the hydroazulenone (249). However, the l a t t e r substance was constructed e n a n t i o s e l e c t i v e l y . Thus, the c h i r a l a,^-unsaturated aldehyde (255) ( r e a d i l y a v a i l a b l e from (R)-(+)-limonene) was converted into the enol ether (256) using standard methodology. Claisen rearrangement of (256) provided the aldehyde (257) s t e r e o s e l e c t i v e l y . The transformation of (257) into the enone (258) was accomplished v i a a two step sequence inv o l v i n g a Grignard a d d i t i o n and oxidation. The f a c i l e a c i d catalyzed olefin-enone c y c l i z a t i o n of (258) afforded the c h i r a l azulenone (259) i n 19% o v e r a l l y i e l d from (255) . Following a r e a c t i o n sequence i d e n t i c a l with that reported by Pattenden, 9 2 (259) was converted, i n four steps i n 19% o v e r a l l y i e l d , to (260). Again, i n a manner s i m i l a r to that reported by Pattenden, 9 2 (260) was oxidized with selenium dioxide and tert-butylhydroperoxide to provide i n 60% y i e l d , a 2:3:1 mixture of (+)-isoamijiol (243), (+)-(239) and (+)-(261) (Scheme 10). 2.3.2 The T o t a l Synthesis of (±)-(14S)-Dolasta-l(15),7,9-trien-14-ol The synthetic planning f o r the t o t a l synthesis of (±)-(14S)-dolasta-1(15),7,9-trien-14-ol (239) was based on the success of preparing the b i c y c l i c diene nucleus. Thus, i t was envisioned that (263) could be r e a d i l y assembled by the general strategy used i n the previously developed annulation process. In f a c t , the successful preparation of the b i c y c l i c diene (170) (see Entry 4, Table 9) served as a model for - 118 -- 119 -t h i s p o t e n t i a l l y c r u c i a l sequence of reactions. The proposed synthetic route to (±)-(239) i s summarized i n Scheme 11. I t was expected that the mono-protected cycloheptanedione (262) could be obtained from the mono-protected cyclohexanedione (261). This transformation was envisaged to involve methylation of (261), Saegusa r i n g expansion 9^ of the r e s u l t i n g methylated ketone and hydrogenation of the enone so produced. Construction of the b i c y c l i c diene nucleus (263) was to be c a r r i e d out, by the coupling of (262) and (154), employing the annulation process developed previously. The remaining carbons of the six-membered r i n g were to be attached to the e x i s t i n g b i c y c l i c nucleus (264) by the use of the donor-acceptor reagent (43). Guided by the previous e f f o r t of Pattenden, 9 2 the sequential a d d i t i o n of the two necessary appendages ((43) and methyl iodide) to the ketone (264) was expected to proceed s t e r e o s e l e c t i v e l y to provide (265). F i n a l l y , i t was hoped that preparation of the v i n y l anion from the v i n y l iodide i n (266), which i n turn was to be prepared from the corresponding vinylstannane (265), would e f f e c t r i n g closure with the desired stereochemistry to f u r n i s h (±)-(14S)-dolasta-l(15),7,9-trien-14-ol (239). I t appeared, from the close i n s p e c t i o n of molecular models, that the c y c l i z a t i o n of (266) should occur i n the desired stereochemical sense i n order to avoid s t e r i c i n t e r a c t i o n with the angular, o-methyl* group present i n (266) (Scheme 11). The a-face r e f e r s to the face of the molecule on the same side as the angular methyl group at C-12 (dolastane numbering) while the /3-face r e f e r s to the opposite face. - 120 -1. methylation 2. Saegusa r i n g expansion 3. hydrogenation 261 262 Me 3 Sn 154 2. enol t r i f l a t e 3. Pd(0) c y c l i z a t i o n hydrolysis 263 264 M e . S r A ^ - / 1 ; X M e l 265 X=SnMe3 266 X=I Scheme 11 239 The s t a r t i n g material chosen f o r the synthesis, 1,4-cyclohexanedione mono-2.2-dimethyltrimethvlene k e t a l (261), i s commercially a v a i l a b l e from A l d r i c h Chemical Co., Inc. T i c and nmr a n a l y s i s of t h i s m a t erial in d i c a t e d that i t was contaminated with a s i g n i f i c a n t amount (-20%) of the d i k e t a l (267). Thus, the commercial mixture was subjected - 121 -to f l a s h chromatography to obtain (261) as a pure substance. Alterna-t i v e l y , (261) could be prepared i n three steps from 1,4-cyclohexanediol (268) by the procedure of Haslanger and Lawton. 9 6 OH OH 268 267 Methylation of the keto k e t a l (261) was c a r r i e d out v i a the corresponding dimethylhydrazone. 9 7 Thus, r e f l u x i n g a benzene s o l u t i o n of (261) and 1,1-dimethylhydrazine (1.2 equivalents) f o r two hours, while removing water with a Dean-Stark apparatus, provided, a f t e r d i s t i l l a t i o n of the crude o i l , the hydrazone (269) i n 99% y i e l d (equation 60). The presence of absorption bands at 2773 cm'^ and 1640 cm"l (NMe2 and C=N absorptions, respectively) i n the i r spectrum of (269) as well as a 6-proton s i n g l e t at 5 2.49 i n the nmr spectrum of (269) demonstrated that the hydrazone moiety was present. Mono-alkylation of the hydrazone (269) according to Corey and E n d e r s 9 7 was e f f e c t e d by treatment of (269) with LDA (1.2 equivalents, 0°C, 1.5 h) followed by the add i t i o n of methyl iodide (2 equivalents) to the l i t h i u m anion so formed. The hydrazone moiety i n the crude methy-la t e d product (270) was o x i d a t i v e l y cleaved with sodium metaperiodate 9 7 (2.2 equivalents) i n aqueous, buffered (pH 7) THF at room temperature. The methylated ketone (271) was i s o l a t e d i n 99% y i e l d from (269) (equation 60). - 122 -261 269 The presence of a 3-proton doublet at 5 1.06 (J - 7 Hz) i n the ^H nmr spectrum of (271) indicated that the o v e r a l l mono-methylation of (261) had taken place. The i r spectrum of (271) displayed a C=0 s t r e t c h at 1711 cm"1. Saegusa and coworkers have reported 9-* that the FeCl3 promoted oxidative cleavage of 1-trimethylsiloxybicyclo[n.1.0]alkanes (272) leads to the formation of the corresponding 2-cycloalkenones (274) v i a the intermediate 3-chlorocycloalkanones (273) (equation 61), providing a new one-carbon r i n g homologation method. 272 273 274 Thus, k i n e t i c deprotonation of (271) with LDA (1.5 equivalents, DME, 0°C), followed by trapping of the r e s u l t i n g l i t h i u m enolate with TMS-C1 (3 equivalents) i n the presence of triethylamine (3 e q u i v a l e n t s ) 9 8 produced the enol t r i m e t h y l s i l y l ether (275) with >97% r e g i o s e l e c t i v i t y (by glc) (equation 62). The 1H nmr spectrum of the crude enol s i l y l - 123 -ether (275) exhibited signals f o r the - S i M ^ protons at 6 0.23 (9-proton s i n g l e t ) and the o l e f i n i c proton at S 4.63 (1-proton m u l t i p l e t ) . Rubottom and Lopez have r e p o r t e d , " 3 along with Murai and cowork-ers, that the cyclopropanation of s i l y l a lkenyl ethers with the Simmons-Smith reagent (CH2l2t Zn-Cu couple) afforded the corresponding s i l y l cyclopropyl ethers. Using the modified Simmons-Smith cyclopropa-nation c o n d i t i o n s 1 0 0 (ZnEt 2, CH 2l2. PhMe, 0 2, 55°C), the crude s i l y l enol ether (275) was converted into a mixture of the isomeric s i l y l c yclopropyl ethers (276) and (277) i n 86% y i e l d from (271) (equation 62). 62) 271 275 277 276 The presence of the cyclopropane moiety was i n d i c a t e d by the absorption at 3073 cm"1 i n the i r spectrum of t h i s mixture. The nmr spectrum of the mixture of (276) and (277) ind i c a t e d that they were present i n a 2:1 r a t i o (signals due to the -SiMe3 protons observed at 6 0.09 and S 0.10, r a t i o 2:1) but i t could not be determined which was the major isomer. One could speculate, on the basis of s t e r i c hindrance of approach of the cyclopropanating reagent to the s i l y l enol ether (275), that (276) should be the major isomer. However, the presence of a mixture of cyclopropyl ether diasteromers i s i r r e l e v a n t since, a f t e r the - 124 -subsequent reaction, only a si n g l e c h i r a l center remains (vide supra). The s i l y l cyclopropyl ether mixture was converted i n t o the 2-cyclo-heptenone (279) employing Saegusa's method.9-* Thus, slow a d d i t i o n (syringe pump, over 2 h) of a DMF-pyridine (1 equivalent) s o l u t i o n of (276) and (277) to a c o l d (O'C) DMF s o l u t i o n of anhydrous F e C l 3 (3 equivalents) was followed by warming of the r e a c t i o n mixture to room temperature (2 h). The rather unstable, crude /9-chloro ketone (278) so produced was d i s s o l v e d i n methanol containing sodium acetate (7 equi-valents) and the r e s u l t i n g mixture was refluxed f o r 15 hours. Workup, chromatography and d i s t i l l a t i o n of the crude product provided the enone (279) i n 62% y i e l d (equation 63). 276,277 278 279 The s p e c t r a l data derived from (279) are i n complete agreement with the assigned structure. The i r spectrum of t h i s material exhibited an enone carbonyl absorption at 1672 cm"1. The nmr spectrum of (279) i n d i c a t e d that the k e t a l moiety was Intact (two 3-proton s i n g l e t s at 6 0.93 and S 1.02 and a 4-proton m u l t i p l e t at S 3.40-3.56). More importantly, the s i g n a l s due to the v i n y l proton resonances of H a and H D were observed as a doublet of doublets (J - 2.3, 12 Hz) at S 6.08 and a doublet of doublets of doublets (J - 5, 7.5, 12 Hz) at 6 6.40, - 125 -r e s p e c t i v e l y . In addition, the 1 3 C nmr spectrum of (279) confirmed the presence of the enone moiety since signals due to the C-C-C-0 carbon resonances were observed at 6 133.0, 6 138.4 and S 204.3. Also, signals f o r 13 unique carbons were observed, with 6 of these d i s p l a y i n g a negative amplitude i n an APT experiment. 1 0 1 Hydrogenation of (279) was smoothly e f f e c t e d upon exposure of a solution-suspension of the enone (279) and Pd-C i n dry hexane to hydrogen gas (1 atm) f o r 2 hours. The cycloheptanone (262) was furnished i n 99% y i e l d (equation 64). 0 Q (64) 279 262 The i r spectrum of t h i s material displayed a carbonyl absorption at 1703 cm"1 while the 1H nmr spectrum exhibited no v i n y l proton s i g n a l s . A d d i t i o n a l l y , s i g n a l s f o r 13 unique carbons, only 4 of which displayed a negative amplitude i n an APT experiment, were observed i n the 1 3 C nmr spectrum of (262). With q u a n t i t i e s of (262) i n hand, the previously developed annulation procedure f o r the preparation of b i c y c l i c dienes was attempted. In the event, a l k y l a t i o n of (262) with the a l l y l i c bromide (154) v i a the potassium enolate of (262) prepared under e q u i l i b r a t i n g conditions - 126 -(KOBu^ Bi^OH-DME) provided a mixture of three products (280), (281) and (282) (equation 65). Chromatography of the crude product mixture on s i l i c a g e l gave a clean separation of the three components which were obtained i n i s o l a t e d y i e l d s of 11%, 2% and 59%, r e s p e c t i v e l y . + 281 282 The f i r s t component to be eluted, (280), proved to be a mixture of diasteromers. The nmr spectrum of t h i s mixture exhibited four s i n g l e t s (-SnMe.3 proton resonances) between 6 0.16 and S 0.19, the r a t i o of which could not be determined. The second compound to be eluted, (281), was a s i n g l e C-7 mono-al k y l a t e d isomer of undetermined stereochemistry. The nmr spectrum of (281) displayed a 3-proton doublet ( 1 - 7 Hz) at 6 1.01 due to the secondary methyl group attached to the 7-membered r i n g . The t h i r d substance to be eluted was the desired ketone (282). The s p e c t r a l data derived from t h i s compound are i n complete agreement with - 127 -the assigned structure. Thus, absorptions due to the carbonyl and -SnMe3 groups were observed at 1706 and 770 cm""1, res p e c t i v e l y , i n the i r spectrum of (282). The 1H nmr spectrum of (282) exhibited resonances due to the -SnMe.3 protons (6 0.20, 9-proton s i n g l e t , 2sn-H ~ 52 Hz), the isopro p y l group (6" 0.99, 6-proton doublet, 2 - 7 Hz), three t e r t i a r y methyl groups (6 0.82, S 1.05 and 6 1.15, a l l 3-proton s i n g l e t s ) and a v i n y l proton (6 5.92, 1-proton t r i p l e t , 2 - 7 Hz, 2sn-H " 1 4 6 H z ) • Further, the 1 3 C nmr spectrum of (282) displayed 20 unique carbon resonances, one of which (6 -6.9) was due to the -Sn(CH3)3 carbons. The ketone (282) was converted into the enol t r i f l a t e (283) employing conditions s i m i l a r to those developed previously. Thus, treatment of the l i t h i u m enolate of (282) (prepared by re a c t i o n of (282) with LDA (1.5 equivalents, THF-HMPA, -78°C to 0°C)) with Tf 2NPh (1.57 equivalents) provided the enol t r i f l a t e (283) a f t e r chromatography of the crude product (equation 66). Absorptions at 1670 and 1412 cm"A i n the i r spectrum of (283) confirmed the presence of the sulfonate moiety. Also, a 2-proton - 128 -m u l t i p l e t at S 5.88-5.98 i n the -^H nmr spectrum of (283) ind i c a t e d the presence of two o l e f i n i c protons. Intramolecular palladium catalyzed coupling of the vinylstannane-enol t r i f l a t e moieties i n (283) proceeded i n THF i n 5 minutes to provide the diene k e t a l (263) (equation 66). The optimized y i e l d s of the two steps associated with t h i s "two-pot" process are about 59% and 93%, r e s p e c t i v e l y . Thus, the o v e r a l l y i e l d of (263) from (282) was approximately 54% (equation 66). However, as explained previously, the y i e l d s associated with a "one-pot" procedure are u s u a l l y s i g n i f i c a n t l y higher than those derived from a "two-pot" process i n v o l v i n g i s o l a t i o n of the p o t e n t i a l l y unstable enol t r i f l a t e p r i o r to c y c l i z a t i o n . Hence, conversion of the ketone (282) into the corresponding enol t r i f l a t e as above, followed by d i r e c t a d d i t i o n of Pd(PPti3)4 (5 mol %) to the r e s u l t a n t THF s o l u t i o n , provided a f t e r 5 minutes at 30°C, an 81% y i e l d of the diene k e t a l (263) (equation 66). The presence of the heteroannular diene moiety i n (263) was evidenced by an absorption at 1647 cm"1 i n the i r spectrum of t h i s material. Furthermore, the 1-proton o l e f i n i c proton resonances at S 5.54 and 8 5.60 (H a and H D, respectively) were observed i n the ^H nmr spectrum of (263) (cf. the ^H nmr spectrum of (170)). M i l d a c i d hydrolysis (HCI, acetone, room temperature) of (263) gave the b i c y c l i c diene ketone (264) i n 99% y i e l d (equation 67). The C=0 s t r e t c h i n g v i b r a t i o n was observed at 1704 cm"1 i n the i r spectrum of (264). Signals due to protons H a and H D were observed at 8 5.64 and 8 5.71, r e s p e c t i v e l y , i n the 1H nmr spectrum of (264). In - 129 -(67) 263 264 addition, resonances due to one of the protons at each of C-13 and C - l l (dolastane numbering) could be c l e a r l y observed i n the nmr spectrum (Figure 17). I r r a d i a t i o n of the l a t t e r three protons i n decoupling experiments (see Experimental) provided support f o r these assignments. Fourteen s i g n a l s , i n c l u d i n g v i n y l i c carbon resonances at 6 115.5, 6 5 3 2 1 0 ppm Figure 17: The 400 MHz *H nmr Spectrum of (264) - 130 -125.8, 6 149.8 and 6 155.3, and a carbonyl carbon resonance at S 211.8 were observed i n the 1 3C nmr spectrum of (264). A l k y l a t i o n of the enolate anion (284) can t h e o r e t i c a l l y take place from e i t h e r face of the molecule. Assuming that the a l k y l a t i o n of t h i s enolate i s under st e r e o e l e c t r o n i c c o n t r o l , with the incoming a l k y l a t i n g agent approaching the enolate anion from an a x i a l or perpendicular d i r e c t i o n , then two t r a n s i t i o n states, (284a) and (284b), leading to products are p o s s i b l e . The l a t t e r t r a n s i t i o n state, (284b), i s d e s t a b i l i z e d r e l a t i v e to t r a n s i t i o n state (284a) f o r two reasons. F i r s t , there i s a s t e r i c i n t e r a c t i o n between the incoming a l k y l a t i n g agent and the angular methyl group i n (284b) which i s absent i n (284a). - 131 -Secondly, assuming that the t r a n s i t i o n state resembles the product of a l k y l a t i o n (at l e a s t to some extent), the t r a n s i t i o n state (284b) i s observed to have a higher energy b o a t - l i k e conformation while t r a n s i t i o n state (284a) has a lower energy, c h a i r - l i k e conformation. Thus, on the basis of s t e r i c and s t e r e o e l e c t r o n i c considerations, along with the close examination of molecular models, i t appeared that a l k y l a t i o n of the enolate anion (284) would take place p r e f e r e n t i a l l y from the side opposite the angular methyl group, v i a t r a n s i t i o n state (284a), to provide s t e r e o s e l e c t i v e l y , the 0-face a l k y l a t e d substance (285) rather than the a-face a l k y l a t e d material (286). A d d i t i o n a l support f o r t h i s l i n e of reasoning was found i n the s t e r e o s e l e c t i v e a l k y l a t i o n s of the analogous ketones (249) and ( 2 5 1 ) 9 z (Scheme 9) . Thus, i n order to set up the required r e l a t i v e stereochemistry between the angular methyl groups present i n (±)-(14S)-dolasta-l(15),7,9-trien-14-ol (239) , add i t i o n of the necessary appendages to the ketone (264) had to be done i n a s p e c i f i c order. Since the angular methyl groups i n (239) are disposed i n a trans fashion on the c e n t r a l 7-membered r i n g , methylation of a s u i t a b l y a l k y l a t e d ketone was required i n order to achieve the desired r e l a t i v e stereochemistry. Unfortunately, attempted a l k y l a t i o n of (264) with 5 - i o d o - 2 - ( t r i -methylstannyl) -1-pentene (43) under a v a r i e t y of conditions f a i l e d to give u s e f u l y i e l d s of the desired product(s) (287) and/or (288) (equation 68). Thus, formation of the enolate anion from (264) with LDA or l i t h i u m tetramethylpiperidide (LTMP) i n THF-HMPA, followed by the a d d i t i o n of a THF s o l u t i o n of (43) provided <2% of the desired ketone (287). - 132 -2. 1 . base Me3Sn 43 264 (68) + Me3Sn 287 288 A l k y l a t i o n of (264), with the enolate anion of (264) being formed under thermodynamically c o n t r o l l e d conditions (KOBu^ Bu^H-DME) , was quite c a p r i c i o u s . Mixtures of the a l k y l a t e d materials (287) and (288) were obtained i n y i e l d s ranging from 34% to 94%. As w e l l , varying amounts of the ketone (264) and other u n i d e n t i f i e d a l k y l a t i o n products, which proved to be very d i f f i c u l t to separate from (287) and (288), were observed i n the crude product mixtures. Drip column chromatography of the crude mixtures provided small amounts of the pure subtances (287) and (288). Due to the unpredictable nature of t h i s r e action, as w e l l as the d i f f i c u l t y encountered i n the p u r i f i c a t i o n of the a l k y l a t e d materials, i t was decided to a l k y l a t e the ketone (264) v i a the corresponding dimethyl hydrazone. 9 7 A methanol s o l u t i o n of the ketone (264) and 1,1-dimethylhydrazine - 133 -(10 equivalents) was refluxed i n the presence of AA molecular sieves. D i s t i l l a t i o n of the crude product provided the hydrazone (289) i n 98% y i e l d (equation 69). / " ^ ^ A H NNMe v M * Me2N~N (69) 264 289 Absorptions due to the hydrazone moiety were observed at 2769 and 1626 cm"1 i n the i r spectrum of (289). This material e x i s t e d as a mixture of geometrical isomers i n a r a t i o of 2:1. Thus, the nmr spectrum of (289) displayed two s i n g l e t s at 6 2.41 and S 2.49 ( r a t i o 1:2) due to the NMeo proton resonances. A d d i t i o n of a THF s o l u t i o n of the hydrazone (289) to LDA (1.2 equivalents, THF, -78°C to 0°C), followed by treatment of the r e s u l t i n g anion with 5-iodo-2-(trimethylstannyl)-1-pentene (43) (1.2 equivalents, THF, 0 oC to room temperature), provided, a f t e r h y d r o l y s i s of the hydrazone moiety as described previously (NaI04, THF-H2O, pH 7 b u f f e r ) , a s i n g l e ketone (287) i n 69% y i e l d (equation 70). The stereochemical assignment f o r (287) was made p r i m a r i l y on the ba s i s of the pr e d i c t i o n s o u t l i n e d above regarding stereocontrol i n the a l k y l a t i o n of the enolate anion (284). A d d i t i o n a l l y , i t was observed that under e q u i l i b r a t i n g conditions (NaOMe, MeOH), (287) p a r t i a l l y epimerized to the more stable isomer (288) (equilibrium r a t i o - 134 -(288):(287) i s 1.4:1 by g l c ) . Ketone (288) was the isomer observed to be i n greater abundance (by glc) when the a l k y l a t i o n of (264) was conducted under e q u i l i b r a t i n g conditions (vide supra). The spectra derived from (287) and (288) are consistent with the assigned structures. The i r spectra of (287) and (288) displayed absorptions due to the ketone and -SnMe3 moieties at 1699 and 768 cm"1 and at 1705 and 768 cm"1, re s p e c t i v e l y . The 1H nmr spectra of (287) and (288) (Figures 18 and 19) f a i l e d to provide conclusive evidence f o r the stereochemical assignments, although the t e r t i a r y methyl group reso-nances at 6 1.08 and S 1.04, re s p e c t i v e l y , are d i s t i n c t i v e as are the o l e f i n i c proton resonances. Regardless of the stereochemical assign-ment, the subsequent methylation of (287) or (288) was a n t i c i p a t e d to be the c r u c i a l step since i t was the r e a c t i o n i n which the r e l a t i v e stereo-chemistry between the angular methyl groups was to be established. In the event, treatment of the potassium enolate of (287), prepared under e q u i l i b r a t i n g conditions (KOBu^ THF-HMPA), with methyl iodide (6 equivalents) provided, a f t e r workup and chromatography of the crude product, a s i n g l e ketone (265) i n 63% y i e l d (equation 71). - 135 -5 3 2 1 0 ppm Figure 18: The 400 MHz 1H nmr Spectrum of the Ketone (287) 5 3 2 1 0 ppm Figure 19: The 400 MHz 1H nmr Spectrum of the Ketone (288) - 136 -287 265 The AH nmr spectrum of (265) displayed two 3-proton s i n g l e t s at 5 1.03 and 6* 1.11 f o r the t e r t i a r y methyl group proton resonances. I t was not p o s s i b l e , on the basis of the s p e c t r a l data derived from t h i s compound, to unequivocally prove that t h i s substance had the r e l a t i v e stereochemistry depicted i n (265). Again, the stereochemical assignment i n (265) was based on the previously described p r e d i c t i o n s regarding the stereocontrol i n the a l k y l a t i o n of the enolate anion (284). The keto vinylstannane (265), upon r e a c t i o n with i o d i n e 1 0 2 (1 equivalent) i n methylene chl o r i d e at room temperature, was smoothly transformed into the keto v i n y l iodide (266) i n 93% y i e l d (equation 72). 265 266 The iH nmr spectrum of (266) f u l l y supported the assigned structure (Figure 20). The t e r t i a r y methyl group proton resonances were observed as 3-proton s i n g l e t s at 6 1.09 and 6 1.13 while the isopropyl methyl proton resonances were found at 6* 1.03 and 6 1.10 as 3-proton doublets - 137 -(J - 7 Hz for each). The olefinic protons were observed as 1-proton signals at 6 5.55 (Hc, doublet of doublets, J. - 6, 8.5 Hz), 6 5.60 (Hd, broad singlet), 6 5.71 (Ha, doublet, J - 1.5 Hz) and S 6.03 (Hb, multiplet). In addition, four resolved multiplets were observed at 5 2.04 (doublet of doublets, 2 - 8.5, 15 Hz), 6 2.14 (doublet of doublets, J - 2, 16 Hz), 6 2.54 (doublet, 1-12 Hz) and 5 2.81 (doublet, 2 - 1 2 Hz) and were assigned to one of the protons at each of C-6, C-ll and both protons at C-13 (dolastane numbering), respectively. 6 5 3 2 1 0 ppm Fig. 20: The 400 MHz XH nmr Spectrum of the Vinyl Iodide (266) On the basis of a number of literature precedents, a variety of methods for effecting ring closure of (266) were contemplated and attempted. However, treatment of the vinyl iodide (266) with lithium - 138 -d i - n - b u t y l cuprate (according to the procedure of Corey and Kuwajima 1 0 3), l i t h i u m and/or sodium metals under various conditions (as described by Luche and Damiano 1 0 4 and Trost and C o p p o l a 1 0 5 ) , B u c L i or B u n L i at -78"C (as o u t l i n e d by Cooke and H o u p i s 1 0 6 ) , or C r C l 2 1 0 7 under various r e a c t i o n conditions, provided none of the desired closure product. In each case, e i t h e r s t a r t i n g material and/or u n i d e n t i f i e d r e a c t i o n products were observed. I t was g r a t i f y i n g to f i n d that the desired conversion could be achieved simply by treatment of the keto v i n y l iodide (266) with small pieces of f r e s h l y ground magnesium metal (-12 equivalents) i n r e f l u x i n g THF f o r 2.5 hours, a f t e r i n i t i a t i o n of the r e a c t i o n with 1,2-dibromo-ethane. Workup and chromatography of the crude r e a c t i o n product provided (±)-(14S)-dolasta-l(15),7,9-trien-14-ol (239) i n 49% y i e l d (equation 73), i n d i c a t i n g that the c y c l i z a t i o n occurred i n the desired stereochemical sense. The crude r e a c t i o n mixture was r e l a t i v e l y clean. The only side product observed was a small amount of a compound which, on the b a s i s of i t s g l c retention time, was presumed to be the uncy-c l i z e d keto alkene (H i n place of I i n (266)). This material was not i s o l a t e d or characterized further. 266 239 - 139 -R e c r y s t a l l i z a t i o n of (±)-(239) from heptane provided a s o l i d (mp 105-106°C) which exhibited spectra (^ H nmr, 1 3 C nmr, mass)* i n good agreement with those derived from natural (239). The nmr spectra of natural (239) and synthetic (±)-(239) are i l l u s t r a t e d i n Figures 21 and 22, r e s p e c t i v e l y . I t i s pertinent to point out several proton assign-ments which Crews was unable to make and also to c o r r e c t an erroneous assignment made by Crews 9 1£ i n the nmr spectrum of (239). The doublet of t r i p l e t s at { 2.60 (J = 6, 12.5 Hz) has been assigned by Crews to the a x i a l proton at C-2. 9 16 I r r a d i a t i o n of t h i s s i g n a l s i m p l i f i e s the broad doublet (J = 12.5 Hz) at 8 1.97 to a broad s i n g l e t and thus, the s i g n a l at 8 1.97 i s due to the resonance of the equatorial proton at C-2. Crews erroneously assigned the resonance at 8 1.97 to one of the protons at C-13. The signals due to the C-13 proton reso-nances can be observed at 5 2.03 and 5 1.48 (each a doublet, J = 14.5 Hz each). H Crews was also unable to assign the resonance of the equatorial proton at C-6 while the C-6 a x i a l proton resonance can be observed at 8 3.22 as a doublet of doublets (J = 4.5, 15 H z ) . 9 1 S I r r a d i a t i o n of t h i s * We thank Professor P. Crews f o r copies of spectra (^ H nmr, 1 3 C nmr, mass) of natural (239). - 140 -ppm F i g u r e 2 1 : T h e 3 0 0 MHz • L H n m r S p e c t r u m o f N a t u r a l ( 2 3 9 ) i n C g D g 5 4 3 2 1 0 ppm F i g u r e 2 2 : T h e 4 0 0 MHz * H n m r S p e c t r u m o f S y n t h e t i c ( ± ) - ( 2 3 9 ) i n C g D g - 141 -s i g n a l 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 doublet of doublets (J - 9.5, 15 Hz) at 6 1.51 to a doublet (J - 9.5 Hz) and thus, the resonance at S 1.51 i s assigned to the equatorial proton at C-6. P a r t i a l assignments of the protons at C-3 and C-4 i n the *H nmr spectrum of (±)-(239) can also be made and the reader i s r e f e r r e d to the Experimental s e c t i o n f o r t h i s purpose. In summary, the f i r s t t o t a l synthesis of (±)-(14S)-dolasta-l(15),7,9-trien-14-ol (239) was achieved, i n 5% o v e r a l l y i e l d , i n 17 steps from the keto k e t a l (261). 2.3.3 The T o t a l Synthesis of (±)-Amijitrienol The synthetic planning f o r the t o t a l synthesis of (±)-amijitrienol (242) i s o u t l i n e d i n Scheme 12, o r i g i n a t i n g from the key b i c y c l i c diene k e t a l (263). I t was expected that the azulenone (249), prepared p r i o r to t h i s work i n racemic form by Pattenden and Robertson, 9 2 could be obtained from the b i c y c l i c diene k e t a l (263) v i a a sequence of reduction and deprotection steps. The establishment of the r e l a t i v e trans stereo-chemistry between the two t e r t i a r y methyl groups i n (290) was to be accomplished i n a se r i e s of reactions i n v o l v i n g an a l d o l condensation between the ketone (249) and the aldehyde (291), oxidation of the re s u l t a n t 2-hydroxy ketone and st e r e o s e l e c t i v e methylation of the 1,3-diketone so produced. A c r u c i a l step f o r the succe s s f u l synthesis of (242) would involve the chemical d i f f e r e n t i a t i o n between the two carbonyl groups i n (290). I t was hoped that chemoselective conversion - 142 -2 9 2 242 Scheme 12 -of the side chain carbonyl group into a masked ketone ( s i l y l enol ether) or protected ketone group X (X - k e t a l ; H, OR) would be possible, l e a v i n g the remaining ketone group to become involved i n the f i n a l c y c l i z a t i o n process. Based on the degree of success achieved previously i n the intramolecular coupling of vinylstannanes and enol t r i f l a t e s , a procedure incorporating t h i s process was to be applied to the keto - 143 -vinylstannane (292) to form the heteroannular diene u n i t present i n (242). F i n a l l y , s u i t a b l e modification of the X group i n t o an alcohol moiety would complete the synthesis of (±)-amijitrienol (242). The s t a r t i n g material f o r the synthesis was the diene k e t a l (263) which had served as a key intermediate i n the t o t a l synthesis of (±)-(239). D i s s o l v i n g metal r e d u c t i o n 1 0 8 of the diene k e t a l (263) was accomplished using l i t h i u m metal i n d i e t h y l ether-ammonia (-2:1) (-48°C, 1.5 h). A mixture of the isomeric alkene ketals (293) and (294) was obtained i n a r a t i o of 1:4, re s p e c t i v e l y , by glc analysis of the crude product mixture (equation 74). 263 293 294 I i I ^ , h e x a n e That these materials were isomeric was demonstrated by the obser-vance of a If4" peak f o r each at m/e 292 i n a g a s - l i q u i d chromatography-low r e s o l u t i o n mass spectrometry experiment. In a d d i t i o n , the presence of the alkene (293) i n the mixture (and not the isomeric alkene (295)) was i n d i c a t e d by the presence of an o l e f i n i c proton s i g n a l at 5 5.41 (—1/2 ™ 1 6 Hz) i n the nmr spectrum of the crude r e a c t i o n product. The o l e f i n i c proton resonance i n a compound such as (295) would be expected to have E\/2 8 5 6 Hz ( c f . compound (263)) i n i t s 1H nmr spectrum. - 144 -The k e t a l s (293) and (294) proved to be very d i f f i c u l t to separate and (294) could be obtained i n pure form only i n very poor y i e l d s a f t e r subjecting the mixture to d r i p column chromatography on s i l i c a g e l . Attempts to apply rhodium t r i c h l o r i d e promoted o l e f i n isomeriza-t i o n 1 0 9 methodology to the mixture of (293) and (294) r e s u l t e d only i n the formation of numerous o l e f i n k e t a l isomers (by glc) i n a d d i t i o n to products r e s u l t i n g from d e k e t a l i z a t i o n of the various isomers. I t was g r a t i f y i n g to f i n d that treatment of the mixture of (293) and (294) with a c a t a l y t i c amount of iodine i n r e f l u x i n g hexane f o r three hours caused quantitative isomerization of (293) into (294). D i s t i l l a -t i o n of the crude product provided the o l e f i n i c k e t a l (294) i n 98% y i e l d from (263) (equation 74). The spectra (mass, i r , nmr) derived from (294) were i n good agreement with the spectra r e p o r t e d 1 1 ^ f o r (294). In p a r t i c u l a r , the nmr spectrum of (294) exhibited three 3-proton s i n g l e t s at 6 0.92, 6 0.97 and 6 1.04 due to the t e r t i a r y methyl group proton resonances and the 1 3 C nmr spectrum of (294) contained signals f o r 19 unique carbons. M i l d a c i d h y d r o l y s i s of (294) (HCI, acetone, room temperature) provided the ketone (249) i n 95% y i e l d (equation 75). The C-0 s t r e t c h i n g v i b r a t i o n i n the i r spectrum of (249) was observed at 1703 - 1 4 5 -(75) 294 249 cm"1. The iH nmr spectrum of this substance (Figure 23) was identical with that derived from material prepared by Pattenden and Robertson.92,* Figure 23: The 400 MHz lB war Spectrum of the Ketone (249) We thank Professor G. Pattenden for a copy of the 1H nmr spectrum of (249). - 146 -The a l d o l condensation between (249) and (291) was the next r e a c t i o n to be attempted (see Scheme 12). The aldehyde (291) was prepared i n two steps from commercially a v a i l a b l e pent-4-yn-l-ol (296). Thus, the o v e r a l l r e g i o s e l e c t i v e hydrostannylation of (296), employing the (trimethylstannyl)copper reagent ( 3 3 ) , 4 7 was accomplished as o u t l i n e d e a r l i e r except that i n t h i s case, i n s i t u protonation was accomplished using methanol 4 9 (equation 76). The known 4-trimethylstannyl-4-penten-l-ol (297), obtained i n 54% y i e l d , e xhibited spectra (^ H nmr, i r , mass) i d e n t i c a l with those reported f o r ( 2 9 7 ) . 1 1 1 Swern o x i d a t i o n 1 1 2 of (297) (o x a l y l c h l o r i d e , DMSO; triethylamine, -78°C) provided, a f t e r d i s t i l l a t i o n of the crude product, the r e l a t i v e l y unstable aldehyde (291) i n y i e l d s ranging from 65-80% (equation 76). This substance tended to decompose even upon storage under argon i n a freezer and so i t was used immediately a f t e r i t s preparation. Me SnCu-SMe ( 3 3 ) , II H-C=C(CH2hCH?0H — - - M e , S r r ^ ^ ^ 0 H *• *• *- MeOH, THF J 296 297 (COC1) 0 , DMSO; 2- : M e 3 S n ^ ^ ^ ^ C H 0 (76> E t N 5 291 The i r spectrum of (291) exhibited absorptions at 2719 and 1728 cm"1 (aldehyde moiety) and 770 cm"1 (Me3Sn group). In addition, the nmr spectrum of t h i s material displayed a 1-proton unresolved s i g n a l (w^/2 " 3 Hz) at S 9.78 due to the aldehyde proton resonance as well as the - 147 -s i g n a l s expected f o r the o l e f i n i c protons at 6 5.21 (1-proton m u l t i p l e t , J S n . H - 71 Hz) and S 5.68 (1-proton m u l t i p l e t , Jgn-H " 1 4 ^ H z ^ -Deprotonation of (249) with LDA (1.3 equivalents, THF, -78°C) and r e a c t i o n of the r e s u l t a n t enolate anion with 4-trimethylstannyl-4-pentenal (291) provided a mixture of keto alcohols (299) i n 62% y i e l d (equation 77). 249 2 9 9 This material, a mixture of three keto alcohols, exhibited three s i n g l e t s between S 0.10 and S 0.20 (three M^Sn groups) i n i t s ^H nmr spectrum. The mixture was not further characterized but was used immediately i n the following reaction. The mixture of keto alcohols (299) was oxidized, employing e i t h e r pyridinium chlorochromate ( P C C ) 1 1 3 or the Swern oxidation conditions. The l a t t e r a l t e r n a t i v e was preferred since i t allowed f o r a more f a c i l e i s o l a t i o n of the rather unstable 1,3-diketone product (300) (equation 78). The diketone (300) was not p u r i f i e d due to i t s exhibited i n s t a b i l i t y towards chromatographic adsorbents. That the diketone (300) had been formed was demonstrated by inspecting the i r spectrum of the crude diketone. Three e x p e c t e d 1 1 4 absorption bands due to the 1,3-diketone moiety are observed i n t h i s spectrum at 1725, 1695 and 1598 cm"1. - 148 -In accordance with predictions based on the insp e c t i o n of molecular models, l i t e r a t u r e precedent, 9 2 and previous experience (see t o t a l synthesis of (±)-(239)), i t was expected that a l k y l a t i o n of the diketone (300) at C-5 (dolastane numbering) would take place p r e f e r e n t i a l l y from the side opposite to the C-12 angular methyl group. In the event, methylation of the crude diketone (300) was accom-p l i s h e d by r e f l u x i n g an acetone s o l u t i o n of (300), methyl iodide (2 equivalents) and potassium carbonate (1.5 equivalents) f o r 15 h o u r s . 1 1 5 The nmr spectrum of the crude product indicated that there were two substances present i n a r a t i o of -2:1 (methyl proton s i n g l e t s at 6 1.23 and 6 1.37; r a t i o 2:1, r e s p e c t i v e l y ) . Drip column chromatography of t h i s mixture on s i l i c a gel provided three f r a c t i o n s , the f i r s t and l a s t to be eluted being the pure substances (290) and (301) which were obtained In i s o l a t e d y i e l d s of 41% and 16%, r e s p e c t i v e l y . The middle f r a c t i o n was comprised of a mixture of (290) and (301) (10% y i e l d ) (equation 79). While the major product from t h i s r e a c t i o n mixture was assigned the structure depicted i n (290), with the expected trans stereochemistry between the t e r t i a r y methyl groups, no fi r m conclusions from the - 149 -301 s p e c t r a l data derived from (290) and (301) (see Figures 24 and 25 f o r the nmr spectra of (290) and (301), r e s p e c t i v e l y ) could be drawn regarding the proposed stereochemical assignments. The 1 3 C nmr spectrum of each isomer ind i c a t e d the presence of twenty unique carbons plus a s i g n a l at 6 -9.5 i n each spectrum due to the -Sn(CH3)3 resonance. Hence, the stereochemical assignments i n (290) and (301) were made p r i m a r i l y on the basis of predictions regarding the p r e f e r r e d face of methylation of (300). The next task at hand was to chemically d i f f e r e n t i a t e between the two carbonyl groups of (290). On the basis of the i n s p e c t i o n of molecular models, i t was f e l t that the carbonyl group on the side chain of (290) was s t e r i c a l l y l e s s hindered than the cycloheptanone carbonyl moiety. Thus, the i n i t i a l plan Involved the projected chemoselective conversion of (290) i n t o the s i l y l enol ether (302), followed by formation of the enol t r i f l a t e (303). S e l e c t i v e deprotection of (303) with f l u o r i d e , followed by Pd(0) catalyzed c y c l i z a t i o n was expected to - 151 -provide the ketone (304), which could then be c a r r i e d on to (±)-(242) (Scheme 13). base; Tf^h Scheme 13 Add i t i o n of a THF s o l u t i o n of (290) to a THF s o l u t i o n of potassium b i s ( t r i m e t h y l s i l y l ) a m i d e (KN(TMS) 2) (1.1 equivalents) at -78°C, followed by the a d d i t i o n of TBDMS-OTf a f t e r one hour, provided i n 80% y i e l d , the s i l y l ether (302). The *H nmr spectrum of (302) displayed a 1-proton - 152 -t r i p l e t (J = 8 Hz) at 5 4.62 due to the newly introduced o l e f i n i c proton resonance and the i r spectrum of (302) exhibited absorptions at 1712 cm"1 (ketone moiety) and 1659 cm"1 (C=C s t r e t c h of enol s i l y l ether). The geometry of the side chain o l e f i n i c band was assigned i n accordance with well known p r e c e d e n t s 1 1 6 regarding the stereochemistry of enolate formation. Unfortunately, the remaining carbonyl group i n (302) could not be converted into the corresponding enol t r i f l a t e under conditions i n which the s i l y l enol ether moiety survived i n t a c t . Only decomposition products were observed by g l c and t i c analyses of the crude r e a c t i o n product mixtures. Apparently, the ketone center i n (302) i s severely s t e r i c a l l y hindered, precluding the deprotonation at the adjacent methylene u n i t under mild conditions. Therefore, the synthetic plan was changed i n the hope that the chemical d i f f e r e n t i a t i o n between the carbonyl groups i n (290) could be accomplished v i a a chemoselective reduction of (290). Reduction of the diketone (290) with DIBAL (1 equivalent, -78°C) i n various solvents (THF, Et20, PhMe) y i e l d e d only complex mixtures of (290), ketols and d i o l s . I t was found, however, that treatment of a THF s o l u t i o n of (290) with excess l i t h i u m chloride (-10 equivalents), followed by cooling of the r e s u l t a n t s o l u t i o n to -78°C and addi t i o n of DIBAL (-4-5 equivalents) provided a sing l e (!) alcohol (303a) which was immediately converted (TBDMS-OTf, DMAP, Et 3N, CH 2C1 2) into i t s s i l y l ether (303). The keto s i l y l ether (303) was obtained i n 79% y i e l d from the diketone (290) (equation 80). - 153 -1. L i C l , DIBAL, THF 2. TBDMS-OTf Me3Sn 303a R=H 303 R=SiMe2Bu (80) The *H nmr spectrum of (303) (Figure 26) exhibited resonances due to the -SnMe_3 protons (5 0.13, 9-proton s i n g l e t , J.Sn-H ™ ^3 Hz), the -SiMe 2Bu t protons (fi 0.08 and S 0.09, 3-proton s i n g l e t s each; S 0.91, 9-proton s i n g l e t ) , two t e r t i a r y methyl groups (5 0.94 and 5 1.09, 3-proton s i n g l e t s each), the -CH0SiR3 proton (S 3.53, 1-proton doublet of doublets, J - 3, 7.5 Hz) and two o l e f i n i c protons (5 5.11 and 5 5.62, 1-proton m u l t i p l e t s each). Absorptions due to the ketone and SnMe3 Me3Sn Bu t Me 2 Si0 •5 4 3 2 ppm Figure 26: The 400 MHz L H nmr Spectrum of the Keto S i l y l Ether (303) - 154 -moieties were observed at 1698 and 774 cm*1, r e s p e c t i v e l y , i n the i r spectrum of (303). However, based on t h i s s p e c t r a l data, no fi r m conclusion could be drawn regarding the stereochemical assignment at C-4. I t was determined subsequently (by the successful synthesis of (±)-(242) from (303)) that the chemo- and s t e r e o s e l e c t i v e reduction at C-4 of (290) had proceeded to e s t a b l i s h the c o r r e c t r e l a t i v e stereoche-mistry at C-4 (vide i n f r a ) . The nature of the r o l e played by l i t h i u m c h l o r i d e i n the conversion of (290) into (302) i s obscure. Coordination of the l i t h i u m c a t i o n with the 1,3-dione system of (290) may be important i n providing a "frozen" conformation of (290) as depicted i n (295). The chemo- and s t e r e o s e l e c t i v e reduction of (290) can then be r a t i o n a l i z e d by inspecting the possible ways i n which a reducing agent would appproach the ketone moieties at C-4 and C-14 i n (295). Approach of a reducing agent from the B-£ace at e i t h e r C-4 or C-14 would be hindered by the a x i a l methyl group at C-5. Approach from the a-face at 295 C-14 would be hindered by the angular methyl group at C-12 while no such s t e r i c i n t e r a c t i o n i s observed i n the approach of the reducing species from the a-face at C-4. Reduction v i a t h i s mode of approach leads to the observed keto alcohol (302). - 155 -In a d d i t i o n , a r e a c t i o n between l i t h i u m c h l o r i d e and DIBAL may provide a b u l k i e r complex reducing species (such as LiAlHClR 2) which would f e e l the e f f e c t of the s t e r i c i n t e r a c t i o n with the methyl groups to a greater degree than DIBAL i t s e l f . Regardless of the r a t i o n a l e , the reduction of (290) proceeded smoothly, e a s i l y (and happily) to provide the keto alcohol (302) and hence, the keto s i l y l ether (303). The c y c l i z a t i o n process, characterized by the w e l l e s t a b l i s h e d intramolecular Pd(0) catalyzed vinylstannane-enol t r i f l a t e coupling, was applied to (303). The ketone (303) was treated sequentially with KN(TMS) 2 (5 equivalents, THF, 0°C) and Tf 2NPh (5 equivalents).* Removal of the solvent under reduced pressure, followed by d i s s o l u t i o n of the crude enol t r i f l a t e In CH3CN-EC3N and a d d i t i o n of Pd(PPh 3)4 (6 mol %) afforded the s i l y l ether t r i e n e (304) a f t e r 30 minutes at r e f l u x . Cleavage of the s i l y l ether linkage (tetra-s-butylammonium f l u o r i d e , THF, r e f l u x ) afforded (±)-amijitrienol (242) i n 88% y i e l d from (303) (equation 81). R e c r y s t a l l i z a t i o n of (242) from hexane provided f i n e , white needles (mp 119-119.5°C) which exhibited spectra (*H nmr, 1 3 C nmr, mass, i r ) i d e n t i c a l * * with those derived from natural ( + ) - a m i j i t r i e n o l . 9 1 J The *H * I t was found that conversion of the ketone (303) into the corresponding enol t r i f l a t e using a l i t h i u m amide base (LDA) could not be accomplished. The reason f o r t h i s i s unclear although i t i s p o s s i b l e that r e a c t i o n of the l i t h i u m enolate anion of (303) with Tf 2NPh i s sluggish i n t h i s p a r t i c u l a r case due to the s t e r i c a l l y hindered nature of the enolate moiety. The use of a l e s s coordina-t i n g counterion (potassium i n t h i s case) may account f o r the success i n forming the enol t r i f l a t e under conditions i n which no reaction occurred using a l i t h i u m enolate. ** We thank Professor M. Ochi f o r copies of the spectra (^ H nmr, mass, i r ) of (+)-(242). - 156 -nmr spectra of synthetic and natural (242) are shown i n Figures 27 and 28. A s i n g l e point regarding the c y c l i z a t i o n procedure deserves mention. Triethylamine was added to the c y c l i z a t i o n r e a c t i o n mixture because the the diene system i n (304) (and (242)) was prone to acid-catalyzed rearrangement. In f a c t , the exocyclic double bond of (304) and (242) r a p i d l y and c l e a n l y isomerized to the C - l - C-2 p o s i t i o n when these substances were dissol v e d i n C D C I 3 that had not been shaken with Na2C03-MgS04 and then f i l t e r e d through basic alumina. Thus, when the *H nmr spectrum of (304) was run i n "untreated" C D C I 3 , the isomeric material (305) was found to be the major component of the sample. S i m i l a r l y , (306) was found to be the major component of a sample of (242) which had been dissolved In "untreated" C D C I 3 . Signals due to the o l e f i n i c protons, Ha, could be observed i n the nmr spectra of (305) and (306) at 6 5.26 and 6 5.37 (multiplets each), r e s p e c t i v e l y . In a d d i t i o n , broad s i n g l e t s due to the v i n y l methyl group proton resonances were observed at 6 1.80 and 6 1.84 i n the spectra of (305) and (306), r e s p e c t i v e l y . - 157 -p p m Figure 27: The 400 MHz LH nmr Spectrum of Natural (+)-Amijitrienol (242) Figure 28: The 400 MHz XH nmr Spectrum of Synthetic (±)-AmijItrienol (242) 158 -Ho-RO 306 305 In summary, the f i r s t t o t a l synthesis of (±)-amijitrienol (242) was achieved, i n 16% o v e r a l l y i e l d , i n 10 steps from the diene k e t a l (263). The synthetic sequences used i n the syntheses of (±)-(239) and (±)-(242) demonstrate the v i a b i l i t y of employing the newly developed annulation procedures, which e f f i c i e n t l y provide a v a r i e t y of b i c y c l i c dienes, to natural product synthesis. - 159 -I I I . EXPERIMENTAL 3.1.0 General Procedures, Solvents and Reagents Proton nuclear magnetic resonance (^ H nmr) spectra were obtained on deuterochloroform solutions (unless stated otherwise) using a Varian model XL-300 spectrometer or Bruker models WP-80, HXS-270 or WH-400 spectrometers. Signal p o s i t i o n s are given i n parts per m i l l i o n (5) from tetramethylsilane (TMS) as the i n t e r n a l standard. For those compounds containing trimethylstannyl and/or t r i a l k y l s l l y l groups, the resonance p o s i t i o n s were determined r e l a t i v e to the chloroform s i g n a l (6" 7 . 2 5 ) . 1 1 7 Coupling constants ( J-values) are reported i n Hz and were measured on sp e c t r a l spacings judged to be f i r s t o r d e r . 1 1 8 The spectra l i s t e d follow the order: chemical s h i f t (ppm), ( m u l t i p l i c i t y , number of protons, assignment (where p o s s i b l e ) , coupling constants (Hz)). The tin-proton coupling constants (J_sn-H) a r e given as an average of the J i 1 7 and J - t i Q values. _ i l / S n - H - l i y S n - H Carbon nuclear magnetic resonance ( 1 3C nmr) spectra were recorded on a Varian model XL-300 spectrometer at 75.3 MHz or on a Bruker model WH-400 spectrometer at 100.4 MHz, using deuterochloroform as the solvent. Signal p o s i t i o n s are given i n parts per m i l l i o n (5) r e l a t i v e to the deuterochloroform s i g n a l (5 7 7 . 0 ) . 1 1 9 Signals with negative i n t e n s i t i e s i n an attached proton t e s t (APT) are so indic a t e d i n brackets (-ve) following the chemical s h i f t . I nfrared ( i r ) spectra were obtained on l i q u i d films (sodium chloride - 160 -p l a t e s ) , chloroform solutions (0.1 mm sodium chl o r i d e c e l l s ) or potas-sium bromide d i s c s , employing a Perkin-Elmer model 1710 Fourier trans-form spectrophotometer ( i n t e r n a l c a l i b r a t i o n ) or a Perkin-Elmer model 710B spectrophotometer c a l i b r a t e d using the 1601 cm"1 band of a polystyrene f i l m . Low r e s o l u t i o n mass spectra were recorded with a Varian/MAT CH4B mass spectrometer. High r e s o l u t i o n mass spectra were recorded with a Kratos/AEI MS 50 or MS 902 mass spectrometer. Low r e s o l u t i o n g a s - l i q u i d chromatography - mass spectrometry (LRGLCMS) was accomplished using a combination of a Carlo Erba model 4160 c a p i l l a r y gas chromatograph (15 m x 0.25 m fused s i l i c a column coated with DB-5) and a Kratos/RFA MS 80 mass spectrometer, i n t e r f a c e d with a hollow c a p i l l a r y tube. A l l compounds which were subjected to high r e s o l u t i o n mass measurements were homogeneous by glc and/or t i c a n a l y s i s . For those compounds containing trimethylstannyl groups, the high r e s o l u t i o n mass spectrometry molecular weight determinations were based on 1 2 0 S n and made on the (M+-CH3) peak. 5 8 Microanalyses were performed i n the M i c r o a n a l y t i c a l Laboratory, U n i v e r s i t y of B r i t i s h Columbia. A n a l y t i c a l g a s - l i q u i d chromatography (glc) analyses were performed on e i t h e r a Hewlett-Packard model 5880 or a 5890 c a p i l l a r y gas chromato-graph, employing 25 m x 0.21 m fused s i l i c a columns coated with cross-l i n k e d SE-54, both using flame i o n i z a t i o n detectors. Thin-layer chromatography ( t i c ) was performed on commercially a v a i l a b l e , aluminum backed sheets, precoated with s i l i c a gel 60 to a thickness of 0.2 mm (E. Merck, type 5554). V i s u a l i z a t i o n of the chromatograms was accomplished with an u l t r a v i o l e t l i g h t (254 nm tube), - 161 -iodine s t a i n and/or heating under a hot gun a sheet stained with a 5% aqueous s o l u t i o n of ammonium molybdate i n 10% aqueous s u l f u r i c a c i d (w/v). Conventional column chromatography (drip) as w e l l as medium pressure and f l a s h chromatography 1 2^ was done on 230-400 mesh s i l i c a gel (E. Merck, S i l i c a gel 60). D i s t i l l a t i o n temperatures (uncorrected) were recorded as air-bath temperatures required f o r short path bulb-to-bulb (Kugelrohr) d i s t i l l a -t i o n . Melting points were measured on a Fisher-Johns melting point apparatus and are uncorrected. A l l dry solvents used were obtained by r e f l u x i n g over and subsequently d i s t i l l i n g from an appropriate drying a g e n t . 1 2 1 Dimethoxy-ethane, d i e t h y l ether and tetrahydrofuran were d r i e d over sodium benzo-phenone k e t y l . Dichloromethane and carbon t e t r a c h l o r i d e were d r i e d over phosphorus pentoxide. Diisopropylamine, N,N-dimethylformamide, dimethyl su l f o x i d e , hexamethylphosphoramide, pyridine and triethylamine were d r i e d over calcium hydride. The petroleum ether used was the f r a c t i o n with b o i l i n g point ca. 30-60°C. Hexamethylditin was obtained from Organometallics, Inc. and was used without fur t h e r p u r i f i c a t i o n i f c o l o u r l e s s . Otherwise i t was d i s t i l l e d under a s p i r a t o r vacuum (bp approximately 80°C) p r i o r to use. N-Phenyltrifluoromethanesulfonimide, obtained from the A l d r i c h Chemical Co., Inc., was used without further p u r i f i c a t i o n . That obtained from PCR Inc. of the SCM Corporation was resublimed p r i o r to use. Tetrakis(triphenylphosphine)palladium(0) was obtained from e i t h e r the A l d r i c h Chemical Co., Inc. or Morton Thiokol Inc. ( A l f a Products). - 162 -Solutions of methyllithium i n d i e t h y l ether and n-b u t y l l i t h i u m i n hexane were obtained from the A l d r i c h Chemical Co., Inc. and were standardized using the method of Kafron and B a c l a w s k i . 1 2 2 Solutions of potassium b i s ( t r i m e t h y l s i l y l ) amide i n toluene, diisobutylaluminum hydride (DIBAL) i n hexane and d i e t h y l z i n c i n toluene were also obtained from A l d r i c h . Phenylthiocopper was prepared by the method of P o s n e r . 1 2 7 Cuprous bromide-dimethyl s u l f i d e complex was prepared by the method of House, 1 2 3 a f t e r washing commercially a v a i l a b l e cuprous bromide with m e t h a n o l . 1 2 4 Saturated aqueous ammonium chloride (pH 8) was prepared by the ad d i t i o n of =50 mL of aqueous ammonium hydroxide (58%) to =1L of saturated aqueous ammonium chlo r i d e . Lithium diisopropylamide (LDA) was prepared by the ad d i t i o n of a s o l u t i o n of methyllithium i n ether to a s o l u t i o n of diisopropylamine (1 equiv) i n dry THF or DME at -78°C. The r e s u l t i n g s o l u t i o n was then s t i r r e d at 0°C f o r 10 min before use. Cold bath temperatures were obtained by using the following combina-tions of solvents and c o o l a n t s : 1 2 5 acetone-ice (-10°C), 27 g CaCl2/ 100 mL H 20/dry i c e (-20°C), 46 g CaCl 2/100 mL H 20/dry i c e (-48°C), chloroform-dry i c e (-63°C), acetone-dry i c e (-78°C) and methanol-N 2 (-98°C). Unless stated otherwise, a l l reactions were c a r r i e d out under an atmosphere of dry argon using glassware that had been thoroughly flame-d r i e d . - 163 -3.2.0 Experimental Procedures 3.2.1 Preparation of Donor-Acceptor Reagents Preparation 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 2 6 To a c o l d (-20°C), s t i r r e d s o l u t i o n of hexamethylditin i n dry THF (»10 mL per mmol) was added a s o l u t i o n of methyllithium i n d i e t h y l ether (1 equiv). The r e s u l t i n g pale, yellow-green s o l u t i o n was s t i r r e d at -20°C f o r 20 min to a f f o r d a s o l u t i o n of trimethylstannyllithium. Preparation of Lithium (PhenvlthioHtrimethylstannyl^cuprate (32) [Me 3SnCuSPh]Li To a c o l d (-20°C), s t i r r e d s o l u t i o n of trime 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 phenylthiocopper (1 equiv). 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, producing a deep red s o l u t i o n of l i t h i u m (phenylthio)(trimethylstannyl)cuprate (32). - 164 -Preparation of the (Trimethylstannvl)copper Reagent (33) Me3SnCu-SMe2 To a c o l d (-78°C), s t i r r e d s o l u t i o n of trim e t h y l s t a n n y l l i t h i u m In dry THF was added s o l i d cuprous bromide-dimethyl s u l f i d e (1 equiv). 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 at -63°C f o r 15 min to a f f o r d a dark red-brown s o l u t i o n of (33). Preparation of 6-Chloro-l-hexvne (46) Cl To a s t i r r e d s o l u t i o n of 5-hexyn-l-ol (2.94 g, 30.0 mmol) i n 50 mL of dry CCI4 was added s o l i d triphenylphosphine (8.26 g, 1.05 equiv). The r e s u l t i n g c o l o u r l e s s s o l u t i o n was refluxed f o r 2 h af f o r d i n g a pale yellow s o l u t i o n and a white p r e c i p i t a t e . A f t e r f i l t r a t i o n and removal of the CCI4 by atmospheric d i s t i l l a t i o n , the r e s u l t i n g residue was mixed with petroleum ether. F i l t r a t i o n of the s l u r r y through F l o r i s i l (40 g, e l u t i o n with petroleum ether), followed by atmospheric pressure d i s t i l -l a t i v e removal of the petroleum ether and then d i s t i l l a t i o n (bp 144-145°C; l i t . bp 142-144°C/760 T o r r 5 3 ) of the crude material y i e l d e d 1.81 g (52%) of the chloride (46) as a colourless l i q u i d ; i r ( f i l m ) : - 165 -3280, 640 cm - 1; 1H nmr (80 MHz, CDC13) 6: 1.45-2.40 (m, 7H), 3.57 ( t , 2H, -CH2C1, J - 6.4 Hz). General Procedure 1: Preparation of 2-Trimethvlstannvl-l-alkenes (36) To a c o l d (-78°), s t i r r e d s o l u t i o n of the (trimethylstannyl)copper reagent (33) (1.3 equiv) i n dry THF (=10 mL per mmol) was added dropwise (dropping funnel) a s o l u t i o n of the appropriate 1-alkyne (1 equiv) i n dry THF (=2 mL per mmol). The r e s u l t i n g dark red mixture was s t i r r e d at -78°C for 6 h and then g l a c i a l a c e t i c a c i d (=0.15 mL per mmol of alkyne), saturated aqueous ammonium chlo r i d e (pH 8) (=5 mL per mmol), methanol (=5 mL per mmol) and d i e t h y l ether (=3.5 mL per mmol) were added i n succession. With vigorous s t i r r i n g , the mixture was warmed to room temperature and s t i r r i n g was continued u n t i l the aqueous phase became deep blue (most conveniently overnight). The layers were separated and the aqueous layer was extracted twice with d i e t h y l ether (same volume used p r e v i o u s l y ) . The combined organic s o l u t i o n was washed with saturated aqueous ammonium chloride u n t i l the washings were co l o u r l e s s , and d r i e d over anhydrous magnesium s u l f a t e . Removal of the solvent i n vacuo afforded a pale yellow o i l which contained, on the basis of g l c analysis, hexamethylditin, one major component along with a Me3Sn"^(CH2)nCl - 166 -minor component (1-15% depending on substrate and/or i n d i v i d u a l experi-ment) having a f r a c t i o n a l l y longer retention time. Subjection of t h i s o i l to e i t h e r d r i p or medium pressure column chromatography on s i l i c a g e l followed by concentration of the appropriate f r a c t i o n s and bulb-to-bulb d i s t i l l a t i o n of the residue afforded the desired 2-trimethyl-stannnyl-1-alkene. The minor component, probably the isomeric ( E ) - l -trimethylstannyl-l-alkene, was not i s o l a t e d , probably due to i t s i n s t a b i l i t y and r e s u l t a n t decomposition on s i l i c a g e l . Preparation of 5-Chloro-2-trimethvlstannyl-l-pentene (38) Following general procedure 1 o u t l i n e d above, commercially a v a i l a b l e 5-chloro-l-pentyne (1.55 mL, 14.6 mmol) was converted into a mixture of two products (94:6 by g l c ) . Subjection of the crude o i l to column chromatography on s i l i c a gel (240 g, e l u t i o n with petroleum ether) provided a c o l o u 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 ir-bath tempera-ture 85-95°C/15 To r r ) , y i e l d e d 2.54 g (65%) of the alkene (38). This material gave i r ( f i l m ) : 1440, 920, 770 cm"1; XH nmr (80 MHz, CDC13) 6: 0.16 (s, 9H, -SnMe3, J S n _ H - 53 Hz), 1.7-2.1 (m, 2H, -CH 2CH 2CH 2-), 2.19 (br t, 2H, a l l y l i c methylene protons, J - 7 Hz), 3.52 ( t , 2H, -CH2C1, J = 6.5 Hz), 5.22 (d of t, 1H, H a, J - 2.5, 1 Hz, J S n . H - 70 Hz), 5.72 - 167 -(d of t, 1H, H b, J - 2.5, 1 Hz, Isn-H " 1 4 8 H z ) • Exact Mass calcd. f o r C 7 H 1 4 3 5 C l S n (M+-Me): 252.9840; found: 252.9836. Preparation of 6-Chloro-2-trimethylstannyl-l-hexene (47) Following general procedure 1 outl i n e d above, 6-chloro-l-hexyne (1.70 g, 14.6 mmol) was converted into a 97:3 mixture of two products. Subjection of the crude reaction product to column chromatography on s i l i c a g el (240 g, e l u t i o n with petroluem ether) provided a colou r l e s s l i q u i d which, following d i s t i l l a t i o n ( air-bath temperature 110-115°C/15 T o r r ) , y i e l d e d 2.96 g (72%) of the alkene (47), which exhibited i r ( f i l m ) : 1440, 920, 772 cm'1; XH nmr (80 MHz, CDC13) 6: 0.16 (s, 9H, -SnMe3, J S n _ H - 53 Hz), 1.35-2.00 (m, 4H, -CH 2CH 2CH 2CH 2-), 2.30 (br t, 2H, a l l y l i c methylene protons, J - 6.5 Hz, Is n-H " 5 0 H z ) • 3 5 2 (fc> 2 H> -CH2C1, J - 6 Hz), 5.16 (d of t, 1H, H a, J - 2.5, 1 Hz, J S n . H - 72 Hz), 5.66 (d of t, 1H, H b, J_ - 2.5, 1.3 Hz, lsn-H ~ 1 5 0 H z ) • Exact Mass calcd. f o r C 8 H 1 6 3 5 C l S n (M+-CH3): 266.9963; found: 266.9968. CI - 168 -General Procedure 2: Preparation of Methyl (E)-3-Trimethylstannyl-2- alkenoates (35) R C 0 2 M e Me 3Sn H To a c o l d (-78°C), s t i r r e d s o l u t i o n of the (trimethylstannyl)copper reagent (33) (1.3 equiv) i n dry THF (»10 mL per mmol) was added dropwise (dropping funnel), a s o l u t i o n of the appropriate a,/9-acetylenic ester (30) (1 equiv) i n dry THF (=2 mL per mmol). The re a c t i o n mixture was s t i r r e d at -78°C f o r 3 h. A f t e r successive a d d i t i o n of saturated aqueous ammonium chlo r i d e (pH 8) (=5 mL per mmol) and d i e t h y l ether (=3 mL per mmol), the mixture was allowed to warm to room temperature with vigorous s t i r r i n g and s t i r r i n g was continued u n t i l the aqueous phase was blue. The layers were separated and the aqueous layer was extracted twice with d i e t h y l ether (same volume used p r e v i o u s l y ) . The combined organic s o l u t i o n was washed with saturated aqueous ammonium chlo r i d e u n t i l the washings were co l o u r l e s s . Following drying over anhydrous magnesium s u l f a t e and removal of the solvent i n vacuo. the residue was subjected to f l a s h chromatography on s i l i c a g e l . Concentration of the appropriate f r a c t i o n s , followed by bulb-to-bulb d i s t i l l a t i o n of the residue, afforded the corresponding methyl (E)-3-trimethylstannyl-2-alkenoate (35). - 169 -General Procedure 3: Preparation of Methyl fZ)-3-Trimethylstannvl-2- alkenoates (34) To a c o l d (-78°C), s t i r 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 -methylstannyl)cuprate (32) (1.3 equiv) i n dry THF («10 mL per mmol) was added the appropriate a,/?-acetylenic ester (30) (1 equiv) as a s o l u t i o n i n dry THF (~2 mL per mmol). The reaction mixture was s t i r r e d f o r 15 min at -78°C, warmed to -48°C and s t i r r e d f o r 4 h. A f t e r successive a d d i t i o n of methanol («2 mL per mmol) and petroluem ether (»5 mL per mmol), the mixture was allowed to warm to room temperature with vigorous s t i r r i n g . The r e s u l t i n g yellow s l u r r y was f i l t e r e d through a plug of C e l i t e and the c o l l e c t e d material was washed with the same volume of petroleum ether as that used above. The combined eluate was concen-tr a t e d and the residue was subjected to f l a s h chromatography on s i l i c a g e l . Concentration of the appropriate f r a c t i o n s , followed by bulb-to-bulb d i s t i l l a t i o n of the residue, afforded the corresponding methyl (Z)-3-trimethylstannyl-2-alkenoate (34). - 170 -Preparation of Methvl 6-Chloro-2-hexvnoate (91) CtfCH2)3C5C-C02Me To a c o l d (-78°C), s t i r r e d s o l u t i o n of 5-chlorohexyne (45) (5.13 g, 50.0 mmol) i n 100 mL of dry THF was added a s o l u t i o n of methyllithium i n d i e t h y l ether (46.0 mL, 1.1 equiv). The r e s u l t i n g c o l o u r l e s s s o l u t i o n was s t i r r e d at -78°C f o r 10 min, warmed to -20°C and s t i r r e d at t h i s temperature f o r 1 h. Methyl chloroformate (4.64 mL, 1.2 equiv) was added and the r e s u l t i n g yellow s o l u t i o n was s t i r r e d f or 30 min at -20°C and at room temperature for 30 min. Saturated aqueous sodium bicarbo-nate (50 mL) and d i e t h y l ether (50 mL) were added. The organic l a y e r was separated and d r i e d over magnesium s u l f a t e . Solvent removal (rotary evaporation) followed by bulb-to-bulb d i s t i l l a t i o n (air-bath temperature 65-75°C/0.1 Torr) of the r e s i d u a l o i l , afforded 7.50 g (93%) of the at,/9-acetylenic ester (91) as a colourless o i l . This material exhibited i r ( f i l m ) : 2228, 1712, 1433, 1259, 1080, 755 cm"1; -^H nmr (80 MHz, CDC13) 8: 2.08 (m, 2H, -CH 2CH 2CH 2-), 2.61 (br t, 2H, «CCH 2-, J - 6.5 Hz), 3.66 ( t , 2H, -CH2C1, J - 6 Hz), 3.78 (s, 3H, -OCH3). Exact Mass cal c d . f o r C 7H 90 2 3 5C1: 160.0292; found: 160.0290. - 171 -Preparation of Methyl 4-Methvl-2-pentvnoate (92) ) -=-co 2 Me Following the procedure used f o r the preparation of methyl 6-chloro-2-hexynoate (91), 3-methyl-1-butyne (3.4 g, 50 mmol) was treated successively with methyl l i t h i u m (34 mL, 1.1 equiv) and methyl chloro-formate (4.64 mL, 1.2 equiv) to y i e l d , a f t e r workup and bulb-to-bulb d i s t i l l a t i o n (air-bath temperature 60-70°C/15 Torr) of the crude product, 5.92 g (94%) of the ester (92) as a colou r l e s s o i l . This material exhibited i r ( f i l m ) : 2220, 1715, 1390, 1370, 1260 cm"1; XH nmr (80 MHz, CDC1 3) 6: 1.18 (d, 6H, Me2CH-, J - 7 Hz), 2.63 (septet, 1H, Me2CH-, J - 7 Hz), 3.70 (s, 3H, -OCH3). Exact Mass calcd. f o r C 7H 1 00 2: 126.0681; found: 126.0686. Preparation of Methyl (E)-6-Chloro-3-trimethylstannvl-2-hexenoate (95) Following general procedure 2, methyl 6-chloro-2-hexynoate (91) (3.00 g, 18.7 mmol) was converted into the ester (95). Flash chromatog-- 172 -raphy of the crude product on s i l i c a g el (240 g, e l u t i o n with petroleum ether-ether, 20:1), followed by d i s t i l l a t i o n ( air-bath temperature 115-120°C/0.6 Torr) of the material thus obtained, y i e l d e d 4.79 g (79%) of the (FJ-hexenoate (95) as a colourless o i l . This material exhibited i r ( f i l m ) : 1710, 1595, 1195, 1175, 777 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.21 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.6-2.1 (m, 2H, -CH 2CH 2Ch 2-), 3.00 (br t, 2H, a l l y l i c methylene protons, 1 - 7 Hz, lsn-U " 5 8 Hz)• 3 - 5 3 (c> 2H, -CH2C1, J - 6.5 Hz), 3.65 (s, 3H, -OCH3), 5.99 ( t , 1H, v i n y l proton, J - 1 Hz, Isn-H " 7 1 H z ) - Exact Mass calcd. f o r C g H 1 6 0 2 3 5 C l S n (M+-CH3): 310.9861; found: 310.9853. Preparation of Methyl (Z)-6-Chloro-3-trimethvlstannyl-2-hexenoate (93) Following general procedure 3, methyl 6-chloro-2-hexynoate (91) (3.00 g, 18.7 mmol) was converted into the ester (93). Flash chromato-graphy of the crude product on s i l i c a gel (240 g, e l u t i o n with petroleum ether-ether, 20:1), followed by d i s t i l l a t i o n (air-bath temperature 106-116°C/0.6 Torr) of the material thus obtained, y i e l d e d 5.30 g (87%) of the (Z)-hexenoate (93) as a colourless o i l . This material exhibited i r ( f i l m ) : 1701, 1600, 1210, 778 cm"1; XH nmr (80 MHz, CDCI3) 6: 0.21 (s, 9H, -SnMe.3, I S n-H " 5 4 H z>> 1-6-2.1 (m, 2H, -CH 2CH 2CH 2-), 2.59 (br MeoSn C0 2 Me - 173 -t, 2H, a l l y l i c methylene protons, J - 7 Hz, Is n-H " 4 6 H z ) - 3 - 5 1 (fc- 2 H> -CH2C1, J - 6.5 Hz), 3.73 (s, 3H, -OCH3), 6.40 ( t , 1H, v i n y l proton, J -1.5 Hz, J S n - H ~ 117 Hz). Exact Mass calcd. f o r C 9 H 1 6 0 2 3 5 C l S n (M+'C^) : 310.9861; found: 310.9862. Preparation of Methyl (Z)-4-Methyl-3-trimethylstannyl-2-pentenoate (94) H C 0 2 Me Me 3 Sn Following general procedure 3, methyl 4-methyl-2-pentynoate (92) (4.40 g, 34.9 mmol) was converted into the ester (94). Flash chromato-graphy of the crude product on s i l i c a g el (240 g, e l u t i o n with petroleum ether-ether, 100:1), followed by d i s t i l l a t i o n ( air-bath temperature 110-115°C/15 Torr) of the material thus obtained, y i e l d e d 8.43 g (83%) of the (Z)-pentenoate (94) as a colourless o i l . This material exhibited i r ( f i l m ) : 1700, 1599, 1210, 780 cm"1; LE nmr (80 MHz, CDCI3) 6: 0.14 (s, 9H, -SnMe3, 2sn-H - 54 Hz), 1.02 (d, 6H, Me2CH-, J - 7 Hz), 2.71 (septet, 1H, Me2CH-, 2 - 7 Hz), 3.70 (s, 3H, -OCH3), 6.35 (d, 1H, v i n y l proton, J - 1 Hz, isn-H "" 1 2 6 Hz). Exact Mass calcd. f o r CgH^yO^n (M+-CH3): 277.0250; found: 277.0252. - 174 -General Procedure 4: Reduction of a.5-Unsaturated Esters to A l l y l i c  Alcohols To a c o l d (-78°C), s t i r r e d s o l u t i o n of the appropriate cr,^-unsatura-ted ester (1 equiv) i n dry d i e t h y l ether («20 mL per g) was added slowly a s o l u t i o n of DIBAL i n hexane (2.5 equiv). The r e a c t i o n mixture was s t i r r e d at -78°C f o r 1 h, warmed to 0°C and s t i r r e d at t h i s temperature fo r 2 h. Saturated aqueous ammonium chl o r i d e (=3 mL per g) was added and the mixture was warmed to room temperature. Anhydrous magnesium s u l f a t e was added to the r e s u l t i n g s l u r r y and the r e s u l t i n g mixture was f i l t e r e d through a plug of C e l i t e . The c o l l e c t e d material was washed twice with d i e t h y l ether (same volume used above). Concentration of the eluate and 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 afforded the corresponding a l l y l i c a l c o h o l . Preparation of (E)- 6 - Chloro - 3 - t r imethyls tannvl - 2 -hexen-1 - o l (101) Following general procedure 4, 3.10 g (9.53 mmol) of methyl (E)-6-chloro-3-trimethylstannyl-2-hexenoate (95) was converted into the a l l y l i c a l c o hol (101). D i s t i l l a t i o n (air-bath temperature 100-110°C/ 0.03 Torr) of the crude material y i e l d e d 2.52 g (89%) of the ( E ) - a l l y l i c OH Me3Sn' H - 175 -alcohol (101) as a colourless o i l which exhibited i r ( f i l m ) : 3300, 1020, 770 cm"1; XH nmr (80 MHz, CDCl 3) 6: 0.15 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.65 (br s, 1H, exchanges with D 20, -CH20H), 1.6-2.0 (m, 2H, -CH 2CH 2CH 2-), 2.45 (br t, 2H, -CCH2CH2-, I - 7 Hz, J-Sn-H ~ 6 7 H z> • 3 - 5 0 ( t , 2H, -CH2C1, J . - 6 Hz), 4.25 (m, d a f t e r a d d i t i o n of D 20, 2H, -CH.20H, 2 - 6 Hz), 5.82 ( t of t, 1H, v i n y l proton, 2 - 0.5, 6 Hz, 2sn-H ~ 7 5 Hz). Exact Mass calcd. f o r C g H 1 6 0 3 5 C l S n (M+'Cl^): 282.9912; found: 282.9919. Preparation of (Z)-6-Chloro-3-trimethvlstannyl-2-hexen-l-ol (100) Following general procedure 4, methyl (Z)-6-chloro-3-trimethyl-stannyl-2-hexenoate (93) (3.44 g, 10.6 mmol) was converted into the a l l y l i c alcohol (100). There was obtained, a f t e r d i s t i l l a t i o n of the crude material (air-bath temperature 100-110°C/0.03 T o r r ) , 3.03 g (97%) of the ( Z ) - a l l y l i c alcohol (100) as a colou r l e s s o i l . This material exhibited i r ( f i l m ) : 3350, 1010, 777 cm"1; lH nmr (80 MHz, CDCI3) 6: 0.19 (s, 9H, -SnMe3, 2sn-H " 5 3 H z>> 1 - 4 1 1 H> exchanges with D20, -CH20H, 2 - 5.5 Hz), 1.6-2.0 (m, 2H, -CH 2CH 2CH 2-), 2.40 (br t, 2H, -CCH2CH2-, 2 - 7 Hz, 2sn-H " 4 9 H z>> 3 - 4 8 2 H> -CH2C1, 2 - 6-5 Hz), 4.08 (m, d a f t e r a d d i t i o n of D20, 2H, -CH20H, 2 - 6 Hz), 6.24 (t of t, - 176 -1H, v i n y l proton, 2 - 1.5, 6 Hz, 2sn-H " * 3 4 Hz). Exact Mass calcd. f o r C 8 H 1 6 0 3 5 C l S n (M+-CH3): 282.9912; found: 282.9917. Preparation of (Z )-4-Methvl-3-trlmethvlstannvl-2-penten-l-ol (153) Following general procedure 4, 6.30 g (21.7 mmol) of methyl (Z)-4-methyl-3-trimethylstannyl-2-pentenoate (94) was converted into the a l l y l i c a l c o hol (153). D i s t i l l a t i o n (air-bath temperature 110-115°C/15 Torr) of the crude material y i e l d e d 5.50 g (97%) of the ( Z ) - a l l y l i c a l c o h ol (153) as a colourless o i l which exhibited i r ( f i l m ) : 3300, 1380, 1360, 1025, 770 cm"1; lH nmr (80 MHz, CDC13) 6: 0.19 (s, 9H, -SnMe3, iSn-H * 5 2 H z ) » 1 - 0 1 <d. 6 H . Me2CH-, 1 - 7 Hz), 1.30 (m, exchanges with D 20, 1H, -CH20H), 2.46 (septet, 1H, Me2CH-, 2 - 7 Hz), 4.08 (br t, 2H, -CH20H, 2 - 6.5 Hz, 2sn-H " 1 1 0 H z ) - 6 - 1 8 < d o f C ' 1 H> v i n y l proton, 2 - 1, 6.5 Hz, 2sn-H " 1 4 4 Hz). Exact Mass ca l c d . f o r C 8H 1 7OSn (M+-CH3): 249.0301; found: 249.0294. - 177 -Preparation of (E)-6-Chloro-l-(methoxymethoxy)-3-trimethylstannyl-2- hexene (103) 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 alcohol (101) (740 mg, 2.49 mmol) i n 5 mL of dry methylene chloride was added seq u e n t i a l l y e t h y l -diisopropylamine (0.65 mL, 1.5 equiv) and chloromethyl methyl ether (M0M-C1) (0.28 mL, 1.5 equiv). The cooling bath was removed and the re a c t i o n mixture was s t i r r e d at room temperature f o r 15 h. Evaporation of the solvent followed by d i s t i l l a t i o n (air-bath temperature 95-105°C/ 0.6 Torr) of the crude o i l thus obtained, y i e l d e d 802 mg (94%) of the ether (103) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1152, 1104, 1042, 772 cm - 1; -^H nmr (80 MHz, CDCI3) 6: 0.14 (s, 9H, -SnMe3, J S n - H ~ 5 3 H z ) • 1-6-2.0 (m, 2H, -CH 2CH 2CH 2-), 2.47 (br t, 2H, -CCH2CH2-, J - 7 Hz, J S n . H - 62 Hz), 3.36 (s, 3H, -OCH3), 3.48 ( t , 2H, -CH2C1, J - 7 Hz), 4.15 (br d, 2H, -CCH20-, J - 6 Hz), 4.63 (s, 2H, -0CH 20-), 5.78 (t of t, 1H, v i n y l proton, J_ - 1.3, 6 Hz, J_sn-H " 7 5 H z> • Exact Mass c a l c d . f o r C 1 0 H 2 o 0 2 3 5 C l S n (M+-CH3): 327.0174; found: 327.0163. Me 3 Sn H - 178 -Preparation of (Z) -6-Chloro-l- (methoxvmethoxy') -3-trimethvlstannvl-2-hexene (102) C I j—V/H Me3Sn ^ - 0 \ To a c o l d (0 8C), s t i r r e d s o l u t i o n of the alcohol (100) (1.90 g, 6.39 mmol) i n 15 mL of dry methylene chloride was added s e q u e n t i a l l y e t h y l -diisopropylamine (1.67 mL, 1.5 equiv) and chloromethyl methyl ether (M0M-C1) (0.73 mL, 1.5 equiv). The cooling bath was removed and the r e a c t i o n mixture was s t i r r e d at room temperature f o r 15 h. Evaporation of the solvent followed by d i s t i l l a t i o n (air-bath temperature 100-105°C/ 0.6 Torr) y i e l d e d 1.90 g (87%) of the ether (102) as a c o l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1156, 1110, 1040, 778 cm - 1; XH nmr (80 MHz, CDC1 3) 6": 0.20 (s, 9H, -SnMe3, J S n - H - 5 3 H z ) . 1-6-2.0 (m, 2H, -CH 2CH 2CH 2-), 2.38 (br t, 2H, -CCH2CH2-, J - 7 Hz, J _ S n _ H ~ 4 8 H z ) » 3 - 3 5 (s, 3H, -OCH3), 3.49 ( t , 2H, -CH2C1, J => 6.5 Hz), 4.00 (br d, 2H, -CCH20-, J - 6 Hz), 4.62 (s, 2H, -0CH 20-), 6.38 (t of t, 1H, v i n y l proton, J - 1.3, 6 Hz, 2sn-H ~ 1 3 4 Hz). Exact Mass ca l c d . f o r C 1 0 H 2 0 0 2 3 5 C l S n (M+-CH3): 327.0174; found: 327.0172. - 179 -Preparation of (E)-1-tert-Butvldimethvlslloxv-6-chloro-3-trimethyl- stannyl -2-hexene (105) Me3Sn H To a s t i r r e d s o l u t i o n of the alcohol (101) (4.10 g, 13.8 mmol) i n 40 mL of dry dimethylformamide at room temperature was added t e r t - b u t y l d i -m e t h y l s i l y l c h l o r i d e (TBDMS-C1) (2.50 g, 1.2 equiv) and imidazole (2.35 g, 2.5 equiv), both as s o l i d s . The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 15 h. Di e t h y l ether (100 mL) was added and the r e s u l t i n g mixture was washed with saturated aqueous sodium bicarbonate (3 x 75 mL) and then was d r i e d over anhydrous magnesium s u l f a t e . Concentration of the s o l u t i o n and d i s t i l l a t i o n (air-bath temperature 155-170°C/11 Torr) of the r e s i d u a l o i l y i e l d e d 4.75 g (84%) of the ( E ) - s i l y l ether (105) as a colourless o i l . This material exhibited i r ( f i l m ) : 1256, 1088, 1006, 839, 775 cm"1; XH nmr (80 MHz, CDC13) 8: 0.08 (s, 6H, -SiMe 2), 0.13 (s, 9H, -SnMe3, J S n - H " 5 3 H z ) . ° - 9 1 (s> 9 H --SiCMe 3), 1.65-2.0 (m, 2H, -CH 2CH 2CH 2-), 2.43 (br t, 2H, -CCH2CH2-, J -7 Hz), 3.49 ( t , 2H, -CH2C1, J - 6 Hz), 4.21 and 4.36 (AB quartet, 1H each, -CH20-, J - 6 Hz each), 5.74 (br t, 1H, v i n y l proton, J - 6 Hz, J_Sn-H - 76 Hz). Exact Mass calcd. f o r C 1 4 H 3 o 0 3 5 C l S i S n (tf^-CH^: 397.0777; found: 397.0782. - 180 -Preparation of (Z)-1-tert-Butvldimethvls iloxv-6-chloro-3-trimethvl-stannyl-2-hexene (104') MejSn To a s t i r r e d s o l u t i o n of the alcohol (100) (3.90 g, 13.1 mmol) i n 40 mL of dry dimethylformamide at room temperature was added t e r t - b u t v l d i -m e t h y l s i l y l c h l o r i d e (TBDMS-C1) (2.37 g, 1.2 equiv) and imidazole (2.23 g, 2.5 equiv), both as s o l i d s . The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 15 h and then d i e t h y l ether (100 mL) was added. The r e s u l t i n g s o l u t i o n was washed with saturated aqueous sodium bicarbo-nate (3 x 75 mL) and then was dr i e d over anhydrous magnesium s u l f a t e . Concentration of the s o l u t i o n and d i s t i l l a t i o n (air-bath temperature 155-170°C/11 Torr) of the re s i d u a l o i l afforded 5.40 g (89%) of the ( Z ) - s i l y l ether (104) as a colourless o i l , which exhibited i r ( f i l m ) : 1256, 1093, 1061, 1006, 838, 776 cm"1; XH nmr (80 MHz, CDC13) 6: 0.06 (s, 6H, -SiMe 2), 0.19 (s, 9H, -SnMe3, I S n . H - 52 Hz), 0.90 (s, 9H, -SiCMe 3), 1.63-2.0 (m, 2H, -CH 2CH 2CH 2-), 2.35 (br t, 2H, -CCH2CH2-, J -6 Hz), 3.50 ( t , 2H, -CH2C1, J - 6 Hz), 4.02 and 4.18 (AB quartet, 1H each, -CH20-, J - 6 Hz each), 6.16 (br t, 1H, v i n y l proton, J - 6 Hz, J S n _ H - 138 Hz). Exact Mass calcd. f o r C 1 4 H 3 0 0 3 5 C l S i S n (M^-C^): 397.0777; found: 397.0780. - 181 -Preparation of (E)-l-Acetoxv-6-chloro-3-trimethylstannyl-2-hexene (106) To a s t i r r e d s o l u t i o n of the alcohpl (101) (1.00 g, 3.36 mmol), 4-N,N-dimethylaminopyridine (41.1 mg, 0.1 equiv), and triethylamine (0.70 mL, 1.5 equiv) i n 20 mL of dry methylene chl o r i d e at room tempera-ture was added, dropwise, a c e t i c anhydride (0.48 mL, 1.5 equiv). The mixture was s t i r r e d at room temperature for 15 h and then was poured into brine (50 mL). The layers were separated and the aqueous phase was extracted with methylene chloride (2 x 30 mL). The combined organic extracts were d r i e d (MgSO^ and concentrated and the r e s i d u a l o i l was d i s t i l l e d ( air-bath temperature 90-100°C/0.03 Torr) to provide the acetate (106) (1.11 g, 97%) as a colourless o i l . This material exhibited i r ( f i l m ) : 1741, 1230, 1028, 769 cm"1; XH nmr (400 MHz, CDC13) S: 0.16 (s, 9H, -SnMe3, I S n-H " 5 2 Hz>< 1 - 8 1 (quintet, 2H, -CH2CH2CH2-, J - 7 Hz), 2.07 (s, 3H, -COCH3), 2.48 (br t, 2H, -CCH2CH2-, J - 7 Hz, J S n . H -60 Hz), 3.49 ( t , 2H, -CE2C1, 2-7 Hz), 4.64-4.70 (m, 2H, -CH.20-), 5.74 (br t, 1H, v i n y l proton, 2 ~ 6»2 Hz, 2sn-H ~ 6 8 Hz). Exact Mass calcd. f o r C 1 0 H 1 8 0 2 3 5 C l S n (M+-CH3): 325.0018; found: 325.0021. - 182 -Preparation of (E)-7-Chloro-4-trimethylstannyl-3-heptene (107) Cl Me3Sn' CH2CH3 To a c o l d (0°C), s t i r r e d suspension of cuprous bromide-dimethyl s u l f i d e complex (1.21 g, 2 equiv) i n dry d i e t h y l ether (80 mL) was added, dropwise, a s o l u t i o n of methyllithium i n d i e t h y l ether (=9.0 mL, 4 equiv) u n t i l the i n i t i a l l y formed b r i g h t yellow p r e c i p i t a t e j u s t dissolved. 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 at 0°C f o r 5 min and then a s o l u t i o n of the ( E ) - a l l y l i c acetate (106) (1.00 g, 2.95 mmol) i n 20 mL of dry d i e t h y l ether was added. The r e s u l t i n g mixture, c o n s i s t i n g of a col o u r l e s s s o l u t i o n and a yellow p r e c i p i t a t e , was s t i r r e d f o r 15 min at 0°C. Saturated aqueous ammonium chloride (100 mL) was added c a r e f u l l y . The mixture was warmed to room temperature with vigorous s t i r r i n g and s t i r r i n g was continued u n t i l the aqueous layer was blue i n colour. The layers were separated and the aqueous phase was extracted with d i e t h y l ether (2 x 50 mL). The combined organic extracts were d r i e d (MgS04) and concentrated and the r e s i d u a l material was d i s t i l l e d ( air-bath tempera-ture 85-95-C/15 Torr) to a f f o r d 757 mg (87%) of the (E)-alkene (107) as a c o l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1609, 776 cm"1; XH nmr (400 MHz, CDC13) 6: 0.12 (s, 9H, -SnMe3, J S n . H - 52 Hz), 0.98 ( t , 3H, -CH2CH3, J - 7 Hz), 1.80 (quintet, 2H, -CH2CH2CH2-, J - 7 Hz), 2.14 (quintet, 2H, -CCH 2CH 3, J - 7 Hz, J S n - H " 5 8 H z>. 2 - 4 2 ( b r t. 2 H --CCH 2CH 2-, J - 7 Hz, I S n . H - 6 1 H z ) > 3 - 5 0 ( t . 2 H> -CH2C1, J - 7 Hz), - 183 -5.60 ( t , 1H, v i n y l proton, J - 7 Hz, J_sn-H " 7 2 H z ) • Exact Mass calcd. f o r C 9 H 1 8 3 5 C l S n (M+-CH3): 281.0119; found: 281.0114. Preparation of (Z)-l-Bromo-4-methvl-3-trimethylstannyl-2-pentene (154) To a c o l d (0°C), s t i r r e d s o l u t i o n of triphenylphosphine (7.07 g, 1.2 equiv) i n 120 mL of dry methylene chloride was added dropwise, bromine (1.38 mL, 1.2 equiv) u n t i l the colourless s o l u t i o n became pale yellow. One more c r y s t a l of s o l i d triphenylphosphine was then added, followed by triethylamine (3.76 mL, 1.2 equiv). The r e s u l t i n g white, cloudy s o l u t i o n was cooled to -10°C and then a s o l u t i o n of the alcohol (153) (5.90 g, 22.5 mmol) i n 15 mL dry methylene chloride was added dropwise ( v i a dropping funnel). The mixture was s t i r r e d f o r 15 min and then the solvent was removed by rotary evaporation. To the r e s u l t i n g s l u r r y was added petroleum ether (100 mL) and the mixture was passed through a plug of C e l i t e . The c o l l e c t e d material was washed with petroleum ether (20 mL). The col o u r l e s s s o l u t i o n was concentrated by rotary evaporation and the petroleum ether washing procedure was repeated two times. The crude, c o l o u r l e s s o i l obtained a f t e r the f i n a l concentration was used immediately i n subsequent reactions since i t proved to be quite unstable, even when stored at -4°C i n the dark. Thus, the a l l y l i c Me3Sn - 184 -bromide (154) was obtained as a colourless o i l (6.30 g, 86%) which appeared, on the basis of g l c and nmr analyses, to be >90% pure. The material exhibited i r ( f i l m ) : 1200, 775 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.25 (s, 9H, SnMe3, J S n . H - 53 Hz), 1.01 (d, 6H, Me2CH-, J - 7 Hz), 2.50 (septet, 1H, Me2CH-, J - 7 Hz), 3.95 (d, 2H, -CH2Br, J - 8 Hz), 6.23 ( t , 1H, v i n y l proton, J_ - 8 Hz). Exact Mass ca l c d . f o r CsHig 7 9BrSn (M+-CH3): 310.9457; found: 310.9442. General Procedure 5: Conversion of Primary A l k v l Chlorides into the  Corresponding Iodides A s t i r r e d s o l u t i o n of the appropriate ch l o r i d e (1 equiv) and sodium iodide (5-10 equiv) i n acetone (=15 mL per 4 mmol of the chloride) was heated at the r e f l u x temperature u n t i l g l c analysis indicated the complete conversion of the chloride into the iodide (from 24-48 h). The acetone was removed by rotary evaporation and to the r e s u l t i n g residue was added d i e t h y l ether (twice the volume of acetone used) and H 20 (= volume of acetone used). The organic phase was separated and the aqueous phase was extracted three times with d i e t h y l ether (same volume used above). The combined organic extracts were d r i e d (MgSO^ and concentrated and the remaining o i l was d i s t i l l e d (bulb-to-bulb) to a f f o r d the corresponding iodide. - 185 -Preparation of 5-Iodo-2-trlmethvlstannvl-l-t>entene (43) H o Y H b Following general procedure 5, the chl o r i d e (38) (2.20 g, 8.24 mmol) was converted into the iodide (43). D i s t i l l a t i o n of the crude o i l (air-bath temperature 95-110°C/15 Torr) provided 2.61 g (88%) of the iodide (43) as a colourless l i q u i d . This material exhibited i r ( f i l m ) : 1225, 915, 760 cm"1; XH nmr (80 MHz, CDC13) 6: 0.20 (s, 9H, -SnMe3, iSn-H - 5 3 H z>> 1-7-2.15 (m, 2H, -CH 2CH 2CH 2-), 2.25-2.55 (m, 2H, -CCH 2-), 3.20 ( t , 2H, -CH 2I, J - 7 Hz), 5.23 (d of t, 1H, H a, J - 2.5, 1Hz, J S r i _ H - 74 Hz), 5.73 (d of t, 1H, H b, J - 2.5, 1.3 Hz, J S n . H = 152 Hz). Exact Mass calcd. f o r C 7H 1 4ISn (M+-CH3): 344.9162; found: 344.9168. Preparation of 6-Iodo-2-trimethvlstannvl-l-hexene (44) Following general procedure 5, 2.90 g (10.3 mmol) of the chloride (47) was converted into the iodide (44). D i s t i l l a t i o n of the crude o i l - 186 -(air- b a t h temperature 60-70°C/0.8 To r r ) , afforded 3.18 g (84%) of the iodide (44) as a colou r l e s s l i q u i d . This material exhibited i r ( f i l m ) : 1210, 915, 765 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.16 (s, 9H, -SnMe3, J S n - H - 53 Hz), 1.30-2.05 (m, 4H, -CH 2CH 2CH 2CH 2-), 2.29 (br t, 2H, -CCH2-, J - 7 Hz, J S n . H - 50 Hz), 3.18 ( t , 2H, -CH 2I, J - 6.5 Hz), 5.15 (br s, 1H, H a, w 1 / 2 - 4 Hz, J S n . H - 72 Hz), 5.65 (d of t, 1H, H b, J -2.5, 1 Hz, Jgn-H " 1 5 0 H z ) • Exact Mass calcd. f o r C g H 1 6 I S n (M+-CH3): 358.9319; found: 358.9307. Preparation of (E)-7-Iodo-4-trimethvlstannvl-3-heptene (114) Following general procedure 5, the chloride (107) (1.45 g, 4.91 mmol) was converted into the iodide (114). D i s t i l l a t i o n of the crude o i l ( a ir-bath temperature 95-105°C/15 Torr) provided 1.78 g (94%) of the iodide (114) as a colourless l i q u i d . This material exhibited i r ( f i l m ) : 1609, 1220, 776 cm - 1; XH nmr (400 MHz, CDCI3) S: 0.12 (s, 9H, -SnMe3, iSn-H " 5 2 H z>> ° - 9 9 <*» 3 H « -CH2CH3, J - 7 Hz), 1.85 (quintet, 2H, -CH2CH2CH2-, J - 7 Hz), 2.16 (quintet, 2H, -CH2CH3, J - 7 Hz), 2.38 (br t, 2H, -CCH 2CH 2-, J - 7 Hz, J S n . H - 53 Hz), 3.16 ( t , 2H, -CH 2I, J - 6 Hz), 5.59 (br t, 1H, v i n y l proton, J = 6.5 Hz, Ign-H " 7 8 H z ) • Exact Mass ca l c d . f o r C 9 H 1 8 I S n (M+-CH3): 372.9477; found: 372.9475. Me3SrY H - 187 -Preparation of Methyl (E)- 6 -Iodo-3-trimethylstannyl-2-hexenoate (109) Me 3Sn Following general procedure 5, the ch l o r i d e (95) (1.00 g, 3.07 mmol) was converted into the iodide (109). D i s t i l l a t i o n of the crude o i l (air-bath temperature 125-135°C/0.6 Torr) provided 1.20 g (94%) of the iodide (109) as a colourless l i q u i d which exhibited i r ( f i l m ) : 1712, 1559, 1195, 1175, 772 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.22 (s, 9H, -SnMe3, Isn-H ~ 5 3 H z ) • 1-7-2.2 (m, 2H, -CH 2CH 2CH 2-), 2.95 (br t, 2H, a l l y l i c methylene protons, J - 7.5 Hz), 3.17 ( t , 2H, -CH 2I, J = 7 Hz), 3.66 (s, 3H, - O C H 3 ) , 5.99 ( t , 1H, v i n y l proton, J - 1 Hz, I s n - H " 7 1 Hz). Exact Mass calcd. f o r C 9 H 1 6 0 2 I S n (M+-CH3): 402.9217; found: 402.9212. Preparation of (E)-6-Iodo-1-(methoxvmethoxy)-3-trimethylstannyl-2- hexene (111) Following general procedure 5, the chloride (103) (1.69 g, 4.95 mmol) was converted into the iodide (111). D i s t i l l a t i o n of the crude o i l - 188 -(air- b a t h temperature 110-115°C/0.6 Torr) provided 2.03 g (95%) of the iodide (111) as a colourless l i q u i d . This material exhibited i r ( f i l m ) : 1156, 1108, 1042, 774 cm'1; XH nmr (80 MHz, CDC1 3) 6: 0.15 (s, 9H, -SnMe3, Isn-H " 5 3 H z ) • 1-6-2.1 (m, 2H, -CH 2CH 2CH 2-), 2.42 (br t, 2H, -CCH2CH2-, J - 7 Hz), 3.14 ( t , 2H, -CH 2I, J - 7 Hz), 3.37 (s, 3H, -OCH3), 4.16 (br d, 2H, -CCH20-, 1 - 6 Hz), 4.64 (s, 2H, -0CH 20-), 5.78 (t of t, 1H, v i n y l proton, J - 1.2, 6 Hz, Js n-H " 7 5 H z ) • Exact Mass calcd. f o r C 1 0 H 2 0 O 2 I 1 1 6 S n (M+-CH3): 414.9527; found: 414.9532. Preparation of (E)-1-tert-Butyldimethylsiloxv-6-iodo-3-trimethylstannvl- 2-hexene (113) Following general procedure 5, the chl o r i d e (105) (5.27 g, 12.8 mmol) was converted into the iodide (113). D i s t i l l a t i o n of the crude o i l (air-bath temperature 175-185°C/11 Torr) provided 5.97 g (93%) of the iodide (113) as a colourless l i q u i d . This material exhibited i r ( f i l m ) : 1256, 1099, 1006, 837, 775 c m 4 ; XH nmr (80 MHz, CDCI3) 6: 0.08 (s, 6H, -SiMe 2), 0.13 (s, 9H, -SnMe3, J S n - H " 5 3 H z>• ° - 9 1 (s> 9 H> -SiCMe 3), 1.63-2.03 (m, 2H, -CH 2CH 2CH 2-), 2.25-2.50 (m, 2H, -CCH 2CH 2-), 3.13 ( t , 2H, -CH 2I, J - 7 Hz), 4.23 and 4.38 (AB quartet, 1H each, -CH20-, J - 6 Hz), 5.71 (t of m, 1H, v i n y l proton, J - 6 Hz, J_sn-H = 7 6 I - 189 -Hz). Exact Mass calcd. f o r C 1 4 H 3 0 O I S i S n (M" 1"-^): 489.0133; found: 489.0126. Preparation of Methyl (Z)-6-Iodo-3-trimethylstannvl-2-hexenoate (108) Following general procedure 5, the chloride (93) (1.80 g, 5.54 mmol) was converted into the iodide (108). D i s t i l l a t i o n of the crude o i l (air-bath temperature 110-116°C/0.6 Torr) provided 2.26 g (98%) of the iodide (108) as a colourless l i q u i d . This material exhibited i r ( f i l m ) : 1706, 1601, 1225, 1210, 780 cm'1; lH nmr (80 MHz, CDCI3) 6: 0.21 (s, 9H, -SnMe3, J S n - H ~ 5 4 H z ) > 1-7-2.1 (m, 2H, -CH 2CH 2CH 2-), 2.55 (br t, 2H, =CCH2CH2-, J = 7 Hz, J S n - H - 4 6 H z ) > 3 - 1 5 ( t . 2 H> "CH 2I, J - 7 Hz), 3.73 (s, 3H, -0CH 3), 6.40 ( t , 1H, v i n y l proton, J - 1.5 Hz, I S n - H " 1 1 7 Hz). Exact Mass calcd. f o r C 9 H 1 6 0 2 I S n (M" 1"-^): 402.9219; found: 402.9231. C02Me - 190 -Preparation of (Z)-6-Iodo-l-(methoxvmethoxv)-3-trimethvlstannyl-2- hexene (110) Following general procedure 5, the chl o r i d e (102) (1.90 g, 5.57 mmol) was converted into the iodide (108). D i s t i l l a t i o n of the crude o i l ( a ir-bath temperature 110-115°C/0.6 Torr) provided 2.26 g (94%) of the iodide (108) as a colourless o i l . This material exhibited i r ( f i l m ) : 1156, 1105, 1035, 779 cm"1; lH nmr (80 MHz, CDCl 3) 6: 0.20 (s, 9H, -SnMe3, J S n _ H - 53 Hz), 1.7-2.1 (m, 2H, -CH 2CH 2CH 2-), 2.34 (br t, 2H, -CCH2CH2-, J - 7 Hz, J S n . H - 48 Hz), 3.14 ( t , 2H, -CH 2I, J - 7 Hz), 3.36 (s, 3H, -OCH3), 4.00 (m, 2H, -CCH 20-), 4.62 (s, 2H, -0CH 20-), 6.21 (t of t, 1H, v i n y l proton, J - 1.2, 6 Hz, Jgri-H " 1 3 4 H z ^ * Exact Mass calcd. f o r C 1 0 H 2 0 0 2 I S n (M+-CH3): 418.9530; found: peak matched. Preparation of (Z)-1-tert-Butvldimethylsiloxv-6-iodo-3-trimethvlstannvl- 2-hexene (112) H Following general procedure 5, the chloride (104) (5.40 g, 13.1 - 191 -mmol) was converted into the iodide (112). D i s t i l l a t i o n of the crude o i l ( a ir-bath temperature 175-185°C/11 Torr) provided 5.65 g (86%) of the iodide (112) as a colourless o i l . This material exhibited i r ( f i l m ) : 1256, 1099, 837, 776 cm - 1; XH nmr (80 MHz, CDC1 3) 6: 0.08 (s, 6H, -SiMe 2), 0.19 (s, 9H, -SnMe3, J_Sn-H ~ 5 2 H z > » ° - 9 0 (s» 9 H> - s i C M £ 3 ) , 1.63-2.05 (m, 2H, -CH2CH.2CH2-) , 2.20-2.45 (m, 2H, -CCH 2CH 2-), 3.15 ( t , 2H, -CH 2I, J - 7 Hz), 4.03 and 4.08 (AB quartet, 1H each, -CH20-, J - 6 Hz each), 6.18 (br t, 1H, v i n y l proton, J - 6 Hz, J_sn-H " 1 3 8 H z ) • Exact Mass ca l c d . f o r C 1 4H3 0OISiSn (M+-CH3): 489.0133; found: 489.0130. 3.2.2 Preparation of B i c y c l i c Dienes General Procedure 6: A l k y l a t i o n of fl-Keto Esters To a well s t i r r e d suspension of potassium hydride (1.1 equiv) i n THF (3 mL per mmol of 0-keto ester) at room temperature was added, dropwise, the appropriate /9-keto ester (1 equiv) i n THF (1 mL per mmol). The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 30-45 min, and then the appropriate a l k y l h a l i d e (1.1 equiv) was added as a s o l u t i o n i n THF (1 mL per mmol). The r e a c t i o n mixture was heated to r e f l u x tempera-ture and a f t e r the r e a c t i o n was determined to have reached completion (by g l c and/or t i c a n a l y s i s ) , u s u a l l y overnight, the mixture was cooled to room temperature and the solvent was removed by rotary evaporation. Flash or medium pressure column chromatography of the r e s u l t i n g o i l - s a l t - 192 -mixture followed by d i s t i l l a t i o n of the crude o i l provided the desired a l k y l a t e d /J-keto ester. Preparation of the fl-Keto Ester (56) Following general procedure 6, commercially a v a i l a b l e methyl 2-oxo-cyclopentanecarboxylate (50) (200 mg, 1.41 mmol) was treated with potassium hydride (62.1 mg, 1.1 equiv), followed by 5-iodo-2-trimethyl-stannyl -1-pentene (43) (355 mg, 1.1 equiv). The re a c t i o n mixture was refl u x e d f o r 8 h. Subjection of the crude product to f l a s h chromato-graphy on s i l i c a g el (27 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath tempera-ture 135-140°C/0.8 Torr) provided 314 mg (60%) of the 0-keto ester (56) as a co l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1750, 1720, 1165, 770 cm'1; XH nmr (400 MHz, CDC13) 6: 0.09 (s, 9H, -SnMe3, J S n - H " 54 Hz), 1.20-1.45 (m, 2H), 1.51 (d of t, 1H, J - 4.5, 9 Hz), 1.80-2.00 (m, 4H), 2.10-2.55 (m, 5H), 3.66 (s, 3H, -OCH3), 5.10 (m, 1H, Hft, I S n-H - 72 Hz), 5.59 (m, 1H, H b, J_sn-H " 1 5 2 H z> • Exact Mass calcd. f o r c 1 4 H 2 3 ° 3 S n (M+-CH3): 359.0669; found: 359.0667. - 193 -Preparation of the fl-Keto Ester (57) SnMe 3 ^ - C 0 2 M e 57 57a Following general procedure 6, methyl 5-methyl-2-oxocyclopentane-carboxylate ( 5 1 ) 5 7 (90.0 mg, 0.577 mmol) was treated with potassium hydride (25.4 mg, 1.1 equiv), followed by 5-iodo-2-trimethylstannyl-1-pentene (43) (228 mg, 1.1 equiv). The rea c t i o n mixture was refluxed f o r 8 h. Subjection of the crude product mixture to medium pressure chromatography on s i l i c a gel (18 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n ( a ir-bath temperature 135-140°C/0.8 Torr) of the r e s u l t i n g o i l provided 127 mg (57%) of a col o u r l e s s o i l which proved to be a mixture of the C- and O-alkylated products (57) and (57a) i n a r a t i o of 96:4 (by g l c ) , r e s p e c t i v e l y . A small amount of pure (57) was obtained by d r i p column chromatography on s i l i c a g el (18 g, e l u t i o n with petroleum ether-ethyl acetate 25:1). This material, a colo u r l e s s o i l , exhibited i r ( f i l m ) : 1750, 1725, 1230, 1165, 770 cm"1; AH nmr (400 MHz, CDC1 3) 6: 0.09 (s, 9H, -SnMe3, J S n - H -53 Hz), 1.01 (d, 3H, -CHCH3, J - 7.5 Hz), 1.19 (m, 1H), 1.49 (m, 1H), 1.63-1.85 (m, 3H), 1.98-2.33 (m, 5H), 2.50 (d of d of d, 1H, J - 1.5, 8, 18 Hz), 3.63 (s, 3H, -OCH3), 5.11 (d of t, 1H, H a, J - 2.8, 1.3 Hz, J S n . H - 72 Hz), 5.61 (d of t, 1H, H b, J - 2.8, 1.4 Hz, J S n . H ~ 1 5 2 H z ) • Exact Mass calcd. f o r C 1 5H250 3Sn ( M * - ^ ) : 373.0825; found: 373.0829. - 194 -Preparation of the fl-Keto Ester (58) 9 C0 2Me H b v H Q SnMe3 Following general procedure 6, methyl 2-oxocyclohexanecarboxylate ( 5 2 ) 5 5 (1.09 g, 6.97 mmol) was treated with potassium hydride (308 mg, 1.1 equiv), followed by 5-iodo-2-trimethylstannyl-l-pentene (43) (3.00 g, 1.2 equiv). The rea c t i o n mixture was refluxed f o r 16 h. Flash chromatography of the crude product mixture on s i l i c a g el (100 g, e l u t i o n with petroleum ether-diethyl ether, 20:1), followed by d i s t i l l a -t i o n ( a i r - b a t h temperature 115-120°C/0.1 Torr) of the r e s u l t i n g o i l provided 2.45 g (91%) of the /3-keto ester (58) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1710, 1200, 770 cm - 1; ^ nmr (400 MHz, CDC1 3) 6: 0.09 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.15-1.78 (m, 7H), 1.83 (d of d of d, 1H, J - 4.5, 11.5, 13 Hz), 1.97 (m, 1H), 2.17-2.32 (m, 2H), 2.35-2.44 (m, 2H), 2.48 (m, 1H), 3.68 (s, 3H, -OCH3), 5.10 (d of t, 1H, H a, J - 2.5, 1 Hz, J S n _ H - 72 Hz), 5.60 (d of t, 1H, H b, J -2.5, 1.5 Hz, Isn-H " 1 5 2 H z ) - Exact Mass calcd. f o r C 1 5H250 3Sn (M+-CH3): 373.0825; found: 373.0824. - 195 -Preparation of the fl-Keto Ester (59) and the Enol Ether (59a) 0 CC^Me H J J ^ H Q SnMe 3 59 59a Following general procedure 6, methyl 6-methyl-2-oxocyclohexane-carboxylate ( 5 3 ) 5 7 (130 mg, 0.765 mmol) was treated with potassium hydride (33.7 mg, 1.1 equiv), followed by 5-iodo-2-trimethylstannyl-l pentene (43) (302 mg, 1.1 equiv). The r e a c t i o n mixture was r e f l u x e d for 16 h. Flash chromatography of the crude product mixture on s i l i c a gel (27 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 132-138°C/0.8 T o r r ) , provided 163 mg (57%) of a mixture of two compounds as a colour-le s s o i l i n a r a t i o of 3:1 (by nmr). Low r e s o l u t i o n g a s - l i q u i d chromatography-mass spectrometry of the mixture ind i c a t e d a (M+-CH3) peak at m/e 387 for each component. On the basis of the nmr data, the major and minor components were determined to be the C- and 0-alkylated compounds (59) and (59a), r e s p e c t i v e l y . These two compounds could not be separated and the mixture exhibited i r ( f i l m ) : 1710, 1195, 770 cm'^; *H nmr (400 MHz, CDC13) 6: 0.13 and 0.14 (s, s, r a t i o 3:1, 9H, -SnMe3, J-Sn-H - 53 Hz each), 1.00 and 1.13 (d, d, r a t i o 1:3, 3H, -CHCH3, J - 7.2 Hz each), 1.16-2.77 (m, 13H), 3.68 and 3.72 (s, s, r a t i o 3:1, 3H, -OCH3), 3.77 ( t , -OCH2CH2- of enol ether, J - 6 Hz), 5.13 and 5.16 (d of t, d of t, r a t i o 3:1, 1H, H a, J = 2.8, 1.3 Hz each, Isn-H = 7 2 H z each), - 196 -5.65 (m, 1H, H b, J_sn_H - 152 Hz). Exact Mass calcd. f o r C 1 5 H 2 7 O 3 S 1 1 ( M + - C H 3 ) : 387.0982; found: 387.0980. Preparation of the /3-Keto Ester (60) Following general procedure 6, methyl 2-oxocycloheptanecarboxylate ( 5 4 ) 5 6 (129 mg, 0.759 mmol) was treated with potassium hydride (33.5 mg, 1.1 equiv), followed by 5-iodo-2-trimethylstannyl-l-pentene (43) (300 mg, 1.1 equiv). The reaction mixture was refluxed f o r 6.5 h. Flash chromatography of the crude product mixture on s i l i c a g el (27 g, e l u t i o n with petroleum ether-ethyl acetate, 14:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 150-155°C/0.8 T o r r ) , provided 280 mg (92%) of the 0-keto ester (60) as a co l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1735, 1710, 1230, 1150, 770 cm - 1; lH nmr (400 MHz, C D C I 3 ) 6: 0.09 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.23-1.77 (m, 11H), 1.93 (m, 1H), 2.07-2.31 (m, 2H), 2.45 (m, 1H), 2.58 (m, 1H), 3.69 (s, 3H, - O C H 3 ) , 5.11 (d of t, 1H, H a, J - 2.8, 1.2 Hz, J S n - H " 7 1 H z ) . 5.61 (d of t, 1H, H b, J - 2.8, 1.4 Hz, J S n . H " 151 Hz). Exact Mass cal c d . f o r C 1 6H 270 3Sn (M+-CH3): 387.0982; found: 387.0977. - 197 -Preparation of the /fl-Keto Ester (61) l j 0 2 M e H b SnMe3 Following general procedure 6, methyl 2-oxocyclopentanecarboxylate (50) (200 mg, 1.41 mmol) was treated with potassium hydride (62.1 mg, 1.1 equiv), followed by 6-iodo-2-trimethylstannyl-l-hexene (44) (577 mg, 1.1 equiv). The r e a c t i o n mixture was refluxed f o r 9 h. Flash chromato-graphy of the crude product mixture on s i l i c a gel (30 g, e l u t i o n with petroleum ether-ethyl acetate, 30:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 145-148°C/0.6 T o r r ) , provided 340 mg (63%) of the /3-keto ester (61) as a c o l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1748, 1719, 1225, 1155, 768 cm"1; XH nmr (400 MHZ> CDC13) 6: 0.11 (s, 9H, -SnMe3, Isn-H ~ 5 3 H z> > 1-10-1.40 (m, 4H), 1.54 (d of d of d, 1H, J - 4.5, 11.5, 13.5 Hz), 1.80-2.05 (m, 4H), 2.28-2.32 (m, 3H), 2.38 (m, 1H), 2.53 (m, 1H), 3.68 (s, 3H, -OCH3), 5.11 (d of t, 1H, H a, J - 2.8, 1.2 Hz, J S n - H ~ 7 2 H z ) . 5 - 6 i < d o f 1 H. Hb> ^ " 2- 8> 1.4 Hz, J_sn-H " I 5 2 H z ) • Exact Mass calcd. f o r C 1 5H 250 3Sn (M^-CH^: 373.0825; found: 373.0824. - 198 -Preparation of the Ketone (62) To a w e l l s t i r r e d s o l u t i o n of potassium tert-butoxide (430 mg, 1.5 equiv) i n a mixture of dry THF (14 mL) and dry t e r t - b u t y l alcohol (2 mL) at room temperature was added, dropwise, neat, commercially a v a i l a b l e 2-methylcyclohexanone (55) (0.31 mL, 2.55 mmol). The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 0.5 h and then 5-iodo-2-trimethyl-stannyl-l-pentene (43) (1.00 g, 1.1 equiv) was added as a s o l u t i o n i n dry THF (10 mL). A f t e r the s o l u t i o n had been s t i r r e d at room tempera-ture f o r 3 h, 50 mL of water was added. The organic layer was separated and the aqueous phase was extracted with d i e t h y l ether (3 x 50 mL). The combined organic extracts were d r i e d (MgS04) and concentrated. Flash chromatography of the r e s u l t i n g crude o i l on s i l i c a gel (50 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 20:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 100-110°C/0.03 T o r r ) , provided 399 mg (46%) of the ketone (62) as a colourless o i l . This material e x h i b i t e d i r ( f i l m ) : 1708, 769 cm"1; XH nmr (300 MHz, CDC13) 6: 0.13 (s, 9H, -SnMe3, J S n . H - 54 Hz), 1.04 (s, 3H, -CCH3), 1.30-2.50 (m, 14H), 5.14 (m, 1H, H a, J S n . H - 71 Hz), 5.64 (m, 1H, H b, J S n . H - 150 Hz). Exact Mass calcd. f o r C^H^sOSn (M+-CH3): 329.0927; found: 329.0927. - 199 -Preparation of the fl-Keto Ester (118) Following general procedure 6, methyl 2-oxocyclopentanecarboxylate (50) (155 mg, 1.09 mmol) was treated with potassium hydride (48.1 mg, 1.1 equiv), followed by methyl (£)-6-iodo-3-trimethylstannyl-2-hexenoate (109) (500 mg, 1.1 equiv). The reaction mixture was refluxed f o r 18 h. Flash chromatography of the crude product mixture on s i l i c a g el (27 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a -t i o n of the r e s u l t i n g o i l (air-bath temperature 169-173°C/0.6 T o r r ) , provided 366 mg (78%) of the /?-keto ester (118) as a colourless o i l . This material exhibited i r ( f i l m ) : 1750, 1720, 1170, 775 cm - 1; AH nmr (400 MHz, CDC1 3) 6: 0.20 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.30-1.50 (m, 2H), 1.62 (d of d of d, 1H, J - 4.5, 11.5, 13.5 Hz), 1.80-2.05 (m, 4H), 2.25 (m, 1H), 2.39 (m, 1H), 2.54 (m, 1H), 2.80-3.00 (m, 2H), 3.68 (s, 3H, -OCH.3), 3.69 (s, 3H, -OCH3), 5.96 (br s, 1H, H a, w 1 / / 2 - 4 Hz, I S n-H - 72 Hz). Exact Mass ca l c d . f o r C 1 6 H 2 5 0 5 S n (M+'C^): 417.0723; found: 417.0686. - 2 0 0 -P r e p a r a t i o n o f t h e fl-Keto E s t e r ( 1 1 9 ) F o l l o w i n g g e n e r a l p r o c e d u r e 6, m e t h y l 2 - o x o c y c l o h e x a n e c a r b o x y l a t e ( 5 2 ) ( 2 0 0 m g , 1 . 2 8 m m o l ) w a s t r e a t e d w i t h p o t a s s i u m h y d r i d e ( 5 6 . 6 m g , 1 . 1 e q u i v ) , f o l l o w e d b y m e t h y l ( E ) - 6 - i o d o - 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 ( 1 0 9 ) ( 5 8 8 m g , 1 . 1 e q u i v ) . T h e r e a c t i o n m i x t u r e w a s r e f l u x e d f o r 9 h . F l a s h c h r o m a t o g r a p h y o f t h e c r u d e p r o d u c t m i x t u r e o n s i l i c a g e l ( 3 5 g , e l u t i o n w i t h p e t r o l e u m e t h e r - e t h y l a c e t a t e , 1 4 : 1 ) , f o l l o w e d b y d i s t i l l a -t i o n o f t h e r e s u l t i n g o i l ( a i r - b a t h t e m p e r a t u r e 1 7 6 - 1 8 1 ° C / 0 . 6 T o r r ) , p r o v i d e d 322 mg (57%) o f t h e 0 - k e t o e s t e r ( 1 1 9 ) a s a c o l o u r l e s s o i l . T h i s m a t e r i a l e x h i b i t e d i r ( f i l m ) : 1 7 1 0 , 1 1 9 5 , 1 1 7 0 , 7 7 5 c m " 1 ; lH n m r ( 4 0 0 M H z , C D C 1 3 ) 6: 0 . 1 9 ( s , 9 H , - S n M e 3 , J S n - H - 53 H z ) , 1 . 2 0 - 1 . 5 0 (m, 3 H ) , 1 . 5 5 - 1 . 8 0 ( m , 4 H ) , 1 . 8 5 - 2 . 0 5 ( m , 2 H ) , 2 . 2 0 - 2 . 5 5 ( m , 3 H ) , 2 . 7 5 - 3 . 0 0 ( m , 2 H ) , 3 . 6 8 ( s , 3 H , -OCH3) , 3 . 7 2 ( s , 3 H , -OCH3) , 5 . 9 6 ( t , 1 H , H a , J -1 . 3 H z , J_sn-H " 7 2 H z > - E x a c t M a s s c a l c d . f o r C 1 7 H 2 7 0 5 S n ( M T ^ - C ^ ) : 4 3 1 . 0 8 8 0 ; f o u n d : 4 3 1 . 0 8 7 3 . - 201 -Preparation of the fl-Keto (Ester (116) Following general procedure 6, methyl 2-oxocyclopentanecarboxylate (50) (300 mg, 1.92 mmol) was treated with potassium hydride (93.1 mg, 1.1 equiv), followed by methyl (Z)-6-iodo-3-trimethylstannyl-2-hexenoate (108) (967 mg, 1.1 equiv). The rea c t i o n mixture was refluxed f o r 18 h. Flash chromatography of the crude product mixture on s i l i c a g el (50 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a -t i o n of the r e s u l t i n g o i l (air-bath temperature 185-189°C/0.6 Torr), provided 564 mg (63%) of the y3-keto ester (116) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1750, 1720, 1705, 1210, 780 cm"1; AH nmr (400 MHz, CDC13) 5: 0.15 (s, 9H, -SnMe.3, J S n - H " 5 3 H z ) > 1-23-1.50 (m, 2H), 1.52 (d of t, 1H, J - 4.5, 13 Hz), 1.80-2.05 (m, 4H), 2.25 (d of t, 1H, J - 19, 8 Hz), 2.34-2.48 (m, 3H), 2.53 (m, 1H), 3.69 (s, 3H, -OCH3), 3.71 (s, 3H, -OCH3), 6.31 ( t , 1H, H a, J - 1 Hz, I S n . H - 119 Hz). Exact Mass calcd. f o r C 1 6H 250 5Sn (M+-CH3): 417.0723; found: 417.0718. - 202 -Preparation of the fl-Keto Ester (117) Following general procedure 6 , methyl 2-oxocyclohexanecarboxylate (52) (300 mg, 1.92 mmol) was treated with potassium hydride (84.8 mg, 1 . 1 equiv), followed by methyl (Z)-6-iodo - 3-trimethylstannyl - 2-hexenoate (108) (881 mg, 1 . 1 equiv). The rea c t i o n mixture was refluxed f o r 18 h. Flash chromatography of the crude product mixture on s i l i c a g el (50 g, e l u t i o n with petroleum ether-ethyl acetate, 1 0 : 1 ) , followed by d i s t i l l a -t i o n of the r e s u l t i n g o i l (air-bath temperature 201-204°C/0.6 T o r r ) , provided 610 mg (71%) of the fl-keto ester (117) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1710, 1 2 1 0 , 780 cm - 1; XH nmr (400 MHz, C D C 1 3 ) 6: 0.16 (s, 9 H , -SnMe3, J _ S n _ H - 5 3 Hz), 1 . 2 0 - 1.80 (m, 7 H ) , 1.86 (d of t, 1 H , J - 4 . 5 , 13 Hz), 2 . 0 0 (m, 1 H ) , 2 . 3 5 - 2.60 (m, 5 H ) , 3.72 (s, 3 H , - O C H 3 ) , 3 . 7 3 (s, 3 H , - O C H 3 ) , 6 . 3 4 ( t , 1 H , H a, J - 1 Hz, J S n . H -118 Hz). Exact Mass calcd. f o r C 1 7H 270 5Sn (M+'C^): 431.0880; found: 431.0881. - 203 -Preparation of the fl-Keto Ester (122) 8 C02Me c n M e 3 ^ / O ^ A ^ H Q R = C H 2 O C H 2 O C H 3 R Following general procedure 6, methyl 2-oxocyclopentanecarboxylate (50) (100 mg, 0.703 mmol) was treated with potassium hydride (31.0 mg, 1.1 equiv), followed by (E)-6-iodo-l-(methoxymethoxy)-3-trimethyl-stannyl-2-hexene (111) (335 mg, 1.1 equiv). The r e a c t i o n mixture was r e f l u x e d f o r 13 h. Flash chromatography of the crude product mixture on s i l i c a gel (18 g, e l u t i o n with petroleum ether-ethyl acetate, 8:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 159-164°C/0.6 To r r ) , provided 210 mg (67%) of the 0-keto ester (122) as a c o l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1750, 1725, 1155, 1050, 775 cm - 1; 1H nmr (400 MHz, CDCI3) 6": 0.11 (s, 9H, -SnMe.3, ^ Sn-H ~ 53 Hz), 1.15-1.44 (m, 2H), 1.53 (d of d of d, 1H, J - 4.5, 12, 13.5 Hz), 1.78-2.04 (m, 4H), 2.17-2.33 (m, 3H), 2.37 (m, 1H), 2.52 (m, 1H), 3.35 (s, 3H, -CH 20CH 3), 3.67 (s, 3H, -COOCH.3), 4.11 (d, 2H, -CCH20-, J - 6 Hz), 4.62 (s, 2H, -OCH.20), 5.72 ( t , 1H, H a, J - 6 Hz, J S n . H - 77 Hz. Exact Mass ca l c d . f o r C 1 7 H 2 9 0 5 S n (M+-CH3): 433.1037; found: 433.1038. - 204 -Preparation of the fl-Keto Ester (123) 3 Following general procedure 6, methyl 2-oxocyclohexanecarboxylate (52) (670 mg, 4.29 mmol) was treated with potassium hydride (189 mg, 1.1 equiv), followed by (E)-6-iodo-l-(methoxymethoxy)-3-trimethylstannyl-2-hexene (111) (2.04 g, 1.1 equiv). The rea c t i o n mixture was refluxed f o r 6 h. Flash chromatography of the crude product mixture on s i l i c a gel (100 g, e l u t i o n with petroleum ether-ethyl acetate, 5:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 164-167°C/0.6 T o r r ) , provided 1.46 g (74%) of the /9-keto ester (123) as a colourless o i l . This material exhibited i r ( f i l m ) : 1710, 1055, 772 cm"1; XH nmr (400 MHz, CDC13) 6: 0.11 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.12-1.35 (m, 2H), 1.42 (m, 1H), 1.52 (d of t, 1H, J - 4.5, 13 Hz), 1.58-1.80 (m, 3H), 1.86 (d of d of d, 1H, J - 4.5, 13, 13.5 Hz), 1.99 (m, 1H), 2.29 (br t, 2H, -CCH 2CH 2-, J - 7.5 Hz, J S n - H " 5 3 H z>- 2.40-2.45 (m, 2H), 2.49 (m, 1H), 3.37 (s, 3H, -CH20CH3), 3.71 (s, 3H, -COOCH3), 4.14 (d, 2H, -CCH20-, I - 6 Hz), 4.63 (s, 2H, -0CH20-), 5.72 (br t, 1H, H a, J_ - 6 Hz, J S n . H - 77 Hz). Exact Mass calcd. f o r C 1 8 H 3 1 0 5 S n (M+-CH3): 447.1193; found: 447.1196. - 205 -Preparation of the fl-Keto Ester (120) Following general procedure 6, methyl 2-oxocyclopentanecarboxylate (50) (670 mg, 4.71 mmol) was treated with potassium hydride (208 mg, 1.1 equiv), followed by (£)-6-iodo-l-(methoxymethoxy)-3-trimethylstannyl-2-hexene (110) (2.24 g, 1.1 equiv). The reaction mixture was refluxed for 14 h. Flash chromatography of the crude product mixture on silica gel (100 g, elution with petroleum ether-ethyl acetate, 7:1), followed by distillation of the resulting o i l (air-bath temperature 170-175<>C/0.6 Torr), provided 1.43 g (68%) of the /3-keto ester (120) as a colourless o i l . This material exhibited i r (film): 1747, 1720, 1155, 1040, 780 cm-1; XH nmr (400 MHz, CDCI3) 6: 0.18 (s, 9H, -SnMe3, J S n . H " 5 4 H z>-1.20-1.42 (m, 2H), 1.53 (d of t, 1H, J - 4.5, 13 Hz), 1.80-2.05 (m, 4H), 2.20-2.32 (m, 3H), 2.39 (m, 1H), 2.54 (m, 1H), 3.35 (s, 3H, -CH20CH3), 3.69 (s, 3H, -COOCH3), 4.01 (d, 2H, -CCH.20-, J - 6 Hz), 4.61 (s, 2H, -OCH.2O-), 6-12 (t, 1H, Ha, J_ - 6 Hz, Isn-H " 1 3 6 Hz>- Exact Mass calcd. for C17H2905Sn (M"*"-^): 433.1037; found: 433.1035. - 206 -Preparation of the fl-Keto Ester (121) Following general procedure 6, methyl 2-oxocyclohexanecarboxylate (52) (740 mg, 4.74 mmol) was treated with potassium hydride (209 mg, 1.1 equiv), followed by (Z)-6-iodo-l-(methoxymethoxy)-3-trimethylstannyl-2-hexene (110) (2.25 g, 1.1 equiv). The rea c t i o n mixture was ref l u x e d f o r 19 h. Flash chromatography of the crude product mixture on s i l i c a gel (120 g, e l u t i o n with petroleum ether-ethyl acetate, 7:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 174-177°C/0.6 T o r r ) , provided 1.53 g (70%) of the 0-V.eto ester (121) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1715, 1040, 779 cm"1; lH nmr (400 MHz, CDC13) 6: 0.15 (s, 9H, -SnMe.3, l S n - H - 53 Hz), 1.13-1.33 (m, 2H), 1.37-1.77 (m, 5H), 1.84 (d of t, 1H, J - 4 . 5 , 13.5 Hz), 1.97 (m, 1H), 2.10-2.30 (m, 2H), 2.37-2.44 (m, 2H), 2.48 (m, 1H), 3.35 (s, 3H, -CH20CH3), 3.70 (s, 3H, -COOCH3), 3.99 (d, 2H, -CCH^O-, J - 6.3 Hz), 4.60 ( s , 2H, -0CH20-), 6.12 ( t , 1H, H a, J_ - 6.3 Hz, J S n . H - 131 Hz). Exact Mass ca l c d . f o r C 1 8 H 3 1 ° 5 S n O ^ - C ^ ) : 447.1193; found: 447.1195. - 207 -Preparation of the ft-Keto Ester Q25) Following general procedure 6, methyl 2-oxocyclohexanecarboxylate (52) (400 mg, 2.56 mmol) was treated with potassium hydride (113 mg, 1.1 equiv), followed by (E)-1-te£t-butyldimethylsiloxy-6-iodo-3-trimethyl-stannyl-2-hexene (113) (1.42 g, 1.1 equiv). The r e a c t i o n mixture was r e f l u x e d f or 24 h. Flash chromatography of the crude product mixture on s i l i c a gel (50 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 200-210°C/0.03 T o r r ) , provided 1.21 g (88%) of the /9-keto ester (125) as a c o l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1741, 1718, 1254, 1093, 837, 776 cm"1; XH nmr (400 MHz, CDC13) 6: 0.07 (s, 6H, -SiMe 2), 0.11 (s, 9H, -SnMe3, J S n - H 5 2 H z > » ° - 9 0 < s« 9 H> -SiCMe 3), 1.12-1.34 (m, 2H), 1.37-1.57 (m, 2H), 1.60-1.88 (m, 3H), 1.85 (d of t, 1H, J -4.5, 13 Hz), 1.99 (m, 1H), 2.23 (br t, 2H, -CCH 2CH 2, I - 7.8 Hz, I S n . H -61 Hz), 2.36-2.45 (m, 2H), 2.49 (m, 1H), 3.71 (s, 3H, -0CH.3), 4.26 (d, 2H, -CCH20-, I - 5.6 Hz), 5.66 (br t, 1H, H a, I - 5.6 Hz, J S n . H - 79 Hz). Exact Mass calcd. f o r C 2 2 H 4 1 0 4 S i S n (M+'CH^: 517.1796; found: 517.1792. - 208 -Preparation of the fi-Keto Ester (124) Following general procedure 6, methyl 2-oxocyclohexanecarboxylate (52) (400 mg, 2.56 mmol) was treated with potassium hydride (113 mg, 1.1 equiv), followed by (Z)-1-tert-butvldimethvlsiloxv-6-iodo-3-trimethyl-stannyl-2-hexene (112) (1.42 g, 1.1 equiv). The r e a c t i o n mixture was refl u x e d f o r 24 h. Flash chromatography of the crude product mixture on s i l i c a gel (50 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (ai r - b a t h temperature 200-210°C/0.03 T o r r ) , provided 940 mg (69%) of the /3-keto ester (124) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1741, 1718, 1255, 1095, 837, 776 cm - 1; XH nmr (400 MHz, CDC1 3) 6: 0.07 (s, 6H, -SiMe 2), 0.17 (s, 9H, -SnMe.3, J S n . H " 52 Hz), 0.90 (s, 9H, -SiCMe 3), 1.15-1.34 (m, 2H), 1.39-1.58 (m, 2H), 1.62-1.79 (m, 3H), 1.85 (d of d of d, 1H, J - 4.5, 13, 13.5 Hz), 2.00 (m, 1H), 2.20 (br t, 2H, -CCH.2CH2-, J - 7 Hz), 2.40-2.54 (m, 3H), 3.72 (s, 3H, -0CH.3) , 4.10 (d, 2H, -CCH.20-, 1-6 Hz), 6.10 ( t , 1H, H a, J - 6 Hz, Isn-H " 1 4 0 H z ) • Exact Mass ca l c d . f o r C 2 2 H 4 1 0 4 S i S n (M+-CH3): 517.1796; found: 517.1790. - 209 -Pr e p a r a t i o n of the fl-Keto E s t e r (126) F o l l o w i n g general procedure 6, methyl 2-oxocyclohexanecarboxylate (52) (1.12 g, 7.18 mmol) was t r e a t e d w i t h potassium hydride (317 mg, 1.1 e q u i v ) , f o l l o w e d by (E)-7-iodo-4-trimethylstannyl-3-heptene (114). The r e a c t i o n mixture was r e f l u x e d f o r 20 h. F l a s h chromatography of the crude product mixture on s i l i c a g e l (180 g, e l u t i o n w i t h petroleum e t h e r - d i e t h y l ether, 15:1), 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 u l t i n g o i l ( a i r - b a t h temperature 140-150°C/0.03 T o r r ) , provided 2.23 g (75%) of the /3-keto e s t e r (126) as a c o l o u 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 ) : 1740, 1716, 1211, 767 cm"1; XH nmr (400 MHz, CDC13) 6: 0.09 ( s , 9H, -SnMe3 , J S n . H - 52 Hz), 0.97 ( t , 3H, -CH 2CH 3, J - 7 Hz), 1.12-1.33 (m, 2H), 1.39-1.80 (m, 5H), 1.88 (d of t , 1H, J = 4, 13 Hz), 2.00 (m, 1H), 2.11 ( q u i n t e t , 2H, =CCH2CH3-, J = 7 Hz), 2.25 (br t , 2H, =CCH2CH2-, J - 8 Hz), 2.40-2.55 (m, 3H), 3.72 (s, 3H, -OCH3), 5.53 (br t , 1H, H a, J - 7 Hz, Isn-H " 7 3 H z>- Exact Mass c a l c d . f o r C 1 7 H 2 9 0 3 S n (M^-CH^: 401.1138; found: 401.1131. - 210 -Preparation of the fl-Keto Ester (157) 0 C0 7Me SnMe3 Following general procedure 6, methyl 2-oxocyclopentanecarboxylate (50) (125 mg, 0.879 mmol) was treated with potassium hydride (38.8 mg, 1.1 equiv), followed by (Z)-l-bromo-4-methyl-3-trimethylstannyl-2-pentene (154) (310 mg, 1.1 equiv). The rea c t i o n mixture was refluxed f o r 1 h. Medium pressure chromatography of the crude product mixture on s i l i c a g e l (27 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 145-149°C/0.6 To r r ) , provided 258 mg (78%) of the 0-keto ester (157) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1740, 1720, 1225, 773 cm - 1; XH nmr (400 MHz, CDC13) 6: 0.19 (s, 9H, -SnMe3, J S n - H " 5 3 Hz), 0.97 (two d separated by 0.9 Hz, 3H each, -CHMe2, J = 7 Hz each), 1.85-2.05 (m, 3H), 2.20 (m, 1H), 2.36-2.50 (m, 4H, 3 unassigned protons plus one of -CCH 2-), 2.63 (d of d, 1H, one of -CCH2-, J - 8, 14.5 Hz), 3.69 (s, 3H, -OCH3), 5.75 (d of t, 1H, H a, J - 1, 8 Hz, J Sn-H " 1 4 4 H z>• I r r a d i a t i o n at 6 5.75 (H a): s i g n a l at 6 2.63 (one of -CCH2-) s i m p l i f i e d to a d (J - 14.5 Hz), m u l t i p l e t at 6 2.36-2.50 s i m p l i f i e d . Exact Mass cal c d . f o r C 1 5 H 2 5 0 3 S n (M+-CH3): 373.0825; found: 373.0821. - 211 -Preparation of the fl-Keto Ester (158) Following general procedure 6, methyl 2-oxocyclohexanecarboxylate (52) (140 mg, 0.897 mmol) was treated with potassium hydride (39.6 mg, 1.1 equiv), followed by (Z)-l-bromo-4-methyl-3-trimethylstannyl-2-pentene (154) (321 mg, 1.1 equiv). The r e a c t i o n mixture was s t i r r e d f o r 2 h at room temperature. Medium pressure chromatography of the crude product mixture on s i l i c a gel (30 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 158-161°C/0.6 To r r ) , provided 302 mg (85%) of the fl-keto ester (158) as a colourless o i l . This material exhibited i r ( f i l m ) : 1710, 1203, 772 cm - 1; XH nmr (400 MHz, CDC13) 6: 0.19 (s, 9H, -SnMe3, J-Sn-H = 5 3 H z ) ' ° - 9 6 <d> 6 H> -CHMe2, J = 7 Hz), 1.33 (d of d of d, 1H J -4.5, 13, 14 Hz), 1.55-1.78 (m, 3H), 2.00 (m, 1H), 2.30 (d of d, 1H, one of -CCH2-, J — 7, 14 Hz), 2.35-2.53 (m, 4H), 2.63 (d of d, 1H, one of -CCH2-, J - 7, 14 Hz), 3.67 (s, 3H, -0CH 3), 5.86 (d of t, 1H, H a, J -1, 7 Hz, J S n _ H - 145 Hz). I r r a d i a t i o n at 8 5.86 (H a): s i g n a l at 8 2.30 (one of -CCH2-) s i m p l i f i e d to a d (J - 14 Hz), s i g n a l at 6 2.63 (one of -CCH2-) s i m p l i f i e d to a d (J - 14 Hz). Exact Mass calcd. f o r C^gH^O^n (M+-CH3): 387.0982; found: 387.0983. - 212 -Preparation of the fl-Keto Ester (159) Following general procedure 6, methyl 2-oxocycloheptanecarboxylate (54) (190 mg, 1.12 mmol) was treated with potassium hydride (49.3 mg, 1.1 equiv), followed by (Z)-l-bromo-4-methyl-3-trimethylstannyl-2-pentene (154) (400 mg, 1.1 equiv). The rea c t i o n mixture was s t i r r e d f o r 1 h at room temperature. Medium pressure chromatography of the crude product mixture on s i l i c a gel (60 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 160-163°C/0.6 To r r ) , provided 367 mg (80%) of the fl-keto ester (159) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1700, 1205, 770 cm"1; XH nmr (400 MHz, CDC13) 6: 0.19 (s, 9H, -SnMe3, J S n . H - 53 Hz), 0.96 (d, 6H, -CHMe2, J - 7 Hz), 1.41 (m, 1H), 1.50-1.80 (m, 6H), 2.10 (d of d, 1H, J - 9.5, 14 Hz), 2.33 (d of d, 1H, one of -CCH2-, J - 7, 14 Hz), 2.39-2.49 (m, 2H), 2.61 (m, 1H), 2.74 (d of d, 1H, one of -CCH2-, J - 7, 14 Hz), 3.68 (s, 3H, -OCH3), 5.81 (d of t, 1H, H a, J - 1, 7 Hz, Isn-H " 1 4 5 H z>• I r r a d i a t i o n at S 5.81 (H a): s i g n a l at S 2.33 (one of -CCH2-) s i m p l i f i e d to a d (J - 14 Hz), s i g n a l at 6 2.74 (one of -CCH2-) s i m p l i f i e d to a d (J - 14 Hz). Exact Mass ca l c d . f o r C 1 7 H 2 9 0 3 S n (M+-CH5): 401.1139; found: 401.1139. - 213 -Preparation of the Ketone (160) To a w e l l s t i r r e d s o l u t i o n of potassium tert-butoxide (140 mg, 0.95 equiv) i n a mixture of dry THF (4 mL) and dry t e r t - b u t y l alcohol (1 mL) at room temperature was added 2-methylcycloheptanone 7 3 (166 mg, 1.32 mmol) as a s o l u t i o n i n dry THF (2 mL). The r e s u l t i n g mixture was s t i r r e d at room temperature f o r 0.5 h and then (Z)-l-bromo-4-methyl-3-trimethylstannyl-2-pentene (154) (430 mg, 1 equiv) was added as a s o l u t i o n i n dry THF (2 mL). A f t e r the s o l u t i o n had been s t i r r e d at room temperature f o r 2 h, the solvent was removed by rotary evaporation. Water (50 mL) was added to the residue and the r e s u l t i n g mixture was extracted with d i e t h y l ether (3 x 25 mL). The combined ethereal extracts were d r i e d (MgS04) and concentrated. Drip column chromato-graphy of the crude product mixture on s i l i c a gel (120 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 40:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 116-119°C/0.1 T o r r ) , provided 205 mg (42%) of the ketone (160) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1700, 760 cm"1; lH nmr (400 MHz, CDC13) 6: 0.20 (s, 9H, -SnMe.3, ^Sn-H ~ 5 3 H z > » 0 9 9 <d- 6 H> -CHMe2, J - 7 Hz), 1.04 (s, 3H, - C C H 3 ) , 1.28-1.80 (m, 8H), 2.18 (d of d, 1H, one of -CCH2-, J •= 7, 14 Hz), 2.22 (d of d, 1H, one of -CCH2-, J - 7, 14 Hz), 2.37-2.49 (m, 2H, - 214 -one of which i s H b), 2.62 (d of t, 1H, J - 2.5, 1 1 . 5 Hz), 5.89 (d of t, 1H, H a, J - 1, 7 Hz, J.sn-H " 1 4 7 H z>- I r r a d i a t i o n at 6 5.89 (H a): s i g n a l at S 2.18 (one of -CCH2-) s i m p l i f i e d to a d (J - 14 Hz), s i g n a l at 6 2.22 (one of -CCH2-) s i m p l i f i e d to a d (J - 14 Hz). Exact Mass cal c d . f o r C 1 6H 2 9OSn (M+-CH3): 357.1241; found: 357.1267. General Procedure 7: Preparation of B i c y c l i c Dienes v i a the Correspond- ing I s olated Enol T r i f l a t e Intermediates To a c o l d (-48°C), well s t i r r e d s o l u t i o n of LDA (1.1-1.5 equiv) i n dry THF (1-1.3 mL per 0.1 mmol of j8-keto ester or ketone) was added, dropwise, a s o l u t i o n of the appropriate j8-keto ester or ketone (1 equiv) i n dry THF (1-2 mL per 0.3 mmol). 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 at -48°C f o r 1 h. E-Phenyltrifluoromethanesulfonimide (Tf 2NPh) (1.17-1.57 equiv) was added as a f i n e l y ground s o l i d and the r e s u l t i n g yellow s o l u t i o n was warmed to room temperature over 30 min. The solvent was removed by rotary evaporation and the r e s i d u a l o i l was subjected to f l a s h chromatography. The o i l thus obtained was not d i s t i l l e d as extensive decomposition occurred during t h i s procedure. The enol t r i f l a t e was characterized and then was used as soon as possible In the subsequent r e a c t i o n . I f storage was required, the enol t r i f l a t e was stored i n a freezer under an argon atmosphere. To a s t i r r e d s o l u t i o n of the appropriate enol t r i f l a t e (1 equiv) i n THF or a c e t o n i t r i l e («5 mL per 0.1 mmol) at room temperature was added palladium tetrakis(triphenylphosphine) (5 mol %) as a s o l i d . The - 215 -r e s u l t i n g s o l u t i o n was heated to the r e f l u x temperature. When the rea c t i o n was determined to have reached completion (by g l c and/or t i c an a l y s i s ) , the mixture was cooled to room temperature. The solvent was removed by rotary evaporation and the r e s i d u a l o i l was subjected to f l a s h chromatography. D i s t i l l a t i o n of the o i l thus obtained provided the expected diene. Preparation of the Diene (73) Following general procedure 7, and employing 1.1 equiv of LDA and 1.17 equiv of Tf 2NPh, the B-keto ester (56) (110 mg, 0.295 mmol) was converted into the enol t r i f l a t e (66 ) . Flash chromatography of the crude product mixture on s i l i c a g el (27 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) and concentration of the appropriate f r a c -tions provided 95 mg (64%) of the enol t r i f l a t e (66) as a colourless o i l . This material exhibited i r ( f i l m ) : 1740, 1650, 1425, 1215, 1145, 770 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.18 (s, 9H, -SnMe.3, ^ Sn-H " 5 3 Hz), 1.10-2.75 (m, 10H), 3.75 (s, 3H, -OCH3), 5.15 (d of t, 1H, H a, J -2.8, 1.3 Hz, J S n - H " 7 2 H z>> 5-65 (d of t, 1H, H b, J = 2.8, 1.4 Hz, H h J C0 2 Me H 0 66 73 - 216 -J S n . H - 152 Hz), 5.78 (m, 1H, H c, wiy 2 - 5 Hz). Exact Mass ca l c d . f o r c 1 5 H 2 2 ° 5 S F 3 S n (M+-CH3): 491.0162; found: 491.0140. Following general procedure 7, the enol t r i f l a t e (66) (87 mg, 0.17 mmol) was converted into the diene (73), using THF as solvent, i n 11 h. Flash chromatography of the crude o i l on s i l i c a g el (18 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 65-68°C/0.8 T o r r ) , provided 27 mg (82%) of the diene (73) as a colourless o i l . This material exhibited i r ( f i l m ) : 1725, 1632, 895 cm"1; lU nmr (400 MHz, CDC13) 6: 1.32 (d of t, 1H, H k, J - 3.5, 13.5 Hz), 1.51 (t of q, 1H, H Q, J - 3.5, 13.5 Hz), 1.75 (m, 1H, H n), 1.83 (d of t, 1H, J - 13, 9 Hz), 2.09 (m, 1H, H p), 2.29-2.47 (m, 4H, H g, H h, Hj, H q), 2.49 (br d, 1H, H m, J - 13.5 Hz), 3.65 (s, 3H, -OCH3), 4.75 ( t , 1H, H d, J - 2 Hz), 5.05 ( t , 1H, H e, J - 2 Hz), 5.84 ( t , 1H, H f, J - 2 Hz). I r r a d i a t i o n at S 4.75 ( H d ) : s i g n a l at 6 2.09 (H p) s i m p l i f i e d to a d of d of t (J - 2, 5, 13.5 Hz). I r r a d i a -t i o n at 5 5.05 (H e): s i g n a l at 6 2.09 (Hp) s i m p l i f i e d to a d of d of t (J - 2, 5, 13.5 Hz). I r r a d i a t i o n at * 5.84 ( H f ) : m u l t i p l e t at S 2.29-2.47 s i m p l i f i e d . Exact Mass calcd. f o r C 1 2 H 1 6 ° 2 : 192.1151; found: 192.1152. - 217 -Preparation of the Diene (74) 67 Following general procedure 7, and employing 1.1 equiv of LDA and 1.17 equiv of Tf2NPh, the 0-keto ester (57) (114 mg, 0.295 mmol) was converted into the enol t r i f l a t e (67). Flash chromatography of the crude product mixture on s i l i c a gel (27 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) and concentration of the appropriate f r a c -tions provided 95 mg (62%) of the enol t r i f l a t e (67) as a colourless o i l . This material exhibited i r ( f i l m ) : 1730, 1650, 1420, 1210, 1138, 765 cm - 1; XH nmr (80 MHz, CDC13) 5: 0.16 (s, 9H, -SnMe3, J S n - H = 5 3 Hz), 1.00 (d, 3H, -CHCH3, J - 6.5 Hz), 1.25-2.75 (m, 9H), 3.73 (s, 3H, -OCH3), 5.15 (m, 1H, H a, W/L/2 - 4.5 Hz, I S n - H ~ 7 2 H z> • 5 - 6 6 < d o f t> 1H, H b, J - 2.8, 1.4 Hz, J S n _ H - 152 Hz), 5.80 (m, 1H, H c, wX/2 = 7 Hz). Exact Mass ca l c d . f o r C 1 6H240 5SF 3Sn ( t f 4 " - ^ ) : 505.0318; found: 505.0335. Following general procedure 7, the enol t r i f l a t e (67) (85 mg, 0.16 mmol) was converted into the diene (74), using THF as solvent, i n 9 h. Flash chromatography of the crude o i l on s i l i c a gel (18 g, e l u t i o n with petroleum ether-ethyl acetate, 30:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 68-70°C/0.8 To r r ) , provided 28 mg - 218 -(82%) of the diene (74) as a colourless o i l . This material exhibited i r ( f i l m ) : 1720, 1620, 890 cm-1; XH nmr (400 MHz, CDCl 3) 6: 0.98 (d, 3H, -CHCH3, J. - 7 Hz), 1.16 (d of t, 1H, Hj, J. - 3.5, 13 Hz), 1.46 (d of d of q, 1H, H^ J. - 3.5, 3.5, 13 Hz), 1.77 (m, 1H, H^, w 1 / / 2 - 23 Hz), 2.08 (m, 1H, H Q), 2.11 (d of d of d, 1H, H g, J - 1 . 9 , 10, 15.5 Hz), 2.23-2.60 (m, 2H, % and Hp), 2.43 (d of d of d, 1H, H h, J. - 3, 7.5, 15.5 Hz), 2.60 (br d, 1H, H k, J - 13 Hz), 3.65 (s, 3H, -OCH3), 4.71 ( t , 1H, H d, J - 2.5 Hz), 5.03 ( t , 1H, H e, J. - 2.5 Hz), 5.87 (d of d, 1H, H f, J - 2, 3 Hz). I r r a d i a t i o n at S 4.71 (H d): s i g n a l at 6 2.08 (H Q) s i m p l i f i e d to a d of d of t (J - 2, 5, 13 Hz). I r r a d i a t i o n at 6 5.03 (H e ) : s i g n a l at S 2.08 (H D) s i m p l i f i e d to a d of d of t (J - 2, 5, 13 Hz). I r r a d i a t i o n at 5 5.87 (H f): s i g n a l at S 2.11 (H g) s i m p l i f i e d to a d of d (J - 10, 15.5 Hz), si g n a l at 6 2.43 (H h) s i m p l i f i e d to a d of d (J - 7.5, 15.5 Hz). Exact Mass calcd. f o r Ci3H l g0 2: 206.1307; found: 206.1300. Preparation of the Diene (75) 68 Following general procedure 7, and employing 1.5 equiv of LDA and - 219 -1.57 equiv of T^NPh, the fl-keto ester (58) (1.32 g, 3.41 mmol) was converted i n t o the enol t r i f l a t e (68). Flash chromatography of the crude product mixture on s i l i c a g el (180 g, e l u t i o n with petroleum ether-ethyl acetate, 20:1) and concentration of the appropriate f r a c -t ions provided 1.24 g (71%) of the enol t r i f l a t e (68) as a colou r l e s s o i l . This material exhibited i r ( f i l m ) : 1735, 1415, 1210, 1142, 770 cm - 1; XH nmr (80 MHz, CDCI3) 6: 0.18 (s, 9H, -SnMe.3, I S n . H - 53 Hz), 0.90-2.50 (m, 12H), 3.75 (s, 3H, -OCH3), 5.15 (d of t, 1H, H a, J - 2.8, 1.3 Hz, J S n - H " 7 2 H z > » 5 6 5 ( d o f t> 1 H> Hb> i " 2- 8> x - 3 H z> iSn-H " 152 Hz), 5.87 ( t , 1H, H c, J - 4 Hz). Exact Mass ca l c d . f o r C 1 6H 240 5SF 3Sn (M+-CH3): 505.0318; found: 505.0350. Following general procedure 7, the enol t r i f l a t e (68) (1.20 g, 2.31 mmol) was converted into the diene (75), using a c e t o n i t r i l e as solvent, i n 3 h. Flash chromatography of the crude o i l on s i l i c a g el (180 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a -t i o n of the r e s u l t i n g o i l (air-bath temperature 75-78°C/0.8 To r r ) , provided 428 mg (90%) of the diene (75) as a colou r l e s s o i l . This material exhibited i r ( f i l m ) : 1720, 895 cm"1; *H nmr (400 MHz, CDCI3) 6: 1.25-1.50 (m, 4H), 1.56-1.78 (m, 2H), 2.05-2.20 (m, 4H), 2.29-2.40 (m, 2H), 3.66 (s, 3H, -OCH3), 4.64 ( t , 1H, H d, J - 2.5 Hz), 4.92 ( t , 1H, H e, J - 2.5 Hz), 5.86 ( t , 1H, H f, J - 4 Hz). In a dif f e r e n c e nuclear Overhauser enhancement (nOe) experiment, i r r a d i a t i o n at S 5.86 (Hf) caused s i g n a l enhancement at 6 4.92 (H e). 1 3 C nmr (75.3 MHz, CDCI3) 5: 19.3, 23.7, 25.9, 34.9, 35.6, 37.5, 49.1, 51.8 (-ve), 108.8, 123.8 (-ve), 139.3, 148.2, 176.2. Exact Mass calcd. f o r C 1 3 H 1 8 0 2 : 206.1307; found: 206.1306. - 220 -Preparation of the Diene (76) H 9 H H h H-SnMe 69 76 Following general procedure 7, and employing 1.2 equiv of LDA and 1.27 equiv of Tf2NPh, the mixture of /?-keto ester (59) and the enol ether (59a) (100 mg, 0.250 mmol) was converted into the enol t r i f l a t e (69) and the unreacted enol ether ( 5 9 a ) . Flash chromatography of the crude product mixture on s i l i c a g el (27 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) and concentration of the appropriate fr a c -tions provided 89 mg (84% based on amount of the £-keto ester (59) i n the s t a r t i n g material mixture) of the enol t r i f l a t e (69) as a colourless o i l . This material exhibited i r ( f i l m ) : 1735, 1675, 1415, 1210, 1145, 770 cm - 1; -^H nmr (80 MHz, CDC13) 6: 0.18 (s, 9H, -SnMe3, J S n - H = 53 Hz), 0.95 (d, 3H, -CHCH3, J - 6.5 Hz), 1.10-2.50 (m, 11H), 3.72 (s, 3H, -OCH3), 5.16 (m, 1H, H a, Isn-H " 7 1 H z ) > 5 - 6 6 < d o f t> 1 H - Hb> i " 2- 8-1.4 Hz, Isn-H " 1 5 1 H z > « 6 - 0 0 (-t> 1 H » Hc> i " 4 H z>- Exact Mass calcd. fo r C 1 7H 260 5SF3Sn (M+-CH3): 519.0475; found: 519.0439. Following general procedure 7, the enol t r i f l a t e (69) (89 mg, 0.167 mmol) was converted into the diene ( 7 6 ) , using THF as solvent, i n 19 h. Flash chromatography of the crude product mixture on s i l i c a gel (10 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) followed by d i s t i l l a -- 221 -t i o n of the r e s u l t i n g o i l (air-bath temperature 74-76°C/0.8 Tor r ) , provided 32 mg (86%) of the diene (76) as a colou r l e s s o i l . This material exhibited I r ( f i l m ) : 1720, 1620, 890 cm"1; 1H nmr (400 MHz, CDC13) 6: 0.91 (d, 3H, -CHCH3, J - 6.5 Hz), 1.14 (d of t, 1H, H,,,, J -4, 13.5 Hz), 1.42-1.62 (m, 4H, H t, Hj, H k, Hp), 1.76 (m, 1H, H Q), 2.06 (d of t of t, 1H, H q, J - 5, 2.5, 13.5 Hz), 2.15 (m, 2H, H g and H h), 2.30 (d of d of d of d, 1H, H r, J - 2.5, 2.5, 4, 13.5 Hz), 2.63 (d of d of d of d, 1H, Hn, J - 2.5, 2.5, 2.5, 13.5 Hz), 3.64 (s, 3H, -OCH3), 4.60 ( t , 1H, H d, J - 2.5 Hz), 4.81 ( t , 1H, H e, J - 2.5 Hz), 5.84 (br t, 1H, H f, J - 4 Hz). I r r a d i a t i o n at 6 1.14 (H m): m u l t i p l e t at 6 1.42-1.62 s i m p l i f i e d , m u l t i p l e t at S 1.76 (H Q) s i m p l i f i e d , s i g n a l at S 2.63 (H n) s i m p l i f i e d to a br s (v1/f2 - 6.5 Hz). I r r a d i a t i o n at S 1.76 (H Q ) : s i g n a l at 6 1.14 ( i ^ ) s i m p l i f i e d to a t (J - 13.5 Hz), m u l t i p l e t at 6 1.42-1.62 s i m p l i f i e d , signals at S 2.06 (H q), 2.30 (H r) and 2.63 (H n) a l l s i m p l i f i e d . I r r a d i a t i o n at S 2.30 (H r): m u l t i p l e t at S 1.42-1.62 s i m p l i f i e d , signals at S 1.76 (H Q), 2.06 (H q), and 2.63 (H n) s i m p l i f i e d . I r r a d i a t i o n at 6 2.63 (H n): s i g n a l at 6 1.14 (H m) s i m p l i f i e d to a d of d (J - 4, 13.5 Hz), m u l t i p l e t at S 1.42-1.62 s i m p l i f i e d , s i g n a l at 6 1.76 (H Q) s i m p l i f i e d , s i g n a l at 6 2.30 (H r) s i m p l i f i e d to a d of d of d (J - 2.5, 4, 13.5 Hz). I r r a d i a t i o n at S 4.60 ( H d ) : s i g n a l at S 2.06 (H q) s i m p l i f i e d to a d of d of t (J - 2.5, 4, 13.5 Hz). I r r a d i a t i o n at S 4.81 (H e): s i g n a l at S 2.06 (H q) s i m p l i f i e d to a d of d of t (J - 2.5, 5, 13.5 Hz). I r r a d i a t i o n at S 5.84 (Hf): m u l t i p l e t at S 2.15 (H g and H h) s i m p l i f i e d . Exact Mass cal c d . f o r C^^oC^: 220.1464; found: 220.1455. - 222 -Preparation of the Diene (77) K i C02Me 70 77 Following general procedure 7, and employing 1.5 equiv of LDA and 1.57 equiv of Tf 2NPh, the 0-keto ester (60) (534 mg, 1.33 mmol) was converted into the enol t r i f l a t e (70). Flash chromatography of the crude product mixture on s i l i c a g el (70 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) and concentration of the appropriate f r a c -tions provided 447 mg (63%) of the enol t r i f l a t e (70) as a colou r l e s s o i l . This material exhibited i r ( f i l m ) : 1733, 1660, 1410, 1215, 1140, 770 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.18 (s, 9H, -SnMe3, J S n - H *" 5 3 Hz), 1.00-2.45 (m, 14H), 3.75 (s, 3H, -OCH3), 5.16 (d of t, 1H, H a, J -2.8, 1.3 Hz, J S n _ H - 72 Hz), 5.66 (d of t, 1H, H b, J - 2.8, 1.4 Hz, J S n . H - 152 Hz), 6.00 ( t , 1H, H c, J - 6.5 Hz). Exact Mass calcd. f o r c 1 7 H 2 6 ° 5 S F 3 S n (M+-CH3): 519.0475; found: 519.0475. Following general procedure 7, the enol t r i f l a t e (70) (101 mg, 0.190 mmol) was converted into the diene (77), using THF as solvent, i n 3 h. Flash chromatography of the crude product mixture on s i l i c a g el (18 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) followed by d i s t i l l a -t i o n of the r e s u l t i n g o i l (air-bath temperature 80-82°C/0.6 Torr), provided 35 mg (85%) of four isomeric dienes (by low r e s o l u t i o n glc-mass - 223 -spectrometry) which appeared, on the basis of g l c an a l y s i s , to contain -85% of the diene (77). This mixture was subjected to d r i p column chromatography on s i l v e r n i t r a t e impregnated s i l i c a g e l (100 mL of a 12.5% aqueous s i l v e r n i t r a t e s o l u t i o n per 50 g of 70-230 mesh s i l i c a gel) (12 g, e l u t i o n with petroleum ether-ethyl acetate, 30:1). A small amount of pure diene (77) was thus obtained and t h i s material exhibited i r ( f i l m ) : 1720, 1615, 895 c m - 1 ; XH nmr (400 MHz, CDC1 3) 6: 1.39 (m, 1H), 1.49-1.80 (m, 6H), 1.87-1.96 (m, 2H), 2.05-2.28 (m, 4H), 2.33 (m, 1H), 4.63 ( t , 1H, H d, I - 2.2 Hz), 4.89 ( t , 1H, H e, J - 2.2 Hz), 5.98 (d of d, 1H, Hf, J - 4.8, 7.5 Hz). Exact Mass calcd. f o r C j ^ ^ o * ^ : 220.1464; found: 220.1463. Preparation of the Diene (78) 71 78 Following general procedure 7, and employing 1.5 equiv of LDA and 1.57 equiv of T^NFh, the 0-keto ester (61) (260 mg, 0.672 mmol) was converted into the enol t r i f l a t e (71). Flash chromatography of the crude product mixture on s i l i c a gel (40 g, e l u t i o n with petroleum ether-ethyl acetate, 30:1) and concentration of the appropriate f r a c -- 224 -tions provided 220 mg (63%) of the enol t r i f l a t e (71) as a pale yellow o i l . This material exhibited i r ( f i l m ) : 1730, 1643, 1420, 1220, 1140, 768 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.14 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.10-2.70 (m, 12H), 3.71 (s, 3H, -OCH3), 5.13 (d of t, 1H, H a, J -2.8, 1.3 Hz, I S n _ H - 72 Hz), 5.63 (d of t, 1H, H b, J - 2.8, 1.4 Hz, Jg n_H - 152 Hz), 5.75 (br s, 1H, H c, 21/2 ~ 5 Hz). Exact Mass calcd. f o r c 1 6 H 2 4 ° 5 S F 3 S n (M +-CH 3): 505.0318; found: 505.0319. Following general procedure 7, the enol t r i f l a t e (71) (100 mg, 0.193 mmol) was converted into the diene (78), using THF as solvent, i n 23 h. Drip column chromatography of the crude o i l on s i l i c a gel (20 g, e l u t i o n with petroleum ether-ethyl acetate, 30:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 69-73°C/0.6 T o r r ) , provided 20 mg (50%) of the diene (78) as a colourless o i l . This material exhibited i r ( f i l m ) : 1724, 1610, 890 cm'1; XH nmr (400 MHz, CDCI3) 6: 1.14-1.53 (m, 3H), 1.73-1.88 (m, 2H), 1.92 (d of d of d, 1H, J = 4, 8, 12 Hz), 2.06 (br t, 1H, J - 13.5 Hz), 2.20-2.48 (m, 5H), 3.70 (s, 3H, -0CH 3), 4.73 (br s, 1H, H d, w 1 / 2 - 5 Hz), 5.18 (br s, 1H, H e, w 1 / 2 - 4.5 Hz), 6.00 ( t , 1H, H f,J - 4.5 Hz). I r r a d i a t i o n at S 4.73 (H d), 5.18 (H e), and 6.00 (Hf) i n separate experiments a l l s i m p l i f i e d the m u l t i p l e t at 6 2.20-2.48. In a differe n c e nuclear Overhauser enhancement (nOe) experiment, i r r a d i a t i o n at S 6.00 (Hf) caused s i g n a l enhancement at S 5.18 ( H e ) . Exact Mass calcd. f o r C 13H 1 80 2: 206.1307; found: 206.1307. - 225 -Preparation of the Diene (139) H, X0 2Me J H H k f m 131 139 Following general procedure 7, and employing 1.1 equiv of LDA and 1.17 equiv of Tf2NPh, the 0-keto ester (118) (190 mg, 0.441 mmol) was converted into the enol t r i f l a t e (131). Flash chromatography of the crude product mixture on s i l i c a gel (40 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1) and concentration of the appropriate f r a c -tions provided 141 mg (57%) of the enol t r i f l a t e (131) as a colourless o i l . This material exhibited i r ( f i l m ) : 1734, 1719, 1642, 1599, 1423, 1210, 1143, 772 cm - 1; AH nmr (80 MHz, CDC13) 6: 0.22 (s, 9H, -SnMe3, *ISn-H " 5 3 H z>- 1-20-3.20 (m, 10H), 3.69 (s, 3H, -OCH3), 3.72 (s, 3H, -OCH3), 5.76 (br s, 1H, H b, w 1 / 2 - 4 Hz), 5.98 ( t , 1H, H a, J - 1 Hz, iSn-H " 7 2 H z>- Exact Mass calcd. f o r C 1 7H 240 7SF 3Sn (M +-CH 3): 549.0216; found: 549.0212. Following general procedure 7, the enol t r i f l a t e (131) (100 mg, 0.178 mmol) was converted into the diene (139), using THF as solvent, i n 3.5 h. Flash chromatography of the crude o i l on s i l i c a g el (20 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a -t i o n of the r e s u l t i n g o i l (air-bath temperature 117-121°C/0.6 T o r r ) , provided 39 mg (89%) of the diene (139) as a colo u r l e s s o i l . This - 226 -material e x h i b i t e d i r ( f i l m ) : 1710, 1620 cm - 1; AH nmr (400 MHz, CDC1 3) 6: 1.43 (d of t, 1H, H i ( J - 3.5, 13 Hz), 1.51 (d of d of q, 1H, H^ J - 3, 4.5, 13 Hz), 1.88-1.78 (m, 2H, H g and H k), 2.06 (m, 1H, H^, 2.35-2.50 (m, 4H, H e, H f, H h and Hj), 3.65 (s, 3H, -OCH3), 3.67 (m, 1H, H 0), 3.69 (s, 3H, -OCH3), 5.97 (d, 1H, H c, 2 - 2.5 Hz), 6.01 (br s, 1H, H d, " 6 H z>- Exact Mass calcd. f o r C 1 4 H 1 8 0 4 : 250.1205; found: 250.1206. Preparation of the Diene (140) Following general procedure 7, and employing 1.1 equiv of LDA and 1.17 equiv of Tf 2NPh, the /9-keto ester (119) (200 mg, 0.450 mmol) was converted i n t o the enol t r i f l a t e (132). Flash chromatography of the crude product mixture on s i l i c a g el (40 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1) and concentration of the appropriate f r a c -t ions provided 160 mg (62%) of the enol t r i f l a t e (132) as a colourless o i l . This material exhibited i r ( f i l m ) : 1732, 1712, 1594, 1415, 1210, 772 cm - 1; lti nmr (80 MHz, CDCI3) 6: 0.20 (s, 9H, -SnMe.3, J S n . H " 5 3 Hz), 1.20-2.40 (m, 10H), 2.85 (m, 2H), 3.68 (s, 3H, -OCH3), 3.72 (s, 3H, - 227 --0CH3), 5.87 ( t , 1H, H b, J - 4 Hz), 5.97 ( t , 1H, H a, J - 1.1 Hz). Exact  Mass ca l c d . f o r C 1 8H 260 7SF 3Sn (M+'CH^: 563.0373; found: 563.0383. Following general procedure 7, the enol t r i f l a t e (132) (110 mg, 0.191 mmol) was converted into the diene (140), using THF as solvent, i n 3.5 h. Flash chromatography of the crude o i l on s i l i c a g e l (18 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a -t i o n of the r e s u l t i n g o i l (air-bath temperature 118-122"C/0.6 To r r ) , provided 45 mg (90%) of the diene (140) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1710, 1615 cm"1; XH nmr (400 MHz, CDC13) 6: 1.35-1.50 (m, 4H), 1.66 (m, 1H), 1.77 (m, 1H), 2.01 (d of d of d of t, 1H, Hp, J - 2.5, 2.5, 5.5, 13.5 Hz), 2.14 (m, 2H, H e and H f), 2.20 (d of d, 1H, J - 5, 11 Hz), 2.30 (m, 1H), 3.65 (s, 3H, -0CH3), 3.69 (s, 3H, -OCH3), 3.82 (br d, 1H, H q, J - 13.5 Hz), 5.85 (d, 1H, H c, J - 2 Hz), 5.96 ( t , 1H, H d, J - 4 Hz). I r r a d i a t i o n at 6 5.85 (H c): s i g n a l at 5 2.01 (Hp) s i m p l i f i e d to a d of d of t (J - 2.5, 5.5, 13.5 Hz). I r r a d i a t i o n at 6 5.96 (H d): m u l t i p l e t at 6 2.14 (H e and Hf) s i m p l i f i e d . In a d i f f e r e n c e nuclear Overhauser enhancement (nOe) experiment, i r r a d i a t i o n at 6 5.96 (H d) caused s i g n a l enhancement at S 5.85 (H c). Exact Mass ca l c d . f o r C15H20P4: 264.1362; found: 264.1362. - 228 -Preparation of the Diene (137) 129 R=C02Me 137 Following general procedure 7, and employing 1.1 equiv of LDA and 1.17 equiv of Tf 2NPh, the 0-keto ester (116) (300 mg, 0.697 mmol) was converted Into the enol t r i f l a t e (129). Flash chromatography of the crude product mixture on s i l i c a gel (40 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1) and concentration of the appropriate f r a c -tions provided 251 mg (64%) of the enol t r i f l a t e (129) as a colourless o i l . This material exhibited i r ( f i l m ) : 1739, 1703, 1645, 1600, 1422, 1215, 770 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.20 (s, 9H, -SnMe.3, J S n . H -55 Hz), 1.20-2.75 (m, 10H), 3.74 (s, 6H, both -OCH3), 5.76 (m, 1H, H b), 6.35 ( t , 1H, H a, I - 1 Hz, lsn-H " 1 1 8 H z>• Exact Mass calcd. f o r c 1 7 H 2 4 ° 7 S F 3 S n (M +-CH 3): 549.0216; found: 549.0215. Following general procedure 7, the enol t r i f l a t e (129) (125 mg, 0.222 mmol) was converted Into the diene (137), using THF as solvent, i n 19 h. Flash chromatography of the crude o i l on s i l i c a gel (27 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 114-117°C/0.6 T o r r ) , provided 42 mg (75%) of the diene (137) as a colourless o i l . This material exhibited i r ( f i l m ) : 1725, 1630 cm"1; XH nmr (400 MHz, CDCI3) 6: 1.45 (d of t, 1H, - 229 -H i t J - 4, 13.5 Hz), 1.69 ( t of q, 1H, H m, J - 4, 13.5 Hz), 1.77-1.90 (m, 2H, H g and H k), 2.19 (d of d of t, 1H, R^, J - 2, 5, 13.5 Hz), 2.33 (br d, 1H, Hj, J - 13.5 Hz), 2.38-2.49 (m, 3H, H f, H h and H D), 2.63 (d of d of d of d, 1H, H e, J. - 2.5, 8.5, 8.5, 17.5 Hz), 3.63 (s, 3H, -0CH 3), 3.66 (s, 3H, -OCH/j), 5.68 (d, 1H, H e, £ - 2 Hz), 6.10 ( t , 1H, H d, J - 2.5 Hz). I r r a d i a t i o n at S 5.68 ( H c ) : s i g n a l at S 2.19 (H n) s i m p l i f i e d to a d of t (2 - 5, 13.5 Hz). I r r a d i a t i o n at S 6.10 ( H d ) : m u l t i p l e t at S 2.38-2.49 s i m p l i f i e d , s i g n a l at 6 2.63 (H e) s i m p l i f i e d to a d of d of d (J - 8.5, 8.5, 17.5 Hz). Exact Mass calcd. f o r Ci^H^O^. 250.1205; found: 250.1207. Preparation of the Diene (138) Following general procedure 7, and employing 1.1 equiv of LDA and 1.17 equiv of Tf2NPh, the £-keto ester (117) (220 mg, 0.495 mmol) was converted into the enol t r i f l a t e (130). Flash chromatography of the crude product mixture on s i l i c a gel (50 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1) and concentration of the appropriate f r a c -tions provided 194 mg (64%) of the enol t r i f l a t e (130) as a colourless - 230 -o i l . This material exhibited i r ( f i l m ) : 1738, 1707, 1601, 1415, 1220, 1150, 779 cm - 1; XH nmr (80 MHz, CDC13) fi: 0.19 (s, 9H, -SnMe3, J S n - H " 54 Hz), 1.20-2.55 (m, 12H), 3.73 (s, 3H, -OCH3), 3.74 (s, 3H, -OCH3), 5.87 ( t , 1H, H b, J - 4 Hz), 6.34 ( t , 1H, H a, J - 1 Hz, J S n - H " 1 1 7 H z>• Exact Mass ca l c d . f o r C 1 8H 2607SF 3Sn (M^-C^): 563.0373; found: 563.0374. Following general procedure 7, the enol t r i f l a t e (130) (150 mg, 0.260 mmol) was converted into the diene (138), using THF as solvent, i n 16 h. Flash chromatography of the crude o i l on s i l i c a gel (27 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 116-118°C/0.6 T o r r ) , provided 52 mg (75%) of the diene (138) as a colourless o i l . This material exhibited i r ( f i l m ) : 1728, 1633 cm'1; XH nmr (400 MHz, CDCI3) fi: 1.40-1.68 (m, 5H), 1.79 (m, 1H, Hn), 2.10 (d of d of d of d, 1H, H e or H f, J - 3, 6, 9.5, 18.5 Hz), 2.15-2.26 (m, 3H, includes H e or H f and H p), 2.30 (m, 1H, H q a n d H m ) , 3.63 (s, 3H, -OCH3), 3.66 (s, 3H, -OCH3), 5.60 (d, 1H, H c, J -2 Hz), 5.99 (d of d, 1H, H d, J - 3, 4 Hz). I r r a d i a t i o n at 5 1.79 (H n): mu l t i p l e t at fi 1.40-1.68 s i m p l i f i e d , m u l t i p l e t at 5 2.15-2.26 s i m p l i f i e d , m u l t i p l e t at fi 2.30 s i m p l i f i e d . I r r a d i a t i o n at fi 5.60 (H c): mu l t i p l e t at fi 2.15-2.26 s i m p l i f i e d . I r r a d i a t i o n at fi 5.99 (H d ) : s i g n a l at fi 2.10 (H e or H f) s i m p l i f i e d to a d of d of d (J_ - 6, 9.5, 18.5 Hz). Exact Mass ca l c d . f o r C 1 5 H 2 o 0 4 : 264.1362; found: 264.1364. - 231 -Preparation of the Diene (143) H 9 H H n 'hi n ' r C 0 2 M e J H H k H f m 135 143 Following general procedure 7, and employing 1.5 equiv of LDA and 1.57 equiv of Tf 2NPh, the 0-keto ester (122) (700 mg, 1.57 mmol) was converted into the enol t r i f l a t e (135). Flash chromatography of the crude product mixture on s i l i c a gel (120 g, e l u t i o n with petroleum ether-ethyl acetate, 8:1) and concentration of the appropriate f r a c t i o n s provided 798 mg (88%) of the enol t r i f l a t e (135) as a colourless o i l . This material exhibited i r ( f i l m ) : 1732, 1643, 1420, 1210, 770 cm-1; AH nmr (80 MHz, CDC13) 5: 0.10 (s, 9H, -SnMe.3, J S n . H - 52 Hz), 1.20-2.70 (m, 10H), 3.35 (s, 3H, -CH2OCH3), 3.68 (s, 3H, -COOCH.3), 4.10 (d, 2H, -CCH20-, J - 6 Hz), 4.61 (s, 2H, -0CH 20-), 5.73 (m, 2H, H a and H b). Exact Mass c a l c d . f o r C 1 8 H 2 8 ° 7 S F 3 S n ( M 4 - - ^ ) : 565.0529; found: 565.0520. Following general procedure 7, the enol t r i f l a t e (135) (87 mg, 0.150 mmol) was converted into the diene (143), using THF as solvent, i n 6 h. Flash chromatography of the crude o i l on s i l i c a g e l (18 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 105-110°C/0.6 To r r ) , provided 33 mg (83%) of the diene (143) as a colourless o i l . This material exhibited i r - 232 -( f i l m ) : 1720, 1640 cm'1; XH nmr (400 MHz, CDC13) 6: 1.35 (d of t, 1H, I - 3.5, 13 Hz), 1.48 (d of d of q, 1H, 1^, J_ - 3, 3.5, 13 Hz), 1.72-1.93 (m, 3H), 2.30-2.45 (m, 3H), 2.49 (br d, 1H, H 0, J - 13 Hz), 2.62 (br d, 1H, H j , 1-13 Hz), 3.38 (s, 3H, -OCH3), 3.65 (s, 3H, -C00CE 3), 4.13 (m, 2H, -CCH 20-), 4.62 and 4.65 (AB quartet, 1H each, -0CH.20-, J - 6 Hz each), 5.73 (d of t, 1H, H c, J - 2.5, 7 Hz), 5.84 ( t , 1H, H d, J - 2.5 Hz). Exact Mass calcd. f o r C 1 5H 2 204: 266.1519; found: 266.1524. Preparation of the Diene (144) R=CH 2 0CH 2 0CH 3 Following general procedure 7, and employing 1.5 equiv of LDA and 1.57 equiv of Tf 2NPh, the 0-keto ester (123) (1.01 g, 2.19 mmol) was converted Into the enol t r i f l a t e (136). Flash chromatography of the crude product mixture on s i l i c a g el (180 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1) and concentration of the appropriate fr a c -t ions provided 1.19 g (92%) of the enol t r i f l a t e (136) as a colourless o i l . This material exhibited i r ( f i l m ) : 1732, 1420, 1210, 770 cm"1; XH nmr (80 MHz, CDCI3) 6: 0.14 (s, 9H, -SnMe3, J S n . H - 53 Hz), 1.20-2.45 - 233 -(m, 12H), 3.38 (s, 3H, -CH 20CH 3), 3.73 (s, 3H, -C00CH 3), 4.13 (d, 2H, -CCH20-, I - 6 Hz), 4.64 (s, 2H, -0CH 20-), 5.74 (br t, 1H, H a, J - 6 Hz, J S n . H - 76 Hz), 5.87 ( t , 1H, H b, J - 4 Hz). Exact Mass calcd. f o r C 1 9 H 3 0 O 7 S F 3 S n (M+-CH5): 579.0686; found: 579.0670. Following general procedure 7, the enol t r i f l a t e (136) (660 mg, 1.11 mmol) was converted into the diene (144), using THF as solvent, i n 15 h. Flash chromatography of the crude o i l on s i l i c a gel (120 g, e l u t i o n with petroleum ether-ethyl acetate, 12:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l ( a i r - b a t h temperature 120-124°C/0.6 To r r ) , provided 262 mg (84%) of the diene (144) as a colourless o i l . This material exhibited i r ( f i l m ) : 1721, 1640 cm"1; XH nmr (400 MHz, CDC13) 6: 1.30-1.50 (m, 4H), 1.62 (m, 1H), 1.73 (m, 1H), 1.86 (br t, 1H, Hp, J - 12 Hz), 2.11 (m, 3H, includes H e and H f), 2.33 (br d, 1H, J - 12 Hz), 2.65 (br d, 1H, J - 14 Hz), 3.37 (s, 3H, -CH 20CH 3), 3.65 (s, 3H, -C00CH 3), 4.09 (d of d, 1H, one of -CCH20-, J - 7, 12 Hz), 4.14 (d of d, 1H, one of -CCH20-, J - 7, 12 Hz), 4.61 and 4.64 (AB quartet, 1H each, -0CH20-, J - 6 Hz each), 5.57 (d of t, 1H, H c, J - 2.4, 7 Hz), 5.82 ( t , 1H, H d, J - 4 Hz). I r r a d i a t i o n at S 5.57 (H c): s i g n a l at S 1.86 (Hp) s i m p l i f i e d to a br d of d (J - 5, 13 Hz). I r r a d i a t i o n at 6 5.82 (H d): m u l t i p l e t at 5 2.11 (includes H e and Hf) s i m p l i f i e d . In a di f f e r e n c e nuclear Overhauser enhancement (nOe) experiment, i r r a d i a t i o n at 6 5.82 (H d) caused s i g n a l enhancement at 6 5.57 (H c). Exact Mass calcd. f o r C^gH^O^.: 280.1675; found: 280.1679. - 234 -Preparation of the Diene (141) 133 141 Following general procedure 7, and employing 1.5 equiv of LDA and 1.57 equiv of Tf 2NPh, the /3-keto ester (120) (700 mg, 1.57 mmol) was converted into the enol t r i f l a t e (133). Flash chromatography of the crude product mixture on s i l i c a gel (90 g, e l u t i o n with petroleum ether-ethyl acetate, 8:1) and concentration of the appropriate f r a c t i o n s provided 766 mg (84%) of the enol t r i f l a t e (133) as a colourless o i l . This material exhibited i r ( f i l m ) : 1739, 1650, 1422, 1218, 1147, 778 cm"1; 1H nmr (80 MHz, CDC13) 6: 0.18 (s, 9H, -SnMe.3, J S n - H " 5 3 H z>' 1.10-2.70 (m, 10H), 3.36 (s, 3H, -CH 20CH 3), 3.71 (s, 3H, -COOCH3), 4.00 (d, 2H, -CCH20-, J - 6 Hz), 4.62 (s, 2H, -0CH 20-), 5.75 (br s, 1H, H b, 21/2 ~ 4 H z ) > 6 - 1 3 < b r t> 1 H> H a, J - 6 Hz, J.Sn-H ~ 1 3 2 H z ) • Exact Mass cal c d . f o r C 1 8 H 2 8 0 7 S F 3 S n (M+-CH3): 565.0529; found: 565.0525. Following general procedure 7, the enol t r i f l a t e (133) (230 mg, 0.397 mmol) was converted Into the diene (141), using THF as solvent, i n 2 h. Flash chromatography of the crude o i l on s i l i c a gel (40 g, e l u t i o n with petroleum ether-ethyl acetate, 7:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 99-105°C/0.6 T o r r ) , provided 91 mg (86%) of the diene (141) as a colourless o i l . This material exhibited i r - 235 -( f i l m ) : 1724, 1640 cm'1; *H nmr (400 MHz, CDC1 3) 6: 1.32 (d of t, 1H, H i ( J - 3.4, 13 Hz), 1.46 (d of d of q, 1H, 1^, J - 3, 3.9, 13 Hz), 1.68 (m, 1H, H k), 1.77 (d of t, 1H, H g, J - 13.3, 9.5 Hz), 2.04 (br t, 1H, Hn, J . - 1 3 Hz), 2.19-2.28 (m, 2H), 2.33 (d of d of t, 1H, H e or H f, J -9.5, 16.5, 2.3 Hz), 2.40-2.53 (m, 2H, includes H f or H e), 3.31 (s, 3H, -CH 20CH 3), 3.57 (s, 3H, -COOCH3), 4.10 (d of d of d, 1H, one of -CCH20-, J_ - 2.4, 6, 12 Hz), 4.17 (d of d of d, 1H, one of -CCH20-, J - 1.2, 7.5, 12 Hz), 4.58 and 4.60 (AB quartet, 1H each, -0CH20-, J - 7 Hz each), 5.43 (d of d of d, 1H, H c, J - 2, 6, 7.5 Hz), 5.60 ( t , 1H, H d, J - 2.3 Hz). I r r a d i a t i o n at 6 5.43 (H c): m u l t i p l e t at 6 2.04 (H n) s i m p l i f i e d , s i g n a l at S 4.10 (one of -CCH20-) s i m p l i f i e d to a d of d (J - 2.4 12 Hz), s i g n a l at S 4.17 (one of =CCH20-) s i m p l i f i e d to a d of d, J - 1.2, 12 Hz). I r r a d i a t i o n at 6 5.60 (H d): s i g n a l at 6 2.33 (H e or H f) s i m p l i f i e d to a d of d of d (J - 2.3, 9.5, 16.5 Hz), m u l t i p l e t at S 2.40-2.53 (includes Hf or H e) s i m p l i f i e d . In a differ e n c e nuclear Overhauser enhancement (nOe) experiment, i r r a d i a t i o n at S 5.60 (H d) caused s i g n a l enhancement at S 4.10 and S 4.17 (=CCH20-). Exact Mass calcd. f o r C 1 5 H 2 2 0 4 : 266.1518; found: 266.1517. - 236 -Preparation of the Diene (142) 134 R = C H 2 O C H 2 O C H 3 142 Following general procedure 7, and employing 1.5 equiv of LDA and 1.57 equiv of Tf 2NPh, the 0-keto ester (121) (820 mg, 1.78 mmol) was converted into the enol t r i f l a t e (134). Flash chromatography of the crude product mixture on s i l i c a gel (100 g, e l u t i o n with petroleum ether-ethyl acetate, 8:1) and concentration of the appropriate f r a c t i o n s provided 950 mg (90%) of the enol t r i f l a t e (134) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1736, 1675, 1418, 1219, 776 cm"1; lE nmr (80 MHz, CDCI3) 6: 0.17 (s, 9H, -SnMe.3, J S n . H - 53 Hz), 1.10-2.50 (m, 12H), 3.36 (s, 3H, -CH 20CH 3), 3.71 (s, 3H, -COOCH3), 3.98 (d, 2H, -CCH20-, J - 6 Hz), 4.60 (s, 2H, -0CH 20-), 5.85 ( t , 1H, H b, J - 4 Hz), 6.13 (br t, 1H, H a, J - 6 Hz, J.sn-H " 1 3 2 H z>- Exact Mass calcd. f o r c 1 9 H 3 0 ° 7 S F 3 S n (M +-CH 3): 579.0686; found: 579.0678. Following general procedure 7, the enol t r i f l a t e (134) (190 mg, 0.321 mmol) was converted into the diene (142), using THF as solvent, i n 2 h. Flash chromatography of the crude o i l on s i l i c a gel (40 g, e l u t i o n with petroleum ether-ethyl acetate, 7:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 108-lll°C/0.6 T o r r ) , provided 78 mg (87%) of the diene (142) as a colourless o i l . This material exhibited i r - 237 -( f i l m ) : 1726, 1645 cm"1; XH nmr (400 MHz, CDC1 3) 6: 1.36-1.59 (m, 4H), 1.61 (m, 1H), 1.72 (m, 1H), 2.00-2.20 (m, 4H, includes H e, H f and Hp), 2.26 (m, 1H), 2.35 (m, 1H), 3.39 (s, 3H, -CH 20CH 3), 3.63 (s, 3H, -COOCH3), 4.19 (d of d of d, 1H, one of -CCH20-, J - 2.3, 6, 12 Hz), 4.21 (d of d of d, 1H, one of -CCH20-, 1 - 1:2, 7.3, 12 Hz), 4.65 and 4.68 (AB quartet, 1H each, -0CH20-, J - 6.5 Hz each), 5.39 (d of d of d, 1H, H c, 1 - 2 , 6, 7.3 Hz), 5.59 (d of d of d, 1H, H d, 1 - 3 , 4.6 Hz). I r r a d i a t i o n at 6 5.39 (H c): m u l t i p l e t at 6* 2.00-2.20 (includes H p) s i m p l i f i e d , s i g n a l at 6 4.19 (one of -CCH20-) s i m p l i f i e d to a d of d (J - 2.3, 12 Hz), s i g n a l at 6 4.21 (one of -CCH20-) s i m p l i f i e d to a d of d (J - 1.2, 12 Hz). I r r a d i a t i o n at 8 5.59 (H d): m u l t i p l e t at 8 2.00-2.20 (includes H e and Hf) s i m p l i f i e d . In a differe n c e nuclear Overhauser enhancement (nOe) experiment, i r r a d i a t i o n at 8 5.59 (H d) caused s i g n a l enhancement at 5 4.19 and 8 4.21 (=CCH20-). Exact Mass calcd. f o r C 1 6 H 2 4 ° 4 : 280.1675; found: 280.1666. Preparation of the Diene (167) 163 167 Following general procedure 7, and employing 1.5 equiv of LDA and - 238 -1.57 equiv of Tf 2NPh, the fl-keto ester (157) (110 mg, 0.284 mmol) was converted into the enol t r i f l a t e (163). Flash chromatography of the crude product mixture on s i l i c a g el (18 g, e l u t i o n with petroleum ether-ethyl acetate, 20:1) and concentration of the appropriate f r a c -tions provided 117 mg (87%) of the enol t r i f l a t e (163) as a colourless o i l . This material exhibited i r ( f i l m ) : 1732, 1422, 1207, 1142, 770 cm - 1; XH nmr (80 MHz, CDC13) 6: 0.18 (s, 9H, -SnMe.3, J_sn-H " 5 2 H z ) > 0.94 (d, 6H, -CHMe2, J - 7 Hz), 1.75-2.75 (m, 7H), 3.71 (s, 3H, -COOCH3), 5.65-5.85 (m, 2H, H a and H b). Exact Mass calcd. f o r C 1 6 H 2 4 0 5 S F 3 S n (M+-CH3): 505.0318; found: 505.0318. Following general procedure 7, the enol t r i f l a t e (163) (90 mg, 0.174 mmol) was converted into the diene (167), using THF as solvent, In 45 min. Flash chromatography of the crude o i l on s i l i c a gel (15 g, e l u t i o n with petroleum ether-ethyl acetate, 20:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 52-55°C/0.1 To r r ) , provided 30 mg (84%) of the diene (167) as a colourless o i l . This material exhibited i r ( f i l m ) : 1735, 1390, 1370, 805 cm"1; XH nmr (400 MHz, CDCI3) 6: 1.10 (d, 3H, -CHCH3, J - 7 Hz), 1.14 (d, 3H, -CHCH3, J - 7 Hz), 1.85 (d of d of d, 1H, H f, J - 8.2, 10, 12.5 Hz), 2.19 (br d, 1H, H h, J - 16 Hz), 2.39 (d of d, 1H, H g, J - 6, 12.5 Hz), 2.54 (m, 1H, -CHMe2), 2.60 (d of d of d, 1H, H d, J - 3.5, 8.2, 16 Hz), 2.83 (d of d of d, 1H, H 1 p J - 0.9, 2.5, 16 Hz), 2.93 (m, 1H, H e), 3.63 (s, 3H, -OCH3), 5.50 (br s, 1H, H c, W]y 2 - 7 Hz), 5.76 (br s, 1H, Hj, w 1 / 2 - 6 Hz). I r r a d i a t i o n at S 1.85 (H c): s i g n a l at S 2.39 (H g) s i m p l i f i e d to a d (J - 6 Hz), s i g n a l at 6 2.60 (H d) s i m p l i f i e d to a d of d (J - 3.5, 16 Hz), m u l t i p l e t at 6 2.93 (H e) s i m p l i f i e d . I r r a d i a t i o n at 6 2.19 (H n): - 239 -m u l t i p l e t at fi 2.54 (-CHMe2) s i m p l i f i e d to a br septet (J - 7 Hz), s i g n a l at fi 2.83 (%) s i m p l i f i e d to a d of d (J - 0.9, 2.5 Hz). I r r a d i a t i o n at fi 2.39 (H g): s i g n a l at fi 1.85 (H f) s i m p l i f i e d to a d of d (J - 8.2, 10 Hz), s i g n a l at fi 2.93 (H e) s i m p l i f i e d to a br d of d (J -10, 16 Hz). I r r a d i a t i o n at fi 2.83 ( H ^ : s i g n a l at fi 2.19 (H h) s i m p l i f i e d to a br s, br s at fi 5.76 (Hj) sharpened. I r r a d i a t i o n at fi 2.93 ( H e ) : s i g n a l at fi 1.85 (H f) s i m p l i f i e d to a d of d (J - 8.2, 12.5 Hz), s i g n a l at fi 2.39 (H g) s i m p l i f i e d to a d (J - 12.5 Hz), s i g n a l at fi 2.60 (H d) s i m p l i f i e d to a d of d (J - 3.5, 8.2Hz), s i g n a l at 5 5.50 (Hi) s i m p l i f i e d to a br d (J - 3.5 Hz). I r r a d i a t i o n at 8 5.50 (H c): s i g n a l at 5 2.60 (H d) s i m p l i f i e d to a d of d (J - 8.2, 16 Hz), s i g n a l at fi 2.93 (H e) s i m p l i f i e d to a br d o f d of d (J - 6, 10, 16 Hz). I r r a d i a -t i o n at fi 5.76 (Hj): br d at fi 2.19 (H h) sharpened, s i g n a l at fi 2.83 (Hi) s i m p l i f i e d to a br d (J - 16 Hz). Exact Mass calcd. f o r C i 3 H i g 0 2 : 206.1307; found: 206.1306. Preparation of the Diene (168) H; H, 9 C 0 2 M e 164 168 Following general procedure 7, and employing 1.5 equiv of LDA and - 240 -1.57 equiv of Tf2NPh, the 0-keto ester (158) (263 mg, 0.656 mmol) was converted i n t o the enol t r i f l a t e (164). Flash chromatography of the crude product mixture on s i l i c a g el (40 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) and concentration of the appropriate f r a c -tions provided 294 mg (84%) of the enol t r i f l a t e (164) as a colourless o i l . This material exhibited i r ( f i l m ) : 1732, 1416, 1215, 1145, 773 cm - 1; lH nmr (80 MHz, CDC13) 8: 0.20 (s, 9H, -SnMe3, 2sn-H " 5 2 H z > » 0.95 (d, 6H, -CHMe2, 1 - 7 Hz), 1.45-1.80 (m, 3H), 2.00-2.65 (m, 6H), 3.73 (s, 3H, -OCH3), 5.75-5.95 (m, 2H, H a and H D). Exact Mass calcd. fo r C 1 7 H 2 6 0 5 S F 3 S n (M" 1"-^): 519.0475; found: 519.0475. Following general procedure 7, the enol t r i f l a t e (164) (269 mg, 0.504 mmol) was converted into the diene (168), using THF as solvent, i n 3 h. Flash chromatography of the crude o i l on s i l i c a g el (30 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 69-73°C/0.6 T o r r ) , provided 92 mg (83%) of the diene (168) as a colourless o i l . This material exhibited i r ( f i l m ) : 1722, 1385, 810 cm*1; XH nmr (400 MHz, CDCI3) 8: 1.09 (d, 3H, -CHCH3, J - 7 Hz), 1.14 (d, 3H, -CHCH3, J - 7 Hz), 1.43-1.55 (m, 2H, H g and H h), 1.75 (m, 1H, H f), 2.10 (m, 1H, H d or H e), 2.24 (m, 1H, H e or H d), 2.34 (br d, 1H, H f, 1 - 1 6 Hz), 2.42 (m, 1H, Hi ) , 2.52 (br septet, 1H, -CHMe2, 2 - 7 Hz), 2.73 (d of d, 1H, H k, 2 -2.5, 16 Hz), 3.63 (s, 3H, -OCH.3), 5.48 (br s, 1H, H,,,, w 1 / 2 - 6 Hz), 5.56 (t , 1H, H c, 2 - 3.8 Hz). I r r a d i a t i o n at S 5.48 (H,^: s i g n a l at 6 2.34 (Hj) s i m p l i f i e d to a d of d (2 - 2, 16 Hz), s i g n a l at 8 2.52 (-CHMe2) s i m p l i f i e d to a d of septets ( 2 - 2 , 7 Hz), s i g n a l a t 6 2.73 (H k) s i m p l i f i e d to a d (2 - 16 Hz). I r r a d i a t i o n at 6 5.56 (H c ) : s i g n a l at 6 - 241 -2.10 ( H d or H e) s i m p l i f i e d to a br d of t (J - 18, 8 Hz), s i g n a l at S 2.24 (H e or H d) s i m p l i f i e d to a br d of d (J - 5, 18 Hz). Exact Mass calcd. f o r C 1 4H 2 0O2: 220.1464; found: 220.1456. Preparation of the Diene (169) Following general procedure 7, and employing 1.5 equiv of LDA and 1.57 equiv of Tf 2NPh, the 0-keto ester (159) (323 mg, 0.779 mmol) was converted into the enol t r i f l a t e (165). Flash chromatography of the crude product mixture on s i l i c a gel (50 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1) and concentration of the appropriate f r a c -tions provided 352 mg (82%) of the enol t r i f l a t e (165) as a colourless o i l . This material exhibited i r ( f i l m ) : 1735, 1418, 1220, 776 c m 4 ; XH nmr (80 MHz, CDC1 3) 6: 0.21 (s, 9H, -SnMe3, J S n - H " 5 2 Hz), ° - 9 6 ( d. 6H, -CHMe2, J - 7 Hz), 1.10-2.85 (m, 11H), 3.74 (s, 3H, -OCH3), 5.89 (br t, 1H, H a, J - 7 Hz, J S n . H - 13 2 Hz), 6.03 ( t , 1H, H b, J - 6 Hz). Exact  Mass calcd. f o r C 1 8 H 2 8 0 5 S F 3 S n (M+-CH3): 533.0631; found: 533.0647. Following general procedure 7, the enol t r i f l a t e (165) (243 mg, 0.444 mmol) was converted into the diene (169), using THF as solvent, i n 30 9 165 169 - 242 -min. Flash chromatography of the crude o i l on s i l i c a g el (30 g, e l u t i o n with petroleum ether-ethyl acetate, 25:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 65-69°C/0.1 T o r r ) , provided 84 mg (81%) of the diene (169) as a colourless o i l . This material exhibited i r ( f i l m ) : 1723, 1385, 832 cm"1; AH nmr (400 MHz, CDC1 3) 6: 1.08 (d, 3H, -CHCH3, I - 6.9 Hz), 1.10 (d, 3H, -CHCH3, J - 6.9 Hz), 1.34 (br q, 1H, J - 12 Hz), 1.54 (d of t, 1H, J - 2.8, 13 Hz), 1.60-1.79 (m, 2H), 1.89 (m, 1H), 2.05-2.26 (m, 3H, includes H d and H e), 2.36-2.50 (m, 2H, -CHMe2 and H f), 2.76 (d of d, 1H, H g, J - 2.5, 17.5 Hz), 3.69 (s, 3H, -OCH3), 5.53 (br s, 1H, H h, w 1 / 2 " 6 H z ) • 5 - 7 9 < d o f d> 1 H » H c 1 ~ 5• 8.5 Hz). I r r a d i a t i o n at 6 2.76 (H g): mu l t i p l e t at 6 2.36-2.50 (includes H f) s i m p l i f i e d . I r r a d i a t i o n at 6 5.53 (H h): m u l t i p l e t at 5 2.36-2.50 (-CHMe2 and H f) s i m p l i f i e d , s i g n a l at 6 2.76 (H g) s i m p l i f i e d to a d (J -17.5 Hz). I r r a d i a t i o n at 6 5.79 (H c): m u l t i p l e t at S 2.05-2.26 (includes H d and H e) s i m p l i f i e d . Exact Mass calcd. f o r C 1 5 H 2 2 ° 2 : 234.1621; found: 234.1617. Preparation of the Diene (170) Following general procedure 7, and employing 1.5 equiv of LDA and e 166 170 - 243 -1.57 equiv of Tf2NPh, the fl-keto ester (160) (50 mg, 0.13 mmol) was converted into the enol t r i f l a t e (166). Flash chromatography of the crude product mixture on s i l i c a g el (15 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 30:1) and concentration of the appropriate f r a c -tions provided 57 mg (84%) of the enol t r i f l a t e (166) as a colourless o i l . This material exhibited i r ( f i l m ) : 1405, 1205, 1140, 768 cm - 1. Exact Mass c a l c d . f o r C 1 7H2g03SF3Sn (M +-CH 3): 489.0733; found: 489.0720. Following general procedure 7, the enol t r i f l a t e (166) (50 mg, 0.10 mmol) was converted into the diene (170), using THF as solvent, i n 5 min at room temperature. Flash chromatography of the crude o i l on s i l i c a gel (5 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 30:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 142-144°C/30 T o r r ) , provided 16 mg (85%) of the diene (170) as a colourless o i l . This material exhibited i r ( f i l m ) : 2890, 830 cm"1; XH nmr (400 MHz, CDC13) 5: 1.03 (d, 3H, -CHCH3, J - 7 Hz), 1.10 (d, 3H, -CHCH3, J - 7 Hz), 1.13 (s, 3H, -CCH3), 1.32 (br q, 1H, J - 12 Hz), 1.48-1.90 (m, 5H), 2.12 (d of d, 1H, H d or H e, J - 2.5, 17 Hz), 2.15-2.42 (m, 4H), 5.54 (d of d, 1H, H c, J - 3.5, 8.5 Hz), 5.57 (d, 1H, H f, J - 2.5 Hz). Exact  Mass c a l c d . f o r C 1 4H 22: 190.1721; found: 190.1721. - 244 -General Procedure 8: Preparation of B i c y c l i c Dienes i n a "One Pot"  Process from the Corresponding fl-Keto Esters or Ketones To a c o l d (-78°C), s t i r r e d s o l u t i o n of LDA (1.5 equiv) i n dry THF (=10 mL per mmol) was added HMPA (2 equiv). The r e s u l t i n g pale yellow s o l u t i o n was s t i r r e d f o r 10 min at -78°C, followed by 10 min at 0°C. A f t e r the s o l u t i o n had been recooled to -78°C, the appropriate ketone or 0-keto ester (1 equiv) was added dropwise as a s o l u t i o n In dry THF (=5 mL per mmol). The r e s u l t i n g mixture was s t i r r e d f o r 10 min at -78°C and then was warmed to 0°C and was s t i r r e d at t h i s temperature for 1 h. N-Phenyltrifluoromethanesulfonimide (Tf 2NPh) (1.57 equiv) was added as a s o l i d and the r e s u l t i n g yellow s o l u t i o n was s t i r r e d at room temperature f o r 30 min. Palladium tetrakis(triphenylphosphine) (Pd(Ph 3P)4) (3 mol %) or palladium acetate (3 mol %) was added as a s o l i d and the r e s u l t i n g s o l u t i o n was heated to the r e f l u x temperature. When the r e a c t i o n was determined to have reached completion (as indic a t e d by gl c and/or t i c a n a l y s i s ) , the s o l u t i o n was cooled to room temperature and then the solvent was removed by rotary evaporation. Column chromatography of the crude r e a c t i o n mixture on s i l i c a g e l , followed by concentration of the appropriate f r a c t i o n s and then d i s t i l l a t i o n (bulb-to-bulb) of the r e s i d u a l o i l provided the corresponding diene. - 245 -Preparation of the Diene (75) CO C0 2 Me Following general procedure 8, the 0-keto ester (58) (1.810 g, 4.681 mmol) was converted into the diene (75), employing Pd(Ph3P)4. The re a c t i o n mixture was refluxed f o r 5 h. Flash chromatography of the crude o i l on s i l i c a g el (180 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 20:1), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 75-78°C/0.8 T o r r ) , provided 693.8 mg (72%) of the diene (75) as a co l o u r l e s s o i l . This material was i d e n t i c a l with that reported previously ( i r , nmr, mass spectra). Preparation of the Diene (81) Following general procedure 8, the ketone (62) (390 mg, 1.14 mmol) was converted into the diene (81), employing Pd(Ph3P)4. The reaction - 246 -mixture was ref l u x e d f o r 30 min. Medium pressure chromatography of the crude o i l on s i l i c a g el (70 g, e l u t i o n with petroleum ether), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 50-70°C/15 T o r r ) , provided 101 mg (55%) of the diene (81) as a colo u r l e s s o i l : i r ( f i l m ) : 1628, 887, 817 cm"1; AH nmr (300 MHz, CDC1 3) 6: 0.98 (s, 3H, -CCH.3), 1.25-2.15 (m, 11H), 2.35 (d of quintets, 1H, 1 - 1 2 , 2 Hz), 4.58 (t , 1H, H a, J. - 2.5 Hz), 4.74 ( t , 1H, H b, J - 2.5 Hz), 5.56 (d of d, 1H, H c, J - 3, 4.5 Hz). Exact Mass calcd. f o r C 1 2 H 1 8 : 162.1409; found: 162.1402. Preparation of the Diene (143) Following general procedure 8, the /?-keto ester (122) (300 mg, 0.672 mmol) was converted into the diene (143), employing PdCPl^P)^. The r e a c t i o n mixture was refluxed f o r 30 min. Flash chromatography of the crude o i l on s i l i c a gel (50 g, e l u t i o n with petroleum ether-ethyl acetate, 8:1), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 86-90°C/0.1 To r r ) , provided 151 mg (84%) of the diene (143) as a c o l o u r l e s s o i l . This material was i d e n t i c a l with that reported previously ( i r , AH nmr, mass spectra). C 0 2 Me - 247 -Preparation of the Diene (141) i C0 2Me Following general procedure 8, the /J-keto ester (120) (300 mg, 0.672 mmol) was converted into the diene (141), employing Pd(Ph3P)4. The re a c t i o n mixture was refluxed f o r 30 min. Flash chromatography of the crude o i l on s i l i c a g el (50 g, e l u t i o n with petroleum ether-ethyl acetate, 8:1), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 99-105°C/0.6 T o r r ) , provided 131 mg (73%) of the diene (141) as a colo u r l e s s o i l . This material was i d e n t i c a l with that reported pre v i o u s l y ( i r , LH nmr, mass spectra). Preparation of the Diene (146) C0 2Me Following general procedure 8, the B-keto ester (125) (500 mg, 0.941 mmol) was converted into the diene (146), employing Pd(Ph3P) 4. The - 248 -re a c t i o n mixture was refluxed f o r 3 h. Flash chromatography of the crude o i l on s i l i c a g el (90 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 15:1), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 135-145°C/0.03 To r r ) , provided 200 mg (61%) of the diene (146) as a colou r l e s s o i l . In an i d e n t i c a l experiment, employing Pd(0Ac) 2 i n place of Pd(Ph 3P)4, 1.15 g (2.17 mmol) of the fl-keto ester (125) was converted into 381 mg (50%) of the diene (146). This material exhibited i r ( f i l m ) : 1729, 1650, 835, 776 cm - 1; lH nmr (400 MHz, CDC13) 6: 0.06 (s, 6H, -SiMe 2), 0.90 (s, 9H, -SiCMe.3) , 1.29-1.48 (m, 4H), 1.58-1.87 (m, 3H), 2.05-2.14 (m, 3H), 2.32 (m, 1H), 2.55 (br d, 1H, J -13 Hz), 3.63 (s, 3H, -OCH3), 4.18 (d of d of d, 1H, one of =CCH20-, J -1, 6.5, 13 Hz), 4.26 (d of d of d, 1H, one of -CCH20-, J - 1, 6.5, 13 Hz), 5.53 (d of t, 1H, H a, J - 2, 6.5 Hz), 5.78 ( t , 1H, H b, J - 3.8 Hz). Exact Mass calcd. f o r C 2 0 H 3 4 0 3 S i : 350.2278; found: 350.2274. Preparation of the Diene (145) C0 2Me Following general procedure 8, the fl-keto ester (124) (500 mg, 0.941 mmol) was converted into the diene (145), employing Pd(Ph3P)4. The re a c t i o n mixture was refluxed f o r 14 h. Flash chromatography of the - 249 -crude o i l on s i l i c a g e l (90 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 20:1), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 140-150°C/0.03 T o r r ) , provided 215 mg (65%) of the diene (145) as a col o u r l e s s o i l . In an i d e n t i c a l experiment, employing Pd(0Ac) 2 i n place of Pd(Ph 3P)4, 2.04 g (3.84 mmol) of the fl-keto ester (124) was converted into 820 mg (61%) of the diene (145). This material exhibited i r ( f i l m ) : 1731, 1650, 837, 776 cm"1; *H nmr (400 MHz, CDC13) 6: 0.07 and 0.08 (s, s, 3H each, -SiMe 2), 0.92 (s, 9H, -SiCMe.3), 1.31-1.76 (m, 6H), 2.01-2.38 (m, 6H), 3.63 (s, 3H, -OCH3), 4.26 and 4.27 (d, d, 1H each, -CCH20-, J - 6.5 Hz each), 5.35 (d of t, 1H, H a, J = 1.9, 6.5 Hz), 5.60 (br t, 1H, H b, J - 3.8 Hz). Exact Mass calcd. f o r c 2 0 H 3 4 ° 3 s i : 350.2278; found: 350.2276. Preparation of the Diene (147) Following general procedure 8, the fl-keto ester (126) (2.232 g, 5.38 mmol) was converted into the diene (147), employing Pd^lvjP)^. The re a c t i o n mixture was refluxed f o r 3.5 h. Flash chromatography of the crude o i l on s i l i c a g el (240 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 15:1), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath - 250 -temperature 70-80°C/0.03 T o r r ) , provided 764.2 mg (61%) of the diene (147) as a c o l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1726, 1649, 813 cm'1; XH nmr (400 MHz, CDC1 3) 6: 0.96 ( t , 3H, -CH2CH.3, J - 7 Hz), 1.24-1.83 (m, 7H), 1.94-2.13 (m, 5H), 2.31 (br d, 1H, J - 12 Hz), 2.59 (br d, 1H, 2 - 1 2 Hz), 3.64 (s, 3H, -OCH3), 5.41 (d of t, 1H, H a, J - 2, 7 Hz), 5.73 ( t , 1H, H b, 2 - 4 Hz). Exact Mass calcd. f o r C 1 5H 2 202: 234.1620; found: 234.1618. Preparation of the Diene (152) To a s t i r r e d s o l u t i o n of the diene (145) (215 mg, 0.613 mmol) i n dry THF (10 mL) at room temperature was added, dropwise, a s o l u t i o n of tetra-n-butylammonium f l u o r i d e i n THF (1.23 mL of a 1 M s o l u t i o n , 2 equiv). The r e s u l t i n g mixture was s t i r r e d f o r 3 h and then was poured in t o water (25 mL). The organic phase was removed and the aqueous phase was extracted with d i e t h y l ether (2 x 25 mL). The combined organic s o l u t i o n was d r i e d (MgSO^ and then was concentrated. The r e s i d u a l o i l was d i s s o l v e d i n dry methylene chloride (20 mL) and to the r e s u l t i n g s t i r r e d s o l u t i o n was added sequentially triethylamine (1.53 mL, 2 C0,Me - 251 -equiv), 4-N,N_-dimethylaminopyridine (7 mg, 0.1 equiv) and p.-nitrobenzoyl c h l o r i d e (153 mg, 1.5 equiv). The r e s u l t i n g mixture was s t i r r e d f o r 15 min at room temperature and then was poured into water (25 mL). The organic phase was removed and the aqueous phase was extracted with methylene c h l o r i d e (2 x 25 mL). The combined organic s o l u t i o n was d r i e d (MgS0 4) and then was concentrated. Flash chromatography of the crude o i l on s i l i c a gel (27 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 8:1) provided 94.3 mg (45%) of a white s o l i d . R e c r y s t a l l i z a t i o n from hexane provided the diene (152) as thi n , needle l i k e plates (mp 131-132 8C). This material exhibited i r (CHCI3): 1719, 1609, 1530, 1347 cm"1; XH nmr (400 MHz, CDCI3) 6: 1.40-2.40 (m, 12H), 3.62 (s, 3H, -OCH3), 5.00 (d of d of d, 1H, one of -CCH20-, J - 2, 6, 12 Hz), 5.07 (d of d, 1H, one of -CCH20-, J - 7.5, 12 Hz), 5.50 (d of d of d, 1H, H a, J - 1.5, 6, 7.5 Hz), 5.66 (d of d, 1H, H b, J - 3, 4 Hz), 8.24 (d, 2H, 2H C, J - 9 Hz), 8.29 (d, 2H, 2H d, J - 9 Hz). 1 3 C nmr (75.3 MHz, CDCI3) 5: 18.9, 24.3, 25.6, 35.7, 36.9, 38.1, 49.4, 51.8 (-ve), 63.9, 118.1 (-ve), 123.4 (-ve), 127.5 (-ve), 130.6 (-ve), 135.7, 135.9, 146.6, 150.4, 164.6, 176.4. Exact Mass calcd. f o r C 2 1H 2 3N0 6: 385.1525; found: 385.1531. Anal, calcd. f o r C 2 1H 2 3N0 6: C 65.44, H 6.02, N 3.63; found: C 65.36, H 5.94, N 3.48. - 252 -3.2.3 Diels-Alder Study of the Dienes (75), (145) and (146) Reaction of the Diene (75) with Dimethyl Acetvlenedicarboxylate C02Me Me02cv^ K Me02C i i C02Me C02Me 175 176 A s t i r r e d s o l u t i o n of the diene (75) (50 mg, 0.24 mmol) and dimethyl acetylenedicarboxylate (DMAD) (70 mg, 2 equiv) i n dry benzene (10 mL) was refluxed and the disappearance of the diene was monitored by g l c . The s o l u t i o n was refluxed f o r 6 h and then the solvent was removed by rotary evaporation. Flash chromatography of the crude product mixture on s i l i c a gel (15 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 3:1) provided 66 mg (78%) of a s l i g h t l y off-white s o l i d (mp 136.5-137°C). Analysis (^ H nmr, 400 MHz) of t h i s crude reaction product ind i c a t e d that i t was a mixture of the two isomeric t r i e s t e r s (175) and (176) (low r e s o l u t i o n g a s - l i q u i d chromatography-mass spectrometry of t h i s mixture indi c a t e d a MT1" peak at m/e 348 f o r each component) . The t r i e s t e r s were present i n a r a t i o of 3:1 although i t could not be determined which was the major component. R e c r y s t a l l i z a t i o n of t h i s s o l i d from d i e t h y l ether-chloroform provided col o u r l e s s , cubic c r y s t a l s (mp 137.5-138.5°C). ^H nmr analysis of t h i s s o l i d i n d i c a t e d that the 3:1 r a t i o of isomers was unchanged. X-ray c r y s t a l l o g r a p h i c a n a l y s i s 7 2 of t h i s c r y s t a l - 253 -indi c a t e d that the major component was the t r i e s t e r (175). This material exhibited i r (CHC1 3): 1719, 1199 cm*1; XH nmr (400 MHz, CDCI3) 6: 1.12-2.34 (m, 12H), 2.67-2.90 (m, 1H), 2.98-3.15 (m, 2H), 3.67 and 3.70 (s, s, 3H, r a t i o 1:3, -OCH3), 3.75 and 3.76 (s, s, 3H, r a t i o 1:3, -OCH3), 3.78 and 3.80 (s, s, 3H, r a t i o 3:1, -OCH3). Exact Mass calcd. f o r C 1 9H 240 6: 348.1573; found: 348.1580. Reaction of the Diene (75) with Tetracyanoethylene C0 2Me C0 2Me 177 180 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 diene (75) (225 mg, 1.09 mmol) i n dry THF (10 mL) was added, dropwise, a s o l u t i o n of tetracyano-ethylene (147 mg, 1.05 equiv) i n dry THF (10 mL). Upon completion of the addition, the re a c t i o n mixture was warmed to room temperature and then s t i r r e d f o r 30 min at t h i s temperature. The r e a c t i o n mixture was concentrated and the r e s i d u a l o i l was subjected to f l a s h chromatography on s i l i c a g e l (35 g, e l u t i o n with petroleum ether-ethyl acetate, 5:1). Concentration of the appropriate f r a c t i o n s provided 302 mg (83%) of a white s o l i d (mp 146-147°C) which was composed of a mixture of two compounds i n a r a t i o of 96:4 (by g l c ) , presumably the two isomeric - 254 -esters (177) and (180). R e c r y s t a l l i z a t i o n of t h i s mixture from d i e t h y l ether-chloroform provided the pure, major ester as co l o u r l e s s , cubic c r y s t a l s (mp 146-147°C). X-ray c r y s t a l l o g r a p h i c a n a l y s i s 7 2 determined t h i s compound to be the ester (177). This material exhibited i r (CHC13): 2255, 1728, 1603 cm'1; ^ nmr (400 MHz, CHCI3) 6: 1.33 (d of t, 1H, J - 3, 13.2 Hz), 1.38-1.75 (m, 5H), 1.90 (m, 1H), 2.00 (br d, 1H, J - 18 Hz), 2.14-2.38 (m, 4H), 2.89 (d, 1H, H a or H b, J - 18 Hz), 3.19 (br d, 1H, H b or H a, J - 18 Hz), 3.31 (br d, 1H, H c, J - 12.5 Hz), 3.73 (s, 3H, -OCH3). I r r a d i a t i o n at 6 1.90: s i g n a l at 5 1.33 s i m p l i f i e d to a t (J - 13.2 Hz), m u l t i p l e t at 6 1.38-1.75 s i m p l i f i e d . I r r a d i a t i o n at 6 2.00: m u l t i p l e t s at S 1.38-1.75 and S 2.14-2.38 s i m p l i f i e d , s i g n a l at S 3.19 (H b or H a) s i m p l i f i e d , s i g n a l at S 3.31 (H c) s i m p l i f i e d . I r r a d i a -t i o n at 5 2.89 (H a or H b): m u l t i p l e t at S 2.14-2.38 s i m p l i f i e d , s i g n a l at 6 3.19 (H b or H a) s i m p l i f i e d to a br s, s i g n a l at 8 3.31 (H c) s i m p l i f i e d . I r r a d i a t i o n at S 3.19 (H b or H a): mu l t i p l e t s at S 1.38-1.75 and 6 2.14-2.38 s i m p l i f i e d , s i g n a l at 6 2.89 (H a or H b) s i m p l i f i e d to a br s. 1 3 C nmr (75.3 MHz, CDCI3) 6: 18.4, 21.2, 29.7, 30.7, 35.5, 36.4, 36.6, 37.5, 41.3 (-ve), 45.3, 48.1, 52.4 (-ve), 109.4, 110.1, 111.1, 111.2, 126.0, 127.7, 174.7. Exact Mass calcd. f o r C i g H ^ C ^ ^ : 334.1431; found: 334.1435. Anal c a l c d . f o r C 1 9H 1 80 2N4: C 68.25, H 5.43, N 16.76; found: C 68.29, H 5.44, N 16.78. From the AH and i 3 C nmr spectra of the crude product mixture, a few peaks from the minor ester (180) could be observed: AH nmr (400 MHz, CDCI3) 6: 3.74 (s, 3H, -OCH3). 1 3 C nmr (75.3 MHz, CDCI3) 6: 38.6 (-ve), 52.0, 125.1, 127.3, 175.2. - 255 -Reaction of the Diene (75) with Nitroethylene 0 2N i C02Me C02Me C02Me 189 190 191 To a s t i r r e d s o l u t i o n of the diene (75) (150 mg, 0.728 mmol) i n dry d i e t h y l ether (7 mL) at room temperature was added neat n i t r o e t h y l e n e 8 2 (=0.5 mL, large excess). The r e s u l t i n g mixture was s t i r r e d f o r 3 h and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a g e l (27 g, e l u t i o n with petroleum ether-ethyl acetate, 15:1) provided 168 mg (83%) of a very pale green s o l i d (mp 124-133°C). This material was a mixture of three isomers (low r e s o l u t i o n g a s - l i q u i d chromatography-mass spectrometry ind i c a t e d the three compounds a l l displayed peaks f o r M+-34 at m/e 245 and exhibited base peaks f or M+-72 at m/e 173) i n a r a t i o of 3:2:1 (by g l c ) . nmr analysis of t h i s mixture was unable to support t h i s r a t i o since the s i g n a l of p r i n c i p a l importance f o r two of the isomers (-OCH3) had the same chemical s h i f t . Drip column chromatography of the crude s o l i d on s i l i c a g el (18 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 20:1) provided a pure sample of the f i r s t compound to be eluted. By analogy with the n i t r o ester (197) (see l a t e r experimental), t h i s compound was determined to be the n i t r o ester (191). Also, by analogy of chemical r e a c t i v i t y and comparison of the nmr spectra with those of the n i t r o esters (195), - 256 -(197) and (196) (see l a t e r experimental), the crude mixture was determined to be composed of the n i t r o esters (189), (191) and (190) i n a r a t i o of 3:2:1 re s p e c t i v e l y . This mixture of compounds exhibited i r (CHC13): 1718, 1541, 1380 cm'1; *H nmr (400 MHz, CDCI3) 6: 1.14-2.43 (m, 16H), 2.75 (m, 1H, H a from a l l 3 Isomers), 3.69 and 3.72 (s, s, 3H, r a t i o 1:2, -OCH3), 4.44 and 4.70-4.76 (d of t, m, 1H, r a t i o 1:2, H c and H b r e s p e c t i v e l y , J_ - 3.8, 10.5 Hz). The pure n i t r o ester (191) exhibited XH nmr (400 MHz, CDC13) 6: 1.20-1.75 (m, 8H), 1.90-2.35 (m, 8H), 2.75 (m, 1H, H a), 3.69 (s, 3H, -OCH3), 4.44 (d of t, lH, H c J - 3.8, 10.5 Hz). I r r a d i a t i o n at 6 4.44 (H c): m u l t i p l e t at 6 1.90-2.35 s i m p l i f i e d , s i g n a l at S 2.75 (H a) s i m p l i f i e d to a br d (J - 13 Hz). Preparation of the Ketone (201) To a s t i r r e d s o l u t i o n of the mixture of the n i t r o esters (189), (191) and (190) (3:2:1 by glc) (162 mg, 0.581 mmol) In s p e c t r a l grade methanol (8 mL) at room temperature was added sodium methoxide (31 mg, 1 equiv) as a s o l i d . The r e s u l t i n g yellow s o l u t i o n was s t i r r e d f o r 20 min. A f r e s h l y prepared s o l u t i o n of titanium t r i c h l o r i d e (358 mg, 4 C0 2Me - 257 -equiv) and ammonium acetate (1.12 g, 25 equiv) i n water (8 mL) was then added. The reac t i o n mixture immediately turned green i n colour and, as the r e a c t i o n progressed, became blue and f i n a l l y yellow with a f i n e l y d i v i d e d white p r e c i p i t a t e . The re a c t i o n mixture was s t i r r e d f o r 3 h and then was suction f i l t e r e d and the r e s i d u a l s o l i d was washed with d i e t h y l ether (50 mL). The organic phase was removed and the aqueous phase was washed with d i e t h y l ether (3 x 25 mL). The combined organic s o l u t i o n was washed with saturated aqueous sodium bicarbonate (20 mL), d r i e d (MgSO^) and then was concentrated. 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 (air- b a t h temperature 132-133°C/0.1 Torr) provided 129 mg (90%) of the ketone (201) as a colourless o i l . This material exhibited i r ( f i l m ) : 1710, 1450, 1226, 1160 cm"1; XH nmr (400 MHz, CDC13) 6: 1.15-1.30 (m, 2H), 1.36 (t of t, 1H, J - 3.2, 13 Hz), 1.45-1.69 (m, 4H), 1.74 (d of quintets, 1H, J - 13, 3.4 Hz), 2.00-2.10 (m, 3H), 2.27-2.57 (m, 5H), 2.82 (br d, 1H, H a, J - 13 Hz), 3.69 (s, 3H, -OCH3). In a difference nuclear Overhauser enhancement (nOe) experiment, i r r a d i a t i o n at 6 2.82 (H a) caused a s i g n a l enhancement at S 3.69 (-OCH3). 1 3 C nmr (75.3 MHz, CDCI3) 6: 19.3, 23.0, 30.6, 30.7, 31.0, 36.0, 37.4, 37.9, 48.4, 48.5, 52.1, 130.1, 130.6, 176.6, 213.0. Exact Mass calcd. f o r C 1 5H 2o03: 248.1413; found: 248.1410. - 258 -Preparation of the Enone (203) i C0 2Me To a s t i r r e d s o l u t i o n of the ketone (201) (10 mg, 4.03 x 1 0 - 5 mol) i n dry THF (5 mL) at room temperature was added potassium tert-butoxide (1 mg, 0.2 equiv). The reac t i o n mixture was s t i r r e d f o r 24 h and then water (5 mL) was added. The organic phase was removed and the aqueous phase was extracted wtih d i e t h y l ether (3 x 20 mL). The combined organic s o l u t ion was dr i e d (MgS04) and then was concentrated. Drip column chromatography of the r e s i d u a l o i l on s i l i c a gel (10 g, e l u t i o n with d i e t h y l ether-petroleum ether, 5:1) and concentration of the appropriate f r a c t i o n s provided 5.5 mg (55%) of the enone (203) as a white, amorphous s o l i d . R e c r y s t a l l i z a t i o n of t h i s s o l i d from d i e t h y l ether provided a white powder (mp 159-160°C) which exhibited i r (CHCI3): 1723, 1668, 1603 cm"1; XH nmr (400 MHz, CDCI3) 6: 1.35-2.42 (m, 15H), 2.50 (d of d of d, 1H, J - 1.8, 5.5, 18.2 Hz), 2.89 (d of d of d, 1H, J - 6, 13, 18.2 Hz), 3.72 (s, 3H, -OCH3). I r r a d i a t i o n at S 2.89: s i g n a l at S 2.50 s i m p l i f i e d to a d of d (J - 1.8, 5.5 Hz). 1 3 C nmr (75.3 MHz, CDCI3) 6: 15.3, 18.3, 22.7, 29.0, 31.0, 33.0, 34.8, 36.4, 47.5, 52.4, 68.3, 133.8, 155.3, 175.8, 199.6. Exact Mass c a l c d f o r C ^ ^ Q C ^ : 248.1413; found: 248.1356. Exact Mass calcd. f o r C 1 5 H 1 8 0 3 (M +-H 2): 246.1257; found 246.1257. - 259 -Isomerization of the Nitro Esters (189). (190) and (191) A heated (80-90'C) s o l u t i o n of a 3:2:1 mixture of the n i t r o esters (189), (191) and (190), r e s p e c t i v e l y (20 mg, 7.17 x 10' 5 mol), and potassium tert-butoxide (4 mg, 0.5 equiv) i n dry t e r t - b u t y l alcohol was s t i r r e d f o r 16 h. D i l u t e aqueous a c e t i c a c i d (5 mL of a 1% s o l u t i o n , v/v), d i e t h y l ether (5 mL) and water (5 mL) were added i n succession. The organic phase was removed and the aqueous phase was extracted with d i e t h y l ether (2 x 10 mL). The combined organic s o l u t i o n was washed with saturated aqueous sodium bicarbonate (2 x 10 mL), d r i e d (MgS04) and concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (10 g, e l u t i o n with petroleum ether-ethyl acetate, 10:1) provided 27.4 mg (87%) of a mixture of the n i t r o esters (190), (191) and (189) i n a r a t i o of 3.1:2:0.7 (by glc) r e s p e c t i v e l y . Reaction of the Diene (75) with Methyl Acrylate C02Me C02Me C02Me 186 187 188 A s t i r r e d s o l u t i o n of the diene (75) (500 mg, 2.43 mmol) and methyl acry l a t e (0.44 mL, 2 equiv) i n dry benzene (50 mL) was heated at the - 260 -r e f l u x temperature and the disappearance of the diene (75) was monitored by g l c . A d d i t i o n a l amounts of methyl acr y l a t e were added a f t e r 22 h and a f t e r 46 h (2 equiv and 1 equiv r e s p e c t i v e l y ) . The r e a c t i o n mixture was concentrated a f t e r a t o t a l of 72 h of heating. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (70 g, e l u t i o n with petroleum ether-d i e t h y l ether, 10:1) provided a mixture of three products, as a colour-l e s s o i l , i n a r a t i o of 2.7:1.7:1 (by *H nmr) (603.1 mg, 85%). Low r e s o l u t i o n g a s - l i q u i d chromatography-mass spectrometry revealed that the three compounds were isomeric (each displayed a peak f o r M"1" at m/e 292) . This mixture exhibited XH nmr (400 MHz, CDC13) 6: 0.94-2.77 (m, 18H), 3.680, 3.681, 3.688, 3.690 and 3.715 ( a l l s, 6H t o t a l , r a t i o of 4.4:1.7:1:1:2.7 resp e c t i v e l y , both -OCH3). The crude mixture was subjected to drip column chromatography on s i l i c a gel (80 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 15:1). Samples of two pure isomers were obtained. The f i r s t compound to be eluted was u l t i m a t e l y i d e n t i f i e d (vide i n f r a ) as the d i e s t e r (188); the second to be eluted was i d e n t i f i e d (vide i n f r a ) as the d i e s t e r (186) and the f i n a l compound to be eluted (and which could not be obtained as a pure compound) was i d e n t i f i e d as the d i e s t e r (187). Thus, the crude mixture was composed of the d i e s t e r s (186), (188) and (187) i n a r a t i o of 2.7:1.7:1 (by glc and XH nmr). The major Diels-Alder adduct, the d i e s t e r (186) ( d i s t i l l a t i o n a i r - b a t h temperature 195-200°C/0.5 To r r ) , exhibited i r ( f i l m ) : 1732 cm"1; XH nmr (400 MHz, CDCI3) 5: 1.15 (d of t, 1H, 1 - 4 , 8 Hz), 1.24 (d of t, 1H, J . - 4 , 12.5 Hz), 1.28-1.73 (m, 7H), 1.77-2.12 (m, 6H), 2.35 (br d, 1H, J = 13 Hz), 2.73 (d of d of d, 1H, H a, J = 2.8, 6, 13 Hz), - 261 -3.67 and 3.71 (s, s, 3H each, two -OCH.3). Exact Mass calcd. f o r C 1 7 H 2 4 ° 4 : 292.1674; found: 292.1674. The d i e s t e r (188) (colourless o i l , d i s t i l l a t i o n a i r - b a t h temperature 160-162°C/0.5 Torr) exhibited i r ( f i l m ) : 1720, 1165 cm*1; XH nmr (400 MHz, CDCI3) 6: 1.21 (m, 1H), 1.33-1.70 (m, 8H), 1.75-2.05 (m, 6H), 2.17 (m, 1H), 2.31 (d of t, 1H, H c, 2 - 3 , 12 Hz), 2.38 (m, 1H), 3.67 and 3.68 (s, s, 3H each, two -OCH.3). Exact Mass ca l c d . f o r C17H24O4: 292.1674; found: 292.1676. To a s t i r r e d s o l u t i o n of a mixture of the die s t e r s (186) and (187) (3:1 r a t i o by g l c , 24.9 mg, 8.52 x 10* 5 mol) i n methanol (20 mL) was added sodium methoxide (10 mg, 0.5 equiv). The r e s u l t i n g s o l u t i o n was reflu x e d f o r 2 weeks. The s o l u t i o n was concentrated and d i e t h y l ether (25 mL) was added to the r e s i d u a l s l u r r y . The r e s u l t i n g mixture was f i l t e r e d and then d r i e d (MgS04). The s o l u t i o n was concentrated and the re s i d u a l o i l was d i s t i l l e d (air-bath temperature 160-170°C/0.6 Torr) to provide 22.0 mg (88%) of a mixture of the die s t e r s (186) and (187) i n a r a t i o of 1:6.1 (by g l c ) . This material exhibited XH nmr (400 MHz, CDCI3) S (for the d i e s t e r (187)): 0.99 (d of q, 1H, 2 - 1 2 Hz), 1.10-2.12 (m, 14H), 2.19-2.27 (m, 2H), 2.49 (br t, 1H, 2 - 1 1 Hz), 3.69 (s, 6H, both -OCH3). - 262 -Preparation of the Diol (199) To a stirred solution of the diester (186) (85.0 g, 0.291 mmol) in dry THF (10 mL) at room temperature was added lithium aluminum hydride (17 mg, 1.5 equiv). The resulting slurry was refluxed for 1 h and then was cooled to room temperature. Aqueous 1 M HCI (5 drops) was added carefully to the reaction mixture and then water (5 mL) was added. The organic phase was removed and the aqueous phase was extracted with diethyl ether (3 x 25 mL). The combined organic solution was dried (MgSO^ .) and then was concentrted to provide 66.8 mg (97%) of the diol (199) as a white solid. This solid was recrystallized from ethanol-hexane to provide colourless crystalline cubes (mp 182.5-184.5°C). X-ray crystallographic analysis 7 2 identified the solid as the diol (199). This material exhibited i r (nujol): 3271, 3189 cm-1. This material was not soluble in the common deuterated solvents (CDCI3, (CD3)2S0, CgDg, (CD3)2C0). *H nmr analysis in CD3OD was uninformative. Exact Mass calcd. for C 1 5H 240 2: 236.1777; found: 236.1777. Anal calcd. for C 1 5H 2 40 2: C 76.23, H 10.24; found: C 76.17, H 10.24. - 263 -Preparation of the D i o l (198) To a s t i r r e d suspension of l i t h i u m aluminum hydride (43 mg, 1.5 equiv) i n dry d i e t h y l ether (20 mL) at 0°C was added, dropwise, a s o l u t i o n of the d i e s t e r (188) (218 mg, 0.747 mmol) i n d i e t h y l ether (10 mL). The r e s u l t i n g mixture was s t i r r e d for 30 min at 0°C and then was warmed to the r e f l u x temperature. The r e a c t i o n mixture was refluxed for 6.5 h and then water (10 mL) and aqueous 1 M HCI (5 mL) were c a r e f u l l y added. The organic phase was removed and the aqueous phase was extracted with d i e t h y l ether (3 x 10 mL). The combined organic s o l u t i o n was d r i e d (MgSO,^) and then was concentrated to provide 146 mg (83%) of the d i o l (198) as a colourless c r y s t a l l i n e s o l i d . This s o l i d was r e c r y s t a l l i z e d from methanol to provide col o u r l e s s , cubic c r y s t a l s (mp 162.5-164°C). X-ray c r y s t a l l o g r a p h i c a n a l y s i s 7 2 i d e n t i f i e d the s o l i d as the d i o l (198). This material exhibited i r ( n u j o l ) : 3310, 3195 cm - 1. This material was not soluble i n the common deuterated solvents (CDCI3, (CD3)2S0, CgDg, (CD3)2CO). XH nmr analysis i n CD3OD was uninformative. Exact Mass calcd. f o r C 1 5H240 2: 236.1777; found: 236.1776. Anal, ca l c d . f o r C 1 5H 240 2: C 76.23, H 10.24; found: C 76.17, H 10.21. - 264 -Preparation of the Aromatic Ester (235) S0 2 Ph H, Ph0 2 S H: C0 2 Me CO^e C02Me C02Me H k 233 234 235 A s t i r r e d s o l u t i o n of the diene (75) (50 mg, 0.243 mmol) and 1,2-bis(phenylsulfonyl)ethylene (90 mg, 1.2 equiv) i n dry benzene (10 mL) was heated at the r e f l u x temperature f o r 24 h. The r e s u l t i n g s o l u t i o n was concentrated and the r e s i d u a l o i l was subjected to f l a s h chromatography on s i l i c a gel (18 g, e l u t i o n with methylene c h l o r i d e -d i e t h y l ether-petroleum ether, 7:2:5) to provide, a f t e r concentration of the appropriate f r a c t i o n s , 102 mg (82%) of the ester (233) as a white amporphous s o l i d (mp 225°C d e c ) . Although t h i s product appeared to be a s i n g l e isomer, the r e l a t i v e stereochemistry was not determined and the compound was c a r r i e d on to the subsequent reaction. This material e x h i b i t e d i r (CHC1 3): 1722, 1321, 1147 cm"1. Exact Mass ca l c d . f o r C 2 7 H 3 0 ° 6 S 2 : 514.1485; found: 514.1485. A mixture of the ester (233) (179 mg, 0.348 mmol), 2% sodium amalgam (2.7 g, 6.8 equiv of sodium) and sodium dihydrogenphosphate monohydrate (615 mg) i n dry methanol (5 mL) was s t i r r e d at room temperature f o r 24 h. The r e a c t i o n mixture was poured into water (10 mL) and the r e s u l t i n g mixture was extracted with d i e t h y l ether (3 x 10 mL). The combined - 265 -organic s o l u t i o n was washed with brine and then was d r i e d (MgS04). Concentration of t h i s s o l u t i o n , followed by f l a s h chromatography of the re s i d u a l o i l on s i l i c a gel (30 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 2:1), provided, a f t e r d i s t i l l a t i o n ( air-bath temperature 120-124°C/0.6 T o r r ) , 69 mg (85%) of the diene (234) as a white, waxy s o l i d (mp 51-52°C). This material exhibited i r (CHCI3): 1715 cm - 1; lR nmr (400 MHz, CDCI3) 8: 1.35-1.80 (m, 8H), 1.95-2.14 (m, 4H), 2.52-2.63 (m, 2H, H d a n d H e ) , 2.70 (m, 1H, H a), 3.67 (s, 3H, -OCH3), 5.60 (br d, 1H, H b, J - 9 Hz), 5.76 (m, 1H, H c). Exact Mass calcd. f o r C 1 5H2o°2: 232.1463; found: 232.1463. To a s t i r r e d s o l u t i o n of the diene (234) (20 mg, 0.086 mmol) i n dry benzene (10 mL) was added 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) (20 mg, 1.02 equiv). The r e s u l t i n g s o l u t i o n was heated to the r e f l u x temperature. The s o l u t i o n was refluxed f o r 30 min, was then cooled to room temperature and was f i l t e r e d . Concentration of the f i l t r a t e and f l a s h chromatography of the r e s i d u a l s o l i d on s i l i c a g el (10 g, e l u t i o n with d i e t h y l ether-petroleum ether, 100:1) provided 17 mg (87%) of the aromatic ester (235) as an off-white s o l i d . R e c r y s t a l l i z a -t i o n of t h i s s o l i d from petroleum ether provided the aromatic ester (235) as a white s o l i d (mp 60-61 oC) which exhibited i r (CHCI3): 3009, 1719 cm - 1; XH nmr (400 MHz, CDCI3) 6: 1.55 (d of t, 2H, 1^, J - 5, 13 Hz), 1.68-1.90 (m, 4H, Hj and H k), 2.35 (d of t, 2H, H^ J - 13, 4 Hz), 2.78-2.85 (m, 4H, H n and U±), 3.65 (s, 3H, -OCH3), 6.95 (br d, 2H, H g, J - 7.5 Hz), 7.11 ( t , 1H, H f, J - 7.5 Hz). I r r a d i a t i o n at 6 2.35 (H^): s i g n a l at S 1.55 (H,,,) s i m p l i f i e d to a d of d (J - 5, 13 Hz), mu l t i p l e t at 6 1.68-1.90 (Hj and H k) s i m p l i f i e d . I r r a d i a t i o n at 5 2.78-2.85 (H h - 2 6 6 -a n d % ) : m u l t i p l e t a t 6 1 . 6 8 - 1 . 9 0 ( H j a n d H k ) s i m p l i f i e d , s i g n a l a t S 6 . 9 5 ( H g ) s h a r p e n e d t o a d ( J - 7 . 5 H z ) . I r r a d i a t i o n a t 6 6 . 9 5 ( H g ) : m u l t i p l e t a t 6 2 . 7 8 - 2 . 8 5 ( H h a n d H t ) s i m p l i f i e d , s i g n a l a t 6 7 . 1 1 ( H f ) s i m p l i f i e d t o a s . 1 3 C n m r ( 7 5 . 3 M H z , C D C 1 3 ) 6: 1 9 . 5 ( t ) , 2 8 . 5 ( t ) , 3 4 . 7 ( t ) , 4 7 . 5 ( s , C i ) , 5 2 . 1 ( q , - O C H 3 ) , 1 2 6 . 1 ( d , C 6 ) , 1 2 6 . 5 ( d , C 7 ) , 1 3 5 . 5 ( s , C 8 ) , 1 3 6 . 5 ( s , C 5 ) , 1 7 7 . 2 ( s , - C O O C H 3 ) . T h e c h e m i c a l s h i f t s a n d t h e m u l t i p l i c i t i e s r e p o r t e d a b o v e w e r e d e r i v e d f r o m t h e p r o t o n n o i s e d e c o u p l e d a n d t h e o f f - r e s o n a n c e d e c o u p l e d 1 3 C n m r s p e c t r a , r e s p e c t i v e l y . E x a c t M a s s c a l c d . f o r C 1 5 H 1 8 0 2 : 2 3 0 . 1 3 0 7 ; f o u n d : 2 3 0 . 1 3 1 1 . R e a c t i o n o f t h e D i e n e ( 1 4 6) w i t h T e t r a c v a n o e t h v l e n e 6o2Me C02Me 178 R=SiMe 2Bu t 181 T o a s t i r r e d s o l u t i o n o f t h e d i e n e ( 1 4 6 ) ( 5 0 . 0 m g , 0 . 1 4 3 m m o l ) i n d r y T H F ( 1 0 m L ) a t r o o m t e m p e r a t u r e w a s a d d e d t e t r a c y a n o e t h y l e n e ( 2 1 . 5 m g , 1 . 1 5 e q u i v ) a s a s o l i d . T h e r e s u l t i n g y e l l o w s o l u t i o n w a s s t i r r e d f o r 1 h a n d t h e n t h e s o l v e n t w a s r e m o v e d b y r o t a r y e v a p o r a t i o n . F l a s h c h r o m a t o g r a p h y o f t h e r e s i d u a l o i l o n s i l i c a g e l ( 1 8 g , e l u t i o n w i t h p e t r o l e u m e t h e r - d i e t h y l e t h e r , 4 : 1 ) p r o v i d e d 5 0 . 5 mg (74%) o f a 7 : 1 m i x t u r e ( b y * H n m r ) o f t h e e s t e r s ( 1 7 8 ) a n d ( 1 8 1 ) , r e s p e c t i v e l y , a s a - 267 -co l o u r l e s s foam. These isomers could not be separated and the mixture exh i b i t e d AH nmr (400 MHz, CDC1 3) 6: 0.15, 0.16, 0.17 and 0.18 ( a l l s, 6H, r a t i o 1:1:7:7, -SiMe 2), 0:94 and 0.97 (s, s, 9H, r a t i o 1:7, -SiCMe 3), 1.20-3.27 (m, 14H), 3.74 and 3.75 (s, s, 3H, r a t i o 1:7, -OCH3), 3.94-4.38 (m, 2H, -CH 20-). Exact Mass ca l c d . f o r C ^ ^ j O j ^ S i (M+-CH3): 463.2165; found: 463.2172. To a c o l d (-78°C), s t i r r e d s o l u t i o n of the diene (146) (100 mg, 0.285 mmol) i n dry THF (4 mL) was added, dropwise, tetracyanoethylene (73 mg, 2 equiv) as a s o l u t i o n i n dry THF (5 mL). 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 f o r 2 h at -78°C and then the s o l u t i o n was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (27 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 4:1) provided 114 mg (84%) of the ester (178), a s i n g l e isomer (by AH nmr), as a colourless foam. C r y s t a l l i z a -t i o n from hexane-acetone afforded the ester (178) as c o l o u r l e s s , needle-l i k e c r y s t a l s (mp 119-120°C). This material exhibited i r (KBr): 2253, 1729, 840, 782 cm"1; XH nmr (400 MHz, CDCI3) 6: 0.17 and 0.18 (s, s, 3H each, -SiMe 2), 0.97 (s, 9H, -SiCMe.3), 1.27 (d of t, 1H, J - 3.5, 13.5 Hz), 1.37-1.50 (m, 3H), 1.72 (m, 1H), 1.87-2.31 (m, 6H), 2.44 (br d, 1H, 1 - 1 3 Hz), 3.10 (br d, 1H, H a, J - 12.5 Hz), 3.25 (m, 1H, H b), 3.75 (s, 3H, -OCH3), 3.98 (br t, 1H, one of -CH20-, 1 - 10.5 Hz), 4.23 (d of d, 1H, one of -CH.20-, 1 - 4.6, 10.5 Hz). I r r a d i a t i o n at 6 2.46: s i g n a l at S 1.27 s i m p l i f i e d to a d of d ( 1 - 3.5, 13.5 Hz), m u l t i p l e t at 6 1.87-2.31 s i m p l i f i e d . I r r a d i a t i o n at 6 3.10 ( H a ) : m u l t i p l e t at S 1.87-2.31 s i m p l i f i e d . I r r a d i a t i o n at S 3.25 ( H b ) : s i g n a l at S 3.98 (one of -CH20-) s i m p l i f i e d to a br d ( 1 - 10.5 Hz), s i g n a l at S 4.23 (one of -CH20-) s i m p l i f i e d to a d ( 1 - 10.5 Hz). I r r a d i a t i o n at S 4.23 (one of - 268 --CH 20-): s i g n a l at S 3.25 (H b) s i m p l i f i e d to a br d (J - 8 Hz), s i g n a l at S 3.98 (one of -CH.20-) s i m p l i f i e d to a br d (J. - 9.5 Hz). 1 3 C nmr (75.3 MHz, CDC1 3) 6: 18.4, 18.5, 23.6, 25.8 (-ve), 28.7, 30.5, 35.7, 38.0, 39.8 (-ve), 43.0, 43.8, 47.6 (-ve), 50.0, 52.7 (-ve), 62.1, 110.3, 110.5, 114.4, 112.3, 126.3, 129.6, 174.9. Exact Mass calcd. f o r c 2 5 H 3 1 ° 3 N 4 S i (M+-CH3): 463.2166; found: 463.2168. Reaction of the Diene (145) with Tetracvanoethvlene N C C N C0 2 Me A s t i r r e d s o l u t i o n of the diene (145) (60.0 mg, 0.171 mmol) and tetracyanoethylene (180 mg, 8 equiv) i n dry d i e t h y l ether (10 mL) was heated at a gentle r e f l u x f o r 15 h. The r e s u l t i n g s o l u t i o n was concen-t r a t e d and the r e s i d u a l o i l was subjected 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 with petroleum e t h e r - d i e t h y l ether, 4:1). Concentration of the appropriate f r a c t i o n s provided 59.1 mg (72%) of the ester (179) as a colourless glass. *H nmr analysis i n d i c a t e d that t h i s compound was a s i n g l e isomer. R e c r y s t a l l i z a t i o n from hexane-aceto-n i t r i l e afforded the ester (179) as colou r l e s s , n e e d l e - l i k e c r y s t a l s (mp 127-128°C). X-ray c r y s t a l l o g r a p h i c a n a l y s i s 7 2 confirmed the structure - 269 -of t h i s s o l i d . This material exhibited i r (CHC13): 2254, 1718 cm"1; AH nmr (400 MHz, CDCI3) fi: 0.17 and 0.18 (s, s, 3H each, -SiMe 2), 0.96 (s, 9H, -SiCMe 3), 1.41-1.77 (m, 6H), 1.82-1.94 (m, 2H), 1.98-2.17 (m, 2H), 2.21-2.36 (m, 2H), 3.26 (ro, 2H, includes H b), 3.70 (s, 3H, -OCH.3), 3.93 (d of d, 1H, one of -CH.20-, J_ - 7.5, 10.5 Hz), 4.25 (d of d, 1H, one of -CH20-, J. - 4.1, 10.5 Hz). I r r a d i a t i o n at fi 4.25 (one of -CH 20-): s i g n a l at fi 3.26 s i m p l i f i e d to a br d (J. - 7.5 Hz), s i g n a l at fi 3.93 (one of -QJ 20-) s i m p l i f i e d to a d (J - 7.5 Hz). 1 3 C nmr (75.3 MHz, CDCI3) fi: 18.4, 19.3, 21.7, 25.8 (-ve), 28.0, 30.5, 35.3, 36.0, 41.7 (-ve), 42.0, 46.6, 46.9 (-ve), 48.7, 52.6 (-ve), 61.9, 109.4, 110.1, 111.5, 112.1, 129.1, 129.6, 175.1. Exact Mass calcd. f o r C 2 6 H3 40 3 N 4Si: 478.2400; found: 478.2406. Anal, calcd. f o r C 2 6 H 3 4 0 3 N 4 S i : C 65.24, H 7.16; found: C 65.40, H 7.12. Reaction of the Diene (146) with Maleic Anhydride O a R=SiMe.Bu t C02Me A s t i r r e d s o l u t i o n of the diene (146) (100 mg, 0.285 mmol) and maleic anhydride (56 mg, 2 equiv) i n dry benzene (20 mL) was heated at the r e f l u x temperature f o r 18 h. The solvent was removed by rotary - 270 -evaporation. Flash chromatography of the r e s i d u a l s o l i d on s i l i c a g el (27 g, e l u t i o n with petroleum eth e r - d i e t h y l ether, 3:2) followed by concentration of the appropriate f r a c t i o n s provided 80.1 mg (63%) of the anhydride (182) as a white s o l i d . R e c r y s t a l l i z a t i o n from hexane afforded the anhydride (182) as col o u r l e s s , cubic c r y s t a l s (mp 103.5-105°C): i r (KBr): 1860, 1781, 1730, 838 cm'1; AH nmr (400 MHz, CDC13) 6: 0.04 and 0.07 (s, s, 3H each, -SiMe 2), 0.89 (s, 9H, -SiCMe 3), 1.21 (d of t, 1H, J - 4, 13 Hz), 1.29-1.68 (m, 5H), 1.74 (m, 1H), 1.92-2.02 (m, 2H), 2.11 (m, 1H), 2.26 (br d, 1H, J - 12.5 Hz), 2.40 (m, 1H), 2.51-2.64 (m, 2H, H a and H d), 3.35 (m, 2H, H b and H c), 3.65 (d of d, 1H, one of -CH20-, J - 5.5, 10.5 Hz), 3.66 (s, 3H, -OCH3), 3.74 (d of d, 1H, one of -CH20-, J - 4, 10.5 Hz). I r r a d i a t i o n at 6 3.35 (H b and H c): m u l t i p l e t at 6 2.51-2.64 (H a and H d) s i m p l i f i e d to two si g n a l s , a br d at 6 2.59 (H a, J - 12 Hz) and a d of d at 6 2.53 (H d, J - 4, 5.5 Hz). I r r a d i a t i o n at 6 3.74 (one of -CH 20-): s i g n a l at S 2.53 (H d) s i m p l i f i e d to a br t (J - 5.5 Hz), s i g n a l at S 3.65 (one of -CH20-) s i m p l i f i e d to a d (J - 5.5 Hz). Exact Mass calcd. f o r C ^ ^ g O g S i : 448.2281; found: 448.2276. - 271 -Reaction of the Diene (145) with Maleic Anhydride ^ JO C02Me A s t i r r e d s o l u t i o n of the diene (145) (100 mg, 0.285 mmol) and maleic anhydride (56 mg, 2 equiv) i n dry benzene (5 mL) was heated at the r e f l u x temperature f o r 3 days. The r e s u l t i n g c o l o u r l e s s s o l u t i o n was f i l t e r e d from the white s o l i d which had been deposited during the re a c t i o n and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a g el (15 g, e l u t i o n with petroleum eth e r - d i e t h y l ether, 5:1) provided 22.4 mg (18%) of the anhydride (183) as a colour l e s s o i l . This material exhibited i r ( f i l m ) : 1864, 1784, 1729, 837, 779 cm"1; lH nmr (400 MHz, CDC13) S: 0.06 and 0.07 (s, s, 3H each, -SiMe 2), 0.89 (s, 9H, -SiCMe 3), 1.15 (m, 1H), 1.35-2.20 (m, 11H), 2.56 (m, 1H, H a), 2.68 (m, 1H, H d), 3.43 ( t , 1H, H b, J - 9 Hz), 3.50 (d of d, 1H, H c, J - 1, 9 Hz), 3.51 (d of d, 1H, one of -CH20-, 2 - 7 , 10 Hz), 3.67 (s, 3H, -OCH3), 3.72 (d of d, 1H, one of -CH20-, 2 - 4 , 10 Hz). I r r a d i a t i o n at 6 2.56 (H a): s i g n a l at S 3.43 (H D) s i m p l i f i e d to a d (J -9 Hz). I r r a d i a t i o n at 6 2.68 (H d): s i g n a l at 6 3.50 (H c) s i m p l i f i e d to a d (2 - 9 Hz), s i g n a l at 6 3.51 (one of -CH20-) s i m p l i f i e d to a d (J -10 Hz), s i g n a l at S 3.72 (one of -CH20-) s i m p l i f i e d to a d (2 - 10 Hz). I r r a d i a t i o n at 6 3.43 (H b): s i g n a l at S 2.56 (H a) s i m p l i f i e d to a br d - 272 -(2 - 12 Hz). I r r a d i a t i o n at 6 3.72 (one of -CH 20-): s i g n a l at S 2.68 (H d) s i m p l i f i e d to a br d (J - 7 Hz). Exact Mass calcd. f o r c 2 4 H 3 6 ° 6 s i : 448.2281; found: 448.2276. The white s o l i d which was deposited during the course of the r e a c t i o n could not be i d e n t i f i e d . The s o l i d was washed with d i e t h y l ether and, a f t e r drying, there was obtained 75.2 mg. This material e x h i b i t e d i r (KBr): 1849, 1779, 1718 c m 4 ; XH nmr (400 MHz, (CD 3) 2SO): no s i g n a l s f o r -SiMe 2 or -SiCHe.3. Low r e s o l u t i o n mass spectrometry (m/e): 414, 386, 355, 327, 299, 282, 253, 235, 209, 181, 167, 153, 141, 128, 115, 91, 55. Exact Mass calcd. f o r C 2 2 H 2 2 0 8 : 414.1315; found: 414.1315. Reaction of the Diene (lAfi) with Nitroethylene C0 2Me C0 2Me C02Me 195 196 197 R=SiMe 2Bu t To a s t i r r e d s o l u t i o n of the diene (146) (190.0 mg, 0.542 mmol) i n dry d i e t h y l ether (5 mL) at room temperature was added neat nitroethy-l e n e 8 2 (0.6 mL, large excess). The r e s u l t i n g mixture was s t i r r e d f o r 3 h and then the solvent was removed by rotary evaporation. The r e s i d u a l - 273 -o i l was passed through a plug of s i l i c a g el ( e l u t i o n with d i e t h y l ether) to remove the nitroethylene polymers. Concentration of the r e s u l t i n g c o l o u r l e s s s o l u t i o n provided an o i l which proved to be a mixture of the three n i t r o esters (195), (196) and (197) (200.2 mg; 87% crude y i e l d ) i n a r a t i o of 3:trace:1 (by AH nmr). Medium pressure chromatography of t h i s crude r e a c t i o n mixture on s i l i c a gel (40 g, e l u t i o n with petroleum et h e r - d i e t h y l ether, 10:1) provided two compounds. The f i r s t compound to be eluted proved to be the n i t r o ester (197). Concentration of the appropriate f r a c t i o n s , and 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 (air-bath temperature 180-195°C/0.03 Torr), provided 56.0 mg (24%) of the n i t r o ester (197) as a colourless o i l ; i r ( f i l m ) : 1729, 1549, 1378, 838, 778 cm - 1; XH nmr (400 MHz, CDC13) 6: 0.07 and 0.08 (s, s, 3H each, -SiMe 2), 0.91 (s, 9H, -SiCMe 3), 1.25-1.75 (m, 8H), 1.88-2.08 (m, 3H), 2.16-2.33 (m, 3H, one unassigned proton and Hp and HJJ or H Q) , 2.46 (d of d of d, 1H, H Q or Hn, J - 0.9, 3, 12 Hz), 2.78 (br t, 1H, H k, J - 12 Hz), 3.50 (d of d, 1H, one of -CH20-, J - 8, 10 Hz), 3.67 (s, 3H, -OCH3), 3.75 (d of d, 1H, one of -CH20-, J - 4, 10 Hz), 4.58 (d of d of d, 1H, H m, J = 3, 10.5, 12 Hz). I r r a d i a t i o n at 6 2.46 (H Q or H n): m u l t i p l e t at 5 2.16-2.33 s i m p l i f i e d , s i g n a l at S 4.58 (H^) s i m p l i f i e d to a d of d (J -10.5, 12 Hz). I r r a d i a t i o n at 5 2.78 (H k): mult i p l e t s at 6 1.25-1.75 and 6 1.88-2.08 s i m p l i f i e d , s i g n a l at 6 4.58 (1^) s i m p l i f i e d to a br d (J -11 Hz). I r r a d i a t i o n at 6 3.50 (one of -CH 20-): m u l t i p l e t at S 2.16-2.33 (includes Hp) s i m p l i f i e d , s i g n a l at 6 3.75 (one of -CH20-) s i m p l i f i e d to a d (J - 4 Hz). I r r a d i a t i o n at S 4.58 (1^): m u l t i p l e t at 6 2.16-2.33 (includes Hjj or H Q) s i m p l i f i e d , s i g n a l at 6 2.46 (H Q or HJJ) s i m p l i f i e d to a d of d (J - 0.9, 12 Hz), s i g n a l at 6 2.78 (H k) s i m p l i f i e d to a br d - 274 -(J - 12 Hz). Exact Mass calcd. f o r C2iH 340 5NSi (M+'O^): 408.2207; found: 408.2203. The second compound to be eluted proved to be the n i t r o ester (195). Concentration of the appropriate f r a c t i o n s provided 130.4 mg (57%) of the n i t r o e s t e r (195) as a white s o l i d . R e c r y s t a l l i z a t i o n from chloroform afforded colourless c r y s t a l s (mp 89-90°C) and X-ray c r y s t a l l o g r a p h i c a n a l y s i s 7 2 confirmed the structure of t h i s s o l i d . This material exhibited i r (CHC13): 1728, 1547, 1384, 838, 777 cm'1; AH nmr (400 MHz, CDCI3) 6: 0.06 and 0.07 (s, s, 3H each, -SiMe 2), 0.90 (s, 9H, -SiCMe 3), 1.11 (d of t, 1H, 1 - 3.9, 13 Hz), 1.23-1.66 (m, 6H), 1.73 (m, 1H), 1.91-2.08 (m, 3H), 2.09-2.17 (m, 2H, H c and H d), 2.33 (m, 1H, H e), 2.44 (br d, 1H, J - 13.4 Hz), 2.69 (m, 1H, H a), 3.66 (d of d, 1H, one of -CH20-, J - 3, 10 Hz), 3.72 (s, 3H, -OCH3), 3.73 (d of d, 1H, one of -CH20-, J - 5, 10 Hz), 4.75 (m, 1H, H b). I r r a d i a t i o n at 6 2.69 (H a): m u l t i p l e t at 1.23-1.66 s i m p l i f i e d , s i g n a l at 6 4.75 (H D) s i m p l i f i e d . I r r a d i a t i o n at S 3.66 (one of -CH20-): s i g n a l at 8 2.33 (H e) s i m p l i f i e d to a br t (J - 8 Hz). I r r a d i a t i o n at 8 4.75 (H D): s i g n a l at 5 2.09-2.17 (H c and H d) s i m p l i f i e d , s i g n a l at 8 2.69 (H a) s i m p l i f i e d to a br d (J -11 Hz). Exact Mass calcd. f o r C 2 1H 340 5NSi (M" 1"-^): 408.2207; found: 408.2212. Anal, calcd. f o r C 2 2 H 3 7 0 5 N S i : C 62.38, H 8.80; found: C 62.49, H 8.92. To a s t i r r e d s o l u t i o n of the n i t r o ester (195) (38.0 mg, 0.09 mmol) i n dry t e r t - b u t y l alcohol (4 mL) was added potassium tert-butoxlde (1.3 mg, «0.13 equiv). The r e s u l t i n g s o l u t i o n was heated to 100°C and s t i r r i n g was continued at t h i s temperature f o r 18 h. The s o l u t i o n was cooled to room temperature and then d i l u t e aqueous a c e t i c a c i d (5 mL), - 275 -d i e t h y l ether (5 mL) and water (5 mL) were added to the rea c t i o n mixture. The organic phase was removed and the aqueous phase was extracted with d i e t h y l ether (3 x 10 mL). The combined organic s o l u t i o n was d r i e d (MgS0 4) and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a g el (10 g, e l u t i o n with petroleum ether-d i e t h y l ether, 10:1) provided 35.0 mg (92%) of the n i t r o ester (196) as a c o l o u r l e s s , c r y s t a l l i n e s o l i d (mp 62-63"C). This material was i d e n t i c a l with the compound which was observed i n trace amounts i n the i n i t i a l crude r e a c t i o n mixture: i r (CHC1 3): 1721, 1548, 1379, 839 cm"1; AH nmr (400 MHz, CDCI3) fi: 0.07 and 0.08 (s, s, 3H each, -SiMe 2). 0.91 (s, 9H, -SiCMe.3), 1.07 (d of q, 1H, J - 3.5, 12.5 Hz), 1.17 (d of t, 1H, 1 - 3.2, 13.1 Hz), 1.23-1.35 (m, 1H), 1.39-1.70 (m, 4H), 1.83-1.94 (m, 2H), 2.09 (m, 1H), 2.14-2.35 (m, 4H, one u n i d e n t i f i e d proton plus H h, % and Hj), 2.84 (m, 1H, H f), 3.59 (d of d, 1H, one of -CH20-, J - 6.3, 10 Hz), 3.68 (d of d, lH, one of -CH20-, J - 3.4, 10 Hz), 3.71 (s, 3H, -0CH 3), 4.68 (d of d of d, 1H, H g, 1 - 4 , 9, 12 Hz). I r r a d i a t i o n at 5 2.84 ( H f ) : s i g n a l at fi 1.07 s i m p l i f i e d to a d of t (J - 3.5, 12.5 Hz), mu l t i p l e t at fi 2.14-2.35 s i m p l i f i e d , s i g n a l at fi 4.68 (H g) s i m p l i f i e d to a d of d (J - 4, 12 Hz). I r r a d i a t i o n at fi 3.59 (one of -CH 20-): m u l t i p l e t at fi 2.14-2.35 (includes H^) s i m p l i f i e d . I r r a d i a t i o n at fi 4.68 ( H g ) : m u l t i p l e t at fi 2.14-2.35 (includes H h and H £) s i m p l i f i e d , s i g n a l at fi 2.84 (Hf) s i m p l i f i e d to a br d Q - 12 Hz). Exact Mass cal c d . f o r C 2 1H340 5NSi (M+-CH3): 408.2206; found: 408.2204. - 276 -Preparation of the Benzoate (206) 0->N N 0 2 C0 2Me C0 2Me 205 206 To a s t i r r e d s o l u t i o n of the s i l y l ether (197) (106 mg, 0.251 mmol) i n dry THF (10 mL) at room temperature was added, dropwise, a s o l u t i o n of tetra-n-butylammonium f l u o r i d e (0.5 mL of a 1 M s o l u t i o n , 2 equiv) i n THF. 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 f or 16 h and then the solvent was removed by rotary evaporation. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (27 g, e l u t i o n with d i e t h y l ether-petroleum ether, 2:1) provided 55.6 mg (72%) of the alcohol (205) as a colourless o i l . This material exhibited i r ( f i l m ) : 3478, 1713, 1546, 1379 cm - 1; XE nmr (400 MHz, CDC13) 6: 1.19-1.79 (m, 7H), 1.92-2.35 (m, 7H), 2.40 (d of d of t, 1H, 1 - 1 , 6.5, 12.5 Hz), 2.80 (m, 1H), 3.60 (d of d, 1H, one of -CH20H, 1 - 1.5, 11 Hz), 3.72 (s, 3H, - O C H 3 ) , 3.90 (d of d of d, 1H, one of -CH20H, 1 - 4 , 10, 12.5 Hz). To a s t i r r e d s o l u t i o n of the crude alcohol (205) (46.9 mg, 0.152 mmol) i n dry THF (10 mL) at room temperature was added 4-N.,N-dimethyl-aminopyridine (22.3 mg, 1.2 equiv) and jj-nitrobenzoyl c h l o r i d e (42.2 mg, 1.5 equiv). The r e s u l t i n g s o l u t i o n was heated to the r e f l u x temperature and a f t e r 1 h, the r e a c t i o n mixture was concentrated. Flash chromatog-raphy of the r e s i d u a l o i l on s i l i c a gel (18 g, e l u t i o n with petroleum - 277 -et h e r - d i e t h y l ether, 1:1), and concentration of the appropriate f r a c -t i o n s , provided 63.0 mg (91%) of a white s o l i d . R e c r y s t a l l i z a t i o n from benzene afforded colourless c r y s t a l s (mp 142.5-143.5°C). X-ray c r y s t a l l o g r a p h i c a n a l y s i s 7 2 of t h i s material i d e n t i f i e d the s o l i d as the benzoate (206). This material exhibited i r (CHC1 3): 1724, 1550, 1530, 1350 cm - 1; XH nmr (400 MHz, CDCI3) 6: 1.23-1.82 (m, 8H), 1.96-2.10 (m, 3H), 2.30-2.49 (m, 3H), 2.65 (m, 1H), 2.82 (br t, 1H, 1 - 1 0 Hz), 3.65 (s, 3H, -OCH3), 4.40 (d of d, 1H, one of -CH.20-, 1 - 7-3, 11.2 Hz), 4.53 (d of d, 1H, one of -CH20-, J - 3, 11.2 Hz), 4.63 (d of t, 1H, H d, J -4, 11 Hz), 8.25-8.35 (m, 4H, aromatic protons). Exact Mass calcd. f o r C 2 3 H 2 6 N 2 0 8 : 458.1689; found: 458.1684. Anal, calcd. f o r C 23H 26N 20 8: C 60.26, H 5.72, N 6.11; found: C 60.05, H 5.70, N 6.00. Preparation of the Ketone (232) Following a procedure i d e n t i c a l with that used f o r the preparation of the ketone (201), the n i t r o ester (195) (81.0 mg, 0.191 mmol) was converted into the ketone (232). Flash chromatography of the crude o i l - 278 -on s i l i c a g e l (27 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 3:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 205-215°C/0.05 T o r r ) , provided 62.2 mg (83%) of the ketone (232) as a co l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1740, 1729, 838, 779 cm - 1; XH nmr (400 MHz, CDC1 3) 6: 0.02 and 0.04 (s, s, 3H each, -SiMe 2), 0.89 (s, 9H, -SiCMe 3), 1.10 (d of q, 1H, I - 3.8, 12.5 Hz), 1.23 (d of q, 1H, 1 - 3 , 12.8 Hz), 1.33 (t of q, 1H, J. - 3.5, 13.5 Hz), 1.42-1.77 (m, 4H), 1.99-2.08 (m, 2H), 2.19-2.31 (m, 3H), 2.50-2.67 (m, 3H), 2.77 (br d, 1H, J - 12 Hz), 3.44 (d of d, 1H, one of -CH20-, J - 6, 10 Hz), 3.53 (d of d, 1H, one of -CH20-, J - 3.4, 10 Hz), 3.70 (s, 3H, - O C H 3 ) . Exact Mass calcd. f o r C 2 2 H 3 6 0 4 S 1 : 392.2384; found: 392.2378. Reaction of the Diene (145) with Nitroethylene R=SiMe„Bu t A s t i r r e d s o l u t i o n of the diene (145) (500.0 g, 1.426 mmol) and n i t r o e t h y l e n e 8 2 (-1 mL, excess) i n dry THF (20 mL) was heated to the r e f l u x temperature. The re a c t i o n mixture was refluxed f o r 7 h and then the s o l u t i o n was concentrated. The r e s i d u a l o i l was passed through a plug of s i l i c a g e l ( e l u t i o n with d i e t h y l ether) to remove the nitroethy-- 279 -lene polymers. Concentration of the r e s u l t i n g s o l u t i o n provided an o i l which contained a mixture of the three n i t r o esters i n a r a t i o of ~2. 5 : t r a c e : l (by XH nmr). Medium pressure chromatography of the crude r e a c t i n mixture on s i l i c a g el (90 g, e l u t i o n with petroleum ether-d i e t h y l ether, 10:1) allowed f o r the complete separation of three compounds. The f i r s t compound to be eluted was the n i t r o ester (197) (126.7 mg, 21%); the second compound to be eluted was the n i t r o ester (196) (18.6 mg, 3%); the t h i r d compound to be eluted was the n i t r o ester (195) (327.6 mg, 54%). These materials gave spectra ( i r , *H nmr, mass) i d e n t i c a l with those reported previously. Reaction of the Diene (146) with Methyl Acrvlate M e O i C v ^ s ^ Q p Me0 2C\ $6 C02Me 192 R=SiMe2Bu Me02C C02Me 194 A s t i r r e d s o l u t i o n of the diene (146) (170.0 mg, 0.485 mmol) and methyl a c r y l a t e (0.18 mL, 4.5 equiv) i n dry benzene (10 mL) was heated at the r e f l u x temperature. An a d d i t i o n a l 2 equiv of methyl acr y l a t e was added to the r e a c t i o n mixture a f t e r 24, 48 and 56 h. The mixture was refl u x e d f o r a t o t a l of 3 days and then the s o l u t i o n was concentrated. The analysis of the crude re a c t i o n mixture ind i c a t e d the presence of at - 280 -l e a s t 3 compounds. Medium pressure chromatography of the crude o i l on s i l i c a g el (40 g, e l u t i o n with petroleum-diethyl ether, 8:1), followed by concentration of the appropriate f r a c t i o n s , y i e l d e d 3 samples. The f i r s t compound to be eluted was i d e n t i f i e d as the d i e s t e r (194) (65.7 mg, 31%). This co l o u r l e s s o i l exhibited i r ( f i l m ) : 1733, 838, 777 cm - 1; •^H nmr (400 MHz, CDC1 3) 6: 0.06 and 0.07 (s, s, 3H each, -SiMe 2), 0.91 (s, 9H, -SiCMe 3), 1.15-1.72 (m, 8H), 1.78 (d of t, 1H, J - 6, 12.5 Hz), 1.87-2.02 (m, 3H), 2.06-2.27 (m, 3H), 2.34-2.46 (m, 2H), 3.44 ( t , 1H, one of -CH20-, J - 10 Hz), 3.65 and 3.67 (s, s, 3H each, two -OCH3), 3.74 (d of d, 1H, one of -CH20-, J - 3.8, 10 Hz). Exact Mass calcd. f o r c 2 4 H 4 0 ° 5 s i : 436.2644; found: 436.2645. The structure of the second compound to be eluted was not assigned but t h i s substance was determined to be a d i e s t e r isomer (4.1 mg, 2%). This c o l o u r l e s s o i l exhibited i r (CHCI3): 1730, 837, 778 cm - 1; 1H nmr (400 MHz, CDCI3) S: 0.03 and 0.04 (s, s, 3H each, -SiMe 2), 0.89 (s, 9H, -SiCMe 3), 0.97 (m, 1H), 1.13-1.36 (m, 3H), 1.40-1.65 (m, 4H), 1.82 (m, 1H), 1.89-2.04 (m, 3H), 2.10-2.34 (m, 3H), 2.58 (m, 1H), 2.72 (d of d of d, 1H, J - 3.2, 4.5, 13.5 Hz), 3.58 (d of d, 1H, one of -CH20-, J -4.5, 10.5 Hz), 3.64 (d of d, 1H, one of -CH20-, J - 7, 10.5 Hz), 3.66 and 3.665 (s, s, 3H each, two -OCH3). Exact Mass ca l c d . f o r C 24H4o°5 sl: 436.2645; found: 436.2649. The t h i r d f r a c t i o n obtained, a colourless o i l , was a 3:1 mixture (by XH nmr) of the di e s t e r s (192) and (193), r e s p e c t i v e l y (118.3 mg, 56%). This mixture was subjected to drip column chromatography on s i l i c a gel (27 g, e l u t i o n with petroleum-diethyl ether, 8:1). A pure sample of the major isomer (192) was obtained i n t h i s manner and t h i s colourless o i l - 281 -exhibited i r ( f i l m ) : 1733, 837, 776 cm"1; % nmr (400 MHz, CDC13) 6: 0.04 and 0.05 (s, s, 3H each, -SiMe 2), 0.89 (s, 9H, -SiCMe.3), 1.09 (d of t, 1H, J - 4, 13.2 Hz), 1.20-2.08 (m, 12H), 2.20 (m, 1H), 2.30 (m, 1H), 2.39 (br d, 1H, J - 13.5 Hz), 2.76 (d of d of d, 1H, J - 2.7, 6, 13.5 Hz), 3.63-3.70 (m, 2H b u r i e d under -OCH3 si g n a l s , -CH 20-), 3.67 and 3.71 (s, s, 3H each, two -OCH3). Exact Mass calcd. f o r C^H^OsSi: 436.2645; found: 436.2643. A pure sample of the minor isomer from t h i s f r a c t i o n was obtained by epimerization of the di e s t e r (192). Thus, a s t i r r e d s o l u t i o n of the di e s t e r (192) (20 mg, 0.458 mmol) and sodium methoxide (1.2 mg, 0.5 equiv) i n methanol (5 mL) was heated to the r e f l u x temperature. The rea c t i o n mixture was refl u x e d f o r 6 days and then the s o l u t i o n was concentrated. ^H nmr analysis of the crude mixture indi c a t e d that i t was comprised of a 9:1 r a t i o of the die s t e r s (193) and (192), respec-t i v e l y . Drip column chromatography of the crude mixture on s i l i c a g el (10 g, e l u t i o n with petroleum eth e r - d i e t h y l ether, 5:1) provided a pure sample of the d i e s t e r (193). This colourless o i l exhibited i r ( f i l m ) : 1735, 837, 777 cm"1; ^  nmr (400 MHz, CDCI3) 6: 0.06 (s, 6H, -SiMe 2), 0.91 (s, 9H, -SiCMe.3), 1.16 (d of t, 1H, J - 3.5, 13.5 Hz), 1.30 (m, 1H), 1.39-1.64 (m, 5H), 1.70-2.06 (m, 5H), 2.16-2.32 (m, 3H), 2.36-2.48 (m, 2H), 3.47 (d of d, 1H, one of -CH20-, J. - 8.5, 10 Hz), 3.66-3.72 (m, 1H buried under -OCH3 si g n a l s , one of -CH 20-), 3.68 and 3.69 (s, s, 3H each, two -OCH3). Exact Mass calcd. f o r C ^ ^ Q O S S I : 436.2645; found: 436.2645. - 282 -Preparation of the Aromatic Esters (227) and (228) Me0 2 C > 226 227 228 A s t i r r e d s o l u t i o n of the diene (147) (760.0 mg, 3.24 mmol) and methyl a c r y l a t e (2.9 mL, 10 equiv) was heated to the r e f l u x temperature. The r e a c t i o n mixture was refluxed f o r 3 days and then the s o l u t i o n was concentrated. Flash chromatography of the crude o i l on s i l i c a gel (100 g, e l u t i o n with petroleum eth e r - d i e t h y l ether, 10:1) without any attempt to separate isomers, provided 872.7 mg (84%) of a mixture of the die s t e r s (226) as a colourless o i l . Low r e s o l u t i o n g a s - l i q u i d chromato-graphy-mass spectrometry indicated that there were at l e a s t f i v e isomers present, a l l e x h i b i t i n g a M"*" peak at m/e 320. This mixture exhibited i r ( f i l m ) : 1733, 1158 cm"1; lE nmr (400 MHz, CDC13) 6: 0.82-2.77 (m, 22H), 3.65-3.71 ( s i x s, 6H, -OCH3 s i g n a l s ) . To a c o l d (0°C), s t i r r e d s o l u t i o n of LDA (2.5 equiv) i n dry THF (6 mL) was added, dropwise, a s o l u t i o n of the mixture of di e s t e r s (226) (50.0 mg, 0.156 mmol) i n dry THF (2 mL). 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 at 0°C f o r 30 min and then was warmed to room temperature and was s t i r r e d f o r a further 30 min. S o l i d phenylselenenyl ch l o r i d e (75 mg, 2.5 equiv) was then added and the r e s u l t i n g s o l u t i o n was s t i r r e d f o r 30 min. Water (1 mL), a c e t i c a c i d (0.04 mL, 4 equiv) and hydrogen - 283 -peroxide (0.18 mL, 10 equiv) were added i n succession and the r e s u l t i n g mixture was s t i r r e d f o r 1 h. Saturated aqueous sodium bicarbonate (10 mL) was added to the r e a c t i o n mixture and the organic phase was removed. The organic s o l u t i o n was washed with brine (10 mL), was d r i e d (MgS0 4), and then was concentrated. The crude o i l was d i s s o l v e d i n dry benzene (10 mL) and to the r e s u l t i n g s t i r r e d s o l u t i o n was added DDQ (40 mg, 1.1 equiv). The r e s u l t i n g s o l u t i o n was heated to the r e f l u x temperature and a f t e r 4 h at t h i s temperature, the solvent was removed by rotary evaporation. Drip column chromatography of the crude o i l on s i l i c a gel (18 g, e l u t i o n with petroleum ether-diethyl ether, 7:1), followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 130-140°C/0.1 To r r ) , provided 40.3 mg (82%) of a mixture of aromatic d i e s t e r s (227) and (228) as a colourless o i l i n a r a t i o of 1.4:1 r e s p e c t i v e l y . This mixture exhibited i r ( f i l m ) : 1724, 1598, 1565 cm - 1; XH nmr (400 MHz, CDC1 3) 6: 1.18 and 1.22 ( t , t, 3H, r a t i o 1:1.4, -CH 2CH 3), 1.43-1.90 (m, 6H), 2.30-2.40 (m, 2H), 2.60 and 2.86 (q, q, 2H, r a t i o 1.4:1, -CH2CH3, J - 7.5 Hz each), 2.69-2.82 (m, H d, H e, H f, H g, % and Hj), 3.00 (d of d of d, H a or H D, J - 18, 7, 4 Hz), 3.20 (d of t, H b or H a, J - 18, 9 Hz), 3.63 and 3.86 and 3.87 (s, s, s, 6H, r a t i o 2.4:1.4:1, -CC0 2CH 3 and two -CC0 2CH 3 r e s p e c t i v e l y ) , 7.38 and 7.59 (s, s, 1H, r a t i o 1:1.4, H n and H c r e s p e c t i v e l y ) . I r r a d i a t i o n at 8 2.60 (major -CH 2CH 3): s i g n a l at 8 1.22 (major -CH2CH3) s i m p l i f i e s to a s. I r r a d i a t i o n at 8 3.20 (H D or H a): s i g n a l at 8 3.00 (H a or H D) s i m p l i f i e s to a d of d (J - 4, 7 Hz). Exact  Mass calcd.' f o r C 1 9 H 2 4 0 4 : 316.1674; found: 316.1683. - 284 -3.2.4 (±)-(14S)-Dolasta-l(15),7,9-trien-14-ol (239) Experimental Preparation of the Hvdrazone (269) A s t i r r e d s o l u t i o n of the commercially a v a i l a b l e ketone (261) (19.5g, 98.3 mmol), and 1,1-dimethylhydrazine (9.0 mL, 1.2 equiv) i n dry benzene (200 mL) was heated to the r e f l u x temperature. The r e a c t i o n mixture was refluxed f o r 2 h and during t h i s time, water was removed using a Dean-Stark apparatus. The r e s u l t i n g s o l u t i o n was d r i e d (MgS04) and then was concentrated. D i s t i l l a t i o n of the r e s i d u a l pale yellow o i l (ai r - b a t h temperature 105-120°C/0.03 Torr) provided 23.5 g (99%) of the hydrazone (269) as a white c r y s t a l l i n e s o l i d (mp 45-46°C). This material exhibited i r (KBr): 2773, 1640 cm*1; AH nmr (80 MHz, CDC13) 5: 0.99 and 1.05 (s, s, 3H each, -CMe2), 1.83-2.15 (m, 4H), 2.20-2.75 (m, 4H), 2.49 (s, 6H, -NMe2). 3.56 (s, 4H, -0CH.2CCH20-) . Exact Mass calcd. f o r C 1 3H 240 2N 2: 240.1837; found: 240.1835. N-NMe 2 - 285 -Preparation of the Ketone (271) 270 271 To a c o l d (0°C), s t i r r e d s o l u t i o n of LDA (1.2 equiv) i n dry THF (100 mL) was added a s o l u t i o n of the hydrazone (269) (23.5 g, 97.8 mmol) i n dry THF (50 mL). 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 f o r 1.5 h at 0°C and then methyl iodide (12.2 mL, 2 equiv) was added. The re a c t i o n mixture was warmed to room temperature and was s t i r r e d at t h i s tempera-ture f or 2 h. Water (100 mL) was added to the re a c t i o n mixture and then the organic solvent was removed by rotary evaporation. The r e s i d u a l mixture was extracted with et h y l acetate (3 x 250 mL) and then with methylene c h l o r i d e (3 x 100 mL). The combined organic s o l u t i o n was d r i e d (MgSO^ and then was concentrated. A small amount of t h i s crude o i l was d i s t i l l e d (air-bath temperature 120-125°C/0.1 Torr) to provide the a l k y l a t e d hydrazone (270) as a pale yellow o i l : i r ( f i l m ) : 2772, 1637 cm - 1; XH nmr (80 MHz, CDC13) 6: 1.00 and 1.02 (s, s, 3H each, -CMe 2), 1.13 (d, 3H, -CHCH3, J - 7 Hz), 1.50-2.50 (m, 6H), 2.45 (s, 6H, -NMe2), 3.00 (m, 1H, -CHCH3), 3.55 (s, 4H, -0CH 2CCH 20-). Exact Mass cal c d . f o r C ^ ^ ^ N ^ 254.1996; found: 254.2003. A mixture of the crude hydrazone (270) and sodium metaperiodate (46.0 g, 2.2 equiv) i n THF (350 mL), water (100 mL) and pH 7 phosphate - 286 -bu f f e r (100 mL) was s t i r r e d (mechanical s t i r r e r ) at room temperature f o r 24 h. The THF was removed by rotary evaporation and the r e s i d u a l mixture was extracted with methylene chl o r i d e (6 x 150 mL). The combined organic s o l u t i o n was dr i e d (MgS04) and then was concentrated. The r e s u l t i n g brown s o l i d was r e c r y s t a l l i z e d from petroleum ether to provide 20.5 g (99%) of the ketone (271) as colou r l e s s needles (mp 66-66.5°C). This material exhibited i r (CHCl 3): 1711, 1115 cm"1; XH nmr (80 MHz, CDCI3) 6: 1.01 and 1.05 (s, s, 3H each, -CMe2), 1.06 (d, 3H, -CHCH3, J - 7 Hz), 1.45-2.00 (m, 2H), 2.20-2.80 (m, 5H), 3.55 and 3.58 (s, s, 2H each, -OCH2CCH20-). Exact Mass calcd. f o r C 1 2H 2 0O 3: 212.1412; found: 212.1413. Preparation of the Cyclopropane S i l v l Ethers (276) and (277) To a c o l d (0°C), s t i r r e d s o l u t i o n of LDA (1.5 equiv) i n dry DME (200 mL) was added, dropwise, a s o l u t i o n of the ketone (271) (31.4 g, 0.148 mol) In dry DME (75 mL). 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 f o r 45 min and then t r i m e t h y l s i l y l c h l o r i d e (56.3 mL, 3 equiv) and triethylamine (61.8 mL, 3 equiv) were added i n succession. The r e a c t i o n mixture was 275 276 277 - 287 -s t i r r e d f o r 30 min at 0°C and then was warmed to room temperature. D i e t h y l ether (100 mL) was added and the r e s u l t i n g s o l u t i o n was washed with c o l d (0°C) aqueous 2% sodium bicarbonate (3 x 50 mL). The organic s o l u t i o n was d r i e d (MgS04) and then was concentrated. The crude s i l y l enol ether (275) was dissolv e d i n dry toluene (200 mL) and to the r e s u l t i n g s t i r r e d s o l u t i o n was added d i e t h y l z i n c (166 mL of a 15% s o l u t i o n i n toluene, 1.36 equiv) and methylene iodide (16.2 mL, 1.36 equiv). The re a c t i o n mixture was heated to 55°C and was s t i r r e d f o r 15 h at t h i s temperature under an a i r atmosphere (drying tube). Diethyl ether (100 mL) and saturated aqueous ammonium chlo r i d e (100 mL) were added and the r e s u l t i n g mixture was extracted with d i e t h y l ether (3 x 150 mL). The combined organic s o l u t i o n was washed with aqueous 2% sodium bicarbonate (100 mL) and then was d r i e d (MgS04) and concentrated. 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 (air-bath temperature 110-115°C/0.1 Torr) provided 37.9 g (86%) of a 2:1 mixture (by XH nmr) of the cyclopropane s i l y l ethers (276) and (277) as a colou r l e s s o i l . This mixture ex h i b i t e d i r ( f i l m ) : 3073, 842, 754cm"1; lE nmr (400 MHz, CDC13) 6: 0.09 and 0.10 (s, s, r a t i o 2:1, 9H, -SiMe 3), 0.22 and 0.55 (t , d of d, r a t i o 1:2, 1H, J - 6 Hz, J - 5.2, 5.6 Hz), 0.70 and 0.73 ( t , d of t, r a t i o 2:1, 1H, J - 8 Hz, J - 1, 4.5 Hz), 0.88, 0.93, 0.935 and 0.94 ( a l l s, r a t i o 2:1:1:2, 6H, -CMe2), 1.04 and 1.12 (d, d, r a t i o 1:2, 3H, -CHCH3, J_ - 6.5 Hz, J - 7 Hz), 1.10-2.68 (m, 6H), 3.34-3.52 (m, 4H, -0CH2CCH20-). Exact Mass calcd. f o r C 1 6H 3o03Si: 298.1965; found: 298.1963. - 288 -Preparation of the Enone (279) CI 0 •cc 12 13 278 279 To a c o l d (0°C), s t i r r e d s o l u t i o n of dry f e r r i c c h l o r i d e (11.3 g, 3 equiv) i n dry DMF (75 mL) was added, dropwise over 2 h (syringe pump), a s o l u t i o n of pyridine (1.87 mL, 1 equiv) and the mixture of s i l y l enol ethers (276) and (277) (6.890 g, 23.2 mmol) i n dry DMF (30 mL). The co o l i n g bath was removed and the r e s u l t i n g mixture was s t i r r e d at room temperature f o r 2 h. Aqueous 2% hydrochloric a c i d (100 mL) was added and the r e s u l t i n g mixture was extracted with d i e t h y l ether (5 x 200 mL). The combined organic s o l u t i o n was washed with brine (150 mL) and then was d r i e d (MgSO^) and concentrated. The crude /J-chloro ketone (278) was di s s o l v e d i n methanol (100 mL), sodium acetate (13.3 g, 7 equiv) was added and the r e s u l t i n g mixture was heated to the r e f l u x temperature. The r e a c t i o n mixture was refluxed f o r 15 h and then was poured into water (50 mL). This mixture was extracted with d i e t h y l ether (5 x 100 mL). The combined organic s o l u t i o n was washed with saturated aqueous sodium bicarbonate (100 mL), d r i e d (MgS04) and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (360 g, e l u t i o n with petroleum ether-ethyl acetate, 4:1-1:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 126-130°C/0.1 To r r ) , provided - 289 -3.22 g (62%) of the enone (279) as a colourless o i l . This material exhibited i r ( f i l m ) : 1672, 1109 cm"1; XH nmr (400 MHz, CDCI3) 8: 0.93 and 1.02 (s, s, 3H each, -CMe2), 1.17 (d, 3H, -CHCH3, J - 7 Hz), 1.83 (d of d, 1H, H e or H f, J - 11.5, 14.7 Hz), 2.33 (d of d, 1H, H f or H e, J -3.3, 14.7 Hz), 2.63-2.77 (m, 2H, H c or H d and H g), 2.88 (d of d, 1H, H d or H c, J - 7.5, 16.5 Hz), 3.40-3.56 (m, 4H, -0CH2CCH20-), 6.08 (d of d, 1H, H a, J - 2.3, 12 Hz), 6.40 (d of d of d, 1H, H b, J - 5, 7.5, 12 Hz). I r r a d i a t i o n at S 2.33 (H f or H e): s i g n a l at 6 1.83 (H e or H f) s i m p l i f i e d to a d (J - 14.7 Hz), m u l t i p l e t at S 2.63-2.77 s i m p l i f i e d . I r r a d i a t i o n at 8 2.88 (H d or H c): mu l t i p l e t at 8 2.63-2.77 s i m p l i f i e d , s i g n a l at 8 6.40 (H b) s i m p l i f i e d to a d of d (J - 5, 12 Hz). I r r a d i a t i o n at 6 6.40 (H b): mu l t i p l e t at S 2.63-2.77 s i m p l i f i e d , s i g n a l at S 2.88 ( H d or H c) s i m p l i f i e d to a d (J - 16.5 Hz), s i g n a l at 8 6.08 (H a) s i m p l i f i e d to a br s. 1 3 C nmr (75.3 MHz, CDCI3) 8: 16.7 (-ve, C 8 ) , 22.4 (-ve, C 1 2 and C 1 3 ) , 29.9 ( C n ) , 36.8 ( C 4 or C 6 ) , 38.4 (Cg or C 4 ) , 41.6 (-ve, C 7 ) , 70.1 (C 9 or C 1 0 ) , 70.6 ( C 1 0 or C 9 ) , 100.2 ( C 5 ) , 133.0 (-ve, C 2 ) , 138.4 (-ve, C3), 204.3 (C^). Exact Mass calcd. f o r C 1 3 H 2 0 0 3 : 224.1412; found: 224.1410. - 290 -Preparation of the Ketone (262) A solution-suspension of the enone (279) (6.20 g, 27.7 mmol) and palladium-on-carbon (~200 mg, palladium content 10%) i n dry hexane (100 mL) was s t i r r e d over hydrogen gas (1 atm) f o r 2 h, employing a sloping manifold hydrogenation apparatus. The r e s u l t i n g mixture was f i l t e r e d through a plug of C e l i t e , washing with d i e t h y l ether (100 mL). The organic s o l u t i o n was d r i e d (MgS04) and then was concentrated. 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 (air-bath temperature 110-114°C/0.1 Torr) provided 6.20 g (99%) of the ketone (262) as a colourless o i l . This material exhibited i r ( f i l m ) : 1703, 1104 cm"1; XH nmr (400 MHz, CDC1 3) 6: 0.99 (s, 6H, -CMe2), 1.10 (d, 3H, -CHCH3, J - 7 Hz), 1.44 (d of d of d, 1H, J - 2.7, 12, 14.5 Hz), 1.56 (d of d, 1H, J - 11.5, 14.9 Hz), 1.69-1.93 (m, 2H), 2.25 (d of t, 1H, J - 14.9, 2.7 Hz), 2.42 (d of d of t, 1H, J - 14.5, 6, 2.2 Hz), 2.49 (d of d, 2H, J - 4.7, 8 Hz), 2.78 (m, 1H), 3.40-3.57 (m, 4H, -0CH.2CCH20-) . 1 3 C nmr (75.3 MHz, CDCI3) 6: 17.4 (-ve), 17.9, 22.5 (-ve), 22.6 (-ve), 30.0, 35.6, 39.08, 39.14 (-ve), 42.3, 69.9, 70.0, 98.3, 215.3. Exact Mass calcd. f o r C 1 3 H 2 2 0 3 : 226.1570; found: 226.1565. - 291 -Preparation of the Alkylated Ketone (282) 280 281 282 To a s t i r r e d s o l u t i o n of potassium tert-butoxide (6.796 g, 2.7 equiv) i n a mixture of dry t e r t - b u t y l alcohol (5 mL) and dry DME (150 mL) was added a s o l u t i o n of the ketone (262) (5.060 g, 22.36 mmol) i n dry DME (50 mL). The r e s u l t i n g mixture was s t i r r e d f o r 45 min at room temperature and then a s o l u t i o n of the bromide (154) (9.800 g, 1.3 equiv) i n dry DME (50 mL) was added. The s o l u t i o n was s t i r r e d f o r 15 min at room temperature and then water (100 mL) was added. The r e s u l t i n g mixture was extracted with et h y l acetate (3 x 150 mL). The combined organic s o l u t i o n was d r i e d (MgS04) and then was concentrated. T i c analysis of the crude product mixture indicated the presence of three products l e s s polar than the ketone (262). Medium pressure chromato-graphy of the r e s i d u a l o i l on s i l i c a g el (360 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 6:1) provided three f r a c t i o n s . The f i r s t compound to be eluted was a mixture of the two diastereomers of the d i a l k y l a t e d ketone (280) (1.761 g, 11%). This colourless o i l exhibited i r ( f i l m ) : 1703, 1611, 770 cm'1; XH nmr (270 MHz, CDC13) 6: 0.164, 0.167, 0.179 and 0.186 ( a l l s, r a t i o undetermined, four -SnMe.3), 0.80-1.15 (-CHMe2 and -CCH3 s i g n a l s ) , 1.15-2.55 ( a l i p h a t i c protons on cycloheptane r i n g - 292 -and side chain), 3.30-3.60 (-0CH2CCH20- protons), 5.75-5.95 ( v i n y l protons). Exact Mass calcd. f o r C3 0H 5 503Sn 2 (M+'C^): 703.2195;-found: 703.2218. The second compound to be eluted was a sing l e monoalkylated isomer (281) of undetermined stereochemistry (210 mg, 2%). This c o l o u r l e s s o i l e x h i b i t e d i r ( f i l m ) : 1707, 1613, 1107, 770 cm"1; AH nmr (270 MHz, CDCl 3) 6: 0.16 (s, 9H, -SnMe.3, J S n . H - 53 Hz), 0.90 and 0.92 (s, s, 3H each, -CMe 2), 0.94 (d, 6H, -CHMe2, J - 7 Hz), 1.01 (d, 3H, -CHCH3, J - 7 Hz), 1.20-1.70 (m, 4H), 1.94-2.05 (m, 2H), 2.18-2.50 (m, 4H), 2.60-2.75 (m, 1H), 3.34-3.47 (m, 4H, -0CH2CCH20-), 5.82 ( t , 1H, v i n y l proton, J - 7 Hz). Exact Mass calcd. f o r C 2 1 H 3 7 0 3 S n (M+-CH3): 457.1765; found: 457.1769. The t h i r d compound to be eluted was the desired ketone. 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 (air-bath temperature 188-193°C/0.1 Torr) provided 6.170 g (59%) of the ketone (282) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1706, 1611, 1100, 770 cm - 1; AH nmr (400 MHz, CDCI3) 6: 0.20 (s, 9H, -SnMe.3, J S n . H - 52 Hz), 0.99 (d, 6H, -CHMe2, J - 7 Hz), 0.82 and 1.05 and 1.15 (s, s, s, 3H each, -CMe2 and -CCH 3), 1.58-1.84 (m, 3H), 2.06 (s, 2H), 2.13-2.27 (m, 3H), 2.38-2.50 (m, 2H, one u n i d e n t i f i e d proton plus -CHMe2), 2.65 (m, 1H), 3.32-3.58 (m, 4H, -0CH 2CCH 20-), 5.92 ( t , 1H, v i n y l proton, 1 - 7 Hz, J S n . H - 146 Hz). 1 3C nmr (75.3 MHz, CDCI3) 6: -6.9, 20.4, 22.3, 22.89, 22.95, 23.0, 23.1, 30.0, 31.8, 38.1, 39.5, 44.6, 46.0, 48.2, 69.8, 70.0, 100.0, 131.1, 154.5, 215.2. Exact Mass calcd. f o r C 2 1 H 3 7 0 3 S n ( M 4 " - ^ ) : 457.1765; found: 457.1772. - 293 -Preparation of the Diene (263) TfO SnMe3 H b 283 263 To a c o l d (-78°C), s t i r r e d s o l u t i o n of LDA (1.5 equiv) i n dry THF (70 mL) was added HMPA (2.59 mL, 2 equiv). The pale yellow s o l u t i o n was s t i r r e d f o r 10 min at -78°C and then at 0°C f o r 10 min. The r e s u l t i n g s o l u t i o n was cooled to -78°C and then the ketone (282) (3.500 g, 7.436 mmol) was added as a s o l u t i o n i n dry THF (30 mL). The re a c t i o n mixture was s t i r r e d f o r 5 min at -78°C and then was warmed to 0°C and s t i r r i n g was continued at t h i s temperature f o r 1 h. N-Phenyltrifluoromethanesul-fonimide (4.14 g, 1.57 equiv) was added as a powdery s o l i d and the r e s u l t i n g mixture was s t i r r e d f o r 2 h at room temperature. Palladium tetrakis(triphenylphosphine) (429 mg, 5 mol %) was added and the so l u t i o n was warmed to the r e f l u x temperature f o r 5 min. The solvent was removed by rotary evaporation and the r e s i d u a l o i l was subjected to f l a s h chromatography on s i l i c a g e l (240 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 20:1). Concentration of the appropriate f r a c t i o n s , followed by d i s t i l l a t i o n of the r e s i d u a l o i l (air-bath temperature 142-146°C/0.1 T o r r ) , provided 1.748 g (81%) of the diene (263) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1647, 1111, 832 cm"1; XH nmr (400 MHz, CDCI3) 6: 0.93, 1.02 and 1.20 (s, s, s, 3H each, -CMe2 and -CCH3), 1.03 and 1.10 (d, d, 3H, each, -CHMe2, J - 7 Hz each), - 294 -1.53 (d, 1H, H c or H d, J - 14 Hz), 1.59 (br d, 1H, H d or H c, J - 14 Hz), 2.03-2.48 (m, 6H), 2.51 (d of d, 1H, J - 2.3, 14 Hz), 3.40-3.60 (m, 4H, -0CH.2CCH.20-). 5.54 (br s, 1H, Ha, w 1 / 2 - 6.5 Hz), 5.60 (d of d, 1H, H b, J - 4.8, 8.2 Hz). 1 3 C nmr (75.3 MHz, CDC13) 6: 20.7, 21.8 (-ve), 22.2 (-ve), 22.7 (-ve), 22.9 (-ve), 25.4 (-ve), 25.6 (-ve), 30.1, 36.5, 42.5, 43.7, 50.0, 69.8, 69.9, 100.4, 116.9 (-ve), 124.6 (-ve), 149.9, 154.9. Exact Mass ca l c d . f o r C19H3o02: 290.2246; found: 290.2248. In a separate experiment, the enol t r i f l a t e (283) was Isolated according to general procedure 7 (240 g s i l i c a g e l , e l u t i o n with petroleum e t h e r - d i e t h y l ether, 10:1 i n f l a s h chromatography). The colou r l e s s o i l exhibited i r ( f i l m ) : 1670, 1412, 1212, 1144, 768 cm"1; ^ nmr (300 MHz, CDCI3) 6: 0.21 (s, 9H, -SnMe3, J S n . H - 52 Hz), 0.94 and 0.97 (s, s, 3H each, -CMe2), 1.00 (d, 6H, -CHMe2, J - 7 Hz), 1.22 (s, 3H, -CCH 3), 1.90-2.30 (m, 7H), 2.39-2.52 (m, 2H), 3.40-3.60 (m, 4H, -0CH2CCH20-), 5.88-5.98 (m, 2H, v i n y l protons). Exact Mass calcd. f o r c 2 2 H 3 6 ° 5 S F 3 S n (M+-CH3): 589.1258; found: 589.1263. Preparation of the Ketone (264) A s o l u t i o n of the k e t a l (263) (1.1372 g, 3.915 mmol) and 5 drops of - 295 -aqueous 1 M hydrochloric a c i d i n acetone (50 mL) was s t i r r e d at room temperature f o r 3 h. The acetone was removed by rotary evaporation and water (50 mL) was added to the residue. The aqueous s o l u t i o n was extracted with d i e t h y l ether (3 x 50 mL) and the organic s o l u t i o n was d r i e d (MgS04) and concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a g e l (70 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 7:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l ( a i r - b a t h tempera-ture 82-85°C/0.1 To r r ) , provided 796.4 mg (99%) of the ketone (264) as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1704, 1640, 831 cm - 1; XH nmr (400 MHz, CDC13) 6: 1.10 (s, 3H, -CCH3), 1.07 and 1.14 (d, d, 3H each, -CHMe2, J - 7 Hz each), 2.22 (d of d, 1H, H e or H f, J - 2.4, 17 Hz), 2.33-2.60 (m, 7H), 2.72 (d, 1H, H c or H d, J - 11.8 Hz), 5.64 (br s, 1H, H a, wX/2 - 6.5 Hz), 5.71 ( t , 1H, H b, J - 6.2 Hz). I r r a d i a t i o n at 5 2.22 (H e or H f): s i g n a l at 5 5.64 (H a) sharpened (wX/2 - 4.5 Hz), mu l t i p l e t at 6 2.33-2.60 s i m p l i f i e d . I r r a d i a t i o n at 6 5.64 (H a): s i g n a l at S 2.22 (H e or Hf) s i m p l i f i e d to a d (J - 17 Hz). I r r a d i a t i o n at S 5.71 ( H b ) : m u l t i p l e t at 5 2.33-2.60 s i m p l i f i e d . 1 3 C nmr (75.3 MHz, CDCI3) 6: 21.7 (-ve), 22.0 (-ve), 23.2, 25.4 (-ve), 25.6 (-ve), 43.3, 45.0, 48.1, 55.2, 115.5 (-ve), 125.8 (-ve), 149.8, 155.3, 211.8. Exact  Mass calcd. f o r C 1 4H 2oO: 204.1515; found: 204.1518. - 296 -Preparation of the Hvdrazone (289) A s t i r r e d s o l u t i o n of the ketone ( 2 6 4 ) (200 mg, 0.979 mmol) and 1,1-dimethylhydrazine (0.74 mL, 10 equiv) i n s p e c t r a l grade methanol (20 mL) was refluxed i n the presence of 3 A molecular sieves (-20) f o r 4.5 h. The s o l u t i o n was cooled to room temperature and then f i l t e r e d , washing with d i e t h y l ether (20 mL). The r e s u l t i n g f i l t r a t e was concen-trate d . 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 (air-bath temperature 95-105°C/0.1 Torr) provided 238 mg (98%) of the hydrazone (289) as a col o u r l e s s o i l . This material, a mixture of geometric isomers i n a r a t i o of -2:1 ( XH nmr), exhibited i r ( f i l m ) : 2769, 1626, 1447, 828 cm"1; XH nmr (400 MHz, CDCI3) 6: 1.07 (s, 3H, -CCH3), 1.04 and 1.11 (d, d, 3H each, -CHMe2. J - 7 Hz each), 1.95-2.65 (m, 8H), 2.41 and 2.49 (s, s, r a t i o 1:2, 6H, -NMe2), 3.31 and 3.59 (m, d of d, r a t i o 2:1, 1H, J - 1.8, 12.4 Hz), 5.58-5.67 (m, 2H, v i n y l protons). Exact Mass calcd. f o r C 1 6H 2 6N 2: 246.2096; found: 246.2095. - 297 -Preparation of the Ketones (287) and (288) 287 288 To a c o l d (0°C), s t i r r e d s o l u t i o n of LDA (1.2 equiv) i n dry THF (10 mL) was added, dropwise, a s o l u t i o n of the hydrazone (289) (345 mg, 1.400 mmol) i n dry THF (10 mL). 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 f o r 1 h at -78°C and f o r 1 h at 0°C. To the deep red re a c t i o n mixture was added a s o l u t i o n of the iodide (43) (502 mg, 1.2 equiv) i n dry THF (6 mL). This s o l u t i o n was warmed to room temperature and was s t i r r e d f o r 1 h. Saturated aqueous ammonium chloride (25 mL) was added and the organic phase was removed. The aqueous s o l u t i o n was extracted with d i e t h y l ether (3 x 100 mL). The combined organic s o l u t i o n was dr i e d (MgS04) and then was concentrated. The r e s i d u a l o i l was dissolv e d i n THF (30 mL) and then water (8 mL), pH 7 phosphate buf f e r (9 mL) and sodium metaper-iodate (1.198 g, 4 equiv) were added. The r e s u l t i n g , s t i r r e d mixture was heated at 40°C f o r 48 h. Saturated aqueous ammonium chlo r i d e (10 mL) was added and the organic phase was separated. The aqueous s o l u t i o n was extracted with d i e t h y l ether (3 x 100 mL) and the combined organic s o l u t i o n was d r i e d (MgS04) and concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a g el (50 g, e l u t i o n with petroleum ether-d i e t h y l ether, 10:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air- b a t h temperature 190-200°C/0.1 Torr) provided 420 mg (69%) of the - 298 -ketone (287) as a colourless o i l . This material exhibited i r ( f i l m ) : 1699, 1641, 915, 841, 768 cm'1; lH nmr (400 MHz, CDC1 3) 6: 0.13 (s, 9H, -SnMe3, J S n . H - 52 Hz), 1.08 (s, 3H, -CCH 3), 1.07 and 1.13 (d, d, 3H each, -CHHe2. J - 7 Hz each), 1.22-1.50 (m, 3H), 1.66 (m, 1H), 2.15-2.65 (m, 8H), 2.40 (br d, 1H, H e or H f, 2 - 1 2 Hz), 2.79 (d, 1H, H f or H e, J - 12 Hz), 5.13 (m, 1H, H a, I S n . H - 71 Hz), 5.52 (d of d, 1H, H c, J -8.5, 4.8 Hz), 5.63 (m, 2H, H b and H d, l S n - H ~ 1 5 2 H z>- U ° m r < 7 5- 3 MHz, CDCI3) 6: -9.5, 21.9, 22.0, 24.9, 25.5, 27.2, 27.7, 30.0, 40.5, 43.4, 48.4, 51.3, 54.6, 112.6, 124.8, 126.1, 149.6, 155.0, 155.2, 213.7. Exact Mass ca l c d . f o r C 2 1H 3 3OSn (M+'C^): 421.1554; found: 421.1545. A small amount of the ketone (287) (10 mg) was dissol v e d i n methanol and to the s t i r r e d s o l u t i o n was added sodium methoxide (-1 mg). This s o l u t i o n was s t i r r e d at room temperature f or 22 h and then the solvent was removed by rotary evaporation. Glc analysis of the crude r e a c t i o n mixture i n d i c a t e d that i t was composed of a mixture of the ketones (288) and (287) i n a r a t i o of 1.4:1, re s p e c t i v e l y . A sample of the ketone (288) was obtained by drip column chromatography of the r e s i d u a l o i l on s i l i c a g e l (5 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 10:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 190-200°C/0.1 T o r r ) . The ketone (288) was obtained as a colo u r l e s s o i l . This material exhibited i r ( f i l m ) : 1705, 1642, 914, 833, 768 cm"1; XH nmr (400 MHz, CDC1 3) S: 0.13 (s, 9H, -SnMe3, Isn-H " 5 4 H z> - ! - 0 4 < s» 3H, -CCH3), 1.05 and 1.13 (d, d, 3H each, -CHMe2, 2 - 7 Hz each), 1.19-1.43 (m, 3H), 1.77 (m, 1H), 2.05-2.52 (m, 8H), 2.55 and 2.61 (d, d, 1H each, H k and ^ , 1 - 1 1 Hz each), 5.13 (m, 1H, H g, J S n . H - 71 Hz), 5.63 (m, 2H, H h and Hj, J S n . H - 152 Hz), 5.67 (d of d, 1H, H i ( J - 4.5, - 299 -9 Hz). 1 3 C nmr (75.3 MHz, CDC13) S: -10.0, 21.7, 22.0, 25.36, 25.38, 27.4, 30.5, 30.6, 40.8, 43.5, 48.0, 54.0, 55.1, 114.7, 124.5, 125.9, 149.7, 155.2, 155.4, 212.1. Exact Mass calcd. f o r C 2iH 3 3OSn (M+'CH;}) : 421.1554; found: 421.1557. Preparation of the Methylated Ketone (265) A s t i r r e d s o l u t i o n of the ketone (287) (150.0 mg, 0.345 mmol) and potassium tert-butoxide (155 mg, 5 equiv) i n a mixture of dry THF (11 mL) and dry HMPA (3 mL) was heated at 60°C f o r 1 h. To the r e s u l t i n g dark red s o l u t i o n was added methyl iodide (0.129 mL, 6 equiv) and the rea c t i o n mixture was s t i r r e d f o r 15 min at 60"C. The s o l u t i o n was poured into water (25 mL). The organic phase was separated and the aqueous phase was extracted with d i e t h y l ether (3 x 50 mL). The combined organic s o l u t i o n was dr i e d (MgS04) and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a g e l (40 g, e l u t i o n with petroleum eth e r - d i e t h y l ether, 20:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 220-230°C/0.1 T o r r ) , provided 97.0 mg (63%) of the ketone (265) as a pale yellow o i l . D i s t i l l a t i o n of Me 3 Sn-- 300 -the material was not done on' a routine basis since decomposition accompanied t h i s process, accounting f o r the coloured product. This o i l e x h i b i t e d i r ( f i l m ) : 1706, 1621, 915, 768 cm'1; *H nmr (300 MHz, CDC13) 6: 0.13 (s, 9H, -SnMe3, J_sn-H " 5 4 H z ) • 1 - 0 3 a n d <s' s» 3 H e a c h > two -CCH 3), 1.01 and 1.08 (d, d, 3H each, -CHMe2, J - 7 Hz each), 1.20-1.70 (m, 4H), 2.00 (d of d, 1H, 1 - 8 , 14 Hz), 2.10 (d of d, 1H, J - 3, 16 Hz), 2.22 (br t, 2H, 1 - 7 Hz), 2.30-2.50 (m, 3H), 2.43 (d, 1H, H e or H f, 1 - 1 2 Hz), 2.83 (d, 1H, H f or H e, 1 - 1 2 Hz), 5.12 (m, 1H, H a - ISn-H " 7 2 H z > » 5.51-5.58 (m, 2H, H c and H d), 5.63 (m, 1H, H b, J S n . H - 154 Hz). Exact Mass calcd. for C22H350Sn (M+-CH3): 435.1710; found: 435.1704. Preparation of the V i n y l Iodide (266) To a s t i r r e d s o l u t i o n of the vinylstannane (265) (65.1 mg, 0.145 mmol) i n dry methylene chl o r i d e (10 mL) was added, dropwise, a s o l u t i o n of iodine i n dry methylene c h l o r i d e (~3.6 mL of a 0.04 M s o l u t i o n , 1 equiv) u n t i l the pale red colour, which indicated the presence of excess iodine, p e r s i s t e d . The pale red s o l u t i o n was s t i r r e d f o r a f u r t h e r 15 min and then water (10 mL) and d i e t h y l ether (100 mL) were added. The - 301 -organic phase was separated and then was washed with saturated aqueous sodium t h i o s u l f a t e u n t i l the organic phase was c o l o u r l e s s . The r e s u l t -ing s o l u t i o n was d r i e d (MgSO^) and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (40 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 20:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (air-bath temperature 210-220°C/0.1 T o r r ) , provided 55.5 mg (93%) of the v i n y l iodide (266) as a pale yellow o i l . D i s t i l l a t i o n of t h i s material was not done on a routine basis since decomposition accompanied t h i s process, accounting f o r the coloured product. This o i l ex h i b i t e d i r ( f i l m ) : 1704, 1617, 893 cm"1; lU nmr (400 MHz, CDC13) 6: 1.09 and 1.13 (s, s, 3H each, two -CCH3), 1.03 and 1.10 (d, d, 3H each, -CHMe2, J - 7 Hz), 1.25-1.65 (m, 4H), 2.04 (d, of d, 1H, tit or Hj, J -8.5, 15 Hz), 2.14 (d of d, 1H, H g or H h, J - 2, 16 Hz), 2.33-2.44 (m, 3H), 2.44-2.52 (m, 2H), 2.54 (d, 1H, H e or H f, J - 12 Hz), 2.81 (d, 1H, H f or H e, J - 12 Hz), 5.55 (d of d, H c, J - 6, 8.5 Hz), 5.60 (br s, 1H, H d, W-L/2 - 6 Hz), 5.71 (d, 1H, H a, J - 1.5 Hz), 6.03 (m, 1H, H b). Exact  Mass ca l c d . f o r C20H29OI: 412.1265; found: 412.1261. - 302 -Preparation of (±)- ( 1 U S ) - D o l a s t a - l f 1 5 ) . 7 . 9 - t r i e n - 1 4 - o l (239) To a s t i r r e d s o l u t i o n of the v i n y l iodide (266) (28.0 mg, 0.068 mmol) i n dry THF (10 mL) was added m e t a l l i c magnesium (small, f i n e l y ground pieces, -20 mg, -12 equiv). This mixture was heated to the r e f l u x temperature and then one drop of 1,2-dibromoethane (passed through a plug of basic alumina immediately p r i o r to use) was added. The rea c t i o n mixture was refluxed f or 2.5 h and then was cooled to room temperature. Saturated aqueous ammonium chloride (5 mL) was added and the organic phase was separated. The aqueous phase was extracted with d i e t h y l ether (3 x 10 mL). The combined organic s o l u t i o n was d r i e d (MgS0 4) and then was concentrated. Drip column chromatography of the r e s i d u a l o i l on s i l i c a gel (7 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 20:1) provided, a f t e r concentration of the appropriate f r a c t i o n s , 9.5 mg (49%) of (±)-(14S)-dolasta-l(15),7,9-trien-14-ol (239) as a white c r y s t a l l i n e s o l i d . R e c r y s t a l l i z a t i o n from heptane provided the alcohol (239) as needle-shaped c r y s t a l s (mp 105-106°C), which exhibited i r (CHC1 3): 3604, 3500, 1639, 1002, 906 cm - 1; XH nmr (400 MHz, C 6D 6) 6: 0.92 (s, 3H, -CCH3 trans to -OH), 1.11 and 1.14 (d, d, 3H each, -CHMe2, J - 7 Hz each), 1.25-1.35 (m, 1H, H e or H f), 1.39 (s, 3H, -CCH3 c i s to - 303 --OH), 1.43-1.66 (m, 2H, H f or H e and H g or H h), 1.48 (d, 1H, H Q or H p, J = 14.5 Hz), 1.51 (d of d, 1H, HL, J - 9.5, 15 Hz), 1.97 (br d, 1H, H c, J - 12.5 Hz), 2.03 (d, 1H, Hp or H Q, J - 14.5 Hz), 2.05-2.15 (m, 2H, H h or H g and H m or H n), 2.22 (br d, 1H, H n or HJJ, J - 17 Hz), 2.42 (septet, 1H, -CHMe2, J = 7 Hz), 2.60 (d of d of d, 1H, H d, J = 6, 12.5, 12.5 Hz), 3.22 (d of d, 1H, H j , J = 4.5, 15 Hz), 4.61 (br s, 1H, H a or H b, wX/2 " 4 Hz), 4.78 (br s, 1H, H b or H a, w 1 / 2 = 4 Hz), 5.46 (d of d, 1H, H k, J -4.5, 9.5 Hz), 5.54 (br s, 1H, H L, wL/2 = 6.5 Hz). I r r a d i a t i o n at 5 2.60 (H d): m u l t i p l e t at 5 1.43-1.66 s i m p l i f i e d , s i g n a l at 8 1.97 (H c) s i m p l i f i e d to a br s. I r r a d i a t i o n at S 3.22 (Hj): s i g n a l at 8 1.51 (H^) s i m p l i f i e d to a d (J = 9.5 Hz), s i g n a l at 5 5.46 (H k) s i m p l i f i e d to a d (J = 9.5 Hz). I r r a d i a t i o n at 5 5.46 (H k): s i g n a l at 8 1.51 (Hi) s i m p l i f i e d to a d (J = 15 Hz), s i g n a l at 8 3.22 (Hj) s i m p l i f i e d to a d (J = 15 Hz). 1 3 C nmr (100.4MHz, CDCI3) 8: 19.8, 22.1, 22.2, 23.2, 25.6, 27.4, 32.0, 35.1, 37.2, 41.5, 43.4, 45.4, 50.9, 79.5, 108.4, 114.4, 124.7, 149.8, 153.9, 154.1. Exact Mass calcd. f o r C 2 0H 3 00: 286.2297; found: 286.2297. Compound (239) exhibited spectra (^-H nmr, i J C nmr, mass) i n good agreement with those derived from natural (14S)-dolasta-1(15),7,9-trien-14-ol. 9 1 S We would l i k e to thank Professor Crews f o r copies of the spectra ( iH nmr, i 3 C nmr, mass) of natural (239). - 304 -3.2.5 (±)-AmijItrienol (242) Experimental Preparation of the Ketone (249) 293 294 To a c o l d (-48°C), s t i r r e d s o l u t i o n of l i t h i u m (535 mg, -10 equiv) i n l i q u i d ammonia (-100 mL), which had previously been s t i r r e d f o r 30 min at -48°C, was added a s o l u t i o n of the diene (263) (2.2390 g, 7.709 mmol) i n dry d i e t h y l ether (50 mL). The dark blue s o l u t i o n was s t i r r e d f o r 1.75 h at -48°C and then saturated aqueous ammonium chlo r i d e (50 mL) was added c a r e f u l l y with vigorous s t i r r i n g . The co o l i n g bath was replaced with a hot water bath (- 50°C) and the ammonia was allowed to evaporate over 2 h. The organic phase was separated and the aqueous phase was extracted with d i e t h y l ether (3 x 200 mL). The combined organic s o l u t i o n was d r i e d (MgS04) and then was concentrated. 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 (air-bath temperature 125-135°C/0.1 Torr) provided 2.2225 g (99%) of a colourless o i l . Glc analysis i n d i c a t e d that t h i s c o l o u r l e s s o i l was a mixture of the ket a l s (294) and (293) i n a r a t i o of 4:1, re s p e c t i v e l y . Both of these compounds displayed a peak f o r the MT*" at m/e 292 i n a low r e s o l u t i o n g a s - l i q u i d chromato-graphy-mass spectrometry experiment. This o i l (2.1225 g, 7.257 mmol) was dissol v e d i n s p e c t r a l grade - 305 -hexane (100 mL) and iodine (184 mg, 0.1 equiv) was added. The s t i r r e d pale red s o l u t i o n was refluxed f o r 3 h and then saturated aqueous sodium t h i o s u l f a t e was added u n t i l the organic s o l u t i o n was co l o u r l e s s . The organic phase was removed and the aqueous phase was extracted with d i e t h y l ether (3 x 25 mL). The combined organic s o l u t i o n was dr i e d (MgS04) and then was concentrated. Glc analysis i n d i c a t e d that the mixture of (293) and (294) had been completely converted into (294). The re s i d u a l o i l was dissolved i n acetone (100 mL) and to the r e s u l t i n g s t i r r e d s o l u t i o n was added aqueous 1 M HCI (-1 mL). This s o l u t i o n was s t i r r e d at room temperature f o r 1 h and then saturated aqueous sodium bicarbonate (50 mL) was added. The organic phase was separated and the aqueous phase was extracted with d i e t h y l ether (3 x 25 mL). The combined organic s o l u t i o n was dr i e d (MgSO^ and then was concentrated. D i s t i l l a t i o n of the crude o i l (air-bath temperature 80-85°C/0.1 Torr) provided 1.3930 g (93%) of the ketone (249) as a colou r l e s s o i l . This material exhibited i r ( f i l m ) : 1703, 1456, 1185 cm - 1; XH nmr (400 MHz, CDC13) 6: 0.95 and 0.98 (d, d, 3H each, -CHMe2, J - 7 Hz), 1.04 (s, 3H, -CCH 3), 1.52-1.74 (m, 3H), 1.88-2.00 (m, 2H), 2.18-2.25 (m, 2H), 2.37-2.44 (m, 2H), 2.55 (s, 2H, H a and H b), 2.61-2.71 (m, 2H). 1 3 C nmr (75.3 MHz, CDC1 3) 6: 21.0 (-ve), 21.5 (-ve), 24.0, 24.2, 24.8 (-ve), 26.6 (-ve), 27.3, 38.1, 43.9, 47.6, 54.9, 138.6, 141.9, 213.1. Exact  Mass c a l c d . f o r C14H220: 206.1671; found: 206.1671. This substance i s s p e c t r a l l y i d e n t i c a l * with material prepared previously by Pattenden and Robertson ( AH nmr). 9 2 We would l i k e to thank Professor Pattenden f o r a copy of the -4" nmr spectrum of (249). - 306 -In a separate experiment, a small amount of the k e t a l (294) was i s o l a t e d a f t e r the iodine isomerization r e a c t i o n by d i s t i l l a t i o n of the crude o i l (air-bath temperature 126-134°C/0.1 T o r r ) . The colo u r l e s s o i l exh i b i t e d i r ( f i l m ) : 2954, 1110 cm - 1; -^H nmr (400 MHz, CDC1 3) 6: 0.92 and 0.97 (s, s, 3H each, -CMe2), 0.93 and 0.94 (d, d, 3H each, -CHMe2, 1 - 7 Hz each), 1.04 (s, 3H, -CCH.3), 1.40-1.51 (m, 2H), 1.70-1.97 (m, 7H), 2.10-2.23 (m, 2H), 2.46 (d of t, 1H, J - 7, 14 Hz), 2.63 (septet, 1H, -CHMe2, J - 7 Hz), 3.39-3.54 (m, 4H, -0CH 2CCH 20-). 1 3 C nmr (75.3 MHz, CDCI3) 6: 20.2, 21.2 (-ve), 21.4 (-ve), 22.76 (-ve), 22.81 (-ve), 23.6, 25.6 (-ve), 26.7 (-ve), 27.1, 30.0, 33.2, 39.5, 45.3, 47.7, 69.8, 69.9, 101.1, 139.2, 140.2. Exact Mass calcd. f o r C 1 9 H 3 2 0 2 : 292.2404; found: 292.2402. This substance exhibited spectra i n good agreement with those reported by Wolf and co-workers (mass, AH nmr, i r ) i i 0 f o r compound (294). Preparation of 4-Trimethylstannvlpent-4-en-l-ol (297) To a c o l d (-78°C), s t i r r e d s o l u t i o n of the (trimethylstannyl)copper reagent (33) (1.5 equiv) i n dry THF (300 mL) was added, dropwise, a s o l u t i o n of commercially a v a i l a b l e pent-4-yn-l-ol (2.454 g, 29.17 mmol) - 307 -i n dry THF (15 mL). Anhydrous methanol (59 mL, -50 equiv) was added and the r e s u l t i n g s o l u t i o n was s t i r r e d f o r 2 h at -78°C and then f o r 1 h at 0°C. Saturated aqueous ammonium chloride (pH 8) (150 mL) and petroleum ether (200 mL) were then added and, with vigorous s t i r r i n g , the r e a c t i o n mixture was warmed to room temperature. S t i r r i n g was continued u n t i l the aqueous phase was blue and then the organic phase was removed. The organic phase was washed with saturated aqueous ammonium ch l o r i d e (pH 8) (3 x 100 mL), d r i e d (MgS04) and then was concentrated. Flash chromato-graphy of the r e s i d u a l o i l on s i l i c a gel (180 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 2:1), followed by d i s t i l l a t i o n of the r e s u l t i n g o i l (ai r - b a t h temperature 95-100°C/20 T o r r ) , provided 3.906 g (54%) of the alcohol (297) as a colourless l i q u i d . This material exhibited i r ( f i l m ) : 3322, 1601, 1059, 916, 769 cm"1; XH nmr (80 MHz, CDC13) 6: 0.16 (s, 9H, -SnMe3, J.sn-H ~ 5 3 H z ) > ! - 3 6 ( D r s ' 1 H> _ 0 H.» disappears on ad d i t i o n of D 20), 1.54-1.88 (m, 2H, -CH 2CH 2CH 2-), 2.38 (br t, 2H, =CCH2-, J - 7 Hz), 3.65 (br t, 1H, -CH20H, J - 7 Hz, sharpens on ad d i t i o n of D 20), 5.18 (m, 1H, H a, J S n . H " 70 Hz), 5.71 (d of t, 1H, H b, J - 2.5, 1.3 Hz, J_sn-H ~ 1 5 1 H z ) • Exact Mass calcd. f o r CyH^OSn (M+-CH3): 235.0144; found: 235.0139. - 308 -Preparation of 4-Trimethylstannylpent-4-en-l-al ( 2 9 1 ) Ho.YHb To a c o l d (-78°C), s t i r r e d s o l u t i o n of o x a l y l c h l o r i d e (1.58 mL, 1.3 equiv) i n dry methylene chl o r i d e (100 mL) was added dry DMSO (1.29 mL, 1.3 equiv). 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 f o r 5 min and then the alcohol (297) (3.4713 g, 13.95 mmol) was added as a s o l u t i o n i n dry methylene c h l o r i d e (50 mL). The reac t i o n mixture was s t i r r e d f o r 20 min and then triethylamine (7.78 mL, 4 equiv) was added. This s o l u t i o n was s t i r r e d f o r 5 min at -78°C and then was warmed to room temperature and was s t i r r e d at t h i s temperature f o r 30 min. Water (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with methylene c h l o r i d e (3 x 50 mL). The combined organic s o l u t i o n was dri e d (MgS04) and then was concentrated. 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 ir-bath temperature 80-90°C/15 Torr) provided 2.1957 g (64%) of the aldehyde (291) as a colourless l i q u i d . This material, which was r e l a t i v e l y unstable and tended to decompose even upon storage under argon i n a freezer, exhibited i r ( f i l m ) : 2719, 1728, 1601, 919, 770 cm'1; XH nmr (80 MHz, CDC13) 6: 0.18 (s, 9H, -SnMe3, J S n - H - 5 3 H z ) . 2.29-2.68 (m, 4H, -CH2CH2-), 5.21 (m, 1H, H a, I S n . H - 71 Hz), 5.68 (m, 1H, H b, Isn-H " 1 4 6 H z ) > 9 , 7 8 ( b r s> 1 H > "CH°« 21/2 - 3 Hz). Exact Mass c a l c d . f o r C 7H 1 3OSn (M +-CH 3): 232.9988; found: 232.9987. - 309 -Preparation of the Diketones (290) and (301) H E Y H Me3Sn Me3Sn 290 301 To a c o l d (-78°C), s t i r r e d s o l u t i o n of LDA (1.3 equiv) i n dry THF (20 mL) was added, dropwise, the ketone (249) (500.0 mg, 2.423 mmol) as a s o l u t i o n i n dry THF (6 mL). 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 f o r 15 min at -78°C and then at 0°C f o r 15 min. The s o l u t i o n was cooled to -78°C and then the aldehyde (291) (717.4 mg, 1.2 equiv) was added as a s o l u t i o n i n dry THF (5 mL). The re a c t i o n mixture was s t i r r e d f o r 15 min at -78°C and then f o r 30 min at room temperature. Water (50 mL) was added and the organic phase was separated. The aqueous phase was extracted with d i e t h y l ether (3 x 30 mL). The combined organic s o l u t i o n was d r i e d (MgSO^ and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (100 g, e l u t i o n with petroleum ether-d i e t h y l ether, 10:1-5:1) provided 126 mg of the s t a r t i n g ketone (249) and 508.1 mg (62% based on reacted ketone (249)) of a mixture of the keto alcohols (299) as a col o u r l e s s o i l . This material (a mixture of three keto alcohols by AH nmr spectroscopy) was not further character-i z e d but was used immediately i n the next reaction. To a c o l d (-78°C), s t i r r e d s o l u t i o n of o x a l y l c h l o r i d e (0.27 mL, 1.3 equiv) i n dry methylene chloride (40 mL) was added DMSO (0.15 mL, 1.3 - 310 -equiv). The s o l u t i o n was s t i r r e d f o r 5 min and then the keto alcohol (299) (750.0 mg, 1.655 mmol) was added as a s o l u t i o n i n dry methylene c h l o r i d e (10 mL). The r e a c t i o n mixture was s t i r r e d f o r 20 min and then triethylamine (0.92 mL, 4 equiv) was added. This s o l u t i o n was s t i r r e d f o r 5 min at -78°C, was warmed to room temperature and then was s t i r r e d f o r 30 min. Water (50 mL) was added and the organic phase was separ-ated. The aqueous phase was extracted with methylene c h l o r i d e (3 x 75 mL). The combined organic s o l u t i o n was d r i e d (MgS04) and then was concentrated. The r e s i d u a l o i l was dissolved i n s p e c t r a l grade acetone (50 mL) and to the r e s u l t i n g s t i r r e d s o l u t i o n was added methyl iodide (0.21 mL, 2 equiv) and dry potassium carbonate (343 mg, 1.5 equiv). The mixture was r e f l u x e d f o r 15 h and then the solvent was removed by rotary evaporation. T i c analysis indicated the presence of two products and nmr analysis indicated that they were present i n a r a t i o of -2:1. Drip column chromatography on s i l i c a gel (120 g, e l u t i o n with petroleum e t h e r - d i e t h y l ether, 30:1) provided three f r a c t i o n s . The f i r s t compound to be eluted was the major diketone (290). D i s t i l l a t i o n of the o i l obtained by concentration of the appropriate f r a c t i o n s (air-bath temperature 180-190°C/0.1 Torr) provided 314.7 mg (41%) of the diketone (290) as a c o l o u r l e s s o i l . This material exhibited i r ( f i l m ) : 1713, 1695, 1600, 918, 770 cm - 1; 1H nmr (400 MHz, CDC1 3) 6: 0.14 (s, 9H, -SnMe3, Isn-H " 5 4 H z>- ° - 9 0 a n d 0 , 9 4 <d' d > 3 H e a c h . -CHMe2, 1 - 6 Hz each), 1.06 and 1.23 (s, s, 3H each, two -CCH 3), 1.40 (d of d of d, 1H, J - 4, 7, 14 Hz), 1.60 (d of d of d, 1H, J. - 3, 6.5, 9 Hz), 1.85 (d of t, 1H, J - 12, 9 Hz), 2.06-2.23 (m, 3H), 2.32 (d, 1H, H c or H d, J. - 11.5 Hz), 2.36-2.68 (m, 7H), 2.77 (d, 1H, H d or H c, J - 11.5 Hz), 5.16 (m, - 311 -1 H . Isn-H - 7 0 H z>> 5 - 6 3 <m> 1 H - H b ' iSn-H ~ 1 4 9 H z>- 1 3 c " » r < 7 5- 3 MHz, CDC13) 5: -9.5 (-ve), 19.7 (-ve), 20.8, 21.1 (-ve), 21.2 (-ve), 25.7 (-ve), 26.8 (-ve), 27.7, 33.2, 33.9, 36.6, 38.2, 47.9, 52.4, 65.6, 125.0, 136.2, 143.4, 153.7, 208.8, 208.9. Exact Mass ca l c d . f o r c 2 2 H 3 5 ° 2 S n ( M 4 - ^ ) : 451.1659; found: 451.1652. The second f r a c t i o n to be eluted contained a mixture of the dike-tones (290) and (301) (75.6 mg, 10%). The t h i r d f r a c t i o n to be eluted was the diketone (301). D i s t i l l a t i o n of the o i l obtained by concentration of the appropriate f r a c t i o n s (air-bath temperature 180-190°C/0.1 Torr) provided 120.1 mg (16%) of the diketone (301) as a colourless o i l . This material exhibited i r ( f i l m ) : 1714, 1694, 917, 770 cm"1; AH nmr (400 MHz, CDCI3) 6: 0.15 (s, 9H, -SnMe3, I S n . H - 53 Hz), 0.93 and 1.00 (d, d, 3H each, -CHMe2, J - 6.5 Hz each), 0.91 and 1.37 (s, s, 3H each, two -CCH3), 1.51-1.73 (m, 3H), 1.83 (d of d of d, 1H, J - 1.5, 8.5, 14 Hz), 2.13-2.28 (m, 3H), 2.40 (d, 1H, H g or H h, J - 11 Hz), 2.40-2.70 (m, 6H), 2.68 (d, 1H, H h or H g, J - 11 Hz), 5.15 (m, 1H, H e, J S n . H - 70 Hz), 5.62 (m, 1H, H f, I S n . H - 150 Hz). 1 3C nmr (75.3 MHz, CDCI3) 8: -9.5, 19.7, 20.1, 21.1, 21.6, 23.3, 26.5, 27.7, 33.7, 33.8, 37.8, 38.7, 48.7, 53.8, 66.6, 124.9, 139.0, 140.7, 153.7, 208.6, 209.7. Exact Mass calcd. f o r C 22H350 2Sn ( M 4 - ^ ) : 451.1659; found: 451.1656. - 312 -Preparation of the S i l y l Ether (303) To a c o l d (-78°C), s t i r r e d s o l u t i o n of the diketone (290) (43.5 mg, 0.094 mmol) and l i t h i u m c h l o r i d e (80 mg, -20 equiv) i n dry THF (10 mL) was added, dropwise, a s o l u t i o n of DIBAL i n toluene (0.37 mL of a 1 M so l u t i o n , 4 equiv). The reac t i o n mixture was s t i r r e d f o r 10 min and then saturated aqueous ammonium chlo r i d e (2 mL) was added. The cooling bath was removed and the s o l u t i o n was s t i r r e d f o r 30 min as i t warmed to room temperature. Magnesium s u l f a t e was added and the mixture was f i l t e r e d , washing with d i e t h y l ether (100 mL). The organic s o l u t i o n was concentrated and t i c analysis of the r e s i d u a l o i l i n d i c a t e d the presence of a si n g l e keto alcohol. This material was dissolv e d i n dry methylene chlo r i d e (20 mL) and to the s t i r r e d s o l u t i o n was added se q u e n t i a l l y at room temperature 4-N,N-dimethylamlnopyridine (2 mg, 0.1 equiv), triethylamine (0.08 mL, 6 equiv) and t e r t - b u t y l d i m e t h y l s i l y l t r i f l a t e (0.11 mL, 5 equiv). 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 f o r 30 min and then water (20 mL) was added. The organic phase was separated and the aqueous phase was extracted with methylene chl o r i d e (3 x 20 mL). The combined organic s o l u t i o n was dr i e d (MgS04) and then was concentrated. Flash chromatography of the r e s i d u a l o i l on s i l i c a gel (27 g, e l u t i o n - 313 -with petroleum eth e r - d i e t h y l ether, 60:1) provided 43.2 mg (79%) of the s i l y l ether (303) as a colourless o i l . This material exhibited i r ( f i l m ) : 1698, 915, 836, 774 cm"1; XH mr (400 MHz, CDCl 3): 0.08 and 0.09 (s, s, 3H each, -SiMe 2), 0.13 (s, 9H, -SnMe3, J_Sn-H " 5 3 H z ) » ° - 8 9 a n d 0.94 (d, d, 3H each, -CHMe2, J - 7 Hz each), 0.91 (s, 9H, -SiCMe.3), 0.94 and 1.09 (s, s, 3H each, two -CCH3), 1.35-1.60 (m, 4H), 1.82 (d of t, 1H, J - 12.5, 10 Hz), 2.04-2.27 (m, 4H), 2.24 (d, 1H, H c or H d, I - 11.5 Hz), 2.38-2.58 (m, 3H), 2.60 (septet, 1H, -CHMe2, J - 7 Hz), 3.07 (d, 1H, H d or H c, J - 11.5 Hz), 3.53 (d of d, 1H, -CH0SiMe 2Bu t, J - 3, 7.5 Hz), 5.11 (m, 1H, H a, J S n . H - 71 Hz), 5.62 (m, 1H, H b, J S n . H - 153 Hz). Exact Mass calcd. f o r C 2 9H 540 2SnSi: 582.2916; found: 582.2917. Preparation of (±)-Amijitrienol (242) 242 R=H To a c o l d (-0°C), s t i r r e d s o l u t i o n of potassium b i s ( t r i m e t h y l s i l y l ) amide (1.07 mL of a 0.5 H s o l u t i o n i n toluene) i n dry THF (15 mL) was added, dropwise, a s o l u t i o n of the ketone (303) (62.1 mg, 0.107 mmol) i n dry THF (5 mL). 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 at room temperature - 314 -fo r 30 min and then s o l i d Tf 2NPh (190 mg, 5 equiv) was added. The pale yellow s o l u t i o n was s t i r r e d f o r 30 min and then the solvent was removed by rotary evaporation. The r e s i d u a l material was dissol v e d i n aceto-n i t r i l e (25 mL) and triethylamine (10 drops), and to the r e s u l t i n g s t i r r e d s o l u t i o n was added palladium tetrakis(triphenylphosphine) (7 mg, 6 mol % ) . The s o l u t i o n was refluxed f o r 30 min and then the solvent was removed by rotary evaporation. Drip column chromatography of the r e s i d u a l o i l on s i l i c a gel (10 g, e l u t i o n with hexane) provided 31.8 mg (74%) of the s i l y l ether (304) as a colourless o i l . This material was used immediately i n the next reaction. A s t i r r e d s o l u t i o n of the s i l y l ether (304) (12.5 mg, 0.031 mmol) and tetra-n-butylammonium f l u o r i d e (0.062 mL of a 1 M s o l u t i o n i n THF, 2 equiv) i n dry THF (10 mL) was refluxed f o r 3.5 h. The re a c t i o n mixture was concentrated and the r e s i d u a l o i l was subjected to drip column chromatography on s i l i c a g el (5 g, e l u t i o n with hexane-diethyl ether, 3:1). Concentration of the appropriate f r a c t i o n s provided 7.8 mg (88%) of (±)-amijitrienol (242) as a white s o l i d . R e c r y s t a l l i z a t i o n of t h i s s o l i d from hexane afforded (±)-amijitrienol (242) as f i n e , white needles (mp 119-119.5°C). This material exhibited i r (CHC1 3): 3626, 1631, 1626, 1455, 900 cm"1; XH nmr (400 MHz, CDCl 3) 6: 0.87 (s, 3H, -C(0H)CCH 3), 0.92 and 0.93 (d, d, 3H each, -CHMe2, J - 7 Hz each), 1.29 (s, 3H, -CH 2CCH 3), 1.34 (d of d of d, 1H, H h, J - 5, 5, 12 Hz), 1.64 (d of d of d, 1H, H Q or Hp, J - 7, 8.5, 12 Hz), 1.72-1.83 (m, 2H, Hp or H Q and H f), 1.94 (d of d of d of d, 1H, H e, J - 2.5, 5, 14, 14 Hz), 2.08 (m, 2H, H m and IL^), 2.16 (d of d of d, 1H, H c, J - 2.5, 5, 13 Hz), 2.30 (m, 1H, H k), 2.47 (d of d of d of d of d, 1H, Hj, J - 2.3, 2.3, 5, 14, - 315 -14 Hz), 2.53-2.65 (m, 2H, H d and H t), 2.63 (septet, 1H, -CHMe2, J - 7 Hz), 3.37 (br s, 1H, H g, w 1 / 2 - 10 Hz), 4.63 (d of d, 1H, H a, J - 2.5, 2.5 Hz), 4.74 (d of d, 1H, H b, J_ - 2.5, 2.5 Hz), 5.81 (s, 1H, H q). I r r a d i a t i o n at 6 3.37 (H g): m u l t i p l e t at S 1.72-1.83 s i m p l i f i e d , s i g n a l at S 1.94 (H e) s i m p l i f i e d to a d of d of d (J - 5, 14, 14 Hz). 1 3 C nmr (75.3 MHz, CDC1 3) 6: 20.5, 20.8, 21.3, 21.9, 26.9, 27.1, 27.2, 28.5, 29.1, 33.3, 42.4, 44.7, 52.2, 78.2, 110.9, 136.6, 138.7, 139.5, 142.5, 150.3. Exact Mass calcd. f o r C 2 0H 3 0O: 286.2297; found: 286.2296. Compound (242) exhibited spectra (^ H nmr, 1 3 C nmr, mass, i r ) i d e n t i c a l * with those derived from natural ( + ) - a m i j i t r i e n o l . 91j The CDCI3 used i n the ^H and 1 3 C nmr experiments were shaken with Na 2C03-MgS0 4 and then f i l t e r e d through basic alumina immediately p r i o r to use. We would l i k e to thank Professor M. Ochi f o r copies of the spectra (*H nmr, i r , mass) of (+ ) - a m i j i t r i e n o l . - 316 -IV. REFERENCES D. Seebach, Angew. Chem. Int. Ed. Engl.. 1979, 18, 239. B. M. Trost, Acc. Chem. Res.. 1978, 11, 453. E. Piers and V. Karunaratne, J . Org. Chem.. 1983, 48, 1774. D. Seebach and P. Knochel, Helv. Chim. Acta. 1984, 67, 261. C. V.C. Prasad and T.H. Chan, J . Ore. Chem.. 1987, 52, 120. E. J . Corey, Pure Appl. Chem.. 1967, 14, 19. See, f o r example, the following as leading references: (a) M. Kumada, Pure Appl. Chem.. 1980, 52, 669. (b) J.P. Beletskaya, J . Organomet. Chem.. 1983, 250, 551. (c) T.N. M i t c h e l l , J . Organomet. Chem.. 1986, 304, 1. (d) J.K. S t i l l e , Angew. Chem. Int. Ed. Engl.. 1986, 25, 508. (e) J.K. S t i l l e , Pure Appl. Chem.. 1986, 57, 1771. (f) R.F. Heck, "Palladium Reagents i n Organic Syntheses", Aca-demic Press, N.Y. , 1985, Chapt. 6. (g) E. Negishi, Accts. Chem. Res.. 1982, 15, 340. (h) J . T s u j i , "Organic Synthesis with Palladium Compounds", Springer-Verlag, B e r l i n , 1980, p. 134-156. ( i ) E. Negishi, i n H. Nozaki (Ed.), "Current Trends i n Organic Synthesis", Pergamon Press, N.Y., 1983, p. 269-280. (j) M. Pereyre, J.-P. Quintard, and A. Rahm, "Tin i n Organic Synthesis", Butterworth, London, 1987, Chapt. 10. S. Baba and E. Negishi, J . Am. Chem. Soc.. 1976, 98, 6729. T. Jeffery-Luong and G. Linstrumelle, Synthesis. 1982, 738. M. Yamamura, I. Moritani, and S.-I. Murahashi, J . Organomet.  Chem.. 1975, 91, C39. - 317 -11. K. Tamao, K. Sumitani, Y. Kiso, M. Zembayashi, A. Fujioka, S.-I. Kodama, I. Nakajima, A. Minato, and M. Kumada, B u l l . Chem. Soc. Jpn.. 1976, 49, 1958. 12. H.P. Dang and G. Linstrumelle, Tet. Let t e r s . 1978, 191. 13. S.-I. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, and K. Kondo, J . Org. Chem.. 1979, 44, 2408. 14. V. Ratovelomanana and G. Linstrumelle, Tet. L e t t e r s . 1981, 22, 315. 15. D. Michelot, Synthesis. 1983, 130. 16. N.Miyaura, K. Yamada, and A. Suzuki, Tet. L e t t e r s . 1979, 3437. 17. N. Miyaura, H. Siginome, and A. Suzuki, Tet. L e t t e r s . 1981, 22, 127. 18. N. Miyaura and A. Suzuki, J . Organomet. Chem.. 1981, 213, C53. 19. A. Suzuki, Pure Appl. Chem.. 1985, 57, 1749. 20. A. Suzuki, J . Am. Chem. Soc.. 1985, 107, 972. 21. N. Miyaura, M. Satoh, and A. Suzuki, Tetra. L e t t e r s . 1986, 27, 3745. 22. M. Satoh, N. Miyaura, and A. Suzuki, Chem. L e t t e r s . 1986, 1329. 23. (a) T. Ishiyama, N. Miyaura, and A. Suzuki, Chem. Let t e r s . 1987, 25. (b) J . Uenishi, J.-M. Beau, R.W. Armstrong, and Y. K i s h i , J . Am.  Chem. S o c . 1987, 109, 4756. 24. E. Negishi, N. Okukado, A.O. King, D.E. Van Horn, and B.I. Spiegel, J . Am. Chem. Soc.. 1978, 100, 2254. 25. K. Takai, K. Oshima, and H. Nozaki, Tet. L e t t e r s . 1980, 21, 2531. 26. M. Sato, K. Takai, K. Oshima, and H. Nozaki, Tet. Le t t e r s . 1981, 22, 1609. 27. E. Negishi, T. Takahashi, S. Baba, D.E. Van Horn, and N. Okukado, J . Am. Chem. Soc.. 1987, 109, 2393. 28. V. Ratovelomanana, A. Hammoud, and G. Linstrumelle, Tet. Le t t e r s . 1987, 28, 1649. 29. E. Negishi and F. Luo, J . Org. Chem.. 1983, 48, 1562. - 318 -W.J. Scott, G.T. Crisp, and J.K. S t i l l e , J . Am. Chem. Soc.. 1984, 106, 4630. G.T. Crisp, W.J. Scott, and J.K. S t i l l e , J . Am. Chem. Soc.. 1984, 106, 7500. W.J. Scott and J.K. S t i l l e , J . Am. Chem. Soc.. 1986, 108, 3033. J.K. S t i l l e and B.L. Groh, J . Am. Chem. Soc.. 1987, 109, 813. J.K. S t i l l e and M. Tanaka, J . Am. Chem. Soc.. 1987, 109, 3785. N. J a b r i , A. Alexakis, andJ.F. Normant, Tet. L e t t e r s . . 1981, 22, 959. N. J a b r i , A. Alexakis, andJ.F. Normant, Tet. L e t t e r s . . 1982, 23, 1589. M. Gardette, N. J a b r i , A. Alexakis, and J.F. Normant, Tetrahe- dron. 1984, 40, 2741. N.O. Okukado, D.E. Van Horn,, W.L. Klima, and E. Negishi, Tet.  Let t e r s . 1978, 1027. See r e f . 7(e) and r e f . 7 ( j ) , Chapt. 2. D. M i l s t e i n and J.K. S t i l l e , J . Am. Chem. Soc.. 1979, 101, 4992. (a) D. M i l s t e i n and J.K. S t i l l e , J . Am. Chem. Soc.. 1978, 100, 3626. (b) D. M i l s t e i n and J.K. S t i l l e , J . Am. Chem. Soc.. 1979, 101, 1613. (c) J.W. Labadie and J.K. S t i l l e , J . Am. Chem. Soc.. 1983, 105, 6129. (a) F.K. Sheffy and J.K. S t i l l e , J . Am. Chem. Soc.. 1983, 105, 7173. (b) F.K. Sheffy, J.P. Godschalx, and J.K. S t i l l e , J . Am. Chem.  Soc., 1984, 106, 4833. J.E. McMurry and W.J. Scott, Tet. Le t t e r s . 1983, 24, 979. M.H. Kowalski and P.J. Stang, Organomet.. 1986, 5, 2392. W.F. Goure, M.E. Wright, P.D. Davis, S.S. Labadie, and J.K. S t i l l e , J . Am. Chem. Soc.. 1984, 106, 6417. - 319 -E. Piers and H.E. Morton, J . Chem. Soc,. Chem. Commun.. 1978, 1033. E. P i e r s , J.M. Chong, and H.E. Morton, Tet. Le t t e r s . 1981, 22, 4905. E. P i e r s , and H.E. Morton, J . Org. Chem.. 1980, 45, 4263. E. Piers and J.M. Chong, J . Chem. S o c . Chem. Commun.. 1983, 934. For methodology see: (a) E. Piers and V. Karunaratne, J . Chem.  S o c . Chem. Commun.. 1983, 935. For a p p l i c a t i o n i n t o t a l synthesis see: (a) E. Piers and V. Karunaratne, Can. J . Chem.. 1984, 62, 629. (b) E. Piers and V. Karunaratne, J . Chem. S o c . Chem. Commun. , 1984, 959. E. Piers and B.W.A. Yeung, J . Org. Chem.. 1984, 49, 4567. E. Piers and B.W.A. Yeung, Can. J . Chem.. 1986, 64, 2475. M. Barbier and M.F. Huegel, B u l l . Chem. Soc. Fr.. 1961, 1324. A.J. Leusink, H.A. Budding, and J.W. Marsman, J . Organomet.  Chem.. 1967, 9, 285. L. Reust, G.Blouin, and P. Deslongchamps, Syn. Commun.. 1976, 6, 169. P.-E. Sum and L. Weiler, Can. J . Chem.. 1977, 55 , 996. (a) H.J. Reich, J.M. Renga, and I.L. Reich, J . Am. Chem. Soc.. 1975, 97, 5434. (b) J.N. Marx, J.H. Cox, and L.R. Norman, J . Org. Chem.. 1972, 37, 4489. (c) E. Piers and H.L.A. Tse, Tet. Le t t e r s . 1984, 25, 3155. (a) J.L. Occolowitz, Tet. Let t e r s . 1966, 5291. (b) H.G. K u i v i l a , K.-H. Tsa i , and D.G.I. Kingston, J . Organomet.  Chem., 1970, 23, 129. For a summary of the methods a v a i l a b l e f o r preparing enol t r i -f l a t e s , see: (a) P.J. Stang, M. Hanack, and L.R. Subramanian, Synthesis. 1982, 85. - 320 -(b) P.J. Stang, Acc. Chem. Res.. 1978, 11, 107. 60. R.M. S i l v e r s t e i n , G.C. Bassler, and T.C. M o r r i l l , i n "Spectromet-r i c I d e n t i f i c a t i o n of Organic Compounds", John Wiley and Sons, N.Y., .1981, p. 166. 61. L.M. Jackman and S. St e r n h e l l , i n "Applications of NMR Spectro-scopy i n Organic Chemistry", Pergamon Press, N.Y., 1969, p. 222, 334. 62. E. P i e r s , J.M. Chong, and B. Keay, Tet. Le t t e r s . 1985, 26, 6265. 63. Vinylcopper and allenoate species have been postulated to be intermediates i n the addi t i o n of alkylcuprate reagents to a,fl-acetylenic esters. See J.P. Marino and R.J. Linderman, J .  Org. Chem.. 1983, 48, 4621. 64. T.I. Moder, C.C.K. Hsu, and F.R. Jensen, J . Org. Chem.. 1980, 45, 1008. 65. H. Booth and J.R. Everett, J . Chem. S o c . Chem. Commun.. 1976, 278. 66. (a) H.C. Brown, J.H. Brewster, and H. Schechter, J . Am. Chem. Soc.', 1954, 76, 467. (b) F. Johnson, Chem. Rev.. 1968, 68, 375. 67. P.A. Grieco, R. L i s , R.F. Z e l l e , and J . Finn, J . Am. Chem. Soc.. 1986, 108, 5908. 68. Reference 60, p. 225. 69. S.E. Diamond and F. Mares, J . Organomet. Chem.. 1977, 142, C55. 70. D.L. Pavia, G.M. Lampman, and G.S. K r i z , i n "Introduction to Spectroscopy", W.B. Saunders Co., Philadelphia, 1979, p. 98. 71. Reference 70, Chapt. 5. 72. We thank Dr. S. Retig f o r performing these x-ray structure deter-minations . (a) A l l compounds reported i n t h i s thesis are racemates. The compound depicted i n the Figure i s the mirror image of the struc-ture indicated. 73. H. Hart, B. Chen, and M. J a f f a r e s , J . Org. Chem.. 1979, 44, 2722. 74. See the discussions of the oxidative a d d i t i o n r e a c t i o n i n : (a) J . T s u j i , i n "Organic Synthesis by Means of T r a n s i t i o n Metal Complexes", Springer-Verlag, B e r l i n , 1975, p. 8-10. - 321 -(b) F.A. Cotton and G. Wilkinson, i n "Advanced Inorganic Chemis-t r y " , John Wiley and Sons, N.Y., 1980, p. 1237-1248. (c) J.K. S t i l l e , i n R. Scheffold (ed.), "Modern Synthetic Meth-ods", John Wiley and Sons, N.Y., 1983, Chapt. 1. 75. Reference 60, p. 235. 76. J . Sauer, Angew. Chem. Int. Ed. Engl.. 1966, 5, 211. 77. J . Sauer, Angew. Chem. Int. Ed. Engl.. 1967, 6 , 16. 78. J . Sauer and R. Sustmann, Angew. Chem. Int. Ed. Engl.. 1980, 19, 779. 79. I. Fleming, i n "Frontier O r b i t a l s and Organic Chemical Reactions", John Wiley and Sons, Inc., N.Y., 1976, p. 86-181. 80. H. Stockmann, J . Org. Chem.. 1961, 2 6 , 2025. 81. Reference 60, p. 124. 82. S. Ranganathan, D. Ranganathan, and A.K. Mehrotra, J . Am. Chem.  Soc.. 1974, 9 6 , 5261. 83. Reference 79, p. 161-164. 84. For the epimerization of a carbon center adjacent to a n i t r o group see: R.J. Ouellette and G.E. Booth, J . Org. Chem.. 1965, 30, 423. 85. (a) J.E. McMurry and J . Melton, J . Org. Chem.. 1973, 38, 4367. (b) J.E. McMurry, Accts. Chem. Res.. 1974, 7, 281. 86. S.D. Kahn, C F . Pau, L.E. Overman, and W.J. Hehre, J . Am. Chem. Soc.. 1986, 108, 7381. 87. M.J.S. Dewar, S. O l i v e l l a , and J.J.P. Stewart, J . Am. Chem. Soc.. 1986, 108, 5771. 88. There has been some debate i n the recent l i t e r a t u r e regarding the concertedness and synchronicity of the Diels-Alder r e a c t i o n as o r i g i n a l l y described i n terms of molecular o r b i t a l s by R.B. Wood-ward and R. Hoffman (Angew. Chem. Int. Ed. Engl.. 1969, 8, 781). For leading references to t h i s f a s c i n a t i n g controversy see: (a) References 78, 86 and 87. (b) M.J.S. Dewar, J . Am. Chem. Soc.. 1984, 106, 209. - 322 -(c) J . J . Gajewski, K.B. Peterson, and J.R. Kagel, J . Am. Chem.  Soc., 1987, 109, 5545. (d) P. Caramella, K.N. Houk, and L.N. Domelsmith, J . Am. Chem. Soc.. 1977, 99, 4511. (a) J . March, i n "Advanced Organic Chemistry", McGraw-Hill Book Co., N.Y., 1985, p. 164. (b) C. Wentrup, i n "Reactive Molecules", John Wiley and Sons, N.Y., 1984, p. 30, re f e r s to r a d i c a l s being s t a b i l i z e d induc-t i v e l y by a l k y l groups. I t i s not unreasonable, therefore, to assume that an in d u c t i v e l y e l e c t r o n withdrawing group should i n a s i m i l a r manner d e s t a b i l i z e a r a d i c a l . S.J. Wratten, D.J. Faulkner, K. Hirotsu, and J . Clardy, Tet.  Let t e r s . 1978, 4345. (a) G.R. P e t i t , R.H. Ode, C.L. Herald, R.B. Van Dreele, and C. Michael, J . Am. Chem. Soc.. 1976, 98, 4677. (b) B.F. Bowden, J.-C. Braeckman, J.C. C o l l , and S.J. M i t c h e l l , Aust. J . Chem.. 1980, 33, 927. (c) M. Ochi, M. Watanabe, I. Miura, M. Taniguchi, and T. Tokoroyama, Chem. Le t t . . 1980, 1229. (d) M. Ochi, M. Watanabe, I. Miura, M. Taniguchi, and T. Tokoroyama, Chem. Le t t . . 1980, 1233. (e) H.H. Sun, O.J. McConnell, W. Fe n i c a l , K. Hirotsu, and J . Clardy, Tetrahedron. 1981, 37, 1237. (f) M. Ochi, I. Miura, and T. Tokoroyama, J . Chem. Soc.. Chem.  Commun.. 1981, 100. (g) P. Crews, T.E. K l e i n , E.R. Hogue, and B.L. Meyers, J . Org.  Chem., 1982, 47, 811. (h) A.G. Gonzales, J.D. Martin, M. Notre, P. Rivera, A. Perales, and J . Fayos, Tetrahedron. 1983, 39, 3355. ( i ) N. Harada, Y. Yokota, J . Iwabuchi, H. Uda, and M. Ochi, J .  Chem. S o c . Chem. Commun.. 1984, 1220. (j) M. Ochi, K. Asao, H. Kotsuki, I. Miura, and K. Shibata, B u l l . Chem. Soc. Jpn.. 1986, 59, 661. (k) C.B. Rao, K.C. Pu l l a i a h , R.K. Surapaneni, B.W. S u l l i v a n , K.F. A l b i z a t i , D.J. Faulkner, H. Cun-heng, and J . Clardy, J . Org.  Chem., 1986, 51, 2736. - 323 -(1) V.L. T e i x e i r a , T. Tomassini, B.G. Fleury, and A. Keleom, J . Nat. Prod.. 1986, 49, 570. 92. G. Pattenden and G.M. Robertson, Tet. Le t t e r s . 1986, 27, 399. 93. G. Mehta and N. Krishnamurthy, Tet. Letters, i n press. 94. (a) L.A. Paquette, H.-S. L i n , O.T. Belmont and J.P. Springer, J . Org. Chem.. 1986, 51, 4807. (b) D.T. Belmont and L.A. Paquette, J . Org. Chem.. 1985, 50, 4102. (c) L.A. Paquette, D.T. Belmont, and Y.-L. Hsu, J . Org. Chem.. 1985, 50, 4667. 95. Y. Ito, S. F u j i i , and T. Saegusa, J . Org. Chem.. 1976, 41, 2073. 96. M. Haslanger and R.G. Lawton, Svn. Commun.. 1974, 4, 155. 97. (a) E.J. Corey and D. Enders, Tet. Le t t e r s . . 1976, 3. (a) E.J. Corey and D. Enders, Chem. Ber.. 1978, 111, 1337. 98. H.O. House, L.J. Czuba, M. G a l l , and H.D. Olmstead, J . Org.  Chem., 1969, 34, 2324. 99. (a) G.M. Rubottom and M.I. Lopez, J . Org. Chem.. 1973, 38, 2097. (b) S. Murai, T. Aya, and N. Sonoda, J . Org. Chem.. 1973, 38, 4354. 100. (a) J . Furukawa, N. Kawabata, and J . Nishimura, Tetrahedron. 1968, 24, 53. (b) S. Miyano and N. Hashimoto, J . Chem. S o c . Chem. Commun.. 1971, 1418. 101. S.L. P i a t t and J.N. Shoolery, J . Magn. Res.. 1982, 46, 535. 102. P. Baekelmans, M. Gielen, P. Malfroid, and J . N a s i e l s k i , B u l l .  Soc. Chim. Beiges.. 1968, 77, 85. 103. E.J. Corey and I. Kuwajima, J . Am. Chem. Soc.. 1070, 92, 395. 104. J.-L. Luche and J.-C. Damiano, J . Am. Chem. Soc.. 1980, 102, 7927. 105. B.M. Trost and B.P. Coppola, J . Am. Chem. Soc.. 1982, 104, 6877. - 324 -106. M.P. Cooke, J r . and I.N. Houpis, Tet. L e t t e r s . . 1985, 26, 4987. 107. (a) K. Takai, K. Kimura, T. Kuroda, T. Hiyama, and H. Nozaki, Tet. L e t t e r s . 1983, 24, 5281. (b) H. J i n , J . Uenishi, W.J. Ch r i s t , and Y. K i s h i , J . Am.Chem.  Soc.. 1986, 108, 5644. 108. H.O. House, i n "Modern Synthetic Reactions", The Benjamin/Cummings Publishing Co., Menlo Park, 1972, p. 188-190. 109. J.F. Harrod and A.J. Chalk, J . Am. Chem. Soc.. 1964, 86, 1776. 110. H. Wolf, M. Kolleck, and W. Rascher, Chem. Ber.. 1976, 109, 2805. 111. J.M. Chong, Ph.D. Thesis, U.B.C., 1983, p. 250. 112. K. Omura and D. Swern, Tetrahedron. 1978, 34, 1651. 113. J.W. Suggs and E.J. Corey, Tet. Le t t e r s . 1975, 2647. 114. Reference 60, p. 118. 115. A.W. Johnson, E. Markham, and R. Price, Org. Svn.. 1973, C o l l .  V o l. 5. 785. 116. See, f o r example: D.W. Moreland, W.G. Dauben, J . Am. Chem. Soc.. 1985, 107, 2264. 117. Reference 60, p. 235. 118. Reference 60, p. 192. 119. Reference 60, p. 288. 120. W.C. S t i l l , M. Kahn, and A. Mitra, J . Org. Chem.. 1978, 43, 2923. 121. D.D. Pe r r i n , W.L.F. Armarego, and D.R. Perr i n , i n " P u r i f i c a t i o n of Laboratory Chemicals", Pergamon Press, Oxford, 1980. 122. W.G. Kofron and L.M. Baclawski, J . Org. Chem.. 1976, 41, 1879. 123. H.O. House, C.Y. Chu, J.M. Wilkens, and M.J. Umen, J . Org. Chem.. 1975, 40, 1460. 124. P.G.M. Wuts, Syn. Commun.. 1981, 11, 139. 125. (a) Y.P. Bryan and R.H. Byrne, J . Chem. Ed.. 1970, 47, 361. (b) A.J. Gordon and R.A. Ford, i n "The Chemist's Companion", John Wiley and Sons, N.Y., 1972, p. 451. - 325 -126. W.C. S t i l l , J . Am. Chem. Soc.. 1977, 99, 4836. 127. G. Posner, D.J. Brunelle, and L. Sinoway, Synthesis. 1974, 622. - 3 2 6 -V. APPENDIX 5.0.0 Appendix 1 : X-ray Crystallographic Data Compound ( 1 5 2 ) ( 1 7 5 ) ( 1 7 7 ) ( 1 7 9 ) formula C 2 i H 2 3 N 0 6 C 1 9 H 2 4 ° 6 C 1 9 H 1 8 N 4 0 2 C 2 6 H 3 4 N 4 O 3 : c r y s t a l system t r i c l i n i c t r i c l i n i c orthorhombic monoclinic space group p i Pbca P 2 ] / c a (A) 7 . 4 7 4 1 ( 7 ) 9 . 2 1 9 0 ( 4 ) 1 2 . 6 4 1 5 ( 5 ) 1 3 . 3 6 7 6 ( 6 ) b ( A ) 7 . 6 5 0 5 ( 8 ) 1 1 . 4 7 5 8 ( 6 ) 1 7 . 5 9 4 1 ( 8 ) 1 8 . 0 3 6 ( 2 ) fi. ( A ) 1 9 . 0 4 0 ( 1 ) 8 . 5 3 4 1 ( 3 ) 1 5 . 6 2 4 0 ( 7 ) 2 3 . 3 5 2 4 ( 6 ) 9 4 . 4 9 0 ( 8 ) 1 0 1 . 1 6 0 ( 4 ) 9 0 9 0 9 6 . 6 8 8 ( 8 ) 8 9 . 0 8 7 ( 4 ) 9 0 1 0 5 . 1 4 4 ( 3 ) 7 ° 1 1 3 . 2 8 9 ( 6 ) 9 5 . 7 2 0 ( 5 ) 9 0 9 0 v (A 3) 9 8 3 . 9 ( 2 ) 8 8 1 . 4 ( 1 ) 3 4 7 5 . 0 ( 3 ) 5 4 3 4 . 6 ( 6 ) z 2 2 8 8 number of r e f l e c t i o n s used i n refinement 1 4 0 1 2 8 7 7 2 3 2 1 5 3 7 5 R 0 . 0 4 8 0 . 0 5 5 0 . 0 4 4 0 . 0 4 3 *w 0 . 0 4 1 0 . 0 7 0 0 . 0 5 8 0 . 0 5 0 - 327 -Appendix 1: continued (198) (199) (195) (206) C15 H24°2 monoclinic 8.5889(7) 18.437(2) 8.9424(7) 90 109.893(7) 90 1331.5(2) 4 C15 H24°2 t r i c l i n i c PI 8.6943(3) 8.7576(3) 9.9939(8) 110.736(4) 97.337(5) 109.162(3) 646.09(6) 2 c 2 2 H 3 7 N 0 5 s i monoclinic PZx/n 13.927(1) 12.858(1) 14.827(1) 90 109.394(6) 90 2504.5(3) 4 C 2 3 H 2 6 N 2 ° 8 t r i c l i n i c PI 11.0580(5) 15.5119(7) 6.9053(5) 78.415(4) 95.034(7) 103.295(5) 1128.2(1) 2 1137 2240 2066 2443 0.065 0.069 0.037 0.050 0.092 0.103 0.051 0.059 

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