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New synthetic methods using β-keto esters and some useful applications in natural products syntheses Sum, Fuk-Wah 1979

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NEW SYNTHETIC METHODS USING B-KETO ESTERS AND SOME USEFUL APPLICATIONS IN NATURAL PRODUCTS SYNTHESES by FUK-WAH SUM B.Sc, Chung Chi College, The Chinese Uni v e r s i t y of Hong Kong, 1971 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF CHEMISTRY We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF July, © FUK-WAH BRITISH COLUMBIA 1979 SUM, 1979 In present ing t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree tha t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r re ference and s tudy. I f u r t h e r agree that permiss ion f o r ex tens ive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s r e p r e s en t a t i v e s . I t i s understood tha t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l ga in s h a l l not be a l lowed wi thout my w r i t t e n pe rm iss i on . Department The U n i v e r s i t y of B r i t i s h Columbia 2075 Wesbrook P lace Vancouver, Canada V6T 1W5 B P 75-5 1 1 E i i ABSTRACT Results from studies on the c y c l i z a t i o n of 3-keto ester derivatives are presented. E l e c t r o p h i l e - and a c i d - i n i t i a t e d c y c l i z a t i o n of unsaturated 3-keto esters, and the c y c l i z a t i o n of epoxy 3-keto esters provide i n t e r e s t i n g routes to some carbocyclic and h e t e r o c y c l i c compounds. Factors determining the predominance of C- or O - c y c l i z a t i o n are discussed. The e f f e c t of o l e f i n and epoxide s u b s t i t u t i o n patterns on the r e a c t i v i t y and mode of c y c l i z a t i o n was b r i e f l y investigated. A novel s t e r e o s p e c i f i c synthesis of substituted alkenes from 3-keto esters was achieved, along with the extension of this method to g-diketones (equation I) . Stereoselective synthesis of the E- and Z-enol phosphates of 3-dicarbonyl compounds was developed. These enol phosphates reacted s t e r e o s p e c i f i c a l l y with l i t h i u m dialkylcuprates to give a,3-unsat-urated carbonyl compounds. An e f f i c i e n t one-pot preparation of 3>3-disub-stituted-a,3-unsaturated esters from methyl acetoacetate based on these findings and the dianion chemistry of 3-keto esters i s also i l l u s t r a t e d . The e f f e c t of a 3-phosphoryloxy substituent on the reduction p o t e n t i a l of an a,3~ethylenic carbonyl compound was estimated to be + 0.1 V. A plaus-i b l e mechanism f o r the reaction between 1,3-dicarbonyl enol phosphates and l i t h i u m dialkylcuprates was proposed. A convenient route to the cyclohexene d e r i v a t i v e 248 i s described. This compound represents a u s e f u l synthetic substrate for the synthesis of i i i several classes of natural products. The f a c i l e introduction of an isoprene u n i t , using methyl acetoacetate, i n a st e r e o s e l e c t i v e manner as indicated by equation i i i s also demonstrated. The syntheses of three n a t u r a l products, v i z . , L a t i a l u c i f e r i n (328), (E, E)-10-hydroxy-3,7-dimethyldeca-2,6-dienoic acid (335) and mokupalide (347) are presented, which i l l u s t r a t e some useful applications of the new synthetic methods developed. While the syntheses of 328 and 335 show improvements over the previous preparations of these compounds, the synthesis of mokupalide (347) represents the f i r s t synthetic approach to this compound. 3 4 7 i v TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v LIST OF SCHEMES v i i LIST OF TABLES i x LIST OF FIGURES x LIST OF ABBREVIATIONS x i ACKNOWLEDGMENTS x i i INTRODUCTION - GENERAL BACKGROUND 1 SECTION I: STUDIES ON CYCLIZATION REACTIONS OF 3-KETO ESTERS 4 Introduction - Some Aspects, of C y c l i z a t i o n Reactions 4 A. Acid-Catalyzed C y c l i z a t i o n of Polyenes 5 B. C y c l i z a t i o n of O l e f i n i c Epoxides 11 C. C y c l i z a t i o n with' P a r t i c i p a t i o n of Acetylenic Bonds 17 D. C y c l i z a t i o n v i a Enol Derivatives 22 E. E l e c t r o p h i l e - I n i t i a t e d C y c l i z a t i o n s 24 Results and Discussion 30 E l e c t r o p h i l e - and Acid-Initiated. C y c l i z a t i o n of Unsaturated 8-Keto Esters 30 C y c l i z a t i o n of Epoxy B-Keto Esters 45 Conclusions 55 V Table of Contents - continued Page SECTION I I : ALKENE SYNTHESIS 58 Introduction - A Survey of Stereoselective Synthesis of T r i - and Tetrasubstituted Alkenes 58 A. Synthesis v i a Addition to Acetylenes 58 B. Synthesis Involving Ring Cleavages 83 C. Synthesis v i a Sigmatropic Rearrangements 90 D. Synthesis Involving A l l y l i c Rearrangements 97 E. Synthesis from Carbonyl Compounds 99 Results and Discussion 109 Synthesis and Reactions of Z-Enol Phosphates of g-Keto Esters 119 Synthesis and Reactions of the E-Enol Phosphate of A c y c l i c g-Keto Esters 138 Synthesis and Reactions of the Enol Phosphate of g-Diketones 140 Mechanism and Scope of the Reaction of 1,3-Dicarbonyl Enol Phosphates with Lithium Dialkylcuprates 146 SECTION I I I : NATURAL PRODUCTS SYNTHESIS 150 Introduction 150 Results and Discussion 151 Synthesis of L a t i a L u c i f e r i n 151 Synthesis of (.E, E)-10-Hydroxy-3,7-dimethyldeca-2,6-dienoic Acid 154 Synthesis of Mokupalide 159 v i Table of Contents - continued Page CONCLUSIONS 178 EXPERIMENTAL SECTION 179 Section I 181 Preparation and Cyclization of Unsaturated B-Keto Esters 181 Preparation and Reactions of Epoxy and a-Diazo B-Keto Esters 190 Section II 198 Preliminary Studies 198 Preparation of Enol Phosphates of 8-Keto Esters and their Reactions with Lithium Dialkylcuprates 203 Preparation of Enol Phosphates of B-Diketones and their Reactions with Lithium Dialkylcuprates 225 Section III 231 Synthesis of Latia Luciferin 231 Synthesis of (E, E)-10-Hydroxy-3,7-dimethyldeca-2,6-dienoic Acid 235 Synthesis of Mokupalide 241 Synthesis and Bromination of 3-Cyclopentyl-2-butenolide 254 BIBLIOGRAPHY 258 SPECTRAL APPENDIX 270 v i i LIST OF SCHEMES Scheme T i t l e Page x x i xv v vx vxx vxxx xx xx xxx xxxx xxv XV XV X C y c l i z a t i o n s with P a r t i c i p a t i o n of Acetylenic Bonds 17 Ring Closure I n i t i a t e d by Acyl a t i o n 27 C- and O-Cyclizations i n the Formation of Five-membered Rings 40 A Proposed Mechanism of the C y c l i z a t i o n of Methyl 3-Oxonon-6-ynoate (104) 44 A Possible Mechanism for the C y c l i z a t i o n of Methyl 6,7-Epoxy-7-methyl-3-oxooctanoate (111) 48 Additions of Organocopper Reagents to 1-Alkynes 69 Additions of Organocopper Reagents to Propar-g y l i c Acetals 72 Reactions of Vinylcopper Complexes Derived from 1-Alkynes 74 Alkene Synthesis v i a Hydroalumination of Sym-metri c a l Acetylenes 76 Synthesis of Alkenes by Methylalumination of 1-Alkynes 77 Synthesis of Alkenes by Hydroalumination of Trim e t h y l s i l y l a c e t y l e n e s 79 Alkene Synthesis v i a Hydroboration of Trimethyl-s i l y l a c e t y l e n e s 81 Alkene Synthesis v i a N i (II) Catalyzed Methyl-metallation of Tr i m e t h y l s i l y l a c e t y l e n e s 82 J u l i a Synthesis of Homoallylic Bromides 84 Synthesis of T r i s u b s t i t u t e d Alkenes from 4-Thiacyclohexanone 87 [2,3]-Sigmatropic Rearrangement of A l l y l i c Sulfoxides 94 v i i i L i s t of Schemes - continued Scheme T i t l e x v i i X V l l l XIX xxx XXII xxxxx XXXV XXV XXV X xxvxx xxvxxx XX XX A l l y l i c Rearrangement of Trimethylvinylsilanes Schlosser Mo d i f i c a t i o n of the W i t t i g Reaction Corey M o d i f i c a t i o n of the W i t t i g Reaction Synthesis of Alkenes from 2-(Trimethylsilyl)methyl 5,6-dihydro-l,3-oxazines Cornforth Synthesis of Substituted Alkenes One-pot Synthesis of 8 , 3-Disubstituted-a,8 -ethylenic Esters from Methyl Acetoacetate A Proposed Mechanism of the Reaction between 1,3-Dicarbonyl Enol Phosphates and Lithium Dialkylcuprates Synthesis of L a t i a L u c i f e r i n (328) Synthesis of (E, E_)-10-Hydroxy-3,7-dimethyldeca-2,6-dienoic Acid (335) Synthesis of (E, E, E_)-12-(2-Tetrahydropyranyloxy) 2,6,10-trimethyl-l-phenylthio-2,6,10-dodeca-t r i e n e (355) Synthesis of (E, E, E)-3,7,ll-Trimethyl-13-(2,6,6-trimethyl-l-cyclohexen-l-yl)trideca-2,6,10-t r i e n - l - o l (364) Synthesis of 3-Cyclopentyl-2-butenolide (367) Synthesis of 3-Phenylsulfonylmethyl-2-butenolide (375) xxx Synthesis of Mokupalide (347) i x LIST OF TABLES Table T i t l e Page 1 1HNMR and IR Data of Methyl a-(E-Tetrahydro-5-phenylselenenylmethyl-2-furylidene) acetate (88) 34 2 Conjugate Addition of Organocopper Reagents to a, 3 - A c e t y l e n i c Esters 68 3 Empirical Rules for Estimating the Reduction Potentials of a, 3 - E t h y l e n i c Carbonyl Compounds 113 4 Reactions of Enol Phosphates of C y c l i c 3-Keto Esters with Lithium Dimethylcuprate 122 5 Reactions of Enol Phosphates of A c y c l i c J3-Keto Esters with Lithium Dimethylcuprate 124 . 6 Selected XHNMR Data of Enol Phosphates of A c y c l i c 8-Keto Esters 126 7 Reactions of 3-Keto Ester Enol Phosphates with Lithium Diethylcuprate 130 8 Reactions of 3-Keto Ester Enol Phosphates with Lithium Di-n-butylcuprate 133 9 Reactions of Methyl 2-(Diethylphosphoryloxy)cyclo-hexenecarboxylate (267) with Lithium Di-sec-butylcuprate and Lithium Di-t-butylcuprate 134 10 Reduction Potentials of Some a, 3 - E t h y l e n i c Car-bonyl Compounds and Lithium Dialkylcuprates 137 11 Reactions of E-Enol Phosphates of A c y c l i c 3-Keto Esters with Lithium Di-n-butylcuprate 139 12 Reactions of 3-Diketone Enol Phosphates with Lithium Dialkylcuprates 141 13 Selected 1HNMR Data of the E_- and the Z-Enol Phosphates of Acetylacetone 142 LIST OF FIGURES Figure T i t l e Page Strategy f o r the Synthesis of Mokupalide (347) 161 Some 1HNMR and Mass. Spectral Data Related to Methyl (E, E, E)-12-Hydroxy-3,7,ll-trimethyl-dodeca-2,6,10^-trienoate (351). 168 x i LIST OF ABBREVIATIONS 13CNMR DAB CO DECP DHP DIBAL DMF eq ether HMPA XHNMR IR LAH NBS py THF THP t i c TMEDA vpc carbon-13 nuclear magnetic resonance 1,4-diazabicyclo[2.2.2]octane d i e t h y l chlorophosphate dihydropyran diisobutylaluminum hydride dimethylformamide equivalent et h y l ether hexamethylphosphoramide proton nuclear magnetic resonance i n f r a r e d l i t h i u m aluminum hydride N-bromosuccinimide pyridine tetrahydrofuran 2 -1 e t r ahy d r qpy r any 1 thin layer chromatography N,N,N',N 1-tetramethylethylenediamine vapor-phase chromatography Abbreviations for. m u l t i p l i c i t i e s of NMR s i g n a l s : br = broad qn = s = s i n g l e t dd d = doublet dt t = t r i p l e t m = q = quartet quintet doublet of doublets doublet of t r i p l e t s m u l t i p l e t XI1 ACKNOWLEDGMENTS I f i n d i t most appropriate, f i r s t of a l l , to express my sincere thanks to Professor Larry Weiler for his advice and guidance during the course of this work. I am much obliged to Professor Richard Pincock and Professor Edward Piers of t h i s Department f o r spending t h e i r precious time to read through the manuscript of this t h e s i s . The valuable opinions they offered have been most b e n e f i c i a l , to the preparation of th i s d i s s e r t a t i o n . I would also l i k e to thank Professor P. J. Scheuer and Dr. M. B. Yunker for kindly providing us with a sample of hydroxymokupalide, along with copies of experimental d e t a i l s for the i d e n t i f i c a t i o n of the moku-palides and the s p e c t r a l data of mokupalide. Copies of the 1HNMR and IR spectra, as we l l as a sample of methyl (E, E)-10-hydroxy-3,7-dimethyldeca-2,6-dienoate, obtained from Professor J . Meinwald and Dr. C. Semmelhack, are much appreciated. The l a s t but not the l e a s t i s my s p e c i a l thanks to my wife, Phaik-Eng. My gratitude for her concern and encouragement throughout the years of my graduate studies i s indescribable i n words. 1 INTRODUCTION Early investigations concerning the chemistry of the dianion of B-keto esters have provided new methodologies of considerable value i n organic synthesis. 1 Since then, i t has been a major i n t e r e s t i n our labora-tory to explore the use of simple B-keto esters as basic synthons i n various synthetic t a c t i c s . F u n c t i o n a l i z a t i o n of the a-carbon of a B-keto ester v i a reactions such as a l k y l a t i o n , a c y l a t i o n and Michael addition i s well documented. Selec t i v e reactions at the y _carbon of the dianion of a B-keto e s t e r 1 f u r -nish the extension of the carbon skeleton at the y _ p o s i t i o n of the molecule. By applying the above two synthetic p o s s i b i l i t i e s to the simplest B-keto ester u n i t , namely, methyl acetoacetate, the following transformation (equa-t i o n 1) can be r e a d i l y accomplished. R1 and R2 i n B-keto esters 1_ represent a l k y l groups with or without f u n c t i o n a l i t i e s . With access to compounds of type 1 secured, i t would be of great synthetic value to e s t a b l i s h ways to achieve extensions at the two carbonyl carbons. In f a c t , one of the reasons f o r adopting a B-keto ester as the basic synthetic substrate i s the possible d i f f e r e n t i a t i o n between the ketone and the ester functions, which would allow further s t r u c t u r a l elaboration. A general and f a c i l e s y n t h e t i c pathway l e a d i n g to the o v e r a l l transformations as i l l u s t r a t e d i n equation 2 would not only serve as a ?3 s t e r e o s p e c i f i c route to s u b s t i t u t e d alkenes, but would a l s o c o n s t i t u t e a u s e f u l method f o r extending carbon skeletons i n organic s y n t h e s i s . The same strate g y could be a p p l i e d to c y c l i c B-keto est e r s as shown i n equation 3. The aim of the work described i n t h i s d i s s e r t a t i o n was to develop two major s y n t h e t i c methodologies based on B-keto e s t e r s , v i z . , r i n g forma-t i o n r e a c t i o n s and s t e r e o s p e c i f i c alkene s y n t h e s i s , and to apply them to n a t u r a l products s y n t h e s i s . I t i s our modest hope that the r e s u l t s of our e f f o r t may f i n d u s e f u l a p p l i c a t i o n s i n modern organic chemistry. I n s e c t i o n s I and I I , b r i e f reviews of some aspects of c a r b o c y c l i -z a t i o n methodologies and s t e r e o s e l e c t i v e alkene syn t h e s i s are given before 3 the respective presentations of our f i n d i n g s . Many of the reactions des-cribed i n the introductions have been broadly used i n modern organic syn-thes i s . Some are included mainly for t h e i r elegance. The v e r s a t i l i t y as well as the l i m i t a t i o n of those more general methods are discussed. The synthesis of several i n t e r e s t i n g natural products, demonstrating the u t i l i t y of a combination of f a c i l e reactions i n v o l v i n g $-keto esters, are presented i n section I I I . 4 SECTION I; STUDIES ON CYCLIZATION REACTIONS OF B-KETO ESTERS I n t r o d u c t i o n - Some A s p e c t s o f C y c l i z a t i o n R e a c t i o n s The c r e a t i o n o f c y c l i c s y s t e m s i s o f t e n i n v o l v e d i n t h e d e s i g n o f s y n t h e t i c s t r a t e g i e s . R i n g s t r u c t u r e s e i t h e r c o n s t i t u t e p a r t o f t h e s y n -t h e t i c g o a l o r s e r v e t o s e t up t h e s p e c i f i c s t e r e o c h e m i s t r y o f a m o l e c u l e . C y c l i z a t i o n r e a c t i o n s a r e o f p a r t i c u l a r i n t e r e s t t o n a t u r a l p r o d u c t s s y n -t h e s i s ow ing t o t h e u b i q u i t o u s e x i s t e n c e o f c y c l i c s y s t e m s i n v a r i o u s c l a s s e s o f n a t u r a l p r o d u c t s , e . g . , a l k a l o i d s , i n s e c t ho rmones , t e r p e n e s and s t e r -o i d s . 3 A r i n g c a n be fo rmed e i t h e r i n t e r m o l e c u l a r l y o r i n t r a m o l e c u l a r l y . The f o r m e r mode o f r i n g f o r m a t i o n f a l l s i n t o t h e c a t e g o r y o f c y c l o a d d i t i o n r e a c t i o n s w h i c h embraces w e l l - k n o w n r e a c t i o n s s u c h as D i e l s - A l d e r r e a c t i o n s f o r t h e f o r m a t i o n o f s i x - m e m b e r e d r i n g s , 1 , 3 - d i p o l a r a d d i t i o n f o r f i v e -membered r i n g s , [2 + 2] a d d i t i o n f o r f ou r -membered r i n g s and c a r b e n o i d a d d i -t i o n f o r t h ree -membered r i n g s . 2 The c a t e g o r y o f i n t r a m o l e c u l a r c y c l i z a t i o n c o v e r s a b r o a d and d i v e r s e s p e c t r u m o f o r g a n i c r e a c t i o n s w i t h c o u n t l e s s e x a m p l e s . D i f f e r e n t t y p e s o f r e a c t i o n s l i k e a l k y l a t i o n , a c y l a t i o n , c o n d e n s a -t i o n , c y c l o a d d i t i o n and e l e c t r o p h i l e - i n i t i a t e d a l k e n e c y c l i z a t i o n s have a l l been u t i l i z e d . I n f a c t , numerous n o v e l r e a c t i o n s have b e e n d e v e l o p e d i n t h e p a s t few d e c a d e s t o s y n t h e s i z e r i n g sys tems , w h i c h o t h e r w i s e w o u l d be a c c e s -s i b l e o n l y w i t h g r e a t d i f f i c u l t y . Many o f t h e s e new s y n t h e t i c methods a r e i n t e r e s t i n g and c h a l l e n g i n g i n t h e i r own r i g h t . 5 A. Acid-Catalyzed Cyclization of Polyenes Of a l l the cyclization methods so far developed, few were more exciting than the biogenetic-type polyene cyclization pioneered by Stork"* and Eschenmoser5 in the mid-fifties, and later explored extensively by Johnson,6 van Tamelen7 and others. 8 The early studies were initiated by the ingenious proposals regarding the biogenesis of cholesterol from acetate. 9 At one stage of this biogenesis, squalene (2) was suggested to undergo enzyme cata-lyzed polycyclization to produce lanosterol (3). It is now well recognized that squalene or squalene 2,3-oxide is the biogenetic precursor of polycyclic H I t r i t e r p e n e s . 9 ' 1 0 ' 1 1 In 1955, Stork 1* 3 and Eschenmoser5a independently suggested that squalene-like polyolefins should have an intrinsic susceptibility to cyclize stereoselectively to a polycyclic system of definite stereochemical configura-tion. Thus the highly stereoselective biological cyclization of squalene could be rationalized on stereoelectronic grounds as illustrated below by the cyclization of squalene 2,3-oxide (4) to give dammaradienol (5). 6 H O . H H 5 The squalene molecule was envisioned to a l i g n i n such a way that t r a n s - a n t i -p a r a l l e l e l e c t r o p h i l i c additions to the o l e f i n i c bonds i n i t i a t e d by an i n c i -pient c a t i o n i c centre at earbon-2 could occur through an a l l - c h a i r conforma-ti o n . An a l l - t r a n s squalene would therefore lead to the a l l - t r a n s fusion of the four rings i n dammaradienol. The Stork-Eschenmoser hypothesis postulates a concerted c y c l i z a -t i o n process. Applying i t to the c a t i o n i c c y c l i z a t i o n of a 1,5-diene to form a cyclohexane system (equation 4), the entering e l e c t r o p h i l e (E) and 7 nucleophile (N) should be trans d i e q u a t o r i a l i n the products. Examples i n accord with t h i s hypothesis have been reported. Ulery and Richards 1 showed that treatment of diene 6^ with deuteroformic and deuterosulfuric acids gave cyclohexyl formate ]_ as the only c y c l i z e d product. H _6_ 7_ The biogenetic c y c l i z a t i o n of squalene i s i n t r i g u i n g to organic chemists f o r two main reasons, namely, the formation of p o l y c y c l i c systems i n one step and the complete stereochemical c o n t r o l over t h i s process. A biomimetic approach to the t o t a l synthesis of p o l y c y c l i c natural products, e.g., steroids and triterpenes, i f successful, would be much more e f f i c i e n t than the conventional strategy of .step-by-step annelations. Indeed, t h i s concept has stimulated many investigations to develop s i m i l a r but nonenzymic c y c l i z a t i o n s i n the laboratory. Results of these studies and t h e i r a p p l i c a -t i o n to the synthesis of steroids and various terpenes have been r e -v i e w e d . 6 ' 7 » 8 ' 1 3 ' l h ' 1 5 Some noteworthy findings w i l l be described below. In a study which represented one of the e a r l i e s t biogenetic-type synthesis of terpenes, cyclogeraniolenes (9) and cyclogeraniol acetates (11) were obtained by acid-catalyzed c y c l i z a t i o n of geraniolene (8_) and geraniol acetate (10), r e s p e c t i v e l y . 1 6 Studies directed toward the bio-10 8-11 a - Ti genetic-type cyclization of farnesol derivatives have provided an attractive route to decalin systems and related sesquiterpenes. Stoll et a l . f i r s t reported the acid promoted cyclization of farnesol semicarbazone (12) to give a- and 8-bicyclofarnesols (13). 1 7 Boron trifluoride catalyzed cycliza-tion of farnesoic acid (14) to form the bicyclic compounds 16a and 16b was found to proceed via an isolable monocyclic intermediate 15. **»18 This result suggests that similar intermediary monocyclic dienes are pro-bably involved in other related cyclizations. Further evidence for the stepwise cyclization came from Eschenmoser's work.19 When the (trans, 9 10 t r a n s ) - , ( c i s , t r a n s )- and (trans, cis)-isomers of desmethyl farnesoic acid 17 and t h e i r methyl esters 1_8 were c y c l i z e d with s u l f u r i c and formic acids, only trans fused products 19_ and ^0 were obtained. C y c l i z a t i o n of the ( c i s , trans)-isomer to a trans fused product i s contrary to the Stork-Eschenmoser hypothesis which would predict c i s fused products i f the c y c l i z a t i o n s were concerted. Monocyclic carbonium ions of s u f f i c i e n t l i f e -time must be involved to allow f o r the formation of the thermodynamically more stable trans-decalin system. The poor n u e l e o p h i l i c i t y of the o l e f i n i c bond conjugated to the carboxyl group may account for the non-concerted nature of t h i s process. In f a c t , s t e r e o s p e c i f i c c y c l i z a t i o n s did occur i n cases where the centre involved i n terminating the r i n g closure process was not reduced i n n u e l e o p h i l i c i t y . Smit ej: a l . have shown that c i s - and trans-geranyl acetone, (21a) and (21b), c y c l i z e d s t e r e o s p e c i f i c a l l y to the corres-ponding b i c y c l i c ethers 22a and 22b. 2 0 Johnson also found that acid-cata-lyzed c y c l i z a t i o n of diene 2_3 gave predominantly the c i s - a n t i - d e c a l o l 24."2 1 Results of acid-promoted c y c l i z a t i o n of geranylgeraniol deriva-t i v e s 25 were u n s a t i s f a c t o r y . 1 9 These reactions i n v a r i a b l y led to complex OR OR R= H,OAc 25 26 11 mixtures with very low y i e l d of the desired t r i c y c l i c material 26. The d i f f i c u l t y appeared to a r i s e from the indiscriminate protonation of various o l e f i n i c bonds, r e s u l t i n g i n a l l sorts of c y c l i z e d products. In order to solve t h i s problem, several groups of workers have searched to f i n d more s e l e c t i v e ways to i n i t i a t e the c y c l i z a t i o n of polyenic systems. The general concept i s to incorporate into a polyenic molecule an appro-p r i a t e l y disposed functional group which i s capable of generating a cat-i o n i c centre under conditions that would not otherwise a f f e c t the o l e f i n i c bonds. The use of polyenic epoxides, 7 sulfonate e s t e r s , 6 a c e t a l s 6 and a l l y l i c a l c o h o l s 6 have been studied extensively and have enjoyed great success i n the synthesis of c y c l i c terpenes. j}. C y c l i z a t i o n of o l e f i n i c epoxides Acid-catalyzed r i n g opening of an epoxide s u i t a b l y placed i n a polyenic molecule would generate a c a t i o n i c centre to i n i t i a t e c y c l i z a t i o n and at the same time produce a hydroxy function i n the c y c l i z e d product. Indeed, a host of 3-hydroxylated p o l y c y c l i c terpenoids have been synthesized v i a s t e r e o s e l e c t i v e c y c l i z a t i o n of terpene terminal epoxides. Simple monoenic epoxides were f i r s t put to test by Goldsmith and van Tamelen. Upon treatment with boron t r i f l u o r i d e or stannic c h l o r i d e , geraniolene monoepoxide 27_ afforded a mixture of b i c y c l i c ether 2_8_ and cyclohexenols 29a and 29b. 2 2 The epoxide of geranyl acetate, 3_0, was con-verted into the cyclohexenol 31 with phosphoric a c i d . 2 3 Mechanistically 13 i n t e r e s t i n g r e s u l t s were obtained from the re a c t i o n of epoxide _32 with boron t r i f l u o r i d e . Three c y c l i c products, 3_3, _34 and 35 were i s o l a t e d . 2 < + Presumably, opening of the oxirane r i n g of _32 with p a r t i c i p a t i o n of the o l e f i n i c bond gave r i s e to the b i c y c l i c ether _33 and the aldehyde 34. Hydride transfer (I ->- II) was suggested to account for the formation of 3J*_. An intermediary aldehyde 35a, derived from opening of the oxirane r i n g without p a r t i c i p a t i o n of the o l e f i n i c bond, was apparently involved i n the formation of 35. One serious problem concerning the u t i l i t y of a c y c l i c epoxypolyene c y c l i z a t i o n s i s the s e l e c t i v e introduction of an epoxide function at the terminal o l e f i n i c bond of a polyenic system. To circumvent t h i s d i f f i c u l t y , van Tamelen and coworkers developed a highly r e g i o s e l e c t i v e epoxidation method. 2 5 The procedure involves s e l e c t i v e mono-bromohydrin formation using N-bromosuccinimide i n aqueous glyme and subsequent treatment of the bromohydrin with base to form the epoxide. As i l l u s t r a t e d by the conversion of squalene (2) to squalene 2,3-oxide (4), the s e l e c t i v i t y f o r the formation of the terminal bromohydrin 3_6 was found to be greater than 95%. A p l a u s i -ble explanation for the high r e g i o s e l e c t i v i t y i s that i n a highly polar 14 medium, a long chain polyenic molecule probably assumes a c o i l e d confor-mation such that the i n t e r n a l carbon-carbon double bonds would be s t e r i -c a l l y shielded, leaving the terminal o l e f i n i c bonds exposed for rea c t i o n . Epoxyfarnesyl d e r i v a t i v e s , prepared by the above epoxidation method, have been investigated for p o l y c y c l i z a t i o n . Epoxides 3_7 and 39, on treatment with acids, c y c l i z e d to the b i c y c l i c compounds 38a, 38b and 40a, 40b r e s p e c t i v e l y . In each case, the r a t i o of the isomers formed varied according to the reaction conditions e m p l o y e d . 7 a ' 2 6 » 2 7 These types of c y c l i z a t i o n s have been shown to be s t e r e o s p e c i f i c , i n contrast to the r e s u l t s of acid-catalyzed c y c l i z a t i o n of polyenes (vide supra). Thus the c i s isomer of 3_9, v i z . , methyl trans, cis-10,11-oxidofarnesoate (41) was converted into the c i s fused decalols 42_ while epoxide 39_ gave only the trans fused decalols 40a and 40b under acid c a t a l y s i s . 2 7 41 42 15 Extending the epoxypolyene c y c l i z a t i o n to the t r i c y c l i c l e v e l , van Tamelen and Nadeau were able to i s o l a t e the t r i c y c l i c alcohol 44 from the stannic chloride catalyzed c y c l i z a t i o n of epoxide 4 3 . 2 8 When squalene 2,3-oxide (4_) was subjected to s i m i l a r r e a c t i o n conditions, two t r i c y c l i c products, namely, the t r i e n i c alcohol 4_5 and the rearranged isomer 4_6 were ob t a i n e d . 2 9 Formation of the five-membered C r i n g was apparently dictated by the development of the more stable c a t i o n i c centre at carbon-15. Based on t h i s f i n d i n g , Sharpless accomplished the biogenetic-type synthesis of 4 16 malabaricanediol (48) by preparing the epoxydiol 47_ and c y c l i z i n g i t with p i c r i c a c i d . 3 0 Similar c y c l i z a t i o n s have also been u t i l i z e d i n the t o t a l syn-thesis of the pentacyclic triterpenes, 6-amyrin ( 5 1 ) 3 1 and tetrahymanol (52) 3 2 , with epoxides _49 and j>0 as t h e i r corresponding a c y c l i c precursors. 51 52 17 C_. Cy c l i z a t i o n s with P a r t i c i p a t i o n of Acetylenic Bonds The acid-catalyzed c y c l i z a t i o n of polyenes inv o l v i n g the p a r t i -c i p a t i o n of acetylenic bonds i s a useful synthetic t o o l f o r constructing p o l y c y c l i c systems, e s p e c i a l l y those possessing a five-membered r i n g moiety. Developed mainly by Johnson and coworkers, 6^> 3 3 t h i s type of cy c l i z a t i o n ; : can be generally represented by Scheme 1. Compounds with p a r t i a l structure Scheme i IV 55 Y = nucleophiles ( i n t e r n a l or external) 53 may c y c l i z e to form either 5_4 or _55, v i a the corresponding intermediary cations I I I or IV, depending on the nature of R. I t has been demonstrated that when R was an a l k y l or a r y l group, III predominated and when R was a 18 t r i a l k y l s i l y l group, IV was favored. The v i n y l i c c ation I I I has been trapped by various external nucleophiles as l i s t e d below. Nucleophilic Acid, solvent Y Formic acid, pentane 1% T r i f l u o r o a c e t i c a c i d , a c e t o n i t r i l e Stannic chloride, benzene T r i f l u o r o a c e t i c acid, -0CH0 - N H C O C H 3 -C 6H 5 OCOCF3 Boron t r i f l u o r i d e , 1,1-dichloro-ethane F attack at the c a t i o n i c centre of III by an i n t e r n a l o l e f i n i c bond has also been reported. C y c l i z a t i o n of alcohol 5b_ with t r i f luoroacetic acid at low temperature gave compound 5]_ i n 70% y i e l d 34 19 Polyene c y c l i z a t i o n s with the p a r t i c i p a t i o n of acetylenes have been successfully applied to the t o t a l synthesis of ste r o i d s . For example, the key step i n a t o t a l synthesis of progesterone involved the conversion of alcohol 5_8 into the pregnenone (59) i n the presence of t r i f l u o r o a c e t i c a c i d and ethylene carbonate. 3 5 It was believed that ethylene carbonate served as a nucleophile to terminate the c y c l i z a t i o n process by forming the s t a b i l i z e d c ation V. 20 Results from a p p l i c a t i o n of s i m i l a r c y c l i z a t i o n s to the synthesis of C - l l - s u b s t i t u t e d steroids indicated e s s e n t i a l l y complete stereochemical co n t r o l by a c h i r a l centre at pro-C-11 ^ of the polyene precursor i n these processes. In theory, c y c l i z a t i o n of the pro-C-ll-methyl alcohols 6OR and 60S would lead to two diastereomeric pairs of enantiomers 61a,b and 62a,b. The alcohol 60R with R configuration at pro-C-11 could c y c l i z e to give 61a or 62a depending whether a back face or a front face attack on the cyclopentene r i n g occurred. S i m i l a r l y alcohol 60S could c y c l i z e to i n the st e r o i d product. 21 form 61b or 62b. However, when alcohols 60R,S were treated with t r i -f l u o r o a c e t i c acid i n t r i f l u o r o e t h a n o l , a racemic mixture of 61a and 61b was 3 6 obtained i n over 60% y i e l d with no detectable amount of 62a and 62b. Obviously, preference of the pro-C-ll-methyl group to assume a pseudo-equatorial p o s i t i o n during the c y c l i z a t i o n d i c t a t e d the stereochemical course. Thus 6OR c y c l i z e d e x c l u s i v e l y at the back face of the cyclopentene r i n g to give 61a with an equatorial C-ll-methyl group, while 60S underwent exclusive front face attack on the cyclopentene r i n g to a f f o r d 61b. This asymmetric induction effected by a pro-C-11 c h i r a l centre has been u t i l i z e d 3 7 i n a t o t a l synthesis of o p t i c a l l y a c t i v e lla-hydroxyprogesterone. P a r t i c i p a t i o n of the t r i m e t h y l s i l y l a c e t y l e n i c group i n the c y c l i z a t i o n of alcohol j>3 resulted i n the formation of a six-membered D r i n g i n the s t e r o i d product 64. 3 3^ The s t a b i l i z a t i o n of a p o s i t i v e charge by a 3 - s i l y l group 3 8 may account f o r the p r e f e r e n t i a l formation of VI which, apparently, was the intermediate leading to ketone 64. Si Me 3 H 6 4 22 D. C y c l i z a t i o n v i a Enol Derivatives Enol d e r i v a t i v e s of ketones and aldehydes have been used success-f u l l y i n several biogenetic-type c y c l i z a t i o n s . Treatment of dihydrocarvone enolacetate (65) with boron t r i f l u o r i d e i n dichloromethane gave camphor (66) i n 90% y i e l d . 3 9 This reaction was applied to the synthesis of cam-pherenone and epicampherenone, i n which enolacetate j67_ was c y c l i z e d to 23 give a mixture of 68a and 68b. 4 0 S i m i l a r l y , i n the key step of a bio-genetic type synthesis of cedrol, enolacetate 69 was converted into the t r i c y c l i c ketone 70. 4 1 Recently, a group of Japanese workers developed a novel c y c l i z a -t i o n of c i t r a l v i a i t s enamine d e r i v a t i v e s . 1 * 2 The c i t r a l p y r r o l i d i n e enamine _71, when treated with a mixture of concentrated s u l f u r i c acid and water, gave a - c y c l o c i t r a l (72a) i n moderate y i e l d , accompanied by only a trace amount of B - c y c l o c i t r a l (72b). An asymmetric synthesis of 72a 72b 24 — ^CHO H % R a - c y c l o c i t r a l (S(+)-72a) was also accomplished by applying the same c y c l i z a t i o n method to some c h i r a l enamines of c i t r a l 73. E. E l e c t r o p h i l e - I n i t i a t e d C y c l i z a t i o n s In the past decade, the r a p i d l y growing number of bromine-containing terpenoids i s o l a t e d from natural sources, e s p e c i a l l y marine organisms, has prompted many inve s t i g a t i o n s to develop e f f i c i e n t synthesis of t h i s c l a s s of compounds. 4 3 Of p a r t i c u l a r i n t e r e s t i n t h i s regard i s the study on d i r e c t brominative r i n g closure of polyenes. A reagent 25 system developed by Faulkner for t h i s purpose consisted of equivalent quantities of bromine and a Lewis acid mixed i n a polar, aprotic solvent.1*"* C y c l i z a t i o n of geranyl d e r i v a t i v e s employing t h i s method gave mediocre y i e l d s of the corresponding bromocyclogeranyl compounds. For example, treatment of geranyl acetate with an equimolar mixture of bromine and s i l v e r fluoroborate i n nitromethane gave the bromo compound 7_4 i n 20% y i e l d . Under s i m i l a r conditions, geranyl acetone afforded the v i n y l ether 75 i n the same y i e l d . Kitahara and Kato used 2,4,4,6-tetrabromo-2,5-cyclohexadienone (77) as a mild source of bromine. 4 3 > 5 In the presence of t h i s bromoketone and an aluminum halide, geranyl cyanide (76) was converted into the mono-c y c l i c compound 7JT i n about 15% y i e l d . Although tetrabromoketone T]_ 26 showed s i g n i f i c a n t s e l e c t i v i t y towards bromination of terminal o l e f i n i c bonds i n polyene systems, 4 5^ the low y i e l d i n g nature of the c y c l i z a t i o n reactions l i m i t s i t s use i n t h i s respect. Brominative c y c l i z a t i o n was also effected by using N-bromosuccini-mide and cupric acetate i n _t-butanol and a c e t i c a c i d . The bromo compound 79 was obtained i n 12% y i e l d from methyl (trans, trans)-farnesoate by using t h i s reagent system. 1* 6 Smit and coworkers investigated the e l e c t r o p h i l i c a d d i t i o n reac-tions of a wide v a r i e t y of cationoid complexes of the type X+BF4 (X + = 27 RCO*, R , N0 2 and RS ) and accomplished, i n t e r a l i a , the phenylsulfenium ion and the acylium ion i n i t i a t e d c y c l i z a t i o n s of methyl geranate (equa-t i o n 5) i n 57 and 56% yie l d s , r e s p e c t i v e l y . 4 7 X = C 6H 5S- , (CH-^C-Another f a c i l e reagent system for promoting s e l e c t i v e a c y l a t i o n of polyenes with concomitant r i n g closure was developed by Kitahara and co-Scheme i i 28 •-workers.48 Equimolar mixture of a n a c y l chloride and .stannic chloride i n nitromethane transformed the geranyl derivatives 80 to the corresponding unsaturated ketones _81_. When aluminum chloride and dichloromethane were used instead of stannic c h l o r i d e and nitromethane, the chloroketones 8_2 were obtained (Scheme i i ) . Mercuric ion induced c y c l i z a t i o n has been applied mainly to the synthesis of lactones and c y c l i c ethers as shown by the following examples (equations 6 U" and 7 5 0 ) . Goutarel and coworkers conducted a d e t a i l e d "study on the r e a c t i v i t y of the B-aldehydo ester group towards an i n t e r n a l o l e f i n i c bond activated by mercuration. 5 1 The mercurinium ion i n i t i a t e d c y c l i z a t i o n of the a l k a l o i d 8_3, followed by demercuration with sodium borohydride, gave a mixture of 0- and C-cyclized products 8_4_ and 8_5 i n 20 and 45% y i e l d s , r e s p e c t i v e l y . 29 I t i s obvious from the,foregoing survey on c y c l i z a t i o n reactions that a c i d - and e l e c t r o p h i l e - i n i t i a t e d c y c l i z a t i o n s of o l e f i n i c and epoxy substrates provide useful and e f f i c i e n t routes to c y c l i c systems. Although these methods have been investigated i n t e n s i v e l y , the u t i l i z a t i o n of enol type nucleophiles i n s i m i l a r reactions remains rather unexploited. In our continuing search for synthetic u t i l i t i e s of B-keto esters, we f e l t that the B-keto ester function would not only serve as a convenient i n t e r n a l nucleophile i n c y c l i z a t i o n s , but also provide useful f u n c t i o n a l i t i e s i n the c y c l i z e d products. The r e s u l t s of our study with the appropriate discussion are presented i n the following part of t h i s section. 30 Results and Discussion A few examples of u t i l i z i n g the 8-keto ester function to con-st r u c t r i n g systems have been reported i n the past decade. Most of these c y c l i z a t i o n reactions were applied to the synthesis of natural products, in t e r . . a l i a , jasmonoids and prostanoids. Among them are the c y c l i z a t i o n of enamine 5 2 and a - d i a z o 5 3 ' 5 4 d e r i v a t i v e s of 8-keto esters i n the synthesis of prostaglandins; the intramolecular condensation of 8j£ _diketo esters i n the synthesis of jasmonoids; 5 5 and the intramolecular a l k y l a t i o n of 8-keto ester enolates with T T - a l l y l p a l l a d i u m complexes i n the synthesis of humulene. We have been interested i n using a c y c l i c 8-keto esters as precursors to c y c l i c compounds, e s p e c i a l l y f i v e - and six-membered r i n g systems. Results of our study on the c y c l i z a t i o n of some unsaturated as well as some epoxy 8-keto esters are described below. E l e c t r o p h i l e - and A c i d - I n i t i a t e d C y c l i z a t i o n of Unsaturated B-Keto Esters C y c l i z a t i o n of the alkenyl 8-keto ester 86 was f i r s t investigated This keto ester was prepared 1 i n good y i e l d by a l k y l a t i o n of the dianion of methyl acetoacetate with a l l y l bromide. Attempts to promote c y c l i z a t i o n O O 1. N a H 2. n-BuL i O 86 3i* of 86_ with acids proved to be f u t i l e . No s i g n i f i c a n t reaction could be detected when J36_ was treated with Lewis or p r o t i c acids at room temperature. Employment of more d r a s t i c conditions (e.g., r e f l u x i n g temperatures and prolonged reaction times) merely led to polymerized and i n t r a c t a b l e mixtures. Bromonium ion i n i t i a t e d cyclization'' 1* of 8_6 i n v a r i a b l y resulted i n formation of mixtures of brominated material which were too complicated to have any synthetic value. Intrigued by the use of phenylselenenyl halides to e f f e c t l a c t o n i z a t i o n of unsaturated a c i d s 5 7 (e.g., equation 8 ) , we studied the p o s s i b i l i t y of i n i t i a t i n g c y c l i z a t i o n of J36 with t h i s reagent. Treat-ment of J36 with phenylselenenyl ch l o r i d e i n dichloromethane at d i f f e r e n t S e P h i temperatures gave only the ad d i t i o n product 8]_, i n almost quantitative y i e l d . The structure of 87_ was evident from i t s s p e c t r a l data. IR absorp-tions at 1715 and 1740 cm - 1, a two-proton s i n g l e t at 6 3.38 i n the H^NMR spectrum and mass fragment at m/e 101 i n the mass spectrum of 8_7 affirma-t i v e l y indicated the i n t a c t 6-keto ester moiety ( \ J^\^C0 2Me ) • Absence of v i n y l proton absorptions i n the XHNMR spectrum and a prominent molecular ion at m/e 348, corresponding to the parent mass of 87_ (based on 3 5C1 and 8 0 S e ) , i n the mass spectrum were consistent with an addit i o n product. Regio-chemistry of the adduct 87_ was assigned by analysis of i t s 1HNMR spectrum, 32 which showed a one-proton m u l t i p l e t at 6 4.1 for the methine proton adjacent to chlorine and a two-proton broad doublet at 6 3.25 for the methylene pro-tons on the carbon bearing the phenylselenenyl group. There were no peaks i n the 6 3.4 to 3.6 region where the regioisomer of 87 would be expected to show absorptions. E l e c t r o p h i l i c addition of phenylselenenyl d e r i v a t i v e s to o l e f i n s 33 has been shown to be a f a c i l e p r o c e s s , 5 8 the mechanism of which i s believed to involve an intermediate episeleniranium ion. In general, the regio-s e l e c t i v i t y of t h i s type of addition to unsymmetrical o l e f i n s i s l o w . 5 8 * 5 9 The unusually high r e g i o s e l e c t i v i t y observed i n the addition of phenylselenenyl chloride to 86 might have a r i s e n from intramolecular p a r t i c i p a t i o n of the keto group as shown below. > 87 I n t e r e s t i n g l y , when 87_ was chromatographed with s i l i c a g e l , c y c l i z a -t i o n took place and enol ether J58 was i s o l a t e d i n 68% y i e l d along with 27% of hemiketal 89_. The l a t t e r was presumably derived from hydration of 88. The IR spectrum of 88_ exhibited an absorption at 1700 cm - 1 i n d i c a t -ing the a,6-unsaturated ester function, and a remarkably intense peak at 1640 cm 1 c h a r a c t e r i s t i c of the double bond stretching of enol ethers. Pre-sence of the phenylselenenyl group was shown by the mass spectrum (m/e 314: 312: 310: 309: 308: 306 = 11: 55: 27: 9: 10: 1; parent peaks of 88, character-i s t i c family of peaks f o r Se due to natural i s o t o p i c abundance), as well as aromatic absorptions i n the IR (1580, 1475 cm - 1) and 1HNMR (6 7 .5 , 7.2) spectra. The structure of 88_ with the enol double bond i n an E_ geometry was confirmed by comparing i t s IR and aHNMR data with those of compound 90 6 0 > 6 1 (Table 1) . P r e f e r e n t i a l formation of the E_ isomer over the Z_ isomer of 88_ 34 Table 1. 1HNMR and IR data of 88. M e Q 2 C H IR (CHC13) 1HNMR (CDCI3) Me0 2 S e P h 88 - 1 1700 cm" 1640 cm - 1 1120 cm - 1 (C-O-C) 6 5.17 (t, C-6H) 4.52 (m, C-5H) 3.60 (s, CO2CH3) 3.2 (m, C-3H) 2.1 (m, C-4H) 90 6 0 . 6 1 1700 cm"1 1640 cm"1 1120 cm - 1 (C-O-C) 6 5.2 (t , C-6H) 4.5 (m, C-5H) 3.60 (s, CO2CH3) 3.2 (m, C-3H), 2.2 (m, C-4H) i s a t t r i b u t e d to the more stable o r i e n t a t i o n of dipole moments i n the former molecule. Hemiketal 8_9_ was characterized by i t s spectroscopic properties. A two-proton s i n g l e t at 6 2.68 i n the 1HNMR spectrum revealed a methylene group between a t e r t i a r y carbon centre and a carbonyl function. The IR absorption at 3530 and 1720 cm - 1 were consistent with an intramolecularly hydrogen bonded hydroxy ester moiety. The mass spectrum showed a parent 35 mass (based on 8 0Se) at m/e 330 and a peak at m/e 312, probably arose from loss of H2O. In fact, when J39 was heated to about 170° C under vacuum, dehydration occurred giving 88 as the d i s t i l l a t e . Mercuric salt promoted cyclization was also explored. Treatment of 86 with mercuric acetate in anhydrous tetrahydrofuran gave a crude product whose spectral data indicated the 0-cyclized mercurial compound 91_ (IR: 1700, 1640 and 1565 cm-1; 1HNMR: 6 5.22 (br s ) , 4.6 (m), 3.62 (s) , 2.23 ( d ) , 6 2 2.03 (s) and 1.6-3.4 (m)). Demercuration of 9_1_ with sodium borohydride re-sulted in generation of the i n i t i a l 3-keto ester 8_6 and i t s reduction product, hydroxy acid 9_2. Failure to obtain the expected demercuration product 9_3 is possibly due to rearrangement of the intermediate r a d i c a l 6 3 V i l a to Vllb. 86 92 36 In order to study the e f f e c t of s u b s t i t u t i o n at the C-6, C-7 o l e f i n i c bond on the c y c l i z a t i o n of e-alkenyl 8-keto esters, compounds 94 and _95 were prepared and subjected to acid-induced c y c l i z a t i o n s . These 8-keto esters feature two i n t e r e s t i n g s t r u c t u r a l analogues of 8_6. In 94, the ease of development of a c a t i o n i c centre at C-6 under a c i d i c conditions i s enhanced by the a d d i t i o n a l methyl group. With two methyl groups on C-7 i n 9_5, the p o t e n t i a l carbonium ion centre would be s h i f t e d from C-6 to C-7. A l k y l a t i o n of the dianion of methyl acetoacetate with 3-chloro-2-methylpropene and l-bromo-3-methyl-2-butene afforded the 8-keto esters 94 and 95 i n 72 and 85% y i e l d s , r e s p e c t i v e l y . In contrast to the inertness 37 95 of 86^  towards acid-initiated cyclization, 9_4_ was transformed cleanly into the cyclic enol ether 9_6 upon treatment with stannic chloride (ca. one equivalent) in dichloromethane at ambient temperature. Undoubtedly, the C-6 methyl group in 9_4_ increases the reactivity of the olefinic bond towards electrophilic reagents, in this case, H . The structure of _% was ascertained by comparing i t s spectroscopic properties with those of 9_0. Again, the Z_ isomer of 9_6 was not detected. 38 The a-furylidene acetate structure was r e a d i l y recognized from the con-spicuous IR absorptions at 1700, 1640 and 1120 cm - 1. That the molecule of j)6 had a plane of symmetry was r e f l e c t e d i n the 1HNMR spectrum, which showed a six-proton s i n g l e t (6 1.35) for the two methyl groups; a t r i p l e t (6 5.17, J = 1.8 Hz) for the v i n y l proton; a doublet of t r i p l e t s (6 3.15, J = 1.8, 7.6 Hz) for the a l l y l i c protons and a t r i p l e t (5 1.87, J = 7.6 Hz) for the methylene group. When 9_5 was exposed to stannic chloride i n dichloromethane at room temperature, the C-cyclized compound 97_, rather than an 0-cyclized mater-i a l analogous to 9_6, was obtained i n almost quantitative y i e l d . In the IR spectrum of 97, absorptions for a six-membered r i n g ketone (1710 cm - 1) and a normal ester (1730 cm - 1) were present. Two d i s t i n c t three-proton sing-l e t s at 6 1.08 and 1.02 i n the ^NMR spectrum revealed d i f f e r e n t environ-ments for the two methyl groups. A one-proton s i n g l e t at 63.13 was assigned to the methine proton at the a - p o s i t i o n of the 8-keto ester. In the mass spectrum, a prominent peak at m/e 100 and the absence of notable mass f r a g -ments at m/e 101 ( c h a r a c t e r i s t i c of 8-keto esters unsubstituted at the a-position) provided further evidence for an a-substituted 8-keto e s t e r . 6 4 Based on the above an a l y s i s , the structure of 9_7 was established. The 39 c h e m i c a l s h i f t o f t h e a - m e t h i n e p o r t i o n ( 6 3 . 1 3 ) shows a s l i g h t u p f i e l d s h i f t f r o m t h e v a l u e n o r m a l l y o b s e r v e d ( c a . 6 3 . 3 - 3 . 5 ) f o r p r o t o n s o f t h i s t y p e , i n d i c a t i n g t h a t i t o c c u p i e s a n a x i a l p o s i t i o n . O t h e r a c i d s ( B F 3'Et20, HC1) were a l s o i n v e s t i g a t e d f o r e f f e c t i n g t h e above c y c l i z a t i o n and a n h y d r o u s s t a n n i c c h l o r i d e was f o u n d t o p r o d u c e t h e most s a t i s f a c t o r y r e s u l t . I t i s o b v i o u s f r o m t h e above f i n d i n g s t h a t i n t h e e l e c t r o p h i l e -i n i t i a t e d c y c l i z a t i o n o f 8 - k e t o e s t e r s o f t y p e 9_8, t h e r e was a s t r o n g p r e f e r -00 ence f o r f o r m a t i o n o f t h e O - c y c l i z e d compound 100 o v e r t h e C - c y c l i z e d m a t e r -i a l 99_. T h i s p r e d o m i n a n c e o f 0 - c y c l i z a t i o n m i g h t be r a t i o n a l i z e d on s t e r e o -e l e c t r o n i c g r o u n d s . Under e l e c t r o p h i l i c c o n d i t i o n s , d e v e l o p m e n t o f a c a t i o n i c c e n t r e a t C -6 i s f a v o r e d and w o u l d a l l o w n u c l e o p h i l i c a t t a c k a t t h i s p o s i t i o n . I n p r i n c i p l e , t h e amb iden t e n o l d e r i v a t i v e o f 98 may unde rgo i n t r a m o l e c u l a r C - a l k y l a t i o n t o g i v e c y c l o p e n t a n o n e 9 9 , o r O - a l k y l a t i o n to p r o d u c e e n o l 40 ether 100 (Scheme i i i ) . A study of molecular models shows that approach Scheme i i i R VHIb 100 X = Lewis ac i d , H of C-6 to C-2 perpendicular to the enol-plane ( V i l l a ) i n order to a t t a i n s u f f i c i e n t o r b i t a l overlap i n the t r a n s i t i o n state for C - c y c l i z a t i o n , i s s t e r i c a l l y d i f f i c u l t . However, O- c y c l i z a t i o n can be e a s i l y achieved by l i n i n g up C-6 with the lone pair of electrons on oxygen within the enol-plane (VHIb). Thus, on the basis of stereoelectronic considerations, formation of enol ether 100 i s f e a s i b l e while that of 99 i s disfavored. 41 This argument i s i n accord with the rules f o r r i n g closure.recently sugges-ted by Baldwin. 6 5 I t was proposed for the c y c l i z a t i o n of enolate 101 that formation of 102 v i a intramolecular C-alkylation i s disfavored while the 101 102 6 103 M = M e t a l i o n ; X = l e a v i n g g r o u p 0-alkylation to give 103 i s a favored process. Although a t r i g o n a l a l k y l a t -ing centre l i k e C-6 i n 9_8 was not discussed i n t h i s p a r t i c u l a r case, the pertinent stereoelectronic argument appears to agree with our observed r e s u l t s . On the other hand, intramolecular C - a l k y l a t i o n at C-7 i n 95_ to form a six-membered r i n g (e.g., IX) i s s t e r e o e l e c t r o n i c a l l y f a c i l e . This accounts for the smooth transformation of 9_5 to the C-cyclized product by ac i d - c a t a l y s t . 101 42 X= L ew i s ac id I n v e s t i g a t i o n on the acid-induced c y c l i z a t i o n of the a l k y n y l 3-keto e s t e r 104 provided some i n t e r e s t i n g r e s u l t s . y - A l k y l a t i o n of the d i a n i o n of methyl acetoacetate w i t h l-bromo-2-pentyne 6 6 f u r n i s h e d the 43 acetylene 104 i n 87% y i e l d . Treatment of 104 with anhydrous stannic ch l o r i d e i n dichloromethane at room temperature led to a mixture of two c y c l i c compounds i n quantitative y i e l d . A f t e r chromatographic separation, the two products were i d e n t i f i e d as the cyclopentenone 105 and the c y c l o -hexenone 106, which were obtained i n a r a t i o of ca. 2:1, r e s p e c t i v e l y . The IR spectrum of 105 exhibited absorptions at 1740, 1710 and 1625 cm - 1 which were ascribable to the ester carbonyl, the conjugated f i v e -membered r i n g ketone and the o l e f i n i c bond. S i m i l a r l y , 106 had IR absorp-tions at 1730, 1675, and 1630 cm - 1 f o r the corresponding ester, ketone and o l e f i n groups. The high i n t e n s i t y of the 1625 and 1630 cm - 1 peaks r e l a t i v e to ordinary o l e f i n i c absorptions was consistent with the conjugated structures. Apparently, the endocyclic double bonds i n 105 and 106 conjugate to a greater extent with the keto groups than with the carbomethoxy side chains, causing l i t t l e lowering i n absorption frequency i n the l a t t e r . Absence of absorp-tions for the a-protons of B-keto esters (<S 3.0-3.5) and presence of s i x -proton m u l t i p l e t s between 6 2.2 and 2.9 (region t y p i c a l f or chemical s h i f t s of methylene protons adjacent to carbonyl and o l e f i n i c groups) i n both 1HNMR spectra supported the s t r u c t u r a l assignments. Existence of the n-propyl side chain i n 105 and the ethyl group i n 106 was also substantiated by the fragmentation patterns i n t h e i r mass spectra. The cycloalkenones 105 and 106 were believed to a r i s e from d i r e c t intramolecular a l k y l a t i o n followed by isomerization of the o l e f i n i c bonds (Scheme i v ) . Although a l t e r n a t i v e mechanisms involving the intermediary ketones 107 and 108 could not be r i g o r o u s l y excluded, the d i r e c t c y c l i z a t i o n 44 Scheme i v 107 1 08 route appears to be more p l a u s i b l e according to the following considerations. F i r s t , neither these t r i c a r b o n y l compounds, 107 and 108, nor t h e i r corres-ponding furan and pyran derivatives (expected side products from 107 and 10.8) were detected i n the crude re a c t i o n product. Secondly, i f hydration 45 of the acetylene i n 104 o c c u r r e d w i t h o u t intramolecular p a r t i c i p a t i o n of the 8-keto ester, formation of e s s e n t i a l l y equal amounts of 107 and 108 would be expected, which should then lead to an approximately 1:1 proportion of the condensation products, 105 and 106. The observed 2:1 r a t i o for the generation of these compounds contradicts the above suggestion. Regio-s e l e c t i v e hydration with p a r t i c i p a t i o n of the keto group 6 7 i n 104 also seemed u n l i k e l y judging from the s i m p l i c i t y of the product mixture, which showed no sign of any 0-cyclized d e r i v a t i v e s at a l l . I t i s i n t e r e s t i n g to note that 104 was found to be unreactive toward boron t r i f l u o r i d e etherate (BF3>Et2 0) i n benzene. Mainly s t a r t i n g material was recovered from the r e a c t i o n mixture even a f t e r three days at room temperature. The cause for t h i s marked change i n r e a c t i v i t y with c a t a l y s t was not c l e a r . C y c l i z a t i o n of Epoxy (3-Keto Esters Successful u t i l i z a t i o n of the epoxide function to i n i t i a t e c y c l i -zations, e s p e c i a l l y those involving polyenes, has been demonstrated (see Introduction). We explored the c y c l i z a t i o n of epoxy 8-keto esters for two major reasons. The oxirane r i n g i s capable of undergoing n u c l e o p h i l i c attack under both a c i d i c and basic conditions, while, at the same time, the 8-keto ester group can act as the n u c l e o p h i l i c component. This allows investigations into both a c i d - and base-catalyzed c y c l i z a t i o n s . Moreover, (2) Precautions were taken to avoid contact with moisture i n carrying out these reactions. 4 6 the hydroxy function which would r e s u l t a f t e r c y c l i z a t i o n would f a c i l i t a t e further synthetic elaboration. Results secured e a r l i e r i n our l a b o r a t o r y 6 8 indicated that a c i d -promoted c y c l i z a t i o n of epoxide 109 gave predominantly the c y c l i c enol ether 110. The preparation of 109 v i a epoxidation of J 5 6 was shown to be low y i e l d -109 110 ing and s l u g g i s h . 6 8 However, thi s , epoxide could be conveniently synthesized by Y - a l k y l a t i o n of the dianion of methyl acetoacetate with epichlorohydrin at 0° C. 109 To determine i f the mode of r i n g closure could be co n t r o l l e d by a l t e r a t i o n of the epoxide s u b s t i t u t i o n pattern, reactions of the epoxy B-keto ester 111 with Lewis acids were examined. Despite the d i f f i c u l t i e s encountered i n epoxidizing 8_6_, epoxidation of _ 9 5 with m-chloroperbenzoic acid proceeded smoothly at 0° C to af f o r d 111 i n almost quantitative y i e l d . 47 I t was found necessary to buffer the re a c t i o n mixture with disodium hydrogen phosphate ( N a 2 H P 0 i t ) , owing to the highly a c i d - s e n s i t i v e nature of 1 1 1 . Based on the f a c i l e C - c y c l i z a t i o n of 9_5 to 9_7_, i t was anticipated that epoxide 1 1 1 might c y c l i z e to give 1 1 3 under s i m i l a r conditions. How-ever, upon treatment with stannic c h l o r i d e at ambient temperature, 1 1 1 was transformed cleanly to the cyclopentenone 1 1 2 a f t e r twenty-three hours. The cross-conjugated cyclopentenone structure was confirmed by S n C I 4 111 > C H 2 C I 2 . r t 112 the IR absorptions at 1 7 4 0 , 1 7 1 0 and 1 6 2 0 cm - 1 . (cf_. compound 1 0 5 ) . A one-proton septet at 6 3 . 5 (J = 7 Hz) and a six-proton doublet at 6 1 . 1 7 (J = 7 Hz) i n the 1HNMR spectrum c l e a r l y indicated presence of the isopropyl group, which was further corroborated by the proton-proton decoupled spectra. 48 A possible mechanism for the formation of 112 was at f i r s t envisioned to involve i n i t i a l C - c y c l i z a t i o n to generate the cyclohexane d e r i v a t i v e 113, which was transformed to 114, followed by cleavage of the cyclopropane r i n g (Scheme v ) . The conversion of 113 into 114, analogous Scheme v to the well known acid-catalyzed a - a l k y l a t i o n of 8-keto esters with second-ary a l c o h o l s , 6 9 seemed to be probable. To test the v a l i d i t y of the l a s t transformation i n Scheme v, the b i c y c l i c compound 114, prepared by copper-49 catalyzed c y c l i z a t i o n 7 0 of a-diazo 6-keto ester 115, ^3' was allowed to react with stannic chloride i n dichloromethane. Indeed, 112 was thus obtained i n quantitative y i e l d . Even though the above mechanism looked convincing i n terms of e f f i c a c y of the involved chemical transformations, attempts to i s o l a t e the suggested intermediates were unsuccessful. When the c y c l i z a t i o n of 111 was conducted at low temperatures (-78° to 0° C) f o r a short period of time (30 min. to 1 h r ) , a mixture of 0-cyclized material 116, 117 and 118 were obtained i n a r a t i o of ^a. 15:5:3. Similar r e s u l t s were also observed for other Lewis acids (BF 3-Et 20, A1C1 3) and solvent ( C H 3 C N ) . Structures of (3) The a-diazo d e r i v a t i v e was prepared by t r e a t i n g 95_ with £-toluene-su l f o n y l azide and triethylamine i n a c e t o n i t r i l e . 7 0 Compound 114 was synthesized v i a 115 i n 71% y i e l d from 95. 50 1 1 OH OH .OH 116 117 118 these compounds were v e r i f i e d by t h e i r s p e c t r a l data. The carbomethoxy v i n y l ether moiety i n 116 and 117 was established by the c h a r a c t e r i s t i c IR absorptions at 1700 and 1640 cm - 1. Assignment of the E_ and the Z_ geo-metry for the o l e f i n i c bonds i n 116 and 117 was based on analysis of t h e i r 1HNMR spectra. The v i n y l proton (C-2 H) and the a l l y l i c methylene protons (C-4 H) i n 116 had chemical s h i f t s at 6 5.27 and 3.07 r e s p e c t i v e l y , while those i n 117 were at 6 4.81 and 2.77. Due to t h e i r c l o s e r proximity to the ether oxygen and the carbomethoxy group, the C-2 and C-4 protons i n the E_ isomer are expected to show lower f i e l d chemical s h i f t s than t h e i r counter-parts i n the isomer. 7 1 Compound 116 was therefore i d e n t i f i e d as the E_ isomer and the Z geometry of 117 followed accordingly. The i s o l a t i o n of 116 and 117 c l e a r l y implies t h e i r intermediary r o l e during the transformation of 111 to 112. To depict the mechanism of t h i s reaction would require a pathway to convert 116 or 117 to 112. I t i s most l i k e l y that, at elevated temperatures (e.g., room temperature), the i n i t i a l l y formed 0-cyclized species were cleaved to give a diketone, 119, which subsequently underwent intramolecular condensation and dehydration to y i e l d 112. This proposal was substantiated by the conversion of 116 51 111 112; 119 to 112 upon treatment with stannic chloride at room temperature. When the reaction time was shortened to 10 to 18 hours, evidence for the existence of the diketone 119 was also observed. The readiness of epoxy 8-keto esters i n undergoing 0 - c y c l i z a -t i o n was i l l u s t r a t e d by the mild conditions used to e f f e c t t h i s process. The generality of t h i s observation i s supported by a recent report on the synthesis of f r o n t a l i n . 7 2 Upon exposure to Lewis a c i d , epoxide 120 was transformed smoothly to the b i c y c l i c k e t a l 121, presumably, v i a an 0-cyclized intermediate X. The dominance of 0 - c y c l i z a t i o n f o r epoxy 52 B-keto esters i n contrast to the exclusive C - c y c l i z a t i o n of 9_5 i s note-worthy. S t e r i c consideration o f f e r s l i t t l e explanation. A promising r a t i o n a l i z a t i o n could be conceived by assuming that the i n t e r a c t i o n between acids and the epoxide oxygen i s f a s t e r than e n o l i z a t i o n of the B-keto ester. Opening of the activated oxirane r i n g with intramolecular p a r t i c i p a t i o n of the keto group would then lead to the enol ether product (equation 9). For the alkenyl B-keto ester 9_5, e n o l i z a t i o n probably pre-ceded protonation of the o l e f i n i c bond to allow for C - c y c l i z a t i o n (equa-t i o n 10) . X = . L e w i s a c i d 53 The p r i n c i p l e of soft and hard acids and b a s e s 7 3 may provide an explanation as well. The oxonium. ion i s a hard leaving group which prefers attack by hard nucleophiles such as oxygen atom, while a soft carbonium ion favors attack by a s o f t enol carbon. According to r e s u l t s obtained by Martel e_t a l . 5 2 and i n our laboratory, 7 1* c y c l i z a t i o n of enamines of type 122 through an S^2" mechanism (equation 11) could be effected with sodium amide or l i t h i u m d i i s o p r o p y l -•C0oMe 1. Base x x / d 2. H 30+ * ( (11) 122 OH amide (LDA). The epoxy enamine 124 was prepared by Y _ a l k y l a t i o n of 123 with epichlorohydrin. Attempts to c y c l i z e 124 by using LDA or Lewis acids were unsatisfactory. o 1. LDA C0 oMe _ ^ X. ^C0 0Me 2 2X1^X1 2 123 However, when epoxy B-keto ester 109 was treated with two equi-valents of LDA i n tetrahydrofuran, at 0° C, the cyclopropyl compound 125 was obtained i n 50% y i e l d . The dianion of the 3-keto ester must be involved 54 i n t h i s reaction. Formation of 125 was not e n t i r e l y unexpected since the y-carbon of 8-keto ester dianions.is more rea c t i v e towards e l e c t r o p h i l e s than the other anionic s i t e s . The preferred mode of c y c l i z a t i o n giving the three-membered r i n g i n t h i s case i s i n agreement with the Baldwin's rules for r i n g c l o s u r e . 6 5 The a l t e r n a t i v e mode of opening the epoxide, leading to a four-membered r i n g , i s probably disfavored on stereoelectronic grounds. 125 Presence of the cyclopropane structure was evident from the high f i e l d absorption pattern i n the 1HNMR spectrum and from the IR si g n a l at 3050 cm - 1, ascribable to the methylene C-H stretching of cyclopropanes. IR bands at 1740 and 1700 cm - 1 confirmed the 8-keto ester structure i n which the keto group i s conjugated with a cyclopropyl moiety. The r e l a t i v e stereo-55 chemistry i n 125 was t e n t a t i v e l y assigned as trans by the following con-sidera t i o n s . The t r a n s i t i o n state leading to the trans isomer i s s t e r i c a l l y more favorable. The 1HNMR spectrum of 125 exhibited four one-proton m u l t i -p l e t s at 6 2.0, 1.7, 1.4 and 1.0 which were assigned to the cyclopropyl protons Hi, H 2, H 3 and H^, re s p e c t i v e l y . Hj, H 3 and H 4 i n the c i s and the trans isomers are expected to have s i m i l a r chemical s h i f t s . The chemical s h i f t of H 2 would be close to that of H 4 i n the c i s isomer, and to that of Hi i n the trans isomer. 7 1 The observed pattern f o r these protons indicated the trans stereochemistry. Conclusions Although l i m i t e d i n v a r i e t y , the 8-keto ester d e r i v a t i v e s used i n t h i s study serve as models for the c y c l i z a t i o n of analogous, more complex 8-keto esters. On the basis of the above r e s u l t s and the rules f o r r i n g closure suggested by Baldwin, 6 5 the following generalizations could be deduced. In the formation of five-membered rings from o l e f i n i c B-keto 56 esters, O - c y c l i z a t i o n i s favored over C - c y c l i z a t i o n , whilst the l a t t e r process i s preferred i n the generation of six-membered rings. Under a c i d i c conditions, epoxy 8-keto esters have a p r e v a i l i n g tendency to 0-cyclize. F i n a l l y , the mode and regiochemistry of the c y c l i z a t i o n may be c o n t r o l l e d by a l t e r i n g the s u b s t i t u t i o n pattern of the o l e f i n or the epoxide involved. o l e f i n c y c l i z a t i o n (see Introduction), the range of n u c l e o p h i l i c multiple bonds u t i l i z e d i n most cases has been l i m i t e d to simple o l e f i n s and acetylenes. The use of 8-keto ester as the n u c l e o p h i l i c component o f f e r s the advantage of r e t a i n i n g useful f u n c t i o n a l i t i e s i n the c y c l i z a t i o n product. Furthermore, sui t a b l y f u n c t i o n a l i z e d a c y c l i c 8-keto ester precursors are r e a d i l y acces-s i b l e . 1 » 2 i n t h i s study provide useful intermediates for synthesis. The u t i l i t y of the cyclohexanone 97_ has been demonstrated i n the synthesis of basic units i n natural products (see Section I I I ) . The O-cyclized products may serve as intermediates for the synthesis of h e t e r o c y c l i c compounds. In p a r t i c u l a r , the a-furylidene acetate d e r i v a t i v e s could be transformed into substituted furans by employing the method developed by Bryson .and Wilson.75 As i l l u s t r a t e d below, formation of the furan 127 from the furylidene acetate 126 involved Despite the intense studies that have been conducted on c a t i o n i c It i s worth noting that some of the c y c l i z a t i o n products reported 1. 2. LDA / THF PhSeBr 3. 126 127 57 y-phenylselenenylation of 126, followed by oxidation, and elimination benzeneseleninic acid with concomitant double bond i s o m e r i z a t i o n . 7 5 58 SECTION I I : ALKENE SYNTHESIS Introduction - A Survey of Stereoselective Synthesis of T r i - and  Tetrasubstituted Alkenes General and f a c i l e synthetic methods devised for the stereo-s e l e c t i v e formation of substituted alkenes play an important r o l e i n modern organic chemistry. The wide-spread occurrence of o l e f i n i c units i n many classes of natural products i s the major impetus to the development of these methods. Studies on polyene c y c l i z a t i o n s also require s t e r e o s e l e c t i v e syn-thesis of alkenes. As can be seen from the above survey on polyene c y c l i -zations, the stereochemistry of the c y c l i z e d products i s often c o n t r o l l e d by the geometry of the o l e f i n i c precursors. The a c t i v i t y of many insect hormones and pheromones i s also governed by the configuration of the o l e -f i n i c bonds i n these substances. Hence, the access to stereochemically pure synthetic alkenes i s of prime importance for investigations i n these areas. Mono- and dis u b s t i t u t e d carbon-carbon double bonds are r e l a t i v e l y easy to prepare, and control over the geometry of the l a t t e r does not impose much d i f f i c u l t y . The development of general and st e r e o s e l e c t i v e synthesis of t r i - and tetrasubstituted alkenes i s s y n t h e t i c a l l y challenging and has been the main goal of many organic chemists. A. Synthesis v i a Addition to Acetylenes Successful use of acetylenes to synthesize t r i s u b s t i t u t e d alkenes was f i r s t reported by Reppe. 7 6 Propargylic alcohols 128, ketones 130 and 59 esters 132 underwent st e r e o s e l e c t i v e a d d i t i o n of formic acid when treated with n i c k e l tetracarbonyl, y i e l d i n g the a,3-unsaturated acids 129, 131 and 1 3 3 ^ r e s p e c t i v e l y . 7 6 ' 7 7 The carboxy group and the hydrogen were added i n a c i s manner with the former attached r e g i o s e l e c t i v e l y to the 8-carbon. Symmetrical acetylenes 134 gave alkenes 135 under s i m i l a r conditions. 134 135 R , R1 = alkyl yield = 3 0 - 5 0 % R 2 = E t , H 60 A l k y l a t i o n of v i n y l halides with l i t h i u m dialkylcuprates has been shown by Corey a n d fosffer, to occur with retention of configuration of the o l e f i n i c bond. 7 8 This r e a c t i o n provides a synthetic route to substituted alkenes v i a v i n y l halides which can be synthesized s t e r e o s e l e c t i v e l y by many methods. Reduction of propargylic alcohols 136 with l i t h i u m aluminum-hydride, followed by addition of iodine, might lead to B-iodo alcohols 137 or a-iodo alcohols 138 depending on the conditions employed. Subsequent reactions of v i n y l iodides 137 and 138 with l i t h i u m dialkylcuprates furnished s t e r e o s p e c i f i c a l l y the alkenes 139 and 140, r e s p e c t i v e l y . 7 9 140 139 61 6 2 Another s t e r e o s p e c i f i c route to v i n y l halides was reported by Peter-son ejt a l . 8 0 The 1,4-halogen s h i f t r e a c t i o n of alkynyl halides 141 i n t r i f l u o r o a c e t i c a c i d gave predominantly the Z-vinyl halides 142. By applying t h i s method to methyl 6-iodo-2-hexynoate (143), Bryson achieved the s t e r e o s p e c i f i c synthesis of v i n y l iodide 144, which was converted to the methyl E-hexenoate 145 by l i t h i u m dimethylcuprate. 8 1 A mechanism involving protonation of the acetylenic bond and synchronous p a r t i c i p a t i o n of the halogen (equation 12) was proposed to account for the stereochemical outcome of these reactions. Kobayashi e_t a l . developed a s t e r e o s e l e c t i v e synthesis of t r i -substituted alkenes, which involved trans addition of benzenethiol to an a,8-acetylenic ester, followed by displacement of the phenylthio group by an a l k y l substituent with retention of c o n f i g u r a t i o n . 8 2 The s e l e c t i v e formation of v i n y l s u l f i d e 147 was effected by t r e a t i n g 146 with sodium 1 4 6 1 4 7 R 2 M g X + C u l R = M e , E t ; R 1 = alkyl ; R 2 = n Bu, Et , Me i X = B r , I . 1 4 8 63 thiophenoxide i n methanol and water. Reaction of 147 with Grignard reagents i n the presence of cuprous iodide afforded a,B-unsaturated esters 148 i n good y i e l d s . Lithium 1 - a l k y n y l t r i a l k y l b o r a t e s (e.g., 149 and 152), which were r e a d i l y prepared by tr e a t i n g l i t h i u m acetylides with t r i a l k y l b o r a n e s , under-went a l k y l a t i o n at C-2 with various a l k y l a t i n g agents accompanied by migra-t i o n of an a l k y l group from boron to C - l of the acetylenic bond. 8 3 Acid-hydrolysis of the v i n y l boranes thus formed led to t r i s u b s t i t u t e d alkenes. Pe l t e r and coworkers 8 3 found that f or simple a l k y l a t i n g agents, l i k e a l k y l 151 150 R = 1 ° a ! k y l ; R1 = 1° alkyl ; R2= 1° alkyl , al lyl , benzyl ; X = halides , etc. 64 65 halides, the alkylation-migration. process (149 -»- 150) proceeded with higher s t e r e o s e l e c t i v i t y (ca. 90%) when a thexyl group was attached to boron i n 149. In t h i s case, the major vinylboranes 150 and the corresponding alkenes 151 were formed with the groups derived from the a l k y l a t i n g agent (R 2) and from boron (R) c i s to each other. A l k y l a t i o n of borates 152 with a-bromocarbonyl compounds gave exc l u s i v e l y v i n y l boranes 153 with the a l k y l group from boron added trans to the a l k y l a t i n g agent. 8 4 T r i s u b s t i t u t e d 8 , Y _ u n s a t u r a t e d carbonyl compounds 154 were obtained from hydrolysis of 153 i n £a. 70% y i e l d . Treatment of 152 with epoxides gave intermediates which were believed to be c y c l i c borates XI. Of p a r t i c u l a r i n t e r e s t i n t h i s presumed formation of XI are the regio-s e l e c t i v e opening of monosubstituted epoxides and the s t e r e o s e l e c t i v e migra-t i o n of the a l k y l group from boron. Hydrolysis of XI with a c e t i c a c i d afforded t r i s u b s t i t u t e d alkenes 155 i n greater than 70% y i e l d , while r e a c t i o n with aqueous sodium hydroxide and then with iodine gave tetrasubstituted alkenes 156. 8 5 Although the aforementioned s t e r e o s e l e c t i v e synthesis of alkenes from acetylenes have t h e i r synthetic u t i l i t y , the most commonly adopted method i n t h i s category i s based on the ad d i t i o n of organometallic reagents to acetylenic bonds. Equation 13 (R 3 = a l k y l groups; M = m e t a l l i c ions (13) 6 6 or complexes; E' = e l e c t r o p h i l i c species) i s representative of t h i s type of reaction. With a few exceptions (vide i n f r a ) , the a d d i t i o n of R 3 and M generally occurs i n a c i s manner. R e g i o s e l e c t i v i t y i n these additions i s c o ntrolled by the nature of the substituents R 1 and R 2. In the past decade, various reagents have been developed to serve the function of R3M i n equation 13. Those of general a p p l i c a b i l i t y are described below. Conjugate add i t i o n of organocopper reagents to a ,8-acetylenic carbonyl compounds has been a useful t o o l for the s t e r e o s e l e c t i v e synthesis of substituted alkenes. Additions of l i t h i u m dialkylcuprates to a,8-ace-t y l e n i c esters were f i r s t reported by Corey 8 6 and S i d a l l 8 7 to give stereo-s e l e c t i v e l y t r i s u b s t i t u t e d alkenes with an a l k y l group from the cuprate added trans to the ester function (equation 14). A s e r i e s of primary a l k y l (14) 157 R = a l k y l ; 1 R - M e , E t , n-Pr , n-Bu , n - h e p t y l . groups (R 1) have been su c c e s s f u l l y transferred i n t h i s manner. 8 8' 8 9 Low temperatures (-78° to -100°) are e s s e n t i a l for obtaining high s t e r e o s e l e c t i -v i t y (greater than 90%) and good y i e l d s (ca. 90%) for these reactions. Reported attempts to trap the intermediate vinylcopper species XII with a l k y l a t i n g agents were unsatisfactory. I t was believed that the higher temperatures required for a l k y l a t i o n of XII caused isomerization to form 67 XIII. However, reactions of XII with iodine to give 158a, and with oxygen and excess l i t h i u m dimethylcuprate to form 158b have been accomplished. 8 6 Organocopper reagents derived from mixing alkylmagnesium halides with the tri-n-butylphosphine copper (I) complex XIV (entries a and b, Table 2) or with cuprous halide and p y r o l i d i n e (entry c, Table 2), as well as mixed dialkylcuprates (entry d, Table 2) were also used for conjugate additions to a,B-acetylenic esters. Successful examples are l i s t e d i n Table 2 . 8 7 ' 8 9 a,8-Acetylenic a c i d s 8 9 ' 9 0 and amides 8 9 also have been reported to undergo s i m i l a r addition reactions with alkylcopper reagents, though the use of these reactions i n alkene syntheses o f f e r s no d i s t i n c t advantage over the use of acetylenic esters. 68 Table 2. Conjugate Addition of.Organocopper Reagents to a,3-Acetylenic Esters. Organocopper Reagents 157 R = CH3 ; R1 -MgBr + [CuI(n-Bu 3P);U XIV b. . Cyclo-C 5H 9CuP(n-Bu) 3 c. CH2=CHCH2CuN J d. (t-BuCuCH 3)Li cyclopentyl a l l y l _t-butyl Normant and coworkers have conducted extensive studies on the addition of organocopper reagents to unactivated acetylenes. Their findings provide s t e r e o s e l e c t i v e routes to a v a r i e t y of substituted alkenes. 9 1 Alkylcopper complexes XV, derived from the corresponding alkylmagnesium bro-mide and cuprous bromide, were shown to add across the t r i p l e bond of non-functional i zed 1-alkynes i n a c i s manner and with copper attached regio-s e l e c t i v e l y to C - l . The resultant vinylcopper complexes XVI could be a l k y l -ated with various a l k y l a t i n g agents i n the presence of t r i e t h y l phosphite to give t r i s u b s t i t u t e d alkenes 159 i n y i e l d s which ranged from 50 to 8 5 % . 9 1 3 Iodination and oxygen-promoted coupling of XVI gave v i n y l iodides 160 and dienes 161,respectively, i n 55 to 75% y i e l d s . 9 1 k The vinylcopper intermediates XVI retained t h e i r stereochemistry i n a l l the above reactions as indicated i n Scheme v i . A l k y l a t i o n of XVI with 1-alkynyl halides 162 was effected i n the presence of TMEDA, affording acetylenic alkenes 163 i n good y i e l d s . 9 1 0 69 Scheme v i R C = C H + R 1Cu-MgBr 2 XV 161 160 159 R = a l k y l ; R1 = Et, n-Bu; R 2X = a l k y l iodides, a l l y l and benzyl bromides, CH3SCH2CI, EtOCH 2Br, C H 3 0 2 C ( C H 2 ) 3 l , ClCH 2CH 20CH 2Br, ClCH 2CH 20CH(CH 3)Br. XVI (R = Me, n-Bu; R 3C: TMEDA :CX R H R = Et) 1 62 Et 163 X = I, Br; R 3 = a l k y l , -SiMe 3, -SEt, -C02Me; TMEDA = tetramethylethylenediamine 70 As an extension of the alkene syntheses shown i n Scheme v i , v i n y l iodides 160 were converted to f u n c t i o n a l i z e d t r i s u b s t i t u t e d alkenes v i a the v i n y l l i t h i u m species XVII, which were formed s t e r e o s p e c i f i c a l l y by i o d i n e - l i t h i u m exchange with a l k y l l i t h i u m at low temperatures. Reac-tions of v i n y l l i t h i u m XVII with r e a c t i v e e l e c t r o p h i l i c compounds such as epoxides and aldehydes led to alkenes 1 6 4 . 9 l e H X R I 1 60 R 3Li - 5 0 ° — -60° R H > . R Li XVII + R3J R 3 = R z = Et, Bu \ ^ ; C H 3CH0 ; HCHO ; C 0 2 - C H 2 C H 2 0 H ; - C H ( C H 3 ) 0 H ; - C H 2 0 H ; - C 0 2 H R R£ 164 71 The addition of ethylcopper complex to the acetylenic a c e t a l 165 was found to take a stereochemically d i f f e r e n t course. Although the ethyl group and copper s t i l l added c i s to each other, the l a t t e r was bonded to C-2 instead of C - l . P a r t i c i p a t i o n of the a c e t a l oxygen during the — CEEECH + EtCu-MgBc. 165 S 167 166 addition was probably responsible for t h i s p r e v a i l i n g r e g i o s e l e c t i v i t y . The vinylcopper intermediate underwent the usual i o d i n a t i o n and carboxy-l a t i o n to furnish. 166 and 167 i n 61 and 55% yields, r e s p e c t i v e l y . Similar' r e s u l t s were observed for propargylic acetals 168 and 169. Examples that i l l u s t r a t e the a p p l i c a t i o n of t h i s type of addition to the synthesis of t r i - and t etrasubstituted alkenes are given i n Scheme v i i . 9 1 c * The use of 72 Scheme v i i n - B u C u ( OBLI^U H CH(OEt)„ H C = CCHCOEtL 168 MeCuCSPh )L i n-Bu CuCOBu^Li H CH(OE t ) 9 \ /-n-Bu H CHCOEtL H CH(OE t ) , HC ^ = CCOOEt / \ Me Cu(SPh )Li M e \ C0 2 ' E t M e G = G C H ( O M e ) 2 169 1. n-BuCu , l_i-2(i-Pr). v e CHCOMe ) . 2. H 2 Q 1. n -BuCuCOBu* ) L i / \ n-Bu H Me CH(OMe)-2. M e l n-Bu Me 1. E t 2 C u L i Me C H ( O M e ) 2 •Br CuL i E t 2. H 2 0 H(OMe) , 73 some heterocuprates, [RCuY]Li (Y = hetero ligand), which have been found superior to dialkylcuprates i n many of these addition reactions are also i l l u s trated.• The addition of alkylcopper complexes to acetylenes was further explored by Helquistand coworkers. 9 2 By^usingthei.dime'thyl sulfide-cuprous bro-mide complex of Grignard reagents, XVIII, they obtained improved y i e l d s of the addition products with 1-alkynes. The vinylcopper complexes XIX so prepared were shown to undergo conjugate additions to a,B-unsaturated ketones, a c y l a t i o n with a c e t y l c h l o r i d e , and a l k y l a t i o n with a l l y l bromide and ethylene oxide (Scheme v i i i ) . 9 30 Hydrometallation of acetylenes with hydride complexes of boron, aluminum, 9 3' 3 t i n , 9 3 c and z i r c o n i u m 9 3 ^ are well known. Use of t h i s type of reaction to synthesize t r i s u b s t i t u t e d alkenes i s l i m i t e d by the generally low r e g i o s e l e c t i v i t y of the addition of these hydride complexes to unsym-me t r i c a l , disubstituted acetylenes. Nevertheless, t r i s u b s t i t u t e d alkenes of the general structure 170 and 171 can be derived from symmetrical acety-lenes. A s t e r e o s e l e c t i v e route to these alkenes based on hydroalumination 74 Scheme v i i i R M g B r + CuBr- (CH ) S a 3 2 R1 C u p C h ^ ^ s ] - M g B r 2 XVIII R2CH=CHCKi -R3 R C = C H R H R 1 Cu [ ( C H 3 ) 2 s J • M g B r 2 XIX R = alkyl , R1 = alkyl ; R 2 ; R3 - alkyl , phenyl. XIX R H ( R = C H , ) :H3 R-E = Br -Cl 75 was developed by Z w e i f e l . 9 4 Diisobutylaluminum hydride was added to acety-lenes 172 i n a c i s manner giving vinylalanes XX, which could undergo various reactions. Direct i o d i n a t i o n of XX yielded v i n y l iodides. Conversion of XX to the vinylalanates XXI with methyl l i t h i u m , followed by treatment with cyanogen, carbon dioxide, paraformaldehyde or a l l y l bromide 9 5 led to the corresponding fun c t i o n a l i z e d alkenes (Scheme i x ) . A l l these reactions of vinylalanes XX and vinylalanates XXI proceeded i n s a t i s f a c t o r y y i e l d s and with retention of configurations. Hydroalumination of di s u b s t i t u t e d alkynes with l i t h i u m d i i s o b u t y l -methylaluminum hydride occurred i n a trans fashion, i n contrast with the c i s addition of diisobutylaluminum h y d r i d e . 9 5 The trans-vinylalanates XXII thus formed could also be transformed into t r i s u b s t i t u t e d alkenes v i a i o d i -nation, carboxylation and condensation as shown i n Scheme i x . Very recently, Negishi and • coworkers reported a .general procedure to synthesize f u n c t i o n a l i z e d E-3-methyl-2-alkenes 173 v i a carboalumination of terminal a c e t y l e n e s . 9 6 Zirconocene d i c h l o r i d e (Cl2ZrCp2) catalyzed methyl-l -Z Z = oxo functional group CH 3 H 1 73 alumination of 1-alkynes with trimethylalane gave stereo- and r e g i o s e l e c t i v e l y the E_-2-methylalkenylalanes XXIII ( r a t i o of terminal to i n t e r n a l a l k e n y l a l -anes ca. 95:5). Treatment of vinylalanes XXIII, or the corresponding alanates XXIV, with the appropriate e l e c t r o p h i l i c reagents afforded the fu n c t i o n a l i z e d 76 Scheme i x 77 t r i s u b s t i t u t e d alkenes shown In Scheme x i n s a t i s f a c t o r y o y e r a l l y i e l d s . Scheme x R H R H Me ^  Al \ / CIC0 2Et \ / R C = C H > > = < • > / = = = \ 2 2 Me AIMe 2 Me C0 2Et XXIII The fa c t that a host of d i f f e r e n t l y f u n c t i o n a l i z e d alkenes 173 can be derived from the common intermediate XXIII enhances the u t i l i t y of th i s method. However, two l i m i t a t i o n s should be noted, v i z . , i t does not provide a route to the ^ -isomer of 173 and i t only allows the addit i o n of a methyl 78 group to the acetylenes. An attempt to transfer an a l k y l group other than methyl by using a trialkylalane-zirconocene d i c h l o r i d e system was reported unsuccessful 96a The hydrometallated and carbometallated v i n y l i c intermediates described above may also be coupled with v i n y l , alkynyl or a r y l h a l i d e s , with both reactants r e t a i n i n g t h e i r stereochemistry. A double metal cata-l y s i s system, consisting of tetrakis(triphenylphosphine)-palladium (or nic k e l ) and z i n c ( I I ) c h l o r i d e , was developed by Negishi et a l . f o r these coupling 9 6b J reactions (equation 15). R 2 MLn R C = C R ' M Ln R2MLn = i-Bu 2AlH, HZr(Cl)Cp 2, Me 3Al-Cl 2ZrCp 2; R 2 = H, Me; R = a l k y l ; R1 = R, H ; R 3 = alkenyl  _ a l k y n y l , a r y l Pd(PPh 3 ) 4 -ZnCI 2 . R 3 X M3 R R J (15) Hydroalumination of heterosubstituted acetylenes 174 with d i a l k y l -aluminum hydride has been studied i n d e t a i l by Eisch and c o w o r k e r s . 9 5 ' 9 7 While t h e i r f indings, i n general, provide s t e r e o s e l e c t i v e routes to hetero-R1C E E CX 174 R1 = a l k y l , a r y l ; X = -NR2, -OR, -SR, -SiR 3 79 v i n y l i c compounds, such as v i n y l i c ethers and s u l f i d e s , t h e i r work on s i l y l -acetylenes i s of p a r t i c u l a r i n t e r e s t f o r alkenes synthesis. As shown i n Scheme x i , t r i m e t h y l s i l y l a c e t y l e n e s 175 can be hydroaluminated stereo-Scheme x i R1 C = ,CS iMe -175 hexane i-Bu 2AIH hexane — R-jN or heptane or heptane - E t 2 0 R A l i -Bu-Si Me-XXV . 1. MeLi 2. R2X R' i Me-H AI j-B LU, XXVI 1. MeLi 2. R 2X ,i Me-H SiMe-176 H R' 177 1 2 R = alkyl, aryl ; R = alkyl ; X ; halogen. 8 0 s e l e c t i v e l y to the E-alkenylsilanes XXV or the Z-alkenylsilanes XXVI by conducting the reaction i n the absence or presence of a Lewis base. 9 8 The regiochemistry of these addition reactions i s c o n t r o l l e d by the s i l y l group. Without any a d d i t i o n a l base, the addition of diisobutylaluminum hydride to 175 gave predominantly the trans adduct XXV, which was believed to a r i s e from isomerization of the i n i t i a l l y formed c i s adduct XXVI. The isomerization i s favored by s t e r i c considerations, and i s probably ass i s t e d by the alumino and/or s i l y l group. Lewis bases coordinate with the aluminum and/or s i l i c o n atoms and hence retard the isomerization of the carbon-carbon double bond. A bulkier s i l y l group (-SiEta) was also found to favor the formation of XXV, supporting the isomerization mechanism. Conversion of the Z_~- and the E-alkenylalanes, XXV and XXVI, to t h e i r corresponding alanates with methyllithium, followed by treatment with a l k y l halides led to the E_- and the ^ - a l k e n y l s i l a n e s , 176 and 177, respec-t i v e l y . 9 7 ' 9 8 The major drawback of t h i s synthetic method, as reported independently by Eisch and by Utimoto, i s the low-yielding nature of some a l k y l a t i o n reactions of the alanates. Despite t h i s l i m i t a t i o n , i t serves as a v e r s a t i l e route to t r i s u b s t i t u t e d alkenes since the t r i a l k y l s i l y l groups of v i n y l s i l a n e s can be replaced s t e r e o s p e c i f i c a l l y by a v a r i e t y of e l e c t r o p h i l e s . 9 9 Another.approach to d i s u b s t i t u t e d v i n y l s i l a n e s i s the hydro-boration of a l k y n y l s i l a n e s reported by •. •Uchida; et_ a l . 1 0 0 Hydroboration of t r i m e t h y l s i l y l a c e t y l e n e s with dicyclohexylborane gave, regio- and stereo-s e l e c t i v e l y , vinylboranes XXVII. Successive treatment of XXVII with methyl-81 Scheme x i i :CSi Me. R 2 B H H BR. XXVII MeL i ( 2 eq.) SiM C u l S i M Cu H Li XXVIII P (OEt ) 3 ~HMPA 2 R X 1 2 • R , R = alkyl • R = cyclohexyl ; R 2 X >iM 178 X = halides ( tosylate. Scheme x i i i R 1 C E = C S i M e 3 + MeMgBr 1 79 N i (Ac Ac )2~ Me^ A I 180 R1 = n-C 6H 1 3; AcAc = acetylacetonate; R 2X = H20 ; I 2 ; RCHO ; C02 ; a l k y l halide R 2 = H ; I ; RCHOH ; C02H ; a l k y l 83 l i t h i u m , cuprous iodide and a l k y l a t i n g agents afforded ^ - a l k e n y l s i l a n e s 178 i n good y i e l d s . With more re a c t i v e a l k y l halides (e.g., methyl iodide and a l l y l bromide), d i r e c t a l k y l a t i o n s of the v i n y l l i t h i u m intermediate XXVIII have also given s a t i s f a c t o r y r e s u l t s (Scheme x i i ) . Snider ej: a l . developed another a p p l i c a t i o n of t r i m e t h y l s i l y l -acetylenes, which i s of p a r t i c u l a r i n t e r e s t for the synthesis of t e t r a -substituted a l k e n e s . 1 0 1 Carbometallation of 1 - t r i m e t h y l s i l y l - l - o c t y n e (179) with methylmagnesium bromide was effected by using a 1:1 mixture of n i c k e l acetylacetonate and trimethylalane as c a t a l y s t . Under optimized conditions, a 9:1 mixture of vinylmetal complexes, XXIXa and XXIXb, were obtained i n ca. 80% y i e l d . The r e l a t i v e l y high r e a c t i v i t y of these organometallic i n t e r -mediates towards e l e c t r o p h i l i c reagents furnished the subsequent reactions (Scheme x i i i ) to give mainly t r i s u b s t i t u t e d v i n y l s i l a n e s 180. Addition of ethylmagnesium bromide to 179, under s i m i l a r conditions, was unsuccessful. The u t i l i t y of t h i s method, therefore, seems to be l i m i t e d to the synthesis of methyl-substituted alkenes. B. Synthesis Involving Ring Cleavages Stereoselective formation of homoallylic bromides 182a,b v i a cleavage of a-cyclopropyl carbinols 181 was f i r s t reported by J u l i a . 1 0 2 The stereochemistry of the predominant o l e f i n i c product i n these reactions can be predicted by considering the t r a n s i t i o n state conformations. An a n t i periplanar 'arrangement-of: the hydroxpnium .leaving-group and the breaking- " j carbon-carbon bond of the cyclopropyl r i n g i s presumed i n the t r a n s i t i o n state. . As : Illustrated,' i n Scheme x i v , when R1 i s bulkier than R2, conforma-84 Scheme x i v 181b 182b t i o n 181a p r e v a i l s and 182a w i l l be the major product. On the other hand, i f R 1 i s l e s s bulky than R2, conformation 181b w i l l be favored, leading to predominant formation of 182b. Low s t e r e o s e l e c t i v i t y was observed when 1 2 10 3 R and R were of s i m i l a r bulkiness. Several modifications of the J u l i a synthesis have been developed to improve both the s t e r e o s e l e c t i v i t y and the v e r s a t i l i t y . Treatment of phenylsulfonyl alcohols 183 with hydrobromic acid and zinc(Il)bromide 85 gave the E-alkenes 184 i n greater than 83% y i e l d s , accompanied by only small amounts of the Z_ isomers. 1 0 4 The r e l a t i v e l y large s i z e of the phenyl-s u l f o n y l group undoubtedly enhances the s t e r e o s e l e c t i v i t y of these reactions (cf. Scheme x i v ) . Moreover, the phenylsulfonyl group also f a c i l i t a t e s the preparation of the alcohol precursors 183 ( i . e . , condensation of the appro-p r i a t e a - s u l f o n y l carbanion with a l k y l cyclopropyl ketone), and further elaboration on the alkene products 184. McCormick and .Barton used magnesium halides to e f f e c t the following transformation (equation 16) with s a t i s f a c t o r y s e l e c t i v i t y . 1 0 5 MgX, 181 ( R1 = Me ; R 2 =Et ) E t 2 0 X= B r , I Me (16) 86 Another v a r i a t i o n of the J u l i a synthesis, developed by Johnson et a l . , also avoids the strong acid-conditions o r i g i n a l l y employed. Secon-dary alcohols 185, with a 1,1-disubstituted cyclopropyl moiety, were con-verted to t r i s u b s t i t u t e d alkenes 186 i n good y i e l d and i n high stereo-s e l e c t i v i t y , by bromination followed by reaction with zinc(Il)bromide i n ether 1 0 6 R1 R 2 P B r 3 - L i Br R1 R 2 O H Br 185 ZnBr 2 / E t 2 0 R' R 2 Br 186 Synthesis of alkenes by s t e r e o s p e c i f i c fragmentation of c y c l i c compounds has the advantage of complete control over stereochemistry. How-ever, successful execution of t h i s method requires f a c i l e , s t e r e o s p e c i f i c synthesis of the c y c l i c precursors. A p p l i c a t i o n of t h i s methodology to the synthesis of a c y c l i c alkenes i s demonstrated by the fragmentation of 87 hydroxy tosylate 187 to di e n i c ketone 1 8 8 . 1 0 7 An alkene synthesis based on the cleavage of c y c l i c s u l f i d e s was reported by Stotter .•} °-8 _ ' Substituted thiacyclohexenes 189 were prepared according to the sequence shown i n Scheme xv. Reduction of 189 with l i t h i u m i n ethylamine, followed by d e s u l f u r i z a t i o n using deactivated Raney n i c k e l Scheme xv R = nucleophiles , e.g. MeMgBr = alkyl or allylic halides. 88 led to alkenes 190 with a c i s ethyl substituent. Symmetry-controlled e l e c t r o c y c l i c opening of halogenocyclo-propanes, e.g., 191a and 191b, occurs i n a s t e r e o s p e c i f i c manner, 1 0 9 form-ing a l l y l i c cations XXXa and XXXb which can be trapped by nucleophiles to give the corresponding alkenes 192a and 192b. For example, the cyclopropyl 194 89 bromide 193 underwent e l e c t r o c y c l i c opening to afford s t e r e o s p e c i f i c a l l y a l l y l i c acetate 194 i n 74% y i e l d n o Stereoselective methods for achieving the following bromocyclo-propane synthesis (equation 17) have been secured i n the past few y e a r s . 1 1 0 Br RX M = metal cation •, R1, R2= al ky I , aryl ; RX = alkylating agents. Br (17) 195 With these bromocyclopropanes 195 now r e a d i l y accessible, the aforementioned s t e r e o s p e c i f i c route to substituted alkenes w i l l c e r t a i n l y become more a t t r a c t i v e . 90 C. Synthesis v i a Sigmatropic Rearrangements The Claisen type rearrangements have been broadly used for the s t e r e o s e l e c t i v e synthesis of t r i s u b s t i t u t e d a l k e n e s . 1 1 1 In general, these reactions involve the [3,3]-sigmatropic rearrangement of a l l y l v i n y l ethers as i l l u s t r a t e d by equation 18. The rearrangement i s believed to occur v i a (18) XXXIb 2?Z R 1 , R2= alkyl ; R3= H , alkyl , OR , OSiR 3 , NR_2 . a c h a i r - l i k e conformation i n the t r a n s i t i o n state (e.g., XXXIa,b). Due to 2 3 the pseudo-1,3-diaxial i n t e r a c t i o n between substituents R and R i n conforma-t i o n XXXIa, the a l t e r n a t i v e chair conformation XXXIb with R 2 i n a pseudo-equatorial p o s i t i o n , i s more favorable. Consequently, the C l a i s e n rearrange-ment of v i n y l ether 196 gives predominantly the E-alkene 197. While the 91 degree of s t e r e o s e l e c t i v i t y may be enhanced by increasing the s t e r i c bulk of R 2 and/or R3, v i n y l ethers of a l l y l i c t e r t i a r y alcohols (e.g., 198) show poor s t e r e o s e l e c t i v i t y . 1 1 2 The side chain c i s to H i n alkene 197 may contain an a l d e h y d e , 1 1 3 k e t o n e , 1 l k carboxylic e s t e r , 1 1 5 a c i d 1 1 6 or amide 1 1 7 depending on the nature of R 3. Another version of the C l a i s e n rearrangement i s the C a r r o l l r e a c t i o n which involves the thermal rearrangement of a l l y l acetoacetate derivatives and concomitant decarboxylation of the rearrangement products. The following transformation of a l l y ! acetoacetate 199 (R 1 = R 2 = CH 3, R 3 = H), to alkene 200 (R 1 = R 2 = CH 3, R3 = H; E:Z_ = 93:7) i l l u s t r a t e s t h i s p r o c e s s . 1 1 8 The dianion of a l l y l d ithioacetates 201 have been d i a l k y l a t e d successively at low temperature to give thioenol ether intermediates XXXII which, on warming to -25° C, underwent [3,3]-sigmatropic rearrangement to y i e l d alkenes 202. The advantages of t h i s procedure i n alkene synthesis are that i t allows for the f a c i l e introduction of R and that the rearrange-ment can be achieved under mild conditions. The methyl thioester group of 92 202 could be converted to the ethyl ester by treatment with cupric c h l o r i d e i n ethanol. Overall y i e l d s of 203 from 201 for the examples shown were 63 to 70% and s t e r e o s e l e c t i v i t i e s f o r the formation of the E isomers of 203 were greater than 9 8 % . 1 1 9 The rearrangement of a l l y l i c thionocarbonate XXXIII was reported 1 2 0 by 'Faulkner. When alcohol 204 was allowed to react with 0-phenyl thiono-chlorocarbonate i n pyridine, the a l l y l i c thiolcarbonate 205 was obtained i n 67% y i e l d with an E to Z isomer r a t i o of 96.5 : 3.5. 93 s-BuLi ( 2eq) _> - 7 8 ° 201 1. R 2X 2. M e l ^ M e H 25 ° '1 R R 202 .0 2 Et CuC^-CuO EtOH Me: XXXII ' i ^ 2 R' R R1= CH. 203 R =.rv-octyl , benzyl ; X - Br Stereoselective synthesis of t r i s u b s t i t u t e d alkenes v i a [2,3]-sigmatropic rearrangements have also been demonstrated. A s t e r e o s e l e c t i v e route to t r i s u b s t i t u t e d a l l y l i c alcohols based on the a l l y l i c s u l f o x i d e -sulfenate interconversion was developed by G r i e c o 1 2 1 and Evans et a l . 1 2 2 Scheme x v i i l l u s t r a t e s the scope of t h i s method. Sulfoxides 207 and 210 were 94 204 XXXIII 2.05 prepared by s e l e c t i v e a - a l k y l a t i o n of the s u l f o x i d e - s t a b i l i z e d a l l y l i c car-banions derived from 206 and 209 r e s p e c t i v e l y . Transformation of these sulfoxides to the corresponding a l l y l i c alcohols, 208 and 211, was effected Scheme x v i Ar = Ph , _p-C6H4Me ; R = alkyl 95 by trimethylphosphite or thiophenoxide i n methanol. S a t i s f a c t o r y y i e l d s and s t e r e o s e l e c t i v i t i e s were reported f o r the o v e r a l l conversions, 206 to 208 and 209 to 211. a-Substituted methallylsulfonium y l i d e s undergo [2,3]-sigmatropic rearrangements to give mainly E_-trisubstituted a l k e n e s . 1 2 3 By heating a mixture of methyl diazomalonate and a-substituted methallyl s u l f i d e 212, i n the presence of cupric s u l f a t e , Grieco et a l . obtained a 9:1 mixture of the E and j£ isomers of alkene 213 i n about 70% y i e l d . N 2 C ( C 0 2 Me ) 2 Cu S 0 4 A SPh 212 - C ( C 0 2 M e ) 2 C ( C Q 2 M e ) 2 213 124 R = n-Bu , Et . Recently, S t i l l and Mitra' reported the Wittig-type rearrangement of a l l y l stannylmethyl ethers 215, generated by a l k y l a t i n g the anion of alcohols 214 with i o d o m e t h y l t r i - n - b u t y l t i n . 1 2 5 Unlike the previously des-cribed [2,3]- and [3,3]-sigmatropic rearrangements which generally give E-alkenes as the major product, the rearrangement of 215, upon treatment with n-butyllithium, gave the Z-alkenes 216 i n greater than 95% stereo-s e l e c t i v i t y . The Z geometry of the predominant products indicates that 96 OH 1. KH 2. Q-BujSnCH I ^Sn(n-Bu). 214 215 n-BuLi 216 OH R = alkyl CH 2 Li conformation XXXIVa, with substituent R i n a pseudo-axial p o s i t i o n , i s more favorable than conformation XXXIVb i n the t r a n s i t i o n state of the rearrange-ment. This unusual preference was a t t r i b u t e d to an early, more reactant-l i k e t r a n s i t i o n state which would s u f f e r s i g n i f i c a n t s t e r i c i n t e r a c t i o n /H H XXXVa XXXVb between R and the v i n y l methyl group i n adopting conformation XXXIVb. 97 D. S y n t h e s i s I n v o l v i n g A l l y l i c R e a r r a n g e m e n t s A l l y l i c a l c o h o l s 2 1 7 , when t r e a t e d w i t h t h i o n y l c h l o r i d e , u n d e r -went c h l o r i n a t i o n w i t h c o n c o m i t a n t a l l y l i c r e a r r a n g e m e n t t o a f f o r d t r a n s a l l y l i c c h l o r i d e s 2 1 8 . 1 2 5 These r e a c t i o n s have been u t i l i z e d t o s y n t h e s i z e t r i s u b s t i t u t e d o l e f i n i c u n i t s o f n a t u r a l p r o d u c t s w i t h s a t i s f a c t o r y s t e r e o -s e l e c t i v i t y . 1 2 6 0 217 218 A l k y l a t i o n s o f a l l y l i c a c e t a t e s 219 w i t h l i t h i u m d i a l k y l c u p r a t e s a l s o o c c u r r e d w i t h s i m u l t a n e o u s a l l y l i c r e a r r a n g e m e n t , l e a d i n g s t e r e o s e l e c -t i v e ^ t o t h e E - a l k a n e s 2 2 0 . 1 2 7 OAc 219 220 By a p p l y i n g t he above methods t o a l l y l i c a l c o h o l s w i t h a t r i m e t h y l v i n y l -s i l a n e m o i e t y , M y c h a j l o w s k i j and Chan d e v e l o p e d two s t e r e o s e l e c t i v e r o u t e s to t r i s u b s t i t u t e d a l k e n e s . 1 2 8 As shown i n Scheme x v i i , a l c o h o l s 2 2 1 , a v a i l a b l e f r o m c o n d e n s a t i o n o f c c - t r i m e t h y l s i l y l v i n y l l i t h i u m w i t h a l d e h y d e s , were c o n -v e r t e d to a l l y l i c c h l o r i d e s 222 ( c a . 90% Z_ i s o m e r s ) by t r e a t m e n t w i t h 98 Scheme x v i i R1 CHO Si M e , L i - 7 8 " Si M e , OH 221 A c 2 0 SOCI ' Si M&, OAc M e 3 S i R' C l H 224 222 ( R 2 ) 2 Cu l_ i or ( R 2 ) 2 C u M g B r ( R ) 2 C u L i M e 3 S i M e 3 S i R 225 223 R1= a l ky l , Ph ; R 2 = a l k y l 99 t h i o n y l c h l o r i d e . Direct displacement of chloride i n 222 with l i t h i u m dialkylcuprates gave the corresponding Z - s i l y l a l k e n e s 223. On the other hand, conversion of alcohols 221 to t h e i r acetates 224 followed by reactions with l i t h i u m dialkylcuprates or dialkylcopper magnesium bromide complexes gave mainly the E - s i l y l a l k e n e s 225 (.E : Z_ ca. 90:10). S t e r e o s e l e c t i v i t y of the transformation of 224 to 225 i s s e n s i t i v e to the s i z e of R1 as well as the nature of the organocopper reagents. I t was found that when R1 was r e l a t i v e l y l e s s bulky (e.g., a primary a l k y l group), s e l e c t i v i t y would be much lower and could be improved by employing the l e s s r e a c t i v e d i a l k y l -copper magnesium bromide reagents. Since s t e r e o s p e c i f i c replacements of the t r i m e t h y l s i l y l group of v i n y l s i l a n e s are now well documented, 9 9 223 and 225, obtainable from the common intermediate 221, could be further elaborated to give various t r i -substituted alkenes. E. Synthesis from Carbonyl Compounds The W i t t i g reaction, i n i t s o r i g i n a l f o r m , 1 2 9 has l i t t l e synthetic value f o r the synthesis of t r i - and tetrasubstituted alkenes owing to the lack of stereochemical c o n t r o l . Later investigations have led to a cl e a r e r understanding of i t s r e a c t i o n mechanism and the introduction of several modifications which improved the y i e l d as well as the stereochemistry of th i s type of r e a c t i o n . 1 3 0 The W i t t i g r e a c t i o n of resonance-stabilized phosphorous y l i d e s with aldehydes serves as a convenient route to trans-disubstituted alkenes. 100 However, i t s use as a general s t e r e o s e l e c t i v e method for the synthesis of t r i s u b s t i t u t e d alkenes i s f a r from s a t i s f a c t o r y . Carbomethoxy ethylidene phosphorane 226 reacts with aldehydes to give mainly the E-alkenes 227  (e.g. , when R = CH 3, E:Z_ = 95:5). 1 3 1 A more d e t a i l e d study on the Me R Me P h 3 P : + RCHO C02;Me H C0 2Me 226 227 O R ( E t O ) 2 P - C - C O O E t + RCHO 228 H R H C 0 2 E t 229a R C 0 2 E t 229b = CH3 ; R = CH 3 100 0 = C 2H 5 84 16 = (CH 3) 2CH 38-27 62-73 = (CH 3) 3C 50 50 = C 2H 5 ; R = CH 3 82 18 = C2H5 59 : 41 = (CH 3) 2CH 10 : 84 = (CH 3) 3C 45 : 55 101 re a c t i o n of phosphonate carbanions 228 with aldehydes indicated that the proportion of the isomeric alkenes 229a,b formed was d r a s t i c a l l y affected by the s i z e of R and R 1. 1 3 2 This e r r a t i c e f f e c t of R and R1 on the stereo-chemical outcome of these reactions impairs t h e i r synthetic u t i l i t y . On the other hand, the r e a c t i o n of carboalkoxy s t a b i l i z e d a l k y l i -dene phosphoranes 230 with a-haloaldehydes 231 showed remarkably high stereo--r1 R i ^CHO Ph3P==( X \ C 0 2 R 230 231 R : M e , t - B u ; R1 = H , Me , E t ; R 2 = H , Me ; X : B r , Cl s e l e c t i v i t y . Stb.tter and".Hill were able to observe s t e r e o s e l e c t i v e (greater than 92%) formation of the E-alkenes 232 i n greater than 84% y i e l d . 1 3 3 Schlosser and Christmann 1 3 "* devised a modification of the W i t t i g reaction i n which the intermediate betaine XXXV was deprotonated with phenyl-l i t h i u m to produce the 8-oxido phosphonium y l i d e XXXVI. Subsequent reactions between XXXVI and a v a r i e t y of e l e c t r o p h i l e s occurred s t e r e o s p e c i f i c a l l y , generating one major betaine diastereomer XXXVII which collapsed to give the E-alkene 233. For the e l e c t r o p h i l i c reagents l i s t e d i n Scheme x v i i i , the corresponding alkenes 233 were obtained i n poor to moderate y i e l d s but i n v a r i a b l y with greater than 90% s t e r e o s e l e c t i v i t y . A s i m i l a r synthetic study conducted by Gorey et a l . 1 3 6 showed that a l k y l a t i n g agents other than methyl iodide f a i l e d to react with the betaine intermediate XXXVI''.-' However, 102 Scheme x v i i i P=CHR1 •CHO O" R'-C CH- CHR XXXV PhLi PhoP O" 1 " : | 2 R - C — CHR^ XXXVI 233 XXXVII R1 = a l k y l ; R 2 = a l k y l , a r y l E l e c t r o p h l l i c reagent E CH 3I CH 3 Br 2 Br FCIO3 F C1 2IC 6H 5 C l H g ( 0 A c ) 2 / L l - I 2 1 3 5 I 103 by using paraformaldehyde as the e l e c t r o p h i l e i n the l a s t step of the above reaction sequence, they achieved a new approach to t r i s u b s t i t u t e d alkenes of type 234 (Scheme x i x ) . 1 3 6 Betaine XXXVIII (R 1 = n-C 6H 1 3) derived from heptanal and ethylidenetriphenyl phosphorane was converted to 8-oxido phosphonium y l i d e XXXIX by n-butyllithium at -78° C. Treatment of XXXIX with paraformaldehyde at 0° C gave E-l-hydroxy-2-methyl-2-nonene (234, R1 = n-C 6H 1 3) i n 73% y i e l d o v e r a l l . In contrast to the above r e s u l t , reaction of XXXIX with another molecule of aldehyde ( f paraformaldehyde) produced predominantly alkene 235 having the oxygen originated i n the second aldehyde eliminated. Although p l a u s i b l e r a t i o n a l i z a t i o n s 1 3 6 ' 1 3 7 for these stereochemical outcomes have been proposed, the exact mechanism i s not yet c l e a r . The o l e f i n a t i o n of carbonyl compounds involving carbanions a to s i l i c o n (equation 19) bears c e r t a i n s i m i l a r i t y to the Witt i g reaction. I t has been shown by many i n v e s t i g a t i o n s 9 9 that t h i s class of reactions usually leads to mixtures of o l e f i n i c isomers. The lack of s t e r e o s e l e c t i v i t y i s (19) 236a 236b 104 Scheme xix P h 3 P = CHCH 3 + R CHO > 234 R 1, R 2 = alkyl , Ph. Ph.,P + O" 3 I I 1 C H 3 , C H - C H R XXXVIII I n-BuLi OH 235 105 believed to a r i s e from the i r r e v e r s i b l e formation of diastereomeric adducts XL which a f t e r elimination produce the corresponding isomeric alkenes 236a and 236b. A s o l u t i o n to the s e l e c t i v i t y problem was found by Sachdev 1 3 8 who u t i l i z e d s i l y l carbanions s t a b i l i z e d with dihydro-l,3-oxazine. Thus, l i t h i u m carbanions derived from 2-(trimethylsilyl)methyl-5,6-dihydro-l,3-oxazine (237) and the b i s - t r i m e t h y l s i l y l m e t h y l d e r i v a t i v e 239 reacted with unsymmetrical ketones and aldehydes, r e s p e c t i v e l y , to a f f o r d alkenes 238 and v i n y l s i l a n e s 240 i n good y i e l d s and s a t i s f a c t o r y s t e r e o s e l e c t i v i t i e s (Scheme xx). Since i t has been proven that 8-hydroxy sila n e s undergo e l i m i -nation i n a syn f a s h i o n , 1 3 9 p r e f e r e n t i a l formation of the diastereomer XLI during the i n i t i a l a d d i t i o n i s obviously responsible for the s e l e c t i v e generation of 238. Two conformers, XLIIa and XLIIb, of the adduct derived from 239 and the aldehyde (R1CH0) are capable of syn elimination. Presumably, s t e r i c i n t e r a c t i o n between R1 and the t r i m e t h y l s i l y l group i s more severe than that between R1 and R, so that elimination proceeding v i a conformer XLIIb i s favored. As methods f o r transforming the dihydro-l,3-oxazine group i n t o an aldehyde or ketone are well e s t a b l i s h e d , 1 4 0 the R group i n alkenes 238 and 240 may be regarded as a masked carbonyl f u n c t i o n a l i t y . The addition of Grignard reagents to a-chloroketones or aldehydes has been demonstrated to occur i n a s t e r e o s p e c i f i c manner. On the basis of t h i s f i n d i n g , Cornforth introduced a general procedure for the s t e r e o s p e c i f i c synthesis of substituted alkenes (Scheme x x i ) . 1 4 1 I t was proposed that 106 Scheme xx RCH2Si Me 3 237 1, n-BuLi , -78 2. C H 3 C O R 1 ,.CI Me 3Si Ol XLI , C 238 1. n-BuLi, - 78' RCH(Si M e 3 ) 2 239 2. R1 CHO Me^Si" Me 3 Si * "R XLIIa •OLf ^ Me3Si" 107 chlorocarbonyl compound 241 prefers a conformation i n which the carbonyl and chlorine groups are i n an a n t i periplanar d i s p o s i t i o n . The s t e r i -Scheme x x i 244 2 4 3 L S R = large group ; R = small group ; R1 = a l k y l or H; R2 = a l k y l c a l l y favored addition of Grignard reagent to the l e a s t hindered side of the carbonyl group would then lead to chlorohydrin 242 as the major d i a -stereomer. Treatment of 242 with base gave epoxide 243 which could be deoxygenated s t e r e o s p e c i f i c a l l y to produce alkene 244 by a two-step reduc-t i v e elimination sequence. This involved conversion of 243 to an iodohydrin using sodium iodide i n buffered a c e t i c a c i d , followed by s t e r e o s p e c i f i c 108 reduction with stannous chloride and phosphorous oxychloride i n pyridine. As could be expected, the s e l e c t i v e generation of 242 i s a f f e c -L S ted by the r e l a t i v e sizes of R and R . Furthermore, successful execution of the Grignard addition also depends on the reaction temperature as well as the nature of the Grignard reagent and solvents used,. These e f f e c t s have, been reported by.Johnson and coworkers : i n a synthesis of Cecropia j u v e n i l e hormone. The s t e r e o s p e c i f i c i t y of the Grignard addition employed was improved by lowering the r e a c t i o n temperature and by changing the Grignard reagent from methylmagnesium iodide i n ether to methylmagnesium chl o r i d e i n THF 1 0 3 ' 1 0 6 The above survey of' s t e r e o s e l e c t i v e synthesis of substituted alkenes demonstrates the various s t r a t e g i e s that have been generally adopted to form carbon-carbon double bonds. Whilst these methods have t h e i r own p a r t i c u l a r synthetic values, the scope of t h e i r u t i l i t y are often l i m i t e d i n c e r t a i n aspects. Using 8-keto esters as precursors, we developed a f a c i l e and s t e r e o s p e c i f i c route to substituted alkenes which may broaden the spec-trum of alkene syntheses. The r e s u l t s of our work and comparison with rel a t e d methods are described i n the following part of t h i s section. 109 Results and Discussion The key steps i n the design of synthetic strategies for o l e f i n i c compounds are often based on a v a i l a b l e methods f o r generating carbon-carbon double bonds that can f u l f i l the desired purpose. A useful alkene synthesis should not only f a c i l i t a t e d e f i n i t e o l e f i n i c geometry i n a c o n t r o l l a b l e manner, but also provide appropriate f u n c t i o n a l i t i e s f or further manipula-t i o n . The u t i l i t y of a synthetic method i s measured by a combination of i t s e f f i c i e n c y , the degree of stereochemical c o n t r o l and the a c c e s s i b i l i t y of precursors. A scrutiny of the methodologies surveyed e a r l i e r reveals that very few alkene syntheses meet with a l l the above c r i t e r i a . General and st e r e o s e l e c t i v e routes to t e t r a s u b s t i t u t e d alkenes are e s p e c i a l l y scarce. O l e f i n synthesis v i a a d d i t i o n to acetylenes has been developed extensively and o f f e r s great v e r s a t i l i t y . Nevertheless, the main use of t h i s methodo-logy i s l i m i t e d to the synthesis of t r i s u b s t i t u t e d alkenes and obviously i t i s not applicable to small and medium-sized cycloalkenes. The 8-keto ester function would be an i d e a l b u i l d i n g block for o l e f i n i c u n i t s . A v a r i e t y of 8-keto esters of type 245 are r e a d i l y a t t a i n -able from methyl acetoacetate v i a w e l l documented r e a c t i o n s . 1 ' 2 Provided that an e f f i c i e n t and s t e r e o s p e c i f i c method could be found which would trans-form 245 into 246 and 247, a host of substituted o l e f i n s could be synthesized with the carboalkoxy group as a u s e f u l handle for further elaboration. Our i n t e r e s t i n f i n d i n g a synthetic pathway to e f f e c t the above transformation (equation 20) p a r t i a l l y originated from the problems that occurred during an i n v e s t i g a t i o n aimed at converting the 8 -keto ester 9_7 110 • C 0 2 Me O R • C 0 2 M e (20) '245 247 into the a,8~unsaturated ester 248. The l a t t e r portrays a valuable i n t e r -mediate for the synthesis of several classes of natural products including vitamin A and carotenoids. Since 9_7_ could be conveniently prepared from methyl acetoacetate, as described i n Section I, t h i s conversion would f a c i -l i t a t e an e f f i c i e n t route to d e r i v a t i v e s of structure 248- A thorough search of the l i t e r a t u r e revealed two synthetic reactions which c l o s e l y resembled equation 20. Casey et a l . reported the s t e r e o s p e c i f i c reaction of B-acetoxy-a,8-ethylenic esters 249 with l i t h i u m dimethylcuprate, y i e l d i n g 8-methyl-a , B - e t h y l e n i c esters (equation 2 1 ) . 1 4 2 Another method involves s i m i l a r O 97 248 I l l replacement of a phenylthio group i n 8-phenylthio-a,8-ethylenic esters 0 2Me C02Me (21) 249 with a methyl group (equation 22)• This has been achieved by tr e a t i n g the thio enol ether with either a large excess (10 equivalents) of l i t h i u m d i -C 0 2 Et (22) R = H or alkyl methylcuprate, 1 M 3 or excess methylmagnesium iodide i n the presence of cuprous iodide 82 144 Casey's method was f i r s t investigated. The keto ester 9_7 was con-verted into i t s enol acetate 250 by heating, under r e f l u x , with a mixture of isopropenyl acetate (excess) and j>-toluenesulfonic acid i n benzene. ?Ac / / OAc / ^ / C O j M e C0 2Me 97 2 50 E f f o r t s to e f f e c t replacement of the acetoxy moiety i n 250 with the methyl group of l i t h i u m dimethylcuprate f a i l e d completely. When the cuprate reaction 112 was c a r r i e d out at low temperatures for a short period of time, the enol acetate was recovered. Employment at higher r e a c t i o n temperatures or pro-longed reaction time led to the regeneration of 9_7, apparently from c l e a -vage of the acetate function. The f a i l u r e of 250 i n undergoing a s u b s t i t u t i o n r e a c t i o n with l i t h i u m dimethylcuprate i s not s u r p r i s i n g i n l i g h t of the theory proposed by House e_t a l . for the conjugate addition of l i t h i u m dialkylcuprates to a, 3-unsaturated carbonyl compounds.11*5 I t i s believed that i n the f i r s t stage of the above process, an electron i s transferred from the cuprate reagent to the unsaturated carbonyl system (e.g., 251) producing an anion r a d i c a l (e.g., XLIII). The conjugate addition i s completed i n the second stage which involves coupling of the anion r a d i c a l with the cuprate r a d i c a l and subsequent intramolecular migration of an a l k y l group from the cuprate to the carbonyl substrate. The f e a s i b i l i t y of the i n i t i a l e l e c t r o n tr a n s f e r w i l l be determined by the electrode p o t e n t i a l ^ (^ r e cj) °^ t n e unsaturated carbonyl compounds and the e l e c t r o d e * p o t e n t i a l ^ ( E G x ) of the cuprate rea-gents. A set of empirical r u l e s has been suggested to estimate E r e ( j of a,8-ethylenic carbonyl systems (Table 3 ) . l k 5 c Based on these r u l e s , Measured against a saturated calomel electrode i n an aprotic solvent. The sign convention used for E , and E i s associated with the c , , . red ox following reaction: Oxidized reactant + e~ <—» Reduced reactant The most powerful reducing agents (cuprates) have the most negative E 0 x while the most d i f f i c u l t l y reduced carbonyl substrates have the most negative E r e < j . 113 Table 3. Empirical Rules for Estimating the Reduction Potentials of a,B-Ethylenic Carbonyl-Compounds. Base value for R1 = R 2 = R 3 = R 4 = H: -1.9 Volt (V) Increment for E r e d (V) Substituent R1 R 2 R3 or R1* a l k y l group -0.1 -0.1 -0.1 f i r s t alkoxy group -0.3 0 -0.3 f i r s t phenyl group +0.4 +0.1 +0.4 (R 3, R1* = acetoxy has about the same e f f e c t as R 3, R1* = H ) 1 4 5 a the calculated E , for red 250 i s -2.4 V. Since i t has been shown that i n order to observe s i g n i f i c a n t conjugate addition i n the reaction of l i t h i u m dimethylcuprate with a,B-unsaturated compounds, E r e c j of the l a t t e r must be within the range of -1.3 to -2.3 V , l l t 5 b the f a i l u r e of 250 to couple with l i t h i u m dimethylcuprate i s not t o t a l l y unexpected. The r e s u l t s reported by Casey jit a l . obviously represented the l i m i t i n g s i t u a t i o n ( E r e c j f or 249 = -2.3 V) for successful coupling. In f a c t , no a-substituted esters were reported i n t h e i r work. 114 The a l t e r n a t i v e route v i a the phenylthio enol ether of 9_7 was severely impaired by the i n e f f i c i e n t y of a v a i l a b l e procedures f o r convert-t i n g 8-keto esters into t h e i r B-phenylthio-a ,B-ethylenic d e r i v a t i v e s . The jD-toluenesulfonic acid catalyzed r e a c t i o n of methyl acetoacetate with benzenethiol has been shown to give a mixture of thio enol ethers 252 and phenylthio k e t a l 253. 1 4 6 A p p l i c a t i o n of s i m i l a r reaction conditions to the 252 253 c y c l i c 8-keto esters 254 and 9_7_ led to mixtures of a,8- and 8,Y-unsaturated esters. While about equal proportions of 255a and 255b were obtained from 254, the 8,Y -unsaturated isomer 256a was the predominant product from 97  (256a:256b~4:1). A s these reactions were conducted under equilibrium con-PhS PhS 254 R = Me , Et 255a 255b 97 256a 256b 115 d i t i o n s , the observed formation of the non-conjugated esters c l e a r l y r e f l e c t e d that t h e i r s t a b i l i t i e s are comparable to or even greater than the corresponding conjugated isomers. S t e r i c e f f e c t s and preference f o r more favorable d i s p o s i t i o n of dipole moments are presumably the cause of t h i s phenomenon. Similar behavior of the enethiol d e r i v a t i v e s of c y c l i c 8-thioxo esters has been reported b e f o r e . 1 1 + 7 To test i f the 8-phenylthio-a,8-unsaturated ester 255b was ade-quate for coupling with cuprate reagents, a m i x t u r e ^ of 255a and 255b was treated with excess (ca. 4 equivalents) l i t h i u m dimethylcuprate i n ether (0° C to room temperature). Indeed, the desired methylated product 257 was i s o l a t e d together with recovered 255a. 255a 255b 257 Since i t was apparent that an e f f i c i e n t preparation of 256b from 9_7 was not f e a s i b l e , attempts were made to synthesize the methyl d e r i v a t i v e 259b. I t was hoped that the smaller methyl group might lead to a greater proportion of the conjugated ester. Methylthio k e t a l 258 was prepared by tre a t i n g 97_ with excess methane t h i o l and zin'c(II) -chloride at -20° C . 1 4 8 Unfortunately, elimination of methane t h i o l from 258 This mixture was d i f f i c u l t to separate. 116 (with HgCl 2, methylating agents, or base) i n v a r i a b l y gave the non-conjugated compound 259a with only i n s i g n i f i c a n t amounts of 259b. B-Halo enones 261 have been suc c e s s f u l l y transformed into the cor-responding B-alkyl enones 262 by r e a c t i o n with organocuprates. 1 4 9 Similar transformations of 8-halo-a,8-ethylenic esters appeared promising. To our knowledge, d i r e c t synthesis of such B-halo d e r i v a t i v e s from B-keto esters by an e f f i c i e n t and general method has not been recorded. Two most s a t i s -(CH n = 1, 2 a: Ph 3P-X 2 b: o x a l y l chloride X = halogen ; R = 1° a l k y l ; Y = R or PhS a or b (CH2)n 2 61 R(Y)CuLi (CH2)rv 262 117 factory methods f or preparing 8-halo enones 261 from 8-diketones 260 were applied to the conversion of 254 into 263. The procedure developed by Piers C 0 2 R 254 C 0 2 R 263 X = halogen and Nagakura,,,150 which involved the use of triphenylphosphine d i h a l i d e com-plexes, was attempted without success. Clark and Heathcock accomplished the synthesis of 8-chloro enones 261 (X = Cl) by treating 8-diketones 260 with o x a l y l chloride i n r e f l u x i n g chloroform, 1 5 1 However, when 8-keto ester 254 was subjected to the same treatment, only the chlorooxalate ester 264 was i s o l a t e d i n ca. 70% y i e l d . ° 2 R 9 9 C I C - C C I 2 54 264 The anticipated 8-chloro-a,8-unsaturated ester was not detected. This r e s u l t coincided with a l a t e r report by •the above workers who showed that the o x a l y l chloride procedure did not convert 8-keto esters into 8-chloro e n o a t e s . 1 5 2 The chlorooxalate d e r i v a t i v e 264 (R = Et) was also observed i n t h i s l a t t e r case. Attempts to synthesize 263 (X = Cl) using t h i o n y l chloride and other o x a l y l chloride p r o c e d u r e s 1 5 3 were unsuccessful. 118 Obviously, i n order to e f f e c t transformation 20 (p. 110) and the analo-gous rea c t i o n f o r c y c l i c 8-keto esters, a f a c i l e and e f f i c i e n t method was needed to convert 8-keto esters into a,8-ethylenic esters 265, i n which group X must be compatible with coupling reactions involving organocuprates. Although Casey's enol acetate r o u t e 1 4 2 succeeded f o r a c y c l i c 8-keto esters 245 265 without a-substituents, i t s u t i l i t y i s f a r from general. The acid and high temperature conditions required f o r ste r e o s e l e c t i v e formation of the Z_ isomer of 8-acetoxy-a,8-ethylenic esters p r o h i b i t the presence of a c i d -s e n s i t i v e f u n c t i o n a l i t i e s i n the 8-keto ester precursors. Furthermore, the s t e r e o s e l e c t i v i t i e s reported i n some cases were not very high. In conceiving p o t e n t i a l l y s u i t a b l e candidates for group X i n 265, the ease with which 8-keto esters could be converted into t h e i r enolates was taken into account. I t would be most convenient to generate 265 by trapping the enolate of 245 with some e l e c t r o p h i l e to form an appropriate leaving group at the 8 - p o s i t i o n . The 0-sulfonate and 0-phosphate groups appeared to s a t i s f y the above r e q u i s i t e s . A f t e r several f u t i l e attempts to ef f e c t reaction between the enol methanesulfonate d e r i v a t i v e of 254 (prepared from the enolate and methanesulfonyl chloride) and l i t h i u m dimethylcuprate, we turned our att e n t i o n to the p o s s i b i l i t y of using enol phosphate d e r i v a t i v e s . 119 It i s well known that ketone enolates react r e a d i l y with chloro-phosphates to form enol phosphates, though s i m i l a r reactions involving the enolates of 8-dicarbonyl compounds has not been reported. The enol d i e t h y l -phosphate esters derived from ketones have been reduced to o l e f i n s with l i t h i u m i n ammonia/_t-butanol, 1 5 4 i n d i c a t i n g that the enol phosphate group i s a reasonable electron acceptor. Blaszczak et a l . 1 5 5 reported that the enol diphenylphosphate ester of some cyclohexanones and a methyl ketone reacted with l i t h i u m di-n-butylcuprate to give the corresponding n-butyl sub-s t i t u t e d o l e f i n s i n f a i r y i e l d s . Reactions of the enol phosphate d e r i v a t i v e s with l i t h i u m dimethylcuprate were unsa t i s f a c t o r y . However, we f e l t that con-jugation of the enol phosphate function with a carboalkoxy group should im-prove the s i t u a t i o n . Synthesis and Reactions of ^ -Enol Phosphates of 6-Keto Esters Our i n t e r e s t i n e x p l o i t i n g the preparation and the synthetic u t i l i t y of enol phosphates of 3-keto esters started with the successful trans-formation of 3-keto ester 266 into the a,8-unsaturated ester 268 v i a the enol phosphate intermediate 267. Successive treatment of 266 with sodium hydride and d i e t h y l chloro-phosphate (DECP) i n ether at ambient temperature afforded the enol phosphate 267 i n quantitative y i e l d . The a,8-ethylenic ester function i n 267 was e v i -dent from i t s IR spectrum which showed absorptions at 1715 and 1660 cm 1. Presence of the d i e t h y l phosphate moiety was revealed by the intense IR ab-sorptions at 1290 and 1030 cm - 1, c h a r a c t e r i s t i c of P = 0 and P-O-C s t r e t c h -120 ings, r e s p e c t i v e l y . A four-proton quintet (J = 7 Hz) at 6 4.15 and a s i x -proton t r i p l e t (J = 7 Hz) at 6 1.35 i n the aHNMR spectrum provided further confirmation of the d i e t h y l phosphate structure. The composition of 267 was corroborated by i t s mass s p e c t r a l data. When the enol phosphate 267 was allowed to react with a s l i g h t excess of l i t h i u m dimethyl cuprate at 0° C, the desired 8-methyl-a,8-ethylenic ester 268 was obtained i n 94% y i e l d . Three other c y c l i c 8-keto esters, v i z . , the substituted c y c l o -hexane d e r i v a t i v e 97., the five-membered r i n g system 269 and the cycloheptane system 270, were also smoothly converted into t h e i r corresponding 8-methyl 121 enoates by using the above enol phosphate formation and l i t h i u m dimethyl-cuprate coupling reaction sequence (Table 4). In a l l cases, the enol phos-phates were obtained i n e s s e n t i a l l y quantitative y i e l d and could be used i n the cuprate reactions without further p u r i f i c a t i o n . 97 269 270 I t should be noted that the two-step procedure described above could also be performed conveniently i n one step without i s o l a t i o n of the enol phosphate intermediate. Thus, when enol phosphates generated _in s i t u from sodio 8-keto esters and d i e t h y l chlorophosphate were treated with l i t h i u m dimethylcuprate at the appropriate temperature, r e s u l t s s i m i l a r to those acquired v i a the two-step sequence were observed. The same applies to a l l the syntheses discussed herein involving enol phosphates derived from sodio 8-keto esters. Extension of t h i s methodology to a c y c l i c 8-keto esters provided a s t e r e o s e l e c t i v e route to substituted a ,8-ethylenic esters. Results sum-marized i n Table 5 for the following 8-keto esters ^  serve to i l l u s t r a t e i t s synthetic u t i l i t y . A c i d - s e n s i t i v e f u n c t i o n a l i t i e s such as the 276 was prepared by a l k y l a t i o n of the dianion of methyl acetoacetate with e t h y l iodide. The syntheses of 277 and 278 -.are.- shown i n Section I I I . 122 Table 4. Reactions of Enol Phosphates of C y c l i c 8-Keto Esters with Lithium Dimethylcuprate.' . C y c l i c 8-Keto Ester Enol Phosphate Me 2CuLi (equiva-lents) 8-Methyl-a,B-unsaturated Ester ( y i e l d ) 0 97 269 270 (EtO) 2OPQ 2 eq 271 (EtO) 2 OPO C0 2 Me 3 eq 2 72 (EtO) 2 OP q 2 M e 2 eq. 273 •C0 2Me (92%) 248 (85%) 274 C 0 2 M e (98%) 275 a b c Prepared by carbomethoxylation of cyclopentanone. 1 5 6 Prepared by carbomethoxylation of cycloheptanone. 1 5 6 A l l y i e l d s are for i s o l a t e d products and represent the o v e r a l l y i e l d from 8-keto ester precursors. 123 THPO 276 277 2 78 279 tetrahydropyranyl (THP) ether group i n 277 are compatible with the conditions used to produce the enol phosphates. The e f f i c i e n t conversion of 279 to 289 demonstrated the a p p l i c a b i l i t y of t h i s method to a c y c l i c , a-substituted 8-keto esters. Enol phosphates 280 - 284 were prepared i n almost quantitative y i e l d s by tr e a t i n g the respective 8-keto ester precursors with sodium hydride and d i e t h y l chlorophosphate i n ether at .0° C (or room temperature). A l l of these enol phosphates were characterized by spectroscopic and chromatographic analyses which i n v a r i a b l y showed the presence of a si n g l e geometric isomer. The Z_ geometry of these enol phosphates was established on the basis of t h e i r 1HNMR spe c t r a l data. The most d i s t i n c t differences between the Z_ and the E isomers are the chemical s h i f t s of the v i n y l and v i n y l methyl protons. A l i s t of the chemical s h i f t s f o r these protons abstracted from the 1HNMR of 280 to 284, along with the corresponding data reported by Fukuto et a l . 1 5 7 1-24 Table 5. Reactions of Enol Phosphates of A c y c l i c B-Keto Esters with Lithium Dimethylcuprate. A c y c l i c g^Keto Ester Enol Phosphate 3. Cuprate Reaction Product ( y i e l d ) b O P O ( O E t ) 2 I /ji s^ /jC0 2Me / 4 ^ C 0 2 M e ^ ^ • C 0 2 M e . (83%) 280 285 276 OPOCOEt ) 2 ^ \ ^ ^ ^ - C 0 2 M e ^^yX^C02Me (83%) 281 286 O P O ( O E t ) 2 277 T H P C ^ ^ \ ^ 4 ^ ^ c o 2 M e T H p 0 ^ ^ ^ 4 ^ - C 0 2 M e ( 8 2 % ) 282 287 OPO(C€t)2 278 283 288 OPO(OEt) 2 ^ L / C 0 2 E t / J ^ / C 0 2 E t 279 T 284 I (85%) 289 a b 1.5 to 2 equivalents of Me2CuLi were used. A l l y i e l d s are for i s o l a t e d products from 8-keto ester precursors. In cases of 286, 287 and 288, the y i e l d s are for the p u r i f i e d E_ isomers. 125 for the E and Z_ isomers of methyl-3-(dimethylphosphoryloxy) crotonate (290) K are given i n Table 6. The data for the E isomers of 280 and 284 (prepared i n a l a t e r part of t h i s section) are also presented for comparison. I t i s clear from the chemical s h i f t s recorded for E_- and Z-290 that the resonances of both the B-methyl protons and the v i n y l proton occur at lower f i e l d i n the E_ than i n the Z_ isomer. While the deshielding e f f e c t on a 8-methyl group c i s to the carboalkoxy moiety of a,8-ethylenic esters i s well known, 7 1' 1 5 9 i t i s i n t e r e s t i n g to note the marked down-field s h i f t of the v i n y l proton caused by the phosphoryloxy group i n the E isomer. The 1HNMR data of 280 and 310 were i n accord with the above findings and hence ascertained t h e i r s t r u c t u r a l assignments. The isomeric p u r i t i e s of 280 and 284 were further v e r i f i e d by combined vpc analyses (3% OV-17 column) of 280 with 310, and 284 with 311. The longer retention times detected for 280 and 284 were also consistent with the i n t r i n s i c a l l y higher p o l a r i t y of the Z isomers. Although the E isomers of enol phosphate 281 and 283 were not a v a i l a b l e f o r comparison, judging from t h e i r XHNMR properties, and the fa c t that they were prepared i n the same manner as 280, the Z geometry of these compounds was established. Stereoselective formation of the Z-e.nol phosphates can be ex-plained by considering the conformation of the sodium enolate of 8-keto esters i n sol u t i o n . Since d i e t h y l ether i s not an e f f e c t i v e solvent for The isomeric mixture of t h i s compound has been prepared through the condensation of trimethyl phosphite and methyl 2-chloro-acetoacetate and t h i s mixture i s used as a wide spectrum i n s e c t i c i d e . 1 5 8 126 Table 6. Selected 1HNMR Data of. Enol Phosphates of A c y c l i c 8-Keto Esters. Enol Phosphate Chemical S h i f t (5) ' V i n y l H 8-Vinyl Methyl (or Methylene) 280  281  282  283 284 C0 2 Me (EtO) 2OPO 310 (EtO) 2 OPO 0 2Et, 311 (MeO)2OPO C 0 2 M e Z-.290-(MeO) 2OP ,C02Me E-290 5.27 5.28 5.33 5.30 5.77 5.47 5.76 2.17 (d, J = 1.4 Hz) 2.37 (methylene) 2.53 (methylene) 2.40 (methylene) 1.83 (a-methyl) 2.10 2.38 (s) 1.87 (a-methyl) 2.40 2.12 2.32 a b Recorded i n CDC13 Recorded i n CCI4 , reference 157. 127 solvating i o n i c species, the U-shaped e n o l a t e 1 6 0 XLIV, being capable of serving as a bidentate ligand f or a s s o c i a t i o n with the sodium ion, i s presumably the most favorable geometric o r i e n t a t i o n of the enolate. Trap-ping t h i s enolate form with d i e t h y l chlorophosphate leads to the Z-enol phosphate; l i t h i u m dimethylcuprate at -78 to -47° C. The cuprate reactions of 280 and 284 were also conducted at 0° C without complication. In cases (e.g., 286 to 288) where geometric isomers might be produced, ste r e o s e l e c t i v e formation of the E-alkene was observed. The E configuration of these products was re a d i l y d i s c e r n i b l e by the downfield s h i f t of the 3-methyl protons i n the 1HNMR. The absorptions ascribed to the 3-methyl protons i n compounds 286 to 288 appeared at around 6 2.1, which i s the expected chemical s h i f t f o r methyl protons c i s to the carbomethoxy group i n a ,3-ethylenic e s t e r s . 7 1 The chemi-c a l s h i f t of v i n y l methyl protons trans to the ester function i n s i m i l a r compounds i s usually at 6 1.8 to 1.9. 7 1 The structures of 287 and 288 were further v e r i f i e d by comparing t h e i r 1HNMR data :with those reported for ana-logous compounds. 8 1 ' 8 2 l° The p r e v a i l i n g retention of geometry about the o l e f i n i c bond during replacement of the phosphoryloxy moiety by an a l k y l group of l i t h i u m + XLIV The enol phosphates l i s t e d i n Table 6 were allowed to react with 1 2 8 dialkycuprates could be r a t i o n a l i z e d i n terms of a proposed mechanism for these reactions (see l a t e r part of t h i s section) . The proportion of the _E compound i n the crude reaction product i n a l l cases was greater than 90%, as estimated from vpc and 1HNMR analyses. According to r e s u l t s secured l a t e r , the s t e r e o s e l e c t i v i t y of the above reactions was believed to be s u b s t a n t i a l l y higher than that suggested by the estimation. One of the merits i n using the enol phosphate of B-keto esters as a synthetic intermediate a r i s e s from the mild and basic conditions under which they could be prepared. This was found p a r t i c u l a r l y u seful i n conjunc-t i o n with the reactions of B-keto ester dianions. The enolate of a B-keto ester, produced a f t e r trapping the dianion with e l e c t r o p h i l e s at the y-carbon, may be quenched d i r e c t l y with d i e t h y l chlorophosphate to give the Y-substituted enol phosphate (Scheme x x i i ) . Subsequent reaction of the Scheme x x i i 129 enol phosphate thus generated, i n s i t u , with l i t h i u m dialkylcuprates would then a f f o r d the corresponding 8-disubstituted-a,8-ethylenic esters. To demonstrate that the above multi-step sequence can indeed be c a r r i e d out i n one single reaction mixture without the i s o l a t i o n of any intermediates, a one-p'ot procedure was developed to e f f e c t the o v e r a l l transformation as shown i n equation 23. The dianion of methyl acetoacetate i n tetrahydrofuran was quenched sequentially with n-pentyl bromide and d i e t h y l chlorophosphate. 0 2 M e 1. NaH 2. n-BuLi 3. p -CgH^Br 4 . CJPO COEt), (23) 5. M e 2 C u L i 291 The r e s u l t i n g mixture was cooled to -47 C and treated with three equivalents of l i t h i u m dimethylcuprate ( i n ether) to afford 291 i n 68% o v e r a l l y i e l d . Reaction of enol phosphates with l i t h i u m d i e t h y l - and di-n-butylcuprates Lithium d i e t h y l - and di-n-butylcuprates were used to explore the e f f i c a c y of replacing the phosphoryloxy group i n enol phosphates with primary a l k y l groups. S a t i s f a c t o r y r e s u l t s were obtained for a series of B-keto esters (Tables 7 and 8), i n d i c a t i n g the general a p p l i c a b i l i t y of primary alkylcuprates i n this olefin-forming reaction. Due to the thermal i n s t a b i l i t y of the dialkylcuprates, i t was necessary to conduct the coupling r e a c t i o n at very low temperatures. The re a c t i o n of enol phosphate 280 with l i t h i u m diethylcuprate yielded a mixture 130 Table 7. Reactions of 3-KetosEster Enol Phosphates with Lithium Diethyl-cuprate. Enol Phosphate Product Temperature Y i e l d (Et 2CuLi) 280 272 267 273 0 2Me + -78° C Z-292 E - 292 293 C0 2Me 2 94 C0 2Me 295 -98° C (2 eq) -98° C (2 eq) (3 eq) -98° C (2 eq) 84% OgMe (1-2 eq) Z:E =1:1 90% Z:E = 5:1 52% 70% -98 u C 79% (2 eq) 82% a b Y i e l d and isomer r a t i o determined by vpc. Ethyl iodide was used to quench the reaction. 131 of E_ and o l e f i n s , 292. The r a t i o of these isomers appeared to be tempera-ture dependent. Lowering of the r e a c t i o n temperature from -78 to -98° C caused a s i g n i f i c a n t increase i n the r e l a t i v e proportion of Z-292 which was formed with retention of configuration. Further decrease i n re a c t i o n temperature (-116° C) resulted i n incomplete reaction (ca. 50% of the enol phosphate was recovered a f t e r 2 hours) and showed l i t t l e improvement i n s t e r e o s e l e c t i v i t y . The change i n geometry about the o l e f i n i c bond may be at t r i b u t e d to intermediates of type XLV 1 4 5^ 3 which can undergo r o t a t i o n about the C2-C3 bond p r i o r to elimination of the phosphoryloxy group. s l i g h t influence on t h e i r reactions with l i t h i u m diethylcuprate. While 273 was converted cleanly to 295, the cuprate reaction products from 272 and 267 were contaminated with the reduced compounds 296 and 297 re s p e c t i v e l y . O" OMe X = e or copper complex XLV The r i n g s i z e of the c y c l i c enol phosphates seemed to have a tf 296 297 Such reduction products were probably derived from protonation of the v i n y l -132 copper species XLVII 1 6.1 which could be generated v i a decomposition of the coupled complex XLVI (see discussion on mechanism). The formation of (Et 2 Li )Cu+ (CH2)n—I n (CH2)n—1 XLVI XLVII s i m i l a r v i n y l - and alkylcopper species i n cuprate reactions has been reported The side reaction was e s p e c i a l l y serious i n the case of 272 and the s i t u a t i o n could be remedied by quenching the r e a c t i o n mixture with e t h y l iodide. The desired ethylated product 293 was obtained i n markedly improved y i e l d by employing t h i s modified procedure. Enol phosphate 284 was smoothly converted to Z-298 i n high stereo-s e l e c t i v i t y by treatment with l i t h i u m di-n-butylcuprate. Only a trace amount of the E_ isomer was detected. This r e s u l t provides a s t e r e o s e l e c t i v e route to tetrasubstituted o l e f i n s . Reduction products 296 and 297 were also observed i n the reaction of 272 and 267 with l i t h i u m di-n-butylcuprate. Again, t h i s complication could be circumvented by quenching the reaction with n-butyl bromide. Low temperature was also c r u c i a l i n order to obtain the n-butyl substituted a , 8 - e t h y l e n i c esters i n good y i e l d . When the reactions were performed at -78° C, s i g n i f i c a n t amounts of enone products, r e s u l t i n g from attack at the carbonyl of the ester function, were detected. previously. 1 6 1 133 Table 8. Reactions of 3-Keto YE sr. er-Enol Phosphates with Lithium Di-n-butylcuprate. Enol Phosphate Product Temperature Isolated (Additive) Y i e l d 284 0 2 E t Z-298 C 0 2 E t -98° C (n-BuBr) c 72% 2% E-298 272 C0 2Me 299 -78° C -98° C (n-BuBr) 67% 81% 267 0 2Me 300 -78° C -98° C (n-BuBr) 54% 73% 273 C0 2Me 301 -98 C 81% (n-BuBr) ° a b c 2 equivalents of (n-Bu) 2CuLi were used. Used to quench the reaction. n-BuBr w a s added merely as a precaution since we were unaware of any reduction products i n these cases. 134 Reaction of enol phosphates with l i t h i u m d i - s e c - b u t y l - and d i - t - b u t y l -cuprates Reactions of the enol phosphate of B-keto esters with secondary and t e r t i a r y dialkylcuprates were complicated by the formation of reduction and 1,2-addition products. T y p i c a l r e s u l t s observed for enol phosphate 267 are described i n Table 9. In the reaction of 267 with l i t h i u m di-sec-butylcuprate, the desired product 302 was obtained only i n low y i e l d Table 9. Reactions of 267 with.Lithium Di-sec-butylcuprate and Lithium Di-t-butylcuprate. Enol Phosphate Temperature Cuprate Products (Yield) 267 -63° C ,sec-Bu ?CuLi (2 eq) ^ ^ ^ - - C O g M e C J + 302 ( 20°/ , ) (ca.40°/ o) . C 0 2 M e 297 (30°/o) -23° to t-Bu 2CuLi -98° C (1.1 to 2 eq) 303 (EtO) 2OPQ Q + 304 + 267 -47° C 4 eq 303 (80%) along with substantial quantities of the reduction product 297 and unreacted enol phosphate. As sec-alkylcuprates are prone to decompose, 1 6 4 an enhanced rate of decomposition of intermediates such as XLVI (vide supra) may 135 explain the preponderant formation of 297 i n t h i s case. House and coworkers have observed the reduction product 306 i n a study of the rea c t i o n between l i t h i u m di-sec-butylcuprate and enone 3 0 5 . 1 h 5 & I t was suggested that p a r t i a l thermal decomposition of the cuprate reagent led to the copper hydride species, (sec-Bu)HCuLi, which reduced the enone at a rate competitive with conjugate addition. Treatment of 267 with one to two equivalents of l i t h i u m di-_t— butylcuprate at temperatures ranging from -23° to -98° C gave varied pro-portions of 303, 304 and unreacted enol phosphate. The desired B-_t-butyl-a , 3-ethylenic ester was not detected i n any of these runs. Formation of the keto enol phosphate 304 indicated that the ketone 303 was produced v i a an i n i t i a l attack of a _t-butyl anion on the methyl ester group to form 304, followed by coupling with excess l i t h i u m di-t-butylcuprate. I n t e r e s t i n g l y , when 267 was exposed to excess l i t h i u m di-t-butylcuprate, 303 was i s o l a t e d i n 80% y i e l d - a r e s u l t i n support of the above concept. House et a l . 1 4 5 a have shown that i n the presence of small amounts of an impurity (presumably a Cu(II) contaminant i n the Cu(I) s a l t used to prepare the cuprate), l i t h i u m di-t-butylcuprate may deteriorate to generate j:-butyllithium which undergoes 1,2-addition with carbonyl functions. Such a side reaction became prominent when E r e ( j of the enone substrate was more negative ^  than -2.1 V ( E o x of (8) See footnote :&j : O n - p . . .112 fo r . sign ..convention. 136 _t-Bu2CuLi), r e s u l t i n g i n a slow re a c t i o n between the cuprate and the enone. Direct involvement of l i t h i u m di-_t-butylcuprate i n the 1,2-addition i s also possible since conversion df c e r t a i n esters into ketones using organocopper reagents has been r e p o r t e d . 1 6 2 E f f e c t of the 8-phosphoryloxy group on E r e < j of a,8-ethylenic carbonyl compounds Results from the reaction between the enol phosphate of 8-keto esters and l i t h i u m dialkylcuprates can be interpreted by means of a mechanism involving electron transfers as suggested by House1'*5 (cf. discussion on mechanism). As a consequence of t h i s mechanistic view, the e f f i c a c y of the desired coupling reaction between an enol phosphate and a cuprate reagent i s determined by the E r e c j of the former as well as the E Q X of the l a t t e r . Enol phosphates with E r e ^ more negative than the E o x of a l i t h i u m d i a l k y l -cuprate would f a i l to y i e l d coupling products upon reaction with the cuprate. Under these circumstances, either the reactants are recovered or side reac-tions may occur giving r i s e to reduction and/or 1,2-addition products. In order to accommodate a l l the r e s u l t s observed, the e f f e c t of a B-phosphoryloxy substituent on the E r e c j of a,8-ethylenic carbonyl systems was estimated to be ca_. +0.1 V, according to House's rules (see Table 3). 1 4 5 This estimate was deduced from the following considerations. The E o x of l i t h i u m d i a l k y l c u p r a t e s 1 4 5 and the calculated E r e ( j for the 8-H analogs of enol phosphates 267, 304 and 280 are l i s t e d i n Table 10. Since 267 coupled smoothly with l i t h i u m dimethylcuprate to give the 8-methyl s u b s t i -tuted ester, i t s E r e ( j should not be more negative than -2.3 V. Hence, sub-s t i t u t i o n of the 8-hydrogen i n 297 with a phosphoryloxy group causes a 137 Table 10. Reduction Potentials, of -Some a,3-Ethylenic Carbonyl Compounds and Lithium Dialkylcuprates". a, 3-Ethylenic Carbonyl Compound Enol Phosphate Cuprate ( E o x ) (-2.4 V) 297 ( E t O ) ? O P O cV 267 CQ 2Me Me 2CuLi (-2.3V) H O 307 (-2.2 V) (EtO) 2 OPQ Q 304 sec-Bu 2CuLi (-2.2 to -2.3 V) 308 C 0 2 M e H (-2.3 V) (EtO) 2 OPO - ^ ^ C 0 2 M e 280 t-Bu 2CuLi (-2.1 V) change (AEphogp^te) no l e s s than +0.1 V i n E r e c j . The reaction of 280 with l i t h i u m di-_t-butylcuprate was sluggish and the coupling product was not detected. This r e s u l t l i m i t s AE , , to be l e s s than +0.2 V. House phosphate et_ aL. have reported that enone 309 ( E r e ( j = '-2.-21 V) coupled s a t i s f a c t o r i l y with l i t h i u m di-sec-butylcuprate while enone 305 ( E r e ( j = -2.35 V) gave 138 309_ ( E r e d =-2.21 V ) 305_ ( E p e d = -2.35 V ) poor r e s u l t s (yields of conjugate addition product varied from 17 to 4 3 % ) . 1 4 5 The observed low y i e l d i n g coupling of 267 with l i t h i u m di-sec-butylcuprate would be most consistent with a E r e c j value f o r 267 close to -2.3 V. Based on the foregoing argument, the appropriate magnitude for AEpk 0 ^ate was estimated to be +0.1 V. Total f a i l u r e of 267 to couple with l i t h i u m di-_t-butylcuprate can now be explained by the fa c t that E r e ( j of 267 (-2.3 V) i s s u b s t a n t i a l l y more negative than -2.1 V. On the other hand, the keto enol phosphate 304 which has an estimated (assuming AE , , = +0.1 V) of -2.1 V, would be ° phosphate r e a able to couple with l i t h i u m di-_t-butylcuprate. This accounts for the e f f i -c ient conversion of 267 into 303 by excess l i t h i u m di-t-butylcuprate, pre-sumably v i a the intermediary 304. Synthesis and Reactions of the E-Enol Phosphate of A c y c l i c 8-Keto Esters. A procedure for the s t e r e o s e l e c t i v e synthesis of E_-8-phosphory-loxy-a,8-ethylenic esters was also developed. Treatment of a c y c l i c 8-keto esters with a s l i g h t excess of triethylamine and d i e t h y l chlorophosphate i n hexamethylphosphoramide at ambient temperature, for ^a. 4 hr, afforded the corresponding E-enol phosphates i n good y i e l d s (Table 11). Formation 139 Table 11. Reactions of E-Enol' :Phosphates of A c y c l i c 8-Keto Esters with Lithium Di-n-butylcuprate. 8-Keto ester Enol Phosphate (yield) Product from Reaction with n-Bu2CuLi (yield) O C 0 2 M e (EtO) 2OPO 310 0 2 Me (90%>) 312 C 0 2 M e ( 7 6 ° / o ) O •C0 2 Et ( EtO) 2OPO C 0 2 E t ( 9 2 » / o ) C02Et ( 7 9 ° / o ) 279 311 E-298 of the E isomers appeared to be exclusive according to vpc and JHNMR analyses (cf. Table 6). An adequate explanation f o r t h i s s t e r e o s e l e c t i v i t y i s offered by the following considerations. In a highly polar aprotic solvent such as hexamethylphosphoramide, the triethylammonium cation i s strongly solvated and would be separated from the enolate anion of the a c y c l i c 8-keto ester. The most stable o r i e n t a t i o n of the free enolate i s expected to be the W-s h a p e d 1 6 0 ' 1 6 3 (or E) conformation XLVIII, i n which i n t e r n a l dipole-dipole repulsion i s minimized. Reaction of d i e t h y l chlorophosphate with t h i s pre-ferred form of the enolate gives the corresponding E-enol phosphate. O 1 R OMe XLVIII E t 3 N H solvent 140 The enol phosphates 310 and 311 were converted s t e r e o s e l e c t i v e l y into the a,B-unsaturated esters 312 and E-298 i n 76 and 79% y i e l d s , res-p e c t i v e l y , upon exposure to two equivalents of l i t h i u m di-n-butylcuprate at -98° C. Only a trace amount (2.9%) of the Z isomer of 312 was obtained i n the o v e r a l l transformation from methyl acetoacetate, i n d i c a t i n g a stereo-s e l e c t i v i t y of ca.. 26:1 for the two-step sequence. The conversion of 279 into E-298 represents another s t e r e o s e l e c t i v e route to tetrasubstituted alkenes. The stereoselective replacement of the phosphoryloxy group i n both E- and ^-enol phosphates with retention of geometry about the o l e f i n i c bond demonstrated the s t e r e o s p e c i f i c i t y of the coupling reactions between these enol phosphates and l i t h i u m d i a l k y l c u p r a t e s . With the access to the E-enol phosphate of B~keto esters also secured, the v e r s a t i l i t y of the present alkene synthesis would be greatly enhanced. Synthesis and Reactions of the Enol Phosphate of B-Diketones The foregoing methodology for synthesizing 8-substituted-a,B ~ ethylenic esters has also been extended to symmetrical 1,3-diketones. Repre-sentative r e s u l t s are summarized i n Table 12. The enol phosphates of these 8-diketones were conveniently prepared, i n excellent y i e l d s , either by the sodium hydride procedure mentioned e a r l i e r for B-keto esters, or by using triethylamine as base instead of sodium hydride. The l a t t e r procedure was found superior i n cases (e.g., 315 and 316) where the diketones and t h e i r corresponding sodium enolates were insoluble i n ether solvents (ether and THF). 141 Table 12. Reactions of 8-Diketone Enol Phosphates with Lithium D i a l k y l -cuprates. 8-Diketone Enol Phosphate Cuprate Product (Yield) (equivalents) ( 83°/o) E-31 7 O O v e r a l l y i e l d of i s o l a t e d product.for the two-step sequence. 142 Some i n t e r e s t i n g r e s u l t s were observed during the preparation of the enol phosphates of acetylacetone (313) , and are summarized below. XX (Et 0) 2OP XX . XX 31 3 Z-317 (EtO^OPO E-317 Reaction Conditions <1 eq NaH, 20 min, r . t . 1.1 eq NaH, 3 hr, r . t . Et3N/HMPA, 3 hr, r . t . Product Proportions 100 1 1 0 7 2.7 Table 13. Selected 1HNMR Data-of the'TS- and the Z-Enol Phosphates of Acetylacetone. Enol Phosphate Chemical S h i f t (6) V i n y l H 3-Methyl Z - 317 5.42 2.17 (d, J = 1.2 Hz) E - 317 6.17 2.33 (s) When the procedure for the preparation of the JZ-enol phosphate of a c y c l i c 8-keto esters (1.1 eq sodium hydride, 1.1 eq d i e t h y l chlorophosphate, 3 hr at room temperature) was applied to 313, the E-enol phosphate, E-317, was obtained as the major product, accompanied by only a small quantity of the Z_ isomer. St r u c t u r a l assignments for E- and Z-317 were based on the 143 same argument as given e a r l i e r f o r the enol phosphates 280 and 310 (cf. Table 6), i . e . , the v i n y l and 8-methyl. protons i n E-317 should have lower f i e l d chemical s h i f t s than the corresponding protons i n Z-317 (see Table 13 for 1HNMR data of both isomers). This unusual predominant formation of the E-enol phosphate under the conditions described above was a t t r i b u t e d to an isomerization of the Z_ isomer. I t was speculated that the most favor-able geometric o r i e n t a t i o n XLIX of the sodium enolate of 313 i n ether i n i -t i a l l y led to formation of the ^-enol phosphate. However, i n the presence of excess sodium hydride, Z-317 could be deprotonated and then isomerized to the presumably more stable sodium dienolate L. Subsequent protonation of L with another molecule of enol phosphate would give r i s e to E-317. 1 4 4 In order to substantiate the above hypothesis, acetylacetone (313) was converted into i t s enolate with s l i g h t l y l e s s than one equivalent of sodium hydride, followed by treatment with d i e t h y l chlorophosphate at room temperature f o r 20 min. E s s e n t i a l l y pure Z-317 was thus obtained with no detectable contamination of the E_ isomer according to 1HNMR and chroma-tographic analyses. In addition, by monitoring the amount of excess sodium hydride present and the time of reaction, we were able to observe varying proportions of the two isomers i n agreement with the proposed isomerization mechanism. I t i s worth noting that the above r e s u l t s provide a common method for the ste r e o s e l e c t i v e synthesis of both E- and Z-enol phosphates of a c y c l i c 1,3-diketones. Employment of excess base and prolonged r e a c t i o n time would a f f o r d predominantly the E_-enol phosphate, while exclusive forma-t i o n of the Z_-enol phosphate could be achieved by ensuring the absence of any excess base. The method which was proved successful i n producing the E-enol phosphate of a c y c l i c 8-keto esters was also investigated for 1,3-diketones (vide supra). Treatment of acetylacetone with triethylamine (1.1 eq) and d i e t h y l chlorophosphate (1.1 eq) i n hexamethylphosphoramide for 3 hr at room temperature yielded a mixture of E- and Z_-317 i n a r a t i o of 2.5:1. This low s t e r e o s e l e c t i v i t y , i n contrast with the exclusive formation of E-enol phosphates observed f o r B-keto esters under s i m i l a r conditions, could be explained by the following considerations. Assuming that the free enol-ate of 313 ex i s t s mainly i n planar conformations (to enable resonance s t a b i -l i z a t i o n ) with minimized i n t e r n a l d i p o le-dipole repulsion, the major enolate forms leading to the enol phosphate products would be LIa,b and c. 145 The two conformers Lib and L i e both contribute to the formation of the E-enol phosphosphate. However, the enolate form L l a - another resonance form of L i b , with an Z_ geometric o r i e n t a t i o n , gives r i s e to the Z-enol phosphate. The above argument also b r i e f l y r a t i o n a l i z e s the approximately two to one proportions of E- and Z-317 obtained. The enol phosphates of B-diketones r e a d i l y reacted with l i t h i u m dialkylcuprates to give the corresponding B-substituted-a,8-ethylenic ketones i n good y i e l d s . I t i s i n t e r e s t i n g to note that 318 was smoothly converted into 323 upon treatment with l i t h i u m di-t-butylcuprate. This contrasts with the r e s u l t observed for the B-keto ester enol phosphate 267 and i s consistent with the suggested intermediary of 304 during the formation of 303 (see Table 9). It i s well known that organocuprates undergo conjugate a d d i t i o n to enones more e a s i l y than to enoate e s t e r s . 8 9 This can be a t t r i b u t e d to the lower ( i . e . , less-negative) E r g ^ of enones than that of the analogous a,B-unsaturated esters (cf. Table 3). Assuming that the increment to E ^ of a,8-ethylenic carbonyl compounds caused by a B-phosphoryloxy group i s ca. +0.1 V (vide supra), even the most highly substituted 8 -diketone enol 146 phosphates have of ca_. -2.1 V which i s compatible with the E q x of most l i t h i u m dialkylcuprates. This should broaden the scope of a p p l i c a t i o n of 1,3-dicarbonyl enol phosphates i n synthesis. Although coupling reactions of enol e t h e r s , 1 4 3 enol s u l f i d e s , 1 4 3 enol a c e t a t e s 1 4 2 3 and enol h a l i d e s 1 4 9 * 1 5 2 of 8-diketones with cuprate rea-gents have been achieved previously, the st e r e o s e l e c t i v e synthesis of the JE and Z isomers of such derivatives for a c y c l i c 8 - d i k e t o n e s 1 4 2 a and the reaction of the compounds with t e r t i a r y a l k y l c u p r a t e s 1 4 9 are rare. The present enol phosphate method not only provides a s t e r e o s e l e c t i v e route to the enol d e r i v a t i v e of 1,3-diketones, but also extends the spectrum of reac-tions with cuprate reagents. The s i m p l i c i t y and e f f i c i e n c y i n the prepara-t i o n of 1,3-dicarbonyl enol phosphates and t h e i r ready reaction with l i t h i u m dialkylcuprates should render such approach to 8-substituted enones a t t r a c t i v e . Mechanism and Scope of the Reaction of 1,3-Dicarbonyl Enol Phosphates with  Lithium Dialkylcuprates Based on the mechanism suggested by House for conjugate ad d i t i o n to unsaturated carbonyl compounds with c u p r a t e s , 1 4 5 b a four-stage mechanism was envisioned for the reaction between 1,3-dicarbonyl enol phosphates and l i t h i u m dialkylcuprates. As i l l u s t r a t e d by the Z^-enol phosphate 326 i n Scheme x x i i i , the f i r s t and second stages involve the transfer of an electron from the cuprate to the enol phosphate and the coupling of the r e s u l t i n g electron transfer complex to form intermediate LII. Expulsion of the phos-phoryloxy moiety i n L I I , followed by rearrangement 1 4 5' 3 of group R from the 147 Scheme x x i i i 3 2 7 I t has been suggested that dialkylcuprates should be formulated as dimers, R4Cu2Li2. 1 k 5 b The empirical formulas are adopted f o r s i m p l i c i t y . 148 R 2 C u L i OPO(OEt) 2 R o C u L i R M e O N R ,2 ( E tO) 2 OPO OPO(OEt) 2 LII LIII LIV cuprate to the carbonyl substrate to give 327 constitute the t h i r d and f i n a l stages of the process. An a n t i periplanar arrangement of the leaving group and the enolate TT-system i s presumably required during elimination of the phosphoryloxy group. This could be achieved by a r o t a t i o n about the C 2 - C 3 bond i n LI I , either v i a mode A (60° rotation) to give LIII or v i a mode B (120° rotation) to give LIV. According to the p r i n c i p l e of l e a s t m o t i o n , 1 5 5 the former conformational change leading to LIII i s favored. Furthermore, a serious s t e r i c i n t e r a c t i o n arises i n passing the bulky phosphate group through the enolate plane during the r o t a t i o n from LII to LIV (mode B), and would disfavor such conformational change. Similar arguments also apply to the reaction between E-enol phosphates and l i t h i u m dialkylcuprates. The mechanism depicted above accounts f o r the retention of geometry about the o l e f i n i c bond observed i n the cuprate reactions of 1,3-dicarbonyl enol phosphates. phosphates of 1,3-dicarbonyl compounds and t h e i r s t e r e o s p e c i f i c a l k y l a t i o n s with l i t h i u m dialkylcuprates constitute a v e r s a t i l e and s t e r e o s p e c i f i c route The f a c i l e and highly s t e r e o s e l e c t i v e syntheses of E- and Z-enol 149 to substituted alkenes (equation 20), This alkene synthesis combined with the dianion chemistry of 3-keto esters represent a useful synthetic t o o l . The u t i l i t y of t h i s methodology was p a r t i a l l y demonstrated i n the syntheses of natural products given i n Section I I I . The +0.1 V increment estimated f o r the e f f e c t of the phosphoryloxy substituent on E r e ( j i s of considerable value for determining the f e a s i b i l i t y of a p a r t i c u l a r reaction between an enol phosphate and a l i t h i u m d i a l k y l -cuprate. Such assessments would enable the use of more e f f e c t i v e cuprate reactions to accomplish the synthesis of more complex alkenes. 150 SECTION I I I : NATURAL PRODUCTS SYNTHESIS Introduction As stated i n the introduction of t h i s t h e s i s , one of the ultimate goals of our continuing e f f o r t i n exploring new synthetic methods based on 8 -keto esters i s the successful a p p l i c a t i o n of these methods to the syntheses of natural products. To i l l u s t r a t e , i n some aspects, the synthe-t i c u t i l i t y of the dianion chemistry of 8-keto esters as well as the c y c l i -zation and o l e f i n forming reactions developed e a r l i e r , we accomplished the stere o s e l e c t i v e t o t a l syntheses of three natural products using a combina-t i o n of the above methods. In the syntheses of these compounds, v i z . , L a t i a l u c i f e r i n , (E, E)-10-hydroxy-3,7-dimethyldeca-2,6-dienoic acid and mokupalide, the basic methyl acetoacetate synthon was u t i l i z e d r e p e t i t i v e l y and e f f i c i e n t l y to construct more complex molecules. A convenient way to introduce s t e r e o s e l e c t i v e l y the isoprene unit LV (equation 24) was also demonstrated. In p r i n c i p l e , the o v e r a l l transformation from methyl aceto-O O E (24) E LV E = elect rophile 151 (25) E 285 LV E = electrophile acetate to LV as shown by equation 24 i s equivalent to the conceptual regio- and ster e o s e l e c t i v e y - a l k y l a t i o n of the a ,B-unsaturated ester 285 (equation 25). Results and Discussion Synthesis of L a t i a L u c i f e r i n L a t i a l u c i f e r i n (328) i s a s p e c i f i c substrate of the bioluminesc-ence enzyme i n the fresh water limpet L a t i a n e r i l o i d e s . 1 6 6 The side-chain o l e f i n i n natural l u c i f e r i n has been shown to have the E geometry. Non-stere o s e l e c t i v e synthesis of L a t i a l u c i f e r i n , s t a r t i n g from 8-ionone, have been reported by two g r o u p s . 1 6 7 Magnus and Roy accomplished a t h i r d syn-thesis of l u c i f e r i n v i a an intermediary a,8-epoxysilane derived from dihydro-(3-ionone. 1 6 8 The l a s t route, though improved i n terms of s t e r e o s e l e c t i v i t y over the previous methods, also gave a mixture of isomeric products con-ta i n i n g ca,. 10% of Z. isomer. A s t e r e o s e l e c t i v e synthesis of l u c i f e r i n (328) was achieved, as shown i n Scheme xxiv, by using methyl acetoacetate as a f a c i l e isoprene b u i l d i n g block. Methyl B-cyclogeranate (248) was prepared by a sequence of 152 Scheme xxiv 95 97 1. NaH,CIPO(OEt ) 2 2. M e 0 C u L i 331 , 329 X - O H 248 1. NaH ,CIPO(OEt) 2 -:; -330 X=Br 2 M e 0 C u L i 328 334 153 reactions described e a r l i e r (vide supra). Thus, the dianion of methyl aceto-acetate was alkylated with d i m e t h y l a l l y l bromide to give 9_5 i n 85% y i e l d . Exposure of 9_5 to stannic ch l o r i d e produced the c y c l i c 8-keto ester 9_7 which, upon successive treatment with sodium hydride, d i e t h y l chlorophos-phate (DECP) and l i t h i u m dimethylcuprate afforded 248 i n 89% y i e l d from 95. Ester 248 was reduced to alcohol 3 2 9 1 6 9 almost q u a n t i t a t i v e l y with l i t h i u m aluminum hydride. Several methods were t r i e d to convert the hydroxy group i n 329 into a leaving group appropriate for dianion a l k y l a t i o n . While many p r o c e d u r e s 1 7 0 ' 1 7 1 ' 1 7 2 f a i l e d to give s a t i s f a c t o r y and reproducible r e s u l t s , i t was found that the bromide 330 could be e a s i l y prepared, i n over 80% y i e l d , by t r e a t i n g 329 with concentrated hydrobromic a c i d 3 2 ' and n-pentane i n a two-phase system at 0° C. The product so obtained was essen-t i a l l y pure according to spectroscopic a n a l y s i s . Due to i t s thermal i n s t a b i -l i t y , bromide 330 was used, immediately a f t e r preparation, to a l k y l a t e the dianion of methyl acetoacetate to give 331 i n ca_. 80% y i e l d . Conversion of 331 into i t s enol phosphate, followed by reaction with l i t h i u m dimethyl-cuprate (2 eq) at -78° C afforded the E-a,8-ethylenic ester 332 i n 93% y i e l d . No detectable amount of the isomer was observed by ^NMR and t i c analyses. Diisobutylaluminum hydride reduction of 332 furnished the corres-ponding alcohol 333 which was then oxidized, with active manganese d i o x i d e 1 ' 7 3 > 1 7 L f i n hexane, to the a,8-unsaturated aldehyde 334 i n good y i e l d . The s p e c t r a l data of 334 were i d e n t i c a l with those r e p o r t e d 1 6 7 b for the J£ isomer of t h i s compound. Since aldehyde 334 has been s t e r e o s e l e c t i v e l y transformed into the 154 formate 328 using anhydrous hydrogen peroxide and selenium d i o x i d e , 1 the above ste r e o s e l e c t i v e synthesis of 334 completed our approach to L a t i a l u c i f e r i n (328). Synthesis of (E_, E)-10-Hydroxy-3,7-dimethyldeca-2,6-dienoic Acid- A Major Component i n the H a i r p e n c i l Secretion of the Male Monarch B u t t e r f l y The major components i n the h a i r p e n c i l secretion of male danaid b u t t e r f l i e s have been i s o l a t e d and i d e n t i f i e d as a family of long chain unsaturated acids and a l c o h o l s . 1 7 5 Among them, the d i o l 3 3 7 1 7 6 from the queen b u t t e r f l y (p_. g i l i p p u s ) , and the hydroxy a c i d 335 1 7 7 and d i a c i d 3 3 6 1 7 8 from the monarch b u t t e r f l y (D. plexippus) represent three c l o s e l y related compounds whose exact functions s t i l l remain unknown. Since i t i s a formidable task to acquire even minute quantities of these substances 336 337 from the natural source, e l u c i d a t i o n of t h e i r b i o l o g i c a l a c t i v i t i e s I t involved the extraction of thousands of b u t t e r f l y h a i r p e n c i l s to obtain merely milligrams of these compounds. 1 7 5 - 1 7 8 155 c a l l s for i n v i t r o preparation of the n a t u r a l compounds. P a r t i a l syntheses of d i o l 3 3 7 1 7 6 and d i a c i d 3 3 6 1 7 8 from trans,  trans-farnesol have been reported by Meinwald et a l . ; however, d e t a i l s of these syntheses were not described. In a l a t e r p u b l i c a t i o n , Meinwald and J o h n s o n 1 7 9 j o i n t l y reported an improved route to 336 and 337 v i a the common intermediate, diester 338, prepared by a five-step sequence from a c r o l e i n dimethyl a c e t a l (339). One serious drawback i n the synthesis of 338 was the low s t e r e o s e l e c t i v i t y observed i n a Wittig-type reaction. Hydroxy acid 335 was also synthesized i n moderate y i e l d from 337 by a two-step transformation which comprised a s e l e c t i v e s i l v e r oxide oxidation. Katzenellen-bogen and C h r i s t y 1 8 0 accomplished a s t e r e o s e l e c t i v e synthesis of d i o l 337, 33 6 339 338 3 3 7 > 3 3 5 i n s i x steps from geraniol, using the [3,3 ]-sigmatropic rearrangement of an a l l y l s i l o x y v i n y l ether intermediate as the key step. Unfortunately, this synthetic scheme was tarnished by a poor y i e l d i n g ozonolysis reaction. By employing the alkene synthesis developed e a r l i e r , we were able to synthesize hydroxy, acid 335 i n an e f f i c i e n t and highly s t e r e o s e l e c t i v e manner (Scheme xxv). Hydroxy acid 335 may be regarded as a precursor to 156 Scheme xxv NaH, DECP ; L1AIH4, E t 2 o ; OH" , H 20 ; b d f Me 2CuLi : (2 eq) ; Li B r , n-BuLi, MeS0 2Cl ; HC1, H 20 157 both d i a c i d 336 and d i o l 337. In f a c t , Melnwald and coworkers have shown that 335 could be converted into d i a c i d 3 3 6 1 7 8 by the Cornforth oxidation method 1 8 1 and into d i o l 3 3 7 1 7 7 by reduction with l i t h i u m aluminum hydride. The tetrahydropyranyl ether of 2-bromoethanol, 340, was allowed to react with two equivalents of the dianion of methyl acetoacetate to give 277 i n 75% y i e l d (based on 340 used). A lower y i e l d (ca. 50%) of the desired product 277 and a s i g n i f i c a n t amount (ca. 30%) of recovered 340 were observed when equivalent amounts of the two reactants were used. The g-keto ester 277 was then converted into i t s enol phosphate and treated with l i t h i u m dimethylcurpate at -78 to -47° C to produce the E-a,g-ethylenic ester 287 i n greater than 82% y i e l d . Subsequent reduction of the ester with l i t h i u m aluminum hydride afforded the a l l y l i c alcohol 341 i n excellent y i e l d . The 13CNMR of d i o l 342, derived from cleavage (p-toluenesulfonic acid, methanol) of the tetrahydropyranyl ether protecting group i n 341, showed absorptions at 6 16.2 and 35.8 ppm, ascribable to Cy and CL,. respec-t i v e l y . These chemical s h i f t s were consistent with the data reported f o r such carbons i n s i m i l a r a l l y l i c alcohols with the E geometry 1 8 2 and provided a d d i t i o n a l evidence for the E configuration of the o l e f i n i c bond i n ester 287. 7 342 158 I n c o r p o r a t i o n of the second isoprene moiety was e f f e c t e d by con-v e r s i o n of a l c o h o l 341 i n t o the corresponding bromide 343, followed by r e p e t i t i o n of the foregoing r e a c t i o n sequence of d i a n i o n a l k y l a t i o n , enol phosphate formation and l i t h i u m dimethylcuprate coupling. S e v e r a l bromina-t i o n m e t h o d s 1 7 1 > 1 8 3 were found u n s a t i s f a c t o r y f o r the p r e p a r a t i o n of bro-mide 343. However, the d i f f i c u l t y was circumvented by adopting Corey's p r o c e d u r e 1 7 0 which i n v o l v e d t r e a t i n g a mixture of a l c o h o l 341 and l i t h i u m bromide i n ether w i t h n - b u t y l l i t h i u m and methanesulfonyl c h l o r i d e at -78° C to room temperature. The bromide 343, owing to i t s unstable nature, was used immediately to a l k y l a t e an excess of the d i a n i o n of methyl acetoacetate. 3-Keto e s t e r 344 was thus obtained i n 70% y i e l d o v e r a l l from a l c o h o l 341. Transformation of 344 i n t o the d i e n i c e s t e r 345 was accomplished i n 92%; y i e l d by u t i l i z i n g the usual enol phosphate and cuprate coupling sequence. To complete the s y n t h e s i s , e s t e r 345 was hydrolyzed w i t h aqueous base, and then t r e a t e d w i t h aqueous a c i d to give the d e s i r e d hydroxy a c i d 335 i n 91% y i e l d . The s p e c t r a l data of 335 were i n e x c e l l e n t agreement w i t h those o r i g i n a l l y reported f o r the n a t u r a l compound. 1 7 7 As a f i n a l c o r r o b o r a t i o n of the s t r u c t u r a l assignments, the tet r a h y d r o p y r a n y l ether p r o t e c t i n g group i n 345 was cleaved (p_-toluenesulfonic a c i d , methanol) to give a l c o h o l 346 whose spe c t r o s c o p i c and chromatographic p r o p e r t i e s were found to be id e n -t i c a l w i t h those of an au t h e n t i c sample. 1 7 7'^ 1°) ( 1 Q) The sp e c t r a and a sample of the methyl e s t e r of 335 were acquired from Dr. C. Semmelhack and Professo r J . Meinwald. 159 345 346 The above synthesis of 335 represents an improvement over the previous routes and demonstrates the synthetic u t i l i t y of 8-keto esters and t h e i r enol phosphates i n the st e r e o s e l e c t i v e synthesis of t r i s u b s t i -tuted alkenes. I t i s also worth noting that during a large scale preparation, i n which the intermediates 287, 341, 344 and 345 were p u r i f i e d simply by evaporative bulb-to-bulb d i s t i l l a t i o n , the alcohol 346 obtained from 345 was found to have a 95% purity of the (E, E)-isomer by vpc an a l y s i s . This r e s u l t implicated that each of the two enol phosphate formation and l i t h i u m dimethylcuprate coupling sequences produced at l e a s t 97% of the correspond-ing E-a,8-unsaturated ester. Synthesis of Mokupalide - a Hexaprenoid from a Marine Sponge Recent investigations i n the chemistry of marine organisms have led to the discovery of numerous novel compounds, most of which have unique s t r u c t u r a l f e a t u r e s . 1 8 4 In the past decade or so, the r a p i d l y growing com-p i l a t i o n of marine natural compounds has opened a new area i n natural products c h e m i s t r y . 1 8 5 The i n t e r e s t i n g b i o l o g i c a l a c t i v i t i e s of many of these com-pounds have attracted increased a t t e n t i o n from organic chemists. In addi-t i o n , the d i v e r s i t y as well as the novelty i n t h e i r structure are of great 160 i n t e r e s t and provide a new challenge to synthetic chemists. The s t r u c t u r a l e l u c i d a t i o n of many marine natural compounds with complex structures often requires t o t a l synthesis as an ultimate, unambiguous proof. Recently, Scheuer and Yunker i s o l a t e d from a P a c i f i c marine sponge three novel hexaprenoids which were a r b i t r a r i l y named mokupalide, hydroxy-mokupalide and acetoxymokupalide. 1 8 6 The mokupalides were shown to have structures 347 - 349 which contained an unusual array of s i x isoprene u n i t s joined together i n a h e a d - t o - t a i l fashion. Our i n t e r e s t i n exploring the 347 R = H ; 348 R = OH ; 349 R = OAc synthetic u t i l i t y of the newly developed 8-keto ester chemistry prompted our e f f o r t to prepare mokupalide 347. A b r i e f examination of structure 347 revealed three major syn-t h e t i c objectives, v i z . , construction of the cyclohexene moiety, stereo-s e l e c t i v e synthesis of the three o l e f i n i c linkages with E geometry and incorporation of the butenolide end group. Accordingly, the target mole-cule was envisioned to be composed of three u n i t s , A, B and C, as shown below. 161 The design of our synthetic route centred upon the separate syntheses of these i n d i v i d u a l units which were assembled at appropriate stages v i a carbon-carbon bond formation. In devising the present synthesis, the mokupalide molecule was a n t i t h e t i c a l l y dissected into the butenolide C' and the hydrocarbon D (Figure 1). By employing s u i t a b l e f u n c t i o n a l i t i e s for W and Z, C and D could be joined together to give, a f t e r removal of the extra f u n c t i o n a l groups, mokupalide (347). The combination of C' and D might be effected by a l k y l a t i n g the anion of C with D or v i c e versa. S i m i l a r l y , D could be derived from the cyclohexene d e r i v a t i v e A' and the long chain t r i e n e B'. Based on the above considerations, the conceptual scheme depicted i n Figure 1 was adopted. 347 Figure 1. Strategy f o r the Synthesis of 347 . 162 A preliminary study was undertaken to determine what function-a l i t y X ( i n A') might be in. order to f u l f i l the desired purpose. A' was at f i r s t conceived as the nucleophile i n the coupling with B'. The phenylthio group appeared to be an i d e a l candidate for X i n t h i s regard. The carbanion of a l l y l phenylthio ethers has been reported to undergo a l k y l a t i o n with a l k y l h a l i d e s . 1 8 7 Furthermore, the a l l y l i c phenylthio moiety could be r e a d i l y removed by reductive c l e a v a g e . 1 8 7 This methodology (equation 26), developed by Biellmann and Ducep, has also been s u c c e s s f u l l y (26) u t i l i z e d by van Tamelen et a l . i n t h e i r j u v e n i l e hormone 1 8 8 and triterpene-^ Z syntheses. S u l f i d e 350 was synthesized i n good y i e l d by t r e a t i n g alcohol 329 (prepared as described before) sequentially with n-butyllithium, methane-s u l f o n y l c h l o r i d e and l i t h i u m thiophenoxide (generated from benzenthiol and n-butyllithium i n T H F ) . 1 8 8 To t e s t the f e a s i b i l i t y of carbanion a l k y l a t i o n of 350, l-bromo-3-methyl-2-butene was used as a model a l k y l a t i n g agent. Exposure of 350 to a 1:1 mixture of methyllithium and diazabicyclo[2.2.2] octane (DABCO), 1 8 7 followed by treatment with d i m e t h y l a l l y l bromide, yielded 163 mainly recovered s t a r t i n g m aterial. The f a i l u r e i n a l k y l a t i o n of 350 was found to a r i s e from unsuccessful generation of the carbanion. This was shown by a serie s of investigations i n which s u l f i d e 350 was exposed to strong bases (MeLi, MeLi-DABCO, jt-BuLi) under various conditions and sub-sequently quenched with deuterium oxide. In a l l cases, no s i g n i f i c a n t deuterium incorporation was detected by spectroscopic analyses. S t e r i c e f f e c t of the methyl groups was suspected to be the cause for the reluctance of 350 to form the a l l y l i c carbanion. I t was then decided to use bromide 330 as the a l k y l a t i n g agent and B' as the nucleophile i n the f i r s t coupling step (see Figure 1). F o l -lowing the same idea of using an a l l y l phenylsulfide carbanion i n the a l k y l a -t i o n step, s u l f i d e 355 was conceived to play the r o l e of B'. A stereo-s e l e c t i v e synthesis of 355 was achieved as described i n Scheme xx v i . The dianion of methyl acetoacetate (1.2 eq) was alkylated with geranyl bromide 164 Scheme xxyi 0 0 M e C 0 2 M e 2 78 1. NaH , C I P O ( O E t ) 2 2 M e 2 C u L i OoMe t-BuOOH ^ is . 12 S e 0 o M e S 0 2 C I , E t 3 N 288 O S C 2 M e 3 5 2 Q 2 M e PhSL i SPh 353 0 2 M e D I B A L SPh 355 OTHP DH P, H + SPh OH 354 165 ( p r e p a r e d by p h o s p h o r o u s t r i b r o m i d e b r o m i n a t i o n o f g e r a n i o l ) t o g i v e 278 i n 95% y i e l d . The 8 - k e t o e s t e r 278 was s t e r e o s e l e c t i v e l y c o n v e r t e d i n t o t h e Z_-enol p h o s p h a t e w h i c h was c o u p l e d w i t h l i t h i u m d i m e t h y l c u p r a t e t o a f f o r d (E_, E ) - m e t h y l f a r n e s o a t e (288) . The above s e q u e n c e i n v a r i a b l y p r o c e e d e d i n g r e a t e r t h a n 90% y i e l d and w i t h g r e a t e r t h a n 98% s t e r e o s e l e c -t i v i t y . T h i s s y n t h e s i s o f ( E , E ) - m e t h y l f a r n e s o a t e showed marked i m p r o v e -ment o v e r a p r e v i o u s r o u t e r e p o r t e d by K o b a y a s h i e t a l . 8 2 ' ' v i a t h i o e t h e r s d e r i v e d f r o m a c e t y l e n e s . The i d e a o f r e g i o s e l e c t i v e o x i d a t i o n was a d o p t e d f o r t h e s e l e c t i v e f u n c t i o n a l i z a t i o n o f C - 1 2 i n 2 8 8 . R e g i o s e l e c t i v i t y i n t h e a l l y l i c o x i d a t i o n o f o l e f i n s w i t h s e l e n i u m d i o x i d e h a s been e x t e n s i v e l y demons t r a t e d . 1 8 9 I n g e n e r a l , t r i s u b s t i t u t e d o l e f i n s w i t h t e r m i n a l d i m e t h y l g r o u p s c a n be o x i d i z e d t o g i v e p r e d o m i n a n t l y E_ a l c o h o l s o r a l d e h y d e s ( e q u a t i o n 2 7 ) . T h i s method OH CHO (27) has been u s e d t o c o n v e r t g e r a n y l a c e t a t e i n t o t h e c o r r e s p o n d i n g a l d e h y d e 3 5 6 1 9 0 w h i c h a f t e r sod ium b o r o h y d r i d e r e d u c t i o n gave a l c o h o l 357 i n s a t i s -f a c t o r y y i e l d ( 4 0 % ) . 1 9 1 T h e o r e t i c a l c o n s i d e r a t i o n s b a s e d on t h e r e p o r t e d f i n d i n g s 1 8 9 p r e s a g e d p l a u s i b l e s e l e c t i v e o x i d a t i o n o f C - 1 2 i n 288 w i t h s e l e n i u m d i o x i d e . E l e c t r o n d e f i c i e n c y o f t h e C - 2 , C - 3 d o u b l e bond due t o 166 conjugation with carbomethoxy group would disfavor a l l y l i c oxidation at C-4. Oxidation at C-8 and C-12 are both m e c h a n i s t i c a l l y 1 8 9 favorable; however, the s t e r i c a l l y less hindered C-12 i s expected to be more susceptible to attack by the o x i d i z i n g agent. The oxidation of 288 with selenium dioxide i n r e f l u x i n g e t h a n o l 1 9 0 gave unsatisfactory r e s u l t s . A modified procedure, developed byUmbreif and S l i a r p l e s s 1 9 2 Involving jt-butyl hydroperoxide and a c a t a l y t i c (or s t o i c h i o -metric) amount of selenium dioxide was then employed. I t was hoped that the mild reaction conditions of t h i s modification might a l l e v i a t e the compli-cations encountered i n using excess selenium dioxide and r e f l u x i n g ethanol. Indeed, by t r e a t i n g 288 with selenium dioxide (0.5 eq) and 70% _t-butyl hydroperoxide^ 1^ (2 eq) i n dichloromethane (4.5 hr, 10° C), the a l l y l i c ^ l l j 90% t-BuOOH was used i n the report by Sharpless et a l . 1 9 2 However, we found that the commercial 70% t-BuOOH was also adequate. l b / alcohol 351 was obtained i n 41% y i e l d along with the regioisomer 358 (8%), the aldehyde 359 (5%) and recovered 288 (19%), Careful monitoring 288 of the reaction conditions was c r u c i a l f o r good r e s u l t s as higher tempera-tures and prolonged r e a c t i o n times led to s i g n i f i c a n t formation of the aldehyde product and le s s e f f i c i e n t conversion into the desired alcohol 351. The regiochemistry of the hydroxy group i n structures 351 and 358 was established by analysis of t h e i r 1HNMR and mass spe c t r a l data. The 1HNMR spectrum of 351 ( i n CCIO showed absorptions at 6 1.60 (s, 3H), 3.83 (s, 2 H) and 5.25 (m, I H ) which were ascribed to protons at C-13, C-12 and C-10 resp e c t i v e l y . Comparison of these data with those reported for the analogous a l l y l i c alcohols E- and Z - 3 6 0 1 2 1 » 1 8 9 (Figure 2, chemical s h i f t s indicated were measured i n CCli*) confirmed the E geometry of the C-10 o l e f i n i c bond i n 351. Prominent mass fragments at m/e 181 and 149 (181 - CH40) (see Figure 2) i n the mass spectrum of 351 also supported the assigned terminal alcohol structure. Alcohol 358 exhibited a t r i p l e t (J = 7 Hz) at 6 3.93. (IH) and a mu l t i p l e t at 6 5.3 (1 H) i n i t s 1HNMR spectrum, which were consistent with absorptions expected f o r protons at 351 6 1.60 6 1.73 C H 2 O H 6 4.00 H « — 6 5.17 E -360 Z -360 Figure 2. Some *HNMR and Mass Spectral Data Related to 351 . C-8 and C-6 i n the suggested structure. The p o s i t i o n of the hydroxy group i n 358 was further substantiated by mass spectroscopy which showed major mass peaks at m/e 197, 165 (197 - CH40) and 113, corresponding to the C 0 2 M e 358 169 fragmentations illustrated above. The structure of aldehyde 359 was ascer tained by comparing i t s 1HNMR absorptions at 6 1.73 (s, 3H), 6.37 (m, IH) and 9.3 (d, 1H) , attributed to the C-13, C-10 and C-12 protons, with those recorded for structure 361. 1 2 0 >19 3 6 1.67 6 H ±- 6 6.37 3 6 1 The a l l y l i c alcohol 351 was converted 1 7 2 into the corresponding mesylate 352, which was immediately treated with lithium thiophenoxide in tetrahydrofuran to give sulfide 353 in 93% overall yield. The ester func-tion in 353 was reduced with diisobutylaluminum hydride at -23° C, and the resulting alcohol 354 was protected as the tetrahydropyranyl ether furnish-ing 355 in 95% yield. The two compounds 330 and 355, representing the subunits A' and B' (Figure 1), were assembled as shown in Scheme xxvii. The anion of 355, generated by n-butyllithium in the presence of DABCO187 (THF, -23° C), was alkylated with bromide 330 to produce the a-alkylation product 362 in 75% yield. Biellmann and Ducep have shown that lithium in ethylamine was super-ior to other methods (Raney nickel, calcium-hexamine, and lithium in ammonia) for the reductive desulfurization of a l l y l i c sulfide in polyene molecules. 1 8 7 1/U Scheme x x v i i 363 R = T H P 3 6 4 R - H 171 However, i t i s quite inconvenient to u t i l i z e t h i s method i n small scale reactions. A n i c k e l c a t a l y s t , prepared from n i c k e l (II) c h l o r i d e and sodium borohydride/ 1 2^has been developed by Truce and Roberts-to d e s u l f u r i z e t h i o k e t a l s . 1 9 4 This so-called n i c k e l boride reagent was l a t e r applied to r eductively cleave benzylthio enol e t h e r s . 1 9 5 The f a c i l i t y i n the preparation and handling of t h i s reagent intrigued our i n t e r e s t i n t e s t i n g i t s effectiveness i n the d e s u l f u r i z a t i o n of the a l l y l i c s u l f i d e 362. In-deed, when 362 was exposed to excess n i c k e l boride i n ethanol, the desul-f u r i z e d compound 363 was obtained i n £a. 72% y i e l d . The hydroxy group was subsequently deprotected to give alcohol 364. The bromination of 3-methyl-2-butenolide (365) to give bromide 366 was f i r s t envisioned as a possible route for the construction of the subunit C' (see Figure 1). According to r e s u l t s we had secured i n an inves-t i g a t i o n related to s t e r o i d a l cardenolides, N-bromosuccinimide (NBS) bromina-The black p r e c i p i t a t e prepared i n t h i s manner has been named " n i c k e l boride." 172 t i o n of the model system 367 (prepared as described i n Scheme x x v i i i ) produced r e g i o s e l e c t i v e l y the bromide 368 i n 74% y i e l d . Bromination of the butenolide moiety was not detected. Nevertheless, the NBS bromination 367 368 of 365 gave r i s e to bromobutenolide 369 instead of 366. 1 9 6 The remarkably d i f f e r e n t outcomes for 365 and 367 i n t h i s type of bromination probably r e f l e c t s the diff e r e n c e i n r e a c t i v i t y between primary, secondary and t e r t i a r y hydrogens towards free r a d i c a l a b s t r a c t i o n . 1 9 7 NBS > o CCI 4 ' 7: ^ 365 369 Since the preparation of a s u i t a b l e C' unit from 365 seemed un-l i k e l y , a route to butenolide 366 (Scheme xxix) reported recently by Martin et a l . 1 9 6 was adopted. Thus, methyl 3-methylbut-2-enoate (285) was bromi-nated with NBS i n carbon t e t r a c h l o r i d e to give the dibromo ester 374, which was converted to bromo butenolide 366 with 48% hydrobromic acid i n s a t i s f a c t o r y o v e r a l l y i e l d . 173 174 Scheme xxix C Q 2 Me N B S > C C L C Q 2 M e 285 374 48 °/o H Br P h S 0 2 Na DMF S 0 2 P h Br 375 366 In a preliminary attempt to assemble the subunits D and C' (Figure 1), the carbanion of the phenylthio ether derived from 364 .(-OH =£> SPh) was treated with the bromo butenolide 366. Only s t a r t i n g materials were recovered from t h i s reaction. Presumably, proton exchange between the butenolide and the thio ether carbanion occurred f a s t e r than 175 the desired a l k y l a t i o n . On the basis of t h i s r e s u l t , i t appeared more f e a s i b l e to use C' as the nucleophile and D as the a l k y l a t i n g agent i n the assembling process. J u l i a and Arnould achieved the .selective y - a l k y l a t i o n . of - the*, a, 3-unsaturated ester 376 with l-bromo-3-methyl-2-butene, i n tetrahydrofuran, using potassium _t-butoxide as b a s e . 1 9 8 The y- and a - a l k y l a t i o n products, 377 (a mixture of E_ and Z_ isomers) and 378, were obtained i n a r a t i o of 89:11. More recently, the anion of y-phenylsulfonyl-a,8-unsaturated 378 ketones were also reported to undergo s e l e c t i v e y - a l k y l a t i o n s with a l k y l halides i n polar solvent systems. 1 9 9 The s u l f o n y l butenolide 375 was therefore chosen to introduce the butenolide end group i n the f i n a l coupling step. Treatment of bromide 366 with sodium benzenesulfinate i n dimethyl-formamide (DMF) at ambient temperature afforded the sulfone 375 i n 85% 176 y i e l d . A l k y l a t i o n of the anion derived from 375 and sodium hydride (or potassium Ji-butoxide 1 9 9 b ) i n DMF (or _t-butanol) i n v a r i a b l y gave s i g n i -f i c a n t quantities of the d i a l k y l a t e d product 380. This complication was a l l e v i a t e d by employing an excess of the s u l f o n y l anion i n the a l k y l a t i o n . With such modification, a markedly improved y i e l d of the desired product 379 was attained. Scheme xxx i l l u s t r a t e d the completion of the f i n a l assembling process i n the synthesis of mokupalide (347). Alcohol 364 was converted into the bromide 381 v i a successive treatment with l i t h i u m bromide, n-b u t y l l i t h i u m and methanesulfonyl c h l o r i d e at -78 to 25° C . 1 7 0 This unstable bromide was immediately alkylated with an excess of the anion of sulfone 375 i n DMF at room temperature to produce the coupled compound 382 i n 60% y i e l d from alcohol 364. The s u l f o n y l group i n 382 was removed redu c t i v e l y with 6% sodium amalgam 2 0 0 i n methanol at -10° C to give i n greater than 80% y i e l d of mokupalide (347). The IR,.1HNMR and mass spe c t r a l data of t h i s synthetic product were i d e n t i c a l with those of the natural compound. ^ 3^ ^ 3^ Copies of the spectra of mokupalide were obtained from Professor Scheuer and Dr. Yunker. 1 7 7 Scheme xxx 364 Li Br n-Bu Li , MsCI v N a - H g v 3 4 7 The above synthesis represents the f i r s t synthetic approach to mokupalide (347) which possibly can lead to hydroxymokupalide (348), and hence acetoxymokupalide (349), v i a f u n c t i o n a l i z a t i o n of the butenolide moiety. 178 CONCLUSIONS The syntheses of natural products presented i n t h i s thesis demon-strates the a p p l i c a t i o n of only l i m i t e d aspects of the r e s u l t s from the c y c l i z a t i o n study and the alkene synthesis. P o t e n t i a l u t i l i t y of the findings other than those already employed s t i l l remains to be explored. While our e x p l o i t a t i o n of the scope of the new alkene synthesis i s by no means thorough, possible extension of the present r e s u l t s to various cuprate reagents and other 1,3-dicarbonyl substrates, such as 8-keto aldehydes and 8-keto lactones, w i l l c e r t a i n l y be the object of future i n v e s t i g a t i o n s . 179 EXPERIMENTAL SECTION A l l temperatures are stated i n degrees centigrade. Melting points were determined on a Kofl e r hot stage microscope and are uncorrected. Kugelrohr d i s t i l l a t i o n s were performed by means of a Biichi Kugelrohr thermo-sta t . Infrared spectra were recorded i n chloroform s o l u t i o n (unless other-wise noted), on Perkin-Elmer Model 700 or 710B spectrophotometers, and were c a l i b r a t e d with the 1601 cm - 1 band of polystyrene. Proton nuclear magnetic resonance spectra were recorded on Varian Model T-60, HA-100 or XL-100 spectrometers, i n deuterochloroform s o l u t i o n unless otherwise s p e c i f i e d . Chemical s h i f t s are reported i n the 6 scale using tetramethylsilane as an i n t e r n a l standard. The m u l t i p l i c i t y , coupling constants ( i f observable) and integrated peak area are indicated i n parenthesis a f t e r each s i g n a l . Low r e s o l u t i o n mass spectra were recorded on an Atlas CH-4B mass spectro-meter, and high r e s o l u t i o n mass measurements were obtained using an AEI MS-9 or MS-50 mass spectrometer. A l l instruments were operated at an i o n i z i n g p o t e n t i a l of 70 eV. A l l mass measurements are reported i n atomic mass un i t s . Elemental microanalyses were performed by Mr. Peter Borda, University of B r i t i s h Columbia. The s i l i c a g el used was supplied by E. Merck. S i l i c a Gel PF-254 was used f o r both a n a l y t i c a l and preparative t h i n layer chromatography, whilst the grade 100-200 mesh ASTM was used f o r column chromatography. V i s u a l i z a t i o n of spots or bands on t i c plates was accom-plished by u l t r a v i o l e t l i g h t and/or with iodine vapor s t a i n i n g . A l l solvent systems are expressed i n r a t i o s by volume (v/v). Vapor-phase chromatographic 180 analyses were conducted on a Hewlett-Packard Model 5830-A chromatograph using 6 f t . x 1/8 i n . columns of 3% OV-17 or 3% OV-101. The petroleum ether used has the b o i l i n g range 30-60°. Dry e t h y l ether and tetrahydrofuran were obtained by d i s t i l l a t i o n from l i t h i u m aluminum hydride. Dichloromethane and methanesulfonyl .chloride were dried by d i s t i l l i n g from phosphorous pentoxide.. Dry dimethylformamide and hexa-methylphosphoramide were obtained by r e f l u x i n g over calcium hydride, f o l -lowed by d i s t i l l a t i o n under reduced, pressure.. Triethylamine was p u r i f i e d and dried by d i s t i l l i n g from barium oxide. The anhydrous stannic chloride used was reagent grade material purchased from Fisher S c i e n t i f i c Company Ltd. D i e t h y l chlorophosphate supplied by A l d r i c h Chemical Company, Inc. was used d i r e c t l y without p u r i f i c a t i o n and was handled under dry nitrogen atmosphere at a l l times. Methyllithium ( i n ether), n-butyllithium ( i n hexane) and sec-butyllithium ( i n cyclohexane) were obtained from A l d r i c h Chemical Company, Inc. , while e t h y l l i t h i u m ( i n benzene) and t - b u t y l -l i t h i u m ( i n pentane) were supplied by A l f a D i v i s i o n , Ventroh Corporation. The a l k y l l i t h i u m solutions were standardized by t i t r a t i o n against a 1.0 M so l u t i o n of _t-butanol i n benzene, using 1,10-phenanthroline as i n d i c a t o r . Sodium hydride (from A l f a D i v i s i o n , Ventron Corporation) was weighed as a 50% dispersion i n mineral o i l and was washed with dry ether to remove the o i l p r i o r to use. 181 SECTION I Preparation and C y c l i z a t i o n of Unsaturated B-Keto Esters General Procedure for the Generation of the Dianion of B-Keto  E s t e r s . 1 - The B-keto ester, dissolved i n dry tetrahydrofuran, was added to a suspension of sodium hydride (1.1 eq) i n the same solvent under a dry nitrogen atmosphere, and with cooling i n an i c e bath. The r e s u l t i n g mixture was s t i r r e d at 0° for 15 min followed by dropwise addition of a s o l u t i o n of ri-butyllithium (1.05 eq) i n hexane. This dianion so l u t i o n was s t i r r e d f o r . another 15 - 20 min at 0° before use. Methyl 3-0xohept-6-enoate (86). - A dianion s o l u t i o n , prepared from 5.806 g (50 mmole) of methyl acetoacetate, 2.64 g (55 mmole) of sodium hydride (50% mineral o i l ) and 32.8 ml (52.5 mmole) of n-butyllithium (1.6 M i n hexane), i n 125 ml of dry tetrahydrofuran was treated with 7.26 g (60 mmole) of a l l y l bromide at 0°. The mixture was s t i r r e d f o r 5 min at the same temperature and for 20 min at room temperature. The r e a c t i o n was then quenched with 100 ml of brine, 10 ml of concentrated hydrochloric acid and 100 ml of ethyl ether, and the aqueous phase was separated and extracted with 2 x 100 ml of ethyl ether. The combined extracts were washed with brine and dried over anhydrous magnesium s u l f a t e . Removal of solvents under reduced pressure gave 7.21 g of crude product which was d i s t i l l e d through a Vigreux column (3 cm) to a f f o r d 6.40 g (82%) of 86_ as a c o l o r l e s s l i q u i d : bp 77-78°/2.2 Torr ( l i t . 1 bp 99-100°/15 Torn):; IR 1742, 1715 and 1640 cm - 1; 1HNMR 6 2.03-2.8 (m, 4H), 3.42 (s, 2H), 3.70 (s, 3H), 4.77 -5.17 (m, 2H) and 5.46-6.1 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 182 156(10), 124(18), 101(50), 83(36), 82(57), 69(32), 59(48), 57(15), 55(100), 54(45), 43(76), 42(20) and 41(27). Methyl 6-Chloro-3-oxo-7-phenylselenenylheptanoate (87). - To a so l u t i o n of 310 mg (1.62 mmole) of phenylselenenyl chloride i n dry d i c h l o r o -methane, kept at 0° and under a dry nitrogen atmosphere, was added 251 mg (1.61 mmole) of methyl 3-oxohept-6-enoate (86) with s t i r r i n g . The r e s u l t i n g s o l u t i o n was maintained at 0° for 1 hr and then at room temperature for 30 min. The solvent was subsequently removed from the re a c t i o n mixture i n vacuo to give 562 mg (ca. 100%) of crude 87_ as an orange o i l : IR 1742, 1715, 1580 and 1475 cm"1; 1HNMR 6 2.1 (m, 2H), 2.7 (m, 2H), 3.25 (br d, J = 4 Hz, 2H), 3.38 (s, 2H), 3.68 (s, 3H), 4.1 (m, IH), 7.2 (m, 3H), and 7.5 (m, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 348(11), 316(28), 314(79), 312(80), 311(29), 310(49), 309(17), 308(19), 234(22), 232(17)-, 159(26), 158(40), 157(100), 156(55), 155(70), 154(45), 153(23), 124(57), 123(72), 101(74), 95(22), 83(54), 82(82), 78(41), 77(76), 69(40), 59(60), 55(94), 54(41), 51(33), 43(45) and 41(25). High Resolution Mass Measurement Calcd for C i 4 H X 7 3 5 C 1 0 3 8 ° S e : 348.0026. Found: 348.0021. Methyl a- (E_-Tetrahydro-5-phenylselenenylmethyl-2-furylidene)-acetate (88) and Methyl a-(Tetrahydro-2-hydroxy-5-phenylselenenylmethyl-furan-2-yl)acetate (89). - The crude product 87_ (560 mg) was chromatographed on a column of s i l i c a gel (100-200 mesh). E l u t i o n with a 10:1 mixture of carbon t e t r a c h l o r i d e and ethyl ether gave two c y c l i z e d compounds, i n order 183 of increasing retention time:- (a) 341 mg (68%) of 88_: c o l o r l e s s l i q u i d ; IR 1700, 1640, 1580, 1475 and 1120 cm"1; 1HNMR 6 1.6-2.4 (m, 2H), 3.1 (br d, J = 4.4 Hz, 2H), 2.7-3.4 (m, 2H), 3.60 (s, 3H), 4.52 (m, IH), 5.17 (t, J = 1.6 Hz, IH), 7.2 (m, 3H) and 7.5 (m, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 314(10.4), 312(52), 310(25.5), 309(8.5), 308(9.5), 306(0.9), 281(10), 280(9), 157(30), 155(71), 123(100), 101(26), 95(26), 91(15), 85(17), 81(20), 77(23), 69(32), 59(18), 55(33), and 51(14). Anal. Calcd for C l l tH 1 60 3Se: C, 54.03; H, 5.18. Found: C, 53.80; H, 5.20. (b) 144 mg (27%) of 89_: c o l o r l e s s l i q u i d ; IR 3530, 1720, 1580 and 1475 cm"1; 1HNMR 6 1.53-2.3 (m, 4H), 2.68 (s, 2H), 3.0 (m, 2H), 3.67 ( s i , 3H), 4.33 (m, IH), 7.2 (m, 3H) and 7.5 (m, 2H); mass spectrum m/e ( r e l in t e n s i t y ) 332(9.2), 330(47), 328(21.8), 327(7.5), 326(8.4), 324(0.8), 312(8), 256(14), 172(36), 170(20), 159(39), 157(21), 155(24), 149(14), 141(100), 127(23), 99(21), 91(16), 85(51) and 55(21). High Resolution Mass Measurement Calcd f o r Ci ^ H i 8 O i l 8 0 S e : 330.0370. Found: 330.0351. Reaction of Methyl 3-0xohept-6-enoate (86) with Mercuric Acetate. -To a s t i r r e d suspension of 160 mg (0.5 mmole) of mercuric acetate i n dry tetrahydrofuran (2 ml) was added 78 mg (0.5 mmole) of 86_ i n a small volume of the same solvent. The mixture turned into a so l u t i o n i n £a. 1 min and af t e r ca. 30 min at room temperature, a g e l a t i n e - l i k e suspension was formed. S t i r r i n g was continued for another 2 hr and then the solvent was removed 184 under reduced pressure. The residue was evaporated at high vacuum (0.05 Torr) for several hours at ambient temperature to give 179 mg of 91: yellow o i l ; IR 1700, 1640 and 1565 cm - 1; 1HNMR 6 1.6-2.4 (m, ca. 2H), 62 2.03 (s, ca. 3H), 2.23 (d, J = 7 Hz, 2H)' ,2.6-3.4 (m, ca. 2H), 3.62 (s, 3H), 4.6 (m, IH) and 5.22 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 204(4), 202(17), 201(7), 200(13), 199(10), 198(6), 156(13), 155(9) , 124(17), 123(8), 101(22), 83(15), 82(21), 69(14), 60(84), 59!(16), 55(11), 45(100), 43(99). Sodium Borohydride Reduction of Mercuration Product j)l_. - (i) The mercuration product prepared from 78 mg (0.5 mmole) of 86^ i n a s i m i l a r manner as described above was treated ^n s i t u with a neutral s o l u t i o n of sodium borohydride (23 mg) i n water. Af t e r 30 min at room temperature, the reaction mixture was quenched with d i l u t e hydrochloric acid and ethyl ether. The organic s o l u t i o n was washed with brine and dried over anhydrous magnesium su l f a t e . Evaporation of solvents gave 77 mg of crude material whose IR, 1HNMR and mass spe c t r a l data and chromatographic property revealed the presence of mainly 86. ( i i ) To 90 mg (ca. 0.25 mmole) of the crude product 9[1_ i n t e t r a -hydrofuran (1 ml) was added a so l u t i o n of sodium borohydride (23 mg, 0.6 mmole) i n 3M sodium hydroxide (0.5 ml) at 0°. The r e s u l t i n g mixture was s t i r r e d for 30 min at 0° and 10 min at room temperature, followed by quench-ing with 5% hydrochloric acid and extraction with ethyl ether. The organic so l u t i o n was dried over magnesium s u l f a t e (anhydrous) and then evaporated 185 under reduced pressure to give 29 mg of residue. Preparative th i n layer chromatography on s i l i c a gel with ethyl ether-carbon t e t r a c h l o r i d e - a c e t i c acid (1:1:trace amount) led to two major components: - (a) 8 mg (21%) of 86_: (see s p e c t r a l data described e a r l i e r ) . ( b) 16 mg (44%) of 3-hydroxy-6-heptenoic acid (92): c o l o r l e s s l i q u i d ; IR 3600-2800 (broad), 1710 and 1640 cm"1; 1HNMR 6 1.4-1.8 (m, 2H), 2.2 (m, 2H), 2.54 (d, J = 5 Hz, 2H), 4.1 (m, IH), 4.92-5.22 (m, 2H), 5.7 (m, IH) and 6.7 (br s, 2H, exchangeable with D 20); mass spectrum m/e ( r e l i n t e n s i t y ) 144(1), 126(31), 111(10), 102(20), 97(19), 89(46), 84(78), 81(98), 71(100), 67(66), 56(45) and 55(63). High Resolution Mass Measurement Calcd for C7H1203: 144.0786. Found: 144.0793. Methyl 6-Methyl-3-oxohept-6-enoate (94). - The dianion of methyl acetoacetate generated from 5.8 g (50 mmole) of methyl acetoacetate, 2.64 g (55 mmole) of sodium hydride (50% o i l ) and 32.8 ml (52.5 mmole) of n-butyl-l i t h i u m (1.6 M) i n 100 ml of dry tetrahydrofuran, according to the general procedure, was allowed to react with 5.37 ml (55 mmole) of 3-chloro-2-methyl-propene for 2 hr at 0° and then f o r 0.5 hr at room temperature. The reac-t i o n mixture was worked up i n the same manner as shown i n the preparation of 86_. The crude product (8.62 g) obtained was d i s t i l l e d through a Vigreux column (3 cm) to y i e l d 6.12 g (72%) of 9_4_, as a co l o r l e s s l i q u i d : bp 74-75°/1.0 Torr; IR 1745, 1720 and 1650 cm"1; 1HNMR 6 1.73 (s, 3H), 2.0-2.9 (m, 4H), 3.43 (s, 2H), 3.70 (s, 3H) and 4.65 (m, 2H); mass spectrum m/e 186 ( r e l i n t e n s i t y ) 170(29), 152(40), 138(54), 127(24), 110(19), 101(67), 97(66), 96(71), 95(48), 93(39), 92(37), 85(30), 81(63), 70(53), 69(100), 68(70), 67(64), 59(73), 57(69), 55(74), 53(57), 43(76) and 41(81). Anal. Calcd f or C 9 H i 4 0 3 : C, 63.51; H, 8.29. Found: C, 63.46; H, 8.33. Methyl 7-Methyl-3-oxoocfr—6'1- enoate .(95) . - A s o l u t i o n of the dianion of methyl acetoacetate i n dry tetrahydrofuran (200 ml), prepared according to the general procedure from 11.6 g (0.1 mole) of methyl aceto-acetate, 5.28 g (0.11 mole) of sodium hydride (50% o i l ) and 65.6 ml (0.105 mole) of n-butyllithium (1.6 M), was treated with 11.6 ml (0.1 mole) of l-bromo-3-methyl-2-butene at 0°. The mixture was s t i r r e d f o r 1 hr 45 min at the same temperature and then worked up as described i n the preparation of 86 to give 18.6 g of crude product. D i s t i l l a t i o n through a Vigreux column afforded 15.68 g (85%) of 95: bp 67-68°/0.1 Torr; IR 1745, 1718 and 1640 cm"1; 1HNMR 6 1.6 (s, 3H), 1.65 (s, 3H), 1.95-2.73 (m, 4H), 3.40 (s, 2H), 3.70 (s, 3H) and 5.0 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 184(13), 169(10), 166(15), 153(10), 149(24), 129(19), 116(27), 111(38), 110(35), 109(20), 101(42), 95(48), 83(36), 82(75), 74(100), 69(98), 67(64), 59(35), 55(45), 43(48) and 41(99). Anal. Calcd f or CIOHIGOS: C, 65.19; H, 8.75. Found: C, 65.35; H, 8.96. 187 Methyl a -(E-Tetrahydro-5,5-dimethyl-2-furylidene)acetate (96). -To a s o l u t i o n of 528 mg (2.0 mmole) of anhydrous stannic chloride i n dry dichloromethane (25 ml) was added 306 mg (1.8 mmole) of 9h_ at ambient temperature. The r e s u l t i n g s o l u t i o n was kept under a dry nitrogen atmos-phere and s t i r r e d f o r 19 hr. The reac t i o n mixture was then poured into 20 ml of i c e - c o l d water and the aqueous phase was extracted with 3 x 20 ml of ethyl ether. The combined extracts were washed with water and brine u n t i l neutral, dried over anhydrous magnesium s u l f a t e and concentrated under reduced pressure to give 298 mg (97%) of crude material, which was reasonably pure by t i c and spe c t r a l analyses. Preparative t h i n layer chromatography of 160 mg of the crude product on s i l i c a gel with petroleum ether-ethyl ether (6:1) yielded 145 mg (88%) of 9_6: c o l o r l e s s l i q u i d ; bp (Kugelrohr d i s t i l l a t i o n ) 56-58°/0.8 Torr; IR 1700, 1640 and 1120 cm - 1; 1HNMR 6 1.35 (s, 6H), 1.87 ( t , J = 7.6 Hz, 2H), 3.15 (d t, J = 7.6 and 1.8 Hz, 2H), 3.60 (s, 3H) and 5.17 ( t , J = 1.8 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 170(65), 139(40), 138(19), 127(27), 110(10), 101(100), 96(23), 70(19), 69(32), 55(12), 43(13) and 41 (14). Anal. Calcd f o r C 9H i l t0 3: C, 63.51; H, 8.29. Found: C, 63.62; H, 8.41. Methyl 2,2-Dimethyl-6-oxocyclohexanecarboxylate (97). - To a so l u t i o n of 9.0 ml (77 mmole) of anhydrous stannic c h l o r i d e i n dry d i c h l o r o -methane (200 ml), kept under a dry nitrogen atmosphere and cooled i n an ice-bath, was added 12.88 g (70 mmole) of 95_ dissolved i n 15 ml of d i c h l o r o -methane (dry). 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 f o r 188 18.5 hr and then poured into 100 ml of ic e - c o l d water. The aqueous phase was extracted with 3 x 150 ml of ethy l ether, and the combined extracts were washed with 50% brine u n t i l neutral and dried over anhydrous magnesium su l f a t e . Removal of solvents under reduced pressure gave r i s e to 12.9 g of crude product which contained e s s e n t i a l l y pure 9_7 according to i t s s p e c t r a l and chromatographic data. D i s t i l l a t i o n of the crude material afforded 11.85 g (92%) of 97: bp 64-66°/0.1 Torr; IR 1750 (shoulder), 1730 and 1710 cm"1; 1HNMR 5 1.02 (s, 3H), 1.08 (s, 3H), 1.2-2.1 (m, 4H), 2.1-2.7 (m, 2H), 3.13 (s, IH) and 3.65 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 184(26), 169(20), 153(38), 141(19), 137(53), 111(58), 100(68), 83(85), 74(74), 69(79), 55(100), 43(96) and 41(87).. Anal. Calcd f o r C i 0 H i 6 0 3 : C, 65.19; H, 8.75. Found: C, 65.00; H, 8.55. Methyl 3-0xonon-6-ynoate (104). - The dianion of methyl aceto-acetate i n dry tetrahydrofuran (15 ml), generated from 348 mg (3 mmole) of methyl acetoacetate, 158 mg (3.3 mmole) of sodium hydride (50% o i l ) and I. 9 ml (3 mmole) of n-butyllithium (1.6 M) according to the usual procedure, was allowed to react with 294 mg (2 mmole) of l-bromo-2-pentyne at 0° for 1.5 hr. The reaction mixture was worked up as indicated i n the preparation of 8l6_ to give 411 mg of crude product. Preparative t h i n layer chromatography on s i l i c a g el with petroleum ether-ethyl ether (5:1) yielded 77 mg (87% based on l-bromo-2-pentyne used) of 104 from 100 mg of the crude material, as a c o l o r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 98-100°/1.0 Torr; IR 1745 and 1720 cm - 1; 1HNMR 6 1.08 ( t , J = 7 Hz, 3H), 1.85-2.9 (m, 6H), 189 3.43 (s, 2H) and 3.70 (s, 3H); mass spectrum m/e ( r e l Intensity) 182(27), 167(38), 154(32), 153(52), 123(45), 122(66), 109(100), 108(30), 107(32), 101(29), 81(41), 80(33), 79(49), 69(33), 67(17), 65(16), 59(44), 53(25) and 41(54). Anal. Calcd f or C i 0 H 1 4 0 3 : C, 65.92; H, 7.74. Found: C, 65.70; H, 7.64. C y c l i z a t i o n of Methyl 3-Oxonon-6-ynoate (104). - A s o l u t i o n of 128 mg (0.49 mmole) of anhydrous stannic chloride i n dry dichloromethane (5 ml) was kept under a dry nitrogen atmosphere and cooled i n an ice-bath. To t h i s was introduced 82 mg (0.45 mmole) of 104, 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 21.5 hr at room temperature. The reaction was quenched with i c e - c o l d water (ca. 10 ml) and the aqueous layer was extracted with ethyl ether (ca. 20 ml). The ethereal extract was washed with 50% brine u n t i l n e u tral, dried over anhydrous magnesium s u l f a t e and concentrated under reduced pressure. The crude material (84 mg) so obtained was chromatographed on s i l i c a gel with petroleum ether-ethyl ether (6:7) to give two c y c l i z e d products:- (a) 50 mg (61%) of methyl 2-n-propyl-5-oxocyclopentenecarboxylate (105): c o l o r l e s s l i q u i d ; R f 0.22; bp (Kugelrohr d i s t i l l a t i o n ) 73-75°/ 0.05 Torr; IR 1740, 1710 and 1625 cm"1; 1HNMR 6 0.98 (t, J = 7 Hz, 3H), I. 2-2.0 (m, 2H), 2.27-2.93 (m, 6H) and 3.78 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 182(45), 151(67), 150(100), 135(79), 122(26), 109(12), 107(13), 95(14), 79(15), 55(14) and 41(18). High Resolution Mass Measurement Calcd for C 1 0 H i i , 0 3 : 182.0943. Found: 182.0941. 190 (b) 27 mg (33%) of methyl 2-ethyl-6-oxocyclohexenecarboxylate (106): c o l o r l e s s l i q u i d ; 0.33; bp (Kugelrohr d i s t i l l a t i o n ) 66-68°/ 0.05 Torr; IR 1730, 1675 and 1630 cm"1; 1HNMR 6 1.13 ( t , J = 7 Hz, 3H), 1.63-2.6 (m, 8H) and 3.78 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 182(29), 151(42), 150(100), 126(12), 122(55), 111(10), 96(17), 94(19), 55(20)and 41(16). Anal. Calcd f o r C 1 0H l l t0 3: C, 65.92; H, 7.74. Found: C, 65.98; H, 7.91. Preparation and Reactions of Epoxy and q-Diazo 8-Keto esters. Methyl 6,7-Epoxy-7-methyl-3-oxooctanoate (111). - To a suspension of 199 mg (1.4 mmole) of anhydrous disodium hydrogen phosphate and 242 mg (1.4 mmole) of m-chloroperbenzoic acid (85%) i n dry dichloromethane (4 ml) was added 184 mg (1 mmole) of methyl 7-methyl-3-oxooct-6-enoate (95) at 0 (this r e a c t i o n was found notably exothermic). The r e s u l t i n g mixture was s t i r r e d at the same temperature f o r 20 min (reaction progress was monitored by t i c a n a l y s i s , 1:1 petroleum ether-ethyl ether). The suspension was then f i l t e r e d with suction and the residue was washed with a small volume of dichloromethane. The f i l t r a t e was d i l u t e d with ethyl ether (20 ml), washed with 10% sodium b i s u l f i t e , 10% sodium bicarbonate and brine, dried over anhydrous sodium s u l f a t e and f i n a l l y , evaporated in_ vacuo. The crude pro-duct (192 mg, 96%) of 111 so obtained was e s s e n t i a l l y pure by s p e c t r a l and chromatographic analyses and was used i n c y c l i z a t i o n study without further p u r i f i c a t i o n . A sample for high r e s o l u t i o n mass spectrum was p u r i f i e d by 191 Kugelrohr d i s t i l l a t i o n at 82-85°/0.05 Torr: c o l o r l e s s o i l ; IR 1745 and 1720 cm"1; 1HNMR 6 1.28 (s, 6H), 1.8 (m, 2H), 2,7 (m, 3H), 3.45 (s, 2H) and 3.70 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 200(36), 185(15), 169(23), 159(12), 142(79), 141(51), 129(100), 127(43), 117(24), 116(24), 111(21), 110(15), 101(48), 99(22), 97(42), 85(46), 83(35), 74(41), 72(99), 71(36), 69(25), 59(73), 57(47), 55(54), 43(72) and 41(33). High Resolution Mass Measurement Calcd f o r C 1 0 H 1 6 O 4 : 200.1049. Found: 200.1048. Methyl 2-Isopropyl-5-oxocyclopentenecarboxylate (112). - (a) From epoxide 111: A so l u t i o n of 173 mg (0.86 mmole) of 111 i n dry dichloromethane was added into a s o l u t i o n of 545 mg (2.1 mmole) of anhydrous stannic c h l o r -ide i n the same solvent (4 ml), at room temperature. After 23 hr, the react i o n mixture was poured into i c e - c o l d water (10 ml) and the aqueous phase was extracted with 2 x 15 ml of ethyl ether. The combined extracts were washed with 50% brine u n t i l n e u t r a l , dried over anhydrous sodium s u l -f ate and concentrated under reduced pressure to give 180 mg of crude product. D i s t i l l a t i o n (Kugelrohr) at 94-98°/0.6 Torr afforded 135 mg (86%) of 112: col o r l e s s l i q u i d ; IR 1740, 1710 and 1620 cm"1; 1HNMR 6 1.17 (d, J = 7 Hz, 6H'; collapsed into a broad s i n g l e t when i r r a d i a t e d at 6 3.5), 2.2-2.85 (m, 4H), 3.50 (septet, J = 7 Hz, IH) and 3.80 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 182(15), 151(43), 150(100), 135(24), 122(18), 109(10), 107(11), 79(17), 55(11) and 41(10). High Resolution Mass Measurement Calcd f or C 1 0 H 1 4 O 3 : 182.0942. Found: 182.0937. 192 (b) From B i c y c l i c Compound 114: To a s o l u t i o n of 116 mg (0.4 mmole) of anhydrous stannic c h l o r i d e i n dry dichloromethane was added 36 mg (0.2 mmole) of 114. The r e s u l t i n g mixture was s t i r r e d for 12 hr at room temperature and then worked up i n the same manner as described above. The crude product i s o l a t e d (36 mg, 100%) was homogeneous by t i c a n a l y s i s , and had i d e n t i c a l spectroscopic and chromatographic properties as 112 (vide  supra). Methyl 2-Diazo-7-methyl-3-oxooct-6-enoate (115). - To 5.52 g (30 mmole) of 8-keto ester 95_, dissolved i n 50 ml of dry a c e t o n i t r i l e ( d i s -t i l l e d over P 2 O 5 ) , was added 4.2 ml (30 mmole) of anhydrous triethylamine. The s o l u t i o n was cooled i n an ice-bath with constant s t i r r i n g while a s o l u -t i o n of 5.91 g (30 mmole) of j D-toluenesulfonyl azide (prepared according to the procedure reported by Regitz et^ al.70") i n dry a c e t o n i t r i l e (5 ml) was slowly introduced. The ice-bath was removed upon complete a d d i t i o n of j>-toluenesulfonyl azide and s t i r r i n g was continued for 4 hr at room temperature. The r e s u l t i n g s o l u t i o n was concentrated under reduced pressure (water a s p i r -ator; bath temperature 35°) to give a residue of o i l and white s o l i d , which was dissolved i n 100 ml of ethyl ether. The ethereal s o l u t i o n was washed with 2 x 35 ml of 5% sodium hydroxide and 2 x 30 ml of brine and dried over anhydrous calcium s u l f a t e . Removal of solvents and v o l a t i l e materials i n  vacuo yielded 6.5 g (ca. 100%) of crude 115 which was d i r e c t l y used i n the next copper-catalyzed c y c l i z a t i o n r e a c t i o n without any p u r i f i c a t i o n . This crude product (a pale yellow o i l ) was homogeneous by t i c and showed s a t i s -factory s p e c t r a l data: IR 2150, 1720, 1650 and 1435 cm"1; 1HNMR 6 1.65 193 (br s, 6H), l,95-2.55(m, 2H), 2.57-3.05(m, 2H), 3.77 (s, 3H) and 5.05 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 210(8), 182(13), 167.(15), 150(86), 135(100), 123(12), 122(20), 113(18), 109(13), 107(16), 82(26), 79(23), 69(43), 67(42), 59(18), 55(29), 53(19), 43(16) and 41(80). High Resolution Mass Measurement Calcd f or C i o H i 4 N 2 O 3 : 210.1004. Found: 210.0983. Methyl 6,6-Dimethyl-2-oxobicyclo[3.1.0]hexane-l-carboxylate (114).-A mixture of 6.4 g (ca. 29 mmole) of the crude a-diazo 8-keto ester 115 and 2.0 g of copper-bronze (commercial grade from B r i t i s h Drug House) i n 50 ml of dry benzene was heated under r e f l u x f o r 30 hr. The suspension was f i l t e r e d and the f i l t r a t e was evaporated under reduced pressure to give 5.6 g of crude product. Vacuum d i s t i l l a t i o n through a short Vigreux column afforded 3.80 g (71% from 95) of 114 as a c o l o r l e s s o i l : bp 72-73°/0.05 Torr; IR 1750 (shoulder) and 1720 cm - 1; 1HNMR 6 1.2 (s, 3H), 1.23 (s, 3H), 1.5-2.6 (m, 5H) and 3.72 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 182(25), 151(39), 150(100), 141(21), 140(21), 135(26), 123(15), 122(27), 109(39), 108(17), 95(15), 94(12), 81(15), 79(20), 73(28), 67(14), 55(16), 53(14) and 41(24). Anal. Calcd f or C 1 0H l l t0 3: C, 65.92; H, 7.74. Found: C, 65.'97; H, 7.70. Controlled C y c l i z a t i o n of Methyl 6,7-Epoxy-7-methyl-3-oxooctanoate  (111). - To a s o l u t i o n of anhydrous stannic chloride (110 mg, 0.42 mmole) i n dry dichloromethane (2 ml), kept under a dry nitrogen atmosphere and 194 cooled i n an ice-bath, was added 76 mg (0.38 mmole) of epoxide 111. Pro-gress of the reaction was traced by t i c analysis which revealed complete disappearance of s t a r t i n g material a f t e r 20 min at 0°. The reac t i o n mixture was then d i l u t e d with i c e - c o l d water (5 ml) and ethyl ether (20 ml), and the organic phase was separated, washed with 50% brine u n t i l neutral and dried over anhydrous sodium s u l f a t e . Evaporation of solvents under reduced pressure gave 69 mg of crude material, which upon chromatography on s i l i c a gel with ethyl ether yielded three c y c l i z e d products: - (a) 38 mg (51%) of methyl a -(E_-tetrahydro-3-hydroxy-2,2-dimethyl-6-pyrylidene)acetate (116) : co l o r l e s s l i q u i d ; R 0.6; bp (Kugelrohr d i s t i l l a t i o n ) 92-95°/0.05 Torr; IR 3500, 1700 and 1640 cm - 1; 1HNMR 6 1.17 (s, 3H), 1.28 (s, 3H), 2.0 (m, 2H), 3.07 (m, 2H), 3.62 (s, 3H), 4.18 ( t , J = 8 Hz, IH) and 5.27 ( t , J = 1.6 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 200(9), 185(7), 169(15), 153(18), 142(100), 110(32), 99(34), 69(16), 59(33) and 43(22). Anal. Calcd f or C^H^O^: C, 59.98; H, 8.05. Found: C, 59.91; H, 7.95. (b) 12 mg (16%) of methyl a -(Z-tetrahydro-3-hydroxy-2,2-dimethyl-6-pyrylidene)acetate (117): c o l o r l e s s l i q u i d ; R f 0.2; IR 3500, 1700 and 1650 cm - 1; 1HNMR 6 1.18 (s, 3H), 1.36 (s, 3H), 2.0 (m, 2H), 2.77 (m, 2H), 3.63 (s, 3H), 4.37 ( t , J = 7 Hz, IH) and 4.81 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 200(10), 185(7), 179(11), 169(17), 153(26), 151(16), 142(100), 127(11), 110(33), 109(16), 99(37), 86(26), 84(38), 69(15), 59(31) and 43(27). High Resolution Mass Measurement Calcd f or CioHieOij: 200.1049. Found: 200.1046. 195 (c) 10 mg (11%) of methyl a-(tetrahydro-3,6-dihydroxy-2,2-dimethylpyran-6-yl)acetate (118): c o l o r l e s s o i l ; 0.4; IR 3500 and 1720 cm"1; 1HNMR 6 1.11 (s, 3H), 1.25 (s, 3H), 1.7-2.4 (m, 4H), 2.79 (s, 2H) , 3.76(s, 3H) and 4.05 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 218(4), 201(100), 200(10), 185(16), 183(64), 169(68), 159(21), 142(52), 141(53), 127(84), 116(27), 109(15), 101(40), 99(47), 85(47), 74(23), 72(16), 71(18), 69(17), 59(69), 57(23), 55(23), 43(71) and 41(20). Methyl E-6,7-Epoxy-3-pyrrolidinohept-2-enoate (124). - A so l u t i o n of 338 mg (2 mmole) of methyl E_-3-pyrrolidinobut-2-enoate (123) (prepared from methyl acetoacetate and py r r o l i d i n e ) i n 5 ml of dry tetrahydrofuran was cooled i n a Dry Ice-chloroform bath (-60°) and kept under a dry n i t r o -gen atmosphere. To t h i s was added 1.25 ml (2 mmole) of n-butyllithium (1.6 M). The mixture was s t i r r e d at -60° for 5 min and then the bath temperature was raised to room temperature over 1 hr. The r e s u l t i n g l i g h t yellow so l u -t i o n was cooled to -60° again, followed by introduction of 278 mg (3 mmole) of epichlorohydrin ( i n ca. 1 ml of dry THF). After 20 min at -60°, the cooling bath was removed and s t i r r i n g was continued for 4.5 hr. The mixture was f i n a l l y poured into 15 ml of i c e - c o l d brine and the aqueous phase was extracted with 3 x 20 ml ethyl ether. The combined extracts were dried over anhydrous sodium s u l f a t e and concentrated under reduced pressure to give 438 mg (97%) of crude product. P u r i f i c a t i o n by Kugelrohr d i s t i l l a t i o n a f f o r 383 mg (85%) of 124 as a co l o r l e s s l i q u i d . Vapor-phase chromatographic analysis (3% OV-17, column temperature 165°) showed one si n g l e compound: bp 95-98°/0.03 Torr; IR 2920, 1670, 1565 and 1150 cm"1; 1HNMR 6 1.5-2.2 196 (m, 6H), 2.3-3.5 (m, 9H), 3.57 (s, 3H) and 4.38 (s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 225(95), 208(20), 194(100), 182(43), 169(42), 168(73), 166(62), 152(66), 136(35), 124(23), 110(96), 96(37), 94(31), 84(35), 70(32), 55(26) and 41(32). High Resolution Mass Measurement Calcd for C 1 2 H 1 9 N O 3 : 225.1364. Found: 225.1361. Methyl 8-(2-Hydroxymethylcyclopropyl ) -3-oxopropanoate (125). -A s o l u t i o n of l i t h i u m d i i s o p r o p y l amide was generated by t r e a t i n g 0.29 ml (2.1 mmole) of anhydrous diisopropylamine i n dry tetrahydrofuran (3 ml) with 1.25 ml (2.0 mmole) of n-butyllithium (1.6 M) at 0° for 20 min. This s o l u t i o n was then added dropwise, through a two-way needle with p o s i t i v e nitrogen pressure, into a s o l u t i o n of 172 mg (1 mmole) of methyl 6,7-epoxy-3-oxoheptanoate (109) i n dry tetrahydrofuran (2 ml) which was cooled i n an ice-bath and kept under a dry nitrogen atmosphere. The r e s u l t i n g suspension was s t i r r e d for 0.5 hr at 0° and 1 hr at room temperature. The r e a c t i o n was quenched with i c e - c o l d 5% hydrochloric acid (5 ml) and the aqueous phase was extracted with 3 x 10 ml of et h y l ether. The combined extracts were washed with brine, dried over anhydrous sodium s u l f a t e and evaporated under reduced pressure to give 130 mg of crude material. Preparative t h i n layer chromatography on s i l i c a gel with carbon t e t r a c h l o r i d e - e t h y l ether (1:2) afforded 53 mg (50%) of 125 as the major component: c o l o r l e s s o i l ; R^ 0.2; bp (Kugelrohr d i s t i l l a t i o n ) 80-83°/0.1 Torr; IR 3550, 3050, 1740 and 1700 cm"1; 1HNMR 6 0.98 (m, IH), 1.4 (m, IH), 1.75 (m, IH), 2.0 (m, IH), 2.57 (br s, IH, enchangeable with D 20), 3.55 (s, 2H), 3.12-3.90 (m, 2H), and 197 3.70 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 172(25), 154(32), 153(17), 141(19), 129(20), 128(14), 116(77) , 114(38) , 112(21), 101(37), 99(100), 98(32), 97(46), 95(31), 94(27), 81(57), 74(29), 69(26), 59(28), 55(45), 43(40) and 41(37). Anal. Calcd f o r CeH^O^: C, 55.81; H, 7.02. Found: C, 55.85; H, 6.96. 198 SECTION II Preliminary Studies Methyl 2-Acetoxy-6,6-dimethyl-l-cyclohexenecarboxylate (250) .-A mixture of 368 mg (2 mmole) of methyl 2,2-dimethyl-6-oxocyclohexanecarboxy-l a t e (97), 1.2 g (12 mmole) of isopropenyl acetate and c a t a l y t i c amount (8 mg) of j>-toluenesulfonic acid monohydrate i n dry benzene (5 ml) was heated under r e f l u x f o r 17 hr. The d i s t i l l a t e was continuously removed and replaced by benzene by means of a Dean-Stark apparatus. The f i n a l mixture was cooled and concentrated under reduced pressure. The crude r e s i -due so obtained was Kugelrohr d i s t i l l e d at 80-85°/1.0 Torr to give 380 mg (84%) of 250 as a c o l o r l e s s l i q u i d : IR 1755, 1720 and 1640 cm"1; 1HNMR 6 1.17 (s, 6H), 1.3-1.97 (m, 4H), 2.05 (s, 3H), 1.97-2.4 (m, 2H) and 3.67 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 226(7), 195(8), 194(9), 184(31), 169(72), 153(20), 152(12), 138(11), 137(100), 100(10), 96(10), 83(11), 81(10), 69(10), 55(18), 43(24) and 41(13). High Resolution Mass Measurement Calcd f or C i 2 H i 8 0i+: 226.1205. Found: 226.1209. Ethy l and Methyl Esters of 2-Phenylthio-2-cyclohexenecarboxylic Acid and 2-Phenylthio-l-cyclohexenecarboxylic Acid, (255a) and (255b). -A mixture of 1.63 g (ca. 9 .9 mmole) of ethyl 2-oxocyclohexanecarboxylate (mixture of 60% ethyl and 40% methyl esters; Aldrich) (254), 1.23 ml (12 mmole) of benzenethiol and 0.1 g of £-toluenesulfonic acid was heated under r e f l u x i n 15 ml of dry benzene. Reflux was continued f o r 20 hr with azeotropic 199 removal of water by means of a Dean-Stark apparatus. The mixture was then cooled and poured into 30 ml of 10% potassium carbonate s o l u t i o n , and ex-tracted with 2 x 35 ml of ethyl ether. The combined extracts were washed with saturated potassium carbonate (20 ml) and brine (20 ml), dried over anhydrous magnesium s u l f a t e and evaporated under reduced pressure. The crude product obtained was d i s t i l l e d (Kugelrohr) at 85-90°/0.2 Torr to y i e l d 2.3 g (ca. 90%) of a mixture (ca. 1:1) of 255a and 255b: IR 3120, 1730 (due to 255a), 1690 (due to 255b) , 1580, 1480, 1440, 1280, 1050 and 1020 cm"1; 1HNMR 6 1.3 ( t , J = 7 Hz, -1.8H), 1.4-2.5 (m, ~7H), 3.17 (m, ~0.5H, due to 255a), 3.57 (s, ~0.6H, due to 255a), 3.73 (s, ~0.6H, due to 255b) , 4.2 (q, J = 7 Hz, ~1.2H), 6.2 (m, ~0.5H, due to 255b) and 7.0-7.5 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 264(5), 263(16), 262(100), 250(3), 249(9), 248(57), 218(15), 217(31), 216(25), 215(13), 189(38), 188(47), 187(28), 160(25), 153(40), 147(28), 139(24), 110(24), 109(23), 81(20), 79(71), 77(28), and 47(15). Methyl 2-Phenylthio-6,6-dimethyl-2-cyclohexenecarboxylate (256a) and Methyl 2-Phenylthio-6,6-dimethyl-l-cyclohexenecarboxylate (256b). -A mixture of 920 mg (5 mmole) of methyl 2,2-dimethyl-6-oxocyclohexane-carboxylate (97), 0.52 ml (5 mmole) of benzenethiol and 50 mg of p-toluene-s u l f o n i c a c i d monohydrate was treated i n the same manner as described above, giving r i s e to 1.358 g of crude material. Preparative t h i n layer chromato-graphy of 150 mg of the crude product on s i l i c a g e l with 10:1 petroleum ether-e t h y l ether (developed three times) afforded two major components:- (a) 256a (96 mg, 63%): c o l o r l e s s o i l ; R f 0.67; IR 1730, 1590, 1480, 1440 and 1160 200 cm"1; 1HNMR 6 0.9 (s, 3H), 0.95 (s, 3H), 1.2-2.0 (m, 2H), 2.0-2.4 (m, 2H), 2.78 (s, IH), 3.57 (s, 3H), 6.22 (t, J = 4 Hz, IH), and 7.2 (br s, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 276(65), 261(17), 229(19), 217(14), 216(24), 201(37), 167(33), 161(7), 135(11), 123(14), 108(11), 107(100), 105(10), 91(12) and 41(11). High Resolution Mass Measurement Calcd for C 1 6 H 2 0 O 2 S : 276.1184. Found: 276.1185. (b) 256b (25 mg, 16%): c o l o r l e s s o i l ; R f 0.78; IR 1720, 1590, 1480, 1440, 1270 and 1060 cm"1; XHNMR 6 1.18 (s, 6H), 1.3-1.9 (m, 4H), 2.1 (m, 2H), 3.73 (s, 3H) and 7.2 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 276(85), 261(84), 245(14), 229(100), 217(15), 201(14), 167(13) and 107(25). High Resolution Mass Measurement Calcd f or C i 6 H 2 o 0 2 S : 276.1184. Found: 276.1187. Ethyl and Methyl esters of 2-Methyl-cyclohexenecarboxylic Acid  (257). - A so l u t i o n of li t h i u m dimethylcuprate was generated by adding 2.26 ml (4 mmole) of methyllithium (1,77 M) to a suspension of 381mg (2 mmole) of cuprous iodide i n dry ethyl ether (5 ml) at 0°. To t h i s s o l u t i o n , kept under dry nitrogen atmosphere, was added 155 mg (0.6 mmole) of a mixture of 255a and 255b (ca. 0.3 mmole of the conjugated isomer 255b). The r e s u l t i n g yellow suspension was s t i r r e d for 1 hr at 0° and 5 hr at room temperature. The reaction was quenched with 10% ammonium chlo r i d e (10 ml) and concentrated ammonium hydroxide (0.5 ml), and the aqueous phase was extracted with 20 ml of et h y l ether. The ether s o l u t i o n was washed with brine, d r i e d over anhydrous magnesium s u l f a t e , and concentrated under reduced pressure to give 105 mg of 201 crude product. Kugelrohr d i s t i l l a t i o n yielded two d i f f e r e n t b o i l i n g f r a c -t i o n s : - (a) 37 mg (76% based on 0.3 mmole of 255b) of 257: c o l o r l e s s l i q u i d ; bp 65-70°/0.2 Torr; IR 1700 and 1640 cm"1; 1HNMR 6 1.25 ( t , J = 7 Hz, -1.8H), 1.4-1.8 (m, 4H), 1.95 (br s, 3H), 1.8-2.4 (m, 4H), 3.68 (s, -1.2H) and 4.1 (q, J = 7 Hz, -1.2H); mass spectrum m/e ( r e l i n t e n s i t y ) 168(90), 154(17), 140(23), 139(44), 123(88), 122(50), 95(100), 94(30), 93(37), 79(38), 77(20), 67(31), 55(19), 53(15) and 41(25). (b) 56 mg of recovered 255a: bp 85-90°/0.2 Torr. Methyl 2,2-Dimethyl-6,6-dimethylthio-cyclohexanecarboxylate (258). Approximately 3 ml of methanethiol was condensed into a septurned f l a s k con-t a i n i n g 544 mg (4 mmole) of anhydrous zinc chloride and 320 mg (1.7 mmole) of methyl 2,2-dimethy-6-oxocyclohexanecarboxylate (97) , cooled at -20°. The re 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 hr at -20° and 10 hr at room temperature. The reaction mixture was then poured i n t o saturated sodium carbonate s o l u t i o n (20 ml) and extracted with 3 x 20 ml of et h y l ether. The combined extracts were washed with brine, dried over anhydrous magnesium s u l f a t e and evapora-ted under reduced pressure to give 456 mg' of crude product. Preparative t i c on s i l i c a g e l with carbon t e t r a c h l o r i d e - e t h y l ether (15:1) afforded 85 mg (84% y i e l d ) of 258 from 101 mg of the crude product: c o l o r l e s s o i l ; bp (Kugel-rohr d i s t i l l a t i o n ) 95-97°/0.05 Torr; IR 1730, 1435 and 1140 cm"*1; XHNMR 6 0.98 (s, 3H), 1.22 (s, 3H), 1.3-2.0 (m, 6H), 1.98 (s, 3H), 2.06 (s, 3H), 2.65 (s, IH). and 3.64 (s, 3H) ; mass spectrum m/e ( r e l i n t e n s i t y ) 262(3), 216 (11), 215(79), 214(11), 197(7), 183(29), 156(17), 155(100), 154(13), 139(16), 135(15), 107(34), 91(8), 69(14) and 41(8), Anal. Calcd f o r C12H22O2S2: C, 54.92; H, 8.45. Found: C, 55.20; H, 8.40. Methyl 6,6-Dimethyl-2-methylthio-2-cyclohexenecarboxylate (259a). -A mixture of 79 mg (ca. 0.3 mmole) of crude 258, 50 mg of mercuric ch l o r i d e and 0.1 ml of anhydrous triethylamine was heated under r e f l u x i n xylene (3 ml) for 5 hr. The reaction mixture was then d i l u t e d with water (10 ml) and ethyl ether (20 ml). The organic s o l u t i o n was separated, washed with brine, and dried over anhydrous magnesium s u l f a t e . Removal of solvents under reduced pressure gave 67 mg of crude residue, which upon chromatography on s i l i c a gel with carbon t e t r a c h l o r i d e - e t h y l ether (15:1) afforded 47 mg (73% from 97_) of 259a as a c o l o r l e s s l i q u i d : R 0.5; IR 1730, 1640 and 1160 cm"1; 1HNMR 6- 0.97 (s, 6H), 1.2-1.6 (m, 2H), 1.8-2.4 (m, 2H), 2.2 (s, 3H), 2.78 (br s, IH), 3.65 (s, 3H) and 5.6 ( t , J = 4 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 214(39), 199(15), 167(20), 155(23), 154(81), 140(17), 139 (100), 127(13), 125(17), 107(34), 91(18) and 41(19). High Resolution Mass Measurement Calcd for C i i H l 8 0 2 S : 214.1027. Found: 214.1026. Reaction of E t h y l (Methyl) 2-0xocyclohexanecarboxylate (254) with Oxalyl Chloride. - To a s o l u t i o n of 254 (329 mg, ca.2 mmole) i n dry chloro-form (3 ml) was added 0.44 ml (5 mmole) of o x a l y l c h l o r i d e . The r e s u l t i n g s o l u t i o n was heated under r e f l u x f o r 4.5 hr. Evaporation of solvent and v o l a t i l e materials i n vacuo, followed by d i s t i l l a t i o n (Kugelrohr) gave 350 mg (70%) of 264 as a c o l o r l e s s o i l : bp 85-89°/0.4 Torr ( l i t . 1 5 2 203 bp 130°/1.5 Torr); IR 1790, 1745, 1720 and 1450 cm"1; 1HNMR 6 1.3 ( t , J = 7 Hz, -1.8H), 1.45-2.17 (m, 4H), 2.2-2.77 (m, 4H), 3.82 (s, -1.2H) and 4.28 (q, J = 7 Hz, ~1.2H); mass spectrum m/e ( r e l i n t e n s i t y ) 234(3), 232(9), 220(2), 218(6), 197(23), 187(27), 169(52), 151(49), 150(41), 141(43), 140(59), 127(81), 126(48), 124(56), 123(100), 113(90), 99(62), 95(43), 68(48), 67(32), 55(80), 44(72) and 41(57). Preparation of Enol Phosphates of g-Keto Esters and t h e i r Reactions with  Lithium Dialkylcuprates General Procedure for the Preparation of the Z_-Enol Phosphate of B-Keto Esters. - To a s t i r r e d suspension of sodium hydride (1.1 eq) i n dry ethyl ether, kept under a dry nitrogen atmosphere and cooled i n an i c e -both, was added a s o l u t i o n of the g-keto ester (1.0 eq) i n ethyl ether. Aft e r 15-20 min at 0° (or 10 min at room temperature), 1.1 eq of d i e t h y l chlorophosphate was introduced and s t i r r i n g was continued for 1-2 hr at 0° (or room temperature). (Progress of the reaction could be e a s i l y monitored by t i c . Although the g-keto ester enolate was usually found reacted within 30 min at 0 , the re a c t i o n was allowed to proceed for a longer period of time to ensure completeness of the transformation.) The enol phosphate was i s o l a t e d from the reaction mixture by either of the following work-up pro-cedures : (a) (for le s s than 5mmole scale preparations) the reaction mixture was s t i r r e d with excess s o l i d ammonium chloride f or 20 min, f i l t e r e d through c e l i t e , and the f i l t r a t e was concentrated i n  vacuo; or, 204 (b) (for larger than 5 mmole scale preparations) the rea c t i o n mixture was quenched with aqueous ammonium chlo r i d e and d i l u t e d with e t h y l ether. The ether s o l u t i o n was then washed with saturated sodium bicarbonate s o l u t i o n , dried over anhydrous magnesium s u l f a t e and evaporated under reduced pressure. The crude enol phosphate so obtained, i n v a r i a b l y i n quantitative y i e l d , was e s s e n t i a l l y pure by spectroscopic and chromatographic analyses, and was used d i r e c t l y i n reactions with l i t h i u m d i a l k y l c u r p a t e s . Methyl 2-(Diethylphosporyloxy)cyclohexenecarboxylate (267): -IR 1715, 1660, 1290 and 1030 cm"1; 1HNMR <5 1.35 ( t , J = 7 Hz, 6H), 1.6 (m, 4H), 2.3 (m, 4H), 3.68 (s, 3H) and 4.15 (qn, J = 7 Hz, 4H); mass spectrum m/e ( r e l i n t e n s i t y ) 292(10), 260(67), 232(35), 204(100), 176(13), 55(14) and 41(11). High Resolution Mass Measurement Calcd f o r C 1 2 H 2 1 O 6 P : 292.1076. Found: 292.1087. Methyl 2-(Diethylphosphoryloxy)-6,6-dimethylcyclohexenecarboxy- late.(271): I R 1725, 1680, 1280 and 1030 cm"1; 1HNMR 6 1.15 (s, 6H), 1.2-1.9 (m, 4H), 1.32 (t, J = 7 Hz, 6H), 2.4 (m, 2H), 3.70 (s, 3H) and 4.10 (qn, J = 7 Hz, 4H); mass spectrum m/e ( r e l i n t e n s i t y ) 320(7), 288 (100), 273(28), 260(25), 245(17), 232(24), 217(28), 137(10), 128(8) and 99(10). High Resolution Mass Measurement Calcd f o r C i i ^ s O e P : 320.1389. Found: 320.1403. 205 Methyl 2-(Diethylphosphoryloxy)cyclopentenecarboxylate (272) :-IR 1710, 1660, 1280 and 1030 cm"1; 1HNMR 6 1.38 ( t , J = 7 Hz, 6H), 1.95 (m, 2H), 2.3-3.0 (m, 4H), 3.67 (s, 3H) and 4.20 (qn, J = 7 Hz, 4H); mass spectrum m/e ( r e l int e n s i t y ) 278(12), 246(60), 218(38), 190(100), 162(7), 141(7), 129(10), 113(14), 109(11), 101(17), 99(11), 81(8) and 55(15). High Resolution Mass Measurement Calcd f o r CnH^OeP: 278.0919. Found: 278.0918. Methyl 2-(Diethylphosphoryloxy)cycloheptenecarboxylate (273):-IR 1718, 1660 (shoulder), 1280 and 1030 cm"1; 1HNMR6 1.34 ( t , J = 7 Hz, 6H), 1.7 (m, 6H), 2.2-2.8 (m, 4H), 3.71 (s, 3H), and 4.13 (qn, J = 7 Hz, 4H); mass spectrum m/e ( r e l i n t e n s i t y ) 306(9), 274(100), 245(42), 218(50), 190(20), 155(21), 127(22), 113(9), 99(33), 55(15) and 41(13).. High Resolution Mass Measurement Calcd for Ci3H 230gP: 306.1232. Found: 306.1242. Methyl Z-3-(Diethylphosphoryloxy)but-2-enoate (280): - Vpc (3% OV-17 column, 140-150°) and ^ NMR analyses showed pure Z-enol phosphate 280, with no detectable E_ isomer i n the crude product. IR 1725, 1675, 1280 and 1030 cm"1; "-HNMR 6 1.38 ( t , J = 7 Hz, 6H) , 2.17 (d, J = 1.4 Hz, 3H) , 3.67 (s, 3H), 4.23 (qn, J = 7 Hz, 4H) and 5.27 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 252(34), 220(70), 207(21), 192(53), 179(25), 164(70), 155(67), 127(64), 113(26), 109(26), 99(100), 67(30) and 43(36). High Resolution Mass Measurement Calcd f o r CgHjyOgP: 252.0763. Found: 252.0739. 206 Methyl Z-3-(Diethylphosphoryloxy)hex-2-enoate (281): IR 1725, 1670, 1280 and 1030 cm"1; -^ HNMR 6 0.95 (_t, J = 7 Hz, 3H) , 1.35 ( t , J = 7 Hz, 6H), 1.6 (m, 2H), 2.37 (m, 2H), 3.65 (s, 3H), 4.21 (qn, J = 7 Hz, 4H) and 5.28 (s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 280(20), 248(23), 220(23), 155(100), 127(5), 113(24), 101(38) and 99(51). High Resolution Mass Measurement Calcd f o r C 1 1H 2 10 6P: 280.1075. Found: 280.1075. Methyl Z-3-(Diethylphosphoryloxy)-6-(2-tetrahydropyranyloxy)hex-2-enoate (282): IR 1725, 1670, 1280 and 1030 cm - 1; XHNMR 6 1.36 ( t , J = 7 Hz, 6H), 1.2-2.2 (m, 8H), 2.53 (br t, J = 7 Hz, 2H), 3.2-4.0 (m, 4H), 3.65 (s, 3H), 4.22 (qn, J = 7 Hz, 4H), 4.50 (m, IH) and 5.33 (s, IH); mass spectrum m/e ( r e l int e n s i t y ) 380(0.1), 349(2), 296(5), 279(6), 251(8), 219(10), 155(100), 142(42), 127(18), 111(25), 99(20) and 85(17). High Resolution Mass Measurement Calcd f o r C15H26O7P (P +-0CH3): 349.1416. Found: 349.1443. Methyl (2Z-, 6E)-3-(Diethylphosphoryloxy)-7,ll-dimethyldodeca-2, 6,10-trienoate (283): IR 1725, 1670, 1280 and 1030 cm"1; ^NMR 6 1.35 (t, J = 7 Hz, 6H), 1.60 (s, 6H), 1.67 (s, 3H), 1.7-2.3 (m, 6H), 2.4 (m, 2H), 3.65 (s, 3H), 4.23 (qn, J = 7 Hz, 4H), 5.0 (m, 2H) and 5.30 (s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 388(12), 357(5), 343(3), 319(4), 287(18), 252(25), 234(20), 220(28), 202(13), 192(14), 155(100), 127(50) and 99(63). High Resolution Mass Measurement Calcd f o r C 1 9H3 30 6P: 388.2015. Found: 388.2024. 207 E t h y l ^-3-(Diethylphosphoryloxy)-2-methylbut-2-enoate (284) : -•LHNMR and vpc (3% OV-17 column, 160°) analyses ind i c a t e d pure Z-enol phos-phate 284, with no detectable E_ isomer i n the crude product. IR 1720, 1660 (shoulder), 1280 and 1030 cm"1; 1HNMR 6 1.1-1.5 (m, 9H), 1.83 (m, 3H), 2.10; (m, 3H) . and ,3.85-4.4 (m, 6H); mass - spectrum m/e ( r e l i n t e n s i t y ) 280 (30), 234(7.5), 206(40), 178(50), 155(75), 150(25), 127(70), 109(15), 99 (100),.81(35), 70(20), 53(25), and 43(45). High Resolution Mass Measurement Calcd f or C 1 1 H 2 i 0 6 P : 280.1076. Found: 280.1076. Methyl 2-Oxocyclohexanecarboxylate ( 2 6 6 ) . 1 5 6 - Into a 500 ml three-neck round bottomed flask, was charged 22.5 g (0.47 mole) of sodium hydride (50% o i l ) and 120 ml of dry tetrahydrofuran. The f l a s k was equipped with a r e f l u x condenser and a pressure-equalized add i t i o n funnel, and the whole system was kept under a dry nitrogen atmosphere. Dimethyl carbonate (33.8 g, 0.38 mole) was then introduced and the mixture was heated to r e f l u x with constant s t i r r i n g . A s o l u t i o n of 14.7 g (0.15 mole),of cyclohexanone i n dry tetrahydrofuran (40 ml) was added dropwise through the a d d i t i o n funnel and ca. 150 mg of potassium hydride (22.4% i n o i l ) was introduced to i n i t i a t e the reaction. A f t e r complete addition of cyclohexanone (over approximately 1 h r ) , the mixture was maintained..refluxing f o r another 0.5 hr. F i n a l l y , the mixture was cooled i n i c e and quenched with 10% hydrochloric a c i d (100 ml) and brine (100 ml). The aqueous phase was/extracted with 2 x 200 ml of chloroform.and the combined organic s o l u t i o n was washed with brine, dried over anhydrous, magnesium s u l f a t e and concentrated under reduced 208 pressure. Vacuum d i s t i l l a t i o n of the crude product gave 21.06 g (90%) of 266 as a col o r l e s s l i q u i d : bp 39-40°/0.,3 Torr ( l i t . 1 5 6 bp 68°/0.8 T o r r ) ; IR 1740 and 1715 cm"1 (due to the keto form),, and 1655 and 1615 cm - 1 (due to the enol form); 1HNMR 6 1.4-2.5 (m, 8H), 3.3 (m, ~0.2H, due to the keto form), 3.70 (s, 3H) and 12.0 (s, ~0.8H, due to the enol form); mass spec-trum m/e ( r e l i n t e n s i t y ) 156(54), 128(24), 125(36), 124(100), 123(14), 100(22), 96(16), 87(14), 69(17), 68(55), 55(46) and 41(30). Methyl 2-0xocyclopentanecarboxylate . (269). 1 5 6 - The above proced-ure was followed, using 4.2 g (50 mmole) of cyclopentanone, 7.5 g (157 mmole) of sodium hydride (50% o i l ) and 10.5 ml (125 mmole) of dimethyl carbonate. D i s t i l l a t i o n of the crude product afforded 3.51 g (49%) of 269 as a colorles: l i q u i d : bp 80°/4.0 Torr; IR 1755, 1730, 1660 and 1620 cm"1; 1HNMR 6 1.7-2.6 (m, 6H) , 3.13 (br t, J = 8 Hz, IH) and 3.70 (s,,3H); mass spectrum m/e ( r e l i n t e n s i t y ) 142(50), 114(76), 111(64), 110(70), 87(88), 83(22), 82(23), 69(10), 68(15), 59(14), 55(100) and 41(17). Methyl 2-0xocycloheptanecarboxylate , (270). - The procedure used fo r the preparation of 266 was followed, s t a r t i n g from 7.5 g (157 mmole) of sodium hydride, 10.5 ml (125 mmole) of dimethylcarbonate and 5.6 g (50 mmole) of cycloheptanone. (The cycloheptanone i n 20 ml of dry tetrahydro-furan was added over 2 hr and. r e f l u x was continued f o r another 4 hr before work-up.) The crude product was d i s t i l l e d to. y i e l d 7.59 g (89%) of 270 as a col o r l e s s l i q u i d : bp 58°/0.1 Torr; IR 1740, 1705, 1640 and 1615 cm - 1; 1HNMR 6 1.1-2.7 (m, 10H)., 3.50 (m, -0.8H, due to the keto form), 3.70 (two overlapping.singlets, 3H) and 12.6 (s, -0.2H, due to the enol 209 form); mass spectrum m/e ( r e l i n t e n s i t y ) 170(53), 142(48), 139(40), 138(91), 127(12), 113(36), 110(56), 97(14), 87(37), 82(43), 74(32), 68(22), 67(21), 55(100) and 41(52). Anal. Calcd for CgHi^Oa: C, 63.51; H, 8.29. Found: C, 63.28; H, 8.37. General Procedures for the Generation of Lithium Dialkylcuprate Reagents:-Lithium Dimethylcuprate: Two equivalents of methyllithium ( i n ethyl ether) was added dropwise to a s t i r r e d suspension of 1 eq of cuprous iodide ( p u r i f i e d according to Kauffman's p r o c e d u r e 2 0 2 ) i n dry ethyl ether at 0° and under a dry nitrogen atmosphere. The r e s u l t i n g l i g h t tan s o l u t i o n was used for coupling r e a c t i o n at the appropriate temperature. Lithium Diethylcuprate: Two equivalents of e t h y l l i t h i u m ( i n benzene) was added dropwise to a s t i r r e d suspension of cuprous iodide (1 eq) i n anhydrous et h y l ether at -78° under nitrogen. The r e s u l t i n g black mixture was s t i r r e d f o r 20 min at -78° before use. Lithium Di-n-butylcuprate: Two equivalents of n-butyllithium ( i n hexane) was added dropwise to a s t i r r e d suspension of cuprous iodide (1 eq) i n dry ethyl ether at -47° under nitrogen. The r e s u l t i n g dark brown s o l u t i o n was maintained at -47° for 15 min before use. 210 Lithium Di-sec-butylcuprate: A s o l u t i o n of sec-butyllithium (2 eq) i n cyclohexane was added slowly to a s t i r r e d suspension of cuprous iodide (1 eq) i n anhydrous ethyl ether at -23° under nitrogen. The r e s u l t i n g dark black mixture was s t i r r e d at -23° for 15 min before use. Lithium Di^t-butylcuprate: A s o l u t i o n of _t-butyllithium (2 eq) i n pentane was added dropwise to a s t i r r e d suspension of cuprous iodide (1 eq) i n dry ethyl ether at -47° under nitrogen. The r e s u l t i n g black mixture was s t i r r e d at -47° for 20 min before use. General Work-up Procedure for the Reactions of Enol Phosphates  with Lithium Dialkylcuprates: The reaction mixture was poured into an i c e -cold mixture of 50% aqueous ammonium chl o r i d e and concentrated ammonium hydroxide (ca. 5:1), and the aqueous phase was extracted with ethyl ether. The combined ether extracts were washed with brine, dried over anhydrous magnesium s u l f a t e and then concentrated under reduced pressure. Methyl 2-Methylcyclohexenecarboxylate (268). - A so l u t i o n of enol phosphate 267 prepared in. s i t u from 312 mg (2 mmole) of methyl 2-oxo-cyclohexanecarboxylate, 106 mg (2.2 mmole) of sodium hydride (50%) and 0.32 ml (2.2 mmole) of diethylchlorophosphate i n 7 ml of e t h y l ether (see general procedure) was added slowly into an ether s o l u t i o n of l i t h i u m dimethylcuprate (3 mmole) with cooling i n an ice-bath. A deep purple color developed within seconds, and s t i r r i n g was continued for 2 hr at 0°, and for another 2 hr with the ice-bath removed. The mixture was worked up according to the general 211 procedure to give 317 mg of crude material. Preparative t i c ( s i l i c a g e l , 50:3 carbon t e t r a c h l o r i d e - e t h y l ether of 110 mg of the crude product afforded 100 mg (94%) of 268: c o l o r l e s s l i q u i d ; bp (Kugelrohr d i s t i l l a -tion) 85-88°/20 Torr; IR 1705, 1640 and 1080 cm"1; 1HNMR 6 1.3-1.7 (m, 4H), 1.97 (br s, 3H), 1.8-2.4 (m, 4H) and 3.69 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 154(75), 139(10), 123(34), 122(32), 90(100), 89(33), 79(22) and 67(16). Anal. Calcd for C 9 H 1 4 O 2 : C, 70.10; H, 9.15. Found: C, 69.96; H, 9.31. Methyl 2,6,6-Trimethylcyclohexenecarboxylate (248).- A s o l u t i o n of 9.3 g (30 mmole) of the enol phosphate 271 i n dry ethyl ether (5 ml) was added to a s t i r r e d s o l u t i o n of l i t h i u m dimethylcuprate (60 mmole) i n ethyl ether (150 ml) at 0°. The r e s u l t i n g dark purple mixture was maintained at 0° for 5 hr and then worked up according to the general procedure. The crude product (5.95 g) was d i s t i l l e d (Kugelrohr) to give 5.03 g (92%) of 248 as a c o l o r l e s s l i q u i d : bp 81-83°/3.5 Torr; IR 1710., 1660 (weak) and 1070 cm"1; 1HNMR 6 1.08 (s, 6H), 1.2-2.1 (m, 6H), 1.64 (s, 3H) and 3.69 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 182(36), 167(80), 151(25), 135 (100), 123(67), 107(48), 81(9), 79(10) and 77(8). Anal. Calcd f o r C u H 1 8 0 z : C, 72.49; H, 9.95. Found: C, 72.20; H, 9.87. Methyl 2-^Methylcyclopentenecarboxylate (274)• - A so l u t i o n of the enol phosphate 272 (1 mmole) i n ethyl ether (5 ml) was prepared from 212 142 mg (1 mmole) of methyl 2-oxocyclqpentanecarboxylate, 53 mg (1.1 mmole) of sodium hydride (50%) and 0.16 ml (1.1 mmole) of d i e t h y l chlorophosphate according to the general procedure (2 hr, room temperature). This mixture was added d i r e c t l y i n t o a so l u t i o n of l i t h i u m dimethylcuprate (3 mmole) i n et h y l ether (10 ml) at 0°. The r e s u l t i n g purple suspension was s t i r r e d at 0° f o r 2 hr and then at.room temperature f o r about 1.5 hr. The crude product (169 mg) obtained a f t e r the usual work-up was chromatographed on s i l i c a g el with carbon t e t r a c h l o r i d e - e t h y l ether (50:3) to y i e l d 119 mg (85%) of 274: co l o r l e s s l i q u i d ; bp (Kugelrohr d i s t i l l a t i o n ) 81-83°/20 Torr; IR 1700, 1645, 1120 and 1060 cm"1; 1HNMR.6 1.4-2.2 (m, 2H), 2.10 (br s, 3H), 2.2-2.8 (m, 4H) and 3.69 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 140(95), 125 (30), 109(100) and 81(95). Anal. Calcd f o r C 8 H 1 2 0 2 : C, 68.55; H, 8.63. Found: C, 68.32; H, 8.90. Methyl 2-Methyleycloheptenecarboxylate (275). - A so l u t i o n of the enol phosphate 273 (2 mmole) i n e t h y l ether was prepared from 340 mg (2 mmole) of methyl 2-oxocycloheptanoate, 106 mg (2.2 mmole) of sodium hydride and 0.32 ml (2.2 mmole) of diethyl.chlorophosphate according to the general pro-cedure (2 hr, room temperature). This mixture was added d i r e c t l y into an ether s o l u t i o n of l i t h i u m dimethylcuprate (4 mmole) at 0° and the r e s u l t i n g purple suspension was s t i r r e d for 2 hr at the same temperature. The cooling bath was then removed and s t i r r i n g was continued for. 2 hr. The reaction mix-ture was. worked up as usual to give 366 mg of crude material. Preparative t i c ( s i l i c a g e l , 50:3 carbon t e t r a c h l o r i d e - e t h y l ether) of 184 mg of the crude product afforded 165 mg (98%) of 275 as a c o l o r l e s s l i q u i d : bp (Kugelrohr 213 d i s t i l l a t i o n ) 78-80°/6 Torr; IR 1705, 1635, 1110 and 1040 cm - 1; "HNMR 6 1.2-1.9 (m, 6H), 1.99 (s, 3H), 2.0-2.6 (m, 4H) and 3.68 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 168(100), 153(15), 137(39), 136(36), 125(18), 109(72), 108(47), 93(41), 81(25), 79(22), 67(38), 55(18) and 41(25). Anal. Calcd for C i 0 H 1 6 0 2 : C, 71.39; H, 9.59. Found: C, 71.14; H, 9.55. 2 0 1 Methyl 3-Methylbut-2-enoate (285). - To a sol u t i o n of l i t h i u m dimethylcuprate (2 mmole) i n ethyl ether, cooled at -23°, was added 252 mg (1 mmole) of the enol phosphate 280. The r e s u l t i n g purple mixture was s t i r r e d at -23° for 45 min and then worked up i n the usual manner. The crude product (113 mg) i s o l a t e d was Kugelrohr d i s t i l l e d at 79-82°/20 Torr, to give 97 mg (83%) of 285: IR 1715, 1655 and 1150 cm"1; ^NMR 6 1.88 (s, 3H), 2.15 (s, 3H), 3.65 (s, 3H) and 5.63 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 114(47), 83(100) and 55(45). Methyl E-3-Methylhex-2-enoate (286). - An ether s o l u t i o n of l i t h i u m dimethylcuprate (2 mmole) was cooled to -78°, and to t h i s was added 280 mg (1 mmole) of the enol phosphate 281. After 10 min at -78°, the temperature was raised to -47° and s t i r r i n g was continued for 1.5 hr. The mixture was worked up i n the usual manner to give 145 mg of crude product, which upon preparative t i c on s i l i c a gel with carbon t e t r a c h l o r i d e - e t h y l ether (50:3) furnished 118 mg (83%) of 286 containing pure E_ isomer by vpc (3% OV-17 column, 60°) and 1HNMR analyses: c o l o r l e s s l i q u i d ; bp (Kugelrohr d i s t i l l a -tion) 89-91°/20 Torr; IR 1715, 1650 and 1155 cm"1; XHNMR 6 0.88 ( t , J = 7 Hz, 3H), 1.2-1.7 (m, 2H), 2.0 (m, 2H), 2.13 (d, J = 2 Hz, 3H), 3.63 (s, 3H) 214 and 5.60 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 142(45), 127(45), 126(40), 125(40), 111(99), 83(100), 69(35), 57(48), 55(55), 43(45) and 41(55). Anal. Calcd f o r C s H i ^ : C, 67.57; H, 9.92. Found: C, 67.28; H, 10.12. Methyl E-3-Methyl-6-(2-tetrahydropyranyloxy)hex-2-enoate (287) . -To a so l u t i o n of l i t h i u m dimethylcuprate (8.4 mmole) i n ethyl ether, cooled at -47°, was added 1.6 g (4.2 mmole) of the enol phosphate 282 (dissolved i n 2 ml of ether). The r e s u l t i n g reddish purple mixture was s t i r r e d at -47° f o r 2 hr and then worked up according to the general procedure. The crude product (1.02 g, ca. 100% y i e l d ) obtained was 97% pure i n 287 by vpc analysis (3% OV-17 column, 150°). Preparative t i c ( s i l i c a g e l , 8:1 carbon t e t r a c h l o r i d e - e t h y l ether) of 90 mg of the crude product yielded 74 mg (82%) of 287 (pure by vpc and 1HNMR analyses): c o l o r l e s s l i q u i d ; bp (Kugelrohr d i s t i l l a t i o n ) 110-112°/0.1 Torr; IR 1715, 1650, 1155 and 1030 cm"1; 1HNMR 6 1.2-2.4 (m, 10H), 2.13 (br s, 3H), 3.0-4.0 (m, 4H), 3.63 (s, 3H), 4.50 (m, IH) and 5.63 (m, IH); mass spectrum m/e ( r e l i n t e n -s i t y ) 242(0.1), 1 5 8(20), 141(8), 127(9), 112(6), 109(8), 85(100), 81(10) and 41(10). Anal. Calcd f or C 1 3 H 2 2 O 4 : C, 64.44; H, 9.12. Found: C, 64.23; H, 9.24. Methyl (2E, 6E)-3,7 ,-ll-Trimethyldodeca-2 ,6 ,10-tr.ienoate (288). -To an ether (30 ml) s o l u t i o n of l i t h i u m dimethylcuprate (10 mmole), cooled at -78°, was added 1.94 g (5 mmole) of the enol phosphate 283 i n 2 ml of 215 e t h y l ether. The r e s u l t i n g orange-yellow suspension was s t i r r e d at -78° for 2 hr (mixture turned reddish brown at t h i s stage) and then at -47° for 1 hr (mixture turned dark purple). The reaction mixture was worked up i n the usual manner to give 1.23 g of crude product. Vpc analysis (3% OV-17 column, 160°) indicated a 93% p u r i t y of the desired (E_, E)-isomer. Preparative t i c ( s i l i c a g e l , 50:3 carbon t e t r a c h l o r i d e - e t h y l ether) of 108 mg of the crude material afforded 96 mg (87%) of 288: bp (Kugelrohr d i s t i l l a t i o n ) 96-98°/0.02 Torr; IR 1715, 1650 and 1155 cm"1; ^INMR 6 1.60 (s, 6H), 1.67 (s, 3H), 1.8-2.3 (m, 8H), 2.15 (d, J = 1.5 Hz, 3H), 3.65 (s, 3H), 5.0 (m, 2H), and 5.62 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 250(35), 219(17), 207(20),.137(30), 136(32), 114(54), 81(43), 69(100) and 41(53). High Resolution Mass Measurement Calcd f o r C 1 6 H 2 6 0 2 : 250.1933. Found: 250.1929. E t h y l 2,3-Dimethylbut-2-enoate (289). - To a s o l u t i o n of l i t h i u m dimethylcuprate (0.75 mmole) i n e t h y l ether (5 ml) was added 140 mg of the enol phosphate 284 at 0°. The r e s u l t i n g purple mixture was s t i r r e d for 1 hr at the same temperature and then worked up i n the usual manner. The crude product (73 mg) was d i s t i l l e d (Kugelrohr) to give 60 mg (85%) of 289 as a c o l o r l e s s l i q u i d : bp 86-88°/20 Torr; IR 1705, 1645 and 1105 cm"1; rHNMR <5 1.27 ( t , J = 7 Hz, 3H), 1.8 (br s, 6H), 1.97 (s, 3H), and 4.14 (q, J = 7 Hz, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 142(100), 127(10), 114(20), 99(46), 97(88), 96(69), 69(57) and 41(65). Anal. Calcd f o r C 8H 1 1 +0 2: C, 67.57; H, 9.92. Found: C, 67.46; H, 9.85. 216 "One-pot" Synthesis of Methyl E-3-Methylnon-2-enoate (291).-The dianion of methyl acetoacetate (116 mg, 1 mmole) i n dry tetrahydrofuran (3 ml) was generated according to the general procedure and treated with 166 mg (1.1 mmole) of 1-bromopentane. The mixture was s t i r r e d at 0° f o r 10 min, warmed to room temperature f o r 25 min and then cooled to 0° again. D i e t h y l chlorophosphate (0.16 ml, 1.1 mmole) was introduced and the r e s u l t i n g mixture was warmed to room temperature and s t i r r e d for 2 hr. This enol phosphate mixture was cooled to -47° and then added, through a two-way needle, into an ether (10 ml) so l u t i o n of l i t h i u m dimethylcuprate (3 mmole) maintained at the same temperature. S t i r r i n g was continued f o r 3.5 hr at -47° and the mixture was worked up i n the usual manner. The crude product (177 mg) obtained was chromatographed on s i l i c a gel with carbon t e t r a c h l o r i d e - e t h y l ether (50:3) to y i e l d 125 mg (68%) of 291 as a co l o r l e s s l i q u i d : bp (Kugelrohr) 108-110°/ 20 Torr; IR 1710, 1650 and 1155 cm"1; XHNMR 6 0.87 (br t, J = 6 Hz, 3H), 1.1 - 1.8 (m, 8H), 1.8-2.3 (m, 2H), 2.13 (d, J = 1.8 Hz, 3H), 3.64 (s, 3H) and 5.60 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 184(16), 153(25), 127 (40), 114(100), 110(30), 83(20), 82(20), 55(18) and 41(17). Anal. Calcd f o r C^^o^z- C, 71.70; H, 10.94. Found: C, 71.59; H, 10.75. Methyl 3-Methylpent-2-enoate (Z- and E - 2 9 2 ) , 2 0 3 - To a so l u t i o n of l i t h i u m diethylcuprate (2 mmole) i n e t h y l ether (10 ml), cooled at -98°, was added 252 mg (1 mmole) of the enol phosphate 280. The r e s u l t i n g mixture, which developed a dark purple color within a few minutes, was s t i r r e d f o r 2 hr at -98°. The crude product (151 mg) obtained a f t e r the usual work-up procedure was Kugelrohr d i s t i l l e d at 75-78°/20 Torr to give 115 mg (90%) of 217 292 as a mixture of geometric isomers. Vpc (3% OV-17 column, 60°) and ^NMR analyses showed a 5:1 r a t i o of Z-292 and E-292 i n the product (a 1:1 r a t i o was observed when the above reaction was c a r r i e d out at -78°): IR 1715, 1655 and 1155 cm"1; :HNMR 6 1.06 ( t , J = 7 Hz, 3H, E + Z) , 1.83 (d, J = 1.8 Hz, Z), 2.13 (d, J = 1.8 Hz, E), 1.9-2.3 (m, E), 2.61 (q, J = 7 Hz, Z), 3.63 (s, 3H, E + Z) and 5.58 (m, IH, E + Z) ; mass spectrum m/e ( r e l i n t e n s i t y ) 128(80), 97(100), 74(35), 43(32) and 41(55). Methyl 2-Ethylcyclopentenecarboxylate (293) . - To a s o l u t i o n of l i t h i u m diethylcuprate (3 mmole) i n e t h y l ether (15 ml) was added 2 78 mg (1 mmole) of the enol phosphate 272 at -98°. After- s t i r r i n g f o r 2 hr at the same temperature, 0.48 ml (6 mmole) of et h y l iodide was introduced. The cooling bath was removed and the mixture was s t i r r e d for another 15 min and then worked up i n the usual manner. The crude product (156 mg) obtained was chromatographed on s i l i c a gel with carbon t e t r a c h l o r i d e - e t h y l ether (50:3) to give 108 mg (70%) of 293 as a c o l o r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 108-110°/20 Torr; IR 1700, 1640 and 1120 cm"1; ^NMR 6 1.01 ( t , J = 7 Hz, 3H), 1.4-2.1 (m, 2H), 2.2-2.8 (m, 6H) and 3.68 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 154(100), 139(18), 123(92), 122(74), 95(88), 91(33), 79(33), 67(38), 55(25), 43(21) and 41(33). High Resolution Mass Measurement Calcd f o r C g H n ^ : 154.0994. Found: 154.1000. Methyl 2-Ethylcyclohexenecarboxylate (294). - The enol phosphate 267 (292 mg, 1 mmole) was treated with l i t h i u m diethylcuprate (2 mmole) i n the same manner as described above. Preparative t i c ( s i l i c a g e l , 50:3 carbon V 218 t e t r a c h l o r i d e - e t h y l ether) of the crude product (154 mg) afforded 132 mg (79%) of 294: c o l o r l e s s l i q u i d ; bp (Kugelrohr d i s t i l l a t i o n ) 89-91°/15 Torr; IR 1705, 1640 and 1080 cm - 1; XHNMR 6 1.03 ( t , J = 7 Hz, 3H), 1.4-1.8 (m, 4H), 1.9-2.5 (m, 6H) and 3.68 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 16.8 (100), 137(58), 136(84), 109(75), 79(46), 67(50), 55(22) and 41(30). Anal. Calcd for C 1 0 H 1 6 0 2 : C, 71.39; H, 9.59. Found: C, 71.20; H, 9.80. Methyl 2-Ethylcycloheptenecarboxylate (295).- The enol phosphate 273 (306 mg, 1 mmole) was treated with l i t h i u m diethylcuprate (2 mmole) i n ethyl ether f o r 2 hr at -98° and then worked up i n the usual fashion. The crude product (172 mg) was chromatographed on s i l i c a gel with 50:3 carbon t e t r a c h l o r i d e - e t h y l ether to y i e l d 151 mg (82%) of 295 as a col o r l e s s l i q u i d : bp (Kugelrohr) 111-113°/15 Torr; IR 1705, 1635 and 1110 cm"1; XHNMR 6 1.04 (t , J = 7 Hz, 3H), 1.2-2.0 (m, 6H), 2.0-2.6 (m, 6H) and 3.68 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 182(100), 151(52), 150(88), 123(55), 122(43), 121(27), 108(27), 107(34), 93(80), 81(85), 79(41), 67(40), 55(38) and 41(46). Anal. Calcd f o r C n H 1 8 0 2 : C, 72.49; H, 9.95. Found: C, 72.70; H, 10.14. E t h y l Z-2,3-Dimethylhept-2-enoate (Z-298). - To a solut i o n of li t h i u m di-n-butylcuprate (1 mmole) i n e t h y l ether (5 ml), cooled at -98°, was added 140 mg (0.5 mmole) of enol phosphate 284. The r e s u l t i n g dark purple mixture was s t i r r e d at -98° for 2.5 hr, followed by addition of 0.27 ml (2.5 mmole) of n-butyl bromide. The cooling bath was removed and s t i r r i n g was continued f o r 20 min p r i o r to the general work-up procedure. The crude 219 product (97 mg) obtained was chromatographed on s i l i c a g e l with 50 : 3 carbon t e t r a c h l o r i d e - e t h y l ether to y i e l d 66 mg (72%) of Z-298: c o l o r l e s s l i q u i d ; R 0.71; bp (Kugelrohr d i s t i l l a t i o n ) 95-97°/20 Torr; IR 1705, 1640 and 1105 cm"1; ^NMR 6 0.90 (d i s t o r t e d t, 3H), 1.28 ( t , J = 7 Hz, 3H), 1.0-1.6 (m, 4H), 1 .77 (s, 3H), 1.83 (br s, 3H), 2.32 (br t, J = 6 Hz, 2H) and 4.13 (q, J = 7 Hz, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 184(63), 169(17), 155(18), 139(100), 127( 4 7 ) , 109(80), 102(30), 69(48), 43(30) and 41(48). Anal. Calcd f o r C n ^ c ^ : C, 71.70; H, 10.94. Found: C, 71.42; H, 10.98. A small quantity ( 3 . 5 mg, 2%) of E-298 was also i s o l a t e d from the t i c : R f 0.63; IR 1700, 1640 and 1105 cm"1; ^NMR 6 0.90 (d i s t o r t e d t, 3H), 1.28 ( t , J = 7 Hz, 3H), 1.2-1.6 (m, 4H), 1.83 (br s, 3H), 1.98 (m, 3H), 2.1 (m, 2H), and 4.19 (q, J = 7 Hz, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 184(17), 169 ( 5 ) , 155 ( 5 ) , 139(100), 127(10), 109(20), 102 ( 9 ) , 69(41), 55(22), 43(11) and 41(23). High Resolution Mass Measurement Calcd f o r C11H20O2: 184.1463. Found: 184.1460. Methyl 2-n-Butylcyclopentenecarboxylate (299). - The above pro-cedure was followed using 278 mg (1 mmole) of enol phosphate 272, 2 mmole of l i t h i u m di-n-butylcuprate and 0 . 5 4 ml (5 mmole) of n-butyl bromide. Preparative t i c ( s i l i c a l g e l , 10:1 carbon t e t r a c h l o r i d e - e t h y l ether) of the crude product (179 mg) gave 148 mg (81%) of 299 as a c o l o r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 67-69°/0 . 9 Torr; IR 1700, 1640 and 1120 cm"1; 1HNMR 6 0 . 9 ( d i s t o r t e d t, 3H), 1.0-2.1 (m, 6H), 2.2-2.8 (m, 6H) and 3.67 220 (s, 3H); mass spectrum m/e ( r e l int e n s i t y ) 182(86), 153(100), 151(58), 140(50), 121(55), 93(40), 81(42), 79(30), 67(25) and 41(25). High Resolution Mass Measurement Calcd f o r C11H13O2: 182.1307. Found: 182.1278. Methyl 2-n-Butylcyclohexenecarboxylate (300). - The procedure described i n the preparation of Z-298 was repeated on 292 mg (1 mmole) of enol phosphate 267, 2 mmole of l i t h i u m di-n-butylcuprate and 0.54 ml (5 mmole) of n-butyl bromide. Preparative t i c ( s i l i c a g e l , 50:3 carbon t e t r a c h l o r i d e -e t h y l ether) of the crude product (193 mg) afforded 143 mg (73%) of 300 as a c o l o r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 68-70°/0.7 Torr; IR 1705, 1635 and 1085 cm"1; XHNMR 6 0.9 ( d i s t o r t e d t, 3H), 1.1-1.9 (m, 8H), 2.0-2.6 (m, 6H) and 3.67 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 196(100), 165(99), -154(41), 135(85), 122(38), 107(50), 95(75), 94(65) and 79(66). Anal. Calcd f o r C 1 2 H 2 0 0 2 : C, 73.43; H, 10.27. Found: C, 73.20; H, 10.20. Methyl 2-n-Butylcycloheptenecarboxylate (301). - The procedure described i n the preparation of Z-298 was followed using 153 mg (0.5 mmole) of the enol phosphate 273 as s t a r t i n g m a t e r i a l . The crude product (112 mg) obtained was chromatographed on s i l i c a g e l (10:1 carbon t e t r a c h l o r i d e - e t h y l ether) to y i e l d 85 mg (81%) of 301 as a c o l o r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 73-75°/0.9 Torr; IR 1705, 1640 and 1110 cm"1; ^NMR 6 0.9 (di s t o r t e d t, 3H), 1.1-1.9 (m, 10H), 2.0-2.6 (m, 6H) and 3.69 (s, 3H); mass spectrum m/e ( r e l int e n s i t y ) 210(100), 179(66), 168(31), 149(90), 136(30), 221 125(20), 121(38), 109(38), 108(42), 107(32), 95(56), 93(38), 81(25), 79(33), 67(30), 55(28) and 41(40). Anal. Calcd f o r C 1 3H 220 2: C, 74.24; H, 10.54. Found: C, 74.14; H, 10.44. Reaction of Methyl 2-(Diethylphosphoryloxy)cyclohexenecarboxylate (267) with Lithium Di-sec-butylcuprate. - To a s o l u t i o n of l i t h i u m d i - s e c -butylcuprate (1 mmole) i n e t h y l ether (8 ml), cooled at -63°, was added 146 mg (0.5 mmole) of the enol phosphate 267. The r e s u l t i n g mixture was s t i r r e d at -63° for 2 hr and then worked up i n the usual manner. The crude product (129 mg) was chromatographed on s i l i c a gel (50:3 carbon t e t r a c h l o r i d e -e t h y l ether) to give 58 mg (40%) of s t a r t i n g material 267 (R^ 0.08) and two products: - (a) methyl 2-sec-butylcyclohexenecarboxylate (302) (20 mg, 20%): col o r l e s s l i q u i d ; IR 1710 and 1635 cm"1; XHNMR <5 0.90 ( t , J = 7 Hz, 3H) , 0.97 (d, J = 7 Hz, 3H), 1.0-2.4 (m, 10H), 2.5-3.2 (sextet, J = 7 Hz, IH), and 3.66 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 196(100), 167(55), 165(85), 149(60), 137(85), 128(34), 107(50), 81(32), 79(36) and 41(30). High Resolution Mass Measurement Calcd f o r C I 2 H 2 Q 0 2 : 196.1463. Found: 196.1474. (b) methyl cyclohexenecarboxylate (297) (22 mg, 31%): c o l o r l e s s l i q u i d ; IR 1705, 1650 and 1090 cm"1; ^NMR 6 1.3-1.9 (m, 4H), 1.9-2.4 (m, 4H), 3.68 (s, 3H) and 6.9 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 140(58), 125(11), 109(44), 108(39), 97(10), 83(12), 81(100), 80(67), 79(46), 77(18), 53(25), and 41(29). High Resolution Mass Measurement Calcd f o r CgH^O;?: 140.0837. Found: 140.0833. 222 Jt-Butyl--2-j:-Butyl-l-cyclohexenyl Ketone (303) . - The enol phos-phate 267 (146 mg, 0.5 mmole) was added to a s o l u t i o n of l i t h i u m d i - j t - b u t y l -cuprate (2 mmole) i n ethyl ether (10 ml) at -47°. The r e s u l t i n g mixture was s t i r r e d at -47° for 1 hr, then warmed to -23° and maintained at th i s temperature, for 1 hr 45 min. A f t e r the usual work-up procedure, 101 mg of crude product was obtained. Preparative t i c of t h i s crude material on s i l i c a g el with 10:1 carbon t e t r a c h l o r i d e - e t h y l ether afforded 72 mg (80%) of 303 as a c o l o r l e s s o i l : bp (Kugelrohr d i s t i l l a t i o n ) 68-70/0.5 To r r : IR 1665 and 1625 cm"1; JHNMR 6 1.03 (s, 9H), 1.24 (s, 9H), 1.4-1.8 (m, 4H), and 1.8-2.3 (m, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 222(3), 207(8), 166(69), 165(100), 137(56), 121(18), 109(28), 107(47), 105(23) , 95(94), 93(53), 91(65), 81(94), 79(86), 77(70), 69(51), 67(74), 65(29), 57(93), 55(75), 53(45), 43(40) and 41(99). Anal. Calcd f o r Ci 5H 260: C, 81.02; H, 11.79. Found: C, 81.01; H, 11.79. General Procedure for the Synthesis of the E-Enol Phosphate of A c y c l i c g-Keto Esters.- The 3-keto ester (1 mmole) was dissolved i n dry HMPA (1.5 ml) and the so l u t i o n was cooled with a cold water-bath (ca.10°) and kept under a dry nitrogen atmosphere. Anhydrous triethylamine (0.15 ml, I. 1 mmole) was added, followed ( a f t e r 15 min) by the introduction of 0.16 ml (1.1 mmole) of d i e t h y l chlorophosphate. The r e s u l t i n g white suspension was s t i r r e d at room temperature f o r 3.5 hr and then d i l u t e d with 50% brine (10 ml) and e t h y l ether (50 ml). The ether layer was washed with 3 x 10 ml of brine, dried over anhydrous magnesium s u l f a t e and evaporated i n vacuo. 223 The crude product so obtained was homogeneous by t i c ( s i l i c a g e l , e t h y l ether) and vpc (3% OV-17 column, 150-160°).analyses. Only the E-enol phosphate was observed.in the crude material (according to •'•HNMR) with no detectable quantity of, the Z. isomer. Methyl E-3-(Diethylphosphoryloxy)but-2-enoate (310). - Prepared according to the general procedure from.116 mg (1 mmole) of methyl aceto-acetate. The crude product (227 mg, 90%) was obtained as a co l o r l e s s o i l and,had,the following s p e c t r a l p r o p e r t i e s : IR 1720, .1660, 1280 and 1030 cm"1; 1HNMR 6 .1.37 ( t , J = 7 Hz, 6H), 2.38 (s, 3H), 3.67 (s, 3H), 4.17 (qn, J = 7 Hz, 4H) and 5.77 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 252(34), 221(30), 220(95), 193(23), 192(72), 165(24), 164(95), 155(97), 127(100),, 113(23), 99(88), 81(38), 67(40) and 43(46). High Resolution Mass Measurement Calcd f o r e 9H 1 70 6P: 252.0763. Found: 252.0766. E t h y l E-3-(Diethylphosphoryloxy)-2-methylbut-2-enoate (311). -Prepared from 288 mg (2 mmole) of e t h y l 2-methyl-3-oxobutanoate (279) by following the general procedure. The crude product (515 mg, 92%), obtained as a co l o r l e s s o i l , was characterized by the following s p e c t r a l data: IR 1715, 1655, 1280 and 1030 cm"1; *HNMR <5 1.28 ( t , J = 7 Hz, 3H), 1.37 ( t , J = 7 Hz, 6H), 1.87 ( t , J = 1.8 Hz, 3H)., 2.40 ( t , J, = 1.8 Hz, 3H) and 3.9-4.4 (m,6H); mass spectrum m/e ( r e l i n t e n s i t y ) 280(31), 235(39), 234 (86), 207(10), 206(45), 179(11)., 178(50), 155(94), 150(28), 127(73), 99(100), 81(15) and 43(16). High Resolution Mass Measurement Calcd f o r C u ^ i O g P : 280.1076. Found: 280.1075. 224 Methyl E-3-Methylhept-2-enoate (312). - The E-enol phosphate 310 (110 mg, 0.44 mmole) was treated with 0.88 mmole of lithium di-n-butyl-cuprate in the same manner as described on p. 218. Preparative t i c ( s i l i c a gel, 50:3 carbon tetrachloride-ethyl ether) of the crude product (98 mg) afforded 52. mg (76%) of 312: Rf 0.60; bp (Kugelrohr di s t i l l a t i o n ) 91-93°/ 20 Torr.; IR 1715, 1650 and 1155 cm"1; XHNMR <5 0.90 (distorted t, 3H) , 1.1-1.8 (m, 4H), 2.13 (d, J = 2 Hz, 3H), 1.9-2.3 (m, 2H), 3.63 (s, 3H), and 5.60 (m, IH); mass spectrum m/e (r e l intensity) 156(25), 141(11), 127(43), 125(36), 114(100), 99(13), 96(15), 95(36), 86(12), 85(16), 83(43), 82(49), 69(17), 67(18), 55(41) and 41(36). High Resolution Mass Measurement Calcd for CgHjg02: 156.1150. Found: 156.1151. Besides the major fraction of 312 a small quantity (2 mg, ^a. 2.9%) of methyl Z_-3-methylhept-2-enoate (Z-312) was. also isolated from the t i c and was characterized by the following spectral data: IR 1715, 1650 and 1155 cm-1; ^NMR (100 MHz, FT) 6 0.9 (distorted t, 3H), 1.1-1.7 (m, 4H), 1.84 (d, J = 2 Hz, 3H), 2.58 (br t, J = 7 Hz, 2H), 3.63 (s, 3H) and 5.63 (br s, IH). Ethyl E-2,3-Dimethylheptr-2-enoate (E-298) . - The enol phosphate 311 (140 mg, 0.5 mmole) was. allowed to react with 1.0 mmole of lithium di-n-butyl-cuprate in the same manner as described on p. 218. The crude product obtained was chromatographed on s i l i c a gel with 20:1 petroleum ether-ethyl ether to yield 73 mg (79%) of E-298: see p. 219 for spectral and analytical data. 225 Preparation of Enol Phosphates of g-Diketones and t h e i r Reactions with  Lithium Dialkylcuprates General Procedures for the Preparation of Enol Phosphates of  g-Diketones:-Method A: The g-diketone (1 eq) was dissolved i n a small volume of dry e t h y l ether (or THF) and added to a suspension of sodium hydride (1.1 eq) i n ethyl ether at 0° under nitrogen. A f t e r s t i r r i n g f o r 0.5 - 1 hr at the same temperature, 1.1 eq of d i e t h y l chloro-phosphate was introduced. The r e s u l t i n g mixture was removed from the cooling bath and s t i r r e d f o r 3.5 hr. The enol phosphate was i s o l a t e d from the reaction mixture by employing the work-up procedure (a) or (b), as described on p. 203. Method B: To a suspension of the g-diketone (1 eq) i n dry e t h y l ether, under nitrogen, was added successively 1.1 eq of anhydrous triethylamine and 1.1 eq of d i e t h y l chlorophosphate. The r e s u l t i n g mixture was s t i r r e d f o r 20 hr at room temperature. The f i n a l suspension was f i l t e r e d and the p r e c i p i t a t e was washed with small volumes of e t h y l ether. The combined f i l t r a t e was washed with 10% aqueous sodium bicarbonate and brine, dried over anhydrous magnesium s u l f a t e , and then evaporated under reduced pressure. The crude enol phosphate so obtained was homogeneous by t i c analysis (with the exception of 317) and had s a t i s f a c t o r y s p e c t r a l data. This crude product was used d i r e c t l y i n reactions with l i t h i u m dialkylcuprates without further p u r i f i c a t i o n . 226 Z _ - 4 - ( D i e t h y l p h o s p h o r y l o x y ) p e n t - 3 - e n - 2 - o n e ( Z - 3 1 7 ) . - To a s u s -p e n s i o n o f 48 mg ( 1 . 0 mmole) o f sod ium h y d r i d e (50%) i n d r y e t h y l e t h e r (10 ml ) was added 105 mg ( 1 . 0 5 mmole) o f a c e t y l a c e t o n e a t 0 ° . The r e s u l t i n g w h i t e s u s p e n s i o n was s t i r r e d f o r 20 m i n a t t he same t e m p e r a t u r e , f o l l o w e d by a d d i t i o n o f 0 . 1 6 m l ( 1 . 1 mmole) o f d i e t h y l c h l o r o p h o s p h a t e . The i c e -b a t h was t h e n removed and s t i r r i n g was c o n t i n u e d f o r 20 m i n . The m i x t u r e was f i l t e r e d t h r o u g h c e l i t e and t he f i l t r a t e was e v a p o r a t e d i n v a c u o t o g i v e 220 mg (93% y i e l d b a s e d on sod ium h y d r i d e used ) o f Z - 3 1 7 w h i c h was p u r e by t i c ( e t h y l e t h e r ) and iffNMR a n a l y s e s : c o l o r l e s s l i q u i d ; I R 1 7 0 0 , 1 6 5 0 , 1275 and 1030 c m " 1 ; -^ HNMR 6 1 .37 ' ( t , J = 7 H z , 6H) , 2 . 1 7 ( d , J = 1 .2 H z , 3 H ) , 2 . 2 8 ( s , 3H), 4 . 2 ( q n , J = 7 H z , 4H) and 5 . 4 2 ( b r s , Iff) ; mass s p e c t r u m m/e ( r e l i n t e n s i t y ) 2 3 6 ( 2 3 ) , 2 2 1 ( 5 ) , 1 9 4 ( 9 ) , 1 9 3 ( 1 0 ) , 1 6 5 ( 1 9 ) , 1 5 5 ( 1 0 0 ) , 1 2 7 ( 6 6 ) , 9 9 ( 3 5 ) , 8 5 ( 1 0 ) , 8 2 ( 1 0 ) , 8 1 ( 1 1 ) , 67 (19 ) and 4 3 ( 5 7 ) . H i g h R e s o l u t i o n Mass Measurement C a l c d f o r CgH^yOsP: 2 3 6 . 0 8 1 4 . F o u n d : 2 3 6 . 0 8 3 4 . E - 4 - ( D i e t h y l p h o s p h o r y l o x y ) p e n t - 3 - e n - 2 - o n e ( E - 3 1 7 ) . - (a ) To a s o l u t i o n o f a c e t y l a c e t o n e (200 mg, 2 mmole) i n 2 m l o f d r y h e x a m e t h y l p h o s -p h o r a m i d e , c o o l e d a t ca. 1 0 ° , was added s u c c e s s i v e l y 0 . 3 m l ( 2 . 2 mmole) o f t r i e t h y l a m i n e ( a n h y d r o u s ) and 0 . 3 2 m l ( 2 . 2 mmole) o f d i e t h y l c h l o r o p h o s p h a t e . The r e s u l t i n g w h i t e s u s p e n s i o n , k e p t unde r a d r y n i t r o g e n a t m o s p h e r e , was s t i r r e d f o r 3 h r a t room t e m p e r a t u r e . The f i n a l m i x t u r e was d i l u t e d w i t h e t h y l e t h e r (80 m l ) , washed w i t h 50% b r i n e and d r i e d o v e r a n h y d r o u s magnes ium s u l f a t e . Remova l o f s o l v e n t s i n v a c u o y i e l d e d 381 mg (81%) o f c r u d e p r o d u c t , t he iffNMR s p e c t r u m o f w h i c h i n d i c a t e d a 2 . 5 : 1 m i x t u r e o f E - 3 1 7 and Z - 3 1 7 . P r e p a r a t i v e t i c o f t h e c r u d e p r o d u c t on s i l i c a g e l w i t h e t h y l e t h e r gave 227 107 mg (22.6%) of Z-317 (_R 0.4; sp e c t r a l data the same as those given above), and 263 (mg) 55.7%) of E-317: c o l o r l e s s l i q u i d ; R 0.6; IR 1695, 1615, 1280 and 1025 cm"1; "-HNMR 6 1.36 ( t , J = 7 Hz, 6H), 2.17 (s, 3H), 2.33 (s, 3H), 4.15 (qn, J = 7 Hz, 4H) and 6.17 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 236(27), 221(6), 193(9), 165(21), 155(100), 127(58), 100(28), 99(58), 85(23), 67(28) and 43(83). High Resolution Mass Measurement Calcd for C 9 H 1 7 O 5 P : 236.0814. Found: 236.0807. (b) Acetylacetone was treated according to method A of the general procedures described above to give, i n quantitative y i e l d , a mixture of E-317 and Z-317 i n a r a t i o of 7:1 (determined by vpc (3% OV-17 column, 150°) and H^NMR analyses) . 3-(Diethylphosphoryloxy)-2-cyclohexenone (318). - The crude 318 was obtained i n quantitative y i e l d from cyclohexane-1,3-dione by using method A: pale yellow o i l ; IR 1675, 1630, 1280 and 1030 cm - 1; *HNMR 6 1.37 ( t , J = 7 Hz, 6H), 1.7-2.7 (m, 6H), 4.18 (qn, J = 7 Hz, 4H) and 5.87 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) , 248(49), 235(14), 220(22), 192(22), 179(12), 164(17), 161(20), 155(73), 145(17), 130(50), 125(45), 104(34), 102(100), 99(49), and 67(45). High Resolution Mass Measurement Calcd f o r C 1 0 H 1 7 O 5 P : 248.0814. Found: 248.0790. 228 3-(Diethylphosphoryloxy)-2-cyclopentenone ( 3 1 9 ) . - The crude enol phosphate 319 was obtained i n quantitative y i e l d from cyclopentane -1 ,3 -dione by using method B: pale yellow o i l ; IR 1710 , 1 610 , 1280 and 1030 cm"1; 1HNMR <5 1 .38 ( t , J = 7 Hz, 6H ) , 2 . 3 - 2 . 9 (m, 4 H ) , 4 .2 (m, 4H) and 5.78 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 2 3 4 ( 1 9 ) , 1 7 9 ( 1 9 ) , 1 6 1 ( 2 2 ) , 1 4 5 ( 6 0 ) , 1 2 9 ( 2 2 ) , 1 1 7 ( 7 8 ) , 1 1 6 ( 1 0 0 ) , 9 9 ( 1 9 ) , 8 1 ( 6 6 ) , 53 (85) and 4 5 ( 2 2 ) . High Resolution Mass Measurement Calcd for C g H 1 5 0 5 P : 2 3 4 . 0 6 5 7 . Found: 2 3 4 . 0 6 4 9 . 3 - (Diethylphosphoryloxy)-2-methyl-2-cyclopentenone ( 3 2 0 ) . - The enol phosphate 320 was obtained i n quantitative y i e l d from 2-methylcyclo-pentane-1,3-dione by using method B: pale yellow o i l ; IR 1710 , 1660 , 1280 , and 1030 cm"1; ^NMR <5 1.3.8 ( t , J = 7 Hz, 6H) , 1.67 (br s, 3H) , 2 . 3 - 2 . 6 (m, 2H ) , 2 . 6 - 3 . 0 (m, 2H) and 4 . 22 (qn, J = 7 Hz, 4H); mass spectrum m/e ( r e l i n t e n s i t y ) 2 4 8 ( 5 ) , 2 3 5 ( 9 ) , 1 7 9 ( 8 ) , 1 6 1 ( 1 3 ) , 1 4 5 ( 8 5 ) , . 1 3 0 ( 7 0 ) , 1 1 9 ( 4 5 ) , 117 ( 1 0 0 ) , 8 1 ( 1 9 ) , 67(55) and 4 5 ( 2 8 ) . High Resolution Mass Measurement Calcd f o r CxoHxyOsP: 2 4 8 . 0 8 1 4 . Found: 2 4 8 . 0 8 1 7 . 4 - Methylpent-3-en-2-one ( 3 2 1 ) . - A s o l u t i o n of l i t h i u m dimethyl-cuprate (2 mmole) i n dry e t h y l ether was cooled to -98° and to t h i s was added 236 mg (1 mmole) of 317 (mixture of E_ and isomers) . The r e s u l t i n g dark red suspension was s t i r r e d f o r 2 .5 hr at the same temperature and then worked up by the usual procedure. Kugelrohr d i s t i l l a t i o n of the crude product afforded 81 mg (83%) of 3 2 1 : bp 128-130° ( l i t . 2 0 4 bp 129°); IR 1685 and 229 1615. cm l; 1HNMR <5 1.85 (d, J = 2 Hz, 3H) , 2.15 (s, 6H) , and 6.02 (m, IH). 3-Methyl-2-eyclohexenone ( 3 2 2 ) . l h 3 - Enol phosphate 318 (248 mg, ' 1 mmole) was allowed to react with 1.1 mmole.of l i t h i u m dimethylcuprate i n 10 ml of dry ethyl ether at -78° for 3 hr. The crude product obtained a f t e r the usual work-up procedure was p u r i f i e d by preparative t i c ( s i l i c a g e l , 4:1 carbon t e t r a c h l o r i d e - e t h y l ether) to give 101 mg .(92%) of 322: IR 1655 and 1630 cm"1; 1HNMR 6 1.95 (br s, 3H), 1.5-2.5 (m, 6H) and 5.80 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 110(100), 82(93) and 54(38). 3-t-Butyl-2-cyclohexenone (323) . 1 1 + 9 - To an ethyl, ether s o l u t i o n (8 ml) of l i t h i u m di-t-butylcuprate (1.0 mmole) cooled at -78°, under n i t r o -gen, was added 124 mg (0.5 mmole) of 318. The mixture was s t i r r e d f o r 3 hr at the same temperature and then worked' up by the usual procedure. Prepara-t i v e t i c of the crude product on s i l i c a g el (4:1 carbon t e t r a c h l o r i d e - e t h y l ether) afforded 63 mg.(83%) of 323: IR 1655 and 1610 cm"1; 1HNMR <5 1.12 (s, 9H), 1.7-2.5 (m, 6H) and 5.88 ( s , l H ) ; mass spectrum m/e ( r e l i n t e n s i t y ) 152(78), 137(20), 124(60), 109(100), 96(90),.81(24), 67(20) and 41(22). 3-Methyl-2-.cyclopentenone G24J.. 2 0 5 - Enol phosphate _319 (125 mg, 0.53 mmole) was treated with l i t h i u m dimethylcuprate (0.59 mmole) i n dry e t h y l ether for 3 hr 45 min at -78°. The reaction mixture was worked up i n the usual manner to give 51 mg of crude product which was d i s t i l l e d (Kugelrohr) to y i e l d 43 mg (84%) of 324: bp 76-78°/20 Torr ( l i t . 2 0 5 bp 74°/ 15 To r r ) ; IR 1700, 1670 and 1620 cm"1; XHNMR .6 2.13 (br s, 3H), 2.2-2.7 (m, 4H) and 5.87 (q, J = 1 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 96 (100), 95(48), 81(64), 67(66), 53(60), 41(28) and 40(38). 230 2,3-Dimethyl-2-cyclopentenone (325) . 2 0 6 - To a s o l u t i o n of li t h i u m dimethylcuprate (1.28 mmole) i n dry eth y l ether (5 ml) cooled at 0°, under nitrogen, was added 160 mg (0.64 mmole) of the enol phosphate 320. The r e s u l t i n g mixture was s t i r r e d f o r 2 hr at 0° and then worked up as usual. The crude product obtained was p u r i f i e d by preparative t i c ( s i l i c a gel, 4:3 petroleum ether-ethyl ether) to a f f o r d 52 mg (74%) of 325: IR 1735 (weak), 1695 and 1650 cm"1; -^ HNMR 6 1.68 (s, 3H) , 2.03 (br s, 4H) and 2.38 (s, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 110(100), 95(38), 67(71) and 41(16). 231 SECTION I I I Synthesis of L a t i a L u c i f e r i n g-Cyclogeraniol (329) . - To a s t i r r e d suspension of l i t h i u m aluminum hydride (95'%',; 44 mg, 1.1 mmole) i n anhydrous e t h y l ether (4 ml) was added dropwise an ether s o l u t i o n of methyl g-cyclogeranate (248) (182 mg, 1.0 mmole) at room temperature. The r e s u l t i n g mixture was brought to r e f l u x under a dry nitrogen atmosphere f o r 2 hr and then cooled i n an ice-bath, followed by quenching with 0.4 ml of 5% aqueous sodium hydroxide S t i r r i n g was continued for 30 min at room temperature and the r e s u l t i n g suspension was f i l t e r e d through anhydrous magnesium s u l f a t e . The residue was washed several times with et h y l ether and the combined f i l t r a t e was evaporated under reduced pressure to give 151 mg (98%) of 329 which was homogeneous on t i c ( s i l i c a g e l , 5:1 carbon t e t r a c h l o r i d e - e t h y l ether) and was 99% pure by vpc (3% 0V-101 column) an a l y s i s . An a n a l y t i c a l sample of 329 was obtained by Kugelrohr d i s t i l l a t i o n of the crude ma t e r i a l : bp 55-57°/0.2 Torr; mp 41°; IR 3670, 3500 and 1650 (weak) cm"1; ^NMR 6 1.05 (s, 6H), 1.3-1.7 (m, 4H), 1.73 (s, 3H), 1.8-2.1 (m, 2H) and 4.10 (s, 2H); mass spectrum m/e ( r e l in t e n s i t y ) 154(28), 139(21), 136(32), 123(43), 121(100), 105(13), 93(30), 79(22) and 41(16). Anal. Calcd for C 1 0H 1 80: C, 77.87; H, 11.76. Found: C, 77.72 H, 11.91. 232 l-Bromomethyl-2,6,6-trimethyl-l-cyclohexene (330). - A p r e c h i l l e d s o l u t i o n of 48% hydrobromic acid (50 ml) was added to 1,222 g (7.9 mmole) of 329 with cooling i n an ice-bath. The mixture, kept under nitrogen, was s t i r r e d f o r 10 min when 30 ml of n-pentane was introduced. S t i r r i n g was continued f o r 3 hr at 0°. The two-phase mixture was then poured into i c e -cold water, and the aqueous layer was extracted with n-pentane. The com-bined extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium s u l f a t e and concentrated under reduced pressure. The crude product 330 (1.402 g, 82%) so obtained was homogeneous by t i c analysis ( s i l i c a g e l , 6:1 carbon t e t r a c h l o r i d e - e t h y l ether) and had s a t i s f a c t o r y s p e c t r a l data: pale yellow o i l ; IR 1645 cm *; ^NMR 6 1.1 (s, 6H), 1.3-1.7 (m, 4H), 1.72 (s, 3H), 2.0 (m, 2H) and 4.02 (s, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 137 (P +-Br, 18), 136 (P +-HBr, 49), 121(100), 107(21), 93(30) and 79(17). Methyl 3-Oxo-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)pentanoate (331). The dianion of methyl acetoacetate (102 mg, 0.88 mmole) i n tetrahydrofuran was generated according to the general procedure (see p. 181). To t h i s dianion s o l u t i o n , cooled i n an ice-bath, was added 174 mg (0.8 mmole) of the crude bromide 330. The r e s u l t i n g yellow suspension was s t i r r e d f o r 1 hr 45 min at 0° and then worked up i n the usual manner (see p. 181). The crude product (181 mg) obtained was chromatographed on s i l i c a g el with 5:1 petroleum ether-ethyl ether to af f o r d 160 mg (79.5%) of 331 as a c o l o r l e s s l i q u i d : IR 1745, 1715, 1655 and 1635 cm"1; H^NMR 6 0.97 (s, 6H), 1.3-1.7 (m, 4H), 1.55 (s, 3H), 1.7-2.8 (m, 6H), 3.40 (s, 2H) and 3.68 (s, 3H); 233 mass spectrum m/e ( r e l i n t e n s i t y ) 252(33), 234(47), 221(33), 220(94), 163 (51), 159(82), 145(94), 137(66), 136(93), 129(53), 123(90), 121(100), 119 (50), 107(82), 105(75), 95(91), 93(94), 91(77), 81(90), 79(86) 69(58) , 67(61), 59(50), 55(90), 43(72) and 41(98). High R e s o l u t i o n Mass Measurement Calcd f o r C 1 5 H 2 4 O 3 : 252.1726. Found: 252.1726. Methyl E - 3 - M e t h y l - 5 - ( 2 , 6 , 6 - t r i m e t h y l - l - c y c l o h e x e n - l - y l ) p e n t - 2 -enoate (332). - The Z-enol phosphate of 331 (72 mg, 0.28 mmole) i n e t h y l ether was prepared i n the same manner as described on p. 203. This enol phosphate s o l u t i o n was syringed i n t o a s o l u t i o n of l i t h i u m dimethylcuprate (0.56 mmole) i n dry e t h y l ether (3 ml), cooled at -78°. The r e s u l t i n g purple mixture was s t i r r e d at -78° f o r 2 hr and then warmed to -47° over 2 h r . The r e a c t i o n mixture was worked up according to the usual procedure (see p. 210) to give 110 mg of crude product which, a f t e r p r e p a r a t i v e t i c ( s i l i c a g e l , 20:1 carbon t e t r a c h l o r i d e - e t h y l ether) p u r i f i c a t i o n , f u r n i s h e d 65 mg (93%) of 332: c o l o r l e s s l i q u i d ; bp (Kugelrohr d i s t i l l a t i o n ) 86-88°/ 0.02 Torr; IR 1715 and 1650 cm"1; !HNMR <5 1.0 ( s , 6H), 1.2-1.7 (m, 4H), 1.57 ( s , 3H), 1.7-2.1 (m, 2H), 2.13 (d, J = 1.5 Hz, 3H), 2.17 (br s, 4H), 3.63 ( s , 3H) and 5.61 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 250(10), 219(4), 176(5), 138(13), 137(100), 121(9), 114(40), 95(30), 81(15) and 41(10). Anal. Calcd f o r C 1 6 H 2 6 0 2 : C, 76.75; H, 10.47. Found: C, 76.80; H, 10.40. 234 E-3-Methyl-5- (2,6 ,6-trimethyl-l-cyclohexen-l-yl) pent-2-en-l-ol (333). - To a s o l u t i o n of 43 mg (0.17 mmole of the ester 332 i n dry hexane (2 ml) was added 0.36 ml (0.36 mmole) of diisobutylaluminum hydride (1 M i n hexane) at -78°. The mixture was s t i r r e d under nitrogen f or 2 hr at the same temperature, followed by quenching with saturated aqueous ammonium chloride. A f t e r warming up to room temperature, the r e s u l t i n g cloudy suspen-sion was a c i d i f i e d with 10% hydrochloric acid u n t i l the aqueous layer turned clear. The aqueous phase was extracted with et h y l ether and the ether solu-t i o n was. washed with brine, dried over.anhydrous magnesium s u l f a t e , and eva-porated under reduced pressure. The crude product (38 mg, 100%) obtained was homogeneous by t i c ( s i l i c a g e l , 5:1 petroleum ether-ethyl ether) analysis and showed e s s e n t i a l l y pure. 333 i n the 1HNMR spectrum. Preparative t i c of the crude product gave an a n a l y t i c a l sample of 333 (36.5 mg, 97%): c o l o r l e s s o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 93-95°/0.05 Torr; IR 3650, 3500 and 1670 cm"1; !HNMR <5 1.0 (s, 6H), 1.2-2.2(m, 6H), 1.6 (s, 3H)., 1.7 (s, 3H) , 2.06 (br s, 4H), 4.1 (br d, J = 7 Hz, 2H) and 5.37 (br t , J = 7 Hz, 1H) ; mass spectrum m/e ( r e l i n t e n s i t y ) 222(6), 204(14), 191(11), 189(12), 149(25), 138(27), 137(96), 136(72), 123(40), 121(66), 119(42), 109(48), 107(56), 105(53), 95(100), 93(79), 91(73), 81(98), 79(79), 77(65), 69(78), 67(84), 65(40), 57(74), 55(86), 53(51), 44(93), 43(77) and 41(98). Anal. Calcd f o r C i 5 H 2 6 0 : C, 81.02; H, 11.79. Found: C, 81.00; H, 11.72. 235 E_-3-Methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl) -2-pentenal (334) . 1 s 7 p - To a s t i r r e d suspension of 340 mg of active manganese dioxide (prepared by Attenburrow's method 1* 7 3 ) i n dry hexane was added 32 mg (0.14 mmole) of alcohol 333 at 0°. S t i r r i n g was continued f o r 1.5 hr at 0° and 0.5 hr at room temperature. The mixture was then f i l t e r e d through C e l i t e and the residue was eluted with n-pentane. The combined f i l t r a t e was evaporated under reduced pressure to give 31 mg (98%) of crude 334 which was homogeneous by t i c analysis ( s i l i c a g e l , 10:1 petroleum ether-ethyl ether) and showed s a t i s f a c t o r y s p e c t r a l data: IR 1670 and 1635 cm - 1; -^ HNMR 6 1.02 (s, 6H), 1.2-1.7 (m, 4H), 1.6 (s, 3H), 1.7-2.1 (m, 2H), 2.2 (br s, 7H), 5.83 (br d, J = 7 Hz, IH) and 9.13 (d, J = 8 Hz, IH); mass spectrum m/e ( r e l in t e n s i t y ) 220(1), 219(2), 191(5), 177(10), 153(17), 139(16), 137(56), 135(34), 125(22), 123(45), 121(39), 119(23), 111(42), 109(63), 107(50), 95(73), 93(55), 91(46), 81(64), 79(50), 77(39), 71(51), 69(71), 67(66), 55(74), 43(100) and 41(75). Synthesis of (E, E)-10-Hydroxy-3,7-dimethyldeca-2,6-dienoic Acid (335) Methyl 3-Oxo-6-(2-tetrahydropyranylo xy)hexanoate (277). - A so l u t i o n of the dianion of methyl acetoacetate was generated i n the same manner as described on p. 181 from 6.96 g (60 mmole) of methyl acetoacetate, 3.02 g (63 mmole) of sodium hydride (50%) and 37.5 ml (60 mmole) of n-butyl-l i t h i u m (1.6 M) i n 130 ml of dry tetrahydrofuran. To t h i s s o l u t i o n , cooled i n an ice-bath, was added 6.27 g (30 mmole) of 2-bromoethanol tetrahydropyranyl ether (340) (prepared from 2-bromoethanol 2 0 7). The r e s u l t i n g yellow suspen-236 sion was s t i r r e d f o r 2 hr at 0° and then poured i n t o 200 ml of i c e - c o l d saturated ammonium, chloride s o l u t i o n . The aqueous phase was extracted with 2 x 200, ml of e t h y l ether and the combined organic s o l u t i o n was washed with brine and dried over anhydrous sodium.sulfate. The crude product obtained a f t e r removal of solvents was Kugelrohr d i s t i l l e d to y i e l d 5.456 g (75%) of. 277 as a c o l o r l e s s o i l : bp 116-118°/0.1 Torr; IR 1745, 1715, 1655, 1630, 1440.and 1030 cm"1; *HNMR 6 1.2-2.2 (m, 8H), 2.63 ( t , J = 7 Hz, 2H), 3.45 (s, 2H), 3.2-4.1 (m, 4H), 3.71 (s, 3H), and 4.5 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 244(2), 190(4), 159.(8), 143(65), 142(65), 111(89), 101(38), 85(99), 84(67), 83(32), 69(100), 55(71) and 41(40). Anal. Calcd f o r C 1 2H2o0 5: C, 59.00; H, 8.25. Found: C, 58.80; H, 8.27. Methyl E-3-Methy1-6-(2-tetrahydropyranyloxy)hex-2-enoate (287). -See p. 214 for preparation and s p e c t r a l data. E-3-Methyl-6-(2-tetrahydropyranyloxy)hex-2-en-l-ol (341). - A so l u t i o n of 3.63 g (15 mmole') of ester 287 i n dry e t h y l ether (10 ml) was added dropwise to a suspension of 374 mg (9.38 mmole) of l i t h i u m aluminum hydride i n 60 ml of e t h y l ether (anhydrous) at room temperature with constant s t i r r i n g . The mixture, kept under nitrogen, was heated under r e f l u x for 1 hr. About 4 ml of 5% aqueous sodium hydroxide was then introduced and s t i r r i n g was continued f o r 45 min. The r e s u l t i n g suspension was f i l t e r e d through anhydrous sodium s u l f a t e and the residue was eluted with more e t h y l ether. The combined f i l t r a t e was concentrated under reduced pressure to give . 3.161 g (98%) of crude 341 which was very pure by t i c ( s i l i c a g e l , 1:1 carbon t e t r a c h l o r i d e - e t h y l ether) and spectroscopic analyses. P u r i f i c a t i o n of the 237 crude product by Kugelrohr d i s t i l l a t i o n furnished 2.983 g (93%) of 341: col o r l e s s o i l ; bp 98-100°/0.05 Torr; IR 3670, 350Q and 1670 cm-1; XHNMR 6 1.2-2.3 (m, 11H), 1.67 (s, 3H), 3.1-3.9 (m, 4H), 4.09 (d, J = 7 Hz, 2H), 4.50 (m, IH) and 5.38 (br t, J = 7 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 214(0.5), 196(1), 130(5), 112(6), 101(10), 97(11), 85(100), 84(20), 69(10), 67(14), 57(15), 55(15), 43(14) and 41(25). High Resolution Mass Measurement Calcd f or C 1 2 H 2 2 0 3 : 214.1569. Found: 214.1579. E_-l-Bromo-3-methyl-6-(2-tetrahydropyranyloxy)-2-hexene (343). -A mixture of alcohol 341 (1.498 g, 7.0 mmole) and anhydrous l i t h i u m bromide (1.97 g, 22.7 mmole) i n dry ethyl ether (70 ml) was cooled at -78° and kept under nitrogen. To t h i s s t i r r e d mixture was added 4.4 ml (7.0 mmole) of n-but y l l i t h i u m (1.6 M i n hexene), followed (after 20 min) by 0.57 ml (7.35 mmole) of methanesulfonyl ch l o r i d e . The r e s u l t i n g mixture was warmed to -10° over 1 hr, maintained at -10° f o r 0.5 hr and then s t i r r e d for 6 hr with-out the cooling bath. The f i n a l suspension was poured into 30 ml of i c e -cold 5% aqueous sodium bicarbonate and the aqueous phase was separated and extracted with 30 ml of ethy l ether. The combined ether s o l u t i o n was washed with brine, dried over anhydrous sodium s u l f a t e and evaporated under reduced pressure. The crude bromide 343 (1.914 g, 99%), obtained as a s l i g h t l y tan o i l , showed s a t i s f a c t o r y s p e c t r a l data: IR 1660, 1120, and 1030 cm 1; 1HNMR 6 1.1-2.4 (m, 10H), 1.72 (s, 3H), 3.1-3.9 (m, 4H), 3.95 (d, J = 8 Hz, 2H), 4.52 (m, IH), and 5.5 (br t, J - 8 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 122(P-C 5H 90-Br, 11), 98(13), 97(100), 85(33), 84(77), 238 83(38), 71(12), 69(13), 67(16), 56(24), 55(93), 54(21), 43(45) and 41(34). Since bromide 343 was sensitive to d i s t i l l a t i o n and chromatographic p u r i f i -cation conditions (the crude material decomposed quite rapidly on standing at room temperature), no satisfactory analytical data could be obtained. Methyl E-7-Methyl-3-oxo-10-(2-tetrahydropyranyloxy)dec-6-enoate (344). - A solution of the dianion of methyl acetoacetate (2.436 g, 21 mmole) in dry tetrahydrofuran (50 ml) was prepared according to the general procedure (p. 181). To this was added 1.91 g (6.9 mmole) of crude bromide 343 (prepared above) at 0°. The resulting yellow suspension was stirred for 2 hr at the same temperature and then worked up in the same way as shown on p. 236. Kugelrohr d i s t i l l a t i o n of the crude product obtained gave 1.529 g (71%) of the alkylation product 344: bp 120-122°/0.04 Torr; IR 1745 and 1715 cm"1; 1HNMR 6 1.2-2.7 (m, 14H), 1.63 (s, 3H), 3.1-3.9 (m, 4H), 3.4 (s, 2H), 3.71 (s, 3H), 4.52 (m, IH), and 5.05 (m, IH); mass spectrum m/e (rel intensity) 312(0.8), 248(10), 228(7), 220(5), 210(4), 206(4), 192(7), 170(5), 164(5), 155(14), 152(5), 149(5), 143(15), 130(6), 127(7) 101(9), 95(11), 94(15), 85(83), 84(83), 83(40), 69(20), 67(14), 56(35), 55(100), 54(32), 43(35) and 41(35). Anal. Calcd for C i 7 H 2 8 0 5 : C, 65.36; H, 9.03. Found: C, 65.38; H, 9.20. Methyl (E_, E_)-3,7-Dimethyl-10-(2-tetrahydropyranyloxy)deca-2,6-dienoate (345). - The enol phosphate of B-keto ester 344 (230 mg, 0.737 mmole) was generated in 5 ml of dry ethyl ether by the procedure described on p. 203. This enol phosphate mixture was added through a two-way needle 239 into an ether s o l u t i o n of l i t h i u m dimethylcuprate (1.48 mmole), cooled at -78°. The r e s u l t i n g orange-yellow suspension was s t i r r e d f o r 0.5 hr at -78° and then for 2 hr at -47° (reaction mixture turned purple a f t e r 20 min at -47°). The reaction mixture was worked up i n the usual manner (p. 210) to give 260 mg of crude product, which upon preparative t i c ( s i l i c a g e l , 4:1 carbon t e t r a c h l o r i d e - e t h y l ether) afforded 210 mg (92%) of 345 as a c o l o r l e s s l i q u i d : bp (Kugelrohr d i s t i l l a t i o n ) 108-110°/0.04 Torr; IR 1710 and 1650 cm"1; 1HNMR <5 1.1-2.5 (m, 14H), 1.61 (s, 3H), 2.14 (d, J = 1.4 Hz, 3H), 3.1-4.0 (m, 4H), 3.64 (s, 3H), 4.52 (m, IH), 5.05 (m, IH) and 5.61 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 310(0.6), 279(0.7), 278(0.7), 227(4), 226(11), 196(5), 195(6), 194(4), 149(5), 121(4), 114(18), 95(43), 85(100), 84(12), 83(14), 67(12), 55(16), 43(11) and 41(14). Anal. Calcd f o r C 1 8H 3o0 4: C, 69.64; H, 9.74. Found: C, 69.80; H, 9.92. Methyl (E, E)-10-Hydroxy-3,7-dimethyldeca-2,6-dienoate (346). -The tetrahydropyranyloxy ester 345 (200 mg, 0.64 mmole) and 10 mg of jp_-toluenesulfonic acid were dissolved i n 10 ml of dry methanol and s t i r r e d for 2 hr at room temperature. The s o l u t i o n was then concentrated under reduced pressure and the residue was d i l u t e d with ethyl ether, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium s u l f a t e . Evaporation xn vacuo yielded 143 mg (99%) of hydroxy ester 346 which was i d e n t i c a l with,an authentic sample (see footnote (i;!o) , p. 155) by vpc (3% OV-17 column, 150°) as w e l l as t i c ( s i l i c a g e l , 1:1 carbon t e t r a c h l o r i d e -ethyl ether) analyses. The s p e c t r a l properties of 346 were i n excellent 240 agreement with those of the authentic material: IR (CH2CI2) 3670, 1715, 1650, 1220 and 1150 cm"1; 1HNMR 6 1.2-2.4 (m, 9H), 1.61 (s, 3H), 2.14 (d, J = 1.4 Hz, 3H), 3.56 (t, J = 6 Hz, 2H), 3.64 (s, 3H), 5.06 (m, IH) and 5.60 (br s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 226(6), 208(3), 196(10), 195(10), 194(8), 167(11), 166(10), 114(50), 95(100), 85(29), 83(22), 82(18), 69(24), 67(30), 55(29), 43(16) and 41(28). (E, E_)-10-Hydroxy-3,7-dimethyldeca-2,6-dienoic acid (335). - To a sol u t i o n of 42 mg (0.135 mmole) of ester 345 i n methanol (2 ml) was added 1 ml of 5% aqueous sodium hydroxide. After s t i r r i n g f o r 3 hr at 60°, the methanol was evaporated under reduced pressure and the aqueous s o l u t i o n was a c i d i f i e d with 5% hydrochloric a c i d . Dioxane . was introduced (ca. 2 ml) u n t i l a homogeneous s o l u t i o n was formed, which was s t i r r e d for 1 hr at room temper-ature. The r e s u l t i n g mixture was saturated with sodium ch l o r i d e and extracted with ethyl ether. The ether s o l u t i o n was dried over anhydrous sodium s u l f a t e and concentrated under reduced pressure. The residue obtained was pa r t i t i o n e d between 10% aqueous sodium bicarbonate and chloroform. A c i d i f i c a t i o n of the bicarbonate phase with concentrated hydrochloric acid, followed by extraction with e t h y l ether, and drying (anhydrous sodium sulfate) and evaporation of the ether extracts furnished 26 mg (91%) of hydroxy acid 335. The spe c t r a l data of t h i s synthetic material were i n excellent agreement with those reported previously f or the natural compound 1 7 7: IR 3600, 3400-2600 (broad), 1690 and 1640 cm - 1; XHNMR 6 1.2-2.4 (m, 8H), 1.6 (s, 3H), 2.15 (s, 3H), 3.58 (t, J = 6 Hz, 2H), 5.05 (m, IH), 5.62 (m, IH) and 6.73 (br s, 2H, exchangeable with D 20); mass spectrum m/e ( r e l i n t e n s i t y ) 212(2), 195(10), 194(13), 241 166(11), 135(10), 125(12), 113(14), 111(15), 100(18), 97(17), 96(16), 95(94), 85(100), 69(16), 67(24), 55(26), 43(52) and 41(27). High Resolution Mass Measurement Calcd f or C 1 2 H 2 0 O 3 : 212.1412. Found: 212.1429. Synthesis of Mokupalide (347) 2,6,6-Trimethyl-l-phenylthiomethyl-l-cyclohexene (350). - To a s t i r r e d s o l u t i o n of alcohol 329 (271 mg, 1.76 mmole) i n dry tetrahydrofuran (8 ml) was added 1.1 ml (1.76 mmole) of n-butyllithium (1.6 M i n hexane), under nitrogen, at -23°. Af t e r 20 min, 0.14 ml (1.86 mmole) of methane-su l f o n y l chloride was introduced and the mixture was warmed to 0° over 30 min S t i r r i n g was continued f o r 1 hr at 0°, followed by the addition of a THF solu t i o n (4 ml) of l i t h i u m thiophenoxide (1.95 mmole, generated from 0.2 ml of benzenethiol and 1.2 ml of n-butyllithium). The r e s u l t i n g mixture was s t i r r e d f o r 1 hr at 0° and then 3 hr at room temperature. The f i n a l r e a c t i o n mixture was d i l u t e d with ethyl ether, washed with 10% aqueous sodium hydroxid and brine, and dried over anhydrous magnesium s u l f a t e . Removal of solvents under reduced pressure gave 389 mg of crude product, which was chromatogra-phed on a short column of s i l i c a g el (100-200 mesh) with carbon t e t r a c h l o r i d e to y i e l d 363 mg (84%) of 350: IR 1585, 1480 and 1440 cm"1; 1HNMR <5 1.09 (s, 6H), 1.2-1.7 (m, 4H), 1.73 (s, 3H), 1.95 (m, 2H), 3.58 (s, 2H) and 7.18 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 246(36), 218(18), 137(100), 136(59) 121(41), 110(30), 109(30), 95(58), 81(33), 69(25) and 41(27). Anal. Calcd f o r C 1 6H 2 2S: C, 77.99; H, 9.00. Found: C, 77.89; H, 9.02. 242 Methyl (6E_)-7,ll-Dimethyl-3-oxododeca-6,10-dienoate (278). -The dianion of methyl acetoacetate (6.96 g, 60 mmole) i n tetrahydrofuran (100 ml) was prepared i n the usual manner (p. 181), Geranyl bromide (10.85 g, 50 mmole) was added to t h i s dianion s o l u t i o n at 0° and the yellow suspension formed was s t i r r e d for 1 hr at the same temperature. Work-up of the reaction mixture by the usual procedure (p. 181) led to 12.8 g of crude product, which was p u r i f i e d by Kugelrohr d i s t i l l a t i o n to give 11.97 g (95% based on geranyl bromide used) of the B-keto ester 278 as a c o l o r l e s s l i q u i d : bp 90-92°/0.02 Torr; IR 1745, 1715, 1650 and 1630 cm - 1; 1HNMR 6 1.62 (s, 6H), 1.67 (s, 3H), 1.97 (br s, 4H), 2.0-2.7 (m, 4H), 3.38 (s, 2H), 3.70 (s, 3H) and 5.02 (m, 2H); mass spectrum m/e ( r e l i n t e n s i t y ) 252(25), 234(18), 209 (13), 191(16), 151(17), 137(16), 136(53), 129(29), 123(27), 121(28), 116(24), 110(17), 109(100), 107(18), 105(26), 101(36), 95(28), 93(25), 81(47), 69(86), 55(22) and 41(53). High Resolution Mass Measurement Calcd f or C 1 5 H 2 1 + O 3 : 252.1725. Found: 252.1740. Methyl (2E, 6E)-3,7,ll-Trimethyldodeca-2,6,10-trienoate (288). -See p. 214 for preparation and s p e c t r a l data. Methyl (E, E_, E)-12-Hydroxy-3,7 ,ll-trimethyldodeca-2,6,10-trienoate (351). - A suspension of 5.58 g (0.05 mole) of selenium dioxide (99.4%) i n dichloromethane (250 ml) was s t i r r e d with 28.7 ml (0.2 mole) of 70% t - b u t y l -hydroperoxide for 30 min at room temperature i n the dark. The r e s u l t i n g b r i e f l y homogeneous so l u t i o n was cooled to 10°, followed by the addition of 25.0 g (0.1 mole) of 288. The mixture was s t i r r e d for 4.5 hr at 10° and 243 then d i l u t e d with 150 ml dichloromethane. The organic s o l u t i o n was washed with 10% aqueous sodium bicarbonate, dri e d over anhydrous magnesium s u l f a t e and evaporated under reduced pressure. The crude material obtained was chromatographed on s i l i c a gel (100-200 mesh) with 3:1 petroleum ether-eth y l ether to give the following components, i n order of el u t i o n : (a) st a r t i n g material 288 (4.750 g, 19%); (b) methyl (E_, E, E)-3, 7,11-t rimethyl-12-oxododeca-2,6,10-trienoate (359) (1.327 g, 5%): c o l o r l e s s o i l ; IR 1690 and 1650 cm - 1; 1HNMR 6 1.62 (s, 3H), 1.73 (s, 3H), 2.15 (s, 3H), 2.0-2.4 (m, 8H), 3.64 (s, 3H), 5.07 (m, IH), 5.60 (m, IH), 6.37 (m, IH) and 9.30 (d, J = 1 Hz, IH) mass spectrum m/e ( r e l i n t e n s i t y ) 264(4),• 233(6), 232(6), 181(18), 165(19), 157(28), 155(28), 151(27), 141(32), 127(53), 125(62), 121(51), 114(100), 113(31), 97(65), 95(99), 83(44), 69(32) and 55(54). High Resolution Mass Measurement Calcd for C i 6 H 2 4 0 3 : 264.1726. Found: 264.1728. (c) methyl (2E, 6E)-8-hydroxy-3,7,ll-trimethyldodeca-2,6,10-trienoate (358) (2.128 g, 8%): c o l o r l e s s o i l ; IR 3600, 1710 and 1650 cm - 1  1HNMR 6 1.63 (s, 6H), 1.70 (s, 3H), 2.17 (s, 3H), 1.9-2.6 (m, 7H), 3.63 (s, 3H), 3.93 (t, J = 7 Hz, IH), 5.03 (m, IH), 5.3 (m, IH) and 5.60 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 266(1), 248(2), 235(2), 197(24), 166(14), 165(100), 147(7), 138(5) (metastable peak = (165) 2/197), 137(11), 135(9), 118(14), 113(10), 108(21), 106(17), 94(12), 92(17), 90(9), 83(16), 70(29), 69(18), 55(23), 43(16) and 41(30). High Resolution Mass Measurement Calcd for C 1 6 H 2 6 0 3 : 266.1882. Found: 266.1870. 244 •(d) 351 (10.906 g, 41%); c o l o r l e s s o i l ; IR 3550, 1715 and 1650 cm - 1; 1HNMR 6 1.60 (s, 3H), 1.63 (s, 3H), 1.8-2.3 (m, 9H), 2.13 (d, J = 1.2 Hz, 3H), 3.63 (s, 3H), 3.94 (s, 2H), 5.05 (m, IH), 5.30 (m, IH) and 5.60 (m, IH); 1HNMR (in CClh) 6 1.60 (s, 6H), 1.8-2.3 (m, 8H), 2.09 (d, J = 1.2 Hz, 3H), 3.15 (br s, IH, exchangeable with D 20), 3.58 (s, 3H), 3.83 (s, 2H), 4.95 (m, IH), 5.25 (m, IH) and 5.51 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 266(4), 248(7), 234(12), 181(31), 164(30), 149(38), 135(50), 125(40), 123(28), 121(100), 114(87), 109(43), 107(66), 105(36), 97(31), 95(68), 93(90), 81(63), 69(50), 67(50), 55(68), 43(62) and 41(60). High Resolution Mass Measurement Calcd f or C i 6 H 2 6 0 3 : 266.1882. Found: 266.1861. Methyl (E, E_, E)-12-Methanesulf onyloxy-3,7 ,11-trimethyldodeca-2,6,10-trienoate (352). - To a so l u t i o n of 1.09 g (4.1 mmole) of the alcohol 351 i n dry dichloromethane (35 ml), cooled at -10° and kept under nitrogen, was added successively 0.86 ml (6.15 mmole) of anhydrous triethylamine and 0.35 ml (4.51 mmole) of methanesulfonyl chloride. The r e s u l t i n g suspension was s t i r r e d for 2.5 hr at -10°, and then poured into 15 ml of ic e - c o l d water. The organic layer was separated, washed with i c e - c o l d 5% aqueous hydrochloric a c i d , saturated aqueous sodium bicarbonate and brine, and dried over anhy-drous magnesium s u l f a t e . Removal of solvent under reduced pressure yielded 1.410 g (100%) of crude 352 as a pale yellow o i l which was homogeneous by t i c analysis ( s i l i c a g e l , 5:1 carbon t e t r a c h l o r i d e - e t h y l ether), and showed s a t i s f a c t o r y s p e c t r a l data: IR 1710, 1650, 1360, 1170 and 1150 cm - 1; JHNMR 6 1.59 (s, 3H), 1.70 (s, 3H), 2.13 (d, J = 1.2 Hz, 3H), 1.9-2.3 (m, 8H), 2.95 (s, 3H), 3.65 (s, 3H), 4.54 (s, 2H), 5.03 (m, lH),5.2-5.7 (m, 2H); 245 mass spectrum m/e ( r e l i n t e n s i t y ) 344(2), 248(34), 217(10), 189(12), 136(19), 135(100), 134(35), 133(22), 121(36), 119(38), 114(51), 109(24), 107(83), 105(35), 96(33), 93(76), 91(31), 81(32), 79(47), 67(25), 55(44), 43(26) and 41(34). High Resolution Mass Measurement Calcd f or CxyHasOsS: 344.165 8-Found: 344.1669. Methyl (E, E, E)-3,7,ll-Trimethyl-12-phenylthiododeca-2,6,10- trienoate (353). - A s o l u t i o n of benzenethiol (0.46 ml, 4.5 mmole) i n dry tetrahydrofuran (15 ml) was allowed to react with 2.58 ml (4.5 mmole) of methyllithium (1.75 M i n ether) for 20 min at 0°, under a dry nitrogen a t-mosphere. To the resultant l i t h i u m thiophenoxide s o l u t i o n was added 1.35 g (3.9 mmole) of 352 and the mixture was s t i r r e d for 4 hr at 0°. The r e a c t i o n mixture was then d i l u t e d with ethyl ether and water. The organic s o l u t i o n was separated, washed with brine, dried over anhydrous magnesium s u l f a t e , and concentrated _in vacuo. The XMMR spectrum of the crude product so obtained (1.44 g) showed e s s e n t i a l l y pure 353. Preparative t i c ( s i l i c a g e l , 6:1 carbon t e t r a c h l o r i d e - e t h y l ether) p u r i f i c a t i o n of 62 mg of the crude material gave 56 mg (93%) of 353 as a c o l o r l e s s l i q u i d : IR 1710, 1650, 1585, 1440 and 1150 cm - 1; 1HNMR 6 1.56 (s, 3H), 1.72 (s, 3H), 1.8-2.3 (m, 8H), 2.14 (d, J =1.6 Hz, 3H), 3.45 (s, 2H), 3.63 (s, 3H), 5.07 (m, 2H), 5.60 (m, IH) and 6.9-7.4 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 359(25), 358(100), 249(10), 218(17), 217(14), 189(25), 177(46), 176(57), 149(16), 135(66), 121(43) 109(40), 107(33), 95(18), 93(24), 81(25), 79(16), 69(18), 67(22), 55(26), 43(20) and 41(29). 246 High Resolution Mass Measurement Calcd f or C 2 2 H 3 0 O 2 S : 358.1966. Found: 358.1956. (E, E, Ej-3,7,ll-Trimethyl-12-phenylthiododeca-2,6,10-trien- l - o l (354). - To a sol u t i o n of 1.181 g (3.3 mmole) of 353 i n dry ethyl ether (45 ml), cooled at -23° and kept under nitrogen, was added 9.9 ml (9.9 mmole) of diisobutylaluminum hydride (1 M i n hexane) i The r e s u l t i n g mixture was s t i r r e d for 1 hr 50 min at -23° and then quenched with 2 ml of methanol. The cooling bath was removed, and a f t e r 20 min, the mixture was treated with 10% aqueous hydrochloric acid u n t i l the aqueous layer turned c l e a r . The ether s o l u t i o n was separated, washed with brine, and dried over anhydrous magnesium s u l f a t e . Evaporation of solvents under reduced pressure afforded 1.080 g (99%) of crude 354 which was e s s e n t i a l l y pure by t i c ( s i l i c a gel) and *HNMR analyses. S a t i s f a c t o r y elemental microanalysis was obtained on a t i c p u r i f i e d ( s i l i c a g e l , 4:1 carbon t e t r a c h l o r i d e - e t h y l ether) sampler c o l o r l e s s o i l ; bp (Kugelrohr d i s t i l l a t i o n ) 145-147°/0.1 Torr; IR 3650, 3500, 1665, 1585 and 1440 cm - 1; 1HNMR 6 1.55 (s, 3H), 1.66.' (s, 3H), 1.71 (s, 3H), 1.8-2.3 (m, 9H), 3.45 (s, 2H), 4.09 (d, J = 7 Hz, 2H), 4.8-5.5 (m, 3H) and 6.9-7.4 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 330(29), 312(10), 221(32), 220(19), 203(46), 177(100), 176(28), 163(30), 147(30), 135(88), 134(63), 121(54), 110(67), 109(89), 107(78), 95(42), 93(72), 81(73), 69(55), 68(45), 67(70), 55(60), 43(45) and 41(75). Anal. Calcd f or C 2iH 3 0OS: C, 76.31; H, 9.15. Found: C, 76.64; H, 9.21. 247 (g.».. 1» Ej-l-(2-Tetrahydropyranyloxy)-3,7,ll-trimethyl-12-phenylthio-2,6,10-dodecatriene (355). - A mixture of 1.026 g (3.1 mmole) of crude 354, 391 mg (4.65 mmole) of dihydropyran and a c a t a l y t i c amount (10 mg) of p-toluenesulfonic acid i n dry dichloromethane (45 ml) was s t i r r e d for 2 hr at room temperature. The r e s u l t i n g s o l u t i o n was d i l u t e d with ethyl ether, washed with 10% aqueous sodium bicarbonate, and dried over anhydrous sodium s u l f a t e . Removal of solvents under reduced pressure gave 1.285 g of crude material, which a f t e r column chromatography ( s i l i c a gel 100-200 mesh, 6:1 petroleum ether-ethyl ether) furnished 1.232 g (95% y i e l d from 353) of 355: c o l o r l e s s l i q u i d ; IR 1670, 1585, and 1440 cm"1; 1HNMR 6 1.56 (s, 3H), 1.67 (s, 3H), 1.72 (s, 3H), 1.3-1.8 (m, 6H), 1.8-2.2 (m, 8H), 3.44 (s, 2H), 3.5-4.2 (m, 4H), 4.56 (m, IH), 5.1 (m, 3H) and 6.97-7.33 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 414(10), 329(10), 202(20), 176(23), 134(28), 123(15), 121(15), 110(21), 109(25), 107(22), 93(16), 86(21), 85(100), 81(23), 69(18), 67(37), 57(36), 55(32), 43(40) and 41(42). High Resolution Mass Measurement Calcd f or C 2 6 H 3 8 O 2 S : 414.2593. Found: 414.2582. (E, E_, JE)-13- (2-Tetrahydropyranyloxy)-3,7,11-trimethyl-1-(2,6, 6-tr i m e t h y l - l - c y c l o h e x e n - l - y l ) - 2 - p h e n y l t h i o - 3 , 7 , l l - t r i d e c a t r i e n e (362). - A so l u t i o n of 1.656 g (4 mmole) of 355 and 448 mg (4 mmole) of d i a z a b i c y c l q -[2.2.2]octane i n dry tetrahydrofuran (25 ml) was kept under nitrogen and cooled to -23°. To t h i s was added 3.75 ml (6 mmole) of n-butyllithium (1.6 M i n hexane) and the r e s u l t i n g orange s o l u t i o n was s t i r r e d f o r 3 hr at -23°. A s o l u t i o n of bromide 330 (1.302 g, 6 mmole) i n dry tetrahydrofuran 248 (2 ml) was then introduced. The l i g h t yellow suspension formed was s t i r r e d at -23° for 3 hr and warmed to 0° over 50 min. The re a c t i o n was worked up by quenching with 20 ml of water and extracting the aqueous phase with 2 x 25 ml of ethyl ether. The ether extracts were washed with brine, dried over anhydrous sodium s u l f a t e and evaporated under reduced pressure to give 2.781 g of crude material, which showed one major spot (besides a f a s t moving component) on t i c . P u r i f i c a t i o n of 100 mg of the crude product by prepara-t i v e t i c ( s i l i c a g e l , 10:1 petroleum ether-ethyl ether) afforded 59 mg (75%) of 362 as a c o l o r l e s s o i l : IR 1670, 1585 and 1440 cm"1; 1HNMR 6 0.98 (s, 3H), 1.05 (s, 3H), 1.51 (s, 3H), 1.66 (br s, 9H), 1.2-2.4 (m, 22H), 3.4-4.2 (m, 5H), 4.57 (m, IH), 4.75-5.47 (m, 3H) and 6.93-7.33 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 550(0.5), 449(2), 440(3), 413(5), 355(11), 338 (14), 329(16), 311(46), 270(15), 255(15), 243(26), 219(32), 203(75), 202(72), 189(61), 187(60), 177(69), 175(64), 173(59), 163(71), 161(74), 159(70), 149(73), 147(79), 145(74), 135(87), 123(84), 119(81), 110(93), 109(96), 107(80), 105(80), 95(84), 93(81), 91(79), 85(96), 84(94), 69(88), 67(85), 57(89), 55(96), 43(100) and 41(88). High Resolution Mass Measurement Calcd f or CaeHs^O^S: 550.3844. Found: 550.3839. (E, E, E)-13-(2-Tetrahydropyranyloxy)-3,7,11-trimethyl-1-(2,6,6-t r i m e t h y l - l - c y c l o h e x e n - l - y l ) - 3 , 7 , l l - t r i d e c a t r i e n e (363). - To a s o l u t i o n of n i c k e l (II) chloride hexahydrate (29.13 g, 122 mmole) i n 400 ml of absolute ethanol, cooled i n an ice-bath, was added simultaneously a s o l u t i o n of 362 (1.760 g, 3.2 mmole) i n ethanol (40 ml) and a s o l u t i o n of sodium borohydride 249 (3.948 g, 102 mmole) i n water with vigorous s t i r r i n g . The addition was completed over 20 min, and the r e s u l t i n g black suspension was removed from the cooling bath and s t i r r e d f o r 26 hr at room temperature. The reaction mixture was then f i l t e r e d through G e l i t e and the p r e c i p i t a t e was washed with ethanol. The combined f i l t r a t e was evaporated under reduced pressure and the residue was dissolved i n ethyl ether. The ether s o l u t i o n was washed with brine and dried over anhydrous magnesium s u l f a t e . The crude product obtained a f t e r removal of solvents was chromatographed on a s i l i c a gel (100-200 mesh) column with 20:1 petroleum ether-ethyl ether to give 1.018 g (72%) of 363 as a c o l o r l e s s o i l : TR 1670 and 1450 cm - 1; JHNMR 6 1.0 (s, 6H), 1.2-2.3 (m, 36H), 3.4-4.2 (m, 4H), 4.57 (m, IH) and 4.8-5.5 (m, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 442(4), 358(5), 357(4), 340(15), 203(10), 189(8), 177(7), 161(6), 147(8), 137(73), 135(12), 123(14), 121(18), 119(11), 109(14), 107(15), 95(36), 93(18), 85(100), 81(35), 69(13), 67(15), 57(17), 55(16) and 41(17). High Resolution Mass Measurement Calcd f or C 3 0 H 5 0 O 2 : 442.3811. Found: 442.3796. (E, E_, E)-13-Hydroxy-3,7,ll-trimethyl-l-(2,6,6-trimethyl-l-c y c l o h e x e n - l - y l ) - 3 , 7 , l l - t r i d e c a t r i e n e (364). - A s o l u t i o n of 363 (486 mg, 1.1 mmole) and _p_-toluenesulfonic acid (20 mg) i n 60 ml of methanol-tetra-hydrofuran (5:1) was s t i r r e d f o r 24 hr at room temperature. The s o l u t i o n was then concentrated under reduced pressure to ca. 1 ml, d i l u t e d with ethyl ether, and washed with saturated aqueous sodium bicarbonate. Af t e r drying over anhydrous magnesium s u l f a t e and removal of solvents, the r e s i -due was evaporated ij\ vacuo to a f f o r d 395 mg (quantitative y i e l d ) of 364, 250 which was homogeneous by t i c ( s i l i c a gel) a n a l y s i s : c o l o r l e s s l i q u i d ; IR 3650, 3500, 1670 and 1450 cm - 1; 1HNMR 6 0.98 (s, 6H), 1.2-2.3 (m, 30H), 4.1 (d, J = 7 Hz, 2H) and 4.8-5.5 (m, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 358(12), 340(10), 204(13), 203(9), 189(9), 177(12), 161(8), 149(8), 147(11), 138(15), 137(100), 136(15), 135(16), 133(16), 123(20), 121(24), 119(14), 109(16), 107(16), 95(23), 81(25), 69(14), 55(16) and 41(15). High Resolution Mass Measurement Calcd f or C 2 5 H 4 2 O : 358.3235. Found: 358.3220. 3-Phenylsulf onylmethyl-2-butenolide (3.Z5J . - Anhydrous sodium benzenesulfinate (1.15 g, 7.0 mmole) and 1.03 g (5.8 mmole) of 3-bromomethyl-2-butenolide (366) (prepared i n the same manner as described by Martin et a l . 1 9 6 ) were dissolved i n 10 ml of dry dimethylformamide. The orange-brown so l u t i o n formed was s t i r r e d for 2 hr at room temperature under a dry n i t r o -gen atmosphere. The reaction mixture was worked up by adding 20 ml of water and extracting the s o l u t i o n with 4 x 30 ml of chloroform-n-pentane (1:1). The combined extracts were washed with brine, dried over anhydrous magnesium s u l f a t e and concentrated under reduced pressure. Removal of re s i d u a l d i -methylf ormamide i n vacuo gave 1.35 g of crude 375 (solid) which was essen-t i a l l y pure by t i c ( s i l i c a gel) and JHNMR analyses. R e c r y s t a l l i z a t i o n from dichloromethane-ethyl ether-n-pentane yielded 1.18 g (85%) of 375 as co l o r -l e s s f l a k e s : mp 125°; IR 1795, 1760, 1650, 1335, 1175 and 1160 cm"1; 1HNMR <5 4.17 (s, 2H), 4.87 (br s, 2H), 5.83 (br s, IH) and 7.4-7.9 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 238(54), 141(100), 126(15), 125(28), 97(29), 77(99), 68(16), 67(16) and 51(27). 251 Anal. Calcd for C i i H 1 0 C \ S : C, 55.45; H, 4.23; S, 13.46. Found: C, 55.31; H, 4.14; S, 13.22. (E, E_, E_)-13-Bromo-3,7,11-trimethy 1-1-(2,6,6-trimethyl-l-cyclo-h e x e n - l - y l ) - 3 , 7 , l l - t r i d e c a t r i e n e (381). - To a mixture of 364 (425 mg, 1.19 mmole) and anhydrous l i t h i u m bromide (413 mg, 4.76 mmole) i n 25 ml of dry eth y l ether, cooled at -78° and kept under nitrogen, was added 0.86 ml (1.31 mmole) of ri-butyllithium (1.52 M i n hexane) with s t i r r i n g . A f t e r 30 min at the same temperature, 0.1 ml (1.31 mmole) of methanesulfonyl ch l o r i d e was introduced. The mixture was warmed to -10° over 1 hr, maintained at -10 for 30 min and then at room temperature for 6 hr. The r e s u l t i n g sus-pension was poured into i c e - c o l d water and the aqueous phase was extracted with 2 x 50 ml of ethyl ether-n-pentane (1:1). The combined organic s o l u -t i o n was washed with brine, dried over anhydrous magnesium s u l f a t e , and evaporated under reduced pressure. The crude bromide 381 (463 mg, 92%) obtained was used d i r e c t l y i n the next a l k y l a t i o n step without any p u r i f i -c ation. S a t i s f a c t o r y s p e c t r a l data were observed for t h i s crude material (a s l i g h t l y tan o i l ) : IR 1665, 1455, 1380 and 1180 cm"1; 1HNMR 6 0.98 (s, 6H), 1.2-2.3 (m, 30H), 3.95 (d, J = 8 Hz, 2H) and 4.7-5.57 (m, 3H); mass spectrum m/e ( r e l i n t e n s i t y ) 422(7), 420(7), 341(6), 340(8), 204(15); 203(9), 189(10), 177(12), 149(10), 147(10), 138(15), 137(100), 136(15), 135(13), 123(18), 121(21), 119(13), 109(16), 107(18), 105(12), 95(36), 81(24), 69(13), 67(13), 55(15) and 41(13). High Resolution Mass Measurement Calcd f or C 2 s H i t l 8 1 B r and C 2 5 H l t i 7 9 B r : 422.2371 and 420.2391. Found: 422.2399 and 420.2391. 252 3-[(E, E, E_)-4,8,12-Trimethyl-14-(2,6,6-trimethyl-l-cyclohexen-l - y l ) - l - p h e n y l s u l f o n y l - 3 , 7 , l l - t e t r a d e c a t r i e n - l - y l ] - 2 - b u t e n o l i d e (382). -To a s t i r r e d suspension of 144 mg (3.0 mmole of sodium hydride (50%) i n dry dimethylformamide (20 ml) was added 714 mg (3.0 mmole) of sulfone 375 (dissolved i n 1 ml of dimethylformamide) at 0°, under nitrogen. The cooling bath was removed, and an orange-yellow s o l u t i o n was formed a f t e r 30 min. To t h i s s o l u t i o n was introduced 460 mg (ca. 1.19 mmole) of the crude bromide 381 and the r e s u l t i n g mixture was s t i r r e d f o r 4 hr at room temperature. The reaction was quenched with i c e - c o l d 5% hydrochloric acid 40 ml and the mix-ture was extracted with 3 x 60 ml of ethyl ether-petroleum ether (1:1). The combined extracts were washed with 2 x 40 ml of 50% brine, dried over anhy-drous magnesium s u l f a t e , and evaporated under reduced pressure to give 572 mg of crude product. P u r i f i c a t i o n of 100 mg of the crude material by pre-parative t i c ( s i l i c a g e l , 2:3 petroleum ether-ethyl ether) afforded 72 mg (60% y i e l d from alcohol 364) of 382 as a thick, c o l o r l e s s o i l : IR 1792, 1760, 1640, 1330 and 1150 cm""1; ^NMR 6 1.0 (s, 6H), 1.1-2.2 (m, 30H), 2.7 (m, 2H), 4.0 (m, IH), 4.8 (d, J = 1.5 Hz, 2H), 4.6-5.2 (m, 3H), 5.8 (m, IH) and 7.3-7.9 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 578(15), 441(3), 435(2), 300(10), 244(18), 237(47), 188(19), 176(21), 164(19), 163(19), 148(18), 146(20), 136(100), 135(38), 134(33), 132(24), 122(34), 120(45), 118(36), 108(37), 106(40), 104(30), 94(60), 81(95), 69(97), 57(40), 55(51) and 41(89). High Resolution Mass Measurement Calcd f o r C3 6HsoOitS: 578.3430. Found: 578.3435. 253 Mokupalide (347). - A mixture of 382 (29 mg, 0.05 mmole) and disodium hydrogen phosphate (28 mg, 0.2 mmole) was dissolved i n 5 ml of dry methanol. To t h i s s o l u t i o n , cooled at -10° and kept under nitrogen, was added 75 mg (0.2 mmole) of 6% sodium amalgam (prepared according to the procedure .'reported ..by.McDonaldand -Relneke 2 1' 3) i n one portion. The r e s u l t i n g mixture was s t i r r e d f o r 20 min at -10°, followed by quenching with saturated aqueous ammonium chloride and extraction with ethyl ether. The combined extracts were washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium s u l f a t e and then concentrated under reduced pressure. The crude residue obtained was chromatographed on s i l i c a g e l with 1:1 petro-leum ether-ethyl ether to fur n i s h 18 mg (82%) of mokupalide ( 3 4 7 ) 1 8 6 : IR 1790, 1755, 1645 and 1450 cm"1; 1HNMR 6 0.99 (s, 6H), 1.1-2.2 (m, 32H), 2.4 (m, 2H), 4.65 (d, J = 1.5 Hz, 2H), 5.05 (m, 3H) and 5.78 (m, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 438(23), 423(5), 395(3), 296(5), 278(4), 245(5), 217(5), 204(12), 189(11), 177(24), 161(13), 149(28), 137(100), 136(36), 135(36), 133(28), 123(32), 121(52), 119(27), 110(29), 108(37), 98(46), 95(65), 93(41), 91(25), 81(83), 79(31), 69(65), 67(32), 57(40), 55(54), 43(28) and 41(52). High Resolution Mass Measurement Calcd f o r C 3 0 H 4 6 O 2 : 438.3497. Found: 438.3519. 3-(4-Methyl-l-phenylsulfonyl-3-penten-l-yl)-2-butenolide (379). -3-Phenylsulfonylmethyl-2-butenolide (375) (48 mg, 0.2 mmole) was alkylat e d with l-bromo-3-methyl-2-butene (15 mg, 0.1 mmole) i n the same manner as described i n the preparation of 382. Preparative t i c ( s i l i c a g e l , 5:1 254 ethyl ether-petroleum ether) of the crude product (27 mg) gave 22 mg (72% y i e l d based on the bromide used) of 379 as c o l o r l e s s flakes ( c r y s t a l l i z e d from petroleum ether-ethyl ether): mp 96°; IR 1792, 1760, 1640, 1595, 1455, 1330 and 1150 cm"1; 1HNMR 6 1.57 (s, 3H), 1.63 (s, 3H), 2.7 (m, 2H), 4.0 (m, IH), 4.80 (br s, 2H), 4.6-5.0 (m, IH), 5.8 (m, IH) and 7.3-7.9 (m, 5H); mass spectrum m/e ( r e l i n t e n s i t y ) 306(8), 238(15), 181(8), 165 (100), 164(100), 137(12), 136(13), 121(33), 120(24), 119(27), 109(17), 107(23), 105(44), 93(28), 91(30), 77(36), 69(29).and 41(38). Anal. Calcd f or C i 6 H i 8 0 ^ S : C, 62.73; H, 5.92; S, 10.46. Found: C, 62.65; H, 5.97; S, 10.38. When approximately 1:1 r a t i o s of 375 and l-bromo-3-methyl-2-butene were used i n the a l k y l a t i o n under various conditions (jt-Bu0K, j:-Bu0H; NaH, THF-HMPA; or NaH, DMF), the mono-alkylation product 379 was obtained i n 40-50% y i e l d s . Synthesis and Bromination of 3-Cyclopentyl-2-butenolide (367) 2-Cyclopentylethanol (370). - Prepared i n 25% y i e l d by the proce-dure reported by Yohe and Adams 2 0 8: bp 80-82°/ll Torr ( l i t . 2 0 8 bp 80-81°/ 11 To r r ) ; IR 3650 and 3500 cm"1; 1HNMR 6 0.9-2.0 (m, 11H), 2.2 (s, IH, exchangeable with D 20) and 3.58 ( t , J = 6 Hz, 2H). 2-Cyclopentylacetaldehyde (371). - A 500 ml round-bottom f l a s k equipped with a magnetic bar and.a drying tube (anhydrous calcium sulfate) was charged with 21.7 g (101 mmole) of pyridinium chlorochromate 2 0 9 and 300 ml of dry dichloromethane. To the r e s u l t i n g deep red s o l u t i o n was added 255 7.65 g (67.1 mmole) of cyclopentylethanol (370) over 5 min. A black p r e c i p i t a t e was formed within a few minutes and the mixture was s t i r r e d f o r 2 hr at room temperature. The rea c t i o n was worked up by f i l t e r i n g through a short pad of F l o r i s i l and washing the residue with 2 x 150 ml of ethyl ether. The combined f i l t r a t e was washed with 250 ml of 5% hydro-c h l o r i c a c i d , 250 ml of 10% aqueous sodium bicarbonate and 250 ml of brine, dried over anhydrous magnesium s u l f a t e , and concentrated under reduced pres-sure. The crude product thus obtained was d i s t i l l e d to give 5.41 g (72%) of 2-cyclopentylacetaldehyde: bp 53-54°/12 Torr ( l i t . 2 1 0 bp 53°/12 To r r ) ; IR 2750 and 1720 cm"1; 1HNMR 6 0.9-2.1 (m, 9H), 2.43 (m, 2H) and 9.8 (t, J = 2 Hz, IH). Condensation of 2-Cyclopentylacetaldehyde (371) with Glyoxylic A c i d . 2 1 1 - To a s o l u t i o n of 4.14 g (37 mmole) of 2-cyclopentylacetaldehyde i n 400 ml of methanol-water (1:1) was added 8.40 g (114 mmole) of g l y o x y l i c acid hydrate i n one portion, followed by 5.50 g (136 mmole) of sodium hydro-xide p e l l e t s i n several portions. 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 for 22 hr at room temperature and then a c i d i f i e d with g l a c i a l a c e t i c a c i d to pH 6. The so l u t i o n was extracted with 3 x 200 ml of ethyl ether, and the extracts were washed with 300 ml of brine and dried over anhydrous magnesium s u l f a t e . A f t e r removal of solvents and vacuum drying, a white s o l i d residue (4.9 g) was obtained. The spe c t r a l data of t h i s material indicated the presence of the hydroxy acid 372, along with some dehydrated product and some butenolide. This crude mixture was used d i r e c t l y i n the subsequent reaction. 256 3-Cyclopentyl-4-hydroxy-2-butenolide (373). - The crude product (4.00 g) acquired from the above rea c t i o n was dissolved i n 180 ml of di c h l o r o -methane saturated with anhydrous hydrogen chl o r i d e . The s o l u t i o n was s t i r r e d for 5 hr at room temperature, and then d i l u t e d with 100 ml of ethyl ether, washed with 75 ml each of 10% aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium s u l f a t e . The crude product obtained a f t e r removal of solvents was d i s t i l l e d (Kugelrohr) to give 3.73 g (73% y i e l d from 2-cyclopentyl-acetaldehyde) of 373 as a co l o r l e s s o i l : bp 100-103°/0.6 Torr; IR 3650, 3400, 1760 and 1640 cm"1; 1HNMR 6 1.4-2.4 (m, 8H), 2.8 (m, IH), 5.3 (br s, IH, exchangeable with D 20), 5.72 (br s, IH) and 6.00 (s, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 168(0.6), 150(5), 139(4), 122(100), 100 (51), 94(28) and 79(21). Anal. Calcd f o r C 9 H i 2 0 3 : C, 64.27; H, 7.19. Found: C, 64.42; H, 7.30. 3-CyclopentyI-2-butenolide (367). - To a so l u t i o n of 3.65 g (21.7 mmole) of 373 and 3 g of sodium hydroxide i n 250 ml of methanol-water (1:1) was added 2.5 g (65.1 mmole) of sodium borohydride with s t i r r i n g at room temperature. 2 1 2 A f t e r 2 hr, the rea c t i o n mixture was a c i d i f i e d with concentrated hydrochloric acid to pH 1 and extracted with 2 x 200 ml of ethyl ether. The combined extracts were washed with 100 ml each of 10% aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium s u l f a t e . Evaporation of solvents gave 3.20 g of l i q u i d residue which upon Kugelrohr d i s t i l l a t i o n afforded 3.01 g (91%) of 367: c o l o r l e s s o i l ; bp 108-110°/0.8 Torr; IR 1785, 1745, 1640, 1040, 1030, 895 and 860 cm""1; 1HNMR 6 1.2-2.2 (m, 8H), 2.8 (m, IH), 4.78 (d, J = 2 Hz, 2H) and 5.82 257 (q, J = 2 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 152(60), 123(100), 107(67), 95(35), 93(43), 69(53), 68(75), 67(75), 60(70), 55(75) and 41(70). Anal. Calcd f o r C9H12O2: C, 71.03; H, 7.95. Found: C, 70.98; H, 7.95. 3-(l-Bromocyclopentyl)-2-butenolide (368). - A mixture of 367 (31 mg, 0.02 mmole), N-bromosuccinimide (36 mg, 0.2 mmole) and a small c r y s t a l of a z o b i s ( i s o b u t y r o n i t r i l e ) was s t i r r e d i n 2 ml of dry carbon t e -tr a c h l o r i d e i n a 5 ml round-bottom f l a s k f i t t e d with a condenser and a drying tube (anhydrous calcium s u l f a t e ) . The mixture was exposed to a 275 W sun lamp with a f i l t e r (Corning no. 7380, X>340 nm) for 45 min. The re s u l t i n g suspension was f i l t e r e d and the f i l t r a t e was evaporated to give a s o l i d residue. R e c r y s t a l l i z a t i o n from isopropyl ether-ethyl ether yielded 34 mg (74%) of 368 as co l o r l e s s p l a t e s : mp 69-70°; IR 1795, 1760, 1635, 1050, 895 and 860 cm"1; 1HNMR 6 1.6-2.6 (m, 8H), 5.08 (d, J = 2 Hz, 2H) and 6.00 ( t , J = 2 Hz, IH); mass spectrum m/e ( r e l i n t e n s i t y ) 231(0.3), 229(0.4), 167(2), 151(100), 123(20), 107(12), 105(9), 95(10), 93(12), 91(7) and 67(8). Anal. Calcd f o r C 9 H n B r 0 2 : C, 46.77; H, 4.76; Br, 34.60. Found: C, 46.77; H, 4.86; Br, 34.40. 258 BIBLIOGRAPHY L. Weiler T J. Am. Chem. S o c , 92, 6702 (1970). S. N. Huckin and L. Weiler, i b i d . , 96, 1082 (1974). S. N. Huckin and L. Weiler, Can. J. Chem., 52, 1343 (1974). S. N. Huckin and L. Weiler, i b i d . , 52, 2157 (1974). H.O. 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M C T R U M HO. t I 272 M t C l K U M NU SPtCTRUM NO 273 274 275 276 277 278 280 SPtCTRU* MO _ | ...SPECTRUM HO 281 282 N c w s i m N » i u i N i i a u OH MClMJOldS V83 285 SPCC1RUM NO 286 „ - C P t C T H U M NU 287 288 S K C T H U M NO 289 290 292 . . S P t C T H U M MO 2 9 3 294 M C t R U M N O SPECTRUM MO. 295 SPtCTftUU NO 296 297 298 299 300 302 304 305 307 SPECTRUM NO. ~ i x v i i i n S N V u i 3 0 8 3 0 9 _ . . ._ WCCIRUM NO I 310 311 . . SPECTRUM MO SPECTRUM NO 312 313 314 315 317 

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