@prefix vivo: . @prefix edm: . @prefix ns0: . @prefix dcterms: . @prefix dc: . @prefix skos: . vivo:departmentOrSchool "Science, Faculty of"@en, "Chemistry, Department of"@en ; edm:dataProvider "DSpace"@en ; ns0:degreeCampus "UBCV"@en ; dcterms:creator "Wong, Timothy"@en ; dcterms:issued "2009-04-10T01:53:01Z"@en, "1993"@en ; vivo:relatedDegree "Doctor of Philosophy - PhD"@en ; ns0:degreeGrantor "University of British Columbia"@en ; dcterms:description """With the use of lithium (trimethylstannyl)(cyano)cuprate (123), α, β -acetylenic esters of general structure 100 were converted into the corresponding alkyl (E)- and (Z)-3- trimethylstannyl-2-alkenoates 89 and 91. Homoallylic diiodides of general structures 98 and 99 were synthesized, via a sequence of transformations, from the corresponding esters 89 and 91, respectively. Deconjugation-alkylation of ailcyl (E)- and (Z)-3-trimethylstannyl-2- ailcenoates 89 and 91 with electrophiles 96 and 97, provided, stereoselectively, the functionalized esters of general structure 206. Palladium(0)-catalyzed intramolecular cross-coupling reaction of esters 206 provided alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates of general structure 219 in good yields and in a stereochemically defmed fashion. Thus, a general strategy for the preparation of alkyl 2,3-bis (alkylidene)cyclpentanecarboxylates possessing E,E-, E,Z- and Z,Z configurations (i.e. 81,82 and 84) was established. The limitations of this palladiumcatalyzed intramolecular coupling reaction were shown by the inability to provide the Z,E diene 230 in a stereocontrolled manner, and by the low yield obtained in the preparation of 229. The dihedral angles between the two exocycic C=C bonds in the (Z,Z)-diene system of general structure 84 were determined by X-ray crystallographic analysis of crystalline derivatives of alkyl (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxylates 222, 228 and 229. The magnitude of the dihedral angles in compounds 237,238,241, 243 and 247 ranges from 48.6° to 58.00. A new CuCl-mediated intramolecular coupling reaction of vinyl halide and vinyltrimethylstannane functions was discovered in conjunction with studies directed toward the synthesis of the Z,E-diene 230 in a stereochemically defined manner and toward the optimization of the yield in the preparation of 229. This method has been applied successfully to the preparation of a number of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates possessing E,E-, E,Z-, Z,E- and Z,Z-configurations (81,82,83 and 84) and to the synthesis of a variety of bicydic compounds containing a conjugated diene system (253,289-293). A provisional mechanism was proposed for this new coupling procedure. The Diels-Alder reactions of the dienophiles TCNE and MVK with the alkyl 2,3- bis(alkylidene)cyclopentanecarboxylates of general slructure 219 as well as the related dienes of general structure 314 were investigated. It was found that these Diels-Alder reactions occur with high face-, endo/exo- and regioselectivities. [chemical compound diagrams]"""@en ; edm:aggregatedCHO "https://circle.library.ubc.ca/rest/handle/2429/7021?expand=metadata"@en ; dcterms:extent "7906570 bytes"@en ; dc:format "application/pdf"@en ; skos:note "SYNTHESIS AND SOME RELATED STUDIES OFALKYL 2,3-BIS (ALKYLIDENE)CYCLOPENTANECARBOXYLATESbyTIMOTHY WONGB. Sc., The Chinese University of Hong Kong, 1986M. Ph., The Chinese University of Hong Kong, 1988A THESIS SUBM1YED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinTHE FACULTY OF GRADUATE STUDIES(Department of Chemistry)We accept this thesis as confirmingto the required standardTEIE UNWERSITY OF BRiTISH COLUMBIADecember 1993© Timothy WongIn presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature)____________________________Department of__________________The University of British ColumbiaVancouver, CanadaDate )-) [3DE.6 (2/88)UABSTRACTWith the use of lithium (trimethylstannyl)(cyano)cuprate (123), aj3-acetylenic esters ofgeneral structure 100 were converted into the corresponding alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91. Homoallylic diiodides of general structures 98 and99 were synthesized, via a sequence of transformations, from the corresponding esters 89and 91, respectively. Deconjugation-alkylation of ailcyl (E)- and (Z)-3-trimethylstannyl-2-ailcenoates 89 and 91 with electrophiles 96 and 97, provided, stereoselectively, thefunctionalized esters of general structure 206.Palladium(0)-catalyzed intramolecular cross-coupling reaction of esters 206 providedalkyl 2,3-bis(alkylidene)cyclopentanecarboxylates of general structure 219 in good yieldsand in a stereochemically defmed fashion. Thus, a general strategy for the preparation ofalkyl 2,3-bis (alkylidene)cyclpentanecarboxylates possessing E,E-, E ,Z- and Z,Zconfigurations (i.e. 81,82 and 84) was established. The limitations of this palladium-catalyzed intramolecular coupling reaction were shown by the inability to provide the Z,Ediene 230 in a stereocontrolled manner, and by the low yield obtained in the preparation of229.The dihedral angles between the two exocycic C=C bonds in the (Z,Z)-diene system ofgeneral structure 84 were determined by X-ray crystallographic analysis of crystallinederivatives of alkyl (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxylates 222, 228 and 229.The magnitude of the dihedral angles in compounds 237,238,241, 243 and 247 rangesfrom 48.6° to 58.00.A new CuC1-mediated intramolecular coupling reaction of vinyl halide andvinyltrimethylstannane functions was discovered in conjunction with studies directed toward111the synthesis of the Z,E-diene 230 in a stereochemically defined manner and toward theoptimization of the yield in the preparation of 229. This method has been appliedsuccessfully to the preparation of a number of alkyl 2,3-bis(alkylidene)cyclopentane-carboxylates possessing E,E-, E,Z-, Z,E- and Z,Z-configurations (81,82,83 and 84) andto the synthesis of a variety of bicydic compounds containing a conjugated diene system(253,289-293). A provisional mechanism was proposed for this new coupling procedure.The Diels-Alder reactions of the dienophiles TCNE and MVK with the alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates of general slructure 219 as well as the related dienesof general structure 314 were investigated. It was found that these Diels-Alder reactionsoccur with high face-, endo/exo- and regioselectivities.[Me3SnCuCNJLI R C02R123 100C02R219R1_HCO2R2Me3Sn H89R96 (X = Br or 1)HRMc3Sn C02R9197 (X = Br or 1)R’99R20CR3X Me3Sn206R3E,E-diene 81Z,E-diene 83R3‘ R3‘%\\q R1LR’ C02R C02RE,Z-diene 82 Z,Z-diene 84%OQDCO2Et CO2Me CO2EtCO2Et230 222 228 229ivH237— HN238D241 —ClMeO2C291cc?C02R219MeO2C253R1 E324 E = C02R325 B =CHOS1Ph(t-Bu)243 247MeO2C289 290292 293CH2OSiPh(t-Bu)314NR3C315 E=C02R316 B =CHOSIPh(t-Bu)VTABLE OF CONTENTSABSTRACT iiTABLE OF CONTENTS vLIST OF TABLES ixLIST OF FIGURES xiLIST OF GENERAL PROCEDURES xiiLIST OF ABBREVIATIONS xiiiACKNOWLEDGEMENTS xxI. INTRODUCTION 11. Palladium-catalyzed coupling reactions and their synthetic applications 12. Previous work on the syntheses of ethyl 2,3-bis(alkylidene)cyclobutane-carboxylates and some related studies 123. Previous synthetic studies of 1,2-bis(allcylidene)cyclopentanes and related1,2-bis-exocyclic dienes 20vi4. Proposal regarding a study of the preparation and chemistry of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 27II. RESULTS AND DISCUSSION 321. Syntheses of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 321.1. Preparation of a,j3-acetylenic esters 321.2. Conversion of a,J.3.acetylenic esters into alkyl (E)- or (Z)-3-trimethyl-stannyl-2-alkenoates 362. Deconjugation-alkylation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 432.1. Preparation of electrophiles: 2-bromo-4-iodo-1-butene, (2)- and (E)diiodoalkenes 432.2. Deconjugation-allcylation of ailcyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates, and of ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoatewith the prepared electrophiles 573. Syntheses of alkyl 2,3-bis(allcylidene)cyclopentanecarboxylates and relatedderivatives 663.1. Stereocontrolled syntheses of alkyl 2,3-bis(alkylidene)cyclopentane-carboxylates and related substances via palladium(O)-catalyzedcoupling reactions 663.2. X-ray analysis of (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxamides 74vii4. Discovery of the CuC1-mediated intramolecular coupling reacon 894.1. Introduction 894.2. Stereocontrolled preparation of alkyl 2,3-bis(alkylidene)cyclopentane-carboxylates via CuC1-mediated intramolecular coupling of vinyltrimethyistannane and vinyl halide functions 964.3. Preparation of bicyclic dienes 1014.4. Preliminary studies on the mechanistic aspects and the limitations ofthe CuC1-mediated coupling process 1175. Diels-Alder reactions of alkyl 2,3-bis(alkylidene)cyclopentancarboxylatesand structurally related substances 1285.1. Introduction 1285.2. Diels-Alder reactions of dienes with tetracyanoethylene (TCNE) 1295.3. Diels-Alder reactions of dienes with methyl vinyl ketone (MVK) 140III. CONCLUSIONS 166IV. EXPERIMENTAL SECTION 1761. General 1761.1. Data Acquisition and presentation 1761.2. Solvents and reagents 1792. Preparation of a,j3-acetylenic esters 1813. Preparation of lithium (trialkylstannyl)(cyano)cuprates 1884. Preparation of alkyl (E)-3-thmethylstannyl-2-alkenoates 189VIII5. Preparation of ethyl (Z)-3-aylstnyl-2-pentenoates 1956. Preparation of alkyl (Z)-2,3-bis(trimethylstannyl)-2-alkenoates 1987. Preparation of aikyl 2-trimethylstannyl- 1-cycloalkenecarboxylates 2008. Preparation of alkylating agents 2039. Preparation of a-alkylated esters and related derivatives 23310. Stereocontrolled preparation of alkyl 2,3-bis(alkylidene)cyclopentane-carboxylates and related substances via intramolecular palladium(0)-catalyzed coupling reactions of vinyl halide and vinyistannane functions 26211. Preparation of ailcyl 2,3-bis(alkylidene)cyclopentanecarboxylates and otherdienes via CuC1-mediated intramolecular coupling reactions of vinyl halideand vinyistannane functions 28312. Preparation of 2,3-bis(alkylidene)cyclopentanecarboxamides 30913. Diels-Alder reactions of dienes with tetracyanoethylene (TCNE) 31914 Diels-Alder reactions of dienes with methyl vinyl ketone (MVK) 326V. REFERENCES 341VI. APPENDIX 359lxLIST OF TABLESTableI. Effect of varying reaction conditions on the coupling reacon 4II. Syntheses of the cyclobutanecarboxylates 37 12ifi. Syntheses of the cycloalkanecarboxylates 41 15IV. Syntheses of the E,E-1,2-bis-exocyclic dienes 60 21V. Effect of the ring size on the yields of E,E-bis(ethylidene)cycloallcanes66 23VI. Syntheses of the 1,2-bis(allcylidene)cyclopentanes 68 24VII. Syntheses of the 1,2-bis(alkylidene)cyclopentanes 68 25VIII. Preparation of alkyl (Z)-3-trimethylstannyl-2-alkenoates 91 38IX. Preparation of alkyl (E)-3-trimethylstannyl-2-alkenoates 89 39X. Deconjugation reactions of the alkyl (E)- and (Z)-3-irimethylstannyl-2-alkenoates 89 and 91, respectively 46XI. Conversions of the alkyl (Z)-3-trimethylstannyl-3-alkenoates 90 into thecorresponding (Z)-diiodoalkenes 98 56XII. Deconjugation-alkylation of ailcyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 with the prepared electrophiles 58-60XIII. Stereocontrolled syntheses of alkyl 2,3-bis(alkylidene)cyclopentane-carboxylates 219 66-68XIV. Dihedral angles between the carbon-carbon double bonds of (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxamides 86XV. Attempted preparation of ethyl (Z,E)-2,3-bis(ethylidene)cyclopentane-carboxylate (230) under different reaction conditions 90XVI. Preparation of ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentane-carboxylate (229) under different reaction conditions 91xXVII. Effect of CuC1 on the preparation of ethyl (Z,E)-2,3-bis(ethylidene)-cyclopentanecarboxylate (230) under different reaction conditions 93XVIII. Effect of different amounts of CuC1 on the preparation of ethyl (E,Z)2,3-bis(ethylidene)cyclopentanecarboxylate (223) 94XIX. Effect of different amounts of CuC1 on the preparation of 1-methoxycarbonyl-4-methylbicyclo[3.3.0]oct-3,5-diene (253) 95XX. CuC1-mediated intramolecular couplings of iodo trimethylstannane 206 97XXI. Deconjugation-alkylation of methyl 2-trimethyistannyl- 1-cyclopentene-carboxylate (258) and methyl 2-trimethylstannyl-1-cyclohexene-carboxylate (259) 109-110XXII. CuC1-mediated intramolecular coupling of monocyclic substrates ofgeneral structure 260 112XXIII. Results of the COSY experiment of compound 289 115 & 295XXIV. Effect of different sources of Cu(I) on the intramolecular coupling ofsubstrate 209 or 211 117-118XXV. Effect of different solvents on the CuCl-mediated intramolecularcoupling of substrate 209 120XXVI. Preparation of some substrates via deconjugation-alkylation 121-122XXVII. Diels-Alder reactions of dienes 219 and 314 with TCNE 130-131XXVIII. Diels-Alder reactions of dienes 219 and 314 with MVK 141-142XXIX. Results of the COSY experiment of compound 291 298XXX. Results of the COSY experiment of compound 253 300XXXI. Results of the COSY experiment of compound 327 328XXXII. Results of the COSY experiment of compound 331 333xiLIST OF FIGURESFigure1. X-ray structure of 237A, 237B, 237C and 237D 762. X-ray structure of 237A and 237B 783. X-ray structure of 237C and 237D 794. X-ray structure of 238 805. X-ray structure of 241 A and 241 B 826. X-ray structure of 243 847. X-ray structure of 247 858. X-ray structure of 257A and 257B 1009. The effect of Lewis acid on the energies of the HOMO and LUMO of thedienophile in the Diels-Alder reaction 160xilLIST OF GENERAL PROCEDURESGeneralprocedure1. Preparation of alkyl (E)-3-trimethylstannyl-2-alkenoates 1892. Preparation of ethyl (Z)-3-thalkylstannyl-2-pentenoates 1953. Preparation of alkyl (Z)-2,3-bis(trimethylstannyl)-2-aikenoates 1984. Preparation of alkyl 2-trimethylstannyl-1-cycloalkenecarboxylates 2005. Preparation of alkyl (Z)-3-trimethylstannyl-3-alkenoates 2036. Preparation of (Z)- or (E)-3-thmethylstannyl-3-alken-1-ols 2087. Preparation of (Z)- or (E)-3-iodo-3-alken-1-ols 2138. Preparation of (Z)- or (E)-dliodoalkenes and 4-iodo-1-butyne 2189. Preparation of 2-bromo-1-alkenes 22310. Deconjugation-alkylation of ailcyl (E)-trimethylstannyl-2-alkenoates(125, 137, 138 and 141), ethyl (Z)-3 -trialkylstannyl-2-pentenoates(124, 295), ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (158)and methyl 2-trimethylstannyl-1 -cyclopentenecarboxylate (258) 23311. Stereocontrolled preparation of ailcyl 2,3-bis(allcylidene)cyclopentane-carboxylates and related substances via intramolecular palladium(0)-catalyzed coupling reactions of vinyl halide and vinyistannanefunctions 26212. Preparation of alkyl 2,3-bis(aikylidene)cyclopentanecarboxylates andother dienes via CuCl-mediated intramolecular coupling reactions ofvinyl halide and vinyistannane functions 28313. Preparation of 2,3-bis(alkylidene)cyclopentanecarboxamides 30914. Diels-Alder reactions of dienes with methyl vinyl ketone (MVK) 326x’ilLIST OF ABBREVIATIONSA angstrom(s)a 1,2 relative positionspecific rotation at the sodium D line (589.3 nm)Anal, elemental analysisAr - argonAr3P - tri-o-tolylphosphine (o- - ortho-)/3 1,3 relative positionB-Br-9-BBN B-bromo-9-borabicyclo[3.3.1]nonaneBF3.Et20 boron trifluoride-etheratebp boiling pointbr broadn-Bu normal-butyl (n- - normal-)t-Bu :err-butyl (ten- - tertiary-)1-Bu2AIH diisobutylaluminum hydride (i- - iso-)n-BuLi n-butyffithiumt-BuMe2SiCl tert-butyldimethylsilyl chloridet-BuPh2SiCl :ert-butylchlorodiphenylsilanen-Bu3SnC1 tributyllin chloride[n-Bu3SnCuCN]Li lithium (tri-n-butylstannyl)(cyano)cuprateO degree CelsiusC concentration in g/100 niLcalcd. calculatedC6D hexadeuteriobenzenecDcl3 deuteriochloroformC6H benzenexivCHC13 chloroformCH21 dichioromethaneCH3N acetonitrile(CH3CN)2PdCl2 bis(acetonitrile)palladium(ll) chloridean centimeter(s)nmr carbon-13 nuclear magnetic resonanceCOSY (1H- homonuclear) rrelation pectroscopCP2T1C1 titanocene dichlorideCpZrCl2 zirconocene dichlorideCuBr.Me2S copper(I) bromide-dimethylsulfideCuC1 copper(I) chlorideCuC12 copper(ll) chlorideCuCN copper(I) cyanideCuT copper(I) iodided doublet3 scale (nrnr), dimensionlessdba dibenzylideneacetoneDBU 1 ,8-diazabicyclo[5.4.O]undec-7-eneDMF N,W-dimethylformamideDMSO dimethylsulfoxide1)20 deuterium oxide1)2S04 SUlfUriC acid-d2molar absorptivityed. editionEd., Eds. editor, editorse.g. - for exampleequiv - equivalent(s)xvet al. and othersE entgegen (configuration)Et ethylEd iodoethaneEt3N iriethylamineEt20 diethyl etherEtOH ethanolg gram(s)- 1,4 relative positiongems gas-chromatography mass spectromeirygic - gas-liquid chromatographyh - hour(s)HgO - mercury(ll) oxideHMPA - hexamethyiphosphoramidenmr - proton nuclear magnetic resonanceH20 - waterHOAc - acetic acidHOMO - highest occupied molecular orbitalhplc - high-performance liquid chromatographyHz - Hertz (s1)i- - iso-ibid. - in the reference cited12 - iodinei.e. - that isir - infraredJ - coupling constant (in Hz)xvi“JSn-H - n bond(s) coupling for tin and proton nuclei (in Hz;n =2 or 3)KN(SiMe3)2 - potassium bis(trimethylsilyl)amideL - liter(s)IDA - lithium dlisopropylamideLiAIH4 lithium aluminum hydrideLIC1 lithium chlorideLiCuC12 lithium dichiorocuprateLilCA lithium N,N-isopropylcyclohexylamidelit. literatureLUMO lowest unoccupied molecular orbitalM molar (mol dnr3), or mega (106)m multipletMe methylMe3AI trimethylaluminumMcii methyffithiumMeOH methanolMel iodometha.ne(Me3Sn)2 hexamethylditin[Me3SnCuCNJLi lithium (trimethylstannyl)(cyano)cuprateMeSnCu.M 2S (trimethylstannyl)copper-dimethylsulfide[Me3SnCuSPh]Li lithium (trimethylstannyl)(phenylthio)cupratemg milligram(s)MgSO4 magnesium sulfateMHz megaHertzmiii minute(s)milliliter(s)xvii- microliter(s)mmol - millimole(s)ji.mol - micromole(s)mol - mol(s)mp - melting pointMVK - methyl vinyl ketone- normalNa(Hg) - sodium amalgamNaHCO3 - sodium bicarbonate (sodium hydrogen carbonate)Nal sodium iodideNaOH sodium hydroxideNH4C1 - ammonium chlorideNH4O - ammonium hydroxidenm nanometer(s)NMP - N-methylpyrrolidinonenOe - nuclear Overhauser effectorthoORD optical rotatory dispersionp pagep- para% percent (parts per hundred)Pd(O) palladium(O)Pd(dba)2 bis(dibenzylideneacetone)palladium(O)Pd2(dba)3 tris(dibenzylideneacetone)dipallarlium(O)Ph phenylpH hydrogen ion concentrationPh3As triphenylarsinexvmPhN(SO2CF3) - N-phenyltrifluoromethanesulfonimidePh3 - triphenyiphosphinePh3Br2 - triphenyiphosphine dibromidePh3=CBr2 - dibromomethylenetriphenyiphosphoranePh3CuC1 - triphenylphosphinecopper(I) chloride(Ph3P)CuC1 - tris(triphenylphosphine)copper(I) chloridePh3.12 - triphenyiphosphine dilodidePh2Me - methyldiphenyiphosphine(Ph3P)4d - tetrakis(triphenylphosphine)palladium(O)(Ph3P)2dBnC1 - benzyl(chloro)bis(triphenylphosphine)palladium(ll)(Ph3P)2dC1 - bis(triphenylphosphine)palladium(ll) chloridePhSCu - phenylthiocopper(I)PMHS polymethythydrosioxanepp pagesc-Pr cyclopropyli-Pr - isopropyl (1- - iso-)n-Pr normal-propyl (n- - normal-)q quartetR rectus (configuration)Rf retardation factor (ratio of distance traveled by thecenter of a zone to the distance simulaneouslytraveled by the mobile phase)S sinister (configuration)s singlet, or second(s)t triplettertiaryTCNE tetracyanoethylenexixtemp temperatuitert- tertiaryTHF tetrahydrofurantic thin-layer chromatographyuv ultravioletVol. volumev/v volume-to-volume ratiowi peak width at half height (in Hz)w/v weight-to-volume ratioZ zusammen (configuration)ZnC12 zinc chloride(+) rotation to the right(-) rotation to the left+ve positive-ye negativexxAC KNOWLEDGEMENTSFirst of all, I wish to express my sincere thanks to my supervisor, Professor EdwardPiers, for his guidance, patience and support during the course of research and thepreparation of this thesis. Thanks to the past and present chemists in “Piers’ Lab” includingLivain, Chantal, Christine, Yongxin (Han), Guy, Pat, Allan, Yee-Fung, Pierre, Fraser,Miguel, Betty-Anne, Richard, Veljko, Jacques, Johanne, Keith, Philip, Francisco, Renata,René, Todd, Anthony, Katherine, Al and Serge for the sharing of chemicals, helpful advice,stimulating discussion as well as multicultural interaction. Special thanks to Christine,Yongxin and Pat for proof-reading my thesis. In addition, I wish to thank Miss Marietta forteaching me how to use the “nmr work-station”. Finally, I wish to express my deepestthanks to my parents for their encouragement and support throughout all these years.1I. INTRODUCTION1. Palladium-catalyzed coupling reactions and their synthetic applicationsFundamental concerns of synthetic organic chemists include the discovery and theexploration of new reagents and new reactions, the investigation of the mechanistic aspects ofthe chemical reactions, the improvement of existing organic reactions, and the application ofthe established reactions in the total syntheses of naturally occurring products or potent drugs.One of the increasingly important areas in organic synthesis is the construction of newcarbon-carbon bonds via the palladium-catalyzed cross-coupling reactions1(Equation 1) oforganostannanes (R’SnR”3)with a variety of organic halides and related electrophiles (RX).Seminal contributions by the late 3. K. Stile laid the groundwork for this critical syntheticoperation and, thus, this reaction is widely known as the Stifle coupling reaction (or the Stilecross-coupling reaction) amongst the synthetic organic community. Some of the merits ofthis catalytic reaction include the mild conditions required, the tolerance towards a widevariety of functional groups on either coupling partner, the accessibility of the many stableand readily available organostannanes, the excellent control5of the configuration of the finalproducts and the high yield of the desired compounds.Pd catalystRX + R’SnR”3 R-R + XSnR”3 (1)The Stifle coupling reaction basically involves the transfer of one organic group R’ fromthe tin atom to the organic group R, which is originally bonded to the “leaving group” X. Itwas found that different organic groups are transferred at different rates from the tin atom,and fortunately, a simple alkyl group has the slowest transfer rate.2 As a result, anorganostannane is generally designed to have three simple, non-transferrable alkyl groups R’2(such as methyl or n-butyl groups) and a transferrable organic group R’, which is usually analkenyl (or vinyl), alkynyl, allyl, aryl or benzyl group.4a Moreover, the organic halides orrelated electrophiles can be acid chlorides, allyl halides, aryl halides, aryl triflates, benzylhalides, enol triflates, cx-haloesters, a-haloketones or vinyl halides.4A variety of palladium reagents have been used to catalyze Stile couplingThe palladium catalysts which have been employed to date includetetrakis(triphenylphosphine)palladium(O) [(Ph3P)4d], bis(triphenylphosphine)palladium(ll)chloride [(Ph3P)2dCl],bis(acetonithle)palladium(ll) chloride [(CH3CN)2PdC1Jandbenzyl(chloro)bis(triphenylphosphine)palladium(II) [(Ph3P)2dBnC1]. In some recentfindings,6 copper(I) salts have been recruited as cocatalysts in the coupling reactions.However, the actual role played by the copper(I) salts in these coupling processes has notbeen determined. Reactions involving enol triflates were found to require the presence of aninorganic salt,2gusually lithium chloride (LiC1). However, in some cases,7it was discoveredthat the presence of LiC1 was not necessary.The coupling reaction is usually performed in the solvent tetrahydrofuran (THF). Inaddition, other solvents such as acetone, acetonitrile (CH3CN), dimethylsulfoxide (DMSO),hexamethylphosphoramide (HMPA) and N,N-dimethylformamide (DMF) can be used.2gReactions can be carried out at ambient temperatures or under reflux.The mechanism of this coupling reaction has been investigated by Stille and coworkers,2Aaand their proposal can be summarized by the catalytic cycle shown in Scheme 1(p 3). The sequence of steps includes oxidative addition2of the organic halide to thepalladium(O) catalyst, transmetalation2of the resulting organopalladium(ll) species with theorganostannane, trans/cis isomerizationdof the bis(organo)palladium(ll) complex and asubsequent reductive elimination2to provide the coupled product. The mechanism3described in Scheme 1 is referred to as that of the “direct coupling”.8 The catalytic cycle wasenvisaged to occur via Pd(O) and Pd(ll) states.9 The transmetalation step was considered tobe the rate-determining step.2R—R’PdL RX(n 2)L) (\\çidative additionR—Pd—L R—Pd—XI ILRSnR3trans/cisisomerization LtransmetalationR—Pd-R’LR = RCH=CH, aryl, RCH=CHCH2, benzyl, RCO or RCOCH2;X = I, Br, OTf or Cl;R’ = RCEC, RCH=CH, aryl, RCH=CHCH2 or RCOCH2; R” = Me or n-BuScheme 1One of the extensively studied areas of the Stile coupling reaction is the synthesis ofconjugated dienes via the palladium-catalyzed cross-coupling reactions of vinyl trialkylstannanes with enol triflates’g,2gor vinyl halidesim (vinyl bromides or vinyl iodides). Ingeneral, these coupling reactions take place with high stereospecificities.4The coupling reactions of enol triflates and vinyl trialkyistannanes require the presence ofLiC1 and a palladium catalyst. For example, the enol triflate 1 coupled in high yield withvinyl tri-n-butylstannane 2 in the presence of 2 mol % of (Ph3P)4d and 3 equivalents ofLiC1 to provide the conjugated diene 3 (Equation 2 and Table I, entry 1).2g As indicated inTable I, no coupling was observed in the absence of (Ph3P)4d (entry 2). When less than 1equivalent of LiCl was used, the reaction did not proceed to completion after 24 h (entries 3and 4). Indeed, the lowest amount of LiCl required was 1 equivalent (entry 5).(Ph3P)4d, LidOTf + n-Bu3Sn”% (2)THF, reflux1 2 3Table I. Effect of varying reaction conditions on thecoupling reactionaentry (Ph3P)4d(mol %) LiCI (equiv) t70 (h)b % yield (glc)c1 1.98 3.0 3.6 952 0.00 3.0 03 1.97 0.0 <104 2.07 0.6 3.0 715 2.04 1.1 3.3 >95a Reaction of 2.5 mmol of 1 with 3.0 mmol of 2 in 25 mL of TNF in the presenceof (Ph3P)4dand LiC1 under Ar at 62 0Cb Time required for a 70% gic yield of 3.C Reaction quenched after 24 h.However, the coupling reactions of vinyl halides and vinyl triaikylstannanes occur in theabsence of LiCl.lm Thus, the coupling of the vinyl iodide 4 with the vinyl tn-nbutyistannane in the presence of 2 mol % of(Ph3P)4dwas complete within 23 h at 50°Cin THF to give a 75% yield of the conjugated diene 6 (Equation 3, p 5).1m5+nBu3Sn’”%iç5(Ph3P)4d(2 mol %)TFIF, 50°C, 23 h75% yield..-6(3)Based on mechanistic studies2gof the coupling reactions of enol triflates and vinyltrialkyistannanes, Stifle and co-workers have proposed a catalytic cycle (Scheme 2). Theinitial oxidative addition of the enol triflate 1 to the catalyst (Ph3P)4dforms the intermediate7, which is followed by transmetalation of the organostannane 2 to yield the correspondingbis(organo)palladium(II) complex 8. This complex rapidly undergoes trans/cisisomerization and reductive elimination to give the product 3, accompanied by regenerationof the palladium(O) catalyst.LL=Ph3P—I--O—Pd-C1Ltransmetalationn-Bu3SnC1PdL4+Eh32Lelimination_j-_Q_OTf + LiC11LiOTf + 2Loxidativeaddition7isomerizatiN.. +c’rL8n-Bu3Sn2Scheme 26The transformation of the enol triflate 1 into the intermediate 7 was proposed2toproceed through one of two different pathways (Equations 4 and 5). Oxidative addition ofthe enol triflate 1 to (Ph3P)4dto form the organopalladium(l1) triflate complex 10, followedby reaction with LiC1, would generate the intermediate 7 (Equation 4). Alternatively, areversible reaction of L1C1 with (Ph3P)4d could form a salt such as 11, which couldundergo oxidative addition with enol triflate 1 to yield the intermediate 7 (Equation 5). Basedon evidence2gfrom the 31P nmr spectral data of 7 and 11, Stile and co-workers havesuggested that the reaction is very likely to proceed via the latter pathway.PdL4 + —f_(-OTf [_I_CjPdL2] ÷ LiCI _f_(j_P’d_Cl (4)L=Ph3P 1 10 7—f_(j_OTfPdL4 + LiC1 Li[PdL2C1T 1-.-1.-.O_Id-C1 (5)L=Ph3P 11 7The scope of this reaction has been illustrated by numerous publications involvingsyntheses of natural products.lghi.lml.hhIJx For example, Stile and co-workersdemonstrated the application of this coupling reaction in a short, convergent synthesis’s ofpleraplysillin-1 (14) (Equation 6) from the enol triflate 12 and the organostannane 13.+,z-Bu3Sn’- (6)12 13 75%yield 147Modified conditions were employed by Farina et a!. in the syntheses10of syntheticderivatives of naturally occurring cephalosporins 17 (Equation 7). Coupling of the enoltriflate 15 and the organostannanes 16 was effected by using bis(dibenzylideneacetone)palladium(O) 10.1Ob [Pd(dba)2] or ths(dibenzylideneacetone)bispalladium(O) [Pd2(dba)3]as the catalyst, and tri(2-furyl)phosphine as the ligand. Moreover, the reactions wereperformed in the presence of zinc ch1otide’101’(ZnC12) or LiC11Oc and with the use of Nmethylpyrrolidinone (NMP) as the solvent.0 n-BuSn R2 0Ph Ph HS 16 R1 ...,_S%1 R2OY’’0Tf Pd(dba)2(2 mole %) OR1CO2HPh 215(4mole%) 17ZnC12 (2 equiv) 65-79% yield25°C, 1-72 h R1,R2 = H, H; H, Me; Me, MeFarina et a!. reported10’that, at an earlier stage of their study, employment of exogenoushalide was necessary, but that their optimized procedure did not seem to require any halide.However, when no ZnC12 was used, the coupling was 2-3 times slower. The effect of ZnC12was attributed to either its water of hydration or to the presence of traces of hydrogenchloride. The beneficial effect of. traces of water in this type of coupling is precedented.2Itwas also mentioned10’1 that the solvent NMP, and the ligand tri(2-furyl)phosphine areeffective in increasing the rate of the coupling reaction. Polar aprotic solvents are known toenhance the coupling rate substantially.2Thus, the coupling rate increased in the followingorder: CHC13 OTf + n-Bu3Sn’-—(j- (2)PcIL4+ H—O_OTf + LIX _f_Cj_r!d_X (12)L=Ph3P 1 X=Brorl 45The initial oxidative intermediate (Scheme 8, step A, p 18) in the intramolecular reactionwould be 46 when the reaction is performed in the absence of LiCl. Apparently, thisintermediate is less stable than the intermediate 43. As the ring size of the palladiummetallocycle intermediate 44 increases, the rate of the transmetalation process (Step B) toproduce 44 decreases. As a result, in the absence of LiC1, the rate of the transmetalation stepis presumably slower than the rate of decomposition (Step C) of 46 and hence, the coupledproduct was not obtained efficiently. However, in the presence of LiCl (Scheme 8) the rateof the transmetalation (Step E) is faster than the rate of decomposition (Step F) of 43. Thus,the coupled product, the cyclopentanecarboxylate 41a (n = 1) or the cyclohexanecarboxylate41b (n = 2), was produced readily. Unfortunately, in the preparation of cycloheptanecarboxylate 41c (n =3) (Scheme 8), the rate of the decomposition is faster than the rate of thetransmetalation process to produce the eight-membered palladium metallocycle 48 (n = 3).Therefore, even in the presence of LiC1, the reaction failed to provide the desired product4 ic.18BrCO2EtMe3Sn—PdL440Br SnMe3CO2Et2LL2BrPd SnMe3CO2Et46BDL = Ph3n = 1 or 2CBr SnMe3LiCI +CO2Et40LiBr + 2LL2C1Pd SnMe3CO2Et43SSdecompositionwith LiC1E44decompositionwithout LiC1PdL4LiC1Me3Sn41cL = Ph34847 decompositionScheme 819In a related study, the various cyclobutanecarboxylates 37 have been employed as dienesin Diels-Alder reactions, and the subsequent Diels-Alder adducts (or the cycloaddtionproducts) were subjected to thermal ring opening reactions.13a,lS For example, a Lewis acidcatalyzed Diels-Alder reaction of the cyclobutanecarboxylate 49 with methyl vinyl ketone(MVK) provided the Diels-Alder adduct 50 as the sole product (Scheme 9). Thermolysis ofcompound 50 (Scheme 9) gave a mixture of two geometrical isomers, keto esters 51 and 52,in a ratio of 11: 1, respectively (1H nmr analysis).37MVKBFrEtJCO2Et cii2 CO2EL0-7849 95% yield 50o CO2ELmesitylene51reflux,lh +85% yieldir02Eto52Scheme 9203. Previous synthetic studies of 1 .2-bis(alkylidenecyclopentanes and related 1 .2-bis-exocvclic dienesCycloalkanes containing a 1,2-bis-exocyclic conjugated diene system16’7have served askey intermediates in the total syntheses of a variety of natural products.Th7Cel8In some ofthe syntheses, these dienes were employed in Diels-Alder reactions for the construction ofpolycycic structures.7c,lS For example, Trost et a!. have reported that the bis(allcylidene)cyclopentane 53 (Scheme 10) reacted with the dienophile 54, and the subsequentintramolecular alkylation of the corresponding adduct using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provided 5518a Compound 55 was used for the syntheses of (-)-sterepolide(56)18a and (-)-merulidial (57)18b (Scheme 10).C6H,80°CR( 2) DBU, room tempOSiMe.2(:-Bu) •Bu)81% yield(R= HOMe)OHCH3vThs/CHO571)545556Scheme 1021Owing to the potential synthetic utility of the 1,2-bis-exocyclic conjugated dienes inDiels-Alder reactions, various methodsl,l3,l7C,9have been developed for the syntheses ofthese dienes. In 1984, Nugent and coworkersl9 accomplished the stereoselectiveconversion of diynes 58 into E,E-1,2-bis-exocyclic dienes 60 by treatment with titanocenedichioride (Cp2TiC1)(59) and sodium amalgam (Na(Hg)) in the presence ofmethyldiphenyiphosphine (Ph2PMe), followed by acid hydrolysis (Equation 13a and TableIV).1)CpTiC12(5,Na(Hg) R1= R’ Ph2Me, THF(() ( )n (13a)= R2 2)HR258 60Table IV. Syntheses of the E,E-1,2-bis-exocyclic dienes 60: eny n R1 R2 %yield1 1 Me Me 602 2 Me Me 803 2 Me i-Pr 714 2 OEt OEL 635 2 Ph Ph 356 3 Me Me 277 4 Me Me 0In general, the diynes 58 with three or four bridging methylene groups (n = 1 or 2,respectively) were transformed via this titanium-mediated cydization into the relativelyunstrained cyclopentanes or cyclohexanes, respectively, in good yields (entries 1-4). Whenbulky substituents are attached to the termini of the diynes (entry 5) or medium-sized rings areto be formed (entries 6 and 7), the reaction is less efficient. A plausible mechanisml9of this22cydization is the initial generation of a phosphine-coordinated titanocene 61 (Equation 13b)or an uncoordinated titanocene “CpTi” 62, followed by the reductive coupling of the diyne58 with either 61 or 62 to give the bicyclic titanium metallocycle 63 (Scheme 11).Subsequent hydrolysis of 63 provides the diene 60 (n =2, Table 1, entry 2) in an 80% yield.The metallocycle 63 (n = 2) was not isolated, but its existence was suggested by adeuterolysis experiment using 20%D2S041D0.Under these conditions, the product 64(Scheme 11) was found to be 91% dideuterated in the two vinylic positions.n PhMeCp2TiCI + 2 Na(Hg) Cp2Ti(PhMe) ‘x “Cp2Ti” (13b).5059 61 6258:: 61or62D2S04,D20R1 = =Me3’R’( )nR26064Scheme 1123A later paperl9c from Nugent and co-workers has shown that eitherCp2TiC12IPh2PMe/Na(Hg) (for the generation of “Cp2Ti”) or Cp2ZrC12IMg.fHgCl2 (for thegeneration of “CpZr”) reagent combinations can be used for the cydlization of diynes 65 toE,E-1,2-bis-exocycic dienes 66 (Equation 14 and Table V). It is interesting to note that thetitanium-mediated cycization is better for five- and six-membered ring compounds (entries 2and 3), while the zirconium-promoted method is superior for four- and seven-memberedrings (entries 1 and 4). Unfortunately, both methods failed to provide the eight-memberedring (entry 5). Similarly, Negishi and co-workers have established20an alternative method togenerate the “Cp2Zr” reagent, from the treatment of Cp2ZrC12 with 2 equivalents of nbutyllithium (n-BuLi), for the conversion of some other diyne derivatives into thecorresponding E,E- 1 ,2-bis-exocycic dienes.Me= Me “Cp2Ti” or “Cp2Zr”Me (cL_ikMe(14)Table V. Effect of the ring size on the yields of E,Ebis(ethylidene)cycloalkanes 66entry n % yield (“CpTi7 % yield (“CpZr”)1’1 0 0 892 1 78 703 2 89 714 3 24 455 4 0 <2a gic yield after 3 h at -20 °C with the reagent “CpTi”.b glc yield after 24 h at room temperature with the reagent “Cp2Zr”.24Another procedure21 for the conversion of diynes 67 into the 1,2-bis(alkylidene)-cyclopentanes 68 was developed by Trost et a!. The transformation required the use of 2.5mol % of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct [Pd2(dba)3.CHC1],10 mol % of tri-o-tolylphosphine (Ar3P), 2 equivalents of acetic acid and 10 equivalents ofpolymethyihydrosiloxane (PMHS) (Equation 15 and Table VI). This catalytic reductivecycization reaction was proposed to proceed via the intermediacy of a hydridopalladiumcarboxylate complex 70.22 This process (Equation 16) includes regioselective hydropalladation on one of the triple bonds, cyclization of the vinylpalladium intermediate 71,followed by reductive cleavage of the second vinylpafladium intermediate 72 to produce thediene 73.3 — 1R3 = R2R4Table VI. Syntheses of the 1,2-bis(alkylidene)cyclopentanes 68entry R1 R2 R3 R4 reaction isolatedtime (mm) % yield1 H H H H 25 342 H CH2OMe Me OSiMe2(t-Bu) 60 703 SiMe3 n-Pr Me OS1Me(t-Bu) 3 894 CO2Me n-Pr Me OSiMe2(t-Bu) 20 95HL2Pd(70KPd L—OAc(16)R1Pddln) .CHC13HOAc, Ar3P, PMHS67(15)6869 71 72 7325Trost et al. have also published methods for the conversion of enynes 74 into 1,2-bis(alkylidene)cyclopentanes 75 using either a palladium(II)-catalyzed23(Table VII, entries1-3) or a nickel-chromium mediated (entry 4) carbocyclization. It was suggested237thatthe hydridopalladium acetate 77 (Scheme 12, p 26) was the catalytically active species in thecyclization process. fl-Hydrogen elimination of the allylic ring hydrogen (Ha) from 79provided the 1,2-bis(alkylidene)cyclopentanes 80.Table VII. Syntheses of the 1,2-bis(alkylidene)cyclopentanes 68entry substrate 74 product 75 % yield123a2231323e424HCO2ELMeO2CMeOCO2Et71706679MeO2C26cRCNPdOAc77- HPdOAc< ‘PdOAcPdOAcScheme 12In summary, the methods described above, including the titanium-mediated,19zirconium-mediated,19c palladium(ll)-catalyzed21-23 and nickel-chromium mediated24cycizations, can provide the required 1,2-bis-exocycic diene systems in good yields.However, these methodsl7c,1926 are limited to the synthesis of 1,2-bis(allcylidene)cyclo-alkanes which may have one or two E-substituted alkylidene moieties. 17c79274. Proposal regarding a study of the preparation and chemistry of alkyl 2.3-.bis(alkvlidene)cvclopentanecarboxvlatesIn view of the versatility of 1 ,2-bis-exocydic diene systems in Diels-Alder reactions andthe limitations of the existing synthetic methods for the stereocontrolled syntheses of thesesubstances, it was our goal to develop a general synthetic strategy for the preparation of alkyl2,3-bis(alkylidene)cyclopentanecarboxylates possessing E,E-, E,Z-, Z,E- or even the Z,Zconfigurations (81, 82, 83, 84, respectively). Exocyclic dienes 81-84 could, in principle,be prepared via the palladium-catalyzed intramolecular variant of the Stille cross-couplingreaction from the corresponding requisite precursors 85-88 (Scheme 13, p 28) respectively,which contain both vinyl halide and vinyltrimethylstannane moieties.R%I o2R1E,Z.diene 82If the preparation of these 1,2-bis-exocyclic dienes turned out to be successful,investigations would be carried out, particularly for theoretical interest, to determine thedihedral angles between the two double bonds of the Z,Z-bis(alkylidene)cyclopentanecarboxylates 84. It is reasonable to predict that, in this type of conjugated diene system,steric interactions between the substituents (or bulky groups) Ri and R3 on the two ends ofthe diene unit would be expected to prevent the diene from attaining planarity and, thus, asignificant dihedral angle would be created between the two double bonds. The magnitude ofthese deviations from planarity in the solid state was to be determined by X-ray crystallographic studies on derivatives of the exocycic dienes 84.E,E-diene 81 Z,E-diene 83 Z,Zdiene 8428R3R3O2R2X = Br or IScheme 13R3 R20C R’X SnMe385R20C R1X SnMe386R3 R20CX SnMe387R20CR3 R1X SnMe388During the course of our study, a new copper(I) chloride-mediated intramolecularcoupling reaction of the vinyl halide and vinyltrimethylstannane functions was discovered.This new reaction was utilized in the preparation of exocycic dienes 8 1-84 from thecorresponding precursors 85-88. Preliminary research on the mechanism and the limitationsof this process have been carried out and the results will be discussed in this thesis.8183R38429Earlier studies28from our laboratory have demonstrated that the reactions of alkyl (E)-3-trimethylstannyl-2-alkenoates 89 with lithium diisopropylamide (LDA) in THF, followed bythe protonation of the resultant enolate anions with a solution of acetic acid (HOAc) in diethylether (Et20), afford exclusively alkyl (Z)-3-trimethylstannyl-3-aikenoates 90 (Equation 17).In a similar manner, alkyl (Z)-3-trimethylstannyl-2-alkenoates 91 are transformed exclusivelyinto the corresponding alkyl (E)-3-trimethylstannyl-3-alkenoates 92 (Equation 18). Morepertinent for the present study was the finding that the deconjugation-alkylation13of esters 89and 91 (Equations 19 and 20) can be achieved by treatment of the generated enolate anionswith an electrophile, such as 2,3-dibromopropene (93), to afford the alkylated products 94and 95, respectively.1)LDA,THFR1—>2Me3Sn CO2R91R1_>,,CO2Me3Sn89M1>4CO2R21) LDA-HMPA, THF2) HOAc, Et201) LDA-HMPA, THF2BrBr(93)1) LDA-HMPA, THF2)BJLT(93)rCO2R2SnMe392(18)(19)(20)R1Me3Sn 2) HOAc, Et2089 90R1SnMe3(17)949530R3 R20C R1 1 R3M’CO2R2IX SnMe3 X85 91 96R2OC R’ 1R3_.ç1 R arv.i R3‘‘‘IMe3Sn C02R XX SnMe386 91 97R320CRt_>_JC02R2 arEl96R3R20C> Rl>,CO2z aixi R3IX SnMe388 89 97X = Br or IScheme 14It seemed clear that the required compounds 85-88 (Scheme 14) could be derived fromthe deconjugation-alkylation of the corresponding alkenoates 89 and 91 with the relatedelectrophiles 96 and 97. Through the application of some known reactions (Scheme 15, p31), the required electrophiles 98 and 99 could be obtained from the deconjugated esters 90and 92, respectively. Clearly, the esters 89 or 91 are the starting materials for thedeconjugation-alkylation procedure described above, and they can be preparedstereoselectively from the reaction of the lithium (trimethylstannyl)(cyano)cuprate[Me3SnCuCN]Li with the corresponding a,j3-unsaturated esters 100 under controlledconditions.29 In the following section of this thesis, the preparation of the requiredprecursors and the related starting materials ll be described in detail.31IitR1(’CO22 j”CO2R2SnMe3 SnMe3it itRl__>,COzR2 Rl__>2Me3Sn Me3Sn CO2R89 91= C02R100Scheme 15It is known that the relative configuration of Diels-Alder cycloaddidon products can becontrolled by the geometry of the requisite dienes and dienophiles. It would be of interest tostudy Diels-Alder reactions of 1,2-bis(alkylidene)cyclopentanecarboxylates 81-84 (p 27)with some selected dienophiles. In addition, cycloaddition products thus formed could beuseful synthetic intermediates for the future planning of the total synthesis of naturalproducts.32II. RESULTS AND DISCUSSION1. Syntheses of alkyl (E- and (Z)-3-trimeth’vlstannyl-2-alkenoates1.1. Preparation of a.fl-acetvlenic estersA number of functionalized a43-acetylenic esters 101-107 of general structure 100were required for this study. Ethyl 2-butynoate (101) and ethyl 2-pentynoate (102) arecommercially available. Each of the remaining substances, except 103 and 107, wereprepared from reaction of the requisite lithium acetylide 108 (Equation 21) with 1 equivalentof either methyl chioroformate (109) or ethyl chioroformate (110).28t-BuMe2SiOCO2EL 101 \\.......‘—---CO2Me 105Cl= CO2Et 102 \\_106CO2Me 103 CO2Me 107<___CO2Et 104 O2R2 100R1 = Li + ClCO2 R1 = C02R (21)108 109R=Me 10011OR2EL R2=MeorEt33The requisite lithium acetylide 108 (Scheme 16) was, in turn, generated from eithertreatment of the corresponding l,1-dibromo-1-alkene 111 with 2 equivalents of methyl-lithium (MeLi), or deprotonation of the corresponding 1-allcyne 112 with either 1 equivalentof MeLi or with 1 equivalent of n-butyffithium (n-BuLi).R! ,Br MeLi MeLiR’ = Li R1 = HBr orn-BuLl108 112111Scheme 16Commercially available 3-methylbutanal (113) (Scheme 17) was treated with 1.1equivalents of dibromomethylenethphenylphosphorane30(Ph3P=CBr2) in dichioromethane(CH2C1)(room temperature, 1 h) to afford the 1,1-dibromo-1-alkene 114 in a 74% yield.28The ir spectrum of compound 114 showed a weak C=C stretching frequency at 1619 cm1.The 1H nmr spectrum of 114 exhibited the expected signals for an isopropyl group (a 6-proton doublet at 60.92 and a 1-proton multiplet at 6 1.68-1.80), an allylic methylene group(a 2-proton triplet at 8 1.98, J= 7 Hz) and a vinylic proton (a 1-proton triplet at 8 6.38, J= 7Hz).c NyBr 2)CiCOt CO2Et113 74% yield 114 91% yield 104Scheme 17Compound 114 was allowed to react first with 2.1 equivalents of MeLi (-78 OC, 1 h;room temperature, 1 h) and then with 1.5 equivalents of ethyl chloroformate (-20 OC, 1 h;room temperature, 1 h) to provide the ester 104 in a 91% yield (Scheme 17).28 The irspectrum of compound 104 displayed a moderate CC stretching frequency at 2234 cm1 and34a strong C=O stretching frequency at 1713 cm1. The 1H nmr spectrum of 104 showed theexpected signals for an isopropyl group (a 6-proton doublet at 6 1.02 and a 1-proton multipletat 6 1.88-1.99) and an ethyl ester group (a 3-proton triplet at 8 1.32, J= 7 Hz and a 2-protonquartet at 64.22, J= 7 Hz). In addition, some characteristic 13C nmr signals31 indicated thepresence of two acetylenic carbons (674.0 and 688.4) and a carbonyl carbon (8 153.9).Protection28 of the hydroxyl group of commercially available 4-pentyn-l-ol (115)(Scheme 18) with 1.3 equivalents of tert-butyldimethylsilyl chloride (t-BuMe2SiC1) and 2.5equivalents of imidazole in DMF (room temperature, 16 h) provided a 95% yield of thealkyne 116. The ir spectrum of compound 116 exhibited a strong C-H stretchingfrequency at 3315 cnr1 and a weak CC stretching frequency at 2121 cm-1. The 1H nmrspectrum of 116 showed the expected signals for a tert-butyldimethylsilyl group (a 6-protonsinglet at 60.03 and a 9-proton singlet at 80.87) and an acetylenic proton (a 1-proton tripletat 6 1.89, J= 2.5 Hz). Deprotonation of 116 with 1.1 equivalents of n-BuLi generated thelithium acetylide 117 (Scheme 18),32 which was treated in situ with 1.2 equivalents ofmethyl chloroformate to provide the ester 105 in an 86% yield.28 The spectral data for 105were in agreement with the expected structure.t-BuMe2SiC1HO”’Nimidazole, DMFt-BuMe2SiV115 11695% yield1) n-BuLi, THF2) C1COMet-BuMe2SiO :-BuMe2SiO’’NCO2Me Li105 86%yield 117Scheme 1835In a similar fashion, commercially available 5-chloro-1-pentyne (118) (Scheme 19) wasconverted into the corresponding ester 106 in an 87% yield.33 The latter substance wastreated with 4.1 equivalents of sodium iodide (Nal) in acetone (reflux, 19 h) to provide theiodo ester 107 in a 90% yield (Scheme 19).331) n-BuLi, THF ci2) C1COMe CO2Me118 10687% yieldNal, acetone90% yieldICO2Me107Scheme 19In the synthesis of methyl 4-cyclopropyl-2-butynoate (103) (Equation 22), a reportedmodification28of Carison’s procedure34was used. Thus, a solution of the dilithio salt ofpropynoic acid, 119, in a 1: 2 THF-HMPA solvent system, was treated with 1.1 equivalentsof cyclopropylmethyl bromide (room temperature, 24 h) and subsequently with 4.0equivalents of iodomethane (room temperature, 24 h) to give the ester 103 in a 48% yield.28The compounds 106, 107 and 103 exhibited spectral data which were in full accord with theassigned structures.1)1: 2 THF-HMPA___&BrLi = CO2Li (22)2) Mel = CO2Me119 48%yield 103361.2. Conversion of a.$-acetvlenic esters into alkyl (F)- or (Z’)-3-trimethylstannyl-2-aikenoatesPrevious reports35 from our laboratory showed that reactions of aj3-acetylenic esters100 with lithium (trimethylstannyl)(phenylthio)cuprate [Me3SnCuSPh]Li (120) in thepresence of a proton source provides, highly stereoselectively, the corresponding alkyl (E)-3-irimethylstannyl-2-alkenoates 89 (Equation 23). Moreover, reaction of 120 under differentreaction conditions provided, also highly stereoselectively, the corresponding alkyl (Z)-3-trimethylstannyl-2-alkenoates 91 (Equation 24). Thus, use of reagent 120, along withchoice of appropriate reaction conditions, resulted in the control of the stereochemical outcome of the overall addition of the unit Me3Sn-H across the triple bond of the cxji-acetylenicesters 100. Furthermore, stereoselective conversion35bof 100 into 89 could be achieved byuse of the (trimethylstannyl)copper(I) reagent 121 (Equation 25). However, this latterreagent was found to be ineffective for the stereocontrolled transfonnation of 100 into 91.[Me3SnCuSPh]Li Me3SnCu•Me2120 121R1 120, THF R1— C02R— COR2 (23)2 R2OH,78°C Me3Sn H100 89R1 1) 120, THF, -48 °C R’— ,HCO R2 (24)— 2 2)R2OH Me3Sr(100 91Rt 1) 121, THF, -48 °C R1 C02RCOR2 —— 2 2)NH4CFNI{0 Me3Sn H100 8937A number of (E)- and (Z)-3-trimethylstannyl-2-aikenoates of general structures 89 and91, respectively, were required for this study. The reagent 120 could serve well in thesyntheses of 89 and 91, but this method has some disadvantages. Firstly, the requisitestarting material phenylthiocopper(I) (PhSCu) is tedious to make.36 Secondly, the latterpreparation requires the use of thiophenol, a chemical with a notably offensive odour. Moreimportantly, PhSCu, like many copper(I) salts, is not very stable, and thus the prolongedstorage of this reagent may decrease the reproduceability in generating the desired cuprate120. Copper(I) cyanide (CuCN), by contrast, is readily available, is a reasonably stablechemical (CuCN is more stable than copper(II) cyanide),37and has been used extensively inthe generation of organocuprates.38 Therefore, a brief study was carried out to determine thefeasibility of the use of the lithium (trimethylstannyl)(cyano)cuprate [Me3SnCuCNjLi (123),which is prepared3S by reaction of trimethylstannyllithium39Me3SnLi (122) with copper(I)cyanide (CuCN) in THF (Equation 26), as an effective alternative to 120 for the stereo-selective transformation of 100 into either 89 or 91.R1— ,C02R H[Me3SnCuSPh]Li — —120 Me3Sn H Me3Sn CO2R89 91THF, -48 °CMe3SnLi + CuCN [Me3SnCuCN]Li (26)122 123Me Me H Me CO2Et Me SnMe3CO2Et — — —Me3Sn CO2EL Me3Sn H Me3Sn CO2Et124 125 126The reaction of [Me3SnCuCN]Li (123) with the commercially available ethyl 2-pentynoate (102) was investigated under a variety of experimental conditions.29 It wasfound that when the reaction was performed at -48 OC for a fairly short period of time (1 h)and then the mixture was warmed to 0 °C and subjected to work-up, the major desiredproduct ethyl (Z)-3-trimethylstannyl-2-alkenoates (124) was accompanied by a minor amount38(<10%) of the geometric isomer ethyl (E)-3-trimethylstannyl-2-pentenoate (125) and asignificant quantity (—20%) of ethyl (E)-2,3-bis(trimethylstannyl)-2-pentenoate (126).40However, further experimentation finally established reaction conditions that effected arelatively clean trans-formation of 102 into 124.29 Thus, reaction of 102 withapproximately 1.1 equivalents of the cuprate 123 at -48 OC for 2 h and then at 0 °C for 2 h(Equation 27 and Table Vifi, entry 1), followed by work-up, gave a product that consistedalmost entirely of 124, accompanied by very minor amounts of 125 and 126. Purificationof this material by a combination of flash chromatography41on silica gel (which separatedand removed 125) and distillation (126 remained in the still-pot) provided the desired Zalkenoate 124 in a 72% yield. Subjection of other a,f3-acetylenic esters 100 (entries 2-7)with cuprate 123 under reaction conditions very similar to those outlined above afforded thecorresponding alkyl (Z)-3-trimethylstannyl-2-alkenoates 91 in good yields.291 1) [Me3SnCuCNJLi (123) 1R R H— r’r o2 THF, -48 °C, 2 h; 0 °C, 2 h —— ‘-‘2 (27)2)NH4CI-NHO Me3Sn C02R100 91Table VIII. Preparation of alkyl (Z) -3-trimethylstannyl-2-alkenoates 91’entry acetylenic R1 R2 equiv of product1’ % yieldcester cuprate124 72131 76132 72133 81134 78135 79136 781 102 Me EL 1.092d 127 (i-Pr)3SiO Et 1.063d 128 CHO(CH20C EL 1.06129 cyclohexyl EL 1.045 105 t-BuMeSiO(CH)2 Me 1.056 106 Cl(CH Me 1.057 130 HCEC(CH Me 1.01a Detailed experimental procedures for entries 2-7 can be found in reference 29.b The isolated crude products contained small amounts (—1-4% and —1-2%, respectively) of thecorresponding alkyl (E)-trimethylstannyl-2-alkenoates and alkyl (E)-2,3-bis(thmethylstannyl)-2-aikenoates. These minor products were, in each case, removed by a combination of flashchromatography and distillation.C Yield of purified, distilled product.d Compounds 127-129 and 13 1-133 were prepared by Mr. Keith A. Ellis. Experimental proceduresfor the preparation of these compounds can be found in reference 29.e A sample of compound 130 was generously provided by Mr. Philip Coish.39Reaction (THF, -78 °C) of acetylenic esters 100 with 1.3-1.5 equivalents of cuprate123 in the presence of 1.3-1.5 equivalents of an alkanolR2OH (methanol for methyl ester;ethanol for ethyl ester) provided the alkyl (E)-3-trimethylstannyl-2-alkenoates 89 in goodyields (Equation 28 and Table TX).29 The major products were accompanied by smallamounts (1-4%) of the Z isomers, but, in each case, the pure E isomer could readily beobtained by subjection of the mixture to flash chromatography and distillation. For example,reaction of the ethyl 2-pentynoate (102) (entry 2) with 1.3 equivalents of cuprate 123 in thepresence of 1.3 equivalents of ethanol gave a crude product that contained a mixture of theethyl (E)- and (Z)-3-trimethylstannyl-2-pentenoates (125) and (124) in a ratio of —97: 3,respectively (glc analysis). Purification of this material by flash chromatography anddistillation provided 125 in a 74% yield.1 1) [Me3SnCuCNJLi (123) 1 2rn2 THF, R OH, -78 °C, 4 h —— (28)2)NH4C1-NBO Me3Sn H100 89Table IX. Preparation of alkyl (E)-3-trimethylstannyl-2-alkenoates 89entry acetylenic R1 R2 equiv of equiv of reaction product1’ % yield’ester cuprate R2OH time (h)1 101 H Et 1.30 1.32 4 137 782 102 Me Et 1.30 1.31 4 125 743 103 cyclopropyl Me 1.51 1.45 7 138 804 104 i-Pr EL 1.56 1.67 6 139 845d 129 cyclohexyl Et 1.50 1.50 7 140 816 105 t-BuMe2SiO(CH) Me 1.30 1.35 4 141 777 106 Cl(CH Me 1.30 1.30 4 142 80ge 130 HCC(CH2) Me 1.30 1.33 4 143 729’ 127 (i-Pr)3SiO Et 1.31 1.31 4 144 7410d 128 CHO(CH0C EL 1.30 1.30 4 145 70a Detailed experimental procedures for entries 5,7-10 can be found in reference 29.b The isolated crude products contained small amounts (-1-5%) of the corresponding alkyl (Z)trimethylstannyl-2-a]kenoates. Flash chromatography of these crude materials provided puredesired products.C Yield of purified, distilled productd Compounds 127-129, 140, 144 and 145 were prepared by Mr. Keith A. Ellis. Experimentalprocedures for the preparation of these compounds can be found in reference 29.e A sample of compound 130 was generously provided by Mr. Philip Coish.40[Me3SuCuCN]U 1 2 1 2R1 (123) R CO2R H R ,CO2RC02RMe3Si’Cu(CN) Me3SnH146 89R1—4 OCu(CN) H R1—\\ H2 “ ‘ 2Me3Sn OR Me3Sn CO2R147 91Scheme 20As shown in Tables VIII and IX (pp 38-39), the procedures for the preparations of both(E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 tolerate the presence of a variety offunctional groups such as silyl ether, acetal, primary alkyl chloride, and terminal alkyne. Apossible pathway for the addition of [Me3SnCuCN]Li (123) to a,$-acetylenic esters 100, togive products 89 and 91, is shown in Scheme 20. It has been established42 thatorganocopper(I) reagents add kinetically to CEC bonds in a cis-fashion. Therefore, it islikely that addition of the cuprate 123 to 100 provides initially the vinylcopper(I)intermediate 146 (Scheme 20).42 Moreover, it has been proposed42 that, depending on anumber of factors, the latter species 146 may rearrange to the corresponding allenoate 147.Protonation of, the “kinetic intermediate” 146, provides the (E)-3-trimethylstannyl-2-alkenoate 89, while protonation of the allenoate 147 occurs from the side opposite the bulkytrimethylstannyl group to produce the (Z)-3-trimethylstannyl-2-alkenoate 91.42 At -48 °C,and/or at a higher temperature such as 0 OC, rearrangement of the species 146 to the allenoate147 is, apparently, facile. Thus, under these conditions, 91 is formed stereoselectively afterthe protonation process. However, at -78 OC, rearrangement of 146 to the allenoate 147 isretarded and the initially formed “kinetic intermediate” 146 is protonated by the addedmethanol or ethanol, or is protonated during the final aqueous work-up to afford the (E)-3-trimethylstannyl-2-alkenoate 89.41R1 C02R R’ HaM) CO2R2M>”CO2R2I SnMe399 92 91As was mentioned earlier (pp 30-31), electrophiles of general structures 96 and 97 wererequired for this study. The requisite (Z)- and (E)-diiodoallcenes 98 and 99 could besynthesized from the alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91,respectively. 2-Bromo-4-iodo-1-butene (148) required a different synthetic strategy, whichwill now be described.Suzuki eta!. have reported46the use of B-bromo-9-borabicyclo[3.3.ljnonane (B-Br-9-BBN) (Scheme 21, p 44) for the conversion of 1-alkynes 149 into 2-bromo-1-alkenes 151.The bromoboration reaction proceeds through addition of the Br-B moiety to the CC bond ina cis-fashion. Protonolysis of the bromoboration intermediate 150 with acetic acid affordsthe desired 2-bromo-1-alkenes 151 in excellent yields. For example, 1-hexyne (152)44(Equation 29) was transformed into 2-bromo-1-hexene (153) in a 99% yield.4BrH ZZ R + 13rB-Br-9-BBNxr151Scheme 21_,,,_,/B-Br-9-BBN(29)152 99% yield 1532-Bromo-4-iodo-1-butene (148) (p 45) could be synthesized via the aforementionedprocedure. A solution of 3-butyn-l-ol (154) (Scheme 22, p 45) in CH21 was added to afreshly prepared solution of triphenyiphosphine diiodide (Ph3P.12)47(1.1 equiv) in CH2C12(room temperature, 4 h) to give, after work-up and distillation of the crude product, 4-iodo-1-butyne (155) in a 76% yield.13a The ir spectrum of 155 showed a strong SC-H stretchingfrequency at 3296 cm1 and a weak CEC stretching frequency at 2121 cur1. The 1H nmrspectrum of 155 exhibited the expected signals for an acetylenic proton (a triplet at 62.17, J=2 Hz) and two different methylene groups (a 2-proton triplet of doublets at 32.80, J= 7,2Hz, and a 2-proton triplet at 63.25, J= 7 Hz). Moreover, high resolution mass spectrometryshowed that 155 had a molecular formula of C4H51.45Addition of a solution of compound 155 (Scheme 22) in CH21 to a solution of B-Br9-BBN (0 0C, 3 h) in CH21 and subsequent protonolysis provided 2-bromo-4-iodo-1-butene (148) in an 86% yield.l3a The ir spectrum of 148 displayed a moderate C=Cstretching frequency at 1632 cm. The 1H nmr spectrum of 148 exhibited the expectedsignals for two different methylene moieties (a 2-proton broad triplet at 32.94, J= 7 Hz, anda 2-proton triplet at 6 3.24, J= 7 Hz) and two geminal olefmic protons (a 1-proton broaddoublet at 6 5.57, J= 2 Hz, and a 1-proton broad doublet of triplets at 3 5.68, J= 2, 1 Hz).High resolution mass spectrometry showed that 148 had a molecular formula of C4H6BrI.Ph3.12,CH21roomtemp,4h154 15576% yield1) B-Br-9-BBN2)H86% yield148Scheme 22R1_>..JCOZR2 R1‘f’CO22_____R’IMe3Sn I89 90 98SnMe391 92 99Scheme 2346For the preparation of the requisite (Z)- and (E)-diiodoalkenes 98 and 99 (Scheme 23, p45), the first step was the stereospecific deconjugation28of the alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 to give the corresponding alkyl (Z)- and (E)-3-trimethylstannyl-3-alkenoates 90 and 92, respectively. Following the reported28 or amodified48procedure, the deconjugation reactions gave the results summarized in Table X.Table X. Deconjugation reactions of the alkyl (E)- and (Z)-3-trimethyl-stannyl-2-alkenoates 89 and 91, respectivelyentry starting material methoda woduct % yield1’j28 MeMe)’A Me%fCO2EtSnMe3125 156228_>..JCO2MeA 87SnMe.3157138348)__\\,CO2EtB f(’CO2Et 82SnMe3158139Me 89428 MeMe>”COEt ‘Co2EtSnMe3124159a Method A: Each of the substrates 125 and 138 was treated with LDA (2.30 equiv) in THF (-78 °C,30 miii; 0 O(, 1 h); the solution was cooled to -78 °C and added (cannulation) to a cold(-98 O) solution of HOAc in Et20.8Method B: (A modified procedure) Substrate 139 was treated with KN(SiMe3)2(2.73 equiv) in THF(-78 °C, 45 mm; -48 °C, 5.5 h) containing HMPA (2.78 equiv). Enolate quenching as inMethod A.48Method C: Substrate 124 was treated with LDA-HMPA (1.52 equiv) in THF (-78 °C, 30 mm; o O(,1 h). Enolate quenching as in Method A.28b Yield of purified, distilled product47Deconjugation28of the esters 125 and 138 with lithium diisopropylamide (LDA) inTHF, followed by protonation of the resultant enolate anions with a solution of HOAc inEt20, provided exclusively ethyl (Z)-3-trimethylstannyl-3-pentenoate (156) and methyl 4-cyclopropyl-3-trimethylstannyl-3-butenoate (157), respectively, in good yields (Table X,entries 1 and 2, p 46). Surprisingly, the reported procedure28for deconjugation of ethyl (E)5-methyl-3-trimethylstannyl-2-hexenoate (139) with 2.3 equivalents of LDA in the presenceof 2.3 equivalents of hexamethylphosphoramide (HMPA) was not satisfactory. The expectedproduct 158 was produced in low yield (16%), and some unidentified side-products werealso present. It seemed likely that the formation of the side-products in this case wasassociated with the relatively sluggish removal of the (hindered) 7-protons of 139 by LDA.After some experimentation, it was eventually found that deprotonation of 139 with 2.73equivalents of potassium bis(trimethylsilyl)amide [KN(SiMe3)2]48in THF in the presence of2.78 equivalents of HMPA, followed by the usual quenching procedure, provided 158 as asingle product in good yield (Table X, entry 3). Deprotonation of 124 with LDA (2.3 equiv)in THF (method A) in the absence of HMPA, followed by protonation, gave a mixturecontaining the starting material 124 (—14%), the expected product 159 (—80%), and anumber of minor components. Deconjugation of 124 was therefore carried out with 1.52equivalents of L.DA in THF containing 1.50 equivalents of HMPA (Table X, entry 4).28The stereochemistry of each àf the esters 156-159 (Table X, p 46) was readily assignedon the basis of 1H nmr spectroscopic data, in particular, the magnitude of the couplingconstants(3JSn-H)43 associated with coupling between the olefinic proton and the tin atom.In the alkyl (Z)-3-trimethylstannyl-3-alkenoates 156-158 (where the Me3Sn moiety andolefinic proton are in a trans relationship), these 3Jsn..H values are —130 Hz, while thecorresponding coupling constant for ethyl (E)-3-trimethylstannyl-3-pentenoate (159) (wherethe Me3Sn moiety and olefinic proton are in a cis relationship) is 73 Hz.48For all the esters 156-159 (Table X, p 46) high resolution molecular mass measurements were determined on the (M+ - Me) fragment and are based on the isotope 120Sn.45Interestingly, the ir spectra of the (Z)- and (E)-conjugated esters (124, 125, 138 and 139,Table X) showed strong C=O stretching frequencies at 1703 cm1 and —1718 cm-1,respectively, while all the deconjugated esters 156-159 exhibited the correspondingfrequencies at the ranges 1733-1737 cm1. In summary, all the prepared esters 156-159showed spectroscopic data in full accord with those found in the literature.Deconjugation-protonation and deconjugation-ailcylation reactions of a,J3-unsaturatedesters have been studied extensively in the last two decades.48’9 In 1972, Rathke andSuffivan49areported that deprotonation of the protons from the a43-unsaturated ester 160(Equation 30) by lithium N,N-isopropylcyclohexylamide (LilCA) in the solvent system THFHMPA, followed by quenching of the resultant dienoate anion with various electrophiles,afforded the corresponding a-alkylated deconjugated esters 161 in good yields.CO Et 1) LilCA, THF-HMPA CO2Et/ 2) RX = Mel BnBr 4/ ‘R160 161R = Me, 87% yieldR = Bn, 62% yieldThe preference for alkylation at the a-position after the generation of dienolate anionsfrom aj3-unsaturated esters was also observed by Schiessinger et al.49b In their study, apresumed 1: 1 complex of LDA and HMPA was generated by the addition of 1.1 equivalentsof HMPA to a THF solution of 1 equivalent of LDA (-78 0(D). Successive addition of 1equivalent of ethyl (E)-2-butenoate (160) (Equation 31, p 49) and iodoethane (Ed) to thissolution gave the expected a-alkylated deconjugated ester 162 in a 96% yield. According tosimple molecular orbital calculations, they attributed the a-alkylations to the location of the49maximum negative charge on the a-carbon atoms in the dienolate anions.49bCO2Et 1) LDA-HMPA, THY CO2Et=1 (31)2) EtI Et160 96%yield 162Studies focusing on the determination of the stereochemical outcome of deconjugationprotonation and deconjugation-alkylation of aj3-unsaturated esters were also carried out. Itwas found49’,for example, that the deconjugation-protonation of ethyl (Z)-2-alkenoates 163(Equation 32) provided, highly stereoselectively, the corresponding (E)-3-alkenoates 164 ingood yields (—95-99%).CO2EL— 1) LDA-HMPA, THY_JR_.r’CO2E 2) HrR—J (32)163 164R = Me, n-Pr or i-Pr —95-99% yieldThe stereochemical outcome in the conversion (Scheme 24, p 50) of (E)-3-trimethyl-stannyl-2-alkenoates 89 into the corresponding (Z)-3-trimethylstannyl-3-alkenoates 90 wascompletely analogous to that of the conversion of 163 into 164. Results obtained from thetransformation of 89 and 163 into 90 and 164, respectively, were rationalized28b,49by theformulations4shown in Scheme 24. For the kinetically controlled deprotonation of the (Z)2-alkenoates 163, there are two ground-state conformations, 165 and 167.49e The C-Habonds in both conformations 165 and 167 are aligned perpendicular to the plane of theconjugated system. The perpendicular orientation of C-Ha bonds in 165 and 167 meet thestereoelectronic requirement for the formation of dienolate anions 173 and 175, respectively,through the corresponding transition states (169 and 171). The transition state 169 derivedfrom 165 would be destabilized by a serious steric interaction (A1’3strain50)between the R1group and the C02R group. In contrast, deprotonation of conformation 167 would occur50R20 R20o>-xR1 R1165X=H 167X=H166 X = SnMe3 168 X = SnMe31A[transition state] [transition state]169X=H 171X=H170 X = SnMe3 172 X = SnMe3- R20 R20Li LiR1H R1173X=H 175X=H174 X = SnMe3 176 X = SnMeCO2EtRCO2Et R163 164 R20R1 C02R R1”%(CO22Me3)” snMe389 90 H—R1164 X = HScheme 24 90 X = SnMe351via transition state 171, in which no severe steric interaction would be involved.Consequently, the pathway 167 — 171 —, 175 would be expected to be energetically morefavourable than that involving 165 into 173 (via 169), and therefore, protonation (of 175)would give the (E)-3-alkenoate 164. Following a similar argument in the deconjugation of(E)-3-trimethylstannyl-2-alkenoates 89, the transition state 172 derived from conformer 168would be destabilized by A1’2 strain50 between the R and Me3Sn group. This interactionwould be considered weaker than the A13 strain associated with the transition state between166 and 170, owing to the length of C-Sn bond (—2 A).4b Thus, again, the pathway 168—* 172 —, 176 would be expected to be favoured, leading eventually to the stereoselectiveformation of (Z)-3-trimethylstannyl-3-alkenoates 90.28Similarly, ethyl (E)-2-pentenoate 177 (R = Me) was converted, by the deprotonationprotonation process,49einto the (Z)-3-pentenoate 178 in a 98% yield (Equation 33).Interestingly, the deconjugation was less stereoselective as the size of the R group increased.For example, the deconjugation of 177 (R = n-Pr) provided (94% yield) a mixture of 178(R = n-Pr) and 164 (R = n-Pr), in a ratio of -6: 1, respectively. When the steric bulk of theR group was further increased, as in the case where the R group was an i-propyl group, theratio of the two products (97% yield) 178 (R = i-Pr) and 164 (R = i-Pr) decreased to-1.8: 1, respectively.1)LDA-NMPA, ThFjO2Et+R_1”178Obviously, deconjugation of the (E)-2-alkenoates 177 would be considered lessstereoselective than that of the (Z)-2-alkenoates 163. In contrast to these findings, thetransformation of the (Z)-3-trimethylstannyl-2-alkenoates 91 (Scheme 25, p 53) into the (E)3-trimethylstannyl-3-alkenoates 92 were found to be completely stereoselective.28 These52results may be rationalized28,49by the formulations49shown in Scheme 25 (p 53). For thekinetically controlled deprotonation of the (E)-2-alkenoate 177, the two ground-stateconformations 179 and 181 have both of their C-Ha bonds aligned perpendicular to the C=Cr system. The corresponding transition states 183 and 185 would be destabilized by AUstrain50 (between the R1 group and the olefinic proton Hb) and A12 strain50 (between the R1group and the /3-proton, X = H), respectively. However, the transition state 183 is favoureddue to the stabilization from the cis R1 group.49eBoth experimental and theoretical studies51have shown that allylic anion structures containing terminal cis alkyl groups are more stablethan those having trans ailcyl groups. Thus, if the transition states 183 and 185 possessallylic anion-type properties, 183 would be expected to be more stabilized than 185. As aresult, the major dienolate anion obtained from the deprotonation of 177 would be 187,which provides 178 upon subsequent protonation. Thus, when 177 (R = Me) wasdeconjugated, 178 (R = Me) was obtained as the only product. As the size of the R group in177 (R = n-Pr or i-Pr) increased, the transition state 183 would be destabilized by A1’3strain and this, in turn, would favour the deconjugation of 177 to proceed through thetransition state 185 to provide 189 and subsequently 164 (R = n-Pr or i-Pr) as the sideproduct.49e In the coversion of the (Z)-3-trimethylstannyl-2-alkenoates 91 into the (E)-3-trimethylstannyl-3-alkenoates 92, it would be expected that the pathway 180 —, 184 —* 188would be more favoured than the pathway 182 —* 186 —* 190, irrespective of the size of theR1 group. This could be explained by the fact that the steric interaction (A12 strain) betweenthe R1 and X (= SnMe3) groups in the transition state 186 would destabilize this speciessignificantly. On the other hand, the relatively small destabilization (AU strain between R1and proton H1,, and A12 strain betweem SnMe3 and H) in the transition state 184 would bepartially compensated by the stabilization from the cis R1 group as mentioned above. Thus,the deprotonations of the (E)-3-trimethylstannyl-2-alkenoates 91 proceeds through 180, 184and 188 to provide the (Z)-3-trimethylstannyl-3-alkenoates 92 in a stereoselective manner.53COR2R>179 X = H180 X = SnMe3LDA[transition state]R20R1HCOR2181 X = H182 X = SnMe3LDA[transition state]189 X = H190 X = SnMe3C02R164 X = H183 X = H184 X = SnMe3Li185 X = H186 X = SnMe3R20• H187 X=H188 X = SnMe3LiCO2EtCO2EtR R177 178R1—rCO2R2Me3Sn CO2Et SnMe391 92Scheme 25H178 X = H92 X = SnMe3 90 X = SnMe354r’CO2Et i-Bu2AIH,Et20-78 °C, 1 h;0°C, 1 h159 93%yield 19112, CH1room temp. 15 miii90% yieldMe MeI Ph3.12,CH2II Ii Et3N, room temp. 4 h i193 98%yield 192Scheme 26A sequence of reactions was employed for the conversion of ethyl (E)-3-trimethylstannyl-3-pentenoate (159) (Scheme 26) into (E)-3,5-diiodo-2-pentene (193).Reduction of the ester 159 in Et20 with a solution of dilsobutylaluminum hydride (iBu2AIH) (2.5 equiv) in hexanes afforded, after appropriate work-up and distillation, thecorresponding trimethyistannyl alcohol 191 in a 93% yield. The ir spectrum of 191exhibited a strong 0-H stretching frequency at 3363 cm-1 and a weak C=C stretchingfrequency at 1614 cm-1. The 1H nrnr spectrum of 191 showed the expected signals for atrimethylstannyl group (a 9-proton singlet at 80.12 with sateffite peaks due to Sn-H coupling,2JSnH 52 Hz), a hydroxyl proton (a 1-proton triplet at 6 1.48, J= 7 Hz, which exchangeswith D20), a vinylic methyl group (a 3-proton doublet at 6 1.73, J= 7 Hz), two methylenegroups (a 2-proton triplet of doublets at 82.57, J= 7, 1 Hz, with satellite peaks due to Sn-Hcoupling,3Js= 61 Hz and a 2-proton quartet at 83.62, J= 7 Hz) and a vinylic proton (a 1-proton quartet of triplets at 8 5.85, J= 7, 1 Hz with satellite peaks due to Sn-H coupling,3Js-w 77 Hz).Vinyl trialkylstannanes may be converted into the corresponding vinyl iodides via55reaction with iodine.4b,33a This transformation is usually both highly efficient andstereospecific, and generally proceeds with retention of C=C bond geometry. Thus, thetrimethyistannyl alcohol 191 (Scheme 26, p 54) was converted into the corresponding iodoalcohol 192, by reaction with 12 (1.1 equiv) in CH212 (room temperature, 15 mm), in a90% yield. The latter compound exhibited spectral data which were in full accord with theproposed structure. For example, the ir spectrum of 192 exhibited a strong 0-H stretchingfrequency at 3333 cnr1 and a weak C=C stretching frenquency at 1635 cm1. The 1H nmrspectrum of 192 showed the expected signals for a hydroxy proton (a 1-proton broad signalat 8 1.60-1.80 which exchanged with D20), a vinylic methyl group (a 3-proton doublet at 81.67,1=7 Hz), two methylene groups (a 2-proton triplet at 6 2.65,1= 6 Hz, and a 2-protonquartet at 33.74,1=6 Hz) and a vinylic proton (a 1-proton quartet at 66.40, J= 7 Hz). Thehigh resolution mass spectrum showed that 192 had a molecular formula ofC5H910.Treatment of the iodo alcohol 192 (Scheme 26, p 54) in CH212 with Ph3.1247in thepresence of triethylamine (Et3N) (room temperature, 4 h) afforded the expected product (E)3,5-diiodo-2-pentene (193) in a 98% yield. The 1H nmr spectrum of 193 displayed theexpected signals for a vinylic methyl group (a 3-proton doublet at 8 1.68, J= 7 Hz), twomethylene groups (a 2-proton triplet at 62.95,1=7 Hz, and a 2-proton triplet at 63.27,1=7Hz) and a vinylic proton (a 1-proton quartet at 66.42,1=7 Hz). Moreover, 193 was shownto have a molecular formula of CSH8I2 by high resolution mass specirometry.By employing the same sequence of reactions described above, ethyl (Z)-3-trimethyl-stannyl-3-pentenoate (156), methyl (Z)-4-cyclopropyl-3-trimethylstannyl-3-butenoate (157)and ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (158) were transformed into thecorresponding (Z)-diiodoallcenes 98: (Z)-3,5-diiodo-2-pentene (198), (Z)-1-cyclopropyl-2,4-diiodo-1-butene (201) and (Z)-1,3-diiodo-5-methyl-2-hexene (204), respectively. Theresults obtained from these transformations (Scheme 27, p 56) are summarized in Table XI.56R14’f”CO22SnMe390156R=Me,R2EL157 =c-Pr,RMe158R=i-Pr,R2EtSTEP Ai-Bu2A1H, Et20-78 °C, 1 h; 0°C, 1 hR’SnMe3194196 R1=Me199 R1=c-Pr202 R1=i-PrSTEP CPh3.12,CH2IEt3N, room temp. 4 hSTEP B‘2, CHIroom temp. 15 mmR1195197 R1=Me200 R1=c-Pr203 R1=i-PrScheme 27Table XI. Conversions of the alkyl (Z)-3-trimethylstannyl-3-alkenoates90 into the corresponding (Z)-diiodoalkenes 98conversion of starting material conversion of starting material conversion of starting material90 into product 194, 194 into product 195, 195 into product 98,i.e. STEP A in Scheme 27, i.e. STEP B in Scheme 27, i.e. STEP C in Scheme 27,90 (R1,R2) —, 194 (% yield)’1 (R1): 194 —, 195 (% yield)’ (R1): 195 —÷ 98 (% yield)a156 (Me, EL) —, 196 (99) (Me): 196 —, 197 (96) (Me): 197 — 198 (95)157 (c-Pr,1’Me)—, 199 (98) (cPr):b 199 —, 200 (89) (cPr):b 200 —, 201 (91)158 (i-Pr,’ EL) — 202 (97) (i-Pr):’ 202 — 203 (90) (iPr):C 203 —, 204 (99)a Yield of purified, distilled product.b c-Pr cyclopropyl group.C i-Pr isopropyl groupR1I198 R1=Me201 R1=c-Pr204 R1=i-Pr572.2. Deconjugation-alkvlation of alkvl (E)- and (Z)-3-trimethylstannyl-2-alkenoates. and ofethyl (Z)-5-methvl-3-trimethvlstann’vl-3-hexenoate with the prepared electrophilesR1_>....,CO2 R1%(NDO22 RI> S4%CO2R2Me3Sn SnMe3 Me3Sn CO2Et SnMe389 90 91 92As mentioned earlier (pp 45-53), the deconjugation-protonation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 provided exclusively ailcyl (Z)- and (E)-3-trimethyl-stannyl-3-alkenoates 90 and 92, respectively. Similarly, the deconjugation-alkylation ofalkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 with electrophiles wereachieved in a stereospecific manner. For example, to a solution of the LDA-HMPA complex(1.3 equiv) in THF was added a solution of ethyl (E)-3-trimethylstannyl-2-pentenoate (125)(Equation 34) in THF and the mixture was stirred (-78 °C, 0.5 h; 0 °C, 0.5 h) to afford abright yellow solution of the corresponding lithium dienolate anion. Cooling of the resultingmixture to -20 OC, followed by addition of (Z)-3,5-diiodo-2-pentene (198) (-20 °C, 1 h)yielded, after chromatography and removal of traces of solvent (vacuum pump), an 89% yieldof ethyl (Z)-5-iodo-2-[(Z)- 1 -trimethylstannyl- 1-propenyl]-5-heptenoate (205).t2Me COt 1) LDA-HNPA,E OCMe)’ 2)Me:MeMeXMe (34)125 I 205198 89% yieldThe deconjugation-alicylation of a number of alkyl 3-trimethylstannyl-2-alkenoates (89,91) and of ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (158) were performed withelectrophiles via the aforementioned procedure. The results of these reactions (Equation 35, p58) are summarized in Table XII (pp 58-60).58R20CR1Me)’1) LDA-HMPA, THFR3111Me3Sn89or91 206x96or97 (X=Brorl)Table XII. Deconjugation-alkylation of alkyl (E)- and (Z)-3-trimethyl-stannyl-2-alkenoates 89 and 91 with the prepared electrophilesentry substrate zxcedut oduct % yield1’89or91 206Me CO,Et A ELO2C 81MS?’137 Br Me.3Sn40a2 Me CO2Et A EtO2C 75M)125 Br Me3Sn207Me3SnCO2EtA EtO2CMe 86124 Br Me3Sn2084 Me CO2EI B EtO2C 89Me>’125 I Me3Sn20559Table XII. Continuedentry substrate procedure’2 product % yield1’89or91 2065 Me B EtO2C Me 89Me>’COzEt Me’fcjMe3Sn1242096 Me CO2EL C Me EtO2C 92M)125 I Me3Sn2107 Me C Me ELO2C Me 86Me)”CO2Et124 I Me3Sn211MeO2C 878 t-BuMe2SiO-MeS’BMe’(OSiMe(tBu)I Me3Sn141 212MeO2C 90AMe3S/138213MeO2C 8310>__>jOzMeBMeSn13821460a Procedure A: 1) LDA-HMPA (—1.3 equiv), THF, -78 °C, 0.5 h; 0°C, 0.5 h;2) 148 (—1.3 equiv), -20 0C, 1 h.Procedure B: 1) LDA-HMPA (—1.3 equiv), THF, -78 °C, 0.5 h; 0°C, 0.5 h;2) 198 (—1.3 equiv), -20 °C, 1 h.Procedure C: 1) LDA-HMPA (—1.3 equiv), THF, -78 °C, 0.5 h; 0 0C, 0.5 h;2) 193 (—1.3 equiv), -20 °C, 1 h.ProcedureD: 1) LDA-HMPA (—1.3 equiv), THF, -78 °C, 0.5 ii; 0°C, 0.5 h;2) 201 (—1.3 equiv), -20 °C, 1 h.Procedure E: 1) LDA-RMPA (—1.3 equiv), THF, -78 °C, 0.5 Ii; 0°C, 0.5 h;2) 204 (—1.3 equiv), -20 °C, 1 h.b Yield of purified, distilled product.204Table XII. Continuedentry substrate89 or 91cedurez product % yieldb20611L>COMeD MeO2C 72Me3Sn ‘iiv13821512 E EtO2C 86Tjf’T’158216kIr%-IMV%(148 193 19820161The preparation of 216 from ethyl (E)-5-methyl-3-trimethylstannyl-2-hexenoate (139)was complicated by two factors. As described earlier (p 47), removal of the hindered ‘protons from 139 with the LDA-HMPA complex (2.3 equiv) was sluggish and thus 158was obtained in a 16% yield. Obviously, the deprotonation of 139 by the LDA-HMPAcomplex followed by subsequent addition of electrophile would therefore afford the alkylatedproduct in low yield.EtO2Cf(’CO2Et216 158These problems were overcome by the following strategy. The a-protons of 158 aremuch less hindered than the protons of 139. Thus, an a-proton from 158 was readilyremoved with the LDA-HMPA complex (1.33 equiv) to provide the corresponding lithiumdienolate anion. Subsequent addition of the electrophile 204 (1.45 equiv) to the resultinganion afforded the alkylated ester 216 in an 86% yield (Equation 36 and Table XII, entry 12,p 60).1) LDA-HMPA, THP EtO2CCO2Et2)158 216204 86% yieldThe structural assignments of all the aikylated esters of general structure 206 (Equation35, p 58) were based on their 1H nnir speciroscopic data, especially the magnitude of thecoupling constant(3Jsnj between the vinylic proton and the tin atom of the Me3Sn moiety.For example, ethyl (Z)-5-iodo-2-[(Z)- 1 -trimethylstannyl- 1-propenyl]-5-heptenoate (205)13962possesses a vinylic proton (Ha) which is trans to the Me3Sn group and thus has a3JSn..Hvalue of 132 Hz. As expected, the vinylic proton (Ha) of the other isomer ethyl (Z)-5-iodo-2-[(E)-1-trimethylstannyl-1-propenyl]-5-heptenoate (209), which is cis to the Me3Sn group,has a3JSn..H value of 74 Hz. Other notable features of their 1H nmr spectra include, in eachcase, the presence of one Me3Sn group (a 9-proton singlet: 205, 6 0.21; 209, 6 0.14), twovinylic methyl groups (two 3-proton doublets: 205, 3 1.73 and 1.77; 209, 8 1.73 and 1.75),an ethyl ester group (5 protons) and two olefinic protons (as mentioned above, one of themhas a pair of satellite peaks owing to the Sn-H coupling). Moreover, both isomers showstrong C=O stretching frequencies at 1728 cur1 in their ir spectra. Thus, it is apparent that,in each case, the C=O group of the ester is not in conjugation with the C=C bond. Inaccordance with previous observations,45all the compounds of general structure 206 exhibitthe expected (M - Me) fragments in their high resolution mass spectra.ELO2C Ha ELO2C MeMefMe Me’4fHI Me3Sn I Me3Sn205 209In a previous part of this thesis (pp 49-53), the stereochemical outcome in the conversionof alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 into alkyl (Z)- and (E)-3-trimethylstannyl-3-alkenoates 90 and 92, respectively, was rationalized byformulations28bA9summarized in Schemes 26 and 27, respectively. In addition, some ofthe background information concerning the development of both deconjugation-protonationand deconjugation-alkylation was presented. Two similar formulations, summarized inSchemes 28 and 29 (pp 64-65), are used to rationalize the stereochemical outcome in thedeconjugation-alkylation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91,respectively.63For the kinetically controlled deprotonation of the (E)-2-alkenoates 89 (Scheme 28, p64), the transition state 170 derived from the conformation 166 would be destabilized by thelarge steric interaction (A13 strain50)between the R1 and the C02R groups. Thus, thepathway 168 — 172 — 176 would be energetically more favoured, leading, after alkylationwith the electrophiles 96 or 97, to the stereoselective formation of 2-[(Z)-1-lrimethystannyl-l-alkenyl]alkenoates 217 (Scheme 28 and Equation 37; typical examples can be found inTable XII, entries 2,4, 6, 8 and 9-11, pp 58-60).Rl__>,,C02LD:-HMPA,THFR3(37)96or97 (X=Brorl)In a similar fashion, for the deprotonation of the (Z)-2-alkenoates 91 (Scheme 29, p 65),the transition state 186 derived from the conformation 182 would be destabilizedsignificantly by the steric interaction (A1’2strain50)between the R1 and the SnMe3 groups.As a result, the pathway 180 —* 184 —, 188 would be energetically more favoured. Thus,2-[(E)-1-trimethystannyl-l-alkenyl]alkenoates 218 (Scheme 29 and Equation 38; typicalexamples can be found in Table XII, entries 3, 5 and 7, pp 5 8-59) were formed stereoselectively after alkylation with the electrophiles 96 or 97.M2R21) LDA-HMPA,THFR3(38)96or97 (X=Brorl)64R’__>_,C02Me3Sn96 or97R20CR3X Me3Sn21789166 168HLDA[transition state]170>:_174LDA[transition state]172-176Li LiR3IR20CR1Me3Sn90Scheme 2865COR2R1—SnMe3180LDA[transition state]184R’—2Me3Sn CO2R91C02RSnMe3182H[transition state]186R20)—SnMesR’—H1LiR20H—SnMe3190Li1881/R20C R1L%rMe3Sn92R3I96 or97R20C R1X Me3Sn218Scheme 29663. Syntheses of alkyl 2.3-bis(aflcvlidene)cyclopentanecarboxylates and related derivatives3.1. Stereocontrolled syntheses of alkvl 2.3-bis(alkvlidenecvclopentanecarboxylates andrelated substances via pa1ladium(0-cata1yzed coupling reactionsAs mentioned in the previous section of this thesis (pp 14-15), ethyl 2,3-bis(methylene)-cyclopentanecarboxylate 41a (Table Xffl, entry 1) was preparedl3by treatment ofcompound 40a, which contains vinyl bromide and vinyltrimethylstannane functions, with(Ph3P)4d(5 mol %) and L1C1 (2 equiv) in dry DMF at 80 OC for 1 h. By employing similarreaction conditions, compounds of general structure 206 (Equation 39) were transformedeffectively and in a stereocontrolled manner into the corresponding alkyl 2,3-bis(alkylidene)-cyclopentanecarboxylates of general structure 219. The results of these coupling reactions(Equation 39) are summarized in Table XIII.R20CI (Ph3P)Pd (5 mol %) RR3Y’%N”R1) MeSi’i LiC1 (2 equiv), DMF206Table XIII. Stereocontrolled syntheses of alkyl 2,3- bis(alkylidene)cyclopentanecarboxylates 219entry substrate pxxluct % yield1’206 219R’219Br Me3Sn56C41a40a67Table XIII. Continuedentry substrate roduct % yield1’206 2192d EtO2C 83Br Me3Sn2073 EtO2C Me 87Br Me3Sn2084 EtO2C 95Me’f”1J MeI Me3Sn2055 EtO2C Me 91Me’%(I Me3Sn2096 Me ELO2C Me 88I Me3Sn2117 MeO2C 72Me’%(’”OSiMe(t-Bu)I Me3Sn220221222223224212 22568Table XIII. Continuedentry substrate ixoduct % yield1’206 2198 MeO2C 942139 MeO2C 97Mey214be MeO2C 86215ii! ELO2C 52216a All coupling reactions were carried Out with the following conditions (unless otherwise stated):(Ph3P)4d(5 mol %) and LiCL (2 équiv) in dry DMF at 80°C for 1 h.b Yield of purified, distilled product.C The low yield in this experiment may be due to the volatility of the product.d Experimental conditions: (Ph3P)4d(5 mol %) and LiC1 (2 equiv) in dry DMF at 80°C for 30 mm.e Experimental conditions: (PhP)d (5 mol %) and LiC1 (2 equiv) in dry DMF at 90°C for 1 h.f Experimental conditions: (Ph3P)4d(5 mol %) and LiC1 (2 equiv) in dry DMF at 105 °C for 1.5 h.22622722822969The coupling reactions were generally canied out as indicated by the following example.Addition of (Ph3P)4d (5 mol %) and LiC1 (2 equiv) to a 0.1 M solution of substrate 205(Table Xffl, entry 4, p 67) in DMF gave a yellowish solution. This solution turned into adark brown solution with formation of a fme black powder (palladium (0)) upon heating at 80OC for 1 h. After work-up, analyses of the crude reaction product by gic and tic indicated thatonly one cyclized product had formed. Purification of this crude product by flashchromatography, followed by distillation, provided ethyl (Z,Z)-2,3-bis(ethylidene)cyclo-pentanecarboxylate 222 in a 95% yield (entry 4).85.38 62.19-2.32 (m),and 82.32-2.49(m)6 1 58 ‘dt 8 1.78-1.92 (m)8J( 6 1.92-2.05 (m)85.48 (br ci)6 3.27-3.4 1 (m)The structure of compound 222 was confirmed in the following manner. The 1H nmrspectrum of 222 showed the expected signals for an ethyl ester group (a 3-proton triplet at 61.23, J= 7 Hz, and a 2-proton multiplet at 8 4.00-4.23), two vinylic methyl groups (Me, a 3-proton doublet of triplets at 8 1.58, J= 7, 1 Hz; Me*, a 3-proton doublet of doublets at 81.62, .1= 7, 1 Hz), two methylene groups (Ha, 1-proton multiplet at 8 1.78-1.92; 11b 1-proton multiplet 8 1.92-2.05; 2 x H, two 1-proton multiplets at 6 2.19-2.32 and 8 2.32-2.49), and a methine proton (H4, a 1-proton multiplet at 83.27-3.41). It is interesting to notethat the signal for the methylene group of the ethyl ester function appears as a multipletbecause these geminal protons are diastereotopic. Other characteristic signals include the two22270olefinic protons (two broad 1-proton quartets at 8 5.38 and 6 5.48, J= 7 Hz in both cases).The assignment of the protons was based on a series of decoupling and nuclear Overhauserenhancement (nOe) difference experiments. In the decoupling experiments, irradiation at 83.34 (Hj changed the doublet of doublets at 8 1.62 (Me*) to a doublet (J= 7 Hz), simplifiedthe two multiplets at 8 1.78-1.92 (Ha) and 8 1.92-2.05 (Hb), and sharpened the broad quartetat 85.48 (Hf). Irradiation at 65.38 (He) simplified the doublet of doublets at 8 1.58 (Me) toa broad singlet (wl/2= 4 Hz), while irradiation at 6 5.48 (Hf) simplified the doublet ofdoublets at 8 1.62 (Me*) to a broad singlet (wl,2= 4 Hz). The configuration of C=C bondsof 222 was shown by nOe difference experiments. Thus, irradiation at 6 1.58 (Me) causedan enhancement of the signal at 65.38 (He), while irradiation at 6 1.62 (Me*) increased theintensity of the resonance at 65.48 (Hj). Irradiation at 6 3.34 (Hd) caused enhancement ofthe signals at 6 1.78-1.92 (Ha) and 6 5.48 (Hj). Irradiation at 8 5.38 (He) increased theintensities of the resonances at 6 1.58 (Me), 6 2.19-2.32 (He) and 6 2.32-2.49 (Hc), whileirradiation at 8 5.48 (Hj) increased the intensities of the signals at 6 1.62 (Me*) and 6 3.27-3.41 (ILj). The ir spectrum of 222 showed a strong absorption at 1737 cnr1 for the C=Ostretching vibration of the ester group. The high resolution mass spectrum of the compound222 confirmed that it has a molecular formula ofC12H802.The structures of the other alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 219 (TableXIII, pp 66-68) were assigned in a manner similar to that described above. All the preparedalkyl 2,3-bis(aikylidene)cyclopentanecarboxylates of general structure 219 exhibited strongC=O stretching frequencies in the region 1734-1738 cm1 in their ir spectra. In each case, thehigh resolution mass spectroscopic measurement was performed on the molecular ion. TheR3219 22271transformation (Equation 39) of the diene esters 206 into the corresponding dienes 219 wasfound to be stereospecific. The confirmation of the configuration of each of the alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 219 (Table XIII) was based on nOe differenceexperiments similar to those outlined above for the diene 222.R20CR3X Me3Sn206As shown in Table XIII (entries 4-6, p 67), ethyl 2,3-bis(ethylidene)cyclopentane-carboxylates 222, 223 and 224 were prepared in a stereocontrolled fashion with therequired Z,Z-, E,Z- and E,E-configurations, respectively. It was surprising that thepalladium(0)-catalyzed ring closure of compound 210 did not provide the expected Z,E-diene230 in a stereoselective manner. Under a number of reaction conditions (differentpalladium(0) catalysts, various solvents, additives and temperatures), compound 210invariably produced mixtures of 230 and 224 (see Section 4.1, pp 89-90). The reason forthis lack of selectivity is not immediately clear. Fortunately, further experimentation to effectthis particular transformation led to the discovery of a new reaction. The details of thisdiscovery and the related studies will be discussed in Section 4.1 of this thesis (pp 90-95).(Ph3P)4d(5 mol %)LiC1 (2 equiv), DMF(39)219222 223 224Me EtO2CI Me3Sn210 23072This coupling process can tolerate the presence of functional groups such as silyl etherand carboxylic ester, as well as the cyclopropyl moiety (entries 7-10, pp 67-68). Moredrastic reaction conditions were required for the preparation of the highly hindered (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxylates 228 and 229 (entries 10 and 11, p 68). Forexample, when substrate 215 was subjected to treatment with (Ph3P)4Pd (5 mol %) and LiC1(2 equiv) at 80 OC for 1 h, only starting material 215 was found in the crude reaction mixture(gic analysis). However, the cyclization of 215 was complete within only 1 h at a highertemperature (90 °C), and provided the desired product 228 in 86% yield. Higher reactiontemperatures (Table XIII, entry 11, at 105 OC for 1.5 h) were also found to be necessary forthe conversion of 216 into the diene 229 (52% yield).MeO2C EtO2C215 216The stereospecific formation of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates219 may be rationalized by the catalytic cycle shown in Scheme 30 (p 73). Oxidativeaddition of the palladium catalyst to the vinyl halide moiety in 231 (Scheme 30) produces theintermediate 232. Intramolecular transmetalation involving the vinyltrimethylstannanefunction then gives a six-membered palladium metallocycle 233 which reductively eliminatesto produce the cyclopentanecarboxylate 234 and regenerate the palladium(0) catalyst. Sincethe oxidative addition,’14transmetalation and reductive elimination steps are known to228 22973R5 R20C R4R3‘fRiCIL2Pd Me3Sn232occur with retention of configuration, an overall retention of configuration of the doublebonds in this coupling process is expected.4aThe lower yield of 229 may be attributed to thesteric congestion involving the bulky groups located on the two double bonds in the reactionintermediate 233 (R1 = R3 = i-Pr, R4 = R5 = H).R20C R3‘%r\\R3’%’11 R1,..L.<’206 219PdL4R3R1234LiC1 +2L231LIX + 2LLR1L = Ph3233Me3SnC1Scheme 3074The intramolecular coupling process is successful for the stereocontrolled preparation ofthe alkyl (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxylates 222, 228 and 229. Obviously,if the diene systems of these substances were to be planar, severe steric repulsion would existbetween the substituents on the termini of the conjugated diene moieties. One would predictthat this repulsion would force the dienes to be non-planar. It was decided to convert 222,228 and 229 from oils into crystalline derivatives to provide single crystals for X-rayanalysis, which would in turn, reveal information about the extent to which these dienesystems are twisted away from planarity.3.2. X-ray analysis of (Z.Z-2.3-bis(a1kvlidenecvclopentanecarboxamides222 228 2297RR676R3%4R%’6PLANAR TWISTED75In order to prepare a crystalline material from the liquid compound 222, (R,S)-(+)- and(R,R)-(-)-N- 1 -phenylethyl-(Z,Z)-2,3-bis(ethylidene)cyclopentanecarboxamides (237 and238) (Scheme 31) were prepared via a procedure developed by Weinreb et al.52 A solutionof (R)-(+)-1-phenylethylamine (235) (2.2 equiv) in benzene was treated with a solution oftrimethylaluminum (Me3A1) (2.2 equiv) in toluene to produce a colorless solution of thecorresponding dimethylaluminum reagent 236 (Scheme 31). Subsequent addition of asolution of ethyl (Z,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate 222 (1 equiv) in C6H toreagent 236, followed by refluxing (4 h), provided, after acidic work-up andchromatography, a 47% yield of amide 237 (the less polar substance) and a 46% yield ofamide 238 (the more polar material).HH2N — Me3AI /Me2A1—N235 236236 I ‘H237 (47%)+H/—\\/23* (46%)222Scheme 3176Recrystallization of the amide 237 from 1: 2 petroleumether-Et20 afforded colorless cube-like crystals (mp 100.5-102OC). A single crystal X-ray analysis53 of 237 (Appendix)indicated that the asymmetric unit contains four molecules237A, 237B, 237C and 237D (Figure 1).Figure 1: X-ray structure of 237A, 237B, 237C and 237D237A237B237CH237237D77The dihedral angles between C-6 - C-2 and C-3 - C-7 of conformations 237A, 237B,237C and 237D are 50.7°, -48.6°, 49.9°, and 42.7°, respectively (Figures 2 and 3, pp 78-79). The sign of the dihedral angle is considered to be positive, if, when looking from atomC-2 to atom C-3, a clockwise motion of atom C-6 atom eclipses with atom C-7.7760 = +ve6The sign of the dihedral angle (0) is considered to be positive, if, whenlooking from atom C-2 to atom C-3, a clockwise motion of atom C-6atom eclipses with atom C-7.456237776 70 = -ye0 -JC,00WiSt C -I -I CM -I C n n C -S C 0) (‘a -J C, 04 t,J (‘a —ILaLa(‘aCal—1.4 C,C,C, 080The single crystal of 237 contains molecules of four different conformations and each ofthe conformations has a different dihedral angle between the two exocydic C=C bonds.Thus, it was of interest to determine the structure of its diastereomer 238 by a single crystalX-ray analysis. In order to achieve this purpose, the amide 238 was recrystallized (1: 2petroleum ether-Et20) to give colorless, needle-like crystals (mp 107-108 Oc). From the Xray analysis53 of 238 (Appendix), it was found that the single crystal of 238 containsmolecules which have only one conformation and the dihedral angle between C-6 - C-2 andC-3 - C-7 is -58.0° (Figure 4).H/—\\/Figure 4: X-ray structure of 238237 238C? C?C6 C681Similarly, N-p-chlorophenyl-(Z,Z)-2,3-bis(cyclopropylmethylene)cyclopentanecarbox-amide (241) (Scheme 32) was prepared52via a procedure employing the dimethylaluminumreagent 240 (Scheme 32). A solution of trimethylaluminum (Me3A1, 1.5 equiv) in toluenewas added to a solution of p-chloroaniine (239) (1.5 equiv) in C6H to give the reagent240. Subsequent addition of a C6H solution of the ester 228 (1 equiv) to the reagent 240,followed by refluxing (4 h) afforded an 83% yield of the amide 241, which wasrecrystallized (1: 1 CH2C12-EtOH) to give colorless needle-like crystals (mp 126-127 OC). Asingle crystal X-ray analysis53of this compound (Appendix) indicated that two enantiomers,each with a distinct conformation, (241A and 241B) (Figure 5, p 82) exist in the singlecrystal. The structures of 241A and 241B differ primarily in the orientation of the phenylring. Dihedral angles between C-6 - C-2 and C-3 - C-7 of 241A and 241B were found tobe -51.0° and 53.2°, respectively.H2N_Q_C1Me3AIMe2\\239 240240H/241(83%)228Scheme 3282Figure 5: X-ray structure of 241A and 241B24 1A24 lB83(R,S)-(÷)- and (R,R)-(-)-N- 1-Phenylethyl-(Z,Z)-2,3-bis(2-methylpropylidene)cyclopen-tanecarboxamides (242) and (243) (Equation 40) were prepared via a procedure utilizing thedimethylaluminum reagent 236 (Scheme 31, p 75) in yields of 40% (the less poiar substance)and 46% (the more polar material), respectively. Aniide 242 is a liquid and is therefore notuseful for X-ray analysis. Recrystallization of aniide 243 from 1: 1 petroleum ether-Et20provided colorless needle-like crystals (mp 110-111 °C). A single crystal X-ray analysis53of243 (Appendix) indicated that the dihedral angle between C-6 - C-2 and C-3 - C-7 of 243 is5750 (Figure 6, p 84).H/242 (40%)(40)236229+243 (46%)84Figure 6: X-ray structure of 243(S,R)-(÷)- and (S,S)- (-)-N- 1 -Phenylethyl- (Z,Z)-2,3-bis(2-methylpropylidene)cyclo-pentanecarboxamides (246 and 247) (Scheme 33, p 85) were prepared in a similar fashionemploying the reagent 245 (Scheme 33). Addition of a solution of the ester 229 (1 equiv) tothe reagent 245 (2.2 equiv), followed by refluxing (4 h), gave a 40% yield of the amide 246(the less polar substance) and a 43% yield of the amide 247 (the more polar material). Amide246 is a liquid and so is not useful for X-ray analysis. Amide 247 was recrystallized (1: 1petroleum ether-Et20) to provide colorless needle-like crystals (mp 111-112 0(D). A singlecrystal X-ray analysis53of 247 (Appendix) indicated that the dihedral angle between C-6 -C-2 and C-3 - C-7 is -58.0° (Figure 7, p 85).24385H2NKD244Me3A1H/MeAI—N —245245o246 (40%)+Scheme 33229247 (43%)Figure 7: X-ray structure of 24786In summary (Table XIV, entry 1), X-ray analysis indicated that compound 237 hasmolecules with four different conformations 237A, 237B, 237C and 237D which havedihedral angles (between C-6 - C-2 and C-3 - C-7) equivalent to 50.7°, -48.6°, 49.9° and42.7°, respectively. The corresponding dihedral angles in 238, 243 and 247 (entries 2, 4and 5) were found (X-ray analysis) to be -58.0°, 57.5° and -58.0°, respectively. Compound241 (entry 3) has two enantiomers which have dihedral angles equal to -51.0° and 53.2°.The magnitude of the dihedral angles between the two exocydic C=C bonds in the (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxamides (237, 238, 241, 243 and 247) are within therange of 48.60 to 58.0°. In conclusion, the extent to which the exocycic diene systems ofOOH237Dt241 —ciLJoQ247Table XIV. Dihedral angles between the carbon-carbon double bondsof (Z,Z)-2,3-bis (alkylidene)cyclopentanecarboxamidesentry amide dihedral angle(s)z1 237 50.7°. -48.6°. 49.9° and 42.7°2 238 58.003 241 -51.0°and532°4 243 57505 247 58.00a Obtained from single crystal X-ray analyses.23824387these substances are distorted from planarity are quitesimilar and there is no clear correlation between the valuesof the dihedral angles and the size of the substituents on thetermini of the diene moieties. Each of the X-ray structuresof 237, 238, 241, 243 and 247, show that the twoprotons Ha are oriented as depicted, so that the non-bondedinteraction between the methyl-methyl, cyclopropylcyclopropyl and isopropyl-isopropyl groups are minimized.Since, in each of the amides, the steric repulsion betweenthe two Ha pmtons is roughly the same, the magnitude ofthe dihedral angle between the C=C bonds is not affectedmuch by the size of the R groups.R7 1CONIIArC-6 atom is twisted awayfrom the amide groupInterestingly, in a single crystal (X-ray analysis) of 237, each of the conformations237A, 237C and 237D has the C-6 atom twisted toward the ainide moiety (p 88, DiagramA), while in the conformation 237B, the twist is in the opposite direction (p 88, Diagram C).R1237, 238241243, 247R,R=H,HR, R = -CH2CR,R=Me,MeIn each of the (Z,Z)-bis(alkylidene)cyclopentanecarboxamides 237, 238,241,243 and247, the C-6 atom can twist, as depicted, either toward the amide group or away from theamide group.76R.6 6C-6 atom is twistedtoward the amide groupPh PhR = Me, c-Pr or i-Pr; Ar = ._ ‘ __Me Me88In the solid state, compound 238 (Diagram B) and the enantiomers 241A and 241B(Diagrams B and A, respectively) have conformations in which C-6 atom is twisted towardthe ainide group. However, each of the enantiomers 243 (Diagram D) and 247 (Diagram C)has the C-6 atom twisted away from the amide functionality.6237A,237C, R=Me;Ar=237D Me241B R=c-PrAr=238 R=Me;Ar=241A R=c-PrAr=—D—ciCONHAr237B R=Me;Ar=MeRPh247 R=i-PrAr= _MePh243 R=i-PrAr= -_Me894. Discovery of the CuCl-mediated intramolecular coupling reaction4 1 TntrrwlnctinnELO2C EtO2C MeMe_%(ø_LVMe Med’LjI Me3Sn I Me3Sn205 209Me ELO2C MeI Me3Sn211The palladium(0)-catalyzed intramolecular coupling reaction, as discussed previously (pp66-73), was applied successfully to the construction of alkyl 2,3-bis(alkylidene)cyclo-pentanecarboxylates with impressive control of the orientation of the two aikyl substituents onboth termini of the two exocyclic double bonds. For example, the ethyl 2,3-bis(ethylidene)-cyclopentanecarboxylates 222, 223 and 224 were prepared in good yields (88-95%) viapalladium(0)-catalyzed intramolecular coupling of 205, 209 and 211, respectively, withcomplete configurational control. Surprisingly, however, in the attempted preparation ofethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate 230 from 210 (Equation 41),mixtures of 230, 224 and 248 were produced under a number of reactionconditions. 10,11,13 Some of the experimental conditions are shown in Table XV (p 90).Me EtO2CMeI Me3Sn210reactionconditionsCO2Et+CO2Et(41)222 223 224230 224 24890reactionMe EtO2CI Me3Sn210CO2Et230+CO2EL248(41)Table XV. Attempted preparation of ethyl (Z,E)-2,3-bis(ethylidene)-acyclopentanecarboxylate (230)conditionsYield of purified, distilled product mixtures.b Structure of compound 248 was tentatively assigned on the basis ofthe 1H nmr spectroscopic data.Some of the 1H nmr signals (CDC13,400 MHz) which were used forthe assignments of 248 are as follows: 8 1.01 (t, CH2CTh, .1= 7 Hz),3.67 (br d, Ha, J= 9 Hz), 5.01 (ci, Hb, 1= 11 Hz), 5.07 (ci, He 1= 17Hz), 6.57 (dci, H. 1= 17, 11 Hz).C In each case, the ratio of the cyclopentanecarboxylates 230, 224 andwas determined on a purified, distilled mixture of thesecompounds by the integration of ‘H nmr signals (CDC13,400 MHz).The ratio was determined by integration of the 1H nmr signals of He of230, Hf of 224 and Hd of 248.The diene 230 displayed the following 1H nmr signals which areidentical with those of an authentic sample of 230: 8 1.23 (t,OCH2CJj3, .1= 7 Hz), 1.72 (br d, =CH1CIj31= 7 Hz), 1.82 (br ci,CHeCIJ3, .1=7 Hz), 3.30-3.37 (m, Hd), 5.60 (br q, H, J7 Hz).The diene 224 displayed the following 1H nmr signals which areidentical with those of an authentic sample of 224: 8 1.22 (t,OCH2C,1= 7 Hz), 1.67 (br d, =CHeCH3, 1= 7 Hz), 1.73 (br d,=CH1CkL3,.1= 7 Hz), 3.60 (hr d, H-Br275260Br284 285SnMe3286SnMe3252110Table XXI. Continuedentry substrate ptvcedwe pduct(s) % yield1’564 258 1) LDA-HMPA (1.3 equiv), THF,-78 °C, 0.5 h; 0 0C, 0.5 h;2) 193 (1.6 equiv), -20 °C, 1 h.287I1935 258 1) LDA-HMPA (1.2 equiv), THF, MeO2C 63-78 OC, 0.5 h; 0 °C, 0.5 h;2) 276 (1.5 equiv), -20 °C, 1 h.I288276a Yield of purified, pumped (vacuum pump) product.The spectral data obtained for the monocyclic substrates of general structure 260(Equation 52, p 109) were found to be in full accord with the assigned structures. Takingcompound 252 (Table XXI, entry 3, p 109) as an example, the ir spectrum of 252 exhibitedan absorption at 1734 cm-1 attributable to the carbonyl stretching frequency of an esterfunction and an absorption at 771 cm-1 attributable to the tin-methyl rocking frequency of atrimethyistannyl group. The 1H nrnr spectrum of 252 displayed the expected signals of atrimethyistannyl group (a 9-proton singlet at 80.14, Hz), two methylene units onthe 5-membered ring (two 1-proton multiplets at 8 1.73-1.83 and at 82.26-2.36; a 2-protonmultiplet at 82.37-2.55), a vinylic methyl group (a 3-proton broad singlet at 82.46, wj= 4Hz), two allylic protons on the side chain (a 1-proton doublet of doublet of multiplets at 61112.20, J= 15,7 Hz for doublets; a 1-proton doublet of doublet of multiplets at 82.65, J= 15,7 Hz for doublets), a methyl ester group (83.65), two olefinic protons (a 1-proton triplet ofmultiplets at 85.25, J= 7 Hz for triplet; a 1-proton triplet at 85.98, J= 2 Hz, Hz).Futhermore, high resolution mass spectrometry showed that the molecular formula of 252 isC14H23IO2Sn.The experiments involving conversion of the monocycic substrates 260 (Equation 53)into the bicyclic dienes of general structure 261 or 262, via the CuCl-mediated method, aresummarized in Table XXII (p 112).MeO2COR cj:— (53)262As can be seen from the data summarized in Table XXII, the cydizations were generallyaccomplished by the use of 2.1-2.7 equivalents of CuC1 in DMF at —60 °C. In one case(entry 6), a higher temperature was found to be beneficial. Treatment of 288 with CuC1 at 60OC for 35 mm produced the bicyclic compound 293 (—74% of the product mixture asindicated by glc analysis; 65% isolated yield) accompanied by three side products, the majorof which (—14% of the mixture) was the uncyclized compound 294, whose structure wasassigned by 1H nn,r spectroscopic data [(CDC13,200 MHz): 8 1.25-1.85 (m, 6H), 2.24-2.53(m, 4H), 3.68 (s, 3H), 5.65-5.73 (m, 2H), 5.82 (dt, 1H, J= 8, 2 Hz), 6.01 (d, 1H, J= 2Hz)] and by high resolution gcms analysis [molecular peak wasMeO2Cfound]. Fortunately, at 90 OC the reaction was clean and theexpected bicyclic diene was produced in 75% yield. In general,Hconversion of the substrates 260 into the corresponding bicyclic 294(260CuC1DMFn’= 1 or2;n”= 1,2or3X = Br or I; R = H or Me261112Table XXII. CuC1-mediated intramolecular coupling of monocyclicsubstrates of general structure 260aentry substrate CuC1 reaction temperature reaction time product % yield1’(equiv) (°C) (mm)1 284 2.4 60 5 289 782 285 2.7 60 5 290 793 286 2.5 64 2 291 804 252 2.1 60 5 253 935 287 2.5 65 10 292 976 288 2.5 90 5 293 75Br Br284 285MJ286C288MeO2Ccb291Mj252MeO2C289MeO2CcMe253290292 293a AU reactions were carried out with 0.1 M 260 in DMF.b Yield of purified, distilled product.C Substrate 285 is not of general structure 260. Product 290 is neither of general structure 261nor 262.113dienes of general structures 261 or 262 was found to be efficient, providing the products ingood to excellent yields (75-97%). Moreover, this method constitutes a good method forsynthesizing functionalized bicyclo[4.2.0]octane (Table XXII, entries 1 and 2, p 112),bicyclo[3.3.0]octane (entries 3-5), and bicyclo[4.3.0]nonane (ently 6) systems.Hf In addition to each of the 1H nmr spectra of the bicycle dienes261 or 262, the structures were assigned with the aid of other 1Hnmr spectroscopic techniques, such as decoupling, COSY or nOedifference experiments. For example, the structure of 1-methoxy-Hh carbonyl-7-methylenebicyclo[4.2.0]oct-5-ene (289) was assigned289on the basis of its nmr spectrum and the results denved from aseries of decoupling experiments, as well as a COSY experiment. The 1H nmr spectrum ofthe diene 289 displayed the expected signals (C6D,400 MHz): 6 1.08 (td, 1H, Ha, J 12,3.5 Hz), 1.48-1.58 (m, 1H, Hb), 1.63-1.76 (m, 1H, He), 1.74-1.86 (m, 1H, Hj), 2.00 (brdd, 1H, He, J= 19, 7 Hz), 2.41 (dt, 1H, Hf, J= 12, 3.5 Hz), 2.49 (dt, 1H, H, J 14, 2.5Hz), 2.88 (dt, 1H, Hg, J= 14, 2.5 Hz), 3.35 (s, 3H, OCH3), 4.64 (br s, 1H, =CH2w=6 Hz), 5.07 (br s, 1H, =cH2W1/2 7 Hz), 5.52 (dd, 1H, Hh J= 4.5, 3 Hz). It isreasonable to assume that the 6-membered ring of compound 289 adopts a conformation asdepicted (p 114). The triplet of doublets (J= 12, 3.5 Hz) at 8 1.08 was attributed to Ha and(MeO2C261 262n’= lor2;n”=1,2or3R=HorMe114the pseudoaxial position of Ha is supported by by the large geminal coupling (J= 12 Hz)between Ha and Hf, as well as the 12 Hz axial-axial vicinal coupling to H.8 1.48-1.58 (m)82.41 (dt,J= 12,3.5Hz)6 200 62.49 (di, 1= 14,2.5 Hz)(br dd, 1= 19,7 Hz) afld 8 2.88 (dl, J= 14,2.5 Hz)/8 1.74-1.86 (m)[Bicydic diene 289In order to further confirm the 1H nmr spectral assignments of 289, a series ofdecoupling experiments were performed. Irradiation at 6 1.08 (Ha) simplified the doublet oftriplets at 6 2.41 (Hf) to a triplet (J= 3.5 Hz) and this provides evidence for the geminalrelationship between Ha and Hf [Note: JHaHf= 12 Hz]. Irradiation at 6 1.53 (Hb) altered thetriplet of doublets at 6 1.08 (Ha) to a triplet (.1= 12 Hz) [Note: JHaHb= 3.5 Hz], and convertedthe doublet of triplets at 62.41 (Hf) into a doublet of doublets (J= 12,3.5 Hz) [Note: JH,Hf=3.5 Hz]. Thus, it is evident that proton Hb is vicinal to protons Ha and Hf. Saturation ofeither Hd (6 1.82) or of He (6 2.00) changed the resonance of proton Hh (a doublet ofdoublets at 65.52, J= 4.5, 3 Hz) to a doublet (J= 3 or 4.5 Hz, respectively). Therefore, it isapparent that proton Hh is vicinal to protons Hj and H. The 1H nmr assignments werefound to be consistent with the results of a COSY experiment, which are summarized in TableXXffl (p 115).6 1.63-1.76 (m)Hd65.52 (dd, J= 4.5,3 Hz)6 1.08 (UI, J= 12, 3.5 Hz)HU115Table XXIII. Results of the COSY experiment of compound 289Hf289Assignment H, 1H nmr (C6D,400 MHz): 6 COSY correlations to H(multiplicity, number of protons,coupling constant(s))Hp 1.08 (td, 1H, J 12, 3.5 Hz) Hb, H, HfHb 1.48-1.58 (m, 1H) Hg, He H3, HfH 1.63-1.76 (m, 1H) Ha, Nb, H1, He, HfNd 1.74-1.86 (m, 1H) Hb, H, H, HhHe 2.00 (br dd, 1H, J= 19, 7 Hz) H, HJ, HhHf 2.41 (dt, 1H, J 12, 3.5 Hz) Hg, Hb, NcH(A) 2.49 (dt, 1H, J= 14, 2.5 Hz) H(B), =CH2(A), =CH2(B)H2(B) 2.88 (dt, 1H, 1= 14, 2.5 Hz) H(A), =CH2(A), =CH2(B)=CH2(A) 4.64 (br s, 1H, wrn= 6 Hz) H(A),H2(B), =CH2(B)=CH2(B) 5.07 (br s, 1H, wrn= 7 Hz) H(A), H(B), =CH2(A)Hh 5.52 (dd, 1H, J= 4.5, 3 Hz) H1J, HeCompound 289 exhibited a strong uv absorption at 242.2 nm (e = 12600, n-pentane),which indicates the presence of a conjugated diene system. In addition, high resolution massspectrometry showed that the molecular formula of 289 is Ci1H402.He116The 1H nmr spectrum (CDC13,400 MHz) of 2-methoxycarbonyl-8-methylenebicyclo-[4.2.0]oct-1-ene (290) exhibited signals for two homoallylic methylene groups (two 1-proton multiplets at 6 1.01-1.15 and at 8 1.38-1.53, and a 2-proton multipet at 8 1.84-1.98),five allylic protons (a 3-proton multiplet at 62.23-2.47, and a 2-proton multiplet at 8 2.67-2.84), a methoxy group (a 3-proton singlet at 8 3.72) and two olefinic protons (two broadsinglets at 8 5.00 and at 65.71 (wl,2= 6 Hz for both broad singlets)). The 3C nmr spectrum(CDC13,50.3 MHz) of 290 indicated the presence of four olefinic carbons (6 111.1, 118.3,146.4 and 155.8) and a carbonyl carbon (8 167.4).31 The ir spectrum of 290 displayed astrong C=O stretching frequency at 1708 cm-1,which showed that C=O functional group isin conjugation with the C=C bond. The presence of a conjugated ic-system was indicated bya strong uv absorption at 266.5 nm (11000, n-pentane). Moreover, 290 was shown to havea molecular formula ofC11H402by high resolution mass spectrometry.The structures of 253,291 and 292 were confirmed with the aid of nOe, decouplingand/or COSY experiments (for details, see Experimental section). The 1H nmr spectrum of293 was found to be in full accord with that reported in the literature.7dMeO2C290MeO2C291MeO2C289MeO2C253 292 2931174.4. Preliminary studies on the mechanistic aspects and the limitations of the CuC1-mediatedcoupling processPreliminary investigations into the mechanistic aspects and the limitations of this newCuC1-mediated intramolecular coupling process were carried out. Since studies (Section 4.1,pp 93-95) employing different amounts of CuC1 suggested that at least two equivalents ofCuCl are preferred, two equivalents of other copper(I) sources were also employed for thecoupling reactions shown in Equations 54 and 55. The results of these experiments aresummarized in Table XXIV.Cu(1), DMFreaction conditionsTable XXIV. the intramolecularCu(I), DMFreaction conditionsELO2C MeMe(’I MeSn209Me EtO2C MeI Me3Sn211223(54)(55)224Effect of different sources of Cu(I) oncoupling of substrate 209 or 211entry substrate Cu(I) reaction temp/ time product % yield1’(equiv) (°C/ mm or h)1C 209 CuC1 (2.1) 60/2 mm 223 832C 209 CuC1 (2.0) 23/ 10 miii 223 903 209 CuBr.Me2S’(2.5) 40/ 125 h 223 904 209 CuBr.MeS’(2.5) 23/ 12 h 2235 209 Cul’ 60/40mm 223 836 211 “(Ph3P)CuCl” (2.1) 60/2 h 224 80118Table XXIV. Continuedentry substrate Cu(1) reaction temp/ time product % yield1’(equiv) (°C/ mm or h)224 0223 01223 O7 211 (Ph3P)3CuCl (2.1) 60/5 h8 209 CuC1 (2.5) + LiC1 (2.5)’ 60/ 15 mm9 209 CuC12 (12)tm 23/2ha All reactions were carried out with 0.1 M 209 or 211 in DMF.b Yield of purified, distilled product (unless otherwise noted). In each case, the product isolated wasfound to be identical to an authentic sample of 223 or 224 by 1H nmr analysis.C Entries 1 and 2 are included for comparison.d CuBr.Me2S was prepared according to reference 64.e The product has -10% of uncharacterized impurities (gic analysis).f Commercially available Cul was purified according to reference 65.g The complex “(Ph3P)CuC1” exists as tetramer and was prepared according to reference 66.h 0.4 equivalents ofPh3was isolated.The complex (PhP)CuC1 was purchased from Aldrich Chem. Co. Inc., and was used withoutfurther purification.1 81% of substrate 211 was recovered and 1 equivalent ofPh3was isolated.k The DMF solution of 209 and LiCl (2.5 equiv) was warmed at 60 °C for 10 mm before CuCl (2.5equiv) was added.88% of substrate 209 was recovered.m CuC12 is a source of Cu(ll).Starting material 209 remained intact under the experimental conditions (glc analysis).When either copper(I) bromide-dimethyl sulfide complex (CuBr.Me2S)64or copper(I)iodide (CuI)65 was used, longer reaction times were required for completion of the couplingreaction as compared to the CuC1-mediated transformations (Table XXIV, entries 3 and 4,respectively). In addition to this problem, more side products were formed when CuBr.Me2Swas utilized. Therefore, CuBr.Me2S and Cul are generally inferior to CuC1 for this couplingprocess. Retardation of the coupling reaction rate was observed when “(Ph3P)CuC1”66(entry6) was used as well. When (Ph3P)3CuC167’8was employed, no coupling was observed(entry 7). Thus, no further attempts were made to utilize these two latter complexes as acatalyst for the coupling reaction. Lithium chloride LiC1 is necessary for effecting efficientintramolecular palladium(0)-catalyzed coupling reactions of vinyl halide and vinylstannanefunctions to produce 5- and 6-membered rings (Sections 1.2 and 3.1, pp 14-18 and pp 66-68,119respectively). Surprisingly, no reaction occurred when 2.5 equivalents of LiC1 (ently 8) wasadded with CuC1. It is likely that CuC1 reacts with LiC1 to give a lithium dichiorocuprate(LiCuC12)68 (Equation 56) which may not be an effective species for this coupling process.It was reported68 that CuC1 undergoes disproportionation to give Cu(0) and CuC12 undercertain conditions. In order to find out whether CuC12 is the active species in this couplingreaction, CuC12 was used for the coupling process (entry 9). Substrate 209 remained intact(glc analysis) in the presence of CuCl2, and no coupling product was isolated. Furtheraddition of Cu(0) powder (electrolytic grade) to this latter reaction mixture showed no sign ofreaction (gic analysis).CuCI + LiC1 Li + CuC12 (56)In general, with DMF as solvent, all the CuC1-mediated intramolecular coupling reactionswere carried out via the following procedure. A DMF (dry) solution of the substratecontaining both vinyl halide and vinylstannane functions was heated at —60 OC for —10 mm(oil bath). Powdered CuC1 (—2-3 equiv) was then added. The added CuC1 immediatelydissolved to give a yellowish solution. After —20-30 s, a yellowish precipitate formed and themixture was stirred at —60 °C for 2-10 mm. Interestingly, the yellowish precipitate, whichwas formed in the reaction, dissolved to give a deep blue solution during work-up withNR1C1-NH4OH(pH = 8). After a series of purification procedures, the corresponding cyclicdiene was afforded in good yield.Solvent effects were also studied in the intramolecular coupling of 209 (Equation 57, p120) and the results are summarized in Table XXV (p 120). In a similar procedure to thatmentioned above, a yellowish solution, but no precipitate was observed when either DMSOorCH3CN was employed as solvent. Wet DMF (entry 3) and DMSO (entry 4) can be usedto provide a medium for the coupling process. The reaction rate was retarded when CH3N120(Table XXV, entry 5) was used as the solvent. It is known68 that four molecules of CH3Ncoordinate with a Cu(I) cation to form a tetrahedral complex (CH3CN)4Cu, and thiscomplex may not be an effective species for the coupling reaction. Tetrahydrofuran (entry 6)was found to be ineffective solvent for the coupling reaction owing to the poor solubility ofthe CuC1 in T.HF. It appears that DMF is the preferred medium for the CuC1-mediatedcoupling reaction.CuCI, solventreaction conditionsentry solvent CuC1 reaction temp/ time % yields’(equiv) (°CI miii or h)1C DMF 2.1 60/2mm 832’ DMF 2.0 23/ 10 mm 903 DMF-H20(v/v = 10: 1) 2.5 60/ 10 mm 833 DMSO 2.2 23/20 mm 914 CH3N 2.5 65/4 h 72d5 2.6 23/10mm Ofa AU reactions were carried out with 0.1 M 209 in the solvent designated.b Yield of purified, distilled product. In each case, the product isolated was found to be identical toan authentic sample of 223 by 1H nmr analysis.C Entries 1 and 2 are included for comparison.d The reaction was incomplete within 4 h and small amount of starting material 209 was present inthe crude reaction mixture (gic analysis).e CuC1 did not dissolve in THF under the reaction conditions.f Starting material 209 remained intact under the experimental conditions (gic analysis).EtO2C MeMe%(”I Me3Sn209(57)223Table XXV. Effect of different solvents on the CuCI-mediatedintramolecular coupling of substrate 2O9121In order to understand better the mechanism and the limitations of this new couplingprocess, other substrates, containing either a vinyl halide or a vinyistannane function orpossessing both of these moieties, were prepared via deconjugation-alkylation processes.The preparation of these substrates is summarized in the Table XXVLTable XXVI. Preparation of some substrates via deconjugation-alkylation1) LDA-HMPA (1.3 equiv),THF, -78 °C, 0.5 h; 0 °C,0.5 h.2) 193 (1.5 equiv), -20 °C, 1h.2M)’CO2E1241) LDA-HMPA (1.1 equiv),THF, -78 0C, 0.5 h; 0 °C,0.5 h;2) 297 (1.3 equiv), -20 °C, 1 h.297Me3Sn2983 ,..CO2MeI IISnMe32841) LDA (2.2 equiv), HMPA (3.4equiv), THF, -20 °C, 1 h;2) 299 (2.8 equiv), -20 °C, 1 h.1entry starting ceduie pmduct % yie1dzma,z-Bu3Sn CO2EI29583EtO2CI n-Bu3Sn296H’19378299 300122Table XXVI. Continuedentry starting pxxedure product % yield’2matenalCO2Me 1) LDA (1.4 equiv), T.HF, -78°C, 30 miii;2273 (1.6 equiv) in A,room temp. 1 h.301 BrkBr3022736667CO2Me 1) LDA (2.2 equiv), TNF, -780C 30 miii;2275 (1.4 equiv) in A,room temp. 1 h.301>‘__Br303275Yield of purified, pumped (vacuum pump) product.It should be noted that, via a procedure29similar to that employed for the preparation ofalkyl (Z)-3-trimethylstannyl-2-alkenoates, addition of lithium (tri-n-butylstannyl)(cyano)cuprate [n-Bu3SnCuCN]Li (304) (Equation 58) to commercially available ethyl pentynoate(102), followed by work-up and purification, provided ethyl (Z)-3-(tri-n-butylstannyl)-2-pentenoate (295) (Table XXVI, entry 1, p 121) in a 72% yield.= CO2Et102n-Bu3Sn CO2Et1) [n-Bu3S CuCN]Li (304)THF, -48 °C, 1.5 h; 0 °C,2.5 h; room temp. 0.5 h2)NH4C1-NHO(58)295123Electrophile 297 (Scheme 40) was prepared as follows. By a procedure46similar to thatdescribed in Section 2.1 (pp 43-45) in this thesis, commercially available 5-chloro-1-pentyne(106) (Scheme 40) was treated with B-Br-9-BBN (2.3 equiv), followed by work-up andpurification, to give 2-bromo-5-chloro-1-pentene (305) in a 77% yield. Subsequent reactionof this latter material with Nal (3 equiv) in acetone (reflux 16.5 h) afforded the expectedelectrophile 297 (Table XXVI, p 121) in an 83% yield. Compounds 299, 273 and 301(Table XXVI) are commercially available. Compounds 124, 193 and 284 (Table XXVI)were prepared according to procedures described in Sections 1.2,2.2 and 4.3 (pp 37-38, 54-55 and 103), respectively. Electrophile 275 (Table XXVI, p 122) was derived fromcommercially available ethyl 2-butynoate (101) in a sequence of reactions that was previouslydescribed in Section 4.3 (pp 105-107).1) B-Br-9-BBN2) H Br106 30577% yieldPh3.12,CH2Iroom temp. 4 h83% yield297Scheme 40Interestingly, when compound 296 (Equation 59, p 124) was heated at 65 °C in DMF inthe presence of CuCl (2.7 equiv) for 10 mm, a 54% yield of the cyclopentanecarboxylate 224and a 67% yield of thbutyltin chloride (n-Bu3SnCl) were produced (for details, seeExperimental section). Thus, in addition to causing the intramolecular coupling of vinylhalide and vinyltrimethylstannane functions, this reaction is also effective for the124intramolecular coupling of vinyl halide and vinyl th-n-butylstannane functions. Moreover, itwas discovered that tributyltin chloride was produced as a side-product in this couplingreaction.Me ELO2C MeI n-Bu3Sn296CuC1, DMF65 °C, 10 miii+ n-Bu3SnC1(67%)(59)CuC1, DMF60°C, 10 mmBr ELO2C MeMe.3Sn298CuCI, DMF60°C, 10 mm306AEXPECTED PRODUCT: (61)306A, NOT FOUND!Br ELO2C Me30611+Br ELO2C306C jY89% (1: 1 mixture)In contrast to the success of the preparation of the 6-membered ring compound 293(Equation 60) from 288 via the CuCl-mediated intramolecular coupling of vinyl iodide andvinyistannane functions (demonstrated in a previous section of this thesis, pp 111-112),attempted intramolecular coupling of vinyl bromide and vinyistannane moieties did not224(54%)MeO2C288(60)293125provide the corresponding 6-membered ring coupling product 306A when 298 (Equation61, p 124) was treated with CuC1 (2.5 equiv) in DMF for 10 mm. Instead, the reactionprovided a liquid that consisted of a mixture of the destannylated uncydized products 306Band 306C (Equation 61) in a ratio oft: 1 (1H nmr analysis) (for details, see Experimentalsection). Thus, it was found that, under the experimental conditions, the trimethylstannylmoiety had been removed from the parent molecule 298 while the vinyl bromide functionremained intact.On the basis of the latter experiment, it is reasonable to propose that, in the CuClmediated coupling reactions, the vinylstannane moiety initially reacts with CuCl, while thevinyl halide itself does not react directly with the copper(I) salt under the experimentalconditions. In order to test these conclusions further, a series of experiments were carriedout, involving the treatment of compounds containing either vinyistannane or vinyl halidefunctions with CuCL These experiments produced the following results.The reaction of 300 (Equation 62) with CuC1 (2.1 equiv) at 60 OC for 10 mm gave aliquid mixture that was comprised of the starting material 300 (15%), the destannylatedproduct 307A (42%) and the dimerized products69’70307B (8%) and 307C (6%) (fordetails, see Experimental section). Thus, it is obvious that the vinyl trimethyistannyl groupreacted with the CuC1 reagent.CO2Mec1DZ ‘°‘ cz + Oj%..øl*S + (62)300 300 307A CO2Me(15%) (42%) 307B (8%)307C (6%)126Moreover, as mentioned earlier, the destannylated side products 254 and 294 wereisolated from the coupling reactions described in Sections 4.1 and 4.3 (pp 95, 111),respectively. Thus, it can be concluded that vinylstannane groups are vulnerable in thepresence of CuC1, while the vinyl halide function tends to be unreactive under the samereaction conditions.254 294In addition, upon heating at 60 °C with CuC1 (—2 equiv) for 10 mm, compounds 302and 303 remained intact and were recovered in >80% yields. Prolonged heating (46 h) of303 (Equation 63) with a large excess of CuC1 (—17 equiv) afforded a 64% yield of halogen-exchanged71 product 307 (for details, see Experimental section). Therefore, it wasdemonstrated that the vinyl halide group remains relatively inactive or intact under theexperimental conditions for the CuC1-mediated coupling process.CuCI, DMF (63)60 °C, 46 h(64%)Based on these experiments, it is possible to provisionally propose the followingmechanism. The coupling reaction of compounds of general structure 309 (Scheme 41, p127) to give dienes 234 is thought to proceed through an initial reaction between thevinyistannane function and CuCl to afford a vinylcopper species 310 throughtransmetalation,72producing triaikylstannyl chloride (R3SnC1) as a by-product. Subsequent302303 308127formation of either a copper(II) metallocycle intermediate 311A or a copper(llI)73metallocycle intermediate 311B followed by reductive elimination would provide the 2,3-bis(allcylidene)cyclopentanecarboxylates of general structure 234. All of the proposedreaction steps (Scheme 41) apparently occur with retention of configuration on both C=Cbonds since compounds 234 were produced with high stereospecificities. Future effortsinvolving mechanistic studies of this coupling reaction will be required to elucidate thestructure of the intermediates.+ CuCI- R3SnC1FFFFR5 R20C R4R3 fR’I [Cu]’310oxidative addition (?)+R5 R20C R4R3I R3Sn309FR4Cu Cf-Cu2i-cr311B-Cu(l)(?)R5- Cu(O) (?)R1R3R1311A 234Scheme 411285. Diels-Alder reactions of alkvl 2.3-bis(alkvlidenecvclopentanecarboxvlates andstructurally related substances5.1. IntroductionThe Diels-Alder reaction is one of the most powerful synthetic methods in organicchemistry and therefore numerous publications have been dedicated to this reaction.74’5 TheDiels-Alder reaction involves a [42r +22r] cycloaddition of a conjugated diene and a dienophileto form a new 6-membered ring skeleton (Equation 64). Cyclic substances containing a 1,2-bis-exocyclic conjugated cliene system can be synthesized or generated in situ fromthermolysis (e.g., generation of orthoquinodimethanes267 from benzocyclobutenes).These dienes have served as important synthetic intermediates18’7678 in a number of totalsyntheses of pharmaceutically important chemicals such as steroids,76 alkaloids77 andanthracycinones.78 In a previous section of this thesis (Scheme 10, p 20), the application ofthe 1,2-bis-exocydic diene 53 to the total syntheses of (-)-sterepolide and (-)-merulidial hadbeen discussed.18 Prompted by these results, we decided to carry out an investigation ofDiels-Alder reactions of the prepared alkyl bis(alkylidene)cyclopentanecarboxylates 219 withsome selected dienophiles. The results of these studies will be described in the followingsections.+ II (64)DIENE DIENOPI-ULE DIELS-ALDER ADDUCE53 2191295.2. Diels-Alder reactions of dienes with tetracyanoethvlene 1CNEGenerally, the greater the number of electron-attracting substituents on the double bondor triple bond the more reactive is the dienophile, due to the lowering of the energy of thelowest unoccupied molecular orbital (LUMO) of the dienophile by the substituents.79 Themost commonly encountered activating substituents for the Diels-Alder reaction are carbonylcontaining moieties, nitrile and nitro groups and dienophiles which contain one or more ofthese groups in conjugation with a double or triple bond react readily with dienes.74CTetracyanoethylene (TCNE), which possesses four conjugated nitrile groups, is a veryreactive dienophile74and was used to investigate the face selectivity of the Diels-Alderreaction of dienes 219.Reaction of the diene 221 (Equation 65) with TCNB (1.2 equiv) in THF at roomtemperature was complete within 1 h (glc analysis). Removal of the solvent andchromatography of the crude product provided a 79% yield of a mixture of the esters 312 and313 in a ratio of 21: 1, respectively (determined by integration of the 1H nmr signals).Recrystallization of this mixture from petroleum ether-diethyl ether gave the ester 312 as acolorless solid (mp 129.5-130 OC). Diels-Alder reactions of other dienes of general structure219 and 314 (Equation 66) with TCNE were also carried out, and the results aresummarized in Table XXVII (pp 130-13 1). The procedure employed for each experiment wassimilar to that outlined above for the preparation of compound 312, unless otherwise noted.N NCTCNE, THF NC—Vr\\I II ) + (65)room temp. 1 h NC4%.ACO2Et312221 31379%(21: 1)R%\\R1L(E219 E = C02R314 E =CHOSiPh(t-Bu)31SE=C02R316 E =CH2OSiPhQ-Bu)Table XXVII. Diels-Alder reactions of dienes 219 and 314 with TCNEentry substrate reaction time product(s) % yie1d’313ratiocof3l2:313=21:1231 h and 45 miii72hdratio’of313:312=6.3:1no reaction87130TCNE, THFroom temp (orotherwise stated)(66)1Nlh221NCNC79CO2Et312N220222131Table XXVII. Continuedentry substrate reaction time product(s) % yield1’I CO2Et223860.5 h0.5 hN CO2EL317N CO2Et318224456953 19eNratio’of318:319=40: 1I —OSiPh2(t-Bu)320N2h 41N321a TCNE (-1.0-1.4 equiv), THF, room temperature, unless otherwise stated.b Yield of purified, pumped (vacuum pump) product(s).C The ratio was determined by the integration of 1H nmr signals (for details, see Experimental section).d The THF solution of substrate 222 and TCNE was subjected to reflux for 72 h.e Compound 319 was not isolated, and its structure was tentatively assigned based on nmr signals(for details, see Experimental section).1 52% of starting material was recovered.132EtO2C Me HO MeMe%(4”f Et78°Cjh Me’(3”fI Me.3Sn 0°C, 1 h (96%) I Me3Sn210 322t-BuPh2SiC1 (1.4 equiv)unidazole (1.8 equiv)CH21 (96%)t-BuPh2SiO(Ph3P)4d(5 mol%) MeLiCI (2 equiv), DMF Me %%OSIPh2(t-Bu) 80°C, 1 h (86%) I Me3Sn320 323Scheme 42It should be noted that compound 320 (Scheme 42) was derived form the alkylated ester210 (p 59) via reduction of the ester moiety with i-Bu2AIH, followed by protection8Oof thereduced alcohol and subsequent palladium(0)-catalyzed cyclization.As shown in Table XXVII (pp 130-131), the cycloaddition products were obtained ingood yields (>80%) except for two experiments (entries 3 and 6). The time required forcompletion of each of the reactions summarized in entries 1, 2, 4 and 5 was quite similar.However, in the case of the (Z,Z)-bis(ethylidene)cyclopentanecarboxylate (222), the stericrepulsion between the two methyl groups on the diene system causes severe distortion fromplanarity (Section 3.2, p 86) and also hinders the approach of the dienophile. Consequently,it is not surprising that no reaction of 222 with TCNE was observed even under more drasticreaction conditions (entry 3). In addition, it is interesting to note that the Diels-Alder reactionof TCNE with the diene 320 did not go to completion within 2 h (entry 6). However, thereason(s) underlying the fact that 320 is somewhat less reactive than 223 is (are) notimmediately obvious.133Another special feature of the Diels-Alder reactions of the dienes of general structures219 and 314 with TCNB is the high face-selectivity of the processes (Table XXVII, pp 130-.131). For example, predominant approach of TCNE from the a-face (which is designated asthe face opposite to the one which has the ester group) of the diene 221 (Scheme 43)provided the corresponding Diels-Alder adducts 312 and 313 in a ratio of 21: 1,respectively (Table XXVII, entry 1). The dienophile prefers to approach the diene functionfrom the a-face so as to avoid the unfavorable steric interaction between TCNE and the estergroup on the 5-membered ring in the transition state (Scheme 43). Similarly, in all otherreactions with TCNE (Table XXVII), the major products are those adducts resulting fromapproach of TCNE from the a-faces of the dienes.EtO2..F/3-fxe approachNCO2Et313221NCa-face approachNCCN312NScheme 43134N The relative stereochemistry of each of the products (TableXXVII, pp 130-13 1) was assigned with the aid of conformationalanalyses, 1H nrnr spectroscopic data and a series of decoupling andnOe difference experiments. For example, there are two “reasonable”conformations for compound 312, i.e. 312A and 312B. In bothconformations, the cyclohexene ring adopts a half-chair conformation. It can be seen that in312A, a serious 1,3-diaxial interaction between the secondary methyl group (Me) and one ofthe nitrile groups (E*) will disfavor this species. Thus, it can be concluded that 312B,which does not possess a 1,3-diaxial interaction between the Me and E* groups, will be themore stable conformation. It is worth noticing that, in 312B, the Me group has a pseudo-equatorial orientation. The proposed conformation 312B was shown to be in agreement withthe results obtained from the nOe difference experiments (p 135).312EEHe.E*312A E=E*=CNE’= EtO2C-EMe4E*EMe312B E=E*=cNE’= EtO2C-1358 3.08 (d),and 83.15 dm) 82.19-2.40 (m),Hb 82.43-2.62(m)8 3.37-3.48(br si)1.5 (d) 312 6 3.56-3.66 (m)The 1H nmr spectrum (CDC13,400 MHz) of 312 displayed signals for a secondarymethyl group (CHeCjj, a 3-proton doublet at 3 1.58, J= 7 Hz), three methylene groups (Haand Hb, a 2-proton multiplet at 32.19-2.40 and a 2-proton multiplet at 62.43-2.62; H, a 1-proton doublet at 6 3.08, J= 18 Hz and a 1-proton doublet of multiplets at 6 3.15, J= 18 Hzfor doublet) and two methine protons (H92%). In these cases, the dienophile MVK approachedthe diene from the a-face (which is designated as the face opposite to the one which has theester or silyloxymethyl group). Clearly, if the MVK approached the 13-face of the diene viaan endo transition state, serious steric hindrance would be experienced between the ester orsilyloxymethyl group on the 5-membered ring of the diene and the acetyl group of thedienophile. Thus, approach of MVK from the a-face is favored and this face-selectivity wasobserved in all of the products obtained. In Schemes 46-48 (pp 155-157), the formation ofeach of the Diels-Alder reaction products is anayized with respect to the correspondingtransition states. In addition to the face-selectivity, information concerning the exo/endoselectivity, as well as the orientations of MVK (regioselectivity) in these transition states areprovided (Schemes 46-48).221R = CH3Oa-face approachendo transition state0 CO2Et326CO2Et220EtO Cc339EtOC340EtO2CtI223 341róQ0 CO2EL328156Peculiar regioselectivity: OBSERVEDGeneral regioselectivity: NOT FOUND9R = cH3o 0 CO2Eta-face approach 345344 endo transition stateEtO2CR = CH3O 0 a cO2Etfl-face approach 347346 endo transition state230342I COEt329R = CH3Oa-face approachendo transition state343R = CH3Ofl-face approachendo transition state330Scheme 47157R = CH3Oa-face approachendo transition statew• CO2Et331I 2O2(t)335R = CH3O o CH2OSIPh(t-Bu)a-face approachendo transition stateScheme 48As shown in transition states 339-342 and 348-351, the dienophile MVK approachedeach of the dienes predominately from the a-face. The only confirmed deviation was foundin the reaction of 230 (Equation 69 and entry 4 of Table XXVffl, p 141) with MVK, where atrace amount of minor product 330 was obtained from the 13-face approach of the dienophile(Scheme 47, p 156). The formation of 330 will be discussed in the next part of this sectionof the thesis (p 159).224 348R = CH3Oa-face approachendo transition statet-BuPh2SiOCHCH2OSIPh(t-Bu) V332 349t-BuPh2SiOCH202(t)320 350333334t-BuPh2SiOCHR = CH3Oafaceapproach 336351 endo transition state158According to the Alder endo rule,7the major cycloaddition product is the one obtainedfrom a transition state with the “maximum accumulation of double bonds”. Thus, the endotransition state 339 depicted in Scheme 49 is favoured over the exo transition state 352.Examination of the structures of all the isolated cycloaddition products in Schemes 46-48 (pp155-157) shows that all the characterized cycloaddition products, including the minor product330 (Equation 69), were obtained via endo transition states.R = CH3Oa-face approachendo transition stateR = CH3Oa-face approachexo transition stateScheme 49%Ylcx0 CO2Et326MVKBF3.EL20-78 °C221 339352230+ (69)329 330(9 1%) (5%)159The regiochemistry of all the cycloaddition products (except those of entry 4, TableXXVIII (diene 230 and products 329 and 330), p 141), are identical. For example, thedienophile MVK approaches the diene 221 with an orientation as depicited in the transitionstate 339 (Scheme 49, p 158). Surprisingly, deviation from this regioselectivity wasconfirmed in the cycloaddition of MVK to the diene 230 (Scheme 47, p 156). The majorproduct 329 (Scheme 50) was obtained from 230 as a result of the approach of MVK via theregiochemical orientation shown in the transition state 342. The formation of minor product330 was formed via approach of MVK from the fl-face of the diene with the sameregiochemical orientation (transition state 343, Scheme 50).R = CH3Oa-face approachendo transition statepeculiar regioselectivity,a reversal of the predominantregioselectivityR = CH3Ofl-face approachendo transition statepeculiar regioselectivity,a reversal of the predominantregioselectivity230329342EC/I3430330Scheme 50The influence ofBF3’Et20on the Diels-Alder reactions of the various 1,2-bis-exocydicdienes of general structures 219 and 314 with MVK can be rationalized by the use of frontiermolecular orbital theory.79 In a normal (electron demand) Diels-Alder reaction,85 the maininteraction is that between the highest occupied molecular orbital (HOMO) (Figure 9) of thediene and the lowest unoccupied orbital (LUMO) of the dienophile. The smaller the energydifference is, the better the orbital overlap and the more readily the reaction occurs.Coordination74cof a Lewis acid such as BF3.Et20 with the carbonyl group of MVK in ourreactions lowers the energies of the frontier orbitals (Figure 9) and alters the distribution ofthe atomic orbital coefficients.Figure 9: The effect of Lewis acid on the energies of theHOMO and LUMO of the dienophile in the DielsAlder reactionLUMO ___/HOMO____HOMO /WiTHOUT LEWIS ACID LEWIS ACIDR3R’160219R’%\\R’L(’CH2OSiPh(t.Bu)314£ LUMOLUMO/HOMO /LUMOIDIENE DIENOPHILE DIENE DIENOPHILE161Because of the smaller energy difference between the HOMO of the diene and the LUMOof the dienophile, the reaction is faster. Indeed, it was observed that, in the presence ofBF3.Et20, reaction of 221 with MVK was complete in 1.5 h at -78 °C, while in the absenceof this Lewis acid, the reaction took 4 h to complete in refluxing benzene. In the latterexperiment, the reaction was not selective and three minor uncharacterized products wereproduced in addition to 326 (1H nnr and gic analyses).CO2Et326R3%(\\R1L(CH2OSIPh(t-Bu)314The observed endo selectivity in the reactions of dienes of general structures 219 and314 with MVK is reinforced by the presence ofBF3.Et20. In the presence of a Lewis acid,the secondary orbital interaction (as shown by dashed lines) is greatly enhanced because of alarge increase in the LUMO coefficient of the carbonyl carbon atom.LUMO221 219HOMO[i1HouT LEWIS ACID WITH LEWIS ACID 1162Another effect of the Lewis acid BF3.Et20 is to further polarize the LUMO of MVK.Thus, the fl-carbon and the a-carbon possess orbitals with larger and smaller coefficients,respectively, as compared to those of the uncoordinated MVK. The atom with the largercoefficient in the dienophile interacts preferentiaily with the atom with the larger coefficient inthe diene to result in a better overlap of orbitals. Consequently, the Diels-Alder reactions oftrisubstituted dienes 221, 220 and 332 with MVK provided products 326, 327 and 333(Table XXVIII, entries 1, 2 and 6, pp 141-142), respectively, with the regioselectivityconsistent with that predicted.HOMOLUMOWITHOUT LEWIS ACIDHOMOLUMOF3B0WITH LEWIS ACIDI CO2Et221I ‘—OSiPh2(t-Bu)3320 ‘ CO2Et ‘—OSiPh2Q-Bu)0220326 327 333163223 E=COt 224E=COEt 230320 E =CHOS1Ph(t-Bu) 335 E =CHOSIPh(t-Bu)%1çxj??O2E328E=COEt 331E=CO2Et 329334 E =CHOSiPh(t-Bu) 336 E =CHOS1Ph(t-Bu)The Diels-Alder reactions of MVK with the tetrasubstituted dienes 223, 224,230,320and 335 (products 328-331, 334 and 336 in Table XXVffl, entries 3-5, 7 and 8, pp 141-142) provided products resulting from two different modes of regioselectivity (p 159). TheDiels-Alder reactions of MVK with dienes 223, 224, 320 and 335 gave products with thesame regiochemistry as those products obtained from Diels-Alder reactions of MVK withtrisubstituted dienes 220, 221 and 332. But in one case, the Diels-Alder reaction of MVKwith tetrasubstituted diene 230 provided products 329 and 330 with a reversedregiochemistry. It is not immediately clear why the predominant regioselectivity, as well asthe reversed regioselectivity (diene 230) are observed in these Diels-Alder reactions.330164It could be speculated that, in the reactions involving the dienes 223 and 224, BF3.Et20chelates concurrently both with the carbonyl group of the ester functionality on the 5-membered ring and the carbonyl group of the acetyl moiety of the MVK. This doublecoordination82ofBF3.Et20would lead to the formation of products with the observedregiochemistry. It would be expected that complexation of BF3•Et20 with the carbonylgroups of ester would be avoided by converting the ester functions on the 5-membered ring tosioxymethyl groups. However, products 334 and 336, with the same regioselectivity, wereobtained from Diels-Alder reactions of the MVK and the sioxymethyl dienes 320 and 335,respectively. Therefore, complexation ofBF3.Et20with the carbonyl group of the esterfunctionality may not be the cause of the observed regioselectivity. This proposed doublecoordination ofBF3.Et20is also made unlikely by formation of 329 and 330 from the DielsAlder reaction of MVK with the diene 230. In the latter reactions, the relative positions ofthe acetyl and the ester groups in the products 329 and 330 are against to the possibility ofthe concurrent chelation of BF3.Et20with the two carbonyl-containing groups in thecorresponding transition states.223 E = CO2Et 224 E = CO2Et320 E =CHOSIPh(t-Bu) 335 E =CHOSiPhQ-Bu)328E=COEt 331E=CO2Et334 E =CHOSiPh(t-Bu) 336 E =CHOSiPh(t-Bu)CO2Et2300-329330165Further research is required to clarify the occurrence of different modes ofregioselectivity, depending on the orientations of the vinylic methyl groups on the 1,2-bis-exocycic diene system (compare the orientation of the vinylic methyl groups in the dienes223, 224 and 230). To our knowledge, the change of regioselectivity due to the change ofthe orientations of these methyl groups is unprecedented. (The reversal of the Diels-Alderregioselectivity by a change of Lewis acid, and of the solvent used, have been observed.)8E E CO2Et223E=COEL 224E=COEt 230R1L%(CH2OSiPh(t-Bu)314In conclusion, the Diels-Alder reactions of dienes of general structures 219 and 314with the dienophiles TCNE and MVK occurred with approach of dienophiles from the a-face. In the Diels-Alder reactions of 219 and 314 with MVK, the observed rateenhancement as well as the observed endo selectivity of the cycloaddition adducts are a resultof the presence of BF3•Et20and can be explained in terms of frontier molecular orbitaltheory.79 However, knowledge about the regioselectivities of the Diels-Alder reactions oftetrasubstituted dienes of general structures 219 and 314 with MVK is very limited, andfurther investigations in this area are required.219166III. CONCLUSIONS1. Development of the use of lithium (trimethylstannyl)(cyano)cuprate forthe conversion of alkyl 2-alkynoates into alkyl (E)- and (Z)-3-trimethyl-stannyl-2-alkenoatesA number of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates of general structures 89and 91 were required for this study. During the course of this study, lithium(trimethylstannyl)(cyano)cuprate ([Me3SnCuCNILi, 123) was found to serve as an effectivereagent, alternative to lithium (trimethylstannyl)(phenylthio)cuprate ([Me3SnCuSPh]Li,120), for the stereoselective conversion of a,f3-acetylenic esters 100 into either of thedesired products 91 and 89 (Equations 27 and 28, respectively). This work was carried outin collaboration with Mr. Keith A. Ellis.[Me3SnCuSPh]Li [Me3SnCuCNJLi120 1231 1) [Me3SnCuCN]Li (123) 1R R HcO2 THF,-48°C,2h;O°C,2h —— (27)2)NH4C1-NHO Me3Sn CO2R100 911 1) [Me3SnCuCN]Li (123) 1 2R 2 R— CO2Rco’2 THF, R OH, -78 °C, 4 h— 2 (28)2)NR4C1-NHOH Me3Sn H100 891672. Stereoselective and regioselective synthesis of electrophilesThe preparation of a number of specifically functionalized and stereochemicallyhomogeneous electrophiles of general structures 98,99, and 353 has been accomplished.In addition, the preparation of compound 275 (Scheme 37, p 106) was carried out.Electrophiles of general structures 98 and 99 (Scheme 51, p 168) were synthesized ingood yields from the corresponding (E)-. and (Z)-trimethylstannyl esters 89 and 91,respectively. In these transformations, a sequence of reactions (deconjugation, reduction,iododestannylation, and transformation of alcohol into the corresponding iodide) wereemployed. Overall, this chemistry constitutes a new strategy for the preparation ofhomoallylic diiodides of general structures 98 and 99.The vinyl halide functionality of compounds of general structure 353 was obtained bythe use of either bromoboration-protonolysis or hydrostannylation-iododestannylationprocedures. A series of known procedures, including the trans addition of H-I to ethyl 2-butynoate (101) (Scheme 37, p 106), reduction, and treatment of the reduced alcohol 280with triphenyiphosphine dibromide (Ph3P.Br2),provided the electrophile 275.98 99 353X’=Brorl,x” = Clor I,n = 1 or 2I>’4_Br = CO2EL I—OH275 101 280168R1M)’ R389 1) base R4rCO22OR 2)H SnMe3R’89—*90M1>’4C02R290 R3= H, R4= R1;92R=1,4H91—,9291 i-Bu2AIH,Et20-78 °C, 1 h; 0 °C, 1 hR3 R312, CH1room Lemp, 15 mmI SnMe3195 R3= H, R4= R’; 194 R3= H, R4= R1;192R=,4 191R=R’,Ph3.12,CH21Et, mom Lemp, 4 hR3R4II98 R3= H, R4=R1;99R=R’,R4HScheme 511693. Preparation of compounds containing vinyl halide and vinyltrimethylstannane functionsThe preparation of compounds of general structure 206 (Equation 35) was accomplishedby the deprotonation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 withLDA, followed by alkylation of the resulting dienolates with electrophiles of generalstructures 96 and 97. On the other hand, compound 216 was synthesized by a two-stepstrategy. Firstly, ethyl (E)-5-methyl-3-trimethylstannyl-2-hexenoate (139) (Equation 70)was deconjugated (KN(SiMe3)2; Hj to provide ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (158) in good yield. Secondly, deprotonation of the latter substance (Equation 36)with LDA, followed by alkylation of the resulting dienolate anion with the electrophile 204,provided compound 216.R1_)_jD02Me3Sn89 or 911) LDA-HMPA, THF2)R3““‘‘IR20CR3X Me3Sn206(35)96or97 (X=Brorl)1) KN(SIMe32,THF2) HOAc, Et20 SnMe3158(70)SnMe31581) LDA-HMPA, THF2)I204EtO2CMe3Sn2161391704. Stereocontrolled syntheses of alkyl 2,3-bis(alkylidene)cyclopentane-carboxylates via palladium(0)-catalyzed coupling reactionsAlkyl 2,3-bis(alkylidene)cyclopentanecarboxylates of general structure 219 wereprepared in good yields and in a stereochemically defined manner from compounds of generalstructure 206 (Equation 39). The ring closure was accomplished by use of a palladium-catalyzed, intramolecular variant of the Stille cross-coupling reaction. Thus, we fuffilled ourinitial goal of developing a general strategy for the preparation of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates possessing E,E-, E,Z- and Z,Z-configurations (i.e.81,82 and 84). This strategy is superior to previously described methods (pp 20-26) whichprovided only 1 ,2-bis(alkylidene)cycloalkanes possessing one or two E-substitutedalkylidene moieties. However, the limitations of this palladium-catalyzed intramolecularcoupling reaction were shown by the inability to provide the Z,E-diene 230 in a stereo-controlled manner, and by the low yield obtained in the preparation of 229.R3%J0cfR1 :::::: (39)206R3O2R2E.E-diene 81 E,Zdiene 82 Z,Zdiene 84R3219Z,E-diene 83230 222 228 2291715. X-ray analysis of alkyl 2,3-bis(alkylidene)cyclopentanecarboxamidesCrystalline derivatives of alkyl (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxylates 222,228 and 229 were prepared. X-ray analysis of these single crystals showed that themagnitude of the dihedral angles between the two exocylic C=C bonds in compounds 237,238,241, 243 and 247 are in the range of 48.6° and 58.0°. Thus, it can be concluded thatthe extent to which the 1,2-bis-exocycic diene systems of these crystalline derivatives aredistorted from planarity are similar, and that there is no clear correlation between the values ofthe dihedral angles and with the size of the substituents on the termini of the diene moieties.241 —H2476. Discovery of the CuC1-mediated intramolecular coupling reactionExtensive efforts to synthesize the Z,E-diene 230 in a stereochemically defined mannerand to optimize the yield of the preparation of 229 resulted in the development of a newCuC1-mediated intramolecular coupling of vinyl halide and vinyltrimethylstannane functions.This method has been applied successfully to the preparation of a number of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates possessing E,E-, E,Z-, Z,E- and Z,Z-configurations(81, 82, 83 and 84, respectively), and a variety of bicyclic compounds containingconjugated diene systems (see structural formulas 253 and 289-293, p 172). In some237 238243172cases, it was found that this CuC1-mediated method is superior to the palladium(O)-catalyzedcoupling process. In addition, with the results obtained from the preliminary studies, aprovisional mechanism was proposed for this new reaction (Scheme 41, p 127). Futurestudies concerning synthetic and mechanistic aspects of this new coupling procedure can beenvisaged.SnMe3MJ286252MeO2C289MeO2CMeMeç287 288MeO2Ccb291Br284 285290253 292 2931737. Investigation of synthetic utility of alkyl 2,3-bis(alkylidene)cyclo-pentanecarboxylates in the Diets-Alder reactionOwing to the versatility of the 1,2-bis-exocyclic diene systems in Diels-Alder reactions,and the importance of the resulting intermediates in a number of total syntheses of naturalproducts, the Diels-Alder reactions of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 219and the related dienes 314 with the dienophiles TCNE and MVK (Equations 65 and 66,respectively) were investigated.R3BF3Et2O(-1 equiv)MVK (-5 equiv)CH21,-78 °C, 1-3 hB219 B = C02R314 E =CHOSIPh(t-Bu)324 E = C02R325 E =CHOSiPh(t-Bu)Interestingly, the Diels-Alder reactions of dienes of general structures 219 and 314occurred with approach of dienophiles (TCNE, MVK) from the a-face (which is designatedas the face opposite to the one which has the ethoxycarbonyl or the siloxymethyl group).This face-selectivity can be attributed to the unfavorable steric hindrance which wasexperienced between the dienophiles and the ester or the siloxymethyl group on the 5-memebered ring, when the dienophiles approach the 13-face of the dienes. Moreover, it wasfound that Diels-Alder reactions of dienes of general structures 219 and 314 with thedienophile MYK occurred with approach of MVK via an endo transition state.R3 TCNB, THFroom temp (orE otherwise stated)219 E=C02R314 B =CHOSIPh(t-Bu)NCNC315E=COR2316 E =CH2OSiPh(t-Bu)(65)(66)0 R1174Another interesting feature of the Diels-Alder reactions of these dienes and MVK is theregiochemistry of the products. The regiochemistry of the products obtained from DielsAlder reactions of the irisubstituted dienes (dienes 220, 221 and 332; products 327, 326and 333) was rationalized on the basis of the frontier molecular orbital theory. The sametype of regiochemistry was observed in Diels-Alder reactions of the tetrasubstituted dienesand the dienophile MVK (dienes 223, 224, 230, 320 and 335; products 328-331, 334CO2Et220I CO2Et221OSIPh2(t-Bu)332r9?O2E327a CO2Et326OSiPh(t-Bu)333223 E=CO2t320 E =CHOSIPhQ-Bu)I B224 E=CO2t335 E =CHOSIPh(t-Bu)CO2EL230s,rcx?o = B328 E=CO2t334 E =CHOSIPh(t-Bu)0E331 E=CO2t336 B =CHOSiPh(t-Bu)330175and 336). In addition, the reversal of the predominant regioselectivity is confirmed in theDiels-Alder reaction of MVK and the diene 230. However, the reasons for the predominantregioselectivity and the reversed regioselectivity in these Diels-Alder reactions are not clear atthis moment.. In order to find out the rationale for these interesting regioselectivities, futureinvestigations will be required.176IV. EXPERIMENTAL SECTION1. General1.1. Data acquisition and presentationMelting points were determined on a Fisher-Johns melting point apparatus and areuncorrected. Distillation temperatures, which refer to short path bulb-to-bulb (Kugelrohr)distillation, are also uncorrected. Infrared (ir) spectra were obtained on liquid films (sodiumchloride plates) or solid pellets (infrared grade potassium bromide) employing a Perkin-Elmermodel 1710 Fourier transform spectrometer with internal calibration.Proton nuclear magnetic resonance (1H nmr) spectra were recorded on deuteriochloroform (CDC13)solutions or hexadeuteriobenzene (C6D)solutions using a Bruckermodel WH-400 (400 MHz) spectrometer. Signals positions (6 values) are given in parts permillion and were measured relative to those of tetramethylsilane (60), benzene (67.14) orchloroform (6 7.25).86 The multiplicity, number of protons, coupling constants (J values,given in the unit Hz) and assignments (where possible) are indicated in parentheses. The tinproton coupling constants (Jsn..H) are given as an average of the 117Sn and 119Sn values. Insome cases, the proton assignments were supported by decoupling(1H- spin decoupling),nOe difference and/or COSY(1H- homonuclear correlation spectroscopy) experiments.These experiments were carried out using a Brucker model WH-400 spectrometer.Carbon nuclear magnetic resonance (13C nmr) spectra were taken on Brucker modelsAC-200E (50.3 MHz), WH-400 (100.6 MHz), AMX-500 (125.8 MHz) spectrometers or aVarian model XL-300 (75.5 MHz) instrument using deuteriochioroform as solvent. Signal177positions (6 values) are given in parts per million and were measured relative to that ofdeuteriochloroform (6 77.O).86Low resolution mass spectra were recorded on an AEI MS9/DS55SM or on a KRATOSMS5O/DS55SM spectrometer. High resolution mass spectra were recorded on a KRATOSMS5O/DS55SM spectrometer. For compounds containing the trimethyistannyl (Me3Sn)moiety, high resolution mass spectrometric measurements are based on 1Sn and were madeon the (M - CH3) peak.45 Microanalyses were performed on a CARLO ERBA CHNelemental analyzer, model 1106, by the Microanalytical Laboratory, University of BritishColumbia.Ultraviolet spectra (uv) were recorded on a Perkin-Elmer Lambda 4B UV/VISspectrometer using spectroscopic grade pentane and/or methanol as solvent. The Ama, themolar absorptivity (e) and the solvent used are reported. Optical rotatory dispersion (ORD)spectra were recorded on a Jasco model J-710 spectropolarimeter using spectroscopic grademethanol as solvent.Gas-liquid chromatography (gic) was performed on either a Hewlett-Packard model5880A or a Hewlett-Packard model 5890 capillary gas chromatograph, both using a flameionization detector and a fused silica column, either a —20 m x 0.32 mm column coated(0.17 IJ.m) with Ultra B (Crosslinked 5% Ph Me silicone) or a —25 m x 0.20 mm columncoated (0.33 tm) with HP-5 (Crosslinked 5% Ph Me silicone), respectively. Thin-layerchromatography (tic) was carried out with commercially available, aluminum backed sheets,precoated with silica gel 60 to a thickness of 0.2 mm (E. Merck, type 5554). Visualization ofthe chromatograms was accomplished with an ultraviolet light and/or with iodine, and thenby heating the chromatogram after staining with commercially available phosphoromolybdicacid in EtOH (20% w/v, Aldrich Chemical Co., Inc.) or with a solution of vanillin in a178sulfuric acid-EtOH mixture. Flash chromatography41was performed with 230-400 meshsffica gel (E. Merck, sffica gel 60). Radial chromatography87was done on a Chromatotron®Model 7924 using 1, 2 or 4 mm thick radial plates (silica gel 60, PF254 with Gypsum,E. Merck #7749).Cold temperatures were maintained by the use of the following baths: 0°C, ice-water;-10 OC, ice-acetone; -20 °C and -48 OC, aqueous calcium chloride-dry ice (27 g and 46 gCaC12/100 mL H20, respectively);88-63 °C, chloroform-dry ice; -78 °C, acetone-dry iceand -98 OC, methanol-liquid nitrogen.All reactions were carried out under an atmosphere of dry argon in flame and/or oven(—140 OC) dried glassware. Glass syringes, needles and poly(tetrafluoroethylene) (Teflon®)cannula for handling anhydrous solvents and reagents were oven dried while plastic syringeswere flushed with a stream of dry Ar prior to use. Microsyringes were placed under vacuum(vacuum pump) for 15-30 mm and then stored under a dry Ar atmosphere prior to use.Concentration, evaporation or removal of the solvent under reduced pressure (wateraspirator) refer to solvent removal via a BUchi rotary evaporator at —20 Torr.1791.2. Solvents and reagentsAll solvents used were dried and distilled using standard procedures.89 Benzene (C6H6)and dichioromethane (CH2C12) were distilled from calcium hydride. Diethyl ether (Et20) andtetrahydrofuran (THF) were distilled from sodium benzophenone ketyl. The fouraforementioned solvents were distilled and used immediately. Diisopropylamine,N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoroamide(HMPA) and triethylamine were distilled from calcium hydride. Methanol (MeOH) andethanol (EtOH) were dried with sodium and distilled. Petroleum ether refers to ahydrocarbon mixture with bp 35-60 °C. All other solvents were used directly as obtainedcommercially.Boron trifluoride-etherate was purified by distillation from calcium hydride underreduced pressure (60 °C/20 Torr).Copper(l) bromide-dimethyl sulfide complex was prepared by the method described byWuts.M Copper(I) chloride (99.995%+ or 99%+) and copper(I) cyanide (99%) werepurchased from Aldrich Chemical Co., Inc., and were used without further purification.Deuteriochloroform, ethyl chioroformate, iodomethane and methyl chioroformate werepassed through a short column of basic alumina activity I, which had been dried in an oven(—140 °C) overnight and then allowed to cool in a desiccator prior to use.Hexa-n-butylditin (or bis(thbutyltin)) and hexamethylditin were obtained from AldrichChemical Co., Inc., and Organometallics Inc., respectively and were used without furtherpurification.180Potassium bis(trimethylsilyl)amide (solid) was purchased from Aldrich Chemical Co.,Inc., and was used without further purification.Tetrakis(triphenylphosphine)palladium(0) was obtained from either Aldrich ChemicalCo., Inc., or Morton Thiokol, Inc. (Alfa Products). This reagent was used without furtherpurification.Solutions of methyllithium (as a complex with lithium bromide) in diethyl ether,n-butyllithium in hexanes, diisobutylaluminum hydride in hexanes and trimethylaluminum intoluene were purchased from Aldrich Chemical Co., Inc., and the former two reagents werestandardized using diphenylacetic acid as primary standard.9°Lithium diisopropylamide (LDA) was prepared by the addition of a solution ofn-butyllithium (1 equiv) in hexanes to a solution of diisopropylamine (1 equiv) in drytetrahydrofuran at -78 OC. The resulting colorless solution was then stirred at 0 OC for10 mm before being used.All other reagents are commercially available and were used without further purification.Aqueous ammonium chioride-ammonium hydroxide (NH4C1-NHOH) (pH = 8)solution was prepared by the addition of—SO mL of aqueous ammonium hydroxide (28-30%)to —950 mL of saturated aqueous ammonium chloride solution.1812. Preparation of a,B-acetvlenic estersPreparation of methyl 4-cyclopropyl-2-butvnoate (1038CO2Me103To a cold (-20 OC), stirred solution of diisopropylamine (0.14 mL, 1.0 mmol) andpropynoic acid (0.62 mL, 10 mmol) in dry THF (7.5 mL) was added a solution of n-BuLi inhexanes (14.3 mL, 21.0 mmol). After the pale yellow slurry had been stirred at -20 OC for10 mm, dry HMPA (15 mL) was added and stirring was continued at -20 0C for 15 mm andat -10 °C for 1.5 h. Commercially available cyclopropylmethyl bromide (1.1 mL, 11 mmol)was added and the mixture was stirred at room temperature for 24 h. lodomethane (2.5 mL,40 mmol) was added to the deep brown mixture and stirring was continued at roomtemperature for 24 h. H20 (50 mL) and Et20 (50 niL) were added, the phases wereseparated and the aqueous layer was extracted with Et20 (5 x 50 niL). The combined organicextracts were washed with H20 (100 niL) and brine (100 niL), dried (MgSO4) andconcentrated. The remaining oil was subjected to flash chromatography (76 g silica gel,25: 1 petroleum ether-Et20). Concentration of the appropriate fractions and distillation(30-55 OC/0.3 Torr) of the remaining oil provided 663 mg (48%) of the ester 103 as acolorless oil that displayed ir (neat): 2237, 1714, 1436, 1260, 1072 cm-1; 111 nmr (CDC13,400 MHz): 8 0.21-0.29 (m, 2H, cyclopropyl methylene protons), 0.50-0.58 (m, 211,cyclopropyl methylene protons), 0.92-1.04 (m, 111, cyclopropyl methine proton), 2.36 (d,211, CCH2, 1= 6 Hz), 3.77 (s, 3H, OCH3); 13C nmr (CDC13,50.3 MHz): 6 4.2, 8.6,23.1, 52.5, 72.9, 88.2, 154.2. Exact mass calcd. for C8H1002: 138.0681; found:138.068 1. Anal. calcd.: C 69.54, H 7.30; found: C 69.47, H 7.35.182Preparation of 1,1 -dibromo-4-methyl- 1 -pentene (11428,30114To a stirred solution of carbon tetrabromide (9.85 g, 29.7 mmol) in dry CH21(100 mL) at room temperature was added, dropwise, a solution of Ph3 (15.5 g,59.1 mmol) in dry CH21 (100 mL) over a period of 15 mm. After the resulting orangesolution had been stirred at room temperature for 5 mm, a solution of 3-methylbutanal (113)(3.0 mL, 28 mmol, freshly distilled from MgSO4) in dry CH21 (100 mL) was addeddropwise over a period of 10 mm. The resulting deep brown mixture was stirred at roomtemperature for 1 h and was then poured into stirred n-pentane (400 mL). The resultingslurry was filtered through a column of Florisil® (18 g) and the column was washed withn-pentane (100 mL). Concentration of the combined eluate (under an atmosphere of dry Ar)and distillation (90-100 OCI100 Torr) of the acquired oil produced 5.03 g (74%) of the alkene114, a colorless liquid that exhibited ir (neat): 1619, 1466, 1386, 1369, 854, 781 cm4;nmr (CDC13, 400 MHz): 8 0.92 (d, 6H, CH(Cjj3)2J= 7 Hz), 1.68-1.80 (m, 1H,Cjj(CH3)2,1.98 (t, 2H, CH2.1= 7 Hz), 6.38 (t, 1H, =CH, J= 7 Hz); 13C nmr (CDC13,50.3 MHz): 6 22.2, 27.7, 41.8, 88.8, 137.8. Exact mass calcd. for C6HO79Br81r:241.9129; found: 241.9123. Anal. calcd. forC6H10Br2:C 29.78, H 4.17; found: C 29.84,H 4.14.183Preparation of ethyl 5-methyl-2-hexynoate (104)28CO2Et104To a cold (-78 Oc), stirred solution of 1,1-dibromo-4-methyl-1-pentene (114) (19.5 g,80.6 mmol) in dry THF (200 mL) was added a solution of MeLi in Et20 (110 mL,167 mmol). After the resulting solution had been stirred at -78 OC for 1 h and at roomtemperature for 1 h, it was cooled to -20 °C (--5 mm) and ethyl chioroformate (11 mL,120 mmol) was added. The reaction mixture was stirred at -20 OC for 1 h and at roomtemperature for 1 h. Saturated aqueous NaHCO3 (300 mL) was added, the phases wereseparated and the aqueous layer was extracted with Et20 (3 x 100 mL). The combinedorganic extracts were washed with brine (200 mL), dried (MgSO4) and concentrated.Distillation (85-105 °C120 Torr) of the remaining liquid afforded 11.3 g (91%) of the ester104 as a colorless oil that showed ir (neat): 2234, 1713, 1389, 1368, 1251 cm1;1H nmr(CDC13,400 MHz): 6 1.02 (d, 6H, CH(Cth)2, J= 7 Hz), 1.32 (t, 3H, OCH2CJj3J= 7 Hz), 1.88-1.99 (m, 1H, Cfl(CH3)2),2.24 (d, 2H, CCH2J= 7 Hz), 4.22 (q, 2H,OCH2,J= 7 Hz); 13C nmr (CDC13,50.3 MHz): 6 14.0, 22.0, 27.5, 27.7, 61.7, 74.0, 88.4,153.9. Exact mass calcd. for C9H 1402: 154.0994; found: 154.0997. Anal. calcd.:C 70.10, H 9.15; found: C 69.90, H 9.12.184Preparation of 1 -(tert-butvldimethvlsiloxv)-4-pentvne (ii6)t-BuMe2SiO’”N116To a stirred solution of imidazole (3.70 g, 54.3 mmol) and tert-butyldimethylsilylchloride (4.25 g, 28.2 mmol) in dry DMF (10 mL) at room temperature was addedcommercially available 4-pentyne-1-ol (115) (2.0 mL, 22 mmol). The resulting mixture wasstirred at room temperature for 16 h. Saturated aqueous NaHCO3 (10 mL) and Et20 (10 mL)were added, the phases were separated and the aqueous phase was extracted with Et20(3 x 20 mL). The combined organic extracts were washed with brine (2 x 60 mL), dried(MgSO4) and concentrated. Flash chromatography (150 g silica gel, 200: 3 petroleum etherEt20) of the residual oil, followed by concentration of the appropriate fractions anddistillation (65-90 oC/0.2 Torr) of the remaining liquid provided 4.0 g (95%) of the silylether 116, a colorless liquid that exhibited ir (neat): 3315, 2121, 1109, 632 cnr1;1H nmr(CDC13,400 MHz): 6 0.03 (s, 6H, Si(CH3)2,0.87 (s, 9H, C(CH3), 1.69 (quintet, 2H,CH2Ca2CH2, J= 7 Hz), 1.89 (t, 1H, CH, J= 2.5 Hz), 2.24 (td, 2H, CCH2J= 7, 2.5 Hz), 3.67 (t, 211, OCH2, J= 7 Hz); 13C nmr (CDC13,50.3 MHz): 6 -5.4, 14.8,18.2, 25.9, 31.5, 61.3, 68.2, 84.1. Exact mass calcd. for C7H13OSi (M - t-Bu):141.0736; found: 141.0728. Anal. calcd. forC11H22OSi: C 66.60, H 11.18; found:C 66.80, H 11.30.185eparation of methyl &(tert-buldimethvlsiloxv)-2-hexynoate (1O5’),32105To a cold (-78 OC), stirred solution of 1-(tert-butyldimethylsiloxy)-4-pentyne (116)(5.30 g, 26.7 mmol) in dry THF (50 mL) was added a solution of n-BuLi in hexanes(18.5 mL, 29.6 mmol). After the resulting solution had been stirred at -78 OC for 15 mmand at -20 °C for 1 h, methyl chioroformate (2.5 mL, 32 mmol) was added and the reactionmixture was stirred at -20 °C for 1 h and at room temperature for 1 h. Saturated aqueousNaHCO3 (25 niL) was added, the phases were separated and the aqueous phase wasextracted with Et20 (2 x 25 mL). The combined organic extracts were washed with brine(50 niL), dried (MgSO4) and concentrated. Distillation (80-100 OC/o.2 Torr) of the oil thusobtained, afforded 5.87 g (86%) of the ester 105 as a colorless oil that displayed ir (neat):2238, 1719, 1260, 1109, 1074 cm1;1H nnir (CDC13,400 MHz): 60.07 (s, 6H, Si(CH3)2,0.90 (s, 9H, C(CH3), 1.78 (quintet, 2H, CH2CthCH2, J= 7 Hz), 2.44 (t, 2H, CCH2,J= 7 Hz), 3.68 (t, 2H, OCH2J= 7 Hz), 3.75 (s, 3H, OCH3);1C nmr (CDC13,50.3 MHz):8 -5.4, 15.2, 18.2, 25.9, 30.6, 52.5, 61.1, 72.9, 89.5, 154.2. Exact mass calcd. forC12H21O3Si (M+ - Me): 241.1260; found: 241.1260. Anal. calcd. forC13H24O3Si:C 60.89 H 9.43; found: C 61.10, H 9.60.186eparation of methyl 6-chloro-2-hexvnoate (106106To a cold (-78 °C), stirred solution of commercially available 5-chloro-1-pentyne (118)(4.0 mL, 38 mmol) in dry THF (80 mL) was added a solution of MeLi in Et20 (26.0 mL,39.0 mmol). After the resulting solution had been stirred at -78 0C for 10 miii and at -20 OCfor 1 h, methyl chioroformate (3.6 mL, 47 mmol) was added and the resulting mixture wasstirred at -20 OC for 1 h and at room temperature for 1 h. Saturated aqueous NaHCO3(80 mL) was added, the phases were separated and the aqueous phase was extracted withEt20 (2 x 40 mL). The combined organic extracts were washed with brine (50 mL), dried(MgSO4) and concentrated. Distillation (60-80 °C/0.3 Torr) of the acquired liquid over basicalumina provided 5.24 g (87%) of the ester 106, a colorless oil that showed ir (neat): 2240,1718, 1262 cm1;1H nrnr (CDC13,400 MHz): 82.04 (quintet, 2H, CH2CaCH J= 7 Hz),2.55 (t, 2H, CCH2J= 7 Hz), 3.65 (t, 2H, CH21, J= 7 Hz), 3.78 (s, 3H, OCH3);13C nmr (CDC13,50.3 MHz): 8 16.0, 30.2, 43.2, 52.3, 73.6, 87.4, 153.9. Exact masscalcd. forC7H935102:160.0292; found: 160.0282. Anal. calcd. forC7H91O2:C 52.35,H 5.65, Cl 22.08; found: C 52.42, H 5.72, Cl 21.90.187Preparation of methyl 6-iodo-2-hexynoate (j97)33CO2Me107A stirred solution of methyl 6-chloro-2-hexynoate (106) (4.23 g, 26.3 mmol) and Nal(16.0 g, 107 mmol) in dry acetone (100 mL) was refluxed for 19 h. Solvent was removed.H20 (30 mL) and Et20 (90 mL) were added to the residual material. The phases wereseparated and the organic phase was dried (MgSO4) and concentrated. Distillation(100-130 OC/0.3 Torr) of the remaining liquid over basic alumina yielded 5.97 g (90%) ofthe ester 107 as a colorless liquid that displayed ir (neat): 2239, 1719, 1435, 1263, 1222,1078 cm1;1H nmr (CDC13,400 MHz): 6 2.05 (quintet, 2H, CHthCH J= 7 Hz),2.49 (t, 2H, CCH2J= 7 Hz), 3.28 (t, 2H, =CH2I, J= 7 Hz), 3.75 (s, 3H, OCH3);l3 nmr (CDC13, 50.3 MHz): 6 4.3, 19.7, 30.9, 52.6, 73.7, 87.2, 153.9. Exact masscalcd. forC7H9102:251.9648; found: 251.9651. Anal. calcd.: C 33.36, H 3.60, I 50.35;found: C 33.19, H 3.66, I 50.14.1883. Preparation of lithium (irialkylstannvfl(cvano’)cupratesPreparation of lithium (trimethylstannyfl(cvano)cuprate35[Me3SnCuCN]Li123To a cold (-20 °C), stirred solution of hexamethylditin (1 equiv) in dry THF (—10 niLper mmol of hexamethylditin) was added a solution of MeLi (1 equiv) in Et20. After the paleyellow solution of trimethylstannyllithium39had been stirred at -20 °C for 20 mm, it wascooled to -48 OC (—5 mm) and solid CuCN (1 equiv) was added in one portion. The mixturewas stirred at -48 OC for 20 mm to produce a red solution of the lithium (trimethyistannyl)(cyano)cuprate (123).Preparation of lithium (trinbutvlstannvfl(cvanocuprate3S[n-Bu3S CuCN]Li304To a cold (-20 OC), stirred solution of hexa-n-butylditin (1 equiv) in dry THF (—10 niLper mmol of hexa-n-butylditin) was added a solution of n-BuLl (1 equiv) in hexanes. Afterthe pale yellow solution of tri-n-butylstannyllithium39had been stirred at -20 °C for 20 mm,it was cooled to -48 OC (—5 mm) and solid CuCN (1 equiv) was added in one portion. Themixture was stirred at -48 OC for 20 mm to produce a red solution of the lithium (tri-n-butylstannyl)(cyano)cuprate (304).1894. Preparation of alkvl (E’)-3-trimethylstannvl-2-alkenoates29General procedure 1R’ C02RR1___________—= C02RMe3Sn100 89To a cold (-78 OC), stirred solution of [Me3SnCuCNJLi (123) (1.3-1.5 equiv) in dryTHF (—5 mL per mmol of the cuprate) was added dry EtOH (1.3-1.5 equiv for ethyl estersubstrates) or dry MeOH (1.3-1.5 equiv for methyl ester substrates). After 5 mm, a solutionof the substrate a,J3-acetylenic ester 100 (1 equiv) in dry THF (—1 niL per mmol of the estersubstrate) was added dropwise over a period of 2 mm and the mixture was stirred at -78 OCfor 4-8 h. AqueousNH4C1-NHO (pH = 8) (one-half the volume of the total volume ofthe reaction mixture) was added. The mixture was opened to the atmosphere, was allowed towarm to room temperature and was stirred vigorously until the aqueous phase became deepblue. The phases were separated and the aqueous phase was extracted three times with Et20.The combined organic extracts were washed with brine, dried (MgSO4) and concentrated.The crude product was purified by flash chromatography on silica gel, followed bydistillation of the acquired liquid.190Preparation of ethyl (E-3-trimethylstannyl-2-butenoate ({37)35jDO2EtMe3Sn137Following general procedure 1 (p 189), commercially available ethyl 2-butynoate (101)was converted into ethyl (E)-3-trimethylstannyl-2-butenoate (137) with the followingamounts of reagents and solvents: [Me3SnCuCN]Li (123), 3.15 mmol, in THF, 16 mL;EtOH, 0.19 mL (3.2 mmol); ethyl 2-butynoate (101), 272 mg (2.43 mmol), in THF,2.4 mL. In this experiment, the reaction time was 4 h. Flash chromatography (45 g silicagel, 200 : 3 petroleum ether-Et20) of the crude product and distillation (46-59 OC/0.6 Torr)of the acquired liquid provided 526 mg (78%) of the ester 137, a colorless liquid thatexhibited ir (neat): 1714, 1604, 1177, 771 cm1; ‘H nmr (CDC13,400 MHz): 60.17 (s, 9H,Sn(CH3)3,2Sn-H 54 Hz), 1.27 (t, 3H, OCH2Cjj3J= 7 Hz), 2.37 (d, 3H, =CCH3J= 2 Hz, 3Sn-H 50 Hz), 4.14 (q, 2H, OCH2J= 7 Hz), 5.96 (q, 1H, =CH, J= 2 Hz,3Sn-H= 72 Hz); 13C nmr (CDC13,50.3 MHz): 6 -10.1, 14.3, 21.4, 59.5, 127.9, 164.5,168.1. Exact mass calcd. forC8H15O2Sn (M - Me): 263.0094; found: 263.0090. Anal.calcd. forC9H18O2Sn: C 39.04, H 6.55; found: C 38.88, H 6.59.191epation of ethyl (-3-methylstannyl-2-ntenoate ‘125)29,35__>,CO2EtMe3Sn125Following general procedure 1 (p 189), commercially available ethyl 2-pentynoate (102)was converted into ethyl (E)-3-trimethylstannyl-2-pentenoate (125) with the followingquantities of reagents and solvents: [Me3SnCuCNjLi (123), 64.4 mmol, in THF, 200 mL;EtOH, 3.8 mL (65 mmol); ethyl 2-pentynoate (102), 6.25 g (49.5 mmol), in THF, 30 niL.In this experiment, the reaction time was 4 h. Flash chromatography (250 g silica gel,200: 3 petroleum ether-Et20) of the crude product and distillation (50-70 oc/o.6 Toff) ofthe oil thus obtained, gave 10.7 g (74%) of the ester 125 as a colorless oil that showedir (neat): 1718, 1598, 1179, 774 cur1; 1H nmr (CDC13, 400 MHz): 8 0.21 (s, 9H,Sn(CH3)3,2JSn-H= 53 Hz), 1.05 (t, 3H, =CCH2CU3, J= 8 Hz), 1.29 (t, 3H, OCH2Ca3,J= 7 Hz), 2.89 (qd, 2H, =CCH2, J= 8, 1 Hz,3Sn-H= 64 Hz), 4.16 (q, 2H, OCH2J= 7 Hz), 5.94 (t, 1H, =CH, J= 1 Hz,3SnH= 74 Hz); 13C nnir (CDC13, 50.3 MHz):8 -9.1, 14.1, 14.3, 27.9, 59.6, 126.9, 164.3, 174.5. Exact mass calcd. forC9H17O2Sn(M - Me): 277.0250; found: 277.0250. Anal. calcd. for C1OH2002Sn: C 41.28, H 6.93;found: C 41.08, H 6.87.192Preparation of methyl (E)-4-cvclopropyl-3-trimethylstannvl-2-butenoate (138__)JCO2MeMe3Sn138Following general procedure 1 (p 189), methyl 4-cyclopropyl-2-butynoate (103) wasconverted into methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138) with thefollowing amounts of reagents and solvents: [Me3SnCuCN]Li (123), 11.5 mmol, in THF,75 mL; MeOH, 0.65 mL (11 mmol); methyl 4-cyclopropyl-2-butynoate (103), 1.05 g(7.60 mmol), in THF, 7.5 mL. In this experiment, the reaction time was 7 h. Flashchromatography (180 g silica gel, 200 : 3 petroleum ether-Et20) of the crude product anddistillation (80-90 OC/0.2 Torr) of the remaining oil provided 1.83 g (80%) of the ester 138,a colorless liquid that displayed ir (neat): 1719, 1594, 1172, 773 cur1;1H nnir (CDC13,400 MHz): 8 0.15-0.19 (m, 2H, cyclopropyl methylene protons), 0.23 (s, 9H, Sn(CH3)3,2SnH 53 Hz), 0.42-0.50 (m, 211, cyclopropyl methylene protons), 0.70-0.82 (m, 1H,cyclopropyl methine proton), 2.83 (dd, 2H, =CCH2J= 7, 1 Hz,3Sn-H= 58 Hz),3.68 (s, 3H, OCH3), 5.99 (t, 1H, =CH, J= 1 Hz, 3Sn-H 74 Hz); 13C nmr (CDC13,50.3 MHz): 8 -8.6, 5.0, 11.3, 39.2, 50.8, 126.7, 164.8, 173.0. Exact mass calcd. forC10H7O2Sn (M - Me): 289.0250; found: 289.0251. Anal. calcd. forC11H2002Sn:C 43.61, H 6.65; found: C 43.68, H 6.53.193parution of ethyl E-5-methyl-3-ü-imethylstannyl-2-hexenoate (139>_>JCO2EtMe3Sn139Following general procedure 1 (p 189), ethyl 5-methyl-2-hexynoate (104) wasconverted into ethyl (E)-5-methyl-3-trimethylstannyl-2-hexenoate (139) with the followingquantities of reagents and solvents: [Me3SnCuCN]Li (123), 24.3 mmol, in THF, 200 mL;EtOH, 1.5 mL (26 mmol); ethyl 5-methyl-2-hexynoate (104), 2.40 g (15.6 mmol), in THF,20 mL. In this experiment, the reaction time was 6 h. Flash chromatography (200 g silicagel, 200: 3 petroleum ether-Et20) of the crude product and distillation (65-85 OC/0.6 Torr)of the liquid thus obtained, afforded 4.18 g (84%) of the ester 139 as a colorless oil thatexhibited ir (neat): 1718, 1598, 1385, 1367, 1176, 771 cnr1;1H nmr (CDC13,400 MHz):o 0.21 (s, 9H, Sn(CH3)3,2Sn..H= 54 Hz), 0.93 (d, 6H, CH(Ca3)2, J= 7 Hz), 1.30 (t, 3H,OCH2Cth, J= 7 Hz), 1.67-1.78 (m, 1H, CH(CH3)2), 2.85 (dd, 2H, =CCH2J= 7, 1 Hz,3.1SnH 63 Hz), 4.17 (q, 2H, OCH2 J= 7 Hz), 6.03 (t, 1H, =CH, J= 1 Hz,3Sn-H 76 Hz); 13C nmr (CDC13,50.3 MHz): 3 -9.0, 14.3, 22.5, 29.1, 43.2, 59.6,128.4, 164.5, 172.5. Exact mass calcd. for C11H2O2Sn (M - Me): 305.0564; found:305.0557. Anal. calcd. forC12H24OSn: C 45.18, H 7.58; found: C 44.99, H 7.57.194Preparation of methyl (E)-6-(tert-butyldimethylsiloxy)-3-trimethylstannyl-2-hexenoate(141)29t-BuMe2SiO\\_>_JCO2MeMe3Sn141Following general procedure 1 (p 189), methyl 6-Qert-butyldimethylsioxy)-2-hexynoate(105) was converted into methyl (E)-6-Qert-butyldimethylsiloxy)-3-thmethylstannyl-2-hexenoate (141) with the following amounts of reagents and solvents: [MeSnCuCNJL1(123), 1.78 mmol, in THE, 9.0 mL; MeOH, 75 L (1.9 mmol); methyl 6-Qert-butyldimethylsiloxy)-2-hexynoate (105), 312 mg (1.37 mmol), in THE, 1.4 mL. In thisexperiment, the reaction time was 4 h. Flash chromatography (30 g silica gel, 200: 3petroleum ether-Et20)of the crude product and distillation (110-130 OC/0.6 Torr) of theacquired liquid produced 446 mg (77%) of the ester 141, a colorless oil that showedir (neat): 1720, 1597, 1256, 1169, 1098, 838, 776 cm1;1H nmr (CDC13,400 MHz):8 0.05 (s, 6H, Si(CH3)2), 0.21 (s, 9H, Sn(CH3)2Sn-H= 54 Hz), 0.90 (s, 9H,C(CH3), 1.58-1.67 (m, 2H, CHa), 2.95 (br t, 2H, =CCH2J= 8 Hz,3Sn-H= 62 Hz), 3.64 (t, 2H, OCH2, J= 6 Hz), 3.69 (s, 3H, OCH3), 5.98 (br s, 1H,=CH,3Sn-H 73 Hz); 1C nmr (CDC13,50.3 MHz): 8 -9.1, -5.7, 18.3, 25.9, 31.5, 32.8,50.8, 63.0, 127.2, 164.6, 173.3. Exact mass calcd. forC15H31OSiSn (M+ - Me):407.1065; found: 407.1070. Anal. calcd. forC16H34OSiSn: C 45.62, H 8.14; found:C 45.80, H 8.08.1955. Preparation of ethyl (Z)-3-triallcylstannyl-2-pentenoates29General procedure 2= CO2Et CO2Et102 124 R=Me295 R=n-BuTo a cold (-48 OC), stirred solution of [R3SnCuCN]Li [123 (R = Me) or 304R = (n-Bu), —1.1 equiv) in dry THF (—5 mL per mmol of the cuprate) was added dropwisea solution of commercially available ethyl 2-pentynoate (102) (1 equiv) in dry THF (—1 mLper mmol of the ester substrate). The mixture was stirred at -48 OC, at 0 OC, and, ifnecessary, at room temperature. Aqueous NH4C1-NH4OH (pH =8) (one-half the volume ofthe total volume of the reaction mixture) was added. The mixture was opened to theatmosphere, was allowed to warm to room temperature and then was stirred until the aqueousphase became deep blue. The phases were separated and the aqueous layer was extractedthree times with Et20. The combined organic extracts were washed with brine, dried(MgSO4) and concentrated. The crude product was purified by sequential chromatographyon silica gel and distillation.196eparation of ethyl (-3-thmethylstannyl-2-pentenoate (12429,35-)=\\Me3Sn CO2Et124Following general procedure 2 (p 195), commercially available ethyl 2-pentynoate (102)was converted into ethyl (Z)-3-trimethylstannyl-2-pentenoate (124) with the followingquantities of reagents and solvents: [Me3SnCuCN]Li (123), 4.38 mmol, in THF, 20 mL;ethyl 2-pentynoate (102), 507 mg (4.02 mmol), in THF, 4.0 mL. In this experiment, thereaction mixture was stirred at -48 OC for 2 h and at 0 OC for 2 h. Flash chromatography(80 g silica gel, 200 : 3 petroleum ether-Et20) of the crude product and distillation(54-84 OC/0.6 Torr) of the oil thus obtained, afforded 843 mg (72%) of the ester 124, acolorless oil that displayed ir (neat): 1703, 1601, 1201, 772 cm1; 1H nmr (CDC13,400 MHz): 3 0.18 (s, 9H, Sn(CH3)3,2Sn-H 55 Hz), 1.04 (t, 3H, =CCH2CJj3J= 7 Hz),1.29 (t, 3H, OCH2CTh, J= 7 Hz), 2.45 (qd, 2H, =CCH2J= 7, 1.5 Hz,3Sn-H= 43 Hz),4.18 (q, 2H, OCH2, J= 7 Hz), 6.36 (t, 1H, =CH, J= 1.5 Hz,3SnH= 120 Hz); 13C nmr(CDC13, 50.3 MHz): 6 -7.5, 13.6, 14.3, 32.9, 60.2, 126.9, 168.1, 177.1. Exact masscalcd. forC9H17O2Sn (M - Me): 277.0250; found: 277.0244. Anal. calcd. forC1OH2002Sn: C 41.28, H 6.93; found: C 41.47, H 7.09.197Preparation of ethyl (Z)-3-(tri-n-butylstannvfl-2-pentenoate (225)n-Bu3Sn CO2Et295Following general procedure 2 (p 195), commercially available ethyl 2-pentynoate (102)was converted into ethyl (Z)-3-(tri-n-butylstannyl)-2-pentenoate (295) with the followingamounts of reagents and solvents: [n-Bu3SnCuCNJLi (304), 4.15 mmol, in T.HF, 21 mL;ethyl 2-pentynoate (102), 505 mg (4.00 mmol), in THF, 3.0 mL. In this experiment, thereaction mixture was stirred at -48 0C for 1.5 h, at 0 OC for 2.5 h and at room temperature for0.5 h. Radial chromatography (4 mm silica gel plate, 15: 1 petroleum ether-CH2C12) of thecrude product and distillation (130-170 Oc/O.3 Torr) of the acquired oil provided 1.20 g(72%) of the ester 295 as a colorless oil that exhibited ir (neat): 1704, 1599, 1326, 1196,876 cur1;1H nmr (CDC13, 400 MHz): 6 0.86 (t, 9H, J= 7.5 Hz), 0.90-0.97 (m, 6H),1.02 (t, 3H, =CCH2CIL3, .1= 7.5 Hz), 1.22-1.33 (m, 9H includes OCH2Cth: t centered at1.26, 3H, J= 7 Hz), 1.35-1.55 (m, 6H), 2.40 (qd, 2H, =CCH2J= 7.5, 1.5 Hz), 4.16 (q,2H, OCH2J= 7 Hz), 6.36 (t, 1H, =CH, J= 1.5 Hz,3JSn-H= 109 Hz); irradiation at 6 1.02simplified the qd at 62.40 to a d (J= 1.5 Hz,3JSn-H= 39 Hz); irradiation at 6 1.26 simplifiedthe q at 64.16 to a s; irradiation at 6 2.40 simplified the t at 6 1.02 to a s; 13C nmr (CDC13,100.6 MHz): 6 11.0, 13.65, 13.7, 14.3, 27.5, 29.2, 33.2, 60.1, 127.2, 168.1, 177.3.Exact mass calcd. forC15H29O2Sn (M - n-Bu): 361.1191; found: 361.1190. Anal. calcd.forC19H38O2Sn: C 54.70, H 9.18; found: C 54.72, H 9.09.1986. Preparation of allcvl (Z)-2.3-bis(trimethvlstannvl)-2-alkenoates3General procedure 3R1 Me3Sn SnMe3El C02R__.)—_OH280To a cold (-78 OC), stirred solution of ethyl (Z)-3-iodo-2-butenoate (279) (1.86 g,7.75 mmol) in dry Et20 (50 mL) was added a 1.0 M solution of i-Bu2A1H (22 mL,22 mmol) in hexanes and the resulting clear solution was stirred at -78 OC for 10 miii and at0 OC for 1.5 h. AqueousNB4C1-NHOH(pH =8) (5 niL) was added and the white slurrywas allowed to stir at room temperature for 1 h. Solid MgSO4 (—0.5 g) was added and theslurry was filtered through a column of Florisil® (16.5 g). The column was washed withEt20 (3 x 50 niL). The combined filtrate was concentrated and the crude product waspurified by radial chromatography (4 mm silica gel plate, 2: 1 petroleum ether-Et20).Concentration of the appropriate fractions and distillation (40-60 °CI0. 15 Torr) of the residualoil over basic alumina, afforded 1.38 g (90%) of the alcohol 280 as a colorless oil thatexhibited ir (neat): 3370 (br), 1651, 1427, 1076, 1010 cm-1;1H nmr (CDC13,400 MHz):3 1.57 (br s, 1H, CH2OU, exchanges with D20), 2.52 (q, 3H, =CCH3J= 1.5 Hz),4.14 (br m, 2H, CthOH, wl/2= 13 Hz), 5.77 (tq, 1H, =CH, J= 6, 1.5 Hz); 13C nmr(CDC13, 50.3 MHz): 3 33.6, 67.2, 101.8, 134.1. Exact mass calcd. forC4H710: 197.9542;found: 197.9546. Anal. calcd.: C 24.26, H 3.56, I 64.09; found: C 24.25, H 3.55, I 63.88.232Preparation of (Z’)-3-iodo- 1-bromo-2-butene (275)275To a cold (0 OC), stirred solution of Ph3 (1.69 g, 6.44 mmol) in dry CH21 (50 niL)was added a solution of bromine (1.02 g, 6.38 mmol) in dry CH21 (3.0 mL). To theresulting pale yellow solution at 0 °C, a few crystals of PPh3 were added until the solutionturned colorless. Stirring was continued at 0 0C for 5 mm. A solution of (Z)-3-iodo-2-buten-1-ol (280) (1.21 g, 5.04 mmol) in dry CH21 (2.0 mL) was added and the resultingmixture was stirred at 0 0C for 5 mm and at room temperature for 1 h. The mixture wasconcentrated (to —3 mL) and was then poured into stirred n-pentane (45 mL). The resultingslurry was filtered through a column of Florisil® (7 g) and the column was washed withn-pentane (3 x 15 mL). Concentration of the combined eluate and distillation(30-50 OC/0.15 Torr) of the residual oil over basic alumina provided 1.23 g (93%) of thealkene 275 as a colorless oil that exhibited ir (neat): 1640, 1426, 1293, 1203, 1166,1068 cm1;1H nmr (CDC13,400 MHz): 6 2.59 (s, 3H, =CCH3), 3.98 (d, 2H, CthBr,J= 7.5 Hz), 5.78 (t, 1H, =CH, J= 7.5 Hz); 3C nmr (CDC13, 50.3 MHz): 6 33.7, 35.7,107.4, 131.1. Exact mass calcd. for C4H679BrI: 259.8698; found: 259.8701. Anal. calcd.for C4H6BrI: C 18.41, H 2.32; found: C 18.48, H 2.27.2339. Preparation of a-allcylated esters and related derivativesDeconiuation-a11cvlation of alkyl (E)-3-trimethylstannvl-2-allcenoates (125. 137. 138 and141). ethyl (Z)-3-trialkylstannvl-2-pentenoates (124. 295. ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (158) and methyl 2-trimethvlstannyl- 1 -cyclopentenecarboxylate (258) 13.2SGeneral procedure 10R’Me3Sn125, 137, 138 and 141y%-CO2EtSnMe158R20CR3X Me3Sn206X = Br or IR3Sn CO2Et124 and 295SnMe3CO2Me258SnMe3260n = 1, 2 or 3To a cold (-78 OC), stirred solution of LDA (—1.3 equiv) in dry THF (—5 mL per mmolof the LDA) was added dry HMPA (—1.3 equiv). After the mixture had been stirred at -78 °Cfor 5 mm, a solution of ailcyl (E)-3-trimethylstannyl-2-alkenoate (125, 137, 138 or 141),ethyl (Z)-3-trialkylstannyl-2-pentenoate (124 or 295), ethyl (Z)-5-methyl-3-trimethyl-234stannyl-3-hexenoate (158) or methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258)(1 equiv) in dry THF (—1 mL per mmol of the ester) was added dropwise over a period of—2 miii. The resulting yellow solution was stirred at -78 OC for 30 miii and at 0 0C for30 mm. After the reaction mixture had been cooled to -20 °C (—5 mm), a solution of aikylhalide (—1.3-1.5 equiv) in dry THF (—1 mL per mmol of the ailcyl halide) was added quicklyto the vigorously stirred solution. The mixture was stirred at -20 °C for 1 h. Saturatedaqueous NaHCO3 (one-half the volume of the total volume of the reaction mixture) wasadded. The phases were separated and the aqueous phase was extracted three times withEt20. The combined organic extracts were washed with brine, dried (MgSO4) andconcentrated. Flash or radial chromatography of the remaining oil on silica gel, followed byconcentration of the appropriate fractions and removal of traces of solvent (vacuum pump)provided the a-alkylated ester of general structure 206 or 260.235Preparation of ethyl 5-bromo-2-fl -(trimethylstannyl)ethenyll-5-hexenoate (4Oal3aEtO2C HbBr Me3Sn40aFollowing general procedure 10 (pp 233-234), ethyl (E)-3-trimethylstannyl-2-butenoate(137) was converted into the diene ester 40a with the following amounts of reagents andsolvents: LDA, 1.68 mmol, in THE, 5.5 mL; HMPA, 0.29 mL (1.7 mmol); ethyl (E)-3-trimethylstannyl-2-butenoate (137), 380 mg (1.37 mmol), in THE, 1.5 mL; 2-bromo-4-iodo-1-butene (148), 509 mg (1.95 mmol), in THF, 1.5 mL. Flash chromatography (45 gsilica gel, 200: 3 petroleum ether-Et20) of the crude product, followed by concentration ofthe appropriate fractions and removal of traces of solvent (vacuum pump) provided 454 mg(8 1%) of the diene ester 40a, a colorless liquid that displayed ir (neat): 1729, 1630, 1177,772 cm1;1H nmr (CDC13,400 MHz): 6 0.19 (s, 9H, Sn(CH3)3,2SnH= 53 Hz), 1.27 (t,3H, OCH2Cjj3J= 7 Hz), 1.68-1.80 (m, 1H, CH2IIH), 2.0 1-2.13 (m, 1H,CH2jjH), 2.32-2.48 (m, 2H, =CBrCH2), 3.19 (t, 1H, CHC=O, J= 7 Hz,3Sn-H 67 Hz), 4.13 (q, 2H, OCH2,J 7 Hz), 5.35 (d, 1H, Ha, J 2 Hz,3jSnH67 Hz), 5.42 (d, 1H, BrC=CH2, J= 2 Hz), 5.58 (d, 1H, BrC=CH2, J= 2 Hz),5.78 (d, 1H, Hb, J= 2 Hz,3SnH= 139 Hz); 13C nmr (CDC13,50.3 MHz): 6 -8.2, 14.2,30.8, 39.0, 55.2, 60.6, 117.2, 128.3, 133.5, 153.1, 174.1. Exact mass calcd. forC12H2079BrOSn(M - Me): 394.9669; found: 394.9668. Anal. calcd. forC13H2BrOSn:C 38.09, H 5.66, Br 19.49; found: C 38.20, H 5.81, Br 19.33.236paration of ethyl 5-bromo-2-[(Z- 1 -ffimethylsnnyl-1-propenyll-5-hexenoate 2O7)13aEtO2CBr Me3Sn207Following general procedure lO(pp 233-234), ethyl (E)-3-trimethylstannyl-2-pentenoate(125) was converted into the diene ester 207 with the following amounts of reagents andsolvents: LDA, 2.25 mmol, in THF, 10 mL; HMPA, 0.39 mL (2.2 mmol); ethyl (E)-3-trimethylstannyl-2-pentenoate (125), 502 mg (1.72 mmol), in THF, 2.0 mL; 2-bromo-4-iodo-1-butene (148), 672 mg (2.58 mmol), in THF, 2.0 mL. Flash chromatography (45 gsilica gel, 200: 3 petroleum ether-Et20) of the crude product, followed by concentration ofthe appropriate fractions and removal of traces of solvent (vacuum pump) produced 546 mg(75%) of the diene ester 207, a colorless liquid that exhibited ir (neat): 1729, 1629, 1177,772 cm-1;1H nmr (CDC13,400 MHz): 5 0.23 (s, 9H, Sn(CH3)3,2Sn-H= 55 Hz), 1.25 (t,3H, OCH2CIj3J= 7 Hz), 1.67-1.80 (m, 1H, CH2LbCH), 1.77 (d, 3H, =CHCH,J= 7 Hz), 2.05-2.16 (m, 1H, CH2CthCH), 2.32-2.46 (m, 2H, =CBrCH2), 3.08 (dd, 1H,CHC=O, J= 9, 6 Hz,3’Sn-H 69 Hz), 4.13 (q, 2H, OCH2J= 7 Hz), 5.42 (d, 1H, =CH2,J= 1 Hz), 5.56 (d, 1H, =CH2J= 1 Hz), 6.13 (q, 1H, =CflCH31= 3Sn-H= 132 Hz);13C nmr (CDC13, 50.3 MHz): 8 -7.3, 14.2, 19.3, 30.4, 39.4, 54.3, 60.5, 117.0, 133.8,137.8, 142.6, 174.5. Exact mass calcd. forC13H2279BrOSn(M - Me): 408.9825; found:408.9826. Anal. calcd. forC14H25BrOSn: C 39.66, H 5.94, Br 18.85; found: C 39.89,H 6.06, Br 19.00.237Preparation of ethyl 5-bromo-2-lIE-1 -irimethyistannyl-1-propenyll-5-hexenoate (20813aFollowing general procedure 10 (pp 233-234), ethyl (Z)-3-trimethylstannyl-2-pentenoate(124) was converted into the diene ester 208 with the following amounts of reagents andsolvents: LDA, 2.57 mmol, in THF, 12 mL; HMPA, 0.45 mL (2.6 mmol); ethyl (Z)-3-trimethylstannyl-2-pentenoate (124), 566 mg (1.95 mmol), in THE, 2.0 mL; 2-bromo-4-iodo-1-butene (148), 732 mg (2.80 mmol), in THE, 2.0 mL. Flash chromatography (45 gsilica gel, 200: 3 petroleum ether-Et20) of the crude product, followed by concentration ofthe appropriate fractions and removal of traces of solvent (vacuum pump) yielded 709 mg(86%) of the diene ester 208, a colorless liquid that showed ir (neat): 1728, 1630, 1178,770 cur1;1H nmr (cDC13,400 MHz): 8 0.14 (s, 9H, Sn(CH3)3,2SnH= 52 Hz), 1.26 (t,3H, OCH2CJJ.3J= 7 Hz), 1.64-1.73 (m, 1H, CH2aH), 1.77 (d, 3H, =CHCIj3J= 7 Hz), 2.03-2.13 (m, 1H, CH2CjbCH), 2.32-2.48 (m, 2H, =CBrCH2), 3.68 (hr t,1H, CHC=O, J= 7 Hz,3Sn.H= 80 Hz), 4.13 (q, 2H, OCH2J= 7 Hz), 5.43 (d, 1H, =CH2J= 1.5 Hz), 5.58 (d, 1H, =CH2J= 1.5 Hz), 5.86 (qd, 1H, =CRCH3, J= 7, 1 Hz,3Sn-H Hz); ‘3C nmr (CDC13,50.3 MHz): 8 -7.6, 14.2, 14.9, 31.3, 39.0, 46.7, 60.6,117.1, 133.7, 137.6, 143.2, 174.6. Exact mass calcd. for C13H2279BrOSn(M+ - Me):408.9825; found: 408.9822. Anal. calcd. forC14H25BrOSn: C 39.66, H 5.94, Br 18.85;found: C 39.79, H 6.02, Br 18.90.208238Preparation of ethyl (Z-5-iodo-2-[(Z)- 1 -trimethvlstannyl- 1 -propenyll-5-heptenoate (205EtO2CI Me3Sn205Following general procedure 10 (pp 233-234), ethyl (E)-3-trimethylstannyl-2-pentenoate(125) was converted into the diene ester 205 with the following amounts of reagents andsolvents: LDA, 2.71 mmol, in THF, 13 mL; HMPA, 0.47 mL (2.7 nimol); ethyl (E)-3-trimethylstannyl-2-pentenoate (125), 615 mg (2.11 mmol), in THF, 2.0 mL; (Z)-3,5-diiodo-2-pentene (198), 980 mg (3.04 mmol), in THF, 2.0 mL. Flash chromatography (45 gsilica gel, 200: 3 petroleum ether-Et20) of the crude product, followed by concentration ofthe appropriate fractions and removal of traces of solvent (vacuum pump) afforded 910 mg(89%) of the diene ester 205, a colorless oil that displayed ir (neat): 1728, 1648, 1620,1162, 771 cm1;1H nmr (CDC13,400 MHz): 6 0.21 (s, 9H, Sn(CH3)2SnH= 52 Hz),1.24 (t, 3H, OCH2CIj3J= 7 Hz), 1.65-1.74 (m, 1H, CH2IjH), 1.73 (d, 3H,=CHCTh, J= 7 Hz), 1.77 (d, 3H, =CHCth, J= 7 Hz), 2.01-2.10 (m, 1H, CH2CthCH),2.38-2.49 (m, 2H, =CICH2),3.06 (dd, 1H, CHC=O, J= 9, 7 Hz,3Jsfl..H=70 Hz), 4.11 (q,2H, OCH2J= 7 Hz), 5.54 (qt, 1H, IC=CH, J= 7, 1 Hz), 6.09 (br q, 1H, SnC=CH,J 7 Hz, 3Sn-H 132 Hz); 13C nmr (CDC13,50.3 MHz): 3 -7.2, 14.3, 19.4, 22.1, 31.9,43.1, 54.1, 60.5, 109.9, 130.2, 137.6, 142.8, 174.6. Exact mass calcd. for C14H24IO2Sn(M - Me): 470.9843; found: 470.9847. Anal. calcd. forC1SH27IO2n: C 37.15, H 5.61,I 26.17; found: C 37.30, H 5.60, I 25.95.239Preparation of ethyl (Z)-5-iodo-2-F(E)- 1 -trimethyistannyl- 1-propenyll-5-heptenoate (209)I Me3Sn209Following general procedure 10 (pp 233-234), ethyl (Z)-3-trimethylstannyl-2-pentenoate(124) was converted into the diene ester 209 with the following amounts of reagents andsolvents: LDA, 1.92 mmol, in THF, 8.0 mL; HMPA, 0.34 mL (2.0 mmol); ethyl (Z)-3-trimethylstannyl-2-pentenoate (124), 434 mg (1.49 mmol), in THF, 1.5 mL; (Z)-3,5-diiodo-2-pentene (198), 650 mg (2.02 mmol), in THF, 1.4 mL. Flash chromatography (45 gsilica gel, 200: 3 petroleum ether-Et20) of the crude product, followed by concentration ofthe appropriate fractions and removal of traces of solvent (vacuum pump) gave 642 mg (89%)of the diene ester 209, a colorless oil that displayed ir (neat): 1728, 1648, 1187, 769 cm1;nmr (CDC13, 400 MHz): ö 0.14 (s, 9H, Sn(CH3)3,2SnH= 55 Hz), 1.25 (t, 3H,OCH2Cth, J= 7 Hz), 1.59-1.70 (m, 1H, CH2CthCH), 1.73 (d, 3H, =CHCth, J= 7 Hz),1.75 (d, 3H, =CHCE3, J= 7 Hz), 1.98-2.10 (m, 1H, CH2thCH), 2.37-2.52 (m, 2H,=CICH2), 3.65 (br t, 1H, CHC=O, J= 7 Hz,3Jsn..H= 84 Hz), 4.12 (q, 2H, OCH2J= 7 Hz), 5.56 (q, 1H, IC=CH, J= 7 Hz), 5.83 (qd, 1H, SnC=CH, J= 7, 1 Hz,3.1nW74 Hz); 13C nmr (CDC13,50.3 MHz): 8 -7.6, 14.3, 15.0, 22.1, 32.8, 42.7, 46.6,60.5, 109.8, 130.3, 137.3, 143.5, 174.7. Exact mass calcd. forC14H24IO2Sn (M+ - Me):470.9843; found: 470.9839. Anal. calcd. forC15H27IOSn: C 37.15, H 5.61, I 26.17;found: C 37.35, H 5.59, I 25.93.240eparation of ethyl (E-5-iodo-2-F(Z)- 1-methylstannyl- 1-propenyll-5-heptenoate (21I Me3Sn210Following general procedure 10 (pp 233-2342), ethyl (E)-3-trimethylstannyl-2-pentenoate (125) was converted into the diene ester 210 with the following amounts ofreagents and solvents: LDA, 3.25 mmol, in THE, 15 mL; HMPA, 0.57 mL (3.3 mmol); ethyl(E)-3-trimethylstannyl-2-pentenoate (125), 791 mg (2.72 mmol), in THE, 2.7 mL; (E)-3,5-dliodo-2-pentene (193), 1.14 g (3.54 mmol), in THE, 3.5 mL. Flash chromatography (45 gsilica gel, 200: 3 petroleum ether-Et20) of the crude product, followed by concentration ofthe appropriate fractions and removal of traces of solvent (vacuum pump) produced 1.21 g(92%) of the diene ester 210, a colorless oil that showed ir (neat): 1728, 1619, 1164,771 cm4;1H mm (CDC13,400 MHz): 6 0.24 (s, 9H, Sn(CH3)2Sn-H 53 Hz), 1.25 (t,3H, OCH2CIj31= 7 Hz), 1.61 (d, 3H, IC=CHCIj3J= 7 Hz), 1.63-1.72 (m, 1H,CH2CthCH), 1.77 (d, 311, SnC=CHCTh, J= 7 Hz), 1.98-2.09 (m, 1H, CH2CthCH),2.34 (t, 2H, =CICH2J= 7 Hz), 3.07 (t, 111, CHC=O, .1=7 Hz,3Sn-H= 69 Hz), 4.14 (q,2H, OCH2, .1=7Hz), 6.12 (br q, 1H, SnC=CH, .1=7 Hz,3Sn-H= 131 Hz), 6.24 (br q, 1H,IC=CH, J= 7Hz); in a decoupling experiment, inadiation at 66.12 simplified the doublet at8 1.77 to a singlet; 13C nmr (CDC13,50.3 MHz): 6 -7.1, 14.3, 16.3, 19.4, 31.3, 36.3,54.0, 60.6, 102.2, 136.0, 137.7, 142.9,. 174.6. Exact mass calcd. forC14H24IO2Sn(M- Me): 470.9843; found: 470.9839. Anal. calcd. for C1SH27IO2Sn: C 37.15, H 5.61,I 26.17; found: C 37.46, H 5.56, I 25.80.241Preparation of ethyl (E)-5-iodo-2-F(E’)-1 -trimethyistannyl- 1-propenvll-5-heptenoate (211)EtO2CL,%%rJI Me3Sn211Following general procedure 1O(pp 233-234), ethyl (Z)-3-trimethylstannyl-2-pentenoate(124) was converted into the diene ester 211 with the following amounts of reagents andsolvents: LDA, 3.25 mmol, in THF, 15 mL; HMPA, 0.57 mL (3.3 mmol); ethyl (Z)-3-trimethylstannyl-2-pentenoate (124), 806 mg (2.77 mmol), in THF, 2.8 mL; (E)-3,5-diiodo-2-pentene (193), 1.16 g (3.60 mmol), in THF, 3.6 mL. Flash chromatography (45 gsilica gel, 200: 3 petroleum ether-Et20) of the crude product, followed by concentration ofthe appropriate fractions and removal of traces of solvent (vacuum pump) provided 1.15 g(86%) of the diene ester 211, a colorless oil that displayed ir (neat): 1727, 1634, 1164,768 cm-1;1H nmr (CDC13,400 MHz): 6 0.13 (s, 9H, Sn(CH3)3,2SnH= 53 Hz), 1.24 (t,3H, OCH2Cfj3J= 7 Hz), 1.55-1.64 (m, 1H, CH2jC ), 1.60 (br d, 3H, IC=CHCj3J= 7 Hz), 1.74 (d, 3H, SnC=CHCJj3, J= 7 Hz), 1.94-2.04 (m, 1H, CH2jjH),2.26-2.42 (m, 2H, =CICH2), 3.64 (br t, 1H, CHC=O, J= 7 Hz,3JSn-H 84 Hz), 4.11 (q,2H, OCH2J= 7 Hz), 5.83 (qd, 1H, SnC=CH, J= 7, 1 Hz,3Sn-H= Hz), 6.22 (br q, 1H,IC=CH, J= 7 Hz); in a decoupling experiment, irradiation at 66.22 simplified the doublet at6 1.60 to a singlet; 13C nmr (CDC13, 50.3 MHz): 8 -7.6, 14.3, 15.0, 16.2, 32.4, 35.8,46.8, 60.6, 102.1, 136.1, 137.3, 143.5, 174.8. Exact mass calcd. forC14H24IO2Sn(M - Me): 470.9843; found: 470.9838. Anal. calcd. for C15H27IO2Sn: C 37.15, H 5.61,I 26.17; found: C 37.30, H 5.69, I 26.00.242Preparation of ethyl (E)-5-iodo-2-[(E)- 1 -ftri-n-butylstannyD- 1-propenyll-5-heptenoate (296)EtO2CI n-BuSn296Following general procedure 10 (pp 233-234), ethyl (Z)-3-(tri-n-butylstannyl)-2-pentenoate (295) was converted into the diene ester 296 with the following amounts ofreagents and solvents: LDA, 1.99 mmol, in THE, 8.0 mL; HMPA, 0.43 mL (2.5 mmol);ethyl (Z)-3-(tri-n-butylstannyl)-2-pentenoate (295), 630 mg (1.51 mmol), in THF, 2.0 mL;(E)-3,5-diiodo-2-pentene (193), 730 mg (2.27 mmol), in THF, 2.0 mL. Radialchromatography (4 mm silica gel plate, 15 :2 petroleum ether-CH2C12) of the crude product,followed by concentration of the appropriate fractions and removal of traces of solvent(vacuum pump) yielded 765 mg (83%) of the diene ester 296, a colorless oil that displayedir (neat): 1728, 1634, 1163 cm1;1H nmr (CDC13,400 MHz): 6 0.77-0.99 (m, 15H),1.18-1.34 (m, 9H), 1.36-1.48 (m, 6H), 1.50-1.62 (m, 1H, CH2CthCH), 1.58 (d, 3H,IC=CHCa3, J= 7 Hz), 1.76 (d, 3H, SnC=CHCth, J= 7 Hz), 1.93-2.05 (m, 1H,CH2IjH), 2.26-2.43 (m, 2H, =CICH2), 3.62 (br t, 1H, CHC=O, J= 7 Hz,3JSn-H 77 Hz), 4.08 (q, 2H, OCH2J= 7 Hz), 5.77 (qd, 1H, SnC=CH, J= 7, 1 Hz,3jSnH65 Hz), 6.23 (q, 1H, IC=CH, J= 7 Hz); in a decoupling experiment, irradiation at6 5.77 simplified the doublet at 6 1.76 to a singlet 1C nmr (CDC13,50.3 MHz): 8 10.8,13.7, 14.2, 15.1, 16.2, 27.5, 29.1, 32.4, 35.8, 46.8, 60.5, 102.3, 136.1, 137.6, 143.0,174.7. Exact mass calcd. for C2OH36IO2Sn (M - n-Bu): 555.0784; found: 555.0790.Anal. calcd. for C24H4SIO2Sn: C 47.16, H 7.42,120.76; found: C 47.31, H 7.46, I 20.55.243eparation of methyl (-5-iodo-2-F(-4-(tert-butyldimethylsiloxy-1 -methylstannyl- 1-butenyll-5-heptenoate (212)MeO2Cj’OSiMe(t-Bu)I Me3Sn212Following general procedure lO(pp 233-234), methyl (E)-6-(tert-butyldimethylsiloxy)-3-trimethylstannyl-2-hexenoate (141) was converted into the diene ester 212 with thefollowing amounts of reagents and solvents: LDA, 1.21 mmol, in THF, 10 mL; HMPA,0.21 mL (1.2 mmol); methyl (E)-6-(tert-butyldimethylsiloxy)-3-trimethylstannyl-2-hexenoate(141), 384 mg (0.911 mmol), in THF, 1.0 mL; (Z)-3,5-diiodo-2-pentene (198), 469 mg(1.46 mmol), in THF, 1.0 mL. Flash chromatography (45 g silica gel, 40: 1 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions andremoval of traces of solvent (vacuum pump) afforded 489 mg (87%) of the diene ester 212as a colorless liquid that exhibited ir (neat): 1733, 1195, 1101, 838, 776 cnr1; 1H nmr(CDC13, 400 MHz): ö 0.02 (s, 6H, Si(CH3)2), 0.19 (s, 9H, Sn(CH3)3,2Sn.H= 54 Hz),0.87 (s, 9H, C(CH3), 1.62-1.72 (m, 1H, CH2JjH), 1.70 (d, 3H, =CHCIj3,1=7 Hz), 1.99-2.19 (m, 1H, CH2IjH), 2.27 (br q, 2H, CIj2HO,1= 7 Hz),2.35-2.43 (m, 2H, =CICH2), 3.06 (dd, 1H, CHC=O, J= 9, 6.5‘3Sn-H 68 Hz),3.60 (t, 2H, CH2O, 1= 7 Hz), 3.62 (s, 3H, OCH3), 5.52 (q, 1H, =CaCH3, 1= 7 Hz),5.98 (t, 1H, SnC=CH, 1= 7 Hz,3SnH= 130 Hz); 13C nmr (CDC13,50.3 MHz): 6 -7.0,-5.3, 18.3, 22.0, 26.0, 31.7, 37.7, 42.9, 51.7, 54.0, 63.0, 109.8, 130.4, 140.2, 143.7,175.0. Exact mass calcd. for C2OH8ISiSn (M - Me): 601.0658; found: 601.0657.Anal. calcd. forC21H4IO3SiSn: C 41.00, H 6.72, I 20.63; found: C 41.18, H 6.66,I 20.44.244eparation of methyl 5-bromo-2-ft-2-cyclopropy1- 1 -(thmethylstannyl)ethenvll-5-hexen-oate (213)MeO2C213Following general procedure 10 (pp 233-234), methyl (E)-4-cyclopropyl-3-trimethyl-stannyl-2-butenoate (138) was converted into the diene ester 213 with the followingquantities of reagents and solvents: LDA, 2.43 mmol, in THF, 10 mL; HMPA, 0.43 roL(2.4 xnmol); methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138), 570 mg(1.88 mmol), in THF, 2.0 mL; 2-bromo--4-iodo-l-butene (148), 742 mg (2.84 mmol), inTHF, 2.0 mL. Flash chromatography (45 g silica gel, 200: 3 petroleum ether-Et20) of thecrude product, followed by concentration of the appropriate fractions and removal of Iraces ofsolvent (vacuum pump) provided 742 mg (90%) of the diene ester 213 as a colorless liquidthat displayed ir (neat): 1732, 1630, 1165, 771 cnr1;1H nmr (CDC13,400 MHz): 30.24 (s,9H, Sn(CH3)3,2Sn-H 53 Hz), 0.35-0.45 (m, 2H, cyclopropyl methylene protons),0.71-0.8 1 (m, 2H, cyclopropyl methylene protons), 1.28-1.38 (m, 1H, cyclopropyl methineproton), 1.67-1.80 (m, 111, CH2CthCH), 2.03-2.16 (m, 1H, CH2CthCH), 2.32-2.48 (m,2H, CBrCH2),3.08 (dd, 1H, CHCO, J 8, 6 Hz,3Sn..H 66 Hz), 3.67 (s, 3H, OCH3),5.38 (br d, 1H, SnC=CH, J= 9 Hz,3SziH= 126 Hz), 5.41 (br d, 1H, =CH2J= 1 Hz),5.55 (br ci, 1H, =CH21= 1 Hz); 13C nmr (CDC13, 75.5 MHz): 6 -7.1, 7.6, 7.7, 15.1, 30.6,39.4, 51.9, 54.0, 117.3, 133.8, 138.6, 148.0, 175.1. Exact mass calcd. forC14H2279BrO2Sn (M - Me): 420.9826; found: 420.9828. Anal. calcd. forC15H2SBrO2Sn:C 41.33, H 5.78, Br 18.33; found: C 41.41, H 5.72, Br 18.11.245Preparation of methyl (Z-5-iodo-24(Z)-2-cvclopropvl-1-ftrimethylstannyl’)ethenvl1-5-hepten-oate (214)MeO2CFollowing general procedure 10 (pp 233-234), methyl (E)-4-cyclopropyl-3-trimethyl-stannyl-2-butenoate (138) was converted into the diene ester 214 with the followingquantities of reagents and solvents: LDA, 2.34 mmol, in THF, 10 mL; HMPA, 0.41 mL(2.4 mmol); methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138), 568 mg(1.87 mmol), in THF, 2.0 mL; (Z)-3,5-diiodo-2-pentene (198), 932 mg (2.90 mmol), inTHF, 2.0 niL. Flash chromatography (45 g silica gel, 200: 3 petroleum ether-Et20) of thecrude product, followed by concentration of the appropriate fractions and removal of traces ofsolvent (vacuum pump) yielded 770 mg (83%) of the diene ester 214 as a colorless liquidthat exhibited ir (neat): 1733, 1648, 1611, 1162, 771 cnr1;1H nnir (CDC13,400 MHz):6 0.24 (s, 9H, Sn(CH3)3,2Sn.H= 53 Hz), 0.36-0.44 (m, 2H, cyclopropyl methyleneprotons), 0.70-0.80 (m, 2H, cyclopropyl methylene protons), 1.28-1.37 (m, 1H,cyclopropyl methine proton), 1.63-1.73 (m, 1H, CH2CthCH), 1.72 (d, 3H, =CHCTh,.1=7 Hz), 2.00-2.10 (m, 1H, CH2CthCH), 2.36-2.51 (m, 2H, =CICH2), 3.05 (dd, 1H,CHC=O, J= 8, 6 Hz,3Sn..H 69 Hz), 3.66 (s, 3H, OCH3), 5.36 (br d, 1H, SnC=CH,.1=9 Hz, 3’Sn-H= 128 Hz), 5.56 (br q, 1H, IC=CH, J=.7 Hz); 13C nmr (CDC13,50.3 MHz): 6 -7.1, 7.5, 14.9, 22.1, 31.9, 42.9, 51.7, 53.7, 109.9, 130.2, 138.7, 147.6,175.0. Exact mass calcd. forCj5HIO2Sn (M - Me): 482.9844; found: 482.9853. Anal.calcd. forC16H27IO2Sn: C 38.67, H 5.48, I 25.53; found: C 38.98, H 5.46, I 25.35.214246Preparation of methyl (Z)-6-cvclopropvl-5-iodo-2-IIZ)-2-cvclopropyl- 1 -ftrimethvlstannyl’)ethenyll-5-hexenoate (215)MeO2CFollowing general procedure 10 (pp 233-234), methyl (E)-4-cyclopropyl-3-trimethyl-stannyl-2-butenoate (138) was converted into the diene ester 215 with the followingquantities of reagents and solvents: LDA, 1.27 mmol, in THF, 5.0 mL; HMPA, 0.22 mL(1.3 mmol); methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138), 297 mg(0.980 mmol), in THF, 1.0 mL; (Z)-1-cyclopropyl-2,4-diiodo-1-butene (201), 501 mg(1.44 mmol), in THF, 1.0 mL. Flash chromatography (45 g sffica gel, 200 : 3 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions andremoval of traces of solvent (vacuum pump) gave 367 mg (72%) of the diene ester 215 as acolorless liquid that showed ir (neat): 1732, 1645, 1611, 1165, 772 cm1;1H nmr (CDC13,400 MHz): 6 0.25 (s, 9H, Sn(CH3)3,2Sn-H= 54 Hz), 0.33-0.48 (m, 4H, cyclopropylmethylene protons), 0.70-0.83 (m, 4H, cyclopropyl methylene protons), 1.25-1.37 (m, 1H,cyclopropyl methine proton), 1.55-1.74 (m, 2H; includes CH2CthCH: m, 1H, cyclopropylmethine proton: m, 1H), 1.98-2.08 (m, 1H, CH2CthCH), 2.31-2.49 (m, 2H, =CICH2),3.04 (dd, 1H, CHCO, J 9, 6 Hz,3SnH 69 Hz), 3.67 (s, 3H, OCH3), 4.93 (d, 1H,IC=CH, 1= 9 Hz), 5.35 (d, 1H, SnC=CH, .1= 9 3JsnH= 128 Hz); 13C nmr (CDC13,50.3 MHz): 6 -7.1, 6.7, 7.45, 7.55, 14.9, 18.3, 31.9, 42.7, 51.7, 53.7, 104.1, 138.8,139.5, 147.5, 175.1. Exact mass calcd. forC17H26IO2Sn (M - Me): 509.0001; found:509.0005. Anal. calcd. forC18H29IO2Sn: C 41.34, H 5.59, I 24.26; found: C 41.61,H 5.57, I 24.07.I215247Preparation of ethyl (Z)-5-iodo-7-methvl-2-[(Z)-3-methyl-1 -trimethylstannyl- 1 -butenyU-5-octenoate (216Following general procedure lO(pp 233-234), ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (158) was converted into the diene ester 216 with the following quantities ofreagents and solvents: LDA, 1.27 mmol, in THF, 5.0 niL; HMPA, 0.22 niL (1.3 mmol);ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (158), 303 mg (0.948 mmol), in THF,1.0 niL; (Z)-1-3-diiodo-5-methyl-3-hexene (204), 481 mg (1.38 mmol), in THF, 1.0 niL.Flash chromatography (45 g silica gel, 200: 3 petroleum ether-Et20) of the crude product,followed by concentration of the appropriate fractions and removal of traces of solvent(vacuum pump) afforded 441 mg (86%) of the diene ester 216 as a colorless liquid thatdisplayed ir (neat): 1729, 1642, 1616, 1177, 1028, 770 cnr1;1H nmr (CDC13,400 MHz):ö 0.22 (s, 9H, Sn(CH3)3,2Sn..H 53 Hz), 0.89-1.08 (m, 12H, 2 x CH(Cth)2), 1.24 (t,3H, OCH2CII3J= 7 Hz), 1.62-1.72 (m, 1H, CH2jjH), 1.99-2.10 (m, 1H,CH2CthCH), 2.21-2.30 (m, 1H, SnC=CCE(CH3)2), 2.32-2.45 (m, 2H, =CICH2),2.45-2.57 (m, 1H, IC=CCIj(CH),3.00 (dd, 1H, CHC=O, J= 9, 6 Hz,3JSnH= 70 Hz),4.12 (m, 2H, OCH2), 5.27 (br d, 1H, IC=CH, J= 8 Hz), 5.78 (br d, 1H, SnC=CH,J= 10 Hz,3Sn..H= 132 Hz); in a series of decoupling experiments, irradiation at 8 0.99simplified the multiplets at 62.21-2.30 and 62.45-2.57 to two doublets (J= 10 Hz, J= 8 Hz,respectively); irradiation at 82.26 simplified the doublet at 65.78 to a singlet irradiation at62.51 simplified the doublet at 8 5.27 to a singlet 13C nmr (CDC13,50.3 MHz): 6 -6.8,14.2, 21.6, 21.7, 23.1, 23.3, 31.6, 34.1, 36.0, 42.7, 53.5, 60.4, 105.3, 138.4, 142.4,I216248151.0, 174.7. Exact mass calcd. forC18H32IO2Sn (M - Me): 527.0471; found: 527.0472.Anal. calcd. forC19H3SIO2Sn: C 42.18, H 6.52, I 23.45; found: C 42.36, H 6.67, I 23.42.Preparation of ethyl 6-bromo-2-[(E)-1-trimethylstannvl- 1-propenyll-6-heptenoate (298Me3Sn298Following general procedure 10 (pp 233-234), ethyl (Z)-3-trimethylstannyl-2-pentenoate(124) was converted into the diene ester 298 with the following amounts of reagents andsolvents: LDA, 2.28 mmol, in THF, 10 mL; HMPA, 0.40 mL (2.3 mmol); ethyl (Z)-3-trimethylstannyl-2-pentenoate (124), 611 mg (2.10 mmol), in THF, 2.0 mL; 2-bromo-5-iodo-1-pentene (297), 729 mg (2.65 mmol), in THF, 3.0 mL. Radial chromatography(4 mm silica gel plate, 10: 1 petroleum ether-CH2C12) of the crude product, followed byconcentration of the appropriate fractions and removal of traces of solvent (vacuum pump)yielded 561 mg (61%) of the diene ester 298, a colorless liquid that displayed ir (neat): 1728,1630, 1186, 769 cm-1; 1H nmr (CDC13, 400 MHz): 6 0.10 (s, 9H, Sn(CH3)2SnH 52 Hz), 1.23 (t, 3H, OCH2Cth, J= 7 Hz), 1.34-1.62 (m, 3H), 1.70-1.84 (m,1H), 1.74 (d, 3H, =CHCIj3, J= 7 Hz), 2.40 (br t, 2H, =CBrCH2J= 7 Hz), 3.62 (br t, 1H,CHC=O, J= 7 Hz,3Sn-H 83 Hz), 4.10 (q, 2H, OCH2, 1= 7 Hz), 5.37 (d, lH, =CH2,1= 2 Hz), 5.55 (d, 1H, =CH2,J= 2 Hz), 5.82 (qd, 1H, =CaCH3J= 7, 1 Hz,3JSnH76 Hz); 13C (CDC13,50.3 M14z: 6 -7.6, 14.3, 14.9, 25.5, 31.9, 41.1, 47.8,60.5, 116.8, 134.1, 137.0, 143.7, 175.0. Exact mass calcd. forC14H279BrOSn249(M - Me): 422.9981; found: 422.9989. Anal. calcd. for CISH27BrO2Sn: C 41.13,H 6.21, Br 18.24; found: C 41.35, H 6.29, Br 18.07.Preparation of methyl 1-F(Z)-3-ioclo-2-propenyll-2-trimethvlstannvl-2-cyclopentenecarboxvl-ate (286Following general procedure 10 (pp 233-234), methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258) was converted into the diene ester 286 with the followingquantities of reagents and solvents: LDA, 1.78 mmol, in THF, 7.5 mL; HMPA, 0.31 mL(1.8 mmol); methyl 2-trimethylstannyl- 1 -cyclopentenecarboxylate (258), 432 mg(1.50 mmol), in THF, 1.0 mL; (Z)-3-bromo-1-iodopropene (274),60 494 mg (2.00 mmol),in THF, 1.5 rnL. Radial chromatography (2 mm silica gel plate, 7 : 1 petroleumether-CH2C12) of the crude product, followed by concentration of the appropriate fractionsand removal of traces of solvent (vacuum pump) afforded 426 mg (63%) of the diene ester286 as a colorless liquid that exhibited ir (neat): 1729, 1227, 1164, 771 cnr1;1H nmr(CDCJ3,400 MHz): 8 0.12 (s, 9H, Sn(CH3)3,2SnH= 54 Hz), 1.70-1.82 (m, 1H),2.22 (ddd, 1H, IC=CHCII2, J= 15, 7, 1 Hz), 2.25-2.34 (m, 1H), 2.35-2.55 (m, 2H,SnC=CHC!j), 2.68 (ddd, 1H, IC=CHDij, J= 15, 7, 1 Hz), 3.62 (s, 311, OCH3), 5.96 (t,111, SnC=CH, J= 2 Hz,3Sn..H= 37 Hz), 6.01 (q, 111, IC=CH, J= 7 Hz), 6.25 (dt, 111,=CHI, J= 7, 1 Hz); in a decoupling experiment, irradiation at 66.01 simplified the signals at8 2.22 and 8 2.68 to two doublet of doublets (both with J= 15, 1 Hz), and simplified theMeO2CSnMe3286250resonance at 8 6.25 to a triplet (J= 1 Hz); 13C nmr (CDC13,50.3 MHz): 6 -8.6, 31.9, 34.0,42.8, 51.8, 64.5, 84.7, 137.2, 144.0, 147.9, 175.9. Exact mass calcd. forC12H8IO2Sn(M - Me): 440.9374; found: 440.9382. Anal. calcd. forC13H21IOSn: C 34.32, H 4.65,I 27.90; found: C 34.61, H 4.58, I 27.72.Preparation of methyl 1 -[(Z)-3-iodo-2-butenyll-2-trimethylstannyl-2-cyclopentenecarboxylate(252IFollowing general procedure 10 (pp 233-234), methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258) was converted into the diene ester 252 with the followingquantities of reagents and solvents: LDA, 4.00 mmol, in THF, 18 mL; HMPA, 0.69 mL(4.0 mmol); methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258), 923 mg(3.19 mmol), in THF, 3.0 mL; (Z)-1-bromo-3-iodo-2-butene (275), 1.18 g (4.52 mmol), inTHF, 2.0 mL. Flash chromatography (80 g silica gel, 7: 1 petroleum ether-CH2C12) of thecrude product, followed by concentration of the appropriate fractions and removal of traces ofsolvent (vacuum pump) gave 1.02 g (68%) of the diene ester 252 as a colorless liquid thatshowed ir (neat): 1734, 1435, 1200, 1056,771 cm4;1H nmr (CDC13,400 MHz): 60.14 (s,9H, Sn(CH3)2Sn-H= 54 Hz), 1.73-1.83 (m, 1H), 2.20 (ddm, 1H, IC=CHCli2,1= 15,7 Hz for doublets), 2.26-2.36 (m, 1H), 2.37-2.55 (m, 2H), 2.46 (br s, 3H,=CICH3, wi= 4 Hz), 2.65 (ddm, 1H, IC=CHCIj2J= 15, 7 Hz for doublets), 3.65 (s,3H, OCH3), 5.25 (tm, 1H, IC=CH, J= 7 Hz for triplet), 5.98 (t, 1H, SnC=CH, J= 2 Hz,MeO2C2522513Sn-H= 37 Hz); 13C nmr (CDC13, 50.3 MHz): 6 -8.6, 32.1, 33.9, 34.0, 45.0, 51.9, 64.9,103.2, 131.4, 144.0, 148.3, 176.4. Exact mass calcd. forC13H20IOSn (M+ - Me):454.9530; found: 454.9537. Anal. calcd. forC14H23IO2Sn: C 35.86, H 4.94; found:C 36.40, H 4.99.Preparation of methyl 1-[(E)-3-iodo-3-pentenyU-2-trimethylstannyl-2-cyclopentenecarboxyl-ate (287)287Following general procedure 10 (pp 233-234), methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258) was converted into the diene ester 287 with the followingquantities of reagents and solvents: LDA, 1.43 mmol, in THF, 6.5 mL; HMPA, 0.25 mL(1.4 mmol); methyl 2-trimethylstannyl- 1 -cyclopentenecarboxylate (258), 323 mg(1.12 mmol), in THF, 1.5 mL; (E)-3,5-diiodo-2-pentene (193), 566 mg (1.76 mmol), inTHF, 1.5 mL. Radial chromatography (2 mm silica gel plate, 7: 1 petroleum ether-CH2C12)of the crude product, followed by concentration of the appropriate fractions and removal oftraces of solvent (vacuum pump) produced 304 mg (56%) of the diene ester 287 as acolorless liquid that displayed ir (neat): 1734, 1634, 1168, 770 cnr’; 1H nmr (CDC13,400 MHz): 8 0.15 (s, 9H, Sn(CH3)2SnH= 54 Hz), 1.48-1.58 (m, 1H), 1.58 (d, 3H,=CHCJj3,J= 7 Hz), 1.72-1.83 (in, 1H), 2.00-2.13 (m, 1H), 2.20-2.58 (m, 5H), 3.65 (s,3H, OCH3), 5.96 (br signal, 1H, SnC=CH, w= 5 Hz,3Sn-H= 37 Hz), 6.16 (q, 1H,=CjjCH3,J= 7 Hz); 13C nmr (CDC13,50.3 MHz): 8 -8.4, 16.1, 32.0, 34.2, 34.4, 37.7,MeO2CSnMe325251.8, 64.9, 102.0, 135.5, 143.5, 148.7, 176.5. Exact mass calcd. forC14H22IO2Sn(M - Me): 468.9688; found: 468.9691. Anal. calcd. forC1SH2SIO2n: C 37.30, H 5.22;found: C 37.80, H 5.33.Preparation of methyl 1-(4-iodo-4-pentenvfl-2-trimethylstannvl-2-cvclopentenecarboxylate(288MeO2CFollowing general procedure 10 (pp 233-234), methyl 2-trimethyistannyl- 1-cyclopentenecarboxylate (258) was converted into the diene ester 288 with the followingquantities of reagents and solvents: LDA, 1.43 mmol, in THF, 6.5 mL; HMPA, 0.25 mL(1.4 mmol); methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258), 327 mg(1.13 mmol), in THF, 1.5 mL; 2,5-diiodo-1-pentene (276), 547 mg (1.70 mmol), in THF,1.5 mL. Radial chromatography (2 mm silica gel plate, 7: 1 petroleum ether-CH2C12) of thecrude product, followed by concentration of the appropriate fractions and removal of traces ofsolvent (vacuum pump) provided 343 mg (63%) of the diene ester 288 as a colorless liquidthat exhibited ir (neat): 1733, 1617, 1142,771 cm1;1H nmr (CDC13,400 MHz): 30.13 (s,9H, Sn(CH3)3,2Sn..H= 54 Hz), 1.25-1.53 (m, 3H), 1.70-1.90 (m, 2H), 2.26-2.60 (m,5H), 3.64 (s, 3H, OCH3), 5.67 (s, 1H, =CH2), 5.94 (br s, 1H, SnC=CH, wl/2= 4 Hz,3Sn-H 37 Hz), 5.98 (s, 1H, =CH2); 13C nmr (CDC13,50.3 MHz): 3 -8.5, 24.4, 32.0,34.1, 36.9, 45.3, 51.8, 65.3, 112.1, 125.7, 143.3, 148.7, 176.8. Exact mass calcd. for288253C14H22IO2Sn (M - Me): 468.9688; found: 468.9696. Anal. calcd. forC1SH2SIO2Sn:C 37.30, H 5.22, I 26.28; found: C 37.48, H 5.14, I 26.12.Preparation of methyl 3-(2-bromo-2-propenyfl-2-trimethylstannyl- 1 -cyclohexenecarboxylate(285 and methyl 1-(2-bromo-2-propenyfl-2-trimethvlstannyl-2-cyclohexenecarboxylate(284285To a cold (-20 OC), stirred solution of LDA (4.00 mmol) in dry TI{F (17 mL) was addeddry HMPA (0.47 mL, 2.7 mmol) and the mixture was stirred at -78 °C for 5 miii. A solutionof methyl 2-thmethylstannyl-1-cyclohexenecarboxylate (259) (535 mg, 1.76 mmol) in dryTHF (2.0 mL) was added dropwise over a period of 30 s. The resulting yellow solution wasstirred at -20 °C for 1 h. After the well-stirred reaction mixture had been cooled to -78 °C(—5 miii), a solution of commercially available 2,3-dibromopropene (273) (1.10 g, technicalgrade, —85%, —4.68 mmol) in dry THF (1.0 mL) was added quickly. The dark mixture wasstirred at -78 °C for 5 mm and at -20 °C for 30 mm. Saturated aqueous NaHCO3 (20 mL)was added. The phases were separated and the aqueous phase was extracted with Et20(3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried(MgSO4) and concentrated. The crude oil was filtered through a plug of silica gel (8.5 g,230-400 mesh), with 3: 1 petroleum ether-CH2C12 (2 x 50 mL) being used for elution. The284254eluate was concentrated and the remaining oil was purified by radial chromatography (4 mmsilica gel plate, 7: 1 petroleum ether-CH2C12). Concentration of the appropriate fractions andremoval of traces of solvent (vacuum pump) afforded 105 mg (14%) of the ester 285 (theless polar component) and 321 mg (43%) of the ester 284 (the more polar component).Ester 285, a colorless liquid, displayed ir (neat): 1701, 1627, 1269, 1248, 770 cnr1;nmr (CDC13,400 MHz): 3 0.15 (s, 9H, Sn(CH3)2SnH= 53 Hz), 1.43-1.72 (m, 4H),2.18 (dd, 1H, =CBrCH2, J= 15, 12 Hz), 2.28-2.40 (m, 2H, SnC=CCII2),2.56 (dt, 1H,=CBrCH2,J= 15, 1.5 Hz), 2.88 (br d, 1H, tertiary proton, J= 12 Hz,3Sn-H= 30 Hz),3.70 (s, 3H, OCH3), 5.47 (t, 1H, =CH2J= 1.5 Hz), 5.57 (t, 1H, =CH2J= 1.5 Hz); in aseries of decoupling experiments, irradiation at 6 2.18 simplified the doublet of triplets at6 2.56 and the doublet at 6 2.88 to a broad singlet (wl/2= 4 Hz) and a broad signal(wia= 8 Hz), respectively; irradiation at 62.56 simplified the doublet of doublets at 62.18to a broad doublet (J= 12 Hz), and simplified the triplets at 65.47 and 35.57 to two doublets(both with J= 1.5 Hz); ‘c nmr (CDC13,50.3 MHz): 6 -6.5, 17.2, 24.1, 26.7, 38.2, 44.5,51.9, 118.6, 132.3, 136.9, 165.3, 169.4. Exact mass calcd. forC13HQ79BrO2Sn(M - Me): 406.9669; found: 406.9665. Anal. calcd. forC14H23BrO2Sn: C 39.85,H 5.49, Br 18.94; found: C 39.58, H 5.57, Br 19.08.Ester 284, a colorless oil, exhibited ir (neat): 1719, 1624, 1211, 1143, 769 cm1;nmr (CDC13,400 MHz): 6 0.12 (s, 9H, Sn(CH3)2Sn.H= 53 Hz), 1.57-1.82 (m, 3H),1.95-2.11 (m, 2H), 2.11-2.23 (m, 1H), 2.55 (d, iN, =CBrCH2, J= 15 Hz), 3.14 (dd, 1H,=CBrCH2, J= 15, 1 Hz), 3.68 (s, 3H, OCR3), 5.50 (d, 1H, =CH2J= 1 Hz), 5.57 (s, 1H,=CH2), 5.98 (t, 1H, SnC=CH, J= 4 Hz,3SnH= 73 Hz); 13C nmr (CDC13,50.3 MHz):6 -6.9, 18.6, 27.3, 29.3, 50.3, 50.9, 52.0, 120.5, 128.9, 140.6, 145.1, 175.8. Exactmass calcd. forC13H2079BrO2Sn (M - Me): 406.9669; found: 406.9674. Anal. calcd. forC14H23BrO2Sn: C 39.85, H 5.49, Br 18.94; found: C 40.23, H 5.52, Br 18.71.255eparafion of methyl 1-(n-propvl-2-methvlstannvl-2-cyclohexenecarxylate (300To a cold (-20 OC), stirred solution of LDA (2.54 mmol) in dry THF (10 niL) was addeddry HMPA (0.70 niL, 4.0 mmol) and the solution was stirred at -78 °C for 5 miii. A solutionof methyl 2-trimethylstannyl-1-cyclohexenecarboxylate (259) (358 mg, 1.18 mmol) in dryTHF (1.5 mL) was added dropwise over a period of 30 s. After the resulting yellow solutionhad been stirred at -20 °C for 1 h, commercially available 1-bromopropane (299) (0.30 niL,3.3 mmol) was added quickly. The mixture was stirred at -20 °C for 1 h. Saturated aqueousNaHCO3 (10 niL) was added and the phases were separated. The aqueous layer wasextracted with Et20 (2 x 10 mL) and the combined organic extracts were washed with brine(15 niL), dried (MgSO4) and concentrated. The residual oil was purified by radialchromatography (2 mm silica gel plate, 50: 9 petroleum ether-CH2C12). Concentration of theappropriate fractions, followed by distillation (104.121 °C/0.15 Torr) of the acquired oilprovided 319 mg (78%) of the ester 300 as a colorless oil that showed ir (neat): 1735, 1213,1153, 769 cnr1;1H nmr (CDC13,400 MHz): 8 0.09 (s, 9H, Sn(CH3)2SnH= 53 Hz),0.86 (t, 3H, CH2CIL3, J= 7 Hz), 1.07-1.21 (m, 1H), 1.21-1.33 (m, 1H), 1.42 (td, 1H,J= 12, 4 Hz), 1.50-1.67 (m, 3H), 1.73 (td, 1H, 1= 12, 5 Hz), 1.91-2.17 (m, 3H),3.63 (s, 3H, OCH3), 5.93 (t, 1H, =CH, J= 4 Hz,3Sn-H= 76 Hz); 13C nmr (CDC13,50.3 MHz): 6 -7.1, 14.5, 17.8, 19.3, 27.3, 30.3, 42.4, 51.1, 51.7, 139.4, 146.0, 177.1.Exact mass calcd. forC13H2O2Sn (M+ - Me): 331.0721; found: 331.0723. Anal. calcd. forC14H26O2Sn: C 48.73, H 7.59; found: C 48.71, H 7.44.300256paion of methyl 1-(2-omo-2-propenvl)cyclohexanecarxylate (302To a cold (-78 OC), stirred solution of LDA (2.37 mmol) in dry THF (5.0 mL) wasadded a solution of commercially available methyl cyclohexanecarboxylate (301) (241 mg,1.69 mmol) in dry THF (1.5 mL). After the resulting mixture had been stirred at -78 OC for30 mm, a solution of commercially available 2,3-dibromopropene (273) (642 mg, technicalgrade, —85%, —2.73 mmol) in dry HMPA (1.0 mL) was added. The mixture was stirred atroom temperature for 1 h. H20 (5 mL) was added and the phases were separated. Theaqueous layer was extracted with Et20 (2 x 5 mL) and the combined organic extracts werewashed with brine (10 mL), dried (MgSO4) and concentrated. The crude oil was filteredthrough a plug of silica gel (2 g, 230-400 mesh), with 1: 1 petroleum ether-CH2C12 (15 mL)being used for elution. The eluate was concentrated and the acquired oil was purified byradial chromatography (2 mm silica gel plate, 3: 1 petroleum ether-CH2C12). Concentrationof the appropriate fractions and distillation (75-100 °CI0.3 Torr) of the acquired liquid yielded291 mg (66%) of the ester 302 as a colorless oil that displayed ir (neat): 1733, 1625, 1215,1138 cm1;1H nmr (CDC13, 400 MHz): 8 1.15-1.44 (m, 5H), 1.46-1.63 (m, 3H),2.03-2.15 (m, 2H), 2.69 (s, 2H, =CBrCH2), 3.67 (s, 3H, OCH3), 5.48 (br d, 1H, =CH2J= 1.5 Hz), 5.50 (br s, 1H, =CH2);‘3C nmr (CDC13,50.3 MHz): 8 22.9, 25.6, 34.0, 47.0,50.8, 51.6, 120.4, 128.4, 176.0. Exact mass calcd. forC11H702(M+ - Br): 181.1229;found: 181.1224. Anal. calcd. for C11H17BrO2: C 50.59, H 6.56, Br 30.60; found:C 50.64, H 6.70, Br 30.44.302257Preparation of methyl 1-[(Z)-3-iodo-2-butenyllcyclohexanecarboxvlate (‘303)Following a procedure (p 256) similar to that described for the preparation of methyl1 -(2-bromo-2-propenyl)cyclohexanecarboxylate (302), commercially available methylcyclohexanecarboxylate (301) was converted into ester 303 with the following quantities ofreagents and solvents: LDA, 2.40 mmol, in THF, 5.0 mL; methyl cyclohexanecarboxylate(301), 155 mg (1.09 mmol), in THE, 1.5 mL; (Z)-l-bromo-3-iodo-2-butene (275), 399 mg(1.53 mmol), in HMPA, 1.5 mL. The crude product was filtered through a plug of silica gel(2 g, 230-400 mesh), with 1: 1 petroleum ether-CH2C1 (15 mL) being used for elution.The eluate was concentrated and the acquired oil was purified by radial chromatography(4 mm silica gel plate, 3 : 1 petroleum ether-CH2C1). Concentration of the appropriatefractions and distillation (62-82 OC/0.15 Torr) of the acquired liquid gave 234 mg (67%) ofthe ester 303 as a colorless oil that exhibited ir (neat): 1729, 1454, 1206, 1134, 1005 cm-1;nmr (CDC13,400 MHz): 8 1.13-1.40 (m, 5H), 1.43-1.61 (m, 3H), 1.95-2.07 (m, 2H),2.28 (cM, 2H, =CHCIj2J= 7, 1 Hz), 2.46 (br d, 3H, =CICH3J= 1 Hz), 3.65 (s, 3H,OCH3), 5.25 (tq, 1H, =CH, J= 7, 1 Hz); 13C nmr (CDC13,50.3 MHz): 3 23.1, 25.7, 33.8,33.9, 46.7, 47.1, 51.6, 103.1, 130.6, 176.6. Exact mass calcd. forC12H902:322.0431;found: 322.0437. Anal. calcd.: C 44.74, H 5.94, I 39.39; found: C 45.13, H 5.94, I 39.05.303258Preparation of (Z)-5-iodo-2-F(E)- 1 -trimethylstannvl- 1 -propenvll-5-hepten-1-01 (322)Following general procedure 6 (p 208), ethyl (Z)-5-iodo-2-[(E)-1-trimethylstannyl-1-propenyl]-5-heptenoate (209) was converted into (Z)-5-iodo-2-[(E)-1-trimethylstannyl-1-propenylj-5-hepten-1-ol (322) with the following quantities of reagents and solvents: ethyl(Z)-5-iodo-2-[(E)- 1-trimethylstannyl- 1-propenyl]-5-heptenoate (209), 1.04 g (2.14 mmol),in Et20, 20 mL; i-Bu2AIH, 5.4 mL (5.4 mmol); Florisil®, 16 g; Et20 for elution, 40 mL.Flash chromatography (40 g silica gel, 3: 1 petroleum ether-Et20) of the crude product,concentration of the appropriate fractions and removal of traces of solvent (vacuum pump)provided 913 mg (96%) of the alcohol 322 as a colorless liquid that showed ir (neat):3410 (br), 1648, 1029, 767 cnr1;1H nmr (CDC13,400 MHz): 6 0.14 (s, 9H, Sn(CH3)2SnH 52 Hz), 1.28-1.40 (m, 2H, includes one ofCH2thCH and CH2OU (exchangeswith D20)), 1.66-1.82 (m, 1H, CH2CM2CH), 1.68 (br d, 3H, =CHCJj3J= 7 Hz),1.72 (br d, 3H, =CHCIj3, J= 7 Hz), 2.30-2.40 (m, 1H, =CICH2), 2.40-2.50 (m, 1H,=CICH2), 2.95-3.04 (m, 1H, CUCH2OH,3Sn-H 93 Hz), 3.3 1-3.39 (m, 1H, Cjj2OH;after D20 exchange: t centered at 3.35, J= 10 Hz), 3.51-3.60 (m, 1H, Cjj2OH; after D20exchange: dd centered at 3.56, J= 10, 6 Hz), 5.53 (hr q, 1H, IC=CH, J= 7 Hz), 5.93 (br q,1H, SnC=CH, J= 7 Hz,3Jsfl..H=78 Hz); 13C nmr (CDC13,50.3 MHz): 3 -7.5, 15.3, 22.1,31.8, 42.8, 43.5, 66.2, 110.7, 129.8, 138.9, 146.5. Exact mass calcd. forC12H2IOSn(M - Me): 428.9739; found: 428.9738. Anal. calcd. forC13H25IOSn: C 35.25, H 5.69,I 28.65; found: C 35.52, H 5.72, I 28.48.322259Preparation of (E-5-iodo-2-[(E)- 1-trimethvlstannyl- 1 -propenvll-5-hepten- 1-01 (255I Me3Sn255Following general procedure 6 (p 208), ethyl (E)-5-iodo-2-[(E)-1-trimethylstannyl-1-propenyl]-5-heptenoate (211) was converted into (E)-5-iodo-2-[(E)- 1 -trimethylstannyl- 1-propenyl]-5-hepten-1-ol (255) with the following quantities of reagents and solvents: ethyl(E)-5-iodo-2-[(E)- 1-trimethylstannyl- 1 -propenyl]-5-heptenoate (211), 1.02 g (2.10 mmol),in Et20, 25 niL; i-Bu2AIH, 5.0 niL (5.0 mmol); Florisil®, 50 g; Et20 for elution, 400 mL.Radial chromatography (4 mm silica gel plate, 4: 1 petroleum ether-Et20) of the crudeproduct, concentration of the appropriate fractions and removal of traces of solvent (vacuumpump) produced 690 mg (74%) of the alcohol 255 as a colorless liquid that displayedir (neat): 3383 (br), 1633, 1036, 768 cm-1; ‘H nmr (CDC13,400 MHz): 3 0.19 (s, 9H,Sn(CH3),2Sn-H= 52 Hz), 1.32-1.43 (m, 1H, CH2thCH), 1.48 (br dd, 1H, CH2OE,J= 7, 2 Hz, exchanges with D20), 1.61 (d, 3H, =CHCth, J= 7 Hz), 1.65-1.76 (m, 1H,CH2CthCH), 1.75 (d, 3H, =CHCTh, J= 7 Hz), 2.32 (br t, 2H, =CICH2J 7 Hz),2.98-3.08 (m, 1H, CfjCH2OH,3Sn.H= 92 Hz), 3.39 (br t, 1H, Cij0H, J= 7 Hz; after1)20 exchange: a sharpened t, J= 7 Hz), 3.55-3.66 (m, 1H, CJjOH; after 1)20 exchange: ddcentered at 3.61, J= 9, 7 Hz), 5.96 (qd, 1H, SnC=CH, J= 7, 1 Hz,3Sn-H 79 Hz),6.24 (q, 1H, IC=CH, .1= 7 Hz); C nmr (CDC13, 100.6 MHz): 6 -7.5, 15.3, 16.3, 31.7,35.3, 43.6, 66.2, 103.4, 135.5, 138.6, 146.6. Exact mass calcd. forC12H22IOSn(M - Me): 428.9739; found: 428.9737. Anal. calcd. forC13H25IOSn: C 35.25, H 5.69,I 28.65; found: C 35.35, H 5.65, I 28.49.260Preparation of (Z’)-5-iodo- 1-(tert-butyldiphenylsi1oxy-2-r(E- 1 -trimethvlstannvl- 1 -propenyll5-heptene (32380To a stirred solution of (Z)-5-iodo-2-[(E)- 1 -trimethylstannyl- 1-propenyl]-5-hepten-1 -ol(322) (387 mg, 0.873 mmol) in dry CH2C12 (8.0 mL) at room temperature was addedimidazole (149 mg, 2.18 mmol) and tert-butylchlorodiphenylsilane (0.32 mL, 1.2 nimol).The reaction mixture was stirred at room temperature for 15 mm. Saturated aqueousNaHCO3 (8 niL) was added and the phases were separated. The aqueous layer was extractedwith Et20 (2 x 8 mL) and the combined organic extracts were washed with H20 (20 niL) andbrine (20 mL), dried (MgSO4) and concentrated. Flash chromatography (30 g silica gel,200 : 3 petroleum ether-Et20) of the crude product, concentration of the appropriate fractionsand removal of traces of solvent (vacuum pump) provided 572 mg (96%) of the silyl ether323 as a colorless liquid that exhibited ir (neat): 1648, 1606, 1428, 1111, 768, 740,702 cm1;1H nmr (CDC13,400 MHz): 6 0.02 (s, 9H, Sn(CH3) 53 Hz),1.04 (s, 9H, C(CH3), 1.12-1.26 (m, 1H, CH2jjH), 1.58 (br d, 3H, SnC=CHCIjJ= 7 Hz), 1.70 (br d, 311, IC=CHDJj, J= 7 Hz), 2.00-2.10 (m, 1H, CH2CthCH),2.26-2.37 (m, 1H, =CICH2), 2.38-2.48 (m, 1H, =CICH2), 2.92-3.01 (m, 111, CJjCH2O,3JSn-H 90 Hz), 3.38-3.52 (m, 2H, OCH2), 5.47 (br q, 1H, IC=CH, J= 7 Hz), 5.72 (br q,1H, SnC=CH, J= 7 Hz,3sn-H= 75 Hz), 7.32-7.45 (m, 6H, aromatic protons),7.62-7.70 (m, 4H, aromatic protons); in a decoupling experiment, irradiation at 6 5.47simplified the doublet at 6 1.70 to a singlet 13C nmr (CDC13,50.3 MHz): 6-7.6, 15.1, 19.2,22.2, 26.9, 32.0, 43.0, 43.6, 67.6, 111.3, 127.6, 129.3, 129.5, 133.9, 135.7, 136.8,t—i323261146.3. Exact mass calcd. forC28H40IOS1Sn (M - Me): 667.0917; found: 667.0921. Anal.calcd. for C29H43IOSiSn: C 51.12, H 6.36, 118.63; found: C 51.40, H 6.30, 118.44.Preparation of (E)-5-iodo- 1-(tert-butv1dipheny1siloxv-2-IiE)-1-trimethvlstannvl-1-propenvU-5-heptene (33880I MeSn338Following a procedure (p 260) similar to that given for the preparation of (Z)-5-iodo-1-(tert-butyldiphenylsiloxy)-2-[(E)- 1-trimethyistannyl- 1-propenyl]-5-heptene (323), (E)-5-iodo-2-[(E)- 1-trimethyistannyl- 1 -propenylj-5-hepten- 1-ol (255) was converted into (E)-5-iodo- 1-(tert-butyldiphenylsioxy)-2-[(E)-1 -trimethyistannyl- 1 -propenylj-5-heptene (338)with the following quantities of reagents and solvents: (E)-5-iodo-2-[(E)-1-trimethylstannyl-1-propenyl]-5-hepten-1-ol (255), 441 mg (0.995 nimol), in CH21, 10 niL; imida.zole,169 mg (2.49 mmol); tert-butylchlorodiphenylsilane, 0.35 mL (1.4 mmol). Radialchromatography (4 mm silica gel plate, 10: 1 petroleum ether-CH2C12) of the crude product,concentration of the appropriate fractions and removal of traces of solvent (vacuum pump)produced 644 mg (95%) of the silyl ether 338 as a colorless liquid that showed ir (neat):1599, 1428, 1113, 768, 702 cm1;1H nmr (CDC13,400 MHz): 8 0.08 (s, 9H, Sn(CH3)2SnH 51 Hz), 1.08 (s, 9H, C(CH3), 1.18-1.32 (m, 1H, CH2ffiCH), 1.59 (br d, 3H,=CHCIj3, J= 7 Hz), 1.65 (br d, 3H, =CHCjj, J= 7 Hz), 2.00-2.12 (m, 1H, CH2jjCH),2.30 (br t, 2H, =CICH2J= 7 Hz), 2.96-3.07 (m, 1H, CUCH2O, 3Sn-H 95 1k)’3.42-3.57 (m, 2H, OCH2), 5.76 (br q, 1H, SnC=CH, J= 7 Hz,3Sn-H= 81 Hz), 6.22 (br q,2621H, IC=CH, J= 7 Hz), 7.33-7.46 (m, 6H, aromatic protons), 7.64-7.74 (m, 4H, aromaticprotons); 13C nmr (CDC13, 100.6 MHz): 6 -7.6, 15.1, 16.3, 19.2, 26.9, 32.0, 35.8, 43.8,67.6, 104.0, 127.6, 129.5, 133.8, 135.3, 135.6, 136.9, 146.5. Exact mass calcd. forC28H40IOSiSn (M - Me): 667.0917; found: 667.0915. Anal. calcd. forC29H43IOSiSn:C 51.12, H 6.36, 118.63; found: C 51.40, H 6.42, 118.40.10. Stereocontrolled preparation of alkyl 2.3-bis(allcvlidene)cvclopentanecarboxvlates andrelated substances via intramolecular palladium(0-catalvzed coupling reactions of vinylhalide and vinyistannane functionsl3aGeneral procedure 11R20C R3R3 R1 R’X Me3Sn C02R206 X=Brorl 219A stirred solution of (Ph3P)4d (5 mol %), LiC1 (2 equiv) and the diene ester 206(1 equiv) in dry DMF (—10 mL per mmol of the diene ester) was heated at 80 OC for 1 h(unless otherwise noted). The reaction mixture was cooled to room temperature, and wasdiluted with 1120 (three times the volume of that of DMF used). The phases were separatedand the aqueous layer was extracted three times with Et20 (one-half the volume of that ofH20used). The combined organic extracts were washed with brine (one-half the volume ofthe total volume ofEt20used), dried (MgSO4) and concentrated. Purification of the cruderesidual oil as indicated in the individual experiments (vide infra), followed by concentrationof the appropriate fractions and distillation of the liquid thus obtained, afforded the alkyl 2,3-bis(alkylidene)cyclopentanecarboxylate 219.263Preparation of ethyl 2.3-bis(methylene)cyclopentanecarboxvlate (41a) 13aHfHgCO2EtHe41aFollowing general procedure 11 (p 262), ethyl 5-bromo-2-[1-(trimethylstannyl)ethenyl]-5-hexenoate (40a) was converted into ethyl 2,3-bis(methylene)cyclopentanecarboxylate(41a) with the following amounts of reagents and solvents: (Ph3P)4d, 52.3 mg(45.3 Ilmol); LiCl, 76.5 mg (1.80 mmol); diene ester 40a, 370 mg (0.902 mmol), in DMF,9 mL. Flash chromatography (20 g silica gel, 40: 1 petroleum ether-Et20) of the crudeproduct, followed by concentration of the appropriate fractions and distillation(37-45 °C/0.6 Torr) of the liquid thus obtained, afforded 84.0 mg (56%) of thecyclopentanecarboxylate 41a as a colorless liquid that displayed ir (neat): 1736, 1179, 1041,890 cnr1; uv: m(E, solvent)= 249.7 nm (9000, n-pentane), 248.6 nm (7900, MeOH);nmr (CDC13, 400 MHz): 8 1.27 (t, 3H, OCH2C, J= 7 Hz), 1.87-1.99 (m, 1H, H2),1.99-2.12 (m, 1H, H2), 2.36-2.49 (m, 1H, Hb), 2.56-2.70 (m, 1H, Hb), 3.43-3.51 (m, 1H,He), 4.11-4.26 (m, 2H, OCH2), 4.94 (t, 1H, HJ, J= 2.5 Hz), 5.11 (d, 1H, He, J 2.5 Hz),5.39 (t, 1H, Hf, J= 2.5 Hz), 5.52 (d, 1H, Hg, J= 2.5 Hz); assignments of protons H1j, H,Hf and Hg are based on nOe difference experiments which were previously studied in ourlaboratory;131C nmr (CDC13,50.3 MHz): 6 14.2, 27.4, 32.4, 50.0, 60.6, 104.8, 106.4,146.6, 147.3, 173.6. Exact mass calcd. forC10H1402: 166.0994; found: 166.0992. Anal.calcd.: C 72.26, H 8.49; found: C 72.42, H 8.38.264Preparation of ethyl (Z)-2-ethylidene-3-methylenecyclopentanecarboxylate (220) 13aI /-Co2EtHfHe220Following general procedure 11 (p 262), ethyl 5-bromo-2-[(Z)-1-trimethylstannyl-1-propenyl]-5-hexenoate (207) was converted into ethyl (Z)-2-ethylidene-3-methylene-cyclopentanecarboxylate (220) with the following amounts of reagents and solvents:(Ph3P)4d, 90.2 mg (78.1 .tmol); LiC1, 132 mg (3.12 mmol); diene ester 207, 661 mg(1.56 mmol), in DMF, 16 mL. The reaction time was 30 mm in this experiment. Flashchromatography (45 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followedby concentration of the appropriate fractions and distillation (40-60 OC/0.6 Torr) of theacquired oil, gave 233 mg (83%) of the cyclopentanecarboxylate 220 as a colorless liquidthat exhibited ir (neat): 1733, 1651, 1189, 1044, 881 cnr1;uv: solvent)= 246.4 nm(10200, n-pentane), 246.3 nm (7380, MeOH); 1H nmr (CDC13, 400 MHz): 6 1.28 (t, 3H,OCH2Cth, 1= 7 Hz), 1.80-1.94 (m, 1H, Ha), 1.89 (dd, 3H, =CHCth, J 7, 1 Hz),1.96-2.08 (m, 1H, Ha), 2.37-2.50 (m, 1H, Hb), 2.60-2.73 (m, 1H, Hb), 3.37-3.44 (m, 1H,Hc), 4.08-4.22 (m, 2H, OCH2), 5.17 (br s, 1H, Hj, wj= 5 Hz), 5.20 (br s, 1H, He,wl/2= 6Hz), 5.80 (br q, 1H, Hf, .1= 7 Hz); assignments of protons Hj, He and Hf arebased on nOe difference experiments which were previously studied in our laboratory;l3nmr (CDC13,50.3 MHz): 3 14.2, 15.5, 27.5, 34.5, 51.2, 60.4, 110.2, 122.8, 138.3,147.3, 174.5. Exact mass calcd. forC11H602:180.1150; found: 181.1151. Anal. calcd.:C 73.30, H 8.95; found: C 73.07, H 9.00.265Preparation of ethyl (E)-2-ethylidene-3-methylenecvclopentanecarboxvlate (221) 13aI / NDO2Et221Following general procedure 11 (p 262), ethyl 5-bromo-2-[(E)-1-trimethylstannyl-1-propenyl]-5-hexenoate (208) was converted into ethyl (E)-2-ethylidene-3-methylene-cyclopentanecarboxylate (221) with the following amounts of reagents and solvents:(Ph3P)4d, 89.0 mg (77.0 jimol); LiCI, 130 mg (3.07 mmol); diene ester 208, 645 mg(1.52 mmol), in DMF, 15 niL. Flash chromatography (20 g silica gel, 40: 1 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions anddistillation (40-50 °C/0.6 Torr) of the acquired oil, gave 274 mg (87%) of thecyclopentanecarboxylate 221 as a colorless liquid that showed ir (neat): 1732, 1627,1181 cm-1;uv: ?.max(E, solvent)= 253.8 nm (10500, n-pentane), 252.3 nm (8000, MeOH);nmr (CDC13,400 MHz): 6 1.29 (t, 3H, OCH2Cj,J= 7 Hz), 1.80 (d, 3H, =CHCth,J= 7 Hz), 1.84-1.96, (m, 1H, Ha), 2.04-2.16 (m, 1H, Ha), 2.41-2.55 (m, 1H, Hb),2.64-2.78 (m, 1H, Hb), 3.65 (br d, 1H, He. 1= 8 Hz), 4.08-4.25 (m, 2H, OCH2),4.83 (br s, 1H, ILj, wl/2= 6 Hz), 5.27 (br s, 1H, He, wl/2= 7 Hz), 6.12 (qd, 111, Hf,J= 7, 1 Hz); assignments of protons F1j, He and Hf are based on nOe difference experimentswhich were previously studied in our laboratory;13‘c nnir (CDC13,50.3 MHz): 8 14.2,15.1, 28.3, 32.8, 47.0, 60.4, 101.8, 119.0, 139.1, 148.2, 174.2. Exact mass calcd. forC11H602:180.1150; found: 181.1148. Anal. calcd.: C 73.30, H 8.95; found: C 73.55,H 9.12.266Preparation of ethyl (ZZ)-2.3-bis(ethylidenecvclopentanecarboxvlate (222Following general procedure 11 (p 262), ethyl (Z)-5-iodo-2-[(Z)-1-trimethylstannyl-l-propenyl] -5-heptenoate (205) was converted into ethyl (Z,Z) -2,3 -bis (ethylidene)cyclopentanecarboxylate (222) with the following amounts of reagents and solvents:(Ph3P)4d, 85.5 mg (74.0 p.mol); LiC1, 120 mg (2.82 mmol); diene ester 205, 674 mg(1.39 mmol), in DMF, 14 mL. Flash chromatography (20 g silica gel, 40: 1 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions anddistillation (60-80 OC/O.6 Torr) of the acquired oil, afforded 256 mg (95%) of thecyclopentanecarboxylate 222 as a colorless liquid that displayed ft (neat): 1737, 1185,1042 cm-1; uv: max(C, solvent)= 234.6 nm (12900, n-pentane), 234.7 nm (7600, MeOH);nmr (CDC13,400 MHz): 6 1.23 (t, 3H, OCH2CHj, 1= 7 Hz), 1.58 (dt, 3H, =CHeC,.1= 7, 1 Hz), 1.62 (dd, 3H, =CHICli3, 1= 7, 1 Hz), 1.78-1.92, (m, 1H, Ha), 1.92-2.05 (m,1H, Hb), 2.19-2.32 (m, 1H, He), 2.32-2.49 (m, 1H, F1), 3.27-3.41 (m, 1H, Hd),400-4.23 (m, 2H, OCH2), 5.38 (br q, 1H, H, 1=7 Hz), 5.48 (br q, 111, Hf, 1=7 Hz); in aseries of decoupling experiments, irradiation at 8 3.34 changed the doublet of doublets at8 1.62 to a doublet (1=7 Hz), simplified the multiplets at 6 1.78-1.92 and 6 1.92-2.05, andsharpened the broad quartet at 6 5.48; irradiation at 65.38 simplified the doublet of triplets at8 1.58 to a broad singlet (wi= 4 Hz); irradiation at 65.48 simplified the doublet of doubletsat 8 1.62 to a broad singlet (wl/2= 4 Hz); in a series of nOe difference experiments,irradiation at 6 1.58 caused an enhancement of the signal at 8 5.38 (12%); irradiation at2222676 1.62 caused an enhancement of the signal at 8 5.48 (12%); irradiation at 6 3.34 causedenhancement of the signals at 8 1.78-1.92 (7%) and 85.48 (4%); irradiation at 85.38 causedenhancement of the signals at 8 1.58 (2%), 6 2.19-2.32 (3%) and 8 2.32-2.49 (3%);irradiation at 6 5.48 caused enhancement of the signals at 6 1.62 (2%) and6 3.27-3.41 (4%); 1C nmr (CDC13, 50.3 MHz): 6 14.2, 17.1, 17.2, 25.7, 32.7, 49.2,60.3, 119.5, 120.8, 138.2, 138.7, 174.8. Exact mass calcd. forC12H802:194.1307;found: 194.1308. Anal. calcd.: C 74.19, H 9.34; found: C 73.99, H 9.32.Preparation of ethyl (EZ)-2,3-bis(ethylidene)cvclopentanecarboxvlate (223)Following general procedure ll(j) 262), ethyl (Z)-5-iodo-2-[(E)-1-trimethylstannyl-1-propenyl]-5-heptenoate (209) was converted into ethyl (E,Z)-2,3-bis(ethylidene)-cyclopentanecarboxylate (223) with the following amounts of reagents and solvents:(Ph3P)4d, 26.2 mg (22.7 .tmol); L1C1, 38.5 mg (0.908 mmol); diene ester 209, 220 mg(0.454 mmol), in DMF, 4.5 mL. Flash chromatography (20 g silica gel, 40: 1 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions anddistillation (50-70 O(/0.6 Torr) of the oil thus obtained, produced 80.4 mg (9 1%) of thecyclopentanecarboxylate 223 as a colorless liquid that exhibited ir (neat): 1734, 1152,1040 cur’; uv: solvent)= 247.1 nm (12000, n-pentane), 246.5 nm (9110, MeOH);nmr (CDC13, 400 MHz): 6 1.23 (t, 3H, OCH2Cjj3J= 7 Hz), 1.80 (br d, 3H,He223268CHeCki3, J= 7 Hz), 1.83 (br d, 3H, =CHdCIj3, .1= 7 Hz), 1.85-2.00, (m, 2H, Ha),2.25-2.36 (m, 1H, Hb), 2.53-2.66 (m, 1H, Hb), 3.58-3.66 (m, 1H, He), 4.05-4.21 (m, 2H,OCH2), 5.52 (br q, 1H, HJ, 1= 7 Hz), 5.93 (br q, 1H, H, J= 7 Hz); in a series ofdecoupling experiments, irradiation at 6 1.80 simplified the broad quartet at 6 5.93 to a broadsinglet (wi= 4 Hz); irradiation at 3 5.93 simplified the doublet at 6 1.80 to a broad singlet(wl,2= 4 Hz), and the multiplet at 6 3.58-3.66 to a doublet of doublets (J= 8, 4 Hz); in aseries of nOe difference experiments, irradiation at 3 1.80 caused enhancement of the signalsat 6 3.58-3.66 (14%) and 6 5.93 (12%); irradiation at 3 1.83 caused enhancement of thesignals at 65.52 (9%) and 85.93 (10%); irradiation at 33.62 caused an enhancement of thesignal at 6 1.80 (1%) and 6 1.85-2.00 (6%); irradiation at 85.52 caused enhancement of thesignals at 8 1.83 (3%), 62.25-2.36 (4%) and 62.53-2.66 (2%); irradiation at 8 5.93 causedenhancement of the signals at 6 1.80 (2%) and 8 1.83 (3%); 13C nmr (CDC13,50.3 MHz):8 14.2, 15.2, 15.6, 28.3, 34.4, 48.1, 60.3, 117.3, 124.1, 139.3, 139.9, 174.7. Exactmass calcd. forC12H802: 194.1307; found: 194.1313. Anal. calcd.: C 74.19, H 9.34;found: C 74.40, H 9.40.269Preparation of (E.Z)-2.3-bis(ethylidene)-1- (tert-butvldiphenylsiloxvmethvl’)cyclopentane(320)Following general procedure 11(j) 262), (Z)-5-iodo-1-(tert-butyldiphenylsioxy)-2-[(E)-1 -trimethyistannyl- 1 -propenyl] -5-heptene (323) was converted into (E,Z)-2,3 -bis(ethylidene)- 1 -(tert-butyldiphenylsiloxymethyl)cyclopentane (320) with the followingamounts of reagents and solvents: (Ph3P)4d, 9.2 mg (8.0 I.Lmol); L1C1, 13.5 mg(0.3 18 mmol); diene 323, 108 mg (0.159 mmol), in DMF, 1.6 mL. After concentration ofthe organic extracts, the acquired crude product was eluted through a plug of silica gel (2 g,230-400 mesh) in a disposable pipette with 10: 1 petroleum ether-Et20 (15 mL). The eluatewas concentrated and was subjected to radial chromatography (2 mm silica gel plate, 40 : 3petroleum ether-CH2C12). Concentration of the appropriate fractions and removal of traces ofsolvent (vacuum pump) provided 53.3 mg (86%) of the cyclopentane 320 as a colorlessliquid that showed ir (neat): 1656, 1590, 1428, 1112, 825, 738, 703 cur1;1H nnir (CDC13,400 MHz): 8 1.05 (s, 9H, C(CH3),1.60 (d, 3H, =CHCjj, J= 7 Hz), 1.62-1.75, (m, 1H,Ha), 1.78 (d, 3H, =CHCjj3J= 7 Hz), 1.87-1.97 (m, 1H, Ha), 2.18-2.31 (m, 1H, Hb),2.32-2.45 (m, lET, Hb), 3.02-3.12 (m, 1H, Jl). 3.43 (t, 1H, OCT12, J= 10 Hz), 3.60 (dd,1H, OCT12, J= 10, 5 Hz), 5.44 (br q, 1H, =CH, J= 7 Hz), 5.78 (br q, 1H, =CH, J= 7 Hz),7.29-7.52 (m, 6H, aromatic protons), 7.60-7.75 (m, 4H, aromatic protons); 13C nmr(CDC13, 100.6 MHz): 6 15.3, 15.4, 19.2, 25.8, 26.8, 32.7, 45.4, 64.6, 116.8, 122.5,Ha320270127.6, 129.5, 134.0, 135.6, 140.6, 141.8. Exact mass calcd. forC26H34OSi: 390.2380;found: 390.2373. Anal. calcd.: C 79.94, H 8.77; found: C 79.85, H 8.86.Preparation of ethyl (E.E-2.3-bis(ethylidene’)cyclopentanecarboxv1ate (224Following general procedure 11 (p 262), ethyl (E)-5-iodo-2-[(E)-1-trimethylstannyl-1-propenyl] -5-heptenoate (211) was converted into ethyl (E,E)-2, 3 -bis (ethylidene)cyclopentanecarboxylate (224) with the following amounts of reagents and solvents:(Ph3P)4Pd, 36.1 mg (31.2 imo1); LiC1, 53.0 mg (1.25 mmol); diene ester 211, 303 mg(0.625 mmol), in DMF, 6.0 mL. Flash chromatography (10 g silica gel, 40: 1 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions anddistillation (55-75 OC(o.6 Torr) of the oil thus obtained, afforded 107 mg (88%) of thecyclopentanecarboxylate 224 as a colorless liquid that displayed ir (neat): 1733, 1185,1043 cnr1; uv: A(e, solvent)= 256.7 nm (10000, n-pentane), 256.1 nm (10000, MeOH);nmr (CDC13, 400 MHz): 8 1.22 (t, 3H, OCH2CJj3J= 7 Hz), 1.67 (br d, 3H,CHeCa3, J= 7 Hz), 1.73 (br d, 3H, =CHfCII3, J= 7 Hz), 1.77-1.87, (m, 1H, Ha),2.02-2.11 (m, 1H, Flb) 2.36-2.59 (m, 2H, He), 3.60 (br d, 1H, 14j, 1= 9 Hz),4.03-4.2 1 (m, 2H, OCH2), 5.72-5.80 (m, 1H, He), 5.90 (br q, 1H, Hf, J= 7 Hz); iii aseries of decoupling experiments, irradiation at 6 1.67 simplified the multiplet at 65.72-5.80to a broad singlet (wip= 6 Hz); irradiation at 8 1.73 simplified the broad quartet at 65.90 to a224271broad singlet (wi= 4 Hz); irradiation at 8 3.60 sharpened the broad quartet at 8 5.90; in aseries of nOe difference experiments, irradiation at 8 1.73 caused enhancement of the signalsat 8 3.60 (4%) and 8 5.90 (3%); irradiation at 83.60 caused enhancement of the signals at8 1.73 (3%) and 8 1.77-1.87 (6%); irradiation at 65.90 caused enhancement of the signals at6 1.73 (6%) and 6 5.72-5.80 (8%); nmr (CDC13,50.3 MHz): 8 14.0, 14.9, 15.0, 27.9,28.8, 47.2, 60.4, 113.0, 115.8, 139.7, 140.3, 174.4. Exact mass calcd. forC12H802:194.1307; found: 194.1305. Anal. calcd.: C 74.19, H 9.34; found: C 74.08, H 9.38.Preparation of (E,E)-2,3-bis(ethvlidene)- 1 -(tert-butyldiphenylsiloxvmethvflcvclopentane(335.)Eu)Following general procedure. ll(J) 262), (E)-5-iodo-1-(tert-butyldiphenylsioxy)-2-[(E)-1-trimethyistannyl- 1 -propenyl] -5-heptene (338) was converted into (E,E)-2,3-bis(ethyli-dene)-1-(tert-butyldiphenylsioxymethyl)cyclopentane (335) with the following amounts ofreagents and solvents: (Ph3P)4Pd, 11.8 mg (10.2 .tmol); LiC1, 17.6 mg (0.415 mmol); diene338, 142 mg (0.208 mmol), in DMF, 2.0 mL. After concentration of the organic extracts,the acquired crude product was eluted through a plug of sifica gel (2 g, 230-400 mesh) in adisposable pipette with 10: 1 petroleum ether-Et20 (15 mL). The eluate was concentratedand was subjected to radial chromatography (2 mm silica gel plate, 40 : 3 petroleumether-CH2C12). Concentration of the appropriate fractions and removal of traces of solvent335272(vacuum pump) provided 72.8 mg (90%) of the cyclopentane 335 as a colorless liquid thatexhibited ft (neat): 1664, 1590, 1428, 1112, 824, 737, 702 cm1; 1H nmr (CDC13,400 MHz): 8 1.05 (s, 9H, C(CH3), 1.52 (d, 3H, =CHCII3J= 7 Hz), 1.57-1.71 (m, 1H,Ha), 1.62 (d, 3H, =CHCTh, J= 7 Hz), 2.01-2.12, (m, 1H, Ha), 2.14-2.27 (m, 1H, Hb),2.30-2.42 (m, 1H, Hb), 2.97-3.06 (m, 1H, He), 3.37 (t, 1H, OCH2J= 10 Hz), 3.54 (dd,1H, .OCH2, J= 10, 5 Hz), 5.64-5.73 (m, 1H, =CH), 5.72 (br q, 1H, =CH, J= 7 Hz),7.3 1-7.44 (m, 6H, aromatic protons), 7.61-7.72 (m, 4H, aromatic protons); 13C nmr(CDC13, 100.6 MHz): 8 14.6, 14.8, 19.2, 25.6, 26.9, 27.4, 44.7, 64.4, 112.1, 113.8,127.7, 129.5, 134.0, 135.6, 141.4, 142.0. Exact mass calcd. forC26H34OSi: 390.2380;found: 390.2370. Anal. calcd.: C 79.94, H 8.77; found: C 80.12, H 8.80.273Preparation of methyl (Z.Z)-2-(3-tert-butylmethvlsiloxvpropylidene)-3-ethylidenecyclo-pentanecarboxvlate (225)Following general procedure 11 (p 262), methyl (Z)-5-iodo-2-[(Z)-4-(tert-butyldimethyl-sioxy)- 1-trimethylstannyl- 1-butenyl]-5-heptenoate (212) was converted into methyl (Z,Z)-2-(3-tert-butylmethylsioxypropylidene)-3-ethylidenecyclopentanecarboxylate (225) with thefollowing amounts of reagents and solvents: (Ph3P)4d, 31.7 mg (27.4 p.mol); LiCl,43.7 mg (1.03 mmol); diene 212, 276 mg (0.449 mmol), in DMF, 3.0 mL. Flashchromatography (20 g silica gel, 25: 1 petroleum ether-Et20) of the crude product, followedby concentration of the appropriate fractions and distillation (100-130 OC/0.6 Torr) of theliquid thus obtained, afforded 105 mg (72%) of the cyclopentanecarboxylate 225 as acolorless liquid that displayed ir (neat): 1742, 1256, 1196, 1167, 1103, 837, 777 cnr1;uv: ma,cXE, solvent)= 235.9 nm (13600, n-pentane), 237.1 nm (7600, MeOH); 1H nmr(CDC13, 400 MHz): 8 0.03 (s, 6H, Si(CH3)2,0.86 (s, 9H, C(CH3), 1.58 (dt, 3H,=CHCa3, J= 7, 1 Hz), 1.78-1.90 (m, 1H, Ha), 1.90-2.02 (m, 1H, Hb), 2.20 (qd, 2H,=CHCth, J= 7, 1 Hz), 2.22-2.30 (m, 1H, He), 2.32-2.54 (m, 1H, F1), 3.37-3.42 (m, 1H,Hd), 3.61-3.66 (m, 2H, OCH2), 3.66 (s, 3H, OCH3), 5.38 (br q, 1H, He, J= 7 Hz),5.43 (br t, 1H, Hf, J= 7 Hz); in a series of decoupling experiments, irradiation at 8 1.58simplified the broad quartet at 6 5.38 to a broad singlet (wl,2= 3 Hz); irradiation at 82.20simplified the multiplet at 6 3.61-3.66 to an AB system (J= 9 Hz) centered at 6 3.64, andchanged the broad triplet at 6 5.43 to a broad singlet (w= 4 Hz); irradiation at 8 3.40225274simplified the multiplets at 6 1.78-1.90 and 8 1.90-2.02, changed the quartet of doublets at62.20 to a quartet (J= 7 Hz), and sharpened the broad triplet at 8 5.43; in a series of nOedifference experiments, irradiation at 8 1.58 caused enhancement of the signals at 82.20(2%) and 6 5.38 (9%); irradiation at 8 2.20 caused enhancement of the signals at 6 1.58(2%), 6 3.63 (6%) and 85.43 (8%); irradiation at 8 3.40 caused enhancement of the signalsat 5 1.78-1.90 (5%) and 8 5.43 (5%); 13C nmr (CDC13, 50.3 MHz): 8 -5.3, 17.0, 18.3,25.6, 25.9, 32.8, 35.0, 49.2, 51.7, 62.8, 119.8, 123.2, 138.1, 138.9, 175.1. Exact masscalcd. forC14H23O3Si(M - t-Bu): 267.1417; found: 267.1416. Anal. calcd.C18H32OSi:C 66.62, H 9.94; found: C 66.49, H 9.90.Preparation of methyl (Z-2-cyclovropylmethy1ene-3-methvlenecyclopentanecarboxylate(226Following general procedure 11 (p 262), methyl 5-bromo-2-[(Z)-2-cyclopropyl-1-(trimethylstannyl)ethenyl]-5-hexenoate (213) was converted into methyl (Z)-2-cyclopropyl-methylene-3-methylenecyclopentanecarboxylate (226) with the following amounts ofreagents and solvents: (Ph3P)4d, 46.7 mg (40.4 tmol); LiCl, 68.8 mg (1.62 mmol); diene213, 343 mg (0.787 mmol), in DMF, 8.0 mL. Flash chromatography (45 g silica gel, 40: 1petroleum ether-Et20) of the crude product, followed by concentration of the appropriatefractions and distillation (70-85 OC/tJ.6 Torr) of the remaining liquid, afforded 142 mg (94%)226275of the cyclopentane 226 as a colorless liquid that exhibited ir (neat): 1734, 1198, 1168,1039 cm-1; uv: A(c, solvent)= 260.0 nm (9800, n-pentane), 260.9 nm (8530, MeOH);111 nmr (CDC13,400 MHz): 6 0.35-0.46 (m, 2H, cyclopropyl methylene protons),0.77-0.86 (m, 2H, cyclopropyl methylene protons), 1.79-1.93 (m, 1H, cyclopropyl methineproton), 1.85-1.96 (m, 1H, Ha), 1.98-2.08 (m, 1H, Hb), 2.39-2.49 (m, 1H, He).2.62-2.72 (m, 111, He), 3.38-3.45 (m, 1H, Hj), 3.67 (s, 311, OCH3), 5.14 (d, 1H, He,J= 8 Hz), 5.15 (br s, 111, Hf, wl/2=5 Hz), 5.47 (br s, 1H, Hg, wl/2=5 Hz); in a series ofdecoupling experiments, irradiation at 8 0.41 simplified the multiplet at 6 0.77-0.86 to adoublet (J= 8 Hz) and the multiplet at 6 1.79-1.93 to a quartet (J= 8 Hz) centered at 1.86;irradiation at 8 5.14 simplified the multiplet at 6 3.38-3.45 to a doublet of doublets(J= 8, 6 Hz); in a series of nOe difference experiments, irradiation at 6 3.42 causedenhancement of the signals at 6 1.85-1.96(9%) and 85.14(9%); irradiation at 65.14 causedan enhancement of the signal at 63.38-3.45 (3%); irradiation at 65.15 caused enhancementof the signals at 82.39-2.49 (2%), 2.62-2.72 (2%), and 6 5.47 (23%); irradiation at 65.47caused enhancement of the signals at 6 1.79-1.93 (7%) and 65.15 (25%); 13C nnir (CDC13,50.3 MHz): 6 8.0, 11.9, 27.4, 34.5, 50.9, 51.8, 109.1, 132.6, 136.5, 147.1, 174.8. Exactmass calcd. forC12H602:192.1151; found: 192.1150. Anal. calcd.: C 74.97, H 8.39;found: C 74.92, H 8.47.276Preparation of methyl (Z.Z)-2-cvclopropvlmethvlene-3-ethylidenecvclopentanecarboxvlate(227Following general procedure 11 (p 262), methyl (Z)-5-iodo-2-[(Z)-2-cyclopropyl-1-(trimethylstannyl)ethenyl]-5-heptenoate (214) was converted into methyl (Z,Z)-2-cyclopropylmethylene-3-ethylidenecyclopentanecarboxylate (227) with the followingamounts of reagents and solvents: (Ph3P)4d, 85.6 mg (74.1 jimol); LiC1, 126.4 mg(2.98 mmol); diene 214, 713 mg (1.44 mmol), in DMF, 15 mL. Flash chromatography(20 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentrationof the appropriate fractions and distillation (90-100 OCfO.6 Torr) of the residual liquid, gave288 mg (97%) of the cyclopentanecarboxylate 227 as a colorless liquid that showed ir (neat):1740, 1167, 1031 cnr1; uv: max(E, solvent)= 248.4 nm (13300, n-pentane), 247.9 nm(9650, MeOH); 1H nrnr (CDC13,400 MHz): 8 0.35-0.44 (m, 2H, cyclopropyl methyleneprotons), 0.75-0.90 (m, 2H, cyclopropyl methylene protons), 1.35-1.46 (m, 1H,cyclopropyl methine proton), 1.78 (dt, 3H, =CHCth, J= 7, 1.5 Hz), 1.84-1.96 (m, 1H,Ha), 1.96-2.05 (m, 1H, Hb), 2.28-2.39 (m, 1H, He),, 2.41-2.51 (m, 1H, Hc),3.37-3.42 (m, 1H, Hij), 3.66 (s, 3H, OCH3), 4.83 (br d, 1H, He, J= 7 Hz), 5.42 (br q,1H, Hf, J= 7 Hz); in a series of decoupling experiments, ilTadiation at 84.83 simplified themultiplet at 83.37-3.42 to a doublet of doublets (J= 9,6 Hz), and the broad quartet at 65.42to a quartet of triplets (J= 7, 1.5 Hz); irradiation at 65.42 simplified the doublet of triplets at8 1.78 to a broad singlet (wi= 5 Hz), and the broad doublet at 8 4.83 to a doublet ofHe227277doublets (J= 7, 1.5 Hz); in a series of nOe difference experiments, irradiation at 8 1.41caused enhancement of the signals at 6 0.75-0.90 and 8 1.78; irradiation at 6 1.78 causedenhancement of the signals at 3 1.35-1.46 and 3 5.42; irradiation at 3 3.40 causedenhancement of the signals at 8 1.84-1.96 and 6 4.83; irradiation at 8 4.83 causedenhancement of the signals at 80.35-0.44 and 8 3.37-3.42; irradiation at 85.42 caused anenhancement of the signal at 6 1.78; 13C nmr (CDC13,50.3 MHz): 6 6.8, 7.5, 14.1, 17.2,25.9, 33.1, 49.1, 51.7, 119.5, 130.8, 134.9, 139.0, 175.1. Exact mass calcd. forC13H802:206.1307; found: 206.1306. Anal. calcd.: C 75.69, H 8.80; found: C 75.49,H 8.75.epantion of methyl 228Following general procedure 11 (p 262), methyl (Z)-6-cyclopropyl-5-iodo-2-[(Z)-2-cyclopropyl- 1 -(trimethylstannyl)ethenyl]-5-hexenoate (215) was converted into methyl(Z,Z)-2,3-bis(cyclopropylmethylene)cyclopentanecarboxylate (228) with the followingamounts of reagents and solvents: (Ph3P)4d, 18.5 mg (16.0 p.mol); LiC1, 28.8 mg(0.679 mmol); diene 215, 169 mg (0.323 mmol), in DMF, 3.2 mL. The resulting mixturewas stirred at 90 °C for 1 h in this experiment. Flash chromatography (20 g silica gel, 40: 1petroleum ether-Et20) of the crude product, followed by concentration of the appropriate228278fractions and distillation (55-70 °Cf0.6 Torr) of the residual oil, gave 64.8 mg (86%) of thecyclopentanecarboxylate 228 as a colorless liquid that displayed ir (neat): 1730, 1167,1044 cm-1;uv: max(E, solvent)= 257.8 nm (11000, n-pentane), 259.3 nm (9890, MeOH);nmr (CDC13, 400 MHz): 6 0.30-0.48 (m, 4H, cyclopropyl methylene protons),0.67-0.83 (m, 4H, cyclopropyl methylene protons), 1.65-1.73 (m, 1H, Ha), 1.73-1.82 (m,1H, JIb). 1.83-1.93 (m, 1H, He). 1.93-2.05 (m, 1H, FLj), 2.23-2.37 (m, 1H, He),2.38-2.50 (m, 1H, He), 3.40 (ddd, 1H, Hf, J= 8, 6, 1.5 Hz), 3.68 (s, 3H, OCH3),4.74 (br d, 1H, Hg, J= 9 Hz), 4.81 (br d, 1H, Hh, 1= 9 Hz); in a series of decouplingexperiments, irradiation at 60.39 simplified the multiplets at 6 1.65-1.73 and at 6 1.73-1.82to two quartets (both with J= 9 Hz) centered at 6 1.69 and at 6 1.78, respectively; irradiationat 6 0.75 simplified each of the multiplets at 6 1.65-1.73 and at 6 1.73-1.82 to a doublet oftriplets (J= 9, 4 Hz) centered at 6 1.69 and at 6 1.78, respectively; irradiation at 8 4.81simplified the multiplet at 6 1.73-1.82, and changed the doublet of doublet of doublets at6 3.40 to a doublet of doublets (J= 8, 6 Hz); in a series of nOe difference experiments,irradiation at 63.40 caused enhancement of the signals at 6 1.83-1.93 (6%) and 64.81(4%);irradiation at 64.74 caused enhancement of the signals at 60.30-0.48 (4%), 6 2.23-2.37(3%) and 6 2.38-2.50 (4%); irradiation at 6 4.81 caused enhancement of the signals at6 0.30-0.48 (4%) and 8 3.40 (2%); 13C nmr (CDC13, 50.3 MHz): 6 7.5, 7.7, 8.1, 13.9,14.2, 26.2, 33.2, 49.4, 51.8, 129.3, 130.7, 135.3, 136.4, 175.2. Exact mass calcd. forC15H202: 232.1464; found: 232.1462. Anal. calcd.: C 77.55, H 8.68; found: C 77.74,H 8.68.279paradon of ethyl Z-2.3-bis(2-methylpropylidenecvclopentanecarxylate (229229Following general procedure 11 (p 262), ethyl (Z)-5-iodo-7-methyl-2-[(Z)-3-methyl-1-trimethyistannyl- 1 -butenylj-5-octenoate (216) was converted into ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxylate (229) with the following amounts of reagentsand solvents: (Ph3P)4d, 22.0 mg (19.0 p.mol); LiCl, 32.0 mg (0.755 mmol); diene 216,205 mg (0.378 mmol), in DMF, 4.0 mL. The resulting mixture was stirred at 105 OC for1.5 h in this experiment. Flash chromatography (20 g silica gel, 40 : 1 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions anddistillation (55-80 OC/0.6 Torr) of the remaining oil, provided 48.9 mg (52%) of thecyclopentanecarboxylate 229 as a colorless liquid that showed ir (neat): 1736, 1160,1041 cm’; uv: m(e, solvent)= 237.1 nm (9800, n-pentane), 236.8 nm (9200, MeOH);nmr (CDC13,400 MHz): 8 0.88-0.98 (4 overlapping doublets centered at 0.91, 0.93,0.94, 0.95; 12H, 2 x CH(C1j3)2, all with J= 7 Hz), 1.23 (t, 3H, OCH2C,J= 7 Hz),1.80-1.90 (m, 1H, Ha), 1.90-2.00 (m, 1H, Hb), 2.16-2.28 (m, 1H, He), 2.28-2.37 (m, 1H,He), 2.37-2.50 (m, 2H, 2 x jj(CH3)2,3.28 (ddd, 1H, Hj, 1= 9, 6, 1 Hz), 4.06-4.20 (m,2H, OCH2), 5.09 (d, 1H, He, .1= 10 Hz), 5.19 (d, 1H, Hf, J= 10 Hz); in a series ofdecoupling experiments, irradiation at 60.93 simplified the multiplet (corresponding to twodifferent protons) at 62.37-2.50 to two doublets (both with J= 10 Hz) centered at 62.41 andat 62.46; irradiation at 8 2.44 simplified the four overlapping doublets at 60.88-0.98 to fourHf280singlets centered at 6 0.91, 0.93, 0.94, 0.95, and simplified the two doublets of doublets at65.09 and 8 5.19 to two broad singlets (wi,= 8, 9 Hz, respectively); irradiation at 8 3.28simplified the two multiplets at 8 1.80-1.90 and 8 1.90-2.00, and sharpened the doublet at65.19; irradiation at 8 5.19 simplified the signal (one of two multiplets) at 32.37-2.50, andsimplified the signal at 6 3.28 to a doublet of doublets (J= 9, 6 Hz); in a series of nOedifference experiments, irradiation at 8 2.44 caused an enhancement of the signals at60.88-0.98 (2%); irradiation at 6 3.28 caused enhancement of the signals at 8 1.80-1.90(6%) and 85.19(4%); irradiation at 8 5.09 caused enhancement of the signals at 62.16-2.28(4%) and 82.28-2.37 (5%); irradiation at 8 5.19 caused an enhancement of the signal at8 3.28 (8%); 13C nmr (CDC13,50.3 MHz): 8 14.2, 22.4, 22.5, 23.15, 23.2, 25.1, 29.2,29.5, 33.2, 49.4, 60.2, 132.6, 133.9, 134.2, 134.8, 174.7. Exact mass calcd. forC16H20:250.1934; found: 250.1928. Anal. calcd.: C 76.75, H 10.47; found: C 76.46,H 10.48.Preparation of (E-2-ethvlidene- 1-hydroxvmethvl-3-methylenecyclopentane (337To a cold (0 °C), stirred solution of lithium aluminum hydride (13.5 mg, 0.356 mmol) indry Et20 (1.0 mL) was added a solution of ethyl (E)-2-ethylidene-3-methylenecyclopentane-carboxylate (221) (82.0 mg, 0.455 mmol) in dry Et20 (1.0 mL). The reaction mixture wasstirred at 0 0C for 2 miii and then at room temperature for 10 miii. Sodium sulfateHb337281decahydrate (110 mg, 0.34 1 mmol) was added and the mixture was stirred at roomtemperature for 10 mm. The resulting solid was removed by filtration through a plug ofFlorisil® (2 g) and the column was eluted with Et20 (2 mL). Concentration of the combinedeluate, followed by distillation (40-60 OC/0.15 Torr) of the material thus obtained, gave50.1 mg (80%) of the alcohol 337, a colorless oil that showed ir (neat): 3320 (br), 1440,1030 cm-1;1H nmr (CDC13,400 MHz): 3 1.37 (dd, 1H, OH, J= 7, 5 Hz, exchanges withD20), 1.64-1.85 (m, 2H, Ha), 1.78 (br d, 3H, =HHj, J= 7 Hz), 2.33-2.53 (m, 2H, Hb),3.03 (br q, 1H, H, J= 7 Hz), 3.40-3.58 (m, 2H, CjjOH; after D20 exchange: simplified toa t centered at 3.44, 1H, 1= 10 Hz and a dd centered at 3.52, 1H, J= 10, 7 Hz), 4.75 (br s,1H, =CH2, wl/2= 5 Hz), 5.20 (br s, 1H, =CH2wl/2= 6 Hz), 6.04 (qd, 1H, =CJjCH3J= 7, 1.5 Hz); 13C nmr (CDC13,50.3 MHz): 6 15.1, 26.0, 31.4, 44.2, 64.1, 101.7, 117.6,141.0, 148.8. Exact mass calcd. forC9H140: 138.1045; found: 138.1043. Anal. calcd.:C 78.21, H 10.21; found: C 75.41, H 9.97.Preparation of 1 -(tert-butvldinhenvlsioxvmethvl)-(E)-2-ethvlidene-3-methvlenecvclopentane(332)OS:h2(tBU)332Following a procedure similar to that given for the preparation of (Z)-5-iodo-1-(tert-butyldiphenylsiloxy)-2-[(E)- 1 -trimethyistannyl- 1 -propenylj-5-heptene (323), (E)-2-ethylidene-1-hydroxymethyl-3-methylenecyclopentane (337) was converted into 1-Qert-282butyldiphenylsiloxymethyl)-(E)-2-ethylidene-3-methylenecyclopentane (332) with thefollowing amounts of reagents and solvents: (E)-2-ethylidene-1-hydroxymethyl-3-methylene-cyclopentane (337), 15.4 mg, (0.111 mmol), in CH21, 1.0 mL; imidazole, 19.0 mg(0.279 mmofl; tert-butylchlorodiphenylsilane, 40 iL (0.15 mmol). Flash chromatography(5 g silica gel, 200: 3 petroleum ether-Et20) of the crude product, concentration of theappropriate fractions and removal of traces of solvent (vacuum pump) produced 41.8 mg(99.5%) of the cyclopentane 332 as a colorless solid (mp 39-41 0C) that exhibited ir (neat):1659, 1626, 1428, 1111, 824, 702 cm-1;1H nmr (CDC13,400 MHz): 6 1.05 (s, 9H,C(CH3), 1.55 (br d, 3H, =CHCJj3.1= 7 Hz), 1.62-1.73 (m, 1H, Ha), 2.002.08, (m,1H, Ha), 2.31-2.45 (m, 2H, Hb), 2.98-3.05 (m, 1H, l1) 3.40 (t, 1H, OCH2J= 10 Hz),3.58 (dd, 1H, OCH2J= 10, 5 Hz), 4.71 (br s, 1H, =CH2wl/2= 5 Hz), 5.15 (br s, 1H,=CH2,wl/2= 5 Hz), 5.92 (qd, 1H, =CJjCH3J= 7, 2 Hz), 7.34-7.43 (m, 6H, aromaticprotons), 7.65-7.70 (m, 4H, aromatic protons); 13C nmr (CDC13,50.3 MHz): 6 14.8, 19.3,25.9, 26.9, 31.4, 44.5, 64.2, 101.0, 117.0, 127.6, 129.5, 133.9, 135.6, 141.2, 149.4.Exact mass calcd. forC25H32OSi: 376.2224; found: 376.2224. Anal. calcd.: C 79.73,H 8.56; found: C 79.78, H 8.56.28311. Preparation of alkyl 2.3-bis(alkylidene)cvclopentanecarboxylates and other dienes viaCuC1-mediated intramolecular coupling reactions of vinyl halide and vinyistannanefunctionsGeneral procedure 12R20CR3X Me3Sn206 X=Ix MeO2C2y260 261 262n’=lor2; n”=12or3; R=HorMe; X=BrorlA stirred solution of the diene ester 206 or 219 (1 equiv) in dry DMF (—10 mL permmol of the diene ester) was, unless stated otherwise, heated at —60 °C with an oil bath(—10 mm). Powdered CuC1 (—2-3 equiv) was added and the mixture was stirred at —60 °Cfor 2-10 mm, unless otherwise noted. The reaction flask was removed from the oil bath,aqueous NH4C1-N 4OH (pH = 8) (three times the volume of that of the DMF used) wasadded, and the mixture was opened to the atmosphere. After a short period of time, Et20(thesame volume as that of the aqueous NB4C1-NHOH (pH = 8) used) was added and themixture was stirred until the aqueous phase became deep blue (—15 mm). The phases wereseparated and the aqueous layer was extracted twice with Et20 (the same volume as that of theR3219284aqueousNH4C1-N 4OH (pH = 8) used). The combined organic extracts were washed withbrine (one-half the volume of the total volume of Et20 used), dried (MgSO4) andconcentrated. Flash or radial chromatography of the remaining liquid on silica gel, followedby concentration of the appropriate fractions and distillation of the residual oil, afforded thecyclic diene 260, 261 or 262.Preparation of ethyl (ZZ)-2.3-bis(ethv1idenecyclopentanecarboxy1ate (222Following general procedure 12 (pp 283-284), ethyl (Z)-5-iodo-2-[(Z)-l-trimethyl-stannyl- 1-propenyl]-5-heptenoate (205) was converted into ethyl (Z,Z)-2,3-bis(ethylidene)-cyclopentanecarboxylate (222) with the following amounts of reagents and solvents: dieneester 205, 127 mg (0.261 mmol), in DMF, 2.6 mL; CuC1, 77.8 mg (0.786 mmol). Thereaction mixture was stirred at 60 OC for 2 mm. Flash chromatography (10 g silica gel, 40: 1petroleum ether-Et20) of the crude product, followed by concentration of the appropriatefractions and distillation (45-70 OC/0.6 Torr) of the acquired liquid, afforded 45.2 mg (89%)of the cyclopentanecarboxylate 222 as a colorless liquid that showed spectra identical withthose recorded earlier (see pp 266-267).222285Preparation of ethyl (E2)-2.3-bis(ethylidene)cyclopentanecarboxylate (223)Following general procedure 12 (pp 283-284), ethyl (Z)-5-iodo-2-[(E)-1-trimethyl-stannyl-1-propenylj-5-heptenoate (209) was converted into ethyl (E,Z)-2,3-bis(ethylidene)-cyclopentanecarboxylate (223) with the following amounts of reagents and solvents: dieneester 209, 117 mg (0.240 mmol), in DMF, 2.4 mL; CuCl, 50.0 mg (0.505 mmol). Thereaction mixture was stirred at 60 °C for 2 mm. Radial chromatography (1 mm silica gelplate, 7: 1 petroleum ether-CH2C12) of the crude product, followed by concentration of theappropriate fractions and distillation (50-70 °C/O.3 Torr) of the oil thus obtained, produced38.9 mg (83%) of the cyclopentanecarboxylate 223 as a colorless liquid that showed spectraidentical with those recorded earlier (see pp 267-268).223286eption of ethyl (E.-2.3-bis(ethylidene)cyc1opentanecarboxy1ate (224)EtO2CI R3Sn211 R=Me296 R=n-Bu(From 211) Following general procedure 12 (pp 283-284), ethyl (E)-5-iodo-2-[(E)-1-trimethylstannyl- 1 -propenyl]-5-heptenoate (211) was converted into ethyl (E,E)-2,3-bis-(ethylidene)cyclopentanecarboxylate (224) with the following amounts of reagents andsolvents: diene ester 211, 209 mg (0.432 mmol), in DMF, 4.4 mL; CuCl, 94.0 mg(0.950 mmol). The reaction mixture was stirred at 62 OC for 3 mm. Radial chromatography(2 mm silica gel plate, 6: 1 petroleum ether-CH2C1)of the crude product, followed byconcentration of the appropriate fractions and distillation (50-70 OC/O.3 Torr) of the liquidthus obtained, yielded 67.4 mg (80%) of the cyclopentanecarboxylate 224 as a colorlessliquid that showed spectra identical with those recorded earlier (see pp 270-271).(From 296) Following general procedure 12 (pp 283-284), ethyl (E)-5-iodo-2-[(E)-1-(tri-n-butylstannyl)- 1 -propenyl]-5-heptenoate (296) was converted into ethyl (E,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (224) with the following amounts of reagents andsolvents: diene ester 296, 135 mg (0.222 mmol), in DMF, 2.0 mL; CuC1, 60.0 mg(0.606 mmol). The reaction mixture was stirred at 65 °C for 10 miii. After normal work-upand concentration, bulb—to-bulb distillation was carried out at 80-85 OC/4() Torr to removeDMF, and then at 100-125 OC/40 Torr to give a distillate which was enriched in the224287cyclopentanecarboxylate 224 (containing trace amounts of DMF and impurities by gicanalysis), and a residue. The distillate thus obtained was subjected to radial chromatography(1 mm silica gel plate, 7 : 1 petroleum ether-CH2C12). Concentration of the appropriatefractions and distillation (45-65 °C/0.3 Torr) of the acquired liquid, gave 23.3 mg (54%) ofthe cyclopentanecarboxylate 224. The aforementioned residue was purified by distillation(120-140 Q’O.3 Torr) to give 48.3 mg (67%) of thbutyltin chloride, the structure of whichwas confirmed by 1H nmr spectroscopy and low resolution mass spectrometry. The 1H nmrspectrum of the isolated tributyltin chloride is identical with that of a commercially availablesample. The low resolution mass spectrum of the isolated compound displayed the fragmentof M - (n-Bu) (m/e= 269, 68.2%), while the low resolution desorption chemical ionization(reagent gas: NH3)mass spectrum of this compound showed the molecular ion complex ofM + NH3 ÷ 1 (m/e= 344, 10.16%) and the fragment of M- (2 x n-Bu) (m/e= 212,34.84%).Preparation of ethyl (Z.E’)-2.3-bis(ethvlidene)cyclopentanecarboxylate (230)Ethyl (E)-5-iodo-2- [(Z)- 1 -trimethylstannyl- 1 -propenyl] -5-heptenoate (210) wasconverted into ethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (230) with thefollowing amounts of reagents and solvents: diene ester 210, 92.3 mg (0.190 mmol), inDMF, 2.0 mL; CuCI, 43.6 mg (0.440 mmol). General procedure 12 (pp 283-284) was230 224288employed, except that the CuC1 was added to the DMF solution of 210 at room temperatureand the reaction mixture was stirred at room temperature for 10 mm. Flash chromatography(10 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentrationof the appropriate fractions and distillation (50-70 OC/O.3 Torr) of the acquired liquidprovided 34.8 mg (94%) of a colorless liquid that consised of a mixture of thecyclopentanecarboxylates 230 and 224, in a ratio of 31: 1 (determined by integration ofnmr signals), respectively. This mixture was purified by semi-preparative hplc (WatersRadia1-Pak cartridge, 25 x 100 mm, 10 j.t .tPorasi1). The hplc system used was composedof a System Controller model 600E and Tunable Absorbance Detector model 486 (tuned at256 nm), both from Waters. The Controller and the Detector were supervised by an IBMclone computer running a Chromatography Workstation Maxima 825 version 3.30 programfrom Dynamic Solution (Millipore). The eluant used was 50:50 hexane-CHZC12. Collectionof the appropriate fractions, followed by removal of traces of solvent (vacuum pump) yielded25.9 mg (70%) of a pure sample of the major isomer, the cyclopentanecarboxylate 230,which exhibited ir (neat): 1734, 1447, 1370, 1186, 1043 cm-1; uv: wmax(e, solvent)=249.1 nm (13000, n-pentane), 248.9 nm (6700, MeOH); 1H nmr (CDC13, 400 MHz):8 1.23 (t, 3H, OCH2CJj3J= 7 Hz), 1.72 (br d, 3H, =CHfCJj3, J= 7 Hz), 1.79-1.91 (m,1H, Ha), 1.82 (br d, 3H, =CHeCIj3, J= 7 Hz), 1.94-2.05 (m, 1H, Hb), 2.30-2.42 (m, 1H,Hc), 2.51-2.63 (m, iN, He), 3.30-3.37 (m, 1H, H(J), 4.05-4.18 (m, 2H, OCH2),5.60 (br q, 1H, He, J= 7 Hz), 5.72-5.82 (m, 1H, Hf); in a series of decouplingexperiments, irradiation at 8 5.60 simplified the doublet at 8 1.82 to a broad singlet(wl/2= 6 Hz); irradiation at 8 5.77 simplified the doublet at 6 1.72 to a broad singlet(wi= 5 Hz); in a series of nOe difference experiments, irradiation at 6 1.72 causedenhancement of the signals at 62.30-2.42 (4%), 8 2.51-2.63 (5%) and 8 5.72-5.82 (5%);irradiation at 8 1.82 caused enhancement of the signals at 85.60 (8%) and 85.72-5.82 (6%);irradiation at 63.34 caused enhancement of the signals at 8 1.79-1.9 1 (6%) and 85.60(3%);irradiation at 65.60 caused enhancement of the signals at 8 1.82 (2%) and 53.30-3.37 (3%);28913C nmr (CDC13, 50.3 MHz): 8 14.2, 15.4, 15.5, 27.1, 29.5, 51.7, 60.3, 119.4, 121.7,139.3, 139.9, 174.7. Exact mass calcd. forC12H802:194.1307; found: 194.1303. Anal.calcd.: C 74.19, H 9.34; found: C 73.92, H 9.50.The minor product 224 (the 1H nmr spectrum of 224 was recorded previously, seepp 270-27 1) showed signals at 3 1.67 (br d, =CHbCIj3, J= 7 Hz), 3.60 (br d, Ha, 1 9 Hz)and 5.90 (br q, H, J= 7 Hz) in the 1H nmr spectrum of the mixture of the cyclopentanecarboxylates 230 and 224, which are in a ratio of 31: 1, respectively. The latter ratio wasdetermined by integration of the 1H nmr signals of Hrj of 230 and Ha of 224.Preparation of 1 -hydroxymethyl-(E,E)-2.3-bis(ethvlidenecvclopentane (256(E)-5-Iodo-2-[(E)- 1-trimethyistannyl- 1 -propenyl]-5-hepten- 1-01(255) was convertedinto 1 -hydroxymethyl-(E,E)-2,3-bis(ethylidene)cyclopentane (256) with the followingamounts of reagents and solvents: dienc alcohol 255, 119 rng (0.268 mmol), in DMF,2.7 mL; CuCl, 66.3 mg (0.670 mmol). General procedure 12 (pp 283-284) was employed,except that the DMF solution of the diene alcohol 255 was heated at 70°C with an oil bath(—10 mm). Powdered CuC1 was added and the reaction mixture was stirred at 70 °C for10 mm. Radial chromatography (1 mm silica gel plate, 1: 1 petroleum ether-Et20) of thecrude product, followed by concentration of the appropriate fractions and distillation256290(45-65 OC/0.3 Torr) of the acquired liquid, provided 35.2 mg (86%) of the cyclopentane256 as a colorless oil that showed ir (neat): 3326 (br), 1141, 1028 cm-1;uv: max(€, solvent)= 254.2 nm (13400, MeOH); 1H nmr (CDC13, 400 MHz):6 1.35 (br signal, 1H, CH2OH.. wl/2= 11 Hz, exchanges with D20), 1.50-1.99 (m, 2H,Ha), 1.63 (d, 3H, =HdCth, 1= 7 Hz), 1.74 (d, 3H, =CHeC, J= 7 Hz), 2.19-2.33, (m,1H, Hb), 2.33-2.52 (m, 111, Hb), 3.02 (q, 1H, H, J= 7 Hz), 3.33-3.62 (m, 2H, CJjOH,simplifies after D20 exchange), 5.68-5.8 1 (m, 1H, HJ, 5.86 (br q, 1H, H, J= 7 Hz); in aseries of decoupling experiments, irradiation at 6 1.63 simpilfied the multiplet at 65.68-5.81to a broad singlet (wia= 6.5 Hz); irradiation at 6 1.74 simplified the broad quartet at 6 5.86to a broad singlet (wl/2= 4 Hz); in a series of nOe difference experiments, irradiation at6 1.74 caused enhancement of the signals at 6 3.02 (10%), 6 3.33-3.62 (3%) and 6 5.86(11%); irradiation at 3 3.02 caused enhancement of the signals at 6 1.74 (1%) and6 3.33-3.62 (2%); irradiation at 6 3.48 caused enhancement of the signals at 6 1.35 (5%),6 1.74 (1%) and 6 3.02 (4%); irradiation at 8 5.75 caused enhancement of the signals at6 1.63 (9%) and 6 5.86 (6%); 13C nmr (CDCI3, 50.3 MHz): 6 14.8, 14.9, 25.7, 27.5,44.4, 64.3, 112.9, 114.5, 140.8, 141.8. Exact mass calcd. forC10Hi6O: 152.1202; found:152.1193. Anal. calcd.: C 78.90, H 10.59; found: C 78.74, H 10.66.291eparation of methyl Z.-2-(3-rert-butvImethyIsiloxropvlidene-3-ethylidenecyc1o-pentanecarboxvlate (225t-BiFollowing general procedure 12 (pp 283-284), methyl (Z)-5-iodo-2-[(Z)-4-(tert-butyldimethylsiloxy)- 1 -trimethylstannyl- 1-butenyl]-5-heptenoate (212) was converted intomethyl (Z,Z)-2-(3-tert-butylmethylsioxypropylidene)-3-ethylidenecyclopentanecarboxylate(225) with the following amounts of reagents and solvents: diene 212, 92.4 mg(0.150 mmol), in DMF, 1.5 mL; CuCl, 45.0 mg (0.455 mmol). The resulting mixture wasstirred at 60 OC for 10 mm. Radial chromatography (2 mm silica gel plate, 25: 1 petroleumether-Et20) of the crude product, followed by concentration of the appropriate fractions andremoval of traces of solvent (vacuum pump) afforded 47.9 mg (98%) of the cyclopentane225 as a colorless liquid that showed spectra identical with those recorded previously (see pp273-274).225292Preparation of methyl (ZZ)-2.3-bis(cyclopropylmethylene)eyclopentanecarboxylate (228)Following general procedure 12 (pp 283-284), methyl (Z)-6-cyclopropyl-5-iodo-2-[(Z)-2-cyclopropyl-l-(trimethylstannyl)ethenyl]-5-hexenoate (215) was converted into methyl(Z,Z)-2,3-bis(cyclopropylmethylene)cyclopentanecarboxylate (228) with the followingamounts of reagents and solvents: diene 215, 104.3 mg (0.199 mmol), in DMF, 2.0 mL;CuC1, 49.3 mg (0.498 mmol). The reaction mixture was stirred at 60 °C for 2 mm. Radialchromatography (1 mm silica gel plate, 4: 1 petroleum ether-CH2C1)of the crude product,followed by concentration of the appropriate fractions and distillation (60-90 OC/0.3 Torr) ofthe residual liquid, gave 37.5 mg (8 1%) of the cyclopentanecarboxylate 228 as a colorlessliquid that showed spectra identical with those recorded earlier (see pp 277-278).228293eparadon of ethyl Z-2.3-bis(2-methvlpropylidenecyclopentanecarxylate (229Following general procedure 12 (pp 283-284), ethyl (Z)-5-iodo-7-methyl-2-[(Z)-3-methyl-1-trimethylstannyl-1-butenyl]-5-octenoate (216) was converted into ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxylate (229) with the following amounts ofreagents and solvents: diene 216, 81.3 mg (0.150 mmol), in DMF, 1.5 mL; CuC1, 37.0 mg(0.374 mmol). The reaction mixture was stirred at 60 OC for 5 mm. Radial chromatography(1 mm silica gel plate, 7: 1 petroleum ether-CH2C12) of the crude product, followed byconcentration of the appropriate fractions and distillation (45-65 °CI0.3 Torr) of the remainingoil, provided 30.5 mg (8 1%) of the cyclopentanecarboxylate 229 as a colorless liquid thatshowed spectra identical with those recorded earlier (see pp 279-280).229294Preparation of 1-methoxycarbonyl-7-methylenebicycloF4.2.Oloct-5-ene (289)Following general procedure 12 (pp 283-284), methyl 1-(2-bromo-2-propenyl)-2-trimethylstannyl-2-cyclohexenecarboxylate (284) was converted into the bicyclic diene 289with the following quantities of reagents and solvents: substrate 284,325 mg (0.770 mmol),in DMF, 8.0 mL; CuC1, 181 mg (1.82 mmol). The reaction mixture was stirred at 60 °C for5 miii. Radial chromatography (2 mm silica gel plate, 1: 1 petroleum ether-CH2C12) of thecrude product, followed by concentration of the appropriate fractions and distillation(43.57 Oc/O.15 Torr) of the remaining liquid yielded 107 mg (78%) of the bicyclic diene289, a colorless oil that displayed ir (neat): 1728, 1681, 1435, 1283, 1193, 1151, 872 cnr1;uv: max(e, solvent)= 242.3 nm (12600, n-pentane), 242.2 nm (14000, MeOH); 1H nmr(C6D, 400 MHz): 8 1.08 (td, 1H, Ha, J= 12, 3.5 Hz), 1.48-1.58 (m, 1H, Hb),1.63-1.76 (m, 1H, Hc), 1.74-1.86 (m, 1H, Hj), 2.00 (br dd, 1H, He, J= 19, 7 Hz),2.41 (dt, 1H, Hf, J= 12, 3.5 Hz), 2.49 (dt, 1H, 11g. J= 14, 2.5 Hz), 2.88 (dt, 1H, Hg,J= 14, 2.5 Hz), 3.35 (s, 3H, OCH3), 4.64 (hr s, 1H, =CH2wrn= 6 Hz), 5.07 (br s, 1H,=CH2, w= 7 Hz), 5.52 (dd, 1H, Hh, J= 4.5, 3 Hz); in a series of decoupling experiments,irradiation at 8 1.08 simplified the doublet of triplets at 8 2.41 to a triplet (J= 3.5 Hz);irradiation at 8 1.53 simplified the triplet of doublets at 6 1.08 to a triplet (J= 12 Hz), andsimplified the doublet of triplets at 82.41 to a doublet of doublets (.1= 12, 3.5 Hz); irradiationat 8 1.82 simplified the multiplet at 8 1.48-1.58 to a doublet of multiplets (J= 12 Hz for the289295doublet), the broad singlet at 8 5.07 to a triplet (J= 2.5 Hz) and the doublet of doublets at85.52 to a doublet (J= 3 Hz); irradiation at 32.00 simplified the broad singlet at 65.07 to atriplet (J= 2.5 Hz) and the doublet of doublets at 65.52 to a doublet (J= 4.5 Hz); irradiationat 82.41 simplified the triplet of doublets at 3 1.08 to a doublet of doublets (J= 12, 3.5 Hz);irradiation at 65.52 simplified the multiplet at 3 1.74-1.86 and sharpened the broad doubletof doublets at 8 2.00; all 1H nmr assignments are consistent with the results of a COSYexperiment (Table XXffl); 13C nmr (CDC13,50.3 MHz): 8 19.8, 24.0, 30.2, 42.6, 50.5,52.1, 101.8, 117.7, 141.7, 147.6, 175.8. Exact mass calcd. forC11H402:178.0994;found: 178.0987. Anal. calcd.: C 74.13, H 7.92; found: C 73.89, H 7.91.Table XXIII. Results of the COSY experiment of compound 289Assignment H 1H nmr (C6D,400 MHz): 3 COSY correlations to H(multiplicity, number of protons,coupling constant(s))Ha 1.08 (td, 1H, J= 12, 3.5 Hz) Hb, H, HfHb 1.48-1.58 (m, 1H) Ha, Hc, Hrj, HfF1 1.63-1.76 (m, 1H) Ha, Hb, FLj, He, HfH1j 1.74-1.86 (m, 1H) Hb, He. He, HhHe 2.00 (br dd, 1H, J= 19, 7 Hz) H, Hd, HhHf 2.41 (dt, 1H, J= 12, 3.5 Hz) Ha, Hb, FTcHg(A) 2.49 (dt, 1H, J= 14, 2.5 Hz) H(B), =CH2(A), =CH2(B)H(B) 2.88 (dt, 1H, J= 14, 2.5 Hz) H(A), =CH2(A), =CH2(B)=CH2(A) 4.64 (br s, 1H, w= 6 Hz) H(A), H(B), =CH2(B)=CH2(B) 5.07 (br s, 1H, wrn= 7 Hz) H(A), H(B), =CH2(A)Hh 5.52 (dd, 1H, J= 4.5, 3 Hz) H3,He296Preparation of 2-methoxvcarbonvl-8-methylenebicvclo[4.2.Oloct- 1 -ene (29OFollowing general procedure 12 (pp 283-284), methyl 3-(2-bromo-2-propenyl)-2-trimethylstannyl-1-cyclohexenecarboxylate (285) was converted into the cyclic diene 290with the following quantities of reagents and solvents: substrate 285, 124 mg (0.295 mmol),in DMF, 3.0 mL; CuC1, 80.0 mg (0.808 mmol). The reaction mixture was stirred at 60 OCfor 5 mlii. Radial chromatography (1 mm silica gel plate, 1: 1 petroleum ether-CH2C1)ofthe crude product, followed by concentration of the appropriate fractions and distillation(40-53 0C10.15 Torr) of the acquired oil produced 41.5 mg (79%) of the cyclic diene 290, acolorless liquid that showed ir (neat): 1708, 1659, 1435, 1262, 1233, 1212, 1195, 1130,1052 cm1;uv: max(E, solvent)= 266.5 nm (11000, n-pentane), 269.4 nm (10500, MeOH);nmr (CDC13,400 MHz): 8 1.01-1.15 (m, 1H), 1.38-1.53 (m, 1H), 1.84-1.98 (m, 2H),2.23-2.47 (m, 3H), 2.67-2.84 (m, 2H), 3.72 (s, 3H, OCH3), 5.00 (br s, 1H, =CH2wl/2= 6 Hz), 5.71 (br s, 1H, =CH2w1/2= 6 Hz); 13C nmr (CDC13,50.3 MHz): 8 21.7,24.7, 26.8, 35.8, 39.3, 51.0, 111.1, 118.3, 146.4, 155.8, 167.4. Exact mass calcd. forC11H402:178.0994; found: 178.0995. Anal. calcd.: C 74.13, H 7.92; found: C 73.89,H 7.86.290297Preparation of 1 -methoxycarbonvlbicvclo[3 .3.Olocta-3.5-diene (29flFollowing general procedure 12 (pp 283-284), methyl 1-[(Z)-3-iodo-2-propenylj-2-trimethylstannyl-2-cyclopentenecarboxylate (286) was converted into cyclic diene 291 withthe following quantities of reagents and solvents: substrate 286, 198 mg (0.436 mmol), inDMF, 4.4 mL; CuC1, 108 mg (1.09 mmol). The reaction mixture was stirred at 64 °C for2 mm. Radial chromatography (2 mm silica gel plate, 3: 1 petroleum ether-CH2C1)of thecrude product, followed by concentration of the appropriate fractions and distillation(35-50 OC/0.3 Torr) of the residual liquid afforded 57.2 mg (80%) of the cyclic diene 291,a colorless oil that exhibited ir (neat): 1724, 1291, 1248, 1163, 1061, 800 cm1;1H nnir(CDCl3, 400 MHz): 8 1.84 (br ddd, 1H, Ha, J= 12, 10, 8 Hz), 2.21 (br d, 1H, Hb,J= 16.5 Hz), 2.39 (dd, 1H, He J= 12, 6 Hz), 2.58 (dddd, 1H, F1d J= 16.5, 8, 3.5, 1 Hz),2.86-3.03 (m, 2H; includes He: dm centered at 2.91, J= 16.5 Hz for doublet, H1 m located at2.96-3.03, 1H), 3.62 (s, 3H, OCH3), 5.50 (br S, 1H, H, wrn= 7 Hz), 6.13-6.25 (m, 2H,Hh and Hj); in a series of decoupling experiments, irradiation at 8 1.84 simplified the doubletof doublets at 62.39 to a doublet (J= 6 Hz), and simplified the signal at 62.58 to a doublet ofdoublet of doublets (J= 16.5, 3.5, 1 Hz); irradiation at 6 2.21 simplified the resonanace at62.58 to a doublet of doublet of doublets (J= 16.5, 8, 3.5 Hz), and the doublet of multipletsat 62.91 to a narrow signal (wi= 4.5 Hz) and the broad singlet at 8 5.50 to a doublet ofdoublets (.1= 3.5, 2 Hz); irradiation at 6 2.39 simplified the broad doublet of doublet ofdoublets at 8 1.84 to a new doublet of doublet of doublets (J= 10, 8, 2 Hz); irradiation at29129882.58 simplified the broad doublet of doublet of doublets at 3 1.84 to a doublet of doublet ofdoublets (J= 12, 10, 2 Hz), irradiation at 8 2.91 simplified the broad doublet at 6 2.21 to abroad singlet (wl/2= 6 Hz); irradiation at 6 5.50 simplified the signal at 8 2.58 to a broaddoublet of doublets (J= 16.5, 8 Hz); irradiation at 66.19 simplified the doublet of multipletsat 6 2.91 to a broad doublet (J= 16.5 Hz); all 1H nmr assignments are consistent with theresults of a COSY experiment (Table XXIX); 13C nmr (CDC13,50.3 MHz): 8 37.1, 37.8,40.8, 52.0, 64.5, 118.4, 126.2, 140.3, 154.3, 176.4. Exact mass calcd. forC10H202:164.0838; found: 164.0836. Anal. calcd.: C 73.15, H 7.37; found: C 73.35, H 7.22.Table XXIX. Results of the COSY experiment of compound 291Assignment H 1H nmr (CDC13,400 MHz): 6 (multiplicity, COSY correlation(s) tonumber of protons, coupling constant(s)) HHa 1.84 (br ddd, 1H, J= 12, 10, 8 Hz) H, Hj, HfHb 2.21 (br d, 1H, J= 16.5 Hz) H, HH 2.39 (dd, 1H, J= 12, 6 Hz) Ha, HfH1j 2.58 (dddd, 1H, J 16.5, 8, 3.5, 1 HZ) Ha, Hf, HH 5.50 (br s, 1H, wrn= 7 Hz)299Preparation of 1-methoxvcarbonyl-4-methylbicyclo[3.3.Olocta-3.5-diene (253’)•Hh(Experiment 1: with 2.09 equiv CuC1). Following general procedure 12 (pp 283-284),methyl 1-[(Z)-3-iodo-2-butenyl]-2-thmethylstannyl-2-cyclopentenecarboxylate (252) wasconverted into cyclic diene 253 with the following quantities of reagents and solvents:substrate 252, 232 mg (0.494 mmol), in DMF, 5.4 mL; CuC1, 102 mg (1.03 mmol). Thereaction mixture was stirred at 60 OC for 5 mm. Radial chromatography (2 mm silica gelplate, 3: 1 petroleum ether-CH2C12) of the crude product, followed by concentration of theappropriate fractions and distillation (40-54 OC/0.3 Torr) of the residual oil gave 81.6 mg(93%) of the cyclic diene 253 as a colorless liquid that displayed ir (neat): 1729, 1435, 1292,1263, 1244, 1168, 1061, 808 cm-1; uv: m(C, solvent)= 243.3 nm (12000, n-pentane),242.2 nm (10600, MeOH); 1H nmr (CDC13,400 MHz): 6 1.78-1.92 (m, 4H; includes Ha:m, 1H; =CHCa3: narrow m centered at 1.82, 3H), 2.15 (br d, 1H, Hb, J= 16 Hz), 2.39(br dd, 1H, H, J= 12, 6 Hz), 2.57 (ddd, 1H, Hj, J= 16, 8, 3.5 Hz), 2.83 (dm, 1H, H,J= 16 Hz for doublet), 2.88-3.00 (m, 1H, Hf), 3.62 (s, 3H, OCH3), 5.50 (br S, 1H, Hg,w= 7 Hz), 5.75 (br s, 1H, Hh, w= 6 Hz); all 1H nmr assignments are consistent withthe results of a COSY experiment (Table XXX); 13C nmr (CDC13,50.3 MHz): 6 13.3, 37.6,37.7, 40.3, 51.9, 64.7, 116.5, 134.7, 135.4, 156.6, 176.6. Exact mass calcd. forC11H402: 178.0994; found: 178.0991. Anal. calcd.: C 74.13, H 7.92; found: C 73.97,H 8.01.253 254300Table XXX. Results of the COSY experiment of compound 253Assignment H 1H nmr (CDC13,400 MHz): 3 (multiplicity, COSY correlations tonumber of protons, coupling constant(s)) HHb 2.15 (br d, 1H, J= 16 Hz) =CHCth, He, HhH 2.39 (br dd, 1H, J= 12, 6 Hz) Ha, He, HfH€j 2.57 (ddd, 1H, J= 16, 8, 3.5 Hz) Ha, Hf, HH8 2.83 (dm, 1H, J= 16 Hz for doublet) =CHCj3,Hb, H, HhHf 2.88-3.00 (m, 1H) Ha, H, Hd, HH 5.50 (br s, 1H, wrn= 7 Hz) Hd, HfHh 5.75 (br s, 1H, w= 6 Hz) =CHCj, Hb, He(Experiment 2: with 1.01 equiv CuCl). Following general procedure 12 (pp 283-284),methyl 1-[(Z)-3-iodo-2-butenyl]-2-trimethyistannyl-2-cyciopentenecarboxylate (252) wasconverted into cyclic diene 253 with the following quantities of reagents and solvents:substrate 252, 233 mg (0.496 mmoi), in DMF, 5.4 mL; CuCl, 49.6 mg (0.501 mmol). Thereaction mixture was stirred at 60 0C for 65 mm. Radial chromatography (2 mm silica gelplate, 3: 1 petroleum ether-CH2C12) of the crude product gave three different components(with Rf = 0.20, 0.23 and 0.25 from tic analysis performing with 3 : 1 petroleumether-CH2C12).Concentration of the fractions with Rf= 0.20 and distillation (40-60 °C/0.3 Torr) of theremaining liquid afforded 62.2 mg (70%) of the cyclic diene 253.Distillation (45-65 °C/0.15 Torr) of the residual oil obtained from the concentration ofthe fractions containing material whose Rf = 0.23 gave 12.0 mg (8%) of the destannylatedcompound 254 as a colorless liquid that exhibited ir (neat): 1732, 1434, 1201, 1059 cur1;301nmr (CDC13,400 MHz): 8 1.75-1.86 (m, 1H), 2.25-2.60 (m, 5H), 2.48 (q, 3H,=CICIj3,J= 1 Hz), 3.67 (s, 3H, OCH3), 5.30 (tq, 1H, IC=CH, 1= 7, 1 Hz), 5.67 (dt, 1H,HC=Cjj, J= 5.5, 2 Hz), 5.83 (dt, 1H, HC=Cjj, J= 5.5, 2 Hz); 13C nmr (CDC13,50.3 MHz): 8 31.8, 32.2, 33.9, 44.9, 52.0, 59.6, 103.4, 131.1, 133.0, 133.2, 176.2.Exact mass calcd. for C1H1502:306.0118; found: 306.0118. Anal. calcd.: C 43.16,H 4.94, I 41.45; found: C 43.40, H 4.87, I 41.29.Concentration of the appropriate fractions containing the component with Rf = 0.25,followed by removal of traces of solvent (vacuum pump), yielded 35.2 mg (15%) of thestarting material 252.Preparation of (E)-4-ethylidene- 1-methoxycarbonvlbicvclo[3.3.rnoct-5-ene (222)Following general procedure 12 (pp 283-284), methyl 1-[(E)-3-iodo-3-pentenylJ-2-trimethylstannyl-2-cyclopentenecarboxylate (287) was converted into cyclic diene 292 withthe following quantities of reagents and solvents: substrate 287, 163 mg (0.337 mmol), inDMF, 3.4 mL; CuCl, 85.0 mg (0.859 mmol). The resulting mixture was stirred at 65°C for10 mm. Radial chromatography (1 mm silica gel plate, 3: 1 petroleum ether-CH2C12) of thecrude product, followed by concentration of the appropriate fractions and distillation(40-60 °CfO.15 Torr) of the remaining oil gave 62.6 mg (97%) of the cyclic diene 292, acolorless oil that displayed ir (neat): 1728, 1660, 1244, 1211, 1170, 1068 cm-1;1H nmr292302(C6D, 400 MHz): 8 1.20-1.32 (m, 1H), 1.51 (br d, 3H, =CHCH.3J= 7 Hz),1.58-1.69 (m, 1H), 2.34-2.59 (m, 4H), 2.77-2.92 (m, 1H), 2.98-3.10 (m, 1H, =CHjj),3.28 (s, 3H, OCH3), 5.61 (br s, 1H, =CaCH2, w112= 7 Hz), 5.72-5.80 (m, 1H,=CjjCH3); in a series of nOe difference experiments, irradiation at 6 1.51 causedenhancement of signals at 62.39-2.56 (part of the signal located at 2.34-2.59, assuming thattwo protons were enhanced) (4%) and 8 5.70-5.80 (6%); irradiation at 6 3.04 causedenhancement of signals at 6 2.34-2.48 (part of the signal located at 2.34-2.59, assuming thattwo protons were enhanced) (10%) and 6 5.61 (2%); irradiation at 8 5.75 caused anenhancement of signal at 6 1.51 (1%); 13C nmr (CDC13,50.3 MHz): 6 14.9, 32.6, 34.9,37.3, 38.4, 51.9, 65.4, 117.3, 119.7, 134.4, 151.7, 176.6. Exact mass calcd. forC12H602:192.1151; found: 192.1151. Anal. calcd.: C 74.97, H 8.39; found: C 74.56,H 8.27.Preparation of 1-methoxycarbonyl-5-methylenebicyclo[4.3.Olnon-6-ene (293)7dMethyl 1-(4-iodo-4-pentenyl)-2-triméthylstannyl-2-cyclopentenecarboxylate (288) wasconverted into cyclic diene 293 with the following quantities of reagents and solvents:substrate 288, 354 mg (0.734 mmol), in DMF, 7.3 mL; CuC1, 182 mg (1.84 mmol).General procedure 12(pp 283-284) was employed, except that the DMF solution of the dienealcohol 288 was heated at 90 °C with an oil bath (—10 mm). Powdered CuC1 was added and293303the reaction mixture was stirred at 90 0C for 5 mm. Radial chromatography (2 mm silica gelplate, 1: 1 petroleum ether-C6H6) of the crude product, followed by concentration of theappropriate fractions and distillation (40-55 OQ).3 Torr) of the residual oil provided 107 mg(75%) of the cyclic diene 293 as a colorless oil that showed ir (neat): 1729, 1630, 1240,1154, 891 cnr1; uv: max(e, solvent)= 224.2 nm (6770, n-pentane), 224.4 nm (5000,MeOH); 1H nmr (CDC13,400 MHz): 6 1.30 (td, 1H, J= 13, 3 Hz), 1.47 (qm, 1H, J= 13 Hzfor quartet), 1.71 (dm, 1H, J= 13 Hz for doublet), 1.80 (dt, 1H, J= 13, 9 Hz), 2.07 (tm,1H, J= 13 Hz for triplet), 2.24-2.42 (m, 4H), 2.46 (dm, 1H, J= 13 Hz for doublet), 3.63 (s,3H, OCH3), 4.71 (t, 1H, olefinic proton, J= 2 Hz), 5.02 (t, 1H, olefinic proton, J= 2 Hz),5.81 (t, 1H, oleflnic proton, J= 2 Hz); all 1H nmr signals are identical with those reported inlit.;7d 13C nmr (CDC13, 50.3 MHz): 3 24.2, 30.5, 34.0, 36.8, 38.7, 51.9, 58.2, 108.9,126.2, 143.1, 144.5, 176.6. Exact mass calcd. forC12H60:192.1151; found: 192.1153.Anal. calcd.: C 74.97, H 8.39; found: C 75.30, H 8.58.304Reactions of ethyl 6-bromo-2-1(E-1-trimethylstannyl-1-propenvl1-6-heptenoate (298 withCul. Isolation of ethyl 6-bromo-2-[(Z)-1-propenvll-6-heptenoate (306B) and ethyl 6-bromo-2-[(E’)- 1 -propenyll-6-heptenoate (3O6CBr EtO2C Br EtO2C Br CO2EtMe3Sn298 306B 306CFollowing general procedure l2(pp 283-284), the following quantities of reagents andsolvents were employed: ethyl 6-bromo-2-[(E)-1-trimethylstannyl- 1 -propenylj-6-heptenoate(298), 63.5 mg (0.145 mmol), in DMF, 1.5 mL; CuC1, 36.2 mg (0.366 mmol). Theresulting mixture was stirred at 60 °C for 10 mm. After normal work-up, the crude productwas eluted through a plug of silica gel (—2 g, 230-400 mesh) in a disposable pipette with 4: 1hexanes-CH2C12 (—10 mL). Concentration of the eluate and distillation (65-80 °C/0.3 Torr)of the remaining liquid afforded 35.7 mg (89%) of the a colorless liquid mixture thatconsisted of a mixture of the esters 306B and 306C in a ratio of 1: 1 (determined byintegration of 1H nmr signals). This unseparated liquid mixture displayed ir (neat): 1733,1631, 1160, 888 cnr1; 1H nmr (C6D,400 MHz): 6 0.88-0.98 (m, 3H, OCH2CTh),1.34-1.54 (m, 311, =CBrCHCjCH and =CBrCH2CH2 fl),1.46 (dd, 1/2 x 3H,=CHCII3 (from one of the two isomers), J= 6, 1 Hz), 1.47 (d, 1/2 x 3H, =CHCjj (fromthe other isomer), J= 5 Hz), 1.64-1.77 (m, 1H, =CBrCH2CthCH2 or =CBrCH2CH2Cth),2.07-2.18 (m, 2H, =CBrCH2), 2.87-2.94 (m, 1/2 x 1H, CHC=O (from one of the twoisomers)), 3.27-3.35 (m, 1/2 x 1H, CHC=O (from the other isomer)), 3.86-4.02 (m, 2H,OCH2), 5.16 (d, 1H, =CH2J= 1 Hz), 5.21 (br s, 1H, =CH2w= 4 Hz), 5.34-5.56 (m,2H, HC=CH); in a decoupling experiment, irradiation at 65.45 simplified both the doubletsof doublets at 6 1.46 and the doublet at 8 1.47 to two singlets. Exact mass calcd. for305C12H1979BrO2: 274.0569; found: 274.0575. Anal. calcd.: C 52.37, H 6.96, Br 29.04;found: C 52.68, H 7.09, Br 28.80.Reactions of l-(n-propyl)-2-trimethylstannyl-2-cyclohexenecarboxylate (300) with CuC1.Isolation of methyl 1-(n-propyl)-2-cyclohexenecarboxvlate (307A) and the dimers 307B.and 307CCO2MeCO2Me300 2 isomers: 307B, 307CFollowing general procedure l2(pp 283-284), the following quantities of reagents andsolvents were employed: 1-(n-propyl)-2-trimethylstannyl-2-cyclohexenecarboxylate (300),319 mg (0.925 mmol), in DMF, 9.0 mL; CuC1, 196 mg (1.98 mmol). The resulting mixturewas stirred at 60°C for 10 mm. After normal work-up, the crude product was subjected toradial chromatography (2 mm silica gel plate, 5: 1 hexanes-CH2C12 (—200 mL) and then 5: 1hexanes-Et20 (—200 niL)). Concentration of the appropriate fractions and distillation (orremoval of traces of solvent (vacuum pump)) of the remaining liquid afforded the followingsubstances in an order of increasing polarity:300: an amount of 47.0 mg (15%) of starting material 300 was recovered afterdistillation (75-90 °C/0.15 Torr).307A306307A: after distillation (75-90 °CI0. 15 Torr), 70.9 mg (42%) of 307A was obtained asa colorless oil that displayed ir (neat): 1733, 1209, 1135 cnr1;1H nrnr (CDC13, 400 MHz):60.85 (t, 3H, CH2jj3.1= 7 Hz), 1.13-1.32 (m, 2H), 1.33-1.70 (m, 5H), 1.86-2.04 (m,2H, =CHCth), 2.14 (ddd, 1H, J= 13, 7, 3 Hz), 3.65 (s, 3H, OCH3), 5.69 (br d, 1H, Ha,J= 10 Hz), 5.76 (dt, 1H, Hb, J= 10, 3.5 Hz); in a decoupling experiment, irradiation at8 1.95 sharpened the broad doublet at 85.69 and simplified the doublet of triplets at 85.76to a doublet (J= 10 Hz); 13C nmr (CDC13, 50.3 MHz): 8 14.5, 17.7, 19.8, 25.0, 30.9, 42.6,47.0, 51.7, 128.3, 129.9, 176.7. Exact mass calcd. forC11H8O2: 182.1307; found:182.1309. Anal. calcd.: C 72.49, H 9.95; found: C 72.31, H 9.98.307B: after removal of traces of solvent (vacuum pump), 13.3 mg (8%) of dimer 307Bwas isolated as a colorless solid (mp 91-92 °C) that exhibited ir (KBr): 1719, 1455, 1227,1161 cm1;1H nmr (CDC13,400 MHz): 8 0.86 (t, 6H, CH2Cth, J= 7 Hz), 1.14-1.34 (m,4H), 1.45-1.78 (m, 8H), 1.79-1.94 (m, 4H), 1.98-2.22 (m, 4H), 3.58 (s, 6H, OCH3),5.58 (t, 2H, =CH, J= 4 Hz); 13C nmr (CDC13,50.3 MHz): 6 14.9, 17.6, 17.8, 25.3, 33.5,39.3, 49.3, 51.4, 126.6, 138.0, 177.8. Exact mass calcd. for C22H3404: 362.2458; found:362.2466. Anal. calcd.: C 72.89, H 9.45; found: C 73.05, H 9.59.307C: after removal of traces of solvent (vacuum pump), 10.1 mg (6%) of dimer 307Cwas isolated as a colorless solid (mp 53-54 )C) that exhibited ir (KBr): 1721, 1456, 1226,1162 cm1;1H nmr (CDC13,400 MHz): 80.86 (t, 6H, CH2Jj3,J=7Hz), 1.15-1.36 (m,4H), 1.47-1.75 (m, 8H), 1.78-1.90 (m, 2H), 1.95-2.15 (m, 6H), 3.55 (s, 6H, OCH3),5.50 (t, 2H, =CH, 1= 4 Hz); 13C nmr (CDC13, 50.3 MHz): 8 14.8, 17.9, 17.95, 25.4,32.2, 38.5, 49.8, 51.4, 128.6, 139.6, 177.0. Exact mass calcd. forC22H3404:362.2458;found: 362.2461. Anal. calcd.: C 72.89, H 9.45; found: C 72.79, H 9.49.307Reactions of methyl 1-1(Z)-3-iodo-2-butenyllcvclohexanecarboxylate (303) with CuC1.Isolation of methyl 1 -F(Z)-3-chloro-2-butenyllcyclohexanecarboxylate (308)CO2MeA stirred solution of methyl l-[(Z)-3-iodo-2-butenyl]cyclohexanecarboxylate (303)(60.0 mg, 0.186 mmol) in dry DMF (2.0 mL) was warmed at 60 °C with an oil bath(—10 mm). Powdered CuCl (40.5 mg, 0.409 mmol) was added and the mixture was stirredat 60 0C for 4.5 h. Another portion of powdered Cud (120 mg, 1.21 mmol) was added andstirring was continued at 60 °C for another 6.5 h. Then powdered CuC1 (150 mg,1.52 mmol) and DMF (1.0 mL) were added, and the mixture was stirred at 60 OC for another35 h. The reaction flask was removed from the oil bath, aqueousNH4C1-NHO (pH =8)(10 mL) was added, and the mixture was opened to the atmosphere. After a short period oftime, Et20 (10 mL) was added and the mixture was stirred until the aqueous phase becamedeep blue (—15 mm). The phases were separated and the aqueous layer was extracted withEt20 (2 x 10 mL). The combined organic extracts were washed with brine (15 mL), dried(MgSO4) and concentrated. Radial chromatography (1 mm silica gel plate, 3: 1 petroleumether-CH2C12) of the crude product, followed by concentration of the appropriate fractionsand distillation (45-55 °CflJ.15 Torr) of the residual oil gave 27.3 mg (64%) of the ester 308as a colorless liquid that exhibited ir (neat): 1733, 1453, 1207,. 1135 cm-1;1H nmr (CDC13,400 MHz): 6 1.11-1.44 (m, 5H), 1.45-1.70 (m, 3H), 1.91-2.18 (m, 2H), 2.04 (br d, 3H,=CC1CH3,J= 1 Hz), 2.35 (br d, 2H, =CCH2J= 7 Hz), 3.65 (s, 3H, OCH3), 5.32 (tm,1H, =CH, J= 7 Hz for triplet); in a series of nOe difference experiments, irradiation at 6 2.04caused an enhancement of the signal at 8 5.32 (7%); irradiation at 6 2.35 caused anenhancement of the signal at 6 5.32 (5%); irradiation at 85.32 caused enhancement of the303 308308signals at 62.04 (2%) and 62.35 (1%); 1C nmr (CDC13,50.3 MHz): 8 23.1, 25.7, 26.4,33.8, 38.9, 47.1, 51.6, 120.8, 132.2, 176.7. Exact mass calcd. forC12H93510230.1075; found: 230.1070. Anal. calcd. forC12H9102:C 62.47, H 8.30; found:C 62.07, H 8.24.30912. Preparation of 2.3bis(a1kvlidene)cyclopentanecarboxamides52General procedure 13R3 R3R1C02R219 363R4 = aromatic or benzylicTo a stirred solution of aniline or benzylic amine (—1.5-2.0 equiv) in dry C6H (—3-5 mLper mmol of aniline or amine) was added a solution of 2.0 M solution of Me3A1 in toluene(—1.5-2.0 equiv). The resulting mixture was stirred at room temperature for 20 mm until nomore bubbling was observed. A solution of the cyclopentanecarboxylate 219 (1 equiv) indry C6H6 (—2.5-6 mL per mmol of the substrate) was added and the reaction mixture wasrefluxed for 4 h. A 2.0 M solution of hydrochloric acid (HC1) was added. The phases wereseparated and the aqueous phase was extracted three times with Et20. The combined organicextracts were washed with brine, dried (MgSO4) and concentrated. Flash or radial chromatography of the crude product, followed by concentration of the appropriate fractions, removalof traces of solvent (vacuum pump) and recrystallization of the substance provided the 2,3-bis(alkylidene)cyclopentanecarboxamides 363.310Preparation of (R .S)-(÷)- and (R .R)-(-)-N- 1 -phenylethyl-(Z2’)-2.3-bis(ethylidene)cyclo-pentanecarboxamides (237) and (238)Following general procedure 13 (p 309), the following amounts of reagents and solventswere used: (R)-(+)-l-phenylethylamine (235), 58.2 mg (0.480 mmol), in C6H,2.5 mL;Me3A1, 0.24 mL (0.48 mmol); ethyl (Z,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate(222), 42.9 mg (0.221 mmol), in C6H, 1.0 mL; 2.0 M HC1, 4.0 mL. Flash chromatography (27 g silica gel, 1: 1 petroleum etherEt20) of the crude product and removal of tracesof solvent (vacuum pump) yielded 28.0 mg (47%) of the amide 237 (the less polarcomponent) and 27.3 mg (46%) of the amide 238 (the more polar component).Recrystallization of the amide 237 from 1: 2 petroleum ether-Et20 afforded the amide237 as a colorless cube-like solid (mp 100.5-102 OC) that displayed ir (KBr): 3264, 1637,1554, 698 cm-1; [aJD= +193.4° (c= 1.00 in MeOH); 1H nrnr (CDC13,400 MHz): 6 1.41 (d,3H, PhCHCTh, J= 7 Hz), 1.62 (dt, 3H, =CHdCIZ3, J= 7, 2 Hz), 1.67 (br d, 3H,=CHeCIj3, 1= 7 Hz), 1.96-2.08, (m, 2H, Ha), 2.29-2.45 (m, 211, Hb), 3.20-3.25 (m, 1H,He), 5.07 (quintet, 111, PhCij, J= 7 Hz), 5.43 (br q, 1H, Hd J= 7 Hz), 5.52 (q, 1H, 11e.J= 7 Hz), 5.95 (hr d, 1H, NH, J= 7 Hz), 7.21-7.39 (m, 5H, aromatic protons); in a seriesof decoupling experiments, irradiation at 85.07 simplified the doublet at 6 1.41 to a singlet,and the broad doublet at 6 5.95 to a broad singlet (wl/2= 9 Hz); irradiation at 6 5.43HbbHaHHa237 238311simplified the doublet of triplets at 8 1.62 to a broad singlet (wj/2= 5 Hz); irradiation at8 5.52 simplified the doublet at 6 1.67 to a broad singlet (wi= 4 Hz); in a series of nOedifference experiments, irradiation at 82.37 caused an enhancement of the signal at 85.43(8%); irradiation at 6 3.23 caused enhancement of the signals at 6 5.52 (5%) and 6 5.95(5%); irradiation at 8 5.43 caused enhancement of the signals at 82.29-2.45 (3%) and 6 1.62(2%); irradiation at 8 5.52 caused enhancement of the signals at 8 1.67 (3%) and 63.20-3.25(7%); 1C nmr (CDC13,50.3 MHz): 6 17.15, 17.2, 21.9, 26.0, 31.8, 48.5, 52.0, 119.7,122.6, 126.0, 127.2, 128.6, 138.8, 139.3, 143.4, 173.5. Exact mass calcd. forC18H23N0: 269.1780; found: 269.1785. Anal. calcd.: C 80.26, H 8.61, N 5.20; found:C 79.99, H 8.76, N 5.10.Recrystallization of the amide 238 from 1: 2 petroleum ether-Et20 gave the amide 238as a colorless needle-like solid (mp 107-108 OC) that exhibited ir (KBr): 3292, 3273, 1642,1561, 1448, 704 cm-1; [cz]D= -20.57° (c= 0.860 in MeOH); 1H nmr (CDC13,400 MHz):8 1.44 (d, 3H, PhCHCth, J= 7 Hz), 1.57 (dt, 3H, =CHCj3, J= 7, 2 Hz), 1.67 (br d,3H, =CHeCth, J= 7 Hz), 1.90-2.05, (m, 211, Ha), 2.292.40 (m, 2H, Hb), 3.22-3.26 (m,1H, He), 5.07 (quintet, 1H, PhcDj, J= 7 Hz), 5.40 (br q, 1H, FLj, J= 7 Hz), 5.53 (q, 1H,He, J= 7 Hz), 5.92 (br d, 1H, NH, J= 7 Hz), 7.17-7.36 (m, 5H, aromatic protons); in aseries of decoupling experiments, irradiation at 8 2.35 simplified the doublet of triplets at6 1.57 to a doublet (J= 7 Hz), and sharpened the quartet at 8 5.40; irradiation at 6 5.07simplified the doublet at 8 1.44 to a broad singlet (wi= 2.5 Hz), and the broad doublet at65.92 to a broad singlet (w= 12 Hz); irradiation at 65.40 simplified the doublet of tripletsat 6 1.57 to a triplet (J= 2 Hz); irradiation at 85.53 simplified the doublet at 8 1.67 to a broadsinglet (wl/2= 3.5 Hz); 13C nmr (CDC13, 50.3 MHz): 8 17.15, 17.2, 21.9, 25.9, 31.6,48.4, 52.1, 119.8, 122.8, 125.8, 127.1, 128.5, 138.7, 139.4, 143.5, 173.5. Exact masscalcd. forC18H23N0: 269.1780; found: 269.1786. Anal. calcd.: C 80.26, H 8.61, N 5.20;found: C 80.33, H 8.59, N 5.09.312Preparation of N-p-chlorophenvl-(Z.Z-2.3-bis(cvclopropvlmethv1ene)cvclopentanecarbox-amide (241)Following general procedure 13 (p 309), the following amounts of reagents and solventswere used: p-chloroaniline (239), 66.3 mg (0.520 mmol), in C6H, 2.6 mL; Me3A1,0.26 mL (0.52 mmol); methyl (Z,Z)-2,3-bis(cyclopropylmethylene)cyclopentanecarboxylate(228), 79.9 mg (0.343 mmol), in C6H6, 2.0 mL; 2.0 M HQ, 4.0 mL. Flash chromatography (20 g silica gel, 4: 1 petroleum etherEt20) of the crude product and removal of tracesof solvent (vacuum pump) produced 93.5 mg (83%) of the amide 241. Recrystallization ofthis material from 1: 1 CH2C12-EtOH gave the amide 241 as a colorless needle-like solid(mp 126-127 OC) that showed ir (KBr): 3255, 1664, 1594, 1494, 1399, 1096, 824 cm1;nmr (CDC13, 400 MHz): 0.42-0.60 (m, 4H, cyclopropyl methylene protons),0.80-0.95 (m, 4H, cyclopropyl methylene protons), 1.77-1.90 (m, 2H, cyclopropyl methineprotons), 2.00-2.10 (m, 1H, Ha), 2.10-2.22 (m, 1H, Hb), 2.35-2.53 (m, 2H, He),3.40 (dd, 1H, Hj, J= 9, 4 Hz), 4.87 (d, 1H, He, J= 10 Hz), 4.96 (d, 1H, Hf, 1= 10 Hz),7.26 (d, 2H, aromatic protons, J= 9 Hz), 7.44 (d, 2H, aromatic protons, J= 9 Hz),7.56 (br S. 1H, NH, wl/2= 8 Hz); in a decoupling experiment, irradiation at 8 1.82simplified the multiplets at 6 0.42-0.60 and 6 0.80-0.95, and simplified the two doublets at24131384.87 and 8 4.96 to two broad singlets (wl/2= 5, 3 Hz, respectively); in a series of nOedifference experiments, irradiation at 6 3.40 caused enhancement of the signals at82.10-2.22 (9%) and 84.96 (10%); irradiation at 84.87 caused enhancement of the signalsat 8 1.77-1.90 (4%) and 6 2.35-2.53 (3%); irradiation at 6 4.96 caused an enhancement ofthe signal at 8 3.40 (4%); 13C nmr (CDC13,50.3 MHz): 6 6.9, 7.1, 8.5, 8.9, 13.8, 14.1,26.9, 31.9, 53.3, 120.6, 128.85, 128.9, 130.2, 133.6, 135.6, 136.2, 136.8, 173.3. Exactmass calcd. forC20H2351N0: 327.1392; found: 327.1384. Anal. calcd. forC20H21N0:C 73.27, H 6.76, N, 4.27; found: C 73.17, H 6.67, N, 4.40.314Preparation of (R.S)-(÷)- and (R.R)-(-)-N- 1 -phenvlethvl-(Z.Z)-2.3-bis(2-methvlpropvli-dene)cyclopentanecarboxamides (242) and (243)Following general procedure 13 (p 309), the following amounts of reagents and solventswere used: (R)-(+)-l-phenylethylamine (235), 94.5 mg (0.780 mmol), in C6H,4.0 mL;Me3Al, 0.39 mL (0.78 mmol); ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentane-carboxylate (229), 87.1 mg (0.348 mmol), in C6H6, 1.0 mL; 2.0 M HC1, 4.0 mL. Flashchromatography (30 g silica gel, 1: 1 petroleum etherEt20) of the crude product and removalof traces of solvent (vacuum pump) produced 45.7 mg (40%) of the ainide 242 as a colorlessliquid (the less polar component) and 52.2 mg (46%) of the anilde 243 as a solid (the morepolar component).The amide 242 displayed ir (neat): 3289, 1645, 1538, 1451, 699 cm1; [a]D= +156.9°(c= 0.875 in MeOH); 1H nmr (CDC13,400 MHz): 80.90 (d, 3H, =CH(Cjj)2J= 6.5 Hz),0.94 (d, 3H, =CHj(Cth)2, J= 6.5 Hz), 1.00 (d, 3H, =CHj(Cth)2, J= 6.5 Hz), 1.02 (d,3H, =CHc(C1j3)2, J= 6.5 Hz), 1.42 (d, 3H, PhCHHj, J= 7 Hz), 1.88-1.97 (m, 1H, Ha),1.98-2.10 (m, 1H, Ha), 2.21-2.31 (m, 2H, Hb), 2.33-2.43 (m, 1H, He), 2.43-2.55 (m, 1H,Hd), 3.19 (dd, 1H, H, J= 9, 5 Hz), 5.07 (quintet, 1H, PhCR, J= 7 Hz), 5.12 (d, 1H,=CaCH, J= 10 Hz), 5.20 (d, 1H, =CHCHd, J= 10 Hz), 6.03 (br d, 1H, NH, J= 7 Hz),7.18-7.38 (m, 5H, aromatic protons); in a series of decoupling experiments, irradiation atHbHaHbH242 2433156 2.38 simplified the doublets at 8 0.90, 8 1.02 and 8 5.12 to three singlets; irradiation at8 2.49 simplified the doublets at 3 0.94, 8 1.00 and 3 5.20 to three singlets; in a series ofnOe difference experiments, irradiation at 32.26 caused an enhancement of the signal at6 5.12 (9%); irradiation at 6 3.19 caused enhancement of the signals at 6 1.98-2.10 (5%),85.20 (7%) and 6 6.03 (3%); irradiation at 6 5.12 caused enhancement of the signals at62.21-2.31(2%) and 62.33-2.43 (2%); irradiation at 35.20 caused an enhancement of thesignal at 6 3.19 (7%); 13C nmr (CDC13,50.3 MHz): 6 21.9, 22.1, 22.2, 23.3, 23.8, 25.6,29.5, 29.6, 33.3, 48.5, 51.8, 125.9, 127.2, 128.6, 132.6, 134.8, 135.2, 136.2, 143.4,173.6. Exact mass calcd. forC22H31N0: 325.2407; found: 325.2414. Anal. calcd.:C 81.18, H 9.60, N 4.30; found: C 81.08, H 9.71, N 4.41.Recrystallization of the amide 243 from 1: 1 petroleum ether-Et20 provided the ainide243 as a colorless needle-like solid (mp 110-111 °C) that exhibited ir (KBr): 3273, 1641,1547, 697 cm-1; [ctJD= -40.07° (c= 0.750 in MeOH); 1H nmr (CDC13,400 MHz): 60.65 (d,3H, =CH(Cli3)2, J= 6.5 Hz), 0.94 (d, 3H, =CHd(Cth)2, 1= 6.5 Hz), 0.95 (d, 3H,=CHc(C1j3)2, J= 6.5 Hz), 1.02 (d, 3H, =CHj(Cfl)2, J= 6.5 Hz), 1.46 (d, 3H, PhCHCjj3J= 7 Hz), 1.86-2.06 (m, 2H, Ha), 2.18-2.35 (m, 3H, two Hb and Hc), 2.40-2.52 (m, 1H,Hd), 3.21 (ddd, 1H, H, J= 9, 5, 1 Hz), 5.01-5.11 (m, 1H, PhCj), 5.06 (d, 1H, =CjjCH,J= 10 Hz), 5.21 (d, 1H, =CUCHd, J= 10 Hz), 6.00 (br d, 1H, NH, J= 6.5 Hz),7.16-7.34 (m, 5H, aromatic protons); in a series of decoupling experiments, irradiation at6 2.27 simplified the doublets at 6 0.65, 60.95 and 6 5.06 to three singlets; irradiation at62.46 simplified the doublets at 6 0.94, 6 1.00 and 3 5.21 to three singlets; in a series ofnOe difference experiments, irradiation at 62.27 caused an enhancement of the signal at6 5.06 (5%); irradiation at 6 3.21 caused enhancement of the signals at 6 5.21 (9%) and66.00 (5%); irradiation at 65.06 caused an enhancement of the signal at 62.18-2.35 (3%);irradiation at 65.21 caused an enhancement of the signal at 63.21(7%); 13C nnir (CDC13,50.3 MHz): 8 22.0, 22.2, 22.3, 23.3, 23.4, 25.5, 29.5, 29.6, 33.2, 48.7, 52.0, 125.9,316127.2, 128.6, 132.7, 134.6, 135.3, 136.1, 143.4, 173.5. Exact mass calcd. forC22H31N0: 325.2407; found: 325.2397. Anal. calcd.: C 81.18, H 9.60, N 4.30; found:C 81.03, H 9.65, N 4.40.Preparation of (S.R)-(+)- and (S.S)-(--N- 1 -phenvlethvl-(Z.Z)-2.3-bis(2-methvlpropvli-denecvc1opentanecarboxamides (246 and (247)Following general procedure 13 (p 309), the following amounts of reagents and solventswere used: (S)-(÷)-1-phenylethylamine (244), 107 mg (0.883 mmol), in C6H6, 3.0 mL;Me3A1, 0.44 mL (0.88 mmol); ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentane-carboxylate (229), 99.2 mg (0.396 mmol), in C6H, 1.0 mL; 2.0 M HC1, 4.0 mL Flashchromatography (30 g sffica gel, 3: 1 petroleum ether Et20) of the crude product and removalof traces of solvent (vacuum pump) yielded 51.0 mg (40%) of the aruide 246 as a colorlessliquid (the less polar component) and 56.0 mg (43%) of the amide 247 as a solid (the morepolar component).The amide 246 exhibited ir (neat): 3284, 1646, 1539, 1451, 761, 699 cm1;[a]D= -151.7° (c= 0.528 in MeOH); 1H nmr (CDC13,400 MHz) and 13C nmr (CDC13,50.3 MHz): identical with those of (R,S)-(-)-N-1-phenylethyl-(Z,Z)-2,3-bis(2-methyl-H/H/246 247317propylidene)cyclopentanecarboxamide (242). Exact mass calcd. forC22H31N0: 325.2407;found: 325.2412. Anal. calcd.: C 81.18, H 9.60, N 4.30; found: C 80.89, H 9.46, N 4.16.Recrystallization of the amide 247 from 1: 1 petroleum ether-Et20 provided the amide247 as a colorless needle-like solid (mp 111-112 °C) that showed ir (KBr): 3271, 1641,1548, 697 cm-1; [a]D= +40.43° (c= 0.800 in MeOH); 1H nmr (CDC13,400 MHz) andnrnr (CDC13, 50.3 MHz): identical with those of (R,R)-(-)-N-1-phenylethyl-(Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxamide (243). Exact mass calcd. forC22H31N0: 325.2407; found: 325.2397. Anal. calcd.: C 81.18, H 9.60, N 4.30; found:C 81.09, H 9.60, N 4.23.Prenaration ofN-p-ch1oronhenvl-(Z.E)-2,3-bis(ethv1idenecvc1onentanecarboxamide (257Following general procedure 13 (p 309), the following amounts of reagents and solventswere used: p-chloroaniline (239), 56.1 mg (0.440 mmol), in C6H6, 2.0 mL; Me3Al,0.22 mL (0.44 mmol); ethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (257),38.8 mg (0.200 mmol), in C6U6, 0.5 mL; 2.0 M HC1, 5.0 mL. Radial chromatographyHbH/257318(2 mm silica gel plate, 3: 1 petroleum etherEt20) of the crude product and removal of tracesof solvent (vacuum pump) gave 54.5 mg (99%) of the amide 257. Recrystallization of thismaterial from 1: 1 hexanes-Et20 provided the amide 257 as a colorless square plate-likesolid (mp 102-104 OC) that showed ir (KBr): 3281, 1658, 1537, 1493, 1400, 830 cm1;1H nrnr (CDC13, 400 MHz): 3 1.74 (br d, 3H, =CHCj, J= 7 Hz), 1.87-1.99 (m, 1H, Ha),1.91 (br d, 3H, =CHCth, J= 7 Hz), 2.17-2.26 (m, 1H, Ha), 2.38-2.59 (m, 2H, Hb),3.30-3.40 (m, 1H, He), 5.71 (br q, 1H, =CHCH3, J= 7 Hz), 5.85-5.94 (m, 1H, =jCH3),7.24 (d, 2H, aromatic protons, J= 9 Hz), 7.43 (d, 2H, aromatic protons, J= 9 Hz),7.57 (br s, 1H, NH, wl/2= 10 Hz); 13C nmr (CDC13, 100.6 MHz): 6 15.4, 15.6, 27.6,29.1, 55.5, 120.9, 121.4, 123.1, 128.9, 129.1, 136.5, 139.5, 140.6, 172.3. Exact masscalcd. forC16H8351N0: 275.1078; found: 275.1079. Anal. calcd. forC16H81N0:C 69.69, H 6.58, N 5.08; found: C 69.32, H 6.59, N 5.03.31913. Diels-Alder reactions of dienes with tetracvanoethvlene (TCNE)Preparation of the ester 31ZNNC•NC•A solution of ethyl (E)-2-ethylidene-3-methylenecyclopentanecarboxylate (221)(71.6 rag, 0.397 mmol) and TCNE (59.0 mg, 0.461 mmol) in dry THF (3.0 mL) wasstirred at room temperature for 1 h. The reaction mixture was concentrated and the crudeproduct was eluted through a plug of silica gel (2 g, 230-400 mesh) with 1: 1 petroleumether-Et20 (20 niL). The eluate was concentrated and purified by radial chromatography(1 mm silica gel plate, 1: 1 petroleum ether-Et20). Concentration of the appropriatefractions and removal of traces of solvent (vacuum pump) afforded 97.1 mg (79%) of amixture of the esters 312 and 313 in a ratio of 21: 1 (determined by integration of 1H nnirsignals), respectively. Recrystallization of this mixture from Et20 provided the ester 312 asa colorless solid (mp 129.5-130 °C) that exhibited ir (KBr): 2255, 1719, 1462, 1446, 1377,1346, 1261, 1211, 1032 cm-1; 1H nmr (CDC13,400 MHz): 6 1.27 (t, 3H, OCH2CII3J= 7 Hz), 1.58 (d, 3H, CHCIj3J= 7 Hz), 2.19-2.40 (rn, 2H), 2.43-2.62 (m, 2H),3.08 (d, 1H, H, J= 18 Hz), 3.15 (dm, 1H, H, J= 18 Hz for doublet),3.37-3.48 (br signal, 1H, CIjCH3wl/2= 18 Hz), 3.56-3.66 (m, 1H, FL3), 4.10-4.25 (m,2H, OCH2); in a decoupling experiment, irradiation at 63.43 simplified the doublet at 3 1.58to a singlet; in a series of nOe difference experiments, irradiation at 3 1.58 causedenhancement of the signals at 83.37-3.48 (15%) and 63.56-3.66 (11%); irradiation at 63.61312 313320caused an enhancement of the signal at 6 1.58 (2%); nmr (C6D,50.3 MHz): 6 14.1,14.4, 26.1, 32.5, 34.4, 37.9, 39.3, 46.0, 50.6, 61.1, 109.7, 110.7, 111.9, 112.0, 132.2,133.2, 171.7. Exact mass calcd. forC17H6N402:308.1275; found: 308.1277. Anal.calcd.: C 66.22, H 5.23, N 18.17; found: C 66.19, H 5.22, N 17.99. The minor product313 (the 1H nmr spectrum of 313 was recorded in the next section (infra vida)) showed thesignals at 6 1.50 (d, CHCJj3J= 7 Hz), 2.09-2.17 (m), 2.29-2.39 (m), 3.47-3.52 (m, Hj) inthe 1H nmr spectrum of the mixture of the esters 312 and 313, which are in a ratio of 21: 1,respectively. The latter ratio is determined by the integration of the signals of CHCj (at6 1.58) of 312 and CHcj (at 5 1.50) of 313.Preparation of the ester 313NH NHbjjbHT CO2Et313A solution of ethyl (Z)-2-ethylidene-3-methylenecyclopentanecarboxylate (220)(31.9 mg, 0.177 mmol) and TCNE (30.7 mg, 0.240 mmol) in dry THF (2.0 mL) wasstirred at room temperature for 1 h and 45 mm. The reaction mixture was concentrated andthe crude product was eluted through a plug of silica gel (2 g, 230-400 mesh) with 1: 1petroleum ether-Et20 (20 mL). The eluate was concentrated and purified by radialchromatography (1 mm silica gel plate, 1: 1 petroleum ether-Et20). Concentration of theappropriate fractions and removal of traces of solvent (vacuum pump) afforded 47.4 mg(87%) of a mixture of the esters 313 and 312 in a ratio of 6.3: 1 (determined by integration312321of 1H nmr signals), respectively. Recrystallization of this mixture from 1: 1 petroleumether-Et20 provided the ester 313 as a colorless solid (mp 113-115 0C) that exhibitedir (KBr): 2255, 1729, 1257, 1032 cm1;1H nmr (CDC13,400 MHz): 6 1.27 (t, 3H,OCH2Ca3, J= 7 Hz), 1.50 (d, 3H, CHCjj3, J= 7 Hz), 2.09-2.17 (m, 1H), 2.29-2.39 (m,2H), 2.70-2.82 (m, 1H), 3.15 (d, 1H, FIG, J= 17 Hz), 3.24 (d, 1H, H, J= 17 Hz),3.24-3.34 (br signal, 1H, CRCH3, W1/2 18 Hz), 3.47-3.52 (m, 1H, Hj), 4.13-4.20 (m,2H, OCH2); in a decoupling experiment, irradiation at 8 1.50 sharpened the broad signal at6 3.24-3.34 to a broad singlet (wl/2= 9 Hz); in a series of nOe difference experiments,irradiation at 6 1.50 caused enhancement of the signals at 63.24-3.34(32%) and 63.47-3.52(19%); irradiation at 6 3.29 caused the enhancement of the signals at 6 1.50 (3%) and6 3.47-3.52 (10%); irradiation at 63.50 caused enhancement of the signals at 6 1.50 (2%),6 2.29-2.39 (8%) and 8 3.24-3.34 (13%); 13C nmr (CDC13, 100.6 MHz): 6 14.1, 14.3,28.9, 33.8, 34.9, 38.4, 39.0, 45.7, 51.7, 61.3, 108.6, 110.5, 111.05, 111.1, 132.2,135.0, 173.4. Exact mass calcd. forC17H6N402: 308.1275; found: 308.1278. Anal.calcd.: C 66.22, H 5.23, N 18.17; found: C 66.09, H 5.21, N 18.23. The minor product312 (the 1H nmr spectrum of 312 was recorded in the previous section (supra vida)) showedthe signals at 6 1.58 (d, CHCjb, .1= 7 Hz), 2.43-2.62 (m), 3.08 (d, J= 18 Hz),3.37-3.48 (br signal, CJjCH3w= 18 Hz), 3.56-3.66 (m, H