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Synthesis and some related studies of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates Wong, Timothy 1993

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SYNTHESIS AND SOME RELATED STUDIES OF ALKYL 2,3-BIS (ALKYLIDENE)CYCLOPENTANECARBOXYLATES  by TIMOTHY WONG  B. Sc., The Chinese University of Hong Kong, 1986 M. Ph., The Chinese University of Hong Kong, 1988  A THESIS SUBM1YED IN PARTIAL FULFILLMENT OF  THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES  (Department of Chemistry)  We accept this thesis as confirming to the required standard  TEIE UNWERSITY OF BRiTISH COLUMBIA  December 1993  © Timothy Wong  In presenting this thesis  in  partial fulfilment  of the requirements for degree at the University of British Columbia, I agree that the Library freely available for reference and study. I further agree that permission copying of this thesis for scholarly purposes may be granted by the department  or  by  his  or  an advanced shall make it for extensive head of my  her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.  (Signature)  Department  of  The University of British Columbia Vancouver, Canada Date  DE.6 (2/88)  )  -)  [3  U  ABSTRACT With the use of lithium (trimethylstannyl)(cyano)cuprate (123), aj3-acetylenic esters of general structure 100 were converted into the corresponding alkyl (E)- and (Z)-3trimethylstannyl-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-2ailcenoates 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 CuC1-mediated intramolecular coupling reaction of vinyl halide and vinyltrimethylstannane functions was discovered in conjunction with studies directed toward  111  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 2,3bis(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.  R  nCuCNJLI [Me S 3  R 2 C0  12 R _HCO2R n Me S 3  R 2 C0  n Mc S 3 91  89  100  123  H  H  R  R  R’ 99  96 (X  =  Br or 1)  97 (X  =  Br or 1)  3 R  C 0 2 R 3 R  R 2 C0  n X 3 Me S  219  206  3 ‘%\ R R1L R 2 C0  q  R‘ 3  R 2 C0 R’ E,Z-diene 82  Z,E-diene 83  %OQD t CO E 2  230  E,E-diene 81  t CO E 2  222  e CO M 2  228  Z,Z-diene 84  t CO E 2 229  iv  —  H  D  H N 238  237  241  —  Cl  247  243  C 2 MeO  289  C 2 MeO  C 2 MeO  290  253  291  cc?  O CH ( 2 t-Bu) SiPh  R 2 C0  292  293  314  219  NR3 C  1 R R 2 315 E=C0  324 E = C0 R 2  O CH ( t-Bu) SIPh 316 B = 2  325 B  =  E  O CH ( 2 t-Bu) S1Ph  V  TABLE OF CONTENTS  ABSTRACT  ii  TABLE OF CONTENTS  v  LIST OF TABLES  ix  LIST OF FIGURES  xi  LIST OF GENERAL PROCEDURES  xii  LIST OF ABBREVIATIONS  xiii  ACKNOWLEDGEMENTS  xx  I.  INTRODUCTION  1  1.  Palladium-catalyzed coupling reactions and their synthetic applications  1  2.  Previous work on the syntheses of ethyl 2,3-bis(alkylidene)cyclobutanecarboxylates and some related studies  3.  12  Previous synthetic studies of 1,2-bis(allcylidene)cyclopentanes and related 1,2-bis-exocyclic dienes  20  vi 4.  Proposal regarding a study of the preparation and chemistry of alkyl 2,3bis(alkylidene)cyclopentanecarboxylates  27  II.  RESULTS AND DISCUSSION  32  1.  Syntheses of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates  32  1.1. Preparation of a,j3-acetylenic esters  32  1.2. Conversion of a,J.3.acetylenic esters into alkyl (E)- or (Z)-3-trimethylstannyl-2-alkenoates  2.  36  Deconjugation-alkylation of alkyl (E)- and (Z)-3-trimethylstannyl-2alkenoates  43  2.1. Preparation of electrophiles: 2-bromo-4-iodo-1-butene, (2)- and (E) diiodoalkenes  43  2.2. Deconjugation-allcylation of ailcyl (E)- and (Z)-3-trimethylstannyl-2alkenoates, and of ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate with the prepared electrophiles  3.  57  Syntheses of alkyl 2,3-bis(allcylidene)cyclopentanecarboxylates and related derivatives  66  3.1. Stereocontrolled syntheses of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates and related substances via palladium(O)-catalyzed coupling reactions 3.2. X-ray analysis of (Z,Z)-2,3-bis(alkylidene)cyclopentanecarboxamides  66 74  vii 4.  Discovery of the CuC1-mediated intramolecular coupling reacon  89  4.1. Introduction  89  4.2. Stereocontrolled preparation of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates via CuC1-mediated intramolecular coupling of vinyl trimethyistannane and vinyl halide functions 4.3. Preparation of bicyclic dienes  96 101  4.4. Preliminary studies on the mechanistic aspects and the limitations of the CuC1-mediated coupling process  5.  117  Diels-Alder reactions of alkyl 2,3-bis(alkylidene)cyclopentancarboxylates and structurally related substances  128  5.1. Introduction  128  5.2. Diels-Alder reactions of dienes with tetracyanoethylene (TCNE)  129  5.3. Diels-Alder reactions of dienes with methyl vinyl ketone (MVK)  140  III.  CONCLUSIONS  166  IV.  EXPERIMENTAL SECTION  176  General  176  1.1. Data Acquisition and presentation  176  1.2. Solvents and reagents  179  2.  Preparation of a,j3-acetylenic esters  181  3.  Preparation of lithium (trialkylstannyl)(cyano)cuprates  188  4.  Preparation of alkyl (E)-3-thmethylstannyl-2-alkenoates  189  1.  VIII  5.  Preparation of ethyl (Z)-3-aylstnyl-2-pentenoates  195  6.  Preparation of alkyl (Z)-2,3-bis(trimethylstannyl)-2-alkenoates  198  7.  Preparation of aikyl 2-trimethylstannyl- 1-cycloalkenecarboxylates  200  8.  Preparation of alkylating agents  203  9.  Preparation of a-alkylated esters and related derivatives  233  10.  Stereocontrolled preparation of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates and related substances via intramolecular palladium(0)catalyzed coupling reactions of vinyl halide and vinyistannane functions  11.  262  Preparation of ailcyl 2,3-bis(alkylidene)cyclopentanecarboxylates and other dienes via CuC1-mediated intramolecular coupling reactions of vinyl halide and vinyistannane functions  283  12.  Preparation of 2,3-bis(alkylidene)cyclopentanecarboxamides  309  13.  Diels-Alder reactions of dienes with tetracyanoethylene (TCNE)  319  14  Diels-Alder reactions of dienes with methyl vinyl ketone (MVK)  326  V.  REFERENCES  341  VI.  APPENDIX  359  lx  LIST OF TABLES  Table I.  Effect of varying reaction conditions on the coupling reacon  4  II.  Syntheses of the cyclobutanecarboxylates 37  12  ifi.  Syntheses of the cycloalkanecarboxylates 41  15  IV.  Syntheses of the E,E-1,2-bis-exocyclic dienes 60  21  V.  Effect of the  ring  size on the yields of E,E-bis(ethylidene)cycloallcanes  66  23  VI.  Syntheses of the 1,2-bis(allcylidene)cyclopentanes 68  24  VII.  Syntheses of the 1,2-bis(alkylidene)cyclopentanes 68  25  VIII.  Preparation of alkyl (Z)-3-trimethylstannyl-2-alkenoates 91  38  IX.  Preparation of alkyl (E)-3-trimethylstannyl-2-alkenoates 89  39  X.  Deconjugation reactions of the alkyl (E)- and (Z)-3-irimethylstannyl-2alkenoates 89 and 91, respectively  XI.  Conversions of the alkyl (Z)-3-trimethylstannyl-3-alkenoates 90 into the corresponding (Z)-diiodoalkenes 98  XII.  86  Attempted preparation of ethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (230) under different reaction conditions  XVI.  66-68  Dihedral angles between the carbon-carbon double bonds of (Z,Z)-2,3bis(alkylidene)cyclopentanecarboxamides  XV.  58-60  Stereocontrolled syntheses of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 219  XIV.  56  Deconjugation-alkylation of ailcyl (E)- and (Z)-3-trimethylstannyl-2alkenoates 89 and 91 with the prepared electrophiles  XIII.  46  90  Preparation of ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxylate (229) under different reaction conditions  91  x XVII.  Effect of CuC1 on the preparation of ethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (230) under different reaction conditions  XVIII.  Effect of different amounts of CuC1 on the preparation of ethyl (E,Z) 2,3-bis(ethylidene)cyclopentanecarboxylate (223)  XIX.  93  94  Effect of different amounts of CuC1 on the preparation of 1methoxycarbonyl-4-methylbicyclo[3.3.0]oct-3,5-diene (253)  95  XX.  CuC1-mediated intramolecular couplings of iodo trimethylstannane 206  97  XXI.  Deconjugation-alkylation of methyl 2-trimethyistannyl- 1-cyclopentenecarboxylate (258) and methyl 2-trimethylstannyl-1-cyclohexenecarboxylate (259)  XXII.  CuC1-mediated intramolecular coupling of monocyclic substrates of general structure 260  XXIII.  Results of the COSY experiment of compound 289  XXIV.  Effect of different sources of Cu(I) on the intramolecular coupling of substrate 209 or 211  XXV.  109-110  112 115 & 295  117-118  Effect of different solvents on the CuCl-mediated intramolecular coupling of substrate 209  120  XXVI.  Preparation of some substrates via deconjugation-alkylation  121-122  XXVII.  Diels-Alder reactions of dienes 219 and 314 with TCNE  130-131  XXVIII. Diels-Alder reactions of dienes 219 and 314 with MVK  141-142  XXIX.  Results of the COSY experiment of compound 291  298  XXX.  Results of the COSY experiment of compound 253  300  XXXI.  Results of the COSY experiment of compound 327  328  XXXII.  Results of the COSY experiment of compound 331  333  xi  LIST OF FIGURES  Figure 1.  X-ray structure of 237A, 237B, 237C and 237D  76  2.  X-ray structure of 237A and 237B  78  3.  X-ray structure of 237C and 237D  79  4.  X-ray structure of 238  80  5.  X-ray structure of 241 A and 241 B  82  6.  X-ray structure of 243  84  7.  X-ray structure of 247  85  8.  X-ray structure of 257A and 257B  100  9.  The effect of Lewis acid on the energies of the HOMO and LUMO of the dienophile in the Diels-Alder reaction  160  xil  LIST OF GENERAL PROCEDURES  General procedure 1.  Preparation of alkyl (E)-3-trimethylstannyl-2-alkenoates  189  2.  Preparation of ethyl (Z)-3-thalkylstannyl-2-pentenoates  195  3.  Preparation of alkyl (Z)-2,3-bis(trimethylstannyl)-2-aikenoates  198  4.  Preparation of alkyl 2-trimethylstannyl-1-cycloalkenecarboxylates  200  5.  Preparation of alkyl (Z)-3-trimethylstannyl-3-alkenoates  203  6.  Preparation of (Z)- or (E)-3-thmethylstannyl-3-alken-1-ols  208  7.  Preparation of (Z)- or (E)-3-iodo-3-alken-1-ols  213  8.  Preparation of (Z)- or (E)-dliodoalkenes and 4-iodo-1-butyne  218  9.  Preparation of 2-bromo-1-alkenes  223  10.  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) 11.  233  Stereocontrolled preparation of ailcyl 2,3-bis(allcylidene)cyclopentanecarboxylates and related substances  via  intramolecular palladium(0)-  catalyzed coupling reactions of vinyl halide and vinyistannane functions 12.  262  Preparation of alkyl 2,3-bis(aikylidene)cyclopentanecarboxylates and other dienes via CuCl-mediated intramolecular coupling reactions of vinyl halide and vinyistannane functions  283  13.  Preparation of 2,3-bis(alkylidene)cyclopentanecarboxamides  309  14.  Diels-Alder reactions of dienes with methyl vinyl ketone (MVK)  326  x’il  LIST OF ABBREVIATIONS  A  angstrom(s)  a  1,2 relative position specific rotation at the  elemental analysis  Anal, Ar Ar3P /3 B-Br-9-BBN BF3.Et20  sodium D line (589.3 nm)  -  -  argon tri-o-tolylphosphine (o- ortho-) -  1,3 relative position B-bromo-9-borabicyclo[3.3. 1]nonane boron trifluoride-etherate  bp  boiling point  br  broad  n-Bu  normal-butyl (n- normal-)  t-Bu  :err-butyl (ten- tertiary-)  1-Bu2AIH n-BuLi  -  -  diisobutylaluminum hydride (i- iso-) -  n-butyffithium  t-BuMe2SiCl  tert-butyldimethylsilyl chloride  t-BuPh2SiCl  :ert-butylchlorodiphenylsilane  n-Bu3SnC1 [n-Bu3SnCuCN]Li O  C  tributyllin chloride lithium (tri-n-butylstannyl)(cyano)cuprate degree Celsius concentration in g/100 niL  calcd.  calculated  D 6 C  hexadeuteriobenzene  3 cDcl  deuteriochloroform  H 6 C  benzene  xiv chloroform  CHC13 C1 2 CH  dichioromethane  N CH C 3  acetonitrile bis(acetonitrile)palladium(ll) chloride  CN)2PdCl2 3 (CH  centimeter(s)  an  carbon-13 nuclear magnetic resonance  nmr  H- homonuclear) rrelation pectroscop 1 ( H  COSY 2 CP2T1C1  titanocene dichloride  2 CpZrCl  zirconocene dichloride copper(I) bromide-dimethylsulfide  CuBr.Me2S CuC1  copper(I) chloride  CuC12  copper(ll) chloride  CuCN  copper(I) cyanide copper(I) iodide  CuT d  doublet  3  scale (nrnr), dimensionless dibenzylideneacetone  dba DBU  1 ,8-diazabicyclo[5.4.O]undec-7-ene  DMF  N,W-dimethylformamide dimethylsulfoxide  DMSO 1)20  deuterium oxide  4 1)2S0  SUlfUriC acid-d2 molar absorptivity edition  ed.  editor, editors  Ed., Eds. e.g.  equiv  -  -  for example equivalent(s)  xv and others  et al. E  entgegen (configuration)  Et  ethyl iodoethane  Ed N 3 Et  iriethylamine  Et20  diethyl ether  EtOH  ethanol  g  gram(s) -  gas-chromatography mass spectromeiry  gems gic h  -  -  HgO  -  HMPA  -  nmr  -  H20  -  HOAc  -  HOMO hplc  Hz iibid. 12 i.e.  ir J  1,4 relative position  -  -  -  -  -  -  -  -  -  gas-liquid chromatography hour(s) mercury(ll) oxide hexamethyiphosphoramide proton nuclear magnetic resonance water  acetic acid highest occupied molecular orbital high-performance liquid chromatography Hertz (s ) 1 isoin the reference cited iodine that is  infrared 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  -  L  -  IDA LiAIH4 LIC1 2 LiCuC1 LilCA lit.  LUMO  -  potassium bis(trimethylsilyl)amide liter(s)  lithium dlisopropylamide lithium aluminum hydride lithium chloride lithium dichiorocuprate lithium N,N-isopropylcyclohexylamide literature lowest unoccupied molecular orbital  M  molar (mol dnr ), or mega (106) 3  m  multiplet  Me Me3AI Mcii MeOH Mel (Me3Sn)2  methyl trimethylaluminum methyffithium methanol iodometha.ne hexamethylditin  [Me3SnCuCNJLi  lithium (trimethylstannyl)(cyano)cuprate  SnCu.Me2S 3 Me  (trimethylstannyl)copper-dimethylsulfide  SnCuSPh]Li 3 [Me mg MgSO4  lithium (trimethylstannyl)(phenylthio)cuprate milligram(s) magnesium sulfate  MHz  megaHertz  miii  minute(s) milliliter(s)  xvii  -  mmol ji.mol mol mp MVK  -  -  -  -  -  -  Na(Hg) 3 NaHCO  -  -  -  -  nOe  mol(s) melting point methyl vinyl ketone normal sodium amalgam sodium bicarbonate (sodium hydrogen carbonate)  ammonium chloride ammonium hydroxide nanometer(s)  nm NMP  micromole(s)  sodium hydroxide  NaOH  OH 4 NH  millimole(s)  sodium iodide  Nal  C1 4 NH  microliter(s)  -  -  N-methylpyrrolidinone nuclear Overhauser effect ortho  ORD  optical rotatory dispersion  p  page  p-  para  %  percent (parts per hundred)  Pd(O) 2 Pd(dba) (dba) 2 Pd 3  palladium(O) bis(dibenzylideneacetone)palladium(O) tris(dibenzylideneacetone)dipallarlium(O)  Ph  phenyl  pH  hydrogen ion concentration  As 3 Ph  triphenylarsine  xvm F 3 C PhN(SO 2 ) P 3 Ph PBr2 3 Ph P=CBr 3 Ph 2 PCuC1 3 Ph uC1 ) P 3 (Ph C .1 2 P 3 Ph PMe 2 Ph d ) 4 P 3 (Ph P ) 2 P 3 (Ph P dBnC1 dC1 ) P 3 (Ph P 2 PhSCu  -  -  -  -  -  -  -  -  -  -  -  -  triphenyiphosphine dibromide dibromomethylenetriphenyiphosphorane triphenylphosphinecopper(I) chloride tris(triphenylphosphine)copper(I) chloride triphenyiphosphine dilodide methyldiphenyiphosphine tetrakis(triphenylphosphine)palladium(O) benzyl(chloro)bis(triphenylphosphine)palladium(ll) bis(triphenylphosphine)palladium(ll) chloride phenylthiocopper(I)  pages  pp c-Pr  n-Pr  triphenyiphosphine  polymethythydrosioxane  PMHS  i-Pr  N-phenyltrifluoromethanesulfonimide  cyclopropyl -  isopropyl (1- iso-) -  normal-propyl (n- normal-) -  q  quartet  R  rectus (configuration)  Rf  retardation factor (ratio of distance traveled by the center of a zone to the distance simulaneously traveled by the mobile phase)  S  sinister (configuration)  s  singlet, or second(s)  t  triplet tertiary  TCNE  tetracyanoethylene  xix  temp tertTHF  temperatui  tertiary tetrahydrofuran  tic  thin-layer chromatography  uv  ultraviolet  Vol.  v/v wi w/v Z ZnC12  volume volume-to-volume ratio peak width at half height (in Hz) weight-to-volume ratio zusammen (configuration) zinc chloride  (+)  rotation to the right  (-)  rotation to the left  +ve  positive  -ye  negative  xx  AC KNOWLEDGEMENTS First of all, I wish to express my sincere thanks to my supervisor, Professor Edward Piers, for his guidance, patience and support during the course of research and the preparation of this thesis. Thanks to the past and present chemists in “Piers’ Lab” including Livain, 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 for teaching me how to use the “nmr work-station”. Finally, I wish to express my deepest thanks to my parents for their encouragement and support throughout all these years.  1  I.  1.  INTRODUCTION  Palladium-catalyzed coupling reactions and their synthetic applications  Fundamental concerns of synthetic organic chemists include the discovery and the exploration of new reagents and new reactions, the investigation of the mechanistic aspects of the chemical reactions, the improvement of existing organic reactions, and the application of  the 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 new 1 (Equation 1) of carbon-carbon bonds via the palladium-catalyzed cross-coupling reactions ) with a variety of organic halides and related electrophiles (RX). 3 organostannanes (R’SnR”  Seminal contributions by the late 3. K. Stile laid the groundwork for this critical synthetic operation and, thus, this reaction is widely known as the Stifle coupling reaction (or the Stile cross-coupling reaction) amongst the synthetic organic community. Some of the merits of this catalytic reaction include the mild conditions required, the tolerance towards a wide  variety of functional groups on either coupling partner, the accessibility of the many stable 5 of the configuration of the final and readily available organostannanes, the excellent control products and the high yield of the desired compounds. Pd catalyst  RX  +  3 R’SnR”  R-R  +  3 XSnR”  (1)  The Stifle coupling reaction basically involves the transfer of one organic group R’ from the tin atom to the organic group R, which is originally bonded to the “leaving group” X. It was found that different organic groups are transferred at different rates from the tin atom, 2 As a result, an and fortunately, a simple alkyl group has the slowest transfer rate. organostannane 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 an a Moreover, the organic halides or 4 alkenyl (or vinyl), alkynyl, allyl, aryl or benzyl group. related electrophiles can be acid chlorides, allyl halides, aryl halides, aryl triflates, benzyl a 4 halides, enol triflates, cx-haloesters, a-haloketones or vinyl halides.  A variety of palladium reagents have been used to catalyze Stile coupling The  palladium  catalysts  which  have  been  employed  to  date  include  P 3 [(Ph P d], ) bis(triphenylphosphine)palladium(ll) tetrakis(triphenylphosphine)palladium(O) 4 C 3 [(CH P J dC1 N) and chloride 2 P 3 [(Ph P ] dCl , ) bis(acetonithle)palladium(ll) chloride 2 P 3 [(Ph P dBnC1]. ) In some recent benzyl(chloro)bis(triphenylphosphine)palladium(II) 2 6 copper(I) salts have been recruited as cocatalysts in the coupling reactions. findings, However, the actual role played by the copper(I) salts in these coupling processes has not been determined. Reactions involving enol triflates were found to require the presence of an g usually lithium chloride (LiC1). However, in some cases, 2 inorganic salt, 7 it was discovered that the presence of LiC1 was not necessary.  The coupling reaction is usually performed in the solvent tetrahydrofuran (THF). In CN), dimethylsulfoxide (DMSO), 3 addition, other solvents such as acetone, acetonitrile (CH g 2 hexamethylphosphoramide (HMPA) and N,N-dimethylformamide (DMF) can be used. Reactions can be carried out at ambient temperatures or under reflux.  The mechanism of this coupling reaction has been investigated by Stille and co Aa and their proposal can be summarized by the catalytic cycle shown in Scheme 1 2 workers, addition of the organic halide to the d (p 3). The sequence of steps includes oxidative 2 palladium(O) catalyst, transmetalation 2 of the resulting organopalladium(ll) species with the isomerization of the bis(organo)palladium(ll) complex and a d organostannane, trans/cis 2 elimination to provide the coupled product. The mechanism e a subsequent reductive 2  3 8 The catalytic cycle was described in Scheme 1 is referred to as that of the “direct coupling”. 9 The transmetalation step was considered to envisaged to occur via Pd(O) and Pd(ll) states. 2 be the rate-determining step.  R—R’  PdL  (n 2) L)  RX  (\çidative addition  R—Pd—X I L  R—Pd—L I  3 RSnR  trans/cis isomerization  L  transmetalation  R—Pd-R’  L ; X = I, Br, OTf or Cl; 2 R = RCH=CH, aryl, RCH=CHCH2, benzyl, RCO or RCOCH R’  =  RCEC, RCH=CH, aryl, RCH=CHCH2 or RCOCH2; R”  =  Me or n-Bu  Scheme 1  One of the extensively studied areas of the Stile coupling reaction is the synthesis of conjugated dienes via the palladium-catalyzed cross-coupling reactions of vinyl trialkyl g or vinyl halidesim (vinyl bromides or vinyl iodides). In 2 stannanes with enol triflates’g, general, these coupling reactions take place with high stereospecificities.  4 The coupling reactions of enol triflates and vinyl trialkyistannanes require the presence of LiC1 and a palladium catalyst. For example, the enol triflate 1 coupled in high yield with vinyl tri-n-butylstannane 2 in the presence of 2 mol % of 4 Pd 3 (Ph P ) and 3 equivalents of LiC1 to provide the conjugated diene 3 (Equation 2 and Table I, entry 1).2g As indicated in Table I, no coupling was observed in the absence of 4 Pd 3 (Ph P ) (entry 2). When less than 1 equivalent of LiCl was used, the reaction did not proceed to completion after 24 h (entries 3 and 4). Indeed, the lowest amount of LiCl required was 1 equivalent (entry 5). P 3 (Ph P 4 d, ) Lid OTf  Sn”% 3 n-Bu  +  (2) THF, reflux  1  2  Table I. Effect  3  of varying coupling reactiona  reaction  conditions  on  the  entry  Pd 3 (Ph P 4 ) (mol %)  LiCI (equiv)  t70 (h)b  % yield (glc)c  1  1.98  3.0  3.6  95  2  0.00  3.0  0  3  1.97  0.0  <10  4  2.07  0.6  3.0  71  5  2.04  1.1  3.3  >95  a Reaction of 2.5 mmol of 1 with 3.0 mmol of 2 in 25 mL of TNF in the presence of 4 Pd 3 (Ph P ) and LiC1 under Ar at 62 0 C b 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 the absence of LiCl.lm butyistannane  Thus, the coupling of the vinyl iodide 4 with the vinyl tn-n  in the presence of 2 mol % of 4 Pd 3 (Ph P ) was complete within 23 h at 50°C  in THF to give a 75% yield of the conjugated diene 6 (Equation 3, p 5).1m  5  +  Pd 3 (Ph P 4 ) (2 mol %)  Sn’”%iç 3 nBu  (3) TFIF, 50°C, 23 h  ..-  75% yield  5  6  studies of the coupling reactions of enol triflates and vinyl g Based on mechanistic 2 trialkyistannanes, Stifle and co-workers have proposed a catalytic cycle (Scheme 2). The initial oxidative addition of the enol triflate 1 to the catalyst 4 Pd 3 (Ph P ) forms the intermediate 7, which is followed by transmetalation of the organostannane 2 to yield the corresponding bis(organo)palladium(II) complex 8.  This complex rapidly undergoes trans/cis  isomerization and reductive elimination to give the product 3, accompanied by regeneration of the palladium(O) catalyst.  +Eh  _j-_Q_OTf 4 PdL  3  2L  LiC1  +  1 oxidative addition  elimination  LiOTf  +  2L  L  P 3 L=Ph  —I--O—Pd-C1 L 7  Sn 3 n-Bu 2 isomerizatiN..  +c’r L 8  Scheme 2  transmetalation  SnC1 3 n-Bu  6 proposed to The transformation of the enol triflate 1 into the intermediate 7 was 2 proceed through one of two different pathways (Equations 4 and 5). Oxidative addition of d ) to form the organopalladium(l1) triflate complex 10, followed 4 P 3 (Ph the enol triflate 1 to P by reaction with LiC1, would generate the intermediate 7 (Equation 4). Alternatively, a ) could form a salt such as 11, which could Pd 3 (Ph P reversible reaction of L1C1 with 4 undergo oxidative addition with enol triflate 1 to yield the intermediate 7 (Equation 5). Based g from the 31 2 P nmr spectral data of 7 and 11, Stile and co-workers have on evidence suggested that the reaction is very likely to proceed via the latter pathway.  4 PdL  +  —f_(-OTf  2 [_I_CjPdL  1  10  P 3 L=Ph  ]  LiCI  ÷  _f_(j_P’d_Cl  (4)  7  —f_(j_OTf  4 PdL  1 +  LiC1  P 3 L=Ph  1T Li[PdL C 2  -.-1.-.O_Id-C1  11  7  (5)  The scope of this reaction has been illustrated by numerous publications involving syntheses of natural products.lghi.lml.hhIJx  For example, Stile and co-workers  demonstrated the application of this coupling reaction in a short, convergent synthesis’s of pleraplysillin-1 (14) (Equation 6) from the enol triflate 12 and the organostannane 13.  +  12  n’,z-Bu S 3  13  (6) 75%yield  14  7  10 of synthetic Modified conditions were employed by Farina et a!. in the syntheses derivatives of naturally occurring cephalosporins 17 (Equation 7). Coupling of the enol triflate 15 and the organostannanes 16 was effected by using bis(dibenzylideneacetone) 1 [Pd2(dba) palladium(O) 10.1Ob [Pd(dba)2] or ths(dibenzylideneacetone)bispalladium(O) ] 3 as the catalyst, and tri(2-furyl)phosphine as the ligand. Moreover, the reactions were Oc and with the use of N 1 ’ (ZnC12) or LiC1 101 performed in the presence of zinc ch1otide’ methylpyrrolidinone (NMP) as the solvent. 0  n-BuSn  2 R  Ph S  16  OY’’0Tf CHPh CO 2  2 (2 mole %) Pd(dba)  1 R  0  Ph  H 1 ...,_S%  2 R  OR1 2  (4mole%) 15 2 (2 equiv) ZnC1  25°C, 1-72 h  17 65-79% yield ,R 1 R 2 = H, H; H, Me; Me, Me  ’ that, at an earlier stage of their study, employment of exogenous 10 Farina et a!. reported halide 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 ZnC12 was attributed to either its water of hydration or to the presence of traces of hydrogen 2 It chloride. The beneficial effect of. traces of water in this type of coupling is precedented. 11 that the solvent NMP, and the ligand tri(2-furyl)phosphine are ’ 10 was also mentioned effective in increasing the rate of the coupling reaction. Polar aprotic solvents are known to  2 Thus, the coupling rate increased in the following enhance the coupling rate substantially. order: CHC13 <THF < CH CN <DMF, DMSO, NMP. In consideration of the ligand, they 3 hypothesized that since the transmetalation, presumably the rate-determining step, consists of a nucleophilic attack of the stannane at the palladium, making the palladium species less electron-rich should enhance the rate of the coupling process. Thus, the phosphine ligand,  8 tri(2-furyl)phosphine, with reduced donicity (or nucleophilicity) was found to enhance the rate of coupling of the enol triflate and the organostannane. Recently, Farina et a!. have 11 on the use of tri(2-furyl)phosphine, published their intriguing mechanistic investigations and triphenylarsine (Ph3As) as palladium ligands, which resulted in large rate accelerations in the Stifle coupling reaction.  The intramolecular version of the coupling reaction is the major concern of our present study, and attention will therefore now be focused on the previous literature examples of the 7 from our laboratory described intramolecular variant of this reaction. Earlier investigations the syntheses of a variety of bicyclic dienes 19 and 21 (Scheme 3) via the palladiumcatalyzed intramolecular coupling reaction of substances of general structures 18 and 20, which contain both enol triflate and vinyl trimethyistannyl moieties. Notably, LiC1 was found 7 which is in contrast to to be unnecessary for the successful formation of the bicycic dienes, the reported results from the intermolecular coupling reactions of enol triflates and vinyl g 2 trialkylstannanes. 3 SnMe  Pd 3 (Ph p 4 ) (5 mol %)  MeO C  Cle  81-84%yield  18  1 R  C 2 MeO  3 SnMe  19  Pd 3 (Ph P 4 ) (5 mol %)  reflux  50-90% yield 21  20  ,R 1 R 2 = H, H; H, CO2Me; CO2Me, H; H, CH2OCH2OCH3; CH2OCH2OCH3, H m=1,2or3;n=lor2  Scheme 3  9 d, from these studies also provided some interesting observations e Detailed experimental 7 mechanistic insights for the understanding of this intramolecular cross-coupling process. The success of the annulations in the absence of LiC1 is likely due to the intramolecular nature of the process. Presumably, the intramolecular coupling reactions of compounds containing  both enol triflate and vinyl trimethylstannyl groups proceed through a catalytic cycle as shown in Scheme 47d L 1 R  2 R  A  24 +  4 PdL  L  =  P 3 Ph  -air  25  R  C  /  B L 2 R 27  2L  26  SnOTf 3 Me  Scheme 4  A similar pathway has been proposed for the intermolecular cross-coupling of enol triflates and vinyl trialkyistannanes (Scheme 2, p 5).  However, in these cases, the  10 intermediate palladium species corresponding to 25 (Scheme 4, p9) (i.e. 23) is, apparently, unstable and the palladium catalyst is transformed into an uncharacterized, catalytically a Thus 23 does not participate in a bimolecular transmetalation step 4 . 2 ineffective complex.  with a vinyl triaikylstannane. This problem is solved by the addition of LiC1, which results in the formation of the palladium(fl) complex 24, a species that is sufficiently stable to take part in the catalytic cycle. In the intramolecular coupling process shown in Scheme 4 (p 9), the internal transmetalation reaction (step B) would be expected to proceed at a much higher rate than the corresponding bimolecular reaction in an intermolecular coupling process. Thus, the “inherent instability” of 25 does not interfere with the overall process and 25 is readily converted, via internal transmetalation, into the palladium metallocycle 26. Subsequent reductive elimination from the cis-bis(organo)palladium(ll) species would give the bicyclic dienes 27.  The aforementioned annulation method developed in our laboratory has been applied e of the natural product (±)-anñjithenol (29) (Equation 8) 7 successfully to the total synthesis from the key intermediate 28 through the palladium-catalyzed coupling reaction and subsequent deprotection. n Me S 3  1) (Ph P)Pd 3  TfO  74% yield F 2)n-Bu. N 4 78% yield  ici t-BuMe S 2 28  29  synthesis of a structurally novel natural product, (±)-8,15c Similarly, in another total 7 diisocyano-11(20)-amphilectene (33) (Scheme 5, p 11), the synthesis of the intermediate 31 was accomplished by a one pot sequence of reactions including deprotonation of 30 with  lithium diisopropylamide (LDA), trapping of the resulting enolate with N-phenykrifluoro  11 methanesulfonimide [PhN(SO2CF3)2] to afford the corresponding enol triflate 32, followed by a palladium-catalyzed intramolecular coupling procedure. SiO 2 t-BuMe Sn 3 Me  1) LDA. THF CF PhN(SO 2 ) 2) 3  t-BuMe S 2 iO’ C A 2 MeO  Pd 3 (Ph P ) 3) 4  86% yield  30  Sn 3 Me  2/  t-BuMe S 2 iO’’ C 2 MeO  A  32 33  Scheme S  a on the intramolecular variant of the coupling 7 A few years after our first publication reaction, Stile and co-workers showedlO that molecules 34 (Equation 9) containing both enol triflate  and vinyl tri-n-butylstannyl moieties at the termini of an ester chain could be  transformed in moderate yields (56-57%), into the corresponding macrocydic lactones 35 by Pd 3 (Ph P ) the use of 4  and LiC1 under high dilution conditions (1O M) in refluxing THF.  Under these conditions, neither E to Z isomerization of the internal double bond nor rearrangement of the exocyclic double bond was observed. 0 Pd 3 (Ph P 4 ) (2 mol %) (9) LiC1 (3 equiv) T.HF, reflux  34  n = 5, 6, 7 or 8  56-57% yield  12 2.  Previous work on the syntheses of ethyl 2.3-bis(alkylidene’)cyclobutanecarboxylates and some related studies  The syntheses of 1,2-bis(methylene)cyclobutane and related substances have been reported 12a and such structures have been studied extensively, particularly from a physical b However, most of these syntheses are cumbersome, inefficient, and 2 organic viewpoint.l stereochemically ambiguous.  In ongoing efforts to study the synthetic uses of the  13 from our intramolecular variant of the Stile coupling reaction, previous investigations laboratory have been carried out on the syntheses of derivatives of 1,2-bis(methylene)cyclobutane, namely, ethyl 2,3-bis(allcylidene)cyclobutanecarboxylates 37 (Equation 10 and Table II).  Pd 3 (Ph P 4 ) (10) Sn 3 Me  DMF, 80°C. 1 h  1 R  37 36  Table II.  Syntheses of the cyclobutanecarboxylates 37 2 R  3 R  ’ 1 % yield  H  H  H  82  &  H  Me  H  89  3  &  Me  H  H  96  4  I  H  Me  Me  97  5  I  Me  H  Me  93  6  &  OMe 2 OCH  H  H  70  7  &  (t-Bu) 2 (CHOSiMe  H  H  92  8  &  H  (CHOH  H  87  entry  X  1  &  2  a 3 (Ph P )4Pd (5 mol %), DMF, 80 °C, 1 h. b Yield of purified, distilled product C 4 N (1 equiv), DMF, 80 °C, 1 h. 3 Pd 3 Ph P ) (10 mol %), Et  13 a 3 The cyclobutanecarboxylates 37 (Equation 10 and Table II, p 12) were synthesizedl effectively and in a stereospecific manner by the treatment of compounds 36, which contain ) Pd 3 (Ph P vinyl halide (X = Br or I) and vinyl trimethyistannane functions, with 5 mol % of 4 in dry DMF at 80 °C for 1 h. As expected, LiC1 is not required for the coupling process of 1 In each case, the reaction was clean and efficient; the vinyl halides and vinylstannanes. isolated yields of purified, distilled products ranged from 70% to 97%. Attempted ring closure of the substance 36 (Table II, entry 6) containing a methoxymethyl group under the conditions mentioned above provided none of the desired products. However, when the ) in the presence of triethylamine (Et3N), Pd 3 (Ph P reaction was carried out with 10 mol % of 4 the product 37 (entry 6) was obtained in a 70% yield.  37  The synthetic method outlined above provided substances of general structure 37 a of this 3 efficiently and in a completely stereocontroiled fashion. A possible mechanisml reaction may be summarized by the catalytic cycle shown in Scheme 6 (p 14). The initial oxidative addition of the vinyl halide group to the catalyst gives the organopalladium(ll) intermediate 38. Then, intramolecular transmetalation of the vinyltrimethyistannane function provides a highly favourable five-membered ring intermediate 39. Finally, reductive elimination from the intermediate 39 produces the cyclobutanecarboxylate 37 and regenerates , transmetalation 14 d 2 2 and reductive the palladium(0) catalyst. Since the oxidative addition, elimination steps are known to occur with retention of configuration, an overall retention a As a result, 4 of the configuration of the double bonds in the coupling reaction is obtainecL  this is an efficient method for the stereospecific preparation of the four-membered ring compounds 37.  14  3 R 1 R  4 PdL  2L  L = Ph P 3 4 PdJ  ft  L R’\  X=Brorl Et 2 CO  2 R  39  38  SnX 3 Me  Scheme 6  The success in the syntheses of the cyclobutanecarboxylates 37 led to an extension of a 41 (Equation 11 and Table ifi, p 3 this process to the syntheses of the larger ring homologsl a to convert 40a (n = 1) into cyclopentanecarboxylate 41a (n = 1) 3 15). In an earlier attemptl via the aforementioned procedure (in the absence of L1C1), it was found from gic analysis that the crude reaction mixture contained the desired coupled product 41a and as well as some other uncharacterized compounds. Thus, a modified procedure 13a was employed to obtain  41a (Table ifi, entry 1). A solution of 40a in dry DMF was heated at 80 OC for 1 h in the Pd and 2 equivalents of LiC1 to provide a mixture of the 4 presence of 5 mol % of (Ph3P)  15 H nmr and gic 1 cyclopentanecarboxylates 41a and 42 in a ratio of 13: 1, respectively ( analyses).  3 SnMe  Br  d ) (5 mol %) 4 P 3 (Ph P  (11) LIC1 (2 equiv)  t CO E 2  40  Table Ill.  DMF,80°C,lh  41  Syntheses of the cycloalkanecarboxylates 41  entiy  n  substrate  product(s)  % yields’  1  1  40a  4laand42  85’  2  2  40b  41b  74  3  3  40c  41c  0  a b  ) (5 mol %), LiC1 (2 equiv), DMF, 80°C, 1 h. Pd 3 (Ph P 4 Yield of purified, distilled product. The product included a small amount of cyclopentanecarboxylate 42. The ratio of 41a : 42 was 13: 1, respectively.  42  In a similar fashion, the transformation of the compound 40b (n  =  2) into the  cyclohexanecarboxylate 41b (n =2) was achieved in a 74% yield via the modified procedure which employed 2 equivalents of LiC1 (entry 2). It must be noted that none of the desired coupled product 41b was obtained when the reaction was performed in the absence of LiC1. Unfortunately, even in the presence of LiCl, the conversion of the compound 40c (n =3) into the cycloheptanecarboxylate 41c (n =3) was unsuccessful, although consumption of the starting material 40c was detected.  16 Thus, it is obvious that LiC1 is necessary for the successful formation of the cyclopentanecarboxylate 41a (n  =  1) and the cyclohexanecarboxylate 41b (n  =  2). In  a 3 2 In view of this, a catalytic cyclel addition, Lid must participate in the coupling process. of this coupling reaction was proposed as shown in Scheme 7. As mentioned before, the initial oxidative addition of the vinyl bromide to the catalyst produces the organopalladium(ll) intermediate 43 with the aid of LiCl. Then, intramolecular transmetalation of the intermediate 43 provides the palladium metallocycle 44, followed by reductive elimination yields the coupled product 41a or 41b.  3 SnMe  Br LiC1  +  Et 2 CO 40  4 PdL  2L  LiBr  P 3 L=Ph  CIPd 2 L  +  2L  3 SnMe  n=lor2 Et 2 CO 43  44  SnC1 3 Me  Scheme 7  Stile and Scott have proposed an oxidative intermediate analogous to 43 for the  intermolecular coupling reaction of 1 and 2 in the presence of Lid and a palladium catalyst (Equation 2, p 17).2g However, when lithium bromide (LiBr) or lithium iodide (Lii) was used instead of LiCl, a faster rate of decomposition of the initial oxidative addition  17 g As a result, longer reaction time or lower 2 intermediate 45 (Equation 12) was observed. yield was detected when lithium bromide (LiBr) or lithium iodide (Lii), respectively, was employed for the coupling reaction of 1 and 2.  +C>OTf  4 PcIL  +  P 3 L=Ph  Sn’ 3 n-Bu  +  H—O_OTf 1  +  LIX  X=Brorl  -—(j-  (2)  _f_Cj_r!d_X  (12)  45  The initial oxidative intermediate (Scheme 8, step A, p 18) in the intramolecular reaction would be 46 when the reaction is performed in the absence of LiCl. Apparently, this intermediate is less stable than the intermediate 43. As the ring size of the palladium metallocycle intermediate 44 increases, the rate of the transmetalation process (Step B) to produce 44 decreases. As a result, in the absence of LiC1, the rate of the transmetalation step is presumably slower than the rate of decomposition (Step C) of 46 and hence, the coupled product was not obtained efficiently. However, in the presence of LiCl (Scheme 8) the rate of 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 cyclohexanecarboxylate  41b (n  =  2), was produced readily. Unfortunately, in the preparation of cycloheptane  carboxylate 41c (n =3) (Scheme 8), the rate of the decomposition is faster than the rate of the transmetalation 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 product  4 ic.  18  Br  Br  3 SnMe  LiCI  3 SnMe  +  Et 2 CO  Et 2 CO  40  40 4 PdL  D  2L  BrPd 2 L  3 SnMe  L = Ph P 3 n = 1 or 2  LiBr  C1Pd 2 L  Et 2 CO 43 S  C  B  S  E  decomposition  decomposition  44  with LiC1  without LiC1  PdL 4 LiC1  48  Et 2 CO Sn— 3 Me 41c  2L  3 SnMe  Et 2 CO 46  Br  +  Sn 3 Me 47  L = Ph P 3 Scheme 8  decomposition  19  37  In a related study, the various cyclobutanecarboxylates 37 have been employed as dienes in Diels-Alder reactions, and the subsequent Diels-Alder adducts (or the cycloaddtion a,lS For example, a Lewis acid 13 products) were subjected to thermal ring opening reactions. catalyzed 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 of compound 50 (Scheme 9) gave a mixture of two geometrical isomers, keto esters 51 and 52, H nmr analysis). 1 in a ratio of 11: 1, respectively (  mesitylene  BFrEtJ  ci 2 cii Et 2 CO MVK -78 49  95% yield  L CO E 2 0 50  o  L CO E 2 51  reflux,lh  +  85% yield ir02Et  o 52  Scheme 9  20 3.  Previous synthetic studies of 1 .2-bis(alkylidenecyclopentanes and related 1 .2-bisexocvclic dienes  17 have served as ’ 16 Cycloalkanes containing a 1,2-bis-exocyclic conjugated diene system el In some of C 7 products.Th key intermediates in the total syntheses of a variety of natural 8 the syntheses, these dienes were employed in Diels-Alder reactions for the construction of c,lS For example, Trost et a!. have reported that the bis(allcylidene) 7 polycycic structures. cyclopentane 53 (Scheme 10) reacted with the dienophile 54, and the subsequent intramolecular alkylation of the corresponding adduct using 1,8-diazabicyclo[5.4.0]undec-7ene (DBU) provided 5518a Compound 55 was used for the syntheses of (-)-sterepolide (56)18a and (-)-merulidial (57)18b (Scheme 10).  1)  54  , 80°C H 6 C 2) DBU, room temp  R( (:-Bu) 2 OSiMe.  (R=  81% yield  •Bu) 55  HOMe)  OH CH3  vThs / CHO 56  Scheme 10  57  21 Owing to the potential synthetic utility of the 1,2-bis-exocyclic conjugated dienes in dsl,l have been developed for the syntheses of ,l l metho , 3 C 7 Diels-Alder reactions, various 9 coworkersl accomplished the stereoselective a In 1984, Nugent and 9  these dienes.  conversion of diynes 58 into E,E-1,2-bis-exocyclic dienes 60 by treatment with titanocene TiC1 (59) and sodium amalgam (Na(Hg)) in the presence of 2 (Cp dichioride ) methyldiphenyiphosphine (Ph2PMe), followed by acid hydrolysis (Equation 13a and Table  IV). 1 R  g) iC1 5,Na(H 2 1)CpT (  (()  = =  Me, THF Ph P 2  R’ 2 R  (  (13a)  )n  2)H 2 R 60  58  Table IV. :  Syntheses of the E,E-1,2-bis-exocyclic dienes 60  eny  n  1 R  2 R  %yield  1  1  Me  Me  60  2  2  Me  Me  80  3  2  Me  i-Pr  71  4  2  OEt  OEL  63  5  2  Ph  Ph  35  6  3  Me  Me  27  7  4  Me  Me  0  In 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 relatively  unstrained cyclopentanes or cyclohexanes, respectively, in good yields (entries 1-4). When bulky substituents are attached to the termini of the diynes (entry 5) or medium-sized rings are b of this 9 to be formed (entries 6 and 7), the reaction is less efficient. A plausible mechanisml  22 cydization 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 diyne 58 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 a  deuterolysis experiment using 20% 2 S D 1 4 0 D 0 . Under these conditions, the product 64 (Scheme 11) was found to be 91% dideuterated in the two vinylic positions. n PhMe TiCI Cp 2  +  2 Na(Hg)  Ti(PhMe) 2 Cp  ‘x  Ti” 2 “Cp  .50 59  62  61  :  61or62  58 S0 D 2 D , 4 0 2 1 R  =  =  ’ 3 Me  R’  (  )n 2 R  60  64  Scheme 11  (13b)  23 c from Nugent and co-workers has shown that either 9 A later paperl Ti”) or Cp2ZrC12IMg.fHgCl2 (for the 2 Cp2TiC12IPh2PMe/Na(Hg) (for the generation of “Cp generation of “CpZr”) reagent combinations can be used for the cydlization of diynes 65 to E,E-1,2-bis-exocycic dienes 66 (Equation 14 and Table V). It is interesting to note that the titanium-mediated cycization is better for five- and six-membered ring compounds (entries 2  and 3), while the zirconium-promoted method is superior for four- and seven-membered rings (entries 1 and 4). Unfortunately, both methods failed to provide the eight-membered 20 an alternative method to ring (entry 5). Similarly, Negishi and co-workers have established generate the “Cp2Zr” reagent, from the treatment of Cp2ZrC12 with 2 equivalents of n butyllithium (n-BuLi), for the conversion of some other diyne derivatives into the corresponding E,E- 1 ,2-bis-exocycic dienes. Me  =  Me  Zr” 2 Ti” or “Cp 2 “Cp (14)  Me  (cL_ikMe  Table V. Effect of the ring size on the yields of E,E bis(ethylidene)cycloalkanes 66  a b  entry  n  % yield (“CpTi7  ’ 1 % yield (“CpZr”)  1  0  0  89  2  1  78  70  3  2  89  71  4  3  24  45  5  4  0  <2  gic yield after 3 h at -20 °C with the reagent “CpTi”. glc yield after 24 h at room temperature with the reagent “Cp2Zr”.  24 21 for the conversion of diynes 67 into the 1,2-bis(alkylidene)Another procedure cyclopentanes 68 was developed by Trost et a!. The transformation required the use of 2.5 , .CHC1 [Pd2(dba) ] mol % of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct 3 10 mol % of tri-o-tolylphosphine (Ar3P), 2 equivalents of acetic acid and 10 equivalents of polymethyihydrosiloxane (PMHS) (Equation 15 and Table VI). This catalytic reductive cycization reaction was proposed to proceed via the intermediacy of a hydridopalladium carboxylate complex 70.22 This process (Equation 16) includes regioselective hydro palladation on one of the triple bonds, cyclization of the vinylpalladium intermediate 71, followed by reductive cleavage of the second vinylpafladium intermediate 72 to produce the diene 73. 1 R 3  1  —  =  R 3 4 R  Pddln) .CHC1 3  (15)  P, PMHS 3 HOAc, Ar  2 R  68  67  Syntheses of the 1,2-bis(alkylidene)cyclopentanes 68  Table VI. entry  1 R  2 R  4 R  time (mm)  reaction  isolated % yield  1  H  H  H  H  25  34  2  H  OMe 2 CH  Me  (t-Bu) 2 OSiMe  60  70  3  3 SiMe  n-Pr  Me  (t-Bu) 2 OS1Me  3  89  4  Me 2 CO  n-Pr  Me  (t-Bu) 2 OSiMe  20  95  Pd( 2 L  H  70  69  3 R  KPd L OAc 71  72  (16) —  73  25 Trost et al. have also published methods for the conversion of enynes 74 into 1,223 (Table VII, entries bis(alkylidene)cyclopentanes 75 using either a palladium(II)-catalyzed suggested 2 d 7 that 1-3) or a nickel-chromium mediated (entry 4) carbocyclization. It was 23 the hydridopalladium acetate 77 (Scheme 12, p 26) was the catalytically active species in the cyclization process. fl-Hydrogen elimination of the allylic ring hydrogen (Ha) from 79 provided the 1,2-bis(alkylidene)cyclopentanes 80.  Table VII.  Syntheses of the 1,2-bis(alkylidene)cyclopentanes 68 substrate 74  entry  product 75  % yield  C 2 MeO 23a 1  71  C 2 MeO  C 2 MeO  H 2231  70  23e 3  66  EL 2 CO 424  Et 2 CO 79  26  NPdOAc  77  <  ‘PdOAc  cR  C  -  HPdOAc  PdOAc  79  Scheme 12  19 In summary, the methods described above, including the titanium-mediated,  24 zirconium-mediated, 19c 2 palladium(ll)-catalyzed 1-23 and nickel-chromium mediated cycizations, can provide the required 1,2-bis-exocycic diene systems in good yields. 1926 c 7 , are limited to the synthesis of 1,2-bis(allcylidene)cycloHowever, these methodsl  alkanes which may have one or two E-substituted alkylidene moieties. 17c  27 4.  Proposal regarding a study of the preparation and chemistry of alkyl 2.3-. bis(alkvlidene)cvclopentanecarboxvlates  In view of the versatility of 1 ,2-bis-exocydic diene systems in Diels-Alder reactions and the limitations of the existing synthetic methods for the stereocontrolled syntheses of these substances, it was our goal to develop a general synthetic strategy for the preparation of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates possessing E,E-, E,Z-, Z,E- or even the Z,Z configurations (81, 82, 83, 84, respectively). Exocyclic dienes 81-84 could, in principle, be prepared via the palladium-catalyzed intramolecular variant of the Stille cross-coupling reaction from the corresponding requisite precursors 85-88 (Scheme 13, p 28) respectively, which contain both vinyl halide and vinyltrimethylstannane moieties.  R%  I  1 R  E,E-diene 81  o2  E,Z.diene 82  Z,E-diene 83  Z,Zdiene 84  If 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 the dihedral angles between the two double bonds of the Z,Z-bis(alkylidene)cyclopentane carboxylates 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 of the diene unit would be expected to prevent the diene from attaining planarity and, thus, a significant dihedral angle would be created between the two double bonds. The magnitude of these deviations from planarity in the solid state was to be determined by X-ray crystallo graphic studies on derivatives of the exocycic dienes 84.  28  3 R C 0 2 R  3 R  R’  3 SnMe  X 85  81  1 R  C 0 2 R  3 R  2 O R 2  3 SnMe  X  86 C 0 2 R  3 R  3 SnMe  X 87  83  C 0 2 R  3 R  1 R  3 R  3 SnMe  X 84  88  X = Br or I Scheme 13  During the course of our study, a new copper(I) chloride-mediated intramolecular coupling 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 the corresponding precursors 85-88. Preliminary research on the mechanism and the limitations of this process have been carried out and the results will be discussed in this thesis.  29 28 from our laboratory have demonstrated that the reactions of alkyl (E)-3Earlier studies trimethylstannyl-2-alkenoates 89 with lithium diisopropylamide (LDA) in THF, followed by the protonation of the resultant enolate anions with a solution of acetic acid (HOAc) in diethyl ether (Et 0), afford exclusively alkyl (Z)-3-trimethylstannyl-3-aikenoates 90 (Equation 17). 2 In a similar manner, alkyl (Z)-3-trimethylstannyl-2-alkenoates 91 are transformed exclusively into the corresponding alkyl (E)-3-trimethylstannyl-3-alkenoates 92 (Equation 18). More 13 of esters 89 pertinent for the present study was the finding that the deconjugation-alkylation and 91 (Equations 19 and 20) can be achieved by treatment of the generated enolate anions with an electrophile, such as 2,3-dibromopropene (93), to afford the alkylated products 94 and 95, respectively. 1)LDA,THF  1 R  1 R  2) HOAc, Et 0 2  n Me S 3  (17)  3 SnMe 90  89  1) LDA-HMPA, THF > R — 1 R2 2 CO  n Me S 3  2 rCO R 2 3 SnMe  0 2 2) HOAc, Et  91  (18)  92  1) LDA-HMPA, THF  1 R R 2 _>,,CO  (19) 2  n Me S 3  (93) BrBr  89  94  1) LDA-HMPA, THF (20) 2 M1>4CO R 2  2)  (93) BJLT 95  30  C 0 2 R  3 R  1 R  3 R  1  I R2 2 M’CO  3 SnMe  X 85  OC 2 R  3 R  X  91 R’  R1  1 _.ç  ‘‘‘  arv.i  Sn 3 Me  3 SnMe  X  96  3 R  X  R 2 C0  97  91  86  I  C 0 2 3 R 2 Rt_>_JC02R  arEl  96 C 0 2 R  >  3 R  Rz 2 Rl>,CO  aixi  I  3 R  3 SnMe  X 88  89  97  X = Br or I Scheme 14  It seemed clear that the required compounds 85-88 (Scheme 14) could be derived from the deconjugation-alkylation of the corresponding alkenoates 89 and 91 with the related electrophiles 96 and 97. Through the application of some known reactions (Scheme 15, p 31), the required electrophiles 98 and 99 could be obtained from the deconjugated esters 90 and 92, respectively.  Clearly, the esters 89 or 91 are the starting materials for the  deconjugation-alkylation procedure described above, and they can be prepared stereoselectively from the reaction of the lithium (trimethylstannyl)(cyano)cuprate [Me3SnCuCN]Li with the corresponding a,j3-unsaturated esters 100 under controlled 29 In the following section of this thesis, the preparation of the required conditions. precursors and the related starting materials ll be described in detail.  31  I  it R2 2 j”CO  2 R1(’CO R 2  3 SnMe  3 SnMe  it  it 2 Rl__>,COzR  Rl__>  Sn 3 Me  Sn 3 Me  CO2 R 2 91  89  =  R 2 C0  100  Scheme 15  It is known that the relative configuration of Diels-Alder cycloaddidon products can be controlled by the geometry of the requisite dienes and dienophiles. It would be of interest to study Diels-Alder reactions of 1,2-bis(alkylidene)cyclopentanecarboxylates 81-84 (p 27) with some selected dienophiles. In addition, cycloaddition products thus formed could be useful synthetic intermediates for the future planning of the total synthesis of natural products.  32  II. RESULTS AND DISCUSSION  1.  Syntheses of alkyl (E- and (Z)-3-trimeth’vlstannyl-2-alkenoates  1.1. Preparation of a.fl-acetvlenic esters  A number of functionalized a43-acetylenic esters 101-107 of general structure 100 were required for this study. Ethyl 2-butynoate (101) and ethyl 2-pentynoate (102) are commercially available. Each of the remaining substances, except 103 and 107, were prepared from reaction of the requisite lithium acetylide 108 (Equation 21) with 1 equivalent of either methyl chioroformate (109) or ethyl chioroformate (110).28  EL 2 CO  101  SiO 2 t-BuMe  \....... 105  Me 2 ‘—---CO Cl  =  Et 2 CO  102  \_ 106  1 R  Me 2 CO  103  Et 2 <___CO  104  = 108  Li  +  2 ClCO  107  Me 2 CO  R2 2 O  1 R  =  100  R 2 C0  109R=Me  100  EL 2 11OR  =MeorEt 2 R  (21)  33 The requisite lithium acetylide 108 (Scheme 16) was, in turn, generated from either treatment of the corresponding l,1-dibromo-1-alkene 111 with 2 equivalents of methyllithium (MeLi), or deprotonation of the corresponding 1-allcyne 112 with either 1 equivalent of MeLi or with 1 equivalent of n-butyffithium (n-BuLi). ,Br  R!  MeLi R’  Br  =  MeLi Li  1 R or n-BuLl  108  111  =  H  112  Scheme 16  Commercially available 3-methylbutanal (113) (Scheme 17) was treated with 1.1 30 (Ph equivalents of dibromomethylenethphenylphosphorane P=CBr2) in dichioromethane 3 28 C1 (room temperature, 1 h) to afford the 1,1-dibromo-1-alkene 114 in a 74% yield. (CH ) 2 The ir spectrum of compound 114 showed a weak C=C stretching frequency at 1619 cm . 1 The 1 H nmr spectrum of 114 exhibited the expected signals for an isopropyl group (a 6proton 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= 7 Hz).  113  c  NyBr  74% yield  114  2)CiCOt 91% yield  CO2Et 104  Scheme 17  Compound 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 ir spectrum of compound 104 displayed a moderate CC stretching frequency at 2234 cm 1 and  34 H nmr spectrum of 104 showed the . The 1 1 a strong C=O stretching frequency at 1713 cm expected signals for an isopropyl group (a 6-proton doublet at 6 1.02 and a 1-proton multiplet at 6 1.88-1.99) and an ethyl ester group (a 3-proton triplet at 8 1.32, J= 7 Hz and a 2-proton 31 indicated the C nmr signals quartet at 64.22, J= 7 Hz). In addition, some characteristic 13 presence of two acetylenic carbons (674.0 and 688.4) and a carbonyl carbon (8 153.9).  28 of the hydroxyl group of commercially available 4-pentyn-l-ol (115) Protection (Scheme 18) with 1.3 equivalents of tert-butyldimethylsilyl chloride (t-BuMe2SiC1) and 2.5 equivalents of imidazole in DMF (room temperature, 16 h) provided a 95% yield of the alkyne 116. The ir spectrum of compound 116 exhibited a strong C-H stretching H nmr . The 1 1 1 and a weak CC stretching frequency at 2121 cmfrequency at 3315 cnr spectrum of 116 showed the expected signals for a tert-butyldimethylsilyl group (a 6-proton singlet at 60.03 and a 9-proton singlet at 80.87) and an acetylenic proton (a 1-proton triplet at 6 1.89, J= 2.5 Hz). Deprotonation of 116 with 1.1 equivalents of n-BuLi generated the lithium acetylide 117 (Scheme 18),32 which was treated in situ with 1.2 equivalents of 28 The spectral data for 105 methyl chloroformate to provide the ester 105 in an 86% yield. were in agreement with the expected structure. iC1 t-BuMe S 2 HO”’N  iV t-BuMe S 2  imidazole, DMF  115  95% yield  116  1) n-BuLi, THF  2) C1CO Me 2 iO t-BuMe S 2  iO’’N :-BuMe S 2 Li  Me 2 CO 105  86%yield Scheme 18  117  35 In a similar fashion, commercially available 5-chloro-1-pentyne (118) (Scheme 19) was 33 The latter substance was converted into the corresponding ester 106 in an 87% yield. treated with 4.1 equivalents of sodium iodide (Nal) in acetone (reflux, 19 h) to provide the iodo ester 107 in a 90% yield (Scheme 19).33 1) n-BuLi, THF  ci Me 2 CO  2) C1CO Me 2 118  106  87% yield  Nal, acetone 90% yield  I  Me 2 CO  107  Scheme 19  In the synthesis of methyl 4-cyclopropyl-2-butynoate (103) (Equation 22), a reported 34 was used. Thus, a solution of the dilithio salt of 28 of Carison’s procedure modification propynoic acid, 119, in a 1: 2 THF-HMPA solvent system, was treated with 1.1 equivalents of cyclopropylmethyl bromide (room temperature, 24 h) and subsequently with 4.0 28 equivalents of iodomethane (room temperature, 24 h) to give the ester 103 in a 48% yield. The compounds 106, 107 and 103 exhibited spectral data which were in full accord with the assigned structures. 1)1: 2 THF-HMPA  Li  =  &Br (22)  Li 2 CO  2) Mel 119  48%yield  = 103  Me 2 CO  36 1.2. Conversion of a.$-acetvlenic esters into alkyl (F)- or (Z’)-3-trimethylstannyl-2aikenoates  35 from our laboratory showed that reactions of aj3-acetylenic esters Previous reports SnCuSPh]Li (120) in the 3 100 with lithium (trimethylstannyl)(phenylthio)cuprate [Me presence of a proton source provides, highly stereoselectively, the corresponding alkyl (E)-3irimethylstannyl-2-alkenoates 89 (Equation 23). Moreover, reaction of 120 under different reaction conditions provided, also highly stereoselectively, the corresponding alkyl (Z)-3trimethylstannyl-2-alkenoates 91 (Equation 24). Thus, use of reagent 120, along with choice of appropriate reaction conditions, resulted in the control of the stereochemical out 3Sn-H across the triple bond of the cxji-acetylenic come of the overall addition of the unit Me conversion of 100 into 89 could be achieved by b esters 100. Furthermore, stereoselective 35 use of the (trimethylstannyl)copper(I) reagent 121 (Equation 25). However, this latter reagent was found to be ineffective for the stereocontrolled transfonnation of 100 into 91.  SnCuSPh]Li 3 [Me  SnCu•Me 3 Me S 2  120  121  120, THF  1 R — —  2 COR 2  — 1 R  (23) OH,78°C 2 R  Sn 3 Me  1) 120, THF, -48 °C  1 R 2 CO2R  (24) 2) R OH 2  Sr( 3 Me 91  1) 121, THF, -48 °C  t R  100  ,H  R’—  100  —  H 89  100  —  R 2 C0  2 COR 2  1 R  R 2 C0 —  2) 4 H CFNI{ NH 0  H  Sn 3 Me 89  37 A number of (E)- and (Z)-3-trimethylstannyl-2-aikenoates of general structures 89 and 91, respectively, were required for this study. The reagent 120 could serve well in the syntheses of 89 and 91, but this method has some disadvantages. Firstly, the requisite 36 Secondly, the latter starting material phenylthiocopper(I) (PhSCu) is tedious to make.  preparation requires the use of thiophenol, a chemical with a notably offensive odour. More importantly, PhSCu, like many copper(I) salts, is not very stable, and thus the prolonged  storage of this reagent may decrease the reproduceability in generating the desired cuprate 120. Copper(I) cyanide (CuCN), by contrast, is readily available, is a reasonably stable 37 and has been used extensively in chemical (CuCN is more stable than copper(II) cyanide), 38 Therefore, a brief study was carried out to determine the the generation of organocuprates. feasibility of the use of the lithium (trimethylstannyl)(cyano)cuprate [Me3 SnCuCNjLi (123), Sa by reaction of trimethylstannyllithium 3 SnLi (122) with copper(I) 3 39 Me which is prepared cyanide (CuCN) in THF (Equation 26), as an effective alternative to 120 for the stereoselective transformation of 100 into either 89 or 91.  —  —  91  89  SnLi 3 Me  THF, -48 °C +  R 2 CO  Sn 3 Me  H  Sn 3 Me  120  H  R 2 ,C0  — 1 R SnCuSPh]Li 3 [Me  CuCN  SnCuCN]Li 3 [Me  (26)  123  122 Me  Me Et 2 CO  H  Me  EL 2 CO  Sn 3 Me  124  Me  H 125  3 SnMe —  —  —  Sn 3 Me  Et 2 CO  Sn 3 Me  Et 2 CO 126  The reaction of [Me3SnCuCN]Li (123) with the commercially available ethyl 229 It was pentynoate (102) was investigated under a variety of experimental conditions. found 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 desired  product ethyl (Z)-3-trimethylstannyl-2-alkenoates (124) was accompanied by a minor amount  38 (<10%) of the geometric isomer ethyl (E)-3-trimethylstannyl-2-pentenoate (125) and a significant quantity (—20%) of ethyl (E)-2,3-bis(trimethylstannyl)-2-pentenoate (126).40 However, further experimentation finally established reaction conditions that effected a relatively clean trans-formation of 102 into 124.29  Thus, reaction of 102 with  approximately 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 consisted almost entirely of 124, accompanied by very minor amounts of 125 and 126. Purification 41 on silica gel (which separated of this material by a combination of flash chromatography and removed 125) and distillation (126 remained in the still-pot) provided the desired Z  alkenoate 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 the  29 corresponding alkyl (Z)-3-trimethylstannyl-2-alkenoates 91 in good yields. 1) [Me SnCuCNJLi (123) 3  R1 —  —  THF, -48 °C, 2 h; 0 °C, 2 h  r’r o2 ‘-‘2  R1  H —  (27)  2) 4 CI-NH NH O H  Sn 3 Me  100  R 2 C0  91  Table VIII. Preparation of alkyl (Z) -3-trimethylstannyl-2-alkenoates 91’ entry  acetylenic ester  1  6  102 127 128 129 105 106  7  130  2 d d 3  5  2 R  equiv of cuprate  ’ 1 product  % yieldc  Me (i-Pr)3SiO OCH 3 CH 0 ) 0 2 (CH cyclohexyl SiO(CH t-BuMe ) 2 2 Cl(CH  EL Et EL EL Me Me  HCEC(CH  Me  1.09 1.06 1.06 1.04 1.05 1.05 1.01  124 131 132 133 134 135 136  72 76 72 81 78 79 78  1 R  a 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 the corresponding alkyl (E)-trimethylstannyl-2-alkenoates and alkyl (E)-2,3-bis(thmethylstannyl)-2aikenoates. These minor products were, in each case, removed by a combination of flash chromatography and distillation. C Yield of purified, distilled product. d Compounds 127-129 and 13 1-133 were prepared by Mr. Keith A. Ellis. Experimental procedures 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.  39 Reaction (THF, -78 °C) of acetylenic esters 100 with 1.3-1.5 equivalents of cuprate OH (methanol for methyl ester; 2 123 in the presence of 1.3-1.5 equivalents of an alkanol R ethanol for ethyl ester) provided the alkyl (E)-3-trimethylstannyl-2-alkenoates 89 in good 29 The major products were accompanied by small yields (Equation 28 and Table TX). amounts (1-4%) of the Z isomers, but, in each case, the pure E isomer could readily be obtained 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 the presence of 1.3 equivalents of ethanol gave a crude product that contained a mixture of the ethyl (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 and distillation provided 125 in a 74% yield. SnCuCNJLi (123) 3 1) [Me  1  —  rn2  —  Sn 3 Me  C1-NB NH O H 2) 4 100 Table IX. entry  1 2  3 4  d 5  6  7 ge  9’ d 10 a b  (28)  H 89  Preparation of alkyl (E )-3-trimethylstannyl-2-alkenoates 89  acetylenic ester 101 102 103 104 129 105 106 130 127 128  2  1  THF, R OH, -78 °C, 4 h  1 R  H Me cyclopropyl i-Pr cyclohexyl SiO(CH t-BuMe ) 2 ) 2 Cl(CH ) 2 HCC(CH (i-Pr)3SiO OCH 3 CH 0 ) 0 2 (CH  2 equiv of R cuprate Et Et Me EL Et Me Me Me Et EL  1.30 1.30 1.51 1.56 1.50 1.30 1.30 1.30 1.31 1.30  equiv of  ’ % yield’ 1 reaction product  OH 2 R  time (h)  1.32 1.31 1.45 1.67 1.50 1.35 1.30 1.33 1.31 1.30  4  137  4  125  7  138 139 140 141 142 143 144 145  6 7 4  4 4  4 4  78 74 80 84 81 77 80 72  74 70  Detailed experimental procedures for entries 5,7-10 can be found in reference 29. 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 pure desired products. C Yield of purified, distilled product d Compounds 127-129, 140, 144 and 145 were prepared by Mr. Keith A. Ellis. Experimental procedures 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 SuCuCN]U 3 [Me  (123)  1 R R 2 C0  CO2 R 2  R1  H  Me S 3 i’Cu(CN) 146  nH Me S 3 89  4 — 1 R  OCu(CN)  Sn 3 Me  OR2 147  ,CO2 R 2  R1  H  H  —\ 1 R “  n Me S 3  CO2 R 2  ‘  91  Scheme 20  As 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 of functional groups such as silyl ether, acetal, primary alkyl chloride, and terminal alkyne. A possible pathway for the addition of [Me3SnCuCN]Li (123) to a,$-acetylenic esters 100, to give products 89 and 91, is shown in Scheme 20.  42 that It has been established  organocopper(I) reagents add kinetically to CEC bonds in a cis-fashion. Therefore, it is likely that addition of the cuprate 123 to 100 provides initially the vinylcopper(I) 42 that, depending on a intermediate 146 (Scheme 20).42 Moreover, it has been proposed number of factors, the latter species 146 may rearrange to the corresponding allenoate 147.  Protonation of, the “kinetic intermediate” 146, provides the (E)-3-trimethylstannyl-2alkenoate 89, while protonation of the allenoate 147 occurs from the side opposite the bulky trimethylstannyl 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 allenoate 147 is, apparently, facile. Thus, under these conditions, 91 is formed stereoselectively after the protonation process. However, at -78 OC, rearrangement of 146 to the allenoate 147 is retarded and the initially formed “kinetic intermediate” 146 is protonated by the added methanol or ethanol, or is protonated during the final aqueous work-up to afford the (E)-3trimethylstannyl-2-alkenoate 89.  41 1 R  R’  R 2 C0 HvaIues  M)<H.  Ha  2 M)CO R 2  JH= 71-87 Hz 3  JSn-H= 3  118-126 Hz  The structural assignments for the (E)-3-trimethylstannyl-2-alkenoates 89 and (Z)-31 nmr spectroscopic data, in particular, trimethylstannyl-2-alkenoates 91 were based on the H the magnitude of the coupling constant ( Jsn) between the a-olefmic proton (Ha) and the tin 3 43 that when a 5n) of the trimethyistannyl (Me3Sn) moiety. It is established n, 119 atom 7 (ll S trialkyistannyl moiety and a proton (Ha) are vicinal on a C=C bond, the J3 Sn-H value is much larger when these moieties are trans than when they are cis. In general, for compounds of general structures 89 and 91, the J3 Sn-H values are in the ranges 71-87 Hz and 118-126 Hz, H nrnr spectrum of ethyl (E)-3-trimethylstannyl-2-pentenoate respectively. For example, the 1 (125) is, with three exceptions, very similar to that of the geometric isomer, ethyl (Z)-3trimethylstannyl-2-pentenoate (124). Firstly, the position of the allylic methylene protons of the ethyl (E)-3-trimethylstannyl-2-pentenoate (125) (82.89) is considerably downfield from that of the ethyl (Z)-3-trimethylstannyl-2-pentenoate (124) (62.45). This difference is in accord with the fact that the allylic protons are cis to the ester group in ester 125 but trans in ester 124.  Secondly, the chemical shift of the vinylic proton in the ester 125 is at 6 5.94,  1nii 120 Hz 3  8 2.89 8 6.36  c.  O 1 2 C 1 Me\ E n Me S 3  125  124  ‘b44%_)  J3 5n-ii= 74HZ  85.94  42 which is at slightly higher field than that of the ester 124 (8 6.36). Again, this difference is expected, since in general, vinylic protons in unsaturated organostannane compounds are 44 by a cis vicinal trialkyistannyl substituent. More importantly, the tin-proton shielded coupling constant ( JSn..H) of the vinylic proton (Ha) in the ester 125 is 74 Hz which is 3 smaller than that of the ester 124  Jsn-w 3 (  120 Hz). Indeed, in some cases where the other  Jsnj) of the vinylic 3 isomer was not prepared, the value of the tin-proton coupling constant ( proton (Ha) of the alkenoate provided the only sufficient diagnostic clue for the structural determination.  Another noticeable difference between compounds 125 and 124 was  observed in their ir spectra. The carbonyl (C=O) stretching frequencies of 125 and 124 , respectively. In general, molecular ions for 1 were found to be 1718 and 1703 cm 45 Thus, high trimethyistannyl compounds were not observed in their mass spectra. resolution mass spectrometric measurements were performed on the (M+ compounds 125 and 124.  -  Me) peaks for  43 2.  Deconjugation-allcylation of alkyl (E’- and (Z’-3-trimethvlstannyl-2-allcenoates  2.1. Preparation of electronhiles: 2-bromo-4-iodo- 1-butene. (Z)- and (E)-diiodoallcenes  1 R %%  R’  I  I  I  X  Br 148  X  97  X=Brorl  R”%f’  z  96  2 R1’CO R 2  i  3 SflMe  98  90  1 R  1 R  R 2 C0  M)-’ 89 R’  I  >  2 CO R 2  3 SnMe  I 99  92  2 M>”CO R 2 91  As was mentioned earlier (pp 30-31), electrophiles of general structures 96 and 97 were required for this study. The requisite (Z)- and (E)-diiodoallcenes 98 and 99 could be synthesized 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, which will now be described.  46 the use of B-bromo-9-borabicyclo[3.3.ljnonane (B-Br-9Suzuki eta!. have reported 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 in a cis-fashion. Protonolysis of the bromoboration intermediate 150 with acetic acid affords the desired 2-bromo-1-alkenes 151 in excellent yields. For example, 1-hexyne (152)  44 4 (Equation 29) was transformed into 2-bromo-1-hexene (153) in a 99% yield.  Br H  ZZ  R  13r  +  B-Br-9-BBN  xr 151 Scheme 21  _,,,_,/  152  B-Br-9-BBN (29)  99% yield  153  2-Bromo-4-iodo-1-butene (148) (p 45) could be synthesized via the aforementioned C1 was added to a CH procedure. A solution of 3-butyn-l-ol (154) (Scheme 22, p 45) in 2 .1 7 (1.1 equiv) in CH2C12 2 P 3 (Ph 4 freshly prepared solution of triphenyiphosphine diiodide ) (room temperature, 4 h) to give, after work-up and distillation of the crude product, 4-iodo-1a The ir spectrum of 155 showed a strong SC-H stretching 13 butyne (155) in a 76% yield. H nmr . The 1 1 1 and a weak CEC stretching frequency at 2121 cur frequency at 3296 cm spectrum 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= 7,2 Hz, and a 2-proton triplet at 63.25, J= 7 Hz). Moreover, high resolution mass spectrometry 1. 5 showed that 155 had a molecular formula of C4H  45 C1 to a solution of B-Br 2 Addition of a solution of compound 155 (Scheme 22) in CH C1 and subsequent protonolysis provided 2-bromo-4-iodo-12 C, 3 h) in CH 9-BBN (0 0 yield.l The ir spectrum of 148 displayed a moderate C=C a butene (148) in an 86% 3 H nmr spectrum of 148 exhibited the expected stretching frequency at 1632 cm. The 1 signals for two different methylene moieties (a 2-proton broad triplet at 32.94, J= 7 Hz, and a 2-proton triplet at 6 3.24, J= 7 Hz) and two geminal olefmic protons (a 1-proton broad doublet at 6 5.57, J= 2 Hz, and a 1-proton broad doublet of triplets at 3 5.68, J= 2, 1 Hz). BrI. 6 High resolution mass spectrometry showed that 148 had a molecular formula of C4H .1 2 2 P 3 Ph , C1 CH roomtemp,4h 154  155  76% yield 1) B-Br-9-BBN 2)H 86% yield  148  Scheme 22  1 R 2 _>..JCOZR  R2 2 R ‘f’CO 1  n Me S 3 89  90  I  R’ I 98  3 SnMe  91  92  Scheme 23  99  46 For the preparation of the requisite (Z)- and (E)-diiodoalkenes 98 and 99 (Scheme 23, p 28 of the alkyl (E)- and (Z)-345), the first step was the stereospecific deconjugation trimethylstannyl-2-alkenoates 89 and 91 to give the corresponding alkyl (Z)- and (E)-328 or a trimethylstannyl-3-alkenoates 90 and 92, respectively. Following the reported 48 procedure, the deconjugation reactions gave the results summarized in Table X. modified  Table X. Deconjugation reactions of the alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91, respectively entry j28  starting material Me  methoda  woduct  A  t Me%fCO E 2 3 SnMe  Me)’  156  125 228  87  A  _>..JCO2Me  3 SnMe. 157  138 348  B t )__\,CO E 2  ’ 1 % yield  t f(’CO E 2  82  3 SnMe  158 139 428  Me  Me Me>”COEt  124  89  t ‘Co E 2 3 SnMe  159 a 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 0. 2 Et (-98 O) solution of HOAc in 28  2 (2.73 equiv) in THF ) 3 Method B: (A modified procedure) Substrate 139 was treated with KN(SiMe (-78 °C, 45 mm; -48 °C, 5.5 h) containing HMPA (2.78 equiv). Enolate quenching as in 48 Method A. Method C: Substrate 124 was treated with LDA-HMPA (1.52 equiv) in THF (-78 °C, 30 mm; o O(, 28 1 h). Enolate quenching as in Method A.  b Yield of purified, distilled product  47 28 of the esters 125 and 138 with lithium diisopropylamide (LDA) in Deconjugation THF, followed by protonation of the resultant enolate anions with a solution of HOAc in Et20, provided exclusively ethyl (Z)-3-trimethylstannyl-3-pentenoate (156) and methyl 4cyclopropyl-3-trimethylstannyl-3-butenoate (157), respectively, in good yields (Table X, 28 for deconjugation of ethyl (E) entries 1 and 2, p 46). Surprisingly, the reported procedure 5-methyl-3-trimethylstannyl-2-hexenoate (139) with 2.3 equivalents of LDA in the presence of 2.3 equivalents of hexamethylphosphoramide (HMPA) was not satisfactory. The expected product 158 was produced in low yield (16%), and some unidentified side-products were also present. It seemed likely that the formation of the side-products in this case was associated 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 2.73 equivalents of potassium bis(trimethylsilyl)amide 48 )2] in THF in the presence of 3 [KN(SiMe 2.78 equivalents of HMPA, followed by the usual quenching procedure, provided 158 as a single 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 mixture containing the starting material 124 (—14%), the expected product 159 (—80%), and a number of minor components. Deconjugation of 124 was therefore carried out with 1.52 equivalents of L.DA in THF containing 1.50 equivalents of HMPA (Table X, entry 4).28  The stereochemistry of each àf the esters 156-159 (Table X, p 46) was readily assigned H nmr spectroscopic data, in particular, the magnitude of the coupling on the basis of 1 constants 43 JSn-H) associated with coupling between the olefinic proton and the tin atom. 3 ( In the alkyl (Z)-3-trimethylstannyl-3-alkenoates 156-158 (where the Me3Sn moiety and olefinic proton are in a trans relationship), these 3 Jsn..H values are —130 Hz, while the corresponding coupling constant for ethyl (E)-3-trimethylstannyl-3-pentenoate (159) (where the Me3Sn moiety and olefinic proton are in a cis relationship) is 73 Hz.  48 For all the esters 156-159 (Table X, p 46) high resolution molecular mass measure ments were determined on the (M+  -  45 Sn. Me) fragment and are based on the isotope 120  Interestingly, the ir spectra of the (Z)- and (E)-conjugated esters (124, 125, 138 and 139, , 1 1 and —1718 cmTable X) showed strong C=O stretching frequencies at 1703 cm respectively, while all the deconjugated esters 156-159 exhibited the corresponding . In summary, all the prepared esters 156-159 1 frequencies at the ranges 1733-1737 cm showed spectroscopic data in full accord with those found in the literature.  Deconjugation-protonation and deconjugation-ailcylation reactions of a,J3-unsaturated 49 In 1972, Rathke and ’ 48 esters have been studied extensively in the last two decades. a reported that deprotonation of the protons from the a43-unsaturated ester 160 49 Suffivan (Equation 30) by lithium N,N-isopropylcyclohexylamide (LilCA) in the solvent system THF HMPA, followed by quenching of the resultant dienoate anion with various electrophiles, afforded the corresponding a-alkylated deconjugated esters 161 in good yields. CO Et  2) RX = Mel  /  t CO E 2  1) LilCA, THF-HMPA  4/  BnBr  ‘R  161  160  R = Me, 87% yield R = Bn, 62% yield  The preference for alkylation at the a-position after the generation of dienolate anions 9b In their study, a 4 from aj3-unsaturated esters was also observed by Schiessinger et al. presumed 1: 1 complex of LDA and HMPA was generated by the addition of 1.1 equivalents of HMPA to a THF solution of 1 equivalent of LDA (-78  0(D).  Successive addition of 1  equivalent of ethyl (E)-2-butenoate (160) (Equation 31, p 49) and iodoethane (Ed) to this solution gave the expected a-alkylated deconjugated ester 162 in a 96% yield. According to simple molecular orbital calculations, they attributed the a-alkylations to the location of the  49  b 49 maximum negative charge on the a-carbon atoms in the dienolate anions. Et 2 CO  =1  Et 2 CO  1) LDA-HMPA, THY  (31)  2) EtI  Et 96%yield  160  162  Studies focusing on the determination of the stereochemical outcome of deconjugation protonation and deconjugation-alkylation of aj3-unsaturated esters were also carried out. It ’, for example, that the deconjugation-protonation of ethyl (Z)-2-alkenoates 163 49 was found (Equation 32) provided, highly stereoselectively, the corresponding (E)-3-alkenoates 164 in  good yields (—95-99%).  —  E 2 R_.r’CO  163  1) LDA-HMPA, THY  EL 2 CO  _J  r  2) H R = Me, n-Pr or i-Pr  R—J  (32)  164 —95-99% yield  The stereochemical outcome in the conversion (Scheme 24, p 50) of (E)-3-trimethylstannyl-2-alkenoates 89 into the corresponding (Z)-3-trimethylstannyl-3-alkenoates 90 was completely analogous to that of the conversion of 163 into 164. Results obtained from the e by the 49 b, 28 transformation of 89 and 163 into 90 and 164, respectively, were rationalized 4 shown in Scheme 24. For the kinetically controlled deprotonation of the (Z) formulations 2-alkenoates 163, there are two ground-state conformations, 165 and 167.49e The C-Ha bonds in both conformations 165 and 167 are aligned perpendicular to the plane of the conjugated system. The perpendicular orientation of C-Ha bonds in 165 and 167 meet the  stereoelectronic requirement for the formation of dienolate anions 173 and 175, respectively, through the corresponding transition states (169 and 171). The transition state 169 derived 1 ) between the R 50 3 strain ’ 1 from 165 would be destabilized by a serious steric interaction (A group and the C0 R group. In contrast, deprotonation of conformation 167 would occur 2  50 0 2 R  0 2 R  o>-x 1 R  1 R  165X=H  167X=H  166 X  168 X  =  3 SnMe  =  3 SnMe  1A [transition state]  [transition state]  169X=H  171X=H  170 X  -  =  172 X  3 SnMe  0 2 R  =  3 SnMe  0 2 R Li  Li  1 R H  1 R 175X=H  173X=H 174 X  =  3 SnMe  176 X  =  SnMe  Et 2 CO RCO E 2 t 163 1 R  R 2 C0  Me ) 3 ” 89  R 164  0 2 R  R1”%(CO R 2 2 3 snMe 90  H— 1 R 164 X  Scheme 24  90 X  =  =  H  3 SnMe  51  via transition state 171, in which no severe steric interaction would be involved. Consequently, the pathway 167  —  171  —,  175 would be expected to be energetically more  favourable 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 168 50 between the R and Me3Sn group. This interaction would be destabilized by A 2 strain ’ 1 would be considered weaker than the A 13 strain associated with the transition state between 166 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 stereoselective  formation of (Z)-3-trimethylstannyl-3-alkenoates 90.28  Similarly, ethyl (E)-2-pentenoate 177 (R  =  Me) was converted, by the deprotonation  e into the (Z)-3-pentenoate 178 in a 98% yield (Equation 33). 49 protonation process, Interestingly, the deconjugation was less stereoselective as the size of the R group increased. For example, the deconjugation of 177 (R (R = n-Pr) and 164 (R  =  =  n-Pr) provided (94% yield) a mixture of 178  n-Pr), in a ratio of -6: 1, respectively. When the steric bulk of the  R group was further increased, as in the case where the R group was an i-propyl group, the ratio of the two products (97% yield) 178 (R  =  i-Pr) and 164 (R  =  i-Pr) decreased to  -1.8: 1, respectively. Et 2 jO 1)LDA-NMPA, ThF  +  R_1”  178  Obviously, deconjugation of the (E)-2-alkenoates 177 would be considered less stereoselective than that of the (Z)-2-alkenoates 163. In contrast to these findings, the transformation 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 These  52 49 by the formulations , 28 rationalized e shown in Scheme 25 (p 53). For the 49 results may be e kinetically controlled deprotonation of the (E)-2-alkenoate 177, the two ground-state conformations 179 and 181 have both of their C-Ha bonds aligned perpendicular to the C=C r system. The corresponding transition states 183 and 185 would be destabilized by AU 1 12 strain 50 (between the R 1 group and the olefinic proton Hb) and A 50 (between the R strain group and the /3-proton, X = H), respectively. However, the transition state 183 is favoured e Both experimental and theoretical studies 49 51 1 group. due to the stabilization from the cis R have shown that allylic anion structures containing terminal cis alkyl groups are more stable than those having trans ailcyl groups. Thus, if the transition states 183 and 185 possess allylic anion-type properties, 183 would be expected to be more stabilized than 185. As a result, the major dienolate anion obtained from the deprotonation of 177 would be 187, which provides 178 upon subsequent protonation.  Thus, when 177 (R  = Me) was  deconjugated, 178 (R = Me) was obtained as the only product. As the size of the R group in 177 (R  3 ’ 1 = n-Pr or i-Pr) increased, the transition state 183 would be destabilized by A  strain and this, in turn, would favour the deconjugation of 177 to proceed through the transition state 185 to provide 189 and subsequently 164 (R  = n-Pr or i-Pr) as the side  e In the coversion of the (Z)-3-trimethylstannyl-2-alkenoates 91 into the (E)-349 product. trimethylstannyl-3-alkenoates 92, it would be expected that the pathway 180 would be more favoured than the pathway 182  —*  186  —*  —,  184  —*  188  190, irrespective of the size of the  12 strain) between 1 group. This could be explained by the fact that the steric interaction (A R 1 and X the R  (= SnMe3) groups in the transition state 186 would destabilize this species  1 significantly. On the other hand, the relatively small destabilization (AU strain between R 3 and H) in the transition state 184 would be ,, and A 1 and proton H 12 strain betweem SnMe 1 group as mentioned above. Thus, partially compensated by the stabilization from the cis R the deprotonations of the (E)-3-trimethylstannyl-2-alkenoates 91 proceeds through 180, 184 and 188 to provide the (Z)-3-trimethylstannyl-3-alkenoates 92 in a stereoselective manner.  53 2 COR  2 COR  R> 179 X  =  H  181 X  =  H  180 X  =  3 SnMe  182 X  =  3 SnMe  LDA  LDA  [transition state]  [transition state]  183 X  =  H  185 X  =  H  184 X  =  3 SnMe  186 X  =  3 SnMe  0 2 R  0 2 R  Li  Li  R1  • H  H 187 X=H 188 X  =  3 SnMe  Et 2 CO  189 X  =  H  190 X  =  3 SnMe  Et 2 CO R  R 177  178  — 1 R Sn 3 Me  Et 2 CO  R 2 C0 rCO R 2 2 3 SnMe  91  92  H 178 X 92 X  =  =  H  3 SnMe  Scheme 25  164 X 90 X  =  =  H  3 SnMe  54  t r’CO E 2  0 2 AIH, Et 2 i-Bu  -78 °C, 1 h;0°C, 1 h 159  191  93%yield  C1 CH 12, 2 room  temp. 15  miii  90% yield Me  Me I  CI CH P.1 2 3 Ph , 2  i  I  N, room temp. 4 h 3 Et  193  98%yield  I  i 192  Scheme 26  A sequence of reactions was employed for the conversion of ethyl (E)-3trimethylstannyl-3-pentenoate (159) (Scheme 26) into (E)-3,5-diiodo-2-pentene (193). 0 with a solution of dilsobutylaluminum hydride (i 2 Reduction of the ester 159 in Et Bu2AIH) (2.5 equiv) in hexanes afforded, after appropriate work-up and distillation, the corresponding trimethyistannyl alcohol 191 in a 93% yield. The ir spectrum of 191 1 and a weak C=C stretching exhibited a strong 0-H stretching frequency at 3363 cmH nrnr spectrum of 191 showed the expected signals for a . The 1 1 frequency at 1614 cmtrimethylstannyl group (a 9-proton singlet at 80.12 with sateffite peaks due to Sn-H coupling, JSnH 52 Hz), a hydroxyl proton (a 1-proton triplet at 6 1.48, J= 7 Hz, which exchanges 2 with D20), a vinylic methyl group (a 3-proton doublet at 6 1.73, J= 7 Hz), two methylene groups (a 2-proton triplet of doublets at 82.57, J= 7, 1 Hz, with satellite peaks due to Sn-H coupling, 3 Js= 61 Hz and a 2-proton quartet at 83.62, J= 7 Hz) and a vinylic proton (a 1proton quartet of triplets at 8 5.85, J= 7, 1 Hz with satellite peaks due to Sn-H coupling, Js-w 77 Hz). 3  Vinyl trialkylstannanes may be converted into the corresponding vinyl iodides via  55 , This transformation is usually both highly efficient and 33 b 4 iodine. reaction with a stereospecific, and generally proceeds with retention of C=C bond geometry. Thus, the trimethyistannyl alcohol 191 (Scheme 26, p 54) was converted into the corresponding iodo alcohol 192, by reaction with 12 (1.1 equiv) in CH C12 (room temperature, 15 mm), in a 2 90% yield. The latter compound exhibited spectral data which were in full accord with the proposed structure. For example, the ir spectrum of 192 exhibited a strong 0-H stretching H nmr . The 1 1 1 and a weak C=C stretching frenquency at 1635 cm frequency at 3333 cnr spectrum of 192 showed the expected signals for a hydroxy proton (a 1-proton broad signal at 8 1.60-1.80 which exchanged with D20), a vinylic methyl group (a 3-proton doublet at 8 1.67,1=7 Hz), two methylene groups (a 2-proton triplet at 6 2.65,1= 6 Hz, and a 2-proton quartet at 33.74,1=6 Hz) and a vinylic proton (a 1-proton quartet at 66.40, J= 7 Hz). The 10. 9 H 5 high resolution mass spectrum showed that 192 had a molecular formula of C  P.1 3 Ph 4 7 in the Treatment of the iodo alcohol 192 (Scheme 26, p 54) in CH C12 with 2 2 N) (room temperature, 4 h) afforded the expected product (E) 3 presence of triethylamine (Et H nmr spectrum of 193 displayed the 3,5-diiodo-2-pentene (193) in a 98% yield. The 1 expected signals for a vinylic methyl group (a 3-proton doublet at 8 1.68, J= 7 Hz), two methylene groups (a 2-proton triplet at 62.95,1=7 Hz, and a 2-proton triplet at 63.27,1=7 Hz) and a vinylic proton (a 1-proton quartet at 66.42,1=7 Hz). Moreover, 193 was shown to have a molecular formula of CSH8I2 by high resolution mass specirometry.  By employing the same sequence of reactions described above, ethyl (Z)-3-trimethylstannyl-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 the corresponding (Z)-diiodoallcenes 98: (Z)-3,5-diiodo-2-pentene (198), (Z)-1-cyclopropyl2,4-diiodo-1-butene (201) and (Z)-1,3-diiodo-5-methyl-2-hexene (204), respectively. The results obtained from these transformations (Scheme 27, p 56) are summarized in Table XI.  56  STEP A  R2 2 1 4’f”CO R 3 SnMe  A1H, Et 2 i-Bu 0 2  R’ 3 SnMe  -78 °C, 1 h; 0°C, 1 h  90  194  =Me,R 1 R = EL 156 2 =c-Pr,R 1 R = Me 157 2 =i-Pr,R 1 R = Et 158 2  196 R =Me 1 199 R =c-Pr 1 =i-Pr 1 202 R STEP B  CI 2 CH room temp. 15 mm ‘2,  STEP C  I  1 R  P.1 2 3 Ph , 2 CI CH  1 R  N, room temp. 4 h 3 Et 195  =Me 1 198 R  197 R =Me 1 200 R =c-Pr 1 203 R =i-Pr 1  201 R =c-Pr 1  204 R =i-Pr 1 Scheme 27  Table XI. Conversions of the alkyl (Z)-3-trimethylstannyl-3-alkenoates 90 into the corresponding (Z)-diiodoalkenes 98 conversion of starting material  conversion of starting material  conversion of starting material  90 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,  ,R 1 ) 2 90 (R  —,  156 (Me, EL)  194 (% yield)’ 1 (R ): 194 1 196  —,  (99)  (Me):  —,  196  157 (c-Pr, ’ Me)—, 199 (98) 1  (cPr):b 199  158 (i-Pr,’ EL)  (i-Pr):’  —  202  (97)  a Yield of purified, distilled product. b c-Pr cyclopropyl group. C i-Pr isopropyl group  202  195 (% yield)’  —,  —,  —  ): 195 1 (R  —÷  197 (96)  (Me):  200 (89)  (cPr):b 200  203 (90)  (iPr):C 203  197  98 (% yield)a  —  —,  —,  198 (95) 201 (91) 204 (99)  57 2.2. Deconjugation-alkvlation of alkvl (E)- and (Z)-3-trimethylstannyl-2-alkenoates. and of ethyl (Z)-5-methvl-3-trimethvlstann’vl-3-hexenoate with the prepared electrophiles  R1%(NDO R 2 2 3 SnMe  R 2 R1_>....,CO Me S 3 n 89  RI>  Sn 3 Me  90  R2 2 S4%CO  SnMe 3 92  Et 2 CO 91  As mentioned earlier (pp 45-53), the deconjugation-protonation of alkyl (E)- and (Z)-3trimethylstannyl-2-alkenoates 89 and 91 provided exclusively ailcyl (Z)- and (E)-3-trimethylstannyl-3-alkenoates 90 and 92, respectively. Similarly, the deconjugation-alkylation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 with electrophiles were achieved 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 a bright yellow solution of the corresponding lithium dienolate anion. Cooling of the resulting mixture 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% yield of ethyl (Z)-5-iodo-2-[(Z)- 1 -trimethylstannyl- 1-propenyl]-5-heptenoate (205).  Me  COt  Et 2 OC  1) LDA-HNPA,  Me Me)’ 125  2)  Me:  I 198  Me  (34)  MeX 205 89% yield  The 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 with electrophiles via the aforementioned procedure. The results of these reactions (Equation 35, p 58) are summarized in Table XII (pp 58-60).  58 C 0 2 R 1) LDA-HMPA, THF  1 R  3 111 R Me)’  Sn 3 Me  89or91  206  x 96or97  (X=Brorl)  Table XII. Deconjugation-alkylation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 with the prepared electrophiles entry  substrate 89or91  CO,Et  Me  zxcedut  oduct 206  ’ 1 % yield  A  C 2 ELO  81  MS?’ Br  137  Sn 3 Me. 40a  2  Et 2 CO  Me  A  C 2 EtO  75  M) Br  125  Sn 3 Me 207  CMe 2 EtO  A  86  SnCO 3 Me E 2 t Br  124  Sn 3 Me  208  4  EI 2 CO  Me  C 2 EtO  B  Me>’ 125  I  Sn 3 Me  205  89  59 Table XII. Continued substrate 89or91  entry  5  product  2 procedure’  B  Me  ’ 1 % yield  206  C 2 EtO  Me  89  Me’fcj  Me>’COzEt  Sn 3 Me  124 209  6  Me  EL 2 CO  C  Me  92  C 2 EtO  M) I  125  Sn 3 Me 210  7  C  Me  Me  C 2 ELO  Me  86  Et 2 Me)”CO Sn 3 Me  I  124  211 8  SiO2 t-BuMe  B  87  C 2 MeO Me’(OSiMe ( 2 tBu) I Me Sn 3  MeS’  212  141  A  C 2 MeO  90  Me3S/ 138 213 B  10  C 2 MeO  >__>jOzMe MeSn 138 214  83  60 Table XII. Continued substrate 89 or 91  entry  11  cedurez  product 206  % yieldb  D  C 2 MeO  72  L>COMe  ‘iiv  n Me S 3 138  215  C 2 EtO  E  12  158  86  Tjf’T’ 216  a Procedure A:  1) LDA-HMPA (—1.3 equiv), THF, -78 °C, 0.5 h; 0°C, 0.5 h; C, 1 h. 2) 148 (—1.3 equiv), -20 0  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.  C, 0.5 h; Procedure C: 1) LDA-HMPA (—1.3 equiv), THF, -78 °C, 0.5 h; 0 0 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.  kI 148  201  MV%( r%-I 193  198  204  61 The 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 158  was obtained in a 16% yield. Obviously, the deprotonation of 139 by the LDA-HMPA complex followed by subsequent addition of electrophile would therefore afford the alkylated product in low yield. C 2 EtO t f(’CO E 2 158  139  216  These problems were overcome by the following strategy. The a-protons of 158 are much less hindered than the protons of 139. Thus, an a-proton from 158 was readily removed with the LDA-HMPA complex (1.33 equiv) to provide the corresponding lithium dienolate anion. Subsequent addition of the electrophile 204 (1.45 equiv) to the resulting anion afforded the alkylated ester 216 in an 86% yield (Equation 36 and Table XII, entry 12, p 60).  1) LDA-HMPA, THP  C 2 EtO  t CO E 2 2) 158  216 204  86% yield  The structural assignments of all the aikylated esters of general structure 206 (Equation H nnir speciroscopic data, especially the magnitude of the 35, p 58) were based on their 1 coupling constant ( Jsnj between the vinylic proton and the tin atom of the Me3Sn moiety. 3 For example, ethyl (Z)-5-iodo-2-[(Z)- 1 -trimethylstannyl- 1-propenyl]-5-heptenoate (205)  62 possesses a vinylic proton (Ha) which is trans to the Me3Sn group and thus has a 3 JSn..H value 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, H nmr spectra include, in each has a 3 JSn..H value of 74 Hz. Other notable features of their 1 case, the presence of one Me3Sn group (a 9-proton singlet: 205, 6 0.21; 209, 6 0.14), two vinylic 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 them  has a pair of satellite peaks owing to the Sn-H coupling). Moreover, both isomers show 1 in their ir spectra. Thus, it is apparent that, strong C=O stretching frequencies at 1728 cur in each case, the C=O group of the ester is not in conjugation with the C=C bond. In 45 all the compounds of general structure 206 exhibit accordance with previous observations, the expected (M Me) fragments in their high resolution mass spectra. -  C 2 ELO  C 2 ELO  Ha  Me  MefMe I Sn 3 Me  Me’4f H Sn 3 Me I  205  209  In a previous part of this thesis (pp 49-53), the stereochemical outcome in the conversion of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 into alkyl (Z)- and (E)-3trimethylstannyl-3-alkenoates  90 and 92, respectively, was rationalized by  e summarized in Schemes 26 and 27, respectively. In addition, some of 9 bA 28 formulations the background information concerning the development of both deconjugation-protonation  and deconjugation-alkylation was presented. Two similar formulations, summarized in Schemes 28 and 29 (pp 64-65), are used to rationalize the stereochemical outcome in the deconjugation-alkylation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91, respectively.  63 For the kinetically controlled deprotonation of the (E)-2-alkenoates 89 (Scheme 28, p 64), the transition state 170 derived from the conformation 166 would be destabilized by the R groups. Thus, the 2 1 and the C0 ) between the R 50 13 strain large steric interaction (A pathway 168  —  172  —  176 would be energetically more favoured, leading, after alkylation  with the electrophiles 96 or 97, to the stereoselective formation of 2-[(Z)-1-lrimethystannyll-alkenyl]alkenoates 217 (Scheme 28 and Equation 37; typical examples can be found in Table XII, entries 2,4, 6, 8 and 9-11, pp 58-60). LD:-HMPA,THF R 2 Rl__>,,C0  3 R  96or97  (37)  (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 destabilized 1 and the SnMe3 groups. 2 strain ’ 1 ) between the R 50 significantly by the steric interaction (A 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; typical examples can be found in Table XII, entries 3, 5 and 7, pp 5 8-59) were formed stereo selectively after alkylation with the electrophiles 96 or 97. 1) LDA-HMPA,THF 3 R 2 M R 2  96or97  (X=Brorl)  (38)  64 R’ R 2 __>_,C0 Sn 3 Me  89  H  168  166  LDA  LDA  [transition state]  [transition state]  170  172  -  >:_  Li  Li  176  174 I  3 R 96 or97  C 0 2 R  C 0 2 R  R1  3 R X  Sn 3 Me  Sn 3 Me  90  217  Scheme 28  65 R’— CO2 R 2  Sn 3 Me  2 COR  R 2 C0  91 3 SnMe  3 —SnMe 1 R 182  180  H  LDA  [transition state]  [transition state]  186  184  1 0 2 R  0 2 R  )—SnMes  Li  3 SnMe H—  R’— H  190  188 I  3 R 1/ 96 or97  C 0 2 R  C 0 2 R  1 R  L%r Sn 3 Me 92  Sn 3 Me  X 218  Scheme 29  1 R  Li  66 3.  Syntheses of alkyl 2.3-bis(aflcvlidene)cyclopentanecarboxylates and related derivatives  3.1. Stereocontrolled syntheses of alkvl 2.3-bis(alkvlidenecvclopentanecarboxylates and related substances via pa1ladium(0-cata1yzed coupling reactions  As mentioned in the previous section of this thesis (pp 14-15), ethyl 2,3-bis(methylene)a by treatment of 3 cyclopentanecarboxylate 41a (Table Xffl, entry 1) was preparedl compound 40a, which contains vinyl bromide and vinyltrimethylstannane functions, with d ) (5 mol %) and L1C1 (2 equiv) in dry DMF at 80 OC for 1 h. By employing similar 4 P 3 (Ph P reaction conditions, compounds of general structure 206 (Equation 39) were transformed effectively 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. C 0 2 R  )Pd (5 mol %) (Ph P 3  I  R’  R3Y’%N”R1 )  LiC1  MeSi’i  R  (2 equiv), DMF 219  206  Table XIII.  entry  Stereocontrolled syntheses of alkyl cyclopentanecarboxylates 219  2,3- bis(alkylidene)  pxxluct 219  substrate 206  ’ 1 % yield  56C  Br  n Me S 3  40a  41a  67 Table XIII. entry  Continued roduct 219  substrate 206  83  C 2 EtO  2d  Br  ’ 1 % yield  Sn 3 Me  220  207  C 2 EtO  3  Br  Me  87  Sn 3 Me  221  208  95  C 2 EtO  4  J’ Me 1 Me’f” Sn 3 Me  I  222  205  5  C 2 EtO  Me  91  Me’%( I  Sn 3 Me 223  209 6  C 2 ELO  Me  I  Me  88  Sn 3 Me  211 224  7  C 2 MeO  72  Me’%(’”OSiMe ( 2 t-Bu) I Me Sn 3  212  225  68  Table XIII. Continued entry  8  substrate 206  ixoduct 219  C 2 MeO  213 9  ’ 1 % yield  94  226  C 2 MeO  97  Mey  214  be  C 2 MeO  215 ii!  227 86  228  52  C 2 ELO  216  229  a All coupling reactions were carried Out with the following conditions (unless otherwise stated): Pd 3 (Ph P 4 ) (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: 4 Pd 3 (Ph P ) (5 mol %) and LiC1 (2 equiv) in dry DMF at 80°C for 30 mm. e Experimental conditions: 4 Pd 3 (Ph P ) (5 mol %) and LiC1 (2 equiv) in dry DMF at 90°C for 1 h. f Experimental conditions: 4 Pd 3 (Ph P ) (5 mol %) and LiC1 (2 equiv) in dry DMF at 105 °C for 1.5 h.  69 The coupling reactions were generally canied out as indicated by the following example. d ) (5 mol %) and LiC1 (2 equiv) to a 0.1 M solution of substrate 205 4 P 3 (Ph Addition of P (Table Xffl, entry 4, p 67) in DMF gave a yellowish solution. This solution turned into a dark brown solution with formation of a fme black powder (palladium (0)) upon heating at 80 OC for 1 h. After work-up, analyses of the crude reaction product by gic and tic indicated that  only one cyclized product had formed.  Purification of this crude product by flash  chromatography, followed by distillation, provided ethyl (Z,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate 222 in a 95% yield (entry 4). 62.19-2.32 (m), and 82.32-2.49(m)  85.38  8 1.78-1.92 (m)  6 1 58 ‘dt  J  8  (  85.48 (br ci)  6 1.92-2.05 (m)  222  6 3.27-3.4 1 (m)  H nmr The structure of compound 222 was confirmed in the following manner. The 1 spectrum of 222 showed the expected signals for an ethyl ester group (a 3-proton triplet at 6 1.23, J= 7 Hz, and a 2-proton multiplet at 8 4.00-4.23), two vinylic methyl groups (Me, a 3proton doublet of triplets at 8 1.58, J= 7, 1 Hz; Me*, a 3-proton doublet of doublets at 8 1.62, .1= 7, 1 Hz), two methylene groups (Ha, 1-proton multiplet at 8 1.78-1.92; 11 b 1proton multiplet 8 1.92-2.05; 2 x H, two 1-proton multiplets at 6 2.19-2.32 and 8 2.32, a 1-proton multiplet at 83.27-3.41). It is interesting to note 4 2.49), and a methine proton (H that the signal for the methylene group of the ethyl ester function appears as a multiplet  because these geminal protons are diastereotopic. Other characteristic signals include the two  70 olefinic 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 Overhauser enhancement (nOe) difference experiments. In the decoupling experiments, irradiation at 8 3.34 (Hj changed the doublet of doublets at 8 1.62 (Me*) to a doublet (J= 7 Hz), simplified the two multiplets at 8 1.78-1.92 (Ha) and 8 1.92-2.05 (Hb), and sharpened the broad quartet at 85.48 (Hf). Irradiation at 65.38 (He) simplified the doublet of doublets at 8 1.58 (Me) to a broad singlet (wl/2= 4 Hz), while irradiation at 6 5.48 (Hf) simplified the doublet of doublets at 8 1.62 (Me*) to a broad singlet (wl,2= 4 Hz). The configuration of C=C bonds of 222 was shown by nOe difference experiments. Thus, irradiation at 6 1.58 (Me) caused an enhancement of the signal at 65.38 (He), while irradiation at 6 1.62 (Me*) increased the intensity of the resonance at 65.48 (Hj). Irradiation at 6 3.34 (Hd) caused enhancement of the signals at 6 1.78-1.92 (Ha) and 6 5.48  (Hj).  Irradiation at 8 5.38 (He) increased the  intensities of the resonances at 6 1.58 (Me), 6 2.19-2.32 (He) and 6 2.32-2.49 (Hc), while irradiation at 8 5.48 (Hj) increased the intensities of the signals at 6 1.62 (Me*) and 6 3.271 for the C=O 3.41 (ILj). The ir spectrum of 222 showed a strong absorption at 1737 cnr  stretching vibration of the ester group. The high resolution mass spectrum of the compound C 1 H . 2 2 8 222 confirmed that it has a molecular formula of 0  3 R  219  222  The structures of the other alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 219 (Table XIII, pp 66-68) were assigned in a manner similar to that described above. All the prepared alkyl 2,3-bis(aikylidene)cyclopentanecarboxylates of general structure 219 exhibited strong 1 in their ir spectra. In each case, the C=O stretching frequencies in the region 1734-1738 cm high resolution mass spectroscopic measurement was performed on the molecular ion. The  71 transformation (Equation 39) of the diene esters 206 into the corresponding dienes 219 was found to be stereospecific. The confirmation of the configuration of each of the alkyl 2,3bis(alkylidene)cyclopentanecarboxylates 219 (Table XIII) was based on nOe difference experiments similar to those outlined above for the diene 222. C 0 2 R  ) (5 mol %) d 4 P 3 (Ph P (39)  3 R X  LiC1 (2 equiv), DMF  n Me S 3  219  206  224  223  222  Me  C 2 EtO  I  n Me S 3 210  230  As shown in Table XIII (entries 4-6, p 67), ethyl 2,3-bis(ethylidene)cyclopentanecarboxylates 222, 223 and 224 were prepared in a stereocontrolled fashion with the  required Z,Z-, E,Z- and E,E-configurations, respectively.  It was surprising that the  palladium(0)-catalyzed ring closure of compound 210 did not provide the expected Z,E-diene 230 in a stereoselective manner.  Under a number of reaction conditions (different  palladium(0) catalysts, various solvents, additives and temperatures), compound 210 invariably produced mixtures of 230 and 224 (see Section 4.1, pp 89-90). The reason for this lack of selectivity is not immediately clear. Fortunately, further experimentation to effect this particular transformation led to the discovery of a new reaction. The details of this discovery and the related studies will be discussed in Section 4.1 of this thesis (pp 90-95).  72 This coupling process can tolerate the presence of functional groups such as silyl ether and carboxylic ester, as well as the cyclopropyl moiety (entries 7-10, pp 67-68). More  drastic reaction conditions were required for the preparation of the highly hindered (Z,Z)-2,3bis(alkylidene)cyclopentanecarboxylates 228 and 229 (entries 10 and 11, p 68). For  P)4Pd (5 mol %) and LiC1 3 example, when substrate 215 was subjected to treatment with (Ph (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 higher temperature (90 °C), and provided the desired product 228 in 86% yield. Higher reaction temperatures (Table XIII, entry 11, at 105 OC for 1.5 h) were also found to be necessary for the conversion of 216 into the diene 229 (52% yield). C 2 MeO  C 2 EtO  215  216  228  229  The stereospecific formation of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 219 may be rationalized by the catalytic cycle shown in Scheme 30 (p 73). Oxidative  addition of the palladium catalyst to the vinyl halide moiety in 231 (Scheme 30) produces the intermediate 232. Intramolecular transmetalation involving the vinyltrimethylstannane function then gives a six-membered palladium metallocycle 233 which reductively eliminates to produce the cyclopentanecarboxylate 234 and regenerate the palladium(0) catalyst. Since 14 transmetalation and reductive elimination steps are known to the oxidative addition,’  73  occur with retention of configuration, an overall retention of configuration of the double a The lower yield of 229 may be attributed to the 4 bonds in this coupling process is expected. steric congestion involving the bulky groups located on the two double bonds in the reaction 1 intermediate 233 (R  =  3 R  =  i-Pr, R 4  =  5 R  =  H).  3 ‘%r\ R  C 0 2 R  R1,..L.<’  1 R3’%’ R 1  219  206  3 R 1 R  LiC1  +  234 231  4 PdL  2L LIX  5 R L = Ph P 3  L  C 0 2 R  2L  4 R  3 ‘fRi R  d CIL P 2  n Me S 3  1 R 232 233  SnC1 3 Me  Scheme 30  +  74 3.2. X-ray analysis of (Z.Z-2.3-bis(a1kvlidenecvclopentanecarboxamides  222  229  228  The intramolecular coupling process is successful for the stereocontrolled preparation of the 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 exist between the substituents on the termini of the conjugated diene moieties. One would predict that 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-ray analysis, which would in turn, reveal information about the extent to which these diene  systems are twisted away from planarity. 7 7 R R 6  6  R  3%4  R%’ 6 PLANAR  TWISTED  75 In 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 and 52 A solution 238) (Scheme 31) were prepared via a procedure developed by Weinreb et al. of (R)-(+)-1-phenylethylamine (235) (2.2 equiv) in benzene was treated with a solution of trimethylaluminum (Me3A1) (2.2 equiv) in toluene to produce a colorless solution of the corresponding dimethylaluminum reagent 236 (Scheme 31). Subsequent addition of a H to 6 solution of ethyl (Z,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate 222 (1 equiv) in C reagent 236, followed by refluxing (4 h), provided, after acidic work-up and chromatography, a 47% yield of amide 237 (the less polar substance) and a 46% yield of amide 238 (the more polar material). H  N 2 H  —  I Me A 3  / N e 1— M A 2  236  235  236  I  ‘  H  222 237  (47%)  +  H  / —  \/ 23*  Scheme 31  (46%)  76 Recrystallization of the amide 237 from 1: 2 petroleum ether-Et20 afforded colorless cube-like crystals (mp 100.5-102  H  OC). A single crystal X-ray analysis 53 of 237 (Appendix) indicated that the asymmetric unit contains four molecules 237A, 237B, 237C and 237D (Figure 1).  Figure 1: X-ray structure of 237A, 237B, 237C and 237D  237A  237B  237C  237D  237  77 The 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 7879). The sign of the dihedral angle is considered to be positive, if, when looking from atom C-2 to atom C-3, a clockwise motion of atom C-6 atom eclipses with atom C-7. 7  4  5 6  237 7  6  6  7  7  7  6 0  =  +ve  0  =  -ye  The sign of the dihedral angle (0) is considered to be positive, if, when looking from atom C-2 to atom C-3, a clockwise motion of atom C-6 atom eclipses with atom C-7.  C,  -J  0  00  La (‘a —1  0  C,  La Cal .4 C, C,  Wi  —I  (‘a  t,J  04  C,  -J  (‘a  0)  C  -S  C  n n  C  -I  CM  -I  -I  St C  80 The single crystal of 237 contains molecules of four different conformations and each of the 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 crystal X-ray analysis. In order to achieve this purpose, the amide 238 was recrystallized (1: 2 petroleum ether-Et20) to give colorless, needle-like crystals (mp 107-108 Oc). From the X is of 238 (Appendix), it was found that the single crystal of 238 contains ray analys 53 molecules which have only one conformation and the dihedral angle between C-6 C-2 and -  C-3 C-7 is -58.0° (Figure 4). -  H  /  —  \/ 238  237  Figure 4: X-ray structure of 238  C?  C?  C6  C6  81 Similarly, N-p-chlorophenyl-(Z,Z)-2,3-bis(cyclopropylmethylene)cyclopentanecarbox52 via a procedure employing the dimethylaluminum amide (241) (Scheme 32) was prepared reagent 240 (Scheme 32). A solution of trimethylaluminum (Me3A1, 1.5 equiv) in toluene H to give the reagent 6 was added to a solution of p-chloroaniine (239) (1.5 equiv) in C H solution of the ester 228 (1 equiv) to the reagent 240, 6 240. Subsequent addition of a C followed by refluxing (4 h) afforded an 83% yield of the amide 241, which was recrystallized (1: 1 CH2C12-EtOH) to give colorless needle-like crystals (mp 126-127 OC). A 53 of this compound (Appendix) indicated that two enantiomers, single crystal X-ray analysis  each with a distinct conformation, (241A and 241B) (Figure 5, p 82) exist in the single crystal. The structures of 241A and 241B differ primarily in the orientation of the phenyl  ring. Dihedral angles between C-6 C-2 and C-3 -  -  C-7 of 241A and 241B were found to  be -51.0° and 53.2°, respectively. AI 3 Me \ 2 Me  N_Q_C1 2 H  240  239  240  H / 228 241  (83%) Scheme 32  82 Figure 5: X-ray structure of 241A and 241B  24 1A  24 lB  83 (R,S)-(÷)- and (R,R)-(-)-N- 1-Phenylethyl-(Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxamides (242) and (243) (Equation 40) were prepared via a procedure utilizing the dimethylaluminum 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 not useful for X-ray analysis. Recrystallization of aniide 243 from 1: 1 petroleum ether-Et20 53 of provided colorless needle-like crystals (mp 110-111 °C). A single crystal X-ray analysis 243 (Appendix) indicated that the dihedral angle between C-6 C-2 and C-3 C-7 of 243 is -  5750  -  (Figure 6, p 84).  H /  236  242  (40%)  (40)  +  229  243  (46%)  84 Figure 6: X-ray structure of 243  243  (S,R)-(÷)- and (S,S)- (-)-N- 1 -Phenylethyl- (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxamides (246 and 247) (Scheme 33, p 85) were prepared in a similar fashion  employing the reagent 245 (Scheme 33). Addition of a solution of the ester 229 (1 equiv) to the 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). Amide 246 is a liquid and so is not useful for X-ray analysis. Amide 247 was recrystallized (1: 1 petroleum ether-Et20) to provide colorless needle-like crystals (mp 111-112  0(D).  A single  crystal X-ray analysis 53 of 247 (Appendix) indicated that the dihedral angle between C-6 C-2 and C-3 C-7 is -58.0° (Figure 7, p 85). -  -  85 H  /  A1 3 Me  MeAI—N  H2NKD  —  245  244  245  o  229  246  (40%) +  247  Scheme 33  Figure 7: X-ray structure of 247  (43%)  86 In summary (Table XIV, entry 1), X-ray analysis indicated that compound 237 has molecules with four different conformations 237A, 237B, 237C and 237D which have dihedral angles (between C-6  -  C-2 and C-3  -  C-7) equivalent to 50.7°, -48.6°, 49.9° and  42.7°, respectively. The corresponding dihedral angles in 238, 243 and 247 (entries 2, 4 and 5) were found (X-ray analysis) to be -58.0°, 57.5° and -58.0°, respectively. Compound  241 (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)-2,3bis(alkylidene)cyclopentanecarboxamides (237, 238, 241, 243 and 247) are within the range of 48.60 to 58.0°.  In conclusion, the extent to which the exocycic diene systems of  Dt  OOH  241  238  237  —  ci  LJ oQ 243  247  Table XIV. Dihedral angles between the carbon-carbon double bonds of (Z,Z)-2,3-bis (alkylidene)cyclopentanecarboxamides  a  dihedral angle(s)z  entry  amide  1  237  50.7°. -48.6°. 49.9° and 42.7°  2  238  58.00  3  241  -51.0°and532°  4  243  5750  5  247  58.00  Obtained from single crystal X-ray analyses.  87 these substances are distorted from planarity are quite similar and there is no clear correlation between the values  of the dihedral angles and the size of the substituents on the termini of the diene moieties. Each of the X-ray structures of 237, 238, 241, 243 and 247, show that the two  1 R  protons Ha are oriented as depicted, so that the non-bonded interaction between the methyl-methyl, cyclopropyl cyclopropyl and isopropyl-isopropyl groups are minimized. Since, in each of the amides, the steric repulsion between  237, 238 241 243, 247  R,R=H,H R, R = 2 CH -CH R,R=Me,Me  the two Ha pmtons is roughly the same, the magnitude of the dihedral angle between the C=C bonds is not affected much by the size of the R groups.  In each of the (Z,Z)-bis(alkylidene)cyclopentanecarboxamides 237, 238,241,243 and 247, the C-6 atom can twist, as depicted, either toward the amide group or away from the amide group. 7  6  R R. 7  6  6  C-6 atom is twisted away from the amide group  C-6 atom is twisted toward the amide group R = Me, c-Pr or i-Pr;  Ar =  Ph ._  Me  1 CONIIAr  Ph ‘  __  Me  Interestingly, in a single crystal (X-ray analysis) of 237, each of the conformations 237A, 237C and 237D has the C-6 atom twisted toward the ainide moiety (p 88, Diagram A), while in the conformation 237B, the twist is in the opposite direction (p 88, Diagram C).  88 In 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 toward the 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.  6 238  237A,237C, R=Me;Ar= 237D  R=Me;Ar=  Me 241A R=c-PrAr=  241B R=c-PrAr=  CONHAr  —D—ci  R  237B R=Me;Ar= Me 247  R=i-PrAr=  Ph _  Me  243 R=i-PrAr=  Ph -_  Me  89 Discovery of the CuCl-mediated intramolecular coupling reaction  4.  41  Tntrrwlnctinn  C 2 ELO  C 2 EtO  Me  Me  C 2 ELO  Me_%(ø_LVMe I Sn 3 Me  Med’Lj I Sn 3 Me  205  209  211  222  223  224  I  Me  Sn 3 Me  The palladium(0)-catalyzed intramolecular coupling reaction, as discussed previously (pp 66-73), was applied successfully to the construction of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates with impressive control of the orientation of the two aikyl substituents on  both 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%) via palladium(0)-catalyzed intramolecular coupling of 205, 209 and 211, respectively, with complete configurational control. Surprisingly, however, in the attempted preparation of ethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate 230 from 210 (Equation 41), mixtures of 230, 224 and 248 were produced under a number of reaction conditions. 10,11,13 Some of the experimental conditions are shown in Table XV (p 90).  Me  C 2 EtO  Me Sn 3 Me I 210  reaction conditions (41)  +  Et 2 CO  Et 2 CO 230  224  248  90  C 2 EtO  Me  reaction (41)  +  I  n Me S 3  L CO E 2  t CO E 2  230  210  248  224  Table XV. Attempted preparation of ethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (230) under different reaction conditions % yielda of isomers 230, 224 and b (ratio,C 230 : 224: 248) 248  reaction conditions  ) (5 mol %), L1CI (2 equiv), 80 d 4 P 3 (Ph P MF. 3 0.1M21O1nD 1  O,  40 mm,  l) (6.7 mol %), d (2.fury P dba)3 (1.7 mol %), 3 Pd ( 2 refluxing temperature, 2 h, 0.1 M 210 in THF.W,fl  39(27:11:7)  90 (1 : 3 : 0)  a Yield of purified, distilled product mixtures. b Structure of compound 248 was tentatively assigned on the basis of  H nmr spectroscopic data. the 1 , 400 MHz) which were used for 3 H nmr signals (CDC1 Some of the 1 follows: 8 1.01 (t, CH2CTh, .1= 7 Hz), as 248 are of the assignments (ci, Hb, 1= 11 Hz), 5.07 (ci, He 1= 17 5.01 Hz), 9 J= (br d, 3.67 Ha, Hz). 11 17, H. 1= (dci, 6.57 Hz), C  Hd  _3[  b  E 2 HC c  248  In each case, the ratio of the cyclopentanecarboxylates 230, 224 and was determined on a purified, distilled mixture of these , 400 MHz). 3 compounds by the integration of ‘H nmr signals (CDC1 H nmr signals of He of The ratio was determined by integration of the 1 230, Hf of 224 and Hd of 248. H nmr signals which are The diene 230 displayed the following 1 identical with those of an authentic sample of 230: 8 1.23 (t, CIj 1= 7 Hz), 1.82 (br ci, 1 =CH , OCH2CJj3, .1= 7 Hz), 1.72 (br d, 3 CHeCIJ3, .1=7 Hz), 3.30-3.37 (m, Hd), 5.60 (br q, H, J7 Hz). H nmr signals which are The diene 224 displayed the following 1 of 224: 8 1.22 (t, sample authentic an of identical with those C, 1= 7 Hz), 1.67 (br d, =CHeCH3, 1= 7 Hz), 1.73 (br d, 2 OCH CkL .1= 7 Hz), 3.60 (hr d, H<j, .1=9 Hz), 5.90 (hr q, Hf, 3= 7 1 =CH , 3 Hz).  d We thank Miss Renaza Oballa for a sample of this phosphine ligand.  230  He  HL.J  J  t lCO E 2  224  91 The yield obtained in the preparation of ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxylate 229 from 216 (Equation 42 and Table XVI, entry 1), via use of the 6 have shown ) procedure, was only 52%. Recently, a number of publications 4 P 3 (Ph P d-LiCl that palladium(0)-catalyzed couplings are facilitated by the use of copper(1) iodide (Cul) as a ’ that in the presence of benzyl(chloro) 61 co-catalyst. For example, Liebeskind et al. reported ) (5 mol %) and Cul (9 mol %) with 2 P 3 [(Ph dBnCl] bis(triphenylphosphine)palladium(ll) P DMF as solvent, iodobenzene 249 (Equation 43) cross-coupled with the stannylated  compound 250 to give product 251 in an 80% yield.  They pointed out that a dramatic  reaction  C 2 EtO  conditions  (42)  Sn 3 Me 229  216  Preparation of ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxylate (229) under different reaction  Table XVI.  conditions % yield’  entiy  reaction conditions  1  Pd 3 (Ph P 4 ) (5 mol %), LiC1 (2 equiv), 105 °C, 1.5 h, 0.1 M 216 in DMF.  52  (Ph P 3 )4Pd (5 mol %), LiC1 (3 equiv), Cul (20 mol %), 85-90 °C, 1 h, 0.08 M 216 in DMF.  55  ) (5 mol %), CuC1 (2.5 equiv), P 3 (Ph P 2 dC1 63 °C, 3 mm, 0.1 M 216 in DMSO.  72  2  3  a Yield of purified, distilled product. The product, obtained in each case, is identical with an  authentic  H nmr analysis. sample of 229 as shown by the 1 +  0-I 249  iPO)O  Sn 3 n-Bu  250  0  ) (5 mol %) 2 P 3 (Ph P dBnCI  (43)  CuT (9 mol %), DMF, room temp. 45 mm  80% yield  251  92 enhancement on the reaction rate was observed when Cul was used as a co-catalyst. In the presence of the palladium catalyst alone, the reaction proceeded slowly, giving an —50% yield of product 251 after 3 days, while with Cul alone as catalyst, only minor decomposition of 250 was observed. By employing similar conditions, diene 229 (Equation 42) was afforded  ) Cul and LiC1. When d, P 3 (Ph P in 55% yield (Table XVI, entry 2, p 91) in the presence of 4 copper(I) chloride (CuC1) (2.5 equiv) was used in conjunction with the palladium(0) catalyst (entry 3), the yield of 229 was increased to 72%.  Since the efficiency of the conversion of 216 into 219 (Table XVI, entry 3, p 91) was  improved by the presence of CuCl, it was of interest to apply these reaction conditions to the coupling of 210 (Equation 44, p 93). The preparation of 230 from 210 was carried out under a number of reaction conditions as summarized in Table XVII (p 93). As shown in Table XVII, the stereoselectivity of the reaction was improved by the use of CuC1 as a co catalyst. It appears that two or more equivalents of CuC1 are necessary to drive the reaction to completion, and to achieve a larger ratio of the final products 230 and 224. Interestingly, under these conditions, the reaction occurred in a relatively short period of time (—0.75-4 mm). These results prompted us to investigate the actual role played by CuCl in this type of coupling reaction.  After some experimentation, it was discovered that the intramolecular coupling of compound 209 (Equation 45, p 94) can be accomplished by use of CuCl in the absence of  any palladium catalyst. In order to determine the amount of CuCi required for accomplishing the coupling reaction in a clean, efficient manner, a series of reactions was carried out using different amounts of CuCl and these results are summarized in Table XVffl (p 94). On the basis of these experiments, it appears that at least 1.5-2.0 equivalents of CuCl should be employed.  93  Me  C 2 ELO  palladium catalyst (44)  I  CuC1, DMSO, 60°C  Sn 3 Me  reaction time 224  230  210  Table XVII. Effect of CuC1 on the preparation of ethyl (Z,E).2,3-bis(ethylidene)cyclopentanecarboxylate (230) under different reaction conditionsa entry  palladium catalyst  CuC1  time  % recovery of start-  % yieldb of isomers 230 and  (mol %)  (equiv)  (mm)  ing material 210  224 (ratio,’ 230 : 224)  1  ) (5) P 3 (Ph P 2 dCl  3.0  2  0  80  (12: 1)  2  ) (5) P 3 (Ph P 2 dCl  2.0  0.75  0  66  (11.5: 1)  3  ) (4) P 3 (Ph P 2 dCl  0.55  3.5  10  68  (5.7: 1)  4  P)Pd 3 (Ph  (5)  2.1  4  0  67  (11: 1)  5  Pd 3 (Ph P 4 )  (5)  0.60  11.5  23  44  (6.6: 1)  a AU reactions were carried out with 0.1 M 210 in DMSO at 60°C.  b Yield of purified, distilled product mixtures. C  In each case, the ratio of the cyclopentanecarboxylates 230 and 224 was determined on a purified, distilled mixture of these compounds by the nmr signals (CDCI , 400 MHz). The ratio was 3 integration of H 1 nmr signals of Hd of 230 and Hd of determined by integration of the 224. H nmr signals which are The diene 230 displayed the following 1 identical with those of an authentic sample of 230: 8 1.23 (t, Ij 7 Hz), 1.72 (br d, =CHfCJj3,J= 7 Hz), 1.82 (br d, J= C 2 OCH , 3 CHeClj3, 1=7 Hz), 3.30-3.37 (m, Hd), 5.60 (br q, He, 1=7 Hz). H nmr signals which are The diene 224 displayed the following 1 identical with those of an authentic sample of 224: 6 1.22 (t, OCH2Ca3, 1= 7 Hz), 1.67 (br d, =CHeCIj3, .1= 7 Hz), 1.73 (br d, CII 1=7 Hz), 3.60 (br d, Hj, 1=9 Hz), 5.90 (br q, Hf, 1=7 Hz). 1 =CH , 3  230  H(”L(\ Hf %L..J  T  HC°2E 224  94 Me  C 2 EtO  CuCI, DMF, 60°C  Me’(’  (45)  reaction time  n Me. S 3  I  223  209  Table XVIII. Effect of different amounts of CuCI on the preparation of ethyl (E,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate  (223)a entry  CuC1 (equiv)  reaction time (mm)  % yields’  1  1.0  10  79”  2  1.5  2  d 5 -j  3  2.1  2  83  4  3.0  2  94  a All reactions were carried out with 0.1 M 209 in DMF at 60 °C b Yield of purified, distilled product. C  A total of 11% of a mixture of 209 and another component, probably its isomer 205 (as H nmr analysis), was isolated. The ratio of 209 : 205 was determined on a determined by 1 H nmr purified, pumped (vacuum pump) mixture of these compounds, by the integration of 1 ratio of This 205. of 3.06) (8 and 209 of Ha 3.65) (8 MHz) of 400 Ha , 3 signals (CDC1 respectively. 1, 3: be to found 209 : 205 was ELOC Me H nmr signals The compound 209 displayed the following 1 Me’%( which are identical with those of an authentic sample of 209: J 7 (br t, Hz), 3.65 55 Ha, ,2 ) 3 60.14 (s, Sn(CH n-H S Sn 3 Me I Hz, 3 JSn-H= 84 Hz), 5.56 (q, IC=CH, J= 7 Hz), 5.83 209 (qd, SnC=CH, J= 7, 1 Hz, 3 sH= 74 11 H nmr signals The compound 205 displayed the following 1 sample of 205: authentic an of which are identical with those (dd, Hz), 3.06 Ha, 1= 9, 7 )3, 2 3 80.21 (s, Sn(CH ’Sn-H= 52 Hz, 3 JSn-w 70 Hz), 5.54 (qt, IC=CH, J= 7, 1 Hz), 6.09 (br q, SnC=CH, J 7 HZ, 3 Sn-H= 132 Hz).  d Trace amounts of starting material 209 were detected in the crude reaction mixture by gic analysis.  C 2 EtO  I  H  n Me S 3  205  95 A study to determine the amount of CuC1 required for efficient conversion of compound 252 (Equation 46) into the bicyclic diene 253 was also carried out. The results are summarized in Table XIX. The preparation of starting material 252 will be discussed in Section 4.3 (p 109). Treatment of compound 252 with 1 equivalent of CuC1 (Table XIX, entry 1) afforded a 70% yield of diene 253 within 65 mm. The starting material 252 was also recovered (15%), along with the destannylated product 254 (8%). The reaction was complete (gic analysis) within 24 mm (entry 2) when 252 was treated with 1.5 equivalents of (entry 3) by the use of 2.1  CuC1. The reaction time was further shortened to 5 mm  equivalents of CuC1. Thus, 2 equivalents of CuC1 was required for the completion of the intramolecular reaction within a short period of time, and therefore this quantity of CuC1 was  used in the preparation of other 2,3-bis(alkylidene)cyclopentanecarboxylates and bicydic dienes. These studies are described in the next section of this thesis. I  MeO2iL  ç 2 MeO  CuC1, DMF, 60°C  (46)  reaction time 3 SnMe 253  252  Table XIX. Effect of different amounts of CuCI on the preparation of 1-methoxycarbonyl-4-methylbicyclo[3.3.O]oct-3,5-diene (253) entiy  CuC1 (equiv)  reaction time (mm)  % yieldb  1  1.0  65  70w’  2  1.5  24  96’  3  2.1  5  d 93  a All reactions were  carried out with 0.1 M 252 in DMF at 60°C. The details of the experimental conditions of entries 1 and 3 are described in the Experimental section. b Yield of purified, distilled product. C The starting material 252 and compound 254 were isolated in yields of 15% and 8%, respectively. d The completion of the reaction was monitored by gic analysis.  254  96 4.2. Stereocontrolled preparation of alkvl 2.3-bis(a1lcvlidenecvclopentanecarboxvlates via  CuC1-mediated intramolecular coupling of vinvltrimethvlstannane and vinyl halide functions  The CuC1-mediated intramolecular coupling reactions were generally carried out in the following manner. After a 0.1 M solution of substrate 206 (Equation 47 and Table XX, p  97) in DMF had been equilibrated at a certain temperature (usually 60 °C) for 10 miii, CuC1 (—2 equiv) was added to give a yellowish solution. A yellow precipitate formed after 20-30 S and stirring of the reaction mixture was continued for 2-10 miii. After work-up, analyses of the crude reaction product by gic and tic indicated that only one product had formed. Purification of this crude material by chromatography, followed by distillation, provided, in each case, the alkyl 2,3-bis(alkylidene)cyclopentanecarboxylate 219 in high yield. The experiments involving this CuC1-mediated ring closure are summarized in Table XX. OC 2 R 2 3 R  ‘  R’  DMF, 2-10mm  -  X  3 R  CuCI (-2 equiv)  Sn 3 Me  (4 °  206 X=I  219  C 2 EtO  C 2 EtO  Me  Me ELO C 2  Me”f’’’j’Me Me’%( I Me Sn 3 I Me Sn 3 205 209  Me EtO C 2 I  Me Me HO I  Me S 3 n 211 C 2 MeO  215  Me S 3 n 255  Me  I  Me S 3 n 210  C 2 MeO MeJ’OSiMe ( 2 t-Bu) Sn 3 I Me 212  C 2 EtO  216  97  t CO E 2 222  I  COEt 223  256  224  230  iO.L 1 S 2 t-BuMe ’  DQ  EL 2 CO 229 Table XX. CuC1-mediated intramolecular couplings of the iodo trimethyl stannanes 206a e CO M 2  e CO M 2  228  225  entry  substrate  CuC1  reaction temperature  reaction time  (equiv)  (°c  (miii)  product  % yields’  1  205  3.0  60  2  222  89  2  209  2.1  60  2  223  83  3  210  3.0  60  2  230  4  210  2.3  23  10  230  5  211  2.2  62  3  224  80  6  255  2.5  70  10  256  86  7  212  3.0  64  2  225  98  8  215  2.5  60  2  228  81  9  216  2.5  60  5  229  81  a All reactions were Carried Out with 0.1 M of 206 in DMF at 60°C (unless otherwise stated). b Yield of purified, distilled product. C  The product obtained consisted of a mixture of 230 and 224 in a ratio of 13:1, respectively. The ratio was determined by the integration of H nmr signals of lLj of 230 and Hd of 224. 1 H nmr signals which are The diene 230 displayed the following 1 identical with those of an authentic sample of 230: 6 1.23 (t, II 7 Hz), 1.72 (br d, =CHfCIj J= C 2 OCH , 3 ,1= 7 Hz), 1.82 (br d, 3 =CHeCIJ3, 1=7 Hz), 3.30-3.37 (m, H(jJ, 5.60 (br q, He, 1=7 Hz). The diene 224 identical with C[j 1 2 OCH , 3 CII 1=7 1 =CH , 3  H nmr signals which are displayed the following 1 those of an authentic sample of 224: 6 1.22 (t, 7 Hz), 1.67 (br d, =CHeCIj3, 1= 7 Hz), 1.73 (br d, Hz), 3.60 (br d, 11 d. J= 9 Hz), 5.90 (br q, H, 1=7 Hz).  d The product obtained consisted of a mixture of 230 and 224 in a ratio of 31: 1, respectively. The ratio was determined by the integration of mnr signals of Rd of 230 and Hd of 224.  230  HJ  T  Hf°2 224  98 The preparation of each of the iodo trimethyistannane compounds, except 255, was discussed in a previous part of this thesis (Section 2.2, pp 57-73).  Compound 255  (Equation 48) was obtained in a 74% yield by reduction of the corresponding ester 211 with 2.5 equivalents of diisobutylaluminum hydride (i-Bu2AIH). Me  ELO2C  Me  BuAIH(I5eq:v)  MS)jMe 3 C  211  0°C,lh  I  (48)  Sn 3 Me. 255  H nmr spectrum of each of the dienes 222-225, 228 and 229 prepared by this The 1 coupling process was found to be identical with each of those obtained previously from the palladium(0)-catalyzed coupling reaction. The configuration of each of the dienes 230 and 256 was confirmed by a series of decoupling and nOe experiments similar to those outlined previously for compound 222 in Section 3.1 (pp 69-70) of this thesis. In general, the conversion of the diene esters 206 into the corresponding dienes 219 was found to be stereospecific and provided the expected products in excellent yields (80-98%).  The only deviation from complete stereospecificity was observed in the synthesis of 230. The dienes 230 and 224 (Table XX, entry 3, p 97) were produced in a ratio of 13: 1, respectively, when substrate 210 was treated with CuC1 (3.0 equiv) in DMF at 60 OC for 2 mm. When the reaction was performed at room temperature (entry 4) for 10 mm, the ratio of the dienes 230 and 224 increased to 31: 1, respectively. As mentioned in the previous section, the palladium(0)-catalyzed ring closures of 210 produced the dienes 230 and 224 (Equation 41 and Table XV, p 90) in ratios such as 27: 11 and 1: 3, respectively, under a  variety of experimental ’ 10 conditions. 1 1 It is obvious that, for the conversion of 210 into 3 230, the CuC1-mediated method is superior to the Pd(0)-catalyzed protocols. The superiority of the CuCl-mediated method to the Pd(0)-catalyzed method was further demonstrated by the increased yield (8 1%) of the highly hindered (Z,Z)-bis(alkylidene)cyclopentanecarboxylate  99 229 (Table XX, entry 9, p 97). Compound 229 was obtained in 52% yield (Table XIII, entry 11, p 68) by the Pd(0)-catalyzed method. Like the Pd(0)-catalyzed method, the CuC1mediated coupling process tolerates the presence of a number of functional groups, including alkoxycarbonyl, hydroxyl, silyl ether and cyclopropyl groups. Thus, the CuC1-mediated  intramolecular coupling of vinyl halide and vinyistannane functions is a new, efficient, stereocontrolled method for the preparation of alkyl bis(alkylidene)cyclopentanecarboxylates. The application of this process to the preparation of bicyclic dienes, via formation of 4-, 5-, 6membered rings, was also investigated and will be discussed in the next section (Section 4.3, pp 111-112) of this thesis. AI 2 Me  N—4j--C1 H 240  H  (49)  230 257  (99%) Compound 230, an oil, was converted into a crystalline derivative to provide single crystals for X-ray analysis. Thus, addition of a C H6 solution of 230 (1 equiv) (Equation 6 49) to reagent 240 (2.2 equiv) afforded, after work-up and purification, a 99% yield of the amide 257. Recrystallization of 257 from 1: 1 hexanes-Et20 afforded colorless square plate-like crystals (mp 102-104 OC). A single crystal X-ray analysis 53 of this compound (Appendix) indicated that molecules with two different conformations 257A and 257B (Figure 8, p 100) are present in a single crystal of 257. The structures of 257A and 257B  differ in both the orientation of the phenyl rings and the magnitudes of the dihedral angles between C-6 C-2 and C-3 -  -  C-i, which are found to be -23.1° and -13.0°, respectively.  Not unexpectedly, these dihedral angles are considerably smaller than those obtained from the  100  (Z,Z)-2,3-bis(alkylidefle)CyClOpefltaflecarbOXamides (Table XIV, p 86).  Figure 8:  X-ray structure of 257A and 257B  257A C6  257B  101 4.3. Preparation of bicycic dienes  In this section, the preparation of methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258), methyl 2-trimethylstannyl-1-cyclohexenecarboxylate (259) and some requisite elecirophiles will be discussed first. An outline of the synthesis of representative monocydic substrates of general structure 260 employed in this study will follow. Finally, the synthetic utility of the CuC1-mediated intramolecular coupling will be demonstrated in the preparation of bicycle dienes of general structures 261 and 262. Me 2 CO  e CO M 2  3 SnMe  U  258  3 SnMe  259  C 2 MeO  C 2 MeO (4jR  ct  C  262  261  260  n’= 1or2;n= 1,2or3;R=HorMe;X=Brorl  33 that the palladium(0)-catalyzed addition of hexamethylditin It has been shown Sn)2) to a,J3-acetylenic esters of general structure 100 (THE, room temperature or 3 ((Me under reflux) provides alkyl (Z)-2,3-bis(trimethylstannyl)-2-alkenoates 263 (Equation 50). 1 R  = 100  n) (1 equiv) 2 S 3 (Me R 2 C0  d, ) THF 4 P 3 (Ph P  (50) n Me S 3  3 SnMe 263  102  1 R  —  Me S 3 n  R 2 C0 3 SnMe 2 S 3 (Me n)  263  2 P 3 (Ph P d ) oxidative  re.ijxtive elimination  Pd 3 (Ph P ) 4 P 3 (Ph P d )  SnMe P—Pd—SnMe Ph 3 P 3 Ph 264  266  stannylpaii&iation  1 R  R 2 C0 3 SnMe  P% 3 Ph % 4  R’ Ph P 3 ’  3 SnMe 265  =  R 2 C0  100  Scheme 34  The proposed 33 pathway 5 ’ 4 for the conversion of esters 100 into the corresponding bis(trimethylstannyl) products 263 is shown in Scheme 34. It is known that, in solution, 4 P 3 (Ph P d ) is in equilibrium 56 with the coordinatively unsaturated species (Ph3P)3Pd and ’ 55 2 P 3 (Ph P d. ) It is generally accepted that the active catalyst in the palladium(0)-catalyzed cross coupling reactions is 2 P 3 (Ph P d. ) Oxidative addition of P 2 P 3 (Ph d ) to the Sn-Sn bond of hexamethylditin would give a square planar complex cis-(Ph P)2Pd(SnMe3)2 264. 3 Coordination of this latter species with the acetylenic ester 100 would provide the complex  265, the CC bond of which would then insert into one of the Sn-Pd bonds to afford the  103 palladium(ll) intermediate 266. If the intermediate 266 has cis geometry of the palladium complex (as depicted in Scheme 34, p 102), reductive elimination would occur to yield P 3 (Ph P d. ) alkyl (Z)-2,3-bis(trlinethylstannyl)-2-alkenoate 263 and the pal.ladium(0) catalyst 2  If the complex 266 has trans geometry, then a trans to cis isomerization must occur before cS Although there is no direct evidence to support 2 place. reductive elimination could take 8 the participation of the proposed catalytic cycle in the conversion of ester 100 into bis(trimethylstannyl) compound 263, it is reasonable to evoke this proposed pathway in order to account for both the formation of 263 and the stereochemical outcome of the addition process. Similar arguments have been used to account for the palladium(0)-catalyzed addition 59 of disilanes to 1-alkynes.  33 that reaction of certain of the addition products containing an ca-halo group It is known  (i.e., 267) with MeLi results in tin-lithium exchange at the trimethyistannyl group adjacent to the ester function to give, presumably, lithium allenoate anions 268. The latter intermediates undergo intramolecular aikylation to provide cyclic f3-trimethylstannyl aj3-unsaturated esters 269 (Scheme 35). X —  Sn 3 Me  MeLi (-1.1 equiv) HMPA (-2 equiv)  R 2 CO  3 SnMe  (j(  THF, -98 °C, 1 h  3 SnMe  267(X=Brorl)  269  /  \Li  [Xç]  268 (X = Br  Scheme 35  or  I)  104 The acetylenic ester 107 (Scheme 36) was allowed to react with (Me3Sn)2 (—1.1 equiv) Pd 3 (Ph P ) (2 mol %) (refluxing THF, 6 h) to provide a 68% yield of the in the presence of 4 bis(trimethylstannyl) product 271. This latter substance was subjected to successive treatment with HMPA (—2 equiv) and MeLi (—1.1 equiv, THF, -98 °C, 1 h) to give methyl 233 Similarly, the trimethylstannyl-1-cyclopentenecarboxylate (258) in an 84% yield. 035b (Scheme 36) was transformed, via compound 272, into methyl 2acetylenic ester 27 33 The spectro trimethylstannyl-1-cyclohexenecarboxylate (259) in an overall 76% yield. scopic data of compounds 271, 272, 258 and 259 were found to be in full accord with a 33 those reported in the literature.  (PhP)2rno1  e 2M X_è*)=<CO  Me 2 X\4\è_..CO THF,reflux,6h  3 SnMe  Sn 3 Me  107X=I,n=1  271X=I,n=1(68%)  270X=Br,n=2  272X=Br,n=2(91%)  MeLi (—1.1 equiv) HMPA (-2 equiv) TifF, -98 °C, 1 h  Me 2 CO  3 SnMe 258 n  =  1 (84%)  259 n=2(83%)  Scheme 36  105 The electrophiles employed in this study include 2,3-dibromopropene (273), (Z)-3bromo- 1-iodopropene (274), (Z)- l-bromo-3-iodo-2-butene (275), (E)-3,5-diiodo-2-pentene (193) and 2,5-diiodo-l-pentene (276). Compound 273 is commercially available and the 60 Synthesis of the diiodo compound electrophile 274 was prepared via known procedures. 193 was described in an earlier part of this thesis (Section 2.2, pp 54-55). Preparation of 275 and 276 will be discussed in this section.  Br  I”\—Br 274  273  H’ 193  275  276  R’  = 277  (51)  R 2 C0 I  2 COR 278  Addition of H-I across the CC bond of acetylenic esters of general structure 277 (Equation 51) in a trans fashion to provide exclusively the corresponding ailcyl (Z)-3-iodo-2alkenoates (278) has been documented. 61 Recently, it was discovered 62 in our laboratory that, via use of modified reaction conditions, this type of transformation can be carried out  highly efficiently on a wide variety of substrates 277. For example, commercially available ethyl 2-butynoate (101) (Scheme 37, p 106) was heated with sodium iodide (1.6 equiv) and glacial acetic acid (6.4 equiv) at 115 °C for 1.5 h to afford, after work-up and distillation, a 98% yield of ethyl (Z)-3-iodo-2-butenoate (279). The ir spectrum of 279 displayed a strong  . The 1 1 C=O stretching frequency at 1728 cnr H nmr spectrum of 279 exhibited the expected signals for an ethyl ester group (a 3-proton triplet at 8 1.28, J= 7 Hz and a 2-proton quartet at  106 NaT (1.6 equiv)  EL 2 CO 101  —  HOAc (6.4 equiv) 115°C,1.5h 98% yield  I  COEt 279 AIH (2.8 equiv) 2 i-Bu  0, -78 °C, 10 miii; 2 Et 0°C, 1.5 h 90% yield  \1= I’  ‘—Br 275  P.Br (1.3 equiv) 3 Ph 2  CI 0 °C, 5 mm; CH , 2 roomtemp,lh  OH 280  93% yield  Scheme 37  84.20,1=7 Hz), a vinylic methyl group (a 3-proton doublet at 82.71,1= 1.5 Hz) and an a olefinic proton (a 1-proton quartet at 66.27, J= 1.5 Hz). The configuration of the C=C bond was determined by nOe difference experiments. Thus, irradiation at 8 2.71 caused an enhancement of the signal at 66.27, while irradiation at 86.27 increased the intensity of the resonance at 62.71. As a result, the cis relationship of the vinylic methyl group and the a olefinic proton was established.  A solution of the ester 279 in Et 0 was treated with diisobutylaluminum hydride (2.8 2 equiv) in hexanes (-78 0 C, 10 mm, o OC, 1.5 h) to give the iodo alcohol 280 (Scheme 37) in a 90% yield. The ir spectrum of 280 exhibited a strong 0-H stretching frequency at 3370 . The T 1 1 and a weak C=C stretching frequency at 1651 cm cm H nmr spectrum of 280 exhibited the expected signals for a hydroxyl group (a 1-proton broad singlet at 8 1.57, exchanges with 1)20), one methylene group (a 2-proton multiplet at 84.14, wjj= 13 Hz)  and a vinylic proton (a 1-proton triplet of quartets at 65.77,1=6, 1.5 Hz). Treatment of the iodo alcohol 280 (Scheme 37) in 2 C1 with 47 CH P.Br2 (0 °C, 10 mm; room temperature, 3 Ph  107 H nmr spectrum 1.5 h) provided (Z)-1-bromo-3-iodo-2-butene (275) in a 93% yield. The 1 of 275 shows the expected signals for a vinylic methyl group (a 3-proton singlet at 6 2.59), one methylene group (a 2-proton doublet at 6 3.98,1= 7.5 Hz) and a vinylic proton (a 1proton triplet at 65.78,1=7.5 Hz). 1) 2 SnCu.Me (121) (1 equiv) 3 Me S  3 SnMe.  TNF, -78 °C, 7 h 118  2) HOAc (1 equiv) CI-NH 1 NK O H 3) 4 51% yield  281  Nal (4.1 equiv) acetone, reflux, 40 h 86% yield  —  276  12(Llequlv),cH2C12  95%yield  282  Scheme 38  The electrophile 2,5-diiodo-1-pentene (276) (Scheme 38) was prepared as follows. Using a procedure 63 developed in our laboratory, commercially available 5-chloro-1-pentyne  (118) (Scheme 38) was allowed to react with 1 equivalent of Me3SnCu.Me2S (121) in THF at -78 °C for 7 h. Work-up afforded an oil that contained (gic analysis), in addition to hexamethylditin and a trace amount of the starting material 118, a 9: 1 mixture of two  products. This mixture was purified by drip column chromatography of the mixture on silica gel (230-400 mesh), to provide the major product 5-chloro-2-trimethylstannyl-1-pentene (281) in a 51% yield. The spectroscopic data of compound 281 were found to be in full 63 Compound 281 (Scheme 38) was treated with accord with those reported in the literature. 4.1 equivalents of Nal in acetone (reflux, 40 h) to provide the iodo comound 282 in an 86% yield. lododestannylation of the latter substance with 1.1 equivalents of 12 in CH2C12 (room  temperature, 15 mm) gave a 95% yield of the desired electrophile 2,5-diiodo-1-pentene  108 (276). The 1 H nmr spectrum of 276 showed the expected signals for three methylene groups (a 2-proton quintet at 62.00,1=7 Hz; a 2-proton broad triplet at 62.50,1=7 Hz; a 2proton triplet at 6 3.15,1=7 Hz) and two geminal olefmic protons (a 1-proton doublet at 8  5.76,1= 1 Hz; a 1-proton quartet at 66.13,1= 1 Hz).  1) LDA, THF-HMPA -20°C,lh  3 SnMe 259  283  Br 2)  L,.Br  (273)  -78 °C, 5 mm; -20 °C, 30 mm  +  3 SnMe  3 SnMe 284  285  Scheme 39  With the electrophiles now in hand, representative monocydic substrates of general structure 260 were prepared via deconjugation-alkylation processes using conditions similar to those outlined in Section 2.2 (pp 57-60) in this thesis. For example, treatment of methyl 2trimethylstannyl-1-cyclohexenecarboxylate (259) (Scheme 39 and Table XXI, entry 1, p 109) with LDA (2.3 equiv) in the presence of HMPA (1.5 equiv) in THF (-20 OC, 1 h) gave the corresponding dienolate anion 283,33 and subsequent addition of 2,3-dibromopropene (273) (2.7 equiv) (-78 °C, 5 mm; -20 OC, 30 miii) to the THF solution of 283 afforded, after work-up and separation, the alkylated esters 284 and 285 in 43% and 14% yields, respectively. The preparation of other monocydic substrates 260 (Equation 52, p 108) is summarized in Table XXI (pp 109-110).  109  (52)  3 SnMe 258 n’  =  260  1  n’= 1or2;n*=1,2or3 X = Br or I; R = H or Me  259 n’=2  Table XXI.  Deconj ugation-alkylation of methyl 2-trimethylstannyl- 1cyclopentenecarboxylate (258) and methyl 2-trimethylstannyl-1-cyclohexenecarboxylate (259)  entry  substrate  procedure  259  1) LDA (2.3 equiv), HMPA (1.5 equiv), THF, -20 °C, 1 h;  % yielda  product(s)  284 (43%)  Br  ai  2) 273 (2.7 equiv), -78 C5ipj•.2O C 0 30 miii.  285 (14%)  284  Br  285  273  2  258  1) LDA-HMPA (1.2 equiv), THF, -78 °C, 0.5 h; 0 °C, 0.5 h; 2) 274 (1.3 equiv), -20  °C,  63  1 h. 3 SnMe  286 274  3  258  68  1) LDA-HMPA (1.3 equiv), THF, C, 0.5 h; 0 OC, 0.5 h; -78 0 2) 275 (1A equiv), -20 OC, 1 h. 3 SnMe  252 >-Br  275  110 Table XXI. entry  substrate  4  258  Continued pduct(s)  ptvcedwe  ’ 1 % yield 56  1) LDA-HMPA (1.3 equiv), THF, C, 0.5 h; -78 °C, 0.5 h; 0 0  2) 193 (1.6 equiv), -20 °C, 1 h. 287 I 193  5  258  1) LDA-HMPA (1.2 equiv), THF, -78 OC, 0.5 h; 0 °C, 0.5 h;  C 2 MeO  63  2) 276 (1.5 equiv), -20 °C, 1 h. I  288  276 a  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. Taking compound 252 (Table XXI, entry 3, p 109) as an example, the ir spectrum of 252 exhibited 1 attributable to the carbonyl stretching frequency of an ester an absorption at 1734 cm1 attributable to the tin-methyl rocking frequency of a function and an absorption at 771 cmH nrnr spectrum of 252 displayed the expected signals of a trimethyistannyl group. The 1 trimethyistannyl group (a 9-proton singlet at 80.14,  Hz), two methylene units on  the 5-membered ring (two 1-proton multiplets at 8 1.73-1.83 and at 82.26-2.36; a 2-proton multiplet at 82.37-2.55), a vinylic methyl group (a 3-proton broad singlet at 82.46, wj= 4 Hz), two allylic protons on the side chain (a 1-proton doublet of doublet of multiplets at 6  111 2.20, 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 of multiplets 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 is 4 1 C I 3 O2Sn. H2  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, are summarized in Table XXII (p 112).  cj:—  C 2 MeO CuC1  (  OR  DMF 260  261  (53)  262  n’= 1 or2;n”= 1,2or3 X = Br or I; R = H or Me  As can be seen from the data summarized in Table XXII, the cydizations were generally accomplished 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 60 OC for 35 mm  produced the bicyclic compound 293 (—74% of the product mixture as  indicated by glc analysis; 65% isolated yield) accompanied by three side products, the major of which (—14% of the mixture) was the uncyclized compound 294, whose structure was , 200 MHz): 8 1.25-1.85 (m, 6H), 2.24-2.53 3 H nn,r spectroscopic data [(CDC1 assigned by 1 (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= 2 Hz)] and by high resolution gcms analysis [molecular peak was found]. Fortunately, at 90 OC the reaction was clean and the expected bicyclic diene was produced in 75% yield. In general, conversion of the substrates 260 into the corresponding bicyclic  C 2 MeO  H 294  112  Br  Br  MJ  286  285  284  C  Mj  288  252  C 2 MeO  C 2 MeO  cb  290  289  291  C 2 MeO  cMe  253  293  292  Table XXII. CuC1-mediated intramolecular coupling of monocyclic substrates of general structure 260a entry  a  substrate  CuC1  reaction temperature  reaction time  (equiv)  (°C)  (mm)  product  ’ 1 % yield  1 2  284  2.4  60  5  289  78  285  2.7  60  5  290  79  3  286  2.5  64  2  291  80  4  252  2.1  60  5  253  93  5  287  2.5  65  10  292  97  6  288  2.5  90  5  293  75  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 261 nor 262.  113 dienes of general structures 261 or 262 was found to be efficient, providing the products in good to excellent yields (75-97%). Moreover, this method constitutes a good method for synthesizing 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.  C 2 MeO  ( 261  262  n’= lor2;n”=1,2or3 R=HorMe  Hf  H nmr spectra of the bicycle dienes In addition to each of the 1 H 261 or 262, the structures were assigned with the aid of other 1 nmr spectroscopic techniques, such as decoupling, COSY or nOe difference experiments. For example, the structure of 1-methoxy-  Hh  289  carbonyl-7-methylenebicyclo[4.2.0]oct-5-ene (289) was assigned on the basis of its  nmr spectrum and the results denved from a  H nmr spectrum of series of decoupling experiments, as well as a COSY experiment. The 1 , 400 MHz): 6 1.08 (td, 1H, Ha, J 12, D 6 the diene 289 displayed the expected signals (C  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 (br dd, 1H, He, J= 19, 7 Hz), 2.41 (dt, 1H, Hf, J= 12, 3.5 Hz), 2.49 (dt, 1H, H, J  14, 2.5  , 4.64 (br s, 1H, =CH OCH ) , w= 2 Hz), 2.88 (dt, 1H, Hg, J= 14, 2.5 Hz), 3.35 (s, 3H, 3 , W1/2 2 6 Hz), 5.07 (br s, 1H, =cH  7 Hz), 5.52 (dd, 1H, Hh J= 4.5, 3 Hz). It is  reasonable to assume that the 6-membered ring of compound 289 adopts a conformation as depicted (p 114). The triplet of doublets (J= 12, 3.5 Hz) at 8 1.08 was attributed to Ha and  114 the 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)  6 1.63-1.76 (m)  82.41 (dt,J= 12,3.5Hz) 62.49 (di, 1= 14,2.5 Hz) afld 8 2.88 (dl, J= 14,2.5 Hz)  6 200 (br dd, 1= 19,7 Hz) Hd  /  8 1.74-1.86 (m)  65.52 (dd, J= 4.5,3 Hz)  6 1.08 (UI, J= 12, 3.5 Hz) [Bicydic diene 289 HU  H nmr spectral assignments of 289, a series of In order to further confirm the 1 decoupling experiments were performed. Irradiation at 6 1.08 (Ha) simplified the doublet of triplets at 6 2.41 (Hf) to a triplet (J= 3.5 Hz) and this provides evidence for the geminal relationship between Ha and Hf [Note: JHaHf= 12 Hz]. Irradiation at 6 1.53 (Hb) altered the triplet of doublets at 6 1.08 (Ha) to a triplet (.1= 12 Hz) [Note: JHaHb= 3.5 Hz], and converted the 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 of either Hd (6 1.82) or of He (6 2.00) changed the resonance of proton Hh (a doublet of doublets at 65.52, J= 4.5, 3 Hz) to a doublet (J= 3 or 4.5 Hz, respectively). Therefore, it is H nmr assignments were apparent that proton Hh is vicinal to protons Hj and H. The 1 found to be consistent with the results of a COSY experiment, which are summarized in Table XXffl (p 115).  115  Table XXIII.  Results of the COSY experiment of compound 289 Hf  He  289  Assignment H,  , 400 MHz): 6 D 6 H nmr (C 1  COSY correlations to H  (multiplicity, number of protons, coupling constant(s))  Hp  1.08 (td, 1H, J 12, 3.5 Hz)  Hb, H, Hf  Hb  1.48-1.58 (m, 1H)  , Hf 3 Hg, He H  H  1.63-1.76 (m, 1H)  , He, Hf 1 Ha, Nb, H  Nd  1.74-1.86 (m, 1H)  Hb, H, H, Hh  He  2.00 (br dd, 1H, J= 19, 7 Hz)  H, HJ, Hh  Hf  2.41 (dt, 1H, J 12, 3.5 Hz)  Hg, Hb, Nc  H(A)  2.49 (dt, 1H, J= 14, 2.5 Hz)  (A), =CH 2 (B) 2 H(B), =CH  (B) 2 H  2.88 (dt, 1H, 1= 14, 2.5 Hz)  H(A), =CH (B) 2 (A), =CH 2  =CH2(A)  4.64 (br s, 1H, wrn= 6 Hz)  (B) 2 H(A), H (B), =CH 2  =CH2(B)  5.07 (br s, 1H, wrn= 7 Hz)  (A) 2 H(A), H(B), =CH  Hh  5.52 (dd, 1H, J= 4.5, 3 Hz)  J, He 1 H  Compound 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 mass spectrometry showed that the molecular formula of 289 is Ci 02. 14 H 1  116  C 2 MeO  289  C 2 MeO  MeO C 2 290  291  292  293  C 2 MeO  253  , 400 MHz) of 2-methoxycarbonyl-8-methylenebicyclo3 The 1 H nmr spectrum (CDC1 [4.2.0]oct-1-ene (290) exhibited signals for two homoallylic methylene groups (two 1proton 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 2.672.84), a methoxy group (a 3-proton singlet at 8 3.72) and two olefinic protons (two broad C nmr spectrum singlets at 8 5.00 and at 65.71 (wl,2= 6 Hz for both broad singlets)). The 3 , 50.3 MHz) of 290 indicated the presence of four olefinic carbons (6 111.1, 118.3, 3 (CDC1 146.4 and 155.8) and a carbonyl carbon (8 167.4).31 The ir spectrum of 290 displayed a , which showed that C=O functional group is 1 strong C=O stretching frequency at 1708 cmin conjugation with the C=C bond. The presence of a conjugated ic-system was indicated by a strong uv absorption at 266.5 nm (11000, n-pentane). Moreover, 290 was shown to have C 1 H 2 1 by high resolution mass spectrometry. 4 a molecular formula of 0  The structures of 253,291 and 292 were confirmed with the aid of nOe, decoupling H nmr spectrum of and/or COSY experiments (for details, see Experimental section). The 1 d 7 293 was found to be in full accord with that reported in the literature.  117 4.4. Preliminary studies on the mechanistic aspects and the limitations of the CuC1-mediated coupling process  Preliminary investigations into the mechanistic aspects and the limitations of this new CuC1-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 of CuCl are preferred, two equivalents of other copper(I) sources were also employed for the coupling reactions shown in Equations 54 and 55. The results of these experiments are  summarized in Table XXIV. Me  C 2 ELO  Cu(I), DMF  Me(’  (54)  reaction conditions  MeSn  I  223  209  Me  Me  C 2 EtO  Cu(1), DMF  (55)  reaction conditions I  Sn 3 Me 224  211  Table XXIV.  Effect of different sources of Cu(I) on the intramolecular coupling of substrate 209 or 211  entry  substrate  Cu(I)  reaction temp/ time  (equiv)  (°C/ mm or h)  product  ’ 1 % yield  1C  209  CuC1 (2.1)  60/2 mm  223  83  C 2  209  CuC1 (2.0)  23/ 10 miii  223  3  209  ’ (2.5) CuBr.Me S 2  40/ 125 h  223  90 90  4  209  ’ (2.5) CuBr.Me S 2  23/ 12 h  223  5  209  Cul’  60/40mm  223  83  6  211  P)CuCl” (2.1) 3 “(Ph  60/2 h  224  80  118 Table XXIV. entry  a b C  d e  f g h  1 k  m  Continued  substrate  Cu(1)  reaction temp/ time  (equiv)  (°C/ mm or h)  product  ’ 1 % yield  7  211  (Ph3P)3CuCl (2.1)  60/5 h  224  0  8  209  60/ 15 mm  223  9  209  CuC1 (2.5) + LiC1 (2.5)’ CuC12 (12)tm  23/2h  223  01 O  All reactions were carried out with 0.1 M 209 or 211 in DMF. Yield of purified, distilled product (unless otherwise noted). In each case, the product isolated was found to be identical to an authentic sample of 223 or 224 by 1 H nmr analysis. Entries 1 and 2 are included for comparison. CuBr.Me2S was prepared according to reference 64. The product has -10% of uncharacterized impurities (gic analysis). Commercially available Cul was purified according to reference 65. The complex “(Ph P)CuC1” exists as tetramer and was prepared according to reference 66. 3 P was isolated. 3 0.4 equivalents of Ph The complex 3 P (Ph C uC1 ) was purchased from Aldrich Chem. Co. Inc., and was used without further purification. 81% of substrate 211 was recovered and 1 equivalent of Ph P was isolated. 3 The DMF solution of 209 and LiCl (2.5 equiv) was warmed at 60 °C for 10 mm before CuCl (2.5 equiv) was added. 88% of substrate 209 was recovered. 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) 64 or copper(I) iodide (CuI) 65 was used, longer reaction times were required for completion of the coupling reaction 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.Me2S was utilized. Therefore, CuBr.Me2S and Cul are generally inferior to CuC1 for this coupling process. Retardation of the coupling reaction rate was observed when “(Ph3P)CuC1” 66 (entry 68 was employed, no coupling was observed ’ 67 6) was used as well. When (Ph3P)3CuC1 (entry 7). Thus, no further attempts were made to utilize these two latter complexes as a catalyst for the coupling reaction. Lithium chloride LiC1 is necessary for effecting efficient intramolecular palladium(0)-catalyzed coupling reactions of vinyl halide and vinylstannane  functions to produce 5- and 6-membered rings (Sections 1.2 and 3.1, pp 14-18 and pp 66-68,  119 respectively). Surprisingly, no reaction occurred when 2.5 equivalents of LiC1 (ently 8) was added with CuC1. It is likely that CuC1 reacts with LiC1 to give a lithium dichiorocuprate 68 (Equation 56) which may not be an effective species for this coupling process. (LiCuC12) 68 that CuC1 undergoes disproportionation to give Cu(0) and CuC12 under It was reported certain conditions. In order to find out whether CuC12 is the active species in this coupling reaction, 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. Further addition of Cu(0) powder (electrolytic grade) to this latter reaction mixture showed no sign of reaction (gic analysis).  CuCI  +  LiC1  Li  +  2 CuC1  (56)  In general, with DMF as solvent, all the CuC1-mediated intramolecular coupling reactions were carried out via the following procedure. A DMF (dry) solution of the substrate containing 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 immediately dissolved to give a yellowish solution. After —20-30 s, a yellowish precipitate formed and the mixture was stirred at —60 °C for 2-10 mm. Interestingly, the yellowish precipitate, which was formed in the reaction, dissolved to give a deep blue solution during work-up with H (pH = 8). After a series of purification procedures, the corresponding cyclic 1-NH 4 C 1 NR O diene was afforded in good yield.  Solvent effects were also studied in the intramolecular coupling of 209 (Equation 57, p 120) and the results are summarized in Table XXV (p 120). In a similar procedure to that mentioned above, a yellowish solution, but no precipitate was observed when either DMSO N was employed as solvent. Wet DMF (entry 3) and DMSO (entry 4) can be used orCH C 3 CN 3 to provide a medium for the coupling process. The reaction rate was retarded when CH  120 CN 3 68 that four molecules of CH (Table XXV, entry 5) was used as the solvent. It is known CN)4Cu, and this 3 coordinate with a Cu(I) cation to form a tetrahedral complex (CH complex 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 of the CuC1 in T.HF. It appears that DMF is the preferred medium for the CuC1-mediated coupling reaction. C 2 EtO  Me  Me%(” I  CuCI, solvent reaction conditions  (57)  Sn 3 Me  223  209  Table XXV.  entry  Effect of different solvents on the CuCI-mediated intramolecular coupling of substrate 2O9 solvent  CuC1  reaction temp/ time  (equiv)  (°CI miii or h)  % yields’  C 1  DMF  2.1  60/2mm  83  2’ 3  DMF  2.0  90  0 (v/v = 10: 1) 2 DMF-H  2.5  23/ 10 mm 60/ 10 mm  DMSO  2.2  23/20 mm  91  2.5  65/4 h  d 72  2.6  23/10mm  Of  3 4 5  CN 3 CH  83  a 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 to H nmr analysis. an authentic sample of 223 by 1 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 in the 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).  121 In order to understand better the mechanism and the limitations of this new coupling process, other substrates, containing either a vinyl halide or a vinyistannane function or possessing both of these moieties, were prepared via deconjugation-alkylation processes. The preparation of these substrates is summarized in the Table XXVL Table XXVI. Preparation of some substrates via deconjugation-alkylation entry  starting ma  ceduie  1 EI 2 CO  Sn 3 ,z-Bu 295  1) LDA-HMPA (1.3 equiv), THF, -78 °C, 0.5 h; 0 °C, 0.5 h. 2) 193 (1.5 equiv), -20 °C, 1 h.  H’  % yie1dz  pmduct  C 2 EtO  I  83  Sn 3 n-Bu 296  193  2 E 2 M)’CO  1) LDA-HMPA (1.1 equiv), THF, -78 0 C, 0.5 h; 0 °C, 0.5 h; 2) 297 (1.3 equiv), -20 °C, 1 h.  Sn 3 Me  124 298 297  3  Me 2 ,..CO  I  II  3 SnMe  1) LDA (2.2 equiv), HMPA (3.4 equiv), THF, -20 °C, 1 h; 2) 299 (2.8 equiv), -20 °C, 1 h.  284 299  78  300  122 Table XXVI. Continued entry  starting matenal  Me 2 CO  301  pxxedure  product  2 % yield’  2) 1) LDA (1.4 equiv), T.HF, -78 °C, 30 miii; 273 (1.6 equiv) in A, room temp. 1 h. Br  66  kBr 302  273 Me 2 CO  1) LDA (2.2 equiv), TNF, -78 2) C 30 miii; 0 275 (1.4 equiv) in A, room temp. 1 h.  67  301  303 >‘__Br 275  Yield of purified, pumped (vacuum pump) product.  29 similar to that employed for the preparation of It should be noted that, via a procedure alkyl (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)-2pentenoate (295) (Table XXVI, entry 1, p 121) in a 72% yield.  =  Et 2 CO  1) 3 [n-Bu S nCuCN]Li (304) THF, -48 °C, 1.5 h; 0 °C, 2.5 h; room temp. 0.5 h  102  2) 4 C1-NH NH O H  Et 2 CO  Sn 3 n-Bu  295  (58)  123  46 similar to that Electrophile 297 (Scheme 40) was prepared as follows. By a procedure described 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 and purification, to give 2-bromo-5-chloro-1-pentene (305) in a 77% yield. Subsequent reaction of this latter material with Nal (3 equiv) in acetone (reflux 16.5 h) afforded the expected electrophile 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, 5455 and 103), respectively. Electrophile 275 (Table XXVI, p 122) was derived from commercially available ethyl 2-butynoate (101) in a sequence of reactions that was previously described in Section 4.3 (pp 105-107). 1) B-Br-9-BBN 2) H 106  77% yield  Br 305  P.1 2 3 Ph , 2 CI CH  room temp. 4 h 83% yield  297  Scheme 40  Interestingly, when compound 296 (Equation 59, p 124) was heated at 65 °C in DMF in the presence of CuCl (2.7 equiv) for 10 mm, a 54% yield of the cyclopentanecarboxylate 224 and a 67% yield of thbutyltin chloride (n-Bu3SnCl) were produced (for details, see Experimental section). Thus, in addition to causing the intramolecular coupling of vinyl halide and vinyltrimethylstannane functions, this reaction is also effective for the  124 intramolecular coupling of vinyl halide and vinyl th-n-butylstannane functions. Moreover, it  was discovered that tributyltin chloride was produced as a side-product in this coupling reaction.  Me  C 2 ELO  Me CuC1, DMF  SnC1 3 n-Bu  +  65 °C, 10 miii I  (59)  (67%)  Sn 3 n-Bu 296  224  (54%)  C 2 MeO  CuC1, DMF  (60)  60°C, 10 mm 288  Br  C 2 ELO  293  Me  CuCI, DMF  EXPECTED PRODUCT:  60°C, 10 mm  306A, NOT FOUND!  (61)  Sn 3 Me. 298  306A Br  C 2 ELO  Me  +  Br  C 2 ELO  30611  306C  Y  j  89% (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 and vinyistannane functions (demonstrated in a previous section of this thesis, pp 111-112), attempted intramolecular coupling of vinyl bromide and vinyistannane moieties did not  125  provide the corresponding 6-membered ring coupling product 306A when 298 (Equation 61, p 124) was treated with CuC1 (2.5 equiv) in DMF for 10 mm. Instead, the reaction provided a liquid that consisted of a mixture of the destannylated uncydized products 306B H nmr analysis) (for details, see Experimental 1 and 306C (Equation 61) in a ratio oft: 1 ( section). Thus, it was found that, under the experimental conditions, the trimethylstannyl moiety had been removed from the parent molecule 298 while the vinyl bromide function remained intact.  On the basis of the latter experiment, it is reasonable to propose that, in the CuCl mediated coupling reactions, the vinylstannane moiety initially reacts with CuCl, while the vinyl halide itself does not react directly with the copper(I) salt under the experimental conditions. In order to test these conclusions further, a series of experiments were carried out, involving the treatment of compounds containing either vinyistannane or vinyl halide functions 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 a liquid mixture that was comprised of the starting material 300 (15%), the destannylated 0 307B (8%) and 307C (6%) (for products 7 ’ product 307A (42%) and the dimerized 69 details, see Experimental section). Thus, it is obvious that the vinyl trimethyistannyl group reacted with the CuC1 reagent. Me 2 CO  c1DZ 300  ‘°‘  cz 300  (15%)  +  Oj%..øl*S 307A (42%)  (62) +  Me 2 CO 307B (8%) 307C (6%)  126 Moreover, as mentioned earlier, the destannylated side products 254 and 294 were isolated 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 the presence of CuC1, while the vinyl halide function tends to be unreactive under the same reaction conditions.  294  254  302  In addition, upon heating at 60 °C with CuC1 (—2 equiv) for 10 mm, compounds 302 and 303 remained intact and were recovered in >80% yields. Prolonged heating (46 h) of 303 (Equation 63) with a large excess of CuC1 (—17 equiv) afforded a 64% yield of halogen71 product 307 (for details, see Experimental section). Therefore, it was exchanged demonstrated that the vinyl halide group remains relatively inactive or intact under the experimental conditions for the CuC1-mediated coupling process. CuCI, DMF  (63)  60 °C, 46 h 303  308  (64%)  Based on these experiments, it is possible to provisionally propose the following mechanism. The coupling reaction of compounds of general structure 309 (Scheme 41, p 127) to give dienes 234 is thought to proceed through an initial reaction between the vinyistannane function and CuCl to afford a vinylcopper species 310 through 72 producing triaikylstannyl chloride (R3SnC1) as a by-product. Subsequent transmetalation,  127 73 formation of either a copper(II) metallocycle intermediate 311A or a copper(llI) metallocycle intermediate 311B followed by reductive elimination would provide the 2,3bis(allcylidene)cyclopentanecarboxylates of general structure 234. All of the proposed reaction steps (Scheme 41) apparently occur with retention of configuration on both C=C bonds since compounds 234 were produced with high stereospecificities. Future efforts involving mechanistic studies of this coupling reaction will be required to elucidate the structure of the intermediates.  C 0 2 R  5 R  4 R  3 R I  C 0 2 R  5 R +  Sn 3 R  -  4 R  CuCI 3 R  SnC1 3 R  fR’  [Cu]’  I 310  309 F F F  F  F  oxidative addition (?)  +  4 R  Cu Cf 311B  2 -Cu  i-cr -Cu(l)(?)  5 R -  Cu(O) (?)  3 R 1 R  1 R 234  311A  Scheme 41  128  5.  Diels-Alder reactions of alkvl 2.3-bis(alkvlidenecvclopentanecarboxvlates and structurally related substances  5.1. Introduction  The Diels-Alder reaction is one of the most powerful synthetic methods in organic  75 The ’ 74 chemistry and therefore numerous publications have been dedicated to this reaction. Diels-Alder reaction involves a [42r +22r] cycloaddition of a conjugated diene and a dienophile to form a new 6-membered ring skeleton (Equation 64). Cyclic substances containing a 1,2bis-exocyclic conjugated cliene system can be synthesized or generated in situ from 6 from benzocyclobutenes). orthoquinodimethanes 7 e thermolysis (e.g., generation of 26  7678 in a number of total ’ 18 These dienes have served as important synthetic intermediates 77 and 76 alkaloids syntheses of pharmaceutically important chemicals such as steroids, 78 In a previous section of this thesis (Scheme 10, p 20), the application of anthracycinones. the 1,2-bis-exocydic diene 53 to the total syntheses of (-)-sterepolide and (-)-merulidial had 18 Prompted by these results, we decided to carry out an investigation of been discussed. Diels-Alder reactions of the prepared alkyl bis(alkylidene)cyclopentanecarboxylates 219 with some selected dienophiles. The results of these studies will be described in the following sections.  +  DIENE  II DIENOPI-ULE  53  (64)  DIELS-ALDER ADDUCE  219  129 5.2. Diels-Alder reactions of dienes with tetracyanoethvlene 1CNE  Generally, the greater the number of electron-attracting substituents on the double bond or triple bond the more reactive is the dienophile, due to the lowering of the energy of the lowest unoccupied molecular orbital (LUMO) of the dienophile by the substituents. 79 The most commonly encountered activating substituents for the Diels-Alder reaction are carbonyl containing moieties, nitrile and nitro groups and dienophiles which contain one or more of C 74 these groups in conjugation with a double or triple bond react readily with dienes. Tetracyanoethylene (TCNE), which possesses four conjugated nitrile groups, is a very c and was used to investigate the face selectivity of the Diels-Alder 74 reactive dienophile reaction of dienes 219.  Reaction of the diene 221 (Equation 65) with TCNB (1.2 equiv) in THF at room temperature was complete within 1 h (glc analysis).  Removal of the solvent and  chromatography of the crude product provided a 79% yield of a mixture of the esters 312 and  313 in a ratio of 21: 1, respectively (determined by integration of the 1 H nmr signals). Recrystallization of this mixture from petroleum ether-diethyl ether gave the ester 312 as a  colorless solid (mp 129.5-130 OC). Diels-Alder reactions of other dienes of general structure 219 and 314 (Equation 66) with TCNE were also carried out, and the results are  summarized in Table XXVII (pp 130-13 1). The procedure employed for each experiment was similar to that outlined above for the preparation of compound 312, unless otherwise noted. N  N C  TCNE, THF  NC—Vr\  room temp. 1 h  %.A 4 NC  I  II )  (65)  +  Et 2 CO 221  312  313 79%(21: 1)  130  R%\  R1L( E 219 E  =  TCNE, THF  R 2 C0  R 2 31SE=C0  O CH ( t-Bu) SiPh 314 E = 2  Table XXVII. entry  (66)  room temp (or otherwise stated)  316 E  =  OSiPh CH Q 2 -Bu)  Diels-Alder reactions of dienes 219 and 314 with TCNE  substrate  % yie1d’  product(s)  reaction time  N lh  1  79  NC NC  221  Et 2 CO 312  N 313 ratiocof3l2:313=21:1  2  1 h and 45 miii  ratio’of313:312=6.3:1  72hd  no reaction  220  3 222  87  131 Table XXVII. Continued substrate  entry  reaction time  ’ 1 % yield  product(s)  86  0.5 h  4  I  Et 2 CO 223  EL 2 CO  N 317  95  0.5 h  5  Et 2 CO  N  224  318  N 3 19e ratio’of318:319=40: 1 N 2h  6  I  41  (t-Bu) 2 —OSiPh 320 N 321  a 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 1 H 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.  132  C 2 EtO  HO  Me  Me%(4”f Sn 3 Me. I  Me  f Me’( ” 3 Sn 3 Me I 322  Et78°Cjh 0°C, 1 h (96%)  210  t-BuPh S 2 iC1 (1.4 equiv) unidazole (1.8 equiv) C1 (96%) CH 2 SiO 2 t-BuPh Pd 3 (Ph P 4 ) (5 mol%)  LiCI (2 equiv), DMF  (t-Bu) 2 OSIPh  Me Me  %%  80°C, 1 h (86%)  Sn 3 Me  I 323  320 Scheme 42  It should be noted that compound 320 (Scheme 42) was derived form the alkylated ester O of the 8 AIH, followed by protection 2 210 (p 59) via reduction of the ester moiety with i-Bu  reduced alcohol and subsequent palladium(0)-catalyzed cyclization.  As shown in Table XXVII (pp 130-131), the cycloaddition products were obtained in  good yields (>80%) except for two experiments (entries 3 and 6). The time required for completion 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 steric repulsion between the two methyl groups on the diene system causes severe distortion from  planarity (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 drastic reaction conditions (entry 3). In addition, it is interesting to note that the Diels-Alder reaction of TCNE with the diene 320 did not go to completion within 2 h (entry 6). However, the reason(s) underlying the fact that 320 is somewhat less reactive than 223 is (are) not immediately obvious.  133 Another special feature of the Diels-Alder reactions of the dienes of general structures 219 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 as the 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 function from the a-face so as to avoid the unfavorable steric interaction between TCNE and the ester group on the 5-membered ring in the transition state (Scheme 43). Similarly, in all other reactions with TCNE (Table XXVII), the major products are those adducts resulting from approach of TCNE from the a-faces of the dienes.  ..F 2 EtO  221 NC  a-face approach N  /3-fxe approach N C  C  N  Et 2 CO  N 312  Scheme 43  313  134 N  The relative stereochemistry of each of the products (Table XXVII, pp 130-13 1) was assigned with the aid of conformational analyses, 1 H nrnr spectroscopic data and a series of decoupling and nOe difference experiments. For example, there are two “reasonable” 312  conformations for compound 312, i.e. 312A and 312B. In both  conformations, the cyclohexene ring adopts a half-chair conformation. It can be seen that in 312A, a serious 1,3-diaxial interaction between the secondary methyl group (Me) and one of the 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 the more stable conformation. It is worth noticing that, in 312B, the Me group has a pseudoequatorial orientation. The proposed conformation 312B was shown to be in agreement with the results obtained from the nOe difference experiments (p 135). E E He.  E* 312A  E=E*=CN E’= EtO C2  4E* E  Me Me  E 312B  E=E*=cN E’= EtO C2  135  8 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)  N  1.5 (d)  312  6 3.56-3.66 (m)  , 400 MHz) of 312 displayed signals for a secondary 3 The 1 H nmr spectrum (CDC1 methyl group (CHeCjj, a 3-proton doublet at 3 1.58, J= 7 Hz), three methylene groups (Ha and Hb, a 2-proton multiplet at 32.19-2.40 and a 2-proton multiplet at 62.43-2.62; H, a 1proton doublet at 6 3.08, J= 18 Hz and a 1-proton doublet of multiplets at 6 3.15, J= 18 Hz for doublet) and two methine protons (H<j, 1-proton multiplet at 8 3.56-3.66; He, 1-proton broad signal at 83.37-3.48, wi= 18 Hz). In a decoupling experiment, irradiation at 63.43 simplified the doublet at 6 1.58 to a singlet. In a series of nOe difference experiments, irradiation at 8 1.58 (CBeCfj) caused enhancement of the signals at 63.37-3.48 (He) and 6  3.56-3.66 (HdJ, while saturation at 63.61 (HiJ increased the intensity of the resonance at 6 1.58 (CHCth). Thus, the cis relationship between Hj and the methyl group on the 6membered ring was established by these nOe difference experiments.  The ir spectrum of 312 showed a weak absorption band at 2255 cnr 1 attributed to the CN stretching vibration. In addition, compound 312 was found to have a molecular formula of N C 1 H 2 0 4 7 by high resolution mass spectrometry. 6  136  E  He  Nd 313A  E=E*=CN E’= EtO C2  Me  E E  313B  E=E*=.CN E’= EtO C2  The cyclohexene ring in each of the conformations 313A and 313B adopts a haif-chair conformation. In the conformation 313B, a serious 1,3-diaxial interaction between the secondary methyl group (Me) and the nitrile group (E*) is enountered and thus, this conformation is disfavored. As a result, the conformation 313A, which does not possess the interaction between Me and E* groups, would be expected to be favored. Upon examination of molecular models of 313A, it can be found that the proton Hj on the 5-membered ring is quite close to the methyl group and to the proton He on the 6-membered ring. Thus, one might expect that these proximities would be shown in nOe difference experiments. This was foundtobe the case (p 137).  137  83.15 (d), and 8 3.24 (d) N  Hb  Ha and H 6 2.09-2.17 (m, 1H), 6 2.29-2.39 (m, 2H), 6 2.70-2.82 (m, 111)  61.50(d)  Hd  N  8324334 (br signal)  83.47-3.52(m) 313  , 400 MHz) of 313 exhibited signals for a secondary 3 The 1 H nmr spectrum (CDC1 methyl group (CHCHj, a 3-proton doublet at 6 1.50, J= 7 Hz), three methylene groups (Ha and Hb, a 1-proton multiplet at 8 2.09-2.17, a 2-proton multiplet at 8 2.29-2.39 and a 1proton mutliplet at 6 2.70-2.82; FTC, a 1-proton doublet at 6 3.15, J= 17 Hz and a 1-proton  doublet at 63.24, J= 17 Hz) and two methine protons (Hrj. 1-proton multiplet at 63.47-3.52; He, 1-proton broad signal at 8 3.24-3.34 w1/= 18 Hz). In a decoupling experiment, ,  irradiation at 6 1.50 (CHeCjj) sharpened the broad signal at 6 3.24-3.34 (He) to a broad ) caused 3 singlet. In a series of nOe difference experiments, irradiation at 6 1.50 (CHCj enhancement of the signals at 6 3.24-3.34 (He) and 6 3.47-3.52 (H<j), while saturation of the signal at 6 3.29 (He) increased the intensities of the signals at 6 1.50 (CHeCIj3) and at 8  3.47-3.52 (Hj). Irradiation at 63.50 (Hj) intensified the resonances at 6 1.50 (CHCij ), 6 3 2.29-2.39 (Ha) and 8 3.24-3.34 (He). Thus, the cis relationship between 11 d and He was established by these nOe difference experiments. Moreover, the proton 11 d on the 5membered ring is found close to the methyl group and to the proton He on the 6-membered ring. In other words, these results are in agreement with the relative stereochemistry of the secondary methyl group as well as the proposed conformation.313A (p 136).  138  Me  N Me 317 R  =  Me*  Me*  N Me*  317A R  Et 2 CO  321 R = 2 O CH ( t-Bu) SiPh  =  317B R = CO Et 2  Et 2 CO  321B R = 2 O CH ( t-Bu) SIPh  321A R = 2 O CH ( t-Bu) SiPh  N Me*  iie 318  Et 2 CO  H* 318B  318A  [E=E*=cN  ]  Conformational analysis shows that the conformations 317A and 321A are disfavored by the two 1,3-diaxial interactions between secondary methyl groups (Me* and Me) and nitrile groups (E or E*). In conformations 317B and 321B, the two secondary methyl groups are in pseudoequatorial positions, and thus the two 1,3-diaxial interactions are not encountered. As a result, it is reasonable to conclude that 317B and 321B will be the favored conformations of compounds 317 and 321, respectively. In contrast, each of the conformations of 318 (318A and 318B) has one 1,3-diaxial interaction between a secondary methyl group (Me or Me*) and a nitrile group (E or E*). conformations would be expected to have similar energies.  Thus, the two  139 N Me*  H*COzEt Et 2 317R=CO  318  321 R = 2 O CH ( t-Bu) SiPh  A series of nOe difference experiments (for details, see Experimental section) provided  good evidence for the cis relationship between H* and the Me group on the 6-membered ring in compounds 317, 318 and 321. In these compounds, the relative stereochemistry of the Me and Me* groups was assigned on the basis of the well-established stereospecificity of Diels-Alder reactions 74a  For example, in nOe difference experiments performed on compound 317, irradiation at 6 1.03 (Me) caused enhancement of the signals at 6 2.91-2.99 (H*) and 6 3.21-3.31 (CjjMe), while saturation of the signal at 82.95 (H*) increased the intensity of the signal at 8 1.03 (Me). Thus, the cis relationship between the proton H* and the Me group was established by these nOe difference experiments. The results of this experiment are also consistent with the proposal that 317 exists primarily in conformation 317B (p 138).  Similarly, in 1 H nOe difference experiments performed on the compound 318, irradiation at 6 1.65 (Me and Me*) caused enhancement of the signals at 83.18-3.28 (CliMe or CijMe*), 8 3.39-3.49 (CIIMe or Ci_jMe*) and 6 3.65-3.74 (H*) while saturation of the signal at 6 3.70 (H*) intensified the resonance at 8 1.65 (Me). Consequently, the cis relationship between the proton H* and the Me group was confirmed by these nOe difference experiments.  140 5.3. Diels-Alder reactions of dienes with methyl vinyl ketone (MYK)  It has been reported that under thermal conditions Diels-Alder reactions of some cyclic substances containing 1,2-bis-exocyclic dienes with dienophiles are neither regio- nor e. The regio- and stereoselectivity of such Diels-Alder reactions can be ’ 8 stereoselectiv a 13 l 1 , l 2 ZnC . 2 a 3 8 , , SnCL 4 or 81 •Et 3 BF 0 ,2 3 improved by the addition of a Lewis acid such as A1C1 reaction. The 83 C, Another known function of Lewis acids is to accelerate the Diels-Alder 74 acceleration is considerable, and often the reaction temperature can be lowered by more than , resulted in Et 2 . 3 BF 7 A commonly used Lewis acid, 0 100 °C with no decrease in rate.  good regio- and stereoselective control in some Diels-Alder reactions which involved the use t had been used dienophile.l Previously, 0 l 8 a 2 E 3 BF of methyl vinyl ketone (MVK) as a 3 successfully in Diels-Alder reactions between 2,3-bis(alkylidene)cyclobutanecarboxylates and .Et was chosen for 3 BF 0 MVK in our laboratory (e.g. Scheme 9, p 19).13a15 Therefore, 2 the Diels Alder reactions of dienes 219 and 314 with MVK (Equation 67). The results of these reactions are summarized in Table XXVffl.  Et (—1 equiv) 2 . 3 BF 0 MVK (-5 equiv)  (67)  C1 -78 °C, 1-3 h CH , 2 E 219 E=C0 R 2 314 E  =  -Bu) OSiPh 2 CH Q  324E=C0 2 R 325 E  =  ) SIPh t-Bu O 2 CH (  141 Table XXVIII. entry  Diels-Alder reactions of dienes 219 and 314 with MVK  substrate  reaction time  % yieldb  pioduct(s)  1.5 h  1  95  o  CO E 2 t 221  Et 2 CO 326  2h  2  55C  220  327  1.5h  3 223  I o  Et 2 CO 328  3h  4  329 (91%)  ad 230 329 0  330  330 (5%)  142 Table XXVIII. Continued substrate  entry  % yie1d’  product(s)  reaction time  92  1.5 h  5  224  —  6  I  (t-Bu) 2 ‘—OSIPh  331  96  2 h and 15 mm  332  333  99  2.5 h  I  (t-Bu) 2 ‘—OSiPh  320  0  I  Q-Bu) 2 OSiPh  334 = I  2h  8  tBu) rOSjph ( 2 0  335  336  a 0 CI -78 °C. CH , 2 . 3 BF Et (—1 equiv), MVK (—5 equiv), 2 b Yield of purified, pumped (vacuum pump) product(s). C The reaction was complete within 2 h (gic analysis). In addition, two uncharacterized side products were found in the crude product (gic analysis).  143 It should be noted that diene 332 (Scheme 44) was obtained in two steps via reduction of compound 221 with lithium aluminum hydride (LiA1H4) and subsequent protection of the alcohol 337 with tert-butylchlorodiphenylsilane (t-BuPh2SiC1). In Section 5.2 (Scheme 42, p 132) of this thesis, a sequence of reactions has been described for the preparation of diene 320. A similar sequence was carried out for the synthesis of the diene 335 (Scheme 45) from the starting material 255 (Section 4.2, p 98). 1) LiAIH , Et 4 0 2 0°C, 2 mm;  room temp, 10 miii  2) 2 S Na . 4 0 10H O 221  OH 337  (80%)  SiC1 2 t-BuPh imidazole C1 (99.5%) CH 2  I  (t-Bu) 2 ‘—OSIPh 332  Scheme 44 HO  Me  Sn 3 Me  I  Me  tBuPh S 2 iCl (1.4 equiv) imidazole (2.5 equiv) C1 (95%) CH 2  SiO 2 t-BuPh Me  Me I  Sa 3 Me 338  255  4 P 3 (Ph P d ) (5 mol%) LiCI (2 equiv), DMF 80°C, 1 h (90%)  335  Scheme 45  144 A typical procedure for the Diels-Alder reactions of the dienes with MYK is illustrated by .Et (1 equiv) to a mixture 3 BF 0 the conversion of the diene 221 into 326. Thus, addition of 2 C1 at -78 °C, followed by a reaction time of 1.5 h, workCH of 221 and MVK (5 equiv) in 2 up and chromatography, gave a 95% yield of a single product 326 (Equation 68, Table XXVffl, entry 1, p 141). .Et (-1 equiv) 3 BF 0 2  I  MVK (—5 equiv)  C1 -78 °C, 1.5 h CH , 2  o  !  (68) Et 2 CO  326  221  6 1.52-1.68 (m)  62.60-2.70 Cm)  83.37-3.43 (m)  62.42 (dt)  326  80.73 (d)  The relative stereochemistry of each of the cycloaddition products was assigned on the basis of 1 H nmr spectroscopic data and a series of decoupling and nOe experiments, as well H nmr as a COSY experiment, if necessary. Taking compound 326 as an example, its 1 spectrum (CDCI3 : C6D6 =4: 3, 400 MHz) displayed the expected signals for a secondary methyl group (a 3-proton doublet at 30.73, J= 7 Hz), an ethyl ester moiety (a 3-proton triplet at 6 1.02, J= 7 Hz and a 2-proton multiplet at 63.97-4.15) and a methyl ketone moiety (a 3proton singlet at 3 1.81). Other assigned protons included: 2  X  Ha, a 2-proton multiplet at 3  1.52-1.68; Hb, a 1-proton doublet of triplets at 62.42, J= 10, 5 Hz; H, a 1-proton multiplet  145 at 8 2.60-2.70 and ELj, a 1-proton multiplet at 8 3.37-3.43. Mixed deuterated solvents were used so as to allow better dispersion of some of the signals. The proposed assignments are summarized on the structural formula shown above (p 144). B C  HaU3)  Ha(13) Ha  A  326  = CH 1 E CO 3 = EtO 2 E C 2  (Ha(a)Im  10 HZ’ Ha(p)Hb= HbHc  Hz)  These spectral assignments were confirmed by a series of decoupling and nOe experiments. In the decoupling experiments, irradiation at 8 1.60 (Ha(a) and Ha(1 )) 3 simplified the doublet of triplets at 62.42 (Hb) to a doublet (J= 5 Hz) [thus, J(a)Jp.,= 10 HZ and JHa(fl)Hb 5 Hz]. Saturation of the signal at 6 2.65 (He) altered the doublet at 8 0.73 (CHcCjj3) to a singlet, and changed the doublet of triplets at 6 2.42 (Hb) to a doublet of doublets (1= 10, 5 Hz) [thus, HbHc= 5 Hz]. In a series of nOe difference experiments, irradiation (A, as depicted in the diagram above) at 60.73 (CHcCjj3) caused enhancement of j). Thus, the 1 the signals at 8 1.52-1.68 (Ha(a)), 8 2.60-2.70 (He) and 8 3.37-3.43 (H secondary methyl group at 80.73 is cis to the proton Hrj at 8 3.37-3.43. Moreover, this methyl group adopts a pseudoaxial position as indicated by the enhancement of the signal attributed to the pseudoaxial proton Ha(a). Saturation (B, as depicted) of the signal at 62.42 (Fib) increased the intensity of the resonances at 8 1.52-1.68 (FIa(J.)) and 62.60-2.70 (Hc). From this result, it is clear that the proton Hb is cis to the proton H and the pseudoequatorial  146 proton Ha(1 ). The pseudoaxial orientation of the proton Hb is confirmed by the coupling 3 constant between protons Ha(a) and Hb (J= 10 Hz). In addition, saturation (C, as shown in the diagram in p 145) of the signal at 62.65 (He) caused the enhancement of the signals 8 0.73 (CHcCj:j3) and 82.42 (Hb), while irradiation (D, as depicted in p 145) at 63.40 (HdJ increased the intensity of the signal at 8 0.73 (CHcC[13). These results are consistent with the previous assignments as well as with the proposed conformation. In summary, it is demonstrated that the secondary methyl group at 80.73 (CHCH) is cis to the proton Hj and that the cyclohexene ring of compound 326 adopts a half-chair conformation with both the proton Hb and the secondary methyl group in the pseudoaxial orientation.  o  EL 2 CO  =  Hd  326  = 1 E  CO 3 CH  = 2 E  C 2 EtO Hd  , 100.6 MHz) of 326 confirmed the presence of two 3 The 13 C nmr spectrum (CDC1 olefinic carbons (3 135.9, 138.8) and two different carbonyl carbons (6 175.2, 210.9).84 1 for the stretching The ir spectrum showed two absorption bands at 1734 and 1720 cnr 5 was 2 0 1 C 2 H frequencies of the two different C=O moieties. The molecular formula 3 determined from the high resolution mass spectrum of compound 326.  147 0 MYK (69)  +  Et 2 • 3 BF 0 -78 °C 230  329  330  (91%)  (5%)  Since the Diels-Alder reaction of the diene 230 with MVK (Equation 69) proceeded with regioselectivity different from the corresponding reactions involving the dienes 223, 224, 320 and 335, it is important to discuss how the constitution and relative stereochemistry of H nmr speciroscopic studies. each of the products 329 and 330 was established by 1  I 223  224  230  SiPh I t-Bu) O 2 CH ( 320  SiPh t-Bu) O 2 CH (  335  , 400 MHz) of compound 329 displayed signals 3 H nmr spectrum (CDC1 The 1 corresponding to two secondary methyl groups (a 3-proton doublet at 60.81, CHfC, J= 7 Hz and a 3-proton doublet at 6 0.88, CHjCij , J= 7 Hz), an ethyl ester functionality (a 33 proton triplet at 8 1.25, J= 7 Hz and a 2-proton multiplet at 34.06-4.17) and a methyl ketone moiety (a 3-proton singlet at 62.15). Other diagnostic signals are those derived from Ha (a 1-proton broad doublet at 6 1.47, J= 13 Hz), 11 b (a 1-proton triplet of doublets at 3 1.84, J= 13, 6 Hz), H (a 2-proton quartet at 6 2.06, J= 7 Hz), H<j (a 1-proton multiplet at 6 2.302.38), He (a 2-proton multiplet at at 6 2.33-2.44), Hf (a 1-proton multiplet at 3 2.63-2.73), Hg (a 1-proton doublet of doublet of doublets at 32.87, .1= 13, 5, 2 Hz) and Hh (a 1-proton broad triplet at 6 3.27, J= 7 Hz). These assignments are summarized on the structural formula shown below (p 148).  148 62.87 (ddd)  80.81(d)  62.63-2.73 (m)  8 2.33-2.44 (m)  8 2.30-2.38 (m)  8 2.06 (q)  8 1. () 83.27rt) 329  61.47(brd) 6 0.88 (d)  A series of decoupling experiments were carried on compound 329. Irradiation at 8 1.84 (Hb) altered the broad doublet at 6 1.47 (Ha) to a broad singlet (wlj2= 3 Hz) and the  signal at 62.87 (Hg) to a broad doublet (J= 5 Hz) [thus, Jii= 13 Hz and JimHg= 13 HZ]. Saturation of the signal at 82.06 (He) simplified the multiplet at 62.33-2.44 (He) to a broad singlet (w1f2= 5 Hz) centered at 82.39, and the broad triplet at 63.27 (Hh) to a broad singlet (wl,2= 4 HZ) [thus, JHc}Th= 7 Hz], while irradiation at 62.34 (Hj changed the doublet at 8  0.88 (CHjj) to a singlet, the broad doublet at 6 1.47  (Ha) to a doublet of doublets (J= 13,  2 HZ), and the triplet of doublets at 6 1.84 (FIb) to a triplet (J= 13 Hz) [thus, JHd= 6 HZ].  Saturation of the signal at 62.68 (He) altered the doublet at 80.81 (CHfCj) to a narrower doublet (J= 1 Hz), the broad doublet at 8 1.47 (Ha) to a doublet of doublet of doublets (J= 13, 2, 1.5 Hz) [thus, proton Hf couples to Ha with a small long-range W-type coupling constant], and the signal at 62.87  (Hg)to  a broad doublet (J= 13 HZ). Moreover, irradiation  at 82.87 (Hg) changed the triplet of doublets at 8 1.84 (FIb) to a doublet of doublets (J= 13,6 Hz) and the multiplet at 62.63-2.73 (Hf)to a quartet (J= 7 HZ) [thus, J1p = 13 HZ]. The 8 H 3 determined coupling constants (JHaJTh= JImHg= 13 Hz, JHbHd= 6 Hz) show the geminal  149 relationship between protons Ha and Hb, and the vicinal relationship between protons Hb and Hg and between protons Hb and Hj. Since the vicinal coupling constant JHbHg= 13 HZ, it is clear that each of the protons Hb and Hg must adopt a pseudoaxial orientation. B  0  329  F  CO; 3 = CH 1 E Et 2 = CO 2 E  HaJ{b= HbHg=  13 Hz, HbHd= 6 Hz  H nmr spectral assignments of 329 were further confirmed with a series of nOe The 1 difference experiments. For example, irradiation (A, as depicted in the diagram above) of the signal at 60.81 (CHfCIj3) caused the enhancement of the signals at 6 1.84 (FIb), 6 2.33-2.44  jCth) 1 (He) and 62.63-2.73 (Hj). Saturation (B, as depicted) of the signal at 6 0.88 (CH increased the intensities of the resonances at 6 1.47 (Ha), 62.30-2.38 (Hj) and 82.87 (Hg).  Moreover, irradiation (C, as depicted) of the signal at 82.34 (H<j) caused enhancement of the signals at 6 0.88 (CHdCth), 6 1.47 (Ha), 6 1.84 (JIb) and 8 3.27 (Hh). In addition, irradiation (D, as depicted) at 8 2.68 (Hf) caused enhancement of the signals at 6 0.81 (CHjC) and 62.87 (Hg). Saturation (E, as depicted) of the signal at 62.87 (Hg) increased the intensities of the signals at 80.88 (CHdCa3), 6 1.47 (Ha) and 62.63-2.73 (Hf), while irradiation (F, as depicted) at 63.27 (Hh) caused enhancement of the signals at 62.06 (He) and 82.30-2.38 (H). Therefore, the proposed constitution and relative stereochemistry of  150 H nmr decoupling and nOe 329 is consistent with the experimental results obtained from the 1 difference experiments. In summary, it was found that cyclohexene ring of 329 adopts a half-chair conformation with two secondary methyl groups pseudoaxial and the acetyl group in a pseudoequatorial orientation. The regiochemistry of the Diels-Alder reaction leading to 329 will be discussed in a later part of this section of the thesis (p 159).  The relative stereochemistry of the compound 330, a stereoisomer of 329, was , 400 MHz) signals 3 H nmr (CDC1 determined in the same fashion. Some of the important 1 of 330 are summarized in the diagram below. 60.82 (d, 3H, J= 7 Hz)  82.75 (ddd, 1H, 1= 13, 5,2.5 Hz)  8 2.58-2.66 (m, 1H)  6 2.28-2.38 (m, 1H)  8 1.89(td, 1HJ= 13,6Hz) 8 3.43-3.52 (m, 1H) 81.50 (brd, 1H,J’= 13Hz)  330 60.99(d,3H,J=7Hz)  In a series of 1 H nmr decoupling experiments carried on 330, irradiation at 8 0.82 (CHJCII3) simplified the multiplet at 8 2.58-2.66 (Hj) to a doublet of multiplets (J= 5 Hz) centered at 62.62 [thus, JHcIHe= 5 Hz]. Saturation of the signal at 6 2.33 (He) changed the doublet at 6 0.99 (CHCth) to a singlet, the broad doublet at 6 1.50 (Ha) to a doublet of doublets (J= 13, 2.5 Hz), and the triplet of doublets at 8 1.89 (Hb) to a triplet (J= 13 Hz) [thus, JHc= 6 Hz]. Futhermore, irradiation at 8 2.62 (Hj) altered the doublet at 6 0.82  151 (CHdCTh) to a singlet and the doublet of doublet of doublets at 6 2.75 (He) to a broad doublet (J= 13 Hz). Saturation of the signal at 82.75 (He) simplified the triplet of doublets at 8 1.89 (FIb) to a doublet of doublets (J= 13, 6 Hz) [thus, JHbHe= 13 Hz]. Thus, it is clear that the tertiary protons FI and Hj are vicinal to the protons Hb and He, respectively. In  addition, each of the protons Hb and He must be placed in a pseudoaxial orientation.  0  Hb  A  a  t CO E 2  330 = CH 1 E CO; 3 = CO 2 E Et 2 6 HZ, HbHe= HbHc B  13 Hz  5 HZ HdHe=  Further confirmation of the proposed relative stereochemistry of 330 was made by a series of nOe difference experiments as following. Irradiation (A, as depicted in the diagram  ) caused enhancement of the signals at 6 1.89 (Hb) and 82.583 above) at 80.82 (CHjCjj 2.66 (CHdCTh), while saturation (B, as depicted) of the signal at 6 0.99 (CHcCIj3)  increased the intensities of the resonances at 6 1.50 (Ha), 62.28-2.38 (He), 62.75 (He) and 83.43-3.52 (Hi). In addition, irradiation (C, as depicted) at 8 233 (He) caused enhancement of the signals at 60.99 (CHCCII3) and 6 1.89 (FIb). Saturation (D, as depicted) of the signal at 82.75 (He) increased the intensities of the signals at 60.99 (CHeCJj ) and 8 1.50 (Ha), 3 while irradiation (E, as depicted) at 63.48 (He) caused an enhancement of the signal at 80.99 (CHCj3). Thus, the proposed constitution and relative stereochemistiy of 330 is consistent  152  H nmr decoupling and nOe difference with the experimental results obtained from the 1 experiments. In addition, it was found that, as in the compound 329, the cyclohexene ring of 330 adopts a half-chair conformation with the two secondary methyl groups and the acetyl group adopting pseudoaxial orientations and a pseudoequatorial orientation, respectively.  o  Et 2 cO  Et 2 CO 327  326  328  329  330  334  336  a  E= 2 O CH ( t-Bu) S1Ph  o  a  o  Et 2 CO  =  333  331.  E  The structure of each of the products 327, 328, 331, 333, 334 and 336 was confirmed in a fashion similar to that employed for compound 326. The constitution, relative stereochemistry and conformation of all these compounds were confirmed by means of a  H nmr decoupling and nOe experiments (for details, see Experimental section) and series of 1 these results are summarized in Figures 9 and 10 (pp 153-154). The arrows in the depicted figures start from the protons being irradiated in the nOe experiments and end at the protons being enhanced after irradiations. Important coupling constants are also provided to support assignments of some of the protons. For example, vicinal protons which are pseudoaxially oriented have mutual coupling constants with a magnitude of—12 Hz. In general, the methyl group that is vicinal to the acetyl group on the cyclohexene ring (with a half-chair conformation) adopts a pseudoaxial position in each of the molecules of 326,328-331, 333, 334 and 336.  However, compound 327 has the secondary methyl group in a  pseudoequatorial orientation.  153  Figure 9:  Relative stereochemistry and conformation of compounds 327 and 328  328  327 9 ‘HaHc  Hz’ HcHd 7 HZ  HaHb  3 ‘‘ HHe Hz imHe  6 HbHc  = 1 [_E  t = 2 2 CO E O; E CH C 3  Hz, HdHe  Hz  154 Figure 10:  Relative stereochemistry and conformation of compounds 331, 333, 334 and 336  331 HaHb= HaHe  333  13 ‘ JHbHe= 2.5 Hz  Hb, ddd, 1H, J= 12, 5, 3  Hd correlated to Ha afld Hb He correlated to Ha, Hb afld Hf  COSY:  336  334 13 HaHb HbHd 2 ‘HaHd  LE1=  ‘  ‘HbHc ‘12  13  HaHb HaHc HaHd  2 ‘ HdHe JImHd  ‘  5 mHc  5  CO, E 3 CH = CO 2 Et, E 2 = OSiPh 3 (t-Bu) 2  I  155  In general, all cycloadditions with MVK were complete within 1-3 h. In each of the reactions, except those of entries 2,4 and 8 of Table XXVIII (pp 141-142), one product was formed exclusively in good yield (>92%). In these cases, the dienophile MVK approached  the diene from the a-face (which is designated as the face opposite to the one which has the ester or silyloxymethyl group). Clearly, if the MVK approached the 13-face of the diene via an endo transition state, serious steric hindrance would be experienced between the ester or silyloxymethyl group on the 5-membered ring of the diene and the acetyl group of the dienophile. Thus, approach of MVK from the a-face is favored and this face-selectivity was observed in all of the products obtained. In Schemes 46-48 (pp 155-157), the formation of each of the Diels-Alder reaction products is anayized with respect to the corresponding transition states. In addition to the face-selectivity, information concerning the exo/endo selectivity, as well as the orientations of MVK (regioselectivity) in these transition states are provided (Schemes 46-48). EtO C  c R=3 CH C O a-face approach 221  326  endo transition state  339  Et 2 CO  0  EtOC  R=3 CH C O a-face approach endo transition state  Et 2 CO 220  340  EL 2 O  327  C 2 EtO tI  223  341  R = CH CO 3 a-face approach endo transition state  Scheme 46  róQ  EL 2 CO  0  328  156 Peculiar regioselectivity: OBSERVED  342  R = CH CO 3 a-face approach endo transition state  343  CO 3 R = CH fl-face approach endo transition state  230  I  COEt  329  330  General regioselectivity: NOT FOUND  344  R = cH co 3 a-face approach endo transition state  0  R = CH CO 3 fl-face approach endo transition state  0  9  Et 2 CO  345  C 2 EtO  346  Scheme 47  a 347  Et 2 cO  157 w  •  R = CH CO 3  a-face approach 224  331  endo transition state  348  Et 2 CO  SiOCH t-BuPh 2  O 2 CH ( t-Bu) SIPh 332  V 349  CO 3 R = CH  a-face approach endo transition state  333  SiOCH t-BuPh 2  202(t) 320  R = CH CO 3  a-face approach 350  endo transition state  351  R = CH CO 3 afaceapproach endo transition state  o  O CH ( 2 t-Bu) SIPh 334  SiOCH t-BuPh 2  I  2O2(t) 335  336  Scheme 48  As shown in transition states 339-342 and 348-351, the dienophile MVK approached each of the dienes predominately from the a-face. The only confirmed deviation was found in the reaction of 230 (Equation 69 and entry 4 of Table XXVffl, p 141) with MVK, where a trace 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 section of the thesis (p 159).  158  7 the major cycloaddition product is the one obtained According to the Alder endo rule, from a transition state with the “maximum accumulation of double bonds”. Thus, the endo transition 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 (pp 155-157) shows that all the characterized cycloaddition products, including the minor product 330 (Equation 69), were obtained via endo transition states.  CO 3 R = CH  a-face approach 221  %Ylcx  t CO E 2  0  326  endo transition state  339  R  =  CO 3 CH  a-face approach exo transition state  352  Scheme 49  MVK (69)  +  EL 2 . 3 BF 0 -78 °C 230  329  330  (9 1%)  (5%)  159 The regiochemistry of all the cycloaddition products (except those of entry 4, Table XXVIII (diene 230 and products 329 and 330), p 141), are identical. For example, the dienophile MVK approaches the diene 221 with an orientation as depicited in the transition state 339 (Scheme 49, p 158). Surprisingly, deviation from this regioselectivity was confirmed in the cycloaddition of MVK to the diene 230 (Scheme 47, p 156). The major product 329 (Scheme 50) was obtained from 230 as a result of the approach of MVK via the regiochemical orientation shown in the transition state 342. The formation of minor product  330 was formed via approach of MVK from the fl-face of the diene with the same regiochemical orientation (transition state 343, Scheme 50).  R = CH CO 3 a-face approach endo transition state peculiar regioselectivity, a reversal of the predominant regioselectivity  329  230 342  EC/I  R = CH CO 3  0  fl-face approach  endo transition state peculiar regioselectivity, a reversal of the predominant regioselectivity  343  Scheme 50  330  160  3 R  R’%\  R’  R’L(’ SiPh(t.Bu) CH O 2 314  219  ’Et on the Diels-Alder reactions of the various 1,2-bis-exocydic 3 BF 0 The influence of 2 dienes of general structures 219 and 314 with MVK can be rationalized by the use of frontier 85 the main 79 In a normal (electron demand) Diels-Alder reaction, molecular orbital theory. interaction is that between the highest occupied molecular orbital (HOMO) (Figure 9) of the diene and the lowest unoccupied orbital (LUMO) of the dienophile. The smaller the energy difference is, the better the orbital overlap and the more readily the reaction occurs. c of a Lewis acid such as BF 74 Coordination .Et20 with the carbonyl group of MVK in our 3 reactions lowers the energies of the frontier orbitals (Figure 9) and alters the distribution of the atomic orbital coefficients.  Figure 9:  £  The effect of Lewis acid on the energies of the HOMO and LUMO of the dienophile in the Diels Alder reaction  I  LUMO  LUMO  LUMO  HOMO  DIENE  / / DIENOPHILE  WiTHOUT LEWIS ACID  /HOMO HOMO  DIENE  / DIENOPHILE LEWIS ACID  161 Because of the smaller energy difference between the HOMO of the diene and the LUMO of the dienophile, the reaction is faster. Indeed, it was observed that, in the presence of .Et20, reaction of 221 with MVK was complete in 1.5 h at -78 °C, while in the absence 3 BF of this Lewis acid, the reaction took 4 h to complete in refluxing benzene. In the latter experiment, the reaction was not selective and three minor uncharacterized products were H nnr and gic analyses). 1 produced in addition to 326 (  R3%(\ R1L(  O CH ( 2 t-Bu) SIPh  Et 2 CO 326  221  314  219  The observed endo selectivity in the reactions of dienes of general structures 219 and  314 with MVK is reinforced by the presence of BF .Et20. In the presence of a Lewis acid, 3 the secondary orbital interaction (as shown by dashed lines) is greatly enhanced because of a large increase in the LUMO coefficient of the carbonyl carbon atom.  HOMO  LUMO  [i1HouT LEWIS ACID  WITH LEWIS ACID  1  162 Another effect of the Lewis acid BF .Et20 is to further polarize the LUMO of MVK. 3 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 larger coefficient in the dienophile interacts preferentiaily with the atom with the larger coefficient in the diene to result in a better overlap of orbitals. Consequently, the Diels-Alder reactions of trisubstituted 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 regioselectivity consistent with that predicted. HOMO LUMO  HOMO LUMO  F3B0 WITH LEWIS ACID  WITHOUT LEWIS ACID  I 220  0  ‘  326  Et 2 CO  I  221  Et 2 CO  332  0 327  (t-Bu) 2 ‘—OSiPh  Q-Bu) 2 ‘—OSiPh 333  163  223 E=CO Et 2 O CH ( t-Bu) S1Ph 320 E = 2  224E=CO E 2 t O CH ( t-Bu) SIPh 335 E = 2  çxj 1 % Et 2 328E=CO 334 E  =  O CH ( 2 t-Bu) SiPh  Et 2 331E=CO 336 E  =  230  ??O2E  329  O CH ( 2 t-Bu) S1Ph  330  The Diels-Alder reactions of MVK with the tetrasubstituted dienes 223, 224,230,320  and 335 (products 328-331, 334 and 336 in Table XXVffl, entries 3-5, 7 and 8, pp 141142) provided products resulting from two different modes of regioselectivity (p 159). The Diels-Alder reactions of MVK with dienes 223, 224, 320 and 335 gave products with the same regiochemistry as those products obtained from Diels-Alder reactions of MVK with trisubstituted dienes 220, 221 and 332. But in one case, the Diels-Alder reaction of MVK with tetrasubstituted diene 230 provided products 329 and 330 with a reversed regiochemistry. It is not immediately clear why the predominant regioselectivity, as well as the reversed regioselectivity (diene 230) are observed in these Diels-Alder reactions.  164 It could be speculated that, in the reactions involving the dienes 223 and 224, BF .Et20 3 chelates concurrently both with the carbonyl group of the ester functionality on the 5membered ring and the carbonyl group of the acetyl moiety of the MVK. This double b of 2 82 coordination .Et would lead to the formation of products with the observed 3 BF 0 regiochemistry. It would be expected that complexation of BF •Et20 with the carbonyl 3  groups of ester would be avoided by converting the ester functions on the 5-membered ring to sioxymethyl groups. However, products 334 and 336, with the same regioselectivity, were  obtained from Diels-Alder reactions of the MVK and the sioxymethyl dienes 320 and 335, .Et with the carbonyl group of the ester 3 BF 0 respectively. Therefore, complexation of 2 functionality may not be the cause of the observed regioselectivity. This proposed double .Et is also made unlikely by formation of 329 and 330 from the Diels 3 BF 0 coordination of 2 Alder reaction of MVK with the diene 230. In the latter reactions, the relative positions of the acetyl and the ester groups in the products 329 and 330 are against to the possibility of Et with the two carbonyl-containing groups in the 2 . 3 BF the concurrent chelation of 0 corresponding transition states.  t CO E 2 223 E = CO Et 2 320 E = 2 SIPh t-Bu) O CH (  224 E = CO Et 2 -Bu) 335 E = 2 OSiPh CH Q  230 0-  329 t 328E=CO E 2 334 E = 2 SiPh t-Bu) O CH (  t 331E=CO E 2 336 E  =  SiPh t-Bu) O 2 CH (  330  165 Further research is required to clarify the occurrence of different modes of regioselectivity, depending on the orientations of the vinylic methyl groups on the 1,2-bisexocycic diene system (compare the orientation of the vinylic methyl groups in the dienes 223, 224 and 230). To our knowledge, the change of regioselectivity due to the change of the orientations of these methyl groups is unprecedented. (The reversal of the Diels-Alder 8 regioselectivity by a change of Lewis acid, and of the solvent used, have been observed.)  E EL 2 223E=CO  t CO E 2  E Et 2 224E=CO  230  R1L%( SiPh t-Bu) O 2 CH ( 219  314  In conclusion, the Diels-Alder reactions of dienes of general structures 219 and 314 with the dienophiles TCNE and MVK occurred with approach of dienophiles from the aface.  In the Diels-Alder reactions of 219 and 314 with MVK, the observed rate  enhancement as well as the observed endo selectivity of the cycloaddition adducts are a result Et and can be explained in terms of frontier molecular orbital 2 • 3 BF of the presence of 0 79 However, knowledge about the regioselectivities of the Diels-Alder reactions of theory. tetrasubstituted dienes of general structures 219 and 314 with MVK is very limited, and further investigations in this area are required.  166  III. CONCLUSIONS 1. Development of the use of lithium (trimethylstannyl)(cyano)cuprate for the conversion of alkyl 2-alkynoates into alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates  A number of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates of general structures 89 and 91 were required for this study.  During the course of this study, lithium  (trimethylstannyl)(cyano)cuprate ([Me3SnCuCNILi, 123) was found to serve as an effective reagent, alternative to lithium (trimethylstannyl)(phenylthio)cuprate ([Me3SnCuSPh]Li, 120), for the stereoselective conversion of a,f3-acetylenic esters 100 into either of the desired products 91 and 89 (Equations 27 and 28, respectively). This work was carried out in collaboration with Mr. Keith A. Ellis.  SnCuSPh]Li 3 [Me  SnCuCNJLi 3 [Me  120  123  1) [Me SnCuCN]Li (123) 3  R1 —  2 cO  THF,-48°C,2h;O°C,2h 2) 4 C1-NH NH O H  R1  (27) Sn 3 Me  100 1) [Me SnCuCN]Li (123) 3 2 co’ 2  THF, R2OH, -78 °C, 4 h 2) 4 C1-NH NR O H  100  R 2 CO  91  R1 —  H —  1 R—  CO2 R 2  Sn 3 Me  H  89  (28)  167 2. Stereoselective and regioselective synthesis of electrophiles  The preparation of a number of specifically functionalized and stereochemically homogeneous 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 in good 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) were employed.  Overall, this chemistry constitutes a new strategy for the preparation of  homoallylic diiodides of general structures 98 and 99.  The vinyl halide functionality of compounds of general structure 353 was obtained by the use of either bromoboration-protonolysis or hydrostannylation-iododestannylation procedures. A series of known procedures, including the trans addition of H-I to ethyl 2butynoate (101) (Scheme 37, p 106), reduction, and treatment of the reduced alcohol 280  with triphenyiphosphine dibromide 2 P.Br 3 (Ph ) , provided the electrophile 275.  98  99  353  X’=Brorl, x” = Clor I, n = 1 or 2  I>’4_Br 275  = 101  EL 2 CO  I—OH 280  168  1 R 3 R  M)’ 89  1) base  OR  2)H  R’ 89—*90 R2 2 M1>’4C0  91—,92  4 rCO R R2 2 3 SnMe = H, R 3 =R 4 ; 1 90 R = 3 92R , 1 = 4 R H R  91  AIH, Et 2 i-Bu 0 2 -78 °C, 1 h; 0 °C, 1 h  3 R  C1 CH 12, 2  3 R  room Lemp, 15 mm 3 SnMe  I 195 R = H, R 3 = R’; 4 = 3 192R , 1 = 4 R H R  194 R = H, R 3 =R 4 ; 1 =R’,R 3 191R = 4 H  P.1 2 3 Ph , 2 C1 CH  Et, mom Lemp, 4 h  3 R I  4 R I  98 R = H, R 3 =R 4 ; 1 =R’,R 3 99R = 4 H  Scheme 51  169 3. Preparation of compounds containing vinyl halide and vinyltrimethyl stannane functions  The preparation of compounds of general structure 206 (Equation 35) was accomplished by the deprotonation of alkyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 89 and 91 with LDA, followed by alkylation of the resulting dienolates with electrophiles of general structures 96 and 97. On the other hand, compound 216 was synthesized by a two-step strategy. 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-3hexenoate (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. C 0 2 R 1 _)_jD0 R R 2  1) LDA-HMPA, THF 3 R  Sn 3 Me 2)  89 or 91  I  3 R  Sn 3 Me 206  ““‘‘  96or97  (35) X  (X=Brorl)  1) KN(SIMe , THF 2 ) 3 (70) 0 2 2) HOAc, Et 139  158  1) LDA-HMPA, THF  3 SnMe  3 SnMe  2)I  158  C 2 EtO  Sn 3 Me 216  204  170 4. Stereocontrolled  syntheses  of alkyl 2,3-bis(alkylidene)cyclopentane-  carboxylates via palladium(0)-catalyzed coupling reactions  Alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates of general structure 219 were  prepared in good yields and in a stereochemically defined manner from compounds of general structure 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 our initial 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) which provided only 1 ,2-bis(alkylidene)cycloalkanes possessing one or two E-substituted alkylidene moieties. However, the limitations of this palladium-catalyzed 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.  R3%J0cfR1  ::::::  206  3 R (39)  219  3 R  R2 2 O  E.E-diene 81  230  E,Zdiene 82  222  Z,E-diene 83  228  Z,Zdiene 84  229  171  5. X-ray analysis of alkyl 2,3-bis(alkylidene)cyclopentanecarboxamides  Crystalline 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 the magnitude 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 that the extent to which the 1,2-bis-exocycic diene systems of these crystalline derivatives are distorted from planarity are similar, and that there is no clear correlation between the values of the dihedral angles and with the size of the substituents on the termini of the diene moieties.  241  238  237  —  H  243  247  6. Discovery of the CuC1-mediated intramolecular coupling reaction  Extensive efforts to synthesize the Z,E-diene 230 in a stereochemically defined manner and to optimize the yield of the preparation of 229 resulted in the development of a new CuC1-mediated intramolecular coupling of vinyl halide and vinyltrimethylstannane functions.  This method has been applied successfully to the preparation of a number of alkyl 2,3bis(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 containing conjugated diene systems (see structural formulas 253 and 289-293, p 172). In some  172 cases, it was found that this CuC1-mediated method is superior to the palladium(O)-catalyzed coupling process. In addition, with the results obtained from the preliminary studies, a provisional mechanism was proposed for this new reaction (Scheme 41, p 127). Future studies concerning synthetic and mechanistic aspects of this new coupling procedure can be envisaged. Br  MJ 3 SnMe 286 284  285  Meç  252  287  C 2 MeO  289  288  C 2 MeO  290  cb 291  C 2 MeO  Me 253  292  293  173 7. Investigation  of synthetic  utility of alkyl  2,3-bis(alkylidene)cyclo-  pentanecarboxylates in the Diets-Alder reaction  Owing 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 natural products, the Diels-Alder reactions of alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates 219 and the related dienes 314 with the dienophiles TCNE and MVK (Equations 65 and 66, respectively) were investigated.  3 R  TCNB, THF  room temp (or otherwise stated)  E  NC NC  (65)  219 E=C0 R 2  2 315E=COR  314 B = 2 O CH ( t-Bu) SIPh  316 E = 2 O CH ( t-Bu) SiPh Et (-1 equiv) 3 BF O 2 MVK (-5 equiv)  R3 B  C1 -78 CH , 2  (66)  °C, 1-3 h  R 2 C0  0 324 E  =  R 1 R 2 C0  314 E = 2 O CH ( t-Bu) SIPh  325 E  =  O CH ( 2 t-Bu) SiPh  219 B  =  Interestingly, the Diels-Alder reactions of dienes of general structures 219 and 314 occurred with approach of dienophiles (TCNE, MVK) from the a-face (which is designated as 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 was experienced between the dienophiles and the ester or the siloxymethyl group on the 5memebered ring, when the dienophiles approach the 13-face of the dienes. Moreover, it was found that Diels-Alder reactions of dienes of general structures 219 and 314 with the dienophile MYK occurred with approach of MVK via an endo transition state.  174  Et 2 CO 220  r9?O2E 327  I  OSIPh ( 2 t-Bu) 332  Et 2 CO 221  OSiPh(t-Bu)  Et 2 CO  a  326  333  EL 2 CO  I  223 320  E=CO E 2 t E=2 OSIPh CH Q -Bu)  B 224 E=CO Et 2 O CH ( t-Bu) SIPh 335 E = 2  230 0  s,rcx? o 328  = B E=CO E 2 t  334 E = 2 O CH ( t-Bu) SIPh  E 331  Et 2 E=CO  336  B=2 O CH ( t-Bu) SiPh  330  Another interesting feature of the Diels-Alder reactions of these dienes and MVK is the regiochemistry of the products. The regiochemistry of the products obtained from Diels Alder reactions of the irisubstituted dienes (dienes 220, 221 and 332; products 327, 326 and 333) was rationalized on the basis of the frontier molecular orbital theory. The same type of regiochemistry was observed in Diels-Alder reactions of the tetrasubstituted dienes and the dienophile MVK (dienes 223, 224, 230, 320 and 335; products 328-331, 334  175 and 336). In addition, the reversal of the predominant regioselectivity is confirmed in the Diels-Alder reaction of MVK and the diene 230. However, the reasons for the predominant regioselectivity and the reversed regioselectivity in these Diels-Alder reactions are not clear at  this moment.. In order to find out the rationale for these interesting regioselectivities, future investigations will be required.  176  IV.  1.  EXPERIMENTAL SECTION  General  1.1. Data acquisition and presentation  Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures, which refer to short path bulb-to-bulb (Kugelrohr) distillation, are also uncorrected. Infrared (ir) spectra were obtained on liquid films (sodium chloride plates) or solid pellets (infrared grade potassium bromide) employing a Perkin-Elmer model 1710 Fourier transform spectrometer with internal calibration.  H nmr) spectra were recorded on deuterio 1 Proton nuclear magnetic resonance ( ) solutions using a Brucker D 6 (CDC1 solutions or hexadeuteriobenzene (C ) chloroform 3 model WH-400 (400 MHz) spectrometer. Signals positions (6 values) are given in parts per million and were measured relative to those of tetramethylsilane (60), benzene (67.14) or chloroform (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 tin Sn values. In Sn and 119 proton coupling constants (Jsn..H) are given as an average of the 117 H- spin decoupling), ( H some cases, the proton assignments were supported by decoupling 1 H- homonuclear correlation spectroscopy) experiments. 1 ( nOe difference and/or COSY H These experiments were carried out using a Brucker model WH-400 spectrometer.  13 nmr) spectra were taken on Brucker models ( Carbon nuclear magnetic resonance C AC-200E (50.3 MHz), WH-400 (100.6 MHz), AMX-500 (125.8 MHz) spectrometers or a Varian model XL-300 (75.5 MHz) instrument using deuteriochioroform as solvent. Signal  177 positions (6 values) are given in parts per million and were measured relative to that of deuteriochloroform (6 77.O).86  Low resolution mass spectra were recorded on an AEI MS9/DS55SM or on a KRATOS MS5O/DS55SM spectrometer. High resolution mass spectra were recorded on a KRATOS Sn) 3 MS5O/DS55SM spectrometer. For compounds containing the trimethyistannyl (Me Sn and were made moiety, high resolution mass spectrometric measurements are based on 1 on the (M  -  45 Microanalyses were performed on a CARLO ERBA CHN ) peak. 3 CH  elemental analyzer, model 1106, by the Microanalytical Laboratory, University of British Columbia.  Ultraviolet spectra (uv) were recorded on a Perkin-Elmer Lambda 4B UV/VIS spectrometer using spectroscopic grade pentane and/or methanol as solvent. The Ama, the molar absorptivity (e) and the solvent used are reported. Optical rotatory dispersion (ORD) spectra were recorded on a Jasco model J-710 spectropolarimeter using spectroscopic grade methanol as solvent.  Gas-liquid chromatography (gic) was performed on either a Hewlett-Packard model 5880A or a Hewlett-Packard model 5890 capillary gas chromatograph, both using a flame ionization 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 column coated (0.33 tm) with HP-5 (Crosslinked 5% Ph Me silicone), respectively. Thin-layer chromatography (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 of the chromatograms was accomplished with an ultraviolet light and/or with iodine, and then by heating the chromatogram after staining with commercially available phosphoromolybdic acid in EtOH (20% w/v, Aldrich Chemical Co., Inc.) or with a solution of vanillin in a  178 41 was performed with 230-400 mesh sulfuric acid-EtOH mixture. Flash chromatography 87 was done on a Chromatotron® sffica gel (E. Merck, sffica gel 60). Radial chromatography , with Gypsum, 254 Model 7924 using 1, 2 or 4 mm thick radial plates (silica gel 60, PF 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 g 0, respectively); 2 88 -63 °C, chloroform-dry ice; -78 °C, acetone-dry ice 100 mL H CaC1 / 2 and -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 syringes were 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 (water aspirator) refer to solvent removal via a BUchi rotary evaporator at —20 Torr.  179 1.2. Solvents and reagents  89 Benzene (C6H6) All solvents used were dried and distilled using standard procedures. and dichioromethane (CH C12) were distilled from calcium hydride. Diethyl ether (Et20) and 2 tetrahydrofuran (THF) were distilled from sodium benzophenone ketyl. aforementioned solvents were distilled and used immediately.  The four  Diisopropylamine,  N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoroamide (HMPA) and triethylamine were distilled from calcium hydride. Methanol (MeOH) and ethanol (EtOH) were dried with sodium and distilled.  Petroleum ether refers to a  hydrocarbon mixture with bp 35-60 °C. All other solvents were used directly as obtained commercially.  Boron trifluoride-etherate was purified by distillation from calcium hydride under reduced pressure (60 °C/20 Torr).  Copper(l) bromide-dimethyl sulfide complex was prepared by the method described by Wuts.M Copper(I) chloride (99.995%+ or 99%+) and copper(I) cyanide (99%) were purchased from Aldrich Chemical Co., Inc., and were used without further purification.  Deuteriochloroform, ethyl chioroformate, iodomethane and methyl chioroformate were passed 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 Aldrich Chemical Co., Inc., and Organometallics Inc., respectively and were used without further purification.  180 Potassium 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 Chemical Co., Inc., or Morton Thiokol, Inc. (Alfa Products). This reagent was used without further purification.  Solutions of methyllithium (as a complex with lithium bromide) in diethyl ether, n-butyllithium in hexanes, diisobutylaluminum hydride in hexanes and trimethylaluminum in toluene were purchased from Aldrich Chemical Co., Inc., and the former two reagents were  standard. ° standardized using diphenylacetic acid as primary 9  Lithium diisopropylamide (LDA) was prepared by the addition of a solution of n-butyllithium (1 equiv) in hexanes to a solution of diisopropylamine (1 equiv) in dry tetrahydrofuran at -78 OC. The resulting colorless solution was then stirred at 0 OC for 10 mm before being used.  All other reagents are commercially available and were used without further purification.  H (pH H) 1-NH (N C 4 Aqueous ammonium chioride-ammonium hydroxide O  =  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.  181  2.  Preparation of a,B-acetvlenic esters  Preparation of methyl 4-cyclopropyl-2-butvnoate (1038  e CO M 2 103  To a cold (-20 OC), stirred solution of diisopropylamine (0.14 mL, 1.0 mmol) and propynoic acid (0.62 mL, 10 mmol) in dry THF (7.5 mL) was added a solution of n-BuLi in hexanes (14.3 mL, 21.0 mmol). After the pale yellow slurry had been stirred at -20 OC for C for 15 mm and 10 mm, dry HMPA (15 mL) was added and stirring was continued at -20 0 at -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 room 0 (50 niL) were added, the phases were 2 0 (50 mL) and Et 2 temperature for 24 h. H separated and the aqueous layer was extracted with Et20 (5 x 50 niL). The combined organic extracts were washed with H20 (100 niL) and brine (100 niL), dried (MgSO4) and concentrated. 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 a , 3 ; 111 nmr (CDC1 1 colorless oil that displayed ir (neat): 2237, 1714, 1436, 1260, 1072 cm-  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, , 50.3 MHz): 6 4.2, 8.6, 3 ; 13 OCH ) C nmr (CDC1 211, CCH2, 1= 6 Hz), 3.77 (s, 3H, 3  23.1, 52.5, 72.9, 88.2, 154.2.  0 138.0681; found: 0 1 H 8 C : Exact mass calcd. for 2  138.068 1. Anal. calcd.: C 69.54, H 7.30; found: C 69.47, H 7.35.  182 Preparation of 1,1 -dibromo-4-methyl- 1 -pentene (11428,30  114  C1 CH To a stirred solution of carbon tetrabromide (9.85 g, 29.7 mmol) in dry 2 P (15.5 g, 3 (100 mL) at room temperature was added, dropwise, a solution of Ph C1 (100 mL) over a period of 15 mm. After the resulting orange CH 59.1 mmol) in dry 2 solution had been stirred at room temperature for 5 mm, a solution of 3-methylbutanal (113) C1 (100 mL) was added CH (3.0 mL, 28 mmol, freshly distilled from MgSO4) in dry 2  dropwise over a period of 10 mm. The resulting deep brown mixture was stirred at room temperature for 1 h and was then poured into stirred n-pentane (400 mL). The resulting  slurry was filtered through a column of Florisil® (18 g) and the column was washed with n-pentane (100 mL). Concentration of the combined eluate (under an atmosphere of dry Ar) and distillation (90-100 OCI 100 Torr) of the acquired oil produced 5.03 g (74%) of the alkene ; 4 114, a colorless liquid that exhibited ir (neat): 1619, 1466, 1386, 1369, 854, 781 cm , J= 7 Hz), 1.68-1.80 (m, 1H, 2 ) 3 nmr (CDC13, 400 MHz): 8 0.92 (d, 6H, CH(Cjj  , 3 C nmr (CDC1 , .1= 7 Hz), 6.38 (t, 1H, =CH, J= 7 Hz); 13 2 , 1.98 (t, 2H, CH Cjj(CH ) 2 ) 3 79 O 1 C6H Br: 81 50.3 MHz): 6 22.2, 27.7, 41.8, 88.8, 137.8. Exact mass calcd. for Br 10 C 29.78, H 4.17; found: C 29.84, H 6 C : 2 241.9129; found: 241.9123. Anal. calcd. for Br  H 4.14.  183 Preparation of ethyl 5-methyl-2-hexynoate (104)28  t CO E 2 104  To a cold (-78  Oc),  stirred solution of 1,1-dibromo-4-methyl-1-pentene (114) (19.5 g,  0 (110 mL, 2 80.6 mmol) in dry THF (200 mL) was added a solution of MeLi in Et 167 mmol). After the resulting solution had been stirred at -78 OC for 1 h and at room temperature 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 room 3 (300 mL) was added, the phases were temperature for 1 h. Saturated aqueous NaHCO  0 (3 x 100 mL). The combined 2 separated and the aqueous layer was extracted with Et organic 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 ester H nmr ; 1 1 104 as a colorless oil that showed ir (neat): 2234, 1713, 1389, 1368, 1251 cm  CJj 2 OCH , , 400 MHz): 6 1.02 (d, 6H, CH(Cth)2, J= 7 Hz), 1.32 (t, 3H, 3 3 (CDC1 , 2.24 (d, 2H, CCH Cfl(CH3) ) , J= 7 Hz), 4.22 (q, 2H, 2 J= 7 Hz), 1.88-1.99 (m, 1H, 2 , 50.3 MHz): 6 14.0, 22.0, 27.5, 27.7, 61.7, 74.0, 88.4, 3 , J= 7 Hz); 13 2 OCH C nmr (CDC1  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.  184 Preparation of 1 -(tert-butvldimethvlsiloxv)-4-pentvne (ii6)  SiO’”N 2 t-BuMe  116  To a stirred solution of imidazole (3.70 g, 54.3 mmol) and tert-butyldimethylsilyl chloride (4.25 g, 28.2 mmol) in dry DMF (10 mL) at room temperature was added commercially available 4-pentyne-1-ol (115) (2.0 mL, 22 mmol). The resulting mixture was stirred at room temperature for 16 h. Saturated aqueous NaHCO3 (10 mL) and Et20 (10 mL) 0 2 were added, the phases were separated and the aqueous phase was extracted with Et (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 ether Et20) of the residual oil, followed by concentration of the appropriate fractions and distillation (65-90 oC/0.2 Torr) of the remaining liquid provided 4.0 g (95%) of the silyl  ; 1 1 H nmr ether 116, a colorless liquid that exhibited ir (neat): 3315, 2121, 1109, 632 cnr , 1.69 (quintet, 2H, C(CH ) ) , 0.87 (s, 9H, 3 Si(CH ) 2 ) , 400 MHz): 6 0.03 (s, 6H, 3 3 (CDC1 , 2 CH2Ca2CH2, J= 7 Hz), 1.89 (t, 1H, CH, J= 2.5 Hz), 2.24 (td, 2H, CCH , 50.3 MHz): 6 -5.4, 14.8, 3 C nmr (CDC1 J= 7, 2.5 Hz), 3.67 (t, 211, OCH2, J= 7 Hz); 13 18.2, 25.9, 31.5, 61.3, 68.2, 84.1.  3OSi (M 1 H 7 Exact mass calcd. for C  -  t-Bu):  1 C 66.60, H 11.18; found: 2 OSi: 1 C 2 141.0736; found: 141.0728. Anal. calcd. for H C 66.80, H 11.30.  185 eparation of methyl &(tert-buldimethvlsiloxv)-2-hexynoate (1O5’),32  105  To 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 mm and at -20 °C for 1 h, methyl chioroformate (2.5 mL, 32 mmol) was added and the reaction  mixture was stirred at -20 °C for 1 h and at room temperature for 1 h. Saturated aqueous 3 (25 niL) was added, the phases were separated and the aqueous phase was NaHCO 0 (2 x 25 mL). The combined organic extracts were washed with brine 2 extracted with Et (50 niL), dried (MgSO4) and concentrated. Distillation (80-100 OC/o.2 Torr) of the oil thus obtained, afforded 5.87 g (86%) of the ester 105 as a colorless oil that displayed ir (neat): , Si(CH ) 2 ) ;1 1 H nnir (CDC1 , 400 MHz): 60.07 (s, 6H, 3 3 2238, 1719, 1260, 1109, 1074 cm , 1.78 (quintet, 2H, CH2CthCH2, J= 7 Hz), 2.44 (t, 2H, CCH2, C(CH ) ) 0.90 (s, 9H, 3 , 50.3 MHz): 3 ; 1 OCH ) C nmr (CDC1 , J= 7 Hz), 3.75 (s, 3H, 3 2 J= 7 Hz), 3.68 (t, 2H, OCH 8 -5.4, 15.2, 18.2, 25.9, 30.6, 52.5, 61.1, 72.9, 89.5, 154.2. i (M+ 2 1 O 1 C 2 H S 3  -  Exact mass calcd. for  i: 3 4 O 1 C 2 H S Me): 241.1260; found: 241.1260. Anal. calcd. for 3  C 60.89 H 9.43; found: C 61.10, H 9.60.  186 eparation of methyl 6-chloro-2-hexvnoate (106  106  To a cold (-78 °C), stirred solution of commercially available 5-chloro-1-pentyne (118) 0 (26.0 mL, 2 (4.0 mL, 38 mmol) in dry THF (80 mL) was added a solution of MeLi in Et C for 10 miii and at -20 OC 39.0 mmol). After the resulting solution had been stirred at -78 0 for 1 h, methyl chioroformate (3.6 mL, 47 mmol) was added and the resulting mixture was 3 stirred at -20 OC for 1 h and at room temperature for 1 h. Saturated aqueous NaHCO (80 mL) was added, the phases were separated and the aqueous phase was extracted with 0 (2 x 40 mL). The combined organic extracts were washed with brine (50 mL), dried 2 Et (MgSO4) and concentrated. Distillation (60-80 °C/0.3 Torr) of the acquired liquid over basic alumina provided 5.24 g (87%) of the ester 106, a colorless oil that showed ir (neat): 2240, , 400 MHz): 82.04 (quintet, 2H, CH2CaCH 3 ; 1 1 H nrnr (CDC1 1718, 1262 cm , J= 7 Hz), 2 ); 3 C1, J= 7 Hz), 3.78 (s, 3H, OCH 2 , J= 7 Hz), 3.65 (t, 2H, CH 2 2.55 (t, 2H, CCH  C nmr (CDC1 3 1 , 50.3 MHz): 8 16.0, 30.2, 43.2, 52.3, 73.6, 87.4, 153.9. Exact mass 3 C1O C 52.35, 9 H 7 C : 35 160.0292; found: 160.0282. Anal. calcd. for 2 9 H 7 C : 2 calcd. for C10  H 5.65, Cl 22.08; found: C 52.42, H 5.72, Cl 21.90.  187 Preparation of methyl 6-iodo-2-hexynoate (j97)33  Me 2 CO  107  A 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. 0 (30 mL) and Et 2 H 0 (90 mL) were added to the residual material. The phases were 2 separated 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%) of the ester 107 as a colorless liquid that displayed ir (neat): 2239, 1719, 1435, 1263, 1222, H nmr (CDC1 , 400 MHz): 6 2.05 (quintet, 2H, 2 3 1078 cm ; 1 1 CthCH J= 7 Hz), CH , 2.49 (t, 2H, CCH , J= 7 Hz), 3.28 (t, 2H, =CH 2 I, J= 7 Hz), 3.75 (s, 3H, OCH 2 ); 3 l3  nmr (CDC13, 50.3 MHz): 6 4.3, 19.7, 30.9, 52.6, 73.7, 87.2, 153.9. Exact mass  calcd. for 2 10 251.9648; found: 251.9651. Anal. calcd.: C 33.36, H 3.60, I 50.35; 9 H 7 C : found: C 33.19, H 3.66, I 50.14.  188 3.  Preparation of lithium (irialkylstannvfl(cvano’)cuprates  a 35 Preparation of lithium (trimethylstannyfl(cvano)cuprate  SnCuCN]Li 3 [Me 123  To a cold (-20 °C), stirred solution of hexamethylditin (1 equiv) in dry THF (—10 niL  per mmol of hexamethylditin) was added a solution of MeLi (1 equiv) in Et20. After the pale trimethylstannyllithium had been stirred at -20 °C for 20 mm, it was yellow solution of 39  cooled to -48 OC (—5 mm) and solid CuCN (1 equiv) was added in one portion. The mixture was stirred at -48 OC for 20 mm to produce a red solution of the lithium (trimethyistannyl) (cyano)cuprate (123).  Sa 3 Preparation of lithium (trinbutvlstannvfl(cvanocuprate  SnCuCN]Li 3 [n-Bu 304  To a cold (-20 OC), stirred solution of hexa-n-butylditin (1 equiv) in dry THF (—10 niL  per mmol of hexa-n-butylditin) was added a solution of n-BuLl (1 equiv) in hexanes. After 39 had been stirred at -20 °C for 20 mm, the pale yellow solution of tri-n-butylstannyllithium it was cooled to -48 OC (—5 mm) and solid CuCN (1 equiv) was added in one portion. The mixture was stirred at -48 OC for 20 mm to produce a red solution of the lithium (tri-n-butyl stannyl)(cyano)cuprate (304).  189 4.  29 Preparation of alkvl (E’)-3-trimethylstannvl-2-alkenoates  General procedure 1 R 2 C0  R’ 1 R  —  =  R 2 C0  Sn 3 Me  89  100  SnCuCNJLi (123) (1.3-1.5 equiv) in dry 3 To a cold (-78 OC), stirred solution of [Me THF (—5 mL per mmol of the cuprate) was added dry EtOH (1.3-1.5 equiv for ethyl ester substrates) or dry MeOH (1.3-1.5 equiv for methyl ester substrates). After 5 mm, a solution of the substrate a,J3-acetylenic ester 100 (1 equiv) in dry THF (—1 niL per mmol of the ester substrate) was added dropwise over a period of 2 mm and the mixture was stirred at -78 OC for 4-8 h. Aqueous 4 C1-NH NH O H (pH  =  8) (one-half the volume of the total volume of  the reaction mixture) was added. The mixture was opened to the atmosphere, was allowed to  warm to room temperature and was stirred vigorously until the aqueous phase became deep blue. The phases were separated and the aqueous phase was extracted three times with Et 0. 2 The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography on silica gel, followed by distillation of the acquired liquid.  190 Preparation of ethyl (E-3-trimethylstannyl-2-butenoate ({37)35 jDO2Et  Sn 3 Me 137  Following general procedure 1 (p 189), commercially available ethyl 2-butynoate (101) was converted into ethyl (E)-3-trimethylstannyl-2-butenoate (137) with the following amounts 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 silica gel, 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 that ; ‘H nmr (CDC1 1 , 400 MHz): 60.17 (s, 9H, 3 exhibited ir (neat): 1714, 1604, 1177, 771 cm Sn(CH3)3, 2 Sn-H  J= 2 Hz, 3 Sn-H  , 3 Cjj J= 7 Hz), 2.37 (d, 3H, =CCH 2 OCH , 54 Hz), 1.27 (t, 3H, 3 , J= 7 Hz), 5.96 (q, 1H, =CH, J= 2 Hz, 2 50 Hz), 4.14 (q, 2H, OCH  , 50.3 MHz): 6 -10.1, 14.3, 21.4, 59.5, 127.9, 164.5, 3 C nmr (CDC1 Sn-H= 72 Hz); 13 3 168.1. Exact mass calcd. for O2Sn 15 (M H 8 C  -  Me): 263.0094; found: 263.0090. Anal.  calcd. for C 8O2Sn: C 39.04, H 6.55; found: C 38.88, H 6.59. 1 H 9  191 epation of ethyl (-3-methylstannyl-2-ntenoate ‘125)29,35  t __>,CO E 2 n Me S 3 125  Following general procedure 1 (p 189), commercially available ethyl 2-pentynoate (102) was converted into ethyl (E)-3-trimethylstannyl-2-pentenoate (125) with the following quantities 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) of the oil thus obtained, gave 10.7 g (74%) of the ester 125 as a colorless oil that showed ; 1 1 , 400 MHz): 8 0.21 (s, 9H, 3 H nmr (CDC1 ir (neat): 1718, 1598, 1179, 774 cur Sn(CH3)3, 2 JSn-H= 53 Hz), 1.05 (t, 3H, =CCH2CU3, J= 8 Hz), 1.29 (t, 3H, OCH2Ca3, , 2 J= 7 Hz), 2.89 (qd, 2H, =CCH2, J= 8, 1 Hz, 3 Sn-H= 64 Hz), 4.16 (q, 2H, OCH , 50.3 MHz): 3 C nnir (CDC1 J= 7 Hz), 5.94 (t, 1H, =CH, J= 1 Hz, 3 SnH= 74 Hz); 13 n 17 H 9 C S 2 8 -9.1, 14.1, 14.3, 27.9, 59.6, 126.9, 164.3, 174.5. Exact mass calcd. for O (M  -  Me): 277.0250; found: 277.0250. Anal. calcd. for C1OH2002Sn: C 41.28, H 6.93;  found: C 41.08, H 6.87.  192 Preparation of methyl (E)-4-cvclopropyl-3-trimethylstannvl-2-butenoate (138  e __)JCO M 2 Sn 3 Me 138  Following general procedure 1 (p 189), methyl 4-cyclopropyl-2-butynoate (103) was converted into methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138) with the following 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. Flash chromatography (180 g silica gel, 200 : 3 petroleum ether-Et20) of the crude product and distillation (80-90 OC/0.2 Torr) of the remaining oil provided 1.83 g (80%) of the ester 138, ;1 1 H nnir (CDC1 , 3 a colorless liquid that displayed ir (neat): 1719, 1594, 1172, 773 cur 400 MHz): 8 0.15-0.19 (m, 2H, cyclopropyl methylene protons), 0.23 (s, 9H, Sn(CH3)3, SnH 2  53 Hz), 0.42-0.50 (m, 211, cyclopropyl methylene protons), 0.70-0.82 (m, 1H,  , J= 7, 1 Hz, 3 2 cyclopropyl methine proton), 2.83 (dd, 2H, =CCH Sn-H= 58 Hz), , 5.99 (t, 1H, =CH, J= 1 Hz, 3 OCH ) 3.68 (s, 3H, 3 Sn-H  , 3 74 Hz); 13 C nmr (CDC1  50.3 MHz): 8 -8.6, 5.0, 11.3, 39.2, 50.8, 126.7, 164.8, 173.0. Exact mass calcd. for n (M 0 7 O C 1 H S 2  -  Me): 289.0250; found: 289.0251. Anal. calcd. for H2002Sn: 11 C  C 43.61, H 6.65; found: C 43.68, H 6.53.  193 parution of ethyl E-5-methyl-3-ü-imethylstannyl-2-hexenoate (139  >_>JCO2Et Sn 3 Me  139  Following general procedure 1 (p 189), ethyl 5-methyl-2-hexynoate (104) was converted into ethyl (E)-5-methyl-3-trimethylstannyl-2-hexenoate (139) with the following quantities 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 silica gel, 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 that exhibited ir (neat): 1718, 1598, 1385, 1367, 1176, 771 cnr ; 1 1 H nmr (CDC1 , 400 MHz): 3  o 0.21  (s, 9H, Sn(CH3)3, 2 Sn..H= 54 Hz), 0.93 (d, 6H, CH(Ca3)2, J= 7 Hz), 1.30 (t, 3H,  , J= 7, 1 Hz, 2 OCH2Cth, J= 7 Hz), 1.67-1.78 (m, 1H, CH(CH3)2), 2.85 (dd, 2H, =CCH .1SnH 3  63 Hz), 4.17 (q, 2H, OCH , J= 7 Hz), 6.03 (t, 1H, =CH, J= 1 Hz, 2  , 50.3 MHz): 3 -9.0, 14.3, 22.5, 29.1, 43.2, 59.6, 3 C nmr (CDC1 Sn-H 76 Hz); 13 3  128.4, 164.5, 172.5. Exact mass calcd. for C11H2 O2Sn (M 1  -  Me): 305.0564; found:  305.0557. Anal. calcd. for 2 2H24O 1 C S n: C 45.18, H 7.58; found: C 44.99, H 7.57.  194 Preparation of methyl (E)-6-(tert-butyldimethylsiloxy)-3-trimethylstannyl-2-hexenoate (141)29 SiO 2 t-BuMe \_>_JCO2Me Sn 3 Me 141  Following general procedure 1 (p 189), methyl 6-Qert-butyldimethylsioxy)-2-hexynoate  (105) was converted into methyl (E)-6-Qert-butyldimethylsiloxy)-3-thmethylstannyl-2SnCuCNJL1 3 hexenoate (141) with the following amounts of reagents and solvents: [Me (123), 1.78 mmol, in THE, 9.0 mL; MeOH, 75 L (1.9 mmol); methyl 6-Qertbutyldimethylsiloxy)-2-hexynoate (105), 312 mg (1.37 mmol), in THE, 1.4 mL. In this experiment, the reaction time was 4 h. Flash chromatography (30 g silica gel, 200: 3 ) of the crude product and distillation (110-130 OC/0.6 Torr) of the ether-Et 0 petroleum 2 acquired liquid produced 446 mg (77%) of the ester 141, a colorless oil that showed , 400 MHz): 3 ; 1 1 H nmr (CDC1 ir (neat): 1720, 1597, 1256, 1169, 1098, 838, 776 cm  ,2 ) 3 , 0.21 (s, 9H, Sn(CH Si(CH3) ) 8 0.05 (s, 6H, 2 Sn-H= 54 Hz), 0.90 (s, 9H, , J= 8 Hz, 2 , 1.58-1.67 (m, 2H, 2 C(CH ) ) 3 H a 2.95 (br t, 2H, =CCH , C CH C )  , 5.98 (br s, 1H, OCH ) Sn-H= 62 Hz), 3.64 (t, 2H, OCH2, J= 6 Hz), 3.69 (s, 3H, 3 3 , 50.3 MHz): 8 -9.1, -5.7, 18.3, 25.9, 31.5, 32.8, 3 C nmr (CDC1 =CH, 3 Sn-H 73 Hz); 1  5 (M+ 1 O 1 C 3 H S iSn 50.8, 63.0, 127.2, 164.6, 173.3. Exact mass calcd. for 3  -  Me):  6 C 45.62, H 8.14; found: 4 1 C 3 H S 3 iSn: 407.1065; found: 407.1070. Anal. calcd. for O C 45.80, H 8.08.  195 29 Preparation of ethyl (Z)-3-triallcylstannyl-2-pentenoates  5.  General procedure 2  =  Et 2 CO  102  t CO E 2  124 R=Me 295 R=n-Bu  To a cold (-48 OC), stirred solution of [R3SnCuCN]Li [123 (R R  =  =  Me) or 304  (n-Bu), —1.1 equiv) in dry THF (—5 mL per mmol of the cuprate) was added dropwise  a solution of commercially available ethyl 2-pentynoate (102) (1 equiv) in dry THF (—1 mL per mmol of the ester substrate). The mixture was stirred at -48 OC, at 0 OC, and, if necessary, at room temperature. Aqueous NH4C1-NH4OH (pH =8) (one-half the volume of the total volume of the reaction mixture) was added. The mixture was opened to the atmosphere, was allowed to warm to room temperature and then was stirred until the aqueous phase became deep blue. The phases were separated and the aqueous layer was extracted three times with Et20. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The crude product was purified by sequential chromatography on silica gel and distillation.  196 eparation of ethyl (-3-thmethylstannyl-2-pentenoate (12429,35  -)=\  t CO E 2  n Me S 3  124  Following general procedure 2 (p 195), commercially available ethyl 2-pentynoate (102) was converted into ethyl (Z)-3-trimethylstannyl-2-pentenoate (124) with the following nCuCN]Li (123), 4.38 mmol, in THF, 20 mL; [Me S quantities of reagents and solvents: 3 ethyl 2-pentynoate (102), 507 mg (4.02 mmol), in THF, 4.0 mL. In this experiment, the reaction 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, a , 3 H nmr (CDC1 ; 1 1 colorless oil that displayed ir (neat): 1703, 1601, 1201, 772 cm  , J= 7 Hz), 3 400 MHz): 3 0.18 (s, 9H, Sn(CH3)3, 2 Sn-H 55 Hz), 1.04 (t, 3H, =CCH2CJj , J= 7, 1.5 Hz, S 2 n-H= 43 Hz), 3 1.29 (t, 3H, OCH2CTh, J= 7 Hz), 2.45 (qd, 2H, =CCH C nmr SnH= 120 Hz); 13 4.18 (q, 2H, OCH2, J= 7 Hz), 6.36 (t, 1H, =CH, J= 1.5 Hz, 3 (CDC13, 50.3 MHz): 6 -7.5, 13.6, 14.3, 32.9, 60.2, 126.9, 168.1, 177.1. Exact mass 7 n (M O 1 H 9 C S calcd. for 2  -  Me): 277.0250; found: 277.0244.  : C 41.28, H 6.93; found: C 41.47, H 7.09. H 20 O 1 C 02Sn  Anal. calcd. for  197 Preparation of ethyl (Z)-3-(tri-n-butylstannvfl-2-pentenoate (225)  t CO E 2  n n-Bu S 3 295  Following 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 following amounts 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, the C for 1.5 h, at 0 OC for 2.5 h and at room temperature for reaction mixture was stirred at -48 0 0.5 h. Radial chromatography (4 mm silica gel plate, 15: 1 petroleum ether-CH2C12) of the crude 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,  H nmr (CDC13, 400 MHz): 6 0.86 (t, 9H, J= 7.5 Hz), 0.90-0.97 (m, 6H), ;1 1 876 cur 1.02 (t, 3H, =CCH2CIL3, .1= 7.5 Hz), 1.22-1.33 (m, 9H includes OCH2Cth: t centered at  , J= 7.5, 1.5 Hz), 4.16 (q, 2 1.26, 3H, J= 7 Hz), 1.35-1.55 (m, 6H), 2.40 (qd, 2H, =CCH JSn-H= 109 Hz); irradiation at 6 1.02 , J= 7 Hz), 6.36 (t, 1H, =CH, J= 1.5 Hz, 3 2 2H, OCH Sn-H= 39 Hz); irradiation at 6 1.26 simplified simplified the qd at 62.40 to a d (J= 1.5 Hz, J3 C nmr (CDC13, the q at 64.16 to a s; irradiation at 6 2.40 simplified the t at 6 1.02 to a s; 13  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. n (M n-Bu): 361.1191; found: 361.1190. Anal. calcd. 5 19 C 2 H Exact mass calcd. for O2S -  for C 9H38O2Sn: C 54.70, H 9.18; found: C 54.72, H 9.09. 1  198 6.  Preparation of allcvl (Z)-2.3-bis(trimethvlstannvl)-2-alkenoates 33  General procedure 3 Sn 3 Me  1 R El  R 2 C0 1 R  100  3 SnMe  __.)—<C0 R 2 263  To a stirred solution of the substrate aj3-acetylenic ester 100 (1 equiv) in dry THF (—15 mL per mmol of the ester) was added hexamethylditin (1 equiv) followed by Pd(PPh 4 ) 3 (—2 mol %) and the mixture was stirred under reflux for 6 h. Concentration of the reaction mixture, followed by flash chromatography of the acquired deep brown liquid on silica gel, concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) provided the alkyl (Z)-2,3-bis(trimethylstannyl)-2-alkenoate 263.  Preparation of methyl (Z)-23-bis(trimethylstannyl’)-6-iodo-2-hexenoate (271) Sn 3 Me  3 SnMe  Me 2 CO 271  Following general procedure 3, methyl 6-iodo-2-hexynoate (107) was converted into methyl (Z)-2,3-bis(trimethylstannyl)-6-iodo-2-hexenoate (271) with the following quantities of reagents and solvents: methyl 6-iodo-2-hexynoate (107), 5.55 g (22.0 mmol), in THF, 300 mL; hexamethylditin, 4.6 mL (22 mmol); 4 Pd(PPh3) 536 mg (464 tmol). Flash ,  199  chromatography (450 g silica gel, 20: 1 petroleum ether-Et20) of the obtained deep brown liquid, concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) provided 8.70 g (68%) of the ester 271 as a colorless oil that exhibited ir (neat): , ) 3 , 400 MHz): 8 0.215 (s, 9H, Sn(CH 3 ; 1 1 H nmr (CDC1 1703, 1191, 770 cnr Sn(CH ) 3, S 2 nH= 51 Hz), 1.88 (quintet, 2H, SnH= 54 Hz), 0.22 (s, 9H, 3 2 Ij 1= 8 Hz), 2.39 (t, 2H, CH CH C 2 ,  ,J 2 CCH  8 Hz, 3 Sn-H  55 Hz), 3.13 Ct, 2H,  , 50.3 MHz): 8 -6.7, -6.6, 5.6, 33.8, 3 ; 13 OCH ) C nmr (CDC1 I, J= 8 Hz), 3.68 (s, 3H, 3 2 CH n2 IO 2 (M 1 C 4 H S 41.9, 51.2, 151.0, 162.8, 172.1. Exact mass calcd. for 2  -  Me):  3 C 26.94, H 4.70, I 21.89; 1 C I 7 O2Sn2: 566.8867; found: 566.8865. Anal. calcd. for H2 found: C 27.19, H 4.87, I 21.73.  Preparation of methyl (Z)-2.3-bisftrimethvlstannvD-7-bromo-2-heptenoate (272’ Sn 3 Me  3 SnMe  272  b (270) was 35 Following general procedure 3 (p 198), methyl 7bromo2heptynoate converted into methyl (Z)-2,3-bis(trimethylstannyl)-7-bromo-2-heptenoate (272) with the following amounts of reagents and solvents: methyl 7-bromo-2-heptynoate (270), 6.01 g , 630 mg 4 ) 3 (27.4 mmol), in THF, 300 mL; hexamethylditin, 6.0 mL (29 mmol); Pd(PPh (545 Itmol). Flash chromatography (450 g silica gel, 20: 1 petroleum ether-Et20) of the  obtained deep brown liquid, concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) yielded 13.6 g (9 1%) of the ester 272, a colorless liquid that H nmr (CDC1 , 400 MHz): 6 0.22 (s, 18H, 3 ; 1 1 showed ir (neat): 1704, 1191, 771 cnr  200 Sn(CH3)3, 2 Sn-H= 53 Hz), 1.45-1.55 (m, 2H, CH2Cj2CH2), 1.84 (quintet, 2H, , J= 7 Hz 3 2 jj J= 7 Hz), 2.34 (t, 2H, =CCH C 2 CH C H, Sn-H= 56 Hz), 3.39 (t, 2H, , 50.3 MHz): 8 -6.8, -6.7, 28.3, 3 ; 13 OCH ) C nmr (CDC1 Br, J= 7 Hz), 3.69 (s, 3H, 3 2 CH 3 19 C 7 6 H2 32.3, 33.6, 39.8, 51.0, 149.7, 164.4, 172.1. Exact mass calcd. for BrO2Sn2 (M  -  Me): 532.9161; found: 532.9159. Anal. calcd. for C 4H29BrO2Sn2: C 30.76, 1  H 5.35, Br 14.62; found: C 30.87, H 5.35, Br 14.50.  7.  33 Preparation of alkvl 2-trimethylstannvl- 1-cvcloalkenecarboxylates  General procedure 4 Sn 3 Me  3 SnMe  3 SnMe  R 2 ÷/__1>_<CO  R 2 CO  269  267 X=Brorl,R=Me n  =  1,2 or 3  To a cold (-98 OC), stirred solution of the substrate alkyl (Z)-2,3-bis(trimethylstannyl)-2alkenoate 267 (1 equiv) in dry THF (—10 mL per mmol of the ester) was added dry HMPA 0 (—1.1 equiv). After the resulting yellow solution 2 (—2 equiv) and a solution of MeLi in Et H (pH C1-NH 4 NH had been stirred at -98 OC for 1 h, aqueous O  =  8) (—2 niL per mmol of  the ester) and Et20 (—20 niL per mmol of the ester) were added. The phases were separated and the organic phase was washed with brine, dried (MgSO4) and concentrated. Chromatography of the remaining oil on silica gel, followed by concentration of the appropriate fractions and distillation of the oil thus obtained, afforded the alkyl 2trimethylstannyl-1-cycloalkenecarboxylate 269.  201 eparation of methyl 2-thmethylstannyl- 1 -cyclopentenecarboxylate (258)  258  Following general procedure 4 (p 200), methyl (Z)-2,3-bis(trimethylstannyl)-6-iodo-2hexenoate (271) was converted into methyl 2-trimethylstannyl-1-cyclopentenecarboxylate (258) with the following quantities of reagents and solvents: methyl (Z)-2,3bis(trimethylstannyl)-6-iodo-2-hexenoate (271), 4.93 g (8.51 mmol), in THF, 110 mL; HMPA, 3.0 mL (17 mmol); MeLi, 6.50 mL (9.75 mmol). Radial chromatography (4 mm silica gel plate, 7 : 1 petroleum ether-CH2C12) of the crude product and distillation  (5575 OC/0.3 Torr) of the acquired liquid provided 2.07 g (84%) of the ester 258 as a colorless oil that displayed ir (neat): 1704, 1592, 1320, 1260, 767 cur ; 1 1 H nmr (CDC1 , 3  400 MHz): 8 0.15 (s, 9H, 3 Sn(CH S , ) 2 n-H= 55 Hz), 1.88 (quintet, 2H, CH2CthCH2, , 3 J= 7 Hz), 2.59 (t, 4H, =CCH2, J= 7 Hz), 3.69 (s, 3H, OCH3); 13 C nmr (CDC1 50.3 MHz): 8 -8.6, 24.3, 33.3, 41.1, 51.2, 143.4, 166.6, 166.7. Exact mass calcd. for 15 (M H 9 C O2Sn  -  Me): 275.0095; found: 275.0092. Anal. calcd. for 1 O C 8 O2Sn: H  C 41.57, H 6.28; found: C 41.84, H 6.40.  202 eparaüon of methyl 2-ffimethvlstannyl- 1 -cyclohexenecarboxylate (259) 3 SnMe e CO M 2 259  Following general procedure 4 (p 200), methyl (Z)-2,3-bis(trimethylstannyl)-7-bromo2-heptenoate (272) was converted into methyl 2-trimethylstannyl- 1-cyclohexenecarboxylate (259) with the following amounts of reagents and solvents: methyl (Z)-2,3-bis(trimethylstannyl)-7-bromo-2-heptenoate (272), 12.7 g (23.2 mmol), in THF, 250 mL; HMPA, 8.0 mL (46 mmol); MeLi, 20 niL (26 mmol). Flash chromatography (300 g silica gel, 200: 3 petroleum ether-Et20) of the crude product and distillation (70-90 OC/0.3 Torr) of the acquired liquid afforded 5.81 g (83%) of the ester 259, a colorless liquid that exhibited , 400 MHz): 3 0.09 (s, 9H, 3 H nmr (CDC1 ; 1 1 ir (neat): 1699, 1593, 1276, 1252, 768 cnr Sn(CH3)3, 2 Sn-H  54 Hz), 1.51-1.69 (m, 4H, CH2CthCthCH2), 2.29-2.45 (m, 4H,  (CDC1 50.3 MHz): 3 -7.4, 22.2, 22.8, 26.5, , C nmr 3 ; 13 OCH ) =CCH2), 3.70 (s, 3H, 3 n (M Me): 289.0251; 0 7 O C 1 H S 34.0, 51.7, 135.9, 163.4, 169.2. Exact mass calcd. for 2 -  found: 289.0244. Anal. calcd. for C11H2002Sn: C 43.61, H 6.65; found: C 43.59, H 6.66.  203 8.  Preparation of alkvlating agents  8 Preparation of alkvl (Z)-3-trimethvlstannyl-3-a1kenoates  General procedure 5  1 R  R2 2 (CO  3 SnMe  90  To a cold (-78 OC), stirred solution of LDA (—2.3 equiv) in dry THE (—4-10 mL per mmol of the LDA) was added dropwise a solution of aikyl (E)-3-trimethylstannyl-2-alkenoate (1 equiv) in dry THF (—1 mL per mmol of the alkenoate) over a period of 5 mm. The resulting yellow solution was stirred at -78 °C for 30 mm and at 0 °C for 1 h. After the reaction mixture had been cooled to -78 OC (—5 mm), it was transferred via cannulation to a 0 2 vigorously stirred, cold (-98 °C) solution of glacial acetic acid (—10 equiv) in dry Et (—10 mL per mmol of the alkenoate).  The mixture was allowed to warm to room  3 was added. The phases were separated and the temperature, and saturated aqueous NaHCO 0. The combined organic extracts were 2 aqueous layer was extracted three times with Et washed with brine, dried (MgSO4) and concentrated. Distillation of the remaining oil afforded the alkyl (Z)-3-irimethylstannyl-3-alkenoate.  204 Ppation of ethyl  -3-thmethylsnnyl-3-pentenoate (156)  t CO E 2 3 SnMe 156  Following general procedure 5 (p 203), ethyl (E)-3-trimethylstannyl-2-pentenoate (125) was converted into ethyl (Z)-3-trimethylstannyl-3-pentenoate (156) with the following amounts of reagents and solvents: LDA, 42.8 mmol, in THF, 180 mL; ethyl (E)-3trimethylstannyl-2-pentenoate (125), 5.40 g (18.6 mmol), in THF, 18 mL; HOAc, 11 niL (190 mmol), in Et20, 180 mL. Distillation (40-60 °C/0.4 Torr) of the acquired oil provided 5.25 g (97%) of the ester 156, a colorless liquid that displayed ir (neat): 1734, 1165, , 400 MHz): 6 0.20 (s, 9H, Sn(CH3)3, 2 3 771 cm ; 1 1 H nmr (CDC1 SnH= 53 Hz), , J= 7, 1 Hz), 3.21 (br signal, 3 1.26 (t, 3H, OCH2Cjb, J= 7 Hz), 1.77 (dt, 3H, =CCH 2H,  , W1/2 3 Hz, 3 2 CCH Sn-H  =CH, J= 7, 1 Hz, 3 Sn..H  52 Hz), 4.12 (q, 2H, OCH2, J= 7 Hz), 6.16 (qt, 1H,  , 50.3 MHz): 6 -8.3, 14.2, 19.6, 45.1, 3 C nmr (CDC1 130 Hz); 13  n (M Me): 277.0250; found: 17 H 9 C S 2 60.5, 137.3, 138.4, 173.0. Exact mass calcd. for O -  0 C 41.28, H 6.93; found: C 41.40, H 7.06. O 1 C 2 H S n: 277.0242. Anal. calcd. for 2  205 Preparation of methyl (Z)-4-cyclopropyl-3-trimethvlstannvl-3-butenoate (157)2 e ’CO 2 y’%( M  157  Following general procedure 5 (p 203), methyl (E)-4-cyclopropyl-3-trimethylstannyl-2butenoate (138) was converted into methyl (Z)-4-cyclopropyl-3-thmethylstannyl-3-butenoate (157) with the following quantities of reagents and solvents: LDA, 11.4 mmol, in THF, 50 mL; methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate  (138), 1.50 g  (4.95 mmol), in THF, 5.0 mL; HOAc, 3.0 mL (52 mmol), in Et20, 50 mL. Distillation  (57-80 OC/0.6 Torr) of the oil thus obtained, afforded 1.31 g (87%) of the ester 157 as a , 3 H nmr (CDC1 ;1 1 colorless liquid that exhibited it (neat): 1737, 1619, 1196, 1163, 770 cm ,2 3 400 MHz): 6 0.22 (s, 9H, Sn(CH3) Sn-H= 54 Hz), 0.38-0.43 (m, 2H, cyclopropyl methylene protons), 0.72-0.78 (m, 2H, cyclopropyl methylene protons), 1.27-1.36 (m, 1H, , J= 1 Hz, 3 2 cyclopropyl methine proton), 3.18 (d, 2H, =CCH SnH= 52 Hz), 3.67 (s, 3H, , 5.43 (br d, 1H, =CH, J= 9 Hz, 3 OCH ) 3 Sn-H  , 50.3 MHz): 3 C nmr (CDC1 127 Hz); 13  0 7 n O C 1 H S 6 -8.2, 7.3, 15.1, 44.7, 51.6, 133.3, 148.2, 173.3. Exact mass calcd. for 2 (M  -  1 C 43.61, H 6.65; 0 n: O 1 C 2 H S Me): 289.0250; found: 289.0258. Anal. calcd. for 2  found: C 43.88, H 6.74.  206 Preparation of ethyl (Z)-5-methyl-3-trimethvlstannyl-3-hexenoate (B8)’ 48  Et 2 %(‘CO SnMe  158  To a cold (-78 OC), stirred solution of potassium bis(trimethylsilyl)amide (1.35g. 6.77 mmol) in dry THF (9.0 mL) was added HMPA (1.2 niL, 6.9 mmol). After the reaction mixture had been stirred at -78 OC for 5 mm, a solution of ethyl (E)-5-methyl-3trimethylstannyl-2-hexenoate (139) (791 mg, 2.48 mmol) in dry THF (2.5 niL) was added dropwise over a period of 5 mm. The resulting yellow solution was stirred at -78 OC for  45 mm and at -48 0 C for 5.5 h. After the reaction mixture had been cooled to -78 °C (—5 mm), and then it was transferred via cannulation to a vigorously stirred, cold (-98 0 C) solution of glacial acetic acid (1.5 mL, 26 mmol) in dry Et 0 (11 niL). The mixture was 2 allowed to warm to room temperature, and saturated aqueous NaHCO 3 (13 mL) was added. The phases were separated and the aqueous phase was extracted with Et 0 (3 x 10 niL). The 2 combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated. Radial chromatography (2 mm silica gel plate, 7: 1 petroleum 2 C1 ether-CH ) of the crude product, followed by concentration of the appropriate fractions and distillation (65-85 °C/0.6 Torr) of the acquired oil gave 651 mg (82%) of the ester 158 as a colorless oil ; 1 1 H nmr (CDC1 that showed ir (neat): 1734, 1369, 1179, 770 cm, 400 MHz): 5 0.18 Cs, 3 9H, 3 Sn(CH3) S , , J= 7 Hz), 1.26 (t, 3H, 2 ) 3 2 n-H= 56 Hz), 0.97 (d, 6H, CH(C1j Cjj J= 7 Hz), 2.16-2.26 (m, 1H, Cjj(CH 2 OCH , 3 ), 3.15 (d, 2H, =CCH 2 ) 3 , J= 1 Hz, 2 ’Sn-H= 3  Sn-H 3  53 Hz), 4.12 (q, 2H, OCH2, J= 7 Hz), 5.83 (br d, 1H, =CH, J= 10 Hz, 131 Hz); 1 C nmr (CDC13, 50.3 MHz): 8 -7.9, 14.2, 23.1, 34.3, 44.9, 60:4,  133.1, 151.6, 173.0. Exact mass calcd. for O 11 C 2 H S 2 n (M+  -  Me): 305.0564; found:  305.0560. Anal. calcd. for O 1n: C 2 H S 2 2 C 45.18, H 7.58; found: C 45.39, H 7.58. 4  207 eparation of ethyl (-3-methylstannyl-3-ntenoate (1S9)  E, 2 L-CO 3 SnMe 159  To a cold (-78 OC), stirred solution of LDA (25.6 mmol) in dry THF (170 mL) was added HMPA (4.5 mL, 26 mmol). After the reaction mixture had been stirred at -78 OC for 5 mm, a solution of ethyl (Z)-3-trimethylstannyl-2-pentenoate (124) (4.90 g, 16.8 mmol) in dry THF (20 mL) was added dropwise over a period of 5 mm. The resulting yellow solution was stirred at -78 °C for 30 mm and at 0 0 C for 1 h. After the reaction mixture had been  cooled to -78 °C (-5 mm), it was transferred via cannulation to a vigorously stirred, cold (-98 °C) solution of glacial acetic acid (9.6 mL, 170 mmol) in dry Et20 (170 mL). The mixture was allowed to warm to room temperature, and saturated aqueous NaHCO3 (200 mL) was added. The phases were separated and the aqueous phase was extracted with Et20 (3 x 100 mL). The combined organic extracts were washed with brine (250 mL), dried (MgSO4) and concentrated. Distillation (50-70 °C/0.6 Torr) of the acquired liquid afforded 4.34g (89%) of the ester 159, a colorless oil that displayed ir (neat): 1733, 1179, 769 cm ; 1  Sn(CH S , ) nmr (CDC1 , 400 MHz): 8 0.12 (s, 9H, 3 3 2 n.H= 56 Hz), 1.25 (t, 3H, , J= 7 Hz), 3.29 (br signal, 2H, =CCH 3 , 2 OCH2Cth, J= 7 Hz), 1.74 (br d, 3H, =CCH w1/2=  4 Hz, 3 Sn-H  54 Hz), 4.13 (q, 2H, OCH , J= 7 Hz), 5.85 (qt, 1H, =CH, 2  J= 7,2 Hz, 3 C nmr (CDC13, 50.3 MHz): 8. -8.8, 14.2, 14.6, 37.2, 60.6, sn-w 73 Hz); 13 137.1, 137.5, 172.7. Exact mass calcd. for C9H17O2Sn (M  -  Me): 277.0250; found:  277.0247. Anal. calcd. for 0 O 1 C 0 2Sn: H2 C 41.28, H 6.93; found: C 41.48, H 6.97.  208 Preparation of (Z)- or (E)-3-trimethylstannvl-3-alken-1-ols  General procedure 6  R’’”°  3 SnMe 194 or 191  To a cold (-78 OC), stirred solution of alkyl (Z)- or (E)-3-trimethylstannyl-3-allcenoate 0 (—10 mL per mmol of the alkenoate) was added a 1.0 M solution of 2 (1 equiv) in dry Et i-Bu2AIH in hexanes (—2.5 equiv) and the resulting clear solution was stirred at -78 °C for H (pH C1-NH 4 NH C for 1 h. Aqueous O 1 h and at 0 0  =  8) (—0.25 mL per mmol of the  alkenoate) was added and the white slurry was allowed to stir at room temperature for 1 h. Solid MgSO4 (—50 mg per mmol of the aikenoate) was added and the slurry was filtered through a column of Florisil®. The column was washed with Et20. Concentration of the combined eluate and distillation of the residual oil afforded the alkyl (Z)- or (E)-3trimethylstannyl-3-alken- 1-ol.  209 Preparation of (Z)-3-trimethvlstannvl-3-penten- 1-01 (196  3 SnMe 196  Following general procedure 6 (p 208), ethyl (Z)-3-irimethylstannyl-3-pentenoate (156) was converted into (Z)-3-trimethylstannyl-3-penten-1-ol (1%) with the following amounts of reagents and solvents: ethyl (Z)-3-trimethylstannyl-3-pentenoate (156), 5.25 g (18.0 mmol), in Et 0, 180 mL; i-Bu2AIH, 45 mL (45 mmol); Florisil®, 10 g; Et 2 0 for elution, 3 x 80 mL. 2 Distillation (50-60 OC/0.6 Torr) of the crude product provided 4.47 g (99%) of the alcohol  ; 1 196, a colorless liquid that displayed ir (neat): 3329 (br), 1623, 1042, 770, 526 cnr Sn(CH S , ) nmr (CDC1 , 400 MHz): 6 0.20 (s, 9H, 3 3 2 n-H  52 Hz), 1.37 (t, 1H,  OJJ., J= 7 Hz, exchanges with D20), 1.75 (dt, 3H, =CCjj, J= 7, 1 Hz), 2.45 (td, 2H, 2 CH 0 exchange: t, 2 =CCth, J= 7, 1 Hz, 3 Sn-H= 56 Hz), 3.56 (q, 2H, CjOH, J= 7 Hz; after D , 50.3 MHz): 3 J= 7 Hz), 6.17 (qt, 1H, =CH, J 7, 1 Hz, 3 C nmr (CDC1 Sn-H 137 Hz); 3 15 (M H 7 C 8 -8.5, 19.7, 43.1, 61.7, 138.2, 140.7. Exact mass calcd. for OSn  -  Me):  235.0144; found: 235.0150. Anal. calcd. for C8H18OSn: C 38.60, H 7.29; found: C 38.39, H 7.31.  210 Preparation of (Z)-4-cyclopropvl-3-trimethvlstannvl-3-buten- 1-01 (199)  199  Following general procedure 6(p 208), methyl (Z)-4-cyclopropyl-3-trimethylstannyl-3butenoate (157) was converted into (Z)-4-cyclopropyl-3-trimethylstannyl-3-buten- 1-01 (199) with the following quantities of reagents and solvents: methyl (Z)-4-cyclopropyl-3trimethylstannyl-3-butenoate (157), 1.17 g (3.86 mmol), in Et 0, 40 mL; i-Bu2AIH, 10 mL 2 (10 mmol); Florisil®, 15 g; Et20 for elution, 3 x 50 mL. Distillation (60-85 °CI0.6 Torr) of the crude oil provided 1.04 g (98%) of the alcohol 199 as a colorless oil that exhibited ir (neat): 3344 (br), 1615, 1047, 769, 525 cm ; 1 1 H nmr (CDC1 , 400 MHz): 60.23 (s, 9H, 3 Sn(CH3)3, 2 Sn-H  53 Hz), 0.38-0.43 (m, 2H, cyclopropyl methylene protons),  0.72-0.78 (m, 2H, cyclopropyl methylene protons), 1.25-1.35 (m, 1H, cyclopropyl methine proton), 1.40 (t, 1H, CH Ojj, J= 6 Hz, exchanges with D20), 2.44 (td, 2H, =CCH2, 2 0 exchange: t, 2 J= 6, 1 Hz, 3 OH, J= 6 Hz; after D 2 Sn..H= 56 Hz), 3.55 (q, 2H, CIL  J= 6 Hz), 5.48 (br d, 1H, =CH, J= 9 Hz, 3 C nmr (CDC1 , 50.3 MHz): 3 SnH= 134 Hz); 13 6 -5.9, 7.4, 15.2, 43.0, 61.8, 136.8, 148.4. Exact mass calcd. for OSn 17 (M H 9 C 261.0301; found: 261.0295.  C 43.86, H 7.37.  -  Me):  Anal. calcd. for 20 oH C 43.68, H 7.33; found: 1 C OSn:  211 Preparation of (Z’-5-methvl-3-trimethylstannyl-3-hexen- 1-ol (202 y%OH  202  Following general procedure 6 (p 208), ethyl (Z)-5-methyl-3-trimethylstannyl-3hexenoate (158) was converted into (Z)-5-methyl-3-trimethylstannyl-3-hexen-1-ol (202) with the following amounts of reagents and solvents: ethyl (Z)-5-methyl-3-trimethylstannyl3-hexenoate (158), 5.38 g (16.9 mmol), in Et20, 150 mL; i-Bu2AIH, 40 mL (40 mmol); Florisil®, 15 g; Et 0 for elution, 3 x 70 mL. Distillation (65-85 °CI0.6 Torr) of the acquired 2 oil gave 4.51 g (97%) of the alcohol 202, a colorless liquid that showed ir (neat): 3326 (br), , ) 3 , 400 MHz): 8 0.21 (s, 9H, Sn(CH 3 H nmr (CDC1 1618, 1048, 769 cm; 1 1 Jj, J= 7 Hz, CH O SnH= 52 Hz), 1.00 (d, 6H, CH(CTh)2, J= 7 Hz), 1.38 (t, 1H, 2 2 , J= 6 Hz, 2 ), 2.42 (t, 2H, =CCH 2 ) 3 0), 2.17-2.27 (m, 1H, Cjj(CH 2 exchanges with D Sn-H= 55 Hz), 3.55 (q, 2H, Cjj0H, J= 6 Hz; after 1)20 exchange: t, J= 6 Hz), 5.92 (d, 3 , 50.3 MHz): 8 -8.2, 23.4, 34.5, 3 C nmr (CDC1 1H, =CH, 1= 10 Hz, 3 SnH= 137 Hz); 13 9OSn (M 1 H 9 42.7, 61.6, 136.4, 152.2. Exact mass calcd. for C  -  Me): 263.0459; found:  263.0453. Anal. calcd. for C OH22OSn: C 43.36, H 8.01; found: C 43.56, H 8.07. 1  212 Preparation of (E)-3-trimethvlstannvl-3-penten- 1-01(191)  LOH  •  3 SnMe 191  Following general procedure 6 (p 208), ethyl (E)-3-trimethylstannyl-3-pentenoate (159) was converted into (E)-3-trimethylstannyl-3-penten-1-ol (191) with the following quantities of reagents and solvents: ethyl (E)-3-trimethylstannyl-3-pentenoate (159), 4.34 g 0 for 2 A1H, 37 mL (37 mmol); Florisil®, 27 g; Et 2 0, 150 mL; i-Bu 2 (14.9 mmol), in Et elution, 3 x 125 mL. Distillation (60-80 OC/0.6 Torr) of the acquired oil provided 3.44 g (93%) of the alcohol 191 as a colorless liquid that displayed ir (neat): 3363 (br), 1614, 1044, H nnir (CDC1 , 400 MHz): 3 0.12 (s, 9H, Sn(CH3)3, 2 3 ; 1 1 766, 525 cnr Sn.H= 52 Hz), , J= 7 Hz), 3 ), 1.73 (d, 3H, =CCH D 0 1.48 (t, 1H, CH OIj, J= 7 Hz, exchanges with 2 2 , J= 7, 1 Hz, 3 2 2.57 (td, 2H, =CCH Sn-H 61 Hz), 3.62 (q, 2H, CthOH, J= 7 Hz; after 0 exchange: t, J= 7 Hz), 5.85 (qt, 1H, =CH, J= 7, 1 Hz, 3 2 D SnH= 77 Hz); C nmr , 50.3 MHz): 5 -9.3, 14.5, 35.3, 62.0, 137.8, 140.5. 3 (CDC1 5 (M OSn 1 H 7 C  -  Exact mass calcd. for  18 C 38.60, H 8 C Me): 235.0144; found: 235.0150. Anal. caled. for OSn:  H 7.29; found: C 38.68, H 7.29.  213 Preparation of (1)- or (E-3-iodo-3-alken-1-ols  General procedure 7  R’(’.  195 or 192  C1 (—10 mL per mmoi of the substrate CH To a stirred solution of 12 (—1.1 equiv) in dry 2 3-alken-1-ol) at room temperature was added a solution of the (Z)- or (E)-3-trimethylstannylC1 (—1 mL per mmol of the 3-allcen-1-ol) and the mixture CH 3-alken-1-ol (1 equiv) in dry 2 was stirred at room temperature for 15 miii. Aqueous 1.0 M sodium thiosulfate (—1 mL per mmol of the 3-aiken-1-ol) was added, the phases were separated and the aqueous layer was extracted three times with CH C12. The combined organic extracts were dried (MgSO4) and 2 concentrated. Flash chromatography of the crude product on silica gel, concentration of the appropriate fractions and distillation of the residual oil afforded the (Z)- or (E)-3-iodo-3alken-1 -ol  214 Preparation of (Z)-3-iodo-3-penten- 1-01 (197)  197  Following general procedure 7 (p 213), (Z)-3-trimethylstannyl-3-penten-1-ol (196) was converted into (Z)-3-iodo-3-penten-1-ol (197) with the following amounts of reagents and solvents: ‘2, 4.81 g, (19.0 mmol), in 2 C1 180 niL; (Z)-3-trimethylstannyl-3-penten-1-ol CH ,  (196), 4.47 g (18.0 mmol), in 2 CI 18 niL. Flash chromatography (120 g silica gel, CH , 3: 1 petroleum ether-Et20) of the crude product and distillation (50-70 OCIO.6 Torr) of the acquired oil afforded 3.64 g (96%) of the alcohol 197, a colorless liquid that displayed ir (neat): 3351 (br), 1650, 1045, 797 cm ; 1 1 , 400 MHz): 8 1.43 (br signal, 3 H nmr (CDC1 1H, 2 CH O jj, w1/2= 12 Hz, exchanges with D20), 1.80 (d, 3H, =CCH3, J= 7 Hz), 2.74 (t, 2H, =CCH , J= 7 Hz), 3.76 (q, 2H, H2OH, J= 7 Hz; after D 2 0 exchange: t, 2  J= 7 Hz), 5.73 (q, 1H, =CH, J= 7 Hz); 13 , 75.5 MHz): 8 22.3, 47.9, 61.0, 3 C nmr (CDC1 105.9, 133.0. Exact mass calcd. for 5 C 1 9 H 0: 211.9699; found: 211.9702. Anal. calcd.: C 28.32, H 4.28; found: C 28.33, H 4.31.  215 Preparation of (Z)-4-cvclopropyl-3-iodo-3-buten- 1-01 (20ffi  V 200  Following general procedure 7(p 213), (2)-4-cyclopropyl-3-trimethylstannyl-3-buten-1ol (199) was converted into (Z)-4-cyclopropyl-3-iodo-3-buten-1-ol (200) with the following C1 3.0 mL; (Z)-4CH , quantities of reagents and solvents: 12, 82 mg, (0.32 mmol), in 2 C1 CH , cyclopropyl-3-trimethylstannyl-3-buten- 1-ol (199), 78 mg (0.28 mmol), in 2  0.5 mL. Flash chromatography (5 g silica gel, 3: 1 petroleum ether-Et20) of the crude product and distillation (55-75 OC/0.6 Torr) of the obtained liquid gave 60 mg (89%) of the ; 1 alcohol 200 as a colorless oil that exhibited ir (neat): 3357 (br), 1646, 1049, 811 cnr , 400 MHz): 6 0.47-0.53 (m, 2H, cyclopropyl methylene protons), 3 nmr (CDC1 0.8 1-0.87 (m, 2H, cyclopropyl methylene protons), 1.40 (br signal, 1H, CH2Oa, w112= 12 Hz, exchanges with D20), 1.59-1.69 (m, 1H, cyclopropyl methine proton),  0 2 , J= 6, 1 Hz), 3.54 (br signal, 2H, CthOH, wrn= 14 Hz; after D 2 2.67 (td, 2H, =CCH  , 50.3 MHz): 8 6.9, 3 C nmr (CDC1 exchange: t, J= 6 Hz), 5.12 (br d, 1H, =CH, J= 9 Hz); 13 18.5, 47.7, 61.0, 99.9, 142.0.  11 237.9855; found: H 7 C Exact mass calcd. for 10:  237.9858. Anal. calcd.: C 35.32, H 4.66, I 53.31; found: C 35.37, H 4.75, I 53.10.  216 Preparation of (Z)-3-iodo-5-methyl-3-hexen-1-ol (203 yOH  203  Following general procedure 7 (p 213), (Z)-5-methyl-3-trimethylstannyl-3-hexen-1-ol (202) was converted into (Z)-3-iodo-5-methyl-3-hexen-1-ol (203) with the following C1 150 mL; (Z)-5CH , amounts of reagents and solvents: 12, 4.40 g, (17.3 mmol), in 2  C1 20 mL. CH , methyl-3-trimethylstannyl-3-hexen-1-ol (202), 4.51 g (16.3 mmol), in 2 Flash chromatography (120 g silica gel, 3: 1 petroleum ether-Et20) of the crude product and distillation (50-70 OC/O.6 Torr) of the acquired oil afforded 3.52 g (90%) of the alcohol 203, ; 1 1 H nmr (CDC1 , 3 a colorless liquid that showed ir (neat): 3346 (br), 1642, 1465, 1049 cm  400 MHz): 6 1.02 (d, 611, CH(Cjj) , J= 7 Hz), 1.34 (t, 1H, CH 2 Ojj, J= 7 Hz, exchanges 2 with D 0), 2.48-2.61 (m, 1H, Cjj(CH 2 ), 2.68 (td, 2H, =CCH 2 ) 3 , J= 7, 1 Hz), 3.75 (q, 2 2H, CthOH, J= 7 Hz; after 1)20 exchange: t, J= 7 Hz), 5.45 (dt, 1H, =CH, J= 7, 1 Hz);  nmr (CDC1 , 50.3 MHz): 8 21.6, 36.2, 47.8, 61.0, 101.1, 144.9. Exact mass calcd. 3 for C 310: 240.0012; found: 240.0012. Anal. calcd.: C 35.02, H 5.46, I 52.86; found: 1 H 7  C 34.93, H 5.44, I 52.69.  217 Preparation of (E-3-iodo-3-penten-1-ol (192  L(OH 192  Following general procedure 7 (p 213), (E)-3-trimethylstannyl-3-penten-1-ol (191) was converted into (E)-3-iodo-3-penten- 1-el (192) with the following quantities of reagents and solvents: 12, 3.70 g, (14.6 mmol), in CH2C12, 140 mL; (E)-3-trimethylstannyl-3-penten-1-ol  (191), 3.44 g (13.8 mmol), in CH2C1 , 5.0 mL. Flash chromatography (150 g silica gel, 2 3: 1 petroleum ether-Et20) of the crude product and distillation (50-70 °C10.6 Torr) of the oil thus obtained yielded 2.65 g (90%) of the alcohol 192 as a colorless liquid that displayed ; 1 1 H nmr (CDC13, 400 MHz): 3 1.60-1.80 (m, 4H, Oj, ir (neat): 3333 (br), 1635, 1046 cm , 2 and =CHCj; after D20 exchange: 1.67, d, 3H, =CHCj, J= 7 Hz), 2.65 (t, 2H, =CCH 0 exchange: t, J= 6 Hz), 6.40 (q, 1H, 2 H, J= 6 Hz; after D jj O J= 6 Hz), 3.74 (q, 2H, 2 , 50.3 MHz): 8 16.6, 41.0, 61.1, 97.9, 138.7. Exact mass 3 =CH, J= 7 Hz); l3 nmr (CDC1 0: 211.9699; found: 211.9702. Anal. calcd.: C 28.32, H 4.28, I 59.85; C 1 9 H caled. for 5 found: C 28.43, H 4.35, I 59.70.  218  a 3 ,l 47 Preparation of (Z’)- or (E)-1.3-diodoalkenes and 4iodolbutvne  General procedure 8  R’%(’  98or99  155  C1 (—10 mL per mmol of the CH P (—1.1 equiv) in dry 2 3 To a stirred solution of Ph alcohol substrate) at room temperature was added 12 (—1.1 equiv), and the resulting yellow  mixture was stirred at room temperature for 10 mm. A solution of the (Z)- or (E)-3-iodo-3alken-1-ol substrate (1 equiv) or of commercially available 3-butyn-1-ol (1 equiv) in dry N (—1.1 equiv) were added. After the 3 C1 (—1 mL per mmol of the alcohol) and dry Et CH 2 resulting orange mixture had been stirred at room temperature for 4 h, it was poured into stirred n-pentane or petroleum ether. The resulting slurry was filtered through a column of Florisil® and the column was washed with n-pentane or petroleum ether. Concentration of the combined eluate (under an atmosphere of dry Ar if necessary) and distillation of the  remaining oil afforded the desired product.  219 Preparation of (Z)-3.5-diiodo-2-pentene (198  198  Following general procedure 8 (p 218), (Z)-3-iodo-3-penten-1-ol (197) was converted into (Z)-3,5-diiodo-2-pentene (198) with the following amounts of reagents and solvents: P, 1.30 g (4.96 tnmol), in 2 3 Ph C1 40 mL; 12, 1.20 g (4.73 mmol); (Z)-3-iodo-3-pentenCH , C1 4.0 mL; Et CH , N, 0.65 mL (4.7 mmol); 3 1-ol (197), 935 mg (4.41 mmol), in 2 petroleum ether, 120 mL; Florisil®, 20 g; petroleum ether for elution, 80 mL. Distillation (60-80 OC/0.6 Torr) of the acquired oil produced 1.30 g (95%) of the diiodide 198, a H nmr (CDC1 , 3 colorless liquid that displayed ir (neat): 1646, 1240, 1144, 813 cnr’; 1 400 MHz): 8 1.75 (dt, 3H, =CHCJj , J= 7, 1 Hz), 2.97 (br t, 2H, =CCH2, J= 7 Hz), 3 , 3 I, J= 7 Hz), 5.70 (qt, 1H, =CH, .1= 7, 1 Hz); 13 2 C nmr (CDC1 3.30 (t, 2H, CH : 321.8719; 2 1 8 H 5 50.3 MHz): 8 5.4, 22.1, 48.4, 107.8, 132.8. Exact mass calcd. for C found: 321.8717. Anal. calcd.: C 18.66, H 2.50; found: C 18.81, H 2.53.  Preparation of (Z)- 1 -cyclopropyl-2.4-diiodo- 1 -butene (201)  201  Following general procedure 8 (p 218), (Z)-4-cyclopropyl-3-iodo-3-buten-1-ol (200) was converted into (Z)- 1 -cyclopropyl-2,4-diiodo- 1-butene (201) with the following quantities of reagents and solvents: Ph P, 2.03 g (7.74 mmol), in 2 3 C1 50 mL; ‘2, 1.91 g CH ,  220 C1 CH , (7.53 mmol); (Z)-4-cyclopropyl-3-iodo-3-buten-1-ol (200), 1.63 g (6.85 mmol), in 2 5.0 mL; Et3N, 1.0 mL (7.2 mmol); n-pentane, 150 mL; Florisil®, 15 g; n-pentane for elution, 2 x 50 mL. Flash chromatography (80 g silica gel, n-pentane) of the concentrated eluate, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) provided 2.16 g (91%) of the diiodide 201 as a colorless oil that exhibited , 400 MHz): 6 0.47-0.53 (m, 2H, 3 ir (neat): 1641, 1243, 1182, 810 cm ; 1 4 H nmr (CDC1 cyclopropyl methylene protons), 0.80-0.87 (m, 2H, cyclopropyl methylene protons), I, 1 7 Hz), 3.28 (td, 2H, 2 1.55-1.65 (m, 1H, cyclopropyl methine proton), 2.91 (t, 2H, CH , 50.3 MHz): 65.3, 3 C nmr (CDC1 , .1=7, 1 Hz), 5.08 (dd, 1H, =CH, 1= 8, 1 Hz); 13 2 =CCH 10 347.8873; found: 347.8874. H 7 C : 2 6.9, 18.4, 48.3, 101.7, 141.9. Exact mass calcd. for 1 Anal. calcd.: C 24.16, H 2.90; found: C 24.29, H 2.95.  Preparation of (Z)- 1 .3-diiodo-5-methvl-3-hexene (204)  204  Following general procedure 8 (p 218), (Z)-3-iodo-5-methyl-3-hexen-1-ol (203) was converted into (Z)-1,3-diiodo-5-methyl-3-hexene (204) with the following amounts of P, 4.50 g (17.2 mmol), in 2 3 C1 170 mL; 12, 4.40 g CH , reagents and solvents: Ph C1 CH , (17.3 mmol); (Z)-3-iodo-5-methyl-3-hexen-1-ol (203), 3.52 g (14.7 mmol), in 2 10 mL; Et N, 2.4 mL (17 mmol); petroleum ether, 500 niL; Florisil®, 40 g; petroleum ether 3 for elution, 100 niL. Distillation (55-75 OC/0.6 Torr) of the afforded oil produced 5.06 g (99%) of the diiodide 204, a colorless liquid that showed ir (neat): 1639, 1239, 1158, ;1 1 H nmr (CDC13, 400 MHz): 8 1.02 (d, 6H, CH(Ca)2, 1=7 Hz), 2.45-2.57 (m, 845 cm  221 I, J= 7 Hz), 2 , J= 7, 1 Hz), 3.30 (t, 2H, CH 2 )2), 2.90 (td, 2H, =CCH 3 1H, Cjj(CH , 50.3 MHz): 6 5.5, 21.4, 36.1, 48.2, 3 5.40 (br d, 1H, =CH, .1= 9 Hz); 3C nmr (CDC1 12 349.9030; found: 349.9038. Anal. calcd.: H 7 C : 2 103.1, 144.8. Exact mass calcd. for 1 C 24.02, H 3.46; found: C 24.30, H 3.50.  Preparation of (E)-3.5-diiodo-2-pentene (193)  H’ 193  Following general procedure 8 (p 218), (E)-3-iodo-3-penten-1-ol (192) was converted into (E)-3,5-diiodo-2-pentene (193) with the following quantities of reagents and solvents: P, 1.77 g (6.75 mmol), in CH 3 Ph C12, 60 niL; ‘2. 1.71 g (6.74 mmol); (E)-3-iodo-3-penten2 N, 1.0 niL (7.2 mmol); petroleum 3 C1 5.0 niL; Et CH , 1-ol (192), 1.36 g (6.41 mmol), in 2 ether, 250 niL; Florisil®, 60 g; petroleum ether for elution, 200 niL.  Distillation  (48-85 OC/0.6 Torr) of the obtained oil provided 2.02 g (98%) of the diiodide 193, a , 3 ; 1 1 H nnir (CDC1 colorless liquid that displayed ir (neat): 1635, 1249, 1139, 820 cnr , J= 7Hz), 3.27 (t, 2H, 2 400 MHz): 6 1.68 (d, 3H, =CHCj, J= 7 Hz), 2.95 (t, 2H, =CCH , 50.3 MHz): 3 4.0, 16.7, 3 C nnir (CDC1 I, J= 7 Hz), 6.42 (q, 1H, =CH, J= 7 Hz); 13 2 CH 41.4, 100.1, 138.2. Exact mass caled. for C H812: 321.8719; found: 321.8717. Anal. 5 calcd.: C 18.66, H 2.50; found: C 18.77, H 2.48.  222 Preparation of 4-iodo-1-butyne (15513a  155  Following general procedure 8 (p 218), commercially available 3-butyn-1-.ol (154) was converted into 4-iodo- 1-butyne (155) with the following quantities of reagents and solvents: C1 60 mL; 12, 3.87 g (15.3 mmol); 3-butyn-1-ol (154), CH , P, 4.38 g (16.7 mmol), in 2 3 Ph N, 2.0 mL (14 mmol); n-pentane, 100 mL; 3 C1 6.0 mL; Et CH , 1.05 mL (13.9 mmcl), in 2 Florisil®, 20 g; n-pentane for elution, 60 mL. Concentration of the combined eluate (under an atmosphere of dry Ar) and distillation (65-80 C 0 /50 Torr) of the acquired oil gave 1.89 g  (76%) of the iodide 155 as a colorless liquid that displayed ir (neat): 3296, 2121, 1250, H nmr (CDC13, 400 MHz): 3 2.17 (t, 1H, CH, J= 2 Hz), 2.80 (td, 211, ; 1 1 1176, 647 cnr , 50.3 MHz): 3 0.8, 3 C nmr (CDC1 1, J= 7 Hz); 13 2 CCH2, J= 7, 2 Hz), 3.25 (t, 2H, c11 1: 179.9445; found: 179.9438. Anal. calcd.: 5 H 4 23.7, 70.2, 82.7. Exact mass calcd. for C C 26.69, H 2.80; found: C 26.49, H 2.80.  223 5.  a 3 ,l 46 Preparation of 2bromo1a1kenes  General procedure 9  362  C1 was CH A commercially available 1.0 M solution of B-Br-9-BBN (2.2 equiv) in 2 diluted with dry 2 C1 (-5 mL per mmol of the B-Br-9-BBN) and the resulting solution CH was stirred at 0 °C for 5 miii. To this cold (0 OC), stirred solution of B-Br-9-BBN in dry  C1 (—1 mL per mmol of the CH CH2C12 was added a solution of the aikyne (1 equiv) in dry 2 alkyne) dropwise over a period of 10 mm. After the reaction mixture had been stirred at 0 °C for 3 h, glacial acetic acid (—10 equiv) was added and the mixture was stirred at 0 0 C for 1 h. Aqueous 4.0 M sodium hydroxide (—20 equiv) and aqueous 30% hydrogen peroxide (-10 equiv) were added slowly at 0 °C. The resulting mixture was opened to the atmosphere  and was stirred at 0 °C for 1 h. The phases were separated and the aqueous layer was extracted twice with petroleum ether. The combined organic extracts were washed (with H20, saturated aqueous NaHCO3 and brine), dried (MgSO4) and concentrated. Flash chromatography of the acquired liquid on silica gel, followed by concentration of the appropriate fractions and distillation of the obtained oil gave the corresponding 2-bromo-1alkene.  224 Preparation of 2-bromo-4-iodo- 1-butene (148Y,13a  148  Following general procedure 9 (p 223), 4-iodo-1-butyne (155) was converted into 2-bromo-4-iodo-1-butene (148) with the following amounts of reagents and solvents: B-Br-9-BBN, 27 mL (27 mmol), in CH2C12, 125 mL; 4-iodo-1-butyne (155), 2.23 g C1 12 niL; HOAc, 7.0 mL (120 mmol); NaOH, 60 niL; H202; CH , (12.4 mmol), in 2 14 niL. Flash chromatography (80 g silica gel, petroleum ether) of the crude product and distillation (30-50 °C/0.6 Torr) of the acquired liquid provided 2.77 g (86%) of the vinyl ;1 1 H nnir bromide 148, a colorless liquid that displayed ir (neat): 1632, 1255, 1171, 894 cnr I, J= 7 Hz), 2 , 1= 7 Hz), 3.34 (t, 2H, CH 2 , 400 MHz): 6 2.94 (br t, 2H, =CCH 3 (CDC1 , 3 C nmr (CDC1 5.57 (br d, 1H, =CH, J= 2 Hz), 5.68 (br dt, 1H, =CH, J= 2, 1 Hz); 13 BrI: 259.8696; found: 79 50.3 MHz): 8 2.1, 44.9, 119.0, 131.8. Exact mass calcd. for C4H6 BrI: C 18.41, H 2.32, I 48.64; found: C 18.62, H 2.28, 6 H 4 259.8696. Anal. calcd. for C I 48.36.  225 Preparation of 2-bromo-5-chloro-1-pentene (3p5y,13a  305  Following general procedure 9 (p 223), commercially available 5-chloro-1-pentyne  (118) was converted into 2-bromo-5-chloro-1-pentene (305) with the following amounts of C1 70 mL; 5-chloro-lCH , reagents and solvents: B-Br-9-BBN, 17 mL (17 mmol), in 2 C1 8.0 niL; HOAc, 4.0 niL (70 mmol); NaOH, CH , pentyne, 0.80 niL (7.5 mmol), in 2 ; 9.0 mL. Flash chromatography (80 g silica gel, petroleum ether) of the crude 0 2 35 niL; H product and distillation (73-82 0C120 Torr) of the acquired liquid produced 1.06 g (77%) of ; 1 the vinyl bromide 305 as a colorless oil that exhibited ir (neat): 1630, 1442, 1114, 892 cm nmr (CDC1 , 400 MHz): 2.03 (quintet, 2H, CH2CthCH2, J= 7 Hz), 2.58 (t, 2H, 3 C1, J= 7 Hz), 5.45 (d, 1H, =CH, J= 1.5 Hz), 2 , J= 7 Hz), 3.54 (t, 2H, CH 2 =CCH , 50.3 MHz): 8 30.4, 38.3, 43.3, 3 C nmr (CDC1 5.63 (br s, 1H, =CH, w1/2= 4 Hz); 13 79 181.9498; found: 181.9498. Anal. 8 H 5 C C1: 35 118.0, 132.5. Exact mass calcd. for Br BrC1: C 32.73, H 4.39; found: C 33.04, H 4.31. 8 H 5 calcd. for C  226 Preparation of 2-bromo-5-iodo- 1 -pentene (297 13a  297  A stirred solution of 2-bromo-5-chloro-1-pentene (305) (450 mg, 2.46 mmol) and Nal (1.10 g, 7.34 mmol) in dry acetone (10 ml.) was refluxed for 16.5 h. The solvent was 0 (10 mL) and n-pentane (30 rnL) were added to the resulting residue. The 2 removed. H phases were separated and the organic phase was dried (MgSO4) and concentrated. Distillation (35-45 0C10.15 Torr) of the remaining oil over basic alumina yielded 563 mg (83%) of the vinyl bromide 297, a colorless liquid that showed ir (neat): 1632, 1222, 1171,  ;1 1 H nmr (CDC13, 400 MHz): 2.07 (quintet, 2H, CH 891 cnr CjCH2, J= 7 Hz), 2.58 (td, 2 I, J= 7 Hz), 5.47 (d, 1H, =CH, J= 2 Hz), 2 2H, =CCH , J= 7, 1 Hz), 3.20 (t, 2H, CH 2 , 50.3 MHz): 3 4.9, 30.9, 41.6, 118.2, 3 C nmr (CDC1 5.68 (dt, 1H, =CH, 1= 2, 1 Hz); 13 132.1. Exact mass calcd. for CSH8 BrI: 273.8854; found: 273.8850. Anal. calcd. for 79 CSH8BrI: C 21.84, H 2.93, I 46.16; found: C 22.10, H 2.91, I 46.19.  227 Preparation of 5-chloro-2-trimethvlstannyl-1-pentene (281)63  3 SnMe Ha%%Cl  281  To a cold (-20 OC), stirred solution of hexamethylditin (4.4 mL, 21 mmol) in dry THF 0 (14.3 mL, 21.5 mmol). After the pale 2 (125 rnL) was added a solution of MeLi in Et 39 had been stirred at -20 OC for 20 mm, it was yellow solution of trimethylstannyllithium cooled to -78 °C (—5 mm). Solid copper(I) bromide-dimethylsulfide complexM (4.40 g, 21.4 mmol) was added in one portion and the mixture was stirred at -78 °C for 5 mm and at -63 OC for 30 mm. The resulting deep brown mixture was cooled to -78 OC for 5 mm and commercially available 5-chloro-1-pentyne (118) (2.20 mL, 20.7 mmol) was added and the reaction mixture was stirred at -78 OC for 7 h. Glacial acetic acid (1.2 mL, 21 mmol) was added at -78 OC and the mixture was stirred at -78 OC for 10 mm. The cooling bath was removed and aqueous NFLtC1-NH OH (pH 4  =  8) (100 mL) was added. The mixture was  opened to the atmosphere, was allowed to warm to room temperature and was stirred vigorously until the aqueous phase became deep blue. The phases were separated and the 0 (2 x 40 mL). The combined organic extracts were 2 aqueous layer was extracted with Et washed with brine (100 mL), dried (MgSO4) and concentrated.  Drip column  chromatography (80g 100-230 mesh silica gel, petroleum ether) of the residue oil, followed by concentration of the appropriate fractions and distillation (120-150 OC/ 16 Torr) of the acquired oil obtained 2.83 g (5 1%) of the compound 281 as a colorless liquid that displayed , ) 3 , 400 MHz): 8 0.15 (s, 9H, Sn(CH 3 ; 1 1 H nmr (CDC1 ir (neat): 1442, 920, 770, 528 cnr SnH 2  , 2 53 Hz), 1.85 (quintet, 2H, CH2C&CH2, J= 7 Hz), 2.40 (br t, 2H, =CCH  C1, J= 7 Hz), 5.20 (dt, 1H, 11 2 J 7 HZ 3 a. J= 2.5, 1 Hz, sn-w 51 Hz), 3.50 (t, 2H, CH  228  Sn-H 3  , 3 C nmr (CDC1 70 Hz), 5.68 (dt, 1H, Hb, J= 2.5, 1 Hz, 3 Sn.H= 150 Hz); 13  5 C1Sn 3 4 1 H 7 50.3 MHz): 6 -9.5, 32.2, 37.6, 44.3, 125.8, 153.8. Exact mass calcd. for C (M+  -  7 C 35.94, H 6.41; C1Sn: 1 H 8 Me): 252.9807; found: 252.9810. Anal. calcd. for C  found: C 35.89, H 6.33.  Preparation of 5-iodo-2-trimethylstannyl-1-pentene (2827d 3 SnMe 1  Ha  282  A stirred solution of 5-chloro-2-trimethylstannyl-1-pentene (281) (1.97 g, 7.37 mmol) and Nal (4.50 g, 30.1 mmol) in dry acetone (30 mL) was refluxed for 40 h. The solvent was 0 (60 mL) were added to the resulting residue. The phases 2 0 (120 mL) and Et 2 removed. H 0 (3 x 60 mL). The combined 2 were separated and the aqueous layer was extracted with Et organic extracts were washed with H20 (80 mL) and brine (100 mL), dried (MgSO4) and concentrated. The crude product was eluted through a column of Florisil® (20 g) with hexanes (2 x 60 mL). Concentration of the eluate and removal of traces of solvent (vacuum pump) gave 2.28 g (86%) of the iodide 282 as a colorless oil that exhibited ir (neat): 1428, , ) 3 , 400 MHz): 6 0.12 (s, 9H, Sn(CH 3 ; 1 1 H nmr (CDC1 1225, 919, 768, 528 cnr , 2 C&CH J= 7 Hz), 2.35 (tt, 2H, =CCH CH , ’SnH 53 Hz), 1.88 (quintet, 2H, 2 2 I, J 7 Hz), 5.19 (dt, 1H, Ha, J 2.5, 1 Hz, 2 J= 7, 1 Hz, 3 SnH= 50 Hz), 3.14 (t, 2H, CH , 3 C nmr (CDC1 JSnH=70 Hz), 5.70 (dt, 1H, Hb, J= 2.5, 1 Hz, 3 3 ’Sn-H= 149 Hz); 13 4 ISn 1 H 7 50.3 MHz): 8 -9.5, 6.3, 33.0, 41.0, 125.9, 153.4. Exact mass calcd. for C  229 (M Me): 344.9163; found: 344.9168. Anal. calcd. for C8H17ISn: C 26.78, H 4.78, -  I 35.37; found: C 26.97, H 4.78, I 35.20.  Preparation of 2.5-diiodo-1-pentene (276  276  C1 (20 mL) at room CH To a stirred solution of 12 (609 mg, 2.40 mmol) in dry 2 temperature was added a solution of 5-iodo-2-trimethylstannyl-1-pentene (282) (782 mg, C1 (2.0 mL) and the mixture was stirred at room temperature for CH 2.18 mmol) in dry 2 15 mm. Aqueous 1.0 M sodium thiosulfate (10 mL) was added and the phases were 0 (3 x 20 mL), dried (MgSO4) and 2 separated. The organic layer was washed with H concentrated. Distillation (60-80 OCfO.3 Torr) of the residue oil over basic alumina provided 667 mg (95%) of the diiodide 276, a colorless oil that showed ir (neat): 1616, 1220, 1170, , 400 MHz): 6 2.00 (quintet, 2H, 2 3 H nmr (CDC1 ; 1 1 898 cm CthCH J= 7 Hz), CH , , J= 7 Hz), 3.15 (t, 2H, CH2I, J= 7 Hz), 5.76 (d, 1H, =CH, 2 2.50 (br t, 2H, =CCH , 50.3 MHz): 8 4.8, 31.9, 45.3, 3 C nmr (CDC1 J= 1 Hz), 6.13 (q, 1H, =CH, J= 1 Hz); 13 : 321.8716; found: 321.8713. Anal. calcd.: 2 1 8 H 5 109.4, 127.2. Exact mass calcd. for C C 18.65, H 2.50; found: C 18.98, H 2.60.  230 Preparation of ethyl (Z)-3-iodo-2-butenoate (279)62  I  COEt 279  A stirred mixture of commercially available ethyl 2-butynoate (101) (655 mg, 5.84 mmol), NaT (1.40 g, 9.34 mmol) in glacial acetic acid (2.1 mL) was warmed at 115 OC (oil bath which was prewarmed at 115 OC for 15 mm) for 1.5 h. While the deep brown mixture was hot, it was diluted with H20 (50 mL) and Et20 (150 mL). The phases were separated and the organic layer was washed with saturated aqueous NaHCO3 (50 mL), aqueous 1.0 M sodium thiosulfate (50 mL), brine (50 mL), dried (MgSO4) and concentrated. Distillation (35-50  OC/0.3  Torr) of the acquired liquid over basic alumina provided 1.37 g  (98%) of the ethyl (Z)-3-iodo-2-butenoate (148) as a colorless liquid that displayed ir (neat): , 400 MHz): 8 1.28 (t, 3H, CH2CIj 3 1728, 1629, 1309, 1180 cnr ; 1 1 H nmr (CDC1 , 3  J= 7 Hz), 2.71 (d, 3H, =CCH3, J= 1.5 Hz), 4.20 (q, 2H, OCH2, J= 7 Hz), 6.27 (q, 1H, =CH, J= 1.5 Hz); nOe difference experiments: irradiation at 62.71 caused an enhancement of the signal at 66.27 (10%), irradiation at 66.27 caused an enhancement of the signal at 82.71 , 50.3 MHz): 3 14.2, 36.5, 60.5, 113.1, 125.6, 164.2. Exact mass 3 (2%); 13 C nmr (CDC1 10 239.9648; found: 239.9646. Anal. calcd.: C 30.02, H 3.78, I 52.87; 9 H 6 C : calcd. for 2 found: C 29.84, H 3.71, I 52.60.  231 Preparation of (Z)-3-iodo-2-buten-1-oI (280  >OH 280  To a cold (-78 OC), stirred solution of ethyl (Z)-3-iodo-2-butenoate (279) (1.86 g, 0 (50 mL) was added a 1.0 M solution of i-Bu2A1H (22 mL, 2 7.75 mmol) in dry Et 22 mmol) in hexanes and the resulting clear solution was stirred at -78 OC for 10 miii and at H (pH =8) (5 niL) was added and the white slurry C1-NH NB O 0 OC for 1.5 h. Aqueous 4 was allowed to stir at room temperature for 1 h. Solid MgSO4 (—0.5 g) was added and the slurry was filtered through a column of Florisil® (16.5 g). The column was washed with 0 (3 x 50 niL). The combined filtrate was concentrated and the crude product was 2 Et  purified 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 residual oil over basic alumina, afforded 1.38 g (90%) of the alcohol 280 as a colorless oil that , 400 MHz): 3 H nmr (CDC1 ; 1 1 exhibited ir (neat): 3370 (br), 1651, 1427, 1076, 1010 cm, J= 1.5 Hz), 3 3 1.57 (br s, 1H, CH2OU, exchanges with D20), 2.52 (q, 3H, =CCH C nmr 4.14 (br m, 2H, CthOH, wl/2= 13 Hz), 5.77 (tq, 1H, =CH, J= 6, 1.5 Hz); 13 10: 197.9542; 7 H 4 (CDC13, 50.3 MHz): 3 33.6, 67.2, 101.8, 134.1. Exact mass calcd. for C found: 197.9546. Anal. calcd.: C 24.26, H 3.56, I 64.09; found: C 24.25, H 3.55, I 63.88.  232 Preparation of (Z’)-3-iodo- 1-bromo-2-butene (275)  275  C1 (50 niL) CH To a cold (0 OC), stirred solution of Ph P (1.69 g, 6.44 mmol) in dry 2 3 C1 (3.0 mL). To the CH was added a solution of bromine (1.02 g, 6.38 mmol) in dry 2 3 were added until the solution resulting pale yellow solution at 0 °C, a few crystals of PPh turned colorless. Stirring was continued at 0 0 C for 5 mm. A solution of (Z)-3-iodo-2buten-1-ol (280) (1.21 g, 5.04 mmol) in dry 2 C1 (2.0 mL) was added and the resulting CH mixture was stirred at 0 0 C for 5 mm and at room temperature for 1 h. The mixture was  concentrated (to —3 mL) and was then poured into stirred n-pentane (45 mL). The resulting slurry was filtered through a column of Florisil® (7 g) and the column was washed with n-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 the alkene 275 as a colorless oil that exhibited ir (neat): 1640, 1426, 1293, 1203, 1166, , 400 MHz): 6 2.59 (s, 3H, =CCH 3 ), 3.98 (d, 2H, CthBr, 3 ; 1 1 H nmr (CDC1 1068 cm , 50.3 MHz): 6 33.7, 35.7, 3 J= 7.5 Hz), 5.78 (t, 1H, =CH, J= 7.5 Hz); 3C nmr (CDC1 107.4, 131.1. Exact mass calcd. for C4H6 BrI: 259.8698; found: 259.8701. Anal. calcd. 79 for C4H BrI: C 18.41, H 2.32; found: C 18.48, H 2.27. 6  233 9.  Preparation of a-allcylated esters and related derivatives  Deconiuation-a11cvlation of alkyl (E)-3-trimethylstannvl-2-allcenoates (125. 137. 138 and  141). ethyl (Z)-3-trialkylstannvl-2-pentenoates (124. 295. ethyl (Z)-5-methyl-3trimethylstannyl-3-hexenoate (158) and methyl 2-trimethvlstannyl- 1 -cyclopentene carboxylate (258) 13.2S  General procedure 10 R’ t CO E 2  n R S 3  n Me S 3  125, 137, 138 and 141  124 and 295 3 SnMe  y%-CO2Et e CO M 2  SnMe  258  158 C 0 2 R 3 R X  3 SnMe  n Me S 3  260  206  X = Br or I  n  =  1, 2 or 3  To a cold (-78 OC), stirred solution of LDA (—1.3 equiv) in dry THF (—5 mL per mmol of the LDA) was added dry HMPA (—1.3 equiv). After the mixture had been stirred at -78 °C for 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-  234 stannyl-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 0 C for 30 mm. After the reaction mixture had been cooled to -20 °C (—5 mm), a solution of aikyl halide (—1.3-1.5 equiv) in dry THF (—1 mL per mmol of the ailcyl halide) was added quickly to the vigorously stirred solution. The mixture was stirred at -20 °C for 1 h. Saturated aqueous NaHCO3 (one-half the volume of the total volume of the reaction mixture) was added. The phases were separated and the aqueous phase was extracted three times with 0. 2 Et  The combined organic extracts were washed with brine, dried (MgSO4) and  concentrated. Flash or radial chromatography of the remaining oil on silica gel, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) provided the a-alkylated ester of general structure 206 or 260.  235 a 3 Preparation of ethyl 5-bromo-2-fl -(trimethylstannyl)ethenyll-5-hexenoate (4Oal C 2 EtO  Br  Hb  Sn 3 Me 40a  Following 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 and solvents: LDA, 1.68 mmol, in THE, 5.5 mL; HMPA, 0.29 mL (1.7 mmol); ethyl (E)-3trimethylstannyl-2-butenoate (137), 380 mg (1.37 mmol), in THE, 1.5 mL; 2-bromo-4-iodo1-butene (148), 509 mg (1.95 mmol), in THF, 1.5 mL. 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) provided 454 mg (8 1%) of the diene ester 40a, a colorless liquid that displayed ir (neat): 1729, 1630, 1177, ; 1 1 H nmr (CDC1 , 400 MHz): 6 0.19 (s, 9H, Sn(CH3)3, 2 3 772 cm SnH= 53 Hz), 1.27 (t, II 2.0 1-2.13 (m, 1H, 3H, 3 Cjj J= 7 Hz), 1.68-1.80 (m, 1H, 2 2 OCH , C CH C H), , 3.19 (t, 1H, CHC=O, J= 7 Hz, =CBrCH ) jj 2.32-2.48 (m, 2H, 2 C 2 CH C H), Sn-H 3  ,J 2 67 Hz), 4.13 (q, 2H, OCH  7 Hz), 5.35 (d, 1H, Ha, J  2 Hz,  jSnH67 Hz), 5.42 (d, 1H, BrC=CH2, J= 2 Hz), 5.58 (d, 1H, BrC=CH2, J= 2 Hz), 3 , 50.3 MHz): 6 -8.2, 14.2, 3 C nmr (CDC1 5.78 (d, 1H, Hb, J= 2 Hz, 3 SnH= 139 Hz); 13 30.8, 39.0, 55.2, 60.6, 117.2, 128.3, 133.5, 153.1, 174.1.  Exact mass calcd. for  n: 3 1 C 2 H S 2 n (M Me): 394.9669; found: 394.9668. Anal. calcd. for BrO 2 0 79 1 C 2 H S 2 BrO -  C 38.09, H 5.66, Br 19.49; found: C 38.20, H 5.81, Br 19.33.  236 paration of ethyl 5-bromo-2-[(Z- 1 -ffimethylsnnyl- 1-propenyll-5-hexenoate 2O7)13a C 2 EtO  Br  n Me S 3 207  Following 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 and solvents: LDA, 2.25 mmol, in THF, 10 mL; HMPA, 0.39 mL (2.2 mmol); ethyl (E)-3trimethylstannyl-2-pentenoate (125), 502 mg (1.72 mmol), in THF, 2.0 mL; 2-bromo-4iodo-1-butene (148), 672 mg (2.58 mmol), in THF, 2.0 mL. 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) produced 546 mg (75%) of the diene ester 207, a colorless liquid that exhibited ir (neat): 1729, 1629, 1177, , 400 MHz): 5 0.23 (s, 9H, Sn(CH3)3, 2 3 ; 1 1 H nmr (CDC1 772 cmSn-H= 55 Hz), 1.25 (t, 3H, 3 CLbCH), 1.77 (d, 3H, =CHCH, 2 CIj J= 7 Hz), 1.67-1.80 (m, 1H, CH 2 OCH , ), 3.08 (dd, 1H, 2 J= 7 Hz), 2.05-2.16 (m, 1H, CH2CthCH), 2.32-2.46 (m, 2H, =CBrCH , J= 7 Hz), 5.42 (d, 1H, =CH2, 2 CHC=O, J= 9, 6 Hz, 3 ’Sn-H 69 Hz), 4.13 (q, 2H, OCH , 1= 3 , J= 1 Hz), 6.13 (q, 1H, =CflCH 2 J= 1 Hz), 5.56 (d, 1H, =CH  Sn-H= 132 Hz); 3  13C nmr (CDC1 , 50.3 MHz): 8 -7.3, 14.2, 19.3, 30.4, 39.4, 54.3, 60.5, 117.0, 133.8, 3 n (M Me): 408.9825; found: 3 2 79 1 C 2 H S 2 137.8, 142.6, 174.5. Exact mass calcd. for BrO -  4 C 39.66, H 5.94, Br 18.85; found: C 39.89, 5 n: BrO 1 C 2 H S 408.9826. Anal. calcd. for 2  H 6.06, Br 19.00.  237 Preparation of ethyl 5-bromo-2-lIE-1 -irimethyistannyl- 1-propenyll-5-hexenoate (20813a  208  Following 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 and solvents: LDA, 2.57 mmol, in THF, 12 mL; HMPA, 0.45 mL (2.6 mmol); ethyl (Z)-3trimethylstannyl-2-pentenoate (124), 566 mg (1.95 mmol), in THE, 2.0 mL; 2-bromo-4iodo-1-butene (148), 732 mg (2.80 mmol), in THE, 2.0 mL. 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) yielded 709 mg (86%) of the diene ester 208, a colorless liquid that showed ir (neat): 1728, 1630, 1178, , 400 MHz): 8 0.14 (s, 9H, Sn(CH3)3, 2 3 H nmr (cDC1 ;1 1 770 cur SnH= 52 Hz), 1.26 (t, , 3 JJ. J= 7 Hz), 1.64-1.73 (m, 1H, 2 3 C 2 OCH 3H, , H), a 1.77 (d, 3H, =CHCIj C CH C ), 3.68 (hr t, 2 J= 7 Hz), 2.03-2.13 (m, 1H, CH2CjbCH), 2.32-2.48 (m, 2H, =CBrCH , 2 , J= 7 Hz), 5.43 (d, 1H, =CH 2 1H, CHC=O, J= 7 Hz, 3 Sn.H= 80 Hz), 4.13 (q, 2H, OCH , J= 1.5 Hz), 5.86 (qd, 1H, =CRCH3, J= 7, 1 Hz, 2 J= 1.5 Hz), 5.58 (d, 1H, =CH , 50.3 MHz): 8 -7.6, 14.2, 14.9, 31.3, 39.0, 46.7, 60.6, 3 C nmr (CDC1 3 n-H Hz); ‘ 3 S 117.1, 133.7, 137.6, 143.2, 174.6. Exact mass calcd. for 79 n (M+ C13H22 S 2 BrO  -  Me):  4 C 39.66, H 5.94, Br 18.85; 5 n: 1 C 2 H S 2 408.9825; found: 408.9822. Anal. calcd. for BrO found: C 39.79, H 6.02, Br 18.90.  238 Preparation of ethyl (Z-5-iodo-2-[(Z)- 1 -trimethvlstannyl- 1 -propenyll-5-heptenoate (205 C 2 EtO  I  Sn 3 Me 205  Following 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 and solvents: LDA, 2.71 mmol, in THF, 13 mL; HMPA, 0.47 mL (2.7 nimol); ethyl (E)-3trimethylstannyl-2-pentenoate (125), 615 mg (2.11 mmol), in THF, 2.0 mL; (Z)-3,5-diiodo2-pentene (198), 980 mg (3.04 mmol), in THF, 2.0 mL. 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 910 mg (89%) of the diene ester 205, a colorless oil that displayed ir (neat): 1728, 1648, 1620, 1162, 771 cm ; 1 1 H nmr (CDC1 , 400 MHz): 6 0.21 (s, 9H, 3 3 Sn(CH S , ) 2 nH= 52 Hz), 1.24 (t, 3H, 3 CIj J= 7 Hz), 1.65-1.74 (m, 1H, C 2 OCH , C 2 CH H), Ij 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, 2 =CICH ) , 3.06 (dd, 1H, CHC=O, J= 9, 7 Hz, 3 Jsfl..H=70 Hz), 4.11 (q, 2H, OCH , J= 7 Hz), 5.54 (qt, 1H, IC=CH, J= 7, 1 Hz), 6.09 (br q, 1H, SnC=CH, 2  J 7 Hz, 3 Sn-H  132 Hz); 13 , 50.3 MHz): 3 -7.2, 14.3, 19.4, 22.1, 31.9, 3 C nmr (CDC1  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. for S 2 S 1 C I 7 H2 O n: C 37.15, H 5.61,  I 26.17; found: C 37.30, H 5.60, I 25.95.  239 Preparation of ethyl (Z)-5-iodo-2-F(E)- 1 -trimethyistannyl- 1-propenyll-5-heptenoate (209)  Sn 3 Me  I 209  Following 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 and solvents: LDA, 1.92 mmol, in THF, 8.0 mL; HMPA, 0.34 mL (2.0 mmol); ethyl (Z)-3trimethylstannyl-2-pentenoate (124), 434 mg (1.49 mmol), in THF, 1.5 mL; (Z)-3,5-diiodo2-pentene (198), 650 mg (2.02 mmol), in THF, 1.4 mL. 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) gave 642 mg (89%) ; 1 of the diene ester 209, a colorless oil that displayed ir (neat): 1728, 1648, 1187, 769 cm nmr (CDC13, 400 MHz): ö 0.14 (s, 9H, Sn(CH3)3, 2 SnH= 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, CH CthCH), 2.37-2.52 (m, 2H, 2 , 3.65 (br t, 1H, CHC=O, J= 7 Hz, =CICH ) 2  Jsn..H= 3  , 2 84 Hz), 4.12 (q, 2H, OCH  J= 7 Hz), 5.56 (q, 1H, IC=CH, J= 7 Hz), 5.83 (qd, 1H, SnC=CH, J= 7, 1 Hz, , 50.3 MHz): 8 -7.6, 14.3, 15.0, 22.1, 32.8, 42.7, 46.6, 3 C nmr (CDC1 .1nW74 Hz); 13 3 4H24IO2Sn (M+ Me): 1 60.5, 109.8, 130.3, 137.3, 143.5, 174.7. Exact mass calcd. for C -  n: C 37.15, H 5.61, I 26.17; H 27 5 1 C S 2 470.9843; found: 470.9839. Anal. calcd. for IO found: C 37.35, H 5.59, I 25.93.  240  eparation of ethyl (E-5-iodo-2-F(Z)- 1-methylstannyl- 1-propenyll-5-heptenoate (21  I  Sn 3 Me  210  Following general procedure 10 (pp 233-2342), ethyl (E)-3-trimethylstannyl-2pentenoate (125) was converted into the diene ester 210 with the following amounts of reagents 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)-3,5dliodo-2-pentene (193), 1.14 g (3.54 mmol), in THE, 3.5 mL. 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) produced 1.21 g (92%) of the diene ester 210, a colorless oil that showed ir (neat): 1728, 1619, 1164, 771 cm ; 1 4 H mm (CDC1 , 400 MHz): 6 0.24 (s, 9H, 3 3 Sn(CH S , ) 2 n-H 53 Hz), 1.25 (t, 3H, 3 CIj 1= 7 Hz), 1.61 (d, 3H, IC=CHCIj 2 OCH , , J= 7 Hz), 1.63-1.72 (m, 1H, 3 CH2CthCH), 1.77 (d, 311, SnC=CHCTh, J= 7 Hz), 1.98-2.09 (m, 1H, CH2CthCH), 2.34 (t, 2H, =CICH , J= 7 Hz), 3.07 (t, 111, CHC=O, .1=7 Hz, 3 2 Sn-H= 69 Hz), 4.14 (q, 2H, OCH2, .1=7Hz), 6.12 (br q, 1H, SnC=CH, .1=7 Hz, 3 Sn-H= 131 Hz), 6.24 (br q, 1H, IC=CH, J= 7Hz); in a decoupling experiment, inadiation at 66.12 simplified the doublet at 8 1.77 to a singlet; 13 C nmr (CDC1 , 50.3 MHz): 6 -7.1, 14.3, 16.3, 19.4, 31.3, 36.3, 3 54.0, 60.6, 102.2, 136.0, 137.7, 142.9,. 174.6. Exact mass calcd. for S 2 4 1 C H24IO n (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.  241 Preparation of ethyl (E)-5-iodo-2-F(E’)-1 -trimethyistannyl- 1-propenvll-5-heptenoate (211)  C 2 EtO  L,%%rJ I  Sn 3 Me  211  Following 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 and solvents: LDA, 3.25 mmol, in THF, 15 mL; HMPA, 0.57 mL (3.3 mmol); ethyl (Z)-3trimethylstannyl-2-pentenoate (124), 806 mg (2.77 mmol), in THF, 2.8 mL; (E)-3,5-diiodo2-pentene (193), 1.16 g (3.60 mmol), in THF, 3.6 mL. 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) provided 1.15 g (86%) of the diene ester 211, a colorless oil that displayed ir (neat): 1727, 1634, 1164, ; 1 1 H nmr (CDC1 , 400 MHz): 6 0.13 (s, 9H, Sn(CH3)3, 2 3 768 cmSnH= 53 Hz), 1.24 (t, , 3 CjCH), 1.60 (br d, 3H, IC=CHCj 2 Cfj J= 7 Hz), 1.55-1.64 (m, 1H, CH 2 OCH , 3H, 3 jj C 2 CH H), J= 7 Hz), 1.74 (d, 3H, SnC=CHCJj3, J= 7 Hz), 1.94-2.04 (m, 1H, C 2.26-2.42 (m, 2H, =CICH2), 3.64 (br t, 1H, CHC=O, J= 7 Hz, 3 JSn-H  84 Hz), 4.11 (q,  2H, OCH , J= 7 Hz), 5.83 (qd, 1H, SnC=CH, J= 7, 1 Hz, 3 2 Sn-H= Hz), 6.22 (br q, 1H, IC=CH, J= 7 Hz); in a decoupling experiment, irradiation at 66.22 simplified the doublet at , 50.3 MHz): 8 -7.6, 14.3, 15.0, 16.2, 32.4, 35.8, 3 C nmr (CDC1 6 1.60 to a singlet; 13 46.8, 60.6, 102.1, 136.1, 137.3, 143.5, 174.8. Exact mass calcd. for C 4H24IO2Sn 1 (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.  242  Preparation of ethyl (E)-5-iodo-2-[(E)- 1 -ftri-n-butylstannyD- 1-propenyll-5-heptenoate (296) C 2 EtO  I  n-BuSn  296  Following general procedure 10 (pp 233-234), ethyl (Z)-3-(tri-n-butylstannyl)-2pentenoate (295) was converted into the diene ester 296 with the following amounts of reagents 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.  Radial  chromatography (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 displayed ; 1 1 H nmr (CDC1 , 400 MHz): 6 0.77-0.99 (m, 15H), 3 ir (neat): 1728, 1634, 1163 cm 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, , 3.62 (br t, 1H, CHC=O, J= 7 Hz, =CICH ) Ij 2.26-2.43 (m, 2H, 2 C 2 CH C H), , J= 7 Hz), 5.77 (qd, 1H, SnC=CH, J= 7, 1 Hz, 2 JSn-H 77 Hz), 4.08 (q, 2H, OCH 3 jSnH65 Hz), 6.23 (q, 1H, IC=CH, J= 7 Hz); in a decoupling experiment, irradiation at 3 , 50.3 MHz): 8 10.8, 3 C nmr (CDC1 6 5.77 simplified the doublet at 6 1.76 to a singlet 1 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.  243 eparation of methyl (-5-iodo-2-F(-4-(tert-butyldimethylsiloxy-1 -methylstannyl- 1butenyll-5-heptenoate (212) C 2 MeO  t-Bu) j’OSiMe ( 2 I  Sn 3 Me 212  Following general procedure lO(pp 233-234), methyl (E)-6-(tert-butyldimethylsiloxy)3-trimethylstannyl-2-hexenoate (141) was converted into the diene ester 212 with the following 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 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) afforded 489 mg (87%) of the diene ester 212  ; 1 1 H nmr as a colorless liquid that exhibited ir (neat): 1733, 1195, 1101, 838, 776 cnr , 0.19 (s, 9H, Sn(CH3)3, 2 Si(CH3) ) (CDC13, 400 MHz): ö 0.02 (s, 6H, 2 Sn.H= 54 Hz), Jj 1.70 (d, 3H, =CHCIj3, C 2 CH H), , 1.62-1.72 (m, 1H, C C(CH ) ) 0.87 (s, 9H, 3 , 1= 7 Hz), CH CIj O Ij 2.27 (br q, 2H, 2 C CH C H), 1=7 Hz), 1.99-2.19 (m, 1H, 2 2.35-2.43 (m, 2H, =CICH2), 3.06 (dd, 1H, CHC=O, J= 9, 6.5  ‘  Sn-H 3  68 Hz),  , 5.52 (q, 1H, =CaCH3, 1= 7 Hz), OCH ) 3.60 (t, 2H, CH2O, 1= 7 Hz), 3.62 (s, 3H, 3 , 50.3 MHz): 6 -7.0, 3 C nmr (CDC1 5.98 (t, 1H, SnC=CH, 1= 7 Hz, 3 SnH= 130 Hz); 13  -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 3 IO (M 8iSn C2OH S  -  Me): 601.0658; found: 601.0657.  1 C 41.00, H 6.72, I 20.63; found: C 41.18, H 6.66, IO 2 C 4 H S iSn: Anal. calcd. for 3 I 20.44.  244 eparation of methyl 5-bromo-2-ft-2-cyclopropy1- 1 -(thmethylstannyl)ethenvll-5-hexen-  oate (213) C 2 MeO  213  Following general procedure 10 (pp 233-234), methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138) was converted into the diene ester 213 with the following quantities 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), in THF, 2.0 mL. 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 Iraces of solvent (vacuum pump) provided 742 mg (90%) of the diene ester 213 as a colorless liquid , 400 MHz): 30.24 (s, 3 ; 1 1 H nmr (CDC1 that displayed ir (neat): 1732, 1630, 1165, 771 cnr Sn(CH ) 3, S 9H, 3 2 n-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 methine proton), 1.67-1.80 (m, 111, CH2CthCH), 2.03-2.16 (m, 1H, CH2CthCH), 2.32-2.48 (m, 2H,  , OCH ) , 3.08 (dd, 1H, CHCO, J 8, 6 Hz, 3 CBrCH ) 2 Sn..H 66 Hz), 3.67 (s, 3H, 3  , J= 1 Hz), 2 5.38 (br d, 1H, SnC=CH, J= 9 Hz, 3 SziH= 126 Hz), 5.41 (br d, 1H, =CH , 1= 1 Hz); 13 2 C nmr (CDC13, 75.5 MHz): 6 -7.1, 7.6, 7.7, 15.1, 30.6, 5.55 (br ci, 1H, =CH 39.4, 51.9, 54.0, 117.3, 133.8, 138.6, 148.0, 175.1.  Exact mass calcd. for  5H2SBrO2Sn: 1 4 (M Me): 420.9826; found: 420.9828. Anal. calcd. for C H22 1 C BrO2Sn 79 -  C 41.33, H 5.78, Br 18.33; found: C 41.41, H 5.72, Br 18.11.  245 Preparation of methyl (Z-5-iodo-24(Z)-2-cvclopropvl-1-ftrimethylstannyl’)ethenvl1-5-hepten-  oate (214) C 2 MeO  214  Following general procedure 10 (pp 233-234), methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138) was converted into the diene ester 214 with the following quantities 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), in THF, 2.0 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) yielded 770 mg (83%) of the diene ester 214 as a colorless liquid that exhibited ir (neat): 1733, 1648, 1611, 1162, 771 cnr ; 1 1 H nnir (CDC1 , 400 MHz): 3 Sn(CH ) 3, S 6 0.24 (s, 9H, 3 2 n.H= 53 Hz), 0.36-0.44 (m, 2H, cyclopropyl methylene protons), 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, ), 3.05 (dd, 1H, 2 .1=7 Hz), 2.00-2.10 (m, 1H, CH2CthCH), 2.36-2.51 (m, 2H, =CICH CHC=O, J= 8, 6 Hz, 3 Sn..H  69 Hz), 3.66 (s, 3H, OCH ), 5.36 (br d, 1H, SnC=CH, 3  .1=9 Hz, 3 C nmr (CDC1 , 3 ’Sn-H= 128 Hz), 5.56 (br q, 1H, IC=CH, J=.7 Hz); 13 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. for Cj HIO2Sn (M Me): 482.9844; found: 482.9853. Anal. 5 -  calcd. for 7 6 1 C I O2Sn: H2 C 38.67, H 5.48, I 25.53; found: C 38.98, H 5.46, I 25.35.  246 Preparation of methyl (Z)-6-cvclopropvl-5-iodo-2-IIZ)-2-cvclopropyl- 1 -ftrimethvlstannyl’) ethenyll-5-hexenoate (215)  C 2 MeO  I 215  Following general procedure 10 (pp 23 3-234), methyl (E)-4-cyclopropyl-3-trimethylstannyl-2-butenoate (138) was converted into the diene ester 215 with the following quantities 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 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) gave 367 mg (72%) of the diene ester 215 as a , 3 H nmr (CDC1 ; 1 1 colorless liquid that showed ir (neat): 1732, 1645, 1611, 1165, 772 cm 3, 2 Sn(CH ) 400 MHz): 6 0.25 (s, 9H, 3 Sn-H= 54 Hz), 0.33-0.48 (m, 4H, cyclopropyl methylene 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, cyclopropyl , =CICH ) methine proton: m, 1H), 1.98-2.08 (m, 1H, CH2CthCH), 2.31-2.49 (m, 2H, 2 3.04 (dd, 1H, CHCO, J 9, 6 Hz, 3 SnH  ), 4.93 (d, 1H, 3 69 Hz), 3.67 (s, 3H, OCH  IC=CH, 1= 9 Hz), 5.35 (d, 1H, SnC=CH, .1= 9  , 3 C nmr (CDC1 JsnH= 128 Hz); 13 3  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, 17 (M C 139.5, 147.5, 175.1. Exact mass calcd. for H26IO2Sn  -  Me): 509.0001; found:  n: 8 C 41.34, H 5.59, I 24.26; found: C 41.61, O 1 C I 9 H2 S 509.0005. Anal. calcd. for 2 H 5.57, I 24.07.  247 Preparation of ethyl (Z)-5-iodo-7-methvl-2-[(Z)-3-methyl-1 -trimethylstannyl- 1 -butenyU-5octenoate (216  I 216  Following general procedure lO(pp 233-234), ethyl (Z)-5-methyl-3-trimethylstannyl-3hexenoate (158) was converted into the diene ester 216 with the following quantities of reagents 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 that ;1 1 H nmr (CDC1 , 400 MHz): 3 displayed ir (neat): 1729, 1642, 1616, 1177, 1028, 770 cnr ö 0.22 (s, 9H, Sn(CH3)3, 2 Sn..H 53 Hz), 0.89-1.08 (m, 12H, 2 x CH(Cth)2), 1.24 (t, C CH C H), jj 1.99-2.10 (m, 1H, 3H, 3 CII J= 7 Hz), 1.62-1.72 (m, 1H, 2 2 OCH , ), 2 CH2CthCH), 2.21-2.30 (m, 1H, SnC=CCE(CH3)2), 2.32-2.45 (m, 2H, =CICH 2.45-2.57 (m, 1H, IC=CCIj(CH ), 3.00 (dd, 1H, CHC=O, J= 9, 6 Hz, 3 2 ) 3 JSnH= 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, 3 Sn..H= 132 Hz); in a series of decoupling experiments, irradiation at 8 0.99 simplified 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 at 62.51 simplified the doublet at 8 5.27 to a singlet 13 C nmr (CDC1 , 50.3 MHz): 6 -6.8, 3 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,  248 151.0, 174.7. Exact mass calcd. for IO2Sn 12 C 3 H 8 (M Me): 527.0471; found: 527.0472. -  Anal. calcd. for H 1 C S 3 IO2Sn: 9 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 (298  Sn 3 Me 298  Following 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 and solvents: LDA, 2.28 mmol, in THF, 10 mL; HMPA, 0.40 mL (2.3 mmol); ethyl (Z)-3trimethylstannyl-2-pentenoate (124), 611 mg (2.10 mmol), in THF, 2.0 mL; 2-bromo-5iodo-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 by concentration 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, , 400 MHz): 6 0.10 (s, 9H, Sn(CH 3 1630, 1186, 769 cm; 1 1 H nmr (CDC1 , ) 3 SnH 52 Hz), 1.23 (t, 3H, OCH2Cth, J= 7 Hz), 1.34-1.62 (m, 3H), 1.70-1.84 (m, 2 , J= 7 Hz), 3.62 (br t, 1H, 2 1H), 1.74 (d, 3H, =CHCIj3, J= 7 Hz), 2.40 (br t, 2H, =CBrCH  CHC=O, J= 7 Hz, 3 Sn-H  83 Hz), 4.10 (q, 2H, OCH2, 1= 7 Hz), 5.37 (d, lH, =CH2,  , J= 2 Hz), 5.82 (qd, 1H, =CaCH 2 1= 2 Hz), 5.55 (d, 1H, =CH , J= 7, 1 Hz, 3 C JSnH76 Hz); 13 3  , 50.3 M14z: 6 -7.6, 14.3, 14.9, 25.5, 31.9, 41.1, 47.8, 3 (CDC1  60.5, 116.8, 134.1, 137.0, 143.7, 175.0.  Exact mass calcd. for 79 14 C 2 H S 2 BrO n  249 Anal. calcd. for CISH27BrO2Sn: C 41.13,  (M Me): 422.9981; found: 422.9989. -  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-cyclopentenecarboxvlate (286  C 2 MeO  3 SnMe  286  Following general procedure 10 (pp 233-234), methyl 2-trimethylstannyl-1cyclopentenecarboxylate (258) was converted into the diene ester 286 with the following quantities 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 petroleum  ether-CH2C12) of the crude product, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) afforded 426 mg (63%) of the diene ester  H nmr ; 1 1 286 as a colorless liquid that exhibited ir (neat): 1729, 1227, 1164, 771 cnr , 400 MHz): 8 0.12 (s, 9H, Sn(CH3)3, 2 3 (CDCJ SnH= 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, 3 Sn..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 at 8 2.22 and 8 2.68 to two doublet of doublets (both with J= 15, 1 Hz), and simplified the  250 resonance at 8 6.25 to a triplet (J= 1 Hz); 13C nmr (CDC1 , 50.3 MHz): 6 -8.6, 31.9, 34.0, 3 42.8, 51.8, 64.5, 84.7, 137.2, 144.0, 147.9, 175.9. Exact mass calcd. for 2 IO C 1 H S 2 8 n (M  -  Me): 440.9374; found: 440.9382. Anal. calcd. for 2 IO 1 C 2 H S 3 C 34.32, H 4.65, 1 n:  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 (252 I  C 2 MeO  252  Following general procedure 10 (pp 233-234), methyl 2-trimethylstannyl-1cyclopentenecarboxylate (258) was converted into the diene ester 252 with the following quantities 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), in THF, 2.0 mL. Flash chromatography (80 g silica gel, 7: 1 petroleum ether-CH2C12) of the crude product, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) gave 1.02 g (68%) of the diene ester 252 as a colorless liquid that showed ir (neat): 1734, 1435, 1200, 1056,771 cm ;1 4 H nmr (CDC1 , 400 MHz): 60.14 (s, 3 9H, 3 Sn(CH S , ) 2 n-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, 2 IC=CHCIj J= 15, 7 Hz for doublets), 3.65 (s, , 3H, 3 OCH ) , 5.25 (tm, 1H, IC=CH, J= 7 Hz for triplet), 5.98 (t, 1H, SnC=CH, J= 2 Hz,  251 C nmr (CDC13, 50.3 MHz): 6 -8.6, 32.1, 33.9, 34.0, 45.0, 51.9, 64.9, Sn-H= 37 Hz); 13 3 n (M+ 3 0 IO 1 C 2 H S 103.2, 131.4, 144.0, 148.3, 176.4. Exact mass calcd. for 2  -  Me):  H2 C 35.86, H 4.94; found: 4 1 C I O2Sn: 454.9530; found: 454.9537. Anal. calcd. for 3 C 36.40, H 4.99.  Preparation of methyl 1-[(E)-3-iodo-3-pentenyU-2-trimethylstannyl-2-cyclopentenecarboxylate (287)  C 2 MeO  3 SnMe 287  Following general procedure 10 (pp 233-234), methyl 2-trimethylstannyl-1cyclopentenecarboxylate (258) was converted into the diene ester 287 with the following quantities 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), in THF, 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 of traces of solvent (vacuum pump) produced 304 mg (56%) of the diene ester 287 as a , 3 H nmr (CDC1 colorless liquid that displayed ir (neat): 1734, 1634, 1168, 770 cnr’; 1 ,2 ) 3 400 MHz): 8 0.15 (s, 9H, Sn(CH SnH= 54 Hz), 1.48-1.58 (m, 1H), 1.58 (d, 3H, , J= 7 Hz), 1.72-1.83 (in, 1H), 2.00-2.13 (m, 1H), 2.20-2.58 (m, 5H), 3.65 (s, 3 =CHCJj , 5.96 (br signal, 1H, SnC=CH, w= 5 Hz, 3 OCH ) 3H, 3 Sn-H= 37 Hz), 6.16 (q, 1H, , 50.3 MHz): 8 -8.4, 16.1, 32.0, 34.2, 34.4, 37.7, 3 , J= 7 Hz); 13 3 =CjjCH C nmr (CDC1  252  51.8, 64.9, 102.0, 135.5, 143.5, 148.7, 176.5. Exact mass calcd. for C 4H22IO2Sn 1 (M Me): 468.9688; found: 468.9691. Anal. calcd. for 2 SH2SIO 1 C S n: 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 (288 C 2 MeO  288  Following general procedure 10 (pp 233-234), methyl 2-trimethyistannyl- 1cyclopentenecarboxylate (258) was converted into the diene ester 288 with the following quantities 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 the crude product, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) provided 343 mg (63%) of the diene ester 288 as a colorless liquid ;1 1 H nmr (CDC1 , 400 MHz): 30.13 (s, 3 that exhibited ir (neat): 1733, 1617, 1142,771 cm 9H, Sn(CH3)3, 2 Sn..H= 54 Hz), 1.25-1.53 (m, 3H), 1.70-1.90 (m, 2H), 2.26-2.60 (m,  ), 5.67 (s, 1H, =CH 3 ), 5.94 (br s, 1H, SnC=CH, wl/2= 4 Hz, 2 5H), 3.64 (s, 3H, OCH ); 13 2 , 50.3 MHz): 3 -8.5, 24.4, 32.0, 3 C nmr (CDC1 Sn-H 37 Hz), 5.98 (s, 1H, =CH 3 34.1, 36.9, 45.3, 51.8, 65.3, 112.1, 125.7, 143.3, 148.7, 176.8. Exact mass calcd. for  253 4H22IO2Sn (M 1 C  -  Me): 468.9688; found: 468.9696. Anal. calcd. for C SH2SIO2Sn: 1  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 (284  285  284  To a cold (-20 OC), stirred solution of LDA (4.00 mmol) in dry TI{F (17 mL) was added dry HMPA (0.47 mL, 2.7 mmol) and the mixture was stirred at -78 °C for 5 miii. A solution of methyl 2-thmethylstannyl-1-cyclohexenecarboxylate (259) (535 mg, 1.76 mmol) in dry THF (2.0 mL) was added dropwise over a period of 30 s. The resulting yellow solution was stirred 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, technical grade, —85%, —4.68 mmol) in dry THF (1.0 mL) was added quickly. The dark mixture was stirred at -78 °C for 5 mm and at -20 °C for 30 mm. Saturated aqueous NaHCO3 (20 mL) 0 2 was added. The phases were separated and the aqueous phase was extracted with Et (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. The  254 eluate was concentrated and the remaining oil was purified by radial chromatography (4 mm silica gel plate, 7: 1 petroleum ether-CH2C12). Concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) afforded 105 mg (14%) of the ester 285 (the less polar component) and 321 mg (43%) of the ester 284 (the more polar component).  ; 1 Ester 285, a colorless liquid, displayed ir (neat): 1701, 1627, 1269, 1248, 770 cnr ,2 ) 3 , 400 MHz): 3 0.15 (s, 9H, Sn(CH 3 nmr (CDC1 SnH= 53 Hz), 1.43-1.72 (m, 4H), ), 2.56 (dt, 1H, 2 2.18 (dd, 1H, =CBrCH2, J= 15, 12 Hz), 2.28-2.40 (m, 2H, SnC=CCII , J= 15, 1.5 Hz), 2.88 (br d, 1H, tertiary proton, J= 12 Hz, 3 2 =CBrCH Sn-H= 30 Hz), , J= 1.5 Hz); in a 2 , J= 1.5 Hz), 5.57 (t, 1H, =CH 2 , 5.47 (t, 1H, =CH OCH ) 3.70 (s, 3H, 3 series of decoupling experiments, irradiation at 6 2.18 simplified the doublet of triplets at 6 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 62.18 to 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);  , 50.3 MHz): 6 -6.5, 3 ‘c nmr (CDC1  51.9, 118.6, 132.3, 136.9, 165.3, 169.4. (M  -  Me): 406.9669; found: 406.9665.  17.2, 24.1, 26.7, 38.2, 44.5,  Exact mass calcd. for BrO2Sn 3 19 C 7 Q 2 H Anal. calcd. for 2 rO n: C 39.85, 4H2 1 C B 3 S  H 5.49, Br 18.94; found: C 39.58, H 5.57, Br 19.08.  ; 1 Ester 284, a colorless oil, exhibited ir (neat): 1719, 1624, 1211, 1143, 769 cm Sn(CH S , ) nmr (CDC1 , 400 MHz): 6 0.12 (s, 9H, 3 3 2 n.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,  , J= 1 Hz), 5.57 (s, 1H, 2 , 5.50 (d, 1H, =CH OCR ) =CBrCH2, J= 15, 1 Hz), 3.68 (s, 3H, 3 C nmr (CDC1 , 50.3 MHz): 3 , 5.98 (t, 1H, SnC=CH, J= 4 Hz, 3 =CH ) 2 SnH= 73 Hz); 13 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.  Exact  mass calcd. for 79 3 (M Me): 406.9669; found: 406.9674. Anal. calcd. for 10 C 2 H BrO2Sn -  H2 C 39.85, H 5.49, Br 18.94; found: C 40.23, H 5.52, Br 18.71. 3 4 1 C B rO2Sn:  255 eparafion of methyl 1-(n-propvl-2-methvlstannvl-2-cyclohexenecarxylate (300  300  To a cold (-20 OC), stirred solution of LDA (2.54 mmol) in dry THF (10 niL) was added dry HMPA (0.70 niL, 4.0 mmol) and the solution was stirred at -78 °C for 5 miii. A solution of methyl 2-trimethylstannyl-1-cyclohexenecarboxylate (259) (358 mg, 1.18 mmol) in dry THF (1.5 mL) was added dropwise over a period of 30 s. After the resulting yellow solution had 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 aqueous NaHCO3 (10 niL) was added and the phases were separated. The aqueous layer was extracted 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 radial chromatography (2 mm silica gel plate, 50: 9 petroleum ether-CH2C12). Concentration of the appropriate fractions, followed by distillation (104.121 °C/0.15 Torr) of the acquired oil provided 319 mg (78%) of the ester 300 as a colorless oil that showed ir (neat): 1735, 1213, ; 1 1 H nmr (CDC1 , 400 MHz): 8 0.09 (s, 9H, 3 3 Sn(CH S , ) 1153, 769 cnr 2 nH= 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), ), 5.93 (t, 1H, =CH, J= 4 Hz, 3 3 3.63 (s, 3H, OCH , 3 C nmr (CDC1 Sn-H= 76 Hz); 13 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. for 3 3H2 1 C O 2Sn (M+ Me): 331.0721; found: 331.0723. Anal. calcd. for -  C14H26O2Sn: C 48.73, H 7.59; found: C 48.71, H 7.44.  256 paion of methyl 1-(2-omo-2-propenvl)cyclohexanecarxylate (302  302  To a cold (-78 OC), stirred solution of LDA (2.37 mmol) in dry THF (5.0 mL) was added 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 for 30 mm, a solution of commercially available 2,3-dibromopropene (273) (642 mg, technical  grade, —85%, —2.73 mmol) in dry HMPA (1.0 mL) was added. The mixture was stirred at 0 (5 mL) was added and the phases were separated. The 2 room temperature for 1 h. H aqueous layer was extracted with Et20 (2 x 5 mL) and the combined organic extracts were washed with brine (10 mL), dried (MgSO4) and concentrated. The crude oil was filtered through 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 by  radial chromatography (2 mm silica gel plate, 3: 1 petroleum ether-CH2C12). Concentration of the appropriate fractions and distillation (75-100 °CI0.3 Torr) of the acquired liquid yielded 291 mg (66%) of the ester 302 as a colorless oil that displayed ir (neat): 1733, 1625, 1215, H nmr (CDC1 , 400 MHz): 8 1.15-1.44 (m, 5H), 1.46-1.63 (m, 3H), 3 1138 cm ; 1 1 , 5.48 (br d, 1H, =CH OCH ) , 2 2.03-2.15 (m, 2H), 2.69 (s, 2H, =CBrCH2), 3.67 (s, 3H, 3 ; 3 =CH ) , 50.3 MHz): 8 22.9, 25.6, 34.0, 47.0, 3 ‘ nmr (CDC1 C J= 1.5 Hz), 5.50 (br s, 1H, 2 1 (M+ 7 0 C 1 H 50.8, 51.6, 120.4, 128.4, 176.0. Exact mass calcd. for 2  -  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.  257 Preparation of methyl 1-[(Z)-3-iodo-2-butenyllcyclohexanecarboxvlate (‘303)  303  Following a procedure (p 256) similar to that described for the preparation of methyl 1 -(2-bromo-2-propenyl)cyclohexanecarboxylate (302), commercially available methyl cyclohexanecarboxylate (301) was converted into ester 303 with the following quantities of reagents 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 C1 (15 mL) being used for elution. 2 (2 g, 230-400 mesh), with 1: 1 petroleum ether-CH The eluate was concentrated and the acquired oil was purified by radial chromatography . Concentration of the appropriate C1 ether-CH ) (4 mm silica gel plate, 3 : 1 petroleum 2 fractions and distillation (62-82 OC/0.15 Torr) of the acquired liquid gave 234 mg (67%) of ; 1 the ester 303 as a colorless oil that exhibited ir (neat): 1729, 1454, 1206, 1134, 1005 cm, 400 MHz): 8 1.13-1.40 (m, 5H), 1.43-1.61 (m, 3H), 1.95-2.07 (m, 2H), 3 nmr (CDC1 =CICH J= 1 Hz), 3.65 (s, 3H, , 2.28 (cM, 2H, =CHCIj , J= 7, 1 Hz), 2.46 (br d, 3H, 3 2 , 50.3 MHz): 3 23.1, 25.7, 33.8, 3 C nmr (CDC1 , 5.25 (tq, 1H, =CH, J= 7, 1 Hz); 13 OCH ) 3 2 322.0431; 9 C 1 H : 2 33.9, 46.7, 47.1, 51.6, 103.1, 130.6, 176.6. Exact mass calcd. for 10  found: 322.0437. Anal. calcd.: C 44.74, H 5.94, I 39.39; found: C 45.13, H 5.94, I 39.05.  258 Preparation of (Z)-5-iodo-2-F(E)- 1 -trimethylstannvl- 1 -propenvll-5-hepten- 1-01 (322)  322  Following general procedure 6 (p 208), ethyl (Z)-5-iodo-2-[(E)-1-trimethylstannyl-1propenyl]-5-heptenoate (209) was converted into (Z)-5-iodo-2-[(E)-1-trimethylstannyl-1propenylj-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): , ) 3 , 400 MHz): 6 0.14 (s, 9H, Sn(CH 3 H nmr (CDC1 ; 1 1 3410 (br), 1648, 1029, 767 cnr OU (exchanges 2 CthCH and CH 2 SnH 52 Hz), 1.28-1.40 (m, 2H, includes one of CH 2 , J= 7 Hz), 3 with D 0)), 1.66-1.82 (m, 1H, CH2CM2CH), 1.68 (br d, 3H, =CHCJj 2 , 2.40-2.50 (m, 1H, =CICH ) 1.72 (br d, 3H, =CHCIj3, J= 7 Hz), 2.30-2.40 (m, 1H, 2  OH; 2 , 2.95-3.04 (m, 1H, CUCH =CICH ) 2 OH, 3 2 Sn-H 93 Hz), 3.3 1-3.39 (m, 1H, Cjj 0 2 OH; after D 2 0 exchange: t centered at 3.35, J= 10 Hz), 3.51-3.60 (m, 1H, Cjj 2 after D exchange: dd centered at 3.56, J= 10, 6 Hz), 5.53 (hr q, 1H, IC=CH, J= 7 Hz), 5.93 (br q, , 50.3 MHz): 3 -7.5, 15.3, 22.1, 3 C nmr (CDC1 1H, SnC=CH, J= 7 Hz, 3 Jsfl..H=78 Hz); 13 2 IOSn 1 C 2 31.8, 42.8, 43.5, 66.2, 110.7, 129.8, 138.9, 146.5. Exact mass calcd. for H (M  -  Me): 428.9739; found: 428.9738. Anal. calcd. for H2 3 C 35.25, H 5.69, 1 C I 5 OSn:  I 28.65; found: C 35.52, H 5.72, I 28.48.  259 Preparation of (E-5-iodo-2-[(E)- 1-trimethvlstannyl- 1 -propenvll-5-hepten- 1-01 (255  I  n Me S 3  255  Following general procedure 6 (p 208), ethyl (E)-5-iodo-2-[(E)-1-trimethylstannyl-1propenyl]-5-heptenoate (211) was converted into (E)-5-iodo-2-[(E)- 1 -trimethylstannyl- 1propenyl]-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 crude product, concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) produced 690 mg (74%) of the alcohol 255 as a colorless liquid that displayed , 400 MHz): 3 0.19 (s, 9H, 3 ; ‘H nmr (CDC1 1 ir (neat): 3383 (br), 1633, 1036, 768 cmCthCH), 1.48 (br dd, 1H, CH2OE, 2 ,2 ) 3 Sn(CH Sn-H= 52 Hz), 1.32-1.43 (m, 1H, CH  J= 7, 2 Hz, exchanges with D20), 1.61 (d, 3H, =CHCth, J= 7 Hz), 1.65-1.76 (m, 1H, ,J 2 CH2CthCH), 1.75 (d, 3H, =CHCTh, J= 7 Hz), 2.32 (br t, 2H, =CICH  7 Hz),  H, S CfjCH O 2.98-3.08 (m, 1H, 2 3 n.H= 92 Hz), 3.39 (br t, 1H, Cij0H, J= 7 Hz; after 1)20 exchange: a sharpened t, J= 7 Hz), 3.55-3.66 (m, 1H, CJjOH; after 1)20 exchange: dd centered at 3.61, J= 9, 7 Hz), 5.96 (qd, 1H, SnC=CH, J= 7, 1 Hz, 3 Sn-H  79 Hz),  , 100.6 MHz): 6 -7.5, 15.3, 16.3, 31.7, 3 6.24 (q, 1H, IC=CH, .1= 7 Hz); C nmr (CDC1 35.3, 43.6, 66.2, 103.4, 135.5, 138.6, 146.6.  Exact mass calcd. for H22IOSn 12 C  3H25IOSn: C 35.25, H 5.69, 1 (M Me): 428.9739; found: 428.9737. Anal. calcd. for C -  I 28.65; found: C 35.35, H 5.65, I 28.49.  260 Preparation of (Z’)-5-iodo- 1-(tert-butyldiphenylsi1oxy-2-r(E- 1 -trimethvlstannvl-1 -propenyll 5-heptene (32380 t—i  323  To 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 added imidazole (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 aqueous NaHCO3 (8 niL) was added and the phases were separated. The aqueous layer was extracted with Et20 (2 x 8 mL) and the combined organic extracts were washed with H20 (20 niL) and brine (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 fractions and removal of traces of solvent (vacuum pump) provided 572 mg (96%) of the silyl ether 323 as a colorless liquid that exhibited ir (neat): 1648, 1606, 1428, 1111, 768, 740, , ) 3 H nmr (CDC1 , 400 MHz): 6 0.02 (s, 9H, Sn(CH 3 ; 1 1 702 cm  53 Hz),  C CH C H), jj 1.58 (br d, 3H, SnC=CHCIj 1.04 (s, 9H, C(CH ), 1.12-1.26 (m, 1H, 2 ) 3 , 3  J= 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, =CICH ), 2.38-2.48 (m, 1H, =CICH2), 2.92-3.01 (m, 111, CJjCH 2 O, 2 JSn-H 90 Hz), 3.38-3.52 (m, 2H, OCH2), 5.47 (br q, 1H, IC=CH, J= 7 Hz), 5.72 (br q, 3 1H, SnC=CH, J= 7 Hz, 3 sn-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 5.47  simplified the doublet at 6 1.70 to a singlet 13 , 50.3 MHz): 6-7.6, 15.1, 19.2, 3 C nmr (CDC1 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,  261 8 (M Me): 667.0917; found: 667.0921. Anal. 20 C 4 H 146.3. Exact mass calcd. for IOS1Sn -  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-propenvU5-heptene (33880  MeSn  I 338  Following 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)-5iodo- 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-trimethylstannylC1 10 niL; imida.zole, 2 CH 1-propenyl]-5-hepten-1-ol (255), 441 mg (0.995 nimol), in , 169 mg (2.49 mmol); tert-butylchlorodiphenylsilane, 0.35 mL (1.4 mmol).  Radial  chromatography (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): , ) 3 H nmr (CDC1 ; 1 1 , 400 MHz): 8 0.08 (s, 9H, Sn(CH 3 1599, 1428, 1113, 768, 702 cm  , 1.18-1.32 (m, 1H, CH C(CH ) ) CffiCH), 1.59 (br d, 3H, 2 SnH 51 Hz), 1.08 (s, 9H, 3 2 CjjCH), 2 =CHCIj3, J= 7 Hz), 1.65 (br d, 3H, =CHCjj, J= 7 Hz), 2.00-2.12 (m, 1H, CH , J= 7 Hz), 2.96-3.07 (m, 1H, CUCH2O, 3 2 2.30 (br t, 2H, =CICH Sn-H  95 1k)’  , 5.76 (br q, 1H, SnC=CH, J= 7 Hz, 3 OCH ) 3.42-3.57 (m, 2H, 2 Sn-H= 81 Hz), 6.22 (br q,  262 1H, IC=CH, J= 7 Hz), 7.33-7.46 (m, 6H, aromatic protons), 7.64-7.74 (m, 4H, aromatic , 100.6 MHz): 6 -7.6, 15.1, 16.3, 19.2, 26.9, 32.0, 35.8, 43.8, 3 protons); 13C nmr (CDC1 67.6, 104.0, 127.6, 129.5, 133.8, 135.3, 135.6, 136.9, 146.5. Exact mass calcd. for 2 C I 0 H4 OSiSn 8 (M  -  23 C 4 H 9 Me): 667.0917; found: 667.0915. Anal. calcd. for IOSiSn:  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 and related substances via intramolecular palladium(0-catalvzed coupling reactions of vinyl a 3 halide and vinyistannane functionsl  General procedure 11  3 R  C 0 2 R 1 R  3 R X  R’  Sn 3 Me  206 X=Brorl  R 2 C0 219  Pd 3 (Ph P ) (5 mol %), LiC1 (2 equiv) and the diene ester 206 A stirred solution of 4 (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 was diluted with 1120 (three times the volume of that of DMF used). The phases were separated 0 (one-half the volume of that of 2 and the aqueous layer was extracted three times with Et 0 used). The combined organic extracts were washed with brine (one-half the volume of 2 H 0 used), dried (MgSO4) and concentrated. Purification of the crude 2 the total volume of Et residual oil as indicated in the individual experiments (vide infra), followed by concentration of the appropriate fractions and distillation of the liquid thus obtained, afforded the alkyl 2,3bis(alkylidene)cyclopentanecarboxylate 219.  263 Preparation of ethyl 2.3-bis(methylene)cyclopentanecarboxvlate (41a) 13a  Hf  Hg t CO E 2 He  41a  Following general procedure 11 (p 262), ethyl 5-bromo-2-[1-(trimethylstannyl)ethenyl]5-hexenoate (40a) was converted into ethyl 2,3-bis(methylene)cyclopentanecarboxylate ) 52.3 mg d, 4 P 3 (Ph (41a) with the following amounts of reagents and solvents: P  (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 crude product, 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 the cyclopentanecarboxylate 41a as a colorless liquid that displayed ir (neat): 1736, 1179, 1041, ; uv: m(E, solvent)= 249.7 nm (9000, n-pentane), 248.6 nm (7900, MeOH); 1 890 cnr , H ) nmr (CDC13, 400 MHz): 8 1.27 (t, 3H, OCH2C, J= 7 Hz), 1.87-1.99 (m, 1H, 2 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, ), 4.94 (t, 1H, HJ, J= 2.5 Hz), 5.11 (d, 1H, He, J 2.5 Hz), 2 He), 4.11-4.26 (m, 2H, OCH , H, H j 5.39 (t, 1H, Hf, J= 2.5 Hz), 5.52 (d, 1H, Hg, J= 2.5 Hz); assignments of protons 1 Hf and Hg are based on nOe difference experiments which were previously studied in our a1 13 laboratory; , 50.3 MHz): 6 14.2, 27.4, 32.4, 50.0, 60.6, 104.8, 106.4, 3 C nmr (CDC1 146.6, 147.3, 173.6. Exact mass calcd. for C1 402: 166.0994; found: 166.0992. Anal. 1 H 0  calcd.: C 72.26, H 8.49; found: C 72.42, H 8.38.  264 Preparation of ethyl (Z)-2-ethylidene-3-methylenecyclopentanecarboxylate (220) 13a  Et 2 IHfHe/-Co 220  Following general procedure 11 (p 262), ethyl 5-bromo-2-[(Z)-1-trimethylstannyl-1propenyl]-5-hexenoate (207) was converted into ethyl (Z)-2-ethylidene-3-methylenecyclopentanecarboxylate (220) with the following amounts of reagents and solvents: ) 90.2 mg (78.1 .tmol); LiC1, 132 mg (3.12 mmol); diene ester 207, 661 mg 4 P 3 (Ph P d, (1.56 mmol), in DMF, 16 mL. The reaction time was 30 mm in this experiment. Flash chromatography (45 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (40-60 OC/0.6 Torr) of the acquired oil, gave 233 mg (83%) of the cyclopentanecarboxylate 220 as a colorless liquid ; uv: 1 that exhibited ir (neat): 1733, 1651, 1189, 1044, 881 cnr  solvent)= 246.4 nm  H nmr (CDC13, 400 MHz): 6 1.28 (t, 3H, (10200, n-pentane), 246.3 nm (7380, MeOH); 1 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 are  a 3 based on nOe difference experiments which were previously studied in our laboratory;l , 50.3 MHz): 3 14.2, 15.5, 27.5, 34.5, 51.2, 60.4, 110.2, 122.8, 138.3, 3 nmr (CDC1 1 180.1150; found: 181.1151. Anal. calcd.: 6 C 1 H : 2 147.3, 174.5. Exact mass calcd. for 0 C 73.30, H 8.95; found: C 73.07, H 9.00.  265 Preparation of ethyl (E)-2-ethylidene-3-methylenecvclopentanecarboxvlate (221) 13a  I  Et 2 / NDO 221  Following general procedure 11 (p 262), ethyl 5-bromo-2-[(E)-1-trimethylstannyl-1propenyl]-5-hexenoate (208) was converted into ethyl (E)-2-ethylidene-3-methylenecyclopentanecarboxylate (221) with the following amounts of reagents and solvents: ) 89.0 mg (77.0 jimol); LiCI, 130 mg (3.07 mmol); diene ester 208, 645 mg d, 4 P 3 (Ph P  (1.52 mmol), in DMF, 15 niL. Flash chromatography (20 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (40-50 °C/0.6 Torr) of the acquired oil, gave 274 mg (87%) of the cyclopentanecarboxylate 221 as a colorless liquid that showed ir (neat): 1732, 1627, ; uv: ?.max(E, solvent)= 253.8 nm (10500, n-pentane), 252.3 nm (8000, MeOH); 1 1181 cmj, J= 7 Hz), 1.80 (d, 3H, =CHCth, OCH C nmr (CDC1 , 400 MHz): 6 1.29 (t, 3H, 2 3  J= 7 Hz), 1.84-1.96, (m, 1H, Ha), 2.04-2.16 (m, 1H, Ha), 2.41-2.55 (m, 1H, Hb), , OCH ) 2.64-2.78 (m, 1H, Hb), 3.65 (br d, 1H, He. 1= 8 Hz), 4.08-4.25 (m, 2H, 2 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 experiments a 13 which were previously studied in our laboratory;  , 50.3 MHz): 8 14.2, 3 ‘c nnir (CDC1  15.1, 28.3, 32.8, 47.0, 60.4, 101.8, 119.0, 139.1, 148.2, 174.2. Exact mass calcd. for 1 180.1150; found: 181.1148. Anal. calcd.: C 73.30, H 8.95; found: C 73.55, 6 0 C 1 H : 2 H 9.12.  266 Preparation of ethyl (ZZ)-2.3-bis(ethylidenecvclopentanecarboxvlate (222  222  Following general procedure 11 (p 262), ethyl (Z)-5-iodo-2-[(Z)-1-trimethylstannyl-lpropenyl] -5-heptenoate (205) was converted into ethyl (Z,Z) -2,3 -bis (ethylidene) cyclopentanecarboxylate (222) with the following amounts of reagents and solvents: d, ) 85.5 mg (74.0 p.mol); LiC1, 120 mg (2.82 mmol); diene ester 205, 674 mg 4 P 3 (Ph P (1.39 mmol), in DMF, 14 mL. Flash chromatography (20 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (60-80 OC/O.6 Torr) of the acquired oil, afforded 256 mg (95%) of the cyclopentanecarboxylate 222 as a colorless liquid that displayed ft (neat): 1737, 1185, 1042 cm; uv: max(C, solvent)= 234.6 nm (12900, n-pentane), 234.7 nm (7600, MeOH); 1 , 400 MHz): 6 1.23 (t, 3H, OCH2CHj, 1= 7 Hz), 1.58 (dt, 3H, =CHeC, 3 nmr (CDC1  .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 a series of decoupling experiments, irradiation at 8 3.34 changed the doublet of doublets at 8 1.62 to a doublet (1=7 Hz), simplified the multiplets at 6 1.78-1.92 and 6 1.92-2.05, and sharpened the broad quartet at 6 5.48; irradiation at 65.38 simplified the doublet of triplets at 8 1.58 to a broad singlet (wi= 4 Hz); irradiation at 65.48 simplified the doublet of doublets at 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 at  267 6 1.62 caused an enhancement of the signal at 8 5.48 (12%); irradiation at 6 3.34 caused enhancement of the signals at 8 1.78-1.92 (7%) and 85.48 (4%); irradiation at 85.38 caused enhancement 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%) and , 50.3 MHz): 6 14.2, 17.1, 17.2, 25.7, 32.7, 49.2, 3 6 3.27-3.41 (4%); 1 C nmr (CDC1 C 1 H : 2 2 194.1307; 8 60.3, 119.5, 120.8, 138.2, 138.7, 174.8. Exact mass calcd. for 0 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)  He  223  Following general procedure ll(j) 262), ethyl (Z)-5-iodo-2-[(E)-1-trimethylstannyl-1propenyl]-5-heptenoate (209) was converted into ethyl (E,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate (223) with the following amounts of reagents and solvents: P 3 (Ph P 4 d, ) 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 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (50-70 O(/0.6 Torr) of the oil thus obtained, produced 80.4 mg (9 1%) of the cyclopentanecarboxylate 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 (CDC1 , 400 MHz): 6 1.23 3  (t,  3H, 3 Cjj J= 7 Hz), 1.80 (br d, 3H, 2 OCH ,  268 CHeCki3, 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, , 5.52 (br q, 1H, HJ, 1= 7 Hz), 5.93 (br q, 1H, H, J= 7 Hz); in a series of OCH ) 2 decoupling experiments, irradiation at 6 1.80 simplified the broad quartet at 6 5.93 to a broad singlet (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 a  series of nOe difference experiments, irradiation at 3 1.80 caused enhancement of the signals at 6 3.58-3.66 (14%) and 6 5.93 (12%); irradiation at 3 1.83 caused enhancement of the signals at 65.52 (9%) and 85.93 (10%); irradiation at 33.62 caused an enhancement of the signal at 6 1.80 (1%) and 6 1.85-2.00 (6%); irradiation at 85.52 caused enhancement of the signals at 8 1.83 (3%), 62.25-2.36 (4%) and 62.53-2.66 (2%); irradiation at 8 5.93 caused , 50.3 MHz): 3 C nmr (CDC1 enhancement of the signals at 6 1.80 (2%) and 8 1.83 (3%); 13 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. Exact mass calcd. for 18 2H 194.1307; found: 194.1313. Anal. calcd.: C 74.19, H 9.34; 1 C 02: found: C 74.40, H 9.40.  269 Preparation of (E.Z)-2.3-bis(ethylidene)-1- (tert-butvldiphenylsiloxvmethvl’)cyclopentane (320)  Ha  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 following d, ) 9.2 mg (8.0 I.Lmol); L1C1, 13.5 mg 4 P 3 (Ph amounts of reagents and solvents: P (0.3 18 mmol); diene 323, 108 mg (0.159 mmol), in DMF, 1.6 mL. After concentration of the 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 eluate was concentrated and was subjected to radial chromatography (2 mm silica gel plate, 40 : 3 petroleum ether-CH2C12). Concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) provided 53.3 mg (86%) of the cyclopentane 320 as a colorless H nnir (CDC13, ;1 1 liquid that showed ir (neat): 1656, 1590, 1428, 1112, 825, 738, 703 cur ), 1.60 (d, 3H, =CHCjj, J= 7 Hz), 1.62-1.75, (m, 1H, ) 3 400 MHz): 8 1.05 (s, 9H, C(CH , J= 7 Hz), 1.87-1.97 (m, 1H, Ha), 2.18-2.31 (m, 1H, Hb), 3 Ha), 1.78 (d, 3H, =CHCjj 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), C nmr 7.29-7.52 (m, 6H, aromatic protons), 7.60-7.75 (m, 4H, aromatic protons); 13 , 100.6 MHz): 6 15.3, 15.4, 19.2, 25.8, 26.8, 32.7, 45.4, 64.6, 116.8, 122.5, 3 (CDC1  270 24 C 3 H 6 390.2380; 127.6, 129.5, 134.0, 135.6, 140.6, 141.8. Exact mass calcd. for OSi: 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 (224  224  Following general procedure 11 (p 262), ethyl (E)-5-iodo-2-[(E)-1-trimethylstannyl-1propenyl] -5-heptenoate (211) was converted into ethyl (E,E)-2, 3 -bis (ethylidene) cyclopentanecarboxylate (224) with the following amounts of reagents and solvents: P)4Pd, 36.1 mg (31.2 imo1); LiC1, 53.0 mg (1.25 mmol); diene ester 211, 303 mg 3 (Ph (0.625 mmol), in DMF, 6.0 mL. Flash chromatography (10 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (55-75 OC(o.6 Torr) of the oil thus obtained, afforded 107 mg (88%) of the cyclopentanecarboxylate 224 as a colorless liquid that displayed ir (neat): 1733, 1185, 1043 cnr ; uv: 1  A(e, solvent)= 256.7 nm (10000, n-pentane), 256.1 nm (10000, MeOH);  CJj J= 7 Hz), 1.67 (br d, 3H, 2 OCH , nmr (CDC1 , 400 MHz): 8 1.22 (t, 3H, 3 3 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 a series of decoupling experiments, irradiation at 6 1.67 simplified the multiplet at 65.72-5.80 to a broad singlet (wip= 6 Hz); irradiation at 8 1.73 simplified the broad quartet at 65.90 to a  271 broad singlet (wi= 4 Hz); irradiation at 8 3.60 sharpened the broad quartet at 8 5.90; in a series of nOe difference experiments, irradiation at 8 1.73 caused enhancement of the signals at 8 3.60 (4%) and 8 5.90 (3%); irradiation at 83.60 caused enhancement of the signals at 8 1.73 (3%) and 8 1.77-1.87 (6%); irradiation at 65.90 caused enhancement of the signals at 6 1.73 (6%) and 6 5.72-5.80 (8%);  nmr (CDC1 , 50.3 MHz): 8 14.0, 14.9, 15.0, 27.9, 3  2 8 0 C 1 H : 28.8, 47.2, 60.4, 113.0, 115.8, 139.7, 140.3, 174.4. Exact mass calcd. for 2 194.1307; 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) 335  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(ethylidene)-1-(tert-butyldiphenylsioxymethyl)cyclopentane (335) with the following amounts of P)4Pd, 11.8 mg (10.2 .tmol); LiC1, 17.6 mg (0.415 mmol); diene 3 reagents and solvents: (Ph 338, 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 a  disposable pipette with 10: 1 petroleum ether-Et20 (15 mL). The eluate was concentrated and was subjected to radial chromatography (2 mm silica gel plate, 40 : 3 petroleum  ether-CH2C12). Concentration of the appropriate fractions and removal of traces of solvent  272 (vacuum pump) provided 72.8 mg (90%) of the cyclopentane 335 as a colorless liquid that , 3 H nmr (CDC1 ; 1 1 exhibited ft (neat): 1664, 1590, 1428, 1112, 824, 737, 702 cm , 1.52 (d, 3H, =CHCII C(CH ) ) 400 MHz): 8 1.05 (s, 9H, 3 , J= 7 Hz), 1.57-1.71 (m, 1H, 3 Ha), 1.62 (d, 3H, =CHCTh, J= 7 Hz), 2.01-2.12, (m, 1H, Ha), 2.14-2.27 (m, 1H, Hb), , J= 10 Hz), 3.54 (dd, 2 2.30-2.42 (m, 1H, Hb), 2.97-3.06 (m, 1H, He), 3.37 (t, 1H, OCH 1H, .OCH2, J= 10, 5 Hz), 5.64-5.73 (m, 1H, =CH), 5.72 (br q, 1H, =CH, J= 7 Hz), C nmr 7.3 1-7.44 (m, 6H, aromatic protons), 7.61-7.72 (m, 4H, aromatic protons); 13 , 100.6 MHz): 8 14.6, 14.8, 19.2, 25.6, 26.9, 27.4, 44.7, 64.4, 112.1, 113.8, 3 (CDC1 6 390.2380; H 2 C 4 OSi: 127.7, 129.5, 134.0, 135.6, 141.4, 142.0. Exact mass calcd. for 3 found: 390.2370. Anal. calcd.: C 79.94, H 8.77; found: C 80.12, H 8.80.  273 Preparation of methyl (Z.Z)-2-(3-tert-butylmethvlsiloxvpropylidene)-3-ethylidenecyclopentanecarboxvlate (225)  225  Following general procedure 11 (p 262), methyl (Z)-5-iodo-2-[(Z)-4-(tert-butyldimethylsioxy)- 1-trimethylstannyl- 1-butenyl]-5-heptenoate (212) was converted into methyl (Z,Z)-2(3-tert-butylmethylsioxypropylidene)-3-ethylidenecyclopentanecarboxylate (225) with the d, ) 31.7 mg (27.4 p.mol); LiCl, 4 P 3 (Ph following amounts of reagents and solvents: P 43.7 mg (1.03 mmol); diene 212, 276 mg (0.449 mmol), in DMF, 3.0 mL.  Flash  chromatography (20 g silica gel, 25: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (100-130 OC/0.6 Torr) of the liquid thus obtained, afforded 105 mg (72%) of the cyclopentanecarboxylate 225 as a ; 1 colorless liquid that displayed ir (neat): 1742, 1256, 1196, 1167, 1103, 837, 777 cnr H nmr uv: ma,cXE, solvent)= 235.9 nm (13600, n-pentane), 237.1 nm (7600, MeOH); 1 , 0.86 (s, 9H, 3 , 1.58 (dt, 3H, Si(CH ) 2 ) C(CH ) ) (CDC13, 400 MHz): 8 0.03 (s, 6H, 3 =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, , 5.38 (br q, 1H, He, J= 7 Hz), OCH ) Hd), 3.61-3.66 (m, 2H, OCH2), 3.66 (s, 3H, 3  5.43 (br t, 1H, Hf, J= 7 Hz); in a series of decoupling experiments, irradiation at 8 1.58 simplified the broad quartet at 6 5.38 to a broad singlet (wl,2= 3 Hz); irradiation at 82.20 simplified the multiplet at 6 3.61-3.66 to an AB system (J= 9 Hz) centered at 6 3.64, and changed the broad triplet at 6 5.43 to a broad singlet (w= 4 Hz); irradiation at 8 3.40  274 simplified the multiplets at 6 1.78-1.90 and 8 1.90-2.02, changed the quartet of doublets at 62.20 to a quartet (J= 7 Hz), and sharpened the broad triplet at 8 5.43; in a series of nOe difference 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 signals , 50.3 MHz): 8 -5.3, 17.0, 18.3, 3 at 5 1.78-1.90 (5%) and 8 5.43 (5%); 13C nmr (CDC1 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 mass 12 C 3 H S 3 8 i: calcd. for O 13 C 2 H S 3 4 i (M t-Bu): 267.1417; found: 267.1416. Anal. calcd. O -  C 66.62, H 9.94; found: C 66.49, H 9.90.  Preparation of methyl (Z-2-cyclovropylmethy1ene-3-methvlenecyclopentanecarboxylate (226  226  Following general procedure 11 (p 262), methyl 5-bromo-2-[(Z)-2-cyclopropyl-1(trimethylstannyl)ethenyl]-5-hexenoate (213) was converted into methyl (Z)-2-cyclopropylmethylene-3-methylenecyclopentanecarboxylate (226) with the following amounts of P 3 (Ph P d, ) 46.7 mg (40.4 tmol); LiCl, 68.8 mg (1.62 mmol); diene reagents and solvents: 4 213, 343 mg (0.787 mmol), in DMF, 8.0 mL. Flash chromatography (45 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (70-85 OC/tJ.6 Torr) of the remaining liquid, afforded 142 mg (94%)  275 of the cyclopentane 226 as a colorless liquid that exhibited ir (neat): 1734, 1198, 1168, 1039 cm; uv: A(c, solvent)= 260.0 nm (9800, n-pentane), 260.9 nm (8530, MeOH); 1 111  , 400 MHz): 6 0.35-0.46 (m, 2H, cyclopropyl methylene protons), 3 nmr (CDC1  0.77-0.86 (m, 2H, cyclopropyl methylene protons), 1.79-1.93 (m, 1H, cyclopropyl methine proton), 1.85-1.96 (m, 1H, Ha), 1.98-2.08 (m, 1H, Hb), 2.39-2.49 (m, 1H, He). , 5.14 (d, 1H, He, OCH ) 2.62-2.72 (m, 111, He), 3.38-3.45 (m, 1H, Hj), 3.67 (s, 311, 3 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 of decoupling experiments, irradiation at 8 0.41 simplified the multiplet at 6 0.77-0.86 to a doublet (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 caused enhancement of the signals at 6 1.85-1.96(9%) and 85.14(9%); irradiation at 65.14 caused an enhancement of the signal at 63.38-3.45 (3%); irradiation at 65.15 caused enhancement of the signals at 82.39-2.49 (2%), 2.62-2.72 (2%), and 6 5.47 (23%); irradiation at 65.47 , 3 caused enhancement of the signals at 6 1.79-1.93 (7%) and 65.15 (25%); 13C nnir (CDC1 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. Exact 2 192.1151; found: 192.1150. Anal. calcd.: C 74.97, H 8.39; 6 0 C 1 H : mass calcd. for 2 found: C 74.92, H 8.47.  276 Preparation of methyl (Z.Z)-2-cvclopropvlmethvlene-3-ethylidenecvclopentanecarboxvlate (227  He 227  Following 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)-2cyclopropylmethylene-3-ethylidenecyclopentanecarboxylate (227) with the following d, ) 85.6 mg (74.1 jimol); LiC1, 126.4 mg 4 P 3 (Ph amounts of reagents and solvents: P (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 concentration of the appropriate fractions and distillation (90-100 OCfO.6 Torr) of the residual liquid, gave 288 mg (97%) of the cyclopentanecarboxylate 227 as a colorless liquid that showed ir (neat): ; uv: max(E, solvent)= 248.4 nm (13300, n-pentane), 247.9 nm 1 1740, 1167, 1031 cnr , 400 MHz): 8 0.35-0.44 (m, 2H, cyclopropyl methylene 3 H nrnr (CDC1 (9650, MeOH); 1 protons), 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), , 4.83 (br d, 1H, He, J= 7 Hz), 5.42 (br q, OCH ) 3.37-3.42 (m, 1H, Hij), 3.66 (s, 3H, 3 1H, Hf, J= 7 Hz); in a series of decoupling experiments, ilTadiation at 84.83 simplified the multiplet at 83.37-3.42 to a doublet of doublets (J= 9,6 Hz), and the broad quartet at 65.42 to a quartet of triplets (J= 7, 1.5 Hz); irradiation at 65.42 simplified the doublet of triplets at 8 1.78 to a broad singlet (wi= 5 Hz), and the broad doublet at 8 4.83 to a doublet of  277 doublets (J= 7, 1.5 Hz); in a series of nOe difference experiments, irradiation at 8 1.41 caused enhancement of the signals at 6 0.75-0.90 and 8 1.78; irradiation at 6 1.78 caused enhancement of the signals at 3 1.35-1.46 and 3 5.42; irradiation at 3 3.40 caused enhancement of the signals at 8 1.84-1.96 and 6 4.83; irradiation at 8 4.83 caused enhancement of the signals at 80.35-0.44 and 8 3.37-3.42; irradiation at 85.42 caused an , 50.3 MHz): 6 6.8, 7.5, 14.1, 17.2, 3 C nmr (CDC1 enhancement of the signal at 6 1.78; 13 25.9, 33.1, 49.1, 51.7, 119.5, 130.8, 134.9, 139.0, 175.1.  Exact mass calcd. for  3 206.1307; found: 206.1306. Anal. calcd.: C 75.69, H 8.80; found: C 75.49, 8 0 C 1 H : 2 H 8.75.  228  epantion of methyl  228  Following general procedure 11 (p 262), methyl (Z)-6-cyclopropyl-5-iodo-2-[(Z)-2cyclopropyl- 1 -(trimethylstannyl)ethenyl]-5-hexenoate (215) was converted into methyl (Z,Z)-2,3-bis(cyclopropylmethylene)cyclopentanecarboxylate (228) with the following ) 18.5 mg (16.0 p.mol); LiC1, 28.8 mg d, 4 P 3 (Ph amounts of reagents and solvents: P (0.679 mmol); diene 215, 169 mg (0.323 mmol), in DMF, 3.2 mL. The resulting mixture was stirred at 90 °C for 1 h in this experiment. Flash chromatography (20 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate  278 fractions and distillation (55-70 °Cf0.6 Torr) of the residual oil, gave 64.8 mg (86%) of the cyclopentanecarboxylate 228 as a colorless liquid that displayed ir (neat): 1730, 1167, 1044 cm; uv: max(E, solvent)= 257.8 nm (11000, n-pentane), 259.3 nm (9890, MeOH); 1 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), ), 3 2.38-2.50 (m, 1H, He), 3.40 (ddd, 1H, Hf, J= 8, 6, 1.5 Hz), 3.68 (s, 3H, OCH 4.74 (br d, 1H, Hg, J= 9 Hz), 4.81 (br d, 1H, Hh, 1= 9 Hz); in a series of decoupling experiments, irradiation at 60.39 simplified the multiplets at 6 1.65-1.73 and at 6 1.73-1.82 to two quartets (both with J= 9 Hz) centered at 6 1.69 and at 6 1.78, respectively; irradiation at 6 0.75 simplified each of the multiplets at 6 1.65-1.73 and at 6 1.73-1.82 to a doublet of triplets (J= 9, 4 Hz) centered at 6 1.69 and at 6 1.78, respectively; irradiation at 8 4.81 simplified the multiplet at 6 1.73-1.82, and changed the doublet of doublet of doublets at 6 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 at C nmr (CDC13, 50.3 MHz): 6 7.5, 7.7, 8.1, 13.9, 6 0.30-0.48 (4%) and 8 3.40 (2%); 13 14.2, 26.2, 33.2, 49.4, 51.8, 129.3, 130.7, 135.3, 136.4, 175.2. Exact mass calcd. for 12: C 0 0 H2 5 232.1464; found: 232.1462. Anal. calcd.: C 77.55, H 8.68; found: C 77.74, H 8.68.  279 paradon of ethyl Z-2.3-bis(2-methylpropylidenecvclopentanecarxylate (229  Hf 229  Following general procedure 11 (p 262), ethyl (Z)-5-iodo-7-methyl-2-[(Z)-3-methyl-1trimethyistannyl- 1 -butenylj-5-octenoate (216) was converted into ethyl (Z,Z)-2,3-bis(2methylpropylidene)cyclopentanecarboxylate (229) with the following amounts of reagents ) 22.0 mg (19.0 p.mol); LiCl, 32.0 mg (0.755 mmol); diene 216, 4 P 3 (Ph d, and solvents: P  205 mg (0.378 mmol), in DMF, 4.0 mL. The resulting mixture was stirred at 105 OC for 1.5 h in this experiment. Flash chromatography (20 g silica gel, 40 : 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation (55-80 OC/0.6 Torr) of the remaining oil, provided 48.9 mg (52%) of the cyclopentanecarboxylate 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 (CDC1 , 400 MHz): 8 0.88-0.98 (4 overlapping doublets centered at 0.91, 0.93, 3 C, J= 7 Hz), 2 0.94, 0.95; 12H, 2 x CH(C1j3)2, all with J= 7 Hz), 1.23 (t, 3H, OCH 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, , 3.28 (ddd, 1H, Hj, 1= 9, 6, 1 Hz), 4.06-4.20 (m, jj(CH ) 2 ) He), 2.37-2.50 (m, 2H, 2 x 3 2H, OCH2), 5.09 (d, 1H, He, .1= 10 Hz), 5.19 (d, 1H, Hf, J= 10 Hz); in a series of decoupling experiments, irradiation at 60.93 simplified the multiplet (corresponding to two different protons) at 62.37-2.50 to two doublets (both with J= 10 Hz) centered at 62.41 and at 62.46; irradiation at 8 2.44 simplified the four overlapping doublets at 60.88-0.98 to four  280 singlets centered at 6 0.91, 0.93, 0.94, 0.95, and simplified the two doublets of doublets at 65.09 and 8 5.19 to two broad singlets (wi,= 8, 9 Hz, respectively); irradiation at 8 3.28 simplified the two multiplets at 8 1.80-1.90 and 8 1.90-2.00, and sharpened the doublet at  65.19; irradiation at 8 5.19 simplified the signal (one of two multiplets) at 32.37-2.50, and simplified the signal at 6 3.28 to a doublet of doublets (J= 9, 6 Hz); in a series of nOe difference experiments, irradiation at 8 2.44 caused an enhancement of the signals at 60.88-0.98 (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 at , 50.3 MHz): 8 14.2, 22.4, 22.5, 23.15, 23.2, 25.1, 29.2, 3 8 3.28 (8%); 13C nmr (CDC1 29.5, 33.2, 49.4, 60.2, 132.6, 133.9, 134.2, 134.8, 174.7.  Exact mass calcd. for  6 250.1934; found: 250.1928. Anal. calcd.: C 76.75, H 10.47; found: C 76.46, 0 1 C 2 H : 2 H 10.48.  Preparation of (E-2-ethvlidene- 1-hydroxvmethvl-3-methylenecyclopentane (337 Hb  337  To a cold (0 °C), stirred solution of lithium aluminum hydride (13.5 mg, 0.356 mmol) in dry Et20 (1.0 mL) was added a solution of ethyl (E)-2-ethylidene-3-methylenecyclopentane0 (1.0 mL). The reaction mixture was 2 carboxylate (221) (82.0 mg, 0.455 mmol) in dry Et C for 2 miii and then at room temperature for 10 miii. Sodium sulfate stirred at 0 0  281 decahydrate (110 mg, 0.34 1 mmol) was added and the mixture was stirred at room temperature for 10 mm. The resulting solid was removed by filtration through a plug of Florisil® (2 g) and the column was eluted with Et20 (2 mL). Concentration of the combined eluate, followed by distillation (40-60 OC/0.15 Torr) of the material thus obtained, gave 50.1 mg (80%) of the alcohol 337, a colorless oil that showed ir (neat): 3320 (br), 1440, H nmr (CDC1 , 400 MHz): 3 1.37 (dd, 1H, OH, J= 7, 5 Hz, exchanges with 3 1030 cm; 1 1 D20), 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 to a 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, , 3 , wl/2= 6 Hz), 6.04 (qd, 1H, =CJjCH 2 1H, =CH2, wl/2= 5 Hz), 5.20 (br s, 1H, =CH , 50.3 MHz): 6 15.1, 26.0, 31.4, 44.2, 64.1, 101.7, 117.6, 3 C nmr (CDC1 J= 7, 1.5 Hz); 13 14 138.1045; found: 138.1043. Anal. calcd.: H 9 C 141.0, 148.8. Exact mass calcd. for 0: C 78.21, H 10.21; found: C 75.41, H 9.97.  Preparation of 1 -(tert-butvldinhenvlsioxvmethvl)-(E)-2-ethvlidene-3-methvlenecvclopentane (332)  (tBU) 2 OS:h 332  Following a procedure similar to that given for the preparation of (Z)-5-iodo-1-(tertbutyldiphenylsiloxy)-2- [(E)- 1 -trimethyistannyl- 1 -propenylj-5-heptene (323), (E)-2ethylidene-1-hydroxymethyl-3-methylenecyclopentane (337) was converted into 1-Qert-  282 butyldiphenylsiloxymethyl)-(E)-2-ethylidene-3-methylenecyclopentane (332) with the following amounts of reagents and solvents: (E)-2-ethylidene-1-hydroxymethyl-3-methyleneC1 1.0 mL; imidazole, 19.0 mg 2 CH cyclopentane (337), 15.4 mg, (0.111 mmol), in , (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 the appropriate fractions and removal of traces of solvent (vacuum pump) produced 41.8 mg C) that exhibited ir (neat): (99.5%) of the cyclopentane 332 as a colorless solid (mp 39-41 0  , 400 MHz): 6 1.05 (s, 9H, 3 H nmr (CDC1 ; 1 1 1659, 1626, 1428, 1111, 824, 702 cm-  , .1= 7 Hz), 1.62-1.73 (m, 1H, Ha), 2.002.08, (m, 3 , 1.55 (br d, 3H, =CHCJj C(CH ) ) 3 , J= 10 Hz), 2 1H, Ha), 2.31-2.45 (m, 2H, Hb), 2.98-3.05 (m, 1H, l ) 3.40 (t, 1H, OCH 1 , wl/2= 5 Hz), 5.15 (br s, 1H, 2 , J= 10, 5 Hz), 4.71 (br s, 1H, =CH 2 3.58 (dd, 1H, OCH , J= 7, 2 Hz), 7.34-7.43 (m, 6H, aromatic 3 , wl/2= 5 Hz), 5.92 (qd, 1H, =CJjCH 2 =CH , 50.3 MHz): 6 14.8, 19.3, 3 C nmr (CDC1 protons), 7.65-7.70 (m, 4H, aromatic protons); 13 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. 5 376.2224; found: 376.2224. Anal. calcd.: C 79.73, 2 OSi: 2 C 3 Exact mass calcd. for H H 8.56; found: C 79.78, H 8.56.  283 11. Preparation of alkyl 2.3-bis(alkylidene)cvclopentanecarboxylates and other dienes via CuC1-mediated intramolecular coupling reactions of vinyl halide and vinyistannane functions  General procedure 12 C 0 2 R  3 R  3 R n Me S 3  X  219  206 X=I  C 2 MeO  x  2y  262  261  260  n’=lor2; n”=12or3; R=HorMe; X=Brorl  A stirred solution of the diene ester 206 or 219 (1 equiv) in dry DMF (—10 mL per mmol 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 °C for 2-10 mm, unless otherwise noted. The reaction flask was removed from the oil bath, 1-NH4OH (pH NH C aqueous 4  =  8) (three times the volume of that of the DMF used) was  0 (the 2 added, and the mixture was opened to the atmosphere. After a short period of time, Et H (pH C1-NH 4 NB same volume as that of the aqueous O  =  8) used) was added and the  mixture was stirred until the aqueous phase became deep blue (—15 mm). The phases were 0 (the same volume as that of the 2 separated and the aqueous layer was extracted twice with Et  284  C1-NH4OH (pH 4 aqueous NH  =  8) used). The combined organic extracts were washed with  brine (one-half the volume of the total volume of Et20 used), dried (MgSO4) and concentrated. Flash or radial chromatography of the remaining liquid on silica gel, followed by concentration of the appropriate fractions and distillation of the residual oil, afforded the cyclic diene 260, 261 or 262.  Preparation of ethyl (ZZ)-2.3-bis(ethv1idenecyclopentanecarboxy1ate (222  222  Following general procedure 12 (pp 283-284), ethyl (Z)-5-iodo-2-[(Z)-l-trimethylstannyl- 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: diene ester 205, 127 mg (0.261 mmol), in DMF, 2.6 mL; CuC1, 77.8 mg (0.786 mmol). The reaction mixture was stirred at 60 OC for 2 mm. Flash chromatography (10 g silica gel, 40: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions 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 with those recorded earlier (see pp 266-267).  285 Preparation of ethyl (E2)-2.3-bis(ethylidene)cyclopentanecarboxylate (223)  223  Following general procedure 12 (pp 283-284), ethyl (Z)-5-iodo-2-[(E)-1-trimethylstannyl-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: diene ester 209, 117 mg (0.240 mmol), in DMF, 2.4 mL; CuCl, 50.0 mg (0.505 mmol). The reaction mixture was stirred at 60 °C for 2 mm. Radial chromatography (1 mm silica gel plate, 7: 1 petroleum ether-CH2C12) of the crude product, followed by concentration of the appropriate fractions and distillation (50-70 °C/O.3 Torr) of the oil thus obtained, produced 38.9 mg (83%) of the cyclopentanecarboxylate 223 as a colorless liquid that showed spectra identical with those recorded earlier (see pp 267-268).  286 eption of ethyl (E.-2.3-bis(ethylidene)cyc1opentanecarboxy1ate (224)  C 2 EtO  I  Sn 3 R  211  R=Me  296  R=n-Bu  224  (From 211) Following general procedure 12 (pp 283-284), ethyl (E)-5-iodo-2-[(E)-1trimethylstannyl- 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: 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 C1 of the crude product, followed by 2 ether-CH (2 mm silica gel plate, 6: 1 petroleum ) concentration of the appropriate fractions and distillation (50-70 OC/O.3 Torr) of the liquid thus obtained, yielded 67.4 mg (80%) of the cyclopentanecarboxylate 224 as a colorless liquid 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)-2,3bis(ethylidene)cyclopentanecarboxylate (224) with the following amounts of reagents and solvents: 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-up and concentration, bulb—to-bulb distillation was carried out at 80-85 OC/4() Torr to remove DMF, and then at 100-125 OC/40 Torr to give a distillate which was enriched in the  287 cyclopentanecarboxylate 224 (containing trace amounts of DMF and impurities by gic analysis), 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 appropriate fractions and distillation (45-65 °C/0.3 Torr) of the acquired liquid, gave 23.3 mg (54%) of the cyclopentanecarboxylate 224. The aforementioned residue was purified by distillation (120-140 0 Q’O.3 Torr) to give 48.3 mg (67%) of thbutyltin chloride, the structure of which  H nmr H nmr spectroscopy and low resolution mass spectrometry. The 1 was confirmed by 1 spectrum of the isolated tributyltin chloride is identical with that of a commercially available sample. The low resolution mass spectrum of the isolated compound displayed the fragment of M (n-Bu) (m/e= 269, 68.2%), while the low resolution desorption chemical ionization -  ) mass spectrum of this compound showed the molecular ion complex of 3 (reagent gas: NH M  +  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)  230  224  Ethyl (E)-5-iodo-2- [(Z)- 1 -trimethylstannyl- 1 -propenyl] -5-heptenoate (210) was converted into ethyl (Z,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (230) with the following amounts of reagents and solvents: diene ester 210, 92.3 mg (0.190 mmol), in  DMF, 2.0 mL; CuCI, 43.6 mg (0.440 mmol). General procedure 12 (pp 283-284) was  288 employed, except that the CuC1 was added to the DMF solution of 210 at room temperature and 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 concentration of the appropriate fractions and distillation (50-70 OC/O.3 Torr) of the acquired liquid provided 34.8 mg (94%) of a colorless liquid that consised of a mixture of the cyclopentanecarboxylates 230 and 224, in a ratio of 31: 1 (determined by integration of nmr signals), respectively. This mixture was purified by semi-preparative hplc (Waters Radia1-Pak cartridge, 25 x 100 mm, 10 j.t .tPorasi1). The hplc system used was composed of a System Controller model 600E and Tunable Absorbance Detector model 486 (tuned at 256 nm), both from Waters. The Controller and the Detector were supervised by an IBM clone computer running a Chromatography Workstation Maxima 825 version 3.30 program from Dynamic Solution (Millipore). The eluant used was 50:50 hexane-CHZC12. Collection of the appropriate fractions, followed by removal of traces of solvent (vacuum pump) yielded 25.9 mg (70%) of a pure sample of the major isomer, the cyclopentanecarboxylate 230, ; uv: wmax(e, solvent)= 1 which exhibited ir (neat): 1734, 1447, 1370, 1186, 1043 cm, 400 MHz): 3 H nmr (CDC1 249.1 nm (13000, n-pentane), 248.9 nm (6700, MeOH); 1  Jj J= 7 Hz), 1.72 (br d, 3H, =CHfCJj3, J= 7 Hz), 1.79-1.91 (m, 3 C 2 OCH 8 1.23 (t, 3H, , 1H, Ha), 1.82 (br d, 3H, =CHeCIj3, J= 7 Hz), 1.94-2.05 (m, 1H, Hb), 2.30-2.42 (m, 1H, , OCH ) Hc), 2.51-2.63 (m, iN, He), 3.30-3.37 (m, 1H, H(J), 4.05-4.18 (m, 2H, 2 5.60 (br q, 1H, He, J= 7 Hz), 5.72-5.82 (m, 1H, Hf); in a series of decoupling experiments, 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 caused  enhancement 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%);  289 13C nmr (CDC1 , 50.3 MHz): 8 14.2, 15.4, 15.5, 27.1, 29.5, 51.7, 60.3, 119.4, 121.7, 3 2 194.1307; found: 194.1303. Anal. 8 0 C 1 H : 139.3, 139.9, 174.7. Exact mass calcd. for 2 calcd.: C 74.19, H 9.34; found: C 73.92, H 9.50.  H nmr spectrum of 224 was recorded previously, see The minor product 224 (the 1 pp 270-27 1) showed signals at 3 1.67 (br d, =CHbCIj3, J= 7 Hz), 3.60 (br d, Ha, 1 9 Hz) H nmr spectrum of the mixture of the cyclopentane and 5.90 (br q, H, J= 7 Hz) in the 1 carboxylates 230 and 224, which are in a ratio of 31: 1, respectively. The latter ratio was H nmr signals of Hrj of 230 and Ha of 224. determined by integration of the 1  Preparation of 1 -hydroxymethyl-(E,E)-2.3-bis(ethvlidenecvclopentane (256  256  (E)-5-Iodo-2-[(E)- 1-trimethyistannyl- 1 -propenyl]-5-hepten- 1-01(255) was converted into 1 -hydroxymethyl-(E,E)-2,3-bis(ethylidene)cyclopentane (256) with the following amounts 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 for 10 mm. Radial chromatography (1 mm silica gel plate, 1: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and distillation  290 (45-65 OC/0.3 Torr) of the acquired liquid, provided 35.2 mg (86%) of the cyclopentane ; 1 256 as a colorless oil that showed ir (neat): 3326 (br), 1141, 1028 cmH nmr (CDC13, 400 MHz): uv: max(€, solvent)= 254.2 nm (13400, MeOH); 1 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 a series of decoupling experiments, irradiation at 6 1.63 simpilfied the multiplet at 65.68-5.81 to a broad singlet (wia= 6.5 Hz); irradiation at 6 1.74 simplified the broad quartet at 6 5.86 to a broad singlet (wl/2= 4 Hz); in a series of nOe difference experiments, irradiation at 6 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%) and 6 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 at , 50.3 MHz): 6 14.8, 14.9, 25.7, 27.5, 3 C nmr (CDCI 6 1.63 (9%) and 6 5.86 (6%); 13 : 152.1202; found: 10 C O 6 44.4, 64.3, 112.9, 114.5, 140.8, 141.8. Exact mass calcd. for Hi 152.1193. Anal. calcd.: C 78.90, H 10.59; found: C 78.74, H 10.66.  291 eparation of methyl Z.-2-(3-rert-butvImethyIsiloxropvlidene-3-ethylidenecyc1opentanecarboxvlate (225  t-Bi  225  Following general procedure 12 (pp 283-284), methyl (Z)-5-iodo-2-[(Z)-4-(tertbutyldimethylsiloxy)- 1 -trimethylstannyl- 1-butenyl]-5-heptenoate (212) was converted into methyl (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 was  stirred at 60 OC for 10 mm. Radial chromatography (2 mm silica gel plate, 25: 1 petroleum ether-Et20) of the crude product, followed by concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) afforded 47.9 mg (98%) of the cyclopentane 225 as a colorless liquid that showed spectra identical with those recorded previously (see pp 273-274).  292  Preparation of methyl (ZZ)-2.3-bis(cyclopropylmethylene)eyclopentanecarboxylate (228)  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 following amounts 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. Radial C1 of the crude product, ether-CH ) chromatography (1 mm silica gel plate, 4: 1 petroleum 2 followed by concentration of the appropriate fractions and distillation (60-90 OC/0.3 Torr) of the residual liquid, gave 37.5 mg (8 1%) of the cyclopentanecarboxylate 228 as a colorless liquid that showed spectra identical with those recorded earlier (see pp 277-27 8).  293 eparadon of ethyl Z-2.3-bis(2-methvlpropylidenecyclopentanecarxylate (229  229  Following general procedure 12 (pp 283-284), ethyl (Z)-5-iodo-7-methyl-2-[(Z)-3methyl-1-trimethylstannyl-1-butenyl]-5-octenoate (216) was converted into ethyl (Z,Z)-2,3bis(2-methylpropylidene)cyclopentanecarboxylate (229) with the following amounts of reagents 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-CH C12) of the crude product, followed by 2 concentration of the appropriate fractions and distillation (45-65 °CI0.3 Torr) of the remaining oil, provided 30.5 mg (8 1%) of the cyclopentanecarboxylate 229 as a colorless liquid that showed spectra identical with those recorded earlier (see pp 279-280).  294 Preparation of 1-methoxycarbonyl-7-methylenebicycloF4.2.Oloct-5-ene (289)  289  Following general procedure 12 (pp 283-284), methyl 1-(2-bromo-2-propenyl)-2trimethylstannyl-2-cyclohexenecarboxylate (284) was converted into the bicyclic diene 289  with 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 for  5 miii. Radial chromatography (2 mm silica gel plate, 1: 1 petroleum ether-CH2C12) of the crude 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 diene  ; 1 289, a colorless oil that displayed ir (neat): 1728, 1681, 1435, 1283, 1193, 1151, 872 cnr H nmr uv: max(e, solvent)= 242.3 nm (12600, n-pentane), 242.2 nm (14000, MeOH); 1 , 400 MHz): 8 1.08 (td, 1H, Ha, J= 12, 3.5 Hz), 1.48-1.58 (m, 1H, Hb), D 6 (C  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, 11 g. J= 14, 2.5 Hz), 2.88 (dt, 1H, Hg, =CH wrn= 6 Hz), 5.07 (br s, 1H, , , 4.64 (hr s, 1H, 2 OCH ) J= 14, 2.5 Hz), 3.35 (s, 3H, 3 =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), and simplified the doublet of triplets at 82.41 to a doublet of doublets (.1= 12, 3.5 Hz); irradiation at 8 1.82 simplified the multiplet at 8 1.48-1.58 to a doublet of multiplets (J= 12 Hz for the  295 doublet), the broad singlet at 8 5.07 to a triplet (J= 2.5 Hz) and the doublet of doublets at  85.52 to a doublet (J= 3 Hz); irradiation at 32.00 simplified the broad singlet at 65.07 to a triplet (J= 2.5 Hz) and the doublet of doublets at 65.52 to a doublet (J= 4.5 Hz); irradiation at 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 doublet H nmr assignments are consistent with the results of a COSY of doublets at 8 2.00; all 1 , 50.3 MHz): 8 19.8, 24.0, 30.2, 42.6, 50.5, 3 C nmr (CDC1 experiment (Table XXffl); 13 1 178.0994; 4 0 C 1 H : 52.1, 101.8, 117.7, 141.7, 147.6, 175.8. Exact mass calcd. for 2 found: 178.0987. Anal. calcd.: C 74.13, H 7.92; found: C 73.89, H 7.91.  Table XXIII.  Assignment H  Results of the COSY experiment of compound 289  H nmr (C 1 , 400 MHz): 3 D 6  COSY correlations to H  (multiplicity, number of protons, coupling constant(s)) Ha  1.08 (td, 1H, J= 12, 3.5 Hz)  Hb, H, Hf  Hb  1.48-1.58 (m, 1H)  Ha, Hc, Hrj, Hf  F1  1.63-1.76 (m, 1H)  Ha, Hb, FLj, He, Hf  j 1 H  1.74-1.86 (m, 1H)  Hb,  He  2.00 (br dd, 1H, J= 19, 7 Hz)  H, Hd, Hh  Hf  2.41 (dt, 1H, J= 12, 3.5 Hz)  Ha, Hb, FTc  Hg(A)  2.49 (dt, 1H, J= 14, 2.5 Hz)  B) H(B), =CH =CH ( (A), 2 2  H(B)  2.88 (dt, 1H, J= 14, 2.5 Hz)  H(A), =CH (A), =CH2(B) 2  =CH2(A)  4.64 (br s, 1H, w= 6 Hz)  H(A), H(B), =CH2(B)  B) =CH ( 2  5.07 (br s, 1H, wrn= 7 Hz)  H(A), H(B), =CH2(A)  Hh  5.52 (dd, 1H, J= 4.5, 3 Hz)  , He 3 H  He. He, Hh  296 Preparation of 2-methoxvcarbonvl-8-methylenebicvclo[4.2.Oloct- 1 -ene (29O  290  Following general procedure 12 (pp 283-284), methyl 3-(2-bromo-2-propenyl)-2trimethylstannyl-1-cyclohexenecarboxylate (285) was converted into the cyclic diene 290  with 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 OC C1 of ether-CH ) for 5 mlii. Radial chromatography (1 mm silica gel plate, 1: 1 petroleum 2 the 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, a colorless liquid that showed ir (neat): 1708, 1659, 1435, 1262, 1233, 1212, 1195, 1130, 1052 cm ; uv: max(E, solvent)= 266.5 nm (11000, n-pentane), 269.4 nm (10500, MeOH); 1 nmr (CDC1 , 400 MHz): 8 1.01-1.15 (m, 1H), 1.38-1.53 (m, 1H), 1.84-1.98 (m, 2H), 3 , 5.00 (br s, 1H, =CH OCH ) , 2 2.23-2.47 (m, 3H), 2.67-2.84 (m, 2H), 3.72 (s, 3H, 3 , 50.3 MHz): 8 21.7, 3 , w1/2= 6 Hz); 13C nmr (CDC1 2 wl/2= 6 Hz), 5.71 (br s, 1H, =CH 24.7, 26.8, 35.8, 39.3, 51.0, 111.1, 118.3, 146.4, 155.8, 167.4. Exact mass calcd. for 1 178.0994; found: 178.0995. Anal. calcd.: C 74.13, H 7.92; found: C 73.89, 4 0 C 1 H : 2 H 7.86.  297 Preparation of 1 -methoxycarbonvlbicvclo[3 .3.Olocta-3.5-diene (29fl  291  Following general procedure 12 (pp 283-284), methyl 1-[(Z)-3-iodo-2-propenylj-2trimethylstannyl-2-cyclopentenecarboxylate (286) was converted into cyclic diene 291 with the following quantities of reagents and solvents: substrate 286, 198 mg (0.436 mmol), in DMF, 4.4 mL; CuC1, 108 mg (1.09 mmol). The reaction mixture was stirred at 64 °C for H of the 1 ether-C C ) 2 mm. Radial chromatography (2 mm silica gel plate, 3: 1 petroleum 2 crude 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, H nnir ;1 1 a colorless oil that exhibited ir (neat): 1724, 1291, 1248, 1163, 1061, 800 cm , 400 MHz): 8 1.84 (br ddd, 1H, Ha, J= 12, 10, 8 Hz), 2.21 (br d, 1H, Hb, 3 (CD Cl 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), 1 m located at 2.86-3.03 (m, 2H; includes He: dm centered at 2.91, J= 16.5 Hz for doublet, H , 5.50 (br OCH ) 2.96-3.03, 1H), 3.62 (s, 3H, 3  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 doublet of doublets at 62.39 to a doublet (J= 6 Hz), and simplified the signal at 62.58 to a doublet of doublet of doublets (J= 16.5, 3.5, 1 Hz); irradiation at 6 2.21 simplified the resonanace at 62.58 to a doublet of doublet of doublets (J= 16.5, 8, 3.5 Hz), and the doublet of multiplets at 62.91 to a narrow signal (wi= 4.5 Hz) and the broad singlet at 8 5.50 to a doublet of doublets (.1= 3.5, 2 Hz); irradiation at 6 2.39 simplified the broad doublet of doublet of doublets at 8 1.84 to a new doublet of doublet of doublets (J= 10, 8, 2 Hz); irradiation at  298 82.58 simplified the broad doublet of doublet of doublets at 3 1.84 to a doublet of doublet of doublets (J= 12, 10, 2 Hz), irradiation at 8 2.91 simplified the broad doublet at 6 2.21 to a broad singlet (wl/2= 6 Hz); irradiation at 6 5.50 simplified the signal at 8 2.58 to a broad doublet of doublets (J= 16.5, 8 Hz); irradiation at 66.19 simplified the doublet of multiplets H nmr assignments are consistent with the at 6 2.91 to a broad doublet (J= 16.5 Hz); all 1 , 50.3 MHz): 8 37.1, 37.8, 3 results of a COSY experiment (Table XXIX); 13C nmr (CDC1 C 1 H : 2 0 2 40.8, 52.0, 64.5, 118.4, 126.2, 140.3, 154.3, 176.4. Exact mass calcd. for 0 164.0838; found: 164.0836. Anal. calcd.: C 73.15, H 7.37; found: C 73.35, H 7.22.  Table XXIX.  Assignment H  Results of the COSY experiment of compound 291  H nmr (CDC1 1 , 400 MHz): 6 (multiplicity, COSY correlation(s) to 3 number of protons, coupling constant(s))  H  Ha  1.84 (br ddd, 1H, J= 12, 10, 8 Hz)  H, Hj, Hf  Hb  2.21 (br d, 1H, J= 16.5 Hz)  H, H  H  2.39 (dd, 1H, J= 12, 6 Hz)  Ha, Hf  j 1 H  2.58 (dddd, 1H, J 16.5, 8, 3.5, 1 HZ)  Ha, Hf, H  H  5.50 (br s, 1H, wrn= 7 Hz)  299 Preparation of 1-methoxvcarbonyl-4-methylbicyclo[3.3.Olocta-3.5-diene (253’)  •Hh  253  254  (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) was converted 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). The reaction mixture was stirred at 60 OC for 5 mm. Radial chromatography (2 mm silica gel plate, 3: 1 petroleum ether-CH2C12) of the crude product, followed by concentration of the appropriate 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, ; uv: m(C, solvent)= 243.3 nm (12000, n-pentane), 1 1263, 1244, 1168, 1061, 808 cm, 400 MHz): 6 1.78-1.92 (m, 4H; includes Ha: 3 H nmr (CDC1 242.2 nm (10600, MeOH); 1 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, , 5.50 (br OCH ) J= 16 Hz for doublet), 2.88-3.00 (m, 1H, Hf), 3.62 (s, 3H, 3  S,  1H, Hg,  H nmr assignments are consistent with w= 7 Hz), 5.75 (br s, 1H, Hh, w= 6 Hz); all 1 , 50.3 MHz): 6 13.3, 37.6, 3 C nmr (CDC1 the results of a COSY experiment (Table XXX); 13 37.7, 40.3, 51.9, 64.7, 116.5, 134.7, 135.4, 156.6, 176.6.  Exact mass calcd. for  1 178.0994; found: 178.0991. Anal. calcd.: C 74.13, H 7.92; found: C 73.97, H 1 C 4 1 02: H 8.01.  300 Table XXX.  Assignment H  Results of the COSY experiment of compound 253  , 400 MHz): 3 (multiplicity, COSY correlations to 3 H nmr (CDC1 1 number of protons, coupling constant(s))  H  Hb  2.15 (br d, 1H, J= 16 Hz)  =CHCth, He, Hh  H  2.39 (br dd, 1H, J= 12, 6 Hz)  Ha, He, Hf  H€j  2.57 (ddd, 1H, J= 16, 8, 3.5 Hz)  Ha, Hf, H  8 H  2.83 (dm, 1H, J= 16 Hz for doublet)  , Hb, H, Hh 3 =CHCj  Hf  2.88-3.00 (m, 1H)  Ha, H, Hd, H  H  5.50 (br s, 1H, wrn= 7 Hz)  Hd, Hf  Hh  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) was converted 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). The C for 65 mm. Radial chromatography (2 mm silica gel reaction mixture was stirred at 60 0 plate, 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 petroleum ether-CH2C12).  Concentration of the fractions with Rf= 0.20 and distillation (40-60 °C/0.3 Torr) of the remaining 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 of the fractions containing material whose Rf = 0.23 gave 12.0 mg (8%) of the destannylated compound 254 as a colorless liquid that exhibited ir (neat): 1732, 1434, 1201, 1059 cur ; 1  301 , 400 MHz): 8 1.75-1.86 (m, 1H), 2.25-2.60 (m, 5H), 2.48 (q, 3H, 3 nmr (CDC1 ), 5.30 (tq, 1H, IC=CH, 1= 7, 1 Hz), 5.67 (dt, 1H, 3 =CICIj J= 1 Hz), 3.67 (s, 3H, OCH , 3 , 3 C nmr (CDC1 HC=Cjj, J= 5.5, 2 Hz), 5.83 (dt, 1H, HC=Cjj, J= 5.5, 2 Hz); 13 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. 15 306.0118; found: 306.0118. Anal. calcd.: C 43.16, H 1 : 2 Exact mass calcd. for C 1 10 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 the  starting material 252.  Preparation of (E)-4-ethylidene- 1-methoxycarbonvlbicvclo[3.3.rnoct-5-ene (222)  292  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 with the following quantities of reagents and solvents: substrate 287, 163 mg (0.337 mmol), in DMF, 3.4 mL; CuCl, 85.0 mg (0.859 mmol). The resulting mixture was stirred at 65°C for 10 mm. Radial chromatography (1 mm silica gel plate, 3: 1 petroleum ether-CH2C12) of the crude 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, a colorless oil that displayed ir (neat): 1728, 1660, 1244, 1211, 1170, 1068 cm; 1 1 H nmr  302 , 400 MHz): 8 1.20-1.32 (m, 1H), 1.51 (br d, 3H, =CHCH. D 6 (C , J= 7 Hz), 3 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, OCH ), 5.61 (br s, 1H, =CaCH2, w112= 7 Hz), 5.72-5.80 (m, 1H, 3 ); in a series of nOe difference experiments, irradiation at 6 1.51 caused 3 =CjjCH enhancement of signals at 62.39-2.56 (part of the signal located at 2.34-2.59, assuming that two protons were enhanced) (4%) and 8 5.70-5.80 (6%); irradiation at 6 3.04 caused enhancement of signals at 6 2.34-2.48 (part of the signal located at 2.34-2.59, assuming that two protons were enhanced) (10%) and 6 5.61 (2%); irradiation at 8 5.75 caused an enhancement of signal at 6 1.51 (1%); 13 , 50.3 MHz): 6 14.9, 32.6, 34.9, 3 C nmr (CDC1 37.3, 38.4, 51.9, 65.4, 117.3, 119.7, 134.4, 151.7, 176.6.  Exact mass calcd. for  C 1 H : 2 0 2 192.1151; found: 192.1151. Anal. calcd.: C 74.97, H 8.39; found: C 74.56, 6 H 8.27.  Preparation of 1-methoxycarbonyl-5-methylenebicyclo[4.3.Olnon-6-ene (293)7d  293  Methyl 1-(4-iodo-4-pentenyl)-2-triméthylstannyl-2-cyclopentenecarboxylate (288) was converted 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 diene alcohol 288 was heated at 90 °C with an oil bath (—10 mm). Powdered CuC1 was added and  303 C for 5 mm. Radial chromatography (2 mm silica gel the reaction mixture was stirred at 90 0 plate, 1: 1 petroleum ether-C6H6) of the crude product, followed by concentration of the appropriate 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 cnr ; uv: max(e, solvent)= 224.2 nm (6770, n-pentane), 224.4 nm (5000, 1 MeOH); 1 H nmr (CDC1 , 400 MHz): 6 1.30 (td, 1H, J= 13, 3 Hz), 1.47 (qm, 1H, J= 13 Hz 3 for 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, OCH ), 4.71 (t, 1H, olefinic proton, J= 2 Hz), 5.02 (t, 1H, olefinic proton, J= 2 Hz), 3 5.81 (t, 1H, oleflnic proton, J= 2 Hz); all 1 H nmr signals are identical with those reported in lit.;7d 13 , 50.3 MHz): 3 24.2, 30.5, 34.0, 36.8, 38.7, 51.9, 58.2, 108.9, 3 C nmr (CDC1 126.2, 143.1, 144.5, 176.6. Exact mass calcd. for 2 2H C 6 1 : 0 192.1151; found: 192.1153. Anal. calcd.: C 74.97, H 8.39; found: C 75.30, H 8.58.  304 Reactions of ethyl 6-bromo-2-1(E-1-trimethylstannyl-1-propenvl1-6-heptenoate (298 with Cul. Isolation of ethyl 6-bromo-2-[(Z)-1-propenvll-6-heptenoate (306B) and ethyl 6bromo-2-[(E’)- 1 -propenyll-6-heptenoate (3O6C Br  C 2 EtO  Br  C 2 EtO  Br  Et 2 CO  Sn 3 Me 298  306B  306C  Following general procedure l2(pp 283-284), the following quantities of reagents and solvents 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). The resulting mixture was stirred at 60 °C for 10 mm. After normal work-up, the crude product was eluted through a plug of silica gel (—2 g, 230-400 mesh) in a disposable pipette with 4: 1 hexanes-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 that consisted of a mixture of the esters 306B and 306C in a ratio of 1: 1 (determined by integration of 1 H nmr signals). This unseparated liquid mixture displayed ir (neat): 1733, , 400 MHz): 6 0.88-0.98 (m, 3H, OCH2CTh), D 6 1631, 1160, 888 cnr ; 1 1 H nmr (C  1.34-1.54 (m, 311, =CBrCHCjCH and 2 CH2Cfl =CBrCH ) , 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 (from the 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 two isomers)), 3.27-3.35 (m, 1/2 x 1H, CHC=O (from the other isomer)), 3.86-4.02 (m, 2H, , J= 1 Hz), 5.21 (br s, 1H, =CH 2 ), 5.16 (d, 1H, =CH 2 OCH , w= 4 Hz), 5.34-5.56 (m, 2 2H, HC=CH); in a decoupling experiment, irradiation at 65.45 simplified both the doublets of doublets at 6 1.46 and the doublet at 8 1.47 to two singlets. Exact mass calcd. for  305 2H19 274.0569; found: 274.0575. Anal. calcd.: C 52.37, H 6.96, Br 29.04; 1 C BrO2: 79 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 307C Me 2 CO  Me 2 CO 300  307A  2 isomers: 307B, 307C  Following general procedure l2(pp 283-284), the following quantities of reagents and solvents 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 mixture was stirred at 60°C for 10 mm. After normal work-up, the crude product was subjected to radial chromatography (2 mm silica gel plate, 5: 1 hexanes-CH2C12 (—200 mL) and then 5: 1 hexanes-Et20 (—200 niL)). Concentration of the appropriate fractions and distillation (or removal of traces of solvent (vacuum pump)) of the remaining liquid afforded the following substances in an order of increasing polarity:  300: an amount of 47.0 mg (15%) of starting material 300 was recovered after distillation (75-90 °C/0.15 Torr).  306 307A: after distillation (75-90 °CI0. 15 Torr), 70.9 mg (42%) of 307A was obtained as  ;1 1 H nrnr (CDC13, 400 MHz): a colorless oil that displayed ir (neat): 1733, 1209, 1135 cnr 60.85  (t,  3H, 3 Cjj .1= 7 Hz), 1.13-1.32 (m, 2H), 1.33-1.70 (m, 5H), 1.86-2.04 (m, 2 CH ,  2H, =CHCth), 2.14 (ddd, 1H, J= 13, 7, 3 Hz), 3.65 (s, 3H, OCH ), 5.69 (br d, 1H, Ha, 3  J= 10 Hz), 5.76 (dt, 1H, Hb, J= 10, 3.5 Hz); in a decoupling experiment, irradiation at 8 1.95 sharpened the broad doublet at 85.69 and simplified the doublet of triplets at 85.76 to a doublet (J= 10 Hz); 13 C 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. for O2: C 1 H 1 182.1307; found: 8 182.1309. 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 307B was isolated as a colorless solid (mp 91-92 °C) that exhibited ir (KBr): 1719, 1455, 1227, 1161 cm ; 1 1 H nmr (CDC1 , 400 MHz): 8 0.86 (t, 6H, CH2Cth, J= 7 Hz), 1.14-1.34 (m, 3 4H), 1.45-1.78 (m, 8H), 1.79-1.94 (m, 4H), 1.98-2.22 (m, 4H), 3.58 (s, 6H, OCH ), 3 , 50.3 MHz): 6 14.9, 17.6, 17.8, 25.3, 33.5, 3 5.58 (t, 2H, =CH, J= 4 Hz); 13 C nmr (CDC1 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 307C was isolated as a colorless solid (mp 53-54 )C) that exhibited ir (KBr): 1721, 1456, 1226, 1162 cm ; 1 1 H nmr (CDC1 , 400 MHz): 80.86 (t, 6H, 3 3 C 2 CH , J= Jj 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), , 50.3 MHz): 8 14.8, 17.9, 17.95, 25.4, 3 5.50 (t, 2H, =CH, 1= 4 Hz); 13 C nmr (CDC1 32.2, 38.5, 49.8, 51.4, 128.6, 139.6, 177.0. Exact mass calcd. for 0 24 C 3 H : 4 2 362.2458; found: 362.2461. Anal. calcd.: C 72.89, H 9.45; found: C 72.79, H 9.49.  307 Reactions of methyl 1-1(Z)-3-iodo-2-butenyllcvclohexanecarboxylate (303) with CuC1. Isolation of methyl 1 -F(Z)-3-chloro-2-butenyllcyclohexanecarboxylate (308) Me 2 CO  303  308  A 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 stirred at 60 0 C for 4.5 h. Another portion of powdered Cud (120 mg, 1.21 mmol) was added and stirring 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 another C1-NH NH O H (pH =8) 35 h. The reaction flask was removed from the oil bath, aqueous 4 (10 mL) was added, and the mixture was opened to the atmosphere. After a short period of 0 (10 mL) was added and the mixture was stirred until the aqueous phase became 2 time, Et deep blue (—15 mm). The phases were separated and the aqueous layer was extracted with Et20 (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 petroleum ether-CH2C12) of the crude product, followed by concentration of the appropriate fractions and distillation (45-55 °CflJ.15 Torr) of the residual oil gave 27.3 mg (64%) of the ester 308 ;1 1 H nmr (CDC1 , 3 as a colorless liquid that exhibited ir (neat): 1733, 1453, 1207,. 1135 cm400 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, , J= 7 Hz), 3.65 (s, 3H, OCH 2 ), 5.32 (tm, 3 , J= 1 Hz), 2.35 (br d, 2H, =CCH 3 =CC1CH 1H, =CH, J= 7 Hz for triplet); in a series of nOe difference experiments, irradiation at 6 2.04 caused an enhancement of the signal at 8 5.32 (7%); irradiation at 6 2.35 caused an enhancement of the signal at 6 5.32 (5%); irradiation at 85.32 caused enhancement of the  308 , 50.3 MHz): 8 23.1, 25.7, 26.4, 3 C nmr (CDC1 signals at 62.04 (2%) and 62.35 (1%); 1 2 9 35 C 1 H : 2 33.8, 38.9, 47.1, 51.6, 120.8, 132.2, 176.7. Exact mass calcd. for C10 2 C 62.47, H 8.30; found: 9 C 1 H : 2 230.1075; found: 230.1070. Anal. calcd. for C10 C 62.07, H 8.24.  309 a 3 l 52 12. Preparation of 2.3bis(a1kvlidene)cyclopentanecarboxamides  General procedure 13  3 R  3 R 1 R R 2 C0  363  219 4 R  =  aromatic or benzylic  H (—3-5 mL 6 To a stirred solution of aniline or benzylic amine (—1.5-2.0 equiv) in dry C per 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 no more bubbling was observed. A solution of the cyclopentanecarboxylate 219 (1 equiv) in dry C H6 (—2.5-6 mL per mmol of the substrate) was added and the reaction mixture was 6 refluxed for 4 h. A 2.0 M solution of hydrochloric acid (HC1) was added. The phases were 0. The combined organic 2 separated and the aqueous phase was extracted three times with Et extracts were washed with brine, dried (MgSO4) and concentrated. Flash or radial chromato graphy of the crude product, followed by concentration of the appropriate fractions, removal of traces of solvent (vacuum pump) and recrystallization of the substance provided the 2,3bis(alkylidene)cyclopentanecarboxamides 363.  310 Preparation of (R .S)-(÷)- and (R .R)-(-)-N- 1 -phenylethyl-(Z2’)-2.3-bis(ethylidene)cyclopentanecarboxamides (237) and (238)  Hb Ha  bHa  H  237  238  Following general procedure 13 (p 309), the following amounts of reagents and solvents , 2.5 mL; H 6 were used: (R)-(+)-l-phenylethylamine (235), 58.2 mg (0.480 mmol), in C  A1, 0.24 mL (0.48 mmol); ethyl (Z,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate 3 Me , 1.0 mL; 2.0 M HC1, 4.0 mL. Flash chromato H 6 (222), 42.9 mg (0.221 mmol), in C 0) of the crude product and removal of traces 2 graphy (27 g silica gel, 1: 1 petroleum ether Et of solvent (vacuum pump) yielded 28.0 mg (47%) of the amide 237 (the less polar component) 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 amide 237 as a colorless cube-like solid (mp 100.5-102 OC) that displayed ir (KBr): 3264, 1637, , 400 MHz): 6 1.41 (d, 3 H nrnr (CDC1 ; [aJD= +193.4° (c= 1.00 in MeOH); 1 1 1554, 698 cm3H, 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, 11 e. J= 7 Hz), 5.95 (hr d, 1H, NH, J= 7 Hz), 7.21-7.39 (m, 5H, aromatic protons); in a series  of 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 5.43  311 simplified the doublet of triplets at 8 1.62 to a broad singlet (wj/2= 5 Hz); irradiation at 8 5.52 simplified the doublet at 6 1.67 to a broad singlet (wi= 4 Hz); in a series of nOe difference 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 , 50.3 MHz): 6 17.15, 17.2, 21.9, 26.0, 31.8, 48.5, 52.0, 119.7, 3 (7%); 1 C nmr (CDC1 122.6, 126.0, 127.2, 128.6, 138.8, 139.3, 143.4, 173.5.  Exact mass calcd. for  8 269.1780; found: 269.1785. Anal. calcd.: C 80.26, H 8.61, N 5.20; found: 3 N0: 1 C 2 H C 79.99, H 8.76, N 5.10.  Recrystallization of the amide 238 from 1: 2 petroleum ether-Et20 gave the amide 238 as a colorless needle-like solid (mp 107-108 OC) that exhibited ir (KBr): 3292, 3273, 1642, H nmr (CDC1 , 400 MHz): 3 cm- [cz]D= -20.57° (c= 0.860 in MeOH); 1 ; 1561, 1448, 704 1 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 a series of decoupling experiments, irradiation at 8 2.35 simplified the doublet of triplets at 6 1.57 to a doublet (J= 7 Hz), and sharpened the quartet at 8 5.40; irradiation at 6 5.07 simplified the doublet at 8 1.44 to a broad singlet (wi= 2.5 Hz), and the broad doublet at 65.92 to a broad singlet (w= 12 Hz); irradiation at 65.40 simplified the doublet of triplets at 6 1.57 to a triplet (J= 2 Hz); irradiation at 85.53 simplified the doublet at 8 1.67 to a broad , 50.3 MHz): 8 17.15, 17.2, 21.9, 25.9, 31.6, 3 singlet (wl/2= 3.5 Hz); 13 C nmr (CDC1 48.4, 52.1, 119.8, 122.8, 125.8, 127.1, 128.5, 138.7, 139.4, 143.5, 173.5. Exact mass 8 269.1780; found: 269.1786. Anal. calcd.: C 80.26, H 8.61, N 5.20; 1 C 3 2 N0: calcd. for H found: C 80.33, H 8.59, N 5.09.  312 Preparation of N-p-chlorophenvl-(Z.Z-2.3-bis(cvclopropvlmethv1ene)cvclopentanecarboxamide (241)  241  Following general procedure 13 (p 309), the following amounts of reagents and solvents were used: p-chloroaniline (239), 66.3 mg (0.520 mmol), in C , 2.6 mL; Me3A1, H 6 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 chromato graphy (20 g silica gel, 4: 1 petroleum ether Et 0) of the crude product and removal of traces 2 of solvent (vacuum pump) produced 93.5 mg (83%) of the amide 241. Recrystallization of this 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 cm ; 1 nmr (CDC1 , 400 MHz): 0.42-0.60 (m, 4H, cyclopropyl methylene protons), 3 0.80-0.95 (m, 4H, cyclopropyl methylene protons), 1.77-1.90 (m, 2H, cyclopropyl methine protons), 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 1.82  simplified the multiplets at 6 0.42-0.60 and 6 0.80-0.95, and simplified the two doublets at  313 84.87 and 8 4.96 to two broad singlets (wl/2= 5, 3 Hz, respectively); in a series of nOe difference experiments, irradiation at 6 3.40 caused enhancement of the signals at 82.10-2.22 (9%) and 84.96 (10%); irradiation at 84.87 caused enhancement of the signals at 8 1.77-1.90 (4%) and 6 2.35-2.53 (3%); irradiation at 6 4.96 caused an enhancement of the signal at 8 3.40 (4%); 13C nmr (CDC1 , 50.3 MHz): 6 6.9, 7.1, 8.5, 8.9, 13.8, 14.1, 3 26.9, 31.9, 53.3, 120.6, 128.85, 128.9, 130.2, 133.6, 135.6, 136.2, 136.8, 173.3. Exact C 2 H 0 2 mass calcd. for 35 C 2 H C1N0: 0 327.1392; found: 327.1384. Anal. calcd. for C1N0: 2  C 73.27, H 6.76, N, 4.27; found: C 73.17, H 6.67, N, 4.40.  314 Preparation of (R.S)-(÷)- and (R.R)-(-)-N- 1 -phenvlethvl-(Z.Z)-2.3-bis(2-methvlpropvlidene)cyclopentanecarboxamides (242) and (243) Hb  Hb Ha H  242  243  Following general procedure 13 (p 309), the following amounts of reagents and solvents  , 4.0 mL; H 6 were used: (R)-(+)-l-phenylethylamine (235), 94.5 mg (0.780 mmol), in C Me3Al, 0.39 mL (0.78 mmol); ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentanecarboxylate (229), 87.1 mg (0.348 mmol), in C6H6, 1.0 mL; 2.0 M HC1, 4.0 mL. Flash 0) of the crude product and removal 2 chromatography (30 g silica gel, 1: 1 petroleum ether Et of traces of solvent (vacuum pump) produced 45.7 mg (40%) of the ainide 242 as a colorless liquid (the less polar component) and 52.2 mg (46%) of the anilde 243 as a solid (the more polar component).  cm [a]D= +156.9° ; The amide 242 displayed ir (neat): 3289, 1645, 1538, 1451, 699 1 , J= 6.5 Hz), 2 , 400 MHz): 80.90 (d, 3H, =CH(Cjj) 3 H nmr (CDC1 (c= 0.875 in MeOH); 1 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 at  315 6 2.38 simplified the doublets at 8 0.90, 8 1.02 and 8 5.12 to three singlets; irradiation at 8 2.49 simplified the doublets at 3 0.94, 8 1.00 and 3 5.20 to three singlets; in a series of nOe difference experiments, irradiation at 32.26 caused an enhancement of the signal at 6 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 at 62.21-2.31(2%) and 62.33-2.43 (2%); irradiation at 35.20 caused an enhancement of the signal at 6 3.19 (7%); 13 , 50.3 MHz): 6 21.9, 22.1, 22.2, 23.3, 23.8, 25.6, 3 C nmr (CDC1 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, 2 325.2407; found: 325.2414. Anal. calcd.: 1 N0: 2 C 3 173.6. Exact mass calcd. for H 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 ainide 243 as a colorless needle-like solid (mp 110-111 °C) that exhibited ir (KBr): 3273, 1641, , 400 MHz): 60.65 (d, 3 H nmr (CDC1 ; [ctJD= -40.07° (c= 0.750 in MeOH); 1 1 1547, 697 cm3H, =CH(Cli3)2, J= 6.5 Hz), 0.94 (d, 3H, =CHd(Cth)2, 1= 6.5 Hz), 0.95 (d, 3H, , 3 =CHc(C1j3)2, J= 6.5 Hz), 1.02 (d, 3H, =CHj(Cfl)2, J= 6.5 Hz), 1.46 (d, 3H, PhCHCjj  J= 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 at 6 2.27 simplified the doublets at 6 0.65, 60.95 and 6 5.06 to three singlets; irradiation at 62.46 simplified the doublets at 6 0.94, 6 1.00 and 3 5.21 to three singlets; in a series of nOe difference experiments, irradiation at 62.27 caused an enhancement of the signal at  6 5.06 (5%); irradiation at 6 3.21 caused enhancement of the signals at 6 5.21 (9%) and  66.00 (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%); 13 C 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,  316 127.2, 128.6, 132.7, 134.6, 135.3, 136.1, 143.4, 173.5.  Exact mass calcd. for  0: 325.2407; found: 325.2397. Anal. calcd.: C 81.18, H 9.60, N 4.30; found: C22H3 N 1 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-methvlpropvlidenecvc1opentanecarboxamides (246 and (247)  H  H  /  /  246  247  Following general procedure 13 (p 309), the following amounts of reagents and solvents were used: (S)-(÷)-1-phenylethylamine (244), 107 mg (0.883 mmol), in C6H6, 3.0 mL; A1, 0.44 mL (0.88 mmol); ethyl (Z,Z)-2,3-bis(2-methylpropylidene)cyclopentane3 Me , 1.0 mL; 2.0 M HC1, 4.0 mL Flash H 6 carboxylate (229), 99.2 mg (0.396 mmol), in C chromatography (30 g sffica gel, 3: 1 petroleum ether Et20) of the crude product and removal of traces of solvent (vacuum pump) yielded 51.0 mg (40%) of the aruide 246 as a colorless liquid (the less polar component) and 56.0 mg (43%) of the amide 247 as a solid (the more polar component).  ; 1 The amide 246 exhibited ir (neat): 3284, 1646, 1539, 1451, 761, 699 cm H nmr (CDC1 , 400 MHz) and 13 3 C nmr (CDC13, [a]D= -151.7° (c= 0.528 in MeOH); 1 50.3 MHz): identical with those of (R,S)-(-)-N-1-phenylethyl-(Z,Z)-2,3-bis(2-methyl-  317 2 325.2407; 20: C N 1 propylidene)cyclopentanecarboxamide (242). Exact mass calcd. for H3 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 amide 247 as a colorless needle-like solid (mp 111-112 °C) that showed ir (KBr): 3271, 1641, , 400 MHz) and 3 H nmr (CDC1 cm- [a]D= +40.43° (c= 0.800 in MeOH); 1 ; 1548, 697 1 nrnr (CDC13, 50.3 MHz): identical with those of (R,R)-(-)-N-1-phenylethyl-(Z,Z)-2,3bis(2-methylpropylidene)cyclopentanecarboxamide (243). Exact mass calcd. for 2 325.2407; found: 325.2397. Anal. calcd.: C 81.18, H 9.60, N 4.30; found: 1 N0: 2 C 3 H C 81.09, H 9.60, N 4.23.  Prenaration of N-p-ch1oronhenvl-(Z.E)-2,3-bis(ethv1idenecvc1onentanecarboxamide (257 Hb  H /  257  Following general procedure 13 (p 309), the following amounts of reagents and solvents were used: p-chloroaniline (239), 56.1 mg (0.440 mmol), in C H6, 2.0 mL; Me3Al, 6 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 chromatography  318 0) of the crude product and removal of traces 2 (2 mm silica gel plate, 3: 1 petroleum ether Et of solvent (vacuum pump) gave 54.5 mg (99%) of the amide 257. Recrystallization of this material from 1: 1 hexanes-Et20 provided the amide 257 as a colorless square plate-like ; 1 solid (mp 102-104 OC) that showed ir (KBr): 3281, 1658, 1537, 1493, 1400, 830 cm H nrnr (CDC13, 400 MHz): 3 1.74 (br d, 3H, =CHCj, J= 7 Hz), 1.87-1.99 (m, 1H, Ha), 1 1.91 (br d, 3H, =CHCth, J= 7 Hz), 2.17-2.26 (m, 1H, Ha), 2.38-2.59 (m, 2H, Hb), , =jCH ) 3.30-3.40 (m, 1H, He), 5.71 (br q, 1H, =CHCH3, J= 7 Hz), 5.85-5.94 (m, 1H, 3 7.24 (d, 2H, aromatic protons, J= 9 Hz), 7.43 (d, 2H, aromatic protons, J= 9 Hz), , 100.6 MHz): 6 15.4, 15.6, 27.6, 3 C nmr (CDC1 7.57 (br s, 1H, NH, wl/2= 10 Hz); 13 29.1, 55.5, 120.9, 121.4, 123.1, 128.9, 129.1, 136.5, 139.5, 140.6, 172.3. Exact mass 6 8 C 1 H 6 275.1078; found: 275.1079. Anal. calcd. for C1N0: 8 35 C 1 H calcd. for C1N0: C 69.69, H 6.58, N 5.08; found: C 69.32, H 6.59, N 5.03.  319 13. Diels-Alder reactions of dienes with tetracvanoethvlene (TCNE)  Preparation of the ester 31Z N NC• NC•  312  313  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) was stirred at room temperature for 1 h. The reaction mixture was concentrated and the crude product was eluted through a plug of silica gel (2 g, 230-400 mesh) with 1: 1 petroleum ether-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 appropriate fractions and removal of traces of solvent (vacuum pump) afforded 97.1 mg (79%) of a H nnir mixture of the esters 312 and 313 in a ratio of 21: 1 (determined by integration of 1 signals), respectively. Recrystallization of this mixture from Et20 provided the ester 312 as a colorless solid (mp 129.5-130 °C) that exhibited ir (KBr): 2255, 1719, 1462, 1446, 1377, H nmr (CDC1 , 400 MHz): 6 1.27 (t, 3H, 3 3 ; 1 1 1346, 1261, 1211, 1032 cmCII 2 OCH ,  J= 7 Hz), 1.58 (d, 3H, CHCIj , J= 7 Hz), 2.19-2.40 (rn, 2H), 2.43-2.62 (m, 2H), 3 3.08 (d,  1H, H, J= 18 Hz), 3.15 (dm, 1H, H, J= 18 Hz for doublet),  ), 4.10-4.25 (m, 3 3.37-3.48 (br signal, 1H, CIjCH , wl/2= 18 Hz), 3.56-3.66 (m, 1H, FL 3  ; in a decoupling experiment, irradiation at 63.43 simplified the doublet at 3 1.58 OCH ) 2H, 2 to a singlet; in a series of nOe difference experiments, irradiation at 3 1.58 caused enhancement of the signals at 83.37-3.48 (15%) and 63.56-3.66 (11%); irradiation at 63.61  320 caused an enhancement of the signal at 6 1.58 (2%);  nmr (C , 50.3 MHz): 6 14.1, D 6  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. for N C 1 H : 2 0 4 7 308.1275; found: 308.1277. Anal. 6 calcd.: C 66.22, H 5.23, N 18.17; found: C 66.19, H 5.22, N 17.99. The minor product 313 (the 1 H nmr spectrum of 313 was recorded in the next section (infra vida)) showed the , J= 7 Hz), 2.09-2.17 (m), 2.29-2.39 (m), 3.47-3.52 (m, Hj) in 3 signals at 6 1.50 (d, CHCJj the 1 H 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 (at 6 1.58) of 312 and CHcj (at 5 1.50) of 313.  Preparation of the ester 313 NH  Hb  N  jjbH  T  Et 2 CO  313  312  A 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) was  stirred at room temperature for 1 h and 45 mm. The reaction mixture was concentrated and the crude product was eluted through a plug of silica gel (2 g, 230-400 mesh) with 1: 1 petroleum ether-Et20 (20 mL). The eluate was concentrated and purified by radial chromatography (1 mm silica gel plate, 1: 1 petroleum ether-Et20). Concentration of the appropriate 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 integration  321 of 1 H nmr signals), respectively. Recrystallization of this mixture from 1: 1 petroleum C) that exhibited ether-Et20 provided the ester 313 as a colorless solid (mp 113-115 0 ; 1 1 H nmr (CDC1 , 400 MHz): 6 1.27 (t, 3H, 3 ir (KBr): 2255, 1729, 1257, 1032 cm 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 at 6 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%) and 6 3.47-3.52 (10%); irradiation at 63.50 caused enhancement of the signals at 6 1.50 (2%), , 100.6 MHz): 6 14.1, 14.3, 3 6 2.29-2.39 (8%) and 8 3.24-3.34 (13%); 13 C nmr (CDC1 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. for N402: C 1 H 7 308.1275; found: 308.1278. Anal. 6 calcd.: C 66.22, H 5.23, N 18.17; found: C 66.09, H 5.21, N 18.23. The minor product 312 (the 1 H nmr spectrum of 312 was recorded in the previous section (supra vida)) showed the signals at 6 1.58 (d, CHCjb, .1= 7 Hz), 2.43-2.62 (m), 3.08 (d, J= 18 Hz), , w= 18 Hz), 3.56-3.66 (m, H<j) in the 1 3 H nmr spectrum of 3.37-3.48 (br signal, CJjCH the mixture of the esters 313 and 312, which are in a ratio of 6.3: 1, respectively. The latter 3 (at 6 1.50) of 313 and ratio is determined by the integration of the signals of CHCJj 3 (at 6 1.58) of 312. CHCJj  322 Preparation of the ester 317  H,  NCHa  cA  t 2 C 4 E O  N 317  A solution of ethyl (E,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate (223) (39.7 mg, 0.204 mmol) and TCNE (27.0 mg, 0.2 10 mmol) in dry THE (2.5 mL) was stirred at room temperature for 0.5 h and then was concentrated. Flash chromatography (2 g silica gel, 1: 1 petroleum ether-Et20) of the crude product, concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) gave 56.7 mg (86%) of the ester 317 as a white H nmr spectroscopy to consist of one component. solid which was shown by 1 Recrystallization of this material from 1: 1 petroleum ether-Et20 produced the ester 317 as a ; 1 colorless solid (mp 110-111 OC) that showed ir (KBr): 2351, 1728, 1184, 1033 cm  CJj 2 OCH , , 400 MHz): 8 0.69 (d, 3H, CHcCII3, J= 7 Hz), 0.85 (t, 3H, 3 D 6 H nmr (C 1 J= 7 Hz), 1.03 (d, 3H, CHeCj3, J= 7 Hz), 1.37-1.51 (m, 2H), 1.83-1.98 (m, 2H), 2.49-2.59 (br signal, 1H, H, wj/2= 19 Hz), 2.91-2.99 (br signal, 1H, Hj, wl/2= 17 Hz), ; in a series of OCH ) 3.21-3.31 (br signal, 1H, He, wl/2= 16 Hz), 3.70-3.89 (m, 2H, 2 decoupling experiments, irradiation at 8 0.69 sharpened the broad signal at 6 2.49-2.59 (w1= 6 Hz); irradiation at 8 1.03 sharpened the broad signal at 6 3.21-3.3 1 (w1= 9 Hz); irradiation at 62.54 simplified the doublet at 60.69 to a singlet; in a series of nOe difference experiments, irradiation at 6 1.03 caused enhancement of the signals at 6 2.91-2.99 (15%) and 83.21-3.31(20%); irradiation at 62.95 caused an enhancement of the signal at 8 1.03 (2%);  ‘c  nmr (CDC1 , 100.6 MHz): 6 14.1, 14.9, 15.0, 25.9, 32.8, 37.7, 38.1, 46.1, 3  46.4, 50.8, 61.4, 108.7, 109.2, 111.2, 111.3, 132.1, 137.5, 171.9. Exact mass calcd. for  323  Ci8H1SN4O2: 322.1431; found: 322.1421. Anal. calcd.: C 67.07, H 5.63, N 17.38; found: C 67.18, H 5.57, N 17.47.  Preparation of the ester 318  NC NC  318  319  A solution of ethyl (EE)-2,3-bis(ethylidene)cyclopentanecarboxylate (224) (42.2 mg, 0.217 mmol) and TCNE (29.0 mg, 0.226 rnmol) in dry THF (3.0 mL) was stirred at room temperature for 0.5 h and then was concentrated. Flash chromatography (2 g silica gel, 1: 1 petroleum ether-Et20) of the crude product, concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) produced 66.4 mg (95%) of the esters 318 and H nmr signals), respectively. 319 in a ratio of 40: 1 (determined by integration of 1 1 produced the ester 318 as a Et C CH 2 Recrystallization of this material from 1: 1 0 colorless solid (mp 95-97  O)  H unir ;1 1 that displayed ir (KBr): 2233, 1715, 1190, 1030 cm  (CDC13, 400 MHz): 3 1.28 (t, 3H, OCH2CLj3, J= 7 Hz), 1.60-1.69 (2 overlapping doublets, 6H, CHCJj3, both CH3 groups centered at 1.65, J= 7 Hz), 2.23-2.36 (m, 2H), ), 3.39-3.49 (m, 1H, CECH3), 3 2.48-2.66 (m, 2H), 3.18-3.28 (m, 1H, CIjCH 3.65-3.74 (m, 1H, He), 4.20 (q, 2H, OCH2, 1= 7 Hz); in a decoupling experiment, irradiation at 8 1.65 sharpened the multiplets at 6 3.18-3.28 and at 6 3.39-3.49, to a singlet and a broad signal (wl/2= 6 Hz), respectively; in a series of nOe difference experiments, irradiation at 8 1.65 caused enhancement of the signals at 6 3.18-3.28 (11%), 8 3.39-3.49  324 (9%) and 6 3.65-3.74 (9%); irradiation at 8 3.70 caused an enhancement of the signal at , 50.3 MHz): 8 14.2, 15.6, 15.8, 26.2, 33.5, 37.7, 38.6, 3 C nmr (CDC1 6 1.65 (3%); 13 43.3, 43.6, 51.3, 61.4, 110.2, 110.25, 111.4, 111.45, 131.8, 137.2, 172.2. Exact mass 8 322.1431; found: 322.1427. Anal. calcd.: C 67.07, H 5.63, calcd. for 4 N C 1 H : 2 0 N 17.38; found: C 66.72, H 5.65, N 17.03. The minor product 319 was not isolated and it CII J= 7 Hz), 2 OCH , was tentatively assigned on the basis of the signals (i.e. 8 1.13 (t, 3 H nmr spectrum of , J= 7 Hz)) displayed in the 1 2 1.80 (d, CHCII , J= 7 Hz), 4.55 (q, OCH 3 the mixture of the esters 318 and 319, which are in a ratio of 40: 1, respectively. The latter ratio is determined by the integration of the signals of OCjj (at 64.20) of 318 and OCj (at 6 4.55) of 319.  Preparation of the silyl ether 321 N  N 321  A solution of ethyl (E,Z)-2,3-bis(ethylidene)-1-Qert-butyldiphenylsioxymethyl)cyclopentane (320) (53.3 mg, 0.136 mmol) and TCNE (17.4 mg, 0.136 inmol) in dry THE (1.5 mL) was stirred at room temperature for 2 h and then was concentrated. Flash chromatography (2 g silica gel, 20 : 3 petroleum ether-CH2C12) of the crude product, concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) yielded 22.6 mg (42%) of the starting material 320 and 40.6 mg (58%) of the silyl ether 321  325 H nmr spectroscopy to consist of one component. as an oil which was shown by 1 Recrystallization of this material from 1: 1 petroleum ether-Et20 produced the silyl ether 321 C) that displayed ir (KBr): 2251, 1470, 1428, 1104, 823, as a colorless solid (mp 144-145 0  D 6 : C 3 ; 1 1 H nmr (CDC1 746, 708 cm-  =  , C(CH3) ) 3 : 1, 400 MHz): 6 0.91 (s, 9H, 3  1.12 (d, 3H, CHJCIL3, J= 7 Hz), 1.22 (d, 3H, CHeCIj3, J= 7 Hz), 1.27-1.39 (m, 1H), 1.58-1.71 (m, 1H), 1.80-1.92 (m, 1H), 2.02-2.13 (m, 1H), 2.64-2.75 (m, 1H, He), , J= 10, 8 Hz), 2 j), 3.18-3.27 (m, 1H, He), 3.27 (dd, 1H, OCH 1 2.83-2.93 (m, 1H, H , J= 10, 6 Hz), 7.12-7.30 (m, 6H, aromatic protons), 7.45-7.55 (m, 2 3.35 (dd, 1H, OCH 4H, aromatic protons); in a series of decoupling experiments, irradiation at 62.70 sharpened the doublet of doublets at 6 3.27 and at 6 3.35 to two doublets (J= 10 Hz); irradiation at 62.88 simplifIed the doublet at 8 1.12 to a singlet; irradiation at 63.22 simplified the doublet at 8 1.22 to a singlet; in a series of nOe difference experiments, irradiation at 6 1.22 caused enhancement of the signals at 6 2.64-2.75 (11%) and 6 3.18-3.27 (16%); irradiation at 62.70 caused enhancement of the signals at 8 1.22 (4%), 8 1.58-1.71 (5%), 8 3.27 (3%) and 63.35 (5%); irradiation at 6 3.23 caused an enhancement of the signal at 6 1.22 (2%); nmr (CDC1 , 100.6 MHz): 8 15.0, 15.5, 19.0, 24.8, 26.7, 32.4, 38.0, 38.4, 46.2, 3 46.5, 47.9, 67.4, 109.1, 109.5, 111.5, 127.8, 129.9, 132.7, 132.8, 134.7, 135.5, 136.6. Si: 2 518.2504; found: 518.2496. Anal. calcd.: C 74.09, 4 C 3 H O 4 Exact mass calcd. for N H 6.61, N 10.80; found: C 74.20, H 6.63, N 10.89.  326 14. Diels-Alder reactions of dienes with methyl vinyl ketone (MYKI  General procedure 14  Preparation of the ketones 324 and 325  R 2 219 E=C0  R 2 324 E=C0  314 E  325 E  =  OSiPh2Q-Bu) 2 CH  =  CH2OSiPh2(t-Bu)  To a cold (-78 OC), stirred solution of the cyclic diene (219 or 314) (1 equiv) in dry Et20 complex .BF 2 (-40 mL per mmol of the ester) was added MVK (5 equiv) and 3 CH2C1 C1 4 C for 1-3 h. Saturated aqueous NH (1 equiv). The reaction mixture was stirred at -78 0 C1 used) was added, the phases were separated and the 2 (the same volume as that of the CH C1 The combined organic extracts were 2 CH aqueous phase was extracted three times with . dried (MgSO4) and concentrated.  Chromatography of the residual oil, followed by  concentration of the appropraiate fractions and removal of traces of solvent (vacuum pump) provided the ketone 324 or 325.  327 Preparation of the keto ester 327  Ha  0 327  Following general procedure 14 (p 326), ethyl (Z)-2-ethylidene-3-methylenecyclopentanecarboxylate (220) was converted into the keto ester 327 with the following amounts C1 4.2 mL; CH , of reagents and solvents: cyclic diene 220, 75.3 mg (0.418 mmol), in 2 .Et 3 BF 0 , 57 p.L (0.46 mmol). The reaction mixture was MVK, 175 pL (2.10 mmol); 2 stirred at -78 °C for 2 h. Radial chromatography (1 mm silica gel plate, 2: 1 petroleum ether-Et20) of the liquid thus obtained and removal of traces of solvent (vacuum pump) gave 87.2 mg of a mixture of keto ester 327 along with two uncharacterized side products (gic analysis). The mixture was purified by reverse phase preparative hplc (Waters Radial-Pak cartridge, 10 x 250 mm, C18 on 10 p. p.Bondapak ). 18 The hplc system used was C composed of a System Controller model 600E and Tunable Absorbance Detector model 486  (tuned at 230 nm), both from Waters. The Controller and the Detector were supervised by an IBM clone computer running a Chromatography Workstation Maxima 825 version 3.30 program from Dynamic Solution (Millipore). The eluant used was 55 : 45 H20-MeOH. Collection of the appropriate fractions, followed by removal of traces of solvent (vacuum pump) yielded 58.2 mg (55%) of a pure sample of the major isomer 327 as a colorless oil ; 1 1 that displayed ir (neat): 1730, 1712, 1366, 1177 cm H nmr (CDC1 , 400 MHz): 3 Cj J= 7 Hz), 1.64-1.75 (m, 1H, 2 OCH , 60.86 (d, 3H, CHcjCj3, J= 7 Hz), 1.22 (t, 3H, 3 ), 3 Ha), 1.86-2.20 (m, 6H; includes Hb: m located at 1.86-1.93, 1H), 2.14 (s, 3H, O=CCH 2.40 (ddd, 1H, H, J= 9, 7, 3 Hz), 2.44-2.55 (m, 1H), 2.55-2.66 (m, 1H, Hd), 3.27-3.36 (m, 1H, He), 4.02-4. 14 (m, 2H, OCH ); in a series of decoupling experiments, 2  328 irradiation at 60.86 narrowed the multiplet at 6 2.55-2.66 to a broad signal (wl,2= 11 Hz); irradiation at 6 1.70 simplified the multiplet at 6 1.86-1.93 and the doublet of doublet of doublets at 6 2.40 to a doublet of multiplets (J= 7 Hz for doublet); irradiation at 3 2.40 simplified the multiplets at 8 1.64-1.75, 6 1.86-1.93 and 3 2.55-2.66; irradiation at 6 2.61 simplified the doublet at 60.86 to a singlet, and simplified the doublet of doublet of doublets at 3 2.4.0 to a doublet of multiplets (J= 9 Hz for doublet); in a series of nOe difference experiments, irradiation at 6 0.86 caused enhancement of the signals at 6 2.40 (9%) and 62.55-2.66 (14%); irradiation at 3 1.70 caused enhancement of the signals at 6 1.86-1.93 (14%) and 8 2.55-2.66 (4.5%); irradiation at 62.40 caused enhancement of the signals at 60.86(1%) and 6 1.86-1.93 (2%); irradiation at 62.61 caused enhancement of the signals at 6 0.86 (1.5%), 8 1.64-1.75 (2%) and 6 3.27-3.36 (2%); irradiation at 6 3.32 caused an H nmr assignments are consistent with enhancement of the signal at 82.55-2.66 (4%); all 1 , 50.3 MHz): 6 14.1, 18.0, 3 C nmr (CDC1 the result of a COSY experiment (Table XXXI); 13 24.3, 25.0, 28.6, 28.8, 31.9, 35.3, 52.6, 55.7, 60.3, 135.2, 139.0, 176.7, 211.5. Exact 5 250.1570; found: 250.1573. Anal. calcd.: C 71.97, H 8.86; 2 0 1 C 2 H : mass calcd. for 3 found: C 72.11, H 9.10.  Table XXXI. Results of the COSY experiment of compound 327  Assignment H  H nmr (CDC13, 400 MHz): 6 (multiplicity, COSY correlation(s) to 1 number of protons, coupling constant(s))  CHjCjj  0.86 (d, 3H, .1=7 Hz)  Ha  1.641.75 (m, 1H)  Hb, H  Hb  1.86-1.93 (m, 111)  Ha, H  H  2.40 (ddd, 1H, .1=9, 7, 3 Hz)  Ha, Hb, FId  Hj  2.55-2.66 (m, 1H)  CHjC, FT  329 Preparation of the keto ester 326 Ha  HcI t CO E 2  o 326  Following general procedure 14 (p 326), ethyl (E)-2-ethylidene-3-methylenecyclopentanecarboxylate (221) was converted into the keto ester 326 with the following amounts C12, 2.2 mL; 2 of reagents and solvents: cyclic diene 221, 39.7 mg (0.220 mmol), in CH , 30 pL (0.24 mmol). The reaction mixture was stirred .Et 3 BF 0 MVK, 92 jiL (1.1 mmol); 2 at -78 OC for 1.5 h. Flash chromatography (5 g silica gel, 3: 1 petroleum ether-Et20) of the crude product and removal of traces of solvent (vacuum pump) gave 52.2 mg (95%) of the ; 1 keto ester 326 as a colorless oil that displayed ir (neat): 1734, 1720, 1179, 1037 cm ]) =4: 3,400 MHz): 8 0.73 (d, 3H, CHCHj, J= 7 Hz), 1.02 (t, 3H, 6 :C 3 nmr (CDC1 , O=CCH ) OCH2CIj J= 7 Hz), 1.52-1.68 (m, 2H, Ha), 1.72-1.85 (m, 2H), 1.81 (s, 3H, 3 , 3 1.85-2.02 (m, 2H), 2.02-2.13 (m, 1H), 2.19-2.31 (m, 1H), 2.42 (dt, 1H, Hb, 1= 10, 5 Hz), 2.60-2.70 (m, 1H, Hc), 3.37-3.43 (m, 1H,  I{rj),  ; OCH ) 3.97-4.15 (m, 2H, 2  in a series of decoupling experiments, irradiation at 6 1.60 simplified the doublet of triplets at 6 2.42 to a doublet (J= 5 Hz); irradiation at 6 2.65 simplified the doublet at 8 0.73 to a singlet, and the doublet of triplets at 82.42 to a doublet of doublets (J= 10,5 Hz); in a series of nOe difference experiments, irradiation at 50.73 caused enhancement of the signals at 6 1.52-1.68 (4%), 62.60-2.70 (13%) and 8 3.37-3.43 (14%); irradiation at 62.42 caused enhancement of the signals at 8 1.52-1.68 (11%) and 82.60-2.70(9%); irradiation at 62.65 caused enhancement of the signals 60.73 (3%) and 62.42(8%); irradiation at 63.40 caused , 100.6 MHz): 8 13.9, 14.4, 3 C nmr (CDCI an enhancement of the signal at 8 0.73 (2%); 1 18.5, 25.3, 26.9, 28.6, 30.1, 34.9, 51.0, 52.3, 60.3, 135.9, 138.8, 175.2, 210.9. Exact  330 mass calcd. for 2 SH2 250.1570; found: 250.1577. Anal. calcd.: C 71.97, H 8.86; 1 C : 3 O found: C 72.14, H 8.92.  Preparation of the keto ester 328  HaThHc  Hbpj_.s..  HdI o  t CO E 2  328  Following general procedure 14 (p 326), ethyl (E,Z)-2,3-bis(ethylidene)cyclopentanecarboxylate (223) was converted into the keto ester 328 with the following amounts of C1 1.5 mL; MVK, 2 CH reagents and solvents: cyclic diene 223, 31.4 mg (0.162 mmol), in , , 20 j.tL (0.16 mmol). The reaction mixture was stirred at Et 2 • 3 BF 67 I.LL (0.81 mmol); 0 -78 °C for 1.5 h. Flash chromatography (2 g silica gel, 5:1 petroleum ether-Et20) of the acquired liquid and removal of traces of solvent (vacuum pump) afforded 42.7 mg (99.8%) ; 1 of the keto ester 328 as a colorless oil that exhibited ir(neat): 1732, 1710, 1185, 1041 cm  , J= 7 Hz), 0.95 (d, 3H, CHcCIL3, 3 , 400 MHz): 6 0.78 (d, 3H, CFLjCIj 3 nmr (CDC1 jj J= 7 Hz), 1.45 (br d, 1H, Ha, J 13 Hz), 1.82 (td, 1H, 3 C 2 OCH J= 7 Hz), 1.23 (t, 3H, , ), 2.20-2.29 (m, 1H, He), 3 Hb, J= 13, 6 Hz), 2.02-2.12 (m, 3H), 2.10 (s, 3H, O=CCH 2.43-2.58 (m, 1H), 2.62-2.7 1 (m, 1H, Hd), 2.77 (ddd, 1H, H, J= 13, 5, 2 Hz),  3.43-3.5 1 (m, 1H, Hf), 4.06-4.20 (m, 2H, OCH2); in a series of decoupling experiments, irradiation at 3 1.82 simplified the doublet at 8 1.45 to a broad singlet (w= 4Hz), changed the multipet at 82.20-2.29 and the doublet of doublet of doublets at 32.77 to a broad doublet  (J= 5 Hz); irradiation at 62.25 simplified the doublet at 30.95 to a singlet, the broad doublet  331 at 6 1.45 to a doublet of doublets (J= 13,2 Hz) and the triplet of doublets at 8 1.82 to a broad triplet (J= 13 Hz); irradiation at 8 2.67 simplified the doublet at 6 0.78 to a singlet, the doublet of doublets of doublets at 82.77 to a broad doublet (J= 13 Hz); irradiation at 82.77 changed the triplet of doublets at 8 1.82 to a doublet of doublets (J= 13,6 Hz) and simplified the multiplet at 6 2.62-2.7 1; in a series of nOe difference experiments, irradiation at 80.78 caused enhancement of the signals at 8 1.82 (8%), 62.62-2.71(10%) and 63.43-3.51(8%); irradiation at 80.95 caused enhancement of the signals at 8 1.45 (6%), 82.20-2.29 (5%) and  62.77 (4%); irradiation at 8 1.82 caused enhancement of the signals at 6 1.45 (20%) and 6 2.20-2.29 (5%); irradiation at 62.67 caused an enhancement of the signal at 60.78 (2%); , 3 C nmr (CDC1 irradiation at 6 3.47 caused an enhancement of the signal at 80.78 (2%); 13 50.3 MHz): 8 13.5, 14.3, 19.0, 25.8, 26.7, 28.6, 29.3, 30.3, 33.2, 47.9, 50.9, 60.2, 6 264.1727; found: 264.1719. 4 0 1 C 2 H : 135.3, 142.9, 175.0, 210.9. Exact mass calcd. for 3 Anal. calcd.: C 72.69, H 9.15; found: C 72.53, H 9.16.  Preparation of the keto ester 331  331  Following general procedure 14 (p 326), ethyl (E,E)-2,3-bis(ethylidene)cyclopentanecarboxylate (224) was converted into the keto ester 331 with the following amounts of C1 3.5 mL; MVK, CH , reagents and solvents: cyclic diene 224, 67.8 mg (0.349 mmol), in 2 , 47 .tL (0.38 mmol). The reaction mixture was stirred at 2 . 3 BF Et 150 jiL (1.8 mmol); 0  332  -78 OC for 1.5 h. Flash chromatography (20 g silica gel, 3: 1 petroleum ether-Et20) of the crude product and removal of traces of solvent (vacuum pump) produced 85.0 mg (92%) of  ; 1 the keto ester 331 as a colorless oil that showed ir (neat): 1733, 1715, 1161, 1040 car nrnr (CDC13: C =1 : 1,400 MHz): 30.70 (d, 3H, CHfCjj3, J= 7 Hz), 0.83 (d, 3H, D 6 CHdCIj3, J= 7 Hz), 1.02 (t, 3H, OCH2Cth, J= 7 Hz), 1.24 (td, 1H, Ha, J= 13, 11 Hz), , 1.85-2.07 (m, 3H; includes O=CCH ) 1.64.(ddd, 1H, Hb, J= 13, 5, 2.5 Hz), 1.82 (s, 3H, 3 H: m located at 1.85-1.93, 1H, H(j: m located at 1.92-2.04, 1H), 2.11-2.19 (m, 2H), 2.48 (ddd, 1H, He, J= 13, 5, 2.5 Hz), 2.55-2.64 (m, 1H, Hf), 3.36-3.44 (m, 1H, Hg), ; in a series of decoupling experiments, irradiation at 6 1.64 OCH ) 3.87-4.05 (m, 2H, 2 simplified the triplet of doublets at 3 1.24 to a doublet of doublets (J= 13, 11 Hz), and the signal at 8 2.48 to a doublet of doublets (J= 13, 5 Hz); irradiation at 6 2.48 simplified the triplet of doublets at 8 1.24 to a doublet of doublets (J= 13, 11 Hz), and the resonance at 6 1.64 to a doublet of doublets (J= 13, 5 Hz); irradiation at 32.60 simplified the doublet at 30.70 to a singlet, and the signal at 62.48 to a broad doublet (f= 13 Hz); in a series of nOe difference experiments, irradiation at 60.70 caused enhancement of the signals at 6 1.24 (6%), 62.55-2.64 (9%) and 63.36-3.44 (7%); irradiation at 8 1.64 caused enhancement of the signals at 6 1.24 (18%) and 62.48 (6%); irradiation at 82.48 caused enhancement of the signals at 6 1.64(4%) and 8 1.92-2.04 (1%); irradiation at 8 2.60 caused enhancement of the signals at 60.70 (2%) and 62.48 (5%); irradiation at 3 3.40 caused enhancement of the H nmr assignments are consistent with the signals at 30.70 (1%) and 6 1.85-1.93 (5%); all 1 result of a COSY experiment (Table XXXII), Hj correlates with CHjC, Ha and Hb, Hf , 50.3 MHz): 8 14.2, 14.4, 19.6, 26.9, 3 C nmr (CDC1 3 and He; 13 correlates with CHfCJj 27.9, 28.4, 30.4, 31.2, 32.3, 51.3, 52.4, 60.3, 135.9, 143.0, 175.2, 210.8. Exact mass calcd. for C 6H2403: 264.1727; found: 264.1724. Anal. calcd.: C 72.69, H 9.15; found: 1 C 72.65, H 9.23.  333 COSY  Results of the  Table XXXII.  1 C = D :6 3 H nmr (CDC1 1  Assignment H,  experiment of compound 331  : 1, 400 MHz):  6 COSY correlation(s) to  (multiplicity, number of protons, coupling constant(s)) CHtCH  0.70 Cd, 3H, J= 7  Hz)  j CH C 1  0.83 (d,  Hz)  3H,  J= 7  Hf  Ha  1.24 (td, 1H, J= 13, 11 Hz)  Hb, Hd, He  Hb  1.64 (ddd, 1H, J 13, 5, 2.5 HZ)  Ha,  Hj  1.92-2.04  CHdCH3, Ha, Hb  He  2.48 (ddd,  Hf  2.55-2.64 (m, 1H)  (m, 1H) 1H,  J 13, 5, 2.5 Hz)  Ha,  H(J,  He  Hb, Hf  CHfC, He  Prenaration of the keto ester 322  0 ed  •HcI He  A  “UHf Et 2 CO  .  a  330  329  Following general procedure  (230) was  carboxylate reagents  and  83 .LL (1.0  14  -78 °C for 3 h.  326),  ethyl (E,Z)-2,3-bis(ethylidene)cyclopentane-  converted into the keto ester  solvents: cyclic diene  nimol);  (p  230, 38.8  , 27 ILL (0.22 Et 2 . 3 BF 0  (From the integration of  mg  329 with  (0.200  mmol).  the following amounts of  mmol), in  12, 2.0 mL; MYK, CH C 2  The reaction  mixture  was  stirred  at  H nmr signals, it was found that the crude product 1  334 contained a mixture of the keto esters 329 and 330 in a ratio of 22: 1, respectively.) Radial chromatography (1 mm silica gel plate, 3: 1 petroleum ether-Et20) of the remaining oil and removal of traces of solvent (vacuum pump) afforded 48.2 mg (9 1%) of the keto ester 329 (the less polar component) and 2.7 mg (5%) of the keto ester 330 (the more polar component).  Keto ester 329 is a colorless oil that showed ir (neat): 1732, 1712, 1370, 1274, 1179, 1042 cm , 400 MHz): 6 0.81 (d, 3H, CHtCth, J= 7 Hz), 0.88 (d, 3H, 3 ; 1 1 H nmr (cDC1 CII3, J= 7 Hz), 1.47 (br d, 1H, Ha, J= 13 Hz), 2 CHdCIL3, J= 7 Hz), 1.25 (t, 3H, OCH ), 3 1.84 (td, 1H, Hb, J= 13, 6 Hz), 2.06 (q, 2H, H, J= 7 Hz), 2.15 (s, 3H, O=CCH 2.30-2.38 (m, 1H, H j), 2.33-2.44 (m, 2H, He), 2.63-2.73 (m, 1H, Hf), 2.87 (ddd, 1H, 1 Hg, J= 13, 5, 2 Hz), 3.27 (br t, 1H, Hh, J= 7 Hz), 4.06-4.17 (m, 2H, OCH ); in a series of 2 decoupling experiments, irradiation at 6 1.84 simplified the broad doublet at 8 1.47 to a broad singlet (w1= 3 Hz) and the signal at 6 2.87 to a broad doublet (J= 5 Hz); irradiation at 82.06 simplified the multiplet at 6 2.33-2.44 to a broad singlet (wl/2= 5 Hz) centered at 82.39, and the broad triplet at 6 3.27 to a broad singlet (wi= 4 Hz); irradiation at 8 2.34 simplified the doublet at 6 0.88 to a singlet, the broad doublet at 8 1.47 to a doublet of doublets (J= 13,2 Hz), and the triplet of doublets at 8 1.84 to a triplet (J= 13 Hz); irradiation at 82.68 simplified the doublet at 60.81 to a narrower doublet (J= 1 Hz), the broad doublet at 6 1.47 to a doublet of doublet of doublets (J= 13, 2, 1.5 Hz), and the signal at 82.87 to a broad doublet (J= 13 Hz); irradiation at 62.87 sjmplified the triplet of doublets at 8 1.84 to a doublet of doublets (J= 13, 6 Hz) and the multiplet at 62.63-2.73 to a quartet (J= 7 Hz); in a series of nOe difference experiments, irradiation at 60.81 caused enhancement of the signals  at 6 1.84 (6%), 6 2.33-2.44 (5%) and 6 2.63-2.73 (10%); irradiation at 6 0.88 caused enhancement of the signals at 6 1.47 (6%), 62.30-2.38 (3%) and 62.87 (9%); irradiation at 82.34 caused enhancement of the signals at 60.88 (1%), 6 1.47 (2%), 8 1.84 (3%) and 8 3.27 (4%); irradiation at 82.68 caused enhancement of the signals at 80.81(2%) and 82.87  335 (4%); irradiation at 32.87 caused enhancement of the signals at 60.88 (1%), 6 1.47 (3%) and 62.63-2.73 (4%); irradiation at 63.27 caused enhancement of the signals at 62.06 (7%) , 50.3 MHz): 6 13.8, 14.2, 19.3, 27.0, 28.0, 28.7, 3 C nmr (CDC1 and 6 2.30-2.38 (5%); 13 29.4, 32.1, 33.1, 47.8, 53.2, 60.4, 136.9, 142.8, 176.3, 211.1. Exact mass calcd. for 14 C 2 H : 3 0 6 264.1727; found: 264.1728. Anal. calcd.: C 72.69, H 9.15; found: C 73.00, H 9.11.  ; 1 1 H nmr Keto ester 330 is a colorless oil that showed ir (neat): 1730, 1710, 1159 cnr , 400 MHz): 6 0.82 (d, 3H, CFLJCII3, J= 7 Hz), 0.99 (d, 3H, CHcCIj3, J= 7 Hz), 3 (CDC1 1.22 (t, 3H, OCH2Cj , J= 7 Hz), 1.50 (br d, 1H, Ha, J 3  13 Hz), 1.89 (td, 1H, Hb,  ), 2.28-2.38 (m, 1H, He), 3 J= 13, 6 Hz), 2.02-2.25 (m, 3H), 2.15 (s, 3H, O=CCH 2.52-2.66 (m, 2H; includes Hj: m located at 2.58-2.66, 1H), 2.75 (ddd, 1H, He, ); in a series of 2 J= 13, 5, 2.5 Hz), 3.43-3.52 (m, 1H, Hf), 4.04-4.18 (m, 2H, OCH decoupling experiments, irradiation at 6 0.82 simplified the multiplet at 6 2.58-2.66 to a doublet of multiplets (J= 5 Hz) centered at 62.62; irradiation at 62.33 simplified the doublet at 6 0.99 to a singlet, the broad doublet at 6 1.50 to a doublet of doublets (J= 13, 2.5 Hz), and the triplet of doublets at 6 1.89 to a triplet (J= 13 Hz); irradiation at 62.62 simplified the doublet at 6 0.82 to a singlet and the doublet of doublet of doublets at 6 2.75 to a broad doublet (J= 13 Hz); irradiation at 6 2.75 simplified the triplet of doublets at 6 1.89 to a doublet of doublets (J= 13, 6 Hz); in a series of nOe difference experiments, irradiation at 60.82 caused enhancement of the signals at 6 1.89 (13%) and 32.58-2.66 (8%, assuming that one proton was enhanced); irradiation at 60.99 caused enhancement of the signals at 6 1.50 (7%), 62.28-2.38 (19%), 62.75 (12%) and 83.43-3.52 (9%); irradiation at 62.33 caused enhancement of the signals at 60.99 (1%) and 8 1.89 (4%); irradiation at 8 2.75 caused enhancement of the signals at 60.99 (1%) and 8 1.50 (3%); irradiation at 63.48 caused an enhancement of the signal at 6 0.99 (1%). Exact mass calcd. for 03: 14 C 2 H 6 264.1727; found: 264.1719.  336 H nmr The minor product 330 showed the signal at 6 3.43-3.52 (m, 1H, Hf) in the 1 spectrum of the mixture of the esters 329 and 330, which are in a ratio of 22 : 1, respectively. The latter ratio is determined by the integration of the signals of Hh (at 83.27) of 329 and Hf (at 6 3.43-3.52) of 330.  Preparation of the keto ether 333 Ha  HcI iIHbA 0  (t-Bu) 2 OSIPh  —  333  Following general procedure 14 (p 326), 1-(tert-butyldiphenylsiloxymethyl)-(E)-2ethylidene-3-methylenecyclopentane (332) was converted into the keto ether 333 with the following amounts of reagents and solvents: cyclic diene 332, 23.3 mg (61.9 imol), in .Et 3 BF 0 , 8.3 ,.iL (68 Ilmol). The reaction C1 1.0 mL; MVK, 26 p.L (0.31 mmol); 2 CH , 2 mixture was stirred at -78 OC for 2 h and 15 mm. Flash chromatography (5 g silica gel, 6: 1  petroleum ether-Et20) of the oil thus obtained and removal of traces of solvent (vacuum pump) gave 26.6 mg (96%) of the keto ether 333 as a colorless oil that displayed ir (neat): ; 1 1 H nmr (CDC13, 400 MHz): 6 0.77 (d, 3H, CHcCjJ.3, 1709, 1429, 1113, 770 cm )), 1.62-1.80 (m, 3H includes Ha: m located at 1.62-1.75, ) 3 J= 7 Hz), 1.06 (s, 9H, C(CH ), 2.21-2.33 (m, 1H), 2.63 (ddd, 1H, Hb, 3 1H), 1.88-2.18 (m, 4H), 2.07 (s, 3H, O=CCH .1= 12, 5, 3 Hz), 2.75-2.82 (m, 1H, He), 2.82-2.91 (m, 1H, Hj), 3.61-3.71 (m, 2H, ), 7.36-7.47 (m, 6H, aromatic protons), 7.67-7.7 1 (m, 4H, aromatic protons); in a 2 OCH series of decoupling experiments, irradiation at 60.77 sharpened the multiplet at 62.75-2.82  337 to a broad signal (w112= 11 Hz); irradiation at 6 2.79 simplified the doublet at 8 0.77 to a singlet, and the signal at 82.63 to a broad doublet (J= 12 Hz); irradiation at 82.87 simplified the multiplet at 6 3.61-3.7 1 to two doublets (J= 10 Hz, AB type) centered at 6 3.63 and at 63.68; in a series of nOe difference experiments, irradiation at 60.77 caused enhancement of the signals at 6 1.62-1.75 (11%, assuming that one proton was enhanced), 62.75-2.82 (14%) and 6 2.82-2.91 (16%); irradiation at 82.79 caused enhancement of the signals at 6 0.77 (4%), 8 2.63 (9%) and 6 3.61-3.7 1 (5%); irradiation at 8 2.87 caused enhancement of the signals at 60.77(2%) and 6 3.61-3.71 (5%); irradiation at 83.65 caused , 3 C nmr (CDC1 enhancement of the signals at 82.75-2.82 (8%) and 62.82-2.91 (11%); 13 75.5 MHz): 8 14.1, 18.6, 19.3, 25.5, 26.4, 26.8, 28.5, 30.0, 34.5, 47.6, 52.6, 66.6, i: 9 8 O 2 C 3 H S 127.6, 129.6, 134.0, 135.6, 136.3, 138.9, 211.5. Exact mass calcd. for 2 446.2642; found: 446.2647. Anal. calcd.: C 77.98, H 8.57; found: C 75.10, H 8.64.  Preparation of the keto ether 334  Ha 1c Hb 4  Hel UUHf gHdA t-Bu) OSiPh ( 2  334  Following general procedure 14 (p 326), (E,Z)-2,3-bis(ethylidene)- 1 -Qert-butyl diphenylsioxymethyl)cyclopentane (320) was converted into the keto ether 334 with the following amounts of reagents and solvents: cyclic diene 320, 52.4 mg (0.134 mmol), in , 19 j.L (0.15 mmol). The reaction Et 2 . 3 BF C1 1.4 mL; MVK, 64 iL (0.77 mmol); 0 2 CH , mixture was stirred at -78 °C for 2.5 h. Radial chromatography (2 mm silica gel plate, 6: 1  338 petroleum ether-Et20) of the remaining liquid and removal of traces of solvent (vacuum pump) afforded 61.4 mg (99.5%) of the keto ether 334 as a colorless oil that exhibited , 3 , 400 MHz): 6 0.77 (d, 3H, CHCij D 6 H nmr (C ;1 1 ir (neat): 1711, 1428, 1113, 703 cm , 1.58 (br d, 1H, Ha, C(CH ) ) J= 7 Hz), 0.88 (d, 3H, CHcCj3, J= 7 Hz), 1.16 (s, 9H, 3 , 1.83-1.95 (m, 2H), 2.01 (td, 1H, O=CCH ) J= 13 Hz), 1.64-1.74 (m, 1H), 1.78 (s, 3H, 3 Hb, 1= 13, 6 Hz), 2.05-2.15 (m, 1H, He), 2.29-2.42 (m, 1H), 2.65 (ddd, 1H, Hrj, J= 13, 5, 2 Hz), 2.68-2.77 (m, 1H, He), 2.77-2.87 (m, 1H, Hf), 3.67 (d, 2H, OCH2, J= 4 Hz), 7.18-7.27 (m, 6H, aromatic protons), 7.72-7.80 (in, 4H, aromatic protons); in a series of decoupling experiments, irradiation at 6 1.58 simplified the triplet of doublets at 62.01 to a doublet of doublets (J= 13, 6 Hz) and the doublet of doublets of doublets at 62.65 to a doublet of doublets (J= 13, 5 Hz); irradiation at 6 2.01 simplified the broad doublet at 6 1.58 to a broad singlet (w= 4 Hz), and the signal at 62.65 to a broad doublet (J= 5 Hz); irradiation at 8 2.10 simplified the doublet at 6 0.88 to a singlet; irradiation at 62.65 sharpened the doublet at 6 1.58 and simplified the triplet of doublets at 62.01 to a doublet of doublets (1= 13, 6 Hz); irradiation at 62.73 simplified the doublet at 60.77 to a singlet and sharpened the doublet at 6 1.58; irradiation at 6 2.82 simplified the doublet at 63.67 to a singlet; in a series of nOe difference experiments, irradiation at 60.77 caused enhancement of the signals at 6 2.01 (3%), 6 2.68-2.77 (8%) and 6 2.77-2.87 (6%); irradiation at 60.88 caused enhancement of the signals at 62.05-2.15 (14%) and 62.65 (10%); irradiation at 6 1.58 caused enhancement of the signals at 62.01(23%) and 62.65 (11%); irradiation at 6 2.82 caused enhancement of the signals at 60.77 (1%) and 8 3.67 (3%); irradiation at 6 3.67 caused enhancement of the signals at 8 2.68-2.77 (9%) and , 125.8 MHz): 6 13.7, 19.2, 19.3, 25.9, 26.2, 26.8, 3 C nmr (CDC1 6 2.77-2.87 (12%); 13 28.6, 29.3, 30.2, 32.8, 47.5, 48.1, 66.5, 127.6, 129.6, 133.9, 135.6, 138.3, 140.9, i: 460.2799; found: 460.2801. Anal. calcd.: 0 O 3 C 4 H S 211.5. Exact mass calcd. for 2 C 78.21, H 8.75; found: C 78.40, H 8.85.  339 Preparation of the keto ether 336  Ha  HbHc  Bel IIHd (t-Bu) 2 OSiPh  —  336  Following general procedure 14 (p 326), (E,E)-2,3-bis (ethylidene)- 1 -(tert-butyl diphenylsioxymethyl)cyclopentane (335) was converted into the keto ether 336 with the following amounts of reagents and solvents: cyclic diene 335, 51.0 mg (0.13 1 mmol), in , 20 p.L (0.16 mmol). The reaction 2 . 3 BF Et C1 1.3 mL; MVK, 55 jiL (0.66 mmol); 0 CH , 2 mixture was stined at -78 OC for 2 h. Radial chromatography (2 mm silica gel plate, 6: 1 hexanes-Et20) of the residue oil and removal of traces of solvent (vacuum pump) produced  54.5 mg of a mixture of the keto ether 336 along with two uncharacterized side products (gic analysis). This mixture was subjected to radial chromatography again (2 mm silica gel plate, 20: 1: 1 petroleum ether-CH2C12-ethyl acetate). Concentration of the appropriate fractions and removal of traces of solvent (vacuum pump) gave 45.2 mg (75%) of a pure sample of the ; 1 major isomer 336 as a colorless oil that showed ir (neat): 1710, 1428, 1112, 703 cm nmr (CDC1 :C 3 D = 1: 1,400 MHz): 80.65 (d, 3H, CHeCII3, J= 7 Hz), 0.88 (d, 3H, 6 , 1.30 (q, 1H, Ha, J= 13 Hz), 1.50-1.61 (m, C(CH ) ) CHcCII3, J= 7 Hz), 1.01 (s, 9H, 3 ), 3 1H), 1.69 (ddd, 1H, Hb, J= 13, 5, 2 Hz), 1.77-1.90 (m, 1H), 1.80 (s, 3H, O=CCH 1.91-1.99 (m, 1H, He), 1.99-2.10 (m, 1H), 2.10-2.21 (m, 1H), 2.47 (ddd, 1H, Hj,  J= 13, 5, 2 Hz), 2.59-2.70 (m, 1H, He), 2.70-2.80 (m, 1H, Hf), 3.52-2.62 (m, 2H, OCH2), 7.15-7.32 (m, 6H, aromatic protons), 7.56-7.66 (m, 4H, aromatic protons); in a series of decoupling experiments, inadiation at 8 1.30 simplified two sets of signals at 6 1.69 and 6 2.47 to two broad signals (wl/2= 5, 10 Hz, respectively); irradiation at 6 1.69  340 simplified the quartet at 8 1.30 to a triplet (J= 13 Hz), and the signal at 6 2.47 to a doublet of doublets (J= 13, 5 Hz); irradiation at 8 1.95 simplified the doublet at 60.88 to a singlet, the quartet at 6 1.30 to a broad triplet (J= 13 Hz), and the resonance at 8 1.69 to a broad doublet (J= 13 Hz); irradiation at 62.47 simplified the quartet at 6 1.30 to a broad triplet (J= 13 Hz), the doublet of doublet of doublets at 8 1.69 to a doublet of doublets (J= 13, 5 Hz) and simplified the multiplet at 8 2.59-2.70; irradiation at 62.65 simplified the doublet at 60.65 to a singlet and the doublet of doublet of doublets at 6 2.47 to a broad doublet (J= 13 Hz); irradiation at 62.75 simplified the multiplet at 6 3.52-3.62 to an AB system (two distorted doublets with J= 10 Hz) centered at 8 3.57; in a series of nOe difference experiments, irradiation at 80.65 caused enhancement of the signals at 6 1.30(8%), 62.59-2.70(8%) and 62.70-2.80 (6%); irradiation at 6 1.30 caused an enhancement of the signal at 60.65 (1%); irradiation at 6 1.69 caused enhancement of the signals at 8 1.91-1.99 (3%) and 82.47 (6%); irradiation at 62.47 caused enhancement of the signals at 8 1.69 (4%), 6 1.91-1.99 (6%) and 62.59-2.70 (5%); irradiation at 62.65 caused enhancement of the signals at 6 0.65 (2%), 82.47 (11%) and 63.52-3.62 (4%); irradiation at 82.75 caused enhancement of the signals at 60.65 (1%) and 63.52-3.62 (6%); irradiation at 63.57 caused enhancement of the signals , 100.6 MHz): 6 14.3, 19.2, 3 C nmr (CDC1 3 at 62.59-2.70 (9%) and 62.70-2.80 (11%); ‘ 19.7, 26.3, 26.7, 28.1, 28.4, 30.1, 31.1, 31.6, 47.7, 52.6, 66.5, 127.6, 129.5, 133.8, i: 460.2799; found: 0 O 3 C 4 H S 135.5, 138.7, 140.6, 211.3. Exact mass calcd. for 2 460.2798. Anal. calcd.: C 78.21, H 8.75; found: C 78.30, H 8.68.  341 V.  REFERENCES  For synthetic studies of palladium-catalyzed coupling reactions by Stile et al., see: (a) (i) Godschalx, 3.; Stile, 3. K. Tetrahedron Lett. 1980,21, 2599. (ii) Godschalx, 3.; Stile, 3. K. Tetrahedron Lett. 1983,24, 1905.  (b) Sheffy, F. K.; Stile, 3. K. J. Am. Chem. Soc. 1983, 105, 7173. (c) (i) Baillargeon, V. P.; Stille, 3. K. .1. Am. Chem. Soc. 1983, 105, 7175. (ii) Baillargeon, V. P.; Stifle, 3. K. J. Am. Chem. Soc. 1986, 108, 452. (d) Pri-Bar, I.; Peariman, P. S.; Stile, 3. K. I. Org. Chem. 1983,48, 4629. (e) Labadie, 3. W.; Tueting, D.; Stile, 3. K. J. Org. Chem. 1983,48, 4634. (f) Labadie, J. W.; Stile, 3. K. Tetrahedron Lett. 1983,24, 4283. (g) Scott, W. 3.; Crisp, 0. T.; Stile, 3. K. J. Am. Chem. Soc. 1984, 106, 4630. (h) Sheffy, F. K.; Godschalx, 3.; Stile, 3. K. J. Am. Chem. Soc. 1984, 106, 4833. (i) Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie, S. 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Tetrahedron Lett. 1992, 33, 3647. Tetrahedron Let:. 1991,32, 4341. (u) Lai, M.-t.; Li, D.; Oh, E.; Liu, H.-w. I. Am. Chem. Soc. 1993, 115, 1619. (v) Nuss, 3. M.; Rennels, R. A.; Levine, B. H. J. Am. Chem. Soc. 1993, 115, 6991. (w) Edwards, 3. P.; Krysan, D. 3.; Liebeskind, L. S. J. Am. Chem. Soc. 1993,115, 9868. (x) Bellina, F.; Carpita, A.; Ciucci, D.; de Santis, M.; Rossi, R. Tetrahedron 1993, 49, 4677. (y) Parrain. 3.-L.; Beaudet, I.; Buchêne, A.; Watrelot, S.; Quintard, 3.-P. Tetrahedron Let:. 1993, 34, 5445. (z) Houpis, L N.; DiMichele, L.; Molina, A. Synlett 1993, 6, 365.  4.  For reviews of palladium-catalyzed coupling reactions, see: (a) Stile, 3. K. Angew. Chem. mt. Ed. Engi. 1986,25, 508. (b) Pereyre, M.; Quintard, 3.-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London, 1987. (c) Scott, W.; McMurry, 3. E. Acc. Chem. Res. 1988,21, 47. (d) Kalinin, V. N. Synthesis 1992, 413. (e) Mitchell, T. N. Synthesis 1992, 803. (0 Ritter, K. Synthesis 1993, 735.  5.  In general, the mild conditions lead to few undesirable side reactions; however, allylic rearrangements were found to occur on the tin partner when allylic bromide and allyl stannanes were subjected to the coupling reactions. For details, see reference la.  344 6.  For the use of copper(I) salts as the co-catalyst in palladium-catalyzed coupling reactions, see: (a) Marino, 3. P.; Long, J. K. I. Am. Chem. Soc. 1988, 110, 7916. (b) Liebeskind, L. S.; Fengi, R. W. J. Org. Chem. 1990,55, 5359. (c) Liebeskind, L. S.; Wang, 3. Tetrahedron Lett. 1990,31, 4293. (d) Gómez-Bengoa, E.; Echavarren, A. M. I. Org. Chem. 1991,56, 3497. (e) Tamayo, N.; Echavarren, A. M.; Paredes, M. C. J. Org. Chem. 1991,56, 6488. (f) Johnson, C. R.; Adams, 3. P.; Braun, M. P.; Senanayake, C. B. W. Tetrahedron Lett. 1992,33, 919. (g) Liebeskind, L. S.; Yu, M. S.; Yu, R. H.; Wang, 3.; Hagen, K. S. J. Am. Chem.  (h) (i) (j) (k) (1)  (m) 7.  Soc. 1993, 115, 9048. Liebeskind, L. S.; Riesinger, S. W. J. Org. Chem. 1993,58, 408. Saá, J. M.; Martorell, G. J. Org. Chem. 1993,58, 1963. Liebeskind, L. S.; Yu, M. S.; Fengi, R. W. J. Org. Chem. 1993,58, 3543. Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1993,34, 2127. Palmisano, G.; Santagostino, S. Tetrahedron Lett. 1993,34, 2533. Levin, 3. I. Tetrahedron Lett. 1993,34, 6211.  For synthetic studies of palladium-catalyzed iniramolecular coupling reactions by Piers  eta!., see: (a) Piers, E.; Friesen, R. W.; Keay, B. A. I. Chem. Soc., Chem. Commun. 1985, 809. (b) Piers, E.; Friesen, R. W. J. Org. Chem. 1986,51, 3405. (c) (i) Piers, E.; Llinas-Brunet, M. J. Org. Chem. 1989,54, 1483. (ii) Piers, E.; Llinas-Brunet, M.; Oballa, R. M. Can. J. Chem. 1993, 71, 1484. (d) Piers, E.; Friesen, R. W.; Keay, B. A. Tetrahedron 1991,47, 4555. (e) Piers, E.; Friesen, R. W. Can. J. Chem. 1992, 70, 1204. (1) Piers, E.; Friesen, R. W.; Rettig, S. 3. Can. J. Chem. 1992, 70, 1385. 8.  Another modification of this coupling reaction is the “carbonylative coupling”, which involves the use of carbon monoxide. For the mechanism of this modified reaction, see reference 4a.  9.  Some evidence was found that coupling reactions may occur via Pd(ll) and Pd(IV) states. For details, see references 2a, 2b, 2d, 2e and 4a.  345 10.  (a) Farina, V.; Baker, S. R.; Benigni, D. A.; Sapino, C. Tetrahedron Lett. 1988,29, 5739. (b) Farina, V.; Baker, S. R.; Sapino, C. Tetrahedron Lert. 1988,29, 6043. (c) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. L; Sapino, C. I. Org. Chem.  1990, 55, 5833. (d) Roth, G. P.; Sapino, C. Tetrahedron Lett. 1991,32, 4073. 11.  (a) Farina, V.; Krishnan, B. I. Am. Chem. Soc. 1991, 113, 9585. (b) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org. Chem. 1993,58, 5434.  12.  (a) For reviews of the synthesis of 1,2-bis(methylene)cyclobutane and related substances, see references 13a, 13b, and references cited therein. (b) For examples of physical organic studies on 1,2-bis(methylene)cyclobutane and related substances, see references 13a, 13b, 15 and 16, and citations therein.  13.  (a) Lu, Y.-F., Ph. D. Thesis, University of British Columbia, Vancouver, B.C., 1988. (b) Piers, E.; Lu, Y.-F. J. Org. Chem. 1988,53, 926.  14.  Coilman, 3. P.; Hegedus, L. S.; Norton, 3. R.; Finke, R. 0. Principles and Applications of Organotransition Metal Chemistry; University Science Books: Mill Valley, California, 1987; pp 7 10-727.  15.  (a) Piers, E.; Lu, Y.-F. I. Org. Chem. 1989,54, 2267. (b) Piers, E.; Effis, K. A. Tetrahedron Lett. 1993,34, 1875.  16. Piers, E.; Friesen, R. W.; Kao, P.; Rettig, S. 3.; Trotter, 3. Can. J. Chem. 1993, 71, 1463.  346 17.  For reviews of cyclic compounds containing an exocycic conjugated diene, see: (a) Fringueffi, F.; Taticchi. A. Dienes in the Diels-Alder Reaction; John Wiley & Sons: New York, 1990; pp 125-147. (b) Vogel, P. In Methods in Stereochemical Analysis, Vol. 3: Stereochemistry and Reactivity of Systems Containing ic Electrons; Watson, W. H., Ed.; Verlag  Chemie International: Deerfield Beach, Florida, 1983; pp 147- 195. (c) Trost, B. M. Acc. Chem. Res. 1990,23, 34. (d) Chariton, J. L.; Alauddin, M. M. Tetrahedron 1987,43, 2873 and citations therein.  mt. Ed.  18.  (a) Trost, B. M.; Hipskind, P. A.; Chung, 3. Y. L.; Chan, C. Angew. Chem. Engl. 1989,28, 1502. (b) Trost, B. M.; Hipskind, P. A. Tetrahedron Lett. 1992,33, 4541. (c) Trost, B. M.; Chung, 3. Y. L. J. Am. Chem. Soc. 1985, 107, 4586.  19.  (a) Nugent, W. A.; Calabrese, J. C. J. Am. Chem. Soc. 1984, 106, 6422. (b) Parshall, G. W.; Nugent, W. A.; Chan, D. M.-T.; Tam, W. Pure Appi. Chem. 1985, 57, 1809. (c) Nugent, W. A.; Thorn, D. L.; Harlow, R. L. J. Am. Chem. Soc. 1987, 109, 2788.  20.  (a) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986,27, 2829. (b) Negishi, E.; Holmes, S. 3.; Tour, J. M.; Miller, 3. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989,111, 3336.  21. Trost, B. M.; Lee, D. C. J.Am. Chem. Soc. 1988, 110, 7255. 22. Trost, B. M.; Rise, F. J. Am. Chem. Soc. 1987, 109, 3161. 23.  (a) Trost, B. M.; Lautens, M. I. Am. Chem. Soc. 1985,107, 1781. (b) Trost, B. M.; Chen, S.-F. I. Am. Chem. Soc. 1986, 108, 6053. (c) Trost, B. M.; MacPherson, D. T. J. Am. Chem. Soc. 1987,109, 3483. (d) Trost, B. M.; Lee, D. C. Rise, F. Tetrahedron Lett. 1989,30, 651. (e) Trost, B. M.; Lee, D. C. J. Org. Chem. 1989,54, 2271. (f) Trost, B. M.; Lautens, M.; Chan, C.; Jebaratnam, D. 3.; Mueller, T. J. Am. Chem. Soc. 1991, 113, 636.  347 24. Trost, B. M.; Tour, 3. M. J. Am. Chem. Soc. 1987, 109, 5268. 25. For example(s) of the synthesis of exocyclic dienes from (a) nickel(0)-catalyzed coupling of vinyl halides, see: (i) lyoda, M.; Tanaka, S.; Nose, M.; Oda, M. I. Chem. Soc., Chem. Commun. 1983, 1058. (ii) Hopf, H.; Maas, G. Angew. Chem. mt. Ed. Engi. 1992, 31, 931 and citations therein. (b) palladium(0)-catalysed intramolecular coupling of vinyl halides, see: (i) Grigg, R.; Stevenson, P.; Worakun, T. J. Chem. Soc., Chem. Commun. 1985, 971. (ii) Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988,44, 2049. (c) palladium- and rhodium-catalysed cydization of compounds containing a vinyl bromide and an ethenyl moieties, see: (i) Grigg, R.; Stevenson, P.; Worakun, T. J. Chem. Soc., Chem. Commun. 1984, 1073. (ii) Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988,44, 2033. (iii) Nagasawa, K.; Ishihara, H.; Zako, Y.; Shimizu, I. J. Org. Chem. 1993,58, (d)  (e)  (f) (g) (h)  2523. palladium-catalysed cydization of compounds containing a vinyl bromide and an ethynyl groups, see: Burns, B.; Grigg, R.; Sridharan, V.; Worakun, T. Tetrahedron Lett. 1988,29, 4325. nickel(0)-catalysed cydization of 1,7-diynes via hydrosilation, see: (i) Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 6478. (ii) Tamao, K.; Kobayashi, K.; Ito, Y. Synlett 1992, 5, 539 and citations therein. rhodium(l)-catalysed cycization of 1,6-enynes, see: Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988,44, 4967. palladium-catalyzed coupling of enynes, see: Wartenberg, F.-H.; Hellendahl, B.; Blechert, S. Synlett 1993,6, 539. zirconium-promoted cydization of 1,7-enynes, followed by iodonolysis and HI elimination, see: Mascareflas, I. L.; Garcia, A. M.; Castedo, L.; Mounilo, A. Tetrahedron Lett. 1992, 33, 7589.  348 25.  (1) palladium-catalyzed polycyclizations of substitued dienynes, see: Meyer, F. E.; Henniges, H.; de Meijere, A. Tetrahedron Lett. 1992,33, 8039. (j) nickel(0)-induced 1,4-dehalogenation of acx’-dihaIo-o-xylene derivatives, see: Inaba, S.; Wehmeyer, R. M.; Forkner, M. W.; Rieke, R. D. J. Org. Chem. 1988, 53, 339. (k) nickel(0)-catalysed cyclooligomerization of 2,5-dimethyl-2,3,4-hexatriene and [nJcumulenes, see: (i) Stehling, L.; Wilke, G. Angew. Chem. mt. Ed. Engi. 1985,24, 496. 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