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Bifunctional organometallic reagents: preparation and use in annulation sequences Kaller, Alan Matthew 1997

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B I F U N C T I O N A L O R G A N O M E T A L L I C R E A G E N T S : P R E P A R A T I O N A N D U S E IN A N N U L A T I O N S E Q U E N C E S by A L A N M A T T H E W K A L L E R B. Comm., The University of Saskatchewan, 1988 B . Sc. (Hons.), The University of British Columbia, 1991 A THESIS S U B M I T T E D IN P A R T I A L F U L F I L L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E O F D O C T O R O F P H I L O S O P H Y in T H E F A C U L T Y O F G R A D U A T E STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y O F BRITISH C O L U M B I A October 1997 © Alan Matthew Kaller, 1997 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of p-» IS The University of British Columbia Vancouver, Canada Date DE-6 (2/88) ABSTRACT The use of bifunctional organometallic reagents (182, 35, and 271) to afford novel annulation products, such as the trans-fused bicyclo[3.3.0]octane (236) and bicyclo[4.3.0]nonane (83) systems and highly functionalized cyclopentene (273) systems, was investigated. The bifunctional reagent 132, was obtained in three steps from the bromo alcohol 134 via the alcohol 133 and the tosylate 158. The novel functionalized allylcopper(I) reagents, 162 and 182, were prepared from the corresponding allylstannanes 132 and 183 by treatment with methyllithium followed by C u B r » M e 2 S . These allylcopper(I) reagents were shown to add in a 1,4-fashion to a variety of oc,P-unsaturated cyclic ketones (30) to provide ketones of general structures 191 and 192. A general annulation method for the preparation of trans-fused bicyclo[3.3.0]octane and bicyclo[4.3.0]nonane systems from a cyclopentanone system 61 was also developed. A palladium(O) catalyzed methoxycarbonylation of the alkenyl triflate 67, obtained from the keto ketal 61, provided the a,P-unsaturated ester 68, which was converted into the corresponding aldehyde 71. Conjugate addition of the allylcopper(I) reagent 182 or the lower order cyanocuprate 35, to the a,f3-unsaturated aldehyde 71, were the key transformations to afford the aldehydes 239 and 80, respectively. Treatment of 239 or 80 with AModosuccinimide provided the alkenyl iodides 238 and 99 which underwent CrCPi/NiCbi-mediated cyclizations to provide the trans-fused bicyclo[3.3.0]octane and bicyclo[4.3.0]nonane systems, 237 and 102 & 103, respectively. These alcohols were converted into the corresponding ketones 236 and 83 in three additional steps. A copper(I) chloride-mediated intramolecular coupling reaction of alkenyltrimethyl-stannane moieties was used to provide highly substituted cyclopentene systems (273). Addition of 271, generated from 183 by treatment with methyllithium, to P-trimethyl-stannyl a,P-unsaturated aldehydes of general structure 275, followed by acetylation of the resultant alcohols provided 274. A n intramolecular copper(I) chloride-mediated coupling of the alkenyltrimethylstannanes of general structure 274 gave the highly functionalized cyclopentenes of general structure 273. GeMe 3 Cu(CN)Li GeMe 3 ^ v / S n M e 3 M 35 132 Cu«MeoS 162M = GeMe 3 182 M = SnMe 3 Br GeMe 3 134 133 R = H 158 R = OTs 236 0 11 0 • 1 •v' 30 191 M 192 M = GeMe 3 = SnMe 3 SnMe 3 183 M = SnMe 3 271 M = Li R 2 Ri 273 R 2 ^ ^ S n M e 3 X R 1 ^ ^ C H O 275 61 67 R = OTf 68 R = C 0 2 M e 71 R = CHO 80 X = GeMe 3 , n = 1 99 X = I, n = 1 239 X = SnMe 3, n = 0 ,*CHO 102 RT = H, R 2 = OH 103 RT = OH, R 2 = H 237 TABLE OF CONTENTS A B S T R A C T ii TABLE OF CONTENTS iv LIST OF TABLES x i LIST OF FIGURES xiii LIST OF GENERAL PROCEDURES xiv LIST OF ABBREVIATIONS xv A C K N O W L E D G M E N T S xix I. INTRODUCTION 1 1. General 1 2 . Background 4 3. Proposals 10 II. DISCUSSION 13 1. Stereocontrolled Annulation Method for the Synthesis of the Tra/is-Fused Bicyclo[4.3.0]nonane Ring System 13 1.1 B a c k g r o u n d 13 1.2 Introductory remarks 15 1.3 Preparation of the cyclopent-1 -enecarbaldehyde substrate 16 1.4 Conjugate addition of the cyanocuprate 35 to the a,|3-unsaturated aldehyde 71 20 1.5 Attempted anionic ring closure 29 1.6 Transition metal mediated ring closure 33 1.7 Conc lus ions 46 2. Functionalized Allylcopper(I) Reagents 48 2.1 B a c k g r o u n d 48 2.2 Introductory remarks 55 2.3 Synthetic Plan 56 2.4 Preparation of 2-(trimemylgermyl)-3-(trimethylstannyl)-propene (132) 57 2.5 Preparation of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) and conjugate additions of 162 to a,pVunsaturated ketones 73 2.6 A new bifunctional reagent: 2-(Trimethylstannyl)-allylcopper(I)-dimethyl sulfide (182) 80 2.7 Conc lus ions 85 3. Stereocontrolled Annulation Method for the Synthesis of the Trans-Fused Bicyclo[3.3.0]octane Ring System 87 3.1 Background 87 3.2 Introductory remarks 94 3.3 Preparation of cyclization precursor iodo aldehyde 238 95 3.4 Ring closure: Cyclization of iodo aldehyde 238 106 3.5 Conc lus ions I l l 4. Copper(I) Chloride-Mediated Intramolecular Coupling of Bis(Alkenyltrimethylstannanes) 113 4.1 B a c k g r o u n d 113 4.2 Introductory remarks 121 4.3 Preparation of ft-trimethylstannyl oc,pVunsaturated aldehydes 123 4.4 Preparation of 2-(trimethylstannyl)allyllithium (271).. 130 4.5 Reaction of 2-(trimethylstannyl)allylhthium (271) with the aldehydes 276, 277, 282, 287, 291, and 292.. 131 4.6 Attempted copper(I) chloride-mediated cyclization of alcohols 302 and 303 134 4.7 Acetylation of the alcohols 299-304 135 4.8 Copper(I) chloride-mediated cyclization of the acetates 307-312 140 4.9 Conc lus ions 144 III. C O N C L U S I O N S 146 I V . E X P E R I M E N T A L 151 1 . G e n e r a l 151 1.1 Data acquisition, presentation and techniques 151 1.2 Solvents and reagents 154 2 . Trans-Fused Bicyclo[4.3.0]nonane R i n g Systems 157 Preparation of the triflate 67 157 Preparation of the ester 68 158 Preparation of the allylic alcohol 70 159 Preparation of the a,P-unsaturated aldehyde 71 161 Preparation of lithium (3-trimethylgermylbut-3-en-l-yl)-(cyano)cuprate (35) 164 Preparation of the aldehyde 80 164 Equilibration of the aldehyde 80 166 Preparation of the alkenyl iodide 99 168 Preparation of the alcohols 102 and 103 169 Preparation of the a-acetate 104 176 Preparation of the P-acetate 105 177 Preparation of the keto a-acetate 106 178 Preparation of the keto P-acetate 107 179 Preparation of the tricyclic ketone 83 from the keto acetate 106 181 Preparation of the tricyclic ketone 83 from the keto acetate 107 182 vii 3. Subs t i t u t ed A H y l c o p p e r ( I ) Reagents 183 Preparation of 2-bromoprop-2-enol (134) 183 Preparation of 2-(triraethylgermyl)prop-2-enol (133) 184 Preparation of 3-bromo-2-(trimethylgermyl)propene (135).. 185 Preparation of 3-/7-toluenesulfonyloxy-2-(trimethylgermyl)-propene (158) 186 Preparation of trimethyltin hydride (160) 187 Preparation of 2-(trimethylgermyl)3-(trimethylstannyl)-propene (132) 188 Preparation of a mixture of 2-(trimethylgermyl)-3-(trimethylstannyl)propene (132) and 2,5-bis(trimethylgermyl)hexa-l,5-diene (148) 189 Preparation of 2,3-bis(trimethylstannyl)propene (183) 191 Preparation of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) 192 Genera l Procedure A : Conjugate addition of 2- (trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) to a,P-unsaturated ketones 192 Preparation of 3-(2-(trimethylgermyl)allyl) cyclohexanone (163) 193 Preparation of ?ran^-4-isopropyl-3-(2-(trimethylgermyl)allyl)-cyclohexanone (164) 194 Preparation of 3-methyl-3-(2-(trimethylgermyl)allyl)-cyclohexanone (165) 195 Preparation of 3-(2-(trimethylgermyl)allyl)-cyclopentanone (166) 196 Preparation of 3-methyl-3-(2-(lrimethylgermyl)allyl)-cyclopentanone (167) 197 Preparation of a mixture of trans- and cw-2-methyl-3- (2-(trimethylgermyl)allyl)cyclopentanone (168) 198 Preparation of a mixture of (2R, 3S, 5R)- and (2S, 3S, 5^?)-2-methyl-5-isopropenyl-3-(2-(trimethylgermyl)allyl)cyclohexanone (169) 199 Preparation of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) 201 Genera l Procedure B : Conjugate addition of 2-(trimelliylstannyl)allylcopper(I)-dimethyl sulfide (182) to a,P-unsaturated ketones and aldehydes 201 Preparation of 3-(2-(trimethylstannyl)allyl)-cyclohexanone (184) 202 viii Preparation of ^an5-4-isopropyl-3-(2-(trimethylstannyl)allyl)-cyclohexanone (185) 203 Preparation of 3-memyl-3-(2-(trimethylstannyl)allyl)-cyclohexanone (186) 204 Preparation of 3-(2-(trimethylstannyl)allyl)-cyclopentanone (187) 205 Preparation of 3-memyl-3-(2-(trimethylstannyl)allyl)-cyclopentanone (188) 206 Preparation of a mixture of trans- and cw-2-methyl-3-(2-(trimethylstannyl)allyl)cyclopentanone (189) 207 Preparation of a mixture of (2R, 35, 5R)- and (25, 35, 5/?)-2-methyl-5-isopropenyl-3-(2-(trimethylstannyl)allyl)cyclohexanone (190) 209 4. ZVa/is-Fused Bicyclo[3.3.0]octane Ring Systems 210 Preparation of the aldehyde 239 210 Preparation of the alkenyl iodides 238 and 241 211 Epimerization of the aldehyde 241 213 Preparation of the alcohol 237 214 Preparation of the allylic acetate 249 216 Preparation of the keto acetate 250 217 Preparation of the triquinane keto ketal 236 219 5. Copper(I) Chloride-Mediated Coupling of Bis(alkenyltrimethylstannanes) 220 Preparation of methyl 2-(trifluoromethanesulfonyloxy)-cyclohept-l-enecarboxylate (283) 220 Preparation of methyl 2-(trimethylstannyl)-cyclohept-l-enecarboxylate (285) 221 Preparation of 2-(trimethylstannyl)-cyclohept-l-enecarbaldehyde (282) 223 General Procedure C: Addition of 2-(trimethylstannyl)-allyllithium (271) to P-(trimethylstannyl) oc,pVunsaturated aldehydes 224 Preparation of (Z)-9-chloro-2,6-bis(trimethylstannyl)-nona-l ,5-dien-4-ol (299) 225 Preparation of (Z)-lO-(terf-butyldimethylsilyloxy)-2,6-bis(trimethylstannyl)deca-l,5-dien-4-ol (300) 226 ix Preparation of (Z)-l l-(terf-butyldimethylsilyl)-2,6-bis(trimethylstannyl)undeca-l,5-dien-10-yn-4-ol (301). 227 Preparation of l-(l-hydroxy-3-(trimethylstannyl)-but-3-en-l-yl)-2-(trimethylstannyl)cyclopentene (302) 229 Preparation of l-(l-hydroxy-3-(trimethylstannyl)-but-3-en-l-yl)-2-(trimethylstannyl)cyclohexene (303) 230 Preparation of l-(l-hydroxy-3-(trimethylstannyl)-but-3-en-l-yl)-2-(trimethylstannyl)cycloheptene (304) 231 General procedure D: Acylation of allylic alcohols 232 Preparation of (Z)-4-acetoxy-9-chloro-2,6-bis(trimethylstannyl)nona-l,5-diene (307) 233 Preparation of (Z)-4-acetoxy-10-(rm-butyldimethyl-silyloxy)-2,6-bis(trimethylstannyl)deca-l,5-diene (308) 234 Preparation of (Z)-4-acetoxy-ll-(terf-butyldimethylsilyl)-2,6-bis(trimethylstannyl)undeca-l,5-dien-10-yne (309) 235 Preparation of l-(l-acetoxy-3-(trimethylstannyl)-but-3-en-l-yl)-2-(trimethylstannyl)cyclopentene (310) 237 Preparation of l-(l-acetoxy-3-(trimethylstannyl)-but-3-en-l-yl)-2-(trimethylstannyl)cyclohexene (311) 238 Preparation of l-(l-acetoxy-3-(trimethylstannyl)-but-3-en-l-yl)-2-(trimethylstannyl)cycloheptene (312) and 1 -(1 -acetoxy-3-(trimethylstannyl)but-3-en- 1-yl)-cycloheptene (313) 239 Alternative procedure for the preparation of l-(l-acetoxy-3-(trimethylstannyl)but-3-en-1 -yl)-2-(trimethylstannyl)-cycloheptene (312) 241 General Procedure E: Copper(I) chloride-mediated intramolecular coupling of bis(alkenyltrimethylstannanes).... 242 Preparation of 3-acetoxy-l-(3-chloropropyl)-5-methylenecyclopentene (316) 243 Preparation of 3-acetoxy-l-(4-(fcrf-butyldimethylsiloxy)-butyl)-5-methylenecyclopentene (317) 244 Preparation of 3-acetoxy-l-(5-(?er?-butyldimethylsilyl)-pent-4-yn-l-yl)-5-methylenecyclopentene (318) 245 Preparation of 2-acetoxy-4-methylene-bicyclo[3.3.0]oct-l(5)-ene (319) 246 Preparation of 7-acetoxy-9-methylene-bicyclo[4.3.0]non-l(6)-ene (320) 248 Preparation of 8-acetoxy-10-methylene-bicyclo[5.3.0]dec-l(7)-ene (321) 249 Alternative procedure for the preparation of 8-acetoxy-10-methylenebicyclo[5.3.0]dec-l(7)-ene (321) 250 V . APPENDICES 251 Appendix 1: X-Ray Crystallographic Data 251 Appendix 2: Additional Experimental Procedures 252 Preparation of (Z)-6-cUoro-3-(trimethylstannyl)-hex-2-enal (291) 252 Preparation of l-(ter^-butyldimethylsilyl)-hepta-l ,6-diyne (297) 253 Preparation of ethyl 8-(?erf-butyldimethylsilyl)-octa-2,7-diynoate (295) 255 Preparation of ethyl (Z) 8-fcrf-butyldimethylsilyl-3-(trimethylstannyl)oct-2-en-7-ynoate (293) 256 Preparation of (Z) 8-ferf-butyldimethylsilyl-3-(trimethylstannyl)oct-2-en-7-ynal (292) 257 VI. REFERENCES AND FOOTNOTES 260 LIST OF TABLES xi Table 1 Energy Difference Between Substituted Cis- and Trans-Bicyclo[4.3.0]nonan-2-one Systems 14 Table 2 Addition of the Cuprate 35 to the oc,P-Unsaturated Aldehyde 71 25 Table 3 Attempted Anionic Ring Closure Reactions 32 Table 4 Germanium - Iodine Exchange Reactions 37 Table 5 Acetylation of the Alcohols 102 and 103 42 Table 6 Ozonolysis of the Exocyclic Methylene Moiety of 104 and 105 44 Table 7 Reductive Removal of the Acetoxy Moieties from 106 and 107 45 Table 8 Nucleophilic Displacement Reactions to Prepare the Bifunctional Reagent 132 68 Table 9 Conjugate Addition of 162 to a,P-Unsaturated Ketones 75 Table 10 Conjugate Addition of 182 to a,p-Unsaturated Ketones 83 Table 11 Transition Metal-Mediated Cyclization of Iodo Aldehyde 238.. 106 Table 12 Intramolecular Coupling Reactions of the Ester 258 118 Table 13 Lithiodestannylation of 2,3-Bis(trimethylstannyl)propene (183) and Reaction of the Resultant 2-(Trimethylstannyl)-allyllithium (271) with Electrophiles 131 Table 14 Synthesis of the Alcohols 299-304 132 Table 15 Synthesis of the Acetates 307-312 136 Table 16 Copper(I) Chloride-Mediated Cyclization of 307-312 141 Table 17 * H nmr (400 M H z , CDCI3) Data for the a,p-Unsaturated Aldehyde 71: C O S Y Experiment 162 Table 18 1 3 C nmr (125.8 M H z , CDCI3) and ! H nmr (500.2 M H z ) Data for the a,pVUnsaturated Aldehyde 71: H M Q C Experiment 163 Table 19 lH nmr (400 M H z , CDCI3) Data for the Allylic Alcohol 102: C O S Y Experiment 171 Table 20 1 3 C nmr (125.8 M H z , CDCI3) and ! H nmr (500.2 M H z ) Data for the Allyl ic Alcohol 102: H M Q C Experiment 172 Table 21 ! H nmr (400 M H z , CDCI3) Data for the Allylic Alcohol 103: C O S Y Experiment 174 Table 22 1 3 C nmr (125.8 M H z , CDCI3) and nmr (500.2 M H z ) Data for the Allyl ic Alcohol 103: H M Q C Experiment 175 X l l l LIST OF FIGURES Figure 1 Bifunctional Conjunctive Reagents 4 Figure 2 cw-Bicyclo[3.3.0]octane-3,7-dione mono-2,2-Dimethylpropylene Ketal (61) 16 Figure 3 Stereoselective Attack of the Cyanocuprate 35 to the Enal 71.... 27 Figure 4 Stereoview of the (3-Acetate 105 43 Figure 5 Products from Addition of the Allylcopper(I) Reagent 182 to Enal 71 97 Figure 6 Stereoview of the Tricyclic Keto Ketal 236 110 Figure 7 Catalytic Cycle of the Stille Coupling Reaction 115 xi v LIST OF GENERAL PROCEDURES General Procedure A: Conjugate addition of 2-(trimethylgermyl)-allylcopper(I)-dimethyl sulfide (162) to a,fJ-unsaturated ketones 192 General Procedure B: Conjugate addition of 2-(trimethylstannyl)-allylcopper(I)-dimethyl sulfide (182) to a,p-unsaturated ketones and aldehydes 201 General Procedure C: Addition of 2-(trimethylstannyl)-allyllithium (271) to P-(trimethylstannyl) a,P-unsaturated aldehydes 224 General procedure D: Acylation of allylic alcohols 232 General Procedure E: Copper(I) chloride-mediated intramolecular coupling of bis(alkenyltrimethylstannanes) 242 X V L I S T O F A B B R E V I A T I O N S A - angstrom (s) a - below the plane of a ring O R 1,2-relative position Ac - acetyl anal. - analysis A P T - attached proton test aq. - aqueous P - above the plane of a ring O R 1,3-relative position bp - boding point br - broad Bu - butyl calcd - calculated C O S Y - ( iH^H) - homonuclear correlation spectroscopy Cp - cyclopentadienyl C-x - carbon number x d - doublet 8 - chemical shift in parts per million from tetramethylsilane dba - dibenzylideneacetone D I B A L - H - diisobutylaluminum hydride D M A P - 4-dimethylaminopyridine D M E - 1,2-dimethoxyethane D M F - N,Af-dimethylformamide D M S - dimethyl sulfide D M S O - dimethyl sulfoxide ed. - edition E d . , Eds. - editor, editors xvi equiv - equivalent(s) Et - ethyl Et20 - diethyl ether = ether F T - Fourier transform G L C - gas liquid chromatography G L C M S - gas - liquid chromatography - mass spectrometry h - hour(s) H M B C - heteronuclear multiple bond coherence H M P A - hexamethylphosphoramide H M Q C - heteronuclear multiple quantum coherence H R M S - high resolution mass spectrometry H-x - hydrogen number x i - iso IR - infrared J - coupling constant in Hz n^Sn-H - n bonds coupling for tin and proton nuclei (in Hz; n = 2, 3, or 4) L D A - hthium diisopropylamide lit. - literature L R M S - low resolution mass spectrometry m - multiplet m - meta m - C P B A - m-chloroperbenzoic acid Me - methyl M e O H - methanol min - minutes mol. - molecular M O M - methoxymethyl = -CH2OCH3 xv i i mp - melting point Ms - methanesulfonyl n - normal NIS - Af-iodosuccinimide N M O - A /-methylmorpholine Af-oxide N M P - N-methylpyrrolidinone nmr - nuclear magnetic resonance OMe - methoxy p - para P C C - pyridinium chlorochromate Ph - phenyl p H - -logi 0[H+] ppm - parts per million Pr - propyl py - pyridine q - quartet rt - room temperature s - singlet t - triplet t - tertiary T B A F - tetrabutylammonium fluoride T B S - te/t-butyldimethylsilyl T B S O - Jm-butyldimethylsilyloxy tert - tertiary T f - trifluoromethanesulfonyl T H F - tetrahydrofuran T L C - thin layer chromatography xviii T M S - trimethylsilyl T M E D A - A^N',N'-tetramethylemylenediamine T P A P - tetrapropylammomum perruthenate Ts - para-toluenesulfonyl, tosyl -ve - negative • - coordination or complex ACKNOWLEDGMENTS I would like to thank my research supervisor, Dr. Edward Piers, for his guidance and support during the course of my graduate studies at the University of British Columbia. Thanks to all the members of the Piers group (1991-97: Christine, Phil, Serge, T i m , Patricia, Jimmy, Katherine, Wen-Lung, Miguel, Todd, Rene, Renata, Krystyna, Shawn, Richard, Ernie, Eva, Debra, Ralph, Pat B . , Livain, Chantal, Han, Jim, Tommy, Rob, Michael, Sebastien, Francisco, Anthony, Veljko, Jacques, Johanne, and Keith) for advice, helpful suggestions regarding my research project, and the sharing of equipment and chemicals (purified and dried solvents and reagents). I hope that all those who worked in the A-304 lab with me and endured hours of my mindless babble day in, day out enjoyed their time as much as I did. Special thanks to Dr. Patricia Gladstone and Dr. Christine Rogers, as well as Dr. Dave McConville, for their help in proof-reading my thesis. The contributions of the support staff of the nmr, mass spectrometry, and elemental analyses laboratories in the Department of Chemistry are gratefully acknowledged. Finally, I wish to express my deepest thanks to my parents for their encouragement and support throughout all these years, no matter what half-baked schemes I concocted. I. INTRODUCTION 1. General The synthetic organic chemist can be classified as a member of either of two groups. Those in the first group are engaged in the total synthesis of a particular substance from simple, readily available, and generally inexpensive starting materials. The goal of these chemists is the synthetic preparation of a known substance, usually a naturally occurring compound or an analogue thereof, which has some desired biological activity. While the methods used to prepare this natural product are important, they are secondary to obtaining the product itself. The second group of synthetic organic chemists investigates methods to achieve particular transformations, to determine the scope of particular reaction types, and to control reactivity in order to achieve selectivity in product formation. For these chemists, the goals are the methods, reactions, and procedures developed that afford a particular transformation. The products obtained, although they may be structurally novel and interesting, are of secondary importance to their method of preparation. Generally, it is hoped that these methodological studies will find subsequent use in the total synthesis of naturally occurring substances. Considerable research effort has been spent developing new methods for the preparation of functionalized ring systems. The term annulation is used to describe the process of constructing a ring onto a pre-existing cyclic or acyclic system.1 The two new carbon-carbon bonds can be formed simultaneously, consecutively in a one-pot process, or separately in two reactions. In principle, the newly formed ring may be of any size, but in the vast majority of cases, five- and six-membered rings are formed. In a broad sense, annulation methods include Diels-Alder reactions, acid-catalyzed olefinic cyclizations, radical cyclizations, photochemical and thermal cyclizations, and most commonly, alkylations or Michael additions followed by ring closure. The investigations of new annulation sequences has led to the development of numerous bifunctional conjunctive reagents,2 which possess two potentially reactive sites and can be incorporated in whole or in part into a more complex system. The reactive sites can be either nucleophilic or electrophilic in nature and have been termed donor (d) or acceptor (a) sites, respectively.3 These bifunctional reagents must be designed in such a manner to both allow the coexistence of the two reactive sites yet facilitate the selective deployment, either sequentially or simultaneously, of the reactive sites (vide infra). While a review of bifunctional reagents is beyond the scope of this thesis, the following examples demonstrate the application of these types of reagents in organic synthesis.4 Some of the pioneering work in the field of bifunctional conjunctive reagents was conducted by Trost 5 nearly two decades ago. The use of 2-acetoxymethyl-3-allyl-trimethylsilane (1), as the synthetic equivalent of the a ^ d 3 prop-l-ene synthon (2), in a methylenecyclopentane annulation sequence was demonstrated (Scheme 1). In a one-pot reaction, the bifunctional reagent 1 underwent a palladium(O) catalyzed cycloaddition reaction with electron poor alkenes (such as 3) to provide the methylenecyclopentane product 4. 5 1 2 3 4 Scheme 1 A notable contribution from Magnus 6 outlined the use of a reagent (5) equivalent to the d 2 , a 4 but-l-ene synthon (6) in the total synthesis of (±) -hirsutene (7) (Scheme 2). In the first step, the donor site of 5 was deployed by converting 5 to the corresponding cuprate via a lithium-halogen exchange and addition of a copper(I) salt. Addition of the bicyclic enone 8 to a solution of this cuprate provided the 1,4-addition adduct 9. Conversion of silyl ether moiety to the better leaving group (para-toluenesulfonate ester) gave 10. A n intramolecular alkylation provided the tricyclic system 11 which was subsequently converted to the natural product 7. Scheme 2 2. B a c k g r o u n d The discovery of new methods for the construction of usefully functionalized five-and six-membered rings has been a primary research objective of the Piers group. These annulation methods have been effected through the use of novel bifunctional reagents (12-16) containing both nucleophilic (donor) and electrophilic (acceptor) sites (Figure 1). SnMe 3 CI 12 SnMe 3 13 SnMe 14 17 SnMe 3 15 GeMe 3 16 18 F i g u r e 1 Bifunctional Conjunctive Reagents Annulation of cyclic ketone systems 19 has been effected by first deploying the acceptor sites of 13 or 15 via alkylation of the dimethylhydrazone derivative of 19, followed by hydrolysis of the hydrazone function. Iododestannylation of 20 or 21 provided the alkenyl iodide 22 or 23 (Scheme 3). A lithium-halogen exchange unmasks the latent donor activity of the alkenyl site. The resultant alkenyllithium species 24 or 25 attacks the carbonyl function resulting in ring closure to give the bicyclic product 26 or 27 with an exocyclic methylene moiety adjacent to an angular hydroxyl group. In this manner, a methylenecyclopentane annulation sequence is achieved using 13 as the synthetic equivalent of the d 2 , a 4 but-l-ene synthon 6, while a methylenecyclohexane annulation sequence is achieved using 15 as the synthetic equivalent of the d 2 , a 5 pent-l-ene synthon 17 . 7 19 26 n = 1 27 n = 2 1) Me2NNH2, EtOH-AcOH, reflux 2) LDA, THF, 0 3) 13 or 15 4) Nal04, THF, H 20 (pH 7), rt 24 n = 1 25 n = 2 SnMe3 20 n = 1 21 n = 2 n-BuLi THF E -78 °C " 2 C H o C I 2 rt 22 n = 1 23n = 2 Scheme 3 With a,P-unsaturated ketones as substrates, alternative methylenecycloalkane annulation sequences can be employed. The bifunctional conjunctive reagents 12 and 14 (equations 1 and 2) serve as the synthetic equivalents of the d 2 , a 4 but-l-ene synthon 6 and the d 2 , a 5 pent-l-ene synthon 17, respectively. The donor activity of these reagents is utilized first by transmetalation with methylhthium. SnMe3 CI 12 SnMe 1) MeLi, THF, -78 °C 2) CuCN 1) MeLi, THF, -78 °C CI 2) MgBr2-Et20 Cu(CN)Li (1) (2) 29 Addition of copper(I) cyanide to the lithio derivative obtained in situ from 12 provides an organocuprate reagent 28 (equation 1), which adds in a conjugate sense to cyclic enone systems (30) to provide 31 (Scheme 4). Alternatively, 14 is converted to the Grignard reagent 29 (equation 2), which can also be added in a conjugate sense to cyclic enones (30) in the presence of catalytic copper(I) to provide 32. The acceptor sites are then deployed in a subsequent intramolecular alkylation to generate the methylenecyclopentane annulated product 338 and the methylenecyclohexane annulated product 349 (Scheme 4). 28, THF -78 °C °r ^ 29 CuBr»Me2S BF3»Et20 THF, -78 °C o KH THF rt 31 n = 1 32 n = 2 J J R 1 33 n = 1 34 n = 2 •). Scheme 4 A methylenecyclopentane annulation sequence, regiochemically complementary to that illustrated in Scheme 4, has also been developed using the bifunctional conjunctive reagent 16 as the synthetic equivalent of the a 2 , d 4 but-l-ene synthon 18 (Scheme 5). B y converting reagent 16 to the organocopper(I) species 35 (equation 3), the donor site of the bifunctional reagent can be utilized in a conjugate addition to an enone (30) to provide the 1,4-addition adduct 36 (Scheme 5). The carbon-germanium bond is stronger than the carbon-tin bond, 1 0 causing the alkenyltrimethylgermyl function in 16 to be more resistant to transmetalation with an alkyllithium than is the corresponding alkenyltrimethylstannyl moiety. Lithium - halogen exchange can be performed chemoselectively on the iodide substituent at carbon-4 of 16 without affecting the trimethylgermyl moiety. < £ e M e 3 1)f-Bul_i,THF,-98°C J^Me3 < ^ ^ ^ \ 2) CuCN, -78 °C -> -35 °C * ^ ^ ^ C u ( C N ) L i ( 3 ) 16 35 Unmasking of the acceptor site of the bifunctional reagent 16 is achieved by converting the alkenyltrimethylgermane adduct 36 to the corresponding alkenyl iodide 37. A palladium(O) catalyzed intramolecular coupling reaction between an enolate carbon (donor) and the alkenyl iodide (acceptor) generates the regiochemically opposite methylenecyclopentane ring 3811 (Scheme 5), compared with 33 (Scheme 4). Scheme 5 The synthetic utility of the annulation sequences outlined in Schemes 4 and 5, employing bifunctional organometallic reagents 12,14, and 16, has been verified by their application in the total syntheses of several natural products including: ( ± ) - p e n t a l e n e n e , 1 2 ( ± ) - A 9 ( 1 2 ) - c a p n e l l e n e , 8 (+)-axamide-l, 9 ( ± ) - a x i s o n i t r i l e - l , 9 ( ± ) - p a l a u o l i d e , 1 3 and (±)-cr inipel l in B . 1 4 The alkenyltrimethylgermane bifunctional reagent 16 has also been employed in a methylenecyclohexane annulation sequence to provide products similar to 27, described in Scheme 3. In this annulation method, the organocopper(I) reagent 35, prepared from the bifunctional conjunctive reagent 16, is used as the synthetic equivalent of the d 2 , d 4 but-l-ene synthon 39. Cu(CN)Li This sequence was employed in the total synthesis of ( ± ) - a m b l i o l B (40) (Scheme 6) . 1 5 A conjugate addition of the organocopper(I) reagent 35, obtained from 16 (equation 3), to the enone 41 deploys the donor site at carbon-4 of 35 to provide the addition adduct 42. The latent donor activity of the alkenyltrimethylgermane is unmasked by an iododegermylation reaction followed by lithium-halogen exchange. The resultant alkenyllithium species attacks the carbonyl carbon in an intramolecular fashion resulting in ring closure to provide the bicyclic product 43. Further synthetic transformations on this compound leads to the synthesis of the target compound (40) (Scheme 6). Scheme 6 3. Proposals Previous work in the Piers lab has shown the utility of bifunctional organometallic reagents in a variety of annulation sequences to provide bicyclo[x.y.O]alkane (x, y = 4; x = 4, y = 3; x, y = 3) ring systems. In most cases, the annulation sequences provided either exclusively or predominately the ds-fused products. Only when the ring junction contained an epimerizable center and at least one of the rings was a cyclohexyl moiety could the trans-fused product be obtained. 1 3 ' 1 6 Thus the trans-fused bicyclo[4.3.0]nonane system could be prepared via epimerization of the cis-fused isomer, but the trans-fused bicyclo[3.3.0]octane ring system was inaccessible using the established annulation protocols. A potentially important extension to the aforementioned annulation methods is the development of a general method for the stereocontrolled synthesis of trans-fused bicyclo[4.3.0]nonane and trans-fused bicyclo[3.3.0]octane systems. The use of 16 as the synthetic equivalent of the d 2 , d 4 but-l-ene synthon (39) in the total synthesis of ( ± ) - a m b l i o l B (40) provided the trans-fused bicyclo[4.4.0]decane ring system 43 (vide supra, Scheme 6). It was proposed that if a cyclopent-l-enecarbaldehyde substrate 44 (Scheme 7) was employed as the a 1 , a 3 propane synthon, it could be combined with the organocopper(I) reagent 35, here employed as the synthetic equivalent of the d 2 , d 4 but-l-ene synthon (39), to provide 45 and ultimately the trans-fused bicyclo[4.3.0]nonane ring system 46 (Scheme 7). Thus, extension of synthetic utility of the bifunctional reagent 16 would be demonstrated. In order to ensure formation of the trans ring junction, the last bond to be formed would not be to a ring fusion atom, and thus the stereochemistry of the ring junction would be established prior to the ring closure step. GeMe3 d d GeMe3 I ^ ^ Cu(CN)Li 16 39 35 Provided that the rrans-fused bicyclo[4.3.0]nonane ring system could be constructed stereoselectively, it was envisaged that a similar approach could be utilized to form the trans-fused bicyclo[3.3.0]octane ring system 47 (Scheme 8). In this case, the synthesis of a reagent equivalent the to d 2 , d 3 prop-l-ene synthon 48 that could be delivered to the P-position of a,P-unsaturated carbonyl compounds would be required. It was thought that the organocopper(I) reagent 49, perhaps the one carbon lower homologue of 35, could function as the d 2 , d 3 prop-l-ene synthon 48. Thus, if the organocopper(I) reagent 49 could be added stereoselectively to 44, it would provide 50. Cyclization of 50 would ultimately generate the trans-fused bicyclo[3.3.0]octane ring system 47. In summary, the development of the annulation methods to prepare stereoselectively trans-fused bicyclo[x.3.0]alkane (x = 3 or 4) rings using bifunctional organometallic reagents containing two donor sites was the primary goal of this work. If a reagent equivalent to the d 2 , d 3 prop-l-ene synthon 48 could be prepared, its utility in other synthetic applications would also be probed. II. DISCUSSION 1. Stereocontrolled Annulation Method for the Synthesis of the Trans-Fused Bicyclo[4.3.0]nonane Ring System 1.1 Background Both the trans-fused (51) and ds-fused (52) bicyclo[4.3.0]nonane ring systems are common structural units in many naturally occurring compounds 1 7 including vitamin D derivatives 1 8 and steroids. 1 9 While a plethora of methods have been developed to prepare these ring systems, 2 0 the stereoselective formation of either the cw-fused or trans-fused rings has been problematic, 2 1 especially when they are substituted in any manner. H H 51 52 A n examination of the parent hydrocarbons shows that the strain energy of the trans-fused isomer 51 is only 1.0 kcal/mol lower than that of the cw-fused isomer 52.22 Because of the small energy difference between the two isomers, substitution or functionalization at any position of the bicyclo[4.3.0]nonane system can dramatically affect the relative thermodynamic stabilities.23 This point is illustrated by the data summarized in Table 1 pertaining to bicyclo[4.3.0]nonan-2-ones. Table 1 Energy Difference Between Substituted Cis- and Tr<ms-Bicyclo[4.3.0]-nonan-2-one Systems 2 3 53 54 55 Entry R R a R p % trans 53 % cis& 54 % cis* 55 Energy Difference Oxal/mol) 1 H H H 24 76 - 0.7 2 C H 3 H H 8 92 - 1.4 3 H C H 3 H 94 - 6 1.6 4 C H 3 C H 3 H 69 - 31 0.4 5 H H C H 3 0 100 - >4.5 6 C H 3 H C H 3 0 100 - >4.5 a The conformational equilibria were determined by * H and 1 3 C nmr spectroscopy. With the substituted hydrindanone systems shown in Table 1, the trans-fused system exists in a rigid conformation (53), while the ds-isomer can exist in two interconvertible conformers (54 and 55) with the six-membered ring in the chair form. In contrast with nonfunctionalized bicyclo[4.3.0]nonanes, where the trans-fused system is more stable than the ds-fused (cf. 51 and 52), the ds-fused isomer of the substituted bicyclo[4.3.0]nonanone system (54 or 55) is actually more stable than the trans-fused isomer (53) (Table 1, entries 1, 2, 5, and 6) except when R « = C H 3 (Table 1, entries 3 and 4). Unfavorable steric and 1,3-^yn-axial interactions were used to explain these relative stabilities. The stereoselective formation of the trans-fused bicyclo[4.3.0]nonane ring system is further complicated by the preferential formation of the ds-fused product when cyclizations are conducted in which the last bond formed is a bond to a ring fusion atom. In most cases, such as intramolecular radical cyclizations 2 4 or intramolecular alkylations, 2 5 the kinetic product has the ds-ring junction. Thus, to stereoselectively form the trans-fused bicyclo[4.3.0]nonane ring system, the final bond formed must not be to a ring fusion atom. 2 6 1.2 Introductory remarks The initial goal of our studies was the development of a general method for the preparation of the trans-fused bicyclo[4.3.0]nonane ring system using the bifunctional reagent 35. W e had envisaged that any cyclopentanone system (56) could function as the starting material for this novel annulation procedure. In order to ensure a trans-fused ring junction, it was decided that the stereochemistry of the ring substituents (57) would be fixed as trans early in the sequence. A retrosynthesis of the proposed annulation sequence is shown in Scheme 9. 56 44 R = H 60 R = OMe Scheme 9 It was proposed that the trans-fused bicyclo[4.3.0]nonane ring system 58 could be obtained from 59 by the intramolecular nucleophilic displacement of a suitable leaving group X by the alkenyllithium function. Oxidative cleavage of the resultant exocyclic methylene moiety would provide 58. Compound 59, could in turn be prepared from 57 by a series of functional group interconversions. A stereoselective 1,4-addition of the cyanocuprate 35 to the a,pVunsaturated aldehyde 44 should provide 57. The cyclopent-1-enecarbaldehyde 44 could be obtained via reduction of the corresponding methyl ester 60. A palladium(O) catalyzed carbonylation 2 7 of the alkenyl triflate derived from the cyclopentanone species 56, in the presence of methanol, should provide the ester 60. 1.3 Preparation of the cyclopent-l-enecarbaldehyde substrate Although in theory any cyclopentanone system could have been used as the starting material for the proposed annulation method, cw-bicyclo[3.3.0]octane-3,7-dione mono-2,2-dimethylpropylene ketal (61) was chosen (Figure 2). Figure 2 c/,?-Bicyclo[3.3.0]octane-3,7-dione mono-2,2-Dimethylpropylene Ketal (61) This keto ketal 61 was prepared previously 2 8 in our laboratories, and is a nonvolatile, stable crystalline material (mp 48 °C) with characteristic nmr and IR signals due to its ketal function (Figure 2). The resonances in the Iff nmr spectrum due to the ketal function generally appear as two 3-proton singlets between 8 0.90 and 8 1.00 (for the methyl groups), and a 4-proton multiplet between 8 3.34 and 8 3.53 (for the methylene groups). The ketal moiety also shows distinctive signals in the 1 3 C nmr spectra: two signals for the methylene carbons at ~8 72, a signal for the quaternary carbon at ~8 30, and two signals for the methyl carbons at ~8 22. A strong C - O - C stretching absorption at -1110 c m - 1 is evident in the IR spectrum of compounds containing the 2,2-dimethylpropylene ketal moiety. COoMe hL . 0 I H O 63 Me02C H C02Me NaOH, MeOH reflux Na + _0 0"Na+ Me02C H C02Me 65 HCI, AcOH H 20 >ocr> H 61 66 p-TsOH-H20 C 6 H 6 , reflux Scheme 10 H O O H 62 Even though ds-bicyclo[3.3.0]octane-3,7-dione (62) is commercially available, it is prepared easily and inexpensively by a base-mediated Weiss-Cook condensation using glyoxal (63) and dimethyl 1,3-acetonedicarboxylate (64), followed by an acid-catalyzed hydrolysis and decarboxylation of the tetraester intermediate (65) (Scheme 10) . 2 9 Protection of one of the carbonyl functions of the dione 62 was accomplished under Dean-Stark conditions by treatment with 2,2-dimethylpropanediol (66) and a catalytic amount of acid. The keto ketal 61 was isolated after chromatographic separation of it from the diprotected ketone and starting material. 2 8 Spectral data and yields obtained were in accordance with the reported values. 2 8 >C>ct>°i ) LDA, THF, -78 °C ^ H H 61 2) PhN(S02CF3); -78 °C -»rt OTf H 67 CO, Pd(OAc)2, Ph3P, Et3N, MeOH, DMF, rt H >c:>o> COoMe H 68 Scheme 11 The method of Scott and M c M u r r y 2 7 a was used to convert the keto ketal 61 into the known alkenyl triflate 67 . 3 0 Thus, deprotonation of 61 with L D A , followed by treatment with N-phenyltrifluoromethanesulfonimide, provided the alkenyl triflate 67 in 90% yield (Scheme 11). The a,(3-unsaturated ester 68 was prepared, in 88% yield, by a palladium(O) catalyzed carbonylation of 67 with carbon monoxide in the presence of methanol 3 1 (Scheme 11). The IR spectrum of 68 exhibited a strong C=0 stretching absorption at 1717 c m - 1 and a weak C=C stretching absorption at 1633 c m - 1 , both consistent with an a,|3-unsaturated ester moiety. The lH nmr spectrum displayed a 3-proton singlet at 8 3.70, indicating the presence of a methyl ester, and a 1-proton signal for the olefinic proton at 8 6.61 (dd, J = 2, 2 Hz). The characteristic signals for the 2,2-dimethyl-propylene ketal, two 3-proton singlets at 8 0.92 and 8 0.94 and a 4-proton multiplet centered at 8 3.44, were also observed in the * H nmr spectrum of 68. While it had initially been hoped that the a,P-unsaturated ester 68 would be a suitable Michael acceptor for the cyanocuprate 35, preliminary studies showed that the organocuprate 35 did not undergo 1,4-addition to 6832 (Scheme 12). Therefore, we proceeded with the preparation of the aldehyde 71 from the ester 68 by a straightforward reduction - oxidation sequence. >od> H C02Me DIBAL-H, THF } -78 °C -» 0 °C H 68 GeMeL X 35 TMSBr, THF, -78 °C *Cu(CN)Li H 69 GeMe 3 >Qct> CHoOH H 70 PCC, Celite, CH2CI2, rt H >Qct>« H 71 Scheme 12 Reduction of the ester 68 in T H F with 2.5 equivalents of D I B A L - H 3 3 afforded, after appropriate workup and chromatography, the allylic alcohol 70 in 95% yield. Attempts to reduce the ester 68 directly to the aldehyde 71 using 1.0 equivalents of D I B A L - H in T H F provided a mixture of the alcohol 70 and recovered ester 68. The IR spectrum of the alcohol 70 exhibited a strong O - H stretching absorption at 3429 c m - 1 , a weak C=C stretching absorption at 1657 c m - 1 , and a strong C - O - C stretching absorption at 1112 c m " 1 . The * H nmr spectrum of 70 showed the expected signals for the 2,2-dimethylpropylene ketal (two 3-protons singlets at 8 0.93 and 8 0.94 and a 4-proton multiplet centered at 8 3.45), a hydroxyl proton (a broad 1-proton signal at 8 1.34, which exchanges with D2O), two hydroxymethyl protons (a broad 2-proton signal at 8 4.12), and an olefinic proton (a broad 1-proton doublet at 8 5.50). Oxidation of 70 with pyridinium chlorochromate 3 4 in methylene chloride provided, after a non-aqueous workup and chromatography, the cyclopent-l-enecarbaldehyde 71 in 86% yield. The IR spectrum of 71 exhibited the expected signals for an a,|3-unsaturated aldehyde, a strong C = 0 stretching absorption at 1681 c m - 1 and a weak C = C stretching absorption at 1617 c m - 1 . The * H nmr spectrum displayed a 1-proton singlet at 8 9.75 attributed to the aldehyde function and a 1-proton doublet of doublets (7 = 2.5, 2 Hz) at 8 6.69 due to the olefinic proton. Characteristic signals for the 2,2-dimethylpropylene ketal were seen in both the * H nmr and IR spectra of 71. The 1 3 C nmr spectrum of 71 contained all of the expected 14 signals. Complete assignment of the signals in the * H nmr and 1 3 C nmr spectra of the oc,p-unsaturated aldehyde 71 was achieved through use of two-dimensional nmr spectroscopy, both C O S Y and H M Q C spectra (Tables 17 and 18, experimental section). 1.4 Conjugate addition of the cyanocuprate 35 to the q.^-unsaturated aldehyde 71 With the a,3-unsaturated aldehyde 71 in hand, we set out to investigate its reactivity in the conjugate addition reaction with the well known lower order cyanocuprate 35.11 The bifunctional reagent 16, the precursor of the cuprate 35, was prepared by two different methods. 3) Nal, acetone reflux (4) 12 16 The original preparation 1 5 involved the use of 4-chloro-2-(trimethylstannyl)-but-l-ene (12) as the starting material (equation 4) . Treatment of 12 in T H F with a solution of methyllithium results in a transmetalation to provide an alkenyllithium species, which can be trapped with trimethylgermanium bromide to afford 4-chloro-2-trimethyl-germylbut-l-ene. This volatile alkenyltrimethylgermane was immediately converted to the iodide 16 using Finkelstein conditions. Although this sequence is not experimentally complex, it does require the prior preparation of 12, a somewhat laborious and tedious procedure8 (equation 5). In addition, the relatively expensive trimethyltin moiety is wasted in this process. 1) Me3SnCu«Me2S, THF, -78 °C 2) MeOH, -78 °C -> 0 °C SnMe3 = V 3)NH4CI-NH4OH,H20(pH8) y X ^ ^ . ( 5 ) ^—OH 4) silica gel chromatography ' CI 7 2 5) Ph3P, Et3N, CCI4, reflux ^ A n alternative and more cost and time effective procedure for the preparation of 16 was developed recently by Piers and Lemieux 3 5 (equation 6). 1) Mel_i, THF, -78 °C 2) TMSCI, -78 °C -> 0 °C 3) Me3GeH, H2PtCI6«xH20, GeMe3 = ~ ^ - O H CH2C'2-0°C^rt - A^X, ( 6 ) 4) p-TsOH-H20, CH2CI2, 30 °C 72 5) Ph3P»l2,imidazole, ig Et20:CH3CN (3:1), rt A palladium catalyzed hydro germ ylation of 4-trimethylsilyloxy-l-trimethylsilybut-l-ene (obtained from 72), followed by a protiodesilylation reaction under acid conditions, were the key steps in the preparation of 3-trimethylgermylbut-3-en-l-ol. The resultant alcohol was converted to the iodide 16 under mild conditions. 3 6- 3 7 G M 1)f-BuLi,THF,-98°C G e M e J[ e M e 3 2) CuCN, -78 °C X (7> 3) warm briefly to -35 °C * —^Cu(CN)Li 16 4) cool to-78 °C 3 5 Preparation of the cyanocuprate 3511-37 was achieved by the treatment of a solution of 16 in cold ( - 9 8 ° C ) T H F with two equivalents of rm-butyllithium (73), followed by addition of one equivalent of copper(I) cyanide and brief warming to -35 ° C , to give a homogeneous tan solution of the required reagent 35 (equation 7). GeMe3 ^ J ^ ^ + f-BuLi 16 th 73 GeMe3 GeMe3 16 78 B GeMe3 78 GeMe3 CH 3 l - C - C H 3 CH 3 74 GeMe, H3C CH 3 H 3 C - C - H + LiT-C-CHa C H 3 74 73 (CH3)3CH + (CH3)2C=CH2 + Lil 75 76 77 Scheme 13 It was necessary to use two equivalents of fm-butyllithium to ensure success of the lithium - iodine exchange reaction (Scheme 13). Reaction of terf-butyllithium (73) with tert-butyl iodide (74), formed from the metal - halogen exchange with 16, is competitive with the initial lithium - iodine exchange process (path A), giving 2-methylpropane (75), 2-methylpropene (76), and lithium iodide (77) (path C).3 8 If less than two equivalents of terf-butyllithium are used, the iodide 16 and the alkyllithium species 78 (produced from 16 by the metal - halogen exchange) are present together in solution and will react to form the coupled product 79 (path B). Furthermore, if te/t-butyllithium is added slowly to 16, then both 16 and 78 are present together in solution for sufficient time that the coupling reaction (path B) predominates. It was also found that, at temperatures higher than -95 ° C , the coupling process indicated (16 + 78 —> 79) becomes the predominate reaction (path B). Thus, to minimize formation of the coupled product 79 and to ensure complete formation of 78, two equivalents of tert-butyllithium must be added rapidly, in one portion, to the cold (-98 °C) reaction mixture. 1 ) GeMe3 11 M ^Cu(CN)Li 0 \ |J Me3SiBr, THF, -78 °C \ T^v^W \ ^ R 2 l ) T ^ O * Y\ ^ 3) NH4CI-NH4OH, H 20 (pH 8) 2 30 36 (8) Previous studies 1 1 ' 3 7 have shown that the 1,4-addition of the cyanocuprate 35 to cold solutions of a,fj-unsaturated ketones (30) in T H F proceed smoothly in the presence of trimethylsilyl bromide 3 9 (equation 8). Reaction times are typically on the order of 4 -8 hours. The resultant silyl enol ether is generally hydrolyzed with water prior to workup with aqueous NH4CI-NH4OH (pH 8) to provide the 1,4-addition adduct 36. When these conditions were applied with the a,P-unsaturated aldehyde 71 (Scheme 14), the desired 1,4-addition product 80 was obtained in low yield (35%), along with recovered 71 (22%), and an unidentified byproduct (Table 2, entry 1). Utilizing essentially the same reaction conditions, but with the addition of two equivalents of H M P A , 4 0 - 4 1 the 1,4-addition product 80 was obtained in yields as high as 80% (Table 2, entries 2-4). In all cases, 80 was isolated as a 3:1 mixture of epimeric aldehydes. However, these yields were variable and were not reproducible (Table 2, entries 1-4). GeMe3 Cu(CN)Li 35 H O 1) 2) 1) 35, Me3SiBr (HMPA), THF / / - C H 0 2,lgr—• 3) NH4CI-NH4OH H 20 (pH 8) Q 35, Me3SiBr & HMPA THF, -78 °C NH4CI-NH4OH H 71 THF, rt H H 82 GeMe, Scheme 14 Table 2 Addition of the Cuprate 35 to the a,f3-Unsaturated Aldehyde 71 (Scheme 14) Entry Reaction Time a Silyl Enol Ether Hydrolysis and Reaction Workup Conditions1 5 Isolated Yield of 80 (%) Other Products Isolated (% yield) 1 4.0 h c H 2 O d ( l h ) , A e (overnight) 35 (45) f 71 (22) ??8 2 60 min H 2 O d (2 h), A e (2 h) 80 (92)f 71 (13) 3 30 min H 2 O d (1 h), Ae (2 h) 70 4 30 min H 2 O d (30 min), Ae (3 h) 38 ??g 5 2.0 h Ae (4 h), T B A F n (1 min) 45 6 20 min Ae (2 h), T B A F n (15 min) 46 82 (49) 7 2.5 h A e (2 h), T B A F h (2 min) 0 71 (40) 82 (57) 8 30 min A e (2 h), M e L i 1 (15 min) 65 (89) f 71 (27) 9 30 min A e (3 h), M e L i 1 (10 min) 75 10 15 min k Ae (3 h), M e L i 1 (10 min) 66 (84)1 81 (18) 11 15 m i n k Ae (3 h), M e L i ' (30 min) 90 12 15 min k Ae (3 h), M e L i 1 (10 min) 84 (95)1 81(11) a A l l reactions were performed by the sequential addition of 3 - 4 equiv Me3SiBr, ~2 equiv H M P A , and 71 to a solution of 1.6 - 2.0 equiv 35 unless otherwise noted. b The method of hydrolysis of the silyl enol ether and reaction workup are listed in the order of performance. The time for each step is given in parenthesis. In entries 1-4, the silyl enol ether was hydrolyzed prior to workup while in entries 5-12, the reaction mixture was worked up to provide the crude silyl enol ether, which was subjected to a non-aqueous cleavage. c Reaction run without the addition of H M P A . d Reaction mixture quenched with water, then warmed to room temperature and stirred open to the air for the indicated time. e A = Reaction mixture poured into a vigorously stirred solution of aqueous N H 4 C I - N H 4 O H (pH 8) and stirred open to the air for the indicated time upon which the aqueous layer turned bright blue. f Yield based on recovered starting material. 8 A spectroscopic analysis of this unidentified byproduct indicated the presence of the following functional groups: 2,2-dimethylpropylene ketal, alkenyltrimethylgermane, and a carbonyl group (1737 cm - 1 ) . h The crude silyl enol ether 81 was isolated, dissolved in T H F and treated with T B A F for the indicated time prior to an aqueous quench. i The crude silyl enol ether 81 was isolated, dissolved in T H F , cooled to -78 ° C , and treated with a solution of M e L i (in E t 2 0 ) for the indicated time prior to an aqueous quench. j Total yield of 1,4-addition products (80+ 81). k H M P A added after the addition of 71. The hydrolysis of the silyl enol ether with water prior to aqueous workup with aqueous NH4CI-NH4OH (pH 8) was believed to be the problematic step. It has been reported 4 2- 4 3 that improved yields of the 1,4-addition product often result if the product aldehyde is isolated by way of the corresponding silyl enol ether rather than by direct hydrolysis of the reaction mixture 4 4 Thus, it was decided to isolate the silyl enol ether and subject it to non-aqueous cleavage conditions. When trimethylsilyl bromide, H M P A , and the oc,p-unsaturated aldehyde 71 were added to a cold solution of 35 in THF, after only 15 minutes a T L C analysis showed complete consumption of 71. The reaction mixture was poured into a vigorously stirred solution of aqueous NH4CI-NH4OH (pH 8), and after workup and chromatography, a sample of pure 81 was isolated. The IR spectrum of 81 exhibited a C-O-C stretching absorption at 1113 c m - 1 , attributed to the ketal, and a germanium - methyl rocking absorption at 841 c m - 1 . The *H nmr spectrum of 81 displayed two 9-proton singlets at 8 0.07 and 8 0.18, indicative of the Me3Si and Me3Ge groups, respectively, a 6-proton singlet at 8 0.93 and two 2-proton singlets at 8 3.41 and 8 3.47, characteristic of the 2,2-dimethylpropylene ketal moiety, and three alkenyl protons positioned at 8 5.14, 8 5.38 , and 8 5.48. The 1 3 C nmr spectrum of 81 contained all the expected signals. In addition to this spectral data, the molecular formula of 81 was confirmed as C22H44Ge03Si by a high resolution mass spectrometric measurement on the molecular ion. Use of TB A F 4 5 in THF to cleave the silyl enol ether in 81 resulted in low yields of 80 (isolated as a 3:1 mixture of epimeric aldehydes), as well as the formation of significant amounts of the acetal 82 (Table 2, entries 5-7). It seemed likely that the ketal hydrolysis and the concomitant acetal formation was catalyzed by the Lewis acidic trimethylsilyl fluoride. Aldehydes can be protected as acetals chemoselectively in the presence of ketones, 4 6 while ketals are generally much more easily hydrolyzed than acetals.4 7 Evidence for the formation of the acetal was obtained by ^H nmr spectroscopy. The *H nmr spectrum of 82 contained a 1-proton doublet (7 = 7 Hz) at 8 4.11, characteristic of an acetal proton, as well as the expected signals for the 2,2-dimethylpropylene acetal, two 3-proton singlets at 8 0.93 and 8 0.96 and a 4-proton singlet at 8 3.47. Also observed in the * H nmr spectrum were signals for two alkenyl protons, at 8 5.50 and 8 5.17, and the Me3Ge moiety at 8 0.19. Treatment of a solution of the silyl enol ether 81 in T H F with methyllithium 4 8- 4 9 at low temperature, followed by protonation with the addition of water proved to be a consistent and reproducible method of cleavage of the trimethylsilyl enol ether, providing 80 in high yields (Table 2, entries 8-12). In all cases, 80 was isolated as an chromatographically inseparable mixture (3:1) of epimeric aldehydes. Although at this point the configuration of the major isomer was unknown, it seemed probable that in the major product the substituents would be trans. P R O D U C T Figure 3 Stereoselective Attack of the Cyanocuprate 35 to the Enal 71 Through an examination of molecular models, the cuprate reagent 35 was predicted to attack stereoselectively from the convex face of the bicyclic system of 71 (Figure 3). Hydrolysis of the resultant silyl enol ether 81 could lead to two epimeric aldehydes. The isomer in which the aldehyde is trans to the butenyl substituent should be the thermodynamically more stable product to minimize torsional strain. 5 0 Epimerization of the 3:1 mixture of aldehydes 80 under thermodynamic conditions (sodium methoxide in dry methanol) improved the product ratio to 9:1, as evidenced by integration of the nmr spectrum. Thus, the thermodynamic product ratio for 80 was 9:1. 5 1 It was expected that the major isomer was the one in which the substituents bore a trans relationship; indeed, this expectation was confirmed by a subsequent X-ray crystallographic study (vide infra). Thus, at this stage the stereochemistry of the ring substituents was fixed as trans. The spectral data obtained for the 9:1 epimeric mixture of aldehydes 80 was fully consistent with the assigned structures. The IR spectrum of 80 showed stretching absorptions at 1724 cm" 1 (aldehyde C=0) and 1116 cm" 1 (ketal C - O - C ) , and a germanium-methyl rocking absorption at 825 c m - 1 . The nmr spectrum of 80 displayed two aldehyde resonances in a 9:1 ratio (oc:f3) at 8 9.50 (doublet, 7 = 4 Hz, a aldehyde) and 8 9.78 (doublet, 7 = 3 Hz, P aldehyde), and a 9-proton singlet for the Me3Ge group at 8 0.17. Resonances for two alkenyl protons and the characteristic signals for the ketal were also seen in the nmr spectrum. The 1 3 C nmr spectrum of 80 contained all of the expected 19 signals. Lastly, the molecular formula was confirmed by a high resolution mass spectrometric measurement on the molecular ion. The 1,4-addition of the cuprate reagent 35 to the cc,P-unsaturated aldehyde 71, in the presence of trimethylsilyl bromide and H M P A , was extremely fast (15 minutes) and no 1,2-addition products were observed. High yields of 80 were readily obtained, providing that the silyl enol ether 81 was isolated prior to its conversion to 80. Although H M P A may be added to the reaction mixture prior to the a,P-unsaturated aldehyde 71 (Table 2, entries 1-9), higher yields of 81 were generally obtained when the H M P A was added after the addition of 71 (Table 2, entries 10-12). The reaction is conveniently run on scales of ~1 mmol of aldehyde 71, but have been successfully performed using 2.5 mmol of 71 with no reduction in the isolated yields (Table 2, entry 12). As for all reactions involving 35, careful temperature control is critical to the successful formation of the cuprate 35 from the iodide 16. Without proper temperature control, the cuprate 35 does not form and the 1,4-addition reaction will fail. 29 1.5 Attempted anionic ring closure 83 85 Scheme 15 The initial synthetic plan called for an anionic ring closure in which an alkenyl lithium displaces a leaving group on a primary carbon in an Sjsj2 fashion to provide the trans-fused bicyclo[4.3.0]nonane system 83 (Scheme 15). Thus, it was necessary to prepare compounds of general structure 84 to attempt the ring closure that would provide compound 85. 80 GeMe3 86 GeMe3 Treatment of a cold solution of the aldehyde 80 (9:1 mixture of epimers) in T H F with D I B A L - H 3 3 provided a chromatographically inseparable mixture of primary alcohols 86 in nearly quantitative yield (equation 9). The IR spectrum of 86 showed the disappearance of the aldehyde signal and the appearance of a strong O - H stretching absorption at 3383 c m - 1 . The * H nmr spectrum of 86 displayed a 9-proton signal for the Me3Ge at 8 0.18, a 2-proton multiplet at 8 3.72 from the hydroxymethyl protons, and two 1-proton multiplets attributed to the alkenyl protons centered at 8 5.15 and 8 5.49. The expected signals for the ketal were observed in both the IR and * H nmr spectra of 86. The desired iododegermylation of 86 did not proceed as planned. The alkenyl-trimethylgermane 86 was treated with iodine in methylene chloride, 5 2 typical conditions for iododegermylation reactions. After aqueous workup and purification by radial chromatography, the corresponding alkenyl iodide 87 and the deketalized adduct 88 were isolated in 63% and 22% yields, respectively (equation 10). Evidence obtained from * H nmr spectroscopy was used to support these structural assignments. The * H nmr spectrum of the alkenyl iodide 87 showed the characteristic signals for the 2,2-dimethylpropylene ketal (two 3-proton singlets at 8 0.90 and 8 0.96 and a 4-proton multiplet centered at 8 3.45), signals for the hydroxymethyl protons at 8 3.51 and 8 3.73, and resonances for the alkenyl protons at 8 5.66 and 8 5.99. The lU nmr spectrum of 88 showed resonances for the alkenyl protons at 8 5.66 and 8 6.00, but did not display the characteristic ketal resonances. The IR spectrum of 88 also exhibited a strong C = 0 stretching absorption at 1735 c m - 1 , attributed to a cyclopentanone. The significant downfield shift of the nmr resonances for the alkenyl protons in 87 and 88 from those in 86 supports the replacement of the Me3Ge group with the more electronegative iodine atom. The unexpected deketalization which occurred during the iododegermylation reaction can be rationalized by the interaction of the oxyphilic Me3GeI, a byproduct of the exchange reaction, with the ketal. It is well known 5 3 that Me3SiI can be used to cleave ketals, and it seemed likely that the Me3GeI byproduct could react in a similar manner to catalyze deketalization. The ketone 88 was easily converted into the ketal 87 under Dean-Stark conditions by treatment of the former substance with 2,2-dimethylpropanediol under acid catalysis. 1 2 90 X = Br Reaction Conditions 87 -> 89: p-TsCI, DMAP, Et3N, CH2CI2, rt 87 ->90: Ph3P»Br2, CH2CI2, rt Scheme 16 With compound 87 in hand, the remaining task was to convert the alcohol into an appropriate leaving group. It was decided that two different leaving groups would be investigated, a halogen (Br) and a sulfonate ester (p-toluenesulfonyl). Treatment of 87 with /?-toluenesulfonyl chloride, triethylamine, and D M A P in methylene chloride provided 89 in 89% yie ld , 5 4 while treatment of 87 with triphenylphosphine - bromide complex 5 5 in methylene chloride provided 90 in 79% yield (Scheme 16). The * H nmr of 89 exhibited two 2-proton doublets (7=8 Hz) at 8 7.32 and 8 7.78 attributed to the aromatic protons, two 1-proton multiplets at 8 5.67 and 8 5.98 attributed to the alkenyl protons, two 1-proton signals at 8 3.89 and 8 4.08 attributed to the methylene protons of the -CH2OTS, a 3-proton singlet at 8 2.45 attributed to the methyl group of the tosylate, and the characteristic ketal resonances. The * H nmr spectrum of the bromide 90 displayed resonances for the alkenyl protons at 8 5.68 and 8 6.01, resonances for the bromomethyl protons centered at 8 3.40 and 8 3.58, and the characteristic resonances for the 2,2-dimethylpropylene ketal. The mass spectrum of 90 showed the molecular ion peaks at 482 and 484. Table 3 Attempted Anionic Ring Closure Reactions 89 X = OTs 91 X = OTs 90 X = Br 92 X = Br Entry Substrate Reaction Conditions Product Yield (%) 1 89 n-BuLi , T H F , -78 ° C -> rt 91 83 2 90 n-BuLi , T H F , -78 ° C - » rt 92 86 3 90 n-BuLi , H M P A , T H F , -78 ° C -> rt 92 81 4 90 n-BuLi , H M P A , 12-crown-4, T H F , -78 °C -> rt 92 89 Having synthesized suitable cyclization precursors, the ring closure reaction was attempted (equation 11). Treatment of 89 with n-butyllithium gave only the protonated alkene 91 in 83% yield (Table 3, entry 1), while treatment of 90 with n-butylhthium under a variety of conditions gave only the protonated alkene 92 (Table 3, entries 2-4). Even the addition of H M P A , 5 6 a polar aprotic co-solvent, and the crown ether 5 7 12-crown-4, additives known to make nucleophiles much more reactive by forming complexes with the cationic counterions and thereby increasing the negative charge density on the alkenyl carbon, did not provide any of the cyclized products. In the lH nmr spectra of 91 and 92, the alkenyl regions showed signals for three distinct protons, including a complex 1-proton multiplet between 8 5.70 and 8 5.90 and two 1-proton signals between 8 4.90 and 8 5.00. There was no indication of any displacement of either the bromide or tosylate leaving groups although the nucleophile had formed as evidenced by the disappearance of the iodine moiety. Clearly, the anionic cyclization was unsuccessful and the synthetic plan needed revision. 1.6 Transition metal mediated ring closure The failure of the anionic cyclization, via the nucleophilic displacement reaction, was believed to be a result of unfavorable orbital overlap. Examination of molecular models indicated that a strained transition state was required in order for this cyclization to attain the correct orientation for a S N 2 displacement. Since the direct nucleophilic displacement did not work, it was decided to investigate the corresponding aldehyde system. A literature review showed that alkenyl iodides have been successfully coupled with aldehydes using chromium(II) chloride and nickel(U) chloride salts in D M F . 5 8 The pathway for the cyclization is postulated to proceed through the following mechanism (Scheme 17). ^ 1 93 OH 98 2 Cr(lll) \ Ni(0) 2 Cr(ll) Ni(ll) • ^ N i ( l l ) 94 Crflll^ 97 Scheme 17 <^Cr(\\l) 9 5 RCHO OCr(lll) OCr(lll) 96 Nickel(II) chloride is first reduced to nickel(O) with two equivalents of chromium(II) chloride. Oxidative insertion of nickel(0) into the alkenyl carbon-iodine bond of 93 then takes place. A transmetalation between the alkenylnickel species 94 and the chromium(UI) salt provides an alkenylchromium species 95 which reacts with the aldehyde to initially yield a chromium alkoxide species 97. The high stability of the oxygen - chromium(III) bond serves as the thermodynamic sink which drives the conversion. 5 9 Subsequent hydrolysis of this species upon workup provides an allylic alcohol 98. Thus, the new plan required the preparation of the iodo aldehyde 99 from 80 through a germanium - iodine exchange reaction. Subsequently, ring closure of 99 would be attempted via the chromium(II) chloride and nickel(II) chloride-mediated cyclization protocol The resultant allylic alcohol 100 would be converted to the ketone 83 (Scheme 18). 80 11 99 H H O H H O H 83 100 Scheme 18 Using the standard conditions for germanium-iodine exchange, 5 2 the alkenyl-trimethylgermane 80 (9:1 epimeric mixture) was treated with iodine in methylene chloride. After aqueous workup and chromatography, none of the desired product 99 was obtained. Instead, the acetal 101 was isolated in 73% yield (Scheme 19). Not only had germanium-iodine exchange occurred, but also cleavage of the ketal along with concomitant formation of the acetal. Scheme 19 The * H nmr spectrum of 101 showed the disappearance of the 9-proton signal at high field, for the Me3Ge moiety. The downfield shift of the alkenyl protons to 8 5.68 and 8 6.00 was characteristic of the replacement of the Me3Ge group with the more electronegative iodine atom. The cleavage of the ketal and formation of an acetal moiety was indicated by a 1-proton doublet (7 = 3.5 Hz) at 8 4.37 attributed to the methine proton of the acetal and the disappearance of the aldehyde signal. In addition, the resonances of the 2,2-dimethylpropylene acetal are significantly different from those of the corresponding ketal in the starting material 80. The acetal 101 displays two 3-proton singlets at 8 0.69 and 8 1.14, a separation of 0.44 ppm, while the ketal 80 displays two 3-proton singlets at 8 0.93 and 8 0.96 for the geminal dimethyl protons. The methylene protons of the ketal and acetal are also different in the ^H nmr spectra. The acetal 101 shows two 1-proton doublets at 8 3.36 (7=11 Hz) and 8 3.38 (7= 11 Hz) and one 2-proton doublet at 8 3.56 (7=11 Hz), while the ketal 80 exhibits a 4-proton broad signal at 8 3.45. The instability of the ketal function to the reaction conditions was not totally unexpected. In the germanium-iodine exchange reaction of 86, partial deketalization had been observed (equation 10). Trimethylgermanium iodide, a byproduct of the iodo-degermylation reaction, was believed to have catalyzed that process. When the silyl enol ether 81 was treated with T B A F , significant transmogrification of the ketal to the more stable acetal 82 was attributed to catalysis by the mildly Lewis acid trimethylsilyl fluoride byproduct (Scheme 14). In the reaction above (Scheme 19), the trimethylgermanium iodide could have played a similar catalytic role in promotion of the undesired side reaction. In order to test the hypothesis that the Me3GeI was responsible for the ketal migration, the exchange reaction was repeated with the addition of triethylamine to the solution of iodine in methylene chloride. It was hoped that the rate of ketal cleavage would be retarded by the addition of the Lewis basic triethylamine. After aqueous workup and chromatography, the desired iodo aldehyde 99 was isolated, albeit in low (43%) yield (equation 12, Table 4, entry 2). Table 4 Germanium - Iodine Exchange Reactions Entry Reaction Conditions Isolated Yield (%) of 99 1 12, C H 2 C 1 2 , rt 0(73)* 2 I 2 , E t 3 N , C H 2 C 1 2 , rt 43 3 NIS, C H 2 C 1 2 , rt 84 a Yield of acetal 101. It became clear that an alternative source of the halonium ion (I+) was required for the germanium - iodine exchange reaction to proceed successfully. While the use of N-bromosuccinimide, a known source of bromonium ion (Br+), has been reported in the literature 5 2 for bromodegermylation reactions, the use of AModosuccinimide to achieve a similar transformation had not , 6 0 - 6 1 even though the latter is a well known source of iodonium i o n . 6 2 Af-Iodosuccinimide has several advantages over iodine as a source of I + . The polarized nitrogen-iodine bond makes NIS more electrophilic than iodine. Loss of the iodonium ion from NIS results in a resonance stabilized anion in which the negative charge resides partially on oxygen. In light of the previous experimental results, in which coordination of the germanium containing byproduct with the ketal oxygens led to undesired hydrolysis, the negatively charged succinimide ion should compete effectively to reduce this unwanted side reaction. Treatment of 80 (9:1 mixture of epimers) with AModosuccinimide in methylene chloride gave exclusively the iodo aldehyde 99 in 84% yield with no sign of acetal formation (Table 4, entry 3). Spectroscopic evidence for the conversion of 80 into 99 was seen in the IR spectrum of 99. Notable absorbances include a weak stretching absorption at 1617 c m - 1 attributed to the alkenyl iodide, a strong stretching absorption at 1722 c m - 1 attributed to the aldehyde, and the characteristic C - O - C stretching absorption of the ketal at 1115 c n r 1 . The * H nmr spectrum of 99 displayed a downfield shift of the alkenyl protons to 8 5.69 and 8 6.01, characteristic of the replacement of the Me3Ge moiety with the more electronegative iodine atom, as well as the disappearance of the 9-proton singlet at high field due to the Me3Ge group. The *H nmr resonances for the 2,2-dimethylpropylene ketal were also observed in their characteristic positions - two 3-proton singlets at 8 0.93 and 8 0.96 and a 4-proton signal at 8 3.45. In the aldehyde region, two doublets at 8 9.51 (7 = 4 Hz, a aldehyde) and 8 9.78 (7 = 3 Hz, (3 aldehyde) in a 9:1 ratio were seen. Thus, the germanium - iodine exchange reaction conditions did not epimerize this mixture. The 9:1 ratio of epimers of 99 was in fact the thermodynamic ratio, as treatment of this mixture with sodium methoxide in methanol for 20 hours did not change the product ratio. With the alkenyl iodide aldehyde 99 in hand, we were ready to attempt the ring closure to provide the trans-fused bicyclo[4.3.0]nonane ring system. 103: R 1 =OH, R 2 = H The alkenyl iodide 99 was added to a slurry of chromium (II) chloride and nickel(II) chloride in dry D M F (equation 13). 5 8 After one hour, T L C analysis of the reaction mixture indicated that all of 99 had been consumed. Analysis of the crude reaction mixture, after workup, by * H nmr spectroscopy revealed that the reaction products lacked both the aldehyde and alkenyl iodide moieties. After purification of the crude material by silica gel chromatography, two major products were isolated and spectroscopic analysis indicated that two epimeric alcohols, 102 and 103, had been formed in yields of 23% and 57%, respectively (equation 13). A minor amount (-9%) of a mixture of ally he alcohols resulting from the ring closure of the cis component of 99 was also produced. The spectroscopic evidence obtained supported the conclusion that the desired cyclized products (alcohols 102 and 103) had formed. The infrared spectra of both 102 and 103 displayed strong O - H stretching absorptions at 3456 c m - 1 and 3436 c m - 1 , respectively, weak C = C stretching absorptions at 1651 c m - 1 in both compounds, and strong C - O - C stretching absorptions for their ketal moieties at 1110 c m - 1 and 1117 c m - 1 , respectively. The * H nmr spectrum of 102 exhibited a broad singlet at 8 4.23 attributed to the carbinol proton and two signals attributed to the alkenyl protons at 8 4.74 and 8 4.83, while the * H nmr spectrum of 103 exhibited a resonance for the carbinol proton at 8 3.81 (dd, J = 11.5, 6 Hz) and resonances for the alkenyl protons at 8 4.77 and 8 4.94. The 1 3 C nmr spectrum of 102 contained all of the expected 18 signals, but the 1 3 C spectrum of 1 0 3 displayed only 17 unique resonances due to coincidental overlap of the signals attributed to the methylene carbons of the ketal. Two dimensional nmr spectroscopy ( C O S Y and H M Q C ) was used to assign all of the proton and carbon resonances in 102 and 103 (Tables 19 - 22, experimental section). Through an examination of the coupling constants of the protons at the ring junction, it was hoped that the ring junction could be proven to be trans-fused. The * H nmr spectra of 103 shows that H - l (8 1.25) and H-6 (8 1.39) are coupled by 11.5 Hz. This large coupling constant, although consistent with a tamy-diaxial relationship of protons on a six membered ring, did not offer conclusive proof that the trans-fused system had been formed. However, a single crystal X-ray structure determination of a derivative of 103 (vide infra) confirmed the relative trans relationship between H - l and H-6. The chromium(II) chloride and nickel(II) chloride mediated cyclization of 99 exhibited a moderate preference for the formation of 1 0 3 , in which the newly formed hydroxyl function is cis to the adjacent angular proton. A n examination of the chair-like transition states, 1 0 2 * and 1 0 3 * , leading to the products shows two competing effects (Scheme 20). In the transition state 1 0 3 * leading to the major product (103) , A 1 - 3 strain between the olefin and the chromium alkoxide is observed. 6 3 On the other hand, in the transition state 1 0 2 * leading to the minor product (102), the A * - 3 strain is relieved by the newly formed hydroxyl group adopting an axial orientation. However, 1 0 2 * does experience 1,3-syn-axial interactions due to the chromium alkoxide adopting an axial orientation. These two effects, A 1 - 3 strain and l,3-,syn-axial interactions, result in little energy difference between the two possible transition states, as can be seen by the product ratio of ~2.5:1 in favor of 103. H 103 102 Scheme 20 It was decided that the two newly formed alcohols 102 and 103 would be converted to the same product, namely ketone 83 (Scheme 18). The allylic alcohols 102 and 103 were converted into their corresponding acetates by treatment of each alcohol with acetic anhydride in methylene chloride in the presence of D M A P and trieuhylamine (equation 14). 6 4 After workup and purification, the acetates 104 and 105 were isolated in excellent yields (Table 5). Table 5 Acetylation of the Alcohols 102 and 103 H H R 1 ! . .R 2 102: Ri = H, R 2 = OH 103: R T = OH, R 2 = H Ac 20 DMAP Et3N CH2CI2 rt 104: R 1 = H, R 2 = OAc 105: R T = OAc, R 2 = H (14) Entry Substrate Product Isolated Yield(%) 1 102 104 98 2 103 105 95 The spectral data of 104 and 105 were found to be in full accord with their assigned structures. The IR spectrum of 105 exhibited a strong absorption at 1742 c m - 1 attributed to the carbonyl stretching absorption of an ester function, a weak absorption at 1652 c m - 1 attributed to the C = C stretching absorption, and a strong absorption at 1117 c m - 1 attributed to the C - O - C stretching absorption of the ketal. Similar absorptions were found in the IR spectrum of 104 at 1739, 1656, and 1112 c m - 1 , respectively. The * H nmr spectrum of 105 displayed a resonance for the acetoxy methine at 8 5.07 (d, J = 9.5 Hz), a significant downfield shift from the resonance of the carbinol proton (8 3.81) in the starting material 103. This finding supported the assertion that the hydroxyl proton was replaced by the electron withdrawing acetyl group since the methine proton would be deshielded by the acetoxy group. A 3-proton singlet attributed to the acetoxy methyl group at 8 2.10 was also seen in the * H nmr of 105. Similarly, the * H nmr spectrum of 104 revealed a resonance for the acetoxy methine at 8 5.40 and a singlet for the acetoxy methyl group at 8 2.01. Additionally, the 1 3 C nmr spectra of 104 and 105 each contained the expected 20 signals. The relative configuration of 105 was confirmed through an X-ray crystallographic analysis. 6 5 The stereoview of this substance is shown below (Figure 4). Figure 4 Stereoview of the (3-Acetate 105 (note that this structure (105) is drawn as the enantiomer to that which was presented earlier in this thesis and a different numbering system has been used to label the atoms in this stereoview diagram) Several assumptions were confirmed by the X-ray structure. The angular protons at the A - B ring junction clearly exhibit a trans relationship, with a torsional angle of 175° . The six membered ring has adopted a chair-like conformation with the acetoxy group in an equatorial orientation. The approach of the cuprate 35 to the a,P-unsaturated aldehyde 71 had, as expected, occurred stereoselectively from the convex face of the substrate, and the major product from the 1,4-addition, after cleavage of the enol silyl ether function, did indeed have the ring substituents in a trans relationship. Oxidative cleavage of the exocyclic methylene groups in 104 and 105 was, in each case, achieved through ozonolysis 6 6 of the compound in cold methanol, followed by reductive workup with dimethyl sulf ide 6 7 (equation 15). After chromatographic purification, the acetoxy ketones 106 and 107 were isolated in excellent yields (Table 6). Table 6 Ozonolysis of the Exocyclic Methylene Moiety of 104 and 105 1)03 MeOH -78 2) Me2S 104: RT = H, R 2 = OAc 105: RT = OAc, R 2 = H 106: RT = H, R 2 = OAc 107: R 1 =OAc, R 2 = H (15) Entry Substrate R i R2 Product Isolated Yield(%) 1 104 H OAc 106 98 2 105 OAc H 107 90 The structural assignments for 106 and 107 were confirmed by IR and * H nmr spectral analysis. The IR spectra of 107 exhibited two strong C=0 stretches: one at 1750 c m - 1 attributed to the acetate carbonyl, and the second at 1728 c m - 1 attributed to the ketone. A strong C - O stretching absorption at 1235 c m - 1 attributed to the acetate moiety, and a strong C - O - C stretching absorption at 1116 c m - 1 attributed to the ketal were also observed. Similar absorptions were found in the IR spectrum of 106 at 1750, 1730, 1225, and 1108 c m - 1 , respectively. The nmr spectra revealed that both 106 and 107 lacked the resonances for the exocyclic methylene protons. The * H nmr spectrum of 107 did display a 3-proton singlet at 8 2.12, attributed to the acetoxy methyl group, a 1-proton doublet (7=12 Hz) at 8 5.03, due to the acetoxy methine proton, and the characteristic signals for the 2,2-dimethylpropylene ketal function. The 1 3 C nmr spectrum of 107 contained all of the 19 expected signals. The nmr (lH and 1 3 C ) spectra of 106 showed features similar to those for 107. Reductive removal of the acetoxy function from 106 and 107 was achieved under mild conditions with SmJ.2 in the presence of a proton source (equation 16). 6 8 Addition of a solution of either 106 or 107 in a 3:1 mixture of T H F and methanol to a cold solution of Sml2 in T H F provided the tricyclic keto ketal 83 in good yield after workup and silica gel chromatography (Table 7). Table 7 Reductive Removal of the Acetoxy Moieties from 106 and 107 H H H R1 7.nRc l 2 Sml2, MeOH^ \/~°\/ f^SL O THF,-78°C* A-Q^-TV \= (16) 106: R 1 = H, R 2 = OAc 107: R T = OAc, R 2 = H H 83 O Entry Substrate R i R2 Product Isolated Yield(%) 1 106 H OAc 83 86 2 107 OAc H 83 94 The structural assignment of 83 was in agreement with the spectral data obtained. The IR spectrum of 83 exhibited as strong C = 0 stretching absorption at 1714 c m - 1 and a strong C - O - C stretching absorption for the ketal moiety at 1117 c m - 1 . From the absorption position for the carbonyl, it can be concluded that no transketalization from the cyclopentanone carbonyl to the cyclohexanone carbonyl had occurred. The 1 3 C nmr spectrum of 83 displayed distinct resonances for each of the 17 carbons in the compound. Notable resonances were the carbonyl signal at 8 211.7, the quaternary ketal carbon signal at 8 110.8, the two ketal methylene carbon signals at 8 71.8 and 8 72.0, the two ketal methyl signals at 8 22.4 and 8 22.6, and four methine signals at 8 40.5, 8 44.7, 8 47.6, and 8 50.9. The * H nmr spectrum of 83 showed the characteristic 2,2-dimethylpropylene ketal resonances, two 3-proton singlets at 8 0.92 and 8 0.98 for the two methyl groups and a 4-proton multiplet centered at 8 3.45 for the methylene protons. In addition, a high resolution mass spectrometric analysis confirmed that the molecular formula of 83 was indeed C17H26O3. 1.7 Conclusions A new stereoselective method for the preparation of the trans-fused bicyclo[4.3.0]-nonane ring system 83 starting from a cyclopentanone system 61 has been developed 6 9 (Scheme 21). The procedure involves the conversion of the cyclopentanone 61 into the a,P-unsaturated aldehyde 71. A stereoselective 1,4-addition of the known cyanocuprate 35 to 71 provides 80 as a mixture of epimeric aldehydes. Conversion of the alkenyltrimethylgermane to an alkenyl iodide yields 99, which can be efficiently cyclized under mild conditions to produce the alcohols 102 and 103. Suitable functional group conversions provide the ketone 83 from the two alcohols. 35 CrCI2 NiCI2 >cxi> CHO H 71 n GeMew Cu(CN)Li 35 102 RT = H, R 2 = OH 103 RT =OH, R 2 = H H H >oci>° H 61 Scheme 21 r >OcDs H H \ _ / ^ 83 O The key steps in this annulation sequence were the stereoselective conjugate addition of 35 to the unsaturated aldehyde 71, the iododegermylation of 80, and the chromium(II) chloride-nickel(II) chloride-mediated cyclization of 99. The effectiveness of an alternative reagent for iododegermylations of alkenyltrimethylgermanes was demonstrated in the course of our studies. The use of AModosuccinimide in methylene chloride provides mild conditions for this conversion, allowing for germanium - iodine exchange in the presence of acid labile groups such as ketals, which are unstable to iododegermylation with iodine in methylene chloride. 2. Functionalized Allylcopper(I) Reagents 2.1 Background The ability of organocopper(I) reagents to effect 1,4-additions of organic ligands to a, P-unsaturated carbonyl systems is undoubtedly one of the most valuable transition metal mediated processes available to synthetic organic chemists . 4 2 ' 7 0 - 7 9 While the literature does contain some examples of the successful 1,4-addition of allylic ligands to enones, oftentimes the allylic cuprates react nonselectively giving mixtures of both 1,4- and 1,2-addition products. 8 0' 8 1 Only recently has a consistently reliable method for the delivery of the allyl group to the P-position of cc,P-unsaturated carbonyl systems been developed. 8 2 - 8 4 + C U ( ' ) S a l t -78 X ' (f^f°UU 0 7 ) 109 108 The tendency of the Gilman-type cuprates, LiCuR.2 (R = alkyl, alkenyl, or aryl), to add in a conjugate sense to a,P-unsaturated carbonyl compounds initially led to investigations of the analogous allyl cuprate. Lithium diallylcuprate (108) is prepared 4 0- 8 5 at low temperature by the addition of a copper(I) salt, such as copper(I)bromide-dimethyl sulfide or copper(I) iodide, to two equivalents of allyllithium (109) (equation 17). Although the reaction of lithium diallylcuprate 108 with cyclohex-2-enone (110) in cold ether did produce the conjugate addition adduct 111 in high (90%) yield (equation 18), with more hindered systems such as the P,P-disubstituted enone 112, only the 1,2-addition product 113 was detected 8 5 (equation 19). 108 Et 2 0, -78 °C 108 Et 2 0, -78 °C (18) (19) 112 113 The high degree of substrate dependence 4 0 ' 8 0 - 8 5 on the successful 1,4-addition of lithium diallylcuprate has resulted in several negative reports regarding this clan of reagents, and because of their temperamental nature, allylcuprates have found very limited use in synthesis. In fact, many syntheses which require an allyl group to be delivered in a 1,4-fashion to an enone instead employ Sakurai's 8 6 Lewis acid catalyzed addition of allyltrimethylsilane to oc,f3-unsaturated ketones. For example, reaction of 112 with titanium tetrachloride and allyltrimethylsilane (114) provides the 1,4-addition product 115 in 85% y ie ld 8 7 (equation 20). 114 SiMe< 112 TiCI4 CH 2 CI 2 , -78 °C (20) 115 Investigations of lithium diallylcuprate (108), prepared in T H F via equation 17, by Lipshutz and coworkers 8 8 using low temperature 1 3 C nmr spectroscopic analysis showed 108 to be thermally unstable. Even at temperatures at or below -78 ° C , significant decomposition of 108 to give the Wurtz-like coupling product, hexa-l,5-diene, is observed. The 1 3 C nmr spectrum of 108 at -95 ° C contained signals for free allyllithium (109), the decomposition product hexa-l,5-diene, another species presumed to be Li(allyl)3Cu2, and the a-bound allylcuprate reagent 108. The method of preparation of 108 seems to determine its success in 1,4-additions to enones. Formation of 108 by the addition of allyllithium to copper(I) iodide and brief warming to effect dissolution severely compromises cuprate formation, and loss of an allyl ligand from 108 produces other species, which undoubtedly have modified reactivity. 8 8 The source and purity of the copper(I) salt can also affect the extent of cuprate formation. Impurities in commercially available copper(I) salts, such as other transition metals or copper(H) salts, are known to cause cuprate decomposition. 8 9 Hence, careful purification of the copper(I) source is oftentimes required. 116 117 118 Further investigations by Lipshutz 8 2 revealed that, if anything, allylic cuprates are overly reactive and are in need of attenuation if discrimination between 1,2- and 1,4-addition is to be achieved. Attempts at conjugate additions using the lower order cyanocuprate 116, prepared from allyllithium and copper(I) cyanide, were completely unsuccessful. Even the thermally more stable higher order cyanocuprate 117,82'88 prepared from two equivalents of allyllithium and one equivalent of copper(I) cyanide, could not effect 1,4-addition of the allyl moiety. Reaction of either 116 or 117 with cyclohex-2-enone resulted only in 1,2-addition,8 2 even in the presence of additives such as trimethylsilyl chloride or boron trifluoride-etherate which normally promote 1,4- over 1,2-addition. 9 0 51 119 1) MeLi, THF, -78 °C 2) Cul*LiCI (21) 118 Allylcopper(I) (118), prepared by the treatment of allyltributylstannane (119) in T H F with methyllithium, followed by the addition of lithium chloride solubilized copper(I) iodide (equation 21), does add to enones such as 110, in the presence of trimethylsilyl chloride, to provide the 1,4-addition product 111 in high (95%) y ie ld 8 2 (equation 22). Me3SiCI 1 1 (22) THF, -78 °C 110 111 This result was quite surprising as non-are organocopper(I) reagents (RCu) are generally quite unreactive towards conjugate addition. 9 1 Subsequent investigations illustrated that allylic groups can be delivered 1,4 to enones using Grignard derived allylcopper reagents, 8 3 ( a l l y l ) C u » M g B r 2 , obtained from allylmagnesium bromide and copper bromide-dimethyl sulfide complex. In this case, the copper(I)-mediated 1,4-addition of the allylic group to the enone 110, in the presence of lithium chloride and trimethylsilyl chloride, proceeded in 86% yield 8 3 (equation 23). CuBr«Me2S LiCl, Me3SiCI 110 THF,-78°C t 1 1 (23) Using either allylcopper(I) (118) or the copper(I)-mediated Grignard protocol, the allyl group can be delivered efficiendy to the pVposition of a,P-unsaturated ketones in high yields with relatively short (10 minutes) reaction times. Nevertheless, examples in the literature of the conjugate addition of allyl moieties to a,pVunsaturated carbonyl systems are still quite rare. In general, only simple allyl groups 9 2 have been added in a conjugate sense to enones. In none of these cases does the allyl group possess a function with potential for facile synthetic manipulations at carbon-2. Rieke and coworkers 9 3 have demonstrated that a highly reactive form of zerovalent copper, C u * , can be prepared by the reduction of copper cyanide-lithium bromide complex 9 4 (CuCN«2LiBr) with lithium naphthalenide. The copper species C u undergoes direct metalation of allyl halides, resulting in an efficient preparation of allylcopper(I) reagents without any Wurtz-like homocoupling. The allylcopperfl) reagent 120, prepared from 121 by this method, reacted with cyclohex-2-enone (110) in the presence of trimethylsilyl chloride to provide the 1,4-addition product 122 in good (81%) y i e ld 9 3 (equation 24). 121 120 122 Limited cases of the conjugate addition of allylcopper(I) reagents functionalized at carbon-1 have been reported. C o r r i u 9 5 prepared the lower order cyanocuprate 123 via the deprotonation of allyltrimethylsilane (114) with n-butyllithium in the presence of T M E D A , followed by the addition of copper(I) cyanide (equation 25). SiMe3 1) n-BuLi, TMEDA Et20, 0 °C Me3Si ^ ^ ^ C u ( C N ) L i ( 2 5 ) 2) CuCN, -78 °C 114 123 This allylcuprate reagent 123, substituted at carbon-1, undergoes highly selective conjugate addition reactions with ct.pVunsaturated esters and ketones in moderate (65-80%) yields, but only afforded 1,2-addition products when reacted with cc,P-unsaturated aldehydes. 9 5 Interestingly, the reaction of 123 with a,f3-unsaturated carbonyls such as 110 proceeded in good yield to provide the 1,4-addition adduct 124 without the addition of trimethylsilyl chloride (equation 26). 9 5 Presumably the trimethylsilyl group at carbon-1 stabilizes 123 such that its reactivity is modified compared with the unsubstituted lithium (allyl)(cyano)cuprate 116, which is reported to add only in a 1,2-fashion to enones. 8 2 Hosomi and coworkers 9 6 prepared a substituted allylcopper(I) species from a ketene dithioacetal bearing a chlorine atom at the allylic position (125) via a ligand exchange reaction with the higher order methyl(cyano)cuprate, Me2Cu(CN)Li2. 9 7 O O (26) 110 124 O (27) 125 126 SMe This carbon-1 substituted allylcopper reagent, when combined with boron trifluoride etherate, gave exclusive 1,4-addition to cyclohex-1-enone (110), to provide 126 in synthetically poor (37%) yield, but with no reported 1,2-addition products 9 6 (equation 27). While the conjugate addition of allylcopper reagents substituted at carbon-2 to a,3-unsaturated carbonyl compounds was, prior to the work described herein, unknown, organocopper reagents containing the allyl moiety functionalized in the 2-position have been prepared, and have been reacted with a variety of electrophiles. Fleming and coworkers prepared the higher order organocopper reagents 127 and 128, containing a carbon-2 substituted allyl ligand, by the silyl-cupration 9 8 and stannyl-cupration9 9 of allene (equations 28 and 29, respectively). 1) Li metal, THF,-10 °C SiMe,Ph 2) CuCN, 0 °C I 2 Me2PhSiCI ^ I — Z T T T * " / < ^k j j 'Cu(CN)Li 2 (28) 3)H2C=C = CH 2 , -78 °C '2 127 Sn(n-Bu)3 « ~ ~ , • 1) CuCN, THF, -78 °C I " ' 2 n-Bu3SnLi J ,, *~ / ^ \ > C u ( C N ) L i 2 (29) 128 2) H 2C=C = C H 2 These reagents (127 and 128) can be trapped with a variety of electrophilic species in good yields. 9 8 - 9 9 However, both of these substituted allylcopper reagents react only in a 1,2-manner with cyclohex-2-enone (110) to provide the tertiary alcohols 129 and 130 (equation 30). 55 127 M = S i M e 2 P h 129 M = S i M e 2 P h 128 M = Sn ( /7 -Bu) 3 130 M = Sn(n-Bu) 3 O v e r m a n 1 0 0 has also demonstrated that the higher order cuprate 127, prepared by the silyl-cupration of allene according to Fleming's procedure, 9 8 efficiently opened a variety of terminal epoxides in moderate to good yields (36-81%) to provide alcohols of general structure 131 (equation 31). However, Overman did not investigate the reactivity of 127 with a,P-unsaturated ketones. 127 131 2.2 Introductory remarks The ultimate goal of our studies of allylcopper(I) reagents was the preparation of a bifunctional reagent that would serve as the synthetic equivalent of the d 2 , d 3 prop-l-ene synthon (48) and that could be added in a conjugate sense to a variety of Michael acceptor substrates. T o achieve this goal, our initial objective was the preparation of an allylstannane that was usefully functionalized at carbon two. Our second objective was to convert this allylstannane to an allylcopper(I) species and investigate its utility in conjugate addition reactions to a,p unsaturated ketones. d GeMe GeMe3 < ^ d SnMe3 48 49 132 It was envisaged that a copper(I) species (49) derived from 2-(trimethylgermyl)-3-(trimethylstannyl)propene (132) could function as the d 2 , d 3 prop-l-ene synthon (48). Work by Lipshutz 8 2 has shown that allylstannanes are useful precursors for allylcopper(I) reagents and that these allylcopper(I) reagents can undergo efficient 1,4-addition to enones. Previous studies1 U4,i5,39b m o u r laboratories have shown the latent synthetic potential of alkenyltrimethylgermanes, especially as stable precursors to alkenyl iodides. 2.3 Synthetic Plan We proposed that 2-(trimethylgermyl)-3-(trimethylstannyl)propene (132) could be prepared as outlined in Scheme 22. It seemed reasonable to conclude that 133 could be obtained by treating the readily available bromo alcohol 134101 with fcrf-butyllithium,102 followed by trapping of the resultant alkenyl anion with trimethylgermanium bromide. Treatment of the alcohol 133 with triphenylphosphine dibromide 5 5 should provide the allylic bromide 135. The allylstannane 132 could be formed by reaction of 135 with trimethyltin chloride and magnesium in refluxing T H F . 1 0 3 Br 136 Br K 2 C0 3 H 20, 90 °C Br 134 OH 1) f-BuLi, Et20, -78 °C 2) Me3GeBr, 0 °C GeMe3 ^J^SnMe 3 132 Me3SnCI, Mg * THF, reflux GeMe3 133 Ph3P»Br2 CH2CI2, rt t GeMe3 135 Scheme 22 2.4 Preparation of 2-(trimemylgerrnyl)-3-(trimethylstannyl')propene (132) 2-Bromoprop-2-enol (134) was prepared by the method described by Hatch and coworkers . 1 0 1 Treatment of commercially available 2,3-dibromopropene (136) with aqueous potassium carbonate at 90 ° C provided, after extraction of the aqueous solution and distillation of the derived oil, 2-bromoprop-2-enol in 94% yield (equation 32). ? r K 2 C0 3 f ^K^Br —— x ^ ^ O H (32) H 20, 90 °C 136 134 Our yield obtained was significantly higher than that originally reported in the literature (47%). 1 0 1 Hatch rationalized the low yield by proposing that the severity of the conditions resulted in the removal of both bromine atoms. However, the low yield was likely a result of an incomplete extraction of the polar, water soluble bromo alcohol 134 from the aqueous solution. In order to efficiently extract 134 from the aqueous solution, we found that 20 extractions with methylene chloride provided good recovery of the alcohol 134 from the aqueous phase. Spectroscopic evidence obtained was in full accord with the above transformation. The IR spectrum of 134 exhibited a strong O - H stretching absorption at 3311 c n r 1 and a strong C=C stretch at 1641 c n r 1 . The * H nmr spectrum of 134 displayed two 1-proton doublets in the alkenyl region at 8 5.89 (7=1 Hz) and 8 5.53 (7= 1 Hz), and a 2-proton doublet (7=6 Hz) at 8 4.16 attributed to the allylic protons. A broad 1-proton signal, due to the hydroxyl proton, at 8 2.02 disappeared with the addition of D2O with a concomitant simplification of the signal at 8 4.16 to a singlet. The mass spectrum of 134 showed the molecular ions at 136 and 138, indicative of a single bromine atom present in the molecule. 1) f-BuLi, Et20, -78 °C -> 0 °C ~ Br ^L D. A O ^ GeMe3 3) p-TsOH»H20, CH2CI2, rt ^ 7 2) Me3GeBr, 0 °C 1 x ^ ^ O H • A>0H (33) 3) p-TsOH-H20, CH2CI2, rt 134 4) silica gel, CH2CI2, rt 133 Conversion of bromo alcohol 134 into the trimethylgermyl alcohol 133 was achieved according to equation 33. Using the procedure developed by C o r e y , 1 0 2 slow addition of te^butylhthium to a cold solution of 134 in diethyl ether, followed by addition of trimethylgermanium bromide to the resultant dianion provided, after appropriate workup procedures and distillation, 2-(trimethylgermyl)prop-2-enol (133) in 72% yield. The * H nmr spectrum of 133 confirmed the replacement of the alkenyl bromide with the Me3Ge group by a 9-proton singlet at 8 0.23. Resonances for the two alkenyl protons at 8 5.28 and 8 5.72 were also present in the * H nmr spectrum of 133. In addition, the IR spectrum of 133 exhibited a strong O - H stretching absorption at 3306 c m - 1 . Several factors regarding this reaction are noteworthy and deserve further explanation. LiBr + 75 + H — = — x f-BuLi, 0"Li+ 140 Li-f-BuLi 141 + 75 0'Li+ Br 134 f-BuLi. Br Li OH J^OU* J^ou 138 + (CH3)3CH 75 137 + (CH3)3CBr 139 C H o C H o H 3 C - C - B r U '» H 3 C - C - H + (H3C)2C=CH2 + LiBr (34) CH 3 CH 3 139 75 76 Scheme 23 Three equivalents of ferf-butylhthium are required to form the dianion 137 (Scheme 23). The first equivalent of terf-butyllithium is used to deprotonate 134, generating the lithium alkoxide 138. The second equivalent is consumed in the lithium-bromine exchange reaction, providing 137 from 138 (via path B). The third equivalent of te/t-butyllithium is required to destroy the tert-butyl bromide (139) that is formed in the lithium-halogen exchange reaction. Reaction of 139 with terf-butyllithium provides the volatile products 2-methylpropane (75) and 2-methylpropene (76) (equation 34). 3 8 The rate of addition of terf-butyllithium to 134 is of critical importance and must be slow (~1 m L ?-BuLi solution in pentane/min) to ensure successful generation of the dianion 137 (via path B). As was suggested by C o r e y , 1 0 2 rapid addition of the ^rf-butyllithium to a solution of 134 promotes the elimination of H B r from 138 (via path A) to provide 140. Reaction of 140 with another equivalent of fer?-butyllithium ultimately generates the dianion of propargyl alcohol (141). Br 134 f-BuLi E t 9 0 p-TsOH«H20 C H o C I GeMe 3 133 + GeMe 3 143 Li 137 + L i ^ ^ ^ O L i -141 GeMe 3 133 Me 3GeBr + M e 3 G e — = — \ OH 142 GeMe 3 A . MeoGe-OGeMe 3 = — \ 144 OGeMe 3 143 143 & 144 are hydrolyzed to 133 & 142 by chromatography on silica gel silica gel GeMe 3 133 Scheme 24 The generation of the byproduct 141, in addition to the desired 137, upon treatment of 134 with terf-butyllithium initially presented considerable problems. Treatment of this mixture (137 and 141) with trimethylgermanium bromide provided four products, the alcohols 133 and 142 and the trimethylgermyl ethers 143 and 144 (Scheme 24). Fortuitously, the trimethylgermyl ethers 143 and 144 were hydrolyzed to the corresponding alcohols 133 and 142 during silica gel chromatography. Thus, when the mixture of the alcohols 133 and 142 and the trimethylgermyl ethers 143 and 144 was applied to a silica gel column, after flash chromatography a single fraction containing 133 and 142 was collected. Unfortunately, 133 and 142 were neither separable by silica gel chromatography nor by a subsequent distillation. Interestingly, an analysis by G L C indicated that ratio of 133 :142 obtained after chromatography was identical with the ratio of 133 and 143 : 142 and 144 in the initial mixture. Thus, the trimethylgermyl ethers 143 and 144 were hydrolyzed to their corresponding alcohols during silica gel chromatography, not simply decomposed. The i H nmr spectrum of the mixture of 142 and 133 displayed unique signals for their Me3Ge functions at 8 0.33 for 142 and 8 0.24 for 133, unique broad signals for their alcohol protons at 8 1.71 for 142 and 8 1.35 for 133, but the hydroxymethyl signals of 142 and 133 overlapped giving a multiplet centered at 8 4.26. Since separation of 133 from 142 was not possible by silica gel chromatography nor simple distillation, it was hoped that some chemical means could be employed. Other studies on the preparation of alkenyltrimethylgermanes in our laboratories3 5 had indicated that 2-(trimethylgermyl)alk-1-enes are stable to certain acidic conditions. It was hoped that the alkynyltrimethyl-germane 142 would be less stable (than 133) to acid and would undergo protio-degermylation upon treatment with acid. To our delight, treatment of the mixture of 133 and 142 with /?-toluenesulfonic acid monohydrate in methylene chloride at room temperature resulted in complete degermylation of 142 while 133 was unaffected. Presumably 142 is converted to propargyl alcohol, which is volatile and easily separated from 133. Unfortunately, the trimethylgermyl ether moiety is also stable to this acidic treatment. 62 MeoGe-H ' J OH 142 GeMe3 ^L^OGeMe 3 143 H + H. Me 3GeV> ^ O H 145 MeoGe 133 Me3Ge GeMe3 147 H HO 146 Scheme 25 A nagging difficulty in this entire process was the generation of trimethylgermyl ethers (Scheme 24). Trimethylgermyl ethers of both 142 and 133 were generated in the reaction of 134 with Jerr-butylhthium and trimethylgermanium bromide. As mentioned previously, these ethers, 143 and 144, could be hydrolyzed by silica gel chromatography. More annoying, however, was the generation of the trimethylgermyl ether 143 in the protiodegermylation reaction. Treatment of a mixture of the alcohols 142 and 133 under acidic conditions, with /7-toluenesulfonic acid monohydrate in methylene chloride, provided the alcohol 133 and the trimethylgermyl ether 143 as well as the volatile propargyl alcohol (Scheme 24). A proposed mechanism for the formation of 143 is given in Scheme 25. Initially, the alkyne 142 is protonated to provide 145, which contains a germanium stabilized ca t ion 1 0 4 P to the trimethylgermyl moiety. Apparently the trimethylgermyl moiety has a very high affinity for oxygen, and a lone pair from the oxygen of 133 attacks this function resulting in the formation of propargyl alcohol (146) and the trimethylgermyl ether 143 via the intermediate 147. More interestingly, a G L C analysis indicated that the ratio of 133:142 in the starting mixture (prior to treatment with acid) was identical with the ratio of 133:143 found in the product mixture (after treatment with acid). The trimethylgermyl ether 143 exhibits a singlet in the nmr spectrum at 8 0.37 for the OGeMe3 moiety, slightly downfield from that attributed to the alkenyltrimethylgermane moiety (8 0.23). Although trimethylgermyl ethers are unstable to silica gel chromatography, and are hydrolyzed to the corresponding alcohol during this process, it was hoped to avoid this purification step as the reaction was essentially clean, yielding only the desired alcohol 133 and the ether 143. The instability of trimethylgermyl ethers to silica gel chromatography led us to attempt a more convenient hydrolysis of these ethers by employing silica gel as the drying agent rather than MgS04. Silica gel itself is a marvelous drying agent 1 0 5 but has not gained favor, due not only to its expense but also because it is acidic, and can therefore react, usually unfavorably, with desired compounds. Fortunately, in our case, silica gel, when used in excess as a drying agent, effectively hydrolyzed the trimethylgermyl ether 143 to provide 133. 1) f-BuLi, Et20, -78 °C -> 0 °C „ f 2 M e 3 G e B r V c G e M e 3 ^OH x ^ ^ O H (33) 3) p-TsOH«H20, CH2CI2, rt 134 4) silica gel, CH2CI2, rt 133 The experimental procedure routinely used to prepare 133 (equation 33) therefore does not require any silica gel chromatography. The bromo alcohol 134 is treated with terf-butylhthium followed by trimethylgermanium bromide. After an aqueous workup, the ethereal solvent is removed. The crude residue is dissolved in methylene chloride and treated with p-toluenesulfonic acid monohydrate. After another aqueous workup, the combined organic phases are dried using silica gel. The slurry is fdtered and concentrated. Fractional distillation of the derived oil provides 133. GeMe 3 133 Ph3P«Br2 »• CH2CI2, rt GeMe 3 135 (35) Preparation of the bromide 135 was straightforward and was achieved under standard conditions. Treatment of the alcohol 133 with triphenylphosphine dibromide 5 5 in methylene chloride provided, after workup and distillation, 135, a volatile oil, in 93% yield (equation 35). The IR spectrum of 135 lacked the O - H stretching absorption which was present in the starting material. The ! H nmr spectrum of 135 displayed a 9-proton singlet at 8 0.29 for the Me3Ge moiety, a 2-proton multiplet at 8 4.16 attributed to the allylic methylene group, and two alkenyl protons at 8 5.34 and 8 5.83. The 1 3 C nmr spectrum of 135 exhibited a resonance for each of the four types of carbon atoms in the molecule. The preparation of 2-(trimethylgermyl)-3-(trimethylstannyl)propene (132) was attempted using a modification of Keek's procedure 1 0 3 for the preparation of allyltributylstannane from tributyltin chloride and allyl chloride. Reaction of 135 with excess trimethyltin chloride and magnesium metal in refluxing T H F provided two products (equation 36). Analysis by G L C M S indicated that the desired allylstannane 132 and the dimer 148 were formed in 87% yield and * H nmr and G L C analysis indicated that 132 and 148 were formed in a 10:1 ratio. These products (132 and 148) proved to be inseparable both by silica gel chromatography as well as by distillation. Although Keck did not report the formation of any dimer (hexa-l,5-diene) in his method, it would have been (36) GeMe 3 135 132 148 much more volatile than allyltributylstannane and would have been readily removed by distillation. The ! H nmr spectrum of this mixture of 132 and 148 exhibited two types of peaks: one set displayed tin-proton coupling while the other set did not display this sort of coupling. This coupling data, along with the integration of the signals, allowed identification of the products and assignment of the * H nmr signals. The resonances attributed to the dimer 148 were a singlet at 8 0.20 (the Me3Ge moieties), a singlet at 8 2.26 (the allylic protons), and two doublets in the alkenyl region at 8 5.18 (7 = 2.5 Hz) and 8 5.52 (7 = 2.5 Hz). The following * H nmr signals were attributed to the desired bifunctional reagent 132: 8 0.07 (9-proton singlet for the Me3Sn moiety with satellite peaks due to tin-proton coupling 27sn-H = 52 Hz), 8 0.17 (9-proton singlet for the Me3Ge moiety), 8 1.96 (2-proton doublet, 7=1 Hz, for the allylic protons with satellite peaks due to tin-proton coupling 2 7s n -H = 69 Hz), 8 4.91 (1-proton doublet, 7 = 2.5 Hz , with satellite peaks due to tin-proton coupling 47sn-H = 25 Hz), and 8 5.28 (1-proton doublet of triplets, 7 = 2.5, 1 Hz, with satellite peaks due to tin-proton coupling 4 7s n -H = 23 Hz). Although disheartened by our continuing chromatographic difficulties, we were encouraged that the reagent (132) could be prepared, and presumably under the appropriate reaction conditions, it could be obtained in a pure form. The dimer byproduct 148 presumably was formed by a Wurtz type coupling reaction, a reaction for which allylic Grignard reagents are notorious 1 0 6 (Scheme 26). GeMe, . ? 3 Mg GeMe3 ^^v^MgBr Me3SnCI . GeMe3 <^J\^SnMe 3 135 149 nucleophile 135 132 GeMe3 t only 132 no 148 148 GeMe3 Scheme 26 Initially, 2-(trimethylgermyl)allylmagnesium bromide (149) is formed by reaction of 135 with magnesium, but it can react with another molecule of the allylic bromide 135, providing the Wurtz type coupling product 148, instead of reacting with trimethyltin chloride, which would give 132. It was hoped that the use of a nucleophilic displacement reaction would suppress the formation of 148. In this case, the allylic bromide would be displaced with an appropriate nucleophilic tin species (Scheme 26). The nucleophilic reagent that was chosen was (trimethylstannyl)lithium (150), which can be generated easily by the treatment of hexamethylditin (151) with methyllithium 1 0 7 (equation 37). (Me3Sn)2 151 MeLi THF, -20 °C Me3SnLi 150 (37) In practice, when 135 was treated with an excess of (trimethylstannyl)lithium (150) , a G L C analysis (Table 8, entry 1) of the crude reaction mixture showed the formation of three products: the desired product 132, the dimer 148, and hexamethylditin (151) (Scheme 27). It was thought that the formation of the dimer was the result of lithium-bromine exchange with (trimethylstannyl)lithium (150) and the allyl bromide 135 giving 2-(trimethylgermyl)-allyllithium (152), which could react with another molecule of 135, giving the dimerized product 148 (Scheme 27). The formation of hexamethylditin (151) in the product mixture was thought to occur either from reaction of 150 with 153 (formed as a byproduct in the dimerization of 135), or from incomplete initial cleavage of the Sn-Sn b o n d 1 0 8 in hexamethylditin by methyllithium (equation 37 and Scheme 27). Separation of these three products (132,148, and 151) by silica gel chromatography proved to be impossible as all three products are very non polar and run with the solvent front, even in 100% petroleum ether. The use of silver nitrate impregnated silica g e l , 1 0 9 useful in the separation of alkene mixtures, was completely unsuccessful as not only was no separation possible, but the silver nitrate impregnated silica gel actually catalyzed the dimerization of 132 so mat only hexamethylditin (151) and the dimer 148 were obtained after chromatography. GeMe 3 135 Me3Snl_i 150 GeMe 3 152 + Me 3SnBr 153 Me3Snl_i (150) GeMe 3 135 Me3Snl_i (150) GeMe 3 132 GeMe 3 + LiBr 148 GeMe, (Me 3Sn) 2 151 LiBr Scheme 27 In an attempt to suppress the proposed lithium-halogen exchange between 150 and 135, and to moderate the activity of the trimethylstannyl nucleophile, a (trimethylstannyl)-copper(I) species was used for the nucleophilic displacement reaction. Organocopper(I) reagents are well known to effect this type of displacement. 1 1 0 While treatment of 135 with M e 3 S n C u » M e 2 S (154) 1 1 1 provided the same three products 132, 148, and 151 (equation 38, Table 8, entry 2), the amount of the dimer 148 formed was reduced. Table 8 Nucleophilic Displacement Reactions to Prepare the Bifunctional Reagent 132 GeMe 3 GeMe 3 GeMe 3 ^ s ^ X ^ » ^ ^ k ^ S n M e , + + (Me 3Sn) 2 (38) 135X = Br - 7 8 ° c 132 148 GeMe 3 151 158 X = OTs Product Distribution ( G L C %) Entry Nucleophile Nuc Leaving Group X 132 148 151 (tole3Sn)2 Recovered Starting Material 1» M e 3 S n L i (150) Br 76 6 18 0 2b M e 3 S n C u » M e 2 S (154) Br 88 2 10 0 3 C M e 3 S n L i (150) OTs 93 0 1 6 4 d M e 3 S n C u ( C N ) L i (155) OTs 58 0 11 14 5^ M e 3 S n L i (150) OTs 75 0 0 15 6f M e 3 S n L i (150) OTs 99 0 0 1 a 1.3 equiv M e 3 S n L i generated from the interaction of to eLi with (to] e 3 Sn) 2 . b 1.5 equiv Me 3 SnCu»Me2S generated from the interaction of toleLi with (tole3Sn)2 followed by addition of CuBr»Me2S. c 0.9 equiv M e 3 S n L i generated from the interaction of M e L i wim (Me3Sn)2. d 0.9 equiv M e 3 S n C u ( C N ) L i generated from the interaction of M e L i with (Me3Sn)2 followed by addition of C u C N . e 0.8 equiv M e 3 S n L i generated from M e 3 S n H . f 0.97 equiv M e 3 S n L i generated from M e 3 S n H . At this juncture, we re-evaluated the situation. It appeared that the formation of the dimer could not be eliminated and that a different leaving group, particularly one that was not prone to this dimerization, was required. In addition, this leaving group should possess some polar functionality such that it would be suitable for chromatographic separation on silica gel. O v e r m a n 1 0 0 reported a one pot procedure for the conversion of 2-(trimethylsilyl)prop-2-enol (156) into its corresponding allylstannane 157 via an in situ displacement of the mesylate derived from 156 with the tributylstannyl anion (equation 39). It was decided that a similar procedure involving the p-toluenesulfonyl group would be employed to prepare the bifunctional reagent 132. After some experimentation, the preparation of the tosylate 158 was achieved in 86% isolated yield through the treatment of 133 in diethyl ether with halide-free methyllithium followed the addition of by p-toluene-sulfonyl chloride (Scheme 28). These atypical conditions 1 1 2 were needed since the use of other conditions (p-TsCl, D M A P , Et3N in C H 2 C I 2 ) resulted in the formation of a mixture of the expected product 158, as well as the allylic chloride 159 through an in situ displacement of the tosylate group. 5 4 Deprotonation of 133 with methyllithium-lithium bromide complex followed by addition of p-toluenesulfonyl chloride gave rise to a mixture of 158 and the allylic bromide 135, the latter product being produced via a similar in situ displacement of the tosylate group with the bromide anion. 156 1) A7-BuLi, THF, -50 °C; MsCI 2) n-Bu3SnLi, -78 °C ->rt MeLi'LiBr, E t 2 0 , -48 °C; GeMe 3 GeMe 3 p-TsCI, 0 °C -> 20 °C 158 135 GeMe 3 MeLi, Et 2 0, -48 °C; 158 GeMe 3 p-TsCI, 0 °C -> 20 °C 133 p-TsCI, DMAP, Et 3N GeMe 3 GeMe 3 CH 2 CI 2 , rt 158 159 Scheme 28 The structural assignment of the tosylate 158 was supported by spectral data. The IR spectrum of 158 displayed a stretching absorption at 1599 c m - 1 (C=C), and two strong absorptions at 1368 and 1176 c m - 1 (SO2). The * H nmr spectrum of 158 exhibited a 9-proton singlet at 8 0.19 for the Me3Ge group, a 3-proton singlet at 8 2.43 for the aromatic methyl group, a 2-proton singlet at 8 4.64 attributed to the allylic protons, two 1-proton singlets at 8 5.33 and 8 5.72 indicative of the two alkenyl protons, and two 2-proton doublets at 8 7.32 (7=8 Hz) and 8 7.78 (7=8 Hz) for the aromatic protons. Our hypothesis about the effect of the leaving group on the success of the reaction proved to be correct. Treatment of an excess of 158 with (trimethylstannyl)lithium (150)107 (Table 8, entry 3) or the corresponding lithium(trimethylstannyl)(cyano)cuprate (155)111 (Table 8, entry 4) still provided a chromatographically inseparable mixture of hexamethylditin (151) and the desired 132, but none of the dimer 148 was evident through G L C and ^H nmr spectroscopic analyses of the crude reaction mixture. The remaining starting material 158 was easily separated from the product mixture by silica gel chromatography. Despite completely suppressing the formation of the dimer 148, the significant problem of contamination from hexamethylditin (151) remained. Whereas the presence of 148 would not affect the further use of 132, the same could not be said for hexamethyl-ditin (151). In order for 132 to be synthetically useful, it needed to be isolated free from hexamethylditin. It was proposed that the presence of hexamethylditin in product mixture was a result of incomplete cleavage of the Sn-Sn bond by methyllithium (equation 37), and studies by Oehlschlager and coworkers 1 0 8 support this hypothesis. A n alternative method for the generation of (trimethylstannyl)lithium which did not require the use of hexamethylditin or an alkylhthium was needed. The generation of (trimethylstannyl)hthium using Still's method, 1 1 3 by treatment of trimethyltin hydride (160) with L D A , has been reported, 1 1 4 but the prospect of using the volatile and highly toxic trimethyltin hydride was not overly appealing. However, Lipshutz has reported 1 1 5 a convenient preparation of this volatile material (160) in triglyme, using conditions similar to those shown in equation 40. LiAIH4 Me3SnCI • Me3SnH (40) diglyme, 65 °C 161 160 Employing a modification of the procedure described by Lipshutz, reduction of trimethyltin chloride (161) was achieved in warm diglyme using lithium aluminum hydride (equation 40) to provide the volatile trimethyltin hydride (160), which was distilled directly from the reaction mixture. After a subsequent distillation to remove trace amounts of solvent, the resonances observed in the * H nmr spectrum of trimethyltin hydride agreed with the reported literature values. 1 1 5 KA a u L D A> THF, 0 °C 0 . . . . . . Me3SnH : • • Me3Snl_i (41) 160 150 We now were ready to see if the source from which (trimethylstannyl)lithium (150) was generated had any effect on the product mixture in the reaction to prepare 132 (equation 38, Table 8). (Trimethylstannyl)lithium (150) was generated by the treatment of trimethyltin hydride (160) with L D A (equation 4 1 ) 1 1 3 and to this mixture was added excess 158 (Table 8, entry 5). After aqueous workup, an analysis of the crude reaction mixture by G L C and ! H nmr spectroscopy showed the presence of 132 and unreacted starting material but there was neither dimer (148) nor hexamethylditin (151) in the product mixture. With the addition of only a slight excess of 158 to a solution of (trimethylstannyl)lithium (150)114 (Table 8, entry 6), the bifunctional reagent 132 was isolated, after workup and silica gel chromatography, in 90% yield (equation 42). GeMe3 ^Jv^ ,SnMe 3 (42) 132 The structural assignment for 132 was in complete agreement with its spectral data. The lH nmr spectrum of 132 displayed two 9-proton singlets, one at 8 0.07 (Me3Sn) and the other at 8 0.17 (Me3Ge). The assignment of these peaks was facilitated by the presence of satellite peaks due to tin-proton coupling (27sn-H = 52 Hz) for the signal at 8 0.07. The allylic protons appeared as a 2-proton doublet (/ = 1 Hz) at 8 1.96 and also exhibited tin-proton coupling (27sn-H = 69 Hz). Resonances for the alkenyl protons appeared at 8 4.91 (a 1-proton doublet, J= 2.5 Hz) and 8 5.28 (a 1-proton doublet of triplets, J = 2.5, 1 Hz), and both displayed long range tin-proton coupling ( 4/sn-H> 25 H z and 23 Hz , respectively). Resonances for each of the 5 different carbon atoms were seen in the 1 3 C nmr spectrum of 132. In addition to this spectral data, the molecular formula of 132 was confirmed by a high resolution mass spectrometric measurement on the molecular ion. Me3SnLi GeMe3 1 5 Q ^ k ^ O T s T H F , -78 ° C 158 2.5 Preparation of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) and conjugate additions of 162 to q.pVunsaturated ketones The crucial transmetalation required for the formation of the allylcopper(I) species could now be investigated. It has been reported 8 2 that allylcopper(I) reagents can be prepared by combining allyllithium (obtained by the treatment of allyltributylstannane with an alkyllithium) and a copper(I) source such as copper(I) iodide. GeMe3 ^ ^ S n M e 3 132 1) MeLi-LiBr, THF, -78 °C 2) CuBr»Me2S, -78 °C GeMe3 162 O 1) 110, Me3SiBr THF, -78 °C; 2) NH4CI-NH4OH H 20 (pH 8) GeMe3 163 Scheme 29 After much experimentation, it was found that treatment of 132 in cold T H F with methyllithium-lithium bromide complex, followed by copper(I) bromide-dimethylsulfide complex, provided 2-(trimethylgermyl)allylcopper(I)-dimethylsulfide (162) (Scheme 29). Evidence for the successful preparation of 162 came from the conjugate addition reaction of this reagent with cyclohex-2-enone in the presence of trimethylsilyl bromide. After appropriate workup and purification, 163 was isolated in 91% yield. The IR spectrum of 163 indicated that a ketone was present and that it was no longer conjugated (1713 cm - 1 ) and the * H nmr spectrum of 163 exhibited a 9-proton singlet at 5 0.18 for the methyl substituents on germanium and two 1-proton signals in the alkenyl region at 8 5.24 and Several ocfJ-unsaturated ketones were used as substrates to test the generality and the viability of the conjugate addition process. Thus, addition of a variety of oc,P-unsaturated ketones (110,170-175) and trimethylsilyl bromide to a solution of the allylcopper(I) reagent (162) in cold (-78 °C) T H F (equation 43, Table 9) provided, after workup and purification, fair to excellent yields of the conjugate addition products 163-169 (Table 9). In each case, the conjugate addition reaction was complete (by T L C analysis) in less than 15 minutes. The conjugate addition reactions have been routinely performed using -0.5 mmol of the enone although no reduction in yields were observed when the reactions were performed on larger scale (~3 mmol of enone). 8 5.48. O O 1 1 0 R = H 171 R = Me 170 175 172 R , =H, R 2 = H 173 RT = H, R 2 = Me 174 RT =Me, R 2 = H 164 169 Table 9 Conjugate Addition of 162 to a,P-Unsaturated Ketones 1) 162, Me3SiBr,THF, -78 °C Enone • Product (43) 2) NH4CI-NH4OH, H 20 (pH 8) Entry Enone Substrate Product Yield(%) a 1 cyclohex-2-enone (110) 163 91 2 4-isopropylcyclohex-2-enone (170) 164 92 3 3-methylcyclohex-2-enone (171) 165 46 4 cyclopent-2-enone (172) 166 85 5 3-raethylcyclopent-2-enone (173) 167 56 6 2-methylcyclopent-2-enone (174) 168 89 b 7 (R)-(-)-carvone (175) 169 86 c a Yield of purified, distilled product. b Consisted of a mixture of C-2 epimers (ratio ~8:1). c Consisted primarily of a mixture of C-2 epimers (ratio -2:1). Also present was a small amount (2-3%) of a corresponding C-3 epimer. The structural assignments for 163 through 169 were based on the spectral data obtained. For example, the IR spectrum of 166 indicated the presence of a cyclopentanone carbonyl group (1746 cm" 1). Similar C = 0 stretching absorptions were seen in the IR spectra of the remaining products, confirming that chemoselective 1,4-addition (and not 1,2-addition) had occurred. Also observed in the fingerprint region of the IR spectra of 163 -169 was a characteristic germanium - methyl rocking absorption at -825 cm-1. The ! H nmr spectrum of 166 exhibited a 9-proton singlet at 8 0.20 for the methyl substituents on germanium and two 1-proton signals in the alkenyl region at 8 5.23 and 8 5.50. Similar resonances were seen in the nmr spectra of the remaining products. The 1 3 C nmr spectra of 163 -169 were also consistent with the assigned structures. Resonances for each of the different carbon atoms in compounds 163 -169 were seen in their 1 3 C nmr spectra. Finally, the molecular formulae of 163 -169 were confirmed by high resolution mass spectrometric measurements on either the molecular ion or the ( M + - Me) fragment. The stereochemistry of the conjugate addition products 164 and 169 deserves further comment. It has been suggested that the preferred mode of attack of organometallic reagents to a,P-unsaturated ketones is antiparallel to the n system of the enone so that continuous overlap of the developing sigma bond with iz system is possible through the transition state. 1 1 6 As conjugate addition reactions are typically under kinetic control , 1 1 7 the stereochemical outcome has often been explained on the basis of attack of the nucleophile perpendicular to the it system of the enone (stereoelectronic control), and from the least hindered side of the molecule (steric control). 1 1 8 The addition of 162 to 4-isopropylcyclohex-2-enone (170) gave the product 164, as a single diastereomer with exclusively trans relative stereochemistry of the ring substituents. 1 1 9 There is ample literature precedent for the stereoselective addition of organocopper reagents to 4-alkylcyclohex-2-enones 1 2 0 (Scheme 30). Two possible half-chair conformations that the enone can adopt are 176 (the more stable conformer due to the pseudo equatorial orientation of the C-4 alkyl group) and 177. Attack of an organocopper nucleophile (Y"), perpendicular to the n system of the enone, from the top face (path A) of 176 proceeds through a chair-like transition state to give the enolate 178. Approach of the nucleophile, in a perpendicular fashion to the enone, from the bottom face (path B) of 176 proceeds through a boat-like transition state to provide the enolate 179. On the other hand, approach of the nucleophile (Y") from the bottom face of the less stable conformer (177) gives the chair-like enolate 180 (path C) while a perpendicular attack on the top face results in 181 (path D). The boat-like intermediate 181 is clearly energetically less favorable than the chair-like 180. The preferential formation of the trans isomer is attributed to steric hindrance in the transition state leading to 178, between the incoming nucleophile and the substituent at carbon four. This steric factor disfavors the formation of the cis isomer. Both the boat-like 179 and the chair-like 180 lead to the formation of the trans isomer without steric interference from the C-4 substituent. As the size of the C-4 alkyl substituent (R) and the incoming nucleophile (Y - ) increase, the stereoselectivity of the addition was found to increase. 1 2 0 b The addition of the organocopper(I) reagent 162 to (/?)-(-)-carvone (175) proceeded in the precedented 1 2 1 stereoselective manner, predominantly trans to the substituent at carbon five (ratio of trans:cis addition -97:3). The *H nmr spectrum of the product indicated that 169 was actually a 65:32:3 mixture of three diastereomers, 1 2 2 with the two major diastereomers being epimeric at carbon two. Signals for the C-2 methyl substituent appeared at 8 1.03 (d, J = 7 Hz), 8 1.08 (d, J = 1 Hz), and 8 1.14 (d, J = 7 Hz) in a ratio of 11:1:22. The addition of the allylcopper(I) reagent 162 to 3-methylcyclohex-2-enone (171) and 3-methylcyclopent-2-enone (173) proceeded only in moderate yields (Table 9, entries 3 and 5, respectively). Both of these enones are disubstituted in the fi-position and therefore are sterically crowded. In many cases, 1,4-addition to p,P-disubstituted enones proceeds only reluctantly without the addition of H M P A or Lewis acids. 1 2 3 In this respect, the yields of 165 and 167 (46% and 56%, respectively) are quite reasonable. There are several noteworthy results from this conjugate addition that require comment. Although either solutions of halide-free methyllithium or the methyllithium-lithium bromide complex in diethyl ether may be used for the initial transmetalation of 132, use of the latter reagent results in the much more rapid dissolution of the copper(I) salt in T H F , and hence a more rapid formation of the required allylcopper(I) reagent. Under the reaction conditions employed, none of the trimethylsilyl enol ether intermediates were isolated. A * H nmr analysis of the crude reaction products indicated that complete hydrolysis of the trimethylsilyl enol ether intermediates had been effected during the workup with aqueous NH4CI-NH4OH (pH 8). The use of recrystallized copper(I) bromide-dimethyl sulfide provides consistently high yields of the 1,4-addition adduct. Although copper(I) iodide can be used as the copper(I) source, the yields using copper(I) iodide are vastly inferior and poor regioselectivity is observed. This competition between 1,2- and 1,4-addition has been rationalized 8 1 as the result of incomplete formation of the allylcopper(I) reagents due to the high sensitivity of the reaction to impurities in the copperfl) salt used to generate the organocopper species. As copper(I) iodide is difficult to prepare in a pure f o r m , 1 2 4 it is likely that impurities in copper(I) iodide prevent complete formation of the allylcopper(I) reagents. However, since copper(I)bromide-dimethyl sulfide can readily be obtained in high purity by recrystallization, 8 9- 1 2 5 complete formation of 162 is assured with the use of this salt. GeMe3 132 1) MeLMJBr, THF, -78 °C 2) CuBr»Me2S, -78 °C GeMe3 ^ v ^ C u » M e 2 S 162 (44) GeMe3 ^ ^ ^ S n M e 3 132 + GeMe3 148 GeMe3 1) MeLMJBr, THF, -78 °C 2) CuBr«Me2S, -78 °C GeMe3 162 + GeMe3 148 GeMe3 (45) Both pure 132 (equation 44) and the mixture of 132 and the dimer 148 (equation 45) can be used to prepare 162. The dimer 148 is unreactive towards alkyllithiums and does not interfere in the preparation of 162. Since the procedure which produces the mixture of 132 and 148 is experimentally more convenient than the protocol used to prepare pure 132, especially on a large scale, and does not require the use of the volatile and toxic trimethyltin hydride, it is the preferred method for the generation of the bifunctional reagent 162. In a typical experiment, treatment of 0.30 g of an -10:1 mixture of 132:148 (-0.86 mmol 132, -0.09 mmol 148) in cold T H F with 0.65 m L of M e L i » L i B r (1.31 M solution in Et20, 0.85 mmol) and 0.18 g of C u B r » M e 2 S (0.88 mmol) provided the organocopper(I) reagent 162 along with unreacted dimer 148. Reaction of this mixture with 70 p L of 4-isopropylcyclohex-2-enone (170) provided 0.13 g of the 1,4-addition product 164 (90% yield). 2.6 A new bifunctional reagent: 2-(TrimethylstannyDallylcopper(I')-dimethyl sulfide (1ST) Given the success in the preparation of 162 and its conjugate addition to 06,(3-unsaturated ketones, it was decided to investigate the reactivity of another functionalized allylic reagent, 2,3-bis(trimethylstannyl)propene (183). W e were intrigued with the possibility of preparing another functionalized allylcopper(I) reagent 182, which would also be equivalent to the d 2 , d 3 prop-l-ene synthon, and we wished to see if it too could be added in a conjugate sense to a,f3-unsaturated ketones. Alkenyltrimethylstannanes are well known for their synthetic utility in coupling reactions and as precursors to alkenyl iodides and alkenylkthium reagents. 1 2 6- 1 2 7 The preparation of 183 was achieved, according to a literature procedure, 1 2 8 by the palladium(O) catalyzed addition of hexamethylditin (151) to allene (equation 46). 48 182 183 Me 3Sn-SnMe 3 151 —C - CH2 Pd(PPh 3) 4 )75 0C SnMe 3 ^ \ ^ S n M e 3 183 (46) While one would expect different reactivities of the allyhc and vinylic tin moieties in 183, it was reported 1 2 8 that when 183 was treated with methyllithium followed by a variety of electrophiles, only low yields of products were isolated. Undaunted, we proceeded with our plans and attempted the formation of an allylcopper species (182) and its conjugate addition to cyclic enones. In our hands, treatment of 183 with 1 equivalent of methyllithium gave cleanly the corresponding allyllithium species, which could be successfully trapped in high yields with a variety of electrophiles (vide infra, Chapter 4). Analysis of these products by l H nmr spectroscopy indicated that no transmetalation of the alkenyl(trimethylstannyl) function had occurred. SnMe3 183 1) MeLi»LiBr, THF, -78 °C 2) CuBr»Me2S, -78 °C SnMe3 ^ i ^ C u » l v 1 e 2 S 182 O 1) 110, Me3SiBr THF, -78 °C; 2) NH4CI-NH4OH H 20 (pH 8) SnMe3 184 Scheme 31 Following a procedure essentially identical with that used for the successful preparation of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162), treatment of a solution of 183 in cold T H F with methyllithium-lithium bromide complex, followed by copper(I) bromide-dimethyl sulfide, provided 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (Scheme 31). Evidence for the successful formation of this species came from its conjugate addition reaction with cyclohex-2-enone (110) in the presence of trimethylsilyl bromide. After suitable workup and purification by silica gel chromatography and distillation, 184 was isolated in 93% yield. The IR spectrum of 184 indicated the presence of a ketone function (1714 cm - 1 ) and the * H nmr spectrum exhibited a 9-proton singlet at 8 0.10 for the methyl substituents on tin, along with satellite peaks due to tin-proton coupling (27sn-H = 53 Hz), and two 1-proton signals in the alkenyl region at 8 5.19 and 8 5.61, along with satellite peaks due to tin-proton coupling ( 37sn-H, 70 H z and 150 Hz, respectively). The generality of this conjugate addition reaction was demonstrated with a variety of a,(3-unsaturated ketones. Treatment of a cold (-78 °C) solution of 182 in T H F with the enones 110 and 170-175 in the presence of trimethylsilyl bromide (equation 47, Table 10) provided, after workup and purification, the 1,4-addition products 184-190, all isolated in fair to excellent yields (Table 10). O O o o 1 1 0 R = H 171 R = Me 170 175 172 R 1 =H, R 2 = H 173 RT = H, R 2 = Me 174 RT =Me, R 2 = H o o o R R 184 R = H 186 R = Me O 185 187 R = H 188 R = Me SnMeo 189 f j * SnMe3 190 Table 10 Conjugate Addition of 182 to a,p-Unsaturated Ketones 1)182, Me3SiBr,THF, -78 ° C Enone 2) NH4CI-NH4OH, H 20 (pH 8) Product (47) Entry Enone Substrate Product Yield(%) a 1 cyclohex-2-enone (110) 184 93 2 4-isopropylcyclohex-2-enone (170) 185 90 3 3-methylcyclohex-2-enone (171) 186 61 4 cyclopent-2-enone (172) 187 88 5 3-methylcyclopent-2-enone (173) 188 54 6 2-methylcyclopent-2-enone (174) 189 82b 7 (R)-(-)-carvone (175) 190 85 c a 1 iem 01 punnea, aismiea proauct. b Consisted of a mixture of C-2 epimers (ratio ~8:1). c Consisted primarily of a mixture of C-2 epimers (ratio -2:1). Also present small amount (2-3%) of a corresponding C-3 epimer. was a The structural assignments for 184-190 were based on the spectral data. For example, the IR spectrum of 187 indicated the presence of a cyclopentanone carbonyl function (1746 cm"1). Similar C = 0 stretching absorptions were seen in the IR spectra of the other products, confirming that 1,4-addition had occurred. Also observed in the fingerprint region of the IR spectra of 184-190 was a characteristic tin - methyl rocking absorption at -769 c n r 1 . The lH nmr spectrum of 187 exhibited a 9-proton singlet at 8 0.13 for the methyl substituents on tin, along with satellite peaks due to tin-proton coupling (27sn-H = 53 Hz) and two 1-proton signals in the alkenyl region at 8 5.19 and 8 5.64, along with satellite peaks due to tin-proton coupling (37sn-H 70 Hz and 150 Hz, respectively). Similar resonances were seen in the nmr spectra of the other products. The 1 3 C nmr spectra of 184-190 were also consistent with the assigned structures. Resonances for each of the different carbon atoms in 184-190 were seen in their 1 3 C nmr spectra. Finally, the molecular formulae of 184-190 were confirmed by high resolution mass spectrometric measurements on either the molecular ion or the ( M + - Me) fragment. The reactivity of 182 with enones was similar to that of 2-(trimethylgermyl)-allylcopper(I)-dimethylsulfide (162) with enones. The addition of 182 to 4-isopropyl-cyclohex-2-enone (170) and (/?)-(-)-carvone (175) proceeded in the precedented stereoselective manner described for the addition of 162 to those e n o n e s . 1 1 9 - 1 2 2 Not unexpectedly, moderate yields were obtained from the reaction of the allylcopper(I) reagent 182 with enones disubstituted in the ^ - p o s i t i o n 1 2 3 (Table 10, entries 3 and 5, respectively). A number of factors are worthy of further comment in this general procedure. The reaction time is short. The allylcopper reagent 182 adds to enones giving the products in less than 15 minutes. While the conjugate addition reactions have been routinely performed using -0.5 mmol of the enone, no reduction in yields were observed when the reactions were performed on larger scale (2.0 mmol of enone). Only the 1,4-addition products were isolated; no 1,2-addition was observed. In the formation of 182, only transmetalation at the allylic trimethylstannyl group of 183 was observed, with no transmetalation at the alkenyl site. Under the reaction conditions employed, none of the trimethylsilyl enol ether intermediates were isolated. A !H nmr analysis of the crude reaction products indicated complete hydrolysis of the trimethylsilyl enol ether intermediates by the workup with aqueous N F I 4 C I - N H 4 O H (pH 8). It is important that, in this workup protocol, the mixture be stirred for the minimum amount of time required to oxidize the copper(I) species. Longer times for this aqueous workup result in significant destannylation of the conjugate addition products. 2.7 Conclusions The preparation of two novel, usefully functionalized allylcopper(I) reagents, 2-(trimethylgermyl)allylcopper(I)-dimethylsulfide (162) and 2-(trimethylstannyl)allyl-copper(I)-dimethylsulfide (182) has been accomplished. These species efficiently transfer, in a 1,4-manner, the 2-(trimethylgermyl)allyl and 2-(trimethylstannyl)allyl groups, respectively, to a,P-unsaturated ketones (30) (Scheme 32) . 1 2 9 The conjugate addition products 191 and 192 are structurally novel, containing an allyl group functionalized at carbon two, which should have great potential in organic synthesis. The synthetic utility of these allylcopper(I) reagents, 162 and 182, in natural product synthesis, remains to be investigated, but looks promising since all of the conversions can be accomplished on relatively large scale. O 2) NH4CI-NH4OH H 20 (pH 8) 162 M = GeMe3 182 M = SnMe3 191 M = GeMe3 192 M = SnMe3 Scheme 32 The conjugate addition reactions of either 162 or 182 to enones are experimentally facile. These allylcopper(I) reagents are extremely reactive and transfer of the substituted allyl group to the (3-position of oc,P-unsaturated ketones (30) proceeds generally in high yields in less than 15 minutes. However, as with many organocopper reactions, in cases where the enone substrate is sterically congested or disubstituted in the p-position (R 2 = alkyl, Scheme 32), lower product yields are obtained. 1 2 3 3. Stereocontrolled Annulation Method for the Synthesis of the Trans-Fused Bicyclo[3.3.0]octane Ring System 3.1 Background The bicyclo[3.3.0]octane ring system is a common structural unit found in many naturally occurring compounds . 1 3 0 - 1 3 1 While in most of the latter compounds the ring fusion is d s , 1 3 0 - 1 3 1 the trans ring fusion is also k n o w n . 1 3 2 The abundance of annulation methods that have been developed to produce fused cyclopentyl rings attest to the importance of this structural unit . 1 3 3 c b <±> H H 193 194 The strain energy of the frans-fused bicyclo[3.3.0]octane (193) is 6.4 kcal/mol greater than that for the ds-fused system (194).22 Oftentimes researchers engaged in the construction of polyquinanes have operated with the basic assumption that the ring junction formed between two fused cyclopentyl rings is necessarily cis, because the transition state producing the ds-fused ring junction should be much less strained, and consequently lower in energy, than that leading to the frans-fused product. However, under the appropriate conditions (vide infra), the trans-fused bicyclo[3.3.0]octane ring systems can be f o r m e d , 1 3 4 1 4 9 and thus, due caution is required when assigning ring junction stereochemistry in polyquinane molecules. The major impetus for investigations into the preparation of the trans-fused bicyclo[3.3.0]octane ring system have been studies of the physical properties of this conformationally rigid, strained system and methodological studies of annulation methods for the construction of fused ring systems. A brief outline of the methods that have been reported to synthesize such systems will follow. In the course of investigating the strain energy of the cis- and trans-fused bicyclo[3.3.0]octane ring system, Linstead and M e a d e 1 4 0 prepared trans-bicyclo-[3.3.0]octan-3-one (195) in low (5%) yield from the diester 196 by a Dieckmann condensation, followed by hydrolysis of the ester and decarboxylation of the resulting carboxylic acid (equation 48). H x 1) Dieckmann H / ^ T ' ^ C 0 2 E t condensation / j — V _ V 4 s ^ C 0 2 E t 2) ester hydrolysis Y - - L - y = 0 ^ H 3) decarboxylation H 196 195 Subsequent modi f i ca t ions 1 4 1 of this procedure using the diacid provided 195 in significantly higher (50%) yields. Investigations by the research groups of N e g i s h i 1 4 2 and W h i t b y 1 4 3 showed that dibutylzirconocene [Cp2Zr(n-Bu)2] mediated cyclizations of 1,6-dienes proceed stereoselectively to produce trans-fused zirconabicyclo[3.3.0]octanes. Carbonylation of the resultant zirconabicycle intermediate provides trans-fused bicyclo[3.3.0]octan-3-ones. Negishi 1 4 2 reported that the zirconocene-mediated cyclization of the geometrically isomeric dienes 197 and 198 provided exclusively the trans-fused zirconabicycles 199 and 200, respectively, which were subsequently converted into the ketones 201 and 202 (equations 49 and 50). Interestingly, the thermodynamically less stable zirconacyclopentane derivative 200 slowly isomerized to the more stable stereoisomer 199. 198 200 202 Yamamoto and coworkers 1 4 4 achieved the formation of a trans-fused bicyclo-[3.3.0]octane ring system by a novel palladium(O) catalyzed cyclization of a 6-substituted octa-2,7-dienyl acetates. For example, the cyclization of 203 under palladium(O) catalysis provided the bicyclic system 204 in 56% yield with exclusive trans diastereoselectivity at the ring junction, along with the monocyclic system 205 in 11% yield (equation 51). 203 R = H 204 R = H 205 R = H However, when 203 was further functionalized (with R=C02Et or R = C H 2 0 M O M ) , only the monocyclic system 205 was produced under these conditions. The failure of the latter intramolecular Heck reactions to form the bicyclic systems was attributed to steric factors. Investigations by Bailey and coworkers 1 4 5 provide an example of tandem anionic ring closure of bis(olefinic) alkyllithiums to provide the trans-fused bicyclo[3.3.0]octane system. Treatment of 4-ethenyl-7-iodoheptene (206) with f-butyllithium, followed by addition of T M E D A and an electrophile to the cyclized intermediate 207, provides a general method for the synthesis of 3-substituted *ran,s-bicyclo[3.3.0]octanes 208 in good (65 -87%) synthetic yields (equation 52). 206 1) f-BuLi pentane - Et 2 0 -78 °C 2) TMEDA I -78 °C -> rt CH2Li CH 2 E 1) electrophile / \ 2) workup (52) 207 208 E = H, C 0 2 H , CH2OH, CHO, Si(CH3)3) I Cooke and G o p a l 1 4 6 conducted similar research into stereoselective tandem anionic cyclizations to provide rrans-fused ring systems. Carbanion stabilizing groups (esters) at the terminal positions of the alkenes moieties (see 209, equation 53) were investigated to alleviate the need for reaction accelerating additives such as T M E D A . When the carbon-5 alkenyl moiety had an E geometry, a mixture of the trans- and c i s - f u s e d bicyclo[3.3.0]octane ring systems 210 and 211, respectively, was obtained in low yield. Incorporation of the Z alkene geometry increased the stereoselectively such that only the trans-fused system 210 was produced in 63% yield. The authors proposed that the stereoselectivity of the reaction originated from destabilization of the transition state leading to the ds-fused product 211, through increased A * - 3 strain in the Z-olefin substrate. In the course of their studies of annulating agents for the construction of five-membered carbocycles, Trost and coworkers 1 4 7 prepared the bifunctional reagent 2-bromo-3-(trimethylsilyl)propene (212). Reagent 212 was added in a Michael fashion to 1-acetylcyclopentene (213) under Lewis acid catalysis to provide an -1:1 mixture of 214 and 215 in 75% yield (equation 54). Br 213 214 215 A n intramolecular Barbier reaction of the trans-isomer 215 produced the highly functionalized mzns-bicyclo[3.3.0]octane system 216 in 44% yield, along with the protiodebrominated byproduct 217 in 48% y i e l d 1 4 7 (equation 55). This annulation method relies on fixing the stereochemistry of the ring substituents prior to cyclization to ensure that the stereochemistry of the ring substituents in the precursor was retained in the cyclized product. It is notable that under the reaction conditions, no epimerization occurred prior to cyclization. 92 OH Li, THF sonication H > C H 3 H 216 H (55) In the process of carrying out the total syntheses of two linearly fused triquinane natural products, hypnophilin and coriolin, Little and coworkers 1 4 8 discovered that the trans-fused bicyclo[3.3.0]octane ring system was easily accessible depending on the identity of R in compound 218-221 (equation 56). Epoxidation of the hydroxyalkene 218 provided a 4:1 mixture of the cis- and trans-fused systems 222 and 223 respectively, in 90% combined yield. Epoxidation of the benzoate protected system 219 provided the trans-fused 225 in preference to the ds-fused 224. Interestingly, epoxidation of the bulky silyl ether 220 provided exclusively the trans-fused 227. More surprisingly, epoxidation of 221, where the hydroxyl moiety had been replaced by hydrogen, provided an -2:1 preference for the trans-fused 229 over the ds-fused isomer 228. Clearly steric factors play a major role in the stereochemical outcome of these epoxidations, but are not the sole factor determining the product ratios. m-CPBA ) NaHC0 3 CHCI3 0 °C Product Ratio 218 R = OH 222 80:20 223 219 R = PhC0 2 224 27:73 225 220 R = OTBS 226 0:100 227 221 R = H 228 35:65 229 Paquette and coworkers 1 4 9 have recently reported that complex polyquinanes can be constructed rapidly by the addition of two alkenyllithium species to a squarate ester (Scheme 33). Sequential addition of 2-propenyllithium and cyclopentenyllithium to the squarate ester 230 would provide an intermediate such as 231. The bridging lithium counterion is believed to play an important role in directing the second nucleophilic attack to the opposite face after the first addition. Cleavage of the cyclobutane ring in 231, followed by an 8 n electrocyclization of 232, provides the bis(enolate) 233. After protonation of 233, a transannular aldol condensation gives the angularly-fused 234 as well as the linearly-fused triquinane 235 containing the frvmy-bicyclo[3.3.0]octane moiety . 1 4 9 b Scheme 33 3.2 Introductory remarks Given the previously described success in developing a useful annulation method for the preparation of the trans-fused bicyclo[4.3.0]nonane ring system, as well as the successful preparation of the substituted allylcopper(I) reagents, we embarked on our goal of developing a general method for the preparation of the trans-fused bicyclo[3.3.0]octane ring system. It was hoped that the annulation sequence used to prepare the trans-fused bicyclo[4.3.0]nonane ring system could be adapted for the preparation of the trans-fused bicyclo[3.3.0]octane ring system. The use of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182), as the synthetic equivalent of the d 2 , d 3 prop-l-ene synthon 48, would be an integral part of the proposed cyclization method. A retrosynthetic plan for the annulation sequence is shown in Scheme 34. H 6 1 Scheme 34 Ketone 236, containing the trans-fused bicyclo[3.3.0]octane ring system, could be obtained from the allylic alcohol 237 by simple functional group interconversions. The key step in this new annulation sequence would be the CrCl2/NiCl2-mediated coupling 5 8 of the alkenyl iodide and aldehyde functions of 238 to provide 237. The iodide 238 could be obtained from the corresponding alkenyltrimethylstannane, which would be prepared by the 1,4-addition of the newly developed, functionalized allylcopper(I) reagent 182 to the enal 71. It was expected that the addition would occur stereoselectively, cis to the adjacent angular proton in 71. The a,P-unsaturated aldehyde 71 is readily available from the keto ketal 61 (vide supra, Chapter 1). 3.3 Preparation of cyclization precursor iodo aldehyde 238 H >C>ct> CHO H 71 1) SnMe3 182 1 Me3SiBr THF, -78 °C; 2) NH4CI-NH4OH H 20 (pH 8) CHO SnMec NIS CH2CI2, rt .-CHO Scheme 35 Using the allylcopper(I) reagent 182, the preparation of compound 239 was achieved. This was accomplished by the addition of the aldehyde 71 to a cold solution of 182 and trimethylsilyl bromide in T H F , followed by aqueous workup and silica gel chromatography, to provide 239 in 75% yield (Scheme 35). A n analysis of this material by ! H nmr spectroscopy showed that 239 was in fact a 2.2:1 mixture of epimeric aldehydes. The addition of 182 had occurred stereoselectively, 1 5 0 exclusively from the more open convex (top) face of the enal 71, while hydrolysis of the enol silyl ether intermediate during the aqueous workup gave rise to two epimers at the center adjacent to the aldehyde moiety. To minimize torsional strain, it was expected that the major isomer was the one in which the substituents bore a trans relationship. 5 0 This expectation was confirmed by a subsequent X-ray crystallographic study (vide infra). When the epimeric mixture of aldehydes 239 was treated with sodium methoxide in dry methanol, the ratio of major to minor epimer could be improved from ~2.2:1 to -8:1. Spectroscopic evidence fully supported the formation of the 1,4-addition product 239. The IR spectrum of 239 exhibited a strong C = 0 stretching absorption at 1723 c n r 1 , characteristic of an unconjugated aldehyde, a C - O - C stretching absorption at 1116 c n r 1 , attributed to the ketal, and a tin-methyl rocking absorption at 769 cm" 1 . The nmr spectrum of 239 displayed two aldehyde resonances in an -2.2:1 ratio (a:f3) at 8 9.48 (doublet, J = 3.5 Hz, a aldehyde) and 8 9.80 (doublet, J = 2 Hz , (3 aldehyde), and a 9-proton singlet for the Me3Sn group at 8 0.13, along with satellite peaks due to tin-proton coupling ( 27sn-H = 53 Hz). Two alkenyl protons were observed and these protons also showed satellite peaks due to tin-proton coupling. The characteristic resonances for the 2,2-dimethylpropylene ketal were also seen in the nmr spectrum of 239. 1,4-Addition Product 1,2-Addition Product H H OH SnMe 3 N T V ^ V C H O   Sn  H SnMe 3 239 3 240 Figure 5 Products from Addition of the Allylcopper(I) Reagent 182 to Enal 71 A small amount of a byproduct (approximately 1%) thought to be the 1,2-addition product 240 (1:1 mixture of epimeric alcohols), on the basis of IR and nmr ( l H and 1 3 C ) spectroscopic analysis, was also detected (Figure 5). The IR spectrum of this epimeric mixture possessed a strong O - H stretching absorption at 3456 cm" 1 , a ketal C - O - C stretching absorption at 1111 c m - 1 , and a tin-methyl rocking absorption at 769 c m - 1 , but no strong absorption in the carbonyl region. The * H nmr spectrum 240 showed three alkenyl protons at 8 5.74, 8 5.48, 8 5.29, the first and last exhibiting tin-proton coupling, while the other showed no such coupling. A 9-proton singlet for the M e 3 S n group at 8 0.14 along with satellite peaks due to tin-proton coupling (27sn-H = 54 Hz), a 1-proton signal at 8 4.16 attributed to the allylic carbinol proton, and the characteristic ketal resonances were also observed. A further complication in the preparation of 239 occurred during the workup with aqueous NH4CI -NH4OH (pH 8). Prolonged treatment of the crude reaction mixture with this solution resulted in undesired destannylation, in addition to hydrolysis of the silyl enol ether intermediate. Thus, it was necessary for the aqueous workup to be conducted rapidly to ensure consistently high yields of the 1,4-addition product 239. The conversion of the alkenyltrimethylstannanes 239 into the corresponding alkenyl iodides was accomplished by treating the 2.2:1 epimeric mixture 239 in methylene chloride with AModosuccinimide. 6 1 The conversion was fast (10 minutes) and facile. After workup, a T L C analysis showed that two distinct, separable products had been formed. Purification of this material by radial chromatography on silica gel provided two crystalline products 238 and 241 in 64% and 27% yields, respectively (Scheme 35). The ring substituents in the major product 238 bore a trans relationship. Treatment of 241 with sodium methoxide in dry methanol provided two products. After purification, 238 was isolated in 79% yield along with recovered 241 (11%). Thus, the thermodynamic product ratio was -7:1 and the overall yield of 238 from 239, after equilibration of the alkenyl iodides, was 85%. The structural assignments of the alkenyl iodides were in full accord with their spectral data. The major product 238 showed stretching absorptions, in its IR spectrum, at 1723 c m - 1 (aldehyde C=0) , 1615 cm" 1 (alkenyl iodide C=C), and 1115 cm" 1 (ketal C - O - C ) . The iff nmr spectrum of 238 exhibited a 1-proton doublet (J = 3.5 Hz) at 8 9.55 for the aldehyde proton and two 1-proton doublets (7 = 1.5 Hz each) at 8 5.70 and 8 6.07 for the alkenyl protons. These alkenyl resonances did not display any satellite peaks due to tin-proton coupling and were shifted downfield from those of the starting material, consistent with the replacement of the Me3Sn group with the more electronegative iodine atom. The absence of a 9-proton singlet at high field in the nmr spectrum of 238 also supported that the conversion of the alkenyltiimethylstannyl moiety to an alkenyl iodide had proceeded. It was extremely gratifying to find that the ketal function was unmolested during this exchange reaction. Two 3-proton singlets at 8 0.91 and 8 0.98 for the gem-dimethyl group of the ketal and the signals at 8 3.41-3.48 (multiplet for three of the methylene protons) and 8 3.57 (doublet, 7 = 11.5 Hz, for one of the methylene protons) in the proton nmr spectrum indicated that the ketal was still intact. The 1 3 C nmr spectrum of 238 contained only 16 of the expected 17 signals. The "missing" signal was attributed to one of the methylene carbons of the ketal. Only one very intense resonance at 8 72.0 appeared for the two methylene carbons of the ketal. Other characteristic resonances in the 1 3 C nmr spectrum of 238 included two methyl signals at 8 22.4 and 8 22.6, and an aldehyde signal at 8 203.2. In addition to this spectral data, the molecular formula of 238 was confirmed by a high resolution mass spectrometric measurement on the molecular ion. The spectral data obtained for the minor product 241 were similar to those of the major epimer. The IR spectrum of 241 exhibited the following stretching absorptions: 1719 c m - 1 (aldehyde C=0) , 1615 cm" 1 (alkenyl iodide C=C), and 1112 cm" 1 (ketal C - O - C ) . The nmr spectrum of 241 displayed resonances similar to those in the spectrum of its epimer 238. The doublet (7 = 2 Hz) for the aldehyde proton in 241 at 8 9.76 was downfield from that in 238, similar to the relative shifts observed in the alkenyltrimethylstannane starting materials. The two alkenyl protons appeared as mutually coupled doublets (7 = 1.5 H z each) at 8 5.73 and 8 6.04. The 1 3 C nmr spectrum of 241 contained all of the expected 17 signals. In this case, the methylene carbons of the ketal displayed unique resonances at 8 72.0 and 8 72.2. In addition to the spectral data, the molecular formula of 241 was confirmed by a high resolution mass spectrometric measurement on the molecular ion. While it was gratifying to obtain the iodo aldehyde required to attempt the cyclization, an alternative route was also investigated. Thus, the possibility of using the allylcopper(I) reagent 162 to prepare the trimethylgermyl aldehyde 242, followed by a germanium-iodine exchange to give 238, was studied (Scheme 36). >c4> C H O H 71 GeMe 3 1) ^j j j^^^Cu'MegS 162 ) Me 3 SiBr T H F , -78 °C; 2) N H 4 C I - N H 4 O H H 2 0 (pH 8) 243 GeMe, C H O GeMe 3 N I S o r l 2 C H 2 C I 2 , rt Scheme 36 . .»CHO Addition of 71 to a solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) and trimethylsilyl bromide in cold T H F provided the 1,4-addition adduct 242 in 70% yield (-2:1 a:|3 mixture of epimeric aldehydes, inseparable by chromatography on silica gel) and the 1,2-addition product 243 in 16% yield (1:1 mixture of epimeric alcohols, inseparable on silica gel). The IR spectrum of 242 exhibited a strong C = 0 stretching absorption at 1723 c m - 1 , indicative of an unconjugated aldehyde, a C - O - C stretching absorption at 1114 c m - 1 , attributed to the ketal, and a germanium-methyl rocking absorption at 826 c m - 1 . The nmr spectrum of 242 displayed two aldehyde resonances in an -2:1 ratio at 5 9.47 (doublet, J = 3.5 Hz, a aldehyde) and 8 9.79 (doublet, J = 2 Hz, P aldehyde) and a 9-proton singlet for the Me3Ge group at 8 0.19. The characteristic resonances for the 2,2-dimethylpropylene ketal, as well as two signals in the alkenyl region, were also seen in the nmr spectrum of 242. Finally, a low resolution mass spectrometric analysis confirmed the presence of a compound with the molecular formula C 2 0 H 3 4 O 3 7 4 G e (M+ = 396). It was concluded that the minor byproduct 243 was the 1,2-addition product based on the spectra data obtained. The IR spectrum of this compound (243) displayed a strong O - H stretching absorption at 3455 c m - 1 , a ketal C - O - C stretching absorption at 1111 c m - 1 , a germanium-methyl rocking absorption at 825 c m _ l , but no strong absorptions in the carbonyl region. The * H nmr spectrum of this compound showed three alkenyl protons at 8 5.33, 8 5.11, 8 5.35 and an allylic carbinol proton at 8 4.20. A 9-proton singlet for die M e 3 G e group at 8 0.21 and the characteristic ketal resonances were also present in the proton nmr spectrum of this compound. Finally, a low resolution mass spectrometric analysis confirmed the presence of a compound with die molecular formula C 2 o H 3 4 0 3 7 4 G e (M+ = 396). When 242 was treated 1 5 1 with either AModosuccinimide or iodine in methylene chloride, a complex mixture of unidentified products was obtained. A G L C analysis of the reaction mixture showed a plethora of products, including a small amount (less than 5%) of 238. It was thought that the close proximity of the carbonyl oxygen of the aldehyde function was interfering with the germanium-iodine exchange through a germanium-oxygen coordination species. While isolated cases of germanium - oxygen coordination have been reported in the l i terature, 1 5 2 studies on organostannanes, where an alkenyltrimethylstannane and electron donating group (oxygen or nitrogen) are held in close proximity, have shown that intramolecular coordination does occur resulting in a pentacoordinate tin species. 1 5 3 More interestingly, this intramolecular coordination affects the normal reactivity of the alkenyltrimethylstannane in halodestannylation reactions such that tin-methyl cleavage occurs in preference to tin-alkene c leavage. 1 5 4 To test the hypothesis that germanium-oxygen coordination was interfering with the halodegermylation reaction, it was proposed to reduce the aldehyde moiety to die primary alcohol, and then to protect the alcohol as a silyl ether and attempt the exchange reaction using this protected substrate (Scheme 37). 242 C H O GeMe, DIBAL-H T H F , -78 °C (30 min) O T B S HF'Pyridine THF, 0 °C 1(90 min) C H 2 O H NIS CH2CI2, rt (60 h) . . . C H 2 O H PCC, Celite CH2CI2, rt (60 min) C H o O H GeMe3 TBSCI Imidazole DMF, rt (60 min) OTBS GeMe, ..rtCHO Overall Yields: 242 -> 247 = 54% 242 -> 248 = 22% 242 -» 238 = 45% Scheme 37 When the 2:1 epimeric mixture of aldehyde 242 in T H F was treated with D I B A L - H , 3 3 for 30 minutes at low temperature, the alcohol 244 was obtained in nearly quantitative yield (Scheme 37). The IR spectrum of 244 displayed a strong O - H stretching absorption at 3427 c m - 1 , a ketal C - O - C stretching absorption at 1115 c n r 1 , a germanium-methyl rocking absorption at 825 c m - 1 , but no absorption in the carbonyl region for an aldehyde. The * H nmr spectrum of 244 showed the appearance of two hydroxymethyl protons with a multiplet centered at 8 3.70. Treatment of the alcohol 244 with AModosuccinimide in methylene chloride also provided a complex mixture of unidentified products. Consistent with the previous proposal, the failure of die halodegermylation reaction with 244 was thought to be a result of germanium - oxygen coordination involving the primary hydroxyl group. To reduce the possibility of intramolecular germanium - oxygen coordination, the alcohol 244 was converted into the silyl ether 245. te^Butyldimethylsilyl ethers are sterically bulky and are known to be non-coordinating. 1 5 5 The reduced Lewis basicity of silyl ethers, when compared with the corresponding alcohols, is due to back donation of nonbonding electrons from oxygen into the low lying empty d orbitals of silicon. Thus, silyl ethers are poorer donor ligands than free alcohols. Using Corey's conditions, 1 5 6 the alcohol 244 was converted into 245 by treatment with terf-butyldimethylsilyl chloride and imidazole in D M F for one hour. The silyl ether 245 was obtained in 97% yield (Scheme 37). The IR spectrum of 245 displayed a broad, strong stretching absorption at 1116 cm" 1 (ketal C - O - C and silyl ether C-O-Si) , and a germanium-methyl rocking absorption at 835 c m - 1 , but no absorption in the O - H stretching region. The * H nmr spectrum of the diastereomeric mixture 245 displayed the expected signals for a terf-butyldimethylsilyl group (a 6-proton signal at 8 0.01 and a 9-proton signal at 8 0.86), a trimethylgermyl group (a 9-proton signal at 8 0.19), and a 2,2-dimethylpropylene ketal function (two 3-proton signals at 8 0.91 and 8 0.94 and a 4-proton multiplet centered at 8 3.44). Finally, a low resolution mass spectrometric analysis confirmed the presence of a compound with the molecular formula C 2 6 H 5o03 7 4 G e S i (M+ = 512). W e were now prepared to test our hypothesis that the failure of 242 to undergo iododegermylation cleanly was an electronic effect, the result of germanium- oxygen coordination, and not due to steric crowding. Our vilification of germanium - oxygen coordination was not unfounded. Treatment of 245 with A M o d o s u c c i n i m i d e 1 5 1 in methylene chloride for 2.5 days provided the alkenyl iodide 246 in 87% yield (Scheme 37). The long reaction time required is indicative of steric crowding. The Iff. nmr spectrum of 246 exhibited two 1-proton signals at 8 5.65 and 8 6.05 for the alkenyl protons and the expected signals for a rerr-butyldimethylsilyl group and the 2,2-dimethylpropylene ketal. The alkenyl resonances were shifted downfield from those of the starting material (8 5.18 and 8 5.53 in 245), consistent with the replacement of the Me3Ge group with the more electronegative iodine atom. The absence of a 9-proton singlet at high field in the * H nmr spectrum of 246 also supported the conversion of the alkenyltrimethylgermyl moiety into an alkenyl iodide. After much experimentation, conditions were found to deprotect the hydroxyl moiety of 246 without disturbing the ketal or alkenyl iodide functions. Treatment of 246 in cool T H F with hydrofluoric acid-pyridine complex 1 5 7 for 90 minutes provided two alcohols (Scheme 37). At this point, chromatographic separation on silica gel was possible, providing pure 247 in 71% yield (54% overall from 242) and the isomeric alcohol 248 in 29% yield (22% overall from 242). The IR spectrum of 247 displayed a strong O - H stretching absorption at 3418 c n r 1 , an alkenyl iodide C = C stretching absorption at 1615 c m - 1 , and a ketal C - O - C stretching absorption at 1112 c m - 1 . The * H nmr spectra of 247 gave further evidence of the successful, clean hydrolysis of the silyl ether. Both the 9-proton and 6-proton signals at high field, characteristic of a te/t-butyl-dimethylsilyl group, had disappeared. The nmr spectrum of 247 did show two 1-proton signals for the alkenyl protons at 8 5.68 and 8 6.07, and two 3-proton singlets at 8 0.91 and 8 0.95 for the gem-dimethyl groups of the ketal. The 1 3 C nmr spectrum of 247 contained all the expected 17 signals. In addition to this spectral data, the molecular formula of 247 was confirmed by a high resolution mass spectrometric measurement on the molecular ion. The structure of 248 was assigned by a similar analysis of the IR and nmr spectral data obtained. The aldehyde 238 was obtained by oxidation of the alcohol 247. Treatment of a solution of 247 in methylene chloride with pyridinium chlorochromate 3 4 for 60 minutes provided 238 in 84% isolated yield (Scheme 37). The structure of this product was confirmed by comparison of the spectral data obtained to the spectral data of 238 obtained by the previously described route. M H 182M = SnMe3 162 M = GeMe-q H H CHO Me3SiBr, THF -78 °C NH4CI-NH4OH H20 (pH 8) CHO 71 M 239 M = SnMe3 242 M = GeMe3 H 1 step CHO 239 SnMe3 Q H " V.-CHO H CHO 5 steps 242 GeMe3 Scheme 38 In summary, either of the substituted allylcopper(I) reagents 1 8 2 or 162 can be added efficiently, in a 1,4-manner, to the a,pVunsaturated aldehyde 71 providing 2 3 9 or 242 in good yield (Scheme 38). While the corresponding alkenyl iodide 238 can easily be prepared from 2 3 9 by an iododestannylation reaction, 2 4 2 does not undergo clean iododegermylation when treated with AModosuccinimide. This difficulty is proposed to be due to intramolecular coordination between the alkenyltrimethylgermane and aldehyde functions. Nonetheless, 2 4 2 can function as a precursor to the alkenyl iodide 2 3 8 . The use of 242 requires a multistep protection - deprotection sequence to inhibit the undesired germanium-oxygen coordination which interferes in the iododegermylation reaction necessary to generate 238 . Thus, the more efficient method to prepare 2 3 8 is through the use of the organocopper(I) reagent 182. 3.4 Ring closure: Cyclization of iodo aldehyde 238 The cyclization of the iodo aldehyde 2 3 8 was attempted using conditions essentially identical with those developed for the preparation of trans-fused bicyclo[4.3.0]nonane ring systems (vide supra, Chapter 1). Thus, addition of 2 3 8 to a slurry of C r C F i and NiCFi in D M F 5 8 (equation 57) provided the trans-fused bicyclo-[3.3.0]octane system (237) in 65% yield (Table 11, entry 1). T a b l e 11 Transition Metal-Mediated Cyclization of Iodo Aldehyde 238 H H 238 237 Entry Solvent Reaction Time % Yield 1 D M F 60 minutes 65 2 4:1 D M F - D M S O 30 minutes 92 Other solvents and solvent pairs, including D M F - D M E , 5 9 D M S O - D M S , 1 5 8 D M S O , 5 8 b and T H F , 1 5 9 have been used in the CrCl2/NiCl2 mediated coupling reaction. The use of D M S O as the solvent has been reported to give a much cleaner, albeit slower, reaction for the coupling of iodo olefins with aldehydes. 5 8 b Changing the solvent for the cyclization to a 4:1 mixture of D M F and D M S O (equation 57), provided immediate rewards (Table 11, entry 2). After only 30 minutes, a T L C analysis showed complete consumption of the starting material. After workup and silica gel chromatography, 237 was obtained in 92% yield. The cyclized product was isolated as a 1:1 mixture of alcohols, epimeric at the carbinol carbon, which were inseparable by silica gel chromatography. The JR spectrum of this mixture displayed stretching absorptions at 3436 c m - 1 (O-H), 1656 c m - 1 (C=C), and 1110 c n r 1 (ketal C - O - C ) . The * H nmr spectrum of 237 exhibited broad resonances, in a 1:1 ratio, for the carbinol protons at 8 4.09 and 8 4.20. The two exocyclic methylene protons were observed at 8 4.98 and 8 5.06 (1:1 ratio) and 8 5.08 and 8 5.21 (1:1 ratio). 2 3 7 A C o O DMAP, Et3N CH2CI2, rt Sml2, MeOH THF, -78 °C OAc >0 249 1) 0 3 , MeOH, CH2CI2, -78 °C; 2) Me2S H m: 236 2 5 0 Scheme 39 At this point, rather than spending excessive amounts of time trying to separate the mixture of allylic alcohols by other chromatographic methods, it was decided to use the mixture directly in the next step, since both of the alcohols are precursors to the desired ketone 236 (Scheme 39). The acetate 249 was prepared under standard conditions by treatment of the alcohol 237 in methylene chloride with acetic anhydride in the presence of D M A P and triethylamine (Scheme 39). 6 4 As expected, the acetate 249 was obtained (96% yield) as a 1:1 mixture of epimers, which again proved to be inseparable by chromatography on silica gel. Evidence for the conversion of the hydroxyl group to an acetate was obtained from the IR spectrum of 249. The O - H stretching absorption at 3436 cm- 1 had disappeared and new stretching absorptions at 1737 cm- 1 (acetate C=0) and 1239 cm- 1 (acetate C-O) appeared. Absorptions at 1657 cm- 1 (C=C) and 1112 cm- 1 (ketal C - O - C ) were also observed in the IR spectrum of 249. In addition, the *H nmr spectrum of 249 displayed resonances for the acetoxy methine proton at 8 4.98 and 8 5.06 (1:1 ratio), shifted significantly downfield from those in the alcohol 237, as would be expected for the conversion of an alcohol to an acetate. Resonances for the methyl protons of the acetate were seen at 8 2.03 and 8 2.09 (1:1 ratio). The two exocyclic methylene protons of 249 were observed at 8 4.96 and 8 4.99 (1:1 ratio) and 8 5.11 and 8 5.25 (1:1 ratio). The efficient preparation of the keto acetate 250 was not as straightforward as might be expected. Treatment of a cold (-78 °C) solution of 249 in methanol with ozone, 6 6 followed by reductive workup with dimethyl sulfide, 6 7 provided 250 in 71% yield along with a polar byproduct. It has been suggested that, in polar hydroxylic solvents such as methanol, the intermediate methoxy hydroperoxide can undergo further oxidations before reduction with dimethyl sulfide can occur . 1 6 0 In less polar, non-hydroxylic solvents such as methylene chloride, the ozonide intermediate is quite stable, and is only slowly reduced by dimethyl sulfide. In a mixed solvent system of methanol and methylene chloride, secondary reactions (such as over-oxidation) are inhibited yet the reduction of the ozonide is still quite rapid. When a solution of 249 in cold methylene chloride containing 1.5 equivalents of methanol 1 6 0 was treated with ozone followed by reductive workup with dimethyl sulfide, the keto acetate 250 was obtained in 90% yield (Scheme 39). A n analysis of the product by ! H nmr spectroscopy indicated a 1:1 mixture of epimers had been isolated. The spectral data obtained from 250 fully supported oxidative cleavage of the exocyclic methylene group. The IR spectrum of 250 showed that the C = C absorption at 1657 cm- 1 had disappeared and was replaced by a broad absorption at 1757 c n r 1 (C=0 cyclopentanone and C = 0 acetate), in addition to the stretching absorptions at 1230 c n r 1 ( C - 0 acetate) and 1110 c n r 1 ( C - O - C ketal). The lH nmr spectrum of 250 offered further proof for the conversion of the exocyclic methylene to a ketone. There were resonances for the acetoxy methine proton at 8 4.88 and 8 4.92 (1:1 ratio), but the resonances of the alkenyl resonances of the exocyclic methylene had disappeared. Reductive removal of the a-acetoxy function was achieved smoomly by addition of a solution of 250 in T H F and methanol to a cold solution of Sml.2 in T H F (Scheme 39). 6 8 After workup and silica gel chromatography, a single compound, the triquinane keto ketal 236, was obtained in 89% yield. The IR spectrum of 236 exhibited strong stretching absorptions at 1745 c m - 1 (C=0) and 1113 c m - 1 (ketal C - O - C ) . The lH nmr spectrum of 236 displayed two 3-proton singlets at 8 0.93 and 8 0.94 and a 4-proton multiplet centered at 8 3.45, which confirmed that the ketal had remained intact. Further proof of the successful reductive cleavage of the acetoxy moiety was seen by the absence of the resonances attributed to the methyl protons of the acetate group in the * H nmr spectrum . The 1 3 C nmr spectrum of 236 contained the expected 16 signals. Characteristic resonances were the carbonyl signal at 8 220.2, the quaternary ketal carbon signal at 8 110.9, the two ketal methylene carbon signals at 8 71.9 and 72.0, the two ketal methyl signals at 8 22.48 and 22.53, and four methine carbon signals at 8 42.3, 44.80, 49.2, and 54.6. In addition to this spectral data, the molecular formula of 236 was confirmed by a high resolution mass spectrometric measurement on the molecular ion. 03 03 Despite good evidence that the proposed cyclization had indeed been successful, none of the recorded data provided conclusive evidence for the assigned relative stereochemistry at the ring junction of 236 (or 237, 249, or 250). As 236 is a single diastereomer (as opposed to the epimeric mixtures 237,249, and 250) and is a crystalline solid (mp 74 - 75 ° C ) which could be recrystallized from n-heptane, an X-ray crystallographic study 6 5 was undertaken. As expected, a single crystal X-ray analysis of 236 (Appendix 2) showed conclusively that the protons at the ring fusion, in the newly formed ring (A-B rings), are in a trans relationship (Figure 6). The reason for difference in the strain energy of the trans- and ris-fused bicyclo[3.3.0] systems can be seen from their respective torsional angles. The trans-fused system (rings A and B) has a torsional angle going from C-a to C-d (via C-b and C-c) of 4 4 . 5 ° , while the cis-fused system (rings B and C) has a torsional angle going from C-e to C-h (via C- f and C-g) of -4 .8° . Several key assumptions made early in our synthesis were confirmed by this X-ray structure. The approach of the allylcopper(I) reagent 182 to the cc,pVunsaturated aldehyde 71 was stereoselective, occurring exclusively from the convex face of the molecule. The major product obtained from this 1,4-addition, after hydrolysis of the silyl enol ether intermediate, did indeed have the ring substituents in a trans relationship. Thus, the annulation strategy developed does provide an efficient method for the construction of the trans-fused bicyclo[3.3.0]octane ring system. 3.5 Conclusions A new method for the stereocontrolled synthesis of the trans-fused bicyclo-[3.3.0]octane ring system has been developed. 6 9 Starting with the bicyclic cyclopentanone system (61), the trans-fused bicyclo[3.3.0]octane ring system (236) can easily be produced. The annulation method employs the substituted allylcopper(I) reagent 2-(trimethylstannyl)allylcopper(I) (182) as the synthetic equivalent of the d 2 , d 3 prop-l-ene synthon (48), sequentially deploying the donor sites at carbon three then carbon two (Scheme 40). Thus, 182 could be combined with the a,pVunsaturated aldehyde 71, obtained from the keto ketal 61, to provide the bicyclo[3.3.0]octane ring system (237). On the basis of molecular model analysis and an X-ray crystallographic study on 236, the stereochemistry of the newly formed ring junction was established as being trans-fused. S n M e 3 ( ; ; ^ ! s v / C u » M e 2 S = 182 H 71 >cxi> o H 61 48 d < ^ \ d 48 H H ^ O 236 237 H Scheme 40 Concurrendy, during our studies to develop the aforementioned annulation method, evidence was obtained in support of germanium-oxygen coordination. It was found that alkenyltrimethylgermanium species can form a chelate species with an electron donating oxygen which is held in close proximity. Furthermore, this chelate species, when subjected to iododegermylation conditions, does not react in the expected manner. Several side reactions, presumably including germanium-methyl cleavage, compete with the expected germanium-alkene cleavage reaction. 4. Copper(I) Chloride - Mediated Intramolecular Coupling of Bis(Alkenyltrimethylstannanes) 4.1 Background The use of transition metal salts, particularly pal ladium, 1 6 1 to mediate carbon-carbon bond formation is a powerful tool for the synthetic organic chemist. One of the most well known reactions of this type is the palladium(O)-catalyzed cross coupling reaction of organostannanes (R'SnR"3) with organic halides and related electrophiles (R-X) (equation 58). This reaction is widely known as the Stille coupling r e a c t i o n 1 2 7 - 1 6 2 ' 1 6 3 to acknowledge the seminal contributions of the late J. K. Stille to the development of this important method. Some of the merits of this catalytic reaction are the mild conditions required to effect coupling, the wide variety of functional groups that can be tolerated on either of the coupling partners, excellent control of the configuration of the final products, and the high yields routinely obtained. Pd(0) catalyst , % R-X + R'SnR"3 — R-R' + XSnR"3 (58) The Stille coupling reaction provides the coupled product (R-R') by the selective transfer of an organic group (R') from the organostannane to the organic group (R) which is originally bonded to the leaving group (X). The rate of transfer of different organic groups from the tin atom varies with the ability of the group to stabilize a negative charge, with simple alkyl group having the slowest transfer rates . 1 6 4 Since both organo-(trimethylstannanes) and organo(tri(n-butylstannanes)) are readily available compounds, 1 2 6 the nontransferable group (R") has generally been chosen as either methyl or n-butyl, while moieties such as alkenyl, alkynyl, allyl, aryl or benzyl have been used for the transferable ligand (R). The electrophilic coupling partner (R-X) oftentimes is an alkenyl halide or a alkenyl triflate, but other activated electrophiles such as acid chlorides, allyl halides, aryl halides, benzyl halides, and aryl triflates have also been used successfully. In addition to the variety of substrates available for coupling, the reaction may be fine-tuned by adjusting the palladium source and the solvent. A number of palladium c a t a l y s t s 1 2 7 have been used for the Stille coupling reaction, including tetrakis-(triphenylphosphine)palladium(O) [Pd(PPh3)4], tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], bis(triphenylphosphine)palladium(II) chloride [Pd(PPh3)2Cl2], and bis(acetonitrile)palladium(II) chloride [Pd(CH3CN)2Cl2]. The palladium-dibenzylidene-acetone complexes are generally used in conjunction with donor ligands such as PPI13 or ASPI13. Since the active catalyst in the coupling reaction is palladium(O), prior to entering the catalytic cycle, palladium(II) catalysts must first be reduced to palladium(O), typically in situ, through the homocoupling of two equivalents of the stannane. Stille coupling reactions have been performed in almost all conceivable solvents at temperatures ranging from ambient to reflux conditions. 1 2 7 While many couplings have been carried out in ethereal solvents, such as T H F or dioxane, polar solvents such as D M F and N M P have become the solvents of choice . 1 2 7 The use of other solvents, including acetone, acetonitrile, benzene, chloroform, 1,2-dichloroethane, D M S O , H M P A , and even water 1 6 5 have been reported in the literature. 1 2 7 The overall reaction pathway for the palladium catalyzed coupling process is shown in Figure 7 . 1 6 2 The catalytic process is widely accepted as involving loss of ligands from the palladium(O) catalyst to form a coordinatively unsaturated palladium(O) species (PdL2), an oxidative insertion of the coordinatively unsaturated palladium(O) catalyst into the carbon-halogen bond of the organic halide (R-X), a transmetalation of the resulting organopalladium(II) species with the organostannane (R'SnR'^), a trans - cis isomerization of the bis(organo)palladium(II) complex, and a subsequent reductive elimination to provide the coupled product (R-R'), accompanied by regeneration of the palladium(O) catalyst. The transmetalation of the organopalladium(II) species with the organostannane (R'SnR"3) is considered to be the rate determining step. F i g u r e 7 Catalytic Cycle of the Stille Coupling Reaction Copper(I) iodide has been employed as a co-catalyst to accelerate the reaction ra te . 1 6 6 The copper(I) salt is thought to have a dual role. In ethereal solvents and in conjunction with highly coordinating ligands (PPh3), the copper(I) co-catalyst acts as a ligand scavenger to facilitate the formation of the coordinatively unsaturated palladium(O) catalyst. In polar solvents ( D M F or N M P ) , it is proposed that the copper(I) salt causes a reversible tin - copper transmetalation (equation 59). The resulting organocopper species (R'Cu) transmetalates with the organopalladium(II) species (R-PdL-2-X, Figure 7) at a rate higher than that of the organostannane itself. R'SnR-'a + Cul ^ ^ R'Cu + R"3Snl (59) Inorganic salts, usually lithium chloride (LiCI), have also been added to the reaction mixture, especially for intermolecular Stille cross couplings employing alkenyl triflates. It has been postulated that substitution of the triflate ligand for a chloride ligand in the initial oxidative addition product (Figure 7, R-PdL2-X, X = O T f —> X = CI) results in a more reactive species. 1 6 7 More recently, it has been found that the addition of LiCI is often not necessary if the reaction is performed in highly polar solvents (NMP or D M F ) . 1 6 8 The synthetic utility of the Stille reaction has been demonstrated by numerous publications involving the synthesis of natural products. Piers and Friesen implemented the palladium(0) catalyzed intramolecular coupling as a key bond forming step in the preparation of (±)-amij i tr ienol (251) from the intermediate 252 (equation 60) . 1 6 9 The palladium catalyzed coupling reaction has also be applied successfully in an intermolecular fashion in the convergent synthesis of pleraplysillin-1 (253), from the alkenyl triflate 254 and the organostannane 255 (equation 61) . 1 7 0 Investigations into the stereocontrolled synthesis of alkyl 2,3-bis(alkylidene)-cyclopentanecarboxylates (256) by Piers and W o n g 1 7 1 revealed an important discovery about the use of a copper(I) salt as a catalyst in the Stille coupling reaction. Under the standard Stille coupling conditions, treatment of a variety of esters of general structure 257, each containing an alkenyl(trimethylstannane) moiety and an alkenyl halide moiety, with Pd(PPh 3)4 (5 mol %) and lithium chloride (2 equiv) in dry D M F at 80 ° C for 1 hour provided the alkyl 2,3-bis(alkylidene)cyclopentanecarboxylates of general structure 256 in good yields with excellent stereoselectivity (equation 62). C 0 2 R 2 r 1 Pd(PPh3)4, LiCl ^ R S - ^ ^ - X SnMe3 DMF,80°C R 1 ^ L ^ ( 6 2 ) C 0 2 R 2 257 256 In the case of the ester 258, however, poor stereocontrol and a low yield was obtained (equation 63, Table 12, entry 1). Using standard palladium(0) coupling conditions, the ester 258, provided three products (259-261). It has been reported that the reaction rate of palladium(O) catalyzed coupling reactions are accelerated by the inclusion of copper(I) salt co-catalysts. 1 6 6 When the above reaction was repeated with added copper(I) chloride, a dramatic improvement in yield and stereocontrol was observed (Table 12, entry 2). Table 12 Intramolecular Coupling Reactions of the Ester 258 258 259 260 261 Entry Reaction Conditions Product Ratio 259:260:261 (Combined Yield of 259+260+261) 1 Pd(PPh 3 ) 4 ) L iCI , D M F , 80 ° C 27:11:7 (39%) 2 Pd(PPh 3 ) 4 , C u C l , D M S O , 60 ° C 11:1:0 (67%) 3 C u C l , D M F , 60 °C 13:1:0 (86%) 4 C u C l , D M F , 23 °C 31:1:0 (94%) After further experimentation, Piers and Wong discovered that the intramolecular coupling of compounds of general structure 257 could be achieved by the use of copper(I) chloride in warm D M F , in the absence of any palladium catalyst (equation 64) . 1 7 1 Most remarkably, with the ester 258 better stereocontrol and yields were obtained by treatment with copperfl) chloride alone in D M F than with traditional Stille coupling conditions (Table 12, entries 3 and 4). In addition, the copper(I) chloride-mediated coupling of 258 proceeded in better yield with greater selectivity when a lower reaction temperature was employed. In this case, the copper(I) chloride protocol is clearly superior to the palladium(O) catalyzed process. C 0 2 R 2 257 256 The use of 2 - 2.5 equivalents of copper(I) chloride was required for the coupling reaction to go to completion in a short (less than 5 minutes) time and with high yields. Preliminary investigations on the mechanism of the reaction revealed that the alkenyl(trimethylstannane) moiety initially undergoes a reversible transmetalation with copper(I) chloride to afford an alkenylcopper species, along with trimethyltin chloride. Studies by Liebeskind using 1 1 9 S n nmr have shown that in polar solvents, copper(I) iodide undergoes a reversible transmetalation with unsaturated stannanes to provide an organocopper species. 1 6 6 a The excess copper(I) salt helps drive the equilibrium towards the tin-copper transmetalation product. Subsequently, the alkenylcopper species reacts with the alkenyl halide to provide the coupled product. The mechanistic details of this step are uncertain. This novel copper(I) chloride mediated intramolecular coupling reaction of an alkenyl halide and an alkenyl(trimethylstannane) has shown utility in the stereospecific synthesis of bicyclic conjugated diene systems such as 263 (equation 65) . 1 7 1 B y altering the ring size in 262 and changing the chain length attached to the alkenyl halide, bicyclic ring systems other than 263 have been prepared containing the conjugated diene moiety. 1 7 1 Subsequent investigations 1 7 2 to examine the scope of this novel copper(I) chloride coupling reaction revealed that alkenyl(trimethylstannanes) can be efficiendy coupled using a solution of copper(I) chloride in D M F . The intermolecular coupling of two (65) 262 263 alkenyl(trimethylstannanes) provides an efficient method for the construction of structurally diverse conjugate dienes (equations 66 and 67). *C02Me MeoSn CuCl DMF, rt C02Me C02Me (66) 264 265 A variety of P-trimethylstannyl-a,fi-unsaturated esters have been coupled in high yields using 2.5 equivalents of copper(I) chloride in D M F at room temperature. For example, the ester 264 provided the diene 265 in 90% yield (equation 66) . 1 7 2 The geometric isomer of 264 also underwent efficient coupling when treated with copper(I) chloride. The coupling of a stannane alcohol (266) as well as the corresponding ether (267) were also successful providing 268 and 2 6 9 , 1 7 2 b but proceeded in lower (51% and 53%, respectively) yields (equation 67) . 1 7 3 SnMe3 266 R = H 267 R = MOM CuCl DMF, rt 268 R = H 269 R = MOM (67) The synthetic utility of the copper(I) chloride mediated coupling reaction has been extended to the preparation of a variety of bicyclic systems via an intramolecular copper(I) chloride mediated coupling of two different alkenyl(trimethylstannane) moieties in the same molecule. 1 7 4 C02Me C02Me CuCl (68) DMF, 60 °C 270 263 The bis(alkenyltrimethylstannane) 270 was successfully cyclized in 15 minutes to provide the bicyclo[4.3.0]nonane system 263 in high yield (equation 68) . 1 7 4 The intramolecular coupling of two different alkenyl(trimethylstannane) moieties in the same molecule has provided an efficient process for the closure of 4-, 5-, 6-, 7-, and 8-membered rings containing a conjugated diene funct ion. 1 7 4 Interestingly, the intramolecular coupling process requires 5 equivalents of copper(I) chloride in warm (60 ° C ) D M F to ensure complete conversion of starting material to product within a relatively short period of time. The mechanistic details of the copper(I) chloride mediated coupling of two alkenyl(trimethylstannanes) remain obscure. Based on previous studies, 1 6 6 3 a tentative proposal suggests an initial reversible transmetalation between one of the trimethylstannyl moieties and copper(I) chloride to provide an alkenylcopper species and Me3SnCl. A subsequent step involving coupling of the alkenylcopper moiety with the other alkenyl(trimethylstannane) provides the cyclized product. 4.2 Introductory remarks The successful use of 2,3-bis(trimethylstannyl)propene (183) (Scheme 41) to prepare the functionahzed allylcopper(I) reagent 2-(trimemylstannyl)aUylcopper(I)-dimethyl sulfide (182) and the conjugate addition of 182 to enones (to provide compounds of general structure 192) were described in Chapter 2 of this thesis. The use of 182 as the synthetic equivalent of the d 2 , d 3 prop-l-ene synthon, suitable for conjugate addition to a,f3-unsaturated carbonyl compounds, in an annulation method for the preparation of rrans-fused bicyclo[3.3.0]octane ring systems was described in Chapter 3. It was also thought that 183 itself might be a synthetically useful reagent. 2-(Trimethylstannyl)-allyllithium (271) is prepared from 183 by treatment with methyllithium. 1 2 8 While 271 would not be expected to undergo 1,4-addition to a,P-unsaturated carbonyl compounds, it was hoped that 271 would react, in synthetically useful yields, with electrophilic species to provide compounds of general structure 272 (Scheme 41). SnMe3 M®Li s n M e 3 THF SnMe^  271 E = Electrophile t SnMe3 272 183 1) MeLi-LiBr SnMe3 THF, -78 °C 7 ^ 0 • • Xu»Me 2S 2) CuBr-Me2S <^^^ 182 O \A^ R L SnMe3 192 Scheme 41 30 Me3SiBr THF, -78 °C It was envisaged that the synthetic utility of 271 could be demonstrated in a new cyclization method to provide highly functionalized cyclopentenyl systems of general structure 273. A retrosynthetic analysis of the proposed annulation procedure is shown in Scheme 42. Me3Sn >=< CHO OAc Me3Sn OAc SnMe3 R R 275 R SnMe3 273 274 271 Scheme 42 It was proposed that 273 could be prepared from compounds such as 274. The key step in this annulation sequence would be a copper(I) chloride mediated intramolecular c o u p l i n g 1 7 2 - 1 7 4 of the alkenyltrimethylstannane moieties in 274. Previous work in our laboratories has provided general methods for the preparation of configurationally defined P-trimethylstannyl a,P-unsaturated carbonyl c o m p o u n d s . 1 7 5 - 1 7 7 A suitable precursor (274) for the intramolecular copper(I) chloride cyclization could be obtained from addition of 271 to P-trimethylstannyl a,P-unsaturated aldehydes (general structure 275), followed by a functional group interconversion, namely conversion of the alcohol into an acetate. 4.3 Preparation of P-trimethylstannyl q.p-unsaturated aldehydes R CHO SnMe3 275 A number of P-trimethylstannyl a,P-unsaturated aldehydes of general structure 275 were required as starting materials for this study and these compounds were prepared using methods previously developed in our laboratories. ^ ^ S n M e , ^ ^ S n M e 3 276 R = CHO 277 R = CHO 278 R = C02Me 279 R = C0 2Et 280 R = CH2OH 281 R = CH2OH The cyclic P-trimethylstannyl a,P-unsaturated a ldehydes 1 7 8 2 76 and 277, prepared by reduction of the es ters 1 7 2 - 1 7 7 2 78 and 279 followed by oxidation of the resultant alcohols 280 and 281, have been reported previously. The spectral data obtained from the purified aldehydes 276 and 277 were in accordance with the reported values. 1 7 8 The previously unreported aldehyde 282, containing the cycloheptenyl moiety, was prepared by a procedure similar to that used for the preparation 276 and 277 (Scheme 43). or 284 1) KH, THF, 0°C 2) PhN(S02CF3)2 0°C-> rt O .C0 2Me SnMe-3 286 R = CH2OH 282 R = CHO 1) DIBAL-H, THF, -78 °C -> rt 2) TPAP, NMO, mol. sieves, CH2CI2, 0 °C -> rt OS0 2 CF 3 283 1) [Me3SnCuSPh]Li, THF-HMPA, -20 °C -» 0 °C 2) NH4CI-NH4OH H 20 (pH 8) G .C0 2Me SnMe-3 285 Scheme 43 The alkenyl triflate 283 was prepared 1 7 7 by treatment of the commercially available methyl 2-oxo-l-cycloheptanecarboxylate (284) with potassium hydride and iV-phenyl-trifluoromethanesulfonimide (Scheme 43 ) . 1 7 2 a After appropriate workup and purification of the crude material by flash chromatography, followed by distillation of the resultant oil, compound 283 was isolated in 89% yield. The IR spectrum of 283 displayed a strong C = 0 stretching absorption at 1728 c n r 1 and a C=C stretching absorption at 1659 c m - 1 . The f H nmr spectrum of 283 exhibited a 3-proton singlet at 5 3.78 attributed to the methoxy protons. The successful incorporation of the trifluoromethanesulfonyl group was confirmed by the presence of a quartet (Jc-F = 4 Hz) at 8 118.3, attributed to the C F 3 carbon, in the proton decoupled 1 3 C nmr spectrum of 283. Reaction 1 7 7 of the alkenyl triflate 283 with lithium (phenylthio)(trimethylstannyl)-cuprate 1 1 1 provided, after aqueous workup and purification of the crude material by chromatography on silica gel, the ester 285 in 82% yield (Scheme 4 3 ) . 1 7 2 a The IR spectrum of 285 showed a strong C = 0 stretching absorption at 1694 c m - 1 for the conjugated ester carbonyl. The nmr spectrum of 285 confirmed incorporation of the Me3Sn group by a 9-proton singlet at 8 0.09 with satellite peaks due to tin-proton coupling (27sn-H = 53 Hz) and a methyl ester by a 3-proton singlet at 8 3.70. Conversion of the ester 285 into the aldehyde 282 was accomplished through a simple reduction - oxidation sequence (Scheme 43). Treatment of a solution of 285 in T H F with D I B A L - H 3 3 provided the corresponding allylic alcohol (286). This material was extremely unstable and rapidly decomposed, especially when neat. Due to the instability of 286, the crude material was immediately oxidized under mild conditions using tetra-n-propylammonium perruthenate ( T P A P ) 1 7 9 to provide the aldehyde 282 in 77% yield from the ester 285, after workup and purification. The spectral data obtained for 282 were in full accord with the above transformation. The IR spectrum of 282 showed, for the conjugated aldehyde, a strong C = 0 stretching absorption at 1680 c m - 1 and a tin-methyl rocking absorption at 772 c m - 1 . The nmr spectrum of 282 indicated the presence of a Me3Sn group (a 9-proton singlet with satellite peaks due to tin-proton coupling at 8 0.23, 2 / s n - H = 53 Hz) and an aldehyde (a 1-proton singlet at 8 9.43, with satellite peaks due to long range tin proton coupling 4 7sn-H = 6 Hz). The 1 3 C nmr spectrum of 282 contained the expected 9 signals. Characteristic resonances were the two alkenyl signals at 8 153.4 and 179.6, the aldehyde signal at 8 193.8, and the signal for the Me3Sn group at 8 -7.2. The close proximity of the alcohol and trimethylstannyl moieties in 286 was thought to be the cause of its instability. A n analysis of molecular models of 286, 281, and 280 showed that the distance between the trimethylstannyl moiety and the hydroxyl group increases with decreasing ring size. The geometric constraints of the cyclopentenyl (280) and cyclohexenyl (281) systems keep the alkenyl substituents rather far apart, but the larger ring size of the cycloheptenyl system (286) allows for their close proximity. In systems with a rigid skeleton, where a coordinating heteroatom substituent such as oxygen is at the y-position relative to the tin atom of an alkenyltrialkylstannane, tin-oxygen coordination via a five membered ring is k n o w n . 1 8 0 It was thought that this tin-oxygen coordination causes the decomposition of 286. However, the stable and isolable alcohols 280 and 281 cannot have intramolecular tin - oxygen coordination without imparting a high degree of angle strain to the molecule. Interestingly, this is also true of the aldehydes 276, 277, and 282 and the corresponding esters 278, 279, and 285. 286 281 280 1) MeLi, THF -78 °C ->-20 °C TBSO-(CH2)4—==—H 2)H2CO -20 °C -> rt * - TBSO-(CH2)4—==—CH2OH 288 289 PCC, NaOAc CH2CI2, rt Me3Sn (Me3Sn)2 TBSO CHO « P d ( p p h 3 ) 4 TBSO-(CH2)4 — = — C H O THF, reflux 287 290 Scheme 44 The preparation of aldehyde 287 has been described previously by Piers and Ti l lyer (Scheme 4 4 ) . 1 7 6 Treatment of 288 1 8 1 in T H F with methyllithium and paraformaldehyde gave the primary alcohol 289, which, upon oxidation with pyridinium chlorochromate 3 4 in the presence of sodium acetate, provided the aldehyde 290. A palladium catalyzed addition of hexamethylditin to the a,P-alkynic aldehyde 290 provided the requisite P-trimethylstannyl a,P-unsaturated aldehyde 287. The spectral data derived from 287 were in full accord with the values reported in the literature. 1 7 6 The aldehydes 291 and 292 were prepared from esters 26 4 1 7 5 and 293 (previously unreported), respectively, by a straightforward sequence using D I B A L - H reduction 3 3 followed immediately by oxidation with T P A P 1 7 9 (Scheme 45). Spectral data obtained for 291 and 292 were fully consistent with the assigned structures. The esters 264 and 293 were prepared by the addition of lithium (trimethylstannyl)(cyano)cuprate111 to the appropriate acetylenic esters 294 and 295 using the general procedure developed by Piers, Wong, and E l l i s 1 7 5 (Scheme 45). 1 2 8 R- •COoR' 295 294 1) Me3SnCu(CN)Li THF, -48 °C -» 0 °C 2) NH4CI-NH4OH, H 20 (pH 8)' R SnMe3 .C0 2 R' 293 264 295, 293: R = TBS-OC-CCH^a ; R' = Et 294, 264: R = CI-(CH2)3 ; R' = Me SnMe3 R A ^ C H O 292 R = TBS-C=C-(CH2)3 291 R = CI(CH2)3 1) DIBAL-H, THF -78 °C -> rt 2) TPAP, NMO 3 A mol. sieves CH2CI2, 0 °C -> rt Scheme 45 The a,P-alkynic esters 294 and 295 were obtained by treatment of the terminal alkynes 296 and 297 with methyllithium followed addition of either ethyl or methyl chloroformate to the resultant lithium acety l ide 1 7 5 (Scheme 46). While 296 is commercially available, the monoprotected alkyne 297 can be prepared from hepta-1,6-diyne (298) by the addition of one equivalent of methyllithium followed by tert-butyl-dimethylsilyl chloride. = — \ 1) MeLi, THF, -78 °C -» -20 °C 2) TBSCI.-20 °C-> rt I C — = ' 298 TBS — 297 1) MeL, THF, -78 °C -» -20 °C „ R H — ' • • R C 0 2 R ' 2) C I C 0 2 R \ -20 °C -» rt 2 296 297 294, 296: R = CI-(CH2)3 ; R' = Me 295, 297: R = TBS-C=C-(CH2)3 ; R' = Et 294 295 Scheme 46 The acyclic aldehydes 287, 291, and 292 contain a range of functional groups including a primary chloride (291), a silyl protected alcohol (287) and a silyl protected terminal alkyne (292), while the cyclic aldehydes 276, 277 and 282 are of varying ring size (5 to 7 membered rings). H R CHO SnMe3 287 R = TBSO-(CH2)4 291 R = CI-(CH2)3 292 R = TBS-C=C-(CH2)3 R 1 V X H 0 T R ^ S n M e 3 275 ^ ^ C H O SnMe3 276 n =1 277 n = 2 282 n = 3 These substrates provide a diverse collection of interestingly substituted P-trimethylstannyl a,P-unsaturated aldehydes of general structure 275 on which to test the scope and hmitations of the proposed annulation method. 130 4.4 Preparation of 2-(trimetfaylstannyl)allyllithium (271) SnMe3 MeLi-LiBr, THF, -78 °C • ' »> SnMe3 ^ k s / S n M e 3 183 271 (69) The generation of 2-(trimethylstannyl)allyllithium (271) from 2,3-bis(trimethyl-stannyl)propene (183) was achieved by the method previously described in connection with the preparation of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide. Thus, treatment of 183 with a solution of methyllithium-lithium bromide complex (1 equiv) in T H F at low temperature provided 2-(trimethylstannyl)allyllithium (271) (equation 69). Evidence for the successful generation of 271 came from the reaction of this reagent with aldehydes 276, 277, 282, 287, 291, and 292 (vide infra). A report by Mi tche l l 1 2 8 indicated that transmetalation of the allylic Me3Sn group in 183 using methyllithium and subsequent reaction of 271 with a variety of electrophiles gave synthetically poor yields of products (equation 70, Table 13). However, in our studies on the preparation of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) and its conjugate addition reaction with oc,P-unsaturated ketones and aldehydes, excellent yields were obtained (vide supra, chapter 2 and 3). Table 13 Lithiodestannylation of 2,3-Bis(trimethylstannyl)propene (183) and Reaction of the Resultant 2-(Trimethylstannyl)allyllithium (271) with Electrophiles 1 2 8 SnMeo SnMe3 JJS^ 1 ) M 6 U ' T H F ' - 7 8° C • A / E ™ ' 2) electrophile,-78 °C->rt ' 183 272 Entry Electrophile E Isolated Yield (%) 1 H 2 0 H 30 2 Me2S04 Me 42 3 M e 3 S i C l M e 3 S i 64 4 M e 2 C O M e 2 C ( O H ) 38 5 PhCOMe PhC(OH)Me 41 6 M e C H O MeCH(OH) 44 7 E t C H O EtCH(OH) 47 8 P h C H O PhCH(OH) 48 4.5 Reaction of 2-(trimethvlstannvl)allvllithium (271) with the aldehydes 276. 277. 282. 287. 291. and 292 299 R = CI-(CH2)3 302 n = 1 300 R = TBSO-(CH2)4 303 n = 2 301 R = TBS-C=C-(CH2)3 304 n = 3 Addition of the aldehyde substrates 291, 287, 292, 276, 277, and 282 to cold solutions of 2-(trimethylstannyl)allyllithium (271) in dry T H F provided the alcohols, 299-304 respectively, in excellent yields (equation 71). The results are summarized in Table 14. Table 14 Synthesis of the Alcohols 299-304 R 2 \ ^ ^ , , ^ 1)271, THF,-78 °C MeoSn CHO 2) NH4CI-NH4OH H 20 (pH 8) R, Me3Sn OH SnMe3 (71) Entry Substrate R i R2 Product % Yielda 1 291 H C1- (CH 2 ) 3 - 299 93 2 287 H T B S O - ( C H 2 ) 4 - 300 94 3 292 H T B S - C = C - ( C H 2 ) 3 - 301 91 4 276 - ( C H 2 ) 3 - 302 94 5 277 - ( C H 2 ) 4 - 303 94 6 282 - ( C H 2 ) 5 - 304 89 a Isolated yields of purified products. For example, when (Z)-6-chloro-3-trimethylstannylhex-2-enal (291) was added to a cold (-78 ° C ) solution of 271 in T H F , after only 20 minutes T L C analysis of the reaction mixture indicated complete consumption of the aldehyde. Upon aqueous workup and purification by silica gel chromatography, the alcohol 299 was isolated in 93% yield (Table 14, entry 1). A l l of the product alcohols 299-304 were acid sensitive, but the cyclic substrates were especially so due to their reduced conformational mobility with respect to their acyclic counterparts. Monodestannylation was observed during silica gel chromatography; the cyclic substrates selectively lose the trimethylstannyl group bound to me ring alkene while the acyclic substrates preferentially lose the trimethylstannyl group bound to carbon-6. Interestingly, the terminal alkenyltrimethylstannyl moiety was quite stable and no destannylation at this position was observed. Destannylation could be minimized through deactivation of the silica gel by adding triethylamine (1%) to the solvent system. The structures assigned to the alcohols 299-304 were confirmed by spectroscopic data. For instance, the IR spectrum of 299 showed a strong O - H stretching absorption at 3558 c m - 1 and a tin-methyl rocking absorption at 770 c m - 1 . The * H nmr spectrum of 299 indicated the presence of two Me3Sn groups (two 9-proton singlets with satellite peaks due to tin-proton coupling at 8 0.15, 2Jsn-H = 54 Hz, and 8 0.16, 2/sn-H = 54 Hz), an hydroxyl group (a 1-proton doublet at 8 1.63, J = 2.5 Hz, which exchanges with D2O), two methylene groups (a 2-proton triplet at 8 3.49, J = 6.5 Hz, and a 2-proton multiplet centered at 8 1.78), four allylic protons (a 3-proton multiplet centered at 8 2.35 and a 1-proton doublet of doublets, with satellite peaks due to tin - proton coupling at 8 2.57, J = 14, 4 Hz , 3 /sn-H = 54 Hz), an hydroxymethine proton (a 1-proton multiplet centered at 8 4.05), and three alkenyl protons (two mutually coupled 1-proton doublets with satellite peaks due to tin - proton coupling at 8 5.35, J = 2.5 Hz, 3/sn-H = 68 Hz , and 8 5.77, J = 2.5 Hz, 37sn-H = 146 Hz, and a 1-proton doublet with satellite peaks due to tin - proton coupling at 8 6.06, J = 6.5 Hz, 37sn-H =137 Hz). The geometry of the internal alkene was unaffected in the reaction and was established as Z by the magnitude of the tin-proton coupling constant 1 8 2 (3/sn-H =137 Hz) between the alkenyl proton (H-5) and the tin atom attached to carbon six. The 1 3 C nmr spectrum of 299 contained the expected 11 signals. The characteristic resonances displayed include the four alkenyl signals at 8 129.0, 142.5, 145.1, and 151.9, the carbinol signal at 8 71.5, and the signals for the two Me3Sn groups at 8 -7.2 and 8 -9.0. In addition to this spectral data, the molecular formula of 299 was confirmed by the high resolution mass spectrometric measurement on the ( M + - Me) fragment. The structural assignments of the remaining alcohols 300-304 were based on spectral data (*H nmr, 1 3 C nmr, and IR) and their molecular formulae also were confirmed by high resolution mass spectrometric measurements on the ( M + - Me) fragment. While the acyclic alcohols 300 and 301 contained three alkenyl protons, the cyclic alcohols 302-304 contained two, and the nmr spectra of these compounds reflected this structural difference. In summary, 2-(trimethylstannyl)allyllithium (271) can be prepared efficiently from 2,3-bis(trimethylstannyl)propene (183) by treatment with methyllithium. Furthermore, 271 reacts with electrophilic species, such as the aldehydes 291, 287, 292, 276, 277, and 282, and provides the corresponding products (299-304) in excellent synthetic yields (equation 71). 4.6 Attempted copperfD chloride-mediated cyclizations of alcohols 302 and 303 302 n = 1 305 n = 1 303 n = 2 306 n = 2 Attempts to effect the intramolecular copper(I) chloride-mediate coupl ing 1 7 4 of the alkenyltrimethylstannane moieties in the alcohols 302 and 303 were unsuccessful (equation 72). When 302 was treated with 5 equivalents of copper(I) chloride in warm (60 °C) D M F , after appropriate workup, not only was none of the cyclized adduct 305 detected, a poor mass balance was obtained. Similarly, treatment of 303 with 5 equivalents of copper(I) chloride D M F , at room temperature, did not provide any of the cyclized adduct 306. Apparently, the presence of an allylic alcohol not only inhibits the coupling reaction, but also promotes decomposition of the substrate. Previous studies 1 7 2 b on the intermolecular copper(I) chloride coupling of alkenyltrialkylstannane substrates containing an hydroxyl moiety at the allylic position were reported to proceed in only moderate yield (-50%). Since it was the presence of the hydroxyl moiety in the alcohols 302 and 303 that was thought to inhibit the copperfl) chloride-mediate coupling reaction of the alkenyltrimethylstannane functions, it was decided to convert the alcohols to the corresponding acetates, before repeating the copper(I) chloride-mediated coupling reactions. 4.7 Acetvlation of the alcohols 299 - 304 307 R = CI-(CH2)3 310 n = 1 312 R = SnMe3 308 R = TBSO-(CH2)4 311 n = 2 313 R = H 309R = TBS-C=C-(CH2)3 Conversion of the alcohols 299-303 into the corresponding acetates 307-311 was achieved under standard conditions 6 4 in nearly quantitative yields (equation 73). Only in the case of the alcohol 304 (Table 15, entries 6 and 7), which contains a seven membered ring, was the acetate 312 obtained in lower yield. The results of trie acetylation reactions are summarized in Table 15. For example, treatment of a solution of the alcohol 299 in methylene chloride with acetic anhydride in the presence of D M A P and triethylamine provided, after workup and silica gel chromatography, the acetate 307 in 99% yield (Table 15, entry 1). With the acyclic substrates 299-301, only short reaction times (2-4 hours) were needed to effect the conversion to the corresponding acetates 307-309; however, with the cyclic substrates 302-304, complete protection of the alcohols required a prolonged (overnight) treatment with acetic anhydride to afford the acetates 310-312. Table 15 Synthesis of the Acetates 307-312 Ri Ri R2-y^Y^^ Ac2Q, DMAP R 2 v ^ ^ \ j ^ Me3Sn OH SnMe3 Et3N, CH2CI2, rt Me3Sn OAc SnMe3 Entry Substrate R i R2 Product % Yield3 lb 299 H C1- (CH 2 ) 3 - 307 99 2b 300 H T B S O - ( C H 2 ) 4 - 308 100 3b 301 H T B S - C = C - ( C H 2 ) 3 - 309 98 4b 302 -(CH 2 )3- 310 99 5b 303 - ( C H 2 ) 4 - 311 97 6b 304 - ( C H 2 ) 5 - 312 (313) 54 c (44)d 7 e 304 - ( C H 2 ) 5 - 312 62 (77)f a Isolated yield of purified products. b General Procedure D ( A c 2 0 , D M A P , Et3N, C H 2 C 1 2 , rt) was employed. c Yield of 312. d Yield of destannylated material 313. e Alternative reaction conditions ( L D A , T H F , 0 °C; A c 2 0 , rt) were employed. f Yield based on recovered starting material 304. While the acetates 307-311 were prepared easily and in high yields from the corresponding alcohols, preparation of the acetate 312 in good yield was not as straightforward. Treatment of a solution of the alcohol 304 in methylene chloride with acetic anhydride in the presence of D M A P and triethylamine provided the expected acetate 312 in 54% yield, as well as the monodestannylated acetate 313 in 44% yield (Table 15, entry 6). The difference in reactivity of 304, as compared with the other cyclic substrates (302 and 303), deserves comment. A n examination of molecular models indicates that in the 5 and 6 membered ring systems (alcohols 302 and 303), the stabilizing influence of tin-oxygen coordination would be offset by the angle strain that would result, but in the 7 membered ring case (alcohol 304) tin-oxygen coordination gives a relatively strain free system (Scheme 47). A proposed mechanism for the protiodestannylation-acetylation of 304 is shown in Scheme 47. Protonation of the internal alkene provides a tertiary cation (314) which is stabilized by the (S-tin a tom. 1 0 4 B y contrast, protonation of the terminal carbon-carbon double bond in the same manner would result in the formation of a primary cation and is not observed. The tin-oxygen coordination 1 8 0 could aid in the protiodestannylation of 304, to provide the trimethylstannyl ether 315, which is then subsequently acylated to provide 313 (Scheme 47). Thus, it is the distance between the alcohol oxygen and the tin atom of the alkenyltrimethylstannyl moiety on the ring that is believed to be responsible for this reactivity. A similar mechanism could rationalize the destannylation of the alcohols 299 -304 which occurred during silica gel chromatography. Other reaction conditions to effect acetylation of 304, while suppressing the unwanted destannylation reaction, were investigated. After much experimentation, it was found that generation of the lithium alkoxide of 304 using a strong base ( L D A ) followed by addition of acetic anhydride, prevented the destannylation reaction and gave only 312. Unfortunately, conditions could not be found such that the reaction would go to completion with high yields of 312. When short reaction times (2 hours) were allowed for trapping the alkoxide with acetic anhydride, some of the starting alcohol 304 was always recovered (20%) along with the acetate 312 in 62% isolated yield (Table 15, entry 7). Prolonged reaction times (overnight), resulted in a poor mass balance and low yield (~50%), although no starting material was then recovered. The acetates 307-312 were found to be more stable to acidic conditions than the corresponding alcohols. While the alcohols 299-304 monodestannylated when chromatographed on silica gel without the addition of triethylamine to the solvent system, the acetates destannylated only upon prolonged exposure to silica gel during chromatography. The acyclic acetates 307-309 could easily be purified by silica gel chromatography without the addition of triethylamine to the solvent system. The cyclic acetatea 310-312, however, were slightly more acid sensitive than the acyclic acetates (307-309) and their purification by silica gel chromatography required the addition of triethylamine (1%) to the solvent system to prevent destannylation. The structural assignments for compounds 307-313 were supported by their spectral data. For instance, the IR spectrum of 307 indicated the presence of an acetoxy moiety by strong stretching absorptions at 1740 c m - 1 (C=0) and 1240 c m - 1 (C-O), and the presence of the Me3Sn group by a tin-methyl rocking absorption at 774 c m - 1 . The * H nmr spectrum of 307 displayed the expected signals for two trimethylstannyl groups (two 9-proton singlets, with satellite peaks due to tin - proton coupling, at 8 0.13, 2 / s n - H = 53 Hz, and 8 0.21, 2 / s n - H = 53 Hz) and an acetate moiety (a 3-proton singlet at 8 1.98). Other notable features in the *H nmr spectrum of 307 include resonances for three alkenyl protons with satellite peaks due to tin-proton coupling at 8 5.92 (a 1-proton doublet, J = 9 Hz , 3 / s n - H = 134 Hz), 8 5.70 (a 1-proton doublet, J = 2.5 Hz, 3 7 S n-H = 147 Hz), and 8 5.28 (a 1-proton doublet, J = 2.5 Hz, 3 / s n - H = 71 Hz), a methine proton at 8 5.16 (a 1-proton signal with coupling to three other protons, J = 9, 7, 5 Hz), four allylic protons at 8 2.57 (a 1-proton doublet of doublets, J = 14, 7 Hz), 8 2.53 (a 1-proton doublet of doublets, J = 14, 5 Hz), and 8 2.35 (a 2-proton triplet, J = 7 Hz, 37sn-H = 50 Hz), and two other methylene groups at 8 3.46 (a 2-proton triplet, J = 6.5 Hz) and 8 1.77 (a 2-proton multiplet). The 1 3 C nmr spectrum of 307 contained the expected 13 signals. Characteristic resonances exhibited were the four alkenyl carbon signals at 8 128.8, 139.6, 147.6, and 150.0, the methine carbon signal at 8 76.0, the acetoxy methyl and carbonyl signals at 8 21.5 and 8 170.0, respectively, and the signals for the two Me3Sn groups at 8 -7.9 and 8 -8.9. In addition to this spectral data, the molecular formula of 307 was confirmed by the high resolution mass spectrometric measurement on the ( M + - Me) fragment. A similar analysis of the spectral data (^H nmr, 1 3 C nmr, and IR) was performed to assign the structures of 308-313, and their molecular formulae also were confirmed by high resolution mass spectrometric measurement on the ( M + - Me) fragment. While the * H nmr spectra of the acetates 308-312 displayed two signals for the Me3Sn moieties, the monodestannylated acetate 313 exhibited only one 9-proton singlet. Upon examination of the alkenyl regions of the * H nmr spectra of 312 and 313, compound 312 was seen to possess two mutually coupled alkenyl protons, while compound 313 showed two mutually coupled alkenyl protons along with an additional alkenyl proton. 4.8 CoppertT) chloride-mediated cyclization of the acetates 307-312 OAc OAc OAc OAc CI 316 319 320 321 OAc OAc TBSO TBS 317 318 Having prepared a variety of bis(alkenyltrimethylstannanes) containing diverse functionality, we were ready to attempt the intramolecular copper(I) chloride-mediated c o u p l i n g 1 7 4 of the two alkenyltrimethylstannane functions. Our hypothesis as to the deleterious effect of the hydroxyl function in the coupling reaction of alcohols 302 and 303 proved to be correct. Treatment of the acetates 307-312 with ~5 equivalents copper(I) chloride in warm D M F for 15 minutes provided the cyclized adducts 316-321 in moderate to good yields (Table 16, equation 74). For example, a solution of 307 in D M F was added to a warm (60 ° C ) slurry of copper(I) chloride in D M F . After 15 minutes, an analysis by T L C showed the disappearance of the starting material and the formation of a new product. Following aqueous workup and silica gel chromatography, the cyclized adduct 316 was isolated in 86% yield (Table 16, entry 1). In the cases where the products are relatively unstrained (Table 16, entries 1, 2, 3, and 5), good yields were obtained. However, in the cyclization of 310 (Table 16, entry 4), angle and torsional strain in the cyclized adduct 319 is thought to result in a lower product yield. With the conformationally less rigid seven membered ring system 312 (Table 16, entries 6 and 7), lower yields of the cyclized system 321 were also obtained. Table 16 Copper(I) Chloride-Mediated Cyclization of 307-312 R ^ j s ^ ^ ^ ^ . 1) CuCl, DMF, 60 °C Me-: OAc Sn OAc SnMe, 2) NH4C. H 20 (74) Entry Substrate R i R 2 Product % Yield* lb 307 H C1- (CH 2 ) 3 - 316 86 2b 308 H T B S O - ( C H 2 ) 4 - 317 79 3b 309 H T B S - C = C - ( C H 2 ) 3 - 318 86 4b 310 -(CH 2 )3- 319 67 5b 311 - ( C H 2 ) 4 - 320 82 6b 312 - ( C H 2 ) 5 - 321 42 7 c 312 - ( C H 2 ) 5 - 321 66 a Isolated yield of purified products. b General Procedure E (~5 equivalents C u C l , D M F , 60 °C) was employed. c Alternative reaction conditions (~5 equivalents C u C l , D M F , 0 °C) were employed. The structures of the cyclized products 316-321 were assigned by analysis of the spectroscopic data. For instance, the IR spectrum of 316 showed the presence of an acetoxy moiety by strong stretching absorptions at 1729 c m - 1 (C=0) and 1240 c m - 1 (C-O), and two alkenyl moieties by stretching absorptions at 1639 c m - 1 and 1618 c m - 1 . Further evidence for the success of the cyclization by the coupling of the two alkenyltrimethylstannyl functions was seen in the l H nmr spectrum of 316. The two 9-proton singlets (attributed to the trimethylstannyl moieties) at high field had disappeared and there was no evidence of tin-proton coupling in any of the signals in the spectrum. The * H nmr spectrum displayed resonances for the three alkenyl protons at 8 5.91 (a 1-proton singlet), 8 4.98 (a 1-proton doublet of doublets J = 2,2 Hz), and 8 4.90 (a 1-proton doublet, 7 = 2 Hz), an allylic methine proton at 8 5.63 (a 1-proton doublet, 7 = 7 Hz), four allylic methylene protons at 8 3.00 (a 1-proton doublet of doublet of triplets, 7 = 17, 7, 2 Hz), 8 2.50 (a 1-proton doublet of doublets, J = 17, 2 Hz), and 8 2.36 (a 2-proton triplet, 7 = 8 Hz), two other methylene groups at 8 2.00 (a 2-proton multiplet) and 8 3.55 (a 2-proton triplet, J = 6.5 Hz), and an acetoxy methyl group at 8 2.01 (a 3-proton singlet). The 1 3 C nmr spectrum of 316 contained the expected 11 signals. Characteristic resonances displayed were the four alkenyl carbon signals at 8 103.7, 131.3, 148.5, and 149.7, the methine carbon signal at 8 76.2, and the acetoxy methyl and carbonyl signals at 8 21.2 and 8 170.9, respectively. In addition to these spectral data, the molecular formula of 316 was confirmed by high resolution mass spectrometric measurement on the molecular ion. The structures of the other cyclized adducts 317-321 were assigned by a similar analysis of their respective nmr (*H and 1 3 C ) and IR spectra, and their molecular formulae also were confirmed by their high resolution mass spectra. Examination of the yields for the copper(I) chloride-mediated coupling reactions (Table 16) reveals that the cyclization proceeded in lower yield for substrate 310 than for 307-309 and 311. Cyclization of 312 under standard conditions also proceeded in poor yield (42%) and gave a poor mass balance (Table 16, entry 6). When the latter cyclization was attempted at a lower temperature (0 °C) , conditions which have been employed in the intermolecular homocoupling of alkenyltrimethylstannanes,1 8 3 a superior, although still modest yield (66%), was obtained (Table 16, entry 7). Examination of molecular models revealed possible reasons for the lower yields of 319 and 321 compared with 320. The cyclized adduct 319, 2-acetoxy-4-methylene-bicyclo[3.3.0]oct-l(5)-ene, has greater angle strain than compounds 316-318 and 320. In addition, the conformational rigidity of 319 precludes relief of torsional strain by ring puckering. 1 8 4 In contrast, cyclization of 312 may be hindered by an intramolecular tin -oxygen coordination. Coordination of the two tin atoms to the carbinol oxygen provides a tricyclic chelate system in 312, containing a seven member ring and two five member rings with a low degree of angle strain. This relatively unstrained system appears not only to disfavor the intramolecular copper(I) chloride-mediated coupling reaction, but may also promote the decomposition of 312, leading to the poor product yields and low mass balance observed for this conversion. 312 Tin-oxygen chelation of this type, between an alkenyltrimethylstannane and an oxygen held in close proximity, has been shown 1 5 4 to affect the normal reactivity of these compounds, particularly in halodestannylation reactions. In these cases, alkyl groups are cleaved from the tin atom in preference to the alkenyl moiety. A similar mechanism may be affecting the tin-copper transmetalation in compound 312. The fused bicyclic compounds 319 and 321 may be particularly susceptible to further reactions once formed. The reaction of a diene system containing an allylic leaving group (acetate) with potential nucleophiles such as chloride ion (from CuCl) , could produce the reactive cyclopentadienyl system by a 1,5 addition. Cyclopentadienes are known substrates for reactions such as polymerization and Diels-Alder cycloadditions. 1 8 5 Thus, further reaction or decomposition of the products (319 and 321) cannot be discounted as an explanation of the low mass balance. 4.9 Conclusions The reaction of methyllithium with 2,3-bis(trimethylstannyl)propene (183) provides 2-(trimethylstannyl)allyllithium (271) , 1 2 8 which was shown to react with electrophilic species in high yields. The synthetic usefulness of 271 was shown in the development of a new methylenecyclopentene annulation sequence. This method involves addition of 271 to P-trimethylstannyl a,P-unsaturated aldehydes (275), followed by protection of the resultant alcohols as the corresponding acetates 274. The key reaction in the cyclization is a copper(I) chloride mediated intramolecular coupling of the two alkenyltrimethylstannane moieties in 274 to provide 273 (Scheme 48). SnMe3 SnMe3 183 271 275 274 CuCl DMF, 60 °C OAc 273 Scheme 48 The annulation method makes use of procedures previously developed in our laboratories for the preparation of configurationally defined P-trimethylstannyl a,p-unsaturated aldehydes and esters, and shows an interesting synthetic use of 2,3-bis(trimethylstannyl)propene (183) and the corresponding 2-(trimethylstannyl)-allyllithium (271). Also illustrated is a further extension of the copper(I) chloride mediated intramolecular coupling reactions of two alkenyltrimethylstannane functions, 1 7 4 effecting the closure of 5-membered rings. A variety of functional groups are tolerated in this cyclization procedure, providing novel monocyclic and bicyclic products of general structure 273, containing highly substituted cyclopentenyl systems. III. C O N C L U S I O N S GeMe3 M SnMe3 35 162 M = GeMe3 271 182 M = SnMe3 •The use of four bifunctional organometallic reagents in annulation sequences has been described in this thesis. Two of these reagents, 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide 1 2 9 (162) and 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide 1 2 9 (182) are novel, and were prepared for the first time during our studies of annulation sequences, while the other two reagents, 35 1 1 and 271 , 1 2 8 had been prepared previously. 162 or 182 Me3SiBr % T M ( 7 5 ) T H F , -78 ° C 191 M = GeMe3 192 M = SnMe3 Michael addition of a functionalized allylic group to a variety of a,|3-unsaturated ketones of general structure 30 can be effected in synthetically useful yields using the allylcopper(I) reagents 162 and 182 in the presence of trimethylsilyl bromide (equation 75) . 1 2 9 The conjugate addition products 191 and 192 contain the structurally interesting 8,e-unsaturated carbonyl moiety, functionalized with a synthetically useful group in the 8-position. 0 191 NIS O 192 Scheme 49 Several potential uses of the conjugate addition products 191 and 192 can be envisaged (Scheme 49). Both 191 and 192 could be converted into the corresponding iodide 322 by treatment with either iodine or AModosuccinimide. 1 8 6 The alkenyl iodides 322, as well as the alkenyl(trimethylstannane) 192, could also be ready sources of the corresponding alkenyllithium 323 via metalation with an alkyllithium ( R L i ) . 1 8 7 If the carbonyl function were protected prior to the lithiation, the alkenyllithium 323 could be reacted with a variety of electrophilic species . 1 8 8 If the carbonyl of 323 were not protected, the alkenylhthium would likely react in either an inter- or intramolecular fashion with the carbonyl function. The alkenyl iodide 322 and the alkenyl(trimethylstannane) 192 could also be used in transition metal catalyzed coupling reactions, such as the Stille cross coupling reaction, 1 2 7 to provide 324. A new method for the stereoselective synthesis of functionalized trans-fused bicyclo[x.3.0]alkanes (x = 3, 4) was developed (Scheme 50). 6 9 Reagents 162 and 182 are the synthetic equivalent of the d 2 , d 3 prop-l-ene synthon (48), and reagent 35 is the synthetic equivalent of the d 2 , d 4 but-l-ene synthon (39). In this capacity, these reagents have been used in annulation reactions with cyclopent-l-enecarbaldehydes (44) to yield products with the angular hydrogens at the newly formed ring junction bearing a trans-relationship. The use of either 162 or 182 yields the trans-fused bicyclo[3.3.0]octane ring M Scheme 50 149 system 325 while use of 35 yields the trans-fused bicyclo[4.3.0]nonane ring system 326. Thus, starting with a cyclopentanone system (56), the trans-fused bicyclic products 327 and 58 can be produced stereoselectively. Clearly this new methodology could be employed in a wide variety of synthetic contexts which required the stereocontrolled construction of trans-fused bicyclic systems. In principle, similar strategies could be developed to prepare trans-fused bicyclic systems other than the bicyclo[3.3.0]octane and bicyclo[4.3.0]nonane systems by varying the size of the cyclic ketone starting material, or by using a higher homologue of the bifunctional reagent 35. These changes would generalize the annulation method so that any tams-fused bicyclo[x.y.O]alkane system (x > y > 3) could be constructed. The synthetic utility of 2-(trimethylstannyl)allyllithium (271) was also demonstrated in a method for the preparation of highly functionalized cyclopentenyl systems (equation 76). Suitable P-trimethylstannyl a,P-unsaturated aldehydes of general structure 275 were combined with 271 in excellent yields. The key step in this annulation sequence utilized a novel intramolecular copper(I) chloride-mediated coupling of two alkenyltrimethylstannane moieties under mild conditions to give the cyclopentenyl systems 273. A variety of functional groups can be tolerated in this annulation procedure, providing usefully functionalized cyclopentenyl systems 273. SnMe3 O OAc 2) A c 2 0 3) CuCl 271 (76) 275 273 The aforementioned annulation method could conceivably be used in the total synthesis of naturally occurring products. Several prostaglandins, such as P G E i , have a carbocyclic framework similar to that of 2 7 3 . 1 8 9 Thus, this annulation sequence could allow rapid access into the prostaglandin family of compounds. I V . E X P E R I M E N T A L 1. General 1.1 Data acquisition, presentation and techniques Proton nuclear magnetic resonance (*H nmr) spectra were recorded on a Bruker model WH-400 (400 M H z ) or A M X - 5 0 0 (500.2 M H z ) spectrometer using deuterio-chloroform (CDCI3) or hexadeuteriobenzene (C6D6) as the solvent. CDCI3 and C6D6 were passed through a short column of dry activated basic aluminum oxide, which had been dried in an oven (-140 °C) overnight and then allowed to cool in a desiccator prior to use. Signal positions (8) are given in parts per million from tetramethylsilane (8 0) and were measured relative to the signal of chloroform (8 7.24) or benzene (8 7.15). Coupling constants (7 values) are given in Hertz (Hz) and are reported to the nearest 0.5 Hz. The tin-proton coupling constants (7sn-H) are given as an average of the 1 1 7 S n and 1 1 9 S n values. The multiplicity, number of protons, coupling constants and assignments (where known) are given in parentheses following the chemical shift. Abbreviations used are: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. In the * H nmr spectra, H-x and H-x' have been used to designate protons on the same carbon, with H-x' being the proton resonating at lower field. In some cases, the proton assignments were supported by two-dimensional ( i H ^ H ) - homonuclear correlation spectroscopy (COSY) , which was carried out using a Bruker WH-400 spectrometer. Carbon nuclear magnetic resonance ( 1 3 C nmr) spectra were recorded on a Varian model XL-300 (75.3 M H z ) spectrometer or on Bruker models A C - 2 0 0 E (50.3 M H z ) or A M X - 5 0 0 (125.8 M H z ) spectrometers using deuteriochloroform (CDCI3) or hexadeuterio-benzene (C6D6) as the solvent. Signal positions (8) are given in parts per million from tetramethylsilane and were measured relative to the signal of deuteriochloroform (8 77.0) or hexadeuteriobenzene (8 128.0). Attached proton tests (APTs), used to differentiate methyl and methine carbons (negative phase signals) from methylene and quaternary carbons (positivie phase signals), were recorded on a Varian XL-300 or Bruker AC-200E spectrometers. Where A P T data is given, signals with negative phases are so indicated in brackets (-ve) following the 1 3 C nmr chemical shifts. In some cases, the proton and carbon assignments were supported by two-dimensional ^ H ^ C ) - heteronuclear multiple quantum coherence experiments ( H M Q C ) and heteronuclear multiple bond correlation experiments ( H M B C ) , which were carried out using a Bruker A M X - 5 0 0 spectrometer. Infrared (IR) spectra were recorded on a Perkin Elmer 1710 Fourier transform spectrophotometer with internal calibration as films between sodium chloride plates (liquid samples) or as potassium bromide pellets (solid samples). Only selected characteristic absorption data are provided for each compound. Low and high resolution mass spectra were recorded on a Kratos M S 80 or on a Kratos Concept II H Q mass spectrometer using an electron impact source. The molecular ion ( M + ) masses are given unless otherwise noted. For some of the compounds containing the trimethylstannyl (Me3Sn), trimethylgermyl (Me3Ge), trimethylsilyl (Me3Si), or ferr-butyldimethylsilyl (f-BuMe2Si) moiety, the high resolution mass spectrometry molecular mass determinations were based on the ( M + - Me) peak. Gas-liquid chromatography-mass spectrometry ( G L C M S ) was performed on a Carlo Erba model 4160 capillary gas chromatograph (15 m x 0.25 m fused silica column coated with DB-5) and a Kratos/RFA M S 80 mass spectrometer. A l l compounds subjected to high resolution mass measurements were homogeneous by G L C and/or T L C analyses. Elemental analyses were performed on a Carlo Erba C H N model 1106 or on a Fisons E A model 1108 elemental analyzer, by the U B C Microanalytical Laboratory. Melting points (mp) were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures (air baths), which refer to bulb-to-bulb (Kugelrohr) distillations, are uncorrected. Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon using glassware that had been oven (-140 °C) dried and/or flame dried. Glass syringes, stainless steel needles, and T e f l o n ® cannulae used to handle various anhydrous solvents and reagents were oven dried and flushed with argon prior to use. Plastic syringes were flushed with argon prior to use. Gas-tight microliter syringes (Hamilton series 1700) were dried under reduced pressure (vacuum pump), stored in a desiccator and flushed with argon prior to use. The small and large bore T e f l o n ® cannulae were purchased from Canlab and have the following dimensions: the small cannulae has an inner diameter of 0.38 mm and a wall thickness of 0.23 mm; the large cannulae has an inner diameter of 0.97 mm and a wall thickness of 0.30 mm. Thin layer chromatography ( T L C ) was performed using commercial aluminum-backed silica gel 60 F 2 5 4 plates (E. Merck, type 5554, thickness 0.2 mm). Visualization of the chromatograms was accomplished using ultraviolet light (254 nm) and/or iodine (iodine which had been adsorbed onto unbound silica gel) followed by heating the plate after staining with one of the following solutions: (a) vanillin in a sulfuric acid-EtOH mixture (6% vanillin w/v, 4% sulfuric acid v/v, and 10% water v/v in EtOH), (b) phosphomolybdic acid in E t O H (20% phosphomolybdic acid w/v, Aldrich), (c) anisaldehyde in a sulfuric acid-EtOH mixture (5% anisaldehyde v/v and 5% sulfuric acid v/v in EtOH) . Flash chromatography 1 9 0 was performed using 230-400 mesh silica gel (E. Merck, Silica Gel 60), following the technique describe by Still. Short column chromatography, 1 9 1 using T L C grade silica gel, was performed using Sigma type H silica gel 10-40 pm, no binder, following the technique described by Taber. Radial chromatography 1 9 2 was carried out on a Chromatotron® Model 7924 using 1, 2, or 4 mm thick radial plates coated with silica gel (silica gel 60, P F 2 5 4 , with Gypsum, E . Merck #7749). Gas-liquid chromatography ( G L C ) was performed on Hewlett-Packard models 5880A and 5890 gas chromatographs, both equipped with flame ionization detectors and fused silica columns (Hewlett-Packard HP-5), -25 m x 0.20 mm coated with 5% phenylmethylsilicone. Concentration, evaporation or removal of solvent under reduced pressure (water aspirator) refers to solvent removal via a Buchi rotary evaporator at - 15 Torr. Cold temperatures were maintained by the use of the following baths: 0 ° C , ice-water; -20 ° C , -35 ° C , -48 ° C , aqueous calcium chloride-dry ice (27, 39, and 47 g C a C i y i O O m L H 2 0 , respectively); 1" -78 ° C , acetone-dry ice; -98 ° C , methanol-liquid nitrogen. 1.2 Solvents and reagents A l l solvents and reagents were purified, dried, and/or distilled using standard procedures. 1 9 4 Benzene and dichloromethane were distilled from calcium hydride. Diethyl ether and tetrahydrofuran were distilled from sodium benzophenone ketyl. The four aforementioned solvents were distilled under an atmosphere of dry argon and used immediately. Diglyme was distilled from sodium benzophenone ketyl and stored over sodium borohydride. Triethylamine, diisopropylamine, dimethylsulfoxide ( D M S O ) , and hexamethylphosphoroamide ( H M P A ) were distilled from calcium hydride. Magnesium was added to methanol and, after refluxing the mixture, the methanol was distilled from the resulting solution of magnesium methoxide. Acetic anhydride was refluxed over and then distilled from phosphorous pentoxide. A^N-Dimethylforamide (DMF) was sequentially dried over 3 A molecular sieves. 1 9 5 The aforementioned reagents were stored under an atmosphere of argon in bottles sealed with a Sure/Seal (Aldrich Chemical Co. , Inc.). Petroleum ether refers to a hydrocarbon mixture with a boiling range of 35-60 ° C . Solutions of methyllithium (both as a complex with lithium bromide (MeLi»LiBr) and halide free (MeLi) forms) in diethyl ether, n-butyllithium in hexanes, and fm-butyl l i thium in pentane were obtained from Aldrich Chemical C o . , Inc. and standardized using the procedure of Kofron and Baclawski . 1 9 6 p-Toluenesulfonyl chloride was purified by the method described by Pelletier, 1 9 7 dried (vacuum pump), and stored under an atmosphere of dry argon. Copper(I) bromide-dimethyl sulfide complex was prepared by the method described by W u t s 1 2 5 (by Rene Lemieux of Dr. Piers' research group at U B C ) and was stored in a desiccator under an atmosphere of dry argon. Copper(I) chloride (99.995%+ or 99%+), copper(I) cyanide, and phenylthiocopper(I) were purchased from Aldrich Chemical Co. , Inc., and were used without further purification. Trimethylsilyl bromide (Me3SiBr) and trimethylgermanium bromide (MesGeBr) (obtained from Organometallics Inc.) were distilled, bulb-to-bulb, from calcium hydride using a Kugelrohr distillation apparatus and were used immediately. Hexamemylditin and trimethyltin chloride were obtained from Organometallics Inc. and Aldrich Chemical Co. , Inc., respectively, and were used without further purification. Tetrakis(triphenylphosphine)palladium(0) was obtained from Aldrich Chemical Co. , Inc. and was used without further purification. Chromium(II) chloride was obtained from Alfa Products and was used without further purification. Nickel(II) chloride was prepared from nickel(II) chloride hexahydrate (NiCi2*6H 2 0) using the procedure described by P r a y . 1 9 8 Samarium(II) iodide (0.1 M solution in T H F ) was prepared by the procedure described by K a g a n 1 9 9 (by Todd Schindeler of Dr. Piers' research group at U B C ) from samarium powder (obtained from Cerac Incorporated) and diiodomethane. Lithium diisopropylamide ( L D A ) was prepared by the addition of a solution of n-butyllithium (1 equiv) in hexanes to a solution of dry diisopropylamine (1.1 equiv) in dry tetrahydrofuran at 0 ° C . The resulting colorless solution was then stirred at 0 ° C for 15 minutes prior to use. Potassium hydride was obtained as a 35% suspension in mineral oil from Aldrich Chemical Co, . Inc. and was rinsed free of oil with dry diethyl ether under a stream of dry argon and dried (vacuum pump) prior to use. A solution of sodium methoxide (NaOMe) in dry methanol (MeOH) was prepared in the following manner: to a cold (-78 °C) flask containing dry sodium hydride (NaH) was added the appropriate amount of dry methanol. The flask was warmed to room temperature and the solution was used immediately. A l l other reagents are commercially available and were used without further purification. Aqueous ammonium chloride-ammonium hydroxide (NH4CI-NH4OH) (pH 8) was prepared by the addition of ~50 m L of concentrated aqueous ammonium hydroxide to 950 m L of a saturated aqueous ammonium chloride solution. Aqueous ammonium chloride-ammonium hydroxide (NH4CI-NH4OH) (pH 7) was prepared by the addition of ~5 m L of concentrated aqueous ammonium hydroxide to ~1 L of a saturated aqueous ammonium chloride solution. 2. Trans-Fused Bicyclo[4.3.0]nonane R i n g Systems Preparation of the triflate 6730 H •0 0 H 67 To a cold (-78 ° C ) , stirred solution of L D A (42.5 mmol, 1.1 equiv) in dry T H F (130 mL) was added cw-bicyclo[3.3.0]octane-3,7-dione mono-2,2-dimethyl-propylene ketal 6128 (8.47 g, 37.8 mmol) as a solution in T H F (20 mL). After 2 hours, A^-phenyltrifluoromethanesulfonimide (14.9 g, 41.6 mmol) was added as a solid and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was treated with saturated aqueous NaHCC»3 (150 mL) and diluted with Et2O (150mL) . The phases were separated, the aqueous phase was extracted with Et20 (4 x 50 mL) , and the combined organic phases were washed sequentially with water (3 x 50 mL) and brine (3 x 50 mL), dried (MgSOa), and concentrated. The crude product was purified by flash chromatography (400 g silica gel, 5:1 petroleum ether -Et20) to provide 12.2 g (90%) of the triflate 67 as a white solid. Recrystallization from hexanes - Et20 afforded the triflate as colorless crystals (mp 80 - 82 °C) . l H nmr (400 M H z , C D C 1 3 ) 8: 0.93 (s, 3H, -CH3), 0.95 (s, 3H, -CH3), 1.64-1.71 (m, 2H), 2.22-2.39 (m, 3H), 2.77-2.87 (m, 2H), 3.15-3.23 (m, 1H, allylic methine), 3.42 (s, 2H, -CH2O-), 3.44 (s, 2H, -CH2O-), 5.45 (dd, 1H, olefinic proton, 7 = 2, 2 Hz). 13C nmr (75.3 M H z , CDCI3) 8: 22.5 (-ve, 2 signals, - C H 3 ) , 30.1, 35.5 (-ve), 37.7, 38.0, 40.8, 42.6 (-ve), 71.8, 72.6, 108.1, 118.5 (q, - C F 3 , 7 = 4 Hz), 121.1 (-ve), 147.6. IR (KBr): 1662, 1416, 1206, 1143, 1110 cm" 1. Exact mass calcd for C14H19F3O5S: 356.0905; found: 356.0908. Anal, calcd for C14H19F3O5S: C 47.19, H 5.37, S 9.00; found: C 47.13, H 5.39, S 9.21. Preparation of the ester 68 To a stirred solution of P d ( O A c ) 2 (0.244 g, 1.09 mmol), P h 3 P (0.606 g, 2.31 mmol), Et3N (10 m L , 72 mmol), and M e O H (55 m L , 1.4 mol) in dry D M F (125 mL), at room temperature, was added the triflate 67 (11.9 g, 33.3 mmol). Carbon monoxide was bubbled through the solution for 30 minutes and a static atmosphere of carbon monoxide was maintained in the flask, over the reaction mixture, using a balloon filled with carbon monoxide. After 5 hours, the mixture was diluted with water (125 mL) and Et20 (250 mL) and the phases were separated. The aqueous phase was extracted with Et20 (3 x 50 mL) and the combined organic phases were washed with brine (4 x 30 mL), dried (MgS04) and concentrated. The crude product was purified by flash chromatography (155 g silica gel, 4:1 petroleum ether - Et20) to provide 7.77 g (88%) of the ester 68 as a white solid. Recrystallization from hexanes - Et20 afforded the ester as colorless needles (mp 93 - 94 °C) . H H 68 ! H nmr (400 M H z , CDCI3) 5: 0.92 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 1.55 (dd, 1H, / = 13.5, 8.5 Hz), 1.66 (dd, 1H, J = 13.5, 6.5 Hz), 2.28-2.39 (m, 3H), 2.73-2.83 (m, 2H), 3.24-3.33 (m, 1H, allylic methine), 3.38-3.50 (m, 4 H , - C H 2 O - ) , 3.70 (s, 3H, -OCH3), 6.61 (dd, 1H, olefinic proton, 7 = 2, 2 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 22.4 (-ve), 22.5 (-ve), 30.0, 37.9 (2 signals), 38.2, 40.4, 47.8 (-ve), 51.4 (-ve), 71.6, 72.7, 108.6, 134.1, 146.2 (-ve), 165.8. 1 3 C nmr (75.3 M H z , C 6 D 6 ) 8: 22.4 (-ve), 22.5 (-ve), 29.9, 38.3 (-ve), 38.6 (2 signals), 40.7, 48.2 (-ve), 50.9 (-ve), 71.6, 72.4, 108.9, 134.7, 146.1 (-ve), 165.4. IR (KBr): 1717, 1633, 1278, 1100 cm-1. Exact mass calcd for C 1 5 H 2 2 O 4 : 266.1518; found: 266.1526. Anal, calcd for C15H22O4: C 67.65, H 8.33; found: C 67.43, H 8.43. Preparation of the allylic alcohol 70 To a cold (-78 ° C ) , stirred solution of the ester 68 (4.86 g, 18.2 mmol) in dry T H F (180 mL) was added D I B A L - H (1.0 M in hexanes, 45.0 m L , 45.0 mmol). After 15 minutes, the reaction mixture was warmed to 0 ° C for an additional 15 minutes. The H H 70 reaction mixture was treated with solid ground N a 2 S O 4 » 1 0 H 2 O (4.5 g, ~0.1g/mmol D I B A L - H ) , warmed to room temperature, diluted with Et20 (180 mL), and stirred open to the air for 30 minutes. The mixture was suction filtered through C e l i t e ® (45 g) and the cake was washed with Et20 (~ 1.5 L). The solvent was removed from the filtrate under reduced pressure and the oil thus obtained was purified by flash chromatography (73 g silica gel, 2:1 petroleum ether - Et20) to provide 4.12 g (95%) of the allylic alcohol 70 as a white solid. Recrystallization from petroleum ether - Et20 afforded the allylic alcohol as colorless crystals (mp 49 - 50 °C) . ! H nmr (400 M H z , C D C 1 3 ) 6: 0.93 (s, 3H, -CH3), 0.94 (s, 3H, - C H 3 ) , 1.34 (br s, 1H, exchanges with D 2 0 , - O H ) , 1.53 (dd, 1H, J = 13, 9 Hz), 1.58 (dd, 1H, J = 13, 6 Hz), 2.08 (d, 1H, J = 16.5 Hz) , 2.26-2.35 (m, 2H), 2.57 (dd, 1H, J = 16.5, 9 Hz), 2.76 (ddddd, 1H, J = 9, 9, 9, 9, 2.5 Hz), 3.11-3.18 (m, 1H), 3.39-3.50 (m, 4 H , -CH2O-), 4.12 (br s, 2H, -CH2OH), 5.50 (br d, 1H, olefinic proton, J = 1.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 22.4 (-ve), 22.5 (-ve), 30.0, 38.1 (-ve), 39.0 (2 signals), 40.6, 47.0 (-ve), 61.9, 71.5, 72.7, 109.2, 129.0 (-ve), 142.2. 1 3 C nmr (75.3 M H z , C 6 D 6 ) 8: 22.48 (-ve), 22.53 (-ve), 30.0, 38.7 (-ve), 39.2, 39.5, 41.2, 47.6 (-ve), 61.9, 71.4, 72.7, 109.5, 128.8 (-ve), 142.9. IR (KBr): 3429, 1657, 1112 cm-1. Exact mass calcd for C14H22O3: 238.1569; found: 238.1561. Anal, calcd for C14H22O3: C 70.56, H 9.30; found: C 70.93, H 9.36. Preparation of the a . fi-unsaturated aldehyde 71 71 To a stirred slurry of P C C (6.83 g, 31.7 mmol) and C e l i t e ® (6.8 g, ~1 g/g P C C ) in dry CH2CI2 (65 mL) , at room temperature, was added the allylic alcohol 70 (3.73 g, 15.7 mmol) in CH2CI2 (15 mL). The initially bright orange slurry turned dark brown. After 1 hour, the mixture was diluted with dry Et20 (200 mL) and then was stirred for an additional hour. The mixture was suction filtered through Florisil (88 g) and the cake was washed with Et20 (~1 L) . The solvent was removed from the filtrate under reduced pressure and the solid thus obtained was purified by flash chromatography (75 g silica gel, 2:1 petroleum ether - Et20) to provide 3.17 g (86%) of the unsaturated aldehyde 71 as a white solid. Recrystallization from hexanes - Et20 afforded the unsaturated aldehyde as colorless crystals (mp 64 - 65 °C) . ! H nmr (500.2 M H z , CDCI3) 8: 0.90 (s, 3H, -CH3), 0.97 (s, 3H, -CH3), 1.58 (dd, 1H, H-2, J = 13.5, 8.5 Hz), 1.75 (dd, 1H, H-4, J = 13.5, 6 Hz), 2.29-2.37 (m, 3H, H-2', H-4' and H-8), 2.70 (dddd, 1H, H-8', J = 16.5, 8.5, 2, 2 Hz), 2.86 (ddddd, 1H, H - l , J = 8.5, 8.5, 8.5, 8.5, 2.5 Hz), 3.34-3.47 (m, 5 H , four from -CH2O- and H-5), 6.69 (dd, 1H, H-6, J = 2.5, 2 Hz), 9.75 (s, 1H, - C H O ) . 1 3 C nmr (125.8 M H z , CDCI3) 8: 22.4 (-ve, - C H 3 ) , 22.6 (-ve -CH3), 30.1 ( C - l l ) , 35.0 (C-8), 38.0 (-ve, C - l ) , 38.7 (C-4), 40.0 (C-2), 48.1 (-ve, C-5), 71.8 ( - C H 2 0 - ) , 72.6 (-CH2O-), 108.6 (C-3), 145.6 (C-7), 155.0 (-ve, C-6), 190.4 (-ve, - C H O ) . IR (KBr): 1681, 1617, 1111 cm" 1. Exact mass calcd for C14H20O3: 236.1412; found: 236.1406. Anal, calcd for C 1 4 H 2 0 O 3 : C 71.16, H 8.53; found: C 71.33, H 8.69. Table 17 * H nmr (400 M H z , C D C I 3 ) Data for the a,f3-Unsaturated Aldehyde 71: C O S Y Experiment 14 12 •0 ,^8 0 •0 4 6 H 71 Assignment H-x * H nmr 8 (multiplicity, J (Hz)) C O S Y Correlations H - l 2.86 (ddddd, J = 8.5, 8.5, 8.5, 8.5, 2.5) H-2, H-2', H-8, H-8', H-5 H-2 1.58 (dd, J = 13.5, 8.5) H-2', H - l H-2 ' part of the mat 2.29-2.37 H-2, H - l H-4 1.75 (dd ,7= 13.5, 6) H-4', H-5 H-4 ' part of the m at 2.29-2.37 H-4, H-5 H-5 part of the m at 3.34-3.47 H - l , H-4, H-4*, H-6 ,H-8' H-6 6.69 (dd, J = 2.5, 2) H-5, H-8' H-8 part of the m at 2.29-2.37 H - l , H-8' H-8 ' 2.70 (dddd, J = 16.5, 8.5, 2, 2) H - l , H-5, H-6, H-8 H-9 9.75 (s) H-10, H-10' H-12, H-12* part of the mat 3.34-3.47 Me-13 Me-14 0.90 (s) 0.97 (s) Table 18 1 3 C nmr (125.8 M H z , CDCI3) and * H nmr (500.2 M H z ) Data for the a,P-Unsaturated Aldehyde 71: H M Q C Experiment 71 Assignment 1 3 C nmr A P T H M Q C C-x 8 ppm * H nmr Correlations (8 ppm) Me-14 22.4 C H or C H 3 Me-14 (0.90) Me-13 22.6 C H or C H 3 Me-13 (0.97) C - l l 30.1 C or C H 2 C-8 35.0 C or C H 2 H-8 (2.29-2.37) H-8' (2.70) C - l 38.0 C H or C H 3 H - l (2.86) C-4 38.7 C or C H 2 H-4 (1.75) H-4" (2.29-2.37) C-2 40.0 C or C H 2 H-2 (1.58) H-2'(2.29-2.37) C-5 48.1 CH or CH3 H-5 (3.34-3.47) C-10 71.8 C or C H 2 H-10 (3.34-3.47) H-10' (3.34-3.47) C-12 72.6 C or C H 2 H-12 (3.34-3.47) H-12' (3.34-3.47) C-3 108.6 C or C H 2 C-7 145.6 C or C H 2 C-6 155.5 C H or C H 3 H-6 (6.69) C-9 190.4 C H or CH3 H-9 (9.75) 164 Preparation of lithium G-trimethylgermylbut-3-en-l-yD(cyano')cuprate (35)n': GeMe Cu(CN)Li 35 To a cold (-98 ° C ) , stirred solution of freshly distilled 4-iodo-2-trimethylgermyl-l-butene (16) (0.684 g, 2.29 mmol) in dry T H F (25 mL) was added rapidly a solution of rerf-butyllithium (2.11 M in pentane, 2.10 m L , 4.43 mmol). ( C A U T I O N : Careful control of the temperature of the cooling bath is critical for the lithium iodine exchange reaction. A t temperatures higher than -98 ° C , dimerization of 16 is the predominant reaction.) The resultant clear yellow solution was stirred at -98 ° C for 10 minutes and was warmed to -78 ° C . Copper(I) cyanide (0.230 g, 2.56 mmol) was added in one portion and the suspension became colorless. The reaction mixture was warmed briefly (~5 minutes) to -35 ° C to provide a light tan homogeneous solution of the cuprate reagent 35, which was cooled to -78 °C and used immediately. ( C A U T I O N : While it is necessary to warm the reaction mixture for the copper(I) cyanide to dissolve, prolonged warming will result in the decomposition of the cuprate reagent.) Preparation of the aldehyde 80 To a cold (-78 ° C ) , stirred solution of the cuprate reagent 35 (2.22 mmol) in dry T H F (25 mL) was added neat trimethylsilyl bromide (0.818 g, 5.24 mmol). After H H 81 80 2 minutes, a solution of the unsaturated aldehyde 71 (0.346 g, 1.46 mmol) in dry T H F (3 mL) was added dropwise (over 5 minutes), using a small bore cannula, followed by dropwise addition of H M P A (0.51 m L , 2.9 mmol). The reaction mixture was stirred at -78 ° C for 15 minutes, then was poured into aqueous N H 4 C I - N H 4 O H (pH 8) (30 mL). The mixture was diluted with Et20 (60 mL) and vigorously stirred open to the air for 3 hours, upon which the aqueous layer turned bright blue. The phases were separated and the aqueous phase was extracted with Et20 (3 x 25 mL). The combined organic phases were washed sequentially with aqueous 10% CUSO4 (2 x 25 mL) and brine (2 x 25 mL), dried (MgSC»4), and concentrated. A small sample was purified by radial chromatography (1 mm plate, 19:1 petroleum ether - E t 2 0 ) to provide the silyl enol ether 81 as a low melting white solid (mp 25 - 26 °C) . ! H nmr (400 M H z , CDCI3) 8: 0.07 (s, 9H, -S1MS3), 0.18 (s, 9 H , - G e M e ^ . 0.93 (s, 6H, - C H 3 ) , 1.41-1.61 (m, 4H), 2.04-2.12 (m, 2H), 2.17-2.25 (m, 1H), 2.28-2.37 (m, 2H), 2.47 (dd, 1H, J = 16, 8.5 Hz), 2.71 (ddddd, 1H, J = 8.5, 8.5, 8.5, 8.5, 2.5 Hz), 3.08-3.12 (m, 1H), 3.41 (s, 2H, -CH2O-) , 3.47 (s, 2H, -CH2O-) , 4.16 (dd, 1H, J = 6, 6 Hz), 5.14 (m, 1H), 5.38 (br s, 1H), 5.48 (m, 1H). 1 3 C nmr (75.3 M H z , CDCI3) 8: -1.9 (-ve), 0.3 (-ve), 22.5 (-ve, 2 signals, C H 3 ) , 30.1, 33.2, 35.4, 37.1, 37.9 (-ve), 38.9, 40.8, 46.7 (-ve), 71.2 (-ve), 71.4, 72.8, 109.1, 121.2, 128.6 (-ve), 144.8, 153.9. IR (neat): 1250, 1113, 1009, 841, 599 cm" 1. Exact mass calcd for C24H44 7 4 Ge0 3 Si : 482.2271; found: 482.2275. Anal, calcd for C 2 4 H 4 4 G e 0 3 S i : C 59.89, H 9.21; found: C 60.24, H 9.30. J 166 The crude oil (compound 81) was dissolved in dry T H F (25 mL) and the solution was cooled to -78 ° C and treated with M e L i (1.40 M in Et20, 1.25 m L , 1.75 mmol). After 30 minutes, the reaction mixture was poured into water (10 mL). The phases were separated and the aqueous phase was extracted with Et20 (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried (MgS04), and concentrated. Purification of the crude product by radial chromatography (2 mm plate, 5:1 petroleum ether - Et20) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.541 g (90%) of the aldehyde 80 as a colorless oil. * H nmr spectroscopic analysis of the oil indicated a 3:1 mixture (a:P) of epimeric aldehydes. ! H nmr (400 M H z , CDCI3) 5: 0.17 (s, 9H, -GeMe3), 0.93 (s, 3H, -CH3), 0.96 (s, 3H, -CH3), 1.37-1.82 (m, 5H), 1.96-2.25 (m, 7H), 2.33-2.40 (m, 1H), 2.55-2.70 (m, 1H), 3.45 (br s, 4H, -CH2O-), 5.14-5.16 (m, 1H), 5.46-5.48 (m, 1H), 9.50, 9.78 (d, J = 4 Hz, d, J = 3 Hz , a:f3 ratio -3 :1 , 1H total, - C H O ) . Equilibration of the aldehyde 80 H To a stirred solution of the aldehyde 80 (0.822 g, 2.01 mmol, 3:1 mixture of epimers), at room temperature, in dry M e O H (20 mL) was added N a O M e (0.5 M in M e O H , 8 m L , 4 mmol). After 4 hours, the M e O H was removed under reduced pressure and Et20 (100 mL) and water (10 mL) were added to the residue. The organic phase was 80 washed with water (3 x 15 mL) and brine (2 x 15 mL), dried (MgSCU), and concentrated. Purification of the crude product by radial chromatography (4 mm plate, 5:1 petroleum ether - E t 2 0 ) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.751 g (91%) of the aldehyde 80 as a colorless oil. * H nmr spectroscopic analysis of the oil indicated a 9:1 mixture (ccpV) of epimeric aldehydes. ! H nmr (400 M H z , CDCI3) 8: 0.17 (s, 9H, - G e M e 3 ) , 0.93 (s, 3H, -CH3) , 0.96 (s, 3H, - C H 3 ) , 1.37-1.82 (m, 5H), 1.96-2.25 (m, 7H), 2.33-2.40 (m, 1H), 2.55-2.70 (m, 1H), 3.45 (br s, 4 H , - C H 2 O - ) , 5.14-5.16 (m, 1H), 5.46-5.48 (m, 1H), 9.50, 9.78 (d, J = 4 Hz, d, J = 3 Hz, a:p ratio -9:1, 1H total, - C H O ) . Signals attributed to the major epimer: 1 3 C nmr (75.3 M H z , C D C 1 3 ) 8: -1.9 (-ve, - G e M £ 3 ) . 22.4 (-ve, - C H 3 ) , 22.5 (-ve, - C H 3 ) , 30.0, 33.9, 34.4, 35.6, 39.4, 40.2, 40.4 (-ve, C H ) , 47.6 (-ve, C H ) , 48.2 (-ve, C H ) , 60.8 (-ve, C H ) , 71.9 ( C H 2 0 - ) , 72.0 ( - C H 2 0 - ) , 110.3 ( O - C - O ) , 121.5 ( C = C H 2 ) , 153.5 ( C = C H 2 ) , 203.8 (-ve, - C H O ) . IR (neat): 2704, 1724, 1237, 1116, 825, 600 cnr*. Exact mass calcd for C 2 i H 3 6 7 4 G e 0 3 : 410.1876; found: 410.1883. Anal, calcd for C 2 i H 3 6 G e 0 3 : C 61.65, H 8.87; found: C 61.70, H 8.91. Preparation of the alkenyl iodide 99 99 To a stirred solution of the alkenyltrimethylgermane 80 (0.503 g, 1.23 mmol, 9:1 mixture of epimers) in dry CH2CI2 (25 mL) , at room temperature, was added A M o d o -succinimide (0.573 g, 2.55 mmol). The pink slurry was stirred, in the dark, for 20 hours. The reaction mixture was poured into a vigorously stirred solution of saturated aqueous Na2S2C»3 (25 mL). The phases were separated and the aqueous phase was extracted with CH2CI2 (3 x 15 mL). The combined organic phases were washed with saturated aqueous Na2S203 (10 mL) , dried (MgS04), and concentrated. The crude product was purified by radial chromatography (4 mm plate, 4:1 petroleum ether - Et20) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.430 g (84%) of the alkenyl iodide 99 as a colorless oil. * H nmr spectroscopic analysis of the oil indicated a 9:1 mixture (a:(3) of epimeric aldehydes. ! H nmr (400 M H z , CDCI3) 8: 0.93 (s, 3H, -CH3), 0.96 (s, 3H, -CH3), 1.51-1.76 (m, 5H), 1.79-1.83 (m, 1H), 1.97-2.27 (m, 5H), 2.33-2.45 (m, 2H), 2.58-2.72 (m, 1H), 3.45 (br s, 4 H , -CH2O-), 5.69 (m, 1H), 6.01 (m, 1H), 9.51, 9.78 (d, J = 4 Hz , d, J = 3 Hz, a:(3 ratio -9:1, 1H total, - C H O ) . Signals attributed to the major epimer: 13c nmr (75.3 M H z , CDCI3) 8: 22.4 (-ve, - C H 3 ) , 22.5 (-ve, - C H 3 ) , 30.0, 34.3, 34.5, 39.4, 39.8, 40.3 (-ve, C H ) , 43.4, 46.7 (-ve, C H ) , 47.5 (-ve, C H ) , 60.6 (-ve, C H ) , 71.9 (2 signals, - C H 2 0 - ) , 110.2, 111.6, 125.8 (C=CH 2 ) , 203.6 (-ve, - C H O ) . IR (neat): 2707, 1722, 1617, 1115 cm" 1. Exact mass calcd for C18H27IO3: 418.1005; found: 418.1000. Anal, calcd for C18H27IO3: C 51.68, H 6.51,1 30.34; found: C 51.49, H 6.47,130.19. Preparation of the alcohols 102 and 103 To a stirred suspension of C r C l 2 (0.825 g, 6.72 mmol) and N1CI2 (0.067 g, 0.52 mmol) in dry D M F (20 mL) , at room temperature, was added the iodo aldehyde 99 (0.506 g, 1.21 mmol, 9:1 mixture of epimers) as a solution in dry D M F (5 mL). After 1 hour, the reaction mixture was diluted with Et20 (50 mL) and brine (25 mL) and the phases were separated. The organic phase was washed with brine (5 x 10 mL), dried (MgS04), and concentrated. The crude product was purified by radial chromatography (2 mm plate, 2:1 petroleum ether - Et20) and the appropriate fractions were concentrated to provide 0.082 g (23%) of 102 and 0.200 g (57%) of 103, both as white solids. Recrystallization of 102 from pentane afforded the oc-alcohol 102 as colorless needles (mp 130 -131 °C) while recrystallization of 103 from petroleum ether - Et20 afforded the pValcohol 103 as colorless needles (mp 97 - 98 °C) . 102 103 a-alcohol 102 * H nmr (400 M H z , CDCI3) 5: 0.92 (s, 3H, -CH3), 0.95 (s, 3H, -CH3), 0.99 (dddd, 1H, H-5 a x ia l , J = 12, 12, 12, 4 Hz), 1.32-1.41 (m, 2H, H-12 and - O H ; after D 2 0 exchange: m, 1H), 1.47 (dddd, 1H, H - l , J = 12, 12, 5.5, 2.5 Hz), 1.62-1.73 (m, 3H, H-6, H-8 and H-10), 1.79-1.85 (m, 1H, H-12*), 1.88-1.96 (m, 2H, H-5 eqUatorial and H-7), 2.10-2.22 (m, 3H, H-4 e quatorial, H-8" and H-10'), 2.34 (br dd, 1H, H-4 a x ia l , J = 13.5, 12 Hz), 2.46-2.55 (m, 1H, H - l l ) , 3.45 (s, 4H, -CH2O-), 4.23 (br s, 1H, -CH(OH)- ) , 4.74 (dd, 1H, H-13, J = 2, 2 Hz), 4.83 (dd, 1H, H-13', J = 2, 2 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 22.5 (-ve, - C H 3 ) , 22.6 (-ve, - C H 3 ) , 29.9 (C-4), 30.0 (C-15), 31.6 (C-5), 33.5 (C-12), 38.3 (C-8 or C-10), 39.2 (-ve, C - l l ) , 40.0 (C-8 or C-10), 43.9 (-ve, C-6), 45.3 (-ve, C-7), 53.0 (-ve, C - l ) , 71.8 ( - C H 2 0 - ) , 72.2 ( - C H 2 O - ) , 73.6 (-ve, - C H ( O H ) - ) , 110.8 ( C = C H 2 ) , 111.1 ( O - C - O ) , 150.6 ( C = C H 2 ) . IR(KBr) : 3456,1651,1110 cm- 1 . Exact mass calcd for C i 8 H 2 8 0 3 : 292.2038; found: 292.2036. Anal, calcd for C i 8 H 2 8 0 3 : C 73.93, H 9.65; found: C 73.81, H 9.75. Table 19 * H nmr (400 M H z , CDCI3) Data for the Allylic Alcohol 102: C O S Y Experiment 102 Assignment H-x *H nmr 8 (multiplicity, 7 (Hz)) C O S Y Correlations H-l 1.47 (dddd, 7= 12, 12, 5.5, 2.5) H-2, H-6, H-12, H-12' H-2 4.23 (br s) H-l, O-H H-4ax 2.34 (brdd,7 = 13.5, 12) H-4ea, H-5ax, H-5ea. H-13, H-13' H-4ea part of the mat 2.10-2.22 H~4ax, H-5^, HSea H-5ax 0.99 (dddd, 7 = 12, 12, 12, 4) H-4^, H-4ea, H-5ea, H-6 H-5ea part of the mat 1.88-1.96 H-4ax, H-4ea, H-5ax, H-6 H-6 part of the m at 1.62-1.73 H-l, H-5ax, H-5ea, H-7 H-7 part of the m at 1.88-1.96 H-6, H-8, H-8', H - l l H-8 part of them at 1.62-1.73 H-7, H-8' H-8' part of the m at 2.10-2.22 H-7, H-8 H-10 part of them at 1.62-1.73 H-10', H - l l H-10' part of the m at 2.10-2.22 H-10, H - l l H - l l 2.46-2.55 (m) H-7, H-10, H-10', H-12, H-12' H-12 part of them at 1.32-1.41 H-l, H - l l , H-12' H-12' 1.79-1.85 (m) H-l, H - l l , H-12 H-13 4.74 (dd, 7 = 2,2) H-4a x , H-13' H-13' 4.83 (dd, 7 = 2, 2) H-4ax,H-13 H-14, H-14' H-16, H-16' part of the signal at 3.45 (s) Me-17 Me-18 0.92 (s) 0.95 (s) O-H part of the mat 1.32-1.41 H-2 Table 20 1 3 C nmr (125.8 M H z , CDCI3) and ! H nmr (500.2 M H z ) Data for the Allylic Alcohol 102: H M Q C Experiment 102 Assignment C-x 1 3 C nmr 8 ppm A P T H M Q C ! H nmr Correlations (8 ppm) C-17 C-18 22.5 22.6 C H or C H 3 Me-17 (0.92) Me-18 (0.95) C-4 29.9 C or C H 2 H - 4 e q (2.10-2.22) H - 4 a x (2.34) C-15 30.0 C or C H 2 C-5 31.6 C or C H 2 H - 5 e a (1.88-1.96) C-12 33.5 C or C H 2 H-12 (1.32-1.41) H-12' (1.79-1.85) C-8 or C-10 38.3 C or C H 2 H-8 or H-10 (1.62-1.73) H-8' or H-10' (2.10-2.22) C - l l 39.2 C H or C H 3 H - l l (2.46-2.55) C-8 or C-10 40.0 C or C H 2 H-8 or H-10 (1.62-1.73) H-8' or H-10' (2.10-2.22) C-6 43.9 C H or C H 3 H-6 (1.62-1.73) C-7 45.3 CH or C H 3 H-7 (1.88-1.96) C - l 53.0 CH or C H 3 H - l (1.47) C-14 C-16 71.8 72.2 C or C H 2 C or C H 2 H-14 (3.45) H-14' (3.45) H-16 (3.45) H-16' (3.45) C-2 73.6 C H or C H 3 H-2 (4.74) C-13 110.8 C or C H 2 H-13 (4.74) H-13'(4.83) C-9 111.1 C or C H 2 C-3 150.6 C or C H 2 p-alcohol 103 ! H nmr (400 M H z , CDCI3) 8: 0.91 (s, 3H, - C H 3 ) , 0.97 (s, 3H, -CH3), 0.99 (dddd, 1H, H - 5 a x i a i , 7 = H - 5 , 11.5, 11.5, 4 Hz), 1.15 (ddd, 1H, H-12, 7 = 8.5, 11.5, 11.5 Hz), I. 25 (dddd, 1H, H - l , 7 = 11.5, 11.5, 11.5, 5.5 Hz), 1.39 (dddd, 1H, H-6, J = 11.5, II. 5, 11.5, 3.5 Hz), 1.56 (d, 1H, - O H , exchanges with D 2 0 , 7 = 6 Hz), 1.71-1.76 (m, 2H, H-8 and H-10), 1.81-1.87 (m, 1H, H-5e quatorial), 1.98-2.15 (m, 4 H , H - 4 a x i a i , H-7, H-8" and H-10'), 2.22 (ddd, 1H, H-12', 7 = 11.5, 8, 5.5 Hz) , 2.42 (ddd, 1H, H-4 e q u atorial, J = 14, 4, 2 Hz), 2.46-2.56 (m, 1H, H - l l ) , 3.41-3.50 (m, 4 H , -CH2O-), 3.81 (dd, 1H, - C H ( O H ) - , 7 = 11.5, 6 Hz; after D 2 0 exchange: d, 7 = 11.5 Hz), 4.77 (br d, 1H, H-13, 7 = 2 Hz), 4.94 (br d, 1H, H-13', 7 = 2 Hz). 1 3 C nmr (125.8 M H z , CDCI3) 8: 22.5 (-ve, -CH3), 22.6 (-ve, - C H 3 ) , 30.1 (C-15), 31.1 (C-5), 34.7 (C-4), 37.1 (C-12), 38.5 (C-8 or C-10), 39.7 (C-8 or C-10), 39.8 ( - v e , C - l l ) , 45.6 (-ve, C-7), 51.3 (-ve, C-6), 56.2 (-ve, C - l ) , 72.0 (2 signals, - C H 2 0 - ) , 76.9 (-ve, -CH(OH)-) , 104.8 (C=CH 2 ) , 111.0 (O-C-O), 151.3 ( C = C H 2 ) . IR (KBr): 3436, 1651, 1117 cm" 1. Exact mass calcd for C i 8 H 2 8 0 3 : 292.2038; found: 292.2038. Anal, calcd for C i 8 H 2 8 0 3 : C 73.93, H 9.65; found: C 74.12, H 9.68. Table 21 ! H nmr (400 M H z , CDCI3) Data for the Allylic Alcohol 103: C O S Y Experiment Assignment H-x i H n m r 8 (multiplicity, 7 (Hz)) C O S Y Correlations H - l 1.25 (dddd, 7 = 11.5, 11.5, 11.5, 5.5) H-2, H-6, H-12, H-12' H-2 3.81 (dd,7 = 11.5, 6) H - l , O - H H-4 a x part of the m at 1.98-2.15 H-4 e n, H-5ax> H-5 eq, H-13, H-13' H-4ea 2.42 (ddd, 7 = 2, 4, 14) H-4 a x , H-5 a x , H - 5 e a H - 5 a x 0.99 (dddd, 7 = 11.5, 11.5, 11.5, 4) H-4 a x , H-4 e a , H-5ea, H-6 H-5ecj 1.81-1.87 (m) H-4 a x , H-4 e a , H-5ax, H-6 H-6 1.39 (dddd, 7 = 11.5, 11.5, 11.5, 3.5) H - l , H-5 a x , H-5 ea, H-7 H-7 part of them at 1.98-2.15 H-6, H-8, H-8', H - l l H-8 part of the m a 1.71-1.76 H-7, H-8' H-8' part of the mat 1.98-2.15 H-8 H-10 part of the m at 1.71-1.76 H-10', H - l l H-10' part of the m at 1.98-2.15 H-10, H - l l H - l l 2.46-2.56 (m) H-7, H-10, H-10', H-12, H-12' H-12 1.15 (ddd, 7= 8.5, 11.5, 11.5) H - l , H - l l , H-12' H-12' 2.22 (ddd, 7 = 5.5, 8.5, 11.5) H - l , H - l l , H-12 H-13 4.77 (br d,7=2) H-2, H-4 a x , H-13' H-13' 4.94 (br d,7=2) H-2, H-4 a x , H-13 H-14, H-14' H-16, H-16' 3.41-3.50 (m) Me-17 Me-18 0.91 (s) 0.97 (s) O - H 1.56 (d,7 = 6) H-2 Table 22 13c nmr (125.8 M H z , CDC1 3 ) and l H nmr (500.2 M H z ) Data for the Allylic Alcohol 103: H M Q C Experiment 103 Assignment C-x 13C nmr 8 ppm A P T H M Q C l H nmr Correlations (8 ppm) C-17 C-18 22.5 22.6 C H or C H 3 Me-17 (0.92) Me-18 (0.95) C-15 30.1 C or C H 2 C-5 31.1 C or C H 2 H - 5 e q (1.81-1.87) H - 5 a x (0.99) C-4 34.7 C or C H 2 H - 4 e q (2.42) H - 4 a x (1.98-2.15) C-12 37.1 C or C H 2 H-12 (1.15) H-12' (2.22) C-8 orC-10 38.5 C or C H 2 H-8 or H-10 (1.71-1.76) H-8' or H-10' (1.98-2.15) C-8 or C-10 39.7 C or C H 2 H-8 or H-10 (1.71-1.76) H-8' or H-10' (1.98-2.15) C - l l 39.8 C H or C H 3 H - l l (2.46-2.56) C-7 45.6 C H or C H 3 H-7 (1.98-2.15) C-6 51.3 C H or C H 3 H-6 (1.39) C - l 56.2 C H or C H 3 H - l (1.25) C-14 C-16 72.0 C or C H 2 H-14 (3.41-3.50) H-14' (3.41-3.50) H-16 (3.41-3.50) H-16' (3.41-3.50) C-2 76.9 C H or C H 3 H-2 (3.81) C-13 104.8 C or C H 2 H-13 (4.77) H-13'(4.94) C-9 111.0 C or C H 2 C-3 151.3 C or C H 2 Preparation of the a-acetate 104 H 104 To a stirred solution of the allylic alcohol 102 (0.080 g, 0.28 mmol) in dry CH2CI2 (3 m L ) , at room temperature, were added sequentially Et3N (57 p L , 0.41 mmol), AC2O (39 U.L, 0.41 mmol) and D M A P (0.050 g, 0.41 mmol). After 2 hours, water (10 mL) and CH2CI2 (10 mL) were added and the phases were separated. The organic phase was washed with brine ( 2 x 5 mL), dried (Na2SC»4), and concentrated. Purification of the crude product by radial chromatography (1 mm plate, 6:1 petroleum ether - Et20) provided 0.091 g (98%) of the a-acetate 104 as a white solid. Recrystallization from pentane afforded the acetate as colorless crystals (mp 85 - 86 °C) . ! H nmr (400 M H z , CDCI3) 8: 0.91 (s, 3H, -CH3), 0.98 (s, 3H, -CH3), 0.96-1.13 (m, 2H), 1.51 (dddd, 1H, J = 12, 12, 6, 2.5 Hz), 1.63-1.73 (m, 3H), 1.79-1.97 (m, 3H), 2.01 (s, 3 H , -C(=0)CH3), 2.07-2.29 (m, 4H), 2.43-2.54 (m, 1H), 3.42-3.50 (m, 4H, -CH2O-), 4.84 (m, 1H), 4.96 (m, 1H), 5.40 (d, 1H, - C H ( O A c ) - , J = 2.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 21.2 (-ve), 22.5 (-ve), 22.7 (-ve), 30.1, 30.7, 31.3, 33.9, 38.5, 39.2 (-ve), 39.5, 44.9 (-ve), 45.0 (-ve), 51.5 (-ve), 71.8, 72.1, 75.1 (-ve), 110.9, 113.4, 146.1, 170.4. IR (KBr): 1739, 1656, 1234, 1112 cm" 1. Exact mass calcd for C20H30O4: 334.2144; found: 334.2136. Anal, calcd for C20H30O4: C 71.82, H 9.04; found: C 71.68, H 8.95. Preparation of the pVacetate 105 H 105 To a stirred solution of the allylic alcohol 103 (0.112 g, 0.381 mmol) in dry CH2CI2 (4 m L ) , at room temperature, were added sequentially E t 3 N ( 8 0 | i L , 0.57 mmol), AC2O (55 u L , 0.58 mmol) and D M A P (0.070 g, 0.57 mmol). After 1 hour, water (10 mL) and CH2CI2 (10 mL) were added and the phases were separated. The organic phase was washed with brine ( 2 x 5 mL), dried (Na2SC«4), and concentrated. Purification of the crude product by radial chromatography (1 mm plate, 6:1 petroleum ether - Et20) provided 0.121 g (95%) of the fJ-acetate 105 as a white solid. Recrystallization from heptane afforded the acetate as colorless needles (mp 92 - 93 °C) . ! H nmr (400 M H z , C D C 1 3 ) 8: 0.91 (s, 3H, -CH3), 0.96 (s, 3H, -CH3), 0.88-1.05 (m, 1H), 1.09-1.18 (m, 1H), 1.39-1.49 (m, 2H), 1.70-1.75 (m, 2H), 1.87 (br d, 1H, J = 12 Hz), 1.99-2.16 (m, 5H), 2.10 (s, 3H, - C ( = 0 ) C H 3 ) , 2.44 (ddd, 1H, J = 14, 4, 2 Hz), 2.46-2.53 (m, 1H), 3.40-3.51 (m, 4 H , -CH2O-), 4.67 (d, 1H, J = 1.5 Hz), 4.73 (d, 1H, J = 1.5 Hz), 5.07 (d, 1H, - C H ( O A c ) - , J = 9.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 5: 20.8 (-ve), 22.4 (-ve), 22.5 (-ve), 30.0, 30.8, 34.6, 36.7, 38.2, 39.4, 39.5 (-ve), 45.4 (-ve), 51.0 (-ve), 53.2 (-ve), 71.8, 71.9, 77.6 (-ve), 105.4, 110.7, 146.3, 170.1. IR (KBr): 1742, 1652, 1239, 1117 c n r 1 . Exact mass calcd for C20H30O4: 334.2144; found: 334.2146. Anal, calcd for C20H30O4: C 71.82, H 9.04; found: C 71.84, H 8.97. Preparation of the keto a-acetate 106 H 106 Ozone was bubbled through a cold (-78 ° C ) , stirred solution of the allylic acetate 104 (0.082 g, 0.25 mmol) in dry M e O H (5 mL) until a blue - grey color persisted (~5 minutes). Dimethyl sulfide (~1 mL) was added and the mixture was stirred at -78 ° C for 10 minutes and then was warmed to room temperature. The solution was purged with argon and the solvent was removed under reduced pressure. The crude oil was purified by flash chromatography (8 g silica gel, 1:1 petroleum ether - Et20) to provide 0.081 g (98%) of 106 as a white solid. Recrystallization from heptane afforded the keto acetate 106 as colorless crystals (mp 100 -101 °C) . * H nmr (400 M H z , CDCI3) 5: 0.91 (s, 3H, -CH3), 1.00 (s, 3H, - C H 3 ) , 1.24-1.40 (m, 2H), 1.73-1.89 (m, 4H), 1.92-2.16 (m, 5H), 2.09 (s, 3 H , - C ( = 0 ) C H 3 ) , 2.22 (br d, 1H, J = 14 Hz), 2.55-2.66 (m, 2H), 3.42-3.52 (m, 4H, -CH2O-), 4.93 (d, 1H, - C H ( O A c ) - , J = 1 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 20.6 (-ve), 22.4 (-ve), 22.6 (-ve), 30.0, 30.1, 33.5, 37.0, 38.6, 39.2, 40.1 (-ve), 43.9 (-ve), 44.0 (-ve), 52.2 (-ve), 71.9, 72.0, 77.7 (-ve), 110.6, 169.7, 207.9. IR (KBr): 1750, 1730, 1225, 1108 cm" 1. Exact mass calcd for C19H28O5: 336.1937; found: 336.1930. Anal, calcd for C19H28O5: C 67.83, H 8.39; found: C 67.84, H 8.50. Preparation of the keto p-acetate 107 H 107 Ozone was bubbled through a cold (-78 ° C ) , stirred solution of the allylic acetate 105 (0.112 g, 0.344 mmol) in dry M e O H (7 mL) until a blue - grey color persisted (~5 minutes). Dimethyl sulfide (~ 1 mL) was added and the mixture was stirred at -78 ° C for 10 minutes and then was warmed to room temperature. The solution was purged with argon and the solvent was removed under reduced pressure. The crude oil was purified by flash chromatography (8 g silica gel, 2:1 petroleum ether - Et20) to provide 0.104 g (90%) of 107 as a white solid. Recrystallization from pentane afforded the keto acetate 107 as colorless needles (mp 144 - 145 °C) . ! H nmr (400 M H z , C D C 1 3 ) 5: 0.91 (s, 3H, -CH3) , 0.99 (s, 3H, -CH3) , 1.20-1.27 (m, 1H), 1.35 (dddd, 1H, J = 13, 13, 13, 5 Hz), 1.72-1.96 (m, 4H), 2.00-2.16 (m, 5H), 2.12 (s, 3 H , - C ( = 0 ) C H 3 ) , 2.42 (dddd, 1H, J = 13.5, 13.5, 13.5, 6.5 Hz), 2.47 (dddd, 1H, J = 13.5, 13.5, 5, 2.5 Hz), 2.59-2.69 (m, 1H), 3.41-3.52 (m, 4 H , - C H 2 O - ) , 5.03 (d, 1H, - C H ( O A c ) - , J = 12 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 5: 20.6 (-ve), 22.4 (-ve), 22.6 (-ve), 29.1, 30.0, 37.4, 38.4, 39.0, 39.8, 40.5 (-ve), 44.8 (-ve), 49.7 (-ve), 51.8 (-ve), 71.7, 72.2, 80.7 (-ve), 110.5, 170.1, 204.2. IR (KBr): 1750, 1728, 1235, 1116 cm" 1. Exact mass calcd for C19H28O5: 336.1937; found: 336.1940. Anal, calcd for C19H28O5: C 67.83, H 8.39; found: C 67.63, H 8.25. Preparation of the tricyclic ketone 83 from the keto acetate 106 H o o o 83 To a cold (-78 ° C ) , stirred solution of SmPi (0.1 M in T H F , 5.4 m L , 0.54 mmol) was added the keto acetate 106 (0.072 g, 0.21 mmol) as a solution in a mixture of dry T H F (3 mL) and dry M e O H (1 mL). The initially deep blue solution turned dark green. After 10 minutes, the reaction mixture was warmed to room temperature for 15 minutes. The mixture was poured into saturated aqueous K2CO3 (10 mL) and the resultant mixture was diluted with saturated aqueous Na2S203 (5 mL) and Et20 (10 mL). The phases were separated and the aqueous phase was extracted with Et20 (5 x 10 mL). The combined organic extracts were dried (MgS0 4 ) and concentrated. The acquired material was purified by radial chromatography (1 mm plate, 2:1 petroleum ether - Et20) to provide 0.050 g (85%) of the ketone 83 as a white solid. Recrystallization from pentane afforded the ketone 83 as colorless plates (mp 72 - 74 °C) . ! H nmr (400 M H z , CDC1 3) 8: 0.92 (s, 3H, -CH3), 0.98 (s, 3H, - C H 3 ) , 1.11 (ddd, 1H, J= 10, 10, 10 Hz), 1.34 (dddd, 1H, J = 12.5, 12.5, 12.5, 5 Hz), 1.52-1.68 (m, 2H), 1.77-1.82 (m, 2H), 1.99-2.17 (m, 6H), 2.22-2.40 (m, 2H), 2.48 (br d, 1H, J = 14 Hz), 2.55-2.65 (m, 1H), 3.41-3.50 (m, 4H, -CH2O-). 1 3 C nmr (75.3 M H z , CDCI3) 8: 22.4 (-ve), 22.6 (-ve), 29.1, 30.0, 38.3, 39.5, 39.7, 40.5 (-ve), 40.8, 44.7 (-ve), 47.2, 47.6 (-ve), 50.9 (-ve), 71.8, 72.0, 110.8, 211.7. IR(KBr) : 1714, 1117 cm- 1 . Exact mass calcd for C17H26O3: 278.1882; found: 278.1876. Anal, calcd for C17H26O3: C 73.35, H 9.41; found: C 73.40, H 9.51. Preparation of the tricyclic ketone 83 from the keto acetate 107 H 8 3 To a cold (-78 ° C ) , stirred solution of Sml2 (0.1 M in T H F , 6 m L , 0.6 mmol) was added the keto acetate 107 (0.080 g, 0.24 mmol) as a solution in a mixture of dry T H F (3 mL) and dry M e O H (1 mL) . The initially deep blue solution turned dark green. After 10 minutes, the reaction mixture was warmed to room temperature for 15 minutes. The mixture was poured into saturated aqueous K 2 C O 3 (10 mL) and the resultant mixture was diluted with saturated aqueous Na2S203 (5 mL) and Et20 (10 mL). The phases were separated and the aqueous phase was extracted with Et20 ( 5 x 1 0 mL). The combined organic extracts were dried (MgS0 4 ) and concentrated. The acquired material was purified by radial chromatography (1 mm plate, 2:1,petroleum ether - Et20) to provide 0.062 g (94%) of the ketone 83 as a white solid, which exhibited spectroscopic data identical with those reported above. 3. Substituted AHylcopper(I) Reagents Preparation of 2-bromoprop-2-enol (134)101 Br 134 To a stirred solution of 10% aqueous K 2 C O 3 (1100 mL) at room temperature was added 2,3-dibromopropene (136) (Aldrich 80% pure, 145 g, 580 mmol). The two phase mixture was heated at 90 ° C for 9 hours and then was cooled to room temperature. The now single phase solution was extracted with C H 2 C I 2 (20 x 50 mL) and the combined organic extracts were dried (MgS04). Removal of the solvent under reduced pressure followed by fractional distillation (bp 88 ° C / 7 0 Torr) of the remaining liquid through a Vigreaux column (1.5 x 15 cm) provided 74.3 g (94%) of the allylic alcohol 134 as a colorless oil. ! H nmr (400 M H z , CDCI3) 5: 2.02 (br s, 1H, - O H , exchanges with D 2 0 ) , 4.16 (d, 2H, -CH2OH, J = 6 Hz; after D 2 0 exchange: s), 5.53 (d, 1H, J = 1 Hz), 5.89 (d, 1H, J = 1 H z ) . 13C nmr (50.3 M H z , CDCI3) 8: 67.6, 116.3, 132.4. IR (neat): 3311, 1641, 1235, 1044, 893 cm- 1 . Exact mass calcd for C 3 H 5 7 9 B r O : 135.9524; found: 135.9521. Anal, calcd for C 3 H 5 B r O : C 26.31, H 3.68; found: C 26.23, H 3.75. 184 Preparation of 2-(trimethylgermyl)prop-2-enol (133) GeMe3 133 To a cold (-78 ° C ) , stirred solution of freshly distilled 2-bromoprop-2-enol (134) (15.6 g, 113 mmol) in dry E t 2 0 (320 mL) was added slowly (1 mL/min) a solution of ?-BuLi (1.7 M in pentane, 200 m L , 340 mmol). The pale yellow, cloudy mixture was warmed to 0 ° C and stirred for 3 hours. Freshly distilled Me3GeBr (24.7 g, 125 mmol) was added and the solution was stirred at 0 ° C for an additional 1 hour. Saturated aqueous NH4CI (100 mL) was added and the phases were separated. The aqueous phase was extracted with Et20 (3 x 50 mL) and the combined organic extracts were washed once with brine (50 mL) , dried (MgS04) , and concentrated. The crude oil was dissolved in C H 2 C l 2 (115 mL) and p - T s O H » H 2 0 (21.7 g, 114 mmol) was added. After the resultant solution had been stirred at room temperature for 3 hours, saturated aqueous N a H C 0 3 (115 mL) was added. The phases were separated and the aqueous phase was extracted with CH2CI2 (4 x 25 mL). Silica gel (230 - 400 mesh, 125 g) was added to the combined organic phases and the slurry was stirred for 15 minutes. The slurry was filtered and the filtrate was concentrated under reduced pressure to provide an orange oil which was fractionally distilled (bp 81 ° C / 2 5 Torr) through a Vigreaux column (1.5 x 15 cm) to provide 14.3 g (72%) of the alkenylgermane 133 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.23 (s, 9H, -GeMe3), 1.35 (br s, 1H, - O H , exchanges with D 2 0 ) , 4.26 (br d, 2H, - C H 2 O H , J = 5.5 Hz; after D 2 0 exchange: s), 5.28 (m, 1H), 5.72 (dt, 1H, J = 2, 2 Hz). " C nmr (75.3 M H z , CDCI3) 8: -2.2, 66.7, 120.1, 153.1. IR (neat): 3306, 1237, 1031, 924, 827, 601 cm" 1. Exact mass calcd for C 5 H i i 7 4 G e O ( M + - Me): 161.0022; found: 161.0028. Anal, calcd for C 6 H i 4 G e O : C 41.23, H 8.07; found: C 41.30, H 8.13. Preparation of 3-bromo-2-(trimethylgermyl)propene (135) G e M e 3 135 T o a cold (-20 ° C ) , stirred solution of PI13P (21.9 g, 83.5 mmol) in dry C H 2 C I 2 (725 mL) was added a solution of bromine (13.4 g, 83.8 mmol) in dry CH2CI2 (25 mL). The resulting pale yellow solution was warmed to room temperature and a few crystals of PI13P were added until the solution turned colorless. A solution of freshly distilled 2-(trimethylgermyl)prop-2-enol (133) (13.2 g, 75.5 mmol) in dry CH2CI2 (10 mL) was added and the resulting mixture was stirred at room temperature for 30 minutes. The majority of the solvent was removed under reduced pressure and the resulting slurry was filtered through a column (7 x 15 cm) of F l o r i s i l ® (300g) and the column was eluted with n-pentane (~2 L) . The appropriate fractions were combined and concentrated under reduced pressure and the remaining oil was distilled bulb-to-bulb (70 -90 ° C / 1 3 Torr) to provide 16.7 g (93%) of the allylic bromide 135 as a colorless oil. ! H nmr (400 M H z , CDCI3) 5: 0.29 (s, 9H, -GeMe3), 4.16 (m, 2H, -CH2Br), 5.34 (m, 1H), 5.83 (dt, 1H, J = 1.5, 1.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 5: -1.6, 38.5, 126.3, 149.2. IR (neat): 1239, 1206, 930, 828, 604 cm" 1. Exact mass calcd for C 5 H i o 7 9 B r 7 4 G e ( M + - Me): 222.9178; found: 222.9169. Anal, calcd for C 6 H i 3 B r G e : C 30.32, H 5.51; found: C 30.52, H 5.58. Preparation of 3-p-toluenesulfonyloxy-2-('trimethylgermyl')propene (158) GeMe3 To a cold (-48 ° C ) , stirred solution of freshly distilled 2-(trimethylgermyl)prop-2-enol (133) (1.07 g, 6.14 mmol) in dry Et20 (55 mL) was added dropwise, over a period of 5 minutes, a solution of M e L i (1.20 M in Et20, 5.70 m L , 6.84 mmol). After the solution had been stirred at -48 ° C for 1.5 hours, a solution of p-toluenesulfonyl chloride (1.39 g, 7.27 mmol) in dry E t 2 0 (5 mL) was added. The mixture was stirred at 0 ° C for 1 hour and at room temperature for 2 hours. Water (20 mL) was added and the phases were separated. The aqueous phase was extracted with Et20 (3 x lO mL). The combined organic phases were dried (MgS04) and concentrated under reduced pressure. Purification of the crude product by radial chromatography (4 mm plate, 15:1 petroleum ether - Et20) provided 1.74 g (86%) of the tosylate 158 as a pale yellow oil. Upon standing in the 158 freezer, the oil solidified to provide a low melting (less than room temperature), white, waxy solid. lH nmr (400 M H z , CDCI3) 8: 0.19 (s, 9H, -GeMej) , 2.43 (s, 3H, - A r - C H 3 ) , 4.64 (s, 2 H , -CH2O-) , 5.33 (s, 1H), 5.72 (s, 1H), 7.32 (d, 2H, 7 = 8 Hz), 7.78 (d, 2H, 7 = 8 H z ) . 1 3 C nmr (75.3 M H z , CDCI3) 8: -2.1 (-ve), 21.6 (-ve), 74.3, 125.1, 127.9 (-ve), 129.8 (-ve), 133.3, 144.7, 146.1. IR (neat): 1599, 1368, 1239, 1176, 1098, 937, 829, 604, 557 cm-1. Exact mass calcd for C i 2 H i 7 7 4 G e 0 3 S ( M + - M e ) : 315.0110; found: 315.0110. Anal , calcd for C i 3 H 2 o G e 0 3 S : C 47.47, H 6.13, S 9.75; found: C 47.59, H 6.05, S 9.75. Preparation of trimethyltin hydride (160V 1 5 M e 3 S n H 160 To a warm (65 ° C ) , stirred solution of L i A l H 4 (0.624 g, 16.5 mmol) in dry diglyme (8 mL) was added slowly by syringe pump a solution of M e 3 S n C l (3.11 g, 15.6 mmol) in dry diglyme (3 mL), over a period of 2.5 hours. The reaction mixture was stirred for an additional 1 hour while the product was distilled directly from the reaction mixture through a short path distillation apparatus connected to a receiving flask cooled to -78 ° C . Bulb-to-bulb distillation (65 - 75 ° C / 7 6 0 Torr) of the acquired liquid provided 2.22 g (86%) of trimethyltin hydride 160 as a colorless oil which was stored in a Schlenk flask in a freezer. ! H nmr (400 M H z , C 6 D 6 ) 5: 0.04 (d, 9 H , Me_3Sn-, J = 2.5 Hz, 2 7sn-H = 56 Hz), 4.75 (m, 1H, -SnH). Preparation of 2-(trimethylgermylV3-(trimethylstannyDpropene (132) GeMe3 To a cold (0 ° C ) , stirred solution of diisopropylamine (0.35 m L , 2.5 mmol) in dry T H F ( l O m L ) was added a solution of n - B u L i (1.67 M in hexanes, 1.42 m L , 2.37 mmol). After the solution had been stirred for 20 minutes, neat Me3SnH (160) (0.274 g, 200 U.L, 1.66 mmol) was added by syringe and stirring was continued at 0 ° C for 30 minutes. The mixture was cooled to -78 ° C and a solution of 3-/?-toluenesulfonyloxy-2-(trimethylgermyl)propene (158) (0.561 g, 1.71 mmol) in dry T H F (1 mL) was added dropwise. The solution was stirred for 30 minutes, was quenched with aqueous N H 4 O H - N H 4 C I (pH 8) (12 mL) and then was warmed to room temperature. The phases were separated and the aqueous phase was extracted with Et20 (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried (MgSCU) and concentrated. Purification of the crude product by radial chromatography (2 mm plate, petroleum ether followed by 15:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (95 - 105 ° C / 1 5 Torr) of the derived oil, provided 0.480 g (90%) of the allylstannane 132 as a colorless oil. 132 ! H nmr (400 M H z , CDCI3) 8: 0.07 (s, 9H, -SnMe3, 2 7 S n - H = 52 Hz), 0.17 (s, 9H, -GeMe_3), 1.96 (d, 2 H , - C H 2 - S n M e 3 , 7 = 1 Hz, 2 7 S n - H = 69 Hz), 4.91 (d, 1H, 7 = 2.5 Hz, 4 7 S n - H = 25 Hz), 5.28 (dt, 1H, 7 =2.5, 1 Hz, 4 7 S n - H = 23 Hz). !3C nmr (75.3 M H z , CDCI3) 8: -9.3, -2.0, 21.1, 117.0, 153.4. IR (neat): 1235, 1213, 824, 764, 599, 526 cm" 1. Exact mass calcd for C 9 H 2 2 7 4 G e 1 2 ( ) S n : 323.9955; found: 323.9960. Anal, calcd for C 9 H 2 2 G e S n : C 33.62, H 6.90; found: C 33.65, H 6.90. Preparation of a mixture of 2-(trimethylgermyD-3-(trimethylstannyl)propene (132) and 2.5-bis(trimethylgermyPhexa-1.5-diene (148) To a cold (0 ° C ) , stirred slurry of magnesium turnings (4.48 g, 184 mmol) in dry T H F (20 mL) was added slowly (0.5 mL/min) by syringe pump a solution of M e 3 S n C l (24.4 g, 142 mmol) and freshly distilled 3-bromo-2-(trimethylgermyl)propene (135) (15.9 g, 67.0 mmol) in dry T H F (45 mL). ( C A U T I O N : the solution refluxes spontaneously and quite vigorously, especially if the rate of addition is too rapid). After the addition was complete, the solution was heated to reflux for 2 hours. The solution was GeMe3 132 148 cooled in an ice water bath and water (10 mL) was added dropwise. The slurry was diluted with Et20 (100 mL), filtered through a sintered glass funnel and the collected material was washed with Et20 (200 mL). Saturated aqueous NH4CI (50 mL) was added to the filtrate and the phases were separated. The aqueous phase was extracted with Et20 (2 x 25 mL) and the combined organic phases were washed with brine (2 x 25 mL), dried (MgSC»4) and concentrated. Bulb-to-bulb distillation (95 - 120 ° C / 1 5 Torr) of the acquired liquid provided 17.2 g (87%) of a colorless oil. * H nmr analysis of the oil inidcated an ~ 10:1 mixture of 2-(trimethylgermyl)-3-(trimethylstannyl)propene (132) and 2,5-bis(trimethylgermyl)hexa-l,5-diene (148), which was found to be inseparable from 132 by silica gel chromatography. Signals attributed to 2-(trimemylgermyl)-3-(trimethylstannyl)propene (132): ! H nmr (400 M H z , CDCI3) 8: 0.07 (s, 9H, - S n M e j , 2 7 S n - H = 52 Hz), 0.17 (s, 9H, - G e M e O . 1.96 (d, 2H, - C H 2 - S n M e 3 , 7 = 1 Hz , 2 7 S n - H = 69 Hz), 4.91 (d, 1H, 7 = 2.5 Hz, 4 7 S n - H = 25 Hz), 5.28 (dt, 1H, 7 = 2.5, 1 Hz, 4 7 S n - H = 23 Hz). Signals attributed to 2,5-bis(trimethylgermyl)hexa-l,5-diene (148): ! H nmr (400 M H z , CDCI3) 8: 0.20 (s, 18H, -GeMe3), 2.26 (s, 4 H , -CH2-), 5.18 (d, 2H, olefinic proton, 7 = 2.5 Hz), 5.52 (d, 2H, olefinic proton, 7 = 2.5 Hz). Analysis of the mixture by G L C M S showed: 324 ( M + (132)) and 303 ( M + - Me (148)). Exact mass calcd for C 9 H i 2 7 4 G e 1 2 0 S n ( M + (132)): 323.9955; found: 323.9955. Exact mass calcd for C n H 2 3 7 4 G e 2 ( M + - M e (148)): 303.0223; found: 303.0232. Preparation of 2.3-bis(trimethylstannyl)propene (183) SnMe3 ^ v / S n M e a 183 Allene was bubbled through a warm (75 ° C ) , stirred solution of 0.1 mol% tetrakis-(triphenylphosphine)palladium(O) (0.10 g, 0.087 mmol) in neat hexamethylditin (151) (25.0 g, 76.4 mmol). After 2.5 hours, the solution was cooled to room temperature, filtered through a cake of C e l i t e ® (10 g), and the cake was washed with n-pentane (150 mL). The filtrate was concentrated under reduced pressure. Bulb-to-bulb distillation (54 - 70 °C /0 .3 Torr) of the residual oi l provided 27.2 g (97%) of the bis(trimethylstannane) 183 as a colorless oil. ! H nmr (400 M H z , CDC1 3 ) 8: 0.07 (s, 9H, 2 7 S n - H = 52 Hz), 0.10 (s, 9 H , 2 7 S n - H = 52 Hz), 2.07 (d, 2H, -CH2-, 7 = 1 Hz , 2 7 S n - H = 67 Hz), 4.85 ( d, 1H, 7 = 2.5 Hz, 3 7sn-H = 71 Hz, 4 7 S n - H = 26 Hz), 5.41 (dt, 1H, 7 = 2.5 Hz, 1 Hz , 3 7 S n - H = 155 Hz, 4 7 S n-H = 23 Hz). 1 3 C nmr (50.3 M H z , CDCI3) 8: -9.6, -9.4, 24.7, 119.8, 154.3. IR(neat): 764,525 cm" 1. Exact mass calcd for C 9 H 2 2 1 2 0 S n 2 : 369.9766; found: 369.9770. Anal, calcd for C 9 H 2 2 S n 2 : C 29.40, H 6.03; found: C 29.76, H 5.95. Preparation of 2-(trimethylgermyl)aUylcopper(I)-dimethyl sulfide (162) GeMe3 162 To a cold (-78 ° C ) , stirred solution of freshly distilled 2-(trimethylgermyl)-3-(trimethyl-stannyl)propene (132) (1 equiv) in dry T H F (~7 mL/mmol of allylstannane) was added M e L i ' L i B r (1 equiv, 1.5 M solution in Et20). After the pale yellow solution had been stirred for 30 minutes, solid C u B r « M e 2 S (1.05 equiv) was added in one portion. The solution turned cloudy, but then after 20 minutes, a homogeneous yellow solution of 2-(trimemylgennyl)allylcopper(I)-dimethyl sulfide (162) was obtained. General Procedure A : Conjugate addition of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) to a.ft-unsaturated ketones To a cold (-78 ° C ) , stirred solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) (-1.75 equiv) in dry T H F (~7 mL/mmol of allylstannane) were added freshly distilled, neat trimethylsilyl bromide (5 to 9 equiv), followed by the appropriate, freshly distilled oc,P-unsaturated ketone (1.0 equiv). After 15 minutes, the reaction mixture was poured into aqueous N H 4 C I - N H 4 O H (pH 8) (~ 1 m L / m L T H F ) and the resultant mixture was diluted with Et20 (~4 m L / m L T H F ) . The mixture was stirred open to the air for 15 minutes before the phases were separated. The aqueous phase was extracted with E12O (3 x ~1 m L / m L T H F ) and the combined organic phases were washed with brine (2 x ~1 m L / m L T H F ) , dried (MgS04) and concentrated. The crude product was purified by radial chromatography and the acquired liquid was distilled. 193 Preparation of 3-(2-(trimethylgeirnyDallyl')cyclohexanone (163) O 163 Following general procedure A , 3-(2-(trimethylgermyl)allyl)cyclohexanone (163) was prepared by treating a solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) (1.74 equiv, 0.90 mmol) in dry T H F (6 mL) with trimethylsilyl bromide (0.618 g, 4.03 mmol) and cyclohex-2-enone (110) (50 p L , 0.52 mmol). Purification of the crude product by radial chromatography (2 mm plate, 10:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (160 - 170 ° C / 8 Torr) of the acquired liquid, provided 0.119 g (91%) of the ketone 163 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.18 (s, 9H, -GeMe3), 1.21-1.32 (m, 1H), 1.54-1.67 (m, 1H), 1.81-2.06 (m, 4H), 2.15-2.28 (m, 3H), 2.31-2.42 (m, 2H), 5.24 (d, 1H, / = 2.5 Hz), 5.48 (dt, 1H, J = 2.5, 1.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -1.8 (-ve), 25.0, 31.1, 37.9 (-ve), 41.4, 45.1, 48.1, 124.0, 151.2, 211.7. IR (neat): 1713, 1237, 919, 826, 599 cm" 1. Exact mass calcd for C n H i 9 7 4 G e O ( M + - M e ) : 241.0648; found: 241.0656. Anal, calcd for C i 2 H 2 2 G e O : C 56.55, H 8.70; found: C 56.70, H 8.90. 1 9 4 Preparation of mms-4-isopropyl-3-(2-(trimethylgermyl)alW^ (164) O 164 Following general procedure A , rrans-4-isopropyl-3-(2-(trimethylgermyl)allyl)-cyclohexanone (164) was prepared by treating a solution of 2-(trimethylgermyl)-allylcopper(I)-dimethyl sulfide (162) (1.71 equiv, 0.885 mmol) in dry T H F (6 mL) with trimethylsilyl bromide (0.658 g, 4.30 mmol) and 4-isopropylcyclohex-2-enone (170) (76 p L , 0.52 mmol). Purification of the crude product by radial chromatography (2 mm plate, 10:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (120 -128 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.142 g (92%) of the ketone 164 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 5: 0.18 (s, 9H, -GeMe^t). 0.84 (d, 3H, J = 1 Hz), 0.98 (d, 3H, J = 7 Hz), 1.28-1.35 (m, 1H), 1.50-1.60 (m, 1H), 1.85-1.97 (m, 4H), 2.00-2.08 (m, 1H), 2.18-2.26 (ddd, 1H, J = 16, 10.5, 5.5 Hz), 2.33-2.42 (m, 2H), 2.57-2.64 (m, 1H), 5.24 (dd, 1H, J = 2.5, 1 Hz), 5.46 (m, 1H). nmr (75.3 M H z , CDCI3) 6: -1.6 (-ve), 16.8 (-ve), 21.5 (-ve), 23.9, 27.0 (-ve), 37.9 (-ve), 40.1, 42.8, 44.9, 46.3 (-ve), 124.5, 151.2, 212.3. IR (neat): 1718, 1236, 920, 825, 599 cm" 1. Exact mass calcd for C i 5 H 2 8 / 4 G e O : 298.1352; found: 298.1349. Anal, calcd for C i 5 H 2 8 G e O : C 60.67, H 9.50; found: C 60.87, H 9.57. Preparation of 3-methyl-3-(2-(uimethylgennyl')allyl')cyclohexanone (165) 165 Following general procedure A , 3-methyl-3-(2-(trimethylgermyl)allyl)cyclohexanone (165) was prepared by treating a solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) (1.73 equiv, 0.79 mmol) in dry T H F (5 mL) with trimethylsilyl bromide (0.416 g, 2.72 mmol) and 3-methylcyclohex-2-enone (171) (52 p L , 0.46 mmol). Purification of the crude product by radial chromatography (1 mm plate, 9:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (160 - 178 °C/11 Torr) of the acquired liquid, provided 0.057 g (46%) of the ketone 165 as a colorless oil. ! H nmr (400 M H z , CDCI3) 5: 0.20 (s, 9H, - G e M e 3 ) , 0.87 (s, 3H, -CH3), 1.48-1.55 (m, 1H), 1.60-1.67 (m, 1H), 1.75-1.96 (m, 2H), 2.03 (d, 1H, J = 12.5 Hz), 2.17 (s, 2H), 2.21-2.30 (m, 3H), 5.41 (d, 1H, J = 2 Hz), 5.55 (br s, 1H). 13c nmr (75.3 M H z , CDCI3) 8: -0.8 (-ve), 22.1, 24.9 (-ve), 36.1, 39.6, 41.0, 48.8, 53.5, 128.2, 150.2, 212.3. IR (neat): 1713, 1235, 923, 826, 598 cm-1. Exact mass calcd for C i 2 H 2 i 7 4 G e O ( M + - Me): 255.0804; found: 255.0806. Anal, calcd for C i 3 H 2 4 G e O : C 58.06, H 9.00; found: C 58.03, H 9.15. Preparation of 3-(2-(trimethylgermyl')allyl)cyclopentanone (166) O Following general procedure A , 3-(2-(trimethylgermyl)allyl)cyclopentanone (166) was prepared by treating a solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) (1.74 equiv, 0.90 mmol) in dry T H F (6 mL) with trimethylsilyl bromide (0.657 g, 4.23 mmol) and cyclopent-2-enone (172) (43 U.L, 0.51 mmol). Purification of the crude product by radial chromatography (1 mm plate, 10:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (153 - 164 ° C / 8 Torr) of the acquired liquid, provided 0.105 g (85%) of the ketone 166 as a colorless oil. l H nmr (400 M H z , CDCI3) 8: 0.20 (s, 9H, -GeMe3), 1.48-1.58 (m, 1H), 1.76-1.84 (m, 1H), 2.06-2.18 (m, 2H), 2.23-2.36 (m, 5H), 5.23 (d, 1H, J = 2.5 Hz), 5.50 (m, 1H). 166 1 3 C nmr (75.3 M H z , CDCI3) 8: -1.9 (-ve), 29.1, 35.7 (-ve), 38.1, 43.6, 45.0, 123.2, 151.8, 219.5. IR (neat): 1746, 1236, 919, 826, 599 cm" 1. Exact mass calcd for C i 0 H i 7 7 4 G e O ( M + - Me): 227.0491; found: 227.0486. Anal, calcd for C n H 2 o G e O : C 54.85, H 8.37; found: C 54.97, H 8.60. Preparation of 3-methyl-3-(2-(trimethylgermyl)allyl)cyclopentanone (167) O 167 Following general procedure A , 3-methyl-3-(2-(trimethylgermyl)allyl)cyclopentanone (167) was prepared by treating a solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) (1.72 equiv, 0.83 mmol) in dry T H F (5.5 mL) with trimethylsilyl bromide (0.466 g, 3.04 mmol) and 3-methylcyclopent-2-enone (173) (48 p L , 0.49 mmol). Purification of the crude product by radial chromatography (1 mm plate, 10:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (128 - 139 ° C / 9 Torr) of the acquired liquid, provided 0.069 g (56%) of the ketone 167 as a colorless oil. 1 H nmr (400 M H z , CDC1 3) 8: 0.21 (s, 9H, - G e M e 3 ) , 1.02 (s, 3H, -CH3), 1.68-1.75 (m, 1H), 1.82-1.90 (m, 1H), 1.96 (dd, 1H, J = 17.5, 1 Hz), 2.15 (d, 1H, J = 17.5 Hz), 2.24-2.30 (m, 4H), 5.39 (d, 1H, J = 2.5 Hz), 5.56 (m, 1H). !3C nmr (75.3 M H z , CDCI3) 8: -1.0 (-ve), 25.7 (-ve), 35.2, 36.5, 40.1, 47.5, 52.1, 127.3, 150.8, 219.7. IR (neat): 1746, 1236, 923, 826, 598 cm- 1 . Exact mass calcd for C n H i 9 7 4 G e O ( M + - M e ) : 241.0648; found: 241.0653. Anal, calcd for C i 2 H 2 2 G e O : C 56.55, H 8.70; found: C 56.80, H 8.62. Preparation of a mixture of trans- and c/5-2-methyl-3-(2-(trimethylgermyl')allyDcyclo-pentanone (168) Following general procedure A , a mixture of trans- and cw-2-methyl-3-(2-(trimethyl-germyl)a l ly l )cyc lopentanone (168) was prepared by treating a solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) (1.70 equiv, 0.87 mmol) in dry T H F (6 mL) with trimethylsilyl bromide (0.454 g, 2.96 mmol) and 2-methylcyclopent-2-enone (174) (50 U.L, 0.51 mmol). Purification of the crude product by radial chromatography (1 mm plate, 10:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (103 - 110 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.116 g (89%) of the ketone 168 as a colorless oil. * H nmr analysis of the oil inidcated an -8:1 mixture of C-2 epimers. * H nmr (400 M H z , C D C 1 3 ) 8: 0.21 (s, 9H, - G e M e O . 0.98, 1.07 (d, J = 7 Hz , d, J = 1 Hz, ratio 1:8, 3 H total), 1.23-1.36 (m, 1H), 1.67-1.92 (m, 2H), 2.01-2.20 (m, 3H), O 168 2.27-2.39 (m, 1H), 2.62-2.67 (m, 1H), 5.25 (d, 1H, J = 2.5 Hz), 5.50, 5.55 (m, m, ratio 1:8, 1H total). Signals attributed to the major epimer: nmr (75.3 M H z , C D C 1 3 ) 5: -1.7 (-ve), 12.7 (-ve), 27.3, 37.2, 43.1, 43.7 (-ve), 50.4 (-ve), 123.5, 151.7, 221.0. IR (neat): 1744, 1236, 918, 825, 599 cm" 1. Exact mass calcd for C i i H i 9 7 4 G e O ( M + - M e ) : 241.0648; found: 241.0652. Anal, calcd for C i 2 H 2 2 G e O : C 56.55, H 8.70; found: C 56.80, H 8.50. Preparation of a mixture of (2R. 35. 5R)- and (25. 35. 5/?V2-methyl-5-isopropenyl-3-(2-(trimethylgermyl')allyl')cyclohexanone (169) Following general procedure A , a mixture of (2R, 35, 5R)- and (25, 35, 5/?)-2-methyl-5-isopropenyl-3-(2-(trimethylgermyl)allyl)cyclohexanone (169) was prepared by treating a solution of 2-(trimethylgermyl)allylcopper(I)-dimethyl sulfide (162) (1.73 equiv, 0.62 mmol) in dry T H F (5 mL) with trimethylsilyl bromide (0.402 g, 2.63 mmol) and (7?)-(-)-carvone (175) (56 U.L, 0.36 mmol). Purification of the crude product by radial O 169 chromatography (1 mm plate, 20:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (132 - 138 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.095 g (86%) of the ketone 169 as a colorless oil. * H nmr analysis of the oil inidcated an -2:1 mixture of C-2 epimers containing a small amount (2-3%) of a corresponding C-3 epimer. * H nmr (400 M H z , C D C 1 3 ) 8: 0.176, 0.184, 0.194 (s, s, s, ratio undetermined, 9 H total, -GeMe3), 1.03, 1.08, 1.14 (d, 7 = 7 Hz, d, 7 = 7 Hz, d, J = 7 Hz, ratio 11:1:22, 3 H total), 1.47-2.79 (m, 12H), 4.66, 4,68 (s, s, ratio 1:2, 1H total), 4.74, 4.78 (s, s, ratio 2:1, 1H total), 5.23, 5.26 (m, m, ratio 2:1, 1H total), 5.48 (m, 1H). Signals attributed to the major epimer: 1 3 C nmr (75.3 M H z , C D C I 3 ) 8: -1.6 (-ve), 11.7 (-ve), 20.7 (-ve), 32.5, 35.6, 39.6 (-ve), 40.4 (-ve), 46.1, 48.1 (-ve), 109.7, 124.0, 147.5, 151.8, 212.8. IR (neat): 1713, 1646, 1447, 1236, 918, 825, 599 cm" 1. Exact mass calcd for C i 6 H 2 8 7 4 G e O : 310.1352; found: 310.1345. Anal, calcd for C i 6 H 2 8 G e O : C 62.20, H 9.13; found: C 62.31, H 9.12. Preparation of 2-(trimemylstannyDaIlylcopperQ)-dimethyl sulfide (182) SnMe3 182 To a cold (-78 ° C ) , stirred solution of freshly distilled 2,3-bis(trimethylstannyl)propene (183) (1 equiv) in dry T H F (~7 mL/mmol of allylstannane) was added M e L i * L i B r (1 equiv, 1.5 M solution in Et20). After the pale yellow solution had been stirred for 30 minutes, solid C u B r » M e 2 S (1.05 equiv) was added in one portion. The solution turned cloudy, but then after 15 minutes, a homogeneous yellow solution of 2-(trimethylstannyl)-allylcopper(I)-dimethyl sulfide (182) was obtained. General Procedure B: Conjugate addition of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) to oc.pVunsaturated ketones and aldehydes To a cold (-78 ° C ) , stirred solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (-1.75 equiv) in dry T H F (-7 mL/mmol of allylstannane) were added freshly distilled, neat trimethylsilyl bromide (5 to 9 equiv), followed by the appropriate, freshly distilled a.pVunsaturated carbonyl compound (1.0 equiv). After 15 minutes, the reaction mixture was poured into aqueous N H 4 C I - N H 4 O H (pH 8) (-1 m L / m L T H F ) and the resultant mixture was diluted with Et20 (-4 m L / m L T H F ) . The mixture was stirred open to the air for 15 minutes before the phases were separated. The aqueous phase was extracted with Et20 (3 x -1 m L / m L T H F ) and the combined organic phases were washed with brine (2 x -1 m L / m L T H F ) , dried (MgS04) and concentrated. The crude product was purified by radial chromatography and the acquired liquid was distilled. Preparation of 3-Q-(trimethylstannyl)allyDcyclohexanone (184) 0 184 Following general procedure B , 3-(2-(trimethylstannyl)allyl)cyclohexanone (184) was prepared by treating a solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (1.76 equiv, 1.09 mmol) in dry T H F (7 mL) with trimethylsilyl bromide (0.691 g, 4.52 mmol) and cyclohex-2-enone (110) (60 p L , 0.62 mmol). Purification of the crude product by radial chromatography (2 mm plate, 10:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (108 - 126 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.173 g (93%) of the ketone 184 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.10 (s, 9H, - S n M e 3 , 2 7 S n - H = 53 Hz), 1.21-1.31 (m, 1H), 1.54-1.64 (m, 1H), 1.74-1.88 (m, 2H), 1.93-2.06 (m, 2H), 2.19-2.40 (m, 5H), 5.19 (m, 1H, 3 7 S n - H = 70 Hz), 5.61 (m, 1H, 3 7 S n - H = 150 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.5 (-ve), 25.0, 30.9, 38.6 (-ve), 41.4, 48.0, 48.1, 126.6, 152.9, 211.6. IR (neat): 1714, 917, 769, 527 cm" 1. Exact mass calcd for C n H i 9 O 1 2 0 S n ( M + - M e ) : 287.0458; found: 287.0460. Anal, calcd for Ci 2 H 2 2 O S n : C 47.89, H 7.37; found: C 48.09, H 7.55. 203 Preparation of frans-4-isopropyl-3-(2-(trimefo (185) O 185 Following general procedure B , £ r a n s - 4 - i s o p r o p y l - 3 - ( 2 - ( t r i m e t h y l s t a n n y l ) a l l y l ) -cyclohexanone (185) was prepared by treating a solution of 2-(trimethylstannyl)-allylcopper(I)-dimethyl sulfide (182) (1.75 equiv, 0.884 mmol) in dry T H F (6 mL) with trimethylsilyl bromide (0.511 g, 3.34 mmol) and 4-isopropylcyclohex-2-enone (170) (74 U.L, 0.50 mmol). Purification of the crude product by radial chromatography (2 mm plate, 10:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (138 -154 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.156 g (90%) of the ketone 185 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 0.12 (s, 9H, -SnMe3, 2 7 S n - H = 53 Hz), 0.83 (d, 3H, 7 = 7 Hz), 0.98 (d, 3H, 7 = 1 Hz), 1.30-1.37 (m, 1H), 1.49-1.59 (m, 1H), 1.77-2.10 (m, 5H), 2.18-2.26 (m, 1H), 2.32-2.39 (m, 2H), 2.66 (ddt, 1H, 7 = 13, 4, 2 Hz , 3 7 S n - H = 41 Hz), 5.20 (m, 1H, 3 7 S n - H = 70 Hz), 5.60 (m, 1H, 3 7 S n - H = 150 Hz). !3C nmr (75.3 M H z , CDCI3) 8: -9.3 (-ve), 16.7 (-ve), 21.5 (-ve), 24.0, 27.0 (-ve), 38.7 (-ve), 40.2, 45.0, 45.8, 46.1 (-ve), 127.1, 153.1, 212.2. IR(neat): 1718,918,769,527 cm" 1. Exact mass calcd for C i 5 H 2 8 0 l z u S n : 344.1162; found: 344.1169. Anal, calcd for C i 5 H 2 8 O S n : C 52.51, H 8.23; found: C 52.46, H 8.29. Preparation of 3-methyl-3-('2-(trimethylstannyl)allyDcyclohexanone (186) O rS SnMe, Following general procedure B , 3-methyl-3-(2-(trimethylstannyl)allyl)cyclohexanone (186) was prepared by treating a solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (1.99 equiv, 1.14 mmol) in dry T H F (7.5 mL) with trimethylsilyl bromide (0.512 g, 3.35 mmol) and 3-methylcyclohex-2-enone (171) (65 u L , 0.57 mmol). Purification of the crude product by radial chromatography (2 mm plate, 10:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (135 - 140 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.110 g (61%) of the ketone 186 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.13 (s, 9H, -SnMe3, 2 7sn-H = 52 Hz), 0.88 (s, 3H, -CH3), 1.47-1.53 (m, 1H), 1.58-1.65 (m, 1H), 1.76-1.96 (m, 2H), 2.03 (dt, 1H, J = 13.5, 1.5 Hz), 2.16-2.32 (m, 5H), 5.35 (br d, 1H, J = 2.5 Hz, 3 7 S n - H = 70 Hz), 5.65 (m, 1H, 3 7 S n - H = 1 5 1 H z ) . 186 nmr (75.3 M H z , CDCI3) 8: -8.4 (-ve), 22.0, 25.0 (-ve), 36.0, 39.5, 40.9, 52.2, 53.5, 130.8, 150.8, 212.1. IR (neat): 1713, 922, 770, 526 cm" 1. Exact mass calcd for C i 2 H 2 i O 1 2 0 S n ( M + - M e ) : 301.0614; found: 301.0606. Anal, calcd for C i 3 H 2 4 0 S n : C 49.57, H 7.68; found: C 49.70, H 7.86. Preparation of 3-(2-(rimethylstannyDallyDcyclopentanone (187) O 187 Following general procedure B , 3-(2-(trimethylstannyl)allyl)cyclopentanone (187) was prepared by treating a solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (1.71 equiv, 0.980 mmol) in dry T H F (6.5 mL) with trimethylsilyl bromide (0.444 g, 2.90 mmol) and cyclopent-2-enone (172) (48 U.L, 0.57 mmol). Purification of the crude product by radial chromatography (2 mm plate, 10:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (185 - 195 ° C / 1 6 Torr) of the acquired liquid, provided 0.145 g (88%) of the ketone 187 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 0.13 (s, 9H, -SnMe_3, 2 / S n - H = 53 Hz), 1.48-1.59 (m, 1H), 1.81 (dd, 1H, J = 17, 7.5 Hz), 2.03-2.45 (m, 7H), 5.19 (m, 1H, 3 7 S n - H = 70 Hz), 5.64 (m, 1H, 3 7 S n - H = 150 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.4 (-ve), 29.0, 36.5 (-ve), 38.1, 44.9, 46.8, 126.2, 153.4, 219.5. IR (neat): 1746, 918, 770, 526 cm" 1. Exact mass calcd for C i o H i 7 0 1 2 0 S n ( M + - Me): 273.0302; found: 273.0302. Anal, calcd for C n H 2 o O S n : C 46.04, H 7.02; found: C 46.34, H 7.27. Preparation of 3-memyl-3-(2-(ujimemylstannyDallyDcyclopentanone (188) O 188 Following general procedure B , 3-methyl-3-(2-(trimethylstannyl)allyl)cyclopentanone (188) was prepared by treating a solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (1.72 equiv, 0.955 mmol) in dry T H F (7 mL) with trimethylsilyl bromide (0.470 g, 3.07 mmol) and 3-methylcyclopent-2-enone (173) (55 p L , 0.56 mmol). Purification of the crude product by radial chromatography (1 mm plate, 10:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (115 -121 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.090 g (54%) of the ketone 188 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.14 (s, 9H, - S n M e j , 2 / S n - H = 52 Hz), 1.01 (s, 3H), 1.67-1.74 (m, 1H), 1.80-1.88 (m, 1H), 1.95 (d, 1H, J = 17 Hz), 2.13 (d, 1H, J = 17 Hz), 2.24-2.29 (m, 2H), 2.36 (s, 2H, 3 7sn-H = 58 Hz), 5.34 (d, 1H, J = 2.5 Hz, 3 7 S n-H = 69 Hz), 5.67 (m, 1H, 3 / S n - H = 150 Hz). 1 3 C nmr (75.3 M H z , C D C I 3 ) 8: -8.5 (-ve), 25.7 (-ve), 35.1, 36.5, 40.0, 51.3, 52.1, 130.2, 151.6, 219.6. IR (neat): 1745, 921, 770, 526 cm" 1. Exact mass calcd for C n H i 9 O 1 2 0 S n ( M + - M e ) : 287.0458; found: 287.0459. Anal, calcd for C i 2 H 2 2 0 S n : C 47.89, H 7.37; found: C 47.97, H 7.35. Preparation of a mixture of trans- and c;'5-2-methyl-3-(2-(trimethylstannyl)allyDcyclo-pentanone (189) Fol lowing general procedure B , a mixture of trans- and c i . s - 2 - m e t h y l -3-(2-(trimethylstannyl)allyl)cyclopentanone (189) was prepared by treating a solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (1.72 equiv, 0.979 mmol) in dry T H F (7 mL) with trimethylsilyl bromide (0.524 g, 3.42 mmol) and 2-methyl-cyclopent-2-enone (174) (56 p L , 0.57 mmol). Purification of the crude product by radial O 189 chromatography (2 mm plate, 10:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (94 - 99 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.140 g (82%) of the ketone 189 as a colorless oil. * H nmr analysis of the oil inidcated an -8:1 mixture of C-2 epimers. ! H nmr (400 M H z , C D C 1 3 ) 5: 0.13 (s, 9H, -SnMe3, 2 / S n - H = 53 Hz), 0.98, 1.07 (d, J = 6.5 Hz , d, J = 6.5 Hz, ratio 1:8, 3H total), 1.22-1.38 (m, 1H), 1.62-1.78 (m, 2H), 1.92-2.19 (m, 3H), 2.27-2.37 (m, 1H), 2.67-2.74 (m, 1H), 5.20 (m, 1H, 3 / s n - H = 70 Hz), 5.64, 5.69 (m, m, ratio 1:8, 1H total, 37sn-H = 150 Hz). Signals attributed to the major epimer: 1 3 C nmr (75.3 M H z , CDCI3) 5: -9.4 (-ve), 12.8 (-ve), 27.3, 37.2, 44.5 (-ve), 46.2, 50.2 (-ve), 126.3, 153.4, 221.0. IR (neat): 1743, 916, 768, 527 cm" 1. Exact mass calcd for C n H i 9 O 1 2 0 S n ( M + - M e ) : 287.0458; found: 287.0463. Anal, calcd for C12H22OS11: C 47.89, H 7.37; found: C 48.02, H 7.21. 209 Preparation of a mixture of (2R. 35. 5R)- and (25. 35. 5fl)-2-methyl-5-isopropenyl-3-(2-(trimethylstannyl)alryl)cyclohexanone (190) O 190 Following general procedure B , a mixture of (2R, 35, 5R)- and (25, 35, 5/?)-2-methyl-5-isopropenyl-3-(2-(trimethylstannyl)allyl)cyclohexanone (190) was prepared by treating a solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (1.75 equiv, 0.85 mmol) in dry T H F (6 mL) with trimethylsilyl bromide (0.508 g, 3.32 mmol) and (7?)-(-)-carvone (175) (76 uX, 0.49 mmol). Purification of the crude product by radial chromatography (2 mm plate, 20:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (136 - 144 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.146 g (85%) of the ketone 190 as a colorless oil. * H nmr analysis of the oil inidcated an ~2:1 mixture of C-2 epimers containing a small amount (2-3%) of a corresponding C-3 epimer. ! H nmr (400 M H z , CDCI3) 5: 0.10, 0.12 (s, s, ratio 1:2, 9 H total, - S n M e j , 2 7sn-H = 53 Hz), 1.02, 1.07, 1.14 (d, J = 7 Hz, d, J = 7 Hz, d, J = 7 Hz , ratio 20:1:10, 3 H total), 1.50-1.78 (m, 4H), 1.84-2.05 (m, 2H), 2.08-2.80 (m, 6H), 4.65, 4.68 (s, s, ratio 1:2, 1H total), 4.74, 4.78 (m, s, ratio 2:1, 1H total), 5.19, 5.22 (m, d, J= 2.5 Hz , ratio 2:1, 1H total, 37 Sn-H = 69 Hz), 5.62 (m, 1H, 3 7 S n-H = 149 Hz). Signals attributed to the major C-2 epimer: 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.4 (-ve), 11.7 (-ve), 20.8 (-ve), 32.6, 38.4 (-ve), 40.1 (-ve), 43.6, 46.1, 48.0 (-ve), 109.7, 126.5, 147.5, 153.5, 212.6. IR (neat): 1713, 1646, 917, 892, 769, 529 c n r 1 . Exact mass calcd for C i 6 H 2 8 O 1 2 0 S n : 356.1162; found: 356.1171. Anal, calcd for C i 6 H 2 8 0 S n : C 54.12, H 7.95; found: C 54.27, H 7.93. 4. Trans -Fused Bicyclo[3.3.0]octane R i n g Systems Preparation of the aldehyde 239 Following general procedure B , the aldehyde 239 was prepared by treating a solution of 2-(trimethylstannyl)allylcopper(I)-dimethyl sulfide (182) (1.79 equiv, 1.05 mmol) in dry T H F (7 mL) with trimethylsilyl bromide (0.550 g, 3.59 mmol), followed by the dropwise addition of a solution of the unsaturated aldehyde 71 (0.139 g, 0.588 mmol) in dry T H F (1 mL). Purification of the crude product by radial chromatography (2 mm plate, 7:1 petroleum ether - E t 2 0 ) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.195 g (75%) of the aldehyde 239 as a colorless oil. * H nmr spectroscopic analysis of the oil indicated an ~2.2:1 mixture (ot:(3) of epimeric aldehydes. H SnMe3 239 * H nmr (400 M H z , CDCI3) 8: 0.13 (s, 9H, - S n M e 3 , 2 J S n - H = 53 Hz), 0.909, 0.913 (s, s, ratio -1:2, 3H total, -CH3), 0.950, 0.956 (s, s, ratio -2:1, 3H total, -CH3), 1.42-1.78 (m, 3H), 1.99-2.43 (m, 8H), 2.54-2.72, 2.89-2.94 (m, m, 1H total), 3.40-3.47 (m, 4 H , -CH2O-), 5.18, 5.20 (d, J = 2.5 Hz , m, ratio -2:1, 1H total, 3 Jsn-H = 69 Hz), 5.63-5.65 (m, 1H, 3 j S n _ H = 151 Hz), 9.48, 9.80 (d, J = 3.5 Hz, d, J = 2 Hz, a:p ratio -2.2:1, 1H total, - C H O ) . 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.5 (-ve, - S n M £ 3 > . -9.3 (-ve, -SnMe3), 22.4 (-ve, - C H 3 ) , 22.5 (-ve, -CH3), 30.0, 32.6, 34.4, 38.5 (-ve, C H ) , 39.4, 39.7, 39.8, 39.9, 40.0 (-ve, C H ) , 41.8, 45.1 (-ve, C H ) , 46.2, 47.5 (-ve, C H ) , 47.9 (-ve, C H ) , 49.0 (-ve, C H ) , 55.1 (-ve, C H ) , 60.5 (-ve, C H ) , 72.0 ( - C H 2 0 - ) , 72.1 ( - C H 2 0 - ) , 109.6 ( O - C - O ) , 110.1 (O-C-O) , 126.4 ( C = C H 2 ) , 127.2 ( C = C H 2 ) , 153.9 ( C = C H 2 ) , 203.7 (-ve, - C H O ) , 204.8 (-ve, - C H O ) . IR (neat): 2710, 1723, 1116, 917, 769, 528 c n r 1 . Exact mass calcd for C 2 o H 3 4 0 3 1 2 0 S n : 442.1530; found: 442.1535. Anal, calcd for C 2 u H 3 4 0 3 S n : C 54.45, H 7.77; found: C 54.26, H 8.00. Preparation of the alkenyl iodides 238 and 241 H H I I 238 241 To a stirred solution of the alkenyltrimethylstannane 239 (0.556 g, 1.26 mmol, 2.2:1 mixture of epimers) in dry C H 2 C 1 2 (25 mL), at room temperature, was added AModo-succinimide (0.425 g, 1.89 mmol). The mixture turned pink immediately and was stirred at room temperature for 10 minutes. Saturated aqueous Na2S203 (25 mL) was added and the phases were separated. The aqueous phase was extracted with CH2CI2 (3 x 25 mL). The combined organic extracts were washed with saturated aqueous Na2S203 (10 mL), dried (Na2SC"4), and concentrated. The crude product was purified by radial chromatography (4 mm plate, 5:1 petroleum ether - E t 2 0 ) to yield two compounds, 0.137 g (27%) of the cw-alkenyl iodide 241 and 0.325 g (64%) of the trans-alkenyl iodide 238, both as white solids. Recrystallization of 241 from pentane - Et20 afforded colorless crystals (mp 80-81 ° C ) , while recrystallization of 238 from pentane afforded colorless plates (mp 55 - 56 °C) . /rans-alkenyl iodide 238 ! H nmr (400 M H z , CDCI3) 8: 0.91 (s, 3H, -CH3) , 0.98 (s, 3H, -CH3) , 1.69-1.78 (m, 2H), 1.94-2.09 (m, 3H), 2.14 (ddd, 1H, J = 13.5, 9, 1 Hz), 2.19-2.27 (m, 1H), 2.34-2.50 (m, 4H), 2.56-2.66 (m, 1H), 3.41-3.48 (m, 3H, three from -CH2O-) , 3.57 (d, 1H, one from - C H 2 O - , J = 11.5 Hz), 5.70 (d, 1H, J = 1.5 Hz), 6.07 (d, 1H, J = 1.5 Hz), 9.55 (d, 1H, - C H O , J = 3.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 22.4 (-ve), 22.6 (-ve), 30.0, 34.3, 38.2, 39.8 (-ve), 40.6, 46.7 (-ve), 47.1 (-ve), 50.3, 59.8 (-ve), 72.0 (2 signals, - O C H 2 - ) , 110.06, 110.12, 127.3, 203.2 (-ve). I R ( K B r ) : 2709, 1723, 1615, 1115 cm- 1 . Exact mass calcd for C i 7 H 2 5 0 3 I : 404.0848; found: 404.0850. Anal, calcd for C17H25O3I: C 50.51, H 6.23,1 31.39; found: C 50.70, H 6.40,131.25. ds-alkenyl iodide 241 ! H nmr (400 M H z , CDCI3) 5: 0.91 (s, 3H, -CH3) , 0.97 (s, 3H, -CH3) , 1.59-1.66 (m, 2H), 1.79 (dd, 1H, 7 = 13.5, 5.5 Hz), 2.07-2.24 (m, 3H), 2.30-2.44 (m, 3H), 2.50-2.55 (m, 1H), 2.59-2.67 (m, 1H), 2.98-3.03 (m, 1H), 3.41-3.48 (m, 3 H , three from - C H 2 O - ) , 3.53 (d, 1H, one from - C H 2 O - , 7 = 11.5 Hz), 5.73 (d, 1H, 7 = 1.5 Hz), 6.04 (d, 1H, 7 = 1.5 Hz), 9.76 (d, 1H, - C H O , 7 = 2 Hz). !3C nmr (50.3 M H z , CDCI3) 8: 22.5 (-ve), 22.6 (-ve), 30.1, 32.8, 38.4, 38.5 (-ve), 41.0, 45.0 (-ve), 46.1, 48.2 (-ve), 55.0 (-ve), 72.0, 72.2, 109.8, 110.9, 127.2, 203.9 (-ve). IR (KBr): 2720, 1719, 1615, 1112 cm- 1 . Exact mass calcd for C17H25O3I: 404.0848; found: 404.0851. Anal, calcd for C17H25O3I: C 50.51, H 6.23,1 31.39; found: C 50.70, H 6.48,131.20. Epimerization of the aldehyde 241 H H 238 241 To a stirred solution of 241 (0.097 g, 0.24 mmol) in dry M e O H (2.5 mL) , at room temperature, was added N a O M e (0.5 M in M e O H , 1.0 m L , 0.5 mmol). After 4 hours, the M e O H was removed under reduced pressure and Et20 (10 mL) and water (5 mL) were added to the residue and the phases were separated. The organic phase was washed with water ( 3 x 5 mL) and brine ( 2 x 5 mL) , dried (MgS04) , and concentrated. Purification of the crude product by radial chromatography (1 mm plate, 5:1 petroleum ether - Et20) provided two compounds, 0.011 g (11%) of 241 and 0.077 g (79%) of 238, both as white solids. Thus the total yield of 238 from the alkenyltrimethylstannane 239 was 85 %. Preparation of the alcohol 237 H 237 To a stirred suspension of C r C h (0.580 g, 4.72 mmol) and N1CI2 (0.060 g, 0.46 mmol) in a mixture of dry D M F (12 mL) and dry D M S O (4 mL), at room temperature, was added the iodo aldehyde 238 (0.316 g, 0.783 mmol) as a solution in dry D M F (4 mL). After 30 minutes, the reaction mixture was diluted with Et20 (40 mL) and brine (20 mL) and the phases were separated. The organic phase was washed with brine (5 x 10 mL), dried (MgS04), and concentrated. The crude product was purified by short column chromatography (20 g T L C grade silica gel, 2:1 petroleum ether - Et20). Removal of trace amounts of solvent (vacuum pump) from the acquired material provided 0.200 g (92%) of 237 as a white solid. * H nmr spectroscopic analysis of the solid indicated a 1:1 mixture of epimeric alcohols. ! H nmr (400 M H z , CDCI3) 5: 0.919, 0.923 (s, s, 3H total, -CH3), 0.950, 0.952 (s, s, 3 H total, -CH3), 1.00-1.10 (m, 1H), 1.18-1.31 (m, 1H), 1.48 (d, 1H, - O H , exchanges with D 2 0 , J = 7.5 Hz), 1.64-1.86 (m, 4H), 1.98-2.26 (m, 4H), 2.40-2.47 (m, 1H), 2.81-2.93 (m, 1H), 3.41-3.49 (m, 4H, -CH2O-), 4.09, 4.20 (br signal, br signal, ratio -1:1, 1H total, -CH(OH)- ) , 4.98, 5.06 (ddd, J = 2.5, 2.5, 2.5 Hz , m, 1H total), 5.08, 5.21 (ddd, J = 2.5, 2.5, 2.5 Hz, m, 1H total). 1 3 C nmr (75.3 M H z , CDCI3) 8: 22.37 (-ve, -CH3), 22.44 (-ve, -CH3), 29.0, 29.9, 33.3, 33.4, 33.7, 37.9, 38.2, 39.6, 39.7, 40.9 (-ve, C H ) , 41.1 (-ve, C H ) , 45.7 (-ve, C H ) , 46.0 (-ve, C H ) , 51.6 (-ve, C H ) , 52.8 (-ve, C H ) , 59.1 (-ve, C H ) , 60.4 (-ve, C H ) , 70.9 (-ve, -CH(OH)- ) , 71.5 ( - C H 2 0 - ) , 71.7 ( - C H 2 0 - ) , 71.9 ( - C H 2 0 - ) , 72.1 ( - C H 2 0 - ) , 75.9 (-ve, -CH(OH)-) , 108.4, 110.9, 111.0, 111.8, 158.9 ( C = C H 2 ) , 160.3 ( C = C H 2 ) . IR (KBr): 3436, 1656, 1110 cm" 1. Exact mass calcd for C i 7 H 2 6 0 3 : 278.1882; found: 278.1879. Anal, calcd for C i 7 H 2 6 0 3 : C 73.35, H 9.41; found: C 73.10, H 9.40. 216 Preparation of the allylic acetate 249 >G 249 To a stirred solution of the allylic alcohol 237 (0.260 g, 0.935 mmol, 1:1 mixture of epimers) in dry CH2CI2 (10 mL) , at room temperature, were added sequentially E t 3 N (260 p L , 1.86 mmol), A C 2 O (175 p L , 1.85 mmol) and D M A P (0.227 g, 1.86 mmol). After 1 hour, water (10 mL) and CH2CI2 (20 mL) were added and the phases were separated. The organic phases was washed with brine (2 x 10 mL) , dried (Na2SC«4), and concentrated. Purification of the crude product by short column chromatography (15 g T L C grade silica gel, 1:1 petroleum ether - Et20) and removal of trace amounts of solvent (vacuum pump) from the acquired liquid provided 0.288 g (96%) of the allylic acetate 249 as a colorless oil. A H nmr spectroscopic analysis of the oil indicated a 1:1 mixture of epimeric acetates. ! H nmr (400 M H z , CDCI3) 8: 0.90, 0.92 (s, s, 3 H total, -CH3), 0.95, 0.96 (s, s, 3H total, -CH3), 0.98-1.08, 1.14-1.22 (m, m, 1H total), 1.64-1.91 (m, 5H), 2.01, 2.06 (s, s, 3 H total, -C(=0)CH_3), 1.93-2.23 (m, 4H), 2.41-2.48 (m, 1H), 2.79-2.89 (m, 1H), 3.41-3.49 (m, 4 H , - C H 2 0 - ) , 4.96, 4.99 (m, m, 1H total), 5.11, 5.25 (m, m, 1H total), 5.20, 5.29 (br d, J = 9.5 Hz, d, J = 4 Hz, ratio -1:1, 1H total, -CH(OAc)- ) . 1 3 C nmr (75.3 M H z , CDCI3) 8: 21.1 (-ve, - C ( = 0 ) - C H 3 ) , 21.2 (-ve, - C ( = 0 ) - C H 3 ) , 22.41 (-ve, - C H 3 ) , 22.46 (-ve, - C H 3 ) , 22.54 (-ve, 2 signals, - C H 3 ) , 30.0, 30.1, 33.65, 33.75, 33.79, 38.19, 38.25, 39.2, 39.7, 40.7 (-ve, C H ) , 41.0 (-ve, C H ) , 45.6 (-ve, C H ) , 45.9 (-ve, C H ) , 52.2 (-ve, C H ) , 53.6 (-ve, C H ) , 57.5 (-ve, C H ) , 57.8 (-ve, C H ) , OAc 7 1 . 6 5 ( - C H 2 0 - ) , 71.86 ( - C H 2 0 - ) , 71.93 ( - C H 2 0 - ) , 72.14 ( - C _ H 2 0 - ) , 73.2 ( - v e , - C H ( O A c ) - ) , 76.7 (-ve, - C H ( O A c ) - ) , 110.0, 110.8, 110.9, 114.4, 153.9 ( C = C H 2 ) , 155.4 ( C = C H 2 ) , 170.7 (C=0), 171.1 (C=0). IR(neat): 1737, 1657, 1239, 1112 cm- 1 . Exact mass calcd for C i 9 H 2 8 0 4 : 320.1988; found: 320.1984. Anal, calcd for C i 9 H 2 8 0 4 : C 71.22, H 8.81; found: C 70.82, H 8.87. Preparation of the keto acetate 250 H 250 Ozone was bubbled through a cold (-78 ° C ) , stirred solution of the allylic acetate 249 (0.243 g, 0.758 mmol, 1:1 mixture of epimers) and dry M e O H (48 p L , 1.2 mmol, 1.5 equiv) in dry C H 2 C 1 2 (15 mL) until a blue - grey color persisted (~5 minutes). Dimethyl sulfide (~2 mL) was added and the mixture was stirred at -78 ° C for 10 minutes and then was warmed to room temperature. The solution was purged with argon and the solvent was removed under reduced pressure. The crude oil was purified by radial chromatography (2 mm plate, 2:1 petroleum ether - E t 2 0 ) . Removal of trace amounts of solvent (vacuum pump) from the acquired liquid provided 0.220 g (90%) of 250 as a colorless oil. * H nmr spectroscopic analysis of the oil indicated a 1:1 ratio of epimeric acetates. * H nmr (400 M H z , CDCI3) 8: 0.90, 0.91 (s, s, 3H total, -CH3), 0.95, 0.96 (s, s, 3H total, - C H 3 ) , 0.99-1.14, 1.19-1.32 (m, m, 1H total), 1.71-1.94 (m, 5H), 2.03, 2.09 (s, s, 3 H total, -C(=0)CH3) , 1.95-2.21 (m, 4H), 2.48-2.53 (m, 1H), 2.75-2.87 (m, 1H), 3.40-3.49 (m, 4H, -CH2O-), 4.88, 4.92 (d, J = 5.5 Hz, d, J = 11 Hz, ratio -1:1, 1H total, -CH(OAc)-) . 1 3 C nmr (75.3 M H z , CDCI3) 8: 20.4 (-ve, - C ( = 0 ) - C H 3 ) , 20.6 (-ve, - C ( = 0 ) - C H 3 ) , 22.31 (-ve, - C H 3 ) , 22.35 (-ve, - C H 3 ) , 22.44 (-ve, 2 signals, - C H 3 ) , 29.9, 30.6, 34.5, 37.9, 38.7, 39.0, 40.8, 42.1 (-ve, C H ) , 42.4 (-ve, C H ) , 42.5, 43.0 (-ve, C H ) , 43.4 (-ve, C H ) , 46.5 (-ve, C H ) , 49.5 (-ve, C H ) , 52.7 (-ve, C H ) , 53.8 (-ve, C H ) , 71 .64 ( - C H 2 O - ) , 71.79 ( - C H 2 O - ) , 71.82 ( - C H 2 0 - ) , 72.01 ( - C _ H 2 0 - ) , 72.6 ( - v e , - C H ( O A c ) - ) , 80.1 (-ve, - C H ( O A c ) - ) , 110.5 ( O - C - O ) , 110.6 ( O - C - O ) , 169.6 ( O C ( = 0 ) C H 3 ) , 170.1 (OC(=0)CH 3 ) , 212.4 (C=0), 214.3 (C=0). IR (neat): 1757, 1230, 1110 cm" 1. Exact mass calcd for C18H26O5: 322.1780; found: 322.1777. Preparation of the triquinane keto ketal 236 H 2 3 6 To a cold (-78 ° C ) , stirred solution of SmL: (0.1 M in T H F , 20 m L , 2.0 mmol) was added the keto acetate 250 (0.250 g, 0.775 mmol, 1:1 mixture of epimers) as a solution in a mixture of dry T H F (12 mL) and dry M e O H (4 mL). The initially deep blue solution turned dark green. After 10 minutes, the reaction mixture was warmed to room temperature for 15 minutes. The mixture was poured into saturated aqueous K2CO3 (25 mL) and the mixture was diluted with saturated aqueous Na2S203 (10 mL) and Et20 (35 mL). The phases were separated and the aqueous phase was extracted with Et20 (5 x 10 mL). The combined organic extracts were dried (MgS04) and concentrated. Purification of the crude product by radial chromatography (2 mm plate, 2:1 petroleum ether - Et20) provided 0.234 g (89%) of the ketone 2 3 6 as a white solid. Recrystallization from heptane afforded ketone 236 as colorless crystals (mp 74 - 75 °C) . ! H nmr (400 M H z , CDCI3) 8: 0.93 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 1.06-1.14 (m, 1H), 1.69-1.89 (m, 6H), 2.07-2.22 (m, 4H), 2.31 (dd, 1H, J = 16, 5.5 Hz), 2.37 (dd, 1H, J = 16, 4 Hz), 2.76-2.87 (m, 1H), 3.44-3.45 (m, 4H, -CH2O-). 1 3 C nmr (75.3 M H z , CDCI3) 8: 22.48 (-ve), 22.53 (-ve), 30.0, 36.0, 37.8, 39.6, 42.3 (-ve), 43.4, 43.77, 44.80 (-ve), 49.2 (-ve), 54.6 (-ve), 71.9, 72.0, 110.9, 220.2. IR(KBr) : 1745, 1113 cm" 1. Exact mass calcd for C16H24O3: 264.1726; found: 264.1725. Anal, calcd for C16H24O3: C 72.69, H 9.15; found: C 73.00, H 9.15. 5 . Copper(I) Chloride-Mediated Coupling of Bis(alkenyltrimethyl-stannanes) Preparation of methyl 2-(trifluoromethanesulfonyloxy)cyclohept-l-enecarboxylate (283)172a To a cold (0 ° C ) , stirred suspension of K H (0.518, 12.9 mmol) in dry T H F (40 mL) was added, dropwise, a solution of freshly distilled methyl 2-oxo-l-cycloheptanecarboxylate (284) (1.71 g, 10.0 mmol) in T H F (10 mL). After 30 minutes, N-phenyltrif luoro-methanesulfonimide (4.35 g, 12.2 mmol) was added as a solid. After an additional 30 minutes, the reaction mixture was warmed to room temperature for 90 minutes. The mixture was suction filtered through Flor i s i l® (20 g) and the cake was washed with Et20 (400 mL). The filtrate was concentrated under reduced pressure and the crude oil was purified by flash chromatography (170 g silica gel, 19:1 petroleum ether - Et20). Bulb-to-bulb distillation (130 - 150 ° C / 0 . 3 Torr) of the acquired liquid provided 2.71 g (89%) of methyl 2-(trifluoromethanesulfonyloxy)cyclohept-l-enecarboxylate (283) as a colorless oil. 283 ! H nmr (400 M H z , CDCI3) 5: 1.60-1.71 (m, 4H), 1.73-1.79 (m, 2H), 2.49-2.52 (m, 2H), 2.56-2.59 (m, 2H), 3.78 (s, 3H, - C 0 2 M e ) . 1 3 C nmr (75.3 M H z , CDCI3) 8: 23.7, 25.2, 28.0, 30.7, 34.0, 52.3 (-ve), 118.3 (q, -CF3, 7 C -F = 4 Hz), 127.8, 155.0, 166.1. IR (neat): 1728, 1659, 1423, 1212, 1141, 1003, 867 cm" 1. Exact mass calcd for C10H13F3O5S: 302.0436; found: 302.0431. Anal, calcd for C10H13F3O5S: C 39.74, H 4.33, S 10.61; found: C 39.97, H 4.41, S 10.57. Preparation of methyl 2-(trimethylstannyDcyclohept-l-enecarboxylate (285) 1 7 2 a G . C 0 2 M e S n M e 3 285 To a cold ( - 2 0 ° C ) , stirred solution of (Me3Sn) 2 (4.21 g, 12.9 mmol) in dry T H F (65 mL) was added M e L i (1.40 M in E t 2 0 , 9.30 m L , 13.0 mmol). After 30 minutes, CuSPh (2.29 g, 13.2 mmol) was added as a solid to the now pale yellow solution. After an additional 30 minutes, methyl 2-(trifluoromethanesulfonyloxy)cyclohept-l-ene-carboxylate (283) (2.52 g, 8.33 mmol) was added as a solution in T H F (10 mL) to the red-brown solution of the cuprate. Sixty minutes later, H M P A (4.60 m L , 26.4 mmol) was added and the reaction mixture was warmed to 0 ° C for 90 minutes. The reaction mixture was poured into aqueous NH4CI-NH4OH (pH 8) (100 mL), the resultant mixture was diluted with 7:3 petroleum ether-Et20 (200 mL), and then was stirred open to the air for 30 minutes, during which time the aqueous layer turned bright blue. The mixture was filtered through a glass wool plug to remove insoluble byproducts. The phases of the filtrate were separated and the aqueous phase was extracted with Et20 (3 x 30 mL) and the combined organic phases were washed sequentially with aqueous 10 % CUSO4 (3 x 40 mL), water (40 mL), and brine (2 x 40 mL). The organic phase was dried (MgSCU) and concentrated under reduced pressure. Purification of the crude product by short column chromatography (53 g T L C grade silica gel, petroleum ether (200 mL) then 30:1 petroleum ether - Et20 (400 mL)), followed by bulb-to-bulb distillation (114 -124 ° C / 0 . 3 Torr) of the acquired l iquid, provided 2.16 g (82%) of methyl 2-(trimethylstannyl)cyclohept-l-enecarboxylate (285) as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.09 (s, 9H, - S n M e 3 , 2 7sn-H = 53 Hz), 1.38-1.45 (m, 4H), 1.75-1.81 (m, 2H), 2.53-2.56 (m, 2H), 2.61-2.63 (m, 2H), 3.70 (s, 3H, -COoMe) . !3C nmr (75.3 M H z , CDCI3) 8: -6.8 (-ve), 24.8, 26.0, 28.3, 32.6, 34.8, 51.9 (-ve), 143.5, 169.7, 170.0. IR (neat): 1694, 1583, 1281, 1259, 1205, 1156, 769 cm-1. Exact mass calcd for C n H i 9 O 2 1 2 0 S n (M+ - Me): 303.0407; found: 303.0407. Anal, calcd for C i 2 H 2 2 0 2 S n : C 45.47, H 7.00; found: C 45.35, H 6.97. Preparation of 2-(trimemylstannyl)cyclohept-l-enecarbaldehvd^ (282) a C H 2 O H a C H O SnMe3 SnMe3 286 282 To a cold (-78 ° C ) , stirred solution of freshly distilled methyl 2-(trimethylstannyl)-cyclohept-l-enecarboxylate (285) (1.01 g, 3.18 mmol) in dry T H F (32 mL) was added D I B A L - H (1.0 M in hexanes, 9.60 m L , 9.60 mmol). After 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 60 minutes. The reaction mixture was treated with solid ground N a 2 S O 4 » 1 0 H 2 O (~ 0.1 g/mmol D I B A L - H ) , diluted with Et20 (40 mL) and stirred open to the air for 30 minutes. The solution was suction filtered through C e l i t e ® (20 g) and the cake was washed with Et20 (200 mL). The filtrate was concentrated under reduced pressure to yield the allylic alcohol 286, an unstable colorless oil, which was used without further purification. To a cold (0 ° C ) , stirred solution of the crude allylic alcohol 286 in CH2CI2 (8 mL) was added sequentially 3 A molecular sieves (1.55 g), N M O (0.565 g, 4.82 mmol), and T P A P (0.115 g, 0.33 mmol). The solution turned green-black immediately. After 30 minutes, the reaction mixture was warmed to room temperature for 60 minutes. The mixture was filtered through silica gel (20 g) and the cake was washed with Et20 (150 mL). The solvent was removed from the filtrate under reduced pressure and the oil thus obtained was distilled bulb-to-bulb (96 - 104 ° C / 0 . 3 Torr) to yield 0.699 g (77% from the ester 285) of 2-(trimethylstannyl)cyclohept-l-enecarbaldehyde (282) as a colorless oil. * H nmr (400 M H z , CDCI3) 8: 0.23 (s, 9H, - S n M e 3 , 2 7sn-H = 53 Hz), 1.37-1.49 (m, 4H), 1.77-1.82 (m, 2H), 2.53-2.56 (m, 2H), 2.63-2.66 (m, 2H, =C(SnMe 3)-CH2-, 3 7 S n-H = 47 Hz), 9.43 (s, 1H, - C H O , 4 J S n - H = 6 Hz). !3C nmr (75.3 M H z , CDCI3) 8: -7.2 (-ve), 25.0, 26.0, 26.3, 32.5, 36.4, 153.4, 179.6, 193.8 (-ve). IR (neat): 2720, 1680, 1562, 772 cm-1. Exact mass calcd for CioHi 7 0 1 2 0 Sn(M+-Me): 273.0302; found: 273.0301. Anal, calcd for C11H20OS11: C 46.04, H 7.02; found: C 46.28, H 7.24. G e n e r a l Procedure C : Addit ion of 2-(trimethylstannyDallyllithium (271) to fi-(trimethylstannyD-a.p-unsaturated aldehydes To a cold (-78 °C), stirred solution of freshly distilled 2,3-bis(trimethylstannyl)propene (183) (1.25 equiv) in dry T H F (10 mL/mmol of allylstannane) was added M e L i ' L i B r (1.10 equiv, 1.5 M in Et20). After the pale yellow solution had been stirred for 30 minutes, me appropriate freshly distilled P-(trimethylstannyl)-a,P-unsaturated aldehyde (1 equiv) was added as a solution in T H F (1 mL/mmol of unsaturated aldehyde). After 20 minutes, the reaction mixture was poured into aqueous NH4CI-NH4OH (pH 8) (~1 m L / m L T H F ) and the mixture was diluted with Et20 (~2 m L / m L T H F ) . The mixture was stirred open to the air for 15 minutes before the phases were separated. The aqueous phase was extracted with Et20 (3 x ~1 m L / m L T H F ) and the combined organic phases were washed with brine (2 x ~1 m L / m L T H F ) , dried (MgS04), and concentrated. The crude product was purified and dried in vacuo. 225 Preparation of (Z)-9-chloro-2.6-bis(trimethylstannylmona-1.5-dien-4-ol (299) Fol lowing general procedure C , the alcohol 299 was prepared by treating 2,3-bis(trimethylstannyl)propene (183) (0.750 g, 2.04 mmol) in dry T H F (20 mL) with M e L i » L i B r (1.5 M in Et20, 1.24 m L , 1.86 mmol), followed by addition of (Z)-6-chloro-3-(trimethylstannyl)hex-2-enal (291) 2 0 0 (0.460 g, 1.56 mmol) in dry T H F (1.5 mL). Purification of the crude product by short column chromatography (50 g T L C grade silica gel, 10:1 petroleum ether - Et20 containing 1% Et3N) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.728 g (93%) of the alcohol 299 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.15 (s, 9H, -SnMe3, 2 7sn-H = 54 Hz), 0.16 (s, 9H, -SnMe_3, 2 7sn-H = 53 Hz), 1.63 (d, 1H, - O H , exchanges with D 2 0 , J = 2.5 Hz), 1.74-1.82 (m, 2H, H-8 and H-8'), 2.25-2.45 (m, 3H, allylic protons H-3, H-7, and H-7"), 2.57 (dd, 1H, allylic proton H-3', J = 14, 4 Hz, 3 / S n - H = 54 Hz), 3.49 (t, 2H, H-9 and H-9', J= 6.5 Hz), 4.02-4.07 (m, 1H, - C H ( O H ) - ) , 5.35 (d, 1H, H - l , J = 2.5 Hz, 3 ^Sn-H = 68 Hz), 5.77 (d, 1H, H - l ' , J = 2.5 Hz, 3 7 S n - H = 146 Hz), 6.06 (d, 1H, H-5, J= 6.5 Hz, 3 7 S n - H = 137 Hz). 13c nmr (75.3 M H z , CDCI3) 8: -9.0 (-ve), -7.2 (-ve)," 32.7, 37.1, 44.2, 49.1, 71.5 (-ve), 129.0, 142.5 (-ve), 145.1, 151.9. Me3Sn OH SnMe3 299 IR(neat): 3558,921,770,526 cm" 1. Exact mass calcd for C i 4 H 2 8 3 5 C l O 1 1 8 S n 1 2 0 S n ( M + - Me): 484.9867; found: 484.9859. Anal, calcd for C i 5 H 3 i C 1 0 S n 2 : C 36.02, H 6.25; found: C 36.36, H 6.33. Preparation of (Z)- 10-( 'fgr^butyldimethylsi lyloxy')-2.6-bis(trimethylstannyl)-deca-1.5-dien-4-ol (300) Following general procedure C , the alcohol 300 was prepared by treating 2,3 bis(trimethylstannyl)propene (183) (1.187 g, 3.23 mmol) in dry T H F (32 mL) with M e L i » L i B r (1.5 M in E t 2 0 , 1.90 m L , 2.85 mmol), followed by addition of (Z)-7-(ferf-butyldimethylsilyloxy)-3-(trimethylstannyl)hept-2-enal (287)201 (0.982 g, 2.42 mmol) in dry T H F (2.5 mL). Purification of the crude product by short column chromatography (50 g T L C grade silica gel, 20:1 petroleum ether - Et20 containing 1% E t 3 N ) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 1.385 g (94%) of the alcohol 300 as a colorless oil. l H nmr (400 M H z , C D C 1 3 ) 8: 0.02 (s, 6H, -SiMfi2-)> 0.14 (s, 9 H , -SnMe3, 2 7 S n - H = 53 Hz), 0.15 (s, 9 H , - S n M e j , 2 J s n - H = 53 Hz), 0.87 (s, 9H, -Si'Bu-), 1.31-1.39 (m, 2H), 1.43-1.52 (m, 2H), 1.57 (d, 1H, - O H , exchanges with D 2 0 , J = 2.5 Hz), 2.20 (t, 2H, allylic protons H-7 and H-7', J = 1 Hz, 3 / sn -H = 55 Hz), 2.37 (dd, 1H, allylic proton H-3, J = 13.5, 9 Hz), 2.55 (dd, 1H, allylic proton H-3', J = 13.5, 3 Hz), 3.58 (t, 2H, H H Me3Sn OH SnMe3 300 H-10 and H-10', 7 = 6.5 Hz), 3.99-4.05 (m, 1H, -CH(OH)- ) , 5.34 (d, 1H, H - l , 7 = 2.5 Hz, 3 7 S n - H = 68.5 Hz), 5.76 (br s, 1H, H - l ' , 3 7 S n - H = 147 Hz), 5.99 (d, 1H, H-5, 7 = 7 Hz, 3 7 S n - H = 140 Hz). 1 3 C nmr (75.3 M H z , C D C 1 3 ) 8: -8.8 (-ve), -7.3 (-ve), -5.2 (-ve), 18.4, 26.1 (-ve), 26.6, 32.5, 40.2, 49.1, 63.1, 72.0 (-ve), 128.8, 141.5 (-ve), 147.5, 152.1. IR (neat): 3450, 1103, 919, 837, 775, 527 cm- 1 . Exact mass calcd for C 2 i H 4 5 O 2 S i 1 2 0 S n 2 ( M + - Me): 597.1233; found: 597.1243. Anal, calcd for C22H4802SiSn 2: C 43.31, H 7.93; found: C 43.68, H 8.00. Preparation of (Z)-1 l - ( r e r ? - b u t y l d i m e t h y l s i l y P - 2 . 6 - b i s ( t r i m e t h y l s t a n n y D -undeca-1.5-dien-10-yn-4-ol (301) Following general procedure C , the alcohol 301 was prepared by treating 2,3-bis(trimethylstannyl)propene (183) (0.491 g, 1.33 mmol) in dry T H F (13 mL) with M e L i » L i B r (1.46 M in Et20 , 0.84 m L , 1.22 mmol), followed by addition of (Z)-8-(rer?-butyldimethylsilyl)-3-(trimethylstannyl)oct-2-en-7-ynal (292) 2 0 2 (0.413 g, 1.03 mmol) in dry T H F (1.0 mL). Purification of the crude product by short column chromatography (51 g T L C grade silica gel, 25:1 petroleum ether - Et20 containing H H 301 1% Et3N) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.565 g (91%) of the alcohol 301 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.06 (s, 6H, -SiMeo-). 0.14 (s, 9 H , -SnMe^t. 2 7sn-H = 54 Hz), 0.16 (s, 9 H , -SnMe3, 2 7 s n - H = 53 Hz), 0.91 (s, 9 H , -Si'Bu-), 1.47-1.55 (m, 2H, H-8 and H-8'), 1.59 (d, 1H, - O H , exchanges with D 2 0 , 7 = 2.5 Hz), 2.20 (t, 2H, H-9 and H-9', 7 = 7 Hz), 2.33 (t, 2H, allylic protons H-7 and H-7', 7 = 7.5 Hz), 2.37 (dd, 1H, allylic proton H-3, 7 = 13.5, 9 Hz), 2.56 (dd, 1H, allylic proton H-3', 7 = 13.5, 3 Hz), 4.01-4.05 (m, 1H, -CH(OH)- ) , 5.35 (d, 1H, H - l , 7 = 2.5 Hz , 3 7 S n - H = 68 Hz), 5.77 (br s, 1H, H - l ' , 3 7 S n - H = 147 Hz), 6.04 (d, 1H, H-5, 7 = 7 Hz, 3 7 S n - H = 137 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -8.9 (-ve), -7.3 (-ve), -4.4 (-ve), 16.5, 19.2, 26.1 (-ve), 28.9, 39.1, 49.1, 71.8 (-ve), 82.9, 107.6, 128.9, 142.1 (-ve), 146.3, 151.9. IR (neat): 3558, 2174, 921, 838, 775, 528 cm-1. Exact mass calcd for C 2 2 H 4 3 O S i 1 2 0 S n 2 ( M + - M e ) : 591.1127; found: 591.1147. Anal, calcd for C 2 3 H 4 6 0 S i S n 2 : C 45.73, H 7.68; found: C 46.00, H 7.84. 229 Preparation of l-Q-hydroxy-3-(trimethyte cyclopentene (302) Following general procedure C , the alcohol 302 was prepared by treating 2,3-bis(triraethylstannyl)propene (183) (0.823 g, 2.24 mmol) in dry T H F (23 mL) with M e L i » L i B r (1.26 M in Et20 , 1.65 m L , 2.08 mmol), followed by addition of 2-(trimethylstannyl)cyclopent-l-enecarbaldehyde (276)203 (0.478 g, 1.85 mmol) in dry T H F (2.0 mL). Purification of the crude product by short column chromatography (50 g T L C grade silica gel, 20:1 petroleum ether - Et20 containing 1% Et3N) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.805 g (94%) of the alcohol 302 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 0.11 (s, 9H, -SnMe_3, 2 7 S n - H = 54 Hz), 0.16 (s, 9H, -SnMe_3, 2 7 s n - H = 53 Hz), 1.79 (d, 1H, - O H , exchanges with D 2 0 , 7 = 2 Hz), 1.84 (quintet, 2H, -CH2-CH2-CH2-, 7 = 7.5 Hz), 2.27-2.34 (m, 2H), 2.38-2.47 (m, 3H) 2.64 (br d, 1H, allylic proton - C H ( O H ) - C H 2 - , 7 = 14 Hz, 3 7sn-H = 35 Hz), 4.22 (br d, 1H, - C H ( O H ) - , 7 = 10.5 Hz), 5.36 (d, 1H, H a , 7 = 2.5 Hz, 3 7 S n - H = 67 Hz), 5.79 (br s, 1H, H b , 3 7 S n - H = 146 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.1 (-ve), -7.9 (-ve), 24.1, 33.8, 39.6, 48.1, 71.0 (-ve), 128.8, 138.1, 152.9, 153.9. IR (neat): 3559, 1617, 926, 770, 529 cm" 1. OH SnMe3 SnMe3 302 Exact mass calcd for C i 4 H 2 7 O 1 2 0 S n 2 ( M + - Me): 451.0106; found: 451.0090. Anal, calcd for C i 5 H 3 0 O S n 2 : C 38.85, H 6.52; found: C 39.08, H 6.82. Preparation of l-(l-hydroxy-3-(trimethylstannyDbut-3-en-l-yl')-2-(trimethylstannyl')-cyclohexene (303) Following general procedure C , the alcohol 303 was prepared by treating 2,3-bis(trimethylstannyl)propene (183) (0.369 g, 1.00 mmol) in dry T H F (10 mL) with M e L i » L i B r (1.48 M in E t 2 0 , 0.61 m L , 0.90 mmol), followed by addition of 2-(trimethylstannyl)cyclohex-l-enecarbaldehyde (277)204 (0.214 g, 0.78 mmol) in dry T H F (1.0 mL). Purification of the crude product by short column chromatography (33 g T L C grade silica gel, 30:1 petroleum ether - E t 2 0 containing 1% E t 3 N ) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.352 g (94%) of the alcohol 303 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 0.08 (s, 9H, - S n M e j , 2 / S n - H = 52 Hz), 0.15 (s, 9H, - S n M e j , 2 / S n - H = 53 Hz), 1.52-1.69 (m, 4H), 1.72 (d, 1H, - O H , exchanges with D 2 0 , / = 1.5 Hz) , 1.91-2.00 (m, 1H), 2.09-2.22 (m, 3H), 2.33 (dd, 1H, allylic proton - C H ( O H ) - C H 2 - , J = 14, 10.5 Hz, 3 7 S n - H = 64 Hz), 2.59 (d, 1H, allylic proton - C H ( O H ) -OH SnMe3 303 C H 2 - , J = 14 Hz , 3 7sn-H = 40 Hz), 3.89 (br d, 1H, - C H ( O H ) - , J = 10.5 Hz), 5.34 (d, 1H, H a , J = 2.5 Hz, 3 7 S n - H = 68 Hz), 5.79 (d, 1H, H b , J = 2.5 Hz, 3 7 S n - H = 146 Hz). 1 3 C nmr (75.3 M H z , C D C 1 3 ) 5: -9.0 (-ve), -6.8 (-ve), 22.7, 24.0, 27.2, 32.6, 47.5, 75.8 (-ve), 128.5, 134.9, 145.9, 153.3. IR(neat): 3552,919,769,526 cm" 1. Exact mass calcd for C i 5 H 2 9 O 1 2 0 S n 2 ( M + - Me): 465.0263; found: 465.0265. Anal, calcd for C i 6 H320Sn 2 : C 40.22, H 6.75; found: C 40.41, H 6.82. Preparation of l-Q-hydroxy-3-(trimethylstannyl)but-3-en-l-yD-2-(trimethylstannyl)-cycloheptene (304) Following general procedure C , the alcohol 304 was prepared by treating 2,3-bis(trimethylstannyl)propene (183) (0.785 g, 2.13 mmol) in dry T H F (21 mL) with M e L i » L i B r (1.44 M in E t 2 0 , 1.37 m L , 1.97 mmol), followed by addition of 2-(trimethylstannyl)cyclo-hept-l-enecarbaldehyde (282) (0.467 g, 1.63 mmol) in dry T H F (2.0 mL). Purification of the crude product by short column chromatography (50 g T L C grade silica gel, 25:1 petroleum ether - Et20 containing 1% Et3N) and removal of OH SnMe3 304 trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.709 g (89%) of the alcohol 304 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 0.08 (s, 9H, - S n M e j , 2 7sn -H = 53 Hz), 0.15 (s, 9H, -SnMe_3, 2 7sn -H = 54 Hz), 1.29-1.50 (m, 4H), 1.68-1.82 (m, 2H), 1.72 (d, 1H, - O H , exchanges with D 2 0 , J = 1.5 Hz), 2.15 (ddd, 1H, J = 14, 8.5, 2 Hz), 2.25-2.42 (m, 4H), 2.56 (br d, 1H, allylic proton - C H ( O H ) - C H 2 - , J = 14 Hz, 3 7 S n - H = 54 Hz), 3.97 (br d, 1H, - C H ( O H ) - , J = 10.5 Hz), 5.35 (d, 1H, H a , J = 2.5 Hz, 3 7 S n - H = 67 Hz), 5.80 (d, 1H, H b , J = 2.5 Hz, 3 7 S n - H = 146.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -8.9 (-ve), -6.4 (-ve), 26.3, 27.1, 30.5, 32.8, 33.9, 47.3, 76.7 (-ve), 128.5, 140.6, 153.0, 153.9. IR (neat): 3550, 918, 767, 525 cm" 1. Exact mass calcd for C i 6 H 3 i O 1 2 0 S n 2 ( M + - Me): 479.0419; found: 479.0407. Anal, calcd for C17H34OS112: C 41.52, H 6.97; found: C 41.83, H 7.00. General procedure D: Acylation of allylic alcohols To a stirred solution of the alcohol (1 equiv) in dry C H 2 C 1 2 (10 mL/mmol of alcohol), at room temperature, were added sequentially Et3N (2 equiv), A c 2 0 (2 equiv) and D M A P (2 equiv). The mixture was stirred at room temperature for the indicated period of time. The reaction mixture was poured into water (-10 mL/mmol of alcohol) and the phases were separated. The aqueous phase was extracted with C H 2 C 1 2 (3 x -10 mL/mmol of alcohol) and the combined organic phases were washed once with brine (-10 mL/mmol of alcohol), dried (Na2SC>4), and concentrated. The crude product was purified by chromatography and dried in vacuo. Preparation of ('Z)-4-acetoxy-9-chloro-2.6-bis(trimethylstannyl')nona-1.5-diene (307) Following general procedure D , the acetate 307 was prepared by treating the alcohol 299 (0.506 g, 1.01 mmol) in dry C H 2 C 1 2 (10 mL) with E t 3 N (0.30 m L , 2.15 mmol), A c 2 0 (190 U.L, 2.01 mmol), and D M A P (0.248 g, 2.03 mmol) for 2 hours. Purification of the crude product by short column chromatography (52 g T L C grade silica gel, 20:1 petroleum ether - E t 2 0 ) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.545 g (99%) of the acetate 307 as a colorless oil. ! H nmr (400 M H z , CDCI3) 5: 0.13 (s, 9H, -SnMe^. 2/sn-H = 53 Hz), 0.21 (s, 9H, -SnMe_3, 2^Sn-H = 53 Hz), 1.72-1.82 (m, 2H, H-8 and H-8'), 1.98 (s, 3H, -C(=0)CH3), 2.35 (t, 2H, allylic protons H-7 and H-7', J = 1 Hz , 37sn-H = 50 Hz), 2.53 (dd, 1H, allylic proton H-3, J = 14, 5 Hz), 2.57 (dd, 1H, allylic proton H-3', J = 14, 7 Hz), 3.46 (t, 2H, H -9 and H -9 ' , J = 6.5 Hz), 5.16 (ddd, 1H, - C H ( O A c ) - , J = 9, 7, 5 Hz), 5.28 (d, 1H, H - l , J = 2.5 Hz , 37Sn-H = 71 Hz), 5.70 (d, 1H, H - l ' , J = 2.5 Hz , 3/Sn-H = 147 Hz), 5.92 (d, 1H, H-5, J = 9 Hz , 37 S n-H = 134 Hz). H H Me3Sn OAc SnMe3 307 1 3 C nmr (75.3 M H z , CDCI3) 8: -8.9 (-ve), -7.9 (-ve), 21.5 (-ve), 32.2, 37.2, 44.0, 45.7, 76.0 (-ve), 128.8, 139.6 (-ve), 147.6, 150.0, 170.0. IR (neat): 1740, 1240, 923, 774, 526 cm" 1. Exact mass calcd for C i 6 H 3 o 3 5 C 1 0 2 1 1 8 S n 1 2 0 S n ( M + - Me): 526.9973; found: 526.9972. Anal, calcd for C17H33CIO2S112: C 37.65, H 6.13; found: C 37.99, H 6.22. Preparation of (Z)-4-acetoxy- 10-(fer?-butyldimethylsilyloxy V2.6-bis(trimethylstannyl')-deca-1.5-diene (308) Following general procedure D , the acetate 308 was prepared by treating the alcohol 300 (1.09 g, 1.78 mmol) in dry CH2CI2 (18 mL) with Et3N (0.50 m L , 3.59 mmol), AC2O (340 p L , 3.60 mmol), and D M A P (0.437 g, 3.58 mmol) for 2 hours. Purification of the crude product by short column chromatography (53 g T L C grade silica gel, 30:1 petroleum ether - Et20) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 1.161 g (100%) of the acetate 308 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.02 (s, 6H, -SiMfi2-), 0.13 (s, 9H, -SnMe^. 27Sn-H = 52 Hz), 0.20 (s, 9 H , -SnMe3, 27sn-H = 52 Hz), 0.87 (s, 9H, -Si'Bu-), 1.30-1.38 (m, 2H), 1.41-1.49 (m, 2H), 1.98 (s, 3H, -C(=0)CH3), 2.20 (t, 2H, allylic protons H-7 and H H Me3Sn OAc SnMe3 308 H-7', 7 = 1 Hz , 3 7 S n-H = 49 Hz), 2.53 (dd, 1H, allylic proton H-3, 7 = 14, 5 Hz), 2.56 (dd, 1H, allylic proton H-3', 7 = 14, 7 Hz), 3.57 (t, 2 H , H-10 and H-10', 7 = 6 Hz), 5.18 (ddd, 1H, - C H ( O A c ) - , J = 9,1,5 Hz), 5.28 (d, 1H, H - l , 7 = 1.5 Hz, 37Sn-H = 70 Hz), 5.70 (d, 1H, H - l ' , 7 = 1.5 Hz, 3 7 S n-H = 148 Hz), 5.88 (d, 1H, H-5, 7 = 9 Hz, 3 7 S n-H = 138 Hz). 1 3 C nmr (75.3 M H z , C D C 1 3 ) 8: -8.9 (-ve), -7.8 (-ve), -5.3 (-ve), 18.3, 21.6 (-ve), 26.0 (-ve), 26.2, 32.3, 40.4, 45.8, 63.0, 76.1 (-ve), 128.8, 138.2 (-ve), 149.8, 150.1, 169.9. IR (neat): 1739, 1239, 1103, 1017, 922, 837, 775, 527 cm" 1. Exact mass calcd for C 2 3 H 4 7 O 3 S i 1 2 0 S n 2 ( M + - Me): 639.1339; found: 639.1339. Anal, calcd for C24H 5 o03SiSn 2 : C 44.20, H 7.73; found: C 44.56, H 7.96. Preparation of (ZV4-acetoxy-1 l-(fgrf-butyldimethylsilyD-2.6-bis(trimethylstannyD-undeca-1.5-dien-10-yne ("309) Following general procedure D , the acetate 309 was prepared by treating the alcohol 301 (0.481 g, 0.80 mmol) in dry CH2CI2 (8 mL) with E t 3 N (225 p L , 1.61 mmol), AC2O (150 p L , 1.59 mmol), and D M A P (0.194 g, 1.59 mmol) for 4 hours. Purification 309 of the crude product by short column chromatography (30 g T L C grade silica gel, 20:1 petroleum ether - Et20) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.506 g (98%) of the acetate 309 as a colorless oil. ! H nmr (400 M H z , CDCI3) 5: 0.06 (s, 6H, -SiMfi2-), 0.13 (s, 9H, -SnMe^. 2 7 S n-H = 53 Hz), 0.21 (s, 9 H , -SnMe3, 27sn-H = 53 Hz), 0.91 (s, 9H, -Si'Bu-), 1.47-1.55 (m, 2H, H-8 and H-8'), 1.98 (s, 3H, -C(=0)CH3), 2.17 (t, 2H, H-9 and H-9', 7 = 7 Hz), 2.32 (t, 2H, allylic protons H-7 and H-7', 7 = 7.5 Hz, 37sn-H = 51 Hz), 2.53 (dd, 1H, allylic proton H-3, 7 = 14, 5 Hz), 2.56 (dd, 1H, allylic proton H-3', 7 = 14, 7 Hz), 5.18 (ddd, 1H, - C H ( O A c ) - , J = 9,1,5 Hz), 5.28 (d, 1H, H - l , 7 = 1 H z , 3 7 S n-H = 70 Hz), 5.71 (d, 1H, H - l ' , 7 = 1 Hz, 3 7 S n-H = 147 Hz), 5.92 (d, 1H, H-5, 7 = 9 Hz, 37 S„-H=135 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 5: -8.9 (-ve), -7.8 (-ve), -4.3 (-ve), 16.6, 19.1, 21.6 (-ve), 26.2 (-ve), 28.6, 39.3, 45.8, 76.1 (-ve), 83.0, 107.5, 128.9, 139.1 (-ve), 148.8, 150.1, 170.0. IR (neat): 2174, 1739, 1370, 1237, 1017, 923, 838, 776, 527 cm" 1. Exact mass calcd for C24H4 5 O2Si 1 2 0 Sn2 ( M + - Me): 633.1233; found: 633.1224. Anal, calcd for C25H4 8 02SiSn 2 : C 46.47, H 7.49; found: C 46.80, H 7.59. 237 Preparation of l-Q-acetoxy-3-ftrimethylstannyl)but-3-en-l-yD-2-(trimethylstann cyclopentene (310) Following general procedure D , the acetate 310 was prepared by treating the alcohol 302 (0.591 g, 1.27 mmol) in dry CH2CI2 (13 mL) with Et3N (0.40 m L , 2.87 mmol), A c 2 0 (240 p L , 2.54 mmol), and D M A P (0.318 g, 2.60 mmol) for 16 hours. Purification of the crude product by short column chromatography (22 g T L C grade silica gel, 20:1 petroleum ether - Et20 containing 1% Et3N) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.638 g (99%) of the acetate 310 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.13 (s, 9H, -SnMe_3, 2 / S n - H = 53 Hz), 0.17 (s, 9H, -SnMe .3 , 2 7 s n - H = 54 Hz) , 1.73-1.83 (m, 2H, - C H 2 - C f i 2 - C H 2 - ) , 1.98 (s, 3H, -C (=0 )CH 3 ) , 2.32-2.48 (m, 5 H), 2.65 (dd, 1H, allylic proton - C H ( O A c ) - C H 2 - , J = 14, 9.5 Hz), 5.24 (d, 1H, H a , J = 2.5 Hz, 3 7sn-H = 70 Hz), 5.44 (dd, 1H, - C H ( O A c ) - , J = 9.5, 4 Hz), 5.70 (d, 1H, H b , J = 2.5 Hz, 3 7 S n - H = 147 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.1 (-ve), -8.9 (-ve), 21.4 (-ve), 23.5, 33.0, 39.7, 44.5, 74.8 (-ve), 127.9, 140.8, 150.7, 150.9, 170.0. IR (neat): 1740, 1616, 1369, 1235, 1020, 920, 770, 530 cm" 1. Exact mass calcd for C i 6 H 2 9 O 2 1 2 0 S n 2 ( M + - Me): 493.0212; found: 493.0217. OAc SnMe3 SnMe3 310 Anal, calcd for C i 7 H 3 2 0 2 S n 2 : C 40.37, H 6.38; found: C 40.70, H 6.58. Preparation of l-Q-acetoxy-3-(trimethylstannyDbut-3-en-l-yD-2-(trirnethvlstannylV cyclohexene (311) Following general procedure D , the acetate 311 was prepared by treating the alcohol 303 (0.265 g, 0.55 mmol) in dry CH2CI2 (5.5 m L ) with E t 3 N (0.155 p L , 1.11 mmol), A c 2 0 (105 p L , 1.11 mmol), and D M A P (0.135 g, 1.11 mmol) for 18 hours. Purification of the crude product by short column chromatography (33 g T L C grade silica gel, 30:1 petroleum ether - E t 2 0 containing 1% E t 3 N ) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.278 g (97%) of the acetate 311 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 0.13 (s, 9 H , -SnMe_3, 2Jsn-H = 53 Hz), 0.16 (s, 9H, -SnMej , 2 7 S n - H = 53 Hz), 1.46-1.64 (m, 4H), 1.99 (s, 3H, -C(=0) -CH 3 ) , 2.00-2.07 (m, 2H), 2.15-2.21 (m, 2H), 2.38 (dd, 1H, allylic proton - C H ( O A c ) - C H 2 - , J = 15, 3.5 Hz, 3 ^Sn-H = 52 Hz) , 2.72 (dd, 1H, allylic proton - C H ( O A c ) - C H 2 - , J = 15, 9.5 Hz , 3 7sn-H = 43 Hz), 5.13 (dd, 1H, - C H ( O A c ) - , J = 9.5, 3.5 Hz), 5.26 (d, 1H, H a , J = 2 Hz, 3 7 S n - H = 71 Hz), 5.72 (d, 1H, H b , J = 2 Hz, 3 7 S n-H = 149 Hz). OAc SnMe3 311 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.1 (-ve), -8.0 (-ve), 21.4 (-ve), 22.5, 23.6, 25.5, 32.3, 43.8, 80.7 (-ve), 127.5, 138.2, 143.8, 151.0, 170.0. IR (neat): 1739, 1619, 1231, 1017, 921, 769, 526 cm" 1. Exact mass calcd for C i 7 H 3 i O 2 1 2 0 S n 2 ( M + - Me): 507.0368; found: 507.0359. Anal, calcd for C i 8 H 3 4 0 2 S n 2 : C 41.59, H 6.59; found: C 41.95, H 6.83. Preparation of l-(l-acetoxy-3-(trimethylstannyl)but-3-en-l-yD-2-(trimethylstannyl')cyclo-heptene (312) and l-Q-acetoxy-S-ftrimethylstannyDbut-S-en-l-yDcycloheptene (313) Following general procedure D, the alcohol 304 (0.511 g, 1.04 mmol) in dry C H 2 C l 2 ( l l m L ) was treated with Et3N (0.30 mL, 2.25 mmol), AC2O (0.20 mL, 2.12 mmol), and D M A P (0.256 g, 2.09 mmol) for 24 hours. Purification of the crude product by short column chromatography (35 g T L C grade silica gel, 40:1 petroleum ether - Et20 containing 1% Et3N), concentration of the appropriate fractions, and removal of trace amounts of solvent (vacuum pump) from the resulting liquids provided 0.302 g (54%) of the desired acetate 312, and 0.170 g (44%) of the destannylated acetate 313, both as colorless oils. 312 313 1 -(1 -acetoxy-3- (trimethylstannyl)but-3-en-1 -yl)-2-(trimethylstannyl)cycloheptene (312): * H nmr (400 M H z , C D C 1 3 ) 5: 0.12 (s, 9 H , - S n M e j , 27sn-H = 53 Hz), 0.17 (s, 9H, -SnMe_3, 2/sn-H = 52 Hz), 1.21-1.50 (m, 4H), 1.64-1.81 (m, 2H), 1.97 (s, 3H, -C(=0)CH3), 2.23-2.39 (m, 5H), 2.69 (dd, 1H, allylic proton -CH(OAc) -CH2- , J = 14.5, 10 Hz) , 5.15 (dd, 1H, - C H ( O A c ) - , J = 10, 4.5 Hz), 5.26 (d, 1H, H a , / = 2 Hz , 3 / S n . H = 69 Hz), 5.72 (d, 1H, H b ) J = 2 Hz, 3/Sn-H = 149 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.0 (-ve), -7.7 (-ve), 21.4 (-ve), 26.1, 27.0, 28.5, 32.9, 34.4, 43.5, 81.6 (-ve), 127.8, 144.9, 150.85, 150.90, 170.0. IR (neat): 1741, 1615, 1234, 1016, 921, 767, 526 cm" 1. Exact mass calcd for C i 8 H 3 3 O 2 1 2 0 S n 2 ( M + - Me): 521.0524; found: 521.0536. Anal, calcd for C i 9 H 3 6 0 2 S n 2 : C 42.75, H 6.80; found: C 43.11, H 6.79. l-(l-acetoxy-3-(trimethylstannyl)but-3-en-l-yl)cycloheptene (313): ! H nmr (400 M H z , CDCI3) 8: 0.14 (s, 9H, - S n M e 3 , 27sn-H = 53 Hz), 1.35-1.56 (m, 4H), 1.62-1.78 (m, 2H), 1.98 (s, 3H, -C(=0)CH3), 2.05-2.13 (m, 4 H), 2.49 (br dd, 1H, allylic proton - C H ( O A c ) - C H 2 - , J = 14, 5.5 Hz), 2.52 (br dd, 1H, allylic proton - C H ( O A c ) -CH2- , J = 14, 8 Hz), 5.11 (dd, 1H, - C H ( O A c ) - , 7 = 8, 5.5 Hz), 5.20 (d, 1H, H a , J = 2.5 Hz, 37Sn-H = 69 Hz), 5.65 (dt, 1H, H b , J = 2.5, 1 Hz, 37Sn-H = 147 Hz), 5.77 (t, 1H, H c , J = 6.5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -9.2 (-ve), 21.3 (-ve), 26.7, 26.8, 28.0, 28.5, 32.5, 44.2, 78.7 (-ve), 127.7, 129.7 (-ve), 141.9, 151.1, 170.0. IR (neat): 1741, 1240, 1019, 919, 769, 528 cm" 1. Exact mass calcd for C i 5 H 2 5 O 2 1 2 0 S n ( M + - Me): 357.0877; found: 357.0879. Anal, calcd for C i 6 H 2 8 0 2 S n : C 51.79, H 7.61; found: C 52.17, H 7.73. Alternative procedure for the preparation of l-d-acetoxy-3-(trimethylstannyl)-but-3-en-l-ylV2-(trimethylstannyl")cycloheptene (312) OAc SnMe3 To a cold (0 ° C ) , stirred solution of L D A (0.994 mmol, 1.3 equiv) in dry T H F (6 mL) was added the alcohol 304 (0.376 g, 0.764 mmol) as a solution in dry T H F (1.5 mL). After 2 hours, A c 2 0 (144 p L , 1.53 mmol) was added and the mixture was warmed to room temperature. After an additional hour, the mixture was poured into aqueous NH4CI-NH4OH (pH 7) (8 mL) and the mixture was diluted with E t 2 0 (8 mL). The phases were separated and the aqueous phase was extracted with E t 2 0 ( 3 x 8 mL). The combined organic phases were washed with brine ( 2 x 8 mL), dried (MgSCvO, and concentrated. Purification of the crude product by short column chromatography (20 g T L C grade silica gel, 40:1 petroleum ether - E t 2 0 containing 1% Et3N), concentration of the appropriate fractions, and removal of trace amounts of solvent (vacuum pump) from the resulting liquids provided 0.253 g (62%, 77% based on recovered 304) of the desired acetate 312 312 and 0.077 g (20%) of recovered starting material, alcohol 304, both as colorless oils. The spectral data for 312 and 304 were identical with those reported above. General Procedure E : CopperfD chloride-mediated intramolecular coupling of bis(alkenyltrimethylstannanes") A stirred solution of C u C l (~5 equiv) in dry D M F (3.3 mL/mmol CuCl) was heated at 60 ° C with an oil bath (preheated) for 5 minutes. A solution of the bis(alkenyl-trimethylstannane) (1 equiv) in dry D M F (5 mL/mmol of bis(alkenyltrimethylstannane)) was added dropwise, using a small bore cannula. The mixture became rust colored. After 15 minutes, the flask was cooled to room temperature and saturated aqueous NH4CI (1 m L / m m o l CuCl ) was added. The resultant solution was diluted with Et20 (-10 mL/mmol CuCl) and stirred open to the air for 15 minutes. The mixture was poured into an additional quantity of saturated aqueous NH4CI (-10 mL/mmol CuCl) and the layers were separated. The aqueous phase was extracted with Et20 (3 x -10 mL/mmol CuCl) and the combined organic phases were washed with 2 portions of brine (2 x -10 mL/mmol CuCl) , dried (MgS04), and concentrated. The crude product was purified by chromatography and the acquired liquid was distilled. Preparation of 3-acetoxy-l-(3-cMoropropyiy5-methylenecyclopentene (316) 316 Following general procedure E , 3-acetoxy-l-(3-chloropropyl)-5-methylenecyclopentene (316) was prepared by the dropwise addition of the bis(alkenyltrimethylstannane) 307 (0.385 g, 0.71 mmol) in dry D M F (3 mL) to a warm (60 °C) solution of C u C l (0.356 g, 3.59 mmol) in dry D M F (11 mL). Purification of the crude product by short column chromatography (30 g T L C grade silica gel, 10:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (132 - 136 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.130 g (86%) of 316 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 1.96-2.03 (m, 2H, CI-CH2-CH2-CH2-), 2.01 (s, 3H, - C ( = 0 ) C H 3 ) , 2.36 (t, 2H, CI-CH2-CH2-CH.2-, 7 = 8 Hz), 2.50 (dd, 1H, H c , 7 = 17, 2 Hz), 3.00 (dddd, 1H, H d , 7 = 17, 7, 2, 2 Hz), 3.55 (t, 2H, CI-CH2-CH2-CH2-, 7 = 6.5 Hz), 4.90 (d, 1H, 7 = 2 Hz), 4.98 (dd, 1H, 7 = 2, 2 Hz), 5.63 (d, 1H, H b , 7 = 7 Hz), 5.91 (s, 1H, H a ) . 1 3 C nmr (75.3 M H z , CDCI3) 8: 21.2 (-ve), 23.9, 30.3, 37.3, 44.5, 76.2 (-ve), 103.7, 131.3 (-ve), 148.5, 149.7, 170.9. IR (neat): 1729, 1639, 1618, 1372, 1240, 1023, 985 c n r 1 . Exact mass calcd for C n H i 5 3 5 C 1 0 2 : 214.0761; found: 214.0752. Anal, calcd for C11H15CIO2: C 61.54, H 7.04; found: C 61.86, H 7.07. Preparation of 3-acetoxy-l-(4-(fe^butyldimethylsiloxy)butyD-5-methylenecyclopentene (317) T B S O 317 Following general procedure E , 3-acetoxy-l-(4-(feAt-butyldimethylsiloxy)butyl)-5-methylenecyclopentene (317) was prepared by the dropwise addition of the bis(alkenyl-trimethylstannane) 308 (0.660 g, 1.01 mmol) in dry D M F (5 mL) to a warm (60 °C) solution of C u C l (0.508 g, 5.13 mmol) in dry D M F (17 mL). Purification of the crude product by short column chromatography (50 g T L C grade silica gel, 15:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (161 - 171 °C/0.3 Torr) of the acquired liquid, provided 0.258 g (79%) of 317 as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.03 (s, 6H, - S i M e o - L 0.87 (s, 9H, -Si 'Bu-) , 1.50-1.62 (m, 4H), 2.01 (s, 3H, -C(=0)CH3), 2.19 (t, 2H, T B S O -CH2-CH2-CH2-CH2- , 7 = 8 Hz), 2.48 (dd, 1H, H c , 7 = 17, 2 Hz), 2.99 (dddd, 1H, H d , 7 = 17, 7, 2, 2 Hz), 3.61 (t, 2H, TBSO -CH2-CH2-CH2-CH2- , 7 = 6 Hz), 4.86 (d, 1H, 7 = 2 Hz), 4.95 (dd, 1H, 7 = 2, 2 Hz), 5.63 (d, 1 H , H b 7 = 7 Hz), 5.87 (s, 1H, H a ) . 1 3 C nmr (75.3 M H z , CDCI3) 5: -5.4 (-ve), 18.2, 21.1 (-ve), 23.7, 25.9 (-ve), 26.5, 32.6, 37.3, 62.8, 76.4 (-ve), 103.2, 130.6 (-ve), 150.0 (2 quaternary carbons), 170.9. 1 3 C nmr (75.3 M H z , C 6 D 6 ) 5: -5.1 (-ve), 18.5, 20.8 (-ve), 24.3, 26.2 (-ve), 26.9, 33.0, 37.9, 63.0, 76.5 (-ve), 103.3, 131.7 (-ve), 150.0, 150.8, 170.1. IR (neat): 1739, 1639, 1617, 1241, 1103, 1021, 838 cm" 1. Exact mass calcd for C18H32O3S1: 324.2121; found: 324.2118. Anal, calcd for C i 8 H 3 2 0 3 S i : C 66.62, H 9.94; found: C 66.27, H 9.98. Preparation of 3-acetoxy-l-(5-(fgr?-butyldimethylsilyl)pent-4-yn-l-yD-5-methylene-cyclopentene (318) 318 Following general procedure E , 3-acetoxy-l-(5-(rer?-butyldimethylsilyl)pent-4-yn-l-yl)-5-methylenecyclopentene (318) was prepared by the dropwise addition of the bis (alkenyltrimethylstannane) 309 (0.290 g, 0.45 mmol) in dry D M F (2 mL) to a warm (60 ° C ) solution of C u C l (0.243 g, 2.45 mmol) in dry D M F (7 mL). Purification of the crude product by short column chromatography (30 g T L C grade silica gel, 10:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (172 - 179 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.123 g (86%) of 318 as a colorless oil. ! H nmr (400 M H z , CDCI3) 5: 0.06 (s, 6H, -SiMe?-) . 0.91 (s, 9 H , -Si 'Bu-) , 1.70-1.77 (m, 2 H , T B S - C = C - C H 2 - C H 2 - C H 2 - ) , 2.01 (s, 3 H , - C ( = 0 ) C H 3 ) , 2.26 (t, 2H, T B S - C = C - C H 2 - C H 2 - C H 2 - , 7 = 7 Hz), 2.32 (br t, 2H, T B S - C = C - C H 2 - C H 2 - C H 2 - , 7 = 8 Hz), 2.49 (dd, 1H, H c , 7 = 17, 2 Hz), 3.00 (dddd, 1H, H d , 7 = 17, 7, 2, 2 Hz), 4.88 (d, 1H, 7 = 2 Hz), 4.98 (dd, 1H, 7 = 2, 2 Hz), 5.63 (d, 1H, H b , 7 = 7 Hz), 5.89 (s, 1H, H a ) . 1 3 C nmr (75.3 M H z , CDCI3) 8: -4.5 (-ve), 16.4, 19.6, 21.1 (-ve), 25.7, 26.0 (-ve), 26.6, 37.3, 76.3 (-ve), 83.1, 103.5, 107.1, 131.0 (-ve), 149.3, 149.8, 170.8. IR (neat): 2173, 1735, 1639, 1618, 1251, 1022, 839 cm" 1. Exact mass calcd for C i 9 H 3 o 0 2 S i : 318.2015; found: 318.2014. Anal, calcd for C i 9 H 3 0 O 2 S i : C 71.64, H 9.49; found: C 71.79, H 9.40. Preparation of 2-acetoxy-4-methylenebicyclor3.3.01oct-l(5')-ene (319) 319 Following general procedure E , 2-acetoxy-4-methylenebicyclo[3.3.0]oct-l(5)-ene (319) was prepared by the dropwise addition of the bis(alkenyltrimethylstannane) 310 (0.209 g, 0.41 mmol) in dry D M F (2 mL) to a warm (60 ° C ) solution of C u C l (0.223 g, 2.25 mmol) in dry D M F (6 mL). Purification of the crude product by short column chromatography (22 g T L C grade silica gel, 20:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (162 - 166 ° C / 1 2 Torr) of the acquired liquid, provided 0.049 g (67%) of 319 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 2.02 (s, 3 H , -C(=0)CH3), 2.25-2.40 (m, 6 H), 2.74 (dd, 1H, H b , J = 11,2 Hz), 3.30 (dddd, 1 H , H c , J = 17, 7, 2, 2 Hz), 4.71 (br s, 1H), 4.72 (br s, 1H), 5.60 (d, 1H, H a , J = 1 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 21.0 (-ve), 25.8, 27.6, 28.4, 42.7, 73.7 (-ve), 102.2, 144.9, 153.5, 153.9, 171.0. IR (neat): 1741, 1644, 1372, 1255, 1029 cm-1. Exact mass calcd for C i 1H14O2: 178.0994; found: 178.0993. Anal, calcd for C11H14O2: C 74.13, H 7.92; found: C 74.03, H 7.82. Preparation of 7-acetoxy-9-methylenebicyclor4.3.01non-l(6Vene (320) 320 Following general procedure E , 7-acetoxy-9-methylenebicyclo[4.3.0]non-l(6)-ene (320) was prepared by the dropwise addition of the bis (alkenyltrimethylstannane) 311 (0.273 g, 0.52 mmol) in dry D M F (2.5 mL) to a warm (60 ° C ) solution of C u C l (0.285 g, 2.88 mmol) in dry D M F (7.5 mL). Purification of the crude product by short column chromatography (20 g T L C grade silica gel, 20:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (96 - 104 ° C / 0 . 3 Torr) of the acquired liquid, provided 0.082 g (82%) of 320 as a colorless oil. * H nmr (400 M H z , C D C 1 3 ) 8: 1.58-1.74 (m, 4H), 2.03 (s, 3H, -C(=0)CH3_), 2.00-2.21 (m, 4H), 2.37 (dd, 1H, H b , J = 17, 2 Hz), 2.99 (dddd, 1H, H c , J = 17, 7, 2, 2 Hz), 4.72 (br s, 1H), 4.77 (br s, 1H), 5.61 (d, 1H, H a , J = 1 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 21.1 (-ve), 21.6, 21.9, 22.3, 23.8, 37.1, 78.3 (-ve), 100.3, 141.5, 142.9, 150.2, 171.1. IR (neat): 1734, 1635, 1371, 1251, 1025 cm" 1. Exact mass calcd for C12HK5O2: 192.1150; found: 192.1149. Anal, calcd for C i 2 H i 6 0 2 : C 74.97, H 8.39; found: C 75.22, H 8.32. 249 Preparation of 8-acetoxy-10-memylenebicyclor5.3.01dec-l(7)-ene (321) A c O H H b H c H H 321 Following general procedure E , 8-acetoxy-10-methylenebicyclo[5.3.0]dec-l(7)-ene (321) was prepared by the dropwise addition of the bis(alkenyltrimethylstannane) 312 (0.250 g, 0.47 mmol) in dry D M F (2 mL) to a warm (60 ° C ) solution of C u C l (0.286 g, 2.89 mmol) in dry D M F (7.5 mL). Purification of the crude product by short column chromatography (30 g T L C grade silica gel, 20:1 petroleum ether - Et20) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.041 g (42%) of 321 as a colorless oil. ! H nmr (400 M H z , C D C 1 3 ) 8: 1.54-1.64 (m, 4H), 1.71-1.79 (m, 2H), 2.03 (s, 3H, - C ( = 0 ) C H 3 ) , 2.16-2.32 (m, 4 H), 2.36 (dd, 1H, H b , J = 17, 2 Hz), 2.99 (dddd, 1H, H c , J = 17, 7, 2, 2 Hz), 4.72 (br s, 1H), 4.81 (br s, 1H), 5.58 (d, 1H, H a , / = 7 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: 21.2 (-ve), 25.2, 26.4, 26.8, 28.0, 31.1, 37.5, 79.4 (-ve), 100.5, 145.3, 146.3, 151.3, 171.3. IR (neat): 1741, 1631, 1371, 1245, 1029 cm" 1. Exact mass calcd for C13H18O2: 206.1307; found: 206.1301. Anal, calcd for C i 3 H i 8 0 2 : C 75.69, H 8.79; found: C 76.00, H 8.92. Alternative Procedure for the preparation of 8-acetoxy-10-methylenebicyclor5.3.01-dec-im-ene (321) To a cold (0 ° C ) , stirred solution of C u C l (0.124 g, 1.25 mmol) in dry D M F (4 mL) was added the bis (alkenyltrimethylstannane) 312 (0.130 g, 0.244 mmol) dropwise using a small bore cannula as a solution in dry D M F (1 mL) . The solution turned orange immediately. After 15 minutes, the reaction mixture was treated with saturated aqueous NH4CI (1 mL), diluted with E t 2 0 (10 mL) and stirred open to the air for 15 minutes. The mixture was poured into an additional quantity of saturated aqueous NH4CI (10 mL) and the layers were separated. The aqueous phase was extracted with E t 2 0 (3 x 10 mL) and the combined organic extracts were washed with brine (2 x 10 mL), dried (MgS04), and concentrated. Purification of the crude product by short column chromatography (12 g T L C grade silica gel, 15:1 petroleum ether - E t 2 0 ) and removal of trace amounts of solvent (vacuum pump) from the resulting liquid provided 0.033 g (66%) of 321 as a colorless oil. The spectral data for 321 were identical with those reported above. OAc 321 V . A P P E N D I C E S Appendix 1: X - R a y Crystal lographic D a t a 6 5 OAc compound formula formula weight crystal habit crystal system space group lattice parameters a (A) *(A) c(A) a(°) Y(°) V (A 3 ) Z value Dcalc (g/cm3) number of reflections used in refinement residuals R; Rw C20H30O4 334.45 needle monoclinic P2i/n (#14) 6.189 (1) 9.608 (1) 31.190 (1) 92.675 (10) 1852.7 (4) 4 1.199 4048 0.031; 0.029 C 1 6 H 2 4 O 3 264.36 prism triclinic P i (#2) 10.618 (1) 11.350 (1) 6.2220 (7) 91.23 (1) 98.213 (9) 100.64 (1) 728.5 (2) 2 1.205 3330 0.040; 0.038 Appendix 2: Additional Experimental Procedures The following compounds were prepared by other members of the Piers research group in connection with ongoing synthetic studies. These procedures and spectral data, thus far, have not been reported elsewhere and are included here only for completeness of the experimental details presented in this thesis. Preparation of (Z)-6-chloro-3-(trimethylstannyl mex-2-enal (291-)205 To a cold (-78 ° C ) , stirred solution of freshly distilled methyl (Z)-6-chloro-3-(trimethylstannyl)hex-2-enoate (264)206 (2.02 g, 6.20 mmol) in dry T H F (70 mL) was added D I B A L - H (1.0 M in hexanes, 18.6 mL, 18.6 mmol). After 45 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 50 minutes. Saturated aqueous NH4CI (6 mL) was added and the white slurry was stirred at room temperature for 30 minutes. Solid MgSC*4 (~1 g) was added and the mixture was stirred for an additional 30 minutes. The mixture was diluted with Et20 (-250 mL) and filtered through F l o r i s i l ® (20 g). The column was washed with Et20 (-80 mL). The combined eluate was concentrated under reduced pressure to yield the allylic alcohol 328, a colorless oil, which was used without further purification. To a cold (0 ° C ) , stirred solution of the crude allylic alcohol 328 in CH2CI2 (16 mL) was added sequentially 3 A molecular sieves (3.67 g), N M O (1.16 g, 9.92 mmol), and T P A P (0.319 g, 0.907 mmol). The solution turned green-black immediately. After 30 minutes, the reaction mixture was warmed to room temperature for 60 minutes. The mixture was filtered through silica gel and the cake was washed with Et20 (-400 mL). Me3Sn Me3Sn 328 291 The solvent was removed from the filtrate under reduced pressure and the oil thus obtained was distilled bulb-to-bulb (120-132 ° C / 0 . 1 Torr) to yield 1.356 g (75% from the ester 264) of (Z)-6-chloro-3-(trimethylstannyl)hex-2-enal (291) as a colorless oil. lH nmr (400 M H z , CDC1 3 ) 8: 0.25 (s, 9H, -SnMej , 2 Jsn-H = 54 Hz), 1.84-1.91 (m, 2H, CI-CH2-CH2-CH2-), 2.63 (td, 2 H , CI-CH2-CH2-CH2-, J = 7.5, 1.5 Hz, 3 7sn-H = 44 Hz), 3.51 (t, 2H, CI-CH2-CH2-CH2-, J = 7.5 Hz), 6.69 (dt, 1H, olefinic proton, J = 5, 1.5 Hz, 3 7 S n - H = H 6 Hz), 9.57 (d, 1H, - C H O , J = 5 Hz , 4 7 S n - H = 5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -7.4 (-ve), 31.5, 37.8, 43.9, 139.2 (-ve), 179.4, 192.3 (-ve). IR (neat): 2746, 1679, 1563, 779, 532 cm" 1. Exact mass calcd for C 8 H i 4 O 3 5 C l 1 2 0 S n (M+ - Me): 280.9755; found: 280.9757. Anal, calcd for C 9 H i 7 O C l S n : C 36.60, H 5.80; found: C 36.78, H 5.72. Preparation of l-Cfgr^-butyldimethylsilyDhepta-l.b-diyne (297) 2 0 7 297 To a cold (-78 ° C ) , stirred solution of hepta-l,6-diyne (298) (2.70 m L , 2.17 g, 23.6 mmol) in dry T H F (100 mL) was added a solution of M e L i (1.56 M in Et20, 20.0 mL, 31.2 mmol). After 10 minutes, the reaction mixture was warmed to -20 ° C and stirred for 60 minutes. teTt-Butyldimethylsilyl chloride (4.95 g, 32.8 mmol) was added in one portion, as a solid, and the resultant solution was stirred at -20 ° C for 15 minutes and then warmed to room temperature for 60 minutes. Saturated aqueous NaHCC«3 (50 mL) was added and the phases were separated. The aqueous phase was extracted with E t 2 0 (3 x 50 m L ) and the combined organic extracts were washed once with brine (50 mL) , dried (MgSO^), and concentrated. Purification of the crude product by flash chromatography (150 g silica gel, petroleum ether), followed by bulb-to-bulb distillation (50 ° C / 0 . 1 Torr) of the acquired liquid, provided 4.07 g (83%) of l-(te?t-butyl-dimethylsilyl)hepta-l,6-diyne (297) as a colorless oil. ! H nmr (400 M H z , CDC1 3) 5: 0.06 (s, 6H, -SiMe2-), 0.90 (s, 9 H , - S i ^ u - ) , 1.69-1.76 (m, 2H, -CH2-CH2-CH2-), 1.93 (t, 1H, - O C - H , 7 = 2.5 Hz), 2.29 (td, 2H, - C H 2 - O C -H , 7 = 7, 2.5 Hz), 2.34 (t, 2H, T B S - C = C -CH2- , 7 = 7 Hz). 1 3 C nmr (125.8 M H z , CDCI3) 8: -4.5 (-ve), 16.5, 17.5, 18.9, 26.1 (-ve), 27.7, 68.7, 83.4, 83.5, 106.6. IR (neat): 3313, 2175, 1251, 839, 776 cm" 1. Exact mass calcd for Ci3H 2 2Si: 206.1491; found: 206.1495. Anal, calcd for C i 3 H 2 2 S i : C 75.65, H 10.74; found: C 75.58, H 10.71. 255 Preparation of ethyl 8-(fe^butyldimethylsilyl)octa-2.7-diynoate (295) 2 0 7 T B S C 0 2 E t 295 To a cold (-78 ° C ) , stirred solution of l-(fm-butyldimethylsilyl)hepta-l,6-diyne (297) (3.67 g, 17.8 mmol) in dry T H F (220 mL) was added a solution of M e L i (1.47 M in Et20, 13.0 m L , 19.1 mmol). After 15 minutes, the reaction mixture was warmed to -20 ° C and stirred for 60 minutes. Ethyl chloroformate (1.90 m L , 21.5 mmol) was added, by syringe, and the resultant mixture was stirred at -20 ° C for 60 minutes, then warmed to room temperature for an additional 60 minutes. Saturated aqueous NaHCC«3 (200 mL) was added and the phases were separated. The aqueous phase was extracted witii Et20 (2 x 200 mL) and the combined organic extracts were dried (MgSCU), and concentrated. Purification of the crude product by flash chromatography (150 g silica gel, 19:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (130 ° C / 0 . 1 Torr) of the acquired liquid, provided 2.75 g (55%) of ethyl 8-(rerr-butyldimethylsilyl)octa-2,7-diynoate (295) as a colorless oil. ! H nmr (400 M H z , CDC1 3) 8: 0.06 (s, 6H, -SiMe?-). 0.90 (s, 9H, -Si%i-) , 1.28 (t, 3H, -CO2CH2CH3, 7 = 7 Hz), 1.74-1.81 (m, 2H, -CH2-CH2-CH2-), 2.34 (t, 2H, 7 = 7 Hz), 2.45 (t, 2H, 7 = 7 Hz), 4.20 (q, 2H, - C 0 2 C H 2 C H 3 , 7 = 7 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -4.6 (-ve), 14.0 (-ve), 16.4, 17.6, 19.0, 26.0 (-ve), 26.7, 61.8, 73.5, 83.9, 88.1, 105.8, 153.6. IR (neat): 2239, 2175, 1713, 1472, 1251, 839, 776 cm" 1. Exact mass calcd for C i 5 H 2 3 0 2 S i (M+- Me): 263.1467; found: 263.1463. Anal, calcd for C i 6 H 2 6 0 2 S i : C 69.01, H 9.41; found: C 69.04, H 9.60. Preparation of ethyl (Z) 8-fe^butyldimethylsilyl-3-(trimethylstannyl)oct-2-en-7-ynoate £2931207 To a cold (-48 ° C ) , stirred solution of hexamethylditin (3.27 g, 9.97 mmol) in dry T H F (45 mL) was added a solution of M e L i (1.56 M in E t 2 0 , 6.30 m L , 9.83 mmol). After the pale yellow solution of (trimethylstannyl)lithium had been stirred for 20 minutes, solid C u C N (0.912 g, 10.2 mmol) was added in one portion. The mixture was stirred at -48 ° C for 25 minutes to provide a pale yellow solution of lithium (trimethylstannyl) -(cyano)cuprate. To this solution was added, dropwise, a solution of ethyl 8-(te/t-butyl-dimethylsilyl)octa-2,7-diynoate (295) (2.47 g, 8.88 mmol) in dry T H F (5 mL). The mixture was stirred at -48 ° C for 2 hours and at 0 ° C for 2 hours. Aqueous N H 4 C I -NH4OH (pH 8) (40 mL) was added and the mixture was warmed to room temperature and stirred open to the air until the aqueous phase became deep blue. The phases were separated and the aqueous phase was extracted with E t 2 0 (3 x 50 mL). The combined organic extracts were washed with brine (150 mL), dried (MgSC^), and concentrated. Purification of the crude product by flash chromatography (200 g silica gel, 40:1 petroleum ether - E t 2 0 ) , followed by bulb-to-bulb distillation (150 ° C / 0 . 1 Torr) of the acquired liquid, provided 3.34 g (85%) of ethyl (Z) 8-te7t-butyldimethylsilyl-3-(trimethylstannyl)oct-2-en-7-ynoate (293) as a colorless oil. 293 ! H nmr (400 M H z , CDCI3) 5: 0.07 (s, 6H, -S iMeoO. 0.16 (s, 9H, -SnMe3, 2 7sn-H = 55 Hz), 0.91 (s, 9H, -StfBu-), 1.27 (t, 3H, -CO2CH2CH3, 7 = 7 Hz), 1.55-1.62 (m, 2H, -CH2-CH2-CH2- ) , 2.23 (t, 2H, T B S - O C - C H 2 - , 7 = 7 Hz), 2.53 (td, 2H, -CH2-C ( S n M e 3 ) = C H - , 7 = 7.5, 1 Hz, 3 7 S n - H = 47 Hz), 4.16 (q, 2H, -CO2CH2CH3, 7 = 7 Hz), 6.36 (br s, 1H, olefinic proton, 37sn-H = 118 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -7.4 (-ve), -4.4 (-ve), 14.3 (-ve), 16.5, 19.3, 26.1 (-ve), 27.9, 38.7, 60.4, 83.4, 107.0, 128.6 (-ve), 167.9, 174.5. IR (neat): 2174, 1703, 1600, 1251, 924, 838, 775, 534 cm-1. Exact mass calcd for C i8H3 3 O2Si 1 2 0 Sn (M+ - Me): 429.1272; found: 429.1269. Anal, calcd for C i9H 3 6 02SiSn: C 51.48, H 8.19; found: C 51.49, H 8.38. Preparation of (Z) 8-fe^butyldimethylsilyl-3-ftrimethylstannyl)oct-2-en-7-ynal (292)207 To a cold (-78 ° C ) , stirred solution of freshly distilled ethyl (Z) 8-tert-butyldimethylsilyl-3-(trimethylstannyl)oct-2-en-7-ynoate (293) (2.97 g, 6.70 mmol) in dry T H F (70 mL) was added D I B A L - H (1.0 M in hexanes, 27.0 m L , 27.0 mmol). After 45 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 60 minutes. Saturated aqueous NH4CI (10 mL) was added and the white slurry was stirred at room 329 292 temperature for 30 minutes. Solid M g S 0 4 (-2 g) was added and the mixture was stirred for an additional 30 minutes. The mixture was diluted with Et20 (-300 mL) and filtered through F lor i s i l® (30 g). The column was washed with Et20 (-100 mL). The combined eluate was concentrated under reduced pressure to yield the allylic alcohol 329, a colorless oil, which was used without further purification. To a cold (0 ° C ) , stirred solution of the crude allylic alcohol 329 in CH2CI2 (18 mL) was added sequentially 3 A molecular sieves (3.55 g), N M O (1.36 g, 11.6 mmol), and T P A P (0.275 g, 0.780 mmol). The solution turned green-black immediately. After 30 minutes, the reaction mixture was warmed to room temperature for 90 minutes. The mixture was filtered through silica gel (30 g) and the cake was washed with Et20 (400 mL). The solvent was removed from the filtrate under reduced pressure. Purification of the crude product by flash chromatography (80 g silica gel, 25:1 petroleum ether - Et20), followed by bulb-to-bulb distillation (140 ° C / 0 . 1 Torr) of the acquired liquid, provided 2.142 g (80% from the ester 293) of (Z) 8-ferf-butyldimethylsilyl-3-(trimethylstannyl)oct-2-en-7-ynal (292) as a colorless oil. ! H nmr (400 M H z , CDCI3) 8: 0.06 (s, 6H, -SiMe2-), 0.25 (s, 9 H , -SnMe^t. 2 7 S n - H = 54 Hz), 0.90 (s, 9H, -Si*Bu-), 1.56-1.64 (m, 2H, -CH2-CH2-CH2-), 2.25 (t, 2H, T B S -O C - C H 2 - , 7 = 7 Hz), 2.59 (td, 2H, -CH2 -C(SnMe 3 )=CH- , 7 = 7.5, 1.5 Hz , 3 7 S n - H = 44 Hz), 6.65 (dt, 1H, olefinic proton, 7 = 5.5, 1.5 Hz, 3 7s n - H = 115 Hz), 9.56 (d, 1H, - C H O , 7 = 5.5 Hz, 4 7 S n - H = 5 Hz). 1 3 C nmr (75.3 M H z , CDCI3) 8: -7.4 (-ve), -4.5 (-ve), 16.5, 19.3, 26.1 (-ve), 27.6, 39.8, 83.7, 106.6, 139.1 (-ve), 180.7, 192.6 (-ve). IR (neat): 2744, 2174, 1685, 1564, 1251, 924, 838, 776, 533 cm-1. Exact mass calcd for C i 6 H 2 9 O S i 1 2 0 S n (M+ - Me): 385.1010; found: 385.1010. Anal, calcd for C i 7 H 3 2 O S i S n : C 51.15, H 8.08; found: C 51.37, H 8.06. 260 V I . R E F E R E N C E S A N D F O O T N O T E S I • Jung, M . E . Tetrahedron 1976, 32, 3. 2 - Trost, B . M . Acc. Chem. Res. 1978,11, 453. 3 - Seebach, D . Angew. Chem. Int. Ed. 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Tetrahedron 1994, 50, 5705. !45. (a) Bailey, W . F. ; Khanolkar, A . D.; Gavaskar, K . V . J. Am. Chem. Soc. 1992, 114, 8053. (b) Bailey, W . F . ; Khanolkar, A . D . Tetrahedron Lett. 1990, 31, 5993. !46. Cooke, M . P., Jr.; Gopal, D . Tetrahedron Lett. 1994, 35, 2837. !47. Trost, B . M . ; Coppola, B . P. J. Am. Chem. Soc. 1982,104, 6879. 148. van Hijfte, L . ; Little, R. D. ; Petersen, J. L . ; Moeller, K . D . J. Org. Chem. 1987, 52, 4647. 149. (a) Paquette, L . A . ; Morwick, T. M . ; Negri, J. T.; Rogers, R. D . Tetrahedron 1996, 52, 3075. (b) Paquette, L . A . ; Morwick, T . J. Am. Chem. Soc. 1995,117, 1451. (c) Negri, J. T.; Morwick, T . ; Doyon, J.; Wilson, P. D . ; Hickey, E . R.; Paquette, L . A . J. Am. Chem. Soc. 1993,115, 12189. 150. The stereoselective addition of the organocopper(I) reagent 182 to the a,P-unsaturated aldehyde 71 was based on the precedented stereoselective addition of the cyanocuprate 35 to the enal 71 (see Chapter 1). 151. (a) For halodegermylation studies, see Reference 52. (b) For similar iododesilylation reactions of alkenyltrimethylsilanes using NIS, see Reference 60. (c) For similar iododestannylation reactions of alkenyltrimethylstannanes using NIS, see Reference 61. 152. ( a) Kawashima, T . ; Iwama, N . ; Tokitoh, N . ; Okazaki, R. J. Org. Chem. 1994, 59,491. . -\ K (b) Castel, A . ; Riviere, P.; Cosledan, F . ; Satge, J . ; Onyszchuk, M . ; Lebuis, A . M . Organometallics 1996,15, 4488. 153. Jousseaume, B . ; Villeneuve, P.; Drager, M . ; Roller, S.; Chezeau, J. M . J. Organometallic Chem. 1988, 349, C I . 154. (a) Jousseaume, B . ; Villeneuve, P. J. Chem. Soc, Chem. Commun., 1987, 513. (b) Piers, E . ; Coish, P. D . Synthesis 1995, 47. 155. See Reference 104(b), pp 10-12. 156. Corey, E . J . ; Venkateswarlu, A . J. Am. Chem. Soc. 1972, 94, 6190. 157. Nicolaou, K . C ; Webber, S. E . Synthesis 1986, 453. 158. Rowley, M . ; Kishi, Y . Tetrahedron Lett. 1988,29, 4909. 159. 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J. Am. Chem. Soc. 1984,106, 4833. 171- (a) Piers, E . ; Wong, T . J. Org. Chem. 1993, 58, 3609. (b) Wong, T . Ph.D. Thesis, University of British Columbia, Vancouver, B . C . , 1993. 172. (a) Piers, E . ; McEachern, E . J.; Romero, M . A . ; Gladstone, P. L . Can. J. Chem. 1997, 75, 694. (b) Piers, E . ; McEachern, E . J . ; Romero, M . A . Tetrahedron Lett. 1996, 37, 1173. 173. For other examples of copper(I) promoted coupling reactions see: (a) Beddoes, R. L . ; Cheeseright, T . ; Wang, J . ; Quayle, P. Tetrahedron Lett. 1995, 36, 283. (b) Takeda, T . ; Matsunaga, K ; Kabasawa, Y . ; Fujiwara, T . Chem. Lett. 1995, 771. (c) Falck, J. R.; Bhatt, R. K . ; Ye , J. J. Am. Chem. Soc. 1995,117, 5973. (d) Ghosal, S.; Luke, G . P.; Kyler, K . S. J. Org. Chem.1987, 52, 4296. (e) Allred, G . D . ; Liebeskind, L . S. J. Am. Chem. Soc. 1996,118, 2748. 174. Piers, E . ; Romero, M . A . J. Am. Chem. Soc. 1996,118, 1215. 175. Piers, E . ; Wong, T.; Ellis, K . A . Can J. Chem. 1992, 70, 2058. 176. Piers, E . ; Tillyer, R. D . Can. J. Chem. 1996, 74, 2048. 177. Piers, E . ; Tse, H . L . A . Can. J. Chem. 1993, 71, 983. 178. Boehringer, E . - M . M.Sc. Thesis, University of British Columbia, Vancouver, B . C . , 1996. 179. Ley, S.; Griffith, W . P. Synthesis 1994, 639. 180. For a review of intramolecular coordination in organotin chemistry, see Jastrzebski, J. T . B . FL; Van Koten, G . Adv. Organomet. Chem. 1993, 35, 241. 181. Nicolaou, K . C ; Ladduwahetty, T . ; Elisseou, E . M . J. Chem. Soc., Chem. Commun. 1985, 1580. 182. Leusink, A . J . ; Budding, H . A . ; Marsman, J. W. ; J. Organomet. Chem. 1967, 9, 285. 183. Unpublished results from Dr. Piers' research group at the University of British Columbia. 184. See Reference 50, pp 758-762. 185. For examples of typical reactions of cyclopentadienes, see: (a) Dols, P. P. M . A . ; Lacroix, L . ; Klunder, A . J. H . ; Zwanenburg, B . Tetrahedron Lett. 1991, 32, 3739. (b) Jung, M . E . ; Buszek, K. R. J. Am. Chem. Soc. 1988,110, 3965. (c) Honeychuck, R. V . ; Bonnesen, P. V . ; Farahi, J.; Hersh, W . H . J. Org. Chem. 1987, 52, 5296. 186. (a) Ref. 52. (b) See Reference 126, pp 136-140. 187. (a) Ref. 38. (b) See Reference 126, pp 151-160. 188. Wakefield, B . J . Organolithium Methods; Academic: New York, 1988. 189. (a) Collins, P. W . ; Djuric, S. W . Chem. Rev. 1993, 93, 1533. (b) Bindra, J. S.; Bindra, R. Prostaglandin Synthesis; Academic: London, 1977. 190. still, W . C ; Kahn, M . ; Mitra, A . J. Org. Chem. 1978,43, 2923. 191- Taber, D . F . J. Org. Chem. 1982, 47, 1351. 192. Harrision, I. T . Instruction Manual; Harrision Research: Palo Alto, 1985. 193. Bryan, W . P.; Byrne, R. H . J. Chem. Ed. 1970, 47, 361. 194. Perrin, D . D . ; Armarego, W . L . ; Perrin, D . R. Purification of Laboratory Chemicals, 3rd ed'.; Pergamon: Oxford, 1988. 195. Burfield, D . R.; Smithers, R. H . J. Org. Chem. 1978, 43, 3966. 196. Kofron, W . G . ; Baclawski, L . H . J. Org. Chem. 1976, 41, 1879. 197. Pelletier, S. W . Chemistry and Industry 1953, 1034. 198. Pray, A . R. In Inorganic Synthesis; Moeller, T. , Ed.; McGraw Hil l , 1957; Vo l . 5, pp 153-156. 199. Girard, P.; Namy, L . ; Kagan, H . B . J. Am. Chem. Soc. 1980,102, 2693. 200- (Z)-6-Chloro-3-(trimethylstannyl)hex-2-enal (291) was generously supplied by Dr. P. L . Gladstone (of Dr. Piers' research group at U B C ) . For the experimental procedure used to prepare 291, refer to appendix 2. 2 0 !• (a) See Reference 176. (b) Mr. James G . K . Yee (of Dr. Piers' research group at U B C ) is gratefully acknowledged for this preparation of this compound (287). 2 0 2 - (Z)-8-te^Butyldimemylsilyl-3-(^ (292) was generously supplied by Mr. James G . K. Yee (of Dr. Piers' research group at U B C ) . For the experimental procedure used to prepare 292, refer to appendix 2. 203- (a) See Reference 178. (b) l-Hydroxymethyl-2-(trimethylstannyl)cyclopentene (280) was generously supplied by Dr. M . A . Romero (of Dr. Piers' research group at U B C ) , and was converted to 2-(trimethylstannyl)cyclopent-l-ene-carbaldehyde (276) via T P A P oxidation. 2 0 4 - (a) See Reference 178. (b) Ethyl 2-(trimethylstannyl)cyclohex-l-enecarboxylate (279) was generously supplied by Dr. P. L . Gladstone (of Dr. Piers' research group at U B C ) , and was converted to 2-(trimethylstannyl)cyclohex-l-enecarbaldehyde (277) via D I B A L - H reduction followed by T P A P oxidation. 205. j ) r p L Gladstone (of Dr. Piers' research group at U B C ) is gratefully acknowledged for this preparation. 2 0 6 - (a) See Reference 175. (b) Methyl (Z)-6-chloro-3-(trimethylstannyl)hex-2-enoate (264) was generously supplied by Mr. Todd Schindeler (of Dr. Piers' research group at U B C ) . 207. Mr . James G . K . Yee (of Dr. Piers' research group at U B C ) is gratefully acknowledged for this preparation. 

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