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Iodocyclopropanes : Stereocontrolled preparation and uses in organic synthesis Coish, Philip Donald Graham 1996

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IODOCYCLOPROPANES. STEREOCONTROLLED PREPARATION AND USES IN ORGANIC SYNTHESIS. by PHILIP DONALD G R A H A M COISH B.Sc, Memorial University of Newfoundland, 1989 A THESIS SUBMITTED IN PARTIAL FULF ILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES Department of Chemistry We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH C O L U M B I A January 1996 © Philip Donald Graham Coish, 1996 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 The University of British Columbia Vancouver, Canada Date OTrAA 16 , 1996 DE-6 (2/88) A B S T R A C T The thesis is divided into three sections. Section 1 describes the stereoselective preparation of 2- and 3-iodo-2-alken-l-ols by a variety of methods and the cyclopropanation of these alkenyl iodides using the Wittig-Furukawa zinc reagent, (ClCH2)2Zn, derived from C1CH2I and Et2Zn. Cyclopropanation employing this reagent in C1CH2CH2C1 following the procedure of Denmark afforded highly functionalized iodocyclopropanes in good to excellent yields (13 examples). The method represents a novel preparation of functionalized iodocyclopropanes. For example, reaction of 26a with (ClCH 2) 2Zn in C1CH2CH2C1 resulted in smooth conversion to 60a in 87% yield. Two applications of iodocyclopropane chemistry to organic synthesis are described in Sections 2 and 3. The first application is the stereospecific synthesis of substituted cis- and trans-1,2-divinylcyclopropanes (7 examples) and l-phenyl-2-vinylcyclopropanes (2 examples), in which the key step is the Pd(0)-catalyzed cross-coupling reaction of a vinylcyclopropylzinc chloride, derived from the corresponding vinyl iodocyclopropane, with an iodo alkene or iodobenzene. For example, treatment of iodocyclopropane 116b with 2.05 equivalents of BuLi , followed by metathesis of the resulting lithiocyclopropane with 1.5 equivalents of ZnCl 2 , provided the requisite cyclopropylzinc chloride. Coupling of the cyclopropylzinc chloride with iodo alkene 123 in the presence of Pd(PPh3)4 gave cw-l,2-divinylcyclopropane 152 in 54% yield. The second application of iodocyclopropane chemistry is the synthesis of spiro[2.4]heptanes via BuLi-mediated cyclization of substituted ds-l-(4-alkynyl)-2-hydroxymethyl-l-iodocyclopropanes (4 examples). For example, treatment of the iodocyclopropane 225 with 2.2 equivalents of BuLi provided the corresponding cyclopropyUithium intermediate, which subsequendy underwent 5-exo-dig cyclization to afford, on workup, the spiro[2.4]heptane 231 in 79% yield. iii iv T A B L E OF CONTENTS A B S T R A C T ii T A B L E OF CONTENTS iv LIST OF T A B L E S vi LIST OF FIGURES ix LIST OF ABBREVIATIONS A N D S Y M B O L S x A C K N O W L E D G E M E N T S xii DEDICATION xiii N O T E TO THE R E A D E R xiv 1. Iodocyclopropanes. 1 1.1. Introduction. 1 1.2. Preparation of the Substrates: stereoselective synthesis of 2- and 3-iodo-2-alken-l-ols. 12 1.3. Cyclopropanation Reactions. 34 A) Modifications of the Simmons-Smith Reaction. 34 B) Preparation of the Iodocyclopropanes. 36 C) Spectral Data. 56 1.4. Conclusions. 68 2. Substituted Vinylcyclopropanes. 71 2.1. Introduction. 71 2.1.1. Mechanism of Pd(0)-Catalyzed Cross-Coupling Reactions of Organozinc Reagents with Unsaturated Halides. 79 2.2. Preparation of the Substrates and Electrophiles. 81 A) Substrates. 81 B) Electrophiles. 87 2.3. Exchange Reactions. 89 2.4. Pd(0)-Catalyzed Cross-Coupling Reactions. 100 A) Synthesis of Highly Substituted 1,2-Divinylcyclopropanes and 1-Phenyl-2-vinylcyclopropanes. 100 B) Spectral Data. / 113 2.5. Conclusions. 120 3. BuLi-Mediated Cychzation of Substituted cw-l-(4-Alkynyl)-2-hydroxymethyl-1-iodocyclopropanes: synthesis of functionalized spiro[2.4]heptanes. 123 3.1. Introduction. 123 3.2. Preparation of the Substrates. 134 3.3. Synthesis of Functionalized Spiro[2.4]heptanes. 137 A) Cychzation Reactions. 137 B) Spectral Data. 141 3.4. Conclusions. 145 4. Considerations for Future Work. 146 5. Experimental Section. 152 5.1. General. . 152 5.1.1. Data Acquistion and Presentation. 152 5.1.2. Solvents, Reagents, and Techniques. 155 5.2. Structural Index. 158 5.3. Experimental Procedures. 163 5.3.1. Esters. 163 5.3.2. Alcohols. 170 5.3.3. Iodo Alkenes and Related Compounds. 180 5.3.4. Cyclopropanes. 221 5.3.5. Aldehydes. 267 5.3.6. Vinylcyclopropanes. 272 5.3.7. 1,2-Divinylcyclopropanes, l-Phenyl-2-vinylcyclopropanes, and Related Compounds. 290 5.3.8. Spiro[2.4]heptanes and Related Compounds. 320 5.3.9. Considerations for Future Work. 349 6. References/Footnotes. 357 vi LIST OF T A B L E S Table 1: Selected Spectral Data of the Stannyl Esters 32b, 32c, 34b, and 34c. 16 Table 2: Reduction of the Alkyl 3-trimethylstannyl-2-alkenoates 32a-c and 34a-d. 18 Table 3: Selected Spectral Data of the 3-Trimethylstannyl-2-alken-l-ols 33a-c and 35a-d. 19 Table 4: Iododestannylation of the 3-Stannyl-2-alken-l-ols 33a-c and 35a-d. 20 Table 5: Cyclopropanation Reactions. 42 Table 6: Selected Cyclopropyl *H N M R Data. 60 Table 7: Selected Cyclopropyl 1 3 C N M R Data. 64 Table 8. Selected Spectral Data of the Formyl Iodocyclopropanes 115a-d. 83 Table 9. Selected Spectral Data of the Vinyl Iodocyclopropanes 116a-d. 86 Table 10. Pd(0)-Catalyzed Cross-Coupling of Cyclopropylzinc Derivatives with Alkenyl Iodides and Iodobenzene. I l l Table 11. Cyclopropyl lH N M R Data of Compounds 152,153,155-159. 117 Table 12. Preparation of Substituted Alkynyl Iodocyclopropanes. 136 Table 13. BuLi-Mediated Cyclization of Substituted cw-l-(4-Alkynyl)-2-hydroxy-methyl-l-iodocyclopropanes. 138 Table 14. Cyclopropyl *H N M R Data of Compounds 231, 233, 235, and 239. 143 Table 15. Cyclopropyl *H N M R Data of Compounds 232,234, 236, 238, and 240. 144 Table 16: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60a (in CeD6). 224 Table 17: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60b (in C 6D 6) . 226 Table 18: lH N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60c (C 6D 6). 228 Table 19: X H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60d (CDCI3). 230 vii Table 20: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60e (C6D6). 234 Table 21: *H N M R (400 MHz), COSY (200 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 61a (in CDC13). 238 Table 22: 'H N M R (400 MHz), COSY (200 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 61b (CDC13). 241 Table 23: lH N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 61c (in 2:1 C 6D 6:CDC1 3). 243 Table 24: *H N M R (400 MHz) and COSY (400 MHz) Data for Iodocyclo-propane 64 (CDC13). 245 Table 25: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 64 (CeD6). 246 Table 26: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 66 (CeD6). 250 Table 27: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 67 (C6D6). 252 Table 28: *H N M R (400 MHz), COSY (200 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 69a (C6D6). 255 Table 29: 'H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 69b (CeD6). 257 Table 30: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Trimethylstannyl Cyclopropane 72 (CeD6). 260 Table 3 1 : ^ N M R (400 MHz) and COSY (200 MHz) Data for 147 (in C 6D 6) . 265 Table 32: *H N M R (400 MHz) and COSY (400 MHz) Data for 116a (in C 6 D 6 ) . 274 Table 33: J H N M R (400 MHz) and COSY (400 MHz) Data for 116c (in CeDe). 277 Table 34: 'H N M R (400 MHz) and COSY (400 MHz) Data for 129 (in C 6D 6) . 282 Table 35: XH N M R (400 MHz) and COSY (200 MHz) Data for 131 (in C<£>6). 285 Table 36: *H N M R (400 MHz) and COSY (200 MHz) Data for 136 (in C 6D 6) . 287 Table 37: *H N M R (400 MHz) and COSY (400 MHz) Data for 139 (in C 6 D 6 ) . 289 VU1 Table 38: Table 39: Table 40: Table 41: Table 42: Table 43: Table 44: Table 45: Table 46: Table 47: Table 48: Table 49: Table 50: Table 51: Table 52: Table 53: H N M R (400 MHz) and COSY (200 MHz) Data for 149 (in CDC13). H N M R (400 MHz) and COSY (200 MHz) Data for 151 (in CDCh). H N M R (400 MHz) and COSY (400 MHz) Data for 152 (in CDC13). H N M R (400 MHz) arid COSY (200 MHz) Data for 153 (in CDC13). H N M R (400 MHz) and COSY (400 MHz) Data for 155 (in C 6 D 6 ) . H N M R (400 MHz) and COSY (400 MHz) Data for 156 (in CDC13). H N M R (400 MHz) and COSY (400 MHz) Data for 157 (in CD2C12). H N M R (400 MHz) and COSY (400 MHz) Data for 158 (in CDC13). H N M R (400 MHz) and COSY (400 MHz) Data for 159 (in CeD6). H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for 154 (in CDC13). H N M R (400 MHz) and COSY (200 MHz) Data for 231 (in C 6 D 6 ) . H N M R (400 MHz) and COSY (400 MHz) Data for 233 (in C 6 D 6 ) . H N M R (400 MHz) and COSY (400 MHz) Data for 235 (in C 6 D 6 ) . H N M R (400 MHz) and COSY (400 MHz) Data for 239 (in C 6 D 6 ) . H N M R (500 MHz) and COSY (400 MHz) Data for 241 (in C 6 D 6 ) . H N M R (400 MHz) and COSY (400 MHz) Data for 258 (in C 6 D 6 ) . 294 297 300 303 306 309 311 313 316 318 332 336 340 345 348 356 ix LIST OF FIGURES Figure 1. Proposed transition state for the reaction of a vinyl trialkyltin compound with I2 showing normal selectivity. 24 Figure 2. Proposed transition state for the reaction of a vinyl trialkyltin compound with I2 showing reverse selectivity. 25 Figure 3. Proposed iodo alkene-zinc reagent complex leading to the transition state for cyclopropanation. 46 Figure 4. Proposed iodo alkene-zinc reagent complexes leading to diastereomeric transition states. 51 Figure 5. Proposed cyclopropyltin-BuLi complex showing unfavorable steric interactions. 97 Figure 6. Steric interactions present in the boat conformation of 152 leading to the transition state required for Cope rearrangement. 105 X LIST OF ABBREVIATIONS A N D S Y M B O L S Anal. (elemental) analysis APT attached proton test br broad calcd calculated COSY correlation spectroscopy d doublet 2D two dimensional DCIMS desorption chemical ionization mass spectroscopy dppf (1,1 '-bisdiphenylphosphino)ferrocene DMF N,A^-dimethylformamide Et 2 0 diethyl ether GLC gas liquid chromatography HMBC heteronuclear multiple bond connectivity HMQC heteronuclear multiple quantum coherence J 1-bond coupling constant in Hertz DJ n-bond coupling constant in Hertz L ligand L D A lithium diisopropylamide m multiplet M metal NOE nuclear Overhauser effect P A D A dipotassium azodicarboxylate q quartet R* rectus (relative configuration) R f retardation factor Red-Al® sodium bis(2-methoxyethoxy)aluminum hydride s singlet S* sinister (relative configuration) t triplet xi TBDMS terf-butyldiraethylsUyl THF tetrahydrofuran TLC thin layer chromatography TMS tetramethylsilane TPAP tetrapropylammonium perruthenate (VII) -ve negative w weak 8 chemical shift in parts per million from TMS coordination or complex * transition state xu A C K N O W L E D G E M E N T S I would like to thank Dr. Edward Piers for the opportunity to work with him, and for the guidance he gave me during my studies at UBC. His commitment to excellence was inspiring. I would like to thank Dr. John Scheffer for reading the thesis prior to its submission, Dr. Ray Andersen for discussions regarding the results of some N M R experiments, and Dr. Larry Weiler for helpful advice along the way. Thanks to Marietta Austria and Liane Darge of the N M R lab, Marshall Lapawa of the mass spectrometry lab, Peter Borda of the microanalysis lab, Milan Coschizza of the electronics shop, Ron Marwick of the mechanical shop, and Carolyn Joyce, Sheri Harbour, and Tilly Schreinders of the Main Office. Thanks to the people of the Piers group; in particular, to Dr. Jacques Roberge, Dr. Tim Wong, Dr. Miguel Romero, Dr. Richard Tillyer, Dr. Christine Rogers, Dr. Romano Andrade, Dr. Veranja Karunaratne, Dr. Johanne Renaud, Alan Kaller, and Serge Boulet for their advice and friendship. Thanks also to Dr. Livain Breau for discussions regarding the preparation of lactone 71, and to Todd Schindeler for his helpfulness in the lab. Special thanks to Katherine Cook for the proofreading of the thesis, and for her support and encouragement. Financial support from the Natural Sciences and Engineering Research Council of Canada was greatly appreciated. xiii to my family xiv N O T E TO THE R E A D E R The reader is referred to the structural index on p 158 for the rapid location of the preparation of a given compound or class of compounds. 1 1 . Iodocyclopropanes. 1.1. Introduction. The importance of cyclopropanes to organic synthesis has been demonstrated by their extensive use as synthetic intermediates. The reason for this popularity is that the cyclopropyl group, unlike other carbocycles, can be considered as a functional group because of its unique bonding and reactivity.1 Substituted cyclopropanes are easily transformed into 3-carbon acyclic units via a wide variety of ring-opening reactions. These reactions, and their application to * 2 3 natural product synthesis, have been extensively reviewed in the literature. ' A class of cyclopropanes that has received very little attention, in spite of its potential for use in synthesis, is that of iodocyclopropanes.4 These substances would appear to be ideal substrates for the preparation of metallocyclopropanes, which in turn can be employed as nucleophilic reagents, or as partners in transition metal-catalyzed cross-coupling reactions (Scheme l ) . 5 Iodocyclopropanes could also serve as convenient sources of functionalized radicals which could undergo reaction with radical acceptors (e.g. multiple bonds) to provide synthetically useful compounds (Scheme 2).6'7 Cyclopropyl anions and radicals could also undergo cyclization reactions to provide spiro or fused bicyclic ring systems if suitable acceptor sites8'9 were placed wimin the substituents on the cyclopropyl ring (see Scheme 3 for examples). Intramolecular reactions such as these would provide synthetically useful annulation methods. Scheme 1 R 1 " ~ T ^ " R 3 metal-iodine R 1 ^ | ^ - - R 3 electrophile E + p 2-^^«l exchange M = metal transition yf metal 3 metal-iodine R ' ^ | f - R 3 catalyst, X . exchange R2 M J^I M = metal, R 4 = alkenyl or aryl Scheme 2 radical acceptor R° Scheme 3 Anionic cyclization reactions. spiro ring system fused ring system a = acceptor, d = donor, M = metal, X = leaving group Radical cyclization reactions. • = donor, o = acceptor 4 The transformations of iodocyclopropanes, including their application to total synthesis, have not been investigated, presumably because an efficient preparation of substituted stereodefined iodocyclopropanes has not been reported.4 The methods that exist in the literature usually provide low to moderate yields of iodocyclopropanes and lack stereocontrol. These methods are reviewed in this section.10 The first preparation of a substituted iodocyclopropane was reported by Oliver and Rao in 1966.11 Reaction of (Z)-2-butene (1) with diiodomethylene, a carbene, provided the diiodocyclopropane 2 in 80% yield (Scheme 4). 1 2 Diiodomethylene was generated in situ from CHI 3 and f-BuOK by an a-elimination reaction. Reduction of 2 using Bu3SnH gave a 3:1 mixture of cis-3 and trans-4 in 70% yield.1 3 Scheme 4 A more direct method of preparing iodocyclopropanes is the addition of a monoiodocarbene to an alkene. Marolewski and co-workers reported in 1968 the reaction of cyclohexene (5) with iodomethylene, which afforded a 1:1 mixture of cis-6 and trans-1 in 70% yield (equation 1, Scheme 5). 1 4 The carbene was generated by the photolysis of CHI 3 in an aqueous solution of H 2 S 0 4 . Other iodocyclopropanes were also prepared in fair to good yield (25-86%), although a mixture of epimers was isolated in most cases. Notably, the 5 cyclopropanations of (Z)- and (E)-2-butene were found to be stereospecific, proof that the reaction proceeds via a carbene addition rather than via a free radical addition to the alkene. Unfortunately, the harsh reaction conditions limit the generality of this method. Scheme 5 The addition of a monoiodocarbenoid to an alkene also constitutes a direct method of preparing iodocyclopropanes. Miyano and Hashimoto reported in 1974 that the reaction of cyclohexene (5) with the zinc iodocarbenoid generated from Et 2Zn and CHI 3 afforded a 45:55 mixture of cis-6 and trans-1 in 50% yield, along with several minor products (equation 2, Scheme Similarly, Kawabata and co-workers reported in 1979 the synthesis of compounds 6 and 7 via a carbenoid addition reaction.10 Reaction of cyclohexene (5) with CHI 3 in the presence of Cui 6 afforded a 1:2 mixture of cis-6 and trans-1 in very low yield (10%) (equation 3, Scheme 5). The active methylating species was thought to be diiodomethylcopper (represented simply as CHI 2Cu). The method provided higher yields of the fluoro (80%), chloro (48%), and bromo (40%) cyclopropanes using Cui and FCHI 2 , C1CHI2, and BrCHI 2 , respectively. Iodocyclopropanes have also been synthesized by the iodination of silyl and stannyl cyclopropanes. Dunogues and co-workers prepared iodocyclopropane (9) in 65% yield by reacting cyclopropyltrimethylsilane (8) with ICI at 90°C, neat, for 24 h (Scheme 6). 1 6 Iodination of 8 with I2 was also attempted but was unsuccessful. Scheme 6 ( ^ S i M e 3 + ICI £ > — I 8 9 Baekelmans and co-workers studied the halodestannylation of cis- and trans-cyclopropyltrialkylstannanes of general structure 10 (Scheme 7). 1 7 The focus of their study was the effect of solvent on the kinetics, stereochemistry, and mechanism of the halodestannylation reaction rather than the preparation of halocyclopropanes. They found that the halodestannylation reactions (10 to 12) occurred with full retention of configuration of the cyclopropyl center, independent of the nature of the solvent (polar vs non-polar) and the halogen (Br2 vs I2). More importantly, in terms of this reaction as a method for preparing halocyclopropanes, the tin-halogen exchange reaction (10 to 12) was accompanied by a competing alkyl-halogen exchange reaction (10 to 11); a significant amount of the cyclopropyl 7 dialkyl(halo)stannane 11 was formed along with the halocyclopropane 12. Unfortunately, isolated yields were not provided. Aratani and co-workers reported the synthesis of a structurally simple iodocyclopropane via an iododecarboxylation reaction.18 Treatment of (+)-trans- and (-)-cis-2-phenylcyclopropanecarboxylic acids (13 and 15, respectively) with Pb(OAc)4 in the presence of I2 under irradiation of a tungsten lamp afforded only the (+)-trans isomer of l-iodo-2-phenylcyclopropane (14) in 43% and 42% yields (Scheme 8). Scheme 8 irradiation P h H 8 The stereochemistry of these reactions was rationalized on the basis of a common intermediate which was thought to be a planar or rapidly inverting cyclopropyl radical. This intermediate is attacked by I2 from the side opposite to the phenyl group to provide the trans-cyclopropane 14. Similar results were obtained for the chlorodecarboxylation of 13 and 15 using Pb(OAc)4 and L iCl . The conversion of 1-alkynes into trans- l-iodo-2-alkylcyclopropanes was reported by Zweifel and co-workers (Scheme 9).19 Reaction of (E)-l-alkenylalanes 17a (R = C4H9) and 17b (R = cyclohexyl) (which were prepared via the cis addition of /-Bu 2AlH to the appropropriate alkyne 16) with CH 2 Br 2 in the presence of a Zn-Cu couple, afforded the frvms-cyclopropylalanes 18a and 18b. Treatment of 18a and 18b with I2 gave, stereoselectively, the corresponding trans-iodocyclopropanes 19a and 19b in 47% and 53% yields, respectively. Scheme 9 R hexane 16a-b 17a-b CH 2Br 2 Zn-Cu Et^O 19a-b 18a-b a R = C 4 H 9 (47%) b R = cyclohexyl (53%) 9 Seebach and co-workers examined the reaction of the lithiated cyclopropane 21 with various electrophiles, including I2 (Scheme 10).2 0 The lithiated cyclopropane 21 was generated from the BHT ester 20 using f-BuLi. Treatment of 21 with I2 afforded the iodocyclopropane 22 in excellent yield (93%). Scheme 10 20 21 22 R = 2,6-di(fer?-butyl)-4-methylphenyl (BHT) The Simmons-Smith reaction of a structurally simple iodo alkene, namely (Z)-3-iodo-2-propen-l-ol (23), has been reported by Moss et al.; the yield of the iodocyclopropane 24, however, was only 30% (Scheme l l ) . 2 1 Scheme 11 HY^' CH2I2, Zn-Cu H^ff"1 H ' ^ / 0 H Et 20, heat, sonicate H ^ \ / 0 H 23 24 10 The Simmons-Smith reaction, which was first reported in 1958,2 2 employs an organozinc reagent that is derived in situ from CH2I2 and a Zn-Cu couple, and usually provides high yields of cyclopropanes. The nature of the zinc species and the mechanism of the cyclopropanation reaction have been extensively reviewed.23 Pertinent to this discussion is the observation that the zinc reagent, represented simply as ICH 2ZnI, behaves as a weak electrophile towards the double bond and, as such, the presence of electron-withdrawing groups (such as an iodo group)24 on or near the double bond results in lower yields of cyclopropanes.23 The iodo group present in (Z)-3-iodo-2-propen-l-ol (23) (Scheme 11) is therefore expected to deactivate the double bond towards the zinc reagent. As such, the low yield of iodocyclopropane 24 was not surprising. In contrast, the presence of the hydroxymethyl group on the double bond is expected to accelerate the cyclopropanation reaction, but not by an electronic effect. It is well established that coordination of the zinc reagent with oxygen functions such as alcohols, ethers, and ketals accelerates the cyclopropanation reaction, simply due to a proximity Qrinetic) effect.23 It is evident from the preceding discussion of iodocyclopropanes that the literature methods of preparing these compounds are generally inefficient and are not highly stereoselective. An investigation of the transformations of iodocyclopropanes, and ultimately the use of iodocyclopropanes as starting materials or as intermediates in natural and unnatural product syntheses, would require an efficient method of preparing these compounds. Given the lack of such a method in the literature, the first goal of our research program was to investigate the preparation of highly functionalized, stereodefined iodocyclopropanes. The method that we chose to study was the cyclopropanation of iodo alfylic alcohols via a modified Simmons-Smith reaction procedure. The method, if successful, would be stereospecific and would employ readily 11 prepared, functionalized iodo alkenes as the substrates. The results of our study are presented in Section 1.3 of this thesis. The second goal of our research program was to investigate the synthetic utility of iodocyclopropanes in organic chemistry. The results of these investigations, which focussed on the cross-coupling reactions of iodocyclopropanes with iodo alkenes and arenes, and on the anionic cyclization reactions of alkynyl iodocyclopropanes, are discussed in Sections 2 and 3 of this thesis. 12 1.2. Preparation of the Substrates: stereoselective synthesis of 2- and 3-iodo-2-alken-l-ols. A variety of iodo alkenes was required for our cyclopropanation study. These alkenes, which are shown in Scheme 12, were chosen for their structural diversity. They vary in their connectivity (e.g. 25b and 26b as compared to 28 and 29), their stereochemistry (compounds 25a and 26a, 25b and 26b, 25c and 26c, 28 and 29 are geometric isomers), their carbon count (compounds 25a and 25b, 26a and 26b, 30a and 30b are homologs), and their functionality. The use of such diverse substrates allowed the limitations of the cyclopropanation method to be determined while leading to the preparation of highly functionalized iodocyclopropanes that have synthetic potential. Scheme 12 25a-c 26a-e 27 a R = H a R H b R = CH2CH2CH3 b R C H 2 C H 2 C H 3 c R = CH2C=CH c R CH2C=CH d R CH2CI CH2CH2OTBDMS e R 28 R, = CH2OH, R2 = I 30a-b 29 R, = I, R2 = CH2OH a R = CH 3 b R = (CH2)4CH3 13 The (Z)-iodo alkenes 25a-c and the (E)-iodo alkenes 26a-d were prepared via the hydrostannylation-reduction-iododestannylation sequences shown in Scheme 13. Scheme 13 = — C 0 2 R 31a-d 34a-d 35a-d 26a-d Substrate Key: 31,32,34 25,26,33,35 a R = H, R'= Et a R = H b R = CH2CH2CH3, R' = Me b R = CH2CH2CH3 c R = CH 2 OCH, R' = Me c R = CH2C=CH d R = CH2CI, R' = Me d R = CH2CI Reagent Key: (a) see Scheme 14 and text;25 (b) M3u 2 AlH, E t 2 0, -78°C to 0°C; (c) I2, CH 2 C1 2 ) r.t. 14 Scheme 14 34c The first step of the sequences is the stereoselective hydrostannylation of the appropriate alkyl 2-alkynoate under carefully defined experimental conditions. Treatment of methyl 2-octynoate (31b)2 6 (Scheme 14, equation 1) with 1.1 equivalents of the trimethylstannylcopper reagent 36 2 7 in THF at -78°C, followed by addition of aq NH4CI-NH4OH (pH 8-9) and warming to r.t., provided methyl (F)-3-trimethylstannyl-2-octenoate (32b) in 67% yield.2 8 The geometric 15 isomer of 32b, compound 34b, was prepared using a procedure that was recently reported by workers in the Piers laboratory.29 The procedure allows for the preparation of both (Z)- and (£)-3-trimethylstannyl-2-alkenoates. Treatment of methyl 2-octynoate (31b)26 (Scheme 14, equation 2) with 1.1 equivalents of the (trimethylstannyl)(cyano)cuprate 37 in THF at -48°C, warming to 0°C , followed by addition of aq NH4CI-NH4OH (pH 8-9) and warming to r.t., provided methyl (Z)-3-trimethylstannyl-2-octenoate (34b) in 58% yield. By conducting the addition reaction at a lower temperature and in the presence of a proton source, (£)-alkenyl esters can be obtained instead of (Z)-alkenyl esters. Thus, treatment of methyl 2,7-octadiynoate (31c)30 (Scheme 14, equation 3) with 1.3 equivalents of the cyanocuprate 37 in THF at -78°C in the presence of MeOH, followed by addition of aq NH4CI-NH4OH (pH 8-9) and warming to r.t., provided methyl (£)-3-trimethylstannyl-2-octen-7-ynoate (32c) in 64% yield. The geometric isomer of 32c, compound 34c, was prepared using a method developed earlier in the Piers group.28 Reaction of methyl 2,7-octadiynoate (31c)30 (Scheme 14, equation 4) with 1.1 equivalents of the (trimethylstannyl)(phenylthio)cuprate 38, in THF at -48°C, followed by work-up (addition of MeOH), provided methyl (Z)-3-lrimethylstannyl-2-octen-7-ynoate (34c) in 61% yield. In the above reactions, each of the crude products contained small amounts (-2-5%) of the corresponding stereoisomer, according to GLC analysis. These minor products were removed during purification. The configuration of each of the alkenyl esters was assigned on the basis of the heteronuclear coupling between the Sn nucleus and the vinyl proton in the ! H N M R spectra. It is known that the coupling is greater when there is a trans relationship between these nuclei.31 The values of the coupling constants are given in Table 1. Also provided in Table 1 are the chemical shifts of the vinyl protons and the IR absorptions of the carbonyl groups, which support the 16 assignments of the double bond configurations. The vinyl protons experience the greatest shielding when they are cis to the tin group.28 Thus, the vinyl protons of compounds 32b and 32c resonate at higher field than the vinyl protons of compounds 34b and 34c. Similarly, the force constant of the C=0 bond of the Z isomers is expected to be decreased relative to that of the E isomers by coordination of the oxygen with the tin atom, and indeed the C=0 stretching absorptions of the Z isomers occur at lower wavenumbers than those of the E isomers. The IR spectra of the Z and E isomers also displayed a characteristic absorption at ~772 cm"1, due to tin-methyl bending (Table 1). Table 1: Selected Spectral Data of the Stannyl Esters 32b, 32c, 34b, and 34c. -SnMe3 34b SnMe3 34c SnMej C02Me Entry Stannyl ester Double bond configuration 3 7 J Sn-(viny] H) (Hz) Chemical shift (8) of the vinyl H Vc=o St V Sn-Mc bending 1 32b E 74 5.93 1721 770 2 34b Z 120 6.33 1709 772 3 32c E 72 5.99 1719 772 4 34c Z 117 6.35 1708 773 17 The next step in the stannylation-reduction-iodination sequences (Scheme 13, p 13) is the reduction of the alkyl 3-trimethylstannyl-2-alkenoates with I'-BU2A1H, which provided the corresponding stannyl alcohols. The results of the reduction experiments are summarized in Table 2. The reactions were straightforward and, as can be seen in Table 2, the yields of the allylic alcohols were excellent. For example, treatment of methyl (Z)-3-trimethylstannyl-2-octen-7-ynoate (34c) in dry E t 2 0 with a solution of I-BU 2 A1H in hexanes (-78°C for 1 h, followed by wanning to 0°C over a period of 1.5 h) afforded the allylic alcohol 35c in 94% yield (entry 6, Table 2). The spectral data of 35c were in full agreement with the assigned structure (entry 6, Table 3). The IR spectrum contained a broad O - H stretching absorption at 3311 cm'1 and an absorption at 772 cm"1 due to tin-methyl bending. The X H N M R spectrum exhibited the expected triplet for the vinyl proton at 8 6.23 and a broad signal at 8 1.28, corresponding to the O H group, which disappeared upon addition of D 2 0 . As in the case of the stannyl esters, the chemical shift of the vinyl proton and the value of the coupling constant, 3 / sn (v in y iH) , are indicative of the double bond configurations of the stannyl alcohols. The vinyl signals of the E isomers are upfield of the vinyl signals of the Z isomers, while the 3J sn-(vinyi H> values are greater for the Z isomers than for the E isomers (see Table 3). 18 Table 2: Reduction of the Alkyl 3-trimethylstannyl-2-alkenoates 32a-c and 34a-d." 34a-d 35a-d Entry Substrate R R' Product Isolated Yield (%) 1 32a H Et 33a 94 2 32b C H 2 C H 2 C H 3 Me 33b 98 3 32c CH2C=CH Me 33c 97 4 34a H Et 35a 86 5 34b C H 2 C H 2 C H 3 Me 35b 96 6 34c CH2C=CH Me 35c 94 7 34d CH2CI Me 35d 94 a Conditions: (a) /-BU2AIH in hexanes, Et 2 0, -78°C for 1 h, followed by warming to 0°C over a period of 1.5 h. 19 Table 3: Selected Spectral Data of the 3-Trimethylstannyl-2-alken-l-ols 33a-c and 35a-d. 33a-c 35a-d Entry Stannyl alcohol R Double bond configuration J Sn-(vinyl H) (Hz) Chemical shift (8) of the vinyl H Vo-H st V Sn-Me bending 1 33a H E 77 5.71 3318 768 2 33b C H 2 C H 2 C H 3 E 78 5.73 3306 767 3 33c CH 2 OCH E 77 5.81 3310 769 4 35a H Z 136 6.20 3325 769 5 35b C H 2 C H 2 C H 3 Z 139 6.17 3334 770 6 35c CH2C=CH Z 133 6.23 3311 772 7 35d CH2CI Z 133 6.23 3347 771 The final step in the preparation of the alkenyl iodides 25a-c and 26a-d (Scheme 13, p 13) was the iododestannylation of the corresponding vinyl stannanes. Treatment of the (E)-stannyl alcohols 33a-c with 1-1.2 equivalents of I2 in CH 2C1 2 provided the (£)-3-iodo-2-alken-l-ols 25a-c in excellent yields (entries 1-3, Table 4). However, treatment of the (Z)-compounds 35b-c under similar reaction conditions did not proceed smoothly and low yields of the iodo alkenes were obtained. A X H N M R study of the iododestannylation of stannanes 35b and 35c revealed a competitive side-reaction that was responsible for the low yields. The first reaction that was investigated was the iododestannylation of substrate 35b in CD 2C1 2 using one equivalent of I2 Table 4: Iododestannylation of the 3-Stannyl-2-alken-l-ols 33a-c and 35a-d.a Entry Substrate R Conditions" Product Isolated Yield (%) 1 33a H A 25a 98 2 33b C H 2 C H 2 C H 3 A 25b 94 3 33c CH2C=CH A 25c 98 4 35a H B 26a 90 5 35b C H 2 C H 2 C H 3 B 26b 90 6 35c CH2C=CH B 26c 61 7 35d CH2CI C 26d 94 a Conditions: (A) 1-1.2 eq I2, CH 2C1 2 , r.t. (B) 2 eq I2, CH 2C1 2 , r.t. (C) 3 eq I2, CH 2C1 2 , r. 21 Scheme 15 (Scheme 15) (see Experimental Section, p 190, for details). After 10 min, *H N M R analysis of the reaction mixture32 indicated the absence of the starting material 35b and the presence of Mel (8 2.16, s), Me 3SnI (8 0.89, s), Me 2SnI 2 (8 1.66, s)3 3 (very small amount), and two products, vinyl dimethyl(iodo)stannane 39 and iodo alkene 26b (scheme 15). The vinyl proton signal of 26b appeared as a triplet of triplets ( 7 = 6 , 1 Hz) at 8 5.82 while the methylene signal of the hydroxymethyl group appeared as a broad signal at 8 4.16. The assignable signals of 39 appeared at 8 0.91 (s, 6H, 2 7 S n - H = 64 Hz, SnI(CH3)2), 4.40 (br s, 2H, CH 2 OH), and 6.22 (br s, IH, 3 7 S n . H = 214 Hz, vinyl H). Integration of the vinyl signals (8 5.82 and 6.22) and of the hydroxymethyl signals (8 4.16 and 4.40) showed that 26b and 39 were present in a ratio of - 1 : 1 . Analysis (XH N M R (400 MHz) spectroscopy) of the reaction mixture after a total of 20 min indicated no further change in the ratio of 26b :39. 2 2 In a similar experiment, the reaction of vinyl stannane 35b with two equivalents of I2 in CD 2C1 2 was followed by lU N M R spectroscopy over a period of 50 min. Spectra were acquired approximately every 10 min. 3 2 Analysis of the spectra during the first 40 min showed that the reaction mixtures contained Mel , MesSnl, decreasing amounts of 39, and increasing amounts of Me 2SnI 2 and 26b. After a total of 50 min, 39 was not present. The results show that the starting material was quickly consumed to afford a mixture of 39 and 26b, and that 39 was then slowly converted into 26b. Similar ^ N M R results were obtained for the iododestannylation of vinyl stannnane 35c. Treatment of 35c with one equivalent of I2 in CD 2C1 2 for 10 min gave a - 1 : 1 mixture of 40 and 26c (Scheme 15). Addition of another equivalent of I2 to this mixture resulted in the smooth conversion of 40 into 26c. The vinyl dimethyl(iodo)stannane 40 was isolated and characterized. The reaction of vinyl trimethylstannane 35c with one equivalent of I2 for 10 min was repeated on a larger scale (0.54 mmol of 35c) than that employed in the N M R experiment (0.039 mmol of 35c) and again a -1 :1 mixture of 40 and 26c was obtained. TLC analyses of the mixture using plates coated with normal phase silica gel, reversed phase silica gel, and basic alumina indicated two major components, the iodo alkene 26c and the vinyl dimethyl(iodo)stannane 40. Stannane 40 appeared as a trailing band regardless of the stationary phase. It was decided that the isolation of stannane 40 would be best accomplished via Uquid-liquid extraction rather than chromatography since it was noticed that compound 40 was sparingly soluble in petroleum ether. Repeated trituration of the mixture of 26c and 40 with petroleum ether (see Experimental Section, p l91, for details) afforded a nearly pure sample of vinyl dimethyl(iodo)stannane 40. The ^ N M R spectrum of 40 contained signals corresponding to the methyl protons of a SnIMe2 group (8 0.73, s, 6H, 2J S n - H = 23 65 Hz), the methylene protons of a hydroxymethyl group (8 4.33, broad signal, 2H), and a vinyl proton (8 6.35, broad singlet, IH, 3J sn-(vinyiH) = 211 Hz). The formation of 39 and 40 represents examples of what is referred to as "reverse selectivity" in SE2 cleavage of mixed tetraorganotin compounds.34 The usual selectivity for the reaction of a 2 3 vinyl trialkyltin compound with h is the cleavage of the sp carbon-tin bond in preference to a sp carbon-tin bond. A transition state that accounts for this observation and that is in accord with that reported by Nasielski et al . 3 5 is shown in Figure 1. The cyclic transition state rationalizes the preferential cleavage of the sp2 carbon-tin bond by involving the n electrons of the double bond; the transition state also rationalizes the retention of double bond configuration. An example of normal selectivity was observed by Jousseaume and co-workers when they treated the stannane 41 with h (Scheme 16). They obtained the expected iodo nitrile 42 in good yield. 3 4 b However, reaction of the ketone 43 with Iz under similar conditions gave the iodo stannane 44 as a result of reverse selectivity (Scheme 16). 3 4 b The results were rationalized by a geometric argument. According to Jousseaume,343 intramolecular coordination of the tin atom with an electronegative group such as C=0 3 6 in the transition state preferentially places the electronegative group in an apical position, leaving the vinyl carbon and two of the butyl groups in equatorial positions, and the remaining butyl group in an apical position, as shown in Figure 2 (p 25). The butyl group in the apical position is the most susceptible to electrophilic attack by h. As a result, the butyl-tin bond is cleaved rather than the vinyl-tin bond and reverse selectivity is observed. Figure 1. Proposed transition state for the reaction of a vinyl trialkyltin compound with I2 showing normal selectivity. 25 Figure 2. Proposed transition state for the reaction of a vinyl trialkyltin compound with I2 showing reverse selectivity. apical position equatorial position "I * Jousseaume also reported that reaction of the stannyl alcohol 45 with I2 provided the "normal selectivity" product 46 (Scheme 16) and concluded that the coordination of the hydroxyl oxygen with the tributylstannyl group "was too weak to change the normal course of the reaction".3 4 b Unfortunately, the number of equivalents of I2 used for this reaction was not provided in the Experimental Section of their report. It is clear from the *H N M R studies which were discussed earlier that the presence of a hydroxymethyl group cis to the vinyl trimethylstannyl group has a significant influence on the iododestannylation process. The results of the *H N M R studies are important in terms of the iododestannylation of (Z)-3-tiimethylstannyl-2-alken-l-ols as a preparative method. Treatment of the (Z)-vinyl stannanes 35a-c with 2 equivalents of I2 in CH 2C1 2 afforded the iodo alkenes 26a-c in good to excellent yields (entries 4-6, Table 4, p 20). Interestingly, 3 equivalents of I2 were necessary to effect smooth conversion of 35d to 26d (entry 7, Table 4). Presumably, coordination of the primary chloride group with the tin atom can also effect reverse selectivity. 26 The spectral data (*H and 1 3 C NMR, IR, MS) of the iodo alkenes were in full agreement with the assigned structures. The relative stereochemistry of each alkene was confirmed by NOE difference experiments, and as expected, the configuration of the double bond was, in each case, retained during the iododestannylation. The iodo alkene 26b was prepared by several methods as shown in Scheme 17. Route A, which has been described, afforded compound 26b in three steps with an overall yield of 50%. Scheme 17 SnMe 3 SnMe 3 C0 2 Me OH 34b 35b C0 2 Me B C0 2 Me 31b 47 26b 49 Conditions: Route A . [Me 3SnCuCN]Li, THF; I - B U 2 A 1 H , E t 2 0; I2, CH 2C1 2 . Route B. Nal , AcOH; /-Bu 2 AlH, Et 2 0. Route C. Red-Al®, E t 2 0 ; I2. 27 Route B provided the iodo alkene 26b in two steps. The first step was the synthesis of the iodo ester 47 by a procedure that was recendy developed in our laboratory.37 According to this procedure, alkynoate 31b26 was allowed to react with 1.6 equivalents of Nal in AcOH at 115°C for 1.5 h to afford the iodo ester 47 in 93% yield. An IR stretching absorption corresponding to the C=0 group was observed at 1734 cm"1 while, in the XH N M R spectrum, the vinyl proton signal appeared at 8 6.30 as a triplet (7=1 Hz) due to weak allylic coupling. The iodo ester 47 was reduced with /-BU2AIH to provide the iodo alkene 26b in 95% yield. The overall yield of the sequence was 88%. In route C, the iodo alkene 26b was prepared via an one-pot hydroalanation-iodination sequence.38 Reaction of 2-octyn-l-ol (48)39 with 3 equivalents of Red-Al®, followed by sequential addition of EtOAc and 5 equivalents of L_, gave iodo alkene 26b in 83% yield. It is thought that the product of the hydroalanation reaction is the intermediate 49.40 While routes B and C gave higher yields of 26b, in general, route A is best suited for the preparation of functionalized (Z)-3-iodo-2-alken-l-ols because of its milder reaction conditions (vide infra). The hydroalanation-iodination method outline in route C above was also used to prepare the (Z)-3-iodo-2-alken-l-ols 27 and 26e (Scheme 18). The reaction of 3-hexyn-2-ol (50)39 with Red-Al® and I2 in THF proceeded smoothly and provided iodo alkene 27 in 83% yield. The spectral data of compound 27 were in full accord with the assigned structure. For example, the IR spectrum showed a double bond absorption at 1646 cm"1 and a broad O-H stetching vibration at 3332 cm"1, and the/H N M R spectrum contained a 1-proton doublet of triplets at 8 5.54 (J = 28 Scheme 18 52 RT = O H , R 2 = I 53 RT = T B D M S O , R 2 = H Conditions: (a) Red-Al®, E t 2 0 ; I2 7.5, 1 Hz) corresponding to the vinyl proton. The multiplicity is a result of vicinal coupling (7 = 7.5 Hz) to the methine proton and weak allylic coupling ( 7 = 1 Hz) to the methylene protons. NOE difference experiments confirmed the Z configuration assigned to the double bond. In contrast, the conversion of 51 to 26e (Scheme 18) via the hydroalanation-iodination method was not facile. Reaction of 7-(ter?-butyldimethylsiloxy)-2-heptyn-l-ol (51) (see Experimental Section, p 179, for preparation) with Red-Al® and I2 under the reaction conditions employed above provided a complex mixture of products according to TLC analysis. The desired iodo alkene 26e was isolated in low yield (9%) while the major product was the diol 52, isolated in 50% yield. 29 The *H N M R spectrum (CDC13, 200 MHz) of 52 consisted of a 4-proton multiplet in the region 8 1.40-1.70 (H-5, H-6), a broad, 2-proton triplet (7 = 6.5 Hz) at 8 2.50 (H-4), a broad, 1-proton signal at 8 2.72 which exchanged with D 2 0 (OH), a broad, 1-proton signal at 8 3.13 which exchanged with D 2 0 (OH), a 2-proton triplet (7 = 6.5 Hz) at 8 3.59 (H-7), a 2-proton doublet (7 = 5.5 Hz) at 8 4.14 (H-l) , and a broad, 1-proton triplet (7 = 5.5 Hz) at 8 5.81 (H-2). High resolution mass spectroscopy gave a M + - H 2 0 (C7HuIO) value of 237.9858 for 52 (calculated value for M + - H 2 0 is 237.9855). Recendy, Mourino and co-workers reported the reductive iodination of the alkynyl alcohol 54, which is structurally similar to 51 in that it contains a tert-butyldimethylsilyl (TBDMS) ether group in a 1,4 relationship to the alkynyl group (Scheme 19).41 Their reductive-iodination method provided the desired iodo alkene 55 in 84% yield. The experimental details given for their reaction were limited, although the number of equivalents of Red-Al® was given as 1.5. Reaction of 7-(?err-butyldimethylsiloxy)-2-heptyn-l-ol (51) under reaction conditions similar to Mourino's provided the desired iodo alkene 26e in 54% yield and the reduction-protonation product 53 in 18% yield. G L C analysis of the crude reaction mixture indicated several minor products, including a trace amount of the diol 52 (~2%). In comparison to the efficient reduction-iodination of the structurally simple alkynyl alcohols 48 and 50, the reduction-iodination of the functionalized alkynyl alcohol 51 was problematic. Scheme 19 1.5 eq Red-Al ® OH toluene; I 2 TBDMSO, OH 54 55 30 The remaining iodo alkenes which were required as cyclopropanation substrates were prepared via metallation-iodination procedures that employed organoaluminum, -stannane, and -magnesium chemistry. Compound 28 was prepared by a hydrostannylation-iodination sequence (Scheme 20).4 2 Reaction of 2-octyn-l-ol (48)39 with one equivalent of Bu 3SnH in the presence of a catalytic amount of (Ph3P)4Pd in PhH gave a brown mixture which was quickly filtered through silica gel and concentrated. The residue was dissolved in CH2CI2 and treated with one equivalent of I2. Workup, followed by purification of the crude product provided the iodo alkene 28 and a regioisomer 25b in 67% and 18% yields, respectively. The stannane intermediate was not isolated since an earlier attempt to do so revealed that the intermediate was unstable on silica gel. The lH N M R spectrum of 28 contained a 2-proton doublet (J = 6.5 Hz) at 5 4.20 corresponding to the methylene protons of the hydroxymethyl group, and a 1-proton triplet (J = 6.5 Hz) at 8 1.77 corresponding to the OH group. The signals are consistent with an A 2 X spin system, which is expected for the CH 2 OH group of 28. Upon addition of D 2 0 , the doublet at 8 4.20 collapsed to a singlet and the triplet at 8 1.77 disappeared. The E configuration of the double bond (a result of syn addition of Bu 3Sn-H across the triple bond) was confirmed by NOE difference experiments. The iodo alkene 29, the geometric isomer of 28, was also prepared from 2-octyn-l-ol (48)39 (Scheme 20), according to the procedure of Corey.4 3 A solution of 2-octyn-l-ol (48) in E t 2 0 was first treated with BuLi for 10 min, and then with /-BU2AIH for ~3 days. Subsequent iodination of the organoaluminum intermediate with I2 afforded the 2-iodinated allylic alcohol 29 in 47% yield. As in the case of compound 28, the regio- and stereochemistry of the alkene 29 were assigned on the basis of *H N M R data. 31 Scheme 20 a + 28 25b OH 48 b OH 29 Conditions: (a) Bu 3SnH, (Ph3P)4Pd (catalytic amount), PhH; I2, CH 2C1 2 ; (b) BuLi , E t 2 0; i-The final two substrates were prepared according to a procedure based on the alkylmagnesiation-iodination method reported by Normant.44 Reaction of 2-propyn-l-ol (56)26 with 2.5 equivalents of CH 3 MgBr (a salt-free solution in E t 2 0) 2 6 and 1 equivalent of Cui in E t 2 0, followed by treatment with 1.4 equivalents of I2, afforded the iodo alkene 30a in 56% yield (Scheme 21). Similarly, compound 30b was prepared in 64% yield from 2-propyn-l-ol (56)26 using n-C 5 HiiMgBr (a salt-free solution in E t 2 0) 2 6 as the Grignard reagent (Scheme 21). Also isolated were small amounts of 29 (5%), the reduction product 57 (<7.5%), and the dimer 58 (1.3%). The yields of 56% and 64% for compounds 30a and 30b, respectively, are acceptable given the generally low yields (33-59%) obtained for this type of reaction.44"47 It should be noted that an earlier attempt to prepare a higher homolog of 30b using a Grignard reagent made from n-C 6 Hi 3 Br and Mg turnings failed. It seems that a salt-free solution of the Grignard reagent is Bu 2 AlH; I2. 32 required for this reaction to succeed. The 'H N M R spectrum of 30b, which contained a 1-proton vinyl signal at 8 6.00 that was broadened by weak allylic coupling, is consistent with the assigned regiochemistry. The configuration of the double bond was confirmed by NOE difference experiments. Saturation of the vinyl proton signal resulted in a positive NOE for the cis-allylic methylene signal, whereas irradiation of the same methylene signal generated a positive NOE for the vinyl proton signal. The 1 3 C spectrum of 30b contained a signal at 8 75.8 corresponding to C-3 (see Scheme 21 for carbon numbering) and a signal at 8 150.3 corresponding to C-2. The upfield shift of C-3 and the downfield shift of C-2 are due to the "heavy atom effect"4 8 2 of the iodine atom. Scheme 21 56 30a 30b 29 57 58 Conditions: (a) CH 3 MgBr, Cui , E t 2 0 ; I2; (b) n-C 5 HnMgBr, Cui , E t 2 0 ; I2. 33 As noted in the Experimental Section, each of the iodo alkenes was distilled from a small piece of Cu wire and was then stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). The purpose of the Cu was to act as a radical inhibitor. Nonetheless, the iodo alkenes gradually discolored. The decomposition was usually not significant and filtration through a short plug of basic alumina (type 1) (elution with a polar solvent such as Et 20) removed the colored impurities. 34 1.3. Cyclopropanation Reactions. A) Modifications of the Simmons-Smith Reaction. The Simmons-Smith reaction has become a popular method of preparing cyclopropanes since it was first reported in 1958.2 2 There have been several modifications which have improved the experimental ease of the reaction and its yields. The most important variant, known as the Furukawa modification,49 employs Et 2Zn in place of the Zn-Cu couple, which is difficult to prepare with consistent quality even though improvements in its preparation have been made.50"53 Reaction of Et 2Zn with CH 2 I 2 provides the methylating reagent, a complex of bis(iodomethyl)zinc, represented simply as (ICH2)2Zn. This reagent was also prepared by Wittig 5 4 from Znl 2 and C H 2 N 2 and so the reagent, and its chloro analog, are sometimes referred to as the Wittig-Furukawa reagents. The major advantages of the Furukawa modification (Et2Zn in place of Zn-Cu), as noted by Motherwell and Nudey5 5 and by Denmark,56 are: (1) the reagents are homogeneous, commercially available, and easily measured; (2) formation of the zinc reagent is rapid and occurs under mild conditions; (3) the reaction conditions are suitable for cationically polymerizable alkenes such as vinyl ethers which tend to polymerize under Simmons-Smith conditions; (4) alkyl and phenyl carbenoids, in addition to methylene carbenoids, can be employed; (5) the reaction can be conducted in non-coordinating solvents rather than in diethyl ether (Simmons-Smith conditions), which is a coordinating solvent that attenuates the reactivity of the zinc reagent. The behavior of the Wittig-Furukawa reagents is similar to that of the Simmons-Smith reagent. Reactions employing the Wittig-Furukawa reagents are stereospecific with respect to substrate geometry and both are accelerated (and directed) by neighbouring oxygen 35 functionalities. The Wittig-Furukawa reagents, like the Simmons-Smith reagent, are electrophilic, and electron-donating groups on the double bond increase the rate and the yield of the reaction. Denmark and co-workers recently examined the solid-state and solution structure of the Wittig-Furukawa reagents.57 They reported the first x-ray crystallographic analysis of an (iodomethyl)zinc compound, bis(iodomethyl)zinc complex 59 (Scheme 22), and reported the X H and 1 3 C N M R spectra of (ClCH 2) 2Zn and (ICH2)2Zn as CD 3 C(0)CD 3 solutions and as D M E complexes in CeD6. Scheme 22 59 During their studies of the Wittig-Furukawa reagents, Denmark made three discoveries which are significant to the preparation of cyclopropanes.56 They were: (1) that the use of C1CH2CH2C1, a non-coordinating solvent, resulted in rapid and efficient cyclopropanation; (2) that the bis(chloromethyl)zinc reagent, represented as (ClCH 2) 2Zn, formed by reacting Et 2Zn with C1CH2I, is more reactive than the bis(iodomethyl)zinc reagent, (ICH2)2Zn, formed by reacting Et 2Zn with CH 2 I 2 ; (3) that the formation of the bis(chloromethyl)zinc reagent, (ClCH 2) 2Zn, prior to the addition of a substrate to which zinc coordination is possible (e.g. alcohols), leads to rapid and high yielding cyclopropanation. 36 B) Preparation of the Iodocyclopropanes. The first goal of our research program was to investigate the cyclopropanation of iodo aUylic alcohols as a method of preparing highly functionalized iodocyclopropanes. Our initial studies in this direction involved attempts to cyclopropanate iodo alkene 26a (equation 1, Scheme 23) using the bis(iodomethyl)zinc reagent, (ICEk^Zn. These reactions were found to be inefficient. For example, addition of 12 equivalents of CH2I2 to a cooled (0°C) solution of compound 26a and Et 2Zn (10 equivalents, obtained from Aldrich Chemical Company as a solution in benzene) in dry, degassed benzene, followed by stirring for 5 min and then warming to r.t. over 55 min, afforded an -8.5:1 mixture of the starting material 26a and the iodocyclopropane 60a (based on *H N M R (400 MHz) spectroscopy). Miyano reported that the cyclopropanation of alkenes by the Et 2Zn-CH 2l2 reagent system is accelerated by the introduction of dry air into the reaction flask.5 8 Miyano proposed that the zinc-carbenoid reagent is formed via a free-radical chain mechanism and that 0 2 initiates this chain reaction, thereby accelerating the rate of reagent formation, and ultimately, the rate of cyclopropanation. Thus, the cyclopropanation of iodo alkene 26a was repeated using Miyano's modification (dry air was introduced into the reaction flask before warming to r.t.). Analysis (*H N M R (400 MHz) spectroscopy) of the crude material indicated improved conversion: the ratio of starting material 26a to iodocyclopropane 60a was - 3 : 2 . A further improvement was derived from the use of toluene in place of benzene.59 Addition of 12 equivalents of CH2I2 to a cooled 37 Scheme 23 Et 2Zn, CH 2 I 2 benzene or toluene 60a eq 2 Et2Zn CICH2I C 1 C H 2 C H 2 C 1 (0°C) solution of iodo alkene 26a and Et 2Zn (10 equivalents, obtained from Aldrich Chemical Company as a solution in toluene) in dry, degassed toluene, followed by the introduction of dry air and warming to r.t. over 1 h, afforded a -1 :5 mixture of the starting material 26a and the iodocyclopropane 60a (based on *H N M R (400 MHz) spectroscopy). An increase in the number of equivalents of CH 2 I 2 so that the ratio of Et 2Zn to CH 2 I 2 was -1 :2 did not result in a significant improvement; in this case, the ratio of starting material 26a to iodocyclopropane 60a was -1 :6 . In contrast, the cyclopropanation of iodo alkene 26a using a procedure similar to that of Denmark56 proceeded smoothly. Addition of 26a to cold (0°C) solution of the preformed (ClCH 2) 2Zn (prepared from Et 2Zn (10 equiv) and C1CH2I (20 equiv)) in C1CH 2CH 2C1, and stirring for 40 min, cleanly afforded the iodocyclopropane 60a in 77% yield (equation 2, Scheme 23; entry 1, Table 5, p 42). No starting material was observed in the *H N M R spectrum of the crude product. A reduction in the number of equivalents of (ClCH 2) 2Zn from 10 to 2 and a decrease in the reaction time from 40 to 10 min afforded iodocyclopropane 60a in 87% yield (entry 2, Table 38 5). The spectral data of 60a were in full agreement with the assigned structure (a complete discussion of spectral data is presented later in Section 1.3.C). In the Denmark procedure,56 Et 2Zn is used as a neat liquid. In this form, it is pyrophoric when exposed to air (i.e. O2).60 In our work, the reagent was transfered using a gas-tight syringe and handled using techniques for air-sensitive materials.61"63 Given the sensitivity of Et 2Zn (and (ClCH2)2Zn) towards 0 2 , the presence of air in the reaction mixture before the addition of the alkene would lead to the decomposition of the zinc reagent. However, the effect of air in the reaction mixture after the addition of the alkene has been debated. As discussed earlier, Miyano reported rate accelerations for cyclopropanations in the presence of dry air. In contrast, Denmark found that the addition of dry air to the reaction mixture resulted in destruction of the zinc reagent and incomplete conversion of the alkenyl substrate to the cyclopropane.56 Our attempts to cyclopropanate iodo alkene 26a using (ICH2)2Zn in the presence of dry air indicated that the reactions were improved by the introduction of dry air, but were not complete (Scheme 23). Further investigation into the effects of 0 2 using iodo alkene 25a and (ClCH 2) 2Zn (generated from Et 2Zn and C1CH2I) provided results that were in agreement with the findings of Denmark56 (Scheme 24). Specifically, dry air was introduced into the flask containing the iodo alkene 25a. The iodo alkene was then transferred to a cooled (0°C) solution of the preformed zinc reagent in C1CH2CH2C1. After 10 min, G L C analysis of a reaction aliquot indicated starting material 25a (4%), iodocyclopropane 61a (75%), and the methyl ether 62a (14%). Similarly, when dry air was introduced after the addition of alkene, G L C analysis of a reaction aliquot after 10 min of stirring indicated starting material 25a (4%), iodocyclopropane 61a (81%), and the methyl ether 62a (12%). In comparison, the same reaction conditions without the introduction of air provided a 39 reaction mixture that contained no starting material 25a, iodocyclopropane 61a (91%), and the methyl ether 62a (6%), according to G L C analysis. Scheme 24 HO. r Et 2Zn, C1CH2I C1CH2CH2C1 25a + HO. + MeO. with or without air (see text for details) 25a 61a 62a In light of these findings and the extreme reactivity of the zinc reagents towards 0 2 , the following conventions were adopted with respect to the handling of the solvents and reagents: the C1CH2I (reagent) and C1CH2CH2C1 (solvent) were purified, degassed via the freeze-pump-thaw method,64 and stored (up to ~1 month) in air-tight Schlenk flasks over Cu wire (a radical inhibitor), whereas the iodo alkenes were distilled under an Ar atmosphere, or degassed and flushed with Ar, prior to their use. In practice, an indication of 02-initiated decomposition of the Et 2Zn and (ClCH 2) 2Zn solutions was the heavy precipitation of white zinc salts. The decomposition of the Et 2Zn solutions was also accompanied by white fuming. Typically, solutions of (ClCH 2) 2Zn appeared slightly opaque - 4 - 5 min after the addition of C1CH2I. Addition of the alkene to such a solution resulted in the heavy precipitation of white solids and efficient cyclopropanation. The results of the cyclopropanation reactions are summarized in Table 5 and Scheme 25. The addition of a solution of iodo alkene in C1CH2CH2C1 to a solution of preformed zinc reagent (2 equivalents), derived from Et 2Zn and C1CH2I, in C1CH2CH2C1 at 0°C, followed by stirring for 40 Scheme 25 (see text and Table 5 for experimental conditions) R ^ ' QCH2i R W - > + R W H HO^ J> HO. MeO. , C1CH2CH2C1 H H 25a-c 61a-c 62a (62b,c not obtained) a R = H b R = CH2CH2CH3 c R = CH2C=CH 26a-e 60a-e 63b,d,e (63a,c not obtained) a R = H b R = CH2CH2CH3 c R = CH 2 OCH d R = CH2CI e R = CH2CH2OTBDMS 27 64 65 continued on next page Scheme 25 - continued from p 40 (see text and Table 5 for experimental details) 41 30a,b a R = CH 3 b R = (CH2)4CH3 69a,b Table 5: Cyclopropanation Reactions." Entry Substrate6 Equivalents'" of Et 2Zn Equivalents'" ofClCH 2 I Reaction Time (min) Product6 Yield* (%) 1 26a 10 20 40 60a 77 2 26a 2 4 10 60a 87 3 25a 2 4 12 61a 16e 4 25a 2 4 100 61a 50 5 25b 2 4 10 61b 66 6 25b 2 4 12 61b 64 7 26b 2 4 10 60b 83 e 8 28 5 10 15 66 31' 9 29 2 4 90 67 65 10 29 4 8 60 67 74* 11 29 4 8 60 67 78* 12 30a 2 4 30 69a 65 13 30b 2 4 45 69b 43 14 30b 2 4 55 69b 47 15 30b 4 8 30 69b 47 16 27 2 4 30 64 84' 17 27 2 4 55 64 86> Continued on next page. 43 Table 5 (continued from previous page). Cyclopropanation Reactions." Entry Substratefc Equivalents0 of Et 2Zn Equivalents'" ofClCH 2 I Reaction Time (min) Product6 Yield* (%) 18 25c 2 4 10 61c 36 19 26c 2 4 10 60c 51 20 26d 2 4 5 60d 68* 21 26d 2 4 5 60d 73' 22 26e 2 4 4 60e S2m,n 23 35b 2 4 15 72 94 a A l l reactions were carried out in C1CH2CH2C1 at 0°C. h See Scheme 25 for structural formulas. c Equivalents per mmol of substrate. d Isolated yield of purified product. e Also isolated was <5% of impure methyl ether corresponding to the product. f Also isolated was 6% of the starting material 28. g Also isolated was 12% of the methyl ether 68. h Also isolated was 11% of the methyl ether 68. ' Also isolated was 1% of the methyl ether 65. ; Also isolated was 3% of the methyl ether 65. * Also isolated was <10% of impure methyl ether 63d.' Also isolated was 4% of the methyl ether 63d. m Also isolated was 2% of the methyl ether 63e." The substrate was added as a solution in dry, degassed PhH because it is sparingly soluble in C1CH2CH2C1. 44 the specified times, were accepted as the standard (reaction) conditions.56 Thus, the reaction of the iodo alkene 25a using standard conditions and a reaction time of 12 min afforded iodocyclopropane 61a in 76% yield, along with impure methyl ether 62a in <5% yield (entry 3, Table 5). When the reaction time was extended from 12 min to 1.7 h, periodic G L C analysis of aliquots taken from the reaction mixture indicated decreasing amounts of 61a and increasing amounts of side-products. Workup and purification of the crude material afforded a poor yield of iodocyclopropane 61a (50%) (entry 4, Table 5). The result indicates that iodocyclopropane 61a is unstable under the reaction conditions, and that methyl ether formation does not increase with extended reaction time. 25a,b 61a, b 62a a R = H b R = C H 2 C H 2 C H 3 Reaction of the iodo alkene 25b, a higher homolog of 25a, using standard conditions and a reaction time of 10 min, afforded the iodocyclopropane 61b in 66% yield (entry 5, Table 5). GLC analysis of the crude product indicated a trace amount of starting material (-3%). When a slightly longer reaction time of 12 min was employed, iodocyclopropane 61b was isolated in 64% (entry 6, Table 5), but again a trace amount of starting material (-3%) was observed in the crude product by G L C analysis. 45 In contrast, cyclopropanation of compound 26b, the geometric isomer of 25b, under the standard reaction conditions, afforded iodocyclopropane 60b in 83% yield (entry 7, Table 5). A small amount (<5%) of impure methyl ether 63b was also isolated. It should be noted that the cyclopropanations of the (Z)-iodo alkenes 26a and 26b were more efficient than those of the (Zs)-iodo alkenes 25a and 25b (compare entries 2 and 7 with entries 3 and 5, respectively, Table 5). A possible rationale for this observation is based on the relative sizes of the geminal iodo and alkyl substituents. Given that the zinc species coordinates to the hydroxyl oxygen during the cyclopropanation process, it is reasonable to assume that the conformational arrangement of the complex (see Figure 3) leading to the transition state is one in which the hydroxyl group is directed out of the plane of the double bond, with one of the methylene units of the zinc reagent (represented simply as the monomer) positioned above the double bond.2 3 In this arrangement, there is steric repulsion between R 3 and the complexed C H 2 O H group, particularly H i . Based on the A-values of the substituents, this interaction is expected to be greater for R 3 = ethyl or pentyl (A-value = 1.8 kcalmol"1) rather than for R3 = I (A-value = 0.47 kcal-mol"1).65 Thus, it is reasonable that the cyclopropanation of the Z isomers (26a,b) is more facile than that of the E isomers (25a,b). 26b 60b 63b 46 Figure 3. Proposed iodo alkene-zinc reagent complex leading to the transition state for cyclopropanation. Compounds 25a,b: R x = H; R 2 = I; R 3 = ethyl, pentyl. Compounds 26a,b: R i = H; R 2 = ethyl, pentyl; R 3 = I. Compound 28: Ri = I; R 2 = H; R 3 = pentyl. Cyclopropanation of iodo alkene 28 using standard conditions was sluggish and was accompanied by side reactions. The use of 5 equivalents of zinc reagent and a reaction time of 15 min gave a mixture consisting primarily of the starting material 28 and the corresponding iodocyclopropane 66, in a ratio of ~1:3, according to N M R spectroscopic analysis of the crude material. When longer reaction times were employed (i.e. 25 and 40 min), the amount of starting material decreased but so did the amount of the desired cyclopropane, along with an increase in the amount of side products. To make matters worse, compounds 28 and 66 could not be separated using silica gel chromatography; even an attempt using A g N 0 3 impregnated silica gel, 6 6 known to be effective for the separation of alkenes, failed. Eventually, the mixture of 28 and 66 28 66 47 was separated by radial chromatography of the corresponding mixture of trimethylsilyl ethers. Hydrolysis of the ethers afforded low yields of the cyclopropane 66 (31%) and starting material 28 (6%) (entry 8, Table 5). Similarly, the cyclopropanation of compound 29, the geometric isomer of 28, using standard conditions and a reaction time of 10 min resulted in incomplete conversion: a 2:1 mixture of starting material 29 and iodocyclopropane 67 was obtained in - 7 7 % (crude) yield. However, in contrast to the cyclopropanation of iodo alkene 28, extension of the reaction time (to 1.5 h) resulted in an increased yield (65%) of 67 (entry 9, Table 5). When the number of equivalents of zinc reagent was increased from 2 to 4 and the reaction time was shortened to 1 h, the reaction afforded the desired iodocyclopropane 67 and the methyl ether 68 in 74% and 12% yields, respectively (entry 10, Table 5). Repetition of the reaction gave 67 and 68 in 78% and 11% yields, respectively (entry 11, Table 5). The reason for the different behavior of 28 and 29 under the reaction conditions is not clear. In the case of the E isomer 28, it is possible that steric interactions (Figure 3, p 46) between Hi and the cis-pentyl group during the cyclopropanation process are significant. Ultimately, the cyclopropanation of iodo alkene 28 was inefficient. It should be noted that the cyclopropanation of iodo alkene 28, which has the iodo and hydroxymethyl groups in a geminal relationship, was slower (and less efficient) than the cyclopropanation of its regioisomer 25b, which has the iodo and hydroxymethyl groups in a 29 67 68 48 vicinal relationship (compare entries 5 and 8, Table 5, p 42). Based on the observed (and estimated)673 1 3 C N M R chemical shift values (Scheme 26), it can be concluded that C-3 is shielded (relative to C-2) in compound 25b and is deshielded (relative to C-2) in compound 28, and that the n systems are polarized as indicated. Whether or not this polarization is responsible for the difference in the efficiency of the cyclopropanation reactions of compounds 25b and 28 is not known. Scheme 26. Observed and estimated (in parentheses) 1 3 C chemical shift values for vinyl carbons (C-2, C-3), and proposed double bond polarizations (8\ 8+). '' 108 (-91) 8" H 140 (-136) 8+ HO. 2 -144 (-136) 5 I 102 (-90) 8" 25b 28 Cyclopropanation of compound 30a using standard conditions and a reaction time of 30 min provided the iodocyclopropane 69a in 65% yield (entry 12, Table 5). Reaction of a higher homolog, 30b, using the same conditions and a reaction time of 45 min afforded the iodocyclopropane 69b in 43% yield (entry 13, Table 5). The same reaction conditions but with a slightly longer reaction time of 55 min gave a 47% yield of compound 69b (entry 14, Table 5). GLC analysis of the crude product indicated a trace amount of starting material (<4%) and side products, while TLC analysis indicated non-polar compounds, which presumably included the methyl ether 70. The use of 4 equivalents of (ClCEk^Zn (as opposed to 2 equivalents) and a 49 reaction time of 30 min afforded the same yield of iodocyclopropane 69b (47%) (entry 15, Table 5). Clearly, an increase in the steric bulk of the alkyl substituent (in this case, methyl vs pentyl) is of consequence to the success of the cyclopropanation. OH R - ^ O H R^fJ 30a,b 69a,b a R = CH 3 b R = (CH2)4CH3 27 64 65 Iodo alkene 27 was chosen as a substrate for the cyclopropanation study because the two faces of its double bond are diastereotopic. Cyclopropanation of compound 27 using standard conditions and a reaction time of 30 min afforded the iodocyclopropane 64 and the methyl ether 65 in 84% and 1% yields, respectively (entry 16, Table 5). Extension of the reaction time to 55 min provided 64 and 65 in 86% and 3 % yields, respectively (entry 17, Table 5). As with the stracturally similar compound 26a, the cyclopropanation of 27 was clean and efficient, but the latter required a longer reaction time (compare entries 2 and 17, Table 5). As confirmation of the structure of the minor component, compound 65 was prepared by methylating compound 64 (NaH, followed by Me l , 75% yield). The lH N M R spectra of the methylation product and of the minor product of the cyclopropanation reaction were identical. 50 Next, the relative stereochemistry of compound 64 was determined. Sequential treatment of cyclopropane 64 with f-BuLi and CO2, followed by acidification, afforded the extremely volatile lactone 71 in low yield (14%) (Scheme 27). No attempt was made to optimize the yield of this reaction. The stereochemistry of the lactone was determined by NOE difference experiments. Saturation of the secondary methyl signal (H-7) at 5 0.96 caused a positive NOE for the H-6b signal at 5 0.57 (Scheme 27). The observed diastereoselectivity of the reaction involving iodo alkene 27 can be rationalized if one considers the well-established directive effect of an allylic hydroxyl group in Simmons-Smith type cyclopropanations.23 Coordination of the zinc reagent to the hydroxyl oxygen leading to the transition state can occur on either face of the double bond, as shown in A and B. In A , there is steric repulsion between the iodo group and the methine proton of the hydroxyethyl group, whereas in B, there is steric repulsion between the iodo group and the secondary methyl group. It is reasonable to conclude that the steric repulsions would be less severe in A and that methylene delivery would therefore occur from the a face, to provide the diastereomer 64. Similar diastereoselectivity in a related case has been observed by Pereyre and workers.68 Scheme 27 64 71 51 Figure 4. Proposed iodo alkene-zinc reagent complexes leading to diastereomeric transition states. A R = ethyl The cyclopropanation of the substrates with remote functional groups (compounds 25c, 26c-e) varied in their success. The cyclopropanation of the geometric isomers 25c and 26c did not proceed smoothly. While it is known that zinc reagents react with triple bonds,23 it was hoped that the reaction of (ClCH2)2Zn with compounds 25c and 26c would be chemoselective and that the terminal alkynyl group would not cause interference; however, this was not the case. Reaction of iodo alkene 25c under the standard conditions, with a reaction time of 10 min, afforded iodocyclopropane 61c in 36% yield (entry 18, Table 5). TLC analysis of the crude reaction mixture indicated a significant amount of baseline material. 25c 61c Similarly, cyclopropanation of iodo alkene 26c, the geometric isomer of 25c, was problematic. Reaction of 26c under the standard conditions, with a reaction time of 10 min, gave 52 an unusual yellowish-brown reaction mixture. Workup and purification of the crude material gave a mixture consisting primarily of the starting material 26c and the corresponding cyclopropane 60c, in a ratio of -1 :6, based on X H N M R spectroscopic integration of the signals corresponding to the methylene protons of the hydroxymethyl groups. The mass of the mixture accounted for an - 7 0 % material balance. Also isolated was 11.5 mg (mass of starting material was 93 mg) of impure material which eluted (silica gel chromatotron plate) after the mixture of 26c and 60c, and 13 mg of impure material which eluted with MeOH. For each of these impure fractions, *H N M R analysis showed that the major component contained a cyclopropyl unit but not a terminal alkynyl group. The reaction was repeated and a similar result was obtained. Iterative chromatography afforded a 51% yield of pure iodocyclopropane 60c (entry 19, Table 5). Increasing the number of equivalents of zinc reagent from 2 to 3 and employing a reaction time of 15 min did result in complete conversion, but TLC analysis of the crude reaction indicated at least 7 components. Chromatography provided impure cyclopropane 60c (<53%). Despite the moderate to low yields of 61c and 60c obtained, the cyclopropanation reactions did provide the functionalized iodocyclopropanes as the major products, and as will be shown in Section 3.3, the l-(4-pentynyl) substituent on the cyclopropyl ring of these substances is a synthetically useful function. Cyclopropanation of the iodo alkene 26d using standard conditions and a reaction time of 5 min afforded the iodocyclopropane 60d in 68% yield and the methyl ether 63d (<10%) (entry 26c 60c 53 20, Table 5). Repetition afforded a 73% yield of the cyclopropane 60d and a 4% yield of the methyl ether 63d (entry 21, Table 5). In both cases, GLC analysis of the crude reaction mixtures indicated little, if any, starting material. 26d,e 60d,e 63d,e d R = CH 2 CI e R = C H 2 C H 2 O T B D M S Reaction of the iodo alkene 26e using standard conditions and a reaction time of 30 min resulted in poor conversion to the desired cyclopropane. Periodic G L C analyses of reaction aliquots after the initial 5 min indicated decreasing amounts of cyclopropane 60e, increasing amounts of the methyl ether 63e, and side products. However, a reaction time of 4 min afforded the iodocyclopropane 60e in high yield (82%) and a trace amount of the cyclopropyl methyl ether 63e (2%) (entry 22, Table 5). GLC analysis of the crude product indicated the absence of starting material. It should be noted that iodo alkene 26e was added to the preformed zinc reagent as a solution in dry, degassed PhH because it is sparingly soluble in C1CH2CH2C1. The iodocyclopropanes are stable compounds that did not require special handling other than storage in a refrigerator (~9°C) during long periods of time. The only exceptions are the alkynyl compounds 60c and 61c and compounds 69a,b, which showed slight discoloration after months of storage. 54 In connection with an investigation into the Pd(0)-catalyzed coupling reactions of cyclopropylzinc compounds (derived from the corresponding iodocyclopropanes) with iodo alkenes (Section 2.4), the cyclopropyl stannane 72 (Scheme 28) was required as a substrate for a comparative study. Cyclopropanation of the stannyl alkene 35b using 2 equivalents of preformed (ClCH 2) 2Zn (derived from Et 2Zn and C1CH2I) in C1CH2CH2C1 at 0°C for 15 min afforded cyclopropylstannane 72 in 94% yield (Entry 23, Table 5). 6 9 The spectral data of 72, which included *H NMR, COSY, HMQC, and 1 3 C N M R data, confirmed the assigned structure. Scheme 28 Et2Zn CICH2I C1CH2CH2C1 35b 72 An occasional minor side-product of the cyclopropanation reactions was the methyl ether of the desired iodocyclopropyl carbinol. The isolated yield of these methyl ethers ranged from 1-12%, but was typically less than 5%. The structural assignment of these relatively non-polar derivatives was, in each case, based primarily on X H N M R and IR data. For example, consider the methyl ether 68 (shown in Scheme 29). In the IR spectrum, the OH stretching absorption was notably absent and a strong C-O-C absorption occurred at 1113 cm"1. The *H N M R spectrum contained a 3-proton singlet at 8 3.49, corresponding to the methoxy group, and three 1-proton cyclopropyl signals at 8 0.23-0.35, 0.73, and 1.11. The 1 3 C N M R spectrum showed the expected 10 signals, and high resolution mass spectroscopy gave a M + value of 282.0478 (calculated M + 55 value is 282.0481). A possible route for the formation of 68, and for the remaining methyl ethers (62a, 63b, 63d, 63e, and 65), is presented in Scheme 29. The first step is the coordination of the zinc reagent, (OCH2)2Zn, with the hydroxyl group of iodocyclopropane 67 to give the complex 73. The second step is the formation of the zincate 74, which is known to be a slow process in comparison to the cyclopropanation reaction.23 Note that the coordination of the chloride atom to the zinc atom in 74 is similar to that which is thought to exist in the cyclopropanating reagent, (ICH2)2Zn.23 The third step is the rearrangement of 74 to provide 75, which then undergoes hydrolysis in the last step to give 68. Scheme 29 67 Z n ( C H 2 C I ) 2 H R = pentyl 73 74 68 ZnCI 75 56 C) Spectral Data. The spectral data of the iodocyclopropanes were in full agreement with the structural assignments. A combination of ID N M R (*H, NOE, 1 3 C, and APT), 2D N M R (COSY, HMQC, and HMBC) , IR, and MS data were used to determine the structure of each compound. Important aspects of these determinations are discussed in this section. The assignment of the relative stereochemistry of each cyclopropane was based on a knowledge of the cyclopropanation process. It is well established that the cyclopropanation of alkenes with Wittig-Furukawa reagents is a stereospecific process in the sense that the geometry of the substrate is retained in the product.23 Thus, the relative stereochemistry of the cyclopropanes could be assigned with confidence since the configurations of the alkenyl substrates had been confirmed by NOE difference experiments. As further confirmation, the relative stereochemistry of a representative cyclopropane was determined by NOE difference experiments. Iodocyclopropane 60a, which was derived from (Z)-3-iodo-2-penten-l-ol (26a), was chosen for study. Saturation of each of the methylene (H-5a, H-5b) signals at 8 1.14 and 1.38 caused enhancement of the cyclopropyl methine (H-2) signal at 8 0.09-0.19, while irradiation of the cyclopropyl methine (H-2) signal caused enhancement of the methylene (H-5a, H-5b) signals (Scheme 30). The reciprocal NOEs indicated that the ethyl substituent and the methine proton are in a cis relationship, as expected for a stereospecific cyclopropanation process. Scheme 30 H-5a v H-5b +NOE 26a 60a 57 H-3b OH 4 60a The assignment of the cyclopropyl proton signals in the X H N M R spectra of each iodocyclopropane was easily accomplished using the value of the chemical shift7 0'7 1 and the signal multiplicity data. For most compounds, the signal of highest multiplicity was assigned to the methine proton, H-2 (see "Structures for Table 6" on p 59 for structural formulae that have numbered atoms) since it is the only cyclopropyl proton that can have large vicinal couplings to more than one proton. This assignment was confirmed for each compound by COSY experiments (see Experimental Section for COSY data). The exceptions to this generality were cyclopropanes 69a and 69b which, because of their substitution pattern, have essentially an A M X cyclopropyl spin system (if small, long range coupling is ignored). The remaining cyclopropyl signals, corresponding to the methylene protons H-3a and H-3b, were assigned based on the general observation that cis-l,2-coupling between cyclopropyl protons is usually greater than trans-1,2-coupling.6 7 b The dihedral angle between the trans-CH bonds is large (-131-134 0) 7 2 in contrast to the zero angle between the cis-CH bonds, and thus the cis-coupling is expected to be greater than the trans-coupling. Typical 7Cis values range from 7 to 13 Hz while /trans values range from 4 to 9.5 Hz. 6 7 b For example, consider the C 6 D 6 X H N M R spectrum of the iodocyclopropane 60a. The spectrum contained three 1-proton signals at 8 0.09-0.19, 0.50, and 0.58. The signal of highest multiplicity appeared at 8 0.09-0.19 and was assigned to H-2. A COSY experiment confirmed that H-2 was coupled to H-3a, H-3b, and H-4. The two remaining signals at 8 0.50 and 0.58, therefore, corresponded to the two methylene protons, H-3a and H-3b. 58 These protons were expected to be coupled to each other and to the vicinal proton, H-2. Consequently, the signals for H-3a and H-3b were expected to appear as doublet of doublets. However, because the geminal coupling constant ( / g e m ) was coincidentally equal to the vicinal coupling for one of these protons, the downfield signal at 8 0.58 appeared as a triplet. The signal was correctly assigned as a doublet of doublets with 7 g e m = J v i c i n a i = 6 Hz. The remaining cyclopropyl proton signal appeared as expected as a doublet of doublets at 8 0.50 with coupling constants of 9.5 and 6 Hz. Since 7 c i s is generally larger than / t r a n s , the signal at 8 0.50 was assigned to H-3a, and the signal at 8 0.58 was assigned to H-3b. The values of the coupling constants were Jc\s = 9.5 and 7 g e m = . /trans = 6 Hz (see CeD6 data in entry 4, Table 60). The assignment of H-3a and H-3b were confirmed by NOE difference experiments. Irradiation of the signal at 8 0.13 (H-2) enhanced the signal at 8 0.50, which, on the basis of / values, had been assigned to H-3a. Irradiation of the methylene signal at 8 3.71 (H-4b) enhanced the signal at 8 0.58, which, on the basis of / values, had been assigned to H-3b. Thus, the assignment of H-3a and H-3b on the basis of 7Ci S and Jtrans values was valid. The *H N M R data for the cyclopropyl protons of the remaining compounds are given in Table 6. The data are given for two solvents, CDC13 and C 6 D 6 . Originally, C 6 D 6 was used in order to obtain better resolution of the cyclopropyl signals for cases in which there was signal overlap in the CDC13 spectrum. For example, consider cyclopropane 60e (entry 8, Table 6). In the *H N M R spectrum obtained using CDC13 as the solvent, the signal corresponding to the cyclopropyl proton H-3b appeared as part of the overlapping signals in the region 8 0.77-0.95. However, in the *H N M R spectrum obtained using CeD6 as the solvent, the signal corresponding to proton H-3b was clearly resolved at 8 0.57, as were the other cyclopropyl proton signals. Since solvent-induced shifts of *H N M R resonances have been reported for 1-bromo- and 1-iodo-59 2-methylcyclopropanes,17 we decided to obtain *H N M R spectra for most of the cyclopropanes in both CDCI3 and C 6 D 6 in order to investigate such effects in our compounds. For compounds 60a-b, 60e, and 64 (entries 4-5, 8, and 9, Table 6), the resolution was better in C 6 D 6 whereas for compound 61a (entry 1), the resolution was better in CDC13. For compound 61c (entry 3), a 2:1 mixture of C 6 D 6 :CDC1 3 provided satisfactory resolution. No significant improvement in signal resolution was found in either solvent for the remaining compounds. Structures for Table 6. H-3b H-3a H-3a 4 61a-c 60a-e 27 a R = H a R = H c R = CH2CteCH b R = CH2CH2CH3 b R = CH2CH2CH3 c R = CH2C=CH d R = CH2CI e R = CH2CH2OTBDMS H-3b H-3b H-3a 66 67 69a,b a R = CH 3 b R = (CH2)4CH3 60 Table 6: Selected Cyclopropyl *H N M R Data. Entry Cyclo-propane Selected *H N M R data (8; multiplicity; J (Hz)) solvent = CDC1 3 Selected *H N M R data (8; multiplicity; J (Hz)) solvent = CeD 6 a H-2 H-3a H-3b H-2 H-3a H-3b 1 61a 1.78-1.88; m 1.26; dd; 9, 6.5 0.57; dd; 6.5, 6.5 1.50-1.60; m 0.94-1.03* 0.05; dd; 6.5, 6.5 2 61b 1.74-1.84; m l21b,c 0.56; dd; 6.5, 6.5 1.10-1.70* 1.07; ddd; 9.5, 6.5, 0.5 0.22; dd; 6.5, 6.5 3 61c 1.56-1.88* 1.28; dd; 9.5, 6.5 0.67; dd; 6.5, 6.5 1.55b'c'd 0.99;d dd; 9.5, 6.5 0.26-/ dd; 6.5, 6.5 . 4 60a 0.44-0.54; m 0.99;* dd; 9.5, 6.5 0.88; br dd; 6.5, 6.5 0.09-0.19; m 0.50; dd; 9.5,6 0.58; dd; 6, 6 5 60b 0.45-0.56; m 0.99; dd; 9.5, 6.5 0.84-0.91* 0.08-0.17; m 0.53; dd; 9.5, 6.5 0.58; dd; 6.5, 6.5 6 60c 0.51-0.62; m 1.04; dd; 9.5, 6.5 0.89; dd; 6.5, 6.5 0.08-0.18; m 0.44-0.55; m 0.44-0.55; m 7 60d 0.54-0.65; m 1.06; dd; 9.5, 6.5 0.91; dd; 6.5, 6.5 e e e 8 60e 0.46-0.57; m 0.99; dd; 9.5, 6.5 0.77-0.95* 0.08-0.20; m 0.52; dd; 9.5, 6 0.57; dd; 6, 6 9 64 0.21; ddd; 8, 8, 8 1.06/ d;8 1.06/ d;8 (-0.22)-(-0.14); m 0.58; dd; 9, 6 0.78; dd; 6,6 Continued on next page 61 Table 6 (continued from previous page) Selected Cyclopropyl *H N M R Data. Entry Cyclo- Selected X H N M R data Selected *H N M R data propane (8; multiplicity; J (Hz)) (8; multiplicity; J (Hz)) solvent = CDC1 3 solvent = C 6 D 6 a H-2 H-3a H-3b H-2 H-3a H-3b 0.59; 1.03-1.37* 0.98; 0.12; 10 66 _j dd; dd; 9, 6.5 dd; 6.5, 6.5 6.5, 6.5 0.23-0.36; 1.11; 0.74; (-0.06)- 0.79; 0.51; 11 67 m ' dd; 9.5, 6.5 dd; 6.5, 6.5 (0.04); dd; dd; m 9.5,6 6, 6 1.98; 0.56; 0.44; 12 69a e e e ddd; 8, 5, dd ;8 ,6 dd; 6, 5 0.5 2.37; 1.06; 0.71; 2.06; 0.62; 0.43; 13 69b ddd; 8, 5, dd; 8,6 dd; 6, 5 ddd; 8, 5, dd; 8, 6 dd; 6, 5 0.5 0.5 a The N M R solvent was C 6 D 6 unless otherwise noted. The signal was among overlapping signals or was overlapped with adjacent signal(s). c Approximate chemical shift (8) based on a COSY experiment. d N M R solvent = 2:1 C6D6:CDCl3. e This data was not acquired. f The signals corresponding to H-3a and H-3b were isochronous. 8 The chemical shift could not be determined due to signal overlap. 62 The effect of solvent on the *H N M R spectrum of compound 64 was significant (entry 9, Table 6). When the spectrum was measured in C 6 D 6 , the cyclopropyl protons appeared as expected in that the methine proton, H-2, resonated at high field as a 1-proton multiplet at 5 (-0.22)-(-0.14) while the methylene protons, H-3a and H-3b, appeared as 1-proton doublets of doublets at 8 0.58 and 0.78, respectively. A COSY experiment confirmed the assignments (see Experimental Section, p 246, for COSY data). However, when the solvent C 6 D 6 was replaced by CDC13, a quite different spectrum was observed. The signal corresponding to H-2 again appeared at high field (8 0.21), but its splitting pattern was simplified. Instead of a multiplet, the appearance of the signal was like that of a quartet (the intensity ratio was, however, - 1 : 2 : 2 : 1). Furthermore, the H-3a and H-3b signals appeared together as a 2-proton doublet (7=8 Hz) at 8 1.06, rather than as two distinct signals as in the CeD6 spectrum. From this it was concluded that, in CDCI3, the methylene protons, H-3a and H-3b, are chemical shift equivalent.73 Furthermore, the fact that a clean doublet was observed indicated that the difference in coupling between H-3a and H-2 (Jcis) and between H-3b and H-2 ( 7 ^ ) was not significant (7 c i s = /u-ans = 8 Hz). 7 4 This conclusion was confirmed by a decoupling experiment: irradiation at 8 3.43-3.51 (H-4) simplified the signal at 0.21 (H-2) to a dd with 7Cis = -Arans = 8 Hz. As for H-2, the coupling between it and H-4 was also 8 Hz. The signal for H-2, which appeared as a "quartet", was therefore assigned as a ddd with three equal coupling constants of 8 Hz. The results of a COSY 63 experiment were in agreement with the signal assignments (see Experimental Section, p 245, for COSY data). A second, more general, solvent effect was observed for compounds 60a, 60b, and 60e (entries 4, 5, and 8, Table 6). When the solvent CDCI3 was replaced by C 6 D 6 , the resonances of the H-2 signals were shifted upfield by -0 .4 ppm while the resonances corresponding to H-3a were shifted upfield by -0 .5 ppm. In comparison, the resonances corresponding to H-3b were shifted upfield by -0.2-0.3 ppm. The result was a reversal of the order of the chemical shift of H-3a and H-3b in CeD6 relative to CDCI3. Presumably, the shielding effect of the solvent C 6 D 6 is more pronounced for the side of cyclopropyl ring containing H-2 and H-3a. Similarly, in compounds 61a-c (entries 1-3, Table 6), H-3b was shielded to a greater extent than were H-2 and H-3a when CDC1 3 was replaced by CeD6. The effect of the iodine atom on chemical shifts of the cyclopropyl protons is unclear, at least from a qualitative evaluation of the data. One obvious effect of the iodine atom is observed for cyclopropanes 69a and 69b (entries 12 and 13, Table 6) which have a cyclopropyl proton and the iodine atom in a geminal relationship. As in the case of iodocyclopropane (76, Scheme 31), the proton which is in a geminal relationship with the iodine atom (H-2 in 69a and 69b, H - l in 76) is deshielded relative to the other cyclopropyl protons, a consequence of the electronegativity of the iodine atom and of the anisotropy of the C-I bond.75 Scheme 31 H-3a 69a-b a R = CH 3 b R = (CH2)4CH3 76 Table 7: Selected Cyclopropyl 1 3 C N M R Data." R 61a-c a R = H b R = CH2CH2CH3 c R = CH2C=CH 60a-e a R = H b R = CH2CH2CH3 c R = CH2C=CH d R = CH2CI e R = CH2CH2OTBDMS 27 HO 66 H i I H OH 1 67 OH a R = CH3 b R = (CH2)4CH3 Entry Cyclopropane Selected 1 3 C N M R data (8) C - l C-2 C-3 lb 61a 13.2 31.7 21.9 2b 61b 11.6 31.4 22.1 3C 61c 10.1 31.2 21.7 4 60a 20.7 26.5 21.8 5 60b 19.8 26.6 21.8 6 60c 17.6 26.4 21.7 Continued on next page 65 Table 7 (continued from previous page) Selected Cyclopropyl C N M R Data." Entry Cyclopropane Selected 1 3 C N M R data (8) C - l C-2 C-3 r 60d 16.7 26.2 21.7 8 60e 18.7 26.6 21.9 9 64 18.3 31.7 22.8 10 66 14.8 30.1 21.8 11 67 23.4 22.4 21.0 12 69a 21.9* -3.8* 21.5 13 69b 25.8" -4.0* 20.4 a The N M R solvent was CeD6 unless otherwise noted. b In this experiment, the N M R solvent was CDC1 3 . c In this experiment, the N M R solvent was a 2:1 mixture of C 6 D 6 and CDC13. d Note that in compounds 69a,b, the carbon with an attached iodine atom is labelled as C-2, as opposed to C - l as in other compounds. The chemical literature contains litde C N M R spectroscopic data for highly functionalized iodocyclopropanes.71 It is known that the oc-carbon of iodocyclopropane (76, Scheme 31, p 63) resonates at high field due to a heavy atom effect,483 but on the whole, it is difficult, if not impossible, to assign the cyclopropyl resonances based on this phenomenon, or on a comparison to the literature data. However, the assignment of the cyclopropyl carbon 66 resonances can be accomplished with the help of APT and HMQC experiments, along with signal intensity and chemical shift information. The 1 3 C N M R data are given in Table 7. The solvent that was chosen for the HMQC experiments was C6D6, unless superior *H signal resolution (which made the 1 3 C assignments possible) was obtained in CDCI3 (or a solvent mixture, see entry 3). The solvent used in APT experiments was the same as that used in the HMQC experiments. As can be seen from Table 7, the range of chemical shifts of the cyclopropyl carbons within a given compound varied from -2.5 ppm for compound 67 (entry 11) to - 3 0 ppm for compound 69b (entry 13). Otherwise, there was little variance within each structural series, regardless of the solvent or the ring substituents (compare entries 1-3, 4-8, and 12-13). The highest field chemical shifts were observed for compounds 69a and 69b (entries 12 and 13) which have an iodine atom and a proton in a geminal relationship. For example, in compound 69a , the chemical shift of C-2 was -3.8 ppm while in compound 69b, it was -4.0 ppm (note that in compounds 69a,b, the carbon with an attached iodine atom is labelled as C-2, as opposed to C - l as in other compounds). The high field shift of C-2 in these compounds is due to a shielding effect associated with the attached iodine atom. 4 8 3 The effect was only evident when the iodine atom was in a geminal relationship with a hydrogen atom (compare entries 12 and 13 with other entries in Table 7). A comparison of the chemical shifts of the cyclopropyl carbons of the compounds 60a-c (entries 4-6) with those of the rrans-isomers 61a-c (entries 1-3) revealed that the C - l signals of the cis isomers were - 7 ppm downfield from those of the trans isomers, while the C-2 signals of the cis isomers were - 5 ppm upfield from those of the trans isomers. The C-3 signal in both isomer series, as in the other cyclopropyl compounds, occurred at approximately the same shift 67 (-21.8 ppm). Clearly, the relative stereochemistry of these compounds has an effect on the chemical shift of the C-1 and C-2 resonances. Entry 8 requires further comment. The assignment of the cyclopropyl quaternary carbon of compound 60e was not straightforward, simply because the presence of the tert-butyldimethylsilyloxy group added a second quaternary carbon to the 1 3 C spectrum. Thus, there were two weak quaternary carbon signals of similar shift in the 1 3 C spectrum which, by the nature of the HMQC experiment (the HMQC experiment is designed to show one-bond C, H correlations), did not show proton correlations. The problem was easily solved with the results of a H M B C experiment (which shows two- and three-bond C, H correlations). The signal at 5 18.7 showed a correlation to H-3a in the H M B C spectrum and was therefore assigned to the cyclopropyl quaternary carbon (C-l). With respect to the IR data of the iodocyclopropanes, two characteristic vibrations were the cyclopropyl C -H absorption, which usually occurs in the range 3012-3095,7 6 and the O-H absorption. The C -H stretching absorption occurs at a frequency higher than that of other aliphatic C -H vibrations because of the relatively high s character of the cyclopropyl C -H bond.7 7 Unfortunately, the C -H stretch was usually weak and was sometimes buried by the aliphatic C-H or the O-H vibrations. An example of a C -H absorption was found in the IR spectrum of cyclopropane 67. This weak absorption occurred at 3070 cm"1. Also observed was a broad O-H absorption at 3354 cm"1. 68 1.4. Conclusions. The results of our investigations show that electron-deficient 2- and 3-iodo-2-alken-l-ols undergo efficient and stereospecific cyclopropanation when treated with the highly reactive bis(chloromethyl)zinc reagent, (ClCH 2) 2Zn. 5 6 Prior to this work, the efficient preparation of Reaction of iodo alkenes 26a,b with (ClCH 2) 2Zn provided the corresponding iodocyclopropanes 60a,b in excellent yields (60a, 87%; 60b, 83%). In comparison, the cyclopropanation of iodo alkenes 25a,b (the trans isomers of 26a,b) provided moderate yields of the corresponding iodocyclopropanes 61a,b (61a, 76%; 61b, 66%), whereas reaction of iodo alkene 27b (a structural isomer of 25a and 26a) provided a low yield (47%) of 69b. On the other hand, the cyclopropanation of 27a, a lower homolog of 27b, was more efficient and provided iodocyclopropane 69a in 65% yield. functionalized iodocyclopropanes had not been reported in the literature.4 26a. I) a R = H b R = CH2CH2CH3 60a,b 25a,b a R = H b R = CH2CH2CH3 61a,b 27a,b a R = CH 3 b R = (CH2)4CH3 69a,b 69 The behavior of iodo alkene 28 under the cyclopropanation conditions was quite different from that of compound 29, the geometric isomer of 28. Reaction of 28 with (C lCH^Zn was very sluggish and a low yield (31%) of iodocyclopropane 66 was obtained after a difficult separation. In contrast, cyclopropanation of iodo alkene 29 proceeded smoothly when an extended reaction time (1 h) and an excess of zinc reagent (4 equivalents) were employed; iodocyclopropane 67 was obtained in 78% yield. 29 67 The functionalized iodo alkenes containing terminal chloro and ferf-butyldimethylsilyloxy functions, compounds 26d and 26e, underwent smooth cyclopropanation to provide 60d and 60e in high yield (73% and 82%, respectively) (see next page for structures). In contrast, iodo alkenes containing terminal alkynyl functions, compounds 25c and 26c, did not undergo clean cyclopropanation. The reaction of the zinc reagent with the alkynyl function resulted in problematic side-reactions. Nonetheless, the cyclopropanation reactions did provide the functionalized iodocyclopropanes 60c and 61c as the major products in 51 and 36% yields, respectively. 70 R 26d,e d R = CH2CI e R = CH2CH2OTBDMS R OH 25c 61c 26c OH OH Finally, a diastereoselective cyclopropanation was observed for substrate 27, which is structurally similar to the (Z)-3-iodo-2-alken-l-ols, 26a,b, but differs in that it contains an asymmetric carbon. Reaction of substrate 27 using standard conditions provided one diastereomer, cyclopropane 64, in excellent yield (86%). The relative stereochemistry of 64 was determined by way of NOE difference experiments which were carried out on the lactone derivative 71. Me 27 64 71 71 2. Substituted Vinylcyclopropanes. 2.1. Introduction. The successful preparation of the functionalized iodocyclopropanes allowed us to focus on the second goal of our research program which was to investigate the synthetic utility of iodocyclopropane chemistry. As mentioned in Section 1.1, these compounds appear to be ideal substrates for the preparation of metallocyclopropanes, which in turn can be employed as partners in transition metal-catalyzed cross-coupling reactions. We therefore decided to investigate the Pd(0)-catalyzed cross-coupling of cyclopropylzinc compounds (derived from the corresponding iodocyclopropanes) with iodo alkenes as a method of preparing highly substituted 1,2-divinylcyclopropanes. The synthesis, which is shown in general terms in Scheme 32, is both convergent and stereospecific. Scheme 32 R = H, alkyl 77 78 79 80 81 72 The first step in the proposed sequence was a lithium-iodine exchange reaction in which the iodocyclopropane (general structure 77) is treated with BuLi to provide the corresponding cyclopropyllithium 78. The lithium derivative was expected to be configurationally stable based on Walborsky's study of chiral cyclopropyl anions.78 Two equivalents of BuLi would be required since the Uthium-iodine exchange reaction generates Bui (in addition to the cyclopropyllithium 78) which can react with the BuLi. The excess BuLi would consume the Bui and ensure complete lithium-iodide exchange.79 The second step in the proposed sequence was a metathesis reaction in which the cyclopropylhthium 78 is treated with ZnCl 2 to provide the requisite cyclopropylzinc derivative 79. It should be noted that the conversion of 77 to 79 would represent a novel preparation of a cyclopropylzinc reagent from an iodocyclopropane.80 The cyclopropylzinc derivative 79 is then coupled with the iodo alkene 80 in the presence of a catalytic amount of Pd(PPh3)4 to provide the highly substituted, stereodefined 1,2-divinylcyclopropane 81.81 We chose highly substituted iodocyclopropanes and electrophiles for our study since we assumed that if the coupling of sterically hindered partners was successful, then examples employing less hindered partners would also be feasible. In keeping with this rationale, we chose in most cases to place a bulky 2-methyl-1-propenyl group on the cyclopropyl ring in a 1,2-cis relationship with the iodo group (see 77, Scheme 32). Furthermore, the zinc moiety of 79 was usually associated with a tertiary cyclopropyl carbon, which would further increase the steric interactions during the coupling process. The synthetic utility of 1,2-divinylcyclopropanes is well established.82 The thermal Cope rearrangement of 1,2-divinylcyclopropanes is generally an efficient method of constructing seven-73 membered rings (Scheme 33) and consequently, the rearrangement has been used extensively in natural product synthesis.82 Scheme 33. Cope rearrangement of cis- and fra/w-1,2-divinylcyclopropane. 82 83 cis 84 85 82 83 trans cis Both cis- and trans- 1,2-divinylcyclopropane (compounds 82 and 84, respectively, Scheme 33) rearrange to give 1,4-cycloheptadiene (83). It is thought that the rra/w-isomer 84 isomerizes to the cw-isomer 82 via the diradical species 85 before rearranging to the Cope product 83. Sometimes, however, the rearrangement of highly hindered trans- 1,2-divinylcyclopropane systems is inefficient and is accompanied by side reactions.83 Furthermore, it has been shown that the Cope rearrangement of enantiomerically pure trans- 1,2-divinylcyclopropane systems are not enantiospecific.84,85 In contrast, the Cope rearrangement of similar cis- 1,2-divinylcyclopropane systems are enantiospecific.85 Thus, in cases where a particular synthesis must be 74 enantioselective, or where the rearrangement of a trans- 1,2-divinylcyclopropane system is inefficient, the stereospecific preparation of the cis- 1,2-divinylcyclopropane system is clearly desirable and a method such as the one outlined in Scheme 32 would be synthetically useful. There are a few naturally occurring compounds that incorporate the 1,2-divinylcyclopropane unit as part of their structure (Scheme 34). Rothrockene (86) is a non-head-to-tail monoterpene which was isolated from the leaves and flower heads of Artemisia tridentata rothrockii by Epstein and Gaudioso.86 The total synthesis of (-)-rothrockene, and its epimer, was reported by Johnson and co-workers in 1984.87 Dictyopterenes A and B (87 and 88, respectively) are the major constituents of the essential oil of the brown Hawaiian seaweeds Dictyopteris plagiogramma and D. australis. They were first isolated by Moore and co-workers8 8 and have since been synthesized by several groups (Dictyopterene A 8 5 , 8 9 , Dictyopterene B 8 9 b ' 9 0). Scheme 34 Et 86 87 88 (-)-rothrockene dictyopterene A dictyopterene B There are several reports in the literature of Pd(0)-catalyzed cross-coupling reactions involving cyclopropylzinc compounds. In 1987, Piers and co-workers reported a method of preparing vinylcyclopropanes that involved the Pd(0)-catalyzed cross-coupling reaction of 75 cyclopropylzinc derivatives with iodo alkenes.91 The cyclopropylzinc derivatives 91 were prepared from cyclopropylstannanes 89 via a two step, one flask reaction sequence (Scheme 35). The first step was a transmetallation reaction in which the cyclopropylstannane 89 was treated with 1.2 equivalents of BuLi (in THF, at -78°C) to provide the cyclopropyllithium 90. Treatment of 90 with 1.2 equivalents of ZnCl 2 (-40°C), afforded the requisite cyclopropylzinc derivative 91. The coupling of 91 with various iodo alkenes 92 in the presence of Pd(PPh3)4 provided the corresponding frans-substituted vinylcyclopropanes 93 (6 examples) in good yields (65-82%). A fran^-l,2-divinylcyclopropane (93, Ri = (CH=CH2), R2 = R* = H R3 = (CH2)3C1) was also prepared using this method in moderate yield (67%). Scheme 35 catalytic 89 90 91 92 93 In 1989, Campbell and co-workers reported a high yielding synthesis of 3-substituted anthranilonitriles 95 that involved the Pd(0)-catalyzed cross-coupling of 3-iodoanthranilonitrile (94) with several organozinc bromides (9 examples), including cyclopropylzinc bromide (Scheme 36).9 2 The organozinc bromides (RZnBr) were prepared by reaction of the corresponding Grignard or organolithium reagent with ZnBr2. The coupling of structurally simple 76 cyclopropylzinc bromide (c-PrZnBr) with 94 provided the 3-cyclopropylanthranUonitrile (95, R = c-Pr) in excellent yield (98%). Scheme 36 The Pd(0)-catalyzed cross-coupling reaction of cyclopropylzinc derivatives with iodo alkenes has also been studied by Harada and co-workers. In 1993, they reported the generation of cyclopropylzinc derivatives 99 and 102 via the 1,2 alkyl migration reaction of zincate carbenoids 98 and 101, which were derived from the corresponding gem-dibromocyclopropane 96 (Scheme 37). 9 3 The zincate carbenoid 98 was prepared by several methods. Notably, reaction of dibromocyclopropane 96 with BuLi (in THF, at -85°C) gave the the hthium carbenoid 97 with high trans selectivity. Successive treatment of 97 with ZnCl 2 (1.0 eq) and R 2 L i (2.0 eq) at -85°C, followed by warming of the resulting zincate carbenoid 98, gave trans-99 with high stereoselectivity. The epimer of 99, compound 102, was also prepared from the dibromide 96 (Scheme 37). Conversion of 96 to 97, followed by chlorination with CC13CC13 or CF2C1CFC12, gave the bromochlorocyclopropane 100. Reaction of 100 with R 2 3 ZnLi (-85°C to r.t.) resulted exclusively in Zn/Br exchange, providing 101, which gave 102 upon warming. 77 Scheme 37 R 1 \ ^ H l e q B u L i ^^f^~H l e ( l Z n C 1 2 R \ / ^ H w a r m i n g R > S ] ^ H B r ^ B r THF, -85°C L i ^ B r 2eqR 2Li LiR 2 Zn Br i,2-alkyl r 2 Z n L migration 96 97 98 99 CCI3CCI3 CF2C1CFC12 R 1 N ^ H R 2 3 Z n L i R\fH 2 Waming, "S/^  n ^ ^ R r r ^ N T / 0 1,2-alkyl l_Zn R 2 CI Br THF, -85°C C l Zn pj2^ j migraUon 100 101 102 Reaction of 99 with aryl and alkenyl bromides (3 equiv) in the presence of Pd(0) (at r.t. for 16-24 h) gave trans-103 in moderate yields (examples are given in equation 1, Scheme 38). Similarly, reaction of 102 with aryl and alkenyl bromides under the same reaction conditions provided cis-104, again in moderate yields (examples are given in equation 2, Scheme 38). It should be noted that while the coupling reactions proceeded without the loss of configuration of the cyclopropylzinc substrates, mixtures of cis- and Jra/w-products were obtained in each case because the intermediates, 99 and 102, were not stereochemically pure. Scheme 38 eq 1 y M Pd(pph 3) 2 ^ y M rVfSnL R 3 X R 2 ^ R 3 99 103 99a R i = Ph, R 2 = Bu, R 3 = Ph (9.1:1 transxis) 103a (60%) 99b Ri = Ph, R 2 = Bu, R 3 = (CH2=CMe) (8.5:1 transxis) 103b (76%) 99c Ri = BnOCH 2 , R 2 = Bu, R 3 = (CH2=CMe) (9.1:1 transxis) 103c (70%) eq 2 D j catalytic D > R l ^ H Pd(PPh 3 ) 2 ) R l > r f H LZn R 2 R 3 X R 3 R 2 102 104 102a R i 102b Ri 102c Ri = Ph, R 2 = Bu, R 3 = Ph (1:16 transxis) = Ph, R 2 = Bu, R 3 = (CH2=CMe) (1:9.2 transxis) = BnOCH 2 , R 2 = Bu, R 3 = (CH2=CMe) (1:>40 transxis) 104a (68%) 104b (45%) 104c (47%) 79 2.1.1. Mechanism of Pd(0)-Catalyzed Cross-Coupling Reactions of Organozinc Reagents with Unsaturated Halides. The cross-coupling reactions of organozinc reagents were first described by Negishi and co-workers in 1977. 9 4 ' 9 5 They investigated the Pd(0)-catalyzed cross-coupling reactions of alkynyl-, benzyl-, and arylzinc reagents with unsaturated halides. The preparations of 107 (65%) and 110 (87%) are representative (Scheme 39). Scheme 39 ==5— ZnCI + catalytic Pd(PPh3)4 105 106 107 Ph-ZnCI + 108 109 110 Mechanistically, such cross-coupling reactions of organozinc compounds are very similar to those of organotin compounds with unsaturated halides and acid chlorides.96'97 Oxidative insertion of the Pd(0) catalyst into the carbon-halide bond of the organohalide 111 provides the 80 palladium (II) intermediate 112 (Scheme 40). This intermediate then undergoes transmetallation with the organozinc compound (R'ZnX) to give 113. Reductive elimination regenerates the Pd(0) catalyst and produces the cross-coupling product 114. Organozinc compounds are suitable coupling partners because the zinc atom has empty low-lying p orbitals that can participate in the transmetallation reaction.96 In addition, the low reactivity of organozinc derivatives (due to the high covalent character of the carbon-zinc bond) towards a wide variety of functional groups permits the preparation of highly functionalized coupling products.96 Scheme 40 X R' R-X PdL2 R-Pd-L R'ZnX R-Pd-L -PdL2 R-R' L -ZnX2 L X = Br, I 111 112 113 114 R - alkenyl, aryl R' = alkenyl, aryl, alkynyl, functionalized alkyl 81 2.2. Preparation of the Substrates and Electrophiles. A) Substrates. Vinyl iodocyclopropanes 116a, 116b, and 116c (Scheme 41) were chosen as substrates in our investigation of the Pd(0)-catalyzed cross-coupling of cyclopropylzinc derivatives with iodo alkenes and iodobenzene (Section 2.4). These substrates were prepared from the corresponding alcohols via an oxidation-olefination sequence. Vinyl cyclopropyltrimethylstannane 116d, which was required for a comparative study (vide infra), was also prepared via this route. The first step of the sequence was the oxidation of the appropriate cyclopropyl carbinol, using TPAP 9 8 and the co-oxidant 4-methylmorpholine N-oxide in CH2CI2, which provided the corresponding formyl cyclopropane in good yield. The results of the oxidation reactions are summarized in Scheme 41. Each aldehyde was isolated as a colorless oil; compounds 115a and 115b, however, quickly discolored at r.t. and continued to do so while standing over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). Hence, compounds 115a and 115b were promptly carried on to the olefination step. The spectral data (*H and 1 3 C NMR, IR, and MS) of compounds 115a-d were in full accord with the assigned structures. Compounds 115c and 115d were sufficiently stable for elemental analysis. The IR spectrum of each aldehyde showed a characteristic C=0 stretching absorption (Table 8, p 83). Notably, the frequency of the C=0 absorption of the stannyl aldehyde 115d was lower than those of the iodo compounds. Presumably, intramolecular coordination of the carbonyl oxygen of 115d with the tin atom weakens the C=0 bond and lowers its absorption frequency. A similar observation was made for the (Z)-alkyl 3-trimethylstannyl-2-alkenoates presented in Section 1.2 (p 16). Conditions: (a) TPAP, N M O , CH 2C1 2 ; (b) (j-Pr)PPh3Br/NaNH2 -> (Me)2C=PPh3, THF; (c) (i-Pr)PPh3Br/BuLi -> (Me)2C=PPh3, THF. 83 Table 8. Selected Spectral Data of the Formyl Iodocyclopropanes 115a-d. 115c 115d Entry Compound IR( v ) Chemical Shift (8), multiplicity, J (Hz) C=0 st H-2 H-3a H-3b CHO 9.09 r 115a 1708 b _ b b d, 3 1.36 1.77 9.06 2 C 115b 1713 b dd, 9, 6.5 dd, 6.5, 6.5 d,5.5 2.00 0.60 0.94 8.92 3a 115c 1713 dd, 7.5,6 dd, 7.5, 6.5 dd, 6.5, 6 s 1.70 1.10 1.18 9.56 4 C 115d 1697 ddd, 8, 3.5, 3.5 dd, 8, 3.5 dd, 3.5, 3.5 d,3.5 a The N M R solvent was CeD6. b The signal was among overlapping signals. c The N M R solvent was CDC13. 84 The *H N M R spectrum of each aldehyde contained a characteristic downfield, 1-proton signal corresponding to the foimyl proton (Table 8), and upfield signals corresponding to the cyclopropyl protons, with the exception of compound 115a. The cyclopropyl protons of compound 115a could not be assigned because of signal overlap; however, assignments were possible for the corresponding vinyl iodo derivative 116a (see Table 9). The second step of the sequence was the olefination of the formyl iodocyclopropanes using iso-propyhdenetriphenylphosphorane, which was prepared by stirring a commercially available, pre-mixed powder consisting of wo-propyltriphenylphosphonium bromide and sodium amide in dry THF (1 h at r.t.).99 Addition of the aldehyde to this suspension at 0°C resulted in efficient olefination. The procedure, which included an easy workup, was straightforward and provided the desired vinyl iodocyclopropanes in good yields. The results of the olefination reactions are summarized in Scheme 41. The olefination of the stannyl aldehyde 115d was accomplished in two ways. The first procedure employed the pre-mixed powder described above and provided compound 116d in good yield (82%). The second procedure employed the same phosphonium salt but a different base, BuLi , and provided a higher yield of the vinyl compound 116d (93%). In this procedure, an excess of phosphonium salt was added in order to ensure complete consumption of the BuLi, which could react with the formyl or stannyl functions of the substrate. The vinylcyclopropanes varied in their stability. Stannane 116d was stored neat, over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C) for long periods (>8 months) without significant decomposition. In contrast, iodides 116a, 116b and 116c showed slight discoloration after several days of storage. The decomposition of 116a was significant. The originally clear, colorless oil ultimately became a brown and cloudy mixture. TLC analysis of the mixture 85 indicated several impurities. The olefination reaction of 115a was repeated and the crude material was purified by column chromatography using Iatrobeads® as the stationary phase.100 The purified material was then used in the coupling reaction without delay. The spectral data ( J H and 1 3 C NMR, IR, and MS) of compounds 116a-d were in full accord with the assigned structures. Compounds 116b, 116c, and 116d were sufficiently stable for elemental analysis. Selected IR and 1 H N M R data are given in Table 9. A very weak C=C stretching absorption was observed in the IR spectra of compounds 116b and 116c, but not in those of compounds 116a and 116d. The absence of the C=C stretching absorption is not uncommon in the spectrum of trisubstituted alkenes.670 The cyclopropyl proton signals in the *H N M R spectra of compounds 116a, 116c, and 116d were easily assigned (with the exception of H-2 of compound 116d). In contrast, all of the cyclopropyl proton resonances of compound 116b were buried among overlapping signals. These signals, however, were present in the spectrum of the reduction product 130 which was prepared by sequential treatment of 116b with BuLi and water (Scheme 45, p 91). In addition, the *H N M R spectrum of each vinylcyclopropane contained a characteristic downfield signal corresponding to a vinyl proton (Table 9). 86 Table 9. Selected Spectral Data of the Vinyl Iodocyclopropanes 116a-d. 116c 116d Entry Compound IR( v ) Chemical Shift (5), multiplicity, J (Hz) C=C st H-2 H-3a H-3b H-4 1° 116a b 2.14-2.25 m 1.37e 0.41 dd, 6, 6 4.70-4.76 m 2d 116b 1675 (w) e e e 4.87-4.95 m 3a 116c 1670(w) 2.26 dd, 8, 5 1.10c 0.79 dd, 5.5,5 5.35 br signal 4d 116d b e 0.62 dd, 8, 4 0.46 dd, 4, 4 4.58-4.64 m a The N M R solvent was C 6 D 6 . b The C=C stretching absorption was absent. c Approximate chemical shift (8) value based on COSY data. d The N M R solvent was CDC13. e The signal was among overlapping signals. 87 B) Electrophiles. The electrophiles that were chosen for our investigation of the Pd(0)-catalyzed cross-coupling of cyclopropylzinc derivatives with iodo alkenes and arenes are shown in Scheme 42. Iodobenzene (117) was obtained from the Aldrich Chemical Company, while 1-iodocyclohexene (118) was prepared according to the procedure of Wiemer and Lee. 1 0 1 Iodo alkene 120 was prepared in 67% yield by iododemetallation of vinylstannane 119. 1 0 2 TLC and G L C analysis of the crude reaction material indicated minor side products which were not characterized. The spectral data of compound 120 were in full accord with the assigned structure. Iodo alkene 123 was prepared according to a two step procedure. Sequential treatment of compound 121 (see Experimental Section, p 178, for preparation) with MeLi and I2 provided iodo alkyne 122 in 93% yield.1 0 3 The 1 3 C N M R spectrum of compound 122 contained a signal at 5 -7.3 corresponding to the terminal alkynyl carbon. The high field chemical shift of this carbon is due to a heavy atom effect associated with the attached iodo group.4 8 3 The second step in the sequence was the reduction of iodo alkyne 122 with diimide, HN=NH, 1 0 4 which afforded the (Z)-iodo alkene 123 in 67% yield. A small amount of an impure mixture was also obtained. GLC-MS analysis of a similar mixture obtained from an earlier reduction of 122 indicated the presence of starting material 122, iodo alkene 123, and a primary iodide (the TBDMS ether of 6-iodohexanol). Fortunately, most of the iodo alkene 123 was easily isolated from the crude reaction mixture using radial chromatography with the aid of U V visualization. The Z configuration of the double bond was confirmed by the results of a decoupling experiment. Irradiation of the allylic methylene proton signal simplified the overlapping signals of the vinyl 88 Conditions: (a) I2, CH 2C1 2 ; (b) MeLi ; I2 (c) HN=NH, MeOH; (d) (r|5-C5H5)ZrH(Cl), CH 2C1 2 ; I2. 89 protons to two doublets with J values of 11.5 Hz, which is typical of vinyl protons in a cis relationship.67d Compound 124 was prepared by the hydrozirconation-iodination of alkyne 121. Sequential treatment (one-pot) of a solution of 121 in CH 2C1 2 with (r|5-C5H5)2ZrH(Cl) (Schwartz's reagent)105 and I2 gave iodo alkene 124 in 74% yield. The spectral data of compound 124 were in full accord with the assigned structure. The E configuration of the double bond was once again assigned on the basis of the vicinal coupling constant of the vinyl protons, which was found to be 14.5 Hz (as compared to the 11.5 Hz coupling in the Z isomer).6 7 d 2.3. Exchange Reactions. Our investigation of the Pd(0)-catalyzed cross-coupling of cyclopropylzinc derivatives with iodo alkenes required various substituted cyclopropyllithium compounds as precursors to the zinc derivatives. The cyclopropyllithium compounds were prepared from the corresponding iodo vinylcyclopropanes. The details of these preparations are discussed in this section. Also included in this section are the details of a study that examined the use of cyclopropylstannanes as potential precursors to the requisite cyclopropyllithium compounds. An efficient method of preparing organohthium reagents is the metal-halogen exchange reaction, represented in Scheme 43 . 1 0 6 The reaction was discovered independently by the research groups of Gilman 1 0 7 and of Wittig. 1 0 8 The reaction is a reversible process109 and proceeds in the direction that places the lithium atom on the carbon of the weakest base. 1 0 9 ' 1 1 0 Consequently, the equilibrium constant is greatly determined by the choice of the R groups shown in Scheme 43. The reaction occurs readily with iodides and bromides111 and is faster in electron-90 donating solvents such as Et 2 0 than in hydrocarbon solvents.1 1 0 , 1 1 2 The reaction is generally rapid and can be conducted at very low temperatures (as low as -120°C).1 1 3 Scheme 43 The first preparation of a cyclopropyllithium derivative via a lithium-iodine exchange reaction was reported by Walborsky and co-workers in 1964.7 8 Treatment of (+)-(5)-l-iodo-l-methyl-2,2-diphenylcyclopropane (125) with excess BuLi (in Et20, at r.t.) provided the corresponding cyclopropyllithium derivative 126, which in turn was allowed to react with either Br 2 or CO2 to provide the cyclopropyl bromide 127 or acid 128 (Scheme 44). Analysis of each product indicated complete retention of configuration and of optical activity. It was also determined that changes in the solvent, temperature or reaction time had very little, if any, effect on the optical purity of the products. Surprisingly, the preparation of cyclopropyllithium derivatives via Uthium-iodine exchange has received very little attention in the literature since Walborsky's report.4 R'-X + R-Li R'-Li + R-X Scheme 44 127 125 126 ph Ph 128 91 In our work, the metal-halogen exchange reactions of the vinyl iodocyclopropanes 116a, 116b, and 116c proceeded smoothly (Scheme 45). Treatment of compounds 116a, 116b, and 116c with 2.2 equivalents of BuLi (in THF, at -48°C) for 15 min, followed by addition of water, provided the corresponding reduction products 129, 130, and 131 in 79%, 88%, and 79% yields, respectively (equations 1, 2, and 3). In addition to the cyclopropyllithium intermediates, the lithium-iodide exchange reaction generated Bui which reacted with the BuLi to give n-octane and L i l . Thus, in order to achieve complete lithium-iodide exchange, two equivalents of BuLi were employed, the second equivalent serving to consume the Bu i . 7 9 The spectral data (*H NMR, including COSY experiments for 129 and 131, 1 3 C NMR, IR, and MS) of compounds 129, 130, and 131 were in full accord with the assigned structures. Scheme 45 B u L i ; water eq 1 116a 129 e q 2 116b 130 e q 3 116c 131 92 A second method of preparing organohthium derivatives is the metal-metal exchange reaction, or transmetallation reaction, represented in Scheme 46. 1 1 4 The reaction was discovered by Seyferth and co-workers.1 1 5 As with the metal-halogen exchange reaction, transmetallation is an equilibrium process that proceeds in the direction that places the hthium atom on the carbon of the weakest base.1 1 6 Thus, the driving force of the reaction is the relative difference in base strengths of the organolithium reagents (R-Li vs R'-Li) shown in Scheme 46. The first preparation of cyclopropyllithium via a transmetallation reaction was reported by Seyferth and Cohen in 1963. 1 1 7 Treatment of tetracyclopropyltin (132) with 2 equivalents of BuLi in pentane gave cyclopropyllithium (133) as a white precipitate in 79% yield (equation 1, Scheme 47). Interestingly, two equivalents of BuLi were found to be optimum for this reaction. Scheme 46 R'-M + R-Li R'-Li + R-M Scheme 47 pentane + 2 BuLi 2 + eq 1 132 133 1 eq BuLi THF, 3 h 0°C eq2 134 135 93 In 1984, Corey and Eckrich reported the preparation of cw-2-ethylcyclopropylhtMum (135) from the corresponding stannane 134 using 1 equivalent of BuLi (in THF, at 0°C) (equation 2, Scheme 47). 1 1 8 Based on the results discussed above, we decided to compare the lithiations of the vinyl iodocyclopropanes 116a and 116b (Scheme 45, p 91), which were shown to proceed smoothly, with the lithiations of the structurally similar vinyl cyclopropyl stannanes 136119 and 116d, respectively (Scheme 48). Sequential treatment of compound 116d with 2.05 equivalents of BuLi (in THF, at -23°C) for 1 h, followed by addition of aq sat. NH4CI, gave a complex mixture (43 mg of crude product were isolated, mass of starting material was 38 mg) (equation 1, Scheme 49). The *H N M R spectrum (C6D6, 400 MHz) of the crude product contained alkyl tin, methyl, vinyl, and cyclopropyl signals. G L C - M S analysis indicated a mixture consisting primarily of starting material 116d, cyclopropylbutyldimethylstannane 137, and cyclopropyldibutylmethylstannane 138, in a ratio of -16:67:14. Interestingly, using the same reaction conditions with MeLi in place of BuLi, gave only starting material 116d according to GLC and *H N M R analysis of the crude material (mole recovery was 83%). Scheme 48 136 116d 94 Scheme 49 116d 137 n = 1 138 n = 2 116d 10 eq BuLi THF, gradual warming from 0°C to r.t. 139 130 + 3 MeLi eq2 Scheme 50 BuaSrv A %>M C f iH 6^11 OMe 140 MeLi THF, r.t./24 h 141 (<10%) eq 1 140 10 eq BuLi THF, 10 h 141 eq2 95 A similar reluctance of a cyclopropylstannane to undergo transmetallation was met by Lautens and workers.1 2 0 Reaction of compound 140 with MeLi (in THF, at r.t.) afforded <10% of the cyclopropyllithium derivative 141 (equation 1, Scheme 50). However, reaction of 140 with 10 equivalents of BuLi (in THF) for 10 h did result in complete transmetallation (equation 2, Scheme 50). The success of this reaction prompted us to try similar conditions for the transmetallation of compound 116d. A cooled (-20°C) solution of 116d in THF was treated with 10 equivalents of BuLi and was gradually warmed to r.t. over a period of 5 h (equation 2, Scheme 49). Surprisingly, the reaction did not provide the expected transmetallation-protonation product 130 as the major product, but rather, the cyclopropyltributylstannane 139 in 75% yield. A small amount of compound 130 (<4%) was detected in the crude product by G L C analysis. The molecular formula of compound 139 was confirmed by HRMS which gave a value of 456.2774 for the molecular ion (calculated value for C24H48 1 2 0Sn is 456.2778), and by elemental analysis. The *H N M R spectrum (C 6D 6 , 400 MHz) of 139 contained the expected cyclopropyl, methyl, vinyl, and tributylstannyl signals and the assignments were confirmed by a COSY experiment. The 1 3 C N M R spectrum showed the expected 16 resonances. The transmetallation of cyclopropyl stannane 136, which has a sterically unhindered stannyl group in comparison to 116a, was studied briefly. Treatment of compound 136 with 2.05 equivalents of BuLi (in THF, at -23°C) for 1 h, followed by addition of aq sat. NH4CI, gave a mixture of products (25.6 mg of crude material were isolated, mass of starting material was 22.6 mg) (Scheme 51). The *H N M R spectrum (C 6 D 6 ,400 MHz) of the crude product contained alkyl tin, methyl, vinyl, and cyclopropyl signals. GLC -MS analysis of the crude product indicated a mixture consisting primarily of cyclopropylbutyldimethylstannane 142, 96 cyclopropyldibutylmethylstannane 143, and cyclopropyltributylstannane 144, in a ratio of -23:67:8. Thus, while methyl-butyl exchange was more facile for the less-hindered ^-isomer, very little, if any of the reduced material 129 (resulting from cleavage of the cyclopropyl carbon-tin bond) was observed. Scheme 51 136 SnMeg 2.05 eq BuLi THF, -23°C/1 h \ ^ ^ ^ N ^ S n M e 3 . n B u n X" 142 n = 1 143 n = 2 144 n = 3 129 n MeLi The methyl-butyl exchange reactions of compounds 116d and 136 can be rationalized in the following way: as mentioned in the introduction to transmetallation reactions, the reaction is an equihbrium process that generally proceeds in the direction that places the hthium atom on the carbon of the weakest base. In Schemes 49 and 51, this is the carbon atom of the methyl anion as opposed to the carbon of the butyl anion. Thus, methyl-butyl exchange is observed. There is an anomaly, however, in that the cyclopropyl-tin bonds of compounds 116d and 136 were expected to be broken preferentially to the alkyl-tin bonds since a cyclopropyl anion is expected to be a weaker base than a methyl or a butyl anion. The anomaly can be rationalized by postulating that the cleavage of the cyclopropyl-tin bond is kinetically disfavored. Assuming that the reaction proceeds via a closed, 4-center transition state, with the cyclopropyl group in an apical position121 97 (see Figure 5), then steric repulsions between the Uthium atom and the substituents on C - l (R3 and -CH.2-) would disfavor cleavage of the cyclopropyl carbon-tin bond. Figure 5. Proposed cyclopropyltin-BuLi complex showing unfavorable steric interactions. Finally, it should be noted that Lautens and co-workers found that compound 145, the epimer of compound 140 (Scheme 52) did undergo transmetallation to provide the corresponding cyclopropyllithium derivative when treated with MeLi (in THF, at 0°C). 1 2 0 They concluded that chelation involving the methoxy group, which is not possible in the trans isomer, is important in the transmetallation process. The exact nature of the chelation is not discussed, but reference is made to the work of Carpenter who invoked chelation between an hydroxyl group and either a Uthium or a tin atom to explain a "directed" transmetallation reaction.122 R2 116d Ri = 2-methyl-l-propenyl; R 2 = H; R3 = pentyl 136 Ri = H; R 2 = 2-methyl-l-propenyl; R 3 = pentyl 98 Scheme 52 Bu 3Srv A xH Bu3Sri 140 145 The result of Lautens (and of Carpenter) encouraged us to attempt the transmetallation reaction of the cw-(hydroxymethyl)cyclopropylstannane 72 with BuLi and with MeL i (equations 1 and 2, Scheme 53). Treatment of compound 72 with 2.05 equivalents of BuLi (in THF, -23°C) for 1 h gave a complex reaction mixture which consisted primarily of cyclopropylstannane derivatives 146a-c and reduced material 147 (equation 1, Scheme 53). In the second attempt, treatment of compound 72 with 2.05 equivalents of MeLi (in THF, at -20°C), followed by warming to r.t. over a period of 19.5 h and addition of aq sat. NFLCl, gave a mixture of compounds (28.7 mg of crude material were isolated, mass of starting material was 48.4 mg). Analysis ( ! H N M R (400MHz) spectroscopy) of the crude product indicated a mixture consisting primarily of reduced material 147 and starting material 72 in a ratio of ~85:15. GLC analysis indicated a 81:19 ratio of reduced material 147 to starting material 72. Scheme 53 '-SnMe 3 2.05 eq BuLi O H THF, -23°C/1 h '-SnMe3.nBu . ^ O H 'n + ,OH e^1 72 146 a n = 1 b n = 2 c n = 3 147 continued on next page 99 Scheme 53-continued In the third attempt, three equivalents of MeLi were employed and the reaction mixture was stirred for -17 h at r.t. Workup and purification provided the reduction product 147 in excellent yield (87%). The spectral data of 147 were in full accord with the assigned structure. The result of this experiment is consistent with that of Lautens and indicates that chelation improves an otherwise sluggish transmetallation reaction. It is apparent from the reactions presented in this section that the metal-halogen exchange reaction is superior to the transmetallation reaction as a method for preparing the requisite vinylcyclopropyllithiums. The use of the vinylcyclopropylhthiums is discussed in Section 2.4. 100 2.4. Pd(0)-Catalyzed Cross-Coupling Reactions. A) Synthesis of Highly Substituted 1,2-Divinylcyclopropanes and l-Phenyl-2-vinylcyclopropanes. The coupling reactions are summarized in Schemes 54-57, 59-63, and in Table 10 (p 111). Reaction of vinyl iodocyclopropane 116b (equation 1, Scheme 54) with 2.05 equivalents of BuLi in THF (-48°C, 30 min), followed by treatment of the resulting lithio derivative with 3 equivalents of ZnCL. (-48°C for 15 min, followed by warming to r.t. over a 45 min period), provided the requisite cyclopropylzinc intermediate. Addition of 0.1 equivalents of Pd(PPh3)4, 1.6 equivalents of iodo alkene 124, and D M F (~5 mL/mmol of iodocyclopropane) gave a yellowish-brown suspension which was stirred at r.t. Periodic GLC analysis of reaction aliquots indicated poor conversion. After 44.5 h of stirring, the ratio of coupling products (1,2-divinylcyclopropane 148 and its Cope rearrangement product, cycloheptadiene 149) to reduced starting material 130 was -1.6:1 (based on G L C analysis of a reaction aliquot).123 Workup and chromatography of the crude product resulted in partial separation of 148 and 149. Combination and concentration of the appropriate fractions afforded a -1 :1 mixture of 148 and 149 in 30% yield (ratio based on X H NMR (400 MHz) spectroscopy). The isolation of hydrocarbon 130 was not attempted due to its volatility. The reaction was repeated using identical conditions, except that the reaction mixture was refluxed for 1 h after the addition of the electrophile 124 (equation 2, Scheme 54). G L C analysis of the crude reaction material indicated improved conversion: the ratio of the coupling products (148 + 149) to the reduced starting material 130 was -9 .6 :1 . The characterization and quantification of the coupling products were simplified by converting 1,2-divinylcyclopropane 148 entirely to the Cope product 149. Thus, the crude product was dissolved in xylenes and the 101 solution was refluxed for 1 h. Purification of the product mixture afforded the cycloheptadiene 149 in 61% yield. The facile Cope rearrangement of 1,2-divinylcyclopropane 148 was not surprising since numerous studies have shown that similar 1,2-divinylcyclopropanes rearrange cleanly under the appropriate conditions.82 Further experiments to optimize the reaction conditions revealed the use of 3 equivalents of ZnCL. to be unnecessary. Indeed, when the reaction was repeated using 1.5 equivalents of ZnCh, the same yield (61%) of cycloheptadiene 149 was obtained (equation 3, Scheme 54). Scheme 54 eq 1 H (1) 2.05 eq BuLi , THF, -48°C, 30 min (2) 3 eq ZnCl 2 , -48°C/15 min, -48°C to r.t./45 min (3) 0.1 Pd(PPh3)4, DMF, E + , r.t., 44.5 h 116b 124 H. OTBDMS 148 149 130 continued on the next page. 102 Scheme 54-continued eq2 (1) as above except that the reaction mixture was refluxed for 1 h after the addition of of the electrophile 124 116b - 149 (2) refluxing xylenes, 1 h (1) 2.05 eq BuLi , THF, -48°C, 30 min (2) 1.5 eq ZnCl 2 , -48°C/15 min, -48°C to r.L/45 min 116b - 149 (3) 0.1 Pd(PPh3)4, DMF, E + , reflux, 1 h (4) refluxing xylenes, 1 h The coupling of the zinc derivative obtained from iodocyclopropane 116b with iodo alkene 120 was also successful (equation 1, Scheme 55). Reaction of 116b with 2.05 equivalents of BuLi in THF (-48°C, 30 min) followed by treatment of the resulting lithio derivative with 1.5 equivalents of ZnCh, provided the requisite cyclopropylzinc intermediate. Addition of 0.1 equivalent of Pd(PPh3)4, 2.1 equivalents of iodo alkene 120, and D M F (~6 mL/mmol of cyclopropane) gave a yellowish-brown suspension which darkened upon warming. After 1 h of refluxing, G L C analysis of the reaction mixture indicated a mixture of coupling products (150 + 151) and reduced starting material 130 in a ratio of -3 .1:1. Chromatography of the crude 103 material afforded a -1.4:1 mixture of 1,2-divinylcyclopropane 150 and cycloheptadiene 151 in 60% yield (ratio based on X H N M R (400 MHz) spectroscopy).124 The reaction was repeated and isolation of the coupling products as the Cope rearrangement derivative afforded a 52% yield of cycloheptadiene 151 (equation 2, Scheme 55). Scheme 55 150 151 130 eq2 (1) 2.05 eq BuLi , THF, -48°C, 30 min (2) 1.5 eq ZnCl 2 , -48°C/15 min, -48°C to r.t./45 min 116b - 151 (3) 0.1 Pd(PPh3)4, DMF, E + , reflux, 1 h E+= r-01 120 (4) refluxing xylenes, 1 h 104 The reaction conditions given in equation 1, Scheme 55, were subsequently used as the standard conditions. The coupling of the cyclopropylzinc chloride derived from iodocyclopropane 116b with iodo alkene 123 under these conditions afforded the desired coupling product, 1,2-divinylcyclopropane 152, in 54% yield (Scheme 56). The yield was slightly lower than that obtained with the (£)-iodo alkene 124 (61%, equation 3, Scheme 54). This was not surprising since the 4-(te^butyldimethylsiloxy)butyl group of 123, which is in a 1,2-cis relationship with the latent coupling center (as opposed to the 1,2-trans relationship of 124), was expected to create unfavorable steric interactions during the coupling process. Scheme 56 (1) 2.05 eq BuLi , THF, -48°C, 30 min (2) 1.5 eq ZnCl 2 , -48°C/15 min, -48°C to r.t./45 min (3) 0.1 Pd(PPh3)4, DMF, E + , reflux, l h 116b 123 152 130 The effect of the 4-(fg^butyldimethylsiloxy)butyl group on the thermal stability of the product is clear: steric repulsions between this group (R2 in Figure 6) and the cyclopropyl proton 105 H-3b, in conjunction with steric repulsions between the methyl group, Me*, and that same cyclopropyl proton, H-3b, disfavored the Cope rearrangement of 152 under the reaction conditions.82 The coupling reaction was repeated with an extended refluxing period (2 h instead of 1 h) in an attempt to improve the yield but this was unsuccessful. The isolated yield of compound 152, in this case, was only 31%. Nonetheless, the initial yield of 54% is satisfactory, given that the product is a trisubstituted cyclopropane that contains a newly created quaternary center and cis-disubstituted and trisubstituted alkenyl groups. Figure 6. Steric interactions present in the boat conformation of 152 leading to the transition state required for Cope rearrangement.82 Me 152 Ri = pentyl R2 = 4-(rert-butyldimethylsiloxy)butyl The coupling of the cyclopropylzinc intermediate derived from iodocyclopropane 116b with 1-iodocyclohexene (118) under standard conditions afforded the 1,2-divinylcyclopropane 153, in good yield (Scheme 57). The side products of this reaction were sufficiendy polar (relative to the product) that simple elution of the crude material through a plug of silica with petroleum ether removed most of the impurities. Concentration of the filtrate and careful distillation of the acquired oil afforded 1,2-divinylcyclopropane 153 in 57% yield. Analysis CH 106 N M R (400 MHz) spectroscopy) of the distilled material indicated a trace amount of the Cope rearrangement product. A sample of 153 was dissolved in o-xylene-dio and the solution was refluxed for 1 h. Analysis ( J H N M R (400 MHz) spectroscopy) of the solution indicated clean isomerization of 153 to the Cope product 154, which was isolated in 92% yield (Scheme 58). 1 2 5 Scheme 57 153 107 The coupling reactions described to this point employed vinyl iodocyclopropane 116b as the substrate. The zinc derivative of this substrate has the 2-methyl-l-propenyl group and the zinc chloride moiety in a 1,2-cis relationship, and as such, the zinc center is sterically hindered. Consequently, the moderate yields (52-61%) of 1,2-divinylcyclopropanes (or Cope rearrangement products) were considered satisfactory. The coupling reactions employing vinyl iodocyclopropane 116a as the substrate (Schemes 59-61) were expected to be more efficient than those employing 116b, simply because the zinc derivative of 116a has a less hindered nucleophilic center, with the 2-methyl-l-propenyl group and the zinc chloride moiety in a 1,2-trans relationship. The use of 116a, however, did not result in higher yields of coupling products for reasons which are not entirely clear. Reaction of the organozinc intermediate obtained from iodocyclopropane 116a with the iodo alkene 124 under standard conditions provided 1,2-divinylcyclopropane 155 in 51% yield (Scheme 59). G L C analysis of the crude material indicated the presence of minor side products. Similarly, reaction of the zinc derivative acquired from iodocyclopropane 116a with iodo alkene 123, the geometric isomer of 124, under standard conditions afforded 1,2-divinylcyclopropane 156 in 49% yield (Scheme 60). It should be noted that the conversions of 116a, along with those of its epimer 116b, show that these reactions are stereospecific. The coupling of the zinc intermediate obtained from iodocyclopropane 116b with iodobenzene (117) under standard conditions afforded the l-phenyl-2-vinylcyclopropane 157 in 43% yield (Scheme 61). Analysis of the crude reaction mixture indicated the presence of reduced material 129 (GLC and TLC) and baseline material (TLC). Although the yield was modest, this reaction demonstrated that a simple aryl iodide can be coupled with the cyclopropane unit. Scheme 59 116a (1) 2.05 eq BuLi, THF, -48°C, 30 min (2) 1.5 eq ZnC^, -48°C/15 min, -48°C to r.t/45 min (3) 0.1 Pd (PPh3) 4 , DMF, E+, reflux, 1 h TBDMSCL / \ / \ M E + = 124 H 1 155 OTBDMS 129 Scheme 60 116a (1) 2.05 eq BuLi, THF, -48°C, 30 min (2) 1.5 eq ZnCl 2, -48°C/15 min, -48°C to r.t./45 min (3) 0.1 Pd(PPh3)4, DMF, E + , reflux, 1 h E + = TBDMSO H 123 T B D M S O 156 129 109 Scheme 61 157 129 The modest product yields from the coupling reactions discussed above were, in part, considered to be a result of the steric hindrance associated with the tertiary coupling center found in the zinc intermediates obtained from compounds 116a and 116b. Vinyl iodocyclopropane 116c (Schemes 62-63) was therefore chosen for further study since its zinc derivative would contain a less hindered secondary coupling center. Reaction of the zinc intermediate acquired from iodocyclopropane 116c with iodobenzene (116) under standard conditions afforded the cw-l-phenyl-2-vinylcyclopropane 158 in modest yield (40%) (Scheme 62), along with reduced starting material 131. Fortunately, the second example using vinyl iodocyclopropane 116c was more successful. Coupling of the zinc derivative obtained from iodocyclopropane 116c with the iodo alkene 123 under standard conditions 110 afforded the 1,2-divinylcyclopropane 159 in 63% yield (Scheme 63). This yield is higher than those obtained using vinyl iodocyclopropanes 116a and 116b and iodo alkene 123. Scheme 62 158 131 Scheme 63 116c (1) 2.05 eq BuLi, THF, -48°C, 30 min (2) 1.5 eq ZnC^, -48°C/15 min, -48°C to r.t./45 min (3) 0.1 Pd(PPh3) 4 , DMF, E+, reflux, 1 h E + _ T B D M S O ^ ^ ^ / s ^ H 123 TBDMSO' X H H H 159 131 I l l The results of the coupling reactions conducted using standard conditions are summarized in Table 10. Table 10. Pd(0)-Catalyzed Cross-Coupling of Cyclopropylzinc Derivatives with Alkenyl Iodides and Iodobenzene." Entry Substrate Electrophile Product Yield (%) 1 116b H ^ l 124 r ^ ^ ^ O T B D M S 149 61* 2 116b 120 151 52* 3 116b 123 152 54 4 116b a1 118 153 57 5 116a H ^ l 124 H ^ ^ \ ^ \ -OTBDMS 155 51 continued on next page 112 Table 10 (continued). Pd(0)-Catalyzed Cross-Coupling of Cyclopropylzinc Derivatives with Alkenyl Iodides and Iodobenzene." Entry Substrate Electrophile Product Yield (%) 6 116a T B D M S O v ^ \ ^ V ^ H 123 156 49 7 116a Q" 117 H H 157 43 8 H ^ l 116c a' 117 158 40 9 116c 123 T B D M S O ^ s / ^ " ^ H 159 63 a The results summarized in Table 10 are from experiments conducted using standard conditions. These conditions are: 2.05 eq BuLi , THF, -48°C/30 min; 1.5 ZnCl 2 , THF, -48°C/15 min, -48°C to r.t./45 min; 0.1 eq Pd(PPh3)4, 2 eq electrophile, ~6 mL D M F per mmol substrate, reflux for 1 h . b In this experiment, the cycloheptadiene was obtained by refluxing the isolated mixture of 1,2-divinylcyclopropane and cycloheptadiene in xylenes for lh. 113 B) Spectral Data. The spectral data (*H NMR, 1 3 C NMR, IR, MS) of the Cope rearrangement products 149 and 151 were in full accord with the assigned structures. For example, the 1 3 C N M R spectrum of compound 149 contained the expected 21 signals. Characteristic resonances were the four alkenyl signals at 8 123.0, 129.2, 142.1, and 143.1 and the signals of the TBDMS group at 8 -5.3 (Si(CH3)2) and 26.0 (C(CH3)3). The *H N M R spectrum of 149 displayed a 1-proton ddd (7=11, 7.5, 3 Hz) at 8 5.40 corresponding to the vinyl proton H-3 (see Scheme 64 for a structural formula of 149 with atom numbering), and overlapping signals at 8 5.10-5.20 corresponding to the remaining vinyl protons, H-4 and H-7. The assignments were confirmed by COSY and decoupling experiments (see Experimental Section, pp 293 and 294). Furthermore, the COSY data showed that H-3 was strongly coupled to one vinyl proton (i.e. H-4) which is consistent with an unconjugated diene system (H-3 would be strongly coupled to two vinyl protons if the diene system were conjugated). The IR spectrum of 149 showed a very weak C=C absorption at 1676 cm"1. The weak absorption is not surprising given the symmetric nature of the C-3, C-4 double bond and the fact that the C - l , C-7 double bond is trisubstituted.67c In contrast, the symmetric deformation frequencies of the gem dimethyl groups of 149 were clearly evident; absorptions were observed at 1361 and 1388 cm" 1 . 6 7 6 The spectral data (*H NMR, 1 3 C NMR, IR, and MS) of the 1,2-divinylcyclopropanes (compounds 152, 153, 155, 156, 159), and of the l-phenyl-2-vinylcyclopropanes (compounds 157, 158) were in full accord with the assigned structures. The *H N M R data, in particular, provided important structural information. 114 Scheme 64. Structural formulae of the coupling and Cope rearrangement products and selected NOEs (see Experimental Section for complete NOE results). continued on the next page. 115 Scheme 64 (continued from p 114) The cyclopropyl proton signals were assigned using a combination of the chemical shift, coupling constant, COSY, and NOE data. The *H N M R spectrum of compound 158 (see Scheme 64 for a structural formula of 158) showed three distinct cyclopropyl signals at 8 0.99, 1.11, and 1.84 (entry 6, Table 11). The cyclopropyl signals at 8 0.99 and 1.84 showed positive NOEs when the aromatic signals were irradiated and so were tentatively assigned to H-2 and H-3b (Scheme 64). The signal at 8 1.11 was therefore assigned to H-3a. Irradiation of the signal at 8 0.99 (H-2 116 or H-3b) caused positive NOEs of the signals at 8 1.11 (H-3a), 4.87 (H-10), and 7.10 (aromatic signals). Thus, the signal at 8 0.99 must correspond to H-3b. The signal at 1.84 was assigned to H-2. The coupling constants for the cyclopropyl protons, then, are as follows: JCiS = 8.5 Hz, 7 ^ = 6 Hz, and / g e m = 4.5 Hz, which agrees with the general observation that •Zeis > Jtrans for cyclopropyl protons.67b For each of the compounds 155, 157, and 159, two distinct cyclopropyl signals were observed in the *H N M R spectra (entries 3, 5, and 7, Table 11). These signals were assigned to the methylene protons, H-3a and H-3b, on the basis of the COSY data (see Experimental Section, pp 306, 311, and 316 for COSY data) and were distinguishable from each other on account of their J values (Jc\s > Jtraas)-61b In each case, the signal corresponding to the remaining cyclopropyl proton, H-2, was buried among overlapping signals and, according to the COSY data, was strongly correlated to H-3a and H-3b, and to the vicinal alkenyl proton. An approximate chemical shift for each of the H-2 protons was determined from the COSY data. The assignments were in agreement with the results of NOE difference experiments (see Scheme 64). For each of compounds 152 and 156 (entries 1 and 4, Table 11), only one cyclopropyl signal was well resolved in the *H N M R spectrum. In each case, it was determined that this signal corresponded to H-3b, which is cis to the 2-methyl-l-propenyl group, by way of NOE difference experiments (i.e. irradiation of the vinyl proton (H-4) signal caused enhancement of the cyclopropyl proton (H-3b) signal, see Scheme 64). The approximate chemical shift of the two remaining cyclopropyl signals was determined from the COSY data (see Experimental Section, pp 300 and 309, for COSY data). The methine proton, H-2, was distinguishable from the methylene proton, H-3a, because the former is coupled to the alkenyl proton, H-4. 117 Table 11. Cyclopropyl *H N M R Data of Compounds 152 ,153 ,155 -159 . Entry Compound" Chemical Shift (8), multiplicity, J (Hz)6 H-3a H-3b H-2 1 152 0.88c 0A2d dd, 4.5, 4.5 1.35c 2 153 0.66 d 0.58-0.69 d 1.30c 3e 155 imf dd, 8.5, 4.5 0.48/ dd, 5.5, 4.5 1.60c 4 156 0.87c 0.37 d dd, 5.5,4 1.45c 5g 157 125s ddd, 8.5, 4.5, 1 0.61' dd, 5.5, 4.5 1.70c 6 158 1.11* dd, 8.5, 4.5 0.99* dd, 6, 4.5 1.84* dd, 8.5, 6 7 e 159 0.937 dd, 8.5, 4.5 0.58/ dd, 4.5, 4.5 1.63c a See Scheme 64, pp 114-115, for structural formulae that have atom numbering. b The NMR solvent was CDCI3 unless otherwise noted. c Approximate chemical shift (8) based on COSY data. d Assignment based on NOE data. e The N M R solvent was CeD6. f Assignment is based on the observation that 7Cis > 7 ^ for cyclopropyl protons and on NOE data. 8 The N M R solvent was CD 2C1 2. 118 For the final compound 1 5 3 , there was partial overlap of two cyclopropyl signals in the X H N M R spectrum (entry 2, table 11). These two signals were assigned to the methylene (H-3a and H-3b) signals upon analysis of the COSY data (see Experimental Section, p 303, for COSY data). The partially resolved upfield signal showed enhancement upon saturation of the alkenyl signals corresponding to H-5 and H-10, and was therefore assigned to H-3b (see Scheme 64). The downfield signal at 8 0.66 was assigned to H-3a. The COSY data provided the approximate chemical shift of the remaining cyclopropyl proton, H-2, which was buried among overlapping signals and was strongly coupled to the alkenyl proton, H-10. The coupling reactions were expected to be stereospecific based on the literature precedents discussed in Section 2 . 1 . 9 1 9 3 For confirmation, the relative stereochemistry of the cyclopropyl unit was confirmed for each compound by a series of NOE difference experiments. The relevent enhancements are indicated in Scheme 64. For example, saturation of the H-8 signal of compound 1 5 2 caused a positive NOE for the H-4 signal, and conversely, irradiation of the H-4 signal caused a positive NOE for the H-8 signal. The reciprocal NOE established unambiguously the cis relationship of the cyclopropyl alkenyl substituents. In addition, the double bond configurations of the newly introduced alkenyl substituents in cyclopropanes 1 5 2 , 1 5 5 , 1 5 6 , and 1 5 9 were retained. The double bond assignments were based on the values of the vicinal couplings between protons H-8 and H-9. For compounds 1 5 2 , 1 5 6 , and 1 5 9 , the 7(H-8)-(H-9) values of 11, 10.5, and 11 Hz, respectively, established the Z configuration of the C8, C9 double bond. For compound 1 5 5 , the larger 7(H-8)-(H-9) value of 15.5 Hz established the E configuration of the C8, C9 double bond. 6 7 d Selective decoupling experiments were required to determine the 7(H-8>-(H-9) values of compounds 1 5 2 and 1 5 5 because signal overlap prevented direct measurement from the X H N M R spectrum. 119 The 1 3 C N M R data were also in full accord with the assigned structures. In most spectra, the expected number of carbon signals were observed, except in the cases of compounds 152, 155, and 156 for which one carbon resonance was not observed (most likely a quaternary carbon signal, based the signal intensities and APT results of the observed signals). The spectra of 1,2-divinylcyclopropanes 152, 153, 155, 156, and 159 contained the expected downfield signals corresponding to the four alkenyl carbons, whereas two such signals were observed for 1-phenyl-2-vinylcyclopropanes 157 and 158 in addition to the four phenyl resonances. Diagnostic absorptions were observed in the IR spectrum of the 1,2-divinylcyclopropanes and of the l-phenyl-2-vinylcyclopropanes. The spectra of compounds 152, 155, 156, and 159, which have TBDMS groups, showed characteristic C-O-Si absorptions. For example, the spectrum of compound 152 contained a C-O-Si absortion at 1102 cm"1. The spectra of the 1-phenyl-2-vinylcyclopropanes showed characteristic aromatic C -H stretching absorptions: 3030 and 3060 cm"1 for 157 and 3040 and 3060 cm"1 for 158. The C=C absorptions were absent in the spectra of compounds 152,153, and 156, but were present in the spectra of 155 (1665 cm"1), 157 (1602 cm"1), 158 (1606 cm"1), and 159 (1651 cm"1). 120 2.5. Conclusions. A new method of preparing highly substituted 1,2-divinylcyclopropanes (7 examples, including 2 examples where the product was characterized as the Cope rearrangement product) and l-phenyl-2-vinylcyclopropanes (2 examples) was presented in Section 2.4. The method is convergent and stereospecific, and involves the Pd(0)-catalyzed cross-coupling of cyclopropylzinc derivatives with alkenyl or aryl iodides. The cyclopropylzinc derivatives were derived from the corresponding iodocyclopropanes via a two step reaction sequence (a Uthium-iodine exchange reaction followed by a metathesis reaction). The Uthium-iodine exchange reactions of vinyl iodocyclopropanes 116a-c were found to proceed smoothly and provided the reduction products 129, 130, and 131, respectively, in high yields (79-88%) upon aqueous workup (see p 121 for structures). An alternative method of preparing the cyclopropylUthium derivatives of 116a and 116b was examined and was found to be inefficient. Specifically, the transmetallation of vinyl cyclopropyltrimethylstannanes 116d and 136, using BuLi under a variety of reaction conditions, did not provide the desired cyclopropylUthium derivatives, but rather, provided the products of an unexpected butyl-methyl exchange reaction. In the case of vmylcyclopropyltrimethylstannane 116d, the reaction was optimized to provide the cyclopropyltributylstannane 139 in 75% yield. In contrast, the transmetaUation of stannylcyclopropylcarbinol 72, for which chelation is possible, did provide the transmetallation-protonation product 147 in good yield (87%). 121 116a H 116b H H ^1 116c BuLi; water as above as above 129 130 H H 131 "A 116(1 136 "A 139 H -SnMe3 OH 72 H 147 r-H OH The coupling reactions provided a variety of highly substituted vinylcyclopropanes in moderate yields (40-63%) (see Table 10, pp 111-112). For example, the coupling of the cyclopropylzinc intermediate derived from 116b with iodo alkene 118 provided the 1,2-divinylcyclopropane 153 in 57% yield (entry 4, Table 10). In general, the yields of the coupling 122 reactions were considered satisfactory because of the sterically congested nature of the reactants and products. For example, 1,2-divinylcyclopropane 152, which was obtained in 54% yield, is a trisubstituted cyclopropane that has cw-disubstituted and trisubstituted alkenyl groups. The synthetic utility of functionalized vinylcyclopropanes, such as 152 and 153 is well established in the literature.82 152 123 3. BuLi-Mediated Cyclization of Substituted cw-l-(4-Alkynyl)-2-hydroxymethyl-l-iodocyclopropanes: synthesis of functionalized spiro[2.4]heptanes. 3.1. Introduction. The preparation of substituted alkylidenecycloalkane systems via the intramolecular addition of organometallic reagents to alkynyl moieties has received considerable attention in the last thirty years (Scheme 65) . 1 2 6 - 1 3 3 The cyclization has been accomplished using a variety of metals, including L i , 1 2 8 M g , 1 2 9 Zn, 1 3 0 A l , 1 3 1 Cu , 1 3 2 and Pd . 1 3 3 In particular, the intramolecular addition of alkyl- and alkenyllithium reagents to alkynyl moieties has been developed into a synthetically useful reaction, primarily through the efforts of Bailey and co-workers. 1 2 8 e f It occurred to us that this method could be extended to include the cyclization of alkynyl cyclopropyllithium compounds. Scheme 65 The first example of an intramolecular addition of an organolithium to a triple bond was reported by Dessy and Kandil in 1965. 1 2 8 a Treatment of l-phenylethynyl-8-bromonaphthalene (160) with BuLi in hexane-Et20 at r.t. provided the lithio derivative 161, which subsequently 124 underwent cyclization to give the addition product 162. Protonation of 162 provided 1-phenylacenaphthylene (163) in 82% yield (Scheme 66). Scheme 66 160 161 162 163 Two years later, Ward reported ° that the treatment of 6-bromo-l-phenyl- 1-hexyne (164) with excess BuLi in hexane-Et20 (5:1) at r.t., followed by aqueous workup, provided benzylidenecyclopentane (167) in 60% yield (Scheme 67), along with minor side products. It was proposed1 2 8 0 that the formation of 165 (and subsequently, 167) proceeded via a radical process, and indeed, subsequent studies134 have indicated that the reaction of alkyllithiums with primary alkyl bromides involves single-electron processes that produce primary alkyl radicals (i.e. 164^165). Scheme 67 + side products 164 165 166 167 125 In 1989, Bailey and co-workers reported that the reaction of the alkynyl alkyl iodide 168 with BuLi provided the lithium derivative 169 and that the subsequent cyclization of 169 to provide 167 was more efficient than that of the radical intermediate 165 studied by Ward. 1 2 8 c The Uthium-iodine exchange reaction,106 in contrast to the Uthium-bromine exchange reaction, does not involve radical intermediates when conducted under appropriate conditions.134 Thus, treatment of 6-iodo-l-phenyl-1-hexyne (168) in n-pentane-Et20 (3:2) at -78°C with 2.2 equivalents of ?-BuLi, foUowed by warming to r.t. and treatment with MeOH, gave benzyUdenecyclopentane (167) in 94% yield (Scheme 68). The only side-product was reduced starting material which was thought to arise from the deprotonation of r-BuI (generated from the reaction of r-BuLi with 168) by 169. The formation of this side-product was rninimized by using 135 ~2 equivalents of f-BuLi, the second equivalent serving to consume the r-BuI. Scheme 68 Ph Ph H 168 169 170 167 Further investigation revealed that 5-hexynylUthiums having trimethylsilyl and n-butyl substituted alkynyl moieties also undergo clean 5-exo-dig cyclization to give the corresponding substituted cyclopentylidenes.128e The reactions presented in Scheme 69 are representative. 126 Scheme 69 •TMS 2.2 eq f -BuLi n-pentane-Et 20 -78°C 171 T M S TMS warming to r.t. Li TMS^ „H M e O H 172 173 5 H 174 (96%) n-Bu as above 175 n-Bu n-Bu^^Li n-Bu^ warming T M e O H to r.t. 177 e q 2 178 (84%) The cyclization method was extended to include 4-exo-dig and 6-exo-dig processes: trimethylsilyl- and phenyl- (but not alkyl) substituted 4-pentynylUthiums and 6-heptynyllithiums underwent regioselective cyclization to provide the corresponding 4- and 6-membered ring compounds (Scheme 70). 1 2 8 e In the case of the 6-heptynyllithiums, it was necessary to introduce gem-dimethyl groups a to the alkyne function in order to suppress allene formation, which was found to be competitive with the desired cyclization reaction when this substitution was not present. Selected results are presented in Scheme 70. Scheme 70 179a,b 180a,b 181a,b a R = Ph (93%) b R = TMS (89%) 185a,b 186a,b 128 The cyclization reactions involving 182a,b require further comment (equation 2, Scheme 70). It was proposed by Bailey and Ovaska 1 2 8 e that these reactions proceeded via a syn addition of the C -L i bond across the triple bond, and that the initially formed (Z)-vmylhthiums 185a,b rapidly isomerized to the (£)-isomers 186a,b at the temperature required to effect cyclization (20°C) (Scheme 70). Because attempts to trap 185a,b with various electrophiles were unsuccessful, Bailey and Ovaska's proposal1 2 8 6 was based on the stereochemical results of the 5-and 4-exo-dig cyclizations of analogously substituted 5-hexynylhtWums and 4-pentynymthiums conducted at various temperatures (see Scheme 71 for selected results). At low temperature, the cyclizations proceeded with high syn selectivity. For example, reaction of 187a,b with BuLi at -78°C gave predominantly the syn addition products 189a,b. However, at higher temperatures, the cyclizations proceeded with low selectivity. Treatment of 187a,b with BuLi at -78°C, followed by warming to 20°C and treatment with MeOH, provided mixtures of 189a,b and 190a,b, indicating that the initially formed vmylUthium intermediates underwent partial isomerization before protonation. Scheme 71 R R 2.2 eq f-BuLi (1) temperature (2) M e O H -78°C 189a,b 190a,b anti addition product 187a,b 188a,b syn addition product a R = Ph b R = TMS At -78°C, 88% of 189a, 6% of 190a 98% of 189b, 0% of 190b At 20°C, 32% of 189a, 63 % of 190a 11% of 189b, 84% of 190b 129 In 1990, Negishi and co-workers reported the intramolecular addition of allenyl-, alkenyl-, and aryllithiums to silylated alkynes to provide 5-membered carbocycles with exocyclic double bonds in high yield. 1 2 8 8 The requisite organolithium intermediates were generated using several methods. For example, reaction of allene 191 with 1 equivalent of f-BuLi in hexane-TMEDA provided the allenyuithium derivative 192 which cyclized to give 193 (equation 1, Scheme 72). Treatment of the reaction mixture with water afforded the isomerically pure triene 194 in 65% yield. Shapiro degradation of p-toluenesulfonylhydrazone 195 in hexane-TMEDA using 2.1 eq of f-BuLi (-78°C to 0°C), followed by quenching, gave diene 198 in 75% yield (equation 2, Scheme 72). Treatment of 199 with 2 eq of r-BuLi in hexane-Et20 (at -78°C), gave 200 via Uthium-iodine exchange. Warming of the reaction mixture to r.t., foUowed by quenching, gave diene 202 in 90% yield (equation 3, Scheme 72). Similarly, reaction of 203 with 2 equivalents of r-BuLi in hexane-Et20 (-78°C to r.t.) provided the arylUthium 204, which cycUzed to the bicycUc compound 205. Quenching of the reaction mixture with water afforded 206 in 95% yield (equation 4, Scheme 72). Scheme 72 1 eq f-BuLi x X •==—TMS H -78°C to 0°C hexane-TMEDA 6 = — T M S Li TMS eq 1 191 192 193 194 continued on next page 130 Scheme 72-continued from previous page n-Hex n-Hex Interestingly, aryl- and alkenyllithiums did not add to alkylated (unactivated) alkynes under the standard reaction conditions. For example, treatment of 207 with f-BuLi gave only the uncyclized compound 209 (Scheme 73). 131 Scheme 73 hexane-Et20 -78°C to 25°C 2 eq I-BuLi H 2 0 n-Bu n-Bu n-Bu 207 208 209 The isomerization of alkynyl vmymthiums was also reported by Bailey and co-workers. A low temperature metal-halogen exchange reaction of bromo alkene 210 with ?-BuLi provided the vmyllithium intermediate 211 which isomerized upon warming to provide the 1,3-bis-exocyclic diene 212 after treatment with MeOH (Scheme 74). The diene was trapped in situ with maleic anhydride (213) to give the Diels-Alder adduct 214 in high yield (80%). Similar yields (63-91%) were obtained for six other Diels-Alder adducts. Scheme 74 -100°C 210 211 (1) warming to 0°C (2) MeOH O PhCH 3, refl. 3h 214 212 132 It is evident that the intramolecular addition of organolithiums to substituted alkynes is an efficient method of preparing alkyUdenecyclopentanoids. Aryl- , vinyl-, and primary alkyllithiums have been shown to add cleanly and stereoselectively in exo-dig fashion to suitably substituted alkynes. The analogous reactions employing cyclopropyllithiums have not been reported.136 As part of our investigation into the synthetic utility of iodocyclopropane chemistry, we decided to investigate the intramolecular addition of cyclopropyUithiums to substituted alkynyl moieties as a method of preparing of functionalized spiro[2.4]heptanes (Scheme 75). The products of these cyclizations would contain a spiro bicyclic ring system and would incorporate the synthetically useful vinylcyclopropane unit.1 3 7 Scheme 75 R R 215 216 217 218 OLi OLi R R 219 220 133 We proposed to conduct the cyclization reactions using 2.2 equivalents of BuLi. Presumably, the first equivalent of BuLi would be consumed by the deprotonation of the hydroxyl group1 3 8 to give 219 and the second equivalent of BuLi would then undergo metal-halogen exchange with the iodine atom to form the dilithium intermediate 216. The process could be complicated if the formation of dianion 216 were to occur before complete deprotonation of the starting material 215, as might be the case if there were localized high concentrations of BuLi in the bulk solution. Intermolecular protonation of the carbanion of 216 by the hydroxyl proton of starting material 215 would give the alkoxide 220, which cannot isomerize to the bicyclic product. In order to avoid such a scenario, the BuLi would be added dropwise to a solution containing the iodocyclopropane while the solution was being stirred vigorously. Finally, only 2.2 equivalents of BuLi would be employed since the consumption of BuLi by the generated Bu i would not be a concern under the reaction conditions (i.e. in E t 2 0, at -78°C). 1 3 9 134 3.2. Preparation of the Substrates. The substituted alkynyl iodocyclopropanes 225-228 were prepared from cis-2-hydroxymethyl-l-iodo-l-(4-pentynyl)cyclopropane (60c) (Scheme 76). The results are summarized in Table 12. Scheme 76 226 227 Treatment of 60c with 2.1-2.5 equivalents of L D A at -30°C gave the alkoxy acetylide 221. Addition of excess electrophile, followed by warming and cleavage of the resultant trialkylsilyl ether linkage (compounds 222 and 223) using AcOH 1 4 0 ' 1 4 1 (entries 1 and 2, Table 12) or the trimethylgermyl ether linkage (compound 224) using silica gel (entries 3 and 4, Table 12), 135 provided the desired substituted alkynyl carbinols 225-227. The highest yield of 227 was obtained when the Me3GeBr was added at -78°C and the reaction mixture was warmed to 0°C (entry 4). Chemoselective alkylation of the alkoxy acetylide 221 with methyl iodide gave the methylated alkynyl carbinol 228 (entry 5). The alcohol 229 was prepared according to a method similiar to that described by Nguyen et al. (Scheme 77). 1 4 2 Treatment of a diisopropylamine solution of 60c with iodobenzene in the presence of catalytic amounts of Cui and PdCl2(PPh3)2 gave the phenyl-substituted alkynyl carbinol 229 in 47% yield and the dimer 230 in 8% yield. The spectral data of compound 229, and similarly those of 225-228, were in full accord with the assigned structures. For example, the X H N M R spectra of 225-229 exhibited the expected signals corresponding to the newly introduced alkynyl substituent: 225 (8 0.11, s, 9H, Si(CH3)3); 226 (8 0.14, s, 6H, Si(CH 3) 2; 8 1.02, s, 9H, C(CH3)3); 227 (8 0.30, s, 9H, Ge(CH3)3); 228 (8 1.73, t, 3H, J = 2.5 Hz, CH3C=); and 229 (8 7.25-7.32, m, 3H, aromatic protons; 8 7.36-7.41, m, 2H, aromatic protons). The IR spectra displayed diagnostic OH absorptions: 225 (3355 cm"1); 226 (3348 cm"1); 227 (3343 cm"1); 228 (3344 cm"1); and 229 (3368 cm"1). Table 12. Preparation of Substituted Alkynyl Iodocyclopropanes." 136 1. L D A , T H F -30°C, 2h ^ 3. Cleavage of ether functions 60c (225-227) A Entry Electrophile Product A R Reaction Time (h)fe Yield c 1 TMSC1 225 TMS 2.2 72* 2 TBDMSC1 226 TBDMS 4.5 47 e 3 Me 3GeBr 227 Me 3Ge 1.3 67 4 Me 3GeBr 227 Me 3Ge 2.f/ 75 5 Me l 228 Me 1.2 5 7 G * a A l l reactions were carried out in dry THF employing 2.5 mmol of L D A and 5 mmol of electrophile per mmol of starting material (unless otherwise noted). b Warming period (-30°C to r.t., unless otherwise noted). c Isolated yield of purified product. * A solution of the crude product in 5% AcOH/MeOH (by volume) was stirred for 15 minutes.6 A solution of the crude product in 3:1:1 AcOH:H 2 0:THF (by volume) was stirred for 12 h. ' i n this experiment, 2.1 mmol of L D A and 1.5 mmol of Me 3GeBr per mmol of starting material were employed. Also, the Me 3GeBr was added at -78°C and the mixture was allowed to warm to 0°C over a 2 h period. s In this experiment, 2.1 mmol of L D A and 2.1 mmol of M e l per mmol of starting material were employed.h This experiment was conducted in a Schlenk flask in order to avoid the loss of Mel . 3.3. Synthesis of Functionalized Spiro[2.4]heptanes. 137 A) Cyclization Reactions. The reactions of the substituted alkynyl iodocyclopropanes with BuLi are summarized in Table 13. Treatment of 225 (R = TMS, entry 1, Table 13) with BuLi in Et20-hexanes (-3.5:1 by volume) at -78°C for 10 minutes, followed by a 30 minute warming period and quenching with water, afforded the spiro[2.4]heptane 231 in good yield (79%). Similarly, the cyclopropyUithium derived from 226 (R = TBDMS, entry 2, Table 13) cyclized to the bicyclic alkenylhthium which on workup provided the spiro[2.4]heptane 233 in 71% yield. Clearly the steric bulk of the alkynyl substituent had little effect on the efficiency of the cyclization. In each reaction, a small amount (7-8%) of the corresponding uncyclized alkyne (232, 234), formed by protonation of the cyclopropylhthium intermediate, was isolated. When the germylated alkyne 227 (R = GeMe3, entry 3) was treated with BuLi for 30 minutes, the resultant cyclopropylhthium underwent cyclization, albeit to a lesser extent than did the silylated alkynes. Extension of the reaction time from 30 to 90 minutes increased the yield of 235 from 40% (entry 3) to 60% (entry 4). 1 4 3 When the reaction was conducted in THF/hexanes (entry 5) rather than Et20/hexanes, a precipitate formed at low temperature which dissolved on warming. In this case, the yield of bicyclic alcohol 235 was quite poor (<14%) and the major product was the uncyclized alkyne 236 (49%). Cyclization of the phenyl-substituted alkynyl iodocyclopropane in Et20/hexanes was inefficient. Reaction of 229 (R = Ph, entry 7) with BuLi , followed by warming over a 30 minute period, afforded a low yield (44%) of the bicyclic alcohol 239 and a considerable amount (40%) 138 Table 13. BuLi-Mediated Cyclization of Substituted cw-l-(4-Alkynyl)-2-hydroxymethyl-l-iodocyclopropanes." R A B Reaction Time Products, Yield (%)c Entry Substrate R (min)6 A B 1 225 TMS 30 231 (79) 232 (7) 2 226 TBDMS 50 233 (71) 234 (8) 3 227 Me 3Ge 30 235 (40) 236 (33) 4 227 Me 3Ge 90 235 (60) 236 (8) 5 227 Me 3Ge 30 235 (<14)* 236 (49)* 6 228 Me 90 237 (0) 238 (83) 7 229 Ph 30 239 (44) 240 (40) 8 229 Ph 90 239 (36) 240 (30) a Procedure: A vigorously stirred solution of iodocyclopropane and dry ether was treated with a solution of BuLi in hexanes (2.2 equiv, -3.5:1 Et20:hexanes) at -78°C. After 10 minutes, the cooling bath was removed. The mixture was allowed to warm for the specified time and was then treated with water. b Warming period (-78°C to r.t.). 0 Isolated yield of purified product. * THF was used instead of Et20; a precipitate formed at low temperature which dissolved on warming. 139 of uncyclized alkyne 2 4 0 upon workup. Extension of the reaction time from 30 minutes (entry 7) to 90 minutes (entry 8) did not improve the yield of the bicyclic alcohol but rather reduced the yields of both cyclized and uncyclized products. Unlike the substrates 2 2 5 - 2 2 7 and 2 2 9 , the methyl-substituted alkynyl iodocyclopropane 2 2 8 did not undergo cyclization when treated with BuLi. G L C and *H N M R analysis of the crude material indicated only the presence of the uncyclized alkyne 238 . Purification of the crude material by distillation afforded the volatile alkyne in 83% yield (entry 6, Table 13). These results suggest that the electronic nature of the alkynyl substituent largely determines the success of the cyclization reactions. The highest yields were obtained when the alkynyl substituent was a trialkylsilyl group (entries 1 and 2 , Table 13). Such groups are well known for their ability to stabilize a-anions1 4 4 and consequently these groups could be expected to stabilize the vinyUithium products that are formed upon isomerization of the cyclopropyllithiums. A phenyl group is also known to have this ability145 and a trimethylgermyl group would be expected to behave similarly;146 however, the cyclization reactions of the phenyl-and trimethylgermyl-substituted alkynes were not as efficient as those of the silylated alkynes (compare entries 1, 2 , 4 and 7), for reasons which as yet are not entirely understood. The methyl-substituted alkynyl iodocyclopropane 2 2 8 did not undergo cyclization when treated with BuLi (entry 6), a result which shows that intramolecular addition of the cyclopropyllithium to the unactivated alkynyl moiety is not a favored process under the reaction conditions. A similar observation was made by Negishi, 1 2 9 g who found that aryl- and alkenyUithiums do not undergo cyclic carbolithiation of alkyl-substituted alkynes. The relative stereochemistry of each spiro[2.4]heptane was determined by ^ NOE difference experiments. Saturation of the vinyl proton signal of each compound resulted in a 140 positive NOE for the signal corresponding to one of the diastereotopic protons of the hydroxymethyl group (Scheme 78). Accordingly, saturation of the same diastereotopic proton caused a positive NOE for the vinyl proton signal. The observed enhancements established, unambiguously, that the hydroxymethyl and vinyl groups have a cis relationship with respect to the cyclopropane ring 1 4 7 and that the double bond has an E-configuration. The observed stereochemical outcome may be rationalized by proposing that the cyclization reaction, which is a 5-exo-dig process, proceeds via a chair-like transition state in which there is coordination of the L i atom with the n system of the triple bond. The model, as first proposed by Bailey and co-workers,1 2 8 e implies that the C -L i bond adds in a syn fashion to the triple bond to provide the E alkenylhthium intermediate, which is subsequently protonated with retention of configuration upon workup. It should be noted that alkenyUithiums that are gerninally substituted with phenyl145 or trimethylsilyl groups1 4 4 b are known to be configurationally labile. However, inversion of the E alkenylhthium intermediate to produce the Z isomer is unlikely in this system as it would place the bulky phenyl and silyl substituents in close proximity to the CH 2 OLi group, causing unfavorable steric interactions (Scheme 79). Furthermore, it is likely that the E alkenyllithium intermediate is stabilized by intramolecular coordination. Scheme 78 + NOE H 141 Scheme 79 E alkenyllithium Z alkenyllithium B) Spectral Data. As discussed in the previous section, the relative stereochemistry of each spiro[2.4]heptane was determined by NOE difference experiments. The observed enhancements established unambiguously that the hydroxymethyl and vinyl groups have a cis relationship with respect to the cyclopropane ring and that the double bond has an ^-configuration. The lU NMR, 1 3 C NMR, MS, and IR data of the spiro[2.4]heptanes were in full accord with the assigned structures. The ^ N M R spectrum of each compound contained a characteristic downfield, 1-proton signal corresponding to the vinyl proton H-9 (Table 14, p 143) and upfield 1-proton signals corresponding to the three cyclopropyl protons. The assignment of the cyclopropyl proton signals in the X H N M R spectra of each spiro[2.4]heptane was easily accomplished using the chemical shift and the signal multiplicity data (see Section 1.3.C for a general discussion of N M R spectra of cyclopropanes). For all compounds, the signal of highest multiplicity was assigned to the methine proton (H - l , see Table 14) since it is the only cyclopropyl proton that can have a large vicinal coupling to more than one proton. This assignment was confirmed for each compound by COSY experiments (see Experimental Section for COSY data). The remaining cyclopropyl signals, corresponding to the methylene protons (H-2a and H-2b), were distinguishable from each other on account of their / values (/cis > /trans)-67b 142 The 1 3 C N M R spectrum of each compound contained the expected number of carbon signals, except in the case of compound 233, for which one carbon resonance was not observed (using CDCI3 or C 6D 6) . Interestingly, the diastereotopic methyl groups of the TBDMS moiety of compound 233 resonated at different chemical shifts, 8 -4.7 and -4.6, in the CDCI3 spectrum, whereas in the C 6 D 6 spectrum, these signals were isochronous and appeared at 8 -4.4. The 1 3 C N M R spectra contained the expected downfield signals corresponding to the two alkenyl carbons, while the spectrum of compound 239, which has a phenyl substituent, displayed four aryl resonances, in addition to the alkenyl resonances. As for the IR data, the spectrum of each spiro[2.4]heptane showed diagnostic C=C stretching absorptions (Table 14). The spectral data ( J H NMR, 1 3 C NMR, IR, and MS) of the uncyclized alkynyl cyclopropanes 232, 234, 236, 238, and 240 were in full accord with the assigned structures. The X H N M R spectrum of each compound contained characteristic upfield signals corresponding to the four cyclopropyl protons, while the IR spectrum of each compound showed diagnostic C^C stretching absorptions, with the exception of compound 238 (Table 15, p 144). The C^C stretching absorption is often absent if the triple bond is disubstituted with alkyl groups or is symmetrical.670 143 Table 14. Cyclopropyl *H N M R Data of Compounds 231, 233, 235, and 239. H-2a H-2a 235 239 Entry Product Chemical Sniff (8), multiplicity, J (Hz) IR ( v ) H - l H-2a H-2b H-9 C=C 1 231 0.94-1.04 m 0.72 dd, 8.5,5 0.66 dd, 5, 5 4.91 dd, 2, 2 1617 2 233 0.94-1.076 0.76 dd, 8.5,5 0.70 dd, 5, 5 4.94 dd, 2, 2 1618 3 235 0.94-1.03 m 0.72 dd, 8.5,5 0.64 dd, 5, 5 5.07 dd, 2, 2 1620 4 239 0.98-1.08 m 0.76 dd, 8.5, 5.5 0.71 dd, 5.5, 5.5 5.85 dd, 2.5, 2.5 1650 a The N M R solvent was C 6 D 6 . h The signal overlapped with that corresponding to the C(CH 3) 3 group. 144 Table 15. Cyclopropyl X H N M R Data of Compounds 232,234, 236, 238, and 240. Entry Product R group Chemical Shiff (5), multiplicity, H count Cyclopropyl proton(s) IR( v ) CiEC 0.00-0.16 0.16-0.33 0.52-0.63 2174 1 232 TMS overlapping signals, 2H - , b IH m, IH 0.03-0.13 0.22-0.30 0.55-0.64 2173 2 234 TBDMS overlapping signals, 2H m, 1 H m, IH 0.01-0.14 0.22-0.40 0.54-0.64 2171 3 236 Me 3Ge overlapping signals, 2H ~, e IH m, IH 0.27-0.40 d 0.54-0.65'' 0.78-0.90 r f 4 238 Me overlapping signals, 2H m, IH m, IH 0.04-0.17 0.26-0.36 0.55-0.66 2230 5 240 Ph overlapping signals, 2H m, IH m, IH a The N M R solvent was CeD6 unless otherwise noted. b The signal overlapped with that corresponding to the Si(CH 3) 3 group. c The signal overlapped with that corresponding to the Ge(CH 3) 3 group. d The N M R solvent was CDC1 3 . e The absorption was absent (see text). 145 3.4. Conclusions. The reactions presented in Section 3.3.A demonstrate the synthetic utility of iodocyclopropanes in the construction of spiro[2.4]heptanes, and represents the first report of an intramolecular addition of a cyclopropyllithium reagent to an alkynyl moiety. cw-l-(5-TrialkylsUyl-4-alkynyl)-2-hydroxymemyl-l-Uthiocyclopropanes, derived from the corresponding iodocyclopropanes via a BuLi mediated Li-I exchange reaction, underwent 5-exo-dig cyclization to afford, stereoselectively, the functionalized spiro[2.4]heptanes 231 and 233 in good yield (79, 71%, respectively). The analogous MeaGe and Ph substituted lithiocyclopropanes also underwent cyclization, albeit to a lesser extent than the silylated alkynes: the MesGe substituted spiro[2.4]heptane 235 was obtained in 60% yield whereas the Ph substituted compound 239 was obtained in 44% yield. In contrast, the methyl substituted alkynyl iodocyclopropane 228 did not undergo cyclization when treated with BuLi , but rather afforded the monocyclic alkyne 238 in 83% yield. The results suggest that the electronic nature of the alkynyl substituent largely determines the success of the cyclization reaction. TMS V u TBDMSV u Me 3Ge v u H H H 231 233 235 H 238 239 146 4. Considerations for Future Work. In Section 3.3, a new method of preparing spiro[2.4]heptanes was described. The preparation involved the intramolecular addition of a cyclopropyllithium to a suitably functionalized acetylenic moiety. It is conceivable that this method could be extended to the intramolecular reaction of a cyclopropyllithium with other electrophilic moieties to provide functionalized spiro[2.n]alkanes. For example, the intramolecular addition of a cyclopropyllithium to a nitrile group would provide a ketimine salt, which would be hydrolyzed to the corresponding spiro[2.5]heptanone upon aqueous workup (Scheme 80). 1 4 8 Scheme 80 ketimine salt A second possibility is the use of a sp3 center bearing a suitable leaving group as the acceptor site.1 4 9 The choice of leaving group would be critical, since the Uthium-iodine exchange reaction at the cyclopropyl carbon-iodine bond must be faster than any reaction of the BuLi with the leaving group (e.g. substitution in the case of a halogen atom). Preliminary work has indicated that a chloride atom would be a suitable leaving group. The iodocyclopropyl chloride 60d was prepared during the course of our cyclopropanation study. Treatment of 60d Scheme 81 245 Scheme 82 148 with 2.1 equivalents of BuLi (in E t 2 0 ; at -78°C for 20 min, followed by warming to r.t. for 45 min) and aqueous workup, provided the spiro[2.3]hexane 244 and the uncychzed material 245 (Scheme 81). The ratio of 244 to 245 in the crude product was -90:10 (based on GLC). Difficulties in isolating the volatile compound 244 resulted in a low yield of impure material (<11%). In order to increase the molecular weight of the products so that volatility would be less of a concern, the reaction was repeated using identical conditions except that PhCOCl 2 6 was added after warming to r.t. (Scheme 82). Unfortunately, the ratio of bicyclic benzoate 246 to uncychzed material 247 in the crude product was only 74:26. The isolated yield of 246, after repeated radial chromatography, was only 37% while the yield of 247 was 22%. The spectral data of 246 and 247 were in full accord with the assigned stmctures (see Experimental Section, p 349). The low ratio of 246:247 (compared to the ratio obtained for 244:245) suggested that the addition of BuLi may have been too rapid (resulting in localized high concentrations of BuLi in the bulk solution) such that intermolecular protonation of the dianion 242 by the hydroxyl proton of starting material 60d resulted in the formation of a significant amount of 248 (and subsequendy 247)138 (Scheme 82). Time restraints prevented the repetition of the reaction; the preliminary results, however, suggest that this reaction may be optimized to provide a synthetically useful method of preparing small ring spiro compounds. Iodocyclopropanes could also serve as sources of functionalized radicals which could undergo intramolecular reaction with radical acceptors to provide spiro[2.n]alkanes. Particularly interesting are atom transfer cyclization reactions in which the iodine atom of the starting material is transferred (intermolecularly) to the cyclization product, thereby terminating the reaction and at the same time propagating the free radical chain mechanism. An example which was taken from the work of Curran and co-workers is given in Scheme 83. 1 5 0 149 Scheme 83 We decided to attempt a similar cyclization reaction using the iodocyclopropyl acetate 249 (Scheme 84).1 5 1 The cyclization reaction was initiated by irradiating a solution of iodocyclopropyl acetate 249 and 0.15 equivalents of Me6Sn2 in CeD6 with a 275-W GE sunlamp. Reaction of 249 under these conditions150 provided a 69% yield of a mixture of products, the major product (~80% of the mixture based on GLC and ^ N M R spectroscopy) being compound 253. The relative stereochemistry of 253 was determined by NOE difference experiments using a sample enriched in 253. Irradiation of the vinyl proton signal of 253 caused enhancement of the cyclopropyl methine signal, and conversely, irradiation of the cyclopropyl methine signal caused enhancement of the vinyl proton signal (Scheme 84). Two of the minor components of the isolated mixture were presumably isomers of 253, based on the vinyl and hydroxymethyl (CH2OH) region of the ^ N M R spectrum. Attempts to separate these components (flash chromatography, HPLC) were unsuccessful. The result indicated the following: (1) that the cyclopropyl radical 250 rapidly inverted6 to provide 251, which subsequently cyclized to give the vinyl radical 252. The ds-isomer 251 is expected to be thermodynamically less stable than the trans-isomer 250 in the ground state based on steric interactions, but the transition state of the cyclization involving 251 must be lower in 150 energy than that involving 250 (because it leads to the product). Such a pathway is in accordance with the Curtin-Hammett principle; (2) that the iodine atom is transferred to the less hindered side of the vinyl radical 252, which is expected to be configurationally labile,1 5 2 to provide the E-isomer 253. Scheme 84 253 In addition to the intramolecular reactions discussed above, intermolecular reactions involving cyclopropyllithiums are also feasible.153 Cyclopropyl halides have been converted to metallocyclopropanes such as Grignard1 5 4 and cuprate reagents,155 and these reagents have been used in intermolecular reactions. It occurred to us that the cyclopropyllithium reagents prepared during our studies of iodocyclopropane chemistry could be employed as nucleophilic reagents in similar reactions. Preliminary work focused on the hydroxyalkylation of the vinylcyclopropyl Uthium reagents 254 and 257, which were derived from the corresponding vinyl 151 iodocyclopropanes 116b and 116a, respectively (Scheme 85). Reaction of 254 with cyclohexanone (255) (in THF, at -78°C to r.t.) provided the alcohol 256, which has two newly created contiguous, quaternary centers, in 64% yield (equation 1). Similarly, reaction of 257, the epimer of 254, with cyclohexanone (255) provided the tertiary alcohol 258 in 55% yield (equation 2). The spectral data of 256 and 258 were in full accord with the assigned stmctures (see Experimental Section, p 354-356). It is thought that this reaction may be extended to include other cyclopropyllithiums and electrophiles. Scheme 85 O r.t./2 h 116a 257 258 152 5. Experimental Section. 5.1 General. 5.1.1. Data Acquistion and Presentation. X H N M R spectra were measured with Varian XL-300 (300 MHz), Bruker AC-200 (200 MHz), Bruker WH-400 (400 MHz), and Bruker AMX-500 (500 MHz) N M R spectrometers using C 6 D 6 , CD 2C1 2 , or CDC13 as the solvent. GDCI3 was passed through a short column of dry N a 2 C 0 3 prior to its use. Chemical shift (8) values were measured relative to tetramethylsilane (8 0.00), C 6 H 6 (8 7.15), CH 2C1 2 (8 5.32), or CHC1 3 (8 7.24) and are given in parts per million (ppm). The multiplicity, number of protons, coupling constant(s), 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. Coupling constants (7) are given in Hertz (Hz). When a proton was observed to be coupled with the same coupling constant to two or three protons which are magnetically non-equivalent, the designations dd or dt are used instead of t or quintet. For compounds with A B X type spin systems, the values quoted for chemical shifts and coupling constants were measured as if they were first order systems, although these values may only approximate the real values.156 The tin-proton coupling constants (7 sn-u) and tin-carbon coupling constants (7 sn-c) are given as the average of the 1 1 7 Sn and 1 1 9 Sn values. Decoupling experiments refer to ^ ^ H spin decoupling experiments. Nuclear Overhauser enhancement (NOE) difference experiments48b were recorded on a Bruker WH-400 spectrometer. Two-dimensional homonuclear (H,H)-correlated N M R spectroscopy480 (COSY) was performed ' • 153 using Bruker AC-200 and WH-400 spectrometers. Two-dimensional heteronuclear multiple quantum (H,C)-correlation (HMQC) experiments157 and the heteronuclear multiple bond (H,C)-correlation (HMBC) experiment157 were recorded on a Bruker AMX-500 ( XH, 500 MHz; 1 3 C, 125 MHz) spectrometer. 1 3 C N M R spectra were measured with Bruker AC-200 (50.3 MHz), Varian XL-300 (75.4 MHz), Bruker AM-400 (100 MHz), and Bruker AMX-500 (125 MHz) N M R spectrometers using CDC13 or C 6 D 6 as the solvent. Chemical shift (8) values were measured relative to CDC13 (8 77.0) or C 6 D 6 (8 128.0) and are given in parts per million (ppm). Attached proton tests (APTs) were measured with a Bruker AC-200 (50.3 MHz) spectrometer. Where APT data is given, signals with negative intensities are so indicated in brackets [(-ve)] following the 1 3 C N M R chemical shifts. Infrared (IR) spectra were obtained from dilute CDC13 solutions of the analyte, from neat liquids suspended between NaCl discs, or from solids which were dispersed in potassium bromide mulls, using a Perkin-Elmer 1710 Fourier transform spectrometer with internal calibration. Selected IR data are provided for each compound. Low resolution gas-liquid mass spectrometry (LRGCMS) was performed on a Carlo Erba (model 4160) gas chromatograph (J & W Scientific DB-5 column) and a Kratos/RFA MS 80 mass spectrometer. Low resolution desorption chemical ionization mass spectrometry (LRDCIMS) was performed with a Desi Nermag R-10- 10c mass spectrometer. The ion type, followed by the m/e value in brackets, is noted. Exact mass calculations were performed on a Kratos MS50/DS55SM high resolution mass spectrometer using an electron impact source, 154 unless otherwise noted. The following atomic masses were used for H R M S calculations: J H 1.007825; 1 2 C 12.0000; 1 6 0 15.994915; 3 5C1 34.968852; 2 8 Si 27.976927; 7 4 Ge 73.921177; 1 2 0 Sn 119.902200; 1271 126.904473. Elemental analyses were performed on a Carlo Erba elemental analyzer, model 1106, by the UBC Microanalytical Laboratory. Gas-liquid chromatography (GLC) was performed using Hewlett-Packard gas chromatographs (models 5880A and 5890) equipped with capillary columns (Hewlett-Packard models HP-5 or Ultra-2) and flame ionization detectors. Radial chromatography158 was carried out on a Chromatotron® using plates coated with silica gel 60 (with CaS04, E. Merck, 1, 2, or 4 mm thick), unless otherwise noted. Radial chromatography was usually aided by UV visualization. Thin-layer chromatography (TLC) was performed using commercial aluminum-backed (E. Merck, type 5554) or glass-backed (E. Merck, type 5715) silica gel plates, glass-backed (Watman, KCig/KCigF) reversed phase plates, and aluminum-backed (E. Merck, type 5731) alumina plates. Visualization of TLC plates was accomplished by irradiation with ultraviolet light (254 nm), followed by heating the plate after staining with one of the following solutions: vanillin in a sulfuric acid-EtOH mixture (6% w/v vanillin, 4% v/v sulfuric acid, and 10% v/v water); anisaldehyde in sulfuric acid-EtOH mixture (5% v/v anisaldehyde, and 5% v/v sulfuric acid); or phosphoromolybdic acid in EtOH (20% w/v phosphoromolybdic acid (Aldrich Chemical Company, Inc.)). Visualization of alkenes and alkynes was also accomplished by treating the TLC plate with I2 which had been adsorbed onto unbound silica gel. Melting points (mp) were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures, which refer to short path (Kugelrohr) distillations, are uncorrected. 155 The reader is referred to the specific procedure for exact amounts, in particular when ranges are given in the general procedure. 5.1.2. Solvents, Reagents, and Techniques. C 6 H 6 and CH2C12 were distilled from CaH 2 ; Et 20 and THF were distilled from sodium benzophenone ketyl. Petroleum ether refers to a hydrocarbon mixture with bp 35-60°C. C1CH2CH2C1 was distilled from CaH 2 into a flame-dried Schlenk flask containing Cu wire and was then degassed via the freeze-pump-thaw method.64 This solvent was stored under an atmosphere of dry Ar in the Schlenk flask, which was covered with aluminum foil. D M F was obtained from Aldrich Chemical Company and was sequentially dried over 3A sieves. Et 2Zn was obtained from Aldrich Chemical Company and was used as received (CAUTION: neat Et 2Zn is pyrophoric).60"63 M e l and CICH2I were obtained from Aldrich Chemical Company and were passed through short columns of oven-dried basic alumina (activity 1) into flame-dried Schlenk flasks containing Cu wire. Dried CICH2I was degassed via the freeze-pump-thaw method64 and was stored under an atmosphere of dry Ar in the Schlenk flask, which was covered with aluminum foil. Iodobenzene was obtained from Aldrich Chemical Company and was distilled prior to its use. Cyclohexanone was obtained from Aldrich Chemical Company and was sequentially dried over 3A sieves. BueSn2 and MeeSn2 were obtained from Aldrich Chemical Company and Organometalhcs Inc. (East Hampstead, NH), respectively, and were distilled prior to their use (CAUTION: both BueSn2 and Me 6 Sn 2 are highly toxic). MesSnCl was used as received from Aldrich Chemical Company Diisopropylamine and MesGeBr (obtained from Organometallics Inc.) were freshly distilled from CaH 2 into flame-dried Schlenk flasks and were 156 stored under an atmosphere of dry Ar. PdCl 2(PPh 3) 2 and Pd(PPh3)4 were used as received from Aldrich Chemical Company Pd(PPh3)4 was also provided by Dr. Charles Stone of Ballard Advanced Materials Corp., North Vancouver, BC , who prepared the catalyst according to the procedure of Coulson. 1 6 0 Cui was obtained from Aldrich Chemical Company and was recrystallized twice using KI, with charcoal treatment, according to the procedure of Kauffman and Teter161 and dried in vacuo over P2O5 for 3 days. Iodine and TBDMSC1 were sublimed prior to their use. The former was stored in the dark. Dipotassium azodicarboxylate (PADA) was prepared according to the procedure of Dieck and Heck 1 0 4 and was stored under a dry Ar atmosphere in a refrigerator (~9°C) (CAUTION: P A D A reacts violently with acid). CuBrMe 2 S complex was prepared according to the procedure of Wuts 1 6 2 and was stored under an atmosphere of dry Ar in a desicator. Solutions of MeL i (LiBr complex in Et 20) and BuLi (in hexanes) were obtained from Aldrich Chemical Company and were standardized using the procedure of Kofron and Baclawski.1 6 3 Lithium diisopropylamide (LDA) solution was prepared by the addition of a solution of BuLi (1.0 equiv) in hexane to a solution of freshly distilled i'-Pr2NH (1.1 equiv) in THF at -78°C. The resulting solution was stirred at 0°C for fifteen minutes before its use. Z ' -BU 2 A1H in hexanes and [(CH 3 OCH 2 CH 2 0) 2 AlH 2 ]Na (Red-Al®) in PhCH 3 were obtained from Aldrich Chemical Company Aq NH4CI-NH4OH (pH 8-9) was prepared by addition of - 5 0 mL of aq NH3 (30%) to -950 mL of sat. aq NH4CI. Cold temperatures were maintained by use of the following baths: 0°C, ice/water; -20°C, -30°C, -40°C, and -48°C, aqueous calcium chloride/C02 (27, 35, 43, 47 g CaCO3/100 mL water, 157 respectively);164 -78°C, acetone/C02. A continuous method of elution, employed in radial chromatography, refers to the repeated application of small portions of crude material to the same plate with sufficient delay between applications to allow separation. This method, used for large amounts of material, is most effective when there are no slow moving impurities relative to the major product. Unless otherwise stated, all reactions were carried out under an atmosphere of dry Ar using glassware that was flame or oven (~140°C) dried. Syringes, needles, and cannulae were oven-dried and/or flushed with dry Ar prior to their use. Substrates were freshly distilled unless otherwise noted. 158 5.2. Structural Index. The following 4 pages list, in order of appearance, the structural formulae of the compounds that are included in Section 5.3, Experimental Procedures. Page numbers are indicated below each structure. Minor products are not included. 159 5.3.1. Esters. 163 167 " C 0 2 M e SnMe3 C C i j M e M e 0 2 C 164 169 S n M & j S n M e s C 0 2 M e ,SnMe3 I . M e O z C 166 5.3.2. Alcohols and Related Compounds ^ — ^ S n M e 3 171 SnMe3 H O . 172 S n M & j H O -173 SnMe3 O H SnMe3 174 SnMe3 176 C I S n M e 3 . O H T B D M S O ^ 177 178 T B D M S O ^ 179 5.3.3. Iodo Alkenes and Related Compounds. 181 C O z M e f t C O z M e 183 C O a M e 184 T M S s X C0 2 Et 185 187 188,198,202 189 197 199 200 201 349 351 354 355 163 5.3. Experimental Procedures. 5.3.1. Esters. 5.3.1.1. Preparation of Methyl 2.7-Octadiynoate (31c). Note: In this experiment, the reaction flask was briefly opened while under a high Ar flow and the ClC02Me was added rapidly to the lithium acetylide mixture using a needle-less syringe.30 To a cold (-78°C), stirred solution of 1,6-heptadiyne (259)jy (10 g, 109 mmol) in dry THF (200 mL) was added a solution of MeLi (109 mmol) in E t 2 0 (78 mL). After the reaction mixture had been stirred at -78°C for 10 min and at -20°C for lh , methyl chloroformate (33.7 ml, 436 mmol) was added rapidly in one portion and the solution was stirred at -20°C for lh and at r.t. for lh . Sat. aq NaHC03 (150 ml) was added and the phases were separated. The organic phase was washed (sat. aq NaHC0 3 (100 ml), water (100 ml), brine (100 ml)), dried (MgS0 4) , and concentrated. Distillation (60-100°C/0.3 torr) of the acquired oil afforded 13.3 g (81%) of the ester 31c as a colorless oil. 164 The spectral data of 31c are as follows: IR (neat): 3292, 2239, 1714, 1435, 1264, 1078, 753 cm"1. X H N M R (CDC13, 400 MHz) 8: 1.78 (quintet, 2H, J = 7 Hz, H-5), 1.96 (t, IH, J = 2.5 Hz, H-8), 2.32 (td, 2H, J = 7, 2.5 Hz, H-6), 2.47 (t, 2H, J = 7 Hz, H-4), 3.73 (s, 3H, C0 2 Me) . 1 3 C N M R (CDCI3, 50.3 MHz) 8: 17.5,17.6, 26.4, 52.5, 69.4, 73.4, 82.6, 88.4,154.0. LRDCIMS (NH3): MH + (151), MNH, + (168). Exact mass calcd for C9H9O2: 149.0602. Found: 149.0593. Anal, calcd for C 9 H 1 0 O 2 : C 71.98, H 6.71. Found: C 71.72, H 6.78. 5.3.1.2. Preparation of Methyl (F)-3-Trimethylstannyl-2-octenoate (32b). 8 6 4 C 0 2 M e SnMe 3 31b 32b To a cold (-20°C), stirred solution of Me 6 Sn 2 (12.52 g, 38.22 mmol) in dry THF (382 ml) was added a solution of MeLi (38.22 mmol) in E t 2 0 (27 ml). The solution was stirred at -20°C for 25 min and then was chilled to -48°C. CuBrMe 2 S (7.87 g, 38.28 mmol) was added in one portion and the mixture was stirred for 15 min. The mixture was chilled to -78°C and a solution of methyl 2-octynoate (31b)26 (4.97 g, 32.24 mmol) in THF (54 ml) was added dropwise. The 165 reaction mixture was stirred at -78°C for 3 h. Aq NH4CI-NH4OH (pH 8-9, 350 ml) was added, the mixture was allowed to warm to r.t., and stirring was continued until the aq phase became deep blue. The phases were separated and the organic phase was washed (aq NH4CI-NH4OH (pH 8-9, 2 x 100 ml)), dried (Na 2S0 4), and concentrated. Radial chromatography (4 mm plate, 98:2 hexanes-Et20, material was applied in 7 approximately equal portions employing a continuous method of elution (see Section 5.1.2 for an explaination of this method) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 6.91 g (67%) of the stannyl ester 32b as a colorless oil. The spectral data of 32b are as follows: IR (neat): 1721, 1596, 1433, 1353, 1168, 770 cm-1. *H N M R (CDCI3, 400 MHz) 8: 0.16 (s, 9H, 2 7 S n - H = 53 Hz, Me 3Sn), 0.86 (t, 3H, / = 7 Hz, H-8), 1.20-1.44 (overlapping signals, H-5, H-6, H-7), 2.85 (td, 2H, J = 7.5, 1.5 Hz, 3J S n . H = 62.5 Hz, H-4), 3.66 (s, 3H, C0 2 Me) , 5.93 (t, IH, J = 1.5 Hz, 3 / S n . H = 74 Hz, H-2). 1 3 C N M R (CDCI3, 50.3 MHz) 8: -9.1 (V Sn-c = 337 Hz), 14.0, 22.5, 29.3, 31.8, 34.7, 50.8, 126.8,164.7, 174.0. Exact mass calcd for CnH2iO 2 1 2 0 Sn(M + -CH 3 ) : 305.0564. Found: 305.0558. Anal, calcd for C i 2 H 2 4 0 2 S n : C 45.18, H 7.58. Found: C 45.39, H 7.70. 166 5.3.1.3. Preparation of Methyl (£)-3-Trimethylstannvl-2-octen-7-ynoate (32c). 6 4 SnMe3 C0 2Me Me0 2C 31c 32c To a cold (-20°C), stirred solution of Me 6 Sn 2 (10.0 g, 30.6 mmol) in dry THF (148 ml) was added a solution of MeLi (30.6 mmol) in E t 2 0 (22 ml). After the solution had been stirred at - 2 0 °C for 25 min, it was chilled to -48°C. CuCN (2.74 g, 30.6 mmol) was added in one portion and the mixture was stirred for 30 min. The mixture was chilled to -78°C, and dry MeOH (1.29 ml, 31.8 mmol) was added. After 8 min, a solution of methyl 2,7-octadiynoate (31c) (p 163) (3.56 g, 23.7 mmol) in THF (3 ml) was added dropwise. The mixture was stirred at -78°C for 4 h. Aq NH4CI-NH4OH (pH 8-9, 150 ml) was added. The mixture was opened to the atmosphere and was stirred at r.t. for 3 h, during which time the aq phase became deep blue. The phases were separated and the aq phase was extracted with E t 2 0 (3 x 100 ml). The combined organic extracts were washed (brine (100 ml)), dried (Na2S04), and concentrated. Flash chromatography (80 g of Merck (grade 60) silica gel, 98:2 hexanes-Et20) of the crude product, followed by distillation (75 -95°C/0.3 torr) of the acquired oil, afforded 4.79 g (64%) of the stannyl ester 32c as a colorless oil. The spectral data of 32c are as follows: IR (neat): 3308, 2119,1719,1596, 1434,1196,1162, 1027, 873, 772 cm' 1. *H N M R (CDCI3, 400 MHz) 5: 0.20 (s, 9H, 2J S n . H = 54 Hz, Sn(CH3)3), 1.57-1.70 (m, 2H, H-5), 167 1.96 (t, IH, J = 2.5 Hz, H-8), 2.22 (td, 2H, 7 = 7, 2.5 Hz, H-6), 2.85-3.08 (m, 2H, V S n- H = 61 Hz, H-4), 3.68 (s, 3H, C0 2 Me) , 5.99 (t, IH, J = 1 Hz, 3 / S n . H = 72 Hz, H-2). 1 3 C N M R (CDC13,75.4 MHz) 8: -9.1,18.5, 28.4, 33.9, 50.9, 68.6, 84.1,127.8,164.6, 172.3. Exact mass calcd for C i iH 1 7 O 2 1 2 0 Sn (M + -CH 3 ) : 301.0250. Found: 301.0251. 5.3.1.4. Preparation of Methyl (Z)-3-Trimethylstannyl-2-octenoate (34b). To a cold (-20°C), stirred solution of Me 6 Sn 2 (10.84 g, 33.13 mmol) in dry THF (150 ml) was added a solution of MeLi (33.10 mmol) in E t 2 0 (26 ml). The solution was stirred at -20°C for 30 min. CuCN (2.96 g, 33.05 mmol) was added in one portion and the mixture was stirred for 15 min. and then cooled to -48°C. A solution of methyl 2-octynoate (31b)26 (4.68 g, 30.35 mmol) in dry THF (30 mL) was added and the mixture was stirred at -48°C for 2 h and then at 0°C for 2 h. Aq NH4CI-NH4OH (pH 8-9, 100 mL) was added. The mixture was opened to the atmosphere and was stirred at r.t. until the aq phase became deep blue. The phases were separated and the aq layer was extracted with E t 2 0 (2 x 100 mL). The combined organic phases were washed (brine), dried (Na2S04), and concentrated. The crude product was filtered through -45 g of Merck (grade 60) silica gel (fritted-glass funnel, water aspirator, elution with 200 mL of 31b 34b 168 9:1 petroleum ether-Et20). Concentration of the filtrate gave an oil that was subjected to preparative HPLC (two "in series" Waters Prep PAK®-500 silica gel columns, 97:3 petroleum ether-CH2Cl2). Distillation (90-110°C/0.3 torr) of the acquired material gave 5.63 g (58%) of the stannyl ester 34b as a colorless oil. The spectral data of 34b are as follows: IR (neat): 1709, 1600, 1436,1331, 1211, 876, 772 cm"1. lH N M R (CDC13, 400 MHz) 8: 0.15 (s, 9H, 2J S n . H = 54 Hz, Sn(CH3)3), 0.86 (t, 3H, J = 7 Hz, H-8), 1.15-1.44 (m, 6H, H-5, H-6, H-7), 2.40 (td, 2H, J = 7, 1 Hz, 3 7 S n - H = 49 Hz, H-4), 3.71 (s, 3H, C0 2 Me) , 6.33 (t, IH, J = 1 Hz, 3J S „ - H = 120 Hz, H-2). 1 3 C N M R (CDC13, 50.3 MHz) 8: -7.5, 14.0, 22.5, 28.9, 31.5, 40.1, 51.4, 127.5, 168.3, 176.3. Exact mass calcd for CnH 2 1 O 2 1 2 0 Sn(M + -CH 3 ) : 305.0564. Found: 305.0558. Anal, calcd for C i 2 H 2 4 0 2 S n : C 45.18, H 7.58. Found: C 45.21, H 7.67. 169 5.3.1.5. Preparation of Methyl (Z)-3-Trimethylstannyl-2-octen-7-ynoate (34c). 6 4 8 ^ SnMe3 C0 2 Me 2 C0 2 Me 31c 34c To a cold (-20°C), stirred solution of Me 6 Sn 2 (854 mg, 2.61 mmol) in dry THF (30 ml) was added a solution of MeLi (2.60 mmol) in E t 2 0 (1.86 ml). The resulting pale yellow solution was stirred at -20°C for 15 min. PhSCu (450 mg, 2.62 mmol) was added and the solution turned a dark reddish brown. It was stirred at -20°C for 15 min and then at -78°C for 5 min. A solution of methyl 2,7-octadiynoate (31c) (p 163) (356 mg, 2.37 mmol) in THF (5 ml) was added and the mixture was stirred at -78°C for 15 min and then at -48°C for 2.75 h. MeOH (40 ml) and hexanes (90 ml) were added and the mixture was allowed to warm to r.t. The mixture was filtered through ~8 g of Florisil® (fritted-glass funnel, water aspirator, elution with Et 2 0). Concentration of the filtrate, followed by flash chromatography (50 g of Merck (grade 60) silica gel, 92:8 hexanes-Et20) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr), afforded 457 mg (61%) of the stannyl ester 34c as a colorless oil. The spectral data of 34c are as follows: IR (neat): 3302, 2119,1708, 1599,1436,1330,1208, 773 cm' 1. X H N M R (CDC13, 400 MHz) 8: 0.15 (s, 9H, 2J S n - H = 55 Hz, Sn(CH3)3), 1.58 (m, 2H, H-5), 1.94 (t, IH, J= 2.5 Hz, H-8), 2.15 (td, 2H, J = 7, 2.5 Hz, H-6), 2.51 (td, 2H, J = 7.5,1 Hz, 3 7 S n - H = 49 170 Hz, H-4), 3.69 (s, 3H, C0 2 Me) , 6.35 (t, IH, 7 = 1 Hz, 3 / S n H = 117 Hz, H-2). 1 3 C N M R (CDC13,100.6 MHz) 8: -7.5,17.8, 27.6, 38.6, 51.4, 68.9, 83.6,128.3,168.1, 174.6. LRDCIMS (NH3): M H + (317); M N H / (334). Exact mass calcd for C 1 iHi 7 O2 1 2 0 Sn(M + -CH 3 ) : 301.0250. Found: 301.0244. Anal, calcd for Ci 2 H 2 0 O 2 Sn: C 45.76, H 6.40. Found: C 45.58, H 6.55. 5.3.2. Alcohols. 5.3.2.1. Preparation of 3-Trimethylstannyl- and 3-Iodo-2-alken-l-ols via Reduction of Alkyl 3-Trimethylstannyl- and 3-Iodo-2-alkenoates. General Procedure 1. In the following procedure, all amounts given are related to the use of 1 mmol of the ester. To a cold (-78°C), stirred solution of the alkyl 2-alkenoate in dry E t 2 0 (-20 mL) was added a solution of J - B U 2 A 1 H (3-3.5 mmol) in hexanes (3-3.5 mL). The resulting clear solution was stirred at -78°C for - 1 h and then was allowed to warm to 0°C over a period of -1 .5 h. Sat. aq NH4CI ( -1 mL) was added and the mixture was stirred at r.t. for - 2 0 min. Dry M g S 0 4 (-1-2 g) was added to the resultant white slurry and stirring was continued for 20 min. The mixture was filtered through a pad of Florisil® (fritted-glass funnel, water aspirator, elution with Et 2 0). Concentration of the filtrate, followed by purification (radial chromatography and/or distillation) provided the 3-trimethylstannyl- or 3-iodo-2-alken-l-ol product. 171 Preparation of (£)-3-Trimethylstannyl-2-penten-l-ol (33a). 32a 33a Following general procedure 1 (p 170), ethyl (£)-3-trimethylstannyl-2-pentenoate (32a) was converted into (£)-3-trimethylstannyl-2-penten-l-ol (33a) with the following quantities of reagents and solvents: ethyl (£)-3-trirnethylstannyl-2-pentenoate (32a), 601 mg (2.06 mmol), in E t 2 0 (41 mL); /-Bu 2AlH, 7.23 mL (7.23 mmol). Radial chromatography (4 mm plate, 4:1 hexanes-Et20) of the crude product, followed by distillation (75-95°C/0.3 torr) of the acquired liquid, gave 479 mg (94%) of the alcohol 33a as a colorless oil. The spectral data of 33a are as follows: IR (neat): 3318 (br), 1457, 1019, 768 c m 1 . X H N M R (CDC13, 400 MHz) 8: 0.12 (s, 9H, 2J S n . H = 52.5 Hz, Sn(CH3)3), 0.95 (t, 3H, J = 7.5 Hz, H-5), 1.39 (br s, IH, exchanges with D 2 0 , OH), 2.29 (qd, 2H, J = 7.5, 1 Hz, 3 J S n . H = 62 Hz, H-4), 4.22 (br d, 2H, J = 5 Hz, H- l ) , 5.71 (tt, IH, J = 5, 1 Hz, 3 7 S n- H = 77 Hz, H-2). 1 3 C N M R (CDCI3, 50.3 MHz) 8: -9.3,15.1, 26.1, 58.8,137.8,150.2. Exact mass calcd for C 7 H 1 5 O 1 2 0 Sn(M + -CH 3 ) : 235.0145. Found: 235.0147. Anal, calcd for C 8 H 1 8 OSn: C 38.60, H 7.29. Found: C 38.58, H 7.24. 172 Preparation of f'£')-3-Trimethylstannyl-2-octeri-l-ol (33b). 8 6 4 SnMe 3 SnMe 3 M e 0 2 C 2 32b 33b Following general procedure 1 (p 170), methyl (£)-3-trimethylstannyl-2-octenoate (32b) (p 164) was converted into (£)-3-trimethylstannyl-2-octen-l-ol (33b) with the following quantities of reagents and solvents: methyl (£)-3-trimethylstannyl-2-octenoate (32b), 328.3 mg (1.03 mmol), in E t 2 0 (20.6 mL); /-Bu 2AlH, 3.09 mL (3.09 mmol). Distillation (130-140°C/0.3 torr) of the crude product gave 292.7 mg (98%) of the alcohol 33b as a colorless oil. The spectral data of 33b are as follows: IR (neat): 3306 (br), 1466,1020, 767 cm"1. X H N M R (CDCI3,400 MHz) 8: 0.10 (s, 6H, 2J s„-c = 52 Hz, Me 3Sn), 0.85 (t, 3H, J = 7 Hz, H-8), 1.10-1.41 (overlapping signals, 6H, H-5, H-6, H-7), 1.47 (br s, IH, exchanges with D z O, OH), 2.26 (t, 2H, J = 7 Hz, 3 7 S D - H = 63 Hz, H-4), 4.2 (br signal, 2H, simplifies to a d, J = 6 Hz, upon addition of D 2 0 , H- l ) , 5.73 (t, IH, J = 6 Hz, 3 J S n . H = 78 Hz, H-2). 1 3 C N M R (CDC1 3 ) 50.3 MHz) 8: -9.3 (\7sn-c = 337 Hz), 14.0, 22.5, 29.9, 31.6, 33.0 ( 2 / S n-c = 42 Hz), 58.9 ( 37 S n -c = 70 Hz), 138.4, 148.7. Exact mass calcd for C i 0 H 2 1 O 1 2 0 S n ( M + - C H 3 ) : 277.0614. Found: 277.0619. Anal, calcd for CnH 2 4 OSn: C 45.40, H 8.31. Found: C 45.00, H 8.30. 173 Preparation of (£)-3-Trimethylstannyl-2-octen-7-yn-l-ol (33c). 6 4 SnMe3 8 ^ SnMe3 2 32c 33c Following general procedure 1 (p 170), methyl (£^-3-trimethylstannyl-2-octen-7-ynoate (32c) (p 166) was converted into (£)-3-trimethylstannyl-2-octen-7-yn-l-ol (33c) with the following quantities of reagents and solvents: methyl (£)-3-trimethylstannyl-2-octen-7-ynoate (32c), 103 mg (0.327 mmol), in E t 2 0 (6.5 mL); /-Bu 2AlH, 1.14 mL (1.14 mmol). Distillation (70-105°C/0.3 torr) of the crude product afforded 91 mg (97%) of the alcohol 33c as a colorless oil. The spectral data of 33c are as follows: IR (neat): 3310 (br), 2119, 1432, 1189, 1009, 769, 711, 634, 527 c m 1 . X H N M R (CDC13, 400 MHz) 8: 0.13 (s, 9H, 2J Sa.u = 53 Hz, Sn(CH3)3), 1.46 (br s, IH, exchanges D 2 0 , OH), 1.50-1.61 (m, 2H, H-5), 1.96 (t, IH, /= 2.5 Hz, H-8), 2.15 (td, 2H, J = 7, 2.5 Hz, H-6), 2.42 (t, 2H, J = 7.5 Hz, 3 7 S D-H= 62 Hz, H-4), 4.23 (br signal, 2H, sharpens to a d, J = 6 Hz, upon addition of D 2 0 , H- l ) , 5.81 (t, IH, J = 6 Hz, 3 7 s „ - H = 77 Hz, H-2). 1 3 C N M R (CDC13, 50.3 MHz) 8: -9.3, 17.8, 28.6, 31.6, 58.8, 68.8, 84.0, 139.7, 147.2. Exact mass calcd for C i 0 H 1 7 O 1 2 0 S n ( M + - C H 3 ) : 273.0300. Found: 273.0298. Anal, calcd for C n H 2 0 O S n : C 46.04, H 7.02. Found: C 46.24, H 7.09. 174 Preparation of (Z)-3-Trimethylstannyl-2-penten-l-ol (35a). 4 SnMe3 SnMe3 C02Et O H 34a 35a Following general procedure 1 (p 170), ethyl (Z)-3-trimethylstannyl-2-pentenoate (34a) was converted into (Z)-3-trimethylstannyl-2-penten-l-ol (35a) with the following quantities of reagents and solvents: ethyl (Z)-3-trimethylstannyl-2-pentenoate (34a), 2.24 g (7.70 mmol), in E t 2 0 (134 mL); /-BU2AIH, 27 mL (27 mmol). Radial chromatography (4 mm plate, 4:1 hexanes-Et20, material was applied in 2 approximately equal portions employing a continuous method of elution (see Section 5.1.2 for an explaination of this method) of the crude product, followed by distillation (85-95°C/0.3 torr) of the acquired liquid, gave 1.66 g (86%) of the alcohol 35a as a colorless oil. The spectral data of 35a are as follows: IR (neat): 3325 (br), 1456, 1191, 1060, 1009,769, 526 c m 1 . *H N M R (CDCI3, 400 MHz) 5: 0.18 (s, 9H, 2J S n-H= 53 Hz, Sn(CH3)3), 0.96 (t, 3H, J = 7.5 Hz, H-5), 1.15 (t, IH, J = 5 Hz, exchanges with D 2 0 , OH), 2.24 (q, 2H, J = 7.5 Hz, 3J S „ - H = 50 Hz, H-4), 4.08 (m, 2H, changes to a d, J = 6.5 Hz, upon addition of D 2 0 , H- l ) , 6.20 (t, IH, J = 6.5 Hz, 3 7 S n - H = 136 Hz, H-2). 1 3 C N M R (CDCI3, 100.6 MHz) 5: -8.1, 14.7, 33.1, 64.3, 136.9, 151.2. Exact mass calcd for C 7 Hi 5 O 1 2 0 Sn (M + -CH 3 ) : 235.0145. Found: 235.0136. Anal, calcd for CgHigOSn: C 38.60, H 7.29. Found: C 38.42, H 7.24. 175 Preparation of (Z)-3-Trimethylstannyl-2-octen-l-ol (35b). 8 6 4 SnMe3 SnMe3 OH C0 2Me 34b 35b Following general procedure 1 (p 170), methyl (Z)-3-trimethylstannyl-2-octenoate (34b) (p 167) was converted into (Z)-3-trirnethylstannyl-2-octen-l-ol (35b) with the following quantities of reagents and solvents: methyl (Z)-3-trimethylstannyl-2-octenoate (34b), 27.3 mg (0.086 mmol), in E t 2 0 (1.7 mL); J -BU 2 A1H, 0.26 mL (0.26 mmol). Distillation (90-120°C/0.5 torr) of the crude product afforded 23.9 mg (96%) of the alcohol 35b as a colorless oil. The spectral data of 35b are as follows: IR (neat): 3334 (br), 1460, 1190,1079,1002,770, 526 cm"1. X H N M R (CDC13, 400 MHz) 8: 0.16 (s, 9H, 2 7 S a . H = 53 Hz, Sn(CH3)3), 0.86 (t, 3H, 7 = 7 Hz, H-8), 1.15 (t, IH, 7 = 6 Hz, exchanges with D 2 0 , OH), 1.20-1.40 (m, 6H, H-5, H-6, H-7), 2.20 (t, 2H, 7 = 7.5 Hz, 3 7 sn-H = 54 Hz, H-4), 4.07 (m, 2H, collapses to a d, 7 = 6.5 Hz, upon addition of D 2 0 , H- l ) , 6.17 (t, 1H, 7= 6.5 Hz, 3 7 S n . H = 139 Hz, H-2). 1 3 C N M R (CDCI3, 50.3 MHz) 8: -8.0,14.0, 22.5, 29.8, 31.4,40.3, 64.4, 137.9,149.9. Exact mass calcd for C i 0 H 2 iO 1 2 0 Sn (M + -CH 3 ) : 277.0613. Found: 277.0619. Anal, calcd for CnH 2 4 OSn: C 45.40, H 8.31. Found: C 45.50, H 8.39. 176 Preparation of (ZV3-Trimethylstannyl-2-octen-7-yn-l-ol (35c). 6 4 SnMe 3 8 SnMe 3 C 0 2 M e OH 34c 35c Following general procedure 1 (p 170), methyl (Z)-3-trimethylstannyl-2-octen-7-ynoate (34c) (p 169) was converted into (Z)-3-trimethylstannyl-2-octen-7-yn-l-ol (35c) with the following quantities of reagents and solvents: methyl (Z)-3-trimethylstannyl-2-octen-7-ynoate (34c), 75.2 mg (0.239 mmol), in E t 2 0 (4.8 mL); J - B U 2 A 1 H , 0.84 mL (0.84 mmol). Distillation (80-110°C/0.3 torr) of the crude product gave 64.7 mg (94%) of the alcohol 35c as a colorless oil. The spectral data of 35c are as follows: IR (neat): 3311 (br), 2118,1431, 1079,1003,772,714, 633 c m 1 . lU N M R (CDC13, 400 MHz) 8: 0.18 (s, 9H, 2J S „ - H = 53 Hz, Sn(CH3)3), 1.28 (br s, IH, exchanges with D 2 0 , OH), 1.47-1.62 (m, 2H, H-5), 1.93 (t, IH, J = 2.5 Hz, H-8), 2.15 (td, 2H, J = 7, 2.5 Hz, H-6), 2.33 (t, 2H, J = 7.5 Hz, 3 7 S n - H = 53 Hz, H-4), 4.09 (br signal, 2H, simplifies to a d, J= 6.5 Hz, upon addition of D 2 0 , H- l ) , 6.23 (t, IH, J= 6.5 Hz, 3 7 S n - H = 133 Hz, H-2). 1 3 C N M R (CDC13, 50.3 MHz) 8: -7.9, 17.8, 28.7, 39.1, 64.3, 68.6, 84.3,139.0, 148.2. Exact mass calcd for C i 0 H 1 7 O 1 2 0 S n (M + -CH 3 ) : 273.0301: Found: 273.0302. Anal, calcd for C u H 2 0 O S n : C 46.04, H 7.02. Found: C 46.35, H 7.19. 177 Preparation of (Z)-6-CMoro-3-trimethylstannyl-2-hexen-l-ol (35d). 6 4 CI SnMe3 CI SnMe3 C0 2 Me OH 34d 35d Following general procedure 1 (p 170), methyl (Z)-6-chloro-3-trimethylstannyl-2-hexenoate (34d)25 was converted into (Z)-6-chloro-3-trimethylstannyl-2-hexen-l-ol (35d) with the following quantities of reagents and solvents: methyl (2T)-6-chloro-3-trimethylstannyl-2-hexenoate (34d), 63.1 mg (0.194 mmol), in E t 2 0 (3.9 mL); *-Bu 2AlH, 0.58 mL (0.58 mmol). Distillation (100-130 °C/0.3 torr) of the crude product gave 54 mg (94%) of the alcohol 35d as a colorless oil. The spectral data of 35d are as follows: IR (neat): 3347 (br), 1626, 1442, 1299, 1000, 771 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.16 (s, 9H, 2J S n . H = 53 Hz, Sn(CH3)3), 1.34 (br t, IH, J = 5 Hz, exchanges with D 2 0 , OH), 1.74-1.85 (m, 2H, H-5), 2.37 (br t, 2H, J = 7.5 Hz, 3 7 S n - H = 52 Hz, H-4), 3.49 (t, 2H, J = 6.5 Hz, H-6), 4.09 (m, 2H, collapses to a d, J = 6 Hz, upon addition of D 2 0 , H- l ) , 6.23 (tt, IH, J = 6, 1 Hz, 3 7 S n - H = 133 Hz, H-2). 1 3 C N M R (CDC13, 50.3 MHz) 8: -7.9, 32.7, 37.1,44.2, 64.2,139.4,147.3. Exact mass calcd for C 8 H 1 6 3 5 ClO 1 2 0 Sn(M + -CH 3 ) : 282.9912. Found: 282.9907. Anal, calcd for C 9 H 1 9 C10Sn: C 36.35, H 6.44, CI 11.92. Found: C 36.49, H 6.45, CI 11.70. 178 5.3.2.2. Preparation of 7-(fe^Butyldimethylsiloxy)-2-heptyn-l-ol (51). (A) Preparation of 6-(fe^Butyldimethylsiloxy)-l-hexyne (121). HO 5 3 TBDMSO 260 121 To a solution of 5-hexyn-l-ol (260)26 (400 mg, 4.08 mmol) in dry CH 2C1 2 (41 ml) was added imidazole (694 mg, 10.19mmol), followed by ?erf-butyldimethylsilyl chloride (984 mg, 6.53 mmol), upon which a white suspension formed. The mixture was stirred at room temperature for 50 min and then was treated with sat. aq NH4CI-NH4OH (pH 8-9, 10 ml). The phases were separated and the aqueous layer was extracted with CH 2C1 2 (2 x 10ml). The combined extracts were washed (brine (100 ml)), dried (Na2S04), and concentrated. Radial chromatography (4 mm plate, 99:1 hexanes-Et20) of the crude product and subjection of the oil thus obtained to reduced pressure (0.3 torr) afforded 852 mg (98%) of the siloxy ether 121 as a colorless oil. The spectral data of 121 are as follows: IR (neat): 3315 (strong and sharp, E E C - H st), 2120, 1473, 1256, 1108, 1007, 975, 837, 777 cm"1. X H N M R (CDC1 3 ) 400 MHz) 5: 0.04 (s, 6H, Si(CH3)2), 0.88 (s, 9H, C(CH 3) 3), 1.52-1.66 (m, 4H, H-4, H-5), 1.93 (t, IH, J = 2.5 Hz, H- l ) , 2.20 (br td, 2H, 7 = 7, 2.5 Hz, H-3), 3.61 (t, 2H, J = 6 Hz, H-6). 1 3 C N M R (CDC13,100.6 MHz) 8: -5.3,18.2,18.4, 25.0, 26.0, 31.8, 62.6, 68.3, 84.5. Exact mass calcd for C i 2 H 2 3 OSi (M + -H ) : 211.1518. Found: 211.1519. Anal, calcd for C i 2 H 2 4 OSi : C 67.86, H 11.39. Found: C 68.00, H 11.37. 179 (B) Preparation of 7-(fg^Butyldimethylsiloxy)-2-heptyn-l-ol (51). T B D M S O 6 4 T B D M S O O H 121 51 To a cold (-78°C), stirred solution of 6-(fcr/-butyldimethylsiloxy)-l-hexyne (121) (p 178) (1.018 g, 4.79 mmol) in dry THF (9.6 mL) was added, dropwise, a solution of MeLi (5.26 mmol) in Et20 (3.8 mL). After the solution had been stirred for 10 min, paraformaldehyde (574 mg) was added and the mixture was stirred at -20° for 1 h and at r.t. for 1 h. Sat. aq NaHC03 (10 mL) was added, the phases were separated, and the aq phase was extracted with CH2CI2 ( 3 x 5 mL). The combined extracts were washed (brine), dried (Na2S04), and concentrated. Radial chromatography (4 mm plate, 85:15 petroleum ether-Et20) of the crude product and distillation (110-125°C/0.3 torr) of the acquired liquid afforded 950 mg (82%) of the substituted 2-alkyn-l-ol 51 as a colorless oil. The spectral data of 51 are as follows: IR (neat): 3359 (br), 2227, 1473, 1389, 1362, 1256, 1105, 1010, 940, 839, 777 cm - 1 . X H N M R (CDCI3, 400 MHz) 8: 0.03 (s, 6H, Si(CH3)2), 0.85 (s, 9H, C(CH 3) 3), 1.49 (br s, IH, exchanges with D 2 0, OH), 1.48-1.64 (m, 4H, H-5, H-6), 2.22 (tt, 2H, / = 7, 2 Hz, H-4), 3.61 (t, 2H, J = 6 Hz, H-7), 4.21 (br signal, 2H, collapsed to a br s on addition of D z O, H-l ) . 1 3 C N M R (CDCI3, 50.3 MHz) 8: -5.3,18.3,18.5, 25.0, 25.9, 31.9, 51.3, 62.6, 78.5, 86.3. Exact mass calcd for Ci2H 2 30 2 Si(M + -CH3): 227.1467. Found: 227.1463. Anal, calcd for C i3H 2 6 0 2 Si : C 64.41, H 10.81. Found: C 64.14, H 10.83. 180 5.3.3. Iodo Alkenes and Related Compounds. 5.3.3.1. Conversion of Alkyl 2-AIkynoates into Alkyl (Z)-3-Iodo-2-alkenoates. General Procedure 2. 3 7 In the following procedure, all given amounts are related to the use of 1 mmol of alkyl 2-alkynoate. An oil bath was preheated at 115°C for 15 min. A flask containing a suspension of the a,p-acetylenic ester, Nal (amount specified in individual experiments) and glacial AcOH (amount specified in individual experiments) was placed in the oil bath and the mixture was stirred at 115°C for the specified time (vide infra). The bath was removed and the brown mixture was transferred while hot to a separatory funnel containing water (~8-10 mL). The reaction flask was washed with a mixture of water (-2-5 mL) and Et20 (-25-30 mL). The washings were added to the separatory funnel. The phases were separated and the aq phase was extracted with Et20. The combined organic phases were washed sequentially with sat. aq NaHCOs, 1 M aq NaS203, and brine (-8-10 mL of each solution), and then were dried (MgS04 or Na 2S0 4) and concentrated. Distillation of the remaining material from basic alumina (-30-50 mg, activity 1) provided the alkyl (Z)-3-iodo-2-alkenoate. 181 Preparation of Methyl (Z)-3,6-Diiodo-2-hexenoate (261). 6 4 CI C0 2 Me C0 2 Me 31d 261 6 4 AcO C0 2 Me 262 Following general procedure 2 (p 180), methyl 6-chloro-2-hexynoate (31d) was converted into methyl (Z)-3,6-diiodo-2-hexenoate (261) employing a reaction time of 2.25 h and the following quantities of reagents and solvents: methyl 6-chloro-2-hexynoate (31d), 192 mg (1.2 mmol); Nal , 719 mg (4.8 mmol); AcOH, 0.893 ml (15.6 mmol). Radial chromatography (2 mm plate, 130 mL of 85:15 petroleum ether-Et20 and then 75:25 petroleum ether-Et20) of the crude product and subjection of the acquired oils to reduced pressure (0.3 torr) gave 0.36 g (80%) of the diiodo ester 261 and 11.5 mg (3%) of the iodo acetate 262 as colorless oils. The spectral data of 261 are as follows: IR (neat): 1730, 1624, 1219, 1175 c m 4 X H N M R (CDC13, 400 MHz) 5: 2.09 (quintet, 2H, J = 7 Hz, H-5), 2.80 (td, 2H, J = 7, 1 Hz, H-4), 3.13 (t, 3H, J= 1 Hz, H-6), 3.73 (s, 3H, C0 2 Me) , 6.44 (t, IH, J= 1 Hz, H-2). 182 1 3 C N M R (CDC1 3 ) 50.3 MHz) 5: 4.2, 32.0, 47.7, 51.7, 118.8, 126.0, 164.7. Exact mass calcd for C 7 H 1 0 IO 2 (M + - I ) : 252.9726. Found: 252.9729. Anal, calcd for C7H10I2O2: C 22.13, H 2.65,1 66.80. Found: C 22.35, H 2.69,1 66.60. The spectral data of 262 are as follows: IR (neat): 1734, 1624, 1243, 1174 cm"1. *H N M R (CDCI3, 400 MHz) 5: 1.92 (quintet, 2H, J = 1 Hz, H-5), 2.02 (s, 3H, AcO), 2.74 (t, 2H, J= 7 Hz, H-4), 3.70 (s, 3H, C0 2 Me) , 4.03 (t, 2H, J= 7 Hz, H-6), 6.34 (s, IH, H-2). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 20.9, 28.2, 44.4, 51.6, 65.5, 119.9, 125.3, 164.7, 170.9. Exact mass calcd for C 9 H 1 3 I0 4 : 311.9859. Found:311.9864. Anal, calcd for C 9 H 1 3 I0 4 : C 34.64, H 4.20,140.66. Found: C 35.00, H 4.22,140.37. 183 Preparation of Dimethyl (Z,Z)-3.6-Diiodo-2,6-octadiendioate (264). 263 264 Following general procedure 2 (p 180), dimethyl 2,6-octadiyndioate (263)165 was converted into dimethyl (Z,Z)-3,6-diiodo-2,6-octadiendioate (264) employing a reaction time of 1.5 h and the following quantities of reagents and solvents: dimethyl 2,6-octadiyndioate (263), 194 mg (1 mmol); Nal , 480 mg (3.2 mmol); AcOH, 0.73 ml (12.8 mmol). The crude product was passed through a short column of basic alumina (1 g, activity 1, elution with CH2CI2). Concentration (water aspirator, then reduced pressure (0.3 torr)) of the filtrate afforded 340 mg (76%) the diiodo diester 264, a crystalline solid which exhibited mp 73-74 °C (from hot petroleum ether-Et20, cooled to r.t.). The spectral data of 264 are as follows: IR (KBr): 1722, 1614, 1427, 1326, 1161, 1053, 875 cm"1. *H N M R (CDCI3, 400 MHz) 5: 2.95 (s, 4H, H-4, H-5), 3.71 (s, 6H, 2 x C0 2 Me) , 6.38 (s, 2H, H-2, H-7). In NOE difference experiments, irradiation at 8 2.95 (H-4, H-5) caused signal enhancement at 6.38 (H-2, H-7); irradiation at 8 6.38 (H-2, H-7) caused signal enhancement at 2.95 (H-4, H-5). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 46.5, 51.7,117.2,126.4, 164.5. Exact mass calcd for C10H12I2O4: 449.8823. Found: 449.8826. Anal, calcd for C i o H n L ^ : C 26.69, H 2.69,156.40. Found: C 26.87, H 2.75,156.46. 184 Preparation of Methyl (Z)-3-Iodo-2-octenoate (47). 8 6 4 C 0 2 M e C 0 2 M e 31b 47 Following general procedure 2 (p 180), methyl 2-octynoate (31b) was converted into methyl (Z)-3-iodo-2-octenoate (47) employing a reaction time of 1.5 h and the following quantities of reagents and solvents: methyl 2-octynoate (31b), 475 mg (3.08 mmol); Nal, 739 mg (4.93 mmol); AcOH, 1.23 ml (21.5 mmol). Distillation (100-115°C/0.2 torr) of the crude product, a yellow oil, from Cu wire afforded 809 mg (93%) of the iodo ester 47 as a colorless oil. The spectral data of 47 are as follows: IR (neat): 1734, 1623, 1434, 1307, 1171, 1067,1010 c m 1 . *H N M R (CDC13, 400 MHz) 8: 0.87 (t, 3H, J = 7 Hz, H-8), 1.19-1.36 (overlapping signals, 4H, H-6, H-7), 1.52-1.62 (m, 2H, H-5), 2.66 (td, 2H, J = 7, 1 Hz, H-4), 3.72 (s, 3H, C0 2 Me), 6.30 (t, IH, 7 = 1 Hz, H-2). In NOE difference difference experiments, irradiation at 8 2.66 (H-4) enhanced the signals at 6.30 (H-2), 1.29-1.36 (H-6, H-7), and 1.52-1.62 (H-5); irradiation at 8 6.30 (H-2) enhanced the signals at 2.66 (H-4) and 1.52-1.62 (H-5). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 13.9, 22.3, 28.9, 30.3,47.9, 51.5,122.2, 124.3, 164.9. Exact mass calcd for C9H15IO2: 282.0117. Found: 282.0117. Anal, calcd for C 9 Hi 5 I0 2 : C 38.32, H 5.36. Found: C 38.33, H 5.39. 185 Preparation of Ethyl (Z)-3-Iodo-3-(trimethylsilyl)propenoate (266). 265 266 267 Following general procedure 2 (p 180), ethyl 3-(trimethylsilyl)propynoate (265)26 was converted into ethyl (Z)-3-iodo-3-(trimethylsilyl)propenoate (266) employing a reaction time of 3.25 h and the following quantities of reagents and solvents: ethyl 3-(trimethylsilyl)propynoate (265), 178 mg (1.1 mmol); Nal , 864 mg (5.76 mmol); AcOH, 0.571 ml (9.98 mmol). Radial chromatography (4 mm plate, 4:1 petroleum ether-CH2Cl2) of the crude product gave three oils, A , B and C. Distillation (80-100°C/20 torr) of A gave 0.34 mg (19%) of starting material. Distillation (40-45°C/0.08 torr) of B gave 110 mg (35%) of the iodo silane 266. Subjection of C to reduced pressure (20 torr) gave 65 mg (28%) of ethyl (Z)-3-iodopropenoate (267). A l l three compounds were colorless oils. Reduction of 266 gave the known alcohol 270 (see p 189). The spectral data of the iodo silane 266 are as follows: IR (neat): 1731, 1290, 1251, 1176, 844 cm"1. *H N M R (CDC13, 400 MHz) 6: 0.23 (s, 9H, Si(CH3)3), 1.31 (t, 3H, / = 7 Hz, C0 2 CH 2 CH 3 ) , 4.23 (q, 2H, / = 7 Hz, C0 2 CH 2 CH 3 ) , 6.89 (s, IH, H-2). 1 3 C N M R (CDC13, 100.6 MHz) 8: -1.7, 14.2, 60.8, 125.6, 134.6, 164.1. Exact mass calcd for C 8 Hi 5 I0 2 Si : 297.9886. Found: 297.9890. Anal, calcd for C 8 Hi 5 I0 2 Si : C 32.22, H 5.07. Found: C 32.27, H 5.00. 186 The J H N M R data of ethyl (Z)-3-iodopropenoate (267) were in accordance with the literature data.1 6 6 The spectral data of 267 are as follows: IR (neat): 1728,1600, 1324, 1198,1166,1028, 807 cm"1. lH N M R (CDC13, 400 MHz) 8: 1.30 (t, 3H, J = 7 Hz, C0 2 CH 2 CH 3 ) , 4.23 (q, 2H, J = 7.0 Hz, C0 2 CH 2 CH 3 ) , 6.86 (d, IH, / = 9 Hz), 7.42 (d, IH, J= 9 Hz). 1 3 C N M R (CDC13, 50.3 MHz) 8: 14.2, 60.8, 94.6, 129.9, 164.6. 187 5.3.3.2. Preparation of (zD-3-Iodopropenoic Acid (269) = - C 0 2 H 268 An oil bath was preheated at 115°C for 15 min. A flask containing a suspension of propiolic acid (268)26 (514 mg, 7.34 mmol), Nal (1.76 g, 11.7 mmol), and glacial AcOH (2.69 mL, 47.0 mmol) was placed in the oil bath and the mixture was stirred at 115°C for 1.5 h. The mixture was cooled to r.t. and the acetic acid was removed under reduced pressure (0.3 torr, -78°C trap, - 1 0 min). The remaining dark oil was treated with dry E t 2 0 (40 mL) and the resulting suspension was filtered (fritted-glass funnel, water aspirator, washing with dry E t 2 0 (-70 mL)). The combined filtrate was washed with sat. aq N a 2 S 2 0 3 (20 mL) and the aq phase was extracted with E t 2 0 (4 x 10 mL). The combined organic extracts were dried (Na2S04) and concentrated. Crystallization of the remaining viscous oil from hot Et20-petroleum ether (cooled to 0°C) gave 1.09 g (75%) of the iodo acid 269, which exhibited mp 62-64°C (lit. mp 63-65°C).1 6 7 The lH N M R data were in accordance with the literature data. 1 6 7 The spectral data of 269 are as follows: 'H N M R (CDC13, 400 MHz) 8: 6.96 (d, IH, J = 9.5 Hz), 7.67 (d, IH, J = 9.5 Hz), 11.95 (br s, IH, C0 2 H) . 1 3 C N M R (CDCI3 , 100.6 MHz) 8: 98.0, 129.4, 169.7. Exact mass calcd for C 3 H 3 I0 2 : 197.9177. Found: 197.9181. 188 5.3.3.3 Preparation of (Z)-3-Iodo-2-octen-l-ol (26b) (see pp 198 and 202 for alternative preparations of 26b). Following general procedure 1 (p 170), methyl (Z)-3-iodo-2-octenoate (47) (p 184) was converted into (Z)-3-iodo-2-octen-l-ol (26b) with the following quantities of reagents and solvents: methyl (Z)-3-iodo-2-octenoate (47), 429.2 mg (1.52 mmol), in E t 2 0 (30 mL); z-Bu 2AlH, 4.56 mL (4.56 mmol). Distillation (95-120°C/0.2 torr) of the crude product gave 366 mg (95%) of the alcohol 26b as a colorless oil. The spectral data of 26b are as follows: IR (neat): 3313 (br), 1645,1458, 1379,1122,1083,1028, 728 c m 1 . ! H N M R (CDC13, 400 MHz) 8: 0.87 (t, 3H, J = 7.5 Hz, H-8), 1.18-1.37 (m, 4H), 1.45-1.56 (m, 2H), 1.92 (br s, 1 H, exchanges with D 2 0 , OH), 2.46 (td, 2H, J = 7.5, 1 Hz, H-4), 4.16 (d, 2H, J = 6 Hz, H- l ) , 5.79 (tt, IH, J = 6, 1 Hz, H-2). In NOE difference experiments, irradiation at 8 2.46 (H-4) increased the intensity of the signal at 5.79 (H-2), while irradiation at 8 5.79 (H-2) caused signal enhancement at 2.46 (H-4) and 4.16 (H-l). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 14.0, 22.4, 28.8, 30.4, 45.2, 67.3, 110.9, 133.3. Exact mass calcd for C 8 Hi 5 IO: 254.0168. Found: 254.0161. Anal, calcd for C 8 H 1 5 IO: C 37.81, H 5.95,149.94. Found: C 37.76, H 6.00,149.80. 189 5.3.3.4. Preparation of (Z)-3-Iodo-3-(trimethylsilylV2-propen-l-ol (270). TMS X TMS O H C02Et 266 270 To a cold (-78°C), stirred solution of ethyl (Z)-3-iodo-3-(triraethylsilyl)propenoate (266) (p 185) (21 mg, 0.07 mmol) in dry E t 2 0 (1.8 mL) was added a solution of j'-Bu 2AlH (0.21 mmol) in hexanes (0.21 mL). The mixture was stirred at -78°C for 1.25 h and at 0°C for 1.6 h. Sat. aq NH4CI (1.5 mL) was added and the mixture was allowed to warm to r.t. Water (15 mL) and E t 2 0 (20 mL) were added and the phases were separated. The aq phase was extracted with E t 2 0 (2 x 20 mL) and the combined organic phases were washed (brine), dried (Na 2S0 4), and concentrated. Radial chromatography (1 mm plate, 85:15 petroleum-Et20) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 13.5 mg (75%) of 270 as a colorless oil. The J H N M R data of 270 were in accordance with the literature data.1 6 8 The spectral data of 270 are as follows: IR (neat): 3331 (br), 1250,1031, 881, 842 cm"1. X H N M R (CDCI3, 400 MHz) 8: 0.18 (s, 9H, Si(CH3)3), 1.65 (br s, IH, OH), 4.26 (d, 2H, J = 5 Hz, H- l ) , 6.49 (t, IH, 7 = 5 Hz, H-2). In NOE difference difference experiments, irradiation at 8 6.49 (H-2) increased the intensity of the signals at 0.18 (Si(CH3)3) and 4.26 (H-l) , while irradiation at 8 0.18 (Si(CH3)3) increased the intensity of the signal at 6.49 (H-2). 1 3 C N M R (CDC13, 50.3 MHz) 8: -1.7, 69.5, 112.6, 146.4. Exact mass calcd for C 6 H 1 3 IOSi: 255.9780. Found: 255.9787. 190 5.3.3.5. Reaction of (Z)-3-Trimethylstannyl-2-octen-l-ol (35b) with h in CD2Ci9. Ipf N M R Experiments. To a solution of (Z)-3-trimethylstannyl-2-octen-l-ol (35b) (p 175) (11.8 mg, 0.041 mmol) in CD 2C1 2 (1 g) was added finely divided, freshly sublimed I2 (10.3 mg, 0.041 mmol) and the mixture was stirred vigorously at r.t. After 10 min, analysis (*H N M R spectroscopy, 400 MHz) of the reaction mixture showed the absence of the starting material 35b and the presence of M e l (8 2.16, s), MesSnl (8 0.89, s), Me 2SnI 2 (8 1.66, s)3 3 (very small amount), and the two products 26b and 39. Signals unique to 26b (see p 188 for full spectral details of 26b) appeared at 8 4.16 (br signal, 2H, H- l ) and 5.82 (tt, IH, J = 6, 1 Hz, H-2), while assignable resonances derived from 39 appeared at 8 0.91 (s, 6H, 2J S n - H = 64 Hz, SnDVle2), 4.40 (br s, 2H, H- l ) , and 6.22 (br s, IH, 3 /(Sn-H) = 214 Hz, H-2). Integration of the resonances at 8 4.16, 4.40, 5.82 and 6.22 showed that 26b and 39 were present in a ratio of - 1 : 1 . In a similar experiment, *H N M R spectroscopy 191 showed that the reaction mixture derived from treatment of 35b with 2 equivalents of h in CD2CI2 at r.t. for 50 min contained 26b, Me l , Me3SnI and Me2SnI2 but no 39. 5.3.3.6. Reaction of (Z)-3-Trimethylstannyl-2-octen-7-yn-l-ol (35c) with L. Isolation of (Z)-3-(Dimethyl(iodo)stannyl)-2-octen-7-yn-l-ol (40). 1 40 To a solution of the trimethylstannane 35c (p 176) (154 mg, 0.537 mmol) in dry CH2Q2 (10.7 mL) was added finely divided, freshly sublimed L (136 mg, 0.536 mmol) and the mixture was stirred vigorously for 10 min. Sat. aq Na 2 S 2 0 3 (-10 mL) was added and the phases were separated. The organic layer was washed (water, 4 x 20 mL), dried (Na2SC»4), and concentrated to afford 75 mg of a crude oil. This mixture (primarily 26c + 40) was repeatedly triturated with petroleum ether (40 x 0.5 mL). Subjection of the remaining oil to reduced pressure (0.3 torr) provided 15 mg of compound 40 as a colorless oil. 192 The spectral data of 40 are as follows: IR (neat): 3281 (sharp), 1588, 1442, 1082 cm-1. *H N M R (CD2C12, 400 MHz) 8: 0.73 (s, 6H, 2 / S n - H = 65 Hz, SnTMe2), 1.60-1.75 (m, 2H, H-5), 1.99 (t, IH, J = 2.5 Hz, H-8), 2.20 (td, 2H, 7 = 7, 2.5 Hz, H-6), 2.48 (br t, 2H, J = 7 Hz, 3 7 S n - H = 70 Hz, H-4), 4.33 (br signal, 2H, H- l ) , 6.35 (br s, IH,  3JSa-u = 211 Hz, H-2). Exact mass calcd for C i 0 H 1 7 O 1 2 0 S n ( M + - I ) : 273.0300. Found: 273.0297. Concentration of the petroleum ether solution derived from the triturations mentioned above gave 55 mg of a mixture of 26c (major) and 40 (minor) (*H N M R spectral analysis). See p 199 for the spectral data of 26c. 193 5.3.3.7. Conversion of Vmyltrimethylstannanes into Iodo Alkenes via Sn-I Exchange Reactions-General Procedure 3. In the following procedure, all given amounts are related to the use of 1 mmol of the stannane. To a stirred solution of the vmyltrimethylstannane in dry CH2CI2 (~20 mL) was added finely divided, freshly sublimed I2 (1-3 mmol) and the dark wine solution was vigorously stirred at r.t. for the specified time (vide infra). Sat. aq Na 2 S 2 0 3 (-10-15 mL) was added and the phases were separated. The aq phase was extracted with CH2CI2 (3 x - 1 5 mL). The combined organic phases were dried (Na 2S0 4) and concentrated. Radial chromatography of the crude product, followed by distillation of the acquired liquid from a small piece of Cu wire, gave the iodo alkene, which was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). 194 Preparation of (F)-3-Iodo-2-penten-l-ol (25a). 4 SnMe 3 5 HO HO 33a 25a Following general procedure 3 (p 193), (£)-3-trimethylstannyl-2-penten-l-ol (33a) (p 171) was converted into (Zs)-3-iodo-2-penten-l-ol (25a) employing a reaction time of 30 min and the following quantities of reagents and solvents: (F)-3-trimethylstannyl-2-penten-l-ol (33a), 77 mg (0.309 mmol), in CH 2C1 2 , 6.2 mL; I2, 78.4 mg (0.309 mmol). Radial chromatography (2 mm plate, 3:2 petroleum ether-Et20) of the crude product, followed by distillation (55-85°C/0.3 torr) of the acquired oil, afforded 64 mg (98%) of the iodide 25a as a colorless oil. The spectral data of 25a are as follows: IR (neat): 3317 (br), 1630, 1455, 1109, 1007 cm"1. X H N M R (CDC13, 400 MHz) 8: 1.06 (t, 3H, / = 7.5 Hz, H-5), 1.46 (t, IH, J = 6 Hz, exchanges with D 2 0 , OH), 2.45 (q, 2H, J = 7.5 Hz, H-4), 4.09 (m, 2 H, simplifies to a d, J = 7 Hz, upon addition of D 2 0 , H- l ) , 6.37 (br t, IH, J -1 Hz, H-2). In NOE difference experiments, irradiation at 8 2.45 (H-4) caused signal enhancement at 4.09 (H-l) and 1.06 (H-5), while irradiation at 8 4.09 (H-l) intensified the resonances at 2.45 (H-4) and 6.37 (H-2). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 14.7, 32.9, 60.0,110.1, 138.9. Exact mass calcd for C5H9IO: 211.9698. Found: 211.9704. Anal, calcd for C5H9IO: C 28.32, H 4.28,159.85. Found: C 28.47, H 4.37,159.70. 195 Preparation of (E)-3-Iodo-2-octen-l-ol (25b). 8 6 4 SnMe3 33b 25b Following general procedure 3 (p 193), (£)-3-trimethylstannyl-2-octen-l-ol (33b) (p 172) was converted into (jE)-3-iodo-2-octen-l-ol (25b) employing a reaction time of 30 min and the following quantities of reagents and solvents: (i^-3-trimethylstannyl-2-octen-l-ol (33b), 293 mg (1.01 mmol), in CH 2C1 2 , 20 mL; I2, 281 mg (1.11 mmol). Radial chromatography (4 mm plate, 7:3 petroleum ether-Et20) of the crude product, followed by distillation (110-120°C/0.2 torr) of the acquired oil, afforded 241 mg (94 %) of the iodide 25b as a colorless oil. The spectral data of 25b are as follows: IR (neat): 3317 (br), 1631,1465, 1122, 1019 cm"1. 'H N M R (CDC13, 400 MHz) 5: 0.88 (t, 3H, J = 1 Hz, H-8), 1.15-1.40 (m, skght overlap with downfield signal, 5H, reduces to 4H upon addition of D 2 0) , 1.40-1.57 (m, slight overlap with upfield signal, 2H), 2.42 (br t, 2H, J = 7 Hz, H-4), 4.09 (dd, 2H, 7 = 7 ,6 Hz, collapses to a d, J = 7 Hz, upon addition of D 2 0 , H- l ) , 6.42 (br t, IH, J = 7 Hz, H-2). In NOE difference experiments, irradiation at 8 2.42 (H-4) caused signal enhancement at 4.09 (H-l) ; irradiation at 8 4.09 (H-l) caused signal enhancement at 2.42 (H-4) and 6.42 (H-2). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 14.0, 22.4, 29.0, 30.5, 39.0, 60.1, 108.4, 139.6. Exact mass calcd for C 8 Hi 5 IO: 254.0168. Found: 254.0173. Anal, calcd for C 8 H 1 5 IO: C 37.81, H 5.95. Found: C 38.10, H 5.96. 196 Preparation of (F)-3-Iodo-2-octen-7-yn-l-ol (25c). 6 4 SnMe3 33c 25c Following general procedure 3 (p 193), (£)-3-trimethylstannyl-2-octen-7-yn-l-ol (33c) (p 173) was converted into (E)-3-iodo-2-octen-7-yn-l-ol (25c) employing a reaction time of 45 min and the following quantities of reagents and solvents: (£)-3-trimethylstannyl-2-octen-7-yn-l-ol (33c), 664 mg (2.31 mmol), in CH 2C1 2 , 26 mL; I2, 645 mg (2.54 mmol). Radial chromatography (4 mm plate, 3:2 petroleum ether-Et20) of the crude product, followed by distillation (75-110°C/0.3 torr) of the acquired oil, afforded 568 mg (98%) of the iodide 25c as a colorless oil. The spectral data of 25c are as follows: IR (neat): 3297 (br), 2117, 1631,1431, 1092,1007, 640 cm"1. *H N M R (CDCI3, 400 MHz) 8: 1.67 (br s, partially overlaps with signal at 1.75, IH, exchanges with D 2 0 , OH), 1.75 (quintet, 2H, J = 1 Hz, H-5), 1.98 (t, IH, J = 2.5 Hz, H-8), 2.19 (td, 2H, J = 7, 2.5 Hz, H-6), 2.58 (t, 2H, J = 7 Hz, H-4), 4.13 (d, 2H, J = 7 Hz, H- l ) , 6.49 (br t, IH, J = 7 Hz, H-2). In NOE difference experiments, irradiation at 8 2.58 (H-4) caused signal enhancement at 4.13 (H-l) and 1.75 (H-5), while irradiation at 8 4.13 (H-l) intensified the resonances at 6.49 (H-2), 2.58 (H-4), and 1.67 (OH). 1 3 C N M R (CDCI3, 75.4 MHz) 8: 16.4, 27.3, 36.8, 60.1, 69.3, 83.6,106.7, 141.3. Exact mass calcd for CgHnIO: 123.0810. Found: 123.0808. Anal, calcd for CgHnIO: C 38.42, H 4.43,150.74. Found: C 38.34, H 4.55,150.65. 197 Preparation of (Z)-3-Iodo-2-penten-l-ol (26a). 4 SnMe3 5 O H O H 35a 26a Following general procedure 3 (p 193), (Z)-3-trimethylstannyl-2-penten-l-ol (35a) (p 174) was converted into (Z)-3-iodo-2-penten-l-ol (26a) employing a reaction time of lh and the following quantities of reagents and solvents: (Z)-3-trimethylstannyl-2-penten-l-ol (35a), 195 mg (0.783 mmol), in CH 2C1 2 , 15.6 mL; I2, 395 mg (1.56 mmol). Radial chromatography (1 mm plate, 3:2 petroleum ether-Et20) of the crude product, followed by distillation (55-85°C/0.3 torr) of the acquired oil, afforded 149.1 mg (90%) of the iodide 26a as a colorless oil. The spectral data of 26a are as follows: IR (neat): 3333 (br), 1646,1455, 1430,1091,1020,909, 734 c m 1 . X H N M R (CDC13, 400 MHz) 8: 1.06 (t, 3H, / = 7.5 Hz, H-5), 2.09 (br s, IH, exchanges with D 2 0 , OH), 2.51 (br q, 2H, J = 7.5 Hz, H-4), 4.16 (d, 2H, J = 6 Hz, H- l ) , 5.79 (br t, IH, J = 6 Hz, H-2). In NOE difference experiments, irradiation at 8 2.51 (H-4) increased the intensity of the signals at 5.79 (H-2) and 1.06 (H-5), while irradiation at 8 5.79 (H-2) caused signal enhancement at 2.51 (H-4), 1.06 (H-5), and 4.16 (H-l). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 14.6, 39.0, 67.2, 112.1, 132.4. Exact mass calcd for C5H9IO: 211.9698. Found: 211.9705. Anal, calcd for C5H9IO: C 28.32, H 4.28,159.85. Found: C 28.47, H 4.37,159.70. 198 Preparation of (Z)-3-Iodo-2-octen-l-ol (26b) (see pp 188 and 202 for alternative preparations'). Following general procedure 3 (p 193), (Z)-3-trimethylstannyl-2-octen-l-ol (35b) (p 175) was converted into (Z)-3-iodo-2-octen-l-ol (26b) employing a reaction time of lh and the following quantities of reagents and solvents: (Z)-3-trimethylstannyl-2-octen-l-ol (35b), 52 mg (0.179 mmol), in CH 2C1 2 , 3.6 mL; I2, 91 mg (0.358 mmol). Radial chromatography (1 mm plate, 3:2 petroleum ether-Et20) of the crude product, followed by distillation (90-120°C/0.2 torr) of the acquired oil, afforded 41 mg (90%) of the iodide 26b as a colorless oil. See p 188 for spectral details of 26b. 199 Preparation of (Z)-3-Iodo-2-octen-7-yn-l-ol (26c). 6 4 SnMe 3 OH 2 OH 35c 26c Following general procedure 3 (p 193), (Z)-3-trimethylstannyl-2-octen-7-yn-l-ol (35c) (p 176) was converted into (Z)-3-iodo-2-octen-7-yn-l-ol (26c) employing a reaction time of lh and the following quantities of reagents and solvents: (Z)-3-trimethylstannyl-2-octen-7-yn-l-ol (35c), 64 mg (0.223 mmol), in CH 2C1 2 , 4.5 mL; I2, 113 mg (0.445 mmol). Radial chromatography (1 mm plate, 3:2 petroleum ether-Et20) of the crude product, followed by distillation (110-120°C/0.3 torr) of the acquired oil, afforded 34 mg (61%) of the iodide 26c as a colorless oil. The spectral data of 26c are as follows: IR (neat): 3298 (br), 2117, 1645, 1430, 1086, 1011, 647 cm"1. X H N M R (CDC13, 400 MHz) 8: 1.74 (quintet, 2H, J= 1 Hz, H-5), 1.89 (br s, IH, exchanges with D 2 0 , OH), 1.95 (t, IH, J= 2.5 Hz, H-8), 2.16 (td, 2H, 7 = 7, 2.5 Hz, H-6), 2.60 (td, 2H, 7 = 7, 1 Hz, H-4), 4.16 (br signal, 2H, simplifies to a d, J = 6 Hz, upon addition of D 2 0 , H- l ) , 5.89 (tt, IH, J = 6, 1 Hz, H-2). In NOE difference experiments, irradiation at 8 2.60 (H-4) caused signal enhancement at 5.89 (H-2) and 1.74 (H-5), while irradiation at 8 5.89 (H-2) increased the signal intensities at 2.60 (H-4) and 4.16 (H-l). 1 3 C N M R (CDCI3,125 MHz) 8: 16.8, 27.6, 43.7, 67.2, 69.0, 83.5,108.7, 134.6. Exact mass calcd for C 8 H 9 I (M + -H 2 0) : 231.9749. Found: 231.9753. Anal, calcd for CgHnIO: C 38.42, H 4.43. Found: C 38.09, H 4.27. 200 Preparation of (Z)-6-Chloro-3-iodo-2-hexen-l-ol (26d). 6 4 CI SnMe 3 CI OH OH 35d 26d Following general procedure 3 (p 193), (Z)-6-chloro-3-trimethylstannyl-2-hexen-l-ol (35d) (p 177) was converted into (Z)-6-chloro-3-iodo-2-hexen-l-ol (26d) employing a reaction time of 1.75 h and the following quantities of reagents and solvents: (Z)-6-chloro-3-trimethylstannyl-2-hexen-l-ol (35d), 197 mg (0.662 mmol), in CH 2C1 2 , 13.3 mL; I2, 506 mg (1.99 mmol). Radial chromatography (2 mm plate, 3:2 petroleum ether-Et20) of the crude product, followed by distillation (85-110°C/0.3 torr) of the acquired oil, afforded 163 mg (94%) of the iodide 26d as a colorless oil. The spectral data of 26d are as follows: IR (neat): 3327 (br), 1645,1441,1290,1083, 1015, 866, 790,727, 656 cm"1. *H N M R (CDC13, 400 MHz) 8: 1.58 (t, IH, J = 5 Hz, exchanges with D 2 0 , OH), 1.99 (m, 2H, H-5), 2.68 (td, 2H, J = 7, 1 Hz, H-4), 3.51 (t, 2H, J = 6.5 Hz, H-6), 4.18 (m, 2H, simplifies to a d, J = 6 Hz, upon addition of D 2 0 , H- l ) , 5.93 (tt, IH, J = 6, 1 Hz, H-2). In NOE difference experiments, irradiation at 8 2.68 (H-4) enhanced the signal intensities at 5.93 (H-2) and 1.99 (H-5), while irradiation at 8 5.93 (H-2) caused signal enhancements at 2.68 (H-4) and 4.18 (H-l). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 31.5, 41.9, 43.1, 67.2, 107.6, 135.3. Exact mass calcd for C 6H 1 0 3 5C1IO: 259.9465. Found: 259.9458. Anal, calcd for C 6H 1 0C1IO: C 27.66, H 3.87. Found: C 27.90, H 3.90. 201 Preparation of 4-Chloro-2-iodo-l-butene (120). 3 CI SnMe3 CI H - i b 119 120 Following a procedure similar to general procedure 3 (p 193), 4-chloro-2-trimethylstannyl-1-butene (119)102 was converted into 4-chloro-2-iodo-l-butene (120) employing a reaction time of 30 min and the following quantities of reagents and solvents: 4-chloro-2-trimethylstannyl-l-butene (119), 783 mg, (3.09 mmol), in CH 2C1 2, 15.6 mL; I2, 1.57 g (6.18 mmol). Radial chromatography (4 mm plate, petroleum ether) of the crude product, followed by distillation (40°C/0.3 torr) of the acquired oil from a small piece of Cu wire, afforded 451 mg (68 %) of the iodide 120, which was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). The spectral data of 120, a colorless oil, are as follows: IR (neat): 1619, 1439, 1300,1181,1104,903, 831 cm"1. *H N M R (CDC13, 400 MHz) 8: 2.80 (br td, 2H, J = 6.5, 1 Hz, H-3), 3.62 (t, 2H, J = 6.5 Hz, H-4), 5.85 (br d, IH, / = 1.5 Hz, H - l a or H-lb), 6.16 (td, IH, J= 1.5,1 Hz, H - l a or H-lb). 1 3 C N M R (CDCI3, 125 MHz) 8: 42.9, 47.7, 105.8, 128.7. Exact mass calcd for C 4H 6 3 5C1I: 215.9203. Found: 215.9199. Anal, calcd for C4H6C1I: C 22.20, H 2.79. Found: C 22.51, H 2.86. 202 5.3.3.8. Preparation of (2D-3-Iodo-2-octen-l-ol (26b) Via Hydroalanation/Iodination (see pp 188 and 198 for alternative preparations). Note: In this large scale preparation, the solution of alkynyl alcohol in THF was cooled to 0°C during the addition of Red-Al® in order to subdue the rapid evolution of H 2 gas. To a stirred solution of 2-octyn-l-ol (48)3y (4.05 g, 32.09 mmol) in dry THF (120 mL) at 0°C was added, dropwise, a solution of Red-Al® (96.32 mmol) in PhCH 3 (28.33 mL) and the solution was stirred for 16.5 h at r.t. The mixture was cooled to 0°C, dry EtOAc (64.19 mmol) was added dropwise, and stirring was continued for 15 min. After the mixture had been cooled to -78°C, finely divided, freshly sublimed I2 (40.6 g, 160 mmol) was added in one portion. The cooling bath was removed and the vigorously stirred mixture was allowed to warm for 15 min. An aq solution (530 mL) of N a 2 S 2 0 3 (484 mmol), K 2 C 0 3 (330 mmol), and Rochelle salt (159 mmol) was added and the phases were separated. The aq phase was extracted with E t 2 0 (3 x 130 mL). The combined extracts were washed (dilute aq Na 2 S 2 0 3 (130 mL)), dried (Na2S04), and concentrated. Radial chromatography (4 mm plate, 4:1 petroleum ether-Et20, material was applied in 8 approximately equal portions employing a continuous method of elution (see Section 5.1.2 for an explanation of this method) of the crude product and distillation (100-120°C/0.3 torr) of the 203 acquired liquid from a small piece of Cu wire gave 6.76 g (83%) of 26b, a colorless oil that was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). See p 188 for spectral details of 26b. 5.3.3.9. Preparation of (Z^-7-(fe^ButyldimethylsiloxyV3-iodo-2-hepten-l-ol (26e1. TBDMSO 53 To a cold (0°C), stirred solution of the 7-(ferf-butyldimethylsiloxy)-2-heptyn-l-ol (51) (p 179) (201 mg, 0.829 mmol) in dry E t 2 0 (10.4 mL) was added, dropwise, a solution of Red-Al® in PhCH 3 (0.42 mL, 1.43 mmol). The solution was allowed to warm to r.t., was stirred for 16 h, and then was cooled to -78°C. A solution of I2 (630 mg, 2.48 mmol) in dry THF (10 mL) was added. The dark solution was stirred at -78°C for 35 min and then was poured into a cold (0°C), vigorously stirred solution derived from adding Rochelle salt (1 g) to a mixture of sat. aq Na 2 S 2 0 3 (20 mL) and sat. aq K 2 C 0 3 (20 mL). The phases were separated and the aq phase was extracted 204 with CH2C12 (2 x 20 mL). The combined organic extracts were dried (Na2S04) and concentrated. Radial chromatography (4 mm plate, 7:1:2 hexanes-CH2Cl2-Et20) of the crude product gave two oils, A and B. Distillation (160-180°C/0.3 torr) of A from a small piece of Cu wire gave 165 mg (54%) of the iodo alkene 26e, a colorless oil that was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). Subjection of B to reduced pressure (0.3 torr) gave 36 mg (18%) of (E)-7-(?e^butyldimethylsiloxy)-2-hepten-l-ol (53). The spectral data of {Z)-l-(tert-butyldimethylsiloxy)-3-iodo-2-hepten-l-ol (26e) are as follows: IR (neat): 3336 (br), 1646, 1472, 1256, 1106, 1007, 837, 777 cm"1. X H N M R (CDCI3, 400 MHz) 8: 0.03 (s, 6H, Si(CH3)2), 0.88 (s, 9H, C(CH 3) 3), 1.43-1.52 (m, 2H), 1.52-1.62 (m, 2 H), 1.66 (br s, 1 H, exchanges with D 20, OH), 2.49 (td, 2H, J = 7, 1 Hz, H-4), 3.59 (t, 2H, J = 6 Hz, H-7), 4.16 (br signal, 2H, simplifies to a d, J = 6 Hz, on addition of D 2 0 , H- l ) , 5.83 (tt, IH, J = 6, 1 Hz, H-2). In NOE difference experiments, irradiation at 8 2.49 (H-4) increased the intensity of the signal at 5.83 (H-2), while irradiation at 8 5.83 (H-2) caused signal enhancement at 2.49 (H-4) and 4.16 (H-l). 1 3 C N M R (CDC13, 50.3 MHz) 8: -5.3,18.3, 25.6, 26.0, 31.3,44.9, 62.8, 67.3,110.6,133.6. Exact mass calcd for C 9 Hi 8 I0 2 Si (M + -C 4 H 9 ) : 313.0121. Found: 313.0113. Anal, calcd for C i 3 H 2 7l0 2 Si : C 42.16, H 7.35,134.27. Found: C 42.46, H 7.44,1 33.95. 205 The spectral data of (^-7-(re^butyldimethylsiloxy)-2-hepten-l-ol (53) are as follows: IR (neat): 3328 (br), 1672,1463 (d), 1388,1256,1104, 1006,971, 837, 776 c m 4 *H N M R (CDC13, 400 MHz) 8: 0.03 (s, 6H, Si(CH3)2), 0.87 (s, 9H, C(CH 3) 3), 1.28 (t, IH, J = 5.5 Hz, exchanges with D 2 0 , OH), 1.35-1.46 (m, 2H), 1.46-1.56 (m, 2H), 2.04 (ra, 2 H, H-4), 3.58 (t, 2H, J = 6.5 Hz, H-7), 4.06 (m, 2H, sharpens to a d, J = 5 Hz, upon addition of D 2 0 , H- l ) , 5.57-5.72 (m, 2H, H-2, H-3). 1 3 C N M R (CDC13, 50.3 MHz) 8: -5.3, 18.4, 25.4, 26.0, 31.9, 32.3, 63.0, 63.8, 129.1, 133.2. Exact mass calcd for C i 3 H 2 6 O S i ( M + - H 2 0 ) : 227.1831. Found: 227.1840. Anal, calcd for C i 3 H 2 8 0 2 S i : C 63.88, H 11.54. Found: C 63.99, H 11.53. 206 5.3.3.10. Preparation of (Z)-4-Iodo-3-hexen-2-ol (21). Note: For large scale preparations, the Red-Al® solution should be added to a cooled (0°C) solution of the substrate in order to subdue the otherwise rapid evolution of Ff2 gas. To a stirred solution of 3-hexyn-2-ol (50)y (470 mg, 4.79 mmol) in dry THF (24 mL) at r.t. was added, dropwise, a solution of Red-Al® in PhCH 3 (4.23 mL, 14.38 mmol) and the solution was stirred for 17.5 h. The mixture was cooled to 0°C, dry EtOAc (9.58 mmol) was added dropwise, and stirring was continued for 10 min. After the mixture had been cooled to -78°C, finely divided, freshly sublimed I2 (6.08 g, 24 mmol) was added in one portion. The cooling bath was removed and the vigorously stirred mixture was allowed to warm for 15 min. An aq solution (30 mL) of N a 2 S 2 0 3 (72 mmol), K 2 C 0 3 (48 mmol), and Rochelle salt (29 mmol) was added and the phases were separated. The aq phase was extracted with E t 2 0 (3 x 20 mL). The combined extracts were washed (dilute aq Na 2 S 2 0 3 (20 mL)), dried (Na2SC»4), and concentrated. Radial chromatography (4 mm plate, 3:1 hexanes-Et20) of the crude product and distillation (35-60°C/0.3 torr) of the acquired liquid from a small piece of Cu wire gave 900 mg (83%) of 27, a colorless oil that was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). 207 The spectral data of 27 are as follows: IR (neat): 3332 (br), 1646,1455, 1370,1113, 1056,916, 864 cm' 1. X H N M R (CDC13, 400 MHz) 8: 1.01 (t, 3H, J = 7.5 Hz, H-6), 1.20 (d, 3H, / = 6 Hz, H- l ) , 2.44 (qd, 2H, J = 7.5, 1 Hz, H-5), 2.81 (br s, IH, exchanges with D 2 0 , OH), 4.30-4.46 (m, IH, H-2), 5.54 (dt, IH, / = 7.5, 1 Hz, H-3). In NOE difference experiments, irradiation at 8 5.54 (H-3) enhanced the signals at 2.44 (H-5) and 4.30-4.46 (H-2), while saturation of the signal at 8 2.44 (H-5) increased signal intensities at 5.54 (H-3) and 1.01 (H-6). 1 3 C N M R (CDC13, 50.3 MHz) 8: 14.6, 22.0, 38.9, 72.8, 110.8, 137.1. Exact mass calcd for C 6 HnIO: 225.9855. Found 225.9857. Anal, calcd for C 6 HnIO: C 31.88, H 4.90,156.14. Found: C 32.02, H 4.93,155.95. 208 5.3.3.11. Preparation of (F)-2-Iodo-2-octen-l-ol (28) via a Pd(0)-Catalyzed Hydrostannylation/Iodination Reaction. 8 6 4 48 28 25b To a stirred solution of 2-octyn-l-ol (48)y (86.2 mg, 0.683 mmol) in dry PhH (2.7 mL) at r.t. were added (Ph3P)4Pd (15.8 mg, 0.014 mmol) and, dropwise, Bu 3SnH (184 u.L, 0.684 mmol) and stirring was continued for 40 min. The brown mixture was filtered through 2.5 g of Sigma (Type H) silica gel (fritted-glass funnel, water aspirator, elution with 20 mL of dry CH2CI2). The filtrate was concentrated and the residue was dissolved in dry CH2CI2 (14 mL). Finely divided, freshly sublimed I2 (173 mg, 0.682 mmol) was added and the mixture was stirred vigorously at r.t. for 15 min. Sat. aq Na2S20 3 (15 mL) was added, the phases were separated, and the aq phase was extracted with CH2Q2 (3 x 10 mL). The combined organic extracts were dried (Na 2 S0 4 ) and concentrated. Radial chromatography (4 mm plate, CH2Q2) of the crude product gave two oils A and B. Distillation (60-85°C/0.3 torr) of A from a small piece of Cu wire afforded 116 mg (67%) of the iodo alcohol 28, a colorless oil that was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). Subjection of B to reduced pressure (0.3 torr) gave 32 mg (18%) of (£)-3-iodo-2-octen-l-ol (25b) (see p 195 for the spectral data of 25b). 209 The spectral data of (£)-2-iodo-2-octen-l-ol (28) are as follows: IR (neat): 3363 (br), 3030 (w), 1628, 1465, 1137, 1024 cm-1. lH N M R (CDC13, 400 MHz) 8: 0.88 (t, 3H, J = 6.5 Hz, H-8), 1.15-1.50 (m, 6H, H-5, H-6, H-7), 1.77 (t, IH, /= 6.5 Hz, exchanges with D 2 0 , OH), 2.06-2.19 (m, 2H, H-4), 4.20 (d, 2H, J = 6.5 Hz, collapses to a singlet upon addition of D 2 0 , H- l ) , 6.31 (t, IH, J = 8 Hz, H-3). In NOE difference experiments, irradiation at 8 2.12 (H-4) caused signal enhancement at 6.31 (H-3), 4.20 (H-l) , and 1.15-1.50 (H-5, H-6, H-7); irradiation at 8 6.31 (H-3) caused signal enhancement at 2.06-2.19 (H-4) and 1.15-1.50 (H-5, H-6, H-7); irradiation at 8 4.20 (H-l) enhanced the signals at 2.06-2.19 (H-4) and 1.77 (OH). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 13.9, 22.4, 28.7, 31.0, 31.2, 64.9, 102.5, 143.9. Exact mass calcd for C 8 Hi 5 IO: 254.0168. Found: 254.0170. Anal, calcd for CgHisIO: C 37.81, H 5.95,149.94. Found: C 37.78, H 5.98,149.75. 210 5.3.3.12. Preparation of (Z)-2-Iodo-2-octen-l-ol (29). 8 6 4 O H O H 48 29 A solution of BuLi in hexanes (2.18 mL, 3.49 mmol) was added to a cold (-23°C), vigorously stirred solution of 2-octyn-l-ol (48)39 (400 mg, 3.17 mmol) in dry E t 2 0 (3.2 mL), and the white slurry was stirred vigorously for 10 min. A solution of 1-BU2AIH (9.5 mmol) in hexanes (9.5 mL) was added, stirring at -23°C was continued for 5 min, and then the mixture was stirred at 35°C (oil bath) for 67 h. The suspension was cooled to 0°C, dry EtOAc (560mg, 6.36 mmol) was added, stirring was continued for 10 min, the solution was cooled to -78°C, and finely divided, freshly sublimed I2 (4.02 g, 15.8 mmol) was added. The cooling bath was removed, and after the mixture had been allowed to warm over a period of 20 min, it was poured into a mixture of sat. aq N a 2 S 2 0 3 (20 mL), sat. aq K 2 C 0 3 (10 mL) and sat. aq Rochelle salt (30 mL). The phases were separated and the aq layer was extracted with CH 2C1 2 (20 mL). The combined organic extracts were washed (water (20 mL)), dried ( N a 2 S 0 4 ) , and concentrated. Radial chromatography (4 mm plate, 4:1 hexanes-Et20) of the crude product and distillation (70-90°C/0.3 torr) of the acquired oil from a small piece of Cu wire gave 382 mg (47%) of the iodo alcohol 29, a colorless oil that was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). 211 The spectral data of 29 are as follows: IR (neat): 3329 (br), 1645,1456,1086, 1004 cm"1. X H N M R (CDC13, 400 MHz) 8: 0.87 (t, 3H, J = 7 Hz, H-8), 1.23-1.47 (m, 6H, H-5, H-6, H-7), 2.07 (t, IH, / = 6.5 Hz, exchanges with D 2 0 , OH), 2.10-2.20 (m, 2H, H-4), 4.22 (br dd, 2H, J = 6.5, 1 Hz, collapses to a d, J = 1 Hz, upon addition of D 2 0 , H- l ) , 5.87 (tt, IH, 7 = 7 ,1 Hz, H-3). In NOE difference experiments, irradiation at 8 4.22 (H-l) caused signal enhancement at 5.87 (H-3); irradiation at 8 5.87 (H-3) caused signal enhancement at 4.22 (H-l) and 2.10-2.20 (H-4). 1 3 C N M R (CDCI3, 125 MHz) 8: 14.0, 22.4, 27.8, 31.3, 35.6,71.6,108.0, 136.6. Exact mass calcd for C 8 H 1 5 IO: 254.0168. Found: 254.0166. Anal, calcd for QH15IO: C 37.81, H 5.95,149.94. Found: C 37.78, H 5.97,149.75. 212 5.3.3.13. Preparation of (Z)-2-Alkyl-3-iodo-2-propen-l-ols via Alkylmagnesiation/Iodination Reactions. General Procedure 4. In the following procedure, all given amounts are related to the use of 1 mmol of 2-propyn-l-ol (56).26 A solution of the required alkylmagnesium bromide (2.5 mmol) in Et20 was added to a cold (-12°C) suspension of Cui (1 mmol), 2-propyn-l-ol (56), and dry E t 2 0 (3.6 mL). After the yellowish suspension had been stirred (using an oversized stir bar) for 5 min, it was allowed to warm to r.t. over a period of 2 h. During the warming period, the mixture became a clear, dark solution and a gum appeared on the sides of the reaction flask. The mixture was chilled to -78°C, finely divided, freshly sublimed I 2 (1.4 mmol) was added using a solid-addition adapter which had been attached to the reaction flask during its assembly, and the resulting solution was allowed to warm to r.t. over a period of 40 min. Upon warming, the mixture became a yellowish brown suspension. The mixture was chilled to 0°C and sat. aq N a 2 S 2 0 3 (~ 4 mL), sat. aq NH4CI (~8 mL); and E t 2 0 (~8 mL) were added. The phases were separated and the organic layer was extracted with E t 2 0 ( 2 x 4 mL). The combined extracts were dried (Na2S04) and concentrated. Purification of the crude product (chromatography, distillation) provided the vinyl iodide. 213 Preparation of (Z)-3-Iodo-2-methyl-2-propen-l-ol (30a). 4 O H O H 56 30a Following general procedure 4 (p 212), 2-propyn-l-ol (56) was converted into (Z)-3-iodo-2-methyl-2-propen-l-ol (30a) with the following quantities of reagents and solvents: 2-propyn-l-ol (56), 204 mg (3.64 mmol), in E t 2 0 , 13 mL; Cui , 694.1 mg (3.64 mmol); CFLMgBr, 2 6 3.04 mL (9.12 mmol); I2, 1.30 g (5.12 mmol). Radial chromatography (4 mm plate, 7:3 petroleum ether-Et 2 0) of the crude product, followed by distillation (90-120°C/8 torr) of the acquired oil from a small piece of Cu wire, afforded 400.4 mg (56%) of 30a, a colorless oil that was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). The spectral data of 30a are as follows: IR (neat): 3315 (br), 3060 (w), 1618, 1435, 1281, 1135, 1013, 774 cm"1. lB N M R (CDC13, 400 MHz) 8: 1.57 (t, IH, J = 5.5 Hz, exchanges with D 2 0 , OH), 1.95 (d, 3H, J = 1.5 Hz, H-4), 4.23 (br d, 2H, J = 5.5 Hz, simplified to br s upon addition of D 2 0 , H- l ) , 5.94-5.98 (m, IH, H-3). In decoupling experiments, irradiation at 8 4.23 (H-l) simplified the signal at 5.94-5.98 (H-3) to a q, J = 1.5 Hz. In NOE difference experiments, irradiation at 8 1.95 (H-4) caused signal enhancement at 5.94-5.98 (H-3); irradiation at 8 5.94-5.98 (H-3) caused signal enhancement at 1.95 (H-4). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 21.6 (C-4), 68.1 (-ve, C - l ) , 74.8 (C-3), 146.0 (-ve, C-2). Exact mass calcd for C4H7IO: 197.9542. Found: 197.9546. Anal, calcd for C4H7IO: C 24.26, H 3.56. Found: C 24.36, H 3.61. 214 Preparation of (Z)-3-Iodo-2-pentyl-2-propen-l-ol (30b). 8 6 4 1 57 58 Following general procedure 4 (p 212), 2-propyn-l-ol (56) was converted into (Z)-3-iodo-2-pentyl-2-propen-l-ol (30b) with the following quantities of reagents and solvents: 2-propyn-l-ol (56), 200 mg (3.57 mmol), in E t 2 0, 3.6 mL; Cul , 679 mg (3.57 mmol); C 5 HnMgBr, 2 6 4.46 mL (8.92 mmol); I2, 1.27 g (5.00 mmol). Radial chromatography (4 mm plate, 7:3 petroleum ether-Et 2 0) of the crude product and concentration of the acquired fractions gave a very polar solid (A) and two oils (B and C). Recrystallization of A from hot petroleum ether-Et20 (cooled to 0°C) afforded 11.4 mg (1.3%) of the dimer 58 as a white solid (mp 63-64°C). Brief subjection of B to reduced pressure (0.3 torr) gave 34 mg (<7.5 %) of impure alcohol 57 as a colorless oil. Radial chromatography (4 mm plate, 8:2 petroleum ether-Et20) of C and subjection of the acquired oils to reduced pressure (0.3 torr) gave 584 mg (64%) of the vinyl iodide (30b) as a colorless oil and 44.3 mg (5%) of (Z)-2-iodo-2-octen-l-ol (29), also a colorless oil (see p 210 for the spectral data of 29). Iodides 29 and 30b were stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). 215 The spectral data of the vinyl iodide 30b are as follows: IR (neat): 3335 (br), 3060 (w), 1611, 1465, 1284, 1029 cm"1. X H N M R (CDC13, 400 MHz) 8: 0.87 (t, 3H, J = 7 Hz, H-8), 1.20-1.36 (overlapping signals, 4H, H-6, H-7), 1.44-1.51 (m, 2H, H-5), 1.54 (br s, IH, exchanges with D 2 0 , OH), 2.29 (td, 2H, J = 7.5, 1 Hz, H-4), 4.24 (s, 2H, H- l ) , 6.00 (br signal, IH, H-3). In NOE difference experiments, irradiation at 8 2.29 (H-4) caused signal enhancement at 6.00 (H-3); irradiation at 8 6.00 (H-3) caused signal enhancement at 2.29 (H-4). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 14.0 (-ve, C-8), 22.4 (C-7), 27.4 (C-6), 31.4 (C-5), 35.7 (C-4), 66.9 (C-l) , 75.8 (-ve, C-3), 150.3 (-ve, C-2). Exact mass calcd for C 8 Hi 5 IO: 254.0168. Found: 254.0169. Anal, calcd for C 8 Hi 5 IO: C 37.81, H 5.95. Found: C 38.10, H 5.97. Assignable signals derived from 57: X H N M R (CDC13, 400 MHz) 8: 0.89 (t, 3H, J = 7.5 Hz, H-8), 2.04 (t, 2H, J = 8 Hz, H-4), 4.06 (s, 2H, H-l ) , 4.85 (br s, IH, H-3a or H-3b), 5.00 (br s, IH, H-3a or H-3b). IR (neat): 3322 (br), 1656 cm"1. The spectral data of the diene 58, a hygroscopic solid, are as follows: IR (KBr): 3403 (br), 3040 (w), 1627, 1467,1363, 1326, 1244,1012 cm"1. J H N M R (CDCI3, 400 MHz) 8: 0.89 (t, 6H, J = 7 Hz, H - l l , H-16), 1.20-1.52 (overlapping signals, 14H, sharpens upon addition of D 2 0 , H-8, H-9, H-10, H-13, H-14, H-15, 2 x OH), 2.17 (t, 4H, J= 7.5 Hz, H-7, H-12), 4.26 (s, 4H, H - l , H-6), 6.22 (s, 2H, H-3, H-4). Exact mass calcd for C i 6 H 3 0 O 2 : 254.2246. Found: 254.2245. 216 5.3.3.14. Preparation of (Z)-6-(fg^ButyldimethylsUoxy)-l-iodo-l-hexene (123). (A) Preparation of 6-(rm-ButyldimemyIsiloxy)-l-iodo-l-hexyne (122). 5 3 T B D M S O T B D M S O 121 122 A solution of MeLi (5.62 mmol) in E t 2 0 (3.75 mL) was added to a cold (-78°C), stirred solution of 6-(fcr?-butyldimethylsiloxy)-l-hexyne (121) (p 178) (1.09 g, 5.13 mmol) in dry E t 2 0 (51 mL). The resulting cloudy mixture was stirred for 15 min. The -78°C cooling bath was replaced with a -20°C bath and the mixture was stirred for 1.7 h, during which time the mixture became clear. Finely divided, freshly sublimed I2 (1.437 g, 5.66 mmol) was added in one portion. The I2 quickly dissolved, causing the mixture to turn yellowish brown. The -20°C bath was kept in place and was allowed to warm to r.t. over a period of 18.5 h. The reaction mixture was cooled to 0°C and a 1:1 mixture of sat. aq Na2S203 (30 mL) and sat. aq NaHC03 (30 mL) was added. The phases were separated and the aq phase was extracted with E t 2 0 (2 x 20 mL). The combined organic extracts were washed (sat. aq NaHC0 3 (20 mL), brine (20 mL)), dried (Na2S04), and concentrated. The acquired oil was filtered through -0 .5 g of basic alumina (activity 1) (fritted glass funnel, water aspirator, elution with ~5 mL of Et 2 0). The filtrate was concentrated and distillation (110-125°C/0.4 torr) of the acquired oil afforded 1.62 g (93%) of the alkyne 122 as a colorless oil. 217 The spectral data of 122 are as follows: IR: (neat): 1467, 1254,1102,1006, 838, 777 c m 1 . J H N M R (CDC13, 400 MHz) 5: 0.03 (s, 6H, Si(CH3)2), 0.88 (s, 9H, C(CH 3) 3), 1.50-1.64 (overlapping signals, 4H, H-4, H-5), 2.36 (t, 2H, J = 6.5 Hz, H-3), 3.60 (t, 2H, J = 6 Hz, H-6). 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: -7.3 (-ve, C - l ) , -5.3 (Si(CH3)2), 18.3 (-ve), 20.6 (-ve), 25.0 (-ve), 26.0 (C(CH3)3), 31.8 (-ve), 62.5 (-ve), 94.6 (-ve). Exact mass calcd for C i 2 H 2 2 I O S i ( M + - H ) : 337.0485. Found: 337.0488. Anal, calcd for C 1 2 H 2 3 IOSi : C 42.60, H 6.85. Found: C 42.80, H 6.89. (B) Preparation of (Z)-6-(ferf-Butyldimethylsiloxy)-l-iodo-l-hexene (123). Glacial acetic acid (7.9 mL) was added dropwise over a period of ~7 min to a suspension of dipotassium azodicarboxylate104 (5.08 g, 26.15 mmol) and 6-(?erf-butyldimethylsiloxy)-l-iodo-l-hexyne (122) (p 216) (422 mg, 1.25 mmol) in dry MeOH (12.5 mL). The slow addition of acid caused the reaction mixture to gently reflux, and when the addition was complete, the reaction mixture became a thick emulsion. After the emulsion had been stirred for 3 min, n-pentane (24 mL) and water (24 mL) were added and the phases were separated. The organic phase was 122 123 218 washed (water (4 x 16 mL) (the pH of the final water washing was neutral)), dried (Na2S04), and concentrated. Radial chromatography (4 mm plate, 8:2 petroleum ether-Et20) of the crude product, followed by subjection of the acquired oil to reduced pressure (0.3 torr) afforded 283 mg (67%) of 123 as a colorless oil. The vinyl iodide was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). The spectral data of 123 are as follows: IR: (neat): 1610, 1467, 1254, 1102, 838, 776 cm - 1 . X H N M R (CDC13, 400 MHz) 5: 0.04 (s, 6H, Si(CH3)2), 0.88 (s, 9H, C(CH 3) 3), 1.42-1.60 (overlapping signals, 4H, H-4, H-5), 2.13 (td, 2H, J = 6.5, 6.5 Hz, H-3), 3.60 (t, 2H, J = 6 Hz, H-6), 6.11-6.19 (overlapping signals, 2H, H - l , H-2). In a decoupling experiment, irradiation at 8 2.13 (H-3) simplified the signal at 6.11-6.19 (H - l , H-2) to two doublets (J= 11.5 Hz). 1 3 C N M R (CDC13, 50.3 MHz) 8: -5.3, 18.3, 24.3, 26.0, 32.2, 34.4, 62.8, 82.3, 141.2. Exact mass calcd for CnH 2 2 IOSi (M + -CH 3 ) : 325.0485. Found: 325.0488. Anal, calcd for C i 2 H 2 5 I O S i : C 42.35, H 7.40. Found: C 42.56, H 7.48. 219 5.3.3.15. Preparation of (£)-6-(rg^Butyldimethylsiloxy')-l-iodo-l-hexene (124). T B D M S O T B D M S O 5 3 ' \ 2 121 124 A solution of 6-(?ert-butyldimethylsiloxy)-l-hexyne (121) (p 178) (475 mg, 2.24 mmol) in dry CH2Q2 (6.4 mL) was cannulated into a r.t. suspension of bis(cyclopentadienyl)zirconium chloride hydride170 ((ri5-C5H5)2ZrH(Cl)) (748 mg, 2.90 mmol) in CH 2C1 2 (5.2 mL). The resulting clear, yellow solution was stirred for 1 h. Finely divided, freshly sublimed I2 (1.13 g, 4.45 mmol) was added and the resulting dark wine solution was stirred for 3.7 h. Sat. aq N a 2 S 2 0 3 (10 mL), sat. aq NH4CI (200 mL), and CH2CI2 (200 mL) were added (these volumes were necessary to break the initially formed emulsion) and the layers were separated. The organic phase was washed (sat. aq NFI4CI (2 x 100 mL)) and dried (Na 2S0 4). Concentration of the organic phase gave a solid / oil mixture. Petroleum ether (~10 mL) was added and the suspension was stored in a refrigerator (~9°C) for 1 h in order to cause further precipitation of dissolved salts. The solution was removed and the salt was washed with cold petroleum ether ( 3 x 1 mL). The organic layers were combined and concentrated. Radial chromatography (2 mm plate, 96:4 petroleum ether-Et20) of the crude product, followed by distillation (120-140/0.2 torr) of the acquired oil from a small piece of Cu wire afforded 559.1 mg (74%) of 124 as a slightly yellow oil. The vinyl iodide was stored over Cu wire, under an Ar atmosphere, in a refrigerator (~9°C). 220 The spectral data of 124 are as follows: IR (neat): 1472,1256,1105, 837, 776 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.04 (s, 6H, Si(CH3)2), 0.88 (s, 9H, C(CH 3) 3), 1.38-1.57 (overlapping signals, 4H, H-4, H-5), 2.07 (tdd, 2H, J = 7.5, 7.5, 1 Hz, H-3), 3.59 (t, 2H, J = 6 Hz, H-6), 5.98 (dt, IH, J= 14.5, 1 Hz, H- l ) , 6.50 (dt, IH, J= 14.5, 7.5 Hz, H-2). 1 3 C N M R (CDC13, 50.3 MHz) 8: -5.3, 18.3, 24.7, 26.0, 32.0, 35.8, 62.8, 74.5, 146.6. Exact mass calcd for Ci 2 H 2 5 IOSi : 340.0719. Found: 340.0724. Anal, calcd for Ci 2 H 2 5 IOSi : C 42.35, H 7.40. Found: C 42.23, H 7.34. 221 5.3.4. Cyclopropanes. 5.3.4.1. Cyclopropanation Reactions. General Procedure 5. NOTE: The cyclopropanation reactions were best carried out in standard tapered 14/20 2-neck round-bottom flasks fitted with natural rubber septa (from Aldrich Chemical Co.) or in Schlenk round-bottom flasks, both under a positive pressure of dry Ar. Neat Et 2Zn (CAUTION: neat Et 2Zn is pyrophoric) was transferred via gas-tight syringe.60"63 Needle-tipped cannulae were used for gas-tight cannulation of solutions. Syringes, needles, and cannulae were oven-dried and/or thoroughly flushed with dry Ar prior to their use. In the following procedure, all given amounts are related to the use of 1 mmol of the iodo alkene. A stirred solution of Et 2Zn (2-5 mmol) in dry, degassed C1CH2CH2C1 (~5 mL) was cooled to 0°C and C1CH2I (4-10 mmol) was added by use of a gas-tight syringe. After the mixture had been stirred at 0°C for 5 min, a solution of the iodo alkene in dry, degassed C1CH2CH2C1 (-1.5 mL) (or benzene, in the case of 26e (p 232) (-1.5 mL)) was added via cannula. Stirring at 0°C was continued for the specified time (vide infra). A 1:1 mixture of sat. aq Na2S 203 and sat. aq NH4CI (-2 mL) was added. The mixture was allowed to warm to r.t. and was then diluted with CH 2C1 2 (-15-20 mL) and sat. aq NH4CI (-15-20 mL). The phases were separated and the aq layer was extracted with CH 2C1 2 (3 x 15 mL). The combined organic extracts were washed (water (-15-20 mL), brine (-15-20 mL)), dried (Na2SO.O, and concentrated. Purification of the crude product (chromatography, distillation) provided the iodocyclopropane. 222 Preparation of m-l-Ethyl-2-(hydroxymethylM-iodocyclopropane (60a). H-3a OH 6 H 2 OH H-3b 4 26a 60a Following general procedure 5 (p 221), (Z)-3-iodo-2-penten-l-ol (26a) (p 197) was converted into cw-l-ethyl-2-(hydroxymethyl)-l-iodocyclopropane (60a) employing a reaction time of 10 min and the following quantities of reagents and solvents: Et2Zn, 0.56 mL (5.46 mmol), in C1CH2CH2C1, 16 mL; C1CH2I, 0.82 mL (11.2 mmol); (Z)-3-iodo-2-penten-l-ol (26a), 577 mg (2.72 mmol), in C1CH2CH2C1, 2.0 mL. Radial chromatography (2 mm plate, 85:15 CCI4-EtOAc) of the crude product, followed by distillation (65-85°C/0.3 torr) of the acquired oil, afforded 537 mg (87%) of the iodocyclopropane 60a as a colorless oil. The spectral data of 60a are as follows: IR (neat): 3345 (br), 1453, 1161,1077,1041, 819 cm"1. *H N M R (CDCI3, 400 MHz) 8: 0.44-0.54 (m, IH, H-2), 0.88 (br dd, IH, J = 6.5, 6.5 Hz, H-3b), 0.99 (dd, slight overlap with downfield signal, IH, J = 9.5, 6.5 Hz, H-3a), 1.04 (dd, slight overlap with upfield signal, 3H, J = 7, 7 Hz, H-6), 1.52 (dq, IH, J = 14, 7 Hz, H-5a), 1.71 (dqd, IH, J = 14, 7, 0.5 Hz, H-5b), 1.80 (br s, IH, exchanges with D 2 0 , OH), 3.47 (dd, IH, J = 12, 9 Hz, H-4), 3.96 (br dd, IH, J = 12, 4 Hz, sharpens upon addition of D 2 O , H-4). See Table 16 on p 224 for further N M R data. 223 In NOE difference experiments (C 6D 6 , 400 MHz), irradiation at 5 0.13 (H-2) increased the intensity of the signals at 0.50 (H-3a), 1.14 (H-5a), 1.38 (H-5b), 3.41 (H-4a), and 3.71 (H-4b); irradiation at 8 1.14 (H-5a) increased the intensity of the signals at 0.09-0.19 (H-2), 0.50 (H-3a), 0.89 (H-6), and 1.38 (H-5b); irradiation at 8 1.38 (H-5b) increased the intensity of the signals at 0.09-0.19 (H-2), 0.50 (H-3a), 0.89 (H-6), and 1.14 (H-5a); irradiation at 8 3.71 (H-4b) caused signal enhancement at 0.09-0.19 (H-2), 0.58 (H-3b), and 3.41 (H-4a). 1 3 C N M R (CDC13, 50.3 MHz) 8: 13.7, 20.4, 21.7, 26.3, 39.1, 69.5. Exact mass calcd for C 6 HnIO: 225.9855. Found: 225.9854. Anal, calcd for C 6 H n I O : C 31.88, H 4.90,1 56.14. Found: C 32.00, H 4.94,1 55.93. 224 Table 16: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60a (in C6D6). ' H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.09-0.19 (m, IH) H-2 H-3a, H-3b, H-4a, H-4b 26.5 (-ve), C-2 0.50 (dd, IH, 7= 9.5, 6 Hz) H-3a fe H-2, H-3b 21.8, C-3 0.58 (dd, 1H,7=6, 6 Hz) H-3b H-2, H-3a 21.8, C-3 0.89 (dd, 3H, 7=7 , 7 Hz) H-6 H-5a, H-5b 13.8 (-ve), C-6 1.14 (dq, 1H,7= 14, 7 Hz) H-5a H-5b, H-6 39.2, C-5 1.38 (dq, 1H,7= 14, 7 Hz) H-5b H-5a, H-6 39.2, C-5 1.99 (br s, IH, exchanges with D 2 0) OH H-4a, H-4b N/A 3.41 (m, IH, collapses to dd, J = 11.5, 9 Hz, upon addition of D 2 0) H-4a H-2, H-4b, OH 69.4, C-4 3.71 (m, IH, collapses to dd, J = 11.5, 6 Hz, upon addition of D 2 0) H-4b H-2, H-4a, OH 69.4, C-4 N/A N/A N/A 20.7, C - l c fl This column organizes the 1 3C signals according to their correlation to the XH signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. The assignment is based on the general observation that J cis ^ ^ trans for cyclopropyl protons. c The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 225 Preparation of c^-2-(Hydroxymemyl)-l-iodo-l-pentylcyclopropane (60b). H-3a H-3a H-3b H-3b .OH H 2 OH H 2 OMe 4 4 26b 60b 63b Following general procedure 5 (p 221), (Z)-3-iodo-2-octen-l-ol (26b) (p 188, 198, 202) was converted into cw-2-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (60b) employing a reaction time of 10 min and the following quantities of reagents and solvents: Et 2Zn, 0.572 mL (5.58 mmol), in C1CH2CH2C1, 14.3 mL; C1CH2I, 0.813 mL (11.16 mmol); (Z)-3-iodo-2-octen-l-ol (26b), 710 mg (2.79 mmol), in C1CH2CH2C1, 4.0 mL. Radial chromatography (4 mm plate, 7:3 petroleum ether-Et20) of the crude material afforded two oils A and B. Distillation (95-115°C/0.3 torr) of A gave 622 mg (83%) of 60b as a colorless oil. Subjection of B to reduced pressure (0.3 torr) gave 36 mg (<5%) of impure methyl ether 63b. The spectral data of cis-1-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (60b) are as follows: IR (neat): 3325 (br), 1466, 1397, 1379, 1195, 1161, 1040, 727 cm"1. X H N M R (CDC13,400 MHz) 5: 0.45-0.56 (m, IH, H-2), 0.84-0.91 (m, 4H, H-3b, H-9), 0.99 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.18-1.41 (m, 4H), 1.41-1.58 (m, 3H), 1.62-1.72 (m, IH), 1.85 (br s, IH, exchanges with D2O, OH), 3.48 (m, IH, sharpens to a dd, J = 12, 9 Hz, upon addition of D 2 0 , H-4), 3.95 (m, IH, changes to a dd, J = 12, 5 Hz, upon addition of D 2 0 , H-4). See Table 17 on p 226 for further N M R data. 1 3 C N M R (CDCI3, 50.3 MHz) 8: 14.0,18.7, 21.8, 22.6, 26.3, 29.2, 30.9, 45.6, 69.5. 226 Exact mass calcd for C 9 H i 7 I O : 268.0324. Found: 268.0322. Anal, calcd for C 9 H 1 7 I O : C 40.31, H 6.39,147.33. Found: C 40.50, H 6.46,147.11. Table 17: XU N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60b (in C 6 D 6 ) . ' H N M R 8 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.08-0.17 (m, IH) H-2 H-3a, H-3b, H-4a, H-4b 26.6 (-ve), C-2 0.53 (dd, IH, 7= 9.5, 6.5 Hz) H-3a fe H-2, H-3b 21.8, C-3 0.58 (dd, IH, 7= 6.5, 6.5 Hz) H-3b H-2, H-3a 21.8, C-3 0.86 (t, 3 H , 7 = 7 H z ) H-9 H-8 14.2 (-ve), C-9 1.04-1.24 (overlapping signals, 5H) H-5a, C H 2 protons H-5b, H-9, 1.36-1.51 45.8, C-5; 22.9, 31.1 1.29 (br signal, IH, exchanges with D 2 0) OH No correlation N/A 1.36-1.51 (overlapping signals, 3H) H-5b, C H 2 protons H-5a, 1.04-1.24 45.8, C-5; 29.5 3.36 (dd, 1H,7= 11.5, 8.5 Hz) H-4a H-4b, H-2 69.4, C-4 3.70 (dd, 1H,7= 11.5, 5 Hz) H-4b H-4a, H-2 69.4, C-4 N/A N/A N/A 19.8, C - l c " This column organizes the 1 3C signals according to their correlation to the *H signals as given by the H M Q C experiment. The quaternary carbon is listed in the final row of the table. The assignment is based on the general observation that J cis ^ ^ trans for cyclopropyl protons. c The assignment is based on the results of the H M Q C and A P T experiments and on the chemical shift (8) value. Selected *H N M R (CeD6, 400 MHz) data of cw-2-(methoxymethyl)-l-iodo-l-pentylcyclopropane (63b) 8: 3.18 (s, 3H, OMe), 3.36 (dd, IH, J= 10, 7.5 Hz), 3.44 (dd, IH, J= 10, 6 Hz). 227 Preparation of c?5-2-(Hydroxymemyl)-l-iodo-l-(4-pentynyDcyclopropane (60c). H-3a OH 9 ^ H 2 OH H-3b 4 26c 60c Following general procedure 5 (p 221), (Z)-3-iodo-2-octen-7-yn-l-ol (26c) (p 199) was converted into cw-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c) employing a reaction time of 10 min and the following quantities of reagents and solvents: Et2Zn, 0.222 mL (2.17 mmol), in C1CH2CH2C1, 5.4 mL; C1CH2I, 0.315 mL (4.32 mmol); (Z)-3-iodo-2-octen-7-yn-l -ol (26c), 271 mg (1.08 mmol), in C1CH2CH2C1, 1.54 mL. Sequential radial chromatography (2 mm and 1 mm plates, 3:2 hexanes-Et20) of the crude product, followed by distillation (110-140°C/0.3 torr) of the acquired liquid from Cu wire, afforded 145 mg (51%) of the iodocyclopropane 60c as a colorless oil. The spectral data of 60c are as follows: IR (neat): 3297 (br), 3060 (w), 2116,1432,1179, 1082, 1039, 638 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.51-0.62 (m, IH, H-2), 0.89 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 1.04 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.55-1.83 (m, 4H, H-5, H-6), 1.87 (br s, IH, exchanges with D2O, OH), 1.92 (t, IH, J = 2.5 Hz, H-9), 2.18-2.29 (m, 2H, H-7), 3.48 (dd, IH, J = 12, 9 Hz, H-4a), 3.95 (dd, IH, J = 12, 5 Hz, H-4b). See Table 18 on p 228 for further N M R data. 1 3 C N M R (CDCI3, 50.3 MHz) 8: 17.2,17.3, 21.7, 26.2, 28.4, 44.0, 68.9, 69.4, 83.9. Exact mass calcd C9H0IO: 264.0011. Found 264.0009. Anal, calcd for C 9 H 1 3 IO: C 40.93, H 4.96,148.05. Found: C 40.75, H 5.04,147.95. 228 Table 18: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60c (C 6D 6). X H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.08-0.18 (m, IH) H-2 H-3a, H-3b, H-4a, H-4b 26.4 (-ve), C-2 0.44-0.55 (m, 2H) H-3a, H-3b H-2 21.7, C-3 1.12-1.22 (m, IH) H-5a H-5b, H-6 44.2, C-5 1.43-1.62 (overlapping signals, 4H) H-5b, H-6, OH H-5a, H-7, H-4a, H-4b 44.2, C-5; 28.7, C-6 1.71 (t, 1H,7=2.5 Hz) H-9 H-7 No correlation6 1.82-2.00 (m, 2H) H-7 H-9, H-6 17.3, C-7 3.24-3.34 (m, IH) H-4a H-2, H-4b, OH 69.2 or 69.3, C-4 3.60-3.70 (m, IH) H-4b H-2, H-4a, OH 69.2 or 69.3, C-4 N/A N/A N/A 69.2 or 69.3, C 9 b , c N/A N/A N/A 17.6, C-ld N/A N/A N/A 84.0, C-8 C a This column organizes the 1 3 C signals according to their correlation to the ! H signals as given by the H M Q C experiment. The quaternary carbons are listed in the final three rows of the table. The H M Q C and APT experiments were not optimized for the large lJ C -H (-250 H Z ) 1 7 1 between H-9 and C-9; thus there was no * H correlation for C-9 in the H M Q C experiment, and in the APT experiment, a positive signal rather than the expected negative signal for C-9 was observed. 0 The assignment is based on the chemical shift (8) value.67f d The assignment is based on the signal intensity, the H M Q C and APT experiments, and the chemical shift (8) value. 229 Preparation of c/5-l-G-Chloropropyl)-2-(hydroxymethyl)-l-iodocyclopropan (60d). 26d 60d 63d Following general procedure 5 (p 221), (Z)-6-chloro-3-iodo-2-hexen-l-ol (26d) (p 200) was converted into cw-l-(3-chloropropyl)-2-(hydroxyraethyl)-l-iodocyclopropane (60d) employing a reaction time of 5 min and the following quantities of reagents and solvents: Et 2Zn, 0.090mL (0.878 mmol), in C1CH2CH2C1, 2.21 mL; C1CH2I, 0.128 mL (1.76 mmol); (Z)-6-chloro-3-iodo-2-hexen-l-ol (26d), 115 mg (0.441 mmol), in C1CH2CH2C1, 0.63 mL. Sequential radial chromatography (2 mm and 2 mm plates, 2:1:1 hexane-CH 2Cl 2-Et 20) of the crude product gave two oils, A and B. Distillation (120-140°C/0.3 torr) of A afforded 88 mg (73%) of the iodocyclopropane 60d as a colorless oil. Radial chromatography (1 mm plate, 9:1 hexanes-Et20) of B, followed by distillation (75-90°C/0.3 torr) of the acquired oil, afforded 4.8 mg (4%) of the methyl ether 63d as a colorless oil. The spectral data of cw-l-(3-chloropropyl)-2-(hydroxymethyl)-l-iodocyclopropane (60d) are as follows: IR (neat): 3385 (br), 3070 (w), 1443,1398,1043, 652 cm"1. See Table 19 on p 230 for N M R data. Exact mass calcd C 7 Hi 2 3 5 ClIO: 273.9621. Found: 273.9617. Anal, calcd for C 7 H 1 2 C1I0: C 30.62, H 4.40,146.23. Found: C 30.90, H 4.49,146.00. 230 Table 19: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60d (CDCI3). *H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.54-0.65 (m, IH) H-2 H-3a, H-3b, H-4a, H-4b 26.2 (-ve), C-2 0.91 (dd, IH, J =6.5, 6.5 Hz) H-3bfc H-3a, H-2 21.7, C-3 1.06 (dd, IH, 7=9.5,6.5 Hz) H-3a H-3b, H-2 21.7, C-3 1.60-1.70 (m, IH) H-5a H-5b, H-6 42.3, C-5 1.78-1.90 (m, 2H, reduces to IH upon addition of D 2 0) H-5b, OH H-4a, H-4b, H-5a, H-6 42.3, C-5 1.96-2.09 (m, 2H) H-6 H-5a, H-5b, H-7 32.5, C-6 3.48 (brdd, 1H,7= 12, 9 Hz, sharpens upon addition of D 2 0) H-4a H-2, H-4b, OH 69.3, C-4 3.52-3.66 (m, 2H) H-7 H-6 43.7, C-7 3.98 (brdd, 1H,7= 12, 5 Hz, sharpens upon addition of D 2 0) H-4b H-2, H-4a, OH 69.3, C-4 N/A N/A N/A 16.7, C - l c a This column organizes die 1 3 C signals according to their correlation to the *H signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. b The assignment is based on the general observation that J & > J a w s for cyclopropyl protons.67b 0 The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 231 The spectral data of cw-l-(3-chloropropyl)-l-iodo-2-(memoxymethyl)cyclopropane (63d) are as follows: *H N M R (CDCI3, 400 MHz) 5: 0.50-0.60 (ra, IH, H-2), 0.87 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 1.07 (dd, IH, J = 9.5, 6 Hz, H-3a), 1.60-1.70 (m, IH, H-5a), 1.79-1.88 (m, IH, H-5b), 1.96-2.12 (m, 2H, H-6), 3.34-3.42 (overlapping signals, including a singlet centered at 8 3.39 (OMe), 4H total, H-4a), 3.54-3.68 (m, 3H, H-7, H-4b). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 21.8, 23.7, 32.5, 42.3, 43.8, 58.6, 77.2, 78.7 Exact mass calcd for C 8 H 1 4 3 5 C1I0: 287.9778. Found: 287.9772. 232 Preparation of ds-l-(4-te^Butyldimem^ (60e): Note: In this experiment, substrate 26e was dissolved in dry benzene, concentrated (water aspirator then 0.3 torr), and placed under an atmosphere of Ar prior to its use. TBDMSO 63e Following general procedure 5 (p 221), (Z)-7-(?er?-butyldimethylsiloxy)-3-iodo-2-hepten-l-ol (26e) (p 203) was converted into cw-l-(4-fe^butyldimethylsiloxybutyl)-2-(hydroxymethyl)-l-iodocyclopropane (60e) employing a reaction time of 4 min and the following quantities of reagents and solvents: Et 2Zn, 0.094 mL (0.917 mmol), in C1CH2CH2C1, 2.3 mL; C1CH2I, 0.134 mL (1.84 mmol); (Z)-7-(terf-butyldimethylsiloxy)-3-iodo-2-hepten-l-ol (26e), 170 mg (0.459 mmol), in C6H 6, 0.66 mL. Sequential radial chromatography (1 mm and 1 mm plates, 7:3 petroleum ether-Et20) of the crude product afforded two oils, A and B. Subjection of A to 233 reduced pressure (0.3 torr) gave 114 mg (82%) of 60e as a colorless oil. Flash chromatography (1 g of Sigma (Type H) silica gel, 95:5 petroleum ether-Et20) of B, and subjection of the acquired liquid to reduced pressure (0.3 torr) gave 3.7 mg (2%) of the methyl ether 63e. The spectral data of cw-l-(4-?e^butyldimethylsiloxybutyl)-2-(hydroxymethyl)-l-iodocyclopropane (60e) are as follows: IR (neat): 3377 (br), 3070 (w), 1472, 1390, 1256, 1103, 1041, 837, 776 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.03 (s, 6H, Si(CH3)2), 0.46-0.57 (m, IH, H-2), 0.77-0.95 (s with buried m, 10H, C(CH 3) 3 , H-3b), 0.99 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.44-1.73 (m, 6H, H-5, H-6, H-7), 1.86-1.93 (br signal, IH, exchanges with D 2 0 , OH), 3.48 (dd, IH, J = 12, 9 Hz, H-4a), 3.58 (t, 2H, / = 6 Hz, H-8), 3.92 (dd, IH, /= 12, 5 Hz, H-4b). See Table 20 on p 234 for further N M R data. 1 3 C N M R (CDC13, 100 MHz) 8: -5.3, 18.2, 18.4, 21.7, 25.8, 25.9, 26.2, 31.7, 45.3, 62.9, 69.2. Exact mass calcd for CioH2oI02Si (M + -C 4 H 9 ) : 327.0277. Found: 327.0276. Anal, calcd for C i 4 H 2 9 I0 2 Si : C 43.75, H 7.60,133.02. Found: C 43.89, H 7.65,132.95. 234 Table 20: X H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 60e (CeD6). *H N M R 5 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 5 (APT (50.3 MHz)), assignment (C-X) Selected H M B C data* 8 (APT (50.3 MHz)), assignment (C-X) 0.07 (s, 6H) Si(CH3)2) No correlation 5.1 (-ve), Si(CH3)2) 0.08-0.20 (m, IH) H-2 H-3a, c H-3b, H-4a, H-4b 26.6 (-ve), C-2 — 0.52 (dd, 1H, 7=9.5, 6 Hz) H-3a H-2, H-3b 21.9, C-3 18 .7 ,C - l ; r f 45.6, C-5 0.57 (dd, 1H,7=6, 6 Hz) H-3b H-2, H-3a 21.9, C-3 — 0.99 (s, 9H) (CH 3) 3C No correlation 26.2 (-ve), (CH 3) 3C 18.5, (CH^C* 1.09-1.19 (m, IH) H-5a H-5b, H-6 45.6, C-5 — 1.29 (dd, 1H,7=8, 4.5 Hz, exchanges with D 2 0) OH No correlation* N/A — 1.34-1.64 (overlapping signals, 5H) H-5b, H-6, H-7 H-5a, H-8 26.3,32.1, C-6, C-7; 45.6, C-5 — Table 20 is continued on the next page. 235 Table 20 continued. 3.36 (m, IH, simplifies to a doublet of doublets, J = 12, 9 Hz, upon addition of D 2 0) H-4a H-2, H-4b 69.4, C-4 — 3.48 (t, 2H, 7=6.5 Hz) H-8 H-7 63.1, C-8 — 3.70 (m, IH, simplifies to a doublet of doublets, J = 12, 5 Hz, upon addition o f D 2 0 ) H-4b H-2, H-4a 69.4, C-4 — N/A N/A N/A 18.5, (CH 3 ) 3 C/ — N/A N/A N/A 18.7, C-ld ~ a This column organizes the 1 3 C signals according to their correlation to the *H signals as given by the HMQC experiment. The quaternary carbons are listed in the final two rows of the table. b Two and three bond correlations. c The assignment is based on the general observation that J & > J a a m for cyclopropyl protons.67b d The assignment is based on the results of the HMBC and APT experiments and on the chemical shift (8) value. e The OH signal appeared downfield among the signals at 8 1.34-1.64 in the J H spectrum of the sample used for the COSY experiment. 236 The spectral data of d,s-l-(4-£m-butyldimemylsnoxybutyl)-l-iod propane (63e) are as follows: IR (neat): 3060 (w), 1732, 1472, 1389, 1361,1256,1106, 837, 776, 662 cm"1. *H N M R (CDCI3, 400 MHz) 5: 0.03 (s, 6H, Si(CH3)2), 0.41-0.52 (m, IH, H-2), 0.74-0.97 (overlapping multiplet and singlet, 10H, C(CH 3) 3 , H-3b), 1.02 (dd, IH, J = 9.5, 6 Hz, H-3a), 1.44-1.70 (m, 6H, H-5, H-6, H-7), 3.38 (s, 3H, OMe), 3.45 (dd, IH, J = 10.5, 7.5 Hz, H-4a), 3.53 (dd, IH, J= 10.5, 6 Hz, H-4b), 3.60 (t, 2H, J= 6.5 Hz, H-8). 1 3 C N M R (CDC13, 100 MHz) 8: -5.3, 17.6, 18.3, 22.1, 23.6, 25.8, 26.0, 31.8, 45.6, 58.6, 63.1, 78.9. Exact mass calcd for CiiH 22l0 2Si (M + -C 4 H 9 ) : 341.0434. Found: 341.0439. Preparation of ^an5-l-Ethyl-2-(hydroxymethyl)-l-iodocyclopropane (61a) 237 H-3b H-3b H-3a H-3a 6 6 HO HO MeO. 2 H 2 H 4 4 25a 61a 62a Following general procedure 5 (p 221), (Zs)-3-iodo-2-penten-l-ol (25a) (p 194) was converted into /rans-l-ethyl-2-(hydroxymethyl)-l-iodocyclopropane (61a) employing a reaction time of 12 min and the following quantities of reagents and solvents: Et 2Zn, 0.135 mL (1.32 mmol), in C1CH2CH2C1, 3.3 mL; C1CH2I, 0.191 mL (2.62 mmol); (£)-3-iodo-2-penten-l-ol (25a), 140 mg (0.660 mmol), in C1CH2CH2C1, 0.94 mL. Radial chromatography (2 mm plate, 3:2 hexanes-Et20) of the crude material afforded two oils A and B. Distillation (60-80°C/0.3 torr) of A gave 113 mg (76%) of 61a as a colorless oil. Subjection of B to reduced pressure (0.3 torr) gave 8.4 mg (<5%) of impure methyl ether 62a. Purification of combined mixtures of 62a obtained from previous cyclopropanations of (£)-3-iodo-2-penten-l-ol (25a) by radial chromatography (96:4 hexanes-Et20) and distillation (35-75°C/0.2 torr) afforded a pure sample of 62a as a colorless oil. The spectral data of frans-l-emyl-2-(hydroxymethyl)-l-iodocyclopropane (61a) are as follows: IR (neat): 3324 (br), 3080 (w), 1452, 1378,1255,1147,1098,1031, 798, 753 cm"1. *H N M R (CsDe, 400 MHz) 5: 0.05 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 0.58 (br s, IH, exchanges with D 2 0 , OH), 0.94-1.03 (overlapping signals, including a triplet (7 = 7 Hz) centered at 5 0.99 238 (H-6), 4H total, H-3a), 1.25-1.33 (m, 2H, H-5), 1.50-1.60 (m, IH, H-2), 3.00-3.15 (m, 2H, H-4). See Table 21 below for further N M R data. 1 3 C N M R (C 6D 6 , 125 MHz) 8: 13.9, 14.8, 21.7, 31.9, 33.0, 61.3. Exact mass calcd for C 6 HnIO: 225.9855. Found: 225.9854. Anal, calcd for C 6 H u I O : C 31.88, H 4.90,1 56.14. Found: C 32.09, H 4.98,1 55.80. Table 21: *H N M R (400 MHz), COSY (200 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 61a (in CDCI3). *HNMR 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.57 (dd, IH, J =6.5, 6.5 Hz) H-3bfc H-2, H-3a 21.9, C-3 1.08 (t, 3 H , / = 7 H z ) H-6 H-5 14.6 (-ve), C-6 1.26 (dd, 1H ,7=9, 6.5 Hz) H-3a H-2, H-3b 21.9, C-3 1.50 (br s, IH, exchanges with D 2 0 ) OH H-4 N/A 1.60 (q, 2H, 7= 7 Hz) H-5 H-6 32.9, C-5 1.78-1.88 (m, IH) H-2 H-3a, H-3b, H-4 31.7 (-ve),C-2 3.59-3.71 (overlapping signals, 2H) H-4 H-2, OH 61.8, C-4 N/A N/A N/A 13.2, C - l c a This column organizes the 1 3 C signals according to their correlation to tie *H signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. b The assignment is based on the general observation that J & > J a m s for cyclopropyl protons.67b ° The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 239 The spectral data of trans-l-Ethyl-l-iodo-2-(methoxymethyl)cyclopropane (62a) are as follows: IR (neat): 3080 (w), 1453, 1402, 1200,1150,1109,971,912, 794,735 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.57 (dd, IH, 7 = 6.5, 6.5 Hz, H-3b), 1.08 (t, 3H, 7 = 7 Hz, H-6), 1.27 (dd, IH, 7 = 9, 6.5 Hz, H-3a), 1.58 (q, 2H, 7 = 7 Hz, H-5), 1.76-1.88 (m, IH, H-2), 3.33 (s, slight overlap with downfield signals, 3H, OMe), 3.36-3.47 (overlapping signals, slight overlap with upfield signal, 2H, H-4a, H-4b). 1 3 C N M R (CDCI3,100 MHz) 8: 14.5, 21.9, 26.6, 29.0, 33.0, 58.4, 71.2. Exact mass calcd for C7H13IO: 240.0011. Found: 240.0022. 240 Preparation of rram-2-(Hydroxymemyl)-l-iodo-l-pentylcyclopropane (61b). H-3b H-3a 9 2 H 4 25b 61b Following general procedure 5 (p 221), (E)-3-iodo-2-octen-l-ol (25b) (p 195) was converted into rrans-2-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (61b) employing a reaction time of 10 min and the following quantities of reagents and solvents: Et2Zn, 0.143 mL (1.40 mmol), in C1CH2CH2C1, 3.5 mL; C1CH2I, 0.203 mL (2.79 mmol); (£)-3-iodo-2-octen-l-ol (25b), 177 mg (0.697 mmol), in C1CH2CH2C1, 1.0 mL. Radial chromatography (2 mm plate, 65:35 petroleum ether-Et20) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 124 mg (66%) of the iodocyclopropane 61b as a colorless oil. The spectral data of 61b are as follows: IR (neat): 3340 (br), 1450, 1150, 1030 cm"1. *H N M R (C 6D 6 , 400 MHz) 8: 0.22 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 0.86 (t, 3H, / = 7 Hz, H-9), 1.07 (ddd, slight overlap with downfield signals, IH, J = 9.5, 6.5, 0.5 Hz, H-3a), 1.10-1.70 (overlapping signals, slight overlap with upfield signals, 10H, H-5, H-6, H-7, H-8, H-2, OH), 3.24 (d, 2H, J = 1 Hz, H-4). See Table 22 on p 241 for further N M R data. 1 3 C N M R (C 6D 6 , 50.3 MHz) 8: 12.1,14.2, 22.0, 22.9, 30.4, 31.3, 31.7, 39.4, 61.4. Exact mass calcd for C 9 H 1 7 IO: 268.0324. Found: 268.0318. Anal, calcd for C9H17IO: C 40.31, H 6.39. Found: C 40.47, H 6.49. 241 Table 22: *H N M R (400 MHz), COSY (200 MHz), 1 3 C (125 MHz), and H M Q C Data for Iodocyclopropane 61b (CDCI3). *HNMR 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and HMQC* 8 (APT (50.3 MHz)), assignment (C-X) 0.56 (dd, IH, J =6.5, 6.5 Hz) H-3b H-2, H-3a 22.1, C-3 0.86 (t, 3 H , 7 = 7 H z ) H-9 H-8 14.0 (-ve), C-9 1.15-1.65 (overlapping signals, 9H) H-5, H-6, H-7, H-8, H-3a (8 1.27)fc H-2, H-3b, H-9 39.2, C-5; 22.1, C-3; 22.5, 30.0, 31.0, C-6, C-7, C-8 1.74-1.84 (m, IH) H-2 H-3a, H-3b, H-4a, H-4b 31.4 (-ve), C-2 1.88 (br s, IH, exchanges with D 2 0) OH No correlationc N/A 3.54-3.70 (overlapping signals, 2H) H-4a, H-4b H-2 61.9, C-4 N/A N/A N/A 11.6, C-\d a This column organizes the 1 3 C signals according to their correlation to the XH signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. * The COSY experiment gave an approximate chemical shift (8) value of 1.27 for H-3a. c The OH signal appeared upfield among the signals at 8 1.15-1.65 in the J H spectrum of the sample used for the COSY experiment. d The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 242 Preparation of frans-2-(Hydroxymemyl)-l-iodo-l-(4-pentynyl)cycto^ (61c). H-3b H-3a 9 ^ 2 H 4 25c 61c Following general procedure 5 (p 221), (Zs)-3-iodo-2-octen-7-yn-l-ol (25c) (p 196) was converted into trans-2-(hydroxymethyl)-1 -iodo- l-(4-pentynyl)cyclopropane (61c) employing a reaction time of 10 min and the following quantities of reagents and solvents: Et2Zn, 0.274 mL (2.67 mmol), in C1CH2CH2C1, 6.7 mL; C1CH2I, 0.390 mL (5.36 mmol); (E)-3-iodo-2-octen-7-yn-l -ol (25c), 334 mg (1.34 mmol), in C1CH2CH2C1, 1.91 mL. Sequential radial chromatography (4 mm, 1 mm, and 1 mm plates, 2:1:1 hexanes-CH2Cl2-Et20) of the crude product, followed by distillation (100-120°C/0.3 torr) of the acquired liquid from Cu wire, gave 128 mg (36%) of 61c as a colorless oil. The spectral data of 61c are as follows: IR (neat): 3296 (br), 3070 (w), 2116,1433, 1180, 1034, 637 cm"1. *H N M R (CDC13, 400 MHz) 5: 0.67 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 1.28 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.56-1.88 (m, 6H total, signal at 6 -1.63 (OH) exchanges with D 2 0 , H-5, H-6, H-2), 1.93 (t, IH, J = 2.5 Hz, H-9), 2.15-2.31 (m, 2H, H-7), 3.60-3.72 (m, 2H, H-4). See Table 23 on p 243 for further N M R data. 1 3 C N M R (CDCI3, 50.3 MHz) 5: 10.3, 17.5, 22.1, 29.2, 31.3, 37.9, 61.7, 69.0, 84.1. Exact mass calcd for C9H13IO: 264.0011. Found: 264.0016. Anal, calcd for C9H13IO: C 40.93, H 4.96,148.05. Found: C 41.12, H 5.06,147.90. 243 Table 23: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 61c (in 2:1 C6D6:CDCl3). *HNMR 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.26 (dd, IH, 7= 6.5, 6.5 Hz) H-3bfc H-2, H-3a 21.7, C-3 0.76 (br s, IH, exchanges with D 2 0) OH No correlation N/A 0.99 (dd, IH, 7= 9.5, 6.5 Hz) H-3a H-2, H-3b 21.7, C-3 1.30-1.57 (overlapping signals, overlap with downfield signals, 3H) H-5, H-2 (81.55)C H-3a, H-3b, H-6 31.2 (-ve), C-2;d 37.7, C-5d 1.57-1.68 (m, overlap with adjacent signals, 2H) H-6 H-5, H-7 29.1, C-6 1.70 (t, slight overlap with upfield signals, 1H,7 = 2.5 Hz) H-9 H-7 No correlation* 1.85-2.03 (tt, 2H , J = 7, 2.5 Hz) H-7 H-6, H-9 17.3, C-7 3.12-3.28 (m, 2H, sharpens upon addition of D 2 0) H-4 H-2 61.2, C-4 N/A N/A N/A 68.8, C -9 e > / N/A N/A N/A 10.1, C - I s N/A N/A N/A 83.7, C-tf " This column organizes die 1 3 C signals according to their correlation to the XH signals as given by the HMQC experiment. The quaternary carbons are listed in the final three rows of the table. b 67b The assignment is based on the general observation that / ^ > / trans for cyclopropyl protons. ° The COSY experiment gave an approximate chemical shift (8) value of 1.55 for H-2. d The assignments of C-2 and C-5 are based on the APT experiment and the chemical shift (8) values. e The HMQC and APT experiments were not optimized for the large lJ C -H (-250 Hz) 1 7 1 between H-9 and C-9; thus there was no *H correlation for C-9 in the HMQC experiment, and in the APT experiment, a positive signal rather than the expected negative signal for C-9 was observed. ^The assignment is based on the chemical shift (8) value.67' 8 The assignment is based on the signal intensity, the HMQC and APT experiments, and the chemical shift (8) value. 244 Preparation of (IR*. 2i?*)-l-Ethyl-2-r(5*)-l-hydroxyethyll-l-iodocyclopropane (64). H-3a H-3a H-3b H-3b 7 7 OH OH OMe 5 5 27 64 65 Following general procedure 5 (p 221), (Z)-4-iodo-3-hexen-2-ol (27) (p 206) was converted into (IR*, 2i?*)-l-ethyl-2-[(5*)-l-hydroxyethyl]-l-iodocyclopropane (64) employing a reaction time of 55 min and the following quantities of reagents and solvents: Et 2Zn, 0.124 mL (1.21 mmol), in C1CH2CH2C1, 3.1 mL; C1CH2I, 0.181 mL (2.48 mmol); (Z)-4-iodo-3-hexen-2-ol (27), 137 mg (0.606 mmol), in C1CH2CH2C1, 0.87 mL. Radial chromatography (2 mm plate, 3:2 hexanes-Et20) of the crude material afforded two oils, A and B. Distillation (70-80°C/0.3 torr) of A from Cu wire afforded 125 mg (86%) of 64 as a colorless oil which solidified as white needles when stored neat at -1°C. Flash chromatography (0.25 g of Sigma (Type H) silica gel, 95:5 hexanes-Et20) of B, and subjection of the acquired liquid to reduced pressure (20 torr), gave 5.1 mg (3%) of the methyl ether 65 as a colorless oil. The spectral data of (1/?*, 2/?*)-l-ethyl-2-[(£*)-l-hydroxyethyl]-l-iodocyclopropane 64 are as follows: IR (neat): 3355 (br), 1451,1377, 1161,1085,1047, 906, 884 cm"1. In decoupling experiments (CDCI3, 400 MHz), irradiation at 8 0.21 (H-2) simplified the signal at 1.06 (H-3a, H-3b) to a singlet and the signal at 3.43-3.51 (H-4) to a quartet, J = 6 Hz; irradiation 245 at 8 3.46 simplified the signal at 0.21 (H-2) to a triplet, J = 8 Hz, and the signal at 1.34 (H-5) to a singlet. See Table 24, below, and Table 25, on p 246, for further N M R data. 1 3 C N M R (CDC13, 50.3 MHz) 8: 13.6, 18.0, 22.2, 22.8, 31.2, 39.4, 75.5. Exact mass calcd for C 7 H 1 3 IO: 240.0011. Found: 240.0006. Table 24: *H N M R (400 MHz) and COSY (400 MHz) Data for Iodocyclopropane 64 (CDC13). *HNMR 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.21 (ddd, 1H,7=8, 8, 8 Hz) H-2 H-3a, H-3b, H-4 1.01 (dd, 3H, 7 = 7 , 7 Hz) H-7 H-6a, H-6b 1.06 (d, l H , / = 8 H z ) H-3a H-2 1.06 (d, l H , / = 8 Hz) H-3b H-2 1.34 (d, 3 H , / = 6 H z ) H-5 H-4 1.44 (dq, 1H,7= 14, 7 Hz) H-6a H-6b, H-7 1.56 (d, IH, 7= 3.5 Hz, exchanges with D 2 0) OH H-4, weak 1.75 (dq, 1H,7= 14, 7 Hz) H-6b H-6a, H-7 3.43-3.51 (m, IH, simplifies upon addition of D 2 0) H-4 H-2, H-5 246 Table 25: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 64 (CeD6). *H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 1 3 C and HMQC" 8 (APT (50.3 MHz)), assignment (C-X) (-0.22) - (-0.14) (m, IH) H-2 H-3a, H-3b, H-4 31.7 (-ve),C-2 0.58 (dd, 1H,7=9, 6 Hz) H-3a* H-2, H-3b 22.8, C-3 0.78 (dd, l H , 7 = 6 , 6 H z ) H-3b H-2, H-3a 22.8, C-3 0.85 (dd, 3 H , 7 = 7 , 7 H z ) H-7 H-6a, H-6b 13.6 (-ve), C-7 0.96 (dq, 1H,7= 14, 7 Hz) H-6a H-6b, H-7 39.6, C-6 1.13 (br s, IH, exchanges with D 2 0) OH H-4 N/A 1.26 (d, 3 H , 7 = 6 H z ) H-5 H-4 22.5 (-ve), C-5 1.46 (dq, 1H,7= 14, 7 Hz) H-6b H-6a, H-7 39.6, C-6 3.28-3.38 (m, IH, simplifies upon addition of D 2 0) H-4 H-2, H-5, OH 75.1 (-ve), C-4 N/A N/A N/A 18.3, C - l c " This column organizes the 1 3 C signals according to their correlation to the XH signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. The assignment is based on the general observation that / cis ^ J trans for cyclopropyl protons. c The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 247 The spectral data of (IR*, 2/?*)-l-ethyl-2-[(5'*)-l-memoxyethyl]-l-iodocyclopropane (65) are as follows (see p 261 for a preparation of 65): IR (neat): 3060 (w), 1451, 1334,1201,1180, 1161,1101,1033, 855, 828 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.09 (ddd, IH, J =9,9,1 Hz, H-2), 1.00 (dd, 3H, J = 7, 7 Hz, H-7), 1.10-1.20 (m, 2H, H-3a, H-3b), 1.29 (d, overlap with downfield signal, 3H, J= 6 Hz, H-5), 1.36 (dq, overlap with upfield signal, IH, J = 14, 7 Hz, H-6a), 1.78 (dq, IH, J = 14, 7 Hz, H-6b), 2.96 (dq, IH, J = 9, 6 Hz, H-4), 3.36 (s, 3H, OMe). 1 3 C N M R (CDC13, 75.4 MHz) 8: 13.6,16.7, 19.2, 24.2, 28.8, 39.5, 56.4, 83.9. LRDCTMS (NH3): M N H / (272). Exact mass calcd for C 8 Hi 5 IO: 254.0168. Found: 254.0176. 248 Preparation of trans-l-(Hydroxymemyl)-l-iodo-2-pentylcyclopropane (66). 28 66 Following general procedure 5 (p 221), (2s)-2-iodo-2-octen-l-ol (28) (p 208) was converted into rran^-l-(hydroxymethyl)-l-iodo-2-pentylcyclopropane (66) employing a reaction time of 15 min and the following quantities of reagents and solvents: Et2Zn, 0.716 mL (6.99 mmol), in C1CH2CH2C1, 7.3 mL; C1CH2I, 1.02 mL (14.0 mmol); (E)-2-iodo-2-octen-l-ol (28), 355 mg (1.40 mmol), in C1CH2CH2C1, 2.0 mL. Radial chromatography (4 mm plate, 7:1:2 hexanes-CH 2C1 2 -Et 20) of the crude product afforded 244 mg of an inseparable mixture of the starting material 28 (minor) and the iodocyclopropane 66 (major). To a solution of this material in dry CH 2C1 2 (10 mL) were added imidazole (164 mg) and Me3SiCl (0.195 mL) and the mixture was stirred at r.t. for 1 h. Sat. aq NaHCC»3 (10 mL) was added, the phases were separated, and the aq phase was extracted with CH 2C1 2 (2 x 10 mL). The combined extracts were dried (Na2SC>4) and concentrated. The resultant mixture of the trimethylsilyl ethers of 28 and 66 (A and B, respectively) were separated by means of sequential radial chromatography (4 mm, 2 mm, and 2 mm plates, 94:6 hexanes-CH2Cl2). A solution of the ether A in 2% AcOH in MeOH (10 mL) was stirred for 10 min. Sat. aq NaHC03 (10 mL) was added and the phases were separated. The aq phase was extracted with CH 2C1 2 ( 3 x 5 mL) and the combined extracts were washed (brine), 249 dried (Na 2S0 4), and concentrated. Radial chromatography (2 mm plate, 7:1:2 hexanes-CH2Cl2-Et 2 0) of the remaining material and subjection of the acquired liquid to reduced pressure (0.3 torr) gave 20 mg (6%) of the starting material 28 as a colorless oil. Similarly, a solution of the ether B in 2% AcOH in MeOH (10 mL) was stirred for 10 min. Sat. aq NaHC03 (10 mL) was added and the phases were separated. The aq phase was extracted with CH 2C1 2 ( 3 x 5 mL) and the combined extracts were washed (brine), dried (Na 2S0 4), and concentrated. Radial chromatography (2 mm plate, 7:1:2 hexanes-CH2Cl2-Et20) of the remaining material and distillation (110-140°C/0.3 torr) of the acquired liquid gave 116 mg (31%) of 66 as a colorless oil. The spectral data of 66 are as follows: IR (neat): 3404 (br), 3060 (w), 1466, 1379, 1140, 1045 cm"1. 'H N M R (CDC13, 400 MHz) 5: 0.59 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 0.89 (t, 3H, J = 7 Hz, H-9), 1.15-1.36 (m, 6H), 1.36-1.47 (m, 2H), 1.47-1.57 (m, IH), 1.57-1.69 (m, IH), 1.83 (t, IH, J - 6.5 Hz, exchanges with D2O, OH), 3.49 (dd, IH, / = 12.5, 6.5 Hz, sharpens to a d, J = 12.5 Hz, upon addition of D2O, H-4a), 3.68 (dd, IH, J = 12.5, 6.5 Hz, sharpens to a d, J = 12.5 Hz, upon addition of D2O, H-4b). See Table 26 on p 250 for further N M R data. 1 3 C N M R (CDCI3, 50.3 MHz) 8: 14.0,14.8, 22.0, 22.5, 28.7, 28.9, 29.9, 31.6, 70.0. Exact mass calcd for C9H17IO: 268.0324. Found: 268.0332. Anal, calcd for C 9 H n I O : C 40.31, H 6.39,147.33. Found: C 40.23, H 6.33,147.05. 250 Table 26: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 66 (C6D6). *HNMR 5 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 1 3 C and HMQC" 8 (APT (50.3 MHz)), assignment (C-X) 0.12 (dd, IH, 7= 6.5, 6.5 Hz) H-3bfe H-2, H-3a 21.8, C-3 0.80-0.94 (overlapping signals, including a triplet, 7=7 Hz, centered at 8 0.84, 4H) H-5a, e H-9 (8 0.84) 1.03-1.37 14.1 (-ve), C-9; 28.8, C -5 C 0.98 (dd, 1H,7=9,6 .5 Hz) H-3a H-2, H-3b 21.8, C-3 1.03-1.37 (overlapping signals, 8H) H-2 (8 1.34)/ H-5b, c H-6, H-7, H-8 H-3a, H-3b, H-5a, c H-9 30.1 (-ve), C-2; 28.8, C -5; c 22.8, 29.1,31.8, C-6, C-7, C-8 1.40 (dd, l H , 7 = 7 , 6 H z , exchanges with D 2 0) OH H-4a, H-4b N/A 3.12 (dd, 1H,7= 13, 7 Hz) H-4a H-4b, OH 69.8, C-4 3.41 (dd, 1H,7 = 13, 6 Hz) H-4b H-4a, OH 69.8, C-4 N/A N/A N/A 14.8, C - l e a This column organizes the 1 3 C signals according to their correlation to the ! H signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. The assignment is based on the general observation that J cis ^ J trans for cyclopropyl protons. c The assignment is uncertain. d The COSY experiment gave an approximate chemical shift (8) value of 1.34 for H-2. e The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 251 Preparation of c/5-l-(Hydroxymemyl)-l-iodo-2-pentylcyclopropane (67). H-3b H-3b r 1 r 1 OMe H-3a 4 4 29 67 68 Following general procedure 5 (p 221), (Z)-2-iodo-2-octen-l-ol (29) (p 210) was converted into cw-l-(hydroxymethyl)-l-iodo-2-pentylcyclopropane (67) employing a reaction time of 1 h and the following quantities of reagents and solvents: Et 2Zn, 0.230 mL (2.24 mmol), in C1CH2CH2C1, 3.0 mL; C1CH2I, 0.325 mL (4.46 mmol); (Z)-2-iodo-2-octen-l-ol (29), 143 mg (0.563 mmol), in C1CH 2CH 2C1,0.80 mL. Radial chromatography (2 mm plate, 4:1 hexanes-Et20) of the crude material afforded two oils, A and B. Distillation (110-130°C/0.3 torr) of A afforded 117 mg (78%) of 67 as a colorless oil. Flash chromatography (1.2 g of Sigma (Type H) silica gel, 96:4 hexanes-Et20) of B, and distillation (70-90°C/0.3 torr) of the acquired liquid, afforded 18.2 mg (11%) of the methyl ether 68 as a colorless oil. The spectral data of ds-l-(hydroxymethyl)-l-iodo-2-pentylcyclopropane (67) are as follows: IR (neat): 3354 (br), 3070 (w), 1456, 1166, 1041,725, 594 cm"1. *H N M R (CDCI3, 400 MHz) 8: 0.23-0.36 (m, IH, H-2), 0.74 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 0.89 (t, 3H, / = 7 Hz, H-9), 1.11 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.20-1.54 (overlapping signals, 8H, H-5, H-6, H-7, H-8), 1.89 (t, IH, J = 6.5 Hz, exchanges with D 2 0 , OH), 3.46 (dd, IH, J = 12, 6.5 Hz, simplifies to a d, J = 12 Hz, upon addition of D2O, H-4a), 3.61 (dd, IH, J = 12, 6.5 Hz, simplifies to a d, J = 12 Hz, upon addition of D 2 0 , H-4b). 252 See Table 27 below for further N M R data. 1 3 C N M R (CDCI3, 100 MHz) 5: 14.0, 21.4, 22.6, 22.8, 23.4, 28.4, 31.6, 36.2, 74.6. Exact mass calcd for C9H17IO: 268.0324. Found: 268.0330. Anal, calcd for C 9 H 1 7 IO: C 40.31, H 6.39,147.33. Found: C 40.41, H 6.33,147.11. Table 27: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 67 (C 6D 6). X H N M R 5 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C a 8 (APT (50.3 MHz)), assignment (C-X) (-0.06) - (0.04) (m, IH) H-2 H-3a,H-3b, H-5 22.4 (-ve), C-2 0.51 (dd, l H , 7 = 6 , 6 H z ) H-3b fc H-2, H-3a 21.0, C-3 0.79 (dd, IH, J =9.5, 6 Hz) H-3a H-2, H-3b 21.0, C-3 0.87 (t, 3 H , 7 = 7 H z ) H-9 H-8 14.2 (-ve), C-9 1.14-1.50 (overlapping signals, 9H) H-5, H-6, H-7, H-8, OH H-2, H-9 23.0, 28.7, 31.9, 36.6, C-5, C-6, C-7, C-8 3.23 (dd, 1H,7= 12, 8 Hz, simplifies to a doublet, 7=12 Hz, upon addition of D 2 0) H-4a H-4b, OH 73.9, C-4 3.40 (dd, 1H,7= 12, 6.5 Hz, simplifies to a doublet, 7=12 Hz, upon addition of D 2 0) H-4b H-4a, OH 73.9, C-4 N/A N/A N/A 23.4, C - l c a This column organizes the 1 3 C signals according to their correlation to the XH signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. b The assignment is based on the general observation that J > J trans for cyclopropyl protons.67b ° The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 253 The spectral data of ds-l-(methoxymethyl)-l-iodo-2-pentylcyclopropane (68) are as follows: IR (neat): 3080 (w), 1456,1379,1195, 1173, 1113 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.23-0.35 (m, IH, H-2), 0.73 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 0.89 (t, 3H, J = 1 Hz, H-9), 1.11 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.25-1.60 (overlapping signals, 8H, H-5, H-6, H-7, H-8), 3.33 (d, IH, J = 11 Hz, H-4a), 3.49 (s, 3H, OMe), 3.52 (d, IH, J = 11 Hz, H-4b). 1 3 C N M R (CDCI3, 100 MHz) 8: 14.1, 16.5, 21.3, 22.6, 22.7, 28.3, 31.6, 36.2, 58.4, 83.3. Exact mass calcd for C10H19IO: 282.0481. Found: 282.0478. 254 Preparation of c^-l-(Hydroxymethyl)-2-iodo-l-methylcyclopropane (69a). H-3a H-3b OH 4 OH 30a 69a Following general procedure 5 (p 221), (Z)-3-iodo-2-methyl-2-propen-l-ol (30a) (p 213) was converted into cw-l-(hydroxymethyl)-2-iodo-l-methylcyclopropane (69a) employing a reaction time of 30 min and the following quantities of reagents and solvents: Et2Zn, 0.237 mL (2.31 mmol), in C1CH2CH2C1, 5.8 mL; C1CH2I, 0.337 mL (4.63 mmol); (Z)-3-iodo-2-methyl-2-propen-l -ol (30a), 229 mg (1.16 mmol), in C1CH2CH2C1, 1.65 mL. Radial chromatography (1 mm plate, 7:3 petroleum ether-Et20) of the crude product and distillation (110-130°C/8 torr) of the acquired oil afforded 158.1 mg (65%) of the iodocyclopropane 69a as a colorless oil. The spectral details of 69a are as follows: IR (neat): 3364 (br), 3060 (w), 1460,1440,1296,1186, 1036,904 cm"1. See Table 28 on p 255 for N M R data. Exact mass calcd for C 5 H 9 IO: 211.9698. Found: 211.9698. Anal, calcd for C 5 H 9 IO: C 28.32, H 4.28. Found: C 28.34, H 4.32. 255 Table 28: *H N M R (400 MHz), COSY (200 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 69a (CeD6). X H N M R 8 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 1 3 C a n d H M Q C f l 8 (AFT (50.3 MHz)), assignment (C-X) 0.44 (dd, IH, 7=6 , 5 Hz) H-3bfe H-2, H-3a, H-5 (very weak) 21.5, C-3 0.56 (dd, IH, 7=8 , 6 Hz) H-3a H-2, H-3b, H-5 (very weak) 21.5, C-3 0.91 (br signal, 3H) H-5 H-2, H-3a, H-3b, H-4a (all weak) 19.4 (-ve), C-5 1.98 (ddd, overlap with downfield signal, IH, 7 = 8 , 5 , 0.5 Hz) H-2 H-3a, H-3b, H-5 (weak) -3.8 (-ve), C-2 C 2.01 (br s, overlap with upfield signal, IH, exchanges with D 2 0) OH H-4a, H-4b N/A 3.40 (brd, 1H,7= 11.5 Hz, sharpens with D 2 0) H-4a H-4b, H-5 (weak), OH 71.7, C-4 3.53 (brd, 1H,7= 11.5 Hz, sharpens with D 2 0) H-4b H-4a, OH 71.7, C-4 N/A N/A N/A 21.9 , .C - l d a This column organizes tie 1 3 C signals according to their correlation to the *H signals as given by the HMQC experiment. The quaternary carbon is listed in the final row of the table. b The assignment is based on the general observation that J ^ > J titm for cyclopropyl protons.67b c The assignment is based on the chemical shift (8) value483 and on the APT experiment. d The assignment is based on the results of the HMQC and APT experiments and on the chemical shift (8) value. 256 Preparation of ds-l-(Hydroxymemyl)-2-iodo-l-pentylcyclopropane (69b). H-3a OH ^H-3b 4^0H H 2 I 30b 69b Following general procedure 5 (p 221), (Z)-3-iodo-2-pentyl-2-propen-l-ol (30b) (p 214) was converted into ds-l-(hydroxymethyl)-2-iodo-l-pentylcyclopropane (69b) employing a reaction time of 55 min and the following quantities of reagents and solvents: Et2Zn, 0.163 mL (1.59 mmol), in C1CH2CH2C1, 2.0 mL; C1CH2I, 0.231 mL (3.17 mmol); (Z)-3-iodo-2-pentyl-2-propen-l -ol (30b), 101 mg (0.397 mmol), in C1CH2CH2C1, 1.14 mL. Radial chromatography (2 mm plate, 4:1 petroleum ether-Et20) of the crude product and distillation (95-110°C/0.2 torr) of the acquired oil afforded 50 mg (47%) of the iodocyclopropane 69b as a colorless oil. The spectral data of 69b are as follows: IR (neat): 3375 (br), 3060 (w), 1466, 1184,1044 cm"1. X H N M R (CDC13, 400 MHz) 8: 0.71 (dd, IH, J = 6, 5 Hz, H-3b), 0.85 (t, IH, J = 1 Hz, H-9), 1.06 (dd, IH, J = 8, 6 Hz, H-3a), 1.11-1.47 (overlapping signals, 7H, H-5a, H-6, H-7, H-8), 1.62-1.80 (overlapping signals, simplified upon addition of D 2 0, 2H, H-5b, OH), 2.37 (ddd, IH, J = 8, 5, 0.5 Hz, H-2), 3.50 (d, IH, J= 12 Hz, H-4a), 3.85 (d, IH, J = 12 Hz, H-4b). See Table 29 on p 257 for further N M R data. 1 3 C N M R (CDCI3, 50.3 MHz) 8: -4.4,14.0, 20.3, 22.6, 26.0, 26.1, 32.0, 33.0, 69.3. 257 Exact mass calcd for C 9 H i 7 I O : 268.0324. Found: 268.0322. Anal, calcd for C 9 H 1 7 I O : C 40.31, H 6.39. Found: C 40.13, H 6.29. Table 29: J H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Iodocyclopropane 69b (C 6D 6). *HNMR 8 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.43 (dd, 1H, 7=6 , 5 Hz) H-3bfe H-2, H-3a 20.4, C-3 0.62 (dd, 1H,7=8, 6 Hz) H-3a H-2, H-3b 20.4, C-3 0.84 (t, l H , 7 = 7 H z ) H-9 H-8 14.3 (-ve), C-9 0.93-1.30 (overlapping signals, 7H) H-5a, H-6, H-7, H-8 H-5b, H-9 33.2, C-5; 22.9, 26.1,32.3, C-6, C-7, C-8 1.36-1.46 (m, IH) H-5b H-5a, H-6 33.2, C-5 1.71 (br s, IH, exchanges with D 2 0) OH H-4a (weak), H-4b N/A 2.06 (ddd, IH, J= 8, 5,0.5 Hz) H-2 H-3a, H-3b, H-4b -4.0 (-ve), C-2 C 3.43 (brd, 1H,7 = 11.5 Hz, sharpens addition of D 2 0) H-4a H-4b, OH (weak) 69.4, C-4 3.64 (brdd, 1H,7= 11.5, 4 H z , collapses to a doublet, J = 11.5 Hz, upon addition of D 2 0) H-4b H-2, H-4a, OH 69.4, C-4 N/A N/A N/A 25.8, C-ld " This column organizes the 1 3C signals according to their correlation to the *H signals as given by the H M Q C experiment. The quaternary carbon is listed i n the final row of the table. * The assignment is based on the general observation that J as > J trans for cyclopropyl protons. 6 7 b c The assignment is based on the chemical shift (5) v a l u e 4 8 3 and on the A P T experiment. d The assignment is based on the results of the H M Q C and A P T experiments and on the chemical shift (8) value. 258 Preparation of ds-2-(Hydroxymemyl)-l-penlyl-l-trimethylsu^ (72) (see p 266 for an alternative preparation). Following general procedure 5 (p 221), (Z)-3-trimethylstannyl-2-octen-l-ol (35b) (p 175) was converted into cis-2-(hydroxymethyl)-1 -pentyl- 1-trimethylstannylcyclopropane (72) employing a reaction time of 15 min and the following quantities of reagents and solvents: Et 2Zn, 0.787 mL (7.68 mmol), in C1CH2CH2C1, 19.2 mL; C1CH2I, 1.12 mL (15.4 mmol); (Z)-3-trimethylstannyl-2-octen-l-ol (35b), 1.117 g (3.838 mmol), in C1CH 2CH 2C1, 5.5 mL. Radial chromatography (4 mm plate, 85:15 petroleum ether-Et20) of the crude product, followed by distillation (100-120°C/0.3 torr) of the acquired oil, afforded 1.10 g (94%) of the trimethylstannyl cyclopropane 72 as a colorless oil. The spectral data of 72 are as follows: IR (neat): 3343 (br), 3060 (w), 1467, 1379, 1189, 1098, 1034, 766 cm"1. lH N M R (CDC13, 400 MHz) 8: 0.06 (s, 9H, 2J Sd.h = 50 Hz, Sn(CH3)3), 0.35 (dd, IH, J = 4, 4 Hz, H-3b), 0.45 (dd, IH, J = 8, 4 Hz, H-3a), 0.62-0.74 (m, IH, H-5a), 0.80-0.95 (overlapping signals, including a triplet, / = 7 Hz, centered at 8 0.85 (H-9), 4H total, H-2), 1.15-1.31 (overlapping signals, overlap with downfield signal, 6H, H-6, H-7, H-8), 1.40 (br s, overlap with upfield signal, IH, exchanges with D 2 0 , OH), 1.69-1.81 (m, IH, H-5b), 3.38 (br dd, IH, 7 = 1 1 , 259 6.5 Hz, sharpens upon addition of D 2 0 , H-4a), 3.49 (br dd, IH, J = 11, 6 Hz, sharpens upon addition of D 2 0 , H-4b). In a decoupling experiment, irradiation at 8 0.68 (H-5a) simplified the signals at 1.15-1.31 (H-6) and 1.69-1.81 (H-5b). See Table 30 on p 260 for further N M R data. 1 3 C N M R (CDC13, 50.3 MHz) 8: -8.9, 14.0, 14.9, 15.2, 22.6, 26.5, 30.2, 31.9, 41.4, 67.1. Exact mass calcd for C 1 1 H 2 3 O 1 2 0 Sn(M + -CH 3 ) : 291.0771. Found: 291.0775. Anal, calcd for C i 2 H 2 6 OSn: C 47.25, H 8.59. Found: C 47.50, H 8.66. 260 Table 30: *H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for Trimethylstannyl Cyclopropane 72 (CeD6). *HNMR 8 (mult, number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 1 3 C and H M Q C 8 (APT (50.3 MHz)), assignment (C-X) 0.15 (s, 9 H , 2 7 sn-H = 50.3 Hz) Sn(CH3)3 No correlation -8.6 (-ve), 17s„-c= 166 Hz, Sn(CH3)3 0.33 (dd, 1H, 7=4, 4 Hz) H-3bfe H-2, H-3a 14.8, C-3 0.38 (dd, 1H, 7=8 , 4 Hz) H-3a H-2, H-3b 14.8, C-3 0.61-0.77 (m, 3H, reduces to 2H upon addition of D 2 0) H-2, H-5a, OH H-3a, H-3b, H-4a, H-4b, H-5b, H-6 26.6 (-ve), C-2; 41.9, C-5 0.90 (t, 3 H , 7 = 7 H z ) H-9 H-8 14.3, C-9 1.14-1.48 (overlapping signals, 6H) H-6, H-7, H-8 H-5a, H-5b, H-9 23.0, 30.6, 32.3, C-6, C-7, C-8 1.75-1.90 (m, IH) H-5b H-5a, H-6 41.9, C-5 3.25 (m, IH, simplifies to a doublet of doublets upon addition of D 2 0 , 7= 11,6.5 Hz) H-4a H-4b, H-2 66.0, C-4 3.41 (m, IH, simplifies to a doublet of doublets upon addition of D 2 0 , J= 11, 6 Hz) H-4b H-4a, H-2 66.0, C-4 N/A N/A N/A 15.1, C - l c a This column organizes the 1 3C signals according to their correlation to the *H signals as given by the H M Q C experiment. The quaternary carbon is listed i n the final row of the table. The assignment is based on the general observation that J cis ^ J trans for cyclopropyl protons. 0 The assignment is based on the results of the H M Q C and A P T experiments and on the chemical shift (8) value. 261 5.3.4.2. Preparation of (1/?*. 2^*)-l-Ethvl-2-r('5*Vl-methoxyethyll-l-iodocyclopropane (65). 64 65 To a cold (0°C) solution of (IR*, 2R*)-l-ethyl-2-[(S*)-l-hydroxyethyl]-l-iodocyclopropane 64 (p 244) (28.9 mg, 0.120 mmol) in dry THF (1 mL) was added, in one portion, NaH (as an 80% dispersion in mineral oil, 15 mg, 0.500 mmol). After the mixture had been stirred for 15 min. at 0°C, methyl iodide (50 pi, 0.80 mmol) was added and the reaction mixture was stirred for 1 h at 0°C. Saturated, aqueous NH4CI (2 mL) was added and the mixture was diluted with CH 2C1 2 (10 mL) and water (10 mL). The phases were separated and the aqueous phase was extracted with CH 2C1 2 (3 x 10 mL). The combined extracts were washed (water (10 mL)), dried (Na2S04), and concentrated. Radial chromatography (2 mm, 95:5 hexanes-ether, then 3:2 hexanes-ether) of the crude product, and distillation of the oils thus obtained afforded 23 mg (75%) of the methyl ether 65 as a colorless oil and 7.2 mg (25%) of starting material (see p 247 for spectral details of 65). 262 5.3.4.3. Preparation of (IR*. 45*. 5^*Vl-Emyl-4-methvl-3-oxabicyclor3.1.01hexan-2-one (71). A solution of ?-BuLi in pentane (0.19 mL, 0.28 mmol) was added dropwise to a cold (-78°C), stirred solution of (IR*, 2/?*)-l-ethyl-2-[(5*)-l-hydroxyethyl]-l-iodocyclopropane (64) (p 244) (22.7 mg, 0.95 mmol) in dry Et20 (0.5 mL) and the solution was stirred for 8 min. After the solution had been allowed to warm to 0°C over a period of 20 min, dry CO2 was bubbled through it, causing precipitation of a white solid. The suspension was allowed to warm to r.t. (10 min) and then was treated with sat. aq NH4CI (2 mL). The phases were separated and the aq phase was extracted with Et20 ( 3 x 2 mL), acidified to pH 2 with 10% aq H2SO4, and then extracted further with E t 2 0 ( 4 x 2 mL). The extracts were combined, dried (Na2SO*4), and concentrated (50-60 torr). Flash chromatography (0.2 g of Sigma (Type H) silica gel, 4:1 hexanes-Et20) gave 2 mg (14%) of the lactone 71 as a colorless, odoriferous, volatile oil. The spectral data of 71 are as follows: IR (neat): 1769, 1461, 1384, 1340, 1148, 1091, 929 cm"1. lH N M R (1:1.2 CDC1 3 -C 6 D 6 ,400 MHz) 8: 0.49 (dd, IH, J = 7.5, 5 Hz, H-6a), 0.57 (dd, IH, J = 5, 5 Hz, H-6b), 0.79 (dd, 3H, J = 7.5, 7.5 Hz, H-9), 0.96 (d, 3H, J = 6 Hz, H-7), 1.20-1.31 (m, H-6a H-6b 64 71 263 IH, H-8), 1.40-1.47 (m, IH, H-5), 1.67-1.79 (m, IH, H-8), 4.19-4.27 (m, IH, H-4). In NOE difference experiments, irradiation at 8 0.96 (H-7) caused signal enhancement at 0.57 (H-6b) and 4.19-4.27 (H-4), irradiation at 8 1.43 (H-5) resulted in signal enhancement at 4.19-4.27 (H-4) and 0.49 (H-6a), and irradiation at 8 4.23 (H-4) caused signal enhancement at 1.40-1.47 (H-5) and 0.96 (H-7). 1 3 C N M R (1:1.2 CDC1 3 -C 6 D 6 , 100 MHz) 8: 11.3, 13.5, 17.7, 21.8, 26.7, 30.8, 74.5, 177.6. Exact mass calcd for C 8 H i 2 0 2 : 140.0837. Found: 140.0831. 5.3.4.4. Preparation of fran5-l-(Hydroxymethyl)-2-pentylcyclopropane (147) 264 H-3a -SnMe3 O H H 1 O H H-3b 4 72 147 A solution of MeL i (0.94 mmol) in E t 2 0 (0.91 mL) was added to a cold (0°C) solution of c w -2-(hydroxymethyl)4-pentyl-l-tximethylstannylcyclopropane (72) (p 258, 266) (136 mg, 0.446 mmol). The resulting clear, colorless solution was stirred at 0°C for 50 min and was then allowed to warm to r.t. over a period of 55 min. G L C analysis of the reaction mixture after 10 min, and again after 35 min of warming, indicated an incomplete reaction and no further change. MeLi (0.443 mmol) in E t 2 0 (0.43 mL) was added1 7 2 and the mixture was stirred for 17.25 h. MeOH (300 ul) was added and the mixture was filtered through 2 g of Merck (grade 60) silica gel (fritted-glass funnel, water aspirator, elution with 35 mL of Et 2 0). Concentration of the filtrate (110°C/20 torr) afforded 55.1 mg (87%) of 147 as a colorless oil. The spectral data of 147 are as follows: IR (neat): 3329 (br), 3064 (w), 1461, 1034 c m 1 . See Table 31 on p 265 for J H N M R data. 1 3 C N M R and APT (C 6D 6 , 75.4 MHz) 8: 10.0, 14.3 (-ve), 17.2 (-ve), 21.5 (-ve), 23.0, 29.6, 32.0, 34.0, 66.6 (C-4). LRDCIMS (NH3): M H + (143), M N H » + (160). Exact mass calcd for C 9 H i 6 (M + -H 2 0) : 124.1252. Found: 124.1256. Table 31: *H N M R (400 MHz) and COSY (200 MHz) Data for 147 (in C 6 D 6 ) . lR N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.10-0.23 (overlapping signals, 2H) H-3a, H-3b H - l , H-2 0.35-0.45 (m, IH) H-2 H - l , H - 3 a , H-3b, H-5 0.64-0.70 (m, IH) H - l H-2, H-3a, H-3b, H-4 0.90 (t, 4H, reduces to 3H upon addition o f D 2 0 , 7 = 7 H z ) H-9, OH H-8 1.07-1.37 (overlapping signals, 8H) H-5, H-6, H-7, H-8 H-2, H-9 3.18-3.30 (overlapping signals, 2H, simplifies upon addition of D 2 0) H-4 H - l 266 5.3A5. Preparation of c/5-2-(Hydroxymemyl)4-pentyl-l-Mmemy (72) (see p 258 for an alternative preparation). A solution of n-BuLi in hexanes (0.46 mL, 0.653 mmol) was added to a cold (-78°C), stirred solution of cw-2-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (60b) (p 225) (80.5 mg, 0.300 mmol) in dry Et 20 (1.5 mL). The resulting clear, colorless solution was stirred at -78°C for 10 min. The -78°C bath was replaced with a 0°C bath and the mixture was stirred for 30 min. Me 3SnCl (145 mg, 0.728 mmol) was added and the resulting white suspension was allowed to warm to r.t. over a period of lh . Sat. aq NH4CI (1 mL), water (2 mL), and Et20 (2 mL) were added, the phases were separated, and the aq phase was extracted with EtaO ( 2 x 2 mL). The combined extracts were dried (Na2S04) and concentrated. Radial chromatography (2 mm plate, 4:1 petroleum ether-Et20) of the crude product, followed by distillation (110-130°C/0.15 torr) of the acquired oil afforded 75.4 mg (83%) of 72 as a colorless oil. See p 258 for the spectral data of 72. H-3a 4 60b 72 267 5.3.5. Aldehydes. 5.3.5.1. TPAP Oxidation of the Iodocyclopropyl Carbinols. General Procedure 6. In the following procedure, all amounts are related to the use of 1 mmol of iodocyclopropyl carbinol. Solid TPAP (0.05 mmol) was added in one portion (CAUTION: the addition of TPAP can lead to an exothermic reaction after a short induction period) to a cold (0°C), stirred solution-suspension of the iodocyclopropyl carbinol, 4-memylmoroholine Af-oxide (1.5 mmol), 4A molecular sieves (500 mg) in dry CH2CI2 (2 mL). The 0°C bath was removed and the black suspension was allowed to warm to r.t. over a period of ~2 h. The mixture was filtered through -2.5 g of Merck (grade 60) silica gel (fritted-glass funnel, water aspirator, elution with -25 mL of Et 2 0). The filtrate was concentrated and the remaining oil was purified by radial chromatography, followed by concentration or distillation, to provide the formyl cyclopropane. 268 Preparation of fran5-2-Formyl-l-iodo-l-pentylcyclopropane (115a). H-3b H-3a 9 OHC 2 X H 4 61b 115a Following general procedure 6 (p 267), rran5-2-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (61b) (p 240) was converted into #Ywts -2-formyl- l - iodo-l -pentylcyclopropane (115a) with the following quantities of reagents and solvents: trans-2-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (61b), 1.83 g (6.82 mmol); 4A molecular sieves, 3.41 g; 4-methylmorpholine iV-oxide, 1.20 g (10.2 mmol); CH 2C1 2 , 13.6 mL; TPAP, 120 mg (0.341 mmol). Radial chromatography (4 mm plate, 95:5 petroleum ether-CEtCL,, material was applied in 3 approximately equal portions employing a continuous method of elution (see Section 5.1.2 for an explanation of this method) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 1.10 g (61%) of 115a as a colorless oil. The oil quickly discolored at r.t. The spectral data of 115a are as follows: IR (neat): 2734,1708,1466,1363,1164,1087 cm"1. *H N M R (C 6D 6 , 300 MHz) 8: 0.80 (t, 3H, 7 = 7 Hz, H-9), 0.96-1.65 (overlapping signals, 10 H), 2.02-2.15 (m, IH), 9.09 (d, IH, 7 = 3 Hz, H-4). 1 3 C N M R (C 6D 6 , 50.3 MHz) 8: 13.6,14.0, 22.7, 26.4, 30.5, 30.8, 38.1, 38.5,196.2. Exact mass calcd for C9H15IO: 266.0168. Found: 266.0171. 269 Preparation of ds-2-Formyl-l-iodo-l-pentylcyclopropane (115b). H-3a H-3b OH 9 H 2 CHO 4 60b 115b Following general procedure 6 (p 267), ds-2-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (60b) (p 225) was converted into cw-2-formyl-l-iodo-l-pentylcyclopropane (115b) with the following quantities of reagents and solvents: cw-2-(hydroxymethyl)-l-iodo-l-pentylcyclopropane (60b), 152 mg (0.567 mmol); 4A molecular sieves, 284 mg; 4-methylmorpholine N-oxide, 99.8 mg (0.852 mmol); CH 2 C1 2 ) 1.14 mL; TPAP, 9.97 mg (0.0284 mmol). Radial chromatography (2 mm plate, 95:5 petroleum ether-CH2Cl2) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 107 mg (71%) of 115b as a colorless oil. The oil quickly discolored at r.t. The spectral data of 115b are as follows: IR (neat): 2720,1713, 1466, 1167, 1048, 926 cm"1. X H N M R (CDC13, 400 MHz) 8: 0.88 (t, 3H, J = 7 Hz, H-9), 1.22-1.34 (overlapping signals, overlap with downfield signal, 5H), 1.36 (dd, overlap with adjacent signals, IH, 7 = 9, 6.5 Hz, H-3a), 1.46-1.74 (overlapping signals, overlap with adjacent signals, 4H), 1.77 (dd, overlap with upfield signals, IH, J= 6.5, 6.5 Hz, H-3b), 9.06 (d, IH, J= 5.5 Hz, H-4). 1 3 C N M R (CDCI3, 100 MHz) 8: 10.0,13.9, 22.5, 24.3, 28.6, 30.6, 32.7,45.2, 202.8. LRDCTMS (NH3): M N H / (284). Exact mass calcd (DCI, wo-butane) for C 9 Hi 6 IO (M++H): 267.0246. Found: 267.0252. 270 Preparation of ds-l-Formyl-2-iodo-l-pentylcyclopropane (115c). H-3a ^CHO OH H 2 I 69b 115c Following general procedure 6 (p 267), dy-l-(hydroxymethyl)-2-iodo-l-pentylcyclopropane (69b) (p 256) was converted into ds-l-formyl-2-iodo-l-pentylcyclopropane (115c) with the following quantities of reagents and solvents: cw-l-(hydroxymethyl)-2-iodo-l-pentylcyclopropane (69b), 135 mg (0.503 mmol); 4A molecular sieves, 250 mg; 4-methylmorpholine N-oxide, 88.6 mg (0.756 mmol); CH 2C1 2 , 1.0 mL; TPAP, 8.90 mg (0.0252 mmol). Radial chromatography (1 mm plate, 9:1 petroleum ether-Et20) of the crude product and distillation (90-105°C/0.2 torr) of the acquired oil afforded 116 mg (87%) of 115c as a colorless oil. The spectral data of 115c are as follows: IR (neat): 2745, 1713, 1466, 1331, 1195, 919 cm"1. 'H N M R (C 6D 6 , 400 MHz) 8: 0.60 (dd, IH, J = 7.5, 6.5 Hz, H-3a), 0.82 (t, 3H, J = 7 Hz, H-9), 0.94 (dd, IH, J = 6.5, 6 Hz, H-3b), 0.98-1.31 (overlapping signals, 8H, H-5, H-6, H-7, H-8), 2.00 (dd, IH, J= 7.5, 6 Hz, H-2), 8.92 (s, IH, H-4). 1 3 C N M R and APT (C 6D 6 , 50.3 MHz) 8: -10.9 (-ve, C-2), 14.2 (-ve), 21.8, 22.7, 26.3, 30.6, 32.1,32.2, 202.3 (-ve, C-4). Exact mass calcd for C9H15IO: 266.0168. Found: 266.0170. Anal, calcd for C 9 H 1 5 IO: C 40.62, H 5.68. Found: C 40.85, H 5.81. 271 Preparation of d.s-2-Formyl-l-pentyl- 1-trimethylstarmylcyclopropane (115d). H-3a '-SnMe3 ^OH 9 ^ H - 3 b -SnMe3 H 2 CHO 4 72 115d Following general procedure 6 (p 267), ds-2-(hydroxymethyl)-l-pentyl-l-trimethylstannylcyclopropane (72) (pp 258, 266) was converted into ds-2-formyl-l-pentyl-l-trimethylstannylcyclopropane (115d) with the following quantities of reagents and solvents: cis-2-(hydroxymethyl)-l-pentyl- 1-trimethylstannylcyclopropane (72), 52.9 mg (0.173 mmol); 4A molecular sieves, 87 mg; 4-methylmorpholine Af-oxide, 30.4 mg (0.259 mmol); CH2Q2, 0.35 mL; TPAP, 3.05 mg (0.00868 mmol). Radial chromatography (1 mm plate, 95:5 petroleum ether-Et 2 0) of the crude product and distillation (60-90°C/0.3 torr) of the acquired oil afforded 39.1 (75%) of 115d as a colorless oil. The spectral data of 115d are as follows: IR (neat): 2724,1697, 1467,1394, 1363,1186,1011, 898,769,720 cm"1. 'H N M R (CDCI3, 400 MHz) 8: 0.10 (s, 9H, 2 7 S n - H = 52 Hz, Sn(CH3)3), 0.70-0.81 (m, IH, H-5), 0.86 (t, 3H, 7 = 7 Hz, H-9), 1.10 (dd, IH, 7 = 8 , 3.5 Hz, H-3a), 1.18 (dd, overlap with downfield signals, IH, 7 = 3.5, 3.5 Hz, H-3b), 1.20-1.40 (overlapping signals, overlap with upfield signal, 6H, H-6, H-7, H-8), 1.70 (ddd, IH, 7 = 8 , 3.5, 3.5 Hz, H-2), 1.84-1.97 (m, IH, H-5), 9.56 (d, 1H,7=3.5 Hz, H-4). 1 3 C N M R (CDC13, 75.4 MHz) 8: -8.1 (-ve, lJ Sa-c = 335 Hz, Sn(CH3)3), 14.0 (-ve), 22.6, 24.2, 26.1, 29.8, 31.8, 34.5 (-ve), 40.8, 203.2 (-ve, C-4). 272 Exact mass calcd for C i 1 H 2 1 O 1 2 0 Sn(M + -CH 3 ) : 289.0614. Found: 289.0621. Anal, calcd for C i 2 H 2 4 OSn: C 47.57, H 7.98. Found: C 47.42, H 8.08. 5.3.6. Vinylcyclopropanes. 5.3.6.1. Wittig Reactions of Formyl Cyclopropanes. General Procedure 7. In the following procedure, all given amounts are related to the use of 1 mmol of aldehyde. A suspension of isopropyltriphenylphosphonium bromide (~2 mmol) and sodium amide (-2.5 mmol)9 9 in dry THF (6.7 mL) was stirred for 1 h at r.t. The resulting deep red suspension was cooled to 0°C and a solution of the aldehyde in THF (1.0 mL) was added by cannula. After 5 min, the 0°C bath was removed and the mixture was allowed to warm to r.t. over a period of - 2 h. The reaction vessel was opened, n-pentane (-2 mL) was added, and the mixture was stirred for 30 min. The resulting white suspension was filtered through -4 .5 g of Merck (grade 60) silica gel (fritted-glass funnel, water aspirator, elution with - 2 5 mL of n-pentane). The filtrate was concentrated and the remaining oil was purified by radial chromatography, followed by concentration or distillation, to provide the substituted (2-methyl-l-propenyl)cyclopropane. This material was stored over Cu wire, under an Ar atmosphere, in a refrigerator. 273 Preparation of fran5-l-Iodo-2-(2-memyl-l-propenyl)4-pentylcyclopropane (116a). 6 115a 116a Following general procedure 7 (p 272), Jrans-2-formyl-l-iodo-l-pentylcyclopropane (115a) (p 268) was converted into /ran5-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a) with the following quantities of reagents and solvents: wo-propyltriphenylphosphonium bromide/sodium amide powder, 3.60 g (-8.28 mmol of phosphonium salt; -10.5 mmol of amide) in THF, 28 mL; /rans-2-formyl-l-iodo-l-pentylcyclopropane (115a), 1.10 g (4.13 mmol), in THF, 4.1 mL. Flash chromatography (30 g of Iatrobeads®, n-pentane)100 of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 1.02 g (84%) of 116a as a colorless oil. The spectral data of 116a are as follows: IR (neat): 1451 (br), 1378, 1153, 1040 cm"1. See Table 32 on p 274 for for X H N M R and COSY data. In NOE difference experiments, irradiation at 8 0.41 (H-3b) caused signal enhancement at 1.37 (H-3a) and 4.73 (H-4); irradiation at 8 2.20 (H-2) caused signal enhancement at 1.37 (H-3a); irradiation at 8 4.73 (H-4) caused signal enhancement at 1.56 (H-6), 0.41 (H-3b), and 1.40 (H-8 (assignment uncertain)). In decoupling experiments, irradiation at 8 2.20 (H-2) simplified the signal at 0.41 to a doublet, 7 = 6 Hz, and the signal at 4.70-4.76 (H-4) to a broad singlet; 274 irradiation at 8 4.73 (H-4) simplified the signal at 2.14-2.25 (H-2) to a doublet of doublets, J = 9.5, 6 Hz. 1 3 C N M R and APT (C 6D 6 , 50.3 MHz) 8: 14.1 (-ve, C-12), 14.8, 18.7 (-ve), 22.9, 25.4 (-ve), 26.2, 29.0 (-ve), 30.0, 31.3,40.5,122.2 (-ve, C-4), 136.0 (C-5). Exact mass calcd for C12H21I: 292.0688. Found: 292.0682. Table 32: *H N M R (400 MHz) and COSY (400 MHz) Data for 116a (in C 6 D 6 ) . ' H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.41 (dd, l H , 7 = 6 , 6 H z ) H-3b H-2, H-3a 0.84 (t, 3 H , / = 7Hz) H-12 H-11 1.07-1.72 (overlapping signals, including two broad singlets centered at 8 1.56 and 1.58, 15H) H-6 (8 1.56)," H-7 (8 1.58)," H-3a(1.37), f c H-8, H-9, H-10, H-11 H-2, H-3b, H-4, H-12 2.14-2.25 (m, IH) H-2 H-3a, H-3b, H-4 4.70-4.76 (m, IH) H-4 H-2, H-6, H-7 a The assignment is based on the results of the N O E difference experiment. The C O S Y experiment gave an approximate chemical shift (8) value of 1.37 for H-3a. 275 Preparation of ct5-l-Iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b). H-3a H-3b CHO H 7 6 115b 116b Following general procedure 7 (p 272), cw-2-formyl-l-iodo-l-pentylcyclopropane (115b) (p 269) was converted into cw-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b) with the following quantities of reagents and solvents: wo-propyltriphenylphosphonium bromide/sodium amide powder, 10 g (~23 mmol of phosphonium salt; - 2 9 mmol of amide) in THF, 77 mL; cw-2-formyl-l-iodo-l-pentylcyclopropane (115b), 3.07 g (11.53 mmol), in THF, 11.5 mL. Radial chromatography (4 mm, 4 mm and 2 mm plates, petroleum ether) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 2.42 g (72%) of 116b as a colorless oil. The spectral data of 116b are as follows: IR (neat): 1675 (w), 1451, 1378, 1147, 1074, 1039, 835 cm"1. lU N M R (CDC13, 400 MHz) 8: 0.82-0.97 (overlapping signals, including a triplet, J = 7 Hz, centered at 8 0.88 (H-12), 5H total), 1.14-1.37 (overlapping signals, 5H), 1.40-1.58 (overlapping signals, 3H), 1.63-1.78 (overlapping signals, including broad two singlets centered at 8 1.70 (H-6 or H-7) and 1.73 (H-6 or H-7), 7H total), 4.87-4.95 (m, IH, H-4). The X H spectrum of 116b in C 6 D 6 was also poorly resolved. 276 1 3 C N M R and APT (CDC13, 75.4 MHz) 8: 14.0 (-ve), 18.7 (-ve), 22.7, 22.8, 23.5 (-ve), 25.6 (-ve), 26.0, 29.2, 31.0,46.0,128.7 (-ve, C-4), 134.0 (C-5). Exact mass calcd for C12H21I: 292.0688. Found: 292.0694. Anal, calcd for Ci 2 H 2 i I : C 49.33, H 7.24. Found: C 49.16, H 7.27. Preparation of ci5-2-Iodo-l-(2-methyl-l-propenyl)-l-pentylcyclopropane (116c). 7 6 115c 116c Following general procedure 7 (p 272), ds-l-formyl-2-iodo-l-pentylcyclopropane (115c) (p 270) was converted into cw-2-iodo-l-(2-methyl-l-propenyl)-l-pentylcyclopropane (116c) with the following quantities of reagents and solvents: wo-propyltriphenylphosphonium bromide/sodium amide powder, 0.280 g (-0.64 mmol of phosphonium salt; -0.82 mmol of amide) in THF, 2.2 mL; cw-l-formyl-2-iodo-l-pentylcyclopropane (115c), 86.2 mg (0.324 mmol), in THF, 0.32 mL. Radial chromatography (1 mm plate, n-pentane) of the crude product and distillation (70-85°C/0.1 torr) of the acquired oil afforded 68.9 mg (73%) of 116c as a colorless oil. 277 The spectral data of 116c are as follows: IR (neat): 1670 (w), 1440, 1377, 1259, 1182, 1065 cm"1. See Table 33 below for X H N M R and COSY data. In a decoupling experiment, irradiation at 8 2.26 (H-2) simplified the signal at 0.79 (H-3b) to a d, 7 = 5.5 Hz. 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: 0.0 (C-2), 14.4 (C-12), 19.8, 23.0 (-ve), 24.4 (-ve), 25.3 (-ve), 25.7, 27.1 (-ve), 32.4 (-ve), 39.4 (-ve), 128.3 (C-4), 137.4 (-ve, C-5). There was overlap of signals in the 1 3 C spectrum of 116c in CeD6. Exact mass calcd for C12H2J: 292.0688. Found: 292.0681. Anal, calcd for C 1 2 H 2 i I : C 49.33, H 7.24. Found: C 49.05, H 7.24. Table 33: *H N M R (400 MHz) and COSY (400 MHz) Data for 116c (in C 6D 6) . f l *H N M R 8 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.79 (dd, IH, 7= 5.5, 5 Hz) H-3b H-2, H-3a 0.84 (t, 3 H , 7 = 7 H z ) H-12 H-11 0.90-1.46 (overlapping signals, 9H) H-3a (1.10),fc H-8, H-9, H-10, H-11 H-2, H-3b, H-12 1.56 (d, 3H ,7 = 1Hz) H-6 or H-7 H-4 1.64 (d, 3H ,7 = 1Hz) H-6 or H-7 H-4 2.26 (dd, l H , 7 = 8 , 5 H z ) H-2 C H-3a, H-3b 5.35 (br signal, IH) H-4 H-6, H-7 a The signal resolution was poor when CDC13 was used as the NMR solvent. b The COSY experiment gave an approximate chemical shift (8) value of 1.10 for H-3a. c The assignment is based on the assignment reported for iodocyclopropane.75 278 Preparation of ds-2-(2-Memyl-l-propenylH-pen^ (116d) Following general procedure 7 (p 272), ds-2-formyl-l -pentyl- 1-trimethyl-stannylcyclopropane (115d) (p 271) was converted into ds-2-(2-methyl-l-propenyl)-l-pentyl-l-trimethylstannylcyclopropane (116d) with the following quantities of reagents and solvents: iso-propyltriphenylphosphonium bromide/sodium amide powder, 0.92 g (~2.11 mmol) in THF, 7 mL; ds-2-formyl-l-pentyl- 1-trimethylstannyIcyclopropane (115d), 320 mg (1.06 mmol), in THF, 1.0 mL. Radial chromatography (2 mm plate, petroleum ether) of the crude product and distillation (80-100°C/0.1 torr) of the acquired oil afforded 285 mg (82%) of 116d as a colorless oil. The spectral data of 116d are as follows: IR (neat): 1453, 1378,1188, 1068, 764 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.01 (s, 9H, 2J S n . H = 51 Hz, Sn(CH3)3), 0.46 (dd, IH, J = 4, 4 Hz, H-3b), 0.62 (dd, IH, / = 8, 4 Hz, H-3a), 0.72-0.82 (m, IH, H-8a), 0.83 (t, 3H, J = 7 Hz, H-12), 1.11-1.42 (overlapping signals, 7H, H-2, H-9, H-10, H-11), 1.63 (br s, 3H, H-6), 1.70 (br s, overlap with downfield m, 3H, H-7), 1.70-1.85 (m, overlap with upfield singlet, IH, H-8b), 279 4.58-4.64 (m, IH, H-4). In NOE difference experiments, irradiation at 8 0.01 (Sn(CH3)3) caused signal enhancement at 0.46 (H-3b) and 4.61 (H-4); irradiation at 8 0.46 (H-3b) caused signal enhancement at 0.62 (H-3a) and 4.61 (H-4); irradiation at 8 0.62 (H-3a) caused signal enhancement at 1.20 (H-2 (assignment uncertain)); irradiation at 8 4.61 (H-4) caused signal enhancement at 0.46 (H-3b) and 1.63 (H-6). 1 3 C N M R and APT (CDC13, 75.4 MHz) 8: -9.2 (-ve, lJ Sn-c = 327 Hz, Sn(CH3)3), 14.1 (-ve), 18.1, (-ve), 19.0, 22.5 (-ve), 22.7, 25.6 (-ve), 30.3, 32.1, 41.8, 128.2 (-ve, C-4), 131.7 (C-5). Exact mass calcd for Ci 5 H 3 0 1 2 0 Sn: 330.1369. Found: 330.1372. Anal, calcd for Ci 5 H 3 0 Sn: C 54.75, H 9.19. Found: C 55.00, H 9.19. Method B. A solution of BuLi in hexanes (0.8 mL, 1.08 mmol) was added to a chilled (-78°C) suspension of wo-propyltriphenylphosphonium bromide (437 mg, 1.13 mmol) in dry THF (3.8 mL). The resulting deep red suspension was allowed to warm for 25 min. The suspension was chilled to -78°C and a solution of cw-2-formyl-l-pentyl- 1-trimethylstannylcyclopropane (115d) (p 88) (81.8 mg, 0.270 mmol) in THF (0.9 mL) was added by cannula. The -78°C bath was removed and the mixture was allowed to warm over a period of -1 .5 h. The reaction vessel was opened, n-pentane (-10 mL) was added, and the mixture was stirred for 15 min. The resulting white suspension was filtered through - 9 g of Merck (grade 60) silica gel (fritted-glass funnel, water aspirator, elution with - 4 0 mL of n-pentane). Concentration of the filtrate, followed by distillation (80-100°C/0.1 torr) of the acquired oil afforded 82.7 mg (93%) of 116d as a colorless oil. See pp 278-279 for the spectral data of 116d. 280 5.3.6.2. Lithium-Iodine Exchange Reactions of Iodo Vinylcyclopropanes. Preparation of 1- and 2-(2-Methyl-l-propenylVl-pentylcyclopropanes. General Procedure 8. In the following procedure, all given amounts are related to the use of 1 mmol of iodo vinylcyclopropane. Substrate 116c was distilled immediately prior to its use, whereas substrates 116a and 116b were eluted through a short column of oven-dried basic alumina (activity 1) with dry E t 2 0 , concentrated (water aspirator), dissolved in dry benzene, and concentrated (water aspirator, then 0.3 torr) prior to their use. A solution of BuLi in hexanes (2.2 mL, 2.2 mmol) was added to a vigorously stirred, cold (-48°C) solution of iodo vinylcyclopropane in dry THF (~10 mL). The resulting clear solution was stirred for 15 min at -48°C. Water (~10 mL) was added and the mixture was allowed to warm to r.t. The layers were separated and the aq layer was extracted with E t 2 0 (2x~10 mL). The combined extracts were dried (Na2S04) and concentrated. Distillation of the acquired oil afforded the vinylcyclopropane product. 281 Preparation of ct5-l-(2-Methyl-l-propenyl)-2-pentylcyclopropane (129). H H 6 7 116a 129 Following general procedure 8 (p 280), /rans-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a) (p 273) was converted into cw-l-(2-methyl-l-propenyl)-2-pentylcyclopropane (129) with the following quantities of reagents and solvents: trans-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a), 77.9 mg (0.267 mmol), in THF, 2.7 mL; BuLi in hexanes, 0.37 mL (0.592 mmol). Concentration (r.t. stillpot/-78°C collection bulb/160 torr) and distillation (r.t. stillpot/-78°C collection bulb/-15 torr) of the acquired oil afforded 35.0 mg (79%) of 129 as a colorless, volatile oil. The spectral data of 129 are as follows: IR (neat): 3060 (w), 1455,1378,1141, 1027, 835 cm"1. See Table 34 on p 282 for X H N M R and COSY data. 1 3 C N M R and APT (C 6D 6, 50.3 MHz) 8: 13.8, 14.2 (-ve), 15.2 (-ve), 18.2 (-ve), 18.3 (-ve), 23.0, 25.8 (-ve), 29.79, 29.84, 32.1,124.7 (-ve, C-4), 132.0 (C-5). Exact mass calcd for C i 2 H 2 2 : 166.1722. Found: 166.1718. 282 Table 34: *H N M R (400 MHz) and COSY (400 MHz) Data for 129 (in C 6 D 6 ) . lH N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.03-0.10 (m, IH) cyclopropyl proton H - l , 0.75-0.85 0.75-0.85 (overlapping signals, overlap with downfield triplet, 2H) cyclopropyl protons H - l , 0.03-0.10 0.89 (t, overlap with upfield signals, 3H, 7= 7 Hz) H-12 H-11 1.15-1.52 (overlapping signals, 9H) H - l (8 1.46)," H-8, H-9, H-10, H-11 0.03-0.10, 0.75-0.85, H-4, H-12 1.69 (br signal, 6H) H-6, H-7 H-4 4.92-4.98 (m, IH) H-4 H - l , H-6, H-7 a The COSY experiment gave an approximate chemical shift (8) value of 1.46 for H- l . 283 Preparation of trans-l-(2-Methyl-l-propenyl')-2-pentylcyclopropane (130). H H H 7 6 116b 130 Following general procedure 8 (p 280), ds-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b) (p 275) was converted into /rans-l-(2-methyl-l-propenyl)-2-pentylcyclopropane (130) with the following quantities of reagents and solvents: ds-l - iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b), 84.8 mg (0.289 mmol), in THF, 3 mL; BuLi in hexanes, 0.52 mL (0.64 mmol). Concentration of the crude product by passing a stream of dry Ar over the solution, followed by distillation (r.t. stillpot/-78°C collection bulb/~15 torr) of the acquired oil afforded 42.4 mg (88%) of 130 as a colorless, volatile oil. The spectral data of 130 are as follows: IR (neat): 3070 (w), 1456,1377,1148,1071, 883, 831 cm"1. *H N M R (CDC13, 400 MHz) 5: 0.36-0.49 (overlapping signals, 2H, cyclopropyl protons), 0.56-0.68 (m, IH, cyclopropyl proton), 0.88 (t, 3H, J = 7 Hz, H-12), 1.08-1.18 (m, slight overlap with downfield signals, IH), 1.18-1.46 (overlapping signals, overlap with upfield multiplet, 9H), 1.66 (br s, 3H, H-6 or H-7), 1.72 (br s, 3H, H-6 or H-7), 4.56 (br d, IH, J = 9 Hz, H-4). The *H spectrum of 130 in CeD 6 was also poorly resolved. 1 3 C N M R (CDC13 ) 125 MHz) 8: 13.8, 14.1, 18.0, 18.1, 20.6, 22.7, 25.5, 29.1, 31.7, 34.0, 128.4, 129.7. 284 Exact mass calcd for C i 2 H 2 2 : 166.1722. Found: 166.1720. Preparation of l-(2-Methyl-l-propenyl)-l-pentylcyclopropane (131). 7 6 116c 131 Following general procedure 8 (p 280), cw-l-iodo-2-(2-methyl-l-propenyl)-2-pentylcyclopropane (116c) (p 276) was converted into l-(2-methyl-l-propenyl)-l-pentylcyclopropane (131) with the following quantities of reagents and solvents: cw-l-iodo-2-(2-methyl-l-propenyl)-2-pentylcyclopropane (116c), 49.5 mg (0.169 mmol), in THF, 1.7 mL; BuLi in hexanes, 0.23 mL (0.368 mmol). Concentration (r.t. stillpot/-78°C collection bulb/160 torr) and distillation (r.t. stillpot/-78°C collection bulb/~20 torr) of the acquired oil afforded 22.1 mg (79%) of 131 as a colorless, volatile oil. The spectral data of 131 are as follows: IR (neat): 3074, 1670 (w), 1457,1378,1195, 1065,1017 c m 1 . See Table 35 on p 285 for *H N M R and COSY data. 1 3 C N M R and APT (C 6D 6 , 75.4 MHz) 8: 14.0 (two carbons), 14.3 (-ve), 19.2 (-ve), 19.8, 23.2, 25.6 (-ve), 27.6, 32.6, 40.3, 128.5 (-ve, C-4), 134.9 (C-5). Exact mass calcd for C i 2 H 2 2 : 166.1722. Found: 166.1722. Table 35: J H N M R (400 MHz) and COSY (200 MHz) Data for 131 (in C 6 D 6 ) . ' H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.42-0.48 (m, 2H) cyclopropyl protons 0.52-0.58 0.52-0.58 (m, 2H) cyclopropyl protons 0.42-0.48 0.89 (t, 3 H , / = 7 H z ) H-12 H - l l 1.18-1.35 (overlapping signals, 6H) C H 2 signals, including H - l l H-12, 1.41-1.51 1.41-1.51 (overlapping signals, 2H) C H 2 signals 1.18-1.35 1.61 (d, 3H ,7= 1Hz) H-6 or H-7 H-4 1.70 (d, 3 H , / = 1.5 Hz) H-6 or H-7 H-4 5.43 (br signal, IH) H-4 H-6, H-7 286 5.3.6.3. Preparation of m^-2-(2-Methyl-l -propenyl)-l -pentyl-l -tri^ I136I Note: Substrate 116a was eluted through a short column of oven-dried basic alumina (activity 1) with dry E t 2 0 , concentrated (water aspirator), dissolved in dry benzene, and concentrated (water aspirator, then 0.3 torr) prior to its use. A solution of BuLi in hexanes (0.49 mL, 0.78 mmol) was added to a vigorously stirred, cold (-48°C) solution of /ra/w-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a) (p 273) (112 mg, 0.384 mmol) in dry THF (1.9 mL). The resulting clear solution was stirred for 30 min at -48°C. A solution of Me 3SnCl (191 mg, 0.960 mmol) in THF (1 mL) was added by cannula and the clear solution was allowed to warm to r.t. over a period of 1.5 h, during which the solution became slightly cloudy. The reaction mixture was concentrated and the residue was diluted with petroleum ether (~2 mL).. The resulting suspension was filtered through ~0.5 g of Merck (grade 60) silica gel (elution with ~6 mL of petroleum ether) in order to remove precipitated salts. The filtrate was concentrated and the acquired oil was purified by flash chromatography (4 g of reversed phase silica gel, crude material applied as a solution in E t 2 0, 287 elution with 95:5 acetonitrile-MeOH) and distillation (80-110°C/0.15 torr) to afford 88.2 mg (70%) of 136 as a colorless oil. The spectral data of 136 are as follows: IR (neat): 3040 (w), 1455, 1377, 1148, 1059, 763 c m 1 . See Table 36 below for *H N M R and COSY data. In NOE difference experiments, irradiation at 8 0.08 (Sn(CH3)3) caused signal enhancement at 0.99 (H-3a); irradiation at 8 0.44 (H-3b) caused signal enhancement at 0.99 (H-3a) and 5.13 (H-4). 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: -10.5 (-ve, Sn(CH3)3), 14.0 (-ve, C-12), 16.6, 18.1 (-ve), 18.7, 19.1 (-ve), 22.6, 25.7 (-ve), 30.2, 32.1, 35.1, 124.4 (-ve, C-4), 132.4 (C-5). Exact mass calcd for C 1 5 H 3 0 1 2 0 Sn: 330.1369. Found: 330.1375. Anal, calcd for C i 5 H 3 0 S n : C 54.75, H 9.19. Found: C 54.57, H 9.21. Table 36: *H N M R (400 MHz) and COSY (200 MHz) Data for 136 (in C 6 D 6 ) . a *HNMR 8 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.08 (s, 9 H , 2 7 S n - H = 50 Hz) Sn(CH3)3 No correlation 0.44 (dd, 1H,7=4.5, 4.5 Hz) H-3b fc H-2, H-3a 0.88 (t, 3H, 7 = 7 Hz) H-12 H-11 0.99 (dd, IH, 7=7.5, 4.5 Hz) H-3a H-2, H-3b 1.20-1.66 (overlapping signals, 9H) H-2 (8 1.50),c H-8, H-9, H-10, H-11 H-3a, H-3b, H-4, H-12 1.71 (overlapping signals, 6H) H-6, H-7 H-4 5.09-5.17 (m, IH) H-4 H-2, H-6, H-7 " The signal resolution was equally poor when CDC13 was used as the NMR solvent. b The assignment is based on the general observation that J > J a w s for cyclopropyl protons.' c The COSY experiment gave an approximate chemical shift (8) value of 1.50 for H-2. 288 5.3.6.4. Preparation of q '5 -2-(2-Methyl-l -propen^ cyclopropane (139). 7 116d 139 A solution of BuLi in hexanes (0.36 mL, 0.50 mmol) was added to a vigorously stirred, cold (-20°C) solution of cw-2-(2-methyl-l-propenyl)-l-pentyl-l-trimethylstannylcyclopropane (116d) (p 278) (16.2 mg, 0.0492 mmol) in dry THF (0.49 mL). The resulting clear, colorless solution was stirred for 1.75 h at -20°C. The -20°C bath was replaced with a -10°C bath and the mixture was stirred for 55 min. Finally, the mixture was allowed to warm to r.t. over a period of 2.25 h. Sat. aq NH4CI (0.5 mL) was added to the yellowish brown reaction mixture, resulting in the rapid evolution of gas. Water (0.5 mL) and Et20 (0.5 mL) were added, the phases separated, and the aq layer was extracted with Et20 (2x1 mL). The combined organic extracts were dried (Na 2S04) and concentrated. Radial chromatography (1 mm plate, crude material applied as a solution in - 2 : 1 n-pentane-Et20, elution with n-pentane) of the crude product and heating of the acquired oil under reduced pressure (r.t. to 140°C/0.4 torr) in order to remove remaining impurities afforded 16.9 mg (75%) of 139 as a colorless oil. 289 The spectral data of 139 are as follows: IR (neat): 3040 (w), 1458, 1377, 1070, 867 cm"1. See Table 37 below for lH N M R and COSY data. I 3 C N M R and APT (CDC13, 75.4 MHz) 8: 9.8 (VSn-c = 310 Hz, Sn(CH 2CH 2 -), 13.7 (-ve), 14.1 (-ve), 18.0 (-ve), 19.3, 19.5, 22.4 (-ve), 22.7, 25.7 (-ve), 27.6, 29.2, 30.4, 32.2, 42.4, 128.9 (-ve, C-4), 131.0 (C-5). Exact mass calcd for C 2 4 H 4 8 1 2 0 S n : 456.2778. Found: 456.2774. Anal, calcd for C 2 4 H 4 8 S n : C 63.31, H 10.62. Found: C 63.17, H 10.69. Table 37: X H N M R (400 MHz) and COSY (400 MHz) Data for 139 (in C 6 D 6 ) . a *H N M R 8 (mult, number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.70 (dd, l H , 7 = 4 ,4Hz ) H-3b fc H-2, H-3a 0.78 (dd, 1H,7= 8, 4 Hz) H-3a H-2, H-3b 0.82-1.12 (overlapping signals, 18H) C H 2 protons 1.20-1.80, H-8 (assignment uncertain) 1.20-1.80 (overlapping signals, including two broad singlets centered at 8 1.71 and 1.75, 26H total) H-2 (1.38),c H-6 (8 1.71 or 1.75), H-7 (81.71 or 1.75), C H 2 protons H-3a, H-3b, H-4, H-8 (assignment uncertain), 0.82-1.12 1.85-1.96 (m, IH) H-8 (assignment uncertain) 0.82-1.12, 1.20-1.80 4.85-4.93 (m, IH) H-4 H-2, H-6, H-7 a The signal resolution was equally poor when CDC13 was used as the NMR solvent. b The assignment is based on the general observation that J & > J a m s for cyclopropyl protons.' c The COSY experiment gave an approximate chemical shift (8) value of 1.38 for H-2. 290 5.3.7. 1,2-Divinylcyclopropanes, l-Phenyl-2-vinylcyclopropanes, and Related Compounds. 5.3.7.1. PaUadium(Q)-Cataryzed Cross Coupling Reactions of Cyclopropylzinc Chlorides with Vinyl and Aryl Iodides: stereospecific syntheses of substituted 1.2-divinylcyclopropanes and 1-phenyl-2-vinylcyclopropanes. General Procedure 9. In the following procedure, all given amounts are related to the use of 1 mmol of iodo vinylcyclopropane. Substrate 116c was freshly distilled prior to its use, whereas substrates 116a and 116b were eluted through a short column of oven-dried basic alumina (activity 1) with dry Et20, concentrated (water aspirator), dissolved in dry benzene, and concentrated (water aspirator, then 0.3 torr) prior to their use. A solution of BuLi in hexanes (-1.4 mL, 2.05 mmol) was added slowly to a vigorously stirred, cold (-48°C) solution of the iodo vinylcyclopropane in dry THF (4 mL). The clear (sometimes slightly yellowish brown) solution was stirred at -48°C for 30 min. A solution of ZnCl 2 (1.50 mmol) in dry THF (3.0 mL) 2 6 was added by gas-tight syringe. The clear solution was stirred at -48°C for 15 min, and then was allowed to warm to r.t. over a period of 45 min. Solid Pd(PPh3)4 (0.100 mmol) was added quickly to the zinc reagent, followed by addition by cannula of a solution of the vinyl or aryl iodide (freshly distilled, unless otherwise noted) (-2 mmol) in dry D M F (-6 mL). The resulting yellowish suspension was refluxed for 1 h (unless otherwise noted). Warming to the reflux temperature caused the mixture to turn dark brown. The reaction mixture was allowed to cool to r.t. and sat. aq NH4CI (-9 mL) was added, followed by water (-9 mL) and 291 Et^O (-23 mL). The layers were separated and the aq layer was extracted with Et20 (2x~23 mL). The combined organic extracts were washed (sat. aq Na2S203 (-23 mL) and water (-23 mL)) and dried (MgSCu or Na2S04). The solvents were removed under reduced pressure (water aspirator) to afford a viscous oil which was triturated with petroleum ether (6x~9 mL) (unless otherwise noted). The combined organic extracts were concentrated to give the crude product, which was purified (vide infra) to provide the 1,2-divinylcyclopropane, or in two cases (vide infra), a mixture of 1,2-divinylcyclopropane and cycloheptadiene (Cope rearrangement) products. In such cases, the pure cycloheptadiene was obtained by refluxing the mixture in xylenes for lh and removing the solvent under reduced pressure (0.3 torr). 292 Preparation of 149. 149 Following general procedure 9 (p 290), ds-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b) (p 275) was converted into the cycloheptadiene 149 employing a reaction time of 1.5 h and the following quantities of reagents and solvents: cw-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b), 112 mg (0.383 mmol), in THF, 1.54 mL; BuLi in hexanes, 0.52 mL (0.79 mmol); ZnCl 2 in THF, 1.15 mL (0.575 mmol); (Ph3P)4Pd, 44.5 mg (0.0385 mmol); ^a/w-6-(fc^butyldimethylsiloxy)-l-iodo-l-hexene (124) (p 219), 243 mg (0.714 mmol) in DMF, 2.31 mL; trituration solvents, volumes: 95:5 petroleum ether-CH 2Cl 2, 9x1 mL. Radial chromatography (2 mm plate, 95:5 petroleum ether-CH2Cl2) of the crude product and subjection of the acquired oil to reduced pressure and heat (0.3 torr/r.t. to 140°C) in order to 293 remove remaining impurities afforded 89.6 mg of a mixture of the substituted 1,2-divinylcyclopropane (148) and cycloheptadiene (149) products. The mixture was dissolved in xylenes (1 mL) and the solution was refluxed for 1 h. Concentration of the solution provided 89.6 mg (61%) of the cycloheptadiene 149 as a colorless oil. The spectral data of 149 are as follows: IR (neat): 1676 (w), 1464, 1388, 1361, 1255, 1103, 1006, 837, 776, 711 c m 1 . See Table 38 on p 294 for J H N M R and COSY data. In decoupling experiments, irradiation at 5 2.99 (H-2b) simplified the signal at 2.25 (H-2a) to a doublet, J = 7.5 Hz, the signal at 5.10-5.20 (H-4), and the signal at 5.40 (H-3) to a doublet of doublets, 7 = 1 1 , 7.5 Hz; irradiation at 8 5.15 (H-4, H-7) simplified the signal at 2.33-2.43 (H-6) to a broad doublet, J = 10.5 Hz, the signal at 5.40 (H-3), and sharpened the signal at 2.94-3.04 (H-2b) to a doublet of doublets, J = 18, 3 Hz; irradiation at 8 5.40 (H-3) simplified the signal at 2.25 (H-2a) to a doublet, J = 18 Hz, the signal at 5.10-5.20 (H-4, H-7), and sharpened the signal at 2.94-3.04 (H-2b). 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: -5.3 (Si(CH3)2), 14.1, 18.3 (-ve), 22.5 (-ve), 23.9, 24.4 (-ve), 26.0 (C(CH3)3), 27.6 (-ve), 29.8, 29.88 (-ve), 30.92 (-ve), 31.4 (-ve), 33.1 (-ve), 37.6 (-ve), 39.0 (-ve), 45.6, 63.3 (-ve, C - l l ) , 123.0, 129.2, 142.1, 143.1 (-ve, C - l ) . Exact mass calcd for C 2 4H460Si: 378.3318. Found: 378.3324. Anal, calcd for C^HteOSi: C 76.12, H 12.24. Found: C 75.95, H 12.20. Table 38: X H N M R (400 MHz) and COSY (200 MHz) Data for 149 (in CDC13). ' H N M R 8 (mult, number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.03 (s, 6H) Si(CH 3) 2 No correlation 0.83-0.92 (overlapping signals, 15H) C(CH 3) 3 , H-12, H-18 H-17 0.99 (s, 3H) H-13 No correlation 1.10-1.60 (overlapping signals, 12H) H-8, H-9, H-10, H-15, H-16, H-17 H-6, H-11, H-14, H-18 1.94-2.01 (m, 2H) H-14 H-7 (weak), H-15 2.25 (dd, 1H,7= 18,7.5 Hz) H-2a H-2b, H-3 2.33-2.43 (m, IH) H-6 H-7, H-8 2.94-3.04 (m, IH) H-2b H-2a, H-3, H-4, H-7 3.59 ( t ,2H,7=6.5 Hz) H-11 H-10 5.10-5.20 (overlapping signals, 2H) H-4, H-7 H-2b, H-3, H-6, H-14 (weak) 5.40 (ddd, IH, J = 11, 7.5, 3 Hz) H-3 H-2a, H-2b, H-4 295 Preparation of 151. Note: The vinyl iodide 120 was eluted through a shorf column of oven-dried basic alumina (activity 1) with dry E t 2 0 , concentrated (water aspirator);'dissolved in dry benzene, and concentrated (water aspirator, then 0.3 torr) prior to its use. ; % 150 151 Following general procedure 9 (p 290), cw-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b) (p 275) was converted into the cycloheptadiene 151 with the following quantities of reagents and solvents: cw-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b), 99.3 mg (0.340 mmol), in THF, 1.36 mL; BuLi in hexanes, 0.46 mL (0.70 mmol); ZnCl 2 in THF, 1.02 mL (0.510 mmol); (Ph3P)4Pd, 39.0 mg (0.0337 mmol); 4-chloro-2-iodo-l-butene (120) (p 201), 138 mg (0.638 mmol) in DMF, 2.04 mL. Radial 296 chromatography (2 mm plate, petroleum ether) of the crude product and subjection of the acquired oil to reduced pressure and heat (0.3 torr/r.t. to 140°C) in order to remove remaining impurities afforded 45.5 mg of a mixture of the substituted 1,2-divinylcyclopropane 150 and the cycloheptadiene 151 products. The mixture was dissolved in xylenes (0.5 mL) and the solution was refluxed for 1 h. Concentration of the solution provided 45.5 mg (52%) of the cycloheptadiene 151 as a colorless oil. The spectral data of 151 are as follows: IR (neat): 1470, 1460, 1375, 1358, 792, 728 cm"1. See Table 39 on p 297 for *H N M R and COSY data. 1 3 C N M R (CDC13, 125 MHz) 8: 14.0, 22.6, 28.3, 29.9, 31.5, 31.8, 34.4, 35.0, 38.6, 42.9, 43.8, 123.1, 128.8, 140.2, 141.6. Exact mass calcd for C i 6 H 2 7 3 5 C l : 254.1801. Found: 254.1805. Anal, calcd for C 1 6 H 2 7 C1: C 75.41, H 10.68. Found: C 75.60, H 10.68. Table 39: *H N M R (400 MHz) and COSY (200 MHz) Data for 151 (in CDC13). ' H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.88 (t, 3 H , 7 = 7 H z ) H-16 H-15 0.96 (singlet, 6H) H - 1 0 , H - l l No correlation 1.20-1.40 (singlet, 6H) H-13,H-14,H-15 H-12,H-16 2.01 (t, 2 H , 7 = 7 H z ) H-12 H-13 2.22 (br signal, 2H) H-7 H-3 (weak), H-5 (weak) 2.52 (t, 2 H , / = 8 H z ) H-8 H-9 2.66 (d, 2H, 7=5.5 Hz) H-3 H-4, H-5, H-7 (weak) 3.44 (t, 2 H , 7 = 8 H z ) H-9 H-8 5.14 (brd, 1H,7= 11.5 Hz) H-5 H-3, H-4, H-7 (weak) 5.42 (dt, 1H,7= 11.5,5.5 Hz) H-4 H-3, H-5 298 Preparation of 152. 7 6 152 Following general procedure 9 (p 290), a's-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b) (p 275) was converted into the 1,2-divinylcyclopropane 152 with the following quantities of reagents and solvents: cw-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b), 65.0 mg (0.222 mmol), in THF, 0.89 mL; BuLi in hexanes, 0.35 mL (0.46 mmol); ZnCi 2 in THF, 0.67 mL (0.34 mmol); (Ph3P)4Pd, 26.0 mg (0.0225 mmol); cis-6-(fm-butyldimethylsiloxy)-l-iodo-l-hexene (123) (p 217), 156 mg (0.458 mmol) in DMF, 1.30 mL. Radial chromatography (2 mm plate, 95:5 petroleum ether-CH2Cl2) of the crude product and subjection of the acquired oil to reduced pressure and heat (0.3 torr/r.t. to 140°C) in order to remove remaining impurities afforded 45.1 mg (54%) of the 1,2-divinylcyclopropane 152 as a colorless oil. 299 The spectral data of 152 are as follows: IR (neat): 3059,1462, 1383,1253,1102, 838, 776 cm"1. See Table 40 on p 300 for *H N M R and COSY data. In decoupling experiments, irradiation at 8 2.08 (H-10) simplified the signal at 5.34-5.48 (H-8, H-9) to two doublets centered at 5.37 (7=11 Hz) and 5.43 (7=11 Hz); irradiation at 8 5.41 (H-8, H-9) simplified the signal at 2.05-2.21 (H-10). In NOE difference experiments, irradiation at 8 0.42 (H-3b) caused signal-enhancement at 0.88 (H-3a), 2.05-2.21 (H-10), 4.63 (H-4), and 5.34-5.48 (H-8, H-9); irradiation at 8 4.63 (H-4) caused signal enhancement at 0.42 (H-3b), 1.66 (H-6), and 5.34-5.48 (H-8, H-9); irradiation at 8 5.41 (H-8, H-9) caused signal enhancement at 2.05-2.21 (H-10) and 4.63 (H-4). 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: -5.3 (Si(CH3)2), 14.0, 18.0, 18.3 (-ve), 21.7 (-ve), 22.7 (-ve), 23.4, 25.7, 25.9 (-ve), 26.0 (C(CH3)3), 26.8 (-ve), 28.4 (-ve), 32.1 (-ve), 32.8 (-ve), 40.9 (-ve), 63.2 (-ve, C-13), 125.7, 130.1, 130.7 (-ve, C-5), 134.2 Exact mass calcd for C 2 4H460Si: 378.3318. Found: 378.3314. Anal, calcd for C 2 4 H 4 6 O S i : C 76.12, H 12.24. Found: C 76.30, H 12.38. 300 Table 40: *H N M R (400 MHz) and COSY (400 MHz) Data for 152 (in CDC13). ' H N M R 8 (mult, number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.03 (s, 6H) Si(CH 3) 2 No correlation 0.42 (dd, IH, 7= 4.5, 4.5 Hz) H-3b a H-2, H-3a 0.80-0.92 (overlapping signals, including a singlet centered at 8 0.87,13H) H-18, C(CH 3) 3 (8 0.87), H-3a (8 0.88)6 H-2, H-3b, H-17 1.12-1.56 (overlapping signals, 13H) H-2 (8 1.35),c H-11, H-12, H-14, H-15,H-16, H-17 H-3a, H-3b, H-4, H-10, H-13,H-18 1.66 (brd, 3H ,7 = 1 Hz) H-6° H-4 1.70 (brd, 3H ,7 = 1 Hz) H-7 H-4 2.05-2.21 (m, 2H) H-10 H-8, H-9, H-11 3.59 (t, 2H,7=6.5 Hz) H-13 H-12 4.59-4.68 (m, IH) H-4 H-2, H-6, H-7 5.34-5.48 (overlapping signals, 2H) H-8, H-9 H-10 a The assignment is based on the results of the NOE difference experiment. b The COSY experiment gave an approximate chemical shift (8) value of 0.88 for H-3a. c The COSY experiment gave an approximate chemical shift (8) value of 1.35 for H-2. 301 Preparation of 153. 153 Following general procedure 9 (p 290), as-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b) (p 275) was converted into the 1,2-divinylcyclopropane 153 with the following quantities of reagents and solvents: cw-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b), 67.1 mg (0.230 mmol), in THF, 0.92 mL; BuLi in hexanes, 0.34 mL (0.47 mmol); ZnCl 2 in THF, 0.69 mL (0.34 mmol); (Ph3P)4Pd, 27.0 mg (0.0234 mmol); 1-iodo-l-cyclohexene (118),101 104 mg (0.500 mmol) in DMF, 1.38 mL. Filtration of the crude product through 1 g of Merck (grade 60) silica gel (elution with 10 mL of petroleum ether), concentration of the filtrate (water aspirator), and distillation (90-110°C/0.4 torr) of the acquired oil afforded 32.3 mg (57%) of the 1,2-divinylcyclopropane 153 as a colorless oil. *H N M R analysis of 153 302 indicated a trace amount of the Cope rearrangement product (see p 317). The spectral data of 153 are as follows: IR(neat): 1449,1377,1070 cm-1. See Table 41 on p 303 for *H N M R and COSY data. In NOE difference experiments, irradiation at 8 4.59 (H-10) caused enhancement at 0.62 (H-3b), 1.64 (H-12), and at 5.41-5.48 (H-5); irradiation at 8 5.44 (H-5) caused enhancement at 0.62 (H-3b) and at 4.59 (H-10). 1 3 C N M R and APT (CDC13, 75.4 MHz) 8: 14.1 (-ve), 18.0 (-ve), 19.1, 22.7, 22.9, 23.1, 23.4 (-ve), 25.3, 25.8 (-ve), 26.5, 27.2, 31.9, 33.9, 37.6, 124.2 (-ve), 125.4 (-ve), 129.9, 137.3. Exact mass calcd for C i 8 H 3 0 : 246.2347. Found: 246.2353. Anal, calcd for C i 8 H 3 0 : C 87.73, H 12.27. Found: C 87.70, H 12.38. 303 Table 41: *H N M R (400 MHz) and COSY (200 MHz) Data for 153 (in CDC13). *HNMR 5 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.58-0.69 (overlapping signals, including a doublet of doublets, 7=8 , 4.5 Hz, centered at 8 0.66, 2H total) H-3a (8 0.66), H-3b a H-2 0 .84( t ,3H,7=7Hz) H-18 H-17 1.10-2.04 (overlapping signals, including two broad singlets centered at 8 1.64 and 1.68, 23H total) H-12 (8 1.64),a H-13 (8 1.68), H-2 (81.30),* H-6, H-7, H-8, H-9, H-14, H-15, H-16, H-17 H-3a, H-3b, H-5, H-10, H-18 4.55-4.61 (m, IH) H-10 H-2, H-12, H-13 5.41-5.48 (m, IH) H-5 H-6 " The assignment is based on the results of the NOE difference experiment. b The COSY experiment gave an approximate chemical shift (8) value of 1.30 for H-2. 304 Preparation of 155. Following general procedure 9 (p 290), frarcs-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a) (p 273) was converted into the 1,2-divinylcyclopropane 155 with the following quantities of reagents and solvents: fra/u-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a), 162 mg (0.554 mmol), in THF, 2.22 mL; BuLi in hexanes, 0.77 mL (1.14 mmol); ZnCl 2 in THF, 1.66 mL (0.830 mmol); (Ph3P)4Pd, 64.0 mg (0.0554 mmol); trans-6-(fert-butyldimethylsiloxy)-l-iodo-l-hexene (124) (p 219), 383 mg (1.12 mmol) in DMF, 3.26 mL. Radial chromatography (2 mm plate, 9:1 petroleum ether-CH2Cl2) of the crude product and subjection of the acquired oil to reduced pressure and heat (0.3 torr/r.t. to 140°C) in order to remove remaining impurities afforded 107 mg (51%) of the 1,2-divinylcyclopropane 155 as a 305 colorless oil. The spectral data of 155 are as follows: IR (neat): 1665, 1462, 1255, 1103, 967, 837, 775 cm"1. See Table 42 on p 306 for J H N M R and COSY data. In decoupling experiments, irradiation at 8 2.03 (H-10) simplified the signals at 5.36-5.51 (H-8, H-9) to two doublets centered at 5.41 (J = 15.5 Hz) and 5.48 (7 = 15.5 Hz). In NOE difference experiments, irradiation at 8 0.48 (H-3b) caused signal enhancement at 1.08 (H-3a) and 5.02 (H-4); irradiation at 8 5.02 (H-4) caused signal enhancement at 0.48 (H-3b) and 1.67-1.70 (H-6); irradiation at 8 5.36-5.51 (H-8, H-9) caused signal enhancement at 1.08 (H-3a), 1.22-1.60 (includes H-2), and 2.03 (H-10). 1 3 C N M R and APT (C 6D 6 , 50.3 MHz) 8: -5.2 (-ve, Si(CH3)2), 14.3 (-ve), 18.4 (-ve), 18.5, 21.6, 23.0, 25.72 (-ve), 25.74 (-ve), 26.1 (-ve, C(CH 3) 3), 26.4, 27.2, 28.5, 32.6, 32.7, 33.2, 63.1 (C-9), 124.6 (-ve), 127.0 (-ve), 133.0, 136.6 (-ve, C - l l ) . Exact mass calcd for C 2 4H460Si: 378.3318. Found: 378.3316. 306 Table 42: *H N M R (400 MHz) and COSY (400 MHz) Data for 155 (in C 6 D 6 ) . *H N M R 8 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.06 (s, 6H) Si(CH 3) 2 No correlation 0.48 (dd, IH, 7= 5.5, 4.5 Hz) H-3b a H-3a, H-2 0.90 (t, 3 H , 7 = 7 H z ) H-18 H-17 0.98 (s, 9H) C(CH 3) 3 No correlation 1.08 (dd, 1H,7=8.5, 4.5 Hz) H-3a H-2, H-3b 1.22-1.65 (overlapping signals, overlap with downfield signals, 13H) H-11, H-12, H-14, H-15,H-16,H-17, H-2 (1.60)fc H-3a, H-3b, H-4, H-10, H-13, H-18 1.67-1.70 (two broad overlapping signals centered at 8 1.68 and 1.69, overlap with upfield signals, 6H) H-6, H-7 H-4 2.03 (dt, 2 H , 7 = 7 , 7 H z ) H-10 H-9, H-11 3.54 (t, 2H,7=6.5 Hz) H-13 H-12 4.99-5.06 (m, IH) H-4 H-2, H-6, H-7 5.36-5.51 (overlapping signals, 2H) H-8, H-9 H-10 a The assignment is based on the general observation that J > J trans for cyclopropyl protons.' b The COSY experiment gave an approximate chemical shift (5) value of 1.60 for H-2. 307 Preparation of 156. 6 7 156 Following general procedure 9 (p 290), *ran£-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a) (p 273) was converted into the 1,2-divinylcyclopropane 156 with the following quantities of reagents and solvents: rra/w-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a), 103 mg (0.352 mmol), in THF, 1.41 mL; BuLi in hexanes, 0.49 mL (0.72 mmol); ZnCl 2 in THF, 1.06 mL (0.530 mmol); (Ph3P)4Pd, 40.8 mg (0.0353 mmol); cis-6-(fert-butyldimethylsiloxy)-l-iodo-l-hexene (123) (p 217), 248 mg (0.729 mmol) in DMF, 2.10 mL. Radial chromatography (2 mm plate, 9:1 petroleum ether-CH2Cl2) of the crude product and subjection of the acquired oil to reduced pressure and heat (0.3 torr/r.t. to 135°C) in order to remove remaining impurities afforded 66.0 mg (49%) of the 1,2-divinylcyclopropane 156 as a 308 colorless oil. The spectral data of 156 are as follows: IR (neat): 1463, 1255, 1102, 837, 775 cm"1. See Table 43 on p 309 for *H N M R and COSY data. In decoupling experiments, irradiation at 8 1.68-1.75 (H-6, H-7) sharpened the signal at 4.88 (H-4); irradiation at 8 2.13 (H-10) simplified the signal at 5.30 (H-9) to a doublet, J = 10.5 Hz, and sharpened the signal at 5.48 (H-8). In NOE difference experiments, irradiation at 8 0.37 (H-3b) caused enhancement at 0.87 (H-3a), 1.25-1.37 (CH 2 protons), and 4.84-4.91 (H-4); irradiation at 8 4.87 (H-4) caused enhancement at 0.37 (H-3b), 1.25-1.37 (CH 2 protons), and 1.68-1.75 (H-6). 1 3 C N M R (CDC13, 125 MHz) 8: -5.3 (-ve, Si(CH3)2), 14.1 (-ve), 18.2 (-ve), 18.4, 22.0, 22.6, 24.3 (-ve), 25.86 (-ve), 25.91, 26.0 (-ve, C(CH 3) 3), 26.8, 28.5, 32.2, 32.8, 34.8, 63.2, 124.2 (-ve), 132.4 (C-5), 132.5 (-ve), 134.1 (-ve). Exact mass calcd for C 2 4 H 4 6 O S i : 378.3318. Found: 378.3316. 309 Table 43: 'H N M R (400 MHz) and COSY (400 MHz) Data for 156 (in CDC13). ' H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.02 (s, 6H) Si(CH 3) 2 No correlation 0.37 (dd, IH, J =5.5, 4 Hz) H-3b f l H-2, H-3a 0.81-0.92 (overlapping signals, including a singlet centered at 8 0.88, 13H total) H-3a (8 0.87),fe C(CH 3) 3 (80.88), H-18 H-2, H-3b, H-17 1.12-1.60 (overlapping signals, 13H) H-2 (8 1.45),c H - l l , H-12, H-14, H-15, H-16,H-17 H-3a, H-3b, H-4, H-10, H-13, H-18 1.68-1.75 (overlapping signals, 6H) H-6, H-7 H-4 2.13 (br dt, 2H, 7=7 , 7 Hz) H-10 H-8, H-9, H - l l 3.59 (t, 2H, 7 =6.5 Hz) H-13 H-12 4.84-4.91 (m, IH) H-4 H-2, H-6, H-7 5.30 (dt, 1H,7= 10.5, 7 Hz) H-9 H-8, H-10 5.48 (brd, 1H,7= 10.5 Hz) H-8 H-9, H-10 a The assignment is based on the results of the NOE difference experiment. b The COSY experiment gave an approximate chemical shift (8) value of 0.87 for H-3a. c The COSY experiment gave an approximate chemical shift (8) value of 1.45 for H-2. 310 Preparation of 157. 157 Following general procedure 9 (p 290), rranj-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a) (p 273) was converted into the l-phenyl-2-vinylcyclopropane 157 with the following quantities of reagents and solvents: frans-l-iodo-2-(2-methyl-l-propenyl)-l-' pentylcyclopropane (116a), 127 mg (0.435 mmol), in THF, 1.74 mL; BuLi in hexanes, 0.56 mL (0.89 mmol); ZnCl 2 in THF, 1.31 mL (0.655 mmol); (Ph3P)4Pd, 50.0 mg (0.0433 mmol); iodobenzene (117),25 180 mg (0.882 mmol) in DMF, 2.65 mL. Radial chromatography (2 mm plate, petroleum ether) of the crude product and distillation (90-110°C/0.3 torr) of the acquired oil afforded 45.4 mg (43%) of 157 as a colorless oil. The spectral data of 157 are as follows: IR (neat): 3060 (w), 3030 (w), 1602,1495, 1446,1376,1154,1125, 1076, 764,700 cm"1. See Table 44 on p 311 for *H N M R and COSY data. 311 In NOE difference experiments, irradiation at 8 0.61 (H-3b) caused signal enhancement at 1.25 (H-3a), 1.53 (CH.2 protons, most likely H-14), 5.04 (H-10); irradiation at 8 5.04 (H-10) caused signal enhancement at 0.61 (H-3b), 1.53 (CH 2 protons, most likely H-14), and 1.76 (H-12). 1 3 C N M R and APT (CDC13, 125 MHz) 8: 14.0 (-ve), 18.3 (-ve), 20.7, 22.5, 24.1 (-ve), 25.8 (-ve), 26.6, 32.0, 32.2, 35.5,123.9 (-ve), 125.7 (-ve), 128.0 (-ve), 128.9 (-ve), 133.4,146.7. Exact mass calcd for C i 8 H 2 6 : 242.2034. Found: 242.2034. Anal, calcd for C 1 8 H 2 6 : C 89.19, H 10.81. Found: C 89.36, H 10.80. Table 44: *H N M R (400 MHz) and COSY (400 MHz) Data for 157 (in CD 2 Cl 2 ) . a *H N M R 8 (mult, number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.61 (dd, IH, J =5.5, 4.5 Hz) H-3bfc H-2, H-3a 0.82 (t, 3 H , 7 = 7 H z ) H-18 H-17 1.10-1.32 (overlapping signals, including a doublet of doublets of doublets, 7= 8.5, 4.5,1 Hz, centered at 8 1.25, 7H total) H-3a (8 1.25), C H 2 protons H-2, H-3b, H-18, 1.43-1.87 1.43-1.87 (overlapping signals, including a broad signal centered at 8 1.76, 9H total) H-2 (8 1.70),c H-12 and H-13 (both at 8 1.76), C H 2 protons H-3a, H-3b, H-10,H-18 5.01-5.07 (m, IH) H-10 H-2, H-12, H-13 7.12-7.31 (overlapping signals, 5H) aromatic protons aromatic protons 0 There was overlap of signals in the X H spectrum of 157 in CDC13. b The assignment is based on the results of NOE difference experiments and on the general observation that J ^ > J trans for cyclopropyl protons.67b c The COSY experiment gave an approximate chemical shift (8) value of 1.70 for H-2. 312 Preparation of 158. Following general procedure 9 (p 290), cw-2-iodo-l-(2-methyl-l-propenyl)-l-pentylcyclopropane (116c) (p 276) was converted into the l-phenyl-2-vinylcyclopropane 158 with the following quantities of reagents and solvents: c/s-2-iodo-l-(2-methyl-l-propenyl)-l-pentylcyclopropane (116c), 59.1 mg (0.202 mmol), in THF, 0.81 mL; BuLi in hexanes, 0.27 mL (0.42 mmol); ZnCl 2 in THF, 0.61 mL (0.30 mmol); (Ph3P)4Pd, 23.4 mg (0.0202 mmol); iodobenzene (117),26 82.0 mg (0.402 mmol) in DMF, 1.23 mL. Radial chromatography (2 mm plate, petroleum ether) of the crude product and distillation (100-125°C/0.3 torr) of the acquired oil afforded 19.4 mg (40%) of 158 as a colorless oil. 313 The spectral data of 158 are as follows: IR (neat): 3100 (w), 3060 (w), 3040 (w), 1606, 1498, 1457, 1378,1091,1072, 1031 cm"1. See Table 45 below for 1 H N M R and COSY data. In a NOE difference experiment, irradiation at 8 7.10 (aromatic protons) caused signal enhancement at 0.99 (H-3b), 1.84 (H-2), and 4.87 (H-10); irradiation at 8 0.99 (H-3b) caused signal enhancement at 1.11 (H-3a), 4.87 (H-10), and 7.10 (aromatic protons). 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: 14.1, 19.1, 20.7 (-ve), 22.8 (-ve), 25.3, 27.0 (-ve), 28.8 (-ve), 29.5, 32.2 (-ve), 41.6 (-ve), 124.1, 125.0, 127.5, 127.7, 136.7 (-ve), 140.4 (-ve). Exact mass calcd for C i 8 H 2 6 : 242.2034. Found: 242.2037. Anal, calcd for C i 8 H 2 6 : C 89.19, H 10.81. Found: C 89.15, H 10.84. Table 45: *H N M R (400 MHz) and COSY (400 MHz) Data for 158 (in CDC13)." ' H N M R 8 (mult., number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.89 (t, 3H,7=7Hz) H-18 H-17 0.99 (dd, 1H,7=6, 4.5 Hz)) H-3b* H-2, H -3a 1.11 (dd, IH, 7= 8.5, 4.5 Hz) H-3a H-2, H-3b 1.20-1.73 (overlapping signals, including two broad signals centered at 8 1.56 and at 8 1.62,14H total) H-12 (8 1.56 or 1.62), H-13 (8 1.56 or 1.62), H-14,H-15, H-16, H-17 H-10,H-18 1.84 (dd, IH, 7= 8.5, 6 Hz) H-2 H-3a, H-3b 4.87 (br signal, IH) H-10 H-12,H-13 6.98-7.26 (overlapping signals, 5H) aromatic protons aromatic protons a TMS was used as the reference. The assignment is based on the results of NOE difference experiments. 314 Preparation of 159. 159 Following general procedure 9 (p 290), c«-2-iodo-l-(2-methyl-l -propenyl)- l -pentylcyclopropane (116c) (p 276) was converted into the 1,2-divinylcyclopropane 159 with the following quantities of reagents and solvents: ds-2-iodo-l-(2-methyl-l-propenyl)-l-pentylcyclopropane (116c), 42.9 mg (0.147 mmol), in THF, 0.59 mL; BuLi in hexanes, 0.20 mL (0.30 mmol); ZnCl 2 in THF, 0.44 mL (0.22 mmol); (Ph3P)4Pd, 17.0 mg (0.0147 mmol); cis-6-(tert-butyldimethylsiloxy)-l-iodo-l-hexene (123) (p 217), 103 mg (0.303 mmol) in DMF, 0.89 mL. Radial chromatography (2 mm plate, 75:25 petroleum ether-CH2Cl2) of the crude product and subjection of the acquired oil under reduced pressure and heat (0.3 torr/r.t. to 130°C) in order to remove remaining impurities afforded 35.0 mg (63%) of the 1,2-divinylcyclopropane 159 as a colorless oil. 315 The spectral data of 159 are as follows: IR (neat): 3060(w), 1651, 1463,1378,1255,1104, 836, 775 cm"1. See Table 46 on p 316 for *H N M R and COSY data. In decoupling experiments, irradiation at 8 2.28 (H-10) sharpened the signal at 5.12 (H-8) and simplified the signal at 5.48 (H-9) to a doublet, J = 11 Hz. In NOE difference experiments, irradiation at 8 0.58 (H-3b) caused signal enhancement at 0.93 (H-3a), 5.12 (H-8), and 5.40 (H-4); irradiation at 8 5.12 (H-8) caused signal enhancement at 0.58 (H-3b), 5.40 (H-4), 5.48 (H-9). 1 3 C N M R and APT (C 6D 6 , 75.4 MHz) 8: -5.2 (-ve, Si(CH3)2), 14.3 (-ve), 18.5, 19.3 (-ve), 22.7, 23.1, 23.6 (-ve), 25.6 (-ve), 26.2 (-ve, C(CH 3) 3), 26.6, 26.8, 27.3, 27.8, 32.5, 32.9, 41.3, 63.2 (C-13), 125.6 (-ve), 128.7 (-ve), 131.7 (-ve), 136.3 (C-5). Exact mass calcd for C 2 4H4 6 OSi : 378.3318. Found: 378.3326. Anal, calcd for C 2 4 H 4 6 O S i : C 76.12, H 12.24. Found: C 76.00, H 12.25. 316 Table 46: *H N M R (400 MHz) and COSY (400 MHz) Data for 159 (in C 6 D 6 ) . ' H N M R 8 (mult, number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.07 (s, 6H) Si(CH 3) 2 No correlation 0.58 (dd, IH, 7=4.5, 4.5 Hz) H-3b* H-2, H-3a 0.86-1.02 (overlapping signals, including a triplet, 7 = 7 Hz, centered at 8 0.89, a doublet of doublets, 7 = 8.5, 4.5 Hz, centered at 8 0.93, and a singlet centered at 8 0.98,13H total) H-18 (8 0.89), H-3a (8 0.93), C(CH 3) 3 (8 0.98) H-2, H-3b, H-17 1.20-1.72 (overlapping signals, including two broad doublets centered at 8 1.64, 7 = 1 Hz, and 1.70,7= 1 Hz, 19H total) H-2 (8 1.63),fc H-6 (81.64 or 1.70), H-7 (8 1.64 or 1.70), H-11, H-12, H-14, H-15, H-16, H-17 H-3-a, H-3b, H-4 H-8, H-10, H-13, H-18 2.28 (tdd, 2H, 7 = 7.5, 7.5, 1.5 Hz) H-10 H-8, H-9, H-11 3.59 (t, 2 H , 7 = 6 H z ) H-13 H-12 5.12(brdd,7= 11,11 Hz) H-8 H-2, H-9, H-10 5.40 (br signal, IH) H-4 H-6, H-7 5.48 (dt, 1H,7= 11,7.5 Hz) H-9 H-8, H-10 The assignment is based on the results of NOE difference experiments and on the general observation that J cis> J trans for cyclopropyl protons.67" b The COSY experiment gave an approximate chemical shift (8) value of 1.63 for H-2. 317 5.3.7.2. Preparation of the bicyclic compound 154. 153 154 A solution of the 1,2-divinylcyclopropane 153 (p 301) (5.3 mg, 0.020 mmol) in o-xylene-dio (1 mL) was refluxed for 1 h. G L C and ! H N M R analyses of the reaction mixture indicated complete and clean rearrangement of the 1,2-divinylcyclopropane to the cycloheptadiene 154. Concentration (0.3 torr) of the mixture afforded 4.8 mg (91%) of the cycloheptadiene 154 as a colorless oil. The spectral data of 154 are as follows: IR (neat): 1655 (w), 1465, 1375,1358 cm - 1 . See Table 47 on p 318 for lH NMR, COSY, 1 3 C, and HMQC data. Exact mass calcd for CigH 3 0 : 246.2347. Found: 246.2347. Anal, calcd for C i 8 H 3 0 : C 87.73, H 12.27. Found: C 87.68, H 12.40. Table 47: 'H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and H M Q C Data for 154 (in CDC13). *H N M R 8 (mult, number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 1 3 C and HMQC f l 8 (APT (50.3 MHz)), assignment (C-X) 0.86 (t, overlap with downfield singlet, 3 H , 7 = 7 H z ) H-18 H-17 14.1 (-ve),C-18 0.89 (s, overlap with upfield triplet, 3H,) H-12 N/A 23.0 (-ve), C-12 0.95 (s, 3H) H-13 N/A 28.6 (-ve), C-13 1.08-1.73 (overlapping signals, 12H) H-8, H-9, H-10, H-15, H-16, H-17 H-7, H - l la , H - l lb , H-14a, H-14b, H-18 21.3, 22.7, 23.4, 28.7, 29.7, 31.6 C-8, C-9, C-10, C-15, C-16, C-17 1.83-1.97 (overlapping signals, 2H) H - l la , H-14a 1.08- 1.73, 2.09- 2.22 ( H - l l b or H-14b), 2.34-2.45 ( H - l l b or H-14b) 24.7, C - l l orC-14; 34.4, C - l l or C-14 2.09-2.22 (overlapping signals, including a doublet of doublets, J= 17, 8.5 Hz, centered at 8 2.16, 2H total) H-3a (8 2.16) H - l lb or H-14b H-3b, H-4, H - l l a or H-14a, 1.08-1.73 31.9, C-3; 34.4, C - l l or C-14 2.34-2.45 (m, IH) H - l lb or H-14b H - l l a or H-14a, 1.08-1.73 24.7, C - l l or C-14 2.78 (dd, 1H,7= 11,6.5 Hz) B-7b H-8 46.9 (-ve), C-7 3.22 (m, IH) H-3b H-3a, H-4, H-5 31.9, C-3 Table 47 is continued on the next page 319 Table 47 (continued). ! H N M R (400 MHz), COSY (400 MHz), 1 3 C (125 MHz), and HMQC Data for 154 (in CDC13). 5.11 (dd, 1H,7= 11.5, 3 Hz) H-5 H-3b, H-4 142.2 (-ve), C-5 5.43 (ddd, 1H,7=11.5, 8.5, 2.5 Hz) H-4 H-3a, H-3b, H-5 123.6 (-ve), C-4 N/A N/A N/A 135.2, C - l or C-2 N/A N/A N/A 135.7, C - l or C-2 N/A N/A N/A 37.5, C-6 f c " This column organizes the 1 3 C signals according to their correlation to the X H signals as given by the HMQC experiment. The quaternary carbons are listed in the final three rows of the table. b The assignment is based in part on the results of the HMQC experiment. 320 5.3.8. Spiro[2.4]heptanes and Related Compounds. 5.3.8.1. Silylation. Germylation. and Methylation of as-2-(HydroxymethylM-iodo-l-(4-pentynyDcyclopropane (60c). General Procedure 10. In the following procedure, all amounts are related to the use of 1 mmol of starting material. To a cold (-30°C), vigorously stirred solution of cw-2-(hydroxymethyl)-l-iodo-l-(4-penrynyl)cyclopropane (60c) (p 227) in dry THF (10 mL) was added a solution of freshly prepared L D A (2.1-2.5 mmol) in THF (2.1-2.5 mL) and the solution was stirred for 2 h. The electrophile (1.5-5 mmol) was added neat with a gas-tight syringe (in the case of 227 (p 324), the reaction mixture was cooled to -78°C before the addition of the electrophile). The cooling bath was removed and the mixture was allowed to warm to r.t. (0°C in the case of 227) for the specified time (vide infra). After the mixture had been cooled to 0°C the vessel was opened and -3 .5 g of Merck (grade 60) silica gel was added. The mixture was allowed to warm while being stirred vigorously for -15 minutes. The suspension was filtered (elution with Et20) and the filtrate was concentrated (water aspirator). Products 225 (p 321) and 226 (p 322) were further treated with AcOH (vide infra). Purification of the crude product (vide infra) provided the functionalized iodocyclopropane. 321 Preparation of ds-2-(Hydroxymethyl)-l-iodo-l-(5-tjim propane (225). H-3a H-3b OH TMS H 2 OH 4 60c 225 Following general procedure 10 (p 320), cw-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c) (p 227) was converted into as-2-(hydroxymethyl)-l-iodo-l-(5-trimethylsilyl-4-pentynyl)cyclopropane (225) employing a warming period (-30°C to r.t.) of 2.2 h and the following quantities of reagents and solvents: cw-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c), 37.3 mg, (0.141 mmol), in THF, 1.4 mL; L D A in THF, 0.35 mL (0.35 mmol); Me 3 SiCl , 0.090 mL (0.71 mmol). The crude product was stirred with 5% v/v AcOH in MeOH (1.5 mL) for 15 minutes and the solution was concentrated (0.3 torr). Radial chromatography (1 mm, 3:2 petroleum ether-Et20) of the crude product, followed by distillation (125-145°C/0.3 torr) of the acquired liquid, afforded 34.0 mg (72%) of 225 as a colorless oil. The spectral data of 225 are as follows: IR (neat): 3355 (br), 3070 (w), 2174, 1430,1250,1039, 843,760 cm"1. *H N M R (CDC13, 400 MHz) 5: 0.11 (s, 9H, Si(CH3)3), 0.50-0.61 (m, IH, H-2), 0.88 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 1.03 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.53-1.68 (overlapping signals, slight overlap with downfield m, 3H, H-5a, H-6), 1.68-1.80 (m, slight overlap with upfield m, IH, H-5b), 1.83 (br signal, IH, exchanges with D 2 0 , OH), 2.22-2.29 (m, 2H, H-7), 3.48 (br dd, IH, J 322 = 12, 9 Hz, sharpens upon D 2 0 addition, H-4a), 3.94 (m, IH, collapses to a dd, J = 12, 4.5 Hz, upon addition of D2O, H-4b). 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: 0.0 (-ve, Si(CH3)3), 17.2, 18.5, 21.6, 26.1 (-ve), 28.4, 44.0, 69.3, 85.1, 106.6. Exact mass calcd for Ci 2 H 2 i IOSi : 336.0406: Found: 336.0397. Anal, calcd. for Ci 2 H 2 1 IOSi : C 42.86, H 6.29. Found: C 42.81, H 6.19. Preparation of cis-1 -(5-fg^ButyldimethylsUyl-4-pentynyl)-2-(hydroxymemyl)-1-iodocyclopropane (226). 4 60c 226 Following general procedure 10 (p 320), cw-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c) (p 227) was converted into cw-l-(5-rerf-butyldimethylsilyl-4-pentynyl)-2-(hydroxymethyl)-l-iodocyclopropane (226) employing a warming period (-30°C to r.t.) of 4.5 h and the following quantities of reagents and solvents: cw-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c), 65.7 mg (0.249 mmol), in THF, 2.5 mL; L D A in THF, 0.62 mL (0.62 mmol); T B D M S O , 188 mg (1.25 mmol). The crude product was stirred with 3:1:1 AcOH:water:THF (by volume) (5 mL) for 12 h and the solution was concentrated (0.3 torr). Sequential radial chromatography (1 mm and 2 mm plates, 3:2 petroleum ether-Et20) of the crude 323 product and subjection of the oil thus obtained to reduced pressure (0.3 torr) afforded 44.0 mg (47%) of 226 as a colorless oil. The spectral data of 226 are as follows: IR (neat): 3348 (br), 3067 (w), 2173, 1471, 1250, 1039, 838, 776 cm"1. J H N M R (C 6D 6 , 400 MHz) 8: 0.14 (s, overlap with downfield m, 6H, Si(CH3)2), 0.10-0.26 (m, overlap with upfield singlet, IH, H-2), 0.54 (dd, overlap with downfield signal, IH, J = 6.5, 6.5 Hz, H-3b), 0.59 (dd, overlap with upfield signal, IH, J = 9.5, 6.5 Hz, H-3a), 1.02 (s, 9H, C(CH 3) 3), 1.19 (dd, IH, J= 8, 5 Hz, exchanges with D 2 0 , OH), 1.22-1.33 (m, IH, H-5a), 1.50-1.66 (m, 3H, H-5b, H-6), 1.98-2.05 (m, 2H, H-7), 3.29 (ddd, IH, J = 12, 8.5, 5 Hz, simplifies to br dd, J = 12, 8.5 Hz, upon addition of D 2 0 , H-4a), 3.66 (ddd, IH, J = 12, 8, 5 Hz, simplifies to dd, J = 12, 5 Hz, upon addition of D 2 0 , H-4b). 1 3 C N M R and APT (C 6D 6 , 50.3 MHz) 8: -4.2, 16.7, 17.5, 18.8, 21.7, 26.3, 26.4, 28.8, 44.3, 69.2, 83.3, 108.0. Exact mass calcd for C 1 5 H 2 7 IOSi : 378.0876. Found: 378.0885. Anal, calcd for C 1 5 H 2 7 IOSi : C 47.62, H 7.19. Found: C 47.93, H 7.17. 324 Preparation of d5-2-(HydroxymemylVl-iodo-l-(5-trimemylgem cyclopropane (227). H-3a OH Me3Ge' H 2 OH H-3b 4 60c 227 Note: In the following procedure, the electrophile (MesGeBr) was added at -78°C and the reaction mixture was stirred at 0°C for 2h. Following general procedure 10 (p 320), cw-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c) (p 227) was converted into cw-2-(hydroxymethyl)-l-iodo-l-(5-trimethylgermyl-4-pentynyl)cyclopropane (227) employing a warming period (-78°C to 0°C) of 2 h and the following quantities of reagents and solvents: ds-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c), 96.7 mg (0.366 mmol), in THF, 3.7 mL; L D A in THF, 0.77 mL (0.77 mmol); Me 3GeBr, 0.071 mL (0.55 mmol). Sequential radial chromatography (1 mm and 1 mm plates, 3:2 petroleum ether-Et20) of the crude product and subjection of the oil thus obtained to reduced pressure (0.3 torr) afforded 105 mg (75%) of 227 as a colorless oil. The spectral data of 227 are as follows: IR (neat): 3343 (br), 3070 (w), 2171,1415, 1240,1032, 833,768 c m 1 . *H N M R (CDC13,400 MHz) 5: 0.30 (s, 9H, Ge(CH3)3), 0.51-0.61 (m, IH, H-2), 0.88 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 1.04 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.52-1.68 (overlapping signals, 325 slight overlap with downfield signal, 2H, reduces to m, IH, upon addition of D 2 0 , H-5a, OH), 1.68-1.86 (overlapping signals, slight overlap with upfield signal, 3H, H-5b, H-6), 2.23-2.30 (m, 2H, H-7), 3.49 (dd, IH, J = 12, 9 Hz, sharpens upon D 2 0 addition, H-4a), 3.96 (dd, IH, J = 12, 5 Hz, sharpens upon D 2 0 addition, H-4b). 1 3 C N M R and APT (CDC13, 75.4 MHz) 5: -0.11(-ve, Ge(CH3)3), 17.4, 18.6, 21.7, 26.2 (-ve), 28.6, 44.1,69.4, 84.8, 105.2. LRDCLMS (NH3): M( 7 4Ge)NH4 + (400). Exact mass calcd for CnHi 8 7 4 GeIO (M + -CH 3 ) : 366.9614. Found: 366.9611. Anal, calcd for Ci 2 H 2 1 GeIO: C 37.85, H 5.56. Found: C 38.00, H 5.68. Preparation of ds-l-(4-Hexynyl)-2-(hydroxymethyl)-l-iodocyclopropane (228). 60c 228 Note: The reaction was conducted in a Schlenk flask in order to avoid the loss of Mel . Following general procedure 10 (p 320), ds-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c) (p 227) was converted into ds-l-(4-hexynyl)-2-(hydroxymethyl)-l-iodocyclopropane (228) employing a warming period (-30°C to r.t.) of 1.2 h and the following quantities of reagents and solvents: c/5-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane 326 (60c), 69.1 mg (0.262 mmol), in THF, 2.6 mL; L D A in THF, 0.55 mL (0.55 mmol); Me l , 0.034 mL (0.55 mmol). Radial chromatography (1 mm plate, 17:3 petroleum ether-Et20) of the crude product, followed by distillation (120-140°C/0.3 torr) of the acquired liquid, afforded 41.3 mg (57%) of 228 as a colorless oil. The spectral data of 228 are as follows: IR (neat): 3344 (br), 2990 (w), 2919, 1441, 1038 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.52-0.62 (m, IH, H-2), 0.89 (dd, IH, J = 6.5, 6.5 Hz, H-3b), 1.04 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.51-1.85 (overlapping signals, including a triplet, J = 2.5 Hz, centered at 8 1.73 (H-10), 7H total, H-5, H-6), 1.94 (br s, IH, exchanges with D 2 0 , OH), 2.13-2.23 (m, 2H, H-7), 3.49 (br dd, IH, J = 12, 9 Hz, sharpens upon addition of D 2 0 , H-4a), 3.95 (br dd, IH, J = 12, 5 Hz, sharpens upon addition of D 2 0 , H-4b). 1 3 C N M R and APT (CDC13, 50.3 MHz) 8: 3.4 (-ve), 17.6, 17.7, 21.7, 26.2 (-ve), 28.9, 44.2, 69.4, 76.0, 78.5. Exact mass calcd for C10H15IO: 278.0168. Found: 278.0173. Anal, calcd for C 1 0 H 1 5 IO: C 43.18, H 5.44. Found: C 43.46, H 5.54. 5.3.8.2. Preparation of a5-2-(HydroxymethylVl-iodo-l-(5-phenyl-4-penty^ propane (229). 327 Iodobenzene (126 mg, 0.616 mmol) was added to a solution-suspension of cis-2-(hydroxymethyl)-l-iodo-l-(4-pentynyl)cyclopropane (60c) (p 227) (54.2 mg, 0.205 mmol), Cul (5 mg, 0.0262 mmol), and PdCl 2(PPh 3) 2 (8.3 mg, 0.0118 mmol) in i -Pr 2 NH (20.5 mL). After the mixture had been stirred at room temperature for 2h, the diisopropylamine was removed under reduced pressure (0.3 torr) and the resulting oil was dissolved in E t 2 0 (20 mL). Water (10 mL) and saturated aqueous NH4CI (20 mL) were added and the phases were separated. The aqueous phase was extracted with E t 2 0 (2 x 20 mL) and the combined extracts were dried (Na2SC»4) and concentrated (water aspirator). Radial chromatography (2 mm plate, 3:2 petroleum ether-Et20) of the crude product and subjection of the oils thus obtained to reduced pressure (0.3 torr) afforded 33.0 mg (47%) of 229 as a colorless oil and a mixture A. The mixture A was further purified by radial chromatography (2mm plate, Et 20) to afford 8.5 mg (8%) of the dimer 230. 328 The spectral data of 229 are as follows: IR (neat): 3368 (br), 3080 (w), 3060 (w), 2990 (w), 2240 (w), 1598, 1490, 1442, 1038, 757, 692 cm"1. lH N M R (CDC13, 400 MHz) 5: 0.57-0.67 (m IH, H-2), 0.93 (dd, IH, 7 = 6.5, 6.5 Hz, H-3b), 1.09 (dd, IH, 7 = 9.5, 6.5 Hz, H-3a), 1.65-1.79 (m, IH, H-5a), 1.81-1.94 (overlapping signals, 4H, reduces to 3H upon addition of D 2 0 , H-5b, H-6, OH), 2.45-2.53 (m, 2H, H-7), 3.52 (m, IH, collapses to a dd, 7 = 12, 9 Hz, upon addition of D 2 0 , H-4a), 3.99 (m, IH, collapses to a dd, 7 = 12, 5 Hz, upon addition of D 2 0 , H-4b), 7.25-7.32 (m, 3H, aromatic protons), 7.36-7.41 (m, 2H, aromatic protons). 1 3 C N M R (CDCI3, 50.3 MHz) 8: 17.8, 18.5, 22.1, 26.5, 28.9, 44.5, 69.7, 81.5, 89.8, 124.0, 127.9, 128.5, 131.8. Exact mass calcd for C15H17IO: 340.0324. Found: 340.0322. Anal, calcd for Ci 5 H 1 7 IO: C 52.96, H 5.04. Found: C 52.84, H 5.10. The spectral data of the dimer 230 are as follows: IR (neat): v = 3339 (br), 1456,1036 cm"1. X H N M R (CDCI3, 400 MHz): 8 = 0.53-0.62 (m, IH, H-2), 0.89 (dd, IH, 7=6.5, 6.5 Hz, H-3b), 1.04 (dd, IH, 7=9.5, 6.5 Hz, H-3a), 1.53-1.67 (m, IH, overlap with downfield m, H-5a), 1.70-1.87 (overlapping signals, 4H, reduces to 3H upon addition of D 2 0 , overlap with upfield m, H-5b, H-6, OH), 2.24-2.40 (m, 2H, H-7), 3.42-3.54 (m, IH, collapses to a dd (8 3.47, 7=12, 7 Hz) upon addition of D 2 0 , H-4a), 3.91-4.03 (m, IH, collapses to a dd (8 3.96, 7=12, 5 Hz) upon addition of D 2 0 , H-4b). HRDCIMS (NH3/CH4): calcd for C 1 8 H 2 5 I 2 0 2 (M + +H) : 526.9944. Found: 526.9932. 329 5.3.8.3. Reaction of the Substituted Alkynyl Iodocyclopropanes 225-229 with BuLi. General Procedure 11. In the following procedure, all amounts are related to the use of 1 mmol of the iodocyclopropane. A solution of BuLi in hexanes (-1.45 mL, 2.2 mmol) was added to a cold (-78°C), vigorously stirred solution of the iodocyclopropane in dry E t 2 0 (-5 mL). The solution was stirred at -78°C for 10 min and then was allowed to warm to r.t. for the specified time (vide infra). Water (-5 mL) was added to the resultant yellowish solution and stirring was continued for - 1 0 min. Water (-10 mL) and E t 2 0 (-10 mL) were added and the phases were separated. The aqueous phase was extracted with E t 2 0 (4x~15 mL). The combined organic phases were dried (Na2S04) and concentrated (water aspirator). Purification of the crude product (vide infra) provided the bicyclic alcohol. 330 Preparation of (IS*. 3£*M-(Hydroxymemyl)-4-(£-trimethy spiro[2.41heptane (2311. Following general procedure 11 (p 329), as-2-(hydroxymetJiyl)-l-iodo-l-(5-trimethylsilyl-4-pentynyl)cyclopropane (225) (p 321) was converted into (IS*, 35*)- l -(hydroxymethyl)-4-(E-uiraemylsilylmetliyUdene)spiro[2.4]heptane (231) employing a warming period (from -78°C) of 30 min and the following quantities of reagents and solvents: cis-2-(hydroxymethyl)-l-iodo-l-(5-1ximethylsilyl-4-pentynyl)cyclopropane (225), 64.5 mg (0.192 mmol), in Et20, 1.0 mL; BuLi in hexanes, 0.30 mL (0.42 mmol). Radial chromatography (2 mm plate, 3:2 petroleum ether-Et20) of the crude product gave two colorless oils. Brief subjection of each oil to reduced pressure (0.3 torr) afforded 31.8 mg (79%) of the bicyclic alcohol 231, and 2.8 mg (-7%) of slightly impure, reduced starting material 232. 331 The spectral data of 231 are as follows: IR (neat): 3322 (br), 3060 (w), 1617, 1403, 1247,1081,1029,1010, 870, 838 c m 1 . See Table 48 on p 332 for ! H N M R and COSY data. In decoupling experiments, irradiation at 8 1.60 (H-6a, H-6b) simplified the signals at 1.09-1.18 (H-7a, to a d, J = 9 Hz), 1.67-1.80 (H-7b), 2.24-2.37 (H-5b, to a dd, J = 17, 2 Hz) and 2.37-2.50 (H-5a, to a dd, J =11,2 Hz). In NOE difference experiments, irradiation at 8 3.33 (H-8b) caused enhancements at 0.66 (H-2b), 3.56 (H-8a), and 4.91 (H-9); irradiation at 8 4.91 (H-9) caused enhancements at 0.66 (H-2b) and 3.33 (H-8b). 1 3 C N M R and APT (C 6D 6 , 50.3 MHz) 8: 0.0 (-ve, Si(CH3)3), 14.5, 24.1, 33.3 (-ve), 34.0, 34.2, 37.9,61.0, 114.6 (-ve), 161.1. Exact mass calcd for C i 2 H 2 2 OSi : 210.1440. Found: 210.1439. Anal, calcd for C 1 2 H 2 2 OSi : C 68.51, H 10.54. Found: C 68.21, H 10.59. Table 48: X H N M R (400 MHz) and COSY (200 MHz) Data for 231 (in C 6 D 6 ) . X H N M R 8 (mult, number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.15 (s, 9H) Si(CH 3) 3 No correlation 0.66 (dd, l H , 7 = 5 ,5Hz) H-2b f l H - l , H - 2 a 0.72 (dd, overlap with downfield signal, IH, 7 = 8.5, 5 Hz,) H-2a H - l ,H -2b 0.78 (br signal, overlap with upfield signal, IH, exchanges with D 2 0) OH H-8a, H-8b (weak) 0.94-1.04 (m, IH) H - l H-2a, H-2b, H-8a, H-8b 1.09-1.18 (m, IH) H-7a H-5a (weak), H-6a, H-6b, H-7b 1.54-1.67 (m, overlap with downfield signal, 2H) H-6a, H-6b H-5a, H-5b, H-7a, H-7b 1.67-1.80 (m, overlap with upfield signal, IH) H-7b H-6a, H-6b, H-7a 2.24-2.37 (m, slight overlap with downfield signal, IH) H-5b H-5a, H-6a, H-6b, H-9 2.37-2.50 (m, slight overlap with upfield signal, IH) H-5a H-5b, H-6a, H-6b, H-7a (weak), H-9 3.33 (dd, 1H,7 = 11.5, 9.5 Hz, sharpens upon D 2 0 addition) H-8b H - l , H-8a, OH (weak) 3.56 (dd, IH, 7= 11.5, 5 Hz, sharpens upon D 2 0 addition) H-8a H - l , H-8b, OH 4.91 (dd, l H , 7 = 2 , 2 H z ) H-9 H-5a, H-5b a The assignment is based on the general observation that / as > J asm for cyclopropyl protons.' 333 The spectral data of 232 are as follows: IR (neat): 3377 (br), 3064 (w), 2174, 1249, 1029, 842 cm"1. *H N M R (C 6D 6 , 400 MHz) 8: 0.00-0.16 (overlapping signals, slight overlap with downfield signals, 2H, cyclopropyl protons), 0.16-0.33 (overlapping signals, including a large singlet centered at 8 0.27 (Si(CH3)3), 10 H total, cyclopropyl proton), 0.52-0.63 (m, slight overlap with downfield signal, IH, cyclopropyl proton), 0.65 (br signal, slight overlap with upfield multiplet, IH, exchanges with D 2 0 , OH), 1.08 (dt, overlap with downfield signal, IH, 7 = 14, 7 Hz, H-5a), 1.16 (dt, overlap with upfield signal, IH, 7 = 14, 7 Hz, H-5b), 1.45 (ddt, 2H, 7 = 1,1,1 Hz, H-6), 2.11 (t, 2H, 7 = 1 Hz, H-7), 3.07 (dd, IH, 7 = 11, 7 Hz, H-4a), 3.19 (dd, IH, 7 = 1 1 , 6.5 Hz, H-4b). 1 3 C N M R and APT (C 6D 6 , 75 MHz) 8: 0.3 Si(CH 3) 3, 9.8, 16.5, 19.8, 21.4, 28.8, 32.8, 66.5, 84.7, 108.0. LRDCIMS (NH3): M N H / (228). Exact mass calcd for C i 2 H 2 iOS i (M + -H ) : 209.1362. Found: 209.1353. 334 Preparation of (IS*. 35*)-4-(£-fe^ButyldimemylsUylmemyh^ spiro[2.41heptane (233). Following general procedure 11 (p 329), cw-l-(5-fe^butyldimethylsilyl-4-pentynyl)-2-(hydroxymethyl)-l-iodocyclopropane (226) (p 322) was converted into (IS*, 3S*)-A-(E-tert-butyldimethylsUyirnemylidene)-l-(hydroxym (233) employing a warming period (from -78°C) of 50 min and the following quantities of reagents and solvents: cw-l-(5-fc^butyldimemylsilyl-4-pentynyl)-2-(hydroxymethyl)-l-iodocyclopropane (226), 21.7 mg (0.0574 mmol), in E t 2 0 , 0.29 mL; BuLi in hexanes, 0.082 mL (0.13 mmol). Radial chromatography (1 mm plate, 9:1 petroleum ether-ethyl acetate) of the crude product gave two colorless oils. Brief subjection of each oil to reduced pressure (0.3 torr) afforded 10.3 mg (71%) of the bicyclic alcohol 233, and 1.2 mg (-8%) of slightly impure, reduced starting material 234. 335 The spectral data of 233 are as follows: IR (neat): 3357 (br), 3060 (w), 1618,1470,1247,1080,1028, 1007, 832 cm"1. See Table 49 on p 336 for X H N M R and COSY data. In decoupling experiments, irradiation at 8 1.66 (H-6a, H-6b) simplified the signals at 1.13-1.21 (H-7a), 1.73-1.85 (H-7b), 2.30-2.45 (H-5b, to a dd, J = 17, 2 Hz), and 2.45-2.57 (H-5a, to a br d, J = 17 Hz). In NOE difference experiments, irradiation at 8 3.36 (H-8b) caused enhancements at 0.70 (H-2b), 3.62 (H-8a), and 4.94 (H-9); irradiation at 8 4.94 (H-9) caused enhancements at 0.70 (H-2b) and 3.36 (H-8b). 1 3 C N M R (CDC13, 75.4 MHz) 8: -4.7, -4.6, 14.6, 17.3, 23.8, 26.5, 32.8, 34.0, 37.6, 61.3, 112.0, 161.3. (C 6 D 6 ,75.4 MHz) 8: -4.4,14.3,17.5, 24.0, 26.7,33.2, 34.3, 37.8, 60.9,111.6,161.6. Exact mass calcd for C 1 5H 28SiO: 252.1910. Found: 252.1912. Anal, calcd for C 1 5 H 2 8 SiO: C 71.36, H 11.18. Found: C 71.52, H 11.16. Table 49: *H N M R (400 MHz) and COSY (400 MHz) Data for 233 (in C 6 D 6 ) . ' H N M R 8 (mult, number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.10 (s, 3H) Si(CH3) No correlation 0.12 (s, 3H) SifCHj) No correlation 0.70 (dd, IH, J=5, 5 Hz) H-2b a H - l , H - 2 a 0.75 (br signal, overlap with downfield signal, IH) OH No correlation 0.76 (dd, overlap with upfield signal, IH, J = 8.5, 5 Hz) H-2a H - l ,H -2b 0.94-1.07 (overlapping signals, including a singlet centered at 8 0.99,10H total) H - l , C(CH 3) 3 (80.99) H-2a, H-2b, H-8a, H-8b 1.13-1.21 (m, IH) H-7a H-6a, H-6b, H-7b 1.60-1.73 (m, overlap with downfield signal, 2H) H-6a, H-6b H-5a, H-5b, H-7a, H-7b 1.73-1.85 (m, overlap with upfield signal, IH) H-7b H-6a, H-6b, H-7a 2.30-2.45 (m, overlap with downfield signal, IH) H-5b H-5a, H-6a, H-6b, H-9 2.45-2.57 (m, overlap with upfield signal, IH) H-5a H-5b, H-6a, H-6b, H-9 3.36 (dd, 1H,7= 11.5, 9.5 Hz) H-8b H - l , H-8a 3.62 (dd, 1H, 7=11.5, 5.5 Hz) H-8a H - l ,H -8b 4.94 (dd, IH, J = 2, 2 Hz) H-9 H-5a, H-5b a The assignment is based on the general observation that J > J ^  for cyclopropyl protons.' 337 The spectral data of 234 are as follows: IR (neat): 3359 (br), 3074 (w), 2173, 1465, 1250, 1026, 838, 775 cm' 1. *H N M R (C 6D 6 , 400 MHz) 5: 0.03-0.13 (overlapping signals, overlap with downfield singlet, 2H, cyclopropyl protons), 0.17 (s, overlap with upfield signals, 6H, Si(CH3)2), 0.22-0.30 (m, IH, cyclopropyl proton), 0.55-0.64 (m, IH, cyclopropyl proton), 0.97-1.24 (overlapping signals, including a large singlet centered at 8 1.04 (SiC(CH3)3), 12H total, H-5, OH), 1.44 (ddt, 2H, J = 7, 7, 7 Hz, H-6), 2.19 (t, 2H, / = 7 Hz, H-7), 3.08 (m, simplified to a dd, J = 11, 7 Hz, upon addition of D 2 0 , IH, H-4a), 3.18 (m, simplified to a dd, J = 11, 6.5 Hz, upon addition of D 2 0 , IH, H-4b). Exact mass calcd for C i 5 H 2 8 OSi : 252.1910. Found: 252.1910. 338 Preparation of (IS*, 35*)-l-(Hydroxymemyl)-4-(i^trimemy^ spiro[2.4]heptane (235). Following general procedure 11 (p 329), cw-2-(hydroxymethyl)-l-iodo-l-(5-trimethylgermyl-4-pentynyl)cyclopropane (227) (p 324) was converted into (IS*, 35*)-1-(hydroxymemyl)-4-(£-trimemylgermylmethylidene)spiro[2.4]h (235) employing a warming period (from -78°C) of 1.5 h and the following quantities of reagents and solvents: cw-2-(hydroxymemyl)-l-iodo-l-(5-trimethylgermyl-4-pentynyl)cyclopropane (227), 101 mg (0.265 mmol), in Et20, 1.3 mL; BuLi in hexanes, 0.38 mL (0.58 mmol). Radial chromatography (1 mm plate, 3:2 petroleum ether-Et20) of the crude material gave two oils, A and B . Distillation (85-110°C/0.3 torr) of A afforded 40.3 mg (60%) of the bicyclic alcohol 235 as a colorless oil. Similarly, distillation (80-105°C/0.3 torr) of B afforded 5.7 mg (8%) of the monocyclic alcohol 339 236 as a colorless oil. The spectral data of (IS*, 3S*)-l-(hydroxymethyl)-4-(£-tamethylgermylmethylidene)spiro[2.4]heptane (235) are as follows: IR (neat): 3343 (br), 3060 (w), 1620, 1411,1235, 1081, 1029, 1010, 824 cm"1. See Table 50 on p 340 for lU N M R and COSY data. In decoupling experiments, irradiation at 8 1.63 (H-6a, H-6b) simplified the signals at 1.10-1.22 (H-7a, to a d, / = 10.5 Hz), 1.71-1.82 (H-7b), 2.26-2.37 (H-5b, to a dd, 7= 17, 2 Hz), and 2.37-2.50 (H-5a, to a dd, J = 17, 2 Hz). In NOE difference experiments, irradiation at 8 0.64 (H-2b) caused enhancements at 3.33 (H-8b) and 5.07 (H-9); irradiation at 8 3.33 (H-8b) caused enhancements at 8 0.64 (H-2b); 8 3.56 (H-8a) and 5.07 (H-9); irradiation at 8 5.07 (H-9) caused enhancements at 0.64 (H-2b) and 3.33 (H-8b). 1 3 C N M R and APT (C 6D 6 , 75.4 MHz) 8: -0.7 (-ve, Ge(CH3)3), 14.3, 24.0, 32.8 (-ve), 33.7, 34.0, 38.1, 61.1, 115.7 (-ve, C-9), 158.5. Exact mass calcd for C i 2 H 2 2 7 4 GeO: 256.0833. Found: 256.0885. Anal, calcd for C 1 2 H 2 2 GeO: C 56.54, H 8.70. Found: C 56.50, H 8.77. Table 50: X H N M R (400 MHz) and COSY (400 MHz) Data for 235 (in C 6 D 6 ) . 340 ' H N M R 5 (mult, number of protons, 7) Assignment (H-X) COSY Correlation (H-X) 0.26 (s, 9H) Ge(CH 3) 3 No correlation 0.64 (dd, IH, 7 = 5 , 5 Hz) H-2b a H - l , H-2a. 0.72 (dd, overlap with downfield signal, IH, 7 =8.5, 5 Hz) H-2a H - l ,H -2b 0.77 (br signal, overlap with upfield signal, IH, exchanges with D 2 0) OH H-8a, H-8b 0.94-1.03 (m, IH) H - l H-2a, H-2b, H-8a, H-8b 1.10-1.22 (m, IH) H-7a H-5a (weak), H-6a, H-6b, H-7b 1.55-1.71 (m, slight overlap with downfield m, 2H) H-6a, H-6b H-5a, H-5b, H-7a, H-7b 1.71-1.82 (m, slight overlap with upfield m, IH) H-7b H-6a, H-6b, H-7a 2.26-2.37 (m, slight overlap with downfield m, IH) H-5b H-5a, H-6a, H-6b, H-9 2.37-2.50 (m, slight overlap with upfield m, IH) H-5a H-5b, H-6a, H-6b, H-7a (weak), H-9 3.33 (m, IH, sharpens to add, 7= 11.5, 9 Hz, upon addition of D 2 0) H-8b H - l , H - 8 a , OH 3.56 (m, IH, sharpens to a dd, 7 = 11.5, 5.5 Hz, upon addition of D 2 0) H-8a H - l , H-8b, OH 5.07 (dd, l H , 7 = 2 ,2Hz) H-9 H-5a, H-5b " The assignment is based on the general observation that J > / tram for cyclopropyl protons.' 341 The spectral data of /raw4-(hydroxymemyl)-2-(5-tjimemylgerm (236) are as follows: IR (neat): 3349 (br), 3064 (w), 2171, 1415, 1240, 1032, 833, 768 cm"1. *H N M R (C 6D 6 , 400 MHz) 8: 0.01-0.14 (overlapping signals, 2H, cyclopropyl protons), 0.22-0.40 (overlapping signals, including a singlet centered at 8 0.32 (Ge(CH3)3), cyclopropyl proton, 10H total), 0.54-0.64 (m, IH, cyclopropyl proton), 0.68 (dd, IH, J = 6, 6 Hz, exchanges with D 2 0 , OH), 1.06-1.26 (overlapping signals, 2H), 1.44-1.54 (m, 2H), 2.16 (dd, 2H, J = 7, 7 Hz), 3.09 (m, IH, sharpens to a dd, J = 11, 7 Hz, upon addition of D 2 0) , 3.21 (m, IH, sharpens to a dd, J = 11, 6 Hz, upon addition of D 2 0). 1 3 C N M R (C 6 D 6 , 75.4 MHz) 8: 0.0 (Ge(CH3)3), 9.8, 16.5, 19.8, 21.5, 29.1, 32.9, 66.5, 84.2, 106.3. Exact mass calcd for CnH 1 9 7 4 GeO(M + -CH 3 ) : 241.0648. Found: 241.0643. Anal, calcd for Ci 2 H 2 2 GeO: C 56.54, H 8.70. Found: C 56.71, H 8.83. 342 Preparation of /ran5-l-(4-Hexynyl)-2-(hydroxymethyl')cyclopropane (238). H-3a Me- O H 10 Me' H 1 O H H-3b 4 228 238 Following general procedure 11 (p 329), cw-l-(4-hexynyl)-2-(hydroxymethyl)-l-iodocyclopropane (228) (p 325) was converted into fra/w-l-(4-hexynyl)-2-(hydroxymethyl)cyclopropane (238) employing a warming period (from -78°C) of 1.5 h and the following quantities of reagents and solvents: cw-l-(4-hexynyl)-2-(hydroxymethyl)-l-iodocyclopropane (228), 36.9 mg (0.133 mmol), in Et20, 0.66 mL; BuLi in hexanes, 0.19 mL (0.29 mmol). Distillation (100-120°C/12 torr) of the crude product afforded 16.7 mg (83%) of the monocyclic alcohol 238 as a colorless oil. The spectral data of 238 are as follows: IR (neat): 3343 (br), 3062 (w), 1440,1029 cm"1. *H N M R (CDC13, 400 MHz) 5: 0.27-0.40 (overlapping signals, 2H, cyclopropyl protons), 0.54-0.65 (m, IH, cyclopropyl proton), 0.78-0.90 (m, IH, cyclopropyl proton), 1.20-1.65 (overlapping signals, 5H, reduces to 4H upon addition of D 2 0 , H-5, H-6, OH), 1.75 (t, 3H, J = 2.5 Hz, H-10), 2.09-2.20 (m, 2H, H-7), 3.42 (d, 2H, J = 7 Hz, H-4). 1 3 C N M R (CDCI3, 50.3 MHz) 5: 3.4, 9.8, 16.7, 18.4, 21.1, 28.9, 32.6, 67.1, 75.6, 79.2. Exact mass calcd for doHifiO: 152.1201. Found: 152.1200. 343 Preparation of (IS*. 3S*yi-(HydroxymemvlV4-(E'-phenvlmemy (239). 4 240 Following general procedure 11 (p 329), c/i ,-2-(hydroxymethyl)-l-iodo-l-(5-phenyl-4-pentynyl)cyclopropane (229) (p 327) was converted into (IS*, 3S*)-l-(hydroxymethyl)-4-(£-phenylmethylidene)spiro[2.4]heptane (239) employing a warming period (from -78°C) of 30 min and the following quantities of reagents and solvents: a'£-2-(hydroxymethyl)-l-iodo-l-(5-phenyl-4-pentynyl)cyclopropane (229), 29.9 mg (0.0879 mmol), in E t 2 0 , 0.44 mL; BuLi in hexanes, 0.12 mL (0.19 mmol). Radial chromatography (1 mm plate, 3:2 petroleum ether-Et20) of the crude material afforded two oils, A and B. Subjection of A to reduced pressure (0.3 torr) afforded 8.3 mg (44%) the bicyclic alcohol 239 as a colorless oil. Similarly, subjection of B to reduced pressure (0.3 torr) afforded 7.5 mg (40%) of the monocyclic alcohol 240 as a colorless oil. 344 The spectral data of (IS*, 35*)-l-(hydroxymemyl)-4-(£-phenylmemyUdene) (239) are as follows: IR (neat): 3348 (br), 3090 (w), 3060 (w), 3028 (w), 1650, 1598, 1492, 1447, 1089, 1031, 1010 cm 1 . See Table 51 on p 345 for ! H N M R and COSY data. In decoupling experiments, irradiation at 8 1.66 (H-6a, H-6b, H-7b) simplified the signals at 1.08-1.18 (H-7a, to a d, J = 8.5 Hz), 2.38-2.52 (H-5b, to a br d, J = 17 Hz), and 2.52-2.63 (H-5a, to a br d, / = 17 Hz). In NOE difference experiments, irradiation at 8 3.30 (H-8b) caused enhancements at 0.71 (H-2b), 3.57 (H-8a) and 5.85 (H-9); irradiation at 8 5.85 (H-9) caused enhancements at 0.71 (H-2b) and 3.30 (H-8b). 1 3 C N M R (C 6D 6 , 75.4 MHz) 8: 13.4, 24.0, 32.3, 32.9, 33.7, 37.5, 61.3, 118.9, 126.1, 126.5, 126.8, 138.6, 144.9. Exact mass calcd for CisHigO: 214.1358. Found: 214.1364. 345 Table 51: *H N M R (400 MHz) and COSY (400 MHz) Data for 239 (in C 6 D 6 ) . ' H N M R 8 (mult, number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.65 (br signal, IH, exchanges with D 2 0) OH H-8a, H-8b 0.71 (dd, IH, J =5.5, 5.5 Hz) H-2b f l H - l , H - 2 a 0.76 (dd, IH, J =8.5, 5.5 Hz) H-2a H - l , H-2b 0.98-1.08 (m, slight overlap with downfield m, IH) H - l H-2a, H-2b, H-8a, H-8b 1.08-1.18 (m, slight overlap with upfield m, IH) H-7a H-6a, H-6b, H-7b 1.53-1.79 (m, 3H) H-6a, H-6b, H-7b H-5a, H-5b, H-7a 2.38-2.52 (m, IH) H-5b H-5a, H-6a, H-6b, H-7b, H-9 2.52-2.63 (m, IH) H-5a H-5b, H-6a, H-6b, H-7b, H-9 3.30 (m, IH, collapses to a dd, J = 9.5, 8 Hz, upon addition of D 2 0) H-8b H - l , H - 8 a , OH 3.57 (m, IH, collapses to a dd, J = 9.5, 6 Hz, upon addition of D 2 0) H-8a H - l ,H -8b , OH 5.85 (dd, IH, J =2.5, 2.5 Hz) H-9 H-5a, H-5b 7.02-7.36 (overlapping signals, 5H) aromatic protons aromatic protons a The assignment is based on the general observation that J as > J ttam for cyclopropyl protons.' 346 The spectral data of trans- l-(hydroxymethyl)-2-(5-phenyl-4-pentynyl)cyclopropane (240) are as follows: IR (neat): 3361 (br), 3080 (w), 3060 (w), 3000 (w), 2230, 1599, 1490, 1442, 1027, 756, 692 cm"1. lU N M R (C 6D 6 , 400 MHz) 8: 0.04-0.17 (overlapping signals, 2H, cyclopropyl protons), 0.26-0.36 (m, IH, cyclopropyl proton), 0.55-0.66 (m, IH, cyclopropyl proton), 0.69 (br signal, IH, exchanges with D 2 0 , OH), 1.10-1.29 (m, 2H), 1.47-1.58 (m, 2H), 2.27 (dd, 2H, 3 = 1,1 Hz), 3.12 (dd, IH, J = 11, 7 Hz, H-4a), 3.22 (dd, IH, J = 11, 6.5 Hz, H-4b), 6.91-7.05 (m, 3H, aromatic protons), 7.44-7.56 (m, 2H, aromatic protons). 1 3 C N M R (CDC13,75.4 MHz) 8: 9.9, 16.6, 19.0, 21.2, 28.6, 32.6, 67.1, 80.8, 90.1, 123.9, 127.5, 128.2, 131.5. LRDCIMS (NH3): M N H / (232). Exact mass calcd for C i 5 H i 8 0 : 214.1358. Found: 214.1353. Anal, calcd for C i 5 H i 8 0 : C 84.07, H 8.47. Found: C 83.65, H 8.53. 347 5.3.8.4. Preparation of the tricyclic ether 241. H-9a xNH-9b TBDMS, TBDMS OH = TBDMS 8 4 226 241 A solution of (IS*, 3S*)-4-(E-te^butyldimemylstt^ spiro[2.4]heptane (233) (p 334) (4.30 mg, 0.0114 mmol) and AcOH (26 pi) in wet Et z O (0.4 mL) was stirred at r.t. for 12 days. TLC analysis of the reaction mixture indicated the formation of a non-polar compound. Concentration (water aspirator) of the solution and purification of the crude product by flash chromatography (0.5 g of Merck (grade 60) silica gel, 19:1 petroleum ether-Et20) and distillation (25-40°C/0.3 torr) of the acquired oil gave 3.6 mg (84%) of the tricyclic ether 241 as a colorless oil. The spectral data of 241 are as follows: IR (neat): 3060 (w), 1464,1251,1067,980, 827 cm"1. See Table 52 on p 348 for *H N M R and COSY data. 1 3 C N M R (C 6D 6 , 75.4 MHz) 8: -4.0, -3.6, 11.5, 16.9, 19.4, 22.2, 26.7, 26.8, 27.1, 35.6, 41.8, 68.2, 91.4. Exact mass calcd for C i 5 H 2 8 O S i : 252.1910. Found: 252.1919. 348 Table 52: *H N M R (500 MHz) and COSY (400 MHz) Data for 241 (in C 6 D 6 ) . *HNMR 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.21 (s,3H) SiCH 3 No correlation 0.25 (s, 3H) SiCH 3 No correlation 0.52 (dd, IH, 7 = 5,5 Hz) H-9a a H-9b, H-4 0.62 (dd, 1H, 7 = 8 , 5 Hz) H-9b H-9a, H-4 0.77-0.82 (m, IH) H-4 H-9a, H-9b, H-3a, H-3b 0.84 (d, 1H,7= 14 Hz) H-lOa H-lOb 0.95 (s, 9H) C(CH 3) 3 No correlation 0.98 (d, 1H,7= 14 Hz) H-lOb H-lOa 1.29-1.38 (m, IH) C H 2 proton 1.54-1.70, 1.78-1.85 1.54-1.70 (m, 4H) C H 2 protons 1.29-1.38, 1.78-1.85 1.78-1.85 (m, IH) C H 2 proton 1.29-1.38, 1.54-1.70 3.65 (d, overlap with downfield signal, IH, 7= 8.5 Hz) H-3a H-4 3.69 (dd, overlap with upfield signal, IH, J = 8.5, 3.5 Hz) H-3b H-4 " The assignment is based on the general observation that J & > J aam for cyclopropyl protons.' 349 5.3.9. Considerations for Future Work. 5.3.9.1. Preparation of Compound 246. 60d 246 247 A solution of BuLi in hexanes (0.084 mL, 2.1 mmol) was added to a cold (-78°C), vigorously stirred solution of cw-l-(3-chloropropyl)-2-(hydroxymethyl)-l-iodocyclopropane (60d) (p 229) (17.5 mg, 0.0637 mmol) in dry E t 2 0 (0.32 mL). The solution was stirred at -78°C for 20 min and was then allowed to warm to r.t. over a 1 h period, producing a white suspension. The solution was cooled to 0°C and neat benzoyl chloride26 was added by gas-tight syringe, causing the suspension to become yellowish. The 0°C bath was removed and the reaction mixture was allowed to warm for 30 min. Water (1 mL) was added and the phases were separated. The aqueous phase was extracted with E t 2 0 ( 3 x 1 mL). The combined organic phases were dried (Na2SC«4) and concentrated (water aspirator). Sequential radial chromatography (1 mm plate, 4:1 petroleum ether-Et20, followed by 1 mm plate, 7:3 petroleum ether-CH2Cl2) of the crude product and subjection of the acquired oils to reduced pressure (0.3 torr), afforded 5.1 mg (37%) of 246 as a colorless oil and 3.5 mg (22%) of 247, also as a colorless oil. 350 The spectral data of 246 are as follows: IR (CDCI3 solution): 1710,1276 cm"1. *H N M R (CDC13, 400 MHz) 8: 0.49 (dd, IH, J = 5, 5 Hz, H-2b), 0.70 (dd, IH, J = 8.5, 5 Hz, H-2a), 1.10-1.21 (m, IH, H- l ) , 2.00-2.30 (overlapping signals, 6H, H-4, H-5, H-6), 4.03 (dd, IH, J= 11.5, 8 Hz, H-7a), 4.28 (dd, IH, J = 11.5, 7 Hz, H-7b), 7.40-7.60 (overlapping signals, 3H, meta and para aromatic protons), 8.03-8.13 (m, 2H, ortho aromatic protons). 1 3 C N M R (CDCI3, 75.4 MHz) 8: 16.9, 17.6, 20.4, 24.6, 26.8, 30.8, 67.4, 128.3, 129.6, 130.6, 132.8, 166.8. Exact mass calcd for Ci4Hi 6 0 2 : 216.1150. Found: 216.1142. The spectral details of 247 are as follows: IR (CDCI3 solution): 1711,1276 cm"1. 'H N M R (CDCI3, 400 MHz) 8: 0.39-0.48 (m, IH, cyclopropyl proton), 0.50-0.59 (m, IH, cyclopropyl proton), 0.70-0.80 (m, IH, cyclopropyl proton), 0.98-1.09 (m, IH, cyclopropyl proton), 1.27-1.65 (overlapping signals, 2H, H-5), 1.80-1.87 (tt, 2H, J= 6.5, 6.5 Hz, H-6), 3.58 (t, 2H, J = 6.5 Hz, H-7), 4.04 (dd, IH, J = 11.5, 8 Hz, H-4a), 4.26 (dd, IH, J = 11.5, 6.5 Hz, H-4b), 7.40-7.60 (overlapping signals, 3H, meta and para aromatic protons), 8.01-8.10 (m, 2H, ortho aromatic protons). 1 3 C N M R (CDCI3, 75.4 MHz) 8: 10.3, 16.9, 17.3, 30.5, 32.5, 44.6, 69.0, 128.4, 129.6, 130.4, 132.8, 166.5. Exact mass calcd for Ci 4 Hi7 3 5 C10 2 : 252.0917. Found: 252.0926. 351 Preparation of 253: OAc 5 6 OCOCH3 249 253 A solution of freshly distilled iodocyclopropane 249 (36.3 mg, 0.199 mmol), freshly distilled Me 6 Sn 2 (3.7 ul, 0.0179 mmol) and degassed C 6 D 6 (0.4 mL) in a 1-piece round bottom-condenser was irradiated with a 275 W General Electric sunlamp (distance of the lamp from the reaction flask was ~4 cm) for 25 min (temperature of the air adjacent to the reaction flask was ~65°C). Analysis (GLC) of a reaction aliquot indicated starting material so the reaction solution was again irradiated for 20 min (temperature of the air adjacent to the reaction flask was ~75°C). Analysis (*H N M R (400 MHz) spectroscopy) of the crude product indicated a mixture consisting primarily of 253. Also present in the mixture were small amounts of two unknowns A and B, which were presumably isomers of 253 based on the hydroxymethyl (CH 2OH) and vinyl regions of the *H N M R spectrum, and a small amount of starting material 249. The ratio of 253:A:B was 11:2.5:1 based the integration of the vinyl region of the *H N M R spectrum. Analysis (TLC) of the crude material using various solvents (8:92 Et20:hexanes, 75:25 CCi4:CH2Cl2, 65:35 hexanes:CH2Cl2, 80:20 PhH:CH 2Cl 2) indicated that the three compounds had virtually identical Rf values. Flash chromatography (8:92 Et20:hexanes) provided three mixtures, each consisting of 253, A , and B (and in one case, starting material). An attempt to further purify one of these mixtures by HPLC using 75:25 CCU:CH 2C1 2 was not successful. The total mass of the three mixtures (25.1 mg) accounted for a - 6 9 % yield (assuming that A and B are isomers of 253). The 352 percent (%) compositions of 253 in these mixtures were estimated to be - 8 0 % based on G L C and *H N M R analysis. The following spectral data was obtained using a sample that was enriched in compound 253: lH N M R (400 MHz, CDC13) 8: 0.86 (dd, IH, J = 6, 6 Hz, H-2b), 0.99 (dd, IH, J = 8.5, 6 Hz, H-2a), 1.33-1.44 (m, IH, H- l ) , 1.70-2.13 (overlapping signals, including a singlet centered at 8 2.06 (OCH 3), 7H total, H-6, H-7), 2.40-2.49 (m, 2H, H-5), 3.84 (dd, IH, J = 12, 8 Hz, H-8a), 4.22 (dd, IH, J = 12, 6 Hz, H-8b), 5.33 (dd, IH, J = 2, 2 Hz, H-9). In a NOE difference experiment, irradiation at 8 1.33-1.44 (H-l) caused signal enhancement at 8 5.33 (H-9), while irradiation at 8 5.33 (H-9) caused enhancement at 8 1.33-1.44 (H-l) . HRGCMS: calcd for C 9 H n I (M + -AcOH): 245.9907. Found: 245.9897. 353 Reaction of Litfaio Vinylcyclopropanes with Cyclohexanone. General Procedure 12. In the following procedure, all given amounts are related to the use of 1 mmol of iodo vinylcyclopropane. Substrates 116a and 116b were eluted through short columns of oven-dried basic alumina (activity 1) with dry E t 2 0, concentrated (water aspirator), dissolved in dry benzene, and concentrated (water aspirator, then 0.3 torr) prior to their use. A solution of BuLi in hexanes (2.2 mL, 2.2 mmol) was added to a vigorously stirred, cold (-48°C) solution of iodo vinylcyclopropane in dry THF (~4 mL). The resulting clear solution was stirred for 30 min at -48°C and was then cooled to -78°C. Cyclohexanone (255) (4.0 mmol) was added by gas-tight syringe and after 5 min, the reaction mixture was allowed to warm to r.t. for the specified time (vide infra). Sat. aq NH4CI (5 mL), water (5 mL) and E t 2 0 (5 mL) were added, the phases separated, and the aq layer was extracted with E t 2 0 (3x10 mL). The combined organic extracts were washed (water (15 mL) and brine (15 mL)), dried (Na 2S0 4), and concentrated. Purification (radial chromatography) provided the cyclopropyl carbinol. 354 Preparation of 256. 13 12 116b 256 Following general procedure 12 (p 353), ds-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b) (p 275) was converted into 256 employing a reaction time of 4.5 h and the following quantities of reagents and solvents: cw-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116b), 58.9 mg (0.202 mmol), in THF, 0.81 mL; BuLi in hexanes, 0.32 mL (0.44 mmol); cyclohexanone, 84 ul (0.81 mmol). Sequential radial chromatography (2 mm plate, 7:3 petroleum ether-Et20, followed by 1 mm plate, 8:2 petroleum ether-Et20) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 34.2 mg (64%) of 256 as a colorless oil. The spectral data of 256 are as follows: IR (neat): 3557 (br), 3080 (w), 1449, 1376, 1259, 1125, 1082 cm"1. *H N M R (C 6D 6 , 400 MHz) 8: 0.65 (dd, IH, J = 9, 4 Hz, H-3a), 0.89 (t, 3H, / = 7 Hz, H-18), 0.97 (s, IH, exchanges with D 2 0 , OH), 1.01-1.88 (overlapping signals, including two broad singlets centered at 8 1.58 (H-12 or H-13) and 1.67 (H-12 or H-13), 26H total), 5.46-5.53 (m, IH, H-10). 1 3 C N M R and APT (C 6D 6 , 125 MHz) 8: 14.3 (-ve), 15.6, 18.6 (-ve), 22.1, 22.3, 23.00 (-ve), 23.04, 25.5 (-ve), 26.4, 27.7, 33.0, 35.2, 35.7, 36.2, 73.0 (C-4), 126.0 (-ve, C-10), 133.7 (C - l l ) . 355 The C spectrum of 256 in CDCI3 also contained only 17 signals. Exact mass calcd for C i 8 H 3 2 0 : 264.2453. Found: 264.2462. Anal, calcd for C i 8 H 3 2 0 : C 81.75, H 12.20. Found: C 82.00, H 12.44. Preparation of 258. 12 13 116a 258 Following general procedure 12 (p 353), /ra/w-l-iodo-2-(2-methyl-l-propenyl)-l-pentylcyclopropane (116a) (p 273) was converted into 258 employing a reaction time of 2 h and the following quantities of reagents and solvents: Jran.s-l-iodo-2-(2-metiiyl-l-propenyl)-l-pentylcyclopropane (116a), 39.3 mg (0.134 mmol), in THF, 0.54 mL; BuLi in hexanes, 0.20 mL (0.30 mmol); cyclohexanone, 56 ul (0.54 mmol). Sequential radial chromatography (1 mm and 1 mm plates coated with Sigma (Type H) silica gel, 8:2 petroleum ether-Et20) of the crude product and subjection of the acquired oil to reduced pressure (0.3 torr) afforded 19.6 mg (55%) of 258 as a colorless oil. The spectral data of 258 are as follows: IR (neat): 3494, 3070 (w), 1449,1376,1254,1144, 1080, 846 c m 1 . See Table 53 on p 356 for X H N M R and COSY data. In NOE difference experiments, irradiation at 8 0.27 (H-3b) caused signal enhancement at 1.02 356 (H-3a) and 5.02 (H-10); irradiation at 8 5.02 (H-10) caused signal enhancement at 0.27 (H-3b) and 1.68-1.73 (H-12). 1 3 C N M R and APT (C 6D 6 , 75.4 MHz) 8: 14.3 (-ve), 16.1, 18.4 (-ve), 18.8 (-ve), 22.17, 22.24, 23.0, 25.8 (-ve), 26.2, 29.1, 30.0, 33.1, 34.7, 34.8, 72.5 (C-4), 125.6 (-ve, C-10), 132.4 (C - l l ) . The 1 3 C spectrum of 258 in CDCI3 also contained 17 signals. Exact mass calcd for C i 8 H 3 2 0 : 264.2453. Found: 264.2445. Anal, calcd for C18H32O: C 81.75, H 12.20. Found: C 81.57, H 12.28. Table 53: *H N M R (400 MHz) and COSY (400 MHz) Data for 258 (in C 6 D 6 ) . f l ' H N M R 8 (mult., number of protons, J) Assignment (H-X) COSY Correlation (H-X) 0.27 (dd, IH, 7= 5.5, 4.5 Hz) H-3bfc H-2, H-3a 0.47 (br s, IH, exchanges with D 2 0) OH No correlation 0.89 (t, 3 H , / = 7 H z ) H-18 H-17 0.94-1.08 (overlapping signals, including a doublet of doublets, 7 = 9, 5.5 Hz, centered at 8 1.02, 3H total) C H 2 protons, H-3a (8 1.02)c H-2, H-3b, 1.15-1.66 1.15-1.66 (overlapping signals, 16 H) C H 2 protons H-18, 0.94-1.08 1.68-1.73 (overlapping signals, 6H) H-12,H-13 H-10 1.83 (ddd, 1H,7 = 9, 8,4.5 Hz) H-2 H-3a, H-3b, H-10 4.99-5.06 (m, IH) H-10 H-2, H-12, H-13 " The signal resolution was equally poor when CDCI3 was used as the NMR solvent. b The assignment is based on the general observation that J & > J ttans for cyclopropyl protons.' c The COSY experiment gave an approximate chemical shift (5) value of 1.02 for H-3a. 357 6. References /Footnotes . 1. For a discussion of the structural features of cyclopropanes, see Wiberg, K.B. In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; John Wiley and Sons: Chichester, 1987; part 1, pp 1-26 and citations therein. 2. The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; John Wiley and Sons: Chichester, 1987; parts 1 and 2. 3. For recent reviews of the use of cyclopropanes in organic synthesis, see: (a) Wong, H.N.C.; Hon, M.Y.; Tse, C.W.; Yip, Y.C. ; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165; (b) Reissig, H.U. In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; John Wiley and Sons: Chichester, 1987; part 1, pp 375-443. 4. Based on the results of a CAS structure search using the following structure: Attributes: (1) all bonds single exact (2) ring fusion blocked (3) Gl=C/H/Si/S/0/N/M 5. For a discussion of metallocyclopropane transformations, see Tsuji, T.; Nishida, S. In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; John Wiley and Sons: Chichester, 1987; part 1, pp 349-351 and citations therein. 6. For a discussion of cyclopropyl radicals, see Walborsky, H.M. Tetrahedron 1981, 37, 1625. 7. For a review of radical reactions in natural product synthesis, see Jasperse, C P . ; Curran, D.P.; Fevig, T.L. Chem. Rev. 1991, 91, 1237. 358 8. For a discussion of ionic donor/acceptor terminology, see Seebach, D. Angew. Chem. Int. Ed. Engl. 1979,18, 239. 9. For a discussion of radical donor/acceptor terminology, see Curran, D.P. Synlett 1991, 63. 10. For the preparation of other monohalocyclopropanes, see Kawabata, N.; Tanimoto, M. ; Fujiwara, S. Tetrahedron 1979, 35, 1919, and references given therein. 11. Oliver, J.P.; Rao, U.V. J. Org. Chem. 1966, 31, 2696. 12. For reviews of 1,1-dihalocyclopropane chemistry, see: (a) Nair, V. In Comprehensive Organic Synthesis; Trost, B .M; Fleming, I., Eds.; Pergamon: Oxford, 1991; vol. 4, Semmelhack, M.E., Ed., pp 1031-1067; (b) Weyerstahl, P. In The Chemistry of Functional Groups, Supplement D; Patai, S.; Rappoport, Z., Eds.; John Wiley and Sons: Chichester, 1983; part 2, pp 1451-1497. 13. For a summary of the various methods of monoreduction of 1,1-dihalocyclopropanes, see Imamoto, I. In Comprehensive Organic Synthesis; Trost, B.M. ; Fleming, I., Eds.; Pergamon: Oxford, 1991; vol. 8, Fleming, I., Ed., pp 806-809. 14. Marolewski, T.A.; Yang, N.C. J. Am. Chem. Soc. 1968, 90, 5644. 15. Miyano, S.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1974, 47, 1500. 16. Grignon-Dubois, M. ; Dunogues, J.; Calas, R. J. Chem. Research (S) 1979, 6. 17. Gielen, M. ; Baekelmans, P.; Nasielski, J. J. Organometal. Chem. 1972, 34, 329. 18. Aratani, T.; Nakanisi, Y. ; Nozaki, H. Tetrahedron 1970, 26, 1675. 359 19. Zweifel, G.; Clark, G.M. ; Whitney, C.C. J. Am. Chem. Soc. 1971, 93, 1305. 20. Haner, R.; Maetzke, T.; Seebach, D. Helv. Chim. Acta 1986, 69, 1655. 21. Moss, R.A.; Wilk, B.; Krogh-Jespersen, K.; Westbrook, J.D. J. Am. Chem. Soc. 1989, 111, 6729. 22. Simmons, H.E.; Smith, R.D. J. Am Chem. Soc. 1958, 80, 5323. 23. For a review, see: Simmons, H.E.; Cairns, T.L.; Vladuchick, S.A.; Hoiness, C M . Org. React. 1973, 20, 1. 24. March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley and Sons: New York, 1985; p 17. 25. Compounds 31d, 32a, 34a, and 34d were generously donated by Dr. Tim Wong of our laboratories. 26. The following compounds were obtained from Aldrich Chemical Company, Inc., and were used as received: methyl 2-octynoate (31b), 2-propyn-l-ol (56), iodobenzene (117), 5-hexyn-l-ol (260), ethyl 3-(trimethylsilyl)propynoate (265), propiolic acid (268), methylmagnesium bromide (CH 3MgBr), pentylmagnesium bromide (CsHnMgBr), benzoyl chloride (PhCOCl), and ZnCyTHF solution. 27. Piers, E.; Morton, H.E.; Chong, J .M. Can. J. Chem. 1987, 65, 78. 28. Piers, E.; Chong, J .M. ; Morton, H.E. Tetrahedron 1989, 45, 363. 29. Piers, E.; Wong, T.; Ellis, K.A. Can. J. Chem. 1992, 70, 2058. 360 30. Methyl 2,7-octadiynoate (31c) was prepared according to a modification of a procedure that was developed in our laboratories for preparing the lower homolog methyl 2,6-heptadiynoate (see Skerlj, R.T., Ph.D. Thesis, University of British Columbia, Vancouver, B.C., April 1988, p 183). The original procedure, which involved the reaction of l-lithio-l,5-hexadiyne and C lC0 2 Me, was altered in three ways. They were: (1) the number of equivalents of MeLi was decreased from 1.3 to 1.0; (2) the number of equivalents of C lC0 2 Me was increased from 1.4 to 4.0; and (3) the C lC0 2 Me was added rapidly to the Uthium acetylide mixture using a needle-less syringe (the reaction flask was quickly opened under a high Ar flow to allow for the addition). The purpose of modification (1) was to avoid dianion formation which would lead to the production of a diester product. The purpose of modifications (2) and (3) was to react the Uthium acetylide with C lC0 2 Me completely before it could react with the acetylenic proton of the mono-ester product. The formation of the mono-ester anion would lead to the production of a diester product. The modified procedure afforded a high yield (81%) of the desired mono-ester 31c in contrast to the lower yield of 36% of the lower homolog, methyl 2,6-heptadiynoate, prepared using the unmodified procedure. The important spectral features of 31c were a strong IR absorption at 1714 cm"1 corresponding to a conjugated ester C=0 group and ! H N M R signals for a methyl ester group (8 3.73) and for an acetylenic proton (8 1.96) (see Experimental Section, p 163, for details). 31. Leusink, A J . ; Budding, H.A.; Marsman, J.W. J. Organomet. Chem. 1967, 9, 285. 32. The reaction mixture was removed from the N M R probe and was therefore exposed to fluorescent lighting between the acquisition of spectra. 33. Richie, K.L.; Eng, G. Inorg. Chim. Acta 1978, 31, 417. 34. For examples of reverse selectivity, see: (a) Jousseaume, B.; Villeneuve, P. J. Chem. Soc, Chem. Commun. 1987, 513; (b) Jousseaume, B.; Villeneuve, P. Tetrahedron 1989, 45, 1145; (c) Pan, H.; Willem, R.; Meunier-Piret, J.; Gielen, M. Organometallics 1990, 9, 2199; (d) Cochran, J.C.; Terrence, K .M. ; PhilUps, H.K. Organometallics 1991, 10, 2411; (e) Gielen, M. ; LeUeveld, P.; de Vos, D.; Pan, H.; Willem, R.; Biesemans, M. ; Fiebig, H.H. Inorg. Chim. Acta 1992, 196, 361 115; (f) Skerlj, R.T. Ph.D. Thesis, University of British Columbia, Vancouver, B.C., April 1988, p 103. 35. Baekelmans, P.; Gielen, M. ; Malfroid, P.; Nasielski, J. Bull. Soc. Chim. Beiges 1968, 77, 85. 36. For a review of intramolecular coordination in organotin chemistry, see Jastrzebski, J.T.B.H.; Van Koten, G. Adv. Organomet. Chem. 1993, 35, 241. 37. The iodo esters 47, 261, 264, and 266 (see Experimental Section, pp 180-186, for structures and procedures) were prepared using a procedure developed principally by Dr. Tim Wong of our laboratories (see Piers, E.; Wong, T.; Coish, P.D.; Rogers, C. Can. J. Chem. 1994, 72, 1816). It is noteworthy that we were able to extend this procedure to the preparation of the iodo acid 269 (see Experimental Section, p 187). 38. Marshall, J.A.; Jenson, T .M. ; DeHoff, B.S. J. Org. Chem. 1987, 52, 3860 and citations therein. 39. The following compounds were obtained from Farchan Chemicals and were used as received: 2-octyn-l-ol (48), 3-hexyn-2-ol (50), and 1,6-heptadiyne (259). 40. Corey, E.J.; Katzenellenbogen, J.A.; Posner, G.H. J. Am. Chem. Soc. 1967, 89, 4245. 41. Mascarefias, J.L.; Garcia, A . M . ; Castedo, L.; Mourino, A. Tetrahedron Lett. 1992, 33, 4365. 42. Rawal, V.H. ; Michoud, C. Tetrahedron Lett. 1991, 32, 1695 and citations therein. 43. Corey, E.J.; Kirst, H.A.; Katzenellenbogen, J.A. J. Am. Chem. Soc. 1970, 92, 6314. 44. Labaudiniere, L.; Hanaizi, J.; Normant, J.F. J. Org. Chem. 1992, 57, 6903. 45. Duboudin, J.G.; Jousseaume, B.; Bonakdar, A. J. Organomet. Chem. 1979,168, 227. 362 46. Rayner, C M . ; Astles, P .C ; Paquette, L.A. J. Am. Chem. Soc. 1992,114,3926. 47. Smith, A.B. , III; Rano, T.A.; Chida, N.; Sulikowski, G.A.; Wood, J.L. J. Am. Chem. Soc. 1992,114, 8008. 48. Friebolin, H. Basic One- and Two-Dimensional NMR Spectroscopy, 2nd ed.; V C H : Weinherm, 1993; (a) p 60; (b) p 275; (c) p 248. 49. Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53. 50. Shank, R.S.; Shechter, H. J. Org. Chem. 1959, 24, 1825. 51. LeGoff, E. J. Org. Chem. 1964, 29, 2048. 52. Repic, O.; Vogt, S. Tetrahedron Lett. 1982, 23, 2729. 53. Rawson, R.J.; Harrison, I.T. J. Org. Chem. 1970, 35, 2057. 54. Wittig, G.; Schwarzenbach, K. Angew. Chem. 1958, 71, 652. 55. Motherwell, W.B.; Nutley, C.J. Contemp. Org. Synth. 1994,1, 219. 56. Denmark, S.E.; Edwards, J.P. J. Org. Chem. 1991, 56, 691A. 57. Denmark, S.E.; Edwards, J.P.; Wilson, S.R. J. Am. Chem. Soc. 1992,114, 2592. 58. Miyano, S.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1973,46, 892. 59. Charette, A .B . ; Cote, B.; Marcoux, J.F. J. Am. Chem. Soc. 1991,113, 8166. 363 60. Coates, G.E.; Green, M.L.H. ; Wade, K. Organometallic Compounds, Metheun: London, 1967; vol. 1, p 129. 61. Kramer, G.W.; Levy, A.B. ; Midland, M . M . In Organic Synthesis via Boranes; Brown, H.C., Ed.; John Wiley and Sons: New York, 1975; p 191. 62. Aldrich Technical Information Bulletin AL-134, Handling Air-Sensitive Reagents. 63. Aldrich Technical Information Bulletin AL-164, Handling Pyrophoric Reagents. 64. Perrin, D.D.; Armarego, W.L.F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988; p 19. 65. Carey, F.A.; Sundberg, R.J. Advanced Organic Chemistry, 2nd ed.; Plenum: New York, 1984; part A , p 118. 66. (a) Piers, E.; Wai, J.S.M. Can. J. Chem. 1994, 72, 146; (b) Morris, L.J. Chemistry and Industry 1962, 1238. 67. Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tables of Spectral Data for Structure Determination of Organic Compounds, 2nd ed.; Springer-Verlag: Berlin, 1989; (a) p C90 (the estimations of chemical shift were calculated using the substituent value for a butyl group rather than that for a pentyl group (as in 25 and 28) since a value for the latter was not provided by the authors); (b) p H185; (c) p 130; (d) p H205; (e) 110; (f) CI 10. 68. Ratier, M. ; Castaing, M. ; Godet, J.Y.; Pereyre, M . J. Chem. Research (M) 1978, 2309. 69. Compound 72 was also prepared via a lithium-iodine exchange-stannylation reaction sequence. Sequential treatment of iodocyclopropane 60b with BuLi and MesSnCl afforded cyclopropylstannane 72 in 83% yield (see Experimental Section, p 266, for details). The lithium-iodine exchange reaction is discussed in Section 2.3. 364 70. Cyclopropyl protons resonate at higher field than other carbocyclic protons. The high field shift is thought to originate from anisotropic effects created by a current of electrons within the three carbon ring, although the existence of such a ring current has yet to be proven (Poulter, C D . ; Boikess, R.S.; Brauman, J.L; Winstein, S. J. Am. Chem. Soc. 1972, 94, 2291). According to this model, substituents in or near the plane of the ring are deshielded, while those above or below the ring are shielded, as in the case of aromatic compounds. Chemical shift, therefore, is useful in assigning cyclopropyl proton signals. 71. For a discussion of X H and 1 3 C N M R spectra of cyclopropanes, see Morris, D.G. In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; John Wiley and Sons: Chichester, 1987; part 1, pp 102-119. 72. Patel, D.J.; Howden, M.E.H.; Roberts, J.D. J. Am. Chem. Soc. 1963, 85, 3218. 73. Because H-3a and H-3b are chemical shift equivalent, their geminal coupling does not result in spin-spin splitting (Pavia, D.L.; Lampman, G.M. ; Kriz, G.S., Jr. Introduction to Spectroscopy; Saunders: Philadelphia, 1979; p 139-145). This was confirmed by a decoupling experiment: irradiation at 8 0.21 (H-2) simplified the signal at 1.01 (H-3a and H-3b) to a singlet. 74. Although H-3a and H-3b are chemical shift equivalent, and are apparendy equally coupled to H-2 (,/cis = /trans), H-3a and H-3b are magnetically non-equivalent because they are diastereotopic. 75. Wiberg, K.B.; Barth, D.E.; Schertler, P.H. J. Org. Chem. 1973, 38, 378. 76. Slabey, V.A. J. Am. Chem. Soc. 1954, 76, 3604. 77. See p 33 of the reference given within footnote 73. 78. Walborsky, H.M.; Impastato, F.J.; Young, A.E. J. Am. Chem. Soc. 1964, 86, 3283. 365 79. Piers, E.; Marais, P.C. Tetrahedron Lett. 1988, 29, 4053. 80. Based on the results of a CAS structure search using the following structure: Attributes: (1) all bonds single exact (2) ring fusion blocked (3) G1=C/H 81. The coupling of an iodocyclopropane with an alkenylstannane (in THF, at r.t.) in the presence of Pd(PPh3)4 was attempted by the Piers group and was found to be unsuccessful (Piers, E.; Jean, M. , unpublished results). The coupling of a cyclopropylstannane with an iodo alkene (in THF, at r.t.) in the presence of Pd(PPh3)4 was also unsuccessful. 82. For reviews of 1,2-divinylcyclopropane chemistry, see: (a) Piers, E. In Comprehensive Organic Synthesis; Trost, B .M; Fleming, I., Eds.; Pergamon: Oxford, 1991; vol. 4, Semmelhack, M.E., Ed., pp 971-998; (b) Hudlicky, T.; Fan, R.; Reed, J.W.; Gadamasetti, K.G. Org. React. 1992, 41, 1. 83. Piers, E.; Morton, H.E.; Nagakura, I.; Thies, R.W. Can J. Chem. 1983, 61,1226. 84. (a) Pettus, J.A., Jr.; Moore, R.E. J. Am. Chem. Soc. 1971, 93, 3087; (b) Moore, R.E. Acc. Chem. Res. 1977,10, 40. 85. Schotten, T.; Boland, W.; Jaenicke, L. Tetrahedron Lett. 1986,27, 2349. 86. (a) Epstein, W.W.; Gaudioso, L.A.; J. Org. Chem. 1982, 47, 175; (b) Epstein, W.W.; Gaudioso, L.A.; Brewster, G.B. J. Org. Chem. 1984, 49, 2748. 366 87. Barbachyn, M.R.; Johnson, C.R.; Glick, M.D. J. Org. Chem. 1984, 49, 2746. 88. Moore, R.E.; Pettus, J.A., Jr.; Mistysyn, J. J. Org. Chem. 1974, 39, 2201. 89. (a) Colobert, F.; Genet, J.P. Tetrahedron Lett. 1985, 26, 2779; (b) Akintobi, T.; Jaenicke, L.; Mamer, F.J.; Waffenschmidt, S. Liebigs Ann. Chem. 1979, 986. 90. (a) A l i , A. ; Sarantakis, D.; Weinstein, B. J. Chem. Soc., Chem. Commun. 1971, 940; (b) Schneider, M.P.; Goldbach, M . J. Am. Chem. Soc. 1980,102, 6114. 91. Piers, E.; Jean, M. ; Marrs, P.S. Tetrahedron Lett. 1987, 28, 5075. 92. Campbell, J.B., Jr.; Firor, J.W.; Davenport, T.W. Synth. Commun. 1989,19, 2265. 93. Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. J. Org. Chem. 1993, 58, 2958. 94. King, A.O.; Okukado, N.; Negishi, E. J. Chem. Soc. Chem. Commun. 1977, 683. 95. Negishi, E.; King, A.O.; Okukado, N. J. Org. Chem. 1977, 42, 1821. 96. Knochel, P.; Singer, R.D. Chem. Rev. 1993, 93, 2117. 97. Stille, J.K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508. 98. Ley, S.; Griffith, W.P. Synthesis 1994, 639. 99. wo-Propyltriphenylphosphonium bromide and sodium amide are commercially available as a pre-mixed powder from Fluka Chemicals. 100. Further investigation revealed that compound 116a decomposed on silica gel TLC plates (E. Merck, type 5554) when the plate was developed in two directions (delay time between elutions 367 was ~5 min). Thus, Iatrobeads , which are suitable for the purification of acid-sensitive compounds, were used as the column stationary phase. The Iatrobeads® were obtained from Iatron Laboratories, Inc. 101. Lee, K.; Wiemer, D.F. Tetrahedron Lett. 1993, 34, 2433. 102. Compound 119 was generously donated by Dr. Veljko Dragojlovic of our laboratories. 103. Ravid, LV, Silverstein, R.M.; Smith, L.R. Tetrahedron, 1978, 34, 1449. 104. Dieck, H.A.; Heck, R.F. J. Org. Chem. 1975, 40, 1083. 105. Hart, D.W.; Blackburn, T.F.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679. 106. For discussions of the metal-halogen exchange reaction, see: (a) Wakefield, B.J. The Chemistry of Organolithium Compounds; Pergamon: Oxford, 1974; pp 51-53; (b) Bailey, W.F.; Patricia, J.J. J. Organomet. Chem. 1988, 352, 1. 107. Gilman, H ; Langham, W.; Jacoby, A.L. /. Am. Chem. Soc. 1939, 61,106. 108. Wittig, G.; Pockels, U.; Droge, H. Ber. 1938, 71,1903. 109. Winkler, H.J.S.; Winkler, H. J. Am. Chem. Soc. 1966, 88, 964. 110. Applequist, D.E.; O'Brien, D.F. J. Am. Chem. Soc. 1963, 55,743. 111. (a) Jones, R.G.; Gilman, H. Org. Reactions, 1951, 6, 339; (b) Batalov, A.P.; Rostokin, G.A.; Korshunov, LA. Tr. Khim. Khim. Tekhnol. 1968, 2,1. 112. (a) Winkler, H.J.S.; Winkler, H. /. Am. Chem. Soc. 1966, 88, 969; (b) Batalov, A.P.; Rostokin, G.A.; Skvortsova, M.A. Zh. Obshch. Khim. 1969, 39, 1840. 368 113. Neumann, H.; Seebach, D. Tetrahedron Lett. 1976, 52, 4839. 114. For a discussion of the transmetallation of organostannanes, see Pereyre, M. ; Quintard, J.P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London, 1987; pp 149-184. 115. (a) Seyferth, D.; Weiner, M.A. Chem. & Ind. 1959, 402; (b) Seyferth, D.; Weiner, M.A. J. Org. Chem. 1959, 24, 1395. 116. (a) Seyferth, D.; Jula, T.F. J. Organomet. Chem. 1974, 66, 195; (b) Seyferth, D.; Vaughan, L.G. 7. Am. Chem. Soc. 1964, 86, 883 and citations therein. 117. Seyferth, D.; Cohen, H.M. Inorg. Chem. 1963, 2, 625. 118. Corey, E.J.; Eckrich, T .M. Tetrahedron Lett. 1984, 25, 2415. 119. Sequential treatment of vinyl iodocyclopropane 116a with BuLi and MesSnCl provided compound 136 in 70% yield (see Experimental Section, p 286, for details). 120. Lautens, M. ; Delanghe, P.H.M. J. Org. Chem. 1992, 57, 798. 121. The cyclopropyl group is more susceptible to electrophihc attack when it is in'an apical position as compared to an equatorial position, see references 17 and 34a. 122. Newman-Evans, R.H.; Carpenter, B.K. Tetrahedron Lett. 1985, 26, 1141. 123. Analysis (GCMS) of the crude product also indicated the presence of a small amount of a side-product, which was presumably the coupling product of BuZnCl (generated from excess BuLi and ZnCL,) with excess electrophile. 369 124. Repetition of the coupling of 116b with 120 without D M F (in THF only) resulted in a slightly lower conversion; the ratio of coupling products to reduced material was -2.5:1 based on GLC analysis of the crude product mixture. Polar solvents such as D M F have been reported to improve the yields of cross-coupling reactions involving zinc compounds, see: (a) Negishi, E.; Owczarczyk, Z.R.; Swanson, D.R. Tetrahedron Lett. 1991, 32, 4453; (b) Labaudiniere, L.; Normant, J.F. Tetrahedron Lett. 1992, 33, 6139; (c) Duchene, A. ; Abarbri, M. ; Parrain, J.L.; Kitamura, M. ; Noyori, R. Synlett, 1994, 524. 125. The carbon skeleton of compound 154 is synthetically interesting because it is very similar to that of the sesquiterpenoid (±)-P-himachalene, shown below (see Piers, E.; Ruediger, E.H. Can. J. Chem. 1983, 61, 1239 for a total synthesis of this natural product). 126. For a review of the carbometallation of alkynes, see: Normant, J.F.; Alexakis, A. Synthesis 1981, 841. 127. Organometallic reagents can also be added in an intramolecular fashion to alkenyl moieties to give alkylcycloalkane systems. For reports on such additions, see: (a) St. Denis, J.; Dolzine, T.; Oliver, J.P. J. Am. Chem. Soc. 1972, 94, 8260; (b) Smith, M.J.; Wilson, S.E. Tetrahedron Lett. 1981, 22, 4615; (c) Ross, G.A.; Koppang, M.D.; Bartak, D.E.; Woolsey, N.F. J. Am. Chem. Soc. 1985, 107, 6742; (d) Chamberlin, A.R.; Bloom, S.H. Tetrahedron Lett. 1986, 27, 551; (e) Chamberlin, A.R.; Bloom, S.H.; Cervini, L.A.; Fotsch, C.H. J. Am. Chem. Soc. 1988,110, 4788; (f) Paquette, L.A.; Gilday, J.P.; Maynard, G.D. J. Org. Chem., 1989, 54, 5044; (g) Broka, C.A.; Shen, T. J. Am. Chem. Soc, 1989, 111, 2981; (h) Cooke, M.P., Jr. J. Org. Chem., 1992, 57, 1495; (i) Krief, A. ; Barbeaux, P. Tetrahedron Lett. 1991, 32, All; (j) Bailey, W.F.; Khanolkar, P-himachalene 370 A.D.; Gavaskar, K.V. J. Am. Chem. Soc. 1992,114, 8053 and citations therein; (k) Bailey, W.F.; Jiang, X . J. Org. Chem. 1994, 59, 6528. 128. (a) Dessy, R.E.; Kandil, S.A. J. Org. Chem. 1965, 30, 3857; see also reference 129b; (b) Kandil, S.A.; Dessy, R.E. J. Am. Chem. Soc. 1966, 88, 3027; (c) Ward, H.R.; Lawler, R.G. J. Am. Chem. Soc. 1967, 89, 5517; (d) Johnson, R; Subramania, R. J. Org. Chem. 1986, 51, 5040; (e) Bailey, W.F.; Ovaska, T.V. J. Am. Chem. Soc. 1993, 115, 3080 and citations therein; (f) Ovaska, T.V.; Warren, R.R.; Lewis, C.E.; Wachter-Jurcsak, N.; Bailey, W.F. /. Org. Chem. 1994, 59, 5868; (g) Wu, G.; Cederbaum, F.E.; Negishi, E. Tetrahedron Lett. 1990, 31, 493. 129. (a) Richey, H.G., Jr.; Rothman, A . M . Tetrahedron Lett. 1968, 1457; (b) Kossa, W.C., Jr.; Rees, T.C.; Richey, H.G., Jr. Tetrahedron Lett. 1971, 3455; (c) Fujikura, S.; Inoue, M. ; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 1999. 130. (a) Yeh, M.C.P.; Knochel, P. Tetrahedron Let. 1989, 30, 4799 and citations therein; (b) Meyer, C ; Marek, I.; Normant, J.F.; Platzer, N. Tetrahedron Lett. 1994, 35, 5645. 131. Miller, J. A.; Negishi, E. Is. J. Chem. 1984, 24, 76. 132. (a) Crandall, J. K.; Battioni, P.; Wehlacz, J.T.; Bindra, R. J. Am. Chem. Soc. 1975, 97, 7171; (b) Sternberg, E.D.; Vollhardt, K.P.C. J. Org. Chem. 1984, 49, 1574; (c) Rao, S.A.; Knochel, P. /. Am. Chem. Soc. 1991,113, 5735. 133. (a) Trost, B .M. ; Lee, D.C. /. Am Chem. Soc. 1988,110, 7255; (b) Zhang, Y. ; Negishi, E. J. Am. Chem. Soc. 1989, 111, 3454. 134. (a) Bailey, W.F.; Patricia, J.J.; Nurmi, T.T.; Wang, W. Tetrahedron Lett. 1986, 27, 1861; (b) Bailey, W.F.; Patricia, J.J.; Nurmi, T.T. Tetrahedron Lett. 1986, 27, 1865. 135. Bailey, W.F.; Punzalan, E.R. J. Org. Chem. 1990, 55, 5404. 136. Based on a CAS search using the following structure: 371 n = 0-4 Note that this search item allows for spiro ring fusion. 137. For a review of vinylcyclopropane chemistry, see Hudlicky, T.; Reed, J.W. In Comprehensive Organic Synthesis; Trost, B .M; Fleming, I., Eds.; Pergamon: Oxford, 1991; vol. 5, Paquette, L.A., Ed., pp 899-970. 138. This assumption is based on the studies of Beak and Gallagher. See Gallagher, D. J.; Beak, P. J. Am. Chem. Soc. 1991,113, 7984. 139. Applequist and O'Brien observed very little coupling during the reaction of n-C 3H 7I and C 2 H 5 L i at -78°C in E t 2 0 ; see reference 110. 140. Kocienski, P. J. In Protecting Groups; Georg Thieme Verlag: Stuttgart, 1994; p 29. 141. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190. 142. Nguyen, P.; Todd, S.; Van den Biggelaar, D.; Taylor, N. J.; Marder, T. B.; Wittmann, F.; Friend, R. H. Synlett 1994, 299. 143. TLC analysis of CDC1 3 solutions of 231 (R = TMS) and 235 (R = Me 3Ge) after several days of storage indicated the formation of a non-polar compound, suggesting that acid-catalyzed isomerization had occurred. On this basis, compound 233 (R = TBDMS) was chosen for study since it was expected to behave similarly and, more importantly, the rearrangement product 372 derived from 233 was expected to be less volatile than those derived from 231 and 235. Treatment of a solution of 233 in E t 2 0 with glacial acetic acid at room temperature for 12 days afforded a non-polar compound; purification of the crude material gave the ether 241 in 84% yield. Model studies of 241, which is an angularly fused tricyclic ring system, indicated that a cis, cis ring fusion should be thermodynamically more stable than a cis, trans ring fusion. Notably absent from the spectra of 241 were the hydroxyl stretch in the IR spectrum and the vinyl proton signal in the 1 H N M R spectrum. See Experimental Section for complete experimental and spectral details (p 347). 144. (a) The increased stability of carbanions a to silicon is thought to arise from the delocalization of the electron density centered in a 2p orbital on carbon into an empty 3d orbital on silicon. See: Weber, W.P. In Silicon Reagents for Organic Synthesis, Springer-Verlag: Berlin, 1983; p 59; (b) Zweifel, G.; Murray, R.E.; On, H.P. J. Org. Chem. 1981, 46, 1292. 145. (a) Curtin, D. Y. ; Koehl, W. J. Jr. /. Am. Chem. Soc. 1962, 84, 1967; (b) Curtin, D. Y.; Crump, J. W. /. Am. Chem. Soc. 1958, 80, 1922. 146. Chvalovsky, V.; Bazant, V. Helv. Chim. Acta 1969,52, 2398. 147. The cyclopropyl anion is configurationally stable unless it is substituted by an anion-stabilizing group at the anionic center, see: (a) Walborsky, H.M.; Hornyak, F.M. J. Am. Chem. Soc. 1955, 77, 6026; (b) Walborsky, H.M.; Periasamy, M.P. J. Am. Chem. Soc. 1974, 96, 3711; (c) Trost, B.M. ; Keeley, D.E.; Arndt, H.C.; Rigby, J.H.; Bogdanowicz, M.J. J. Am. Chem. Soc. 1977, 99, 3080; (d) Hiyama, T.; Kanakura, A.; Morizawa, Y. ; Nozaki, H. Tetrahedron Lett. 1982, 23, 1279. 233 241 373 148. For an example of an intramolecular addition of a Grignard reagent to a nitrile group, see Larcheveque, M. ; Debal, A.; Cuvigny, T.H. J. Organomet. Chem. 1975, 87, 25. 149. For an example of an intramolecular displacement of bromide by a vinyllithium reagent, see Negishi, E.; Zhang, Y. ; Bagheri, V. Tetrahedron Lett. 1987, 28, 5793. 150. Curran, D.P.; Chen, M. ; K im, D. J. Am. Chem. Soc. 1986,108, 2489. 151. The acetate 249 was prepared from the corresponding alcohol 60c according to a procedure similar to that of Friesen (see Friesen, R.W., Ph.D. Thesis, University of British Columbia, Vancouver, B.C., January 1988, p 181). Acetate 249: yield, 92 %; X H N M R (400 MHz, CDC13) 8: 0.58-0.68 (m, IH, H-2), 0.93 (dd, IH, 7 = 6.5, 6.5 Hz, H-3b), 1.10 (dd, IH, J = 9.5, 6.5 Hz, H-3a), 1.51-1.61 (m, IH, H-5a), 1.71-1.89 (overlapping signals, 3H, H-5b, H-6), 1.92 (t, IH, J = 2.5 Hz, H-9), 2.07 (s, 3H, OCH 3), 2.21-2.29 (m, 2H, H-7), 3.98 (dd, IH, J= 12, 8.5 Hz, H-4a), 4.36 (dd, IH, J= 12, 6 Hz, H-4b). 152. Simamura, O. Top. Stereochem. 1969, 4, 21. 153. For examples of intermolecular reactions involving cyclopropyllithiums, see: (a) Marino, J.P.; Browne, L.J. Tetrahedron Lett. 1976, 3245; (b) Wender, P.A.; Filosa, M.P. J. Org. Chem. 1976, 41, 3490. H-3a 4 249 374 154. For examples of intermolecular reactions involving cyclopropyl Grignard reagents, see: (a) Nesmeyanova, O.A.; Rudashevskaya, T.Y.; Dyachenko, A.I.; Savilova, S.F.; Nefedov, O.M. Synthesis, 1982, 296; (b) Walborsky, H.M.; Young, A.E. J. Am. Chem. Soc. 1964, 86, 3288. 155. For examples of intermolecular reactions involving cyclopropylcuprates, see: (a) Piers, E.; Nagakura, I.; Morton, H.E. J. Org. Chem. 1978, 43, 3630; (b) Morgans, D.J. Jr.; Feigelson, G.B. J. Am. Chem. Soc. 1983, 105, 5477; (c) Piers, E.; Reissig, H.U. Angew. Chem. Int. Ed. Engl. 1979,18, 791; (d) Yamamoto, H.; Kitatani, K.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 5816. 156. Cooper, J.W. Spectroscopic Techniques for Organic Chemists; John Wiley and Sons: New York, 1980; pp 94-96. 157. Summers, M.F.; Marzilli, L.G.; Bax, A. J. Am, Chem. Soc. 1986,108, 4285 and references cited therein. 158. See the experimental section of Harrison, I.T. Instruction Manual; Harrison Research: 1985. 159. Burfield, D.R.; Smithers, R.H. J. Org. Chem. 1978, 43, 3966. 160. Coulson, D.R. Inorg. Syn. 1972,13, 121. 161. Kauffman, G.B.; Teter, L.A. Inorg. Syn. 1963, 7, 9. 162. Wuts, P.G.M. Synth. Commun. 1981,11,139. 163. Kofron, W.G.; Baclawski, L .M. J. Org. Chem. 1976,41, 1879. 164. Bryan, Y.P. ; Byrne, R.H. J. Chem. Ed. 1970, 47, 361. 375 165. Dimethyl 2,6-octadiyndioate was prepared by Dr. R. Skerlj of our laboratories. 166. Biougne, J.; Theron, F. CR. Acad. Sci. Paris, 1971, 272c, 858. 167. Jung, M.E.; Hagenah, J.A.; Long-Mei, Z. Tetrahedron Lett. 1983, 24, 3973. 168. Denmark, S.E.; Habermas, K.L.; Hite, G.A. Helv. Chim. Acta 1988, 71, 168. 169. In order to avoid the necessity of concentrating large volumes of solvent containing the volatile product, the molarity of the substrate in the reaction mixture was increased four-fold. 170. Bis(cyclopentadienyl)zirconium chloride hydride [(ri5-C5H5)2ZrH(Cl)] was generously donated by Dr. Murugesapillai Mylvaganam. This reagent is also available from Aldrich Chemical Company, Inc. 171. Silverstein, R.M.; Bassler, G.C.; Morrill, T.C.; Spectrometric Identification of Organic Compounds, 4th ed.; John Wiley and Sons: New York, 1981; p 273. 172. It is thought that the three equivalents of MeLi could be added together at the start of the reaction rather than sequentially without affecting the outcome of the reaction. 

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