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Synthesis and thermal electrocyclic reactions of substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-1(6)-enes Ellis, Keith Alfred 1997

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SYNTHESIS A N D T H E R M A L ELECTROCYCLIC REACTIONS OF SUBSTITUTED 7-(ETHOXYCARBONYL)BICYCLO[4.2.0]OCT- 1(6)-ENES by KEITH A L F R E D ELLIS B.Sc.(H), The University of Western Ontario, 1988 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA February 1997 © Keith A. Ellis In presenting this thesis in. partial fulfilment of the requirements for an advanced degree at the University of British Columbia/ I agree that the . Library shall make it freely available for reference , and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia Vancouver, Canada Date T-AvlOCCM \\\{l\rffr DE-6 (2/88) A B S T R A C T The a,3-acetylenic esters of general structure (18) were converted into the corresponding ethyl (£)- and (Z)-3-trimethylstannyl-2-alkenoates of general structures (133) and (134), respectively. Deconjugation-alkylation of ethyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates (133) and (134) with alkylating agents of general structure (32) provided, stereo selectively, the functionalized esters of general structure (33). Palladium(0)-catalyzed intramolecular cross-coupling reactions of esters (33) provided the ethyl 2,3-bis(alkyhdene)cyclobutanecarboxylates of general structure (34) in good yields. The Diels-Alder reactions of the 1-substituted 2,3-bis(methylene)cyclobutanes (243) and ethyl 2,3-bis(alky]idene)cyclobutanecarboxylates of general structure (34) (R' = H) with the dienophiles TCNE and M V K were investigated. It was found that Diels-Alder reactions to prepare cycloaddition products (11), (14), (255-268) occurred with high face-and in some instances endo/exo- and regioselectivities. The conformations of some of these products (11), (14), (265-268) was determined by N M R analysis and a series of decoupling and N O E difference experiments. The torquo selectivity of the thermally-induced, conrotatory ring opening reaction of each of the bicyclic cyclobutenes (11), (14), (255-262), (264-268) to produce dienes of general structures (273) and (274) or (25) and (26) was investigated. Thermolysis of (262) produced only the product resulting from the outward rotation of the -CLTjOH group. Thermolysis of (255-262) and (264-268) produced mixtures of varying ratios of the outward (273) and inward (274) (or (25) and (26)) thermolysis products. The differing ratios of products was rationalized on the basis of electronic and / or steric factors. R C02Et R H 18 Me 3 Sn H Me 3 Sn COsEt 133 134 -Br 32 B l S j / " N ^ V S n M e 3 RJ C02B 33 RJ 34 4? W W= CIHjOH, CN, C 0 2 H 243 NC NC-NC-W NC 255 W = CQ>Et 262 W = CBjOH 263 W = CN 264 W = COjH ^COoEt R 14 R = Me 265 R = /-Pr 267 R = c-Hex NC NC-NC-Et NC R 256 R = Me 258 R = /-Pr 260 R = c-Hex NC NC-NC-X O s E t NC R XIOsEt 11 R = Me 266 R = /-Pr 268 R = c-Hex 257 R = Me 259 R = /-Pr 261 R = c-Hex 26 T A B L E O F C O N T E N T S ABSTRACT ii T A B L E OF CONTENTS iv LIST OF TABLES viii LIST OF FIGURES x LIST OF ABBREVIATIONS xi ACKNOWLEDGMENTS xiv I. INTRODUCTION 1 1. Overview of this Research Project 1 2. Objectives of this Research Project 7 3. Background information 8 3.1 Previous work on the synthesis of alkyl 2,3-bis-alkylidenecyclobutanecarboxylates and related compounds 8 3.2 Previous X-ray crystallographic studies on crystalline derivatives of 2,3-bis-alkylidenecyclobutanecarboxylates 15 3.3 Diels-Alder reactions of the 2,3-bis-alkylidenecyclobutane-carboxylates 17 3.4 Thermolysis of the cyclobutenes and related compounds 19 H. RESULTS A N D DISCUSSION 36 I. Synthesis of ethyl (£)- and (Z)-3-trimethylstannyl-2-alkenoates 36 1.1 Preparation of the a , P-acetylenic esters 37 1.2 Preparation of ethyl ( E ) - and (Z)-3-trimethylstannyl-2-alkenoates. 38 2. Deconjugation-alkylation of ethyl (E)- and (Z)-3-triraethylstannyl-2-alkenoates 50 2.1 Preparation of the ethyl (E)- and (Z)-3-trimethylstannyl-3-alkenoates 50 2.2 Preparation of the alkylating agents 58 2.2.1 Preparation of the 1,1-dibromo-l-alkenes 59 2.2.2 Preparation of the 2-alkyn-l-ols 60 2.2.3 Preparation of the alkyl(Z)-2-bromo-2-alkene-l-ols 61 2.2.4 Preparation of the alkyl (Z)-l,2-dibromo-2-alkenes 63 2.3 Deconjugation- alkylation of ethyl (E)- and (Z)- 3 -trimethylstannyl-2- alkenoates 64 2.4 Deprotonation-alkylation of ethyl (E)- and (Z)-3-trirnethylstannyl-3- alkenoates 65 3. Synthesis of alkyl 2,3-bis(alkylidene)cyclobutanecarboxylates and related derivatives 70 3.1 Preparation of the alkyl 2,3-bis(alkylidene)cyclobutane-carboxylates via palladium(0)-catalyzed coupling reactions 70 3.2 Preparation and X-ray analysis of (Z,Z)-2,3-bis(alkylidene)-cyclobutanecarboxamides 80 3.3 Preparation of the l-substituted-2,3-bis(methylene)cyclobutanes. . 84 3.3.1 Preparation of l-(hydroxymethyl)-2,3-bis(methylene)-cyclobutane 85 3.3.2 Preparation of l-formyl-2,3-bis(methylene)cyclobutane. . . 86 3.3.3 Preparation of l-cyano-2,3-bis(methylene)cyclobutane. . . 87 3.3.4 Preparation of 2,3-bis(methylene)cyclobutanecarboxyhc acid 88 vi 4. Diels-Alder reactions of alkyl 2,3-bis(alkylidene)cyclobutanecarboxylates and related compounds 89 4.1 Diels-Alder reactions of dienes with tetracyanoethylene (TCNE). . . 90 4.2 Diels-Alder reactions of dienes with methyl vinyl ketone (MVK). . 1 0 1 5. Thermal ring opening of the functionalized bicyclo[4.2.0]oct-l(6)-enes. I l l 5.1 Introduction I l l 5.2 Preparative thermal ring opening of the functionalized bicyclo-[4.2.0]oct-l(6)-enes I l l 5.3 Small scale thermal ring opening of the functionalized bicyclo-[4.2.0]oct-l(6)-enes 123 m . EXPERIMENTAL SECTION 134 1. General 134 1.1 Data acquisition and presentation of results 134 1.2 Reagents and solvents 136 2. Preparation of the 1,1-dibromo olefins 137 3. Preparation of the 1-alkynes 141 4. Preparation of the a,P-acetylenic Esters 142 5. Preparation of Uthium (cyano)(trimethylstannyl)cuprate 146 6. Preparation of ethyl (£)- and (Z)-3-trimethylstannyl-2-alkenoates 147 7. Preparation of ethyl (£)- and (Z)-3-trimethylstannyl-3-alkenoates 157 8. Preparation of alkylating agents 162 9. Preparation of the diene esters 170 10. Preparation of the ethyl 2,3-bis(alkylidene)cyclobutanecarboxylates 180 11. Preparation of the cyclobutanecarboxamides 192 12. Preparation of the l-substituted-2,3-bis(methylene)cyclobutanes 197 13. Diels-Alder reactions 205 14. Preparative thermal ring opening of the functionalized bicyclo[4.2.0]oct-l(6)-enes 227 vii 15. Small scale thermal ring opening of the functionalized bicyclo [4.2.0]oct-l(6)-enes and direct determination of product ratios by N M R spectroscopy 258 IV. REFERENCES 264 V. APPENDIX 269 viii L IST O F T A B L E S Table 1. Synthesis of the ethyl 2,3-bis-alkylidenecyclobutanecarboxylates 34. . . . 12 2. Synthesis of the cyclopentanecarboxylates 69-72 and cyclohexanecarboxylates 73-75 14 3. Products of the pyrolysis of 3,3-disubstituted cyclobutenes 75 21 4. Calculated Z:E diene ratios based on steric effects 22 5. Substituent effects on the stereochemistry of cyclobutene electrocyclizations 24 6. Predicted change in activation energy of cyclobutene opening (Ea=32 kcal/mol) by C-3 substituents 25 7. Thermal electrocyclic ring opening of c/s-3,4-disubstitutedcyclobutenes . . 32 8. Preparation of the a,P-acetylenic esters 38 9. Reaction of a,|3-acetylenic esters with (trimethylstannyl)copper(I) reagents 135-140 42 10. Preparation of alkyl (Z)-3-trimethylstannyl-2-alkenoates 44 11. Preparation of alkyl (£)-3-trimethylstannyl-2-alkenoates 46 12. Partial ! H N M R data for (^-3-trrmethylstannyl-2-alkenoates 133 48 13. Partial ! H N M R data for (Z)-3-trimethylstannyl-2-alkenoates 134 49 14. Deprotonation-alkylation of ethyl (£)-3-trrmethylstannyl-3-alkenoates with 2,3-dibromopropene 66 15. Deprotonation-alkylation of ethyl (Z)-3-trimethylstannyl-3-alkenoates with 2,3-dibromopropene 67 16. Partial N M R spectra data of the diene esters 164 and 211 68 17. Stereocontrolled synthesis of alkyl 2,3-bis(alkylidene)-cyclobutanecarboxylates 221 75 18. Diels-alder reactions of the cyclobutanecarboxylates 221 with tetracyanoethylene 92 19. Diels-alder reactions of the l-substituted-2,3-bis(methylene)cyclobutanes with tetracyanoethylene 94 20. Diels-alder reactions of the cyclobutane carboxylates 221 with M V K 104 21. Preparative thermal ring opening of the functionalized bicyclo[4.2.0]oct-l(6)-enes272 115 22. Preparative thermal ring opening of the functionalized bicyclo[4.2.0]oct-l(6)-enes23 118 23. Partial lft N M R data for dienes 291 and 292 122 ix 24. Small scale thermolysis of the substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-l(6)-enes of general structure 293 124 25. Small scale thermolysis of the substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-l(6)-enes of general structure 296 125 26. Small scale thermolysis of the substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-l(6)-enes of general structure 297 126 27. Small scale thermolysis of the substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-l(6)-enes of general structure 300 127 28. Small scale thermolysis of the substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-l(6)-enes of general structure 254 128 X LIST OF FIGURES Figure 1. Diagramatic view of the two possible directions that the dieneophile TCNE may approach the ethyl 2,3-bisalkylidenecyclobutanecarboxylates 18 2. HOMO and L U M O of the cyclobutene transition structure and the occupied p orbital of a donor orbital 23 3. i H N M R spectrum of ester 233 78 4. Stereoview of cyclobutane carboxamide 240 83 5. Diagramatic view of the two possible directions that the dieneophile TCNE may approach the ethyl 2,3-bisalkylidenecyclobutanecarboxylates 91 6. Stereoview of ester 256 97 7. Favoured half-chair conformations of the Diels-Alder adducts (257-261).... 100 8. The effect of a Lewis acid on the energies of the HOMO and L U M O of the dieneophile in the Diels-Alder reaction 101 9. Frontier orbitals showing the increased polarization of the L U M O of the double bond in the dieneophile in a Lewis acid catalyzed Diels-Alder reaction . . . 102 10. Frontier orbitals showing the increased secondary orbital interaction in the Lewis acid catalyzed Diels-Alder reaction 103 11. Relative configuration and preferred conformation of ester 14 108 12. Relative configuration and preferred conformation of ester 11 108 13. Relative configuration and preferred conformation of ester 265 109 14. Relative configuration and preferred conformation of ester 267 109 15. Relative configuration and preferred conformation of ester 268 110 16. Conformations of the thermolysis precursors 129 17. Product conformations of the thermolysis reactions 132 xi LIST O F ABBREVIATIONS a - 1,2 relative position Anal. - elemental analysis P - 1 , 3 relative position bp - boiling point br - broad n-Bu - normal-butyl (n- - normal-) H -BuL i - «-butyllithium c - concentration in g/100 mL l^C N M R - carbon-13 nuclear magnetic resonance COSY - (lH-lHhomonuclear) correlation spectroscopy CuBr»Me2S - copper(I) bromide-dimethylsulfide d - doublet 8 - scale (nmr), dimensionless Dibal - diisobutyl aluminium hydride DMF - A^A^-dimemylformamide DMSO - dimethylsulfoxide D 2 O - deuterium oxide s - molar absorptivity e.g. - examplin gratia; for example equiv. - equivalent(s) et al. - et alia; and others E - entgegen (configuration) y - 1,4 relative position GLC - gas-liquid chromatography h - hour(s) H M P A - hexamethylphosphor amide * H nmr - proton nuclear magnetic resonance HOAc - acetic acid HOMO - highest occupied molecular orbital hplc - high-performance liquid chromatography /- - iso-ibid. - ibidem; in the reference cited i.e. - idest;thatis IMID - imidazole xii IR J KN(S iMe 3 ) 2 L D A L i A l H 4 lit. L U M O M m (Me 3 Sn) 2 [Me 3SnCuCN]Li Me3SnCu»Me2S [Me 3SnCuSPh]Li MHz min mp M V K n-NBS NOE o-P P-Pd(0) Ph pH Ph 3 P Ph 3 P=CBr 2 (Ph 3 P) 4 Pd PP c-Pr z-Pr «-Pr q R infrared coupling constant (in Hz) n bond(s) coupling for tin and proton nuclei (in Hz; n = 2 or 3) potassium bis(trmiethylsilyl)amide lithium diisopropylamide lithium aluminum hydride literature lowest unoccupied molecular orbital molar (moi dm" 3), or mega (10^) multiplet hexamethylditin Kthium (trimethylstannyl)(cyano)cuprate (trimemylstannyl)copper-dmemylsulfide HtMum(trimethylstannyl)(phenylthio)cuprate megaHertz minute(s) melting point methyl vinyl ketone normal-N-bromosuccinimide nuclear Overhauser effect ortho-page para-palladium(0) phenyl hydrogen ion concentration triphenylpho sphine dibromomethylenetriphenylphosphorane tetrakis(triphenylphosphine)palladium(0) pages cyclopropyl isopropyl (z- - iso-) normal-propyl (n- - normal-) quartet rectus (configuration) xiii R f - retention factor (ratio of distance traveled by the center of a zone to the distance simultaneously traveled by the mobile phase); chromatographic term S - sinister (configuration) s - singlet, or second(s) t - triplet t- - tertiary TCNE - tetracyanoethylene tert- - tertiary-TI IF - tetrahydrofuran TLC - thin-layer chromatography uv - ultraviolet Vol. - volume Z - zusammen (configuration) ZnCi2 - zinc chloride (+) - rotation to the right (-) - rotation to the left +ve - positive -ve - negative XIV A C K N O W L E D G E M E N T S I would first like to express my thanks to my supervisor, Professor Edward Piers, for his guidance, patience and support throughout the course of my research and especially throughout the lengthy preparation of this thesis. Thanks to all of the past members in the "Piers Lab" including Livain, ChantaL Tim, Christine, Han, Guy, Fung, Pierre, Fraser, MigueL Betty-Anne, Richard, Veljko, Jacques, Johanne, Philip, Francisco, Renata, Rene, Todd, Anthony, Katherine, A l and Serge for helpful advice, sharing of chemicals, and friendly discussions. Special thanks to Livain, Chantal, and Veljko for proofreading my introduction and experimental and to Dr. Piers and Ingrid for proof-reading my discussion. Financial Assistance in the form of several NSERC postgraduate scholarships is gratefully acknowledged. When a student leaves the department prematurely to begin a career elsewhere, such that working full time on a thesis is not possible, extra demands are placed upon the supervisor, family, and friends for support throughout this time. If not for the emotional support of my wife Ingrid and the extra work she has done raising our children George and Sarah in order to give me free time to work on my thesis, this thesis never would have been completed. 1 I. INTRODUCTION .1. Overview of this research project and / or ( D Thermolysis of cyclobutene results in an electrocyclic ring opening to produce 1,3-butadiene. This process proceeds via a thermally allowed conrotatory pathway. 1 The C3-monosubstituted cyclobutene (1) can open via one or both of two conrotatory pathways to give one or both of the "inward" or "outward" rotation products (Equation 1). Similarly, C 3 , C 4 trans-disubstituted cyclobutenes (2) may open to give either one or both of the (E,E) or the (Z,Z) isomers (3) and (4) (Scheme 1). In contrast, the C 3 , C 4 c/s-disubstituted cyclobutenes (5) or C3,C3-disubstituted cyclobutenes (8) must have one group rotating inward and one group rotating outward (Scheme 1). 2 and / or and / or Y 7 X and / or 8 10 Scheme 1: Possible outcomes of the thermal ring opening of disubstituted cyclobutenes. A number of studies by Frey,2 -4 Crigee,^ D o l b i e r , ^ ^ Stevens, ^  Houk, 10 and Piers 1 ! have shown that the nature of the substituents at C 3 affects the outcome of the thermal ring opening of substituted cyclobutenes of general structures (1) and (8). Studies by Frey^-4 and Crigee^ have shown that alkyl substituents tend to rotate preferentially outward due to the steric bulk of these substituents. On the basis of computational and experimental work, Houk proposed that it is the electronic nature of certain substituents that determines the direction of rotation (inward or outward) of the substituent. 12 Houk 3 predicted that groups that are good electron donors should prefer outward rotation while strongly electron withdrawing groups that are good electron acceptors should favour inward rotation. 12 For example, Houk predicts on the basis of ab initio' calculations that the ester function should have a small (1.7-2.5 kcal/mol) preference for outward rotation. 13,14,15 Thus, the ratio of outward to inward rotation products is expected to fall between 7:1-18: lat l65°C. Piers and Lu have provided some evidence supporting this prediction.H For example, ester (11) was thermolyzed in refluxing mesitylene (165°C for 1 h) to produce an 11:1 mixture of the outward (12) and the inward (13) rotation products (Scheme 2). 11 165°C, 1h XC^Et O = CC^Et O 12 (11:1) 13 COsEt 165°C, 1h C0 2 Et 14 O ' C0 2 Et O 15 (1:1) 16 C0 2Et Scheme 2 Interestingly, the diastereomer of (11), compound (14), was thermolyzed under the same conditions to produce a 1:1 mixture of outward (15) and inward (16) rotation products (Scheme 2). An inspection of molecular models indicates that the ester group 1 Ab initio calculations are quantum mechanical calculations where the Schrodinger equation is approximated. 4 would have to slide past the pseudoequatorial Me group of (14) in the transition state leading to outward rotation product (15). This destabilizing steric interaction would be expected to increase the transition state energy for outward rotation, making inward rotation more competitive. One of the objectives of this research program was to test the predictions of Houk regarding the effect of the nature of the substituent on the ratio of outward to inward rotation products. Efforts were to be made to develop new synthetic sequences to compounds of general structure (17) where W= -C02Et, - C N , - C 0 2 H , - C 0 2 " , - C H 2 O H These compounds were then to be thermolyzed and the results of these experiments were to be compared with the predictions of Houk. 13,14,15 The second objective of this research endeavor was to study the effect of increasing the steric bulk of the C-5 alkyl substituent (R) on various 5-substituted 7-(ethoxycarbonyl)- bicyclo[4.2.0]oct-l(6)-enes (23) or (24) on the ratios of outward (25 and 27) to inward (26 and 28) rotation thermolysis products (Scheme 3). Using methodology that had been previously developed in our laboratories, 16,17 it appeared that compounds of general structure (23) and (24) (where R=H, Me, /-Pr, c-Hex) could readily be prepared (Scheme 3). A conformational study on all of the 5-substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-l(6)-enes synthesized would allow one to determine if the R groups on the six membered rings are in pseudoaxial or pseudoequatorial orientations. This should provide insight of the effects of non-bonding interactions involving these groups on the torquo selectivity" of the reaction. u Torquoselectivity is referred to as the selectivity for outward or inward twisting of the breaking C-C cyclobutene bond. 34 5 Scheme 3 6 The strained compound (29), which, in the solid state, has a torsion angle of 23° between carbons a and b of the cisoid diene unit, has been prepared. ^ By using the methodology outlined in Scheme 3 where (20) is replaced by reagents of general structure (32), highly strained dienes (30) and (31) could be synthesized and the torsion angles deterrnined from X-ray analysis (Scheme 4). The transformation of (33) to (34) can be accomplished using a Pd(0)-catalyzed cross coupling between the vinyltrimethylstannyl and the vinyl bromide moieties. Thus, a third objective of this research project was the synthesis and study of the reactivity of these highly strained molecules while determining the scope and limitations of the intramolecular Pd(0)-catalyzed cross-coupling procedure. a 34 Scheme 4 7 2. Objectives of this research project w 17 1. The first objective of this research project was to develop new synthetic sequences to compounds of general structure (17) where W= - C 0 2 E t , - C N , - C O 2 H , -CO2", - C H 2 O H . These compounds were then to be thermolyzed and the results of these experiments were to be compared with the predictions of Houk. 13,14,15 C 0 2 E t C 0 2 E t 2. The second objective of this research endeavor was to study the effect of increasing the steric bulk of the C-5 alkyl substituent (R) on various 5-substituted 7-(ethoxycarbonyl)- bicyclo[4.2.0]oct-l(6)-enes (23) or (24) on the ratios of outward (25 and 27) to inward (26 and 28) rotation thermolysis products (Scheme 3, page 5) /-Pr /-Pr H 30 0 P h c-Hex c-Hex H 31 0 P h 3. The third objective of this research project was the synthesis and study of the reactivity of the highly strained dienes (30 and 31) and determining the scope and limitations of the intramolecular Pd(0)-catalyzed cross-coupling procedure used to prepare them 3. Background information 3.1 Previous work on the synthesis of alkyl 2.3-to-allcyMenecyclobutanecarboxylates (36) and related compounds.(37) and (38) R I ^ V ^ R , A t i ) n T J 0 2 R " 35 36 n=1 37 n=2 38 n=3 Traditional methods for the syntheses of substituted l,2-/3w-alkylidenecyclobutanes of general structure (35) are inefficient, stereochemically ambiguous, and difficult to carry out in the laboratory. 18,19,20,21 p o r example, the preparation of (35) (R=R-H), which proceeds via a thermal [n^s + n^s] cycloaddition or dimerization of allene, requires passing allene through a tube packed with glass balls and heated to 500°C. ^  The pyrolysate was collected in a flask cooled with dry ice, was fractionally distilled to remove unreacted allene, and the allene recycled 10 times to afford 25% of 1,2-/3/5-methylidenecyclobutane (35, R=R'=H). Recently, Pasto and co-workers have developed a low temperature method of converting substituted /3/s-allenes into substituted 3,4-/3/5-alkyhdenecyclobutenes.22 For example, the /3/5-allene (39) was heated at 65°C in deuteriochloroform in the presence of cuprous chloride to produce quantitatively the trialkene (40) (Equation 2). Interestingly, a strictly thermally-induced ring closure of tetraene (39) to (40) could not be accomplished. 9 C H 3 I I C H 3 CuCI H H' C H , C H 3 C H 3 C H 3 (2) 39 40 However, when the starting Z>/s-allene does not have four identical substituents at C\ and Cg, there is only modest stereoselectivity favouring the less strained product. Thus, heating of the bisallene (41) at 65°C in deuteriochloroform in the presence of cuprous chloride provided a 1:2 mixture of (42) and (43), while heating of the bisallene (41) in the gas phase at 322°C produced about a 1:1 mixture of these two products (Equation 3). 22 41 42 43 10 C 0 2 R M 36 n=1 37 n=2 38 n=3 Piers and Lu have developed an efficient and stereoselective method for the synthesis of various alkyl 2,3-i/s-aUcyhdenecyclobutanecarboxylates (36) and higher ring homologs (37) and (38). 16,23 j ^ e s t e p ^ a synthetic route to the cyclobutanecarboxylates involves preparing a suitable ethyl (E) or (Z)-3-trimethylstannyl-2-alkenoate (19) via Morton and Chong's methodology developed in our laboratories. I 7 Treatment of alkenoates of general structure (19) with L D A in a THF-HMPA solvent under conditions previously reported,^ followed by alkylation with the appropriate (E) or (Z)-l,2-dihalo-2-alkene (44) afforded the corresponding diene esters (45) (Scheme 5). Palladium (O)-catalyzed intramolecular cross coupling of the diene esters (45) results in formation of the stereochemically denned cyclobutanecarboxylates (34) (Scheme 5). R1 X 21 X^/ ,-™°C R . 1/ LDA, THF, HMPA, -78°C, 0°C x t,y co 2Et 45 SnMe 3 Me 3 Sn 19 P d ( P P h 3 ) 4 DMF, 80°C R' R, C 0 2 E t 34 Scheme 5 11 Several ethyl 2,3-/3«-alkyhdenecyclobutanecarboxylates (34) were prepared via this general method and the results are summarized in Table 1. It is important to note that in all cases the conversions of the diene esters (45) into their corresponding cyclobutanecarboxylates (34) were completely stereoselective and proceeded in good to excellent yields. A sUghtly modified procedure for entries 4 and 5 was required because standard reaction conditions gave none of the desired cyclobutanecarboxylate. ^ When Et3N (1 equiv.) was added to the reaction rnixture, the reaction proceeded to give the desired products in the indicated yields. 12 Table 1: Synthesis of the ethyl 2,3-fe-alkylidenecyclobutanecarboxylates 34.16 a D ^ V ~SnMe3 *" C O 2 B X 45 *C0 2 Et 34 Entry Substrate Product Yield(%)b Br. ^SnMe3 ^SnMe3 J1 v C0 2 Et 53 *C0 2 Et 82 89 4 c 5C SnMe3 MO MO. Br. Br. "SnMe3 C0 2 Et 49 OMOM *SnMe3 "SnMe3 SnMei 54 C0 2 Et 55 C0 2 Et OMOM 56 MO MO C0 2 Et 57 r C0 2 Et 58 C0 2 Et 59 96 68 70 97 93 aPd(PPh3)4 (0.05 equiv.), DMF, 80 °C, 1 h unless otherwise noted. bYield of purified, distilled product. cPd(PPh3)4 (0.1 equiv.), Et3N (1 equiv.), DMF, 80 °C, 1 h. 13 Ethyl 2,3-/3/s-aIkylidenecyclopentane- (37) and cyclohexanecarboxylates (38) were synthesized by carrying out synthetic sequences similar to those outlined above. Thus, by alkylation of the vinylstannane esters of general structure (19) with alkylating agents (60) or (61), Lu was able to prepare selectively the diene esters (62) through (68) (Table 2). Treatment of these substrates with Pd(Ph3P)4/DMF/LiCl/80°C for 1 h gave the corresponding cyclopentanecarboxylates (69-72) and cyclohexanecarboxylates (73-75) in good yields. However, in the absence of LiCL the palladium(0)-catalyzed coupling reactions of diene esters (62) and (65) leading to cyclopentanecarboxylates (69) and (72) were not as efficient. Compounds (76) and (77) were produced as side products in entries 1 and 4, respectively. L iC l (2 equiv.) was required to effect efficient transformation of (62) and (65) into (69) and (72), respectively. In the absence of LiCL a mixture of products was obtained. ^ R-Me 3 Sn CQ 2 Et 1/ LDA, THF, HMPA, -78 C, 0 C 19 21 \ , -78 C X R SnMe 3 R C 0 2 E t 60 n=2 61 n=3 Pd(PPh 3 ) 4 DMF, 80°C R d)n ^C0 2 Et 51 n=2 52 n=3 14 Table 2: Synthesis of the cyclopentanecarboxylates 69-72 and cyclohexanecarboxylates 73-75.16 Entry Substrate Product Yield(%)b 4 a SnMe3 63 CO a Et SnMe3 SnMe3 C 0 2 E t 65 SnMe ; SnMe3 C 0 2 E t 67 MOMO SnMe3 85 c *C0 2 Et 69 84 ~C0 2 Et 70 79 "C0 2 Et 71 83 d 72 *C0 2 Et 74 C 0 2 E t 73 68 C 0 2 E t 74 54 68 C 0 2 E t SnMe3 MOMO. C 0 2 E t 75 ' Pd(PPh 3) 4 (0.05 equiv.), LiCI (2 equiv.), DMF, 8ffC, 1h. 'Yield of purified, distilled product. was produced in the absence of LiCI 76 u u 2 C O „ B was produced in the absence of LiCI 77 " a * 15 Though the above methodology proved to be effective for the synthesis of the 4-, 5- and 6-membered ring carboxylates, all attempts to synthesize the 7-membered ring homolog (79) were unsuccessful. Indeed, treatment of (78) under the conditions shown gave no coupled product (79) (Equation 4). C 0 2 E t Pd(PPfe)4, LiCI SnMe 3 DMpi'V&rc, 1h (4) 78 C 0 2 E t 79 3.2 Previous X - ray crystallographic studies on crystalline derivatives of 2.3-/3/5-alkyhdenecyclobutanecarboxylates C0 2 R" 34 Following his initial synthetic work on the cyclobutanecarboxylates (34), Lu noted that the cyclobutanecarboxylates (54), (55) and (59) should be quite strained. In particular compound (59) will be very strained due to the steric repulsion between the two vinylic methyl groups. To determine the effect of this repulsion on the geometry of the cisoid diene unit, Lu prepared crystalline derivatives of compounds (54), (55) and (59) via a procedure previously reported by Weinreb24 (Scheme 6). 16 Me3AI, p-chloroaniline a 'COzEt benzene, reflux, 4 h b ^ ^ H 87% 54 60 Y o XI Me3AI, p-chloroaniline H C O Et benzene, reflux, 4 h ^ v - ^ 55 9 4 / 0 61 O Me3AI, p-chloroaniline i=t benzene, reflux, 4 h 77% 59 H b il 29 0 Scheme 6 X-ray analyses of the crystalline derivatives (60), (61) and (29) showed that the torsional angle between carbons a and b of the cisoid diene units were 3.9°, 4.8°, and 25.4°, respectively. 16 The latter result provides a rationale why (59) does not undergo Diels-Alder cycloaddition reactions, since the four carbons of the cisoid diene unit must be in a planer or nearly planer conformation in order for the Diels-Alder reaction to proceed. Other researchers have found results similar to those observed by Lu. Kiefer and Fukunaga have shown that the diene (62) readily undergoes an antarafacial 1,5 hydrogen shift to afford compound (63) (Scheme 7).^5 Kiefer concluded that "serious Van der Waal repulsion between the 'endo' allylic methyl groups in the planer configuration of (64) is most efficiently relieved by a combination of ring puckering and conrotatory torsion of the isopropylidene groups". 2 5 17 62 hv Scheme 7 63 3.3 Diels- Alder Reactions of the 2.3-toalkyh\ienecyclobutanecarboxvlates (34) R C0 2 R" 34 Since the initial publication by Kurt Alder and Otto Diels on [4+2]-cycloadditions (the Diels-Alder Reaction),26 there have been numerous papers published on the synthetic application and mechanistic aspects of this reaction due to its importance in organic chemistry.27,28,29 Studies were performed in our laboratories on Diels-Alder reactions of alkyl 2,3-bis(alkyhdene)cyclobutanecarboxylates with tetracyanoethylene (TCNE) and methyl vinyl ketone (MVK). 16 in the case of TCNE the dieneophile approaches the diene unit from the side opposite to the carboxylate group (Figure 1) to minimize steric repulsion. Thus, reaction of (65) and (66) with TCNE produced the cycloadducts (67) and (68), respectively (Scheme 7). 18 NC E t 0 2 C N C E t 0 2 C C N C N NC-i NC N C N Favoured Disfavoured Figure 1: Diagramatic view of the two possible directions that the dieneophile TCNE may approach the ethyl 2,3-bis(alkylidene)cyclobutane carboxylates. M O M O . NC T C N E , THF,1 h C 0 2 E t 87% NC NC MOMO NC 65 67 'COzEt M O M O . T C N E , THF, 24 h NC 88% X 0 2 E t NC MOMO 66 C 0 2 E t Scheme 8 It was also found that reaction of the diene (54) with methyl vinyl ketone in refluxing benzene for 8 h resulted in a mixture of (11), (14) and two other adducts in a ratio of 14:4:4:3 (Scheme 9). ^ The stereoselectivity for the process was improved by treatment of the diene (54) with the dieneophile in the presence of BF3-Et20, a Lewis 19 acid, at -78°C for 1 h in methylene chloride. Under these conditions the cycloadduct ( 1 1 ) was produced exclusively in 99% yield. 54 MVK, benzene reflux, 8 h, 91% 'C0 2 Et 11 14 * C 0 2 E t ^ < | 14 4 C 0 2 E t + two other adducts 54 MVK, BF3-Et20(1 equiv.) > C H 2 C I 2 , -78°C, 1 h, 99% 11 Scheme 9 A complete discussion of the rationale behind these observations will be presented in the discussion section of this thesis. Nevertheless, by using the above methodology, it appeared that a general synthetic route to the 5-substituted 7-(ethoxycarbonyl)bicyclo[4.2.0]oct-l(6)-enes, with defined stereochemistry at C-5, was available. R 3.4 Thermolysis of the cyclobutenes and related compounds Studies undertaken by Frey,2>3,4 Crigee^ and co-workers on the thermolysis of cyclobutenes with alkyl substituents at C-3 or at C-3 and C-4 (Scheme 10) showed that alkyl groups preferentially rotate outward. Thus, thermolysis of the trans-1,2,3,4-tetramethylcyclobutene (69) produces exclusively the (E,£)-isomer (70)5 (Scheme 10) while thermolysis of 3-methylcyclobutene (72) gives only frwis-piperylene (73)3 (Scheme 9). 20 72 73 74 Scheme 10 The exclusive formation of (70) and (73) was attributed to the destabilizing steric interactions in the transition states leading to the more strained inward rotation products (71) and (74). Later studies by Dolbier6>7,8 m ^ Stevens^ contradict this argument. These workers found that in the thermolysis of certain substituted cyclobutenes, steric effects contribute little to the overall direction of conrotatory ring opening. Curry and Stevens synthesized a number of 3-alkyl-3-methyl cyclobutenes (75) and heated them under thermolysis conditions (180°C) to produce the Z isomers (76) (resulting from outward rotation of the methyl group and inward rotation of the R group) and the E isomers (77) (Me in, R out) (Equation 5).9 The results of this study are summarized in Table 3.9 21 Table 3: Products of the pyrolysis of 3,3-disubstituted cyclobutenes (75). Rin(75) Z-isomer (76) it-isomer (77) /-Butyl 32 68 /-Propyl 65.5 34.5 ^-Propyl 62 38 Cyclopropyl 43 57 Ethyl 68 32 C 2 D 5 61 39 Phenyl 30 70 4-Methoxyphenyl 52 48 3 -Methoxyphenyl 32 68 4-Cyanophenyl 45 55 A-priori, based upon steric arguments, one would expect that the larger R is relative to methyl, the greater the ratio of (77) to (76) should be. Clearly this is not the case as the ratio of (77): (76) (inward R: outward R) is «2:1 when R=isopropyL n-propyl, or ethyl and «1:1 for R=cyclopropyl and 4-methoxyphenyl (Table 3). Furthermore, if one calculates the Z.E ratios expected based upon the A-values of the substituents, the observed ratios are clearly less than those expected (Table 4).9 22 Table 4: Calculated Z:E diene ratios based on steric effects. R in (76) and (77) Et P r n Pr 1 cyclopropyl But Ph ( A R - A]yie)/kcal moi" 1 0.11 0.41 0.41 - 3.41 1.23 Calc. Z.E 42:58 25:75 25:75 50:50 2:98 1:5 Obs. Z:£ 68:32 62:38 66:34 43:57 32:68 30:70 In 1984 Houk proposed an elegant theory, based upon extensive computational calculations, which provides insight into rotational preference of certain substituents. Houk proposed that it was the electronic nature of certain substituents that determines the direction of rotation (inward or outward) of the substituent. 12 Based upon these calculations, Houk predicted that groups that are good electron donors should prefer outward rotation while strongly electron withdrawing groups that are good electron acceptors should favour inward rotation. Calculations by Houk on the transition state for cyclobutane conrotatory electrocyclic opening show that the HOMO is primarily a stretched and twisted a bond orbital while the LTJMO is primarily a stretched and twisted o~* orbital. 13 The filled p orbital of a donor(D) substituent and the cr and a orbitals are sketched in Figure 2. 23 LUMO (o* ) HOMO (G) Figure 2: HOMO and L U M O of the cyclobutene transition structure and the occupied p orbital of a donor orbital. In Houk's words, 13 "Upon outward rotation of a donor substituent, the donor orbital can mix with the L U M O , resulting in stabilization and lowering of the activation energy. This is only partially counteracted by the destabilizing antiaromatic four-electron interaction of the donor orbital with the distorted cyclobutene HOMO. Because of the location of the donor orbital upon outward rotation (shown by the dashed lines labeled "out"), the donor orbital overlaps primarily with the atomic orbital at C 3 . Upon inward rotation, the donor orbital will move into the location marked by the dashed orbital labeled "in". In this location the donor orbital overlaps with the atomic orbitals at both C 3 and C 4 . The interaction of an inwardly rotating donor orbital with the distorted cyclobutene L U M O is less than that of an outwardly rotating donor orbital, because the signs of the neighboring lobes of the atomic orbitals at C 3 and C 4 are opposite. Consequently, stabilization upon inward rotation of the donor is less than upon outward rotation. At the same time, the donor orbital overlaps more with the distorted cyclobutene H O M O upon inward rotation than upon outward rotation, due to overlap at both C 3 and C 4 . This destabilizing interaction is larger for inward rotation that outward rotation. Thus, both interactions favor outward rotation, and the extent of this preference depends upon the donor ability of the substituent. With 71-acceptor substituents, orbital 24 interactions also occur between the HOMO of cyclobutene and the empty orbital of the acceptor. This two-electron stabilizing interaction is maximized when the acceptor rotates inward and may cause acceptors to preferentially rotate inward. "13 Houk has made extensive ab initio molecular orbital calculations on hypothetical molecules in the gas phase using the Gaussian 82-90 programs with the STO-36 and 6-3116** basis sets developed by Pople and co-workers.30 Some of Houk's predictions are outlined in Tables 513 and 6.13,14,15 The substituents are listed in order of increasing GR° values) in Table 5. 1 Table 5: Substituent effects on the stereochemistry of cyclobutene electrocyclizations R ° R ° Ea(in-out) kcal moi" 1 (6-31G*//3-21G) N H 2 -0.48 17.5 O H -0.43 17.2 F -0.34 16.9 C H 3 -0.11 6.8 H 0.0 0.0 C N 0.13 4.3 N 0 2 0.15 7.4 CHO 0.24 -4.6 NO 0.32 -2.6 BH? - -18.2 25 Table 6: Predicted change in activation energy of cyclobutene opening (Ea=32 kcal moi" 1) by C-3 substituents. Calculations are 6-3 lG*//3-21G. Substituent AE a(out) AE a(in) AAEa(in-out) kcal moi" 1 kcal moi" 1 kcal moi" 1 -co2- -6.4 +0.9 +7 .3 1 3 - C N -2.3 +2.3 +4.6 1 3 - C 0 2 M e -4.2 -1.7 +2.513 - C 0 2 M e -3.0 -1.3 +I .7I 4 - C 0 2 H -4.3 -2.0 +2.313,15 - C 0 2 H -3.1 -1.6 +1.514 -CHO -2.3 -6.9 -4.613 - C 0 2 H 2 + -10.2 -15.8 -5.613 - C 0 2 H 2 + -11.0 -15.8 -4.815 -Me -1 +3 +412 -CI -3 +6 +912 -OR -9 +5 +1412 As can be seen in Table 5, groups such as N H 2 , O H and F strongly prefer outward rotation (Ea(in-out) = 17.5, 17.2, 16.9 kcal/moL respectively) while -CHO, NO, and B H 2 (good 71 electron acceptors) prefer inward rotation (Ea(in-out) = -4.6, -2.6, and -18.2 kcal/moL respectively). 13 In Table 6, we see that the mild electron withdrawing nature of the carboxylic acid group (which prefers outward rotation by 1.5 kcal/mol)14 can be changed by deprotonation to the carboxylate or protonation to the protonated acid. The carboxylate group has donor character and prefers outward rotation by 7.3 kcal/mol!3 while the protonated acid is a strong electron-withdrawing group and prefers 26 inward rotation by 11.0 kcal/mol. 1 3 Experimental results by Houk, i 4 > 3 1,32,33,34 Piers,11 Trost,3^ Wallace,36,37,38 Rickborn, 3^ Rimbault and co-workers4^ support some of these predictions. For example, when 3-fer^butyl-3-(trimethylsiloxy) cyclobutene (78) is heated in C D C I 3 at 90-95°C for 4 hr only the product (79) resulting from inward rotation of the tert-butyl group and outward rotation of the TMSO group is observed (Equation 6). 3 3 OSiMec But 90-95°C 4h, CDCI3 OSiMe 3 But (6) 78 79 To determine if there was any steric effect by the large trimethylsilyl group, Houk and co-workers prepared and thermolyzed 3-methoxy-3-ter^-butylcyclobutene (80). Again, only the product (81) resulting from outward rotation of the methoxy group and inward rotation of the "bulky" tert-butyl group was produced (Equation 7 ) . 3 3 OMe OMe 90-95°C 6.5h, C 6 D 6 But (7) 80 81 Sammes and co-workers found that thermolysis of a-methoxybenzocyclobutene (82) to a-methoxy-o-xylylene (83) occurs with exclusive formation of the E (outward rotation) product and that the methoxy substituent lowers the activation energy for this ring opening by 9 kcal/mol as compared to the unsubstituted case (Equation 8 ) . 4 i 27 O C H 3 . O C H 3 82 (8) 83 Rimbault and co-workers^O found that 2-methyl-3-hydroxybutene (84) undergoes thermolysis to give only the product resulting from outward rotation of the alcohol group to afford (85), which rearranges to give (86) (Equation 9). As mentioned previously in this introduction, Houk predicts that the ester function should have a slight (1.7-2.5 kcal/mol) preference for outward rotation. 13,14 Thus, the ratio of outward to inward rotation products is expected to fall between 7:1-18:1 at 165°C. Piers and Lu have provided evidence supporting this prediction. 11 Ester (11) was thermolyzed in refluxing mesitylene (165°C for 1 hr) to obtain an 11:1 mixture of the outward (12) to the inward (13) rotation products (Scheme 11). 14 15 (1:1) 16 Scheme 11 Interestiagly, the (3 isomer of (11), compound (14), was thermolyzed under the same conditions to produce a 1:1 mixture of outward (15) and inward (16) rotation products (Scheme 11). An inspection of molecular models indicated that the ester group would have to slide past the pseudoequatorial Me group of (14) in the transition state leading to outward rotation product (15). This destabilizing interaction may increase the transition state energy for outward rotation, making inward rotation more competitive. A good 7i acceptor substituent such as the formyl group is predicted to prefer inward rotation over outward rotation by 4.6 kcal/mol (Table 6). Houk and co-workers4^ thermolyzed 3-formyl butene (87) and found that only the product (88) resulting from inward rotation of the formyl group was produced (Equation 10). .CHO 25-75°C 87 j ^ C H O 88 (10) 29 Houk and co-workers thermolyzed the 3,3-^substituted cyclobutene (89) and found, not surprisingly, that only the product (90) resulting from outward rotation of the ester and inward rotation of the aldehyde group was produced (Scheme 2 ) . 1 4 This compound, once formed, reversibly isomerizes to the (2H)-pyrane (91), which could not be isolated in pure form. Its structure was confirmed by trapping with one equivalent of tetracyanoethylene at 70°C to form the Diels-Alder adduct (92). C 0 2 M e C 0 2 M e Scheme 12 Piers and Lu observed a similar result when aldehyde (93) was thermolyzed (Equation 11). H Thermolysis of (93) produced the inward rotation products (94) and (95) in a ratio of 1:2, respectively. Compound (95) is formed by reversible electrocyclic ring closure of dienal (94). These compounds slowly interconvert at room temperature and thus could not be obtained pure. 30 (11) O 95 Recently, Houk and co-workers have predicted the acetyl group should favour outward rotation by 1.2 kcal/mol. 3^ However, if a Lewis acid such as ZnL) is added, it was calculated that inward rotation would then be favoured over outward rotation by » 1.5 kcal/mol. Houk proceeded to thermolyze 3-acetylcyclobutene (96) in deuteriobenzene at 80°C to give initially a 2:1 mixture of outward (97) to inward (98) rotation products (Scheme 13). The study was complicated by the fact that inward rotation isomer (98) is unstable and isomerizes to (97) overnight. In contrast, treatment of (96) with Zn±2/Na2C03 in benzene at 80°C produced a 17:83 mixture of outward (97) to inward (98) rotation products where the major product results from inward rotation of the acetyl group. Thus, Houk has given evidence suggesting that the "torquoselectivity" can be reversed by addition of a Lewis acid catalyst. 31 - C 0 C H 3 C 6 D 6 / " V C 0 C H 3 + O CH3OC 96 97 98 66 22 Z n l 2 / N a C 0 3 s C 6 D 6 , A 17 83 Scheme 13 For 3,4 ^substituted cyclobutenes the effects of the substituents are thought to be additive. 12 Wallace and co-workers3 6 oxidized the alcohol (99) by Swern conditions and were unable to isolate the aldehyde (100) as it spontaneously opened to give the product (107) resulting from rotation of the aldehyde group in and rotation of the alkoxymethyl group out (Equation 12). OH .OR [Swern] 99 ,CHO . O R 100 CHO - s (12) 101 OR Wallace has synthesized a number of other cz5-3,4-hetero-disubstituted cyclobutenes (102) and compared the relative torquoselectivities of the two functional groups (Table 7) . 3 A 3 ^ 32 Table 7: Thermal electrocyclic ring opening of cw-3,4-disubstituted-cyclobutenes. A A s J B 102 I B 103 104 Entry A B Solvent Temp(°C) Time(hr) Ratio(103:104) 1 -CHO - C 0 2 M e PhMe 110 1 2:1 2 - C 0 2 H - C 0 2 R a C1CH 2 CH 2 C1 83 10 1:1 3 - C 0 2 R a - C 0 2 M e PhMe 110 1 1.4:1 4 -COC1 - C 0 2 M e PhMe 110 1 4:1 5 -CHO - O P M B b C H 2 C 1 2 <20 <0.5 >20:1 6 -CHO - O P M B b THF <20 <0.5 >20:1 7 -CHO -Et C H 7 C I 9 . <20 <0.5 >20:1 aR=2-naphthyl bpMB=£>-methoxybenzyl The results in this table indicate that the tendency towards inward rotation of the acyl functional group decreases along the order COC1 > C 0 2 H > C02(2-naphthyl) > C 0 2 M e . This is in good accord with the theoretical predictions of Houk. Apparently the solvent may play some role in the ratio of outward to inward rotation product produced. Trost and co-workers3 5 synthesized the cyclobutene (105) and thermolyzed it in dimethyl sulfoxide at 110°C and found a 1:1 ratio of products (106) and (107) (Equation 13). When the same starting material was heated in dichlorethane there was a significant increase in the amount of (106) relative to (107). 33 co2a ,co2a DMSO, 110°C co2a CO2H (13) (1:1) C O 2 H 105 106 107 So far there have been few reports in the literature concerning the use of cyclobutene conrotatory ring openings in a total synthesis. Wal lace 3 7 envisioned that the two conjugated dienes (108) and (109), generated by ring opening of a derivative of (110), would be structural components towards a total synthesis of leukotriene B4 (111) (Scheme 15). Though Wallace has met with some success with model studies directed towards the synthesis of diene units (108) and (109), a complete synthesis of (110) using this chemistry has not yet been reported. HO .CHO CHO' 110 C6H11 108 109 V sOH .OH 111 Scheme 14 34 Trost and co-workers have carried out a number of model studies directed towards the synthesis of verrucarin A (112).3 5 One of the three fragments required was the (Z,E) di-acid (113), which was thought to be accessible from the thermal ring opening of a cyclobutene (Equation 14). 112 113 Trost and co-workers prepared the verrucarin A model macrocycle (114). Thermal ring opening of cyclobutene (114) afforded a 2:1 mixture of (115) and the corresponding (E,Z) isomer (116) (Equation 15). 36 H. R E S U L T S A N D DISCUSSION 1. Synthesis of ethyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates 1.1 Preparation of the a . P-acetylenic esters Several a , P-acetylenic esters of general structure 18 (i.e. 123-128) were required for this study. Ethyl 2-butynoate (123) and ethyl 2-pentynoate (124) are available commercially. The reniaining a , P-acetylenic esters (125-128) were prepared from either the corresponding 1,1-dibromo-l-alkene of general structure 117 or the corresponding 1-alkyne of general structure 118 via the procedures outlined in Table 8. R — B r Br 117 R = /-Pr (119) R = c-Hex (120) R' H 118 R = TIPSO (121) R = MEMO (122) 1/n-Bul_i 21 EtOCOCI 1 /MeLi 21 EtOCOCI. R ^ 18 C 0 2 E t 123 - C 0 2 E t C 0 2 E t 124 125 C 0 2 E t 126 C 0 2 E t TIPSO' C 0 2 E t M E M O ' C 0 2 E t 127 128 37 Addition of n-butyllithiuni(2.5 equiv.) to a THF solution of l,l-dibromo-3-cyclohexylpropene (120) (-78°C, 1 h; room temperature, 1 h) afforded the corresponding hthium acetylide which, upon reaction with ethyl chloroformate (1.1 equiv., -20°C, 1 h; room temperature, 1 h), yielded ethyl 4-cyclohexyl-2-butynoate (126) (90%, Table 8, Entry 2). In a similar manner, ethyl 5-methyl-2-hexynoate (125) was prepared from l,l-dibromo-4-methyl-l-pentene (119) (82%, Table 8, Entry l ) . 4 3 Addition of methyUithium (1 equiv.) to a THF solution of 3-(trhsopropylsiloxy)propyne (121) (-78°C, 15 min; -20°C, 1 h) afforded the corresponding hthium acetylide which, upon reaction with ethyl chloroformate (1 equiv., -20°C, 1 h; room temperature, 1 h) yielded ethyl 4-(triisopropylsiloxy)-2-butynoate (127) (76%, Table 8, Entry 3). In a similar manner, ethyl 4-[(2-methoxyethoxy)methoxy]-2-butynoate (128) was prepared from 3-[(2-methoxyethoxy)methoxy]propyne (122) (79%, Table 8, Entry 4). The spectral data derived from the a , P-acetylenic esters (125-128) were consistent with the assigned structures. For example, each of the a , P-acetylenic esters (125-128) exhibited a O C stretch in the IR spectrum in the region 2232 - 2241 c m - 1 (Table 8). 38 Table 8: Preparation of the a . P-acetylenic esters R- < Br or Br -H - C 0 2 E t 117 118 18 Entry Substrate Procedure3 R Product Yield (%)b I R O C stretching absorption (cm"1) 1 119 A /-Pr 125 82 2232 2 120 A c-Hex 126 90 2234 3 121 B ( (CH 3 ) 2 CH) 3 SiO 127 76 2241 4 122 B C H 3 O C H 7 C H 2 O C H 7 O 128 79 2240 a A . (Starting material of general structure 117) 1. «-BuLi(2.5 equiv.), THF, -78°C, 1 h; room temperature, 1 h. 2. Ethyl chloroformate (1.1 equiv.), -20°C, 1 h; room temperature, 1 h. a B . (Starting material of general structure 118) 1. MeLi (1 equiv.), THF, -78°C, 15 min; -20°C, 1 h. 2. Ethyl chloroformate (1 equiv.), -20°C, 1 h; room temperature, 1 h. DYield of purified, distilled product. 39 The 1,1-dibromo-l-alkenes of general structure 117 (119 and 120) were prepared from the corresponding commercially available aldehydes of general structure 129 (Scheme 15). R \ Ph3P=CBr2 R — \ v Br J CH2CI2 ^ ^ B r H 117 D l 129 R = /-Pr (130) R = /'-Pr (119) R = c-Hex (131) R = c-Hex (120) Scheme 15 For example, treatment of cyclohexylethanal (131) with 2 equiv. of dibromomethylenetriphenylphosphorane43 in dichloromethane (room temperature, 30 min) afforded l,l-dibromo-3-cyclohexylpropene (120) in a 89% yield. In a similar manner l,l-dibromo-4-methyl-l-pentene (119) was prepared in a 81% yield from 3-methylbutanal (130). It should be noted that it is important to cool the reaction mixture below 50°C when synthesizing the dibromomethylenetriphenylphosphorane reagent (from triphenylphosplune and carbon tetrabromide) as the reaction is extremely exothermic. The spectral data derived from the 1,1-dibromo-l-alkenes (119 and 120) were consistent with the assigned structures. For example, the N M R spectrum of alkene (120) displayed the expected signals for the trisubstituted alkene moiety (a one proton triplet at 8 6.42, J= 7 Hz) and two allylic protons (a two proton doublet of doublets at 8 2.05, J= 7, 7 Hz). The IR spectrum of alkene (120) displayed a C=C stretching absorption at 1621 cm' l . 40 The 1-alkynes of general structure 118 (121 and 122) were prepared by reaction of 2-propyn-l-ol (132) with the appropriate reagent (Scheme 16). ( (CH 3 ) 2 CH) 3 SiCI, IMID ,, H — / = — n HO o r C H 3 O C H 2 C H 2 O C H 2 C I , (/-Pr)2NEt 132 118 R= ( (CH 3 ) 2 CH) 3 SiO-(121) R= C H 3 O C H 2 C H 2 O C H 2 0 - (122) Scheme 16 For example, treatment of 2-propyn-l-ol (132) in dry dichloromethane with 1.5 equiv. of imidazole and 0.95 equiv. of triisopropylsilyl chloride (room temperature, 2 h) afforded 3-(trhsopropylsiloxy)propyne (121) in a 75% yield. In a similar manner, 2-propyn-l-ol was treated with dhsopropylethylamine ((/-Pr)2NEt) and (2-methoxyethoxy)methyl chloride to afford 3-[(2-methoxyethoxy)methoxy]propyne (122) in a 79% yield. The spectral data for the 1-alkynes (121 and 122) were consistant with the assigned structures. For example, 3-(triisopropylsiloxy)propyne (121) displayed the expected signal for a triisopropylsiloxy moiety (an 18 proton doublet at 8 1.06, J= 6 Hz, and a three proton multiplet at 5 1.08-1.14), a teraiinal alkyne proton (a one proton triplet at 8 2.46, J= 2 Hz) and a two proton doublet at 8 4.37, J= 2 Hz, -OCH2S1R3. 1.2 Preparation of ethyl (EV and (Z)-3-trimethylstannyl-2-alkenoates Several ethyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates of general structure 133 and 134 were required for this study. Morton and Chong, in our laboratories, have studied the reaction of (trialkylstannyl)copper(I) reagents with a,(3-acetylenic esters.4^ By a proper choice of the appropriate (trialkylstannyl)copper(I) reagent and the reaction 41 conditions, either the (£)-(133) or (Z)-3-trimethylstannyl-2-alkenoate (134) can be produced stereoselectively. R C 0 2 E t R — v H M e 3 S n H M e 3 S n C 0 2 E t 133 134 For example, addition of ethyl 2-pentynoate (124) to a solution of hthium (phenyltMo-trimethylstannyl)cuprate (135) (THF, -100°C, 15 min; -78°C, 3 h) in the presence of 1.7 equiv. of methanol produced, upon workup, the (E) isomer in >99% isomeric purity (Table 9, Entry 1).44 m contrast, reaction of (135) with (124) (THF, -78°C, 15 min, -48°C, 4 h), followed by quenching with MeOH, afforded the (Z) isomer in —98% isomeric purity (Table 9, Entry 2). The nature of the stannylcopper(I) reagent also affects the stereochemical outcome of the reaction ( Table 9, Entries 3, 4, and 5). Treatment of ethyl 2-butynoate (123) with (135) (THF, -78°C, 15 min, -48°C, 4 h), followed by protonolysis with MeOH, afforded the (Z) isomer in -98% isomeric purity (Table 9, Entry 3). In contrast, treatment of (123) with (trimethylstannyl)copper(I)-dimethyl sulphide (136) or HtMum(trimethylstannyl)-(cyano)cuprate (137) under similar reaction conditions produced the (E) isomer in >99% and 96% isomeric purities, respectively (Table 9, Entries 4 and 5). 44 While high stereoselectivities were obtained from the reaction of reagent (135) with a,P-acetylenic esters with an alkyl function on the y carbon as outlined above, anomalous results were obtained when the substrate contained an ether function on the y carbon (Table 9, Entry 6). For example, reaction between (135) and (138) under the conditions described gave the desired (Z) isomer in only 29% yield, while the product (139) resulting from transfer of the phenylthio group predominated (35% yield).44 42 Table 9: Reaction of a,p-acetylenic esters with (trnuethylstannyI)copper (I) reagents (135-140) R C 0 2 E t R — , H R ^ ^ ^ C O 2 B R E A G E N T > + M 18 M e 3 S n H M e 3 S n C 0 2 E t 133 134 Entry Starting Material R Reagent, Conditions3 Product Ratio (E/Z) Yield (%) 1 124 Me 135 [Me 3SnCuSPh]Li, A >99:1 79 2 124 Me 135 [Me 3SnCuSPh]Li, B 2:98 76 3 123 H 135 [Me 3SnCuSPh]Li, B 2:98 76 4 123 H 136 Me 3SnCu«Me 2S,B >99:1 68 5 123 H 137 [Me 3SnCuCN]LL C 96:4 86 6 138 r-BuMe 2SiO- 135 [Me 3SnCuSPh]Li, B <7:>93D 29 7 138 f-BuMe?SiO- 140[Me3SnCu(2-Th)(CN)]Li2, C <5:>95 65 a A : THF, 2.0 equiv. 135, 1.7 equiv. MeOH, -100°C, 15 min, -78°C, 3 h. a B : THF, 1.3 equiv. reagent, -78°C, 15 min, -48°C, 4 h, then quench with MeOH. a C : THF, 1.3 equiv. reagent, -78°C, 3 h, then quench with NH4CI. DCompound 139 was the major product. f -BuMe 2 S iOCH 2 H H PhS C 0 2 R 139 43 Tillyer, in our laboratories, has prepared the higher order cuprate, dnitMum(trhriethylstannyl)(2-thienyl)(cyano)cuprate (140), which has been useful in overcoming these difficulties.45 Treatment of substrate (138) with (140) (THF, -78°C, 3 h) afforded the (Z) isomer in -95% isomeric purity and in a 65% yield (Table 9, Entry 7). Thus, it can be seen that by a proper choice of the appropriate lower or higher order cuprate reagent and reaction conditions, the a,(3-acetylenic esters can be stereoselectively converted into the corresponding (E)- or (Z)-3-trimethylstannyl-2-alkenoates. There are, however, some drawbacks to using reagent (135) for the synthesis of (133) and (134). The required starting material, phenylthiocopper(I) (PhSCu), for the preparation of (135) is tedious to make.46 To prepare phenylthiocopper(I) one must use thiophenoL a chemical with a notably offensive odour. More importantly PhSCu, like many copper(I) salts, is not very stable and thus storage for a prolonged period makes the PhSCu unsuitable for the synthesis of reagent (135). In contrast, copper(I) cyanide (CuCN) is readily available, reasonably stable,47 and has been used extensively for the generation of organocuprates. Therefore, we carried out a brief study to determine whether or not hthium (trimethylstannyl)(cyano)cuprate [Me3SnCuCN]Li (141), which is prepared by reaction of trimethylstannynithium (Me3SnLi) (142) with CuCN in THF (Equation 16), could be used as a substitute for reagent (135) in the transformation of (18) into (133). THF, -48°C Me 3Snl_i + CuCN *• [Me 3 SnCuCN]Li (16) 142 141 This project was carried out in collaboration with a Mr. Timothy Wong from our laboratories.^ Reaction of (143) with approximately 1.05 equiv. of the cuprate (141) in THF at -48°C for 2 h and then at 0°C for 2 h, followed by workup, gave a crude product 44 consisting almost entirely of the desired Z-alkenoate (144) (Table 10). Very little of the corresponding .E-alkenoate (145) was produced. Purification of the crude product by flash chromatography4^ 0 n silica gel, followed by distillation, provided the pure Z-alkenoate. For example, treatment of ethyl 4-cyclohexyl-2-butynoate (126) with 1.04 equiv. of cyanocuprate (141) under the reaction conditions outlined above provided ethyl (Z)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (152) in a 81% yield (Table 10, Entry 4). Table 10: Preparation of allcyl(Z)-3-trimethylstannyl-2-alkenoates5Q p. 1/[Me 3SnCuCN]Li (141), THF, R — V , H ^ — C ^ C - C 0 2 R ' 5 5 *- ) = ( - 4 8 C , 2 h ; O C , 2 h / \ 1 4 3 21 NH4CI, NH 4OH, H 2 0 1 4 4 Entry Acetylenic ester R R' Equiv. of cuprate Product3 Yield (%)b 1 124 Me Et 1.09 149 72 2 127 (/-Pr) 3SiO- Et 1.06 150 76 3 128 M E M O - Et 1.06 151 72 4 126 c-Hex- Et 1.04 152 81 5 146 c ?-BuMe 2 SiO(CH 2 ) 2 Me 1.05 153° 78 6 147 c C1(CH 2 ) 2 Me 1.05 154° 79 7 148 c HC=C-(CH 7 ) 7 Me 1.01 155° 78 3The isolated crude products contained small amounts (-1-4% and 1-2%, respectively) of the corresponding alkyl (E)-trimethylstannyl-2-alkenoates and alkyl (£)-2,3-bis-trimethylstannyl-2-alkenoates. These minor products could, in each case, be removed by a combination of flash chromatography and distillation. ^Yields refer to purified, distilled products. cCompounds 146-148 and 153-155 were prepared by Mr. Timothy Wong. 45 It was determined that cyanocuprate (141) was also suitable for transformation of the acetylenic esters (143) into the (^-enoates (156-162) listed in Table 11. For example, reaction of ethyl-2-pentynoate (124) with 1.30 equiv. of cyanocuprate (141) at -78°C in THF for 4 h in the presence of 1.3 equiv. of ethanol provided a crude product that consisted of a mixture of the (£)- and (Z)-2-pentenoates (156) and (149) in a ratio of 97:3, respectively. Purification of this crude product by flash chromatography and distillation provided pure (156) in 69% yield (Table 11, Entry 1). Treatment of acetylenic esters (126-128) and (146-148) under similar conditions produced the corresponding alkyl (£)-3-trimethylstannyl-2-alkenoates (157-162) in good yields (Table 11). The structural assignments for the (£)- (133) and (Z)-3-trimethylstannyl-2-alkenoates (134) were supported by the *H NMR spectral data obtained for these compounds. The two isomers could be distinguished from each other by three methods, including the chemical shifts of the allylic protons, the chemical shifts of the vinyl protons, and, most importantly, the tin-proton coupling values (3«/sn-tl) between the olefinic proton and the tin atoms ( 1 1 7 Sn, 1 1 9Sn) (Tables 12 and 13). Tin-proton coupling values (Vsn-ft) for the (E)-trimethylstannyl esters (133), in which the olefinic proton is cis to the trimethylstannyl moiety, are typically 70-90 Hz, while for the (Z) counterparts, in which the olefinic proton is trans to the trimethylstannyl moiety, they are typically 115-130 H z . 5 1 46 Table 11: Preparation of alkyl (iT)-3-trimethylstarmyl-2-alkenoates5Q p. 1/ [Me 3 SnCuCN]Li (141), THF, R — \ C 0 2 R ' ^ — C E E C — C 0 2 R ' *• ) = ( R'OH,-78°C,4h . . . / \ iAi M e 3 S n H 1 4 3 21 NH 4 CI, N H 4 O H , H 2 0 1 4 5 Entry Acetylenic R R' Equiv. of Product3 Yield ester cuprate (%)b 1 124 Me Et 1.30 156 69 2 127 (z-Pr)3SiO- Et 1.31 157 74 3 128 MEMO- Et 1.30 158 70 4 126 c-Hex- Et 1.50 159 81d 5 146° f-BuMe2SiO(CH2)2 Me 1.30 160 77 6 147c C1(CH2)2 Me 1.30 161 80 7 148c HOC-(CH 7) ? Me 1.30 162 72 3The isolated crude products contained small amounts (-1-5%) of the corresponding alkyl (Z)-trimethylstannyl-2-alkenoates . This minor product could, in each case, be removed by a combination of flash chromatography and distillation. ^Yields refer to purified, distilled products. cCompounds 146-148 and 160-162 were prepared by Mr. Timothy Wong. T^he reaction time in this experiment was 7 h rather than 4 h. 47 For example, in the * H N M R spectrum of ethyl (£)-4-[(2-methoxyethoxy)methoxy]-3-trimethylstannyl-2-butenoate (158), the ^Jsn-H value is 73 Hz (Table 12, Entry 3) while in the spectrum of the (Z)-isomer (151), the 3^sn-H value is 112 Hz (Table 13, Entry 3). In Table 12 it can be seen that the chemical shift of the allylic methylene protons of the (E)-alkenoates (133) are downfield in each case as compared to the corresponding chemical shifts of the (Z)-alkenoates (134) (Table 13). This is caused by the fact that the deshielding ester moiety for each of the (E)-alkenoates (133) is cis to the allylic methylene protons. Furthermore, it can be seen that the chemical shifts of the olefinic protons of the (E)-alkenoates (133) (Table 12) are upfield as compared to the corresponding resonances of the (Z)-alkenoates (Table 13). This is expected as it is known that the electron rich trimethylstannyl moiety shields olefinic protons that are cis to itself as is the case with the f£)-alkenoates (133). 48 Table 12: Partial lH N M R Data for (gyS-trirnethvlstannvl^-alkenoates (133) C 0 2 Et Me 3 Sn H 133 Entry 2-Alkenoate R 3jSn-H O F the olefinic proton 8 ofthe alb/lie methylene protons 8 ofthe olefinic protons 1 156 Me 74 2.89 5.94 2 157 (/-Pr) 3SiO 78 4.95 5.89 3 158 M E M O 73 4.79 5.92 4 159 c-Hex 82 2.83 6.03 5 163 /-Pr 76 2.82 6.03 49 Table 13: Partial lH N M R Data for (ZV3-tiMethvlstannvl-2-alkenoates (134) M e 3 S n C 0 2 E t 134 Entry 2-Alkenoate R 3« /Sn-H o f the olefinic proton 8 ofthe aUylic methylene protons 8 ofthe olefinic protons 1 149 Me 120 2.45 6.36 2 150 0-Pr)3SiO 114 4.52 6.72 3 151 M E M O 112 4.38 6.63 4 152 c-Hex 124 2.28 6.29 5 164 /-Pr 120 2.28 6.26 50 2. Deconjugation-alkylation of ethyl (E)- and (Z)-3-trimemylstannyl-2-alkenoates 2.1 Preparation ofthe Ethyl (E)- and (Z)-3-trimethylstannyl-3-alkenoates The next stage ofthe research project involved deconjugation-alkylation of various ethyl (^-3-trimethylstannyl-2-alkenoates of general structure (133) with 2,3-dibromopropene (20) to afford trimethyl stannyl alkenoates ofthe general structure (165) (Equation 17). R—v C 0 2 E t 133 Me 3 Sn 1/ LDA, THF-HMPA 21 B r ,-78 C nMe 3 (17) 20 R = Me (156) R = c-Hex (159) 0 2 Et 165 R = Me (48) R = c-Hex (165) Deprotonation of (156) with lithium diisopropylamide (LDA) in THF followed by alkylation with 2,3-dibromopropene (20) to give (48) had been previously reported^, 23 and was stated to proceed in satisfactory yield (72%). Unfortunately, the same procedure when applied to vinylstannane (159) was not satisfactory. The expected product (165) was produced in only 12% yield and was accompanied by numerous, unidentified side products. Numerous attempts were made to improve this reaction using a variety of experimental conditions. Eventually, it was discovered that hindered vinylstannanes such as (159) and (166) could be deconjugated to the corresponding ethyl (Z)-3-trimethylstannyl-3-alkenoates (i.e. 167 and 168) using potassium bis(trimethylsilyl)amide [KN(SiMe3)2] as the base (Equation 18). 51 R-Me 3 Sn J C 0 2 E t 1 / 2 4 e q u j v [KN(SiMe3)2], THF, 133 2.3 equiv. HMPA, - 7 8 t (1 h), -48 °C (4 h) 21 cannulation into a cold (-98 C) Me 3 S sol'n of HOAc in E t 2 0 „C0 2 Et (18) R = c-Hex (159) R = /-Pr(166) Yield R = c-Hex (167) 85% R = /-Pr(168) 90% It should be noted that freshly prepared and distilled starting materials (159) and (166) must be used for this procedure. Substrates that were not freshly purified gave inferior, anomolous results. The configurations ofthe esters (167) and (168) (Equation 18) were readily assigned on the basis of A H N M R spectroscopic data, in particular the magnitude ofthe coupling constant ( 3^Sn-H) between the olefinic proton and the tin atom. For example in (167) and (168), where the olefinic proton is in a trans relationship to the Me3Sn moiety, the 3 ^Sn-H values are ~131 Hz, as expected. ^ 1 As anticipated, the IR spectra ofthe (Z)-esters (167) and (168) showed strong C=0 stretching frequencies at -1734 c m " l , which is at a higher frequency than their (E)-conjugated counterparts (159) and (166) at ~ 1704 cm" 1 . The synthesis ofthe ethyl (i^-3-trimethylstannyl-3-pentenoates (169) and (170) involved deconjugation of the corresponding ethyl (Z)-3-trimethylstannyl-2-alkenoates (152) and (171) (Equation 19). A 1/2.4 equiv. [KN(SiMe 3) 2 ] , THF, 2.3 equiv. HMPA, -78 °C (1 h), -48°C (4 h) M o COoEt 2 / cannulation into a cold (-98 °C) ivie3on 2 ., , u r v . „ ;„ ct r\ sol'n of HOAc in E t 2 0 R = c-Hex (152) R = /-Pr(171) SnMe 3 (19) C 0 2 E t Yield R = c-Hex (169) g io / o R = /'-Pr(170) 87% 52 Reports on deconjugation and deconjugation-alkylation reactions of a,P-unsaturated esters have been numerous in the past two decades because ofthe synthetic potential of these methods. A paper by Rathke and Sullivan in 1972^2 reported that deprotonation of ethyl (£)-2-butenoate (172) with Hthium N-isopropylcyclohexylamide (Li lCA) in THF-HMPA at -78°C, followed by quenching the resultant dieneolate anion with various electrophiles, afforded the corresponding unconjugated esters (173) in good yields (Equation 20). y C 0 2 E t 1/ LilCA, T H F - H M P A 2/ R X = CHoBr or PhCHofcr C 0 2 E t (20) 172 173 Similar results indicating the preference for alkylation at the a-carbon after formation ofthe dienolate anions from a,(3-unsaturated esters was observed by Schlessinger et a l .^ 3 in their study, a 1:1 complex of FfMPA and L D A was formed by addition of H M P A (1.1 equiv.) to a THF solution of L D A (1 equiv.) (30 min, -78°C). Sequential addition of ethyl (£)-2-butenoate (172) (1 equiv.) (10 min, -78°C) and iodoethane to this solution afforded the oc-alkylated adduct (174) in a 96% yield (Equation 21). According to their simple molecular orbital calculations on the dienolate anion of (172), alkylation occurred at the position of maximum negative charge (the a-carbon atom). Et C 0 2 E t T / 1/ LDA-HMPA, THF J \ 21CH3CH2I < ^ C 0 2 E t (21) 172 96% 174 53 Studies examining the stereochemical outcome ofthe deconjugation-alkylation of a series of a,P-unsaturated esters have been carried out by Kende and Toder.^ 4 It was found, for example, that the deconjugation-methylation of the ethyl (Z)-2-alkenoates (175) proceeds to give exclusively the corresponding alkylated (E)-3-alkenoates (176) in good yields (88-90%) (Equation 22). R — \ COoEt ) — C 0 2 E t ^ / 2 1/ LDA-HMPA, THF / — "27CH3I / <2 2> R 175 R = Me, n-Pr, or /-Pr ^ 7 6 88-90% Yield In contrast, it was found that the deconjugation-methylation ofthe ethyl (E)-2-alkenoates (177) to provide the corresponding alkylated (Z)-3-alkenoate (178) was less selective (Equation 23), with the stereoselectivity decreasing as the size ofthe R group increased. 177 R = Me R = n-Pr R = /-Pr C0 2 Et 1/LDA-HMPA, THF 2/CH3I r J—C02Et / \ X 0 2 E t (23) 176 0% 14% 35% 178 90% 78% 62% The stereoselectivity of these transformations (Equations 22 and 23) is suggested to arise in the deprotonation step^4 and a modified version of Kende and Toder's 54 formulations (Schemes 17 and 18) is believed to provide a reasonable rationale for the transformations given on page 50 (Equations 18 and 19). For the kinetically-controlled deprotonation ofthe (£)-3-trimethylstannyl-2-alkenoates (Scheme 17), two possible ground state conformations (179) and (180) can be envisioned where a C-H bond is aligned perpendicular to the plane ofthe conjugated % system Removal of H2 from (180) leads to an extended enolate (184) via a transition state (182) which would be destabilized by the strain^ between the R and Me3Sn groups. In contrast, the transition state (181) generated by removal of from (179) would have severe A M strain^ between the R and CC^Et groups. The A 1 ' 3 strain in (181) would be expected to be greater than the A 1 ^ strain in (182) due to the length of the Sn-C bond (~2A). Thus, the pathway (180)->(182)->(184)->(185) would be favoured leading to the formation ofthe (Z)-3-trimethylstannyl-2-alkenoates. EtO S n M e 3 179 LDA T [transition state]: 181 EtO i 183 Scheme 17 180 LDA T [transition state]* 182 EtO I 185 56 Similarly, for the kinetically-controlled deprotonation ofthe (Z)-3-trimethylstannyl-2-alkenoates (Scheme 18), two possible ground state conformations (186) and (187) can be envisioned where a C-H bond is aligned perpendicular to the plane ofthe conjugated n system Removal of H2 from (187) leads to a transition state (189) which is destabilized by the A\2 strain^ between the R and Me3Sn groups. This destabilization would be expected to be greater than the relatively small destabilizations in the transition state (188) from the A ^ 3 strain^ between the R group and olefinic proton (H3) and the A*>2 strain between the SnMe3 group and the allyhc proton H2. Thus the deconjugation ofthe (Z)-3-trimethylstannyl-2-alkenoates should proceed via the pathway (186)-*(188)->(l 90)-»(l 92) to provide the (Z)-3-trimethylstannyl-3-alkenoates exclusively. In summary, it was found that the deconjugation-alkylation ofthe ethyl (E)-3-trimethylstannyl-2-alkenoates (133) with 2,3-dibromopropene (20) to afford the 3-trimethylstannyl-3-alkenoates (165) did not proceed satisfactorily (Equation 17, page 49). On the other hand, deconjugation of the ethyl (E)- and (Z)-3-trimethyl stannyl-2-alkenoates could be accomplished satisfactorily using potassium bis(trimethylsilyl)amide as the base (Equation 18, page 50). 192 Scheme 18 58 2.2 Preparation ofthe alkylating agents At this stage ofthe project it became necessary to produce (Z)-l,2-dihalo-2-alkenes ofthe general structure (44) for use as alkylating agents to lead to the diene esters (193) (Scheme 19). R Me 3 Sn C 0 2 E t y 1/ LDA, THF, HMPA, -78°C, 0°C 133 R' 21 V X 44 , -78°C SnMe 3 Scheme 19 The sequence employed utilized several steps and is outlined in Scheme 20. 194 R R Br V=o p h 3 P = C B r 2 W / CH 2 CI 2 / \ H 2 2 H B Br 195 1/nBuLi, THF 2 / (CHO) n ^ 3/ sat. aq. NaHCOg "OH 196 R Br H x — B r Ph 3 PBr 2 CH2CI2 R Br r H N — O H 1/ nBuLi, Dibal, heat 21 EtOAc 3/ NBS, CH 2 CI 2 4/ sat. aq. sodium potassium tartrate 32 197 Scheme 20 2.2.1 Preparation ofthe 1.1-dibromo-l-alkenes The 1,1-dibromo-l-alkenes of general structure (195) (200 and 201) were prepared from the corresponding commercially available aldehydes of general structure (194) (Equation 24). R R Br H 2 2 H Br 194 195 R = /-Pr(198) R = /-Pr(200) R = c-Hex (199) R = c _Hex (201) Following the procedure given on page 38 ofthe Discussion provided l,l-dibromo-3-methyl-l-butene (200) in 82% yield from 2-methylpropanal (198) and l,l-dibromo-2-cyclohexylethene (201) in 89% yield from cyclohexanecarboxaldehyde (199).43 The spectral data derived from the 1,1-dibromo-l-alkenes (200 and 201) were consistent with the assigned structures. For example, the N M R spectrum of alkene (200) displayed the expected signals for the trisubstituted alkene moiety (a 1-proton doublet at 8 6.22, J= 9 Hz) and one allylic proton (a 1-proton multiplet at 8 2.57). The IR spectrum of alkene (200) displayed a C=C stretching absorption at 1609 cm'*. 60 2.2.2 Preparation ofthe 2-alkyn-l-ols The 2-alkyn-l-ols of general structure (196) (202 and 203) were prepared from the corresponding 1,1-dibromo-l-alkenes of general structure (195) (200 and 201) (Equation 25) . 4 3 R , , B r 1 /nBuLi, THF ) = { 21 (CHO)n (25) H Br 3 / s a t - a q N a H C 0 3 OH 195 196 R = /-Pr (200) R = /.p r (202) R = c-Hex (201) R = c-Hex (203) Addit ion 4 3 of «-butynithium (2.5 equiv.) to a THF solution of l,l-dibromo-3-methyl-1-butene (200) (-78°C, 1 h; room temperature, 1 h) afforded the corresponding hthium acetylide which, upon reaction with paraformaldehyde (3.0 equiv., -20°C, 1 h; room temperature, 1 h), produced 4-methyl-2-pentyn-l-ol (202) in 79% yield. In a srrrdlar manner, 3-cyclohexyl-2-propyn-l-ol (203) was prepared from l,l-dibromo-2-cyclohexylethene (201) in 81% yield. The spectral data for the 2-alkyn-l-ols (202 and 203) were consistent with the assigned structures. For example, the A H N M R spectrum of alkyne (202) displayed the expected signal for a C H 2 group next to an alkyne and hydroxy group (a two proton doublet at 8 4.22, J= 3 Hz) and an O H group (a one proton triplet at 8 1.60, J= 3 Hz). The IR spectrum ofthe alkyne (202) displayed a C=C stretching absorption at 2256 cm"l and an O-H stretching absorption at 3400 cm" 1 . 61 2.2.3 Preparation ofthe (Z)-2-bromo-2-alken-l-ols The (Z)-2-bromo-2-alken-l-ols of general structure (197) (204 and 205) were prepared from the corresponding 2-alkyn-l-ols of general structure (196) (202 and 203) (Equation 26). 1/ nBuLi, Dibal, heat 21 EtOAc, 0°C R Br T>H 3/ N B S , CH 2 CI 2 , -78°C rf \ Q H 1 9 6 4/sat. aq. sodium potassium tartrate 197 R = /-Pr (202) R = /-Pr (204) R = c-Hex (203) R = c-Hex (205) The procedure used was a modification of that developed by Corey et al. $6 to transform proparglylic alcohols (206) into (Z)-2-iodo-2-alken-l-ols (208) via a vinyl aluminum derivative (207) (Equation 27). (26) R Al K A K — HL ( 2 7 ) H ^ - O — H V - O H "OH 206 207 208 Corey's procedure, which utilizes iodine to convert the vinylaluminum derivatives (207) into the alcohols (208), was initially successfully used to synthesize (Z)-2-iodo-4-methyl-2-pentene-l-ol(209). 62 Unfortunately, the alkylating agent derived from (209), (Z)-l-bromo-2-iodo-4-methyl-2-pentene, was unsuitable in later steps and efforts were made to modify Corey's method to produce the bromo equivalent of (209), compound (204). (Z)-l,2-Dibromo-4-methyl-2-pentene, derived from (204), was later found to be of synthetic utility. Sequential addition of «-butylhthium (1.0 equiv.) and Dibal (3 equiv.) to a cold (-20°C) Et20 solution of 4-methyl-2-pentyn-l-ol (202) followed by heating at 35°C for 64 h and recooling to 0°C afforded a solution ofthe corresponding vinylaluminum derivative, to which was added ethyl acetate (2 equiv.). The resulting mixture was stirred at 0°C for 10 min, cooled to -78°C, and cannulated into a cold (-78°C) solution of NBS (5 equiv.). Work-up and purification ofthe crude product produced (Z)-2-bromo-4-methyl-2-pentene-l-ol (204) in 63% yield. In a similar manner, 3-cyclohexyl-2-propyn-l-ol (203) was converted into (Z)-2-bromo-3-cyclohexyl-2-propen-l-ol (205) in 52% yield. The spectral data for the (Z)-2-bromo-2-alken-l-ols (204 and 205) were consistent with the assigned structures. For example, the A H N M R spectrum ofthe alkene (204) displayed the expected signal for an allylic C H 2 group containing a hydroxyl group (a 2-proton doublet at 8 4.20, J= 8 Hz), an O H group (a 1-proton triplet at 8 1.87, J= 8 Hz), and a vinyl proton (a 1-proton doublet at 8 5.80, J = 8 Hz). A A H N M R NOE difference experiment supported the assignment ofthe stereochemistry ofthe double bond as the irradiation ofthe allylic protons at 8 4.20 led to enhancement ofthe olefinic proton at 8 5.80. The IR spectrum ofthe alkene (204) displayed C=C and O-H stretching absorptions at 1657 and 3348 c m _ i , respectively. High resolution mass spectrometry showed that the molecular formula for (204) was CgHj jBrO. 63 2.2.4 Preparation ofthe (Z)-1.2-dibromo-2-alkenes The (Z)-dibromoalkenes of general structure (32) (206 and 207) were prepared from the corresponding (Z)-2-bromo-2-alkene-l-ols of general structure (197) (204 and 205) (Equation 28). R Br R Br M X <28) H V - O H 2 2 H \ _ B r 197 32 R = /-Pr (204) R = /-Pr (206) R = c-Hex (205) R = C -Hex (207) To a stirred solution of triphenylphosphine (1.1 equiv.) and bromine (1.1 equiv.) in dry CH2CI2 was added (Z)-2-bromo-4-methyl-2-penten-l-ol (204). After the mixture had been stirred for 3.5 hours, pentane was added. Work-up produced (Z)-l,2-dibromo-4-methyl-2-pentene (206) in 76% yield. In a similar manner (Z)-2-bromo-3-cyclohexyl-2-propen-l-ol (205) was converted into (Z)-2,3-dibromo-l-cyclohexylpropene (207) in 73% yield. The spectral data derived from the (Z)-dibromoalkenes (206 and 207) were consistent with the assigned structures. For example, the N M R spectrum of the alkene (206) displayed the expected signals from the allyhc CFL^Br (a 2-proton singlet at 8 4.21) and the olefinic proton (a 1-proton doublet at 8 5.91, J= 9 Hz). A * H N M R NOE difference experiment supported the assignment of the stereochemistry of the double bond. Thus, irradiation ofthe allyhc protons at 8 4.21 led to enhancement ofthe olefinic proton at 8 5.91. The IR spectrum of alkene (206) displayed a C=C stretching absorption at 1643 cm' l . High resolution mass spectrometry showed that the molecular formula for (206) was C 6 H 1 0 B r 2 . 64 2.3 Deconjugation-alkylatiori of ethyl (EV and (ZV3-trimethylstannyl-2-alkenoates Deconjugation-alkylation of certain ethyl (£)- and (Z)-trrmethylstannyl-2-alkenoates (Equations 29 and 30) with 2,3-dibromopropene (20) was accomplished readily. 1 1 ' 16 For example, addition of a THF solution of ethyl (Z)-3-trimethylstannyl-2-pentenoate (149) to a stirred solution of L D A / H M P A (2.3 equiv.) in THF (-78°C, 0.5 h; 0°C, 0.5 h) afforded a yellow solution ofthe corresponding hthium dienolate (Equation 29). Cooling ofthe solution to -78°C followed by addition of 2,3-dibromopropene (20) (1.5 equiv.) and stirring ofthe reaction mixture at -78°C for 1 h, provided, after work-up and purification ofthe crude product by distillation, ethyl (E)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (47) in 72% yield. Me 3 Sn c ° 2 E t 149 1/ LDA, THF-HMPA 21 Br-,-78°C nMe 3 (29) 0 ? Et 47 20 3/ N a H C 0 3 Using a similar procedure, ethyl (£)-3-trimethylstannyl-2-pentenoate (156) and ethyl (£)-3-trimethylstannyl-2-butenoate (208) were converted into ethyl (Z)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (48) and ethyl 4-bromo-2-[l-(trimethylstannyl) ethenyl]-4-pentenoate (46) in 75% and 61% yields, respectively (Equation 30). Also produced as a side product from the deconjugation-alkylation of (208) was the y-alkylated product (209) in 8% yield. 65 R 7 C0 2 Et v L D A THF-HMPA Me3Sn 133 R = H 208 R = Me 156 21 20 3/ NaHCQ 3 Br-,-78C 0 2Et 165 R = H 46 R = Me 48 nMe3 (30) Yield 61a 75 Et was also produced in 8% yield. nMe-3 209 2.4 Deprotonation-alkylation of ethyl (E)- and (Z)-3-trimethylstaririyl-3-alkeiioates R — \ C0 2 Et R - H < Me 3 Sn H Me 3 Sn C0 2 Et 133 134 A procedure similar to that employed to deconjugate-alkylate the ethyl (E)- and (Z)-3-trimethylstannyl-2-alkenoates (133) and (134), respectively, was used to deprotonate-alkylate the ethyl (E)- and (Z)-3-trimethylstannyl-3-alkenoates (210) and (214) (Tables 14 and 15). For example, ethyl (£)-5-methyl-3-trimethylstannyl-3-hexenoate (170) was converted into ethyl (E)-2-(2-bromo-2-propenyl)-5-methyl-3-trimethylstannyl-3-hexenoate (212) in 87% yield (Table 14, Entry 1). In a similar fashion, the ester (169) was transformed efficiently into (213), (Table 14, Entry 2). Similar results were obtained for the (Z)-alkenoates (Table 15). For example, ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (168) was converted into ethyl (Z)-2-(2-bromo-2-propenyl)-5-methyl-3-trimethylstannyl-3-hexenoate (216) in 84% yield 66 (Table 15, Entry 1). While the conversion of ester (167) into (217) proceeded in high yield (Table 15, Entry 2) this was not the case for the conversion of esters (168) and (167) into dienes (218) and (219) which proceeded in lower yields. Analysis ofthe crude product by TLC and GLC analysis indicated a significant amount of starting material remained for the later two reactions. Table 14: Deprotonation-alkylation of ethyl (^-3-trimethylstannyl-3-alkenoates with 2.3-dibromopropene v . Me3Srr ^ ^ C 0 2 E t CI fr XnMe 3 C0 2Et 210 211 Entry Substrate R Product Y ie ld b 1 170 /-Pr 212 87% 2 169 c-Hex 213 91% a l . L D A / H M P A (2.3 equiv.), THF, -78°C, 0.5 h; 0°C, 0.5 h. 2. 2,3-Dibromopropene (20) (1.5 equiv.), -78°C, 1 h. b Yie ld of purified, distilled product 67 Table 15: Deprotonation-alkylation of ethyl (Z)-3-trimemylstarmyl-3-alkenoates with various alkylating agents M e 3 S r r ^ ^ C ° 2 E t 214 Bi \ R-.R SnMe 3 0 2 E t 215 Entry Substrate R R' Product Y ie ld 0 1 168 z-Pr H 216 84% 2 167 c-Hex H 217 93% 3 168 z-Pr /-Pr 218 72% 4 167 c-Hex c-Hex 219 60% a l . L D A / H M P A (2.3 equiv.), THF, -78°C, 0.5 h; 0°C, 0.5 h. 2. Reagent (32) (1.5 equiv.), -78°C, 1 h. DYield of purified, distilled product The X H N M R spectral data for the diene esters of general structure (165) and (211) were consistent with their structural assignments. When the spectra ofthe (Z)-diene esters (165) and (£)-diene esters (211) were compared, three consistent differences in the l H N M R spectra were evident, including the chemical shifts of the methine proton vicinal to the ethyl ester group, the chemical shift ofthe olefinic proton vicinal to the trimethylstannyl moiety, and the tin-proton coupling constant ( 3^Sn-H) associated with the olefinic proton vicinal to the trimethylstannyl moiety and the H^Sn and H^Sn isotopes (Table 16). 68 Table 16: Partial N M R spectra data ofthe diene esters (164) and (211) Entry Cmpd. Cmpd. R 8 of methine 8 of olefinic "^Sn-H ofthe 165 211 proton next proton olefinic proton to -C02Et vicinal to (Hz) vicinal to SnMe 3 SnMe 3 1 48 Me 3.56 6.18 128 2 216 z-Pr 3.43 5.86 126 3 217 c-Hex 3.43 5.89 128 4 47 Me 4.06-4.20 5.86 73 5 212 z-Pr 4.03 5.48 72 6 213 c-Hex 4.03 5.50 76 For example, the * H N M R spectrum of ethyl (Z)-2-(2-bromo-2-propenyl)-5-trimemyl-3-trimethylstannyl-3-hexenoate (216) displayed the expected signal for a trimethylstannyl group (a 9-proton singlet at 8 0.18 with ^Jsn-H = ^2 Hz), an isopropyl group (two 3-proton doublets at 8 0.92 and 8 0.95, J= 6 Hz and a 1-proton multiplet at 8 2.13-2.21), an ethyl ester moiety (a 3-proton triplet at 8 1.22, J= 7 Hz and a 2-proton multiplet at 8 4.06-4.15), a 2-bromopropenyl moiety (two 1-proton doublet of doublets at 8 2.54 and 8 2.93, .7= 15,8 and 15, 6 Hz, respectively, and two 1-proton broad singlets at 69 8 5.39 and 5.50) and a methine proton adjacent to the CO^Et function at 8 3.43 (a 1-proton doublet of doublets, J= 8, 6 Hz, 3 ^Sn-H = 5 6 H 2)- A 0 1 i e proton doublet at 8 5.86, J= 10 Hz with a tin proton coupling Vsn-H = 1 2 6 H z 5 1 accounted for an olefinic proton trans to the trimethylstannyl group. The A H N M R spectrum ofthe corresponding (£)-diene ester (212) was very similar to that of (216) except for three notable differences. Firstly, the position ofthe methine proton next to the ethyl ester moiety was now upfield at 8 4.03 as the R group is now in a cis relationship with respect to this methine proton. Secondly, the position ofthe olefinic proton vicinal to the SnMe3 function was upfield at 8 5.48 as it is cis to the electron rich SnMe3 group and the tin-proton coupling value 3 ^Sn-H ^ 72 Hz corresponds to an olefinic proton cis to the trimethylstannyl groups 1 These three consistant differences between dienes (48) and (47) and between dienes (217) and (213) can be seen in Table 16. These three trends noted above were also observed with the A H N M R spectral data for diene esters (218) and (219). For example, the methine proton attached to the ethyl ester group of (218) displayed a chemical shift of 8 3.50, consistent with the (Z)-diene esters (165, Table 16). The olefinic proton displayed a chemical shift of 8 5.85 and a tin-proton coupling constant 3 . /Sn-H = 126 Hz consistent with the olefinic proton being trans to the trimethylstannyl 70 group in (218). 5 1 Diene ester (219) displayed similar A H N M R spectral data with respect to the methine and olefinic protons. 3. Synthesis of alkyl 2,3-bis(alkyhdene)cyclobutanecarboxylates and related derivatives 3.1 Preparation ofthe alkyl 2,3-bis(alkyhdene)cyclobutanecarboxylates via palladium (O)-catalyzed coupling reactions With the diene esters of general structure (220) in hand, the 2,3-bis(alkylidene)-cyclobutanecarboxylates (221) were accessible via a palladium (O)-catalyzed intramolecular coupling ofthe vinylstannane and the vinyl halide functions (Equation 31). 220 221 Carbon-carbon bond formation is one ofthe most important operations that a synthetic chemist must consider when designing a synthesis and chemists have increasingly been making use of various "cross-coupling" reactions. In general, the term "cross-coupling" refers to "the process of single bond C-C formation between two hydrocarbon groups on the basis ofthe reaction of an organometal compound with an organic halide or similar electrophilic derivative (Equation 32)."57 R 1 M + R 2 M *- R 1 - R 2 + M X ( 3 2 ) 71 Ofthe many organometallic reagents available, organostannanes have found wide applications as they can be prepared via a number of methods, are not particularly air or moisture sensitive, and can be purified and stored. Furthermore, cross-coupling reactions involving organostannanes and a palladium (0) catalyst are mild, tolerant of a wide variety of functional groups, are stereospecific and regioselective, and often give high yields of product.58,59 ^he r e a c t i o n is ofthe general type (Equation 33) where the "leaving group" X is generally a halide or triflate and the palladium catalysts employed depend upon the nature of the particular groups being coupled, though tetrakis(triphenylphosphine)palladium (0) is the most widely used. RX + R'SnR"3 [ P d L " ] » R-R' + X S n R " 3 (33) The driving force for the reaction is the formation of triorganotin halide.5 ° As can be seen in Equation 33, only one ofthe groups (R') on tin participates in the coupling reaction as a second group (R") leaves the Sn atom «100 x slower than the first.58 If the four groups are not identical it is the nature ofthe R group which determines which group is to be transferred from the tin. 60 Preference for transfer follows the order RC=C > RC=CH > Aryl > RCH=CH-CH 2 = A r y l C H 2 > H 3 C O C H 2 > CnK2n-l-5S A simple alkyl group transfers the slowest and, therefore, when an organostannane contains three methyl groups and one alkenyl or aryl group, the latter group will transfer exclusively. The use of trimethylorganostannes is often preferred over other trialkylorganostannes (e.g. tri(«-butyi)organostannanes). This is because the by-product ofthe coupling reaction, trimethylstannyl chloride, is water soluble and thus can be easily removed from the desired product while tri(n-butyl)stannyl chloride is not water soluble and therefore not easily removed. 72 J .K Stille, a pioneer in this field, had extensively studied the palladium (0)-catalyzed intermolecular cross couplings of alkyl and aryl stannanes with acyl hahdes,61 benzyl halides,62 a l ly l halides,63 vinyl halides,64, 68 ^ jayi triflates,65 aryl halides,66 and aryl triflates.67 Of these studies, those in which a vinyl group on the organotin substrate moiety is transferred, are of special interest as conjugated dienes are produced with a suitable substrate.^9 Both vinyl halides and vinyl triflates have been shown to be useful substrates in this regard. (E)- or (Z)- Substituted vinyl halides couple with (E)- or (Z)- vinylstannanes to give good yields of unsymmetrical dienes in which retention of double bond configuration has occurred.68 Thus, treatment of (£)-l-iodo-l-hexene (222) with ethyl (Z)-3-tri-n-butylstannyl-2-propenoate (223) under the reported conditions provided the (E-Z) product (224), while treatment of (Z)-l-iodo-l-hexene (225) with (223) provided the (Z-Z) isomer (227) (Scheme 21)68 Both vinyl iodides and vinyl bromides can be used in the coupling reaction though vinyl bromides require longer reaction times and higher temperatures (e.g. 100°C vs. 25°C) than their iodo counterparts.^8 _ J (CH 3 CN) 2 PdCI 2 = ^ C O E t n B u ^ + n B U 3 S n C ° 2 B DMF, 25°C, 78% n B u ^ 222 223 224 + / = = \ (CH 3 CN) 2 PdCI 2 C0 2 Et "Bu I "BuaSn C 0 2 E t DMF, 25°C, 62% * n B u X=/ 225 223 Scheme 21 227 73 Many studies have been published regarding the mechanism for palladium (0) cross coupling of vinylstannanes with vinyl halides or vinyl triflates.63,65 T h e catalytic cycle proposed by Stille for the direct coupling reaction of a vinylstannane and vinyl halide is shown in Scheme 22.^8 R'SnR"3 X S n R " 3 230 Scheme 22 74 Oxidative addition ofthe palladium (0) catalysts into the R X bond yields the palladium(II) intermediate (228). Transmetalation between (228) and a vinyltrialkylstannane then occurs to give intermediate (229) and a trialkylstannyl halide (230). The intermediate (229) then undergoes trans-cis isomerization to give (231), followed by rapid reductive elimination, to release the coupled product (232). The coupling of a vinyl triflate and organostannane was proposed by Stille to proceed via an analogous pathway.65,69 Recently, Farina has performed 3 *P N M R and kinetic studies which suggest that ligand dissociation is a key step in the transmetalation step outlined above and that a % complex between the Pd(II) intermediate and the olefinic stannane is formed in one ofthe steps in the mechanism (Equation 34).^0 SnnBu. Products (34) Treatment of diene esters (220), which contain vinyl bromide and vinyl trimethylstannane functions, with ( P l ^ P ^ P d (5 moi %) in dry DMF at 80°C for 1 h provided a synthetic pathway to the alkyl 2,3-bis(alkyhdene)cyclobutanecarboxylates (221) (Table 17). 75 Table 17: Stereocontrolled synthesis of alkyl 2J-bis(alkyhdene)cyclobutanecarboxylates 22ia ,R Pd(0) R' Br R v S n M e 3 0 9 E t ^ X 0 2 E t 220 221 Entry Substrate 220 Product 221 % Yie ld b SnMe. C 0 2 E t 82 C 0 2 E t 53 SnMe 3 ^ 80 C 0 2 E t 54 S n M e 3 \ ^ 85 * C 0 2 E t 55 SnMe 3 }_pr 79 C 0 2 E t 233 212 76 Table 17 (cont) 5 90 C 0 2 E t S n M e 3 C0 2 Et 234 S n M e 3 83 c-Hex 235 c - H e x ^ ^ ^ C 0 2 E t 79 *C02Et C0 2 Et 217 236 83 c C 0 2 E t 237 2 1 d , 84 e *C0 2 Et 238 a A l l reactions were carried out under the following conditions (unless otherwise noted): (Ph 3 P) 4 Pd (5 moi %) in dry DMF at 80°C for 1 h. 77 Table 17 (cont.) D Yield of purified distilled product. cExperimental Conditions: (Ph 3 P) 4 Pd (10 moi %) in dry DMF at 80°C for 2.5 h. dExperimental Conditions: (Ph 3 P) 4 Pd (10 moi %) in dry DMF at 80°C for 48 h. eExperimental Conditions: CuCl (2.8 equiv.) in dry DMF at 60°C for 10 min. For example, addition of (Ph 3 P) 4 Pd (5 moi %) to a 0.07 M solution of ethyl (E)-2-(2-bromo-2-propenyl)-5-methyl-3-trimethylstannyl-3-hexenoate (212) in D M F gave a pale yellow solution. Upon heating at 80°C for 1 h the solution turned dark brown. GLC analysis of a solution ofthe crude product indicated that only one product had formed. Flash chromatography ofthe crude product and distillation ofthe acquired oil afforded 79% of ethyl (£,)-2-(2-methylpropyhdene)-3-methyhdenecyclobutanecarboxylate (233) as a colourless oil. The assigned structure of (233) was confirmed in the following manner. The l H N M R spectrum of (233) (Figure 3) showed the expected signals for an ethyl ester moiety (a 3-proton triplet at 8 1.25, J = 7 Hz, and a 2-proton multiplet at 8 4.13-4.18), a methylene group (H D , a 1-proton doublet of doublets of doublets of doublets at 8 2.79, *^ bc = 15 Hz, J D a = 9 Hz, J\)Q = 2.5 Hz, ,/D(j = 2 Hz; and H^, a 1 proton multiplet at 8 2.84-2.91), a methine proton (H a , a 1-proton multiplet at 8 3.68-3.73), and an isopropyl group (two 3-proton doublets at 8 0.93 and 8 0.96, J = 7 Hz each and a 1-proton multiplet at 8 2.45-2.55). It should be noted that the signal for the methylene group ofthe ethyl ester moiety is a multiplet because the geminal protons are diastereotopic. There were also the expected signals for three olefinic protons (FLj, a 1-proton doublet of doublets at 8 4.66, J^b = Jfo = 2 Hz; H e , a 1-proton doublet of doublets at 8 5.09, = Jec = 2.5 Hz; and Hf, a 1-proton doublet of doublets at 8 5.54, J f a = 3 Hz, ^ ( C H 3 ) 2 C H - f = ^ H 2 ) In a series of NOE difference experiments irradiation at 8 2.50 ( -CH(CH 3 ) 2 ) caused enhancement ofthe signals at 8 0.93 (one o f -CH(CH 3 ) 2 ) , 8 0.96 (one o f -CH(CH 3 ) 2 ) , 78 and 5 3.68-3.73 (Ha) while irradiation at 5 3.70 (Ha) caused enhancement ofthe signals at 8 0.93 (one of -CH(CH 3) 2), 5 0.96 (one of-CH(CH 3) 2), 8 2.50 (-CH(CH3)2) and 8 2.79 (H^). Irradiation at 5 5.54 (Hf) caused enhancement ofthe signals at 8 0.93 (one of -CH(CH 3) 2), 8 0.96 (one of-CH(CH 3) 2) and 8 5.09 (He). The IR spectrum of (233) showed a strong C=0 stretching frequency at 1736 cm"1 and the molecular formula of (233) was shown to be C i 2 H i g 0 2 by high resolution mass spectrometry. r I 1 1 1 1 1 ' 1 • | ' ' ' 1 • ' ' I ' | ' I I I | I I I I | | | | T 0 6.0 5.0 4.0 3.0 2.0 1 0 ' i PPM Figure 3: NMR of ester 233 79 In a similar fashion, the diene esters (46-48) (213) and (216-219) were converted into the corresponding alkyl 2,3-bis(alkyhdene)cyclobutanecarboxylates (53-55) and (234-238) in good yields (Table 17). Of noteworthy mention are the longer reaction times and the greater amount of catalyst required to transform the diene esters (218) and (219) into the esters (237) and (238). The transformation of (219) into (238) also produced the product (238) in low (21%) yield (Table 17, Entry 9). Fortunately, a new method of coupling vinylstannanes and vinyl halides using CuCl had been developed in our laboratories.4 8' 7 1 Thus, treatment of (219) with CuCl (2.8 equiv.) in dry DMF at 60°C for 10 min provided, upon workup and distillation ofthe acquired oil, a 84% yield of ester (238). I f i N M R analyses, including NOE difference and decoupling experiments, were performed on all ofthe cyclobutanecarboxylates (221) (Table 17) to confirm their structures. A l l ofthe cyclobutanecarboxylates exhibited absorption bands at 1735-1740 cm" A for C=0 stretching vibration ofthe ethyl ester moiety in their IR spectra. High resolution mass spectrometry confirmed the molecular formula in each case. 80 3.2 Preparation and X-ray analysis ofthe (Z,Z)-23-bis(alkyMene)cyclobutane-carboxamides (239-242) The cisoid diene units ofthe crystalline compounds (60), (61) and (29) have been found by X-ray analysis to be non-planar. ^  The torsion angles between carbons a and b ofthe cisoid diene units were found to be 3.9°, 4.8°, and 25.4°, respectively.16 a The cyclobutanecarboxylates (237) and (238) should be highly strained compounds due to the severe steric repulsion between the two vinylic isopropyl groups in (237) and two vinylic cyclohexyl groups in (238) particularly i f the diene systems are planar. Indeed, it would be expected that the cisoid diene units of (237) and (238) would be non-planar and that the torsion angle between carbons a and b ofthe cisoid diene units of (237) and (238) would be larger than that of (29). Esters (237) and (238) are oils, so it was necessary to prepare suitable amide derivatives to provide crystals appropriate for X -ray analysis. , - P r ^ r - n C y ^ n ' ' - P r ^ ^ C 0 2 E t C y ^ U ^ C 0 2 E t 237 238 81 H Y V h O Me R = / - Pr (239) R = c - H e x (241) R ^ V H irV O Me P h R = / - Pr (240) R = c - Hex (242) To that end, the crystalline amide derivatives (239-242) were prepared from cyclobutanecarboxylates (237) and (238) (Equations 35 and 36) employing a procedure developed by Weinreb et al?^ Only derivative (240) was found to be suitable for X-ray analysis. H 2 N v ^ - P h Me , Me;jAI benzene-toluene /-Pr- Y Y O Me + / - P r ^ S Ph /-Pr- Ph (35) Me 237 239 32% 240 33% For example, to a stirred solution of (R)-(+)-l-phenylemylamine (2.24 equiv.) in dry benzene (16 mL) was added, dropwise, a solution of trimetJiylalurninum (2.24 equiv.) in toluene (room temperature, 20 min) to produce a yellowish solution. Addition ofthe cyclobutanecarboxylate (237) (1 equiv.) in 2 mL dry benzene, followed by refluxing (4 h), provided, after acidic work-up, radial chromatography, and recrystallization from a petroleum ether - Et20 mixture, 32% and 33% yields ofthe cyclobutanecarboxamides (239) and (240), respectively. The cyclobutanecarboxamide (240) exhibited colourless, needle-like crystals of melting point, 110-111°C, while the diastereomer (239) consisted of colourless, needle-like crystals of melting point, 103-104°C. 82 In a similar fashion, the cyclobutanecarboxamides (241) and (242) were prepared from (238) in 39% and 36% yields, respectively (Equation 36). j , Me3AI c - H e x ^ V n Me c - H e x ^ y ^ h + c - H e x ^ H . P h ( 3 6 ) Hex-^i—kc^gt benzene-toluene0"1^*^^— j f ^ Y ^ — O Me o Me 2 3 8 241 242 39% 36% The cyclobutanecarboxamide (241) was recrystallized as colourless needle-like crystals (melting point, 163-165°C dec.) and (242) as colourless needle-like crystals (melting point, 169-170°C dec). Compounds (241) and (242) were thermally stable on a short-term basis (less that 1 day) and complete spectral data were obtained. However, it was impossible to obtain suitable crystals for analysis by single crystal X-ray crystallography before both of these compounds decomposed. Thus, only single crystal X-ray analysis on (240) was obtained. Single crystal X-ray analysis of (240) (Appendix 1) indicated that the torsional angle between the C-5-C-2 (for the purpose of this discussion, the numbering system used for compound (240) is that in Figure 4) and C-3-C-6 bonds is 38.7° (Figure 2). The bond lengths between the carbon atoms in the four-membered ring are as follows: C- l-C-2, 1.537(3)A; C-2-C-3, 1.490(3)A; C-3-C-4, 1.519(3)A; and C-4-C-1, 1.546(3)A (Figure 4). The x-ray analysis clearly shows that the four-membered ring of (240) is not a perfect square. The C-2-C-3 bond is somewhat shorter than the rest of the cyclobutane C-C bonds. The cisoid diene unit of (240) was found to have its planarity severely disrupted, with the torsional angle being 38.7°. This distortion from planarity is due to the severe steric repulsion between the two isopropyl groups should the cisoid diene unit adopt a planar conformation. It is noteworthy to mention that the torsional angle of (240) 83 (38.7°) is greater than that of compound (29) (25.4°), which differs in having two vinylic methyl groups instead of two vinylic isopropyl groups. / - P r ^ V - , ' - P r - - ^ O Me 240 Figure 4: Stereoview of the cyclobutanecarboxamide 240 84 3.3 Preparation ofthe l-substituted-2.3-bis (methylene) cyclobutanes Compounds of general structure (17) where W = - C N , - C O 2 H , and -CFFjOH were also required as thermolysis precursors. C 0 2 E t w 53 W 243 W = - C N , - C 0 2 H , - C H 2 O H 17 After some experimentation, it was found that the most expedient route to compounds of general structure (17) was via conversion ofthe ethyl ester group of (53) into the desired functional group of (243) followed by a 47i +2TT cycloaddition ofthe 1-substituted 2,3-bis(methylene)cyclobutane (243) with a suitable dienophile. To this end, several l-substituted-2,3-bis(methylene)cyclobutanes of general structure (243) were prepared as shown in Scheme 23. X 0 2 E t 322 NaOH <^ T O , H 344 LAH Et 2 0 ^ X H 2 O H 340 PCC, CH 2 CI 2 NaOAc N 343 Scheme 23 SOCI 2 DMAP X H O 341 NH2OH-HCI pyridine 342 NOH 85 3.3.1 Preparation of l-(hydroxymemylV2,3-bis(memylene)cy^ (244) LAH * C 0 2 E t E t 2 0 92% (37) C H 2 O H 53 244 The alcohol (244) was readily obtained from the cyclobutanecarboxylate (53). Treatment ofthe cyclobutanecarboxylate (53) with hthium aluminum hydride (1.0 equiv.) (0°C, 10 min; room temperature, 10 min) afforded, after work-up, radial chromatography, and distillation ofthe crude reaction product, a 92% yield of the alcohol (244) (Equation 37). The X H N M R spectrum of (244) showed signals similar to those found in the A H N M R spectrum of (53) with the exception that the signals for the ethyl ester moiety were replaced by those of a - C H 2 O H group (a 1-proton broad singlet at 8 1.53 and a two proton multiplet at 8 3.65-3.77). The IR spectrum of (244) showed a strong broad absorption at 3351 c m ' 1 indicating the presence of an O H moiety. The high resolution mass spectrum of alcohol (244) indicated that it had a molecular formula of C7H10O. 86 3.3.2 Preparation of l-formyl-2.3-bis(methylene)cyclobutane (245) P C C , C H 2 C I 2 NaOAc (38) ' C H 2 O H 'CHO 244 70% 245 The aldehyde (245) was readily obtained from the alcohol (244) via the following procedure. Addition of (244) to a stirred solution of pyridinium chlorochromate (2.0 equiv.) and sodium acetate (3.5 equiv.) in dry CH2CI2 (room temperature, 2 h) afforded, after filtration ofthe crude reaction mixture (through a column of Florisil), and distillation ofthe acquired o i l a 70% yield ofthe aldehyde (245) (Equation 38). Compound (245) proved to be extremely unstable (polymerizing rapidly after distillation) and thus had to be used immediately in subsequent synthetic sequences. Furthermore, during the filtration step ofthe work-up, (245) partially isomerized to the aldehyde (249) i f the elution rate ofthe crude reaction mixture through the Florisil was slow. The NMR spectrum of (245) was similar to that ofthe alcohol (244) with the exception that the - C H 2 O H signals were replaced with the resonances of an aldehyde group (a 1-proton doublet at 5 9.68, J= 2 Hz). The IR spectrum of (245) exhibited a strong absorption at 1719 cm~l indicating the presence ofthe -CHO moiety. The high resolution mass spectrum ofthe aldehyde (245) indicated that it had a molecular formula 'CHO 249 o f C 7 H 8 0 . 87 3.3.3 Preparation of l-cyano-2.3-bis(methylene)cyclobutane (247) NH 2OH-HCI ^ S C H O pyridene 245 6 'CHO 249 247 Scheme 24 246 B O H 74% SOCI 2 DMAP 82% 250 NOH 14% To a stirred solution ofthe aldehydes (245) and (249) (6:1 mixture as determined by N M R spectroscopy) in dry DMF was added hy(koxylamine hydrochloride (5.1 equiv.) and dry pyridine (5.1 equiv.) and the resultant mixture was stirred for 1 h. Workup, radial chromatography, and recrystalhzation (1:1 hexanes - Et20) ofthe crude product, afforded the oxime (246) in a 74% yield and the oxime (250) in a 14% yield (Scheme 24). Compound (246) consisted of a 3:2 mixture of geometric isomers with respect to the oxime function. The high resolution mass spectrum of (246) indicated that it had a molecular formula of C7H9NO. The oxime (246) was added to a cold (-10°C) stirred solution of thionyl chloride (1.1 equiv.) and D M A P (1.25 equiv.) in CH2CI2 (-10°C, 2 min) to produce a yellow solution. More D M A P (1.25 equiv.) was added, the solution warmed (room temperature, 30 min) and upon work-up, chromatography, and distillation ofthe crude product there was obtained 82% ofthe nitrile (247) as a volatile oil (Scheme 24). The i f f N M R spectrum of (247) was similar to that of aldehyde (245). The IR spectrum of (247) displayed a strong absorption at 2240 cm"l which indicated the presence of a nitrile 88 moiety. The high resolution mass spectrum of (247) indicated that it had a molecular formula of C7H7N. 3.3.4 Preparation of 2.3-bis(methylene)cyclobutanecarboxvnc acid (248) ^ NaOH ^ + (39) ^ ~ S ) 0 2 E t 9 0 % <^~^C02H ^ ^ C 0 2 H 53 248 251 6 1 Treatment of a solution ofthe cyclobutanecarboxylate (53) in an ethanol-water mixture with NaOH (1.25 equiv.) (room temperature, 2 h) afforded, after work-up, a 90% yield of a 6:1 mixture of the acids (248) and (251) (Equation 39). Attempts to separate these products by radial and flash chromatography on silica gel were unsuccessful and this mixture was used without further purification in later synthetic steps. The JR spectrum of the mixture displayed the absorptions expected for a carboxylic acid moiety (a strong, broad absorption at 3390-2670 cm" 1 and a strong absorption at 1705 cm" 1). The high resolution mass spectrum ofthe mixture indicated that it had a molecular formula of C7Hg02-89 4. Diels-Alder reactions of alkyl 2 J-bis(alkyndene)cyclobutanecarboxylates and related substances The Diels-Alder reaction involves a [4n + 2n] cycloaddition of a conjugated diene and dienophile to form a 6-membered ring (Equation 40). (40) diene dienophile Diels-Alder Adduct With the availabihty of several alkyl 2-alkylidene-3-methylenecyclobutanecarboxylates (221) (Scheme 25) and 1-substituted 2,3-bis(methylene)cyclobutanes (243) (Equation 41), the Diels-Alder reactions of these compounds with a variety of dienophiles was investigated. The products of these Diels-Alder reactions, the bicyclo[4.2.0]oct-l(6)-enes (252-254), are the substrates of the thermolysis studies which will be discussed in detail in the final chapter of this Discussion. 90 4.1 Diels-Alder reactions of dienes with tetracyanoethylene (TCNE) The greater the number of electron-attracting substituents on a double bond, the more reactive is the dienophile due to a lowering ofthe energy ofthe lowest unoccupied molecular orbital ( L U M O ) . 7 3 Tetracyanoethylene (TCNE) is a highly reactive dienophile because it possesses four conjugated nitrile groups.^4 It was important to use a highly reactive dienophile like TCNE because ofthe instability of two of the dienes (243) (W = CHO, CN). As tetracyanoethylene (TCNE) is symmetrical, it can also be used to show the face selectivity ofthe Diels-Alder reactions for dienes with at least one 91 substituent on the diene. The Diels-Alder adduct produced is typically the one resulting from a-face approach ofthe TCNE (Figure 5). This is because there is relatively little steric hindrance in the transition state resulting from a-face approach as compared to the transition state resulting from P-face approach where there is an ester group present. p- face approach a - face approach Figure 5: Diagramatic view of the two possible directions that the dienophile TCNE may approach the 2,3-bis(alkyhdene)cyclobutanecarboxylates The general procedure for the preparation ofthe TCNE adducts of dienes (221) and (243) is as follows. To a stirred solution ofthe appropriate ethyl cyclobutanecarboxylate (221) or the l-substituted-2,3-bis(methylene)cylobutane (243) (1 equiv.) in dry CH2CI2 (8-12 mL/mmol of substrate) was added tetracyanoethylene (1 equiv., unless noted otherwise). The reaction mixture was stirred for 0.5 hours at room temperature (unless noted otherwise) and the solvent was removed under reduced pressure. Radial chromatography ofthe crude product followed by recrystallization (1:1 hexanes-Et20) ofthe acquired solids afforded the corresponding products (253) and (254) respectively, as crystalline solids. The results from these Diels-Alder reactions are summarized in Tables 18 and 19. Table 18: Diels-Alder reactions ofthe cyclobutanecarboxylates 221 with tetracyanoethylene Entry Substrate Equiv. Reaction Product TCNE Time Yield 1.0 0.5 h 53 *C0 2Et 1.0 0.5 h s C0 2 Et 55 1.0 ^ X 0 2 E t 54 ;-Pr-X0 2 Et 234 X502Et /-Pr 233 0.5 h 1.5 4 days 1.1 0.5h NC NC-NC-68 ^ C C ^ E t NC 255 NC NC-NC-77 " x C ^ E t 256 NC NC-NC-78 ~ X Q 2 E t NC 257 NC 65 NC-NC-~XC>2Et NC /-Pr 258 NC 66 NC-NC-^ C C ^ E t NC /-Pr 259 Table 18 (cont.) 6 <V 1.5 -Hex. A—L xo2 236 4 days NC NC-NC-73 " x C ^ E t NC c-Hex 260 1.0 X O z E t :-Hex 235 2.0 0 2Et 0.5 h 4 days NC NC-NC-70 ^ C O j E t NC c-Hex 261 no reaction 237 2.0 4 days no reaction 238 a Yield of purified, recrystallized product. 94 Table 19: Diels-Alder reactions ofthe l-substituted-2.3-bis(methylenelcyclobutanes with tetracyanoethylene3-NC T C N E <T > W C H 2 C I 2 NC-NC-W 243 NC 254 Entry Substrate C H 2 O H 244 C N 247 Product NC Yield 73 NC-NC-NC 262 NC 69 NC-NC-CN NC 263 3C C 0 2 H 248 NC 44 NC-NC-NC 264 a T C N E (1 equiv.), CH2CI2, room temperature, 0.5 h. D Yield of purified, recrystalhzed product. cSubstrate was a 6:1 mixture of 248 and 251. C 0 2 H 251 95 For example, the diene (53) was treated with TCNE (1 equiv.) in CH2CI2 at room temperature for 30 min. GLC analysis ofthe reaction mixture showed that no starting material was left. Radial chromatography and recrystallization (1:1 hexanes - Et20) ofthe acquired solid afforded a 68% yield ofthe ester (255) as fine white crystals (melting point 128-129°C). The procedures and yields were similar for the other dienes listed on Tables 18 and 19, the most notable differences being the extended reaction times required for the dienes (234) and (236) and the fact that the dienes (237) and (238) failed to react at all. This can be attributed to the number and geometry ofthe substituents on the diene moiety. The presence of one cis-substituent increases the required reaction time from 0.5 h to 4 days, presumably due to steric hindrance by the cis-substituent towards the approaching dienophile and the non planarity ofthe cisoid diene unit. In the case of dienes (237) and (238), two c«-substituents on the diene moiety causes the diene to be severely distorted from planarity and thus the Diels-Alder reaction cannot proceed. The spectral data were consistent with the assigned structures and where the diene has a substituent the structure resulting from a-face approach ofthe dienophile TCNE. For example, the IR spectrum of (256) displayed absorptions at 2258 cm" 1 and N M R spectrum of (256) exhibited the signals for an ethyl ester moiety (a 3-proton triplet at 8 1.27, J - 7 Hz and a 2-proton multiplet at 8 4.12-4.22), a methyl group (a 3-proton 256 1731 cm" 1 , corresponding to C=N and C=0 stretching frequencies, respectively. The ^H 96 doublet at 5 1.50, J= 7 Hz), and six allylic protons. Ester (256) was shown to have a molecular formula of C15H12O2N4 by high resolution mass spectrometry. The relative configuration of each ofthe products (Tables 18 and 19) was considered by conformational analysis and A H N M R data, including a series of decoupling and N O E difference experiments. For example, ester (256) would be expected to have two "reasonable" conformations, (256a) and (256b) where the cyclohexane ring adopts a half-chair conformation. Z z ^ ^ C 0 2 B t He H a 256a Z = Z*= -CN Z' = E t 0 2 C -Of the two conformations, (256b) would be expected to be less stable because of the 1,3-diaxial interaction between the Me and Z group. Conformation (256a), which has the methyl group in a pseudoequatorial orientation, has no such interaction and thus would be expected to be the favoured conformation. The proposed conformation was supported by a series of NOE difference experiments and by single crystal X-ray analysis (Figure 6). For example in a series of NOE experiments, irradiation ofthe methyl group at 8 1.50 led to enhancement ofthe signal at 8 3.27-3.32 leading one to conclude that this signal is due to proton EL,. Irradiation at 8 3.73 (H a , which is always the more deshielded ofthe methine protons) led to enhancement ofthe signals at 8 3.27-3.32 (Hg) and 8 2.90 (H D). This experiment 97 suggests that ester (256) has adopted conformation (256a) as a strong NOE enhancement would be expected to be observed for the axial protons H e and H a in (256a). Figure 6: Stereoview of ester (256) 98 In a similar fashion Diels-Alder adducts (257-261) were prepared, and conformations analyzed on the basis of * H N M R data and a series of decoupling and NOE difference experiments. Unlike compound (256) where single crystal X-ray analysis could support the assigned conformation in the solid state, irrefutable evidence supporting one product conformation for adducts (257-261) was not obtained. For example, ester (257) would be expected to have two "reasonable" conformations, (257a) and (257b) where the cyclohexane ring adopts a half-chair conformation. Ofthe two conformations, (257a) would be expected to be less stable because of the 1,3-diaxial interaction between the Me and Z group. Conformation (257b), which has the methyl group in a pseudoequatorial orientation, has no such interaction and thus would be expected to be the favoured conformation. Ester (257), as do all of compounds (256-261), exhibit a ^NMR spectrum complicated by the fact that almost all ofthe signals are multiplets i.e.( X H N M R (400 MHz) 5: 1.28 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.57 (d, 3H, J= 7 Hz, - C H C H 3 ) , 2.82-2.88 (m, 1H, H c ) , 2.93-3.00 (m, 1H, H b ) , 3.09-3.20 (m, 2H, ILj), 3.31-3.40 (m, 1H, H e ) , 3.74-3.78 (m, 1H, H a ) , 4.18 (q, 2H, J= 7 Hz, -OCH2CH3)). A series of decoupling experiments were performed and proved useful in determining which protons were coupled together, however, most ofthe original multiplets were only sharpened rather than being resolved. In a series of NOE difference 99 experiments irradiation ofthe signal at 8 1.57 ( -CHCH3) led to enhancement of the signals at 8 3.31-3.40 (H e ) and 8 3.74-3.78 (H a ) while irradiation ofthe signal at 8 3.36 (H e) led to the enhancement ofthe signal at 8 1.57 ( -CHCH3). Irradiation ofthe signal at 8 3.76 (H a) led to the enhancement ofthe signals at 8 1.57 ( -CHCH3) and 8 2.93-3.00 (HD). These NOE difference experiments might suggest that ester (257) adopts the conformation (257a) where the methyl group and H a are in a pseudoaxial orientation and a strong N O E enhancement should be observed. Closer inspection of a molecular model of (257b), however, reveals that the methyl group and H a are still relatively close together in proximity and an NOE enhancement between these groups would be expected. Thus without any conclusive evidence, it was assumed that in each case, the half chair conformation in which the alkyl group adopts a pseudoequatorial orientation was preferred due to steric factors (Figure 7). 261 Z = . C N Figure 7: Favoured half-chair conformations ofthe Diels-Alder adducts (257-261). 101 4.2 Diels-Alder reactions of dienes with methyl vinyl ketone (MVK) It has been reported previously in this laboratory that, under thermal conditions, Diels-Alder reactions of some 1,2-bis-exocyclic dienes with dienophiles is neither stereo-nor regioselective. 16 Previous experimentation has shown that addition of a Lewis acid, such as BF3«Et20, to the Diels-Alder reaction improves the stereo- and regioselectivity of the Diels-Alder reaction as well as the rate of reaction. 16,73 This effect of BF3-Et20 on these Diels-Alder reactions can be rationalized using frontier molecular orbital theory. ^3, 7^-11 jja the Diels-Alder reaction, the principle interaction is between the HOMO ofthe diene and the L U M O ofthe dienophile (Figure 8). The energy difference between these two orbitals governs the overall rate ofthe Diels-Alder reaction. Addition of a Lewis acid such as BF3-Et20, which co-ordinates with the carbonyl group ofthe dienophile, lowers the energy ofthe HOMO and L U M O orbitals ofthe dienophile. This makes the HOMO (diene) -> L U M O (dienophile) transition less energetic and thus increases the rate ofthe reaction. LUMO LUMO LUMO Energy HOMO Energy LUMO HOMO diene dienophile diene dienophile Without Lewis acid catalyst With Lewis acid catalyst Figure 8: The effect of a Lewis acid on the energies of the HOMO and L U M O ofthe dienophile in the Diels-Alder reaction. 102 Addition of BF 3 « E t 2 0 to M V K also causes the L U M O ofthe M V K to have greater polarization, with the a-carbon and the P-carbon having orbitals with larger and smaller co-efficients as compared to those of uncoordinated M V K (Figure 9). This increased polarization in M V K increases the regio selectivity ofthe reaction. R HOMO R HOMO O - B F 3 -LUMO Without Lewis acid catalyst With Lewis acid catalyst Figure 9: Orbitals showing the increased polarization ofthe L U M O ofthe double bond in the dienophile in the Lewis acid catalyzed Diels-Alder reaction Finally, the endo selectivity ofthe Diels-Alder reactions (from secondary orbital interactions) is greatly enhanced because of an increase in the L U M O coefficient ofthe carbonyl carbon atom (Figure 10). 103 HOMO LUMO Without Lewis acid catalyst With Lewis acid catalyst Figure 10: Frontier orbitals showing the increased secondary orbital interaction in the Lewis-acid catalyzed Diels-Alder reaction Therefore BF3»Et20 was chosen as a Lewis acid catalyst for the Diels-Alder reactions ofthe cyclobutanecarboxylates (221) with M V K . The results ofthe reactions are summarized in Table 20. The stereochemistry of each ofthe products was assigned on the basis of N M R data and a series of decoupling and NOE experiments. Table 20: Diels-Alder reactions ofthe cyclobutanecarboxylates 221 with M V K g MVK "C0 2 Et B F 3 - E t 2 0 R CH 2 CI 2 221 0 C 0 2 E t R 252 Entry Substrate Reaction Time Product Yield (%t_ 3 h Et 55 ^ c o 2 58% Et 14 1.5 h r 54 XC^Et ;-Pr-8 h c X02Et 234 88% x;o2Et 11 50% •*C02Et O /-Pr 265 2 h ^ C O o E t /-Pr 233 84% O /-Pr 266 8hc -Hex-. — i2Et 236 75% X O z E t O c-Hex 267 105 Table 20 (cont.) 3.5 h c-Hex 235 Y 87% ^ C C ^ E r . c-Hex 268 a M V K ( 5 equiv.), BF 3 «Et 2 0 (1 equiv.), C H 2 C 1 2 , -78°C DYield of purified product that had been kept under reduced pressure (vacuum pump) for 2h. cThe reaction temperature was -48°C for this reaction. For example, addition of BF3»Et 20 (1 equiv.) to a mixture of (233) and M V K (5 equiv.) in C H 2 C 1 2 at -78°C, followed by a reaction time of 2 h, work-up and radial chromatography, gave an 84% yield of (266) (Table 20, Entry 4). The A H N M R spectrum of (266) displayed the expected signals for an isopropyl group (two 3-proton doublets at 8 0.82 and 8 0.92, J= 7 Hz and a 1-proton multiplet at 8 1.57-1.65), an ethyl ester moiety (a 3-proton triplet at 8 1.26, J= 7 Hz and a 2-proton multiplet at 8 4.15) and a methyl ketone moiety (a 3-proton singlet at 8 2.15). 106 Other assigned protons included: H a , a 1-proton multiplet at 8 3 .62-3 .67; H D , a 1-proton multiplet at 8 2 .72-2 .78; 2 x Hf, a 2-proton multiplet at 8 1.95-2.01; one of H g , a 1-proton multiplet at 8 1.75-1.85; one of Hg, a 1-proton multiplet at 8 1.85-1.94; and H c and HQ 1, a 2-proton multiplet at 8 2 .50-2.59. These spectral assignments were confirmed by a series of decoupling and NOE experiments. Only the key data required to determine the orientation ofthe isopropyl group will be reported here. Complete decoupling and NOE data can be found on page 2 2 1 of the experimental. In the decoupling experiments, irradiation at 8 1.60 ( -CH(CH 3 ) 2 ) converted the doublets at 8 0 .82 (one o f -CH(CH 3 ) 2 ) and 8 0 .92 (one o f -CH(CH 3 ) 2 ) into singlets; irradiation at 8 2 .55 (He, H Q ) shriplified the multiplet at 8 2 .80-2 .87 (Hg) into a doublet of doublets, J - 9, 3 Hz [thus, ^ HeHg(a) = 9 Hz and ^ HeHg(P) = 3 Hz]- Irradiation at 8 1.80 (one of Hg) converted the multiplet at 8 2 .80-2 .87 (Hg) into a doublet of doublets (J= 9, 6 Hz) [thus, ^ HeHd = 6 H 2 ! In a series of NOE difference experiments, irradiation at 8 3.65 (H a ) caused enhancement ofthe signals at 8 0 .82 (one o f -CH(CH 3 ) 2 ) , 8 0 .92 (one o f - C H ( C H 3 ) 2 , 8 1.26 ( - O C H 2 C H 3 ) and 8 2 .72-2 .78 (H D) as depicted in the diagram above. Thus, the isopropyl group is cis to the proton H a and adopts a pseudoaxial orientation. If this is 266 z 1 = CH 3 CO Z 2 = Et02C-107 true, then proton Hg should assume a pseudoaxial orientation. This is supported by the NOE experiments. Saturation ofthe signal at 8 2.82 (Hg) caused enhancement ofthe signals at 8 1.75-1.85 (H g(p)), 8 1.95-2.01 (Hf(3)), 8 2.15 (CH3CO-), and 8 2.54-2.59 (HQ). There is also confirmation ofthe proposed conformation of (266) from the coupling constant between protons Hg and Hg(cc) (J =9 Hz). Thus, in summary, it is demonstrated that the isopropyl group is cis to the proton H a and that the cyclohexene ring of (266) adopts a half-chair conformation with both the proton H e and the isopropyl group in pseudoaxial orientations. The I R spectrum of (266) showed absorptions at 1731 and 1709 c m - i for the stretching frequencies ofthe two different carbonyl groups. High resolution mass spectrometry confirmed that compound 2 6 6 has a molecular formula of C16H24O3. Similar conformational analyses were performed on the other cycloaddition products ( 1 1 , 1 4 , 2 6 5 , 2 6 7 , 268 , Table 26) to determine the relative stereochemistry and orientation ofthe alkyl group of these compounds. The results are summarized in Figures 11-15 showing key data from decoupling and NOE experiments and the conformation of each compound. In each case except for (14) the alkyl substituent on C-5 adopts a pseudoaxial orientation. For esters ( 265) and (267) this is due presumably to minimize the steric repulsion between the alkyl substituent and the neighbouring acetyl group. For compound (14) the conformation where both the acetyl and methyl group adopt a pseudoequatorial orientation is favoured. Presumably the steric repulsion between the acetyl and methyl group is of less consequence than the 1,3-diaxial interactions which would occur between H f and the Me group on (14) i f the Me group adopted a pseudoaxial orientation. Support for these conformational assignments has appeared in a paper by Houk^ 8 there M M 2 calculations were performed to determine the most stable reactant conformations and orientation (pseudoaxial or pseudoequatorial) ofthe R group on esters (255-259) , (11), (14) and (265-266) . The computational results were in agreement with the experimental results for all compounds except for (265). For ester (265) , Houk 108 predicted that the pseudoequatorial orientation ofthe P-z-Pr group would be preferred over the pseudoaxial orientation.^ Houk doesn't have a clear explanation for why experimentally the P-z-Pr group is in a pseudoaxial orientation, but he suggests that steric repulsion between the z-Pr group and neighbouring acetyl group (when both substituents are in a pseudoequatorial orientation) promotes the pseudoaxial orientation ofthe P-z-Pr group. (JHcHe = 11 Hz, JHcHf = 3 Hz, JHcHd = 8 Hz) Z 1 = CH 3 CO Z 2 = Et0 2 C-Figure 11: Relative configuration and preferred conformation of ester (14). (ddd, J= 12, 5, 2.5 Hz) Z 1 = CH3CO Z 2 = Et0 2 C-Figure 12: Relative configuration and preferred conformation of ester (11). 109 (ddd, J = 8, 7, 3 Hz) JHcHd = 7 Hz, JHcHf(3) = 8 Hz, JHcHf(<x) = 3 Hz Z 1 " C H 3 C ° Z 2 = E t 0 2 C -Figure 13: Relative configuration and preferred coriformation of ester (265). Figure 14: Relative configuration and preferred conformation of ester (267). 110 Figure 15: Relative configuration and preferred conformation of ester (268). I l l 5. Thermal ring opening ofthe functionalized bicyclo[4.2.0]oct-l(6)-enes 5.1 Introduction and / or 269 270 ( 4 2 ) Thermolysis of cyclobutene results in an electrocychc ring opening to produce 1,3-butadiene. This process proceeds via a thermally-allowed conrotatory pathway. 1 The C-3 substituted cyclobutene (1 ) can open via one or both of two conrotatory pathways to give one or both ofthe "inward" (270) or "outward" (269) rotation products (Equation 42). Houk proposed that it was the electronic nature of certain substituents that determines the direction of rotation (inward or outward) ofthe substituent. i2-15 Based upon ab initio calculations, Houk predicted that groups that are good electron donors should prefer outward rotation while strongly electron withdrawing groups that are good electron acceptors should favour inward rotation. i 3 From the work described above, a variety of bicyclo[4.2.0]oct-l(6)-enes with different C-7 substituents ( - C H 2 O H , CC^Et, C O 2 H , CN) were available and thus the thermal ring opening reaction ofthe substrates could be investigated. 5.2 Preparative thermal ring opening ofthe functionalized bicyclo[4.2.0]oct-l(6)-enes It is well known that cyclobutenes (1 ) in which X is a methyl or substituted methyl afforded exclusively the outward rotation product (269). Computations by Houk have predicted that, when W = CH3 outward rotation should be favoured by 5.3 kcal/mol.79 Houk interprets this as a steric effect which, in part, involves repulsion between the filled 112 orbital ofthe methyl and 8 orbital ofthe breaking bond.^9 Thus, we would expect substrate (262), which has a C H 2 O H substituent, to undergo ring opening to give exclusively the product resulting from outward rotation (Equation 43). NC NC-NC-NC mesitylene *CH2OH reflux, 4 h, 84% 262 271 A solution of (262) in dry mesitylene was refluxed at 165°C for 4 h under an argon atmosphere. Analysis ofthe crude reaction mixture by GLC and TLC indicated that only one product had been formed. The reaction mixture was cooled to room temperature and the mesitylene was removed by radial chromatography on silica gel. The N M R spectrum ofthe crude product confirmed that only diene (271) had been produced. Recrystallization (1:1 pet. ether:ether) afforded an 84% yield of (271) as colourless crystals (m.p. 118-119°C). The spectral data for (271) was in accord with the assigned structure. The l H N M R spectrum of (271) displayed the expected signals for a - C H 2 O H group (a 1-proton broad singlet at 8 1.55 and a 2-proton doublet at 8 4.32, J= 7 Hz), two allyhc methylene groups (two 2-proton singlets at 8 3.15 and 8 3.34, respectively), and three olefinic protons ( H c and H D , two 1-proton singlets at 8 5.20 and 5.42, respectively, and H a , a 1-proton triplet at 8 6.13, J 7 Hz). The geometry of (271) was assigned on the basis of N O E difference experiments. Thus, irradiation at 8 3.15 (H^) caused enhancement ofthe signal at 8 5.20 (H c ) while irradiation at 8 3.34 (H e ) caused enhancement ofthe signal at 8 4.32 (-CH2OH). Irradiation at 8 4.32 ( -CH2OH) caused enhancement ofthe signals at 8 3.34 (H e ) and 8 6.13 (H a) while irradiation at 8 5.20 (H c ) 113 caused enhancement ofthe signals at 8 3.15 (Hj) and 8 5.42 (H D). Irradiation at 8 5.42 (H D) caused enhancement ofthe signals at 8 5.20 (H c ) and 8 6.13 (H a ) while irradiation at 8 6.13 (H a ) caused enhancement ofthe signals at 8 4.32 (-CH2OH) and 8 5.42 (HD). These experiments are summarized in the formula (271) given below. 271 Using a procedure similar to that reported above, the bicyclo[4.2.0]oct-l(6)-enes (255-262) (Table 21) and ( 11 ,14 , 265-268) (Table 22) were thermolyzed. The ratio of the products was determined by A H N M R analysis on the crude product by integration of the signals H a on the outward rotation (273 or 25) and H D on the inward rotation (274 or 26) isomers (Tables 21 and 22). The signals H a and H D on (273, 274, 25 and 26) were chosen as they were well resolved from .other signals in the A H N M R spectrum ofthe mixture, often appeared as broad singlets, and had chemical shifts close enough to each other such that the integration ratios were more accurate. To confirm that these integration ratios were accurate, spectra were often replotted and reintegrated and the ratios of other distinct signals belonging to the inward and rotation isomers in the A H N M R ofthe crude mixture were determined and compared with the ratio of H a to H D . To confirm that the thermolysis products were stable under the reaction conditions employed, a small sample of each ofthe purified products (273 or 25) and (274 or 26) were heated seperately as a CgDg solution in a sealed glass tube. After being subjected 114 to thermolysis conditions the I f l -NMR spectrum of each product was examined. There was no indication of product rearrangement and thus each ofthe thermolysis products was found to be stable under the conditions employed. For example, in one experiment, the ester (258) (Table 21, Entry 4) was thermolyzed and the solvent was removed to give a crude product. Integration ofthe signals due to H a (a 1-proton broad singlet at 8 5.35) in (279) and Ffjj (a 1-proton broad singlet at 8 5.30) in (280) in the N M R spectrum of this material showed that the outward (279) to inward (280) rotation isomers had been produced in a ratio of 1:1.5. The crude product was subjected to radial chromatography on silica gel to give the separated outward and inward rotation products in yields of 32 percent and 44 percent, respectively. The experimental procedure and overall yields of both isomers were similar of the other experiments summarized in table 21. For example, the ester (259) (Table 21, Entry 4) was thermolyzed and the solvent was removed to give a crude product. Integration of the signals due to H a (a 1-proton broad singlet at 8 5.35) in (279) and H D (a 1-proton broad singlet at 8 5.30) in (280) in the N M R spectrum of this material showed that the outward (279) to inward (280) rotation isomers had been produced in a ratio of 1:1.6. The crude product was subjected to radial chromatography on silica gel to give the separated outward and inward rotation products in yields of 27 percent and 41 percent, respectively. 115 Table 21: Preparative thermal ring opening of the functionalized bicyclo[4.2.0]oct-l(6)-Ha enes(272) NC NC NC-NC-mesitylene reflux, 6 h NC 272 274 Entry Substrate Outward Inward Rotation ^ H N M R Yield Rotation Product Product 274 ratioa (%)b> c 273 273:274 273 274 id 2e 3« NC NC-NC-^DC^Et NC 255 NC NC-NC-T ^ E t 256 NC NC-NC-NC 257 NC NC-NC-XO2ET. NC /-Pr 258 NC NC-NC-XC^Et NC /-Pr 259 NC CC^Et NC 1 275 NC N C — NC I J. CC^Et 277 NC N C — ' ^ ^ > NC I J. COzEt 277 NC N C M l NC ,_pr r>f /-Pr COzEt 279 NC NC -Y NC ,_ o r r-i /-Pr CC^Et 279 NC NC 276 NC N C - - ^ ^ NC I 278 NC N C - s J ^ C C ^ E t NC I 278 NC NC '•-/-Pr 280 NC NC-NC-NC /-Pr 280 OjEt 18:1 2.6:1 4.3:1 1:1.5 1:1.6 80 5 53 21 56 14 32 44 27 41 116 Table 21 (cont.) NC NC NC aThe ratio ofthe products was determined directly by the integration ofthe signals due to and H g (formulas 273 and 274). byield of purified, recrystallized product. cEach ofthe products was found to be stable under the thermolysis conditions employed. modified procedure where a reaction temperature of 145°C and a time of 3.5 h was used. e A modified procedure where the reaction time was 4 hours was used. 117 Each ofthe experiments in Table 22 was carried out in a fashion similar to that in Table 22. For example, a solution of compound (14) in dry mesitylene was heated to 165°C and refluxed for 4 h under argon atmosphere (Table 22, Entry 1). The mesitylene showed a ratio of outward rotation diene (15) to inward rotation diene (16) of 1:1. The mixture was again subjected to radial chromatography and trace amounts of solvent removed (vacuum pump) from the acquired liquids to give dienes (15) and (16) in 37% and 38% yields, respectively. Other experiments is Table 22 gave similar overall yields ranging from 67 percent (Entry 2) to 87 percent (Entry 5). In each case, all ofthe products were fully characterized. Stereochemical assignments were made by N M R spectroscopy, primarily NOE difference experiments. For example, the spectral data for (15) and (16) were in accord with the assigned structures. was removed by radial chromatography and the A H N M R spectrum ofthe crude product 15 1 1 8 Table 22: Preparative thermal ring opening ofthe functionalized bicyclo[4.2.0]oct-l(6)-enes(23) 23 25 26 Entry Substrate (23) Outward Inward Rotation ^ H N M R Yield Rotation Product (26) Ratio 3 (%)b, c Product (25) 25:26 25 26 2 3 4 119 Table 22 (cont.) 5 6 aThe ratio of products was determined directly by the integration ofthe signals due to EL\ and Hg (formulas 25 and 26). byield of purified product that had been kept under a vacuum pump for 2 h. cEach of the products was found to be stable under the thermolysis conditions employed. 120 The A H N M R spectrum of (15) exhibited the signals for three olefinic protons (H a , a 1-proton singlet at 8 5.80; H D , a 1-proton doublet of doublets at 8 5.00, J = 2, 2 Hz; and H c , a 1-proton doublet at 8 4.83, J= 2 Hz). The signal due to (a 1-proton broad quartet, J= 7 Hz) was observed at 8 4.52, suggesting that it is in the deshielding cone of the carbonyl group ofthe ester moiety and that the double bond must have an (£)-geometry. The assigned steroechemistry of (15) was consistent with A H N M R NOE difference experiments. Thus, irradiation at 8 1.15 ( -CHCH3) caused enhancement ofthe signals at 8 2.50-2.55 (H e ) and 8 4.52 (H^) and irradiation at 8 5.80 (H a ) caused enhancement ofthe signal at 8 5.00 (H D). The A H N M R spectrum of (16) was similar to, but slightly different from, that of (15) . Most notably, the chemical shift of H j (a 1-proton multiplet) appeared at 8 2.60-2.65, which suggests the double bond had a (Z)-geometry. The order ofthe chemical shifts ofthe three olefinic protons in (16) was slightly different from those of (15). In (16) , the chemical shifts of H a (a 1-proton doublet, J= 2 Hz), H D (a 1-proton broad singlet) and HQ (a 1-proton broad singlet) were 8 5.59, 8 4.80, and 8 4.91 ppm respectively. Thus we see that though H a remains as the most downfield proton, H D is 16 121 now upfield of H c as compared to outward rotation diene (15). The two differences in the N M R spectra ofthe outward rotation (15) and inward rotation (16) isomers were also observed with other pairs of thermolyses products and the results are summarized in Table 15. The assigned stereochemistry of (16) was consistent with Iff N M R NOE difference experiments. Thus, irradiation at 8 1.0 ( -CHCH3) caused enhancement ofthe signals at 8 2.45 (H e), 8 2.60-2.65 (H d ) , and 8 5.59 (H a ) while irradiation at 8 2.60 (H d ) caused enhancement ofthe signals at 8 1.60-1.70 (one o fH g ) , 8 1.00 ( -CHCH3) and 8 5.59 (H a). Irradiation at 8 4.78 (H b ) caused enhancement ofthe signal at 8 4.91 (H c ) while irradiation at 8 4.91 (H c ) caused enhancement ofthe signals at 8 4.80 (Hp) and 8 2.49 (one ofHf). Irradiation of 8 5.59 (H a ) caused enhancement ofthe signals at 8 2.60-2.65 (H d ) and 8 1.00 ( -CHCH3). 122 Table 23: Partial lK N M R Data for dienes (291) and (292) HF He 0 H b ^ / H a R Hd C 0 2 E t 291 ^ H b YVY C° 2 B O R* Hd HA 292 Entry Outward Inward R 8 of H d 8 of H a 8 of Ffjj 8 of FL^ Rotation Rotation Diene Diene (291) (292) 1 15 p-Me 4.52 5.80 5.00 4.83 2 16 p-Me 2.60- 5.59 4.80 4.91 2.65 3 12 cc-Me 4.54- 5.79 5.00 4.87 4.63 4 13 cx-Me 2.90- 5.72 4.86 5.05 2.98 5 283 P-z-Pr 4.08- 5.83 4.91 4.76 4.17 6 284 P-z-Pr 2.26- 5.59 4.80 4.96 2.33 7 285 a-z-Pr 4.43 5.81 4.95 4.82 8 286 a-z-Pr 2.49- 5.68 4.87 5.02 2.55 123 Table 23 (cont.) 9 287 p-c-Hex 4.18 5.83 4.88 4.75 10 288 p-c-Hex 2.38 5.53 4.77 4.94 11 289 a-c-Hex 4.48 5.82 4.93 4.83 12 290 a-c-Hex 2.48- 5.66 4.85 5.03 2.62 5.3 Small Scale Thermal Ring Opening ofthe Functionalized Bicyclo[4.2.0]oct-1(6)-enes With one exception, each ofthe thermolyses were carried out by heating a solution ofthe appropriate bicyclo[4.2.0]oct-l(6)-ene (272) or (23) in either dry deuteriobenzene or deuteriomethylene chloride in a sealed tube at 160-165°C (4-6 h). For substrate (255), the reaction was carried out at 143- 145°C (3.5 h) to avoid partial product isomerization to the corresponding P-y unsaturated ester. There were several advantages to this procedure. Firstly, the product ratios can be determined directly by integration ofthe appropriate olefinic protons in the N M R spectrum ofthe crude reaction mixture. Secondly, since very little ofthe starting material is required for the reaction, the experiments can be carried out in duplicate and triplicate, thus allowing a more statistically accurate ratio ofthe thermolysis products to be determined. A summary ofthe results can be seen in Tables 24 through 28. 124 Table 24: Small scale thermolysis ofthe substituted 7-(ethoxycarbonyl) bicyclo[4.2.0]oct-l(6)-enes of general structure (293) NC NC NC 293 294 295 255 R = H 275 R = H 276 R = H 257 R = Me 277 R = Me 278 R = Me 259 R = z - P r 279 R = z- Pr 280 R = i!- Pr 261 R = c - Hex 281 R = c - Hex 282 R = c - Hex Expt Substrate Solvent Time Temp. Ratio of Products 1 255 C 6 D 6 3.5 h 145°C 16 1 2 255 C 6 D 6 3.5 h 145°C 18 1 3 257 C 6 D 6 4 h 165°C 4.3 1 4 257 C 6 D 6 4 h 165°C 4.1 1 5 257 C 6 D 6 4 h 165°C 4.3 1 6 259 C 6 D 6 6 h 165°C 1 1.5 7 259 C 6 D 6 6 h 165°C 1 1.4 8 259 C 6 D 6 6 h 165°C 1 1.5 9 261 C 6 D 6 6h 165°C 1 1.4 10 261 C 6 D 6 6 h 165°C 1 1.3 11 261 6 h 165°C 1 1.4 125 Table 25: Small scale thermolysis ofthe substituted 7-(ethoxycarbonyl) bicyclo[4.2.0]oct-l(6)-enes of general structure (296) NC NC NC 296 294 205 256 R = Me 277 R = Me 278 R = Me 258 R = z - P r 279 R = z - Pr 280 R = z - P r 260 R = c - Hex 281 R= c - Hex 282 R = c - Hex Expt Substrate Solvent Time Temp. Ratio of Products 12 256 C 6 D 6 4 h 165°C 2.5 1 13 256 C 6 D 6 4 h 165°C 2.6 1 14 256 C 6 D 6 4 h 165°C 2.7 1 15 258 C 6 D 6 6 h 165°C 1 1.5 16 258 C 6 D 6 6 h 165°C 1 1.4 17 260 C 6 D 6 6 h 165°C 1 1.5 18 260 C 6 D 6 6 h 165°C 1 1.4 126 Table 26: Small scale thermolysis ofthe substituted 7-(ethoxycarbonyD bicyclo[4.2.0]oct-l(6Venes of general structure (297) 11 R = Me 266 R = z - P r 268 R = c - H e x 12 R = Me 285 R = / - Pr 289 R = c - Hex 13 R = Me 286 R = / - P r 290 R = c - H e x Expt Substrate Solvent Time Temp. Ratio of Products 19 11 C 6 D 6 4 h 165°C 10 1 20 11 C 6 D 6 4 h 165°C 11 1 21 266 C 6 D 6 4 h 165°C 4.0 1 22 266 6h 165°C 3.6 1 23 266 C 6 D 6 6 h 165°C 4.3 1 24 268 C 6 D 6 6 h 165°C 3.8 1 25 268 C6D6 6 h 165°C 3.7 1 127 Table 27: Small Scale thermolysis ofthe substituted 7-(ethoxycarbonyl) bicyclo[4.2.0]oct-l(6)-enes of general structure (300) O R O R C 0 2 E t O C 0 2 E t 300 301 302 14 R = Me 265 R = / - P r 267 R = c - Hex 15 R = Me 283 R = / - P r 287 R = c - Hex 16 R = Me 284 R = / - P r 288 R = c - H e x Expt Substrate Solvent Time Temp. Ratio of Products 26 14 C 6 D 6 4 h 165°C 1.0 1 27 14 C 6 D 6 4 h 165°C 1.0 1 28 265 C 6 D 6 4 h 165°C 1 2.4 29 265 C 6 D 6 4 h 165°C 1 2.2 30 265 C 6 D 6 4 h 165°C 1 2.4 31 267 C 6 D 6 4 h 165°C 1 2.6 32 267 C 6 D 6 4 h 165°C 1 2.5 33 267 4 h 165°C 1 2.8 128 Table 28: Small scale thermolysis of several substituted bicyclo[4.2.0]oct-l(6)-enes of general structure (254) 255 W= 262 W 264 W C 0 2 E t C H 2 O H - C Q 2 H 275 W = - C 0 2 E t 276 W = - C 0 2 E t 271 W = - C H 2 O H 271b W = - C H 2 O H 305 W = - C 0 2 H 306 W = - C 0 2 H Expt Substrate Solvent Time Temp. Ratio of Products 1 255 C 6 D 6 3.5 h 145°C 16 1 2 255 C 6 D 6 3.5 h 145°C 18 1 34 255 C D 2 C 1 2 3.5 h 145°C 17 1 35 262 C 6 D 6 4 h 165°C >99 1 36 262 C 6 D 6 4 h 165°C >99 1 37 264 C 6 D 6 4 h 165°C 7.3 1 38 264 C 6 D 6 4 h 165°C 7.4 1 39 264 C 6 D 6 4 h 165°C 7.0 1 129 Having the results from several series of thermolysis reactions (Tables 21, 22, and 24-28) in hand, it is necessary to interpret these results with respect to both the functional group at C-7 ofthe bicyclo[4.2.0]oct-l(6)-ene and the alkyl group on C-5. To aid in interpretation ofthe results, the orientations ofthe alkyl group on the half chair conformations ofthe thermolysis precursors are summarized in Figure 16. o NC NC R 404 CQ2Et NC-NC NC NC NC CCsEt CC^Et R 400 R 403 (11) R = Me(a) (14) R = Me(e) (266) R = z-Pr (a) (265) R = z-Pr (a) (255) R = H (257) R = Me (e) (255) R = H (256) R = Me (e) (268) R = c-Hex (a) (267) R = c-Hex (a) (259) R = z-Pr (e) (258) R = z-Pr (e) (261) R = c-Hex (e) (260) R = c-Hex (e) (a) = axial (pseudoaxial) (e) — equatorial (pseudoequatorial) Figure 16: Conformational data for the thermolysis precursors (11), (14), (255-261) and (265-268) Compound (255) where R = H structurally is the closest compound to the 3-methoxycarbonylcyclobutene for which Houk performed his calculations. ^ We would expect the steric effects on the outward rotation ofthe ester group to be minimal as R = H for (255) and thus (255) should represent the "parent" compound from which the tendency of an ester group to rotate outward can be determined. Thermolysis of (255) provided the outward and inward rotation products (275) and (276) in an average ratio of 17:1 (Expts 1 and 2, Table 24). The calculated energy of activation difference between the two transition states based upon this ratio is ~2.4 kcal/mol. This is compared to a value of 130 1.7 kcal/mol calculated by Houk and co-workers. 1 3 Although Houk performed his calculations on 3-methoxycarbonyl cyclobutene, this result still suggests the tendency of an ester group to rotate outward may be more than predicted. Thermolysis of (11) where R is an a-Me group gave an 11:1 ratio of outward rotation and inward rotation products (12) and (13) (Expts 19 and 20, Table 26). The decrease in the ratio of outward and inward rotation products presumably results from a weak steric interaction between the a-Me group and the ester moiety in the transition state leading towards the outward rotation product. As the size ofthe a -R group increases from R = Me to R = /-Pr to R = c-hex, this steric effect becomes more pronounced and the ratio of outward to inward rotation products drops further (Expts 21-25, Table 26). The steric interaction between a |3-R group and an ester group is apparently more severe then a steric interaction between an a-R group and an ester group as seen by a comparison ofthe data in Tables 27 and Table 26. When R is a pseudoequatorial P-Me group, the ratio of outward rotation to inward rotation products drops to 1:1 (Expts 26 and 27, Table 27) as compared to 11:1 for an a-Me group (Expts 19 and 20, Table 26). Similarly, pseudoaxial P-/-Pr and P-c-Hex groups hinders outward rotation more than their a counterparts (Expts 28-33, Table 27). In fact, for these substrates, the major product was the inward rotation product, which is contrary to the electronic tendency of the ester function to rotate outwards. There seems to be only a slight increase in inward rotation product for a pseudoaxial P-c-Hex group (1:2.6 outward:inward, Expts 31-33, Table 27) as compared to a pseudoaxial P-/-Pr (1:2.3 outward:inward, Expts 28-30, Table 27). When examining the data on Tables 24 and 25 for substrates which have either a P-R group or an a-R group, we see that the tendency for the ester group to rotate outwards is less than that ofthe parent compound (255) (Expts 1-18, Table 24 and 25). The amount ofthe outward rotation product decreases as the R group increases in size 131 from methyl to isopropyl or cyclohexyl (compare Expts 3-5 with Expts 6-11, Table 24) or (compare Expts 12-14 with Expts 15-18, Table 25). Surprisingly, unlike the data from Tables 26 and 27, the ratios of products obtained from pseudoequatorial P-R groups was similar to that obtained from pseudoequatorial oc-R groups (compare Expts 3-11, Table 24 with Expts 12-18, Table 25). Thus, in terms of steric inhibition towards the outward rotation ofthe ester group, pseudoequatorial a-R and pseudoequatorial P-R groups are similar. The results ofthe thermolysis reactions (Tables 24-28) were published in a paper by Piers and Ellis in 1993.80 "inspired" by this publication, Houk and Nakamura undertook a study designed to predict the experimental results using extensive quantum mechanical calculations and a transition state force field model for the compounds (255-259), (11), (14) and (265-266).78 Houk first performed MM2 calculations to determine the most stable reactant conformations and orientation (pseudoaxial or pseudoequatorial) ofthe R group on reactants (255-259), (11), (14) and (265-266). The computational results were in agreement with the experimental results for all compounds except for (265). For ester (265), Houk predicted that the pseudoequatorial orientation ofthe P-/-Pr group would be preferred over the pseudoaxial orientation.78 Houk doesn't have a clear explanation for why the experimental results differ from his predictions, experimentally the p-/-Pr group is in a pseudoaxial orientation, but he suggests that steric repulsion between the z-Pr group and neighbouring acetyl group (when both substituents are in a pseudoequatorial orientation) promotes the pseudoaxial orientation ofthe P-/-Pr group. Houk determined that there are two possible conformations, chair and twist boat, for each ofthe thermolysis products (Figure 17). 7 8 M M 2 computations were performed to determine the energies of these product conformations (i.e. inward-twist boat, outward chair, inward chair, and outward-twist !32 P-R cm \ a-R i f J \ V, P-quasi axial a-quasi equatorial Reactant fi-i-t m P-quasi equatorial a-quasi axial > Transition state 6 f Product - f t Inward-twist boat Outward-chair Inward-chair Outward-twist boat Figure 17: Product conformations ofthe thermolysis reactions.78 133 boat) for substrates (255-259), (11), (14) and (265-266). The energy difference between these products' conformations was compared with the experimental ratios of products. Houk found no correlation between the experimental ratios of outward and inward pathways and the product stabilities. ^  8 However, when a transition state modeling analysis using ab initio orbital calculations was used to calculate the energies ofthe various transition state structures, a good correlation between the calculated energy difference ofthe outward transition state and inward transition state, and the experimental ratio of products was found. ^ 8 Thermolysis of (264) where W is a carboxylic acid group provided the outward rotation (305) and inward rotation (306) products in an average ratio of 7.2:1 (Expts 37-39, Table 28). This compares to an average value of 17:1 (outward to inward) for the ester (255) (Expts 1, 2, and 34, Table 28). Calculations by Houk have shown that the C O 2 H group prefers outward rotation by 1.5 kcal mol ' l as compared to the ester function which prefers outward rotation by 1.7 kcal moi" 1.14 it is not surprising, therefore, to find that the ratio of outward to inward rotation products for (264) where W is a carboxylic acid group is somewhat less than for (255) where R is an ester group. In summary, the substituted bicyclo[4.2.0]oct-l(6)-enes (255-268), (11) and (14) were thermolyzed and the ratio of outward and inward rotation products compared to the predictions by Houk and co-workers. 12> 13> 14 For simple systems (255), (262), and (264) where steric effects were minimized the results are in good agreement with Houk's calculations. 14 For more complicated systems, those which contain P-R groups on C-5, the electronically induced tendancy for the ester funtion to prefer rotate outward was changed such that the inward rotation product was preferred for substates (265) and (267). This result can be rationalized on the basis of a steric effect between the alkyl group and the ester function in the transition states leading towards the outward and inward rotation products. Finally, Houk has shown that the results of these thermolysis reactions can be rationalized on the basis of ab initio and M M 2 calculations. ^  8 134 IV. EXPERIMENTAL SECTION 1. G E N E R A L 1.1 Data Acquisition and Presentation of Results Infrared (IR) spectra were recorded on liquid films between sodium chloride plates or on potassium bromide pellets using a Perkin-Elmer model 1710 Fourier Transform Infrared (FTIR) Spectrophotometer with internal calibration. Proton nuclear magnetic resonance (^H NMR) spectra were recorded on a Bruker model WH-400 spectrometer using deuteriochloroform ( C D C I 3 ) as the solvent unless otherwise noted. Signal positions are given in 8 units in parts per million from tetramethylsilane and are measured relative to the chloroform signal at 8 7.24 or the benzene signal at 8 7.15. The multiphcity, number of protons, coupling constants, and assignments (when known) are given in parentheses. Coupling constants (/values) are given in Hertz (Hz). Abbreviations used are: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. When a hydrogen was observed to be coupled with the same coupling constant to two, three, or four protons which are chemically and magnetically non-equivalent, the designation dd, ddd, dddd, and dddt are used instead of using t, q, quintet and hextet, respectively. For compounds exhibiting AB and A B X type spin systems, the quoted values for chemical shifts and coupling constants are measured as if they were first order systems, although these values only approximate the real values. Decoupling experiments refer to i H - ^ H spin decoupling experiments. The nuclear Overhauser enhancement (NOE) difference experiments were recorded on a Bruker WH-400 N M R spectrometer. 4 I -1H Homonuclear correlation (COSY) experiments were recorded on a Bruker AC-200 spectrometer. The tin-proton coupling constants (^sn-H) a r e give11 a s m average ofthe H^Sn and H^Sn values (unless otherwise stated). Carbon nuclear magnetic resonance (^ 3 C NMR) spectra were recorded on a Varian model XL-300 spectrometer at 75.3 MHz, or on Bruker AM-200 (50.3 MHz), AM-400 (100.4 MHz) or AMX-500 (125.8 MHz) spectrometers, using deuteriochloroform as the solvent unless 135 otherwise noted. Signal positions are given in 8 units in parts per million and are measured relative to the chloroform signal at 8 77.0.81 Low resolution electron impact mass spectra were recorded on an AEIMS9/DS55SM or on a KRATOS MS50/DS55SM mass spectrometer. High resolution electron impact mass spectra were recorded on a KRATOS MS50/DS55SM mass spectrometer.For compounds containing the M ^ S n moiety, high resolution mass spectrometric measurements are based on 120 Sn and were made on the (M + -Me) signal. Elemental analyses were performed on a Carlo erba C H N elemental analyzer, model 1106, at University of British Columbia Microanalytical Laboratory. Gas-hquid chromatography (GLC) analyses were performed on a Hewlett-Packard model 5880A or 5890 capillary chromatograph, both using flame ionization detectors and a 25 m x 0.32 mm fused silica column coated with cross-linked 5% phenylmethyl silicone. Thin layer chromatography (TLC) was carried out on commercially available aluminum backed silica gel plates (E. Merck, type 5554, 0.2 mm). Visualization was accomplished with ultraviolet light (254 nm), and/or a 5% aqueous solution of ammonium molybdate in 10% aqueous sulfuric acid (w/v). Flash chromatography was performed using 230-400 mesh silica gel (E. Merck, Silica Gel 60). Radial chromatography^ was done on a Chromatotron Model 7924 using 1, 2, or 4 mm thick radial plates (silica gel 60, PF 254, with calcium sulfate, E. Merck #7749). Melting points were measured on a Fisher-Johns melting point apparatus and are uncorrected. Distillation temperatures refer to air-bath temperatures of bulb-to-bulb (Kugelrohr) distillations and are uncorrected. Unless otherwise stated, all reactions were carried out under an atmosphere of dry argon using glassware that had been thoroughly flame and/or oven (~150 °C) dried. Concentration, evaporation or removal of the solvent under reduced pressure (water aspirator) refer to solvent removal via a Buchi rotary evaporator at ~15 Torr. Cold temperatures were maintained by use ofthe following baths: 0°C, ice/water; -20°C, aqueous calcium chloride/C0 2 (27g CaCl/100 mL H 2 0 ) ; -48°C, cyclohexane/C02; 136 -78°C, acetone/C02; -98°C, MeOH/liquid nitrogen. 1.2 Reagents and Solvents Solvents and reagents were purified and dried using established procedures. 8 3 Petroleum ether refers to a hydrocarbon mixture with bp 35-60°C. Ether refers to diethyl ether. Ether and TEDF were distilled from sodium benzophenone ketyl. Benzene, dichloromethane, dhsopropylamine, DMF, DMSO, HMPA, acetonitrile, mesitylene, and pyridine were refluxed over and then distilled from calcium hydride. DMF, HMPA, and pyridine were stored over 4A molecular sieves. Sodium was added to EtOH and EtOH was distilled from the resulting solution of sodium ethoxide. Solutions of methylhthium (LiBr complex in ether) and butyUithium (in hexane) were obtained from Aldrich Chemical Co., Inc. and were standardized using the procedure of Kofron and Baclawski.84 Lithium diisopropylamide (/-Pr 2NLi) solution was prepared by the addition of a solution of butyUithium (1.0 equiv.) in hexane to a solution of dhsopropylamine (1.1 equiv.) in THF at -78°C. The resulting colourless or faintly yellow solution was stirred at 0°C for ten minutes prior to use. Aqueous N H 4 C I - N H 4 O H solution (pH 8) was prepared by the addition of 50 mL of aqueous ammonia (58%) to 950 mL of saturated aqueous ammonium chloride. Boron trifluoride-ether ate was purified by distillation from calcium hydride (1 g per 250 mL of B F 3 E t 2 0 ) under reduced pressure (60 °C/20 Torr) . 8 5 137 Preparation of cyclohexylethanal (131) O H 131 To a stirred mixture of pyridinium chlorochromate (33.7g, 156 mmol) and sodium acetate (3.2g, 39 mmol) in dry CH2CI2 (200 mL) was added a solution of commercially available 2-cyclohexylethanol (308) (10.0 g, 78.0 mmol) in dry C H 2 C l 2 (300 mL). The mixture was stirred at room temperature for 2 hours. Diethyl ether (400 mL) was added and the resultant mixture was filtered through a column of Florisil (6 cm diameter, 7.5 cm depth). The column was eluted with 1 L of Et20. Concentration ofthe combined eluate, followed by distillation (50-56 °C/15 Torr) ofthe remaining liquid, gave 9.03 g (92%) of cyclohexylethanal (4), a colourless oil that exhibited IR (neat): 1725, 1441 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 5: 0.95-1.10 (m, 2H), 1.10-1.23 (m, 1H), 1.25-1.37 (m,2H), 1.65-1.80 (m, 5H), 1.85-1.95 (m, 1H, -CHR 2 ) , 2.29 (dd, 2H, J= 6, 2 Hz, -CH 2 CHO) , 9.75 (t, 1H, J= 2 Hz, -CHO); Exact Mass calcd. for C 8 H 1 4 0 ( M + - 1 ) : 125.0966; found: 125.0960. 2. General Procedure 1: Preparation of the Ll-dibromoolefins (117)43 R Br H Br 117 To a solution of C B ^ (2 equiv.) in dry CH2CI2 (-5.3 ml ./mmol of aldehyde substrate) was added slowly (at a rate such that the temperature ofthe reaction mixture remained below 138 50°C) a solution of triphenylphosphine (4 equiv.) in dry CH2CI2 (-5.3 mL/mmol of aldehyde substrate). After the resultant mixture had been stirred for 5 min., a solution ofthe appropriate aldehyde (1 equiv.) in dry C H 2 C 1 2 (-10.6 mL/mmol of aldehyde) was added over a period of 10 min. and the mixture was then stirred at room temperature for an additional 30 min. Pentane (three-quarters the volume ofthe total volume ofthe reaction mixture) was added and the resultant mixture was filtered through a column of Florisil (6 cm diameter, 1.65 g Florisil/mmol aldehyde). The column was eluted with pentane (1.5 times the volume ofthe total volume of the reaction mixture). The combined eluate was concentrated and the remaining oil was distilled via bulb-to-bulb distillation to afford the corresponding dibromoolefin. Preparation of Ll-dibromo-3-methyl-l-butene (200)86,43 Following general procedure 1 outlined above, commercially available 2-methylpropanal (198) was converted into the (ubromoolefin (200). The following amounts of reagents and solvents were used: CBr4 (36.8 g, 111 mmol) in 300 mL dry CH2CI2, triphenylphosphine (58.2 g, 222 mmol) in 300 mL dry CH2CI2, 2-methylpropanal (198) (4.00 g, 55.5 mmol) in 600 mL dry C H 2 C 1 2 . Normal workup, followed by distillation (45-47°C/10 Torr) ofthe material thus obtained, afforded 10.41 g (82%) of l,l-dibromo-3-methyl-l-butene (6) as a colourless oil which exhibited IR (neat): 1609, 1465, 1276, 777 cm" 1 ; lH N M R (400 MHz) 6: 1.03 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 2.57 (m, 1H, -CH(CH 3 ) 2 ) , 6.22 (d, 1H, J= 9 Hz, =CH); 1 3 C N M R (75.3 MHz) 8: 21.2, 33.1, 86.8, 145.1. Anal, calcd. for C 5 H 8 B r 2 : C 26.35, H 3.54; found: C 26.47, H 3.54. Exact Mass calcd. for C 5 H 8 7 9 B r 8 l B r : 227.8974; found: 227.8972. Br 200 139 Preparation of Ll-dibromo-4-methyl-l-pentene (119)43 Br Br 119 Following general procedure 1 outlined above, commercially available 3-methylbutanal (130) was converted into the dibromoolefin (119). The following amounts of reagents and solvents were used: CBr4 (15.4 g, 46.4 mmol) in 125 mL dry CH2CI2, triphenylphosphine (24.3 g, 92.7 mmol) in 125 mL dry CH 2 Cl2 , 3-methylbutanal (130) (2.00 g, 23.2 mmol) in 250 mL dry CH2CI2. Normal workup, followed by distillation (60-63 °C/15 Torr) ofthe material thus obtained, afforded 4.54 g (81 %) of l,l-dibromo-4-methyl-l-pentene (119) as a colourless oil which exhibited JK (neat): 1619, 1466, 1386, 1369, 854, 781 cm" 1 ; 41 N M R (400 MHz) 5: 0.92 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.68-1.80 (m, 1H, -CH(CH 3 ) 2 ) , 1.98 (dd, 2H, j= 7, 7 Hz, =C-CH 2-) , 6.38 (t, 1H, J= 7 Hz, olefinic proton); 1 3 C N M R (50.3 MHz) 5: 22.2, 27.7, 41.8, 88.8, 137.8. Anal, calcd. for C 6 H 1 0 B r 2 : C 29.78, H 4.17; found: C 29.84, H 4.14. Exact Mass calcd. for C 6 H 1 0 7 9 B r 8 1 B r : 241.9129; found: 241.9123. Preparation of Ll-dibromo-3-cyclohexylpropene (120)43 Br Br 120 140 Following general procedure 1 outlined above, commercially available cyclohexylethanal (131) was converted into the dibromoolefin (120). The following amounts of reagents and solvents were used: CBr4 (18.71 g, 56.4 mmol) in 150 mL dry CH2CI2, triphenylphosphine (29.59 g, 112.8 mmol) in 150 mL dry C H 2 C 1 2 , cyclohexylethanal (131) (3.55 g, 28.1 mmol) in 300 mL dry C H 2 C 1 2 . Normal workup, followed by distillation (125-130°C/15 Torr) ofthe material thus obtained, afforded 6.56 g (83%) of l,l-dibromo-3-cyclohexylpropene (120) as a colourless oil which exhibited IR (neat): 1621, 1448, 785 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 5: 0.90-1.05 (m, 2H), 1.10-1.30 (m, 3H), 1.35-1.50 (m, 1H), 1.55-1.90 (m, 5H), 2.05 (dd, 2H,«/= 7, 7 Hz, =C-CH 2-) , 6.42 (t, 1H, J= 7 Hz, olefinic proton); 1 3 C N M R (75.3 MHz) 8: 26.2, 26.3, 32.9, 37.2, 40.6, 88.7, 137.8. Anal, calcd. for C 9 H 1 4 B r 2 : C 38.33, H 5.01; found: C 38.60, H 5.13. Exact Mass calcd. for C 9 H 1 4 7 9 B r 8 1 B r : 281.9443; found: 281.9440. Preparation of l.l-dibromo-2-cyclohexylethene (201) Following general procedure 1 outlined above, commercially available cyclohexanecarboxaldehyde (199) was converted into the dibromoolefin (201). The following amounts of reagents and solvents were used: C B r 4 (36.8 g, 111 mmol) in 300 mL dry CH2CI2, triphenylphosphine (58.2 g, 222 mmol) in 300 mL dry CH2CI2, cyclohexanecarboxaldehyde (199) (6.23 g, 55.5 mmol) in 600 mL dry CH2C1 2 . Normal workup, followed by distillation (85-88 °C/15 Torr) ofthe material thus obtained, afforded 13.29 g (89 %) of l,l-dibromo-2-cyclohexylethene (201) as a colourless oil which exhibited IR (neat): 1611, 1448 Br Br 201 141 cm" 1 ; 4 l NMR (400 MHz) 8: 1.03-1.34 (m, 5H), 1.60-1.81 (m, 5H), 2.20-2.31 (m, 1H, alfylic proton), 6.22 (d, 1H, J= 9 Hz, olefinic proton); 1 3 C N M R (75.3 MHz) 5: 25.5, 25.7, 31.2, 42.4, 87.0, 143.7. Anal, calcd. for C 8 H 1 2 B r 2 : C 35.85, H 4.52; found: C 35.74, H 4.42. Exact Mass calcd. for C 8 H 1 2 7 9 B r 8 1 B r : 267.9287; found: 267.9284. 3. Preparation ofthe 1-alkynes of general structure (309)^0 RO 309 H Preparation of 3-(triisopropylsiloxy)pror>vne (121)^0 H T1PSO 121 To a stirred solution of 2-propyn-l-ol (1.02 g, 18.2 mmol) in dry C H 2 C 1 2 (30 mL) was added sequentially imidazole (1.86 g, 27.3 mmol) and triisopropylsilyl chloride (3.33 g, 17.3 mmol) and the resultant mixture was stirred at room temperature for 2 h. Aqueous N H 4 C I - N H 4 O H (pH 8) (25 mL) was added and the mixture was extracted thoroughly with C H 2 C 1 2 . The combined extracts were washed with brine, dried (MgSC>4) and concentrated. Flash chromatography (35 g silica gel, hexanes) ofthe crude oil obtained and distillation (45-47°C/0.15 Torr) gave 2.75 g (75%, based on (z-Pr)3SiCl) of 3-(triisopropylsiloxy)propyne (121), as a colourless oil that displayed IR (neat): 3313, 2123, 1465, 1107 cm" 1 ; ^ H N M R (400 MHz) 8: 1.06 (d, 18H, J= 6 Hz, ( (CH 3 ) 2 -CH) 3 Si- ) , 1.10 (m, 3H, ( (CH 3 ) 2 -CH) 3 Si-) , 2.46 (t, 1H, J= 2 Hz, =CH), 4.37 (d, 2H, J= 2 Hz, - O C H 2 S i R 3 ) ; 1 3 C N M R (100.4 MHz) 5: 11.9, 17.8, 51.7, 72.5, 82.4. Anal, calcd. for C 1 2 H 2 4 O S i : C 67.86, H 11.39; found: C 67.86, H 11.43. Exact Mass calcd. for C 1 2 H 2 4 O S i : 212.1598; found: 212.1604. 142 Preparation of 3-[(2-methoxyemoxy)methoxy]propyne (122pu / H MEMO 122 To a cold (0°C), stirred solution of 2-propyn-l-ol (1.02 g, 18.2 mmol) and ( i -Pr^NEt (3.53 g, 27.3 mmol) in dry CH2CI2 (30 mL) was added, over a period of 1 minute , 2.16 g (17.3 mmol) of MeOCH.2CH2OCH.2Cl and the resulting mixture was stirred at 0°C for 3.5 h. Hydrochloric acid (2 N, 15 mL) was added and the mixture was extracted with CH2CI2 (3 x 20 mL). The combined extracts were washed with brine, dried (MgS04), and concentrated. Flash chromatography (50 g silica geL 4:1 hexanes-Et20) ofthe rermining crude oil and distillation (65-68°C/10 Torr) ofthe liquid thus obtained gave 1.98 g (79%) of 3-[(2-methoxyethoxy)methoxy]propyne (122), as a colourless oil that showed IR(neat): 3262, 2118, 1454, 1110 cm" 1 ; * H N M R (400 MHz) 5: 2.40 (t, 1H, J= 2 Hz, - O C - H ) , 3.38 (s, 3H, -OCH3), 3.52-3.56 (m, 2H), 3.68-3.72 (m, 2H), 4.22 (d, 2 H , J= 2 Hz, -OCH 2 C=CH), 4.78 (s, 2H, - O C H 2 0 - ) ; 1 3 C N M R (100.4 MHz) 5: 54.1, 58.9, 67.1, 71.6, 74.2, 79.3, 93.8. Anal, calcd. for C 7 H 1 2 0 3 : C 58.32, H 8.39; found: C 58.56, H 8.49. Exact Mass calcd. for C 7 H n 0 3 (M+-1): 143.0704; found: 143.0700. 4 Preparation ofthe ocfj-acetylenic esters 4.1 General Procedure 2: Preparation ofthe a.p-acetylenic esters (18) from L 1-dibromo- l-alkenes^3 R / s - C 0 2 E t 18 143 To a cold (-78 °C), stirred solution ofthe appropriate 1,1-dibromo-l-alkene (117) (1 equiv.) in dry THF (12-13 mL/mmol) was added, dropwise, a solution of «-butylhthium (2.5 equiv.) in hexanes. The mixture was stirred at -78°C for 1 hour, at room temperature for 1 hour and was then recooled to -20°C. Ethyl chloroformate (1.1 equiv.) was added and the mixture was stirred at -20°C for 1 hour and at room temperature for 1 hour. Saturated aqueous NaHCC<3 solution (three-quarter the volume ofthe total volume ofthe reaction mixture) was added and the mixture thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgS04), and concentrated. Flash chromatography ofthe crude product followed by bulb-to-bulb distillation ofthe acquired oil afforded the corresponding a, P- acetylenic ester. Preparation of ethyl 4-cyclohexyl-2-butynoate (126) = C 0 2 E t 126 Following general procedure 2 outlined above, l,l-dibromo-3-cyclohexylpropene (120) was converted into the a, P-acetylenic ester (126). The following amounts of reagents and solvents were used: substrate (120) (2.50 g, 8.86 mmol) in 115 mL dry THF, «-butylhthium (22.2 mmol) in hexanes, and ethyl chloroformate (1.06 g, 9.76 mmol). Normal workup, followed by flash chromatography (75 g silica gel, 95:5 petroleum ether - Et20) ofthe crude product and distillation (90-96°C/12 Torr) ofthe acquired liquid provided 1.55 g (90%) of ethyl 4-cyclohexyl-2-butynoate (126) as a colourless oil which exhibited IR (neat): 2232, 1713, 1249, 1076 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 0.97-1.08 (m, 2H), 1.12-1.30 (m, 2H), 1.32 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.50-1.60 (m, 2H), 1.65-1.87 (m, 5H), 2.25 (d, 2H, J= 7 Hz, =C-CH 2-), 144 4.24 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) ; 1 3 C N M R (100.4 MHz) 5: 14.1, 25.8, 25.9, 26.4, 32.7, 36.7, 61.8, 74.0, 88.6, 153.8. Anal, calcd. for C 1 2 H 1 8 0 2 : C 74.20, H 9.35; found: C 74.40, H 9.41. Exact Mass calcd. for C 1 2 H 1 8 0 2 : 194.1307; found: 194.1309. Preparation of ethyl 5-methyl-2-hexynoate (125) Following general procedure 2 outlined above, l,l-dibromo-4-methyl-l-pentene (119) was converted into the cc,P-acetylenic ester (125). The following amounts of reagents and solvents were used: substrate (119) (4.00 g, 16.5 mmol) in 200 mL dry THF, n-butylhthium (41 mmol) in hexanes, and ethyl chloroformate (1.97 g, 18.1 mmol). Normal workup, followed by flash chromatography (75 g silica gel, 95:5 petroleum ether - Et 2 0) ofthe crude product and distillation (90-100°C/20 Torr) ofthe acquired liquid provided 2.08 g (82%) of ethyl 5-methyl-2-hexynoate (125) as a colourless oil which exhibited IR (neat): 2234, 1713, 1389, 1251 cm" L , ltt N M R (400 MHz) 8: 1.02 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.32 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.88-1.99 (m, 1H, -CH(CH 3 ) 2 ) , 2.24 (d, 2H, J= 6 Hz, - C H 2 O C - ) , 4.22 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) ; 1 3 C N M R (50.3 MHz) 8: 14.0, 22.0, 27.5, 27.7, 61.7, 74.0, 88.4, 153.9. Anal, calcd. for C 9 H 1 4 0 2 : C 70.10, H 9.15; found: C 69.90, H 9.12. Exact Mass calcd. for C 9 H 1 4 0 2 : 154.0994; found: 154.0997. 125 4.2 General Procedure 3: Preparation ofthe a. P-acetylenic esters (18) from 1-alkynes 145 To a cold (-78°C), stirred solution ofthe appropriate 1-alkyne (1 equiv.) in dry THF (4.5-6.5 mL/mmol) was added, dropwise, a solution of methymthium (1 equiv.) in Et20. After the solution had been stirred at -78°C for 15 minutes and at -20°C for 1 hour, ethyl chloroformate (1 equiv.) was added. The resulting mixture was stirred at -20°C for 1 hour and at room temperature for 1 hour. Saturated aqueous N a H C 0 3 solution (equal volume as the total volume ofthe reaction mixture) was added and the mixture was extracted thoroughly with Et20. The combined extracts were washed twice with brine and then were dried (MgS04) and concentrated. Distillation ofthe remaining oil afforded the corresponding a, P-acetylenic ester. Preparation of ethyl 4-(Triisopropylsiloxy)-2-butvnoate (127)^ 0 / = C 0 2 E t TIPSO 127 Following general procedure 3 outlined above, 3-(triisopropylsiloxy)propyne (121) was converted into the a, P-acetylenic ester (127). The following amounts of reagents and solvents were used: substrate (121) (500 mg, 2.36 mmol) in 15 mL dry THF, methyuithium (2.36 mmol), and ethyl chloroformate (256 mg, 2.36 mmol). Normal workup, followed by distillation (98-99°C/0.11 Torr) ofthe remaining oil yielded 512 mg (76%) of ethyl 4-(triisopropylsiloxy)-2-butynoate (127) as a colourless oil that exhibited JJR (neat): 2241, 1718, 1465, 1258 cm" 1 ; ^H N M R (400 MHz) 8: 1.04 (d, 18H, J= 6.0 Hz, ( (CH 3 ) 2 -CH) 3 Si- ) , 1.07-1.14 (m, 3H, ( (CH 3 ) 2 -CH) 3 Si- ) , 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 4.20 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.49 (s, 2H, -OCH 2 C=C-); 1 3 C N M R (100.4 MHz) 8: 11.9, 13.9, 17.7, 51.4, 61.9, 76.4, 85.7, 155.5. Anal, calcd. for C 1 5 H 2 8 0 3 S i : C 63.33, H 9.92; found: C 63.34, H 9.84. Exact Mass calcd. for C 1 2 H 2 1 0 3 S i ( M + - /-Pr): 241.1260; found: 241.1261. 146 Preparation of ethyl 4-[(2-methoxyethoxy)memoxy]-2-butvnoate (128)^ 0 / = C 0 2 E t M E M O 128 Following general procedure 3 outlined above, 3-[(2-methoxyethoxy)methoxy]propyne (122) was converted into the cx,P-acetylenic ester (128). The following amounts of reagents and solvents were used: substrate (122) (500 mg, 3.47 mmol) in 15 mL dry THF, methyUithium (3.47 mmol), and ethyl chloroformate (377 mg, 3.47 mmol). Normal workup, followed by distillation (85-87°C/0.11 Torr) ofthe remaining oil yielded 595 mg (79%) of ethyl 4-[(2-methoxyethoxy) methoxy]-2-butynoate (128) as a colourless oil that exhibited IR (neat): 2240, 1718, 1450, 1254, 1045 cm" 1 ; X H N M R (400 MHz) 5: 1.30 (t, 3H, J= 7.5 Hz, - O C H 2 C H 3 ) , 3.39 (s, 3H, -OCH 3 ) , 3.51-3.55 (m, 2H), 3.69-3.73 (m, 2H), 4.20 (q, 2H, J= 7.5 Hz, - O C H 2 C H 3 ) , 4.34 (s, 2H, -OCH 2 C=), 4.77 (s, 2H, - O C H 2 0 - ) ; 1 3 C N M R (100.4 MHz) 5: 14.0, 54.0, 59.0, 62.1, 67.4, 71.6, 77.8, 83.0, 94.3, 153.1. Anal, calcd. for : C 1 0 H 1 6 O 5 : C 55.55, H 7.46; found: C 55.51, H 7.47. Exact Mass calcd. for C 1 0 H 1 5 O 5 (M+-1): 215.0920; found: 215.0918. 5 Preparation of UtMum(cyano)(trimethylstannyl)cuprate (137)44 [Me 3 SnCuCN]Li 137 To a cold (-20°C), stirred solution of hexamethylditin in dry THF (~5 mL per mmol of Me3SnSnMe3), under an argon atmosphere, was added a solution of methyUithium in diethyl ether (1 equiv.). The resulting pale yeUow-green solution was stirred at -20°C for 20 min and was recooled to -48°C and copper(I) cyanide (1 equiv.) was added. The resulting mixture 147 was stirred at -48°C for 20 min, producing a pale yellow solution of lithium (cyano)(trimethylstannyl)cuprate (137). 6 Preparation of ethyl (E\- and (Z)-3-trimethylstannyl-2-alkenoates50 6.1 General Procedure 4: Preparation of ethyl (E)-3-trimethylstannyl-2-alkenoates (133) To a cold (-78°C), stirred solution of [Me 3SnCuCN]Li (137) (1.09-1.50 equiv.) in dry THF was added dry ethanol (1.09-1.50 equiv.). After 5 min, a solution ofthe appropriate a,P-acetylenic ester (1.0 equiv.) in dry THF was added dropwise and the mixture was stirred at -78°C for 4 h. Aqueous N H 4 C I - N H 4 O H (pH 8) (one-half the volume ofthe total volume ofthe reaction mixture) was added, the mixture was opened to the atmosphere, was allowed to warm to room temperature, and was stirred vigorously until the aqueous phase became deep blue. The phases were separated and the aqueous phase was extracted thoroughly with Et20. The combined organic extracts were washed with brine, dried (MgS04), and concentrated. The crude product was purified by flash or radial chromatography followed by distillation to afford the corresponding ethyl (£')-3-trimethylstannyl-2-alkenoate (133). Me3Sn H 133 148 Preparation of ethyl (ff)-3-trimemylstannyl-2-butenoate (208)44 C 0 2 E t Me3Sn 208 Following general procedure 4 outlined above, commercially available ethyl 2-butynoate (123) was converted into the ester (208). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137) (77.9 mmol) in 350 mL of dry THF, EtOH (4.57 mL, 77.9 mmol) and ethyl 2-butynoate (123) (8.00 g, 71.3 mmol) in 35 mL of dry THF. Flash chromatography (350 g silica geL 200:3 hexanes-Et20) ofthe crude product and distillation (55-60°C/0.12 Torr) ofthe acquired liquid afforded 13.9 g (71%) of ethyl (E)-3-trimethylstannyl-2-butenoate (208) as a colourless oil that exhibited JK (neat): 1714, 1604, 1177, 771 cm" 1 ; A H N M R (400 MHz) 8 : 0.17 (s, 9H, 2 J S n _ H = 54 Hz, -Sn(CH 3 ) 3 ) , 1.27 (t, 3H, J= 1 Hz, - O C H 2 C H 3 ) , 2.37 (d, 3H, J= 2 Hz, 3 J S n . H =50 Hz, =CCH 3 ) , 4.14 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.96 (q, 1H, J= 2 Hz, 3J S n .H=72 Hz, =CH); 1 3 C N M R (50.3 MHz) 8: -10.1, 14.3,21.4, 59.5, 127.9, 164.4, 168.0. Anal, calcd. for C 9 H 1 8 0 2 S n : C 39.04, H 6.55; found: C 38.88, H 6.59. Exact Mass calcd. for C 8 H 1 5 0 2 S n ( M + - C H 3 ) : 263.0094; found: 263.0090. Preparation of ethyl (£)-3-trimethylstannyl-2-pentenoate (149)^ 0 149 Following general procedure 4 outlined above, commercially available ethyl 2-pentynoate (124) was converted into the ester (149). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137) (1.03 mmol) in 5 mL of dry THF, EtOH (0.060 149 mL, 1.0 mmol) and ethyl 2-pentynoate (124) (100 mg, 0.792 mmol) in 0.5 mL of dry THF. Radial chromatography (4 mm plate, 98:2 hexanes-Et20) ofthe crude product and distillation (48-61°C/0.12 Torr) ofthe acquired liquid afforded 159 mg (69%) of ethyl (£)-3-timethylstannyl-2-pentenoate (149), a colourless oil that exhibited IR (neat): 1718, 1598, 1179, 774 cm" 1 ; A H N M R (400 MHz) 8: 0.21 (s, 9H, 2 Jsn-H= 5 4 Hz> "Sn(CH 3 ) 3 ) , 1.05 (t, 3H, J= 8 Hz, = C C H 2 C H 3 ) , 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.89 (qd, 2H, J= 8, 1 Hz, 3J S n.H=64 Hz, = C C H 2 C H 3 ) , 4.16 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.94 (t, 1H, J= 1 Hz, 3J S n_H=74Hz, =CHR); 1 3 C N M R (50.3 MHz) 8: -9.1, 14.1, 14.3, 27.9, 59.6, 126.9, 164.3, 174.5. Anal, calcd. for C i 0 H 2 0 O 2 S n : C 41.28, H 6.93; found: C 41.08, H 6.87. Exact Mass calcd. for C 9 H 1 7 0 2 S n (M+-CH 3): 277.0250; found: 277.0250. Preparation of ethyl (E)-4-(trnsopropylsUoxy)-3-trimethylstannyl-2-butenoate (157)^ 0 Following general procedure 4 outlined above, ethyl 4-(triisopropylsiloxy)-2-butynoate (127) was converted into the ester (157). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137) (0.46 mmol) in 3 mL of dry THF, EtOH (0.027 mL, 0.46 mmol) and ethyl 4-(triisopropylsiloxy)-2-butynoate (127) (100 mg, 0.352 mmol) in 0.5 mL of dry THF. Flash chromatography (10 g silica geL 97:3 hexanes-Et20) ofthe crude product and distillation (115-120°C/0.11 Torr) ofthe acquired liquid afforded 117 mg (74%) of ethyl (^-4-(trhsopropylsuoxy)-3-trimethylstannyl-2-butenoate (157), a colourless oil that exhibited IR(neat): 1712, 1603, 1184, 1047 cm" 1 ; A H N M R (400 MHz) 8: 0.21 (s, 9H, 2 J S n . H = 57Hz, -Sn(CH 3 ) 3 ) , 1.05 (d, 18H, J= 6 Hz, ( (CH 3 ) 2 CH) 3 Si-)) , 1.09-1.15 (m, 3H, ( (CH 3 ) 2 CH) 3 Si- ) , 1.27 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 4.12 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.95 (d, 2H, J= 2.5 M e 3 S n 157 150 Hz, 3J S n .H=30 Hz, =CCH 2 0) , 5.89 (t, 1H, J= 2.5 Hz, 3JS n_H=78 Hz, =CH); 1 3 C N M R (100.4 MHz) 5: -7.9, 11.9, 14.3, 18.0, 59.8, 67.2, 123.4, 161.8, 178.5. Anal, calcd. for C 1 8 H 3 8 0 3 S i S n : C 48.12, H 8.52; found: C 48.23, H 8.58. Exact Mass calcd. for C 1 7 H 3 5 0 3 S i S n ( M + - C H 3 ) : 435.1376; found: 435.1374. Preparation of ethyl (i?)-4-[(2-methoxyethoxy)methoxy1-3-trimethy (158V4 9 Following general procedure 4 outlined above, ethyl 4-[(2-methoxyethoxy) methoxy]-2-butynoate (128) was converted into the ester (158). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137), 0.60 mmoL in 4 mL of dry THF, EtOH (0.035 mL, 0.60 mmol) and ethyl 4-[(2-methoxyethoxy) methoxy]-2-butynoate (128), (100 mg, 0.462 mmol), in 0.5 mL of dry THF. Flash chromatography (10 g silica gel, 3:1 hexanes-Et20) ofthe crude product and distillation (85-93°C/0.11 Torr) ofthe acquired liquid afforded 122 mg (70%) of ethyl (£)-4-[(2-methoxyemoxy)methoxy]-3-trimethylstannyl-2-butenoate (158), a colourless oil that exhibited IR (neat): 1709, 1608, 1370, 1186 cm" 1 ; lH N M R (400 MHz) 5: 0.19 (s, 9H, 2 J S n . H = 56 Hz, -Sn(CH 3 ) 3 ) , 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 3.37 (s, 3H, -OCH 3 ) , 3.51-3.56 (m, 2H), 3.63-3.68 (m, 2H), 4.13 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.72 (s, 2H, -OCH 2 0 - ) , 4.79 (d, 2H, /= 2.5 Hz, 3 J S n . H = 3 0 Hz, =CCH 2 ) , 5.92 (t, 1H, J= 2.5 Hz, 3 J S n . H = 7 3 Hz, =CH); 1 3 C N M R (100.4 MHz) 8: -8.1, 14.2, 59.0, 59.9, 66.9, 71.7, 72.1, 95.2, 124.5, 164.3, 173.6. Anal, calcd. for C i 3 H 2 6 0 5 S n : C 40.98, H 6.88; found: C 41.23, H 7.01. Exact Mass calcd. for C 1 2 H 2 3 0 5 S n ( M + - C H 3 ) : 367.0567; found: 367.0564. 151 Preparation of ethyl (£V5-methyl-3-trimethylstarmyl-2-hexenoate (166) C 0 2 E t Following general procedure 4 outlined above, ethyl 5-methyl-2-hexynoate (125) was converted into the ester (166). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137), 39.9 mmol, in 400 mL of dry THF, EtOH (2.30 mL, 39.9 mmol), and ethyl 5-methyl-2-hexynoate (125) (4.10 g, 26.6 mmol) in 25 mL of dry THF. Flash chromatography (100 g silica gel, 98:2 hexanes-Et20) ofthe crude product and distillation (70-85°C/0.12 Torr) ofthe acquired liquid afforded 8.11 g (95%) of ethyl (£)-5-memyl-3-trimethylstannyl-2-hexenoate (166), a colourless oil that exhibited IR (neat): 1718, 1598, 1385, 1367, 1176, 771 cm" 1 ; lH N M R (400 MHz) 8: 0.21 (s, 9H, 2 J S n . H =54 Hz, -Sn(CH 3 ) 3 ) , 0.93 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.66-1.70 (m, 1H, -CH(CH 3 ) 2 ) , 2.82 (dd, 2H, J= 7,1 Hz, 3 J S n _ H =62 Hz, -CH 2 C=), 4.17 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 6.03 (t, 1H, J= 1 Hz, 3JS n_H=76 Hz, =CH); 1 3 C N M R (50.3 MHz) 8: -9.0, 14.3, 22.5, 29.1, 43.2, 59.6, 128.4, 164.5, 172.5. Anal, calcd. for C 1 2 H 2 4 0 2 S n : C 45.18, H 7.58; found: C 44.99, H 7.57. Exact Mass calcd. for C n H 2 1 0 2 S n ( M + - C H 3 ) : 305.0564; found: 305.0557. Preparation of ethyl (i?)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (159)^0 MesSn 159 152 Following general procedure 4 outlined above, ethyl 4-cyclohexyl-2-butynoate (126) was converted into the ester (159). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137), 30.9 mmoL in 320 mL of dry THF, EtOH (1.78 mL, 30.9 mmol), and ethyl 4-cyclohexyl-2-butynoate (126) (4.00 g, 20.6 mmol) in 10 mL of dry THF. Flash chromatography (50 g silica geL 98:2 hexanes-Et20) ofthe crude product and distillation (120-130°C/0.12 Torr) ofthe acquired liquid afforded 5.98 g (81%) of ethyl (£)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (159), a colourless oil that exhibited IR (neat): 1718, 1598, 1177, 770 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 6: 0.19 (s, 9H, 2 J S n .H=56 Hz, -Sn(CH 3 ) 3 ) , 0.95-1.05 (m, 2H), 1.13-1.23 (m, 3H), 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.32-1.40 (m, 1H), 1.60-1.75 (m, 5H), 2.83 (d, 2H, J= 8 Hz, 3 J s n - H = 6 1 ^ =CCH 2 ) , 4.16 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 6.03 (s, 1H, 3 J S n - H = 8 2 ^ = C H ) ; 1 3 C N M R (50.3 MHz) 5: -9.0, 14.3, 26.39, 26.44, 33.2, 38.7, 41.9, 59.6, 128.4, 164.5, 172.4. Anal, calcd. for C 1 5 H 2 8 0 2 S n : C 50.17, H 7.86; found: C 50.40, H 7.88. Exact Mass calcd. for C 1 4 H 2 5 0 2 S n ( M + - C H 3 ) : 345.0877; found: 345.0881. 6.2 General Procedure 5: Preparation of ethyl (Z)-trimethylstannyl-2-alkenoates (134)^0 To a cold (-48°C), stirred solution of [Me 3SnCuCN]Li (137) (1.01-1.09 equiv.) in dry THF was added, drop wise, a solution ofthe appropriate a , (3-acetylenic ester (1.0 equiv.) in dry THF and the mixture was stirred at -48°C for 2 hours and at 0°C for 2 hours. Aqueous N H 4 C I - N H 4 O H (pH 8) (one-half the volume of the total volume ofthe reaction mixture) was added, the mixture was opened to the atmosphere, was allowed to warm to room temperature, and was stirred vigorously until the aqueous phase became deep blue. The phases were M e 3 S n C 0 2 E t 134 153 separated and the aqueous phase was extracted thoroughly with Et20. The combined organic extracts were washed with brine, dried (MgSOzi), and concentrated. The crude product was separated by flash or radial chromatography and purified by distillation to afford the corresponding ethyl (Z)-3-trimethylstannyl-2-alkenoate (134). Preparation of ethyl (Z)-3-trimethylstannyl-2-pentenoate (149)5° Following general procedure 5 outlined above, commercially available ethyl 2-pentynoate (124) was converted into the ester (149). The following amounts of reagents and solvents were used: [Me3 SnCuCNJLi (137) (0.86 mmol) in 4 mL of dry THF and ethyl 2-pentynoate (124) (100 mg, 0.792 mmol) in 0.5 mL of dry THF. Radial chromatography (4 mm plate, 98:2 hexanes-Et20) ofthe crude product and distillation (52-60°C/0.12 Torr) of the acquired liquid afforded 163 mg (70%) of ethyl (Z)-3-timethylstannyl-2-pentenoate (149), a colourless oil that exhibited IR (neat): 1703, 1601, 1201, 772 cm" 1 ; lH N M R (400 MHz) 5: 0.18 (s, 9H, 2 J S n - H = 5 5 H 2 ' " S n( cH3)3), 104 (t, 3H, J= 8 Hz, = C C H 2 C H 3 ) , 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.45 (qd, 2H, J= 7, 1.5 Hz, 3 J S n - H = 4 3 Hz, = C C H 2 C H 3 ) , 4.18 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 6.36 (t, 1H, J= 1.5 Hz, 3 J S n . H =120 Hz, =CH); 1 3 C N M R (50.3 MHz) 5: -7.5, 13.6, 14.3, 32.9, 60.2, 126.9, 168.1, 177.1. Anal, calcd. for C 1 0 H 2 0 O 2 S n : C 41.28, H 6.93; found: C 41.47, H 7.09. Exact Mass calcd. for C 9 H 1 7 0 2 S n (M+-CH 3): 277.0250; found: 277.0244. M e 3 S n C 0 2 E t 149 154 Preparation of ethyl (Z)-4-(trusopropylsUoxyV3-trimemylstamyl-2-butenoate (150)50 TIPSO \ C 0 2 E t 150 Following general procedure 5 outlined above, ethyl 4-(triisopropylsiloxy)-2-butynoate (127) was converted into the ester (150). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137), 0.37 mmoL in 3 mL of dry THF and ethyl 4-(triisopropylsiloxy)-2-butynoate (127) (100 mg, 0.35 mmol) in 0.5 mL of dry THF. Flash chromatography (10 g silica geL 97:3 hexanes-Et20) ofthe crude product and distillation (100-104°C/0.11 Torr) ofthe acquired liquid afforded 120 mg (76%) of ethyl (Z)-4-(trhsopropylsUoxy)-3-trimethylstannyl-2-butenoate (150), a colourless oil that exhibited IR(neat): 1702, 1609, 1465, 1299, 1191, 1044 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 0.18 (s, 9H, 2 j S n - H = 5 6 Hz, -Sn(CH 3 ) 3 ) , 1.05 (d, 18H, J= 6 Hz, ( (CH 3 ) 2 CH) 3 Si-) ) , 1.08-1.15 (m, 3H, ( (CH 3 ) 2 -CH) 3 Si- ) , 1.27 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 4.15 (q, 2H, J= 1 Hz, - O C H 2 C H 3 ) , 4.52 (d, 3H, J= 2.5 Hz, 3 J S n-H= 1 9 ^  =CCH 2 0) , 6.72 (t, 1H, J= 2 Hz, 3JSn_H=114 Hz, =CH); 1 3 C N M R (100.4 MHz) 8: -7.9, 11.9, 14.2, 17.9, 60.3, 68.6, 124.6, 168.3, 171.6. Anal, calcd. for C 1 8 H 3 8 0 3 S i S n : C 48.12, H 8.52; found: C 48.14, H 8.60. Exact Mass calcd. for C 1 7 H 3 5 0 3 S i S n ( M + - C H 3 ) : 435.1376; found: 435.1360. Preparation of ethyl (Z)-4-[(2-methoxyemoxy)methoxy]-3-trimethylstannyl-2-butenoate (151)49 M E M O M e 3 S n C 0 2 E t 151 155 Following general procedure 5 outlined above, ethyl 4-[(2-methoxyethoxy) methoxy]-2-butynoate (128) was converted into the ester (151). The following amounts of reagents and solvents were used: [Me3SnCuCN]Li (137), 0.49 mmoL in 4 mL of dry THF and ethyl 4-[(2-methoxyethoxy) methoxy]-2-butynoate (128) (100 mg, 0.46 mmol) in 0.5 mL of dry THF. Flash chromatography (10 g silica gel, 85:15 hexanes-Et20) ofthe crude product and distillation (95-98°C/0.11 Torr) ofthe acquired liquid afforded 127 mg (72%) of ethyl (Z)-4-[(2-methoxyemoxy)memoxy]-3-trimethylstannyl-2-butenoate (151), a colourless oil that exhibited IR (neat): 1702, 1608, 1368, 1198 cm" 1 ; X H N M R (400 MHz) S: 0.18 (s, 9H, 2 J S n . H = 56 Hz, -Sn(CH 3 ) 3 ) , 1.28 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 3.37 (s, 3H, -OCH 3 ) , 3.52 (m, 2H,), 3.71 (m, 2H), 4.17 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.38 (d, 2H, J= 2 Hz, 3 J S n - H = 2 ° H 2 * =CCH 2 ) , 4.75 (s, 2H, -OCH 20-), 6.63 (t, 1H, J= 2 Hz, 3 J S n . H =112 Hz, =CH); 1 3 C N M R (100.4 MHz) 8: -7.7, 14.2, 58.9, 60.4, 66.9, 71.7, 72.4, 95.0, 125.8, 167.5, 168.7. Anal, calcd. for C 1 3 H 2 6 0 5 S n : C 40.98, H 6.88; found: C 41.20, H 7.01. Exact Mass calcd. for C 1 2 H 2 3 0 5 S n ( M + - C H 3 ) : 367.0567; found: 367.0575. Preparation of ethyl (Z)-5-methyl-3-trimethylstannyl-2-hexenoate (171) Following general procedure 5 outlined above, ethyl 5-methyl-2-hexynoate (125) was converted into the ester (171). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137), 1.09 mmol, in 5 mL of dry THF and ethyl 5-methyl-2-hexynoate (125), (154 mg, 1.00 mmol), in 0.5 mL of dry THF. Flash chromatography (20 g silica geL 98:2 hexanes-Et20) ofthe crude product and distillation (82-90°C/0.12 Torr) ofthe acquired liquid M e 3 S n C 0 2 E t 171 156 afforded 268 mg (84%) of ethyl (2^-5-methyl-3-trimethylstamiyl-2-hexenoate (171), a colourless oil that exhibited JJR (neat): 1704, 1598, 1385, 1365, 1176, 769 cm" 1 ; Iff N M R (400 MHz) 5: 0.15 (s, 9H, 2 J s n - H = 5 6 Hz, -Sn(CH 3 ) 3 ) , 0.86 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.28 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.61-1.68 (m, 1H, -CH(CH 3 ) 2 ) , 2.28 (dd, 2H, J= 7, 1 Hz, 3J S n_H=54 Hz, -CH 2 C=), 4.17 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 6.29 (t, 1H, J= 1 Hz, 3J S n_H=120 Hz, =CH); 1 3 C N M R (75.3 MHz) 8: -7.3, 14.3, 22.4, 27.9, 49.4, 60.3, 129.1, 129.2, 174.7. Anal, calcd. for C i 2 H 2 4 0 2 S n : C 45.18, H 7.58; found: C 45.45, H 7.49. Exact Mass calcd. for C n H 2 1 0 2 S n ( M + - C H 3 ) : 305.0564; found: 305.0558. Preparation of ethyl (Z)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (152)^ 0 Following general procedure 5 outlined above, ethyl 4-cyclohexyl-2-butynoate (126) was converted into the ester (152). The following amounts of reagents and solvents were used: [Me 3SnCuCN]Li (137), 0.54 mmol, in 4.5 mL of dry THF and ethyl 4-cyclohexyl-2-butynoate (126) (100 mg, 0.515 mmol) in 1 mL of dry THF. Flash chromatography (12 g silica geL 97:3 hexanes-Et20) ofthe crude product and distillation (104-107°C/0.12 Torr) ofthe acquired liquid afforded 149 mg (81%) of ethyl (2T)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (152), a colourless oil that exhibited IR (neat): 1703, 1599, 1064 cm" 1 ; X H N M R (400 MHz) 8: 0.15 (s, 9H, 2 J S n - H = 5 5 Hz* "Sn(CH 3 ) 3 ) , 0.80-0.92 (m, 2H), 1.10-1.21 (m, 4H), 1.26 (t, 3H, /= 7 Hz, - O C H 2 C H 3 ) , 1.30-1.36 (m, 1H), 1.56-1.71 (m, 4H), 2.28 (d, 2H, J= 7 Hz, 3J S n_H=56 Hz, =CCH 2 R), 4.15 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 6.26 (s, 1H, 3 J s n - H = 1 2 4 ^ =CH); 1 3 C N M R (100.4 MHz) 8: -7.3, 14.3, 26.4, 26.5, 33.2, 37.5, 47.9, 60.3, 129.1, 167.8, 174.6. Anal, calcd. 152 157 for C 1 5 H 2 8 0 2 S n : C 50.17, H 7.86; found: C 50.10, H 7.82. Exact Mass calcd. for C 1 4 H 2 5 0 2 S n ( M + - C H 3 ) : 345.0877; found: 345.0871. 7 Preparation of ethyl (E)- and (Z)-3-trimemylstannyl-3-alkenoates 7.1 General Procedure 6: Preparation of ethyl (Z)-3-trimemylstannyl-3-alkenoates (214) To a cold (-78°C), stirred solution of commercially available potassium hexamethyldisilizide (2.4 equiv.) in dry THF (-10 mL/mmol of ester) was added, dropwise, H M P A (2.3 equiv.). After the resultant mixture had been stirred for 5 minutes, a solution ofthe appropriate ethyl (£)-3-trimethylstannyl-2-alkenoate (133) (1 equiv.) in dry THF (~1 mL/mmol of ester) was added dropwise, over a period of 10 minutes. The mixture was stirred at -78°C for 1 hour, at -48°C for 4 hours, recooled to -78°C, and cannulated into a cold (-98°C), stirred solution of glacial acetic acid (~ 0.33 mL/mmol of ester) in dry Et20 (-3 mL/mmol of ester). The solution was allowed to warm to room temperature and saturated aqueous N a H C 0 3 solution (one-half the volume ofthe total volume ofthe reaction mixture) was added and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgS0 4 ) , and concentrated. Flash chromatography ofthe crude product, followed by bulb-to-bulb distillation of the acquired oil, afforded the corresponding alkyl (Z)-3-trimethylstannyl-3-alkenoate (214). It is important to note that the alkyl (£)-3-trimethylstannyl-2-alkenoate (133) must be of high purity and freshly distilled prior to use R 133 214 158 or the product resulting from the above reaction will be the corresponding alkyl (^-3-trimethylstannyl-3-alkenoate (210). Preparation of ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (168) 168 Following general procedure 6 outlined above, ethyl (£)-5-methyl-3-trimethylstannyl-2-hexenoate (166) was converted into the ester (168). The following amounts of reagents and solvents were used: potassium hexamethyldisilizide (0.60 g, 3.0 mmol) in 13 mL dry THF, H M P A (0.516 g, 2.88 mmol), and ethyl (^-S-methyl-S-trimethylstannyl^-hexenoate (166) (400 mg, 1.25 mmol) in 1 mL of dry THF. Flash chromatography (50 g silica geL 98:2 hexanes-Et20) of the crude product and distillation (70-85°C/0.12 Torr) ofthe acquired liquid afforded 359 mg (90%) of ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (168), a colourless oil that exhibited JR. (neat): 1734, 1369, 1179, 770 cm" 1 ; X H N M R (400 MHz) 8: 0.18 (s, 9H, 2 J S n - H = 5 6 Hz, -Sn(CH 3 ) 3 ) , 0.97 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.16-2.26 (m, 1H, -CH(CH 3 ) 2 ) , 3.15 (d, 2H, J= 1 Hz, 3 J S n - H = 5 3 H 2 * =C-CH 2-) , 4.12 (q, 2H, J= 1 Hz, - O C H 2 C H 3 ) , 5.82 (dt, 1H, J= 10, 1 Hz, 3 J S n . H =131 Hz, =CH); 1 3 C N M R (50.3 MHz) 8: -7.9, 14.2, 23.1, 34.3, 44.9, 60.4, 133.1, 151.6, 173.0. Anal, calcd. for C 1 2 H 2 4 0 2 S n : C 45.18, H 7.58; found: C 45.39, H 7.58. Exact Mass calcd. for C i i H 2 1 0 2 S n ( M + - C H 3 ) : 305.0564; found: 305.0560. 159 Preparation of ethyl (2^-4-cvclohexyl-3-trimemylstannyl-3-b^ (167) C y . > ^ / C 0 2 E t Me3Sn 167 Following general procedure 6 outlined above, ethyl (E)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (159) was converted into the ester (167). The following amounts of reagents and solvents were used: potassium hexamethyldisilizide (0.348 g, 1.74 mmol) in 7 mL dry THF, H M P A (0.300 g, 1.67 mmol), and ethyl (£,)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (159) (260 mg, 0.724 mmol) in 1 mL of dry THF. Flash chromatography (25 g silica geL 97:3 hexanes-Et20) ofthe crude product and distillation (115-120°C/0.12 Torr) ofthe acquired liquid afforded 221 mg (85%) of ethyl (Z)-4-cyclohexyl-3-trimetnylstannyl-3-butenoate (167), a colourless oil that exhibited JR. (neat): 1734, 1622, 1164 cm" 1 ; A H N M R (400 MHz) 8: 0.18 (s, 9H, 2 J S n -H= 5 4 ^ -Sn(CH 3 ) 3 ) , 1.05-1.20 (m, 4H), 1.24 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.55-1.75 (m, 6H), 1.80-1.90 (m, 1H), 3.18 (s, 2H, 3 J S n - H = = 5 6 Hz* =C-CH 2-) , 4.11 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.86 (d, 1H, /= 9 Hz, 3JS n_H=132 Hz, =CH); 1 3 C N M R (100.4 MHz) 8: -8.0, 14.2, 25.9, 26.0, 33.3, 44.4, 44.8, 60.4, 134.0, 150.3, 173.0. Anal, calcd. for C 1 5 H 2 8 0 2 : C 50.17, H 7.86; found: C 50.47, H 7.89. Exact Mass calcd. for C 1 4 H 2 5 0 2 ( M + - C H 3 ) : 345.0877; found: 345.0878. 160 7.2 General Procedure 7: Preparation of ethyl (£)-3-trimemylstamyl-3-alkenoates (210) To a cold (-78°C), stirred solution of potassium hexamethyldisihzide (2.4 equiv.) in dry THF (~10 mL/mmol of ester) was added, dropwise, H M P A (2.3 equiv.). After the resultant mixture had been stirred for 5 minutes, a solution ofthe appropriate ethyl (Z)-3-trimethylstannyl-2-alkenoate (134) (1 equiv.) in dry THF (~1 mL/ mmol of ester) was added dropwise over a period of 10 minutes. The mixture was stirred at -78°C for 1 hour, at -48°C for 4 hours, recooled to -78°C, and cannulated into a cold (-98°C), stirred solution of glacial acetic acid ( -0 .33 mL/mmol of ester) in dry Et20 (-3 mL/mmol of ester). The solution was allowed to warm to room temperature and saturated aqueous NaHCC>3 (one half the volume ofthe total volume ofthe reaction mixture) was added and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgSC«4), and concentrated. Flash chromatography ofthe crude product followed by bulb-to-bulb distillation ofthe acquired oil afforded the corresponding ethyl (£)-3-trimethylstannyl-3-alkenoate (210). Preparation of ethyl (^-S-methyl-S-trimethylstannyl-S-hexenoate (170) R M e 3 S n C 0 2 E t C 0 2 E t 134 210 C0 2 Et 170 161 Following general procedure 7 outlined above, ethyl (Z)-5-methyl-3-trimethylstannyl-2-hexenoate (171) was converted into the ester (170). The following amounts of reagents and solvents were used: potassium hexamethyldisilizide (0.24 g, 1.2 mmol) in 5 mL dry THF, H M P A (0.21 g, 1.2 mmol), and ethyl (Z)-5-memyl-3-trimethylstannyl-2-hexenoate (171), (159 mg, 0.499 mmol), in 0.5 mL of dry THF. Flash chromatography (10 g silica geL 98:2 hexanes-Et20) ofthe crude product and distillation (70-73°C/0.10 Torr) ofthe acquired liquid afforded 139 mg (87%) of ethyl (£)-5-methyl-3-trimethylstannyl-3-hexenoate (170), a colourless oil that exhibited I R (neat): 1733, 1611, 1465, 1298, 1181 cm" 1 ; ! H N M R ( 4 0 0 M H Z ) 8: 0.10 (s, 9H, 2 J S n . H =54 Hz, -Sn(CH 3 ) 3 ) , 0.93 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.22 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.64-2.72 (m, 1H, -CH(CH 3 ) 2 ) , 3.26 (d, 2H, J= 1.5 Hz, 3 J S n - H = = 5 5 H 2 * =C-CH 2-) , 4.09 (q, 2H, J= 1 Hz, - O C H 2 C H 3 ) , 5.50 (dt, 1H, J= 6, 1.5 Hz, 3 J S n . H =75 Hz, =CH); 1 3 C N M R (100.4 MHz) 8: -8.8, 14.2, 22.9, 27.7, 37.7, 60.5, 132.9, 151.1, 172.7. Anal, calcd. for C 1 2 H 2 4 0 2 S n : C 45.18, H 7.58; found: C 45.21, H 7.52. Exact Mass calcd. for C n H 2 1 0 2 S n (M+-CH 3): 305.0564; found: 305.0560. Preparation of ethyl (iT)-4-cyclohexyl-3-trimethylstannyl-3-butenoate (169) Cy C 0 2 E t 169 Following general procedure 7 outlined above, ethyl (Z)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (152) was converted into the ester (169). The following amounts of reagents and solvents were used: potassium hexamemyldisilizide (0.200 162 g, 1.00 mmol) in 5 mL dry THF, H M P A (0.17 g, 0.95 mmol), and ethyl (Z)-4-cyclohexyl-3-trimethylstannyl-2-butenoate (152) (150 mg, 0.418 mmol) in 0.5 mL of dry THF. Flash chromatography (10 g silica geL 97:3 hexanes-Et20) ofthe crude product and distillation (84-85°C/0.11 Torr) ofthe acquired liquid afforded 137 mg (91%) of ethyl (£)-4-cyclohexyl-3-trJmethylstannyl-3-butenoate (169), a colourless oil that exhibited IR (neat): 1733, 1610, 1180 cm" 1 ; A H N M R (400 MHz) 5: 0.09 (s, 9H, 2 Jsn -H= 5 4 ^ -Sn(CH 3 ) 3 ) , 1.00-1.12 (m, 2H), 1.13-1.20 (m, 2H), 1.23 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.54-1.73 (m, 6H), 2.30-2.40 (m, 1H), 3.26 (d, 2H, J= 1.5 Hz, 3 J S n - H = 5 6 ^ =C-CH 2-) , 4.10 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.51 (dt, 1H, J= 9, 1.5 Hz, 3 J S n-Hr 7 6 H 2 * = C H ) ; 1 3 C N M R (50.2 MHz) 8: -8.7, 14.2, 25.9, 26.0, 32.9, 37.6, 37.7, 60.6, 133.6, 149.7, 204.1. Anal, calcd. for C 1 5 H 2 8 0 2 S n : C 50.17, H 7.86; found: C 50.55, H 7.86. Exact Mass calcd. for C 1 4 H 2 5 0 2 S n ( M + - C H 3 ) : 345.0877; found: 345.0874. 8 Preparation of alkylating agents 8.1 General Procedure 8: Preparation of 2-alkyn-l-ols (196) from Ll-dibromo-l-alkenes (195)43 196 To a cold (-78 °C), stirred solution ofthe appropriate 1,1-dibromo-l-alkene (196) (1 equiv.) in dry THF ( ~10 mL/mmol of the substrate) was added, dropwise, a solution of «-butywthium (2.5 equiv.) in hexanes. The mixture was stirred at -78°C for 1 hour, at room temperature for 1 hour, and was then recooled to -20°C. Paraformaldehyde (3 equiv.) was added and the mixture was stirred at -20°C for 1 hour and at room temperature for 1 hour. Saturated aqueous N a H C 0 3 solution (three-quarter the volume ofthe total volume ofthe 163 reaction mixture) was added and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgSC>4), and concentrated. Distillation of the acquired oil afforded the corresponding 2-alkyn-l-ol (196). Preparation of 4-methyl-2-pentvn-l-ol (202) Following general procedure 8 outlined above, l,l-dibromo-3-methyl-l-butene (200) was converted into the alcohol (202). The following amounts of reagents and solvents were used: substrate (200) (10.0 g, 43.9 mmol) in 450 mL dry THF, «-butyUithium (110 mmol) in hexanes, and paraformaldehyde (3.95 g, 132 mmol). Normal workup, followed by distillation (63-64°C/12 Torr) ofthe crude product provided 3.42 g (79%) of 4-methyl-2-pentyn-l-ol (10) as a colourless oil which exhibited IR (neat): 3400 (br), 2256, 1465, 1320, 1055 cm" 1 ; X H N M R (300 MHz) 5: 1.14 (d, 6H, J= 7.5 Hz, -CH(CH 3 ) 2 ) , 1.60 (t, 1H, J= 3 Hz, -OH), 2.51-2.61 (m, 1H, -CH(CH 3 ) 2 ) , 4.22 (br d, 2H, J= 3 Hz, =C-CH 2 OH); 1 3 C N M R (125 MHz) 6: 20.5, 22.9, 51.3, 88.0, 91.9. Exact Mass calcd. for C 6 H 1 0 O : 98.0732; found: 98.0732. Preparation of 3-cyclohexyl-2-propyn-l-ol (203) OH 202 203 164 FoUowing general procedure 8 outlined above, l,l-dibromo-2-cyclohexylethene (201) was converted into the alcohol (203). The following amounts of reagents and solvents were used: substrate (201) (13.1 g, 48.9 mmol) in 500 mL dry THF, ^-butyUithium (122 mmol) in hexanes, and paraformaldehyde (4.40 g, 147 mmol). Normal workup, foUowed by distiUation (91°C /12 Torr) ofthe crude product, provided 5.87 g (87%) of 3-cyclohexyl-2-propyn-l-ol (11) as a colourless oU which exhibited IR (neat): 3360 (br), 2229, 1449, 1018 cm" 1 ; i H N M R (400 MHz) 8: 1.20-1.71 (m, 11H), 2.31-2.41 (m, 1H, - O C C H ) , 4.23 (dd, 2H, J- 6, 1 Hz, -CH 2 OH) ; 1 3 C N M R (100.4 MHz) 8: 24.8, 25.7, 29.0, 32.5, 51.4, 78.1, 90.6. Anal, calcd. for C 9 H 1 4 0 : C 78.21, H 10.21; found: C 78.24, H 10.30. Exact Mass calcd. for C 9 H 1 4 0 : 138.1045; found: 138.1043. 8.2 General Procedure 9: Preparation ofthe (ZV2-bromo-2-alken-l-ols (197) 5 6 R Br R = OH H ^ O H 196 197 To a cold (-20°C), stirred solution ofthe appropriate 2-alkyne-l-ol (196) in dry E t 2 0 (~ 1 mL/mmol ofthe alcohol) were added sequentiaUy, drop wise, solutions of //-butyUithium (1 equiv.) in hexanes and Dibal (3 equiv.) in hexanes. The mixture was heated at 35°C for 64 hours, and was then recooled to 0°C. Ethyl acetate (2 equiv.) was added and the mixture was stirred at 0°C for 10 min., cooled to -78°C, and cannulated into a cold (-78°C) solution of NBS (5 equiv.) in dry C H 2 C 1 2 (~20 mL/mmol ofthe substrate alcohol). The resultant mixture was stirred at -78°C for 15 minutes. Saturated aqueous sodium potassium tartrate (one half the volume ofthe total volume of the reaction mixture) was added and the mixture was thoroughly extracted with E t 2 0 . The combined extracts were washed with brine, dried (MgS0 4 ) , and 165 concentrated. Hash or radial chromatography of the crude product followed by bulb-to-bulb distillation ofthe acquired oil afforded the corresponding (Z)-2-bromo-2-alken-l-ol (197). Preparation of (Z)-2-bromo-4-methyl-2-penten-l-ol (204) Following general procedure 9 outlined above, 4-mefhyl-2-pentyn-l-ol (202) was converted into the alcohol (204). The following amounts of reagents and solvents were used: substrate (202) (0.250 g, 2.55 mmol) in 3 mL dry Et20, «-butyUithium (2.55 mmol) in hexanes, Dibal (7.65 mmol) in hexanes, EtOAc (0.49 mL, 5.1 mmol), and NBS (2.27 g, 12.8 mmol) in 50 mL dry C H 2 C I 2 . Normal workup, followed by flash chromatography (25g silica gel, 3:1 hexanes-Et20) ofthe crude product and then distillation (45-50°C/12 Torr) ofthe acquired liquid provided 286 mg (63%) of (Z)-2-bromo-4-methyl-2-penten-l-ol (204) as a colourless oil which exhibited I R (neat): 3348 (br), 1657, 1466, 1083 cm" 1 ; ! H N M R ( 4 0 0 M H Z ) 5: 1.00 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.87 (t, 1H, J= 8 Hz, -OH), 2.65-2.75 (m, 1H, -CH(CH 3 ) 2 ) , 4.20 (d, 2H, J= 8 Hz, =C-CH 2 OH), 5.80 (d, 1H, J= 8 Hz, =CH); N O E difference experiment: irradiation at 8 4.20 led to enhancement ofthe signal at 8 5.80; 1 3 C N M R (75.3 MHz) 8: 21.6, 30.6, 68.5, 124.3, 137.1. Exact Mass calcd. for C 6 H n 7 9 B r O : 177.9992; found: 177.9980. 166 Preparation of (Z)-2-bromo-3-cyclohexyl-2-propen-l-ol (205) Br OH 205 Following general procedure 9 outlined above, 3-cyclohexyl-2-propyn-l-ol (203) was converted into the alcohol (205). The following amounts of reagents and solvents were used: substrate (203) (1.20 g, 8.68 mmol) in 8.5 mL dry Et^O, «-butylhthium (8.68 mmol) in hexanes, Dibal (26 mmol) in hexanes, EtOAc (1.67 mL, 17.4 mmol), and NBS (7.75 g, 43.4 mmol) in 160 mL dry CH2CI2. Normal workup, followed by radial chromatography (4 mm plate, 3:1 hexanes-Et20) ofthe crude product and distillation (60-65°C/0.12 Torr) ofthe acquired liquid provided 985 mg (52%) of (Z)-2-bromo-3-cyclohexyl-2-propen-l-ol (205) as a colourless oil which exhibited IR (neat): 3343 (br), 1449, 1082 cm" 1 ; X H N M R (400 MHz) 8: 1.03-1.42 (m, 5H), 1.61-1.75 (m, 5H), 1.85 (t, 1H, J= 7 Hz, -OH), 2.41 (m, 1H, =C-CH), 4.20 (d, 2H, J= 7 Hz, =C-CH 2 OH), 5.80 (d, 1H, J= 9 Hz, =CH); 1 3 C N M R (100.4 MHz) 5: 25.5, 25.8, 31.6, 39.9, 68.5, 124.4, 135.5. Anal, calcd. for C 9 H 1 5 O B r : C 49.33, H 6.90; found: C 49.60, H 6.90. Exact Mass calcd. for C 9 H 1 5 8 1 B r O : 220.0287; found: 220.0289. Preparation of (Z)-2-iodo-4-methyl-2-penten-l-ol (209) OH 209 167 To a cold (-20°C), stirred solution of 4-methyl-2-pentyn-l-ol (202) (100 mg, 1.02 mmol) in dry Et20 (1 mL) were added sequentially, dropwise, solutions of n-butyllithium (1.02 mmol) in hexanes and Dibal (3 mmol) in hexanes. The mixture was heated at 35°C for 48 hours, and was then recooled to 0°C. Ethyl acetate (0.200 g, 2.08 mmol) was added and the mixture was stirred at 0°C for 10 min., cooled to -78°C, and was cannulated into a cold (-78°C) solution of iodine (2.4 g, 9.0 mmol) in dry CH2CI2 (20 mL). The resultant mixture was stirred at -78°C for 15 minutes. Saturated aqueous sodium thiosulphate (13 mL) was added and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgS04), and concentrated. Flash chromatography (10 g silica geL 4:1 petroleum ether-Et20) ofthe crude product followed by distillation (80-90°C/15 Torr) ofthe acquired oil afforded 105 mg (46%) of (Z)-2-iodo-4-methyl-2-penten-l-ol (209) as a colourless oil which exhibited IR (neat): 3347 (br), 1641, 1465, 1270 cm" 1 ; A H N M R (400 MHz) 5: 1.02 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 1.82 (br s, 1H, -OH), 2.52-2.62 (m, 1H, -CH(CH 3 ) 2 ) , 4.21 (s, 2H, =C-CH 2 OH), 5.68 (d, 1H, J= 9 Hz, =CH); NOE difference experiment: irradiation at 5 5.68 led to enhancement ofthe signal at 4.21; 1 3 C N M R (75.3 MHz) 5: 21.4, 35.4, 71.6, 128.3, 142.8. Exact Mass calcd. for C 6 H u I O : 225.9855; found: 225.9855. 8.3 General Procedure 10: Preparation of the (Z)-L2-dibromo-2-alkenes (32) R Br R Br X > H ^ O H H ^ B r 197 32 To a stirred solution of triphenylphosphine (1.1 equiv.) in dry CH2CI2 (~4 mL/mmol of the alcohol substrate) was added, dropwise, bromine (1.1 equiv.) until a faint yellow colour persisted and then a few crystals of triphenylphosphine were added until the solution became colourless. The mixture was stirred for 10 minutes at room temperature and a solution ofthe 168 appropriate alcohol (197) (1 equiv.) in dry CH2CI2 (-2.7 mL/mmol of alcohol) was added. The resultant mixture was stirred at room temperature for 3.5 hours. «-Pentane (equal volume to the total volume ofthe reaction mixture) was added and the resultant slurry was poured onto a short column of Florisil (1 g Florisil/mmol of alcohol substrate). The column was eluted with 5 volumes of pentane (each of equal volume to the total volume ofthe reaction mixture) and the combined eluate was concentrated. Radial chromatography ofthe crude product, followed by bulb-to-bulb distillation ofthe acquired oil, gave the corresponding (Z)-l,2-dibromo-2-alkene Following general procedure 10 outlined above, (Z)-2-bromo-4-methyl-2-penten-l-ol (204) was converted into the dibromide (206). The following amounts of reagents and solvents were used: triphenylphosphine (1.29 g, 4.91 mmol) in 18 mL of dry CH2CI2, bromine (0.78 g, 4.9 mmol), and alcohol (204) (0.800 g, 4.47 mmol) in 12 mL dry CH2CI2. Normal workup, followed by radial chromatography (4 mm plate, 97:3 hexanes-Et20) and distillation (35-40°C/12 Torr) afforded 0.81g (76%) of (Z)-l,2-dibromo-4-methyl-2-pentene (206) as a colourless oil that exhibited IR (neat): 1643, 1213 cm" 1 ; X H N M R (400 MHz) 5: 1.02 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 2.62-2.71 (m, 1H, -CH(CH 3 ) 2 ) , 4.21 (s, 2H, =CCH 2 Br), 5.91 (d, 1H, J= 9 Hz, =CH); NOE difference experiment: irradiation at 8 4.21 led to enhancement ofthe signal at 5.91; 1 3 C N M R (75.3 MHz) 8: 21.3, 39.1, 31.35, 120.1, 141.2. Exact Mass calcd. for C 6 H 1 0 8 1 B r 7 9 B r : 241.9131; found: 241.9133. (32). Preparation of (Z)-L2-dibromo-4-methyl-2-pentene (206) 169 Preparation of (Z)-2.3-dibromo-l-cyclohexyl-l-propene (207) B r B r 207 Following general procedure 10 outlined above, (Z)-2-bromo-3-cyclohexyl-2-propen-l-ol (205) was converted into the dibromide (207). The following amounts of reagents and solvents were used: triphenylphosphine (1.05 g, 4 . 0 0 mmol) in 16 mL dry CH 2Ci2, bromine (0.64 g, 4 .0 mmol), and alcohol (205) (0.800 g, 3.65 mmol) in 10 mL dry C H 2 C I 2 . Normal workup, followed by radial chromatography (4 mm plate, 97:3 hexanes-Et20) and distillation (58-63°C/0.12 Torr) afforded 0.756 g (73%) of (Z)-2,3-dibromo-l-cyclohexyl-l-propene (207) as a colourless oil that exhibited IR (neat): 1641, 1241 cm"1; 1 HNMR(400 MHz) 8: 1.03-1.37 (m, 6 H ) , 1.60-1.78 (m, 4 H ) , 2.32-2.43 (m, 1 H ) , 4 .21 (s, 2 H , =C-CH2Br), 5.92 (d, 1 H , J= 9 Hz, =CH); NOE difference experiment: irradiation at 8 4 .21 led to enhancement ofthe signal at 5.92; 1 3 C NMR ( 1 0 0 . 4 MHz) 8: 25.4, 25.8, 31.3, 39 .2 , 40.7, 120.4 , 139.8. Anal, calcd. for C 9 H 1 4 B r 2 : C 38.33, H 5 .00; found: C 38.60, H 5 .00. Exact Mass calcd. for C 9 H 1 4 8 1 B r 7 9 B r : 281.9444; found: 281.9445. Preparation of (Z)-l-Bromo-2-iodo-4-methyl-2-pentene (311) 311 170 Following general procedure 10 outlined above, (Z)-2-iodo-4-methyl-2-penten-l-ol (209) was converted into (Z)-l-bromo-2-iodo-4-methyl-2-pentene (311). The following amounts of reagents and solvents were used: triphenylphosphine (0.320 g, 1.22 mmol) in 5 mL dry C H 2 C 1 2 , bromine (0.19 g, 1.2 mmol), and alcohol (209) (0.250 g, 1.11 mmol) in 5 mL dry C H 2 C 1 2 . Normal workup, followed by distillation (45-50°C/12 Torr) afforded 0.17 g (53%) of (Z)-l-bromo-2-iodo-4-methyl-2-pentene (311) as a colourless oil that exhibited IR (neat): 1631, 1464, 1209 cm" 1 ; A H N M R (400 MHz) 5: 1.04 (d, 6H, J= 7 Hz, -CH(CH 3 ) 2 ) , 2.48-2.56 (m, 1H, -CH(CH 3 ) 2 ) , 4.32 (s, 2H, =CCH 2 Br), 5.74 (d, 1H, J= 9 Hz, =CH); 1 3 C N M R (75.3 MHz) 5: 21.2, 36.1, 43.5, 128.4, 147.2. Exact Mass calcd. for C 6 H 1 0 8 1 B r I : 289.8994; found: 289.8996. 9. General Procedure 11: Preparation ofthe diene esters (215) M e 3 S n C 0 2 E t M e 3 S n H 134 133 R R ^ C ° 2 B C 0 2 E t MeaSn 214 210 R X 215 171 To a cold (-78°C), stirred solution of lithium diisopropylamide (1.1-2.4 equiv.) in dry THF (6.4 - 14.5 mL/mmol of ester substrate) was added, dropwise, H M P A (1.1-2.4 equiv). After the resultant mixture had been stirred for 15 minutes, a solution ofthe appropriate ethyl 3-trimethylstannyl-2-alkenoate (133 or 134) or ethyl 3-trimethylstannyl-3-alkenoate (210 or 214) in dry THF (0.95-1.8 mL/mmol of ester substrate) was added dropwise. The mixture was stirred at -78°C for 30 minutes, at 0°C for 30 minutes, and recooled to -78°C. The appropriate allylic halide (1.3-1.5 equiv.) was added rapidly and the reaction mixture was stirred at -78°C for 1 hour. Saturated aqueous NaHCC«3 solution (one half the volume ofthe total volume of the reaction mixture) was added and the mixture thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgSC«4), and concentrated. Flash, radial, or liquid chromatography ofthe crude product, followed by bulb-to-bulb distillation ofthe acquired oil, afforded the corresponding diene ester (215). Preparation of ethyl 4-bromo-2-[l-(trimethylstannyl)ethenyl]-4-pentenoate (46)16 Following general procedure 11 outlined above, ethyl (£)-3-trimethylstannyl-2-butenoate (208) was converted into the diene ester (46). The following amounts of reagents and solvents were used: L D A (9.3 mmol) in 55 mL of dry THF, H M P A (1.7 g, 9.3 mmol), ethyl (£)-3-trimethylstannyl-2-butenoate (208) (2.33 g, 8.41 mmol) in 8 mL of dry THF, and 2,3-dibromopropene (20) (2.52 g, 12.6 mmol). Radial chromatography (4 mm plate, 97:3 hexanes-Et20) ofthe crude product followed by distillation Br 46 209 172 (78-84°C/0.12 Torr) ofthe acquired oils afforded 2.03 g (61%) ofthe more polar diene ester (46) as a colourless oil and 0.25 g (8%) ofthe less polar diene ester ( 2 0 9 ) also as a colourless oil. Diene ester (46) exhibited IR (neat): 1728, 1631, 1277, 771 cm" 1 ; N M R (400 MHz) 5: 0.18 (s, 9H, 2 J S n - H = 5 4 Hz, -Sn(CH 3 ) 3 ) , 1.24 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.53 (dd, 1H, J= 15, 8 Hz, one of =C(Br)-CH 2), 2.92 (dd, 1H, J= 15, 8 Hz, one of=C(Br)-CH 2), 3.58 (br t, 1H, J= 8 Hz, 3 J S n _ H =62 Hz, -CHC0 2 Et ) , 4.08-4.16 (m, 2H, - O C H 2 C H 3 ) , 5.34 (d, 1H, J= 2 Hz, 3 J S n -H= 6 6 Hz, H a ) , 5 4 1 (<*, 1H, J= 2 Hz, one of-(Br)C=CH 2), 5.54 (d, 1H, J= 2 Hz, one of-(Br)C=CH 2), 5.82 (dd, 1H, J= 2, 1 Hz, 3 J S n - H = 1 3 7 ^ H b ) ; 1 3 c ( 1 0 0 - 4 M H z ) 6: -8.2, 14.2, 44.2, 54.3, 60.9, 118.9, 128.7, 130.9, 151.4, 173.3. Anal, calcd. for C 1 2 H 2 i B r 0 2 S n : C 36.43, H 5.35; found: C 36.23, H 5.28. Exact Mass calcd. for C n H 1 8 7 9 B r 0 2 S n ( M + - C H 3 ) : 380.9511; found: 380.9508. Diene ester ( 2 0 9 ) exhibited IR (neat): 1703, 1630, 1209, 772 cm" 1 ; X H N M R (400 MHz) 8: 0.21 (s, 9H, 2JS n_H=54 Hz, -Sn(CH 3 ) 3 ) , 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.50 (br t, 2H,J= 8Hz ,=CCH 2 ) , 2.70 (brt, 2H, J= 8 Hz, =CCH 2 ) , 4.18 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.40 (br d, 1H, J= 2 Hz, one of-(Br)C=CH 2), 5.55 (br d, 1H, J= 2 Hz, one of -(Br)C=CH 2), 6.40 (dd, 1H, J= 2, 1 Hz, 3 J S n . H =118 Hz, H a ) . Anal, calcd. for C 1 2 H 2 1 B r 0 2 S n : C 36.43, H 5.35; found: C 36.19, H 5.27. Exact Mass calcd. for C n H 1 8 7 9 B r 0 2 S n ( M + - C H 3 ) : 380.9511; found: 380.9511. Preparation of ethyl (E)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (47)^ Br 47 173 Following general procedure 11 outlined above, ethyl (Z)-3-trimethylstannyl-2-pentenoate (149) was converted into the diene ester (47). The following amounts of reagents and solvents were used: L D A (0.79 mmol) in 5 mL of dry THF, H M P A (142 mg, 0.792 mmol), ethyl (Z)-3-trimethylstannyl-2-pentenoate (149) (100 mg, 0.344 mmol) in 0.5 mL of dry THF, and 2,3-dibromopropene (20) (103 mg, 0.516 mmol). Flash chromatography (10 g of silica gel, 19:1 hexanes-Et20) of the crude product followed by distillation (85-90°C/0.12 Torr) ofthe acquired oil afforded 101 mg (72%) of ethyl (£)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (47) as a colourless oil that exhibited IR (neat): 1728, 1631, 1180, 770 cm" 1 ; LH N M R (400 MHz) 5: 0.13 (s, 9H, 2J S n_ H=54 Hz, -Sn(CH 3 ) 3 ) , 1.24 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.81 (d, 3H, J= 6.5 Hz, =CHCH 3 ) , 2.44 (ddd, 1H, J= 14, 6.5, 1 Hz, one of =C-CH 2 R), 2.94 (ddd, 1H, J= 14, 8, 1 Hz, one of=C-CH 2 R), 4.06-4.20 (m, 3H, - O C H 2 C H 3 and -CHC0 2 Et ) , 5.42 (d, 1H, J= 2 Hz, one of-(Br)C=CH 2), 5.56 (br d, 1H, J= 2 Hz, one of - ( B r ) O C H 2 ) , 5.86 (qd, 1H, J= 6.5, 1 Hz, 3 J S n - H = 7 3 =CHCH 3 ) . Exact Mass calcd. for C 1 2 H 2 0 7 9 B r O 2 S n ( M + - C H 3 ) : 394.9667; found: 394.9662. Preparation of ethyl (Z)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (48)16 Br 48 Following general procedure 11 outlined above, ethyl (i^-3-trrmethylstannyl-2-pentenoate (156) was converted into the diene ester (48). The following amounts of reagents and solvents were used: L D A (0.79 mmol) in 5 mL of dry THF, 174 H M P A (142 mg, 0.79 mmol), ethyl (£)-3-trimethylstannyl-2-pentenoate (156) (100 mg, 0.344 mmol) in 0.5 mL of dry THF, and 2,3-dibromopropene (20) (103 mg, 0.516 mmol). Flash chromatography (10 g of silica geL 19:1 hexanes-Et20) ofthe crude product followed by distillation (85-90°C/0.12 Torr) ofthe acquired oil afforded 106 mg (75%) of ethyl (Z)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (47) as a colourless oil that exhibited IR (neat): 1729, 1631, 1178, 777 cm" 1 ; A H N M R (400 MHz) 8: 0.20 (s, 9H, 2J S N_H=52 Hz, -Sn(CH 3 ) 3 ) , 1.23 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.79 (d, 3H, J= 7 Hz, =CHCH 3 ) , 2.53 (dd, 1H, J= 15, 7 Hz, one of =C-CH 2 R), 2.94 (dd, 1H, J= 15, 7 Hz, one of =C-CH 2 R), 3.50 (br t, 1H, J= 7 Hz, 3 J S N - H = 6 8 ^ -CHC0 2 Et ) , 4.11 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.39 (d, 1H, J= 1.5 Hz, one of-(Br)C=CH 2), 5.51 (br s, 1H, one of -(Br)C=CH 2), 6.18 (q, 1H, J= 1 Hz, 3J S N_H=128 Hz, =CHCH 3 ) . Exact Mass calcd. for C 1 2 H 2 0 7 9 B r O 2 S n ( M + - C H 3 ) : 394.9667; found: 394.9674. Preparation of ethyl (^)-2-(2-bromo-2-propenyl)-5-methyl-3-trimethylstannyl-3-hexenoate Following general procedure 11 outlined above, ethyl (^-5-metJiyl-3-trimethylstannyl-3-hexenoate (170) was converted into the diene ester (212). The following amounts of reagents and solvents were used: L D A (9.38 mmol) in 26 mL of dry THF, H M P A (1.69 g, 9.43 mmol), ethyl (i^-5-methyl-3-trimethylstannyl-3-hexenoate (170) (1.30 g, 4.08 mmol) in 5 mL of dry THF, and 2,3-dibromopropene (20) (1.21 g, 6.06 mmol). Flash chromatography (100 g of silica geL 97:3 hexanes-Et20) ofthe crude product followed (2121 212 175 by distillation (90-92°C/0.12 Torr) ofthe acquired oil afforded 1.55 g (87%) of ethyl (£)-2-(2-bromo-2-propenyl)-5-methyl-3-trimethylstannyl-3-hexenoate (212) as a colourless oil that exhibited IR (neat): 1733, 1611, 1465, 1298, 1181 cm" 1 ; N M R (400 MHz) 8: 0.12(s, 9H, 2JSn-H=54 Hz> -Sn(CH 3 ) 3 ) , 0.96 (d, 6H, J= 6 Hz, -CH(CH 3 ) 2 ) , 1.22 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.42 (dd, 1H, J= 15, 7 Hz, one of =C(Br)CH 2R), 2.78-2.87 (m, 1H, -CH(CH 3 ) 2 ) , 2.93 (dd, 1H, J= 15, 7 Hz, one of =C(Br)CH 2R), 4.03 (t, 1H, J= 7 Hz, 3JSn_H=62 Hz, -CHC0 2 Et ) , 4.09 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.40 (d, 1H, J= 1 Hz, one of -(Br)C=CH 2), 5.48 (d, 1H, J= 9 Hz, 3JSn-H=72 ^ =CH/Pr), 5.53 (br s, 1H, one of -(Br)C=CH 2); 1 3 C N M R (100.4 MHz) 8: -7.5, 14.1, 23.0, 28.0, 45.0, 47.4, 60.7, 118.6, 131.0, 137.4, 152.0, 173.9. Anal, calcd. for C 1 5 H 2 7 B r 0 2 S n : C 41.13, H 6.22; found: C 41.35, H 6.19. Exact Mass calcd. for C 1 4 H 2 4 7 9 B r 0 2 S n ( M + - C H 3 ) : 422.9982; found: 422.9976. Preparation of ethyl (Z)-2-(2-bromo-2-propenyl)-5-methyl-3-trirnethylstannyl-3-hexenoate Following general procedure 11 outlined above, ethyl (Z)-5-memyl-3-trimethylstannyl-3-hexenoate (168) was converted into the diene ester (216). The following amounts of reagents and solvents were used: L D A (0.72 mmol) in 2.5 mL of dry THF, H M P A (0.13 g, 0.73 mmol), ethyl (Z)-5-memyl-3-trimethylstannyl-3-hexenoate (168) (100 mg, 0.313 mmol) in 0.5 mL of dry THF, and 2,3-dibromopropene (20) (94 mg, 0.47 mmol). Flash chromatography (10 g of silica gel, 97:3 hexanes-Et20) ofthe crude product followed by distillation (95-102°C/0.12 Torr) ofthe acquired oil afforded 115 mg (84%) of (216) Br 216 176 ethyl (Z)-2-(2-bromo-2-propenyl)-5-methyl-3-trMethylstannyl-3-hexenoate (216) as a colourless oil that exhibited IR (neat): 1729, 1631, 1276, 1179 cm" 1 ; A H N M R (400 MHz) 5: 0.18 (s, 9H, 2 J S n - H = 5 2 Hz, -Sn(CH 3 ) 3 ) , 0.92 (d, 3H, J= 6 Hz, one o f -CH(CH 3 ) 2 ) , 0.95 (d, 3H, J= 6 Hz, one o f -CH(CH 3 ) 2 ) , 1.22 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.13-2.21 (m, 1H, -CH(CH 3 ) 2 ) , 2.54 (dd, 1H,V= 15, 8 Hz, one of =C(Br)CH 2), 2.93 (dd, 1H, J= 15, 6 Hz, one of =C(Br)CH 2), 3.43 (dd, 1H, J= 8, 6 Hz, 3J S n_H=56 Hz, -CHC0 2 Et ) , 4.06-4.15 (m, 2H, - O C H 2 C H 3 ) , 5.39 (br s, 1H, one of-(Br)C=CH 2), 5.50 (br s, 1H, one of-(Br)C=CH 2), 5.86 (d, 1H, J= 10 Hz, 3J S n_H=126 Hz, =CH(7Pr)); 1 3 C N M R (75.3 MHz) 5: -7.0, 14.2, 23.0, 23.2, 34.3, 43.7, 52.3, 60.7, 118.7, 131.7, 136.2, 151.6, 173.7. Anal, calcd. for C 1 5 H 2 7 B r 0 2 S n : C 41.13, H 6.22; found: C 41.51, H 6.19. Exact Mass calcd. for C 1 4 H 2 4 8 1 B r 0 2 S n ( M + - C H 3 ) : 424.9962; found: 424.9954. Preparation of ethyl (E) 2-(2-cyclohexyl-l-trrmethylstannylethenyl)-4-bromo-4-pentenoate Following general procedure 11 outlined above, ethyl (£)-4-cyclohexyl-3-trimethylstannyl-3-butenoate (169) was converted into the diene ester (213). The following amounts of reagents and solvents were used: L D A (8.32 mmol) in 26 mL of dry THF, H M P A (1.50 g, 8.37 mmol), (JE)-4-cyclohexyl-3-trimethylstannyl-3-butenoate (169) (1.30 g, 3.62 mmol) in 5 mL of dry THF, and 2,3-dibromopropene (20) (1.09 g, 5.46 mmol). Radial chromatography (4 mm plate, 97:3 hexanes-Et20) ofthe crude product followed by distillation (122-125°C/0.12 Torr) ofthe acquired oil afforded 1.57 g (91%) of ethyl £2131 Cy Br 213 177 (ii^-2-(2-cyclohexyl-l-trimethylstannyto (213) as a colourless oil that exhibited IR (neat): 1728, 1621, 1179, 769 cm" 1 ; lH N M R (400 MHz) 5: 0.10 (s, 9H, 2J S n_H=54 Hz, -Sn(CH 3 ) 3 ) , 0.99-1.11 (m, 2H), 1.12-1.20 (m, 1H), 1.23 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.24-1.36 (m, 2H), 1.55-1.73 (m, 5H), 2.40 (dd, 1H, J= 14, 7 Hz, one of =C(Br)CH 2R), 2.45-2.55 (m, 1H), 2.93 (dd, 1H, J= 14, 7 Hz, one of=C(Br)CH 2R), 4.03 (br t, 1H, J= 7 Hz, 3J S n. j j=82 Hz, -CHC0 2 Et ) , 4.03-4.16 (m, 2H, - O C H 2 C H 3 ) , 5.40 (d, 1H, J= 1.5 Hz, one of -(Br)C=CH 2), 5.50 (d, 1H, J= 8 Hz, 3 J S n - H = 7 6 ^ =CHCy), 5.52 (d, 1H, J= 1.5 Hz, one of-(Br)C=CH 2); 1 3 C N M R (100.4 MHz) 8: -7.1, 14.1, 25.6, 25.7, 25.8, 33.0, 33.3, 43.6, 44.3, 52.2, 60.6, 118.7, 131.6, 136.9, 150.2, 173.7. Anal, calcd. for C 1 8 H 3 1 B r 0 2 S n : C 45.22, H 6.54; found: C 45.47, H 6.48. Exact Mass calcd. for C 1 7 H 2 g 7 9 B r 0 2 S n ( M + - C H 3 ) : 463.0295; found: 463.0295. Preparation of ethyl (Z)-2-(2-cyclohexyl- l-trmiethylstannylethenyl)-4-bromo-4-pentenoate Fohowing general procedure 11 outlined above, ethyl (Z)-4-cyclohexyl-3-trirnethylstannyl-3-butenoate (167) was converted into the diene ester (217). The following amounts of reagents and solvents were used: L D A (9.98 mmol) in 30 mL of dry THF, H M P A (1.80 g, 9.99 mmol), ethyl (Z)-4-cyclohexyl-3-trimethylstannyl-3-butenoate (167) (1.56 g, 4.34 mmol) in 5 mL of dry THF, and 2,3-dibromopropene (20) (1.3 g, 6.5 mmol). Radial chromatography (4 mm plate, 97:3 hexanes-Et20) ofthe crude product followed by distillation (125-129°C/0.12 Torr) ofthe acquired oil afforded 1.92 g (93%) of ethyl (217) Cy Br 217 178 (Z)-2-(2-cyclohexyl-l-trniiethylstannylem^ (217) as a colourless oil that exhibited IR (neat): 1730, 1631, 1449, 1179 cm" 1 ; ! H N M R ( 4 0 0 MHz) 5: 0.17 (s, 9H, 2 J s n - H = 5 4 Hz, -Sn(CH 3 ) 3 ) , 1.03-1.17 (m, 6H), 1.22 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.48-1.72 (m, 4H), 1.80-1.90 (m, 1H, -CHR 2 ) , 2.53 (dd, 1H, J= 14, 8 Hz, one of=C(Br)CH 2R), 2.92 (dd, 1H, J= 14, 6 Hz, one of=C(Br)CH 2R), 3.43 (dd, 1H, J= 8, 6 Hz, 3 J S n - H = 6 0 Hz, -CHC0 2 Et ) , 4.05-4.15 (m, 2H, - O C H 2 C H 3 ) , 5.37 (d, 1H, J= 1 Hz, one of-BrC=CH 2 ) , 5.50 (br s, 1H, one of-BrC=CH 2 ) , 5.89 (d, 1H, J= 10 Hz, 3 J S n - H = 1 2 8 Hz, =CHCy); 1 3 C N M R (75.3 MHz) 8: -7.0, 14.2, 25.69, 25.74, 25.8, 33.1, 33.3, 43.7, 44.4, 52.3, 60.6, 118.7, 131.7, 137.0, 150.2, 173.7. Anal, calcd. for C i 8 H 3 1 B r 0 2 S n : C 45.22, H 6.54; found: C 45.53, H 6.43. Exact Mass calcd. for C 1 7 H 2 8 7 9 B r 0 2 S n (M+-CH 3): 463.0295; found: 463.0289. Preparation of ethyl (Z)-4-bromo-6-methyl-2-((Z)-3-methyl- 1-trimethylstannyl- l-butenyl)-4-heptenoate (218) Following general procedure 11 outlined above, ethyl (Z)-5-memyl-3-trirnethylstannyl-3-hexenoate (168) was converted into the diene ester (218). The following amounts of reagents and solvents were used: L D A (4.32 mmol) in 16 mL of dry THF, H M P A (0.78 g, 4.3 mmol), ethyl (Z)-5-methyl-3-trimethylstannyl-3-hexenoate (168) (600 mg, 1.88 mmol) in 2 mL of dry THF, and (Z)-l,2-dibromo-4-methyl-2-pentene (206) (600 mg, 2.48 mmol). Radial chromatography (4 mm plate, 97:3 hexanes-Et20) ofthe crude product followed by removal of traces of solvent under reduced pressure (vacuum pump) from the acquired material afforded 650 mg (72%) of ethyl Br 218 179 (Z)-4-bromo-6-methyl-2-((2^-3-methyl-l-trimethylstamy (218) as a colourless oil that exhibited IR (neat): 1729, 1617, 1181, 771 cm" 1 ; lH N M R (300 MHz) 5: 0.20 (s, 9H, 2 J S n - H = 5 4 Hz, -Sn(CH 3 ) 3 ) , 0.90-0.99 (m, 12H, 2 x -CH(CH 3 ) 2 ) , 1.23 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.13-2.23 (m, 1H, one o f -CH(CH 3 ) 2 ) , 2.51 (dd, 1H, J= 14, 9 Hz, one of =C(Br)CH 2R), 2.60-2.70 (m, 1H, one o f -CH(CH 3 ) 2 ) , 2.93 (dd, 1H, J= 14, 6 Hz, =C(Br)CH 2R), 3.50 (dd, 1H, J= 9, 6 Hz, 3 J S n . H = 71 Hz, -CHC0 2 Et ) , 4.03-4.16 (m, 2H, - O C H 2 C H 3 ) , 5.39 (d, 1H, J= 9 Hz,-BrC=CHR), 5.85 (d, 1H, J= 10 Hz, 3 J S n . H = 126 Hz, -SnC=CHR); 1 3 C N M R (75.3 MHz) 8: -6.9, 14.2, 21.8, 22.0, 23.09, 23.13, 31.0, 34.3, 43.7, 52.9, 60.6, 122.9, 136.4, 138.0, 151.4, 174.0. Anal, calcd. for C 1 8 H 3 3 B r 0 2 S n : C 45.03, H 6.93; found: C 45.31, H 6.96. Exact Mass calcd. for C 1 7 H 3 0 8 1 B r O 2 S n ( M + - C H 3 ) : 465.0452; found: 465.0443. Preparation of ethyl (Z)-4-bromo-5-cyclohexyl-2-((Z)-2-cyclohexyl-l-trimemylstannylemen^ (219) Following general procedure 11 outlined above, ethyl (2^-4-cyclohexyl-3-trimethylstannyl-3-butenoate (167) was converted into the diene ester (219) The following amounts of reagents and solvents were used: L D A (0.64 mmol) in 2 mL of dry THF, H M P A (0.12 g, 0.67 mmol), ethyl (Z)-4-cyclohexyl-3-trimethylstannyl-3-butenoate (167) (100 mg, 0.279 mmol) in 0.5 mL of dry THF, and (Z)-2,3-dibromo-l-cyclohexylpropene (207) (110 mg, 0.390 mmol). Radial chromatography (2 mm plate, 97:3 hexanes-Et20) ofthe crude product followed by distillation (135-140°C/0.12 Torr) ofthe acquired liquid afforded 93 mg Cy Br Cy 219 180 (60%) of ethyl (Z)-4-bromo-5-cyclohexyl-2-((Z)-2-cyclohexyl- l-trimethylstannylethenyr)-4-pentenoate (219) as a colourless oil that exhibited IR (neat): 1729, 1449, 1185 cm" 1 ; A H N M R (400 MHz) 5: 0.15 (s, 9H, 2 J S n - H = 5 4 - S n ( C H 3)3)> 1.01-1.30 (m, 12H), 1.22 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.55-1.71 (m, 8H), 1.80-1.88 (m, 1H, one o f=CHCHR 2 ) , 2.27-2.35 (m, 1H, one of =CHCHR 2 ) , 2.51 (dd, 1H, J= 14, 9 Hz, one of =C(Br)CH 2R), 2.88 (ddd, 1H, J= 14, 6, 1 Hz, =C(Br)CH 2R), 3.46 (dd, 1H, J= 9, 6 Hz, 3 J S n - H = 7 2 ^ -CHC0 2 Et ) , 4.02-4.13 (m, 2H, - O C H 2 C H 3 ) , 5.40 (br d, 1H, J= 9 Hz,-BrC=CHR), 5.87 (d, 1H, J= 10 Hz, 3J S n -H= 1 3 6 ^ -SnC-CHR); 1 3 C N M R (75.3 MHz) 8: -6.9, 14.1, 14.2, 25.7, 25.8, 25.9, 31.6, 33.2, 40.5, 43.8, 44.3, 53.1, 60.5, 123.1, 136.4, 137.4, 150.0, 174.0. Anal, calcd. for C 2 4 H 4 i B r 0 2 S n : C 51.45, H 7.38; found: C 51.08, H 7.57. Exact Mass calcd. for C 2 3 H 3 8 8 1 B r 0 2 S n (M+-CH 3): 545.1078; found: 545.1076. 10. General Procedure 12: Preparation ofthe ethyl 2.3-bis(alkyhdene)cyclobutane-carboxylates (221)16 A stirred solution of tetrakis(triphenylphospliine)palladium (0) (-0.05 equiv., unless noted otherwise) and the appropriate diene ester (215) (1.00 eq.) in dry D M F (8.2-24 mL/mmol ester) was heated at 80°C for 1.5 hours, unless noted otherwise. The reaction mixture was cooled to room temperature, water (equal volume to the total volume ofthe reaction mixture) was added and the mixture was thoroughly extracted with «-pentane. The combined extracts were washed with brine, dried (MgSC>4), and concentrated. Flash or radial chromatography, unless noted R' R 215 221 181 otherwise, ofthe crude product followed by bulb-to-bulb distillation ofthe acquired oil afforded the corresponding ethyl 2,3-bis(alkyhdene)cyclobutanecarboxylate (221). Preparation of ethyl 2.3-bis(methylene)cyclobutanecarboxylate (53)16 Following general procedure 12 outlined above, ethyl 4-bromo-2-[(l-trirnethylstannyl)ethenyl]-4-pentenoate (46) was converted into the cyclobutanecarboxylate (53). The following amounts of reagents and solvents were used: Pd(PPh 3 ) 4 (168 mg, 0.145 mmol) and ethyl 4-bromo-2-[(l-trimethylstannyl)ethenyl]-4-pentenoate (46) (1.40 g, 3.54 mmol) in 40 mL of dry DMF. Normal workup followed by distillation (60-70°C/15 Torr) ofthe crude product afforded 439 mg (82%) of ethyl 2,3-bis(methylene)cyclobutanecarboxylate (53) as a colourless oil which exhibited fR (neat): 1736, 1682, 1181, 1041, 888 cm" 1 ; lH N M R (400 MHz) 8: 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.81 (dddd, 1H, J= 15, 9, 2.5, 2 Hz, H b ) , 3.06 (dddd, 1H, J= 15, 6, 2.5, 2 Hz, H c ) , 3.68-3.78 (m, 1H, H a ) , 4.10-4.24 (m, 2H, - O C H 2 C H 3 ) , 4.81 (br s, 1H, H d ) , 5.01 (br d, 1H, J= 2 Hz, H g ) , 5.23 (dd, 1H, J= 2.5, 2.5 Hz, H e ) , 5.26 (d, 1H, J= 3 Hz, Hf); in a series of decoupling experiments, irradiation at 8 2.81 (H D) converted the signal at 8 3.06 (H c) to a multiplet, the multiplet at 8 3.68-3.78 (H a ) was sharpened, and the doublet of doublets at 8 5.23 (H e ) was converted to a doublet (J= 2.5 Hz); irradiation ofthe signal at 8 3.06 (H c ) converted the signal at 8 2.81 (H D) into a multiplet, simplified the multiplet at 8 3.68-3.78 (H a), and the doublet of doublets at 8 5.23 (H e ) into a doublet {J- 2.5 Hz); irradiation at 8 3.73 (H a) converted the signal at 8 2.81 (H D) into a ddd (J= 15, 2.5, 2 Hz), the signal at 8 3.06 (H c ) into '9 53 182 a ddd (J= 15, 2.5, 2 Hz), and the signals at 8 5.01 (H g ) and 8 5.26 (Hf) were converted into singlets; irradiation at 8 5.23 (Hg) converted the signal at 8 2.81 (H D) into a ddd (J= 15, 9, 2 Hz) and the signal at 8 3.06 (H c ) into a ddd (J= 15, 6, 2 Hz); irradiation at 8 5.26 (Hf) simplified the multiplet at 8 3.68-3.78 (H a). NOE difference experiments: irradiation at 8 5.26 (Hf) caused enhancement ofthe signal at 8 5.01 (Hg); irradiation at 8 3.73 (H a ) caused enhancement ofthe signal at 8 2.81 (H b). 1 3 C N M R (50.3 MHz) 8: 14.2, 31.1, 43.8, 60.8, 105.1, 145.7, 146.4, 163.2, 174.5. Exact Mass calcd. for C 9 H 1 2 0 2 : 152.0837; found: 152.0843. Preparation of ethyl (Z)-2-ethyMene-3-methylenecyclobutanecarboxylate (55)16 Following general procedure 12 outlined above, ethyl (Z)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (48) was converted into the cyclobutanecarboxylate (55). The following amounts of reagents and solvents were used: Pd(PPh 3 ) 4 (230 mg, 0.199 mmol), and ethyl (Z)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (48) (1.60 g, 3.90 mmol) in 40 mL of dry DMF. Normal workup followed by distillation (82-94°C/15 Torr) ofthe crude product afforded 550 mg (85%) of ethyl (Z)-2-ethyMene-3-methylenecyclobutanecarboxylate (55) as a colourless oil which exhibited spectral characteristics identical to those previously reported. 16 55 183 Preparation of ethyl (EV2-ethyMene-3-methylenecyclobutariecarboxylate (54) H f ^ — k H a C0 2Et 54 Following general procedure 12 outlined above, ethyl (£)-2-(2-bromo-2-propenyl)-3-trirnethylstannyl-3-pentenoate (47) was converted into the cyclobutanecarboxylate (54). The following amounts of reagents and solvents were used: Pd(PPh 3 ) 4 (145 mg, 0.125 mmol) and ethyl (£)-2-(2-bromo-2-propenyl)-3-trimethylstannyl-3-pentenoate (47) (1.00 g, 2.44 mmol) in 20 mL of dry DMF. Normal workup followed by distillation (80-90°C/15 Torr) ofthe crude product afforded 326 mg (80%) of ethyl (£)-2-efhyhdene-3-methylenecyclobutanecarboxylate (55) as a colourless oil which exhibited exhibited spectral characteristics identical to those previously reported. 1 °" Preparation of ethyl (Z)-2-(2-methylpropyhdene)-3-methylenecyclobutanecarboxylate (234) 234 184 Following general procedure 12 outlined above, ethyl (Z)-2-(2-bromo-2-propenyl)-5-methyl-3-trirnethylstannyl-3-hexenoate (216) was converted into the cyclobutanecarboxylate (234). The following amounts of reagents and solvents were used: Pd(PPh3)4 (14 mg, 12 umol), and ethyl (Z)-2-(2-bromo-2-propenyl)-5-methyl-3-trimethylstannyl-3-hexenoate (216) (100 mg, 0.228 mmol) in 3 mL of dry DMF. Normal workup followed by flash chromatography (10 g silica geL 95:5 hexanes-Et20) ofthe crude product and distillation (46-48°C/0.12 Torr) ofthe acquired oil afforded 40 mg (90%) of ethyl (Z)-2-(2-methylpropyhdene)-3-methylenecyclobutanecarboxylate (234) as a colourless oil which exhibited IR (neat): 1737, 1179, 873 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 0.97 (d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , LOO (d, 3H, J= 6.5 Hz, one of -CH(CH 3 ) 2 ) , 1.25 (t, 3H, J= 7 Hz, - 0 C H 2 C H 3 ) , 2.64-2.76 (m, 2H, - C H ( C H 3 ) 2 , H b ) , 2.90-2.99 (m, 1H, He), 3.54-3.60 (m, 1H, H a ) , 4.08-4.22 (m, 2H, - O C H 2 C H 3 ) , 4.87 (d, 1H, J= 1 Hz, FLj), 5.09 (dd, 1H, J= 2.5, 2.5 Hz, Hg), 5.29 (d, 1H, J= 9.5 Hz, Hf); NOE difference experiments: irradiation at 8 0.97 caused enhancement ofthe signals at 8 2.64-2.76 ( -CH(CH 3 ) 2 ) and 8 5.29 (Hf); irradiation at 8 3.57 (H a) caused enhancement ofthe signals at 8 2.68-2.72 (H D) and 8 5.29 (Hf); irradiation at 8 5.09 (H e ) caused enhancement ofthe signals at 8 2.64-2.76 ( -CH(CH 3 ) 2 ) and 8 4.87 (H d). 1 3 C N M R (75.3 MHz) 8: 14.3,22.4(2 carbons), 28.0,30.9, 42.6, 60.6, 107.5, 134.1, 135.5, 145.8, 153.8. Anal, calcd. for C 1 2 H 1 8 0 2 : C 74.19, H 9.34; found: C 74.00, H 9.40. Exact Mass calcd. for C 1 2 H 1 8 0 2 : 194.1306; found: 194.1312. Preparation of ethyl (•£')-2-(2-methylpropyhdeneV3-methylenecyclobutanecarboxvlate (233) 233 185 Following general procedure 12 outlined above, ethyl (£)-2-(2-bromo-2-propenyl)-5-memyl-3-trirnethylstannyl-3-hexenoate (212) was converted into the cyclobutanecarboxylate (233). The following amounts of reagents and solvents were used: Pd(PPh3)4 (14 mg, 12 umol), and ethyl (£)-2-(2-bromo-2-propenyl)-5-methyl-3-trimethylstannyl-3-hexenoate (212) (100 mg, 0.228 mmol) in 3 mL of dry DMF. Normal workup followed by flash chromatography (10 g silica gel, 95:5 hexanes-Et20) ofthe crude product and distillation (36-38°C/0.12 Torr) ofthe acquired oil afforded 35 mg (79%) of ethyl (£)-2-(2-methylpropyhdene)-3-methylenecyclobutanecarboxylate (233) as a colourless oil which exhibited IR (neat): 1736, 1650, 1178, 865 cm" 1 ; lH N M R (400 MHz) 5: 0.93 (d, 3H, J= 1 Hz, one o f -CH(CH 3 ) 2 ) , 0.96 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 1.25 (t, 3H, J= 7 Hz, - 0 C H 2 C H 3 ) , 2.45-2.55 (m, 1H, -CH(CH 3 ) 2 ) , 2.79 (dddd, 1H, J= 15, 9, 2.5, 2.0 Hz, H b ) , 2.84-2.91 (m, 1H, H c ) , 3.68-3.73 (m, 1H, H a ) , 4.13-4.18 (m, 2H, - O C H 2 C H 3 ) , 4.66 (dd, 1H, J= 2, 2 Hz, H ^ , 5.09 (dd, 1H, J= 2.5, 2.5 Hz, H e ) , 5.54 (dd, 1H, J= 10, 3 Hz, Hf); NOE difference experiments: irradiation at 8 2.50 ( -CH(CH 3 ) 2 ) caused enhancement ofthe signals at 8 0.93 ( one o f -CH(CH 3 ) 2 ) , 8 0.96 ( one o f -CH(CH 3 ) 2 ) , and 8 3.68-3.73 (H a ) ; irradiation at 8 3.70 (H a ) caused enhancement ofthe signals at 8 0.93 ( one o f -CH(CH 3 ) 2 ) , 8 0.96 ( one of -CH(CH 3 ) 2 ) , 8 2.50 ( -CH(CH 3 ) 2 ) and 8 2.79 (H b ) ; irradiation at 8 5.54 (Hf) caused enhancement ofthe signals at 8 0.93 ( one o f -CH(CH 3 ) 2 ) , 8 0.96 ( one o f -CH(CH 3 ) 2 ) and 8 5.09(H e). 1 3 C N M R (125.8 MHz) 8: 14.2,22.5,22.6,27.6,31.9,42.6,60.8, 102.5, 130.0, 135.7, 146.2, 173.4. Anal, calcd. for C 1 2 H 1 8 0 2 : C 74.19, H 9.34; found: C 73.98, H 9.36. Exact Mass calcd. for C 1 2 H 1 8 0 2 : 194.1306; found: 194.1307. 186 Preparation of ethyl (Z)-2-cyclohexylmethylene-3-methylenec^^ (236) Following general procedure 12 outlined above, ethyl (Z)-2-(2-cyclohexyl-l-trirnethylstannylethenyl)-4-bromo-4-pentenoate (217) was converted into the cyclobutanecarboxylate (236). The following amounts of reagents and solvents were used: Pd(PPh3)4 (7 mg, 6 umol), and ethyl (Z)-2-(2-cyclohexyl-l-trimethylstannylethenyl)-4-bromo-4-pentenoate (217) (50 mg, 0.10 mmol) in 2 mL of dry DMF. Normal workup followed by flash chromatography (5 g silica geL 97:3 hexanes-Et20) ofthe crude product and distillation (52-54°C/0.12 Torr) ofthe acquired oil afforded 18.5 mg (79%) of ethyl (Z)-2-cyclohexylmethylene-3-methylenecyclobutanecarboxylate (236) as a colourless oil which exhibited IR (neat): 1737, 1645, 1178 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 1.00-1.30 (m, 6H), 1.24 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.55-1.74 (m, 4H), 2.32-2.43 (m, 1H, =CCHR 2 ) , 2.69 (dddd, 1H, J= 16, 8, 2.5, 2.0 Hz, H D ) , 2.90-2.98 (m, 1H, H.), 3.54-3.60 (m, 1H, H a ) , 4.09-4.21 (m, 2H, - O C H 2 C H 3 ) , 4.86 (br d, 1H, J=2 Hz, Hrf), 5.07 (dd, 1H, J= 2.5, 2.5 Hz, H e ) , 5.32 (d, 1H, J= 9.5 Hz, Hf); NOE difference experiments: irradiation at 8 2.38 (=CCHR 2) caused enhancement ofthe signals at 8 1.55-1.74, 8 5.07 (Hg) and 8 5.32 (Hf); irradiation at 8 3.57 (H a ) caused enhancement ofthe signals at 8 2.69 (H D) and 8 5.32 (Hf); irradiation at 8 5.07 (H e ) caused enhancement ofthe signals at 8 2.32-2.43 (=CCHR 2) and 8 4.86 (H a ) ; irradiation at 8 5.32 (Hf) caused enhancement ofthe signals at 8 1.00-1.30, 8 2.32-2.43 (=CCHR 2), and 8 3.54-3.60 (H a). 1 3 C N M R (100.4 MHz) 8: 14.3, 25.8, 25.9, 26.0, 30.9, 32.39, 32.44, 37.7, 42.7, 60.5, 107.3, 132.6, 135.9, 145.9, 172.8. Anal, calcd. for C 1 5 H 2 2 0 2 : C 76.88, H 9.47; found: C 76.79, H 9.39. Exact Mass calcd. for C 1 5 H 2 2 0 2 : 234.1619; found: 234.1624. 236 187 Preparation of ethyl (£)-2-cyclohexyhmethylene-3-met^^ (235) Following general procedure 12 outlined above, ethyl (E) 2-(2-cyclohexyl-l-trirnethylstannylethenyl)-4-bromo-4-pentenoate (213) was converted into the cyclobutanecarboxylate (235). The following amounts of reagents and solvents were used: Pd(PPh 3)4 (7 mg, 6 Ltmol), and ethyl (^-2-(2-cyclohexyl-l-trimethylstannylethenyl)-4-bromo-4-pentenoate (213) (50 mg, 0.10 mmol) in 2 mL of dry DMF. Normal workup followed by flash chromatography (5 g silica geL 97:3 hexanes-Et20) ofthe crude product and distillation (48-49°C/0.12 Torr) ofthe acquired oil afforded 19.5 mg (83%) of ethyl (£)-2-cyclohexylmethylene-3-methylenecyclobutanecarboxylate (235) as a colourless oil which exhibited IR (neat): 1735, 1650, 1154 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 1.00-1.11 (m, 2H), 1.11-1.22 (m, 2H), 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.55-1.74 (m, 6H), 2.13-2.24 (m, 1H, =C-CHR 2 ) , 2.78 (dddd, 1H, J= 16, 9, 2.5, 2.0 Hz, H b ) , 2.85-2.93 (m, 1H, He), 3.68-3.74 (m, 1H, H a ) , 4.15 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.66 (dd, 1H, J= 2, 2 Hz, H d ) , 5.08 (dd, 1H, J= 2.5, 2.5 Hz, Hg), 5.56 (dd, 1H, J= 9.5, 2.5 Hz, Hf); NOE difference experiments: irradiation at 8 2.19 (=CCHR 2) caused enhancement ofthe signals at 8 1.55-1.74, 8 3.68-3.74 (H a) and 8 5.56 (Hf); irradiation at 8 3.71 (H a ) caused enhancement ofthe signals at 8 2.13-2.24 (=CCHR 2) and 8 2.78 (H D ) ; irradiation at 8 5.56 (Hf) caused enhancement ofthe signals at 8 1.11-1.22, 8 2.13-2.24 (=CCHR 2), and 8 5.08 (Hg). 1 3 C N M R (75.3 MHz) 8: 14.3,25.8, 26.0, 31.9, 32.6, 37.1, 42.7, 60.8, 102.5, 128.6, 136.3, 146.4, 173.5. Anal, calcd. for c-Hex 235 188 C 1 5 H 2 2 ° 2 : c 7 6 88> H 9 - 4 7 ; f o u n d : C 7 6 - 7 4 > H 9 5 L E x a c t M a s s c a l c d - f o r C 1 5 H 2 2 ° 2 : 234.1619; found: 234.1617. Preparation of ethyl (Z.Z)-2.3-bis(2-methylpropylidene)cyclobutanecarboxylate (237) Following a modified version of general procedure 12 outlined above in which the reaction time was 2.5 hours and the amount of the catalyst was 0.1 eq., ethyl (Z)-4-bromo-6-methyl-2-((Z)-3-methyl- 1-trimethylstannyl- l-butenyl)-4-heptenoate (218) was converted into the cyclobutanecarboxylate (237). The following amounts of reagents and solvents were used: Pd(PPh3)4 (50 mg, 43 umol), and ethyl (Z)-4-bromo-6-methyl-2-((Z)-3-methyl- 1-trimethylstannyl- l-butenyl)-4-heptenoate (218) (200 mg, 0.417 mmol) in 10 mL of dry DMF. Normal workup followed by flash chromatography (10 g silica gel, 95:5 hexanes-Et20) ofthe crude product and distillation (47-50°C/0.12 Torr) ofthe acquired oil afforded 82 mg (83%) of ethyl (Z,Z)-2,3-bis(2-methylpropyUdene)cyclobutanecarboxylate (237) as a colourless oil which exhibited IR (neat): 1737, 1466, 1176 cm" 1 ; 41 N M R (400 MHz) 5: 0.95-1.01 (m, 12H, 2 x -CH(CH 3 ) 2 ) , 1.25 (t, 3H, J= 7 Hz, - 0 C H 2 C H 3 ) , 2.50-2.61 (m, 3H, 2 x - C H ( C H 3 ) 2 , H b ) , 2.82 (ddd, 1H, J= 14, 6.5, 2 Hz, H c ) , 3.48 (ddd, 1H, J= 8, 6.5, 2 Hz, H a ) , 4.11-4.22 (m, 2H, - O C H 2 C H 3 ) , 4.92 (br d, 1H, J= 10 Hz, H d ) , 5.08 (br d, 1H, J= 10 Hz, H e ) ; NOE difference experiments: irradiation at 8 3.48 (H a) caused enhancement ofthe signals at 8 2.50-2.57 (H b ) and 8 5.08 (H e ) ; irradiation at 8 4.92 (H,j) caused enhancement ofthe signals at 8 0.95-0.99 (-CH(CH 3 ) 2 ) , 8 2.50-2.60 ( -CH(CH 3 ) 2 , H b ) , and 8 2.82 (He); irradiation at 8 5.08 (H e) caused Hd H e 237 189 enhancement ofthe signals at 8 0.97-1.01 (-CH(CH 3 ) 2 ) , 8 2.53-2.61 ( -CH(CH 3 ) 2 ) , and 8 3.48 (H a). 1 3 C N M R (100.4 MHz) 8: 14.3, 22.77, 23.13, 23.27, 23.34, 29.3, 29.5, 31.0, 43.2, 60.4, 131.2, 131.3, 133.5, 135.1, 172.9. Anal, calcd. for C 1 5 H 2 4 0 2 : C 76.22, H 10.24; found: C 75.98, H 10.30. Exact Mass calcd. for C i 5 H 2 4 0 2 : 236.1777; found: 236.1777. Preparation of ethyl (Z.Z)-2J-bis(2-methylpropyhdene)cyclobutanecarboxylate (237) by CuCl methodology4 8, 84 To a hot (60°C), stirred solution of cuprous chloride (318 mg, 3.21 mmoL 2.8 equiv.) in 20 mL DMF was added a solution of ethyl (Z)-4-bromo-6-methyl-2-((Z)-3-methyl-1-trimethylstannyl- l-butenyl)-4-heptenoate (52) (550 mg, 1.15 mmol) in 20 mL of dry DMF. The reaction mixture was stirred for 10 minutes at 60°C and was then cooled to room temperature. Aqueous N H 4 C I - N F L 4 O H (pH 8, 50 mL) was added and the mixture was thoroughly extracted with E t 2 0 . The combined extracts were washed with brine, dried (MgS0 4 ) , and concentrated. Radial chromatography (2 mm plate, 19:1 hexanes-E t 2 0 ) ofthe crude product, followed by removal of traces of solvent (vacuum pump) from the acquired liquid afforded 221 mg (81%) of ethyl (Z,Z)-2,3-bis(2-methylpropyhdene)cyclobutanecarboxylate (60), a colourless oil that exhibited spectra identical with those reported in the last experiment. 237 190 Preparation of ethyl (Z.Z)-2.3-bis(cyclohexylmethylerie)cyclobutanecarboxvlate (238) Following a modified version of general procedure 12 outlined above in which the reaction time was 48 hours and the amount of the catalyst was 0.1 eq., ethyl (Z)-4-bromo-5-cyclohexyl-2-((2^-2-cyclohexyl-l-trimethylstannylethenyl)-4-pentenoate (219) was converted into the cyclobutanecarboxylate (238). The following amounts of reagents and solvents were used: Pd(PPh3)4 (11 mg, 9 umoi), and ethyl (Z)-4-bromo-5-cyclohexyl-2-((Z)-2-cyclohexyl-l-trimethylstannylethenyl)-4-pentenoate (219) (50 mg, 0.089 mmol) in 2.5 mL of dry DMF. Normal workup followed by flash chromatography (10 g silica geL 95:5 hexanes-Et20) ofthe crude product and distillation (47-50°C/0.12 Torr) ofthe acquired oil afforded 6 mg (21%) of ethyl (Z,Z)-2,3-bis(cyclohexylmethylene)cyclobutanecarboxylate (238), a colourless oil that exhibited IR(neat): 1740, 1692, 1449, 1173 cm" 1 ; *HNMR(400 MHz) 8: 1.01-1.32 (m, 13Hincluding at 8 1.25 a triplet, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.61-1.77 (m, 10H), 2.15-2.27 (m, 2H, =C-CHR 2 ) , 2.53 (ddd, 1H, J= 16, 9, 2 Hz, H D ) , 2.82 (ddd, 1H, J= 16, 6, 2 Hz, H c ) , 3.49 (ddd, 1H, J= 9, 6, 2.5 Hz, H a ) , 4.10-4.20 (m, 2H, - O C H 2 C H 3 ) , 4.93 (br d, 1H, J= 10 Hz, H(j), 5.11 (br d, 1H, J= 10 Hz, H e ) ; NOE difference experiments: irradiation at 8 2.53 (H D) caused enhancement ofthe signals at 8 2.82 (Hg), 8 4.93 (FLj) and 8 3.49 (H a ) ; irradiation at 8 2.82 (He) caused enhancement ofthe signal at 8 2.53 (H D ) ; irradiation at 8 3.49 (H a) caused enhancement ofthe signals at 8 2.53 (H D) and 8 5.11 (Hg); irradiation at 8 5.11 (H e) caused enhancement ofthe signals at 8 1.01-1.20 and 8 3.49 (H a). 1 3 C N M R (75.3 MHz) 8: 14.4, Hd 238 191 25.88, 25.97, 26.01, 30.9, 33.4, 33.5, 33.6, 39.0, 39.2, 43.3, 60.4, 129.4, 129.7, 134.0, 135.7, 173.0. Anal, calcd. for C21H32O2: C 79.69, H 10.20; found: C 79.42, H 10.31. Exact Mass calcd. for C21H32O2: 316.2402; found: 316.2408. Preparation of ethyl (Z.Z)-2 J-bis(cyclohexylmetiiylene)cyclobutanecarboxylate (238) by CuCl To a hot (60°C), stirred solution of cuprous chloride (25 mg, 0.25 mmol, 2.8 equiv.) in 2 mL of dry D M F was added a solution of ethyl (Z)-4-bromo-5-cyclohexyl-2-((Z)-2-cyclohexyl-l-trimethylstannylethenyl)-4-pentenoate (219) (50 mg, 0.089 mmol) in 2 mL of dry DMF. The reaction mixture was stirred for 10 minutes at 60°C and was then cooled to room temperature. Aqueous NFL4CI-NFL4OH (pH 8, 4 mL) was added and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried MgS04, and concentrated. Radial chromatography (1 mm plate, 2:1 CCLi-CgHg) ofthe crude product followed by removal of traces of solvent (vacuum pump) from the acquired liquid afforded 24 mg (84%) of ethyl (Z,Z)-2,3-bis(cyclohexylmethylene)cyclobutanecarboxylate (239), a colourless oil that exhibited spectra identical with those reported in the last experiment. methodology4 8. 238 192 11. General Procedure 13: Preparation of cyclobutanecarboxamides (311 and312) 7 i R' 221 R H C 0 2 E t R^S O Me 0 Me 311 312 To a stirred solution of (i?)-(+)-l-phenylethylamine ( -2 .24 equiv.) in dry benzene (15-19 mL/mmol of ester) at room temperature was added, dropwise, a solution of trimethylaluminum in toluene (2.24 equiv.). After the resultant mixture had been stirred for 20 minutes, a solution of the appropriate cyclobutanecarboxylate (221) (1 equiv.) in dry benzene (2.4-5.0 mL/mmol of ester) was added and the resulting mixture was refluxed for 4 hours. Hydrochloric acid (2 M , equal volume to the total volume ofthe reaction mixture) was added and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgSC^), and concentrated. Radial chromatography ofthe crude product followed by recrystallization ofthe acquired solids afforded the diastereoisomers (311) and (312). 193 Preparation ofthe cyclobutanecarboxamides (239) and (240) Hd /-Pr /-Pr H, H b | H C • H a H , / N Ph r Y O Me 240 H d ,-Pr^S /-Pr H b H r H N. O Me 239 Following general procedure 13 outlined above, ethyl (Z,Z)-2,3-bis(2-methylpropyhdene)cyclobutanecarboxylate (237) was converted into the cyclobutanecarboxamides (239) and (240). The following amounts of reagents and solvents were used: (R)-(+)- 1-phenylethylamine (231 mg, 1.91 mmol) in 16 mL of dry benzene, trimethylaluminum(1.90 mmol), and ethyl (Z,Z)-2,3-bis(2-methylpropyhdene)cyclobutanecarboxylate (237) (200 mg, 0.846 mmol) in 2 mL of dry benzene. Normal workup, followed by radial chromatography (2 mm plate, 2:1 hexanes-Et20) and recrystallization (1:1 petroleum ether-Et20) ofthe acquired solids afforded 85 mg (32%) of cyclobutanecarboxamide (240) as a colourless solid (melting point, 110-111°C) and 88 mg (33%) of cyclobutanecarboxamide (239) as a colourless solid (melting point, 103-104°C). Cyclobutanecarboxamide (240) exhibited IR (KBr): 3337, 1724, 1654, 1524, 1234 cm" 1 ; i H N M R ( 4 0 0 MHz) 5: 0.92-1.02 (m, 12H, 2 x -CH(CH 3 ) 2 ) , 1.47 (d, 3H, J= 7 Hz, -N C H C H 3 ) , 2.50-2.63 (m, 3H, 2 x - C H ( C H 3 ) 2 , H b ) , 2.75 (ddd, 1H, J= 14, 8, 2 Hz, H.), 3.39 (ddd, 1H, J= 8, 6, 2.5 Hz, H a ) , 4.96 (br d, 1H, J= 9 Hz, H a ) , 4.98 (br d, 1H, J= 9 Hz, Hg), 5.12 (quintet, 1H, J= 7 Hz, - N C H C H 3 ) , 6.02 (br d, 1H, J= 7 Hz, -NH), 7.23-7.33 (m, 5H, aromatic); in a series of decoupling experiments, irradiation at 8 2.75 (H c ) simplified the multiplet at 8 2.55-2.63 (H D) and converted the signal at 8 3.39 (H a ) to a doublet of doublets (J= 6, 2.5 Hz); irradiation at 8 3.39 (H a ) simplified the multiplet at 8 2.55-2.63 (H 0 ) , converted the signal at 8 2.75 (H c ) to a (dd, J= 14, 2 Hz), and sharpened the doublet at 8 4.98 (H e ) ; 194 irradiation at 5 4.97 (H^, H e ) simplified the multiplet at 8 2 .50-2 .63 (2 x - C H ( C H 3 ) 2 , H D ) , changed the signal at 8 2.75 (Hg) to a (dd, J= 14, 8 Hz), and altered the signal at 8 3.39 (H a) to a (dd, J= 8, 6 Hz); irradiation at 8 5.12 ( - N C H C H 3 ) simplified the doublet at 8 1.47 ( - N C H C H 3 ) to a singlet and sharpened the broad doublet at 8 6.02 (-NH) to a broad singlet; irradiation at 8 6.02 (-NH) simplified the quintet at 8 5.12 ( - N C H C H 3 ) to a quartet (J= 7 Hz); NOE difference experiments: irradiation ofthe signal at 8 2.75 (H c ) led to enhancement ofthe signals at 8 2.55-2.63 (H D) and 8 3.39 (H a ) ; irradiation ofthe signal at 8 3.39 (H a ) led to the enhancement ofthe signals at 8 2.75 (H c ) , 8 4 .98 (H e ) , and 8 6.02 ( -NH); irradiation ofthe signal at 8 4.97 (Hj, H e ) led to the enhancement ofthe signals at 8 0.92-1.02 (2 x -CH(CH 3 ) 2 ) , 2 .50-2 .63 (2 x - C H ( C H 3 ) 2 , H D ) , 8 2.75 (H c ) , 8 3.39 (H a), and 8 6.02 (-NH) ; irradiation ofthe signal at 8 5.12 ( - N C H C H 3 ) led to the enhancement ofthe signals at 8 1.47 ( N C H C H 3 ) and 8 7.23-7.33; irradiation ofthe signal at 8 6.02 (-NH) led to the enhancement ofthe signals at 8 3.39 (H a), 8 4 .98 (He), 8 5.12 ( - N C H C H 3 ) and 8 7.23-7.33; 1 3 C N M R (100.4 MHz) 8: 21.9, 23.0, 23.2, 23.3, 29 .6 , 33.2, 45.5, 48.4, 126.0, 127.3, 128.7, 132.0, 132.1, 133.5, 136.3, 143.2, 171.9. Anal, calcd. for C 2 1 H 2 9 N O : C 80 .98 , H 9.39, N 4 .50; found: C 80 .30, H 9.35, N 4 .36. Exact Mass calcd. for C21H29NO: 311 .2249 ; found: 311 .2251 . X-Ray crystallographic data for compound (240) can be seen in appendix V. Cyclobutanecarboxamide (239) exhibited IR (KBr): 3318 , 1726, 1654 cm" 1 ; i H N M R (400 MHz) 8: 0.92-1.02 (m, 12H, 2 x -CH(CH 3 ) 2 ) , 1.47 (d, 3H, J= 7 Hz, N C H C H 3 ) , 2.49-2.61 (m, 3H, 2 x - C H ( C H 3 ) 2 , He), 2.73 (ddd, 1H, J= 14, 9, 2 Hz, Hj>), 3.39 (ddd, 1H, J= 9, 6, 2 Hz, H a ) , 4.94 (br d, 1H, J= 10 Hz, ELY), 5.01 (br d, 1H, J= 10 Hz, Hg), 5.12 (quintet, 1H, J= 7 Hz, - N C H C H 3 ) , 6.01 (br d, 1H, J= 7 Hz, -NH), 7.23-7.33 (m, 5H, aromatic); in a series of decoupling experiments, irradiation at 8 2.73 (H D ) simplified the multiplet at 8 2.55-2.61 (HQ) and the changed signal at 8 3.39 (H a ) to a doublet of doublets (J= 6, 2 Hz); irradiation at 8 3.39 (H a ) simplified the multiplet at 8 2.55-2.61 (H c ) and sharpened the signal at 8 2.73 (H D) to a (dd, J= 14, 2 Hz); irradiation at 8 4.94 (H u ) simplified the multiplet at 8 2.49-2.61 195 (-CH(CH3)2, H c ) , and converted the signal at 8 2.73 (H D) to a doublet of doublets (J= 14, 9 Hz); irradiation at 8 5.01 (H e ) simplified the signal at 8 3.39 (H a ) to a doublet of doublets (J= 9, 6 Hz); irradiation at 8 5.12 ( - N C H C H 3 ) simplified the doublet at 8 1.47 ( - N C H C H 3 ) to a singlet and changed the broad doublet at 8 6.01 (-NH) to a broad singlet; irradiation at 8 6.01 (-NH) simplified the quintet at 8 5.12 ( - N C H C H 3 ) to a quartet (J= 7 Hz); NOE difference experiments: irradiation of the signal at 8 2.73 (H D) led to enhancement ofthe signals at 5 2.55-2.61 (H c ) and 8 3.39 (H a ) ; irradiation of the signal at 8 3.39 (H a ) led to the enhancement of the signals at 8 2.73 (H D ) ; irradiation ofthe signal at 8 5.01 (Hg) led to the enhancement ofthe signals at 8 0.92-1.02 ( -CH(CH 3 ) 2 ) ; irradiation ofthe signal at 8 5.12 ( - N C H C H 3 ) led to the enhancement ofthe signals at 8 1.47 ( - N C H C H 3 ) ; irradiation ofthe signal at 8 6.01 (-NH) led to the enhancement ofthe signals at 8 3.39 (H a ) and 8 5.01 (H e ) ; 1 3 C N M R (100.4 MHz) 8: 21.9, 23.0, 23.2, 23.3, 29.5, 29.6, 45.5, 48.4, 125.9, 127.3, 128.6, 132.0, 132.1, 133.7, 136.0, 142.4, 171.9. Anal, calcd. for C21H29NO: C 80.98, H 9.39, N 4.50; found: C 80.90, H 9.22, N 4.36. Exact Mass calcd. for C21H29NO: 311.2249; found: 311.2254. Preparation ofthe cyclobutanecarboxamides (241) and (242) c-Hex c-Hex Hd A, Hb H, H C H a H rV P h O Me 242 c-Hex c-Hex Hd A- H b H, H -rtxVPh Ho O Me 241 Following general procedure 13 outlined above, ethyl (Z,Z)-2,3-bis(cyclohexylmethylene)cyclobutanecarboxylate (238) was converted into the cyclobutanecarboxamides (241) and (242). The following amounts of reagents and solvents were used: (7?)-(+)-l-phenylethylamine (110 mg, 0.908 mmol) in 6 mL of dry benzene, 196 trimethylalummum (0.91 mmol), and ethyl (Z,Z)-2,3-bis(cyclohexylmethylene)cyclobutanecarboxylate (238) (130 mg, 0.411 mmol) in 2 mL of dry benzene. Normal workup, followed by radial chromatography (2 mm plate, 1:1 hexanes-Et20) and recrystallization (1:1 petroleum ether-Et20) ofthe acquired solids afforded 62 mg (39%) of cyclobutanecarboxamide (242) as a colourless solid (melting point, 163-165°C, dec.) and 58 mg (36%) of cyclobutanecarboxamide (241) as a colourless solid (melting point, 169-170°C dec). Cyclobutanecarboxamide (242) exhibited IR (KBr): 3397, 1733, 1637, 1178 cm" 1 ; A H N M R (400 MHz) 8: 0.98-1.33 (m, 8H), 1.45 (d, 3H, J= 7 Hz, N C H C H 3 ) , 1.60-1.76 (m, 12H), 2.14-2.29 (m, 2H, =C-CHR 2 ) , 2.60 (ddd, 1H, J= 14, 6, 2 Hz, H D ) , 2.76 (ddd, 1H, J= 14, 9, 2 Hz, H c ) , 3.35-3.41 (m, 1H, H a ) , 4.94 (br d, 1H, J= 10 Hz, H d ) , 5.01 (br d, 1H, J= 10 Hz, Hg), 5.10 (quintet, 1H, J= 7 Hz, -NCHCH 3 ) , 6.02 (br d, 1H, J= 7 Hz, -NH), 7.25-7.34 (m, 5H, aromatic); NOE difference experiments: irradiation of the signal at 8 2.60 (H D) led to enhancement ofthe signals at 8 2.76 (H c ) and 8 4.94 (H d ) ; irradiation of the signal at 8 2.76 (H c ) led to the enhancement of the signals at 8 2.60 (H^) and 3.35-3.41 (H a ) ; irradiation ofthe signal at 8 3.37 (H a ) led to the enhancement ofthe signals at 8 2.76 (H c ) , 8 5.01 (H e), and 8 6.02 (-NH); irradiation ofthe signals at 8 4.94-5.05 ( H d , H e ) led to the enhancement ofthe signals at 8 1.09-1.20, 8 2.20-2.29 (K>CHR 2 ) , 6 2.60 (H D), 8 2.76 (H c ) , 8 3.35-3.41 (H a), and 8 6.02 (-NH); irradiation ofthe signal at 8 5.10 ( -NCHCH 3 ) led to the enhancement ofthe signals at 8 1.45 ( -NCHCH 3 ) , 8 6.02 (-NH), and 8 7.25-7.34; irradiation ofthe signal at 8 6.02 (-NH) led to the enhancement ofthe signals at 8 2.76 (H c ) , 8 3.35-3.41 (H a), 8 5.01 (H e), 8 5.10 ( -NCHCH 3 ) , and 8 7.25-7.34; 1 3 C N M R (100.4 MHz) 8: 21.9, 25.8, 25.9, 26.0, 33.1, 33.3, 33.40, 33.44, 33.5, 39.1, 39.3, 45.5, 48.4, 126.0, 127.3, 128.6, 130.6, 130.7, 134.0, 136.9, 143.2, 172.4. Exact Mass calcd. for C 2 7 H 3 7 O N : 391.2875; found: 391.2874. Cyclobutanecarboxamide (241) exhibited IR (KBr): 3301, 1708, 1651, 1242 cm" 1 ; A H N M R (400 MHz) 8: 1.01-1.14 (m, 4H), 1.15-1.31 (m, 4H), 1.46 (d, 3H, J= 7 Hz, N C H C H 3 ) , 1.60-1.76 (m, 12H), 2.13-2.28 (m, 2H, =C-CHR 2 ) , 2.57 (ddd, 1H, J= 14, 6, 2 Hz, 197 H c ) , 2.74 (ddd, 1H, J= 14, 10, 2 Hz, H D ) , 3.35-3.41 (m, 1H, H a ) , 4.95 (br d, 1H, J= 10 Hz, H d ) , 5.04 (br d, 1H, J= 10 Hz, H e ) , 5.10 (quintet, 1H, J= 7 Hz, - N C H C H 3 ) , 6.05 (br d, 1H, ./= 7 Hz, -NH), 7.25-7.33 (m, 5H, aromatic); NOE difference experiments: irradiation ofthe signal at 5 2.57 (H c ) led to enhancement ofthe signal at 8 2.74 (H D ) ; irradiation ofthe signal at 8 2.74 (H D) led to the enhancement ofthe signals at 8 2.57 (H c ) and 8 3.35-3.41 (H a ) ; irradiation ofthe signal at 8 3.38 (H a) led to the enhancement ofthe signals at 8 2.74 (H D) and 8 5.04 (Hg); irradiation ofthe signal at 8 5.04 (Hg) led to the enhancement ofthe signals at 8 1.20-1.31, 8 1.60-1.71, 8 3.35-3.41 (H a ) ; irradiation ofthe signal at 8 5.10 ( - N C H C H 3 ) led to the enhancement ofthe signals at 8 1.46 ( - N C H C H 3 ) and 8 7.25-7.33; irradiation ofthe signal at 8 6.05 (-NH) led to the enhancement ofthe signals at 8 3.35-3.41 (H a ) , 8 5.04 (H e), 8 5.10 ( - N C H C H 3 ) , and 8 7.25-7.33. Exact Mass calcd. for C27H37ON: 391.2875; found: 391.2880. 12. Preparation ofthe l-substituted-2.3-bis(methylene)cyclobutanes (243) W 243 Preparation of l-(hydroxymethyl)-2,3-bis(methylene)cyclobutane (244) '9 244 198 To a cold (0°C), stirred solution of lithium aluminum hydride (125 mg, 3.29 mmol) in 12 mL of dry Et20 was added dropwise a solution of ethyl 2,3-bis(methylene)cyclobutanecarboxylate (53) (500 mg, 3.29 mmol) in 4 mL of dry Et20. The reaction mixture was stirred at 0°C for 10 minutes, warmed to room temperature, and then was stirred for a further 10 minutes. A saturated aqueous solution of sodium-potassium tartrate (Rochelles salt) (10 mL) was added dropwise (caution-exomermic) and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgS04), and concentrated. Radial chromatography (4 mm plate, Et20) ofthe crude product, followed by distillation (90-93°C/15 Torr) ofthe acquired oil, gave 332 mg (92%) of l-(hydroxymethyl)-2,3-bis(methylene)cyclobutane (244) as a colourless oil which exhibited I R (neat): 3351 (br), 1653, 1028, 883 cm" 1 ; ! H N M R ( 4 0 0 MHz) 8: 1.53 (br s, 1H, -OH), 2.38-2.46 (m, 1H, H b ) , 2.74 (dddd, 1H, J= 15, 9, 2.5, 2.5 Hz, H c ) , 3.05-3.13 (m, 1H, H a ) , 3.65-3.77 (m, 2H, -CH 2 OH) , 4.75 (dd, 1H, J= 2.5, 2.5 Hz, HQ), 4.82 (d, 1H, J= 1.5 Hz, H g ) , 5.19 (dd, 1H, J= 2.5, 2.5 Hz, H e ) , 5.21 (d, 1H, J= 2.5 Hz, Hf). In a series of decoupling experiments, irradiation at 8 2.41 (H D) converted the signal at 8 2.74 (H c ) to a doublet of doublet of doublets (J= 9, 2.5, 2.5 Hz), converted the doublet of doublets at 8 4.75 (H d ) to a doublet (J= 2.5 Hz), converted the doublet of doublets at 8 5.19 (H e ) to a doublet (J= 2.5 Hz) and simplified the multiplet at 8 3.05-3.13 (H a ) ; irradiation at 8 2.74 (H c ) simplified the multiplets at 8 2.38-2.46 (H D) and 8 3.05-3.13 (H a ) and converted the doublet of doublets at 4.75 (H Q ) and 8 5.19 (H e ) to doublets (J= 2.5 Hz in each case); irradiation at 8 3.10 (H a) simplified the multiplet at 8 2.38-2.46 (H b ) to a doublet of doublet of doublets (J= 15, 2.5, 2.5 Hz), simplified the signal at 8 2.74 (He) to a doublet of doublet of doublets (J= 15, 2.5, 2.5 Hz), simplified the multiplet at 8 3.65-3.77 (-CH 2 OH), and converted the doublets at 8 4.82 (H g ) and 8 5.21 (Hf) to singlets; irradiation at 8 5.19 (H e ) converted the signal at 8 2.38-2.46 (H D ) to a doublet of doublet of doublets (J= 15, 6, 2.5 Hz), and converted the signal at 8 2.74 (EL^) to a doublet of doublet of doublets (J= 15, 9, 2.5 Hz). NOE difference experiments; irradiation at 8 2.41 (H D) caused 199 enhancement ofthe signals at 8 2.74 (H c ) and 8 3.05-3.13 (H a ) ; irradiation at 8 2.74 (H c ) caused enhancement ofthe signal at 8 2.38-2.46 (H D ) ; irradiation at 8 3.05 (H a ) caused enhancement ofthe signals at 8 2.38-2.46 (H b ) , 8 3.65-3.77 (-CH 2 OH) and 8 4.82 (H g ) ; irradiation at 8 4.75 (H d ) caused enhancement ofthe signals at 8 5.19 (H e ) and 8 2.38-2.46 (H 0). 1 3 C N M R (100.4 MHz) 8: 31.3,42.4,65.1, 103.6, 104.6, 146.6, 150.1. Anal, calcd. for C 7 H 1 0 O : C 76.32, H 9.16; found: C 76.31, H 9.33. Exact Mass calcd. for C 7 H 1 0 O : 110.0731; found: 110.0730. Preparation of l-formyl-2.3-bis(methylene)cyclobutane (245) To a stirred mixture of pyridinium chlorochromate (391 mg, 1.81 mmol) and sodium acetate (264 mg, 3.22 mmol) in dry C H 2 C 1 2 (250 mL) was added a solution of l-(hydroxymethyl)-2,3-bis(methylene)cyclobutane (244) (100 mg, 0.908 mmol) in dry C H 2 C 1 2 (5 mL). The mixture was stirred at room temperature for 2 hours. Diethyl ether (200 mL) was added and the resultant mixture was filtered through a column of Florisil (6 cm diameter, 2 cm depth). The column was eluted quickly with 200 mL of E t 2 0 . Concentration ofthe combined eluate (100 Torr), followed by distillation (40-45 °C/45 Torr) ofthe remaining liquid, gave 69 mg (70%) of l-formyl-2,3-bis(methylene)cyclobutane (245). This compound was found to be extremely unstable at room temperature, polymerizing within 15 minutes of distillation. It should be noted that the aldehyde (245) isomerizes to the conjugated diene (249) upon exposure to silica gel. Thus one must filter the crude reaction mixture quickly (pressurized) through a short and wide plug of Florisil. Flash or radial chromatography cannot be used to purify this g 245 249 200 compound after filtration. If one does obtain a mixture of aldehyde products one can use this mixture without further purification in the next step (conversion to the oxime) and separate the oxime isomers by radial chromatography. Compound (245), a colourless oil, exhibits IR (neat): 2715, 1719, 1655, 1407, 888 cm-1; X H N M R (400 MHz) 8: 2.82 (dddd, 1H, J= 15,9,2.5,2.5 Hz, H D ) , 2.94-3.01 (m, 1H, H c ) , 3.66-3.74 (m, 1H, H a ) , 4.82 (dd, 1H, J= 2.5, 2.5 Hz, H d ) , 4.92 (br d, 1H, J= 2 Hz, H g ) , 5.23 (dd, 1H, J= 2.5, 2.5 Hz, H e ) , 5.34 (d, 1H, J= 3 Hz, Hf), 9.68 (d, 1H, J= 2 Hz, -CHO); in a series of decoupling experiments, irradiation at 8 2.82 (Hb) sharpened the multiplets at 8 2.94-3.01 (H c ) and 8 3.66-3.74 (H a), and converteed the doublet of doublets at 8 4.82 (H d ) and 8 5.23 (H e ) each to doublets (J= 2.5 Hz); irradiation at 8 2.98 (He) sharpened the multiplet at 8 3.66-3.74 (H a), converted the signal at 8 2.82 (Hb) to a doublet of doublet of doublets (J= 9, 2.5, 2.5 Hz) and converted the doublet of doublets at 8 4.82 (H d ) and 8 5.23 (Hg) each to doublets (J= 2.5 Hz); irradiation at 8 3.70 (H a ) simplified the signal at 8 2.82 (Hb) to a doublet of doublet of doublets (J= 15, 2.5, 2.5 Hz), converted the signal at 8 2.94-3.01 (H c ) to a doublet of doublet of doublets (J= 15, 2.5, 2.5 Hz), and converted the signals at 8 4.92 (Hg), 8 5.34 (Hf) and 8 9.68 (-CHO) to singlets; irradiation at 8 5.23 (H e ) converted the signal at 8 2.82 (Hb) to a doublet of doublet of doublets (J= 15, 9, 2.5 Hz) and the signal at 8 2.94-3.01 (H c ) to a doublet of doublet of doublets (J= 15, 6, 2.5 Hz); irradiation at 8 5.34 (Hf) simplified the multiplet at 8 3.66-3.74 (H a). NOE difference experiments; irradiation at 8 2.82 (Hb) caused enhancement ofthe signals at 8 2.94-3.01 (H c) and 8 3.66-3.74 (H a ) ; irradiation at 8 2.98 (H c ) caused enhancement of the signals at 8 2.82 (Hb) and 8 4.82 (H d ) ; irradiation at 8 3.70 (H a) caused enhancement ofthe signals at 8 2.82 (Hb) and 8 9.68 (-CHO); irradiation at 8 4.82 (H d ) caused enhancement of the signal at 8 5.23 (Hg); irradiation at 8 5.23 (H e ) caused enhancement ofthe signal at 8 4.82 (H d ) ; irradiation at 8 5.34 (Hf) caused enhancement ofthe signal at 8 4.92 (H g ) . 1 3 C N M R (100.4 MHz) 8: 28.6, 51.8, 105.8, 106.6, 144.6, 145.3, 199.0. Exact Mass calcd. for C 7 H 8 0 : 108.0575; found: 108.0578. 201 The A H N M R signals that are assigned to aldehyde (249) (when produced as a mixture with (245)) were the following: 8 2.11 (t, 3H, J= 2 Hz, =CCH 3 ) , 3.03 (br s, 2H, H a ) , 5.01 (br s, 1H, one of H D ) , 5.27 (br s, 1H, one of H D ) , 9.92 (s, 1H, -CHO). Preparation of l-(formyl)-2.3-bis(methylene)cyclobutane oxime (246) , , ' i H a 1 246 NOH ^1 250 NOH To a stirred solution ofthe aldehydes (245) and (249) (6:1 mixture as determined by i H N M R spectroscopy, 125 mg, 1.16 mmol, 1.00 equiv.) in dry DMF (10 mL) was added hydroxylamine hydrochloride (410 mg, 5.9 mmoL 5.1 equiv.) and dry pyridine (0.47 mL, 5.1 equiv.). The resultant solution was heated to 70°C and stirred for 1 hour. The solution was cooled to room temperature, water (10 mL) was added, and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgS04), and concentrated. Radial chromatography (1 mm plate, 3:1 hexanes-Et20) ofthe crude product followed by removal of traces of solvent (vacuum pump) from the acquired materials gave 105 mg (74%) of (246) as a viscous oil and 20 mg (14%) of (250) as a colourless solid (melting point, 120-121°C after recrystallization from 1:1 hexanes-Et20). X H N M R (400 MHz) analysis of oxime (246) indicated that it consisted of a 3:2 mixture of geometric isomers with respect to the oxime function. A l l attempts to separate these two isomers proved unsuccessful. The following A H N M R signals (400 MHz) could be assigned to the major isomer of oxime (246): 8 2.62-2.72 (m, -0.6H, one of H D ) , 8 2.93-3.06 (m, -0.6H, one of H D ) , 8 3.67-3.75 (m, -0.6H, H a ) , 7.48 (d, -0.6H, J= 7 Hz, -CH=NOH). The following A H N M R signals (400 MHz) could be assigned to the minor isomer of oxime (246): 8 2.52-2.62 (m, -0.4H, one of H D ) , 8 2.85-2.92 (m, -0.4H, one of H D ) , 8 4.29-4.35 (m, -0.4H, H a ) , 6.82 (d, -0.4H, J= 7 Hz, 202 -CH=NOH). The following IjT N M R signals (400 MHz) could not be specifically assigned to either ofthe two isomers of (246): 8 4.80-4.92 (m, 2H, olefinic), 8 5.21-5.31 (m, 2H, olefinic). Mixture (246) also exhibited IR (neat): 3398 (br), 1673, 1279, 974 c m " 1 . Anal, calcd. for C7H9NO: C 68.27, H 7.37, N 11.35; found: C 68.20, H 7.29, N 11.70. Exact Mass calcd. for C7H9NO: 123.0684; found: 123.0684. l H N M R (400 MHz) analysis of oxime (250) indicated that it consisted of a 12:1 mixture of geometric isomers. Attempts to separate these two isomers were unsuccessful. The i H N M R signals (400 MHz) assigned to the major isomer were: 8: 1.85 (t, 3H, J= 2 Hz, =CRCH 3 ) , 3.01 (br s, 2 H , H a ) , 4.65 (s, 1H, one of =CH 2), 4.83 (br s, 1H, one of =CH 2 , 7.95 (s, 1H, =CHNOH). The * H N M R signals (400 MHz) assigned to the minor isomer were: 8: 2.09 (t, J= 2 Hz, =CRCH 3 ) , 3.30 (br s, one of H a ) , 4.72 (br s, =CH 2 ) , 4.91 (br s, =CHNOH). The mixture exhibited IR (neat): 3195 (br), 1673, 975 cm" 1 . Anal, calcd. for C7H9NO: C 68.27, H 7.37, N 11.35; found: C 68.26, H 7.17, N 11.05. Exact Mass calcd. for C7H9NO: 123.0684; found: 123.0685. Preparation of l-cyano-2.3-bis(methylene)cyclobutane (247) To a cold (-10°C), stirred solution of thionyl chloride (1.1 equiv., 47 uL) in dry C H 2 C 1 2 (4 mL) was added D M A P (1.25 equiv., 89 mg) and the resultant mixture was stirred at -10°C for 5 minutes. Oxime (246) (70 mg, 0.58 mmol) was added, the mixture was stirred for 2 minutes, and D M A P (1.25 equiv., 89 mg) was added. The mixture was warmed to room temperature and stirred for an additional 30 minutes. Water (4 mL) was added and the mixture '9 247 203 was thoroughly extracted with CH2CI2. The combined extracts were washed with brine, dried (MgS04), and concentrated. Radial chromatography (1 mm plate, 1:1 hexanes-Et20) ofthe crude product followed by distillation (45-50°C/45 mm Hg) ofthe acquired oil gave 49 mg (82%) of l-cyano-2,3-bis(methylene)cyclobutane (247) as a colourless oil (Caution: stench, unstable, volitile), which exhibited IR (neat): 2240, 1656, 894 cm" 1 ; X H N M R (400 MHz) 8: 2.97-3.03 (m, 2H, H D , H c ) , 3.65-3.73 (m, 1H, H a ) , 4.88 (dd, 1H, .7=2.5, 2.5 Hz, H d ) , 5.09 (br s, 1H, H g ) , 5.27 (dd, 1H, J= 2.5, 2.5 Hz, He), 5.37 (d, 1H, J= 2.5 Hz, Hf); NOE difference experiments: irradiation of the signal at 8 5.37 (Hf) led to enhancement ofthe signal at 8 5.09 (Hg); irradiation ofthe signal at 8 5.09 (Hg) led to enhancement ofthe signal at 8 5.37 (Hf); irradiation ofthe signal at 8 4.88 (H d ) led to enhancement ofthe signal at 8 2.97-3.01 (H c ) and 8 5.27 (H e ) ; irradiation ofthe signal at 8 3.70 (H a) led to enhancement ofthe signal at 8 2.99-3.03 (H b ) and 8 5.09 (Hg); irradiation ofthe signal at 8 3.00 (H D , H c ) led to enhancement of the signals at 8 4.88 (H d ) and 8 3.65-3.73 (H a). In a series of decoupling experiments, irradiation at 8 3.70 (H a ) simplified the multiplet at 8 2.97-3.03 (H D , H c ) and converted the signals at 8 5.09 (Hg) and 8 5.37 (Hf) into sharp singlets; irradiation at 8 3.00 (H D , H c ) simplified the multiplet at 8 3.65-3.73 (H a), and the converted the signals at 8 4.88 (H d ) and 8 5.27 (H e) to singlets. Exact Mass calcd. for C7H7N: 105.0578; found: 105.0575. Preparation of 2.3-bis(methylene)cyclobutanecarboxyUc acid (248) 248 251 To a stirred solution of ethyl 2,3-bis(methylene)cyclobutanecarboxylate (53) (150 mg, 0.990 mmol) in 4 mL of 1:1 E t O H - H 2 0 was added NaOH (1.25 equiv., 59 mg). The resultant 204 mixture was stirred at room temperature for 2 hours. The solution was extracted with Et20 (2 x 4 mL) to remove residual amounts of starting material and the aqueous layer was acidified until pH 2 with 3M hydrochloric acid. The acidified aqueous layer was extracted with Et20 (3 x 4 mL). The extracts were washed with brine, dried (MgS04), and concentrated. Removal of trace amounts of solvent (vacuum pump) from the acquired liquid gave 110 mg (90%) of a 6:1 mixture (4i N M R spectroscopy) of acids (248) and (251), as a viscous oil. Attempts to separate compounds (248) and (251) were unsuccessful and this material was used without further purification. The *H N M R (400 MHz) signals assigned to acid (248) were: 8: 2.83 (dddd, 1H, J= 16, 10, 2.5, 2.0 Hz, H b ) , 3.00-3.07 (m, 1H, H c ) , 3.72-3.79 (m, 1H, H a ) , 4.81 (dd, 1H, J= 2,2 Hz, H d ) , 5.03 (d, 1H, J= 2 Hz, H g ) , 5.22 (dd, 1H, J= 2.5, 2.5 Hz, H e ) , 5.30 (d, 1H, J= 3 Hz, Hf). In a series of decoupling experiments, irradiation at 8 5.30 (Hf) converted the multiplet at 8 3.72-3.79 to a doublet of doublets of doublets (/= 10, 7, 2 Hz); irradiation at 8 5.22 (H e ) converted the multiplet at 8 3.00-3.07 (H c ) to a doublet of doublet of doublets (J= 16, 7, 2 Hz) and the signal at 8 2.83 (H b ) to a doublet of doublet of doublets (J= 16, 10, 2 Hz); irradiation at 8 3.75 (H a ) converted the doublets at 8 5.03 (H g ) and 8 5.30 (Hf) to singlets, converted the multiplet at 8 3.00-3.07 (H c ) to a doublet of doublet of doublets (J= 16, 2.5, 2.0 Hz) and converted the signal at 8 2.83 (H D) to a doublet of doublet of doublets (J= 16, 2.5, 2.0 Hz); irradiation at 8 3.05 (H c ) simplified the signals at 8 4.81 (H d ) and 8 5.22 (H e ) to doublets (J= 2.0, 2.5 Hz, respectively), sharpened the multiplet at 8 3.72- 3.79 (H a ) and converted the signal at 8 2.83 (H D ) to a doublet of doublet of doublets (J= 10, 2.5, 2.0 Hz); irradiation at 8 2.83 (H D) converted the signals at 8 4.81 and 8 5.22 (Hg) to doublets (J= 2.0, 2.5 Hz, respectively) and simplified the multiplets at 8 3.72-3.79 (H a ) and 8 3.00-3.07 (H c). The X H N M R (400 MHz) signals assigned to acid (59a) were: 8: 2.01 (dd, 3H, J= 2, 2 Hz, -CH 3 ) , 3.02-3.08 (m, 2H, -CH 2 - ) , 4.89 (br s, 1H, one of=CH 2 ) , 5.12 (br s, 1H, one of =CH 2). The mixture exhibited IR (neat): 2970 (br), 1705, 1440, 1250 cm - 1.- Exact mass calcd. for C 7 H 8 0 2 : 125.0424; found: 125.0420. 205 13. Diels-Alder reactions 13.1 General Procedure 14: Preparation ofthe functionalized bicyclo[4.2.0]oct-l(6)-enes (252) and (254) R' C 0 2 E t * C 0 2 E t 243 N C N C N C N C W W 254 To a stirred solution of the appropriate ethyl cyclobutanecarboxylate (221) or the l-substituted-2,3-bis(methylene)cylobutane (243) (1 equfv.) in dry CH2CI2 (8-12 mL/mmol of substrate) was added tetracyanoethylene (1 equiv., unless noted otherwise). The reaction mixture was stirred for 0.5 hours at room temperature (unless noted otherwise) and the solvent was removed under reduced pressure. Radial chromatography ofthe crude product followed by recrystallization (1:1 hexanes-Et20) ofthe acquired solids afforded the corresponding products (252) and (254), respectively, as crystalline solids. 206 Preparation ofthe ester (255) NC NC NC * Hd = C 0 2 E t Ha 255 Following general procedure 14 outlined above, ethyl 2,3-bis(methylene)cyclobutanecarboxylate (53) was converted into the ester (255). The following amounts of reagents and solvents were used: ethyl 2,3-bis(methylene)cyclobutanecarboxylate (53) (500 mg, 3.29 mmol) in 36 mL of dry CH2CI2 and tetracyanoethylene (427 mg, 3.29 mmol). Normal workup, followed by radial chromatography (4 mm plate, CH2CI2) ofthe crude product and recrystallization (1:1 hexanes-Et20) ofthe acquired solid afforded 630 mg (68%) of ester (255) as fine colourless crystals (melting point 128-129°C). This material exhibited IR (KBr): 2255, 1729, 1264, 1199 cm" 1 ; l H N M R (400 MHz) 5: 1.27 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 2.85 (dm, 1H, J= 14 Hz, H c ) , 3.05 (dm, 1H, J= 14 Hz, H D ) , 3.09-3.34 (m, 4H, Hd), 3.76-3.81 (m, 1H, H a ) , 4.15-4.23 (m, 2H, J= 7 Hz, - O C H 2 C H 3 ) ; NOE difference experiments: irradiation ofthe signals at 8 3.20 (H^) led to the enhancement ofthe signal at 8 3.76-3.81 (H a ) ; irradiation ofthe signal at 8 3.77 (H a ) led to the enhancement ofthe signal at 8 3.05 (H b ) ; 1 3 C N M R (125.8 MHz) 8: 14.2, 32.5, 33.4, 35.4, 38.06, 38.13, 45.6, 61.4, 110.39, 110.40, 110.43, 110.45, 135.1, 137.9, 170.2. Anal, calcd. for C 1 5 H 1 2 0 2 N 4 : C 64.31, H 4.28, N 19.99; found: C 64.16, H 4.38, N 20.13. Exact Mass calcd. for C 1 5 H 1 2 0 2 N 4 : 280.0970; found: 280.0964. 207 Preparation ofthe ester (256) NC LHd H b NC NC NC » 'H e H a Me 6 3 H f C 0 2 E t 256 Following general procedure 14 outlined above, ethyl (Z)-2-ethyUdene-3-methylenecyclobutanecarboxylate (55) was converted into the ester (256). The following amounts of reagents and solvents were used: ethyl (Z)-2-ethyhdene-3-methylenecyclobutanecarboxylate (55) (250 mg, 1.51 mmol) in 13 mL of dry CH2CI2 and tetracyanoethylene (198 mg, 1.51 mmol). Normal workup, followed by radial chromatography (4 mm plate, CH2CI2) ofthe crude product and recrystallization (1:1 hexanes-Et20) ofthe acquired solid afforded 340 mg (77%) of ester (256) as colourless crystals (mp 110-111°C). This material exhibited IR (KBr): 2258,1731,1256,1034 cm" 1 ; i H N M R (400 MHz) 8: 1.27 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.50 (d, 3H, J= 7 Hz, - C H C H 3 ) , 2.81 (dm, 1H, J= 14 Hz, H c ) , 2.90 (dm, 1H, J= 14 Hz, H D ) , 3.09 (dm, 1H, J= 16 Hz, H d ) , 3.22 (br d, 1H, J= 16 Hz, Hd-), 3.27-3.32 (m, 1H, H e ) , 3.70-3.75 (m, 1H, H a ) , 4.12-4.22 (m, 2H, - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 5 2.81 (H c ) converted the doublet of multiplets at 8 2.90 (H D) to a multiplet and sharpened the signals at 8 3.09 (ELY), 8 3.22 (Hd>), and 8 3.70-3.75 (H a ) ; irradiation at 8 2.90 (H D) converted the doublet of multiplets at 8 2.81 (H c ) to a multiplet and sharpened the signals at 8 3.22 (Hd«) and 8 3.70-3.75 (H a ) ; irradiation at 8 3.09 (ELY) converted the doublet at 8 3.22 (Hd>) to a broad singlet, sharpened the doublet of multiplets at 8 2.81 (H c ) , and converted the signal at 8 2.90 (H D) to a doublet of doublet of doublets (J= 14, 3, 3 Hz); irradiation at 8 3.22 (Hd>) sharpened the signals at 8 2.81 (H c ) and 8 2.90 (H D), and converted the broad doublet at 8 3.09 (H d ) to a broad 208 singlet; irradiation at 8 3.73 (H a ) sharpened the signals at 8 2.81 (H c ) , 8 2.90 (H D) and 8 3.27-3 32 (H e). N O E difference experiments: irradiation ofthe signal at 8 1.50 ( -CHCH3) led to enhancement ofthe signal at 8 3.22 (H d ' ) and 8 3.27-3.32 (H e ) ; irradiation ofthe signal at 8 2.81 (H c ) led to the enhancement of the signal at 8 2.90 (H D ) ; irradiation ofthe signal at 8 2.90 (H D) led to the enhancement ofthe signals at 8 2.81 (H c ) and 8 3.70-3.75 (H a ) ; irradiation ofthe signal at 8 3.73 (H a ) led to the enhancement ofthe signal at 8 2.90 (Hb) and 8 3.27-3.32 (Hg); 1 3 C N M R (75.3 MHz) 8: 13.1, 14.1, 33.4, 34.5, 37.7, 38.6, 44.6, 45.3, 61.4, 108.5, 110.4, 110.7, 110.8, 138.0, 139.0, 170.7. Anal, calcd. for C 1 6 H 1 4 0 2 N 4 : C 65.29, H 4.80, N 19.04; found: C 65.28, H 4.82, N 19.00. Exact Mass calcd. for C 1 6 H 1 4 0 2 N 4 : 294.1118; found: 294.1123. X-Ray crystallographic data for compound (256) can be seen in Appendix V. Preparation ofthe ester (257) Following general procedure 14 outlined above, ethyl (JE)-2-ethyhdene-3-methylenecyclobutanecarboxylate (54) was converted into the ester (257). The following amounts of reagents and solvents were used: ethyl (£)-2-ethyhdene-3-methylenecyclobutanecarboxylate (54) (150 mg, 0.903 mmol) in 10 mL of dry CH2CI2 and tetracyanoethylene (116 mg, 0.906 mmol). Normal workup, followed by radial chromatography (4 mm plate, CH2CI2) ofthe crude product, and recrystallization (1:1 hexanes-Et20) ofthe acquired solid afforded 185 mg (70%) of ester (257) as fine colourless crystals (mp 152-153°C). This material exhibited IR (KBr): 2255, 1737, 1190, 1028 cm" 1 ; NC }/He H a 257 209 A H N M R (400 MHz) 8: 1.28 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.57 (d, 3H, J= 7 Hz, -CHCH 3 ) , 2.82-2.88 (m, 1H, H c ) , 2.93-3.00 (m, 1H, H b ) , 3.09-3.20 (m, 2H, ELj), 3.31-3.40 (m, 1H, H e ) , 3.74-3.78 (m, 1H, H a ) , 4.18 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 5 1.57 ( -CHCH 3 ) sharpened the signal at 8 3.31-3.40 (H e ) ; irradiation at 5 2.85 (He) sharpened the multiplets at 8 2.93-3.00 (H D) , 8 3.09-3.20 (H a ) and 8 3.74-3.78 (H a ) ; irradiation at 8 2.97 (H D) sharpened the multiplets at 8 2.82-2.88 (H c), 8 3.09-3.20 (H<j) and 8 3.74-3.78 (H a ) ; irradiation at 8 3.36 (H e ) converted the doublet at 8 1.57 ( -CHCH 3 ) to a singlet and sharpened the multiplet at 8 3.74-3.78 (H a ) ; irradiation at 8 3.77 (H a) converted the multiplet at 8 2.82-2.88 (H c ) to a doublet of doublets (J= 14, 3 Hz) and the multiplet at 8 2.93-3.00 (H D) to a broad doublet of doublets (J= 14, 2.5 Hz), and sharpened the multiplet at 8 3.31-3.40 (Hg). NOE difference experiments: irradiation of the signal at 8 1.57 ( -CHCH 3 ) led to enhancement ofthe signals at 8 3.31-3.40 (H e ) and 8 3.74-3.78 (H a ) ; irradiation ofthe signal at 8 3.36 (H e ) led to the enhancement ofthe signal at 8 1.57 ( -CHCH 3 ) ; irradiation ofthe signal at 8 3.76 (H a ) led to the enhancement of the signals at 8 1.57 (-CHCH 3 ) and 8 2.93-3.00 (Hb); 1 3 C N M R (125.8 MHz) 8: 13.2, 14.2, 33.4, 34.4, 37.7, 39.1, 44.6, 45.1, 61.5, 108.9, 110.1, 110.7, 110.9, 136.7, 139.8, 170.1. Anal, calcd. for C 1 6 H 1 4 0 2 N 4 : C 65.29, H 4.80, N 19.04; found: C 65.10, H 4.85, N 19.00. Exact Mass calcd. for C 1 6 H 1 4 0 2 N 4 : 294.1118; found: 294.1117. Preparation of the ester (260) 260 210 Following a modified version of general procedure 14 outlined above, in which the reaction mixture was allowed to stir at room temperature for 4 days instead of 0.5 hours and 1.5 equiv. tetracyanoethylene was used, ethyl (Z)-2-cyclohexy]methylene-3-methylenecyclobutanecarboxylate (236) was converted into the ester (260). The following amounts of reagents and solvents were used: ethyl (Z)-2-cyclohexylmethylene-3-methylenecyclobutane-carboxylate (236) (200 mg, 0.854 mmol) in 9 mL of dry CH2CI2 and tetracyanoethylene (167 mg, 1.30 mmol). Normal workup, followed by radial chromatography (4 mm plate, CH2CI2) ofthe crude product, and recrystallrzation (1:1 petroleum ether-Et20) ofthe acquired solid afforded 224 mg (73%) of ester (260) as fine colourless crystals (mp 138-139°C). This material exhibited JJR (KBr): 2252, 1725, 1329, 1166 cm" 1 ; * H N M R (400 MHz) 8: 1.04-1.46 (m, 9H, includes triplet at 8 1.28, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.66-2.05 (m, 5H), 2.68 (dm, 1H, J= 14 Hz, H.), 2.80-2.89 (m, 2H, H D , Hg), 3.07 (br d, 1H, J= 18 Hz, one of H d ) , 3.22 (br d, 1H, J= 18 Hz, one of H d ) , 3.74-3.78 (m, 1H, H a ) , 4.10-4.23 (m, 2 H , - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 8 2.68 (He) sharpened the multiplets at 8 2.80-2.89 (H D) and 8 3.74-3.78 (H a ) ; irradiation at 8 2.85 (H D , Hg) converted the doublet of multiplets at 8 2.68 (Hg) to a multiplet and sharpened the multiplet at 8 3.74-3.78 (H a ) ; irradiation at 8 3.07 (one of Hd) converted the broad doublet at 8 3.22 (one of H d ) to a broad singlet and sharpened the doublet of multiplets at 8 2.68 (Hg); irradiation at 8 3.22 (one of H d ) converted the broad doublet at 8 3.07 (one of Hd) to a broad singlet and sharpened the multiplet at 8 2.80-2.89 (Hg); irradiation at 8 3.76 (H a ) simplified the broad doublet at 8 2.68 (H c ) and the multiplet at 8 2.85 ( H b , H e ) . NOE difference experiments: irradiation ofthe signal at 8 2.68 (Hg) led to enhancement ofthe signal at 8 2.85 (H D) ; irradiation ofthe signal at 8 2.85 (H D , Hg) led to the enhancement ofthe signals at 8 2.68 (Hg) and 8 3.74-3.78 (H a ) ; irradiation ofthe signal at 8 3.07 (one of Hd) led to the enhancement of the signal at 8 3.22 (one of Hd); irradiation ofthe signal at 8 3.22 (one of Hd) led to the enhancement ofthe signal at 8 3.07 (one of Hd); irradiation ofthe signal at 8 3.76 (H a ) led to the enhancement ofthe signals at 8 1.79-1.93 and 8 2.80-2.89 (H D , Hg); 1 3 C N M R (100.4 MHz) 8: 14.8, 25.6, 26.0, 26.4, 30.5, 32.86, 32.93, 35.1, 39.7, 40.6, 42.6, 47.0, 47.5, 61.5, 211 109.7, 110.2, 111.0, 111.7, 137.5, 139.4, 170.8. Anal, calcd. for C21H22O2N4: C 69.59, H 6.12, N 15.46; found: C 69.69, H 6.16, N 15.48. Exact Mass calcd. for C21H22O2N4: 362.1743; found: 362.1734. Preparation ofthe ester (261) Following general procedure 14 outlined above, ethyl (£')-2-cyclohexyhnethylene-3-methylenecyclobutanecarboxylate (235) was converted into the ester (261). The following amounts of reagents and solvents were used: ethyl (£')-2-cyclohexylmethylene-3-methylenecyclobutanecarboxylate (235) (125 mg, 0.533 mmol) in 5 mL of dry CH2CI2, and tetracyanoethylene (70 mg, 0.54 mmol). Normal workup, followed by radial chromatography (4 mm plate, CLT^CL?) ofthe crude product, and recrystallization (1:1 petroleum ether-Et20) ofthe acquired solid afforded 136 mg (70%) of ester (261) as fine colourless crystals (mp 147-148°C). This material exhibited IR (KBr): 2271, 1727, 1326, 1186 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 5: 1.10-1.45 (m, 9H, includes triplet at 6 1.25, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.68-2.04 (m, 5H), 2.62-2.69 (dm, 1H, J=14 Hz, He), 2.97-3.06 (m, 2H, H b , Hg), 3.07 (d, 1H, J= 14 Hz, one of H^), 3.14 (br d, 1H, J= 14 Hz, one of H j ) , 3.79-3.83 (m, 1H, H a ) , 4.18 (q, 2 H , J= 7 Hz, - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 8 2.65 (H c ) simplified the multiplets at 8 3.00-3.06 (H b ) and 8 3.79-3.83 (H a), and sharpened the broad doublet at 8 3.14 (one of Hd); irradiation at 8 3.03 ( H b , Hg) converted the doublet of multiplets at 8 2.62-2.69 (H c ) to a multiplet, sharpened the broad doublet at 8 3.14 (one of H^) NC £ H e H a c-Hex 261 212 and sharpened the multiplet at 8 3.79-3.83 (H a ) ; irradiation at 8 3.14 (one of H d ) converted the doublet of multiplets at 8 2.62-2.69 (H c ) to a broad doublet of doublets (J= 14, 2.5 Hz) and converted the broad doublet at 8 3.07 (one of Hr\) to a broad singlet; irradiation at 8 3.82 (H a) converted the multiplet at 8 2.62-2.69 (H^) to a doublet of doublets (J= 14, 3 Hz) and simplified the multiplet at 8 2.97-3.06 (H D , H e ) . NOE difference experiments: irradiation ofthe signal at 8 2.65 (H c ) led to enhancement ofthe signal at 8 3.00-3.06 (H D ) ; irradiation ofthe signal at 8 3.03 (H D , H e ) led to the enhancement ofthe signals at 8 1.85-2.00, 8 2.62-2.69 (H c), and 8 3.79-3.83 (H a ) ; irradiation of the signal at 8 3.82 (H a ) led to the enhancement ofthe signals at 8 1.95-2.04 and 8 3.00-3.06 (H D ) ; 1 3 C N M R (100.4 MHz) 8: 14.1, 25.3, 25.6, 26.4, 31.4, 32.6, 33.1, 34.8, 38.0, 41.0, 41.8, 46.6, 48.0, 61.2, 108.7, 110.7, 111.0, 112.1, 138.2, 139.4, 171.3. Anal, calcd. for C21H22O2N4: C 69.59, H 6.12, N 15.46; found: C 69.60, H 6.03, N 15.63. Exact Mass calcd. for C21H22O2N4: 362.1743; found: 362.1738. Preparation ofthe ester (258) Following a modified version of general procedure 14 outlined above in which the reaction mixture was allowed to stir at room temperature for 4 days instead of 0.5 hours and 1.5 equiv. tetracyanoethylene was used, ethyl (Z)-2-(2-methylpropyhdene)-3-methylenecyclobutane-carboxylate (234) was converted into the ester (79). The following amounts of reagents and solvents were used: ethyl (Z)-2-(2-methylpropyhdene)-3-methylenecyclobutanecarboxylate (69) (100 mg, 0.515 mmol) in 6 mL of dry CH2CI2, and tetracyanoethylene (100 mg, 0.779 mmol). Normal workup, followed by radial chromatography (4 mm plate, 3:1 hexanes-Et20) ofthe crude product, and /'-Pr 258 213 recrystallization (1:1 petroleum ether-Et20) ofthe acquired solid afforded 107 mg (65%) of ester (258) as fine colourless crystals (mp 80-81°C). This material exhibited IR (KBr): 2253, 1729, 1474, 1262, 1198 cm" 1 ; i H N M R (400 MHz) 8: 1.09 (d, 3H, J= 6.5 Hz, one of -CH(CH 3 ) 2 ) , 1.27 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.30 (d, 3H, J= 6.5 Hz, one of -CH(CH 3 ) 2 ) , 2.18-2.28 (m, 1H, -CH(CH 3 ) 2 ) , 2.69 (dm, 1H, J= 12 Hz, H c ) , 2.78-2.83 (m, 1H, He), 2.83-2.88 (dm, J= 12 Hz, 1H, H b ) , 3.07 (br d, 1H, J= 18 Hz, one of H d ) , 3.24 (br d, 1H, J= 18 Hz, one of H d ) , 3.76-3.81 (m, 1H, H a ) , 4.17 (m, 2H, - O C H 2 C H 3 ) ; NOE difference experiments: irradiation ofthe signal at 8 2.22 ( -CH(CH 3 ) 2 ) led to enhancement ofthe signals at 8 1.09 (one o f -CH(CH 3 ) 2 ) , 8 1.30 (one o f -CH(CH 3 ) 2 ) , and 8 2.78-2.83 (H e ) ; irradiation of the signal at 8 3.24 (one of H d ) led to the enhancement of the signals at 8 3.07 (one of H d ) and 8 1.09 (one o f -CH(CH 3 ) 2 ) ; irradiation of the signal at 8 3.79 (H a ) led to the enhancement of the signals at 8 2.78-2.83 (H e ) and 8 2.83-2.88 (H b ) ; 1 3 C N M R (100.4 MHz) 8: 14.0, 21.3, 21.7, 28.6, 33.0, 34.7, 41.0, 42.4, 46.8, 48.7, 61.3, 108.7, 110.6, 110.9, 112.0, 138.1, 138.8, 171.2. Anal, calcd. for C 1 8 H 1 8 0 2 N 4 : C 67.06, H 5.63, N 17.38; found: C 66.81, H 5.68, N 17.31. Exact Mass calcd. for C 1 8 H 1 8 0 2 N 4 : 322.1430; found: 322.1432. Preparation ofthe ester (259) Following a modified version of general procedure 14 outlined above, in which 1.1 equiv. tetracyanoethylene was used, ethyl (£)-2-(2-methylpropyMene)-3-methylenecyclobutanecarboxylate (233) was converted into the ester (259). The following amounts of reagents and solvents were used: ethyl /-Pr 259 214 (E)-2-(2-memylpropyMene)-3-methylenecyclobutanecarboxylate (233) (150 mg, 0.773 mmol) in 9 mL of dry CH2CI2, and tetracyanoethylene (110 mg, 0.852 mmol). Normal workup, followed by radial chromatography (4 mm plate, CH2CI2) ofthe crude product, and recrystallization (1:1 petroleum ether-Et20) ofthe acquired solid afforded 162 mg (66%) of ester (259) as fine colourless crystals (mp 87-88°C). This material exhibited JR (KBr): 2253, 1729, 1467, 1263, 1042 cm" 1 ; lU N M R (400 MHz) 8: 1.20 (d, 3H, J= 1 Hz, one of -CH(CH 3 ) 2 ) , 1.22 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.26 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 2.18-2.26 (m, 1H, -CH(CH 3 ) 2 ) , 2.65-2.72 (dm, 1H, J= 14 Hz, H c ) , 3.03-3.07 (m, 2H, H b , H e ) , 3.10-3.19 (m, 2H, H d ) , 3.79-3.83 (m, 1H, H a ) , 4.13-4.22 (m, 2H, - O C H 2 C H 3 ) ; NOE difference experiments: irradiation of the signal at 8 2.20 (-CH(CH 3 )2) led to enhancement of the signals at 8 1.20 (one o f -CH(CH 3 ) 2 ) , 8 1.26 (one o f -CH(CH 3 ) 2 ) , and 8 3.04-3.07 (H e); irradiation ofthe signal at 8 2.68 (H c ) led to the enhancement of the signals at 8 3.04-3.07 (H b ) ; irradiation ofthe signal at 8 3.81 (H a) led to the enhancement ofthe signals at 8 1.20 (one of -CH(CH 3 ) 2 ) and 8 3.04-3.07 (H b ) ; 1 3 C N M R (100.4 MHz) 8: 14.2, 19.9, 22.8, 29.8, 32.9, 35.2, 41.2, 42.9, 46.8, 47.9, 61.5, 109.5, 110.1, 111.0, 111.6, 137.8, 139.2, 170.7. Anal, calcd. for C 1 8 H 1 8 0 2 N 4 : C 67.06, H 5.63, N 17.38; found: C 66.86, H 5.72, N 17.17. Exact Mass calcd. f o r C 1 8 H 1 8 0 2 N 4 : 322.1430; found: 322.1427. Preparation ofthe alcohol (262) c 262 Following general procedure 14 outlined above, l-(hydroxymethyl)-2,3-bis(methylene)cyclobutane (244) was converted into the alcohol (262). 215 The following amounts of reagents and solvents were used: l-(hydroxymethyl)-2,3-bis(methylene)cyclobutane (244) (275 mg, 2.50 mmol) in 30 mL of dry CH2CI2, and tetracyanoethylene (326 mg, 2.50 mmol). Normal workup, followed by radial chromatography (4 mm plate, CH2CI2) ofthe crude product and recrystallization (1:1 petroleum ether-Et20) ofthe acquired solid, afforded 433 mg (73%) of alcohol (262) as fine colourless crystals (mp 94-95°C). This material exhibited IR (KBr): 3345 (br), 2257, 1659, 1437, 1029 cm" 1 ; N M R (400 MHz) 8: 1.63 (br s, 1H, -OH), 2.36 (dm, 1H, J= 15 Hz, one of H D ) , 2.78 (dm, 1H, J= 15 Hz, one of H D ) , 3.05-3.31 (m, 5H, H a , H c ) , 3.67 (dd, 1H, J= 12, 8 Hz, one o f -CH 2 OH) , 3.90 (dd, 1H, J= 12, 6 Hz, one o f -CH 2 OH) ; 1 3 C N M R (acetone-d6, 100.4 MHz) 5: 33.2, 33.6, 34.2, 39.7, 40.0, 46.7, 64.4, 112.36, 112.41, 112.47, 112.52, 136.8, 139.8. Anal, calcd. for C 1 3 H 1 0 O N 4 : C 65.54, H 4.23, N 23.52; found: C 65.53, H 4.37, N 23.28. Exact Mass calcd. for C 1 3 H 1 0 O N 4 : 238.0854; found: 238.0849. Preparation ofthe nitrile (263) Following general procedure 14 outlined above, l-(cyano)-2,3-bis(methylene)cyclobutane (247) was converted into the nitrile (263). The following amounts of reagents and solvents were used: l-(cyano)-2,3-bis(methylene)cyclobutane (247) (40 mg, 0.38 mmol) in 4 mL of dry CH2CI2, and tetracyanoethylene (50 mg, 0.39 mmol). Normal workup, followed by radial chromatography (1 mm plate, CH2CI2) ofthe crude product and recrystallization (1:1 petroleum ether-Et20) ofthe acquired solid, afforded 61 mg (69%) of nitrile (263) as fine C 263 216 colourless crystals (mp 163-165°C). This material exhibited IR (KBr): 2245, 1663, 1436, 912 cm" 1 ; i H N M R (400 MHz) 8: 3.06-3.33 (m, 6H, H b , H c ) , 3.81 (dd, 1H, J= 2, 2 Hz, H a ) ; Anal, calcd. for C 1 3 H 7 N 5 : C 66.95, H 3.03, N 30.03; found: C 67.15, H 2.98, N 29.90. Exact Mass calcd. for C13H7N5: 233.0701; found: 233.0702. Preparation ofthe acid (264) Following general procedure 14 outlined above, a 2.5:1 mixture of acids (248) and (251) were used to synthesize the acid (264). The following amounts of reagents and solvents were used: l-(carboxy)-2,3-bis(methylene)cyclobutane (248) and l-carboxy-3-methylene-2-methylcyclobut-l-ene (251) (2.5:1 mixture) (125 mg, 1.01 mmol) in 12 mL of dry CH2CI2, and tetracyanoethylene (132 mg, 1.02 mmol). Normal workup, followed by radial chromatography (1 mm plate, E t 2 0 ) ofthe crude product and recrystallization (1:1 hexanes-Et20) ofthe acquired solid, afforded 112 mg (44%) of acid (264) as fine colourless crystals (mp 165-166°C dec). This material exhibited IR (KBr): 3750-2400, 2256, 1709, 1436, 1252 cm" 1 ; ^ H N M R (400 MHz) 8: 2.94 (dm, 1H, J= 14 Hz, H b ) , 3.07-3.22 (m, 4H, H c , 3 of H j ) , 3.32 (br d, 1H, J= 16 Hz, one o f H d ) , 3.88 (br s, 1H, H a ) ; NOE difference experiment: irradiation ofthe signal at 8 2.94 (H D) enhanced the signal at 8 3.88 (H a ) ; irradiation ofthe signal at 8 3.88 (H a) enhanced the signals at 8 2.94 (H D) and 8 3.07-3.15 (one of H<i). Anal, calcd. for C13H8O2N4: C 61.90, H 3.20, N 22.21 found: C 61.88, H 3.30, N 22.18. Exact Mass calcd. for C 1 3 H 8 0 2 N 4 : 252.0647; found: 252.0646. 264 217 13.2 General Procedure 15: Preparation ofthe keto esters (252) r C 0 2 E t o R ' C 0 2 E t 221 252 To a cold (-78°C), stirred solution ofthe appropriate diene (221) (1 equiv.) in dry dichloromethane (10-12 mL/mmol ester) was added sequentially methyl vinyl ketone (MVK) (5 equiv.) and boron trifluoride-etherate (1 equiv.). The reaction mixture was stirred at -78°C for 1.5-3.5 hours (unless noted otherwise). Saturated aqueous NH4CI-NEL4OH (pH 8) (equal volume to the total volume ofthe reaction mixture) was added, the resultant mixture was allowed to warm to room temperature, and the mixture was thoroughly extracted with Et20. The combined extracts were washed with brine, dried (MgSC>4), and concentrated. The residual oil was subjected to either flash or radial chromatography and traces of solvent were removed (vacuum pump) from the acquired material to afford the corresponding keto ester (252). 218 Preparation ofthe keto ester (14) Following general procedure 15 outlined above, ethyl (Z)-2-ethyHdene-3-methylenecyclobutanecarboxylate (55) was converted into the keto ester (14). The reaction time was 3 hours. The following amounts of reagents and solvents were used: ethyl (Z)-2-ethyhdene-3-methylenecyclobutanecarboxylate (55) (225 mg, 1.35 mmol) in 15 mL of dry CH 2 Ci2 , methyl vinyl ketone (475 mg, 6.77 mmol), and BF 3«Et20 (192 mg, 1.35 mmol). Normal workup, followed by radial chromatography (4 mm plate, 3:1 hexanes-Et20) of the crude product and removal of traces of solvent (vacuum pump) from the acquired liquid afforded 185 mg (58%) ofthe keto ester (14) as a colourless oiL which exhibited JR (neat): 1731, 1712, 1177, 1033 cm" 1 ; A H N M R (400 MHz) 5: 0.88 (d, 3H, J= 1 Hz, -CHCH 3 ) , 1.24 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.59-1.69 (m, 1H, H e ) , 1.89-1.94 (m, 1H, Hf), 1.95-2.02 (m, 1H, H g ) , 2.08-2.14 (m, 1H, Hg«), 2.15 (s, 3H, -COCH 3 ) , 2.40 (ddd, 1H, J= 11, 8, 3 Hz, H c ) , 2.50-2.58 (m, 1H, Hd), 2.58-2.66 (m, 2H, H D ) , 3.52-3.57 (m, 1H, H a ) , 4.11 (q, 2H, J= 1 Hz, -OCH2CH 3 ) ; in a series of decoupling experiments, irradiation at 8 1.63 (H e ) simplified the multiplets at 8 1.89-1.94 (Hf), 1.95-2.02 (H g ) , 8 2.08-2.14 (Hg-) and 8 2.40 (He); irradiation at 8 1.91 (Hf) simplified the multiplets at 8 1.59-1.69 (H e), 1.95-2.02 (H g ) , and 8 2.08-2.14 (Hg-) and converted the signal at 8 2.40 (H^.) to a doublet of doublets (J= 11, 8 Hz); irradiation at 8 2.00 (H g ) simplified the multiplets at 8 1.59-1.69 (He), 8 1.89-1.94 (Hf) and 2.08-2.14 (H g-); irradiation at 8 2.12 (H g0 simplified the multiplets at 8 1.59-1.69 (H e), 8 1.89-1.94 (Hf) and 1.95-2.02 (H g ) ; irradiation at 8 2.40 (EL.) simplified the multiplets at 8 1.59-1.69 (Hg), 8 1.89-1.94 (Hf), and 8 2.50-2.58 (Hd); irradiation at 8 2.54 (Hd) converted the doublet at 8 0.88 219 (-CHCH3) to a singlet and converted the signal at 8 2.40 (H c ) to a doublet of doublets (J= 11, 3 Hz); irradiation at 8 3.55 (H a ) simplified the multiplet at 2.58-2.66 (H D). NOE difference experiments: irradiation at 8 0.88 (-CHCH3) enhanced the signals at 8 2.40 (H c ) and 8 2.50-2.58 (Hd); irradiation at 8 1.64 (Hg) caused enhancement ofthe signals at 8 1.89-1.94 (Hf), 8 1.95-2.02 (H g ) , 2.15 (-COCH3), and 2.50-2.58 (Hd); irradiation at 8 2.08-2.16 (H g-, -COCH3) caused enhancement ofthe signals at 8 1.89-1.94 (Hf), 8 2.40 (H c ) and 8 2.50-2.58 (Hd); irradiation at 8 2.40 (Hg) caused enhancement ofthe signals at 8 0.88 (-CHCH3), 8 1.89-1.94 (Hf), 2.08-2.16 (H g-), and 8 2.15 (-COCH3); irradiation at 8 2.54 (H d ) caused enhancement ofthe signals at 8 0.88 (-CHCH3), 8 1.59-1.69 (H e ) and 8 3.52-3.57 (H a). 1 3 C N M R (100.4 MHz) 8: 14.2, 16.3,24.2, 25.6, 29.5,31.9, 33.8,45.3,55.9, 60.3, 143.1, 143.2, 177.8, 206.9. Anal, calcd. for C14H20O3: C 71.15, H 8.54; found: C 71.35, H 8.75. Exact Mass calcd. for C 1 4 H 2 o 0 3 : 236.1412; found: 236.1417. Preparation ofthe keto ester (11) Fohowing general procedure 15 outlined above, ethyl (£')-2-ethyhdene-3-methylenecyclobutanecarboxylate (54) was converted into the keto ester (11). The reaction time was 1.5 hours. The following amounts of reagents and solvents were used: ethyl (JE)-2-ethyhdene-3-methylenecyclobutanecarboxylate (54) (150 mg, 0.903 mmol) in 10 mL of dry CH2CI2, methyl vinyl ketone (317 mg, 4.52 mmol), and BF3*Et20 (128 mg, 0.903 mmol). Normal workup, followed by radial chromatography (4 mm plate, 3:1 hexanes-Et20) ofthe crude product and removal of traces of solvent (vacuum pump) from the 11 220 acquired liquid, afforded 187 mg (88%) of keto ester (11) as a colourless oil, which exhibited IR (neat): 1730, 1709, 1179, 1038 cm" 1 ; i H N M R (400 MHz) 5: 0.81 (d, 3H, J= 7 Hz, -CHCH 3 ) , 1.27 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.62-1.72 (m, 1H), 1.78 (ddd, 1H, J= 14, 2.5, 2.5 Hz), 1.94-2.00 (m, 2H), 2.13 (s, 3H, -COCH 3 ) , 2.60-2.70 (m, 2H, H b ) , 2.70-2.77 (m, ILL H d ) , 2.81 (ddd, 1H, J= 12, 5, 2.5 Hz, H c ) , 3.58-3.62 (m, 1H, H a ) , 4.15 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) . irradiation at 5 0.81 ( - C H C H 3 ) sharpened the multiplet at 5 2.70-2.77 (Hd); irradiation at 8 3.60 (H a ) sharpened the multiplet at 5 2.60-2.70 (H D). N O E difference experiments: irradiation at 8 0.81 ( - C H C H 3 ) caused enhancement ofthe signals at 8 1.62-1.72, 8 2.70-2.77 (Hd) and 8 3.58-3.62 (H a ) ; irradiation at 8 3.60 (H a ) caused enhancement ofthe signals at 8 0.81 ( - C H C H 3 ) and 8 2.60-2.66 (H b). 1 3 C N M R (100.4 MHz) 8: 13.5, 14.3, 19.1, 25.0, 28.7, 29.8, 34.2, 43.7, 51.6, 60.3, 143.4, 160.9, 175.5, 207.8. Anal, calcd. for C 1 4 H 2 o 0 3 : C 71.15, H 8.54; found: C 71.40, H 8.48. Exact Mass calcd. for C 1 4 H 2 0 O 3 : 236.1412; found: 236.1414. Preparation ofthe keto ester (265) 265 Following a modified version of general procedure 15 outlined above, in which the reaction mixture was warmed to -48°C after the addition of BF 3 »Et 2 0 , ethyl (Z)-2-(2-methylpropyMene)-3-methylenecyclobutanecarboxylate (234) was converted into the keto ester (265). The reaction time was 8 hours. The following amounts of reagents and solvents were used: ethyl (Z)-2-(2-methylpropyhdene)-3-methylenecyclobutanecarboxylate (265) (40 mg, 0.21 mmol) in 4 mL of dry C H 2 C 1 2 , methyl vinyl ketone (72 mg, 1.0 mmol), and 221 BF 3 »Et 2 0 (30 mg, 0.21 mmol). Normal workup, followed by flash chromatography (10 g silica/4:1 hexanes-Et20) ofthe crude product and removal of traces of solvent (vacuum pump) from the acquired hquid, afforded 28 mg (50%) of keto ester (94) as a colourless oil, which exhibited IR (neat): 1733, 1705, 1469, 1369, 1155 cm" 1 ; * H N M R (400 MHz) 8: 0.82 (d, 6H, J= 6.5 Hz, -CH(CH 3 ) 2 ) , 1.23 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.65-1.77 (m, 2H, - C H ( C H 3 ) 2 , one of Hf), 1.81-1.87 (m, 1H, one of Hf), 1.87-1.96 (m, 1H, one of H e ) , 2.02-2.12 (m, 1H, one of EL.), 2.17 (s, 3H, -COCH 3 ) , 2.48-2.53 (m, 1H, Hd), 2.54-2.65 (m, 2H, H b ) , 2.66-2.72 (ddd, 1H, J= 8, 7, 3 Hz, H c ) , 3.54-3.58 (m, 1H, H a ) , 4.06-4.16 (m, 2H, - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 8 1.65-1.77 ( -CH(CH 3 ) 2 , one of Hf) converted the doublet at 8 0.82 into a singlet, sharpened the multiplet at 8 1.83 (one of Hf), converted the multiplet at 8 2.02-2.12 (one of Hg) into a broad doublet (J= 14 Hz), and converted the signal at 8 2.66-2.72 (H c ) to a doublet of doublets (J= 8, 7 Hz); irradiation at 8 2.48-2.53 (Hd) sharpened the multiplets at 8 1.65-1.77 ( -CH(CH 3 ) 2 ) and 8 1.87-1.96 (one of H e ) , converted the doublet of doublet of doublets at 8 2.66-2.72 (H c ) into a doublet of doublets (J= 8, 3 Hz), and sharpened the multiplet at 8 3.54-3.58 (H a ) ; irradiation at 8 3.54-3.58 (H a ) sharpened the multiplets at 8 2.48-2.53 (Hd) and 8 2.54-2.65 (H D). NOE difference experiments: irradiation at 8 2.50 (Hd) enhanced the signals at 8 0.82, 8 1.65-1.77 ( -CH(CH 3 ) 2 ) , 2.17 (-COCH 3 ) , and 3.54-3.58 (H a ) ; irradiation at 8 2.69 (H c ) caused enhancement ofthe signals at 8 0.82, 8 1.81-1.87 (one of Hf), 8 2.17 ( -COCH 3 ) , and 8 2.48-2.53 (Hd); irradiation at 8 3.56 (H a) caused enhancement ofthe signals at 8 2.48-2.53 (Hd) and 8 2.54-2.62 (H D ) ; 1 3 C N M R (75.3 MHz) 8: 14.2, 19.6, 20.1, 23.4, 25.5, 28.7, 29.1, 34.0, 43.0, 46.5, 49.1, 60.3, 141.2, 145.6, 174.1, 211.6. Anal, calcd. for C 1 6 H 2 4 0 3 : C 72.69, H 9.16; found: C 72.73, H 9.11. Exact Mass calcd. for C 1 6 H 2 4 0 3 : 264.1725; found: 264.1731. 222 Preparation ofthe keto ester (266) C02Et 266 Following general procedure 15 outlined above, ethyl (£)-2-(2-methylpropyhdene)-3-methylenecyclobutanecarboxylate (233) was converted into the keto ester (266). The reaction time was 2 hours. The following amounts of reagents and solvents were used: ethyl (£)-2-(2-methylpropylidene)-3-methylenecyclobutanecarboxylate (233) (50 mg, 0.26 mmol) in 4 mL of dry CH2CI2, methyl vinyl ketone (91.0 mg, 1.30 mmol), and B F 3 * E t 2 0 (37 mg, 0.26 mmol). Normal workup, followed by flash chromatography (10 g silica/4:1 hexanes-Et20) ofthe crude product and removal of traces of solvent (vacuum pump) from the acquired liquid, afforded 57 mg (84%) of keto ester (266) as a colourless oil, which exhibited IR (neat): 1731, 1709, 1177 cm" 1 ; X H N M R (400 MHz) 8: 0.82 (d, 3H, J = 7 H z , one o f -CH(CH 3 ) 2 ) , 0.92 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.57-1.65 (m, 1H, -CH(CH 3 ) 2 ) , 1.75-1.85 (m, 1H, one of H g ) , 1.85-1.94 (m, 1H, one of H g ) , 1.95-2.01 (m, 2H, Hf), 2.15 (s, 3H, - C O C H 3 ) , 2.50-2.59 (m, 2H, H c , H j ) , 2.72-2.78 (m, 1H, H D ) , 2.80-2.87 (m, 1H, He), 3.62-3.67 (m, 1H, H a ) , 4.15 (q, 2H, J= 1 Hz, - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 8 1.60 (-CH(CH3)2) converted the doublets at 8 0.82 (one o f -CH(CH 3 ) 2 ) and 8 0.92 (one o f -CH(CH 3 ) 2 ) into singlets; irradiation at 8 1.80 (one of Hg) simplified the multiplet at 8 1.85-1.94 (one of Hg) and converted the multiplet at 8 2.80-2.87 (H e ) into a doublet of doublets (J= 9, 6 Hz); irradiation at 8 1.90 (one of H g ) sharpened the multiplets at 8 1.75-1.85 (one of H g ) and 8 1.95-2.01 (Hf) and converted the multiplet at 8 2.80-2.87 (H e ) into a broad doublet (J= 6 Hz); irradiation at 8 2.55 ( H c , H^) converted the multiplet at 8 1.57-1.65 (-CH(CH 3)2) into a heptet (J= 1 Hz), 223 converted the multiplet at 8 2.72-2.78 (H b ) into a doublet (J= 5 Hz), simplified the multiplet at 8 2.80-2.87 (Hg) into a doublet of doublets (J= 9, 3 Hz), and simplified the multiplet at 8 3.62-3.67 (H a ) ; irradiation at 8 2.76 (H D) sharpened the multiplets at 8 2.50-2.58 (H c ) and 8 3.62-3.67 (H a ) ; irradiation at 8 2.84 (H e ) simplified the multiplets at 8 1.75-1.85 (one of H g ) , 8 1.85-1.94 (one of H g ) , and 8 2.50-2.59 (H d ) ; irradiation at 8 3.64 (Ha)simplified the multiplet at 8 2.50-2.58 (Hg) and converted the signal at 8 2.72-2.78 (H b ) into a broad doublet (J= 14 Hz). NOE difference experiments: irradiation at 8 1.60 ( -CH(CH 3 ) 2 ) enhanced the signals at 8 0.82 (one o f -CH(CH 3 ) 2 ) , 8 0.92 (one o f -CH(CH 3 ) 2 ) , and 8 2.54-2.59 (H<i); irradiation at 8 2.76 (H D ) caused enhancement ofthe signals at 8 2.50-2.58 (H c ) and 8 3.62-3.67 (H a ) ; irradiation at 8 2.82 (H e ) caused enhancement ofthe signals at 8 1.75-1.85 (one o fH g ) , 8 1.85-1.94 (one of H g ) , 8 1.95-2.01 (Hf), 8 2.15, and 8 2.54-2.59 (H d ) ; irradiation at 8 3.65 (H a) caused enhancement ofthe signals at 8 0.82 (one o f -CH(CH 3 ) 2 ) , 8 0.92 (one of -CH(CH 3 ) 2 ) , 8 1.26, and 8 2.72-2.78 (H b ) ; 1 3 C N M R (75.3 MHz) 8: 14.3, 20.0, 21.4, 23.6, 23.8, 25.5, 29.2, 34.6, 41.5, 49.9, 51.7, 60.3, 139.7, 145.9, 173.6, 210.6. Anal, calcd. for C 1 6 H 2 4 0 3 : C 72.69, H 9.16; found: C 72.72, H 9.19. Exact Mass calcd. for C 1 6 H 2 4 0 3 : 264.1725; found: 264.1725. Preparation ofthe keto ester (267) 267 Following a modified version of general procedure 15 outlined above in which the reaction mixture was warmed to -48°C after the addition of BF 3 «Et 2 0 , ethyl (Z)-2-cyclohexylmethylene-3-methylenecyclobutanecarboxylate (236) was converted into the 224 keto ester (267). The reaction time was 10 hours. The following amounts of reagents and solvents were used: ethyl (Z)-2-cyclohexylmethylene-3-methylenecyclobutanecarboxylate (236) (200 mg, 0.854 mmol) in 10 mL of dry C H 2 C 1 2 , methyl vinyl ketone (298 mg, 4.27 mmol), and B F 3 - E t 2 0 (122 mg, 0.855 mmol). Normal workup, followed by radial chromatography (4 mm plate/4:1 hexanes-Et20) ofthe crude product and removal of traces of solvent (vacuum pump) from the acquired liquid, afforded 194 mg (75%) of keto ester (267) as a colourless oiL which exhibited IR (neat): 1734, 1714, 1155 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 0.90-1.20 (m, 4H), 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.30-1.39 (m, 2H), 1.53-1.75 (m, 6H), 1.80-1.95 (m, 2H, one of Hf, one o f H g ) , 2.01-2.11 (m, 1H, one o f H g ) , 2.16 (s, 3H, -COCH 3 ) , 2.44-2.50 (m, 1H, HY), 2.54-2.63 (m, 2H, H D , H c ) , 2.70-2.76 (m, 1H, H e ) , 3.52-3.58 (m, 1H, H a ) , 4.08-4.16 (m, 2H, - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 8 1.85 (one of Hf, one ofHg) converted the multiplet at 8 2.70-2.76 (Hg) into a doublet of doublets (J= 7, 7 Hz); irradiation at 8 2.47 (Hd) sharpened the multiplet at 8 1.30-1.39 and converted the multiplet at 8 2.70-2.76 (H e) into a doublet of doublets (J= 7, 3 Hz); irradiation at 8 2.60 (H D , Hg) sharpened the multiplets at 8 1.89-1.95 (Hf) and 8 3.52-3.58 (H a ) ; irradiation at 8 2.73 (Hg) simplified the multiplets at 8 1.80-1.89 (one ofHg) and sharpened the signal at 8 2.44-2.50 (ELY) ; irradiation at 8 3.55 (H a ) sharpened the multiplets at 8 2.44-2.50 (Hd) and 8 2.54-2.63 (H D , H c ) . NOE difference experiments: irradiation at 8 1.35 enhanced the signal at 8 2.44-2.50 (Hd); irradiation at 8 1.85 (one of Hf, one of H g ) enhanced the signals at 8 1.56-1.75 and 8 2.70-2.76 (Hg); irradiation at 8 2.47 (Hd) enhanced the signals at 8 1.30-1.39, 8 2.16, 8 2.70-2.76 (H e) and 8 3.52-3.58 (H a ) ; irradiation at 8 2.75 (Hg) caused enhancement ofthe signals at 8 0.90-1.05, 8 1.80-1.90 (one of H g ) , 8 2.16, and 8 2.44-2.50 (Hd); irradiation at 8 3.55 (H a ) enhanced the signals at 8 2.44-2.50 (H d ) and 8 2.54-2.60 (H D ) ; 1 3 C N M R (75.3 MHz) 8: 14.2, 23.4, 25.4, 26.4, 26.82, 26.83, 28.7, 30.0, 31.2, 33.9, 39.8, 42.6, 46.6, 49.1, 60.4, 141.3, 145.3, 174.2, 211.5. Anal, calcd. for C 1 9 H 2 8 0 3 : C 74.96, H 9.28; found: C 74.79, H 9.28. Exact Mass calcd. for C 1 9 H 2 8 0 3 : 304.2039; found: 304.2038. 225 Preparation ofthe keto ester (268) 268 Following general procedure 15 outlined above, ethyl (JE,)-2-cyclohexylmethylene-3-methylenecyclobutanecarboxylate (235) was converted into the keto ester (268). The reaction time was 3.5 hours. The following amounts of reagents and solvents were used: ethyl (ii)-2-cyclohexylmethylene-3-methylenecyclobutanecarboxylate (238) (125 mg, 0.533 mmol) in 5 mL of dry CH2CI2, methyl vinyl ketone (186 mg, 2.66 mmol), and BF3»Et20 (76 mg, 0.53 mmol). Normal workup, followed by radial chromatography (4 mm plate/4:1 hexanes-Et20) ofthe crude product and removal of traces of solvent (vacuum pump) from the acquired hquid, afforded 142 mg (87%) of keto ester (268) as a colourless oil, which exhibited IR (neat): 1729, 1709, 1177 cm" 1 ; * H N M R (400 MHz) 5: 0.80-0.92 (m, 1H), 1.02-1.18 (m, 4H), 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.46-1.74 (m, 7H), 1.80-1.90 (m, 1H, one ofHg), 1.92-2.00 (m, 2H, Hf), 2.15 (s, 3H, - C O C H 3 ) , 2.52-2.60 (m, 2H, He, Hd), 2.70-2.77 (m, 1H, H b ) , 2.78-2.85 (m, 1H, Hg), 3.63-3.68 (m, 1H, H a ) , 4.11-4.19 (m, 2H, - O C H 2 C H 3 ) ; in a series of decoupling experiments, irradiation at 8 1.85 (Hg) converted the multiplet at 8 2.78-2.85 (Hg) into a broad doublet of doublets(/= 4, 4 Hz) and sharpened the multiplet at 8 1.92-2.00 (Hf); irradiation at 8 2.54 (Hg, ELj) simplified the multiplet at 8 2.70-2.77 (H D) , converted the multiplet at 8 2.78-2.85 (H e ) into a doublet of doublets (J= 10, 4 Hz), and sharpened the multiplet at 8 3.63-3.68 (H a ) ; irradiation at 8 2.75 (H D) sharpened the multiplets at 8 2.52-2.60 (H c ) and 8 3.63-3.68 (H a ) ; irradiation at 8 3.68 (H a ) simplified the multiplet at 8 2.52-2.60 (H c ) and converted the multiplet at 8 2.70-2.77 (H D) into a doublet of doublets (J= 12, 1.5 Hz). NOE difference experiments: irradiation at 8 1.66 caused 226 enhancement of the signals at 8 0.80-0.90 and 8 1.02-1.18; irradiation at 8 1.84 (one of Hg) caused enhancement ofthe signal at 8 2.78-2.85 (Hg); irradiation at 8 1.97 (Hf) caused enhancement ofthe signal at 8 2.78-2.85 (Hg); irradiation at 8 2.15 ( C O C H 3 ) caused enhancement ofthe signals at 8 2.52-2.60 (Hd) and 8 2.78-2.85 (Hg); irradiation at 8 2.54 (H c , Hd) caused enhancement ofthe signals at 8 2.15 (COCH3), 8 2.70-2.77 (H D) and 8 2.78-2.85 (Hg); irradiation at 8 2.75 (H D) caused enhancement ofthe signals at 8 2.52-2.60 (H c ) and 8 3.63-3.68 (H a ) ; irradiation at 8 2.82 (Hg) caused enhancement ofthe signals at 8 1.80-1.90 (H g ) and 8 2.52-2.60 (Hd); irradiation at 8 3.68 (H a ) enhanced the signals at 8 2.52-2.56 (H c ) and 8 2.70-2.77 (H D ) ; 1 3 C N M R (75.3 MHz) 8: 14.3, 21.9, 24.0, 26.2, 26.3, 26.8, 29.3, 31.0, 33.6, 34.5, 39.3, 41.3, 47.0, 51.8, 60.3, 140.3, 145.3, 173.7, 210.8. Anal, calcd. for C 1 9 H 2 8 0 3 : C 74.96, H 9.28; found: C 74.98, H 9.34. Exact Mass calcd. for C 1 9 H 2 8 0 3 : 304.2039; found: 304.2043. 227 14. General Procedure 16: Preparative thermal ring opening of the fiinctionalized bicyclo[4.2.0]oct- l(6)enes NC R O R 314 Ha 315 ^ R'Sv^ v T ^ N ^ ^ H b R ' ^ Y ^ ^ R ' ^ % R I G i R 316 317 A solution ofthe appropriate bicyclo[4.2.0]oct-l(6)ene (314) or (315) in dry mesitylene (10-15 mL/mmol of substrate) was heated to and refluxed at 165°C for 4 hours (unless noted otherwise) under an argon atmosphere. The reaction mixture was cooled to room temperature and then subjected to radial chromatography to afford a mixture of outward rotation isomer (316) and inward rotation isomer (317) as thermolysis products. After deterrrhning the ratio of (150):(151) by A H N M R spectroscopic analysis (ratio of H a : H 0 in all cases unless noted otherwise), the crude product was again subjected to radial chromatography. Removal of traces of solvent (vacuum pump) from the acquired products gave the corresponding outward (316) and inward (317) rotation products. 228 Preparation ofthe tetranitrile ester dienes (275) and (276) from the ester (255) 275 276 Following a modified version of general procedure 16, in which the reaction mixture was heated to 145°C for 3.5 hours before cooling to room temperature, the ester (255) was converted into the tetranitrile ester dienes (275) and (276). The following amounts of substrate and solvent were used: ester (255) (75 mg, 0.27 mmol) in 3 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes then Et20) afforded 72 mg (96%) of a mixture ofthe diene (275) and the diene (276) in a ratio of 18:1, respectively (4l N M R analysis of signals H c (275) and Hb (276). The mixture was again subjected to radial chromatography (1 mm plate, 3:1 hexanes-Et20). Recrystallization (1:1 petroleum ether-Et20) ofthe acquired solids afforded 60 mg (80%) ofthe diene (275) as a colourless solid (melting point 84-85°C), and 3.5 mg (5%) ofthe diene (276), also as a colourless solid (melting point 56-57°C). The major isomer, resulting from outward rotation ofthe ester group, the diene (275), exhibited IR (KBr): 2264, 1716, 1649, 1193 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 5: 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 3.25 (s, 2H, Kbj), 4.01 (br s, 2H, Hg), 4.23 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.36 (s, 1H, Hg), 5.58 (s, 1H, Hb), 6.21 (br s, 1H, H a ) ; NOE difference experiments: 229 irradiation at 8 3.25 (H d ) caused enhancement ofthe signal at 8 5.36 (H c ) ; irradiation at 8 5.36 (H c ) caused enhancement of the signals at 8 3.25 (H d ) and 8 5.58 (H b ) ; irradiation at 8 5.58 (H D) caused enhancement ofthe signals at 8 5.36 (H c ) and 8 6.21 (H a ) ; irradiation at 8 6.21 (H a) caused enhancement ofthe signal at 8 5.58 (H b). * H N M R (CgDg, 400 MHz) 8: 0.93 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.92 (br s, 2H, H d ) , 3.47 (d, 2H, J= 2 Hz, H e ) , 3.84 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.22 (s, 1H, H c ) , 4.56 (s, 1H, H b ) , 5.65 (t, 1H, J= 2 Hz, H a ) ; 1 3 C N M R (100.4 MHz) 8: 14.0, 33.0, 39.2, 40.2, 40.7, 61.2, 109.63, 109.67, 109.71, 109.73, 121.8, 122.3, 134.6, 142.2, 164.6. Anal, calcd. for C 1 5 H 1 2 0 2 N 4 : C 64.28, H 4.32, N 19.99; found: C 64.35, H 4.45, N 20.00. Exact Mass calcd. for C 1 5 H 1 2 0 2 N 4 : 280.0960; found: 280.0967. The minor isomer, resulting from inward rotation ofthe ester group, the diene (276), exhibited IR (KBr): 2259, 1713, 1650, 1200 cm" 1 ; X H N M R (400 MHz) 8: 1.26 (t, 3H, J= 1 Hz, - O C H 2 C H 3 ) , 3.14 (br s, 2H, H e ) , 3.21 (br s, 2H, H d ) , 4.18 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.54 (s, 1H, H b ) , 5.56 (br s, 1H, H c ) , 6.01 (br s, 1H, H a ) ; NOE difference experiments: irradiation at 8 3.14 (H e ) caused enhancement ofthe signal at 8 6.01 (H a ) ; irradiation at 8 3.21 (H d ) caused enhancement ofthe signal at 8 5.56 (H c ) ; irradiation at 8 5.56 (H c ) caused enhancement ofthe signal at 8 3.21 (H d ) ; irradiation at 8 6.01 (H a ) caused enhancement of the signal at 8 3.14 (H e). X H N M R ( C 6 D 6 , 400 MHz) 8: 0.87 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.76 (br s, 2H, H e ) , 1.94 (br s, 2H, H d ) , 3.83 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.59 (s, 1H, H b ) , 5.02 (br s, 1H, H c ) , 5.23 (br s, 1H, H a ) ; Anal, calcd. for C 1 5 H 1 2 0 2 N 4 : C 64.28, H 4.32, N 19.99; found: C 64.47, H 4.34, N 20.07. Exact Mass calcd. for C 1 5 H 1 2 0 2 N 4 : 280.0960; found: 280.0959. 230 Preparation ofthe tetranitrile ester dienes (278) and (277) from the ester (256) NC NC ^ C 0 2 E t Me 256 NC H d H c Hb NC Hb C 0 2 E t NC NC NC I I Me C 0 2 E t 277 278 Following general procedure 16 outlined above, the ester (256) was converted into the tetranitrile ester dienes (278) and (277). The following amounts of substrate and solvent were used: ester (256) (50 mg, 0.17 mmol) in 2 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, followed by CH2CI2) afforded 42 mg (84%) of a mixture ofthe diene (277) and the inward rotation diene (278) in a ratio of 2.6:1, respectively ( A H N M R analysis of signals H c (277) and H D (278)). The mixture was again subjected to radial chromatography (1 mm plate, CH2CI2). Recrystallization (1:1 petroleum ether-Et20) ofthe solids obtained afforded 26.5 mg (53%) ofthe diene (277), as a colourless solid (melting point 127-128°C), and 10.5 mg (21%) ofthe diene (278), also as a colourless solid (melting point 85-86°C). The major isomer, resulting from outward rotation of the ester group, the diene (277), exhibited IR (KBr): 2255, 1714, 1645, 1207, 1133 cm" 1 ; A H N M R (400 MHz) 8: 1.29 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.60 (d, 3H, J= 7 Hz, - C H C H 3 ) , 3.21-3.31 (m, 2H, H d ) , 4.21 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.00 (q, 1H, J= 7 Hz, - C H C H 3 ) , 5.42 (br s, 1H, H c ) , 5.57 (d, 1H, J= 2 Hz, H D ) , 6.09 (s, 1H, H a ) ; NOE difference experiments: irradiation at 8 3.27 (H Q) caused 231 enhancement ofthe signal at 8 5.42 (He); irradiation at 8 5.42 (HQ) caused enhancement ofthe signals at 8 3.21-3.31 (H d ) and 8 5.57 (H b ) ; irradiation at 8 5.57 (H b ) caused enhancement of the signals at 8 5.42 (H c ) and 8 6.09 (H a ) ; irradiation at 8 6.09 (H a ) caused enhancement ofthe signal at 8 5.57 (H b ) . X H N M R ( C 6 D 6 , 400 MHz) 8: 0.88 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.26 (d, 3H, J= 7 Hz, - C H C H 3 ) , 1.82 (ddd, 1H, J= 16, 2, 2 Hz, one of Hd), 2.19 (ddd, 1H, J= 16, 2, 2 Hz, one of Hd), 3.78-3.86 (m, 2H, - O C H 2 C H 3 ) , 4.33 (dd, 1H, J= 2, 2 Hz, He), 4.60 (dd, 1H, J= 2, 2 Hz, H b ) , 4.93 (q, 1H, J= 7 Hz, -CHCH 3 ) , 5.60 (br s, 1H, H a ) ; 1 3 C N M R (100.4 MHz) 8: 14.0, 16.6, 38.0, 39.4, 39.5, 44.2, 61.2, 109.9, 110.5, 110.6, 110.9, 120.9, 123.1, 133.3, 149.0, 164.4. Anal, calcd. for C 1 6 H 1 4 0 2 N 4 : C 65.29, H 4.80, N 19.04; found: C 65.45, H4.82, N 19.14. Exact Mass calcd. for C 1 6 H 1 4 0 2 N 4 : 294.1116; found: 294.1115. The minor isomer, resulting from inward rotation ofthe ester group, the diene (278), exhibited IR (KBr): 2256, 1729, 1648, 1193 cm" 1 ; lU N M R (400 MHz) 8: 1.25 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.61 (d, 3H, J= 7 Hz, -CHCH 3 ) , 3.17 (dq, 1H, J= 2.5, 7 Hz, -CHCH 3 ) , 3.20-3.24 (m, 2H, Hd), 4.18 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.38 (br s, 1H, H b ) , 5.45 (br s, 1H, He), 5.96 (d, 1H, J= 2.5 Hz, H a ) ; NOE difference experiments: irradiation at 8 5.38 (H b ) caused enhancement ofthe signal at 8 5.45 (H c ) ; irradiation at 8 5.45 (H c ) caused enhancement ofthe signals at 8 5.38 (H b ) and 8 3.20-3.24 (Hd); irradiation at 8 5.96 (H a ) caused enhancement ofthe signals at 8 1.61 ( -CHCH 3 ) and 8 3.17 (-CHCH 3 ) . ! H N M R ( C 6 D 6 , 400 MHz) 8: 0.63 (d, 3H, J= 7 Hz, -CHCH 3 ) , 0.82 (t, 3H, J= 1 Hz, - O C H 2 C H 3 ) , 2.30-2.38 (m, 3H, H d , - C H C H 3 ) , 3.75-3.85 (m, 2H, - O C H 2 C H 3 ) , 4.67 (d, 1H, J=2 Hz, H b ) , 4.88 (d, 1H, J= 2 Hz, He), 5.35 (d, 1H, J= 2.5 Hz, H a ) . 1 3 C N M R (100.4 MHz) 8: 13.9, 14.2, 40.5, 42.1, 43.2, 48.2, 61.2, 107.9, 109.7, 110.3, 110.4, 122.1, 122.4, 132.7, 144.3, 164.4. Anal, calcd. for C 1 6 H 1 4 0 2 N 4 : C 65.29, H 4.80, N 19.04; found: C 65.50, H 4.79, N 19.00. Exact Mass calcd. f o r C 1 6 H 1 4 0 2 N 4 : 294.1116; found: 294.1120. 232 Preparation ofthe tetranitrile ester dienes (278) and (277) from the ester (257) Me C0 2 Et Me H a 277 278 Following general procedure 16 outlined above, the ester (257) was converted into the tetranitrile ester dienes (278) and (277). The following amount of substrate and solvent were used: ester (257) (50 mg, 0.17 mmol) in 2 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then CH2CI2) afforded 40 mg (80%) of a mixture ofthe diene (277) and the diene (278) in a ratio of 4.3:1, respectively ( A H NMR analysis of signals H c (277) and H D (278)). The mixture was again subjected to radial chromatography (1 mm plate, CH2CI2). Recrystallization (1:1 petroleum ether-Et20) ofthe acquired solids afforded 28 mg (56%) ofthe diene (277) as a colourless solid (melting point, 127-128°C) and 7 mg (14%) ofthe diene (278), also as a colourless solid (melting point 85-86°C). The spectral data derived from these substances were identical with those reported in the last experiment. 233 Preparation ofthe tetranitrile ester dienes ( 2 7 9 ) and ( 2 8 0 ) from the ester ( 2 5 8 ) NC NC ^ C 0 2 E t Ha /-Pr 258 NC H b C 0 2 E t NC NC NC NC 1 1 /-Pr C 0 2 E t 280 279 Following a modified version of general procedure 16 in which the reaction time was 6 hours, the ester ( 258 ) was converted into the tetranitrile ester dienes ( 2 7 9 ) and (280) . The following amounts of substrate and solvent were used: ester ( 2 5 8 ) (50 mg, 0.16 mmol) in 2.5 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) afforded 43 mg (86%) of a mixture ofthe outward rotation diene ( 2 7 9 ) and inward rotation diene ( 280) in a ratio of 1:1.5 respectively ( A H N M R analysis ofthe signals H c ( 2 7 9 ) and H D (280)) . The mixture was again subjected to radial chromatography (1 mm plate, CH2CI2). Recrystallization (1:1 petroleum ether-Et20) ofthe solids obtained afforded 16 mg (32%) ofthe diene (279) , as a colourless solid (melting point 142-143°C), and 22 mg (44%) ofthe diene (280) , also as a colourless solid (melting point, 98-99°C). The minor isomer, resulting from outward rotation ofthe ester group, the diene (279) , exhibited LR (KBr): 2256, 1716, 1202 cm" 1 ; A H N M R (400 MHz) 8: 0.93 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 1.30 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.41 (d, 3H, J= 7 Hz, one of -CH(CH 3 ) 2 ) , 2.36-2.46 (m, 1H, -CH(CH 3 ) 2 ) , 3.23-3.33 (m, 2H, Hd), 4.21 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.76 (d, 1H, J= 9 Hz, -CH(/-Pr)), 5.35 (br s, 1H, H c ) , 5.46 (br s, 1H, H D ) , 6.16 234 (s, 1H, H a ) ; NOE difference experiments: irradiation at 8 3.30 (H a ) caused enhancement ofthe signal at 8 5.35 (EL^); irradiation at 8 5.35 (H c ) caused enhancement ofthe signals at 8 3.23-3.33 (Hj) and 8 5.46 (H D ) ; irradiation at 8 5.46 (H D) caused enhancement ofthe signals at 8 5.35 (H c ) and 8 6.16 (H a ) ; irradiation at 8 6.16 (H a ) caused enhancement ofthe signal at 8 5.46 (H D). i H N M R ( C 6 D 6 , 400 MHz) 8: 0.62 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 0.88 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.20 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 195 (br d, H i , J= 16 Hz, one of Hd), 2.20 (br d, 1H, J= 16 Hz, one of Hd), 2.21-2.31 (m, 1H, -CH(CH 3 ) 2 ) , 3.77-3.87 (m, 2H, - O C H 2 C H 3 ) , 4.28 (br s, 1H, He), 4.55 (br s, 1H, H D ) , 4.79 (d, 1H, J= 9 Hz, -CH(/-Pr)), 5.74 (s, 1H, H a ) . 1 3 C N M R (100.4 MHz) 8: 14.0, 20.3, 22.8, 30.0, 38.7, 39.6, 43.0, 48.7, 61.2, 110.5, 110.7, 110.92, 110.94, 120.9, 123.9, 135.2, 147.7, 164.7. Anal, calcd. for C 1 8 H 1 8 0 2 N 4 : C 67.06, H 5.63, N 17.38; found: C 67.08, H 5.84, N 16.95. Exact Mass calcd. for C 1 8 H 1 8 0 2 N 4 : 322.1429; found: 322.1423. The major isomer, resulting from inward rotation of the ester group, the diene (280), exhibited LR (KBr): 2256, 1716, 1202 cm" 1 ; 1 H N M R (400 MHz) 8: 1.18 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.39 (d, 3H, J= 7 Hz, one of -CH(CH 3 ) 2 ) , 2.37-2.46 (m, 1H, -CH(CH 3 ) 2 ) , 2.86 (d, 1H, J= 7 Hz, -CH(/-Pr)), 3.28-3.36 (m, 2H, Hd), 4.17 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.30 (br s, 1H, H D ) , 5.43 (br s, 1H, 1^), 6.00 (s, 1H, H a ) ; NOE difference experiments: irradiation at 8 2.86 (-CH(/-Pr)) caused enhancement of the signals at 8 1.18 (one o f -CH(CH 3 ) 2 ) , 8 1.39 (one o f -CH(CH 3 ) 2 ) , 8 2.37-2.46 ( -CH(CH 3 ) 2 ) and 8 6.00 (H a ) ; irradiation at 8 3.33 (Hd) caused enhancement ofthe signal at 8 5.43 (Hg); irradiation at 8 5.43 (HV) caused enhancement ofthe signals at 8 3.28-3.36 (Hd) and 8 5.30 (H D ) ; irradiation at 8 6.00 (H a ) caused enhancement ofthe signals at 8 2.37-2.46 ( -CH(CH 3 ) 2 ) and 8 2.86 (-CH(/-Pr)). A H N M R ( C 6 D 6 , 400 MHz) 8: 0.47 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 0.84 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 0.85 (d, 3H, J= 7 Hz, one of -CH(CH 3 ) 2 ) , 1.77-1.87 (m, 1H, -CH(CH 3 ) 2 ) , 2.13 (d, 1H, J= 7 Hz, -CH(/-Pr)), 2.25-2.37 (m, 2H, H d ) , 3.87 (q, 2H, J= 1 Hz, - O C H 2 C H 3 ) , 4.65 (br s, 1H, H b ) , 4.83 (br s, 1H, H c ) , 5.52 (br s, 1H, H a ) . 1 3 C N M R (100.4 MHz) 8: 14.0, 21.0, 21.1, 29.3, 29.7, 40.6, 44.3, 55.4, 61.2, 109.6, 110.5, 110.6, 111.0, 121.5, 124.5, 132.1, 143.8, 164.0. Anal, calcd. for C 1 8 H 1 8 0 2 N 4 : 235 C 67.06, H 5.63, N 17.38; found: C 67.36, H 5.72, N 16.91. Exact Mass calcd. for C 1 8 H 1 8 0 2 N 4 : 322.1429; found: 322.1423. Preparation ofthe tetranitrile ester dienes (279) and (280) from the ester (259) NC i H b NC NC r . H r = X 0 2 E t NC = H e H a /-Pr H d H c 259 H b NC C 0 2 E t NC Hd H c Following a modified version of general procedure 16 in which the reaction time was 6 hours, the ester (259) was converted into the tetranitrile ester dienes (279) and (280). The following amounts of substrate and solvent were used: ester (259) (50 mg, 0.16 mmol) in 2.5 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes then Et 2 0) afforded 46 mg (92%) of a mixture of the outward rotation diene (279) and the inward rotation diene (280) in a ratio of 1:1.6 respectively ( X H N M R analysis of signals UQ (279) and H D (280)). The mixture was again subjected to radial chromatography (1 mm plate, CH 2 C1 2 ) . Recrystallization (1:1 petroleum ether-Et20) ofthe acquired solids afforded 13.5 mg (27%) ofthe diene (279) as a colourless solid (melting point 142-143°C) and 20.5 mg (41%) ofthe diene (280), also as a colourless solid (melting point, 98-99°C). The spectral data obtained from these materials was identical with those reported for the last experiment. 236 Preparation ofthe tetranitrile ester dienes (281) and (282) from the ester (260) NC NC ^ C 0 2 E t i H e H a c-Hex 260 NC NC Hb C 0 2 E t NC NC NC 1 1 c-Hex C 0 2 E t 281 282 Following a modified version of general procedure 16 in which the reaction time was 6 hours, the ester (260) was converted into the tetranitrile ester dienes (281) and (282). The following amounts of substrate and solvent were used: ester (260) (100 mg, 0.276 mmol) in 3 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then CH2CI2) afforded 84 mg (84%) of a mixture ofthe diene (281) and the diene (282) , in a ratio of 1:1.2 respectively ( l H N M R analysis of signals H c (281) and H b (282)). The mixture was again subjected to radial chromatography (1 mm plate, CH2CI2). Recrystallization (1:1 petroleum ether-Et20) of the solids obtained gave 32 mg (32%) ofthe diene (281) as a colourless solid (melting point 148-149°C) and 39 mg (39%) ofthe diene (282) , also as a colourless solid (melting point, 102-103°C). The minor isomer, resulting from outward rotation ofthe ester group, the diene (281), exhibited IR (KBr): 2253, 1708, 1645, 1208 cm" 1 ; X H N M R (400 MHz) 5: 0.93-1.02 (m, 2H), 1.10-1.22 (m, 2H), 1.30 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.42-1.51 (m, 1H), 1.56-1.82 (m, 4H), 2.02-2.11 (m, 1H), 2.26-2.34 (m, 1H), 3.23-3.31 (m, 2H, H<i), 4.22 (q, 2H, J= 7 Hz, 237 - O C H 2 C H 3 ) , 4.75 (d, 1H, J= 8 Hz, =CCH(c-Hex)), 5.34 (br s, 1H, H c ) , 5.46 (br s, 1H, H b ) , 6.16 (s, 1H, H a ) ; NOE difference experiments: irradiation at 8 3.28 (H d ) caused enhancement ofthe signal at 8 5.34 (H c ) ; irradiation at 8 5.34 (H c ) caused enhancement ofthe signals at 8 3.23-3.31 (H d ) and 8 5.46 (H b ) ; irradiation at 8 5.46 (H b ) caused enhancement ofthe signals at 8 5.34 (H c ) and 8 6.16 (H a ) ; irradiation at 8 6.16 (H a ) caused enhancement ofthe signals at 85.46(H b ) . l H N M R (CgDg, 400 MHz) 8: 0.87-1.14 (m, 7H, including triplet at 8 0.92, -O C H 2 C H 3 ) , 8 1.32-1.54 (m, 5H), 1.93 (d, 1H, J= 16 Hz, one of Hrf), 2.10-2.20 (m, 1H), 2.23 (ddd, 1H, J=16, 2, 2 Hz, one of H d ) , 2.30-2.37 (m, 1H), 3.81-3.91 (m, 2H, -OCH^CHg). 4.30 (d, 1H, J= 2 Hz, H c ) , 4.60 (d, 1H, J= 2 Hz, H b ) , 4.83 (d, 1H, /= 7 Hz, =CCH(c-Hex)), 5.79 (s, 1H, H a ) . 1 3 C N M R (100.4 MHz) 8: 14.1, 25.4, 25.7, 26.1, 26.2, 29.6, 33.6, 38.5, 39.6, 43.0, 47.7, 61.1, 110.4, 110.6, 110.9, 111.0, 121.0, 124.0, 136.0, 147.1, 163.6. Anal, calcd. for C 2 1 H 2 2 ° 2 N 4 ; c 6 9 5 9 > H 6.12, N 15.46; found: C 69.43, H 6.08, N 15.51. Exact Mass calcd. for C 2 1 H 2 2 O 2 N 4 : 362.1743; found: 362.1753. The major isomer, resulting from inward rotation ofthe ester group, the diene (282), exhibited IR (KBr): 2265, 1719, 1639, 1204 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 1.25-1.40 (m, 7H, includes triplet at 8 1.28, J= 7 Hz, - O C H 2 C H 3 ) , 1.69-1.75 (m, 1H), 1.80-1.91 (m, 4H), 1.96-2.02 (m, 1H), 2.04-2.11 (m, 1H), 2.87 (d, 1H, J= 6 Hz, =CCH(c-Hex)), 3.29-3.34 (m, 2H, H d ) , 4.16 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 5.30 (br s, 1H, H b ) , 5.43 (br s, 1H, H c ) , 5.95 (s, 1H, H a ) ; NOE difference experiments: irradiation at 8 2.87 (=CCH(c-Hex)) caused enhancement ofthe signal at 8 5.95 (H a ) ; irradiation at 8 3.32 (H d ) caused enhancement of the signal at 8 5.43 (H c ) ; irradiation at 8 5.30 (H b ) caused enhancement ofthe signals at 8 5.43 (H c ) ; irradiation at 8 5.43 (H c ) caused enhancement ofthe signals at 8 3.29-3.34 (H d ) and 8 5.30 (H b ) ; irradiation at 8 5.95 (H a ) caused enhancement ofthe signal at 8 2.87 (=CCH(c-Hex)). i H N M R ( C 6 D 6 , 400 MHz) 8: 0.77-1.05 (m, 8H, including triplet at 8 0.89, J = 7 Hz, - O C H 2 C H 3 ) , 1.30-1.48 (m, 3H), 1.60-1.71 (m, 1H), 1.95-2.03 (m, 1H), 2.25-2.40 (m, 3H), 3.88 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.57 (br s, 1H, H b ) , 4.72 (br s, 1H, H c ) , 5.56 (br s, 1H, H a ) . 1 3 C N M R (100.4 MHz) 8: 14.1, 25.4, 26.1, 26.2, 26.3, 29.7, 33.61, 33.62, 39.62, 39.63, 47.7, 61.2, 110.4, 238 110.6, 110.9, 111.0, 121.1, 124.0, 135.6, 147.1, 164.7. Anal, calcd. for C21H22O2N4: C 69.59, H 6.12, N 15.46; found: C 69.69, H 6.10, N 15.60. Exact Mass calcd. for C 2 1 H 2 2 ° 2 N 4 : 362.1743; found: 362.1739. Preparation ofthe tetranitrile ester dienes (281) and (282) from the ester (261) c-Hex C02Et c-Hex H a 281 282 Fonowing a modified version of general procedure 16 in which the reaction time was 6 hours, the ester (261) was converted into the tetranitrile ester dienes (281) and (282). The following amounts of substrate and solvent were used: ester (261) (100 mg, 0.276 mmol) in 3 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes then CLTjCL)) afforded 94 mg (94%) of a mixture ofthe outward rotation diene (281) and the inward rotation diene (282) in a ratio of 1:1.3 respectively ( A H N M R analysis of signals He (281) and H D (282)). The mixture was again subjected to radial chromatography (1 mm plate, CH2CI2). Recrystallization (1:1 petroleum ether-Et20) ofthe acquired solids afforded 36 mg (36%) ofthe diene (281) as a colourless solid (melting point, 148-149°C) and 51 mg (51%) ofthe diene (282), also as a colourless solid (melting point, 102-103°C). The spectral data obtained from these materials was identical with those reported for the last experiment. 239 Preparation ofthe tetranitrile alcohol diene (271) from the alcohol (262) NC H b NC Hd H c NC | I Hb NC NC = C H 2 O H H a 262 271 Following general procedure 16 outlined above, the alcohol (262) was converted into the alcohol (271). The following amounts of substrate and solvent were used: alcohol (262) (50 mg, 0.21 mmol) in 2.5 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) and recrystallization (1:1 petroleum ether-ether) afforded 42 mg (84%) ofthe diene (271) as colourless crystals (melting point, 118-119°C), which exhibited IR (KBr): 3466 (br), 1642, 1441, 1007 cm" 1 ; ! H N M R ( 4 0 0 M H Z ) 8: 1.55 (br s, 1H, -CH 2 OH) , 3.15 (s, 2H, Hd), 3.34 (s, 2H, Hg), 4.32 (d, 2H, J= 7 Hz, -CH 2 OH) , 5.20 (s, 1H, Hg), 5.42 (s, 1H, H b ) , 6.13 (t, 1H, J= 7 Hz, H a ) ; N O E difference experiments: irradiation at 8 3.15 (Hd) caused enhancement ofthe signal at 8 5.20 (Hg); irradiation at 8 3.34 (Hg) caused enhancement ofthe signal at 8 4.32 (-CH2OH); irradiation at 8 4.32 (-CH2OH) caused enhancement ofthe signals at 8 3.34 (H e ) and 8 6.13 (H a ) ; irradiation at 8 5.20 (H c ) caused enhancement ofthe signals at 8 3.15 (FLY) and 8 5.42 (H b ) ; irradiation at 8 5.42 (H b ) caused enhancement ofthe signals at 8 5.20 (H c ) and 8 6.13 (H a ) ; irradiation at 8 6.13 (H a ) caused enhancement ofthe signals at 8 4.32 ( -CH 2 OH) ^ d 8 5.42 (H b). ! H N M R ( C 6 D 6 , 400 MHz) 8: 0.52 (t, 1H, J= 7 Hz, -CH 2 OH) , 1.95 (br s, 2H, Hd), 2.30 (br s, 2H, Hg), 3.34 (dd, 2H, J= 7, 7 Hz, -CH 2 OH) , 4.25 (br s, 1H, Hg), 4.63 (br s, 1H, H b ) , 5.37 (t, 1H, J= 7 Hz, H a ) . Anal, calcd. for C 1 3 H 1 0 O N 4 : C 65.54, H 4.23, N 23.52; found: C 65.36, H 4.33, N 23.58. Exact Mass calcd. for C 1 3 H 1 0 O N 4 : 238.0855; found: 238.0856. 240 15 16 Following general procedure 16 outlined above, the keto ester (14) was converted into the keto ester dienes (15) and (16). The following amounts of substrate and solvent were used: keto ester (14) (75 mg, 0.32 mmol) in 3.2 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) afforded 63 mg (83%) of a mixture ofthe outward rotation diene (15) and the inward rotation diene (16) in a ratio of 1:1 respectively (4l N M R analysis of signals H b (15) and H c (16)). The mixture was again subjected to radial chromatography (1 mm plate, 3:1 hexanes-Et20). Removal of trace amounts of solvent (vacuum pump) from the acquired hquids afforded 28 mg (37%) ofthe diene (15), as a colourless oil, and 29 mg (38%) ofthe diene (16), also as a colourless oil. The product resulting from outward rotation ofthe ester group, the diene (15), exhibited IR (neat): 1713, 1635, 1176, 1137 cm" 1 ; i H N M R (400 MHz) 8: 1.15 (d, 3H, J= 7 Hz, - C H C H 3 ) , 1.28 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.84-1.90 (m, 1H, one of H g ) , 1.97-2.04 (m, ILL one o f H g ) , 2.18 (s, 3H, -COCH 3 ) , 2.25-2.40 (m, 2H, Hf), 2.50-2.55 (m, 1H, H e ) , 4.12-4.20 (m, 2H, - O C H 2 C H 3 ) , 4.52 (br q, 1H, J= 7 Hz, H<i), 4.83 (d, 1H, J= 2 Hz, H c ) , 5.00 241 (dd, 1H, J= 2, 2 Hz, H D ) , 5.80 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 8 1.15 (-CHCH3) simplified the quartet at 8 4.52 (Hd) to a broad singlet; irradiation at 8 1.86 (one ofHg) sharpened the multiplets at 8 1.97-2.04 (one of H g ) , 2.25-2.40 (Hf), and 2.50-2.55 (Hg); irradiation at 8 1.99 (one ofHg) sharpened the multiplets at 8 1.84-1.90 (one ofHg), 8 2.25-2.40 (Hf), and 8 2.50-2.55 (H e ) ; irradiation at 8 2.31 (Hf) converted the signal at 8 1.84-1.90 (one of H g ) into a doublet of doublets (J= 16, 4 Hz), the signal at 8 1.97-2.04 (one of H g ) into a doublet of doublets (J= 16, 2 Hz), and the signals at 8 4.83 (Hg) and 8 5.00 (H D) to singlets; irradiation at 8 2.53 (Hg) sharpened the multiplets at 8 1.84-1.90 (one ofHg), 8 1.97-2.04 (one of H g ) and the broad quartet at 8 4.52 (Hd); irradiation at 8 4.52 (Hd) converted the doublet at 8 1.15 (-CHCH3) to a singlet, and simplified the multiplet at 8 2.50-2.55 (H e). NOE difference experiments: irradiation at 8 1.15 (-CHCH3) caused enhancement ofthe signals at 8 2.50-2.55 (Hg) and 8 4.52 (Hd); irradiation at 8 5.80 (H a) caused enhancement ofthe signal at 8 5.00 (H 0). 1 3 C N M R (125.8 MHz) 8: 14.2, 20.1, 21.9, 28.3, 31.0, 32.2, 54.3, 59.7, 113.0, 113.8, 146.5, 162.8, 166.3, 210.1. Anal, calcd. for C14H20O3: C 71.15, H 8.54 ; found: C 70.81, H 8.60. Exact Mass calcd. for C 1 4 H 2 o 0 3 : 236.1412; found: 236.1410. The product resulting from inward rotation ofthe ester group, the diene (16), exhibited LR(neat): 1721, 1713, 1635, 1192, 899 cm" 1 ; ! H N M R (400 MHz) 8: 1.00 (d, 3U,J= 7 Hz, -CHCH3), 1.22 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.60-1.70 (m, 1H, one of H g ) , 1.92-2.00 (m, 1H, one ofHg), 2.15 (s, 3H, -COCH3), 2.26-2.35 (m, 1H, one of Hf), 2.45 (dd, 1H, J= 10, 4 Hz, H e ) , 2.49 (ddd, 1H, J= 14, 4, 4 Hz, one of Hf), 2.60-2.65 (m, 1H, Hd), 4.10 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.80 (br s, 1H, H b ) , 4.91 (br s, 1H, Hg), 5.59 (d, 1H, J= 2 Hz, H a ) ; in a series of decoupling experiments, irradiation at 8 1.00 (-CHCH3) converted the multiplet at 8 2.60-2.65 (Hd) to a doublet (J= 10 Hz); irradiation at 8 1.65 (one of H g ) simplified the multiplets at 8 1.92-2.00 (one of H g ) and 8 2.26-2.35 (one of Hf), and simplified the doublet of doublet of doublets at 8 2.49 (one of Hf) to a doublet of doublets (J= 14, 4 Hz); irradiation at 8 1.95 (one of H g ) simplified the multiplets at 8 1.60-1.70 (one of H g ) and 8 2.26-2.35 (one of Hf), simplified the doublet of doublets at 8 2.45 (Hg) to a broad doublet (J= 10 Hz), and 242 simplified the doublet of doublet of doublets at 8 2.49 (one of Hf) to a doublet of doublets (J= 14, 4 Hz); irradiation at 8 2.30 (one of Hf) simplified the multiplets at 8 1.60-1.70 (one ofHg) and 8 1.92-2.00 (one ofHg), and simplified the signal at 8 2.49 (one of Hf) to a broad doublet of doublets (J= 4, 4 Hz); irradiation at 8 2.45 (H e ) simplified the multiplet at 8 1.60-1.70 (one ofHg) to a broad doublet of doublets (J= 15, 15 Hz), converted the multiplet at 8 1.92-2.00 (one ofHg) to a broad doublet of doublets (J= 15, 4 Hz), and simplified the multiplet at 8 2.60-2.65 (Hd); irradiation at 8 2.49 (one of Hf) simplified the multiplets at 8 1.60-1.70 (one ofHg), 8 1.92-2.00 (one of H g ) , and 2.26-2.35 (one of Hf); irradiation at 8 2.64 (Hd) converted the doublets at 8 1.00 ( -CHCH3) and 8 5.59 (H a ) to singlets, and the doublet of doublets at 8 2.45 (Hg) to a doublet (J= 4 Hz); irradiation at 8 5.59 (H a ) simplified the multiplet at 8 2.60-2.65 (Hd). NOE difference experiments: irradiation at 8 1.00 ( -CHCH3) caused enhancement ofthe signals at 8 2.45 (H e), 8 2.60-2.65 (Hd), and 8 5.59 (H a ) ; irradiation at 8 2.30 (one of Hf) caused enhancement ofthe signals at 8 1.60-1.70 (one of H g ) , 8 1.92-2.00 (one ofHg), 8 2.49 (one of Hf), and 8 4.91 (He); irradiation at 8 2.60 (Hd) caused enhancement ofthe signals at 8 1.60-1.70 (one o f H g ) , 1.00 ( -CHCH3), and 8 5.59 (H a ) ; irradiation at 8 4.78 (H D) caused enhancement ofthe signal at 8 4.91 (He); irradiation at 8 4.91 (H c ) caused enhancement ofthe signals at 8 4.80 (H 0 ) and 8 2.49 (one of Hf); irradiation at 8 5.59 (H a) caused enhancement ofthe signals at 8 2.60-2.65 (Hd), and 8 1.00 ( -CHCH3). 1 3 C N M R (125.8 MHz) 8: 14.0, 16.2, 29.1, 29.4, 34.8, 40.9, 58.3, 60.0, 111.7, 114.0, 145.3, 159.2, 167.0, 210.1. Anal, calcd. for C 1 4 H 2 o 0 3 : C 71.15, H 8.54 ; found: C 71.40, H 8.63. Exact Mass calcd. for C 1 4 H 2 o 0 3 : 236.1412; found: 236.1420. Preparation ofthe keto ester dienes (12) and (13)16 11 243 Following general procedure 16 outlined above, the keto ester (11) was converted into the keto ester dienes (12) and (13). The following amounts of substrate and solvent were used: keto ester (11) (75 mg, 0.32 mmol) in 3.2 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) afforded 60 mg (79%) of a mixture ofthe outward rotation diene (12) and the inward rotation diene (13) in a ratio of 11.5:1 respectively ( * H N M R analysis of signals H c (12) and H b (13)). The mixture was again subjected to radial chromatography (1 mm plate, 3:1 hexanes-Et20). Removal of trace amounts of solvent (vacuum pump) from the liquids obtained afforded 46 mg (61%) ofthe diene (12), as a colourless oil, and 4.5 mg (6%) of the diene (13), also as a colourless oil. The major isomer, resulting from outward rotation of the ester group, the diene (12) exhibited IR (neat): 1712, 1635, 1184, 1137 cm" 1 ; N M R (400 MHz) 5: 0.84 (d, 3H, J= 1 Hz, - C H C H 3 ) , 1.28 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.70-1.77 (m, 1H, H g.), 1.83 (ddd, 1H, J= 13, 13, 5.5 Hz, H g ) , 2.06 -2.20 (m, 1H, Hf), 2.18 (s, 3H, -COCH 3 ) , 2.48 (ddd, 1H, J= 14, 5.5, 2 Hz, H f ) , 2.67 (ddd, 1H, J= 13, 4, 4 Hz, Hg), 4.17 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.54-4.63 (m, 1H, Hd), 4.87 (dd, 1H, J= 2, 2 Hz, H c ) , 5.00 (dd, 1H, J= 2, 2 Hz, H b ) , 5.79 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 5 0.84 ( -CHCH 3 ) converted the multiplet at 8 4.54-4.63 (Hd) to a doublet (J= 4 Hz); irradiation at 8 2.10 (Hf) simplified the multiplet at 8 1.70-1.77 (Hgt), and converted the signal at 8 2.48 (Hf) to a doublet of doublets (J= 2, 5.5 Hz) and converted the signals at 8 4.87 (H c ) and 8 5.00 (H D) to doublets (J= 2 Hz); irradiation at 8 2.48 (Hf) simplified the multiplet at 8 1.70-1.77 (Hg«), converted the doublet of doublet of doublets at 8 1.83 (H„) into a doublet of doublets (J= 13, 13 Hz), and simplified the multiplet at 244 8 2.06-2.20 (Hf); irradiation at 8 2.67 (H e) sharpened the signal at 8 1.70-1.77 (H g-), converted the signal at 8 1.83 (Hg) into a doublet of doublets (J= 5.5, 13 Hz) and converted the multiplet at 8 4.54-4.63 (H d ) to a broad quartet (J= 7 Hz); irradiation at 8 4.56 (H d ) converted the doublet at 8 0.84 ( -CHCH3) to a singlet and the signal at 8 2.67 (H e ) to a doublet of doublets (J= 13, 4 Hz). NOE difference experiments: irradiation at 8 2.48 (Hf) caused enhancement of the signals at 8 1.83 (H g ) , 8 2.06-2.20 (Hf), and 8 4.87 (H c ) ; irradiation at 8 2.67 (H e) caused enhancement ofthe signals at 8 4.54-4.63 (H d ) , and 8 1.70-1.77 (Hg<); irradiation at 8 4.59 (H(i) caused enhancement ofthe signals at 8 0.84 ( -CHCH3), 2.18 ( -COCH3), and 8 2.67 (H e); irradiation at 8 4.87 (H c ) caused enhancement of the signals at 8 2.48 (Hf) and 8 5.00 (H D) ; irradiation at 8 5.00 (H D) caused enhancement ofthe signals at 8 4.87 (H c ) , and 8 5.79 (H a ) ; irradiation at 8 5.79 (H a ) caused enhancement ofthe signal at 8 5.00 (H b). ^H (CgDg, 400 MHz) 8: 0.91 (d, 3H, J= 7 Hz, - C H C H 3 ) , 1.01 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.51-1.57 (m, 1H), 1.75-1.84 (m, 5H, includes singlet at 8 1.77, - C O C H 3 ) , 2.13-2.24 (m, 2H), 4.03 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.60 (dd, 1H, J= 2, 2 Hz, H c ) , 4.75-4.81 (m, 1H, H d ) , 4.83 (dd, 1H, J= 2, 2 Hz, Hfe), 5.94 (br s, 1H, H a ) . 1 3 C N M R (125.8 MHz) 8: 14.1, 14.2, 20.9, 28.1, 32.5, 33.5, 53.6, 59.9, 112.9, 113.4, 146.2, 163.5, 166.3, 209.5. Anal, calcd. for C 1 4 H 2 o 0 3 : C 71.15, H 8.54; found: C 71.00, H 8.50. Exact Mass calcd. for C 1 4 H 2 o 0 3 : 236.1412; found: 236.1411. The minor isomer, resulting from inward rotation ofthe ester group, diene (13) exhibited spectral characteristics identical to those previously reported. ^ Preparation ofthe keto ester dienes (283) and (284) 265 245 Following general procedure 16 outlined above, the keto ester (265) was converted into the keto ester dienes (283) and (284). The following amounts of substrate and solvent were used: keto ester (265) (60 mg, 0.23 mmol) in 2.5 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) afforded 56 mg (93%) of a mixture ofthe outward rotation diene (283) and the inward rotation diene (284) in a ratio of 1:2.2 respectively ( A H N M R analysis of signals H c (283) and H b (284)). The mixture was again subjected to radial chromatography (1 mm plate, 4:1 hexanes-Et20). Removal of trace amounts of solvent under (vacuum pump) from the acquired liquids afforded 15 mg (25%) ofthe diene (283), as a colourless oiL and 36 mg (60%) ofthe diene (284), also as a colourless oil. The minor isomer, resulting from outward rotation ofthe ester group, the diene (283), exhibitedLR(neat): 1714, 1635, 1198, 1175, 1037 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 5: 0.84 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 1.03 (d, 3H, J= 7 Hz, one of -CH(CH 3 ) 2 ) , 1.26 (t, 3H, J= 1 Hz, - O C H 2 C H 3 ) , 1.64-1.74 (m, 2H, - C H ( C H 3 ) 2 , Hg>), 1.96-2.04 (m, 1H, H g ) , 2.18 (s, 3H,. -COCELj); 2.24-2.33 (m, 1H, Hf), 2.48-2.61 (m, 1H, Hf), 2.79-2.83 (m, 1H, He), 4.08-4.17 (m, 3H, H d , - O C H 2 C H 3 ) , 4.76 (dd, 1H, J= 2, 2 Hz, H c ) , 4.91 (dd, 1H, J= 2, 2 Hz, H b ) , 5.83 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation ofthe signal at 8 1.72 (Hg>) sharpened the multiplets at 8 1.96-2.04 (H g ) , 8 2.24-2.33 (Hf), 8 2.48-2.61 (Hf), and 8 2.79-2.83 (H e ) ; irradiation at 8 2.00 (H g ) sharpened the multiplets at 8 1.64-1.74 (Hgt), 8 2.24-2.33 (Hf), and 8 2.48-2.61 (Hf); irradiation at 8 2.55 (Hf) simplified the multiplet at 8 2.24-2.33 (Hf), converted the signal at 8 1.96-2.04 (H g ) to a doublet of multiplets (J= 14 Hz) and converted the signals at 8 4.76 (H c ) and 8 4.91 (H D) to doublets (J= 2 Hz). NOE difference experiments: 246 irradiation at 8 2.54 (Hf) caused enhancement ofthe signals at 8 1.96-2.04 (H g ) , 8 2.24-2.33 (Hf); irradiation at 8 2.81 (Hg) caused enhancement ofthe signals at 8 1.03 (one of -CH(CH 3 ) 2 ) , 8 1.64-1.74 (H g.), 8 1.96-2.04 (H g ) , 8 2.18 ( - C O C H 3 ) , and 8 4.08-4.17 (H^); irradiation at 8 4.91 (H D) caused enhancement ofthe signals at 8 4.76 (Hg) and 8 5.83 (H a ) ; irradiation ofthe signal at 8 5.83 (H a ) caused enhancement ofthe signal at 8 4.91 (HD). * H N M R ( C 6 D 6 , 400 MHz) 8: 0.82 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 0.95 (d, 3H, J= 7 Hz, one of -CH(CH 3 ) 2 ) , 0.96 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.12-1.20 (m, 1H), 1.30-1.41 (m, 1H), 1.68-1.75 (m, 1H), 1.89-1.94 (m, 1H), 2.05 (s, 3H, - C O C H 3 ) , 2.45 (br s, 1H), 2.70-2.78 (m, 1H), 3.96-4.05 (m, 2H, - O C H 2 C H 3 ) , 4.35 (br d, 1H, J= 10 Hz, H<i), 4.55 (dd, 1H, J= 2, 2 Hz, H c ) , 4.77 (dd, 1H, J= 2, 2 Hz, H b ) , 6.01 (br s, 1H, H a ) . 1 3 C N M R (125.8 MHz) 8: 14.2, 19.9, 20.2, 21.1, 28.2, 29.2, 31.3, 44.3, 50.4, 59.7, 111.3, 116.0, 147.9, 161.4, 166.5, 210.7. Anal, calcd. for C 1 6 H 2 4 0 3 : C 72.69, H 9.16 ; found: C 72.55, H 9.15. Exact Mass calcd. for C 1 6 H 2 4 0 3 : 264.1725; found: 264.1724. The major isomer, resulting from inward rotation ofthe ester group, the diene (284), exhibited IR (neat): 1713, 1636, 1191, 1035 cm" 1 ; * H N M R (400 MHz) 8: 0.85 (d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , 0.95 (d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , 1.20 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.69-1.80 (m, 2H, - C H ( C H 3 ) 2 , H g ' ) , 2.00-2.08 (m, 1H, H g ) , 2.14 (s, 3H, -COCH 3 ) , 2.26-2.33 (m, 2H, H^, Hf) , 2.43-2.54 (m, 1H, Hf), 2.73-2.78 (m, 1H, Hg), 4.02-4.11 (m, 2H, - O C H 2 C H 3 ) , 4.80 (dd, 1H, J= 2, 2 Hz, H D ) , 4.96 (dd, 1H, J= 2, 2 Hz, H c ) , 5.59 (br s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 8 2.05 (H g ) sharpened part ofthe multiplet at 8 1.69-1.75 (Hg«), converted the multiplet at 8 2.26-2.33 (H^, Hf) to a broad doublet (J= 6 Hz) and doublet of doublets (J= 12, 2 Hz), and converted the multiplet at 8 2.43-2.54 (Hf) to a broad doublet of doublet of doublets (J= 12, 12, 2 Hz); irradiation at 8 2.50 (Hf) converted the multiplet at 8 2.00-2.08 (H g ) to a doublet of multiplets (J= 14 Hz), sharpened the multiplet at 8 2.29-2.33 (Hf) and converted the doublet of doublets at 8 4.80 (H D) and 8 4.96 (H c ) to doublets (J= 2 Hz); irradiation at 8 2.75 (H e ) sharpened the multiplet at 8 2.26-2.30 (Ebj). NOE difference experiments: irradiation at 8 2.05 (H g ) caused enhancement ofthe signals at 8 1.69-1.80 (H„«), 5 2.48-2.54 (Hf) and 8 2.73-2.78 (Hg); irradiation at 8 2.50 247 (Hf) caused enhancement ofthe signals at 8 2.00-2.08 (Hg) and 8 2.26-2.33 (Hf); irradiation at 8 4.80 (H D) caused enhancement ofthe signal at 8 4.96 (H c ) ; irradiation ofthe signal at 8 4.96 (H c ) caused enhancement of the signals at 8 2.30-2.33 (Hf) and 8 4.80 (H D ) ; irradiation ofthe signal at 8 5.59 (H a ) caused enhancement ofthe signal at 8 2.26-2.33 (Hd). A H N M R (CgDg, 400 MHz) 8: 0.63 (d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , 0.74 (d, 3H, J= 6.5 Hz, one of -CH(CH 3 ) 2 ) , 0.97 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.29-1.40 (m, 2H), 1.50-1.58 (m, 1H), 1.67 (s, 3H, - C O C H 3 ) , 1.69-1.74 (m, 1H), 2.05-2.13 (m, 1H), 2.24-2.30 (m, 1H), 2.60-2.70 (m, 1H), 3.93-4.01 (m, 2H, - O C H 2 C H 3 ) , 4.93 (dd, 1H, J= 2, 2 Hz, H D ) , 4.97 (dd, 1H, J= 2, 2 Hz, H c ) , 5.72 (br s, 1H, H a ) . 1 3 C N M R (125.8 MHz) 8: 14.0, 20.2, 20.8, 23.2, 27.8, 28.0, 32.8, 51.8, 54.3, 59.8, 112.6, 117.2, 143.3, 157.5, 165.9, 209.3. Anal, calcd. for C 1 6 H 2 4 0 3 : C 72.69, H 9.16 ; found: C 72.43, H 9.33. Exact Mass calcd. for C i 6 H 2 4 0 3 : 264.1725; found: 264.1725. Preparation ofthe keto ester dienes (285) and (286) 266 Hb C02Et 285 286 248 Following general procedure 16 outlined above, the keto ester (266) was converted into the keto ester dienes (285) and (286). The following amounts of substrate and solvent were used: keto ester (266) (50 mg, 0.19 mmol) in 2 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) afforded 46 mg (92%) of a mixture ofthe outward rotation diene (285) and inward rotation diene (286) in a ratio of 3.9:1, respectively ( A H N M R analysis). The mixture was again subjected to radial chromatography (1 mm plate, 4:1 hexanes-Et20). Removal of trace amounts of solvent (vacuum pump) from the acquired liquid afforded 34 mg (68%) ofthe diene (285), as a colourless oil, and 9 mg (18%) of the diene (286), also as a colourless oil. The major isomer, resulting from outward rotation of the ester group, the diene (285), exhibited IR (neat): 1713, 1635, 1369, 1218, 1180 cm" 1 ; A H N M R (400 MHz) 8: 0.76(d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , 0.79 (d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , 1.30 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.68-1.76 (m, 1H, -CH(CH 3 ) 2 ) , 1.80-1.92 (m, 2H, H g ) , 2.10-2.19 (m, 1H, one of Hf), 2.26 (s, 3H, -COCH 3 ) , 2.49-2.57 (m, 2H, Hg, one of Hf), 4.18 (q, 2H, /= 7 Hz, - O C H 2 C H 3 ) , 4.43 (dd, 1H, J= 8.5, 2 Hz, H a ) , 4.82 (dd, 1H, J= 2, 2 Hz, H c ) , 4.95 (dd, 1H, J= 2, 2 Hz, H D ) , 5.81 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 8 1.72 ( -CH(CH 3 ) 2 ) converted the doublets at 8 0.76 ( -CH(CH 3 ) 2 ) and 8 0.79 ( -CH(CH 3 ) 2 ) to singlets and converted the signal at 8 4.43 (Hd) to a broad doublet (J= 2 Hz); irradiation at 8 1.84 (Hg) sharpened the multiplet at 8 2.10-2.19 (one of Hf) and converted the multiplet at 8 2.49-2.57 (H e , one of Hf) to a doublet (J= 2 Hz, H e ) and a doublet of doublets (J= 15, 2 Hz, one of Hf); irradiation at 8 2.15 (one of Hf) sharpened the multiplet at 8 1.80-1.92 (Hg), converted the signals at 8 2.49-2.57 (H e , Hf) into multiplet (Hf) and doublet of doublet of doublets (J= 12, 3, 2 Hz, H e ) and conveted the signals at 8 4.82 (H c ) and 8 4.95 (H D) into doublets (J= 2 Hz); irradiation at 8 2.52 (H e , one of Hf) sharpened the multiplets at 8 1.80-1.92 (H g ) and 8 2.10-2.19 (one of Hf) and converted the signal at 8 4.43 (Hd) to a doublet (/= 8.5 Hz); irradiation at 8 4.43 (Hd) sharpened the multiplet at 8 2.49-2.57 (Hg) and converted the multiplet at 8 1.68-1.76 into a heptet (J= 6.5 Hz). NOE difference experiments: irradiation at 8 2.52 (H e , one of Hf) caused enhancement ofthe signals at 8 1.80-1.92 (H g ) , 8 2.10-2.19 (one 249 of Hf), 8 2.26 ( -COCH3), 8 4.43 (H d ) , and 8 4.82 (H c ) ; irradiation at 8 4.43 (H d ) caused enhancement ofthe signals at 8 2.51-2.57 (H e ) and 8 2.26 ( -COCH3); irradiation at 8 5.81 (H a) caused enhancement ofthe signal at 8 4.95 (HD). lH N M R ( C 6 D 6 , 400 MHz) 8: 0.82 (d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , 0.88 (d, 3H, J= 6.5 Hz, one o f -CH(CH 3 ) 2 ) , 1.01 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.61-1.70 (m, 2H), 1.74-1.85 (m, 2H), 2.06 (s, 3H, - C O C H 3 ) , 2.12-2.22 (m, 2H), 4.03 (q, 2 H , J= 7 Hz, - O C H 2 C H 3 ) , 4.55 (dd, 1H, J= 2, 2 Hz, H c ) , 4.62 (dd, 1H, J= 8.5, 2 Hz, Hd), 4.78 (dd, 1H, J= 2, 2 Hz, H b ) , 5.94 (s, 1H, H a ) . 1 3 C N M R (125.8 MHz) 8: 14.3, 20.61, 20.65, 21.1, 27.6, 28.2, 33.8, 44.8, 55.3, 59.9, 112.2, 114.1, 147.5, 163.3, 166.7, 210.5. Anal, calcd. for C 1 6 H 2 4 0 3 : C 72.69, H 9.16; found: C 72.55, H 9.04. Exact Mass calcd. f o r C 1 6 H 2 4 0 3 : 264.1725; found: 264.1724. The product resulting from inward rotation ofthe ester group, the diene (286) exhibited IR (neat): 1714, 1635, 1198, 1035 cm" 1 ; lU N M R (400 MHz) 8: 0.75 (d, 3H, J= 7 Hz, one of -CH(CH 3 ) 2 ) , 0.81 (d, 3H, J= 7 Hz, one o f -CH(CH 3 ) 2 ) , 1.23 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.79-1.89 (m, 2H, - C H ( C H 3 ) 2 , H g ) , 1.90-1.98 (m, 1H, H g.), 2.20 (s, 3H, - C O C H 3 ) , 2.22-2.28 (m, 1H, one of Hf), 2.49-2.55 (m, 2 H , H d , one of Hf), 2.61 (ddd, 1H, J= 12, 3.5, 3.5 Hz, H e ) , 4.07-4.14 (m, 2H, - O C H 2 C H 3 ) , 4.87 (dd, 1H, J= 2, 2 Hz, H b ) , 5.02 (dd, 1H, J= 2, 2 Hz, Hg), 5.68 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 8 1.85 (-CH(CH3) 2 , H g ) sharpened the multiplets at 8 2.22-2.28 (one of Hf) and 8 2.49-2.55 ( H d , one of Hf), converted the doublets at 8 0.75 ( -CH(CH 3 ) 2 ) and 8 0.81 ( -CH(CH 3 ) 2 ) to singlets, and converted the signal at 8 2.61 (H e) to a doublet of doublets (J= 3.5, 3.5 Hz); irradiation at 8 1.95 (H g-) sharpened the multiplets at 8 1.79-1.89 (H g ) and 8 2.22-2.28 (one of Hf) and converted the signal at 8 2.61 (Hg) to a doublet of doublets (J= 12, 3.5 Hz); irradiation at 8 2.25 (one of Hf) sharpened the multiplets at 8 1.83-1.89 (H g ) , 8 1.90-1.98 (H g-), and 8 2.22-2.28 (one of Hf) and converted the signals at 8 4.87 (H b ) and 8 5.02 (Hg) into doublets (J= 2 Hz); irradiation at 8 2.50 ( H d , one of Hf) sharpened the multiplets at 8 1.79-1.89 (H g ) , 8 1.90-1.98 (Hg'), and converted the signal at 8 2.61 (Hg) to a broad doublet of doublets (J= 12, 3.5 Hz); irradiation at 8 2.61 (Hg) simplified the multiplets at 8 1.79-1.89 (H g ) and 250 8 2.49-2.55 (H d ) and converted the multiplet at 8 1.90-1.98 (H g-) to a doublet of doublets (J= 15, 7 Hz). NOE difference experiments: irradiation at 8 4.87 (H D) caused enhancement ofthe signal at 8 5.02 (H c ) ; irradiation at 8 5.02 (H c ) caused enhancement ofthe signals at 8 2.49-2.55 (one of Hf) and 8 4.87 (H D ) ; irradiation of the signal at 8 5.68 (H a ) caused enhancement of the signal at 8 2.49-2.55 (H d ) . l H N M R ( C 6 D 6 , 400 MHz) 8: 0.62 (d, 3H, J = 7 Hz, one of -CH(CH 3 ) 2 ) , 0.71 (d, 3H, J = 7 Hz, one o f -CH(CH 3 ) 2 ) , 1.03 (t, 3H, J = 7 Hz, - 0 C H 2 C H 3 ) , 1.27-1.34 (m, 1H), 1.60-1.73 (m, 2H), 1.75 (s, 3H, -COCH 3 ) , 2.01-2.10 (m, 2H), 2.20-2.27 (m, 2H), 3.99-4.06 (m, 2H, - O C H 2 C H 3 ) , 4.92 (dd, 1H, J = 2, 2 Hz, H b ) , 4.96 (dd, 1H, J = 2, 2 H z , H c ) , 5.64 (s, 1H, H a ) . 1 3 C N M R (125.8 MHz) 8: 14.1,20.6,21.6,22.6,26.8,28.3, 34.5, 55.3, 56.2, 60.0, 113.8, 115.4, 142.9, 159.3, 166.4, 209.7. Anal, calcd. for C 1 6 H 2 4 0 3 : C 72.69, H 9.16; found: C 72.52, H 9.26. Exact Mass calcd. for C 1 6 H 2 4 0 3 : 264.1725; found: 264.1728. Preparation ofthe keto ester dienes (287) and (288) c-Hex 267 Hb C 0 2 E t 287 288 251 Following general procedure 16 outlined above, the keto ester (267) was converted into the keto ester dienes (287) and (288). The following amounts of substrate and solvent were used: keto ester (267) (100 mg, 0.329 mmol) in 3.5 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) afforded 93 mg (93%) of a mixture ofthe outward rotation diene (287) and the inward rotation diene (288) in a ratio of 1:2.6, respectively ( I f l N M R analysis of signals LEg (287) and H D (288)). The mixture was again subjected to radial chromatography (1 mm plate, 7:3 hexanes-Et20). Removal of trace amounts of solvent (vacuum pump) from the acquired liquid afforded 25 mg (25%) ofthe diene (287), as a colourless oil, and 62 mg (62%) ofthe diene (288), also as a colourless oil. The minor isomer, resulting from outward rotation ofthe ester group, the diene (287), exhibited IR (neat): 1714, 1633, 1196 cm" 1 ; A H N M R (400 MHz) 6: 0.89-1.20 (m, 5H), 1.26 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.30-1.42 (m, 1H), 1.53-1.73 (m, 4H), 1.73-1.80 (m, 1H), 1.83-1.91 (m, 1H), 1.94-2.02 (m, 1H, one of H g ) , 2.16 (s, 3H, - C O C H 3 ) , 2.24-2.33 (m, 1H, one of Hf), 2.50-2.61 (m, 1H, one of Hf), 2.85-2.90 (m, 1H, He), 4.08-4.16 (m, 2H, - O C H 2 C H 3 ) , 4.18 (d, 1H, J= 10 Hz, Hd), 4.75 (dd, 1H, J= 2, 2 Hz, H c ) , 4.88 (br d, 1H, J= 2, 2 Hz, H D ) , 5.83 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 5 2.00 (one ofHg) sharpened the multiplets at 5 2.24-2.33 (one of Hf) and 6 2.50-2.61 (one of Hf) and 5 2.85-2.90 (Hg); irradiation at 8 2.55 (one of Hf) sharpened the multiplet at 8 2.24-2.33 (one of Hf), converted the multiplet at 8 1.94-2.02 (one ofHg) to a doublet of multiplets (J= 15 Hz) and converted the doublet of doublets at 8 4.75 (Hg) and 8 4.88 (H D ) to doublets (J= 2 Hz), respectively; irradiation at 8 4.18 (Hd) sharpened the multiplet at 8 1.30-1.42 and 8 2.85-2.90 (H e). NOE difference experiments: irradiation at 8 2.55 (one of Hf) caused enhancement ofthe signals at 8 1.94-2.02 (one ofHg) and 8 2.30 (one of Hf); irradiation at 8 2.85 (H e ) caused enhancement ofthe signals at 8 1.83-1.91, 8 1.94-2.02 (one ofHg), and 8 4.18 (Hd); irradiation at 8 4.18 (Hd) caused enhancement ofthe signals at 8 0.92-1.09, 8 1.30-1.42, 8 2.16 (-COCH3), and 8 2.85 (H e ) ; irradiation at 8 4.75 (Hg) caused enhancement ofthe signals at 252 8 2.24-2.33 (one of Hf) and 8 4.88 (H b ) ; irradiation at 8 4.88 (H D) caused enhancement ofthe signals at 8 4.75 (Hg) and 8 5.83 (H a ) ; irradiation at 8 5.83 (H a ) caused enhancement ofthe signal at 8 4.88 (H b). A H N M R ( C 6 D 6 , 400 MHz) 8: 0.85-1.10 (m, 7H, includes triplet at 8 0.94, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.22-1.42 (m, 4H), 1.55-1.71 (m, 4H), 1.91-1.97 (m, 1H), 2.06-2.13 (m, 4H, includes singlet at 8 2.09, -COCH 3 ) , 2.49-2.53 (m, 1H), 2.72-2.83 (m, 1H), 3.95-4.01 (m, 2H, - O C H 2 C H 3 ) , 4.43 (br d, 1 H , J= 10 Hz, Hd), 4.55 (dd, 1H, J= 2, 2 Hz, He), 4.77 (br d, 1H, J= 2, 2 Hz, H b ) , 6.03 (s, 1H, H a) . 1 3 C N M R (125.8 MHz) 8: 14.2, 21.2, 26.2, 26.4, 26.5, 28.2, 29.8, 30.4, 31.3, 38.2, 43.0, 49.7, 59.7, 111.3, 116.2, 148.0, 161.2, 166.6, 210.9. Anal, calcd. for C i 9 H 2 8 0 3 : C 74.96, H 9.28 ; found: C 75.16, H 9.27. Exact Mass calcd. for C 1 9 H 2 8 0 3 : 304.2039; found: 304.2039. The major isomer, resulting from inward rotation ofthe ester group, the diene (288), exhibited LR(neat): 1713, 1634, 1171 cm" 1 ; 1 H N M R ( 4 0 0 MHz) 8: 0.71-0.91 (m, 2H), 1.09-1.22 (m, 6H includes triplet at 8 1.21, J= 7 Hz, - O C H 2 C H 3 ) , 1.37-1.40 (m, 1H, - C H of c-Hex), 1.60-1.82 (m, 6H), 2.00-2.06 (m, 1H, one o f H g ) , 2.14 (s, 3H, - C O C H 3 ) , 2.28-2.35 (m, 1H, one of Hf), 2.38 (br dd, 1H, J= 10, 2 Hz, Hd), 2.45-2.55 (m, 1H, one of Hf), 2.73-2.78 (m, 1H, EL.), 4.01-4.10 (m, 2H, - O C H 2 C H 3 ) , 4.77 (dd, 1H, J= 2, 2 Hz, H b ) , 4.94 (dd, 1H, J= 2, 2 Hz, H c ) , 5.53 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 8 1.40 ( - C H of c-Hex ring) converted the broad doublet of doublets at 8 2.38 (Hd) into a broad doublet (J= 2 Hz); irradiation at 8 2.03 (one ofHg) converted the signal at 8 2.28-2.35 (one of Hf) into a doublet of doublet of doublets (/= 14, 4, 2 Hz) and sharpened the multiplet at 8 2.45-2.55 (one of Hf); irradiation at 8 2.38 (Hd) sharpened the multiplet at 8 1.37-1.40 ( - C H of c-Hex) and converted the multiplet at 8 2.73-2.78 (Hg) into a broad doublet of doublets (J= 3.5, 3.5 Hz); irradiation at 8 2.50 (one of Hf) sharpened the multiplets at 8 1.94-2.02 (one of Hg) and 8 2.28-2.35 (one of Hf) and converted ofthe doublet of doublets at 8 4.77 (H b ) and 8 4.94 (Hg) and doublets (J=2 Hz) respectively; irradiation at 8 2.77 (H e ) sharpened the signal at 8 2.00-2.06 (one of H g ) and converted the signal at 8 2.38 (Hd) into a doublet (J= 10 Hz). NOE difference experiments: irradiation at 8 2.50 (one of Hf) caused enhancement ofthe 253 signals at 8 2.28-2.35 (one of Hf) and 8 2.00-2.06 (one of H g ) ; irradiation at 8 2.75 (Hg) caused enhancement ofthe signals at 8 1.71-1.82, 8 2.14 ( -COCH3), and 8 2.38 (Hd); irradiation at 8 4.77 (H D) caused enhancement ofthe signal at 8 4.94 (H c ) ; irradiation at 8 4.94 (Hg) caused enhancement ofthe signals at 8 2.28-2.35 (one of Hf) and 8 4.77 (H D ) ; irradiation at 8 5.53 (H a) caused enhancement ofthe signal at 8 2.38 (H d). X H N M R ( C 6 D 6 , 400 MHz) 8: 0.50-0.68 (m, 2H), 0.95 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.05-1.10 (m, 1H), 1.22-1.50 (m, 5H), 1.55-1.72 (m, 7H, includes singlet at 8 1.70, - C O C H 3 ) , 1.88-1.99 (m, 1H), 2.09-2.15 (m, 1H), 2.22 (br d, 1H, J= 10 Hz, H d ) , 2.29-2.36 (m, 1H), 2.62-2.72 (m, 1H), 3.93-4.03 (m, 2H, - O C H 2 C H 3 ) , 4.92 (dd, 1H, J= 2, 2 Hz, H b ) , 4.95 (dd, 1H, J= 2, 2 Hz, H c ) , 5.71 (s, 1H, H a ) . 1 3 C N M R (125.8 MHz) 8: 14.0, 23.1, 26.1, 26.22, 26.25, 27.8, 30.3, 31.0, 32.7, 36.8, 50.9, 52.7, 59.8, 112.5, 117.3, 143.3, 157.2, 165.8, 209.5. Anal, calcd. for C 1 9 H 2 8 0 3 : C 74.96, H 9.28 ; found: C 75.16, H 9.24. Exact Mass calcd. for C 1 9 H 2 8 0 3 : 304.2039; found: 304.2040. Preparation ofthe keto ester dienes (289) and (290) 289 290 254 Following general procedure 16 outlined above, the keto ester (268) was converted into the keto ester dienes (289) and (290). The following amounts of substrate and solvent were used: keto ester (268) (100 mg, 0.329 mmol) in 3.5 mL of dry mesitylene. Radial chromatography (1 mm plate, hexanes, then Et20) afforded 93 mg (93%) of a mixture ofthe outward rotation diene (289) and the inward rotation diene (290) in a ratio of 4:1 respectively ( l H N M R analysis of signals H c (289) and H D (290)). The mixture was again subjected to radial chromatography (1 mm plate, 7:3 hexanes-Et20). Recrystallization (1:1 petroleum ether-Et20) ofthe acquired solids afforded 67 mg (67%) ofthe diene (289) as a colourless solid (melting point, 72-73°C) and 17 mg (17%) ofthe diene (290), also as a colourless solid (melting point, 82-83°C). The major isomer, resulting from outward rotation ofthe ester group, the diene (289), exhibited IR (KBr): 1704, 1654, 1175 cm" 1 ; *H N M R (400 MHz) 5: 0.75-0.93 (m, 2H), 0.99-1.11 (m, 2H), 1.30 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.32-1.44 (m, 1H, - C H of c-Hex), 1.44-1.68 (m, 6H), 1.76-1.82 (m, 1H, H g ) , 1.88-1.97 (m, 1H, H g0, 2.08-2.22 (m, 1H, one of Hf), 2.26 (s, 3H, - C O C H 3 ) , 2.47 (ddd, 1H, J= 12, 2.5, 2.5 Hz, H e ) , 2.51-2.59 (m, 1H, one of Hf), 4.18 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.48 (dd, 1H, J= 9, 2.5 Hz, H d ) , 4.83 (dd, 1H, J= 2, 2 Hz, H c ) , 4.93 (dd, 1H, J= 2, 2 Hz, H D ) , 5.82 (s, 1H, H a ) ; in a series of decoupling experiments, irradiation at 8 1.79 (H g ) sharpened the multiplets at 8 1.88-1.97 (H g ' ) and 8 2.51-2.59 (one of Hf), converted the signal at 8 2.47 (H e) to a broad doublet of doublets (J= 2.5, 2.5 Hz); irradiation at 8 1.92 (Hg<) sharpened the signals at 8 1.76-1.82 (H g ) , 8 2.08-2.20 (one of Hf) and at 8 2.51-2.59 (Hf), and converted the signal at 8 2.47 (Hg) to a doublet of doublets (J= 12, 2.5 Hz); irradiation at 8 2.15 (one of Hf) sharpened the signal at 8 1.76-1.82 (H g ) , converted the signal at 8 1.88-1.97 (H g ' ) into a doublet of multiplets (J= 14 Hz), sharpened the signal at 8 2.51-2.59 (one of Hf) and converted the doublet of doublets at 8 4.83 (H c ) and 8 4.93 (H D) to doublets (J= 2 Hz); irradiation at 8 2.47 (H e ) sharpened the multiplets at 8 1.76-1.82 (H g ) and 8 1.88-1.97 (Hg-) and converted the doublet of doublets at 8 4.48 (H d ) into a doublet (J= 9 Hz); irradiation at 8 4.48 (H d ) simplified the multiplet at 8 1.32-1.44 (-CH 255 of c-Hex) and converted the signal at 5 2.47 (H e ) into a doublet of doublets (J= 12, 2.5 Hz). NOE difference experiments: irradiation at 8 4.48 (H a ) caused enhancement ofthe signals at 5 0.79-0.90, 8 2.26 ( -COCH3), and 8 2.47 (H e ) ; irradiation at 8 4.83 (H c ) caused enhancement ofthe signals at 8 2.51-2.59 (one of Hf) and 8 4.93 (H D ) ; irradiation at 8 4.93 (H D) caused enhancement ofthe signals at 8 4.83 (H c ) and 8 5.82 (H a ) ; irradiation at 8 5.82 (H a) caused enhancement ofthe signal at 8 4.93 (H D). ! H N M R ( C 6 D 6 , 400 MHz) 8: 0.75-0.93 (m, 2H), 0.88-1.15 (m, 7H, includes triplet at 8 1.01, J= 7 Hz, - O C H 2 C H 3 ) , 1.45-1.70 (m, 5H), 1.83-1.89 (m, 3H), 2.09 (s, 3H, - C O C H 3 ) , 2.12-2.18 (m, 1H), 2.20-2.26 (m, 1H), 4.05 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.57 (dd, 1H, J= 2, 2 Hz, H c ) , 4.74 (dd, 1H, J= 9, 2.5 Hz, H d ) , 4.79 (dd, 1H, J= 2, 2 Hz, H D ) , 6.00 (br s, 1H, H a ) . 1 3 C N M R (125.8 MHz) 8: 14.3, 21.0, 26.1, 26.4, 26.5, 28.2, 30.2, 30.6, 33.8, 37.1, 43.7, 55.2, 59.9, 112.2, 114.3, 147.5, 163.2, 166.7, 210.5. Anal, calcd. for C 1 9 H 2 8 0 3 : C 74.96, H 9.28 ; found: C 74.74, H 9.30. Exact Mass calcd. f o r C 1 9 H 2 8 0 3 : 304.2039; found: 304.2030. The minor isomer, resulting from inward rotation ofthe ester group, the diene (290) exhibited IR (neat): 1723, 1694, 1650, 1180 cm" 1 ; A H N M R (400 MHz) 8: 1.00-1.13 (m, 2H), 1.00-1.13 (m, 3H), 1.23 (t, 3H, J= 7 Hz, - O C H 2 C H 3 ) , 1.39-1.70 (m, 6H), 1.74-1.86 (m, 1H, one ofHg), 1.91-1.99 (m, 1H, one of H g ) , 2.20 (s, 3H, - C O C H 3 ) , 2.21-2.29(m, 1H, one of Hf), 2.48-2.62 (m, 3H, H Q , H e , one of Hf), 4.11 (q, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.85 (dd, 1H, J= 2, 2 Hz, H D ) , 5.03 (dd, 1H, J= 2, 2 Hz, H c ) , 5.66 (s, 1H, H a ) ; In a series of decoupling experiments, irradiation at 8 1.79 (one ofHg) sharpened the multiplets at 8 1.91-1.99 (one of Hg) and 8 2.48-2.58 (H e , one of Hf); irradiation at 8 2.25 (one of Hf) simplified the multiplets at 8 1.74-1.86 (one of H g ) , 8 1.91-1.99 (one of H g ) and 8 2.48-2.56 (one of Hf), and converted the doublet of doublets at 8 4.85 (Hp) and 8 5.03 (H c ) into doublets (J- 2 Hz) respectively. NOE difference experiments: irradiation at 8 4.85 (H b ) caused enhancement ofthe signal at 8 5.03 (H c ) ; irradiation at 8 5.03 (Hg) caused enhancement ofthe signals at 8 2.50-2.55 (one of Hf) and 8 4.85 (H D ) ; irradiation at 8 5.66 (H a ) caused enhancement ofthe signal at 8 2.56-2.62 (Hd). i H N M R ( C 6 D 6 , 400 MHz) 8: 0.58-0.67 (m, 2H), 0.92-1.05 (m, 5H, includes triplet at 256 5 1.01, J= 7 Hz, - O C H 2 C H 3 ) , 1.43-1.60 (m, 7H), 1.63-1.80 (m, 5H, includes singlet at 5 1.74, -COCH 3 ) , 2.02-2.10 (m, 2H), 2.23-2.30 (m, 1H), 2.30-2.37 (m, 1H), 4.00-4.07 (m, 2H, J= 7 Hz, - O C H 2 C H 3 ) , 4.92 (dd, 1H, J= 2, 2 Hz, H D ) , 4.97 (dd, 1H, J= 2, 2 Hz, H c ) , 5.67 (s, 1H, H a);. 1 3 C N M R (125.8 MHz) 8: 14.1, 22.5, 26.1, 26.36, 26.39, 28.2, 30.6, 31.3, 34.5, 36.1, 54.1, 56.0, 60.0, 113.8, 115.6, 143.0, 160.0, 167.4, 209.4. Anal, calcd. for C 1 9 H 2 8 0 3 : C 74.96, H 9.28 ; found: C 75.08, H 9.18. Exact Mass calcd. for C19H28O3: 304.2039; found: 304.2037. 257 15. General Procedure 17: Small scale thermal ring opening ofthe functionalized bicyclo[4.2.0]oct-l(6)enes and direct determination of product ratios by N M R spectroscopy NC R O R 314 315 Ha R G R 316 317 A solution ofthe appropriate bicyclo[4.2.0]oct-l(6)ene (315) or (315) in either dry deuteriobenzene (0.8 mL) or deuteriomethylene chloride (1 gram) was placed in a glass tube (10 mm diameter walls 2 mm thick) sealed at one end. The solution was placed under argon atmosphere and cooled with Uquid nitrogen until frozen. The glass tube was then evacuated (vacuum pump) and the open end ofthe glass tube was sealed with a methane/oxygen torch. After the sealing process, the glass tube was allowed to warm to room temperature and was then placed into a hot (165±2°C unless noted otherwise) steel bomb for 4-6 hours. Note that care should be taken at this stage ofthe experiment as the sealed glass tube may explode if any structural defects are present in the tube. A l l ofthe thermolysis cleanly produced two products and, in each case, the ratio of products was determined directly by integration ofthe signals due to H a and H D (see formulas (316) and (317)) in the N M R spectrum ofthe reaction mixture. For compound (255) the ring opening was carried out at 143-145°C (3.5 hours) to avoid sigmatropic rearrangement ofthe outward rotation product. A l l experiments were carried out at least in duplicate and were found to be reproducible. To determine product stability a small 258 sample of each pure product (prepared from the experiments previously mentioned) was dissolved in CgDg and subjected to the above experimental conditions. In each case the starting material showed no signs of decomposition or rearrangement. A summary ofthe experimental conditions and results can be seen in Charts 1 through 5. 259 CHART 1. 255 R = H 275 R = H 276 R = H 257 R = Me 277 R = Me 278 R = Me 259 R = z - Pr 279 R = / - Pr 280 R = / - Pr 261 R = c - H e x 281 R = c - H e x 282 R = c - H e x Expt Substrate Mass Solvent Time Temp. Ratio of Products 1 255 4 mg C 6 D 6 3.5 h 145°C 16 1 2 255 4 mg C 6 D 6 3.5 h 145°C 18 1 3 257 4 mg C 6 D 6 4 h 165°C 4.3 1 4 257 4 mg C 6 D 6 4 h 165°C 4.1 1 5 257 4 mg C 6 D 6 4 h 165°C 4.3 1 6 259 4 mg C 6 D 6 6h 165°C 1 1.5 7 259 4 mg C 6 D 6 6 h 165°C 1 1.4 8 259 4 mg C 6 D 6 6 h 165°C 1 1.5 9 261 4 mg C 6 D 6 6 h 165°C 1 1.4 10 261 4 mg C 6 D 6 6 h 165°C 1 1.3 11 261 4 mg C 6 D 6 6 h 165°C 1 1.4 260 CHART 2. NC NC NC 256 R = Me 277 R = Me 278 R = Me 258 R 260 R = ; - P r = c - Hex 279 281 R = / -R = c-Pr Hex 280 282 R = z R - c Expt Substrate Mass Solvent Time Temp. Ratio of Products 12 256 4mg C 6 D 6 4 h 165°C 2.5 1 13 256 4mg C 6 D 6 4 h 165°C 2.6 1 14 256 4mg C 6 D 6 4 h 165°C 2.7 1 15 258 4mg C 6 D 6 6 h 165°C 1 1.5 16 258 4mg C 6 D 6 6 h 165°C 1 1.4 17 260 4mg C 6 D 6 6 h 165°C 1 1.5 18 260 4mg C 6 D 6 6 h 165°C 1 1.4 CHART 3. O C 0 2 E t R 11 R = Me 266 R = / - Pr 268 R = c - H e x O "1  R C 0 2 E t O 12 R = Me 13 285 R = / - P r 286 289 R = c - Hex 290 R c - Hex Expt Substrate Mass Solvent Time Temp. Ratio of Products 19 11 4 mg C 6 D 6 4h 165°C 10.4 20 11 4 mg C 6 D6 4h 165°C 11.2 21 266 4 mg C 6 D 6 4h 165°C 4.0 22 266 4 mg C 6 D 6 6h 165°C 3.6 23 266 4 mg C 6 D 6 6h 165°C 4.3 24 268 4 mg C 6 D 6 6h 165°C 3.8 25 268 4 mg C 6 D6 6h 165°C 3.7 262 CHART 4. 14 R = Me 15 R = Me 16 R = Me 265 R = / - Pr 283 R = / - Pr 284 R = / - Pr 267 R = c - Hex 287 R = c - Hex 288 R = c - Hex Expt Substrate Mass Solvent Time Temp. Ratio of Products 26 14 4 mg C 6 D 6 4 h 165°C 1.0 1 27 14 4 mg C 6 D 6 4 h 165°C 1.0 1 28 265 4 mg C 6 D 6 4 h 165°C 1 2.4 29 265 4 mg C 6 D 6 4 h 165°C 1 2.2 30 265 4 mg C 6 D 6 4 h 165°C 1 2.4 31 267 4 mg C 6 D 6 4 h 165°C 1 2.6 32 267 4mg C 6 D 6 4 h 165°C 1 2.5 33 267 4 mg C 6 D 6 4 h 165°C 1 2.8 263 CHART 5. - C 0 2 E t - C H 2 O H - C 0 2 H 275 G = - C 0 2 E t 276 G = - C 0 2 E t 271 G = - C H 2 O H 271bG = - C H 2 O H 305 G = - C 0 2 H 306 G = - C 0 2 H Expt Substrate Mass Solvent Time Temp. Ratio of Products 1 255 4mg C 6 D 6 3.5 h 145°C 16 1 2 255 4 mg C 6 D 6 3.5 h 145°C 18 1 34 255 4 mg C D 2 C 1 2 3.5h 145°C 17 1 35 262 4 mg C 6 D 6 4 h 165°C 100 0 36 262 4 mg C 6 D 6 4 h 165°C 100 0 37 264 0.25 mg C 6 D 6 4 h 165°C 7.3 1 38 264 0.25 mg C 6 D 6 4 h 165°C 7.4 1 39 264 0.25 mg Cf iD 6 4 h 165°C 7.0 1 264 IV. R E F E R E N C E S 1. Woodward, R.B.; Hoffmann, R. The Conservation of Orbital Symmetry; Verlag Chemie: International. Deerfield Beach, FL, 1970. 2. 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Appendix 1: X-ray Crystallographic Data Compound 3 3 2 3 52 formula C 2 i H 2 9 N O C i 6 H 1 4 N 4 0 2 formula weight 311.47 294.31 crystal system orthorhombic monoclinic space group V2\2\l\ P2j /C a(A) 13.1014(7) 8.604(4) b(A) 27.057(1) 19.370(3) c(A) 5.280(1) 9.633(3) B(deg) - 104.69(3) Z 4 4 Dcalc(g/cm 3) 1.11 1.259 radiation Cu-K Cu-K temperature (°C) 21 21 20max(deg) 155.1 155.5 No reflections with I > 3 8 (I) 1640 2287 No. variables 325 200 R 0.030 0.035 Rw 0.029 0.036 goodness of fit 1.86 2.58 largest residual peak (eA - 3) 0.09 0.016 

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