Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Stereocontrolled radical cyclization reactions to yield exocyclic alkenes Lowinger, Timothy Bruno 1991

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1991_A1 L69.pdf [ 8.2MB ]
Metadata
JSON: 831-1.0059795.json
JSON-LD: 831-1.0059795-ld.json
RDF/XML (Pretty): 831-1.0059795-rdf.xml
RDF/JSON: 831-1.0059795-rdf.json
Turtle: 831-1.0059795-turtle.txt
N-Triples: 831-1.0059795-rdf-ntriples.txt
Original Record: 831-1.0059795-source.json
Full Text
831-1.0059795-fulltext.txt
Citation
831-1.0059795.ris

Full Text

STEREOCONTROLLFX) RADICAL CYCLIZATION REACTIONS TO YIELD EXOCYCLIC ALKENES. By Timothy Bruno Lo winger B.Sc.(Hons.), University of British Columbia, 1986 A THESIS SUBMITTED IN PARTIAL FUIJTLIJvIENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA July 1991 ©Timothy Bruno Lowinger, 1991 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 C The University of British Columbia Vancouver, Canada Date 2i; mi DE-6 (2/88) ABSTRACT The intramolecular reactions of a number of (£)- and (Z)-3-tri(/i-butyl)stannyl-2-alkenoates with co-alkyl radicals generated from alkyl iodides, epoxides, and aldehydes were investigated. These reactions were found to generate exocyclic alkenes in a stereoselective, and in some cases stereospecific, manner via a consecutive radical addition-fragmentation mechanism. In most cases, the geometry of the resulting exocyclic alkene was determined by the geometry of the starting vinylstannane. For example, reaction of the (£)-vinylstannane 75 with bis(cyclopentadienyl)titanium(III) chloride affords the (£)-exocyclic alkene 82 exclusively, whereas the analogous reaction of the (Z)-vinylstannane 76 affords the (Z)-exocyclic alkene 83 as the exclusive product. The formation of exocyclic alkenes via intramolecular addition reactions of secondary alkyl radicals to cc,|3-alkynyl esters was also investigated. The stereoselectivity of these reactions was found to be highly dependent on the reaction conditions. For example, reaction of 146 with tri(«-butyl)tin hydride in refluxing benzene affords predominantly the (£)-exocyclic alkene 142. In contrast, reaction of 146 with tris(trimethylsilyl)silane at low temperature affords predominantly the (Z)-exocyclic alkene 144. 82 75 76 83 MeC^C 146 144 142 T A B L E OF CONTENTS ABSTRACT i i LIST OF TABLES viii LIST OF FIGURES ix LIST OF ABBREVIATIONS x ACKNOWLEDGEMENTS xii CHAPTER I INTRODUCTION 1.1 BASIC PRINCIPLES OF FREE RADICAL REACTIONS 1 1.1.1 RADICAL ABSTRACTIONS 3 1.1.2 RADICAL ADDITION REACTIONS 4 1.2 METHODS FOR CONDUCTING FREE-RADICAL REACTIONS 9 1.2.1 THE TIN HYDRIDE METHOD 9 1.2.2 THE FRAGMENTATION METHOD 20 1.2.3 THE ATOM TRANSFER METHOD 26 CHAPTER n RESULTS AND DISCUSSION 32 2.1 SYNTHESIS OF METHYL (£)- AND (Z)-8-IODO-7,7-DIMETHYL-3-TRI(n-BUTYL) STANNYL-OCT-2-ENOATE (50 and 51) 34 2.2 ADDITION-FRAGMENTATION REACTIONS OF 50 AND 51 38 2.3 A N ALTERNATIVE ROUTE TO COMPOUNDS 48 AND 49 54 2.4 SYNTHESIS OF METHYL (£)-8-IODO-5^-DIMETHYL-3-TRI(n-BUTYL) STANNYL-OCT-2-ENO ATE (67) 55 2.5 ADDrnON-FRAGMENTATION REACTIONS OF COMPOUND 67.... 56 2.6 ADDITION-FRAGMENTATION REACTIONS OF RADICALS GENERATED FROM EPOXIDES 59 2.7 ADDITION-FRAGMENTATION REACTIONS OF RADICALS GENERATED FROM ALDEHYDES 67 iv 2.8 A D D m O N - F R A G M E N T A T I O N REACTIONS OF SECONDARY A L K Y L RADICALS 76 2.9 C O N C L U S I O N 90 2.10 SUGGESTIONS FOR F U T U R E W O R K 91 CHAPTER III E X P E R I M E N T A L 3.1 G E N E R A L 92 3.2 l -BROMO-3-(TETRAHYDROPYRANYLOXY) PROPANE (53) 95 3.3 2,2-DjMETHYL-5-(TTiIRAHYDROPYRANYLOXY)PENTANOIC A C I D (54) 96 3.4 2>DJMETHYL-5-(TETRAHYDROPYRANYIJOXY)-P E N T A N - 1 - O L (55) 97 3.5 2 , 2 - D I M E T H Y L - 5 - B R O M O P R O P A N - l - O L (56) 98 3.6 l - (TETRAHYDROPYRANYLOXY)-2£-D]METHYL-5-BROMOPENTANE (57) 99 3.7 7- (TETRAHYDROPYRANYLOXY)-6 ,6-DMETHYL-H E P T - 1 - Y N E (58) 100 3.8 M E T H Y L 8-(TETRAHYDROPYRANYLOXY)-7J-DIMETHYL-2- O C T Y N O A T E (59) 101 3.9 M E T H Y L (£)-8-(TETRAHYDROPYRANYIXDXY)-7 J - D I M E T H Y L -3- T R I ( / i - B U T Y L ) S T A N N Y L - O C T - 2 - E N O A T E (60) 102 3.10 M E T H Y L (£)-8-HYDROXY-7,7-DIMETHYL-3-TRI(n-BUTYL) STANNYL-OCT-2-ENO A T E (61) 103 3.11 M E T H Y L (£)-8-IODO-7,7-DIMETHYL-3-TRI(/ i -BUTYL)STANNYL-OCT-2-ENOATE (50) 104 3.12 M E T H Y L (Z) - 8-(TETRAH YDROPYRAN Y L O X Y) -7,7-DIMETH Y L -3 - T R I ( / i - B U T Y L ) S T A N N Y L O C T - 2 - E N O A T E (62) 105 3.13 M E T H Y L (Z)-8-HYDROXY-77-DMETHYL-3-TRI(/i-BUTYL) STANNYL-OCT-2-ENO A T E (63) 106 3.14 M E T H Y L (Z)-8-IODa7,7-DIMETHYL-3-TRI(n-BUTYL)STANNYL-OCT-2-ENOATE (51) 107 3.15 l - IODa2 ,2 -DIMETHYI^5- (JET^^YDROPYRANYirjXY)^ P E N T A N E (68) 108 V 3.16 4,4-DJJViETHYI^7-(TETRAHYDROPYRAN^ 1- HEPTYNE 109 3.17 METHYL 5,5-DIMETHYL-8-(TETRAHYDROPYl^ 2- OCTYNOATE (70) 110 3.18 METHYL 5^-DDvIETHY1^8-IOrX)-2-OCTmOATE (74) I l l 3.19 METHYL (£)-3-TRI(n-BUTYL)STANNYI^5^-DIMETHYL-8-(TTin^YDROPYRANTljOXT)-OCT-2-EN (71) 112 3.20 METHYL (£)-3-TRI(n-BUTYL)STANNYI^5^-DIMETHYL-8-HYDROXY-OCT-2-ENOATE (72) 113 3.21 M E T H Y L ( £ ) - 3 - T W ( H - B U T Y L ) S T A N N Y ^ ^ 8-IODO-OCT-2-ENOATE (67) 114 3.22 METHYL (£)-(33-DIMETHYLCYCLOHEXYLIDENE)-ACETATE (48) 115 3.23 METHYL (Z)-(33-DIMETHYL£:YCIX)HEXYLIDENE)-ACETATE (49) 116 3.24 METHYL OCT-2-YNE-7-ENOATE (79) 117 3.25 METHYL NON-2-YNE-8-ENOATE (86) 118 3.26 METHYL (£)-3-TRI(n-BUTYL)STANNYL-2,7-OCTADLENOATE (80) 119 3.27 METHYL (£)-3-TRI(/i-BUTYL)STANNYL-2,8-NONADIENOATE (87) 120 3.28 METHYL (Z)-3-TRI(n-BUTYL)STANNYL-2,7-OCTADLENOATE (81) 121 3.29 METHYL (Z)-3-TRI(n-BUTYL)STANNYL-2,8-NONADIENOATE (88) 122 3.30 METHYL (£)-3-TRI(/i-BUTYL)STANNYL-7-EPOXY-2-OCTEN OATE (75) 123 3.31 METHYL (Z)-3-TRI(n-BUTYL)STANNYL-7-EPOXY-2-OCTENOATE (76) 124 3.32 METHYL (£)-3-ra(n-BUTYL)STANNYL-8-EPOXY-2-NONENOATE (89) 125 3.33 METHYL (Z)-3-TRI(n-BUTYL)STANNYL-8-EPOXY-2-NONENOATE (90) 126 3.34 M E T H Y L (£)-3-IODO-8-EPOXY-2-NONENOATE (95) 127 vi 3.35 METHYL (£H2-(HYDR0XYMmTTiT)C^ A C E T A T E (82) 128 3.36 METHYL (Z)-[2-(HYDR0XYMETHYL)CYCIX)P^ A C E T A T E (83) 129 3.37 6-(TETRAH YDROPYRANYLOX Y) -1 -HEXYNE (105) 130 3.38 METHYL 7-(TETRAHYDROPYRANYLOXY)-2-HEPTYNOATE (106) 131 3.39 METHYL 7-HYDROXY-2-HEPTYNOATE (125) 132. 3.40 METHYL 7-0X0-2-HEPTYNOATE (126) 133 3.41 METHYL (£)-7-(TFnilAHYDROPYRjWiTjOXY)-3-TRI(n-BUTYL)STANNYL-HEPT-2-ENOATE (107) 134 3.42 METHYL (£)-3-TRJ(/i-BUTYL)STANNYL-7-HYDROXY-HEPT-2-ENOATE (108) 135 3.43 METHYL (£)-3-TRI(n-BUTYL)STANNYL-7-OXO-HEPT-2-ENOATE (102) 136 3.44 METHYL (Z) -7 - (TETRAH YDROPYRAN YLOX Y) - 3-TRI(n-BUTYL)STANNYL-HEPT-2-ENOATE (111) 137 3.45 METHYL (Z)-3-TRI(n-BUTYL)STANNYL-7-HYDROXY-HEPT-2-ENOATE (114) 138 3.46 METHYL (Z)-3-TRI(/i-BUTYL)STANNYL-7-OXO-HEPT-2-ENOATE (103) 139 3.47 METHYL (£)-[2-(HYDROXY)CYCmPE>nTIJDENE]-A C E T A T E (109) 140 3.48 METHYL 7-HYDROXY-2-OCTYNOATE (127) 141 3.49 METHYL 7-IODO-2-OCTYNOATE (128) 142 3.50 METHYL (£)-3-TRI(/i-BlJTYL)STANNYL-7-HYDROXY-2-OCTYNOATE (119) 143 3.51 METHYL (£)-3-Tm(/i-BUTYL)STANNYL-7-IOLX)-2-OCTYNOATE (117) 144 3.52 METHYL (Z)-3-TW(/i-BUTYL)STANTNYL-7-HYDROXY-2-OCTYNOATE (120) 145 3.53 METHYL (Z)-3-TRI(n-BUTYL)STANNYL-7-IODO-2-OCTYNOATE (118) 146 3.54 METHYL (£)-(2-METHYIXYCLOPENTYLIDENE)-ACETATE (121) 147 3.55 M E T H Y L (Z)-(2-METHYLCYCLOPENTYLIDENE)-A C E T A T E (122) 148 3.56 6-BROMO-2-HEX A N O L (135) 149 3.57 6 - B R O M O - 2 - ( T E T R A H Y D R O P Y R A N Y L O X Y ) H E X A N E (136) 150 3.58 7 - ( T E T R A H Y D R O P Y R A N Y L O X Y ) - 1 -OCTYNE (137) 151 3.59 M E T H Y L 8-(TT£TRAHYDROPYRANYLOXY)-2 - N O N Y N O A T E (138) 152 3.60 M E T H Y L 8 - H Y D R O X Y - 2 - N O N Y N O A T E (147) 153 3.61 M E T H Y L 8-IOLX)-2-NONYNOATE (146) 154 3.62 M E T H Y L (£)-3-TRI(n-BUTYL)STANNYL-8-(TETRAHYDROP Y R A N Y L O X Y) -2 -NONENOATE (139) 155 3.63 M E T H Y L (£)-3-TRI(n-BUTYL)STANNYL-8-H Y D R O X Y - 2 - N O N E N O A T E (140) 156 3.64 M E T H Y L (£)-3-TW(n-BUTYL)STANNYL-8-IOrX)-2 - N O N E N O A T E (132) 157 3.65 M E T H Y L (Z)-3-TRI(/i-BUTYL)STANNYL-8-H Y D R O X Y - 2 - N O N E N O A T E (141) 158 3.66 M E T H Y L (Z)-3-TRI(/i-BUTYL)STANNYL-8-IOrX>-2 - N O N E N O A T E (133) 159 3.67 M E T H Y L (£) - (2-METHYLCYCLOHEXYLIDENE)-A C E T A T E (142) 160 - 3.68 M E T H Y L (Z)-(2-METHYLCYC3JOHEXYLJX)ENE)-A C E T A T E (144) 161 R E F E R E N C E S .162 S P E C T R A L APPENDIX 167 LIST OF TABLES Table Title Page I. Electronic Nature of Heteroatom Radicals 2 II. Relative Rates of Addition of Nucleophilic Radicals to Diethylvinylphosphonate 4 III. Effect of Hectron-Withdrawing Group on Relative Rate of Addition of Cyclohexyl Radical to an Alkene 5 IV. Steric Effects on Addition Regioselectivities: Addition of Dicyanomethyl Radicals to Various Alkenes 5 V. Experimental Kinetic Data for Ring Closure of to-Alkenyl and Related Radicals 7 VI. Reaction of Methyl (£)-8-iodo-7,7-dimethyl-3-tri(n-butyl)stannyl-oct-2-enoate (50) 40 VII. Ratio of Cyclic Products versus Time for the Tri(n-butyl)tin Hydride Mediated Reaction of Compound 50 42 VIII. Tri(n-butyl)tin Hydride Mediated Reaction of Compound 51 43 IX. Bis(trimethylstannyl)benzpinacol Mediated Reactions of Compounds 50 and 51 46 X. Low-temperature Reactions of Compounds 50 and 51 52 XI. Reaction of 50 and 51 with Tris(trimethylsilyl)silane 54 XII. Reaction of 75 and 76 with Bis(cyclor^ ntadienyl)titanium(IJI) Chloride 62 XIII. Tri(n-butyl)tin Hydride Mediated Reactions of 103 72 XIV. Reaction of 102 and 103 with Zinc and TMS-C1 75 XV. Radical Addition-Fragmentation Reactions of Compound 117 78 XVI. Radical Addition-Fragmentation Reactions of Compound 118 79 XVLT. Radical Cyclization Reactions of Compound 128 83 X VIII. Reactions of Compound 132 '. 86 XIX. Reactions of Compound 133 87 XX. Radical Cyclization Reactions of Compound 146 89 ix LIST OF FIGURES Figure Title Page 1. Selective Chlorine Atom Abstraction by Tri(n-butyl)tin Radical 3 2. Model Transition Structures for 5-Hexenyl Radical Cyclization 7 3 The Tin Hydride Mediated Addition of an Alkyl Halide to an Alkene 10 4. Possible Steps in a Tin Hydride Mediated Addition Reaction 11 5. General Mechanism for a Free Radical Atom Transfer Reaction 27 6. General Strategy for Stereospecific Exocyclic Alkene Formation via a Radical Addition-Fragmentation Mechanism 32 7. The Mechanism of Stork's Trialkyltin Halide/Sodium Cyanoborohydride System for the In Situ Generation of Trialkyltin Hydride 47 8. Intermolecular Mechanism for the Formation of Compound 64 48 9. Intramolecular Mechanism for the Formation of Compound 64 49 10. 300 MHz *H NMR Spectrum of Compound 64 Isolated from the Tri(/i-butyl)tin Deuteride Mediated Reaction of Compound 50 50 11. 2 H NMR Spectrum of Compound 64 Isolated from the Tri(/i-butyl)tin Deuteride Mediated Reaction of Compound 50 50 12. Transition States for Allylic Hydrogen Atom Abstraction for the Radicals Generated from Compounds 50 and 67 57 13. Cyclization of a Radical Generated from an Epoxide by Reaction with Bis(cyclopentadienyl)titanium(III) Chloride 60 14. Intramolecular Cyclization of a Radical Generated from an Aldehyde 68 15. Samarium(II) Iodide Promoted Coupling Reaction of an Aldehyde and an a.p-Unsaturated Ester 73 16. Mechanism for Samarium(H) Iodide Promoted Coupling Reaction of an Aldehyde and an ^^-Unsaturated Ester 73 17. Samarium(LT) Iodide Promoted Intramolecular Coupling Reaction of an Aldehyde and an a,f3-Alkynyl Ester 74 18. Radical Cyclization Mechanism for Compound 128 83 X LIST OF ABBREVIATIONS Ac acetyl AIBN 2,2'-azobisisobutyroru1rile Bn benzyl bp boiling point Bu butyl calcd calculated Cp cyclopentadiene d doublet dd double doublet DHP dihydropyran DMAP 4,4-dimethylammopyridine dmgH dimethylglyoximato DMSO dimethyl sulphoxide EDA emylenediamine Et ethyl equiv equivalent(s) FT Fourier Transform GC gas chromatography HMPA hexamethylphosphoramide HRMS high resolution mass spectrometry IR infrared J coupling constant LDA lithium dtisopropylamide LRMS low resolution mass spectrometry m multiplet x i M + molecular ion m/z mass to charge ratio /nCPBA meta chloroperbenzoic acid Me methyl n normal NMR nuclear magnetic resonance <P phenyl py pyridine q quartet Rf rate factor RT retention time (GC) s singlet t triplet Tf trifluoromethanesulphonyl Ts toluenesulphonyl THF tetrahydrofuran THP tetrahydropyran TLC thin layer chromatography TMS trimethylsilyl x i i ACKNOWLEDGEMENTS First and foremost, I would like to thank Professor Larry Weiler for his guidance and encouragement during this project, and for his helpful advice in the preparation of this thesis. I am also very grateful to Professor Frank Harris for developing the synthesis of compounds 50 and 51, and for performing initial reactions with these compounds. The friendly help of the NMR and Mass Spec, staff and the services of the microanalytical laboratory are greatly appreciated. I would also like to thank my lab-mates, both past and present, for providing comic relief to the daily routine. Finally, I would like to thank my wife, Kathleen, for her unending patience and understanding during the preparation of this thesis. This thesis is dedicated to my parents. 1 CHAPTER I INTRODUCTION The first report of the use of a radical reaction in organic synthesis was in 1937, when Hey and Waters1 described the phenylation of aromatic compounds by benzoyl peroxide as a radical reaction. In that same year, Kharasch et al. recognized that the anti-Markovnikov addition of HBr to alkenes proceeds via a radical chain process.2 In the years that followed, pioneering research into the formation, structure, and reactions of radicals was carried out which laid the foundation for the recent prominence free radical reactions have achieved in organic synthesis. Several features of radical reactions make them very useful for synthetic application. They are often highly chemo-, regio-, and stereoselective, and the mild, neutral reaction conditions tolerate virtually all oxygenated functional groups without the need for protection. In addition, steric crowding, particularly on the radical center, is often tolerated, making radical reactions useful vehicles for the formation of hindered carbon-carbon bonds. Most free radicals are highly reactive species and, unlike anions and cations, react with themselves by combination or disproportionation at rates approaching the diffusion-controlled limit Therefore, a free-radical reaction must be carefully designed to meet certain requirements for its successful application in synthesis. To understand these requirements and the considerations one must make when planning such a reaction, an understanding of the principles of free radicals is helpful. U BASIC PRINCIPLES OF FREE RADICAL REACTIONS Several recent reviews outline the basic principles of free radical reactions, as well as their application to synthesis.3"7 Because of the high reactivity of radicals, it is often advantageous to maintain a low concentration of radicals over the course of a reaction. Chain INTRODUCTION 2 reactions are ideally suited to meet this requirement. All free radical chain reactions can be divided into three discrete mechanistic phases: 1) initiation; 2) propagation; and 3) termination. To be synthetically useful, a given chain reaction must generate radicals site-selectively, and these radicals must have sufficient lifetime to react The propagation, or "chain-transfer" step is the crucial step which controls the lifetime of the radicals in solution. For the successful use of radical chain reactions in synthesis, two conditions must be met: 1) the selectivities of the radicals involved in the chain must differ from each other; and 2) the reactions between radicals and non-radicals must be faster than radical combination reactions. Nearly all the useful reactions of free radicals can be grouped into two broad categories: atom (or group) abstraction, or addition to multiple bonds. It is the electronic nature of a free radical that controls its subsequent reactions. Simple alkyl radicals and those that are substituted with electron-releasing groups (alkyl, alkoxy, amino etc.) are considered nucleophilic, and as such seek electron poor addition or abstraction sites, whereas carbon radicals with electron-withdrawing groups are electrophilic, and prefer to react at sites of higher electron density. In the case of heteroatom-centered radicals, radicals centered on atoms significantly more electronegative than carbon are considered electrophilic, and those on atoms less electronegative than carbon form nucleophilic radicals (Table I).8 Table I. Electronic Nature of Heteroatom Radicals.8'' Entry Radical Electronegativity 1 2 3 4 RO' R 2 N' cr Br* RS* 3.44 1 3.04 3.16 > electrophilic 5 2.96 2.58 j 6 7 8 9 R3C* R3Ge R3Sn* R3Si* 2.55 1 2.01 1.96 1.90 , > nucleophilic INTRODUCTION 3 1.1.1 RADICAL ABSTRACTIONS The groups that are available for abstraction by a radical are limited to mono- or divalent atoms, due in part to their steric accessibility. Therefore, sites of abstraction are hydrogen, halogens, and occasionally sulfides, selenides, and tellurides.8 Nucleophilic heteroatom radicals, such as trialkylstannyl radicals, preferentially abstract halogen atoms over hydrogen, due to the unfavourable enthalpy of hydrogen abstraction:10 BrH 2C-H + Me3Sn* - *CH2Br + Me3SnH AH « 3 2 kcal / mol CH 3-Br + Me3Sn* -+ *CH 3 + Me3SnBr AH»-14 kcal / mol Because of the mildness and selectivity of stannyl radicals, they are by far the most frequently used chain transfer reagents in free radical reactions.11 If there is more than one possible site for abstraction by a stannyl radical, the site of abstraction usually is that with the lowest C-X bond energy, as illustrated below (Figure l) . 1 2 H H Figure 1. Selective chlorine atom abstraction by tri(n-butyl)tin radical. In contrast to nucleophilic radicals, electrophilic heteroatom radicals prefer hydrogen abstraction, again due to the large enthalpy differences:8 (CH3)3C-0* + Br-CH 3 - (CH3)3COBr + *CH 3 AH« 13 kcal/mol (CH3)3C-0* + H-CH 2Br - (CH 3) 3COH + *CH2Br AH « -2 kcal/mol INTRODUCTION 4 1.1.2 RADICAL ADDITION REACTIONS The vast majority of free radical reactions used for carbon-carbon bond formation involve the addition of a radical to a multiple bond. These additions are very sensitive to substituent effects, both on the attacking radical itself and on the a- and p-positions of the unsaturated acceptor. As one would predict, nucleophilic radicals prefer addition to electron-poor olefins, whereas electrophilic radicals preferably interact with electron-rich olefins. The addition of electron-donating substituents at the radical center increases the nucleophilicity of the radical, and as a result an increase in the rate of addition to electron-deficient olefins is observed. This is illustrated by the following data for additions to diethylvinylphosphonate (Table II). Table II. Relative Rates of Addition of Nucleophilic Radicals to H2C=CHPO(OEt)2.13'14 0 || R' + 0 II J>(OE\)2 /(OEt) 2 R R: 'CH 3 CH^CH^ CHoOCHj *CH(CH3)2 'C(CH 3) 3 1 1 2.7 4.8 24 It is interesting that this electronic effect offsets both the increased stability of the attacking radical and any steric hindrance to addition that might be expected. The effect of electron-withdrawing groups at the P-position of olefins on the relative rate of addition is even more significant As the data in Table HI illustrate, the rate of addition of a radical to an alkene is greatly accelerated by the presence of strongly electron-withdrawing groups on the alkene. INTRODUCTION 5 Table HJ. Effect of Electron-Withdrawing Group on Relative Rate of Addition of Cyclohexyl Radical to an Alkene.15 O' — -E C 4 H 9 H Q Ph C 0 2 C H 3 CN CHO k^ 1 3.75 30 250 1675 6000 8500 An electron-withdrawing group also influences the regioselectivity of radical addition, directing the attacking radical P to itself, as one would predict from a polar transition state. However, steric effects resulting from alkene substitution also have a pronounced influence on the regioselectivity of radical additions to alkenes. The magnitude of these effects is illustrated by the data in Table IV. Table IV. Steric Effects on Addition Regioselectivities: Addition of Dicyanomethyl Radical to Various Alkenes.8 Entry Alkene % addition to C a C b 1 a b ^ y ^ ^ >95 <5 1.0 2 a b / s ^ / >95 <5 15.9 3 ca. 50 ca. 50 2 x 0.54 INTRODUCTION 6 Because the rate at which an addition reaction takes place is often crucial for its success in synthesis, it is important to note that steric effects are significantly greater at the P-position than at the a-position of an alkene, and the difference can be dramatic. For example, an a f-butyl group slows addition by a factor of 4, whereas the same group in the P-position slows addition by a factor of 20,000.16 'Oft, + C 0 2 C H 3 H C 6 H n CO2CH3 (• H 1 C 0 2 C H 3 Bu 1 = 0.24 C 6 H n . CO2CH3 ^ t Bu C-O2CH3 H ^ , = 5x10 - 5 C 6 H Bu H CO2CH3 Intramolecular radical addition reactions (cyclizations) are used extensively in synthesis, and thorough summaries outlining important considerations for these reactions are available. 6 1 7 - 2 1 The 5-hexenyl, 6-heptenyl, and 7-octenyl radicals all exhibit a marked preference to add to the alkene in an exo- fashion to yield the cycloalkylcarbinyl radicals, which are the less thermodynamically stable products.17 Radical ring closures are known to be under kinetic and steroelectronic rather than thermodynamic control,8 and the preference for exo ring closure of the 5-hexenyl radical can be explained by invoking a chair-like transition state, as depicted in Figure 2. Computer calculations have shown that the relative strain energy in the transition state leading to ew-cyclization of the 5-hexenyl radical is 2.8 kcal / mol lower than that in the corresponding e/u/o-cyclization.22 INTRODUCTION 7 Exo Endo Figure 2. Model Transition Structures for 5-Hexenyl Radical Cyclization.22 The rate of to-alkenyl radical ring closure by both exo- and endo- modes depends on substitution on the alkene and on the alkyl chain. Experimental kinetic data for representative examples are given in Table V . 2 2 Table V. Experimental Kinetic Data for Ring Closure of to-Alkenyl and Related Radicals.22 Entry Radical k25 (exo)" k25 (endo)" 2 3 2.3 x 10 5 5.2 x 10 3 1.2 x 10 2 6.1 x 10 3 5.2 x 10 6 8.5 x 10 6 4.1 x 10 3 8.3 x 10 2 <7 x 10 1 9.0 x 10 3 <1 x 10 5 <1 x 10 5 2.8 x 10 <6 x 10 2 * rate constants at 25 °C in s - l INTRODUCTION 8 The ring closure of substituted 5-hexenyl systems is often highly stereoselective, and guidelines for predicting the stereoselectivity in these systems have been put forth by Beckwith:23 - 1- or 3- substituted hexenyl radicals preferentially give c«-cyclopentyl products. - 2- or 4- substituted hexenyl radicals preferentially give rra/w-cyclopentyl products. The magnitude of this effect is illustrated by the examples below.24 65 25 35 75 83 17 These stereoselectivities are easily understood by considering the two possible e x o transition state structures with a chair-like conformation. The substituents on carbon atoms 2,3, or 4 will preferentially occupy equatorial positions, and therefore control the stereoselectivity. The following diagram illustrates the two possible chair-like transition-state structures for the extf-cyclization of a 3-substituted 5-hexenyl radical. In more complex systems predicting the INTRODUCTION 9 - • - c r stereoselectivity can be difficult. However, recently force-field models for the quantitative prediction of transition state energies for intramolecular radical addition reactions have been devised, and are very helpful in predicting the regie- and stereoselectivity of radical cyclizations accurately.22'25 1.2 METHODS FOR CONDUCTING FREE-RADICAL REACTIONS Several methods for conducting free-radical reactions in synthesis are known, and each offers distinct advantages and disadvantages. Three of the most common and versatile methods currently used are the tin hydride method, the fragmentation method, and the atom-transfer method. A discussion of each of these methods, illustrated with recent examples from the literature, will serve to demonstrate its specific requirements for successful application in synthesis, as well as its inherent advantages and disadvantages. 1.2.1 THE TIN HYDRIDE METHOD The most common method for the application of free-radical chain reactions in synthesis is the tin hydride mediated reduction of an organic functional group, a reaction which was discovered in the 1960's.26 Several reviews extensively detail the requirements for the successful application of this method to synthesis,3-4*11 and a brief overview is provided here. INTRODUCTION 10 An example of this reaction is the well-known addition of an alkyl halide to an alkene, as illustrated in Figure 3. Figure 3. The Tin Hydride Mediated Addition of an Alkyl Halide to an Alkene.4 When the reaction is depicted as in Figure 3 above, the chain mechanism is readily apparent. It is important to note that each of the radicals in the chain is present in solution simultaneously. Each of these radicals has several possible reaction pathways open to it, and it is necessary to control the reactivity of each radical such that the desired product is formed, and the chain is maintained. Figure 4 lists the possible, individual steps that must be considered in a tin hydride mediated addition reaction, and helps to illustrate the necessary requirements for its successful application in synthesis. Control over the reactivity of each of the radicals in the chain can result from the electronic effects discussed in section 1.1. The initially formed 2-cyanopropyl radical 1, formed by the thermolytic cleavage of AIBN, can abstract a hydrogen atom from tri(n-butyl)tin hydride (path b), or add to the alkene (path c). If the substituent, E, on the alkene is electron-E INTRODUCTION N C ^ - N = N - ^ C N N C ^ ' + Bu 3SnH 1 N C ^ • + N 2 | 1 NoV* + Bu 3Sn' / 2 NC Bu 3Sn + R—X 2 BuqSnX + R BusSn + 2 Bu 3 Sn' R + Bu 3SnH 3 R-H + Bu 3Sn 2 R + 3 R/ \ ' + Bu 3SnH + Bu 3Sn 2 R Figure 4. Possible Steps in a Tin Hydride Mediated Addition Reaction8 INTRODUCTION 12 withdrawing, then the rate of addition of the electrophilic 2-cyanopropyl radical 2 to the electron-poor alkene will not compete with the relatively fast abstraction reaction b, (kn » 2 x 106 M^s"1),3 and abstraction will predominate. The resulting tri(/i-butyl)tin radical 2 also has two possible reaction pathways (d and e) open to it. In this case, the nucleophilic stannyl radical can readily add to an electron-deficient alkene. However, because of the weak carbon-tin bond (ca. 65 kcal/mol),27 this addition is reversible. Therefore, the competition between pathways d and e depends on the rate of abstraction of X. Beckwith and Pigou28 have established a reactivity scale for the tri(/i-butyl)tin radical which is useful in synthetic planning. Iodine is often the preferred precursor, as the rate constant for iodine atom abstraction approaches the diffusion-controlled limit.29 Thus, if X in the above reaction is iodine, the desired pathway d leading to the formation of alkyl radical 3 will predominate. Radical 3 also has two competing pathways to follow, f and g. Again, the partitioning between these two pathways depends on their relative rates. An electron-withdrawing substituent on the alkene will accelerate addition, as discussed earlier. Also, substituents at the radical center will accelerate addition, while having little effect on the rate of hydrogen atom abstraction.3 Thus, proper substitution of the radical center or the alkene can help to control the fate of radical 3. In this case, however, another very powerful method exists to control the partitioning of radical 3. Both addition and hydrogen atom abstraction are bimolecular reactions, and as such their rates are dependent upon alkene- and tri(/i-butyl)tin hydride concentration respectively. Therefore, by using an excess of alkene, or by maintaining a low concentration of tri(n-butyl)tin hydride over the course of a reaction, radical 3 can be controlled to follow the addition pathway g. Several methods for maintaining a low tri(n-butyl)tin hydride concentration over the course of a reaction have been developed, including syringe-pump techniques and catalytic tri(/*-butyl)tin halide / NaBH3CN systems.30 The final requirement for the success of the desired chain reaction is that the adduct radical 4 will react preferentially via pathway h to afford the desired product and the chain-carrying tri(n-butyl)tin radical 2, and avoid polymerization via pathway i. Again, if the INTRODUCTION 13 substituent E on the alkene is electron-withdrawing, radical 4 will be electrophilic in nature, and therefore addition to the alkene will be slow in comparison with hydrogen atom abstraction. A discussion of examples of free radical chain reactions from the recent literature reveals the versatility of the tin hydride method, and also illustrates the advantages radical reactions offer the synthetic chemist. One of the most impressive recent developments in radical cyclization reactions is Curran's tandem radical cyclization approach to linear and angular triquinanes.31 The general strategy involves a preformed central cyclopentene ring, which serves as the "relay" for the tandem addition reaction, and also ensures the correct stereochemical outcome. The application of this methodology to the synthesis of hirsutene is shown below. 7 8 9 H Several features of this reaction are noteworthy. First, the reaction is very efficient, and hirsutene is produced in 80% yield in a single step from the relatively simple trans-3,5-disubstituted cyclopentene 6 upon reaction with tri(n-butyl)tin hydride and AIBN in refluxing benzene. This reaction also demonstrates that radicals are well suited for the formation of sterically hindered carbon-carbon bonds. As can be seen above, the initially-formed radical 7, which is flanked by a gem-dimethyl group on the a-carbon, adds efficiently to the alkene to INTRODUCTION 14 afford the tertiary radical 8. In turn, radical 8 adds to the alkyne to give the vinyl radical 9, forming a quaternary center in the process. Finally, radical 9 abstracts a hydrogen atom from tri(n-butyl)tin hydride to afford hirsutene, and the chain-carrying tri(n-butyl)tin radical. The reaction is also an excellent example of good synthetic planning. Each of the cyclizations is a relatively fast intramolecular 5-hexenyl addition, and therefore competitive intermolecular reduction of radicals 7 and 8 is not a problem. In addition, the necessary sequencing of the cyclizations, as well as control of the stereochemistry, is obtained through the use of the preformed, central ring. Radical cyclization reactions conducted by the tin method are not restricted only to the formation of 5- and 6-membered rings. Although there are no reports of radical cyclizations creating 8-10 membered rings, radical closures forming rings of 11-20 atoms have been achieved.32 One such example is Pattenden and Hitchcock's synthesis of the natural product (-)-zearalenone, in which a novel 14-endo -trig macrocyclisation is employed as a key step.33 The reaction was performed by the slow addition of tris(trimethylsilyl)silane, or tri(n-butyl)tin hydride, over a period of 8 hours. In this manner a low concentration of the hydride is maintained, thereby minimizing the amount of reduction prior to cyclization, and the cyclic product was obtained in 55% yield. The regioselectivity of addition to the alkene is controlled by the electron-wimclrawing carbonyl functionality, which also serves to accelerate the cyclization. Presumably the aromatic ring and the olefinic linkage in the chain facilitate the cyclization as well. The authors also report encountering one of the common drawbacks to the tin method. INTRODUCTION 15 Although the tri(/t-butyl)tin hydride mediated reaction proceeds in 60% yield, removal of small traces of tin residues from the final product was very difficult. This situation was avoided by using the recently developed tin hydride substitute, tris(trimethylsilyl)silane.34 Radical reactions conducted by the tin method are not restricted to alkyl radicals. Vinyl radicals can also be employed, and offer some advantages over alkyl radicals. For example, Curran states that "a useful rule of thumb proposes that the rate constant for a reaction of an aryl or vinyl radical will be a factor of 103 greater than the corresponding rate constant of a related alkyl radical." 3 However, he also points out that this increased reactivity is only an asset if the cyclization rate is increased relative to the hydrogen abstraction rate. A great deal of the chemistry of vinyl radicals has been developed by Stork and co-workers.35 In their first report of a vinyl radical cyclization, Stork and Baine produced the vinyl radical by the reaction of a vinyl bromide with a stannyl radical.36 Such a vinyl radical cyclization is a useful method for introducing a double bond in a predetermined position on the newly formed ring. Interestingly, the stereochemistry of the vinyl bromide has no effect on the outcome of the radical cyclization, as is illustrated in the cyclization of 10 to l l . 3 7 Stork and Baine observed that the yield of the cyclic product 11 INTRODUCTION 16 was approximately 7 5 % , regardless of the stereochemistry of the vinyl bromide radical precursor 10. This lack of dependence upon the stereochemistry of the vinyl bromide is a result of the fact that the intermediate vinyl radicals are rapidly inverting. Another versatile and synthetically powerful method for the generation of vinyl radicals has been developed by Stork and Mook.38 In this method, illustrated below, the vinyl radical 13 is generated by the addition of a stannyl radical to an alkyne 12. The intermediate vinyl radical 13 then undergoes a 5-ex»-trig cyclization onto the alkene followed by hydrogen atom abstraction to afford the cyclic vinylstannane 14. Such vinylstannanes can be used as intermediates for further synthetic elaboration via reactions such as palladium-catalyzed coupling or tin-lithium exchange, or they are readily protiodestannylated by simply stirring the vinylstannane in methylene chloride in the presence of silica gel. Although carbon-carbon multiple bonds are the most common radical acceptors, other groups such as nitriles,39 oxime ethers,40 and carbonyls41 have also been used with considerable success, particularly in intramolecular additions. For example, Fraser-Reid and Tsang have recently reported an interesting radical cyclization in which they compare a nitrite and an aldehyde as radical acceptors.42 INTRODUCTION 17 The carbohydrate-derived iodo-aldehyde 15 was reacted with tri(n-butyl)tin hydride. Surprisingly, a 4:1 mixture of 16:17 was obtained, in a combined yield of 91 %. What was surprising was that product 16, which results from a 6-exo cyclization onto the aldehyde, predominated over product 17, which is formed via a series of two 5-exo cyclizations. This result prompted a further investigation, and they performed the following competition experiment.43 OH 85 % not observed In this case, the product resulting from a 6-exo cyclization onto the aldehyde was formed exclusively; the product from addition to the alkene via a 5-exo pathway was not observed. This served to show that 6-exo cyclization onto an aldehyde is a very facile process. INTRODUCTION 18 In an effort to overcome this problem in preparing 17, they investigated the use of a nitrile as radical acceptor.43 In this case, reaction of the iodo-nitrile 18 with tri(n-butyl)tin hydride resulted in its smooth conversion to the ketone 19, obtained in 91 % yield after chromatography on silica gel. This ketone could then be converted to the alcohol 17 by reduction with a suitable reducing agent. Free radical reactions have also been developed which allow for the stereochemically controlled formation of carbon-carbon bonds. One of the pioneers in this area is Stork, who has developed reactions which permit the regio- and stereocontrolled formation of two adjacent chiral centers.44 The basis of Stork's method is illustrated schematically below. The source of the regio- and stereoconrrol is the allylic alcohol, which is used to anchor a two-atom tether terminating in a carbon-centered radical. The length of the tether insures that the radical adds to the proximal end of the alkene, thus controlling the regiochemistry of addition. Also, the transition-state geometry of the addition allows only for a ris-fusion of the newly formed five-membered ring, thereby ensuring that the newly formed carbon-carbon bond is syn to the allylic hydroxyl. The stereochemistry at the distal end of the alkene is also controlled; because the intermediate, bicyclic radical is cup-shaped, trapping of this radical is restricted INTRODUCTION 19 largely to the convex side. Stork has devised tethers that are easily cleaved after they have served their purpose of controlling stereochemistry, and the hydroxyl group to which the tether was attached can then be removed, or used for subsequent synthetic elaboration. The following example illustrates this methodology.463 The bicyclic allylic alcohol 20 was converted to the silyl ether 21 by reaction with commercially available (bromomethyl)chlorodimethylsilane. When 21 was reacted with tri(n-butyl)tin hydride, the siloxane 22 was formed in 65 % yield, as only one isomer. The tether was then readily cleaved by reaction with KF in DMF, in the presence of H2O2. Overall, a hydroxy-methylene unit has been added regio- and stereoselectively to the alkene, and the stereochemistry of the ring junction in the decalin system has been controlled. In addition to the silyl ether tether methodology discussed above, Stork has developed a mixed-acetal tether which results in the addition of a functionalized two-carbon chain to the a-carbon of the alkene.4615 Also, the radical trap is not limited to hydrogen, and other groups have been used with success, thereby increasing the versatility of this method. An example of this conceptually similar methodology is given below.4615 The allylic alcohol 24 is readily INTRODUCTION 20 OEt OEt OH O •I EtO Bu3SnCl, NaCNBH; N-iodosuccini mide 24 25 26 Z = CN, CO^Me, COEt, PO(OEt)2, SC^Me, or SOsPh. converted to the mixed iodo-acetal 25 in greater than 90 % yield. Compound 25 can then be reacted with tri(n-butyl)tin hydride, generated in situ via a catalytic tri(n-butyl)tin chloride/sodium cyanoborohydride system, in the presence of 10 equivalents of a radical trap, to give compound 26 in yields of 55 - 75 %. All of the radical traps have electron-withdrawing substituents on the alkene, thereby increasing the rate of the intermolecular addition relative to hydrogen atom abstraction. In addition, the catalytic tin hydride system employed ensures that the tri(n-butyl)tin hydride concentration is low and constant throughout the reaction, and therefore competitive hydrogen atom abstraction by the intermediate, bicyclic radical is minimized. Thus, the overall result of this reaction is the regio- and stereocontrolled formation of two adjacent chiral centers. 1.2.2 THE FRAGMENTATION METHOD In the tin hydride method described above, the chain-carrying tri(n-butyl)tin radical is generated by hydrogen-atom abstraction from tri(n-butyl)tin hydride. An alternative method for the generation of the chain-transfer agent is via a fragmentation reaction. The fragmentation of Q 28 29 27 an appropriate C-Q bond produces Q*, which may itself be the chain-transfer agent or which may generate the chain-transfer agent via reaction with a neutral molecule.3 The advantage to this INTRODUCTION 21 method is that tin hydride is not required to maintain the chain, and therefore the lifetimes of the radicals in the chain are not limited by the rate of hydrogen atom abstraction, a common complication in the tin hydride method. As a result, slower reactions are permitted, and the use of dilute conditions is not required. The fragmentation method also introduces a double bond in a specific position, which is useful for further synthetic manipulation. Intermediates such as 27 are usually formed via an addition reaction of a radical with a suitably substituted allyl or vinyl compound, as shown below. The net result of such a reaction is the allylation or vinylation of the alkyl radical R*. Several groups have been used as the leaving group Q, including cobaloxime,45 trialkyltin, thiophenyl, iodine, bromine, phenylsulphonyl, and mercury (I) chloride.46 The use of allylstannanes for the free-radical allylation of carbon radicals has been developed extensively by Keck and co-workers.47 The overall reaction process is illustrated by the example below. The cyclohexyl radical 30 adds to the allylstannane 31 to give the allylated INTRODUCTION 22 O + 31 nR3 + R3Sn' 30 32 33 i r + R3Sn* o + R3SnBr 33 30 product 32 and the chain-carrying trialkyltin radical 33. Thus, the chain requirement of the reaction is fulfilled. However, this reaction brings up an interesting point. The yields of this type of reaction are high, which implies that the allylic trialkyl-tin moiety must have an activating effect upon addition to the double bond. If there were no activating effect, addition of radical 30 to the product alkene 32 would be competitive, and mixtures of products would be expected. Curran et al. have investigated this phenomenon, and have found that allylstannanes are at least one order of magnitude more reactive than simple alkenes toward alkyl radicals.48 This activation is sufficient to ensure the desired product is formed in high yield. Keck and co-workers have applied this reaction to a variety of substrates with good success. A selection of examples follows.47 Ph Ph OH OH AIBN, 80 *C 92% INTRODUCTION 23 o X  o o X  o As is evident from the above examples, the reaction is tolerant of a high level of functionality in the substrate, and a variety of radical precursors can be used successfully. The reaction can be initiated either thermally, with reagents such as AIBN, or photochemicaUy, and yields above 80 % are common. Substitution on the allylstannane does have a pronounced effect on the outcome of the reaction. Substituents at the 2 position are tolerated, as evidenced by the successful use of methylallylstannanes.47 This allows one to use electron-withdrawing substituents at C-2, and thereby increase the rate of addition. Substituents at the 3-position are usually not tolerated, as they retard the rate of addition below the useful limit, and therefore unwanted side reactions predominate. Substituents at the 1-position are also not tolerated, because rearrangement of the 1-substituted allylstannane to an unreactive 3-substituted allylstannane is competitive. INTRODUCTION 24 A recent report from Padwa, Murphree, and Yeske of a free-radical allylation using an allylsulphone illustrates how free-radical reactions often complement their ionic counterparts.49 Treatment of 2,3-bis(phenylsulphonyl)-l-propene (34) with a variety of organometallic reagents (RM) results in the formation of the allene 35 via fj-elimination of the phenylsulphonyl group. However, reaction of 34 with a radical results in the production of the substituted vinylsulphone 36 via an addition-elimination sequence. Thus this is an example of how, in certain cases, free-radical reactions can act as a surrogate for inaccessible ionic reactions. As mentioned earlier, appropriately substituted vinyl compounds can also be employed in the fragmentation method. In this case, however, electron-withdrawing groups must be used to control the regioselectivity of the addition, as otherwise the steric crowding due to the leaving group would result in addition to the undesired end of the alkene. Baldwin and co-workers have developed this method, using a tri(n-butyl)tin group as the leaving group, and have applied it in synthesis.50 Examples from their work are shown below. 35 34 36 COjEt Br AIBN A 49% P h OMe 82% OMe INTRODUCTION 25 Baldwin and Kelly found that the (£)-geometry about the newly formed alkene predominated, regardless of the stereochemistry of the starting vinylstannane50b. They also found that the phenyl group was less effective than the ester group at activating the vinylstannane for addition, which is understandable based upon the relative electron-withdrawing ability of these two groups. Russell and co-workers have also studied this method extensively, and have found that phenylsulphonyl, phenylsulphinyl, and phenylthio groups, as well as halides and mercuric halides, are suitable leaving groups in this reaction.46 In contrast to the work of Baldwin and co-workers,50 in some cases Russell et al. do observe a dependence of the product alkene geometry on the stereochemistry of the vinyl derivative used. The extent of this selectivity, however, appears to be very dependent upon the substrates used, as well as the reaction conditions employed. Keck and Burnett have applied this methodology to the synthesis of the prostaglandin PGF2o>51 The key reaction in the synthesis involves a free-radical cyclization, followed by an intermolecular addition-fragmentation. The reaction is very similar to one by Stork and Sher,44b hv INTRODUCTION 26 discussed earlier ( p. 20). Heating of the mixed iodo-acetal 37 in toluene at 110 °C, in the presence of an initiator, affords the intermediate radical 38 after intramolecular addition to the alkene. Radical 38 then adds to the vinylstannane 39, followed by elimination of the tri(/i-butyl)tin radical, to give the product 40 in 72 % yield. Because the chain-carrying tri(n-butyl)tin radical is formed via a fragmentation reaction, no tin hydride is required and complications arising from hydrogen atom abstraction are avoided without having to resort to high dilution techniques. In addition, the reaction conducted by the fragmentation method introduces an alkenyl side-chain, in contrast to the alkyl side-chain introduced in the tin hydride mediated reaction reported by Stork and Sher.44b 1.2.3 THE ATOM TRANSFER METHOD Another very powerful method for the application of free-radical chain reactions is the atom-transfer method. The basic reaction is the addition of a reagent X-Y across a multiple C-C bond. A general mechanism for this reaction is shown below (Figure 5). In the INTRODUCTION 27 X-Y + In" ^. X-In + Y* step 1 step 2 + X-Y ^ / ^ + Y' step 3 Y 42 Figure 5. General Mechanism for a Free Radical Atom Transfer Reaction. first step, an initiator reacts with X-Y to generate the chain-carrying radical Y*. This radical Y* then undergoes addition to the alkene to afford the adduct radical 41. Radical 41 in turn abstracts an atom X from the reagent X-Y, producing the product 42 and the chain-carrying radical Y*. No external chain-transfer reagent is required, as the reagent X-Y serves as both the chain-transfer agent and the radical trap. A great variety of groups have been used successfully as the atom-transfer reagent X-Y. Perhaps the best-known example is HBr, in the peroxide-initiated addition of HBr to an alkene, a reaction discussed in most introductory textbooks of organic chemistry. T + HBr R O O R ' > ^ Br H Electron-donating and electron-withdrawing groups both stabilize radicals and weaken adjacent C-H bonds. Therefore, a large variety of groups can be used to activate C-H bonds such that they are useful in atom-transfer reactions resulting in the formation of carbon-carbon bonds. Two such examples from the work of Walling and Huyser52 are shown here. INTRODUCTION 28 ( .C0 2 CH 3 •C0 2CH 3 R O O R / A 7 3 % C 0 2 C H 3 C0 2 CH ; '3 C 0 2 C H 3 C0 2CH; Bu R O O R / A 60% OBu There are difficulties, however, in using C-H bonds in atom-transfer additions. First, if more than one relatively weak C-H bond is present in the molecule, site selective radical formation is a problem, and mixtures of products will result. Second, even the most activated C-H bonds are barely reactive enough to transfer hydrogen atoms to carbon-centered radicals at a rate that will sustain a radical chain.3 Curran and co-workers have extensively developed reactions which employ C-I groups as the X-Y reagent in atom-transfer reactions.53 Because C-I bonds are kinetically superior atom donors to C-H bonds,54 radical chains are easily maintained, and site-selective radical generation is readily achieved. An example of this reaction is provided below.55 An additional advantage to the iodine-atom transfer reaction is that the iodine atom is retained in the product, in contrast to similar reactions conducted by the tin hydride method. This iodine atom is very useful for subsequent synthetic elaboration. However, even if the iodine atom is not desired in the final product, iodine-atom transfer may still be the method of choice. As in the fragmentation method, no tin hydride is required for the reaction, and therefore the lifetimes of the intermediate radicals in the chain are not limited by the rate of hydrogen atom 8 3 % INTRODUCTION 29 abstraction. This fact makes the atom-transfer method ideal for the sequencing of radical reactions, particularly when slow, intermolecular additions are involved. An example of such a reaction from the work of Curran and Chen serves to illustrate this point.56 The product 44 can 65 % (E/Z =2.5/1) be readily de-iodinated to give 45 by reaction with tri(«-butyl)tin hydride. However, Curran and Chen report that all attempts to synthesize 45 directly via a tin hydride mediated reaction met with failure. This is understandable when one considers the requirements of the individual steps in the tin hydride mediated reaction. For the successful intermolecular addition of the radical generated from 43 to methyl acrylate ( step 1), which is expected to be slow, a low concentration of tin hydride is required to avoid competitive reduction. However, in the INTRODUCTION 30 chain-transfer step (3) a high concentration of tri(n-butyl)tin hydride is required. Clearly, both of these requirements cannot be met simultaneously, and the reaction is not possible via the tin hydride method. Carbon-cobalt complexes have also been used extensively in atom-transfer reactions, due to the relative ease of homolysis of C-Co bonds (bond energy of C-Co = 20-30 kcal/mole). The required cobalt complexes are often prepared by nucleophilic reaction of a Co(I) complex with an organic halide or tosylate.3'57 A typical example of the preparation of such a Co(IU) complex is shown below.3'58 These intermediate cobalt(III) species are often isolable and relatively stable. Thus Pattenden has referred to them as "radical-in-bottle-reagents" for organic synthesis.59 J 1. THF, -78 °C I NaCo(dmgH)2 + ^ ^ 2. Pyridine ^^Co(dmgH)2(py) One of the significant advantages of conducting atom-transfer reactions with a cobalt complex is the possibility to introduce a variety of functional groups into the product. Pattenden and co-workers have developed this methodology extensively, and the examples below illustrate some of the possible functional groups that can be introduced.59,60 !o(salen)(py) Co(salen), 1 % NaHg, dark, 25 *C ^ 4 6 4 7 Reaction of the aryl iodide 46 with Co(salen), in the presence of sodium-mercury amalgam, in the dark, followed by recrystallization from pyridine-water, afforded the cyclized cobalt(LTJ) INTRODUCTION 31 derivative 47 in 70 % yield. This black solid could then be reacted to introduce a variety of functional groups, as shown in the following diagram. 1. TEMPO 2. Zn,CH3COOH /0(salen)(py) N-OH 85% *0—N sal en tetramemylpiperidino oxide (TEMPO) 32 CHAPTER H RESULTS AND DISCUSSION The work by Russell46 and Baldwin,50 described in the introduction, clearly established the utility of radical addition-fragmentation reactions for the formation of 1,2-disubstituted alkenes. In some cases these reactions were found to proceed in a stereospecific manner, although the selectivity in forming (Z)-1,2-disubstituted alkenes from a (Z)-precursor was usually low. All of the examples that Russell46 and Baldwin50 investigated were intermolecular reactions. We were intrigued with the possibility of applying these reactions in an intramolecular fashion, to generate exocyclic alkenes. Our general strategy is illustrated in Figure 6. Figure 6. General Strategy for Stereospecific Exocyclic Alkene Formation via a Radical Addition-Elimination Reaction. RESULTS AND DISCUSSION 33 As seen in Figure 6, radical abstraction of the substituent X affords an alkyl radical. Addition of this radical to an appropriately substituted alkene, followed by elimination of the radical leaving group, Q, results in the formation of an exocyclic alkene. If the rate of elimination of Q is faster than inversion or rotation about the C1-C2 bond in the intermediate, cyclic radical, the exocyclic double bond will be formed stereoselectively, and its geometry will be determined by the geometry of the initial, acyclic alkene. The purpose of this project was to investigate intramolecular radical addition-fragmentation reactions under a variety of conditions, with the aim of developing methods to stereospecifically form exocyclic alkenes. For our first investigation into exocyclic alkene formation via a radical addition-fragmentation reaction, we chose as our targets the two compounds illustrated below. Both of these compounds are known, as they have been prepared previously as intermediates in the synthesis of boll weevil sex pheromones.61 From these results, we knew that it was possible to separate the two isomers, and to assign the stereochemistry of the alkene using J H NMR. We envisaged that compounds 50 and 51 would serve as suitable substrates for a radical addition-elimination sequence leading to 48 and 49 respectively. The decision to use the tri(/i-butyl)tin moiety as the radical leaving-group was based upon several considerations. First, the work of Baldwin,50 Russell,46 and Keck47 has shown that this group is very effective as a leaving group in radical fragmentation reactions. Second, each of the vinylstannanes can be prepared in a stereochemically pure form from a common intermediate, following the procedure Me02C, .C02Me 48 RESULTS AND DISCUSSION 34 of Piers, Chong, and Morton.62 These researchers have developed reagents and reaction conditions to prepare alkyl (£)- and (Z)-3-trialkylstannyl-2-alkenoates via an addition reaction to the corresponding a,P-acetylenic ester. 2.1 SYNTHESIS OF METHYL (E)- AND METHYL (Z)-8-IODO-7.7-DIMETHYL-3- TRI(w-BUTYL)STANNYL-OCT-2-ENOATE (50 and 51). Our synthesis of the a,P-acetylenic ester 59, a common intermediate in the syntheses of 50 and 51, is illustrated in Scheme I. Starting with commercially available 3-bromo-l-propanol (52), the hydroxyl functionality was protected by conversion to the tetrahydropyranyloxy ether 53. Next, we introduced the ge/w-dimethyl group and extended the chain by two carbon atoms in one step, via a dianion alkylation reaction.63 Thus, the dianion of isobutyric acid was reacted with bromide 53 to give acid 54 in high yield. Because 54 decomposed slowly upon standing, it was reduced to the corresponding alcohol 55 immediately upon its isolation. The next step in the synthesis required that we convert the THP ether functionality of 55 into a suitable leaving group for a subsequent nucleophilic substitution reaction. Schwarz, RESULTS AND DISCUSSION 35 Scheme I. 59 i. DHP, /?-TsOH»H20, 95%; ii. isobutyric acid, LDA, 98%; iii. LiAlH 4, 77%; iv. Ph3P, Br2, 62%; v. DHP, p-TsOH'H20, 74%; vi. UCCH'EDA, 88%; vii. MeLi, CICOOMe, 97% et al. have reported that THP ethers are readily converted into the corresponding bromides by reaction with triphenylphosphine and bromine.64 Although hydroxyl groups can also be converted into bromides under these conditions, in this case we expected that the ge/H-dimethyl substituents (3 to the hydroxyl functionality would sufficiently retard this process such that protection of the alcohol would not be necessary at this stage. When compound 55 was RESULTS AND DISCUSSION 36 subjected to these conditions, two products were isolated. The first product, obtained in 62% yield, was the expected bromo-alcohol 56. To our surprise, the second product, obtained in 24% yield, was identified as compound 57, in which the THP ether of 55 had been converted into the bromide, and the unprotected hydroxyl group had been transformed into the THP ether. Before the bromide could be displaced, the hydroxyl group in 56 required protection. We decided to protect it as the THP ether 57, as we already had a significant amount of this compound from the side reaction mentioned above. The bromide in 57 was then displaced by reaction with lithium acetylide-ethylene diamine complex, following the procedure of Smith and Beumel,65 to give the alkyne 58 in 88% yield. Finally, alkyne 58 was deprotonated with methyllithium and the resulting anion acylated by reaction with methyl chloroformate, to give the a,P-acetylenic ester 59 in 97% yield. With the acetylenic ester now in hand, we proceeded to convert it to the cyclization precursors 50 and 51 following the procedure outlined in Scheme II. Following the method of Piers et al., 6 2 the a,p-acetylenic ester 59 was selectively transformed into both the (E)-vinylstannane 60 and the (Z)-vinylstannane 62 in separate reactions. Reaction of 59 at -78 °C with the (tri(rt-butyl)stannyl)copper-dimethyl sulphide reagent affords the kinetic product, 60, whereas reaction of 59 at -48 °C with lithium (phenylthio)(tri(«-butyl)stannyl)-cuprate affords the thermodynamic product, 62. The THP ethers of compounds 60 and 62 were hydrolyzed to afford the corresponding alcohols 61 and 63 in high yield. The final step required in the syntheses of 50 and 51 was the conversion of the hydroxyl groups of 61 and 63 to the corresponding iodides. Because of the neighbouring ge/w-dimethyl group, this conversion proved to be quite challenging. We investigated several possibilities, and found that the best yield was obtained via a two-step procedure, in which the alcohol was converted to the triflate, which was subsequently displaced RESULTS AND DISCUSSION 37 Scheme II. i. Bu3SnCu»SMe2, -78 °C, 88%; ii. p-TsOH'H20, 98%; iii. Tf 2 0, pyridine, then (ii) B114NI, 4>H, A, 93%; iv. [Bu3SnCuSPh]Li, -48 'C, 86%; v. />-TsOH*H20, 94%; vi. Tf 2 0, pyridine, then B114NI, 4>H, A, 88 %; RESULTS AND DISCUSSION 38 by reaction with tetra(n-butyl)ammonium iodide in refluxing benzene. In this manner the iodides 50 and 51 could be prepared from the alcohols 61 and 63 in yields of 85-95 %. 22. A D D m O N - r ^ G M T i N T A T I O N REACTIONS OF COMPOUNDS 50 A N D 51. With cyclization precursors 50 and 51 prepared, we were ready to investigate their reactivity under a variety of conditions for conducting free radical reactions. The first reaction we studied was the tin hydride mediated addition-elimination reaction of compound 50. A benzene solution of compound 50,1.0 equiv. of tri(/?-butyl)tin hydride, and a catalytic amount of AIBN was heated to reflux, and the reaction was monitored by T L C . After 2 hours T L C indicated no starting material remained, and the reaction mixture was allowed to cool to room temperature. After the benzene was removed by rotary evaporation, a pale yellow oil was obtained, which was purified by flash chromatography to give three products. The first product, isolated in 27% yield, was identified as the (Z)-vinylstannane 64, in which reduction rather than cyclization had occurred, and the double bond geometry was isomerized. The geometry of the alkene in 64 was assigned from the Jsn-H for the vinyl proton and tin. This coupling constant was 108 Hz, which is consistent with a trans relationship between the vinyl proton and tin. 6 6 The other two products were identified as the cyclic compounds 48 and 49, and were isolated in 15% and 10% yields respectively. The stereochemistry of the alkenes in these compounds was assigned by comparison of their *H NMR spectral data with that reported by Tumlinson et al. for the same compounds.61 The spectrum of compound 49 exhibited a one-proton singlet at 5 5.55 (the vinyl proton) and a RESULTS AND DISCUSSION 39 6 2.73 5 2.61 two-proton singlet at 6 2.61 (the methylene protons at C-2). This latter signal indicated a deshielding of the methylene at the 2 position of the ring due to the spatially adjacent carbomethoxy group. In contrast, the ] H NMR spectrum of the (£)-alkene 48 exhibited a one-proton singlet at 6 5.42 (the vinyl proton), and a two-proton triplet at 6 2.73 (the methylene protons at C-6). This latter signal is also in accord with a deshielding effect of the syn carbomethoxy group. The analogous methylene at C-2 of the (Z)-alkene 49 produced a triplet at 6 2.12. We next proceeded to vary the reaction conditions in an effort to improve the yield of cyclic product. We thought that by reducing the amount of tri(/i-butyl)tin hydride used in the reaction, the amount of reduction product 64 could be minimized, and therefore a higher yield of cyclic products might be obtained. Several reactions were conducted as described above, in which less than one equivalent of tri(/i-butyl)tin hydride was used. In all cases the reactions resulted in incomplete conversion of starting material, and analysis of the crude products by *H NMR indicated that a 1:1 ratio of reductiomcyclization products [64/(48+49)] was formed. The reaction proceeded to completion only when a minimum of one equivalent of tri(«-butyl)tin hydride was employed at the rjeginning of the reaction. At first it was somewhat perplexing that the reaction required an equivalent of tri(n-butyl)tin hydride to go to completion. Since the tri(n-butyl)tin radical is produced in the RESULTS AND DISCUSSION 40 fragmentation step, in theory only initiation is required to start a chain reaction which should result in complete reaction of the starting material. However, not all of the starting material is undergoing the addition-fragmentation sequence to liberate the chain-carrying tri(/z-butyl)tin radical. The reduction product 64, formed in approximately a 1:1 ratio with cyclization product, does not release the tri(n-butyl)tin group. Therefore, it was understandable that at least 0.5 equivalents of tri(/i-butyl)tin hydride would be required to compensate for the tri(n-butyl)tin group retained in the reduction product 64. In an effort to use the minimum amount of tri(w-butyl)tin hydride possible for complete conversion of starting material, we altered the reaction conditions. A solution of tri(/i-butyl)tin hydride in benzene was added dropwise to a refluxing benzene solution of compound 50 and a catalytic amount of AIBN, and the progress of the reaction was monitored by TLC. By performing the reaction in this manner, the amount of tri(n-butyl)tin hydride required for complete conversion of starting material could be reduced to 0.6-0.8 equivalents. When TLC analysis of the reaction mixture indicated an absence of compound 50, the reaction was stopped, and the products were isolated. The results of three reactions conducted in this manner are given in Table VI. Table VI. Reaction of Methyl (£)-8-iodo-7,7-dimethyl-3-tri(/i-butyl)stannyloct-2-enoate (50). Entry Yield(%) of 64 Yield(%) of 48 Yield(%) of 49 E : Z R a t i ° ° f ^ c l i c F m d a c ^ 1 54 26 17 60:40 2 48 37 2 95:5 3 47 29 7 80:20 * as determined by GC RESULTS AND DISCUSSION 41 Two features of these reactions are noteworthy. First, in all cases a substantial amount of the reduction product 64 was formed in the reaction, although none of the reduction product with an (£)-geometry about the alkene was observed. Second, the ratio of the stereoisomers 48 and 49 varied considerably, despite the fact that all of the reactions were performed under similar conditions. Although TLC analysis of the reaction mixture was sufficient to indicate when complete conversion of starting material had occurred, it did not provide us with any quantitative information on the stereoselectivity of the reaction as it progressed. Therefore, using pure samples of compounds 48 and 49, we developed GC conditions which allowed us to identify these compounds in a reaction mixture, and determine their relative amounts. Thus, by using GC analysis we were now able to determine the stereoselectivity of the reaction from initiation to completion. The reaction of compound 50 with tri(/i-butyl)tin hydride was repeated. As before, a benzene solution of tri(n-butyl)tin hydride was added dropwise to a refluxing benzene solution of compound 50 and a catalytic amount of AIBN. In this case, however, the progress of the reaction was monitored by GC analysis at 20 minute intervals. The results of this analysis are presented in Table VU. RESULTS AND DISCUSSION 42 Table VH. Ratio of Cyclic Products versus Time for the Tri(n-butyl)tin Hydride Mediated Reaction of Compound 50. Entry Time (min) Ratio of 48:49* 1 20 >98:1 2 40 74:1 3 60 52:1 4 80 29:1 5 100 24:1 6 120 7:1 7 140 4:1 *as determined by GC. The stereoselectivity was found to be very high at the beginning of the reaction, but as the reaction proceeded it rapidly diminished. The reaction was carried out several times. Although the final outcome varied, the overall trend was the same. The degree of stereoselectivity in the final products was disappointing, however the fact that the reaction initially was highly stereoselective was very encouraging. We suspected that the diminished stereoselectivity at longer reaction times was due to the initially formed product isomerizing under the reaction conditions. This suspicion was proven to be true by the following experiment. A benzene solution of tri(n-butyi)tin hydride was added 48 4 8 49 dropwise to a refluxing benzene solution of compound 48 and a catalytic amount of AIBN. The reaction mixture was monitored by GC, and after a total reaction time of two hours GC indicated RESULTS AND DISCUSSION 43 that a 1:1 mixture of compounds 48 and 49 was present. Thus, the cyclic product 48 does isomerize in the presence of AIBN and tri(n-butyl)tin hydride. We next turned our attention to the cyclization reaction of compound 51. A solution of tri(n-butyl)tin hydride was added dropwise to a refluxing benzene solution of compound 51 and a catalytic amount of AIBN. The reaction was monitored by GC and TLC. When TLC indicated an absence of starting compound 51 the reaction was stopped, and the products were isolated. The results of four of these reactions are presented in Table VIII. Table V m . Tri(«-butyl)tin Hydride Mediated Reaction of Compound 51. * " * « * . < % > < * « ™ a n ? i d 9 ( % ) %X 1 47 44 1:8 2 48 48 1:77 3 43 42 1:26 4 39 35 1:29 * as determined by GC. Several features of the tin hydride mediated reaction of compound 51 are noteworthy. First, approximately equal yields of the products of reduction (64), and cyclization (48 and 49) are obtained. Second, the reaction was found to proceed in a stereoselective manner, although the degree of stereoselectivity is variable. However, as was found in the reaction of compound 50, GC analysis of the reaction mixture over the course of the reaction indicates that initially the stereoselectivity is very high, but decreases over time. Again, this is likely due to the isomerization of the cyclic product after it is formed. In general, the overall stereoselectivity at the end of reaction was higher for compound 51 than for compound 50. This is probably due to RESULTS AND DISCUSSION 44 the fact that compound 51 reacted considerably faster than compound 50. Therefore, the overall reaction time for compound 51 is shorter, and consequently the extent of isomerization of the product is less. A typical time for complete reaction of 50 was 2 hours, in contrast to 1.25 hours for 51. Two significant problems in the reactions of compounds 50 and 51 became apparent from the results of these initial experiments. First, the desired cyclic products were obtained in only low to moderate yield, accompanied by a significant amount of the reduction product 64. Second, although the stereoselectivity of the reaction was initially very high, isomerization of the products during the course of the reaction resulted in only moderate control over the stereochemistry of the final products. For these reactions to be synthetically useful, both of these problems would have to be overcome. It was clear that to increase the amount of cyclized product in the reactions of 50 and 51, we would need to find a way to minimize the production of the reduction product 64. As was discussed in the introduction, it is not uncommon for reduction to compete with cyclization in a tin hydride mediated radical reaction, particularly if the cyclization reaction is slow. A common approach to overcome this problem is to maintain a low concentration of the tin hydride over the course of the reaction. In our case the tin hydride can be replaced by another source of the chain-carrying tri(«-butyl)tin radicals, as the cyclization products 48 and 49 do not require a hydrogen atom source for their formation, in contrast to the reduction product 64, which does. Thus, replacement of tri(/i-butyl)tin hydride with another source of trialkylstannyl radicals was expected to eliminate the formation of the reduction product, and hopefully result in an increased yield of cyclic products. The first alternative chain-transfer agent we employed was hexa(n-butyl)ditin, which is known to undergo photolytic dissociation to give tri(/i-butyl)tin radicals on irradiation with ultraviolet light.55'56 Following the method of Curran et al.,55>56 a solution of compound 50 and 0.2 equivalents of hexa(n-butyl)ditin in benzene was irradiated with a sunlamp, and the reaction was monitored by TLC and GC. As the reaction progressed, a large number of RESULTS AND DISCUSSION 45 products were formed, as evidenced by numerous spots on XLC. Analysis by GC did allow for the tentative identification of the cyclization products 48 and 49 in the mixture, but because of the large amount of by-products formed, it was not possible to isolate these materials and determine their yield. In an effort to find cleaner reaction conditions, a series of similar experiments with both compounds 50 and 51 were performed in which concentration, temperature and the amount of hexa(n-butyl)ditin used was varied. However, none of these reactions proved successful, and although GC analysis indicated that small amounts of compounds 48 and 49 were present in the reaction mixture, it was not possible to separate these compounds from the large amount of by-products. Similar difficulties with distannane photolysis have also been reported by Stork and Sher,30 and by Neumann et al. 6 7 In 1989 Neumann and co-workers reported new methods for the production of trialkyl tin radicals for use in synthesis,67 which are free from the drawbacks associated with distannane photolysis or tri(/i-butyl)tin hydride. One of the reagents they reported was bis(trimethylstannyl)benzpinacol (65), which can be prepared photochemically from benzophenone and hexamethylditin. Compound 65 is stable, and can be stored for prolonged Me 3 SnO OSnMe, hv,20'C | | • Ph2C—CPh2 65 O p hX^ sv p h + Me 3 SnSnMe 3 periods at low temperature. However, at temperatures above 60 °C, it irreversibly dissociates into benzophenone and trimethylstannyl radicals. O Me 3 SnO OSnMe 3 > 0 YJ ' C >L I I >» 2 Me 3Sn + 2 PrT T>h P h 2 C — C P h 2 65 RESULTS AND DISCUSSION 46 We prepared compound 65 and used it to mediate the cyclization reactions of compounds 50 and 51. In a typical experiment, a 0.03 M benzene solution of the vinylstannane 50 or 51 and 0.5 equivalents of compound 65 was warmed to reflux, and the reaction was monitored by TLC and GC. The results of these reactions are given in Table IX. The reactions are stereoselective, and as expected none of the reduction product 64 was detected. However, the yield of cyclic products was still only moderate, and no other identifiable products were isolated which could account for the low yield. Table LX. Bis(trimethylstannyl)benzpinacol Mediated Reactions of Compounds 50 and 51. Entry Cyclization Precursor of Cyclization (48 + 49) - r e l r ( ! L E:Z Ratio of Cyclic Products (48:49)* M e ° 2 C W ^ ^ ^ \ , 43 8:1 Me02C SnBu3 51 40 1:9 as determined by GC. As mentioned earlier, Stork and Sher have reported that the amount of reduction product in a tin hydride mediated radical cyclization reaction can be minimized by employing a catalytic trialkyltin halide/sodium cyanoborohydride system to generate the trialkyltin hydride.30 The mechanism of this reaction is illustrated in Figure 7. When a trialkyltin radical abstracts a halogen atom from an alkyl halide, an alkyl radical and a trialkyltin halide are produced The R E S U L T S A N D DISCUSSION 47 In-H R-X Bu 3 SnH Bu 3 SnX NaCNBH 3 Figure 7. The Mechanism of Stork's Trialkyltin Halide/Sodium Cyanoborohydride System for the In Situ Generation of Trialkyltin Hydride. sodium cyanoborohydride reduces the trialkyltin halide to the corresponding trialkyltin hydride, which after reaction with an initiator such as AIBN produces trialkyltin radical, and the cycle continues. An additional feature of this methodology is that the amount of trialkyltin species required for the reaction can be drastically reduced, as the trialkyltin halide produced in the reaction is recycled. We reacted compound 50 following Stork's procedure, with interesting results. A 0.04 M solution of compound 50,0.1 equivalents of tri(rc-butyl)tin chloride, 2.0 equivalents of sodium cyanoborohydride, and a catalytic amount of AIBN was prepared in dry r-butanol. This solution was heated to reflux, and the reaction was monitored by T L C . After 4 hours, T L C indicated an absence of starting material, and therefore the reaction was worked up, and the products were isolated. A 21:1 mixture of the cyclic products 48 and 49 was obtained in a combined yield of 19%. An 18% yield of the reduction product 64 was also isolated from this reaction. RESULTS AND DISCUSSION 48 The formation of approximately equimolar amounts of the reduction and cyclization products in this reaction was surprising, as it was expected that the low tin hydride concentration would disfavour the reduction pathway, and therefore cyclization would predominate. This led us to reconsider the mechanism by which the reduction product is formed. We had thought that 64 was formed directly, via a hydrogen atom abstraction by the initial alkyl radical, as shown in Figure 8. Although the geometry of the vinylstannane has isomerization w Me0 2 C SnBu 3 64 Figure 8. Intermolecular Mechanism for the Formation of Compound 64. changed from E to Z, this was attributed to isomerization of the initially formed reduction product under the reaction conditions, as the (Z)-isomer is known to be more stable.62 A report by Leonard and Livinghouse68 prompted us to consider another possible mechanism for the formation of 64. It is possible that the initial alkyl radical first abstracts a hydrogen atom intramolecularly, via a favourable 6-membered cyclic transition state, to give a stabilized allylic radical. This allylic radical may then abstract a hydrogen atom from tri(/j-butyl)tin hydride to give the reduction product 64. This mechanism is illustrated in Figure 9. RESULTS AND DISCUSSION 49 50 Figure 9. Intramolecular Mechanism for the Formation of Compound 64. To determine by which of the above two pathways the reduction product 64 was being formed, we performed a labelling experiment. A benzene solution of tri(n-butyl)tin deuteride was added dropwise to a refluxing benzene solution of compound 50 and a catalytic amount of AIBN. The reaction was monitored by TLC, and when no 50 remained the products were isolated. The *H NMR and 2 H NMR spectra of the reduction product 64 isolated from this experiment are shown in Figure 10 and Figure 11 respectively. The LK NMR spectrum (Figure 10) clearly shows that the reduction product isolated is the (Z)-vinylstannane, as evidenced by the tin-proton coupling constant of 108 Hz for the vinyl proton (5 6.37). This spectrum differs from the *H NMR spectrum of product 64 isolated from a tri(w-butyl)tin hydride mediated reaction in one important aspect. The signal at 6 2.34, assigned to the allylic protons, integrates for less than 2 protons, which may be indicative of deuterium incorporation at the allylic position. RESULTS AND DISCUSSION 50 I 1 1 1 ' | ' ' ' I I ' T I I | I I I I | I I I I | I I I I | I I I I | | I I I , . , I . , I I I , , I I I I I I I I I I I I I ! | | "| | | | ! | | | | | | 1 6 5 4 i 2 1 6 "Pit Figure 10. 300 MHz 'H NMR Spectrum of Compound 64 Isolated From the Tri(n-butyl)tin Deuteride Mediated Reaction of Compound 50. RESULTS AND DISCUSSION 51 The presence and position of deuterium in the product is readily determined from the 2 H NMR spectrum (Figure 11), in which two signals are clearly identified. The signal at 6 0.9 indicates the presence of deuterium in a methyl group, which is in accord with a direct reduction of the initial alkyl radical via abstraction of a deuterium atom from tri(n-butyl)tin deuteride. The signal at 6 2.3 is indicative of deuterium incorporation at the allylic position, which is in agreement with the *H NMR spectrum. The presence of deuterium at the allylic position is in accord with an intramolecular hydrogen atom abstraction of the initial alkyl radical to give an allylic radical, which subsequently abstracts a deuterium atom from tri(n-butyl)tin deuteride to give the reduction product 64. It is clear from the integration ratio of these two signals (ca. 4:1) that the intramolecular hydrogen abstraction pathway, leading to the allylic radical before reduction, is predominant. This explains why lowering the tin hydride concentration does not result in a significant increase in the amount of cyclization versus reduction product formed. The partitioning of the initial radical between cyclization and intramolecular hydrogen atom abstraction is independent of the tin hydride concentration. Because free radical reactions are known to be under kinetic control, there was still one possible change in reaction conditions which could alter the ratio of cyclization to reduction product formed. By lowering the temperature of reaction, greater selectivity between the two pathways would be expected. Although it is difficult to predict a priori which pathway would predominate at lower temperature, it was possible that the ratio of cyclization to reduction could improve. To conduct the reaction at low temperature, we required an alternative to thermal initiation. Unfortunately, the most common alternative, photochemical initiation, had proven to be unsuitable for compounds 50 and 51. A report by Barton et al., 6 9 as well as reports by Oshima and co-workers,70 brought to our attention a possible solution to this problem. These RESULTS AND DISCUSSION 52 researchers report that triethylborane, when reacted with air, will initiate a radical chain reaction over a wide temperature range. Using this initiation method, we investigated the reactions of compounds 50 and 51 over a range of temperature. A typical experiment was performed as follows. To a T H F solution of the radical precursor 50 or 51 and 0.75 equivalents of tri(/i-butyl)tin hydride at the reaction temperature was added 0.25 equivalents of triethylborane (1.0 M in hexanes). A sufficient volume of air (see Experimental section) was then slowly bubbled via syringe through the reaction mixture. The results of these reactions are given in Table X. Entry Table X . Low-Temperature Reactions of Compounds 50 and 51. Radical Precursor Yield (%) E: Z Ratio of „ Yield(%) Temp(°Q of Cyclization Cyclic Products of Reduction (48 and 49) (48 : 49) (64) 50 -78 no reaction 51 -78 no reaction 50 0 10 3:1 67 51 0 23 1:7 55 determined by G C . At -78 °C no reaction took place, even after prolonged reaction times, and with larger quantities of initiator. However, at 0 °C the reaction did proceed, although with disappointing results. Unfortunately, the temperature change was found to alter the ratio of cyclization to reduction in favour of the reduction product. RESULTS AND DISCUSSION 53 One final change in reaction conditions for compounds 50 and 51 was investigated. Tris(trimethylsilyl)silane, a tin hydride substitute developed by Chatgilialoglu et al.,3 4 was reported to be as effective a chain-transfer agent as tin hydride, but to be a poorer hydrogen atom donor. Although the reduction product 64 is formed primarily via an intramolecular hydrogen abstraction, the tri(n-butyl)tin deuteride mediated reaction discussed earlier had shown that approximately 20% of this product was formed as a result of deuterium atom abstraction from the tin deuteride by the initial alkyl radical. In theory, by using a poorer hydrogen atom donor this latter pathway to 64 could be avoided, and as a result a small increase in the yield of cyclization could be expected. The reactions of 50 and 51 with tris(trimethylsilyl)silane were performed as follows. To a refluxing benzene solution of the radical precursor 50 or 51 and 0.60 equivalents of tris(trimethylsilyl)silane was added 0.25 equivalents of triethylborane (1.0 M in hexane). A volume of air based upon the amount of triethylborane used (see Experimental section) was then bubbled through the reaction mixture. The reaction was monitored by GC and TLC, and when TLC indicated an absence of starting material, the products were isolated. The results of these reactions are given in Table XI. A slight increase in the yield of cyclization products was observed in these reactions. However, the effect of this reagent on the stereoselectivity of the reaction was much more significant. Both compounds 50 and 51 were observed to undergo completely stereoselective cyclization in the presence of tris(trimethylsilyl)silane. Thus, under these conditions the reaction is highly stereospecific, and no isomerization of the cyclic product occurs. RESULTS AND DISCUSSION 54 Table XI. Reaction of 50 and 51 with Tris(trimethylsilyl)silane. Entry Radical Precursor Yield (%) of 48 Yield (%) of 49 Yield(%) of Reduction (64) 1 Me02C _^ SnBu3 ' 50 ^ 48 0 41 2 Me02C SnBu3 ' 51 ' ^ I ^ o 55 40 2.3 AN ALTERNATIVE ROUTE TO COMPOUNDS 48 AND 49 When we planned our route to the cyclic products 48 and 49 we recognized that the (o-iodo-vinylstannanes 66 and 67 could also serve as suitable reactants in an addition-fragmentation reaction leading to these compounds. To determine if 66 and 67 offered any 49 67 RESULTS AND DISCUSSION 55 significant advantages over 50 and 51 as reactants in a radical addition-elimination sequence, we decided to prepare compound 67 and investigate its reaction under a variety of conditions. 2A SYNTHESIS OF METHYL (EV8-IOIX)-5.5-DlMETHYL-3- TRI(^BUTYDSTANNYLOCT-2-ENOATE (67). Our synthesis of compound 67 is outlined in Scheme III. Compound 55, which had been prepared previously en route to compounds 50 and 51, was used as the starting material for the synthesis. The subsequent steps in the synthesis are all straightforward, and very similar to those employed in the synthesis of compounds 50 and 51. Therefore, they will not be discussed in detail here. Scheme III. i. Tf20, pyridine, then BU4NI, <I>H, A, 86%; ii. LiCCH'EDA, 86%; iii. MeLi, CICOOMe, 92%; iv. Bu3SnCu»SMe2, -78 °C, 73%; v./?-TsOH»H20, 95%; vi. Ph3P, I2, 93%. RESULTS AND DISCUSSION 56 2.5 ADDmON-FRAGMENTATION REACTIONS OF COMPOUND 67. Our first experiment with compound 67 was a tri(«-butyl)tin hydride mediated reaction. A benzene solution of tri(/i-butyl)tin hydride was added dropwise to a refluxing benzene solution of compound 67 and a catalytic amount of AIBN. The reaction was monitored by GC and TLC, and when TLC indicated an absence of 67 the reaction was stopped. The crude product mixture obtained from this reaction was noticeably different from those obtained in the analogous reactions of compounds 50 and 51. The solution was brown, and when concentrated by rotary evaporation a dark-brown, viscous oil was obtained, in contrast to the pale yellow oil obtained from the reaction of compounds 50 and 51. The dark brown oil was purified by flash chromatography to give a 1.0:1.4 mixture of compounds 48 and 49, obtained in a combined yield of 36%. As in the reactions of 50 and 51, GC analysis of the reaction mixture over the course of the reaction indicated that the reaction was highly stereoselective, but the initially-formed cyclic product 49 was isomerizing under the reaction conditions. A third product, isolated in 18% yield, was identified as compound 73. The geometry of the alkene in this product was assigned from the Jsn-H for the vinyl proton and tin. This coupling constant was 67 Hz, which is in accord with a cis relationship between the vinyl proton and tin.66 The selectivity and yield of cyclic products obtained from the reaction of 67 was very similar to that obtained in the analogous reactions of compounds 50 and 51. However, it was interesting that the reduction product, 73, retained the (£)-geometry about the alkene. This suggested that 73 may not be the product of an intramolecular hydrogen atom abstraction, as the Bu3Sn 73 RESULTS AND DISCUSSION 57 resulting allylic radical would be expected to isomerize quickly to give the more stable (Z)-vinylstannane as the reduction product. To determine if 73 was the product of an allylic hydrogen atom abstraction similar to the ones observed for 50 and 51, we again performed a deuterium incorporation experiment, repeating the reaction as above except replacing tri(«-butyl)tin hydride with tri(n-butyl)tin deuteride. This gave a 14% yield of compound 73, in which the position of deuterium incorporation was determined by NMR spectroscopy. The 2 H NMR spectrum of 73 obtained from this experiment consisted of only one signal, at 6 0.89. This indicated that 73 was formed as a result of the initial, primary alkyl radical abstracting a deuterium atom from the tin deuteride, and not via an allylic hydrogen atom abstraction. Analysis of molecular models provides a possible explanation for why the radical generated from compound 73 does not undergo allylic hydrogen atom abstraction, whereas the radical generated from 50 does. Figure 12 illustrates the transition states for allylic hydrogen atom abstraction by both the radical generated from 50 and the radical generated from 67. A Radical generated Radical generated from 50 from 67 Figure 12. Transition States for Allylic Hydrogen Atom Abstraction for the Radicals Generated from Compounds 50 and 67 severe steric interaction between the gem-dimethyl group and the tri(n-butyl)tin moiety is present in the transition state for the radical generated from 67, which is not present for the radical RESULTS AND DISCUSSION 58 generated from 50. Therefore, it is understandable that the radical generated from 67 does not undergo such a reaction. The reaction of compound 67 with bis(trimethylstannyl)benzpinacol (65) was also investigated. A benzene solution of the oo-iodovinylstannane 67 and 0.5 equivalents of compound 65 was warmed to reflux, and the reaction was monitored by TLC and GC. As in the tin hydride mediated reaction described above, the crude product obtained from this reaction was a dark brown, viscous oil. Purification of this material provided a 34% yield of a 1.0:2.6 mixture (as determined by GC) of compounds 48 and 49. No other products were isolated. The final cyclization reaction of compound 67 investigated was performed following the conditions that gave the optimum yield and stereoselectivity for the analogous reactions of compounds 50 and 51. Thus, to a refluxing benzene solution of compound 67 and 0.60 equivalents of tris(trimethylsilyl)silane was added 0.25 equivalents of triethylborane (1.0 M in hexane). A volume of air based upon the amount of triethylborane used (see Experimental section) was then slowly bubbled through the reaction mixture. The reaction was monitored by GC and TLC. When TLC indicated an absence of starting material, the reaction was stopped. As in the other cyclization reactions of 67, the crude reaction mixture was a dark brown oil. Purification of this oil by radial chromatography gave only one product, isolated in 40% yield, which was identified as the cyclic product 49. Thus, the addition-fragmentation of compound 67 was also found to be highly stereoselective under these reaction conditions. Although intramolecular hydrogen atom abstraction was shown not to be significant in the reactions of compound 67, the yields of cyclic products was still disappointingly low. The dark brown colour of the crude reaction mixture, as well as a large amount of material appearing at the baseline of TLC analyses, indicated that other undesirable chain termination steps were competing with cyclization in the reactions of 67. One final radical cyclization approach leading to compounds 48 and 49 was investigated. The co-iodo-alkynyl ester 74 is also a suitable substrate for a free radical cyclization reaction leading to compounds 48 and 49. We prepared compound 74 in order to compare the RESULTS A N D DISCUSSION 59 M e 0 2 C — = ^ ^ ^ ^ ^ ^ 1 74 efficiency of its radical cyclization reaction with that of the radical addition-fragmentation reactions already performed. The cyclization of compound 74 was performed as follows. A solution of tri(/i-butyl)tin hydride was added dropwise to a refluxing benzene solution of compound 74, 1.3 equivalents of tri(n-butyl)tin hydride, and a catalytic amount of AIBN, and the reaction was monitored by GC. After 45 minutes GC analysis indicated no starting material remained. The reaction mixture was cooled, and then concentrated to give a pale yellow oil, which was purified by radial chromatography. This gave an 83% yield of a mixture of compounds 48 and 49, in a 1:1 ratio, as determined by GC and lH NMR. The cyclization of compound 74 is clearly much higher yielding than the addition-fragmentation reactions of compounds 50, 51, or 67. Also, the reaction was found to be much faster, which is explained by the fact that addition to the alkyne is facile compared to addition to the sterically-hindered vinylstannane. However, as expected the reaction of 74 was completely non-stereoselective, giving a 1:1 mixture of compounds 48 and 49. 2.6 ADDITION-FRAGMENTATION REACTIONS OF RADICALS GENERATED  FROM EPOXIDES. In 1988, Nugent and RajanBabu reported a new method for the generation of radicals for use in organic synthesis.71 This method, which does not involve a chain mechanism, is based upon analogy to the facile rearrangement of cyclopropylmethyl radical to homoallyl radical. As shown below, a cr-complex of an epoxide with a paramagnetic transition metal having an unpaired d-electron represents an electronic analogue to the cyclopropylmethyl moiety,71 and relief of ring strain drives the homolytic cleavage of the C-0 bond. RESULTS AND DISCUSSION 60 Nugent and RajanBabu have applied this reaction to the synthesis of cyclopentane derivatives.71 As shown in Figure 13, reaction of an epoxide with a titanium(III) reagent results in the homolytic cleavage of the C-0 bond, resulting in the formation of a secondary carbon-centered radical. This radical undergoes cyclization in the usual fashion, and after hydrolytic work-up a cyclopentane derivative bearing a hydroxy-methylene unit is obtained. Thus, this O Figure 13. Cyclization of a Radical Generated From an Epoxide by Reaction with Bis(cyclopentadienyl)titanium(in) Chloride.71 methodology offers one the opportunity to introduce additional functionality into the cyclic product, via subsequent reactions of the newly-formed hydroxyl group. To investigate the application of this methodology to addition-fragmentation reactions, we prepared the to-epoxy vinylstannanes 75 and 76, following the procedure outlined in Scheme IV. RESULTS A N D DISCUSSION t 61 Scheme IV. i. LiCCH'EDA; ii. MeLi, CICOOMe, 82%; iii. Bu3SnCu»SMe2,-78 °C, 96%; iv. wCPBA, 73%; v. [Bu3SnCuSPh]Li, -48 °C, 85%; vi. /wCPBA, 75%. Starting with 5-bromo-l-pentene (77), the alkyne was introduced by reaction with lithium acetylide-emylenediamine complex in DMSO, to give 78. This reaction was quite clean by TLC and GC analyses, but attempted isolation of 78 resulted in a deeply coloured bquid, and low yield. This could be avoided by not isolating the product. Instead, the reaction mixture was diluted with water, and extracted several times with THF. After drying over MgS04 these RESULTS AND DISCUSSION 62 extracts were used directly in the subsequent reaction with methyllithium and methylchloroformate. In this manner the alkynyl ester 79 could be prepared from 5-bromo-1 -pentene (77) in yields of 80-85 %. The alkynyl ester 79 was transformed into the (£)- and (Z)-vinylstannanes 80 and 81 as before, following the method of Piers et al.6 2 Finally, chemoselective epoxidation of the monosubstituted alkene in 80 and 81 afforded the desired epoxides 75 and 76 respectively. Compounds 75 and 76 were reacted with bis(cyclopentadienyl)titanium(III) chloride, prepared following the procedure of Manzer.71 In a typical reaction, a dark green solution of 2.0 molar equivalents of bis(cyclopentadienyl)titanium(III) chloride in THF was added to a colourless solution of the w-epoxy vinylstannane 75 or 76 in THF at room temperature. Immediately upon addition, a colour change from dark green to bright orange was observed. When TLC indicated an absence of starting material, the reaction was quenched, and the crude product was extracted and purified by radial chromatography. Table XII. Reaction of 75 and 76 with Bis(cyclopentadienyl)titanium(III) chloride. Entry Radical Precursor Product Yield RESULTS AND DISCUSSION 63 The results of the cyclizations of compounds 75 and 76 are summarized in Table XII. These reactions were found to be highly stereospecific, and result from an addition-elimination sequence which involves "retention" of the stereochemistry of the double bond. Analysis of the crude reaction products by GC shows that in each case only one stereoisomer is present; none of the other stereoisomer is observed. The reactions proceed smoothly at room temperature, and are typically complete in less than 30 minutes. Encouraged by these results, we decided to investigate the analogous reactions leading to the formation of 6-membered rings. For this study, we required the oo-epoxy vinylstannanes 89 and 90. Starting with 6-bromo-l-hexene (84), these compounds were prepared in a manner analogous to the preparation of compounds 75 and 76. The synthesis of 89 and 90 is outlined in Scheme V. RESULTS AND DISCUSSION 64 Scheme V. 84 85 r i. LiCCH'EDA; ii. MeLi, CICOOMe, 77%; iii. Bu3SnCu*SMe2,-78'C, 84%; iv. mCPBA, 72%; v. [Bu3SnCuSPh]Li, -48 °C, 82%; vi. /nCPBA, 72%. Compounds 89 and 90 were reacted under identical conditions to those employed for the successful cyclization of compounds 75 and 76. However, these reactions did not yield any of the desired cyclic compounds 91 or 92, even after prolonged reaction times. Instead, the only product obtained at room temperature was the corresponding acyclic alcohol, 93 or 94, resulting from reduction of the intermediate secondary radical. RESULTS AND DISCUSSION 65 not observed The retention of stereochemistry in the reduction product 93 indicates that this product is probably not formed via intramolecular allylic hydrogen atom abstraction, as isomerization of the intermediate allylic radical would be expected. Instead, it is more likely that the initially-formed radical abstracts a hydrogen atom from the solvent, as THF is known to act as a hydrogen atom donor in radical reactions.67 In an effort to promote cyclization, the reactions of compounds 89 and 90 were repeated in refluxing benzene. However, this change in reaction conditions did not lead to the formation of cyclic products. Instead, the product obtained from reaction of 89 or 90 with bis(cyclopentadienyl)titanium(III) chloride in benzene was the corresponding alkene, 87 or 88, resulting from deoxygenation of the epoxide. RESULTS AND DISCUSSION 66 It is not completely surprising that compounds 75 and 76 undergo cyclization, and compounds 89 and 90 do not Beckwith has shown that the rate of 6-heptenyl radical cyclization is considerably slower than that of 5-hexenyl radical cyclization.248-73 Consequently, the intermediate radical generated from 89 or 90, being slow to cyclize, preferentially follows a different, competing reaction pathway. It is well known that bulky substituents on an alkene retard the rate of radical addition to that alkene. Thus, the tri(/i-butyl)tin moiety in compounds 89 and 90 undoubtedly retards the rate of cyclization to some extent. Therefore, we investigated the use of a different substituent to serve as the radical leaving group. Alkyl (£)-3-trialkylstannyl-2-alkenoates can readily be converted to the corresponding alkyl (£)-3-iodo-2-alkenoates via reaction with iodine in CH2CI2. 7 4 Thus, we converted compound 89 into the corresponding vinyl iodide 95. 89% Russell and Ngoviwatchai46 have shown that iodine is a suitable leaving group for a radical addition-fragmentation reaction. It was hoped that substitution of the tri(n-butyl)stannyl RESULTS AND DISCUSSION 67 group with the comparatively less sterically demanding iodine would result in an increased rate of cyclization. A solution of bis(cyclopentadienyl)utanium(III) chloride in THF was added to a THF solution of compound 95, and the reaction was monitored by TLC. When TLC indicated an absence of starting material, the products were isolated. No cyclic products were isolated. Instead, only a mixture of compounds 96 and 97 were obtained. Thus, substitution of the tri(n-butyl)stannyl group with iodine did not overcome the problem of the slow rate of cyclization. 2.7 ADDrTION-FRAGMENTATIQN REACTIONS OF RADICALS GENERATED  FROM ALDEHYDES. Several methods exist for the generation of carbon-centered radicals from aldehydes. For example, Enholm and Prasad75 have reported the reaction depicted in Figure 14, in which reaction of tri(/j-butyl)tin hydride with the aldehyde 98 results in the formation of an intermediate carbon-centered radical, 99. Radical 99 undergoes an addition reaction to the activated alkene, followed by abstraction of a hydrogen atom, to yield the cyclic intermediate 100, and after work-up compound 101 is obtained, which bears a hydroxyl group on the newly-formed ring. RESULTS AND DISCUSSION 68 C0 2 CH 3 101 Figure 14. Intramolecular Cyclization of a Radical Generated from an Aldehyde.75 To investigate the use of aldehydes as radical precursors for addition-fragmentation reactions, we prepared compounds 102 and 103. 102 103 The synthesis of compound 102 is outlined in Scheme VI. Starting with commercially available 5-hexyn-l-ol (104), the alcohol was protected as the corresponding THP ether 105 via reaction with dihydropyran and />-toluenesulphonic acid monohydrate. The alkyne in 105 was then deprotonated with methyUithium, and the resulting anion acylated by reaction with methyl chloroformate to give the a.P-alkynyl ester 106 in high yield. Compound 106 was converted to the corresponding (£)-vinylstannane 107 following the procedure of Piers et al.6 2 The THP ether of 107 was hydrolyzed to afford the corresponding alcohol 108. Finally, Swern oxidation76 of alcohol 108 gave the desired aldehyde 102. RESULTS AND DISCUSSION 69 Scheme VI. 108 102 i. /?TsOH»H20, DHP, 98%; ii. MeLi, CICOOMe, 99%; iii. Bu3SnCu*SMe2, -78 °C, 87%; iv./?TsOH'H20, MeOH, 94%; v. DMSO, C1COOCC1, Et3N, 96%. The first addition-fragmentation reaction of compound 102 was carried out following the conditions described by Enholm and Prasad.75 A solution of compound 102 in benzene (0.10 M) with AIBN (0.01 equiv.) and tri(/i-butyl)tin hydride (1.50 equiv.) was heated to reflux, and the reaction was monitored by TLC and GC. After 2.5 hours, GC indicated an absence of compound 102. Therefore, the reaction was stopped, and the products were isolated. A 1:1 mixture (as determined by *H NMR) of the cyclic products 109 and 110 was obtained in a combined yield of 19%. However, the major product, isolated in 61 % yield, was identified as the aldehyde 103, which has a (Z)-geometry of the vinylstannane. This indicated that isomerization of the (£)-vinylstannane 102 to the more stable (Z)-vinylstannane 103 occurs faster than cyclization. RESULTS AND DISCUSSION 70 Me0 2C, ,C02Me .H Me0 2 C 109 110 103 To determine approximately how fast isomerization of the (£)-vinylstannane to the (Z)-vinylstannane occurs under these reaction conditions, a separate experiment was performed. A solution of compound 107 in benzene (0.10 M) with AIBN (0.01 equiv.) and tri(n-butyl)tin hydride (1.50 equiv.) was heated to reflux, and the reaction was monitored by GC. Within two hours, GC indicated that none of compound 107 remained. The reaction mixture was concentrated and purified by flash chromatography to give the (Z)-vinylstannane 111 in 96% yield. Me0 2 C / X Bu3SnH . ^ ^ v . . 0 . The reaction of compound 102 was repeated as before, except the reaction time was extended until GC analysis indicated that neither aldehyde 102 nor aldehyde 103 was present in the reaction mixture. Purification of the crude reaction mixture afforded a 3:1 mixture of the cyclic products 109 and 110 in a combined yield of 77%. Because aldehyde 102 isomerizes to 103 over the course of the reaction, the ratio of cyclic products 109 and 110 obtained is not an accurate reflection of the stereoselectivity of the addition-fragmentation reaction. Also, it seemed likely that the products of the reaction, the O-stannyl compounds 112 and 113 shown below, would also isomerize under the reaction conditions, thereby affecting the ratio of 109 and 110 obtained. AIBN, A benzene Me0 2 C 107 111 RESULTS AND DISCUSSION 71 112 113 To determine if isomerization of the products was occurring, the reaction was repeated. In this case, however, when GC indicated an absence of aldehydes 102 and 103 in the reaction mixture, the reaction was not immediately stopped. Instead, reflux was maintained for an additional 2 hours. The reaction was then worked up and purified to give compound 109 exclusively, in 72% yield. The reaction of compound 102 was carried out several times, and the dependence of the stereoselectivity on reaction time was shown to be reproducible. Thus, at short reaction times (less than 6 hours) ca. 1:1 mixtures of 109 and 110 were obtained, whereas at longer reaction time (greater than 8 hours) only the (£)-isomer 109 was isolated. Thus, this shows that isomerization of the products does occur. To investigate the addition-fragmentation reaction of the (Z)-vinylstannane 103 under these reaction conditions, we prepared this compound as shown in Scheme VII. Scheme VII. 114 103 i. Bu3SnH, AIBN, 96%; ii. />-TsOH'H20, MeOH, 93%; iii. DMSO, QCOOCCl, Et3N, 95% RESULTS AND DISCUSSION 72 Compound 107 was isomerized to compound 111 as discussed earlier. Hydrolysis of the THP ether in 111 afforded the corresponding alcohol 114, which was subsequently converted to the aldehyde 103 in high yield via Swem oxidation.76 Compound 103 was also reacted following the procedure described by Enholm and Prasad.75 A solution of compound 103 in benzene (0.10 M), with AIBN (0.01 equiv.) and tri(«-butyl)tin hydride (1.50 equiv.), was heated to reflux, and the reaction was monitored by TLC and GC. The results of three reactions conducted in this manner, in which the total time of reaction was varied, are presented in Table XIII. Table XIII. Tri(n-butyl)tin Hydride Mediated Reactions of 103. i w r i ^ n i w Yield (%) of E:Z Ratio of Entry Reaction lime Cyclic Products Cyclic Products (nours) (109+110) (109:110)* 1 5 85 36:64 2 6 83 58:42 3 8 76 >95:<5 *as determined by *H NMR. Several features of these reactions are noteworthy. First, as expected no isomerization of compound 103 to 102 was observed in these reactions, and analysis of the reaction mixture by GC indicated that complete conversion of starting material had taken place after a total reaction time of 5 hours. Isolation of the products at this time (Entry 1, Table XIII) shows that the addition-fragmentation reaction of 103 is modestly stereoselective, favouring the (Z)-isomer 110. However, at longer reaction times the stereoselectivity changes in favour of the (£)-isomer 109, and after a total reaction time of 8 hours, 109 is obtained almost exclusively. In an effort to find reaction conditions which do not cause isomerization of starting materials or products, we investigated other methods of generating radicals from aldehydes. The RESULTS AND DISCUSSION 73 first alternative method we tried is based on the one-electron reduction of aldehydes to ketyls, via reaction with samarium(II) iodide. Several research groups have reported successful samarium(II) iodide promoted coupling reactions of aldehydes and ketones with a,P-unsaturated esters.77 For example, Enholm and Trivellas77* have reported the reaction depicted in Figure 15. C0 2 CH 3 H 53% 17% Figure 15. Samarium(II) Iodide Promoted Coupling Reaction of an Aldehyde and an a,P-Unsaturated Ester.77a A report by Fukuzawa et al . 7 7 e suggests that the mechanism of this reaction is as illustrated in Figure 16. The reaction proceeds via one-electron reduction of the aldehyde to a radical-radical coupling Figure 16. Mechanism for Samarium(II) Iodide Promoted Coupling Reaction of an Aldehyde and an a.p-Unsaturated Ester.77e RESULTS AND DISCUSSION 74 ketyl, with subsequent coupling of this to an allylic radical resulting from a one-electron transfer from Sm2 + to the a,P-unsaturated ester. It should be noted that for successful application of this method to an addition-fragmentation reaction of compound 102 or 103, it is necessary that the samarium(LT) iodide reduction be chemoselective. Preferential reduction of the aldehyde in the presence of the P-stannyl-a,P-unsaturated ester must occur. Several reactions of both compound 102 and 103 with samarium (II) iodide were carried out, in which temperature, concentration, solvent, amount of samarium(II) iodide employed, and reaction time were varied. However, in all cases only a mixture of unidentifiable products was obtained. Analysis of the crude reaction mixtures by *H NMR and IR spectroscopy indicated that both the ester functionality and the aldehyde functionality were not present in the products, as the characteristic signals for these groups were absent. During the course of this work, Shim et al.78 reported the successful samarium(II) iodide promoted cyclization reaction shown in Figure 17. Intramolecular coupling of the aldehyde and the ot,P-alkynyl-ester in 115 gave the (£)-exocyclic alkene 116 in 65% yield. Figure 17. Samarium(II) Iodide Promoted Intramolecular Coupling of an Aldehyde and an a,P-Alkynyl Ester.78 Another method for the generation of carbon-centered radicals from carbonyl compounds has been reported by Corey and Pyne.79 They note that reaction of a ketone with zinc, in the presence of trimethylsilyl chloride (TMS-C1), results in electron-transfer and silylation to give an a-trimethylsilyloxy radical, which adds to a 6,e-multiple bond to form a 5-membered ring, as shown below. RESULTS AND DISCUSSION 75 Following Corey and Pyne's procedure,79 we reacted compounds 102 and 103 with zinc and TMS-C1. In a typical reaction, a solution of compound 102 or 103 in THF (0.05 M), with 20 equivalents of zinc, and 6 equivalents of TMS-C1, was heated to reflux and monitored by GC and TLC. After 24 hours, the reaction was worked up, and the crude product was purified by radial chromatography. The results of these reactions are given in Table XTV. Table XIV. Reaction of 102 and 103 with Zinc and TMS-C1. Entry Cyclization Precursor Product Yield(%) 103 109 The reaction was found to be stereoselective, giving exclusively the (Zs)-isomer 109, regardless of the stereochemistry of the starting vinylstannane. In this case, however, it does not appear that this stereoselectivity is due to isomerization of the product. No isomerization of RESULTS AND DISCUSSION 76 compound 102 to 103 was observed when the reaction mixture was analyzed by GC, and even at short reaction time none of the (Z)-isomer 110 was detected. Instead, it appears that because of the bulky trimethylsilyloxy substituent, the addition-fragmentation reaction of the (Z)-vinylstannane 103 yields the (£)-exocyclic alkene 109 as a result of bond rotation in the intermediate radical, as shown below. 103 . .,C02Me Bu3Sry \ ^arm^ / N y ^ O T M S Me0 2 C Bu3Srv Me0 2 C TMS -Bu3Sn OTMS 2.8 ADDITION-FRAGMENTATION REACTIONS OF SECONDARY ALKYL  RADICALS. For our first investigation of the addition-fragmentation reactions of secondary alkyl radicals, we chose to study the reactions of compounds 117 and 118, shown below. Me0 2 C 117 Me0 2 C SnBu3 j 118 Compounds 117 and 118 were readily prepared from the corresponding aldehydes 102 and 103, as outlined in Schemes VIII and IX. RESULTS AND DISCUSSION 77 Scheme VIII. 117 i. MeMgCl, 75%; ii. (a) p-TsC\, DMAP, Et3N, then (b) B 1 1 4 N I , <I>H, A, 88%. Scheme IX. 11 fc Me02C SnBu3 j 118 i. MeMgCl, 72%; ii. (a) />-TsCl, DMAP, Et3N, then (b) BU4NI, <*>H, A, 82%. We investigated the reactions of compounds 117 and 118 under a variety of conditions. The results for the reactions of compound 117 are presented in Table XV. RESULTS AND DISCUSSION 78 Table XV. Radical Addition-Fragmentation Reactions of Compound 117. Entry Chain Transfer Reagent Initiator Temp (°Q Solvent E:Z Ratio8 (121:122) Yield(%) 1 Bu3SnHb AIBN6 80 96:4 80 2 (TMS)3SiHb AIBNe 80 4>H 98:2 84 3 (TMS^SiH* EtaB/ar/ 25 4>H 88:12 91 4 <P2SiH2d Et3B/airf 0 THF 89:11 88 5 (TMS)3SiHc £136/31/ -78 THF 88:12 90 6 d)2SiH2d Et3B/airf -78 THF 90:10 87 a as determined by GC. b 1.3 equiv. c 0.25 equiv. d 1.1 equiv. e 0.01 equiv. f 0.25 equiv. In addition to reaction with tri(n-butyl)tin hydride and tris(trimethylsilyl)silane, the reaction of compound 117 was also studied with the chain-transfer reagent diphenylsilane. Barton et al. have recently reported that diphenylsilane is very similar in reactivity to tris(trimethylsilyl) silane.69 The addition-fragmentation reactions of compound 117 were found to be stereoselective, favouring the (£)-exocyclic alkene 121 over the (Z)-isomer 122. A dramatic difference in 121 122 RESULTS AND DISCUSSION 79 the length of time required for complete reaction of compound 117 was observed, depending on the method of initiation used. The reactions initiated with AIBN at 80 *C required 1-2 hours for completion, whereas the reactions initiated with triethylborane and air were complete in less than 10 minutes, even at -78 °C. All of the reactions proceeded in high yield, and compounds 121 and 122 were the only products isolated. Encouraged by these results, we turned our attention to the addition-fragmentation reactions of compound 118. The results of these reactions are presented in Table XVI. Table XVL Radical Addition-Fragmentation Reactions of Compound 118. Entry Chain Transfer Reagent Initiator Temp (°C) Solvent E:Z Ratio* (121:122) Yield(%) 1 Bu3SnHb AIBN6 80 <PH 84:16 83 2 (TMS)3SiHc Et3B/airf 25 <I>H 42:58 86 3 <P2SiH2 Et3B/airf 25 <£H 40:60 80 4 <I>2SiH2 E^B/aii* 0 THF 45:55 75 5 (TMS)3SiHc Et3B/airf -78 THF 46:54 83 6 4>2SiH2 Et3B/airf -78 <*>CH3 45:55 84 7 <J>2SiH2 Et3B/airf -98 THF 41:59 81 as determined by GC. b 1.3 equiv. c 0.25 equiv. d 1.1 equiv. e 0.01 equiv. f 0.25 equiv. Except for the tri(n-butyl)tin hydride mediated reaction (Entry 1, Table XVI), the addition-fragmentation reactions of compound 118 were found to be only marginally RESULTS AND DISCUSSION 80 stereoselective, favouring the (Z)-exocyclic alkene 122. However, when compared to the stereoselectivity obtained in the reactions of compound 117, it is clear that the geometry of the vinylstannane does have an effect on the stereoselectivity of the reaction. We suspected that the low stereoselectivity in forming the (Z)-isomer 122 was due to isomerization of this product under the reaction conditions. This suspicion was shown to be true in a separate experiment. A benzene solution of compound 122 (0.02 M), 1.0 equivalent of tri(/i-butyl)tin hydride and a catalytic amount of AIBN was heated to reflux. After one hour, GC analysis indicated that a 98:2 mixture of compounds 121 and 122 was present in the reaction mixture. Bu3SnH, AIBN benzene, A 122 121 The reactions of compound 118 indicate that the methyl substituent on the ring does have a significant effect on the stereoselectivity of the reaction. This can be understood by considering the individual steps in the reaction of compound 118, as shown below. RESULTS AND DISCUSSION 81 . ^C0 2Me Bu3Srv I }<annpa*{ M e 0 2 C v BuaSrv^ Me0 2C 123 -Bu3Sn +Bu3Sn 124 121 ,C02Me -Bu3Sn* +Bu3Sn* Abstraction of the iodine atom in 118 affords a secondary alkyl radical, which adds to the vinylstannane to give the cyclic radical 123. Elimination of tri(/j-butyl)tin radical from 123 gives the (Z)-exocyclic alkene 122 as the product. However, there is a steric interaction between the methyl group and the ester moiety in 123, which is alleviated by bond rotation to give the more stable rotamer 124, and elimination of tri(n-butyl)tin radical from 124 gives the (£) -exocyclic alkene 121. Another possible route to compounds 121 and 122 involves a radical cyclization of an a,fj-alkynyl ester. To compare this route to the addition-fragmentation reactions already performed, we prepared compound 128, as shown in Scheme X. The synthesis of 128 starts with compound 106, which was prepared previously, enroute to compounds 117 and 118. The reactions involved are analogous to those used in the preparation of 117 and 118, and therefore will not be discussed in detail here. RESULTS AND DISCUSSION 82 Scheme X. Me02C I 128 i. /*-TsOH*H20, MeOH, 93%; ii. DMSO, C1COOCC1, Et3N, 98%; iii. MeMgCl, 78%; iv. p-TsCl, DMAP, E13N, then B114NI, <I>H, A, 88%. The free-radical cyclization reaction of compound 128 was performed under a variety of reaction conditions, and the results of these reactions are presented in Table XVII. Interestingly, the stereoselectivity obtained in these reactions varies significantly, and depends on the conditions employed. The varying stereoselectivity in these reactions can be understood if one considers the individual steps in the reaction, as depicted in Figure 18. Abstraction of the iodine atom from 128 affords the secondary alkyl radical 129. Addition of this radical to the alkyne gives a vinyl radical, which can exist in two isomeric forms, 130 and 131. The final step required in the reaction is the abstraction of a hydrogen atom from the reducing agent, R-H [tri(/j-butyl)tin hydride or tris(trimethylsilyl)silane)]. For reduction of the isomeric form 130, which leads to the (£)-exocyclic alkene 121, the reducing agent must approach the molecule from the side bearing the methyl group. This is disfavoured because of a severe steric interaction between the bulky reducing agent and the methyl group. RESULTS AND DISCUSSION 83 Table XVH. Radical Cyclization Reactions of Compound 128. Entry Chain Transfer Reagent Initiator Temp CQ Solvent E:Z Ratio* (121:122) Yield(%) 1 Bu3SnHb AIBN0 80 98:2 82 2 (TMS)3SiHb AIBN0 80 <PH 34:66 86 -3 Bu3SnHb Et3B/aird -78 THF 60:40 84 4 (TMS)3SiHb ^ ^, . d Et3B/arr -78 THF 11:89 85 a as determined by GC. b 1.3 equiv. c 0.01 equiv. d 0.25 equiv. 121 122 Figure 18. Radical Cyclization Mechanism for Compound 128. RESULTS AND DISCUSSION 84 However, for reduction of the isomeric form 131 leading to the (Z)-exocyclic alkene 122, the reducing agent approaches the molecule from the side opposite the methyl group. Therefore, in this transition state steric interaction between the bulky reducing agent and the methyl group is avoided. Thus, reaction of compound 128 with the very bulky reducing agent tris(trimethylsilyl)silane (Entries 2 and 4, Table XVII) results in a predominance of the (Z)-exocyclic alkene 122. However, reaction of 128 with tri(/i-butyl)tin hydride (Entries 1 and 3, Table XVII) results in a predominance of the (£)-exocyclic alkene 121. This is understandable, as it has already been shown that tri(/i-butyl)tin radical effects isomerization of 122 to 121. We also investigated the radical reactions leading to exocyclic alkenes on six-membered rings. For these studies, we prepared the vinylstannanes 132 and 133, shown below. The synthesis of compound 132 is outlined in Scheme XI. Oxy-mercuration of 6-bromo-l-hexene (134) gives the secondary alcohol 135 in high yield. Because the subsequent steps in the synthesis are all straightforward, and very similar to those employed in the syntheses of compounds 50 and 117 discussed earlier, they will not be discussed further here. RESULTS AND DISCUSSION 85 140 132 i. Hg(OAc)2, NaOH, NaBILj, 83%; ii. DHP, /T-TSOH'H 20, 93%; iii. LiCCH-EDA, 77%; iv. MeLi, CICOOMe, 99%; v. Bu3SnCu»SMe2, -78 °C, 85%; vi. /T-TSOH*H 20, 93%; vii. />-TsCl, DMAP, Et3N, then B114NI, <I>H, A, 84%. The synthesis of compound 133 is illustrated in Scheme XII. The (£)-vinylstannane 140, prepared in the synthesis of compound 132, was isomerized to the corresponding (Z)-vinylstannane 141 by reaction with tri(/i-butyl)tin hydride and AIBN in refluxing benzene. The hydroxyl group in 141 was then transformed into an iodide to give compound 133. RESULTS AND DISCUSSION 86 Scheme XII. Me02C S n B u a 133 i. Bu3SnH, AIBN, *H, A, 93%; ii. p-TsCl, DMAP, Et3N, then BU4NI, <*>H, A, 80%. Three addition-fragnientation reactions of compound 132 were performed. The results of these reactions are presented in Table XVLTI. Table XVITJ. Reactions of Compound 132. N U • T f Yield(%)of Yield(%)of Entry Chain Transfer Initiator Temp(°Q Cyclization Reduction Reagent (142) ( 1 4 3 ) 1 Bu3SnH Et3B/air 25 70 19 2 (TMS)3SiH Et3B/air 25 82 10 3 Bu3SnH Et3B/air 0 51 44 All of the reactions were conducted at a concentration of 0.02 M in 132, using 0.6 equivalents of the chain transfer reagent, and 0.25 equivalents of triethylborane/air. RESULTS AND DISCUSSION 87 The addition-fragmentation reactions of compound 132 were found to be highly stereoselective, giving the (£)-exocyclic alkene 142 as the only cyclic product, accompanied by varying amounts of the acyclic reduction product 143. The retention of alkene configuration in Me02C. 142 143 the reduction product 143 indicates that this product is not formed via an intramolecular allylic hydrogen atom abstraction, as isomerization of the resulting allylic radical would be expected. To compare the reactions of compound 132 to those of compound 133, two addition-fragmentation reactions of compound 133 were performed. Each of these were conducted at a concentration of 0.02 M in 133, using 0.6 equivalents of the chain transfer reagent, and 0.25 equivalents of triethylborane/air. The results of these reactions are presented in Table XLX. Table XIX. Reactions of Compound 133. . Yield of E:Z* Yield of Entry Cham Transfer initiator Temp(°Q Cyclization Ratio Reduction Reagent (142 + 144) (142:144) (145) 1 Bu3SnH Et3B/air 25 73 75:25 13 2 (TMS)3SiH Et3B/air 25 81 77:23 7 *as determined by GC. In contrast to the reactions of compound 132, the reactions of compound 133 exhibited poor stereoselectivity, producing a ca. 3:1 mixture of the cyclic products 142 and 144, accompanied by a small amount of the (Z)-reduction product 145. However, this poor RESULTS AND DISCUSSION 88 142 144 145 stereoselectivity was not unexpected. As was found in the reactions of compound 118 (Table XVI), the methyl substituent on the ring has a significant effect on the stereoselectivity of the reaction, resulting in the formation of a predominance of the (£)-exocyclic alkene. Based on analogy to the cyclization reactions of compound 128 discussed earlier (Table XVII and Figure 18), we expected that by carefully choosing the reaction conditions it would be possible to prepare compounds 142 and 144 stereoselectively, via cyclization reactions of the a,|3-alkynyl ester 146. To investigate this possibility, we prepared compound 146 as shown in Scheme XIII. Scheme XIII. 146 i./>-TsOH'H20, 92%; ii./>-TsCl, DMAP, Et3N, then BU4NI, 4>H, A, 87%. RESULTS AND DISCUSSION 89 Compound 146 was reacted under the optimum conditions found for the analogous reactions of compound 128 (Table XVII). The results of the reactions of compound 146 are presented in Table XX. Table XX. Radical Cyclization Reactions of Compound 146. Entry C ^ g ™ s f e r Initiator TempCQ Solvent ci^iUA) Yield(%> 1 Bu3SnH AIBN 80 d>H >98:2 79 2 (TMS)3SiH Et3B/air -78-25 THF 9:91 82 * as determined by GC. Reaction of compound 146 with 1.1 equivalents of tri(/i-butyl)tin hydride and a catalytic amount of AIBN in refluxing benzene resulted in the stereoselective formation of the (£)-exocyclic alkene 142 in 79% yield. Because it has been shown that isomerization of alkenes occurs under these reaction conditions, it was expected that the (£)-isomer would predominate in this reaction, as it is the more stable product Next, the reaction of compound 146 with tris(trimethylsilyl)silane at low temperature was investigated. A THF solution of compound 146 (0.02M) with 1.1 equivalents of tris(trimethylsilyl)silane was cooled to -78 °C, and 0.25 equivalents of triethylborane were added. A sample of dry air was slowly bubbled through the reaction mixture, and the reaction was monitored by GC. This analysis showed that the reaction was highly stereoselective, favouring the (Z)-exocyclic alkene 144. However, the reaction was very slow, and did not proceed to completion at -78 °C. Therefore, the reaction conditions were modified slightly. The reaction was set up as described above, and initiated at -78 °C with 0.25 equivalents of triethylborane/air. However, immediately after initiation, the reaction mixture was slowly warmed to 25 °C, over a period of approximately 45 minutes. Under these conditions the RESULTS AND DISCUSSION 90 reaction remained highly stereoselective, favouring the (Z)-isomer 144, and complete conversion of starting material was achieved within 45 minutes. The cause of the observed stereoselectivity in this reaction is attributed to selective reduction of the intermediate vinyl radical from the less sterically hindered side of the molecule, as was discussed earlier for the analogous reaction of compound 128 (Figure 18). Thus, by specific choice of reaction conditions, it is possible to prepare either compound 142 or compound 144 stereoselectively, from the same precursor. 2,9 CONCLUSION The intramolecular reactions of radicals with both (£)- and (Z)-3-tri(«-butyl)stannyl alk-2-enoates under non isomerizing conditions was found to be stereospecific, with the geometry of the resulting exocyclic alkene controlled by the geometry of the starting vinylstannane. Exocyclic alkenes with no ring substituents a to the double bond, 48 and 49, are formed in a highly stereospecific manner via this type of reaction. It was found that isomerization of the initially-formed product occurs under certain reaction conditions, and as a result the stereoselectivity obtained can be diminished This is most noticeable in the formation of the (Z)-isomer of exocyclic alkenes with ring substituents a to the double bond, such as 122 and 144. Exocyclic alkenes can also be formed via an addition reaction of a radical to an a,6-alkynyl ester. In the case of exocyclic alkenes with ring substituents a to the double bond, both the (£)- and the (Z)-isomers can be formed stereoselectively. Under non isomerizing conditions, with a bulky hydrogen-atom source, the (Z)-isomer is formed selectively, whereas under isomerizing conditions the (£)-isomer is the predominant product. RESULTS AND DISCUSSION 91 2.10 SUGGESTIONS FOR FUTURE WORK Because tri(n-butyl) stannyl radical can isomerize exocyclic alkenes, a substitute radical leaving group which does not isomerize alkenes should be sought. The work of Boothe et al. suggests that the phenylsulphinyl group may be a suitable alternative.80 It is possible that the yield of cyclic products, particularly in the case of six-membered rings, could be increased by substitution of the ester moiety with stronger electron-withdrawing groups, such as a nitrile or aldehyde functionality. These groups are known to significantly accelerate the rate of radical addition to an alkene (see Table IH). The use of chiral epoxides in the titanium-promoted radical addition-fragmentation reactions is also worthy of investigation. 92 CHAPTER HI EXPERIMENTAL 3.1 GENERAL Unless otherwise stated, all reactions were performed under a nitrogen atmosphere using flame-dried glassware. Cold temperature baths were prepared as follows: -98 °C (liquid N 2 -methanol), -78 °C (dry ice - acetone), -48 "C (dry ice - acetonitrile), -25 to -10 °C (dry ice -aqueous CaCl2),81 and 0 °C (ice - water). Anhydrous reagents and solvents were purified and prepared according to the procedure given in the literature.82 The low-boiling fraction (35-60 °C) of petroleum ether was used. Alkyllithium reagents were standardized by titration against diphenylacetic acid in THF and were obtained from Aldrich Chemical Co. Triethylborane was obtained as a 1.0 M solution in hexane from the Aldrich Chemical Co. For reactions initiated with triethylborane/air, 104 uL of air were used for each umol of triethylborane employed.69 Tri(/j-butyl)tin hydride and tri(n-butyl)tin deuteride were prepared from tri(n-butyl)tin chloride following the procedure of Kuivila and Beumel,83 bis(cyclopentadienyl)titanium(IIi) chloride was prepared following the procedure of Manzer,71 and copper (I) bromide - dimethyl sulphide complex was prepared following the procedure of House et a l . 8 4 Phenylthiocopper was prepared by the method of Posner et al., 8 5 as modified by Chong. 8 6 Bis(trimethyltin) and bis(trimethylstannyl)-benzpinacolate were prepared following the procedure of Hart87 Analytical gas-liquid chromatography (GC) was performed on a Hewlett-Packard model 5880A gas chromatograph, equipped with a split mode capillary injection system and a flame ionization detector, using 0.22 mm x 12m capillary columns with OV-101 (column A), Carbowax (column B) or DB-210 (column C) as the stationary phase. GC analyses were performed either isothermally, or with the following temperature program: 100 °C for 6 min, EXPERIMENTAL 93 then a temperature increase to 220 °C at a rate of 20 °C per min, and a final time of 10 min at 220 °C. Helium was used as the carrier gas in all cases. Preparative flash column chromatography88 was performed using silica gel 60,230-400 mesh, supplied by E. Merck Co. A solvent system was chosen such that the desired product had an Rf of approximately 0.35 on TLC. Radial chromatography was performed on a Harrison Chromatotron™ model 8924, using silica gel 60, PF254 with gypsum binder as the adsorbent. In the cases where Kugelrohr (short-path) distillation was performed, boiling points are given as the oven temperature in degrees Celsius, followed by the pressure in torr. Infrared (IR) spectra were recorded on a Bomem Michelson 100 FT-IR spectrometer using internal calibration. IR spectra were taken on the neat liquid between two NaCl plates of 3 mm thickness. Proton nuclear magnetic resonance spectra (*H NMR) were recorded in deuteriochloroform solutions on a Varian XL-300 (300 MHz) or a Bruker WH-400 (400 MHz) spectrometer. Chemical shifts are given in parts per million (ppm) on the 6 scale versus tetramethylsilane (6 0 ppm) or chloroform (5 7.27 ppm) as internal standards. Signal multiplicity, spin-spin coupling constants (where possible), and integration ratios are indicated in parentheses. The tin-proton coupling constants (Jsn-H) are given as an average of the coupling constants for the 1 1 7Sn and 1 1 9Sn isotopes, and are not included in determining the multiplicity of a signal. Deuterium NMR spectra were recorded in chloroform, using deuteriochloroform (5 7.24) as internal standard. Low and high-resolution electron impact mass spectral analyses were performed on a Kratos-AEI model MS 50 mass spectrometer. Only peaks with greater than 20% relative intensity or those which were analytically useful are reported. In cases of compounds with tri(n-butyl) stannyl groups the molecular weight determinations (high resolution mass spectrometry) were based on 1 2 0 Sn and were usually made on the (M+-C4H9) peak.89 An ionization potential of 70 eV was used in all measurements. EXPERIMENTAL 94 Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 pre-coated aluminum sheets. Visualization was achieved by irradiation with ultraviolet light at 254 nm and/or by spraying with anisaldehyde reagent ( a solution of 1 mL anisaldehyde, 5 mL cone. H2SO4, and 10 mL glacial acetic acid in 90 mL methanol) followed by heating. For products with exocyclic alkenes, only the optimal reaction conditions, based on yield and stereoselectivity, are presented here. Microanalyses were carried out at the microanalytical laboratory of the University of British Columbia Chemistry Department using a Carlo Erba Elemental Analyzer 1106. EXPERIMENTAL 95 3.2 l-Bromo-3-(tetrahydropyranyloxy)propane (53). 53 To a solution of 3-bromo-l-propanol (20.00 g, 144 mmol) and /Moluenesulphonic acid monohydrate (274 mg, 1.44 mmol) in 125 mL of CH2CI2 at 0 °C was added dihydropyran (14.4 mL, 158 mmol) dropwise. After addition was complete the cooling bath was removed and the solution stirred overnight. The reaction mixture was diluted with diethyl ether, washed twice with saturated NaHC03 solution and once with brine. The organic layer was dried (MgSC>4), filtered and concentrated by rotary evaporation to afford a pale yellow oil which was distilled (160-162 °C 10.04 torr) from a small amount of anhydrous K2CO3 to afford 29.78 g (95%) of 53 as a clear, colourless oil. GC (column B, 145 °C, isothermal) 100%, R j = 1.54 min. IR (neat, cm-l) 2917, 1448, 1350, 1275, 1196, 1126, 1079, 1030, 971, 906, 870, 814. IH NMR (CDC13, 300 MHz) 6 1.55 (m, 4 H), 1.75 (m, 2 H), 2.12 (m, J = 6 Hz, 2 H) 3.52 (m, 4 H), 3.85 (m, 2 H), 4.60 (m, 1 H). LRMS (m/z) 223 (8, M+), 221(8, M+), 85 (100), 56(35), 55(25), 41(60). HRMS calcd for C8H15O2 8 1 Br: 224.0237, found: 222.0247; calcd for CgHi50279Br: 222.0256, found: 222.0255. EXPERIMENTAL 96 3.3 2,2-Dimethyl-5-(tetrahydropyranyIoxy)pentanoic acid (54). 54 To a solution of diisopropylamine (24.9 mL, 178 mmol) in 150 mL of THF at -78 *C was added n-butyllithium (119 mL of 1.5 M in hexanes, 179 mmol) dropwise. Upon complete addition the solution was allowed to warm to 25 °C, and was stirred at this temperature for 30 min; it was then cooled to 0 °C and isobutyric acid (8.2 mL, 89 mmol) was added dropwise. The resulting solution was stirred at 0 °C for 15 min, then warmed to 25 °C and stirred for 45 min. It was again cooled to 0 °C and l-bromo-3-(tetrahydropyranyloxy)propane (53) (18.0 g, 80.7 mmol) in 20 mL THF was cannulated in dropwise, resulting in a cloudy solution. The solution was allowed to warm to 25 °C and was stirred overnight The reaction was quenched by the addition of 100 mL of 3N HC1. The layers were separated, and the aqueous layer was saturated with NaCl and extracted five times with ethyl acetate. The combined organics were washed once with brine and dried (MgSC>4). This was filtered and concentrated by rotary evaporation. Residual solvent was removed by pumping at 0.02 torr overnight to afford 18.15 g (98%) of 54 as a pale yellow oil. No further purification of this compound was performed prior to the next step in the synthesis. GC (column B , 120 "C, isothermal) >94% pure, R T = 2.01 min. IR (neat, cm*1) 3420-2905, 1714, 1475, 1370, 1150, 1020. lH NMR (CDC13,300 MHz) 6 1.31 (s, 6 H), 1.52 (m, 4 H), 1.80 (m, 3 H), 1.92 (m, 2 H), 3.38 - 4.10 (m, 4 H), 4.32 (t, J = 7 Hz, 2 H), 4.95 (m, 1 H). LRMS (m/z) 212 (0.4), 129 (96), 101 (25), 85 (100), 84 (36), 83 (63), 69 (44), 57 (59), 56 (51), 55 (89), 43 (48), 41 (81). EXPERIMENTAL 3.4 2,2-Dimethyl-5-(tetrahydropyranyloxy)pentan-l-ol (55). 97 A solution of LiAULj. (9.00 g, 237 mmol) in 300 mL THF was cooled to 0 °C, and 2,2-dimethyl-5-(tetrahydropyranyloxy)pentanoic acid (54) (18.2 g, 78.9 mmol) in 25 mL of THF was added dropwise. The cooling bath was removed and the mixture stirred at 25 "C for 3 h, at which time TLC indicated no 54 remained. The reaction mixture was cooled to 0 °C and quenched by the slow addition of saturated Na2SC>4 solution, resulting in the formation of a white precipitate. This mixture was filtered through a Biichner funnel and the precipitate was washed well with ethyl acetate. The filtrate was transferred to a separatory funnel, and the layers separated. The organic layer was washed consecutively with 100 mL of each of the following: 5% NaHCC»3 solution, water, and brine and dried (MgSCU). This was filtered and solvent removed by rotary evaporation to yield a yellow liquid which was purified by Kugelrohr distillation (120 °C / 0.05 torr) to afford 13.59 g (77%) of 55 as a clear, colourless oil. GC (column A, 150 °C, isothermal) 100%, RT= L92 min. IR (neat, cm-i) 3410, 2930, 1462, 1377, 1155, 1013. iH NMR (CDC13,300 MHz) 8 0.90 (s, 3 H), 0.92 (s, 3 H), 1.3 (m, 2 H), 1.5-1.9 (m, 8 H), 2.7 (s, 1 H, exchanges with D20), 3.32 (s, 1 H), 3.33 (s, 1 H), 3.35-3.85 (m, 4 H), 4.56 (m, 1 H) LRMS (m/z) 198 (2, M +-H 20), 115 (35), 101 (35), 97 (52), 85 (100), 57 (30), 56 (32), 55 (65), 43(36), 41(37). HRMS calcd for Ci 2H 230 3 (M+-l): 215.1647, found: 215.1656. EXPERIMENTAL 98 3.5 2^-Dimethyl-5-bromopropan-l-ol (56). Triphenylphosphine (23.00 g, 87.7 mmol) was dissolved in 75 mL of CH2CI2 and cooled to 0 °C. Bromine (4.40 mL, 85.1 mmol) was added dropwise to form a yellow suspension, which was stirred for 15 min before 2,2-dmethyI-5-(tetxahydropyranyloxy)pentan-l-oI (55) (5.60 g, 25.8 mmol) in 10 mL CH 2Cl2 was added dropwise. The cooling bath was removed and the reaction mixture was stirred at 25 °C for 2.5 h, at which time TLC indicated no 55 remained. The reaction mixture was diluted with C H 2 C 1 2 until a homogeneous solution was obtained. This was subsequently washed once with 25 mL of water, twice with 25-mL portions of 1 M NaOH, and once more with 25 mL of water, followed by drying (MgS04), filtration and solvent evaporation to afford a mixture of a colourless oil and a beige solid. This was diluted with 10% diethyl ether/pet. ether and filtered through a column of silica gel, which was further eluted with 10% diethyl ether/pet. ether. The filtrate was concentrated on the rotary evaporator and the residue was purified by flash chromatography, eluting with 10% diethyl ether/pet, ether, to afford 3.11 g (62%) of 56 as a clear, colourless oil, as well as 1.70 g (24%) of 57. Data for 56: GC (column A , 120 °C, isothermal) 100%, RT = 1.23 min. IR (neat,cm-l) 3390,2940, 1485, 1410, 1305, 1090. *H NMR (CDCI3, 300 MHz) 8 0.92 (s, 6 H), 1.4 (m, 2 H), 1.85 (m, 2 H), 3.2 (s, 1 H, exchanges with D2O), 3.38 (s, 2 H), 3.42 (t, J = 8 Hz, 2 H). LRMS (m/z) 195 (6, M+), 193 (6), 179 (5), 175 (5), 165 (32), 163 (32), 83 (70), 57 (23), 56 (34), 55 (100), 43 (62), 41 (77). HRMS calcd for C 7Hi 50 8 1Br: 196.0286, found: 196.0293; calcd for C 7Hi 50 7 9Br: 194.0306, found: 194.0294. 3.6 EXPERIMENTAL l-(Tetrahydropyranyloxy)-2,2-dimethy!-5-bromopentane (57). 99 57 Following the procedure described in section 3.3,2,2-dimethyl-5-bromopropan-l-ol (56) (7.70 g, 39.6 mmol) was converted to 57. The crude product was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether to afford 8.22 g (74%) of 57 as a clear, colourless oil. GC (column B, 160 °C, isothermal) 100%, RT = 1.99 min. IR (neat, cm-*) 2940, 1495, 1380, 1210, 1035. J H NMR (CDC13, 300 MHz) 6 0.92 (s, 3 H), 0.93 (s, 3 H), 1.45-1.85 (m, 9 H), 3.0 (d, J = 9 Hz, 1 H), 3.35-3.50 (m, 4 H), 3.85 (m, 1 H), 4.55 (m, 1 H). LRMS (m/z) 279 (1, M +), 277 (1), 179 (2), 177 (2), 97 (20), 85 (100), HRMS calcd for Ci2H230281Br: 279.0961, found: 279.0965; calcd for Ci2H230279Br: 278.0881, found: 278.0878. 3.7 EXPERIMENTAL 7-(TetrahydropyranyIoxy)-6,6-dimethylhept-l-yne (58). 100 58 Lithium acetylide-ethylenediamine complex (684 mg of 90% purity, 6.72 mmol) was suspended in 3.36 mL of dimethyl sulphoxide, and the suspension was stirred and cooled to approximately 5 °C. To this was slowly added l-(tetrahydropyranyloxy)-2,2-dimethyl-5-bromopentane 57 (1.50 g, 5.38 mmol) over a period of 20 min. The cooling bath was removed and the reaction was stirred at 25 °C for 2 hours. The reaction mixture was cooled to 0 °C and quenched by the slow addition of 35 mL of water. This was extracted four times with 30-mL portions of 1:1 diethyl ether/pet. ether, and the combined extracts were washed consecutively with water (30 mL) and brine (30 mL) and dried (MgS04). The organic extracts were filtered and concentrated to yield a pale yellow oil which was purified by flash chromatography, eluting with 2% diethyl ether/hexanes, to give 1.06 g (88%) of 58 as a clear, colourless liquid. GC (column B, 140 °C, isothermal) 100%, Rj = 2.14 min. IR (neat, cm"1) 3305, 2950, 2110, 1475, 1390, 1140, 1040, 890. *H NMR (CDC13, 300 MHz) 5 0.88 (s, 3 H), 0.90 (s, 3 H), 1.38 (m, 2 H), 1.5-1.7 (m, 7 H), 1.95 (t, J = 3 Hz, 1 H), 2.16 (dt, J = 3 Hz, 2 Hz, 2 H), 3.0 (d, J = 9 Hz, 1 H), 3.5 (m, 3 H), 3.72 (m, 1 H), 4.55 (m, 1 H). LRMS (m/z) 223 (4, M +-l), 209 (2), 115 (52), 101 (22), 85 (20), 81(86), 67 (100), 57 (58), 55 (91), 43 (77), 41 (92). HRMS calcd for C14H23O2 (M+-l): 223.1698, found: 223.1696. 3JJ EXPERIMENTAL Methyl 8-(tetrahydropyranyloxy)-7,7-dimethyl-2-octynoate (59). 101 59 A solution of 7-(tetrahydropyranyloxy)-6,6-dimethylhept-l-yne (58) (500 mg, 2.23 mmol) in 9 mL of T H F was cooled to -78 "C and methyllithium (2.0 mL of 1.4 M in hexanes, 2.8 mmol) was added dropwise. The resulting solution was stirred at -78 "C for 20 min, and then the cooling bath was changed to -20 °C, and the reaction mixture was stirred for a further 30 min. Methyl chloroformate (0.22 mL, 2.8 mmol) was then added dropwise, and the reaction mixture was stirred at -20 "C for 1 hour. The cooling bath was then removed and the reaction mixture was stirred at 25 °C for a further 1.5 h, at which point T L C indicated the reaction was complete. The reaction mixture was diluted with 30 mL of diethyl ether and washed twice with 20-mL portions of saturated NaHCC»3 solution, and dried (MgSC>4). This was filtered and concentrated to afford a pale yellow oil. Purification by flash chromatography, eluting with 5% diethyl ether/hexanes, afforded 610 mg (97%) of 59 as a clear, colourless oil, which was one spot by T L C . IR (neat, cm"1) 2920, 2240, 1713, 1405, 1270, 1075, 1005. ! H N M R (CDC1 3, 300 MHz) 8 0.88 (s, 3 H), 0.90 (s, 3 H), 1.35 (m, 2 H), 1.5-1.85 (m, 8 H), 2.3 (m, 2 H), 3.0 (d, J = 10 Hz, 1 H), 3.45 (d, J = 10 Hz, 1 H), 3.5 (m, 1 H), 3.75 (s, 3 H), 3.8 (m, 1 H), 4.55 (m, 1 H). L R M S (m/z) 281 (1, M M ) , 267 (12), 220 (2), 121 (22), 85 (100), 84 (42), 79 (26), 67 (32), 57 (28), 56 (30), 55 (80), 43 (36), 40 (56). H R M S calcd for C16H25O4: 281.1752, found: 281.1755. EXPERIMENTAL 102 3.9 Methyl (£^-8-(tetrahydropyranyloxy)-7,7-dimethyl-3-(tri(n-butyl)stannyl)-oct-2-enoate (60). A solution of bis(tri(n -butyl)tin) (0.66 mL, 1.3 mmol) in 10 mL of THF was cooled to 0 "C, and n -butyllithium (0.81 mL of 1.6 M in hexanes, 1.3 mmol) was added dropwise. The resulting solution was stirred at 0 °C for a further 20 min, and then cooled to -78 °C. Copper bromide-dimethyl sulphide complex (267 mg, 1.30 mmol) was added in one portion, and the resulting reddish-brownYeaction mixture was stirred for a further 30 min before the alkynyl ester 59 (282 mg, 1.00 mmol) in 3 mL of THF was added. The reaction mixture was stirred for 3 h and then diluted by the addition of 0.5 mL of ethanol, 5 mL of 20:1 saturated N H 4 C I : N H 4 O H , and 30 mL diethyl ether. The cooling bath was removed and the mixture was stirred overnight, open to the atmosphere. The layers were separated, and the aqueous phase was extracted three times with 5-mL portions of diethyl ether. The combined organics were washed with 10 mL of 20:1 saturated NH4CI : N H 4 O H solution and dried (MgSO*). After filtration and rotary evaporation a pale-yellow oil was obtained, which was purified by flash chromatography, eluting with 5% diethyl ether/pet. ether, to give 504 mg (88%) of 60 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 2940, 1718, 1540, 1465, 1210, 1015. IH NMR (CDCI3, 300 MHz) 6 0.90 (m, 21 H), 1.25-1.90 (m, 22 H), 2.82 (br m, 2 H), 2.98 (d, J = 9 Hz, 1 H), 3.45 (d, J = 9 Hz, 1 H), 3.5 (m, 1 H), 3.70 (s, 3 H), 3.85 (m, 1 H), 4.55 (m, 1 H), 5.92 (m, J S n -H = 66 Hz, 1 H). LRMS (m/z) 517 (12, M + - C 4 H 9 ) , 433 (95), 432 (38), 431 (72), 429 (40), 85 (100). HRMS calcd for C 2 4H45O 4 1 2 0 Sn (M+-C4Ho): 517.2339, found: 517.2343. 60 EXPERIMENTAL 103 3.10 Methyl (^ )-8-hydroxy-7,7-dimethyl-3-(tri(n-butyl)stannyl)-oct-2-enoate (61). Compound 60 (4.68 g, 8.17 mmol) was dissolved in 40 mL of methanol and p-toluenesulphonic acid monohydrate (156 mg, 0.82 mmol) was added. The resulting solution was stirred for 5 hours, at which time TLC indicated no 60 remained. The methanol was removed by rotary evaporation and the residue was dissolved in 100 mL of diethyl ether, washed consecutively with 20 mL of saturated NaHC03 solution and 20 mL of brine and dried (MgS04). Filtration and evaporation of solvent gave a clear oil which was purified by flash chromatography, eluting with 30% diethyl ether/pet. ether. This afforded 3.19 g (98%) of 61 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm'l) 3460, 2875, 1710, 1580, 1450, 1135, 1020. iH NMR (CDC13, 300 MHz) 6 0.9 (m, 21 H), 1.25-1.70 (m, 17 H), 2.82 (t, J = 6 Hz, 2 H), 3.32 (s, 2 H), 3.7 (s, 3 H), 5.95 (m, JSn-H = 66 Hz, 1 H). LRMS (m/z) 434 (20, M + -C4H 9 ) , 433 (98), 432 (38), 431 (82), 430 (38), 429 (28), 415 (58), 414 (24), 413 (35), 411 (22), 401 (50), 400 (22), 399 (38), 397 (22), 383 (26), 381 (20), 345 (40), 343 (22), 289 (35), 287 (31), 265 28), 235 (38), 233 (34), 231 (22), 179 (58), 177 (65), 175 (45), 151 (40), 149 (52), 147 (20), 135 (20), 121 (40), 55 (32), 41 (48). HRMS calcd for Ci9H37O 3 1 2 0Sn (M+-C4H 9): 433.1765, found: 433.1770. Me0 2 C "OH 61 EXPERIMENTAL 104 3.11 Methyl (£)-8-iodo-7,7-dimethyl-3-(tri(n-butyl)stannyl)oct-2-enoate (50). A solution of trifluoromethanesulphonic anhydride (0.69 mL, 4.1 mmol) in 6 mL of CH2Q2 was added dropwise to a -10 °C solution of pyridine (0.36 mL, 4.5 mmol) in 15 mL of CH2CI2, resulting in the formation of a thick white paste. This mixture was stirred for 10 min and alcohol 61 (1.00 g, 2.05 mmol) in 10 mL of CH2CI2 was added dropwise. The resulting yellow mixture was stirred at -10 °C for 1.5 h, and then poured into ice water and shaken. The aqueous layer was extracted twice with 20-mL portions of CH2Cl2, and the combined organics were dried (MgSCU). The extracts were filtered and solvent was removed by rotary evaporation. The residue was dissolved in hexanes and filtered through glass wool to remove a small amount of a yellow precipitate. The filtrate was concentrated to give 1.27 g of a pale yellow oil which was immediately dissolved in 40 mL of benzene. To this was added /1-BU4NI (1.51 g, 4.09 mmol), and the resulting solution was refluxed for 1.5 h, at which time TLC indicated the reaction was complete. The solvent was removed by rotary evaporation and the residue was triturated with hexanes to precipitate excess /1-BU4NI. The mixture was then filtered through Florisil, and the filtrate concentrated to give a pale yellow oil which was purified by flash chromatography, eluting with 2% diethyl ether/pet ether. This gave 1.15 g (93%) of 50 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"l) 2956, 1717, 1592, 1460, 1359, 1176, 869. *H NMR (CDCI3, 300 MHz) 8 0.90(t, J = 7 Hz, 9 H), 0.95 (m, 6 H), 1.05 (s, 6 H), 1.28-1.55 (m, 16 H), 2.82 (t, J = 8 Hz, 2 H), 3.15 (s, 2 H), 3.70 (s, 3 H), 5.95 (s, JSn-H = 66 Hz, 1 H). LRMS (m/z) 543( 8, M + - C4H9), 415 (32), 413 (24), 361 (100), 360 (32), 359 (75), 358 (30), 357 (45), 305 (40), 303 (32), 301 (22), 177 (20). HRMS calcd for Ci9H36O2l120Sn (M+-C4Ho): 543.0782, found: 543.0784. Me0 2 C, 1 50 EXPERIMENTAL 105 3.12 Methyl (Z)-8-(tetrahydropyranyIoxy)-7,7-dimethyl-3-(tri(n -butyI)stannyl)oct-2-enoate (62). 62 To a solution of bis(tri(n-butyl)tin) (6.60 mL, 13.1 mmol) in 100 mLof THF at 0 °C was added n-butyllithium (8.20 mL of 1.6 M in hexanes, 13.1 mmol) dropwise, and the resulting solution was stirred for 30 min at 0 "C. It was then cooled to -20 °C and phenylthiocopper (2.26 g, 13.1 mmol) was added in one portion. The now dark-red solution was stirred at 20 °C for 30 min and then cooled to -78 "C before the alkynyl ester 59 (3.08 g, 10.9 mmol) in 5 mL THF was added dropwise. This solution was stirred at -78 °C for 15 min, and then the cooling bath was changed to -48 °C and stirring was continued for a further 4 h. The reaction was diluted by the addition of 1.5 mL of ethanol and 150 mL of diethyl ether and allowed to warm to room temperature. The reaction mixture was filtered through a short column of Florisil, which was subsequently washed well with diethyl ether. The filtrate was concentrated to afford a yellow oil, which was purified by flash chromatography, eluting with 4% diethyl ether/pet. ether, to give 5.40 g (86%) of 62 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm-*) 2951, 1709, 1592, 1467, 1208, 1017,987. IH NMR (CDC13, 300 MHz) 5 0.92 (m, 21 H), 1.21-1.88 (m, 22 H), 2.35 (br m, 2 H), 2.96 (d, J = 8 Hz, 1 H), 3.46 (d, J = 8 Hz, 1 H), 3.50 (m, 1 H), 3.70 (s, 3 H), 3.82 (m, 1 H), 4.51 (m, 1 H), 6.41 (s, J S n-H = HO Hz, 1 H). LRMS (m/z) 517 (6, M+-C4H9), 433 (88), 432 (38), 431 (65), 430 (25), 429 (37), 85 (100), 59 (22). HRMS calcd for C24H45O 4 1 2 0Sn (M+-C4H9): 517.2339, found: 517.2337. EXPERIMENTAL 106 3.13 Methyl (Z)-8-hydroxy-7,7-dimethyI-3-(tri(n-butyI)stannyI)-oct-2-enoate (63). The tetrahydropyranyl ether 62 (2.24 g, 3.68 mmol) was converted to compound 63 following the procedure outlined in section 3.10. The crude oil was purified by flash chromatography, eluting with 25% diethyl ether/pet ether, to afford 1.69 g (94%) of 63 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 3442, 2904, 1708, 1578, 1447, 1020, 837. !H NMR (CDC13, 300 MHz) 5 0.88 (m, 21 H), 1.24-1.70 (m, 17 H), 2.34, (m, 2 H), 3.33 (s, 2 H), 3.70 (s, 3 H), 6.39 (s, JSn-H = 108 Hz, 1 H). LRMS (m/z) 434 (26, M+-C4H9), 433 (100), 432 (39), 431 (83), 430 (39), 429 (30), 415 (44), 414 (18), 413 (27), 401 (67), 400 (28), 399 (50), 383 (22), 345 (37), 235 (34), 121 (44), 55 (60). HRMS calcd for Ci9H3 7O31 2 0Sn (M+-C4H9): 433.1765, found: 433.1772. 'OH 63 EXPERIMENTAL 107 3.14 Methyl (Z)-8-iodo-7,7-dimethyl-3-(tri(n-butyl)stannyl)-oct-2-enoate (51). Me0 2 C SnBu 3 51 Alcohol 63 (1.00 g, 2.05 mmol) was converted into 51 following the procedure outlined in section 3.11. The crude product was purified by flash chromatography, eluting with 2% diethyl ether/pet. ether, to afford 1.08 g (88%) of 51 as a clear, colourless oil, which was one spot by TLC. IR (neat, cnr*) 2910, 1709, 1597, 1461, 1435, 1375, 1329, 1200, 1072, 876. *H NMR (CDC13, 400 MHz) 6 0.87 (t, J = 7 Hz, 9 H), 0.95 (m, 6 H), 1.20 (s, 6 H), 1.25-1.52 (m, 16 H), 2.37 (br m, 2 H), 3.15 (s, 2 H), 3.73 (s, 3 H), 6.39 (s, J S n-H = 108 Hz, 1 H). LRMS (m/z) 543 (20, M+-C4H9), 416 (20), 415 (100), 414 (40), 413 (78), 412 (30), 411(42). HRMS calcd for Ci9H 3 6O2 1 2 0SnI (M+- C4H9): 543.0782, found: 543.0787. EXPERIMENTAL 108 3 . 1 5 l - Iodo-2,2-dimethyl-5-(tetrahydropyranyloxy)pentane (68). c r o 68 Alcohol 55 (2.16 g, 1.00 mmol) was converted to 68 following the procedure outlined in section 3.11. The colourless liquid was purified by flash chromatography, eluting with 2% diethyl ether/pet. ether, to afford 2.80 g (86%) of 68 as a clear, colourless o i l . G C (column A , 150 °C, isothermal) 100%, RT = 3.60 min. IR (neat, cnr*) 2943, 1460, 1365, 1200, 1127, 1075, 1032, 872, 814. I H N M R (CDCI3, 400 MHz) 8 1.04 (s, 6 H), 1.39 (m, 2 H), 1.55 (m, 6 H), 1.73 (m, 1 H), 1.85 (m, 1 H), 3.17 (s, 2 H), 3.40 (m, 1 H), 3.52 (m, 1 H), 3.74 (m, 1 H), 3.89 (m, 1 H), 4.59 (m, 1 H). L R M S (m/z) 325 (6, M M ) , 97(22), 85(100), 55 (60), 41 (41). H R M S calcd for C12H23O2I: 326.0745, found: 326.0723. EXPERIMENTAL 109 3.16 4,4-Dimethyl-7-(tetrahydropyranyloxy)-l-heptyne (69). 69 Following the procedure outlined in section 3.7, the iodide 68 (2.00 g, 6.14 mmol) was converted to alkyne 69. The crude product was purified by flash chromatography, eluting with 5% diethyl ether/pet. ether, to afford 1.18 g (86%) of 69 as a clear, colourless liquid. GC (column A, 150 °C, isothermal) 100%, RT = 1.81 min. IR (neat, cm-1) 3304, 2906, 2120, 1450, 1345, 1240, 1113, 1030. IH NMR (CDC13, 400 MHz) 6 0.98 (s, 6 H), 1.35 (m, 2 H), 1.55 (m, 6 H), 1.68-1.88 (m, 2 H), 1.97 (t, J = 3 Hz, 1 H), 2.80 (d, J = 3 Hz, 2 H), 3.39 (m, 1 H), 3.51 (m, 1 H), 3.72 (m, 1 H), 3.88 (m, 1 H), 4.59 (m, 1 H). LRMS (m/z) 223 (0.2, M M ) , 209 (8), 101 (38), 85 (84), 84 (42), 83 (82), 81 (44), 67 (32), 57 (31), 56 (42), 55 (100), 43 (55), 41 (78). HRMS calcd for C14H23O2 (MM): 223.1698, found: 223.1695. EXPERIMENTAL 110 3.17 Methyl 5,5-dimethyl-8-(tetrahydropyranyIoxy)-2-octynoate (70). 70 Following the procedure outlined in section 3.8, alkyne 69 (2.00 g, 8.92 mmol) was converted to the a,|3-alkynyl ester 70. The crude product was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether, to afford 2.32 g (92%) of 70 as a clear, colourless oil. GC (column A, 180 °C, isothermal) 100%, Rj = 2.84 min. IR (neat, cm"1) 2916, 2234, 1716, 1446, 1258. !H NMR (CDC13, 400 MHz) 5 1.00 (s, 6 H), 1.36 (m, 2 H), 1.55 (m, 6 H), 1.72 (m, 1 H), 1.83 (m, 1 H), 2.23 (s, 2 H), 3.38 (m, 1 H), 3.51 (m, 1 H), 3.73 (m, 1 H), 3.76 (s, 3 H), 3.88 (m, 1 H), 4.58 (m, 1 H). LRMS (m/z) 281 (0.2, M M ) , 267 (10), 251 (10), 85 (100), 83 (32), 55 (34), 41 (22). HRMS calcd for C16H25O4 (MM): 281.1752, found: 281.1746. EXPERIMENTAL 111 3.18 Methyl 5,5-dimethyl-8-iodo-2-octynoate (74). C02Me 74 To a solution of triphenylphosphine (623 mg, 2.38 mmol) in 2 mL of CH2CI2 at 0 °C was added iodine (594 mg, 2.34 mmol), resulting in the formation of a yellow paste. The cooling bath was removed, and the tetrahydropyranyl ether 70 (200 mg, 0.71 mmol) in 1 mL of CH2C12 was added dropwise. The reaction flask was wrapped in aluminum foil and the reaction mixture was stirred overnight. It was then diluted with 25 mL of ethyl acetate and washed successively with 15-mL portions of water, 1 M NaOH, water and brine, and dried (MgS04). Filtration and evaporation of solvent yielded a brown oil which was purified by flash chromatography, eluting with 5% diethyl ether/pet. ether, to afford 167 mg (76%) of 74 as a pale yellow oil, which was one spot by TLC. BR (neat, cm"1) 2939, 2235, 1714, 1433, 1258, 1076, 751. !H NMR (CDCI3, 400 MHz) 5 1.00 (s, 6 H), 1.42 (m, 2 H), 1.92 (m, 2 H), 2.23 (s, 2 H), 3.17 (t, J = 7 Hz, 2 H), 3.75 (s, 3 H). LRMS (m/z) 308 (2, M+), 277 (38), 211 (100), 169 (65), 155 (80), 121 (98), 107 (46), 98 (80), 83 ( 97), 83 (95), 69 (60), 55 (99), 41 (98). HRMS calcd for C11H17O2I: 308.0275, found: 308.0282. EXPERIMENTAL 112 3.19 Methyl (£>3-(tri(n-butyl)stannyl)-5,5-dimethyl-8-(tetrahydropyranyIoxy)-oct-2-enoate (71). Me0 2 C Bu3Sn 71 The a,p-alkynyl ester 70 (500 mg, 1.75 mmol) was converted into 71 following the procedure outlined in section 3.9. The crude product was purified by flash chromatography, eluting with 6% diethyl ether/pet. ether, to afford 728 mg (73%) of 71 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm-*) 2930, 1720, 1582, 1454, 1360, 1257, 1174, 1018. J H NMR (CDC13, 400 MHz) 5 0.88-1.00 (m, 21 H), 1.26-1.88 (m, 22 H), 2.91 (s, Jsn-H=64 Hz, 2 H), 3.35 (m, 1 H), 3.50 (m, 1 H), 3.67 (s, 3 H), 3.71 (m, 1 H), 3.88 (m, 1 H), 4.58 (m, 1 H), 6.10 (s, JSn-H = 68 Hz, 1 H). LRMS (m/z) 517 (8, M+-C4H9), 433 (100), 432 (40), 431 (78), 430 (20), 429 (42), 85 (38). HRMS calcd for C24H45O4120Sn (M+-C4H9): 517.2340, found: 517.2339. EXPERIMENTAL 113 3.20 Methyl (£)-3-(tri(n-butyl)stannyl)-5,5-dimethyl-8-hydroxy oct-2-enoate (72). The tetrahydropyranyl ether 71 (700 mg, 1.22 mmol) was converted to the corresponding alcohol 72 following the procedure outlined in section 3.10. The crude product was purified by flash chromatography, eluting with 30% diethyl ether/pet. ether, to afford 567 mg (95%) of 72 as a clear, colourless oil, which was one spot by TLC. BR (neat, cm"1) 3385, 2918, 1718, 1582, 1455, 1360, 1256, 1170, 1030. *H NMR (CDC13, 400 MHz) 5 0.88-0.98 (m, 21 H), 1.26-1.62 (m, 17 H), 1.91 (s, J S n - H = 64 Hz, 2 H), 3.62 (t, J = 8 Hz, 2 H), 3.68 (s, 3 H), 6.11 (s, J Sn-H = 68 Hz, 1 H). LRMS (m/z) 433 (92, M + -C4H 9 ) , 432 (42), 431 (75), 430 (32), 429 (47), 401 (55), 400 (22), 399 (44), 397 (24), 345 (59), 344 (20), 343 (52), 341 (29), 235 (52), 233 (44), 231 (30), 179 (90), 178 (30), 177 (100), 176 (32), 175 (66), 149 (72), 135 (24), 121 (46), 85 (32), 83 (40), 81 (24), 55 (76), 43 (42), 41 (90), 31 (36). HRMS calcd for Ci9H37O3120Sn (M+-C4H9): 433.1765, found: 433.1769. 'OH 72 EXPERIMENTAL 114 3.21 Methyl (£)-3-(tri(n-butyl)stannyl)-5,5-dimethyl-8-iodo-oct-2-enoate (67). M e 0 2 C v Bu3Sn 67 Alcohol 72 (1.01 g, 2.06 mmol) was converted to 67 following the procedure outlined in section 3.18. The crude product was purified by flash chromatography, eluting with 15% diethyl ether/pet. ether, to afford 1.15 g (93%) of 67 as a pale yellow oil, which was one spot by TLC. IR (neat, cm"1) 2920, 1718, 1563, 1450, 1158. *H NMR (CDC13, 400 MHz) 8 0.89-1.10 (m, 21 H), 1.26-1.60 (m, 14 H), 1.85 (m, 2 H), 2.91 (s, Jsn-H = 62 Hz, 2 H), 3.16 (t, J = 7 Hz, 2 H), 3.69 (s, 3 H), 6.10 (s, JSn-H = 66 Hz, 1 H). LRMS (m/z) 543 (43, M+-C4Ho), 541 (32), 451 (43), 449 (28), 417 (38), 416 (27), 415 (100), 414 (41), 413 (72), 412 (25), 411 (36), 361 (86), 361 (86), 360 (26), 359 (54), 358 (22), 357 (33), 305 (39), 303 (33), 301 (21), 269 (79), 267 (54), 265 (37), 235 (43), 233 (34), 213 (34), 211 (26), 179 (66), 177 (87), 176 (30), 175 (59), 151 (20), 149 (38), 147 (26), 121 (29), 119 (25), 83 (37), 81 (32), 57 (46), 55 (60), 43 (40), 41 (95). HRMS calcd for CioH36O2l120Sn (M+- C4H9): 543.0784, found: 543.0773. EXPERIMENTAL 115 3.22 Methyl (2i)-(3,3-dimethylcyclohexylidene)acetate (48) Me0 2 C 48 To a solution of the vinylstannane 50 (119 mg, 0.199 mmol) in 10 mL of benzene was added tris(trimethylsilyl)silane (36 uL, 0.12 mmol). The resulting solution was heated to reflux, and triethylborane (50 uL, 0.05 mmol) was added via syringe. Dry air (5.2 mL) was then slowly bubbled through the solution over a period of one minute. When TLC indicated none of compound 50 remained, the reaction mixture was cooled, and concentrated by rotary evaporation. The yellow oil thus obtained was purified by radial chromatography, eluting with 2% diethyl ether/pet. ether, to give 17.5 mg (48%) of 48 as a clear, colourless oil. IR (neat, cm"1) 2930, 2847, 1716, 1641,1454, 1228, 1167, 870. IH NMR (CDC13,400 MHz) 5 0.89 (s, 6H), 1.33 (m, 2H), 1.67 (m, 2H), 1.96 (s, 2H), 2.73 (t, J = 6 Hz, 2H), 3.62 (s, 3H), 5.52 (s, IH). LRMS (m/z) 182 (6, M+), 167 (14), 152 (24), 151 (8), 135 (12), 57 (40), 41 (100). Elem. Anal, calcd for CnHisQj: C 72.49, H 9.95; found: C 72.38. H 10.02. EXPERIMENTAL 116 3.23 Methyl (Z)-(3,3-dimethyIcyclohexylidene)acetate (49). ,C0 2Me Following the procedure outlined in section 3.21, the (Z)-vinylstannane 51 (288 mg, 0.481 mmol) was transformed into the (Z)-exocyclic alkene 49. Concentration of the reaction mixture by rotary evaporation afforded a yellow oil, which was purified by radial chromatography, eluting with 3% diethyl ether/pet. ether, to give 48.2 mg (55%) of 49 as a clear, colourless oil. IR (neat, cnr1) 2932, 2844, 1715, 1642, 1231, 1167, 868. IH NMR (CDC13, 300 MHz) 6 0.92 (s, 6H), 1.38 (m, 2H), 1.62 (m, 2H), 2.14 (t, J = 6 Hz, 2H), 2.62 (s, 2H), 3.68 (s, 3H), 5.69 (s, IH). LRMS (m/z) 182 (8, M+), 167 (27), 152 (22), 151 (11), 135 (16), 57 (43), 41 (100). Elem. Anal, calcd for C11H18O2: C 72.49, H 9.95; found: C 72.40. H 9.99. E X P E R I M E N T A L 117 3.24 Methyl oct-2-yne-7-enoate (79). Me0 2 C 79 To a suspension of lithium acetylide-ethylenediamine complex (1.64 g, 16.1 mmol) in 8 mL of dimethyl sulphoxide at 0 °C was added 5-bromo-l-pentene (1.59 mL, 13.4 mmol), dropwise via syringe. The cooling bath was removed, and the reaction mixture was stirred for 3 hours. It was re-cooled to 0 "C and quenched by the dropwise addition of water, until a homogeneous solution was obtained. This was extracted three times with 25-mL portions of THF, and the combined extracts were dried over MgSC>4 and then filtered through a short column of silica. The clear, colourless filtrate was cooled to -78 °C, and methyllithium (14.4 mL of 1.4 M in hexanes, 20.2 mmol) was added dropwise. The resulting solution was stirred at -78 °C for 20 min, and then at -20 °C for 30 min. Methyl chloroformate (1.55 mL, 20.1 mmol) was added dropwise via syringe, and the resulting solution was stirred at -20 °C for 20 min, and then at room temperature for 2 hours. The reaction mixture was diluted with 75 mL of diethyl ether, washed once with 50 mL of saturated NaHCC>3 solution, and dried (MgSC«4). Filtration and evaporation of solvent from the organic extracts afforded a yellow liquid which was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether, to give 1.67 g (82%) of 79 as a clear, colourless liquid. GC (column C, 100 °C, isothermal) 100%, RT = 3.35 min. IR (neat, cm-l) 2961, 2237, 1720, 1641, 1440, 1393, 1369, 1164, 994, 916, 847, 814. J H NMR (CDC13, 400 MHz) 5 1.65 (m, J = 8 Hz, 2 H), 2.17 (m, 2 H), 2.36 (t, J = 8 Hz, 2 H), 3.77 (s, 3 H), 4.98-5.08 (m, 2 H), 5.78 (m, 1 H). LRMS (m/z) 151 (18, M M ) , 137 (36), 121 (15), 93 (100), 77 (60), 59 (20), 55 (40). HRMS calcd for C9H11O2 (MM): 152.0792, found 152.0788. EXPERIMENTAL 118 3.25 Methyl non-2-yne-8-enoate (86). Me0 2 C 86 Following the procedure outlined in section 3.24, 6-bromo-l-hexene (2.19 g, 13.4 mmol) was reacted with lithium acetylide-ethylenediamine complex (1.64 g, 16.1 mmol) to give a THF solution of l-octen-7-yne, which was further reacted with methyllithium (14.4 mL of 1.4 M in hexanes, 20.2 mmol) and methyl chloroformate (1.55 mL, 20.1 mmol). The pale yellow liquid obtained after work-up was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether, to afford 1.71 g (77%) of 86 as a clear, colourless liquid. GC (column C, 100 °C, isothermal) 100%, R T = 5.11 min. IR (neat, cm'l) 2938, 2237, 1730, 1641, 1442, 1395, 1369, 1167, 1103, 1078, 995, 864. IH NMR (CDC13, 400 MHz) 5 1.48-1.65 (m, 4 H), 2.08 (q, J = 7 Hz, 2 H), 2.35 (t, J = 7 Hz, 2 H), 3.77 (s, 3 H), 4.95-5.04 (m, 2 H), 5.80 (m, 1 H). LRMS (m/z) 165 (14, M+-l), 151 (41), 135 (17), 107 (100), 91 (49), 77 (34). HRMS calcd for C i 0 Hi 3 O 2 (M+-l) : 165.0916, found: 165.0919. EXPERIMENTAL 119 3.26 Methyl (£)-3-(tri(n-butyl)stannyl)-2,7-octadienoate (80). Me0 2 C ~, S n B u 3 80 Following the procedure outlined in section 3.9, the a,|3-alkynyl ester 79 (500 mg^  3.29 mmol) was transformed into the vinylstannane 80. The crude product was purified by flash chromatography, eluting with 2% diethyl ether/pet. ether, to afford 1.41 g (96%) of 80 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm-i) 2937, 1719, 1644, 1590, 1459, 1432, 1377, 1071, 1026, 961, 867. IH NMR (CDC13, 400 MHz) 5 0.88-1.00 (m, 15 H), 1.24-1.54 (m, 14 H), 2.11 (q, J = 8 Hz, 2 H), 2.90 (m, JSn-H = 64 Hz, 2 H), 3.70 (s, 3 H), 4.95-5.05 (m, 2 H), 5.85 (m, 1 H), 5.97 (s, Jsn-H = 68 Hz, 1 H). LRMS (m/z) 387 (3, M + - C4H9), 291 (59), 290 (21), 289 (44), 287 (25), 235 (91), 234 (30), 233 (70), 232 (25), 231 (41), 179 (100), 178 (30), 177 (86), 176 (30), 175 (57), 121 (24), 41 (25). HRMS calcd for Ci7H3iO2120Sn (M+-C4H9): 387.1346, found: 387.1343. EXPERIMENTAL 120 3.27 Methyl (£>3-(tri(n-butyl)stannyl)-2,8-nonadienoate (87). Me02C 87 Following the procedure outlined in section 3.9, the a,f3-alkynyl ester 86 (1.00 g, 6.02 mmol) was converted into the corresponding (E)-vinylstannane 87. The crude product was purified by flash chromatography, eluting with 2% diethyl ether/pet. ether, to afford 2.31 g (84%) of 87 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 2934, 1719, 1641, 1592, 1460, 1433, 1176, 1027, 961, 909, 867. IH NMR (CDC13, 400 MHz) 5 0.88-1.02 (m, 15 H), 1.27-1.54 (m, 16 H), 2.08 (q, J = 7 Hz, 2 H), 2.89 (br m, J S n - H = 64 Hz, 2 H), 3.71 (s, 3 H), 4.92-5.03 (m, 2 H), 5.82 (m, 1 H), 5.95 (s, Jsn-H = 66 Hz, 1 H). LRMS (m/z) 401 (100, M +-C 4H 9), 400 (39), 399 (75), 398 (30), 397 (42), 265 (22),151 (22) HRMS calcd for Ci 8H33O2 1 2 0Sn (M+- C4H9): 401.1502, found: 401.1506. EXPERIMENTAL 121 3.28 Methyl (Z)-3-(tri(n-butyl)stannyl)-2,7-octadienoate (81). Me0 2 C 81 Following the procedure outlined in section 3.12, the a,p-alkynyl ester 79 (500 mg, 3.29 mmol) was converted into the corresponding (Z)-vinylstannane 81. The crude product was purified by flash chromatography, eluting with 0.5% diethyl ether/pet. ether, to afford 1.25 g (85%) of 81 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm-i) 2955, 2923, 2851, 1708, 1641, 1597, 1459, 1375, 1327, 1202, 1071, 912. IH NMR (CDCI3, 400 MHz) 5 0.88-1.04 (m, 15 H), 1.26-1.55 (m, 14 H), 2.07 (q, J = 7 Hz, 2 H), 2.41 (m, J S n . H = 60 Hz, 2 H), 3.71 (s, 3 H), 4.95-5.04 (m, 2 H), 5.80 (m, 1 H), 6.37 (s, Jsn-H = 108 Hz, 1 H). LRMS (m/z) 387 (100, M+-C4H9), 386 (38), 385 (76), 384 (30), 383 (45), 151 (37). HRMS calcd for Ci7H 3iO2 1 2 0Sn (M+-C4H9): 387.1347, found: 387.1347. EXPERIMENTAL 122 3.29 Methyl (Z)-3-(tri(n-butyl)stannyl)-2,8-nonadienoate (88). Me0 2 C Following the procedure outlined in section 3.12, the a,P-alkynyl ester 86 (240 mg, 1.45 mmol) was converted into the corresponding (Z)-vinylstannane 88. The crude product was purified by flash chromatography, eluting with 0.8% diethyl ether/pet. ether, to afford 561 mg (82%) of 88 as a clear, colourless oil, which was one spot by TLC. IR (neat, cnr*) 2930, 1709, 1597, 1448, 1329, 1203, 911. IH NMR (CDC13, 400 MHz) 8 0.86-1.02 (m, 15 H), 1.25-1.52 (m, 16 H), 2.07 (m, 2 H), 2.41 (m, Jsn-H = 64 Hz, 2 H), 3.72 (s, 3 H), 4.93-5.03 (m, 2 H), 5.80 (m, 1 H), 6.36 (s, J S n -H = 110 Hz, 1 H). LRMS (m/z) 401 (100, M+-C4H9), 400 (40), 399 (76), 398 (30), 397 (44), 151 (50), 149 (38), 147 (23), 56 (34), 55 (25), 49 (25), 41 (96), 39 (38). HRMS calcd for Ci 8 H3 3 O2 1 2 0 Sn (M+-C4H9): 401.1503, found: 401.1509. EXPERIMENTAL 123 3.30 Methyl (£)-3-(tri(n-butyI)stannyl)-7-epoxy-2-octenoate (75). To a solution of the alkene 80 (474 mg, 1.05 mmol) in 7.5 mL of CH2Cl2 at 0 °C was added /wCPBA (300 mg of 80 mol%, 1.36 mmol) in one portion. The cooling bath was removed, and the solution stirred at 25 °C for six hours, at which time TLC indicated that the reaction was complete. The mixture was diluted with 25 mL of pet. ether and filtered through a fine sintered glass funnel to remove a white precipitate. The filtrate was washed consecutively with 15-mL portions of NaHS03 solution and saturated NaHC03 solution and dried (MgSC»4). Filtration of the organic extracts followed by evaporation of solvent gave a clear oil which was purified by flash chromatography, eluting with 4% diethyl ether/pet ether, to afford 361 mg (73%) of 75 as a clear, colourless oil. GC (column C, 200 'C, isothermal) 100%, Rj = 5.48 min. IR (neat, cm-i) 2934, 2854, 1718, 1592, 1459, 1432, 1195, 1167, 960, 862. !H NMR (CDC13, 400 MHz) 5 0.87-1.03 (m, 15 H), 1.25-1.65 (m, 16 H), 2.47 (dd, J = 6 Hz, 3 Hz, 1 H), 2.77 (dd, J = 5 Hz, 4 Hz, 1 H), 2.94 (br m, 3 H), 3.70 (s, 3 H), 5.98 (s, J S n -H = 64 Hz, 1 H). LRMS (m/z) 403 (0.4, M M ^ g ) , 387 (100), 386 (39), 385 (76), 384 (31), 383 (43), 355 (18), 291 (43), 289 (31), 265 (42), 263 (34), 235 (80), 233 (63), 231 (39), 179 (83), 177 (81), 175 (52), 151 (34), 149 (29), 121 (23), 41 (43). HRMS calcd for Ci7H 3iO 3 1 2 0Sn (M+-C4H9): 403.1295, found: 403.1302. Me02C. 75 EXPERIMENTAL 124 3.31 Methyl (Z)-3-(tri(n-butyI)stannyl)-7-epoxy-2-octenoate (76). Following the procedure outlined in section 3.30, the alkene 81 (330 mg, 0.73 mmol) was converted to the epoxide 76. The crude product was purified by radial chromatography, eluting with 3% diethyl ether/pet. ether, to afford 258 mg (75%) of 76 as a clear, colourless oil, which was one spot by TLC. IR (neat, cnr*) 2923, 1708, 1596, 1448, 1330, 1206, 865. *H NMR (CDC13, 400 MHz) 5 0.87-1.04 (m, 15 H), 1.25-1.65 (m, 16 H), 2.47 (m, 3 H), 2.77 (m, 1 H), 2.93 (m, 1 H), 3.73 (s, 3 H), 6.38 (s, JSn-H = 108 Hz, 1 H). LRMS (m/z) 403 (100, M+-C4H9), 402 (38), 401 (77), 400 (31), 399 (45), 387 (6), 151 (25). HRMS calcd for Ci7H 3iO 3 1 2 0Sn (M+-C4H9): 403.1295, found: 403.1300. 76 EXPERIMENTAL 125 3.32 Methyl (£>3-(tri(n-butyl)stannyI)-8-epoxy-2-nonenoate (89). Following the procedure outlined in section 3.30, the alkene 87 (1.47 g, 3.20 mmol) was converted to the epoxide 89. The crude product was purified by flash chromatography, eluting with 6% diethyl ether/pet. ether, to afford 1.08 g (72%) of 89 as a clear, colourless oil. GC (column C, 200 °C, isothermal) 100%, R T = 7.09 min. IR (neat, cnr*) 2933, 2854, 1718, 1592, 1450, 1349, 1174, 1026, 861. IH NMR (CDC13, 400 MHz) 5 0.88-1.05 (m, 15 H), 1.26-1.60 (m, 18 H), 2.47 (dd, J = 5 Hz & 4 Hz, 1 H), 2.75 (dd, J = 4 Hz & 4 Hz, 1 H), 2.90 (m, 3 H), 3.70 (s, 3 H), 5.97 (s, J S n -H = 68 Hz, 1 H). LRMS (m/z) 417 (100, M +-C 4H 9), 416 (38), 415 (76), 414 (30), 413 (43), 401 (10), 387 (25), 385 (22), 265 (62), 263 (46), 261 (28), 235 (36), 233 (33), 179 (65), 177 (66). HRMS calcd for Ci8H330312<>Sn (M+-C4H9): 417.1452, found: 417.1458. 89 EXPERIMENTAL 126 3.33 Methyl (Z)-3-(tri(n-butyl)stannyl)-8-epoxy-2-nonenoate (90). Following the procedure outlined in section 3.30, the alkene 88 (290 mg, 0.64 mmol) was converted into the corresponding epoxide 90. The crude product was purified by radial chromatography, eluting with 3% diethyl ether/pet. ether, to afford 217 mg (72%) of 90 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 2913,1708, 1596, 1449, 1376, 1328, 1202, 1070, 861. IH NMR (CDC13, 400 MHz) 6 0.87-1.04 (m, 15 H), 1.20-1.1.60 (m, 18 H), 2.42 (br m, 2 H), 2.47 (dd, J = 4 Hz & 4 Hz, 1 H), 2.76 (m, 1 H), 2.92 (1 H), 3.73 (s, 3 H), 6.37 (s, J S n -H= 108 Hz, 1 H). LRMS (m/z) 417 (93, M + -C 4 H 9 ), 416 (35), 415 (70), 414 (28), 413 (39), 401 (93), 400 (36), 399 (71), 398 (28), 397 (39), 179 (24), 177 (27), 151 (100), 150 (26), 149 (75). HRMS calcd for Ci 8 H 3 3O3 1 2 0 Sn (M+-C4H 9): 417.1452, found: 417.1456. .0 90 EXPERIMENTAL 127 3.34 Methyl (E)-3-iodo-8-epoxy-2-nonenoate (95). Me0 2 C, 95 To a solution of the vinylstannane 89 (180 mg, 0.38 mmol) in 15 mL of CH2CI2 was added iodine (97 mg, 0.38 mmol) in one portion, and the resulting solution was stirred for 15 minutes, at which time TLC indicated the reaction was complete. The mixture was diluted with 10 mL of CH2CI2, washed with 10 mL of saturated Na2S2C»3 solution and dried (MgSO*). The organic extracts were filtered and concentrated to give a clear liquid which was purified by radial chromatography, eluting with 8% diethyl ether/pet. ether, to afford 105 mg (89%) of 95 as a colourless oil, which was one spot by TLC. IR (neat, cnr*) 2939, 2862, 1716, 1609, 1433, 1332, 1268, 1201. I H NMR (CDCI3, 400 MHz) 5 1.48-1.70 (m, 6 H), 2.48 (m, 1 H), 2.76 (m, 1 H), 2.91 (m, 1 H), 3.13 (m, 2 H), 3.70 (s, 3 H), 6.65 (s, 1 H). Because this compound was found to slowly decompose it was not further characterized. EXPERIMENTAL 128 3.35 Methyl (Zi)-[2-(hydroxymethyl)cyclopentylidene]acetate (82). To a solution of the epoxide 75 (195 mg, 42.5 mmol) in 5 mL of THF was added a dark green solution of bis(cyclopentadienyl)titanium(III) chloride (181 mg, 84.9 mmol) via cannula. Immediately upon addition the colour changed from dark green to bright orange. TLC analysis after 30 minutes indicated the reaction was complete. The reaction was quenched by the addition of 15 mL of 10% H2SO4, and then extracted three times with 25-mL portions of diethyl ether. The combined organic extracts were washed consecutively with 15-mL portions of saturated NaHCC»3 solution, water and brine and dried (Na2SC>4). Filtration and solvent evaporation afforded a cloudy yellow oil, which was purified by radial chromatography, eluting with 30% diethyl ether/pet. ether. This gave 63.7 mg (86%) of 82 as a clear, colourless oil. IR (neat, cm"1) 3410, 2918, 1706, 1650, 1440, 1362, 1287, 1209, 1134, 1026, 962, 864. IH NMR (CDCI3, 400 MHz) 5 1.65 (m, 3 H), 1.90 (m, 2 H), 2.77 (m, 2 H), 2.96 (m, 1 H), 3.68 (dd, J = 8 Hz & 3 Hz, 2 H), 3.71 (s, 3 H), 5.87 (m, 1 H). LRMS (m/z) 170 (7, M+), 152 (59), 139 (50), 137 (26), 124 (28), 108 (68), 93 (95), 79 (100), 67 (51), 41 (60). Elem. Anal, calcd for C9H14O3: C 63.51, H 8.29; found: C 63.48, H 8.27. EXPERIMENTAL 129 3.36 Methyl (Z)-[2-(hydroxymethyl)cycIopentyIidene]acetate (83). Following the procedure outlined in section 3.35, the epoxide 76 (104 mg, 0.23 mmol) was reacted with bis(cyclopentadienyl)titanium(III) chloride (97 mg, 0.46 mmol). The yellow oil obtained after work-up was purified by radial chromatography, eluting with 30% diethyl ether/pet ether, to give 33 mg (84%) of 83 as a clear, colourless oil. IR (neat, cm"1) 3408, 2931, 1708, 1651, 1435, 1363, 1212, 1027, 866. *H NMR (CDCI3, 400 MHz) 6 1.60-1.80 (m, 3 H), 1.80-1.90 (m, 1 H), 2.45 (m, 1 H), 2.60 (m, 1 H), 3.12 (br s, exchanges with D2O, 1 H), 3.53-3.72 (m, 3 H), 3.72 (s, 3 H), 5.94 (s, 1 H) LRMS (m/z) 170 (0.1, M+), 140 (56), 108 (100), 107 (29), 84 (32), 79 (38), 49 (33). Elem. Anal, calcd for C9H14O3: C 63.51, H 8.29; found: C 63.45, H 8.22. 83 EXPERIMENTAL 130 3.37 6-(Tetrahydropyranyloxy)-l-hexyne (105). 105 Following the procedure outlined in section 3.3, 5-hexyn-l-ol (2.50 g, 25.5 mmol) was converted to compound 105. The crude product was purified by flash chromatography, eluting with 5% diethyl ether/pet. ether, to afford 4.39 g (98%) of 105 as a clear, colourless liquid, which was one spot by TLC. IR (neat, cm-») 3290, 2939, 2117, 1454, 1439, 1353, 1137, 1120, 1030, 989, 905, 869, 813 *H NMR (CDC13, 400 MHz) 5 1.50-1.90 (m, 10 H), 1.96 (t, J = 4 Hz, 1 H), 2.22 (dt, J = 4 Hz & 8 Hz, 2 H), 3.42 (m, 1 H), 3.50 (m, 1 H), 3.75 (m, 1 H), 3.85 (m, 1 H), 4.58 (m, 1 H). LRMS (m/z) 181 (0.5, M M ) , 85 (100), 81 (25), 79 (35), 67 (24), 56 (26), 41 (40). HRMS calcd for C11H17O2 (MM): 181.1228, found: 181.1224. EXPERIMENTAL 131 3.38 Methyl 7-(tetrahydropyranyloxy)-2-heptynoate (106). 106 Following the procedure outlined in section 3.8, the alkyne 105 (1.80 g, 9.89 mmol) was converted to the corresponding alkynyl ester 106. The crude product was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether, to afford 2.36 g (99%) of 106 as a clear, colourless liquid, which was one spot by TLC. IR (neat, cnr1) 2917, 2236, 1716, 1438, 1351, 1258, 1128, 1074, 1031, 905, 869, 814, 752. *H NMR (CDC13, 400 MHz) 6 1.50-1.88 (m, 10 H), 2.40 (t, J = 8 Hz, 2 H), 3.42 (m, 1 H), 3.52 (m, 1 H), 3.76 (s, 3 H), 3.78 (m, IH), 3.86 (m, 1 H), 4.57 (m, 1 H). LRMS (m/z) 239 (0.2, M M ) , 225 (0.4), 209 (1), 181 (5), 85 (100), 79 (32), 41 (25). HRMS calcd for C13H19O4 (MM): 239.1283, found:239.1292. EXPERIMENTAL 132 3,29 Methyl 7-hydroxy-2-heptynoate (125). .OH Me02C 125 Following the procedure outlined in section 3.10, the tetrahydropyranyl ether 106 (400 mg, 1.66 mmol) was converted to the corresponding alcohol 125. The crude product was purified by flash chromatography, eluting with 50% diethyl ether/pet. ether, to afford 242 mg (93%) of 125 as a clear, colourless liquid, which was one spot by TLC. IR (neat, cm'1) 3396, 2921, 2236, 1709, 1436, 1263, 1071, 753. *H NMR (CDC1 3 , 400 MHz) 5 1.32 (br s, 1 H, exchanges with D2O), 1.68 (m, J = 4 Hz, 4 H), 2.38 (t, J = 6 Hz, 2 H), 3.65 (br m, 2 H), 3.73 (s, 3 H). LRMS (m/z) 156 (29, M+), 138 (3), 124 (100), 123 (47), 98 (22), 96 (43), 69 (78), 55 (30). HRMS calcd for C8H12O3: 156.0786, found: 156.0779. \ EXPERIMENTAL 133 3.40 Methyl 7-oxo-2-heptynoate (126). O Me0 2 C H 126 To a solution of oxalyl chloride (194 uL, 2.23 mmol) in 12 mL of C H 2 C I 2 at -78 °C was added dropwise a solution of dimethyl sulphoxide (380 mg, 4.87 mmol) in 2 mL of C H 2 C I 2 . This solution was stirred for 1 0 minutes and then a solution of the alcohol 125 (317 mg, 2.03 mmol) in 4 mL of C H 2 C 1 2 was added slowly via cannula. The resulting solution was stirred for 1 0 minutes. Triethylamine (1.41 mL, 1 0 . 2 mmol) was added via syringe and the cooling bath was removed. When the reaction mixture had warmed to room temperature, it was diluted with 5 mL of water, and the layers were separated. The aqueous layer was extracted twice with 5-mL portions of CH 2 C 1 2 . The combined organic extracts were dried (MgS04), filtered and concentrated to afford a pale yellow oil, which was purified by flash chromatography, eluting with 2 0 % diethyl ether/pet. ether. This gave 306 mg (98%) of 126 as a clear, colourless liquid. GC (column C, temp, program) 100%, Rj = 8.65 min. IR (neat, cnr1) 2930, 2237, 1713, 1436,1263, 1072, 753. I H NMR (CDCI3, 400 MHz) 5 1.90 (m, J = 6 Hz, 2 H), 2.40 (t, J = 6 Hz, 2 H), 2.62 (t, J = 6 Hz, 2 H), 3.76 (s, 3 H), 9.78 (s, 1 H). LRMS (m/z) 154 (3, M+), 122 (56), 111 (45), 98 (75), 94 (35), 79 (92), 66 (100), 55 (56). HRMS calcd for C 8 H 1 0 O 3 : 154.0630, found: 154.0628. EXPERIMENTAL 134 3.41 Methyl (£)-7-tetrahydropyranyloxy-3-(tri(n-butyl)stannyI)-Following the procedure outlined in section 3.9, the a,P-alkynyl ester 106 (1.00 g, 4.17 mmol) was converted to the (£)-vinylstannane 107. The crude product was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether, to give 1.92 g (87%) of 107 as a clear, colourless oil. GC (column C, temp, program) 100%, RT = 15.40 min. IR (neat, cnr*) 2915, 1719, 1592, 1449, 1257, 1164, 1122, 1075, 1030, 868. IH NMR (CDC13, 400 MHz) 6 0.88-1.04 (m, 15 H), 1.25-1.90 (m, 22 H), 2.92 (t, J = 8 Hz, Jsn-H = 60 Hz, 2 H), 3.42 (m, 1 H), 3.52 (m, 1 H), 3.70 (s, 3 H), 3.75 (m, 1 H), 3.88 (m, 1 H), 4.60 (m, 1 H), 5.97 (s, JSn-H = 64 Hz, 1 H). LRMS (m/z) 475 (6, M+-C4H9), 391 (100), 390 (40), 389 (78), 388 (31), 387 (47), 177 (24), 85 (80), 55 (34), 41 (64), 32 (88). HRMS calcd for C2iH39O4120Sn (M+-C4H9): 475.1870, found: 475.1870. 2-heptenoate (107). 107 EXPERIMENTAL 135 3.42 Methyl (E)-3-(tri(n-butyl)stannyI)-7-hydroxy-2-heptenoate (108). Following the procedure outlined in section 3.10, the tetrahydropyranyl ether 107 (428 mg, 0.79 mmol) was converted to the corresponding alcohol 108. The crude product was purified by flash chromatography, eluting with 30% diethyl ether/pet ether, to afford 340 mg (94%) of 108 as a clear, colourless oil, which was one spot by TLC. ER (neat, cnr*) 3430, 2912, 1716, 1591, 1450, 1349, 1245, 1177, 1053, 868. J H NMR (CDCI3, 400 MHz) 6 0.87-1.05 (m, 15 H), 1.2-1.68 (m, 16 H), 1.79 (br m, 1 H, exchanges with D2O), 2.88 (m, Jsn-H = 60 Hz, 2 H), 3.70 (m, 2 H overlapping with s, 3 H), 5.96 (s, Jsn-H = 64 Hz, 1 H). LRMS (m/z) 416 (5, M+-OCH3), 391 (12, M +-C 4H 9), 390 (5), 389 (11), 388 (5), 387 (7), 359 (54), 358 (21), 357 (38), 356 (15), 355 (21), 303 (75), 302 (25), 301 (54), 300 (19), 299 (29), 247 (43), 246 (15), 245 (39), 244 (13), 243 (24), 233 (20), 179 (31), 177 (37), 175 (24), 97 (20), 81 (21), 57 (31), 56 (38), 55 (30), 41 (100). HRMS calcd for Ci 9H 37O2 1 2 0Sn (M+-OCH3): 417.1816, found: 417.1814. 108 EXPERIMENTAL 136 3.43 Methyl (£)-3-(tri(n-butyl)stannyl)-7-oxo-2-heptenoate (102). Following the procedure outlined in section 3.40, alcohol 108 (300 mg, 0.67 mmol) was oxidized to the corresponding aldehyde 102. The crude product was purified by flash chromatography, eluting with 13% diethyl ether/pet. ether, to afford 288 mg (96%) of 102 as a clear, colourless oil. GC (column C, temp, program) 100%, RT = 13.52 min. IR (neat, cm-l) 2956, 2925, 1720, 1592, 1459, 1433, 1377, 1347, 1256, 1193, 1163, 869. IH NMR (CDC13, 400 MHz) 6 0.88-1.07 (m, 15 H), 1.25-1.61 (m, 12 H), 1.76 (m, J = 7 Hz, 2 H), 2.50 (dt, J = 8 Hz & 3 Hz, 2 H), 2.92 (m, J = 8 Hz & JSn-H = 56 Hz, 2 H), 3.70 (s, 3 H), 6.00 (s, Jsn-H = 64 Hz, 1 H), 9.79 (t, J = 3 Hz, 1 H). LRMS (m/z) 415 (2, M + - OCH3), 389 (85, M+-C4H9), 388 (33), 387 (65), 386 (24), 385 (36), 357 (12), 265 (100), 264 (33), 263 (77), 262 (32), 261 (45), 235 (59), 233 (52), 231 (33), 179 (82), 178 (23), 177 (80), 176 (26), 175 (51), 151 (44), 149 (35), 147 (21), 121 (22), 41 (48), 32 (45). HRMS calcd for Ci 6H 29O3 1 2 0Sn (M+-C4H9): 389.1139, found: 389.1139. 102 EXPERIMENTAL 137 3.44 Methyl (Z)-3-(tri(n-butyI)stannyl)-6-(tetrahydropyranyIoxy)-2-heptenoate (111). The (£)-vinylstannane 107 (100 mg, 0.19 mmol) was dissolved in 5 mL of benzene, and AIBN (4 mg, 0.02 mmol) was added, followed by tri(n-butyl)tin hydride (51 uL, 55 mg). The resulting solution was refluxed for 2 hours, at which time GC analysis indicated that isomerization was complete. Solvent was removed by rotary evaporation, and the residue was purified by radial chromatography, eluting with 10% diethyl ether/pet. ether. This gave 96 mg (96%) of 111 as a clear, colourless oil. GC (column C, temp, program) 100%, RT = 14.62 min. IR (neat, cm-l) 2915, 1708, 1596, 1449, 1329, 1204, 1137, 1121, 1071, 1030, 871. IH NMR (CDC13, 400 MHz) 6 0.85-1.05 (m, 15 H), 1.24-1.86 (m, 22 H), 2.43 (t, J = 6 Hz, 2 H), 3.38 (m, 1 H), 3.50 (m, 1 H), 3.70 (s, 3 H), 3.72 (m, 1 H), 3.86 (m, 1 H), 4.58 (m, 1 H), 6.37 (s, Jsn-H = 108 Hz, 1 H). LRMS (m/z) 475 (12, M+-C4H9), 474 (5), 473 (9), 472 (4), 471 (5), 391 (100), 390 (38), 389 (79), 388 (30), 387 (43), 151 (37), 149 (28), 85 (66), 81 (26), 67 (26), 57 (26), 56 (29), 55 (36), 41 (93), 39 (43). HRMS calcd for C2iH39O4120Sn (M+-C4H9): 475.1870, found: 475.1872. I l l EXPERIMENTAL 138 3.45 Methyl (Z)-3-(tri(n-butyl)stannyl)-7-hydroxy-2-heptenoate (114). Following the procedure outlined in section 3.10, the tetrahydropyranyl ether 111 (277 mg, 0.52 mmol) was converted to the corresponding alcohol 114. The crude product was purified by flash chromatography, eluting with 30% diethyl ether/pet. ether, to give 214 mg (93%) of 114 as a clear, colourless oil. GC (column C, temp, program) 100%, RT = 12.23 min. IR (neat, cnr*) 3350, 2910, 1708, 1596, 1459, 1435, 1376, 1329, 1201, 1058, 925, 871. J H NMR (CDC13, 400 MHz) 5 0.85-1.05 (m, 15 H), 1.19 (br s, 1 H, exchanges with D2O), 1.23-1.62 (m, 16 H), 2.42 (m, JSn-H = 42 Hz, 2 H), 3.65 (q, becomes t upon addition of D 20, J = 6 Hz, 2 H), 3.72 (s, 3 H), 6.38 (s, JSn-H = 108 Hz, 1 H). LRMS (m/z) 391 (75, M +-C 4H 9), 390 (28), 389 (64), 388 (24), 387 (38), 333 (21), 179 (22), 177 (26), 151 (49), 149 (38), 147 (23), 81 (23), 56 (34), 55 (22), 41 (100), 39 (43). HRMS calcd for Ci 6H 3i03 1 2 ( )Sn (M+-C4H9): 391.1295, found: 391.1300. .OH 114 EXPERIMENTAL 139 3.46 Methyl (Z)-3-(tri(n-butyl)stannyI)-7-oxo-2-heptenoate (103). Following the procedure outlined in section 3.40, alcohol 114 (200 mg, 0.45 mmol) was oxidized to the corresponding aldehyde 103. The crude product was purified by radial chromatography, eluting with 15% diethyl ether/pet. ether, to give 189 mg (95%) of 103 as a clear, colourless oil. GC (column C, temp, program) 100%, R T = 12.50 min. IR (neat, cm"1) 2910, 2718, 1717, 1597, 1449, 1376, 1329, 1202, 1063, 960, 873. IH NMR (CDCI3, 400 MHz) 6 0.86-1.06 (m, 15 H), 1.22-1.55 (m, 12 H), 1.76 (m, J = 8 Hz, 2 H), 2.46 (2 overlapping m, 4 H), 3.74 (s, 3 H), 6.38 (s, JSn-H = 108 Hz, 1 H), 9.78 (s, 1 H). LRMS (m/z) 389 (100, M + - C 4 H 9 ) , 388 (38), 387 (76), 386 (31), 385 (41), 151 (40), 149 (32), 41 (41). HRMS calcd for Ci6H 29O3 1 2 0Sn (M+- C4H9): 389.1139, found: 389.1139. 103 EXPERIMENTAL 140 3.47 Methyl (2T)-[2-(hydroxy)cyclopentylidene]acetate (109). 09 The aldehyde 102 (178 mg, 0.400 mmol) was dissolved in 4 mL of benzene, and tri(n-butyl)tin hydride (161 uL, 0.600 mmol) and a catalytic amount of AIBN were added. The resulting solution was heated to reflux for a period of 11 hours. Concentration of the reaction mixture by rotary evaporation gave a yellow oil, which was purified by radial chromatography, eluting first with 10% diethyl ether/pet. ether to remove alkyltin by-products, and then with 30% diethyl ether/ pet. ether to afford 44.5 mg (72%) of 109 as a clear, colourless oil, which was one spot by TLC. IR (neat,cm-i) 3414,2954, 1710, 1662, 1435, 1358, 1207, 1140,867. IH NMR (CDC13, 400 MHz) 5 1.52-1.70 (m, 3 H), 1.71 (m, 1 H), 2.08 (m, 1 H), 2.86 (m, 2 H), 3.72 (s, 3 H), 4.42 (br m, 1 H), 6.01 (s, 1 H). LRMS (m/z) 156 (4, M+), 138 (20), 125 (32), 124 (88), 100 (100), 97 (39), 96 (42), 79 (32), 69 (43), 68 (77), 67 (35), 55 (34), 41 (67), 39 (53). HRMS calcd for C 8 Hi 2 0 3 : 156.0786, found: 156.0788. EXPERIMENTAL 141 3.48 Methyl 7-hydroxy-2-octynoate (127). Me0 2 C The aldehyde 126 (530 mg, 3.44 mmol) was dissolved in 20 mL of THF and cooled to -78 °C. Methylmagnesium chloride (1.20 mL of 3.0 M in hexanes, 3.61 mmol) was added, and the resulting solution was stirred at -78 "C for 10 minutes before the cooling bath was removed. TLC analysis of the reaction mixture after warming to 25 °C indicated the reaction was complete. The reaction mixture was diluted with 10 mL of saturated NH4CI solution and 20 mL of diethyl ether. The layers were separated, and the aqueous layer was extracted twice with 10-mL portions of diethyl ether. The combined organic extracts were dried (MgS04), filtered, and concentrated to afford a pale yellow oil, which was purified by flash chromatography, eluting with 30% diethyl ether/pet. ether. This gave 455 mg (78%) of 127 as a clear, colourless oil, which was one spot by TLC. 127 IR (neat, cnr1) 3401, 2936, 2237, 1709, 1436, 1374, 1265, 1127, 1079, 971, 861, 753. *H NMR (CDCI3, 400 MHz) 6 1.20 (d, J = 6 Hz, 3 H), 1.31 (br s, exchanges with D2O, 1 H), 1.50-1.73 (m, 4 H), 2.36 (t, J = 8 Hz, 2 H), 3.72 (s, 3 H), 3.81 (m, J = 7 Hz, 1 H). LRMS (m/z) 170 (2, M+), 155 (10), 152 (5), 139 (31), 138 (34), 137 (26), 123 (49), 111 (42), 98 (100), 97 (48), 96 (25), 95 (44), 94 (30), 93 (44), 81 (53), 79 (65), 77 (30), 71 (41), 69 (55), 68 (35), 67 (55), 66 (73), 65 (31), 59 (38), 55 (72), 53 (50), 51 (27), 45 (82), 43 (71), 42 (52), 41 (47), 40 (22), 39 (55), 38 (31), 31 (31). HRMS calcd for C9H14O3: 170.0943, found: 170.0940. EXPERIMENTAL 142 3.49 Methyl 7-iodo-2-octynoate (128). Me02C To a solution of the alcohol 128 (300 mg, 1.76 mmol) in 10 mL of C H 2 C I 2 was added Et3N (0.49 mL, 3.5 mmol), followed by p-TsO (436 mg, 2.29 mmol) and DMAP (42 mg, 0.35 mmol). The resulting solution was stirred overnight, and diluted with 30 mL of diethyl ether. The organic solution was washed consecutively with 10-mL portions of 1 M HC1, saturated NaHC03 solution, and brine, and dried (MgS04). The organic extracts were filtered and concentrated to afford a clear, pale yellow oil, which was dissolved in 15 mL of benzene. To this was added /1-BU4NI (933 mg, 2.64 mmol), and the resulting mixture was refluxed for two hours, at which time TLC indicated the reaction was complete. Benzene was removed by rotary evaporation, and the residue was triturated with pet. ether to precipitate a yellow solid. The mixture was filtered through a short pad of Florisil, and the filtrate was concentrated to give a pale yellow oil, which was purified by flash chromatography, eluting with 3% diethyl ether/pet. ether to give 435 mg (88%) of 128 as a clear, colourless oil. 128 GC (column C, temp, program) 100%, RT = 9.77 min. IR (neat, cm"1) 2941, 2237, 1714, 1437, 1378, 1260, 1139, 1076, 814, 752. J H NMR (CDCI3, 400 MHz) 5 1.60-1.90 (m, 4 H), 1.93 (d, J = 8 Hz, 3 H), 2.38 (t, J = 7 Hz, 2 H), 3.72 (s, 3 H), 4.13 (m, 1 H). LRMS (m/z) 280 (0.4, M+), 249 (5), 121 (24), 93 (100), 91 (25), 79 (29), 77 (26), 55 (29). HRMS calcd for C9H13O2I: 279.9960, found: 279.9957. EXPERIMENTAL 143 3.50 Methyl (^)-3-(tri(n-butyl)stannyl)-7-hydroxy-2-octynoate (119). Following the procedure outlined in section 3.48, the aldehyde 102 (200 mg, 0.46 mmol) was converted to alcohol 119. The crude product was purified by radial chromatography, eluting with 20% diethyl ether/pet. ether, to give 159 mg (75%) of 119 as a clear, colourless oil, which was one spot by TLC. IR (neat, cnr*) 3422, 2922, 1714, 1591, 1452, 1176, 868. *H NMR (CDC13, 400 MHz) 5 0.88-1.04 (m, 15 H), 1.20 (d, J = 8 Hz, 3 H), 1.25-1.58 (m, 16 H), 1.92 (d, exchanges with D 20, 1 H), 2.71 (m, 1 H), 3.00 (m, 1 H), 3.69 (s, 3 H), 3.88 (m, 1 H), 5.97 (s, J S n -H = 64 Hz, 1 H). LRMS (m/z) 405 (42, M +-C4H 9), 404 (17), 403 (41), 402 (16), 401 (29), 387 (90), 386 (35), 385 (70), 384 (28), 383 (40), 271 (25), 269 (52), 267 (35), 265 (43), 263 (25), 261 (30), 235 (23), 213 (23), 179 (76), 178 (24), 177 (100), 176 (34), 175 (73), 173 (29), 155 (32), 153 (27), 151 (94), 150 (26), 149 (72), 148 (24), 147 (45), 137 (30), 135 (28), 121 (97), 120 (38), 119 (74), 118 (26), 117 (31), 95 (25). HRMS calcd for Ci7H33O3120Sn(M+-C4H9):405.1452, found: 405.1454. 119 EXPERIMENTAL 144 3.51 Methyl (£)-3-(tri(n-butyl)stannyl)-7-iodo-2-octenoate (117). Following the procedure outlined in section 3.49, the alcohol 119 (855 mg, 1.85 mmol) was converted to the corresponding iodide 117. The crude product was purified by flash chromatography, eluting with 2% diethyl ether/pet. ether, to give 895 mg (85%) of 117 as a clear, colourless oil, which was one spot by TLC. IR (neat, cnr*) 2935, 2853, 1718, 1592, 1458, 1432, 1377, 1348, 1253, 1175, 1074, 870. *H NMR (CDCI3, 400 MHz) 5 0.88-1.08 (m, 15 H), 1.28-1.90 (m, 16 H), 1.93 (d, J = 8 Hz, 3 H), 2.88 (m, 2 H), 3.70 (s, 3 H), 4.21 (m, 1 H), 5.98 (s, JSn-H = 64 Hz, 1 H). LRMS (m/z) 515 (1, M+-C4Ho), 514 (0.4), 513 (0.8), 512 (0.3), 511 (0.4), 387 (62), 386 (24), 385 (46), 384 (18), 383 (25), 271 (38), 269 (85), 268 (26), 267 (59), 265 (37), 213 (34), 211 (27), 179 (28), 177 (46), 175 (34), 151 (35), 123 (27), 121 (22), 95 (53), 79 (28), 67 (32), 57 (44), 55 (48), 41 (100), 39 (44). HRMS calcd for Ci7H32O2120SnI (M+-C4H9): 515.0469, found: 515.0470. 117 EXPERIMENTAL 145 3.52 Methyl (Z)-3-(tri(n-butyl)stannyl)-7-hydroxy-2-octynoate (120). Following the procedure outlined in section 3.48, the aldehyde 103 (500 mg, 1.15 mmol) was converted to the corresponding alcohol 120. The crude product was purified by flash chromatography, eluting with 20% diethyl ether/pet. ether, to give 382 mg (72%) of 120 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 3360, 2912, 1707, 1597, 1460, 1435, 1375, 1328, 1199, 1126, 1070, 875. *H NMR (CDC13, 400 MHz) 6 0.85-1.02 (m, 15 H), 1.18 (d, J = 6 Hz, 3 H), 1.20-1.1.52 (m, 17 H), 2.40 (m, 2 H), 3.70 (s, 3 H), 3.78 (m, 1 H), 6.36 (s, JSn-H = 108 Hz, 1 H). LRMS (m/z) 405 (100, M +-C 4H 9), 404 (40), 403 (83), 402 (33), 401 (48), 387 (19), 177 (27), 151 (54), 149 (42), 147 (27), 41 (54), 39 (25). HRMS calcd for Ci7H33O3120Sn(M+-C4H9):405.1452, found: 405.1451. 120 EXPERIMENTAL 146 3.53 Methyl (Z)-3-(trl(n-butyl)stannyl)-7-iodo-oct-2-enoate (118). Following the procedure outlined in section 3.49, the alcohol 120 (331 mg, 0.69 mmol) was converted into the corresponding iodide 118. The crude product was purified by flash chromatography, eluting with 3% diethyl ether/pet. ether, to give 333 mg (82%) of 118 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 2935, 2851, 1709, 1597, 1448, 1376, 1329, 1267, 1198, 1070, 960, 875. J H NMR (CDCI3, 400 MHz) 5 0.85-1.03 (m, 15 H), 1.22-1.62 (m, 16 H), 1.93 (d, J = 8 Hz, 3 H), 2.41 (m, 2 H), 3.72 (s, 3 H), 4.18 (m, 1 H), 6.39 (s, JSn-H = 106 Hz, 1 H). LRMS (m/z) 515 (15, M +-C 4H 9), 514 (6), 513 (12), 512 (5), 511 (7), 387 (100), 386 (39), 385 (75), 384 (30), 383 (40), 151 (32), 95 (34), 55 (21), 41 (43). HRMS calcd for Ci7H32O2120SnI (M+-C4H9): 515.0469, found: 515.0473. 118 EXPERIMENTAL 147 3 . 5 4 Methyl (£)-(2-methylcyclopentylidene)acetate (121). Me02C, •CH3 121 Method A. Via an addition-fragmentation reaction of compound 117. The (£)-vinylstannane 117 (231 mg, 0.405 mmol) was dissolved in 20 mL of benzene, and tris(trimethylsilyl)silane (187 uL, 0.527 mmol) and a catalytic amount of AIBN were added. The resulting solution was refluxed for 2 hours, at which time TLC indicated that no 117 remained. The reaction mixture was concentrated by rotary evaporation to give a yellow oil, which was purified by radial chromatography, eluting with 3% diethyl ether/pet. ether, to give 51.2 mg (82%) of 121 as a clear, colourless oil. Method B. Via a cyclization reaction of compound 128. tri(n-butyl)tin hydride (75 uL, 0.27 mmol) and a catalytic amount of AIBN were added. The resulting solution was refluxed for 2 hours, at which time GC indicated no 128 remained. Concentration of the reaction mixture by rotary evaporation afforded a pale yellow oil, which was purified by radial chromatography, eluting with 3% diethyl ether/pet ether. This gave 25.9 mg (80%) of 121 as a clear, colourless oil. IR (neat, cm-1) 2953, 2871, 1716, 1653, 1443, 1358, 1323, 1304, 1269, 1202, 1136, 860. J H NMR (CDC13, 300 MHz) 6 1.12 (d, J = 7 Hz, 3 H), 1.22 (m, 1 H), 1.58 (m, 1 H), 1.88 (m, 2 H), 2.52 (m, 1 H), 2.74 (m, 1 H), 2.92 (m, 1 H), 3.70 (s, 3 H), 5.70 (m, 1 H). LRMS (m/z) 154 (72, M+), 139 (27), 123 (35), 122 (36), 95 (100), 94 (54), 81 (36), 79 (45), 77 (35), 67 (30), 55 (46), 41 (94). Elem. Anal, calcd for C9H14O2: C 70.10, H 9.15; found: C 70.25, H 9.06. Compound 128 (60 mg, 0.21 mmol) was dissolved in 10 mL of benzene, and EXPERIMENTAL 148 3.55 Methyl (Z)-(2-methylcycIopentylidene)acetate (122). 122 To a solution of the alkyne 128 (57.3 mg, 0.20 mmol) in 10 mL of THF at -78 °C was added triethylborane (50 uL of 1.0 M in hexane). A 5.2 mL sample of dry air was then slowly bubbled through the solution. After 15 min, the reaction was allowed to warm to room temperature. Concentration of the reaction mixture by rotary evaporation gave a colourless oil, which was purified by radial chromatography, eluting with 3% diethyl ether/pet. ether, to give 23.1 mg (76%) of 122 and 2.9 mg(9%) of 121 as clear, colourless oils. Data for 122: IR (neat, cnr*) 2953, 2869, 1717, 1655, 1550, 1531, 1463, 1432, 1373, 1272, 1205, 865. *H NMR (CDC13, 300 MHz) 5 1.10 (d, J = 7 Hz, 3 H), 1.52-1.90 (m, 4 H), 2.35 (m, 1 H), 2.52 (m, 1 H), 3.46 (m, 1 H), 3.70 (s, 3 H), 5.72 (m, 1 H). LRMS (m/z) 154 (60, M+), 139 (20), 123 (43), 121 (28), 95 (100), 94 (54), 81 (38), 80 (33), 79 (50), 67 (34), 55 (35), 41 (36). Elem. Anal, calcd for C9H14O2: C 70.10, H 9.15; found: C 70.19, H 9.13. EXPERIMENTAL 149 3.56 6-Bromo-2-hexanol (135). 135 A solution of 6-bromo-l-hexene (3.26 g, 20.0 mmol) in 20 mL of THF was added to a bright yellow solution of mercuric acetate (6.70 g, 21.0 mmol) in 20 mL of water to give a colourless solution. This was stirred for 20 minutes and 60 mL of 3 M NaOH solution was added, followed immediately by the addition of 60 mL of 0.5 M NaBH* solution in 3 M NaOH. The resulting dark grey mixture was stirred for 10 minutes, and allowed to settle. The supernatant was removed by decantation, and the residue was washed with 30 mL of diethyl ether, which was also removed by decantation. The combined supernatants were saturated with NaCl, and the layers were separated. The aqueous layer was extracted three times with 20-mL portions of diethyl ether, and the combined organic extracts were then washed with 30 mL of brine and dried (MgS04). Filtration and evaporation of solvent gave a cloudy oil which was purified by Kugelrohr distillation (110° / 2 torr) to afford 3.02 g (83%) of 135 as a clear, colourless oil which was one spot by TLC, developing with 25% diethyl ether/pet. ether. IR (neat, cnr*) 3352, 2918, 1449, 1374, 1261, 1202, 1122, 1029, 936, 837, 736. *H NMR ( C D C 1 3 , 400 MHz) 6 1.18 (d, J = 7 Hz, 3 H), 1.28 (d, J = 4 Hz, 1 H, exchanges with D 2 O ) , 1.40-1.60 (m, 4 H), 1.82 (m, 2 H), 3.38 (t, J = 8 Hz, 2 H), 3.79 (m, 1 H). LRMS (m/z) 181 (0.2, M + with 8lBr), 179 (0.2, M + with 7 9Br), 167 (16), 165 (17), 85 (29), 83 (30), 67 (24), 57 (33), 55 (42), 45 (100), 44 (47), 43 (57), 42 (20), 41 (51), 39 (37). HRMS calcd for C 6Hi 30 7 9Br: 180.0150, found: 180.0153; calcd for C6Hi3081Br: 182.0129, found: 182.0124. EXPERIMENTAL 150 3.57 6-Bromo-2-(tetrahydropyranyloxy)hexane (136). 136 Following the procedure outlined in section 3.2, the alcohol 135 (2.80 g, 16.6 mmol) was converted into compound 136. The crude product was purified by flash chromatography, eluting with 20% diethyl ether/pet. ether, to give 4.05 g (93%) of 136 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm'1) 2938, 2867, 1448, 1376, 1321, 1259, 1127, 1076, 1026, 940, 870, 812, 737 IH NMR (CDCI3, 400 MHz) 6 1.15 (d, J = 8 Hz, 1.5 H), 1.20 (d, J = 8 Hz, 1.5 H), 1.32-1.90 (m, 12 H), 3.37 (m, 2 H), 3.46 (m, 1 H), 3.66-3.92 (m, 2 H), 4.60 (m, 0.5 H), 4.67 (m, 0.5 H). LRMS (m/z) 265 (0.6, M + - l with 81Br), 263 (0.6, M M with 7 9Br), 185 (15), 165 (48), 163 (49), 129 (35), 101 (52), 85 (100), 83 (67), 67 (35), 57 (51), 56 (70), 55 (69), 45 (30), 43 (66), 41 (68), 39 (38). HRMS calcd for Ci iH 2 0O2 8 1Br (MM): 265.0626, found: 265.0627; calcd for CnH2o0279Br (MM): 263.0646, found: 263.0642; EXPERIMENTAL 151 3.58 7-(Tetrahydropyranyloxy)-l-octyne (137). 137 Following the procedure outlined in section 3.7, the bromide 136 (3.10 g, 11.7 mmol) was converted into the corresponding alkyne 137. The crude product was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether, to give 1.91 g (77%) of 137 as a clear, colourless liquid, which was one spot by TLC. IR (neat, cm"1) 3291, 2937, 2865, 2117, 1450, 1376, 1260, 1127, 1076, 1026, 995, 870. I H NMR (CDC13, 400 MHz) 5 1.13 (d, J = 6 Hz, 1.5 H), 1.25 (d, J = 6 Hz, 1.5 H), 1.40-1.90 (m, 12 H), 1.96 (m, 1 H), 2.22 (m, 2 H), 3.50 (m, 1 H), 2.70-2.98 (m, 2 H), 4.65 (m, 0.5 H), 4.71 (m, 0.5 H). LRMS (m/z) 209 (0.1, M +-l), 85 (100), 67 (47), 56 (26), 55 (22), 41 (34). HRMS calcd for C13H21O2 (MM): 209.1542, found: 209.1538. EXPERIMENTAL 3.59 Methyl 8-(tetrahydropyranyloxy)-2-nonynoate (138). 152 138 Following the procedure outlined in section 3.8, the alkyne 137 (940 mg, 4.48 mmol) was converted to the alkynyl ester 138. The crude product was purified by flash chromatography, eluting with 25% diethyl ether/pet, ether, to afford 1.19 g (99%) of 138 as a clear, colourless liquid, which was one spot by TLC. IR (neat, cnr1) 2939, 2236, 1716, 1437, 1256, 1132, 1076, 1026, 932, 753. *H NMR (CDC13, 400 MHz) 6 1.12 (d, J = 6 Hz, 1.5 H), 1.23 (d, J = 6 Hz, 1.5 H), 1.38-1.88 (m, 11 H), 2.37 (dt, J = 7 Hz & 3 Hz, 2 H), 3.50 (m, 1 H), 3.72-3.96 (m, 3 H), 3.76 (s, 3 H), 4.63 (m, 0.5 H), 4.70 (m, 0.5 H). LRMS (m/z) 253 (0.1, M +-CH 3), 237 (0.1), 209 (0.2), 167 (18), 135 (43), 107 (100), 85 (53), 79 (41), 67 (35), 55 (35), 43 (35), 41 (43). HRMS calcd for C14H21O4 (M+-CH3): 253.1434, found: 253.1436. EXPERIMENTAL 153 3.60 Methyl 8-hydroxy-2-nonynoate (147). OH Me0 2 C 147 Following the procedure outlined in section 3.10, the tetrahydropyranyl ether 138 (350 mg, 1.31 mmol) was converted into the corresponding alcohol 147. The crude product was purified by flash chromatography, eluting with 40% diethyl ether/pet. ether, to give 222 mg (92%) of 147 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm-i) 3404, 2940, 2865, 2236, 1711, 1435, 1374, 1262, 1127, 1078, 936, 821. *H NMR (CDC13, 400 MHz) 6 1.18 (d, J = 7 Hz, 3 H), 1.20-1.70 (m, 7 H), 2.33 (t, J = 8 Hz, 2 H), 3.72 (s, 3 H), 3.74 (m, 1 H). LRMS (m/z) 184 (8, M+), 166 (11), 111 (42), 109 (27), 108 (76), 107 (71), 106 (26), 105 (30), 97 (25), 91 (51), 81 (39), 79 (100), 77 (24), 69 (34), 68 (29), 67 (42), 55 (25). HRMS calcd for C10H16O3: 184.1100, found: 184.1097. EXPERIMENTAL 154 3.61 Methyl 8-iodo-2-nonynoate (146). I Me0 2 C 146 Following the procedure described in section 3.49, the alcohol 147 (170 mg, 0.92 mmol) was converted into the corresponding iodide 146. The crude product was purified by flash chromatography, eluting with 3% diethyl ether/pet. ether, to give 236 mg (87%) of 146 as a clear, colourless liquid. GC (column C, temp, program) 100%, RT = 10.41 min. IR (neat, cm-i) 2938, 2863, 2236, 1715, 1379, 1258, 1139, 1076, 752. *H NMR (CDC13, 400 MHz) 6 1.48-1.88 (m, 6 H), 1.92 (d, J = 8 Hz, 3 H), 2.35 (t, J = 6 Hz, 2 H), 3.73 (s, 3 H), 4.13 (m, 1 H). LRMS (m/z) 294 (0.1, M+), 263 (17), 167 (27), 135 (57), 107 (100), 79 (28). HRMS calcd for C10H15O2I: 294.0117, found: 294.0123. EXPERIMENTAL 155 3.62 Methyl (E)-3-(tri(n-butyl)stannyI)-8-(tetrahydropyranyloxy)-2-nonenoate (139). 139 Following the procedure outlined in section 3.9, the oc,P-alkynyl ester 138 (1.00 g, 3.73 mmol) was converted into the corresponding (£)-vinylstannane 139. The crude product was purified by flash chromatography, eluting with 10% diethyl ether/pet. ether, to give 1.77 g (85%) of 139 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 2914, 1719, 1591, 1451, 1357, 1168, 1076, 1025, 869. *H NMR (CDC13, 400 MHz) 5 0.86-1.05 (m, 15 H), 1.10 (d, J = 6 Hz, 1.5 H), 1.22 (d, J = 6 Hz, 1.5 H), 1.26-1.88 (m, 22 H), 2.88 (br m, 2 H), 3.49 (m, 2 H), 3.68 (s, 3 H), 3.68-3.96 (m, 3 H), 4.62 (m, 0.5 H), 4.70 (m, 0.5 H), 5.94 (s, J S n -H = 65 Hz, 1 H). LRMS (m/z) 503 (6, M+-C4Ho), 179 (26), 177 (31), 175 (23), 151 (30), 149 (22), 121 (24), 85 (100). HRMS calcd for C 23H43O 4 1 2 0Sn (M+-C4Ho): 503.2183, found: 503.2180. EXPERIMENTAL 156 3.63 Methyl (ii)-3-(tri(n-butyl)stannyI)-8-hydroxy-2-nonenoate (140). Following the procedure outlined in section 3.10, the tetrahydropyranyl ether 139 (970 mg, 1.73 mmol) was converted into the corresponding alcohol 140. The crude product was purified by flash chromatography, eluting with 35% diethyl ether/pet. ether, to give 761 mg (93%) of 140 as a clear, colourless oil, which was one spot by TLC. IR (neat,cm-i) 3411,2912, 1714, 1591, 1451, 1374, 1175, 1022,868. lH NMR (CDC13, 400 MHz) 6 0.86-1.03 (m, 15 H), 1.19 (d, J = 7 Hz, 3 H), 1.26-1.60 (m, 19 H), 2.87 (m, 2 H), 3.70 (s, 3 H), 3,79 (m, J = 6 Hz, 1 H), 5.96 (s, JSn-H = 65 Hz, 1 H). LRMS (m/z) 461 (0.8, M+-OH), 419 (100, M+-C4H9), 418 (39), 417 (85), 416 (35), 415 (52), 401 (73), 400 (29), 399 (56), 398 (22), 397 (32), 265 (40), 263 (29), 179 (64), 178 (21), 177 (78), 176 (28), 175 (56), 151 (93), 150 (25), 149 (72), 148 (23), 147 (44), 137 (27), 121 (35), 119 (26). Elem. Anal, calcd for C22H4403Sn: C 55.60, H 9.33; found: C 55.46, H 9.40. OH 140 EXPERIMENTAL 157 3.64 Methyl (£)-3-(tri(n-butyl)stannyl)-8-iodo-2-nonenoate (132). Following the procedure outlined in section 3.49, the alcohol 140 (300 mg, 0.63 mmol) was converted into the corresponding iodide 132. The crude product was purified by flash chromatography, eluting with 3% diethyl ether/pet ether, to give 295 mg (84%) of 132 as a clear, colourless oil. GC (column C, temp, program) 100%, RT= 14.33 min. BR (neat,cm-l) 2934,2854, 1718, 1592, 1450, 1376, 1347, 1173, 868. J H NMR (CDC13, 400 MHz) 6 0.88-1.03 (m, 15 H), 1.28-1.60 (m, 16 H), 1.63 (m, 1 H), 1.87 (m, 1 H), 1.92 (d, J = 7 Hz, 3 H), 2.88 (m, 2 H), 3.70 (s, 3 H), 4.19 (m, J = 6 Hz, 1 H), 5.95 (s, Jsn-H = 65 Hz, 1 H). LRMS (m/z) 529 (22, M+-C4H9), 528 (8), 527 (16), 526 (6), 525 (9), 401 (75), 400 (29), 399 (52), 398 (17), 397 (22), 361 (100), 360 (31), 359 (76), 358 (27), 357 (44), 305 (45), 303 (35), 301 (22), 291 (25), 289 (24), 287 (20), 265 (25), 235 (27), 179 (45), 177 (53), 175 (40), 151 (58), 149 (46), 147 (29), 121 (26), 67 (31), 55 (30), 41 (99). HRMS calcd for Ci8H34O2l120Sn (M+-C4H9): 529.0627, found: 529.0618. 132 EXPERIMENTAL 158 3.65 Methyl (Z)-3-(tri(n-butyl)stannyI)-8-hydroxy-2-nonenoate (141). Following the procedure outlined in section 3.44, the (£)-vinylstannane 140 (384 mg, 0.81 mmol) was isomerized to the corresponding (Z)-vinylstannane 141. The crude product was purified by flash chromatography, eluting with 30% diethyl ether/pet ether, to give 369 mg (96%) of 141 as a clear, colourless oil, which was one spot by TLC. IR (neat, cm"1) 3360, 2933, 2854, 1707, 1596, 1460, 1375, 1328, 1201, 1125, 1071, 930. IH NMR (CDC13, 400 MHz) 6 0.84-1.02 (m, 15 H), 1.17 (d, J = 7 Hz, 3 H), 1.20-1.54 (m, 19 H), 2.39 (m, 2 H), 3.70 (s, 3 H), 3.76 (m, 1 H), 6.33 (s, JSn-H = 108 Hz, 1 H). LRMS (m/z) 419 (100, M+-C4Ho), 418 (41), 417 (79), 416 (32), 415 (49), 401 (6), 151 (24), 149 (19). HRMS calcd for Ci8H 3 5O 3 1 2 0 Sn (M+-C4H 9): 419.1608, found: 419.1615. OH 141 EXPERIMENTAL 159 3.66 Methyl (Z)-3-(tri(n-butyl)stannyl)-8-iodo-2-nonenoate (133). Following the procedure outlined in section 3.49, alcohol 141 (160 mg, 0.33 mmol) was converted into the corresponding iodide 133. The crude product was purified by radial chromatography, eluting with 2% diethyl ether/pet. ether, to give 156 mg (80%) of 133 as a clear, colourless oil. GC (column C, temp, program) 100%, RT = 13.32 min. IR (neat, cm"1) 2932, 2853, 1708, 1597, 1449, 1376, 1328, 1200, 1072, 871. !H NMR (CDC13, 400 MHz) 5 0.83-1.02 (m, 15 H), 1.21-1.62 (m, 16 H), 1.70 (m, 1 H), 1.82 (m, 1 H), 1.90 (d, J = 7 Hz, 3 H), 2.39 (m, 2 H), 3.70 (s, 3 H), 4.15 (m, 1 H), 6.32 (s, JSn-H = 108 Hz, 1 H). LRMS (m/z) 529 (1.8, M +-C 4H 9), 528 (0.8), 527 (1.4), 526 (0.5), 525 (0.8), 437 (7), 435 (5), 401 (100), 400 (41), 399 (76), 398 (31), 397 (42), 151 (37), 149 (28), 41 (43). HRMS calcd for Ci9H 34O2l 1 2 0Sn ( M + - C 4 H 9 ) : 529.0627, found: 529.0623. 133 EXPERIMENTAL 3.67 Methyl (£M2-methylcycIohexylidene)acetate (142). 160 142 Method A: Via an addition-fragmentation reaction of 132. To the (£)-vinylstannane 132 (172 mg, 0.294 mmol) in 16.2 mL of benzene was added tris(trimethylsilyl)silane (56 uL, 0.176 mmol), followed by triethylborane (74 uL of 1.0 M in hexane, 74 umol). A 7.7 mL sample of air was then slowly bubbled through the solution over a period of 10 minutes. When TLC indicated no 132 remained, the reaction mixture was concentrated by rotary evaporation to give a yellow oil. This oil was purified by radial chromatography, eluting with 3% diethyl ether/pet. ether, to give 40.3 mg (82%) of 142 as a clear, colourless oil. Method B: Via cyclization of compound 146. To a solution of compound 146 (50 mg, 0.17 mmol) in 8.5 mL of benzene was added tri(/i-butyl)tin hydride (51 uL, 0.19 mmol) and a catalytic amount of AIBN. The resulting solution was refluxed for 2 hours. The reaction mixture was then cooled to room temperature, and concentrated by rotary evaporation to give a yellow oil. This oil was purified as above to give 22.4 mg of 142 as a clear, colourless oil. BR (neat, cm"1) 2935, 2855, 1719, 1644, 1452, 1379, 1225, 1163, 1135, 1024, 867. ! H NMR (CDC13, 400 MHz) 6 1.06 (d, J = 8 Hz, 3 H), 1.24 (m, 2 H), 1.48 (m, 2 H), 1.68-1.88 (m, 2 H), 2.1-2.32 (m, 2 H), 3.50 (m, 1 H), 3.69 (s, 3 H), 5.56 (s, 1 H). LRMS (m/z) 168 (73, M+), 153 (15), 137 (43), 136 (25), 121 (31), 109 (32), 108 (46), 95 (37), 94 (100), 93 (35), 81 (24), 79 (39), 67 (38). Elem. Anal, calcd for C10H16O2: C 71.39, H 9.59; found: C 71.27, H 9.63. EXPERIMENTAL 3.68 Methyl (Z)-(2-methyIcyclohexyIidene)acetate (144). 161 144 To a solution of the cc.p-alkynyl ester 146 (86 mg, 0.29 mmol) and tris(trimethylsilyl)silane (99 uL, 0.32 mmol) in 14.5 mL of THF at -78 °C was added triethylborane (73 uL, 0.073 mmol). A 7.6 mL sample of dry air was slowly bubbled through this solution, over a period of 5 min. The reaction mixture was then allowed to slowly warm to room temperature over a period of 45 min. Concentration of the reaction mixture gave a pale yellow oil, which was purified by radial chromatography, eluting with 3% diethyl ether/pet. ether, to give 36 mg of 144, as well as 4 mg of 142, as clear, colourless oils. IR (neat, cnr*) 2933, 2859, 1718, 1643, 1436, 1385, 1265, 1225, 1163, 1135, 1032, 849. *H NMR (CDCI3, 400 MHz) 6 1.13 (d, J = 8 Hz, 3 H), 1.19-1.70 (m, 6 H), 1.84 (m, 1 H), 2.03 (m, 1 H), 3.68 (s, 3 H), 4.00 (m, 1 H), 5.51 (s, 1 H). LRMS (m/z) 168 (46, M+), 137 (29), 121 (27), 109 (25), 108 (39), 95 (33), 94 (100), 93 (28), 91 (27), 79 (44), 67 (41), 41 (29). Elem. Anal, calcd for C10H16O2: C 71.39, H 9.59; found: C 71.24, H 9.70. 162 R E F E R E N C E S 1. Hey, D.H; Waters, W.A. Chem. Rev. 1937, 21, 169. 2. Kharasch, M.S.; Margolis, E.T.; Mayo, F.R. J. Org. Chem. 1937, 2, 393. 3 . (a) Curran, D.P. Synthesis 1988, 9, 417. (b) Curran, D.P. Synthesis 1988, 9, 489. 4 . Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press, Oxford, 1986. 5. Hart, D J . Science 1984, 223, 883. 6 . Beckwith, A.L.J . Tetrahedron 1981, 37, 3073. 7 . Ramaiah, M . Tetrahedron 1987,43, 3541. 8 . Jorgensen, W.L.; Laird, E.R. J. Org. Chem. 1990, 55, 9. 9. Allred, A . L . J. Inorg. Nucl. Chem. 1961,17, 215. 10. Beckwith, A.L.J . ; Pigou, P.E. Aust. J. Chem. 1986, 39, 77. 11 . Neumann, W.P. Synthesis 1987, 8, 665. 12 . Nagashimo, H. ; Wakamatsu, H. ; Itoh, K. J. Chem. Soc, Chem. Commun. 1984, 652. 13 . Caronna, T.; Citterio, A.; Ghirardini, M . ; Minisci, F. Tetrahedron 1977, 33, 793. 14 . Baban, J.A.; Roberts, B.P. J. Chem. Soc, Perkin Trans. 2 1981, 161. 15 . Giese, B. Angew. Chem., Int. Ed. Engl 1983, 22, 753 16 . Giese, B.; Lachein, S. Angew. Chem., Int. Ed. Engl. 1981, 20, 967. 17 . Beckwith, A.L.J . ; Moad, G. J. Chem. Soc, Chem. Commun. 1974, 472. 18. Beckwith, A.L.J . ; Lawrence, T. /. Chem. Soc, Perkin Trans. 2, 1979, 1535. 19. Beckwith, A.L.J . ; Lawrence, T.; Serelis, A . K . J. Chem. Soc, Chem. Commun. 1980, 484. 20 . Beckwith, A . L J . ; Phillipou, G.; Serelis, A . K . Tetrahedron Lett. 1981, 22, 2811. 21. Beckwith, A.L.J . ; Roberts, D.H. J. Am Chem. Soc, 1986, 108, 5893. 22 . Beckwith, A.L.J . ; Schiesser, C H . Tetrahedron Lett. 1985, 26, 373. 23. Beckwith, A.L.J . ; Easton, C.J.; Serelis, A .K. ; J. Chem Soc, Chem. Commun. 1980, 482. 163 24. (a) Beckwith, A.L.J.; Schiesser, C.H.; Tetrahedron 1985, 41, 3925. (b) Beckwith, A.L.J.; Meijs, G.F. /. Chem. Soc., Perfdn Trans. 2 1979, 1535. 25 . Houk, K.N.; Spellmeyer, D.C. J. Org. Chem. 1987, 52, 959. 26 . Kuivila, H.G. Acc. Chem. Res. 1968,1, 299. 27. Jackson, R.A. J. Organomet. Chem. 1979,166, 17. 28 . Beckwith, A.LJ.; Pigou, P.E. Aust. J. Chem. 1986, 39, 1151. 29. Ingold, K.U.; Lusztyk, J.; Scaiano, J.C. J. Am. Chem. Soc. 1984, 106, 343. 30. Stork, G.; Sher, P.M. J. Am. Chem. Soc. 1986, 108, 303. 31. (a) Curran, D.P.; Rakiewicz, D.M. Tetrahedron, 1985,47, 3943. (b) Curran, D.P.; Rakiewicz, D.M. J. Am. Chem. Soc. 1985, 707, 1448. (c) Curran, D.P.; Chen, M.H. Tetrahedron Lett. 1985,26, 4991. (d) Curran, D.P.; Kuo, S.C. J. Am. Chem. Soc. 1986,708, 1106. (e) Curran, D.P.; Jasperse, CP. J. Am. Chem. Soc. 1990, 772, 5601. 32 . Porter, N.A.; Chang, V.H.-T. J. Am. Chem. Soc. 1987,109, 4976. 33. Pattenden, G.; Hitchcock, S.A. Tetrahedron Lett. 1990, 31, 3641. 34. Giese, B.; Kopping, B.; Chatgilialoglu, C. Tetrahedron Lett. 1989,50, 681. 35 . (a) Stork, G., in Current Trends in Organic Synthesis, Nozaki, H. (ed.), Pergamon Press, Oxford, 1983, p. 359. 36 . Stork, G.; Baine, N.H. J. Am. Chem. Soc. 1982, 104, 3720. 37. Stork, G.; Baine, N.H. J. Am. Chem. Soc. 1982, 104, 2321. 38 . Stork, G.; Mook, R. Jr. / Am. Chem. Soc. 1987, 709, 2829. 39. (a) Angoh, A.G.; Chve, D.L.J. J. Chem. Soc, Chem. Commun. 1985, 980. (b) Clive, D.LJ.; Beaulieu, P.L.; Set, L. J. Org. Chem, 1984, 223, 883. 40. (a) Bartlett, P.A.; McLaren, K.L.; Ting, P.C. J. Am. Chem. Soc. 1988, 110, 1633. (b) Enholm, EJ.; Burroff, J.A.; Jaramillo, L.M. Tetrahedron Leu. 1990,57, 3727. 41. Beckwith, A.LJ.; Hay, B.P. J. Am. Chem. Soc. 1989, 777, 2674. 42. Fraser-Reid, B.; Tsang, R. /. Am. Chem. Soc. 1986,108, 2116. 43. Fraser-Reid, B.; Tsang, R. J. Am. Chem. Soc. 1986,108, 8102. 164 44. (a) Stork, G.; Kahn, M. J. Am. Chem. Soc. 1985,107, 500. (b) Stork, G.; Sher, P.M. J. Am. Chem. Soc. 1986, 108, 303. 45. (a) Johnson, M.D. Acc. Chem. Res. 1983, 16, 343. (b) Gaudemer, A.; Nguyen van duong, N.; Shahkarami, N.; Achi, S.S.; Frostin-Rio, M.; Pujol, D. Tetrahedron 1985,41, 4095. 46. (a) Russell, G.A.; Ngoviwatchai, P. Tetrahedron Lett., 1985, 26, 4975. (b) Russell, G.A.; Ngoviwatchai, P. Tetrahedron Lett., 1986, 27, 3479. (c) Russell, G.A.; Tashtoush, H.; Ngoviwatchai, P. J.Am.Chem.Soc. 1984,106, 4622. 47. (a) Keck, G.E; Enholm, E.J.; Yates, J.B.; Wiley, M.R. Tetrahedron 1985,41, 4079. (b) Keck, G.E.; Yates, J.B. J. Am. Chem. Soc. 1982,104, 5829. 48. Curran, D.P.; van Elburg, P.A.; Giese, B.; Gilges, S. Tetrahedron Lett. 1990, 31, 2861. 49. Padwa, A.; Murphree, S.; Yeske, P. Tetrahedron Lett. 1990, 31, 2983. 50. (a) Baldwin, J.E.; Kelly, D.R.; Ziegler, C. J. Chem. Soc, Chem. Commun., 1984, 133. (b) Baldwin, J.E.; Kelly, D.R. J. Chem. Soc, Chem. Commun., 1985, 682. 51 . Keck, G.E.; Burnett, D.A. J. Org. Chem 1987,52, 2960. 52 Walling, C; Huyser, E.S. Org. React. 1963,13, 91. 53. Curran, D.P.; Chang, CT. J. Org. Chem 1989, 54, 3140. 54 . Danen, W.C, in: Methods in Free Radical Chemistry, Vol. 5, Huyser, RS. (ed.), Marcel Dekker, New York, 1974. 55. Curran, D.P.; Chang, CT. Tetrahedron Lett. 1981,28, 2477. 56. Curran, D.P.; Chen, M.H. J. Am. Chem. Soc. 1987, 109, 6558. 57. Schrauzer, G.N. Angew. Chem. Int. Ed. Engl. 1976, 15, 417. 58.. Samsel, E.G.; Kochi, J.K. J. Am. Chem. Soc. 1986, 108, 3925. 59. Pattenden, G. Chem. Soc. Rev. 1988, 17, 361. 60. Pattenden, G.; Patel, V.F. Tetrahedron Lett., 1981, 28, 1451. 165 61 . Tumlinson, J.H.; Gueldner, R.C.; Hardee, D.D.; Thompson, A.C; Hedin, P.A.; Minyard, J.P. J. Org. Chem. 1971, 36, 2616. 62. Piers, E ; Chong, J.M.; Morton, H.E. Tetrahedron 1989,45, 363. 63. Creger, P.L. J. Am. Chem. Soc. 1967, 45, 2500. 64. Schwarz, M.; Oliver, J.E.; Sonnet, P.E J. Org. Chem. 1975, 40, 2410. 65. Smith, W.N.; Beumel, O.F. Synthesis, 1974, 441. 66. Leusink, AJ.; Budding, H.A.; Massman, J.W. /. Organomet. Chem. 1967, 9, 285. 67. Neumann, W.P.; Hillgartner, H.; Baines, K.M.; Dicke, R.; Vorspohl, K.; Kobs, U.; Nussbeutel, U. Tetrahedron 1989,45, 951. 68. Leonard, W.R.; Livinghouse, T. Tetrahedron Lett. 1985,26, 6431. 69. Barton, D.H.R.; Jang, D.O.; Jaszberenyi, J.C. Tetrahedron Lett. 1990,57,4681. 70. (a) Oshima, K.; Ichinose, Y.; Fugami, K. Tetrahedron Lett. 1989,30, 3155. (b) Oshima, K.; Nozaki, K.; Utimoto, K. Tetrahedron 1989,45, 923. 71. Nugent, W.A.; RajanBabu, T.V. /. Am. Chem Soc. 1988,110, 8561. 72. Manzer, L.E. Inorg. Synth. 1982, 21, 84. 73. Beckwith, A.L.J.; Tetrahedron 1981, 37, 3073. 74. Tillyer, R. Ph.D. Thesis, University of British Columbia, 1990. 75. Enholm, E.J.; Prasad, G. Tetrahedron Lett. 1989,30, 4939. 76. Omura, K.; Swern, D. Tetrahedron 1978,34, 1651. 77. (a) Enholm, EJ.; Trivellas, A. Tetrahedron Lett. 1989,30, 1063. (b) Ujikawa, O.; Inanaga, J.; Yamaguchi, M. Tetradron Lett. 1989,30, 2837. (c) Enholm, E.J.; Satici, H.; Trivellas, A. J. Org. Chem 1989,54, 5841. (d) Enholm, EJ.; Trivellas, A. J. Am Chem Soc. 1989, 777, 6463. (e) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem Soc., Perkin Trans. I, 1988, 1669. (f) Fevig, T.L.; Elliott, R.L.; Curran, D.P. J. Am. Chem. Soc. 1988,110, 5064. (g) Fukuzawa, S.; Iida, M.; Nakanishi, A.; Fujinami, T.; Sakai, S. J. Chem. Soc, Chem. Commun. 1987, 920. 78. Shim, S.C; Hwang, J.T. Tetrahedron Lett. 1990, 31, 4765. 79 Corey, EJ.; Pyne, S.G. Tetrahedron Lett. 1983, 24, 2821. 80. Boothe, T.E; Greene, J.L.; Shevlin, P.B.; Willcott, M.R.; Inners, R.R.; Cornells, A. J. Am. Chem. Soc. 1978, 700, 3875. 81. Bryan, W.P.; Byrne, R.H. /. Chem Ed. 1970, 47, 361. 166 82. Perrin, D.D.; Armarego, W.L.F.; Perrin, D.R. Purification of Laboratory Chemicals; Pergamon Press: New York, 1966. 83. KuivilaJLG.; Beumel, O.F. J. Am. Chem. Soc. 1961, 83, 1246. 84. House, H.O.; Chu, C.Y.; Wilkins, J.M.; Umen, M.J. /. Org. Chem. 1978, 43, 2923. 85. Posner, G,; Brunelle, DJ.; Sinoway, L. Synthesis 1974, 622. 86. Chong, J.M. Ph.D. Thesis, University of British Columbia, 1983. 87. Hart, David J. Personal communication. 88. Still, W.C.,; Kahn, M.; Mirta, A. J. Org. Chem 1978, 43, 2923. 89. Occolowitz, J.L. Tetrahedron Lett. 1966,5921. SPECTRAL APPENDIX SPECTRAL APPENDIX 168 SPECTRAL APPENDIX 170 SPECTRAL APPENDIX 171 SPECTRAL APPENDIX SPECTRAL APPENDIX 175 SPECTRAL APPENDIX 176 SPECTRAL APPENDIX 177 SPECTRAL APPENDIX 179 r SPECTRAL APPENDIX 181 SPECTRAL APPENDIX 182 SPECTRAL APPENDIX 183 T T — I I | I i | i i i i—r~r 4 i | i i i i I i i i i | 3 2 I i i—i i | i i i i | i i i i | 1 0 i—i—i—r 100-1 1 1 1 1 1 1 1 1 1 1 i 1 1 1—i 1 1 1 1 1 i BOH KH 4 H an 1 fi "lOOO. CM-1 4000. 3400. i 1 1 1 1 1 1 1 1—x 2600. 2200. 1600. SPECTRAL APPENDIX SPECTRAL APPENDIX 185 SPECTRAL APPENDIX 186 SPECTRAL APPENDIX 187 SPECTRAL APPENDIX 188 SPECTRAL APPENDIX 189 SPECTRAL APPENDIX 190 SPECTRAL APPENDIX 191 SPECTRAL APPENDIX 193 SPECTRAL APPENDIX 194 SPECTRAL APPENDIX 195 SPECTRAL APPENDIX 202 SPECTRAL APPENDIX 203 SPECTRAL APPENDIX 205 SPECTRAL APPENDIX 206 SPECTRAL APPENDIX 207 100-SPECTRAL APPENDIX —i—i—i—i—i—i—i • i • — i — i — i -J 4 i • i — 1 i • i—•—i—•—i • i ' i—•—r-3 j I • ! • I 100—» i i 1 1 i 1 1 1 1 1 i 1 i i 1 1 i i i 1 i r — i BOH 40H 2 0 H —i—i—i—|—i—i—i—p 4000. 3400. 2800. T I 1 1 1 1 1 1 1 1 1 1— 2200. 1600. 1000. CM-1 SPECTRAL APPENDIX 209 SPECTRAL APPENDIX 2 1 0 T SPECTRAL APPENDIX 213 SPECTRAL APPENDIX 215 SPECTRAL APPENDIX 217 SPECTRAL APPENDIX 219 SPECTRAL APPENDIX 222 137 400 MHz -t-ACt 100-80-60-40-20--i 1 1 1 1 1 1 1 1- ~i 1 1 1 1 1 1 1 r 4000. i — i — i — i — i — | — i — i — i — r 3400. 2800. 2200. - i 1 1 1 1 1 1 r 1600. 1000. CM-1 SPECTRAL APPENDIX 226 SPECTRAL APPENDIX 227 228 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.831.1-0059795/manifest

Comment

Related Items