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Studies toward the total synthesis of salicylihalamide A Chandler, Melanie K. 2001

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STUDIES TOWARD THE TOTAL SYNTHESIS OF SALICYLIHALAMIDE A by Melanie K. Chandler B. Sc. (Hons.), McGill University, 1997 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE 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 2001 © Melanie K. Chandler, 2001 UBC Special Collections - Thesis Authorisation Form Page 1 of 1 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e for reference and study. I further agree that permission for extensive copying of th i s thesis f o r s c h o l a r l y purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or p u b l i c a t i o n of t h i s thesis f o r f i n a n c i a l gain s h a l l not be allowed without my written permission. 0 The U n i v e r s i t y of B r i t i s h Columbia Vancouver, Canada http://www.library.ubc.ca/spcoll/thesauth.html 7/17/01 A B S T R A C T 1 This thesis describes studies toward the synthesis of enamide macrolide salicylihalamide A (1). The convergent synthetic plan requires assembly of three main subunits whose eventual coupling should provide salicylihalamide A. Construction of two key fragments encompassing the sensitive (Z, Z)-diene sidechain (177) and the functionalized aromatic portion (142) of the target 1 have been realized, Compound 142 was efficiently synthesized using the accelerative effects of CuCI on the Pd(0)-catalyzed Stille coupling between o-substituted aromatic triflate 140 and allyl tributylstannane. The diene 177 was generated using a copper(l) thiophenecarboxylate mediated cross-coupling between vinyl stannane 181 and iodide 180. The reaction was stereospecific, rapid and mild enough to allow efficient construction of this hindered and labile sidechain. Preliminary investigations into the enantioselective synthesis of the remaining subunit culminated in the formation of aldehyde 95. During the course of this work a new protocol for generating Z-vinyl stannanes such as 181 from (trimethylsilyl)acetylene was also developed. T A B L E O F C O N T E N T S ABSTRACT ii TABLE OF CONTENTS iii LIST OF SCHEMES v LIST OF FIGURES viii LIST OF ABBREVIATIONS ix ACKNOWLEDGMENTS xiii I. INTRODUCTION 1 1.1 Background 1 1.2 Methodology Related to Enamide Formation 5 1.3 Methodology Related to (Z,Z)-Diene Formation 12 1.4 Organometallic Coupling Reagents 17 1.4.1 The Stille Coupling 18 II. RESULTS AND DISCUSSION 23 2.1 Synthetic Strategy 23 2.2 Total Synthesis of Salicylihalamide A 26 2.3 Toward the Total Synthesis of Salicylihalamide A 32 2.3.1 Preparation of the Aromatic Fragment 142 ' 32 2.3.2 Partial Preparation of the Central Fragment 34 2.3.3 Preparation of the a, p\ 8, y-Unsaturated Fragment 35 2.4 Conclusions and Future Work 47 III. EXPERIMENTAL 4 8 3.1 General 48 3.1.1 Data Acquisition, Presentation, and Experimental iv Techniques 48 3.1.2 Solvents and Reagents 51 3.2 Chemical Methods 52 REFERENCES AND FOOTNOTES 70 V L I S T O F S C H E M E S Scheme 1. Transformation of a carboxylic acid to a carbamate via the Curtius rearrangement. 6 Scheme 2. Snider's synthesis of model enamide side chain 25 (from reference 16). 7 Scheme 3. Kitahara's synthesis of (Z)-isocyanate 29 (from reference 17) 7 Scheme 4. Synthesis of the model oximidine side chain 34 (from reference 17). 8 Scheme 5. Brettle's acyl exchange protocol via the trifluoroacetamide 41 (from reference 20). 9 Scheme 6. Brettle's acyl exchange protocol via the carbamate 44 (from reference 20). 10 Scheme 7. Transformation of amide 43 to vinyl amide 45 catalysed by copper(l) thiophenecarboxylate (from reference 21). 11 Scheme 8. Synthesis of O-methyloxime side chain derivatives 50 and 51 (from reference 21). 12 Scheme 9. Schlosser's synthesis of (2Z,4Z)-dienol derivative 55 (from reference 34). 14 Scheme 10. General equation for the Cadiot-Chodkiewicz reaction (from reference 37). 15 Scheme 11. General equation for unsymmetrical diyne formation via hypervalent alkynyl iodonium salts (from reference 41). 15 Scheme 12. Triene (67) synthesis using alkenyliodonium salt 65 (from reference 44). 16 Scheme 13. General equation for the Stille cross-coupling reaction (from reference 50). 18 Scheme 14. Stille coupling of densely functionalized fragments in Nicolaou's Synthesis of sanglifehrin A (from reference 61). 20 Scheme 15. An aryl triflate/allyl tin Stille coupling in Furstner's synthesis of (Ff)-(+)-lasiodiplodin (3) (from reference 62). 21 Scheme 16. Postulated catalytic cycle for the Stille reaction (from vi reference 63). 22 Scheme 17. Retrosynthetic analysis of salicylihalamide A (1). 23 Scheme 18. Retrosynthesis of aromatic fragment 82. 24 Scheme 19. Retrosynthesis of central fragment 83. 25 Scheme 20. Retrosynthesis of diene fragment 84. 25 Scheme 21. De Brabander's synthesis of 1 (from reference 64). 28 Scheme 22. Salicylihalamide stereoisomers and dimeric compounds Synthesized by the De Brabander group (from reference 67) 29 Scheme 23. Georg's synthesis of salicylihalamide precursor 138 (from reference 68). 31 Scheme 24. Synthesis of aromatic fragment 142. 32 Scheme 25. Stoichiometric Cul provides rate enhancement in the cross-coupling of aryl iodide 143 and vinyl stannane 144 (from reference 70). 33 Scheme 26. Corey's conditions for the Stille coupling of sterically congested substrates (from reference 73). 33 Scheme 27. Synthesis of chiral oxazolidinone 152. 34 Scheme 28. Synthesis of chiral aldehyde 95. 35 Scheme 29. Proposed synthesis of diyne 158 using the Cadiot-Chodkiewicz reaction. 35 Scheme 30. Proposed synthesis of diyne ester 161. . . . . . . . . 36 Scheme 31. Synthesis of hypervalent iodonium salt 166. 36 Scheme 32. Proposed synthesis of diyne 170 via the hypervalent iodonium salt 169. 37 Scheme 33. Norin's synthesis of (Z, Z)-diene ester 172 via reduction of enyne 171 (from reference 84). 37 Scheme 34. Retrosynthesis of 161 via a retro-Horner-Wadsworth-Emmons reaction. 38 Scheme 35. Retrosynthesis of diene ester 177 via a retro-Stille reaction 39 Scheme 36. Proposed synthesis of vinyl iodide 179. 39 vi Scheme 37. Synthesis of (Z)-vinyl iodoester 180. 40 Scheme 38. Proposed alkylation of stannyl alkyne 185. 40 Scheme 39. Alkylation of 157 to provide silyl alkyne 165. 41 Scheme 40. Transformation of silyl acetylene 165 into (Z)-vinyl tin 181 41 Scheme 41. Stille coupling of vinyl subunits 181 and 180. 42 Scheme 42. Ullmann-like homocoupling of (Z)-vinyl bromoester 188 in the presence of Ni(0) (from reference 92). 42 Scheme 43. Stille's synthesis of (Z, Z)-diene ester 191 (from reference 94) 43 Scheme 44. Cross-coupling of vinyl species 181 and 180 using Liebeskind's CuTC protocol. 45 L I S T O F F I G U R E S viii Figure 1. Representative natural products isolated from marine sponges of the genus Haliclona. 2 Figure 2. Furstner's truncated salicylate macrolide 3 exhibited no specificity in vitro (from reference 3). 3 Figure 3. The apicularens A (4) and B (5) (from reference 4). 3 Figure 4. Other enamide salicylate macrolides isolated from various natural sources (from references 5-8). 4 Figure 5. Lansamide I (35) and the lansiumamides A (36) and B (37) (from reference 19). 9 Figure 6. Bond disconnections in Negishi's synthesis of xerulin (from reference 49). The metal species indicated were instrumental in forming the corresponding carbon-carbon bonds. 17 Figure 7. Stille coupling bond disconnections in Nicolaou's synthesis of sanglifehrin A (73) (from reference 61). 19 Figure 8. Salicylihalamide derivatives made by De Brabander and coworkers (from reference 67). 30 Figure 9. Cross-coupling of vinyl and aryl iodides and stannanes mediated by CuTC (from reference 95). 44 Figure 10. Catalytic cycle for CuTC-mediated cross-coupling of vinyl and aryl iodides and stannanes (from reference 95). 45 Figure 11. NOE enhancements observed in diene ester 177. 46 ix L I S T O F A B B R E V I A T I O N S a below the plane of a ring or 1,2-relative position Ac acetyl Ar aryl (3 above the plane of a ring or 1,3-relative position bp boiling point br broad bu butyl bz benzene °C degrees Celsius calcd calculated CI chemical ionization cone concentrated CuTC copper(l) thiophenecarboxylate Cp cyclopentadienyl C-x carbon number x d day(s) or doublet 5 chemical shift in parts per million from tetramethylsilane A n m double bond between carbons n and m dba dibenzylideneacetone DCI desorption chemical ionization DIPA diisopropylamine DMF A/,A/-dimethylformamide DMSO dimethylsulfoxide X DPPA diphenylphosphorazide £ entgegen (configuration) ed edition Ed., Eds Editor, editors El electron ionization equiv equivalent(s) Et ethyl g gram(s) Y 1,4-relative position GUo concentration at which 50% growth inhibition is observed glc gas-liquid chromatography h hour(s) HMPA hexamethylphosphoramide HRMS high resolution mass spectrum or spectrometry HWE Horner-Wadsworth-Emmons H-x hydrogen number x i iso IR infrared IC50 inhibitory concentration (for 50% of a biological sample) J coupling constant in Hertz n J s n - H n bond coupling fortin and proton nuclei (in Hertz) L litre(s) or ligand LAH lithium aluminum hydride LDA :. lithium diisopropylamide xi LRMS low resolution mass spectrum or spectrometry m multiplet M molar M+ molecular ion Me methyl mg milligram(s) MHz ..megahertz min minute(s) ml_ millilitre(s) mm millimeter(s) yiM micromolar mmol millimole(s) mol mole(s) mp melting point n normal ng nanogram(s) nM nanomolar NMP 1-methyl-2-pyrrolidinone nmr nuclear magnetic resonance P page PCC pyridinium chlorochromate Ph phenyl ppm parts per million Pr. propyl pyr pyridine xi q quartet R.... rectus (configuration) Rf retention factor or ratio-to-front rt room temperature s singlet S sinister (configuration) sp species t triplet t tertiary TBS tert-butyldimethylsilyl TEA triethylamine THF tetrahydrofuran TMSA (trimethylsilyl)acetylene TFA trifluoroacetic acid Tf trifluoromethanesulfonyl tic thin-layer chromatography TMS trimethylsilyl uv ultraviolet v/v volume-to-volume ratio w/v weight-to-volume ratio Z zusammen (configuration) • coordination or complex A C K N O W L E D G M E N T S xm I would like to acknowledge the personal and professional guidance of my research supervisor, the late Dr. Larry Weiler. Thanks to all members of the Weiler group, past and present, that I have had the pleasure to know and for having provided an enjoyable and stimulating work environment. In particular I would like to thank the Fenster brothers for their support and encouragement over the years. I thank Dr. Piers and present members of the Piers' research group for invaluable discussions regarding this research. I thank Dr. John Scheffer and Dr. Michael Pungente for their guidance in preparing this thesis. The assistance of the nmr and technical support staff in the UBC chemistry department is gratefully acknowledged. I thank my parents for their continued support and encouragement. Lastly, my most sincere thanks and appreciation to Shawn D. Walker for his tireless patience, support and encouragement in all aspects of my life. 1 C H A P T E R O N E I N T R O D U C T I O N 1.1 Background Marine sponges, notably those from the genus Haliclona, are recognised as a valuable source of interesting and novel bioactive natural products, most commonly alkaloids.1 The bioactivity of these compounds varies from cytotoxic to antifungal or antimicrobial in nature. Representative examples reported from this genus are depicted below. Included among these are the first of a new class of antitumour macrolides, the salicylihalamides 1 and 2 (Figure 1). manzamine A manzamine B manzamine C 2 26 25 26 haliclonacyclamine A (A ' ) 1 (17£) haliclonacyclamine B ( A 2 9 ! 3 0 ) 2 (117) Figure 1. Representative natural products isolated from marine sponges of the genus Haliclona. Salicylihalamides A (1) and B (2) were isolated in 1997 by Erickson and co-workers from an Australian collection of an unidentified species of Haliclona.2 Their unique structure, elucidated primarily on the basis of two-dimensional nmr spectroscopy, incorporates a salicylic acid moiety, a 12-membered lactone ring, and a conjugatively unsaturated enamide side chain. These compounds displayed a striking pattern of differential cytotoxicity in the NCI 60-cell line human tumour assay with a mean activity GI5o level of 15 nM, and highest sensitivity (GI5o = 7 ± 2 nM) against melanoma cell lines. This cytotoxicity profile was of particular interest since it did not display any significant correlation to those profiles shown by other known antitumour compounds. Furstner and co-workers3 have effectively synthesized a truncated salicylate macrolide, 3 (Figure 2). This compound contains the core structure of the salicylate macrolides, but lacks the enamide side chain. Assays revealed relatively uniform in vitro activity (GI50 = 0.2-50 u,M) but surprisingly showed no specificity for any of the cell lines tested. Thus it was proposed that the unique side chain is predominantly responsible for the observed biological specificity. 3 OMe O 3 Figure 2. Furstner's truncated salicylate macrolide 3 exhibited no specificity in vitro (from reference 3). This discovery was followed by the isolation by Kunze and co-workers of the cytostatic macrolides apicularens A (4) and B (5) from several species of myxobacteria of the genus Chondromyces (Figure 3).4 These compounds are of particular interest, as they share with 1-2 the unusual and highly reactive A/-((1£)-alkenyl)-(2Z,4Z)-heptadienamide side chain. Apicularen A (4) was found to be highly cytotoxic for cultivated human and animal cells, with IC50 values ranging between 0.1 and 3 ng/mL. OR 4 R = H 5 R = N-acetyl-p-D-glucosamine Figure 3. The apicularens A (4) and B (5) (from reference 4). Subsequently, the isolation of the oximidines I (6) and II (7) from Pseudomonas sp. Q52002;5 the lobatamides A6-F (8-13) from Aplidium lobatum, Aplidium sp., and from an unidentified Philippine ascidian;7 and of CJ-12,950 (14) and CJ-13,357 (15) from Mortierella verticillata was reported (Figure 4).8 These compounds share a 4 common core structure with 1-2 and 4-5, but host different substitution patterns on the lactone ring, and contain an O-methyloxime moiety at the terminus of the enamide side chain. In addition, the lobatamides contain a 15-membered bis-lactone instead of the 12-membered lactone characteristic of the previously mentioned molecules. These compounds also exhibit antitumour activity. Compounds 6 and 7 selectively inhibit the growth of rat 3Y1 cells transformed with E1 A, ras, or src oncogenes. Compounds 8-13 exhibit a characteristic pattern of differential cytotoxicity in human tumour cell lines (G l 5 0 level of 1.6 nM) with a high profile correlation among themselves as well as with 1 and 2. 8-13 [(R = H, 24Z, 26E), (R = OH, 24Z, 26E), 14 (17£) (R = H, 24Z, 26Z), (R = OH, 24Z, 26Z), 15 (17Z) (R = H, 24E, 26E), (R = OH, 24E, 26E)] Figure 4. Other enamide salicylate macrolides isolated from various natural sources (from references 5-8). 5 The fact that compounds 1-2 and 8-13 exhibit characteristic and unique behaviour in cytotoxicity assays is suggestive of a novel mechanism of antitumour action in vitro. The salicylate enamide macrolides are therefore attractive targets for total synthesis, due to their intrinsically interesting structural features and their significant bioactivity. They represent potential lead compounds for a new class of antitumour agent. A cursory examination of the enamide macrolide molecules reveals that the formation of the side chain is of great importance. The most noteworthy features of the side chain are the enamide moiety and the conjugated (Z,Z)-diene. It is thus of interest to devise a method for forming these two integral sections of the target molecule. The following discussion will attempt to highlight recent advances in methodology related to enamide formation and (Z,Z)-diene synthesis relevant to this endeavour. 1.2 Methodology Related to Enamide Formation The isolation and structural elucidation of the salicylihalamides and other members of this emerging class of macrolides has stimulated the development of more efficient methods to synthesize them. The majority of this work has focused on the formation of the highly reactive and unstable enamide side chain. Described within the literature are a wide variety of methods for forming enamides, including the Curtius rearrangement9 of a,f3-unsaturated acyl azides, palladium(ll)-catalysed amidation of alkenes,10 direct addition of amides to alkynes,11 acylation of imines,12 acid-catalysed condensation of aldehydes and amides,13 amide Peterson olefination,14 as well as Horner-Wittig and Wadsworth-Emmons reactions.15 That which has received the most interest pertaining to the synthesis of conjugatively unsaturated enamides such as those encountered in 1-2 and 4-15 is the Curtius rearrangement. The Curtius rearrangement is a classical method for the conversion of a carboxylic acid into the corresponding amine containing one less carbon atom, such as 16-20 in Scheme 1. Typically, the reaction is performed in alcohol as solvent, and the carbamate derivative 19 is isolated. The intermediate acyl azide 17 and isocyanate 18 are proven, often isolable intermediates. 6 O 16 NaN3 or O DPPA» Jl OH R'OH, Et3N ,R N3 17 O VT N—N=N R O n /NH 2 20 DPPA= N3-P N-OPh OPh LAH NH ^O-R' O 19 R'OH O J I / 7 R' .N=C=0 18 Scheme 1. Transformation of a carboxylic acid to a carbamate via the Curtius rearrangement. Snider and co-workers16 synthesized a model compound containing the requisite side chain moiety (25b) via alkenylation of an alkenyl isocyanate (Scheme 2). Treatment of the alkyllithium (21a or 21b) with copper bromide-methyl sulfide complex at -40 °C afforded the corresponding organocuprate. Addition of acetylene at -50 °C provided the (1Z)-alkenylcuprate, via carbocupration of acetylene. A second equivalent of acetylene inserted at -10 °C to give the (1Z,3Z)-alkadienylcuprate 22, along with residual alkenylcuprate and (1Z,3Z,5Z)-trienylcuprate. Subsequent treatment with hexamethylphosphortriamide, triethylphosphite, and (1 £)-pentenyl isocyanate 23, prepared via the Gurtius rearrangement of the corresponding acyl azide yielded, upon warming, the enamide homologues. Flash chromatography on silica gel afforded 60-65% of a 3:1:1 mixture of desired dienamides 25, enamides 24, and trienamides 26 respectively, which proved separable by flash chromatography ,on silver nitrate impregnated silica gel. 7 3 RLi 1.1.5 equiv. CuBr • SMe2, ether -40 to -30 °C, 30 min 2. 6 equiv. HC=CH -50 to -30 °C, 30 min 21a, R = A7-Bu 3 . 6 e q u i v . HC=CH LiCu R 22 21b, R = Et -10 °C, 10 min 23 HMPA, P(OEt)3 * -78 to 0 °C, 1 h Scheme 2. Snider's synthesis of model enamide side chain 25 (from reference 16). Kitahara's group17 described an efficient stereoselective entry to (Z)-enamides in an effort directed toward the synthesis of the oximidines (Schemes 3-4). The study began with the stereoselective synthesis of the (Z)-isocyanate 29. Treatment of the (Z)-a.p-unsaturated acid 27 with diphenylphosphorazide (DPPA)18 in THF provided a 4:1 mixture of the (Z)-acyl azide 29 and the corresponding (E)-isomer, which were readily separable by flash chromatography. O OH NaH, DPPA, THF (80%, 4:1 Z:£) O O _Q_ toluene, 100 °C 27 'OBn 28 ^OBn 29 'OBn Scheme 3. Kitahara's synthesis of (Z)-isocyanate 29 (from reference 17). 8 In order to elaborate the desired oximidine side-chain, a methoxyimino-(Z)-enamide system was required. Accordingly, propargyl alcohol (30) was iodinated by treatment with n-butyllithium followed by quenching with iodine (Scheme 4). Manganese dioxide then effected oxidation of the propargylic alcohol to the aldehyde, which was subsequently transformed into the corresponding O-methyloxime 31 by treatment with Omethylhydroxylamine hydrochloride. Diimide reduction afforded the vinyl iodide 32, which upon brief exposure to n-butyllithium underwent lithium-halogen exchange to provide the vinyl lithium reagent 33. Introduction of a toluene solution of isocyanate 29 to reagent 33 afforded the (Z)-enamide 34 in reasonable overall yield. 30 OH 1. a)n-BuLi,THF b) l 2 2. Mn02, benzene 3. CH3ONH3CI, pyr MeOH (21% for 3 steps) *OBn 34 K0 2CN=NC0 2K 31 AcOH, MeOH/pyr 32 OCH 3 OCH a (61%) n-BuLi hexane -78 °C, 5 min Solution of 29 in toluene -78 °C (63% for 2 steps) 33 O C H 3 Scheme 4. Synthesis of the model oximidine side chain 34 (from reference 17). A similar approach was applied to the synthesis of the simple (£)- and (Z)-enamides lansamide I (35) and lansiumamides A (36) and B (37). Taylor and co-workers19 attempted to preserve the olefin stereochemistry of (Z)-cinnamic acid by installing a trimethylsilyl group at the a-position as in 38 (Figure 5). Azidation followed by Curtius rearrangement and trapping of the incipient isocyanate by a styryl Grignard reagent afforded a 1:1 mixture of (£)- and (Z)-vinyl enamides. They reported that the reaction sequence, when performed on the underivatized (Z)-cinnamic acid, yielded exclusively the isomerized (E)-vinyl enamide. 9 R I Ph O 36 R = H 37 R = Me ,C02H SiMe3 38 Figure 5. Lansamide I (35) and the lansiumamides A (36) and B (37) (from reference 19). Interestingly, in a previous study by Brettle et al.,20 it was found that the Curtius rearrangement of (Z)-acyl azides proceeds with retention of olefin stereochemistry. (£)-and (Z)-a,(3-unsaturated acids can be subjected to azidation and rearrangement, and further modifications with careful choice of reaction conditions. Relevant to our work is the late-stage transformation (Scheme 5) in which an A/-acyl protecting group was exchanged for a different acyl group. Ar. ,H O 39 1. CIOC02Et, Et3N, Ar. acetone, 0 °C >• 2.i. NaN3, H20-acetone, 15 °C ii. reflux, bz H TFA, bz, 65 °C, 16 h Ar. Ck (45 % overall) NH X F 3 40 41 Ac20, pyr, 100 °C, 40 h + NH O ^ C H ? (18%) (42%) 43 42 Scheme 5. Brettle's acyl exchange protocol via the trifluoroacetamide 41 (from reference 20). 10 In this case, (£)-cinnamic acid 39 was converted, via the acyl azide, into the vinyl isocyanate 40. The isocyanate was then transformed into the trifluoroacetamide 41, which underwent an apparent acyl substitution to provide predominantly the N-acetylated derivative 42 upon treatment with acetic anhydride in pyridine. Minor amounts of the A/,A/-diacetylated 43 were also formed. (Z)-cinnamic acid could similarly be carried through to (Z)-40, however exposure to strong acid resulted in isomerization to(£)-41. Both (£)- and (Z)-a,|3-unsaturated acids could be used if the carbamate was formed in lieu of the trifluoroacetamide (Scheme 6), proceeding from the (£)- or (Z)-isocyanate 40 (the E is shown). Carbamate formation by exposure to methanol proceeded with retention of stereochemistry to provide (£)- and (Z)-44, which were subsequently transformed into the acyl derivatives 45. Finally, treatment with lithium iodide trihydrate in refluxing acetonitrile converted 45 into the desired A/-acyl derivative 42 in moderate yield. Ar. .H MeOH Ar> ,H (46-97% Ccv based on acid) 40 O NH 44 O X 1. NaH 2.i. MeCOX, 0 °C ii. reflux, 36 h OMe (33-64%) Ar H X = -CI or -OCOMe x NH CT X H 3 42 Lil-3H20 CH3CN pyr (35-85%) OMe Scheme 6. Brettle's acyl exchange protocol via the carbamate 44 (from reference 20). In the final example, a general strategy was devised for the synthesis of (£)-enamides bearing either (£)- or (Z)-0-methyloxime amide groups. There is literature precedence for transition-metal catalysed vinylic substitution reactions of vinyl iodides and amides to provide enamides and related compounds. In this investigation,21 11 Liebeskind's copper(l) thiophenecarboxylate (CuTC) was discovered to catalyse the transformation depicted in Scheme 7. Enamides related to the salicylate antitumour macrolides were prepared as depicted in Scheme 8. Treatment of malealdehydic acid (46) with aqueous O-methylhydroxylamine hydrochloride led to the formation of (Z)-Omethyloxime acid 47. The (Z)-0-methyloxime amide 48 was prepared by formation of the mixed anhydride of 47 and subsequent reaction with aqueous ammonia. (Z)-amide 48 could be fully isomerized to 49 using concentrated hydrochloric acid in methanol. The (£)- and (Z)-amides 49 and 48 were then coupled with an (E)-vinyl iodide in the presence of CuTC with cesium carbonate or rubidium carbonate as base, respectively, to afford the enamide products 50 and 51. 43 44 45 O Scheme 7. Transformation of amide 43 to vinyl amide 45 catalysed by copper(l) thiophenecarboxylate (from reference 21). 12 OMe I N MeONH2-HCI ^ p 1. EtOCOCI, Et3N, THF H20 (92%) 47 0 H 2. NH4OH (95%) OMe O MeO^ NHo cone. HCI/MeOH (1:2),4h 49 (81%) VC*H S n 1 1 CuTC, CS2CO3, DMA, 12h,90°C (57%) 5 n 1 1 O MeO^ ,C5H 11 OMe I N CuTC, RD2CO3, DMA, 1.5 h, 90 °C (36%) ^ / C 5 H 11 50 51 Scheme 8. Synthesis of O-methyloxime side chain derivatives 50 and 51 (from reference 21). 1.3 Methodology Related to (Z,Z)-Diene Formation We were interested in developing a synthetic strategy which allowed for flexibility in terms of the synthetic intermediates such that each of the salicylate macrolides or derivatives thereof could be synthesized. As such, we envisaged a coupling event to install the carbon-carbon bond flanked by double bonds in the side chain in a stereoselective fashion. Stereocontrol in carbon-carbon bond formation is crucial, because the geometry of the unsaturated bonds in natural polyenes,23 including pheremones, retinoids and antibiotics, can be integral to their activities. Within the last decade, and particularly the last few years, interest has abounded in the development of methods to couple sp, sp2, and sp3 carbon centres. This can 13 largely be ascribed to the continued investigation and refinement of palladium and nickel catalysts for performing coupling reactions, as well as continued interest in the Wittig and related reactions. While comprehensive reviews of such methods can be found elsewhere,24 the paragraphs that follow will attempt to describe a few of the methods directly applicable to our work. Recent developments in the Wittig methodology are of particular interest in the synthesis of molecules containing the (2Z,4Z)-heptadienamide subunit. A Horner-Wadsworth-Emmons (HWE) reaction could be envisaged as occurring between the aldehyde obtained from oxidation of commercially available c/s-2-penten-1-ol and a particular phosphonoester reagent25 under suitable HWE reaction conditions. This method is limited, however, by the base-sensitivity of some a,|3-unsaturated aldehydes, or by their enhanced reactivity due to the proximity of electron-withdrawing groups 2 6 These inherent difficulties have been overcome for destabilized aldehydes in recent syntheses27 using a one-pot Swern28 oxidation-olefination protocol developed by Ireland and co-workers 2 9 Barrett30 and Taylor31 have expanded the utility of Ireland's protocol for the one-pot oxidation-olefination of allylic alcohols, employing the Dess-Martin periodinane32 and activated manganese dioxide as oxidation reagents, respectively. The products of the one-pot reactions are (E,Z)-a,|3-unsaturated dienoic esters. Both groups reported only the formation of (E,Z)-subunits, and have since applied these methods to the total synthesis of members of the manumycin family of antibiotics.33 Related investigations by Schlosser and co-workers34 into the one-pot olefination of vinyl iodides provided an entry into the (2Z,4Z)-2,4-heptadien-1-ol derivative 55 (Scheme 9). The vinyl iodide 52, upon treatment with £-butyllithium and N,N-dimethylformamide formed the lithium a-(/V,/V-dimethylamino)alkoxide 53. Upon neutralisation, such compounds form the corresponding hemiaminal, which spontaneously decompose to provide an aldehyde. The mineral acid used for neutralisation can be replaced by a phosphonium salt,35 thus producing simultaneously a phosphorus ylide and an aldehyde, which condense in a Wittig olefination. 14 1. f-BuLi 2. DMF (CH3)2 52 OTBS OLi V 53 OTBS H20 (40%) OTBS O 54 e e (H5C6)3P-CH-C 2H5 (45%) 1. KO-f-Bu e e 2. [(H5C6)3P-C3H7]Br (41% overall) 55 OTBS *OTBS 56 Scheme 9. Schlosser's synthesis of (2Z,4Z)-dienol derivative 55 (from reference 34). If the entire protocol was performed in one-pot, the desired (Z,Z)-adduct 55 was isolated as the major stereoisomer (Z,Z:Z,£ 83:17) in 40% overall yield. Neutralisation of the intermediate lithium alkoxide predominantly resulted in isomerization to the (£)-aldehyde 54, the (Z,E)-adduct of which (56) was employed in a synthesis of A13-(Z)-retinol (vitamin A).38 Each of the aforementioned in situ olefination protocols of latent aldehydes suffers from the presence of lithium salts and other polar compounds, all of which are known to hinder optimal c/s-selectivities. The Z:E ratios observed are generally lower than those obtainable ideally under salt-free conditions.36 A plausible alternative to the Wittig reaction is the formation and manipulation of an unsymmetrical conjugated diyne. We were, intrigued by the possibility of forming such a diyne, which could potentially be partially reduced in a stereoselective fashion to afford the desired diene. 15 The requisite diyne could be formed via any of a number of sp-sp carbon coupling methods, most of which are effected by copper catalysis. The Cadiot-Chodkiewicz37 reaction is most commonly employed in syntheses of natural products containing unsymmetrically substituted diyne moieties.38 The heterocoupling occurs between the 1-bromoalkyne 57 and a terminal alkyne (58) in the presence of an aliphatic amine and a catalytic amount of a copper(l) salt (Scheme 10). Similarly, treatment of 57 with an alkynyl Grignard derivative in the presence of catalytic amounts of copper(l) or cobalt(l) salts yields the corresponding diyne 59.39 In each case homocoupling of the terminal alkyne (or Grignard reagent) can be a significant impediment.40 EtNH2, MeOH, H20, CuCI R—=—Br + = R' • R — = =—R ' 57 58 59 ° NH2OH • HCI, 30-40 °C 0 * Scheme 10. General equation for the Cadiot-Chodkiewicz reaction (from reference 37). Conjugated diynes have recently been synthesized by the cross-coupling of alkynyl(phenyl)iodonium salts41 to form liquid-crystalline aryl diacetylenes42 and simple unsymmetrical diacetylenes.43 The coupling partners in the latter case have been aryl, alkyl, orsilyl acetylenes (Scheme 11). © Pd(OAc)2, NaHC03, R — = — H + Ph—I E E — P h > R — = = = — P h 60 ® B F 4 MeCN-H20(4:1), 61 rt, 5-20 min, 62 (90-93%) R = -Ph, -Bu, -TMS, OBn Scheme 11. General equation for unsymmetrical diyne formation via hypervalent alkynyl iodonium salts (from reference 41). 16 Kang and co-workers44 have broadened the scope of this process to include alkenyl iodonium salts which undergo cross-coupling with organostannanes in a Stille-type reaction mediated by transition metal catalysis (Scheme 12). R — = -60 Cp2Zr(H)CI R Phl(OAc)2 R •H THF, rt 63 ZrCp2CI THF, rt C02Et 66 C02Et Me3Sn SnMe3 (0.5 equiv.) PdCI2, DMF 30 min (49%, R=Ph) \ 64 l(Ph)OAc aq. NaBF4 CH2CI2 (80-85%) R Nl(Ph)BF4 65 Scheme 12. Triene (67) synthesis using alkenyliodonium salt 65 (from reference 44). In this example, the triene 67, containing a central trisubstituted double bond was synthesized in a stereocontrolled fashion, starting from the terminal acetylene 60. Hydrozirconation of 60 afforded the (£)-vinyl zirconate 63, which upon treatment with bis(acetoxy)iodosobenzene yielded the vinyl iodonium species 64. This was transformed into the hypervalent iodonium salt 65 upon washing with sodium tetrafluoroborate. A Stille-type cross-coupling was then performed between 65 and the 1,1-bis(trimethyl-stannyl)ethene derivative 66, in the presence of a palladium(O) source, to give 67 in moderate yield. Thus far only conjugated (£,Z)-dienes have been synthesized from the corresponding (£)-alkenyl(phenyl)iodonium salts45 and (Z)-vinyl trimethylstannanes. However, other groups have reported the synthesis of (Z)-alkenyl(phenyl)iodonium salts 4 6 which could in principle participate in similar reactions to yield the desired (Z,Z)-dienes. 17 1.4 Organometallic Coupling Reagents In recent years there has been a surge in the isolation and synthesis of polyene and eneyne natural products,47 necessitating the stereocontrolled introduction of alkenyl and alkynyl units. Alkenyl units are often introduced as vinyl metal derivatives, which characteristically undergo addition reactions with total retention of configuration at the sp2 carbon centre bound to the metal. The nature of the metal in alkenyl and alkynyl organometallic reagents varies widely, from tellurium48 to the more commonly encountered copper, magnesium, and zinc. Tin and boron vinyl reagents are employed in Stille and Suzuki coupling reactions, respectively. 1-Haloalkenes and (£)- or (Z)-1,2-dihaloethylenes are common substrates, used in combination with vinyl metal reagents, in transition metal-mediated cross-coupling reactions. A representative example of the stereocontrolled stepwise installation of alkenyl units is Negishi's total synthesis of xerulin (68).49 Xerulin is a polyenynyl (Z)-y-butenolide, containing six carbon-carbon double bonds and two carbon-carbon triple bonds in conjugation. The bond disconnections indicated suggest a modular approach to the synthesis of this intrinsically challenging molecule. Figure 6. Bond disconnections in Negishi's synthesis of xerulin (from reference 49). The metal species indicated were instrumental in forming the corresponding carbon-carbon bonds. 18 1.4.1 The Stille Coupling We were particularly interested in one specific method of sp2-sp2 carbon-carbon bond formation, that being the Stille coupling50 procedure. The Stille coupling involves the palladium-catalysed substitution of an organotin reagent (69) and an organohalide or triflate (70) to afford the cross-coupled product 71 (Scheme 13): [Pd] R3Sn-R' + R"-X - » R'-R" + R3Sn-X 69 70 S 0 l v e n t 71 72 Scheme 13. General equation for the Stille cross-coupling reaction (from reference 50). Generally, R = Me or Bu, X = halide or triflate, R" = vinyl or aryl, and R' = a wide variety of organic residues. The palladium sources also vary, the most common being tetrakis(triphenylphosphine)palladium. The solvent and additives used depend upon the nature of the substrates involved. The principal features of the Stille reaction include the conservation of olefin geometry in most cases, the regiospecificity of the newly formed carbon-carbon a bond, and the tolerance for a large array of functional groups in the coupling partners. The reaction has found usefulness in natural product synthesis,51 the construction of new materials,52 heterocycle preparation,53 carbohydrate chemistry,54 and in bioorganic research 5 5 It has proven amenable to combinatorial chemistry,56 and fluorous phase57 and supercritical solvent chemistry.58 Recent research has focused upon Stille couplings catalytic in tin, so as to minimize exposure to the toxic tin reagents,59 and upon replacing the tin species with more environmentally inert silicon derivatives.60 Of greatest concern were two types of Stille reactions, namely the coupling of an alkenyl halide with an alkenyl tin reagent, and the coupling of an aryl triflate with an allyl tin reagent. The vinyl iodide/vinyl tin system has been used widely in organic synthesis. Nicolaou and co-workers61 employed this method in their synthesis of sanglifehrin A (73) (Figure 7). 19 vinyl tin vinyl iodide vinyl tin Figure 7. Stille coupling bond disconnections in Nicolaou's synthesis of sanglifehrin A (73) (from reference 61). The second of the couplings, that on the left side of the molecule, provides an excellent example of the power of the Stille coupling procedure. The coupling was effected in moderate yield by a catalytic amount of palladium(O) tetrakistriphenylarsine, generated in situ, in DMF at slightly elevated temperature. Fragments 74 and 75 were densely functionalized with acid and base sensitive moieties, with polar functional groups and a conjugated diene. They also contained a number of stereogenic centres, which were preserved in the final product as were all other features in the fragments. The mild nature of the procedure makes it suitable for the late-stage coupling of structurally complex molecular fragments. 20 Pd2(dba)3-CHCI3, AsPh3, /Pr2NEt, DMF, 40 °C, 5 h (45%) Scheme 14. Stille coupling of densely functionalized fragments in Nicolaou's synthesis of sanglifehrin A (from reference 61). Furstner and co-workers62 employed an aryl triflate/allyl tin coupling in their synthesis of (fl)-(+)-lasiodiplodin (Scheme 15). This example illustrates the utility of the Stille reaction in the functionalization of aromatic rings with alkyl groups in a regiocontrolled manner. The coupling was effected by treatment of aryl triflate 76 with allyltributylstannane, in the presence of a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and lithium chloride, to furnish the allyl derivative 77 in excellent yield. 21 3 Scheme 15. An aryl triflate/allyl tin Stille coupling in Furstner's synthesis of (R)-{+)-lasiodiplodin (3) (from reference 62). At this point it would be useful to consider the generally accepted mechanism for the cross-coupling reactions mediated by palladium(O) catalysts, including the Stille reaction. The catalytically active complex is commonly believed63 to be the co-ordinatively unsaturated 14-electron palladium(O) species 78, co-ordinated with weak donor ligands (commonly tertiary phosphines) (Scheme 16). This species is generated in situ by loss of phosphine ligands. The initial step is the oxidative addition of the organic halide R1X to the palladium(O) species in which the frans-a-palladium(ll) complex 79 is formed, presumably via the less thermodynamically stable c/s-o-intermediate. This step is followed by transmetallation to give 80, with resultant displacement of the halide by the substrate from the organometallic species. Isomerization to the c/s-palladium complex 81, followed by reductive elimination generates the coupled product and regenerates the palladium(O) complex. P d U ' -L Pdl_3 Ik L R 3SnX 80 Scheme 16. Postulated catalytic cycle tor the Stille reaction (from reference 63). 23 CHAPTER TWO RESULTS AND DISCUSSION 2.1 Synthetic Strategy We devised a convergent synthesis of salicylihalamide A involving the coupling of three target subunits (Scheme 17). A disconnection at C-1 via a retro-esterification reaction, and a retro-ring-closing metathesis reaction at C-9/C-10 would furnish the subunit 82. A retro-acylation at C-19 would provide the enamine 83 and the acyl diene derivative 84. 10 1 82 8 Scheme 17. Retrosynthetic analysis of salicylihalamide A (1). The aromatic fragment 82 could arise (Scheme 18) via either a Stille or Suzuki coupling of the bis-protected aryl halide/triflate 85 with the appropriate allyl derivative 86. Aryl halide/triflate 85 could be derived via di-protection and functional group interconversion of acid 87. Alternatively a partial reduction of the anhydride 89 could afford the useful latent aldehyde 88. 24 O P G O O H O 88 89 Scheme 18. Retrosynthesis of aromatic fragment 82. The synthesis of the central fragment was envisaged (Scheme 19) to be an enantioselective process involving the stepwise installation of the three stereogenic centres via either chiral auxiliaries or by chelate control from centres already present in the molecule. The target molecule, the N-protected enamine 83, was envisioned as arising from the Curtius rearrangement of acyl azide 90. The acyl azide in turn could be formed via oxidation of unsaturated aldehyde 91, followed by azidation. The requisite inversion of stereochemistry of the unprotected hydroxyl function at C-15 in 91 could be effected by treatment of the diol under Mitsunobu conditions. Aldehyde 91 could arise from opening of the epoxide in 92 with the three-carbon umpolung reagent 93, equivalent to the donor molecule shown, followed by treatment of the adduct with mercuric chloride. The epoxide could be formed diastereoselectively via hydroxyl-directed epoxidation of the homoallylic alcohol 94, which in turn could be formed via enantioselective allylation of aldehyde 95. The chiral aldehyde could be made via alkylation of substrate 96 employing the appropriate chiral auxiliary (X*). 25 Scheme 19. Retrosynthesis of central fragment 83. Many strategies were considered for forming the Z, Z-diene subunit 84. The two major synthetic routes (Scheme 20) involve bond formation at C-21/C-22. A disconnection at this position reveals the two vinyl subunits 97 and 98 containing functional groups A and B, respectively. Alternatively, retro-reduction of the double bonds in 84 suggests diyne 99 as an intermediate. The diyne could be formed via cross-coupling of alkyne subunits 100 and 101, containing functional groups C and D. 84 97 98 Z . , Z 99 100 101 Scheme 20. Retrosynthesis of diene fragment 84. 26 2.2 Total Synthesis of Salicylihalamide A In the course of preparing this thesis J. K. De Brabander and coworkers64 reported the first asymmetric total synthesis of salicylihalamide A (1) (Scheme 21). Enantioselective allylation of aldehyde 102 with an isocaranyl borane reagent established the C-15 configuration in homoallylic alcohol 103. Silylation and oxidative double-bond cleavage provided the corresponding aldehyde 104. Diastereoselective aldol reaction with the Z-(0)-titanium enolate of bornanesultam 105 yielded exclusively the adduct 106. The corresponding MOM ether was reduced with Super Hydride® to provide primary alcohol 107, which was deoxygenated via reduction of the corresponding tosylate. Subjection to fluoride liberated the C-15 alcohol 108. The aromatic ester (109) portion of the molecule was then introduced via a Mitsunobu reaction to provide the RCM precursor 110. Exposure to a catalytic amount of Grubbs' ruthenium carbene complex produced the macrolide 111 with a 10:1 E:Zratio.65 Oxidative deprotection of the p-methoxy benzyl ether with DDQ followed by oxidation of the resultant alcohol with the Dess-Martin periodinane provided aldehyde 112. Homologation via a HWE reaction and global deprotection with tribromoborane afforded the a,p-unsaturated ester 113 as a chromatographically separable 4:1 E:Z mixture of C-17 stereoisomers. Hydrolysis of the major E-methyl ester and global protection by TBSCI provided the acid 114 which was transformed into the corresponding isocyanate 115 by treatment with DPPA. The heptadiene side chain was introduced as bromodiene 116, which resulted in contamination with approximately 20% of the undesired 22E isomer. Finally, removal of the TBS groups with fluoride and subsequent preparative HPLC purification afforded synthetic 1. Synthetic salicylihalamide A proved to be identical to the natural compound according to spectroscopic and physical measurements with the exception of optical rotation. The optical rotation of the synthetic material was of opposite sign to that of the natural compound. Synthetic 1 was also ineffective in inhibiting the growth of a human melanoma cancer cell-line reported to be sensitive to the natural salicylihalamides (Gl50 of 100 nM). An X-ray crystal structure of a p-bromobenzoate derivative confirmed the absolute configuration of synthetic 1. Based upon these results the authors revised the absolute configuration of natural salicylihalamide A to enM.1 27 v * » . i) 2-dlcr2B(allyl), Et20 OPMB .73 OQ 1. TBSO, irrid, DMAP, DMF (94%) 'OPMB 2. cat. Os04) NMO, acetone/H20 O 102 i) NaOOH (96%) 103 3. Pb(OAc)4, pyr, phH (77% for 2 steps) TBS 1. MOMCI,Nal, iPr2NEt, CH2Q2| (91%) 2. LiEtgBH, THF, -78°C->rt OPMB O2S--1 Tia 4 , jPr2NEt, CH2CI2, -78 °C (95%) TBS' 'OPMB T B S C r N I.TsQ, Et3N, DMAP, CH2Q2 (91%) OMOM 2. LiEtgBH, THF, I -78°C-^rt / Q m OH 107 3.TBAF,THF(98%) OPMB O P M B DEAD.PPhg, Et20(96%) OMOM O M e OMe O * \ _ 1,01 10rrd% ^-ci PCy 3 M CH2a 2 (99%) (EZ= 10:1) OMe O JNAO"" sOPMB 'OMOM S 110 V * ^ CHO 28 1. DDQ, CH 2CI 2/H 20 (96%) • 2. DMP, CH 2CI 2 (97%) C0 2 H OMe O 1. trimethyl phosphonoacetate, OMOM NaH, THF, 0 °C (90%) 112 2. BBr3, CH 2CI 2, -78 °C (90%) (17E:17Z=4:1) OTBSO ,C02Me OH O 0 T B S 1. Ba(OH)2 • 8H 20, MeOH f j ^ y ^ c f r 114 1. (PhO)2P(0)N3, Et 3N, PhH 2. PhH, 80 °C (70% for 2 steps) NCO 2. TBSCI, imid, DMF (50-70%) 113 OTBSO 1 1 K OTBS 1. B / ~ W 116 'BuLi, Et 20, -78->0 °C (55-65%) *• 2. HF • pyr, pyr/THF (40-60%) (=20% 22 E) Scheme 21. De Brabander's synthesis of 1 (from reference 64). The De Brabander group has since synthesized 1 as individual C-22 E and Z isomers, and an equimolar mixture of C-22 E:Z isomers of enM.67 Testing in the NCI 60-cell line screen of each of these compounds was performed to compare their activities with that of natural salicylihalamide A. The mixture of E:Zisomers of enM proved to be active (GI5o 0.07 JLIM against SK-MEL-5), while the corresponding enantiomers (1E and 1Z) were not. In the course of the synthesis of enM some other unique compounds were incidentally formed. The salicylihalamide dimers 118 and 119 were produced in comparable yield to the mixture of monomers. Interestingly, the dimers, which differ only in the configuration at C-22, displayed significant activity against the human melanoma cell line SK-MEL-5. The most significant activity was exhibited by the Z, Z-dimer 118, at Gl 5 0 = 0.04 \M. 29 enM R = Z,Z-hexadienyl (10%) 118 R = Z.Z-hexadienyl (10%) 117 R = ZE-hexadienyl (10%) 119 R = Z,E-hexadienyl (10%) Scheme 22. Salicylihalamide stereoisomers and dimeric compounds synthesized by the De Brabander group (from reference 67). A number of analogues of 1 and 118 have been made and tested against a single human melanoma cell line. The structural modifications have involved alterations in the heptadienamide side chain (120-124) and in the macrocyclic skeleton (125). Preliminary results have indicated the importance of the vinyl amide group and the endocyclic double bond to growth inhibitory activity. 30 124 125 Figure 8. Salicylihalamide derivatives made by De Brabander and coworkers (from reference 67). A partial synthesis stemming from diacetone-D-glucose (126) was performed by Georg and coworkers.68 Conversion of known alcohol 127 to the corresponding triflate 128 followed by displacement with a higher order allylcyanocuprate provided compound 129. The acetonide function was cleaved with acetic acid and the resulting anomeric alcohol selectively oxidized to generate lactone 131. Esterification under Mitsunobu coniditions provided the RCM precursor 133, but this material proved unreactive upon treatment with Grubbs' ruthenium alkylidene catalyst. Consequently the lactone was reduced to lactol 135 using DIBAL-H and treatment of this material with catalyst afforded the desired reaction product 137 with a predominance of the Zisomer (E:Z 31 15:85). RCM of the TBDPS-protected intermediate 136 provided a separable mixture of products in a 70:30 E:Z ratio. The introduction of the sterically demanding silyl ether apparently promotes a conformational change in the transition state of the RCM reaction that favours formation of the E-alkene. Cu(CN)Li2 THF, -78 °C (78%) Tf20, DMAP, j — 127 R = H 0°C, 1.5 h L^128R = Tf ^ \ 70% aq. AcOH, f 70 °C, 6h (98%) H 130 OH Ag^C03-Celite®, 0 H 80 °C, 1 h (85%) Ph3P, DEAD, THF, -20->0 °C, 1 h (85%) ~P DIBAL-H, Et20, -78 °C, 2 h (80%j TBDPSa, imid, i—133R=H DMF, rt, 1 h (85%)U»134 R = TBDPS PCy3 O c i ^ i ^ p h PCy3 >• CH2CI2, A, 3 h (60%) HO OR O H 135 R = H 136 R = TBDPS TBAF, THF, i— 137 R = TBDPS rt, 1 h(85%)L*-138R = H Scheme 23. Georg's synthesis of salicylihalamide precursor 138 (from reference 68). 32 2.3 Towards The Total Synthesis of Salicylihalamide A 2.3.1 Preparation of the Aromatic Fragment 142 The inexpensive symmetrical acid 87 was desymmetrized by protection of the acid and one hydroxyl functionality as an acetonide. The remaining hydroxyl group was converted to the corresponding triflate 14069 by treatment with triflic anhydride and pyridine. The allyl substituent was introduced by a Stille coupling with allyl stannane 141. I (99%) Bu3SnH Scheme 24. Synthesis of aromatic fragment 142. The triflate 140 is relatively hindered owing to its ortho-substitution pattern. These types of hindered substrates have often exhibited slow reaction rates with low to moderate yields under the standard Stille coupling conditions fortriflates [Pd(Ph3P)4 (5 mol %), LiCI (2 equiv), 105 °C, 1.5 h, DMF or DMSO]. Farina et al. have shown the general rate accelerating effects, often by a thousand fold, of co-catalytic Cul in Pd(0) catalyzed Stille couplings.70 The copper (I) salt is thought to have two major roles. Firstly, the copper(l) could act as a ligand scavenger in solution thus increasing the amount of catalytically active coordinatively unsaturated Pd(0) species (Pdl_2). Secondly, in polar solvents often employed for Stille reactions, a reversible Sn-Cu transmetalation occurs, which produces an 33 organocopper(l) derivative. The organocopper(l) species undergoes transmetalation with the palladium(ll) species at a rate faster than the palladium-tin transmetalation. This is consistent with results from the labs of Piers71 and Liebeskind72 involving copper(l) chloride and copper(l) thiophenecarboxylate, respectively, which demonstrate a reversible Cu-Sn transmetalation. Pd(0), Ph3P Cul, dioxane 50 °C 145 Scheme 25. Stoichiometric Cul provides rate enhancement in the cross-coupling of aryl iodide 143 and vinyl stannane 144 (from reference 70). In the example above (Scheme 25), the cross-coupling of aryl iodide 143 with vinyl stannane 144 proceeds with 5-fold rate enhancement when one equivalent of Cul is used. Employing two equivalents of Cu(l) salt results in a 100 fold rate enhancement. Based on these results Corey and coworkers73 have described optimized conditions for the Stille cross-coupling of sterically congested substrates. These conditions involve the use of Pd(0) with co-catalytic CuCI to accelerate the rate of reaction and make possible couplings which otherwise had not proceeded, or proceeded to give a mixture of products. In the example below, aryl triflate 146 and vinyl stannane 147 cross-couple efficiently to provide adduct 148 after 46 h. Bu3Sn" Pd(PPh3)4 n-CsHu LiCI.CuCI, DMSO,60°C OH 147 n-C5H 11 148 Scheme 26. Corey's conditions for the Stille coupling of sterically congested substrates (from reference 73). In our case, treatment of the triflate 140 with allyl stannane 141 in the presence of Pd(0), LiCI and Cu(l)CI in warm DMSO effected near-quantitative cross-coupling in 34 only 5 h. Similar ortfrosubstituted substrates have required from 36 h 7 4 to 5 d 6 2 (Scheme 15) to proceed to completion under standard Stille reaction conditions. 2.3.2 Partial Preparation of the Central Fragment The requisite chiral auxiliary was prepared via Evans' method75 using L-valine as an inexpensive, enantiopure starting material. Reduction of the amino acid 149 with borane provided aminoalcohol 150 as a low-melting solid (Scheme 27). Reaction with diethyl carbonate provided oxazolidinone 151 which was acylated with propionyl chloride to afford 152. 0 BF 3-Et 20 (EtO)2CO 1 BHs'Me2S N H 2 ^ THF, reflux (50%) 149 150 A i MI-, renux i (50%) X (87%) O i. nBuLi, THF,-78 ° C O O II ii. propionyl chloride, II II HlsT^O -78 ° C -> 0 ° C \ A N A 0 (89%) 151 1! 152 Scheme 27. Synthesis of chiral oxazolidinone 152. 75 The acyl oxazolidinone was transformed to the lithium Z-enolate and subsequently alkylated with allyl iodide to provide 153 as a single diastereomer. Reduction with lithium aluminum hydride removed the chiral auxiliary to liberate primary alcohol 154. Oxidation with pyridinium chlorochromate furnished the aldehyde 95.76 35 O O N ^ O i. LDA, THF, -78 °C -46 °C -> -35 °C, 2.5 h 1 \ I iii. NH4CI, H20 (83%; de > 99%) 152 LAH, THF, 0 °C (83%) PCC, Celite® CH2CI2 • (90%) 154 95 Scheme 28. Synthesis of chiral aldehyde 95. 2.3.3 Preparation of the a, fi, y, 5-Unsaturated Fragment 84 Our initial strategy entailed a Cadiot-Chodkiewicz reaction37 to couple the bromoalkyne 156 and (trimethylsilyl)acetylene (157), which could be readily transformed into the diyne precursor 158 of the desired diene ester (Scheme 29). OH 155 KOH, Br2 HoO B r — = -156 157 OH ^ ^ ™ S /OH ' U M • T M S — = = ' Cul, pyrrolidine Scheme 29. Proposed synthesis of diyne 158 using the Cadiot-Chodkiewicz reaction. The procedure by Hatch and Kidwell Jr.77 for the formation of a terminal bromoalkyne from the alkyne using a hypobromite solution proved unfruitful. The dense oily product ignited during work-up, a phenomenon which has been reported for similar substrates upon exposure to air.78 Rather than attempt a potentially dangerous scale-up of the procedure the approach was abandoned. We also considered starting from the symmetrical diyne 159, formed via oxidative coupling of 157 in the presence of a copper(l) salt (Scheme 30). The procedure involves bubbling air through a solution of TMS-acetylene in the presence of Hay's79 catalyst, formed by combining N,N,N',N'-tetramethylmethylenediamine with an excess of copper(l) chloride in acetone. Experimentally it was observed that using TMS-36 acetylene could prove challenging, due to its volatility in combination with the relatively long reaction times required to effect homocoupling. The subsequent steps would have involved the selective unmasking of one end of the bis-protected diyne80 with MeLi • LiBr complex and alkylation with ethyl iodide. A second unmasking and methoxycarbonylation would yield the requisite diyne ester 161. CuCI, TMEDA, 1. MeLi-LiBr „. acetone, air 2. Etl 2 Me3Si =- • Me3Si = =—SiMe 3 *-157 ( 8 6 % ) 159 1. MeLi • LiBr o 0 . _ _ 2. Me02CCI >^ = = . 160 161 Scheme 30. Proposed synthesis of diyne ester 161. Another potential approach involved the use of hypervalent iodonium salts. These substrates have recently received much attention, particularly from the groups of Stang and Zhdankin.81 Initially, iodosobenzene (164) was treated with 1-trimethylsilyl-1-butyne (165) and BF3OEt2, followed by washing with sodium tetrafluoroborate solution, to form the hypervalent iodonium salt 166 (Scheme 31). Unfortunately, this salt was difficult to isolate in pure form. C H 3 C O O O H / = \ NaOH " \ ^ - J - O C O C H a (K i _ ^ 0 N ( 6 3 OCOCH3 H 20 (59%) 2. BF 3-OEt 2 3. NaBF4 Scheme 31. Synthesis of hypervalent iodonium salt 166. An inherently more stable hypervalent iodonium salt derived from iodosobenzoic acid has been reported to provide higher yields and greater ease of handling 8 2 Accordingly, iodosobenzoic acid (167) was treated with TMSOTf (Scheme 32). The triflate 168 thus formed in situ was treated with silyl alkyne 165, effecting a substitution to provide the salt 169 as a crystalline solid. 37 l x TMSOTf CH2CI2, rt, 3h 168 O J 165 / 1. Me3Si = ' CH2CI2, 0->20 °C, 1 h 2. H 2 0 a, (87%) 0 OTf C0 2 H 169 - = — C H 2 O H Pd(OAc)2, NaHCOs MeCN:H20 (4:1), rt HO. 170 Scheme 32. Proposed synthesis of diyne 170 via the hypervalent iodonium salt 169. Initial investigations were made into the applicability of a Pd-catalyzed coupling83 between this reagent and propargyl alcohol. This route, and the other routes involving a diyne intermediate, were ultimately abandoned in favour of alkene-alkene coupling protocols due to concerns about stereoselective reduction and isolation of the desired stereoisomer in reasonable yield. Our concerns were shared by other researchers who prepared Z, Zdiene esters via reduction of the corresponding diyne. In Norin and coworkers' synthesis84 of the pentyl derivative 172 (Scheme 33) hydrogenation of the remote alkyne in 171 over Lindlar's catalyst provided a mixture of all four possible stereoisomers. Preparative GC was required to isolate pure (Z, Z)-172. H2 /// Me02C MeOsC, Lindlar Pd 172 all possible isomers 87% ZZ Scheme 33. Norin's synthesis of (Z, Z)-diene ester 172 via reduction of enyne 171 (from reference 84). Our efforts thus turned to alkene-alkene coupling protocols so as to avoid the potentially troublesome reduction step. Immediately, our thoughts turned to the Wittig reaction, which could conceivably provide the desired ester in a two-step sequence: 38 M e 0 2 C , * 173 C F 3 C H 2 O II => J ; P - C H 2 C 0 2 M e + 0= C F 3 C H 2 C T 174 H 175 176 Scheme 34. Retrosynthesis of 161 via a retro-Horner-Wadsworth-Emmons reaction. Oxidation of allylic alcohol 176, available commercially as a single isomer, to the corresponding aldehyde 175 and subsequent Wittig reaction with the indicated phosphonoester85 (174) should provide the diene ester 173. The oxidation of alcohol 176 was attempted under a variety of reaction conditions. Initially both a Swern oxidation and a chromate oxidation with PDC in CH2CI2 afforded complex mixtures. Corey86 proposed that a chromate oxidation in DMF at reduced temperature may inhibit isomerization, however, In each case, a 1:1 mixture of E:Zaldehydes was obtained. The 1H nmr spectrum of the mixture contained two aldehyde proton resonances at 8 9.49 (J = 8 Hz) and at 8 8.59 (J = 1, 4 Hz). Additionally there were four vinyl proton signals which exhibited coupling constants of 8 and 16 Hz, indicative of c/sand trans disubstituted alkenes, respectively. The phosphonoester to be used was prepared by a literature method85 by first treating trimethylphosphonoacetate with phosphorous pentachloride to afford dichloromethylphosphonoacetate. Following removal of excess PCI5 and byproduct POCI3 by distillation at reduced pressure, the crude compound was treated with trifluoroethanol in the presence of diisopropylethyl amine to generate the hexafluorophosphonoester. The structure was readily confirmed by 1H nmr. It is known that allylic alcohols may undergo EJZisomerization upon exposure to various oxidizing conditions. As discussed previously, methods have since been developed for in situ oxidationAA/ittig reactions of such sensitive allylic substrates. It would be of interest and of general synthetic value to further the methodology to include the synthesis of Z,Z-diene esters, as this sensitive subunit is present in a number of potentially important natural products. 39 Rather than risking a potentially non-stereospecific HWE reaction, we turned our attention to organometallic alkene-alkene coupling reactions to stereospecifically cross-couple appropriately functionalized alkene subunits as depicted in Scheme 35. The coupling partners under consideration were either 178 and 179, or 180 and 181 (Scheme 35). Et( O E t c r \ = X = 177 SnBu3 + o 178 Bu3Sh 179 O 180 181 Scheme 35. Retrosynthesis of diene ester 177 via a retro-Stille reaction. Initially 179 was targeted as a substrate. Stork described a procedure87 for the stereoselective preparation of Z-vinyl iodides via the Wittig reaction of iodomethylenetriphenylphosphorane with an aldehyde. The iodide salt 182 was prepared (Scheme 36) by treatment of triphenylphospine with diiodomethane in warm benzene, in the dark. The white solid thus obtained was treated with base and propionaldehyde in THF/HMPA at -78 °C. The material obtained upon work-up proved prone to decomposition and was not successfully characterized. CH2I2, bz r PPh, 50 °C (85%) © Ph 3P-CH 2l 2 182 © 1. NaN(TMS)2 I — H Et 179 Scheme 36. Proposed synthesis of vinyl iodide 179. We then turned our focus to the 180/181 reactant pair, starting with the known acrylic iodide 184 (Scheme 37). Conversion of propiolic acid (183) to 184 was accomplished via two standard methods. The first method88 involved treatment with lithium iodide in warm acetic acid, and necessitated the use of column chromatography to isolate pure acid. A superior method, however89 involved stirring 183 in warm dilute HI and provided highly pure product without requiring chromatographic purification. 40 O Li I, AcOH, 70 °C (84%) EtOH, H 2S0 4 HO > *- HOOC reflux (89%) *• Et0 2C 183 or HI, H20, 50 °C (91%) 184 180 Scheme 37. Synthesis of (Z)-vinyl iodoester 180. Conversion of the acid to the ethyl ester 180 was accomplished under typical reaction conditions, affording stereoisomerically pure material in good yield. The 1H and 1 3C nmr spectra of 184 and 180 were in complete agreement with those previously reported.88'89 The next task was preparation of the vinyl stannane 181. Its synthesis from the corresponding vinyl iodide was not feasible due to the poor stability noted above. Lipshutz et al.90 have reported a general and convenient method for the stereoselective synthesis of Z-vinyl stannanes from the corresponding alkynyl stannanes via a hydrozirconation-protonation sequence. The requisite alkynyl stannanes are typically accessed via stannylation of a terminal alkyne. We elected to alkylate the anion derived from (tributylstannyl)acetylene (185). In the event, treatment of (tributylstannyl)acetylene with base (LDA or KHMDS) followed by addition of ethyl iodide afforded none of the desired homologated compound 186, presumably due to competitive C-Sn bond cleavage under the basic conditions employed. Scheme 38. Proposed alkylation of stannyl alkyne 185. We turned to (trimethylsilyl)acetylene (157) as a more stable alternative to the stannyl acetylene. The protected alkyne was alkylated via two alternative methods. Treatment of 157 with butyllithium followed by exposure to ethyl iodide afforded 165 in 85% yield. Alternatively (Scheme 39), treatment of 157 with butyllithium and triethylborane91 formed the boron ate complex 187. Titration with iodine then furnished alkyne 165, presumably via the intermediates 188 and 189, in 98% yield. The second i. base 185 186 41 alkylation method provided 165 in higher yield, presumably due to the efficiency of intramolecular ethyl group delivery from the boron ate complex. Me3Si — 2 . Et3B 1.nBuLi r-Me3Si 157 187 Me3Si, BEt? 189 0 •BEt3 © Li Me3Si-165 Me3Si- BEt2 © j0 188 Scheme 39. Alkylation of 157 to provide silyl alkyne 165. A silicon-tin exchange was effected (Scheme 40) by treatment of the silyl acetylide 165 with methyllithium and lithium bromide in THF at room temperature for 4 h, followed by cooling to -78 °C and addition of one equivalent of freshly distilled tributyltin chloride. The yield was significantly higher when flame-dried lithium bromide was added separately (99%) rather than using commercially available methyllithium-lithium bromide complex (35%). TMS — E E 165 1. MeLi-LiBr, THF, 3.5 h, rt 2. Bu3SnCI, -78 °C Bu3Sn-186 i. Cp2Zr(H)CI, CH2CI2 ii. H20 >- Bu3Sn (98% from 165) 181 Scheme 40. Transformation of silyl acetylene 165 into (Z)-vinyl tin 181. Hydrozirconation proceeded regioselectively to install zirconium at the carbon bearing the tin atom. This is the less hindered site, owing to the long C-Sn bond. Protonation of the zirconocene followed by purification provided the vinylstannane 181 in 98% yield from 165. 42 The identity of the product was verified by IR, MS, and NMR. The 1H nmr spectrum confirmed the stereochemistry of the double bond; the 72 Hz coupling constant ( 2 J s n - H ) is characteristic for Z-disubstituted vinyl stannanes. The vinyl stannane appeared to be temperature sensitive as Kugelrohr distillation provided a 1:1 mixture of EZisomers, determined by 1H nmr. However, flash chromatography on triethylamine-treated silica gel provided the vinyl stannane as a clear colourless oil. On standing, this compound slowly acquired a yellow colour and developed a precipitate. Storage under argon in the dark in the freezer failed to impede this, however 1H nmr showed no appreciable changes. The material was used in this condition several weeks after preparation without diminished performance. We attempted a Stille coupling using the conditions described previously for the aryl triflate (Scheme 41). However the diene diester 187 was the exclusive product. The 1H NMR displayed the anticipated AA'XX' pattern. (PPh3)4Pd, CuCI, DMSO, 55 "C^ (14%) Bu3Sn Et02C I (pph3)4Pd, DMSO, 181 180 55 ° c • EtO OEt 1 8 7 Et02C (not isolated) Scheme 41. Stille coupling of vinyl subunits 181 and 180. 177 The Ullmann-type coupling of pVhaloacrylates is not unprecedented. Zero-valent nickel92 and copper93 are both known to catalyze dimerization of similar substrates (Scheme 42). The process is stereoselective, proceeding with retention of configuration to provide diene diesters. / = \ N i ( 0 ) , MeQ2C / = \ 2 Me02C Br Et20, nBu3P x = / C02Me 188 5 h, rt (91%) 189 Scheme 42. Ullmann-like homocoupling of (Z)-vinyl bromoester 188 in the presence of Ni(0) (from reference 92). 43 In the event, coupling in the absence of CuCI (Scheme 41) furnished the product 177, however purification proved challenging. Flash chromatography on silica gel provided a complex mixture of products. Pretreatment of the silica gel with triethylamine failed to prevent decomposition. Additionally, it proved necessary to pre-develop the TLC plates with triethylamine prior to use to monitor reaction progress as the product otherwise decomposed on the TLC plates. The decomposition products were evident in the 1H nmr spectrum and included signals at -8-8.5 ppm. Isolated pure material was not obtained by this method. A similar approach was used by Stille and Groh94 to prepare the homologated analogue 191 (Scheme 43). The reaction required five days to provide the diene ester in 62% yield under optimized conditions. The authors reported the use of a relatively low reaction temperature to minimize isomerization of the product once formed. No isomeric ratio was specified. The product was isolated by flash column choromatography on untreated silica gel, and additionally was reported to have survived bulb-to-bulb distillation. (CH3CN)2PdCI2 n B n B u X X l + n Bu 3 Sn / C02Et * \ = X N C 0 2 E I 190 178 DMF, 25 C 1 91 Scheme 43. Stille's synthesis of (Z, Z)-diene ester 191 (from reference 94). Ultimately, we turned to Liebeskind's CuTC complex, which has been used to effect the cross-coupling of organostannes with organic iodides.95 Treatment of the reactants with 1.5 equivalents of copper(l) thiophene-2-carboxylate (CuTC) in NMP at 0 °C to rt for five minutes produces the cross-coupled products in excellent yield with stereochemical integrity (Figure 9). 44 1.5 equiv. CuTC Figure 9. Cross-coupling of vinyl and aryl iodides and stannanes mediated by CuTC (from reference 95). The mechanism presumably involves reversible transmetalation from tin to copper. This could occur either prior to or following oxidative addition of the organic halide to the copper species, ie. RSnBu3 can transmetalate with either RCuX2 or CuX. The two pathways are shown in the upper and lower portions of Figure 10, respectively. An excess of copper(l) species is used to drive the reaction by promoting the reversible transmetalation step. 45 RSnBu3 XSnBu3 R'CuX 2 R'RCuX CuX RSnBu3 R'RCuX RCu R'-X Figure 10. Catalytic cycle for CuTC-mediated cross-coupling of vinyl and aryl iodides and stannanes (from reference 95). Treatment of vinyl iodide 180 with vinyl stannane 181 in NMP with CuTC at 0 °C for 5 min, followed by warming to rt and stirring an additional 5 min effected the coupling (Scheme 44). A subtle colour change from red-brown to green-brown accompanied the reaction. Rapid filtration through a thin pad of alumina and washing of the solids with Et20 provided a solution which was repeatedly washed with water to remove NMP. The diene ester 177 was purified by Kugelrohr distillation. CuTC, NMP, . 0 °C^rt, 5 min p t n r , » E t ° 2 C \ = / = ^ B0 2 C . 180 ( 8 5 / o ) 177 Scheme 44. Cross-coupling of vinyl species 181 and 180 using Liebeskind's CuTC protocol. It was necessary to use a two-fold excess of vinyl stannane to prevent competetive self-coupling of the vinyl iodide. No dimer was detected when the stannane was present in excess. Liebeskind and coworkers96 also noted Ullmann-like reductive coupling of aryl, heteroaryl and vinyl halides under the reaction conditions described above. 46 The stereochemistry of the product was confirmed by nOe experiments. O Hv Hs » / Hp H H Figure 11. NOE enhancements observed in diene ester 177. Complementary nOe enhancements were observed for each pair of c/s protons, as well as for the allylic protons upon irradiation of the the (3-H. 47 2.4 Conclusions and Future Work 181 177 The aromatic portion of 1 (blue) was synthesized efficiently using the accelerative effects of co-catalytic Cu(l) salts on the Stille reaction to form 142. An important new protocol has been developed for forming Z-vinyl stannanes such as 181 from the corresponding (trimethylsilyl)acetylenes. The (Z,Z)-diene 177 corresponding to the sidechain (red) was assembled using Liebeskind's copper(l) thiophenecarboxylate-mediated cross-coupling reaction. This further highlights the mildness and general utility of the method for rapid construction of hindered or labile diene systems. Preliminary efforts were made toward the synthesis of the central fragment (magenta). The bulk of the future work must extend this through conversion of the intermediate 95 to advanced intermediate 83 (Scheme 19). Although a number of difficult steps remain, construction of this strategic subunit would allow work to proceed for the convergent couplings of all targeted subunit fragments in order to assemble salicylihalamide A. CHAPTER THREE EXPERIMENTAL 48 3.1. General 3.1.1 Data Acquisition, Presentation, and Experimental Techniques Melting points were recorded on a Fisher-Johns melting point apparatus and are uncorrected. In cases where Kugelrohr (bulb-to-bulb) distillation was performed, boiling points are given as the air-bath temperature and are uncorrected. Infrared (IR) spectra were recorded on either a Bomem Michelson 100 FT-IR spectrophotometer or a Perkin-Elmer 1710 Fourier transform spectrophotometer with internal calibration. IR spectra were taken as either a neat liquid or a chloroform solution of the analyte between two 3 mm sodium chloride plates. Proton nuclear magnetic resonance (1H nmr) spectra were recorded on a Bruker model WH-400 (400 MHz) spectrometer using deuteriochloroform (CDCI3) or acetone-cfe ( C D 3 C O C D 3 ) solutions, as indicated. Signal positions (8 values) are given in parts per million (ppm) from tetramethylsilane (8 0 ppm) and were measured relative to the signals for chloroform (8 7.24 ppm) or acetone (8 2.04 ppm). Coupling constants (J values) are given in Hertz (Hz). The tin-proton coupling constants (Jsn-H) are given as an average of the 117Sn and 119Sn values. The spectral data are reported in the following format: chemical shift (ppm), (multiplicity, number of protons, coupling constant(s), and assignments (when known)). The abbreviations used for the multiplicities are: s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad. In the 1H nmr spectral assignments, H-x indicates a proton attached to the carbon labelled C-x, and the numbering has been designated according to the rules devised by the International Union of Pure and Applied Chemistry (IUPAC) for the nomenclature of organic compounds. Carbon nuclear magnetic resonance (13C nmr) spectra were recorded on a Bruker model AV-400 (100 MHz) spectrometer or a AV-300 (75 MHz) spectrometer, using deuteriochloroform or acetone-d6 as indicated. Signal positions (8 values) are given in parts per million (ppm) from tetramethylsilane and were measured relative to 49 the signals of chloroform-c/ (5 77.0 ppm) or acetone-cfe (8 29.80 ppm). The carbon assignment is indicated in parentheses after the chemical shift (when known). Low (LRMS) and high resolution (HRMS) mass spectra were recorded on the following instruments: in desorption chemical ionization (DCI) mode, on a Delsi Nermag R10-10 C spectrometer; in chemical ionization (CI) mode, on either a Kratos MS 80 spectrometer or a Kratos Concept II HQ spectrometer; in electron ionization (El) mode, on a Kratos-AEI model MS 50 spectrometer. The molecular ion (M+) masses are given unless otherwise noted. All compounds subjected to high resolution mass measurement were homogeneous by glc and/or tic anlayses. Optical rotations were determined with a Perkin-Elmer 141 polarimeter at 20-25 °C. Concentrations are in grams of solute per 100 mL of solution. Gas-liquid chromatography (glc) was performed on a Hewlett-Packard model 5890 gas chromatograph, equipped with a flame ionization detector and a fused silica capillary column, of dimensions 25 m x 0.21 m (HP-5, cross-linked with 5% phenylmethyl silicone). Thin layer chromatography (tic) was performed using commercially available aluminum-backed silica gel 60 F254 plates (E. Merck, type 5554, thickness 0.2 mm). Visualization was accomplished by using uv and/or iodine absorbed onto silica gel, followed by heating the chromatogram after staining with one of the following solutions: anisaldehyde in a sulfuric acid-EtOH mixture (5% anisaldehyde v/v, and 5% sulfuric acid v/v in EtOH); potassium permanganate in a potassium carbonate-water mixture (1% KMn04 w/v; 7% K 2C0 3 w/v; and 0.1% w/v NaOH in water). Flash chromatography was performed with 230-400 mesh silica gel (E. Merck, Silica Gel 60) using the technique described by Still.97 In most cases, a solvent system was chosen such that the desired product had an Rf of 0.30-0.35 on TLC. Concentration, evaporation, or removal of solvent under reduced pressure (water aspirator) refers to solvent removal via a Buchi rotary evaporator at -15 Torr. Unless otherwise noted, all reactions were performed under an atmosphere of dry argon using glassware that had been oven (-140 °C) and/or flame dried, and cooled under a stream of dry argon. The glass syringes, stainless steel needles, and polyethylene cannulae used to handle anhydrous solvent and reagents were oven dried, cooled in a dessicator, and flushed with dry argon prior to use. The plastic 50 syringes were flushed with dry argon before use. The polyethylene cannulae were purchased from Becton Dickenson, and have an inner diameter of 1.57 mm and an outer diameter of 2.08 mm. Cold temperatures were maintained by the use of the following cold baths: -78 °C (dry ice, acetone), -46 °C (dry ice, cyclohexanone), -40 °C (dry ice, acetonitrile), 0 °C (ice, water). Reactions at elevated temperature were maintained by heating a silicone oil bath to the desired temperature. 51 3.1.2. Solvents and Reagents All solvents and reagents were purified and dried using known procedures.98 Dichloromethane was distilled from calcium hydride, and diethyl ether and tetrahydrofuran (THF) were distilled from sodium benzophenone ketyl. These solvents were distilled under an atmosphere of dry argon and used immediately. /V./V-diisopropylamine (DIPA), triethylamine (TEA), and pyridine were distilled under an atmosphere of dry argon, from calcium hydride. Dimethyl sulfoxide (DMSO) and 1-methyl-2-pyrrolidinone (NMP) were distilled from calcium hydride under reduced pressure. A/,A/-Dimethylformamide (DMF) was distilled from magnesium sulfate under reduced pressure. All other solvents were obtained commercially and used without further purification. Petroleum ether refers to a hydrocarbon mixture with a boiling range of 30-60 °C. Solutions of n-butyllithium in hexanes, obtained from Acros Organics, were standardized by titration against diphenylacetic acid in THF at 0 °C to a faint yellow colour indicative of endpoint, according to the methods of Kofron and Baclawski.99 Lithium diisopropylamide (LDA) was prepared by adding a solution of methyllithium (1.0 equiv.) in diethyl ether or n-butyllithium (1.0 equiv.) in hexanes to a solution of diisopropylamine (-1.1 equiv.) in dry THF at 0 °C. The resulting solution was stirred at 0 °C for 15-20 min prior to use. Boron trifluoride diethyl etherate and tri-n-butyl tin chloride were purified by distillation from calcium hydride under reduced pressure. Ethyl iodide, allyl bromide, and allyl iodide were either distilled over calcium hydride under an atmosphere of dry argon, or were passed through a short column of basic alumina activity I which had been dried in an oven (-140 °C) and cooled in a dessicator before use. Lithium bromide, lithium chloride, and lithium iodide were flame dried under reduced pressure immediately prior to use. Copper (I) chloride was dried under high pressure (vacuum pump) overnight before use. Copper(l) thiophenecarboxylate was generously provided by Dr. Denise Andersen. All other reagents were used as purchased without further purification. 52 3.2 Chemical Methods Preparation of (Z)-3-lodo-2-propenoic acid (183) HOOC N l 183 (a) Treatment of propiolic acid with Li I and HOAc To a stirred suspension of lithium iodide (2.55 g, 19.1 mmol, 1.1 equiv.) in glacial acetic acid (17.0 mL, 297 mmol) was added propiolic acid (1.06 mL, 17.2 mmol, 1 equiv.). The resulting red solution was heated to 70 °C and was stirred for 24 h. The mixture was allowed to cool to room temperature, and was concentrated under reduced pressure. The crude product was purified by flash chromatography (1:1 petroleum ether:ethyl acetate) yielding 183 (2.87 g, 84%) as pale yellow needles. mp: 62-63 °C; lit.88 mp: 63-64 °C. IR (CCI4): 3014, 2713, 2617, 1708, 1600, 1406, 1314, 1235, 1177, 923, 634 cm"1. 1H nmr (CDCI3, 400 MHz) S: 11.01 (br s, 1H), 7.66 (d, 1H, J = 9 Hz), 6.97 (d, 1H, J = 9 Hz). 1 3C nmr (CDCI3, 75 MHz) 8: 169.98, 129.46, 98.18. HRMS (El) m/zcalcd. for C3H302l: 197.9178; found: 197.9174. (b) Treatment of propiolic acid with HI To a solution of aqueous 47% hydroiodic acid (24.0 mL, 151 mmol, 1.5 equiv.) in H20 (30 mL, 0.90 mol, 9 equiv.) was added propiolic acid (6.15 mL, 100 mmol, 1 equiv.). This yellow solution was heated to 50 °C and stirred for 48 h. The yellow-orange mixture was cooled to room temperature and was poured into diethyl ether (75 mL). The phases were separated, and the aqueous layer was extracted with diethyl 53 ether (3 x 30 ml_). The combined organic extracts were washed with saturated Na2S2C»3 (50 ml_), dried over anhydrous MgS04, filtered, and concentrated under reduced pressure. The yellow residue was washed with hexanes to yield the (Z)-iodo acid (17.97 g, 91%) as a pale yellow solid with spectral data in agreement with that reported above. Preparation of (Z)-3-lodo-2-propenoate (180) Et02C N l 180 To a solution of sulfuric acid (6.0 ml_, 110 mmol, 1.5 equiv.) in ethyl alcohol (180 mL, 3.1 mol, 40 equiv.) was added 183 (15.0 g, 75.8 mmol, 1 equiv). The solution was heated to reflux and stirred for 4 h. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was filtered through a plug of silica gel, eluting with diethyl ether (500 mL) followed by ethyl acetate (200 mL). The appropriate fractions were combined and concentrated in vacuo to yield the ester 180 (15.2 g, 89%) as a fragrant pale yellow oil. IR (neat): 3064, 2981, 1724, 1600, 1367, 1323, 1196, 1165, 1027, 807 cm"1. 1H nmr (CDCI3, 400 MHz) 8: 7.41 (d, 1H, J = 9 Hz), 6.86 (d, 1H, J = 9 Hz), 4.22 (q, 2H, J=7Hz), 1.29 (t, 3H, J=7Hz). 1 3C nmr (CDCI3, 75 MHz) 8: 164.52, 129.87, 94.62, 60.74, 14.14. HRMS (DCI(+), ammonia/methane) m/zcalcd. for C5H802l: 226.9569; found: 226.9572. 54 Preparation of (S)-Valinol (150) 150 To a 500 mL three-necked round bottomed flask, equipped with a water condenser and two pressure-equalizing dropping funnels, containing (L)-valine (19.0 g, 162 mmol, 1 equiv.), was added dry THF (80 mL). Boron trifluoride diethyl etherate (20 mL, 162 mmol, 1 equiv.) was added dropwise via one addition funnel over 30 min. The mixture was heated at reflux for 2 h. Borane-methylsulfide complex (18.6 mL of a 10 M solution in THF, 186 mmol, 1.15 equiv.) was added slowly via the second addition funnel over approximately 60 min, such that a suitable reflux rate was maintained. The colourless solution was heated for an additional 5 h, and was subsequently allowed to cool to room temperature. The reaction mixture was quenched by the careful addition of H2O(10mL). A 5 M aqueous NaOH solution (120 mL, 600 mmol, 3.7 eqiuv.) was added, and the biphasic mixture was heated at reflux for 16 h. The mixture was allowed to cool to room temperature, and was filtered through a sintered glass funnel (fine). The solids were washed with THF (2 x 60 mL). The volatiles were removed by rotary evaporation, and the resulting slurry was extracted with methylene chloride (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was distilled under reduced pressure (58-59 °C at 2.0 Torr) to afford 150 (8.3 g, 50%) as a colourless oil, which solidified to a white crystalline solid upon standing. bp: 58-59 °C, 2.0 Torr. IR (CCI4): 3363, 3305, 2960, 2873, 1587, 1467, 1388, 1369, 1053 cm1. 1H nmr (CDCI3, 400 MHz) 8: 3.61 (dd, 1H, J= 4, 10 Hz), 3.26 (dd, 1H, J= 9, 9 Hz), 2.53 (ddd, 1H, J = 4, 6, 9 Hz), 1.77 (br s, 3H), 1.54 (d septets, 1 H, J = 7, 7 Hz), 0.90 (d, 3H, J= 7 Hz), 0.89 (d, 3H, J= 7 Hz). 55 [a]D = + 44.3° (cO.19, CHCI3) Preparation of 1-Trimethylsilyl-1-butyne (165) Me3Si = / 165 (a) Alkylation of (trimethvlsilvl)acetylene with triethylborane91 A dry 500 mL round bottomed flask equipped with a stir bar, septum inlet, and large (100 mL) dropping funnel was charged with THF (25 mL) and triethylborane (4.40 mL, 30.5 mmol, 1 equiv.), and the solution was cooled (0 °C). A second dry flask was charged with THF (50 mL) and (trimethylsilyl)acetylene (TMSA) (4.30 mL, 30.5 mmol, 1 equiv.). The flask was cooled (0 °C), and n-butyllithium (18.8 mL of a 1.6 M solution in hexanes, 30.0 mmol, 0.98 equiv.) was added. The resulting lithium acetylide solution was then transferred, via cannula, into the flask containing the triethylborane solution. The resulting mixture was cooled (-78 °C), and a solution of iodine (7.75 g, 30.5 mmol, 1 equiv.) in diethyl ether (75 mL) was added via the addition funnel over approximately 30 min. The mixture was stirred for an additional 45 min at -78 °C, and was subsequently allowed to warm to room temperature. The deep red-brown reaction mixture was washed with 3 N NaOH (2 x 20 mL) containing 5% saturated aqueous Na2S203 (5 mL). The aqueous fraction was extracted with diethyl ether (25 mL). The combined organic extracts were treated with 3 N aqueous NaOH (32 mL), followed by the careful addition of 30% H 20 2 (10.5 mL). The organic layer was then dried over solid K2C03, filtered, and concentrated under reduced pressure to yield a red oil, which was purified by short-path distillation to afford 165 (3.72 g, 98%) as a colourless oil. bp: 115-116 °C. IR (neat): 2962, 2178, 1315, 1251, 1077, 1043, 907, 844, 760, 638 cm"1. 56 1H nmr (CDCI3, 400 MHz) 5: 2.21 (q, 2H, J= 7 Hz), 1.12 (t, 3H, J= 7 Hz), 0.12 (s, 9H). 1 3C nmr (CDCI3, 75 MHz) 8: 108.94, 83.40, 13.79, 13.48, 0.13. HRMS (El) m/zcalcd. for C7Hi4Si: 126.0865; found: 126.0869. (b) Alkylation of TMSA with ethyl iodide To a cooled (-78 °C) solution of TMSA (14.4 mL, 102 mmol, 1 equiv.) in THF (500 mL) in a 1 L round bottomed flask equipped with a large addition funnel, was added n-butyllithium (64.0 mL of a 1.6 M solution in hexanes, 102 mmol, 1 equiv.) via syringe. The mixture was stirred for 3 h at -78 °C. Ethyl iodide (82 mL, 1.02 mol, 10 equiv.) was added slowly via addition funnel to the lithium acetylide solution, and the mixture was warmed to rt and stirred for an additional 13 h. The mixture was quenched by the addition of 75 mL of H20, at which point the colourless mixture turned yellow. The layers were separated and the organic layer was washed with saturated aqueous NaHS03, brine, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to a yellow oil. The oil was purified by distillation to afford 165 (80%) as a colourless oil with spectral data in agreement to that reported above. 57 Preparation of (4S)-4-lsopropyl-1,3-oxazolidin-2-one (151) O x HN O (S)-Valinol (150) (5.28 g, 51.1 mmol, 1 equiv.), diethyl carbonate (12.4 mL, 103 mmol, 2 equiv.) and anhydrous K 2C0 3 (0.74 g, 5.35 mmol, 0.1 equiv.) were heated at reflux for 14 h. The mixture was allowed to cool, and was diluted with diethyl ether (30 mL). The solution was then filtered through a sintered glass funnel (medium), and the solids were washed with diethyl ether (2 x 20 mL). Concentration of the ether washings under reduced pressure yielded a dark orange oil, from which the product crystallized upon stirring under high vacuum. Filtration and isolation of two additional crops of crystals from the mother liquor, followed by filtration of the remaining mother liquor through a pad of pre-wetted silica gel, eluting with 1:1 ethyl acetate - petroleum ether afforded 151 (5.76 g, 87%) as a white crystalline solid. mp: 67-68 °C. IR (CCI4): 3470, 3251, 2961, 1752, 1479, 1406, 1245, 1091, 1010, 936, 551 cm"1. 1H nmr (CDCI3l 400 MHz) S: 5.68 (br s, 1H), 4.42 (dd, 1H, J = 9, 9 Hz), 4.09 (dd, 1H, J = 9, 6 Hz), 3.58 (ddd, 1H, J= 9, 7, 6 Hz), 1.72 (d septets, 1H, J = 7, 7 Hz), 0.94 (d, 3H, J = 7 Hz), 0.88 (d, 3H, J= 7 Hz). 1 3C nmr(CDCI3, 100 MHz) 5: 160.57, 68.53, 58.34, 32.61, 17.87, 17.55. HRMS (El) m/zcalcd. forC6HnN02: 129.07908; found: 129.0794. [a]D = + 24.4° (cO.18, CHCI3); (lit.753 + 14.8°, c7.0, CHCI3). 58 Preparation of (4S)-4 lsopropyl-3-propanoyl-1,3-oxazolidin-2-one (152) O O yj 152 To a cooled (-78 °C) solution of 151 (5.45 g, 42.2 mmol, 1 equiv.) in THF (230 mL) was added n-butyllithium (27.7 mL of a 1.6 M solution in hexanes, 44.3 mmol, 1.05 equiv.), dropwise via syringe. The resulting thick slurry was stirred for 10 min, and propionyl chloride (4.03 mL, 46.6 mmol, 1.1 equiv.) was added dropwise via syringe. After stirring for 10 min at -78 °C, the dry ice-acetone bath was replaced with an ice bath, and stirring was continued at 0 °C for an additional 50 min. An aqueous solution of 1 M K2CO3 (48 mL, 48 mmol, 1.1 equiv.) was added and the mixture was stirred 1.5 h. The volatiles were removed via rotary evaporation, and the aqueous phase was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with H20 (50 mL) and brine (50 mL), dried over anhydrous MgSCM, filtered, and concentrated under reduced pressure. The pale yellow oil thus obtained was purified by flash chromatography (3:7 ethyl acetate - petroleum ether). The appropriate fractions were combined and concentrated in vacuo to yield 152 (6.99 g, 89%) as a pale yellow oil. IR (neat): 2968, 1780, 1703, 1391, 1303, 1207, 1120, 1073, 1026, 984, 774 cm"1. 1H nmr(CDCI3, 400 MHz) 8: 4.41 (ddd, 1H, J = 4, 4, 8 Hz), 4.17-4.26 (m, 2H), 2.83-3.01 (m, 2H), 2.36 (d septets, 1H, J = 4, 7 Hz), 1.15 (t, 3H, J = 7 Hz), 0.89 (d, 3H, J = 7 Hz), 0.85 (d, 3H, J=7Hz). 1 3C nmr (CDCI3, 100 MHz) 8: 173.94, 154.03, 63.30, 58.32, 29.02, 28.32, 17.84, 14.56, 8.34. HRMS (El) m/zcalcd. forC9Hi5N03: 185.1052; found: 185.1056. [cc]D = + 90.6° (cO.50, CHCI3); (lit.753 + 96.8°, c8.7, CH2CI2). 59 Preparation of 1-Tri-n-butylstannyl-1-butyne (186) Bu 3 Sn—= / 186 (a) Silicon-tin exchange of TMS-butyne with LiBr and MeLi Lithium bromide (344 mg, 3.96 mmol, 1 equiv.) was weighed into a 25 mL round bottomed flask and was flame-dried. Dry argon was introduced, and THF (5 mL) was added. Compound 165 (502 mg, 3.98 mmol, 1 equiv.) was introduced via syringe, and the solution became slightly yellow. Methyllithium (2.5 mL of a 1.6 M solution in diethyl ether) was added dropwise via syringe, while stirring at room temperature. The cloudy yellow mixture was stirred an additional 4 h, and was subsequently cooled (-78 °C). Tri-/>butyltin chloride (1.07 mL, 3.94 mmol, 1 equiv) was added via syringe, and the solution was allowed to warm to room temperature over 13 h. The reaction mixture was cooled (0 °C) and was treated with aqueous 5% NaHC03 (5 mL). The phases were separated, and the aqueous layer was extracted with diethyl ether (3x5 mL). The combined organic extracts were washed with 5% NaHC03 (5 mL), brine (5 mL), and dried over anhydrous MgS04, with stirring, for 30 min. Isolation by filtration and concentration under reduced pressure, followed by removal of residual solvents under high vacuum yielded 186 (1.352 g, 99%) as a yellow oil which was used without further purification. IR (neat): 2927, 2151, 1463, 1377, 1072, 877, 672 cm-1. 1Hnmr(CDCI3, 400 MHz) 8: 2.23 (q, 2H, J= 7 Hz,), 1.46-1.66 (m, 14H), 1.25-1.41 (m, 17H), 1.12 (t, 3H, J=7Hz), 0.86-1.02 (m, 28H). 60 Preparation of (2)-1-Tri-n-butylstannyl-1-butene (181) Bu3Sn^ 181 To a pale yellow solution of 186 (1.024 g, 2.98 mmol, 1 equiv) in THF (20 mL) was added, all at once, bis(cyclopentadienyl)zirconium hydride chloride (1.00 g, 3.88 mmol, 1.3 equiv.). The dark red, opaque mixture was stirred under dry argon at room temperature for 3.5 h. To this mixture was then added H20 (0.47 mL, 26 mmol, 9 equiv.) adsorbed on basic alumina (3.13 g), and the bright yellow mixture was stirred an additional 30 min. The mixture was filtered through a plug of silica gel (8.0 g), eluting with petroleum ether (60 mL). The solution was concentrated under reduced pressure to a yellow oil containing a white precipitate. The residue was refiltered through silica gel (3.0 g), eluting with petroleum ether (30 mL). Concentration under reduced pressure yielded a pale yellow oil. Purification by flash chromatography (hexanes), afforded 181 (1.10 g, 99%) as a colourless oil. IR (neat): 2927, 1599, 1463, 1377, 1071, 875, 693 cm'1. 1H nmr (CDCI3, 400 MHz) 8: 6.48 (dt, 1H, J= 7, 12 Hz, 3 J S n -H = 141 Hz), 5.73 (dt, 1H, J = 12, 1 Hz, 2 J S n -H = 72 Hz), 2.01 (dqd, 2H, J= 7, 7, 1 Hz), 1.40-1.54 (m, 7H), 1.24-1.33 (m, 6H), 0.97 (t, 3H, J= 7 Hz), 0.84-0.90 (m, 15H). 1 3C nmr (CDCI3, 100 MHz) 8: 150.70, 127.04, 30.29 (C-3), 29.21 (Sn-CH2CH2-CH2CH3), 27.31 (Sn-CH2CH2CH2CH3), 14.38 (C-4), 13.67 (Sn-CH2CH2CH2-CH3), 10.25 (Sn-CH2CH2CH2CH3). 61 Preparation of 2,2-Dimethyl-5-hydroxy-benzo[1,3]dioxin-4-one (139) 139 To a cold (0 °C) suspension of 2,6-dihydroxybenzoic acid (5.00 g, 32.4 mmol, 1 equiv.) in trifluoroacetic acid (40.0 mL, 519 mmol, 16 equiv.) were added trifluoroacetic anhydride (25.0 mL, 177 mmol, 5.5 equiv.) and acetone (6.0 mL, 81.7 mmol, 2.5 equiv.). The mixture was allowed to warm slowly to room temperature, and was stirred for an additional 24 h. The volatiles were removed via rotary evaporation, and the residue was poured slowly into a cold (0 °C) saturated aqueous solution (200 mL) of NaHC03, and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with H20 (30 mL) and brine (30 mL), and dried over anhydrous MgS04. The orange solution was filtered and concentrated to a yellow solid residue. Flash chromatography (1:1 ethyl acetate - petroleum ether) of the solids afforded 139 (3.30 g, 52%) as colourless crystals. mp: 57-58 °C. IR (CCI4): 3209, 3004, 2945, 1698, 1632, 1587, 1473, 1392, 1354, 1274, 1229, 1079, 922, 695 cm"1. 1H nmr (CD3OCD3, 400 MHz) 8: 9.61 (br s, 1H), 6.78 (t, 1H, J = 8 Hz), 6.23 (d, 1H, J = 8 Hz), 5.78 (d, 1H, J = 8 Hz), 1.01 (s, 6H). 1 3C nmr (CD3OCD3, 75 MHz) 8: 166.01, 162.20, 156.53, 138.00, 111.31, 108.17, 107.94, 100.18, 25.59. HRMS (El) m/zcalcd. for C10H10O4: 194.0579; found: 194.0580. 62 Preparation of 2,2-Dimethyl-5-(trifluoromethanesulfonyl)-benzo[1,3]dioxin-4-one (140) 140 To a cold (0 °C) solution of 139 (3.00 g, 15.4 mmol, 1 equiv.) in pyridine (80.0 mL, 0.99 mol, 64 equiv.) was added trifluoromethanesulfonic anhydride (2.86 mL, 17.0 mmol, 1.1 equiv.), dropwise via syringe. The orange solution was maintained at 0 °C for an additional 12 h, and was allowed to warm to room temperature slowly over 12 h. The volatiles were removed in vacuo, and the remaining dark orange oil was diluted with ethyl acetate (80 mL) and diethyl ether (320 mL). The mixture was washed with H20 (3 x 100 mL) and brine (50 mL), dried over anhydrous MgS04, filtered and concentrated under reduced pressure to afford a yellow solid. Filtration and washing with cold ethyl acetate provided 2.93 g of white crystals. Flash chromatography (3.5:6.5 ethyl acetate - petroleum ether) of the mother liquor yielded an additional crop (1.59 g) of 140 (95%). mp: 113-114 °C; lit.69 mp: 114-115 °C. 1H nmr (CD3OCD3, 400 MHz) 8: 7.85 (t, 1H, J= 8 Hz), 7.23-7.26 (m, 2H), 1.76 (s, 6H). 13Cnmr (CD3OCD3, 75 MHz) 8: 158.28, 157.55, 149.32, 138.03, 121.01, 119.23, 117.65, 108.92, 107.80, 25.47. HRMS (El) m/zcalcd. for CnHi906F3S: 326.0072; found: 326.0073. 63 Preparation of 2,2-Dimethyl-5-allyl-benzo[1,3]dioxin-4-one (142) ^ 4 2 Lithium chloride (390 mg, 9.19 mmol, 6 equiv.) was added to a dry 50 mL round bottomed flask and was flame dried at reduced pressure. Argon was introduced, and after cooling, tetrakis(triphenylphosphine)palladium(0) (177 mg, 0.153 mmol, 0.1 equiv.) and copper (I) chloride (760 mg, 7.66 mmol, 5 equiv.) were added. The solid mixture was degassed under high vacuum with an argon purge. Dimethyl sulfoxide (12 mL), 140 (500 mg, 1.53 mmol, 1 equiv.), and allyl tri-n-butyltin 141 (590 u1_, 1.84 mmol, 1.2 equiv.) were introduced and the resultant mixture was degassed (2 x) by the freeze-pump-thaw technique. The mixture was heated at 65 °C for 48 h. The reaction mixture was then allowed to cool, and was diluted with diethyl ether (180 mL), and the resultant mixture was washed with a mixture of brine (240 mL) and aqueous NH3 (48 mL of a 5% solution). The aqueous extracts were extracted with diethyl ether (2 x 90 mL), and the combined organic extracts were washed successively with H20 (2 x 240 mL) and brine (2 x 240 mL), and were dried (MgS04). Filtration and concentration under reduced pressure afforded a green-coloured residue, which was purified by flash chromatography (1:4 ethyl acetate - hexanes) to yield 142 (320 mg, 96%) as a yellow oil. IR (neat): 3079, 2999, 1741, 1606, 1585, 1478, 1448, 1390, 1315, 1210, 1045, 920, 779, 689 cm"1. 1H nmr (CDCI3, 400 MHz) 8: 7.41 (t, 1H, J = 8 Hz), 6.95 (d, 1H, J = 8 Hz), 6.82 (dd, 1H, J = 1, 8 Hz), 6.02 (ddt, 1H, J = 7, 11, 19 Hz), 5.00-5.05 (m, 2H), 3.88 (d, 2H, J = 6 Hz), 1.68 (s, 6H). 64 1 3C nmr (CDCI3, 75 MHz) 8: 160.17, 157.05, 145.14, 136.64, 135.25, 124.87, 115.95, 115.52, 112.00, 105.08, 38.12, 25.57. HRMS (DCI(+), ammonia/methane) m/zcalcd. forC 1 3H 1 50 3: 219.1021; found: 219.1017. Preparation of Allyl tri-n-butyl tin (141) 141 To a cool (0 °C) solution of DIPA (960 \iL, 6.88 mmol, 2 equiv.) in THF (2.0 mL) was added n-butyllithium (4.65 mL of a 1.48 M solution in hexanes, 6.88 mmol, 2 equiv.) via syringe. Tributyltin hydride (920 \\L, 3.44 mmol, 1 equiv.) was added dropwise via syringe, and the resultant solution was stirred for an additional 1 h at 0 °C. The solution was then cooled (-78 °C) and allyl bromide (2.98 mL, 34.4 mmol, 10 equiv.) was added slowly. The mixture was stirred 1 h at -78 °C, and was then quenched by the addition of a saturated solution of NaHC03 (3 mL). After warming to room temperature, the mixture was poured into water (15 mL) and diethyl ether (15 mL), and the layers were separated. The organic phase was dried over anhydrous MgS04, filtered, and concentrated in vacuo to a yellow oil. Kugelrohr distillation (air bath T = 75-125 °C @ 0.25 Torr) afforded 141 (1.12 g, 99%) as a very pale yellow oil. 1H nmr(CDCI3, 400 MHz) 8: 5.91 (ddt, 1H, J=8, 10, 17 Hz), 4.76 (ddt, 1H, J= 1, 2, 17 Hz, 4 J S n -H = 36 Hz), 4.62 (ddt, 1H, J= 1, 2, 10 Hz, 4 J S n - H = 29.14 Hz), 1.75 (dt, 2H, J= 1, 8 Hz, 2 J S n . H = 60.27 Hz), 1.36-1.57 (m, 7 H), 1.23-1.33 (m, 6H), 0.76-0.96 (m, 15H). 1 3C nmr (CDCI3, 75 MHz) 8: 138.16 (C-2), 109.12 (C-1), 29.11 (Sn-CH 2CH2CH 2CH 3), 27.32 (Sn-CH2CH 2CH 2CH 3), 17.78 (C-3), 13.70 (Sn-CHsC^CHsCHg), 9.11 (Sn-CH2CH2CH2CH3). 65 Preparation of Imide 153 To a cool (0 °C) solution of DIPA (3.11 mL, 22.2 mmol, 1.1 equiv.) in dry THF (70 mL) was added n-butyllithium (13.7 mL, 1.6 M solution in hexanes, 21.9 mmol, 1.1 equiv.) via syringe, and the resultant solution was stirred for 20 mins. The mixture was then cooled (-78 °C) and 152 (3.67 g, 19.8 mmol, 1 equiv.) dissolved in THF (8 mL) was introduced dropwise via cannula. The resultant solution was stirred for an additional 30 min at -78 °C, and was warmed to -46 °C. Allyl iodide (5.43 mL, 59.4 mmol, 3 equiv.) in THF (8 mL) was then added dropwise via cannula to the pale yellow solution. After allowing the mixture to slowly warm to -35 °C over 2.5 h, a solution of 1:1 NH4CI:H20 (20 mL) was added, and the resultant mixture was allowed to warm to room temperature. The volatiles were removed by rotary evaporation, and the residue was extracted into dichloromethane (3 x 30 mL). The combined organic extracts were washed successively with saturated NaHS03, H20, and brine (25 mL each), and dried over anhydrous MgS04. Filtration and concentration in vacuo afforded a golden oil which was purified by flash chromatography (1:5 ethyl acetate - petroleum ether) to yield a single diastereomer (glc) of 153 (3.7 g, 83%) as a pale yellow oil IR (neat): 3080, 2968, 1780, 1703, 1387, 1242, 1206 cm"1. 1H nmr (CDCI3, 400 MHz) 8: 5.77 (ddt, 1H, J= 7, 10, 17 Hz), 4.99-5.08 (m, 2H), 4.43 (dt, 1H, J = 4, 8 Hz), 4.15-4.26 (m, 2H), 3.86 (dq, 1H, J = 7, 7 Hz), 2.45-2.51 (m, 1H), 2.30 (d septets, 1H, J=4, 7 Hz), 2.14-2.21 (m, 1H), 1.12 (d, 3H, J=7 Hz), 0.88 (d, 3H, J = 7 Hz), 0.84 (d, 3H, J = 7 Hz). 13Cnmr (CDCI3, 100 MHz) 8: 176.33, 153.63, 135.17, 116.97, 63.05, 58.38, 38.92, 38.12, 37.05, 28.33, 17.86, 16.11, 14.57, 14.00. HRMS (El) m/zcalcd. for C12H19O3N: 225.1365; found: 225.1362. 66 [a]D = + 57.2° (c0.43, CHCI3). Preparation of (2R)-2-Methyl-4-pentenol (154) 154 To a cool (0 °C) solution of 153 (2.50 g, 11.1 mmol, 1 equiv.) in dry THF (50 mL) was added, in several portions, lithium aluminum hydride (LAH) (1.26 g, 33.3 mmol, 3 equiv.). The mixture was stirred for 1 h at 0 °C, and ice-cold water (15 mL) was added. The resulting slurry was poured into a cool (0 °C) 1M solution of HCI (220 mL), and was stirred for 1 h. The mixture was extracted with diethyl ether (3 x 75 mL), and the combined organic extracts were washed with brine (75 mL) and were dried over anhydrous MgS04. Filtration and concentration under reduced pressure afforded a pale orange oil, which was purified by flash chromatography (1:4 diethyl ether -petroleum ether, polar flush with diethyl ether). The non-polar fractions afforded 154 (0.92 g, 83%) as a colourless oil, and the polar fractions yielded recovered oxazolidinone 151 (0.45 g, 31%) as colourless crystals. IR (neat): 3346, 3077, 2926, 1641, 1459, 1044, 993, 912 cm"1. 1H nmr (CDCI3, 400 MHz) 8: 5.79 (ddt, 1H, J= 7, 10, 17 Hz), 4.98-5.06 (m, 2H), 3.42-3.52 (m, 2H), 2.12-2.19 (m, 1H), 1.87-1.97 (m, 1H), 1.66-1.78 (m, 1H), 1.30 (br s, 1H), 0.91 (d, 3H, J=7 Hz). 1 3C nmr(CDCI3) 75 MHz) 8: 136.95, 116.07, 67.89, 37.83, 35.59, 16.32. HRMS (DCI(+), ammonia/methane) m/zcalcd. for C 6H 1 30 (M+ +1): 101.0966; found: 101.0969. 67 [a]D = + 2.56° (c 0.28, CHCI3); lit.76 [a]D = + 2.6° (c 1.5, CHCI3). Preparation of (2R)-2-Methyl-4-pentenal (95) O 95 To a mixture of flame-dried Celite (3.95 g) and pyridinium chlorochromate (PCC) (1.29 g, 5.92 mmol, 1.5 equiv.) in dichloromethane (30 mL) was added 154 (400 mg, 3.95 mmol, 1 equiv.) in dichloromethane (10 mL) via cannula. The mixture was stirred at room temperature for 2 h. Diethyl ether (150 mL) was added, and the mixture was stirred an additional 30 min. The mixture was briefly sonicated (2 min) and filtered through wetted Florisil® (45 g), eluting with diethyl ether (850 mL). The filtrate was concentrated under reduced pressure to provide 95 as a yellow oil (360 mg, 93 %). 1H nmr (CDCI3, 400 MHz) 8: 9.64 (d, 1H, J= 1 Hz), 5.74 (ddt, 1H, J = 7, 10, 17 Hz), 5.04-5.09 (m, 2H), 2.39-2.49 (m, 2H), 2.10-2.17 (m, 1H), 1.09 (d, 3H, J = 7 Hz). 1 3C nmr (CDCI3, 75 MHz) 8: 204.55, 134.92, 117.26, 45.80, 34.74, 13.02. [a]D = -3.21°(c0.14, CHCI3). 68 Preparation of Ethyl hexa-2Z, 4Z-diene-1,6-dioate (187) B0 2 C / = x \ = / C02Et 187 A solid mixture of copper (I) chloride (144 mg, 1.45 mmol, 5 equiv.) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 29 |umol, 0.1 equiv.) was degassed under high vacuum in a 10 mL round-bottomed flask. Z-vinyl iodoester 180 (66 mg, 290 umol, 1 equiv.), Z-vinyl stannane 181 (120 mg, 348 |umol, 1.2 equiv.), and DMSO (3.0 mL) were introduced sequentially via syringe, and the mixture was degassed rigorously (2 x) by the freeze-pump-thaw technique. The mixture was stirred under dry argon at rt for 6 h, and was then warmed to 55 °C and stirred for an additional 2.5 h. The reaction mixture was allowed to cool to rt, and was diluted with diethyl ether (35 mL). The ethereal mixture was then washed with a mixture of brine (45 mL) and 5% aqueous NH4OH (10 mL). The aqueous portion was extracted with diethyl ether (2 x 20 mL), and the combined organic extracts were washed with H20 (2 x 45 mL) and brine (2 x 45 mL), dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to a brown oil. Flash chromatography (1:4 diethyl ether - petroleum ether) of the residue afforded 187 (8.3 mg, 14%) as fragrant orange crystals. IR (CCI4): 3077, 2961, 2359, 1719, 1591, 1371, 1354, 1223, 1165, 1097, 1030, 831 cm"1. 1H nmr (CDCI3, 400 MHz) 8: 7.82-7.90 (m, 2H), 5.91-5.99 (m, 2H), 4.19 (q, 4H, J = 7 Hz), 1.28 (t, 6H, J = 7Hz). 13, C nmr (CDCI3) 75 MHz) 8: 165.69, 137.83, 124.23, 60.42, 14.20. HRMS (DCI(+), ammonia/methane) m/zcalcd. for Ci0Hi5O4: 199.0970; found: 199.0972. Preparation of Ethyl hepta-2Z, 4Z-dienoate (177) 69 177 A solution of Z-vinyl iodoester 180 (41 mg, 0.18 mmol, 1 equiv.) and Z-vinyl stannane 181 (134 mg, 0.39 mmol, 2.2 equiv.) in NMP (1.5 mL) was cooled to 0 °C under a nitrogen atmosphere. Solid CuTC (148 mg, 0.78 mmol, 4.4 equiv.) was added all at once. The resultant orange-red suspension was stirred for 5 min at 0 °C followed by 5 min at rt, during which time the colour changed to green-yellow. The mixture was diluted with diethyl ether (10 mL) and filtered through a sintered glass funnel (medium) containing a thin layer of alumina to remove the copper salts. The filter cake was washed with ether (2x5 mL). The combined filtrates were washed exhaustively with water (10x10 mL) to remove NMP. The clear yellow organic layer was then dried (MgS04), filtered, and concentrated in vacuo to afford a fragrant pale yellow oil. The ester was purified by Kugelrohr distillation (air-bath T = 25-45 °C @ 0.25 Torr) to provide diene ester 177 as a pale yellow oil (24 mg, 86%). IR (neat): 2926, 1719, 1632, 1593, 1461, 1442, 1181 cm"1. 13Cnmr (CDCI3, 75 MHz) 5: 174.90, 166.43, 142.81, 138.60, 123.14, 117.38, . 1H nmr (CDCI3, 300 MHz) 5: 7.18 (t, 1H, J = 12 Hz), 6.87 (t, 1H, J = 12 Hz), 5.79-5.88 (m, 1H), 5.61 (d, 1H, J = 12 Hz), 4.13 (q, 2H, J = 6 Hz), 3.32 (t, 3H, J = 6 Hz). HRMS (El(+)) m/zcalcd. for C9H402: 154.0994; found: 154.0994. 70 REFERENCES AND FOOTNOTES 1. (a) Charan, R. D.; Garson, M. J.; Brereton, I. M.; Willis, A. C; Hopper, J. N. A. Tetrahedron 1996, 52, 9111; (b) Baker, B. J.; Scheuer, P. J.; Shoolery, J. N. J. Am. Chem. 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