Copyright is owned by the Author of the thesis. Permission is given for a copy to be downloaded by an individual for the purpose of research and private study only. The thesis may not be reproduced elsewhere without the permission of the Author. The Bisspiroketal Moiety of epi-17-Deoxy-(0-8)-salinomycin. A thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University. Geoffrey Martyn Williams. November 1991 Massey University Library Thesis Copyright Form . . ;ire B1$p1 roke:fol fllo, el? of Title of thesis: e..pi -17- Oeo?- ( 0-3)- 8::i lino??; n (1) (a) I give permission for my thesis to be made available to readers in Massey University Library under conditions determin'ed by the Librarian. ?do not wish my thesis to be made available to readers without my written consent for ... months. (2) (a) I agree that my thesis, or a copy, may be sent to another institution under conditions determined by the Librarian. ??I do not wish my thesis, or a copy, to be sent to another institution without my written consent for months. (3) (a) I agree that my thesis may be copied for Library use. ? do not wish my thesis to be copied for Library use for ... months. SignU ? _..,/ S ?? Date ??-- Tl-4 I The copyright of this thesis belongs to the author. Readers must sign their name in the space below to show that they recognise this. They are asked to add their permanent address. NMIE AND ADDRESS DATE 15 - -- --- --? - ? - -- -- ---- - ? ? - ? MA"SSEY UNIVERSITJ\? l!SR.t\RY To my family for their support and patience. Acknowledgements. I wish to express my sincere thanks to Dr. Margaret Brimble who, in her role as supervisor, has provided me with invaluable assistance, guidance and encouragement throughout the course of this work. In addition, she has introduced me to an area of research that has proved stimulating, thought-provoking and immensely rewarding and for this I am extremely grateful. I would also like to acknowledge the support provided by my eo-supervisor Assoc. Professor Ken Jolley, who has also introduced me to the intricacies of high field nuclear magnetic resonance spectroscopy. It remains for me to thank Dr. Mark Brimble for his assistance in proof reading this thesis, and especially my friend and colleague Michael Nairn who, in addition to helping with the proof reading, has made life in the laboratory bearable when things became a little trying. Finally I wish to acknowledge Professor Ray Baker of Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, for the gift of chemicals which made a significant portion of this work possible. Abstract. The synthesis of 2-(3,4-epoxy-3-methylbutan-1-yl)-1 ,7 -dioxaspiro[S.S]undec-4-ene 188 is described, the key step in it's formation being an addition of the lithium acetylide derivative of S-tert-butyldiphenylsilyloxy-2-methyl-2-trimethylsilyloxy-7 -octyn-1-p? toluenesulphonate 182 to o-valerolactone. The epoxide 188 was then converted to the hydroxy spiroketal 4-(1,7-dioxaspiro[S.S]undec-4-en-2-yl)-2-methyl-2-butanol 149 which underwent a Barton-type oxidative cyclisation to afford both the cis- and trans-2,2-dimethyl- 1,6,8-trioxadispiro[ 4.1.S.3]pentadec-13-enes 192 and 152. The ring system of this latter compound is analogous to the unsaturated bisspiroketal present in the polyether antibiotic epi-17-deoxy-(0-8)-salinomycin 8. Subsequently the route was modified to afford the trans- and cis-(2-methyl-1,6,8- trioxadispiro[4.1.S.3]pentadec-13-en-2-yl)methanols 211-214, since it was expected this terminal hydroxyl group would provide a 'handle' by which these molecules could be further elaborated. This required conversion of the epoxide 188 to 4-(1,7- dioxaspiro[S.S]undec-4-en-2-yl)-1-iodo-2-methyl-2-butanol 200, which was followed by a Barton-type oxidative cyclisation, to give the cis- and trans-2-iodomethyl-2-methyl-1,6,8- trioxadispiro[4.1.S.3]pentadec-13-enes 201-204, which were then converted to the alcohols 211-214. The techniques used to construct these relatively simple bisspiroketal analogues were then applied to an enantioselective synthesis of the bisspiroketal portion of epi-17 -deoxy-(0- 8)-salinomycin. The two key intermediates required for this were (l'S, 3R, SS, 6S)-(+)-6- [1'-(tert-butyldiphenylsilyloxymethyl)propyl]-3,S-dimethyl-tetrahydropyran-2-one 84 and (SR, 2S)- and (SS, 2S)-2-methyl-2,S-bis(trimethylsilyloxy)-7-octyn-1-p-toluenesulphonate 231. The lactone 84 was prepared, using Evans' directed aldol methodology, from (4R, SS)-(+ )-4-methyl-3-(1'-oxobutyl)-S-phenyloxazolidin-2-one 219 and (S)-( + )-2,4-dimethyl- 4-pentenal 218. The acetylene 231 was prepared from levulinic acid 174, and the procedure incorporated a resolution step which enabled the 2S configuration of 231 to be introduced. The lactone 84 and the the lithium acetylide derivative of acetylene 231 were combined and subsequently converted to the (1"S, 2S, 2'S, 6'R, 8'S, 9'S, ll'R)-(-)- and (l"S, 2S, 2'R, 6'R, 8'S, 9'S, ll'R)-(+)-4-{8-[1-(tert-butyldiphenylsilyloxymethyl)propyl] -9,11-dimethyl-1,7 -dioxaspiro[S.S]undec-4-en-2-yl}-1-iodo-2-methyl-2-butanols 245 and 246. These hydroxy spiroketals were transformed, again using the Barton-type oxidative cyclisation methodology, to the cis-(l'S, 2S, SR, 7S, 9S, lOS, 12R)-(-)- and the trans? (l'S, 2S, SS, 7S, 9S, lOS, 12R)-(-)-9-[l-(tert-butyldiphenylsilyloxymethyl)propyl]-2- iodomethyl-2,10,12-trimethyl-1 ,6,8-trioxadispiro[ 4.1.S.3]pentadec-13-ene 248 and 247, the latter of which resembles precisely the corresponding portion of epi-17-deoxy-(0-8)? salinomycin. In addition, the termini of the bisspiroketal 247 are selectively functionalised, which will allow further elaboration to the entire natural product 8. The synthesis of the cis- and trans-2, 2-dimethy l -1S-hydroxy-1 , 6 ,8 - trioxadispiro[4.1.S.3]pentadec-13-enes 156 and 159, and of cis-2,2-dimethyl-13-hydroxy- 1,6,8-trioxadispiro[4.1.S.3]pentadec-14-ene 268 is described. These were formed firstly by allylic bromination of the cis- and trans-2,2-dimethyl-1,6,8-trioxadispiro[4.1.S.3]pentadec- 13-enes 192 and 152 to give the cis- and trans-1S-bromo-2,2-dimethyl-1,6,8- trioxadispiro[ 4.1.S. 3 ]pentadec-13-enes 262 and 265, and cis-13-bromo-2,2-dimeth y l- 1,6,8-trioxadispiro[4.1.S.3]pentadec-14-ene 261. These bromides were then displaced by an oxygen nucleophile to afford the alcohols 268, 156, 159, a procedure which involved both SN2 and anti-SN2' processes. Chapter 1 Chapter 2 Contents. Introduction. 1 . 1 1 .2 Biosynthesis of Polyether Antibiotics. 1 .3 Total Syntheses of Salinomycin and Narasin by Kishi et al. 1 .4 The Total Synthesis of Salinomycin by Yonemitsu et al. 1 .5 Synthesis of Tricyclic Bisspiroketals. Synthesis of 1 .6.8-Trioxadispiro[ 4. 1 .5.3lpentadec- 13-ene Ring Systems. 2 . 1 Retrosynthesis and Synthetic Strategy. 2.2 Synthesis of the Cyclisation Precursor 4-( 1',7'-Dioxa spiro[5.5]undec-4'-en-2'-yl)-2-methyl-2-butanol 149. 2.3 Synthesis of 2,2-Dimethyl- 1 ,6,8-trioxadispiro [ 4 .1 .5.3]pentadec- 13-ene 152 , 192 . 2.4 Synthesis of the Cyclisation Precursor 4-(1 ',7'- Dioxaspiro[5.5]undec-4'-en-2'-yl)- 1-iodo-2-methyl-2- butanol 200. 2.5 Synthesis of the (2'-Methyl- 1 ',6',8'-trioxadispiro Page 1 5 1 1 27 37 43 44 5 1 58 [ 4. 1 .5.3]pentadec- 13'-en-2'-yl)methanols 211-214. 60 Chapter 3 Chapter 4 Chapter 5 Synthesis of the Bisspiroketal Moiety of eQi-17-Deoxy-(0-8)- salinomycin. 3.1 The Optically Active Lactone 84. 3.2 Enantioselective Synthesis of the Cyclisation Precursors 245, 246. 3.3 Assembly of the Bisspiroketal Moiety of epi-17 -Deoxy-(0-8)-salinomycin. 3.4 Summary. 4.1 Allylic Oxidation of 2,2-Dimethyl-1,6,8-trioxa dispiro[ 4.1.5.3]pentadec-13-ene. 4.2 Summary. Experimental References 72 77 84 99 102 110 112 143 Abbreviations. AIBN = 2,2'-azobisisobutyronitrile ax = axial Bzl = benzyl cat. = catalytic COSY = correlation spectroscopy CSA = camphorsulphonic acid DDQ = 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone DHP = dihydropyranyl DIBAL = diisobutylaluminium hydride DMAP = 4-dimethylaminopyridine DMF = N, N-dimethylformamide DMSO = dimethylsulphoxide eq = equatorial equiv. = equivalent HET COR = heteronuclear correlation spectroscopy imid = imidazole MCPBA = meta-chloroperoxybenzoic acid Ms = methanesulphonyl NBS = N-bromosuccinimide NCS = N-chlorosuccinimide NMO = N-methylmorpholine-N-oxide nmr = nuclear magnetic resonance PCC = pyridinium chlorochromate PPTS = pyridinium p-toluenesulphonate Py = pyridine RT = room temperature Tf = trifluoromethanesulphonyl 1FA = trifluoroacetic acid 1FAA = trifluoroacetic anhydride THF = tetrahydrofuran THP = tetrahydropyrany 1 tic = thin layer chromatography TMS = trimethylsilyl Ts = p-toluenesulphonyl TSA = p-toluenesulphonic acid Chapter 1 Introduction 1.1 Polyether Antibiotics. The class of compounds known as the polyether antibiotics are all microbial in origin, generally being isolated as fermentation products from different strains of the Streptomyces genus of microorganism. Representative members of the class appear in figures 1 and 2 and an immediately apparent structural feature is the numerous oxygen atoms distributed along the carbon chain, often as cyclic ethers. This gives rise to a distinguishing chemical characteristic which is the ability to form neutral, lipid soluble complexes with one of a variety of cations. These associations are stabilised by ion induced dipole interactions and a terminal carboxylate often serves to secure the resulting cyclic structure, which presents an exterior array of alkyl groups, thereby imparting solubility in an hydrophobic environment. The ability to extract ions into an organic solvent has been noted since the first isolation 1,2 of the polyethers, and places them in the ever expanding family of ionophores - a group that includes the crown ethers and cryptates. However, the polyethers, being acidic, yield neutral salt complexes and are thus distinguished from these other ionophores which are neutral structures affording charged ion complexes. Within the polyether class there exists a certain level of affinity for monovalent ions over divalents, or the reverse, and Westley3 used this distinction as the basis for a classification system. This resulted in division of the polyethers into four groups, the first of which contains the monovalent and monovalent glycoside polyethers, reflecting an affinity for the transport of monovalent cations, and include monensin 1 and the glycosylated dianemycin 2. Similarly, the second group, termed the divalents and divalent glycosides, contains those members that transport divalent cations more efficiently, and include lasalocid A 3 and antibiotic 6016 4. The remaining classes distinguish those polyethers which possess pyrrole ethers, such as antibiotic A23187 5 , and those with acyl tetronic acid functionalities. Historical interest in the polyether antibiotics since their discovery during the 1950s,1,2 has centred on their inherent pharmacological activity. The strong ion binding and lipophilic transportation properties of the compounds results in disruption of the permeability barriers to ion transport across biological membranes,3.4 a consequence of which is that they often exhibit potent antimicrobial activity, usually against gram positive bacteria and mycobacteria and some also show significant activity against phytopathogenic bacteria and fungi.5 Although possessing notable antimicrobial properties in vitro, the intrinsic parenteral toxicity of the compounds in vivo has precluded their use as clinical antibiotics. However, 1 HOOC M eO HOOC Me HO HOOC Me Me Me COOH Figure 1 Monensin 1 OH ,, Me' Dianemycin 2 : R=6 Me Lasalocid A 3 OMe Antibiotic 6016 4: R=6 Me Et N ? NHMe V I Antibiotic A23187 5 MOCOOH 0 # 2 Me Me ("i ?''OMe ..-+-oh Me H 6 certain members, particularly lasalocid A 3, monensin 1 and salinomycin 7, have enjoyed considerable commercial success in veterinary medicine - primarily as coccidiostats in poultry6, due to a fairly specific toxicity against various coccidial parasites of the intestinal tract combined with minimal absorption of the drug by the host, and as growth promotants in ruminant livestock , since a claimed? increase in feed efficiency has been observed after administration of the drugs. Polyether Antibiotics Containing a Bisspiroketal Ring System. In 1973 salinomycin 7, isolated8,9 from the fermentation medium of Streptomyces albus, was found to exhibit marked activity against mycobacteria and fungi in addition to the characteristic antibacterial and anticoccidial properties. X-ray crystallographic analysis of the p-iodophenacyl ester derivative of this polyether by Kinashi et a[ 8 in 1973 revealed the presence of a then unique unsaturated tricyclic bisspiroketal ring system. Using the same S. albus culture and a different culture medium, Westley et a[ lO later isolated two C-17 epimers of deoxy-(0-8)-salinomycin. The predominant isomer, epi-17 -deoxy-(0-8)-salinomycin 8, the structure of which was confirmed by X-ray crystallographic analysis10 of the free acid, was found to be present at much greater levels than the corresponding deoxy-(0-8)? salinomycin 9. Narasin A (or simply 'narasin') 10 was isolatedll from a culture of S. aurefaciens under similar conditions, and was confirmed as being 4-methyl-salinomycin after mass spectral comparison 12 with salinomycin itself. The methyl group was later established to be l3 on the tetrahydropyran ring by Be nmr analysis.l3 Since then further bisspiroketal containing polyether antibiotics have been reported. Noboritomycins A 11 and B 12 were isolated as fermentation products of the strain Streptomyces noboritoensis by Keller-Juslen et a[,14 and X-ray crystallographic analysis of the silver salt complexes of 11 and 12 established the presence of this key structural feature. A species of Dactylosporangium yielded antibiotic CP44,16115 13, and more recently Westley et a[ 16 reported the first bisspiroketal-containing halogenated polyether X-14766A 14. The list of structural analogues continues to grow with the addition of such members as epi-17-deoxy-(0-8)-narasin 15,17 deoxy-(0-8)-narasin 1617 and narasins B 17 and D 18.18 With the attributes of structural complexity and unique structural features, this class of compounds will continue to provide a challenge to the synthetic chemist in the quest to design and implement new synthetic strategies and methodologies. 3 1 HOOC HOOC OH OH Me Figure 2 Me ??'' OH Salinomycin 7: R1=H:Rz=R3=Me, R4=0H Deoxy-(0-8)-salinomycin 9: R1=H, Rz=R3=Me, R4=H Narasin A 10: R1=R2=R3=Me, R4=0H Deoxy-(0-8)-narasin 16: R1=R2=R3=Me, Rz=H Narasin B 17: R1=R2=Me, R3=Et, R4=0H Narasin D 18: R1=R3=Me, R2=Et, R4=0H epi-17-Deoxy-(0-8)-salinomycin 8: R1=H epi-17-Deoxy-(0-8)-narasin 15: R1=Me Noboritomycin A 11: R1=Me, R2=H Noboritomycin B 12: R 1 =Et, R2=H Antiobiotic X-14766A 14: R1=Me, R2=Cl Antibiotic CP44,161 13 4 OH Et OH OEt Me 1 .2 Biosynthesis of Polyether Antibiotics. Initial biosynthetic studies into members of the polyether class of compounds indicated that they were constructed predominantly from combinations of acetate, propionate and butyrate units in a manner analogous to the classical biosynthesis of fatty acids. l9 The investigation by Dorman et af 20 into the biogenesis of narasin 10; in which cultures of S. aureofacies were grown in media containing 13C labelled precursors and the enrichment pattern in the 13C nmr spectra of the product? observed, indicated that five acetate, seven propionate and three butyrate units were required for it s construction (figure 3). However the acetate labelled experiments were inconclusive, probably due to isotope dilution factors. HO Salinomycin 7: R=H Narasin 10: R=Me Figure 3 Salinomycin: R=H : BtsAtJ iii 1 4 3 R=H, Me, Ph, 23% R 0 R OH R=H, 33%; R=Me, 43%; R=Ph, 50% OH R=H, 70%; R=Me, 68%; R=Ph, 23% Reagents and conditions: (i) W, CHz=CHCHO, 100?C, 2-5 h.; (ii) Hz, copper chromite, l20?C/130 atrn, EtOH; (iii) Ni cathode, C anode, NH4Br, MeOH. Some time was to elapse before Descotes et al 55 described the photolytic generation of 4, 1 1-dihydroxy-4, 1 1-dimethyl- 1 ,6,8-trioxadispiro[ 4. 1 .4.3]tetradecane 144 employing a Norrish type II reaction (scheme 3 1). Irradiation of compounds such as 145 and 146, in which there is an acetal hydrogen o to the carbonyl and no hydrogen atoms in the y position, 56 results in hydrogen abstraction and spirocyclisation of the intermediate biradical. 57 The non-stereoselective nature of this cyclisation gave rise to varying ratios of all six possible stereoisomers, each of which was isolated and characterised.5 5 ,58 The diastereoselectivity of these compounds was subsequently investigated under thermodynamic conditions. 59 After treating isomers A, C and E with camphorsulphonic acid and examining the product ratios, predominantly the cis isomer E was observed with trace quantities of C, and, similarly, equilibration of isomers B, D and F afforded equimolar mixtures of the cis isomers D and F. Thus, thermodynamic equilibration of a given isomer gave the cis arrangement of the bisspiroketal, in which the C-0 bonds of the terminal rings 37 0 HO? TsOH A From Z 15% From E : - ? HO HO D From Z : 13% From E : - Scheme 31 MeO?O? ? MeO (Lo. benzene J"'-V 145 E 68% B 28% 18% ? hu, benzene I;bff.OH HO ... E 16% OH 0 9) ?0? HO 1 4 6 z 32% 1 4 4 HO c 3 1% F 5% occupy axial positions on the tetrahydropyran ring, which itself adopts a chair conformation. This maximises the number of stabilising anomeric effects47-50 and relieves the steric interactions between terminal ring oxygen atoms and opposing methyl groups - effects which are pronounced in the trans isomers and force the central rings to adopt unfavourable skew boat configurations. Studies by Baker and Brimble,60 directed at modelling the unsaturated bisspiroketal moiety of salinomycin 7, focused firstly on an acid catalysed cascade ring <:;losure of keto epoxide 14 7 (scheme 32). This afforded 1-(2-methyl- 1 ,6,8-trioxadispiro[ 4. 1 .5 .3] 38 pentadecan-2-yl)methanol 148, the conformation of which was not definitively assigned. However, attempts to construct the unsaturated ring system, which corresponds to that present in the natural product, by the same acid catalysed procedure were unsuccessful. ? Me I'LoJ\ OH 'oVo? 1 4 8 1 --- V ---- Scheme 32 rl = ?SiM? "'? l....o...f'-? OMe Me ? 0 OMe Me 0 1 4 7 . . ?SiM? 11 ----- 0 OMe Me 0 , . . . 1 5 1 tlll ? 0 OMe Me 0 Reagents and conditions: (i) a: n-BuLi, THF, -78?C, o-valerolactone; b: MeOH, Amberlite IR 1 1 8 resin; c: Me3SiCl, NEt3, THF; (ii) a: MCPBA, CHzClz, NaOAc; (iii) a: n-Bu?, THF; b: H2, Pd/C, EtOAc; (iv) DMSO, 1FAA, CHzCl2, -60?C then NEt3; (v) CSA, CH2Cl2? An alternative approach was therefore undertaken, which involved construction of 2,2-dimethyl-1 ,6,8-trioxadispiro[ 4. 1 .5.3]pentadec- 13-ene via a photolytically induced free radical process (scheme 33). The spiroketal 149 was formed by an acid catalysed cyclisation of the ketal 150, derived from an intermediate 151 of the previous route (see scheme 32). Scheme 33 1 5 1 -? ....... ii OMe ?iH 1 5 0 J? rvMe 't;;::f'o/?e 1 5 2 IV 1 4 9 Reagents and conditions: (i) Hz, Pd/CaC03-Pb(OAc)z, pentane; (ii) LiAffi4 (0.5 eq.), EtzO; (iii) CSA, CHzClz; (iv) Phi(OAc)z (1 eq.), Iz (0.5 eq.), cyclohexane, hu. 39 Me OH Me OH The conformation of the spiro centre of 149 is one in which the C-0 bonds of that centre adopt axial positions with respect to their respective neighbouring rings, thereby deriving maximum stability from anomeric effects.47-50 A Barton-type oxidative cyclisation, employing iodobenzenediacetate, afforded the bisspiroketal 152 , the stereochemistry of which was assigned by spectroscopic means. Elaboration of this work61 ,62 forms part of the basis for this thesis. During the course of this work, Albizati and Perron63 and Kocienski et al 64 independently reported an elegant procedure to construct the 15-oxo-2,2-dimethyl- 1 ,6,8- trioxadispiro[4. 1 .5.3]pentadec-13-enes 153 and 154 via the oxidation and rearrangement of a 2-furyl ketone 155 (scheme 34). 0 0 .... ?) A + (1 : 1) Scheme 34 ( OP ? 0 ii ?v f\jMe o?o/\ B Me %. ?Me 't;;;;:t:d 'Me 0 1 5 4 iv Reagents and conditions: (i) n-BuLi, THF, -23?C then A; (ii) n-BuLi, EtzO, TMEDA, -23?C then B; (iii) NBS, THF/HzO, 0?C; (iv) HF, CH3CN, 0?C. A 1 : 1 ratio of the diastereomeric bisspiroketals 153 and 154 was obtained in both instances and although the cis isomer 153 derives maximum stabilisation from anomeric effects, it did not predominate in the product mixture, probably due to unfavourable dipole interactions which are largely obviated in the trans isomer 154. At this point it was envisaged that facile reduction of the carbonyl group (scheme 35) would afford, from the cis isomer, the allylic alcohol with stereochemistry resembling that of salinomycin and narasin. Indeed, Albizati reported this to be the case, obtaining compounds 156 and 157 - in direct contrast to the results of similar experiments performed by Kocienski, in which predominantly the alternative configurations 158 and 159 were obtained. The more 40 comprehensive nature of these latter experiments coupled with findings reported65 later in this thesis serve to support Kocienski's results on this point. !fJ!Me 0 0 ::::,.... 0 1 5 3 .. w? Me 0 1 54 (i) Albizati: LiBHEt3 (ii) Kocienski: NaBH4 Scheme 35 ?Me 0 0 H 1 5 6 H + Me 1 5 7 H Albizati f/d)Me 0 H ::::,.... 1 5 8 OH + 1 5 9 OH Kocienski Me Brimble et af 66 recently reported a method for constructing a bisspiroketal ring system which involved a low temperature nucleophilic attack of an a-sulphonyl anion on a lactone (scheme 36). 14-Phenylsulphonyl- 1 ,7 ,9-trioxadispiro[5 . 1 .5 .3]hexadecane was obtained as a 1 : 1 mixture of isomers 160 and 161, the structures of which were assigned by X-ray crystallographic analysis in the case of 161 and nmr spectroscopy in the case of 1 6 0. Reduction of the phenylsulphonyl group of the individual isomers afforded the corresponding cis and trans 1 ,7 ,9-trioxadispiro[5. 1 .5.3]hexadecanes, 162 and 16 3, along with the spiroketal 164 as the major product. This was found to readily undergo oxidative cyclisation, using conditions alluded to previously,60 to afford a separable mixture of 162 and 1 6 3. Further work, which will be discussed in this thesis, will extend the application of the methodology originally employed by Baker and Brimble60 (see scheme 33) to the synthesis of more highly functionalised bisspiroketals, and ultimately to a synthesis of the bisspiroketal moiety of epi-11 -deoxy-(0-8)-salinomycin 8. 41 Scheme 36 0 PhS? ii PhO,S? ------0 OMe OMe pii iv Ph02S? ...,._ HO S02Ph +V A 1 6 0 1 6 1 A vii c:P??,? vii ...,.__ ----- 1 6 2 1 6 4 HO 1 6 3 Reagents and conditions: (i) a : n-BuLi, THF, 55?C then PhS(CHz)3Br; b: Amberlite IR 120 resin, MeOH; (ii) a: NaB03AHzO, KOH, MeOH; b: Amberlite IR 120 resin, MeOH, ?; (iii) n-BuLi, THF, -78?C then o-valerolactone; (v) CSA, CHzClz; (vi) Raney nickel; (vii) Iodobenzenediacetate, lz, cyclohexane, hu. 42 Chapter 2 Synthesis of 1 ,6,8-Trioxadispiro[ 4. 1 .5.3Jpentadec- 13-ene Ring Systems. 2 . 1 Retrosynthesis and Synthetic Strategy The synthetic strategies of Yonemitsu et a[ 42,46 and Kishi et az,30 by which the bisspiroketal fragment 27 of salinomycin 7 or narasin 10 was synthesised, possessed certain similar characteristics. Key aspects of both were that the terminal tetrahydropyran ring was constructed, with appropriate stereochemical features, prior to assembly of the bisspiroketal moiety itself. This tricyclic unit was in turn built up in a stepwise fashion requiring, in the case of both syntheses, acid catalysed intramolecular ketalisation steps to form both spiro centres. A proposed extension of this to an acid catalysed cascade ring closure of an epoxide 165 (equation 2),to form an unsaturated bisspiroketal ring system had been shown to be ineffective,60 and therefore an alternative route was proposed by which those polyether antibiotics containing a bisspiroketal such as salinomycin 7 might be synthesised. Equation 2 OH 1 6 5 Based on the precedent set by the work of Baker and Brimble60 (see scheme 33), in which an unsaturated bisspiroketal 152 was generated under photolytic conditions, it was envisaged this methodology could be extended to a synthesis of the natural products themselves. In that instance, the spiro centre joining the six membered rings of 149 was formed under thermodynamic acid catalysed conditions, giving the conformation in which the C-0 bonds adjoining the rings adopt axial positions, in accordance with the anomeric effect.47-50 The stereochemistry of that centre is retained throughout the remainder of the procedure, affording a product with a ring system resembling that of epi- 1 7 -deoxy-(0-8)? salinomycin 8 and not that of salinomycin 7, which is epimeric at that corresponding C17 centre (figure 8). Accordingly the synthetic target is 8. 43 Figure 8 Me 0 Rz ? trans-2,2-Dimethyl-1 ,6,8-trioxadispiro [4.1 .5.3]pentadec-13-ene 152 Me epi -17-Deoxy-(0-8)? salinomycin 8 Salinomycin 7 A comparison between the bisspiroketal conformations of the model compound 152, obtained by Baker and Brirnble, epi-deoxy-(0-8)-salinomycin 8 and salinomycin 7 (or narasin 10) shows which of these natural products is the approriate synthetic target. Me A proposed retrosynthesis of this natural product (scheme 37) which incorporates this alternative methodology makes use of the same retro-aldol disconnection, previously employed by both Yonemitsu (see scheme 26) and Kishi (see scheme 4), to afford the left and right hand fragments 25 and 166 respectively. The right hand portion is then further simplified to the bisspiroketal 167, which is selectively functionalised at the termini to permit subsequent elaboration. 167 is generated via an oxidative cyclisation of the spiroketal 168, it in turn being derived from the epoxide 169. The synthetic precursors for 169 are the optically active lactone 84 and functionalised acetylene 170. Before embarking on such a synthetically demanding undertaking, it was decided that the feasibility of the procedure should be established using as comprehensive a model system as possible, which allows for circumvention of some of the pitfalls that inevitably arise in the course of any lengthy synthesis. Additionally, such a model permits a full investigation, in a stepwise manner, into the pertinent stereochemical attributes of these bisspiroketals formed under the proposed conditions. 2.2 Synthesis of the Cyclisation Precursor 4-Cl ',7'-Dioxaspiro[5.5lundec-4'-en-2'-yl)- 2-Methyl-2-Butanol. 149 trans-2,2-Dimethyl- 1 ,6,8-trioxadispiro[4. 1 .5.3]pentadec- 13-ene 152 is a simple analogue of the tricyclic system of epi- 17 -deoxy-(0-8)-salinomycin 8 and was formed, as described earlier60 (see scheme 33), from the spiroketa1 149 under photolytic conditions. For the purpose of that investigation, the cyclisation precursor, spiroketal 149, was synthesised60 from methallyl alcohol (scheme 38). This alcohol was firstly elaborated to the acetylene 171, the lithium acetylide derivative of which was coupled with 8-valerolactone. 44 HOOC HOOC 25 PO PO PO MeY"(Me t-BuPh2SiO?O?O Et 8 4 + Scheme 37 + 1 6 7 Me H 1 6 8 Me H 1 6 9 OH epi-11-Deoxy-(0-8)-salinomycin 7 Me + OH ?}Et 0 ,; ,; 0? ' ''Me Me H 1 6 6 ?Et ? ll. Me OH ?OTs Me OH 170 45 Scheme 38 0 OH y i -loo- Vy iii, iv -loo- OSiM? ? Me v, iv -loo- vii -loo- 1 7 2 1 5 0 Me vi -loo- viii -loo- 1 7 1 1 5 1 1 4 9 Reagents and conditions: (i) EtOCH=CH2, Hg(02CCF3h; (ii) 120?C, 24 h.; (iii) HC=CCH2Br, Zn, THF , 0?C; (iv) Me3SiCI, NEt3, THF; (v) a: n-BuLi, THF, -78?C then o-valerolactone, -78?C; b: MeOH, Amberlite IR 1 18 resin; (vi) MCPBA, CH2Cl2, NaOAc; (vii) a: H2, Lindlar catalyst, pentane; b: LiAlfLt, Et20; (viii) CSA, CH2Cl2. Me Further steps, involving ketalisation, epoxidation and hydrogenation, followed, culminating in an acid catalysed intramolecular cyclisation of 150 to generate the spiro centre of 149. Although not a consideration for the original study, the sequence could not be amended to resolve C7 of the epoxide 151, coming as it did from the olefin 172. This is an important factor if the scheme is to be extended to an enantioselective synthesis since, with reference to the proposed retrosynthetic procedure (see scheme 37), this centre will give rise to C2' of the bisspiroketal 167, the S configuration of which is essential. A synthesis was therefore adopted which would enable the construction of a related acetylene which possessed the required stereochemistry at this centre. This was achieved (scheme 39) from the racemic lactonic acid 173, which could be prepared on a large scale using the procedure of Iwami and Kawai67 in which levulinic acid 174 was treated with sodium cyanide and the resulting cyanohydrin hydrolysed and esterified with hydrochloric acid. The acid was resolved using Mori's method68 in which the salt of the (-)-acid, formed with the vegetable alkaloid 'cinchonine', being highly crystalline, could be separated from the non crystalline antipodal salt of the (+)-acid. Acidic hydrolysis of the resolved crystalline 46 Scheme 39 Me ??H ii M Q OOH 0 (S)-(-)-173 OH iii ? .. ,.... OH Me OH 1 7 5 0 1 7 4 ? iv OH 0 OH ? ...l .-._ /'.._ "-"" 3 ?e'"\-j-?0 vi ?0 V ?-;-0 1 7 8 1 7 7 ? 1 7 6 ? ? vii ? @ @ @ ? viii ? l ...... ...... ix ? l ...... ...... ,. 0 ___... -............,?> . Formation of the diastereomeric bisspiroketals 192 and 152 during the photolytic spirocyclisation process may be rationalised in terms the depicted mechanism (scheme 44). 1 4 9 OH hu Me t Scheme 44 tpMe Me trans 152 54% O? [l ,S]H Me OH Me t !fJ5Me 0 0 ::,.... cis 192 26% 1 9 4 l OH Me The spiroketal centre of the cyclisation precursor 149 is formed under acid catalysed conditions (see scheme 42) giving the most thermodynamically favourable arrangement, in which the ring oxygen atoms adopt axial positions with respect to their neighbouring rings. This affords maximum stabilisation from the anomeric effect47-50 and is consistent with similar such cyclisations reported by Hanessian et a[ 77 and Baker et af.78 The oxy-radical 193, generated photolytically from 149, undergoes a 1 ,5-hydrogen transfer to give the stabilised carbon centered radical 194. This species is subsequently oxidised by iodine to 57 the carbocation 195 which is then trapped by the hydroxyl group, predominantly at the less hindered a face - avoiding pseudo-1 ,3 diaxial dipolar interactions - giving rise to the trans isomer 152. Competitive trapping of the carbocation from the more sterically demanding ? face of the unsaturated ring also occurs to a lesser extent affords the cis isomer 192 as the minor product. The net dipole of the minor (in this case) cis isomer 192 is significantly greater than that of the trans isomer 1 52 , which facilitates separation of the two by flash chromatography. This polarity difference may be used as a preliminary indicator to distinguish formation of these isomeric types in other similar reactions, since the cis arrangement should usually be more polar. 2 .4 Synthesis of the Cyclisation Precursor 4-0'.7'-Dioxaspiro[S.Slundec-4'-en-2'-yl)- 1-iodo-2-methyl-2-butanol. 200 Having re-examined the synthesis of 2,2-dimethyl- 1 ,6 ,8 -trioxadispiro [4. 1 .5.3]pentadec-13-ene, the trans isomer 152 of which is analogous to the bisspiroketal moiety of epi-deoxy-(0-8)-salinomycin 8, the existing model scheme was modified in order to incorporate a suitable functionality 'X' (equation 4) which would permit further elaboration of the molecule. This corresponds to a requirement in the proposed synthetic strategy of the natural product (see scheme 37) for some 'handle' on the bisspiroketal 167 which would enable subsequent construction of the terminal tetrahydropyran, or E ring, portion of epi--11 -deoxy-(0-8)-salinomycin 8. Equation 4 The spiroketal epoxide 188 is admirably suited to forming, by an SN2 opening of the epoxide functionality with an appropriate nucleophile (equation 5), any one of a variety of cyclisation precursors 196 which would then give rise to a functionalised bisspiroketal 197 . 58 Equation 5 X However, a requirement of this group, or handle, is that it be compatible with the Barton-type oxidative cyclisation methodology, which has a pivotal role in the overall synthetic strategy. Hence, two key considerations are that formation of the oxy-radical intermediates 198 (scheme 45) should not be inhibited, and the competitive fragmentation process, which gives rise? to the methyl ketone 199, is not facilitated. Scheme 45 hu X 1 9 6 1 9 8 '*' , l ... ? scission Me + ?CH2X 1 9 9 Attempts by Brimble79 to effect spirocyclistion of hydroxy spiroketals bearing either a tosylate, alcohol, chloride or bromide group at Cl (equation 6) using the same conditions previously used for 149, in which X=H (see scheme 43), were unsuccessful, giving either no reaction, or complex product mixtures. However, successful cyclisation to the required bisspiroketal was observed for X=iodide, moreover in reasonable yield. Equation 6 X X=OMs, OTs, Cl, Br 59 To obtain the iodohydrin precursor, a solution of the epoxide 1 88 in tetrahydrofuran was cooled to -50?C and an excess of lithium iodide in tetrahydrofuran added80 (scheme 46). After treating the solution with a small quantity of boron trifluoride diethyl etherate, a gradual formation of the iodohydrin 2 00 was observed completion of the reaction, was isolated and purified in 90% yield. Scheme 46 1 8 8 2 0 0 Reagents and conditions: (i) Lil (1 .2 equiv.), THF, -50?C, BF3.Et20 (cat), 90%. which, after The appearance of an hydroxyl group absorbance at 3600-3313 cm-1 in the infra? red spectrum was the preliminary evidence for formation of the iodohydrin 2 00, and this was confirmed by mass spectrometry, which afforded a molecular ion at m/ z 366 corresponding to a formula of C14H2303I. A satisfactory elemental analysis for the same formula was also obtained. This iodohydrin was obtained as a 1 : 1 mixture of diastereomers due to the functionality at Cl and although inseparable, they could be distinguished in the lH nmr spectrum since two methyl resonances of equal intensity were evident at OH 1 .38 and 1 .39, as were two very distinct hydroxyl group resonances at OH 2.40 and 2.53. 2 .5 Synthesis of the (2'-Methyl- 1 ',6'.8'-trioxadispiro[4. 1 .5.3Jpentadec-13'-en-2'-yl) methanols. 2 11-2 14 The iodohydrin 2 00 was subjected to the photolytic conditions required to induce spirocyclisation. A solution of 2 00, iodobenzenediacetate (3 equivalents) and iodine (2 equivalents) was irradiated (scheme 47) for several hours with a tungsten lamp whilst rigorously excluding oxygen from the reaction vessel. Again it was necessary to maintain temperatures at or below about 20?C using a controlled water bath to avoid thermal decomposition. 60 2 0 1 23% 2 0 2 23% Scheme 47 2 0 0 2 0 3 12% Reagents and conditions: (i) Iodine (2 equiv.), Iodobenzenediacetate (3 equiv.), cyclohexane, hu, 70%. 2 0 4 12% Four diastereomers of 2-iodomethyl-2-methyl-1,6,8-trioxadispiro[ 4. 1 .5.3]pentadec - 13-ene 2 01-2 04 were generated under these conditions, an outcome which can be explained by examining the proposed reaction mechanism (scheme 48). The cyclisation precursor 2 00 was obtained as a 1 : 1 mixture of diastereomers in which the spiroketal centre adopts the most thermodynamically favourable arrangement, with the ring oxygen atoms occupying axial positions and the side chain in a sterically favourable pseudo-equatorial orientation. Upon irradiation of this mixture, the oxy-radicals 2 05 and 2 06 are formed which then undergo a [ 1 ,5]H shift to afford the carbon radicals 2 07 and 2 08. In the presence of iodine 2 07 and 2 08 are oxidised to the carbocations 2 09 and 2 1 0, each of which is trapped by the hydroxyl group. This occurs at the more accessible a face of the unsaturated ring to give a 1 : 1 mixture of the trans isomers 2 01 and 2 02 , but trapping also occurs at the more sterically demanding ? face to afford the cis isomers 2 03 and 2 04, again in a 1 : 1 ratio. The overall ratio of isomers 2 01:2 02 :2 03:2 04 was 2:2: 1 : 1 , which reflected a preference for formation of the trans bisspiroketals over the cis under these reaction conditions - an effect observed previously for the 2,2-dimethyl- 1 ,6,8-trioxadispiro[4. 1 .5.3] pentadec-13-enes 152 and 192 (see scheme 43). The two cis diastereomers 2 03 and 2 04, being slightly more polar due to the enhanced dipole of this bisspiroketal configuration, were separated by flash chromatography69 from the trans isomers 2 01 and 2 02 . However, the individual trans isomers were inseparable as were the individual cis isomers and therefore were characterised as mixtures. Both configurations afforded, expectedly, identical mass spectra with a 61 Scheme 48 + + 205 206 ?[1,5]H + + 2 1 0 ? y ? l[J5Me W CH,I 0 2 0 + ? ? Ill Ill Ill Ill etA, Me ?H2I ?Me H2I ?Nfu H2I 203 204 2 0 1 Ratio 202:203:204:201 = 2 : 1 : 1 : 2 62 molecular ion at mlz 364, consistent with the formula C14H21 03I, and the characteristic retro-Diels-Alder fragment at mlz 124 (CsH120) (see equation 3 , p. 52). However, these iodides, unlike the iodohydrin precursor 2 00, proved to be somewhat unstable at room temperature and particularly photosensitive, hence satisfactory elemental analyses were not obtained. The 28 resonances of the complex 13C nmr spectrum recorded for the mixture of trans isomers were impossible to assign individually to either 2 01 or 2 02 , but the four quaternary resonances at oc 96.3, 96.4, 107.4 and 107.7 were indicative of spiroketal centres. The 1 H nmr spectrum, in addition to confirming the mixture was indeed a 1 : 1 mixture of diastereomers, afforded the key conformational information. The multiplet resonating at OH 2.66-2.75, integrating for two protons, was assigned to the 4-H protons of each trans isomer. This? deshielding effect, due to the proximity of these protons to the opposing ring oxygen atoms, is not observed for the cis isomers 2 03 and 2 04 since for these the corresponding resonances occur in the multiplet at OH 1 .52-2.30. This confmns the trans arrangement of the bisspiroketals 2 01 and 2 02 . Of the two methyl resonances in the spectrum of the trans mixture, at OH 1 .44 and 1 .67, the latter can be attributed to the C2 configuration of isomer 2 02 , since in this case the methyl group occupies a position 1 ,3-syn to a C-0 bond of the central ring, and is therefore deshielded relative to the methyl resonance of trans isomer 2 01 (the same effect as that depicted in figure 1 1 , p. 54). Similar conclusions may be drawn for the minor product, the mixture of cis diastereomers 2 03 and 2 04. Of the 28 resonances in the 13C nmr, the four quaternary peaks at oc 93.8, 93.9, 105.3 and 105.5 are due to the spiroketal centres of the two isomers. The 1 H nmr spectrum confirmed they were were formed in equal amounts and also showed the lack of deshielded 4-H resonances (occurring in the multiplet at OH 1 .52-2.30 compared with OH 2.66-2.75 in the trans), confirming a cis arrangement of the bisspiroketal. The two methyl resonances at OH 1 .39 and 1 .631 of which the latter, deshielded by a 1 ,3-syn orientation to a C-0 bond (the same effect as that depicted in figure 1 1 , p. 56), can be assigned to C2 of 2 04 and hence the less deshielded methyl resonance to 2 03. Conversion to the alcohols 2 11-2 14 It was originally envisaged in the retrosynthesis (scheme 37) that the bisspiroketal 167 would be extended via a terminal aldehyde group, obtained from the corresponding alcohol. Extension of this to the model system required conversion of the iodide functionality to the synthetically more useful alcohol group, and it was expected this could most readily be achieved by direct SN2 displacement of the iodide group by an oxygen nucleophile. However, this process proved difficult due to the steric demands of the neopentyl-like configuration of the primary iodide, a problem encountered by Moffatt et a[ 81 63 for a similarly disposed iodide group. Hence an attempted conversion of the mixture of trans iodides 2 01 and 2 02 to the alcohols 2 11 and 2 12 by hydroxide in an aprotic solvent was ineffective (scheme 49), despite using elevated temperatures and 18-crown-6 to enhance the nucleophilicity of the anion. Scheme 49 I OH + I ? ? 201 . 2 0 2 ,11 2 1 1 2 1 2 No Reaction Reagents and conditions: (i) K? (excess), DMSO/THF, 18-crown-6 (excess), RT, 81 %; (ii) KOH, DMSO, 18-crown-6, !:J.. OH Success was achieved by treating a solution of 2 01 and 2 02 and 1 8-crown-6, dissolved in a mixture of dimethyl sulphoxide and tetrahydrofuran at room temperature, with potassium superoxide (scheme 49), as described by Corey et al. 82 These trans alcohols 211 and 2 12 were obtained in 8 1% yield and were separated by flash chromatography. The polarity difference which enabled them to be separated was attributed to the extent of intramolecular hydrogen bonding between the hydroxyl group and the spiroketal ring oxygens (figure 12). The effect is more pronounced in isomer 2 11 , thereby rendering it markedly less polar than 2 12 . Figure 12 Me 211 trans, hydrogen bonded. 212 trans, non-hydrogen bonded. Me OH 213 cis, hydrogen bonded, 214 cis, non-hydrogen bonded. very unfavourable dipole effects. 64 Subjecting the more delicate cis iodides to the same reaction conditions was invariably accompanied by rapid equilibration (scheme 50) to give an approximately 1 :2 mixture of the cis and trans iodides 201-204. This was then followed by slower conversion of these iodides to a mixture of the corresponding four alcohols 211-214 - the two distinct trans alcohols 211 and 212 and, by virtue of similar intramolecular hydrogen bonding effects (figure 12), the distinct cis alcohols 213 (less polar) and 214. Scheme 50 I 203 , 2 0 4 lK02, 18-crown-6, DMSO/THF I I 20 1 , 2 0 2 203 , 2 0 4 l tfi J[;j5Me OH :0.. 0 Me + + 0 :::,.... 2 1 1 2 1 2 2 1 3 2 1 4 \.. ) V Inseparable by chromatography However, a frustrating consequence of obtaining these alcohols as a mixture was that, although the less polar trans isomer 211 and more polar cis isomer 214 could be separated and purified, the more polar trans 212 and the less polar cis 213 isomers could not since the hydrogen bonding effect in 213 exactly compensated for the enhanced polarity of the cis conformation of the bisspiroketal. In order to obtain a sample of 213 it was necessary to modify the reaction conditions and, by omitting the tetrahydrofuran component from the solvent mixture (scheme 5 1), the initial equilibration of 203 and 204 was avoided and the individual cis alcohols 213 and 214 could be isolated. However, the cis alcohol 65 2 1 3 proved to be very unstable, possibly due to the number of dipole interactions (see figure 12, p. 64), and could not be isolated with a high degree of purity. Scheme 5 1 I OH + OH 203 , 2 0 4 2 1 3 2 1 4 Reagents and conditions: (i) KOz (excess), DMSO, 18-crown-6 (excess), RT. All four isomers 2 11-2 14 afforded identical mass spectra, giving a parent ion at mlz 254, which is consistent with a molecular formula of C14H2204. Base peaks were observed at mlz 223, corresponding to M-CH20H, and also at mlz 99, corresponding to a formula of CsH702. This latter peak and that at mlz 124 (CsH120) arise from a retro-Diels? Alder fragmentation process (equation 7). Equation 7 + + 01:? + ~ + Me C14Hzz04, mlz 254 CsHizO, mlz 124 CsH10z, mlz 99 Be nmr spectroscopy established each isomer to be diastereomerically pure, except 2 1 3 which, as mentioned previously, was not isolated in a pure form. The lH nmr spectra of 2 11 , 2 12 and 2 14 are reproduced (figures 13, 14 and 15 respectively) and some of the chemical shifts of the four alcohols 2 11-2 14 (table 2) provide confirmation of the assigned stereochemistry for each isomer. The deshielded 4'-H resonances of 2 11 and 2 12 , at OH 2.79 and 2.70 respectively, are indicative of the trans conformation of these bisspiroketals. The corresponding resonances for isomers 2 1 3 and 2 14 occur upfield as part of the multiplets at OH 1 .53-2. 15 and 1 .80-2.09, which establishes a cis arrangement of the bisspiroketals. The stereochemistry at C-2' of each isomer is inferred by the chemical shifts of the methyl groups; for trans isomer 2 12 the methyl resonance at OH 1 .47 indicates it is 1 ,3-syn to a C-0 bond of the neighbouring ring, whereas for trans isomer 2 11 the 66 67 (T) lO 68 69 Table 2 lH NMR Chemical Shifts of (2'-Methyl- 1 ',6',8'-trioxadispiro[4. 1 .5 .3l pentadec- 13'-en-2'yl)-methanols.a OH OH 2 1 1 2 1 2 OH 2 1 3 2 1 4 Compound 1-H 211 3 .56, 3 .60 212 3.37, 3 .61 213 3.37 3 .61 214 3.35, 3 .42 Compound 9'-Heq 11 13'-H 14'-H 11 15'-H' 15'-H OH 211 3 .70 7 5?? 2. 13 2.52-2.61 3.56 (d) 212 3 .68 5.60 5.84 2.48 2. 15 1 .53-2.05 213 3 .71 I 6 .17 I 5.97 2.23 I 2.47 I 4.26 (d) 214 3 .65 5.74 I 5.89 2.38 2.16-2.27 2.99 (s) a Recorded at 270 MHz in CDCl3 relative to SiMe4 70 corresponding methyl resonance appears upfield at 8H 1 .20 implying that it is not in the same 1 ,3 syn arrangement. Similar conclusions may be drawn for the cis isomers, of which 214, possessing a correspondingly deshielded methyl resonance (at 8H 1 .37 compared with 8H 1 . 1 1 for 213), must possess the indicated stereochemistry at C2', which positions the group 1 ,3-syn to a C-0 bond of the central ring. 7 1 Chapter 3 Synthesis of the Bisspiroketal moiety of evi- 17 -Deoxy-C0-8)-salinomycin 8 3 . 1 The Optically Active Lactone 84 With the synthesis of a suitable model system for the bisspiroketal moiety of epi- 17-deoxy-(0-8)-salinomycin 8 well in hand, attention was turned to the task of extending the methodology to a synthesis of the natural product. As outlined in the retrosynthetic analysis (see scheme 37), the two necessary precursors are the optically active lactone 84 and the acetylene 170. Me?Me t-BuPh2SiO?OA,O Et Required synthetic precursor 84 Figure 16 We Me HO 0 H Me Prelog-Djerassi lactone 215 A synthesis of the lactone was detailed previously since it was an intermediate in the synthesis of salinomycin carried out by Kishi et af 30 (see scheme 15). However, the methodology developed by Evans and Bartroli83 in their synthesis of the structurally similar Prelog Djerassi lactone84 2 15 (figure 1 6) was recently employed by Brimble85 in a synthesis of 84. In this procedure the lactone was formed (scheme 52) by a catalytic oxidation of the diol 2 16. This was in turn obtained from the oxazolidinone 2 17 in which the stereochemistry at C2' and C3' had been constructed via a directed aldol condensation between the aldehyde 218 and butanoyloxazolidinone 2 19. The aldehyde 2 18 was initially prepared according to the literature procedure85 (scheme 53), the final step of which used the Parikh86 modification of the Moffatt oxidation (pyridine-sulphur trioxide) to oxidise the alcohol 2 2 0. It had been established that this reagent was exceptional in that only a minimal degree (0. 1%) of racemisation occurred in the course of reaction, but other shortcomings were noteworthy. The procedure was characterised by incomplete reaction even after extended periods, and the volatility of the product, as noted by Still and Shaw87 was such as to make workup and subsequent purification steps difficult, further contributing to a reduced yield. 72 lll Scheme 52 Me liMe t-BuPh2SiO?O?O Et 8 4 ? OH ? t-BuPh2SiO?OH Et Me Me 2 1 6 OH 0 0 ? ---.. A:?.? A T l T -N ? Me Me ?t H. Me Ph 2 1 7 0 0 Et 11 A ?0 Me Me 2 1 8 Scheme 53 0 0 Me ll A ?N 0 M)--{ Ph Y'('oH iv Me Me 220 ?N 0 2 1 9 H. Me Ph ii ?0 Me Me 2 1 8 Reagents and conditions: (i) n-BuLi ( 1 equiv.), THF, -78?C, CH3CH2COC1, 96%; (ii) Li(i-Pr)z, -78?C, 0.5 h. then H2C=C(CH3)CH2I, -50?C to -20?C, 3h. 82%; (iii) LiAIH4, Et20, ooc, 1 h.; (iv) Py.S03 (3 equiv), NEt3 (7equiv.), DMSO, RT, 3 h., 64% OR (iv) tetra-n-propylammonium perruthenate (cat), NMO (1.5 equiv.), CH2Clz, 4A molecular sieves (powder), 5 h., 80%. 73 A more expedient means of oxidising 2 2 0 employed the tetra-n-propylammonium perruthenate catalyst88 and N-methylmorpholine-N-oxide, conditions also shown not to cause appreciable racemisation. Oxidation was near quantitative by tlc and the subsequent workup very straightforward, and although the volatility of the product remained a problem the yields were nevertheless improved (80-85% ). The second precursor required for a synthesis of the lactone, butanoyloxazolidinone 2 19, was prepared85 (scheme 54) in 9 1% yield by lithiation of the oxazolidinone 2 2 1 with n-butyllithium followed by treatment with butanoyl chloride. Reacting 2 19 with a slight excess ( 1 . 1 equiv.) of 9-borabicyclo[3.3. 1 ]nonyl trifluoromethanesulphonate89 in the presence of triethylamine ( 1 .2 equiv), afforded the Z-boron enolate90 2 2 2 , which condensed with the aldehyde 2 18 to give the crossed aldol product 2 17, with the required stereoselectivity,90-92 in 76% yield. Under these conditions the desired 2', 3'-erythro- 3', 4'-threo product 2 17 was formed with the 2' , 3'-threo- 3', 4'-threo product in a ratio of 6 : 1 , an improvement on the reported85 ratio of 3 : 1 . Protection of the resulting hydroxyl group as the trimethylsilyl ether to give 2 2 3 was more effectively achieved using 1 - (trimethylsilyl)irnidazole in dichloromethane (94%) than with trimethylsilyl diethylamine85 (85%). M?SiQ 0 0 ? /'-... ?'? 2')l 1 1 T Tj"T .N AO Me Me ?t )--\ 223 Me Ph Scheme 54 iii ii ?o ? Me Me 2 1 8 OH 0 0 ? /'-... 4 '? 2 ')l 1 1 T jj"T .N AO Me Me Et )--\ 2 1 7 Me Ph Reagents and conditions: n-BuLi (1 equiv.), CH3CHzCHzCOCl, 96%; (ii) R2BOS02CF3 (1.1 equiv.)(RzB=9-borabicyclo[3.3.1]non-9-yl), NEt3 (1.2 equiv.), CH2Ciz, 0?C, 1 h. then -78?C, 218, RT, 2 h., 76%; (iii) 1-(Me3Si)imidazole, CH2CI2, RT, 94%. 74 Hydroboration of the olefin 2 2 3 was carried out (scheme 55) using freshly prepared thexylborane in tetrahydrofuran at 0?C. This was followed by a bicarbonate? peroxide workup to afford a separable mixture of the 6'R- and 6'S- alcohols 2 24 and 2 2 5 in a ratio of 2: 1 . Modifying this procedure so that the thexylborane solution was cooled to - 40?C prior to adding the olefin 2 2 3, then slowly warming the reaction mixture to 0?C, resulted in an improved diastereoselectivity of 3.6: 1 in favour of the desired isomer 2 24, in 9 3 % overall yield. The resulting hydroxyl group was then protected as a tert? butyldimethylsilyl ether 2 2 6, using tert-butyldimethylsilyl triflate in dichloromethane, in very high yield (98%). Scheme 55 ? ;??2.1 T Tj? y -xc Me Me Et 223 ?i ?6.;??2.1 ROr T lj . y -xc Me Me Et . . r- 224: R=OH 11 ? 226: R=t-BuMe2Si + HO? X, Me Me Et 225 0?C ratio 224 : 225 = 2 : 1 -40 ? ooc ratio 224 : 225 = 3. 7 : 1 Reagents and conditions: (i) BH3 (2 equiv.), (CH3hC=C(CH3h (2 equiv.), 0?C, 1 h. then. -40?C, 223 ? 0?C over 1.5 h., 93%; (ii) t-BuMe2SiOTf (1 .2 equiv.), 2,6-lutidr ne (2.5 equiv.), CH2Cl2, 0?C, 98%; Attempted removal of the chiral auxiliary by treating 2 2 6 with lithium borohydride in tetrahydrofuran93 (scheme 56) afforded nearly equal quantities of the alcohol 2 2 7 and the undesired amide 2 2 8. This occurred because the site of nucleophilic cleavage of N-acyloxazolidinones is subject to both steric and electronic factors and, in the absence of significant steric crowding, the exocyclic carbonyl group is more susceptible to nucleophilic attack. However, as the steric interactions in the vicinity of this carbonyl group increase, competitive attack at the endocyclic carbonyl group is observed, affording the amide, in this case 2 28, in increasing quantities. This problem may possibly be circumvented by using lithium hydro ?peroxide, 75 Scheme 56 QPI P20?0H ? ? !1 1 w e OH PzOr l l '( -7? Me Me Et 2 27 . !ii ?PI P20?0P3 Me Me Et 2 2 9 Mej'(Me P30?0?0H Et 2 3 0 + 1 : 1 iii Me Me Et H Ph 22 8 OH HO?OP3 Me Me Et 2 1 6 Reagents and conditions: (i) LiBI4 (1 equiv.), THF, 24 h., RT, 48% 227; (ii) imidazole (5 equiv.), t-BuPhzSiCl (1.3 equiv.), NEt3 (5 equiv.), CHzClz, RT, 96%; (iii) PPTS (cat), EtOH, 82%; (iv) NMO (2 equiv.), Ru(PPh3)3Clz, 4A molecular sieves (powder), acetone, 87% from 229. iv since this reagent has been shown94 to effectively remove this chiral auxiliary from imides in which the reactivity of the exocyclic carbonyl group has been suppressed by steric factors. An alternative method for excising the auxiliary may lie in the use of a lithium benzyloxide transesterification,95 which gives the alcohol after reduction of the resulting ester with lithium aluminium hydride. Recently Evans et af 96 employed an effective technique which relied on enhancing the nucleophilic susceptibility of the exocyclic carbonyl group by firstly generating the boron aldolate of that group which was then reduced in high yield to the 76 alcohol using lithium borohydride. Thus, alternative methods exist whereby an improved yield for removing the chiral auxiliary might be achieved. Having obtained the alcohol 2 2 7 the hydroxyl group was protected as the tert? butyldiphenylsilyl ether to give 2 2 9, which enabled selective removal of the trimethylsilyl and tert-butyldiphenyl ether groups, in mildly acidic conditions97 (pyridinium-p ? toluenesulphonate in ethanol), to give the diol 2 1 6 . This was finally oxidised, using tris(triphenylphosphine)ruthenium(II) chloride as catalyst and N-methylmorpholine-N-oxide as oxidant in acetone, to the lactol 2 30 and then to the lactone 84. All intermediates in this synthesis of the lactone 84, from the aldehyde 218 and butanoyloxazolidinone 2 19, afforded spectroscopic data and optical rotations which were in agreement with those previously reported. 85 3 .2 Enantioselective Synthesis of the Cyclisation Precursors 245, 246 Enantioselective syntheses of the optically active lactone 84 and (S)-(-)-acetylene 181 were now achieved (figure 16), as part of the requirements the proposed retrosynthesis (see scheme 37) of epi-17 -deoxy-(0-8)-salinomycin 8. Figure 16 Me I"'( Me t-BuPh2SiO?OAO Et 8 4 OSiPh2t-Bu ? 1 ::... -? -??x-??OTs Me OH 1 8 1 However, prior to utilising these precursors to construct the bisspiroketal 167, a decision was made to retain the large tert-butyldiphenylsilyl ether of the lactone component throughout the remainder of the procedure to facilitate manipulation of the small molar quantities of material. In order to distinguish the silyl ether group of 84 from the protected secondary alcohol of the acetylene 181, the tert-butyldiphenylsilyl ether of 181 was reprotected as the more labile trimethylsilyl ether. Incorporating this modification, firstly into the model procedure (scheme 57), required removal of the tert-butyldiphenylsilyl ether from the (':!")-acetylene 181 using a 2% solution of hydrofluoric acid in acetonitrile73 (the use of tetra-n-butylammonium fluoride would cause immediate and undesired epoxidation of 181). This gave the diol 170, which was reprotected as the bis-trimethylsilyl ether 2 31 using 1 -(trimethylsilyl)imidazole. Since 77 the secondary sily 1 ether was somewhat labile, considerable care was required during purification, using florisil for column chromatography. OR ? 1 ...... ? ? '-../' ?-X":oTs Me OH i 1 181: R=t-BuPh2Si ? 170: R=H OSiM? 232 Scheme 57 ii iii iv Reagents and conditions: (i) a: 2% HF (excess), CH3CN, RT, 95%; (ii) l-(Me3Si)imidazole (2.2 equiv.), CH2Cl2, 95%; (iii) n-BuLi (1 equiv.), THF, -78?C, then o-valerolactone (1 . 1 equiv.); (iv) Amberlite 1R 120 resin, MeOH, 75% from 231. Treatment of 2 31 with n-butyllithium at -78?C followed by addition of o? valerolactone gave the hemiketal 2 32 which was not isolated and purified but immediately dissolved in methanol and stirred with acidic Amberlite IR 1 20 resin. This effectively removed the trimethylsilyl protecting groups and generated the ketal 2 3 3 in 7 5 % yield. From this coupling step, a synthesis of of the model spiroketal epoxide 188 (see scheme 42) was now possible (scheme 58). Firstly, the acetylene 2 33 was partially hydrogenated to the cis olefin 2 34 using Lindlar catalyst. No attempt was made to isolate the product, but by directly treating a solution of 2 34 in dichloromethane with pyridinium-p-toluenesulphonate the spiroketal tosylate 2 35 was formed as an inseparable 1 : 1 mixture of diastereomers. This was clearly evident from the 1H nmr spectrum which showed two methyl resonances at OH 1 . 1 8 and 1 .20 and two hydroxyl group resonances of equal intensity at OH 2.66 and 2.86. The stereochemistry of the spiro centre was assumed to be that in which the C-0 bonds adjoining the spiro centre adopt axial positions on their respective neighbouring rings, as determined by the anomeric effect,47-50 and the side chain is assumed to adopt the more sterically favourable pseudo-equatorial position on the unsaturated ring. Treatment of the tosylate 2 35 with sodium hydride in tetrahydrofuran afforded the previously obtained epoxide 188 in 94% yield. Having satisfactorily modified the model procedure whereby the protected secondary alcohol group of acetylene 181 was reprotected as a trimethylsilyl ether, the stage 78 Scheme 58 ii 234 23 5 1 ? ? ? t lll 1 8 8 Reagents and conditions: (i) H2, Lindlar catalyst, hexane/EtOAc, RT, 1.5 h.; (ii) PPTS (cat), CH2CI2, RT, 0. 1 h., 76% from 233; (iii) NaH, THF, RT, 4 h., 94%. Scheme 59 OP1 ? l " ...._ 2 ...._ ? ? ? ??-=:oTs Me OH 1 8 1 OP2 ? 1 - ..... ...._ iii - ??X'??OTs ___ _,_ 23 1Me OPz Me?Me P1o?oAo Et 8 4 OH ? l ...._ ...._ ? ? ? X'?-=:oTs Me OH 170 ii ?iv Reagents and conditions: (i) 2% HF (excess), CH3CN, RT, 95%; (ii) 1-(Me3Si)imidazole (2.2 equiv.), CH2CI2, 95%; (iii) n-BuLi (1 equiv.), THF, -78?C, 0.5 h. then 84; (iv) MeOH, Amberlite IR 120 resin, 1 h., RT, 84% from 84. 79 had now been reached at which the information and insight gathered during the course of the model studies could be applied to an enantioselective construction of the bisspiroketal moiety of epi-17 -deoxy-(0-8)-salinomycin 8. Firstly the (S)-(-)-acetylene 181 (see scheme 39) was converted (scheme 59), via the diol 170, to the corresponding (S)-bis-trimethylsilyl ether 2 31. Treatment of 2 31 with n-butyllithium at -78?C afforded the lithium acetylide derivative which reacted with the optically active lactone 84 to give the hemiketal 2 36. Due to the small scale of this reaction, a very slight excess of the acetylene 2 31 was used, which precluded competitive attack on the lactone by any residual butyllithium. The unreacted acetylene could later be recovered from the reaction mixture by flash chromatography.69 After quenching with water, drying and evaporating the solvent, hemiketal 2 36 was quickly filtered through a short column of florisil to remove inorganic salts, then dissolved in methanol and stirred with acidic Amberlite IR 120 resin for one hour to afford the moderately unstable ketal-diol 2 37 in 84% yield. The 1 H nmr spectrum of 2 37 showed it to be a mixture of two diastereomers since two resonances were evident at OH 3.35 due to the ? (axial) methoxy group and at OH 3 .43 due to the a (equatorial) methoxy group, occurring in a 3 : 1 ratio98 (figure 17). Assignment of this stereochemistry is based on the stability of each isomer due to the anomeric effect, which favours an axial orientation of the C-0 bond of the methoxy group on the ring. R = R' = t-BuPh2SiO"'Y Et Figure 17 H I M,e OMe R??Me R' ? anomer 3 : 1 a anomer A solution of 2 37 in ethyl acetate and hexane was partially hydrogenated (scheme 60) using Lindlar catalyst, to afford the cis olefin 2 38 which was not purified but directly dissolved in dichloromethane and treated with pyridinium-p-toluenesulphonate. This gave a 1 : 1 mixture of the less polar spiroketal tosylate 2 39 and the more polar diastereomer 240, which were separated by flash chromatography.69 The optical rotations of each product were surprisingly different when the structural similarity of the two is considered - [a]'f? - 1 8.5?, (c, 1 .090, Et20) for 2 39 and [aH ? +38 . 8? , (c, 1 .034, Et20) for 240, but the mass 80 spectrum of each diastereomer was identical, affording, under chemical ionisation (NH3) PO P=t-BuPhzSi I l l Scheme 60 [a]o -18.5? 42% 2 anomeric effects Pseudo-axial side chain PO I l l [a]0 +38.8? 42% 2 anomeric effects Pseudo-equatorial side chain Reagents and conditions: (i) Hz, Lindlar catalyst, hexane/EtOAc; (ii) pyridinium-p-toluenesulphonate, CHzClz, RT, 84% from 237. conditions, a molecular ion at mlz 749, consistent with the molecular formula C43Htio07SSi +H. Be nmr spectroscopy confirmed the diastereomeric purity of each product, with most resonances being assigned on the basis of 2D lH- lH COSY and Bc_IH HETCOR nmr experiments. The key resonances at oc 96.8 for 2 39 and at 8c 98.3 for 240 were indicative of spiroketal centres of six membered rings. The structures of 2 39 and 240 were ascertained by considering both steric and anomeric effects. The favoured conformation of the spiroketal centre of both isomers is that in which the C-0 bonds adopt axial or psuedo-axial positions on their respective neighbouring rings, as dictated by the anomeric effect.47-SO The difference between the isomers arises from the unresolved C5 of the cyclisation precursor 2 38. On spirocyclisation 50% of the mixture will afford that isomer 240 with a pseudo-equatorial side chain, and the remaining 50% that isomer 2 39 with the side chain placed in the relatively unfavourable 8 1 pseudo-axial position. Each can be distinguished by comparing the 1 H mm spectra, since the 2'-H of 240 possesses a pseudo- 1,3 diaxial relationship to a C-0 bond and it's resonance is therefore deshielded - occurring as a multiplet at OH 3.94-4.05, relative to the resonance for the same proton of isomer 239 which occurs upfield, in the multiple! at OH 3.65-3.78 . This contrasts with the corresponding model system, the products from which were obtained exclusively with the side chain in the pseudo-equatorial position. This is because the spiro centre of that half of the mixture which would be expected to give the product 241, bearing a pseudo-axial substituent (step a, scheme 61), can invert in the acidic medium and, when accompanied by a conformational change of the rings to restore two anomeric effects, shift the orientation of the side chain to the pseudo-equatorial position. Since these compounds are racemic this product is simply the mirror image of that half of the mixture which gives the pseudo-equatorial side chain directly (step b). Scheme 61 a OMe 234 mirror R = ?OTs Me OH However, this scenario cannot apply to the tosylate 239 as it possesses a number of chiral substituents on the saturated ring. If the spiroketal centre was to invert, then undergo a conformational change to restore two anomeric effects (scheme 62) to give 242, Scheme 62 2 3 9 Inversion of spiro centre and conformational change 2 anomeric effects Unfavourable pseudo-1 ,3-diaxial interactions 82 Me 242 2 anomeric effects Extremely unfavourable 1 ,3-diaxial interactions then a pseudo-equatorial side chain at C2'would indeed result, relieving this steric tension. But in addition, that conformational change of the rings would also force the substituents of the unsaturated ring, normally equatorial, into the indicated unfavourable 1 ,3-diaxial relationships. So, when this steric effect is taken into account, the favoured conformation of the tosylate is that of 2 39, for which the side chain occupies a pseudo-axial position at C2'. Having separated the diastereomeric tosylates 2 39 and 240, the remainder of the synthetic procedure was conducted on the individual isomers, each being treated in precisely the same fashion. PO PO PO 2 3 9 ?i 2 4 3 2 4 5 Scheme 63 PO [a.]o -18.5? PO [a.]o -13.7? PO [a.]o -20.2? P=t-BuPh2Si Me H 2 4 0 ?i [a.]o +38.8 Me H 2 4 4 ?ii [a.]o +42.4 Me H 2 4 6 [a.]o +40.1 Reagents and conditions: (i) NaH, THF, RT, 97%; (ii) Lil, THF, BF3.Et20, -50?C, 91%. Thus, 2 39 was converted to the epoxide 243 (scheme 63) in high yield (97 %) using sodium hydride in tetrahydrofuran, and similarly the other diastereomeric epoxide 244 was obtained from 240 under the same conditions. The stereochemistry of each epoxide resembles that of the tosylate from which it is derived, since a relatively deshielded resonance, at OH 3 .98-4.07 is observed in the lH nmr spectrum of 244, due to a pseudo- 1 ,3-diaxial interaction of 2-H with a C-0 bond, whereas the corresponding resonance for the other epoxide 243 occurs upfield at OH 3.65-3.7 1 . The methylene group of the terminal epoxide was also apparent, the protons resonating as as two doublets at OH 2.37 and 2.43 for isomer 243 and at OH 2.49 and 2.70 for 2 44. The 1 3C nmr spectrum exhibited 83 distinctive epoxide resonances, at oc 53.7 and 57.0 for 243 and at oc 53.9 and 56.8 for 244. The optical rotations of each isomer were similar to the respective tosylate precursors 239 and 240, [a]1J - 13.7? (c, 0.766, Et20) for 243 and [a]l? +42.4? (c, 0.752, Et20) for 244 . The iodohydrins 245 and 246 were obtained by a nucleophilic ring opening of the epoxide functionality by lithium iodide80 in tetrahydrofuran at low temperature, catalysed by boron trifluoride etherate. Hence each diastereomer, 245 and 246 , possessed a stereochemistry analogous to the epoxide from which it was derived. The appearance of an hydroxyl group absorbance in the infra-red spectrum confirmed a ring opening of the epoxide, and the mass spectrum afforded a molecular ion at mlz 704, consistent with a molecular formula of C36Hs304ISi. Satisfactory lH and Be nmr data were also obtained for both isomers. The optical rotations were again similar to those of the corresponding precursors, [a]l? -20.2? (c, 0.60, Et20) for 245 and [a]l? +40.1 ? (c, 0.5 1 , Et20) for 246. 3 . 3 Assembly of the Bisspiroketal Moiety of epi -17-Deoxy-OC -8)-salinomycin. Having obtained the iodohydrins 245 and 246, spirocyclisation to the bisspiroketal was then attempted using the same controlled photolytic conditions developed for the model systems (see scheme 47). Irradiation of a solution of iodohydrin 245 (scheme 64) in cyclohexane, containing iodine and iodobenzenediacetate under nitrogen, with a tungsten fllament lamp afforded two less polar products. Although the Rr values differed only very slightly, they could nevertheless be separated by careful flash chromatography69 to afford the trans-bisspiroketal 247 and the more polar cis-bisspiroketal 248 in a ratio of 1 .7 : 1 , in 54 % overall yield. The mass spectrum of each product was identical, giving a parent ion at mlz 702, consistent with the molecular formula C36Hs1 04ISi. The yield of this cyclisation step was somewhat lower than that of the corresponding model systems, which may be due in part to the steric influence of the chiral substituents during cyclisation. If this is the case then replacing the tert-butyldiphenylsilyl ether by a less bulky protecting group would be appropriate. However, it was noted, in contrast to this step for the model experiments, that the reaction did not proceed as cleanly by tic and hence it would appear that the increased structural complexity of these compounds may also be promoting competitive side reactions. Both isomers exhibited two quaternary resonances in the 13C nmr spectrum, at oc 99. 1 and 1 07.4 for 247 and at oc 96.6 and 106.3 for the cis isomer 248, resonances characteristic of spiroketal centres. lH nmr spectroscopy readily distinguished the trans isomer since the spectrum (figure 1 8) exhibited the characteristic resonance at OH 2.57 due to the 4-H proton which is deshielded, owing to it's proximity to a ring oxygen, relative to that in the spectrum of the cis isomer (figure 19) in which 4-H occurs at OH 2.02-2. 1 1 . 84 Scheme 64 PO 245 P=t-BuPh2Si ?i Me Me I + I PO PO 247 1 .7 : 1 248 I l l I l l I [a]o -10.5o Reagents and conditions: (i) Iodine (2 equiv.), iodobenzenediacetate (2 equiv.), 1 8?C, hu, 54%. PO 246 P=t-BuPh2Si Me H Scheme 65 247 + 248 Reagents and conditions: (i) Iodine (2 equiv.), iodobenzenediacetate (2 equiv.), 18?C, hu, ratio 247:248, 1 .7 : 1 . 85 86 2: 0... 0.. lO 87 The stereochemistry of C2 is inferred by examining the chemical shifts of the 2-Me group. Since the C2 centre possesses an S configuration then, after spirocyclisation, the methyl group on the five membered ring of the trans isomer 247 must adopt a 1 ,3-syn orientation with a C-0 bond of the central ring (see scheme 64) and therefore be somewhat deshielded relative to the corresponding methyl group of the cis isomer, which cannot adopt the same 1 ,3-syn orientation to that C-0 bond. This is indeed the case as spectrum of the trans isomer 247 exhibits the C2 methyl resonance as a singlet at 8H 1 .57 compared to 8H 1 .28 for the cis isomer 248. Subjecting the the second iodohydrin 246 to the same photolytic conditions (scheme 65) used above gave rise to precisely the same mixture of products in exactly the same ratio ( 1 : 1 . 7 cis :trans ) in similar overall yield, an outcome which may be explained by the proposed reaction mechanism (scheme 66). The oxygen radicals 249 and 250, formed photolytically from the iodohydrins 245 and 246, undergo a 1 ,5-hydrogen shift to give the stabilised carbon radical 251. An important consequence of forming this intermediate is that because radicals of this type are considered99,100 to be almost planar and freely inverting, the distinction between the diastereomeric precursors 245 and 246 is now lost. The radical species 251 is then assumed to be oxidised by iodine to the planar carbocation 252 which is subsequently trapped, predominantly from the least hindered a face to give the trans bisspiroketal 24 7, and from the more hindered ? face of the unsaturated ring to give the cis isomer 248 as the minor product. Thus, according to this mechanism, regardless of which iodohydrin, 245 or 246, is subjected to these photolytic conditions, indistinguishable radical and carbocation intermediates are formed and hence the same product mixture results. The trans-bisspiroketal 247 obtained by this procedure resembles exactly the bisspiroketal moiety of epi- 17-deoxy-(0-8)-salinomycin 8, and a comparison of key 1H nmr chemical shifts and coupling constants with those of the natural product75 and this fragment (table 3) serves toh'?"l?t the similarities. Although 4-H is more deshielded in the natural product, the coupling constants are remarkably similar to those of the synthetic analogue 247, (14,4 12.5, 14,3 7.5, 14,3 1 .0 Hz for 8 and 14,4 12.6, 14,3 8. 1 , 14,3 0.4 for 247). The chemical shifts of the 2-methyl resonances are similar ( 1 .43 for 8 and 1 .57 for 247), in accordance with the stereochemistry of this centre (compare 8H 1 .28 for the cis isomer 248 which has the opposite relative stereochemistry of C2), as are those shifts of the chiral substituents which are not greatly influenced by R and R', notably the 1 0-methyl and 12- methyl groups - which also possess the same coupling constants. Examination of the vinylic ( 1 3-H and 14-H) and allylic (15-H) regions show them to be almost identical with respect to both chemical shifts the coupling constants of the resonances (compare h3 ,14 10.0, 113,15 1 .0, 113 ,1 5 3 .0 and h5,15 16.8 Hz for 8 and 113 ,14 10. 1 , 11 3 , 1 5 0, 113 ,15 2.4 and h 5 , 1 5 1 6.8Hz for 247. 88 Scheme 66 I ? ?]H I I 34% [a.]0 -10.5? 89 ::::,...... Me S]H/ 2 5 0 [1 ,/ I I I Me 20% [a.]0 -31 .6? Table 3 Key 1 H NMR Chemical Shift Values and Coupling Constants for eni- 17 -Deoxy-C0-8)? salinornycin and Synthetic trans-1 .6.8-Trioxadispiro[ 4. 1 .5.3Jpentadec-13-ene Analogues. R 8 epi -17-Deoxy-(0-8)-salinomycin : R = H02C 247 : R = t-BuPh2SiOCH2; R' = CH2I 255 : R = HOCH2; R' = CH2I Chemical Shiftsa Compound 11 2-Me 1 1 3-H 8 I 1 .43 ?s? 11 2.09 247 I 1 .57 {s2 11 2.03-2.14 1 1 3-H' 11 1 .95 11 1 .75 1 1 11 11 255 1 .89 (s) 1 1 2. 14-2.23 11 2. 14-2.23 11 Corn ound 8 247 255 Coupling Constants (Hz) 10-Me 12-Me 6.4 6.5 6.4 6.2 6.6 6.6 Compound 14, 15 1 1 14,1 5' 15, 15' 1 1 4, 4 8 2.0 I 16.8 11 12.5 247 I 6.4 11 2.1 I 16.8 1 ') 6 255 6.2 1 1 2.4 16.8 12.6 R' 4-H 1 1 3.01 {ddd2 11 2.57 (ddd) 11 2.57 (ddd) 1 1 1 1 4, 3' 11 7.5 11 8 . 1 1 1 5 . 1 ; R' = 9-H 3.80 {dd? 3.72 {dd2 3.83 (dd) 15-H' 2.03 2.03-2.14 2. 14-2.23 13, 15 1 .0 0.0 0.8 1 1 4, 3 11 1 .0 11 0.4 11 5 . 1 OH ? Et +o) .,,Me H 10-Me I 0.86 (d) I 0.82 (d) 0.8 1 (d) 13, 15' 3 .0 2.4 3 .0 18, 17 I 7.5 I 7.5 7.1 a The spectrum of 8 was recorded at 360 MHz in CDCl3 relative to SiMe4; the spectra of 247 and 255 were recorded at 270 MHz in CDCl3 relative to SiMe4 90 Table 4 Key ?C NMR Chemical Shift Values for eri-17-Deoxy-(Q-8)-salinomycin and Synthetic trans-1.6.8-Trioxadispirof 4. 1 .5.3Jpentadec-1 3-ene Analogues. R 8 epi -17-Deoxy-(0-8)-salinomycin : R = H02C 247 : R = t-BuPh2SiOCH2; R' = CHzl 255 : R = HOCH2; R' = CH2I Chemical Shiftsa Compound 2 5 8 I 88.5 I 105.0 247 I 82.8 I 107.4 255 82.8 107.5 7 : 99.0 99.1 99.3 R' 9 I 71 .6 I 75.6 81 . 1 R' = 13 121 .8 125.2 126.2 OH ? Et +o).,,Me H 14 125.6 129.6 128.7 a The spectrum of 8 was recorded at 25. 1 MHz in CDC13 relative to SiMe4; the spectra of 247 and 255 were recorded at 67.8 MHz in CDCl3 relative to SiMe4 9 1 Some of the distinctive chemical shifts in the Be nmr spectrum of the natural productlOI also correspond closely to those of the synthetic product 247 (table 4). Very important are the two quaternary spiro resonances, occurring at 8c 105.0 and 99.0 for C5 and C7 respectively for the natural product 8 , and at 8c 107.4 and 99. 1 for 247. The remaining deshielded resonances, for C2 and C9 and for the vinylic carbons C13 and C14, of both 8 and 247 correspond well, as do the methyl group resonances 10-Me, 12-Me and C18. Such regularities in the nmr data leave little room for doubt that the structure and conformation of the synthetic bisspiroketal 247 does indeed resemble that of corresponding portion of epi- 17-deoxy-(0-8)-salinomycin 8. The more polar diastereomer 248 possesses a cis arrangement of the bisspiroketal but the ring system does not resemble that present in salinomycin 7. For 7 the spiro junction of the six membered rings adopts a relatively unfavourable configuration (figure 20), since only one anomeric effect is exhibited, to give a cis bisspiroketal with the opposite stereochemistry, with respect to the chiral substituents of the tetrahydropyran ring, to that of 248. Figure 20 Me The bisspiroketal conformation of 248. The bisspiroketal conformation of salinomycin 7. Hence this synthetic route cannot be applied to a synthesis of the deoxy? salinomycin series of compounds. However it can, on the basis of Kishi's work,3 0 reasonably be asserted that should an allylic hydroxyl group be introduced with the appropriate stereochemistry and the remainder of the synthesis completed, then salinomycin would be obtained on thermodynamic equilibration of that product. Equation 8 PO I PO OH 247 253 92 The next stage in the procedure required conversion of the iodide group of the trans bisspiroketal 247 to the alcohol 253 (equation 8), which would then enable subsequent construction of the terminal tetrahydropyran ring to give the right hand fragment 166 (see scheme 37) of the natural product 8. This, however, presented certain difficulties because treatment of 247 with potassium superoxide in dimethylsulphoxide containing 1 8-crown-6 (scheme 67) for an extended period (12 h.), conditions82 applied successfully in the model systems, not only caused displacement of the halogen but also removed the silyl ether to give the spiroketal-diol 254. This is not a useful outcome since both alcohol groups are primary and virtually indistinguishable, rendering further synthetic manipulation difficult. Shorter reaction times under the same conditions ( < 2 h.) exclusively resulted in formation of the iodo-alcohol 255, which confirmed the tert-butyldiphenylsilyl ether to be, unexpectedly, the more labile of the terminal groups. HO 2 54 Scheme 67 y 247 OH HO (i) KOz, DMSO, 18-crown-6, -12 h. (ii) KOz, DMSO, 18-crown-6, <2 h. I I 2 5 5 Milder reagents and conditions were then used in an attempt to remove the iodide whilst leaving the silyl ether intact. Ganem and Boeckmanl02 successfully employed silver tetrafluoroborate to assist with an SN2 displacement of alkyl halides by dimethylsulphoxide, the resulting intermediate then fragmenting to the aldehyde. Extending this method firstly to the model trans bisspiroketal iodides 201, 202 (scheme 68), however, resulted in a complex product mixture and therefore was not be applied to the case of the iodide 247. This does not, of course, preclude the possibility of using other silver salts to facilitate an SN2 removal of the iodide group of 247. 93 Scheme 68 Complex product mixture ii No Reaction I iii No Reaction 20 1 , 2 0 2 iv ? (i) AgBF4 (2 equiv.), DMSO, NEt3 (excess). (ii) KOH (2 equiv.), DMSO, 18-crown-6 (1 equiv.), !l. (iii) Me3NO (excess), DMSO, !l. (iv) Tetraphenylphosphoniumdiacetatodioxodichlororuthenate, NMO, CHzClz. However, using SN 1 conditions to remove the iodide would most probably be inappropriate when the precedent of Kishi et a[ 30 is considered (see scheme 14), since SNl conditions were used to effect a ring expansion of the tetrahydrofuran 74 to the tetrahydropyran 70. Since the iodomethyl tetrahydrofuran portion of 247 is structurally similar, an analogous ring expansion to the tetrahydropyran 256 is also likely to occur in the same fashion (scheme 69). T 247 Agl Scheme 69 Me sjJo : Nuc c; .,, ?? 0 2 5 6 >< )lr Another method used to convert a halide directly to an aldehyde, employing trimethylamine-N-oxide in dimethylsulphoxide103 at elevated temperatures (scheme 68), gave no reaction when applied to the model iodide system, emphasising the extremely hindered nature of what is otherwise a good leaving group. The recently reported tetraphenylphosphoniumacetatodichlorodioxoruthenate104 catalyst and N-methylmorpholine-N-oxide has been shown to convert alkyl halides directly to the corresponding aldehydes in reasonable yield, and therefore may find an application in resolving the present difficulty. 94 Failing this, the obvious way to circumvent the problem of selectively removing the iodide group is to reprotect the iodo alcohol 255 with another group which is more compatible with the potassium superoxide reaction conditions. Having already speculated that the large tert-butyldiphenylsilyl group may be adversely influencing the photolytic spirocyclisation process (see page 84) it would seem appropriate to introduce this alternative protecting group, possibly a benzyl ether, earlier in the synthesis (step iii, scheme 70). Having prepared the iodo-alcohol 255, the optical purity of the product was assessed. It would be expected that after conversion of 255 to the Mosher ester derivative 257, using (R)-( + )-a-methoxy-a-(trifluoromethyl)phenylacetyl chloridel05, 106 (scheme 7 1 ), an examination of the 1H nmr spectrum of this ester would reveal any resulting diastereomeric resonances. HO Scheme 7 1 I 2 5 5 Reagents and conditions: (i) (R)-( + )-a.-methoxy-a.-(trifluoromethyl) phenylacetyl chloride (slight excess), CCl4, pyridine, RT, 12 h. I 257 By comparing the spectrum of the alcohol 255 (figure 21 ) with that of the ester 257 (excluding the aromatic region) (figure 22), the optical purity of the indicated enantiomer of 255 was established to be in excess of 96% e.e. (the multiplicity of the methoxy resonance at OH 3.57 in the spectrum of 257 (figure 22) is due to long range coupling with fluorine). Furthermore, the 19F nmr spectruml07 of 257 exhibited a single broad peak (due to coupling with the methoxy group) at Op - 104. 1 (relative to Ce>F6 at op - 163.0), and also implied an enantiomeric excess greater than 96%. 95 \0 0'1 MeyyMe t-BuPh2Si0?0/??0 + Et 84 ii ... t-BuPh2SiO iv ... PO Scheme 70 OSiM? ? 1 ? -.. OTs -"'-../ ? Xo?M? Me 231 Me H 239, 240 Me OH P=protecting group (eg. C6HsCH2) ... iii ... ... ? t-BuPh2SiO PO Me Me H 1 6 6 Reagents and conditions: (i) a: n-BuLi, THF, -78?C, 0.5 h . then 84; b: MeOH, Amberlite IR 120 resin, 1 h.; (ii) a: H2, Lindlar catalyst, hexane; b: PPTS, CH2Cl2; (iii) a: n-Bu4NF, THF, RT; b: Protect (eg. C6H5CH2); c: Lil, THF, -50?C, BF3.Et20; (iv) a: Phi(OAch, 12, cyclohexane, 15?C, hu; b: K02, DMSO/THF, 18-crown-6. OH OH Me 0 ::r:: 97 98 3 .4 Summary. The feasibility of the chosen route for constructing the unsaturated bisspiroketal ring system present in epi- 17 -deoxy-(0-8)-salinomycin 8 has now been reasonably established. The essence of the final enantioselective synthesis was initially mapped out using a relatively simple model (equation 9) which allowed an investigation into the stereochemistry of these ring systems. In the first instance, the original work of Baker and Brimble60 (see scheme 33) was modified and extended so that o-valerolactone and the acetylene 181 could be combined to afford both the known trans and the novel cis 2,2-dimethyl- 1 ,6 ,8- trioxadispiro[ 4. 1 .5 .3]pentadec- 13-enes 152 and 192. -- OSiPh2t-Bu ? 1. :.. ? ..........,.-?-;K"?OTs Me OH 1 8 1 Equation 9 149: X=H 200 : X=l CH2X ? OH Me CH2X 152, 192: X=H 20 1-204: X=l 211-214: X=OH Subsequently the route was modified to incorporate an appropriate terminal functionality, an iodide group, (equation 9) which was both compatible with the critical Barton-type oxidative cyclisation reaction, which generates the bisspiroketal, and also provided a 'handle' by which the resulting cis and trans 2-iodomethyl-2-methyl- 1 ,6,8- trioxadispiro[4. 1 . 5 . 3]pentadec-1 3-enes 201-204 might be further elaborated after conversion to the corresponding alcohols 211-214. When the methodology was extended to the enantioselective portion of the synthesis, the optically active lactone 84 and acetylene 231 were combined (equation 10) to generate the trans and cis bisspiroketals 247 and 248, the former of which possesses a stereochemistry corresponding to that of the natural product epi- 17 -deoxy-(0-8)-salinomycin 8, and is functionalised at the termini to selectively permit further elaboration of the fragment. 99 MASSEY UNIVERSITil. LIBRARY: :;r:xMe t-BuPh2SiO H 0 Et 8 4 OSiM? ? ,. OTs Me'' OSiM? 2 3 1 Equation 10 t-BuPh2SiO t-BuPh2SiO Me 2 47 2 4 8 I I In addition to improving certain steps of the existing pathway, it now remains to convert the trans bisspiroketal fragment 247 into the right hand portion of epi- 17 -deoxy-( 0- 8)-salinomycin, and thence into the entire natural product 8. Two syntheses of the left hand portion 25 (see pages 1 1 and 36) have already been described, but a possible means of achieving a synthesis of the novel right hand fragment 166 may be gleaned by analysing the total synthesis of lasalocid A 3 carried out by Kishi et a! ,3 1 -33 Application of the methodology used in that synthesis to the case in question (scheme 72) would require Grignard addition of the bromo-olefin 258 to the spiroketal aldehyde 167 which could then be stereoselectively converted to the y, 8-unsaturated ketone 259. A sequence of steps requiring selective epoxidation, cyclisation to the tetrahydrofuran 260 and a ring expansion would then ensue, affording the right hand fragment of epi-17-deoxy-(0-8)-salinomycin 8. However, a disadvantage of this synthetic sequence lies in the number of steps performed following formation of the bisspiroketal fragment 167 since, due to the length of the synthesis, the quantities of this material will undoubtedly be small. Hence it would be appropriate to develop an alternative strategy which makes use of a more synthetically advanced form of the tetrahydropyran unit prior to a coupling with 167. 100 ,_.. 0 ,_.. Me OH iii ... 260 iiv OH V Et .. Me P==t-BuPh2Si or an alternative protecting group 166 Et :o OH Et (i) a: Mg turnings, Et20 then 167; b: oxidation; (ii) epoxidation; (iii) a: LiAlH4, dl -2-(o-2-toluidinomethyl)pyrroli dine, Et20, -78?C;b: AcOH; (iv) a: MsCl, Pyridine; b: Ag2C03, acetone; (v) a: deprotection; b: oxidation; c: EtMgBr. Chapter 4 4. 1 Allylic Oxidation of 2.2-Dimethyl-1. 6. 8-trioxadispiro[ 4. 1 .5 .3lpentadec-13-ene. In line with the search for novel synthetic strategies for constructing the salinomycin? related polyether antibiotics, an investigation was undertaken into the possibility that allylic functionalisdiDrt of the bisspiroketal moiety of epi- 17 -deoxy-(0-8)-salinomycin 8 would provide a method of entry into the salinomycin 7 ring system (equation 1 1). Equation 1 1 Me epi -17-Deoxy-(0-8)-salinomycin 8 3 anomeric effects Favourable arrangement of dipoles Me Salinomycin 7 3 anomeric effects Unfavourable arrangement of dipoles In addition to the obvious functionality difference at the allylic position, the conformations of the tricyclic ring systems of the natural products 7 and 8 also differ. S alinomycin 7 possesses a cis arrangement of the bisspiroketal whereas that of epi- 17- deoxy-(0-8)-salinomycin 8 adopts an apparently more favourable trans arrangement, alleviating dipolar interactions. However, experiments carried out by Kishi et a/ 30 showed that the allylic hydroxyl group of salinomycin 7 participated in long range intramolecular hydrogen bonding, and these interactions served to stabilise the observed conformation of this natural product. The implication of this work, therefore, is that if an allylic hydroxyl group were to be introduced onto the spiroketal of epi- 17-deoxy-(0-8)-salinomycin 8 with the appropriate stereochemistry, then thermodynamic equilibration of this product would afford salinomycin 7. An investigation was undertaken into an allylic oxidation of the 2,2-dimethyl- 1 ,6,8- trioxadispiro[ 4. 1 .5 .3 ]pentadec- 1 3-enes 152 and 192 with a view to designing a methodology whereby epi-17-deoxy-(0-8)-salinomycin 8 might be converted directly into salinomycin 7. Although Deslongchamps et a/ 108 successfully oxidised a bicyclic spiroketal at the allylic position using selenium dioxide, a common reagent for this purpose, the method 102 proved to be ineffective when extended to the tricyclic bisspiroketals 152 and 192 ( scheme 73). Scheme 73 SeOz 1s2 , 1 9 2 ?s ?ygen Nucleophile Owing to the scarcity of other satisfactory mild allylic oxidation procedures a more indirect approach was adopted in which an allylic bromide would firstly be generated and subsequently displaced by an oxygen nucleophile to afford the required alcohol (scheme 73), a procedure which required careful evaluation of regio- and stereochemical outcomes. Heating a solution of the cis-2,2-dimethyl- 1 ,6,8-trioxadis piro[ 4. 1 .5.3]pentadec-1 3- ene 192 in carbon tetrachloride with a slight excess of N-bromosuccinimide and anhydrous potassium carbonate (scheme 74) resulted in the formation of two diastereomeric products, crystalline cis- 1 3-bromo-2,2-dimethyl-1 ,6,8-trioxa-dis piro[ 4. 1 .5 .3]pentadec-14-ene 261 in 42% yield, and the more polar cis-15-bromo-2,2-dimethyl-1 ,6,8-trioxa-dis piro[ 4. 1 .5 .3] pentadec-13-ene 262 in 23% yield. 1 9 2 Scheme 74 Me NBS, CCl4 KzC03, Ll + 42% Both products exhibited similar 1 H nmr spectra, the resonances at OH 4.29 for 262 and OH 4.27 for 261 being attributed to an allylic CHBr proton (table 5) in each case. The mass spectrum of both products exhibited a molecular ion at mlz 3 16, 3 18 , which is consistent with a molecular formula of C14H21 03Br, and a base peak at mlz 237 which corresponds to M-Br. Assignment of the regiochemistry for the allylic bromides 261 and 262 was made on the basis of the fragmentation pattern in the mass spectrum of each. The 103 spectrum of 262 exhibited peaks at mlz 202 and 204, corresponding to a formula of C8Hn0Br, which arises from a retro-Diels-Alder fragmentation (equation 1 2) of the unsaturated bisspiroketal substituted at C15. Equation 12 Me ---- + Table 5 + ?Br ? CsH110Br mlz 202, 204 Vinyl and Allyl Chemical Shifts of 2.2-Dimethyl-1 ,6,8-trioxadispiro[ 4.1 .5.3Jpentadecenes Substituted at the Allylic Position. 261: X=Br 268: X=OH 269: X=OAc Chemical shiftsa Compound 261 262 265 268 156 159 269 270 CHX 4.27 (d) 4.29 (d) 4.55 (dct) 3 .57-3.66 3 .57-3 .66 4.15 (ddd) 4.89 (d) 4.86 (d) 262: X=Br 156: X=OH 270: X=OAc CH=CH-CHX 5.68 (d) 5.81 (d) 5.62 (dct) 5.78 (d) 5.88 (d) 5.62 (dct) 5.87 (d) 5.97 (d) a Recorded at 270 MHz in CDCI3 relative to SiMe4 104 265: X=Br 159: X=OH CH=CH-CHX 6.10 (dd) 6.13 (dd) 6.03 (dd) 6.08 (dd) 6.1 1 (dd) 5.88 (dd) 5.99 (dd) 6.05 (dd) The mass spectrum of the other bromide 261 also showed a similar pair of peaks, but at mlz 216 and 218, corresponding to the formula C9H130Br, a fragment consistent with a retro-Diels-Alder fragmentation of the allylic bromide substituted at C13 (equation 13). Equation 13 + + ? Br 0\?' C9H130Br mlz 216, 218 Formation of these two products is easily rationalised by considering the reaction mechanism (scheme 75). On heating 192 with N-bromosuccinimide an allylic radical intermediate is generated which undergoes a rearrangement to give a mixture of the two radicals 263 and 264. These are then trapped by bromine to afford the bromides 261 and 262 in the ratio 2: 1 . 109 The allylic radicals are assumed to be trapped at the a face of the ring, it being less hindered due to the steric influence of the oxygen atoms of the adjacent terminal rings. This assignment of the stereochemistry, which cannot be supported at this stage, will later be confirmed (vide infra). Scheme 75 t;pMe Br 262 23% 105 261 42% The trans-2,2-dimethyl- 1 ,6,8-trioxadispiro[4. 1 .5.3]pentadec- 13-ene 152 was also treated with N-bromosuccinimide under the same conditions (scheme 76) as above to afford the unrearranged allylic bromide 265 in 30% yield. Scheme 76 Me NBS, CCl4 + 2 6 6 + 1 5 2 1 5 2 2 6 7 The 1H nmr spectrum exhibited an allylic CHBr resonance at OH 4.55 (table 5 , page 104) and the mass spectrum exhibited a molecular ion at mlz 3 1 8 and 3 16, corresponding to the formula C14H21 03Br, a base peak at mlz 237 (M-Br) and a retro-Diels-Alder fragmentation at mlz 202, 204 indicating an introduction of bromine at C15 (see equation 12, p . 104). The steric considerations are such that trapping of the radical intermediate was assumed to occur from above, or ?. on the central ring, an assignment which will later be confirmed (vide infra). A second fraction from this reaction was isolated by flash chromatography69 and 1 H nmr spectroscopy showed it to be a complex mixture, comprising starting materia1 152, and the trans bromides 266 and 267. However, since these products could not be individually isolated, further experimentation with this fraction was not pursued. Having obtained the one trans 265 and two cis 261 , 262 bromides, an SN2 displacement of the halogen was attempted using an oxygen nucleophile. The trans bromide 265 was treated with potassium superoxide in dimethylsulphoxide containing 1 8-crown-6 (scheme 77) to afford the 1 5-hydroxy-2,2-dimethyl- 1 ,6,8-trioxadispiro[4. 1 .5.3]pentadec- 13-ene 159. Scheme 77 Me KOz, 18-crown-6 DMSO, 58% 2 6 5 1 59 106 The stereochemistry of this product was confirmed by comparing it's 1 H nmr spectroscopic data with those obtained by Kocienski et al for the same product, l lO which had been derived from the ketone 15464 (see scheme 35). Also, by implication of an SN2 process having occurred, the stereochemistry of the bromide group of 265, previously uncertain, was now established to have been ? on the central ring. Treatment of the cis- 13-bromo-2,2-dimethyl- 1 ,6,8-trioxadispiro[ 4. 1 .5 .3]pentadec- 14-ene 261 with potassium superoxide and 18-crown-6 in dimethylsulphoxide (scheme 78), in the same way as above, afforded an inseparable mixture of the 13-hydroxy-2,2-dimethyl- 1 ,6,8-trioxadispiro[ 4. 1 .5 .3]penta-dec-14-ene 268 and the 15-hydroxy-2,2-dimethyl- 1 ,6,8- trioxadispiro[ 4. 1.5. 3]penta-dec-13-ene 156 in the ratio 1: 1 .5, in 65% overall yield. Scheme 78 Me KOz, DMSO 18-crown-6, RT 2 6 1 + 1 : 1 .5 65% 156 anti SN2' product The presence of both diastereomers in the mixture was apparent after examining the mass spectrum, which exhibited a single molecular ion at mlz 254 - corresponding to the molecular formula C14H2204 - but two base peaks at mlz 154 (C9H 1402) and 140 (CgH1202). If a retro-Diels-Alder process is invoked to account for these fragments (equations 14 and 15) then both the 15- and 1 3- hydroxy compounds must be present in the mixture. Equation 14 + (]I ; ......... O?OH CsH1202 mlz 140 Equation 15 + + HO )0 ' C9H1402 mlz 154 107 Formation of the two products 268 and 156 from the single bromide isomer 261 may be accounted for by considering both SN2 and competitive SN2' processes. Thus, the 13-hydroxy product 268 arises from direct SN2 displacement of the bromide, and the 15- hydroxy product 156 from SN2' displacement. Furthermore, the fact that the 1 H nmr chemical shifts of the CHOH protons of each isomer are coincident (table 5, page 104), resonating as part of a multiplet at OH 3.57-3.66, implies that the orientation of these protons on their respective ring systems is the same - both are up (?), or both are down (a). If the relative orientations differed then the resulting 1 ,2-syn relationship of one CHOH proton with a C-0 bond of a neighbouring ring would cause a significant deshielding effect and the resonances would no longer be coincident. I l l Since both protons possess the same relative orientations on the ring then the SN2' process must also have occurred anti to the leaving group. l 12 Further analysis of the 1 H nmr spectrum showed that the two alcohols 268 and 156 were not formed in equal quantities and therefore either the SN2 or SN2' process was favoured. Conversion of the mixture of alcohols to the now separable acetate derivatives 269 and 270 (scheme 79) established the stereochemistry of the hydroxyl groups of 268 and 156 and also determined which displacement process was favoured. HO Scheme 79 26 9 + ?Me ? )I "o'?e 108 1 5 6 ! Me Me OH AczO,NEt3, CHzClz, RT 2 7 0 The acetate 270, derived from the major component of the alcohol mixture, gave ? 1H nmr data as that previously reported by Kocienski et af.64 This established that the acetoxy group of this isomer was attached to C15, further confirmed by the retro-Diels? Alder in the mass spectrum giving a base peak at mlz 140, and that the stereochemistry of the group was 13 , or 1 ,2-syn, to the C-0 bond of the five membered ring. Therefore, the hydroxyl group of the alcohol 156 must also have possessed the same stereochemistry and, because of the SN2 process, the bromide precursor 261 the inverse stereochemistry, placing it 1 ,2-anti to the C-0 bond of the neighbouring ring as originally assumed (see page 105). The acetate 269, derived from the minor alcohol of the mixture, is therefore the isomer with an acetoxy group attached to Cl3. This is confirmed by a base peak in the mass spectrum at mlz 154 from a retro-Diels-Alder fragmentation (scheme 79). Furthermore, the similarity between the chemical shifts of the CHOAc resonance in the 1H nmr spectrum of 269 (table 5, page 104), occuring at OH 4.89, and that of the major acetate 270, at OH 4.86, indicates the acetoxy groups of both have the same orientation on the central ring, and therefore that of 269 is also 13 on the ring. Finally, having assessed the regio- and stereochemistry of the acetate derivatives 269 and 270, the 1 H nmr resonances in the spectrum of the mixture of alcohols 268 and 156 were then assigned to the individual diastereomers. This established that the 15- hydroxy-spiroketal 156 was preferentially formed from the 1 3-bromo-spiroketal 261 (as indicated in scheme 78), and hence the anti-SN2' process must have been favoured under the given reaction conditions. 2 6 2 Me K02, DMSO 18-crown-6, RT Scheme 80 + anti SN2' product 1 .5 : 1 156 SN2 product The 1 5-bromo-2,2-dimethyl-1 ,6,8-trioxadispiro[ 4. 1 .5.3]pentadec-13-ene 262 was also treated with potassium superoxide and 18-crown-6 (scheme 80) in dimethylsulphoxide and an inseparable mixture of the alcohols 268 and 156 was again obtained. Since the stereochemistry of the hydroxyl group of these alcohols has been shown to be 13 on the central ring, then the bromide group of the precursor 262 is confirmed to have been a, or down, on the ring, and that the SN2' process has occurred anti to the leaving group. In this instance the 1 3-hydroxy compound 268 predominated in the product mixture, it being 109 formed with the 15-hydroxy product 156 in the ratio 1 .5 : 1 , which demonstrates that the SN2' process is again favoured. 4.2 Summary. In summary, an hydroxyl group has now been introduced at C15 (the allylic position) of the model trans-2,2-dimethyl- 1 ,6,8-trioxadispiro[ 4. 1 .5.3]pentadec- 13-ene 152 (equation 16) with the indicated stereochemistry. Equation 16 If this synthetic method were to be incorporated into the existing enantioselective synthesis then the right hand portion 166 of epi- 17 -deoxy-(0-8)-salinomycin (see scheme 72) could conceivably be converted into the previously reportect30,42,46 right hand fragment of salinomycin (equation 17). However, the feasibility of this methodology is marred by poor yields and a variety of regiochemical and stereochemical outcomes. Equation 17 1 6 6 9 9 An hydroxyl group has also been introduced at the allylic position of the model cis- 2,2-dimethyl- 1 ,6 ,8 -trioxadispiro [4 . 1 . 5 .3]pentadec- 1 3-ene 192 with the indicated stereochemistry (equation 18). Incorporation of the methodology into an enantioselective synthesis utilising the chiral bisspiroketal 248 should introduce an allylic hydroxyl group (equation 19) , with a similar stereochemistry at C15 , to give 271 . However, the consideration of yields and regiochemical outcomes aside, this stereochemistry of the allylic hydroxyl group of2 7 1 renders it unsuitable for use in a total synthesis of salinomycin since 1 10 the relative orientation of the hydroxyl group at C15 with respect to the chiral substituents of the terminal rings is opposite to that required for the natural product 7. Equation 1 8 ll,o?Me ll,o?Me 'oVo"ke 'o???e 1 9 2 1 5 6 Eqyation 19 1 1 1 Chapter 5 Experimental. General Details Melting points were determined using a Kofler hot stage apparatus and are uncorrected. Infra-red spectra were recorded using a BIO-RAD FfS-7 or a BIO-RAD FfS-40 spectrophotometer as nujol mulls or thin films between sodium chloride plates. Absorption maxima are expressed in wavenumbers ( cm-1) with the following abbreviations: s = strong, m = medium, w = weak and br = broad. 1 H nuclear magnetic resonance spectra were obtained at 270 MHz using a JEOL GX270 spectrometer. lH nuclear magnetic resonance data are expressed in parts per million downfield shift from tetramethylsilane as an internal reference and are reported as position (OH), relative integral, multiplicity (s = singlet, d = doublet, dd = double doublet, ddd = double double doublet, t = triplet, q = quartet and m = multiplet), coupling constant (J Hz) and assignment. 13C nuclear magnetic resonance were obtained at 67.8 MHz using a JEOL GX270 spectrometer. 13C nuclear magnetic resonance data are expressed in parts per million downfield shift from tetramethylsilane as an internal reference and are reported as position (Oc), multiplicity in the single frequency off-resonance decoupled spectrum and assignment. Mass spectra were recorded using a Varian VG70-250S double focusing magnetic sector mass spectrometer with an ionisation potential of 70eV. Major fragmentations are given as percentages relative to the base peak intensity. Elemental Analyses were performed at the microanalytical laboratory, University of Otago, Dunedin. Flash chromatography was performed according to the procedure of Still et at 69 using Merck Kieselgel 60 (230-400 mesh) with the indicated solvents. 1 12 Thin layer chromatography was performed using precoated silica gel plates (Merck Kieselgel 60F254) and compounds were visualised by ultra-violet fluorescence or by staining with iodine or vanillin in methanolic sulphuric acid. Solvents were dried and purified according to the methods of Perrin, Perrin and Amarego. l l3 1 13 (-:!")-CTetrahydro-2-methyl-5-oxofuran-2-yl)carboxylic acid 173 Acetic acid (43 ml) was dissolved in water (65 ml) neutralised to pH 6 with sodium hydroxide (21 .5 g) and cooled to 0?C. Levulinic acid 174 (250 g, 2.2 mol) and a solution of sodium cyanide ( 108 g, 2.2 mol) in water ( 150 ml) were added separately and simultaneously over a period of 1 h. The resulting brown solution was stirred at room temperature for 0.5 h. and concentrated hydrochloric acid (560 ml) was added followed by heating at reflux for 4 h . After concentration by distillation at reduced pressure the precipitated salts were removed by filtration, the filter cake washed with acetone and the washings added to the filtrate to further precipitate inorganic salts. The procedure was repeated several times then the solvent was removed at reduced pressure to afford a brown oil which was distilled under vacuum to give ("!:')-(tetrahydro-2-methyl-5-oxofuran-2- yl)carboxylic acid 173 (220 g, 75%) as a colourless, viscous oil which solidified on cooling, b.p. 148- 150?C/0.02 mm Hg (lit.67, b.p. 163-167?C/1 .5 mm Hg). Recrystallisation from hexane/ether gave a colourless crystalline solid, m.p. 72-73?C (lit. 1 14 m.p. 72- 73.50C). (S)-(-)-(Tetrahydro-2-methyl-5-oxofuran-2-yl)carboxylic acid 173 S-(-)-(Tetrahydro-2-methyl-5-oxofuran-2-yl)carboxylic acid 173 was prepared from (-:!")-(tetrahydro-2-methyl-5-oxofuran-2-yl)carboxylic acid 173 by resolving the cinchonine salt, according to the procedure described by Mori, to give colourless elongated prisms m.p. 88-89?C (lit.68, m.p. 88-89?C); [aJiy, - 16.0? (c, 1 .78, H20) (1it.68 [a]1f - 16.2? (c, 1 . 86, H20)). (S)-( + )-2-Methylpentane-1 ,2,5-triol 17 5 The title compound was prepared from (S)-(-)-(tetrahydro-2-methyl-5-oxofuran-2- yl)carboxylic acid 173 according to the procedure described by Mori.68 An improved yield (65%) was obtained by repeatedly refluxing the salt residues in tetrahydrofuran for 3 h., filtering, and evaporating the solvent, b.p. 1 18-120?C/0. 1 mm Hg (lit.68, b.p. 1 37?C/0.5 mm Hg); [aliJ 2.2? (c, 2.40, EtOH) (1it.68, [a]1f 1 .7? (c, 1 .85, EtOH)). 1 14 (S)-(-)-3-(2' ,2' ,4'-Trimethyl-1 ' .3'-dioxolan-4'-yl)propan- 1 -ol 176 The title compound was prepared from (S)-(+)-2-methylpentane- 1 ,2,5-triol 175 according to the procedure described by Mori,68 in 85% yield as a colourless oil, b.p. 72- 740C/0.2 mm Hg (1it.68, b.p. 83?C/0.4 mm Hg); [a]j? -0.75? (c, 1 .38, acetone) (lit.,68 [a]1? -0.5? (c, 2.25, acetone). CS)-(+ )-3-(2'.2'.4'-Trimethyl- 1 '.3'-dioxolan-4'-yl)propan- 1 -al 177 A solution of dry dimethylsulphoxide (1 .88g, 24 mmol) in dry dichloromethane (12 ml) was cooled to -65?C under nitrogen and trifluoroacetic anhydride (3.8 g , 18 mmol) dissolved in dry dichloromethane (6 ml) was added in a dropwise fashion, not allowing the temperature to exceed -60?C. The resulting white slurry was stirred 10 min at this temperature and to it was slowly added a solution of S-(-)-3-(2,2,4-trimethyl- 1 ,3-dioxolan- 4-yl)propan-1-ol 176 (2.09 g, 12 mmol) in dry dichloromethane (6 ml). After stirring for 0.25 h. the solution was warmed to -20?C, dry triethylamine (3 g, 30 mmol) carefully introduced, and the reaction vessel brought to room temperature. Water (5 ml) was added and the mixture extracted with dichloromethane (2x 80 ml) which was washed with water (2x30 ml) and brine (50 ml), and dried over potassium carbonate. Evaporation of the solvent at reduced pressure and purification of the residue by flash chromatography, using an hexane/ethyl acetate eluant (9: 1) , afforded the title compound71 177 ( 1 .61 g, 78%) as a colourless oil [aJI5 +1 .65? (c, 2.55, CHCl3) (Found: C, 62.8; H, 9.4%. C9H1603 requires C, 62.6; H, 9. 1%); Umax (film) 3005, 2940 (s, C-H), 2880 (m, H-CO), 2723 (w, H-CO) and 1730 cm-1 (s, C=O); DH (360 MHz; CDCl3) 1 .28 (3H, s, 4'-Me), 1 .38 (6H, s, 2x 2'? Me), 1 .79-2.02 (2H, m, CfuCMeO), 2.53-2.59 2H, m, CfuCHO), 3 .75 ( IH, d, J 8.6 Hz, C.H.AHBO), 3.79 ( 1H, d, J 8.6 Hz, CHAiiBO) and 9.80 ( 1H, t, J 1 Hz, CHO); 8c (90.6 MHz; CDCl3) 25.0 (q, 4'-Me), 27. 1 (q, 2'-Me), 27.2 (q, 2'Me), 32.0 (t, C-3), 39.2 (t, C-2), 74.3 (t, c-5'), 80.2 (s, C-4'), 109.6 (s, C-2') and 201.7 (d, C- 1) ; mlz 157 (M-Me, 1 %), 1 1 5 (C6H1 102, 3), 97 (C6H90, 3), 72 (C4HgO, 4), 57 (5), 44 (5), 43 (100), 42 ( 17) and 41 ( 19). (3R. 4'S)- and C3S. 4'S)-(-)-1 -C2'.2'.4'-Trimethyl- 1 ',3'-dioxolan-4'-yl)-5-hexyn-3-ol 178 Activated magnesium turnings ( 430 mg, 17.5 mmol) and mercuric chloride ( -5 m g) were covered with dry ether ( 15 ml) and cooled to 0?C under nitrogen. A solution of 1 15 propargyl bromide ( 1 .95 ml of 80% w/v solution in toluene, 1 3 mmol) was slowly added over 1 h. with appropriate heating of the vessel to initiate the reaction. After a further 0.5 h. a solution of (S)-(+)-3-(2,2,4-trimethyl-1 ,3-dioxolan-4-yl)propan- l -ai71 177 in dry ether (30 rnl) was added in a dropwise fashion to the grey suspension and stirring continued for 0.25 h. The reaction was quenched with saturated aqueous ammonium chloride ( 10 rnl) and the mixture extracted with ethyl acetate (80 rnl) which was washed with water (2x 20 rnl) and brine (50 ml), and dried over potassium carbonate. The solvent was evaporated at reduced pressure and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 : 1 ), to afford a 1 : 1 mixture of (3R , 4'S)- and (3S , 4'S)- 1 - (2' ,2' ,4'? trimethyl- 1 ' ,3'-dioxolan-4'-yl)-5-hexyn-3-ol7 1 178 (1.71 g, 89%) [a]l5 -3 .66? (c, 2.68, CC4) (Found: C, 65.8; H, 8.5%; M+H (Cl, CH4), 255. 1593. C14H2204 requires C, 66. 1 ; H, 8.7%; M+H, 255. 1596); Umax (film) 3650-3 150 (br, s, OH), 3300 (s , =CH) , 2995, 2940, 2880 (s, C-H) and 2120 cm-1 (w, C=C); OH (360 MHz; CDCl3) 1 .28, 1 .29 (3H, s, 4'-Me), 1 .38 (6H, s, 2x 2'-Me), 1 .52- 1 .83 (4H, m, 2x CH2), 2.06 ( lH, m, =CH), 2.36- 2.42 2H, m, ::CCH2), 2.59-2.95 (lH, br., s, OH) and 3.7 1 -3 . 8 1 (3H, m, CH20 and CHO); oc (90.6 MHz; CDCl3) 24.8 (q, 4'-Me), 27. 1-27.4 (q, 2'-Me), 3 1 .0 (t, C- 1) , 35.7 (t, C-2), 36.3 (t, C-4), 69.9-70.8 (d, C-6 and C-3), 74.4 (t, C-5') , 80.9, 8 1 .0 (s, C-4' and C-5) and 109.5 (s, C-2'); mlz 197 (M-Me, 3%), 1 15 (C6H1 102, 1 8) , 97 (C6H90, 12), 72 (C4HgO, 27), 69 ( 15), 59 (23), 57 (26), 43 (100) and 41 (24). (3R. 4'S) and C3S, 4'S)-(-)-3-tert-Butyldiphenylsilyloxy- 1 -(2',2',4'-trimethyl- 1 ',3'? dioxolan-4'-yl)-5-hexyne 179 A solution of (3R, 4'S)- and (3S, 4'S) -1 - (2',2' ,4'-trimethyl- 1 ' ,3'-dioxolan-4'-yl)- 5 -hexyn-3-ol7 1 178 (720 mg, 3.4 mmol), imidazole (360 mg, 5 .3 mmol) and tert? butyldiphenylsilyl chloride (1 .02 g, 3 .7 mmol) in dry dichloromethane ( 10 rnl) under nitrogen was stirred for 8 h. at room temperature. Water (0.2 ml) was then added and, after stirring a further one hour, the solvent was removed at reduced pressure. The residue was purified by flash chromatography, using an hexane/ethyl acetate eluant (9: 1 ), to afford the title compound 179 (1 .38 g, 96%) as a colourless oil [a]l5 -2.76? (c, 3 .40, CHCl3); Umax (film) 3315 (m, =CH), 3074 (w, Ar-H), 2930, 2855 (s, -CH), 2120 (w, -C=) and 1390, 1 372 cm-1 (s, CMe2); OH (270 MHz; CDCl3) 1 .06 (9H, s, t-Bu), 1 . 18 , 1 .20 (3H, s, 4'? Me), 1 .33, 1 .38 (3H, s, 2'-Me), 1 .54- 1 .64 (4H, m, 2x CH2), 1 .92 ( 1H, m, =CH), 2.30- 2.33 (2H, m, CH2-C::), 3.61-3.70 (2H, m, CH20), 3.82-3.9 1 ( 1H, m, CHO), 7 .25-7.43 (6H, m, Ar-H) and 7.66-7.69 (4H, m, Ar-H); oc (67.8 MHz; CDCl3) 1 9.3 (s, CMe3), 24.7 (q, 4'-Me), 26.3 (t, C- 1), 27.0 (q, CMe3 and 2'-Me), 30.5 (t, C-2), 34.7 (t, C-4), 70.2 (d, 1 16 C-6), 7 1 .3 (d, C-3), 73.9 (t, C-5'), 77.2 (s, C-4'), 80.9 (s, C-5), 109.0 (s, C-2') , 127.6 (d, C-2") , 129.8 (d, C-4"), 133.9 (s, C- 1") and 135.7 (d, C-3''); mlz 435 (M-Me, 2%), 335 (C22H270Si, 73), 239 (C16H19Si, 5), 22 1 (56), 199 (C12HuOSi, 100), 139 ( 1 1) , 135 ( 19) and 1 19 ( 19). (5R, 2S) and C5S. 2S)-(-)-5-tert-Butyldiphenylsilyloxy-2-methyl-7-octyn-1.2-diol 180 A solution of (3R, 4'S) and (3S, 4'S)-(-)-3-tert-butyldiphenylsilyloxy- 1 - (2' ,2' ,4'? trimethyl- 1 ' ,3'-dioxolan-4'-yl)-5-hexyne 179 (650 mg, 1 .44 mmol) in methanol (30 ml) was stirred with Amberlite IR 120 resin for 36 h. Subsequent filtration and evaporation of the solvent at reduced pressure gave a yellow oil which was purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 : 1) , to afford the title compound 180 (480 mg, 8 1 %) as a colourless oil, [a]YS - 1 .36? (c, 1 .4 1 , CHCl3) (Found: C, 72.8; H, 8.45%. C25H3403Si requires C, 73. 1 ; H, 8.45%); Umax (film) 3590-3210 (br, s, OH), 3309 (m, =CH), 2935. 2235 (s, -CH) and 21 15 cm-1 (w, -C=); OH (270 MHz; CDCl3) 1 .07 (9H, s, t-Bu), 1 .08 (3H, s, Me), 1 .46- 1 .72 (4H, m, 2x CH2), 1 .94 ( 1H, m, =CH), 2.34 (2H, dd, 16,8 2.2 and 16,5 5.1 Hz, CH2C::), 3.33-3.37 (2H, m, CH20), 3.87-3 .94 ( lH, m, CHO), 7.26-7.44 (6H, m, Ar-H) and 7.66-7.70 (4H, m, Ar-H); 8c (67.8 MHz; CDCl3) 1 9.3 (s, CMe3), 22.9 (q, 2-Me), 26.2 (t, C-3), 27.0 (q, CMe3) , 29.6 (t, C-4), 33. 1 (t, C- 6), 69.6 (t, C- 1 ), 70.3 (d, C-8), 7 1 .3 (d, C-5), 72.6 (s, C-2), 8 1 .0 (s, C-7), 127 .6 (d, C- 2'), 129.8 (d, C-4'), 133.8 (s, C- 1 ') and 135.9 (d, C-3'); mlz 353 (M-tBu, 1 %), 335 (M? tBu-H20, 19), 222 (CI6H140Si, 6), 199 (C12HuOSi), 139 ( 18), 1 35 ( 19), 123 ( 10), 105 (22) and 77 (C6Hs, 10). (5R, 2S) and (55. 2S)-(-)-5-tert-Butyldiphenylsilyloxy-2-hydroxy-2-methyl-7 -octyn-1-p? toluenesulphonate 181 A solution of (5R, 2S) and (5S, 2S)-(-)-5-tert-butyldiphenylsilyloxy-2-methyl-7- octyn- 1 ,2-dio1 180 (533 mg, 1 .3 mmol) and p-tolunesulphonyl chloride (323 mg, 1 .7 mmol) in dry pyridine (6 ml) under nitrogen was stirred at room temperature for 22 h. This solution was then diluted with ethyl acetate (100 ml) and the organic phase washed with 5% hydrochloric acid (2x 15 ml), water (20 ml) and brine (30 ml), and dried over magnesium sulphate. Evaporation of the solvent at reduced pressure followed by purification of the residue by flash chromatography, using an hexane/ethyl acetate eluant (4: 1) , afforded the 1 17 title compound 181 (630 mg, 82%) as a colourless oil [aJ15 -2.05? (c, 2.50, CHCl3) (Found: C, 67.95; H, 7.3; S, 5.7%. C32If4o05SSi requires C, 68.05; H, 7 . 1 ; S, 5.7%.); Umax (film) 3605-3280 (br, s, OH), 3285 (m, =CH), 2960 2921 , 2848 (s, CH), 2124 (w, ? C:::) and 1367, 1 178 cm-1 (s, S020); BH (270 MHz; CDCl3) 1 .05 (9H, s, t-Bu), 1 .07 (3H, s, 2-Me), 1 .43- 1 .61 (4H, m, 2x CH2), 1 .92 ( 1H, t, 1 2.6 Hz, =CH), 2.27 (2H, dd, 16,8 2.6 and 16,5 5.9 Hz, CH2C:::) , 2.44 (3H, s, Ar-Me), 3.75-3.77 (2H, m, CH20), 3.77-3.86 ( 1H, m, CHO), 7.32-7.46 (8H, m, Ar-H), 7.75-7.77 (4H, m, Ar-H) and 7.79 (2H, d, 1 8.4 Hz, Ar-H); Be (67.8 MHz; CDCl3) 19.3 (s, CMe3), 21 .7 (q, 4'-Me), 23. 1 (q, 2-Me), 26.2 (t, C-3), 27.0 (q, CMe3), 29.2 (t, C-4), 33.0 (t, C-6), 70.4 (d, C-8), 7 1 . 1 (d, C-5), 76.2 (t, C- 1), 80.8 (s, C-7), 127.6 (d, C-2"), 128.0 (d, C-2'), 129.8, 129.9 (d, C-3' and C-4"), 132.7 (s, C-4') , 1 33.8 (s, C-1"), 135.9 (d, C-3'') and 145.0 (s, C- 1 '); m/z 489 (M-tBu-H20, 2%), 335 (M-tBu-TsOH, 34) and 199 (C12HnOSi, 100). 5-tert-B utyldiphenylsilyloxy-2-methyl-2-trimethylsilyloxy-7 -octyn-1-v-tol uenesulphonate 1 8 2 A solution of ("t )-5-tert-butyldiphenylsilyloxy-2-hydroxy-2-methyl-7-octyn-1 -p? toluenesulphonate 181 (625 mg, 1 . 12 mmol) and 1-(trimethylsilyl)imidazole (628 mg, 4.5 mmol) was stirred in dry dichloromethane (10 ml) under argon for 16 h. The solvent was evaporated and the residue purified by flash chromatography, using an hexane-ethyl acetate eluant (4: 1) , to give the title compound 182 (692 mg, 98%) as a colourless oil; 'Umax (film) 3305 (s, =CH), 2955, 2917, 2850 (s, -CH), 2 1 1 8 (w, -C=) and 1364, 1 173 (s, S020); BH (270 MHz; CDCl3) 0. 1 , 0.2 (3H, s, SiMe3), 1 .05 (9H, s, t-Bu), 1 . 1 1 , 1 . 1 3 (3H, s, 2-Me), 1 .26- 1 .59 (4H, 2x CH2), 1 .9 1 ( lH, t, 1 2.6 Hz, =CH), 2.23 (2H, dd, 16,8 2.6 and 16 ,5 5.5 Hz, CH2C:::), 2.44 (3H, s, Ar-Me), 3.69 (2H, d, 1 2.6 Hz, CH20), 3.7 1 -3.83 ( lH, m, CHO), 7 .32-7.45 (8H, m, Ar-H), 7.64-7.67 (4H, m, Ar-H) and 7.77 (2H, d, 1 1 .8 Hz, Ar? H); Be (67.8 MHz; CDCl3) 2.33 (q, SiMe3), 19.3 (s, CMe3), 21 .6 (q, 4'-Me), 24.4 (q, 2- Me), 26.4 (t, C-6), 27.0 (q, CMe3), 29.5 (t, C-4), 34.6 (t, C-3), 70.3 (d, C-8), 7 1 .4 (d, C- 5), 74.0 (s, C-2), 75.6 (t, C- 1) , 80.9 (s, C-7), 127.6 (d, C-2"), 129.7 (d, C-2') , 1 29.7 (d, C-3') , 1 29.8 (d, C-4"), 1 33.0 (s, C-4') , 1 33.8 (s, C-1") , 135.9 (d, C-3'') and 1 44.7 (s, C- 1 ' ) . 1 1 8 5-tert-Butyldiphenylsilyloxy-2-hydroxy-8-(tetrahydro-2'-methoxypyran-2'-yl)-2-methyl-7- octyn-1-v-toluenesulphonate 184 A solution of 5-tert-butyldiphenylsilyloxy-2-methyl-2-trimethylsilyloxy-7-octyn-1-p? toluenesulphonate 182 ( 1 .59 g, 2.5 mmol) in dry tetrahydrofuran (30 ml) was cooled to - 78?C under nitrogen and n-butyllithium ( 1 .6 ml of a 1 .6 M solution in hexane, 2.6 mmol) was added. After stirring for 0.5 h. A solution of o-valerolactone (300 mg, 3 mmol) in dry tetrahydrofuran (8 ml) was slowly added and the reaction brought to -50?C over 1 h. On quenching with 10% water in tetrahydrofuran (5 ml) the mixture was warmed to room temperature and extracted with ether ( 150 ml), washed with water (25 ml) and brine (30 ml), and dried over potassium carbonate. The solvent was evaporated at reduced pressure and the residue dissolved in methanol (30 ml) and stirred 2 h. with Amberlite lR 120 resin. After filtering, the solvent was removed and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 : 1) , to afford the title compound 184 ( 1 .21 g, 7 1 %) as a colourless oil (Found: (Cl, NH3) M+H, 679.3 120. C3sHso07SSi requires M+H 679.3 125); Umax (film) 3620-3220 (br, s, OH), 2956, 2835 (s, C-H), 2220 (m, C=C) and 1365, 1 178 cm-1 (s, S020); OH (270 MHz; CDCl3) 1 .04 (12H, s, t-Bu and 2-Me), 1 .25-1 .90 ( 13H, m, 6x CH2 and OH), 2.34-2.37 (2H, m, CH2C=), 2.45 (3H, s, Ar-Me), 3.35 (3H, s, OMe), 3.64-3.89 (5H, m, 2x CH20 and CHO), 7.33-7.43 (8H, m, Ar-H) and 7.65-7.79 (6H, m, Ar-H); oc (67.8 MHz; CDCl3) 19.2 (t, C-4' or C-5'), 1 9.2 (s, CMe3), 21 .7 (q, 4"-Me), 22.9, 23 . 1 (q, 2-Me), 24.6 (t, C-4' or C-5'), 26.3 (t, C-3), 27.0 (q, CMe3), 29.3 (t, C-4), 33.0 (t, C-6), 36.6 (t, C-3'), 50.6 (q, OMe), 62.2 (t, C-6') , 70.7 (s, C-2), 7 1 .0 (d, C-5), 76.2 (t, C- 1) , 80.0, 8 1 .8 (s, C-7 and C-8), 95.0 (s, C-2'), 127.6 (d, C-2"'), 127.9 (d, C- 2"), 129.8, 129.9 (d, C-3" and C-4'"), 132.6 (s, C-4"), 133.6 (s, C- 1 "'), 135. 8 (d, C- 3"') and 145.0 (s, C-1 "); mlz (Cl, NH3) 679 (M+H, 3%), 647 (M-OMe, 100), 589 (M? tBu-MeOH, 14), 492 (44), 475 (M-OMe-TsOH, 88), 417 (M-tBu-MeOH-TsOH, 27), 219 (66) and 192 (41). 5-tert-Butyldiphenylsilyloxy-2-hydroxy-8-(tetrahydro-2'-methoxypyran-2'-yl)-2-methyl-7- octen-1-p-toluenesulphonate 189 5-tert-Butyldiphenylsilyloxy-2-hydroxy-8-(tetrahydro-2'-methoxypyran-2'-yl)-2- methyl-7 -octyn- 1 -p-toluenesulphonate 184 (257 mg, 0.38 mmol) was dissolved in 1 : 1 hexane:ethyl acetate (100 ml), and stirred vigorously with a small quantity ofLindlar catalyst (-3 mg) under an hydrogen atmosphere. After 15 h. the solution was filtered, the solvent evaporated, and the residue purified by flash chromatography, using an hexane/ethyl acetate 1 19 eluant (2: 1) , to afford the title compound 189 (220 mg, 85%) as a colourless oil (Found: (Cl, NH3) M-H, 679.3 1 14. C3sHs207SSi requires M-H 679.3 125); Umax (film) 3625-3230 (br. s, OH), 3035 (w, C=CH), 2970, 2965, 2845 (s, C-H), 1655 (w, C=C) and 1365, 1 177 cm-1 (s, S020); BH (270 MHz; CDCl3) 0.98-1 .0 (3H, s, 2-Me), 1 .05 (9H, s, t-Bu), 1 .25-2. 10 ( 1 1H, m, 5x CH2 and OH), 2.44 (3H, s, Ar-Me), 3.07 (3H, s, OMe), 3.57-3.74 (5H, m, 2x CH20 and CHO), 5 .23-5.62 (2H, m, CH=CH), 7.32-7.41 (8H, m, Ar-H) and 7.65-7.78 (6H, m, Ar-H); Be (67.8 MHz; CDCl3) 1 8.8 (t, C-4' or C-5'), 19.2 (s, CMe3), 2 1 .7 (q, 4"-Me), 22.9-23 .4 (q, 2-Me), 24.9 (t, C-4' or C-5') , 25.6 (t, C-3), 27 . 1 (q, CMe3), 29.7 (t, C-4), 33. 1 (t, C-6), 34.7 (t, C-3'), 48.7 (q, OMe), 60.8 (t, C-6'), 70.9 (s, C-2), 72.9 (d, C-5), 76.3, 76.5 (t, C- 1), 99. 1 (s, C-2'), 127.5 (d, C-7 and C-2'") , 127.9 (d, C-2"), 129.2 (d, C-8), 129.6 (d, C-4"') , 129.9 (d, C-3"), 132.6 (s, C-4"), 1 34.2 (s, C- 1" ') , 135 .9 (d, C-3'") and 144.9 (s, C-1 ") ; mlz (Cl, NH3) 679 (M-H, 4%), 649 (M? OMe, 3), 477 (M-OMe-TsOH, 10), 428 (73), 274 (100) and 196 (61) . 2-(3.4-Epoxy-3-methylbutan-1-yl)-1 ,7 -dioxaspiro[5.5Jundec-4-ene 188 Tetra-n-butylammonium fluoride (1 .5 ml of a 1 . 1 M solution in tetrahydrofuran, 1 .6 mmol) was added to a solution of 5-tert-butyldiphenylsilyloxy-2-hydroxy-8-(tetrahydro-2'? methoxypyran-2'-yl)-2-methyl-7-octen-1-p-toluenesulphonate 189 (680 mg, 0.29 mmol) in dry tetrahydrofuran (15 ml) at room temperature under nitrogen. After stirring for 2 h., the solvent was evaporated and the residue columned on silica gel, using an hexane/ethyl acetate eluant (2: 1). The resulting oil was then dissolved in dichloromethane and a catalytic quantity (-5 mg) pyridinium-p-toluenesulphonate added. After stirring for 0.25 h. the solvent was removed and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant (9: 1) to afford the title compound 188 (56 mg, 80%) as a colourless oil (Found: C, 70.2; H, 9.2%; M+, 238. 1536. C14H2203 requires C, 70.5; H, 9.3%; M+, 238 . 1 568); Umax (film) 3040 (m, =CH), 1660 (w, C=C), 1270 (m, CO (epoxide)), 1010 (s, CO), 900 and 820 cm-1 (s, CO (epoxide)); BH (360 MHz; CDCl3) 1 .35 (3H, s, 3'-Me), 1 .48-2.24 ( 12H, m, 6x CH2), 2.57-2.78 (2H, m, CH2 (epoxide)), 3.56-3.93 (3H, m, CH20 and CHO), 5 .57 -5.66 (lH, m , 5-H) and 5.82-5.95 ( 1H, m, 4-H); Be (90.6 MHz; CDCl3) 1 8 .6 (t, C- 10) , 2 1 . 1 (q, 3'-Me), 25.2 (t, C-9), 30.8, 3 1 .3, 33. 1 , 35 .1 (t, C-1 ' , C-2', C-3 and C- 1 1), 53.6 (t, C-4'), 54.0 (s, C-3'), 60.9 (t, C-8) , 66.9 (d, C-2), 93.9 (s, C-6), 127.4 (d, C-5) and 130.7 (d, C-4); mlz 238 (M+, 4%), 124 (CsH120, 100), 1 14 (C6H1002, 35), 95 (91) , 69 (59), 68 (6 1), 55 (93), 43 (76) and 41 (97). 120 1 8 8 7.8-Epoxy-7 -methyl-1 -(tetrahydro-2'-methoxypyran-2'-yl)- 1-octyn-4-o1 191 Tetra-n-butylammonium fluoride (0.5 ml of a 1 . 1 M solution in tetrahydrofuran, 0.55 mmol) was added to a solution of 5-tert-butyldiphenylsilyloxy-2-hydroxy-8- (tetrahydro-2'-methoxypyran-2'-yl)-2-methyl-7 -octyn- 1 -p-toluenesulphonate 184 (8 1 mg, 0 .12 mmol) in dry tetrahydrofuran (8 ml) at room temperature under nitrogen. After stirring for 2 h. , the solvent was evaporated and the oily residue purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 : 1) to afford the title compound 191 (32 mg, 99%) as a colourless oil (Found: M+, 268 . 1674. C1sH2404 requires M+, 268 . 1765); Umax (film) 3690-3200 (br, s, OH), 2944, 2868, 2830 (s, C-H); 2246 (w. C::C); OH (270 MHz; CDCl3) 1 .2 1 (3H, s, Me), 1 .47- 1 .90 (lOH, m, 5x CH2), 2.43 (2H, d, J 6.23 Hz, CH2C=), 2.59-2.67 (2H, m, CH20(epoxide)), 3 . 17-3.27 ( 1H, m, OH), 3.40 (3H, s, OMe), 3 .67- 3 .82 (3H, m, CH20 (ring) and CHOH); oc (67 .8 MHz; CDCl3) 1 8.8 (t, C-4' or C-5'), 20.5, 20.7 (q, 7-Me), 24.3 (t, C-4' or C-5'), 27.2, 3 1 .2, 32.2 (t, C-3 , C-5 and C-6), 36.3 (t, C-3'), 50.2 (q, OMe), 53.6 (t, C-8), 56.6, 56.7 (s, C-7), 6 1 . 8 (t, C-6'), 69. 1 , 69.3 (d, C-4), 79.9, 80.0, 8 1 .6, 8 1 .7 (s, C-1 and C-2) and 94.6 (s, C-2'); mlz 268 (M+, 2%), 237 (M-OMe, 20), 1 54 (C9H1402, 74), 122, (CgHIQO, 54) , 1 1 5 (C6Hl l 02, 100) and 97 (C6H90, 44). 2-(3'.4'-Epoxy-3'-methylbutan- 1 '-yn-1 .7-dioxaspiro[5.5lundec-4-ene 188 A solution of 7,8-epoxy-7-methyl- 1-(tetrahydro-2'-methoxypyran-2'-yl)- 1-octyn-4- ol 191 ( 230 mg, 0.86 mmol) was dissolved in 1 : 1 hexane:ethyl acetate (100 ml), and stirred vigorously with a small quantity of Lindlar catalyst (-3 mg) under an hydrogen atmosphere. After 1 .5 h. the solution was filtered, the solvent evaporated, and the residue dissolved in dichloromethane and a catalytic quantity ( -5 mg) pyridinium-p ? toluenesulphonate added. After stirring for 0.5 h. the solvent was removed and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant (9: 1 ) to afford a 121 product (175 mg, 77%) with identical properties to that compound 188 prepared from 5- tert-butyldiphenylsilyloxy-2-hydroxy-8-(tetrahydro-2'-methoxypyran-2'-yl)-2-methyl-7- octen-1-p-toluenesulphonate 189. 4-C1'.7'-Dioxaspiro[5.5Jundec-4'-en-2'-yl)-2-methyl-2-butanol 149 A solution of 2-(3' ,4'-epoxy-3'-methylbutan-1 '-yl)- 1 ,7 -dioxaspiro[5.5]undec-4-ene 188 (410 mg, 1 .72 mmol) in dry ether (50 ml) was cooled to 0?C under nitrogen and lithium aluminium hydride (30 mg, 0.8 mmol) added. After stirring for 1 h. the reaction was quenched with water (0.1 ml) and extracted with ether ( 100 ml) which was washed with water (2x 20 ml) and brine (25 ml), and dried over magnesium sulphate. Removal of the solvent at reduced pressure and purification of the residue by flash chromatography, using an hexane/ethyl acetate eluant, afforded the title compound60 149 (380 mg, 92%) as a colourless oil with spectroscopic data identical to those previously reported.60 2.2-Dimethyl- 1 .6.8-trioxadispirof 4. 1 .5.3Jpentadec- 13-ene 152, 192 A solution of 4-( 1 ' ,7'-dioxaspiro[5.5]undec-4'-en-2'-yl)-2-methyl-2-butanol 149 (700 mg, 2.9 mmol), ground iodine ( 1 .48 g, 5.8 mmol) and iodobenzenediacetate ( 1 .86 g, 5.8 mmol) in cyclohexane (350 ml) was purged with nitrogen and irradiated with two 250 watt tungsten fllament lamps. After 12 h., during which the temperature was not allowed to exceed 20?C, the reaction mixture was diluted with ether (200 ml) which was washed with 10% aqueous sodium thiosulphate (50 ml), water (50 ml) and brine (50 ml), and dried over potassium carbonate. The solvent was removed at reduced pressure to afford crude 2,2- dimethyl- 1 ,6,8-trioxadispiro[4. 1 .5 .3]pentadec-13-ene as a mixture of diastereomers. These were separated and purified by flash chromatography, using an hexane/ethylacetate eluant (9: 1) , to give the previously reported trans isomer60 152 (375 mg, 54%) as a colourless oil; OH (360 MHz; CDCl3) 1 .24 (3H, s, Me), 1 .48 (3H, s, Me), 1 .49-2. 12 (9H, m, 3-H, 3-H', 4-H', 10ax-H, 10eq-H, l lax-H, l leq-H, 12ax-H and 12eq-H), 2. 1 6 ( lH, ddd, h5, 15 1 6.9, h5,14 5 .8 and h5,13 1 .2 Hz, 15-H'), 2.45 (1H, ddd, h5,15 16.9, h5,14 2.6 and h5,13 2.6 Hz, 1 5-H), 2.65 ( 1H, dd, 14,4 10.2 and 14,3 7.2 Hz, 4-H), 3.67 (lH, m, 9eq-H), 4.02 (lH, ddd, 19ax,9eq 1 1 .3, 19ax,10ax 1 1 .3 and 19ax,10eq 3.3 Hz, 9ax-H), 5.59 ( lH, ddd, 113,14 10.0, 113, 15 2.6 and h3,15 1 .2 Hz, 13-H) and 5.86 (lH, ddd, h4,13 10.0, 1!4, 15 5.8 and h4, 15 2.6 Hz, 14-H), and the cis isomer 192 (175 mg, 25%) also as a colourless oil (Found: M+, 122 238. 1 578. C14H2203 requires M+, 238. 1569); Umax (film) 3035 (w, =C-H), 2943, 2875 (s, C-H) and 1655 cm-1 (w, C=C); OH (270 MHz; CDCI3) 1 . 1 5 (3H, s, Me), 1 .39 (3H, s, Me), 1 .48-2. 19 (l lH, m, 3-H, 3-H', 4-H, 4-H', 10ax-H, 10eq-H. l lax-H, l leq-H, 1 2ax-H, 12eq-H and 15-H), 2.37 ( 1H, ddd, h5,15 1 6.9, h5,14 2.8 and h5,13 2.3 Hz, 15-H'), 3.61 ( 1H, m, 9eq-H). 4.03 ( 1H, ddd, 19ax,9eq 1 1 .5, 19ax,10ax 1 1 .5 and 19ax,l0eq 2.8 Hz, 9ax-H), 5 .71 ( lH, ddd, 113,14 10.2, h3,15 2.8 and h3, 15 1 . 1 Hz, 13-H) and 5.86 ( lH, ddd, h4,13 10.2, h4,15 5.9 and h4,15 2.2 Hz, 14-H); oc (67.8 MHz; CDCl3) 18.7, 25.2 (t, C-10 and C- 1 1) , 28. 1 (q, Me), 28.9 (q, Me), 35. 1 , 36.5, 37. 1 , 39.0 (t, C-3, C-4, C-12 and C-15), 6 1 .3 (t, C-9), 82.9 (s , C-2), 93.6 (s , C-7), 104.2 (s , C-5) , 124. 1 (d, C- 13) and 1 30.2 (d, C-14); mlz 238 (M+, 42%), 151 (C9H1 102, 29), 124 (CsH120, 100) and 75 (70). Me 152 , 1 9 2 :H 4-Cl' .7'-Dioxaspiro[5.5lundec-4'-en-2'-yl)- 1 -iodo-2-methyl-2-butanol 200 A solution of 2-(3',4'-epoxy-3'-methylbutan-1 '-yl) - 1 ,7-dioxaspiro[5.5]undec-4- ene 188 ( 100 mg, 0.42 mmol) in dry tetrahydrofuran (25 ml) was cooled to -50?C under nitrogen and to it was added anhydrous lithium iodide (72 mg, 0.54 mmol) in dry tetrahydrofuran ( 1 .5 ml) and boron trifluoride etherate (0. 1 ml) . After stirring at this temperature for 5 h. the reaction was quenched with saturated aqueous ammonium chloride (1 .5 ml) and the mixture diluted with ether (80 ml). The ethereal solution was washed with water ( 15 ml) and brine ( 15 ml), then dried over magnesium sulphate. Removal of the solvent at reduced pressure and purification of the residue by flash chromatography, using an hexane/ethyl acetate eluant ( 1 : 1), afforded the title compound 200 ( 145 mg, 90%) as an inseparable 1 : 1 mixture of diastereomers in the form of a colourless oil (Found: C, 45.88; H, 6. 17; I, 34.48%; M+, 366.0673. C14H2303I requires C, 45.91 ; H, 6.33; I, 34.65%; M+, 366.0692); Umax (film) 3600-33 15 (br, s, OH), 3030 (w, =CH), 2943, 2880, 2830 (s, C-H) and 1655 cm-1 (w, C=C); OH (270 MHz; CDCl3) 1 .38, 1 .39 (3H, s, Me), 1 .54-2. 17 ( 12H, m, 6x CH2), 2.40 (0.5H, s, OH), 2.53 (0.5H, s, OH), 3 .38, 3 .39 (2H, s, CH2I) , 3 .61-3 .66 ( 1H, m, CHO), 3.80-3.94 (2H, m, CH20), 5 .61 (lH, ddd, 15'.4' 9.9, Js?,3' 2 and 1s',3' 2 Hz, =CH) and 5 .90 (lH, ddd, 14',5' 9.9, 14',3' 3 .6 and 14',3' 3 .6 Hz, =CHCH2); oc 123 (67.8 MHz; CDCl3) 1 8.5 (t, C-9' or C-10'), 22.4, 22.5 (t, C-1) , 25.0 (t, C-9' or C- 10'), 25.9 (q, 2-Me), 30.0, 30.5, 34.9, 36.6 (t, C-3, C-3', C-4 and C- 1 1') , 6 1 . 1 (t, C-8'), 67. 1 (d, C-2'), 70.3, 70.4 (s, C-2), 94.0 (s, C-6'), 127.4 (d, C-5') and 130.3 (d, C-4'); mlz 366 (M+, 4%), 349 (M-OH, 4), 239 (M-I, 17), 225 (M-CH2I, 33), 221 (M-I-H20, 33), 183 (C4H3I, 78) and 124 (CsH120, 100). 2 0 0 2-Iodomethyl-2-methyl-1 .6. 8-trioxadi spiro[ 4. 1 . 5 .3lpentadec-13-ene 201-204 A solution of 4-(1 ' ,7'-dioxaspiro[5.5]undec-4'-en-2'-yl)- 1-iodo-2-methyl-2-butanol 2 0 0 (450 mg, 1 .23 mmol), finely ground iodine (630 mg, 2.5 mmol) and iodobenzenediacetate (780 mg, 2.45 mmol) in cyclohexane (230 ml) was purged with nitrogen and irradiated with two 250 watt tungsten filament lamps. After 18 h . , during which the temperature was maintained below 20?C, the mixture was diluted with ether (150 ml) which was washed with 10% aqueous sodium thiosulphate (30 ml), water (30 ml) and brine (50 ml), and dried over magnesium sulphate. The solvent was evaporated at reduced pressure and the residue purified by flash chromatography to afford: (i) the trans iodides 201 and 202 (*) (215 mg, 47%) as an inseparable 1 : 1 mixture of diastereomers in the form of a colourless oil (Found: M+, 364.0533. C14H2103I requires M+, 364.0533); Umax (film) 3035 (w, =CH), 2945, 2885, 2840 (s, C-H) and 1 655 cm- 1 (w, C=C); OH (270 MHz; CDCl3) 1 .44 (3H, s, Me), 1 . 67 (3H, s, Me*), 1 .49-1 . 64 ( l OH, m, 10ax-H, 10ax-H*, 10eq-H, 10eq-H*, 1 1eq-H, l leq-H*, 12ax-H, 12ax-H*, 12eq-H and 12eq-H*), 1 .72- 1 .94 (6H, m, 3-H', 3-H'*, 4-H', 4-H'*, 1 1ax-H and 1 1ax-H*) , 2 . 1 1 -2.20 (3H, m, 3-H, 15-H' and 15-H'*), 2.33 ( lH, m, 3-H*), 2.42-2.56 (2H, m, 1 5-H and 15- H*), 2.66-2.75 (2H, m, 4-H and 4-H*), 3.27 ( lH, d, J 10. 1 Hz, CfuHBI*), 3.30 (lH, d, J 10 . 1 Hz, CHAHBI*), 3 .45 ( lH, d, J 9.5 Hz, CfuHBI) , 3.55 ( lH, d, J 9.5 Hz, CHAHBI), 3.66-3.72 (2H, m, 9eq-H and 9eq-H*), 3.96-4.06 (2H, m, 9ax-H and 9ax-H*) , 5.58-5.63 (2H, m, 13-H and 13-H*) and 5.82-5.89 (2H, m, 14-H and 14-H*) ; mlz 364 (M+, 72%), 237 (M-I, 46), 223 (M-CH2I, 1 6) , 124 (CsH120, 100) and 1 13 (C6H902, 21); (ii) the cis iodides 203 and 204 (*) (102 mg, 23%) as an inseparable 1 : 1 mixture of two diastereomers in the form of a colourless oil (Found: M+, 364.0535. C14H21 03I 124 requires M+, 364.0533); Umax (film) 3035 (w, =CH), 2945, 2885, 2840 (s, C-H) and 1655 cm-1 (w, C=C); OH (270 MHZ; CDCl3) 1 .39 (3H, s, Me), 1 .63 (3H, s, Me*), 1 . 52-2.42 (24H, m, 3-H, 3-H*, 3-H', 3-H'*, 4-H, 4-H*, 4-H', 4-H'* , 10ax-H, 10ax-H*, lOeq-H, 1 0eq-H*, l leq-H, l leq-H*, 12ax-H, 12ax-H*, 12eq-H and 12eq-H*, 15-H, 15-H*, 15-H' and 15-H'*), 3.21 (2H, d, 1 2.2 Hz, CH2I*) , 3.36 ( 1H, d, 1 9.5 Hz, CfuHBI), 3.46 ( lH, d, 1 9.5 Hz, CHAHBI), 3.62-3.70 (2H, m, 9eq-H and 9eq-H*), 3.92-4.07 (2H, m , 9ax-H and 9ax-H*), 5.7 1-5.78 (2H, m, 13-H and 13-H*) and 5.86-5.94 (2H, m, 14-H and 14- H*); mlz 364 (M+, 72%), 237 (M-I, 52), 223 (M-CH2I, 1 8) , 124 (CsH120, 100) and 1 13 (C6H902, 1 8). 20 1-2 04 :H: trans-C2'-methyl- 1 '.6' .8 '-trioxadispiro[4. 1 .5 .3lpentadec- 13 '-en-2'-yl)methanol 211 , 212 A solution of the trans-iodomethyl-2-methyl- 1 ,6,8-trioxadispiro[ 4. 1 .5 .3]pentadec- 1 3-enes 201 and 202 (70 mg, 0.2 rnmol) in dry tetrahydrofuran (7 rnl) was added to a solution of potassium superoxide (55 mg, 0.8 mmol) and 18-crown-6 (203 mg, 0.8 rnmol) in dry dimethylsulphoxide (5 rnl) under argon. After stirring for 1 8 h. saturated aqueous sodium chloride (2 ml) was added, the tetrahydrofuran evaporated from the mixture and the residue extracted with ether (2x 30 rnl). The ethereal solution was then washed with brine (20 rnl) and dried over potassium carbonate. The solvent was evaporated at reduced pressure and the residual colourless oil was purified by flash chromatography, using an hexane/ethyl acetate eluant (1 : 1), to afford: (i) The trans alcohol 211 ( 17 mg, 36%) as a colourless oil (Found: C, 66.29; H, 8.68%; M+, 254. 1534. C14H2204 requires C, 66. 12; H, 8 .72%; M+, 254. 15 1 8) ; Umax (film) 3600-3 1 15 (br, s, OH), 3042 (w, =CH) and 1 643 cm-1 (w, C=C); OH (270 MHz; CDCl3) 1 .20 (3H, s, Me, 1 .53- 1 .80 (8H, m, 3'-H', 4'-H', 1 0ax-H, 10eq-H, l lax-H, 1 1?? H, 12ax-H and 12eq-H), 2. 1 3 ( lH, ddd, hs. 1s 17.2, hs. 14 6.2 and hs,13 1 Hz, 1 5'-H'), 2.52-2.6 1 (2H, m, 3'-H and 15'-H), 2.79 ( lH, dd, 14,4 12.1 and 14 ,3 7.7 Hz, 4'-H), 3.40 ( lH, t, 1 10.6 Hz, CfuHBOH), 3.56 (lH, d, 1 10.6 Hz, OH), 3 .64 (1H, d, 1 1 0.6 Hz, CHAH.BOH), 3.63-3.70 (1H, m, 9eq-H), 4.06 ( 1H, ddd, 19ax,9eq 1 1 .9, 19ax,10ax 9 .2 and 125 19ax,10eq 6. 1 Hz, 9ax-H), 5.57 ( lH, ddd, 113, 14 10.1 , 113, 15 3 . 1 and 113, 15 1 Hz, 13'-H) and 5.85 ( lH, ddd, h4, 13 10. 1 , h4,1 5 6.2 and h4, 15 2.2 Hz, 14'-H); 8c (67 .8 MHz; CDCl3) 24.2 (q, Me), 1 8.6, 24.9, 30.3, 34.3, 35.9, 36.2 (t, C-3', C-4', C- 10', C- 1 1 ' , C- 12' and C- 15'), 61 .8 (t, C-9'), 67.7 (t, C- 1) , 86.3 (s, C-2'), 97. 1 (s, C-7'), 106.4 (s, C- 5'), 124.9 (d, C-13') and 129.8 (d, C- 14'); mlz 254 (M+, 26%), 237 (M-OH, 10) , 223 (M? CH20H, 96), 124 (CsH120, 55) and 99 (C5H702, 100). (ii) The trans alcohol 212 (17 mg, 36%) as a colourless oil (Found: C, 66. 12; H, 8.90%; M+, 254. 1537. C14H2204 requires C, 66. 12; H, 8 .72%; M+, 254. 15 1 8) ; Umax (film) 3600-3 120 (br, s, OH), 3045 (w, =CH) and 1641 cm-1 (w, C=C); OH (270 MHz; CDCl3) 1 .47 (3H, s, Me), 1 .53-2.05 (lOH, m, 3'-H, 3'-H', 4'-H, lOax-H, 10eq-H, l l!lx? H, l leq-H, 12!lx-H, 12eq-H and OH), 2. 1 5 (lH, ddd, h5,15 17.0, h5.14 5.7 and h5, 13 1 .3 Hz, 15'-H'), 2.48 ( lH, ddd, h5,15 17.0, h5.14 2.8 and h5, 13 2.8 Hz, 15'-H), 2.70 ( lH, ddd, 14,4 12.6, 14,3 6.3 and 14,3 4.7 Hz, 4'-H), 3.39 ( lH, dd, 1HA,HB 1 1 .4 and 1HA,OH 6.0 Hz, CfuHBOH), 3.47 (lH, dd, 1HA,HB 1 1 .4 and 1HB,OH 6.0 Hz, CHAfiBOH), 3.65-3.7 1 ( lH, m, 9eq-H), 4.01 ( lH, ddd, 19ax,9eq 1 1 . 1 , 19ax,10ax 3.8 and 19ax,10eq 3.8 Hz, 9!lx-H), 5 .60 ( lH, ddd, 113 ,14 10. 1 , 113 ,15 2.8 and 113 ,15 1 .3 Hz, 13'-H) and 5.84 ( lH, ddd, h4,13 10. 1 , h4,15 5.7 and h4, 1 5 2.8 Hz, 14'-H); 8c (67.8 MHz; CDCl3) 25.2 (q, Me), 18 .8, 25.2, 33.2, 34.3, 36.3, 36.9 (t, C-3', C-4', C- 10' , C-1 1 ' , C- 12' and C-15'), 61 .8 (t, C-9), 69.3 (t, C-1 ), 85. 1 (s, C-2'), 96.4 (s, C-7'), 107.4 (s, C-5'), 124.8 (d, C- 13'), 1 29.9 (d, C- 14'; mlz 254 (M+, 25), 237 (M-OH, 7), 223 (M-CH20H, 100), 124 (CsH120, 5 1 ) and 99 (C5H702, 100). 2 1 1 . 2 1 2 :H: cis-(2'-Methyl-1 ' ,6' ,8'-trioxadispiro[ 4. 1 .5 .3lpentadec- 13'-en-2'yl)methanol 213, 214 Conversion of the cis-2-iodomethyl-2-methyl- 1 ,6,8-trioxadispiro[ 4. 1 .5.3]pentadec- 1 3-enes 203, 204 to the corresponding alcohols employed a modified procedure to that described above. The tetrahydrofuran component of the solvent mixture was omitted and the 126 iodides were dissolved in dry dimethylsulphoxide before being introduced into the K02f18- crown-6 solution. This afforded: (i) the cis alcoho1 213 ( 19 mg, 40%) as a colourless oil (Found: M+, 254 . 1534. C14H2204 requires M+, 254. 15 18); Umax (film) 3600-3 1 15 (br, s, OH), 3042 (w, =CH) and 1 643 cm-1 (w, C=C); OH (270 MHz; CDCl3) 1 . 1 1 (3H, s, Me), 1 .46-2. 1 6 (lOH, m, 3'? H, 3'-H',4'-H, 4'-H', 1 0ax-H, 10?-H, 1 1ax-H, 1 1?q-H, 12ax-H and 12?q-H), 2. 1 2 ( lH, ddd, h5,15 17.0, h5,14 6.2 and h5,13 0.5 H?, 15'-H), 2.47 ( lH, ddd, h5,15 17.0, h5,14 2.6 and 115 , 1 3 2.6 Hz, 15'-H'), 3 .37 (lH, dd, 1HA,HB 10.8 and 1HA.OH 10.8 Hz, CfuHBOH), 3.61 (1H, d, 1 10.8 Hz, CHAH.BOH), 3.66-3.75 ( lH, m, 9?q-H). 3 .89-4.05 ( 1H, m, 9ax-H), 4.26 (H, br., d, 1 10.8 Hz, OH), 5 .97 ( 1H, ddd, 113 , 14 10.3, 113 , 15 5.9 and 113 ,15 2.4 Hz, 14'-H) and 6 . 17 ( 1H, ddd, h4, 13 10.3, h4,15 2.8 and h4,15 1 . 1 Hz, 1 3'-H); mlz 254 (M+, 26%), 237 (M-OH, 10), 223 (M-CH20H, 96), 124 (CsH120, 55) and 99 (C5H702, 100). (ii) the cis alcohol 214 (20 mg, 41 %) as colourless prisms, m.p. 80-81 ?C (Found: C, 66. 1 5; H, 8 .82%; M+, 254. 1 530. C14H2204 requires C, 66. 12; H, 8.72%; M+, 254. 15 18); Umax (film) 3600-3 120 (br, s, OH), 3045 (w, =CH) and 1 640 cm-1 (w, C=C); OH (270 MHz; CDCl3) 1 .37 (3H, s, Me), 1 .53-2. 1 8 (9H, m, 3'-H, 3'-H', 4'-H, 10ax-H, 10?q-H, 1 1ax-H, 1 1?q-H, 12ax-H and 12?q-H), 2. 16-2.27 (2H, m, 4'-H' and 15'-H), 2.38 ( lH, ddd, h5,15 17.0, h5,14 2.5 and ft5 . 13 2.5 Hz, 15'-H'), 2.99 ( 1H, s, OH), 3.35 ( lH, d, 1 1 1 .3 Hz, CfuHBOH), 3.42 ( lH, d, 1 1 1 .3 Hz, CHAHBOH), 3.61 -3.68 ( lH, m, 9?? H), 4.06 ( lH, ddd, 19ax,9eq 1 1 .4, 19ax,10ax 2.9 and 19ax,10eq 2.9 Hz, 9ax-H), 5.74 ( lH, ddd, h3,14 10.3, h3,15 2.5 and 113 , 15 0.9 Hz, 13'-H) and 5.89 ( 1H, ddd, h4, 1 3 1 0.3, h4,15 5.7 and h4,15 2.5 Hz, 14'-H); oc (67.8 MHz; CDCl3) 24.0 (q, Me), 18 .7 , 25. 1 , 32.6, 34.6, 36.4, 39.3 (t, C-3', C-4', C-10' , C- 1 1 ' , C-12' and C-15'), 6 1 .5 (t, C-9'), 68.6 (t, C-1), 85. 1 (s, C-2'), 93.8 (s, C-7'), 105.0 (s, C-5'), 123.9 (d, C- 13' ) and 130.2 (d, C- 14'); mlz 254 (M+, 26%), 237 (M-OH, 10), 223 (M-CH20H, 96), 124 (CsH120, 55) and 99 (C5H702, 100). 213 , 2 1 4 :H: 127 (5R, 2$) and C5S. 2S)-(-)-2,5-Dihydroxy-2-methyl-7 -octyn- 1-v-toluenesulphonate 170 40% aqueous hydrofluoric acid (5 ml) was added to a solution of (5R, 2S) and (5S, 2S)-(-)-5-tert-butyldiphenylsilyloxy-2-hydroxy-2-methyl-7 -octyn-1-p-toluenesulphonate 181 ( 4 g, 7 .1 mmol) in acetonitrile (80 ml) and the mixture stirred for 24 h. The solvent was then evaporated at reduced pressure and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 : 1 ), to afford the title compound 170 (2.21 g, 96%) as a colourless oil [a]1? -2.4? (c, 3 . 1 6, CHC13 ) (Found: (Cl, NH3) M+H, 327 . 1 367 ; C1sH2406S requires M+H, 327.1266); Umax (film) 3678-3290 (br, s, OH), 3305 (s, C=H), 2983, 2961 , 2920 (s, C-H), 2120 (w, -C=) and 1355, 1 173 cm-1 (s, SOzO); OH (270 MHz; CDCl3) 1 . 14 (3H, s, 2-Me), 1 .45- 1 .76 (4H, m, 2x CHz), 2.04 ( lH, t, J 2.7 Hz, =CH) , 2 .31 -2.39 (3H, m, CHzC= and OH), 2.43 (3H, s, Ar-Me), 3.7 1-3.82 (4H, m, CHzO, CHO and OH), 7.33 (2H, d , J 8 .4 Hz, Ar-H) and 7.77 (2H, d , J 8 .4 Hz, Ar-H); oc (67.8 MHz; CDCI3) 21 .6 (q, 4'-Me), 23.2, 23.8 (q, 2-Me), 27.2 (t, C-3), 29.5 (t, C-4) , 34. 1 , 34.2 (t, C-6), 70.0, 70. 1 (d, C-5 and C-8), 70.9 (s, C-2), 75.6, 76.2 (t, C-1), 80.6 (s, C- 7), 127.9 (d, C-2'), 129.9 (d, C-3'), 132.4 (s, C-4') and 145 . 1 (s, C-1') ; mlz (Cl, NH3) 327 (M+H, 100%), 309 (M-OH, 41), 269 (C13H1704S , 43), 155 (M-OTs, 40) and 1 37 (M? OTs-HzO, 95). Conversion of the diol to the monoacetate derivative afforded an analytical sample (Found: C, 58 .48; H, 6.52; S , 8 .85%. C1sH2406S requires C, 58.68; H, 6.57; S , 8 .70%); (5R, 2S) and C5S, 2S)-2-Methyl-2,5-bis(trimethylsilyloxy)-7 -octyn-1-p-toluenesulphonate 2 3 1 A solution of (5R, 2S) and (5S, 2S)-(-)-2,5-dihydroxy-2-methyl-7-octyn- 1 -p ? toluenesulphonate 170 (150 mg, 2.4 mmol) and 1 -(trimethylsilyl)imidazole (258 mg, 9.6 mmol) in dry dichloromethane (15 ml) was stirred for 7 h. under nitrogen. The solvent was evaporated at reduced pressure and the residue purified by rapid column chromatography on florisil, using an hexane/ethylacetate eluant (9: 1), to afford the title compound 231 (205 mg, 95%) as a colourless oil; Umax (film) 3305 (s, C=H), 2985, 2950, 2920 (s, C-H), 2120 (w, -C=) and 1355, 1 173 cm-1 (s, SOzO); OH (270 MHz; CDCl3) 0. 14 ( 18H, s, 2x SiMe3) , 1 . 17 (3H, s, 2-Me), 1 .45- 1 .76 (4H, m, 2x CHz), 2.01 (lH, t, J 2.8 Hz, =CH), 2.44-2.47 (2H, m, CHzC=), 2.46 (3H, s, Ar-Me), 3.83 (2H, s, CHzO), 4.87-4.90 ( lH, m, CHO), 7.37 (2H, d, J 8.4 Hz, Ar-H) and 7.80 (2H, d, J 8 .4 Hz, Ar-H). 128 2,5-Dihydroxy-8-Ctetrahydro-2'-methoxypyran-2'-yl)-2-methyl-7-octyn-1-p toluenesulphonate 233 A solution of (:!")-2-methyl-2,5-bis(trimethylsilyloxy)-7 -octyn-1-p-toluenesulphonate 231 (450 mg, 0.96 mmol) in dry tetrahydrofuran (20 ml) was cooled to -78?C under nitrogen and to it was added was added n-butyllithium (0.72 ml of a 1 .6 M solution in hexane, 1 . 15 mmol). After 0.5 h. a solution of 8-valerolactone (120mg, 1 .2 mmol) in dry tetrahydrofuran ( 1 ml) was introduced followed by stirring a further 0.5 h. at this temperature. After the addition of 10% water in tetrahydrofuran (1 ml), the mixture was brought to room temperature and the solution dried over potassium carbonate. The solvent was then removed at reduced pressure and the residue purified by rapid column chromatography on florisil, using an hexane/ethyl acetate eluant (1 : 1 ). The lactol thus obtained was dissolved in methanol (80 ml) and stirred overnight with Amberlite IR 120 resin. The solution was filtered, triethylamine (0. 1 ml) added and the solvent evaporated at reduced pressure with the residue being quickly purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 : 1) , to afford the title compound 233 (320 mg, 76%) as an unstable colourless oil; Umax (film) 3690-3285 (br, s, OH), 2983, 2961 , 2920 (s, C-H), 2120 (w, -C=) and 1355, 1 173 cm-1 (s, S020); OH (270 MHz; CDCl3) 1 . 15 (3H, s, 2-Me), 1 .46- 1 .86 ( 10H, m, 5x CH2), 2.35-2.45 (3H, s, CH2C= and OH), 2.45 (3H, s, Ar-Me), 3 .37 (3H, s, OMe), 3.35-3.83 (6H, m, CHO, 2x CH20 and OH), 7 .36 (2H, d, J 8 .4 Hz, Ar-H) and 7.79 (2H, d, J 8.4 Hz, Ar-H); oc (67.8 MHz; CDCl3), 19.0, 24.6 (t, C-4' and C-5'), 2 1 .7 (q, 4"-Me), 23.4, 24.0 (q, 2-Me), 27.5 (t, C-3), 29.7 (t, C-4), 34.2 (t, C-6), 36.6 (t, C-3'), 50.5 (q, OMe), 62. 1 (t, C-6'), 70.0 (d, CHO), 70.8 (s, C-2), 75.7, 76.4 (t, C-1) , 80.4 (s, C-7), 8 1 .7 (s, C-8), 94.9 (s, C-2') , 128.0 (d, C-2") , 1 30.0 (d, C-3''), 1 32.6 (s, C-4") and 145.0 (s, C-1"); mlz 269 (M-OTs, 12%), 236 (M-OTs-OMe, 1 2), 205 (M-OTs-OMe-H20, 56), 172 (TsOH, 79) and 1 15 (O,Hn02, 100). 4-(1 ',7'-Dioxaspiro[5.5lundec-4'-ene-2'-yl)-2-hydroxy-2-methylbutan-1-p? toluenesulphonate 235 A solution of 2,5-dihydroxy-8-(tetrahydro-2'-methoxypyran-2'-yl)-2-methyl-7- octyn- 1-p-toluenesulphonate 233 (300 mg, 0.68 mmol) in 1 : 1 hexane:ethyl acetate ( 150 ml) was stirred vigorously with Lindlar catalyst ( -5mg) under an hydrogen atmosphere. After 1 .5 h. the solution was filtered and the solvent evaporated at reduced pressure to give an oil that was dissolved in dichloromethane (10 ml) and stirred with a trace amount of pyridinium? p-toluenesulphonate for 0.25 h. The solvent was then removed and the residue purified by 129 flash chromatography, using an hexane/ethyl acetate eluant (4: 1 ) , to afford the title compound 235 (212 mg, 7 1 %) as an inseparable 1 : 1 mixture of diastereomers in the form of a colourless oil (Found: C, 6 1 .29; H, 7.3 1 ; S , 7.74%; M+, 410. 1761 . C21H3o06S requires C, 6 1 .44; H, 7.37; S , 7 .81 %; M+, 410. 1763); OH (270 MHz; CDCl3) 1 . 17 , 1 . 1 8 (3H, s, 2-Me), 1 .52- 1 .94 (12H, m , 6x CH2), 2.45 (3H, s , Ar-Me), 2.66 (O.SH, s , OH), 2.86 (O.SH, s, OH), 3.60-3.92 (SH, m, 2x CH20 and CHO) , 5.60 ( 1H, d, 1 9.9 Hz, 5'? H), 5.87 (1H, ddd, 14',5' 9.9, 14',3' 3.6 and 14',3' 3.6 Hz, 4'-H), 7 .36 (2H, d, 1 8.4 Hz, Ar? H) and 7 .81 (2H, d, 1 8.4 Hz, Ar-H); oc (67.8 MHz; CDCl3) 1 8.5 (t, C-9' or C-10'), 21 .7 (q, 4"-Me), 23 .7, 23.8 (q, 2-Me), 24.9, 25.0 (t, C-9' or C-10'), 28.9, 29.0, 30.5 , 34.2, 34.4, 34.8 (t, C-3, C-4, C-3' and C- 1 1') , 6 1 . 1 (t, C-8'), 67.2 (d, C-2'), 70.8, 70.9 (s, C- 2), 76.0 (t, C- 1) , 94.0, 94. 1 (s, C-6'), 127.4 (d, C-5'), 128.0 (d, C-2"), 129.9 (d, C-3''), 1 30.3 (d, C-4'), 1 32.7 (s, C-4") and 145.0 (s, C- 1"); mlz 410 (M+, 5%), 392 (M-H20, 9), 269 (C13H1704S , 24), 238 (M-TsOH, 8) and 124 (CsH120, 100). 2 3 5 2-(3'.4'-Epoxy-3'-methylbutan- 1 '-yn-1 .7-dioxaspirofS .Slundec-4-ene 188 Sodium hydride ( 1 5 mg of a 40% dispersion in oil, 0.25 mmol) was added to a solution of 4-( 1 ' ,7'-dioxaspiro[S.S]undec-4'-ene-2'-yl)-2-hydroxy-2-methylbutan- 1 -p? toluenesulphonate 235 (1 00 mg, 0.24 mmol) in dry tetrahydrofuran (25 ml) under nitrogen. After stirring at room temperature for 3 h., reaction was quenched with saturated aqueous sodium dihydrogen phosphate solution and the mixture extracted with ether (3x 25 ml) which was washed with water and dried over potassium carbonate. Evaporation of the solvent under reduced pressure and purification of the residue by flash chromatography, using an hexane/ethylacetate eluant (9: 1) to afford a product (54 mg, 94%) with identical physical properties to that compound 188 prepared from 5-tert-butyldiphenylsilyloxy-2- hydroxy-8-(tetrahydro-2'-methoxypyran-2'-yl)-2-methyl-7 -octen-1-p-toluenesulphonate 189 . 130 4-{ 8'-[ 1 "-(tert-B utyldiphenylsilyloxymethyl)propyll-9', 1 1 '-dimethyl- 1 ', 7' -dioxaspiro [5.5Jundec-4'-en-2'-yl l-2-hydroxy-2-methylbutan- 1-p-toluenesulphonate 239, 240 The acetylene 231 (7 1 mg, 0. 15 mmol) was dissolved in dry tetrahydrofuran (4 ml) and cooled to -75?C under nitrogen. n-Butyllithium (0.094 ml of a 1 .6 M solution in hexane, 0. 15 mmol) was added and the reaction stirred at this temperature for 1 h. whereupon a solution of the lactone 84 (52 mg, 0.12 mmol) in dry tetrahydrofuran (1 ml) was introduced in a dropwise fashion. After stirring for a futher 0.5 h. the reaction was quenched with 10% water in tetrahydrofuran (0.5 ml), the solution brought to room temperature and dried over anhydrous potassium carbonate. The solvent was evaporated at reduced pressure and the residue columned on florisil to afford an oil which was dissolved in methanol and stirred with Amberlite IR 120 resin for 1 h. This solution was filtered and the methanol evaporated under reduced pressure to give a yellow residue which was purified by flash chromatography to afford the keta1 237 (73 mg, 82%). This colourless, somewhat unstable oil was quickly dissolved in 1 : 1 hexane:ethyl acetate (20 ml) and stirred vigorously with Lindlar catalyst (-2 mg) under an hydrogen atmosphere for 5 h. The solution was filtered and the solvent evaporated to afford a residue which was dissolved in dichloromethane (10 ml) and stirred with a catalytic quantity of pyridinium-p-toluenesulphonate for 0 .2 h . The solvent was removed and the resulting diastereomers separated and purified by flash chromatography, using an hexane/ethyl acetate eluant (4: 1) , to afford the less polar ? 2S. 2'S, 6'R, 8'S, 9'$, l l 'R) tosylate 239 (30 mg, 42% from 84) as a colourless oil [a]1f - 1 8.5? (c, 1 .09, Et20) (Found: (Cl, NH3) M+H, 749.3900. C43H6o07SSi requires M+H, 749.3907); 'Umax (film) 3670-3290 (br, s, OH), 3035 (m, =CH), 2945, 2870 (s, C-H), (1635, C=C) and 1362, 1 175 cm-1 (s, S020); OH (270 MHz; CDCl3) 0.74 (3H, t, 1 7.6 Hz, CH2Cfu), 0.745 (3H, d, 1 6.8 Hz, 9'-Me), 0.79 (3H, d, 1 6.6 Hz, 1 1 '-Me), 1 .03 (3H, s, 2-Me), 1 .04 (9H, s, t-Bu), 1 .07- 1 .68 ( l lH, m, CHEt, CH2CH3, 3x CH2 and 2x CHMe), 1 .79- 1 . 87 (2H, m, =CCH2), 2.43 (3H, s, Ar-Me), 2.97 ( lH, s, OH), 3.59 ( lH, dd, 1s?ax,9'ax 10.4 and 1s?ax,I" 1.3 Hz, 8ax-H), 3.65-3.78 (5H, m, 2x CH20 and 2'-H), 5.42 ( lH, ddd, 15',4' 10. 1 , 15',3' 2.8 and 15',3' 2.8 Hz, 5'-H), 5 .87 (lH, ddd, 14',5' 10. 1 , 14',3' 5 . 1 and 14',3' 2.4 Hz, 4'-H), 7.3 1 -7.41 (8H, m, Ar-H) 7.63-7.67 (4H, m, Ar-H) and 7.78 (2H, d, 1 8.3 Hz, Ar-H); oc (67.8 MHz; CDCl3) 1 3.0 (q, C-3"), 1 6.0 (q, 9'-Me), 17.8 (q, 1 1 '-Me), 18 . 1 (t , C-2"), 19.2 (s, CMe3), 21 .6 (q, Ar-Me), 24.3 (q, 2-Me), 27.0 (q, CMe3), 29.8 (t, C-3'), 28.3, 33.0, 36.3 (t, C-3, C-4 and C-10'), 3 1 .7 , 38 .6, 43.7 (d, C? l", C-9' and C- 1 1 ') , 65.4 (t, C-1 "'), 66.3 (d, C-2'), 70.4 (s, C-2), 74.9 (d, C-8'), 75.7 (t, C- 1) , 96.8 (s, C-6') , 127 .5, 127.6 (d, C-2""') , 127.6 (d, C-4') , 128.0 (d, C-2""), 129.4 (d, C-4""'), 129 .8 (d, C-3''") , 129.9 (d, C-5'), 1 32.8 (s, C-4""), 1 34.0, 1 34.2 (s, C- 1 '"") , 135.5, 1 35.6 (d, C-3""') and 144.8 (s, C- 1 ""); mlz (Cl, NH3) 749 (M+H, 25%), 730 (M-H20, 15), 691 (M-tBu, 9), 673 (M-tBu-H20, 16) , 577 (M-OTs, 8), 559 (M- 131 OTs-H20, 17), 5 19 (M-OTs-tBu, 12) and 199 (C12HnOSi, 100), and Cl"S. 2S. 2'R, 6'R. 8 'S. 9'S, 1 1 'R) tosylate 240 (30 mg, 42% from 84) as a colourless oil [aH5 +38 .8? (c, 1 .034, Et20) (Found: (Cl, NH3 ) M+H, 749.3901 . C43H6o07SSi requires M+H , 749.3907); Umax (film) 3670-3290 (br, s, OH), 3035 (m, =CH), 2945, 2870 (s, C-H), 1 634 (w, C=C) and 1362, 1 175 cm-1 (s, S020); OH (270 MHz; CDCl3) 0.75 (3H, d, 1 6.4 Hz, 9'-Me), 0.76 (3H, t, 1 7.4 Hz, CH2Cfu), 0.8 1 (3H, d, 1 6.4 Hz, 1 1 '-Me), 1 .02 (9H, s, t-Bu), 1 . 1 4 (3H , s, 2-Me), 1 .07- 1 .85 ( l lH, m, CHEt, CfuCH3, 3x CH2 and 2x CHMe), 1 . 89- 1 .95 (2H, m, =CCH2), 2.41 (3H, s, Ar-Me), 2.43 ( lH, s, OH), 3 .54-3.80 (5H, m, 2x CH20 and 8ax-H), 3.94-4.05 ( lH, m, 2'-H), 5.95 ( lH, ddd, 14',5' 1 0.4, 14',3' 3.6 and 14',3 ' 3.6 Hz, 4'-H), 6.08 (1H, d, 1 10.4 Hz, 5 '-H), 7.30-7.41 (8H, m, Ar-H), 7 .63-7.67 (4H, m, Ar-H) and 7.78 (2H, d, 1 8.4 Hz, Ar-H); oc (67.8 MHz; CDCl3) 1 3.0 (q, C-3"), 1 5.7 (q, 9'-Me), 17.0 (t, C-2"), 17. 1 (q, 1 1 '-Me), 19. 1 (s, CMe3), 2 1 .6 (q, Ar-Me), 23.6 (q, 2-Me), 26.8 (q, CMe3), 3 1 .2 (t, C-3'), 29.2, 34.6, 38.8 (t, C-3, C-4 and C- 10'), 3 1 .6, 39.2, 43.8 (d, C- 1" , C-9' and C- 1 1 ') , 63.3 (t, C-1 '") , 68.8 (d, C-2'), 70.4 (s, C-2), 76.3 (d, C-8'), 76.8 (t, C- 1), 98.3 (s, C-6'), 123.8 (d, C-5'), 127.4, 127.5 (d, C- 2"'"), 128.0 (d, C-2""), 128.7 (d, C-4'), 129.4, 129.5 (d, C-4'""), 129.8 (d, C-3'"'), 1 32.7 (s, C-4""), 134.0, 134. 1 (s, C- 1 '""), 135.5, 135.6 (d, C-3'"") and 144.7 (s, C? l ""); mlz (Cl, NH3) 749 (M+H, 25%), 730 (M-H20, 15), 69 1 (M-tBu, 9), 673 (M-tBu? H20, 1 6), 577 (M-OTs, 8), 559 (M-OTs-H20, 17), 5 19 (M-OTs-tBu, 12) and 199 (C12HuOSi, 100). t-BuPh2SiO 239 , 240 8-[ 1" -(tert-B utyldiphenylsilyloxymethyl)propyll-9, 1 1-dimethyl-2-(3' ,4'-epoxy-3'-methyl- 1-butyl2- 1 , 7-dioxaspiro[5.5Jundec-4-ene 243, 244 To a solution of the (-)-tosylate 239 (52 mg, 0.07 mmol) in dry tetrahydrofuran (20 ml) under a drying tube was added sodium hydride ( 15 mg of a 40% dispersion in oil, 0.25 mmol) and the supension stirred overnight at room temperature. After quenching with water (0.05 ml) the solvent was evaporated at reduced pressure and the oily solid residue purified by flash chromatography, using an hexane/ethyl acetate eluant (4: 1), to afford the Cl"S, 2S, 132 3 'S, 6R , 8S, 9S. 1 1R) epoxide 243 (39 mg, 97%) as a colourless oil [a]1J - 1 3 .7? (c, 0.766, EtzO) (Found: M+, 576.3640. C36Hs204Si requires M+, 576.3635); Umax (film) 3070 (w, Ar-H), 3039 (w, =CH), 2958 , 2928, 2856 (s, C-H) and 1656 (w, C=C); OH (270 MHz; CDCl3) 0.74 (3H, t, 1 7.5 Hz, CHzCfu), 0.76 (3H, d, 1 6.6 Hz, 9-Me), 0 .80 (3H, d, 1 6.4 Hz, 1 1 -Me), 1 .06 (9H, s, t-Bu), 1 . 19 (3H, s, 3'-Me), 1 .05-1 .70 ( 1 1H, m, CHEt, CfuCH3, 3x CH2 and 2x CHMe), 1 . 80-1 .85 (2H, m, =CCHz), 2.37 (1H, d, 1 4.9 Hz, CJ::!AHBO (epoxide)), 2.43 ( 1H, d, 1 4.9 Hz, CHA.HBO (epoxide)), 3.59 (lH, dd, 1sax,9ax 10.4 and 1sax,l " 1 .5 Hz, 8ax-H), 3.65-3.7 1 (3H, m, CHzOSi and 2-H), 5.43 (lH, ddd, 1s,4 10. 1 , 15,3 2.0 and 15,3 2.0 Hz, 5-H), 5.88 ( 1H, ddd, 14,5 10. 1 , 14,3 4.5 and 14,3 3.0 Hz, 4- H), 7.34-7.42 (6H, m, Ar-H) and 7.64-7.69 (4H, m, Ar-H); oc (67.8 MHz; CDCl3) 13 . 1 (q, C-3"), 1 6. 1 (q, 9-Me), 17.9 (q, 1 1 -Me), 18 .2 (t, C-2"), 19.2 (s, CMe3), 21 .0 (q, 3'? Me), 27.0 (q, CMe3), 30.3 (t, C-3), 38.7 , 43.8 (d, C-1 " and C- 1 1) , 53.7 (t, C-4'), 57.0 (s, C-3'), 65.6 (t, C- 1"'), 66. 1 (s, C-2), 74.8 (d, C-8), 96.2 (s, C-6), 127.5, 127.6 (d, C- 2""), 127.6 (d, C-4), 129.5 (d, C-4""), 130.2 (d, C-5), 134. 1 , 1 34.3 (s, C- 1"") and 1 35.5, 1 35.7 (d, C-3""); mlz 576 (M+, 2%), 5 19 (M-tBu, 23), 337 (6), 323 (5), 295 (7), 207 (C14H230, 10) and 199 (C12HuOSi, 1 00). Repetition of this procedure using the corresponding ( + )-tosylate 240 (52 mg, 0.07 mmol) afforded the (l"S, 2R, 3'S. 6R, 8S. 9$, 1 1R) epoxide 244 (38 mg, 95%) also as a colourless oil [aH5 +42.4? (c, 0.752, EtzO) (Found: M+, 576.3629. C36Hs204Si requires M+, 576.3635); Umax (film) 3070 (w, Ar-H), 3039 (w, =CH), 2958, 2928, 2856 (s, C-H) and 1656 (w, C=C); OH (270 MHz; CDCl3) 0.76 (3H, d, 1 6.6 Hz, 9-Me), 0.79 (3H, t, 1 7.5 Hz, CHzCfu), 0.83 (3H, d, 1 6.4 Hz, 1 1-Me), 1 .02 (9H, s, t-Bu), 1 .30 (3H, s, 3'-Me), 0.97- 1 .80 (1 1H, m, CHEt, CfuCH3, 3x CHz and 2x CHMe), 1 .89- 1 .95 (2H, m, =CCHz), 2.49 ( 1H, d, 1 5.0 Hz, CfiAHBO (epoxide)), 2.70 ( 1H, d, 1 5.0 Hz, CHAHBO (epoxide)), 3.56-3.69 (3H, m, CHzOSi and 8ax-H), 3.98-4.07 ( 1H, m, 2-H), 5.94 (lH, ddd, 14,5 10.4, 14,3 3.8 and 14,3 3.8 Hz, 4-H), 6. 1 1 (1H, ddd, 15,4 10. 1 , 15 ,3 1 . 8 and 15,3 1 . 8 Hz, 5-H), 7 .33-7.43 (6H, m, Ar-H) and 7.64-7.70 (4H, m, Ar-H); oc (67.8 MHz; CDCl3) 13 . 1 (q, C-3"), 1 5.9 (q, 9-Me), 17.2 (q, 1 1 -Me), 17.3 (t, C-2"), 19.2 (s, CMe3), 2 1 . 1 (q, 3 '-Me), 26.8 (q, CMe3), 3 1 . 1 , 3 1 .2, 3 1 .9, 39.0 (t, C-1 ', C-2', C-3 and C- 10), 3 1 .7 , 39.2, 43.9 (d, C-1" , C-9 and C-1 1 ), 53.9 (t, C-4') , 56.8 (s, C-3 '), 63.3 (t, C- 1 '") , 67.0 (d, C-2), 76. 1 (d, C-8), 98. 1 (s, C-6), 124.4 (d, C-5), 127.4, 127.5 (d, C-2""), 128.5 (d, C-4), 129.4, 129.5 (d, C-4"") , 134.0, 1 34.2 (s , C-1 "") and 135.5, 135.6 (d, C-3""); mlz 576 (M+, 2%), 5 19 (M-tBu , 36), 477 (C29H3704Si, 7), 405 (C26H3302Si, 4), 337 ( 16), 323 (27), 295 ( 1 0) , 207 (C14H230, 35) and 199 (C12HnOSi, 100). 133 Me H t-BuPh2SiO 243 , 2 44 4-{8 '-[1 "-Ctert-Butyldiphenylsilyloxymethyl)propyll-9'. 1 1 '-dimethyl-1 ',7'? dioxaspiro[5.5lundec-4'-en-2'-yll - 1-iodo-2-methyl-2-butanol 245, 246 A solution of the (-)-epoxide 243 (37 mg, 0.064 mmol) in dry tetrahydrofuran (9 ml) was cooled to -50?C under nitrogen. Lithium iodide (17 mg, 0. 1 3 mmol), dissolved in dry tetrahydrofuran (1 ml), was then introduced followed with boron trifluoride etherate (0.02 ml). The reaction was stirred at this temperature for 1 h., quenched with 5% water in tetrahydrofuran (0.5 ml) and brought to room temperature. The solution was dried over anhydrous potassium carbonate, the solvent evaporated, and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant (4: 1) , to afford the Cl"S, 2S. 2'S, 6'R. 8'S. 9'S. l l 'R) iodohydrin 245 (41 mg, 9 1%) as a colourless oil [a]1J -20.2? (c, 0.6, Et20) (Found: M+, 704.2744. C36H5304Sil requires M+, 704.2756); Umax (film) 3570- 3200 (br, s, OH), 3069 (w, Ar-H), 3047 (w, =CH), 2958. 2923, 2856, (s, C-H) and 1653 (w, C=C); OH (270 MHz; CDCl3) 0.77 (3H, d, 1 6.6 Hz, 9'-Me), 0.79 (3H, t, 1 8.2 Hz, CH2CH3) , 0.8 1 (3H, d, 1 6.2 Hz, 1 1 '-Me), 1 .05 (9H, s, t-Bu), 1 .20 (3H, s, 2-Me), 1 .06- 1 .7 1 (1 1H, m, CHEt, CfuCH3, 3x CH2 and 2x CHMe), 1 .82- 1 .90 (2H, m, =CCH2) , 2.25 ( lH, s, OH), 3 . 14 (2H, s, CHzl), 3.59 (lH, dd, 1s?ax,9'ax 10.3 and 1s?ax, l" 1 .5 Hz, 8?x-H), 3.7 1-3.74 (3H, m, CHzO and 2'-H), 5 .45 (1H, ddd, 15',4' 10.0, 15',3 ' 2.4 and 15',3' 1 .5 Hz, 5'-H), 5.89 ( lH, ddd, 14',5' 10.0, 14',3' 4.8 and 14',3' 2.6 Hz, 4'-H), 7 .32-7.45 (6H, m, Ar-H) and 7.65-7.70 (4H, m, Ar-H); oc (67.8 MHz; CDCl3) 1 3.2 (C-3"), 16 .1 (q, 9'-Me), 17.8 (q, 1 1 '-Me), 18 .3 (t, C-2"), 19.3 (s , CMe3), 22.0 (t, C- 1) , 25.9 (q, 2- Me), 27.0 (q, CMe3) , 29.6 (t, C-3'), 30.0, 35.6, 36.4 (t, C-3, C-4 and C-10'), 3 1 . 8, 38.7, 43.7 (d, C-1", C-9' and C- 1 1 '), 65.8 (t, C-1'"), 66.2 (d, C-2'), 70.2 (s, C-2), 75.0 (d, C- 8') , 96.6 (s, C-6') , 127 .5, 127.6 (d, C-2""), 127.7 (d, C-4') , 1 29.5, 129.6 (d, C-4""), 1 30. 1 (d, C-5'), 1 34.2, 1 34.4 (s, C- 1 "") and 1 35.5, 1 35.7 (d, C-3""); mlz 704 (M+, 1 %), 647 (M-tBu, 34), 629 (m-tBu-H20, 7), 577 (M-I, 3), 519 (M-tBu-I, 7), 43 1 (9), 337 (21) , 323 (12) , 225 (C6H 100I, 37) and 199 (C12HuOSi, 1 00). Repetition of this procedure, using the corresponding (+)-epoxide 244 (33 mg, 0.057 mmol) afforded the Cl"S, 2S. 2'R, 6'R, 8 'S, 9'S. l l 'R) iodohydrin 246 (37 mg, 92%) also as a colourless oil [a]1J +40. 1 ? (c, 0.5 1 , EtzO) (Found: M+, 704.2744. C36H5304Sil requires M+, 134 704.2756) ; Umax (film) 3570-3200 (br, s, OH), 3069 (w, Ar-H), 3047 (w, =CH), 2958. 2923, 2856, (s, C-H) and 1 653 (w, C=C); OH (270 MHz; CDCl3) 0.77 (3H, d, J 6.6 Hz, 9 '-Me), 0.7 8 (3H, t, J 8.4 Hz, CH2CH3), 0.82 (3H, d, J 6.6 Hz, 1 1 '-Me), 1 .02 (9-H, s, t? Bu), 1 .33 (3H, s, 2-Me) , 1 .08-1 .80 ( 1 1H, m, CHEt, CfuCH3, 3x CH2 and 2x CHMe) , 1 .92- 1 .9 8 ( lH, m, =CCH2), 3.27 (H, s, OH), 3.32 (2H, s, CH2I), 3 .54-3.78 (3H, m, CH20 and 83x-H), 4.00-4. 10 ( lH, m, 2'-H), 5 .95 ( 1H, ddd, J4',5' 10.3, J4',3 ' 3.3 and J4',3 ' 3.3 Hz, 4'-H), 6 . 10 ( lH, d, J 10.3 Hz, 5'-H), 7 .34-7 .42 (6H, m, Ar-H) and 7 . 64-7.68 (4H, m, Ar-H); oc (67 .8 MHz; CDCl3) 1 3.0 (q, C-3") , 15 .8 (q, 9'-Me), 17. 1 (t, C-2"), 17.2 (q, 1 1 '-Me), 19.2 (s, CMe3), 22.7 (t, C- 1 ) , 26.2 (q, 2-Me), 26.8 (q, CMe3), 3 1 . 1 (t, C-3'), 30.0, 36.5, 38 .9 (t, C-3, C-4 and C- 10') , 3 1 .6, 39. 1 , 43.9 (d, C- 1" , C-9' and C- 1 1 ') , 63.3 (t, C- 1 '"), 68 .5 (d, C-2'), 69.9 (s, C-2) , 77.2 (d, C-8') , 98.3 (s, C-6 ') , 124. 1 (d, C-5 ') , 1 27.4, 127.5 (d, C-2"") , 128.6 (d, C-4') , 1 29.4, 1 29.5 (d, C-4""), 1 34.0 (s, C- 1"") and 1 35.5, 1 35 .6 (d, C-3' '") ; mlz 704 (M+, 1 %), 647 (M-tBu, 34), 629 (M-tBu? H20, 7) , 577 (M-1, 3) , 5 19 (M-tBu-1, 7) , 43 1 (9) , 337 (2 1) , 323 (12), 225 (C6Hw01, 37) and 199 (C12HnOSi, 100). t-BuPh2SiO Me 1 ' H 0 245 , 2 4 6 I 9-[l'-(tert-B utyldiphenylsilyloxymethyl)propyll-2-iodomethyl-2,1 0, 12-trimethyl- 1 ,6,8- trioxadispiro[ 4. 1 .5 .3lpentadec- 1 3-ene 247, 248 A solution of the (-)-iodohydrin 245 (42 mg, 0.06 mmol), iodine (32 mg, 0. 13 mmol) and iodobenzenediacetate (42 mg, 0. 1 3 mmol) in cyclohexane ( 10 ml) was purged with nitrogen and irradiated with a 270 watt tungsten filament lamp. After 1 .5 h . , during which time the temperature was maintained at about 18?C, the solution was diluted with ether (50 ml) then washed with 1 0% aqueous sodium thiosulphate ( 10 ml), water ( 10 ml) and brine (20 ml) , and dried over potassium carbonate. The solvent was evaporated under reduced pressure and the mixture of two diastereomers - were separated and purified by flash chromatography, using an hexane/ethyl acetate eluant (95 :5), to afford the (l'S, 2S, SS, 7S, 9S, 10S, 12R) trans iodide 247 (15 . 1 mg, 36%) as a colourless oil [a]1} - 10.5? (c, 0.39, CHCl3) (Found: M+, 702.2603 . C36Hs104Sil requires M+, 702.260 1); 135 Umax (film) 3070 (w, Ar-H), 3040 (w, =CH), 295 1 , 2927, 2860 (s, C-H) and 1 654 (w, C=C); OH (270 MHz; CDCl3) 0.66 (3H, t, 1 7.5 Hz, CH2Cfu), 0.77 (3H, d, 1 6.2 Hz, 12- Me), 0.82 (3H, d, 1 6.4 Hz, 10-Me), 1 .06 (9H, s, t-Bu) 1 .57, (3H, s, 2-Me), 1 . 17- 1 .88 (9H, m, 3-H', 4-H', 2x CHMe, CHEt, CfuCH3, 1 1ax-H and 1 1eq-H), 2.03-2. 17 (2H, m, 3-H and 1 5-H'), 2.36 ( 1H, ddd, h5, 15 16.8, h5, 14 2 .1 and h5, 13 2.4 Hz, 15-H), 2.5 1 - 2.61 ( 1H, m, 4-H), 3 . 16 ( lH, d, 1 10. 1 Hz, C.fiAHBI), 3.22 ( lH, d , 1 10. 1 Hz, CHAfui), 3 .62 (2H, d, 1 6.6 Hz, CH20), 3 .72 ( 1H, dd, 19ax,10a? 10. 1 and l9ax,l ' 0.6 Hz, 9ax-H), 5 .40 ( 1H, dd, 113,14 10 .1 and 113 ,15 2.4 Hz, 13-H), 5 .86 ( 1H; ddd, h4,13 10. 1 , h4, 15 6.4 and h4,15 2 . 1 Hz, 14-H), 7 .32-7 .43 (6H, m, Ar-H) and 7.63-7.68 (4H, m, Ar-H); oc (67.8 MHz; CDCl3) 12.9 (q, C-3'), 1 6.0 (q, 10-Me), 17.8 (t, C-2'), 1 8.2 (t, C-1 "'), 1 8 .3 (q, 12-Me), 19. 1 (s, CMe3), 27.0 (q, CMe3), 28.4 (q, 2-Me), 33.9, 35.6, 35.9, 36.7 (t, C- 3, C-4 C- 1 1 and C- 15), 3 1 .8 , 39.4, 44. 1 (d, C-1 ', C-10 and C- 12), 65.0 (t, C-1 ") , 75.6 (d, C-9), 82.8 (s, C-2), 99. 1 (s, C-7), 107.4 (s, C-5), 125.2 (d, C- 13), 127.5, 127.6 (d, C-2'"') , 129.4, 129.5, 129.6 (d, C-4"" and C- 14), 1 33.9 , 134.2 (s, C- 1 "") and 1 35.5, 1 35 .8 (d, C-3'"'), and the more polar Cl 'S, 2S. 5R, 7S. 9S. 10S. 12R) cis iodide 248 (8.9 mg, 21 %) as a colourless oil [aH5 -3 1 .6? (c, 0.215, CHCl3) (Found: M+, 702.2603. C36H5104Sil requires M+, 702.2601) ; Umax (film) 3070 (w, Ar-H), 3040 (w, =CH), 295 1 , 2927, 2860 (s, C-H) and 1 654 (w, C=C); OH (270 MHz; CDCl3) 0.70 (3H, d, 1 6.6 Hz, 12-Me), 0.84 (3H, t, 1 7.3 Hz, CH2Cfu), 0.86 (3H, d, 1 6.5 Hz., 10-Me), 1 .06 (9H, s, t? Bu), 1 .28 (3H, s, 2-Me), 1 .03- 1 .92 (9H, m, 3-H', 4-H', 2x CHMe, CHEt, CfuCH3, l lax-H and 1 1eq-H), 2.02-2. 1 1 (3H, m, 3-H, 4-H and 15-H), 2.27 ( lH, ddd, h5,15 1 6.5, h5,14 5.1 and h5, 13 1 .6 Hz, 15-H'), 3. 15 ( 1H, d, 1 9.3 Hz, CfuHBI), 3 .29 ( 1H, d, 1 9.3 Hz, CHAfiBl), 3.55 ( 1H, dd, 19ax,10ax 10.4 and 19ax,1 ' 1.8 Hz, 9ax-H), 5.61 ( lH, ddd, h3,14 9.9, h3, 15 1 .6 and 113, 15 1 .6 Hz, 13-H), 5 .93 ( 1H, ddd, h4, 13 9.9, h4, 1 5 5 . 1 and h4,15 3 .7 Hz, 14-H), 7.32-7.43 (6H, m, Ar-H) and 7.63-7.68 (4H, m, Ar-H); oc (67.8 MHz; CDCl3) 13 .6 (q, C-3'), 15 .8 (q, 10-Me), 17.4 (t, C-2'), 1 8 .4 (q, 12-Me), 19.2 (s, CMe3), 20.6 (t, C-1"'), 25.6 (q, 2-Me), 27.0 (q, CMe3), 34.5, 36.0, 36.5, 39. 1 (t , C-3, C-4 C-1 1 and C- 15), 32.5, 39.3, 45.6 (d, C-1 ' , C-10 and C-12) , 64.9 (t, C- 1") , 77.2 (d, C-9), 83.5 (s, C-2), 96.6 (s, C-7), 106.3 (s, C-5), 125.3 (d, C-13), 127.5, 127.6 (d, C- 2'"'), 129.4 (d, C-4"") , 1 30.5 (d, C- 14) , 1 34.2 (s, C- 1 "") and 1 35.7, 135 .8 (d, C- 3'"'); mlz 702 (M+ , 6%), 645 (M-tBu, 100), 567 (7) , 39 1 (C16H240 3I, 1 2), 320 (C2oH3203, 16) , 303 ( 12), 200 ( 12), 199 (C12HnOSi, 66), 1 83 ( 18 , 1 35 (26), 1 1 1 ( 12) and 97 ( 12). The procedure was repeated, irradiating a solution of the ( + )-iodohydrin 246, iodine and iodobenzenediacetate in cyclohexane, to again form a diastereomeric mixture of bisspiroketals 247, 248 which, on separation, exhibited identical spectroscopic properties to those isomers already described. 136 247 , 2 4 8 C2S, 2'S, 5'S, 7'S, 9'S , 1 0'S, 12'R)-2-(2'-Hydroxymethyl-2' , 1 0 ' , 1 2 '-trimethyl- 1 ' ,6' . 8 ' ? trioxadispiro[ 4. 1 .5.3Jpentadec- 13 '-en-9'-yl)butan- 1 -ol 254 A solution of the (-)-iodide 24 7 ( 4 mg) , 1 8-crown-6 (5 m g) and potassium superoxide (5 mg) in dry dimethylsulphoxide (1 ml) under nitrogen was stirred ovenight at room temperature. Water (0.05, m?was added and the mixture extracted with ethyl acetate (50 ml) which was washed with water (10 ml) and brine ( 10 ml), then dried over potassium carbonate. The solvent was removed under reduced pressure and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant (1 :2) to afford the title compound 254 (-1 mg) as a colourless oil (Found: M+, 354.2375 . C2oH3405 requires M+, 324.2406), OH (270 MHz; CDCl3) 0 .81 (3H, d, 1 6.6 Hz, 1 0'-Me or 12'-Me), 0.82 (3H, d, 1 6.6 Hz, 1 0'-Me or 12'-Me), 0.98 (3H, t, 1 7 . 1 Hz, CH2C.I::I3), 1 .44 (3H, s, 2'-Me), 1 .30- 1 .86 (8H, m, CHEt, 2x CHMe, CfuCH3, l lax-H, l leq-H and 4'H') , 2.04-2. 15 (3H, m, 1 5'-H', 3 ' -H and 3 '-H'), 2.41 ( lH, ddd, h5', 15' 16.7, h5' ,14' 2.4 and h 5', 1 3 ' 3.0 Hz, 15'? H), 2.59 ( lH, ddd, 14',4' 12.8, 14',3' 6.3 and 14',3' 4.4 Hz, 4'-H), 2.89 ( 1H, dd, 1HA,OH 9.2 and 1HB ,OH 0.7 Hz, 1-0H), 3 .38-3.55 (2H, m, 2x 1"-H), 3 .69-3 .82 (2H, m, 2x 1 -H), 3 . 87 ( 1H, dd, 19'ax, I O'ax 10.4 and 19'ax,2 1 . 8 Hz, 9 '-H) , 5 .49 ( 1H, ddd, h 3' , 14' 1 0. 1 , h 3 ' , 1 5' 3 . 1 and h 3 ' , 15 ' 0.9 Hz, 1 3'-H) and 5 .93 ( 1H, ddd, h4', 13 ' 10. 1 , h4', 1 5' 6.4 and h4',15' 2.2 Hz, 14' -H); mlz 354 (M+, 36%), 323 (M-CH20H, 73), 28 1 (M-C4HsOH, 58), 2 10 (C12H1s03, 100), 199 (100), 198 (82), 1 8 1 (65), 162 (69) and 99 (C5H702, 55). HO 2 5 4 14' .:. H 1 37 (25, 2'S, 5'S, 7'S, 9'S, 10'5, 12'R)-2-(2'-lodomethyl-2' , 1 0' , 1 2' - trimethyl- 1 ' ,6 ' ,8 ' ? trioxadispiro[ 4. 1 .5 .3Jpentadec-1 3' -en-9'-yl)butan-1-ol 255 To a solution of the trans iodide (4 mg) in dry tetrahydrofuran (1 ml) under nitrogen was added tetra-n-butylammonium fluoride (0.5 ml of a 1 molar solution in tetrahydrofuran, 0 .5 mmol) and the mixture stirred overnight. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography, u sing an hexane/ethyl acetate eluant (2: 1 ) , to afford the title compound 255 (?2.5 mg) as colourless prisms, m.p. 83- 84.50C (Found: M+, 464. 1457. C2oH3304I requires M+, 464. 1424); OH (270 MHz; CDCl3) 0 .80 (3H, d , 1 6.6 Hz, 1 0'-Me or 12' -Me), 0 .8 1 (3H, d, 1 6.6 Hz, 1 0'-Me or 1 2'-Me), 0.98 (3H, t, 1 7 . 1 Hz, CH2Cfu), 1 .66 (3H, s, 2 '-Me) , 1 .25 - 1 .79 (7H, m, CHEt, 2x CHMe, CH2CH3, 1 1?x-H and l l?q-H, 1 .89 ( 1H, dd, 14',4' 12.6, 14',3' 10 and 14',3' 10 Hz, 4'-H') , 2 . 14-2.23 (3H, m, 3 '-H, 3'-H' and 15 ' -H') , 2.41 ( 1H, ddd, hs' , l 5' 16. 8 , hs ', l4' 2.4 and h5', 13' 3.0 Hz, 15 '-H), 2.57 ( lH, ddd, 14',4' 12.6, 14', 3 ' 5 . 1 and 14',3' 5 . 1 Hz, 4'? H) , 2 .85 ( 1H, dd, 1HA,OH 10.5 and 1HB ,OH 1 .7 Hz, OH) , 3 .27 ( 1H, d, 1 1 0.3 Hz, CHAHBI), 3.32 (1H, d, 1 10.3 Hz, CHAfui), 3 .67-3.78 (2H, m, CH20), 3.83 ( lH, dd, 19', 10' 1 0.4 and 19',2 1 .6 Hz, 9 '-H), 5 .48 ( lH, ddd, h3', 14' 1 0. 1 , 113', 1 5' 3.0 and h3',15' 0.8 Hz, 1 3' -H) and 5.94 ( lH, ddd, h4',13 ' 1 0. 1 , h4', 1 5' 6.2 and h4', 1 5' 2.4 Hz, 14'-H); oc (67 .8 MHz; CDCl3) 12.3 (q, C-4), 15.9 (q, 1 0'-Me), 1 6. 1 (t, C-1 "), 17.5 (t, C-3), 17.6 (q, 12' -Me), 28.4 (q, 2'-Me), 3 1 . 8 , 39.5, 4 1 .7 (d, C-2, C- 10' and C- 12'), 33.8 (t, C- 15'), 35 .5 , 36.3, 37.0 (t, C-3' , C-4' and C- 1 1 ' ) , 64. 8 (t, C- 1 ) , 8 1 . 1 (d, C-9'), 82.8 (s, C-2'), 99.3 (s, C-7') , 1 07.5 (s, C-5 ') , 126.2 (d, C-13 ') and 128 .7 (d, C- 14') ; mlz 464 (M+, 22%), 446 (M-H20, 6), 39 1 (M-C4H80H, 29), 337 (M-I, 5) , 320 (M-OH-I, 37), 309 ( 100) , 308 (46), 29 1 (30), 224 (C14H2402 , 19) , 163 (26), 1 13 (C6H902, 1 4), 99 (CsH702, 8) and 97 (25). HO 2 5 5 14' = H Conversion of trans alcohol 255 to the Mosher Ester derivative105 257 was performed as follows: To a solution of the alcohol 255 (2 mg) and pyridine (0. 1 ml) in carbon tetrachloride ( 1 ml) under nitrogen was added a solution of (R)-( + )-a-methoxy-a? (trifluoromethyl)phenylacetyl chloride105 (5 mg) in carbon tetrachloride (0.5 ml) and the 1 38 reaction stirred overnight at room temperature. Water ( 1 ml) was added and the mixture extracted with ether (50 ml) which was washed with water (15 ml) and dried over potassium carbonate. Evaporation of the solvent under reduced pressure and purification of the residue by flash chromatography, using an hexane/ethyl acetate eluant (9: 1) , afforded the Mosher ester 257; DH (270 MHz; CDCl3) 0.77 (3H, d, J 6.4 Hz, 10'-Me or 12'-Me), 0.80 (3H, d, J 6.4 Hz, 10'-Me or 12'-Me), 0.95 (3H, t, J 7.5 Hz, CH2Cfu), 1 .56 (3H, s, 2'-Me), 1 . 17- 2.02 (10H, m, 2x CHMe, CHEt, 3'-H', 3'-H, 4'-H', CH2CH3, l lax-H and l l?q-H), 2. 1 1 ( 1H, dd, hs', IS' 16.7 and hs',l4' 6.4 Hz, 15'-H') , 2.37 ( lH, ddd, hs',IS' 16.7, h5',14' 2.6 and hs', l3' 2.6 Hz, 15'-H), 2.45-2.52 ( lH, m, 4'-H), 3 . 17 ( lH, d, J 10.3 Hz, CfuHBI), 3 .25 ( 1H, d, J 10.3 Hz, CHA CJiBI), 3.57 (3H, q, J 1 .3 Hz, OMe), 3 .64 ( lH, dd, 19'ax,IO'ax 10.7 and 19'ax,2 1 .2 Hz, 9ax-H), 4 . 10 ( 1H, dd, lHA,HB 10.8 and 1HA,2 7 .7 Hz, CfuHBO), 4.55 (1H, dd, lHB,HA 10.8 and 1HB,2 5 .5 Hz, CHAJiBO), 5.43 ( 1H, dd, h3', 14' 10.1 and h3', 15' 2.6 Hz, 13'-H) and 5.90 ( lH, ddd, h4', 1 3' 10. 1 , h4', 1 5' 6.4 Hz and 114', 15' 2.6 Hz, 14'-H). 1 3-Bromo-2.2-dimethyl-1.6.8-trioxadispiro[ 4. 1 .5 .3lpentadec-14-ene 261 and 15-bromo-2.2-dimethyl-1.6.8-trioxadispiro[ 4. 1 .5 .3lpentadec- 13-ene 262 Potassium carbonate (83 mg, 0.6 mmol) and N-bromosuccinimide (35 mg, 0.2 mmol) were suspended in a solution of the cis-2,2-dimethyl- 1 ,6,8-trioxadispiro[ 4. 1 .5.3] pentadec-13-ene 192 (36 mg, 0. 15 mmol) in carbon tetrachloride (3 ml) under nitrogen. The mixture was heated under reflux for 5.5 h. then poured into ether (30 ml) which was washed with water (10 ml) and brine (10 ml), and dried over potassium carbonate. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant (9: 1) , to give the less polar cis-13-bromo-2,2-dimethyl-1.6.8- trioxadispiro[ 4. 1 .5 .3Jpentadec- 14-ene 261 (20 mg, 42%) as colourless prisms m.p. 62- 630C (Found: M+, 3 1 8.0655 and 316.0673. C14H2103Br requires M+, 3 1 8 .0654 and 3 16.0674); DH (270 MHz; CDCl3) 1 .22 3H, s, Me), 1 .48 (3H, s, Me), 1 .37-2.26 ( 1 0H, m, 5x CH2), 3.64 ( lH, m, 9eq-H), 4. 1 8 ( lH, ddd, 19ax,9eq 1 1 .7, 19ax,8ax 1 1 .7 and 19ax,8eq 3.8 Hz, 9ax-H), 4.27 ( lH, d, J 5.9 Hz, CHBr), 5 .68 ( lH, d, J 9.9 Hz, 15-H) and 6 . 10 ( 1H, dd, h4,15 9.9 and h4,13 5.9 Hz, 14-H); mlz 3 18 (M+, 30%), 3 16 (M+, 30), 237 (M-Br, 100), 218 (C9H130Br, 35) and 216 (C9H130Br, 34), and cis- 1 5-bromo-2.2-dimethyl- 1.6.8-trioxadispiro[ 4. 1 .5.3lpentadec-13-ene 262 (1 1 mg, 23%) as a colourless oil (Found: M+, 3 1 8.0655 and 316.0673. C14H21 03Br requires M+, 3 1 8.0654 and 3 16.0674); DH (270 MHz; CDCl3) 1 . 17 (3H, s, Me), 1 .38 (3H, s, Me), 1 .47-2. 15 (8H, m, 3-H, 4-H and 4x CH2), 3.65 (lH, m, 9eq-H), 4.05 (lH, ddd, 19ax,9eq 1 1 .4, 19ax,8ax 1 1 .4 and 19ax,8eq 3.2 Hz, 9ax-H), 4.29 ( lH, d, J 5.9 Hz, CHBr), 5 .8 1 ( lH, d, J 9.9 Hz, 13-H) and 6. 13 ( lH, 139 dd, h4, 13 9.9 and h4, 15 5.9 Hz, 14-H); mlz 3 18 (M+, 32%), 3 1 6 (M+, 32), 237 (M-Br, 1 00), 204 (C3HuOBr, 32) and 202 (C3HuOBr, 3 1). 1 5-bromo-2.2-dimethyl-1 .6.8-trioxadispirof4. 1 .5 .3]pentadec- 13-ene 265 Potassium carbonate (47 mg, 0.35 mmol) and N-bromosuccinimide ( 15 mg, 0. 1 mmol) were suspended in a solution of trans-2,2-dimethyl-1 ,6,8-trioxadispiro[4. 1 .5 .3] pentadec-13-ene 152 (20 mg, 0.085 mmol) in carbon tetrachloride (2 ml) under nitrogen and the mixture heated under gentle reflux for 8 h. The solution was diluted with ether (30 ml) which was washed with water ( 10 ml) and brine (10 ml), and dried over potassium carbonate. The solvent was removed under reduced pressure and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant (9: 1 ) , to afford trans-15-bromo- 2.2-dimethyl- 1.6.8-trioxadispiro[5 . 1 .5 .3 lpentadec- 1 3-ene 265 (10 mg, 37% ) as a colourless oil (Found: M+, 3 1 8.0662 and 3 16.0663. C14H21 03Br requires M+, 3 18 .0654 and 3 16.0674); OH (270 MHz; CDCl3) 1 .26 (3H, s, Me), 1 .43 (3H, s, Me), 1 .45-2.42 (9H, m, 3-H, 3-H' , 4-H' and 3x CH2), 2.54 ( 1H, ddd, 14,4 13 .4, 14,3 7.8 and 14,3 3 . 8 Hz, 4- H), 3.74 ( lH, m, 9eq-H), 4.02 ( 1H, ddd, 19,9 1 1 .0, 19,8 1 1 .0 and 19,8 3 .8 Hz, 9ax-H), 4.55 ( 1H, dd, h5,14 3.5 and h5,13 1 .7 Hz, CHBr), 5.62 ( lH, dd, h3 ,14 10. 1 and 113 , 15 1 .7 Hz, 1 3-H) and 6.03 ( lH, dd, h4,13 10. 1 and h4,1 5 3.5 Hz, 14-H) ; mlz 3 1 8 (M+, 38%), 3 16 (M+, 38), 237 (M-Br, 100), 204 (C3HuOBr, 69) and 202 (C3HuOBr, 74). 2.2-flimethyl- 15-hydroxy-1 .6.8-trioxadispirof4. 1 .5.3lpentadec- 13-ene 159 A solution of 1 8-crown-6 ( 10 mg, 0.04 mmol) and trans-15-bromo-2,2-dimethyl- 1 , 6 , 8 -trioxadispiro [5 . 1 . 5 .3 ]pentadec- 13 -ene 265 ( 12 mg, 0.038 mmol) in dry dimethylsulphoxide (1 ml) was stirred with potassium superoxide ( 15 mg, 0.2 mmol) for 8 h. under nitrogen. Water ( 1 ml) was added and the mixture extracted with ether (30 ml) which was washed with water (2x 10 ml) and brine ( 10 ml), and dried over potassium carbonate. The solvent was evaporated at reduced pressure and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 :2), to give trans-2,2-dimethyl- 15- hydroxy- 1 ,6,8-trioxadispiro[5 . 1 .5.3]pentadec- 13-ene63,64 159 as a colourless oil (7 mg, 65%) (Found: M+, 254.9525. C14H2204 requires M+, 254.95 1 8); OH (270 MHz; CDCl3) 1 .25 (3H, s, Me), 1 .48 (3H, s, Me), 1 .45-2.23 (9H, m, 3-H, 3-H' , 4-H' and 3x CH2), 2.41 ( 1H, ddd, 14,4 13.0, 14,3 7.4 and 14,3 3.1 Hz, 4-H), 3 .70 ( lH, m, 9eq-H), 4.01 ( 1H, 140 m, 9ax-H), 4. 1 5 ( 1H, ddd, h5,0H 4.9, h5, 14 2.4 and h5, 1 3 2.4 Hz, CHOH), 5 .62 (lH, dd, h3,14 10. 1 and h3, 15 2.4 Hz, 13-H) and 5 .88 ( 1H, dd, h4, 13 1 0. 1 and h4,15 2.4 Hz, 14-H); mlz 254 (M+, 5%), 236 (M-H20, 10) and 140 (C9H1402, 100). 2,2-Dimethyl- 13-hydroxy-1,6,8-trioxadispiro[ 4. 1 .5.3Jpentadec- 14-ene 268 and 2.2-dimethyl- 15-hydroxy-1 ,6,8-trioxadispiro[ 4. 1 .5.3Jpentadec- 13-ene 156 A solution of 1 8-crown-6 (16 mg, 0.06 mmol) and cis- 13-bromo-2,2-dimethyl- 1 ,6 , 8- trioxadispiro[4. 1 .5 . 3]pentadec- 1 4-ene 261 ( 1 8 mg, 0.056 mmol) in dry dimethylsulphoxide ( 1 ml) was stirred with potassium superoxide (15 mg, 0.2 mmol) for 8 h. under nitrogen. Water ( 1 ml) was added and the mixture extracted with ether (30 ml) which was washed with water (2x 10 ml) and brine (10 ml), and dried over potassium carbonate. The solvent was evaporated at reduced pressure and the residue purified by flash chromatography, using an hexane/ethyl acetate eluant ( 1 :2), to give an inseparable mixture of cis-2,2-dimethyl- 15-hydroxy- 1 ,6,8-trioxadispiro[4. 1 .5 .3]pentadec-1 3-ene63,64 156 and cis-2.2-dimethyl- 13-hydroxy-1.6,8-trioxadispiro[ 4. 1 .5 .3Jpentadec- 14-ene 268 (*) in the ratio of 1 .5 : 1 and in the form of a colourless oil ( 1 1 mg, 65%) (Found: M+, 254.9525. C14H2204 requires M+, 254.95 18); OH (270 MHz; CDCl3) 1 . 17 (3H, s, 2-Me), 1 .23 (3H, s, 2-Me*), 1 .40 (3H, s, 2-Me), 1 .48 (3H, s, 2-Me*), 1 .46-2. 18 ( 19H, m, 3-H, 3-H' , 3- H*, 3-H'*, 4-H', 4-H*, 4-H'*, 3x CH2 and 3x CH2*), 2.27-2.40 ( lH, m, 4-H), 3 .57- 3 .66 (4H, m, 2x CHOH and 2x 9eq-H), 4.05 ( 1H, ddd, 19ax,9eq 1 1 .5, 19ax,8ax 1 1 .5 and 19ax,8eq 3.2 Hz, 9ax-H), 4 .19 ( 1H, ddd, 19ax,9eq 1 1 .5, 19ax,8ax 1 1 .5 and l9ax,8eq 3.2 Hz, 9ax-H*) , 5.78 ( lH, d, J 10. 1 Hz, 15-H*), 5 .88 ( lH, d, J 10. 1 Hz, 1 3-H), 6.08 ( lH, dd, h4,15 10. 1 and h4,13 5.8 Hz, 14-H*) and 6. 1 1 (lH, dd, h4,13 10. 1 and h4,15 5 .5 Hz, 14- H); mlz 254 (M+, 4%), 236 (M-H20, 8), 154 (C9H1402, 98) and 140 (C9H1402, 100). Repetition of the above procedure, using the corresponding cis- 15-bromo-2,2-dimethyl- 1 ,6,8-trioxadispiro[5. 1 .5.3]pentadec- 13-ene 262 afforded the same alcohols 156 and 268 in the ratio 1 : 1 .5 . 1 3-Acetoxy-2,2-dimethyl- 1 ,6,8-trioxadispiro[ 4. 1 .5.3Jpentadec-14-ene 269 and 1 5-acetoxy-2.2-dimethyl-1 ,6,8-trioxadispiro[ 4. 1 .5.3]pentadec-13-ene 270 A solution of the mixture of the cis -2 , 2-dimethyl- 1 5 - hydroxy - 1 , 6 , 8 - trioxadispiro[4. 1 .5 .3]pentadec- 13-ene 156 and the cis-2,2-dimethyl- 13-hydroxy- 1 ,6,8- trioxadispiro[ 4. 1 .5 .3]pentadec-14-ene 268, triethylamine (5 drops), acetic anhydride (2 drops) and a catalytic quantity of dimethylaminopyridine in dichloromethane (2 ml) was 141 stirred at room temperature for 2 h. The solution was diluted with ether (20 ml) which was washed with water (5 ml) and dried over potassium carbonate. the solvent was removed under reduced pressure to afford a separable mixture of the acetates 269 and 270, which were purified by flash chromatography, using an hexane/ethyl acetate eluant (4: 1) , to afford the less polar cis- 13-acetoxy-2,2-dimethyl-1 .6.8-trioxadispiro[ 4. 1 .5.3lpentadec- 14-ene 269 as a colourless oil (Found: M+, 296. 1588. C16H2405 requires M+, 296. 1624); OH (270 MHz; CDCl3 1 .23 (3H, s, 2-Me), 1 .48 (3H, s, 2-Me), 1 .24-2. 15 ( 10H, m, 5x CH2), 2.05 3H, s, OAc), 3.62 ( lH, m, 9eq-H), 4. 1 8 ( lH, m, 9ax-H), 4. 89 ( lH, d, J 5.7 Hz, CHOAc), 5 .87 (1H, d, J 10. 1 Hz, 15-H) and 5.99 ( lH, dd, h4, 15 10. 1 Hz and h4,13 5.7 Hz); mlz 296 (M+, 3%), 254 (M-AcOH, 7), 196 (CnH1603, 38) and 154 (C9H1402, 100), and cis- 15-acetoxy-2,2-dimethyl- 1 ,6,8-trioxadispiro[ 4. 1 .5.3]pentadec-13-ene64 270 as a colourless oil (Found: M+, 296. 1613. C16H2405 requires M+, 296. 1624); OH (270 MHz; CDCI3) 1 . 1 8 (3H, s, 2-Me), 1 .40 (3H, s , 2-Me), 1 .48-2.17 ( 10H, m, 5x CH2), 2.07 (3H, s , OAc), 3.65 ( 1H, m, 9eq-H), 4.04 (lH, ddd, 19ax,9eq 1 1 .5, 19ax,8ax 1 1 .5 and 19ax.8eq 3. 1 Hz, 9ax-H), 4.86 ( 1H, d, J 5.5 Hz, CHOAc), 5.97 (1H, d, J 10. 1 Hz, 13-H) and 6.05 ( lH, dd, h4, 13 1 0. 1 and h4,15 5.5 Hz, 14-H); mlz 1.96 (M+, 3%) , 254 (M-Ac, 23), 236 (M-AcOH, 1 5) , 1 82 (CwH1403, 10) and 140 (CgH1204, 100). 142 References 1 R. L. Hanard, P. H. Harter, C. J. Corum and K. L. Jones, Antibiotics and Chemotherapy, 1951 , 1, 594. 2 J. Berger, A. I. Rachlin, W. E. Scott, L. H. Sternbach and M. W. Goldberg, J. Am. Chem. Soc., 195 1 , 73, 5295. 3 Westley J. W., Polyether Antibiotics: Carboxylic Ionophores (Vol I: Biology, Vol II: Chemistry), Marcel Dekker: New York, 1982. 4 B. C. Pressman; Annu. Rev. Biochem, 1976, 45, 501 . 5 J. W. Westley, in Antibiotic, Chemotherapeutic and Antibacterial Agents for Disease Control, Ed. J. M. 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I am grateful to Prof. Kocienski and Dr. Whitby for making the data available. 1 1 1 This relative deshielding effect has been observed by Kocienski et al in the course of their work on this ring system. See reference 64. 150 1 12 Both syn and anti SN2' displacements can occur, depending on the nature of the nucleophile and the leaving group. See Stork and Kreft, J. Am. Chem. Soc., 1977, 99, 3850; T. Oritani and K. H. Overton, J. Chem. Soc. Chem. Comm., 1978, 454; C. B. Chapleo, M. A. W. Finch, S. M. Roberts, G. T. Woolley, R. F. Newton and D. W. Selby, J. Chem. Soc. Perkin Trans. /, 1980, 1 847. 1 13 D. D. Perrin, D. R. Perrin and W. L. F. Amarego, Purification of Laboratory Chemicals, Pergamon Press Ltd, Oxford, 1966 1 14 J. J. Partridge, S . Shiney, N. K. Chadha, E. G. Baggiolini, J. F. Blount and M. R. Uskokovic, J. Am. Chem. Soc., 198 1 , 103, 1253. 151