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Stereocontrol in the Synthesis of Nonactin A STEREOCONTROL IN THE SYNTHESIS OF NONACTIN A thesis presented by Hiten Sheth in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of the University of London Department of Chemistry, Imperial College, London SW7 2AY October 1982 ACKNOWLEDGEMENTS I wish to thank Dr A.G.M. Barrett for his advice, guidance and friendship during this project. I am grateful to Ashley Fenwick, Barrett Kalindjian and Mark Russell for friendship and help. A special thanks to Mrs Denise Elliott for typing this thesis and to Tara, Gunvant, Bharat and Sonal for encouragement and support. Thanks are also due to the SERC for a studentship, and to W.R. Grace and Co., Research Division, Columbia, Maryland for support. A special thanks to Mrs. Maria Serrano-Widdowson for helping out at times of crises. ABSTRACT The racemic and chiral syntheses, of nonactic acid, in the literature are reviewed. Our approaches to the synthesis of racemic nonactic acid utilized activated derivatives of pentane-1, 2R(S), 4S(R) triol (101); 2R(S), 4S(R) dihydroxypentanoic acid (133) and 2R(S), 4S(R) dihydroxypentanal (119). The key intermediate, 3R(S) acetoxy-5S(R)-methyltetra- hydrofuran-2-one (99), was prepared from the double elimination of 2,3,5-tri-0-acetyl-D-ribonolactone to give the desired 3-acetoxy- 5-methylene-2,5-dihydrofuran-2-one. Steric-approach controlled hydrogenation yielded the tetrahydrofuran-2-one (99). The lactol (119), derived from the di-isobutylaluminiumhydride reduction of the tetrahydrofuran-2-one (99) was condensed with the ylide, ethoxycarbonylmethylenetriphenylphosphorane, the resultant enoate being hydrogenated and acidified to yield the lactone, 5S(R) - [2S(R) hydroxypropyl ] tetrahydrofuran-2-one (120). Protection of the hydroxyl group as the t-butyldimethylsilyl ether and condensation with t-butyl 2-lithiopropanoate, on acidification gave the E- enoate, 2S(R)-[2S(R)-(t-butyldimethylsilyloxy) propyl]-5-[l-(t- butyloxycarbonyl) ethylidene] tetrahydrofuran (122). Steric-approach controlled hydrogenation gave the racemic nonactic acid derivative, t-butyl 8-0-t-butyl-dimethylsilylnonactate (123). i. As proof of structure, compound (123) was converted to the known diol, 2S(R)-[2S(R) hydroxypropijl]-5R(S)-[2-hydroxy-lS(R)- (methyl)ethyl]tetrahydrofuran, which was identical with authentic material obtained from the reduction of nonactin. Other routes which were explored, but proved to be unsuccessful, included the reduction of the compound (99) to the triol (101) and after activation, gave the derivatives 2S(R), 4R(S)- bis(t-butyldimethylsilyloxy)-l-iodopentane (105) and 2S(R) - [2R(S )-(t-butyldimethylsilyloxy)propyl] oxirane (112(a)). Neither (105) nor (112(a)) reacted with the dianions of methyl 2-methyl- 3-oxo-butanoate (106(a)), and methyl 2-methyl-3-(methylamino)but- 2-enoate (107(a)). Condensation of the dianion of t-butyl 2-methyl-3-oxo- butanoate (108(a)) with the lactone (99) and elaboration of the adduct gave the desired compound, 2-[3-(t-butyloxycarbonyl)-2- oxobutyl]-3R(S) acetoxy-5S(R)-methyltetrahydrofuran (117(a). Ring fragmentation, via its dianion, of the tetrahydrofuran-4-butanoic acid (117(a)) failed. ii. CONTENTS ABSTRACT i - ii INTRODUCTION 1-2 SYNTHETIC APPROACHES TO THE NACTINS 3-16 CHIRAL SYNTHESES OF (+) AND (-) METHYL NONACTATE 17 - 23 CONSTRUCTION OF NONACTIN FROM NONACTIC ACID 24 - 27 RESULTS AND DISCUSSION 28 - 75 EXPERIMENTAL 76 - 143 REFERENCES 144 - 148 APPENDIX "A Concise Synthesis of (±)-t-Butyl 8-O-t-Butyldimethyl- silylnonactate" A.G.M. Barrett and Hiten G. Sheth J.C.S. Chem. Commun., 1982, 170. INTRODUCTION The polyether antibiotics 1 are a group of compounds possessing the ability to form lipid soluble complexes that mediate cation transport across lipid barriers. This characteristic ion-bearing property led to their being named ionophores. The macrotetrolides (1) are all constructed from four tetrahydrofuranyl hydroxyacids linked together as lactones. The key feature of the stereochemistry in this particular class of ionophores is that two of the hydroxyacids are of opposite configuration to the alternating pairs of acids. Thus nonactin is a meso compound comprising of alternating enantiomers of nonactic acid. Nonactin and its homologues, the macrotetrolides, have been isolated^,20 fr0m several Strentomvces cultures. These are neutral ionophores which mediate an active uptake of cations including potassium ions into mitochondria. The passive diffusion of excess potassium ions across membranes, is probably the primary effect of the many different biological activities reported for the polyethers. The actins afford one to one complexes with many alkali/ alkaline earth metal ions. Specifically, nonactin + + + + + exhibits a selectivity sequence of NH4 >K ^Rb >Cs >Na > Ba2 + 21. 1. R1 = R2=R3=R4= Me Nonactin R1 = R2 = R3 = R4 = Me Monactin r2 = Et, RL = R3 = R4 = Me Dinactin r2 = R4 = Et, Rx - R3 = Me Trinactin r2 = R3 = R4 = Et, Ri = Me Tetranactin Rx = R2 = R3 = R4 = Et 2. Synthetic Approaches to the Nactins*^>^ Degradation^ of nonactin (and tetranactin) by base hydrolysis yielded racemic nonactic acid (and tetranactic acid respectively). Thus routes to the nactins require the synthesis of (it) or (+) and (-) nonactic acid (or tetranactic acid) followed by oligomerization in the correct sequence and lactonization to the macrolide. The synthetic precursor to nonactin, the linear tetramer of subunits has been assembled both with^*^ and without ^ controlling the alternating chirality required. A number of syntheses (including the synthesis of each separate enantiomer^>^>^»®) of the nonactic acid subunit have been reported.^,18# None, with the exception of Bartletts'^ is to any great degree stereoselective at each and every stage. 2-epi OH OH 8-epi 3. Controlling the configurations at C-2 and C-8 are the real synthetic problems, since the cis stereochemistry of the tetrahydrofuran ring (C-3 and C-6) could be established by hydrogenation of a suitably functionalized 2,5 disubstituted furan. In the first synthesis of nonactic acid to be reported*0, (Scheme 1), no control of the two extracyclic'chiral centres was attempted. Beck and Henseleit*** used methyl furan-2-acetate (6) which after monomethylation, was condensed with 3-methyl-3-buten-2- one under Lewis acid conditions to give a 2,5 disubstituted furan (7). Catalytic hydrogenation of (7) over rhodium on alumina yielded the cis substituted 2,5 tetrahydrofuran ring as a mixture of 4 stereoisomers (9). Subsequent conversion of the acetyl group into a hydroxyl group afforded methyl nonactate (2) accompanied by the three diastereoisomers (3), (4) and (5). Several of the other routes intersect at various intermediates, and take advantage of two observations for controlling stereochemistry at the C-2 and C-8 centres. Firstly, base-catalyzed epimerization with a cis tetrahydrofuran ring, favours the threo relationship between C-2 and C-3 positions. (This equilibration proceeds without ring opening since the cis stereochemistry of the tetrahydrofuran ring is preserved.) Gerlach** reported that the equilibration of the 8-keto derivatives (14) and (15) favoured the threo isomer by a ratio of 4:1. Schmidt et al.2>5 and white et al.*^ were able to enrich methyl nonactate (2) using sodium methoxide in methanol over the C-2 epiraer (3) by only 3:2. Secondly, catalytic hydrogenation or L-selectride reduction*1» 4. Scheme 1 Beck and Henseleit 197110 0 •o OMe OMe (0 60% •v Me * OMe iv 73% UAC OH 0 CO,Me m OMe H °H i H °H (0+(j0+00+(s) (i) NaH/Mel; o (ii) 3-methyl-3-buten-2-one, BF3.0Et2/60 C; (iii) H2/Rh-Al203, MeOH; (iv) CF3CO3H,CH2CI2,A ; (v) OH " ; (vi) H + ; (vii) CH2N2 5. of the 8-keto-derivative (14) gave 8-epi-methyl nonactate (4) as the predominant diastereomer (9:1). The natural isomer was then obtained by Walden inversion of configuration. White*2 suggested that the stereoselectivity observed resulted from the coordination of boron with both the ketone carboxyl and ether oxygens as shown; followed by hydride attack from the least hindered side in the complex. OMe 8-epi product The strategy adopted by Gerlach and Wetter** suffered from a non stereoselective introduction of the two chiral centres of the side chains. They condensed acetonylfuran (10) with the chloronitrone (11) to yield a furan nitrone which on acid hydrolysis gave the aldehyde (12), in 79% yield. Oxidation and esterification gave the ketoester (13). Catalytic hydrogenation over rhodium on alumina gave the 8-keto-tetrahydrofurans (14) and (15). Using base catalyzed epimerization they enriched the threo composition of their product to 4:1. Subsequent borohydride reduction afforded methyl nonactate (2) and the 8-epi compound (4) (1:1), without any selectivity at C-8. 6. Scheme 2 Gerlach and Wetter*! OMe 1:1 (i) AgBF4, CH2C12, -20°C; (ii) HC1/H20; (ill) Cr03; (iv) CH2N2; (v) Rh/Al203, MeOH; (vi) NaOMe/MeOH; (vii) NaBH4/H20/Me0H 7. Schmidt et al.2>5,6 synthesized methyl nonactate as shown in Scheme 3. By combining both the selectivity of the ketone hydrogenation and the ability to epimerize the C-2 centre, they then developed a method for enriching in methyl nonactate (2), a mixture of equal amounts of all four C-2 and C-8 diastereoisomers. Propylene oxide was condensed with 2-lithiofuran (16) to give the alcohol (17). Acetylation of (17) followed by a Vilsmeier reaction afforded the aldehyde (19). This was converted to the vinylfuran (20) by a Wittig reaction. Hydroformylation employing a rhodium catalyst gave the aldehyde (21). Subsequent oxidation with the silver oxide,
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