ASYMMETRIC SYNTHESES MEDIATED BY CHIRAL ACETAL TEMPLATES

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Recent studies in the PI's laboratories have led to the discovery of the Lewis acid-catalyzed coupling of an acetal derived from a chiral diol, e.g., S,S- or R,R-2,4-pentanediol, with a number of nucleophiles, e.g., trimethylsilylcyanide. These reactions proceed highly diastereoselectively to give, after removal of the chiral auxiliary, chiral secondary OH compounds, e.g., cyanohydrins, Alpha-hydroxy esters, etc., predictably in either the R or S form and in high optical purity. It is proposed to examine the scope of this reaction by studying a large variety of nucleophiles as well as acetals of a number of chiral diol variants with the hope of finding the "ideal" diol, i.e., one that is highly effective and inexpensively made in high optical purity. The rest of the proposal is mainly concerned with the synthetic exploitation of the new methodology which shows promise of providing facile, new and improved ways of producing certain important chiral structures as follows: (a) difficultly accessible, biologically important Alpha-amino acids (e.g., components of semisynthetic penicillins); (b) (S)-Alpha-cyano-3-phenoxybenzyl alcohol (component of important pyrethroid insecticides); (c) GABOB types (anticonvulsants); (d) (+)-negamycin (antibiotic vs. gram-negative bacteria); (e) the chiral erythro-1,3-diol system, as illustrated by plans for synthesizing (i) nonactic acid, the key synthon for the ionophore nonactin, (ii) compactin (hypocholesteremic substance) and (iii) the two chiral fragments for producing the antibiotic amphotericin B; (f) a generalized method or forming vicinal chiral centers carrying alternating OH and Me groups as found in propionate-derived natural products, and illustrated by plans for the synthesis of (i) intermediates for producing erythronolide A, rifamycin S, and the antileukemic agent maytansine, (ii) digitoxose (component of cardiac glycosides), (iii) olivose (component of chlorothricin) and (iv) naproxen (anti-inflammatory analgesic); (g) the vicinal secondary-tertiary hydroxy array found in antibiotics like erythromycin; (h) ephedrine and related sympathomimetics; (i) corticoids; (j) fused-ring Alpha-methylenebutyrolactones (tumor-inhibitors); (k) vitamin D3 metabolites including calcitriol (active against osteodystrophy).