Chiral nonracemic amines containing nitrogen attached to stereogenic carbon are ubiquitous in nature. Examples include protein and non-protein alpha- and beta-amino acids as well as allylic and homoallyic amines. These amines are also widely used as chiral synthons for the enantioselective construction of bioactive materials including aziridines, beta-lactams, peptide antibiotics, amino sugars, HIV-1 protease inhibitors and alkaloids. Of particular significance is the absolute stereochemistry, upon which biological activity often critically depends. The principal objective of the proposed work is to employ chiral nonracemic sulfinimines [ArS(O)N=CRR'] in new methodology for the enantioselective synthesis of biologically relevant primary amines (RR'R""""""""C-NH2) and their derivatives. To this end, we will explore the diastereoselective addition of organometallic reagents and enolates to sulfinimines (chiral ammonia-imine synthons). Important advantages conferred by the N-sulfinyl group include, (i) powerful stereodirecting effects, (ii) activation of the C-N double bond toward addition, (iii) configurational stability of the sulfinamide product [ArS(O)-NHCRR'R""""""""] and (iv) removal under mild conditions without racemization. A second major objective is the elucidation of the factors responsible for the molecular recognition. New and improved methods for the synthesis of enantiopure sulfinimines will also be devised. Complementary studies will focus on the chemistry of the product sulfinamides including N-sulfinyl alpha- and beta-amino acids, aziridines, and allylic and homoallylic amines. Here we will survey the compatibility of the N-sulfinyl auxiliary with various functional group transformations and assess its usefulness as a stereodirecting group. Concurrently we will exploit this chemistry in syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include (i) vinyl glycines, which inhibit amino acid decarboxylase enzymes, (ii) alpha-hydroxy-beta-amino acids, constituents of antifungal and antitumor agents, intermediates in the synthesis of beta-lactams and the aminosaccharide fragments of the anticancer drugs daunorubicin and adrimycin, and (iii) syn-beta-hydroxy-alpha-amino acids, components of numerous peptide antibiotics. Improved enantioselective approaches to these bioactive amines are expected to result.
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