EFFICIENT SYNTHESIS OF ENANTIOPURE ALPHA AMINO ACIDS

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DESCRIPTION: (Principal Investigator's) Alpha-Amino acids are the basic building blocks of peptides and proteins, which are responsible for the structure and function of most living things. They are extensive employed as chiral templates and subunits in the asymmetric construction of many biologically and pharmacologically active compounds, and are widely used in the pharmaceutical, agrochemical and food industries. In addition non- proteinogenic D- and L-alpha-amino acids are increasingly utilized to study enzyme mechanism and to modify and enhance protein activity. The principal objective of the proposed work is to develop a practical and efficient asymmetric Strecker synthesis of alpha-amino acids, exploiting the diastereoselective addition of "Et2AlCN/ROH" to chiral non-racemic sulfinimines (ArS(O)N=CRR'). Important advantages conferred by the N- sulfinyl group include (i) powerful stereodirecting effects; (ii) activation of the C-N double bond toward addition; and (iii) auxiliary removal and hydrolysis of the N-sulfinyl alpha-amino nitrile (ARs(o)- NHC(CN)RR') to alpha-amino acids under exceedingly mild conditions, such that racemization does not occur. A second major objective is the elucidation of the factors responsible for the molecular recognition, which in turn should permit the rational design of improved methodology. Complementary studies will focus on the chemistry of the N-sulfinyl alpha- amino nitrile products (ArS(O)-NHRR'CN. We will examine the conversion of these species to: (i) N-alkyl alpha-amino acids constituents of antibiotics such as vancomycin; (ii) alpha-alkyl alpha-amino acids, modifiers of protein activity; and (iii) piperidines and pyrrolidines, classes of alkaloids possessing a range of significant biological and medicinal properties. Concurrently we will employ this chemistry in syntheses of biologically relevant amino-acid that are difficult or impossible to prepare via other methodologies. Targets include: (i) the amino acids in the clinically important antibiotic vancomycin (i.e., arylglycines, beta-hydroxy alpha- amino acids, and bis(alpha-amino acids)); (ii) vinyl glycines, which inhibit amino acid decarboxylase enzymes; (iii) beta-amino, beta-hydroxy and beta-fluoro alpha-amino acids, constituents of a number of antibiotics and antitumor agents, respectively; (iv) cyclic amino acids such as D- proline and D-homoproline; and (v) oxo and halo alpha-amino acids, important non-racemic building blocks for the synthesis of more complex derivatives.