Synthesis and Applications of Alpha-Aminophosphonothioic Acids

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With the support of the Organic Synthesis Program, Professor Charles M. Thompson, of the Department of Chemistry at the University of Montana, studies the synthesis and applications of alpha-aminophosphonothioic acids (APTA's). APTA's are a new class of molecules in which the carboxylic acid group of an alpha-amino acid has been replaced by a phosphonothioic acid moiety. The APTA's are chiral at phosphorus and additionally can display tautomerization between the P(O)SH and P(S)OH forms. Professor Thompson is developing new synthetic routes for the preparation of APTA's in both racemic and nonracemic form, relying on the addition of thiophosphites to imines, aza-Claisen rearrangement, and alkylation of 1,3-N,C-dianions derived from phosphonates. In addition, he exploits the tautomeric equilibrium to generate a site for disulfide bond formation, offering the possibility of peptide intra-strand and inter-chain linkage and the generation of novel beta-sheet structures in synthetic peptides incorporating APTA's. The ability of APTA's to serve as asymmetric transition state analog inhibitors and to serve as central elements in molecular systems designed to display marked conformational changes upon metal ion complexation are also under exploration. Replacement of the amino acids in biological proteins with `unnatural` amino acids or functionally related derivatives offers the possibility of modifying and controlling the structure and reactivity of proteins. With the support of the Organic Synthesis Program, Professor Charles M. Thompson, of the Department of Chemistry at the University of Montana, carries out the synthesis and study of unusual amino acid analogs known as alpha-aminophosphonothioic acids (APTA's), in which a P(O)SH group replaces the C(O)OH group found in amino acids. The incorporation of APTA's in model protein structures allows the use of the pendant sulfur atoms to effect the linking of protein chains, affording access to novel protein architectures. Professor Thompson also explores the possibility that APTA-containing proteins may function as inhibitors for various enzymes, and additionally uses APTA's as central elements in the design of molecules designed to undergo extreme changes in molecular form upon interaction with metal ions.