CHIRAL SYNTHON: 1,2-OXAPHOSPHETANE 2-OXIDES

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DESCRIPTION: (Principal Investigator's Abstract) The diverse biological activities of alpha-amino-alpha-alkylphosphonic acids and their analogues include transition state analogue inhibitors of proteases, haptens for antibody production, pesticides, herbicides, fungicides and growth control regulators. These structural phosphorus based analogues of the natural proteinogenic amino acids will continue to play an integral role in the design of drugs, in pariticular the design of inhibitors of important protease enzymes. Despite the elegant methods to synthesize enantiomerically pure compounds, there exists a need for methodology that will allow the rapid synthesis of a variety of side chain analogues with a known, predetermined absolute configuration. The objective of this proposed research is to develop methodology to introduce a variety of side chains into a "chiral synthon" precursor; 1 ,2-oxaphosphetane 2-oxide; and evaluate the regioselectivity of nucleophile additions. We propose to develop and exploite this synthon by leveraging the available methods to synthesize enantiomerically pure (D)- and (L)-phosphonoserine. Synthesis of a series of enantiopure phosphonoserine monoesters, evaluation of ring closure conditions, stability determination of the series of 1 ,2-oxaphosphetane 2-oxides using variable temperature P31 NMR, and evaluation of the regioselectivity of ring opening by various nucleophiles will be undertaken. The ultimate long-range objective of this research is to synthesize a library of alpha-amino-alpha alkylphosphonic acids for incorporation into a variety of protease substrates including CaaX peptides for testing as inhibitors of recombinant Ras- and a-Factor CaaX converting enzymes.