Research Project
6440464
The proposal seeks to develop an efficient and practical method for the asymmetric synthesis of alpha-aminophosphonic acids. Several methods have been developed, but none has found general, widespread applicability. Alpha-Aminophosphonic acids are an important molecular structure because they can serve as alpha- amino acid analogues in enzyme inhibitors. Inhibition of enzyme activity can be used for therapeutic purposes in many disease states. The current proposal uses established asymmetric synthetic methods combind with the facile, stereoselective Curtius rearrangement to provide quick and easy access to chiral alpha- alkyl-alpha-aminophosphonic acids. The alpha-alkyl-alpha- aminophosphonic acids are then ready for incorporation into peptide structures which would mimic natural enzyme substrates. The application of this methodology to the asymmetric synthesis of diphenyl alpha-aminophosphonates, known serine protease inhibitors, will further demonstrate the utility of this method. The stereochemically pure diphenyl alpha-aminophosphonates will be tested for enzyme inhibition to analyze the importance of the stereochemistry at the alpha-position in these alpha-amino acid analogues.
