New Methods for the Synthesis of Unusual Amino Acids

Cook, Gregory

Abstract

(Principal Investigator's) The primary goal of this project is the development of stereoselective methods for the synthesis of unusual amino acids. We will examine the use of transition metal- mediated equilibration and kinetic resolution processes to obtain chiral 1,2-aminoalcohols and 1,2-diamines from alpha-amino acids in diastereomerically pure form. Vinylaminoalcohols are valuable precursors to gamma-amino-beta-hydroxy amino acids such as statine, found in the naturally occurring aspartic protease inhibitor, pepstatin. Peptides containing statine and analogs of statine, have shown promise in the treatment of hypertension, HIV, and cancer. The first part of the proposal describes a study of the thermodynamic equilibration of 5-vinyloxazolines utilizing a palladium-catalyzed ring- opening /ring-closing reaction. The vinyloxazolines are prepared by the addition of vinylmagnesium bromide to alpha-aminoaldehydes with poor stereoselectivity. The isomerization process will extend the application of a poor addition reaction by providing a pathway for equilibration. Even more promising is the potential for obtaining very high selectivity through a dynamic kinetic resolution. As the isomerization process involves rapidly equilibrating pi-allyl palladium intermediates, kinetic trapping with nitrogen nucleophiles can lead to diastereomerically pure diamines. Diamino acid analogs of statine are emerging as important components of protease inhibitors, and few syntheses of these acids have been reported. A study to address some of the fundamental issues involved in this dynamic resolution encompasses the second part of the proposal. The kinetic trapping will be studied with intramolecular nucleophiles as well. These products will lead to the synthesis of conformationally constrained amino acids. We develop the synthesis of a number of known and new functionalized amino acids in the remainder of the proposal. The same vinyloxazoline precursors will be utilized for the preparation of alpha,beta-, beta,gamma-, and beta,gamma,delta-functionalized amino acids. The synthesis of other peptide isosteres containing olefin replacements for amide bonds are also proposed.