Solid-phase synthesis of N-carboxyalkyl unnatural amino acids

Lindsey Gayle Fischer, Purdue University

Abstract

A novel route has been developed for the solid-phase synthesis of N-carboxyalkyl unnatural amino acids as potential metalloprotease inhibitors. The key step involves a nitrogen alkylation of resin-bound amino acids with α-bromoesters. Alkylation of the benzophenone imine of glycine on Wang resin was used to introduce unnatural amino acid side chains onto the resin-bound glycine. The benzyl α-bromoesters [BrCH(R2)CO2Bn], starting materials for the C-N bond construction, were prepared in solution by diazotization of naturally-occurring amino acids to form the α-bromoacids, followed by benzylation of the carboxylic acid to form the benzyl α-bromoesters. N-Alkylation of the resin-bound, unnatural amino acids with the benzyl α-bromoesters and subsequent cleavage from resin gave the benzyl ester monoacid intermediates. Exploration of reverse-phase cyano-silica gel chromatography and preparative liquid chromatography provided effective purification of the benzyl ester intermediates. Hydrolysis of the analytically pure benzyl ester monoacids afforded clean products as the diacids. The two points of variation introduced through the two on-resin alkylation steps, C-alkylation of the benzophenone imine of glycine and N-alkylation with the benzyl α-bromoesters, allow for the combinatorial synthesis of a library of target compounds.

Degree

M.S.

Advisors

O'Donnell, Purdue University.

Subject Area

Analytical chemistry|Organic chemistry

COinS