Practical, asymmetric synthesis of aromatic-substituted bulky and hydrophobic tryptophan and phenylalanine derivatives

Abstract

Aromatic ring substituted tryptophans and phenylalanines can provide valuable tools in developing highly potent and selective peptide ligands with specific structural features in addition to providing a large lipophilic surface for binding to receptors and for crossing membrane barriers. An efficient method for the synthesis of these novel amino acids has been developed. In the approach, asymmetric hydrogenations of α-enamides using Burk's DuPHOS-based Rh (I) catalysts generated high enantiomerically pure α-amino acid derivatives, which subsequently underwent Suzuki cross couplings with boronic acid derivatives to afford these aromatic substituted amino acids in high yields and high enantioselectivity. The method can allow for the preparation of such amino acids in large scales for extensive structure–activity studies.