Stereoselective Synthesis of Aliphatic α-Amino Acids by Chemo-Enzymatic Hydroamination-Hydrodesulfurisation

Abstract

Phenylalanine ammonia lyase (PAL) enzymes have been extensively exploited to produce differently substituted arylalanine analogues, but their use in the stereoselective synthesis of aliphatic fatty amino acids has never been addressed. In this work, a two-step hydroamination-hydrodesulfurisation process has been investigated for the production of aliphatic L-α-amino acids from thienylacrylic acids, easily accessible by condensation from the corresponding arylaldehyde. Wild-type PALs from Planctomyces brasiliensis and Streptomyces rimosus were selected as the most promising candidates and improved by site-directed mutagenesis, thus unlocking the hydroamination of a broad panel of 10 different thienylacrylic acids bearing aliphatic and aromatic substituents. The subsequent hydrodesulfurisation step, accomplished by means of inexpensive Raney nickel in mild conditions and aqueous medium, afforded the corresponding aliphatic α-amino acids in 10-63% overall isolated yield and perfect enantiopurity. This chemo-enzymatic process represents the first example of aliphatic amino acid production using PALs, circumventing a major limitation of those biocatalysts.