Chemoenzymatic Synthesis of Fluorinated L-α-Amino Acids

Fluorinated amino acids play a crucial role as fundamental components in drug synthesis owing to their favorable attributes that enhance the pharmacokinetic properties of drugs. Nevertheless, the conventional chemical synthesis of fluorinated amino acids faces challenges in achieving stereoselectivity control. Additionally, the high cost of substrates and the intricate cofactor recycling process in enzymatic synthesis have limited their industrial production and applications. In this study, we developed a three-step chemoenzymatic cascade for the asymmetric synthesis of chiral fluorinated amino acids. The methodology involves the utilization of a variety of cost-effective aldehydes as starting materials, enabling economical aldol reactions catalyzed by aldolase. Subsequent chemical decarboxylation produces substrates for reductive amination through phenylalanine ammonia lyase, resulting in a diverse library of fluorinated aromatic L-alpha-amino acid products with a relative high yield and high enantiomeric purity (up to 99%). Furthermore, we synthesized three pharmaceutically relevant fluorinated L-alpha-amino acids on a preparative scale using whole-cell biocatalysts, demonstrating the versatility of the approach. This study has introduced a simplified, efficient, and cost-effective route for synthesizing fluorinated l-alpha-amino acids under mild conditions, offering insights into the production of valuable fluorine-containing pharmaceuticals and other biologically active compounds.