Concise construction of β-branched aromatic D-amino acids via transaminase-catalyzed dynamic kinetic resolution

The synthesis of non-canonical amino acids (ncAAs) has recently made tremendous progress in the field of biocatalysis, with enzymes such as transaminases, dehydrogenases, and ammonia lyases being used. Frameworks of β-branched aromatic D-amino acids are crucial for the efficacy of pharmaceuticals, influencing spatial conformation, binding modes with receptors and pharmacokinetic properties. However, there is a scarcity of studies on the efficient synthesis of β-branched D-amino acids, which has significantly hindered the advancement of structure-activity relationship (SAR) studies. Here, we present the asymmetric synthesis of β-branched aromatic D-amino acid analogues catalyzed by PLP-dependent transaminase BsDAAT (from Bacillus sp. strain YM-1), an efficient transamination system that relies on the dynamic kinetic resolution (DKR) process. Through docking analysis and concise enzyme engineering, we successfully obtain various aromatic D-amino acids with β-substitution in high yields (up to 99%), dr ratios (>20:1) and ee values (up to 99%). These β-branched aromatic D-amino acids are then successfully introduced into the modifications of the antineoplastic reagent Lanreotide. Frameworks of β-branched aromatic D-amino acids are crucial for the efficacy of pharmaceuticals, but the synthesis of such scaffolds remained undeveloped. Here, authors present the first asymmetric synthesis of β-branched aromatic D-amino acid analogues via the transaminase BsDAAT catalyzed dynamic kinetic resolution (DKR) process.