Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture

TLDR

Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. The study presents a biocatalytic process that replaces a rhodium‑catalyzed asymmetric enamine hydrogenation for large‑scale sitagliptin production. Using substrate walking, modeling, and mutation, the authors engineered a transaminase from an inactive enzyme and further optimized it by directed evolution for large‑scale chiral amine synthesis. The resultant biocatalysts showed broad applicability toward chiral amine synthesis previously limited to resolution, underscoring the maturation of biocatalysis to enable efficient, economical, and environmentally benign pharmaceutical manufacturing.

Abstract

Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.