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Advancements in enzyme discovery and protein engineering have accelerated development of green, efficient synthetic routes to complex molecules and broadened implementation of biocatalysis for scalable manufacture of pharmaceutical intermediates. (S)-3-isobutyl-γ-aminobutyric acid (S-Pregabalin API), is a generic drug for the treatment of epilepsy and neuralgia. It has been previously synthesized via kinetic resolution and re-racemization under harsh conditions, which is inefficient and not eco-friendly. Herein, we describe the development of an enantioselective desymmetrization of 3-isobutylglutarimid utilizing an evolved D-hydantoinase to produce the Pregabalin Intermediate (IM) (R)-3-isobutyl glutaric acid monoamide en route to S-Pregabalin. Three rounds of computer-guided directed evolution were implemented towards improved activity, enantioselectivity and reduced substrate/product inhibition, providing a final variant that enables the full conversion of 240 g/L substrate into Pregabalin IM with excellent enantiomeric excess (ee) of >99.5%. The promising results demonstrated an economical and sustainable synthesis of S-Pregabalin starting from a prochiral substrate using an evolved D-hydantoinase.

Olefin metathesis is a powerful tool that enables unique bond disconnection strategies via carbon-carbon bonds. It has been employed in commercial scale synthesis across multiple industries and in multiple reaction types including ring-closing, cross, and ring-opening metathesis. Among these, macrocyclization by ring-closing metathesis stands out as a hallmark of the technology. However, ring-closing metathesis can also serve as a highly efficient entry to smaller rings. In this article, we highlight retrosynthetic strategies toward 5- and 6-membered nitrogen heterocycles, including in the context of a commercial drug manufacturing process.