Amination of a Green Solvent via Immobilized Biocatalysis for the Synthesis of Nemtabrutinib

Enzymesare capable of unique and selective transformations thatcan enable efficient chemical production. While many industrial processeshave been developed using free enzymes in aqueous solutions, immobilizingenzymes on a solid support can offer considerable advantages, includingimproved reaction efficiency, enzyme stability, the ability to performreactions in non-aqueous media, and simplified separation of the productfrom the enzyme. Herein, we describe the development of a biocatalytictransaminase reaction of Cyrene (2) utilizing an immobilized,evolved transaminase enzyme in an organic solvent to provide amineintermediate 3a en route to Bruton's tyrosinekinase (BTK) inhibitor nemtabrutinib. Enzyme immobilization is criticalto facile isolation of the water-soluble product. Improved reactionkinetics and diastereoselectivity were achieved by bridging directedenzyme evolution with the selection of an optimal reaction solventand solid support for immobilization, enabling a unified solvent systemand direct isolation of 3a as a crystalline salt with dr > 50:1.