Utilizing Biocatalysis and an Unprecedented Sulfolane-mediated Reductive Acetal Opening to Access Nemtabrutinib from Cyrene

The chiral building block 5-amino-2-hydroxymethyltetrahydropyran 1a has been previously synthesized through a cumbersome 9-step synthesis from tri-O-acetyl-D-glucal, which renders access to nemtabrutinib (2), a BTK inhibitor currently being evaluated for the treatment of various hematologic malignancies, inefficient and wasteful. Herein, we describe the development of a protecting group-free, 2-step synthesis of 1a from Cyrene, a biorenewable feedstock. The improved synthesis involves a biocatalytic transamination reaction of Cyrene to install the desired amine-stereocenter in a single step with high diastereoselectivity. The enzymatic reaction is followed by a stereo-retentive reductive acetal opening reaction of the chiral cyrene amine intermediate 3a to furnish 1a. A mechanistic investigation of the acetal opening reaction is also described which uncovered unprecedented reaction conditions for the in-situ generation of diborane mediated by the sulfolane co-solvent. The streamlined synthesis of 1a from Cyrene resulted in a > 27% yield improvement and a significant reduction in the environmental impact of the synthesis.