Biocatalytic Synthesis of (R)-3-Aminotetrahydropyran through a Direct Transamination at Kilogram Scale

Chiral amines with a low molecular weight are useful intermediates in the synthesis of active pharmaceutical ingredients (APIs). Here, we present a scalable one-step synthesis of (R)-3-aminotetrahydropyran through a straightforward biocatalytic transamination (vs previous five-step synthesis). The product was isolated by direct precipitation of salt without the need for organic solvent extraction or chromatography. The highlights of this process include differentiation of the two enantiotopic faces of the ketone substrate via a biocatalyst as well as providing a solution to isolate the reasonably volatile product directly from reaction mixture. The process was optimized using design of experiment (DoE) principle combined with enzyme kinetic studies and successfully demonstrated at kilogram scale, achieving 53% isolation yield and an enantiomeric ratio of 96:4 of the amine product.