Synthesis of Enantiopure Fluoropiperidines via Biocatalytic Desymmetrization and Flow Photochemical Decarboxylative Fluorination

Low-molecular weight chiral amines are valuable components in medicinal chemistry as they serve as core templates, linking units, and substituent appendages. The piperidine scaffold is particularly useful among privileged small amines, with substituted variants having a great number of potential regio- and diastereoisomers, which allow for high stereochemical definition to enable a variety of productive protein interactions. Herein, we describe the successful enablement, scale-up, and delivery of >400 g of a single isomer, (3S,5S)-1-((benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid (>98% de and >96% ee), via 450 g-scale biocatalytic desymmetrization and 335 g-scale flow photochemical decarboxylative fluorination.