Chemo-Enzymatic flow synthesis of Chiral Piperidine scaffolds

Environmental regulations and the increasing demand for enantiopure compounds as high-value products across different sectors require the integration of traditional chemical synthetic methods with greener (bio)catalytic approaches. Since nitrogen-containing heterocycles represent a privileged structure in many APIs, this work focuses on the asymmetric synthesis of enantiopure piperidines as high-value scaffolds for the preparation of various alkaloids. ATA-117 was selected and immobilized on Eupergit®C, enhancing its stability and reusability, to perform a stereoselective transamination followed by a spontaneous intramolecular aza-Michael reaction (IMAMR) to synthesize natural (-)-pinidinone. First, two chemical steps (an oxidation reaction and a Wittig olefination) were performed in batch to prepare the desired substrate 1. Subsequently, the biotransformation was optimized in a continuous-flow system evaluating substrate concentration, isopropylamine equivalents, reaction temperature, residence time, type and amount of cosolvent. A dual- feed flow configuration enabled complete conversion of compound 6 with high stereoselectivity, while an integrated in line work-up improved automation and reduced manual handling. The protocol was extended to different substrates.