Flow-based chemoenzymatic synthesis of chiral piperidine derivatives

Chiral amines constitute key building blocks in approximately 40–45% of small-molecule pharmaceuticals and are widely used in the production of fine chemicals and agrochemicals.[1] Increasing environmental regulations, together with the growing demand for enantiopure compounds as high-value products, have driven the integration of traditional synthetic methodologies with greener (bio)catalytic approaches.[2] Nitrogen-containing heterocycles are privileged motifs in many active pharmaceutical ingredients (APIs).[3] In this work we report the asymmetric synthesis of enantiopure piperidines as valuable scaffolds for alkaloid synthesis.[4] A pyridoxal 5′-phosphate (PLP)-dependent transaminase (ATA-117), immobilized for this purpose, enables a stereoselective transamination, followed by a spontaneous intramolecular aza-Michael reaction (IMAMR) (Scheme 1), ultimately affording the natural product (−)-pinidinone (6).[5] The synthetic route began with two batch chemical steps to prepare substrate 1, namely an oxidation followed by a Wittig olefination using commercially available ylides. After enzyme expression and purification, several immobilization strategies were evaluated. Covalent immobilization on Eupergit® C was identified as optimal, enhancing both operational stability and reusability of the (R)-selective biocatalyst. Subsequently, the reaction was optimized under continuous flow conditions by varying substrate concentration, isopropylamine equivalents, temperature, residence time, and the type and amount of cosolvent. Finally, the developed protocol was extended to a range of substrates, enabling the synthesis of diverse 2,6-disubstituted chiral piperidines