A Modular Approach to Trisubstituted Chiral Piperidines

We report a modular strategy for the synthesis of trisubstituted chiral piperidines. First, a scalable, chiral-pool synthesis of an orthogonally protected piperidine tricarboxylic acid diester was developed. This synthesis involves a formal 4 + 2 cyclization between choro-homoserine and acetylene dicarboxylate, followed by a diastereoselective reduction, cyclic anhydride formation, and regioselective ring-opening process to give the final product as a single enantio- and diastereomer at >50 g scale. Next, we demonstrated that the piperidine tricarboxylate intermediate can undergo sequential decarboxylative functionalizations using modern transition metal-catalyzed or photocatalytic methodologies. As the result, highly elaborated chiral piperidines and pipecolic esters were prepared in a chemo- and stereoselective manner.