Chemodivergent Preparation of Various Heterocycles via Phase-Transfer Catalysis: Enantioselective Synthesis of Functionalized Piperidines

In this work, a new chemodivergent domino approach for the preparation of various saturated heterocycles, based on phase-transfer catalysis (PTC), is presented. The versatile nature of doubly electrophilic substrates, showing both a Michael acceptor and a ketone, tethered by a heteroatom, enables three different domino reaction pathways. The nucleophile dictates the chemoselectivity of the reaction. Sulfa-Michael/aldol, cyanide addition/oxa-Michael and Michael/H-shift/aldol processes, along with the variation of the tethering heteroatom, results in the formation of six different classes of saturated heterocycles. DFT calculations account for the observed chemo- and diastereoselectivity of the two most productive processes. Moreover, an extensive investigation on the sulfa-Michael/aldol pathway was carried out, ultimately leading to the development of a new enantioselective domino approach to multi-substituted piperidines based on PTC. (Figure presented.).