Cerium(IV)-catalyzed allylic oxidation of 3-sulfolene: An efficient tool for the synthesis of 4-substituted sulfol-2-enes with antiproliferative activity.

Abstract

Cyclic sulfones play an important role in the field of drug discovery and design due to their valuable properties and their broad range of applications. Herein, we report an efficient cerium(IV)-catalyzed allylic oxidation of a simple 3-sulfolene. This process provides a straightforward and facile approach to sulfol-2-en-4-one, a versatile synthetic intermediate. Notably, this study represents the first instance of cerium catalysis employed in allylic oxidation. Furthermore, we demonstrated the transformation of sulfol-2-en-4-one into 4-substituted sulfol-2-enes with therapeutic applications. In silico analysis performed using the SwissAdme tool indicated that the obtained 4-amine (7a - 7d) and 4-carbamate (9a and 9b) derivatives of sulfol-2-en-4-one met the rules imposed on small-molecule drugs. Moreover, these compounds inhibited the proliferation (MTT assay) of colon cancer and osteosarcoma cells. Notably, compounds 7b and 7c, which exhibited the best selectivity index (ratio of IC50 calculated for normal and cancer cells), induced cell cycle arrest and apoptosis (flow cytometry analysis). Considering the present results, the cerium-catalyzed allylic oxidation of sulfol-3-ene proves to be an efficient and practical method for synthesizing sulfol-2-en-4-one, a versatile chemical synthon for developing sulfolane derivatives, including those with promising anticancer potential.