Meeting Organocatalysis with Drug Discovery: Asymmetric Synthesis of 3,3′-Spirooxindoles Fused with Tetrahydrothiopyrans as Novel p53-MDM2 Inhibitors

Abstract

An organocatalytic enantioselective Michael-Michael cascade reaction is developed for the synthesis of chiral spirotetrahydrothiopyrans. This highly functionalized scaffold was assembled in moderate to good yield (55-74%) and excellent diastereo- and enantioselectivities (>30:1 dr, ≥ 99% ee) with the creation of four consecutive stereogenic centers. The novel spiro-oxindole scaffold is validated as a new class of p53-MDM2 protein-protein interaction inhibitors with good antitumor activity.