Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation

Abstract

Herein, we report a nine-step synthesis of belzutifan enabled by a novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, the final ketone reduction in the synthesis proceeds with high diastereoselectivity, leading to the expedient assembly of the stereotriad. In contrast to the original 16-step synthesis, this route avoids a lengthy bromination−oxidation sequence and introduces the sulfone functionality via nucleophilic aromatic substitution, obviating the need for transition metal catalysis.