LC Campeau, Merck

Kohout Lecture - Spring 2024

Host: Ramesh Giri (865-0063)

"Changing the World, One Reaction at a Time"

Abstract: Belzutifan (MK-6482) is a first-in-class oral hypoxia-inducible factor 2α (HIF-2α) inhibitor used for the treatment of patients with renal cell carcinoma associated von Hippel-Lindau (VHL) disease. The program achieved FDA breakthrough designation in 2020 and was approved in 2021 for VHL associated renal cell carcinoma.

A key step in the current synthesis is the installation of a chiral benzylic alcohol on an indanone core, to install the stereo-triad of MK-6482 and was the most significant challenge of its synthesis. This presentation details our efforts to develop a scalable route to MK-6482, culminating in the development of a direct enantioselective biocatalytic hydroxylation that forges the desired C-O bond in a single step, avoiding redundant redox processes and significantly improving overall efficiency.