posted on 2024-02-05, 17:37authored byDaniel A. DiRocco, Yong-Li Zhong, Diane N. Le, Scott D. McCann, J. Caleb Hethcox, Jungchul Kim, Joshua N. Kolev, Birgit Kosjek, Stephen M. Dalby, Jonathan P. McMullen, Rekha Gangam, William J. Morris
An
improved synthesis has been developed for belzutifan, a novel
HIF-2α inhibitor for the treatment of Von Hippel–Lindau
(VHL) disease-associated renal cell carcinoma (RCC). The efficiency
of previous supply and commercial routes was encumbered by a lengthy
5-step sequence, needed to install a chiral benzylic alcohol by traditional
methods. Identification and directed evolution of FoPip4H, an iron/α-ketoglutarate
dependent hydroxylase, enabled a direct enantioselective C–H
hydroxylation of a simple indanone starting material. While this enabling
transformation set the stage for a greatly improved synthesis, several
other key innovations were made including the development of a base-metal-catalyzed
sulfonylation, a KRED-catalyzed dynamic kinetic resolution, and a
facile SNAr reaction in water. Together, these improvements
resulted in a significantly shorter synthesis (9 steps) versus the
supply route (16 steps) and a 75% reduction in process mass intensity
(PMI), while also removing the reliance on third-row transition metals
and toxic solvents.