posted on 2021-11-16, 17:10authored byWilliam P. Gallagher, John R. Coombs, Carlos A. Guerrero, Boguslaw M. Mudryk, Kishta Katipally, Candice L. Joe, Sanjeewa Rupasinghe, Jason Zhu, Francisco González-Bobes
The
cyclohexyl fragment 1 in BMS-986251 was synthesized
starting from Hagemann’s ester 2 in 7 steps and
5 isolations. The route is highlighted by a dynamic kinetic resolution
(DKR), a telescoped enol nonaflation followed by a palladium-catalyzed
carbonylation, and a rhodium-catalyzed directed diastereoselective
olefin hydrogenation. The optimized process was demonstrated on 1
kg scale, with an overall 51% yield and >99% ee and dr.