Asymmetric Synthesis of the Cyclohexyl Fragment in
RORγt Inhibitor (BMS-986251) Enabled by a Dynamic Kinetic Resolution
of Hageman’s Ester

Gallagher, William P.; Coombs, John R.; Guerrero, Carlos A.; Mudryk, Boguslaw M.; Katipally, Kishta; Joe, Candice L.; Rupasinghe, Sanjeewa; Zhu, Jason; González-Bobes, Francisco

doi:10.1021/acs.oprd.1c00339.s001

op1c00339_si_001.pdf (238.39 kB)

Asymmetric Synthesis of the Cyclohexyl Fragment in RORγt Inhibitor (BMS-986251) Enabled by a Dynamic Kinetic Resolution of Hageman’s Ester

journal contribution

posted on 2021-11-16, 17:10 authored by William 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.

Asymmetric Synthesis of the Cyclohexyl Fragment in RORγt Inhibitor (BMS-986251) Enabled by a Dynamic Kinetic Resolution of Hageman’s Ester

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