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Synthesis of BMS-932481
Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution.
J. Org. Chem. 2018;
19 November 2018 (online)
Key wordsBMS-932481 - γ-secretase modulator - vinylogous dynamic kinetic resolution - asymmetric hydrogenation - Noyori asymmetric transfer hydrogenation - intramolecular hydroacylation
BMS-932481 is a γ-secretase modulator that is of interest for the treatment of Alzheimer’s disease. A six-step synthesis of BMS-932481 based on a vinylogous dynamic kinetic resolution (VDKR) of rac-E delivered the target molecule in 38% overall yield and >99% ee. The VDKR was a consequence of rapid epimerization via dienolate I.
An alternative seven-step synthesis of BMS-932481 based on a rhodium-catalyzed asymmetric hydrogenation of the alkene J proceeded in 16.3% overall yield and >99% ee. The high pressure of hydrogen required (1000 psi) and the expense of the rhodium catalyst were dis-advantageous to this route.