Synfacts 2018; 14(12): 1215
DOI: 10.1055/s-0037-1611139
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of BMS-932481

Contributor(s):
Philip Kocienski
Strotman NA. et Al. Bristol-Myers Squibb, New Brunswick, USA
Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution.

J. Org. Chem. 2018;
83: 11133-11144
Further Information

Publication History

Publication Date:
19 November 2018 (online)

 

Significance

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.


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Comment

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.


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