Enantioselective Synthesis of a γ‑Secretase Modulator via Vinylogous Dynamic Kinetic Resolution

• Published in: Journal of organic chemistry 2018-09, Vol.83 (18), p.11133-11144
• Main Authors: Strotman, Neil A, Ramirez, Antonio, Simmons, Eric M, Soltani, Omid, Parsons, Andrew T, Fan, Yu, Sawyer, James R, Rosner, Thorsten, Janey, Jacob M, Tran, Kristy, Li, Jun, La Cruz, Thomas E, Pathirana, Charles, Ng, Alicia T, Deerberg, Joerg
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.8b01734

Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer’s disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.