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

• DOI: 10.1021/acs.joc.8b01734
• Publication Date: 2018-08-13T15:47:13Z
• Authors: Neil A. Strotman; Antonio Ramirez; Eric M. Simmons; Omid Soltani; Andrew T. Parsons; Yu Fan; James R. Sawyer; Thorsten Rosner; Jacob M. Janey; Kristy Tran; Jun Li; Thomas E. La Cruz; Charles Pathirana; Alicia T. Ng; Joerg Deerberg
• Keywords: Kinetic resolution

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