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

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.