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.

Insight to the thermodynamic stability of molecular crystals through crystallographic studies of a multipolymorph system.

Five solvent-free polymorphs of a pharmaceutical compound were discovered during polymorph screening. Out of the five polymorphs, only one has strong intermolecular N-H···N hydrogen bonding, whereas the others exhibit only weak C-H···N and π-π stacking interactions in addition to all the other weak C-H···X and van der Waals interactions. The relative thermodynamic stability relationships among the polymorphs are not intuitive and quite complex due to enantiotropic phase behavior.