Homochiral β-CF3, -SCF3 and -OCF3 secondary alcohols: catalytic stereoconvergent synthesis, bioactivity and flexible crystals

An optimized catalytic protocol for enantio- and diastereoselective reduction of racemic α-CF3, α-SCF3 and α-OCF3 aryl ketones is described. The reaction involves a dynamic kinetic resolution (DKR) based on ruthenium catalyzed Noyori–Ikariya asymmetric transfer hydrogenation for simultaneous construction of two contiguous stereogenic centers. A range of previously inaccessible fluorinated secondary alcohols was prepared in excellent stereomeric purity (up to above 99.9% ee, up to above 99.9:0.1 dr) and in high isolated yield (up to 99%). The origin of DKR (exceptional stereoselectivity and racemization mechanism) is rationalized by density functional theory calculations. Pharmaceutically relevant further transformations of the products are demonstrated including incorporation into heat shock protein 90 inhibitor with in vitro anti-cancer activity. Moreover, needle-shaped crystals of representative stereopure products are mechanically responsive: either elastically or plastically flexible, opening the door to novel class of functional materials based on chiral molecular crystals.