Optimized catalytic enantioselective aryl transfer process provides access to mGlu2 receptor potentiators

ORGN 659

Michael A. Staszak, Staszak_Michael_A@lilly.com, Global Process Research and Development, Eli Lilly and Company, 1555 S. Kentucky Avenue, Indianapolis, IN 46285

Diarylmethanol 1, and acetate derivative 2, are key chiral intermediates for the preparation of mGlu2 receptor potentiators.  Formation of 1 via a racemic Grignard protocol followed by chiral chromatography was acceptable for multi-gram scale purposes.  However, for multi-kilogram amounts, an asymmetric synthesis of 1 was required.  After evaluating enzymatic resolutions, asymmetric hydrogenations, and chiral hydridic reductions (e.g. CBS reagents), enantioselective aryl transfer chemistry was developed to afford the desired diarylmethanol.  The process involved preparing a proposed arylalkylzinc species from a boroxine and diethylzinc, followed by reaction with the appropriate aldehyde in the presence of a chiral ligand.  While optimizing this chemistry, an understanding of stoichiometry and reaction times was gained through the use of React-IR and analysis of off-gases via real time gas analysis/mass spectrometry.  Ultimately, crystalline 2 was obtained in high yield with >99% ee.