ORGN 659 |
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.
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Technical Achievements in Organic Chemistry Award Symposium
9:00 AM-11:55 AM, Wednesday, August 22, 2007 BCEC -- 254 A/B, Oral
Division of Organic Chemistry |