Halpern's classic study of the origin of enantioselectivity in rhodium catalyzed asymmetric hydrogenation is a textbook example of the Curtin Hammett principle and one of the enduring lessons in catalysis. Recently our laboratory, in combination with the Catalyst Discovery Group at Merck, reported a new mode of activation of bis(phosphine) cobalt catalysts involving zinc in methanol that enables high activity and enantioselectivity for the asymmetric hydrogenation of a broad range of alkenes. Among these was the asymmetric synthesis of Levetiracetam, a medication for epilipsy, on a 200 gram pilot scale in methanol with enantioselectivity and activity superior to reported rhodium catalyzed methods. Open questions include: (i) how do these catalysts operate?, (ii) what oxidation states comprise the catalytic cycle and (iii) what is enantiodetermining step of the reaction? My lecture will focus on our efforts to answer these questions and the unique features of the first row metal that are not operative in more traditional precious metal catalyzed reactions. Is the Curtin-Hammett principle operative? Stay tuned!

Understanding the mechanism of cobalt-catalyzed asymmetric hydrogenation: Halpern's lessons from rhodium redux?

256th National Meeting (2018)

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