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Carbonyl catalysis enables a biomimetic asymmetric Mannich reaction

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Science  29 Jun 2018:
Vol. 360, Issue 6396, pp. 1438-1442
DOI: 10.1126/science.aat4210

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Inspiration from a vitamin

Organic synthesis of molecules with defined stereochemistry requires a chiral center, which in turn may involve a chiral catalyst. Chen et al. developed an organic catalyst, modeled on vitamin B6, which contains an electron-withdrawing pyridine ring adjacent to an aldehyde group. This catalyst works like the vitamin by reacting with an amine, a derivative of the amino acid glycine, to create an activated species. An appendage on the catalyst coordinates the subsequent reactions, allowing for stereoselective formation of a product with two adjacent amines.

Science, this issue p. 1438

Abstract

Chiral amines are widely used as catalysts in asymmetric synthesis to activate carbonyl groups for α-functionalization. Carbonyl catalysis reverses that strategy by using a carbonyl group to activate a primary amine. Inspired by biological carbonyl catalysis, which is exemplified by reactions of pyridoxal-dependent enzymes, we developed an N-quaternized pyridoxal catalyst for the asymmetric Mannich reaction of glycinate with aryl N-diphenylphosphinyl imines. The catalyst exhibits high activity and stereoselectivity, likely enabled by enzyme-like cooperative bifunctional activation of the substrates. Our work demonstrates the catalytic utility of the pyridoxal moiety in asymmetric catalysis.

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