The rational design and implementation of enantiodivergent enamine catalysis is reported. A simple secondary amine catalyst, 2-methyl-l-proline, and its tetrabutylammonium salt function as an enantiodivergent catalyst pair delivering the enantiomers of α-functionalized aldehyde products in excellent enantioselectivities. This novel concept of designed enantiodivergence is applied to the enantioselective α-amination, aldol, and α-aminoxylation/α-hydroxyamination reactions of aldehydes.

A combination of experimental C kinetic isotope effects (KIEs) and high-level density functional theory (DFT) calculations is used to distinguish between "enamine" and "enol" mechanisms in the Michael addition of acetone to trans-β-nitrostyrene catalyzed by Jacobsen's primary amine thiourea catalyst. In light of the recent findings that the widely used O-incorporation probe for these mechanisms is flawed, the results described in this communication demonstrate an alternative probe to distinguish between these pathways. A key advantage of this probe is that quantitative mechanistic information is obtained without modifying experimental conditions. This approach is expected to find application in resolving mechanistic debates, while providing valuable information about the key transition state of organocatalyzed reactions involving the α-functionalization of carbonyls.

The rational design and implementation of enantiodivergent enamine catalysis is reported. As imple secondary amine catalyst, 2-methyl-l-proline,a nd its tetrabutylammonium salt function as an enantiodivergent catalyst pair delivering the enantiomers of a-functionalized aldehyde products in excellent enantioselectivities.T his novel concept of designed enantiodivergence is applied to the enantioselective aamination, aldol, and a-aminoxylation/a-hydroxyamination reactions of aldehydes. Scheme 1. Mechanistic framework for proline-enamine catalysis.