Bifunctional organocatalysis combining covalent and noncovalent activation is presented. The hybrid peptide− thiourea catalyst features a N-terminal proline moiety for aldehyde activation and a thiourea unit for electrophile activation. This catalyst effectively promotes asymmetric Michael additions of aldehydes to challenging but biologically relevant heterocyclecontaining nitroalkenes. The catalyst can be used under solvent-free conditions. Spectroscopic and density functional theory studies elucidate the catalyst structure and mode of action.
Enantioselective catalytic formation of polyfunctional molecules, such as non‐natural amino acids, is important for the efficient production of many chiral compounds. To this end, we present here the synthesis and evaluation of the catalytic activity of bifunctional peptide–thiourea organocatalysts. These hybrid organocatalysts consist of Pro‐Pro dipeptide and thiourea moiety connected via a 1,2‐diaminocyclohexane unit. These catalysts promoted challenging Mannich reaction between α‐imino esters and pyruvates, providing orthogonally protected oxo‐glutamate derivatives. The N‐tosyl‐protected imino ester, as the most active imine, was required to compensate for the poor reactivity of pyruvates. DFT calculations, NMR, and CD spectroscopy help elucidate the mode of action of these catalysts. Configuration of the dipeptide Pro‐Pro moiety is responsible for the sense of the stereoinduction of the Mannich reaction.
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