Suppression of rapid deactivation of catalytic tetrapeptides in the asymmetric Michael addition of aldehydes to nitroolefins by supporting them on polymers

Abstract

The limited efficiency of N-primary amine-based peptides as organocatalysts for the asymmetric Michael addition of aldehydes to nitroolefins is largely attributed to their rapid deactivation, a phenomenon whose underlying mechanism remains poorly understood. In this work, grafting readily deactivated N-primary amine-based tetrapeptides onto polymers dramatically suppressed their rapid deactivation and enhanced their performance, delivering high yields and excellent stereoselectivity under mild reaction conditions. The supported catalyst SP-1 exhibited broad substrate compatibility with both α-unbranched and α-branched aldehydes, achieving unprecedented enantioselectivities of 99% for all investigated α-unbranched aldehydes. Mechanistic studies revealed that the acidic environment created by the C-terminal carboxylic acid group significantly accelerated catalyst deactivation. Additionally, this work demonstrated that the rapid catalyst deactivation involves multiple complex reaction pathways, with the dominant mechanism being a nitro-Michael/nitro-Mannich/acetalization/dehydration/oxidation cascade leading to the formation of novel, reddish, densely substituted N-peptidyl-1,2-dihydropyridines.