β-Acyloxyl alkenyl amide synthesis via multiple defluorination: α-Trifluoromethyl ketone–amine as synergystic peptide coupling reagent

Abstract

β-Acyloxyl alkenyl amides (AAAs) are vinylogous esters with high activity toward acylation reactions. However, only one synthetic procedure consisting of five independent operation steps involving highly sensitive amino alkynone intermediate is available for their synthesis to date, depressing rigidly the application of AAAs in peptide synthesis and expanded acylation reactions. Herein, by combining consecutive trifold defluorination, acyl migration, and multicomponent reactions, a considerably simpler one-step protocol has been established for AAA synthesis with the α-trifluoromethyl ketones, amines, and carboxylic acids/amino acids as starting materials using Cs 2 CO 3 as the only promoter. The resulting AAAs have been verified with excellent performance in the synthesis of esters, amides, and peptides. In all investigated examples of peptide synthesis, no racemization or epimerization has been observed, documenting the high application potential of AAAs as a complementary option in peptide synthesis and other related acylation reactions.