A ynamide-mediated ketone synthesis from readily available carboxylic acids and Grignard reagents is described. It takes advantage of a nucleophilic attack reaction of C-nucleophile to α-acyloxyenamides to facilitate an efficient C-C bond formation under mild conditions. Direct use of carboxylic acids and the one-pot strategy enhance the practicality and generality of the strategy by obviating the need for purification of intermediates. Notably, N-protected α-amino acids and peptidyl acids are compatible with this protocol, allowing direct access to their corresponding ketones with retention of stereochemical integrity. It provides a practical and efficient approach for peptidyl ketones, where precise chiral fidelity is crucial for biological activity.
Zhang et al. (2026) studied this question.