Water-removable ynamide coupling reagent for racemization-free syntheses of peptides, amides, and esters?

Green Chemistry Pub Date: 2021-11-03 DOI: 10.1039/D1GC03498G

Abstract

A novel ynamide coupling reagent, the by-product of which can be removed by water, was reported. It promotes the direct coupling between carboxylic acids and amines, alcohols or thiols to provide amides, peptides, esters and thioesters, respectively. No detectable racemization was observed for all the coupling reactions of carboxylic acids containing an α-chiral center. Importantly, a simple acidic aqueous work-up removed the by-product readily to afford pure coupling products in good to excellent yields without the use of column chromatography, thus making this method more environmentally benign, user friendly and cost-effective. The robustness of the water-removable ynamide coupling reagent was further exemplified by the racemization/epimerization-free synthesis of carfilzomib, in which no column chromatography purification was involved for the entire 12-step synthesis.

Graphical abstract: Water-removable ynamide coupling reagent for racemization-free syntheses of peptides, amides, and esters
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