Amide and Peptide Couplings Mediated by Pivaloyl Mixed Anhydrides in Aqueous Media
Carolin Manske, Marco Schmiedtchen, Siebo Gellhaar, Michael Kiesel, Jochen Becker
Abstract
From the wide range of different chemical transformations used in the pharmaceutical industry, amide and peptide couplings belong to the most important and widely applied. This is due to the relevance of the amide moiety in pharmaceutical compounds. Unfortunately, traditional amidation reaction conditions require hazardous reagents and organic solvents which generate significant amounts of waste. Therefore, finding greener alternatives that are transferrable to industrial applications on a large scale is an important area of process research and development. This approach is essential for increasing sustainability in the pharmaceutical and chemical industries. In this article, we describe our efforts to develop a sustainable, practical, and scalable protocol for amide and peptide couplings. Our approach is based on pivaloyl chloride as an inexpensive and readily obtainable coupling reagent in water as the main reaction media. The conditions developed were applied to the synthesis of a range of amides and peptides. We then investigated the scope of the transformation and the effect of the surfactant TPGS-750-M by comparing the outcome and the selectivity of reactions carried out in an aqueous solution containing 2 wt % of surfactant and solely in aqueous media.