Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides. Issue 4 (6th March 2020)

• Record Type: Journal Article
• Authors: Mata, Alejandro; Weigl, Ulrich; Flögel, Oliver; Baur, Pius; Hone, Christopher A.; Kappe, C. Oliver
• Is Part Of: Reaction chemistry & engineering. Volume 5:Issue 4(2020)
• Page Start: 645
• Page End: 650
• Publication Date: 2020-03-06
• Subjects: Reaction mechanisms (Chemistry) -- Periodicals; Chemical engineering -- Periodicals; Chemical engineering; Reaction mechanisms (Chemistry); Periodicals; 547.705
• DOI: 10.1039/d0re00034e
• Languages: English
• ISSNs: 2058-9883

Abstract

Abstract : Acyl azides were safely generated by using nitrous acid in water and reacted in situ within a flow system. The acyl azide was efficiently extracted into the organic phase containing an amine nucleophile for a highly enantioselective peptide coupling. Abstract : The development of new protocols for peptide bond formation which avoid side reactions, including epimerization, are very important. The acyl azide method for the preparation of peptides is very good at maintaining chiral integrity, however; acyl azides are considered to be highly unstable and potentially explosive intermediates. Thus, the acyl azide method is underutilized by the synthetic community. Acyl azides were safely generated and reacted in situ within a continuous-flow system. The acyl azide was generated by using nitrous acid in water, and efficiently extracted into the organic phase containing the amine nucleophile for peptide coupling. The protocol has been used to prepare a number of dipeptides (5 examples) without epimerization (<1%). A tripeptide, d -Ala-d -Ala-l -Ala-OBn, was also synthesized.