Issue 4, 2020
From the journal:

Reaction Chemistry & Engineering

Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides†

Alejandro Mata,ab   Ulrich Weigl,c   Oliver Flögel,c   Pius Baur,c   Christopher A. Hone ORCID logo *ab  and  C. Oliver Kappe ORCID logo *ab  

* Corresponding authors

a Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
E-mail: christopher.hone@rcpe.at

b Institute of Chemistry, University of Graz, NAWI Graz Heinrichstrasse 28, 8010 Graz, Austria
E-mail: oliver.kappe@uni-graz.at

c Cilag AG, Hochstrasse 201, 8200 Schaffhausen, Switzerland

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.

Graphical abstract: Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides

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Article information

DOI
https://doi.org/10.1039/D0RE00034E
Article type
Communication
Submitted
23 Jan 2020
Accepted
02 Mar 2020
First published
02 Mar 2020
This article is Open Access
Creative Commons BY-NC license

React. Chem. Eng., 2020,5, 645-650

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Acyl azide generation and amide bond formation in continuous-flow for the synthesis of peptides

A. Mata, U. Weigl, O. Flögel, P. Baur, C. A. Hone and C. O. Kappe, React. Chem. Eng., 2020, 5, 645 DOI: 10.1039/D0RE00034E

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