[en] Despite extensive research into peptide synthesis, coupling of amino acids with weakly nucleophilic heterocyclic amines remains a challenge. The need for microwave technology to promote this coupling interferes with the scalability of the process. By applying the microwave-to-flow paradigm, a library of (α-aminoacyl)amino-substituted heterocycles was continuously produced at near quantitative conversions and the reaction was scaled up successfully. Various N-Cbz-protected amino acids were activated using BtH/SOCl2 under continuous-flow conditions with excellent yields. Their coupling with heterocyclic amines was accomplished in MeCN—NMP on a preparative scale. However, performing both steps in-line resulted in an inconvenient work-up. Therefore, a two-step approach was taken, isolating the intermediate Bt-activated amino acid via simple filtration. This allows for a solvent switch to DMSO for the coupling reaction which led to excellent conversions for a broad range of substrates.
Disciplines :
Chemistry
Author, co-author :
Seghers, Sofie; Ghent University > Department of Sustainable Organic Chemistry and Technology
Van Waes, Frederik E. A.; Ghent University > Department of Sustainable Organic Chemistry and Technology
Cukalovic, Ana; Ghent University > Department of Sustainable Organic Chemistry and Technology
Monbaliu, Jean-Christophe ; Université de Liège > Département de chimie (sciences) > Center for Integrated Technology and Organic Synthesis
De Visscher, Jeroen; Ghent University > Department of Sustainable Organic Chemistry and Technology
Thybaut, Joris; Ghent University > Department of Chemical Engineering and Technical Chemistry
Heugebaert, Thomas S.A.; Ghent University > Department of Sustainable Organic Chemistry and Technology
Stevedns, Christian V.; Ghent University > Department of Sustainable Organic Chemistry and Technology
Language :
English
Title :
Efficient Continuous Flow Benzotriazole Activation and Coupling of Amino Acids
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