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Journal of Flow Chemistry

, Volume 5, Issue 4, pp 220–227 | Cite as

Efficient Continuous-Flow Benzotriazole Activation and Coupling of Amino Acids

  • Sofie Seghers
  • Frederik E. A. Van Waes
  • Ana Cukalovic
  • Jean-Christophe M. Monbaliu
  • Jeroen De Visscher
  • Joris W. Thybaut
  • Thomas S. A. Heugebaert
  • Christian V. Stevens
Full Paper

Abstract

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.

Keywords

continuous flow microreactor amino acids benzotriazole amide bond formation 

Supplementary material

41981_2015_5040220_MOESM1_ESM.pdf (628 kb)
Supplementary material, approximately 643 KB.

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Copyright information

© Akadémiai Kiadó 2015

Authors and Affiliations

  • Sofie Seghers
    • 1
  • Frederik E. A. Van Waes
    • 1
  • Ana Cukalovic
    • 1
  • Jean-Christophe M. Monbaliu
    • 2
  • Jeroen De Visscher
    • 1
  • Joris W. Thybaut
    • 3
  • Thomas S. A. Heugebaert
    • 1
  • Christian V. Stevens
    • 1
  1. 1.SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience EngineeringGhent UniversityGentBelgium
  2. 2.Center for Integrated Technology and Organic Synthesis, Department of ChemistryUniversity of LiègeLiègeBelgium
  3. 3.Laboratory for Chemical Technology, Department of Chemical Engineering and Technical Chemistry, Faculty of Engineering and ArchitectureGhent UniversityGentBelgium

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