Efficient continuous-flow benzotriazole activation and coupling of amino acids
- Author
- Sofie Seghers, Frederik Van Waes (UGent) , Ana Cukalovic (UGent) , Jean-Christophe Monbaliu (UGent) , Jeroen De Visscher, Joris Thybaut (UGent) , Thomas Heugebaert (UGent) and Christian Stevens (UGent)
- Organization
- 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 (alpha-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
- microreactor, continuous flow, amino acids, benzotriazole, amide bond formation, N-ACYLBENZOTRIAZOLES, MICRO REACTORS, BETA-PEPTIDES, REAGENTS, ALPHA, HETEROCYCLES, DERIVATIVES, INHIBITORS, DESIGN, FMOC-ALPHA-AMINOACYL)BENZOTRIAZOLES
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-7221978
- Chicago
- Seghers, Sofie, Frederik Van Waes, Ana Cukalovic, Jean-Christophe Monbaliu, Jeroen De Visscher, Joris Thybaut, Thomas Heugebaert, and Christian Stevens. 2015. “Efficient Continuous-flow Benzotriazole Activation and Coupling of Amino Acids.” Journal of Flow Chemistry 5 (4): 220–227.
- APA
- Seghers, Sofie, Van Waes, F., Cukalovic, A., Monbaliu, J.-C., De Visscher, J., Thybaut, J., Heugebaert, T., et al. (2015). Efficient continuous-flow benzotriazole activation and coupling of amino acids. JOURNAL OF FLOW CHEMISTRY, 5(4), 220–227.
- Vancouver
- 1.Seghers S, Van Waes F, Cukalovic A, Monbaliu J-C, De Visscher J, Thybaut J, et al. Efficient continuous-flow benzotriazole activation and coupling of amino acids. JOURNAL OF FLOW CHEMISTRY. 2015;5(4):220–7.
- MLA
- Seghers, Sofie, Frederik Van Waes, Ana Cukalovic, et al. “Efficient Continuous-flow Benzotriazole Activation and Coupling of Amino Acids.” JOURNAL OF FLOW CHEMISTRY 5.4 (2015): 220–227. Print.
@article{7221978,
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 (alpha-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.},
author = {Seghers, Sofie and Van Waes, Frederik and Cukalovic, Ana and Monbaliu, Jean-Christophe and De Visscher, Jeroen and Thybaut, Joris and Heugebaert, Thomas and Stevens, Christian},
issn = {2062-249X},
journal = {JOURNAL OF FLOW CHEMISTRY},
keyword = {microreactor,continuous flow,amino acids,benzotriazole,amide bond formation,N-ACYLBENZOTRIAZOLES,MICRO REACTORS,BETA-PEPTIDES,REAGENTS,ALPHA,HETEROCYCLES,DERIVATIVES,INHIBITORS,DESIGN,FMOC-ALPHA-AMINOACYL)BENZOTRIAZOLES},
language = {eng},
number = {4},
pages = {220--227},
title = {Efficient continuous-flow benzotriazole activation and coupling of amino acids},
url = {http://dx.doi.org/10.1556/1846.2015.00029},
volume = {5},
year = {2015},
}
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