N-Triazinylammonium Tetrafluoroborates. A New Generation of Efficient Coupling Reagents Useful for Peptide Synthesis
Abstract
A new generation of triazine-based coupling reagents (TBCRs), designed according to the concept of "superactive esters", was obtained by treatment of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium (DMTMM) chloride with lithium or silver tetrafluoroborate. The structure of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate was confirmed by X-ray diffraction. Activation of carboxylic acids by using this reagent proceeds via triazine "superactive ester". The coupling reagent was successfully used for the synthesis of Z-, Boc-, and Fmoc-protected dipeptides derived from natural and unnatural sterically hindered amino acids and for fragment condensation, in 80-100% yield and with high enantiomeric purity. The manual SPPS of the ACP(65-74) peptide fragment (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH) proceeded significantly faster than with TBTU or HATU, as well as the automated SPPS of the same fragment gave a purer product than by using TBTU or PyBOP. The reagent was also demonstrated to be efficient in on-resin head-to-tail cyclization of constrained cyclopeptides, in SPPS synthesis of Aib peptides, and in the synthesis of esters from appropriate acids, alcohols, and phenols. The high efficiency and versatility of this new generation of TBCRs confirm, for the first time, the usefulness of the concept of "superactive esters" in rational design of the structure of coupling reagents.
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The ynamide-mediated thioamide bond formation strategy is not limited to thioamide substituted peptides; it can also be applied to common thioamides.
“This strategy is not limited to thioamide substituted peptides; it can also be applied to common thioamides.42”
From Ynamide Coupling Reagents: Origin and Advances (2024) · cites this paper as [42]
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- Authors
- Kamiński, Z. J., Kolesińska, B., Kolesińska, J., Sabatino, G., Chelli, M., Rovero, P., Błaszczyk, M., Główka, M. L., & Papini, A. M.
- Affiliations
- Contribution from the Institute of Organic Chemistry, Łódź University of Technology, 90-924 Łódź, Poland, Laboratory of Peptide and Protein Chemistry and Biology, Polo Scientifico, Università di Firenze, I-50019 Sesto Fiorentino, Florence, Italy, Dipartimento di Chimica Organica “Ugo Schiff” and CNR-ICCOM, Polo Scientifico, Università di Firenze, I-50019 Sesto Fiorentino, Florence, Italy, Dipartimento di Scienze Farmaceutiche, Università di Firenze, I-50019 Sesto Fiorentino, Florence, Italy, and...
- Lodz University of Technology (PL)
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-11-10
- Volume
- 127
- Issue
- 48
- Pages
- 16912-16920
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2001451367
- Cited by
- 155
- References
- 44
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 10 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 11
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- tetrafluoroborate, peptide synthesis, solid-phase peptide synthesis, fragment condensation, asymmetric synthesis, unnatural amino acids, esterification, carboxylic acid activation
- MeSH terms
- Amides, Amino Acids, Borates, Esters, Fluorenes, Morpholines, Oligopeptides, Peptides, Peptides, Cyclic, Triazines, X-Ray Diffraction, Molecular Structure, Silver Compounds
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