title: 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.
authors.affiliation: Institute of Organic Chemistry, Łódź University of Technology, Poland. kaminsz@mail.p.lodz.pl
authors.forename: Zbigniew J
authors.initials: ZJ
authors.lastname: Kamiński
authors.forename: Beata
authors.initials: B
authors.lastname: Kolesińska
authors.forename: Justyna
authors.initials: J
authors.lastname: Kolesińska
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sabatino
authors.forename: Mario
authors.initials: M
authors.lastname: Chelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Rovero
authors.forename: Michał
authors.initials: M
authors.lastname: Błaszczyk
authors.forename: Marek L
authors.initials: ML
authors.lastname: Główka
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Papini
mesh_terms: D000577:Amides / Q000138:chemical synthesis; D000596:Amino Acids / Q000737:chemistry; D001881:Borates / Q000138:chemical synthesis / Q000737:chemistry*; D004952:Esters / Q000138:chemical synthesis; D005449:Fluorenes / Q000737:chemistry; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis; D010455:Peptides / Q000138:chemical synthesis*; D010456:Peptides, Cyclic / Q000138:chemical synthesis; D018030:Silver Compounds / Q000737:chemistry; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: C467606:4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; D000577:Amides; D000596:Amino Acids; D001881:Borates; D004952:Esters; D005449:Fluorenes; D009025:Morpholines; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D018030:Silver Compounds; D014227:Triazines; C064097:silver tetrafluoroborate