| Abstract
| - A new generation of triazine-based coupling reagents (TBCRs), designed according to the conceptof “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 ofcarboxylic acids by using this reagent proceeds via triazine “superactive ester”. The coupling reagent wassuccessfully used for the synthesis of Z-, Boc-, and Fmoc-protected dipeptides derived from natural andunnatural sterically hindered amino acids and for fragment condensation, in 80−100% yield and with highenantiomeric 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 automatedSPPS of the same fragment gave a purer product than by using TBTU or PyBOP. The reagent was alsodemonstrated to be efficient in on-resin head-to-tail cyclization of constrained cyclopeptides, in SPPSsynthesis 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 usefulnessof the concept of “superactive esters” in rational design of the structure of coupling reagents.
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