N-Triazinylammonium Tetrafluoroborates. A New Generation of Efficient Coupling Reagents Useful for Peptide Synthesis

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.

新一代基于三嗪的偶联试剂（TBCRs）的生成，依据“超活性酯”的概念设计，通过4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉（DMTMM）氯化物与四氟硼酸锂或银的相互作用获得。通过X射线衍射技术确认了4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉四氟硼酸盐的结构。使用该试剂活化羧酸，通过三嗪“超活性酯”机制进行。该偶联试剂成功应用于从天然和合成空间位阻氨基酸衍生出的Z-, Boc-, 和Fmoc-保护的二肽的合成，以及片段缩合，产率在80%-100%，且对映选择性高。手动SPPS合成ACP(65-74)肽片段（H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH）的速度显著快于使用TBTU或HATU，而自动SPPS合成相同片段的产品纯度也高于使用TBTU或PyBOP。此外，该试剂在受限环状肽的树脂上头尾环化、Aib肽的SPPS合成，以及从适当的酸、醇和酚中合成酯的过程中也表现出高效性。这一代TBCRs的高效性和多功能性首次证实了“超活性酯”概念在偶联试剂结构理性设计中的实用性。