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设计合成了一类新型的、分别基于HOBt、HOAt、HOOBt、HOPfp和HOSu的亚胺正离子型缩合剂。其中HOBt衍生的亚胺正离子型缩合剂,无论是在反应活性还是产物光学纯度方面都大大优于脲正离子型缩合剂。这类缩合剂不仅可以用于酰胺和酯的合成,而且可以用于固、液相法合成小肽及生物活性肽,例如Leu 脑啡肽的合成。对这类缩合剂参与酰胺键形成反应的机理,也进行了研究。在卤代脲正离子型缩合剂基础上,设计并合成了α 卤代吡啶正离子型缩合剂BEP、FEP、BEPH、FEPH、α 卤代噻唑正离子型缩合剂BEMT和α 卤代苯并咪唑正离子型缩合剂CMBI。与目前应用较广的卤代脲正离子型缩合剂和卤代磷正离子型缩合剂相比,这些缩合剂具有反应活性高、产物消旋小、收率高等优点,既可以用于液相合成也可用于固相合成。采用这些缩合剂,不仅合成了一系列的小肽,而且还成功地合成了Dolas tatin 1 5的肽链部分、CyclosporinA的 8～ 1 1片段和ActinomycinD的酯肽链部分等富含N 甲基氨基酸的、具有高空间位阻的多肽。为进一步验证这些新型缩合剂的性能,以具有高空间位阻的生物活性环肽CyclosporinO为目标分子,选取新型亚胺正离子型缩合剂BDMP、噻唑正离子型缩合剂BEMT和吡啶正离子型缩合剂BEP,从氨基酸衍生物出发,以 1 8% - 2 3%的总收率实?
A series of novel imine cation type condensing agents based on HOBt, HOAt, HOOBt, HOPfp and HOSu were designed and synthesized. Among them, the HOBt-derived imine cation type condensing agent is greatly superior to urea positive ion type condensing agent in terms of reactivity and optical purity of the product. Such condensing agents can be used not only for the synthesis of amides and esters, but also for the synthesis of small and biologically active peptides by solid and liquid phase methods such as the synthesis of Leu enkephalin. The mechanism of the participation of such condensing agents in the amide bond formation reaction has also been studied. On the basis of halourea positive ion type condensing agent, α-halopyridine positive ion type condensing agent BEP, FEP, BEPH and FEPH was designed and synthesized, α-halogenated thiazole positive ion type condensing agent BEMT and α-halobenzimidazole Cationic condensing agent CMBI. Compared with the currently widely used halogenated urea positive ion type condensing agent and halogenated phosphorus positive ion type condensing agent, these condensing agents have the advantages of high reactivity, small racemic product and high yield, and can be used in liquid phase Synthesis can also be used for solid-phase synthesis. These condensing agents not only synthesize a series of small peptides but also successfully synthesize the peptide chain part of Dolas tatin 1 5, N methyl amino acid which is rich in N-methyl amino acid such as 8-1 1 fragment of Cyclosporin A and ester peptide chain part of Actinomycin D Of polypeptides with high steric hindrance. To further verify the performance of these new condensing agents, CyclosporinO, a novel bioactive cyclic peptide with high steric hindrance, was selected as the target molecule. A new type of iminium cation condensate BDMP, a thiazole positive ion condensator BEMT and a pyridinium cation Mixture of BEP, starting from the amino acid derivatives, in 18% - 23% of the total yield of real?