新型高效多肽缩合剂的研究(英文)  

Studies of Novel and Highly Efficient Peptide Coupling Reagents

作　　者：李鹏[1] 徐杰诚[1] 

机构地区：[1]中国科学院上海有机化学研究所,上海200032

出　　处：《中国科学院研究生院学报》2004年第1期125-134,共10页Journal of the Graduate School of the Chinese Academy of Sciences

基　　金：supportedbytheNationalNaturalScienceFoundationofChina(9772 0 45 )

摘　　要：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 number of novel and highly efficient immonium-, pyridinium-, thiazolium-, and benzimidazolium-type peptide coupling reagents, such as BOMI, BDMP, BPMP, BEP, FEP, BEPH, FEPH, BEMT, and CMBI were designed and synthesized. The high efficiency of these onium salts has been evaluated and proved by model reaction tests and the successful synthesis of various oligopeptides and biologically active peptides both in solution and in the solid-phase, for example Leu-enkephalin, the pentapeptide moiety of Dolastatin 15 and the immunosuppressive undecapeptide Cyclosporin O. Based upon extensive studies of the structure-activity relationship of these coupling reagents, a preliminary guideline for the molecular design of onium-type coupling reagents was developed. These novel reagents have proved to be very useful in the synthesis of structurally challenging peptides and peptidomimetics.

关 键 词：缩合剂 分子设计 多肽合成 消旋 反应活性 

分 类 号：O629.72[理学—有机化学]