海洋环肽stylissamide Ⅰ的全合成研究
投稿时间:2018-10-31  修订日期:2019-02-13  点此下载全文
引用本文:陆东涛,刘超,秦路平,邹燕.海洋环肽stylissamide Ⅰ的全合成研究[J].药学实践杂志,2019,37(5):444~449
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作者单位E-mail
陆东涛 海军军医大学长海医院 药材科, 上海 200433  
刘超 海军军医大学 药学院, 上海 200433  
秦路平 海军军医大学 药学院, 上海 200433  
邹燕 海军军医大学 药学院, 上海 200433 zouyan0622@126.com 
基金项目:海军军医大学军事课题(2017JS11)
中文摘要:目的 采用固相合成/液相环化方法合成海洋环肽stylissamide Ⅰ。方法 以2-氯三苯甲基氯树脂(简称二氯树脂)为载体,选用6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)和N,N-二异丙基乙胺(DIPEA)为缩合试剂依次连接9-笏甲氧羰基保护的氨基酸,在三氟乙醇(TFE)的作用下将直链肽从树脂上切割下来,然后使用(3H-1,2,3-三唑并吡啶-3-氧基)三-1-吡咯烷基六氟磷酸盐(PyAOP),N-羟基-7-氮杂苯并三氮唑(HOAt)和N-甲基吗啡啉(NMM)在溶液中完成环合,最后在三氟乙酸(TFA)的处理下脱去侧链保护基,获得环肽粗品。经反相高效液相色谱对所合成的环肽粗品进行纯化,终产物纯度98.9%。通过高分辨质谱、600 MHz 1H-NMR和13C-NMR鉴定,确定所合成环肽为目标环肽。结果 首次完成海洋环肽stylissamide Ⅰ的全合成,总收率为67%。结论 此法具有快捷、简便、高效的特点,较好地为stylissamide Ⅰ的固相全合成提供了参考。
中文关键词:stylissamide Ⅰ  固相合成  环肽
 
The total solid synthesis of marine cyclopeptide stylissamide Ⅰ
Abstract:Objective The marine cyclopeptide stylissamide Ⅰ was synthesized through a solid phase synthesis and cyclization in solution(SPS-CS).Methods 2-chlorotrityl chloride resin was used as solid support for the total synthesis.Each amino acid protected by 9-fluorenylmethyloxycarbonyl(Fmoc) group was coupled with N,N-diisopropylethylamine(DIPEA)/O-(6-chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro- phosphat(HCTU) as condensing agents.The linear peptide was cleaved from resin by 2,2,2-trifluoroethanol(TFE) and cyclized in the presence of(7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyAOP)/1-hydroxy-7-azabenzotriazole(HOAt)/N-methyl morphofine(NMM).Finally,the crude cyclopeptide was obtained through global deprotection with trifluoroacetic acid(TFA).The target compound was purified by preparative RP-HPLC to 98.9% pure and its structure was identified by 1H-NMR,13C-NMR and Q-TOF LC/MS.Results The first total synthesis of the marine cyclopeptide stylissamide Ⅰ was successfully realized with a yield of 67%.Conclusion A rapid,simple and high-efficient method of stylissamide Ⅰ total synthesis was successfully established.
keywords:stylissamide Ⅰ  solid phase synthesis  cyclopeptide
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