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海洋环肽stylissamide Ⅰ的全合成研究

陆东涛,  刘超,  秦路平,  邹燕

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文章导航 > 药学实践与服务  > 2019 >  37(5): 444-449
陆东涛, 刘超, 秦路平, 邹燕. 海洋环肽stylissamide Ⅰ的全合成研究[J]. 药学实践与服务, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
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]. 药学实践与服务, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
shu
LU Dongtao, LIU Chao, QIN Luping, ZOU Yan. The total solid synthesis of marine cyclopeptide stylissamide Ⅰ[J]. Journal of Pharmaceutical Practice and Service, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
Citation: LU Dongtao, LIU Chao, QIN Luping, ZOU Yan. The total solid synthesis of marine cyclopeptide stylissamide Ⅰ[J]. Journal of Pharmaceutical Practice and Service, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
shu

海洋环肽stylissamide Ⅰ的全合成研究

doi: 10.3969/j.issn.1006-0111.2019.05.011
  • 1.

    海军军医大学长海医院 药材科, 上海 200433

  • 2.

    海军军医大学 药学院, 上海 200433

基金项目: 海军军医大学军事课题（2017JS11）

The total solid synthesis of marine cyclopeptide stylissamide Ⅰ

  • 1.

    Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai 200433, China

  • 2.

    School of Pharmacy, Naval Medical University, Shanghai 200433, China

  • 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。
    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.
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海洋环肽stylissamide Ⅰ的全合成研究

doi: 10.3969/j.issn.1006-0111.2019.05.011
  • 1. 海军军医大学长海医院 药材科, 上海 200433
  • 2. 海军军医大学 药学院, 上海 200433
    • 基金项目:  海军军医大学军事课题（2017JS11）
  • 收稿日期: 2018-10-31
  • 修回日期: 2019-02-13

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。

English Abstract

陆东涛, 刘超, 秦路平, 邹燕. 海洋环肽stylissamide Ⅰ的全合成研究[J]. 药学实践与服务, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
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]. 药学实践与服务, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
shu
LU Dongtao, LIU Chao, QIN Luping, ZOU Yan. The total solid synthesis of marine cyclopeptide stylissamide Ⅰ[J]. Journal of Pharmaceutical Practice and Service, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
Citation: LU Dongtao, LIU Chao, QIN Luping, ZOU Yan. The total solid synthesis of marine cyclopeptide stylissamide Ⅰ[J]. Journal of Pharmaceutical Practice and Service, 2019, 37(5): 444-449. doi: 10.3969/j.issn.1006-0111.2019.05.011
shu

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