化学学报 ›› 2019, Vol. 77 ›› Issue (10): 999-1007.DOI: 10.6023/A19060233 上一篇    下一篇

研究论文

灯盏花甲素、乙素等天然黄酮-7-O-糖苷的合成

邵文博a, 安泉林b, 曹鑫b*(), 俞飚a*()   

  1. a 中国科学院上海有机化学研究所 生命有机化学国家重点实验室 上海 200032
    b 复旦大学附属中山医院实验研究中心 上海 200032
  • 收稿日期:2019-06-25 出版日期:2019-10-15 发布日期:2019-07-17
  • 通讯作者: 曹鑫,俞飚 E-mail:caox@fudan.edu.cn;byu@sioc.ac.cn
  • 基金资助:
    项目受国家自然科学基金委基金(21432012);项目受国家自然科学基金委基金(21621002);中国科学院先导B专项(XDB20020200);中科院青年创新促进会(2017300);王宽诚率先人才计划资助

Efficient Synthesis of Representative Flavone-7-O-Glycosides

Shao, Wenboa, An, Quanlinb, Cao, Xinb*(), Yu, Biaoa*()   

  1. a State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
    b Institute of Clinical Science, Zhongshan Hospital, Shanghai Medical School, Fudan University, Shanghai 200032
  • Received:2019-06-25 Online:2019-10-15 Published:2019-07-17
  • Contact: Cao, Xin,Yu, Biao E-mail:caox@fudan.edu.cn;byu@sioc.ac.cn
  • Supported by:
    Project supported by the Funds from the National Natural Science Foundation of China(21432012);Project supported by the Funds from the National Natural Science Foundation of China(21621002);the Chinese Academy of Sciences(Strategic Priority Research Program)(XDB20020200);the Youth Innovation Promotion Association(2017300);the K.C. Wong Education Foundation.

灯盏花甲素(apigenin-7-O-β-D-glucuronide, 1)和乙素(scutellarin, scutellarein-7-O-β-D-glucuronide, 2)是灯盏花素(breviscapine)中的两种主要黄酮苷成分, 具有抗氧化、抗肿瘤和治疗老年痴呆等生理活性; 大波斯菊苷(apigetrin, 3)、车前子苷(plantaginin, 4)、apigenin 7-O-β-D-xylopyranoside (5)、apigenin 7-O-α-L-rhamnopyranoside (6)等黄酮-7-O-糖苷也具有相似的结构和生理活性. 本工作针对黄酮苷元(芹菜素7和野黄芩素8)溶解度差、7位羟基酸性强而亲核性较弱以及糖醛酸糖基化给体反应活性较弱的问题, 综合利用使苷元有效增溶的保护基策略、金(I)催化的糖苷化方法和后期糖醛酸氧化策略, 高效构建了黄酮-7-O-葡萄糖醛酸结构, 并经统一的保护基脱除完成了灯盏花甲素(1) (36%)和乙素(2) (7%)的合成. 采用相似的策略, 从苷元出发分别以4~7步完成了天然黄酮-7-O-糖苷3~6的合成.

关键词: 灯盏花甲素, 灯盏花乙素, 黄酮-7-O-糖苷, 金催化糖苷化, 合成

Apigenin-7-O-β-D-glucuronide (1) and scutellarin (scutellarein-7-O-β-D-glucuronide, 2) are two major flavone glucuronide components occurring in breviscapines, which are prepared from the traditional Chinese herb Erigeron breviscapus. These two flavone glycosides show potent anti-oxidative, anti-inflammatory and neuroprotective activities in various evaluations. Synthesis of these natural glycosides in an efficiently manner would facilitate studies on their structure activity relationships. As a persistent effort on the chemical syntheses of the diverse glycoconjugates from traditional Chinese herbs in our group, we report herein the synthesis of these two representative flavone O-glucuronides. It is known that the solubility of flavone compounds is rather low and this property would greatly hinder their glycosylation reactions. In order to increase the solubility of the flavone derivatives in the glycosylation solvents, hexanoyl and benzyl groups were selected as the permanent protecting groups for the hydroxyl groups of apigenin (7) and scutellarein (8). The construction of the phenolic O-glucuronide is known to be a difficult task, especially the glycosylation of the poorly nucleophilic 7-hydroxyl group which locates at the para-position of the flavone carbonyl group. We achieved the glycosylation of the flavone 7-OH with 2,3,4-tri-O-benzoyl-6-O-TBDPS-glucopyranosyl ortho-alkynylbenzoate (9) under the catalysis of Ph3PAuNTf2 (0.2 equiv., 4 ? MS, CH2Cl2, r.t., 5 h) in excellent yields. After that, the 6-O-TBDPS groups were removed, and the requisite glucuronides were then elaborated by oxidation of the resulting 6-OH under the conditions of DAIB/TEMPO (CH2Cl2/H2O, VV=2∶1, r.t.) in good yields. After global deprotection, the desired products apigenin-7-O-β-D-glucuronide (1) and scutellarin (2) were obtained in overall yields of 36% (5 steps) and 7% (9 steps), respectively, from the starting flavone aglycones. Following the same strategy, four naturally occurring flavone-7-O-glycosides, namely apigetrin (3), plantaginin (4), apigenin 7-O-β-D-xylopyranoside (5) and apigenin 7-O-α-L-rhamnopyranoside (6), were smoothly synthesized in 4~7 steps with the overall yields of 61%, 13%, 58% and 61%, respectively.

Key words: apigenin-7-O-β-D-glucuronide, scutellarin, flavone glycoside, Au(I)-catalyzed glycosylation, synthesis