灯盏花甲素、乙素等天然黄酮-7-O-糖苷的合成

doi:10.6023/A19060233

摘要/Abstract

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, V∶V=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

引用此文

邵文博, 安泉林, 曹鑫, 俞飚. 灯盏花甲素、乙素等天然黄酮-7-O-糖苷的合成[J]. 化学学报, 2019, 77(10): 999-1007.

Shao, Wenbo, An, Quanlin, Cao, Xin, Yu, Biao. Efficient Synthesis of Representative Flavone-7-O-Glycosides[J]. Acta Chimica Sinica, 2019, 77(10): 999-1007.

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图/表 4

图式1. 灯盏花甲素(1)、灯盏花乙素(2)、大波斯菊苷(3)、车前子苷(4)、apigenin 7-O-β-D-xylopyranoside (5)和apigenin 7-O-α-L-rhamno-pyranoside (6)的化学结构及逆合成分析

Scheme 1. Structures and retrosynthetic analysis of apigenin-7-O-β-D-glucuronide (1), scutellarin (2), apigetrin (3), plantaginin (4), apigenin 7-O-β-D-xylopyranoside (5) and apigenin 7-O-α-L-rhamnopyranoside (6)

图式2. 7-羟基芹菜素受体(10)和7-羟基野黄芩素受体(14)的制备

Scheme 2. Synthesis of the glycosylation receptors 10 and 14 for apigenin and scutellarein aglycons Reagents and conditions: (a) hexanoyl chloride, DMAP, pyridine/ CHCl3 (V∶V=2∶1), –78~–20 ℃, 90%; (b) 4-thiocresol, imidazole, NMP, 0 ℃ to r.t., 78% (for 10); (c) Ac2O, pyridine, 0 ℃ to r.t., 71%; (d) AllBr, KI, K2CO3, DMF, r.t., 68%; (e) conc. HCl, EtOH, reflux, 96%; (f) KI, BnBr, K2CO3, acetone, reflux, 50%; (g) (Ph3P)4Pd, NaBH4, THF, r.t., 57%.

图式3. 灯盏花甲素(1)和乙素(2)的合成

Scheme 3. Synthesis of apigenin-7-O-β-D-glucuronide (1) and scutellarin (2) Reagents and conditions: (a) Ph3PAuNTf2 (0.2 equiv.), 4 ? MS, CH2Cl2, r.t., 5 h, 92%; (b) TBAF, HOAc, THF, 0 ℃ to r.t.; (c) DAIB, TEMPO, CH2Cl2/H2O (V∶V=2∶1), r.t., 55% for 16 and 59% for 18 (2 steps); (d) K2CO3, MeOH, r.t., 98%; (e) 10% Pd/C, 101 kPa H2, MeOH/THF (V∶V=1∶1), r.t., 99%.

表1. 灯盏花素类似物3~6的合成

Table 1. Synthesis of natural flavone-7-O-glycosides 3~6

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