天然药物小檗碱的化学合成研究进展

doi:10.6023/cjoc202012053

摘要/Abstract

小檗碱(Berberine, BBR)是一种重要的天然药物, 是具有独特四环结构的异喹啉类生物碱. 近年来药理学研究发现, 小檗碱有望用于肿瘤及糖尿病等多发病的临床治疗. 结合Woodward等提出的生源合成理论, 综述了截至目前已报道的小檗碱的全合成策略与方法.

关键词: 天然药物, 小檗碱, 苄基异喹啉, 全合成

Berberine is an important natural drug and a kind of benzyl isoquinoline alkaloid, which has unique four-ring structure. In recent years, pharmacological research has found berberine is expected to be used in the clinical treatment of cancer, diabetes and other frequently occurring diseases. Based on the Woodward’s biosynthetic hypothesis, a schematic review on the synthetic studies towards berberine is provided.

Key words: natural drug, berberine, benzyl isoquinoline, total synthesis

引用此文

严锡飞, 郑剑峰, 李卫东. 天然药物小檗碱的化学合成研究进展[J]. 有机化学, 2021, 41(6): 2217-2227.

Xifei Yan, Jianfeng Zheng, Wei-Dong Z. Li. Studies on the Chemical Synthesis of Natural Drugs Berberine[J]. Chinese Journal of Organic Chemistry, 2021, 41(6): 2217-2227.

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图/表 14

图1. 小檗碱及其类似物结构

Figure 1. Structures of berberine and its analogues

图式1. 小檗碱的生物合成途径

Scheme 1. Biosynthetic route of berberine

图式2. 主流的单萜吲哚生物碱生物合成途径、Robinson-Woodward的单萜吲哚生物碱生物合成假说和小檗碱的生物合成猜想

Scheme 2. Major biosynthesis routes of monoterpene indole alkaloids, the Robinson-Woodward’s biosynthetic hypothesis of monoterpene indole alkaloids and proposed major biosynthesis routes of berberine

图式3. 小檗碱的全合成以及骨架合成策略

Scheme 3. Strategies of total synthesis or formal synthesis of berberine

图式4. 甲醛参与的小檗碱骨架合成

Scheme 4. Synthesis of framework of berberine with formaldehyde

图式5. 其它甲酰化试剂参与的小檗碱骨架合成

Scheme 5. Synthesis of framework of berberine with other formylation reagent

图式6. C1分子内环化策略构建小檗碱及其骨架

Scheme 6. Synthesis of berberine and its framework using C1 intramolecular cyclization

图式7. C2分子内环化策略小檗碱及其骨架

Scheme 7. Synthesis of berberine and its framework using C2 intramolecular cyclization

图式8. 安静娴等小组全合成小檗碱及其骨架

Scheme 8. Total synthesis of berberine and its framework by An’s group et al.

图式9. 小檗碱的骨架合成

Scheme 9. Synthesis of framework of berberine

图式10. 金属催化全合成小檗碱

Scheme 10. Metal-catalyzed total synthesis of berberine

图式11. 李卫东小组的形式合成小檗碱骨架

Scheme 11. Formal synthesis of berberine skeleton by Li’s group

图2. 白毛茛碱及其类似物结构

Figure 2. Structures of (–)-β-hydrastine and its analogues

分类	年份	研究组	步骤数^a	总收率^b/%	关键中间体		参考文献
分类	年份	研究组	步骤数^a	总收率^b/%	A	B	参考文献
C1环化法	1969	Kametani	>6	<8			[33]
C1环化法	2007	亚邦制药	6	67			[40]
C2环化法	1972	安静娴	7	6.4^c			[42]
C2环化法	2018	Clift	4	54			[52]
其它金属催化合成法	2014	Donohobe	7	28			[53]
	2015	Anand	4	32			[54]
	2016	童荣标	6	19			[55]
	2020	张延东	5	7.6			[57]

表1. 小檗碱全合成研究工作总结

Table 1. Summary of total synthesis of berberine

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