天然产物的化学-酶法合成：方法与策略的演进

张守祺; 王涛; 孔尧; 邹家胜; 刘元宁; 徐正仁

doi:10.12211/2096-8280.2024-028

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天然产物的化学-酶法合成：方法与策略的演进

特约评述 | 更新时间：2025-03-19

- 天然产物的化学-酶法合成：方法与策略的演进
- Chemoenzymatic synthesis of natural products: evolution of synthetic methodology and strategy
- 合成生物学 2024年5卷第5期页码：913-940
- 作者机构：
  
  北京大学药学院，天然药物及仿生药物全国重点实验室，北京 100191
- 作者简介：
  
  [ "张守祺（1998—），男，博士研究生。研究方向为活性二萜的化学-酶法合成。 E-mail：shouqizhang_pku@pku.edu.cn" ]
  [ "王涛（1991—），男，博士研究生。研究方向为活性二萜的化学-酶法合成。 E-mail：1005704167@qq.com" ]
  [ "徐正仁（1983—），男，研究员，博士生导师。研究方向为活性天然产物的化学-酶法合成、新颖生物催化反应的发现与应用、天然药物化学等。 E-mail：zhengrenxu@bjmu.edu.cn" ]
- 基金信息：
  
  国家自然科学基金(81991525;81973197)
- DOI：10.12211/2096-8280.2024-028
  中图分类号： Q816
- 收稿：2024-03-25，
  
  修回：2024-05-28，
  
  纸质出版：2024-10-31
- 稿件说明：
移动端阅览
张守祺，王涛，孔尧，邹家胜，刘元宁，徐正仁. 天然产物的化学-酶法合成：方法与策略的演进［J］. 合成生物学， 2024， 5（5）： 913-940

ZHANG Shouqi， WANG Tao， KONG Yao， ZOU Jiasheng， LIU Yuanning， XU Zhengren. Chemoenzymatic synthesis of natural products： evolution of synthetic methodology and strategy［J］. Synthetic Biology Journal， 2024， 5（5）： 913-940
张守祺，王涛，孔尧，邹家胜，刘元宁，徐正仁. 天然产物的化学-酶法合成：方法与策略的演进［J］. 合成生物学， 2024， 5（5）： 913-940 DOI： 10.12211/2096-8280.2024-028.

ZHANG Shouqi， WANG Tao， KONG Yao， ZOU Jiasheng， LIU Yuanning， XU Zhengren. Chemoenzymatic synthesis of natural products： evolution of synthetic methodology and strategy［J］. Synthetic Biology Journal， 2024， 5（5）： 913-940 DOI： 10.12211/2096-8280.2024-028.

摘要

天然产物是小分子药物和探针的重要来源，其合成研究一直以来是有机合成中一个备受关注而又极具挑战性的领域。随着色谱分离技术和结构分析技术的不断发展，微量活性天然产物的发现速度不断加快，其结构的多样性和复杂性也不断增加，而对其构效关系、靶标鉴定、体内活性等方面的研究则需要供应足够量的天然产物，因而对天然产物的合成在效率、经济性和规模等方面都提出了更高的要求。化学-酶法的方式为天然产物的合成研究提供了多维的视角，一方面提供了高效高选择性的酶催化合成方法，另一方面，酶催化反应的引入可以给原先合成策略的设计模式带来突破，并快速、高效地实现天然产物的多样化合成，从而成为近期研究的热点。其中酶催化反应如何有机地整合到天然产物的合成中便成为目前化学-酶法合成成功的关键，本文从当前天然产物化学-酶法的合成实践中总结了酶催化反应所发挥的三方面作用：①对合成起点的改变，即酶催化反应可以在合成原料中引入关键的手性中心或官能团，以体外酶促或体内发酵的方式提供复杂的合成前体，如多取代芳（杂）环、手性池等；②合成后期通过酶催化方式对多官能团底物或复杂骨架的惰性位置进行化学、区域和立体选择性的官能团化；③酶催化反应作为关键步骤在母核骨架构建中关键碳碳键形成方面的策略性应用。最后，本文从合成策略的设计、合成方法的开发以及研究人员思维等三个方面讨论了化学-酶法策略在当下所面临的挑战和未来的发展趋势。在此背景下，化学合成与生物催化等多学科手段的深度交叉融合将为天然产物的合成科学带来新的活力。

Abstract

Natural product is an important source of small-molecule drugs and probes

but its synthesis is challenging and has attracted lasting attention in the field of organic chemistry. With the continuous advancement of chromatographic techniques for separation and spectroscopic methods for structural analysis

the pace of discovering tiny bioactive natural products is accelerating

concomitantly leading to an increase in the diversity and complexity of the newly identified structures. However

to meet the demand of the quantity for the study of their structure-activity relationships

target identification

in vivo

activity evaluation

etc

growing challenges in the requirement for the synthetic efficiency

economy

and scalability of natural products are emerging. Synthetic practices in a chemoenzymatic way have provided multi-dimensional visions for natural product research

which emerged as a hot research topic in recent years. On the one hand

enzymatic catalysis has provided highly efficient and selective synthetic methodologies that would complement traditional synthetic methods. On the other hand

the introduction of enzyme-catalyzed reactions would bring a new mode of strategic design for synthesis

enabling the rapid and diverse synthesis of natural products with high efficiency. In this context

how to integrate the enzyme-catalyzed reactions into the synthesis of natural products is the key to a successful chemoenzymatic synthesis. We herein summarized three roles played by the applications of enzyme-catalyzed reactions in the current practices of chemoenzymatic synthesis of natural products. ①The involvement of biocatalysis would introduce a chiral center or a key functional group into the starting material

or supply complex synthetic precursors (

e.g

polysubstituted (hetero)aromatics

chiral pools

etc

via in vitro

enzyme-catalyzed reactions or fermentation

hence advancing the starting line of synthesis; ②Late-stage enzyme-catalyzed chemo-

regio-

and stereoselective modifications of substrates with heavily substituted functional groups or inert positions of complex skeletons; ③The strategic application of enzymatic catalysis as a key carbon-carbon bond-forming step in the construction of the skeleton of natural product. Finally

we have also discussed the current challenges and future trends of the chemoenzymatic synthesis of natural products in three facets

including the design of synthetic strategy

the development of synthetic methods

as well as persons involved in the research. Thus

the integration of interdisciplinary methods and technologies

including chemical synthesis and biocatalysis

would invigorate the synthesis of natural products.

关键词

Keywords

references

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