点击化学作为分子连接工具: 机遇与挑战

doi:10.1016/S1872-2067(23)64434-1

催化学报 ›› 2023, Vol. 49: 8-15.DOI: 10.1016/S1872-2067(23)64434-1

点击化学作为分子连接工具: 机遇与挑战

汪琛^,¹, 杨俊祝^,¹, 卢元^*()

清华大学化学工程系, 工业生物催化教育部重点实验室, 北京 100084

收稿日期:2023-03-01 接受日期:2023-03-21 出版日期:2023-06-18 发布日期:2023-06-05
通讯作者: ^*电子信箱: yuanlu@tsinghua.edu.cn (卢元).
作者简介:第一联系人：
¹共同第一作者.
基金资助:
国家重点研发计划(2018YFA0901700);国家自然科学基金(22278241);清华大学国强研究院(2021GQG1016);清华大学化工系-iBHE专项合作联合基金

Click chemistry as a connection tool: Grand opportunities and challenges

Chen Wang^,¹, Junzhu Yang^,¹, Yuan Lu^*()

Key Laboratory of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China

Received:2023-03-01 Accepted:2023-03-21 Online:2023-06-18 Published:2023-06-05
Contact: E-mail: yuanlu@tsinghua.edu.cn (Y. Lu).
About author:Yuan Lu is an Associate Professor at Tsinghua University. After receiving B.S. (2004) and Ph.D. (2009) in chemical engineering from Tsinghua University, China, Yuan Lu received postdoctoral training from Johns Hopkins University (2009-2010) and Stanford University (2010-2014), USA. He was a project researcher from 2014 to 2016 at the University of Tokyo, Japan. Dr. Lu joined the faculty of Chemical Engineering at Tsinghua University in 2016. The central paradigm of his research is using interdisciplinary approaches in engineering, biology, chemistry, physics, and computer science to manipulate biomolecules and complex biological systems. The main focus lies on developing and applying synthetic biology and other cutting-edge technologies to engineer nucleic acids, proteins, pathways, and networks for addressing the most daunting challenges in human health.
First author contact:¹ Contributed equally to this work.
Supported by:
National Key R&D Program of China(2018YFA0901700);National Natural Science Foundation of China(22278241);Institute Guo Qiang, Tsinghua University(2021GQG1016);Department of Chemical Engineering‐iBHE Joint Cooperation Fund

摘要/Abstract

摘要：

2022年诺贝尔化学奖授予点击化学以及生物正交化学领域的三位科学家, 显示了点击化学在当代合成领域的重要地位. 点击化学本质是一类连接反应, 旨在通过将不同单元分子高效地拼接在一起, 最终得到具有特定结构与功能的分子. 在传统有机化学中, 碳碳键的合成通常具有较大难度, 因为它们涉及较低的化学驱动力和较多的副反应. 点击化学强调开发基于碳杂原子键的新型组合化学反应, 并通过这些反应简单有效地获得多样性分子. 点击化学的发展将科学家们从复杂、专业性强的有机合成中解放出来, 使他们可以专注于分子功能的开发, 一定程度拓宽了合成化学的应用范围. 基于点击化学的优越性能, 其在聚合物合成以及生物医学等领域表现出了非常广泛的应用前景. 本文简要概述了几种涉及不同底物和催化剂类型的典型点击反应, 并尝试解释这一领域背后的发展逻辑. 此外, 阐述了点击化学在现代科学, 尤其是聚合物合成和生命科学等领域的应用, 及其目前存在的局限性和未来可能的发展方向.

点击反应的主要特征包括产率高、选择性好、副产物无害且易分离、反应条件简单、原料易得、符合原子经济性和应用范围广等. 典型的点击化学包括亲核开环反应、环加成反应、保护基反应、碳碳多键加成反应和施陶丁格反应等, 这些反应大多在点击化学概念提出之前就已被开发. 通过改变反应条件, 选择合适的底物和催化剂, 这些反应可以更加满足点击标准. 而随着点击化学在生命科学领域的应用, 不依赖于催化剂的反应逐渐受到重视, 因为他们更有希望在生物体内保持点击活性. 环应力可以在无催化剂存在下有效改善反应动力学, 针对底物分子应力的研究成为了点击化学领域的重点. 此外, 近年来光催化点击反应和解离反应也受到广泛关注, 这些“智能”点击反应可以提供有效的时空控制、可逆的连接-释放过程, 代表了点击化学新的突破. 在应用方面, 点击化学可以提供高原子经济性的分子合成方法, 因而被广泛用于聚合物的合成, 它也为聚合物的功能修饰提供了简便方法. 然而在生命科学领域, 无催化剂反应显然更有利于生理环境下的分子合成, 这也体现了点击化学背后受应用驱动的发展逻辑. 当然, 不同应用场景也为点击反应提出了新要求. 本文强调了生物相容性、可扩展性以及智能化会是点击化学未来发展面临的主要挑战, 需要深入研究点击化学在复杂应用场景中的反应机制, 引入计算机技术帮助提高可扩展性, 以及开发光、磁等物理因素控制的反应类型. 相信通过新理论、新技术的引入, 点击化学领域将会取得更大的突破.

关键词: 点击化学, 生物正交化学, 组合化学, 高分子材料, 生物医学

Abstract:

Although the concept of click chemistry was proposed more than twenty years ago, the research progress of click chemistry has emerged with great vitality, and this year's Nobel Prize in chemistry has once again highlighted the importance of the field of click chemistry. Click chemistry is a reaction in which a variety of molecules are quickly and reliably synthesized by piecing together small units. In particular, it emphasizes the development of new combinatorial chemistry methods based on the synthesis of carbon-heteroatomic bonds and the simple and efficient acquisition of molecular diversity through these reactions. Based on the superior reaction characteristics of click chemistry, click chemistry methods for production are advancing toward precision, simplicity, and high returns, especially in producing polymer materials and some bright biomedical applications. Here, we describe the development logic of typical click reactions with different substrates and catalysts. The latest technologies of click chemistry in the structure control and functional properties of polymers, as well as in the field of biomedicine and its expanding applications, are discussed. Finally, we identify the challenges of click chemistry in reaction mechanisms and engineering applications, and suggest potential future development directions in the future.

Key words: Click chemistry, Bioorthogonal chemistry, Combinatorial chemistry, Polymer material, Biomedical science

汪琛, 杨俊祝, 卢元. 点击化学作为分子连接工具: 机遇与挑战[J]. 催化学报, 2023, 49: 8-15.

Chen Wang, Junzhu Yang, Yuan Lu. Click chemistry as a connection tool: Grand opportunities and challenges[J]. Chinese Journal of Catalysis, 2023, 49: 8-15.

×
扫码分享

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://www.cjcatal.com/CN/10.1016/S1872-2067(23)64434-1

https://www.cjcatal.com/CN/Y2023/V49/I6/8

图/表 4

Fig. 1. Available reaction types in click chemistry and their development to meet the needs of the application. Click chemistry aims to synthesize molecules through the simple linkage of functional modules, just like a strap connector. The criteria of click chemistry have instructed us to find several available reaction types. These reactions are not perfect at the beginning and still need improvement. Since the application fields have been broadly enlarged, click reactions should be further developed in two main directions, meaning they should be more condition-relaxed and more intelligent. In this case, strain-activated substrates have been proven to accelerate reactions in the physiological environment. Light-triggered and dissociative click reactions have provided new breakthroughs to make this field smarter and more controllable.

Table 1 Common click reaction types and their conditions. Most click reactions happen under mild conditions, but they could still need proper catalysts.

Reaction category	Catalyst	Substrate	Temperature	Solvent
Nucleophilic opening of spring-loaded rings	—	spring-loaded cyclic electrophile (epoxides, aziridines, cyclic sulfates, etc.), nucleophile	ambient or slightly higher than 100 °C	no solvents, water; alcohol
Huisgen 1,3-dipolar cycloaddition	Cu(I), Cu(II), strain-promoted	dipoles (propargyl, allyl, mesoionics), dipolarophiles (alkynes, allenes, etc.)	ambient	water, polar organic solvents
Diels-Alder reactions	lewis acid, strain-promoted	conjugated diene, dienophile (substituted olefin)	< 200 °C	water, organic solvent
“Protecting Group” reactions	acid	idol, hydroxysulfonamides, aldehydes/ketones	ambient	without water
Michael addition	acid, base, noble metal	activated alkynes, soft nucleophiles	ambient or slightly higher than 100 °C	solvent tolerant, high-polar solvent preferred
Staudinger reactions	—	triarylphosphines, azides	ambient	water

Fig. 2. The potential application of click chemistry in the field of polymer science and biomedical. Click chemistry could facilitate the accurate structure control and flexible function modification in polymer synthesis. It also brings new breakthroughs in bioconjugation, further applied to biomarker/imaging, drug delivery, and drug target screening fields.

Fig. 3. Challenges and possible solutions in click chemistry. The various application fields have proposed new challenges to click chemistry. Summarily, click reactions should be more biocompatible and easily happen in physiological conditions. They should also be more extensible to facilitate the construction of a molecule library. Smart click chemistry is also encouraged to bring intelligent control to this process. To face these challenges, we propose to further explore the detailed mechanism of click reactions, especially in complicated application scenarios. Computer science might provide solutions for constructing a large-scale molecule library and high-throughput screening based on click reactions. Additionally, physical factors, such as light and magnetism, could be introduced as controllable elements, which might promote smart click chemistry.

参考文献

[1]	H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed., 2001, 40, 2004-2021.
[2]	W.-C. Yang, C.-Y. Chen, J.-F. Li, Z.-L. Wang, Chin. J. Catal., 2021, 42, 1865-1875.
[3]	D. Ferraris, W. J. Drury, C. Cox, T. Lectka, J. Org. Chem., 1998, 63, 4568-4569.
[4]	M. Breugst, H.-U. Reissig, Angew. Chem. Int. Ed., 2020, 59, 12293-12307.
[5]	L. Liang, D. Astruc, Coord. Chem. Rev., 2011, 255, 2933-2945.
[6]	J. C. Worch, C. J. Stubbs, M. J. Price, A. P. Dove, Chem. Rev., 2021, 121, 6744-6776.
[7]	T. K. Heiss, R. S. Dorn, J. A. Prescher, Chem. Rev., 2021, 121, 6802-6849.
[8]	E. Haldon, M. C. Nicasio, P. J. Perez, Org. Biomol. Chem., 2015, 13, 9528-9550.
[9]	E. M. Sletten, C. R. Bertozzi, Angew. Chem. Int. Ed., 2009, 48, 6974-6998.
[10]	G. Wittig, A. Krebs, Chemische Berichte, 1961, 94, 3260-3275.
[11]	B. D. Fairbanks, L. J. Macdougall, S. Mavila, J. Sinha, B. E. Kirkpatrick, K. S. Anseth, C. N. Bowman, Chem. Rev., 2021, 121, 6915-6990.
[12]	J. Tu, M. Xu, R,. M. J. C. Franzini, ChemBioChem, 2019, 20, 1615-1627.
[13]	R. Tian, S. M. Xu, Q. Xu, C. Lu, Sci. Adv., 2020, 6, eaaz6107.
[14]	J. Wang, J. Mei, W. Yuan, P. Lu, A. Qin, J. Sun, Y. Ma, B. Z. Tang, J. Mater. Chem., 2011, 21, 4056-4059.
[15]	B. Yao, T. Hu, H. Zhang, J. Li, J. Z. Sun, A. Qin, B. Z. Tang, Macromolecules, 2015, 48, 7782-7791.
[16]	Z. S. Geng, J. J. Shin, Y. M. Xi, C. J. Hawker, J. Polym. Sci., 2021, 59, 963-1042.
[17]	Q. Zhang, A. Anastasaki, G.-Z. Li, A. J. Haddleton, P. Wilson, D. M. Haddleton, Polym. Chem., 2014, 5, 3876-3883.
[18]	P. A. Szijj, K. A. Kostadinova, R. J. Spears, V. Chudasama, Org. Biomol. Chem., 2020, 18, 9018-9028.
[19]	C. J. Pickens, S. N. Johnson, M. M. Pressnall, M. A. Leon, C. J. Berkland, Bioconjug. Chem., 2018, 29, 686-701.
[20]	B. Stump, Chembiochem, 2022, 23, e202200016.

点击化学作为分子连接工具: 机遇与挑战

Click chemistry as a connection tool: Grand opportunities and challenges

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

扫码分享

图/表 4

参考文献

相关文章 2

编辑推荐

Metrics

[1]	高凯;袁丽威;乔元兴;白吉玲;王利. 紫外吸收光谱法在高通量筛选中的应用[J]. 催化学报, 2005, 26(8): 688-692.
[2]	孙波;;孟祥举;王世超;孙淑清;肖丰收*. 利用化学指示剂在多相催化反应中进行高通量筛选[J]. 催化学报, 2005, 26(5): 349-351.