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劉臻 博士

Zhen Liu, Ph.D.

Assistant Investigator, NIBS, Beijing

Email: liuzhen@nibs.ac.cn

Group website: http://www.liuzhenlab.com/

教育經(jīng)歷 Education

2015.8-2019.8  化學博士, 美國斯克里普斯研究所 (TSRI)

導師：Prof. Keary M. Engle

2015.8-2019.8 Ph.D. in Chemistry, The Scripps Research Institute, US.

Supervisor: Prof. Keary M. Engle

2011.9–2015.6  化學學士, 北京大學化學與分子工程學院

導師：王劍波教授，張艷教授

2011.9–2015.6 Bachelor in Chemistry, College of Chemistry and Molecular Engineering, Peking University, China

Supervisors: Prof. Jianbo Wang and Prof. Yan Zhang

工作經(jīng)歷 Professional Experience

2022.9至今 研究員，北京生命科學研究所

2022.9–present Assistant Investigator, NIBS, Beijing

2020.9–2022.8，副研究員（博士后），美國加州理工學院

導師：Prof. Frances H. Arnold

2020.9–2022.8 Postdoctoral Research Associate, California Institute of Technology, Frances H. Arnold laboratory, US

2019.9–2020.8，助理研究員（博士后），美國加州理工學院

導師：Prof. Frances H. Arnold

2019.9–2020.8 Postdoctoral Research Fellow, California Institute of Technology, Frances H. Arnold laboratory, US

研究概述 Research Description

酶是自然界各類生命體中的催化劑，是多種生理過程賴以維系的重要組分。人類在很早的時代就開始利用生物催化來進行社會生產(chǎn)，一個典型的例子就是我國古代的釀造工藝。近幾十年來，隨著定向進化以及多種分子生物學技術(shù)的飛速發(fā)展，科學家對于酶催化劑的改造能力得到了空前的提高，使得我們不僅可以快速地優(yōu)化酶的天然活性，拓寬底物范圍，甚至可以賦予他們未知的催化性能。這一進步極大地拓寬了生物催化在有機合成以及藥物研發(fā)領(lǐng)域的應用范圍和發(fā)展前景。

我們在北京生命科學研究所（NIBS）的實驗室將圍繞著發(fā)展高效新穎的生物催化反應為中心展開，研究目標在于解決化學合成和藥物開發(fā)過程中的難題，降低生產(chǎn)成本，推動這些新方法的工業(yè)化應用。課題組的研究方向主要有以下三個方面：

一． 通過定向進化或理性設計等手段發(fā)展非天然的高效酶促反應；

二． 發(fā)展多步酶催化或酶催化-化學反應相結(jié)合的串聯(lián)過程以實現(xiàn)活性有機小分子的高效合成；

三． 發(fā)展綠色經(jīng)濟的過渡金屬催化的有機反應方法學。

我們實驗室歡迎所有對有機化學，酶催化以及化學生物學感興趣的科研工作者加入到我們的團隊，來共同解決合成化學以及酶學領(lǐng)域中的現(xiàn)有難題。實驗室的訓練將使你對多個學科有所了解，為你未來的學術(shù)發(fā)展或者科研工作打下堅實的基礎。

Enzymes are nature’s catalysts for performing chemical transformations and generating structurally complex and functionally important molecules. Mankind has been fascinated by nature’s ability to evolve enzymes for various functions; numerous enzymes have been discovered in nature that perform a myriad of chemical reactions, some of which are difficult to mimic under synthetic conditions. With the clean and sustainable nature of biocatalysis, it is beneficial to utilize these transformations as powerful tools in organic synthesis. However, a substantial fraction of natural enzymes are not heterologously stable or expressible in common bacterial hosts, which limits biological studies and synthetic applications of these enzymes and is one of the major challenges of biocatalysis. So far, only a small number of enzymatic reactions can be reliably performed at industrial scale. Some enzymes can be used on laboratory scale to prepare challenging molecular structures, but the reaction types are still limited compared to small-molecule catalysis. Furthermore, many enzymes have exquisite substrate specificity, hindering their use with different substrates.

To expand the repertoire of enzymatic transformations and generate efficient synthetic strategies based on existing biocatalytic methods, my research group will focus on engineering enzymes for new-to-nature activities and developing chemoenzymatic cascade reactions. Specifically, my research program can be divided into three parts:

I. Developing novel chemoenzymatic cascade reactions to construct challenging structural motifs. Chemoenzymatic cascades combine one or more synthetic steps with enzymatic reactions, which benefits from the diverse reactivity of small-molecule catalysis and high selectivity of enzyme catalysis. Unfortunately, such a powerful strategy has not been widely utilized by synthetic chemists, partly due to the limited methods in the toolbox. Through developing efficient chemoenzymatic processes, we seek to demonstrate the full potential of this strategy.

II. Repurposing enzymes for new activities through engineering techniques. Exploring enzyme promiscuity toward different substrates and reactions is a common strategy to search for novel catalytic activities. With the emergence of directed evolution, we now have the ability to improve an enzyme’s promiscuous activity in an efficient manner.

III. Developing transition metal-catalyzed reactions for chemoenzymatic processes. Notably, these three parts are synergistic and complementary; synthetic methodology will be designed to provide substrate analogs for our new enzymes obtained from protein engineering and will be strictly performed under biocompatible conditions for integration into chemoenzymatic cascades. The proposed work will enable the rapid assembly of challenging structural motifs in organic synthesis.

發(fā)表文章 Publications

34. Zeng, Q.-Q.^?; Zhou, Q.-Y.^?; Calvó-Tusell, C.; Dai, S.-Y.; Zhao, X.; Garcia-Borràs, M.*; Liu, Z.* “Biocatalytic Desymmetrization for Synthesis of Chiral Enones Using Flavoenzymes,” Nat. Synth. 2024, 3, 1340–1348. (^?Authors contributed equally)

33. Yin, H.-N.; Wang, P.-C.; Liu, Z.* “Recent Advances in Biocatalytic C–N Bond-forming Reactions,” Bioorg. Chem. 2024, 144, 107108.

32. Qin, Z.-Y.^?; Gao, S.^?; Zou, Y.; Liu, Z.; Wang, J. B.; Houk, K. N.; Arnold, F. H. “Biocatalytic Construction of Chiral Pyrrolidines and Indolines via Intramolecular C(sp³)–H Amination,” ACS Cent. Sci. 2023, 9, 2333–2338. (^?Authors contributed equally)

31. Calvó-Tusell, C.^?; Liu, Z.^?,*; Chen, K.; Arnold, F. H., Garcia-Borràs, M. “Reversing the Enantioselectivity of Enzymatic Carbene N–H Insertion through Mechanism-guided Protein Engineering,” Angew. Chem. Int. Ed. 2023, 6, e202303879. (^?Authors contributed equally)

30. Ni, H.-Q.; Karunananda, M. K.; Zeng, T.; Yang, S.; Liu, Z.; Houk, K. N.; Liu, P.; Engle, K. M. “Redox-Paired Alkene Difunctionalization Enables Skeletally Divergent Synthesis,” J. Am. Chem. Soc. 2023, 145, 12351–12359.

29. Liu, Z.^?; Qin, Z.-Y.^?; Zhu L.; Athavale, S. V.; Sengupta, A.; Jia, Z.-J.; Garcia-Borràs, M.; Houk, K. N.; Arnold, F. H. “An Enzymatic Platform for Primary Amination of 1-Aryl-2-alkyl Alkynes,” J. Am. Chem. Soc. 2022, 144, 80–85. (^?Authors contributed equally)

28. Liu, Z.; Calvó-Tusell, C.; Zhou, A. Z.; Chen, K.; Garcia-Borràs, M.; Arnold, F. H. “Dual-Function Enzyme Catalysis for Enantioselective Carbon–Nitrogen Bond Formation,” Nat. Chem. 2021, 13, 1166–1172.

27. Athavale, S. V.^?; Gao, S.^?; Liu, Z.; Mallojjala, S. C.; Hirschi, J. S.; Arnold, F. H. “Biocatalytic, Intermolecular C–H Bond Functionalization for the Synthesis of Enantioenriched Amides,” Angew. Chem. Int. Ed. 2021, 60, 24864–24869. (^?Authors contributed equally)

26. Liu, Z.; Arnold, F. H. “New-to-nature Chemistry from Old Protein Machinery: Carbene and Nitrene Transferases,” Curr. Opin. Biotechnol. 2021, 69, 43–51.

25. Wang, X.; Li, Z.-Q.; Mai, B. K.; Gurak, J. A., Jr.; Xu, J. E.; Tran, V. T.; Ni, H.-Q.; Liu, Z.; Liu, Z.; Yang, K. S.; Xiang, R.; Liu, P.; Engle, K. M. “Controlling Cyclization Pathways in Palladium(II)-catalyzed Intramolecular Alkene Hydro-functionalization via Substrate Directivity,” Chem. Sci. 2020, 11, 11307–11314.

24. Liu, Z.; Chen, J.; Lu, H.-X.; Li, X.; Gao, Y.; Coombs, J. R.; Goldfogel, M.; Engle, K. M. “Pd(0)-Catalyzed Directed syn-1,2-Carboboration and -Silyation: Alkene Scope, Applications in Dearmoatization, and Stereocontrol via a Chiral Auxiliary,” Angew. Chem. Int. Ed. 2019, 58, 17068–17073.

23. Liu, Z.; Gao, Y.; Zeng, T.; Engle, K. M. “Transition-Metal-Catalyzed 1,2-Carboboration of Alkenes: Strategies, Mechanisms, and Stereocontrol,” Isr. J. Chem. 2020, 60, 219–229.

22. Liu, Z.; Li, X.; Zeng, T.; Engle, K. M. “Directed, Palladium(II)-Catalyzed Enantioselective anti-Carboboration of Alkenyl Carbonyl Compounds,” ACS Catal. 2019, 9, 3260–3265.

21. Zeng, T.; Liu, Z.; Schmidt, M. A.; Eastgate, M. D.; Engle, K. M. “Directed, Palladium(II)-Catalyzed Intermolecular Aminohydroxylation of Alkenes Using a Mild Oxidation System,” Org. Lett. 2018, 20, 3853–3857.

20. Gao, D.-W.; Xiao, Y.; Liu, M.; Liu, Z.; Karunananda, M. K.; Chen, J. S.; Engle, K. M. “Catalytic, Enantioselective Synthesis of Allenyl Boronates,” ACS Catal. 2018, 8, 3650–3654.

19. Liu, Z.; Ni, H.-Q.; Zeng, T.; Engle, K. M. “Catalytic Carbo- and Aminoboration of Alkenyl Carbonyl Compounds via Five- and Six-Membered Palladacycles,” J. Am. Chem. Soc. 2018, 140, 3223–3227.

18. Liu, Z.; Wang, Y.; Wang, Z.; Zeng, T.; Liu, P.; Engle, K. M. “Catalytic Intermolecular Carboamination of Unactivated Alkenes via Directed Aminopalladation,” J. Am. Chem. Soc. 2017, 139, 11261–11270.

17. Derosa, J.; Cantu, A. L.; Boulous, M. N.; O’Duill, M. L.; Turnbull, J. L.; Liu, Z.; De La Torre, D. M.; Engle, K. M. “Directed Palladium(II)-Catalyzed anti-Hydrochlorination of Unactivated Alkynes with HCl,” J. Am. Chem. Soc. 2017, 139, 5183–5193.

16. Liu, Z.; Zeng, T.; Yang, K. S.; Engle, K. M. “β,γ-Vicinal Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Directed Nucleopalladation,” J. Am. Chem. Soc. 2016, 138, 15122–15125.

15. Yang, K. S.; Gurak, J. A., Jr.; Liu, Z.; Engle, K. M. “Catalytic, Regioselective Hydrocarbofunctionalization of Unactivated Alkenes with Diverse C–H Nucleophiles,” J. Am. Chem. Soc. 2016, 138, 14705–14712.

14. Liu, Z.; Derosa, J.; Engle, K. M. “Palladium(II)-Catalyzed Regioselective syn-Hydroarylation of Disubstituted Alkynes Using a Removable Directing Group,” J. Am. Chem. Soc. 2016, 138, 13076–13081.

13. Gurak, J. A., Jr.; Yang, K. S.; Liu, Z.; Engle, K. M. “Directed, Regiocontrolled Hydroamination of Unactivated Alkenes via Protodepalladation,” J. Am. Chem. Soc. 2016, 138, 5805–5808.

12. Liu, Z.; Xia, Y.; Feng, S.; Zhang, Y.; Wang, J. “Rh(I)-Catalyzed Coupling of 2-Bromoethyl Aryldiazoacetates with Tertiary Propargyl Alcohols through Carbene Migratory Insertion,” Org. Chem. Front. 2016, 3, 1691–1698.

11. Feng, S.; Mo, F.; Xia, Y.; Liu, Z.; Liu, Z.; Zhang, Y.; Wang, J. “Rhodium(I)-Catalyzed C–C Bond Activation of Siloxyvinylcyclopropanes with Diazoesters,” Angew. Chem. Int. Ed. 2016, 55, 15401–15405.

10. Xia, Y.; Ge, R.; Chen, L.; Liu, Z.; Xiao, Q.; Zhang, Y.; Wang, J. “Palladium-Catalyzed Oxidative Cross-Coupling of Conjugated Enynones with Organoboronic Acids,” J. Org. Chem. 2015, 80, 7856–7864.

9. Xia, Y.; Liu, Z.; Ge, R.; Xiao, Q.; Zhang, Y.; Wang, J. “Pd-Catalyzed Cross-Coupling of Terminal Alkynes with Ene-Yne-Ketones: Access to Conjugated Enynes via Metal Carbene Migratory Insertion,” Chem. Commun. 2015, 51, 11233–11235.

8. Liu, Z.; Xia, Y.; Feng, S.; Wang, S.; Qiu, D.; Zhang, Y.; Wang, J. “Rh(I)-Catalyzed Stille-Type Coupling of Diazoesters with Aryl Trimethylstannanes,” Aust. J. Chem. 2015, 68, 1379–1384.

7. Xia, Y.; Feng, S.; Liu, Z.; Zhang, Y.; Wang, J. “Rh(I)-Catalyzed Sequential C(sp)–C(sp³) and C(sp³)–C(sp³) Bond Formation through Carbene Migratory Insertion,” Angew. Chem. Int. Ed. 2015, 54, 7891–7894.

6. Xia, Y.; Liu, Z.; Feng, S.; Ye, F.; Zhang, Y.; Wang, J. “Rh(I)-Catalyzed Cross-Coupling of α-Diazoesters with Arylsiloxanes,” Org. Lett. 2015, 17, 956–959.

5. Xia, Y.; Liu, Z.; Feng, S.; Zhang, Y.; Wang, J. “Ir(III)-Catalyzed Aromatic C–H Bond Functionalization via Metal Carbene Migratory Insertion,” J. Org. Chem. 2015, 80, 223–236.

4. Xia, Y.; Xia, Y.; Liu, Z.; Zhang, Y.; Wang, J. “Palladium-Catalyzed Cross-Coupling Reaction of Diazo Compounds and Vinyl Boronic Acids: An Approach to 1,3-Diene Compounds,” J. Org. Chem. 2014, 79, 7711–7717.

3. Xia, Y.; Xia, Y.; Ge, R.; Liu, Z.; Xiao, Q.; Zhang, Y.; Wang, J. “Oxidative Cross-Coupling of Allenyl Ketones and Organoboronic Acids: Expeditious Synthesis of Highly Substituted Furans,” Angew. Chem. Int. Ed. 2014, 53, 3917–3921.

2. Xia, Y.; Liu, Z.; Liu, Z.; Ge, R.; Ye, F.; Hossain, M.; Zhang, Y.; Wang, J. “Formal Carbene Insertion into C–C Bond: Rh(I)-Catalyzed Reaction of Benzocyclobutenols with Diazoesters,” J. Am. Chem. Soc. 2014, 136, 3013–3015.

1. Xia, Y.; Qu, S.; Xiao, Q.; Wang, Z.-X.; Qu, P.; Chen, Li.; Liu, Z.; Tian, L.; Huang, Z.; Zhang, Y.; Wang, J. “Palladium-Catalyzed Carbene Migratory Insertion Using Conjugated Ene-Yne-Ketones as Carbene Precursors” J. Am. Chem. Soc. 2013, 135, 13502–13511.