刘臻博士

科学研究

刘臻博士

Zhen Liu, Ph.D.

Assistant Investigator, NIBS, Beijing

Email: liuzhen@xinjundu.com

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

研究概述 Research Description

酶是自然界各类生命体中的催化剂，是多种生理过程赖以维系的重要组分。人类在很早的时代就开始利用生物催化来进行社会生产，一个典型的例子就是我国古代的酿造工艺。近几十年来，随着定向进化以及多种分子生物学技术的飞速开展，科学家对于酶催化剂的改造能力得到了空前的提高，使得我们不仅可以快速地优化酶的天然活性，拓宽底物范围，甚至可以赋予他们未知的催化性能。这一进步极大地拓宽了生物催化在有机合成以及药物研发领域的应用范围和开展前景。

我们在北京科学生命球友(中国)qy（NIBS）的实验室将围绕着开展高效新颖的生物催化反应为中心展开，研究目标在于解决化学合成和药物开发过程中的难题，降低生产成本，有助于这些新方法的工业化应用。课题组的研究方向主要有以下三个方面：

一．顺利获得定向进化或理性设计等手段开展非天然的高效酶促反应；

二．开展多步酶催化或酶催化-化学反应相结合的串联过程以实现活性有机小分子的高效合成；

三．开展绿色经济的过渡金属催化的有机反应方法学。

我们实验室欢迎所有对有机化学，酶催化以及化学生物学感兴趣的科研工作者加入到我们的团队，来共同解决合成化学以及酶学领域中的现有难题。实验室的训练将使你对多个学科有所分析，为你未来的学术开展或者科研工作打下坚实的基础。

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.

发表文章 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.