Zhen Liu, Ph.D.

Assistant Investigator, NIBS, Beijing

Email: liuzhen@nibs.ac.cn

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

Education

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

Supervisor: Prof. Keary M. Engle

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

Supervisors: Prof. Jianbo Wang and Prof. Yan Zhang

Professional Experience

2022.9–present Assistant Investigator, NIBS, Beijing

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

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

Research Description

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.

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, 107–108.

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.