University of Groningen

Biocatalytic asymmetric synthesis of unnatural amino acids using C-N lyasesFu, Haigen

DOI:10.33612/diss.95563902

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2019

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Fu, H. (2019). Biocatalytic asymmetric synthesis of unnatural amino acids using C-N lyases.Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.95563902

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 21-07-2021

AcknowledgementList of PublicationAbout the Author

A P P E N D I C E S

352 APPENDICES

Acknowledgements

Throughout my PhD journey, I have received a great deal of guidance, support, and assis-tance from my supervisors, colleagues, friends, and family members. I would like to take this opportunity to acknowledge you all from the bottom of my heart.

First and foremost, I would like to express my sincere gratitude to my supervisor Prof. Gerrit J. Poelarends for the continuous support of my PhD study, for your patience, moti-vation, trust, and immense knowledge. Your guidance helped me in all the time of research and writing of this thesis. I will never forget what I have learned from you, and I will use them in my future career.

I would like to thank my second supervisor Prof. Wim J. Quax for creating and maintaining such a comfortable academic atmosphere at the Department of Chemical and Pharmaceu-tical Biology (CPB) and for your suggestions and remarks during group meetings.

In the meantime, I would like to thank the members of the reading committee, Prof. Marco. W. Fraaije, Prof. Gerard Roelfes, and Prof. Ulf Hanefeld, for taking time to read and eval-uate my thesis.

My sincere thanks also go to Prof. Wiktor Szymanski, Prof. Dirk J. Slotboom, Mark W.H. Hoorens, Dr. Valentina Arkhipova, and Dr. Lucien Lameijer, who were friendly involved in the photoswitchable-TBOA project, for the great and fruitful collaborative work in Chapter 4. Many thanks to Prof. Anders A. Jensen and Prof. Lennart Bunch (University of Copenhagen), who helped us to evaluate the EAATs inhibitory activity of my newly pre-pared Asp derivatives. Without their precious support, it would not be possible to conduct the research in Chapter 3. Moreover, I would like to thank André for the assistance of recording NMR spectra, and Marcel for measuring HRMS of all my samples.

Many thanks to all my colleagues at CFB. To Prof. Frank J. Dekker, Prof. Hidde Haisma, Dr. Ykelien Boersma, Dr. Robbert H. Cool for the insightful discussions and useful sug-gestions during our group meetings. Special thanks to our lovely and helpful technicians Pieter, Ronald, and Rita, without your selfless and timely assistance it would not be pos-sible for me to finish my PhD within four years. To our secretaries Yvonne and Janita for helping me out of the paperwork, it made my life much easier. To my labmates and officemates Alex, Andreas, Chao, Eleonora, Fabiola, Faizan, Guangcai, Jielin, Laura B., Lieuwe, Marie, Michele, Sabry, Saif, Saravanan, Tjie, Yan Ni, and Zainal, for the stimulat-ing discussions, for the wonderful days we were working together, and for all the good times

353

APP

END

ICES

we have had in and outside of the lab. Particularly, I am grateful to Guangcai and Lieuwe for being my paranymphs. To the former and current members of CFB, Abel, Ali, Baojie, Bin, Christel, Dan, Deng, Fangyuan, Gea, Hao, Hannah, Hegar, Ingy, Jan, Jane, Joko, Laura F.S., Linda, Magda, Martijn, Olivia, Petra, Putri, Roberta, Siqi, Siwei, Shanshan, Thea, Xinyu, Yizhou, Yafeng, and Zhangping, thank you for your kind assistance.

Special thanks to my Chinese friends, Chentao Ji, Chao Wang, Duligen, Huatang Cao, Huala Wu, Ji Zhang, Jingyao Li, Kai Gao, Keni Yang, Lin Zhou, Luo Ge, Liang Xu, Min-gming Shi, Na Qing, Qi Xu, Shanshan Ge, Suriguga, Tianyu, Wenjia Wang, Wenxuan Zhang, Wang Qian, Xingchen Yan, Xiaohong Peng, Xiaodong Cheng, Xiaoyin Fang, Yuanze Wang, Yafei Guo, Yiming Guo, Yuanyuan Wang, Yang Zhang, Yuzhen Qin, Yehan Tao, Yana Geng, Zhenchen Tang, Zhi Zhou, for the wonderful days and nights we spent together in The Netherlands, and for all your likes to my WeChat updates.

I will never forget the full support from Prof. Danqing Song, my MS supervisor in PUMC, without your generous help it would be difficult for me to study abroad. I am grateful to Prof. Yanxiang Wang for enlightening me the first glance of doing research. My sincere thanks to Dr. Lichen Liu, a true friend, for arranging several academic (gourmet) trips, with insightful and stimulating midnight chats.

Last but foremost, I would like to express my deepest gratitude to my lovely family, my par-ents and sister, for their unconditional support and understanding throughout my whole life, especially when I am doing my PhD in the past four years. My heartfelt thanks to Xiaoxuan, for your sacrifices, for always being around, for preparing nice foods and taking care of me, and more. No words can express how important you are to me.

感谢我的父母，焉得谖草，言树之背，养育之恩，无以回报，你们永远健康快乐是我最大的心愿。最后，谨以此书献给我亲爱的奶奶，愿您一切安好，永远怀念您。

HaigenGroningen

July 2019

354 APPENDICES

List of Publications

1. H. Fu, A. Prats-Luján, L. Bothof, J. Zhang, P.G. Tepper, and G.J. Poelarends*. Biocata-lytic asymmetric synthesis of N-aryl-functionalized amino acids and substituted pyra-zolidinones. ACS Catal. 2019, 9, 7292–7299.

2. J. Zhang, H. Fu, P.G. Tepper, G.J. Poelarends*. Biocatalytic enantioselective hydroam-inations for production of N-cycloalkyl-substituted L-aspartic acids using two C-N lyases. Adv. Synth. Catal., 2019, 361, 2433–2437.

3. H. Fu+, J. Zhang+, M. Saifuddin+, G. Cruiming, P.G. Tepper, G.J. Poelarends*. Chemo-enzymatic asymmetric synthesis of the metallo-β-lactamase inhibitor Aspergillomaras-mine A and related aminocarboxylic acids. Nat. Catal., 2018, 1, 186–189.

4. H. Fu, J. Zhang, P.G. Tepper, L. Bunch, A.A. Jensen*, and G.J. Poelarends*. Chemo-enzymatic synthesis and pharmacological characterization of functionalized aspartate analogues as novel excitatory amino acid transporter inhibitors. J. Med. Chem., 2018, 61, 7741–7753.

5. M.W.H. Hoorens+, H. Fu+, R.H. Duurkens, G. Trinco, V. Arkhipova, B.L. Feringa, G.J. Poelarends, D.J. Slotboom, W. Szymanski*. Glutamate transporter inhibitors with pho-to-controlled activity. Adv. Therap. 2018, 1, 1800028.

6. H. Fu+, S.H. Younes+, M. Saifuddin, P.G. Tepper, J. Zhang, E. Keller, A. Heeres, W. Szy-manski, G.J. Poelarends*. Rapid chemoenzymatic route to glutamate transporter inhib-itor L-TFB-TBOA and related amino acids. Org. Biomol. Chem., 2017, 15, 2341–2344.

Before Groningen

7. H. Fu+, Z. Li+, X. Hu, S. Si, X. You, S. Tang*, Y. Wang *, D. Song. Synthesis and biologi-cal evaluation of quinoline derivatives as a novel class of broad-spectrum antibacterial agents. Molecules, 2019, 24, 548.

8. H. Fu+, X. Hu+, C. Li, Y. Li, Y. Wang, J. Jiang, C. Bi, S. Tang, X. You*, D. Song*. Design, synthesis and biological evaluation of monobactams as antibacterial agents against gram-negative bacteria. Eur. J. Med. Chem., 2016, 110, 151–163.

355

APP

END

ICES

9. C. Bi, C. Zhang, Y. Li, S. Tang, S. Wang, R. Shao, H. Fu, F. Su, D. Song*. Synthesis and biological evaluation of sophoridinol derivatives as a novel family of potential antican-cer agents. ACS Med. Chem. Lett., 2014, 5, 1225–1229.

10. Y. Li+, H. Fu+, F. Su, L. Gao, S. Tang, C. Bi, Y. Li, Y. Wang, D. Song*. Synthesis and struc-ture-activity relationship of 8-substituted protoberberine derivatives as a novel class of antitubercular agents. Chem. Cent. J., 2013, 7, 117.

11. Y. Wang, H. Fu, Y. Li, J. Jiang, D. Song*. Synthesis and biological evaluation of 8-sub-stituted berberine derivatives as novel anti-mycobacterial agents. Acta Pharm. Sin. B, 2012, 2, 581–587.

(+co-first author)

356 APPENDICES

Conferences

1. Netherlands’ Catalysis and Chemistry Conference (Noordwijkerhout, NL, Mar. 2016).

2. The 5th International Conference on Novel Enzymes (Groningen, NL, Oct. 2016).

3. Chemistry as Innovating Science (Eindhoven, NL, Dec. 2016).

4. The 1st International Symposium on Photopharmacology (Groningen, NL, Feb. 2017).

5. Netherlands’ Catalysis and Chemistry Conference (Noordwijkerhout, NL, Mar. 2017).

6. Biotrans (Budapest, Hungary, July 2017). Poster presentation: Chemoenzymatic syn-thesis of unnatural amino acids as excitatory amino acid transporter (EAAT) blockers.

7. The 6th Gratama Workshop (Groningen, NL, Oct. 2017).

8. Chemistry as Innovating Science (Eindhoven, NL, Dec. 2017). Oral presentation: Rapid enzymatic synthesis of metallo-β-lactamase inhibitor AMA and related compounds.

9. Netherlands’ Catalysis and Chemistry Conference (Noordwijkerhout, NL, Mar. 2018). Oral presentation: A rapid enzymatic route towards metallo-β-lactamase inhibitor AMA and related aminocarboxylic acids.

10. GRC on Biocatalysis (Biddeford, ME, USA, July 2018). Poster presentation: Chemo-enzymatic synthesis of the metallo-β-lactamase inhibitor Aspergillomarasmine A and related aminocarboxylic acids.

11. Chemistry as Innovating Science (Eindhoven, NL, Dec. 2018).

12. Netherlands’ Catalysis and Chemistry Conference (Noordwijkerhout, NL, Mar. 2019).

13. Biotrans (Groningen, NL, July 2019). Poster presentation: Chemoenzymatic asymmet-ric synthesis of functionalized aspartic acids using C-N lyases.

357

APP

END

ICES

About the author

Haigen Fu was born on the 13th October 1990 in Jiangxi, China. He won the first prize of the National Chemistry Olympiad in 2007 during his high school period. In July 2012, he obtained his Bachelor degree in Pharmaceutical Engineering from Qingdao University of Science and Technology. In June 2015, he earned his Master degree in Medicinal Chemistry from Peking Union Medical College under the supervision of Prof. Danqing Song. In the Master program, he was trained as a syn-thetic organic chemist to handle multiple-step synthesis of small mol-ecules for exploring new antibiotics against drug-resistant bacteria. In October 2015, he moved to The Netherlands to pursue his doctoral degree in the Department of Chemical and Pharmaceutical Biology, University of Groningen, under the supervision of Prof. Gerrit J. Poelarends. His doctoral research focuses attention on biocatalytic asymmetric synthesis of complex unnatural amino acids using C-N lyases, of which the results are described in this thesis.