作者：石油醚
文章来源：トッド・ハイスター Todd K. Hyster | Chem-Station (ケムステ)
简介
Todd K. Hyster（1985年10月10日－）是美国籍有机化学家，现任普林斯顿大学教授。
教育背景及工作经历
2008: B.S., University of Minnesota, Twin Cities (Advisor: Professor Christopher J. Douglas)
2013: Ph.D., Colorado State University (Advisor: Professor Tomislav Rovis)
During this period: Internship at the University of Basel (Advisor: Professor Thomas R. Ward)
2013–2015: Postdoctoral Researcher , California Institute of Technology (Advisor: Professor Frances H. Arnold)
2015–2020: Assistant Professor, Princeton University
2021–2023: Associate Professor, Cornell University
2023–present: Professor, Princeton University
获奖情况
2026 – Earl Muetterties Memorial Lectureship, University of California, Berkeley
2026 – Tetrahedron Young Investigator Award For Organic Synthesis
2025 – OMCOS 22 Prize
2025 – EuroJOC Lectureship Award, SMOS-12
2025 – Andrew S. Kende Distinguished Lectureship, University of Rochester
2025 – Gassman Lectureship, University of Minnesota
2024 – 50 Scientists that Inspire, Cell Press
2023 – Presidential Lecture The Scripps Research Institute
2023 – EuroJIC Lectureship Award, EUCOMC XXV
2023 – 22/23 Chemical Communications Emerging Investigator Lectureship
2023 – 2023 Young Investigator Award Group Leader RSEQ
2022 – SN10 Scientists to Watch, class 2022, Science News Journal
2022 – Padwa Lectureship, Columbia University (NY, USA)
2022 – Merck Organic Chemistry Lecturer, University of Illinois Urbana-Champaign
2022 – Organometallics Distinguished Author Award
2021 – Novartis Early Career Award 2021
2021 – Kyoto Rising Star Lectureship (MSD Life Science Foundation – Japan)
2021 – Heinz Maier-Leibnitz-Preis 2021 (Deutsche Forschungsgemeinschaft)
2020 – ORCHEM Nachwuchspreis 2020
2020 – Bayer Early Excellence in Science Award 2020
2020 – Ruhrpreis für Kunst und Wissenschaft 2020
2020 – Otto Röhm Gedächtnisstiftung Forschung Preis 2020
2020 – C&EN Talented 12 – Class 2020
2020 – Dozentenpreis des Fonds (Fonds der Chemischen Industrie)
2020 – Marcial Moreno Mañas Award (Real Sociedad Española de Quimica-Catalan Section)
2020 – ERC Starting Grant
2019 – Münster Symposium-CEC Young Researcher Award
2019 – Junior Scientist Program Fellowship (JSP – Bürgenstock)
2018 – Sachkostenzuschüsse Fonds der Chemischen Industrie
2018 – Thieme Chemistry Journals Award
2017 – Independent Max-Planck Research Group Leader
prior to MPI
2016 – TSRI Travel Award (Society of Fellows)
2015 – Beatriu de Pinos Postdoctoral Fellowship (Prof. Phil S. Baran)
2013 – Marie Skłodowska-Curie Fellowship (Prof. Ruben Martin)
2012 – COFUND Postdoc Fellowship (Prof. Ruben Martin)
研究概要
自2015年独立建组以来，致力于开发基于光酶催化的新型不对称自由基反应。
光酶催化新型不对称自由基反应
酶是以化学、区域和立体选择性催化特定反应（如代谢）的高效生物催化剂。但高选择性与反应多样性往往难以兼顾，限制了其在精细有机合成中的应用。光生自由基反应活性高，若借助酶调控其反应路径与立体化学，即可实现酶催化的非天然反应。
◎光酶催化的新型不对称自由基反应
烟酰胺腺嘌呤二核苷酸磷酸（Nicotinamide Adenine Dinucleotide Phosphate， NADP+）和黄素类（Flavin Adenine Dinucleotide；FAD及Flavin Mononucleotide；FMN）作为氧化还原酶辅因子，其可在生物体系中被还原为NADPH、FADhq和FMNhq。其还原态经光激发后成为强一电子还原剂（E° > –2.2 V vs. SCE），进而成功用于多种α-卤代羰基化合物的不对称脱卤转化[1]。如，蓝光照射下，Lactobacillus kefiri醇脱氢酶（LKADH）催化外消旋α-溴内酯的不对称自由基氢化脱卤反应：底物与NADPH形成电荷转移（CT）配合物，光激发引发单电子转移，生成α-羰基自由基和NADPH•+；随后NADPH•+立体选择性地提供氢原子（HAT）得到手性产物。类似地，黄素依赖性烯还原酶GluER T36A可催化含苯乙烯或肟基的α-氯酰胺发生分子内自由基环化。进一步通过定向进化获得突变体GluER-G6，显著提升环化效率（产率提高约3倍）。此外，该策略还拓展至α-氯-N-芳基酰胺和烷基碘的分子内环化。
此外，黄素依赖性酶催化剂也被成功用于分子间反应[2]：蓝光照射下，GluER T36A催化α-氯酰胺与二取代烯烃发生Giese加成；通过酶筛选，该策略进一步拓展至α-溴酮、氯甲基吡啶和二氯酰胺；改造变体PagER则实现了吲哚C4位的区域选择性烷基化。尽管辅因子介导的HAT可能干扰分子间反应，但光谱证据表明，酶/FMN/卤代底物/烯烃可形成四组分电荷转移（CT）复合物，从而有效抑制HAT竞争。
利用Caulobacter segnis的烯醇还原酶（CsER）催化α-氯羰基化合物与硝基烷烃之间亲电交叉偶联反应[3]。此反应中，FMN、底物及原位生成的硝基阴离子在酶活性中心形成四组分电荷转移（CT）络合物；光照触发单电子转移生成α-羰基自由基，进而与硝基阴离子加成得到硝基自由基阴离子；随后经脱硝基与氢原子转移（HAT），立体选择性地完成偶联。换用改造酶GkOYE-G7后，FMN半醌（FMNsq）可氧化该硝基自由基阴离子，实现硝基烷烃的不对称α-烷基化。
分子内氢-胺化反应[4]：在AcCHMO改造酶AcHYAM催化下，蓝光照射即可高对映选择性地生成取代吡咯烷。反应不生成热力学更稳定的哌啶环产物。机理如下：光激发FADhq*对烯烃单电子还原，质子化得苄基自由基；该自由基在酶活性中心定向取向，与苯胺氮孤对电子形成桥式n–π相互作用，从而促进其被FADsq单电子氧化，并同步发生环化，高效构建手性吡咯烷。
◎光催化剂与酶协同催化的不对称自由基反应
光催化剂与辅酶协同催化的新型体系[5]，用光催化剂替代辅酶承担的氧化还原功能。该体系通过抑制溶液中自由基外消旋化，实现高立体选择性控制。例如：绿光下，玫瑰红（RB）与烟草双键还原酶（NtDBR）协同催化α-乙酰氧基四氢萘酮的不对称脱乙酰氧基化，经单电子还原生成酮基自由基，继而发生1,2-自旋中心转移（1,2-SCS）脱去乙酰氧基，并由NADPH供氢完成；该单电子还原在溶液中难以进行，但在NtDBR活性中心因氨基酸残基配位而被显著促进。蓝光下，枯草芽孢杆菌YqjM与钌催化剂联用，实现分子内氢胺化合成内酰胺；OYE3与邻近定位的钌催化剂协同，驱动N-芳基甘氨酸与乙烯基吡啶脱羧偶联，实现α-氨基烷基自由基加成及对映选择性氢化。此外，该策略还拓展至乙烯基吡啶不对称氢化、酮的不对称还原及非天然氨基酸合成。
◎新型光酶催化剂
光酶催化剂常因使用497 nm而引发副反应和失活[6]。为拓展其响应波长，可将长波长吸收型有机染料共价偶联至酶上——如ATTO 565-GluER T36A在绿光（530 nm）下催化α-氯酰胺还原环化，内酰胺产率由19%提升至85%。进一步地，借助MutComputeX机器学习模型（基于酶三维结构预测有益突变位点），结合定向进化，获得含六个突变点（T36A/K317M/Y343F/T36E/S118C/K283G）的GluER变体，可在红光（620 nm）下高效驱动同一反应，产率达99%，且对映选择性不变；该体系已成功放大至10 g规模。
◎酶催化动态动力学拆分（DKR）
与MacMillan合作[7]，实现了难发生外消旋化的β-取代环状酮的动态动力学拆分（DKR）。在蓝光照射下，联合使用MacMillan报道的铱/HAT/吡咯烷催化体系[8]和LKADH酶，高收率、高对映选择性地获得γ-取代醇：烯胺自由基介导β位差向异构化，LKADH选择性还原单一构型酮。另以PLP催化剂与KRED酶协同，由外消旋α-氨基酮立体选择性合成1,2-氨基醇。两种策略均通过切换酶种，可分别获取全部四种立体异构体。
参考文献：
- (a) Emmanuel, M. A.; Greenberg, N. R.; Oblinsky, D. G.; Hyster, T. K. Accessing Non-Natural Reactivity by Irradiating Nicotinamide-Dependent Enzymes with Light. Nature 2016, 540, 414–417. DOI: 1038/nature20569 (b) Biegasiewicz, K. F.; Cooper, S. J.; Gao, X.; Oblinsky, D. G.; Kim, J. H.; Garfinkle, S. E.; Joyce, L. A.; Sandoval, B. A.; Scholes, G. D.; Hyster, T. K. Photoexcitation of Flavoenzymes Enables a Stereoselective Radical Cyclization. Science 2019, 364, 1166–1169. DOI: 10.1126/science.aaw1143 (c) Gao, X.; Turek-Herman, J. R.; Choi, Y. J.; Cohen, R. D.; Hyster, T. K. Photoenzymatic Synthesis of α-Tertiary Amines by Engineered Flavin-Dependent “Ene”-Reductases. J. Am. Chem. Soc. 2021, 143, 19643–19647. DOI: 10.1021/jacs.1c09828(d) Nicholls, B. T.; Oblinsky, D. G.; Kurtoic, S. I.; Grosheva, D.; Ye, Y.; Scholes, G. D.; Hyster, T. K. Engineering a Non-Natural Photoenzyme for Improved Photon Efficiency. Angew. Chem., Int. Ed. 2022, 61, e202113842. DOI: 10.1002/anie.202113842 (e) Black, M. J.; Biegasiewicz, K. F.; Meichan, A. J.; Oblinsky, D. G.; Kudisch, B.; Scholes, G. D.; Hyster, T. K. Asymmetric Redox-Neutral Radical Cyclization Catalysed by Flavin-Dependent ‘Ene’-Reductases. Nat. Chem. 2020, 12, 71–75. DOI: 10.1038/s41557-019-0370-2 (f) Clayman, P. D.; Hyster, T. K. Photoenzymatic Generation of Unstabilized Alkyl Radicals: An Asymmetric Reductive Cyclization. J. Am. Chem. Soc. 2020, 142, 15673–15677. DOI: 10.1021/jacs.0c07918
- (a) Page, C. G.; Cooper, S. J.; DeHovitz, J. S.; Oblinsky, D. G.; Biegasiewicz, K. F.; Antropow, A. H.; Armbrust, K. W.; Ellis, J. M.; Hamann, L. G.; Horn, E. J.; Oberg, K. M.; Scholes, G. D.; Hyster, T. K. Quaternary Charge-Transfer Complex Enables Photoenzymatic Intermolecular Hydroalkylation of Olefins. Am. Chem. Soc. 2021, 143, 97–102. DOI: 10.1021/jacs.0c11462 (b) Ouyang, Y.; Turek-Herman, J.; Qiao, T.; Hyster, T. K. Asymmetric Carbohydroxylation of Alkenes Using Photoenzymatic Catalysis. J. Am. Chem. Soc. 2023, 145, 17018–17022. DOI: 10.1021/jacs.3c06618 (c) Bender, S. G.; Hyster, T. K. Pyridylmethyl Radicals for Enantioselective Alkene Hydroalkylation Using “Ene”-Reductases. ACS Catal. 2023, 13, 14680–14684. DOI: 10.1021/acscatal.3c03771 (d) Liu, Y.; Bender, S. G.; Sorigue, D.; Diaz, D. J.; Ellington, A. D.; Mann, G.; Allmendinger, S.; Hyster, T. K. Asymmetric Synthesis of α-Chloroamides via Photoenzymatic Hydroalkylation of Olefins. J. Am. Chem. Soc. 2024, 146, 7191–7197. DOI: 10.1021/jacs.4c00927 (e) Page, C. G.; Cao, J.; Oblinsky, D. G.; MacMillan, S. N.; Dahagam, S.; Lloyd, R. M.; Charnock, S. J.; Scholes, G. D.; Hyster, T. K. Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes. J. Am. Chem. Soc. 2023, 145, 11866–11874. DOI: 10.1021/jacs.3c03607
- (a) Fu, H.; Cao, J.; Qiao, T.; Qi, Y.; Charnock, S. J.; Garfinkle, S.; Hyster, T. K. An Asymmetric sp3–sp3 Cross-Electrophile Coupling Using ‘Ene’-Reductases. Nature 2022, 610, 302–307. DOI: 1038/s41586-022-05167-1 (b) Fu, H.; Qiao, T.; Carceller, J. M.; MacMillan, S. N.; Hyster, T. K. Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis. J. Am. Chem. Soc. 2023, 145, 787–793. DOI: 10.1021/jacs.2c12197
- Raps, F. C.; Rivas-Souchet, A.; Jones, C. M.; Hyster, T. K. Emergence of a Distinct Mechanism of C–N Bond Formation in Photoenzymes. Nature 2025,637, 362–368. DOI: 1038/s41586-024-08138-w
- (a) Biegasiewicz, K. F.; Cooper, S. J.; Emmanuel, M. A.; Miller, D. C.; Hyster, T. K. Catalytic Promiscuity Enabled by Photoredox Catalysis in Nicotinamide-Dependent Oxidoreductases. Chem. 2018, 10, 770–775. DOI: 10.1038/s41557-018-0059-y (b) Ye, Y.; Cao, J.; Oblinsky, D. G.; Verma, D.; Prier, C. K.; Scholes, G. D.; Hyster, T. K. Using Enzymes to Tame Nitrogen-Centred Radicals for Enantioselective Hydroamination. Nat. Chem. 2023, 15, 206–212. DOI: 10.1038/s41557-022-01083-z (c) Sun, S.-Z.; Nicholls, B. T.; Bain, D.; Qiao, T.; Page, C. G.; Musser, A. J.; Hyster, T. K. Enantioselective Decarboxylative Alkylation Using Synergistic Photoenzymatic Catalysis. Nat. Catal. 2024, 7, 35–42. DOI: 10.1038/s41929-023-01065-5 (d) Sandoval, B. A.; Kurtoic, S. I.; Chung, M. M.; Biegasiewicz, K. F.; Hyster, T. K. Photoenzymatic Catalysis Enables Radical-Mediated Ketone Reduction in Ene-Reductases. Angew. Chem., Int. Ed. 2019, 58, 8714–8718. DOI: 10.1002/anie.201902005 (e) Nakano, Y.; Black, M. J.; Meichan, A. J.; Sandoval, B. A.; Chung, M. M.; Biegasiewicz, K. F.; Zhu, T.; Hyster, T. K. Photoenzymatic Hydrogenation of Heteroaromatic Olefins Using ‘Ene’-Reductases with Photoredox Catalysts. Angew. Chem., Int. Ed. 2020, 59, 10484–10488. DOI: 10.1002/anie.202003125 (f) Ouyang, Y.; Page, C. G.; Bilodeau, C.; Hyster, T. K. Synergistic Photoenzymatic Catalysis Enables Synthesis of α-Tertiary Amino Acids Using Threonine Aldolases. J. Am. Chem. Soc. 2024, 146, 13754–13759. DOI: 10.1021/jacs.4c04661
- (a) Cesana, P. T.; Page, C. G.; Harris, D.; Emmanuel, M. A.; Hyster, T. K.; Schlau-Cohen, G. S. Photoenzymatic Catalysis in a New Light: Gluconobacter “Ene”-Reductase Conjugates Possessing High-Energy Reactivity with Tunable Low-Energy Excitation. J. Am. Chem. Soc. 2022, 144, 17516–17521. DOI: https://doi.org/10.1021/jacs.2c06344 (b) Carceller, J. M.; Jayee, B.; Page, C. G.; Oblinsky, D. G.; Mondragón-Solórzano, G.; Chintala, N.; Cao, J.; Alassad, Z.; Zhang, Z.; White, N.; Diaz, D. J.; Ellington, A. D.; Scholes, G. D.; Dong, S. S.; Hyster, T. K. Engineering a Photoenzyme to Use Red Light. Chem 2025,11, 1–11. https://doi.org/10.1016/j.chempr.2024.09.017
- (a) DeHovitz, J. S.; Loh, Y. Y.; Kautzky, J. A.; Nagao, K.; Meichan, A. J.; Yamauchi, M.; MacMillan, D. W. C.; Hyster, T. K. Static to Inducibly Dynamic Stereocontrol: The Convergent Use of Racemic β-Substituted Ketones. Science 2020, 369, 1113–1118. DOI: 1126/science.abc9909 (b) Cao, J.; Hyster, T. K. Pyridoxal-Catalyzed Racemization of α-Aminoketones Enables the Stereodivergent Synthesis of 1,2-Amino Alcohols Using Ketoreductases. ACS Catal.2020, 10, 6171–6175. DOI: 10.1021/acscatal.0c01502.
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