Chemodivergent C(sp3)-H and C(sp2)-H cyanomethylation using engineered carbene transferases

被引:13
|
作者
Zhang, Juner [1 ,3 ]
Maggiolo, Ailiena O. [1 ]
Alfonzo, Edwin [1 ]
Mao, Runze [1 ]
Porter, Nicholas J. [1 ]
Abney, Nayla M. [1 ,4 ]
Arnold, Frances H. [1 ,2 ]
机构
[1] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
[2] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA
[3] Princeton Univ, Dept Chem, Princeton, NJ USA
[4] Stanford Univ, Dept Bioengn, Stanford, CA USA
基金
美国国家卫生研究院; 瑞士国家科学基金会;
关键词
H BOND FUNCTIONALIZATION; ARYL-ALPHA-DIAZOACETATES; DIRECTED EVOLUTION; HEME-PROTEINS; IRON; DIVERSIFICATION; ACTIVATION; MOLECULES; CATALYSTS; LIGAND;
D O I
10.1038/s41929-022-00908-x
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
The ubiquity of C-H bonds presents an opportunity to efficiently elaborate and build complexity in organic molecules. Methods for selective functionalization, however, must differentiate among multiple, chemically similar C-H bonds: enzymes are attractive because they can be finely tuned using directed evolution to achieve divergent reaction outcomes. Here we present engineered enzymes that effect a new-to-nature C-H alkylation (C-H carbene insertion) with distinct selectivities: cytochrome P450-based carbene transferases deliver an alpha-cyanocarbene either into the alpha-amino C(sp(3))-H bonds or the ortho-arene C(sp(2))-H bonds of N-substituted arenes. These two transformations proceed via different mechanisms, yet only minimal changes to the protein scaffold were needed to adjust the enzyme's chemoselectivity. Structural studies of the C(sp(3))-H alkylase reveal an active-site helical disruption, which alter the structure and electrostatics of the substrate-binding pocket compared to the native enzyme. Overall, this work demonstrates advantages of using highly tuneable enzymes as C-H functionalization catalysts for divergent molecular derivatization.
引用
收藏
页码:152 / +
页数:11
相关论文
共 50 条
  • [21] Au(I)-Catalyzed Formal Intermolecular Carbene Insertion into Vinylic C(sp2)-H Bonds and Allylic C(sp3)-H Bonds
    Cui, Xiao-Yuan
    Ye, Zhong-Tian
    Wu, Hai-Hong
    Ji, Chang-Ge
    Zhou, Feng
    Zhou, Jian
    ACS CATALYSIS, 2023, 13 (03) : 1554 - 1561
  • [22] Multicomponent double Mannich alkylamination involving C(sp2)-H and benzylic C(sp3)-H bonds
    Lai, Zhencheng
    Wu, Rongkai
    Li, Jiaming
    Chen, Xing
    Zeng, Linwei
    Wang, Xi
    Guo, Jingjing
    Zhao, Zujin
    Sajiki, Hironao
    Cui, Sunliang
    NATURE COMMUNICATIONS, 2022, 13 (01)
  • [23] Ruthenium(II) Biscarboxylate-Catalyzed Borylations of C(sp2)-H and C(sp3)-H Bonds
    De Sarkar, Suman
    Kumar, N. Y. Phani
    Ackermann, Lutz
    CHEMISTRY-A EUROPEAN JOURNAL, 2017, 23 (01) : 84 - 87
  • [24] Transition-Metal-Catalyzed Acyloxylation: Activation of C(sp2)-H and C(sp3)-H Bonds
    Moghimi, Setareh
    Mahdavi, Mohammad
    Shafiee, Abbas
    Foroumadi, Alireza
    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2016, 2016 (20) : 3282 - 3299
  • [25] Multicomponent double Mannich alkylamination involving C(sp2)–H and benzylic C(sp3)–H bonds
    Zhencheng Lai
    Rongkai Wu
    Jiaming Li
    Xing Chen
    Linwei Zeng
    Xi Wang
    Jingjing Guo
    Zujin Zhao
    Hironao Sajiki
    Sunliang Cui
    Nature Communications, 13
  • [26] Palladium-Catalyzed Chemoselective Oxygenation of C(sp2)-H and C(sp3)-H Bonds in Isatins
    Vijaykumar, Muniyappa
    Pradhan, Chandini
    Gonnade, Rajesh G.
    Punji, Benudhar
    ORGANIC LETTERS, 2023, 25 (11) : 1862 - 1867
  • [27] Copper-Catalyzed Intramolecular C(sp3)-H and C(sp2)-H Amidation by Oxidative Cyclization
    Wang, Zhen
    Ni, Jizhi
    Kuninobu, Yoichiro
    Kanai, Motomu
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2014, 53 (13) : 3496 - 3499
  • [28] Determination of the sp3/sp2 ratio of a-C:H by XPS and XAES
    Leung, TY
    Man, WF
    Lim, PK
    Chan, WC
    Gaspari, F
    Zukotynski, S
    JOURNAL OF NON-CRYSTALLINE SOLIDS, 1999, 254 : 156 - 160
  • [29] Catalytic functionalization of low reactive C(sp3)-H and C(sp2)-H bonds of alkanes and arenes by carbene transfer from diazo compounds
    Caballero, Ana
    Diaz-Requejo, M. Mar
    Fructos, Manuel R.
    Olmos, Andrea
    Urbano, Juan
    Perez, Pedro J.
    DALTON TRANSACTIONS, 2015, 44 (47) : 20295 - 20307
  • [30] Scalable Electrochemical Dehydrogenative Lactonization of C(sp2/sp3)-H Bonds
    Zhang, Sheng
    Li, Lijun
    Wang, Huiqiao
    Li, Qian
    Liu, Wenmin
    Xu, Kun
    Zeng, Chengchu
    ORGANIC LETTERS, 2018, 20 (01) : 252 - 255