CaltechAUTHORS
  A Caltech Library Service

Enzymatic assembly of carbon–carbon bonds via iron-catalysed sp^3 C–H functionalization

Zhang, Ruijie K. and Chen, Kai and Huang, Xiongyi and Wohlschlager, Lena and Renata, Hans and Arnold, Frances H. (2019) Enzymatic assembly of carbon–carbon bonds via iron-catalysed sp^3 C–H functionalization. Nature, 565 (7737). pp. 67-72. ISSN 0028-0836. PMCID PMC6440214. https://resolver.caltech.edu/CaltechAUTHORS:20181025-100754288

[img] PDF - Accepted Version
See Usage Policy.

1236Kb
[img] PDF (experimental procedures, information about enzyme variants, Supplementary Figures 1–15, Supplementary Tables 1–13, and additional data) - Supplemental Material
See Usage Policy.

19Mb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20181025-100754288

Abstract

Although abundant in organic molecules, carbon–hydrogen (C–H) bonds are typically considered unreactive and unavailable for chemical manipulation. Recent advances in C–H functionalization technology have begun to transform this logic, while emphasizing the importance of and challenges associated with selective alkylation at a sp^3 carbon. Here we describe iron-based catalysts for the enantio-, regio- and chemoselective intermolecular alkylation of sp^3 C–H bonds through carbene C–H insertion. The catalysts, derived from a cytochrome P450 enzyme in which the native cysteine axial ligand has been substituted for serine (cytochrome P411), are fully genetically encoded and produced in bacteria, where they can be tuned by directed evolution for activity and selectivity. That these proteins activate iron, the most abundant transition metal, to perform this chemistry provides a desirable alternative to noble-metal catalysts, which have dominated the field of C–H functionalization. The laboratory-evolved enzymes functionalize diverse substrates containing benzylic, allylic or α-amino C–H bonds with high turnover and excellent selectivity. Furthermore, they have enabled the development of concise routes to several natural products. The use of the native iron-haem cofactor of these enzymes to mediate sp^3 C–H alkylation suggests that diverse haem proteins could serve as potential catalysts for this abiological transformation, and will facilitate the development of new enzymatic C–H functionalization reactions for applications in chemistry and synthetic biology.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41586-018-0808-5DOIArticle
https://rdcu.be/bdUdbPublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440214PubMed CentralArticle
ORCID:
AuthorORCID
Zhang, Ruijie K.0000-0002-7251-5527
Chen, Kai0000-0002-3325-3536
Huang, Xiongyi0000-0001-7156-8881
Renata, Hans0000-0003-2468-2328
Arnold, Frances H.0000-0002-4027-364X
Alternate Title:Enzymatic assembly of carbon–carbon bonds via iron-catalysed sp3 C–H functionalization
Additional Information:© 2019 Springer Nature Limited. Received 18 July 2018; Accepted 01 November 2018; Published 19 December 2018. This work was supported by the National Science Foundation (NSF), Division of Molecular and Cellular Biosciences (grant MCB-1513007). R.K.Z. acknowledges support from the NSF Graduate Research Fellowship (grant DGE-1144469) and the Donna and Benjamin M. Rosen Bioengineering Center. X.H. is supported by a Ruth L. Kirschstein National Institutes of Health Postdoctoral Fellowship (grant F32GM125231). L.W. received support from the Austrian Marshall Plan Foundation. We thank A. Z. Zhou for experimental assistance; N. W. Goldberg, S. C. Hammer, K. E. Hernandez, Z. Jia, A. M. Knight, G. Kubik, R. D. Lewis, C. K. Prier, D. K. Romney and J. Zhang for discussions; S. Virgil, M. Shahgholi and D. VanderVelde for analytical support; and B. Stoltz for use of polarimeter and gas chromatography equipment. Data availability: All relevant data are provided in Supplementary Information. Any additional information is available from the corresponding author on request. Author Contributions: R.K.Z. designed the overall research with F.H.A. providing guidance. R.K.Z. and H.R. designed and conducted the initial screening of haem proteins; R.K.Z. and L.W. performed the directed evolution experiments. R.K.Z., K.C. and X.H. designed and performed the substrate scope studies. R.K.Z. and F.H.A. wrote the manuscript with input from all authors. Competing interests: A provisional patent application has been filed through the California Institute of Technology based on the results presented here.
Group:Rosen Bioengineering Center
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
NSF Graduate Research FellowshipDGE-1144469
Donna and Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
NIH Postdoctoral FellowshipF32GM125231
Austrian Marshall Plan FoundationUNSPECIFIED
Issue or Number:7737
PubMed Central ID:PMC6440214
Record Number:CaltechAUTHORS:20181025-100754288
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20181025-100754288
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90410
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:19 Dec 2018 19:21
Last Modified:14 Oct 2019 18:41

Repository Staff Only: item control page