CaltechAUTHORS
  A Caltech Library Service

Biocatalytic Carbene Transfer Using Diazirines

Porter, Nicholas J. and Danelius, Emma and Gonen, Tamir and Arnold, Frances H. (2022) Biocatalytic Carbene Transfer Using Diazirines. Journal of the American Chemical Society, 144 (20). pp. 8892-8896. ISSN 0002-7863. doi:10.1021/jacs.2c02723. https://resolver.caltech.edu/CaltechAUTHORS:20220513-557783000

[img] PDF - Submitted Version
Creative Commons Attribution Non-commercial No Derivatives.

7MB
[img] PDF (Supplementary figures, materials, experimental methods, compound synthesis and characterization, HPLC and GC-FID calibration curves, HPLC and SFC traces) - Supplemental Material
See Usage Policy.

5MB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20220513-557783000

Abstract

Biocatalytic carbene transfer from diazo compounds is a versatile strategy in asymmetric synthesis. However, the limited pool of stable diazo compounds constrains the variety of accessible products. To overcome this restriction, we have engineered variants of Aeropyrum pernix protoglobin (ApePgb) that use diazirines as carbene precursors. While the enhanced stability of diazirines relative to their diazo isomers enables access to a diverse array of carbenes, they have previously resisted catalytic activation. Our engineered ApePgb variants represent the first example of catalysts for selective carbene transfer from these species at room temperature. The structure of an ApePgb variant, determined by microcrystal electron diffraction (MicroED), reveals that evolution has enhanced access to the heme active site to facilitate this new-to-nature catalysis. Using readily prepared aryl diazirines as model substrates, we demonstrate the application of these highly stable carbene precursors in biocatalytic cyclopropanation, N–H insertion, and Si–H insertion reactions.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.2c02723DOIArticle
https://doi.org/10.26434/chemrxiv-2022-9v4j1DOIDiscussion Paper
ORCID:
AuthorORCID
Porter, Nicholas J.0000-0002-9803-5310
Danelius, Emma0000-0002-7322-9661
Gonen, Tamir0000-0002-9254-4069
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2022 American Chemical Society. Received: March 12, 2022; Published: May 13, 2022. N.J.P. thanks Merck and the Helen Hay Whitney Foundation for their support through the Merck-Helen Hay Whitney Foundation Postdoctoral Fellowship. Supplies for this work were funded by the United States Army Research Office under Contract W911NF-19-0026 for the Institute for Collaborative Biotechnologies. We also thank Nathaniel W. Goldberg, Patrick J. Almhjell, David C. Miller, Bruce J. Wittmann, Kadina E. Johnston, and Sabine Brinkmann-Chen for helpful discussions and comments on the manuscript. We thank Dr. Scott C. Virgil for his assistance with chiral-phase HPLC experiments. We further thank Mona Shahgholi for HRMS analysis and Dr. Jens Kaiser and the Molecular Observatory for access to crystallography resources. E.D. thanks The Wenner-Gren Foundations for their support through the Wenner-Gren Postdoctoral Fellowship. This study was supported by the National Institutes of Health P41GM136508. The Gonen laboratory is supported by funds from the Howard Hughes Medical Institute. We also thank Dr. Johan Unge for helpful discussions and assistance on solving the MicroED structure. The authors declare no competing financial interest. The coordinates and structure factors for the structure of ApePgb GLVRSQL has been deposited to the PDB under accession code 7UTE. The corresponding density map has been deposited to the EMDB under code 26768.
Funders:
Funding AgencyGrant Number
Helen Hay Whitney FoundationUNSPECIFIED
Army Research OfficeW911NF-19-0026
Wenner-Gren FoundationUNSPECIFIED
NIHP41GM136508
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Bioinorganic chemistry, Carbene compounds, Cyclopropanation, Genetics
Issue or Number:20
DOI:10.1021/jacs.2c02723
Record Number:CaltechAUTHORS:20220513-557783000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220513-557783000
Official Citation:Biocatalytic Carbene Transfer Using Diazirines. Nicholas J. Porter, Emma Danelius, Tamir Gonen, and Frances H. Arnold. Journal of the American Chemical Society 2022 144 (20), 8892-8896; DOI: 10.1021/jacs.2c02723
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114724
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:18 May 2022 14:35
Last Modified:31 May 2022 17:48

Repository Staff Only: item control page