Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes
Abstract
Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. Here, we postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, > 70:1 dr, > 75% yield, and ~10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenesmore »
- Authors:
-
- Department of Chemistry, University of California, Berkeley, California 94720, United States, Chemical Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
- Department of Chemistry, University of California, Berkeley, California 94720, United States
- Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States, Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1349533
- Alternate Identifier(s):
- OSTI ID: 1411658
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Published Article
- Journal Name:
- ACS Central Science
- Additional Journal Information:
- Journal Name: ACS Central Science Journal Volume: 3 Journal Issue: 4; Journal ID: ISSN 2374-7943
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Citation Formats
Key, Hanna M., Dydio, Paweł, Liu, Zhennan, Rha, Jennifer Y. -E., Nazarenko, Andrew, Seyedkazemi, Vida, Clark, Douglas S., and Hartwig, John F. Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes. United States: N. p., 2017.
Web. doi:10.1021/acscentsci.6b00391.
Key, Hanna M., Dydio, Paweł, Liu, Zhennan, Rha, Jennifer Y. -E., Nazarenko, Andrew, Seyedkazemi, Vida, Clark, Douglas S., & Hartwig, John F. Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes. United States. doi:10.1021/acscentsci.6b00391.
Key, Hanna M., Dydio, Paweł, Liu, Zhennan, Rha, Jennifer Y. -E., Nazarenko, Andrew, Seyedkazemi, Vida, Clark, Douglas S., and Hartwig, John F. Tue .
"Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes". United States. doi:10.1021/acscentsci.6b00391.
@article{osti_1349533,
title = {Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes},
author = {Key, Hanna M. and Dydio, Paweł and Liu, Zhennan and Rha, Jennifer Y. -E. and Nazarenko, Andrew and Seyedkazemi, Vida and Clark, Douglas S. and Hartwig, John F.},
abstractNote = {Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. Here, we postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, > 70:1 dr, > 75% yield, and ~10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenes with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Altogether, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.},
doi = {10.1021/acscentsci.6b00391},
journal = {ACS Central Science},
number = 4,
volume = 3,
place = {United States},
year = {2017},
month = {4}
}
DOI: 10.1021/acscentsci.6b00391
Web of Science
Works referencing / citing this record:
Highly Diastereo- and Enantioselective Synthesis of Nitrile-Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer Catalysis
journal, November 2018
- Chandgude, Ajay L.; Fasan, Rudi
- Angewandte Chemie International Edition, Vol. 57, Issue 48
General Cyclopropane Assembly by Enantioselective Transfer of a Redox-Active Carbene to Aliphatic Olefins
journal, February 2019
- Montesinos-Magraner, Marc; Costantini, Matteo; Ramírez-Contreras, Rodrigo
- Angewandte Chemie International Edition, Vol. 58, Issue 18
Near-Infrared Phosphorescent Supramolecular Alkyl/Aryl-Iridium Porphyrin Assemblies by Axial Coordination
journal, September 2018
- Qin, Lin; Guan, Xiangguo; Yang, Chen
- Chemistry - A European Journal, Vol. 24, Issue 54
Iridium porphyrin complexes with μ-nitrido, hydroxo, hydrosulfido and alkynyl ligands
journal, January 2019
- So, Shiu-Chun; Cheung, Wai-Man; Chiu, Wai-Hang
- Dalton Transactions, Vol. 48, Issue 23
Biosystems design by directed evolution
journal, July 2019
- Wang, Yajie; Yu, Xiaowei; Zhao, Huimin
- AIChE Journal
Biosystems design by directed evolution
journal, July 2019
- Wang, Yajie; Yu, Xiaowei; Zhao, Huimin
- AIChE Journal
General Cyclopropane Assembly by Enantioselective Transfer of a Redox‐Active Carbene to Aliphatic Olefins
journal, April 2019
- Montesinos‐Magraner, Marc; Costantini, Matteo; Ramírez‐Contreras, Rodrigo
- Angewandte Chemie, Vol. 131, Issue 18
Highly Diastereo- and Enantioselective Synthesis of Nitrile-Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer Catalysis
journal, November 2018
- Chandgude, Ajay L.; Fasan, Rudi
- Angewandte Chemie International Edition, Vol. 57, Issue 48
Near-Infrared Phosphorescent Supramolecular Alkyl/Aryl-Iridium Porphyrin Assemblies by Axial Coordination
journal, September 2018
- Qin, Lin; Guan, Xiangguo; Yang, Chen
- Chemistry - A European Journal, Vol. 24, Issue 54
Iridium porphyrin complexes with μ-nitrido, hydroxo, hydrosulfido and alkynyl ligands
journal, January 2019
- So, Shiu-Chun; Cheung, Wai-Man; Chiu, Wai-Hang
- Dalton Transactions, Vol. 48, Issue 23
An Artificial Heme Enzyme for Cyclopropanation Reactions
journal, May 2018
- Villarino, Lara; Splan, Kathryn E.; Reddem, Eswar
- Angewandte Chemie, Vol. 130, Issue 26
Asymmetrische reduktive Carbocyclisierung durch modifizierte En-Reduktasen
journal, May 2018
- Heckenbichler, Kathrin; Schweiger, Anna; Brandner, Lea Alexandra
- Angewandte Chemie, Vol. 130, Issue 24
Highly Diastereo- and Enantioselective Synthesis of Nitrile-Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer Catalysis
journal, November 2018
- Chandgude, Ajay L.; Fasan, Rudi
- Angewandte Chemie, Vol. 130, Issue 48
Site‐Selective Functionalization of (sp 3 )C−H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium‐Porphyrin Cofactor
journal, July 2019
- Gu, Yang; Natoli, Sean N.; Liu, Zhennan
- Angewandte Chemie, Vol. 131, Issue 39
Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases
journal, May 2018
- Heckenbichler, Kathrin; Schweiger, Anna; Brandner, Lea Alexandra
- Angewandte Chemie International Edition, Vol. 57, Issue 24
General Cyclopropane Assembly by Enantioselective Transfer of a Redox-Active Carbene to Aliphatic Olefins
journal, February 2019
- Montesinos-Magraner, Marc; Costantini, Matteo; Ramírez-Contreras, Rodrigo
- Angewandte Chemie International Edition, Vol. 58, Issue 18
Site‐Selective Functionalization of (sp 3 )C−H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium‐Porphyrin Cofactor
journal, September 2019
- Gu, Yang; Natoli, Sean N.; Liu, Zhennan
- Angewandte Chemie International Edition, Vol. 58, Issue 39
Recent advances in heme biocatalysis engineering
journal, September 2019
- Schmitz, Lisa Marie; Rosenthal, Katrin; Lütz, Stephan
- Biotechnology and Bioengineering, Vol. 116, Issue 12
Orthogonal Expression of an Artificial Metalloenzyme for Abiotic Catalysis
journal, November 2017
- Reynolds, Evan W.; Schwochert, Timothy D.; McHenry, Matthew W.
- ChemBioChem, Vol. 18, Issue 24
Broadening the Scope of Biocatalysis in Sustainable Organic Synthesis
journal, April 2019
- Sheldon, Roger A.; Brady, Dean
- ChemSusChem, Vol. 12, Issue 13
Proteins as Macromolecular Ligands for Metal-Catalysed Asymmetric Transfer Hydrogenation of Ketones in Aqueous Medium: Proteins as Macromolecular Ligands for Metal-Catalysed Asymmetric Transfer Hydrogenation of Ketones in Aqueous Medium
journal, March 2018
- de Jesús Cázares-Marinero, José; Przybylski, Cédric; Salmain, Michèle
- European Journal of Inorganic Chemistry, Vol. 2018, Issue 12
Design of artificial metalloproteins/metalloenzymes by tuning noncovalent interactions
journal, December 2017
- Hirota, Shun; Lin, Ying-Wu
- JBIC Journal of Biological Inorganic Chemistry, Vol. 23, Issue 1
Engineering new catalytic activities in enzymes
journal, January 2020
- Chen, Kai; Arnold, Frances H.
- Nature Catalysis, Vol. 3, Issue 3