Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity
Abstract Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules—water and carbon dioxide—to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generate...
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Online Access: | http://dx.doi.org/10.1002/anie.202407111 https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202407111 |
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crwiley:10.1002/anie.202407111 2024-10-13T14:06:36+00:00 Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity Chen, Reichi Kayrouz, Colby S. McAmis, Eli Clark, Douglas S. Hartwig, John F. U.S. Department of Energy 2024 http://dx.doi.org/10.1002/anie.202407111 https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202407111 en eng Wiley http://onlinelibrary.wiley.com/termsAndConditions#vor Angewandte Chemie International Edition ISSN 1433-7851 1521-3773 journal-article 2024 crwiley https://doi.org/10.1002/anie.202407111 2024-09-17T04:52:30Z Abstract Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules—water and carbon dioxide—to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site‐selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate. Article in Journal/Newspaper Carbonic acid Wiley Online Library Angewandte Chemie International Edition |
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Wiley Online Library |
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English |
description |
Abstract Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules—water and carbon dioxide—to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site‐selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate. |
author2 |
U.S. Department of Energy |
format |
Article in Journal/Newspaper |
author |
Chen, Reichi Kayrouz, Colby S. McAmis, Eli Clark, Douglas S. Hartwig, John F. |
spellingShingle |
Chen, Reichi Kayrouz, Colby S. McAmis, Eli Clark, Douglas S. Hartwig, John F. Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity |
author_facet |
Chen, Reichi Kayrouz, Colby S. McAmis, Eli Clark, Douglas S. Hartwig, John F. |
author_sort |
Chen, Reichi |
title |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity |
title_short |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity |
title_full |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity |
title_fullStr |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity |
title_full_unstemmed |
Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity |
title_sort |
carbonic anhydrase variants catalyze the reduction of dialkyl ketones with high enantioselectivity |
publisher |
Wiley |
publishDate |
2024 |
url |
http://dx.doi.org/10.1002/anie.202407111 https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202407111 |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_source |
Angewandte Chemie International Edition ISSN 1433-7851 1521-3773 |
op_rights |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
op_doi |
https://doi.org/10.1002/anie.202407111 |
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Angewandte Chemie International Edition |
_version_ |
1812812805115478016 |