A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones
Chiral cyclopropane rings are key pharmacophores in pharmaceuticals and bioactive natural products, making libraries of these building blocks a valuable resource for drug discovery and development campaigns. Here, we report the development of a chemoenzymatic strategy for the stereoselective assembl...
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ftpubmed:oai:pubmedcentral.nih.gov:8865612 2023-05-15T18:26:46+02:00 A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones Nam, Donggeon Steck, Viktoria Potenzino, Robert J. Fasan, Rudi 2021-02-10 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865612/ http://www.ncbi.nlm.nih.gov/pubmed/33497207 https://doi.org/10.1021/jacs.0c09504 en eng http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865612/ http://www.ncbi.nlm.nih.gov/pubmed/33497207 http://dx.doi.org/10.1021/jacs.0c09504 J Am Chem Soc Article Text 2021 ftpubmed https://doi.org/10.1021/jacs.0c09504 2022-02-27T01:49:09Z Chiral cyclopropane rings are key pharmacophores in pharmaceuticals and bioactive natural products, making libraries of these building blocks a valuable resource for drug discovery and development campaigns. Here, we report the development of a chemoenzymatic strategy for the stereoselective assembly and structural diversification of cyclopropyl ketones, a highly versatile yet underexploited class of functionalized cyclopropanes. An engineered variant of sperm whale myoglobin is shown to enable the highly diastereo- and enantioselective construction of these molecules via olefin cyclopropanation in the presence of a diazoketone carbene donor reagent. This biocatalyst offers a remarkably broad substrate scope, catalyzing this reaction with high stereoselectivity across a variety of vinylarene substrates as well as a range of different α-aryl and α-alkyl diazoketone derivatives. Chemical transformation of these enzymatic products enables further diversification of these molecules to yield a collection of structurally diverse cyclopropane-containing scaffolds in enantiopure form, including core motifs found in drugs and natural products as well as novel structures. This work illustrates the power of combining abiological biocatalysis with chemoenzymatic synthesis for generating collections of optically active scaffolds of high value for medicinal chemistry and drug discovery. Text Sperm whale PubMed Central (PMC) Journal of the American Chemical Society 143 5 2221 2231 |
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Article Nam, Donggeon Steck, Viktoria Potenzino, Robert J. Fasan, Rudi A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones |
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Article |
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Chiral cyclopropane rings are key pharmacophores in pharmaceuticals and bioactive natural products, making libraries of these building blocks a valuable resource for drug discovery and development campaigns. Here, we report the development of a chemoenzymatic strategy for the stereoselective assembly and structural diversification of cyclopropyl ketones, a highly versatile yet underexploited class of functionalized cyclopropanes. An engineered variant of sperm whale myoglobin is shown to enable the highly diastereo- and enantioselective construction of these molecules via olefin cyclopropanation in the presence of a diazoketone carbene donor reagent. This biocatalyst offers a remarkably broad substrate scope, catalyzing this reaction with high stereoselectivity across a variety of vinylarene substrates as well as a range of different α-aryl and α-alkyl diazoketone derivatives. Chemical transformation of these enzymatic products enables further diversification of these molecules to yield a collection of structurally diverse cyclopropane-containing scaffolds in enantiopure form, including core motifs found in drugs and natural products as well as novel structures. This work illustrates the power of combining abiological biocatalysis with chemoenzymatic synthesis for generating collections of optically active scaffolds of high value for medicinal chemistry and drug discovery. |
format |
Text |
author |
Nam, Donggeon Steck, Viktoria Potenzino, Robert J. Fasan, Rudi |
author_facet |
Nam, Donggeon Steck, Viktoria Potenzino, Robert J. Fasan, Rudi |
author_sort |
Nam, Donggeon |
title |
A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones |
title_short |
A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones |
title_full |
A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones |
title_fullStr |
A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones |
title_full_unstemmed |
A Diverse Library of Chiral Cyclopropane Scaffolds via Chemoenzymatic Assembly and Diversification of Cyclopropyl Ketones |
title_sort |
diverse library of chiral cyclopropane scaffolds via chemoenzymatic assembly and diversification of cyclopropyl ketones |
publishDate |
2021 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865612/ http://www.ncbi.nlm.nih.gov/pubmed/33497207 https://doi.org/10.1021/jacs.0c09504 |
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Sperm whale |
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Sperm whale |
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J Am Chem Soc |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865612/ http://www.ncbi.nlm.nih.gov/pubmed/33497207 http://dx.doi.org/10.1021/jacs.0c09504 |
op_doi |
https://doi.org/10.1021/jacs.0c09504 |
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Journal of the American Chemical Society |
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143 |
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5 |
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2221 |
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2231 |
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1766208743058440192 |