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Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach

Macrocyclic compounds occupy an important chemical space between small molecules and biologics and are prevalent in many natural products and pharmaceuticals. The growing interest in macrocycles has been fueled, in part, by the design of novel synthetic methods to these compounds. One appealing stra...

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Autores principales: Mangold, Shane L., Grubbs, Robert H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618480/
https://www.ncbi.nlm.nih.gov/pubmed/26509000
http://dx.doi.org/10.1039/c5sc01507c
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author Mangold, Shane L.
Grubbs, Robert H.
author_facet Mangold, Shane L.
Grubbs, Robert H.
author_sort Mangold, Shane L.
collection PubMed
description Macrocyclic compounds occupy an important chemical space between small molecules and biologics and are prevalent in many natural products and pharmaceuticals. The growing interest in macrocycles has been fueled, in part, by the design of novel synthetic methods to these compounds. One appealing strategy is ring-closing metathesis (RCM) that seeks to construct macrocycles from acyclic diene precursors using defined transition-metal alkylidene catalysts. Despite its broad utility, RCM generally gives rise to a mixture of E- and Z-olefin isomers that can hinder efforts for the large-scale production and isolation of such complex molecules. To address this issue, we aimed to develop methods that can selectively enrich macrocycles in E- or Z-olefin isomers using an RCM/ethenolysis strategy. The utility of this methodology was demonstrated in the stereoselective formation of macrocyclic peptides, a class of compounds that have gained prominence as therapeutics in drug discovery. Herein, we report an assessment of various factors that promote catalyst-directed RCM and ethenolysis on a variety of peptide substrates by varying the olefin type, peptide sequence, and placement of the olefin in macrocycle formation. These methods allow for control over olefin geometry in peptides, facilitating their isolation and characterization. The studies outlined in this report seek to expand the scope of stereoselective olefin metathesis in general RCM.
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spelling pubmed-46184802016-08-01 Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach Mangold, Shane L. Grubbs, Robert H. Chem Sci Chemistry Macrocyclic compounds occupy an important chemical space between small molecules and biologics and are prevalent in many natural products and pharmaceuticals. The growing interest in macrocycles has been fueled, in part, by the design of novel synthetic methods to these compounds. One appealing strategy is ring-closing metathesis (RCM) that seeks to construct macrocycles from acyclic diene precursors using defined transition-metal alkylidene catalysts. Despite its broad utility, RCM generally gives rise to a mixture of E- and Z-olefin isomers that can hinder efforts for the large-scale production and isolation of such complex molecules. To address this issue, we aimed to develop methods that can selectively enrich macrocycles in E- or Z-olefin isomers using an RCM/ethenolysis strategy. The utility of this methodology was demonstrated in the stereoselective formation of macrocyclic peptides, a class of compounds that have gained prominence as therapeutics in drug discovery. Herein, we report an assessment of various factors that promote catalyst-directed RCM and ethenolysis on a variety of peptide substrates by varying the olefin type, peptide sequence, and placement of the olefin in macrocycle formation. These methods allow for control over olefin geometry in peptides, facilitating their isolation and characterization. The studies outlined in this report seek to expand the scope of stereoselective olefin metathesis in general RCM. Royal Society of Chemistry 2015-08-01 2015-05-21 /pmc/articles/PMC4618480/ /pubmed/26509000 http://dx.doi.org/10.1039/c5sc01507c Text en This journal is © The Royal Society of Chemistry 2015 http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemistry
Mangold, Shane L.
Grubbs, Robert H.
Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach
title Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach
title_full Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach
title_fullStr Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach
title_full_unstemmed Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach
title_short Stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach
title_sort stereoselective synthesis of macrocyclic peptides via a dual olefin metathesis and ethenolysis approach
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618480/
https://www.ncbi.nlm.nih.gov/pubmed/26509000
http://dx.doi.org/10.1039/c5sc01507c
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