Diversity-oriented synthesis of glycomimetics

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with dive...

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Autores principales: Meanwell, Michael, Fehr, Gaelen, Ren, Weiwu, Adluri, Bharanishashank, Rose, Victoria, Lehmann, Johannes, Silverman, Steven M., Rowshanpour, Rozhin, Adamson, Christopher, Bergeron-Brlek, Milan, Foy, Hayden, Challa, Venugopal Rao, Campeau, Louis-Charles, Dudding, Travis, Britton, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9814271/
https://www.ncbi.nlm.nih.gov/pubmed/36697548
http://dx.doi.org/10.1038/s42004-021-00520-3
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author Meanwell, Michael
Fehr, Gaelen
Ren, Weiwu
Adluri, Bharanishashank
Rose, Victoria
Lehmann, Johannes
Silverman, Steven M.
Rowshanpour, Rozhin
Adamson, Christopher
Bergeron-Brlek, Milan
Foy, Hayden
Challa, Venugopal Rao
Campeau, Louis-Charles
Dudding, Travis
Britton, Robert
author_facet Meanwell, Michael
Fehr, Gaelen
Ren, Weiwu
Adluri, Bharanishashank
Rose, Victoria
Lehmann, Johannes
Silverman, Steven M.
Rowshanpour, Rozhin
Adamson, Christopher
Bergeron-Brlek, Milan
Foy, Hayden
Challa, Venugopal Rao
Campeau, Louis-Charles
Dudding, Travis
Britton, Robert
author_sort Meanwell, Michael
collection PubMed
description Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates.
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spelling pubmed-98142712023-01-10 Diversity-oriented synthesis of glycomimetics Meanwell, Michael Fehr, Gaelen Ren, Weiwu Adluri, Bharanishashank Rose, Victoria Lehmann, Johannes Silverman, Steven M. Rowshanpour, Rozhin Adamson, Christopher Bergeron-Brlek, Milan Foy, Hayden Challa, Venugopal Rao Campeau, Louis-Charles Dudding, Travis Britton, Robert Commun Chem Article Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates. Nature Publishing Group UK 2021-06-24 /pmc/articles/PMC9814271/ /pubmed/36697548 http://dx.doi.org/10.1038/s42004-021-00520-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Meanwell, Michael
Fehr, Gaelen
Ren, Weiwu
Adluri, Bharanishashank
Rose, Victoria
Lehmann, Johannes
Silverman, Steven M.
Rowshanpour, Rozhin
Adamson, Christopher
Bergeron-Brlek, Milan
Foy, Hayden
Challa, Venugopal Rao
Campeau, Louis-Charles
Dudding, Travis
Britton, Robert
Diversity-oriented synthesis of glycomimetics
title Diversity-oriented synthesis of glycomimetics
title_full Diversity-oriented synthesis of glycomimetics
title_fullStr Diversity-oriented synthesis of glycomimetics
title_full_unstemmed Diversity-oriented synthesis of glycomimetics
title_short Diversity-oriented synthesis of glycomimetics
title_sort diversity-oriented synthesis of glycomimetics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9814271/
https://www.ncbi.nlm.nih.gov/pubmed/36697548
http://dx.doi.org/10.1038/s42004-021-00520-3
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