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Synthesis of chiral sulfinate esters by asymmetric condensation

Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores(1–3), although sulfoximine, with its unique physicochemical and pharmacokinetic properties...

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Autores principales: Zhang, Xin, Ang, Esther Cai Xia, Yang, Ziqi, Kee, Choon Wee, Tan, Choon-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985065/
https://www.ncbi.nlm.nih.gov/pubmed/35158370
http://dx.doi.org/10.1038/s41586-022-04524-4
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author Zhang, Xin
Ang, Esther Cai Xia
Yang, Ziqi
Kee, Choon Wee
Tan, Choon-Hong
author_facet Zhang, Xin
Ang, Esther Cai Xia
Yang, Ziqi
Kee, Choon Wee
Tan, Choon-Hong
author_sort Zhang, Xin
collection PubMed
description Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores(1–3), although sulfoximine, with its unique physicochemical and pharmacokinetic properties(4,5), has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centres, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide, have started to attract attention. The diversity and complexity of these sulfur stereogenic centres have the potential to expand the chemical space for drug discovery(6–10). However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here we report straightforward access to enantioenriched sulfinate esters via asymmetric condensation of prochiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification(11,12) of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres.
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spelling pubmed-89850652022-04-06 Synthesis of chiral sulfinate esters by asymmetric condensation Zhang, Xin Ang, Esther Cai Xia Yang, Ziqi Kee, Choon Wee Tan, Choon-Hong Nature Article Achiral sulfur functional groups, such as sulfonamide, sulfone, thiol and thioether, are common in drugs and natural products. By contrast, chiral sulfur functional groups are often neglected as pharmacophores(1–3), although sulfoximine, with its unique physicochemical and pharmacokinetic properties(4,5), has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centres, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide, have started to attract attention. The diversity and complexity of these sulfur stereogenic centres have the potential to expand the chemical space for drug discovery(6–10). However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here we report straightforward access to enantioenriched sulfinate esters via asymmetric condensation of prochiral sulfinates and alcohols using pentanidium as an organocatalyst. We successfully coupled a wide range of sulfinates and bioactive alcohols stereoselectively. The initial sulfinates can be prepared from existing sulfone and sulfonamide drugs, and the resulting sulfinate esters are versatile for transformations to diverse chiral sulfur pharmacophores. Through late-stage diversification(11,12) of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres. Nature Publishing Group UK 2022-02-14 2022 /pmc/articles/PMC8985065/ /pubmed/35158370 http://dx.doi.org/10.1038/s41586-022-04524-4 Text en © The Author(s), under exclusive licence to Springer Nature Limited 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Article
Zhang, Xin
Ang, Esther Cai Xia
Yang, Ziqi
Kee, Choon Wee
Tan, Choon-Hong
Synthesis of chiral sulfinate esters by asymmetric condensation
title Synthesis of chiral sulfinate esters by asymmetric condensation
title_full Synthesis of chiral sulfinate esters by asymmetric condensation
title_fullStr Synthesis of chiral sulfinate esters by asymmetric condensation
title_full_unstemmed Synthesis of chiral sulfinate esters by asymmetric condensation
title_short Synthesis of chiral sulfinate esters by asymmetric condensation
title_sort synthesis of chiral sulfinate esters by asymmetric condensation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985065/
https://www.ncbi.nlm.nih.gov/pubmed/35158370
http://dx.doi.org/10.1038/s41586-022-04524-4
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