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 pharmacophores1-3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,...

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Main Authors: Zhang, Xin, Ang, Esther Cai Xia, Yang, Ziqi, Kee, Choon Wee, Tan, Choon-Hong
Other Authors: School of Physical and Mathematical Sciences
Format: Article
Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/161789
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1617892022-09-20T04:55:20Z Synthesis of chiral sulfinate esters by asymmetric condensation Zhang, Xin Ang, Esther Cai Xia Yang, Ziqi Kee, Choon Wee Tan, Choon-Hong School of Physical and Mathematical Sciences Institute of Chemical and Engineering Sciences, Singapore Science::Chemistry Sulfonamide Stereoselectivity 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 pharmacophores1-3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, 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 discovery6-10. 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 diversification11,12 of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres. Ministry of Education (MOE) Nanyang Technological University We acknowledge support from Nanyang Technological University for Tier 1 grant (RG2/20). This research was supported by the Ministry of Education, Singapore, under its Academic Research Fund Tier 2 (MOE2019-T2-1-091). 2022-09-20T04:55:19Z 2022-09-20T04:55:19Z 2022 Journal Article Zhang, X., Ang, E. C. X., Yang, Z., Kee, C. W. & Tan, C. (2022). Synthesis of chiral sulfinate esters by asymmetric condensation. Nature, 604(7905), 298-303. https://dx.doi.org/10.1038/s41586-022-04524-4 0028-0836 https://hdl.handle.net/10356/161789 10.1038/s41586-022-04524-4 35158370 2-s2.0-85127645921 7905 604 298 303 en RG2/20 MOE2019-T2-1-091 Nature © 2022 The Author(s), under exclusive licence to Springer Nature Limited. All rights reserved.
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Chemistry
Sulfonamide
Stereoselectivity
spellingShingle Science::Chemistry
Sulfonamide
Stereoselectivity
Zhang, Xin
Ang, Esther Cai Xia
Yang, Ziqi
Kee, Choon Wee
Tan, Choon-Hong
Synthesis of chiral sulfinate esters by asymmetric condensation
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 pharmacophores1-3, although sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, 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 discovery6-10. 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 diversification11,12 of celecoxib and other drug derivatives, we demonstrate the viability of this unified approach towards sulfur stereogenic centres.
author2 School of Physical and Mathematical Sciences
author_facet School of Physical and Mathematical Sciences
Zhang, Xin
Ang, Esther Cai Xia
Yang, Ziqi
Kee, Choon Wee
Tan, Choon-Hong
format Article
author Zhang, Xin
Ang, Esther Cai Xia
Yang, Ziqi
Kee, Choon Wee
Tan, Choon-Hong
author_sort Zhang, Xin
title Synthesis of chiral sulfinate esters by asymmetric condensation
title_short 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_sort synthesis of chiral sulfinate esters by asymmetric condensation
publishDate 2022
url https://hdl.handle.net/10356/161789
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