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Synthesis of chiral sulfinate esters by asymmetric condensation

Updated: Apr 14, 2022

Xin Zhang, Esther Cai Xia Ang, Ziqi Yang, Choon Wee Kee and Choon-Hong Tan, Nature, 2022, 604, 298-303


Achiral sulfur functional groups such as sulfonamide, sulfone, thiols and thioethers are common in drugs and natural products. However, chiral sulfur functional groups are often neglected as pharmacophores1–3; but sulfoximine, with its unique physicochemical and pharmacokinetic properties4,5, has been recently incorporated into several clinical candidates. Thus, other sulfur stereogenic centers, such as sulfinate ester, sulfinamide, sulfonimidate ester and sulfonimidamide have started to attract attention. The diversity and complexity of these sulfur stereogenic centers have the potential to expand chemical space for drug discovery6–10. However, the installation of these structures enantioselectively into drug molecules is highly challenging. Here, we report the straightforward access to enantioenriched sulfinate esters via asymmetric condensation of pro-chiral 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 centers.

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