Synthesis of chiral sulfinate esters by asymmetric condensation

Abstract

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.

One-Pot Synthesis of Thio-Augmented Sulfonylureas via a Modified Bunte’s Reaction

“… 25 − 27 An additional innovation would be to generate novel, nontraditional chemotypes with S-bearing stereocenters, which are one of the underexplored pharmacophores in the biological realm ( Figure 1 A). 28 …”

Synthetic Approach toward Enantiopure Cyclic Sulfinamides

“… 8 The fact that the general value of enantiopure sulfinamides has been long recognized is eloquently demonstrated by the sheer effort dedicated to their preparation over the years. 9 …”

“…In particular, recently developed stereoselective methodologies toward increasingly more popular sulfoximines and sulfonimidamides rely on enantiopure sulfinamides as synthetic precursors . The fact that the general value of enantiopure sulfinamides has been long recognized is eloquently demonstrated by the sheer effort dedicated to their preparation over the years …”

Asymmetric organocatalytic sulfenylation for the construction of a diheteroatom-bearing tetrasubstituted carbon centre

“…Sulfur-containing compounds manifest themselves as biologically relevant molecules, 1 ligands or synthetic intermediates in organic transformations 2 because of their diverse oxidation states 3 (Scheme 1a). In the past few decades, significant advances have been made for the enantioselective construction of new carbon–sulfur bonds, 4 including sulfur-addition, cross-coupling, substitution or ring-opening, and sulfenylation.…”