Stereochemical Tuning in CF₃-Sulfinyl Transfer: Glucose-Derived Sulfinates toward Chiral Sulforaphane Isosteres

Introduction

Chiral trifluoromethyl sulfoxides are underexplored fluorinated sulfur motifs with growing relevance in asymmetric synthesis and medicinal chemistry. In the scaffold of the phytochemical sulforaphane replacement of CH₃SO group by a CF₃SO unit provides a direct fluorinated isostere, but requires a stereochemically controlled transfer.

Methods

Trifluoromethanesulfinyl chloride was reacted with glucose-derived chiral alcohols under different base and solvent conditions. Although base-controlled stereodifferentiation is well established for related alkylsulfinyl chlorides, trifluoromethanesulfinyl chloride required specific re-optimization because of its distinct reactivity profile. DAG-derived sulfinates were used to evaluate base-dependent stereochemical induction, whereas the more robust DCG platform was selected because its diastereomeric trifluoromethanesulfinates could be purified by silica gel column chromatography. Diastereomeric ratios were determined by ¹H NMR. Enantiomeric excesses were measured by chiral HPLC.

Results

DAG screening showed complementary stereochemical bias: DIPEA/THF favored Ss-sulfinate, whereas collidine/THF favored Rs derivative. However, DAG sulfinates showed limited stability toward silica gel. Fortunatelly, DCG enabled chromatographic isolation of both diastereomeric trifluoromethanesulfinates, affording the Ss- and Rs- epimers in 66% and 60% yield, respectively. Grignard reagents mainly afforded symmetrical sulfoxides through double nucleophilic substitution at sulfur. Conversely, 3-azidopropoxide underwent productive CF₃-sulfinyl transfer, giving enantioenriched 3-azidopropyl trifluoromethanesulfinates in 30–35% yield and 65–70% ee. Subsequent azido-to-isothiocyanate conversion enabled access to the CF₃-sulfinyl sulforaphane isostere.

Conclusions

Glucose-derived trifluoromethanesulfinates provide an enantiodivergent platform for CF₃-sulfinyl transfer. Although double substitution at sulfur remains the main limitation, the synthesis of enantioenriched sulforaphane isosteres validates this strategy for fluorinated chiral sulfoxide design.

Acknowledgment

PID2019-104767RB-I00/AEI/10.13039/501100011033) and DGP_PRED_2024_01383.