Cyclodextrin-Assisted Enantioselective Organic Reactions: Supramolecular Recognition and Chiral Induction in Aqueous Media

Introduction: The development of sustainable methods for asymmetric oxidation is important for the preparation of optically active sulfoxides used as pharmaceutical and fine-chemical intermediates. β-Cyclodextrin (β-CD) is a renewable and water-compatible oligosaccharide whose hydrophobic cavity can selectively accommodate organic substrates and create a chiral reaction microenvironment. This study investigated β-CD as a supramolecular host for the enantioselective oxidation of thioanisole to methyl phenyl sulfoxide using hydrogen peroxide in aqueous medium.

Methods: The effects of the β-CD/thioanisole molar ratio, pH, temperature, hydrogen peroxide concentration, and reaction time were systematically evaluated. Formation of the thioanisole–β-CD inclusion complex was examined by UV–Visible spectroscopy, FTIR, and ¹H NMR. Thioanisole conversion, methyl phenyl sulfoxide yield, sulfoxide selectivity relative to overoxidation products, and enantiomeric composition were determined chromatographically. A parallel reaction performed without β-CD served as the control.

Results: Spectroscopic changes associated with the internal H3/H5 protons of β-CD and with characteristic thioanisole bands supported formation of a host–guest inclusion complex and preferential accommodation of the aromatic substrate inside the cyclodextrin cavity. Under the optimized conditions, the β-CD-assisted system achieved 81.7% thioanisole conversion, 70.5% methyl phenyl sulfoxide yield, and 86.3% sulfoxide selectivity. An enantiomeric excess of 26.4% ee was obtained, with preferential formation of the (R)-enantiomer. In the absence of β-CD, conversion and sulfoxide yield decreased to 52.4% and 43.1%, respectively, while the enantiomeric excess was only 3.8%. The enhanced activity and stereoselectivity are attributed to hydrophobic inclusion, hydrogen-bonding interactions, and steric confinement within the chiral β-CD cavity.

Conclusions: β-CD significantly improved thioanisole conversion, sulfoxide yield, chemoselectivity, and enantioselectivity under mild aqueous conditions. The comparison with the β-CD-free control demonstrates that supramolecular substrate recognition and chiral confinement play central roles in the oxidation process. These findings support cyclodextrin-assisted oxidation with hydrogen peroxide as a green, metal-free strategy for the selective synthesis of optically enriched sulfoxides.