1,3-Dithiolane as a Privileged Scaffold in Bioactive Derivatives: Chiral Resolution and Assignment of Absolute Configuration

The 1,3-dithiolane ring has been recently rehabilitated as a chemical scaffold in drug design. However, for derivatives that are substituted in position 4, the introduction of a chiral center on the heterocycle demands the separation and characterization of the stereoisomers. We report the first chiral resolution and absolute configuration (AC) assignment for (1,4-dithiaspiro[4.5]decan-2-yl)methanol (<i>R/S</i>)-<b>1</b>, a key synthon for dithiolane-based biologically active compounds. Using (semi)preparative enantioselective HPLC, we isolated enantiomeric <b>1</b>. The AC was assigned by using (+)-<b>1</b> for the enantioselective synthesis of (+)-<b>BS148</b>, a sigma receptor modulator. An X-ray diffraction analysis established the (<i>R</i>)-configuration of (+)-<b>BS148</b> and, by extension, of (<i>+</i>)-<b>1</b>. This method provides a reliable approach for preparing enantiopure 1,3-dithiolane scaffolds and establishes reference standards for AC determination of related compounds.