Catalyst-free electrochemical synthesis of ursodeoxycholic acid: mixed-solvent optimization and solvent-dependent selectivity

Ursodeoxycholic acid is a highly valued therapeutic agent, yet its synthesis often relies on metal catalysts or complex biological processes. In this study, the electrochemical reduction of 7-ketolithocholic acid to ursodeoxycholic acid was investigated using an uncoated copper cathode in aprotic media. Building on our previous comparison of aprotic media, DMI, HMPA, DMPU, and DMF were reassessed. DMI produced UDCA without detectable CDCA, whereas HMPA afforded the highest 7 K-LCA conversion; these complementary outcomes motivated the subsequent evaluation of a mixed DMI-HMPA electrolyte. The solvent-dependent product distributions and LSV responses motivate tentative mechanistic hypotheses involving Li⁺ solvation and hydrogen delivery, but the reactive intermediates and electron-transfer sequence remain unverified. Based on the solvent-screening results, a mixed-solvent system was optimized using response surface methodology, achieving a validated HPLC-based ursodeoxycholic acid yield of 84.88 ± 2.45% with complete substrate conversion and a chenodeoxycholic acid byproduct yield of 13.27 ± 2.76% after 12 h (mean ± SD, n = 3). Additionally, an estimated average current density of 31.25 mA/cm² and an estimated faradaic efficiency of approximately 14% were calculated for the optimized electrolysis. This study demonstrates the electrochemical synthesis of UDCA in a mixed-solvent system and highlights solvent-dependent differences in product distribution.