Bioinspired Aerobic Oxidation to Functionalize the CD Ring of the Steroid Framework: Synthesis and Stereochemical Assignments of Gargalol C and Related Oxysterols

Aerobic oxidation to insert oxygen functional groups into the CD ring of the steroid framework was investigated using several 5,6-α-epoxysterol precursors. Oxidation under Schenck-ene conditions provided oxysterols with a hydroxyl group at either C8, C9, C11, C14, or C15, depending on the structure and configuration of the precursors. Meanwhile, aerobic oxidation using a catalytic amount of N-hydroxyphthalimide and Co(acac)2 gave exclusively 14β-hydroxysterols, regardless of the position of the allylic double bond. The selected oxidation products were converted into fungus-derived oxysterols with a hydroxyl group at either C14 or C15, resulting in the first syntheses and the structure elucidation/revision of known natural products. This study not only provides a facile approach to rare oxysterols with a functionalized CD ring but also aids in the future structure determination of advanced oxysterols of biological interests. Moreover, the overall biomimetic synthetic approach starting from ergosterol proposes possible biosynthetic pathways occurring in nature.