Reaction of oridonin with p-toluenesulfonic anhydride/p-toluenesulfonic acid: An unexpected cascade rearrangement

Under reflux conditions, oridonin ( 1 ) reacted with p -toluenesulfonic anhydride/ p -toluenesulfonic acid to afford an unexpected cascade double rearrangement product ( 6 ), rather than the anticipated hemiketal-hydrolysis product ( 5 ). Compound 6 features a 6/6/7 tricyclic carbon framework, whose structure was unambiguously established by spectroscopic analyses and single-crystal X-ray diffraction. A plausible cascade mechanism involving nucleophilic substitution and retro-Aldol steps is proposed. However, biological assays revealed that 6 did not show any antiproliferative activity, indicating that the intact C/D ring system is crucial for the cytotoxicity of oridonin. • Treatment of oridonin ( 1 ) with p -Ts₂O/ p -TsOH afforded a novel di-rearranged 6/6/7-tricyclic scaffold ( 6 ). • The transformation proceeded via a cascade of hydrolysis, nucleophilic substitution, and retro‑Aldol reactions. • The structure of 6 was confirmed by single-crystal X-ray diffraction analysis. • C and D rings constitute an essential pharmacophore for the anticancer activity of oridonin.