Temporary thio-derivatization in the synthesis of (+)-4-acetylbromoxone.

A stereocontrolled synthesis of the marine natural products (+)-bromoxone (1) and (+)-4-acetylbromoxone (2) is reported. The sequence features the enzymatic kinetic resolution of 4-hydroxycyclohexenone (6) via its S-benzyl adduct. Thereafter, a base-mediated elimination–silylation generated an optically active (-)-4S-4-tert-butyldimethylsilyoxycyclohexenone (5), which then underwent diastereoselective epoxidation. Saegusa–Ito oxidation enabled formation of the corresponding α,β-unsaturated ketone 13. Bromination–elimination and subsequent removal of the silicon protecting group afforded (+)-bromoxone (1) which was converted into (+)-(4S,5R,6R)-4-acetoxy-2-bromo-5,6-epoxycyclohex-2-enone (2) [(+)-4-acetylbromoxone]. Using a luciferase gene reporter assay ED50 for NF-kB inhibition of 9 μM was determined.