Fomitellic acids, isolated from the mycelium of a basidiomycete, Fomitella fraxinea, are specific inhibitors of DNA polymerase α and β. It was also reported that inhibition of DNA polymerase activity by fomitellic acids induced neurite outgrowth in PC-12 cells. Structurally, fomitellic acids belong to the triterpenoid family of compounds, which are characterized by a highly oxygenated steroidal AB ring moiety. Herein, we report a total synthesis of fomitellic acid B (2) based on a radical cascade cyclization of epoxypolyene. Our synthetic approach began with the vinylogous Mukaiyama aldol reaction between the enal 11 and the vinylketene silyl N,O-acetal 12. After protection of the secondary alcohol in aldol adduct 13, the chiral auxiliary was removed to give allylic alcohol 14 with 95% ee. Sharpless asymmetric epoxidation of 14 gavd epoxyalcohol 15, which was converted into a key intermediate 17 in 3 step. The vinyl iodide 27, stereoselectively prepared from (-)-Wieland-Miescher ketone, was treated with t-BuLi, and the resulting vinyl lithium was then reacted with the aldehyde 17. Subsequent acetylation of the secondary alcohol provided the cyclization precursor 28a. The trans-decaline skeleton was stereoselectively constructed by means of titanium(III)-mediated radical cascade cyclization of epoxypolyene 28a. The cyclization product 29 was found to possess the desired stereochemistry and to be formed via a trans-fused chair/boat-like transition state. After protection of the secondary alcohol in 29, treatment of the resulting benzoate ester with HCl provided diol 31, which was converted into carboxylic acid 33 in 4 sreps. Allylic oxidation at C7 position with NaClO_2, followed by construction of the side chain moiety afforded enone 35. Finally, deprotection of acetyl and benzoyl groups with NaOH completed the synthesis of fomitellic acid B (2).
