Radical-Mediated Three-Component Reaction: A Study toward the Total Synthesis of Resiniferatoxin

This review summarizes the efforts to develop a radical-mediated three-component reaction and its application to a convergent approach to synthesize the 5/7/6-tricyclic framework (ABC-rings) of the densely functionalized dephnane diterpene, resiniferatoxin. The alpha-alkoxy bridgehead radical species, which was designed as the radical donor of the three-component reaction, was generated from O, Se- and O,Te-acetals under two different conditions. The generated alpha -alkoxy bridgehead radical effectively underwent the three-component reaction with alpha, beta-unsaturated ketones and allyltributyltin/aldehyde under each of the conditions, giving rise to a wide variety of multiply functionalized 2,3-trans disubstituted cyclopentenone moieties. One of the established reactions was utilized as the key assembling reaction of the ABC-tricyclic framework of resiniferatoxin. The reaction of the bridgehead radical of the highly functionalized 6-membered C-ring, the 5-membered A-ring, and an allyltributyltin derivative effectively produced the C4-branched AC-rings. The last B-ring was constructed from the coupling adduct in two steps through the 7-endo cyclization, delivering the tricyclic framework possessing the correct C8 and 9-stereocenters of resiniferatoxin. The present methods demonstrate the power of the three-component reaction using an alpha-alkoxy bridgehead radical in a convergent approach to the complex architectures of daphnane diterpenes.