| Ingenol (1), a diterpene polyol initially isolated from the Euphorbia Ingens species in 1968, is of considerable interest due to its structural complexity and spectacular biological activities. Biologically, esters of ingenol have been shown to possess potent tumor promoting, anti-leukemic, and anti-HIV properties. Structurally, the unique ingenol framework featuring a rare example of “inside-outside” bicyclic topological isomerism represents a formidable challenge to synthetic organic chemists. Despite the efforts of many groups, ingenol did not yield to total synthesis until very recently. Herein are described efforts toward the total synthesis of ingenol.; The complete carboskeleton of ingenol has been prepared in an efficient 13-step sequence from known cycloheptenone 49, highlighted by the construction of the highly strained “inside-outside” ingenol BC ring system via ring-closing metathesis (i.e. 127 → 128). The A ring of 128 has been functionalized in another 7 steps to furnish highly advanced intermediate 136. Subsequent attempts to introduce the ingenol B ring functionality via a singlet oxygen-ene reaction have yielded no success. Current work stands only a few transformations away from a total synthesis of ingenol. |
