This proposal outlines a novel strategy for the total synthesis of typical members of the irritant and cocarcinogenic ingenane and tigliane classes of diterpenes. These compounds have been isolated from certain species of the genus Euphorbia. Derivatives of these compounds have received considerable attention recently, particularly in terms of examining tumor promotion and related studies. The unusual ingenane carbon skeleton exhibited by these compounds is characerized by a bicyclo [4.4.1]undecane ring system fused to a cyclopentenol moiety. The approach proposed for entry into this system will focus on a novel application of a thermal [6+4] cycloaddition between a suitably substituted diene partner and tropone. Subsequent annulation of the fused five-membered ring would complete the construction of the basic architecture of the molecule in a stereoselective fashion. Adjustment of the various oxidation levels around the periphery of the compound would lead to ingenol the parent diterpene from which other medicinally important derivatives will be prepared. Synthetic approaches to phorbol and related species will also be investigated. The novel 5-7-6 tricyclic ring system of these compounds will be assembled from a rigid hydroazulenic precursor. Application of this strategy of the preparation of several phorbol derivatives is planned.
|Rigby, James H; Bazin, Berangere; Meyer, J Hoyt et al. (2002) Synthetic studies on the ingenane diterpenes. An improved entry into a trans-intrabridgehead system. Org Lett 4:799-801|