The structurally related tigliane, daphnane, and ingenane diterpene esters, occurring in Euphorbiaceae and Thymelaeaceae, exhibit toxic, irritant, cocarcinogenic as well as antileukemic activities. This proposal is directed towards the synthesis of one of these families of compounds, the ingenane diterpenes, of which ingenol, 1, is a typical member. Several formidable challenges are apparent in any effort to assemble the carbocyclic system of the ingenanes, with four carbocyclic rings and eight stereocenters. Of particular note is the """"""""inside-outside"""""""" intrabridgehead stereochemistry of the (4.4.1)-BC-ring system, a stereochemical feature of the ingenanes which has thwarted all synthetic efforts reported to date. Out-lined herein are two different approaches to the synthesis of the ingenanes, both of which employ the intramolecular dioxolenone photocycloaddition that we have developed to establish the critical intrabridgehead stereochemistry.
| Winkler, Jeffrey D; Rouse, Meagan B; Greaney, Michael F et al. (2002) The first total synthesis of (+/-)-ingenol. J Am Chem Soc 124:9726-8 |
