The long-term objectives of this research program are to complete the total synthesis of the potent tumor-promoting diterpenes ingenol and phorbol as well as to develop synthetic approaches into the important anticancer agent, taxol. Long chain fatty acid esters of ingenol and phorbol are known to be among the most potent tumor-promoting natural products yet identified; consequently, these materials have become significant probes for understanding carcinogenesis. Taxol has emerged as one of the most promising current clinical agents against ovarian, breast and other cancers. The limited availability of this compound from natural sources renders total or partial synthesis an attractive alternative for providing additional supplies of the drug. The focal point of the synthetic methodology to be examined during this research project is a novel class of transition-metal promoted higher- order cycloaddition processes suitable for delivering advanced intermediates that can be transformed into the target natural products. Specifically, the chromium(0) mediated [6pi+4pi] cycloaddition reaction is projected to provide organic intermediates that are amenable to selective conversion into taxol, ingenol and phorbol. Pertinent observations made to date suggest that the new Cr(0) cycloaddition methodology could produce the products in optically pure form with a high-level of efficiency. One of the principal features of the proposed research program is the development of a """"""""unified"""""""" entry into the ingenane, tigliane (phorbol) and taxane ring systems from a common advanced bicyclo[4.4.i]undecane intermediate. The advent of the chromium(0) promoted [6pi+4pi] cycloaddition technology permits the convenient accessing of a wide range of highly functionalized and stereochemically rich bicyclo[4.4.1]undecane products. Appropriately modified bicyclo[4.4.1] species will afford avenues from which each of the target natural products can be prepared selectively.
|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|