The long-term objectives of this research are to develop new, fully synthetic routes to biologically active members of the pentacyclic quassinoid family. Since the important structural requirements for bioactivity have now been delineated (A-ring enone, pentacyclic framework, D-ring lipophilic substituent), it is now possible to design new, potent antitumor agents in sufficient quantity for further clinical evaluation. Using our convergent synthesis of the pentacyclic quassinoid skeleton, we will develop efficient and streamlined synthetic routes to modified quassinoids and quassinoid analogues. Specifically: C13-ether-bridged pentacyclics with n-alkyl groups on ring D and the quasimarin A-ring substituent pattern. A simpler A-ring enone could be prepared even more easily. C11-ether-bridged pentacyclics with comparable substitution patterns. These are now synthetically accessible thanks to our recent discovery of a facile isomerization of C13-to-C11-bridged intermediates. C13-bridged pyrrolidine analogues of pentacyclic quassinoids. Also routes to the corresponding C11-bridged analogs. These structures have NH in place of the tetrahydrofuran oxygen. We expect that new types of active structures emerging from our investigation will open up promising avenues for new drug research.
