A small, but structurally diverse collection of naturally occurring non-taxane microtubule stabilizing agents (MTS) has been discovered over the last decade. These include the epothilones (EPO), eleutherobin, laulimalide, and discodermolide. (+)-Discodermolide (1) is a novel polyketide natural product first isolated from extracts of the marine sponge Discodermia dissoluta by researchers at Harbor Branch Oceanographic Institution (HBOI). Discodermolide stabilizes microtubules faster and more potently than any of the other known MTS agents, is a potent inhibitor of tumor cell growth in vitro including paclitaxel- (PTX) and EPO-resistant cells. Discodermolide also demonstrates significant human tumor growth inhibition in hollow fiber and xenograft mouse models (including paclitaxel-resistant tumors). Discodermolide is currently undergoing Phase 1 clinical trials.

This presentation will discuss in some detail the strategy and tactics that lead to the production of 60 g of (+)-discodermolide for phase 1 clinical trials. Several of the key steps in the synthesis will also be presented with respect to scalability and problems encountered. Some workable solutions to the difficulties will be presented.