TOTAL SYNTHESIS OF THE LATRUNCULINS: MACROLIDE MARINE TOXINS (LATRUNCULIA MAGNIFICA)

Latrunculins A and B were isolated, in 1980 by Kashman and co-workers, from colonies of the sponge Latrunculia magnifica (Keller). This soft sponge is brightly colored and grows exposed on rocks at depths of up to 30 m in the Red Sea. Part of the defense mechanism of the sponge is to expel a reddish fluid which causes fish to flee the vicinity. In fact, if this fluid is squeezed manually into an aquarium of fish, the fish suffer tremors, hemorrhage, loss of balance, and after 4-6 min, death. The chemical substance that defends Latrunculia magnifica against predation and biodegradation was shown to be latrunculin A and B (1 and 2), see p. 2 in dissertation . Studies by Spector and co-workers on the effect of the latrunculins employing cultured mouse neuroblastoma and fibroblast cells demonstrated that submicromolar amounts of the latrunculins induce changes in the cell morphology which proved reversible upon removal of the toxins. Specifically, the latrunculins were found to bind to the actin fibers (i.e., the cytoskeletal proteins) causing major reorganization of the microfilaments without effecting the structure of the microtubular system. Chapter I describes the details of the first total synthesis of latrunculin B. The goal of our design was to develop a similar advanced intermediate for both latrunculin A and B (see p. 9 in dissertation). Our synthesis served to confirm the structure and absolute configuration assignment of latrunculin B. Chapter II (p. 201 ff in dissertation) reports our progress toward the total synthesis of latrunculin A