SYNTHESIS OF SPONGISTATIN ANTITUMOR AGENTS

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The principal goal of this research program is to develop a practical synthetic approach to spongipyran 1 (1), the most potent member of a new family of architecturally unique bisspiroketal macrolides which possess extraordinary antitumor activities. Three research groups have isolated members of the spongipyran family which they designated the spongistatins 1-9, cinachyrolide A, and the altohyrtins A, B and C, respectively. The spongistatins appear to be the most potent inhibitors of cancer cell growth discovered to date. The specific aims for the next four year period are: (A) to compete our first-generation synthesis of spongistatin 2 (2); (B) to devise a highly efficient second-generation synthetic strategy capable of delivering a minimum of one gram of spongistatin 1(1), exploiting where appropriate new methodology developed in our laboratory; and (C) to prepare a carefully designed library of spongistatin analogs to elucidate the pharmacophore of this important class of antitumor agents. Towards the latter end, we have a long standing collaboration with Professor Pettit, Director of the Cancer Research Institute, Arizona State University, who has agreed not only to assay our designed analogs and advanced synthetic intermediates, but also to explore the mode of action of the most promising antitumor candidates, for possible further development. Apart from the anticipated pharmaceutical impact, success in this venture would constitute a major achievement for complex molecule synthesis in general. In addition, this program will serve as excellent training for graduate and postdoctoral students for careers in both academia and the pharmaceutical industry. In conjunction with the proposed synthesis of spongistatin 1 (1), we will (D) investigate our multicomponent linchpin coupling of silyl dithianes with aziridines and other potential electrophiles. This builds upon our extensive experience with dithiane coupling in the assembly of complex structures. Finally, we will (E) develop a new bifunctional reagent for accessing a variety of homoallylic building blocks taking advantage of the Brown asymmetric allylboration. This method holds promise as a valuable protocol for efficient assembly of complex polyol fragments, as well as substituted pyran rings, both of which play an important role in natural product synthesis. A central theme of this and related programs in our laboratory is (and will continue to be) the development of effective synthetic strategies that are not single-target oriented, but instead will permit construction of entire classes of natural products. We believe that this philosophy of "unified" synthetic strategies" will be amply demonstrated in this proposal.