THE SYNTHESIS OF SOME COMPLEX CYTOTOXIC COMPOUNDS

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It is our intention to accomplish the following synthetic goals within the time frame requested for this grant application. Firstly, we intend to complete, as proposed, the total synthesis of vertisporin, a potent cytotoxic drug which belongs to the roridin family of antibiotics. Vertisporin is probably the most complex member of this class of compounds, and contains, among other functionality, a 16-membered bislactone ring which is itself unusual. Vertisporin in available is submilligram amounts, and as a result, we have assembled intermediates in sufficient quantity to allow us to prepre up to 2.0 grams of the natural product. Secondly, we are intending to embark on the total synthesis of a very new natural product, sesbanimide. Apparently, only a very few milligrams of this substance are available, since the isolation method required to obtain this substance is arduous in the extreme. Because sesbanimide is described as an extremely potent cytotoxic material, clearly in short supply, and most interestingly possessed of a novel and unusual structure, we have designed a 10-step synthetic construction of the molecule. The projected synthesis has, in part, been quided by a series of computer calculations which represents a new departure for this group. The synthesis of sesbanimide starts from a readily available sugar, and on the assumption that a viable synthesis scheme is developed, it should be possible to prepare large quantities of this most interesting natural product. Both vertisporin and sesbanimide will be submitted to the CCNS for testing.