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 finish the vertisporin problem, which should only take a year of one graduate student's time. We have invested a lot of time in this problem, but we now know how to do it properly. A major component of this problem, in terms of learning new chemistry, concerns the application of some organotin reagents to reaction with sugar-derived ketones. These reactions yield stereochemistry that is the reverse of the more usual stereochemistry observed with ketones of this type. Thus, along with finishing the synthesis of vertisporin, we intend to examine the stereochemistry of organostannane reagents in reaction with a number of sugar-derived ketones. Secondly, we intend to embark on a rather ambitious project, the total synthesis of okadaic acid. This molecule is a complex cytotoxic ionophore, the structure of which asks many interesting stereochemical questions. Over the past year, we have developed, via a consideration of ionophores in general, new methods, based on the chemistry of vinylogous urethanes, to deal with the intricate stereochemical problems presented by these natural products. Okadaic acid holds within its structural framework a majority of the stereochemical problems presented by ionophores. Since the molecule has the additional virtue of being a known anti-tumor substance, and further since the structure of okadaic acid presents stereochemical problems of current significance, we intend to use this natural product to demonstrate and further develop the efficacy of our new methods.