The purpose of this proposed research program is to develop new general methods for the construction of several biologically active polypropionate natural products. The key step in the syntheses of these compounds involves a concerted Lewis acid-promoted rearrangement of an optically active epoxy alcohol to generate a 2-methyl-3-trialkylsilyloxyalkanal, namely an aldol product by a non-aldol route. We have shown that all four possible enantiomers can be easily prepared in high optical purity and good yields by this approach. We plan to extend this research to prepare polypropionate chains with various absolute stereochemistries. In particular, in order to illustrate the efficiency of this process, we will finish the synthesis of two extremely strongly cytotoxic agents, 13-deoxytedanolide 1 and tedanolide 2, and their close structural analogues, by an application of this new approach to polypropionates. 13-Deoxytedanolide is extremely cytotoxic (IC50 94 pg/ml (P388)) and has high antitumor activity (T/C 189 percent (P388) at 125 microg/kg) while tedanolide is also extremely tumor inhibitory (ED50's 250 pg/ml (KB) and 16 pg/ml (PS)) and causes accumulation of cells in the S phase at very low concentrations (10 ng/ml). Thus they are very promising leads as new agents for cancer treatment. The development of good general routes for their synthesis would not only provide a potentially useful preparation of them (both were isolated from marine sponges and are present in very small quantities) but also would allow one to prepare several structural analogues unavailable from natural sources which may show enhanced chemotherapeutic properties. We will also carry out total syntheses of the important antibacterial agents, erythromycin A 3 and oleandomycin 4. All of the advanced synthetic materials in the tedanolide series will be tested for antitumor activity. In this way, we hope to figure out just what parts of these complex molecules are required for the potent activity and hopefully to prepare some simpler structures which still show reasonable activity. Likewise the synthetic analogues of erythromycin and oleandomycin will be tested for antibiotic activity. The successful accomplishment of the research described in this proposal-namely, the development of a really useful synthetic route to polypropionates and the synthesis of the tedanolides, erythromycin A and oleandomycin and their analogues-would be of great significance to medicinal chemistry. Because of the medicinal importance of the targets, the efficiency of bond construction in the syntheses, and the high intrinsic value of the new methods themselves, the likelihood of an important contribution to health-related science is quite high.
