The purpose of this proposed research program is to develop new general methods for the construction of 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 an 2-methyl-3-trialkylsilyloxy-alkanals, 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 synthesize the two extremely strongly cytotoxic agents, 13-deoxytedanolide 1 and tedanolide 2, and their close structural analogues and diastereomers, 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% (P388) at 125 mug/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 intend to make several analogues (e.g., the 13-epimer of 2, analogues with shorter side chain and ones with different groups and/or stereochemistries). All of the advanced synthetic materials will be tested for antitumor activity. In this way, we hope to figure out just what parts of this complex molecule are required for the potent antitumor activity and hopefully to prepare some simpler structures which still show reasonable 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 potent cytotoxic agents 13-deoxytedanolide 1 and tedanolide 2 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.