A stereoselective approach to the chemical synthesis of fused pyran ring systems corresponding to subunits of the cytotoxic marine natural products okadaic acid (1) and halichondrin B (2) isolated from the sea sponge Halichondria okadia Kadora is described. An enantioselective approach to the chemical synthesis of (+)- sesbanimide A (3), a potent cytotoxic agent isolated from plant extracts of Sesbania drummundii seed, and six structurally related analogues is proposed. Analogues of 3, that correspond to structural modifications of the B- and C-rings will be prepared and evaluated as potential cytotoxic agents. A profile of antitumor activity versus changes in structure will be developed in an effort to correlate cytotoxicity with differences in structural features. The B-ring analogues were designed on the basis that the approach to 3 is enantiodivergent and allows for the preparation of both antipodes. The C-ring analogues are designed in an attempt to increase the chemical stability of the tetrahydrofuran ring which contains a labile hemiacetal. The approach is based on the potential for C1-oxygenated allylsilanes to behave as bifunctional carbon nucleophiles. The chemical synthesis of the sesbanimide structures is designed on the expectation that homochiral C1- oxygenated allylsilanes will participate in addition reactions with chiral aldehydes as configurationally stable, sp3 hybridized, alpha- alkoxy allyl anion equivalents for the construction of optically active 1,2-diol units. The synthetic approach to the fused pyran subunits of okadaic acid and halichondrin B is based on the ability of C1-oxygenated allylsilanes and E-crotylsilanes to function as homoenolate equivalents for the stereoselective introduction of a propionaldehyde equivalent by traping an oxonium ion generated on a pyran or furan ring.
