| Progress toward a total synthesis of the cell-specific apoptosis inducer, (-)-apoptolidin, is described. A first-generation synthesis of the lactol moiety from C20 to C28 using two sequential syn-aldol condensations is described. These titanium (IV) mediated condensation are very diastereoselective when aided by the presence of the diamine base (-)-sparteine and NMP as an additive. Extensive work toward developing a second-generation approach to the same lactol piece using an asymmetric hetero Diels-Alder reaction commenced as well. Progress in the development of an optimal chiral boron or aluminum cycloaddition catalyst is also described.; The northern hemisphere, which had been previously synthesized in our labs, was closely analyzed and synthesized again, with an improvement in the final three steps so that a more isomerically pure product resulted (15:1 now vs. 3:1 before). Finally, a crucial Suzuki coupling reaction of the northern and southern hemispheres was performed, which allowed the diol moiety at C19 and C20 to remain unprotected. This was followed by a saponification reaction to bring us to a very advanced carboxylic acid intermediate, one step from the closed 20-membered macrocycle. |
