Epothilones: Total syntheses, conformation, and biological activities

Epothilones have similar biological activity to taxol, but they are more active against multi-drug-resistant cells. The important biological activity of epothilone B combined with some interesting synthetic problems initiated a variety of different research projects of their total synthesis.; The synthesis of the natural products epothilone B and D described in this dissertation is highlighted by an intramolecular Reformatsky reaction, an aldol reaction using Kiyooka's promoter and an efficient generation of a C12–C13 trisubstituted olefin, which exploits a sequential Nozaki-Hiyama-Kishi coupling followed by a stereoselective thionyl chloride rearrangement.; Four C14-methyl analogues of epothilone B and D were prepared based on the same strategy used in the total synthesis of natural epothilones. Conformational analysis with computational modeling, X-ray crystallography, and NMR studies showed that the stereochemistry at C14 has an obvious effect on the conformation of the C11–C15 region. Biological assays indicated significant differences in their biological activity. Substitution that stabilized conformer I retained significant biological activity. In contrast, substitution that stabilized conformer II provided analogues with no measurable cytotoxicity. Since both types of conformers exist in the natural epothilones, the conformation-activity relationships revealed strongly support conformer I as the bioactive conformation at the C11–C15 region of epothilone. Additional C14 substituted analogues of epothilone will be prepared. Moreover, this conformationally directed strategy may be useful to the rational design of epothilone analogues with modification at other regions, and to the structure/conformation-activity studies of other biologically active polyketide macrolides.