Synthesis, Profiling and Bioactive Conformation of trans‐Cyclopropyl Epothilones

A series of new 3-deoxy-C(12),C(13)-trans-cyclopropyl-epothilones have been prepared, bearing benzothiazole, quinoline, thiazol-5-ylvinyl, or isoxazol-3-ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring-closure was based on ring-closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole-containing 16-desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring-closure either by RCM or by macrolactonization. Benzothiazole- and quinoline-based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol-5-ylvinyl or an isoxazol-3-ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)-C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 degrees C(10)-C(11) torsion angle in the tubulin-bound conformation of 12,13-trans-epothilones.