Substitutions at the Thiazole Moiety of Epothilone

Epothilone A is metalated at low temperature with an excess of butyllithium preferentially at C19 of the thiazole moiety.After addition of various carbon and heteroatom electrophiles the correspondmg substitution products were obtained.Some of them have similar cytotoxic activity than the starting material.Epothilones are currently of great interest due to their potential as anticancer agents.'.2In previous papers we reported various derivatizations of the macrocycle and of the adjacent double bond of epothilones?Modification of the thiazole moiety of epothilone A (1) via a selective deprotonation-electrophile addition sequence should easily access a variety of analogs to study structure activity relationships, although it was difficult to predict whether strong nucleophilic bases like BuLi deprotonate the thiazole group regioselectively (Scheme 1). Scheme 1 Possible reaction sites of epothilone A (I) with nucleophilic bases. deprotonation deprotonation addition dThus in a first experiment, epothilone A (1) was treated with 5 equivalents of B S i in THF at -90 OC.The solution soon turned orange and after 15 minutes acetic acid-& was added.TLC of the pale yellow reaction mixture showed just starting material and two minor spots.After usual workup and chromatographic separation three fractions were obtained in 70, 10 and 5% yields.