New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation

The epothilones are naturally occurring cytotoxic molecules that possess th e remarkable ability to arrest cell division through the stabilization of m icrotubule assemblies. Our in vivo studies with 12,13-desoxyepothilone B (d EpoB), have established that the desoxy compound is well tolerated and virt ually curative against a variety of sensitive and resistant xenograft tumor s in animal models. In light of these discoveries, we sought a chemical syn thesis of dEpoB that would be able to support a serious and substantial dis covery research program directed toward the clinical development of this mo lecule. The overall strategy for this endeavor assumed the ability to synth esize dEpoB from three constructs which include an achiral beta,delta-diket o ester construct A, an (S)-2-methylpentenal moiety B, and the thiazoyl-con taining vinyl iodide moiety C. We envisioned that a diastereoselective aldo l condensation between an achiral C5-C6 (Z)-metalloenolate derived from con struct A and an (S)-2-methylalkanal fragment, B, would generate the desired C6-C7 bond. Second, a B-alkyl Suzuki coupling between the vinyl iodide con struct C and an alkyl borane would form the C11-C12 bond. Finally, a late-s tage reduction of the C3 ketone to the requisite C3 alcohol with high asymm etric induction would permit us to introduce the beta,delta-diketo ester fr agment A, into the synthesis as a readily accessible achiral building block . The governing concepts for our new synthesis are described herein.