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

Abstract

The epothilones are naturally occurring cytotoxic molecules that possess the remarkable ability to arrest cell division through the stabilization of microtubule assemblies. Our in vivo studies with 12,13-desoxyepothilone B (dEpoB), have established that the desoxy compound is well tolerated and virtually curative against a variety of sensitive and resistant xenograft tumors in animal models. In light of these discoveries, we sought a chemical synthesis of dEpoB that would be able to support a serious and substantial discovery research program directed toward the clinical development of this molecule. The overall strategy for this endeavor assumed the ability to synthesize dEpoB from three constructs which include an achiral β,δ-diketo ester construct A, an (S)-2-methylpentenal moiety B, and the thiazoyl-containing vinyl iodide moiety C. We envisioned that a diastereoselective aldol condensation between an achiral C5−C6 (Z)-metalloenolate derived from construct 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 construct C and an alkyl borane would form the C11−C12 bond. Finally, a late-stage reduction of the C3 ketone to the requisite C3 alcohol with high asymmetric induction would permit us to introduce the β,δ-diketo ester fragment A, into the synthesis as a readily accessible achiral building block. The governing concepts for our new synthesis are described herein.

Optimizing the heterologous production of epothilone D in Myxococcus xanthus

“…Although the chemical synthesis of epothilone D has recently been achieved (Harris et al, 1999;2 Meng et al, 1997;Sinha et al, 1998), the complex 20-step process is not an economically viable method for the large-scale production of the compound. To exploit the potential of using fermentation as a means of production, the epothilone biosynthetic genes were cloned from the natural microbial producer, genetically modi®ed, and integrated to the chromosome of a surrogate host that is more amenable to industrial fermentation.…”

Der Weg zu Fludelon: ein Tumortherapeutikum mit außergewöhnlichen Eigenschaften

“…[27] [28] mithilfe der Oxazolidinon-Methode von Evans [29] hergestellt, bei der ein geeignetes Auxiliar den diastereofacialen Sinn der C2-C3-Verknüpfung steuert. Die Suzuki-Kupplung von 26 und 27 lieferte 28.…”

The B-Alkyl Suzuki-Miyaura Cross-Coupling Reaction: Development, Mechanistic Study, and Applications in Natural Product Synthesis

“…Compound 121 was converted into epothilone derivative 122 by using the same overall strategy (Scheme 23). [84] Unfortunately, several attempts to effect Suzuki-macrocyclizations in this context (e.g. 123 3124) have thus far been unsuccessful (Scheme 24).…”