Total Synthesis of Epothilone E and Analogues with Modified Side Chains through the Stille Coupling Reaction

Abstract

Ring‐closing metathesis (step a in the scheme below), deprotection (b), Stille coupling (c), and epoxidation (d) are the key steps in the first total synthesis of the naturally occurring epothilone E (1). An advanced intermediate, the product of the olefin metathesis, allows access to a range of epothilone E analogues having different aromatic moieties in the side chain. TBS = tBuMe2Si.

Discovery, Synthesis, and Biological Evaluation of Novel SMN Protein Modulators

“…Starting with 2,4-dibromothiazole, selective amination occurred at the 2-position of the thiazole ring to give the key building block 1-(4-bromothiazol-2-yl)piperidine-4-carboxamide. 42 Then, a mixture of an arylboronic acid or its corresponding pinacol ester and 1-(4-bromothiazol-2-yl)piperidine-4-carboxamide was irradiated under microwaves to induce a Suzuki type of cross-coupling reaction 43 using tetrakis(triphenylphosphine)palladium(0) as a catalyst to furnish the final 4-arylthiazolyl piperidine analogues. Alternatively, the route (b), a Suzuki coupling at the 4-position of the 2-methylthio-4-bromothiazole, followed by MCPBA oxidation of the methylthioyl group to the methylsulfonyl moiety provided another building block 4-aryl-2-(methylsulfonyl)thiazole.…”

Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity

“…In this work, all stereocenters were probed for their relevance for biological activity, the alkyl groups on C8 127 and C16 128,129 were removed, or new ones were added at C10 130 and C14. 113,119,129 Another obvious modification, the ring closure of C27 with the thiazole ring, was first realized by the Novartis group only in 2000 with the synthesis of benzthiazole, benzoxazole, and quinoline analogs. 49,115,119,128,[132][133][134][135][136] C17-C18 Stille coupling allowed the introduction of a great variety of five-and six-membered heterocyclic side-chains, optionally carrying additional substituents.…”

“…Shortly after, the Danishefsky and Nicolaou groups published biological data for a great variety of analogs, and industrial groups at Novartis and Schering followed. 113 However, good to moderate activity was observed with certain 17-and 18-membered epothilones. In vitro tubulin polymerization depends even more on the experimental conditions used.…”

“…Unfortunately, the data generated for cytotoxicity/growth inhibition by different groups are hardly comparable on a quantitative basis because of the broad range of sensitivity of the various cell lines used. 113,176 The substituents in the box may be modified to a certain extent. 138,175 In this review, we classify activity as high (>50% of the parent compound), moderate (5%-50%), low (1%-5%), and inactive.…”

“…Both 4desmethylepothilones A 1 and A 2 4 and 16-desmethylepothilone 129 are highly active, whereas replacement of 8-Me by hydrogen drastically reduces activity. 113 Integration of the C16, C17 spacer in a benzene ring to give benzothiazole, benzoxazole (28), and quinoline (27) analogs confers high biological activity. 64 An extra methyl in the 14α position reduces activity Likewise, thiazoles linked by their C2 or C5 position are inactive.…”