Synthesis of the C6–C21 fragment of epothilone analogues

Valeev, R. F.; Bikzhanov, R. F.; Мифтахов, М. С.

doi:10.1016/j.mencom.2014.11.022

Cited by 7 publications

(2 citation statements)

References 15 publications

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“…There are some reported examples of aldehydes containing 2,4-disubstituted thiazole moieties that were efficiently reacted with sulfone partners under Julia-Kocienski's optimised conditions, for example, the coupling of aldehyde 303 with sulfone 304 to provide diene 305 in the synthesis of epothilone (Scheme 2.29). 229 Therefore, the interference of thiazole with the reaction between enal 297 and the sulfone anion derived from 277 was presumed not to be the major cause of the failure.…”

Section: Model Julia-kocienski Olefinationmentioning

confidence: 99%

“…Scheme 2.29 Julia-Kocienski reaction of thiazole-containing aldehyde 303 in the synthesis of epothilone. 229 It was of note that sulfone starting material 277 could be partially recovered and the Julia-Kocienski reaction of TBS-protected sulfone 299 had provided the olefination product 301 with enal 297 in moderate yield (Scheme 2.27). It was then proposed that the steric effect of the protecting group in sulfone 277 could be enhanced dramatically by the presence of a relatively rigidified thiazole ring, which would make access of the bulky base KHMDS to the proton at the α-position of the sulfone slow.…”

Section: Model Julia-kocienski Olefinationmentioning

confidence: 99%

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Towards Synthesis of Simplified Analogues of Pateamine A

Xu¹

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<p>Pateamine A (22) is a natural product that was isolated from a marine sponge inhabiting the coast of New Zealand. It exhibits potent inhibition of protein synthesis and nonsense-mediated mRNA decay through binding with eIF4A isoforms. Due to the scarcity of pateamine A (22) in the natural source and the low yield of total synthesis of pateamine A, it is necessary to prepare structurally simplified analogues which would allow further research on structure-activity relationships (SAR) of pateamine A (22). Based on the structure-activity relationship studies reported by Romo and co-workers, a simplified triazole analogue 182 lacking methyl groups was synthesized by Hemi Cumming, a previous Ph.D. student who studied at Victoria University of Wellington. The antiproliferative activity of this analogue was found to be significantly lower than that of pateamine A, suggesting that the thiazole embedded within the molecule or the excised methyl groups are crucial for its potency. Therefore, to further explore the necessary features for its selective activity for eIF4A isoforms, new thiazole analogues 183 – 186 and triazole analogues (10S)-and (10R)-analogue 187 were targeted in this project. The preparation of the thiazole-containing macrocyclic core of analogues 183 and 184 was achieved. It features: (1) gold-catalysed thiazole formation through coupling between an alkyne fragment and a thioamide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of a δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. The synthesis of the triazole-containing macrocyclic core of (10S)-analogue 187 was completed. It features: (1) a copper-catalysed triazole formation through 1,3-dipolar cycloaddition between an alkyne fragment and an azide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. Studies on the preparation of a side-chain fragment with suitable functionalities to allow coupling with the various macrocycles through olefination reactions were also conducted. The attachment of the side-chain fragment onto the macrocyclic cores for the synthesis of the targeted analogues 183 and 184 and (10S)-analogue 187 will be investigated in future work. These experimental results will inform the synthesis of new generation analogues to further study the key structures required for effective binding to the protein target eIF4A and selectivity between isoforms.</p>

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Section: Model Julia-kocienski Olefinationmentioning

confidence: 99%

Section: Model Julia-kocienski Olefinationmentioning

confidence: 99%

Towards Synthesis of Simplified Analogues of Pateamine A

Xu¹

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The J ulia– K ocienski Olefination

Blakemore¹,

Sephton

Ciganek

2018

Organic Reactions

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The Julia–Kocienski olefination is a direct connective synthesis of alkenes via the addition of metalated aryl alkyl sulfones to carbonyl compounds. The activating aromatic group associated with the sulfone must possess electrophilic character, and alkene formation occurs via β‐alkoxy sulfone formation, transfer of the aryl group from sulfur to oxygen via a Smiles rearrangement, and then elimination of sulfur dioxide and an aryloxide anion from the resulting β‐aryloxy sulfinate anion. The olefination process itself and the methods used to prepare the requisite sulfone substrates are tolerant of a wide variety of functional groups, and a variety of alkene targets can be prepared. Stereoselectivity is dependent on the nature of the sulfone, the carbonyl compound, the activating aryl moiety, and the reaction conditions. This chapter describes theoretical and operational aspects of the Julia–Kocienski olefination such that the reader will be able to obtain optimal results in his/her own research. A detailed mechanistic overview is included to account for the factors that influence stereoselectivity and yield. Methods for introducing sulfone activators into fragments of interest, best practices for generating sulfone anions, and optimal strategies for targeting different classes of alkene targets are discussed. Functional group compatibilities, reaction variants, and a comparison to other methods of alkene synthesis are also presented. Tabular surveys are organized according to type of alkene synthesized, with an emphasis on the degree of substitution and the level of conjugation about the newly formed double bond. The literature is covered from the initial disclosure of the Julia–Kocienski olefination in 1991 to the first quarter of 2016.

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