Total Synthesis and Biological Activity of (±)‐Rocaglamide and Its 2,3‐Di‐<i>epi</i> Analogue

“…Oxidative aglafolin (3a) and its isomers were synthesized according to our previously reported method (Scheme 1) [5]. Two diastereoisomers of 2a (cis) and 2b (trans) (the ratio of 2.24 to 1) were afforded via Michael addition of benzylidene malonate to 1 in the presence of Bu 4 N + OH À .The structure of 2a had been confirmed by X-ray diffraction analysis [6].…”

Section: Resultsmentioning

confidence: 99%

“…Solvents used were purified and dried by standard procedures. Compound 1 was synthesized according to literature procedure [5].…”

Section: Chemistrymentioning

confidence: 99%

Studies on Synthesis and Biological Activity of Oxidative Aglafolin Derivatives

Wang

Xie

et al. 2014

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).The synthesis of the key intermediate of rocaglamide, oxidative aglafolin, was studied, and its diastereoisomers were obtained. The amination of oxidative aglafolin was also investigated, affording amino derivatives. The preliminary bioassay results indicate that these new aglafolin derivatives showed certain degree of insecticidal and repellent activity against Plutella xylostella and Laphygma exigua.

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“…For the cleavage of the methyl ether at the C1 position in 22 , MgI 2 was freshly prepared in ether, the solution was diluted with toluene, 22 was added, and the solution heated to 90 °C for 15 min leading to 23 in 92 % yield 26. Reduction of the keto group in the last step was accomplished according to a published procedure,10n furnishing (−)‐rocaglamide in 73 % yield (99:1 e.r.). (+)‐Rocaglamide was prepared in the same way, except using ent ‐ 7 as the ligand for the catalytic asymmetric cyclization.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Each Enantiomer of Rocaglamide by Means of a Palladium(0)‐Catalyzed Nazarov‐Type Cyclization

Zhou

Tius

2015

Angewandte Chemie

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A recently reported Pd 0 -catalyzed asymmetric Nazarov-type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (À)-rocaglamide (natural) and (+)-rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents.Rocaglamide was isolated in 1982 by King and co-workers from Aglaia elliptifolia, a tree native to south-east Asia, the extracts from which are used in traditional medicine.[1] More than 100 related compounds have been isolated from related Aglaia species.[2] Pharmacological interest in this class of compounds derives from their potent cytostatic and antiinflammatory activities, [3][4][5] which are the result of rocaglamide impairing multiple targets. Rocaglamide targets protein translation initiation by targeting the eukaryotic initiation factor eIF4A and thereby inactivates heat shock factor 1 (HSF1), which is a transcriptional regulator that controls the heat shock response and processes essential for anabolic metabolism. As such these compounds can deprive cancer cells of energy and impair the proliferation of malignant and premalignant cells.[6] Rocaglamide has also been reported to impair transcription factor NFkB signaling (which contributes to its anti-inflammatory activity) and the kinase pathway cRAF-MEK-ERK. [7,8] Significant progress toward clinical development has only taken place during approximately the last three years, in large part because of problems with supply of materials. There are barriers in scaling up the isolation of rocaglamide from the natural source because it occurs as a mixture with structurally related compounds which are difficult to separate. Trost et al. published the first chiral-pool total synthesis of rocaglamide in 1990.[9] Since then several syntheses of racemic rocaglamide have been described.[10] The biogenetically inspired enantioselective synthesis by Porco and co-workers provides the ponapensin-thapsakon family of compounds as well as rocaglamide and is the current state-ofthe-art procedure.[10a] We describe an efficient and scalable synthesis [11] of both enantiomeric forms of rocaglamide that makes use of a Nazarov-type cyclization that we have recently described in the key step. [12] The core of rocaglamide is a fully substituted cyclopentane ring containing adjacent quaternary centers at the C3a and C8b positions. Stereochemical control, especially at the C3 position, has been a challenge for many of the previously published syntheses. Embedded within the rocaglamide we perceived a structure that we could access enantioselectively through a Pd 0 -catalyzed Nazarov-type cyclization that we have recently developed.[12] Although Frontier and co-workers [10o] and Magnus et al. [10p] have prepared racemic rocaglamide by means of Nazarov cyclizations, our strategy disconnects the molecule differently. The first steps of our synthesis are summ...

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Total Synthesis and Biological Activity of (±)‐Rocaglamide and Its 2,3‐Di‐epi Analogue

Cited by 29 publications

References 32 publications

Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae)

Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae)

Studies on Synthesis and Biological Activity of Oxidative Aglafolin Derivatives

Synthesis of Each Enantiomer of Rocaglamide by Means of a Palladium(0)‐Catalyzed Nazarov‐Type Cyclization

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