Enantioselective Synthesis of Spliceostatin G and Evaluation of Bioactivity of Spliceostatin G and Its Methyl Ester

Ghosh, Arun K.; Reddy, Guddeti Chandrashekar; MacRae, Andrew J.; Jurica, Melissa S.

doi:10.1021/acs.orglett.7b03456

Cited by 17 publications

(24 citation statements)

References 34 publications

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“…Reaction of this diol with 2,4,6-triisopropylbenzenesulfonyl chloride (TPSCl) in pyridine at 0 °C to 23 °C for 24 h furnished sulfonate derivative 17 in 88% yield over 2-steps. 39 Sulfonate 17 was reduced with LAH in THF at 0 °C to 65 °C for 1.5 h to furnish the reduced product 18 in 95% yield.…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition

et al. 2018

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Thailanstatin A has been isolated recently from the fermentation broth of B. thailandensis MSMB43. We describe here an enantioselective convergent synthesis of thailanstatin A methyl ester and evaluation of its splicing activity. Synthesis of both highly functionalized tetrahydropyran rings were carried out from commercially available tri- O-acetyl-d-glucal as the key starting material. Our convergent synthesis involved the synthesis of both tetrahydropyran fragments in a highly stereoselective manner. The fragments were then coupled using cross-metathesis as the key step. The synthesis of the diene subunit included a highly stereoselective Claisen rearrangement, a Cu(I)-mediated conjugate addition of MeLi to set the C-14 methyl stereochemistry, a reductive amination reaction to install the C16-amine functionality, and a Wittig olefination reaction to incorporate the diene unit. The epoxy alcohol subunit was synthesized by a highly selective anomeric allylation, a Peterson olefination, and a vanadium catalyzed epoxidation that installed the epoxide stereoselectively. Cross-metathesis of the olefins provided the methyl ester derivative of thailanstatin A. We have carried out in vitro splicing studies of the methyl ester derivative, which proved to be a potent inhibitor of the spliceosome.

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Section: Resultsmentioning

confidence: 99%

Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition

et al. 2018

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“…Ghosh used a similar cross-metathesis/Suzuki-Miyaura coupling sequence for the preparation of spliceostatin G (11, Scheme 25) [43]. The catalyst loading for the coupling of 130 with methyl (E)-3-iodoacrylate (20 mol %) was twice the amount used by Nicolaou (10 mol %).…”

Section: Fragment Union Via Pd-catalyzed Sp 2 -Sp 2 Couplingmentioning

confidence: 99%

Syntheses of spliceostatins and thailanstatins: a review

Donaldson¹

2020

Beilstein J. Org. Chem.

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The spliceostatins/thailanstatins are a family of linear peptides/polyketides that inhibit pre-mRNA splicing, and as such act as potent cytotoxic compounds. These compounds generally contain 9 stereocenters spread over a common (2Z,4S)-4-acetoxy-2-butenamide fragment, an (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran fragment and a terminal oxane ring joined by a dienyl chain. Due to the impressive antitumor properties of these compounds, along with their complex structure, a number of total syntheses have been reported. This review will compare the synthetic strategies reported through the end of 2019.

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“…Ghosh et al. reduced the tosylate intermediate 92 using LAH in THF at 0 °C to 65 °C for 1 h to afford the reduction product, the methyl derivative 93 (Scheme ) …”

Section: C‐methylationmentioning

confidence: 99%

Advances in the Synthesis of Methylated Products through Indirect Approaches

Chen

2019

Adv Synth Catal

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Methylation is a well‐known structural modification in organic and medicinal chemistry. In addition to using conventional methylation reagents for direct methylation, indirect methylation approaches have been also successfully applied, particularly to tackle the isolation difficulty among the methylated product, the unreacted starting material, and the dimethylated by‐product due to the structural similarities between them. This review summarizes recent advances in the synthesis of methylated products through indirect approaches – transforming functionalized intermediates into the methylated products. The indirect methodologies surveyed in this review are useful for chemists to select appropriate methylation strategies, particularly for the challenging synthesis of methylated products at a large scale in drug discovery. Abbreviations: AIBN: azobisisobutyronitrile; Cbz: carbobenzyloxy; DBU: 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; DIBAL: diisobutylaluminium hydride; FA: formic acid; Fmoc: fluorenylmethyloxycarbonyl; KOTMS: potassium trimethylsilanolate; LAH: lithium aluminium hydride; LiHBEt3: lithium triethylborohydride; PC: photocatalyst; PMHS: polymethylhydrosiloxane; PSMS: zinc bis(phenylsulfonylmethanesulfinate); SAM: S‐adenosylmethionine; SET: single electron transfer; TBAF: tetra‐n‐butylammonium fluoride; TBS: tert‐butyldimethylsilyl; TEA: trimethylamine; TFA: trifluoroacetic acid; TMS: trimethylsilyl; Ts: 4‐toluenesulfonyl.

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Enantioselective Synthesis of Spliceostatin G and Evaluation of Bioactivity of Spliceostatin G and Its Methyl Ester

Cited by 17 publications

References 34 publications

Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition

Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition

Syntheses of spliceostatins and thailanstatins: a review

Advances in the Synthesis of Methylated Products through Indirect Approaches

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