Lithiation and electrophilic substitution of dimethyl triazones

Han, Sunkyu; Siegel, Dustin S.; Movassaghi, Mohammad

doi:10.1016/j.tetlet.2012.04.121

Cited by 5 publications

(9 citation statements)

References 24 publications

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“…While we successfully validated a range of conditions for activation of ketone 18 as a C4-nucleophile, 26 the oxidation of C8 to generate the necessary electrophile 19 (Scheme 3) proved difficult. 27,28 In contrast to significant literature precedent for the oxidation of amines, the oxidation of amides is rare.…”

Section: Resultsmentioning

confidence: 99%

“…The addition of a lithiated 34 triazone intermediate, 26 prepared by treatment of triazone 27 with s- butyllithium, to methyl ester (±)- 26a gave ketone (±)- 28 in 70% yield. 26 Exposure of triazone (±)- 28 to methanolic hydrogen chloride solution led to spontaneous condensative cyclization 35 to form the imidazolone D-ring in 66% yield (Scheme 5). 26 …”

Section: Resultsmentioning

confidence: 99%

“…26 Exposure of triazone (±)- 28 to methanolic hydrogen chloride solution led to spontaneous condensative cyclization 35 to form the imidazolone D-ring in 66% yield (Scheme 5). 26 …”

Section: Resultsmentioning

confidence: 99%

“…26 The keto-triazone (±)- 34 was treated with samarium iodide (73% yield) followed by solvolysis in aqueous hydrochloric acid and methanol mixture to afford imidazolone (±)- 35 (67% yield, Scheme 7). Unfortunately, when imidazolone (±)- 35 was treated with TFA–water mixture in acetonitrile, the elimination of methanol occurred to give pyrrolopyrazinone 36 in 95% yield (Scheme 7).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids

et al. 2013

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The full details for our enantioselective total syntheses of (−)-agelastatins A–F (1–6), the evolution of a new methodology for synthesis of substituted azaheterocycles, and the first side-by-side evaluation of all known (−)-agelastatin alkaloids against nine human cancer cell lines are described. Our concise synthesis of these alkaloids exploits the intrinsic chemistry of plausible biosynthetic precursors and capitalizes on a late-stage synthesis of the C-ring. The critical copper-mediated cross-coupling reaction was expanded to include guanidine-based systems, offering a versatile preparation of substituted imidazoles. The direct comparison of the anticancer activity of all naturally occurring (−)-agelastatins in addition to eight advanced synthetic intermediates enabled a systematic analysis of the structure activity relationship within the natural series. Significantly, (−)-agelastatin A (1) is highly potent against six blood cancer cell lines (20–190 nM) without affecting normal red blood cells (>333 μM). (−)-Agelastatin A (1) and (−)-agelastatin D (4), the two most potent members of this family, induce dose dependent apoptosis and arrest cells in the G2/M-phase of the cell cycle; however, using confocal microscopy we have determined that neither alkaloid affects tubulin dynamics within cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…26 Exposure of triazone (±)- 28 to methanolic hydrogen chloride solution led to spontaneous condensative cyclization 35 to form the imidazolone D-ring in 66% yield (Scheme 5). 26 …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids

et al. 2013

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“…In addition to streamlining our synthesis of all known agelastatin alkaloids, this strategy provides the foundation for access to various derivatives. 3,7 Our synthesis enables late-stage diversification to two series of agelastatin derivatives with variations at the N1- and C5-positions of the agelastatin core, respectively. Herein we discuss the synthesis of these agelastatin derivatives and their evaluation along with natural agelastatins in a three-dimensional (3D) co-culture assay to determine their impact on fibroblasts in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Agelastatin Derivatives as Potent Modulators for Cancer Invasion and Metastasis

Antropow

Xu²,

Buchsbaum³

et al. 2017

J. Org. Chem.

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The synthesis of new agelastatin alkaloid derivatives and their anticancer evaluation in the context of the breast cancer microenvironment is described. A variety of N1-alkyl and C5-ether agelastatin derivatives were accessed via application of our strategy for convergent imidazolone synthesis from a common thioester along with appropriately substituted urea and alcohol components. These agelastatin derivatives were evaluated in our three-dimensional co-culture assay for the effects of mammary fibroblasts on associated breast cancer cells. We have discovered that agelastatin alkaloids are potent modulators for cancer invasion and metastasis at non-cytotoxic doses. Herein we discuss the increased potency of (−)-agelastatin E as compared to (−)-agelastatin A in this capacity, in addition to identification of new agelastatin derivatives with activity that is statistically equivalent to (−)-agelastatin E. The chemistry described in this report provides a platform for the rapid synthesis of agelastatin derivatives with excellent potency (50–100 nM) as modulators for cancer invasion and metastasis.

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ChemInform Abstract: Lithiation and Electrophilic Substitution of Dimethyl Triazones.

2012

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Lithiation and Electrophilic Substitution of Dimethyl Triazones. -Lithiation of dimethyl triazones and subsequent reaction with electrophiles provides various derivatives. The stannylated triazinone (VIa) is shown be an efficient source of lithiated triazone, which can be converted to product (IIIc). Keto-triazinones such as (IX) and (XIII) are suitable precursors for the formation of imidazolones. -(HAN, S.; SIEGEL, D. S.; MOVASSAGHI*, M.; Tetrahedron Lett. 53 (2012) 29, 3722-3726, http://dx.

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Lithiation and electrophilic substitution of dimethyl triazones

Cited by 5 publications

References 24 publications

Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids

Synthesis and Anticancer Activity of All Known (−)-Agelastatin Alkaloids

Synthesis and Evaluation of Agelastatin Derivatives as Potent Modulators for Cancer Invasion and Metastasis

ChemInform Abstract: Lithiation and Electrophilic Substitution of Dimethyl Triazones.

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