Towards Isocoumarin‐Fused Enediyne Systems through the Electrophilic Cyclization of Methyl <i>o</i>‐(Buta‐1,3‐diynyl)benzoates

Danilkina, Natalia A.; Gurskaya, Larisa Yu.; Vasilyev, Aleksander V.; Балова, Ирина А.

doi:10.1002/ejoc.201501262

Cited by 14 publications

(6 citation statements)

References 46 publications

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“…43 The synthesis of enediyne 1 is based on the synthetic route towards unsymmetrically substituted heterocyclefused acyclic enediynes developed earlier -a stepwise formation of o-functionalized (buta-1,3-diynyl)arenes, their iodocyclization with the formation of iodoethynylheterocycles and the second Sonogashira coupling of C-I atom with an appropriate alkyne. [49][50][51] Following this way and using starting materials with essential functional groups, i.e., oiodothioanisol (4), MeOCH 2 -substitited TMS-butadiyne 5, and N-tosylbut-3-yn-1-amine (8), acyclic enediyne 9 was obtained in good overall yield (Scheme 3).…”

Section: Letter Syn Lettmentioning

confidence: 99%

10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

Danilkina¹,

Rumyantsev²,

Lyapunova³

et al. 2018

Synlett

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The Nicholas-type macrocyclization through NH-tosyl functional group has been found to be an efficient technique for the synthesis of a 10-membered azaenediyne system annulated with a benzothiophene. To compare the activity of azaenediyne synthesized with similar oxa- and carbocyclic enediynes the Bergman cyclization activation energies and the ability of enediynes to cleave DNA (pBR322 plasmid) were investigated. The order of reactivity predicted by DFT calculations (N-enediyne < C-enediyne < O-enediyne) was confirmed by DSC analysis data. Surprisingly azaenediyne was found to be more active in the DNA cleavage assay than the C-analogue.

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Section: Letter Syn Lettmentioning

confidence: 99%

10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

Danilkina¹,

Rumyantsev²,

Lyapunova³

et al. 2018

Synlett

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“…Recently we have reported the synthetic approach to acyclic enediynes fused to heterocycles based on iodocyclization of o -functionalized (buta-1,3-diynyl)arenes and the Sonogashira coupling as key steps (Scheme ). − Depending on functional groups in starting acetylenes, acyclic enediynes can contain a required functional group at a precise triple bond. This regioselectivity came from the synthetic route and is of crucial importance for the macrocyclization stage. ,, …”

Section: Introductionmentioning

confidence: 99%

Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization

et al. 2018

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To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothiophene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas-type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

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“…The choice of structures was based on preliminary calculations of the Bergman cyclization’s free activation energies and the synthetic accessibility of acyclic enediyne precursors. − According to the calculated free activation energy values, these heterocycles help to attenuate activation barriers in an ∼3 kcal/mol interval, providing target 10-membered structures with a different balance of stability/reactivity . Moreover, indole and isocoumarine scaffolds can be found in numerous natural products, biologically active compounds, and drugs.…”

Section: Resultsmentioning

confidence: 99%

“…A remarkable feature of the whole synthetic sequence is a two-step synthesis of 3-iodo-4-ethynylisocoumarin 21 . In contrast to the diacetylenic methyl benzoates, I 2 -promoted cyclization of ester 19 led to the formation of several products along with the remaining starting material even when 1 equiv of iodine was added. Using the iodine in excess, only 3-iodoisocoumarin 20 with an iodinated triple bond was isolated (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Intramolecular Nicholas Reactions in the Synthesis of Heteroenediynes Fused to Indole, Triazole, and Isocoumarin

et al. 2020

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The applicability of an intramolecular Nicholas reaction for the preparation of 10-membered O- and N-enediynes fused to indole, 1,2,3-triazole, and isocoumarin was investigated. The general approach to acyclic enediyne precursors fused to heterocycles includes inter- and intramolecular buta-1,3-diyne cyclizations with the formation of iodoethynylheterocycles, followed by Sonogashira coupling. The nature of both a heterocycle and a nucleophilic group affects the possibility of a 10-membered ring closure by the Nicholas reaction. Among oxacycles, an isocoumarin-fused enediyne was obtained. In the case of O-enediyne annulated with indole, instead of the formation of a 10-membered cycle, BF3-promoted addition of an OH-group to the proximal triple bond at the C3 position afforded dihydrofuryl-substituted indole. For 1,2,3-triazole-fused analogues, using NH-Ts as a nucleophilic functional group allowed obtaining 10-membered azaenediyne, while the substrate with a hydroxyl group gave only traces of the desired 10-membered oxacycle. An improved method for the deprotection of Co-complexes of cyclic enediynes using tetrabutylammonium fluoride in an acetone/water mixture and the investigation of the 10-membered enediynes’ reactivity in the Bergman cyclization are also reported. In the solid state, all synthesized iodoethynylheterocycles were found to be involved in halogen bond (XB) formation with either O or N atoms as XB acceptors.

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Towards Isocoumarin‐Fused Enediyne Systems through the Electrophilic Cyclization of Methyl o‐(Buta‐1,3‐diynyl)benzoates

Cited by 14 publications

References 46 publications

10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

10-Membered Azaenediyne Fused to a Benzothiophene through the Nicholas Macrocyclization: Synthesis and DNA Cleavage Ability

Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization

Intramolecular Nicholas Reactions in the Synthesis of Heteroenediynes Fused to Indole, Triazole, and Isocoumarin

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