Thieme Chemistry Journals Awardees: Where Are They Now? One-Pot Synthesis of Versatile Buckle Units for Click Chemistry: 4,8-Diazacyclononynes (DACNs)

Igawa, Kazunobu; Aoyama, Shin; Kawasaki, Yuuya; Kashiwagi, Takeru; Seto, Yuki; Ni, Runyan; Mitsuda, Naoto; Tomooka, Katsuhiko

doi:10.1055/s-0036-1588839

Cited by 19 publications

(9 citation statements)

References 5 publications

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“…The approach combines electrophile-promoted cyclization , with the Sonogashira coupling , for the construction of a heterocycle and the introduction of essential functional groups for one of two key stepsthe Nicholas reaction − ,− aimed at closing a medium-sized strained alkyne ring. The synthesis is completed by another key stage: decomplexing the products of the Nicholas reaction from cobalt.…”

Section: Resuts and Discussionmentioning

confidence: 99%

“…Among molecules with annulated rings, dibenzo- ( DIBO , DIBAC , BARAC , ODIBO ) ABC , and others, along with the most reactive triannulated cyclooctyne B , (Figure , group II) benzo- ( 3,4-MOBO , COMBO ), cyclopropane- ( BCN ), and pyrrole-fused carbocyclooctynes ( PYRROC , SYPCO , TRIPCO ) (Figure , group III) should be highlighted. It is noteworthy that the TS stabilization approach compared to benzoannulation approach allowed switching from eight-membered cyclic alkynes ( SNO-OCT , E , and others) to the quite reactive nine-membered alkynes ( D , F , , ABSACN ) and even cyclodecynes ( rac- BINOC ) (Figure , group IV). Finally, TS state stabilization through the introduction of both endocyclic and exocyclic σ-acceptors led to the incredibly reactive structure dF-SNO-OCT useful for orthogonal bioorthogonal conjugation …”

Section: Introductionmentioning

confidence: 99%

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Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

et al. 2021

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In the search for fundamentally new, active, stable, and readily synthetically accessible cycloalkynes as strain-promoted azide–alkyne cycloaddition (SPAAC) reagents for bioorthogonal bioconjugation, we integrated two common approaches: the reagent destabilization by the increase of a ring strain and the transition state stabilization through electronic effects. As a result new SPAAC reagents, heterocyclononynes fused to a heterocyclic core, were created. These compounds can be obtained through a general synthetic route based on four crucial steps: the electrophile-promoted cyclization, Sonogashira coupling, Nicholas reaction, and final deprotection of Co-complexes of cycloalkynes from cobalt. Varying the natures of the heterocycle and heteroatom allows for reaching the optimal stability-reactivity balance for new strained systems. Computational and experimental studies revealed similar SPAAC reactivities for stable 9-membered isocoumarin- and benzothiophene-fused heterocycloalkynes and their unstable 8-membered homologues. We discovered that close reactivity is a result of the interplay of two electronic effects, which stabilize SPAAC transition states (πin* → σ* and π* → πin*) with structural effects such as conformational changes from eclipsed to staggered conformations in the cycloalkyne scaffold, that noticeably impact alkyne bending and reactivity. The concerted influence of a heterocycle and a heteroatom on the polarization of a triple bond in highly strained cycles along with a low HOMO–LUMO gap was assumed to be the reason for the unpredictable kinetic instability of all the cyclooctynes and the benzothiophene-fused oxacyclononyne. The applicability of stable isocoumarin-fused azacyclononyne IC9N-BDP-FL for in vitro bioconjugation was exemplified by labeling and visualization of HEK293 cells carrying azido-DNA and azido-glycans.

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Section: Resuts and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

et al. 2021

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“…Additionally, N-tosyl functional group provides synthetic applicably for a cycle formation through the Nicholas reaction. 10,[18][19][20] Moreover, known active N-tosylazaenediynes 32 allowed to consider the target azacycle as a promising object for biological trials with a good balance of stability/reactivity. 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.…”

Section: Letter Syn Lettmentioning

confidence: 99%

“…The latter are known to be synthesized by intramolecular Nicholas cyclization [10][11][12][13][14][15][16] and from two or more starting compounds by tandem cycloaddition process with the Nicholas-type reaction on a C-N bond-formation step. [17][18][19][20][21] Cycles of different sizes from 5-to 21-memebered rings have been prepared using these methodologies. Among 10-membered cyclic alkynes enediyne antibiotics with a (Z)-3-ene-1,5-diyne system in a 10-membered cycle are of special interest because of their ability to undergo the Bergman cycloaromatization under mild condi-tions with the formation of diradicals.…”

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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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“…The Nicholas reaction , is a general synthetic method based on the interaction of Co 2 (CO) 6 -stabilized propargylic carbocations with nucleophiles. This reaction has a broad application in the organic synthesis. , The significant bending of bond angles in Co-complexes and stability of Co-protected propargylic carbocations allowed this reaction to be employed as a unique macrocyclization tool in the synthesis of cycloalkynes − including natural enediynes . There are recent examples of interaction of Co 2 (CO) 6 -stabilized propargylic carbocations derived from different functional groups in a propargylic position, i.e., OH, − OR, , COH, cyclopropane 1,1-diester), with different nucleophiles (heteroatom functions, − ,− arenes with electron donating groups, ,, enoles, ,, allylsilanes ,, and double bonds ,, ) (Scheme ).…”

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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Thieme Chemistry Journals Awardees: Where Are They Now? One-Pot Synthesis of Versatile Buckle Units for Click Chemistry: 4,8-Diazacyclononynes (DACNs)

Cited by 19 publications

References 5 publications

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

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

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