Applications of the Nicholas Reaction in the Synthesis of Natural Products

Kann, Nina

doi:10.2174/138527212799499949

Cited by 37 publications

(7 citation statements)

References 52 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%

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%

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

et al. 2021

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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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“…Electrophile-promoted cyclization , and CuAAC of 1-iodoacetylenes , being applied to diacetylenes , with subsequent Sonogashira coupling , have been suggested as key steps for the construction of acyclic enediyne systems. The Nicholas reaction was chosen for the final macrocyclization step as a unique synthetic tool for the construction of various cyclic alkyne derivatives including natural enediynes and their analogues. − …”

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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Applications of the Nicholas Reaction in the Synthesis of Natural Products

Cited by 37 publications

References 52 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

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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