Design and Synthesis of Aza‐Bicyclononene Dienophiles for Rapid Fluorogenic Ligations

Siegl, Sebastian J.; Vázquez, Arcadio; Dzijak, Rastislav; Dračínský, Martin; Galeta, Juraj; Rampmaier, Robert; Klepetářová, Blanka; Vrábel, Milan

doi:10.1002/chem.201705188

Cited by 29 publications

(17 citation statements)

References 60 publications

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“…In addition, we and others have reported that reactions between 1,2,4,5‐tetrazines and particular dienophiles also lead to fluorescent products without the need for attachment of an extra fluorophore moiety . Despite successful application of this chemistry for bioimaging, we found that only the axially substituted hydroxy trans ‐cyclooctene and azabicyclononene dienophiles afforded fluorescent dihydropyridazine products. This limited scope of dienophiles suitable for fluorogenic labeling hampers broader utility of the methodology.…”

Section: Figurementioning

confidence: 92%

An Extended Approach for the Development of Fluorogenic trans‐Cyclooctene–Tetrazine Cycloadditions

et al. 2019

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Inverse‐electron‐demand Diels–Alder (iEDDA) cycloaddition between 1,2,4,5‐tetrazines and strained dienophiles belongs among the most popular bioconjugation reactions. In addition to its fast kinetics, this cycloaddition can be tailored to produce fluorescent products from non‐fluorescent starting materials. Here we show that even the reaction intermediates formed in iEDDA cycloaddition can lead to the formation of new types of fluorophores. The influence of various substituents on their photophysical properties and the generality of the approach with use of various trans ‐cyclooctene derivatives were studied. Model bioimaging experiments demonstrate the application potential of fluorogenic iEDDA cycloaddition.

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Section: Figurementioning

confidence: 92%

An Extended Approach for the Development of Fluorogenic trans‐Cyclooctene–Tetrazine Cycloadditions

et al. 2019

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“…[24] The more recently described aza-TCO also displays rapid reactivity that is intermediate between s-TCO and d-TCO. [93] aza-TCO has been utilized in the formation of fluorescent products in tetrazine ligations that do not require attachment of an extra fluorophore moiety.…”

Section: Trans-cyclooctenes In Bioorthogonal Chemistrymentioning

confidence: 99%

“…Since our original description of the flow photoisomerization protocol, it has been employed by a number of groups for trans ‐cyclooctene synthesis with applications that include radiochemistry, cellular imaging, drug delivery and materials science . There have also been a number of modifications to the flow procedure that have been introduced.…”

Section: Figurementioning

confidence: 99%

“…With the same tetrazine, d‐TCO reacts with a rate of 3.7×10 5 M −1 s −1 , and displays better long‐term stability toward isomerization . The more recently described aza‐TCO also displays rapid reactivity that is intermediate between s‐TCO and d‐TCO . aza‐TCO has been utilized in the formation of fluorescent products in tetrazine ligations that do not require attachment of an extra fluorophore moiety.…”

Section: Figurementioning

confidence: 99%

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Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Pigga

Fox

2019

Israel Journal of Chemistry

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trans-Cyclooctenes and trans-cycloheptenes have long been the subject of physical organic study, but the broader application had been limited by synthetic accessibility. This account describes the development of a general, flow photochemical method for the preparative synthesis of trans-cycloalkene derivatives. Here, photoisomerization takes place in a closed-loop flow reactor where the reaction mixture is continuously cycled through Ag(I) on silicagel. Selective complexation of the trans-isomer by Ag(I) during flow drives an otherwise unfavorable isomeric ratio toward the transisomer. Analogous photoreactions under batch-conditions are low yielding, and flow chemistry is necessary in order to obtain trans-cycloalkenes in preparatively useful yields. The applications of the method to bioorthogonal chemistry and stereospecific transannulation chemistry are described.The unusual reactivity and well-defined chiral structure of trans-cycloalkenes has made them attractive targets for synthesis for nearly 70 years. [1][2][3] For example, trans-cyclooctene possesses planar chirality and displays a high barrier to racemization (E a = 35.6 kcal/mol), [4] and the most stable "crown" conformer has an alternating sequence of equatorial and axial hydrogens that is akin to chair cyclohexane. [5][6] The double bond of trans-cyclooctene is twisted severely in the crown conformation, [7] and as a consequence the HOMO of trans-cyclooctene is relatively high in energy. [8] trans-Cycloheptene also has a rigid structure with a distorted alkene. [7] The double bonds of medium-ring trans-alkenes are twisted. [7] trans-Cycloalkenes display unusual reactivity in HOMOalkene controlled cycloaddition reactions with dienes, [9] 1,3dipoles [8] and ketenes. [10] Strained trans-cycloalkenes also serve as ligands for transition metals. [11][12][13][14][15][16] This reactivity profile has made trans-cycloalkanes interesting targets for applications in synthesis and biology.The broadest applications of trans-cycloalkenes are in the field of bioorthogonal chemistry. The inverse-electron demand Diels-Alder reaction between tetrazines and strained alkenes has a rich history in physical organic and synthetic chemistry (Figure 1). [17][18][19] In 2008, three groups described the bioorthogonal reactions of tetrazines with strained alkenes. [20][21][22] The variant introduced by our group that used trans-cyclooctene is marked by exceptionally rapid kinetics, with rate constants that can exceed 10 6 M À 1 s À 1 in the fastest cases. [23][24] With the advances including the development of fluorogenic tetrazines [25] and reactions in live cells [26] and animals, [27] the tetrazine ligation has become a widely used tool for applications that span chemical biology, biomedical imaging, and materials science. [28][29][30][31][32][33][34][35][36][37] This account describes the development of general, flow photochemical methods for the preparative synthesis of transcycloalkene derivatives and enabled applications in synthesis and bioorthogonal chemistry. Selectiv...

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“…18 This result is in sharp contrast to related tetrazine motifs, which react vigorously with a variety of alkenes and alkynes. 12,13,[20][21][22][23][24][25][26][27][28] To expand upon the unique features of triazines, we aimed to synthesize and examine the reactivities of alternatively substituted rings. 1,2,4-Triazines react with dienophiles to form new bonds across C3 and C6.…”

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confidence: 99%

Isomeric triazines exhibit unique profiles of bioorthogonal reactivity

et al. 2019

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Design and Synthesis of Aza‐Bicyclononene Dienophiles for Rapid Fluorogenic Ligations

Cited by 29 publications

References 60 publications

An Extended Approach for the Development of Fluorogenic trans‐Cyclooctene–Tetrazine Cycloadditions

An Extended Approach for the Development of Fluorogenic trans‐Cyclooctene–Tetrazine Cycloadditions

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Isomeric triazines exhibit unique profiles of bioorthogonal reactivity

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