Functionalized Cyclopropenes As Bioorthogonal Chemical Reporters

Patterson, David M.; Nazarova, Lidia A.; Xie, Bryan J.; Kamber, David N.; Prescher, Jennifer A.

doi:10.1021/ja3060436

Cited by 336 publications

(366 citation statements)

References 51 publications

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“…Furthermore, terminal alkynes, which are highly reactive in CuAAC reactions, only react with tetrazines, unless electron-donating substituents are present or relatively harsh reaction conditions are applied. The combination of iEDDA dienophiles (TCO 43 and methylcyclopropene, 44 respectively) and dibenzocyclooctyne as the SPAAC acceptor finally allowed a copper-free, mutually orthogonal and bioorthogonal protocol. DFT (density functional theory) calculations revealed that the introduction of the two fused benzene rings in dibenzocyclooctyne derivatives raised the distortion energy necessary to attain the first transition state TS in iEDDA reactions, 18 so that the reaction rate for tetrazines and dibenzocyclooctyne was drastically reduced.…”

Section: Mutual Orthogonality With Other Click Reactionsmentioning

confidence: 99%

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

2013

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Inverse electron demand Diels-Alder reactions (iEDDA) between 1,2,4,5-tetrazines and olefins have emerged into a state-of-the art concept for the conjugation of biomolecules. Now, this reaction is also increasingly being applied in polymer science and materials science. The orthogonality of this exciting reaction to other well-established click chemistry schemes, its high reaction speed and its biocompatibility are key features of iEDDA making it a powerful alternative to existing ligation chemistries. The intention of this tutorial review is to introduce the reader to the fundamentals of inverse electron demand Diels-Alder additions and to answer the question whether iEDDA chemistry is living up to the criteria for a ''click'' reaction and can serve as a basis for future applications in postsynthetic modification of materials. Key learning points(1) Electron-rich dienophiles and electron-poor dienes (e.g. tetrazines) react in an inverse electron demand Diels-Alder reaction (iEDDA).(2) iEDDA fulfils Sharpless' criteria for a ''click'' reaction while offering advantages over already established ''click'' chemistry schemes.

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Section: Mutual Orthogonality With Other Click Reactionsmentioning

confidence: 99%

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

2013

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“…[6] Fort his alkene,t he (Z)-isomer of 5 showed alower rate constant than (E)-5.Introduction of an electrondonating substituent on the phenyl ring of 8 increased the rate constant further to 27 m À1 s À1 . To evaluate the effect of the boronic acid on the alkenes reactivity,wecompared the rate constants of the fastest VBAs (E)-5 and 8 to the alkene derivatives lacking the boronic acid (Table 1, Entries 4a nd 5).…”

mentioning

confidence: 97%

Vinylboronic Acids as Fast Reacting, Synthetically Accessible, and Stable Bioorthogonal Reactants in the Carboni–Lindsey Reaction

Eising¹,

Lelivelt²,

Bonger³

2016

Angewandte Chemie

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Bioorthogonal reactions are widely used for the chemical modification of biomolecules.T he application of vinylboronic acids (VBAs) as non-strained, synthetically accessible and water-soluble reaction partners in ab ioorthogonal inverse electron-demand Diels-Alder (iEDDA) reaction with 3,6-dipyridyl-s-tetrazines is described. Depending on the substituents,VBA derivatives give second-order rate constants up to 27 m À1 s À1 in aqueous environments at room temperature, which is suitable for biological labeling applications.T he VBAs are shown to be biocompatible,n on-toxic, and highly stable in aqueous media and cell lysate.F urthermore,V BAs can be used orthogonally to the strain-promoted alkyne-azide cycloaddition for protein modification, making them attractive complements to the bioorthogonal molecular toolbox.Inthe last decades,t he development of selective reactions between two reactants that are unaffected by any of the naturally occurring biological functionalities has been amajor research area in chemical biology.[1] These bioorthogonal reactions ( Figure 1A)m ake it possible to chemically modify biomolecules in their native cellular environment and gain ab etter understanding of their role in as pecific biological system or process.The bioorthogonal reaction should be high yielding and rapid, and the reactants and product(s) should be soluble and stable in aqueous media and non-toxic to the biological system. Theu se of small reactants is preferred to minimize steric interactions with the biomolecule or to facilitate incorporation by the endogenous cellular machinery.TheCarboni-Lindsey (CL) reaction between an electronpoor tetrazine ( Figure 1B, I)a nd an alkene has gained considerable attention for use in bioorthogonal applications. [2] As linear and unmodified alkenes ( Figure 1B, VI)s howed only poor reaction rates with tetrazines, [3] most research has been directed to the development and use of strained alkenes such as trans-cyclooctene (TCO), [4] norbornene, [5] cyclopropene, [6] or N-acylazetine [7] ( Figure 1B, II-V). In addition to strain, the rate of the CL reaction can be significantly enhanced by the introduction of electron-donating substituents on the alkene bond.[8] This aspect, however,h as been poorly investigated in relation to bioorthogonal applications.Vinylboronic acids ( Figure 1B, VII)a re an interesting class of compounds with unique electronic properties,w hich are due to their vacant p-orbital. As aresult of the inductive effect that is caused by the electronegativity difference of boron and carbon, the electronic deficiencyofboron and the electron-donating oxygens attached to boron, boronic acid is considered to be aw eak electron-donor.[9] Furthermore, boronic acids are mild organic Lewis acids,w hich in basic aqueous media are in equilibrium with their boronate anion ( Figure 1B, VIII), which is as trong electron-donor. [9] Although Diels-Alder reactions are known to proceed faster in aqueous media, the CL reactions of vinylboronic acids and alkylboronic acids are re...

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“…Importantly, CpK was shown to direct site-specific modification of green fluorescent protein inside HEK293T cells via the tetrazole-based photoclick chemistry. Notably, the cyclopropene moiety has also been used as a reaction partner in tetrazine ligation [53,54], with its reactivity preference between the tetrazine and tetrazole chemistries depending on the substitution pattern [55]. Realizing the cyclopropene reactivity can be further increased by reducing the steric hindrance at position 3, we fused a cyclobutane ring with the cyclopropene to generate spiro[2.3]hex-1-ene (Sph) [56].…”

Section: Site-specific Labeling Of Proteins Via the Photoinduced Tetrmentioning

confidence: 99%

Photo-Triggered Click Chemistry for Biological Applications

Herner¹,

Qi²

2015

Cycloadditions in Bioorthogonal Chemistry

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In the last decade and a half, numerous bioorthogonal reactions have been developed with a goal to study biological processes in their native environment, i.e., in living cells and animals. Among them, the photo-triggered reactions offer several unique advantages including operational simplicity with the use of light rather than toxic metal catalysts and ligands, and exceptional spatiotemporal control through the application of an appropriate light source with pre-selected wavelength, light intensity and exposure time. While the photoinduced reactions have been studied extensively in materials research, e.g., on macromolecular surface, the adaptation of these reactions for chemical biology applications is still in its infancy. In this chapter, we review the recent efforts in the discovery and optimization the photo-triggered bioorthogonal reactions, with a focus on those that have shown broad utility in biological systems. We discuss in each cases the chemical and mechanistic background, the kinetics of the reactions and the biological applicability together with the limiting factors.

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Functionalized Cyclopropenes As Bioorthogonal Chemical Reporters

Cited by 336 publications

References 51 publications

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

Vinylboronic Acids as Fast Reacting, Synthetically Accessible, and Stable Bioorthogonal Reactants in the Carboni–Lindsey Reaction

Photo-Triggered Click Chemistry for Biological Applications

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