Orthogonal Inverse-Electron-Demand Cycloaddition Reactions Controlled by Frontier Molecular Orbital Interactions

Svatunek, Dennis; Chojnacki, Konrad; Deb, Titas; Eckvahl, Hannah; Houk, K. N.; Franzini, Raphael M.

doi:10.1021/acs.orglett.3c02265

Cited by 5 publications

(4 citation statements)

References 34 publications

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“…Expanding on this understanding, Svatunek et al demonstrated that while isonitriles quickly react with tetrazines that have significant steric demands, they remain unreactive with dienes like tetrachlorocyclopentadienone ethylene ketal (TCK) or 4,4-difluoro-3,5-diphenyl-4H-pyrazole (DFP) [ 129 ]. The reactivity of these dienes with strained alkynes is discussed in section 4.3.…”

Section: [4 + 2] Cycloadditionsmentioning

confidence: 99%

“…47 Orthogonality between isonitrile/tetrazine and BCN/TCK cycloadditions. TCK Tetrachlorocyclopentadienone ethylene ketal Reprinted with permission from [ 129 ] …”

Section: [4 + 2] Cycloadditionsmentioning

confidence: 99%

“…47 Orthogonality between isonitrile/tetrazine and BCN/TCK cycloadditions. TCK Tetrachlorocyclopentadienone ethylene ketal Reprinted with permission from [129] García-Aznara and Escorihuela explored the reaction through computational means [131]. Employing DIA across a reaction coordinate, they demonstrated that the superior reactivity of norbornene compared to cyclohexene stems from enhanced interaction energy rather than a decrease in strain energy (Fig.…”

Section: Reaction With Norbornene and Norbornene Derivativesmentioning

confidence: 99%

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Computational Organic Chemistry: The Frontier for Understanding and Designing Bioorthogonal Cycloadditions

Svatunek

2024

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Computational organic chemistry has become a valuable tool in the field of bioorthogonal chemistry, offering insights and aiding in the progression of this branch of chemistry. In this review, I present an overview of computational work in this field, including an exploration of both the primary computational analysis methods used and their application in the main areas of bioorthogonal chemistry: (3 + 2) and [4 + 2] cycloadditions. In the context of (3 + 2) cycloadditions, detailed studies of electronic effects have informed the evolution of cycloalkyne/1,3-dipole cycloadditions. Through computational techniques, researchers have found ways to adjust the electronic structure via hyperconjugation to enhance reactions without compromising stability. For [4 + 2] cycloadditions, methods such as distortion/interaction analysis and energy decomposition analysis have been beneficial, leading to the development of bioorthogonal reactants with improved reactivity and the creation of orthogonal reaction pairs. To conclude, I touch upon the emerging fields of cheminformatics and machine learning, which promise to play a role in future reaction discovery and optimization.

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Section: [4 + 2] Cycloadditionsmentioning

confidence: 99%

“…47 Orthogonality between isonitrile/tetrazine and BCN/TCK cycloadditions. TCK Tetrachlorocyclopentadienone ethylene ketal Reprinted with permission from [ 129 ] …”

Section: [4 + 2] Cycloadditionsmentioning

confidence: 99%

Section: Reaction With Norbornene and Norbornene Derivativesmentioning

confidence: 99%

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Computational Organic Chemistry: The Frontier for Understanding and Designing Bioorthogonal Cycloadditions

Svatunek

2024

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“…Modifying two proteins with either a bulky DTTz or tetrachlorocyclopentadienone ethylene ketal (TCK) FMCD allowed selective protein modification using an isonitrile and a BCN, respectively (Fig. 18 ) [ 118 ]. In this example, the fluorophore was conjugated to the isonitrile.…”

Section: Tuning the Reaction Partners For Dual And Triple Orthogonal ...mentioning

confidence: 99%

Mutually Orthogonal Bioorthogonal Reactions: Selective Chemistries for Labeling Multiple Biomolecules Simultaneously

Venrooij,

de Bondt,

Bonger

2024

Top Curr Chem (Z)

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Bioorthogonal click chemistry has played a transformative role in many research fields, including chemistry, biology, and medicine. Click reactions are crucial to produce increasingly complex bioconjugates, to visualize and manipulate biomolecules in living systems and for various applications in bioengineering and drug delivery. As biological (model) systems grow more complex, researchers have an increasing need for using multiple orthogonal click reactions simultaneously. In this review, we will introduce the most common bioorthogonal reactions and discuss their orthogonal use on the basis of their mechanism and electronic or steric tuning. We provide an overview of strategies to create reaction orthogonality and show recent examples of mutual orthogonal chemistry used for simultaneous biomolecule labeling. We end by discussing some considerations for the type of chemistry needed for labeling biomolecules in a system of choice.

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Tetrazine‐Isonitrile Bioorthogonal Fluorogenic Reactions Enable Multiplex Labeling and Wash‐Free Bioimaging of Live Cells

Deng,

Shen,

et al. 2024

Angewandte Chemie

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Developing fluorogenic probes for simultaneous live cell labeling of multiple targets is crucial for understanding complex cellular events. The emerging [4+1] cycloaddition between tetrazine and isonitriles holds promise as a bioorthogonal tool, yet existing tetrazine probes lack reactivity and fluorogenicity. Here, we present the development of a series of tetrazine‐functionalized bioorthogonal probes. By incorporating pyrazole adducts into the fluorophore scaffolds, the post‐reacted probes displayed remarkable fluorescence turn‐on ratios, up to 3184‐fold. Moreover, these modifications are generalizable to various fluorophores, enabling a broad emission range from 473 to 659 nm. Quantum chemical calculations further elucidate the turn‐on mechanisms. These probes enable simultaneous labeling of multiple targets in live cells, without the need for a washing step. Consequently, our findings pave the way for advanced multiplex imaging and detection techniques for cellular studies.

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Orthogonal Inverse-Electron-Demand Cycloaddition Reactions Controlled by Frontier Molecular Orbital Interactions

Cited by 5 publications

References 34 publications

Computational Organic Chemistry: The Frontier for Understanding and Designing Bioorthogonal Cycloadditions

Computational Organic Chemistry: The Frontier for Understanding and Designing Bioorthogonal Cycloadditions

Mutually Orthogonal Bioorthogonal Reactions: Selective Chemistries for Labeling Multiple Biomolecules Simultaneously

Tetrazine‐Isonitrile Bioorthogonal Fluorogenic Reactions Enable Multiplex Labeling and Wash‐Free Bioimaging of Live Cells

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