Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening

Narayanam, Maruthi Kumar; Liang, Yong; Houk, K. N.; Murphy, Jennifer M.

doi:10.1039/c5sc03259h

Cited by 85 publications

(87 citation statements)

References 66 publications

(23 reference statements)

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“…This prediction points to the intriguing possibility of developing bioorthogonal reactions that employ two or more different 1,3-dipoles with two or more different cycloalkynes to afford mutually orthogonal reactivity. 1,5,19 Such strategies offer the ability to label various components of complex processes either sequentially 19a,b,f–h or simultaneously. 19c–e,i While the majority of efforts in this area have utilized the small size of the azide or other dipoles to afford selectivity over the sterically bulky, yet highly reactive, tetrazine moiety, 19c–g,j few reports of utilizing electronic differences in dipoles 5 and dipolarophiles 4g have been disclosed.…”

Section: Resultsmentioning

confidence: 99%

“…1,5,19 Such strategies offer the ability to label various components of complex processes either sequentially 19a,b,f–h or simultaneously. 19c–e,i While the majority of efforts in this area have utilized the small size of the azide or other dipoles to afford selectivity over the sterically bulky, yet highly reactive, tetrazine moiety, 19c–g,j few reports of utilizing electronic differences in dipoles 5 and dipolarophiles 4g have been disclosed. Previous reports have shown complete selectivity of diazoacetamides over the analogous azides; however, these systems suffer from either relatively slow reaction kinetics 5a or unstable reacting partners, 5c,f shortcomings that our new cycloalkyne scaffolds can be employed to overcome with further optimizations.…”

Section: Resultsmentioning

confidence: 99%

“…18 This strategy provides advantages not just in terms of preventing unwanted side reactions, but also allows for the development of mutually orthogonal chemistries. 1,5,19 Advances in our ability to predictably tune the electronics of the dipolarophile could enable even better matching between the FMOs of the cycloalkyne and the desired 1,3-dipole.…”

Section: Introductionmentioning

confidence: 99%

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Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

et al. 2017

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The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative 8 outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

et al. 2017

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“…21a The calculated activation barriers and relative rate constants are shown in Figure 12. The sterically less encumbered nitrile imine is less sensitive to the steric effect at C3 of cyclopropene.…”

Section: Applications To Bioorthogonal Cycloadditionmentioning

confidence: 99%

“…29 Our collaborators, the Prescher group at UCI, tested the biological stability of 1,2,4-triazines and confirmed their potential as a new class of bioorthogonal reagents. 21b …”

Section: Applications To Bioorthogonal Cycloadditionmentioning

confidence: 99%

Bioorthogonal Cycloadditions: Computational Analysis with the Distortion/Interaction Model and Predictions of Reactivities

2017

Self Cite

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CONSPECTUS Bioorthogonal chemistry has had a major impact on the study of biological processes in vivo. Biomolecules of interest can be tracked by using probes and reporters that do not react with cellular components and do not interfere with metabolic processes in living cells. Much time and effort has been devoted to the screening of potential bioorthogonal reagents experimentally. This Account describes how our groups have performed computational screening of reactivity and mutual orthogonality. Our collaborations with experimentalists have led to the development of new and useful reactions. Dozens of bioorthogonal cycloadditions have been reported in the literature in the past few years, but as interest in tracking multiple targets arises, our computational screening has gained importance for the discovery of new mutually orthogonal bioorthogonal cycloaddition pairs. The reactivities of strained alkenes and alkynes with common 1,3-dipoles such as azides, along with mesoionic sydnones and other novel 1,3-dipoles, have been explored. Studies of “inverse-electron-demand” dienes such as triazines and tetrazines that have been used in bioorthogonal Diels–Alder cycloadditions are described. The color graphics we have developed give a snapshot of whether reactions are fast enough for cellular applications (green), adequately reactive for labeling (yellow), or only useful for synthesis or do not occur at all (red). The colors of each box give an instant view of rates, while bar graphs provide an analysis of the factors that control reactivity. This analysis uses the distortion/interaction or activation strain model of cycloaddition reactivity developed independently by our group and that of F. Matthias Bickelhaupt in The Netherlands. The model analyzes activation barriers in terms of the energy required to distort the reactants to the transition state geometry. This energy, called the distortion energy or activation strain, constitutes the major component of the activation energy. The strong bonding interaction between the termini of the two reactants, which we call the interaction energy, overcomes the distortion energy and leads to the new bonds in the products. This Account describes how we have analyzed and predicted bioorthogonal cycloaddition reactivity using the distortion/interaction model and how our experimental collaborators have employed these insights to create new bioorthogonal cycloadditions. The graphics we use document and predict which combinations of cycloadditions will be useful in bioorthogonal chemistry and which pairs of reactions are mutually orthogonal. For example, the fast reaction of 5-phenyl-1,2,4-triazine and a thiacycloheptyne will not interfere with the other fast reaction of 3,6-diphenyl-1,2,4,5-tetrazine and a cyclopropene. No cross reactions will occur, as these are very slow reactions.

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[3 + 2] Cycloadditions of Azomethine Imines

Grošelj

Svete

2020

Organic Reactions

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In spite of their late discovery in the middle of 20 th century, the importance of azomethine imines and their [3+2] cycloaddition reactions has grown constantly throughout the decades. Today, [3+2] cycloadditions of azomethine imines have become indispensable in the preparation of pyrazole derivatives with all degrees of saturation. The structural diversity of azomethine imines is wide and comprises acyclic, C , N ‐cyclic, N , N ‐cyclic, and C , N , N ‐cyclic 1,3‐dipoles. Although electron‐deficient dipolarophiles are preferred, electron‐rich dipolarophiles, such as enol ethers and enamines, are also commonly used in these reactions. Compared to cyclocondensation methods and [3+2] cycloadditions with diazoalkanes and nitrile imines, [3+2] cycloadditions with azomethine imines provide access to a greater diversity of pyrazole derivatives with all degrees of saturation. As with other 1,3‐dipolar cycloadditions, a concerted and nearly synchronous mechanism has been proposed for most [3+2] cycloadditions of azomethine imines, although a stepwise mechanism may be viable in some cases. Several examples of asymmetric [3+2] cycloadditions of azomethine imines that afford non‐racemic cycloadducts with high enantioselectivity have been reported. These asymmetric cycloadditions are performed with various types of transition metal catalysts and organocatalysts, and indicate their potential for the asymmetric synthesis of saturated pyrazole derivatives. Finally, many examples of copper‐catalyzed and thermal, strain‐promoted [3+2] cycloadditions of azomethine imines (in particular sydnones) clearly indicate wide applicability of these reactions in bioconjugation, fluorescent labelling, materials functionalization, and other applications outside the realm of pure organic synthesis.

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Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening

Abstract: The sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions are both bioorthogonal and mutually orthogonal, used for simultaneous labeling of two targets.

Cited by 85 publications

References 66 publications

Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

Bioorthogonal Cycloadditions: Computational Analysis with the Distortion/Interaction Model and Predictions of Reactivities

[3 + 2] Cycloadditions of Azomethine Imines

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