1,3-Dipolar Cycloadditions of Diazo Compounds in the Presence of Azides

Aronoff, Matthew R.; Gold, Brian; Raines, Ronald T.

doi:10.1021/acs.orglett.6b00278

Cited by 66 publications

(82 citation statements)

References 56 publications

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“…Previously, we reported that the reaction of 1 and 8 proceeds with a rate constant of k = 1.6 × 10 −3 M −1 s −1 (Figure 1), which is 10 2 -fold less than that of trifluorocrotonate 2 . 10 Here, we found the rate constant for cycloaddition with crotonate 9 to be k = 5.8 × 10 −7 M −1 s −1 , which is 10 5 -fold less than that for trifluorocrotonate 2 . Notably, the effect of allylic fluorination in this reaction is much larger than is the effect of propargylic fluorination on the cycloaddition of azides (∼400-fold).…”

Section: Resultsmentioning

confidence: 63%

“…22 Relative to the unfluorinated crotonate 9 , trifluorocrotonate 2 displays decreased distortion energies for both reacting partners, in addition to significantly larger interaction energies. The increased reactivity over acrylate 8 , however, stems not from a decreased distortion energy, as observed for typical cycloadditions of diazoacetamides, 10 but from a large increase in interaction energy (Δ E int ) that results from an N–H···F–C hydrogen bond formed between the diazoacetamide and a fluoro group of the trifluorocrotonate, along with hyperconjugative assistance to bond formation. Both hydrogen-bond formation 12d,23 and hyperconjugative assistance to bond formation have been asserted previously for cycloadditions with azides.…”

Section: Resultsmentioning

confidence: 88%

“…9 Recently, we explored 1,3-dipolar cycloadditions of diazo compounds in the presence of azides. 10 Although we were able to achieve diazo group-specific conjugation in the absence of a catalyst (Scheme 1), the reaction rates were low—comparable to those obtained with early SPAAC reagents and exceeded by new SPAAC reagents. 8c,11 Hence, we sought a faster cycloaddition.…”

Section: Introductionmentioning

confidence: 76%

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Rapid cycloaddition of a diazo group with an unstrained dipolarophile

Aronoff

Gold

Raines

2016

Tetrahedron Letters

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The cycloaddition of a diazoacetamide with ethyl 4,4,4-trifluorocrotonate proceeds with k = 0.1 M−1s−1. This second-order rate constant rivals those of optimized strain-promoted azide– alkyne cycloadditions, even though the reaction does not release strain. The regioselectivity and a computational distortion/interaction analysis of the reaction energetics are consistent with the formation of an N–H…F–C hydrogen bond in the transition state and the electronic character of the trifluorocrotonate. Analogous reactions with an azidoacetamide dipole or with an acrylate or crotonate dipolarophile were much slower. These findings suggest a new strategy for the design of diazo-selective reagents for chemical biology.

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Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 76%

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Rapid cycloaddition of a diazo group with an unstrained dipolarophile

Aronoff

Gold

Raines

2016

Tetrahedron Letters

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“…16 Accordingly, we observed an increase in reactivity for diazo groups with dipolarophiles containing electron-withdrawing substituents ( d and e ). 5,15b In contrast, azides show ambiphilic character—benefitting from both donors and acceptors on the dipolarophile. Still, electron-donating substituents on an alkene ( e.g.…”

Section: Resultsmentioning

confidence: 99%

Decreasing Distortion Energies without Strain: Diazo-Selective 1,3-Dipolar Cycloadditions

2016

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The diazo group has attributes that complement those of the azido group for applications in chemical biology. Here, we use computational analyses to provide insights into the chemoselectivity of the diazo group in 1,3-dipolar cycloadditions. Dipole distortion energies are responsible for ~80% of the overall energetic barrier for these reactions. Here, we show that diazo compounds, unlike azides, provide an opportunity to decrease that barrier substantially without introducing strain into the dipolarophile. The ensuing rate-enhancement is due to the greater nucleophilic character of a diazo group compared to that of an azido group, which can accommodate decreased distortion energies without pre-distortion. The tuning of distortion energies with substituents in a diazo compound or dipolarophile can enhance reactivity and selectivity in a predictable manner. Notably, these advantages of diazo groups are amplified in water. Our findings provide a theoretical framework that can guide the design and application of both diazo compounds and azides in “orthogonal” contexts, especially for biological investigations.

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“…21,22 Similarly, the diazo group is particularly attractive as a photoprobe and has enabled novel modications of proteins and nucleic acids 23 (New) because of its small size and ease of introduction within a short time. 24,25 The rst example of PAL was achieved with a diazoacetate.…”

Section: Diazo Compoundsmentioning

confidence: 99%

Current advances of carbene-mediated photoaffinity labeling in medicinal chemistry

Chen

et al. 2018

RSC Adv.

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Photoaffinity labeling (PAL) in combination with a chemical probe to covalently bind its target upon UV irradiation has demonstrated considerable promise in drug discovery for identifying new drug targets and binding sites. In particular, carbene-mediated photoaffinity labeling (cmPAL) has been widely used in drug target identification owing to its excellent photolabeling efficiency, minimal steric interference and longer excitation wavelength.Specifically, diazirines, which are among the precursors of carbenes and have higher carbene yields and greater chemical stability than diazo compounds, have proved to be valuable photolabile reagents in a diverse range of biological systems. This review highlights current advances of cmPAL in medicinal chemistry, with a focus on structures and applications for identifying small molecule-protein and macromolecule-protein interactions and ligand-gated ion channels, coupled with advances in the discovery of targets and inhibitors using carbene precursor-based biological probes developed in recent decades.

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1,3-Dipolar Cycloadditions of Diazo Compounds in the Presence of Azides

Cited by 66 publications

References 56 publications

Rapid cycloaddition of a diazo group with an unstrained dipolarophile

Rapid cycloaddition of a diazo group with an unstrained dipolarophile

Decreasing Distortion Energies without Strain: Diazo-Selective 1,3-Dipolar Cycloadditions

Current advances of carbene-mediated photoaffinity labeling in medicinal chemistry

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