Rapid cycloaddition of a diazo group with an unstrained dipolarophile

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

doi:10.1016/j.tetlet.2016.04.020

Cited by 17 publications

(24 citation statements)

References 62 publications

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“…The large decrease in the cost of distortion is the source of additional acceleration provided by the dual Au catalysis. Scheme illustrates that the ortho -Au group significantly decreases positive charge at C 5 of the product and leads to very interesting electron density redistribution in the TS …”

Section: Resultsmentioning

confidence: 99%

Drawing Catalytic Power from Charge Separation: Stereoelectronic and Zwitterionic Assistance in the Au(I)-Catalyzed Bergman Cyclization

Gomes

Alabugin

2017

J. Am. Chem. Soc.

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The synergy between bond formation and bond breaking that is typical for pericyclic reactions is lost in their mechanistic cousins, cycloaromatization reactions. In these reactions, exemplified by the Bergman cyclization (BC), two bonds are sacrificed to form a single bond, and the reaction progress is interrupted at the stage of a cyclic diradical intermediate. The catalytic power of Au(I) in BC stems from a combination of two sources: stereoelectronic assistance of C-C bond formation (i.e., "LUMO umpolung") and crossover from a diradical to a zwitterionic mechanism that takes advantage of the catalyst's dual ability to stabilize both negative and positive charges. Not only does the synergy between the bond-forming and charge-delocalizing interactions lead to a dramatic (>hundred-billion-fold) acceleration, but the evolution of the two effects results in continuous reinforcement of the substrate/catalyst interaction along the cyclization path. This cooperativity converts the BC into the first example of an aborted [3,3] sigmatropic shift where the pericyclic "transition state" becomes the most stable species on the reaction hypersurface. Aborting the pericyclic path facilitates trapping of cyclic intermediate by a variety of further reactions and provides a foundation for the discovery of new modes of reactivity of polyunsaturated substrates. The application of distortion/interaction analysis allows us to quantify the increased affinity of Au-catalysts to the Bergman cyclization transition state as one of the key components of the large catalytic effect.

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Section: Resultsmentioning

confidence: 99%

Drawing Catalytic Power from Charge Separation: Stereoelectronic and Zwitterionic Assistance in the Au(I)-Catalyzed Bergman Cyclization

Gomes

Alabugin

2017

J. Am. Chem. Soc.

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“…Hence, increased electrophilicity of reacting partners—attained by incorporating electron-withdrawing substituents—becomes more important than in cycloadditions with azido congeners. 5,32 …”

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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“…Moreover, diazo compounds can react chemoselectively with certain alkenes and alkynes in the presence of an azide. In essence, a diazo group is more electron-rich and thus a better nucleophile in normal-electron-demand cycloadditions with electron-deficient dipolarophiles. − Detailed insight is attainable from computational analyses. Distortion energies account for a majority (80%) of the activation energy for 1,3-dipolar cycloadditions.…”

Section: Cycloadditionsmentioning

confidence: 99%

Diazo Compounds: Versatile Tools for Chemical Biology

2016

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Diazo groups have broad and tunable reactivity. That and other attributes endow diazo compounds with the potential to be valuable reagents for chemical biologists. The presence of diazo groups in natural products underscores their metabolic stability and anticipates their utility in a biological context. The chemoselectivity of diazo groups, even in the presence of azido groups, presents many opportunities. Already, diazo compounds have served as chemical probes and elicited novel modifications of proteins and nucleic acids. Here, we review advances that have facilitated the chemical synthesis of diazo compounds, and we highlight applications of diazo compounds in the detection and modification of biomolecules.

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Rapid cycloaddition of a diazo group with an unstrained dipolarophile

Cited by 17 publications

References 62 publications

Drawing Catalytic Power from Charge Separation: Stereoelectronic and Zwitterionic Assistance in the Au(I)-Catalyzed Bergman Cyclization

Drawing Catalytic Power from Charge Separation: Stereoelectronic and Zwitterionic Assistance in the Au(I)-Catalyzed Bergman Cyclization

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

Diazo Compounds: Versatile Tools for Chemical Biology

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