Aromatic ynamines or N-alkynylheteroarenes are highly reactive alkyne components in Cu-catalyzed Huisgen 3 + 2 cycloaddition (“click”) reactions. This enhanced reactivity enables the chemoselective ...formation of 1,4-triazoles using the representative aromatic ynamine N-ethynylbenzimidazole in the presence of a competing aliphatic alkyne substrate. The unique chemoselectivity profile of N-ethynylbenzimidazole is further demonstrated by the sequential click ligation of a series of highly functionalized azides using a heterobifunctional diyne, dispelling the need for alkyne protecting groups.
A one-pot cascade reaction for the synthesis of 2-BMIDA 6,5-bicyclic heterocycles has been developed using Cu(i)/Pd(0)/Cu(ii) catalysis. 2-Iodoanilines and phenols undergo a Cu(i)/Pd(0)-catalyzed ...Sonogashira reaction with ethynyl BMIDA followed by in situ Cu(ii)-catalyzed 5-endo-dig cyclization to generate heterocyclic scaffolds with a BMIDA functional group in the 2-position. The method provides efficient access to borylated indoles, benzofurans, and aza-derivatives, which can be difficult to access through alternative methods.
A chemoselective tandem reaction of a multi-reactive, two electrophile + two nucleophile, system is reported. An allylation/cross-coupling process of a haloaryl aldehyde, an aryl BPin, and an allyl ...BPin can be controlled using a temperature gradient to overcome natural reactivity profiles and allow two sequential chemoselective C-C bond formations without intervention. This process offers efficient access to an array of functionalised products including pharmaceutical and natural product scaffolds.
A modular synthesis of functionalised biaryl phenols from two boronic acid derivatives has been developed via one-pot Suzuki-Miyaura cross-coupling, chemoselective control of boron solution ...speciation to generate a reactive boronic ester in situ, and oxidation. The utility of this method has been further demonstrated by application in the synthesis of drug molecules and components of organic electronics, as well as within iterative cross-coupling.
The elucidation of protein interaction networks is critical to understanding fundamental biology as well as developing new therapeutics. Proximity labeling platforms (PLPs) are state-of-the-art ...technologies that enable the discovery and delineation of biomolecular networks through the identification of protein-protein interactions. These platforms work via catalytic generation of reactive probes at a biological region of interest; these probes then diffuse through solution and covalently “tag” proximal biomolecules. The physical distance that the probes diffuse determines the effective labeling radius of the PLP and is a critical parameter that influences the scale and resolution of interactome mapping. As such, by expanding the degrees of labeling resolution offered by PLPs, it is possible to better capture the various size scales of interactomes. At present, however, there is little quantitative understanding of the labeling radii of different PLPs. Here, we report the development of a superresolution microscopy-based assay for the direct quantification of PLP labeling radii. Using this assay, we provide direct extracellular measurements of the labeling radii of state-of-the-art antibody-targeted PLPs, including the peroxidase-based phenoxy radical platform (269 ± 41 nm) and the high-resolution iridium-catalyzed µMap technology (54 ± 12 nm). Last, we apply these insights to the development of a molecular diffusion-based approach to tuning PLP resolution and introduce a new aryl-azide-based µMap platform with an intermediate labeling radius (80 ± 28 nm).
We report a kinetic and spectroscopic analysis of alkyne‐dependent chemoselectivity in the copper‐catalyzed azide–alkyne click (CuAAC) reaction. Studies of six alkyne subtypes reveal that the ...rate‐determining step (RDS) of an aromatic ynamine class is shifted from acetylide formation to the azide ligation/migratory insertion event allowing chemoselectivity independent of overall rate.
Kehrtwendung: Eine kinetische Analyse der vom Alkin abhängigen Chemoselektivität in der Cu‐katalysierten Azid‐Alkin‐Reaktion (CuAAC) wird vorgestellt. Untersuchungen von sechs Alkintypen ergeben, dass sich bei einer aromatischen Inaminklasse der geschwindigkeitsbestimmende Schritt (RDS) von der Acetylidbildung zur Azidligation/migratorischen Insertion verschiebt, woraus eine von der Gesamtgeschwindigkeit unabhängige Selektivität resultiert.
Modern proximity labeling techniques have enabled significant advances in understanding biomolecular interactions. However, current tools primarily utilize activation modes that are incompatible with ...complex biological environments, limiting our ability to interrogate cell- and tissue-level microenvironments in animal models. Here, we report µMap-Red, a proximity labeling platform that uses a red light-excited Sn
IV
chlorin e6 catalyst to activate a phenyl azide biotin probe. We validate µMap-Red by demonstrating photonically-controlled protein labeling
in vitro
through several layers of tissue, and we then apply our platform
in cellulo
to label
EGFR
microenvironments and validate performance with STED microscopy and quantitative proteomics. Finally, to demonstrate labeling in a complex biological sample, we deploy µMap-Red in whole mouse blood to profile erythrocyte cell-surface proteins. This work represents a significant methodological advance toward light-based proximity labeling in complex tissue environments and animal models.
A chemoselective tandem reaction of a multi-reactive, two electrophile + two nucleophile, system is reported. An allylation/cross-coupling process of a haloaryl aldehyde, an aryl BPin, and an allyl ...BPin can be controlled using a temperature gradient to overcome natural reactivity profiles and allow two sequential chemoselective C-C bond formations without intervention. This process offers efficient access to an array of functionalised products including pharmaceutical and natural product scaffolds.
Chemoselective control of a multi-reactive system allows two sequential C-C bond formations
via
two distinct reactivity modes, accessing pharmaceutical and natural product scaffolds.
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