We present a systematic investigation of the structural and electronic changes that occur in an Fe(0)–N2 unit (Fe(depe)2(N2); depe = 1,2-bis(diethylphosphino)ethane) upon the addition of exogenous ...Lewis acids. Addition of neutral boranes, alkali metal cations, and an Fe2+ complex increases the N–N bond activation (Δ νNN up to 172 cm–1), decreases the Fe(0)–N2 redox potential, polarizes the N–N bond, and enables –N protonation at uncommonly anodic potentials. These effects were rationalized using combined experimental and theoretical studies.
A new bifunctional pincer ligand framework bearing pendent proton-responsive hydroxyl groups was prepared and metalated with Ru(II) and subsequently isolated in four discrete protonation states. ...Stoichiometric reactions with H2 and HBPin showed facile E–H (E = H or BPin) activation across a Ru(II)–O bond, providing access to unusual Ru–H species with strong interactions with neighboring proton and boron atoms. These complexes were found to promote the catalytic hydroboration of ketones and nitriles under mild conditions, and the activity was highly dependent on the ligand’s protonation state. Mechanistic experiments revealed a crucial role of the pendent hydroxyl groups for catalytic activity.
Many disease pathologies can be understood through the elucidation of localized biomolecular networks, or microenvironments. To this end, enzymatic proximity labeling platforms are broadly applied ...for mapping the wider spatial relationships in subcellular architectures. However, technologies that can map microenvironments with higher precision have long been sought. Here, we describe a microenvironment-mapping platform that exploits photocatalytic carbene generation to selectively identify protein-protein interactions on cell membranes, an approach we term MicroMap (μMap). By using a photocatalyst-antibody conjugate to spatially localize carbene generation, we demonstrate selective labeling of antibody binding targets and their microenvironment protein neighbors. This technique identified the constituent proteins of the programmed-death ligand 1 (PD-L1) microenvironment in live lymphocytes and selectively labeled within an immunosynaptic junction.
We present a systematic investigation of the structural and electronic changes that occur in an Fe(0)-N
unit (Fe(depe)
(N
); depe = 1,2-bis(diethylphosphino)ethane) upon the addition of exogenous ...Lewis acids. Addition of neutral boranes, alkali metal cations, and an Fe
complex increases the N-N bond activation (Δ ν
up to 172 cm
), decreases the Fe(0)-N
redox potential, polarizes the N-N bond, and enables -N protonation at uncommonly anodic potentials. These effects were rationalized using combined experimental and theoretical studies.
Cell surface proteins represent ideal therapeutic targets because of their accessibility to antibodies, T cell-directed therapies, and radiotherapies, but there are only 25 therapeutically relevant ...cell surface targets for which cancer therapies are approved in the United States or European Union. This commentary calls for intensified research into mapping the universe of cell surface proteins - the cell surfaceome - in order to accelerate cancer drug development.
The difluoromethyl group (R–CF2H) imparts desirable pharmacokinetic properties to drug molecules and is commonly targeted as a terminal functional group that is not amenable to further modification. ...Deprotonation of widely available Ar–CF2H starting materials to expose nucleophilic Ar–CF2 – synthons represents an unexplored, yet promising route to construct benzylic Ar–CF2–R linkages. Here we show that the combination of a Brønsted superbase with a weak Lewis acid enables deprotonation of Ar–CF2H groups and capture of reactive Ar–CF2 – fragments. This route provides access to isolable and reactive Ar–CF2 – synthons that react with a broad array of electrophiles at room temperature. The methodology is highly general in both electrophile and difluoromethyl (hetero)arene and can be applied directly to the synthesis of benzylic difluoromethylene (Ar–CF2–R) linkages, which are useful lipophilic and metabolically resistant replacements for benzylic linkages in medicinal chemistry.
A fluoroform‐derived borazine CF3− transfer reagent is used to effect rapid nucleophilic reactions in the absence of additives, within minutes at 25 °C. Inorganic electrophiles spanning seven groups ...of the periodic table can be trifluoromethylated in high yield, including transition metals used for catalytic trifluoromethylation. Organic electrophiles included (hetero)arenes, enabling C−H and C−X trifluoromethylation reactions. Mechanistic analysis supports a dissociative mechanism for CF3− transfer, and cation modification afforded a reagent with enhanced stability.
A trifluoromethylating matter: A stable fluoroform‐derived reagent facilitates the nucleophilic trifluoromethylation of a broad array of inorganic and organic electrophiles (E) at room temperature. The reaction scope includes 18 inorganic elements, nucleophilic aromatic substitution, and CF3− addition to carbonyl and imine compounds. Kinetic analysis supports a dissociative mechanism.
We present a strategy to rationally prepare CF3 – transfer reagents at ambient temperature from HCF3. We demonstrate that a highly reactive CF3 – adduct can be synthesized from alkali metal hydride, ...HCF3, and borazine Lewis acids in quantitative yield at room temperature. These nucleophilic reagents transfer CF3 – to substrates without additional chemical activation, and after CF3 transfer, the free borazine is quantitatively regenerated. These features enable syntheses of popular nucleophilic, radical, and electrophilic trifluoromethylation reagents with complete recycling of the borazine Lewis acid.
Over half of new therapeutic approaches fail in clinical trials due to a lack of target validation. As such, the development of new methods to improve and accelerate the identification of cellular ...targets, broadly known as target ID, remains a fundamental goal in drug discovery. While advances in sequencing and mass spectrometry technologies have revolutionized drug target ID in recent decades, the corresponding chemical-based approaches have not changed in over 50 y. Consigned to outdated stoichiometric activation modes, modern target ID campaigns are regularly confounded by poor signal-to-noise resulting from limited receptor occupancy and low crosslinking yields, especially when targeting low abundance membrane proteins or multiple protein target engagement. Here, we describe a broadly general platform for photocatalytic small molecule target ID, which is founded upon the catalytic amplification of target-tag crosslinking through the continuous generation of high-energy carbene intermediates via visible light-mediated Dexter energy transfer. By decoupling the reactive warhead tag from the small molecule ligand, catalytic signal amplification results in unprecedented levels of target enrichment, enabling the quantitative target and off target ID of several drugs including (+)-JQ1, paclitaxel (Taxol), dasatinib (Sprycel), as well as two G-protein-coupled receptors-ADORA2A and GPR40.
Modular but geometrically constrained ligands were used to investigate the impact of key ligand design parameters (charge and bite angle) on CO2 hydrogenation and formic acid dehydrogenation ...activity. These studies yielded an optimized catalyst that achieved over 118 000 turnovers in CO2 hydrogenation, 247 000 turnovers in HCO2H dehydrogenation, was applied in a hydrogen storage device used for 6 cycles of hydrogen storage/release without requiring changes in pH or solvent, and generated H2/CO2 gas at a pressure of 190 atm from formic acid.
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