Photochemical Organocatalytic Synthesis of Thioethers from Aryl Chlorides and Alcohols.

Thioethers, often found in pharmaceuticals and natural compounds, typically involve metal cross-coupling reactions, high temperatures, and the use of disagreeable thiols for their synthesis. Here we present a straightforward, thiol-free organocatalytic protocol that uses mild conditions to stitch together inexpensive alcohols and aryl chlorides, yielding a diverse array of aryl alkyl thioethers. Central to this approach was the discovery that tetramethylthiourea can serve as a simple sulfur source upon intercepting photochemically generated aryl radicals. To form radicals, we used a readily available indole thiolate organocatalyst that, when excited with 405 nm light, gained a strongly reducing power, enabling the activation of typically unreactive aryl chlorides via single-electron transfer. Radical trapping by the thiourea, followed by an alcohol attack via a polar path, resulted in the formation of thioether products.

Activity-Based Sensing of Ascorbate by Using Copper-Mediated Oxidative Bond Cleavage.

Ascorbate is an important biological reductant and enzyme cofactor. Although direct detection through ascorbate-mediated reduction is possible, this approach suffers from poor selectivity due to the wide range of cellular reducing agents. To overcome this limitation, we leverage reduction potential of ascorbate to mediate a copper-mediated oxidative bond cleavage of ether-caged fluorophores. The copper(II) complexes supported by a {bis(2-pyridylmethyl)}benzylamine or a {bis(2-pyridylmethyl)}(2-methoxybenzyl)amine ligand were identified as an ascorbate responsive unit and their reaction with ascorbate yields a copper-based oxidant that enables rapid benzylic oxidation and the release of an ether-caged dye (coumarin or fluorescein). The copper-mediated bond cleavage is specific to ascorbate and the trigger can be readily derivatized for tuning photophysical properties of the probes. The probes were successfully applied for the fluorometric detection of ascorbate in commercial food samples, human plasma, and serum, and within live cells by using confocal microscopy and flow cytometry.

Photoredox Organocatalysis for the Enantioselective Synthesis of 1,7-Dicarbonyl Compounds.

We describe an asymmetric organocatalytic method to synthesize 1,7-dicarbonyl compounds containing a ß-stereocenter. The chemistry relies on the formation of γ-keto radicals, generated upon oxidative ring opening of cyclobutanols mastered by an organic photoredox catalyst. These nonstabilized primary radicals are stereoselectively intercepted by an iminium ion intermediate, formed upon activation of aliphatic and aromatic enals by a chiral secondary amine catalyst. This organocatalytic photoredox method served to prepare scaffolds found in natural products and drug molecules.

Fluorescein-Containing Superoxide Probes with a Modular Copper-Based Trigger.

Fluorescein-derived superoxide probes featuring a copper(II) complex that can be activated by superoxide to initiate ether bond cleavage and uncage a fluorescein reporter for imaging in live cells are described. Compared to other superoxide sensing moieties, this bond cleavage strategy can be modularly adapted to fluorescent reporters with different properties without compromising the superoxide reactivity and selectivity. A green-emitting probe and its lysosome-targeting analogue have been successfully developed. Both probes are sensitive with more than 30-fold fluorescence enhancement towards superoxide and are highly selective with no significant response towards other reactive oxygen species. A structure-activity relationship study of the copper-based superoxide trigger showed that the secondary coordination environment of the copper(II) center is important for the superoxide reactivity and selectivity. The probes have been applied in imaging changes in intracellular superoxide level in live HeLa and HEK293T cells upon menadione stimulation and also in a cellular inflammation model in RAW 264.7 cells.