Photocatalytic Vicinal Aminopyridylation of Methyl Ketones by a Double Umpolung Strategy.

A photocatalytic double umpolung strategy for the vicinal aminopyridylation of ketones was developed using pyridinium N-N ylides. The inversion of the polarity of the pyridinium N-N ylides by single-electron oxidation successfully enables radical-mediated 1,3-dipolar cycloadditions with enolsilanes formed in situ from ketones, followed by homolytic cleavage of the N-N bond. Intriguingly, the nucleophilic amino and electrophilic pyridyl groups in the ylides can be installed at the nucleophilic α-position and electrophilic carbonyl carbon, respectively, which are typically inaccessible by their innate polarity-driven reactivity. This method accommodates a broad scope, and the utility was further demonstrated by the late-stage functionalization of complex biorelevant molecules. Moreover, the strategy can be successfully applied to enamides.

N-Heterocyclic carbene-catalyzed deaminative cross-coupling of aldehydes with Katritzky pyridinium salts.

By employing an N-heterocyclic carbene (NHC) catalyst, we developed a versatile catalytic system that enables deaminative cross-coupling reactions of aldehydes with redox-active pyridinium salts. Katritzky pyridinium salts behave as single-electron oxidants capable of generating alkyl radicals enabled by the redox properties of the enolate form of Breslow intermediates. The resultant alkyl radical undergoes efficient recombination with the NHC-bound aldehyde-derived carbonyl carbon radical for the formation of a C-C bond. The mild and transition metal-free reaction conditions tolerate a broad range of functional groups, and its utility has been further demonstrated by the modification of a series of peptide feedstocks and application to the three-component dicarbofunctionalization of olefins.

Visible-Light-Induced C-O Bond Formation for the Construction of Five- and Six-Membered Cyclic Ethers and Lactones.

Visible-light-induced intramolecular C-O bond formation was developed using 2,4,6-triphenylpyrylium tetrafluoroborate (TPT), which allows the regiocontrolled construction of cyclic ethers and lactones. The reaction is likely to proceed through the single-electron oxidation of the phenyl group, followed by the formation of a benzylic radical, thus preventing a competing 1,5-hydrogen abstraction pathway. Detailed mechanistic studies suggest that molecular oxygen is used to trap the radical intermediate to form benzyl alcohol, which undergoes cyclization. This new approach serves as a powerful platform by providing efficient access to valuable five- and six-membered cyclic ethers and lactones with a unified protocol.

Palladium(II)-Catalyzed Tandem Synthesis of Acenes Using Carboxylic Acids as Traceless Directing Groups.

A straightforward synthetic strategy for generating useful anthracene derivatives was developed involving palladium(II)-catalyzed tandem transformation with carboxylic acids as traceless directing groups. Carboxyl-directed C-H alkenylation, carboxyl-directed secondary C-H activation and rollover, intramolecular C-C bond formation, and decarboxylative aromatization are proposed as the key steps in the tandem reaction pathway. This novel synthetic route utilizes a broad range of substrates and provides a convenient synthetic tool that allows access to acenes.

Identification of ß-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma.

The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high-throughput screening and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar ß-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and ß-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure-activity relationships by incorporating electron-withdrawing substituents at C8 position of ß-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.