Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important α-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.

A solution to the unmet synthetic challenge of achieving highly atropo-enantioselective transesterification of Bringmann's lactones has been realized, employing a chiral bifunctional amine thiourea as promoter. The synergistic activation of the lactones and alcohols/phenols by the respective thiourea and amine groups is crucial for achieving the highly enantioselective, high-yielding dynamic kinetic resolution process. This protocol gives highly optically pure, axially chiral biaryl compounds with a broad substrate scope under mild reaction conditions.

An approach for efficient synthesis of Cglycosyl amino acids is described. Different from typical photoredox-catalyzed reactions of imines, the new process follows a pathway in which α-imino esters serve as electrophiles in chemoselective addition reactions with nucleophilic glycosyl radicals. The process is highlighted by the mild nature of the reaction conditions, the highly stereoselectivity attending C−C bond formation, and its applicability to C-glycosylations using both armed and disarmed pentose and hexose derivatives.C-Glycosyl amino acids are a unique class of compounds widely present in nature that have an enormously diverse array of biological properties. 1 Notable examples of substances in this family include the peptidyl nucleoside antibiotics amipurimycin, polyoxins, and nikkomycin, which have potent antimycotic activities against various human pathogenic fungi and bacteria (Scheme 1A). 2,3 More pronounced impacts of Cglycosyl amino acids arise from their broad application in biomedical and drug discovery studies of glycopeptides and proteins. 4,5 Finally, the presence of C−C linkages to anomeric centers gives members of this family higher metabolic stabilities and lipophilicities than those of O−C bondcontaining counterparts. In many instances, this feature leads to improved biological activities, membrane permeabilities, and bioavailabilities. 4,5 In routes developed to date for the synthesis of C-glycosyl amino acids, installation of an amino acid moiety onto a glycosyl framework has relied on the use of well-established αamino acid synthesis strategies, such as alkylation of α-amino acid equivalents, Strecker reactions, hydrogenation of dehydroamino acids, and multicomponent Ugi reactions with sugar derivatives (Scheme 1B). 6 In addition, de novo synthesis of Cglycosyl amino acids has been shown to be a viable approach to access unnatural substances in this family. Although often reliable, these polar bond disconnection based methods are inherently limited by a number of factors including the need for lengthy synthetic sequences, harsh reaction conditions, and/or a limited substrate scope. 7 As part of a recent program to develop radical-based crosscoupling processes for selective C−C bond formation, 8 we envisaged that an open-shell pathway might be applicable to the concise synthesis of C-glycosyl amino acids under mild conditions. 9,10 Specifically, we believed that addition of glycosyl radicals, generated from appropriate glycosyl pre-cursors, to readily available α-imino esters would constitute a viable approach to the preparation of these substances (Scheme 1C). To our knowledge, a strategy of this type has

A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel- and organic-dye-mediated photoredox catalysis is reported. Distinct from widely used palladium-catalyzed formylation processes, this reaction proceeds by a two-step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN-mediated photoredox reaction. The formyl-radical equivalent then undergoes nickel-catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products. Significantly, besides aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. Since the mild conditions involved in this reaction tolerate a plethora of functional groups, the process can be applied to the efficient preparation of diverse aromatic aldehydes.

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