Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome.

The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3.

Tetraethylammonium Salts as Solid, Easy to Handle Ethylene Precursors and Their Application in Mizoroki-Heck Coupling.

In this study, we introduce a convenient Heck vinylation protocol that eliminates the requirement for ethylene gas as a coupling partner. In contrast to traditional methodologies, quaternary ammonium salts can serve as solid olefin precursors under ambient atmosphere conditions. The practicality of this method, distinguished by its convenience and safety in a one-pot reaction, renders it appealing for applications in research and discovery context.

The intriguing role of USP30 inhibitors as deubiquitinating enzymes from the patent literature since 2013.

Introduction: Ubiquitin specific peptidase 30 (USP30) is a mitochondrial deubiquitinase that antagonizes ubiquitination-mediated mitophagy of damaged or impaired mitochondria driven by the activity of PARK2/Parkin ubiquitin ligase and PINK1 protein kinase. Researchers have related low levels of USP30 to enhanced mitophagy and therefore have been pursuing mitophagy activation utilizing USP30 inhibitors as an alternative approach to target neurodegenerative disorders and other human diseases associated with defective mitophagy.

Areas Covered: This review covers the research and patent literature on the discovery and development of USP30 inhibitors since 2013.

Relative Strength of Common Directing Groups in Palladium-Catalyzed Aromatic C-H Activation.

Efficient functionalization of C-H bonds can be achieved using transition metal catalysts, such as Pd(OAc). To better control the regioselectivity in these reactions, some functional groups on the substrate may be used as directing groups, guiding the reactivity to an ortho position. Herein, we describe a methodology to score the relative strength of such directing groups in palladium-catalyzed aromatic C-H activation.

Collected mass spectrometry data on monoterpene indole alkaloids from natural product chemistry research.

This Data Descriptor announces the submission to public repositories of the monoterpene indole alkaloid database (MIADB), a cumulative collection of 172 tandem mass spectrometry (MS/MS) spectra from multiple research projects conducted in eight natural product chemistry laboratories since the 1960s. All data have been annotated and organized to promote reuse by the community. Being a unique collection of these complex natural products, these data can be used to guide the dereplication and targeting of new related monoterpene indole alkaloids within complex mixtures when applying computer-based approaches, such as molecular networking.

General Cyclopropane Assembly by Enantioselective Transfer of a Redox-Active Carbene to Aliphatic Olefins.

Asymmetric cyclopropane synthesis currently requires bespoke strategies, methods, substrates, and reagents, even when targeting similar compounds. This approach slows down discovery and limits available chemical space. Introduced herein is a practical and versatile diazocompound and its performance in the first unified asymmetric synthesis of functionalized cyclopropanes.

Diastereospecific Gold(I)-Catalyzed Cyclization Cascade for the Controlled Preparation of N- and N,O-Heterocycles.

The reaction of oxime-tethered 1,6-enynes with a cationic gold(I) catalyst demonstrates a great potential for the synthesis of a range of heterocycles in a diastereospecific fashion. The control of the configuration of the oxime and the alkene of the enyne moiety is the key to selectively obtain dihydro-1,2-oxazines, isoxazolines or dihydropyrrole-N-oxides as single diastereoisomers. As supported by DFT calculations, these cascade reactions proceed stepwise, by the intramolecular addition of the O or N atom of the oxime onto cyclopropyl gold(I) carbene intermediates.

Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship.

The total synthesis of seven members of the lapidilectine and grandilodine family of alkaloids has been accomplished in racemic and enantiopure form without protection/deprotection of functional groups. The two key steps, an 8- endo-dig hydroarylation and a 6- exo-trig photoredox cyclization, were catalyzed using gold. A rationale for the formation of the cyclopropane ring of the lundurines is also provided.

Broad Scope Aminocyclization of Enynes with Cationic JohnPhos-Gold(I) Complex as the Catalyst.

A practical aminocyclization of 1,6-enynes with a wide variety of substituted anilines, including N-alkyl anilines, has been achived by using cationic [JohnPhosAu(MeCN)]SbF6 as a general purpose catalyst. The resulting adducts can be easily converted into polycyclic compounds by palladium- and gold-catalyzed reactions.

Gold carbene or carbenoid: is there a difference?

By reviewing the recent progress on the elucidation of the structure of gold carbenes and the definitions of metal carbenes and carbenoids, we recommend to use the term gold carbene to describe gold carbene-like intermediates, regardless of whether the carbene or carbocation extreme resonance dominates. Gold carbenes, because of the weak metal-to-carbene π-back-donation and their strongly electrophilic reactivity, could be classified into the broader family of Fischer carbenes, although their behavior and properties are very specific.

Enantioselective total synthesis of (-)-nardoaristolone B via a gold(I)-catalyzed oxidative cyclization.

The first enantioselective total synthesis of (-)-nardoaristolone B is accomplished by the implementation of an enantio- and diastereoselective copper(I)-catalyzed conjugate addition/enolate trapping sequence and a gold(I)-catalyzed oxidative cyclization (intermolecular oxidant), employed for the first time in total synthesis.

Meeting the challenge of intermolecular gold(I)-catalyzed cycloadditions of alkynes and allenes.

The development of gold(I)-catalyzed intermolecular carbo- and hetero-cycloadditions of alkynes and allenes has been more challenging than their intramolecular counterparts. Here we review, with a mechanistic perspective, the most fundamental intermolecular cycloadditions of alkynes and allenes with alkenes.

Formal (4+1) cycloaddition of methylenecyclopropanes with 7-aryl-1,3,5-cycloheptatrienes by triple gold(I) catalysis.

7-Aryl-1,3,5-cycloheptatrienes react intermolecularly with methylenecyclopropanes in a triple gold(I)-catalyzed reaction to form cyclopentenes. The same formal (4+1) cycloaddition occurs with cyclobutenes. Other precursors of gold(I) carbenes can also be used as the C1 component of the cycloaddition.

Exploiting a novel size exclusion phenomenon for enantioselective acid/base cascade catalysis.

A novel size exclusion phenomenon between PS-BEMP and sterically bulky BPAs, has been discovered and exploited in a one-pot base-catalysed Michael addition/acid-catalysed enantioselective N-acyliminium cyclisation cascade, allowing the preparation of structurally complex β-carbolines with moderate to good enantiocontrol.

Direct enantioselective Brønsted acid catalyzed N-acyliminium cyclization cascades of tryptamines and ketoacids.

A direct enantio- and diastereoselective N-acyliminium cyclization cascade through chiral phosphoric acid catalyzed condensation of tryptamines with γ- and δ-ketoacid derivatives to provide architecturally complex heterocycles has been developed. The reaction is technically simple to perform, atom-efficient, and broad in scope. Employing 10 mol % of (R)-BINOL derived chiral phosphoric acids in refluxing toluene allowed the polycyclic product materials to be generated in good yields (53-99%) and moderate to high enantioselectivities (68-98% ee).

Enantioselective Brønsted acid-catalyzed N-acyliminium cyclization cascades.

An enantioselective Brønsted acid-catalyzed N-acyliminium cyclization cascade of tryptamines with enol lactones to form architecturally complex heterocycles in high enantiomeric excess has been developed. The reaction is technically simple to perform as well as atom-efficient and may be coupled to a gold(I)-catalyzed cycloisomerization of alkynoic acids whereby the key enol lactone reaction partner is generated in situ. Employing up to 10 mol % bulky chiral phosphoric acid catalysts in boiling toluene allowed the product materials to be generated in good overall yields (63-99%) and high enantioselectivities (72-99% ee).