Intermolecular Asymmetric Arylative Dearomatization of 1-Naphthols.

Arylative dearomatization forms quaternary stereocenters in cyclic systems with the concomitant introduction of an aromatic ring. Pd-catalyzed arylative dearomatization, which uses conditions analogous to cross-coupling, has emerged as a powerful method in an intramolecular context. But translating this from intramolecular cyclizations to an intermolecular process has proven extremely challenging: examples are scarce, and those that exist have not been rendered enantioselective, despite the potential for broad application in medicinal chemistry and natural product synthesis.

A chiral hydrogen atom abstraction catalyst for the enantioselective epimerization of -diols.

Hydrogen atom abstraction is an important elementary chemical process but is very difficult to carry out enantioselectively. We have developed catalysts, readily derived from the Cinchona alkaloid family of natural products, which can achieve this by virtue of their chiral amine structure. The catalyst, following single-electron oxidation, desymmetrizes -diols by selectively abstracting a hydrogen atom from one carbon center, which then regains a hydrogen atom by abstraction from a thiol.

Assessment of Δ9-THC and Δ9-THCCOOH bias, precision, and ionization suppression/enhancement between solid tissue homogenate and supernatant by LC-MS-MS.

Liquid chromatography-triple quadrupole mass spectrometry (LC-MS-MS) assays are frequently utilized for screening and confirmatory purposes in the forensic toxicology laboratory. While these techniques are excellent for the targeted identification and quantitation of a wide variety of drug classes, validation and determining fit-for-purpose is a significant requirement for each method. In the USA, the American National Standards Institute and Academy Standards Board first edition of Standard 036 currently serves as a primary resource in forensic toxicology method validation and mandates that laboratories evaluate critical performance characteristics to help ensure the production of forensically defensible results.

Enantioselective Nitrene Transfer to Hydrocinnamyl Alcohols and Allylic Alcohols Enabled by Systematic Exploration of the Structure of Ion-Paired Rhodium Catalysts.

This work describes highly enantioselective nitrene transfer to hydrocinnamyl alcohols (benzylic C-H amination) and allylic alcohols (aziridination) using ion-paired Rh (II,II) complexes based on anionic variants of Du Bois' esp ligand that are associated with cinchona alkaloid-derived chiral cations. Directed by a substrate hydroxyl group, our previous work with these complexes had not been able to achieve high enantioselectivity on these most useful short-chain compounds, and we overcame this challenge through a combination of catalyst design and modified conditions. A hypothesis that modulation of the linker between the anionic sulfonate group and the central arene spacer might provide a better fit for shorter chain length substrates led to the development of a new biaryl-containing scaffold, which has allowed a broad scope for both substrate classes to be realized for the first time.

Identification and Biosynthesis of an N-Glucuronide Metabolite of Camonsertib.

Camonsertib is a novel ATR kinase inhibitor in clinical development for advanced cancers targeting sensitizing mutations. This article describes the identification and biosynthesis of an N-glucuronide metabolite of camonsertib. This metabolite was first observed in human hepatocyte incubations and was subsequently isolated to determine the structure, evaluate its stability as part of bioanalytical method development and for use as a standard for estimating its concentration in Phase I samples.

Tertiary Amides as Directing Groups for Enantioselective C-H Amination using Ion-Paired Rhodium Complexes.

Enantioselective C-H amination at a benzylic methylene is a vital disconnection towards chiral benzylamines. Here we disclose that butyric and valeric acid-derived tertiary amides can undergo highly enantioselective benzylic amination using an achiral anionic Rh complex that is ion-paired with a Cinchona alkaloid-derived chiral cation. A broad scope of compounds can be aminated encompassing numerous arene substitutions, amides, and two different chain lengths.

Application of sSPhos as a Chiral Ligand for Palladium-Catalyzed Asymmetric Allylic Alkylation.

Palladium-catalyzed asymmetric allylic alkylation is a versatile method for C-C bond formation. Many established classes of chiral ligands can perform allylic alkylation reactions enantioselectively, but identification of new ligand classes remains important for future development of the field. We demonstrate that enantiopure sSPhos, a bifunctional chiral monophosphine ligand, when used as its tetrabutyl ammonium salt, is a highly effective ligand for a benchmark Pd-catalyzed allylic alkylation reaction.

Catalytic, asymmetric carbon-nitrogen bond formation using metal nitrenoids: from metal-ligand complexes metalloporphyrins to enzymes.

The introduction of nitrogen atoms into small molecules is of fundamental importance and it is vital that ever more efficient and selective methods for achieving this are developed. With this aim, the potential of nitrene chemistry has long been appreciated but its application has been constrained by the extreme reactivity of these labile species. This liability however can be attenuated by complexation with a transition metal and the resulting metal nitrenoids have unique and highly versatile reactivity which includes the amination of certain types of aliphatic C-H bonds as well as reactions with alkenes to afford aziridines.

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant .

Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics).

sSPhos: A General Ligand for Enantioselective Arylative Phenol Dearomatization via Electrostatically-Directed Palladium Catalysis.

Arylative phenol dearomatization affords complex, cyclohexanone-based scaffolds from simple starting materials, and asymmetric versions allow access to valuable enantioenriched structures. However, bespoke chiral ligands must typically be identified for each new scaffold variation. We have addressed this limitation by applying the concept of electrostatically-directed palladium catalysis whereby the chiral sulfonated ligand sSPhos engages in electrostatic interactions with a phenolate substrate via its associated alkali metal cation.

-Selective amination of arene carboxylic acids rearrangement of acyl -hydroxylamines.

Direct amination of arene C-H bonds is an attractive disconnection to form aniline-derived building blocks. This transformation presents significant practical challenges; classical methods for -selective amination require strongly acidic or forcing conditions, while contemporary catalytic processes often require bespoke directing groups and/or precious metal catalysis. We report a mild and procedurally straightforward -selective amination of arene carboxylic acids, arising from a facile rearrangement of acyl -hydroxylamines without requiring precious metal catalysts.

Discovery and Development of the Enantioselective Minisci Reaction.

ConspectusThe class of reactions now known as Minisci reactions is broadly defined as the addition of nucleophilic carbon-based radicals to basic heteroarenes with subsequent rearomatization to form a new carbon-carbon bond. Since the pioneering work of Minisci in the 1960s and 1970s, these reactions are now widely used in medicinal chemistry due to the ubiquity of basic heterocycles in druglike molecules. One of the long-standing challenges of Minisci chemistry has been that of regioselectivity due to the mixtures of positional isomers commonly obtained on many substrates if there is a choice between similarly activated sites.

Substrate-Directed Enantioselective Aziridination of Alkenyl Alcohols Controlled by a Chiral Cation.

Alkene aziridination is a highly versatile transformation for the construction of chiral nitrogen-containing compounds. Inspired by the success of analogous substrate-directed epoxidations, we report an enantioselective aziridination of alkenyl alcohols, which enables asymmetric nitrene transfer to alkenes with varied substitution patterns, including those not covered by the current protocols. We believe that our method is effective because it is substrate-directed, exploiting a network of attractive non-covalent interactions between the substrate, an achiral dianionic rhodium(II,II) tetracarboxylate dimer, and its two associated cinchona alkaloid-derived cations.

He Kāinga Oranga: reflections on 25 years of measuring the improved health, wellbeing and sustainability of healthier housing.

This paper reflects on the influences and outcomes of He Kāinga Oranga/Housing and Health Research Programme over 25 years, and their impact on housing and health policy in Aotearoa and internationally. Working in partnership particularly with Māori and Pasifika communities, we have conducted randomised control trials which have shown the health and broad co-benefits of retrofitted insulation, heating and remediation of home hazards, which have underpinned government policy in the Warm Up NZ-Heat Smart programme and the Healthy Homes Standards for rental housing. These trials have been included as evidence in the WHO Housing and Health Guidelines and led to our designation as a WHO Collaborating Centre on Housing and Wellbeing.

Enantioselective Giese Additions of Prochiral α-Amino Radicals.

Amines featuring an adjacent stereocenter are important building blocks, and recent years have seen remarkable growth in methods forming these via prochiral α-amino radical intermediates. However, very few can exert control over the newly formed stereocenter. We disclose a strategy to overcome this in the context of one of the most widely used radical carbon-carbon bond forming reactions, the Giese reaction.

Strategies That Utilize Ion Pairing Interactions to Exert Selectivity Control in the Functionalization of C-H Bonds.

Electrostatic attraction between two groups of opposite charge, typically known as ion-pairing, offers unique opportunities for the design of systems to enable selectivity control in chemical reactions. Catalysis using noncovalent interactions is an established and vibrant research area, but it is noticeable that hydrogen bonding interactions are still the main interaction of choice in system design. Opposite charges experience the powerful force of Coulombic attraction and have the ability to exert fundamental influence on the outcome of reactions that involve charged reagents, intermediates or catalysts.

Indoor air quality, largely neglected and in urgent need of a refresh.

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An Enantioselective Suzuki-Miyaura Coupling To Form Axially Chiral Biphenols.

Axial chirality features prominently in molecules of biological interest as well as chiral catalyst designs, and atropisomeric 2,2'-biphenols are particularly prevalent. Atroposelective metal-catalyzed cross-coupling is an attractive and modular approach to access enantioenriched biphenols, and yet existing protocols cannot achieve this directly. We address this challenge through the use of enantiopure, sulfonated (), an existing ligand that has until now been used only in racemic form and that derives its chirality from an atropisomeric axis that is introduced through sulfonation.

Dung biomass smoke exposure impairs resolution of inflammatory responses to influenza infection.

Epidemiological studies associate biomass smoke with an increased risk for respiratory infections in children and adults in the developing world, with 500,000 premature deaths each year attributed to biomass smoke-related acute respiratory infections including infections caused by respiratory viruses. Animal dung is a biomass fuel of particular concern because it generates more toxic compounds per amount burned than wood, and is a fuel of last resort for the poorest households. Currently, there is little biological evidence on the effects of dung biomass smoke exposure on immune responses to respiratory viral infections.

An Aminative Rearrangement of O-(Arenesulfonyl)hydroxylamines: Facile Access to ortho-Sulfonyl Anilines.

Ortho-sulfonyl anilines are important building blocks for a range of applications. We report the discovery of an aromatic rearrangement reaction of O-(arenesulfonyl)hydroxylamines which leads directly to ortho-sulfonyl anilines through formation of a new C-N bond with excellent levels of regiocontrol for the ortho position(s) over all others. We establish that the rearrangement is proceeding through an intermolecular mechanism and propose that the regiocontrol observed is the result of attractive non-covalent interactions occurring during the C-N bond-forming step.

Hydrogen Atom Transfer Driven Enantioselective Minisci Reaction of Alcohols.

Catalytic enantioselective Minisci reactions have recently been developed but all instances so far utilize α-amino radical coupling partners. We report a substantial evolution of the enantioselective Minisci reaction that enables α-hydroxy radicals to be used, providing valuable enantioenriched secondary alcohol products. This is achieved through the direct oxidative coupling of two C-H bonds on simple alcohol and pyridine partners through a hydrogen atom transfer (HAT)-driven approach: a challenging process to achieve due to the numerous side reactions that can occur.

Enantioselective Intermolecular C-H Amination Directed by a Chiral Cation.

The enantioselective amination of C()-H bonds is a powerful synthetic transformation yet highly challenging to achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C-H amination, Rh(esp), with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired catalysts enable high levels of enantioselectivity to be achieved in the benzylic C-H amination of substrates bearing pendant hydroxyl groups.

Regioselective Radical Arene Amination for the Concise Synthesis of -Phenylenediamines.

The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactive -centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the arene position.