Cognitive impairment in people living with HIV: consensus recommendations for a new approach.

Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury - including active or pretreatment legacy damage - from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies.

Insight into Stereocontrol in the Asymmetric Intramolecular Allylation with a tert-Butylsulfinamide Nucleophile: Application in the Synthesis of Chiral Isoindoline-1-Carboxylic Acid Esters.

The asymmetric induction afforded by a chiral sulfinyl group in a palladium/Brønsted-acid-catalyzed intramolecular allylic amination was investigated. Predictions of the diastereoselectivity for various substrates under assumed total thermodynamic control were obtained from density functional theory (DFT), and the correlation with experimental data demonstrates abrupt changes to kinetic control across the substrate scope. The resulting heterocyclic product was readily converted to valuable isoindoline-1-carboxylic acid esters by a two-step oxidation sequence, providing asymmetric access to a key unnatural α-amino acid scaffold.

Analyzing mechanisms in Co(i) redox catalysis using a pattern recognition platform.

Redox catalysis has been broadly utilized in electrochemical synthesis due to its kinetic advantages over direct electrolysis. The appropriate choice of redox mediator can avoid electrode passivation and overpotential, which strongly inhibit the efficient activation of substrates in electrolysis. Despite the benefits brought by redox catalysis, establishing the precise nature of substrate activation remains challenging. Herein, we determine that a Co(i) complex bearing two N,N,N-tridentate ligands acts as a competent redox catalyst for the reduction of benzyl bromide substrates. Kinetic studies combining electroanalytical techniques with multivariable linear-regression analysis were conducted, disclosing an outer-sphere electron-transfer mechanism, which occurs in concert with C-Br bond cleavage. Furthermore, we apply a pattern recognition platform to distinguish between mechanisms in the activation of benzyl bromides, found to be dependent on the ligation state of the cobalt(i) center and ligand used.

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling.

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that nucleophilic attack to the π-allylpalladium intermediate is the enantio-determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C-O bonds at fully substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.

Mechanistic Studies into the Oxidative Addition of Co(I) Complexes: Combining Electroanalytical Techniques with Parameterization.

The oxidative addition of organic electrophiles into electrochemically generated Co(I) complexes has been widely utilized as a strategy to produce carbon-centered radicals when cobalt is ligated by a polydentate ligand. Changing to a bidentate ligand provides the opportunity to access discrete Co(III)-C bonded complexes for alternative reactivity, but knowledge of how ligand and/or substrate structures affect catalytic steps is pivotal to reaction design and catalyst optimization. In this vein, experimental studies that can determine the exact nature of elementary organometallic steps remain limited, especially for single-electron oxidative addition pathways. Herein, we utilize cyclic voltammetry combined with simulations to obtain kinetic and thermodynamic properties of the two-step, halogen-atom abstraction mechanism, validated by analyzing kinetic isotope and substituent effects. Complex Hammett relationships could be disentangled to allow understanding of individual effects on activation energy barriers and equilibrium constants, and DFT-derived parameters used to build predictive statistical models for rates of new ligand/substrate combinations.

A synthetic chemist's guide to electroanalytical tools for studying reaction mechanisms.

Monitoring reactive intermediates can provide vital information in the study of synthetic reaction mechanisms, enabling the design of new catalysts and methods. Many synthetic transformations are centred on the alteration of oxidation states, but these redox processes frequently pass through intermediates with short life-times, making their study challenging. A variety of electroanalytical tools can be utilised to investigate these redox-active intermediates: from voltammetry to in situ spectroelectrochemistry and scanning electrochemical microscopy. This perspective provides an overview of these tools, with examples of both electrochemically-initiated processes and monitoring redox-active intermediates formed chemically in solution. The article is designed to introduce synthetic organic and organometallic chemists to electroanalytical techniques and their use in probing key mechanistic questions.

Investigating the Role of Ligand Electronics on Stabilizing Electrocatalytically Relevant Low-Valent Co(I) Intermediates.

Cobalt complexes have shown great promise as electrocatalysts in applications ranging from hydrogen evolution to C-H functionalization. However, the use of such complexes often requires polydentate, bulky ligands to stabilize the catalytically active Co(I) oxidation state from deleterious disproportionation reactions to enable the desired reactivity. Herein, we describe the use of bidentate electronically asymmetric ligands as an alternative approach to stabilizing transient Co(I) species. Using disproportionation rates of electrochemically generated Co(I) complexes as a model for stability, we measured the relative stability of complexes prepared with a series of N, N-bidentate ligands. While the stability of Co(I)Cl complexes demonstrates a correlation with experimentally measured thermodynamic properties, consistent with an outer-sphere electron transfer process, the set of ligated Co(I)Br complexes evaluated was found to be preferentially stabilized by electronically asymmetric ligands, demonstrating an alternative disproportionation mechanism. These results allow a greater understanding of the fundamental processes involved in the disproportionation of organometallic complexes and have allowed the identification of cobalt complexes that show promise for the development of novel electrocatalytic reactions.

Stereospecific Allylic Functionalization: The Reactions of Allylboronate Complexes with Electrophiles.

Allylboronic esters react readily with carbonyls and imines (π-electrophiles), but are unreactive toward a range of other electrophiles. By addition of an aryllithium, the corresponding allylboronate complexes display enhanced nucleophilicity, enabling addition to a range of electrophiles (tropylium, benzodithiolylium, activated pyridines, Eschenmoser's salt, Togni's reagent, Selectfluor, diisopropyl azodicarboxylate (DIAD), MeSX) in high regio- and stereocontrol. This protocol provides access to key new functionalities, including quaternary stereogenic centers bearing moieties such as fluorine and the trifluoromethyl group. The allylboronate complexes were determined to be 7 to 10 orders of magnitude more reactive than the parent boronic ester.

Stereospecific functionalizations and transformations of secondary and tertiary boronic esters.

The formation of highly enantioenriched boronic esters through both stoichiometric and catalytic methods has received much attention over the past decade. Accordingly, the transformations of the boronic ester moiety into other functional groups is of considerable interest in synthesis. Specifically, transformations which retain the high enantioenrichment of the starting boronic ester, either through a stereoretentive or a stereoinvertive pathway, lead to the formation of new C-C, C-O, C-N, C-X, or C-H bonds at stereogenic centres. This feature article summarises the current state of the art in stereospecific transformations of both secondary and tertiary boronic esters into other functionalities and groups, whilst considering critically the transformations that are currently unattainable and would represent future advances to the field.

Merging Photoredox with 1,2-Metallate Rearrangements: The Photochemical Alkylation of Vinyl Boronate Complexes.

Vinyl boronates react with electron-deficient alkyl iodides in the presence of visible light to give boronic esters in which two new C-C bonds have been created. The reaction occurs by radical addition of an electron-deficient alkyl radical to the vinyl boronate followed by electron transfer with another molecule of alkyl iodide, continuing the chain, and triggering a 1,2-metalate rearrangement. In a number of cases, the use of a photoredox catalyst enhances yields significantly. The scope of the radical precursor includes α-iodo ketones, esters, nitriles, primary amides, α-fluorinated halo-acetates and perfluoroalkyl iodides.

Conjunctive functionalization of vinyl boronate complexes with electrophiles: a diastereoselective three-component coupling.

A method for the conjunctive functionalization of vinyl boronate complexes with electrophiles is described. The overall process represents a three-component coupling between a vinyl boronic ester, carbon nucleophile and an electrophile, thus affording complex multifunctionalized products from simple starting materials. The diastereoselectivity (syn or anti) of this process is strongly dependent upon the nature of the electrophile.

Enantiospecific Trifluoromethyl-Radical-Induced Three-Component Coupling of Boronic Esters with Furans.

In the presence of trifluoromethylsulfonium reagents, boronate complexes derived from 2-lithio furan and non-racemic secondary and tertiary alkyl or aryl boronic esters undergo deborylative three-component coupling to give the corresponding 2,5-disubstituted furans with excellent levels of enantiospecificity. The process proceeds via the reaction of boronate complexes with a trifluoromethyl radical, which triggers 1,2-metallate rearrangement upon single-electron oxidation. Alternative electrophiles can also be used in place of trifluoromethylsulfonium reagents to effect similar three-component coupling reactions.

Bifunctional Iminophosphorane Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α-Substituted Acrylate Esters.

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated α-substituted acrylate esters catalyzed by a bifunctional iminophosphorane organocatalyst under mild conditions is described. The strong Brønsted basicity of the iminophosphorane moiety of the catalyst provides the necessary activation of the alkyl thiol pro-nucleophile, while the two tert-leucine residues flanking a central thiourea hydrogen-bond donor facilitate high enantiofacial selectivity in the protonation of the transient enolate intermediate. The reaction is broad in scope with respect to the alkyl thiol, the ester moiety, and the α-substituent of the α,ß-unsaturated ester, affords sulfa-Michael adducts in excellent yields (up to >99%) and enantioselectivities (up to 96% ee), and is amenable to decagram scale-up using catalyst loadings as low as 0.05 mol %.

Synthesis of Enantioenriched Alkylfluorides by the Fluorination of Boronate Complexes.

The enantiospecific conversion of chiral secondary boronic esters into alkylfluorides is reported. Boronate complexes derived from boronic esters and PhLi were used as nucleophiles, with Selectfluor II as the electrophilic fluorinating agent, to afford alkylfluorides in short reaction times. The addition of styrene as a radical trap was found to enhance enantiospecificity. A broad range of alkyl boronic esters were converted into alkylfluorides with almost complete enantiospecificity by this method.

Evaluation of PIMA point-of-care CD4 testing in a large UK HIV service.

OBJECTIVES: To evaluate the performance and patient acceptability of the PIMA point-of-care (POCT) CD4 test. METHODS: Parallel POCT and laboratory CD4 testing were performed in newly diagnosed HIV patients and those with chronic infection attending routine or emergency clinics. Demographics, clinical status and time taken for CD4 results to be available were recorded. Patient acceptability was assessed using a five-point Likert scale. POCT and laboratory results were compared. RESULTS: 283 patients underwent POCT and laboratory CD4 testing. Paired laboratory and POCT results were available in 269 patients. After excluding 15 patients tested during the lead-in period, the test comparison was based on 254 results. Most patients were asymptomatic, male and white British reflecting this patient cohort. 236 patients were chronically infected and 47 were newly diagnosed HIV positive. The POCT result was available within 30 min (86%). The laboratory and POCT results were strongly correlated, r=0.93 (p<0.001), but were generally lower for the POCT (201/254 (79%): p<0.001). As a percentage of the laboratory count, the median (95% range) POCT was 87% (57%-126%). The difference between the POCT and laboratory result was greater for those patients attending the emergency clinic. The sensitivity and specificity of the POCT, to identify patients with laboratory CD4 below 350, were 95% (95% CI 88% to 98%) and 88% (95% CI 82% to 93%), respectively. 235 (83%) patients completed the questionnaire and the POCT was highly acceptable. CONCLUSIONS: POCT CD4 was highly correlated with laboratory CD4 testing in this cohort, provided immediate results and was highly acceptable to patients.