Metal-free photoinduced C(sp3)-H borylation of alkanes.

Boronic acids and their derivatives are some of the most useful reagents in the chemical sciences1, with applications spanning pharmaceuticals, agrochemicals and functional materials. Catalytic C-H borylation is a powerful method for introducing these and other boron groups into organic molecules because it can be used to directly functionalize C-H bonds of feedstock chemicals without the need for substrate pre-activation1-3. These reactions have traditionally relied on precious-metal catalysts for C-H bond cleavage and, as a result, display high selectivity for borylation of aromatic C(sp2)-H bonds over aliphatic C(sp3)-H bonds4. Here we report a mechanistically distinct, metal-free borylation using hydrogen atom transfer catalysis5, in which homolytic cleavage of C(sp3)-H bonds produces alkyl radicals that are borylated by direct reaction with a diboron reagent. The reaction proceeds by violet-light photoinduced electron transfer between an N-alkoxyphthalimide-based oxidant and a chloride hydrogen atom transfer catalyst. Unusually, stronger methyl C-H bonds are borylated preferentially over weaker secondary, tertiary and even benzylic C-H bonds. Mechanistic studies indicate that the high methyl selectivity is a result of the formation of a chlorine radical-boron 'ate' complex that selectively cleaves sterically unhindered C-H bonds. By using a photoinduced hydrogen atom transfer strategy, this metal-free C(sp3)-H borylation enables unreactive alkanes to be transformed into valuable organoboron reagents under mild conditions and with selectivities that contrast with those of established metal-catalysed protocols.

Simultaneous Stereoinvertive and Stereoselective C(sp3)-C(sp3) Cross-Coupling of Boronic Esters and Allylic Carbonates.

With increasing interest in constructing more three-dimensional entities, there has been growing interest in cross-coupling reactions that forge C(sp3)-C(sp3) bonds, which leads to additional challenges as it is not just a more difficult bond to construct but issues of stereocontrol also arise. Herein, we report the stereocontrolled cross-coupling of enantioenriched boronic esters with racemic allylic carbonates enabled by iridium catalysis, leading to the formation of C(sp3)-C(sp3) bonds with single or vicinal stereogenic centers. The method shows broad substrate scope, enabling primary, secondary, and even tertiary boronic esters to be employed, and can be used to prepare any of the four possible stereoisomers of a coupled product with vicinal chiral centers. The new method, which combines the simultaneous enantiospecific reaction of a chiral nucleophile with the enantioselective reaction of a chiral electrophile in a single process, offers a solution for stereodivergent cross-coupling of two C(sp3) fragments.

"In the wilderness dealing with difficult situations": Knowledge exchange with care home staff in England on managing seizures and epilepsy - An initial exploration.

PURPOSE: With epilepsy increasingly affecting older adults, seizure-related care needs arise in new settings. Persons in these settings must receive optimal support and challenges identified for remediation. This may entail the epilepsy community researching in unfamiliar environments. One setting is care homes. Seizure-related ambulance incidents in them are common. We conducted the first qualitative study with care home staff to explore their experiences and challenges in managing suspected seizures. METHODS: Three online focus groups were organised for January 2024 to explore ambulance calls, post-incident procedures, and challenges faced by care home staff when managing seizures. Persons were eligible to participate if they worked as a care assistant, nurse or manager in a care home in North-West England. Different recruitment pathways were employed including direct approach, a managers' network, social media and a register of research interested homes. Focus group audio recordings were transcribed and analysed using Hamilton's Rapid Analysis. RESULTS: Recruitment was difficult; 13 care home staff from 12 different homes were ultimately recruited. Despite data saturation not being achieved, insights were gained regarding ambulance call decisions, paperwork navigation, and follow-up care challenges. Patients not having meaningful seizure action plans in place and regulatory restrictions were identified as factors that contributed to potentially avoidable calls for ambulance help being made. CONCLUSION: This study highlights systemic issues in care homes' seizure care, emphasizing the need for further research. The epilepsy community may need to innovate to better research within this increasingly important setting. This study offers insights into the effectiveness of different recruitment strategies.

'Knowledge exchange' workshops to optimise development of a risk prediction tool to assist conveyance decisions for suspected seizures - Part of the Risk of ADverse Outcomes after a Suspected Seizure (RADOSS) project.

PURPOSE: Suspected seizures present challenges for ambulance services, with paramedics reporting uncertainty over whether or not to convey individuals to emergency departments. The Risk of ADverse Outcomes after a Suspected Seizure (RADOSS) project aims to address this by developing a risk assessment tool utilizing structured patient care record and dispatch data. It proposes a tool that would provide estimates of an individual's likelihood of death and/or recontact with emergency care within 3 days if conveyed compared to not conveyed, and the likelihood of an 'avoidable attendance' occurring if conveyed. Knowledge Exchange workshops engaged stakeholders to resolve key design uncertainties before model derivation. METHOD: Six workshops involved 26 service users and their significant others (epilepsy or nonepileptic attack disorder), and 25 urgent and emergency care clinicians from different English ambulance regions. Utilizing Nominal Group Techniques, participants shared views of the proposed tool, benefits and concerns, suggested predictors, critiqued outcome measures, and expressed functionality preferences. Data were analysed using Hamilton's Rapid Analysis. RESULTS: Stakeholders supported tool development, proposing 10 structured variables for predictive testing. Emphasis was placed on the tool supporting, not dictating, care decisions. Participants highlighted some reasons why RADOSS might struggle to derive a predictive model based on structured data alone and suggested some non-structured variables for future testing. Feedback on prediction timeframes for service recontact was received, along with advice on amending the 'avoidable attendance' definition to prevent the tool's predictions being undermined by potential overuse of certain investigations in hospital. CONCLUSION: Collaborative stakeholder engagement provided crucial insights that can guide RADOSS to develop a user-aligned, optimized tool.

Convergent Deboronative and Decarboxylative Phosphonylation Enabled by the Phosphite Radical Trap "BecaP".

Carbon-phosphorus bond formation is significant in synthetic chemistry because phosphorus-containing compounds offer numerous indispensable biochemical roles. While there is a plethora of methods to access organophosphorus compounds, phosphonylations of readily accessible alkyl radicals to form aliphatic phosphonates are rare and not commonly used in synthesis. Herein, we introduce a novel phosphorus radical trap "BecaP" that enables facile and efficient phosphonylation of alkyl radicals under visible light photocatalytic conditions. Importantly, the ambiphilic nature of BecaP allows redox neutral reactions with both nucleophilic (activated by single-electron oxidation) and electrophilic (activated by single-electron reduction) alkyl radical precursors. Thus, a broad scope of feedstock alkyl potassium trifluoroborate salts and redox active carboxylate esters could be employed, with each class of substrate proceeding through a distinct mechanistic pathway. The mild conditions are applicable to the late-stage installation of phosphonate motifs into medicinal agents and natural products, which is showcased by the straightforward conversion of baclofen (muscle relaxant) to phaclofen (GABAB antagonist).

Copper-Mediated Dehydrogenative C(sp3)-H Borylation of Alkanes.

Borylations of inert carbon-hydrogen bonds are highly useful for transforming feedstock chemicals into versatile organoboron reagents. Catalysis of these reactions has historically relied on precious-metal complexes, which promote dehydrogenative borylations with diboron reagents under oxidant-free conditions. Recently, photoinduced radical-mediated borylations involving hydrogen atom transfer pathways have emerged as attractive alternatives because they provide complimentary regioselectivities and proceed under metal-free conditions. However, these net oxidative processes require stoichiometric oxidants and therefore cannot compete with the high atom economy of their precious-metal-catalyzed counterparts. Herein, we report that CuCl2 catalyzes radical-mediated, dehydrogenative C(sp3)-H borylations of alkanes with bis(catecholato)diboron under oxidant-free conditions. This is a result of an unexpected dual role of the copper catalyst, which promotes oxidation of the diboron reagent to generate an electrophilic bis-boryloxide that acts as an effective borylating agent in subsequent redox-neutral photocatalytic C-H borylations.

Iridium-Catalyzed Asymmetric Difunctionalization of C-C σ-Bonds Enabled by Ring-Strained Boronate Complexes.

Enantioenriched organoboron intermediates are important building blocks in organic synthesis and drug discovery. Recently, transition metal-catalyzed enantioselective 1,2-metalate rearrangements of alkenylboronates have emerged as an attractive protocol to access these valuable reagents by installing two different carbon fragments across C═C π-bonds. Herein, we report the development of an iridium-catalyzed asymmetric allylation-induced 1,2-metalate rearrangement of bicyclo[1.1.0]butyl (BCB) boronate complexes enabled by strain release, which allows asymmetric difunctionalization of C-C σ-bonds, including dicarbonation and carboboration. This protocol provides a variety of enantioenriched three-dimensional 1,1,3-trisubstituted cyclobutane products bearing a boronic ester that can be readily derivatized. Notably, the reaction gives trans diastereoisomers that result from an anti-addition across the C-C σ-bond, which is in contrast to the syn-additions observed for reactions promoted by PdII-aryl complexes and other electrophiles in our previous works. The diastereoselectivity has been rationalized based on a combination of experimental data and density functional theory calculations, which suggest that the BCB boronate complexes are highly nucleophilic and react via early transition states with low activation barriers.

Statins as an antiepileptogenic or disease-modifying treatment? A survey of what UK patients and significant others think about repurposing and trialing them for epilepsy.

OBJECTIVE: To identify the views of people with epilepsy (PWE), and their significant others, on the repurposing and trialing of statins as a potential antiepileptogenic or disease-modifying treatment for those who have had the first seizure. METHODS: Online questionnaire. Participants needed to be aged ≥ 16 years, UK residents, and able to independently complete a questionnaire in English. User groups distributed study adverts. Embedded infographics explained repurposing, why anti-seizure treatment is not typically started after a first seizure and the nature of randomized placebo-controlled trials (RCTs). The questionnaire asked participants to reflect and rate their expected willingness to have started an unspecified treatment after their first seizure/s (or that of the person with epilepsy they knew). They also rated willingness if the treatment were a statin, views of statins, the importance of an RCT of statins to their community, the outcomes it should assess, and their willingness to have taken part in it. The estimated number needed for the survey was 324. RESULTS: Responses from 213 persons were analyzed; 111 (52.1%) were PWE and 102 (47.9%) significant others. The median years diagnosed was 10 and PWE suffered from relatively severe epilepsy. One hundred and seventeen (54.9%) said they would have started an unspecified treatment after their first seizure/s (or supported the person with epilepsy they knew to have). A similar proportion (55.4%) said they would have started the treatment if it were a statin. Participants' main concern about statins, expressed by 79%, was their possible side effects. Repurposing was a concern for only 25%. Most (85.8%) rated an RCT of statins as of extreme or high importance; 54.4% said they would have participated. CONCLUSION: The PWE and significant others (SOs) responding to our survey expressed views towards repurposing statins that were generally positive and indicate a trial in those who have had a first seizure might be feasible. Concerns regarding side effects are common. Our findings could help optimize a future trial's design and the case for funding. Limitations include that we did not survey persons who had experienced a first seizure and did not go on to develop epilepsy. Also, persons with uncontrolled epilepsy were overrepresented.

Raring to go? A cross-sectional survey of student paramedics on how well they perceive their UK pre-registration course to be preparing them to manage suspected seizures.

BACKGROUND: Paramedics convey a high proportion of seizure patients with no clinical need to emergency departments (EDs). In a landmark study, only 27% of UK paramedics reported being "Very…"/ "Extremely confident" making seizure conveyance decisions. Improved pre-registration education on seizures for paramedics is proposed. Clarity is needed on its potential given recent changes to how UK paramedics train (namely, degree, rather than brief vocational course). This study sought to describe UK student paramedics' perceived readiness to manage seizures and educational needs; compare this to what they report for other presentations; and, explore subgroup differences. METHODS: Six hundred thirty-eight students, in year 2 or beyond of their pre-registration programme completed a cross-sectional survey. They rated perceived confidence, knowledge, ability to care for, and educational needs for seizures, breathing problems and, headache. Primary measure was conveyance decision confidence. RESULTS: For seizures, 45.3% (95% CI 41.4-49.2) said they were "Very…"/"Extremely confident" to make conveyance decisions. This was similar to breathing problems, but higher than for headache (25.9%, 95% CI 22.6-29.5). Two hundred and thirty-nine participants (37.9%, 95% CI 34.1-41.8) said more seizure education was required - lower than for headache, but higher than for breathing problems. Subgroup differences included students on university-based programmes reporting more confidence for conveyance decisions than those completing degree level apprenticeships. CONCLUSIONS: Student paramedics report relatively high perceived readiness for managing seizures. Magnitude of benefit from enhancements to pre-registration education may be more limited than anticipated. Additional factors need attention if a sizeable reduction to unnecessary conveyances for seizures is to happen.

Photoredox-Catalyzed Decarboxylative Bromination, Chlorination and Thiocyanation Using Inorganic Salts.

Decarboxylative halogenation reactions of alkyl carboxylic acids are highly valuable reactions for the synthesis of structurally diverse alkyl halides. However, many reported protocols rely on stoichiometric strong oxidants or highly electrophilic halogenating agents. Herein, we describe visible-light photoredox-catalyzed decarboxylative halogenation reactions of N-hydroxyphthalimide-activated carboxylic acids that avoid stoichiometric oxidants and use inexpensive inorganic halide salts as the halogenating agents. Bromination with lithium bromide proceeds under simple, transition-metal-free conditions using an organic photoredox catalyst and no other additives, whereas dual photoredox-copper catalysis is required for chlorination with lithium chloride. The mild conditions display excellent functional-group tolerance, which is demonstrated through the transformation of a diverse range of structurally complex carboxylic acid containing natural products into the corresponding alkyl bromides and chlorides. In addition, we show the generality of the dual photoredox-copper-catalyzed decarboxylative functionalization with inorganic salts by extension to thiocyanation with potassium thiocyanide, which was applied to the synthesis of complex alkyl thiocyanates.

Strain-Release Driven Epoxidation and Aziridination of Bicyclo[1.1.0]butanes via Palladium Catalyzed σ-Bond Nucleopalladation.

The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and aziridines containing a cyclobutane motif. In a two-step one-pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross-coupled with an aryl triflate through C-C σ-bond alkoxy- or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring-opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three-dimensional structures into target molecules.

Stereospecific Conversion of Boronic Esters into Enones using Methoxyallene: Application in the Total Synthesis of 10-Deoxymethynolide.

Enones are widely utilized linchpin functional groups in chemical synthesis and molecular biology. We herein report the direct conversion of boronic esters into enones using commercially available methoxyallene as a three-carbon building block. Following boronate complex formation by reaction of the boronic ester with lithiated-methoxyallene, protonation triggers a stereospecific 1,2-migration before oxidation generates the enone. The protocol shows broad substrate scope and complete enantiospecificity is observed with chiral migrating groups. In addition, various electrophiles could be used to induce 1,2-migration and give a much broader range of α-functionalized enones. Finally, the methodology was applied to a 14-step synthesis of the enone-containing polyketide 10-deoxymethynolide.

Stereocontrolled Total Synthesis of Bastimolide B Using Iterative Homologation of Boronic Esters.

Bastimolide B is a polyhydroxy macrolide isolated from marine cyanobacteria displaying antimalarial activity. It features a dense array of hydroxylated stereogenic centers with 1,5-relationships along a hydrocarbon chain. These 1,5-polyols represent a particularly challenging motif for synthesis, as the remote position of the stereocenters hampers stereocontrol. Herein, we present a strategy for 1,5-polyol stereocontrolled synthesis based on iterative boronic ester homologation with enantiopure magnesium carbenoids. By merging boronic ester homologation and transition-metal-catalyzed alkene hydroboration and diboration, the acyclic backbone of bastimolide B was rapidly assembled from readily available building blocks with full control over the remote stereocenters, enabling the total synthesis to be completed in 16 steps (LLS).

Worth the paper they are printed on? Findings from an independent evaluation of the understandability of patient information leaflets for antiseizure medications.

OBJECTIVE: The Patient Information Leaflet (PIL) is an authoritative document that all people with epilepsy in the EU receive when prescribed antiseizure medication (ASM). We undertook the first independent, comprehensive assessment to determine how understandable they are. Regulators state that when patients are asked comprehension questions about them, ≥80% should answer correctly. Also, recommended is that PILs have a maximum reading requirement of US grade 8. METHODS: Study 1: We obtained 140 current ASM PILs written in English. "Readability" was assessed using four tests, with and without adjustment for influence of familiar, polysyllabic words. A total of 179 online materials on epilepsy were also assessed. Study 2: Two PILs from Study 1 were randomly selected (Pregabalin Focus; Inovelon) and shown to 35 people from the UK epilepsy population. Their comprehension was assessed. Study 3: To understand whether the student population provides an accessible alternative population for future examination of ASM PILs, Study 3 was completed, using the same methods as Study 2, except that participants were 262 UK university students. RESULTS: Study 1: No PIL had a reading level of grade 8. Median was grade 11. Adjusting for context, the PILs were still at grade 10.5. PILs for branded ASMs were most readable. PILs were no more readable than (unregulated) online materials. Study 2: Users struggled to comprehend the PILs' key messages. The eight questions asked about pregabalin were typically answered correctly by 54%. For Inovelon, it was 62%. Study 3: Most student participants comprehended the PILs' key messages. The questions about Inovelon were answered correctly by 90%; for pregabalin it was 86%. SIGNIFICANCE: This is the first independent and comprehensive examination of ASM PILs. It found that PILs being used fail to meet recommendations and regulatory requirements and risk not being understandable to a substantial proportion of users. In finding that people from the epilepsy population differ markedly in comprehension of PILs compared to students, this study highlights the importance of completing user testing with the target population.

Diastereodivergent Synthesis of Cyclopentyl Boronic Esters Bearing Contiguous Fully Substituted Stereocenters.

The synthesis of molecules bearing two or more contiguous, quaternary stereocenters is challenging, owing to the difficulty in controlling stereochemistry whilst simultaneously constructing a sterically congested motif. Herein, we report the electrophile-induced ring contractive 1,2-metallate rearrangement of 6-membered cyclic alkenyl boronate complexes for the synthesis of cyclopentyl boronic esters bearing two contiguous, fully substituted stereocenters with high levels of stereocontrol. Remarkably, simple variation of the reaction solvent enabled their diastereodivergent construction with facile access to complementary diastereomeric pairs. The utility of our methodology is demonstrated in the asymmetric total synthesis of (+)-herbertene-1,14-diol.

Strain-Release-Driven Friedel-Crafts Spirocyclization of Azabicyclo[1.1.0]butanes.

The identification of spiro N-heterocycles as scaffolds that display structural novelty, three-dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain-release-driven Friedel-Crafts spirocyclization of azabicyclo[1.1.0]butane-tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro-tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel-Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel-Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels-Alder adduct in one-pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain-release-driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.

Facile Conversion of α-Amino Acids into α-Amino Phosphonates by Decarboxylative Phosphorylation using Visible-Light Photocatalysis.

Amino phosphonates exhibit potent inhibitory activity for a wide range of biological processes due to their specific structural and electronic properties, making them important in a plethora of applications, including as enzyme inhibitors, herbicides, antiviral, antibacterial, and antifungal agents. While the traditional synthesis of α-amino phosphonates has relied on the multicomponent Kabachnik-Fields reaction, we herein describe a novel and facile conversion of activated derivatives of α-amino acids directly to their respective α-amino phosphonate counterparts via a decarboxylative radical-polar crossover process enabled by the use of visible-light organophotocatalysis. The novel method shows broad applicability across a range of natural and synthetic amino acids, operates under mild conditions, and has been demonstrated to successfully achieve the late-stage functionalization of drug molecules.

Four-Component Strain-Release-Driven Synthesis of Functionalized Azetidines.

Despite the favorable properties that azetidine rings can engender on drug-compounds, methods for the diversity-oriented synthesis of azetidine-based structures are significantly underdeveloped. Herein, we report the successful realization of a multicomponent [1,2]-Brook rearrangement/strain-release-driven anion relay sequence and its application to the modular synthesis of substituted azetidines. The rapidity of the reaction, as confirmed by in situ infra-red spectroscopy, leverages the strain-release ring-opening of azabicyclo[1.1.0]butane to drive the equilibrium of the Brook rearrangement. The three electrophilic coupling partners, added sequentially to azabicyclo[1.1.0]butyl-lithium, could be individually varied to access a diverse compound library. The utility of this methodology was demonstrated in a 4-step synthesis of the EP2 receptor antagonist PF-04418948.

Dual Nickel/Photoredox-Catalyzed Site-Selective Cross-Coupling of 1,2-Bis-Boronic Esters Enabled by 1,2-Boron Shifts.

Site-selective transition-metal-catalyzed mono-deboronative cross-couplings of 1,2-bis-boronic esters are valuable methods for the synthesis of functionalized organoboron compounds. However, such cross-couplings are limited to reaction of the sterically less hindered primary boronic ester. Herein, we report a nickel/photoredox-catalyzed mono-deboronative arylation of 1,2-bis-boronic esters that is selective for coupling of the more sterically hindered secondary/tertiary position. This is achieved by taking advantage of a 1,2-boron shift of primary ß-boryl radicals to the thermodynamically favored secondary/tertiary radicals, which are subsequently intercepted by the nickel catalyst to enable arylation. The mild conditions are amenable to a broad range of aryl halides to give ß-aryl boronic ester products in good yields and with high regioselectivity. This method also allows stereodivergent coupling of cyclic cis-1,2-bis-boronic esters to give trans-substituted products.

Selective Coupling of 1,2-Bis-Boronic Esters at the more Substituted Site through Visible-Light Activation of Electron Donor-Acceptor Complexes.

1,2-Bis-boronic esters are useful synthetic intermediates particularly as the two boronic esters can be selectively functionalized. Usually, the less hindered primary boronic ester reacts, but herein, we report a coupling reaction that enables the reversal of this selectivity. This is achieved through the formation of a boronate complex with an electron-rich aryllithium which, in the presence of an electron-deficient aryl nitrile, leads to the formation of an electron donor-acceptor complex. Following visible-light photoinduced electron transfer, a primary radical is generated which isomerizes to the more stable secondary radical before radical-radical coupling with the arene radical-anion, giving ß-aryl primary boronic ester products. The reactions proceed under catalyst-free conditions. This method also allows stereodivergent coupling of cyclic cis-1,2-bis-boronic esters to provide trans-substituted products, complementing the selectivity observed in the Suzuki-Miyaura reaction.