D4-Symmetric Dirhodium Tetrakis(binaphthylphosphate) Catalysts for Enantioselective Functionalization of Unactivated C-H Bonds.

Dirhodium tetrakis(2,2'-binaphthylphosphate) catalysts were successfully developed for asymmetric C-H functionalization with trichloroethyl aryldiazoacetates as the carbene precursors. The 2,2'-binaphthylphosphate (BNP) ligands were modified by introduction of aryl and/or chloro functionality at the 4,4',6,6' positions. As the BNP ligands are C2-symmetric, the resulting dirhodium tetrakis(2,2'-binaphthylphosphate) complexes were expected to be D4-symmetric, but X-ray crystallographic and computational studies revealed this is not always the case because of internal T-shaped CH-π and aryl-aryl interactions between the ligands. The optimum catalyst is Rh2(S-megaBNP)4, with 3,5-di(tert-butyl)phenyl substituents at the 4,4' positions and chloro substituents at the 6,6' positions. This catalyst adopts a D4-symmetric arrangement and is ideally suited for site-selective C-H functionalization at unactivated tertiary sites with high levels of enantioselectivity, outperforming the best dirhodium tetracarboxylate catalyst developed for this reaction. The standard reactions were conducted with a catalyst loading of 1 mol % but lower catalyst loadings can be used if desired, as illustrated in the C-H functionalization of cyclohexane in 91% ee with 0.0025 mol % catalyst loading (29,400 turnover numbers). These studies further illustrate the effectiveness of donor/acceptor carbenes in site-selective intermolecular C-H functionalization and expand the toolbox of catalysts available for catalyst-controlled C-H functionalization.

A proof of concept model to calculate white and grey matter AIS injuries in pedestrian collisions.

In the real world, the severity of traumatic injuries is measured using the Abbreviated Injury Scale (AIS) and is often estimated, in finite element human computer models, with the maximum principal strains (MPS) tensor. MPS can predict when a serious injury is reached, but cannot provide any AIS measures lower and higher from this. To overcome these limitations, a new organ trauma model (OTM2), capable of calculating the threat to life of any organ injured, is proposed. The OTM2 model uses a power method, namely peak virtual power, and defines brain white and grey matters trauma responses. It includes human age effect (volume and stiffness), localised impact contact stiffness and provides injury severity adjustments for haemorrhaging. The focus, in this case, is on real-world pedestrian brain injuries. OTM2 model was tested against three real-life pedestrian accidents and has proven to reasonably predict the post mortem (PM) outcome. Its AIS predictions are closer to the real-world injury severity than the standard maximum principal strain (MPS) methods currently used. This proof of concept suggests that OTM2 has the potential to improve forensic predictions as well as contribute to the improvement in vehicle safety design through the ability to measure injury severity. This study concludes that future advances in trauma computing would require the development of a brain model that could predict haemorrhaging.

Thoracic Society of Australia and New Zealand clinical practice guideline on adult home oxygen therapy.

This Thoracic Society of Australia and New Zealand Guideline on the provision of home oxygen therapy in adults updates a previous Guideline from 2015. The Guideline is based upon a systematic review and meta-analysis of literature to September 2022 and the strength of recommendations is based on GRADE methodology. Long-term oxygen therapy (LTOT) is recommended for its mortality benefit for patients with COPD and other chronic respiratory diseases who have consistent evidence of significant hypoxaemia at rest (PaO2 ≤ 55 mm Hg or PaO2 ≤59 mm Hg in the presence of hypoxaemic sequalae) while in a stable state. Evidence does not support the use of LTOT for patients with COPD who have moderate hypoxaemia or isolated nocturnal hypoxaemia. In the absence of hypoxaemia, there is no evidence that oxygen provides greater palliation of breathlessness than air. Evidence does not support the use of supplemental oxygen therapy during pulmonary rehabilitation in those with COPD and exertional desaturation but normal resting arterial blood gases. Both positive and negative effects of LTOT have been described, including on quality of life. Education about how and when to use oxygen therapy in order to maximize its benefits, including the use of different delivery devices, expectations and limitations of therapy and information about hazards and risks associated with its use are key when embarking upon this treatment.

Rhodium(II)-Catalyzed Asymmetric Cyclopropanation and Desymmetrization of [2.2]Paracyclophanes.

Chiral [2.2]paracyclophane derivatives are of considerable interest because of their potential in asymmetric catalysis and the development of chiral materials. This study describes the scope of rhodium-catalyzed reactions of aryldiazoacetates with [2.2]paracyclophanes. The reaction with the parent [2.2]paracyclophane resulted in cyclopropanation at two positions, the ratio of which is catalyst-controlled. Because of the strain in the system, one of the cyclopropanes exists primarily as the norcaradiene structure, whereas the other preferentially exists as the cycloheptatriene conformer. In contrast, the reaction with [3.3]paracyclophane results in benzylic C-H functionalization. The reactions with substituted [2.2]paracyclophanes using chiral catalysts can result in either kinetic resolution or desymmetrization. The Rh2(S-p-PhTPCP)]4-catalyzed reaction of monosubstituted paracyclophanes results in kinetic resolution with a selectivity (s) factor of up to 20, whereas reactions on C2v-symmetric disubstituted [2.2]paracyclophanes with Rh2(S-TPPTTL)4 [TPPTTL = 2-(1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] results in effective desymmetrization to form cycloheptatriene-incorporated paracyclophanes in 78-98% ee.

Heterogeneous Fe-N-C Catalyst for Aerobic Dehydrogenation of Hydrazones to Diazo Compounds Used for Carbene Transfer.

Organic diazo compounds are versatile reagents in chemical synthesis and would benefit from improved synthetic accessibility, especially for larger scale applications. Here, we report a mild method for the synthesis of diazo compounds from hydrazones using a heterogeneous Fe-N-C catalyst, which has Fe ions dispersed within a graphitic nitrogen-doped carbon support. The reactions proceed readily at room temperature using O2 (1 atm) as the oxidant. Aryl diazoesters, ketones, and amides are accessible, in addition to less stable diaryl diazo compounds. Initial-rate data show that the Fe-N-C catalyst achieves faster rates than a heterogeneous Pt/C catalyst. The oxidative dehydrogenation of hydrazones may be performed in tandem with Rh-catalyzed enantioselective C-H insertion and cyclopropanation of alkenes, without requiring isolation of the diazo intermediate. This sequence is showcased by using a flow reactor for continuous synthesis of diazo compounds.

Diaryldiazoketones as Effective Carbene Sources for Highly Selective Rh(II)-Catalyzed Intermolecular C-H Functionalization.

A novel donor/acceptor carbene intermediate has been developed using diaryldiazoketones as carbene precursors. In the presence of the chiral dirhodium catalyst, Rh2(S-TPPTTL)4, diaryldiazoketones undergo highly regio-, stereo-, and diastereoselective C-H functionalization of activated and unactivated secondary and tertiary C-H bonds. Computational studies revealed that the arylketo group behaves differently than the carboxylate acceptor group because the orientation of the arylketo group predetermines which face of the carbene will be attacked.

Anhydrous and Stereoretentive Fluoride-Enhanced Suzuki-Miyaura Coupling of Immunomodulatory Imide Drug Derivatives.

Immunomodulatory imide drugs form the core of many pharmaceutically relevant structures, but Csp2-Csp2 bond formation via metal-catalyzed cross coupling is difficult due to the sensitivity of the glutarimide ring ubiquitous in these structures. We report that replacement of the traditional alkali base with a fluoride source enhances a previously challenging Suzuki-Miyaura coupling on glutarimide-containing compounds with trifluoroborates. These enabling conditions are reactive enough to generate these derivatives in high yields but mild enough to preserve both the glutarimide and its sensitive stereocenter. Experimental and computational data suggest a mechanistically distinct process of π-coordination of the trifluoroborate enabled by these conditions.

Use of exercise tests in screening for pulmonary arterial hypertension in systemic sclerosis: A systematic literature review.

Background and objective: Patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH) have a poor prognosis, accounting for 30% of all SSc-related deaths. Guidelines recommend annual screening for PAH regardless of symptoms, as early treatment improves outcomes. Current protocols include combinations of clinical features, biomarkers, pulmonary function tests, and echocardiography. None include exercise testing, although early-stage PAH may only be evident during exercise. This systematic review assessed the performance of exercise tests in predicting the presence of PAH in patients with SSc, where PAH was confirmed through right heart catheterisation (RHC). Methods: Comprehensive literature searches were performed using MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trails, CINAHL, Scopus and Web of Science from inception to May 2023. Articles were screened for eligibility by two independent reviewers. Eligibility criteria included the use of a non-invasive exercise test to screen adult patients to detect PAH in a population without a previous diagnosis of PAH, with diagnosis confirmed by RHC. Results: Eight studies met the inclusion criteria, describing at least one of three different non-invasive exercise tests: cardiopulmonary exercise test, six-minute walk test and stress Doppler echocardiography. All studies found that exercise tests had some ability to predict the presence of PAH, with sensitivity between 50% and 100% and specificity from 73% to 91%. Conclusion: Exercise tests are infrequently used for screening for PAH in SSc but can predict the presence of PAH. More data are required to establish which tests are most effective.

Stereoselective Synthesis of Either Exo- or Endo-3-Azabicyclo[3.1.0]hexane-6-carboxylates by Dirhodium(II)-Catalyzed Cyclopropanation with Ethyl Diazoacetate under Low Catalyst Loadings.

Although cyclopropanation with donor/acceptor carbenes can be conducted under low catalyst loadings (<0.001 mol %), such low loading has not been generally effective for other classes of carbenes such as acceptor carbenes. In this current study, we demonstrate that ethyl diazoacetate can be effectively used in the cyclopropanation of N-Boc-2,5-dihydropyrrole with dirhodium(II) catalyst loadings of 0.005 mol %. By appropriate choice of catalyst and hydrolysis conditions, either the exo- or endo-3-azabicyclo[3.1.0]hexanes can be formed cleanly with high levels of diastereoselectivity with no chromatographic purification.

Enantioselective Intermolecular C-H Functionalization of Primary Benzylic C-H Bonds Using ((Aryl)(diazo)methyl)phosphonates.

Catalyst-controlled C-H functionalization using donor/acceptor carbenes has been shown to be an efficient process capable of high levels of site control and stereocontrol. This study demonstrated that the scope of the donor/acceptor carbene C-H functionalization can be extended to systems where the acceptor group is a phosphonate. When using the optimized dirhodium catalyst, Rh2(S-di-(4-Br)TPPTTL)4, ((aryl)(diazo)methyl)phosphonates undergo highly enantioselective (84-99% ee) and site-selective (>30:1 r.r.) benzylic C-H functionalization. The phosphonate group is much more sterically demanding than the previously studied carboxylate ester group, leading to much higher selectivity for a primary site versus more sterically crowded positions. The effectiveness of this methodology has been demonstrated by the late-stage primary C-H functionalization of estrone, adapalene, (S)-naproxen, clofibrate, and gemfibrozil derivatives.

Editor's Choice - Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL) Prospective Cohort Study and the Generalisability of the BASIL-2 Randomised Controlled Trial.

OBJECTIVE: The Bypass versus Angioplasty in Severe Ischaemia of the Leg-2 (BASIL-2) randomised controlled trial has shown that, for patients with chronic limb threatening ischaemia (CLTI) who require an infrapopliteal (IP) revascularisation a vein bypass (VB) first revascularisation strategy led to a 35% increased risk of major amputation or death when compared with a best endovascular treatment (BET) first revascularisation strategy. The study aims are to place the BASIL-2 trial within the context of the CLTI patient population as a whole and to investigate the generalisability of the BASIL-2 outcome data. METHODS: This was an observational, single centre prospective cohort study. Between 24 June 2014 and 31 July 2018, the BASIL Prospective Cohort Study (PCS) was performed which used BASIL-2 trial case record forms to document the characteristics, initial and subsequent management, and outcomes of 471 consecutive CLTI patients admitted to an academic vascular centre. Ethical approval was obtained, and all patients provided fully informed written consent. Follow up data were censored on 14 December 2022. RESULTS: Of the 238 patients who required an infrainguinal revascularisation, 75 (32%) had either IP bypass (39 patients) or IP BET (36 patients) outside BASIL-2. Seventeen patients were initially randomised to BASIL-2. A further three patients who did not have an IP revascularisation as their initial management were later randomised in BASIL-2. Therefore, 95/471 (20%) of patients had IP revascularisation (16% outside, 4% inside BASIL-2). Differences in amputation free survival, overall survival, and limb salvage between IP bypass and IP BET performed outside BASIL-2 were not subject to hypothesis testing due to the small sample size. Reasons for non-randomisation into the trial were numerous, but often due to anatomical and technical considerations. CONCLUSION: CLTI patients who required an IP revascularisation procedure and were subsequently randomised into BASIL-2 accounted for a small subset of the CLTI population as a whole. For a wide range of patient, limb, anatomical and operational reasons, most patients in this cohort were deemed unsuitable for randomisation in BASIL-2. The results of BASIL-2 should be interpreted in this context.

A Novel 7H-[1,2,4]Triazolo[3,4-b]thiadiazine-based Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Directed toward Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit marginal clinical benefit or detrimental effects or have a form of the disease not approved or unlikely to respond using CFTR modulation. We tested hit compounds from a 300,000-drug screen for their ability to augment CFTR transepithelial transport alone or in combination with the FDA-approved CFTR potentiator ivacaftor (VX-770). A subsequent SAR campaign led us to a class of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines that in combination with VX-770 rescued function of G551D mutant CFTR channels to approximately 400% above the activity of VX-770 alone and to nearly wild-type CFTR levels in the same Fischer rat thyroid model system.

Diruthenium Tetracarboxylate-Catalyzed Enantioselective Cyclopropanation with Aryldiazoacetates.

A series of chiral bowl-shaped diruthenium(II,III) tetracarboxylate catalysts were prepared and evaluated in asymmetric cyclopropanations with donor/acceptor carbenes derived from aryldiazoacetates. The diruthenium catalysts self-assembled to generate C4-symmetric bowl-shaped structures in an analogous manner to their dirhodium counterparts. The optimum catalyst was found to be Ru2(S-TPPTTL)4·BArF [S-TPPTTL = (S)-2-(1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate, BArF = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate], which resulted in the cyclopropanation of a range of substrates in up to 94% ee. Synthesis and evaluation of first-row transition-metal congeners [Cu(II/II) and Co(II/II)] invariably resulted in catalysts that afforded little to no asymmetric induction. Computational studies indicate that the carbene complexes of these dicopper and dicobalt complexes, unlike the dirhodium and diruthenium systems, are prone to the loss of carboxylate ligands, which would destroy the bowl-shaped structure critical for asymmetric induction.

One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates.

Rapid access to 2,2-difluorobicylco[1.1.1]pentanes is enabled from an α-allyldiazoacetate precursor in a one-pot process through cyclopropanation to afford a 3-aryl bicyclo[1.1.0]butane, followed by reaction with difluorocarbene in the same reaction flask. The modular synthesis of these diazo compounds affords novel 2,2-difluorobicyclo[1.1.1]pentanes that were inaccessible through previously reported methods. The reactions of chiral 2-arylbicyclo[1.1.0]butanes in the same manner generate altogether different products with high asymmetric induction, methylene-difluorocyclobutanes. Larger ring systems including bicyclo[3.1.0]hexanes are also rapidly furnished due to the modular nature of the diazo starting material.

Stereoselective Synthesis of Highly Functionalized Cyclohexenes via Strong-Acid-Mediated Endocyclic C-C Bond Cleavage of Monocyclopropanated Cyclopentadienes.

A stereoselective, solvent- and metal-free endocyclic C-C bond cleavage of monocyclopropanated cyclopentadienes mediated by strong acids was developed, leading to highly functionalized six-membered carbocycles with high stereocontrol. The critical step for this ring-expansion is the formation of a cyclopropyl carbocation that undergoes endocyclic ring opening via an SN2'-type attack of various nucleophiles. Subsequent synthetic transformations show the versatility of the resulting cyclohexenes for the synthesis of new compounds with nonconventional substitution patterns.

Enantioselective Synthesis of Triarylmethanes via Intermolecular C-H Functionalization of Cyclohexadienes with Diaryldiazomethanes.

Rhodium-catalyzed C-H functionalization of cyclohexadiene derivatives with diaryldiazomethanes followed by oxidation with DDQ provides ready access to triarylmethanes. Two chiral dirhodium tetracarboxylates, Rh2(S-PTAD)4 and Rh2(S-TPPTTL)4, were found to be the optimum chiral catalysts for these transformations. This method showcases the ability of diaryldiazomethanes to perform intermolecular C-H insertion with high enantioselectivity and good yields. The method has a broad substrate scope, leading to triarylmethane products with a variety of aryl and heteroaryl substituents, including benzofuran and pyridine heterocycles.

N-Phthalimide as a Site-Protecting and Stereodirecting Group in Rhodium-Catalyzed C-H Functionalization with Donor/Acceptor Carbenes.

The rhodium-catalyzed enantioselective C-H functionalization of unactivated C-H bonds by means of donor/acceptor carbene-induced C-H insertion was extended to substrates containing nitrogen functionality. The rhodium-stabilized donor/acceptor carbenes were generated by rhodium-catalyzed decomposition of aryldiazoacetates. The phthalimido group was the optimum nitrogen protecting group. C-H functionalization at the most sterically accessible methylene site was achieved using Rh2(S-2-Cl-5-BrTPCP)4 as catalyst, whereas Rh2(S-TPPTTL)4 was the most effective catalyst for C-H functionalization at tertiary C-H bonds and for the desymmetrization of N-phthalimidocyclohexane.

Dirhodium C-H Functionalization of Hole-Transport Materials.

Hole-transport materials (HTMs) based on triarylamine derivatives play important roles in organic electronics applications including organic light-emitting diodes and perovskite solar cells. For some applications, triarylamine derivatives bearing appropriate binding groups have been used to functionalize surfaces, while others have been incorporated as side chains into polymers to manipulate the processibility of HTMs for device applications. However, only a few approaches have been used to incorporate a single surface-binding group or polymerizable group into triarylamine materials. Here, we report that Rh-carbenoid chemistry can be used to insert carboxylic esters and norbornene functional groups into sp2 C-H bonds of a simple triarylamine and a 4,4'-bis(diarylamino)biphenyl, respectively. The norbenene-functionalized monomer was polymerized by ring-opening metathesis; the electrochemical, optical, and charge-transport properties of these materials were similar to those of related materials synthesized by conventional means. This method potentially offers straightforward access to a diverse range of HTMs with different functional groups.