Synthesis of ureas in the bio-alternative solvent Cyrene

Cyrene as a bio-alternative solvent: a highly efficient, waste minimizing protocol for the synthesis of ureas from isocyanates and secondary amines in the bio-available solvent Cyrene is reported. This method eliminated the use of toxic solvents, such as DMF, and established a simple work-up procedure for removal of the Cyrene, which led to a 28-fold increase in molar efficiency versus industrial standard protocols

Exploring the reactivity of 2-trichloromethylbenzoxazoles for access to substituted benzoxazoles

The reactivity of 2-trichloromethylbenzoxazoles towards various nucleophiles, under metal free or iron-catalyzed conditions, for the synthesis of substituted benzoxazoles is described. These methods allow for selective substitution at either the 2- or 2’- position of the benzoxazoles using the same starting materials / reagents. This approach allows for the controlled synthesis of a variety of key derivatives from a single 2-trichloromethylbenzoxazole starting material

Exploring the reactivity of 2-trichloromethylbenzoxazoles for access to substituted benzoxazoles

The reactivity of 2-trichloromethylbenzoxazoles towards various nucleophiles, under metal free or iron-catalyzed conditions, for the synthesis of substituted benzoxazoles is described. These methods allow for selective substitution at either the 2- or 2’- position of the benzoxazoles using the same starting materials / reagents. This approach allows for the controlled synthesis of a variety of key derivatives from a single 2-trichloromethylbenzoxazole starting material

Oxa-Michael-initiated cascade reactions of levoglucosenone

The reactions of aromatic aldehydes and levoglucosenone promoted by methoxide gives bridged α,β-unsaturated ketones, formed by a series of oxa-Michael-initiated cascade reactions in yields of up to 91% (14 examples). A complex series of equilibria operate during the reaction, and the formation of the bridged species is thermodynamically favored, except in the case of 5-methylfurfural and pyrrole-2-carboxaldehyde. This is the first report detailing this type of aldol/Michael cascade involving oxa-Michael initiation

Understanding the retinal basis of vision across species

The vertebrate retina first evolved some 500 million years ago in ancestral marine chordates. Since then, the eyes of different species have been tuned to best support their unique visuoecological lifestyles. Visual specializations in eye designs, large-scale inhomogeneities across the retinal surface and local circuit motifs mean that all species' retinas are unique. Computational theories, such as the efficient coding hypothesis, have come a long way towards an explanation of the basic features of retinal organization and function; however, they cannot explain the full extent of retinal diversity within and across species. To build a truly general understanding of vertebrate vision and the retina's computational purpose, it is therefore important to more quantitatively relate different species' retinal functions to their specific natural environments and behavioural requirements. Ultimately, the goal of such efforts should be to build up to a more general theory of vision

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Sustainable Methodology Development using Renewable Feedstock: Dehydrative Mizoroki-Heck Reaction and the use of Cyrene™ as a Solvent in Chemical Synthesis

The work presented in this thesis regards: 1) the development of a base free dehydrative cross-coupling process, utilising palladium(0) nanoparticles formed in situ under acidic conditions, 2) the development of synthetic protocols using the bio-available solvent Cyrene™ as a replacement dipolar aprotic solvent and 3) the use of Cyrene™ as a chiral scaffold. 1) The use of sugars for the in situ formation of palladium nanoparticles has been previously developed in the Camp group. Building upon this work, a base free Mizoroki-Heck crosscoupling process for the synthesis of substituted stilbenes was developed and optimised, whereby glucose performed a dual role: stabilisation of the palladium(0) nanoparticles and regeneration of the active catalyst species. Due to the base free nature of this process, the reaction mixture becomes acidic. Relatively few protocols have been developed in which the feedstock of the Mizoroki-Heck reaction has changed from the standard alkene substrates. Typically, alkenes are reacted with aryl or alkyl halides in order to cross-couple and form a new C-C bond. Herein, a dehydrative method for the in situ formation of styrene and tandem cross-coupling process in a base free, H2O/MeCN solvent system has been developed, taking advantage of the acidic nature of the reaction mixture. After optimisation, the steric, electronic and substrate scope of the reaction conditions were investigated. The molar efficiency (Mol. E%) was calculated and evaluated against similar methods for the synthesis of substituted stilbenes. 2) The need for a green replacement dipolar aprotic solvents has become crucial due to the placement of N,N-dimethylformamide (DMF) and N-methylpyrrolidine (NMP) on the REACH list of restricted chemicals. In recent years, the chemical Cyrene™ has been investigated as a bio-available replacement for the dipolar aprotic solvents. The synthesis of ureas, amides and carbamates in Cyrene™ was developed and optimised from either isocyanates or acid chlorides with amines or alcohols. The synthesis of carbamates was monitored by in situ 19F NMR to determine the rate of the reaction in several solvents including Cyrene™. Additionally the large scale reaction, recycling of solvent and reuse was successfully performed. 3) Chiral scaffolds are useful tools as they allow the synthesis of several compounds of similar structure. The use of Cyrene™ as a chiral scaffold was investigated by several academic groups including the Camp group. Aldol condensation reactions were performed on Cyrene™ with a variety of aryl aldehydes in the presence of a strong base. Nine examples of condensation products were synthesised in very poor to moderate yields. X-ray crystallography was used to confirm the structure of the compounds synthesised. Interestingly, a bis-addition product was detected in one of the Aldol examples, efforts to synthesise this along with generality afforded two of these dimers as sole products

A simple one-pot preparation of N-allenyl amides, ureas, carbamates and sulfonamides using a DMSO/tBuOK protocol

A one-pot transformation of amides, ureas, carbamates and sulfonamides into synthetically useful N-allenyl analogues using a tBuOK/DMSO protocol is reported. The procedure is experimentally simple and robust, and provides N-allenyl analogues, commonly used within the literature, in yields comparable to the benchmark two-step approach