Alkene anti-dihydroxylation with malonoyl peroxides

Malonoyl peroxide 1, prepared in a single step from the commercially available diacid, is an effective reagent for the anti-dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of acetic acid at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (35-92%) with up to 13:1 anti-selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed

Acute high altitude exposure, acclimatization and re-exposure on nocturnal breathing

Background: Effects of prolonged and repeated high-altitude exposure on oxygenation and control of breathing remain uncertain. We hypothesized that prolonged and repeated high-altitude exposure will improve altitude-induced deoxygenation and breathing instability. Methods: 21 healthy lowlanders, aged 18-30y, underwent two 7-day sojourns at a high-altitude station in Chile (4-8 hrs/day at 5,050 m, nights at 2,900 m), separated by a 1-week recovery period at 520 m. Respiratory sleep studies recording mean nocturnal pulse oximetry (SpO2), oxygen desaturation index (ODI, >3% dips in SpO2), breathing patterns and subjective sleep quality by visual analog scale (SQ-VAS, 0-100% with increasing quality), were evaluated at 520 m and during nights 1 and 6 at 2,900 m in the 1st and 2nd altitude sojourn. Results: At 520 m, mean ± SD nocturnal SpO2 was 94 ± 1%, ODI 2.2 ± 1.2/h, SQ-VAS 59 ± 20%. Corresponding values at 2,900 m, 1st sojourn, night 1 were: SpO2 86 ± 2%, ODI 23.4 ± 22.8/h, SQ-VAS 39 ± 23%; 1st sojourn, night 6: SpO2 90 ± 1%, ODI 7.3 ± 4.4/h, SQ-VAS 55 ± 20% (p < 0.05, all differences within corresponding variables). Mean differences (Δ, 95%CI) in acute effects (2,900 m, night 1, vs 520 m) between 2nd vs 1st altitude sojourn were: ΔSpO2 0% (-1 to 1), ΔODI -9.2/h (-18.0 to -0.5), ΔSQ-VAS 10% (-6 to 27); differences in acclimatization (changes night 6 vs 1), between 2nd vs 1st sojourn at 2,900 m were: ΔSpO2 -1% (-2 to 0), ΔODI 11.1/h (2.5 to 19.7), ΔSQ-VAS -15% (-31 to 1). Conclusion: Acute high-altitude exposure induced nocturnal hypoxemia, cyclic deoxygenations and impaired sleep quality. Acclimatization mitigated these effects. After recovery at 520 m, repeated exposure diminished high-altitude-induced deoxygenation and breathing instability, suggesting some retention of adaptation induced by the first altitude sojourn while subjective sleep quality remained similarly impaired. Keywords: altitude (MeSH); hypoxia; respiration - physiology; respiratory polygraphy; sleep-disordered breathing

A prospective cohort study about the effect of repeated living high and working higher on cerebral autoregulation in unacclimatized lowlanders

Cerebral autoregulation (CA) is impaired during acute high-altitude (HA) exposure, however, effects of temporarily living high and working higher on CA require further investigation. In 18 healthy lowlanders (11 women), we hypothesized that the cerebral autoregulation index (ARI) assessed by the percentage change in middle cerebral artery peak blood velocity (Δ%MCAv)/percentage change in mean arterial blood pressure (Δ%MAP) induced by a sit-to-stand maneuver, is (i) reduced on Day1 at 5050 m compared to 520 m, (ii) is improved after 6 days at 5050 m, and (iii) is less impaired during re-exposure to 5050 m after 7 days at 520 m compared to Cycle1. Participants spent 4-8 h/day at 5050 m and slept at 2900 m similar to real-life working shifts. High/low ARI indicate impaired/intact CA, respectively. With the sit-to-stand at 520 m, mean (95% CI) in ΔMAP and ΔMCAv were − 26% (− 41 to − 10) and − 13% (− 19 to − 7), P < 0.001 both comparisons; mean ± SD in ARI was 0.58 ± 2.44Δ%/Δ%, respectively. On Day1 at 5050 m, ARI worsened compared to 520 m (3.29 ± 2.42Δ%/Δ%), P = 0.006 but improved with acclimatization (1.44 ± 2.43Δ%/Δ%, P = 0.039). ARI was less affected during re-exposure to 5050 m (1.22 ± 2.52Δ%/Δ%, P = 0.027 altitude-induced change between sojourns). This study showed that CA (i) is impaired during acute HA exposure, (ii) improves with living high, working higher and (iii) is ameliorated during re-exposure to HA

Combining two-directional synthesis and tandem reactions. Part 21: Exploitation of a dimeric macrocycle for chain terminus differentiation and synthesis of an sp3-rich library

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp3-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp3-rich natural product-like library

Metal-free syn-dioxygenation of alkenes

Reactions employing inexpensive reagents from sustainable sources and with low toxicity are becoming increasingly desirable from an academic and industrial perspective. A fascinating example of a synthetic transformation that requires development of alternative procedures is the osmium catalysed dihydroxylation. Recently there has been considerable interest in achieving this reaction through metal-free procedures. This review describes the methods available for metal-free syn-dioxygenation of alkenes

Expedient synthesis of an atypical oxazolidinone compound library

In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels-Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Metal-free syn-dihydroxylation of alkenes using malonoyl peroxides

This thesis was previously held under moratorium from 8th May 2014 until 8th May 2016.This thesis describes the successful application of cyclopropyl malonoyl peroxide II in the metal-free syn-dihydroxylation of alkenes I. Chapter 1 outlines the available metal-free methods for achieving syn-1,2- dioxygenation of alkenes. The use of hypervalent iodine, selenium, sulfur and peroxide reagents are discussed in terms of the advantages and limitations of each method. Chapter 2 details a mechanistic investigation into the dihydroxylation reaction using cyclopropyl malonoyl peroxide II. Through kinetic studies, Hammett analysis, multiple isotopic labelling experiments, NMR investigations and trapping experiments an ionic, stepwise mechanism has been proposed. Minor competing reaction pathways have also been identified in addition to an alternative reaction mechanism in the absence of water. Chapter 3 describes the current scope of the cyclopropyl malonoyl peroxide II mediated dihydroxylation reaction by alkene class. An application of the dihydroxylation protocol is presented in the stereoselective synthesis of a 5-deoxy-L-arabinose derivative. Interaction of cyclopropyl malonoyl peroxide II with non-alkene nucleophiles is also discussed, and a novel allylic oxidation protocol using peroxide II is introduced. Chapter 4 discusses catalysis of the dihydroxylation reaction. Alcoholic hydrogen-bond donors with a pKa of 5-8 were found to be the most effective catalysts, achieving up to 4-fold rate acceleration. Chiral hydrogen-bond catalysts are also investigated. Chapter 5 outlines the design, synthesis and reaction of chiral C2-symmetric malonoyl peroxides. The first enantioselective metal-free syn-dihydroxylation of alkenes using a peroxide reagent is reported. Chapter 6 presents preliminary investigations into a complementary antidihydroxylation protocol using cyclopropyl malonoyl peroxide II in anhydrous acetic acid.This thesis describes the successful application of cyclopropyl malonoyl peroxide II in the metal-free syn-dihydroxylation of alkenes I. Chapter 1 outlines the available metal-free methods for achieving syn-1,2- dioxygenation of alkenes. The use of hypervalent iodine, selenium, sulfur and peroxide reagents are discussed in terms of the advantages and limitations of each method. Chapter 2 details a mechanistic investigation into the dihydroxylation reaction using cyclopropyl malonoyl peroxide II. Through kinetic studies, Hammett analysis, multiple isotopic labelling experiments, NMR investigations and trapping experiments an ionic, stepwise mechanism has been proposed. Minor competing reaction pathways have also been identified in addition to an alternative reaction mechanism in the absence of water. Chapter 3 describes the current scope of the cyclopropyl malonoyl peroxide II mediated dihydroxylation reaction by alkene class. An application of the dihydroxylation protocol is presented in the stereoselective synthesis of a 5-deoxy-L-arabinose derivative. Interaction of cyclopropyl malonoyl peroxide II with non-alkene nucleophiles is also discussed, and a novel allylic oxidation protocol using peroxide II is introduced. Chapter 4 discusses catalysis of the dihydroxylation reaction. Alcoholic hydrogen-bond donors with a pKa of 5-8 were found to be the most effective catalysts, achieving up to 4-fold rate acceleration. Chiral hydrogen-bond catalysts are also investigated. Chapter 5 outlines the design, synthesis and reaction of chiral C2-symmetric malonoyl peroxides. The first enantioselective metal-free syn-dihydroxylation of alkenes using a peroxide reagent is reported. Chapter 6 presents preliminary investigations into a complementary antidihydroxylation protocol using cyclopropyl malonoyl peroxide II in anhydrous acetic acid

Extravascular lung water and cardiac function assessed by echocardiography in healthy lowlanders during repeated very high-altitude exposure

Background High-altitude pulmonary edema is associated with elevated systolic pulmonary artery pressure (sPAP) and increased extravascular lung water (EVLW). We investigated sPAP and EVLW during repeated exposures to high altitude (HA). Methods Healthy lowlanders underwent two identical 7-day HA-cycles, where subjects slept at 2900 m and spent 4–8 h daily at 5050 m, separated by a weeklong break at low altitude (LA). Echocardiography and EVLW by B-lines were measured at 520 m (baseline, LA1), on day one, two and six at 5050 m (HA1–3) and after descent (LA2). Results We included 21 subjects (median 25 years, body mass index 22 kg/m2, SpO2 98%). SPAP rose from 21 mmHg at LA1 to 38 mmHg at HA1, decreased to 30 mmHg at HA3 (both p < 0.05 vs LA1) and normalized at 20 mmHg at LA2 (p = ns vs LA1). B-lines increased from 0 at LA1 to 6 at HA2 and 7 at HA3 (both p < 0.05 vs LA1) and receded to 1 at LA2 (p = ns vs LA1). Overall, in cycle two, sPAP did not differ (mean difference (95% confidence interval) −0.2(−2.3 to 1.9) mmHg, p = 0.864) but B-lines were more prevalent (+2.3 (1.4–3.1), p < 0.001) compared to cycle 1. Right ventricular systolic function decreased significantly but minimally at 5050 m. Conclusions Exposure to 5050 m induced a rapid increase in sPAP. B-lines rose during prolonged exposures to 5050 m, despite gradual decrease in sPAP, indicating excessive hydrostatic pressure might not be solely responsible for EVLW-development. Repeated HA-exposure had no acclimatization effect on EVLW. This may affect workers needing repetitive ascents to altitude and could indicate greater B-line development upon repeated exposure