Horeau amplification in the sequential acylative kinetic resolution of (±)-1,2-diols and (±)-1,3-diols in flow.

The sequential acylative kinetic resolution (KR) of C2-symmetric (±)-1,2-syn and (±)-1,3-anti-diols using a packed bed microreactor loaded with the polystyrene-supported isothiourea, HyperBTM, is demonstrated in flow. The sequential KRs of C2-symmetric (±)-1,2-syn and (±)-1,3-anti-diols exploits Horeau amplification, with each composed of two successive KR processes, with each substrate class significantly differing in the relative rate constants for each KR process. Optimisation of the continuous flow set-up for both C2-symmetric (±)-1,2-syn and (±)-1,3-anti-diol substrate classes allowed isolation of reaction products in both high enantiopurity and yield. In addition to the successful KR of C2-symmetric (±)-1,2-syn and (±)-1,3-anti-diols, the application of this process to the more conceptually-complex scenario involving the sequential KR of C1-symmetric (±)-1,3-anti-diols was demonstrated, which involves eight independent rate constants.

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to para-Quinone Methides.

The isothiourea-catalyzed enantioselective 1,6-conjugate addition of para-nitrophenyl esters to 2,6-disubstituted para-quinone methides is reported. para-Nitrophenoxide, generated in situ from initial N-acylation of the isothiourea by the para-nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of para-nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides at up to 99% yield. Although low diastereocontrol is observed, the diastereoisomeric ester products are separable and formed with high enantiocontrol (up to 94:6 er).

TMEDA in Iron-Catalyzed Hydromagnesiation: Formation of Iron(II)-Alkyl Species for Controlled Reduction to Alkene-Stabilized Iron(0).

N,N,N',N'-Tetramethylethylenediamine (TMEDA) has been one of the most prevalent and successful additives used in iron catalysis, finding application in reactions as diverse as cross-coupling, C-H activation, and borylation. However, the role that TMEDA plays in these reactions remains largely undefined. Herein, studying the iron-catalyzed hydromagnesiation of styrene derivatives using TMEDA has provided molecular-level insight into the role of TMEDA in achieving effective catalysis. The key is the initial formation of TMEDA-iron(II)-alkyl species which undergo a controlled reduction to selectively form catalytically active styrene-stabilized iron(0)-alkyl complexes. While TMEDA is not bound to the catalytically active species, these active iron(0) complexes cannot be accessed in the absence of TMEDA. This mode of action, allowing for controlled reduction and access to iron(0) species, represents a new paradigm for the role of this important reaction additive in iron catalysis.

Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-Hydroxy Esters.

A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous-flow process using a polymer-supported variant of the catalyst.

NHC-catalyzed enantioselective synthesis of ß-trifluoromethyl-ß-hydroxyamides.

The N-heterocyclic carbene (NHC)-catalyzed formal [2 + 2] cycloaddition between α-aroyloxyaldehydes and trifluoroacetophenones, followed by ring opening with an amine or a reducing agent is described. The resulting ß-trifluoromethyl-ß-hydroxyamide and alcohol products are produced with reasonable diastereocontrol (typically ≈70:30 dr) and excellent enantioselectivity, and they can be isolated in moderate to good yield as a single diastereoisomer.

Mechanism of the Bis(imino)pyridine-Iron-Catalyzed Hydromagnesiation of Styrene Derivatives.

Iron-catalyzed hydromagnesiation of styrene derivatives offers a rapid and efficient method to generate benzylic Grignard reagents, which can be applied in a range of transformations to provide products of formal hydrofunctionalization. While iron-catalyzed methodologies exist for the hydromagnesiation of terminal alkenes, internal alkynes, and styrene derivatives, the underlying mechanisms of catalysis remain largely undefined. To address this issue and determine the divergent reactivity from established cross-coupling and hydrofunctionalization reactions, a detailed study of the bis(imino)pyridine iron-catalyzed hydromagnesiation of styrene derivatives is reported. Using a combination of kinetic analysis, deuterium labeling, and reactivity studies as well as in situ 57Fe Mössbauer spectroscopy, key mechanistic features and species were established. A formally iron(0) ate complex [ iPrBIPFe(Et)(CH2═CH2)]- was identified as the principle resting state of the catalyst. Dissociation of ethene forms the catalytically active species which can reversibly coordinate the styrene derivative and mediate a direct and reversible ß-hydride transfer, negating the necessity of a discrete iron hydride intermediate. Finally, displacement of the tridentate bis(imino)pyridine ligand over the course of the reaction results in the formation of a tris-styrene-coordinated iron(0) complex, which is also a competent catalyst for hydromagnesiation.

Isothiourea-Catalysed Regioselective Acylative Kinetic Resolution of Axially Chiral Biaryl Diols.

An operationally simple isothiourea-catalysed acylative kinetic resolution of unprotected 1,1'-biaryl-2,2'-diol derivatives has been developed to allow access to axially chiral compounds in highly enantioenriched form (s values up to 190). Investigation of the reaction scope and limitations provided three key observations: i) the diol motif of the substrate was essential for good conversion and high s values; ii) the use of an α,α-disubstituted mixed anhydride (2,2-diphenylacetic pivalic anhydride) was critical to minimize diacylation and give high selectivity; iii) the presence of substituents in the 3,3'-positions of the diol hindered effective acylation. This final observation was exploited for the highly regioselective acylative kinetic resolution of unsymmetrical biaryl diol substrates bearing a single 3-substituent. Based on the key observations identified, acylation transition state models have been proposed to explain the atropselectivity of this kinetic resolution.

Chiral AuI - and AuIII -Isothiourea Complexes: Synthesis, Characterization and Application.

During an investigation into the potential union of Lewis basic isothiourea organocatalysis and gold catalysis, the formation of gold-isothiourea complexes was observed. These novel gold complexes were formed in high yield and were found to be air- and moisture stable. A series of neutral and cationic chiral gold(I) and gold(III) complexes bearing enantiopure isothiourea ligands was therefore synthesized and fully characterized. The steric and electronic properties of the isothiourea ligands was assessed through calculation of their percent buried volume and the synthesis and analysis of novel iridium(I)-isothiourea carbonyl complexes. The novel gold(I)- and gold(III)-isothiourea complexes have been applied in preliminary catalytic and biological studies, and display promising preliminary levels of catalytic activity and potency towards cancerous cell lines and clinically relevant enzymes.

Early planned removal versus expectant management of peripherally inserted central catheters to prevent infection in newborn infants.

BACKGROUND: Duration of use may be a modifiable risk factor for central venous catheter-associated bloodstream infection in newborn infants. Early planned removal of peripherally inserted central catheters (PICCs) is recommended as a strategy to reduce the incidence of infection and its associated morbidity and mortality. OBJECTIVES: To determine the effectiveness of early planned removal of PICCs (up to two weeks after insertion) compared to an expectant approach or a longer fixed duration in preventing bloodstream infection and other complications in newborn infants. SEARCH METHODS: We searched of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 4), Ovid MEDLINE, Embase, Maternity & Infant Care Database, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (until April 2018), and conference proceedings and previous reviews. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that assessed the effect of early planned removal of umbilical venous catheters (up to two weeks after insertion) compared to an expectant management approach or a longer fixed duration in preventing bloodstream infection and other complications in newborn infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility independently. We planned to analyse any treatment effects in the individual trials and report the risk ratio and risk difference for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals. We planned to use a fixed-effect model in meta-analyses and explore potential causes of heterogeneity in sensitivity analyses. We planned to assess the quality of evidence for the main comparison at the outcome level using "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methods. MAIN RESULTS: We did not identify any eligible randomised controlled trials. AUTHORS' CONCLUSIONS: There are no trial data to guide practice regarding early planned removal versus expectant management of PICCs in newborn infants. A simple and pragmatic randomised controlled trial is needed to resolve the uncertainty about optimal management in this common and important clinical dilemma.

A C=O⋠⋠⋠Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols.

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Early planned removal of umbilical venous catheters to prevent infection in newborn infants.

BACKGROUND: Lengthy duration of use may be a risk factor for umbilical venous catheter-associated bloodstream infection in newborn infants. Early planned removal of umbilical venous catheters (UVCs) is recommended to reduce the incidence of infection and associated morbidity and mortality. OBJECTIVES: To compare the effectiveness of early planned removal of UVCs (up to two weeks after insertion) versus an expectant approach or a longer fixed duration in preventing bloodstream infection and other complications in newborn infants.To perform subgroup analyses by gestational age at birth and prespecified planned duration of UVC placement (see "Subgroup analysis and investigation of heterogeneity"). SEARCH METHODS: We used the standard Cochrane Neonatal search strategy including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4), Ovid MEDLINE, Embase, and the Maternity & Infant Care Database (until May 2017), as well as conference proceedings and previous reviews. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared effects of early planned removal of UVCs (up to two weeks after insertion) versus an expectant approach or a longer fixed duration in preventing bloodstream infection and other complications in newborn infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently undertook data extraction. We analysed treatment effects and reported risk ratio (RR) and risk difference (RD) for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We planned to use a fixed-effect model in meta-analyses and to explore potential causes of heterogeneity in sensitivity analyses. We assessed the quality of evidence for the main comparison at the outcome level using GRADE methods. MAIN RESULTS: We found one eligible trial. Participants were 210 newborn infants with birth weight less than 1251 grams. The trial was unblinded but otherwise of good methodological quality. This trial compared removal of an umbilical venous catheter within 10 days after insertion (and replacement with a peripheral cannula or a percutaneously inserted central catheter as required) versus expectant management (UVC in place up to 28 days). More infants in the early planned removal group than in the expectant management group (83 vs 33) required percutaneous insertion of a central catheter (PICC). Trial results showed no difference in the incidence of catheter-related bloodstream infection (RR 0.65, 95% CI 0.35 to 1.22), in hospital mortality (RR 1.12, 95% CI 0.42 to 2.98), in catheter-associated thrombus necessitating removal (RR 0.33, 95% confidence interval 0.01 to 7.94), or in other morbidity. GRADE assessment indicated that the quality of evidence was "low" at outcome level principally as the result of imprecision and risk of surveillance bias due to lack of blinding in the included trial. AUTHORS' CONCLUSIONS: Currently available trial data are insufficient to show whether early planned removal of umbilical venous catheters reduces risk of infection, mortality, or other morbidity in newborn infants. A large, simple, and pragmatic randomised controlled trial is needed to resolve this ongoing uncertainty.

Feasibility and utility of portable ultrasound during retrieval of sick preterm infants.

AIM: Document the incidence of haemodynamic pathology in critically ill preterm newborns requiring transport. METHOD: A transport neonatologist performed cardiac and cerebral ultrasound before and after transportation of infants born ≤30 weeks gestation. RESULTS: Forty-four newborns were studied in 2008-2015; of them, 21 were transported by road, 19, by helicopter and four, by fixed wing: median birthweight, 1130 g (680-1960 g) and median gestation, 27 weeks (23-30); 30 of 44 were male babies. Antenatal steroid course was complete in two babies. Ultrasound in the referring hospital was at a mean of two hours: 47 minutes (00:15-7:00) of age. Low systemic blood flow was common: 50% had right ventricular output <150mL/kg/min and 23%, a superior vena cava flow <50mL/kg/min. at stabilisation. Cranial US: 10 Grade I IVH, 2 Grade II IVH, 1 Grade IV IVH and 32 normal scans pretransport. After transport, three further Grade I IVH were reported. Mortality was higher in the babies with low systemic blood flow: 4 of 12 (33%) died vs 1 of 31 (6%) in the normal flow group (OR = 7.2, 95% CI: 1.1 to 47, p = 0.022). CONCLUSION: Point-of-care ultrasound during the retrieval of preterm infants confirms a high incidence of haemodynamic pathology. The use of ultrasound during transport may provide an opportunity for earlier targeted circulatory support.

Aryloxide-Facilitated Catalyst Turnover in Enantioselective α,ß-Unsaturated Acyl Ammonium Catalysis.

A new general concept for α,ß-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,ß-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,ß-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,ß-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

Enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofurans using a Brønsted base/thiourea bifunctional catalyst.

The diastereo- and enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofuran derivatives (15 examples, up to 96 : 4 dr, 95 : 5 er) via intramolecular Michael addition has been developed using keto-enone substrates and a bifunctional tertiary amine-thiourea catalyst. This methodology was extended to include non-activated ketone pro-nucleophiles for the synthesis of 2,3-disubstituted indane and 3,4-disubstituted tetrahydrofuran derivatives.

Comparison of trunk mechanics and spatiotemporal outcomes in caregivers using a robotic assisted transfer device and a mobile floor lift.

OBJECTIVE: The purpose of this study was to compare trunk mechanics, distance covered, and average instantaneous velocity and acceleration recorded with caregivers performing transfer tasks using a research mannequin with both a prototype robotic assisted transfer device (RATD) and a mobile floor lift. DESIGN: Cross-Sectional. SETTING: Biomechanics Lab and Human Engineering Research Laboratories. PARTICIPANTS: Caregivers (N = 21). INTERVENTION: Robotic Assisted Transfer Device. OUTCOME MEASURES: Range of flexion-extension, lateral bend, and axial rotation; distance covered; average instantaneous velocity and acceleration. RESULTS: Caregivers performing transfers using the RATD as compared to when using the moble floor lift reported significantly smaller range of trunk flexion-extension, lateral bending, and axial rotation, and reported lower pelvic based distance covered and slower average instantaneous velocity and acceleration (P < 0.001). CONCLUSION: The design and usability of a RATD indicates design driven mobility advantages over clinical standard mobile floor lifts due to its ability to expand the workspace while further reducing risk factors for low back pain. While the concept is promising, further testing is required to address limitations and confirm the concept for clinical applications.

Iron-catalyzed, highly regioselective synthesis of α-aryl carboxylic acids from styrene derivatives and CO2.

The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl(2), bis(imino)pyridine 6 (1 mol %), CO(2) (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield). The catalyst was found to be equally active with a loading of 0.1 mol %. Preliminary mechanistic investigations show that an iron-catalyzed hydrometalation is followed by transmetalation and reaction with the electrophile (CO(2)).

Clinical and Ergonomic Comparison Between a Robotic Assisted Transfer Device and a Mobile Floor Lift During Caregiver-Assisted Wheelchair Transfers.

BACKGROUND: The robotic assisted transfer device was developed as an updated lift technology to reduce adjustments in posture while increasing capabilities offered by transfer devices. The purpose of this study was to compare the trunk biomechanics of a robotic assisted transfer device and a mechanical floor lift in the transfer of a care recipient by a caregiver during essential transfer tasks. METHODS: Investigators enrolled 28 caregiver/care recipient dyads to complete 36 transferring tasks. Surface electromyography for the back muscles and motion data for trunk range of motion were collected for selected surfaces, phase, and direction tasks using a robotic assisted transfer device and a mechanical floor lift. RESULTS: Robotic assisted transfer device transfers required significantly smaller range of trunk flexion (P < 0.001), lateral bend (P < 0.001), and axial rotation (P = 0.01), in addition to smaller distance covered (P < 0.001), average instantaneous velocity (P = 0.01), and acceleration (P < 0.001) compared with a mobile floor lift. The robotic assisted transfer device transfers required significantly smaller peak erector spinae (left: P = 0.001; right: P < 0.001) and latissimus dorsi (right: P < 0.001) and integrated erector spinae left (P = 0.001) and latissimus dorsi right (P = 0.01) electromyography signals compared with the floor lift. CONCLUSIONS: The robotic assisted transfer device provides additional benefits to mobile floor lifts which, coupled with statistically lower flexion, extension, and rotation, may make them an appealing alternative intervention.

Usability and task load comparison between a robotic assisted transfer device and a mechanical floor lift during caregiver assisted transfers on a care recipient.

INTRODUCTION: The RATD represents a novel methodology to reduce strain, manoeuvring, and cognitive load a caregiver experiences when conducting transfers on a mannequin. However, caregivers who used this new technology report suggested adjustments regarding the robot's human machine interface and shape as to improve transfer efficiency and comfort for care recipients. The purpose of this study was to test a redesigned RATD and compare its ergonomics during a transfer to those of a mechanical floor lift. METHODS: This was cross sectional protocol. As opposed to prior research which used a mannequin, caregivers in this study (N = 28) partnered with, and transferred, a mobility device user (N = 28) at three unique surfaces. Information about task demand and usability was collected from surveys after use of each device at each surface. RESULTS: Results indicated reduced physical demand (p = .004) and discomfort frequency (p = .01) in caregivers conducting the transfers with the RATD compared to the mechanical floor lift. Care recipients reported no significant differences between both transfer devices. Critiques with the interface, the harness and sling, and the robot's rigidity indicated more work is needed before introducing this technology to a larger market. Conclusions: The RATD represents a promising new intervention for transferring and handling care recipients who use wheelchairs. However, while caregivers report reduced physical demand and discomfort, more work is required to advance the ease of the human machine interface, the amount of space allowed for the robot to operate, and the ability of the care recipient to operate the technology independently.IMPLICATIONS FOR REHABILITATIONCaregivers report significant physical and mental stress while transferring clients in and out of a wheelchair.Clinical standard transfer equipment is limited in the space which it can be used.Robots, particularly those portable and powered, have the ability to not only make the transfer experience safer, but also expand the applications this equipment can provide.