Mechanism of Asymmetric Homologation of Alkenylboronic Acids with CF3-Diazomethane via Borotropic Rearrangement.

Density functional theory calculations have been performed to investigate the mechanism for the BINOL-catalyzed asymmetric homologation of alkenylboronic acids with CF3-diazomethane. The reaction proceeds via a chiral BINOL ester of the alkenylboronic acid substrate. The calculations reveal a complex scenario for the formation of the chiral BINOL-alkenylboronate species, which is the key intermediate in the catalytic process. The aliphatic alcohol additive plays an important role in the reaction. This study provides a rationalization of the stereoinduction step of the reaction, and the enantioselectivity is mainly attributed to the steric repulsion between the CF3 group of the diazomethane reagent and the γ-substituent of the BINOL catalyst. The complex potential energy surface obtained by the calculations is analyzed by means of microkinetic simulations.

Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones.

Asymmetric hydrogenation (AH) of tetrasubstituted olefins generating two stereocenters is still an open topic. There are only a few reports on the AH of tetrasubstituted olefins with conjugated functional groups, while this process can create useful intermediates for the subsequent elaboration of relevant end products. Most of the tetrasubstituted olefins successfully submitted to AH belong to a small number of functional classes; remarkably, the AH of tetrasubstituted acyclic enones still represents an unsolved challenge. Herein, we disclose a class of air-stable Ir-P,N catalysts, prepared in three steps from commercially available amino alcohols, that can hydrogenate, in minutes, a wide range of electronically and sterically diverse acyclic tetrasubstituted enones (including exocyclic ones) with high yields and high enantioselectivities. The factors responsible for the excellent selectivities were elucidated by combining deuterogenation experiments and theoretical calculations. The calculations indicated that the reduction follows an IrI /IrIII mechanism, in which enantioselectivity is controlled in the first migratory insertion of the hydride to the most electrophilic olefinic Cß and the formation of the hydrogenated product via reductive elimination takes place prior to the coordination of dihydrogen and the subsequent oxidative addition. The potential of the new catalytic systems is demonstrated by the derivatization of hydrogenation products.

Electrophilic Fluorination of Alkenes via Bora-Wagner-Meerwein Rearrangement. Access to ß-Difluoroalkyl Boronates.

The electrophilic fluorination of geminal alkyl substituted vinyl-Bmida derivatives proceeds via bora-Wagner-Meerwein rearrangement. According to DFT modelling studies this rearrangement occurs with a low activation barrier via a bora-cyclopropane shaped TS. The Bmida group has a larger migration aptitude than the alkyl moiety in the Wagner-Meerwein rearrangement of the presented electrophilic fluorination reactions.

Enantioselective Construction of Tertiary Fluoride Stereocenters by Organocatalytic Fluorocyclization.

1,1-Disubstituted styrenes with internal oxygen and nitrogen nucleophiles undergo oxidative fluorocyclization reactions with in situ generated chiral iodine(III)-catalysts. The resulting fluorinated tetrahydrofurans and pyrrolidines contain a tertiary carbon-fluorine stereocenter. Application of a new 1-naphthyllactic acid-based iodine(III)-catalyst allows the control of tertiary carbon-fluorine stereocenters with up to 96% ee. Density functional theory calculations are performed to investigate the details of the mechanism and the factors governing the stereoselectivity of the reaction.

P-Stereogenic N-Phosphine-Phosphite Ligands for the Rh-Catalyzed Hydrogenation of Olefins.

We have identified a successful family of simple P-stereogenic N-phosphine-phosphite ligands for the Rh-catalyzed asymmetric hydrogenation of olefins. These catalysts show excellent enantiocontrol for α-dehydroamino acid derivatives and α-enamides (ee's up to >99%) and promising results for the more challenging ß-analogues (ee's up to 80%). The usefulness of these catalytic systems was further demonstrated with the synthesis of several valuable precursors for pharmacologically active compounds, with ee's at least as high as the best ones reported previously (up to >99%).

Giving a Second Chance to Ir/Sulfoximine-Based Catalysts for the Asymmetric Hydrogenation of Olefins Containing Poorly Coordinative Groups.

This work identifies a family of Ir/phosphite-sulfoximine catalysts that has been successfully used in the asymmetric hydrogenation of olefins with poorly coordinative or noncoordinative groups. In comparison with analogue Ir/phosphine-sulfoximine catalysts previously reported, the presence of a phosphite group extended the range of olefins than can be efficiently hydrogenated. High enantioselectivities, comparable to the best ones reported, have been achieved for a wide range of olefins containing relevant poorly coordinative groups such as α,ß-unsaturated enones, esters, lactones, and lactams as well as alkenylboronic esters.

Extending the substrate scope of bicyclic p-oxazoline/thiazole ligands for Ir-catalyzed hydrogenation of unfunctionalized olefins by introducing a biaryl phosphoroamidite group.

This study identifies a series of Ir-bicyclic phosphoroamidite-oxazoline/thiazole catalytic systems that can hydrogenate a wide range of minimally functionalized olefins (including E- and Z-tri- and disubstituted substrates, vinylsilanes, enol phosphinates, tri- and disubstituted alkenylboronic esters, and α,ß-unsaturated enones) in high enantioselectivities (ee values up to 99 %) and conversions. The design of the new phosphoroamidite-oxazoline/thiazole ligands derives from a previous successful generation of bicyclic N-phosphane-oxazoline/thiazole ligands, by replacing the N-phosphane group with a π-acceptor biaryl phosphoroamidite moiety. A small but structurally important family of Ir-phosphoroamidite-oxazoline/thiazole precatalysts has thus been synthesized by changing the nature of the N-donor group (either oxazoline or thiazole) and the configuration at the biaryl phosphoroamidite moiety. The substitution of the N-phosphane by a phosphoroamidite group in the bicyclic N-phosphane-oxazoline/thiazole ligands extended the range of olefins that can be successfully hydrogenated.

P-Stereogenic Ir-MaxPHOX: A Step toward Privileged Catalysts for Asymmetric Hydrogenation of Nonchelating Olefins.

The Ir-MaxPHOX-type catalysts demonstrated high catalytic performance in the hydrogenation of a wide range of nonchelating olefins with different geometries, substitution patterns, and degrees of functionalization. These air-stable and readily available catalysts have been successfully applied in the asymmetric hydrogenation of di-, tri-, and tetrasubstituted olefins (ee's up to 99%). The combination of theoretical calculations and deuterium labeling experiments led to the uncovering of the factors responsible for the enantioselectivity observed in the reaction, allowing the rationalization of the most suitable substrates for these Ir-catalysts.

Extending the Substrate Scope in the Hydrogenation of Unfunctionalized Tetrasubstituted Olefins with Ir-P Stereogenic Aminophosphine-Oxazoline Catalysts.

Air-stable and readily available Ir-catalyst precursors modified with MaxPHOX-type ligands have been successfully applied in the challenging asymmetric hydrogenation of tetrasubstituted olefins under mild reaction conditions. Gratifyingly, these catalyst precursors are able to efficiently hydrogenate not only a range of indene derivatives (ee's up to 96%) but also 1,2-dihydronapthalene derivatives and acyclic olefins (ee's up to 99%), which both constitute the most challenging substrates for this transformation.

Stereospecific S(N)2@P reactions: novel access to bulky P-stereogenic ligands.

The stereospecific hydrolysis of bulky aminophosphine boranes is reported for the first time. The resulting phosphinous acid boranes, upon activation, undergo stereospecific nucleophilic substitution reaction at the phosphorous center with amine nucleophiles. The combination of these two processes provides a novel access to bulky P*-ligands.

Predicción del riesgo coronario en la Artritis Reumatoide mediante variables asociadas a su actividad inmunológica / Prediction of coronary risk in Rheumatoid Arthritis by variables associated with its immunological activity

Introducción: el pronóstico del riesgo coronario a partir de la actividad en la artritis reumatoide constituye un problema aún vigente. Objetivos: evaluar la capacidad predictiva de factor reumatoide, proteína C reactiva, C3-C4 complemento, y el índice de actividad de la enfermedad empleándose 28 articulaciones sobre el riesgo coronario en esta enfermedad Métodos: se realizó un estudio longitudinal-prospectivo en una muestra de 50 pacientes. Los niveles séricos de: factor reumatoide, proteína c reactiva, C3, C4 complemento, lipoproteína(a), apolipoproteínas B y A1 fueron determinados por método inmunoturbidimétrico, mientras Colesterol total, colesterol de lioproteína de baja y alta densidad colesterol por ensayo enzimocolorimétrico. La velocidad de sedimentación globular fue determinada por método de Westergreen. El riesgo coronario se definió según valores deseables, o no, de los indicadores: lipoproteína (a), cocientes Apolipoproteína B/Apolipoproteína A1, colesterol de lipoproteína de baja densidad/colesterol de lipoproteína de alta densidad, Apolipoproteína B/colesterol de lipoproteína de baja densidad e índice aterogénico. Se empleó el programa estadístico SPSS, versión 18.0 para el análisis. Resultados: el perfil de actividad inmunoinflamatoria de la captación mostró adecuada capacidad predictiva sobre el riesgo coronario [regresión logística: Test de Hosmer y Lemeshow: (p= 0,54), porciento global de predicción correcta: 64 y 90 por ciento, al primer y tercer mes]. Las variables C3 complemento, C4 complemento e índice de actividad de la enfermedad contribuyeron a la predicción directa del riesgo coronario según cocientes Apolipoproteína B/Apolipoproteína A1, colesterol de lipoproteína de baja densidad/colesterol de lipoproteína de alta densidad e índice aterogénico (p asociada al Odds ratio ≤ 0,05). Los marcadores del metabolismo lipoproteico estudiados, excepto el cociente Apolipoproteína B/colesterol de lipoproteína de baja densidad, correspondientes al mes y tercer mes de seguimiento fueron pronosticados a partir de C4, C3 complemento, índice de actividad de la enfermedad y proteína C reactiva al momento de la captación (regresión lineal: R2 con p asociada ≤ 0,05). El factor reumatoide no contribuyó a la predicción longitudinal del riesgo coronario estudiado. Conclusiones: se demostró la utilidad del perfil de marcadores de actividad de la artritis reumatoide analizados en la predicción del riesgo coronario(AU)

Introduction: the prognosis of coronary risk from the activity in rheumatoid arthritis is still a problem. Objectives: to evaluate the predictive capacity of rheumatoid factor, C-reactive protein, C3-C4 complement, and the activity index of the disease using 28 joints on coronary risk in this disease Methods: a longitudinal-prospective study was carried out in a sample of 50 patients. The serum levels of: rheumatoid factor, c-reactive protein, C3, C4 complement, lipoprotein (a), apolipoproteins B and A1 were determined by immunoturbidimetric method, while total cholesterol, low-density lipoprotein cholesterol and high-density cholesterol by enzyme-correlated assay. The erythrocyte sedimentation rate was determined by the Westergreen method. Coronary risk was defined according to desirable values, or not, of the indicators: lipoprotein (a), Apolipoprotein B / Apolipoprotein A1 ratios, low density lipoprotein cholesterol / high density lipoprotein cholesterol, Apolipoprotein B / low lipoprotein cholesterol density and atherogenic index. The statistical program SPSS, version 18.0 was used for the analysis. Results: the profile of immunoinflammatory activity of the uptake showed adequate predictive capacity on coronary risk [logistic regression: Hosmer and Lemeshow test: (p = 0.54), overall percentage of correct prediction: 64 and 90 percent, to the first and third month]. The variables C3 complement, C4 complement and index of disease activity contributed to the direct prediction of coronary risk according to the Apolipoprotein B / Apolipoprotein A1, low density lipoprotein cholesterol / high density lipoprotein cholesterol and atherogenic index (p associated with Odds ratio ≤ 0.05). The lipoprotein metabolism markers studied, except for the Apolipoprotein B / low density lipoprotein cholesterol ratio, corresponding to the month and third month of follow-up were predicted from C4, C3 complement, disease activity index and C-reactive protein at the time of the uptake (linear regression: R2 with associated p≤0.05). The rheumatoid factor did not contribute to the longitudinal prediction of coronary risk studied. Conclusions: the usefulness of the profile of activity markers of rheumatoid arthritis analyzed in the prediction of coronary risk was demonstrated(AU)

Actividad de la enfermedad y riesgo coronario en la artritis reumatoide. Evidencia de relación causal

La alteración simultánea de marcadores inflamatorios y de riesgo coronario en la artritis reumatoide sustenta la hipótesis de actividad autoinmune como causa de riesgo coronario en esta enfermedad. Para analizar la evolución y asociación temporal de los marcadores de actividad de la enfermedad y riesgo coronario: factor reumatoide, proteína C reactiva, C3-C4 complemento, DAS28, lipoproteína(a) e índices aterogénicos se realizó un estudio longitudinal-prospectivo en pacientes portadores de artritis reumatoide atendidos en el servicio de Reumatología del hospital Faustino Pérez de Matanzas. Fueron determinados los marcadores antes mencionados en los momentos: inclusión (sin tratamiento), primer y tercer mes luego de inicio de terapia con fármacos antirreumáticos inductores de remisión. El programa estadístico SPSS, versión 18.0, fue empleado para el procesamiento de los datos. Los marcadores: DAS28, factor reumatoide (en subgrupo seropositivo para este anticuerpo), lipoproteína(a), índice LDL/HDL colesterol e índice aterogénico disminuyeron al mes de comenzar tratamiento [Test de Friedman: (p0,05). Los resultados apoyan el papel causal de la actividad inflamatoria crónica sobre la dislipoproteinemia aterogénica en la artritis reumatoide

The simultaneous alteration of inflammatory and coronary risk's markers on the rheumatoid arthritis support the autoimmunity activity as cause of coronary risk hypothesis in that disease. In order to analyze the evolution and temporary association between the activity and coronary risk markers: rheumatoid factor, c reactive protein, C3-C4 complement, DAS-28, lipoprotein(a) and atherogenic indexes was carried out a longitudinal-prospective study in rheumatoid arthritis patients attended on the Faustino Perez hospital rheumatology's service, Matanzas city. The markers above mentioned was assessmented at: baseline (without treatment), first and third months after of disease modifier anti rheumatic drogs therapy beginning. The 18.0 version SPSS program was used for analyzing results. The DAS-28, rheumatoid factor (in seropositive patients), lipoprotein(a), LDL/HDL cholesterol and atherogenic index markers declined first month after starting treatment [Friedman's Test: (p 0,05). The results support the chronic inflammatory activity's causal role on the atherogenic dislipoproteinemia on the rheumatoid arthritis

Factor reumatoide con marcadores de riesgo aterogénico en pacientes con artritis reumatoide / Rheumatoid factor with atherogenic risk markers in rheumatoid arthritis patients

INTRODUCCIÓN: el factor reumatoide ha sido el autoanticuerpo más asociado a la artritis reumatoide. A pesar de los avances logrados en el conocimiento de su patogenia, el análisis de la relación entre este anticuerpo y marcadores de riesgo coronario no ha sido agotado en esta enfermedad. OBJETIVOS: evaluar la asociación del factor reumatoide con los marcadores de riesgo coronario lipoproteína (a), índices apolipoproteína B/apolipoproteína A1, LDL/HDL colesterol, Apolipoproteína B/LDL colesterol e índice aterogénico; así como el valor predictivo de dicho anticuerpo sobre estos marcadores. MÉTODOS: se realizó un estudio observacional analítico y transversal en una muestra de pacientes portadores de artritis reumatoide y controles, aparente sanos, de la provincia de Matanzas, en el período junio/2011 a marzo/2014. El programa estadístico SPSS fue empleado para el análisis de los resultados. RESULTADOS: el factor reumatoide mostró asociación con los índices aterogénico, LDL/HDL colesterol y Apolipoproteína B/LDL colesterol; utilidad para estimar los dos primeros, y valor predictivo sobre el índice aterogénico independiente de los marcadores de actividad de la enfermedad: proteína c reactiva, C3 complemento, C4 complemento, y DAS28 en pacientes con la variedad seropositiva para éste autoanticuerpo [r de Pearson = 0,632; 0,345; (-) 0,359; R2= 0,406; 0,119 (p < 0,05), al respecto]. CONCLUSIONES: la presente investigación demostró relación, valor predictivo, y posible estratificación del riesgo coronario indirecto, a partir del título sérico de factor reumatoide IgM en pacientes con artritis reumatoide seropositiva; y motiva a profundizar el estudio de igual problema científico con autoanticuerpos asociados a enfermedades autoinmunes relacionadas con elevada morbimortalidad cardiovascular.

INTRODUCTION: rheumatoid factor is the autoantibody most commonly associated with rheumatoid arthritis. Despite the considerable progress achieved in the study of its pathogenesis, further analysis is required of the relationship between this antibody and coronary risk markers. OBJECTIVES: evaluate the association between rheumatoid factor and the coronary risk markers lipoprotein(a), apolipoprotein B / apolipoprotein A1, LDL / HDL cholesterol, apolipoprotein B / LDL cholesterol, and atherogenic index, as well as the predictive value of this antibody with respect to such markers. METHODS: an observational cross-sectional analytical study was conducted of a sample of patients with rheumatoid arthritis and apparently healthy controls from the province of Matanzas from June 2011 to March 2014. Results were analyzed with the statistical software SPSS. RESULTS: rheumatoid factor showed an association with atherogenic indices, LDL / HDL cholesterol and apolipoprotein B / LDL cholesterol, as well as usefulness to estimate the first two and predictive value for the atherogenic index irrespective of markers of disease activity: C-reactive protein, C3 complement, C4 complement and DAS28 in patients seropositive for this autoantibody [Pearson r = 0.632; 0.345; (-) 0.359; R2= 0.406; 0.119 (p < 0.05), respectively]. CONCLUSIONS: the study showed the relationship, predictive value and possible indirect stratification of coronary risk based on the serum levels of rheumatoid factor IgM in patients with seropositive rheumatoid arthritis. Further examination should be conducted of this scientific problem in reference to autoantibodies associated with autoimmune diseases of high cardiovascular morbidity and mortality.

Marcadores de respuesta inflamatoria y riesgo coronario en pacientes con artritis reumatoide / Markers of inflammatory response and coronary risk in patients with rheumatoid arthritis

Objetivo: evaluar la asociación entre los niveles séricos de Proteína C Reactiva e índices Apoproteína B/Apoproteína A1, Apoproteína B/LDL colesterol, LDL/HDL colesterol, índice aterogénico, lipoproteína (a) y componentes C3 y C4 del complemento sérico; así como la capacidad predictiva de la proteína C Reactiva, C3 y C4 complemento sobre los parámetros del lipidograma mencionados, se realizó un estudio transversal en pacientes portadores de Artritis Reumatoide y controles sanos de la provincia Matanzas. Métodos: las determinaciones de los parámetros individuales fueron realizadas por método inmunoturbidimétrico y enzimocolorimétrico. El Software estadístico SPSS, versión 18,0 fue empleado para el procesamiento de los resultados. Resultados: la correlación de Spearman detectó asociación de la proteína C Reactiva con los índices ApoB/LDL colesterol y LDL/HDL colesterol exclusivamente en los pacientes, Rho de Spearman= 0,439 (p=0,002); -0,300 (p=0,043), respectivamente; mientras manifestó asociación de esta con el C4 complemento en ambos grupos, Rho de Spearman= 0,355 (p=0,015); 0,376 (p=0,000), pacientes y controles, respectivamente. La proteína C reactiva predijo el índice ApoB/LDL colesterol mediante el análisis de regresión lineal en los pacientes: R²=0,192 F=10,488 (p=0,002), en tanto las proteínas del complemento C3 y C4 estimaron significativamente el nivel de lipoproteína(a); R²=0,170 F=4,396 (p=0,018). Los resultados apoyan la hipótesis del vínculo entre respuesta inflamatoria y predominio de Lipoproteínas de baja densidad más proaterogénicas; así como la posible estimación de marcadores del riesgo coronario relacionados con el metabolismo lipoproteico a partir de los niveles séricos de Proteína C Reactiva, C3 y C4 complemento en pacientes con Artritis Reumatoide...

Objective: evaluate the association between serum levels of C-reactive protein and the indices apoprotein B/apoprotein A1, apoprotein B/LDL cholesterol, LDL/HDL cholesterol, atherogenic index, lipoprotein (a) and serum complement components C3 and C4, as well as the prediction capacity of C-reactive protein, C3 and C4 complement with respect to the above mentioned lipidogram parameters. A cross-sectional study was conducted of patients with rheumatoid arthritis and healthy controls from the province of Matanzas. Methods: individual parameters were determined by immunoturbidimetry and enzymatic colorimetry. Results were processed with the statistical software SPSS version 18.0. Results: spearman rank correlation spotted an association of C-reactive protein with indices ApoB/LDL cholesterol and LDL/HDL cholesterol exclusively in patients, Spearman's Rho = 0.439 (p=0.002); -0.300 (p=0.043); -0.300 (p=0.043), respectively; and an association of C-reactive protein with C4 complement in both groups, Spearman's Rho = 0.355 (p=0.015); 0.376 (p=0.000), patients and controls, respectively. C-reactive protein predicted the ApoB/LDL cholesterol index by linear regression analysis in patients: R²=0.192 F=10.488 (p=0.002), whereas C3 and C4 complement proteins significantly estimated the level of lipoprotein (a): R²=0.170 F=4.396 (p=0.018). Results support the hypothesis about the link between inflammatory response and the predominance of more proatherogenic low density lipoproteins, as well as the potential estimation of coronary risk markers related to lipoprotein metabolism based on serum levels of C-reactive protein, C3 and C4 complement in patients with rheumatoid arthritis...

Minimally invasive tibial bone harvesting under intravenous sedation.

PURPOSE: Collecting high amounts of autogenous bone often results in considerable donor site morbidity. The hypothesis evaluated with this prospective study is that a modified approach for tibial bone harvesting using a minimally invasive access under local anesthesia plus sedation in an office setting compares favorably in terms of amount of bone harvested, morbidity, and patient satisfaction with more aggressive approaches previously reported. PATIENTS AND METHODS: Thirty-eight patients (18 women, 10 men) were treated using this method and followed prospectively. A medial approach to the proximal tibia was performed in all cases. A 10 mm incision gives access to an 8 mm manual trephine, which creates a bony window. Cancellous bone is released from the proximal compartment and a bone filter connected to suction allows fast removal of bone particles. Amount of bone harvested (compressed and non-compressed), surgical time, and complications were recorded. RESULTS: Mean surgical time was 14 minutes (range, 9 to 20 minutes). Volume of compressed cancellous bone ranged between 18 and 30 cc (mean, 28 cc). CONCLUSION: Tibial bone harvesting through a medial minimally invasive approach with a bone filter yields satisfactory results in terms of bone volume, surgical time, and patient satisfaction.