BIMP-Catalyzed 1,3-Prototropic Shift for the Highly Enantioselective Synthesis of Conjugated Cyclohexenones.

A bifunctional iminophosphorane (BIMP)-catalysed enantioselective synthesis of α,β-unsaturated cyclohexenones through a facially selective 1,3-prototropic shift of β,γ-unsaturated prochiral isomers, under mild reaction conditions and in short reaction times, on a range of structurally diverse substrates, is reported. α,β-Unsaturated cyclohexenone products primed for downstream derivatisation were obtained in high yields (up to 99 %) and consistently high enantioselectivity (up to 99 % ee). Computational studies into the reaction mechanism and origins of enantioselectivity, including multivariate linear regression of TS energy, were carried out and the obtained data were found to be in good agreement with experimental findings.

Highly Enantioselective Extraction of Phenylglycine by a Chiral Macrocyclic Receptor Based on Supramolecular Interactions.

Using supramolecular interactions, a novel macrocyclic receptor is able to selectively extract zwitterionic phenylglycine from neutral aqueous solutions into chloroform with up to 91.8% . Modeling studies, nuclear magnetic resonance experiments, and X-ray diffraction analysis were carried out to explain the high enantioselectivity observed.

The True Catalyst Revealed: The Intervention of Chiral Ca and Mg Phosphates in Brønsted Acid Promoted Asymmetric Mannich Reactions.

The acetylacetone-benzaldimine Mannich reaction catalyzed by Mg(II) and Ca(II) salts of chiral phosphoric acids (CPA) has been investigated computationally by QM/MM methods. Enantioselectivity in this reaction is both larger than and in the opposite sense to that observed for the same reaction catalyzed by the protic CPA catalyst alone. We present a mechanistic model from which the characteristic differences between these metal and metal-free catalysts, which can coexist in the same reaction mixture, can be understood.

Enantioselectivity in CPA-catalyzed Friedel-Crafts reaction of indole and N-tosylimines: a challenge for guiding models.

Qualitative reaction models or predicting guides are a very useful outcome of theoretical investigations of organocatalytic reaction mechanism that allow forecasting of the degree and sense of the enantioselectivity of reactions involving novel substrates. However, application of these models can be unexpectedly challenging in reactions affected by a large number of conformations and potential control of the enantioselectivity by different reaction steps. The QM/MM study of the Friedel-Crafts reaction between indole and the N-tosylimide of benzaldehyde catalysed by different CPA reveals that the reaction consists of two CPA-assisted steps: the addition of the two reagents to yield a Wheland intermediate, and its re-aromatization.

A cleft type receptor which combines an oxyanion hole with electrostatic interactions.

A receptor for carboxylic acids which combines an oxyanion-hole structure with electrostatic forces has been prepared. X-ray diffraction studies have been carried out to evaluate the geometry of both the free receptor and its associated species with several carboxylic acids and many different arrangements have been discovered for the H-bond pattern in the associated species.

Phosphazene Catalyzed Addition to Electron-Deficient Alkynes: The Importance of Nonlinear Allenyl Intermediates upon Stereoselectivity.

An ONIOM(QM/MM) study on the mechanism of the Michael addition to triple bonds catalyzed by chiral diiminophosphorane catalysts has been performed to understand the stereoselectivity of the product olefin. Our results are consistent with the experimental enantioselectivity, but more importantly, reveal that the Z vs E preference depends on the influence of the catalyst upon the geometry of the allenyl enolate formed in the addition step. These intermediates show an innate preference for a (Z)-configuration, although this can be suppressed by steric interactions due to a catalyst.

A molecular receptor selective for zwitterionic alanine.

A molecular receptor has been synthesized joining an aza-crown ether with a chiral chromane which mimics the oxyanion hole of the enzymes. With this receptor an apolar host-guest complex with zwitterionic alanine has been achieved through the formation of up to seven H-bonds. This complex allows the extraction of aqueous alanine to a chloroform phase, while other natural amino acids are poorly extracted or are not extracted at all.

A bio-inspired enantioselective small-molecule artificial receptor for β adrenergic agonists and antagonists and its application for enantioselective extraction.

Administration of enantiomerically pure β-adrenergic agonists and antagonists increases their activity and reduces side effects. We report here a small-molecule artificial receptor (SMAR) that, by mimicking the β-adrenergic receptor, is able to enantioselectively extract commercial β-adrenergic interacting drugs. The selectivity is justified according to DFT calculations and X-ray diffraction experiments.

A Practical Guide for Predicting the Stereochemistry of Bifunctional Phosphoric Acid Catalyzed Reactions of Imines.

Chiral phosphoric acids have become powerful catalysts for the stereocontrolled synthesis of a diverse array of organic compounds. Since the initial report, the development of phosphoric acids as catalysts has been rapid, demonstrating the tremendous generality of this catalyst system and advancing the use of phosphoric acids to catalyze a broad range of asymmetric transformations ranging from Mannich reactions to hydrogenations through complementary modes of activation. These powerful applications have been developed without a clear mechanistic understanding of the reasons for the high level of stereocontrol.

QM/MM study on the enantioselectivity of spiroacetalization catalysed by an imidodiphosphoric acid catalyst: how confinement works.

The mechanism for the spiroacetalization of enol-ethers 1 and 2 promoted by chiral phosphoric acid (CPA) catalyst (I) and by chiral imidodiphosphoric acid catalyst (II) has been investigated by QM/MM methods. The computed levels of enantioselectivity following exhaustive conformational analysis is in close agreement with the sense and magnitude of experimental results. Small substrates fit inside catalyst I to yield both enantiomers, in agreement with the absence of asymmetric induction for this reaction, while for catalyst II chiral discrimination between TS structures is possible.

Prevalence of Dirofilaria immitis in dogs from Barcelona: Validation of a geospatial prediction model.

Like other vector borne infections, the distribution of dirofilariosis caused by Dirofilaria immitis is influenced by climatic factors, which regulate the diversity and abundance of mosquito species able to transmit the parasite. Geographical Information Systems (GIS) can predict the distribution and epidemiological behavior of dirofilariosis based on temperature and humidity data. This study analyses the prevalence and current distribution of canine dirofilariosis in the province of Barcelona (Northeastern Spain), and uses a GIS model to evaluate the relationship between the spatial distribution of positive cases and different geo-environmental factors.

Human subcutaneous/ocular dirofilariasis in the Russian Federation and Belarus, 1997-2013.

Objectives: This study was performed to determine the yearly frequency, trends in spread, and clinical-epidemiological characteristics of human subcutaneous/ocular dirofilariasis (HSOD) in the Russian Federation and Belarus.

Methods: The surveillance data of HSOD cases occurring between January 1997 and June 2013, obtained from the regional health administrations of the Russian Federation and Belarus, were analyzed. The spatial distribution of cases was assessed using a GIS map, and the clinical-epidemiological characteristics were defined using 719 cases for which information on anatomical location, age, sex, and area of residence was available.

Origins of asymmetric phosphazene organocatalysis: computations reveal a common mechanism for nitro- and phospho-aldol additions.

We report a hybrid density functional theory-molecular mechanics study of the mechanism of the addition of nitroalkanes and phosphonates to benzaldehyde catalyzed by a chiral phosphacene catalyst developed by Ooi and co-workers. Our results are consistent with a reaction mechanism in which a catalyst molecule simultaneously interacts by hydrogen bonds with the nucleophile and the electrophile, transferring a proton to the aldehyde in concert with carbon-carbon bond formation. Despite the C2 symmetry of this class of organocatalyst, substrate recognition, and asymmetric induction in both reaction classes studied relies on interactions with nonequivalent N-H bonds that break symmetry.

Regional warming and emerging vector-borne zoonotic dirofilariosis in the Russian Federation, Ukraine, and other post-Soviet states from 1981 to 2011 and projection by 2030.

We analyze through a climatic model the influence of regional warming on the geographical spreading and potential risk of infection of human dirofilariosis in Russia, Ukraine, and other post-Soviet states from 1981 to 2011 and estimate the situation by 2030. The model correctly predicts the spatiotemporal location of 97.10% of 2154 clinical cases reported in the area during the studied period, identified by a retrospective review of the literature.

Intergrative health care method based on combined complementary medical practices: rehabilitative acupuncture, homeopathy and chiropractic.

Background: There are various models of health care, such as the epidemiological, psychosocial, sociological, economic, systemic of Neuman, cognitive medicine or ecological, ayurvedic, supraparadigmatic among others. All of them are seeking to combine one or more elements to integrate a model of health care. The article presents a systemic approach to health care with complementary medicines such as rehabilitative acupuncture, homeopathy and chiropractic through the application of a method of holistic care and integrated approach.

Geo-environmental model for the prediction of potential transmission risk of Dirofilaria in an area with dry climate and extensive irrigated crops. The case of Spain.

Zoonotic filarioses caused by Dirofilaria immitis and Dirofilaria repens are transmitted by culicid mosquitoes. Therefore Dirofilaria transmission depends on climatic factors like temperature and humidity. In spite of the dry climate of most of the Spanish territory, there are extensive irrigated crops areas providing moist habitats favourable for mosquito breeding.

[Elaboration of the SPM template for the standardization of SPECT images with 123I-Ioflupane].

Purpose: Statistical parametric mapping (SPM) is a widely used produced for normalization of functional images. This study has aimed to develop a normalization template of (123)I-Ioflupane SPECT-imaging DaTSCAN(®), GE Healthcare), not available in SPM5, and to validate it compared to other quantification methods.

Material And Methods: In order to write the template we retrospectively selected 26 subjects who had no evidence of nigrostriatal degeneration and whose age distribution was similar to that of the patients in the usual practice of our Department: 2 subjects (7.

Mechanism of amination of β-keto esters by azadicarboxylates catalyzed by an axially chiral guanidine: acyclic keto esters react through an E enolate.

The mechanism of the reaction between di-tert-butyl azadicarboxylate and 1,3-dicarbonyl compounds catalyzed by an axially chiral guanidine is investigated by density functional theory methods. The results show that the catalyst acts simultaneously as a Brønsted base and an acid catalyst, and the mechanism is similar to that of the related BINOP organocatalysts. Surprisingly, cyclic and acyclic β-keto esters yield opposite enantiomers; the calculations demonstrate that this is a consequence of the preferred enolate geometry in the transition structures.

Hydrogen-bond stabilization in oxyanion holes: grand jeté to three dimensions.

We recently reported crystallographic evidence that the hydrogen bonds which can stabilize oxygen-centered negative charge within enzyme oxyanion holes are rarely found in the place they should be expected on the basis of the analysis of small-molecule crystal structures. We investigated this phenomenon using calculations on simplified active site models. A recent paper suggested that several aspects of the analysis required further exploration.

Sulfonamide carbazole receptors for anion recognition.

Carbazole-based receptors functionalized with two sulfonamide groups have been synthesized and their properties as anion receptors have been evaluated. The receptor with bis(trifluoromethyl)aniline groups has shown a very high affinity for halide ions, especially remarkable as only two hydrogen bonds are formed in the complexes. (1)H NMR and fluorescence titrations have been carried out and binding constants up to 7.

A model for the enantioselectivity of imine reactions catalyzed by BINOL-phosphoric acid catalysts.

BINOL-phosphoric acid catalysts have been used successfully in many reactions involving imines. In this paper, we present a model, based on DFT calculations, for describing the degree and sense of the enantioselectivity of these reactions that is able to predict the correct enantioselectivity for the reactions in more than 40 recent publications. We rationalize the different factors on which the enantioselectivity depends, focusing on the E- or Z-preference of the transition structures and the orientation of the catalyst with respect to the electrophile.

Synthesis of monoacylated derivatives of 1,2- cyclohexanediamine. Evaluation of their catalytic activity in the preparation of Wieland-Miescher ketone.

Ureas, carbamoyl derivatives, amides, and sulfonamides can be easily prepared from the strained (R,R)-cylohexanediamine urea (1) in high yield, leaving a free amino group that shows good catalytic activity in intramolecular aldol condensations. The preparation of Wieland-Miescher ketone has been studied with these catalysts.

How reliable are DFT transition structures? Comparison of GGA, hybrid-meta-GGA and meta-GGA functionals.

There have been many comparisons of computational methods applied to ground states, but studies of organic reactions usually require calculations on transition states, and these provide a different test of the methods. We present calculations of the geometries of nineteen covalent-bond forming transition states using HF and twelve different functionals, including GGA, hybrid-GGA and hybrid meta-GGA approaches. For the calculation of the TS geometries, the results suggest that B3LYP is only slightly less accurate than newer, computationally more expensive methods, and is less sensitive to choice of integration grid.

Imidazolidinone intermediates in prolinamide-catalyzed aldol reactions.

The reaction between acetone and 4-nitrobenzaldehyde catalyzed by aniline prolinamide 1 was studied in depth. Working in different solvents with equimolar amounts of reagents and monitoring the reaction by 1H NMR, we detected and identified several imidazolidinones, such as those of the acetone 4, the aldol products 5a and 5b, and aldehydes 10a and 10b. According to our results, these compounds could influence the reaction rate and diminish product enantioselectivity.