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

A bifunctional iminophosphorane (BIMP)-catalysed enantioselective synthesis of α,ß-unsaturated cyclohexenones through a facially selective 1,3-prototropic shift of ß,γ-unsaturated prochiral isomers, under mild reaction conditions and in short reaction times, on a range of structurally diverse substrates, is reported. α,ß-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.

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. Alkaline earth salts with chiral phosphate counterions are found to be more catalytically active than the protic form, and the Ca(II) and Mg(II) CPA salts react via different mechanisms, with a higher coordination number favored by calcium over magnesium. In the well-ordered chiral cavities around these metal centers, asymmetric induction arises from the steric interaction with the imine protecting group in the unfavorable pathway, with both substrates adopting well-defined conformations. These mechanistic models have allowed us to rationalize the stereochemical outcome across a range of bimolecular reactions promoted by divalent metal phosphates formed with different CPAs.

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. The relevance of the second step depends on the catalyst: it changes the sense of the expected stereoselectivity for a BINOP-derived CPA but is irrelevant in the reaction catalysed by a VAPOL-derived imidodiphosphoric acid catalyst. Although the relative energies of the TSs can be rationalized considering the steric interactions with the catalyst, the possibility of additional H-bonds, or the relative stability of the conformation of the reagents, predicting the enantioselectivity is not possible using qualitative guides.

Low-Power Highly Robust Resistance-to-Period Converter.

This paper presents a novel structure of Resistance- to-Period (R-T) Converter highly robust to supply and temperature variations. Robustness is achieved by using the ratiometric approach so that complex circuits or high accuracy voltage references are not necessary. To prove the proposed architecture of R-T converter, a prototype was implemented in a 0.18 µ m CMOS process with a single supply voltage of 1.8 V and without any stable reference voltage. Experimental results show a maximum ±1.5% output signal variation for ±10% supply voltage variation and in a 3⁻95 ° C temperature range.

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. This Account describes investigations into the mechanism of the phosphoric acid catalyzed addition of nucleophiles to imines, focusing on binaphthol-based systems. In many cases, the hydroxyl phosphoric acid can form a hydrogen bond to the imine while the P═O interacts with the nucleophile. The single catalyst, therefore, activates both the electrophile and the nucleophile, while holding both in the chiral pocket created by the binaphthol and constrained by substituents at the 3 and 3' positions. Detailed geometric and energetic information about the transition states can be gained from calculations using ONIOM methods that combine the advantages of DFT with some of the speed of force fields. These high-level calculations give a quantitative account of the selectivity in many cases, but require substantial computational resources. A simple qualitative model is a useful complement to this complex quantitative model. We summarize our calculations into a working model that can readily be sketched by hand and used to work out the likely sense of selectivity for each reaction. The steric demands of the different parts of the reactants determine how they fit into the chiral cavity and which of the competing pathways is favored. The preferred pathway can be found by considering the size of the substituents on the nitrogen and carbon atoms of the imine electrophile, and the position of the nucleophilic site on the nucleophile in relation to the hydrogen-bond which holds it in the catalyst active site. We present a guide to defining the pathway in operation allowing the fast and easy prediction of the stereochemical outcome and provide an overview of the breadth of reactions that can be explained by these models including the latest examples.

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. This leads to two distinct mechanisms in which the kinetic basis for (E) or (Z)-stereoselectivity is determined by a different step. Bifunctional iminophosphorane catalysts are found to use steric interactions to override innate stereoelectronic effects of the allenyl enolate reactive intermediate.

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. Due to the chiral nature of the receptor, enantioselective extraction from the aqueous alanine solution to a chloroform phase takes place. X-Ray analysis combined with anisotropic effects, NOE and CD studies revealed the absolute configuration of both strong and weak complexes. Modelling studies also support the proposed structures. The presence of an oxyanion-hole motif in this structure was corroborated by X-ray diffraction studies.

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.

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. Unlike reactions catalysed by CPA or CPA derivatives in which steric effects and substrate distortion controls enantioselectivity, we show that chiral discrimination results from the restricted area and direction of possible hydrogen-bonding interactions with a more confined catalyst structure.

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. The origin of the stereo and diastereoselectivity is discussed in terms of steric effects and of the conformations adopted by the reactants, and the most favorable transition structure results from minimal geometric distortion energies. A rational model for predicting the major stereoisomer of reactions catalyzed by this chiral phosphacene, based on the qualitative assessment of steric interactions, is given.

Application of matrix-assisted laser desorption and ionization time of flight mass spectrometry to the study of the proteinaceous binders in paint: blue paint composition in the series "The Life of Virgin" by Alonso Cano (17th century) as a case study.

The identification of proteinaceous materials in paint constituents provides very valuable information regarding the techniques used by the painter and the most suitable procedures for conserving and restoring their works. Although the analysis of proteinaceous materials is nowadays a common task when dealing with works of art, the reliable detection and identification of protein traces is still complicated, particularly when very small samples can be taken that may contain a mixture of different organic materials (oils, waxes, resins, gums etc.). We therefore proposed a proteomic approach to investigate protein materials in paintings at trace levels in order to obtain a better understanding of the painter's technique. After trypsin digestion of the paint samples, mass spectra were obtained by matrix-assisted laser desorption and ionization time of flight mass spectrometry (MALDI-TOF-MS) and they were compared with the Mascot database and with theoretical digested proteins. This study contributes to the knowledge about the technique used by Alonso Cano (Granada, Spain, 1601-1667), one of the most original and brilliant artists from the Spanish Golden Age (17th century), in the series called the Life of the Virgin (six paintings), part of the iconographic program about the life of the Virgin Mary, nowadays seen in the main chapel of Granada Cathedral. The objective of the present study was to test the use of proteinaceous material, mainly egg yolk, in the paint used by Cano, as suggested in previous research, although this would have been unusual at that time when most artists used oil paints. Based on the results of the analysis here presented, the use of protein in the binding media can most likely be excluded.

An integrated low-power lock-in amplifier and its application to gas detection.

This paper presents a new micropower analog lock-in amplifier (LIA) suitable for battery-operated applications thanks to its reduced size and power consumption as well as its operation with single-supply voltage. The proposed LIA was designed in a 0.18 µm CMOS process with a single supply voltage of 1.8 V. Experimental results show a variable DC gain ranging from 24.7 to 42 dB, power consumption of 417 µW and integration area of 0.013 mm2. The LIA performance was demonstrated by measuring carbon monoxide concentrations as low as 1 ppm in dry N2. The experimental results show that the response to CO of the sensing system can be considerably improved by means of the proposed LIA.

Mechanism of amination of ß-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 ß-keto esters yield opposite enantiomers; the calculations demonstrate that this is a consequence of the preferred enolate geometry in the transition structures. Literature evidence suggests that other organocatalytic reactions show similar behavior.

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. In this paper we: (i) review the results of our crystallographic study; (ii) report molecular dynamics studies which investigate the effect of protein movement; (iii) report ONIOM calculations which trace the reaction coordinate for an oxyanion hole reaction in the presence of a complete enzyme active site. These results show that the limitations of gas phase calculations on simplified models do not invalidate our comparison of competing active site geometries. These new results reaffirm the conclusion that oxyanion holes are not usually stabilized by planar arrangements of H-bonds, and that this sub-optimal transition state stabilization leads to better overall catalysis.

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.

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. We conclude that the use of B3LYP and related functionals is still appropriate for many studies of organic reaction mechanisms.

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 7.9 × 10(6) M(-1) have been reached. X-ray structures have been obtained and a modelling study has shown the possible reasons for the large affinity of these compounds for halide anions.

Parameterizing a tumor humeral prosthesis and development of a set.

BACKGROUND: The reconstruction of the proximal humerus is possible from the resection of the tumor and the placement of a prosthesis. In some cases, they do not meet the anthropometric aspects of the patients. OBJECTIVE: To determine the parameters to size the components of a humeral prosthesis and the development of a set, using design software. METHOD: Forty patients were selected for prostheses, radiographs and CT scans were analyzed and statistical tests were applied to the measurements. RESULTS: The length of the tumors was 8-20 cm. The minimum length of the humerus was 28 cm and 33 cm the maximum. Correlation was observed between the humerus and the tumor and the height of the patient with p = 0.93088 and p = 0.904564, respectively; humerus diameter, p = 0.2345. The set will include three components, diameter 6-10 mm, and length of 24, 26 and 28 cm. Three modular spacers with lengths of 6, 8.5 and 13 cm. Crowns 6.5 and 8.5 cm long, 1.3 cm in diameter and 5 mm nut. CONCLUSION: With the development of the set, poorly calculated resections and adaptation to any humerus size can be resolved.

ANTECEDENTES: La reconstrucción del húmero proximal es posible a partir de la resección del tumor y la colocación de una prótesis. En algunos casos, las prótesis no cumplen con los aspectos antropométricos de los pacientes. OBJETIVO: Determinar los parámetros para dimensionar los componentes de una prótesis de húmero y el desarrollo de un set, mediante software de diseño. MÉTODO: Se seleccionaron 40 pacientes para prótesis, se analizaron radiografías y tomografías computarizadas, y se aplicaron pruebas estadísticas a las mediciones. RESULTADOS: La longitud de los tumores fue de 8-20 cm. La longitud mínima del húmero fue de 28 cm y la máxima fue de 33 cm. Se observó correlación entre el húmero y el tumor y la altura del paciente, con p = 0.93088 y p = 0.904564, respectivamente; para el diámetro del húmero, p = 0.2345. El set incluye tres componentes, con diámetro de 6-10 mm y longitud de 24, 26 y 28 cm; tres espaciadores modulares con longitudes de 6, 8,5 y 13 cm; coronas de 6,5 y 8,5 cm de largo, 1,3 cm de diámetro y tuerca de 5 mm. CONCLUSIÓN: Con el desarrollo del set se pueden resolver resecciones mal calculadas y la adaptación a cualquier tamaño de húmero.

Interaction between the N-terminal SH3 domain of Nck-alpha and CD3-epsilon-derived peptides: non-canonical and canonical recognition motifs.

The first SH3 domain (SH3.1) of Nckalpha specifically recognizes the proline-rich region of CD3varepsilon, a subunit of the T cell receptor complex. We have solved the NMR structure of Nckalpha SH3.1 that shows the characteristic SH3 fold consisting of two antiparallel beta-sheets tightly packed against each other. According to chemical shift mapping analysis, a peptide encompassing residues 150-166 of CD3varepsilon binds at the canonical SH3 binding site. An exhaustive comparison with the structures of other SH3 domains able and unable to bind CD3varepsilon reveals that Nckalpha SH3.1 recognises a non-canonical PxxPxxDY motif that orientates at the binding site as a class II ligand. A positively charged residue (K/R) at position -2 relative to the WW sequence at the beginning of strand beta3 is crucial for PxxDY recognition. A 14-mer optimised Nckalpha SH3.1 ligand was found using a multi-substitution approach. Based on NMR data, this improved ligand binds Nckalpha SH3.1 through a PxxPxRDY motif that combines specific stabilising interactions corresponding to both canonical class II, PxxPx(K/R), and non-canonical PxxPxxDY motifs. This explains its higher capacity for Nckalpha SH3.1 binding relative to the wild type sequence.

Enzyme catalysis by hydrogen bonds: the balance between transition state binding and substrate binding in oxyanion holes.

Oxyanion holes stabilize oxygen anions in transition states. Data have been gathered both from enzyme structures and from corresponding structures from the Cambridge Crystallographic Database. The two data sets show a striking contrast. The small molecule interactions in the Cambridge database optimize hydrogen bonding. The enzyme active sites do not. Analyzing the data with the help of DFT calculations on theozyme-like models, we conclude that enzymes have not optimized binding to the transition state structures in reaction pathways involving oxyanion holes, because the best binding arrangement for the anions also optimizes binding for the starting materials of the reactions. Instead, enzymes arrange the hydrogen bonds so that the oxyanions are stabilized reasonably, but suboptimally, in order to avoid overstabilization of the ground state.