A Cu-BOX catalysed enantioselective Mukaiyama-aldol reaction with difluorinated silyl enol ethers and acylpyridine N-oxides.

A Cu(II)/BOX complex catalyses the enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides. The reaction provides difluorinated chiral tertiary alcohols of great interest in medicinal chemistry. These compounds are obtained in moderate to excellent yields and with high enantioselectivities. The stereochemical outcome of the reaction has been explained by DFT calculations.

An Expedient Method for the Umpolung Coupling of Enols with Heteronucleophiles.

In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3-dicarbonyl compounds with a large range of heteroatom nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO2 . The scope of the reaction also extends to carbon-based nucleophiles. The reaction relies on the use of 1-bromo-3,3-dimethyl-1,3-dihydro-1λ3 [d][1,2]iodaoxole, which provides a key α-brominated carbonyl intermediate. The reaction mechanism has been studied experimentally and by DFT, and we propose formation of an unusual enolonium intermediate with a halogen-bonded bromide.

Organocatalytic enantioselective Mannich reaction of isoxazol-5(4H)-ones to isatin-derived ketimines.

An efficient organocatalytic asymmetric Mannich reaction between isoxazol-5(4H)-ones and isatin-derived ketimines has been developed. A bifunctional squaramide/Brønsted base organocatalyst catalyzed the enantioselective Mannich addition to afford chiral 3-aminooxindoles bearing a tetrasubstituted stereocenter at C3 decorated with an isoxazole moiety in good yields and with excellent enantioselectivities. Additionally, several synthetic transformations were described showing the versatility of the prepared compounds.

Unraveling the Mechanism of the IrIII -Catalyzed Regiospecific Synthesis of α-Chlorocarbonyl Compounds from Allylic Alcohols.

We have used experimental studies and DFT calculations to investigate the IrIII -catalyzed isomerization of allylic alcohols into carbonyl compounds, and the regiospecific isomerization-chlorination of allylic alcohols into α-chlorinated carbonyl compounds. The mechanism involves a hydride elimination followed by a migratory insertion step that may take place at Cß but also at Cα with a small energy-barrier difference of 1.8 kcal mol-1 . After a protonation step, calculations show that the final tautomerization can take place both at the Ir center and outside the catalytic cycle. For the isomerization-chlorination reaction, calculations show that the chlorination step takes place outside the cycle with an energy barrier much lower than that for the tautomerization to yield the saturated ketone. All the energies in the proposed mechanism are plausible, and the cycle accounts for the experimental observations.

Enantioselective Synthesis of 5-Trifluoromethyl-2-oxazolines under Dual Silver/Organocatalysis.

The first enantioselective formal [3 + 2] cycloaddition between α-isocyanoesters and trifluoromethylketones to give 5-trifluoromethyl-2-oxazolines bearing two contiguous stereogenic centers, one of them being a quaternary stereocenter substituted with a CF3 group, has been developed. The reaction is based upon a multicatalytic approach that combines a bifunctional Brønsted base-squaramide organocatalyst and Ag+ as Lewis acid. The reaction could be achieved with a range of aryl and heteroaryl trifluoromethyl ketones, and the resulting oxazolines were obtained with good to excellent diastereo- and enantioselectivity.

Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates.

The first method to access unsymmetrical aliphatic acyloins is presented. The method relies on a fast 1,3-hydride shift mediated by an IrIII complex in allylic alcohols followed by oxidation with TEMPO+ . The direct conversion of allylic alcohols into acyloins is achieved in a one-pot procedure. Further functionalization of the Cα' of the α-amino-oxylated ketone products gives access to highly functionalized unsymmetrical aliphatic ketones, which further highlights the utility of this transformation.

Base-Catalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through Ion-Pairing.

A mild base-catalyzed strategy for the isomerization of allylic alcohols and allylic ethers has been developed. Experimental and computational investigations indicate that transition metal catalysts are not required when basic additives are present. As in the case of using transition metals under basic conditions, the isomerization catalyzed solely by base also follows a stereospecific pathway. The reaction is initiated by a rate-limiting deprotonation. Formation of an intimate ion pair between an allylic anion and the conjugate acid of the base results in efficient transfer of chirality. Through this mechanism, stereochemical information contained in the allylic alcohols is transferred to the ketone products. The stereospecific isomerization is also applicable for the first time to allylic ethers, yielding synthetically valuable enantioenriched (up to 97% ee) enol ethers.

Catalytic Enantioselective Conjugate Alkynylation of α,ß-Unsaturated 1,1,1-Trifluoromethyl Ketones with Terminal Alkynes.

The first catalytic enantioselective conjugate alkynylation of α,ß-unsaturated 1,1,1-trifluoromethyl ketones has been carried out. Terminal alkynes and 1,3-diynes were treated with trifluoromethyl ketones in the presence of a low catalytic load of a Cu(I) -MeOBIPHEP complex (2.5 mol %) and triethylamine (10 mol %) to give the corresponding trifluoromethyl ketones bearing a propargylic stereogenic center at the ß position with good yields and excellent enantiomeric excesses in most of the cases. No 1,2-addition products were formed under the reaction conditions. The procedure showed broad substrate scope for alkyne, diyne, and enone. A rationale for the observed stereochemistry has been provided. Finally, the potential application of the reaction products in the synthesis of chiral tetrahydrofurans bearing a trifluoromethylated quaternary stereocenter has been devised.

Effects of Bacillus thuringiensis var. israelensis on nonstandard microcrustacean species isolated from field zooplankton communities.

The toxicity of Bacillus thuringiensis var. israelensis on zooplanktonic microcrustaceans was evaluated using individuals collected in coastal wetlands where this larvicide has been used for mosquito control over the last decades. We tested five zooplankton species that coexist with mosquito larvae: two copepods (both nauplii and adults of Tropocyclops prasinus and Acantocyclops americanus), and three cladocerans (Ceriodaphnia reticulata, Chydorus sphaericus, and Daphnia cf. pulex). Our experiments included seven replicates of six concentrations (Bti Vectobac12AS 1200 Bti ITU/mg): 0, 5, 25, 50, 250, and 500 mg L-1. We analyzed acute and sub-chronic effects after a single inoculation. Despite the high variability of responses among our tested organisms, we found a general pattern of increasing mortality with concentration and time. We conclude that negative effects at the community level are not unlikely as some species were affected at doses close to those used in field applications.

Hydroxyl-directed stereoselective diboration of alkenes.

An alkoxide-catalyzed directed diboration of alkenyl alcohols is described. This reaction occurs in a stereoselective fashion and is demonstrated with cyclic and acyclic homoallylic and bishomoallylic alcohol substrates. After oxidation, the reaction generates 1,2-diols such that the process represents a method for the stereoselective directed dihydroxylation of alkenes.

Highly enantioselective copper(I)-catalyzed conjugate addition of terminal alkynes to 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones: new ester/amide surrogates in asymmetric catalysis.

A highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated enones, namely 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones, is described. The reaction products are obtained with good yields and excellent enantioselectivities (from 92 to 99% ee). The ß-alkynylated difluoro(phenylsulfonyl) ketones can be converted into the corresponding ß-alkynylated difluoro- and trifluoromethyl ketones, esters and amides. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones as substrates in an enantioselective reaction, which have been shown to be new ester/amide surrogates.

Selective C-H Iodination of Weinreb Amides and Benzamides through Iridium Catalysis in Solution and under Mechanochemical Conditions.

The acid mediated ortho-iodination of Weinreb amides using a readily available catalyst is described. The selective ortho-iodination of Weinreb amides, challenging substrates in directed C-H activations, and also of benzamides is achieved. The process works under mild conditions and tolerates air and moisture, having a great potential for industrial applications. The methodology can be applied under mechanochemical conditions maintaining the reaction outcome and selectivity.

Real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes in Spain: The Dapa-ON multicenter retrospective study.

OBJECTIVE: To assess real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes mellitus (T1DM). METHODS: We conducted a multicenter retrospective study in Spain including data from 250 people living with T1DM receiving dapagliflozin as add-on therapy to insulin (80.8 % on-label use). The number of diabetic ketoacidosis (DKA) events was calculated over a 12-month follow-up (primary outcome). Changes in body weight, HbA1c, total daily insulin dose, and continuous glucose monitoring (CGM) metrics from baseline (at dapagliflozin prescription) to 12 months were also evaluated. RESULTS: A total of five DKA events (2.4 % [95 % CI 0.3;4.5] were reported in patients with a 12-month follow-up, n = 207): two events related to insulin pump malfunction, two events related to concomitant illnesses, and one event related to insulin dose omission. DKA events were more frequent among insulin pump users than among participants on multiple daily injections (7.7 % versus 1.2 %). Four of the reported DKA events occurred within the first six months after initiation of dapagliflozin. No deaths or persistent sequelae due to DKA were reported. No severe hypoglycemia episodes were reported. Significant reductions in mean body weight (-3.3 kg), HbA1c (-0.6 %), and total daily insulin dose (-8.6 %), P < 0.001, were observed 12 months after dapagliflozin prescription. Significant improvements in TIR (+9.3 %), TAR (-7.2 %), TBR (-2.5 %), and coefficient of variation (-5.1 %), P < 0.001, were also observed in the subgroup of patients with available CGM data. Finally, an improvement in urinary albumin-to-creatinine ratio (UACR) was found among participants with UACR ≥ 30 mg/g at baseline (median decrease of 99 mg/g in UACR, P = 0.001). CONCLUSION: The use of dapagliflozin in people living with T1DM has an appropriate safety profile after careful selection of participants and implementation of strategies to reduce the risk of DKA (i.e., prescribed according to the recommendations of the European Medicines Agency), and also leads to clinical improvements in this population.

Synthesis of α,α-Diaryl-α-amino Acid Precursors by Reaction of Isocyanoacetate Esters with o-Quinone Diimides.

A novel procedure for the synthesis of α,α-diaryl-α-amino acid derivatives has been developed. Silver oxide catalyzes the conjugate addition of α-aryl isocyanoacetates to o-quinone diimide, affording the corresponding α,α-diarylisocyano esters in excellent yields and regioselectivities in short reaction times. Acid hydrolysis of the isocyano group provides the corresponding amino acids bearing a diarylated tetrasubstituted carbon atom. The reaction is also amenable to the synthesis of α-alkyl-α-arylisocyano esters, while the reaction with 3-hydroxy o-quinone diimides provides 4H-benzo[e][1,3]oxazines via a conjugate addition/cyclization process.

Enantioselective zinc-mediated conjugate addition of terminal alkynes to enones.

Zinc for conjugate alkynylation: The enantioselective conjugate addition of terminal alkynes to 2-arylidene-1,3-diketones in the presence of diethylzinc and a catalytic amount of (R)-VANOL has been developed. The reaction can be applied to different aromatic and heteroaromatic alkynes and enones, giving the expected products in good yield and with enantiomeric excesses up to 91%. The products can be enantiomerically enriched up to 99% ee by crystallization (see scheme).

Enantioselective copper-aminopyridine-catalyzed aza-Henry reaction with chelating N-(2-pyridyl)sulfonyl imines.

This article describes a copper-catalyzed aza-Henry reaction. Copper complexes of camphor-derived aminopyridines catalyze the addition of nitromethane to N-(2-pyridyl)sulfonyl aldimines to give the corresponding ß-nitrosulfonamides with good yields and variable enantiomeric excesses (up to 83%). An example of transformation of these compounds into N-(2-pyridyl)sulfonyl-α-amino acids and deprotection of the sulfonamide with Mg-MeOH is provided.

[Use of systemic glucocorticoids for the treatment of severe asthma: Spanish Multidisciplinary Consensus]. / Uso de glucocorticoides sistémicos para el tratamiento del asma grave: Consenso multidisciplinar español.

Background and aim: Since their effectiveness was initially demonstrated, oral corticosteroids (OCS) have been routinely used to treat asthma. We now know that their usage is linked to the development of side effects such osteoporosis and adrenal insufficiency. This is an observational study based on Delphi methodology. The questionnaire was divided into 4 sections: OCS generalities, maintenance treatment, short-term treatment, and adverse events. Materials and methods: Two rounds of a 68-item questionnaire were completed by a panel of 48 allergists and pneumologists. Results: Definitions were agreed upon, as was the proper use of OCS in the treatment of severe asthma. The experts agreed that the use of OCS should be minimized as much as possible and that in the event of maintenance treatments, a slow and progressive tapering strategy should be used. They also emphasized the importance of standardizing the technique for measuring the amount of SCG delivered in both cases. Conclusions: This consensus document attempts to bring together scientifically supported suggestions from specialists in the management of asthma to reduce the use of OCS in Spain.

Metal-Free Diastereo- and Enantioselective Dearomative Formal [3 + 2] Cycloaddition of 2-Nitrobenzofurans and Isocyanoacetate Esters.

The diastereo- and enantioselective dearomative formal [3 + 2] cycloaddition of 2-nitrobenzofurans and α-aryl-α-isocyanoacetate esters provides tricyclic compounds bearing the 3a,8b-dihydro-1H-benzofuro[2,3-c]pyrrole framework with three consecutive stereogenic centers. The reaction was enabled by a cupreine-ether organocatalyst. The reaction products were obtained with almost full diastereoselectivity and with excellent enantiomeric excesses for a number of substituted 2-nitrobenzofurans and isocyanoacetates.

Fluoresceination of FepA during colicin B killing: effects of temperature, toxin and TonB.

We studied the reactivity of 35 genetically engineered Cys sulphydryl groups at different locations in Escherichia coli FepA. Modification of surface loop residues by fluorescein maleimide (FM) was strongly temperature-dependent in vivo, whereas reactivity at other sites was much less affected. Control reactions with bovine serum albumin showed that the temperature dependence of loop residue reactivity was unusually high, indicating that conformational changes in multiple loops (L2, L3, L4, L5, L7, L8, L10) transform the receptor to a more accessible form at 37 degrees C. At 0 degrees C colicin B binding impaired or blocked labelling at 8 of 10 surface loop sites, presumably by steric hindrance. Overall, colicin B adsorption decreased the reactivity of more than half of the 35 sites, in both the N- and C- domains of FepA. However, colicin B penetration into the cell at 37 degrees C did not augment the chemical modification of any residues in FepA. The FM modification patterns were similarly unaffected by the tonB locus. FepA was expressed at lower levels in a tonB host strain, but when we accounted for this decrease its FM labelling was comparable whether TonB was present or absent. Thus we did not detect TonB-dependent structural changes in FepA, either alone or when it interacted with colicin B at 37 degrees C. The only changes in chemical modification were reductions from steric hindrance when the bacteriocin bound to the receptor protein. The absence of increases in the reactivity of N-domain residues argues against the idea that the colicin B polypeptide traverses the FepA channel.

Stereospecific Isomerization of Allylic Halides via Ion Pairs with Induced Noncovalent Chirality.

A regioselective protocol for the synthesis of substituted allylic chlorides, bromides, and fluorides has been established. Remarkably, the method can be applied to the enantioselective synthesis of challenging chiral allylic chlorides. When the allylic halides are treated with the base triazabicyclodecene as the catalyst, a [1,3]-proton shift takes place, giving the corresponding vinyl halides in excellent yields with excellent Z:E ratios. Furthermore, the [1,3]-proton shift takes place with an outstanding level of chirality transfer from chiral allylic alcohols (≤98%) to give chiral trifluoromethylated vinyl chlorides.