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Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereo- and enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl- and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.

Synthesis of complex bioactive molecules is substantially facilitated by transformations that efficiently and stereoselectively generate polyfunctional compounds. Designing such processes is hardly straightforward, however, especially when the desired route runs counter to the inherently favored reactivity profiles. Furthermore, in addition to being efficient and stereoselective, it is crucial that the products generated can be easily and stereodivergently modified. Here, we introduce a catalytic process that delivers a versatile and otherwise difficult-to-access organoboron entities by combining an allenylboronate, a hydride, and an allylic phosphate. Two unique selectivity problems had to be solved: avoiding rapid side reaction of a Cu–H complex with an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly utilised boron–copper exchange. The utility of the approach is demonstrated by applications to concise preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and enantioselective synthesis and structure confirmation of netamine C, a member of a family of anti-tumor and anti-malarial natural products. Completion of the latter routes required the following noteworthy developments: 1) A two-step all-catalytic sequence for conversion of a terminal alkene to a monosubstituted alkyne. 2) A catalytic S(N)2’- and enantioselective allylic substitution method involving a mild alkylzinc halide reagent. 3) A diastereoselective [3+2]-cycloaddition protocol to assemble to polycyclic structure of a guanidyl polycyclic natural product.

Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine. Successful implementation requires that competing copper-based catalysts be present simultaneously and that the slower-forming and less reactive one engages first. This challenge was addressed by incorporation of a nonproductive side cycle, fueled selectively by inexpensive additives, to delay the function of the more active catalyst. The utility of this approach is highlighted by its application to the efficient preparation of the anticancer agent (+)-tangutorine.

Producción Científica, The easily prepared hemilabile ligand 1-(PPh2),2-(trans-CH═CHCOPh)–C6F4 (PhPEWO-F) and other PEWO ligands are well-known promoters of C–C reductive eliminations and very effective in Negishi couplings. As an example, the efficient Negishi coupling of (C6F5)–I and Zn(C6F5)2 is reported. The thorough experimental study of the steps involved in the catalytic cycle uncovers the potential weakness of this ligand that could frustrate at some points the desired cycle and provide some simple precautions to keep the catalytic cycle working efficiently. Density functional theory (DFT) calculations complete the experimental study and provide insight into nonobservable transition states and intermediates, comparing the potential conflict between reductive elimination and olefin insertion. Our results showcase the importance the transmetalation step, facilitated by the strong trans effect of the electron-withdrawing ligand, and the choice of organozinc nucleophiles, critical to ensure fast group exchange and a positive outcome of the catalytic reactions., Ministerio de Economía, Industria y Competitividad (project CTQ2017-89217-P), Junta de Castilla y León (project VA062G18)

A widely applicable, practical, and scalable strategy for efficient and enantioselective synthesis of β,γ-unsaturated ketones that contain an α-stereogenic center is disclosed. Accordingly, aryl, heteroaryl, alkynyl, alkenyl, allyl, or alkyl ketones that contain an α-stereogenic carbon with an alkyl, an aryl, a benzyloxy, or a siloxy moiety can be generated from readily available starting materials and by the use of commercially available chiral ligands in 52–96% yield and 93:7 to >99:1 enantiomeric ratio. To develop the new method, conditions were identified so that high enantioselectivity would be attained and the resulting α-substituted NH-ketimines, wherein there is strong C=N→B(pin) coordination, would not epimerize before conversion to the derived ketone by hydrolysis. It is demonstrated that the ketone products can be converted to an assortment of homoallylic tertiary alcohols in 70–96% yield and 92:8 to >98:2 dr – in either diastereomeric form – by reactions with alkyl-, aryl-, heteroaryl-, allyl-, vinyl-, alkynyl-, or propargyl-metal reagents. The utility of the approach is highlighted through transformations that furnish other desirable derivatives and a concise synthesis route affording more than a gram of a major fragment of anti-HIV agents rubriflordilactones A and B and a specific stereoisomeric analogue.

Catalytic enantioselective methods are introduced that allow access to a variety of allyl boronates and silanes that contain a difluoroalkene unit; the resulting products may be used for the preparation of organofluorine compounds in high enantiomeric purity. Furthermore, a number of key mechanistic aspects of the transformations have been investigated and analyzed. Thus, first, an NHC-Cu-catalyzed method for boryl substitution with F

An emerging area of research in chemistry requires that we learn how to manage the characteristics of a pair of co-catalysts so that a transformation proceeds as we wish it to. These are processes during which one catalyst first generates a non-isolable intermediate, which then in situ undergoes a reaction that is promoted by a

A rapidly emerging set of catalytic reactions involves intermediates that contain a copper-substituted stereogenic carbon centre. Here, we demonstrate that intimate understanding of this distinction provides ways for addressing limitations in reaction scope and explaining why unexpected variations in enantioselectivity often occur. By using catalytic enantioselective Cu–boryl addition to alkenes as the model process, we have been able to elucidate several key mechanistic principles. We show that higher electrophile concentration can lead to elevated enantioselectivity; this is because diastereoselective Cu–H elimination may be avoided and/or achiral Cu–boryl intermediates can be converted to allyl–B(pin) rather than add to an alkene. We illustrate that lower alkene amounts and/or higher chiral ligand concentration can minimize the deleterious influence of achiral Cu–alkyl species, resulting in improved enantiomeric ratios. Moreover, and surprisingly, we find that enantioselectivities are higher with the less reactive allylphenyl carbonates as chemoselective copper–hydride elimination is faster with an achiral Cu-alkyl species.

Despite notable progress, olefin metathesis methods for preparation of ( Z)-α,β-unsaturated carbonyl compounds, applicable to the synthesis of a large variety of bioactive molecules, remain scarce. Especially desirable are transformations that can be promoted by ruthenium-based catalysts, as such entities would allow direct access to carboxylic esters and amides, or acids (in contrast to molybdenum- or tungsten-based alkylidenes). Here, we detail how, based on the mechanistic insight obtained through computational and experimental studies, a readily accessible ruthenium catechothiolate complex was found that may be used to generate many α,β-unsaturated carbonyl compounds in up to 81% yield and ≥98:2 Z/ E ratio. We show that through the use of a complex bearing an unsaturated N-heterocyclic carbene (NHC) ligand, for the first time, products derived from the more electron-deficient esters, acids, and Weinreb amides (vs primary or secondary amides) can be synthesized efficiently and with high stereochemical control. The importance of the new advance to synthesis of bioactive compounds is illustrated through two representative applications: an eight-step, 15% overall yield, and completely Z-selective route leading to an intermediate that may be used in synthesis of stagonolide E (vs 11 steps, 4% overall yield and 91% Z, previously), and a five-step, 25% overall yield sequence to access a precursor to dihydrocompactin (vs 13 steps and 5% overall yield, formerly).

A Pd complex, cis-[Pd(C6 F5 )2 (THF)2 ] (1), is proposed as a useful touchstone for direct and simple experimental measurement of the relative ability of ancillary ligands to induce C-C coupling. Interestingly, 1 is also a good alternative to other precatalysts used to produce Pd0 L. Complex 1 ranks the coupling ability of some popular ligands in the order Pt Bu3 >o-TolPEWO-F≈tBuXPhos>P(C6 F5 )3 ≈PhPEWO-F>P(o-Tol)3 ≈THF≈tBuBrettPhos≫Xantphos≈PhPEWO-H≫PPh3 according to their initial coupling rates, whereas their efficiency, depending on competitive hydrolysis, is ranked tBuXPhos≈Pt Bu3 ≈o-TolPEWO-F>PhPEWO-F>P(C6 F5 )3 ≫tBuBrettPhos>THF≈P(o-Tol)3 >Xantphos>PhPEWO-H≫PPh3 . This "meter" also detects some other possible virtues or complications of ligands such as tBuXPhos or tBuBrettPhos.

Racemic vinylallenes are shown to be attractive substrates for catalytic multicomponent diastereo-, and enantioselective 1,6-conjugate addition of multifunctional allyl moieties to easily accessible α,β,γ,δ−unsaturated diesters. Reactions may be catalyzed by 5.0 mol % of a readily accessible NHC–Cu complex at ambient temperature, and other than a vinylallene, involve B(2)(pin)(2), and an α,β,γ,δ-unsaturated diester. By just one operation, a variety of vinylallenes were converted to products bearing a Z-trisubstituted alkenyl–B(pin) moiety, a vinyl group, a β,γ-unsaturated diester unit, and vicinal stereogenic centers in up to 67% yield, 87:13 Z:E ratio, >98:2 d.r., and 98:2 e.r. A variety of chemoselective modifications involving the alkenyl–B(pin), vinyl, or the 1,2-disubstituted olefin moieties were carried out to demonstrate versatility and utility. Stereochemical models, based on mechanistic and DFT studies, demonstrate the dynamic behavior of intermediated Cu–allyl species and account for various selectivity profiles. These studies foreshadow the use of vinylallenes as starting materials in a wide range of multicomponent reactions, those catalyzed by Cu–H or Cu–B(pin) complexes.

Catalytic enantioselective boron–hydride additions to 1,3-enynes, which afford allenyl–B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine–Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl-substituted 1,3-enynes. Trisubstituted allenyl– B(pin) products were generated in 52–80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8–99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substitutents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu–C cleavage. This is particularly a problem when trapping of the Cu–allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron–hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under un-optimal conditions (e.g., lower boron–hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding ortho-aryl substituent considerable amounts of the propargyl–B(pin) isomer may be generated (25– 96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl–B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl–B(pin) compound might proceed with high stereospecificity (e.g., phosphine–Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine–Cu-catalyzed allylic substitution).

Producción Científica, In addition to the expected products, trans- and cis- [PdRfMe(PPh3)2], the transmetalation between ZnMe2 and trans- [PdRfCl(PPh3)2] yields [PdMeCl(PPh3)2] and ZnRfMe as the result of secondary transmetalation processes. ZnRfMe is also formed by reaction of trans and cis-[PdRfMe(PPh3)2] with ZnMe2. The different competitive reaction mechanisms that participate in the transmetalations have been studied experimentally and by DFT calculations. The relative contribution of each reaction pathway in the formation of the unwanted product ZnRfMe has been measured. The effect of excess ligand (PPh3) on the several transmetalations has been stablished., Ministerio de Economía, Industria y Competitividad (CTQ2013-48406-P), Ministerio de Economía, Industria y Competitividad (CTQ2012-37734), Ministerio de Economía, Industria y Competitividad (CTQ2015-68794-P), Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA256U13), Centro de Supercomputación de Galicia (CESGA, ICTS240-2013 and ICTS257-2014)

Background Patients’ satisfaction with methadone maintenance treatment (MMT) is a key measure of treatment quality. The main objective of the present study is to identify independent factors that contribute significantly to satisfaction with MMT. Method Participants were a representative sample of methadone-maintained patients ( n = 123) from the region of La Rioja. Satisfaction with MMT was assessed with the Verona Service Satisfaction Scale for Methadone Treatment (VSSS-MT), and mental health status with the General Health Questionnaire-28 (GHQ-28). Multivariate linear- and logistic-regression analyses were performed to identify variables independently associated with satisfaction with MMT. Results Multiple linear regression analysis revealed that the variables independently associated with VSSS-MT total score were number of hours per week that the centre dispensed methadone ( β = 0.193), number of patients per centre ( β = 0.233), perceived frequency of receiving information about methadone dose changes ( β = 0.246), perceived influence on these changes ( β = 0.194), and Social Dysfunction subscale of GHQ-28 ( β = −0.179). Multivariate binary logistic regression showed that the variables independently associated with the likelihood of being satisfied with MMT were number of years of education completed (OR = 0.835), number of patients per centre (OR = 1.009), perceived frequency of receiving information about methadone dose changes (OR = 1.571), and Social Dysfunction subscale of GHQ-28 (OR = 0.748). Conclusions Patients from larger centres, who perceive themselves as participating to some extent in treatment decisions, and showing lower deterioration in social functioning are more likely to be satisfied with MMT.

El objetivo principal de este Trabajo Final de Grado (TFG), es el estudio y el análisis de la propuesta de Real Decreto relativo a los Mecanismos de capacidad e hibernación de centrales térmicas. En concreto, se analiza cómo se implantaron los Pagos por Capacidad y sus posteriores evoluciones, así como la propuesta de hibernación de determinadas centrales térmicas (Ciclos Combinados de Gas). También se realiza un estudio del Índice de Cobertura y se lleva a cabo un ejercicio donde se calcula el mismo. Además, el TFG tiene como objetivo secundario el análisis de la evolución de la demanda punta, la potencia instalada y la garantía de suministro del sistema peninsular eléctrico español en los últimos años. Este estudio servirá para describir el contexto en el que se pretende aplicar la propuesta de Real Decreto sobre mecanismos de capacidad e hibernación de centrales térmicas y mostrar cómo se ha llegado a la necesidad de esta propuesta. Ingeniería Eléctrica

Methadone programs have been organized in each Spanish region in a specific way. In spite of the regional interests to manage those programs in a more efficient way, so far the costs of the programs are unknown. As a previous step, it would be desirable to understand the activities related to these programs as well as their respective costs. This article aims to calculate the cost of the Methadone program in the autonomous community of La Rioja, and to understand those parameters which generate a greater cost to this programme.The study followed a similar structure as the research recently applied to the region of Murcia. The reference year for the study of the annual costs of the Methadone program was 2010. Data were obtained from different registries of several institutions involved in the regional program. Costs were classified according to different stages and dispensation centres which participated in this programme.Data analysis, for a concentration of 2 mg/ml of methadone, showed an approximate annual cost of 165.759 euros. Taking the total number of patients into consideration the individual cost was 412,34 euros.Dispensation is the stage which caused the largest cost to the programme, the highest per patient cost corresponded to the centre with less patients due to the fact that fixed costs are shared by a smaller group of persons; the biggest global cost of the programme came from Logroño's center but its average cost is lower.

El objetivo del artículo es revisar las grandes áreas de trabajo en drogodependencias atendiendo a la perspectiva de género y se analizan los recientes aportes de la literatura científica. Partiendo de algunos datos epidemiológicos diferenciales, el autor aborda en un primer capítulo la etiología del problema. Los siguientes apartados ofrecen una visión crítica de la prevención, el tratamiento y la investigación del problema del abuso de drogas entre el colectivo femenino. AbstractThis paper's goal is to review the main working areas in the field of drug-abuse from a gender perspective and analyse the recent contributions of the scientific literature. Taking into account some differential epidemic data, the author approaches in a first chapter the etiology of the problem. The following sections offer a critical vision of the prevention, the treatment and the research of the problem of the drug-abuse within the feminine community.