Catalytic Access to Chiral δ-Lactams via Nucleophilic Dearomatization of Pyridine Derivatives.

Nitrogen-bearing rings are common features in the molecular structures of modern drugs, with chiral δ-lactams being an important subclass due to their known pharmacological properties. Catalytic dearomatization of preactivated pyridinium ion derivatives emerged as a powerful method for the rapid construction of chiral N-heterocycles. However, direct catalytic dearomatization of simple pyridine derivatives are scarce and methodologies yielding chiral δ-lactams are yet to be developed. Herein, we describe an enantioselective C4-dearomatization of methoxypyridine derivatives for the preparation of functionalised enantioenriched δ-lactams using chiral copper catalysis. Experimental 13 C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity.

Small-molecule inhibition of aging-associated chromosomal instability delays cellular senescence.

Chromosomal instability (CIN) refers to the rate at which cells are unable to properly segregate whole chromosomes, leading to aneuploidy. Besides its prevalence in cancer cells and postulated implications in promoting tumorigenesis, studies in aneuploidy-prone mouse models uncovered an unanticipated link between CIN and aging. Using young to old-aged human dermal fibroblasts, we observed a dysfunction of the mitotic machinery arising with age that mildly perturbs chromosome segregation fidelity and contributes to the generation of fully senescent cells. Here, we investigated mitotic mechanisms that contribute to age-associated CIN. We found that elderly cells have an increased number of stable kinetochore-microtubule (k-MT) attachments and decreased efficiency in the correction of improper k-MT interactions. Chromosome mis-segregation rates in old-aged cells decreased upon both genetic and small-molecule enhancement of MT-depolymerizing kinesin-13 activity. Notably, restored chromosome segregation accuracy inhibited the phenotypes of cellular senescence. Therefore, we provide mechanistic insight into age-associated CIN and disclose a strategy for the use of a small-molecule to inhibit age-associated CIN and to delay the cellular hallmarks of aging.

Electrophilic Trapping of Semibenzenes.

In this work, we demonstrate how allylative dearomatization of benzyl chlorides can provide direct access to a variety of semibenzenes. These scaffolds behave as highly reactive nucleophiles in the presence of carbocations. In addition, semibenzenes are susceptible to intramolecular rearrangements rendering a broad scope of functionalized arenes. An analysis of this new reactivity is reported, as well as the rationale behind the observed intramolecular reorganizations.

Violations to the principle of least motion: the shortest path is not always the fastest.

The reaction between two molecules is usually envisioned as following a least-motion path with both molecules travelling minimum distances to meet each other. However, the reaction path of lowest activation energy is not only determined by practicality but mainly by the orbital symmetry of the involved reactants and the efficiency of their mutual interaction. The term non-least-motion was born to design those reactions in which reactants follow, in their route to products, pathways longer than those intuitively expected. In this review we summarize the theoretical and experimental studies that describe and rationalize reactions following non-least-motion paths, starting with the dimerizations of carbenes and followed by additional processes of these and other reactive species (silylenes, carbynes) such as insertions into single bonds and additions to π-bonds. Other examples involving less reactive partners are also included.

Direct Synthesis of α-Aryl-α-Trifluoromethyl Alcohols via Nickel Catalyzed Cross-Electrophile Coupling.

A nickel-catalyzed reductive cross-electrophile coupling between the redox-active N-trifluoroethoxyphthalimide and iodoarenes is documented. The protocol reproduces a formal arylation of trifluoroacetaldehyde under mild conditions in high yields (up to 88 %) and with large functional group tolerance (30 examples). A combined computational and experimental investigation revealed a pivotal solvent assisted 1,2-Hydrogen Atom Transfer (HAT) process to generate a nucleophilic α-hydroxy-α-trifluoromethyl C-centered radical for the Csp2 -Csp3 bond forming process.

Manganese(I)-Catalyzed H-P Bond Activation via Metal-Ligand Cooperation.

Here we report that chiral Mn(I) complexes are capable of H-P bond activation. This activation mode enables a general method for the hydrophosphination of internal and terminal α,ß-unsaturated nitriles. Metal-ligand cooperation, a strategy previously not considered for catalytic H-P bond activation, is at the base of the mechanistic action of the Mn(I)-based catalyst. Our computational studies support a stepwise mechanism for the hydrophosphination and provide insight into the origin of the enantioselectivity.

Nucleophilic Dearomatization of N-Heteroaromatics Enabled by Lewis Acids and Copper Catalysis.

Dearomative functionalization of heteroaromatics, a readily available chemical feedstock, is one of the most straightforward approaches for the synthesis of three-dimensional, chiral heterocyclic systems, important synthetic building blocks for both synthetic chemistry and drug discovery. Despite significant efforts, direct nucleophilic additions to heteroaromatics have remained challenging because of the low reactivity of aromatic substrates associated with the loss of aromaticity, as well the regio- and stereoselectivities of the reaction. Here we present a catalytic system that leads to unprecedented, high-yielding dearomative C-4 functionalization of quinolines with organometallics with nearly absolute regio- and stereoselectivities and with a catalyst turnover number (TON) as high as 1000. The synergistic action of the chiral copper catalyst, Lewis acid, and Grignard reagents allows us to overcome the energetic barrier of the dearomatization process and leads to chiral products with selectivities reaching 99% in most cases. Molecular modeling provides important insights into the speciation and the origin of the regio- and enantioselectivity of the catalytic process. The results reveal that the role of the Lewis acid is not only to activate the substrate toward a potential nucleophilic addition but also to subtly control the regiochemistry by preventing the C-2 addition from happening.

Lewis Acid Promoted Dearomatization of Naphthols.

Two-step dearomative functionalization of naphthols promoted by Lewis acids and copper(I) catalysis was developed. Initially, Lewis acid complexation inverted the electronic properties of the ring and established an equilibrium with the dearomatized counterpart. Subsequent trapping of the dearomatized intermediate with organometallics as well as organophosphines was demonstrated and provided the corresponding dearomatized products.

Synthesis and Functionalization of Allenes by Direct Pd-Catalyzed Organolithium Cross-Coupling.

A palladium-catalyzed cross-coupling between in situ generated allenyl/propargyl-lithium species and aryl bromides to yield highly functionalized allenes is reported. The direct and selective formation of allenic products preventing the corresponding isomeric propargylic product is accomplished by the choice of SPhos or XPhos based Pd catalysts. The methodology avoids the prior transmetalation to other transition metals or reverse approaches that required prefunctionalization of substrates with leaving groups, resulting in a fast and efficient approach for the synthesis of tri- and tetrasubstituted allenes. Experimental and theoretical studies on the mechanism show catalyst control of selectivity in this allene formation.

Positive youth development, thriving and social engagement: An analysis of gender differences in Spanish youth.

The framework of Positive Youth Development (PYD) arose from a strength-based conception of the transition to adulthood. Although previous literature has provided evidence for some PYD correlates, little is known about gender differences in PYD and its outcomes in thriving and social engagement, which could improve interventions" effectiveness. Thus, this study aimed to examine gender differences in PYD dimensions (i.e., competence, confidence, connection, caring, and character), individual thriving (i.e., psychological adjustment, academic adjustment, and healthy lifestyles) and social engagement, and to examine the associations between them. Data from the 'PYD in a Cross-National Perspective Project" in Spain were collected by administering a paper-based self-report to students from high school and university. Results showed greater scores in connection, caring, and character in women, as well as greater social engagement and academic adjustment. Men presented higher competence and confidence, more frequent physical activity and better psychological adjustment. In addition, more PYD was related to greater social engagement, better psychological and academic adjustment, and healthier lifestyles. Some practical implications for program design may be derived, which underscore the need to promote the five PYD dimensions equally in female and male youths in order to improve their individual thriving and social engagement.

Love and Dating Patterns for Same- and Both-Gender Attracted Adolescents Across Europe.

Sexual orientation is a multidimensional phenomenon, which includes identity, behavior, and attraction. The attraction component, however, is less studied than the other two. In this article, we present the development of a two-item measure to identify adolescents who prefer same- and both-gender partners for love and dating. The questions were administered to nationally representative samples of 15-year-old adolescents in eight European countries and regions participating in the Health Behaviour in School-aged Children (HBSC) cross-national study. The distribution of attraction, as operationalized by preference for the gender of love and dating partners, was similar across countries. These questions offer an alternative or supplementary approach to identify same- and both-gender attracted youth, without administering questions related to sexual identity.

Dream Teens: Adolescents-Led Participatory Project in Portugal in the Context of the Economic Recession.

This article describes the implementation process of a nationwide project to enhance young people's participation and active citizenship in the context of Portugal's economic recession. This project used an innovative Positive Youth Development approach that engaged Portuguese youth (aged 11-18 years) through social media tools to facilitate their civic engagement and development. Participants from all over the country were empowered (1) to design and conduct research activities on topics of their choice and about their life contexts and (2) to create ways to improve youth civic participation in their communities, while developing supportive interactions with adults and peers. Overall, youth were engaged in their activities, felt their voices were heard, and felt that they were viewed as experts of their own well-being and living contexts. Youth research actions and preliminary findings were then compiled in a set of recommendations that was formally received by a high commissioner of the Ministry of Health. The article concludes with a discussion of the next steps for the project and its limitations so far.

Microparticles derived from obese adipose tissue elicit a pro-inflammatory phenotype of CD16+, CCR5+ and TLR8+ monocytes.

Macrophage infiltration into adipose tissue (AT) is a hallmark of the chronic inflammatory response in obesity and is supported by an intense monocyte migration towards AT. Although it has been detected an increased proportion of circulating CD16+ monocyte subsets in obese subjects, the mechanisms underlying this effect and the contribution of these cells to the inflamed profile of obese AT are still poorly understood. We investigated whether factors secreted by human obese omental AT could polarize monocytes to CD16+ enriched phenotype, and how these changes could modify their migratory capacity towards adipose tissue itself. We show that explants of human obese omental AT, obtained during bariatric surgery, released higher levels of MIP1-α, TNFα, leptin and also VEGF, together with increasing amounts of microparticles (MP), when compared to explants of lean subcutaneous AT. A higher content of circulating MP derived from preadipocytes and leukocytes was also detected in plasma of obese subjects. Conditioned media or MP released from obese omental AT increased CD16 and CCR5 expression on CD14+CD16- monocytes and augmented their migratory capacity towards the conditioned media from obese omental AT, itself. This effect was inhibited when MIP1-α was neutralized. Additionally, we demonstrate that MP derived from obese omental AT carry and transfer TLR8 to monocytes, thus triggering an increase in CD16 expression in those cells. Our data shows a positive feedback loop between blood monocytes and obese omental AT, which releases chemotactic mediators and TLR8-enriched MP, thus inducing an up-regulation of CD16+ monocytes, favoring leukocyte infiltration in the obese omental AT.

Gold-Catalyzed Dearomatization of 2-Naphthols with Alkynes.

The site-selective dearomatization of naphthols is realized in a straightforward manner through a gold(I)-catalyzed [3,3]-sigmatropic rearrangement/allene functionalization cascade sequence. The method employs readily available naphthylpropargyl ethers as starting materials. A range of densely functionalized dihydrofurylnaphthalen-2(1H)-ones are obtained in high yields (up to 98 %) and extremely mild reaction conditions (reagent grade solvent, air, 10 minute reaction time). A complete theoretical elucidation of the reaction machinery is also proposed, providing a rationale for important issues such as regio- and chemoselectivity.

Synthesis of Benzodihydrofurans by Asymmetric C-H Insertion Reactions of Donor/Donor Rhodium Carbenes.

Metal carbenes appended with two electron-donating groups, known as "donor/donor" carbenes, undergo diastereo- and enantioselective rhodium-catalyzed C-H insertion reactions with ether substrates to form benzodihydrofurans. Unlike the reactions of metal carbenes with electron-withdrawing groups attached, the attenuated electrophilicity enables these reactions to be conducted in Lewis basic solvents (e.g., acetonitrile) and in the presence of water. The diazo precursors for these species are prepared in situ from hydrazone using a mild and chemoselective oxidant (MnO2 ). Although this sequence often can be performed in one-pot, control experiments have elucidated why a "two-pot" process is often more efficient. A thorough screening of achiral catalysts demonstrated that sterically encumbered catalysts are optimal for diastereoselective reactions. Although efficient insertion into allylic and propargylic C-H bonds is observed, competing dipolar cycloaddition processes are noted for some substrates. The full substrate scope of this useful method of benzodihydrofuran synthesis, mechanisms of side reactions, and computational support for the origins of stereoselectivity are described.

[MoO2]2+-Mediated Oxygen Atom Transfer via an Unusual Lewis Acid Mechanism.

Density functional theory is applied to the study of the oxygen atom transfer reaction from sulfoxide (DMSO) to phosphine (PMe3) catalyzed by the [MoO2]2+ active core. In this work, two fundamentally different roles are explored for this dioxometal complex in the first step of the catalytic cycle: as an oxidizing agent and as a Lewis acid. The latter turns out to be the favored pathway for the oxygen atom transfer. This finding may have more general implications for similar reactions catalyzed by the same [MoO2]2+ core.

Sexual Health questions included in the Health Behaviour in School-aged Children (HBSC) Study: an international methodological pilot investigation.

BACKGROUND: This paper describes the methodological developments of the sexual health items included in the Health Behaviour in School-aged Children (HBSC) study since their mandatory inclusion in the study in 2002. The current methodological, ethical and pedagogical challenges in measuring young people's sexual health behaviours are discussed along with the issues associated with the sexual health items introduced to the HBSC study in 2002. The development and piloting of new cross-national items for use in the 2013/14 HBSC data collection are presented and discussed. METHODS: An international pilot study was undertaken to determine the impact of these proposed changes. Questionnaires and classroom discussion groups were conducted in five pilot countries in 2012/2013 (France, Hungary, Ireland, Portugal and Romania) with a total of 612 school-aged children (age M = 15.55 years, SD = 0.95). RESULTS: The majority of participants in each country provided positive feedback about the appropriateness of the questions. Some small cross-national differences were found in the self-reported quantitative data relating to the appropriateness of the questions (χ2 = 22.831, df = 9, p = .007, V = .117). Qualitative feedback suggests that for the vast majority of students the phrasing and age-targeting of the questions were considered appropriate. With the exception of a small number of respondents who commented on the clarity and/or personal nature of the content, no specific issues with the questions were identified. CONCLUSIONS: These findings provide guidance on the answerability (including the extent of missing and inconsistent data), understandability, acceptability (including in different cultures) and relevance of questions to potential participants. The findings from the pilot study suggest that in general, the questions are understandable, acceptable, and of a high priority to the target population, and that the simplification has significantly reduced the proportion of missing data. The new developments thus enhance the capacity of the questions to measure cross-nationally, sensitive aspects of young people's sexual behaviour. These questions were included in the 2013/2014 round of the HBSC survey and will continue to be used to monitor trends in adolescent sexual health and behaviours, and to inform and influence health services and health education policy and practice at local, national and international levels.

Rational Design in Catalysis: A Mechanistic Study of ß-Hydride Eliminations in Gold(I) and Gold(III) Complexes Based on Features of the Reaction Valley.

ß-Hydride eliminations for ethylgold(III) dichloride complexes are identified as reactions with an unusually long prechemical stage corresponding to the conformational preparation of the reaction complex and spanning six phases. The prechemical process is characterized by a geared rotation of the L-Au-L group (L = Cl) driving methyl group rotation and causing a repositioning of the ligands. This requires more than 28 kcal/mol of the total barrier of 34.0 kcal/mol, according to the unified reaction valley approach, which also determines that the energy requirements of the actual chemical process leading to the ß-elimination product are only about 5.5 kcal/mol. A detailed mechanistic analysis was used as a basis for a rational design of substrates (via substituents on the ethyl group) and/or ligands, which can significantly reduce the reaction barrier. This strategy takes advantage of either a higher trans activity of the ligands or a tuned electronic demand of the ethyl group. The ß-hydride elimination of gold(I) was found to suffer from strong Coulomb and exchange repulsion when a positively charged hydrogen atom enforces a coordination position in a d(10)-configured gold atom, thus triggering an unassisted σ-π Au(I)-C conversion.

A Radical Mechanism for the Vanadium-Catalyzed Deoxydehydration of Glycols.

We propose a novel mechanism for the deoxydehydration (DODH) reaction of glycols catalyzed by a [Bu4N][VO2(dipic)] complex (dipic = pyridine-2,6-dicarboxylate) using triphenylphosphine as a reducing agent. Using density functional theory, we have confirmed that the preferred sequence of reaction steps involves reduction of the V(V) complex by phosphine, followed by condensation of the glycol into a [VO(dipic)(-O-CH2CH2-O-)] V(III) complex (6), which then evolves to the alkene product, with recovery of the catalyst. In contrast to the usually invoked closed-shell mechanism for the latter steps, where 6 suffers a [3+2] retrocycloaddition, we have found that the homolytic cleavage of one of the C-O bonds in 6 is preferred by 12 kcal/mol. The resulting diradical intermediate then collapses to a metallacycle that evolves to the product through an aromatic [2+2] retrocycloaddition. We use this key change in the mechanism to propose ways to design better catalysts for this transformation. The analysis of the mechanisms in both singlet and triplet potential energy surfaces, together with the location of the MECPs between them, showcases this reaction as an interesting example of two-state reactivity.

Gendered trends in early and very early sex and condom use in 20 European countries from 2002 to 2010.

BACKGROUND: Sexual activity is often initiated during the adolescent period, and previous research suggests that the age of first sexual intercourse and condom use are crucial determinants of later sexual health. This study examined trends in adolescent sexual behaviours from 2002 to 2010 in 20 countries across four geographical regions of Europe. METHODS: Data were collected by self-report questionnaires from 15-year-olds in classrooms during 2002, 2006 and 2010. Linear time trends were determined through logistic regression models, stratified for gender. RESULTS: No linear trend over time was documented for most countries for sexual intercourse at the age of 13 or younger. Increased initiation among girls in Eastern Europe and decreased very early initiation among girls in Northern Europe emerged, along with a general increase in condom use in boys and most notably in girls. CONCLUSION: Overall prevalence of early and very early sexual intercourse initiation was quite stable in Europe between 2002 and 2010, while condom use increased. More detailed research and policy attention to the antecedents of non-condom use among young people is warranted; and further study of the relationships between age of sexual initiation and condom or pill use would be particularly valuable.