Syntheses of Functionalized Benzylic Compounds: Development of Palladium-Catalyzed Decarboxylative Benzylation Reactions

Carbon-carbon bond formation between the benzyl carbon and a functional group is important in organic synthesis because majority of the compounds in the chemical literature contain aromatic cores appended with different functionalities in the benzyl carbon. These compounds are utilized in pharmaceuticals and medicinal chemistry. While current literature in Pd-catalyzed benzylations is increasingly becoming recognized, conventional methodologies require the use of toxic benzyl halides, stoichiometric bases and/or performed organometallics which not only generate benzyl compounds but also give side products and toxic metal wastes. Our research group has a long-standing interest using decarboxylation as a tool in constructing diverse compounds without the need of base and preformed organometallics. Previously applied in the synthesis of functionalized allylic compounds from allyl esters, we envisioned to utilize this tool towards the synthesis of functionalized benzylic compounds from benzyl esters. We thought that it would be feasible and ideal to perform decarboxylative benzylation (DcB) based from well-explored decarboxylative allylation (DcA) methodology. Indeed, we were able to show that Pd-catalyzed DcB was an indispensable tool in synthesizing functionalized benzylic compounds in good to high yields. This was shown in the syntheses of benzyl ketones and benzyl alkynes. In the DcB of ketones, simple and benzo-fused β-ketoesters underwent decarboxylation affording benzyl ketones in good to high yields. DcB was also regiospecific, the kinetically preformed enolate did not undergo thermodynamic isomerization resulting to direct functionalization to the carbon next to the carboxylate group where it was once located. In addition to naphthyl and simple benzyls, heteroaromatics were also used as coupling partners with enolate. The nature of substituents in the ring and its position from the benzyl moiety affected benzylation. Depending on the nature of heterocycle, regioselective benzylation occurred resulting in formation of C-benzylation ketone, C-arylation ketone, or O-benzylation enol ether. The utility of DcB methodology was also used towards the synthesis of Nabumetone. In the DcB of alkynes, simple and benzo-fused propiolates underwent decarboxylation to generate benzyl alkynes in good to high yields. The use of biphenyl derived ligand was crucial in the synthesis of simple benzyl alkynes. The benzylic carbon in diaryls and heterocycles can also be used as coupling partners with alkynes

The Other SiO2: Investigating Oxidation of Alcohols Using (NH4)2Cr2O7 in Sand

Oxidation of alcohols to aldehydes and ketones is one of the classical reactions in organic chemistry which is utilized frequently in medicine, industry, and pharmaceuticals. Classical effective reagents in oxidation include pyridinium chlorochromate, potassium permanganate, Jones reagent, bleach, and Swern conditions. There has been an increasing interest throughout the years to use supported-based reagents in tandem with these reagents, particularly with silica gel especially towards Cr-based oxidizing agents. Despite the abundance of reported reactions in the literature pertaining to silica gel, little is known about sand, despite both are silicon dioxide and exhibit similar porosity and crystallinity. It is not clear as why silica gel is frequently used in chemical reactions compared to sand. Herein, we report some of our results regarding the utilization of washed sand in oxidation of primary and secondary alcohols. Using an appropriate solvent under reflux, primary and secondary alcohols are oxidized cleanly into aldehydes and ketones based on TLC monitoring and 1H and 13C-NMR of the crude material. More importantly, reactions can be carried out in lower reagent loading compared to silica-gel based oxidations

Limit cycles in the Holling-Tanner model

This paper deals with the following question: does the asymptotic stability of the positive equilibrium of the Holling-Tanner model imply it is also globally stable? We will show that the answer to this question is negative. The main tool we use is the computation of Poincaré-Lyapunov constants in case a weak focus occurs. In this way we are able to construct an example with two limit cycles

Decarboxylative Benzylations of Alkynes and Ketones

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/:10.1021/ja1035557.Utilization of palladium π-benzyl complexes in cross-coupling reactions is becoming increasingly important in organic synthesis.1 However, methods for benzylic cross-couplings typically rely on the use of basic reagents or preformed organometallics. For example, Buchwald reported the cross-coupling of benzyl halides with alkynes using stoichiometric Cs2CO3; unfortunately, the basic reaction conditions often induce isomerization of the product benzylic alkynes to isomeric allenes.2 Negishi reported the benzylic cross-coupling with acetylides via stoichiometric alkynyl zinc bromides that must be prepared from ZnBr2.3 Not only do these methods require stoichiometric bases or organometallics, but they also utilize benzyl halides that are expensive, hazardous, and more difficult to handle than related benzyl alcohol derivatives. Legros, Kuwano and others have reported catalytic benzylation of stabilized nucleophiles using activated benzylic alcohol derivatives.4 While benzylations of highly stabilized enolates (pKa ~ 10-13),4a-d phenols (pKa ~ 10),4e and arene sulfinates (pKa ~ 7)4f have been successful, the reaction of less stabilized nucleophiles has proven difficult.5 Since we have previously developed decarboxylative coupling strategies that allow allylation of nonstabilized nucleophiles without the use of an external base or organometallic, we hypothesized that a similar strategy might allow decarboxylative coupling of benzylic esters with nonstabilized nucleophiles (eq. 1).5-

Promoting Positive Masculinities to Address Violence Against Women in Young People: Evidence From the PositivMasc Project

Violence against women (VAW) is a global problem of significant magnitude that negatively affects women, men and society as a whole and is becoming more pervasive at earlier ages. In the European Union in 2015, one in three women reported having experienced physical or sexual abuse since age 15. According to the World Health Organization (WHO), one in four young women ages 15-24 who has been in a relationship will have experienced violence by an intimate partner by her mid-twenties. New forms of violence against women, such as cyber-harassment, image-based sexual violence and controlling behavior via social media are quickly emerging as young people embrace technology in their socialization. This is disturbing, given that VAW has devastating consequences for society as a whole. It not only affects the health and well-being of both women and men, it is estimated to cost the EU about 366 billion euros annually. Recent research suggests that societal gender norms and harmful understandings of manhood are at the root of VAW. Men who believe that manhood is about dominance and being in control are more likely to commit VAW. These harmful ideas not only affect women through intimate partner violence (IPV - one form of VAW), they also negatively impact men’s health and well-being, in terms of violence towards other men, poor health, fatherhood and increased risk behaviors among young men. Gender norms are changing along with legislation that favors gender equality, but harmful forms of manhood still persist, and young people face considerable difficulty in navigating these changes. Research shows that educational interventions that incorporate and support positive understandings of manhood, referred to as positive “masculinities” in research literature, are a promising approach to VAW prevention in young people. This brief reports findings from PositivMasc, a multi-country research project that aims to understand how young people think about manhood and VAW and to identify strategies to promote positive masculinities in efforts to reduce gender-based violence. The project’s findings suggest that VAW policies and interventions should explicitly reference manhood and gender roles. They should also integrate a gendertransformative approach in VAW prevention education in schools, among families and in communities, to build gender equity and cultivate empathy and understanding among men. Given that long-term violence can begin and endure if VAW is normalized at young ages, reshaping gender norms must begin early. Supporting the development of positive forms of manhood among young people is crucial to continuing to make progress in eliminating VAW

Educational intervention guide. Promoting positive masculinities for the prevention of violence against women. Conceptual toolbox and activities

Violence against women (VAW) is one of the world’s most persistent and destructive societal problems. It does not occur in isolation as it is strongly influenced by the ways gender relations are constructed and by the ways femininities and masculinities are culturally represented and negotiated in daily interactions. Many of the beliefs, behaviours and attitudes that sustain VAW are related to gendered expectations and norms. That is why it is so important to work on our understanding of gender relations and roles in VAW prevention. This educational intervention guide was created in the context of the PositivMasc Project, which was carried out from 2019-2022 by researchers in Ireland, Israel, Spain and Sweden and funded by the GENDER-NET European research network. The PositivMasc project aims to explore discourses of non-violent forms of masculinity and ways in which to support and promote positive masculinities for the prevention of VAW among young people and in society (Salazar et al., 2020). In fact, more positive expressions of masculinities (non-violent, inclusive, empathetic, caring, or egalitarian) are emerging in society, advocated by women and men fighting against different forms of VAW (Elliott, 2016). One of the key concepts underpinning this document is positive masculinities, which refers to potential alternatives to hegemonic masculinity and ways of promoting more inclusive, empathetic, caring and equitable forms of manhood and gender equity (Foley et al., 2015; Pérez-Martínez et. al, 2021). As part of the PositivMasc project goals related to research dissemination and research impact, we present this guide which includes a conceptual toolbox and activities for engaging young people in actively rethinking gender relations and promoting gender-equitable and healthy relationships free of VAW.This work was supported by GENDER NET Plus Co-Fund (reference number 2018-00968). We also want to acknowledge the financial support received from the Swedish Research Council (Grant number: 2018-00968); the Irish Research Council; The Ministry of Science & Technology of Israel (3-15662) and the Ministry of Science and Innovation of Spain (Ref. PCI2019-103580)

Promoting Positive Masculinities to Address Violence Against Women: A Multicountry Concept Mapping Study

Interventions engaging men that challenge unequal gender norms have been shown to be effective in reducing violence against women (VAW). However, few studies have explored how to promote anti-VAW positive masculinity in young adults. This study aims to identify key multicountry strategies, as conceived by young adults and other stakeholders, for promoting positive masculinities to improve gender equity and prevent and target VAW. This study (2019–2021) involved young adults (aged 18–24 years) and stakeholders from Ireland, Israel, Spain, and Sweden. We applied concept mapping, a participatory mixed-method approach, in phases: (1) brainstorming, using semi-structured interviews with young adults (n = 105) and stakeholders (n = 60), plus focus group discussions (n = 88), to collect ideas for promoting anti-VAW positive masculinity; (2) development of an online questionnaire for sorting (n = 201) and rating ideas emerging from brainstorming by importance (n = 406) and applicability (n = 360); (3) based on sorting and rating data, creating rating maps for importance and applicability and clusters/strategies using multidimensional scaling and hierarchical cluster analysis with groupwisdom™ software; and (4) interpretation of results with multicountry stakeholders to reach agreement. The cluster map identified seven key strategies (41 actions) for promoting anti-VAW positive masculinities ranked from highest to lowest: Formal and informal education and training; Preventive education and activities in different settings/areas; Skills and knowledge; Empathy, reflection, and understanding; Media and public efforts; Policy, legislation, and the criminal justice system; and Organizational actions and interventions. Pattern matches indicated high agreement between young people and stakeholders in ranking importance (r = 0.96), but low agreement for applicability (r = 0.60). Agreement in the total sample on prioritizing statements by importance and applicability was also low (r = 0.20); only 14 actions were prioritized as both important and applicable. Young people and stakeholders suggested seven comprehensive, multidimensional, multi-setting strategies to facilitate promoting positive masculinity to reduce VAW. Discrepancy between importance and applicability might indicate policy and implementation obstacles.The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: This work was part of a multisite study supported by GENDER NET Plus CoFund (reference number 2018-00968). It was funded by the Ministry of Science and Innovation of Spain (Ref. PCI2019-103580), the Swedish Research Council (Grant number: 2018-00968), the Irish Research Council, and the Ministry of Science & Technology of Israel (315662)

Multilayered safety framework for living diagnostics in the colon

Introduction: Colorectal cancer is the second most deadly cancer worldwide. Current screening methods have low detection rates and frequently provide false positive results, leading to missed diagnoses or unnecessary colonoscopies. To tackle this issue, the Wageningen UR iGEM team from 2022 developed “Colourectal”, a living diagnostic tool for colorectal cancer. Following a synthetic biology approach, the project used an engineered Escherichia coli Nissle 1917 strain capable of binding to tumour cells that detects two distinct cancer biomarkers, and secretes a coloured protein observable in stool. Due to the utilization of genetically modified bacteria in vivo, precautionary biosafety measures were included within a three level safe-by-design strategy.Results: The first genetic safeguard ensured confinement of the living diagnostic to the colon environment by implementing auxotrophy to mucin that is abundant in the colon lining. For this, a synthetic chimeric receptor was generated to ensure expression of essential genes in the presence of mucin. The second strategy limited the viability of the engineered bacteria to the human body, preventing proliferation in open environments. The use of a temperature sensitive kill switch induced bacterial cell death at temperatures below 37°C. The third biocontainment strategy was installed as an emergency kill switch to stop the Colourectal test at any point. By inducing a highly genotoxic response through CRISPR-Cas-mediated DNA degradation, cell death of E. coli Nissle is triggered.Discussion: While the use of engineered microorganisms in human applications is not yet a reality, the safety considerations of our multi-layered strategy provide a framework for the development of future living diagnostic tools

Substituted N-(Biphenyl-4′-yl)methyl (R)-2-Acetamido-3-methoxypropionamides: Potent Anticonvulsants That Affect Frequency (Use) Dependence and Slow Inactivation of Sodium Channels

, We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound’s whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed

Chimeric derivatives of functionalized amino acids and α-aminoamides: Compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels

Six novel 3″-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4′-((3″-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4′-((3″-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI = TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNav1.1, rNav1.3, hNav1.5, or hNav1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation