NOVEL SYNTHETIC ORGANOCATALYTIC METHODOLOGIES

The objective of this PhD study was to apply organocatalytic synthetic methods for the regio- and stereoselective synthesis of highly functionalized compounds. We exploited different organocatalytic activation modes to peculiar substrates we identified as suitable building blocks for versatile products in enantiomerically enriched form. In particular the developed projects relied on stereoselective amino- and hydrogen bonding organocatalysis, employing beta-nitroacrylates, beta-trifluoromethylated nitroalkenes and 2,2,2-trifluoroethyl 2-[(1,3-dithian)-2-yl]-ethanthioate in combination with various reaction partners, thus finding entries to valuable intermediates suitable for further subsequent transformations. The first Chapter of this thesis aim to give a general overview on those fields of organocatalysis related to the research topics studied in this PhD program, the second Chapter offers a literature background of the employed substrates. Following five Chapters (3-7) and Appendix report the discussion on the obtained results. According to our opinion, this PhD study offers solid examples of robustness, versatility and effectiveness of stereoselective organocatalytic strategies, which have been applied to interesting starting materials and in innovative reaction media, thus giving a reliable contribution to expand the boundaries of this field

Metal-free α-trifluoromethylthiolation and α-trifluoromethylselenolation of carbonyl derivatives

The incorporation of a SCF3 or a SeCF3 group into organic molecules is a topic of great interest, especially for the pharmaceutical and agrochemical industries. Due to their high lipophilicity and high electron-withdrawing character (Hansch lipophilicity parameter piR =1.44 (SCF3) vs piR =1.29 (SeCF3)), these moieties represent a powerful opportunity to influence the pharmacokinetics properties of a drug molecule. In the last years, new structural units, rising from the association between chalcogens and fluorinated moieties, have been introduced into carbonyl compounds, as emerging class with potential applications on several fields. New reagents have been developed as sources of electrophilic SCF3 and SeCF3 groups; however, a widespread use of such fluorinated compounds is hampered by the very limited number of strategies available for their preparation. In this contest, we have developed two methodologies for the preparation of alpha-SCF3 and alpha-SeCF3 substituted carbonyl derivatives starting from non activated ketones or their derivatives

A global assessment of Echinococcus multilocularis infections in domestic dogs: proposing a framework to overcome past methodological heterogeneity

Echinococcus multilocularis, the aetiological agent of human Alveolar Echinococcosis, is transmitted between small mammals and wild or domestic canids. Dogs infected with E. multilocularis as dead-end hosts. Whereas E. multilocularis infections in wild hosts and humans have been well-studied in recent decades, infections in domestic dogs are sparsely reported. This literature review and meta-analysis highlighted gaps in the available data and provided a re-assessment of the global distribution of domestic dog E. multilocularis infections. We found 46 published articles documenting the prevalence of E. multilocularis in domestic dogs from 21 countries across Europe, Asia and North America. Apparent prevalence estimates ranged from 0.00% (0.00–0.33%) in Germany to 55.50% (26.67–81.12%) in China. Most studies were conducted in areas of high human Alveolar Echinococcosis. By accounting for reassessed diagnostic sensitivity and specificity, we estimated true prevalence in a subset of studies, which varied between 0.00% (0.00–12.42%) and 41.09% (21.12–65.81%), as these true prevalence estimates were seldom reported in the articles themselves. Articles also showed a heavy emphasis on rural dogs, dismissing urban ones, which is concerning due to the role urbanisation plays in the transmission of zoonotic diseases, especially those utilising pets as definitive hosts. Lastly, population studies on canine Alveolar Echinococcosis were absent, highlighting the relative focus on human rather than animal health. We thus developed a framework for investigating domestic dog E. multilocularis infections and performing risk assessment of dog-associated transmission to fill the gaps found in the literature

A review on invasions by parasites with complex life cycles: The European strain of Echinococcus multilocularis in North America as a model

In a fast-changing and globalized world, parasites are moved across continents at an increasing pace.Co-invasion of parasites and their hosts is leading to the emergence of infectious diseases at a global scale, underlining the need for integration of biological invasions and disease ecology research.In this review, the ecological and evolutionary factors influencing the invasion process of parasites with complex life cycles were analyzed, using the invasion of the European strain of Echinococcus multilocularis in North America as a model.The aim was to propose an ecological framework for investigating the invasion of parasites that are trophically transmitted through predator-prey interactions, showing how despite the complexity of the cycles and the interactions among multiple hosts, such parasites can overcome multiple barriers and become invasive Identifying the key ecological processes affecting the success of parasite invasions is an important step for risk assessment and development of management strategies, particularly for parasites with the potential to infect people (i.e.zoonotic)

Phosphazene-Catalyzed Desymmetrization of Cyclohexadienone by Dithiane Addition

We report a desymmetrization of cyclohexadienones by intramolecular conjugate addition of a tethered dithiane nucleophile. Mild reaction conditions allow the formation of diversely functionalized fused bicyclic lactones. The products participate in facially selective additions from the convex surface, leading to allylic alcohol derivative

Host spatiotemporal overlap in a park with high endemicity of Echinococcus multilocularis

There has been a spate of recent cases of human alveolar echinococcosis (AE) in Alberta, Canada. Alveolar echinococcosis is caused by Echinococcus multilocularis, which is prevalent among coyote populations and present in domestic dogs in Alberta. Using qPCR, we estimated the seasonal fecal prevalence of E. multilocularis in coyotes and dogs in a multiuse recreation area close to Edmonton, Alberta, where we also setup remote cameras to model seasonal changes in the overlap in temporal activity and the spatial intensity of use among coyotes, humans, and dogs, as a proxy of potential transmission. We detected E. multilocularis in 18 of 137 wild canid feces and none in 44 dog feces. After correcting for the qPCR test’s sensitivity and specificity, we estimated at 15.7% (9.7-22.7%, 95% CrI) the true fecal prevalence for coyotes. Temporal overlap between coyotes and both humans and dogs increased in the fall and winter relative to the spring and summer. Coyote intensity of use showed seasonal variations and was higher on maintained trails and locations closer to visitor parking and at sites with high intensity of dog use. Our results reinforce the need of an integrated approach, typical of both One-Health and Eco-Health, to park management for minimizing the likelihood of transmission where human and dog activity results in significant overlap with the one of the natural definitive hosts of zoonotic parasites

Metal-Free Alpha Trifluoromethylselenolation of Carbonyl Derivatives under Batch and Flow Conditions

Trifluoromethylselenolated carbonyl compounds represent an emerging class with potential applications in several fields; however, a widespread use of such compound is hampered by the very limited number of strategies for their preparation. In this study we developed a method for the preparation of alpha-SeCF3 substituted carbonyl derivatives using an in situ generated electrophilic ClSeCF3 species. We also implemented an in-flow protocol to improve the safety features of the process

Organocatalytic strategies for enantioselective metal-free reductions

One of the most important chemical transformations is the reduction of multiple bonds, carbon-carbon as well as carbon-heteroatom double bonds, since it leads very often to the generation of new stereocenters in the molecule. The replacement of metal-based catalysts with equally efficient metal-free counterparts is very appealing in view of possible future applications of non toxic, low cost, and environmentally friendly promoters on an industrial scale. This perspective will focus specially, but not exclusively, on the enantioselective reduction of the carbon nitrogen double bond; despite the historical need for and continued interest in chiral amines, their synthesis remains challenging. Three metal-free catalytic methodologies available for the reduction of carbon-nitrogen double bond will be discussed: i) binaphthol-derived phosphoric acids catalyzed reductions, with dihydropyridine-based compound as the reducing agent; ii) trichlorosilane mediated reductions, in the presence of catalytic amounts of chiral Lewis bases; iii) metal-free hydrogenation of imines through FLP (Frustrated Lewis Pair) methodology, that involves the use of a combination of a strong Lewis acid with a variety of sterically encumbered Lewis bases, for examples phosphines or tertiary amines, to activate hydrogen at ambient conditions. Special attention will be devoted to the most recent applications of the last five years

Thresholds in layered neural networks with variable activity

The inclusion of a threshold in the dynamics of layered neural networks with variable activity is studied at arbitrary temperature. In particular, the effects on the retrieval quality of a self-controlled threshold obtained by forcing the neural activity to stay equal to the activity of the stored paterns during the whole retrieval process, are compared with those of a threshold chosen externally for every loading and every temperature through optimisation of the mutual information content of the network. Numerical results, mostly concerning low activity networks are discussed.Comment: 15 pages, Latex2e, 6 eps figure