Simplifying Access to Targeted Protein Degraders via Nickel Electrocatalytic Cross-Coupling.

C-C linked glutarimide-containing structures with direct utility in the preparation of cereblon-based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial α-bromoglutarimide through a unique Brønsted-acid assisted Ni-electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi-step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time-consuming aspect of reaction setup is weighing out the starting materials.

Iridium-Catalyzed Double Convergent 1,3-Rearrangement/Hydrogenation of Allylic Alcohols.

Enantioconvergent catalysis has the potential to convert different isomers of a starting material to a single highly enantioenriched product. Here we report a novel enantioselective double convergent 1,3-rearrangement/hydrogenation of allylic alcohols using an Ir-N,P catalyst. A variety of allylic alcohols, each consisting of a 1:1:1:1 mixture of four isomers, were converted to the corresponding tertiary alcohols with two contiguous stereogenic centers, in up to 99% ee and 99:1 d.r. DFT calculations, and control experiments suggest that the 1,3-rearrangement is the crucial stereodetermining element of the reaction.

Asymmetric Full Saturation of Vinylarenes with Cooperative Homogeneous and Heterogeneous Rhodium Catalysis.

Homogeneous and heterogeneous catalyzed reactions can seldom operate synergistically under the same conditions. Here we communicate the use of a single rhodium precursor that acts in both the homogeneous and heterogeneous phases for the asymmetric full saturation of vinylarenes that, to date, constitute an unmet bottleneck in the field. A simple asymmetric hydrogenation of a styrenic olefin, enabled by a ligand accelerated effect, accounted for the facial selectivity in the consecutive arene hydrogenation. Tuning the ratio between the phosphine ligand and the rhodium precursor controlled the formation of homogeneous and heterogeneous catalytic species that operate without interference from each other. The system is flexible in terms of both the chiral ligand and the nature of the external olefin. We anticipate that our findings will promote the development of asymmetric arene hydrogenations.

Combined Theoretical and Experimental Studies Unravel Multiple Pathways to Convergent Asymmetric Hydrogenation of Enamides.

We present a highly efficient convergent asymmetric hydrogenation of E/Z mixtures of enamides catalyzed by N,P-iridium complexes supported by mechanistic studies. It was found that reduction of the olefinic isomers (E and Z geometries) produces chiral amides with the same absolute configuration (enantioconvergent hydrogenation). This allowed the hydrogenation of a wide range of E/Z mixtures of trisubstituted enamides with excellent enantioselectivity (up to 99% ee). A detailed mechanistic study using deuterium labeling and kinetic experiments revealed two different pathways for the observed enantioconvergence. For α-aryl enamides, fast isomerization of the double bond takes place, and the overall process results in kinetic resolution of the two isomers. For α-alkyl enamides, no double bond isomerization is detected, and competition experiments suggested that substrate chelation is responsible for the enantioconvergent stereochemical outcome. DFT calculations were performed to predict the correct absolute configuration of the products and strengthen the proposed mechanism of the iridium-catalyzed isomerization pathway.

Enantioconvergent and enantiodivergent catalytic hydrogenation of isomeric olefins.

The asymmetric catalytic hydrogenation of olefins is one of the most widely studied and utilised transformations in asymmetric synthesis. This straightforward and atom-economical strategy can provide excellent enantioselectivity for a broad variety of substrates and is widely relevant for both industrial applications and academic research. In many instances the hydrogenation is stereospecific in the regard that the E-Z-geometry of the olefin governs the stereochemistry of the hydrogenation, producing an enantiodivergent outcome. Interestingly, the possibility to hydrogenate E- and Z-isomer mixtures to a single stereoisomer in an enantioconvergent manner has been reported. This avoids the need for synthesis of geometrically pure alkene starting materials and therefore constitutes a significant practical advantage. This review article aims to provide an overview of the different stereochemical outcomes in the hydrogenation of olefins. Although the field is well developed and selectivity models have been proposed for a number of catalytic systems, an organized collection of enantioconvergent results, as opposed to the more common enantiodivergent case, might promote new investigation into these phenomena.

Stereodivergent Synthesis of Trisubstituted Enamides: Direct Access to Both Pure Geometrical Isomers.

A stereodivergent strategy has been developed to access either (E)- or (Z)-isomers of trisubstituted enamides. Starting from an extensive range of ketones, it was possible to synthesize and isolate the desired pure isomer by switching the reaction conditions. Lewis acid activation enables the formation of the (E)-isomers in high stereoselectivity (>90:10) and good yields. On the other hand, the use of a Brønsted acid allows the preparation of the (Z)-isomers, again in high selectivity (up to 99:1), with moderate yields.

Synthesis of Benzofuranones via Malonates Desymmetrization: Yield Increase by the Portion-wise Addition of Quinones.

The organocatalyzed addition of several malonates to 1,4-benzoquinones affords benzofuranones bearing a quaternary stereocenter with good enantioselectivity. This reaction is an intramolecular desymmetrization since it proceeds through the formation of an arylated achiral malonate that cyclizes to give the reaction product. The addition rate of the quinone dramatically affects the reaction yield which was originally low. The yield was considerably increased, in some cases, from less than 20 % to over 95 %, by adding the quinone in portions rather than at once, keeping similar enantioselectivity. A possible rationalization for the preferential formation of the indicated enantiomer has been investigated by DFT calculations.

Organocatalysis and catalyst aggregation: a study using the asymmetric synthesis of benzofuranones as a test reaction.

A common problem encountered in enantioselective organocatalysis is the aggregation of the catalyst, which can result in a relevant decrease of the efficiency and selectivity of the process. In the asymmetric synthesis of chiral benzofuranones, recently reported by us, we noted a remarkable increase of the reaction yield upon the addition of one of the reagents in a portionwise manner rather than in a single addition. We investigated this phenomenon by several experimental techniques such as 1D and 2D NMR experiments, UV-Vis spectroscopy, circular dichroism and dynamic light scattering. In addition, we studied the kinetic profile of this reaction using a simple numerical model and carried out in silico investigations. All these different approaches point to the conclusion that in the reaction medium a supramolecular polymerization/aggregation phenomenon, based on weak interactions, occurs and such a process is promoted by a quinone, which is one of the reagents of the benzofuranone synthesis. The portionwise mode of addition is a known strategy which can improve the performance of many synthetic procedures and this strategy is commonly adopted on account of empirical experience. However, our results provide an explanation, based on a chemical kinetic model, of the reason why the portionwise addition affects in such a dramatic way the yield of the benzofuranone synthesis catalyzed by Cinchona alkaloids.

The Potential Role of Naringin and Naringenin as Nutraceuticals Against Metabolic Syndrome.

Metabolic syndrome, an increasing problem in western society, is a cluster of conditions that affect cardiovascular health, lipid and glucose management, increasing the risk of heart diseases, stroke and diabetes. Bioactive flavonoids are a great resource of compounds with proven antiinflammatory activities. Naringin, a natural flavanone found in citrus fruits, and its aglycone have demonstrated to ameliorate obesity, dyslipidemia, and insulin resistance in animal models. The principal mechanisms by which these flavonoids exert their action involve AMPK and PPARα up-regulation and the down-regulation of genes involved in lipid metabolism. Although different studies have been carried out to define the pharmacological effects of these flavonoids, their therapeutic use is still limited.

Catalytic enantioselective synthesis of fluoromethylated stereocenters by asymmetric hydrogenation.

Fluoromethyl groups possess specific steric and electronic properties and serve as a bioisostere of alcohol, thiol, nitro, and other functional groups, which are important in an assortment of molecular recognition processes. Herein we report a catalytic method for the asymmetric synthesis of a variety of enantioenriched products bearing fluoromethylated stereocenters with excellent yields and enantioselectivities. Various N,P-ligands were designed and applied in the hydrogenation of fluoromethylated olefins and vinyl fluorides.

Entomophagy: A Narrative Review on Nutritional Value, Safety, Cultural Acceptance and A Focus on the Role of Food Neophobia in Italy.

In recent years, the consumption of insects, or entomophagy, has produced an increasing interest amongst scientists and ecologists as a potential source of animal protein. Eating insects is also interesting in terms of low greenhouse gas emissions and low land use. In contrast to tropical countries, where most of the 2000 edible insect species are traditionally consumed, the concept of eating insects is still new to Western culture and diet. Culture and eating habits exert a great influence on what is considered edible in the Mediterranean area, especially in Italy, where the preservation of culinary traditions is a predominant factor affecting dietary behaviour. The purpose of this narrative paper is to provide an overview of the main topics related to entomophagy. The introduction presents some information about the nutrient content and safety aspects, the second part summarises the cultural acceptance of insect in the world, while the role of food neophobia on the intention to consume insects in Italy is focused on in part three. The discussion displays important viewpoints of previously published studies and based on these perspectives it can be concluded that the Italian diet is still clearly influenced by local tradition. In conclusion, in order to introduce insects into the Italian diet, psychological motivation has to be enhanced.

Suicide identification during on-site inspection. Proposal and application of an interpretative method for death scene investigation.

Death scene investigation (DSI) is critically important for the identification of the manner of death. The present study aims to present a scoring system for the correct framing of a case as a suicide starting from the DSI and its preliminary application. The method is based on five items: (1) statistical frequency of the method adopted; (2) victim's history of mental illness; (3) circumstantial data; (4) number of means; (5) compatibility of means and injuries with suicidal dynamics; and the application of a correction factor if suicide risk indicators are present. We blindly analyzed 180 cases of violent deaths equally divided into suicides, homicides and accidental deaths and the results obtained were compared with the established dynamics of death. The proposed method has proven to be efficient in the identification of suicide at the DSI, but further on-site studies making use of a wider number of cases is necessary.

Double origin of the superior cerebellar artery associated with homolateral haemorrhagic infarction of cerebellum.

The superior cerebellar artery (SCA) shows the least variable course and the lowest incidence of anatomical variations among cerebellar arteries. In the present study, an 84-year-old woman was affected by a cerebellar infarction which underwent haemorrhagic evolution in the following days. Neuroimaging investigations also showed a probable double origin of the left SCA. Neuropathological examination confirmed the presence of a large haemorrhagic infarction at the level of the superior portion of the left cerebellar hemisphere and vermis. The left SCA arose from two small arteries arising from the left aspect of the basilar artery and joining together after a course of 9 mm. Previous studies have reported the association of cerebrovascular pathologies, such as intracranial aneurysms, with fenestrations and double origins of the posterior inferior cerebellar artery. In the present case, the occurrence of an haemorrhagic infarction in the vascular field of an SCA with double origin is intriguing in suggesting a possible pathophysiological association.

Unusual suicide in Italy: criminological and medico-legal observations-a proposed definition of "atypical suicide" suitable for international application.

This work is the result of a kind of categorization of suicidal conduct based on an empirical-phenomenological approach, with integrated assessment of certain criteria, such as the dynamics, correlation of types of injury and how they were produced, evidence gathered during official inspections in loco, and case history findings about "suicide." This categorization is an attempt to provide a nosographic definition of atypical suicide, that is, cases in which the parameters of "typical" suicide are missing. Case studies are described, taken from a systematic exploration mainly of the Italian specialized literature of the 20th century, supplemented by earlier references when deemed significant. In-depth analysis of atypical suicide can supply additional interpretations of the problem of differential diagnosis of suicide, homicide, and accidental death, that is, the real punctum dolens in overall medico-legal determination of the cause of death in scenarios in which death cannot be definitely traced to a deliberate act.