Synthesis of Nitro Alcohols by Riboflavin Promoted Tandem Nef-Henry Reactions on Nitroalkanes

We disclose a unprecedented riboflavin promoted Nef reaction of primary nitroalkanes coupled with a nitroaldol reaction. This tandem process allows the synthesis of functionalized nitro alcohols under mild reaction conditions. Secondary nitroalkanes fail to give the expected nitroaldol products although they are consumed under the reaction conditions

CeCl3 catalyzed imino Diels-Alder reactions: hydrated vs anhydrous

Aza-Diels-Alder reaction is a straightforward way to synthesize useful nitrogen containing heterocyclic structures.1 In particular, the known reaction between imines and Danishefsky’s diene has proved to be an excellent way to obtain the 1,2-substituted-2,3-dihydropyridinone scaffold, widely present in bioactive small molecules and versatile building block for the synthesis of more complex structures.2 The reaction of Danishefsky’s diene with aromatic imines has been widely studied in last years, anyway less examples of the same reaction involving imines derived from aliphatic amines or aldehydes are present. For this reason the possibility to extend the potentiality of this reaction performing it on a large variety of imines was studied, under the Lewis acid promoting system CeCl3.7H2O/CuI, previously applied with success3 in many other synthetic methodologies. Imines 3 were prepared by direct condensation of aliphatic or aromatic amines and aldehydes and then the diene was added together with the catalyst, obtaining dihydropyridinones 4 with good to excellent yields in short reaction times. To extend the scope of this work, also imines derived from aminoacids were tested as dienophiles. The only moderate diastereoselectivity and the long time needed with some homochiral dienophiles prompted us to have a deeper insight into the mechanism, with the conclusion that the reaction proceed also through a slower competitive Mannich-Michael pathway, favoured by the presence of water in the catalyst. 1) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099-6138. 2) Cant, A. A.; Sutherland, A. Synthesis 2012, 44, 1935-1950. 3) Bartoli, G.; Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104-6143

Recent Developments in Chemical Derivatization of Microcrystalline Cellulose (MCC): Pre-Treatments, Functionalization, and Applications.

Microcrystalline Cellulose (MCC) is an isolated, colloidal crystalline portion of cellulose fibers, and it is a valuable alternative to non-renewable fossil-based materials. It is used for a large plethora of different fields, such as composites, food applications, pharmaceutical and medical developments, and cosmetic and material industries. The interest of MCC has also been driven by its economic value. In the last decade, particular attention has been driven to the functionalization of its hydroxyl groups to expand the field of applications of such biopolymer. Herein, we report and describe several pre-treatment methods that have been developed to increase the accessibility of MCC by breaking its dense structure allowing further functionalization. This review also collects the results that have appeared in the literature during the last two decades on the utilization of functionalized MCC as adsorbents (dyes, heavy metals, and carbon dioxide), flame retardants, reinforcing agents, energetic materials, such as azide- and azidodeoxy-modified, and nitrate-based cellulose and biomedical applications

An efficient synthesis of bio-based Poly(urethane-acrylate) by SiO2-Supported CeCl3·7H2O–NaI as recyclable Catalyst

Poly(urethane-acrylates) (PUAs) are UV-curable resins used for biomedical applications, coatings, adhesives, and many others. Their syntheses usually involve the use of aromatic diisocyanates and polyols coming from fossil-based resources, in the presence of tin-based catalysts, which present a very well-known toxicity. In the last years the increase of environmental and economic issues related to the depletion of limited sources, the increase of greenhouse gas emissions, the release of toxic degradation compounds and the catalyst contamination has shifted the attention toward more sustainable solutions. In this study a low-impact, sustainable and efficient procedure for the synthesis of bio-based PUA promoted by solid supported CeCl3·7H2O–NaI/SiO2 was developed. This catalytic system provides the target compounds with good monomer conversion and molecular weights and allow the synthesis under heterogeneous conditions as main advantage, with the final recovery of the catalyst. We also confirmed its rapid separation, stability, and efficient recycling of the catalyst, obtaining comparable results over a seven reactions cycles. The goodness of the polymerization process under heterogeneous condition was confirmed by chemical and thermal characterizations

The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents

We synthesized and characterized MOMO as a new small molecule analog of the cytotoxic natural product climacostol efficiently activated in mild extracellular acidosis. The synthesis of MOMO had a key step in the Wittig olefination for the construction of the carbon-carbon double bond in the alkenyl moiety of climacostol. The possibility of obtaining the target (Z)-alkenyl MOMO derivative in very good yield and without presence of the less active (E)-diastereomer was favored from the methoxymethyl ether (MOM)-protecting group of hydroxyl functions in aromatic ring of climacostol aldehyde intermediate. Of interest, the easy removal of MOM-protecting group in a weakly acidic environment allowed us to obtain a great quantity of climacostol in biologically active (Z)-configuration. Results obtained in free-living ciliates that share the same micro-environment of the climacostol natural producer Climacostomum virens demonstrated that MOMO is well-tolerated in a physiological environment, while its cytotoxicity is rapidly and efficiently triggered at pH 6.3. In addition, the cytostatic vs. cytotoxic effects of acidified-MOMO can be modulated in a dose-dependent manner. In mouse melanoma cells, MOMO displayed a marked pH-sensitivity since its cytotoxic and apoptotic effects become evident only in mild extracellular acidosis. Data also suggested MOMO being preferentially activated in the unique extra-acidic microenvironment that characterizes tumoural cells. Finally, the use of the model organism Drosophila melanogaster fed with an acidic diet supported the efficient activity and oral delivery of MOMOmolecule in vivo.MOMO affected oviposition ofmating adults and larvae eclosion. Reduced survival of flies was due to lethality during the larval stages while emerging larvae retained their ability to develop into adults. Interestingly, the gut of eclosed larvae exhibited an extended damage (cell death by apoptosis) and the brain tissue was also affected (reduced mitosis), demonstrating that orally activated MOMO efficiently targets different tissues of the developing fly. These results provided a proof-of-concept study on the pHdependence of MOMO effects. In this respect, MOM-protection emerges as a potential prodrug strategy which deserves to be further investigated for the generation of efficient pH-sensitive small organic molecules as pharmacologically active cytotoxic compounds

Bioactivity and Structural Properties of Novel Synthetic Analogues of the Protozoan Toxin Climacostol

Climacostol (5-[(2Z)-non-2-en-1-yl]benzene-1,3-diol) is a resorcinol produced by the protozoan Climacostomum virens for defence against predators. It exerts a potent antimicrobial activity against bacterial and fungal pathogens, inhibits the growth of several human and rodent tumour cells, and is now available by chemical synthesis. In this study, we chemically synthesized two novel analogues of climacostol, namely, 2-methyl-5 [(2Z)-non-2-en-1-yl]benzene-1,3-diol (AN1) and 5-[(2Z)-non-2-en-1-yl]benzene-1,2,3-triol (AN2), with the aim to increase the activity of the native toxin, evaluating their effects on prokaryotic and free-living protists and on mammalian tumour cells. The results demonstrated that the analogue bearing a methyl group (AN1) in the aromatic ring exhibited appreciably higher toxicity against pathogen microbes and protists than climacostol. On the other hand, the analogue bearing an additional hydroxyl group (AN2) in the aromatic ring revealed its ability to induce programmed cell death in protistan cells. Overall, the data collected demonstrate that the introduction of a methyl or a hydroxyl moiety to the aromatic ring of climacostol can effectively modulate its potency and its mechanism of action

Functionalization of Cyclic Structures for Advanced Biological and Pharmaceutical Applications

The key components of the scaffold in pharmaceutical chemistry are ring systems, of different sizes, and are the fundamental factors of most of the drugs on the market today. Nowadays, the importance of cyclic structures is well understood by medicinal chemists, since they play a significant role in molecular properties such as the electronic distribution, three dimensionality, and molecule rigidity. They are often key factors in whole molecule properties such as lipophilicity or polarity and can determine molecular reactivity, metabolic stability, and toxicity. Cyclic structures have always fascinated organic and medicinal chemists, and many organic molecules form cycles with appealing biological properties. Research in cyclic chemistry continued to advance in synthetic methods development, conformational studies and investigation of their role for controlling biological functions. This work, carried out in the Prof. Marcantoni’s research group at the University of Camerino (Camerino, Italy) with the collaboration of Dompé S.p.A. (L’Aquila, Italy) from December 2015 to December 2018 and in the Prof. Poli’s research group from January 2018 to July 2018 at the University Pierre and Marie Curie (Paris, France), had the objective to investigate new synthetic methodologies for the functionalization of cyclic compounds, as well as the formation of cyclic structures from acyclic precursor, for advanced biological purposes. The first chapter focuses on the functionalization of the primary face of a β-cyclodextrin, in order to obtain a synthetic human receptor model, used for studying the possible interactions of this compound with a new class of biologically active compounds in development at Dompé S.p.A. The second chapter, carried out in the Poli’s research group, describes the selective C-3 functionalization trials of 2-furaldehyde and its derivatives by Directed ortho Metalation (DoM) chemistry in presence of organolithium compounds and focuses on the study of degradation products. The reaction of an alkyllithium compound with an aromatic structure bearing a Direct Metalation Group (DMG) normally leads to an ortho-metalated intermediate. Good DMGs are strong complexing or chelating groups that have the effect of increasing the kinetic acidity of protons in the ortho position. The third chapter focuses on the in-depth study of the mechanistic aspect on the formation of 5acylaminothiazoles starting from α-chloroglycinates, obtained by a new synthetic methodology developed in the Marcantoni’s research group. Finally, the fourth chapter focuses on the study of the role of Cerium trichloride in the formation of cyclic compounds via Nazarov cyclization

Sustainable and fast synthesis of functionalized quinoxalines promoted by natural deep eutectic solvents (NADESs)

Functionalized quinoxalines, embedding acid sensitive protecting groups, can be prepared with a fast (5 min) and high yielding (>90%) protocol using a choline chloride/water NADES at room temperature without any additional activation. The products obtained after solvent extraction do not require any further purification. The NADES used can be recycled up to six times maintaining the same efficiency level