Total Synthesis of 4-epi-Bengamide E.

Bengamide E is a bioactive natural product that was isolated from Jaspidae sponges by Crews and co-workers in 1989. It displays a wide range of biological activities, including antitumor, antibiotic, and anthelmintic properties. With the aim of investigating the structural feature essential for their activity, several total syntheses of Bengamide E and its analogues have been reported in the literature. Nevertheless, no synthesis of the stereoisomer with modification of its configuration at C-4 carbon has been reported so far. Here, we report the first total synthesis of the 4-epi-Bengamide E. Key reactions in the synthesis include a chemoenzimatic desymmetrization of biobased starting materials and a diastereoselective Passerini reaction using a chiral, enantiomerically pure aldehyde, and a lysine-derived novel isocyanide.

Synthesis of symmetric bis-α-ketoamides from renewable starting materials and comparative study of their nucleating efficiency in PLLA.

An efficient and smart synthesis of bis-α-ketoamides has been disclosed. The desired products have been obtained through a Passerini multicomponent reaction using biobased aldehydes, acetic acid and bis-isocyanides (prepared from the corresponding biobased diamides), followed by a deprotection/oxidation step. The effect of the synthesized compounds on the crystallization behavior of poly(l-lactide) (PLLA) has been investigated by differential scanning calorimetry (DSC) in non-isothermal conditions. Among all the synthesized compounds, only a few are able to meaningfully enhance the nucleation of PLLA, as confirmed by a shift of the polymer crystallization peak temperature towards higher values. With the research of active polymer nucleating agents being mostly empirical, the combinatorial synthetic approach proposed herein, coupled with the possibility of a small scale mixing procedure, can potentially represent a useful strategy for the discovery of new efficient biobased polymer additives.

Study and application of graphene oxide in the synthesis of 2,3-disubstituted quinolines via a Povarov multicomponent reaction and subsequent oxidation.

The carbocatalyzed synthesis of 2,3-disubstituted quinolines is disclosed. This process involved a three-component Povarov reaction of anilines, aldehydes and electron-enriched enol ethers, which gave the substrate for the subsequent oxidation. Graphene oxide (GO) was exploited as a heterogeneous, metal-free and sustainable catalyst for both transformations. The multicomponent reaction proceeded under simple and mild reaction conditions, exhibited good functional group tolerance, and could be easily scaled up to the gram level. A selection of tetrahydroquinolines obtained was subsequently aromatized to quinolines. The multistep synthesis could also be performed as a one-pot procedure. Investigation of the real active sites of GO was carried out by performing control experiments and a by full characterization of the carbon material by X-ray photoelectron spectroscopy (XPS) and solid-state nuclear magnetic resonance (ssNMR).

Fluorescence Properties of a Novel Isoquinoline Derivative Tested in an Invertebrate Chordate, Ciona intestinalis.

3-Hydroxyisoquinolines (ISOs) and their tautomeric isoquinolin-3-ones are heterocycles with attractive biological properties. Here we reported the revisited synthesis of a highly functionalized ISO that showed blue fluorescence and the characterization of its biological properties in an invertebrate animal model, the ascidian Ciona intestinalis. Larvae exposed to ISO at concentrations higher than 1 µM showed an intense fluorescence localized in the cell nuclei of all tissues. Moreover, exposure to ISO interfered with larval ability to swim; this neuromuscular effect was reversible. Overall, these results suggested that ISOs can have promising applications as novel fluorescent dyes of the cell nuclei.

Into the Blue: Ketene Multicomponent Reactions under Visible Light.

For the first time, a detailed study on the photophysical properties of variously substituted diazoketones and on their photoreactivity under blue LED irradiation was carried out. Despite very limited absorbance in the visible region, we have demonstrated that, independently from their structure, α-diazoketones all undergo a very efficient Wolff rearrangement. Contrarily to the same UV-mediated reaction, where photons can give rise to side processes, in this case, almost all absorbed photons are selective and effective, and the quantum yield is close to 100%. If the rearrangement is carried out in the presence of isocyanides and carboxylic acids/silanols, the photoreactivity is not affected, and the resulting ketenes can afford α-acyloxy- and α-silyloxyacrylamides through two distinct multicomponent reactions, performed both in batch and under continuous flow, with improved selectivity and broader scope. These photoinduced multicomponent reactions can be coupled with other visible-light-mediated transformations, thus increasing the diversity of the molecules obtainable by this approach.

The 100 facets of the Passerini reaction.

This perspective aims at celebrating the 100th anniversary of the discovery of the Passerini three component reaction. After being nearly neglected for many years, now this reaction has become quite popular, thanks to the achievements of the last 30 years, which have revealed several chances of exploitation in organic synthesis. Though not being comprehensive, this review means to show the various ways that have been used in order to expand the utility of the Passerini reaction. Post-MCR transformations to give heterocycles or peptidomimetics, variants through single component replacement, stereochemical issues, and applications in total syntheses will be especially covered.

Synthesis, Photoisomerization, Antioxidant Activity, and Lipid-Lowering Effect of Ferulic Acid and Feruloyl Amides.

The Ugi four-component reaction employing naturally occurred ferulic acid (FA) is proposed as a convenient method to synthesize feruloyl tertiary amides. Applying this strategy, a peptoid-like derivative of ferulic acid (FEF77) containing 2 additional hydroxy-substituted aryl groups, has been synthesized. The influence of the configuration of the double bond of ferulic acid and feruloyl amide on the antioxidant activity has been investigated thanks to light-mediated isomerization studies. At the cellular level, both FA, trans and cis isomers of FEF77 were able to protect human endothelial cord vein (HECV) cells from the oxidative damage induced by exposure to hydrogen peroxide, as measured by cell viability and ROS production assays. Moreover, in steatotic FaO rat hepatoma cells, an in vitro model resembling non-alcoholic fatty liver disease (NAFLD), the molecules exhibited a lipid-lowering effect, which, along with the antioxidant properties, points to consider feruloyl amides for further investigations in a therapeutic perspective.

Stable and Size Tunable CsPbBr3 Nanocrystals Synthesized with Oleylphosphonic Acid.

We employed oleylphosphonic acid (OLPA) for the synthesis of CsPbBr3 nanocrystals (NCs). Compared to phosphonic acids with linear alkyl chains, OLPA features a higher solubility in apolar solvents, allowing us to work at lower synthesis temperatures (100 °C), which in turn offer a good control over the NCs size. This can be reduced down to 5.0 nm, giving access to the strong quantum confinement regime. OLPA-based NCs form stable colloidal solutions at very low concentrations (∼1 nM), even when exposed to air. Such stability stems from the high solubility of OLPA in apolar solvents, which enables these molecules to reversibly bind/unbind to/from the NCs, preventing the NCs aggregation/precipitation. Small NCs feature efficient, blue-shifted emission and an ultraslow emission kinetics at cryogenic temperature, in striking difference to the fast decay of larger particles, suggesting that size-related exciton structure and/or trapping-detrapping dynamics determine the thermal equilibrium between coexisting radiative processes.

Synthesis of Polyoxygenated Heterocycles by Diastereoselective Functionalization of a Bio-Based Chiral Aldehyde Exploiting the Passerini Reaction.

A chiral bio-based building block, prepared by the lipase-mediated desymmetrization of an erythritol derivative, was further functionalized and then submitted to stereoselective Passerini reactions, allowing the synthesis of a small library of new molecules. Thanks to the presence of different functional groups, further cyclizations were performed providing bicyclic polyoxygenated heterocycles.

Regioselective Photooxidation of Citronellol: A Way to Monomers for Functionalized Bio-Polyesters.

Dye-sensitized photooxygenation reaction of bio-based double bond-containing substrates is proposed as sustainable functionalization of terpenes and terpenoids to transform them into polyoxygenated compounds to be employed for the synthesis of new bio-based polyesters. As proof of concept, citronellol 1 has been regioselectively converted into diol 4 using singlet oxygen (1O2), a traceless reagent that can be generated from air, visible light and zeolite supported-photosensitizer (Thionine-NaY). With our synthetic approach, diol 4 has been obtained in two-steps, with good regioselectivity, using green reagents such as light and air, and finally a solvent-free oxidation step. From this compound, a citronellol-based copolyester of poly(butylene succinate) (PBS) has been synthesized and fully characterized. The results obtained evidence that the proposed copolymerization of PBS with the citronellol-based building blocks allows to obtain a more flexible and functionalizable material, by exploiting a largely available natural molecule modified through a green synthetic path.

Stereodivergent access to all four stereoisomers of chiral tetrahydrobenzo[f][1,4]oxazepines, through highly diastereoselective multicomponent Ugi-Joullié reaction.

Starting from easily accessible chiral enantiopure 1,2-amino alcohols and salicylaldehydes, a concise route to cyclic imines has been developed. These chiral cyclic imines undergo a highly diastereoselective Ugi-Joullié reaction to give trans tetrahydrobenzo[f][1,4]oxazepines with the introduction of up to 4 diversity inputs. The cis isomer may also be attained, thanks to a thermodynamically controlled base catalysed epimerization. Free secondary amines have been obtained using an unprecedented "removable" carboxylic acid.

Biophysical and in Vivo Studies Identify a New Natural-Based Polyphenol, Counteracting Aß Oligomerization in Vitro and Aß Oligomer-Mediated Memory Impairment and Neuroinflammation in an Acute Mouse Model of Alzheimer's Disease.

In this study natural-based complex polyphenols, obtained through a smart synthetic approach, have been evaluated for their ability to inhibit the formation of Aß42 oligomers, the most toxic species causing synaptic dysfunction, neuroinflammation, and neuronal death leading to the onset and progression of Alzheimer's disease. In vitro neurotoxicity tests on primary hippocampal neurons have been employed to select nontoxic candidates. Solution NMR and molecular docking studies have been performed to clarify the interaction mechanism of Aß42 with the synthesized polyphenol derivatives, and highlight the sterical and chemical requirements important for their antiaggregating activity. NMR results indicated that the selected polyphenolic compounds target Aß42 oligomeric species. Combined NMR and docking studies indicated that the Aß42 central hydrophobic core, namely, the 17-31 region, is the main interaction site. The length of the peptidomimetic scaffold and the presence of a guaiacol moiety were identified as important requirements for the antiaggregating activity. In vivo experiments on an Aß42 oligomer-induced acute mouse model highlighted that the most promising polyphenolic derivative (PP04) inhibits detrimental effects of Aß42 oligomers on memory and glial cell activation. NMR kinetic studies showed that PP04 is endowed with the chemical features of true inhibitors, strongly affecting both the Aß42 nucleation and growth rates, thus representing a promising candidate to be further developed into an effective drug against neurodegenerative diseases of the amyloid type.

Multicomponent Synthesis of Polyphenols and their in vitro Evaluation as Potential ß-Amyloid Aggregation Inhibitors.

While plant polyphenols possess a variety of biological properties, exploration of chemical diversity around them is still problematic. Here, an example of application of the Ugi multicomponent reaction to the combinatorial assembly of artificial, yet "natural-like", polyphenols is presented. The synthesized compounds represent a second-generation library directed to the inhibition of ß-amyloid protein aggregation. Chiral enantiopure compounds, and polyphenol-ß-lactam hybrids have been prepared too. The biochemical assays have highlighted the importance of the key pharmacophores in these compounds. A lead for inhibition of aggregation of truncated protein AßpE3-42 was selected.

Corrigendum: Exploitation of the Ugi 5-Center-4-Component Reaction (U-5C-4CR) for the Generation of Diverse Libraries of Polycyclic (Spiro)Compounds.

[This corrects the article DOI: 10.3389/fchem.2018.00369.].

Multi-Gram Synthesis of Enantiopure 1,5-Disubstituted Tetrazoles Via Ugi-Azide 3-Component Reaction.

Tetrazoles have been widely studied for their biological properties. An efficient route for large-scale synthesis of 1,5-disubstituted tetrazoles (1,5-DTs) is presented. The strategy exploits a reductive approach to synthetize a cyclic chiral imine substrate which is then converted into the target product through an Ugi-azide three-component reaction (UA-3CR). The final products are equipped with additional functionalities which can be further elaborated for the generation of combinatorial libraries of enantiopure heterocycles.

Exploitation of the Ugi 5-Center-4-Component Reaction (U-5C-4CR) for the Generation of Diverse Libraries of Polycyclic (Spiro)Compounds.

An Ugi multicomponent reaction with chiral cyclic amino acids, benzyl isocyanide and cyclic ketones (or acetone) has been exploited as key step for the generation of peptidomimetics. After a straightforward set of elaborations, the peptidomimetics were converted into polycyclic scaffolds displaying two orthogonally protected secondary amines. Libraries of compounds were obtained decorating the molecules through acylation/reductive amination reactions on these functional groups.

Photoinduced Multicomponent Synthesis of α-Silyloxy Acrylamides, an Unexplored Class of Silyl Enol Ethers.

The photoinduced, multicomponent reaction of α-diazoketones, silanols, and isocyanides affords α-silyloxy acrylamides, formally derived from α-keto amides. The presence of a secondary amido group makes classic preparative methods for silyl enol ethers unfeasible in this case, while the mild conditions required by this photochemical approach allow their synthesis in good yields; moreover, the general structure can be easily modified by varying each component of the multicomponent reaction. Fine-tuning of the reaction conditions (i.e., solvents, radiation, additives) can be exploited to obtain complete Z selectivity. The reactivity of this overlooked class of silyl enol ethers has been investigated, and features that could pave the way to new applications have been found.

Multicomponent, fragment-based synthesis of polyphenol-containing peptidomimetics and their inhibiting activity on beta-amyloid oligomerization.

A new and short fragment-based approach towards artificial (but "natural-based") complex polyphenols has been developed, exploiting the Ugi multicomponent reaction of phenol-containing simple substrates. The resulting library of compounds has been tested for its capacity to inhibit ß-amyloid protein aggregation, as a possible strategy to develop new chemical entities to be used as prevention or therapy for Alzheimer's disease. Some of the members of this library have demonstrated, in thioflavin assays, a highly promising activity in inhibiting aggregation for two ß-amyloid peptides: Aß1-42 and the truncated AßpE3-42.

Photocatalyzed synthesis of isochromanones and isobenzofuranones under batch and flow conditions.

Photocatalyzed reactions of 2-(alkoxycarbonyl)benzenediazonium tetrafluoroborates with various alkenes afforded isochromanones in good yields, according to a mechanism that was investigated. The advantage of using highly soluble esters rather than carboxylic acids as starting compounds became evident when the reactions were performed under flow conditions. On the other hand, when 2-vinylbenzoic acid derivatives were employed as reagents, isobenzofuranones were obtained together with unprecedented benzo[e][1,3]oxazepin-1(5H)-ones, with the latter derived from incorporation of the solvent (acetonitrile).