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.

Chemo-Enzymatic Derivatization of Glycerol-Based Oligomers: Structural Elucidation and Potential Applications.

Switching from oil-based to bio-based feedstocks to ensure the green transition to a sustainable and circular future is one of the most pressing challenges faced by many industries worldwide. For the cosmetics and personal and house care industries there is a strong drive to accelerate this transition from the customers that starts favoring the purchase of naturally derived and bio-degradable products over the traditionally available products. In this work we developed a series of fully biobased macromolecules constituted of a glycerol-based oligoester backbone. Based on the subsequent derivatization with fatty acids or peptides, the resulting products may find application as emulsifiers, wetting agents, and potential vectors for the delivery of bioactive peptides. All steps of the resulting macromolecules were conducted following the green chemistry principles with no toxic or environmentally damaging compounds that were used in the overall production process.

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 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.

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.

Integrating biocatalysis and multicomponent reactions.

While often multicomponent reactions (MCR) are used for the diversity-oriented synthesis of racemic (or achiral) molecular entities, this short review describes two alternative approaches for accessing enantiopure products exploiting the power of biocatalysis. Enzymes or microorganisms may be used for preparing enantiopure MCR inputs or for resolving racemic (or achiral) MCR adducts.

Enzymatically promoted release of organic molecules linked to magnetic nanoparticles.

Magnetite-based magnetic nanoparticles have been successfully coupled to an organic system constituted of a fluorescent molecule, a tripeptide specifier and a spacer. The system is able to selectively release the fluorescent molecule upon targeted enzymatic hydrolysis promoted by a lysine/arginine specific protease.

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.

Passerini Reactions on Biocatalytically Derived Chiral Azetidines.

The purpose of this study was to explore a series of Passerini reactions on a biocatalytically derived enantiopure azetidine-2-carboxyaldehyde in order to obtain, in a diastereoselective manner, polyfunctionalised derivatives having the potential to be cyclized to chiral bridged bicyclic nitrogen heterocycles. While diastereoselectivity was poor under classical Passerini conditions, a significant increase of diastereoselectivity (up to 76:24) was gained by the use of zinc bromide as promoter. The methodology has a broad scope and yields are always good.

Switching the Photochromic Activity of Acenaphthylene Derivatives through a Tandem Nucleophile-Promoted Addition Reaction.

New acenaphthylene-based dithienylethenes have been prepared. Surprisingly they did not show photochromism. However, they readily underwent a tandem addition of a nucleophile and an electrophile, leading to a small library of dearomatized colourless analogues, which, on the contrary, were endowed with photochromic activity. In the absence of the electrophile, the intermediate obtained by C-attack readily aromatizes to give, surprisingly, a final product of direct aromatic nucleophilic substitution, which was not photochromically active.

Diastereoselective Passerini Reaction of Biobased Chiral Aldehydes: Divergent Synthesis of Various Polyfunctionalized Heterocycles.

Lewis acid catalyzed Passerini reactions on chiral aldehydes derived from desymmetrized erythritol take place with unprecedented diastereoselectivity. The resulting adducts have been selectively and efficiently converted into a variety of densely functionalized, polyoxygenated heterocycles.

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction.

Enantiomerically pure ß-aminoalcohols, produced through an organocatalytic Mannich reaction, were subjected to an Ugi multicomponent reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good. This approach represents a step-economical path to enantiomerically pure, polyfunctionalized peptidomimetics endowed with three stereogenic centers, allowing the introduction of five diversity inputs.

An Intraoperative Site-specific Bone Density Device: A Pilot Test Case.

AIM: This paper reports a case of all-on-four rehabilitation where bone density at implant sites was assessed both through preoperative computed tomographic (CT) scans and using a micromotor working as an intraoperative bone density measurement device. BACKGROUND: Implant-supported rehabilitation is a predictable treatment option for tooth replacement whose success depends on the clinician's experience, the implant characteristics and location and patient-related factors. Among the latter, bone density is a determinant for the achievement of primary implant stability and, eventually, for implant success. The ability to measure bone density at the placement site before implant insertion could be important in the clinical setting. CASE DESCRIPTION: A patient complaining of masticatory impairment was presented with a plan calling for extraction of all her compromised teeth, followed by implant rehabilitation. A week before surgery, she underwent CT examination, and the bone density on the CT scans was measured. When the implant osteotomies were created, the bone density was again measured with a micromotor endowed with an instantaneous torque-measuring system. The implant placement protocols were adapted for each implant, according to the intraoperative measurements, and the patient was rehabilitated following an all-on-four immediate loading protocol. CONCLUSION: The bone density device provided valuable information beyond that obtained from CT scans, allowing for site-specific, intraoperative assessment of bone density immediately before implant placement and an estimation of primary stability just after implant insertion. CLINICAL SIGNIFICANCE: Measuring jaw-bone density could help clinicians to select implant-placement protocols and loading strategies based on site-specific bone features.

Ugi and Passerini reactions of biocatalytically derived chiral aldehydes: application to the synthesis of bicyclic pyrrolidines and of antiviral agent telaprevir.

Lipase mediated desymmetrization of a meso-diol (1,2-cyclopentanedimethanol) allows the synthesis of both enantiomers of some chiral aldehydes, whose behavior in Passerini and Ugi reactions has been explored. Exploiting these two complementary multicomponent reactions and coupling them with a subsequent cyclization process, we observed that 6 out of all 8 possible stereoisomers of peptidomimetic pyrrolidines can be obtained in good yields. The potential of these protocols has been proved by the development of a new efficient synthesis of antiviral drug telaprevir.

Synthesis of triazolo-fused benzoxazepines and benzoxazepinones via Passerini reactions followed by 1,3-dipolar cycloadditions.

Azidobenzaldehydes can be used in Passerini three-component condensations to synthesize small collections of triazolo-fused heterocycles in an efficient and combinatorial fashion upon post-condensation azide-alkyne cycloadditions. Triazolo-fused benzoxazepinones were obtained in moderate to good overall yields with a concise two-step protocol. Triazolo-fused benzoxazepines were instead prepared by means of a longer, yet straightforward route comprising a Passerini reaction, hydrolysis of the ester moiety, O-alkylation with propargylic bromides, and 1,3-dipolar cycloaddition.

OPHA (oxidation-Passerini-hydrolysis-alkylation) strategy: a four-step, one-pot improvement of the alkylative Passerini reaction.

Multicomponent reactions are often recognized for their efficiency and convergency, if compared with multistep organic synthesis. Nevertheless, we here demonstrate that a four-step-one-pot approach (named OPHA strategy for the initials of the four steps involved) is not only able to afford compounds that could not be obtained by an alkylative Passerini reaction but also capable of generating them with minimal loss of atoms and high operational simplicity, as in a typical multicomponent approach.