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.

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 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.

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.

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.

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.

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.

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.

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.

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.

Three in the spotlight: Photoinduced stereoselective synthesis of (Z)-acyloxyacrylamides through a multicomponent approach.

We report a straightforward approach to synthesize 2-acyloxyacrylamides, which are useful synthons in organic synthesis. This involves a photoactivated multicomponent reaction, performed both in batch and under continuous flow conditions. This process affords the desired compounds in a stereoselective fashion from readily available starting materials in one step, without the aid of metal catalysis. This paper illustrates the preliminary work, the extensive experiments carried out to understand the limitations of the approach, and the optimization of the conditions for the synthesis of these particular captodative olefins.

Enantio- and diastereoselective synthesis of highly substituted benzazepines by a multicomponent strategy coupled with organocatalytic and enzymatic procedures.

Enantiomerically pure 4,5-dihydro-1H-benzo[c]azepines with three contiguous stereogenic centers have been assembled by convergent strategy with a good control of diastereoselectivity. The two steps are as follows: an asymmetric organocatalytic Mannich reaction performed on Boc-imines of o-(azidomethyl)benzaldehydes, followed by a one-pot Staudinger/aza-Wittig/Ugi-Joullié sequence. The latter reaction represents one of the first examples of diastereoselective Ugi three-component reaction on a seven-membered cyclic imine. The o-azidomethylbenzaldehydes have been synthesized employing a simple and efficient chemoenzymatic strategy from commercially available building blocks.

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.

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization.

An operationally simple protocol for the synthesis of 2,3-dihydrobenzo[f][1,4]oxazepin-3-ones, based on an Ugi reaction of an ortho-(benzyloxy)benzylamine, glycolic acid, an isocyanide and an aldehyde, followed by an intramolecular Mitsunobu substitution was developed. The required ortho-(benzyloxy)benzylamines have been in situ generated from the corresponding azides, in turn prepared in high yields from salicylic derivatives.

The homo-PADAM protocol: stereoselective and operationally simple synthesis of α-oxo- or α-hydroxy-γ-acylaminoamides and chromanes.

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α-oxo-γ-acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection-acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo-Passerini-amine deprotection-acyl migration (PADAM) strategy. Highly stereoselective reduction of the α-oxo-γ-acylaminoamides afforded α-hydroxy-γ-acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.

Diversity oriented and chemoenzymatic synthesis of densely functionalized pyrrolidines through a highly diastereoselective Ugi multicomponent reaction.

A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process.

Development of a stereoselective Ugi reaction starting from an oxanorbornene ß-amino acid derivative.

We have synthesised a novel oxanorbornene ß-aminoacid derivative and employed it in a stereoselective Ugi reaction. Hypothesis regarding the mechanism taking place during the reaction have been made and validated through the determination of the relative and absolute configuration of the Ugi adducts. Use of the correct choice of solvents can increase stereoselection. The resulting bicyclic peptidomimetics can be used as a novel class of pluripotent substrates to be elaborated according to the synthetic strategies previously elaborated in our laboratories.

A new diversity oriented and metal-free approach to highly functionalized 3H-pyrimidin-4-ones.

A new synthesis of 3H-pyrimidin-4-ones, characterized by four different sets of decorations, is presented. The strategy is based on the synthetic elaboration of readily available α-substituted ß-ketoesters that, upon transformation into the corresponding acyl enamines, have been cyclized to give 6H-1,3-oxazin-6-ones. These reactive intermediates have been in turn cleanly converted into highly functionalized pyirimidinones, by treatment with an appropriate primary amine. The whole sequence does not need the use of any metal mediator or catalyst.