Passerini Three-component Reaction Research Articles

Solution-state self-assembly of novel poly(carbamoyl methacrylate)s synthesized via combining Passerini three-component reactions and free radical polymerizations

Coupling multicomponent reactions (MCRs) with other polymerizations has excellent advantages in inducing multifunctionality and syntheses of complex macromolecular structures. Herein, a straightforward combination method using aqueous Passerini three-component reaction (P3CR(aq)) and conventional free radical polymerization (FRP) (termed as P3CR(aq)-Є-FRP) was applied using mild conditions. Firstly, an environmental-friendly and efficient aqueous P3CR was applied to synthesize various carbamoyl methacrylate (CMA) monomers from methacrylic acid, cyclohexyl isocyanide, and four different aldehydes with high yield (ca. 90 %) and purity. This is plausibly prompted by the key factors of high cohesive energy density of water and facile isolation by the poor solubility of CMAs in aqueous. Then, poly(carbamoyl methacrylate)s (PCMAs) were obtained via FRP with 2,2′-azobis(isobutyronitrile) (AIBN) in dimethylformamide (DMF). Characterizations of both synthesized noble monomers, polymers, solubilities in different solvents, and thermal properties, as well as the solution-state self-assembly behaviors of the polymers by dynamic light scattering (DLS), scanning electron microscope (SEM), and small-angle X-ray scattering (SAXS), including micellized particle sizes, critical micelle concentrations (CMCs), and micelle morphology, were investigated. PCMAs can self-assemble into stable globular micellar nanoparticles (ca. 170–310 nm) with low CMC values (1.6 × 10−5–4.0 × 10−9 mg/mL).

Mystery of the Passerini Reaction for the Synthesis of the Antimicrobial Peptidomimetics against Nosocomial Pathogenic Bacteria.

The first example of applying salicylaldehyde derivatives, as well as coumarin with the formyl group at the C8 position in its structure, as carbonyl partners in a three-component Passerini reaction, is presented. As a result of research on the conditions of the Passerini reaction, the important role of the hydroxyl group in the salicylaldehyde used in the course of the multicomponent reaction was revealed. When an aldehyde with an unprotected hydroxyl group is used, only two-component α-hydroxy amide products are obtained. In contrast, the use of acylated aldehyde results in three-component α-acyloxy amide products with high efficiency. The developed protocol gives access to structurally diversified peptidomimetics with good yield. The compounds were also evaluated as antimicrobial agents against selected strains of nosocomial pathogenic bacteria. The structure-activity relationship revealed that inhibitory activity is strongly related to the presence of the trifluoromethyl group (CF3) or the methyl group at the C4 position in an unsaturated lactone ring of the coumarin scaffold. MIC and MBC studies were carried out on eight selected pathogenic bacteria strains (Gram-positive pathogenic Staphylococcus aureus strain (ATCC 23235), as well as on Gram-negative E. coli (K12 (ATCC 25404), R2 (ATCC 39544), R3 (ATCC 11775), and R4 (ATCC 39543)), Acinetobacter baumannii (ATCC 17978), Pseudomonas aeruginosa (ATCC 15442), and Enterobacter cloacae (ATCC 49141) have shown that the tested compounds show a strong bactericidal effect at low concentrations. Among all agents investigated, five exhibit higher antimicrobial activity than those observed for commonly used antibiotics. It should be noted that all the compounds tested showed very high activity against S. aureus, which is the main source of nosocomial infections that cause numerous fatalities. Additionally, the cytotoxicity of sixteen derivatives was measured with the use of the MTT test on BALB/c3T3 mouse fibroblast cell lines. The cytotoxicity studies revealed that the tested substances exert a similar or lower effect on cell proliferation than that observed for commonly used antibiotics within the range of therapeutic doses. A parallel MTT assay using ciprofloxacin, bleomycin, and cloxacillin showed that these antibiotics are more cytotoxic when tested in mammalian cells, and cell viability is in the range of 85.0-89.9%. Furthermore, we have shown that the studied coumarin-based peptidomimetics, depending on their structural characteristics, are nonselective and act efficiently against various Gram-positive and Gram-negative pathogens, which is of great importance for hospitalised patients.

Insight into the hydrophobic functionalization of cellulose microfibrils using the Passerini three-component reaction

The aqueous catalyst-free one-pot Passerini 3-component reaction (P-3CR) was employed for the functionalization of dialdehyde cellulose (DAC) derived from the periodate oxidation of microfibrillated cellulose (MFC) with insights provided by 13C and 15N CP-MAS NMR and FTIR analyses. The kinetics of the P-3CR revealed rapid progress within the initial 2 h, reaching a plateau between 6 and 18 h. The reaction achieved a maximum degree of substitution (DS) with only 1 equivalent of carboxylic acid and isocyanide with respect to the number of aldehydes, therefore demonstrating the atom economy character of the P-3CR performed on MFC. Variable DS values (0.08 to 0.37) were achieved by altering the degree of oxidation of DAC (ranging from 0.48 to 1.1) when reacted with heptanoic acid and tert-butyl isocyanide. Additionally, aliphatic chain lengths of carboxylic acids from C4 to C11 were successfully used for the functionalization of DAC with distinct hydrophobic chains. Furthermore, while cosolvents negatively affected the DS when using heptanoic acid, a significant increase was observed in the case of undecanoic acid due to an improved solubility of the reagent. The aqueous medium P-3CR can thus be considered a versatile tool to tailor the functionalization of MFC and provide it with hydrophobicity.

A non-spherical nanoparticles system for the delivery of peptides using polymer grafted nanocellulose

AbstractPeptide drugs are increasingly used to treat a variety of diseases ranging from cancer, and infections to cardiovascular diseases. However, peptides can suffer from low stability in the bloodstream. Entrapment of peptides into nano-sized carriers of various types has widely been explored, but all of them have spherical shapes. Nanocellulose can in contrast serve as a non-spherical nanoparticle with a high aspect ratio. After the isolation of nanocellulose by TEMPO-mediated oxidation, the material needs to be modified with polymers to generate nanoparticles with high water-solubility that can also favourably interact with peptide drugs. We have here chosen insulin as the model drug, which can strongly interact with cationic polymers. As it is known that cationic polymer may retain charged drugs too tightly, we have selected poly(2-(dimethylamino)ethyl acrylate) PDMAEA as a degradable polymer that undergoes self-hydrolysis to poly(acrylic acid) in water. This polymer was compared to poly(N-(3-(dimethylamino)propyl) acrylamide) PDMAPAA, which is a stable cationic polymer. The cationic polymer was co-grafted with poly(2-hydroxyethyl acrylate) PHEA as a water-soluble neutral polymer using the three-component Passerini reaction. A combination of fluorescence and UV-Vis techniques were used to quantify the amount of polymer that was conjugated to the surface. The polymer-coated nanocellulose was labelled with the fluorescent cyanine dye Cy5 while insulin was labelled with Cy3 creating a FRET system that allows monitoring of the interaction between insulin and polymer in cell growth media. We observed that despite the self-hydrolysis of PDMAEA into a negatively charged polymer, the negatively charged insulin was not released in buffer solution according to the FRET studies. Only the addition of serum-supplemented cell growth media led to insulin release. The limited release was explained with the fact that insulin, as well as other peptides, have a mixture of negative and positive charges, with the pH value and the isoelectric point determining the balance between both. Negative-charged polymers can therefore still interact favourably with negatively charged peptides by interacting with cationic amino acids. Graphical Abstract

Innovative synthesis of drug-like molecules using tetrazole as core building blocks.

Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes. It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods.

Mechanism and origin of enantioselectivity for asymmetric Passerini reaction in the synthesis of ɑ-acyloxyamide catalyzed by chiral phosphoric acid

The enantioselective control of the three-component Passerini reaction was successfully achieved using chiral phosphoric acid as a catalyst with a wide range of substrates and high stereoselectivity. Quantum mechanical calculations reveals the detailed reaction mechanism and enantioselective origin of the reaction. The calculations revealed that the chiral phosphoric acid first forms a stable heterodimer with the carboxylic acid substrate, followed by C-C and C-O bond formations, the generation of a five-membered cyclic intermediate, and finally acyl migration to yield the product. Four reaction paths for the overall process were identified and compared to determine the optimal major and by-product paths. The enantioselective origin of the reaction has been elucidated systematically using distortion/interaction theory and truncated model system. QTAIM and IGMH analyses demonstrated the type and strength of interaction between catalyst and the substrates. The calculated e.e. value was 93 %, which was in good agreement with the experimental value. It is expected that the results of this study will offer new insights into the field of asymmetric Passerini reactions.

Passerini three-component reaction for the synthesis of saccharide branched cellulose

In this work, we investigate a multicomponent synthetic method for combining saccharides with cellulose to produce saccharide branched cellulose (b-Cel). First, cellulose is modified conventionally using carboxymethyl to create carboxyl functional groups for multicomponent reactions. The Passerini three-component reaction (Passerini-3CR) is then used to synthesize the saccharide b-Cel, with particular attention paid to the scope of the substrate and reaction process optimization. The structure of saccharide b-Cel is regulated by modifying the carboxyl group of cellulose molecules, the kind of saccharide molecules (including glucose, galactose, lactose, cellobiose, and cellulose), and the degree of branching. The branched structure of saccharide b-Cel greatly influenced its rheological characteristics and solubility. This work presents a practical method for the synthesis of artificial branching polysaccharides and is crucial for the development of innovative materials based on biomass.

A Facile Synthetic Approach to UV-Degradable Hydrogels.

Light-degradable hydrogels have a wide range of application prospects in the field of biomedicine. However, the provision of a facile synthetic approach to light-degradable hydrogels under mild conditions remains a challenge for researchers. To surmount this challenge, a facile synthetic approach to UV-degradable hydrogels is demonstrated in this manuscript. Initially, an UV-degradable crosslinker (UVDC) having o-nitrobenzyl ester groups was synthesized in a single step through the employment of the Passerini three-component reaction (P-3CR). Both 1H NMR and MS spectra indicated the successful synthesis of high-purity UVDC, and it was experimentally demonstrated that the synthesized UVDC was capable of degradation under 368 nm light. Furthermore, this UVDC was mixed with 8-arm PEG-thiol (sPEG20k-(SH)8) to promptly yield an UV-degradable hydrogel through a click reaction. The SEM image of the fabricated hydrogel exhibits the favorable crosslinking network of the hydrogel, proving the successful synthesis of the hydrogel. After continuous 368 nm irradiation, the hydrogel showed an obvious gel-sol transition, which demonstrates that the hydrogel possesses a desirable UV-degradable property. In summary, by utilizing solely a two-step reaction devoid of catalysts and hazardous raw materials, UV-degradable hydrogels can be obtained under ambient conditions, which greatly reduces the difficulty of synthesizing light-degradable hydrogels. This work extends the synthetic toolbox for light-degradable hydrogels, enabling their accelerated development.

Synthesis of photoresponsive biobased adhesive polymers via the Passerini three-component reaction

Synthesis of photoresponsive biobased adhesive polymers via the Passerini three-component reaction

4-(N-Phthalimido)phenyl Isonitrile as a Novel Convertible Isocyanide Analogue with the Odorless Property as an Extra Bonus.

We explored a new isonitrile, namely 4-(N-phthalimido)phenyl isonitrile, with extraordinary features. The novel isocyanide has a pharmacophore, the phthalimido (Pht) group, that possesses promising pharmaceutical activities. We found that the novel isonitrile is unexpectedly odorless as an extra bonus which makes its handling easy in organic synthesis to serve as a scaffold for building several new amide derivatives through multicomponent reactions, overcoming the stink of common aromatic isonitriles such as phenyl isonitrile, benzyl isonitrile, p-nitrophenyl isonitrile, and ethyl 4-isocyano benzoate. The novel isonitrile 9 serves as a source of N-protected isonitrile with a Pht group, where the Pht group can be easily removed via hydrazinolysis, affording the corresponding primary amine/alcohol scaffold which could be used as a precursor to synthesize Passerini products via acylation directly to afford Passerini adducts 14 and 15 without carrying out the traditional Passerini three-component reaction; this new isonitrile is considered as a novel convertible isocyanide analogue.

Functionalization of tetrahydroindol-4-one derivatives

Available and effective methods of tetrahydroindol-4-one derivatives transformation are described, which include functionalization of the nitrogen atom, carbonyl group, side chains in positions 1,2,3,7 of the bicycle, as well as aromatization of the cyclohexene fragment in the presence of dehydrogenating agents. Original preparative approaches to the synthesis of [4,5]-fused indole derivatives (pyrroles, thiophenes, pyrazoles, isoxazoles, thiazoles, 1,2,3-triazoles, pyridazinones), implemented by introducing functional groups in the α-position to the carbonyl group with subsequent cyclocondensations (Hanch, Paal-Knorr, [4+2] and [3+2]-cyclization reactions) are reviewed. Beckman and Schmidt rearrangements in the chemistry of tetrahydroindolones are accompanied by a cycle expansion with the formation of lactams or their transformation products. The Fischer reaction allows to obtain polyheterocycles with a new indole ring at the same time as the Dimrot rearrangement allows to synthesize pyrroloquinolones. Among the ways of modifying side chains of tetrahydroindolone, the three-component Passerini reaction is the most promising one, which provides quick access to indolone-N-amino acid derivatives.

Innovations and Inventions: Why Was the Ugi Reaction Discovered Only 37 Years after the Passerini Reaction?

This year represents the 100th anniversary of the discovery of the Passerini three-component reaction. The related Ugi four-compound reaction was discovered 37 years after the Passerini reaction. Undoubtedly, both reactions are very important multicomponent reactions but the Ugi reactions outperform the Passerini reactions in terms of combinatorial space according to the equation xy [x is the number of building blocks per component, and y is the order of the multicomponent reaction (for Passerini, y = 3; for Ugi, y = 4)]. In this work, a historical but contemporary perspective of the discoveries and innovations of the two reactions is given. From a bird's eye view and in a more general sense, the discovery of novel reactions is discussed and how it relates to inventions and innovations.

Protection-Free Strategy for the Synthesis of Boro-Depsipeptides in Aqueous Media under Microwave-Assisted Conditions.

In this report, 19 boron-containing depsipeptides were synthesized via microwave-assisted Passerini three-component reaction (P-3CR) in an aqueous environment. The linker-free DAHMI fluorescent tagging approach was used on selected boron-containing compounds to study the relationship between their structures and their level of cellular uptake of HEK293 cells. The biological data retrieved from the DAHMI experiments indicated that while the structures of tested compounds may be highly similar, their bio-distribution profile could be vastly distinctive. The reported optimized one-pot synthetic strategy along the linker-free in vitro testing protocol could provide an efficient platform to accelerate the development of boron-containing drugs.

One-pot cascade polycondensation and Passerini three-component reactions for the synthesis of functional polyesters

A one-pot cascade four-component polymerization and post-polymerization modification reaction is introduced to synthetic polymer chemistry.

Green and three-component synthesis of 2-cyclohexylamino-2-oxo-1-arylethyl/alkyl thiophene-3-carboxylates in aqueous medium

From the Passerini three-component reaction between cyclohexyl isocyanide, thiophene-2-carboxylic acid and aryl/alkyl aldehydes, some new compounds of 2-cyclohexylamino-2-oxo-1-arylethyl/alkyl thiophene-3-carboxylates have been synthesized in 30-45 min in yields in the range of 85% to 90%. Reactions were performed in water solvent and room temperature. The structure of the synthesized compounds was characterized using infrared (IR) and nuclear magnetic resonance (NMR). The use of water as a green solvent, the reaction without energy consumption and at room temperature, no use of catalyst, separation without the use of chromatographic techniques, and the high yields of the reaction are the significant advantages of this Passerini reaction. The antibacterial properties of the synthesized compounds were also tested. The results of experiments showed that these compounds exhibit good antibacterial properties.

Streamlined access to end-functionalized thermoresponsive polymers via a combination of bulk RAFT polymerization and quasi solvent-free Passerini three-component reaction

Streamlined access to end-functionalized thermoresponsive polymers via a combination of bulk RAFT polymerization and quasi solvent-free Passerini three-component reaction

Low-Power Near-Infrared-Responsive Upconversion Nanovectors

Activating upconversion nanoparticle-based photoresponsive nanovectors (UCPNVs) by upconversion visible light at low-power near-infrared (NIR) excitation can realize deeper biotissue stimulation with a minimized overheating effect and photodamage. Here, we demonstrate a facile strategy to construct new surface-decorated UCPNVs based on Passerini three-component reaction (P-3CR) in highly convenient and effective manners. Such UCPNVs materials have a tailored deprotecting wavelength that overlaps upconversion blue light. By using 3-perylenecarboxaldehyde, Tm3+/Yb3+ ion-doped UCNP-containing isocyanides, and antitumor agent chlorambucil as the three components, the resulting monodisperse UCPNV exhibits an efficient release of caged chlorambucil under a very low 976 nm power. This approach expands the synthetic toolbox to enable quick development of UCPNVs for UCNP-assisted low-power NIR photochemistry.

Polymeric micelles amplify tumor oxidative stresses through combining PDT and glutathione depletion for synergistic cancer chemotherapy

Cancer has been one of the major healthcare burdens, which demands innovative therapeutic strategies to improve the treatment outcomes. Combination therapy hold great potential to leverage multiple synergistic pathways to improve cancer treatment. Cancer cells often exhibit an increased generation of reactive oxygen species (ROS) and antioxidant species compared with normal cells, and the levels of these species can be further elevated by common therapeutic modalities such as photodynamic therapy (PDT) or chemotherapy. Taking advantage that cancer cells are vulnerable to further oxidative stress, we aim to design a drug delivery system by simultaneously increasing the cellular ROS level, reducing antioxidative capacity, and inducing anticancer chemotherapy in cancer cells. Here, we designed a star-shape polymer, PEG(-b-PCL-Ce6)-b-PBEMA, based on the Passerini three-component reaction, which can both enhance ROS generation during PDT and decrease the GSH level in cancer cells. The polycaprolactone conjugated with photosensitizer Ce6 served as hydrophobic segments to promote micelle formation, and Ce6 was used for PDT. The H2O2-labile group of arylboronic esters pendent on the third segment was designed for H2O2-induced quinone methide (QM) release for GSH depletion. We thoroughly investigated the spectral properties of blank micelle during its assembling process, ROS generation, and H2O2-induced QM release in vitro. Moreover, this polymeric micelle could successfully load hydrophobic anti-cancer drug Doxorubicin (DOX) and efficiently deliver DOX into cancer cells. The triple combination of ROS generation, GSH elimination, and chemotherapy dramatically improved antitumor efficiency relative to each of them alone in vitro and in vivo.

Polymers of lignin-sourced components as a facile chemical integrant for the Passerini three-component reaction

In this work, poly(methacrylated vanillin) (PMV) was investigated for its reactivity in multicomponent reactions as a reactive polymer that can be sourced from lignin-based components. To achieve sustainable polymer chemistry, the PMV reactivity in a Passerini three-component reaction (Passerini-3CR) was investigated because the reactants in the Passerini-3CR can be abundantly sourced from biobased compounds. First, the Passerini-3CR of the PMV in solution phases revealed that the PMV pendant aldehydes can be converted into the corresponding α-acyloxy amides with >90% conversions under the optimized conditions. Taking advantage of this high reactivity of PMV, its immobilized cellulose fabric (Cell-g-PMV), a wood biomass-sourced organic hybrid, was subjected to the Passerini-3CR. Although the aldehydes were not completely converted, the PMV segments surrounding the fabric surfaces successfully reacted via the Passerini-3CR to engraft carboxylic acid and isocyanide components on the cellulose-based fabrics. Poly(methacrylated vanillin) (PMV) was investigated for its reactivity in multicomponent reactions as a reactive polymer that can be sourced from lignin-based components. The Passerini three-component reaction (Passerini-3CR) of the PMV in solution phases revealed that the PMV pendant aldehydes can be converted into the corresponding α-acyloxy amides with >90% conversions under the optimized conditions. Taking advantage of this high reactivity of PMV in solution phase, its immobilized cellulose fabric (Cell-g-PMV), a wood biomass-sourced organic hybrid, was subjected to the Passerini-3CR, enabling an engraftment of carboxylic acid and isocyanide components on the cellulose-based fabrics.

Reading mixtures of uniform sequence-defined macromolecules to increase data storage capacity

In recent years, the field of molecular data storage has emerged from a niche to a vibrant research topic. Herein, we describe a simultaneous and automated read-out of data stored in mixtures of sequence-defined oligomers. Therefore, twelve different sequence-defined tetramers and three hexamers with different mass markers and side chains are successfully synthesised via iterative Passerini three-component reactions and subsequent deprotection steps. By programming a straightforward python script for ESI-MS/MS analysis, it is possible to automatically sequence and thus read-out the information stored in these oligomers within one second. Most importantly, we demonstrate that the use of mass-markers as starting compounds eases MS/MS data interpretation and furthermore allows the unambiguous reading of sequences of mixtures of sequence-defined oligomers. Thus, high data storage capacity considering the field of synthetic macromolecules (up to 64.5 bit in our examples) can be obtained without the need of synthesizing long sequences, but by mixing and simultaneously analysing shorter sequence-defined oligomers.