Ugi Four-component Condensation Research Articles

An integrated self-optimizing programmable chemical synthesis and reaction engine

Robotic platforms for chemistry are developing rapidly but most systems are not currently able to adapt to changing circumstances in real-time. We present a dynamically programmable system capable of making, optimizing, and discovering new molecules which utilizes seven sensors that continuously monitor the reaction. By developing a dynamic programming language, we demonstrate the 10-fold scale-up of a highly exothermic oxidation reaction, end point detection, as well as detecting critical hardware failures. We also show how the use of in-line spectroscopy such as HPLC, Raman, and NMR can be used for closed-loop optimization of reactions, exemplified using Van Leusen oxazole synthesis, a four-component Ugi condensation and manganese-catalysed epoxidation reactions, as well as two previously unreported reactions, discovered from a selected chemical space, providing up to 50% yield improvement over 25–50 iterations. Finally, we demonstrate an experimental pipeline to explore a trifluoromethylations reaction space, that discovers new molecules.

Application of the Ugi reaction for preparation of submicron capsules based on sugar beet pectin.

The Ugi four-component condensation in diluted liposomal suspensions was used to prepare pectin-based submicron capsules. A set of isocyanides and aldehydes was used to optimize the synthesis of capsule shells. Modified sugar beet pectin was selected as a natural polymer with pronounced surface activity to create a capsule shell. At first, liposomal composition was optimized in order to select suitable conditions for capsule formation. Then, the wide set of capsules constructed on modified sugar beet pectin scaffold has been synthesized. The choice was determined by level of substitution degree and possible chemical diversity of the modified surface. Detailed characterization of products has been performed for polysaccharide particles with liposomal core prepared with various processing parameters (concentration, cross-linking components, the density of linkage). The chemical structure, average size, polydispersity index, morphology, stability, and cytotoxicity of obtained particles have been investigated in dependence on the shell content. The obtained submicrometer cross-linked capsules (220-240nm) with controlled colloidal properties showed high stability and low toxicity. Thus, the proposed carriers have a great potential as sustained drug delivery systems for different administration routes.

Self-assembled oleylamine grafted alginate aggregates for hydrophobic drugs loading and controlled release

Amphiphilic alginate derivatives obtained by hydrophobic functionalization of alginates are commonly used as the nano-bio materials for hydrophobic drugs delivery and controlled release. In this research, we proposed an optimization protocol to introduce oleylamine into the alginate backbone for the preparation of amphiphilic alginate derivative via Ugi four-component condensation reaction (Ugi-4CR), using odorless, environmental friendly, and inexpensive tosylmethyl isocyanide (TOSMIC) to replace the commonly used cyclohexyl isonitrile. The structure of the oleylamine grafted alginate (Ugi-FOlT) conjugate was confirmed by Fourier-transformed infrared spectrometry (FT-IR), 1H nuclear magnetic resonance (1H NMR), X-ray diffraction (XRD), and thermal gravimetric analysis (TGA). The degree of substitution (DS) of Ugi-FOlT determined by elemental analysis (EA) was about 40.89%, and its yield was approximately 76.4%. The self-assembled performance of Ugi-FOlT was investigated using fluorescence spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM). The critical aggregation concentrations (CAC) of Ugi-FOlT was 0.043 mg/mL in 0.15 mol/L NaCl aqueous solution. Ibuprofen, a hydrophobic nonsteroidal anti-inflammatory drug (NSAIDs), was encapsulated into the self-assembled Ugi-FOlT nanoparticles by dialysis method. The drug loading content (DLC) and encapsulation efficiency (EE) determined by the UV-Vis spectrophotometer were 16.7% and 83.5%, respectively. In vitro, drug release studies revealed that almost 65.6% of ibuprofen were released from the Ugi-FOlT nanoparticles in PBS (pH = 7.4) at 37 °C. Moreover, the drug release rate was obviously dependent on the pH values of the release medium. In vitro cytotoxicity tests revealed that the blank Ugi-FOlT nanoparticles showed negligible toxicity against the murine macrophage RAW264.7 cell. Thus, the novel synthesized amphiphilic Ugi-FOlT could be used to prepare self-assembled nanoparticles for hydrophobic functional ingredients or drug delivery and sustained release.

Versatile and Tunable Poly(Ethylene Glycol)‐Based Hydrogels Crosslinked through the Ugi Reaction

The four-component Ugi condensation reaction has been investigated to assemble chemically crosslinked hydrogels using multivalent star-shaped poly(ethylene glycol) components. The resulting biocompatible hydrogels are highly versatile in composition and function. It is shown that acid, aldehyde, and cyanide components can be varied yielding materials with precise structure and tunable stiffness. Additionally, the resulting hydrogels were proven extremely robust to consecutive drying-swelling cycles. This property was explored to develop a reversible humidity colorimetric sensor gel. Overall, this work demonstrates the application of the four-component Ugi reaction as a powerful tool to quickly generate crosslinked gels with precise control in chemical composition.

One Step Synthesis of Fmoc-Aminoacyl-N-alkylcysteine via the Ugi Four-Component Condensation Reaction.

A prompt preparation method of the Fmoc-aminoacyl-N-alkylcysteine dipeptide by an Ugi four-component condensation reaction is described. Through a reaction with a commercially available Fmoc-amino acid, an amine, an isocyanide, and a mercaptoacetaldehyde derivative, one step synthesis of dipeptides containing 20 kinds of natural amino acid residues was achieved, which avoided the problematic N-alkylation of S-tritylcysteine and its coupling reaction. The dipeptide was applied to the Fmoc-solid-phase peptide synthesis, and peptide thioesters were successfully obtained in high efficiency via N-alkylcysteine (NAC)-assisted thioesterification.

In Silico and in Vitro Studies of Fluorinated Chroman-2-Carboxilic Acid Derivatives as an Anti-tubercular Agent.

Despite the use of traditional method, Ugi reaction currently is a well-established multicomponent reaction. Chromane motif itself possesses a variety of biological functions. In order to improve its anti-tubercular activity, it is necessary to modify it accordingly. To ensure relation between in silico and in vitro study, we have carried out in vitro screening against H37Rv anti-tubercular agent. Ugi four-component condensation (U-4CCRs) between 6-fluorochroman-2-carboxylic acid, various aryl aldehyde, 3,4,5-trimethoxy amine and tert-butyl isocyanide, gave N-((tert-butylcarbamoyl)(4-substitutedphenyl) methyl)-6-fluoro-N-(3,4,5-trimethoxyphenyl) chroman-2-carboxamide. The molecular level insight of all compounds was carried out by molecular docking study against the receptor tyrosine phosphatase PtpB. All these newly synthesized compounds were screened for their anti-microbial activity against Mycobacterium tuberculosis H37Rv to determine the MIC, IC50 and IC90 of the compound. The compound 5d also shows large hydrophobic surface contact on the face of the α7-α8 (Ile 207, Phe 211, Met 206, Ile203, Phe161, Phe80, Met126, Tyr130, Val231 and Leu101) that lines one side of the entrance to the active site of the receptor. The compound 5d bind with tyrosine phosphatase PtpB with predicted docking geometric score of 4664, whereas a score of rifampicin was 6586 determined. From the docking studies, compound 5d, was considered to be the potent inhibitor, which gave strong supportive coordinate with the in vitro study. It is highly active against H37Rv, having MIC and IC50 value of was 70 μM and 53 μM respectively in in vitro study.

A Novel Strategy of Ugi-4CR/Huisgen 1,3-Dipolar Synthesis of 1H-1,2,3-Triazole-Modified Peptidoimetics

In this protocol, we report a novel approach for the synthesis of a new class of heterocyclic 1H-1,2,3-triazole-modified peptidomimetic compounds. The process consists of an Ugi four-component condensation reaction of amines, an isocyanide, an aldehyde and acids followed by a Huisgen 1,3-dipolar cycloaddition reaction with an azide group in the presence of a catalytic amount of CuSO4.5H2O/sodium ascorbate. The copper-catalyzed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3-triazoles being good peptide bond mimics. This protocol was highly efficient for structurally diverse heterocyclic molecules containing an active aldehyde group and will find applications in combinatorial chemistry, diversity-oriented synthesis, and drug discovery.

Fluorinated polymer surfactants bearing an alternating peptide skeleton prepared by three-component polycondensation.

A new species of fluorinated polymer surfactant was developed by three component polycondensation analogous to Ugi four-component condensation. The surfactant exhibited unique surface properties, which made cellulose-based materials hydrophobic and decreased the surface tension of CHCl3. It turned out that the polymer forms micelles in CHCl3.

Synthesis, molecular docking, antimicrobial, antioxidant and toxicity assessment of quinoline peptides

A series of quinoline based peptides were synthesized by a one-pot reaction through Ugi-four component condensation of lipoic acid, cyclohexyl isocyanide, aniline derivatives and 2-methoxy quinoline-3-carbaldehyde derivatives under microwave irradiation. The products were obtained in excellent yields and high purity. Solvent optimization and the effect of microwave irradiation with various powers were also observed. All the synthesized compounds were characterized by FTIR, NMR spectral data and elemental analysis. A total of eight peptides were subjected to antimicrobial, antioxidant and toxicity evaluation. Among them, four peptides showed potential towards antibacterial screening with Bacillus cereus, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis and Candida albicans, Candida utilis and three peptides showed antioxidant test positive (DPPH). Besides, toxicity of all the peptides were evaluated by using brine shrimp and it was observed that four peptides showed mortality rate less than 50% up to 48h. Molecular docking studies revealed that the higher binding affinity of the two peptides toward DNA gyrase than ciprofloxacin based on Libdock score. The described chemistry represents a facile tool to synthesize complex heterocycles of pharmaceutical relevance in a highly efficient and one-pot fashion. The advantages of this method are its green approach, inexpensive solvent, shorter reaction times and excellent yields.

Paclitaxel-loaded PLA/PEG/fluorescein anticancer agent prepared by Ugi reaction

ABSTRACTTwo different fluorescent block copolymers of poly(lactic acid) (PLA) and polyethylene glycol (PEG) containing fluorescein grafted to the polymer chain were synthesized by Ugi four-component condensation (UFCC). The structure of these PEG–PLA copolymers was confirmed by 1H-NMR and fluorescence spectroscopy. Paclitaxel-loaded fluorescent microspheres (PCT-FMS1 and PCT-FMS2) were prepared from them by the single-emulsion solvent evaporation method. A kinetic study of drug release in vitro using high-performance liquid chromatography showed a prolonged and controlled release of paclitaxel. Anticancer activity of release medium against colorectal cancer cell line (Caco-2) was determined using the cell viability assay. Paclitaxel-loaded microspheres were able to inhibit cancer cell growth and colony formation. The main contribution of this work is to propose a new application for UFCC in the preparation of biomasked fluorescent drug delivery systems able to improve cancer treatment.

Ultrasonicated synthesis of novel quinoline-lipoyl peptides through Ugi-four component condensation by using Ca/BN catalyst

ABSTRACTAn efficient one pot Ugi four-component condensation reaction was implemented for the development of new quinoline-peptides. Lipoic acid, 2-methoxy-3-formyl quinoline carboxaldehyde derivatives, aniline derivatives and cyclohexyl isocyanide were employed to synthesize quinoline-lipoyl peptides. This one-pot condensation reaction was successfully carried out by using a new green heterogeneous catalyst: calcium loaded boron nitride (Ca/BN), under ultrasonication at room temperature. The Ca/BN can be easily synthesized by stirring at room temperature. It can also be separated by simple filtration and recycled more than five times. The catalyst was characterized by XRD, SEM with EDX, Raman spectroscopy, BET, DSC-TGA and FTIR. A novel series of N-(2-(cyclohexylamino)-1-(2-methoxyquinolin-3-yl)-2-oxoethyl)-5-((R)-1,2-dithiolan-3-yl)-N-phenylpentanamide (Ugi-adduct) were easily synthesized. All the compounds were characterized by FTIR, 1H-NMR, 13C-NMR and elemental analysis. A total of 14 peptides with good yield is reported herein.

An Efficient One-Pot Synthesis of Densely Functionalized Fused-Quinolines via Sequential Ugi4CC and Acid-Mediated Povarov-Type Reaction.

A divergent synthesis of fused-quinolines has been explored by performing Ugi four-component condensation and sulfuric acid promoted deprotection/Povarov-type reaction in one-pot. The process involves Ugi condensation of propiolic acids, aldehydes/ketones, aminoaldehyde acetals and isocyanides followed by sulfuric acid promoted deprotection and Povarov-type reaction with anilines in ethanol. This method enables straightforward access to the structurally diverse 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-ones (DHPQ), 3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-ones (DHBN), and 2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinolin-1-ones (THAQ), starting from readily available starting materials.

One-pot synthesis of cross-linked sub-micron microgels from pure cellulose via the Ugi reaction and their application as emulsifiers

A novel method for obtaining cross-linked microgels of cellulose has been introduced. This method is based on the Ugi four-component condensation in colloidal suspensions of carboxymethylcellulose with a low degree of substitution. Several types of cellulose, including Avicel, cotton linters and filter paper were used as the starting material for the cellulose microgels. Using various processing parameters (polysaccharide concentration, type of crosslink, optimal pH range and temperature) sub-micrometre particles with controlled colloidal properties were obtained. Cellulose microgels have proved to be an effective Pickering emulsifier at low concentrations, forming stable oil-in-water emulsions. This approach provides access to novel stabilizers of emulsions on the basis of one-pot modification of native cellulose.

Accessible Method for the Development of Novel Sterol Analogues with Dipeptide-like Side Chains That Act as Neuroinflammation Inhibitors.

A number of novel sterol derivatives with dipeptide-like side chains were synthesized using an Ugi four-component condensation method and assayed to test their anti-inflammatory effects in activated microglial cells. Compound 18b ((3S,10R,13S)-N-((R)-1-(tert-butylamino)-1-oxo-3-phenylpropan-2-yl)-3-hydroxy-N,10,13-trimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide) was identified as the most potent anti-inflammatory agent in the series of compounds analyzed. Compound 18b markedly inhibited the expression of proinflammatory factors, including inducible nitric oxide synthase, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and cyclooxygenase-2 in lipopolysaccharide-stimulated microglial cells. Further studies showed that compound 18b significantly suppressed the transcriptional activity of AP-1 and NF-κB in activated microglial cells, which was likely mediated by the inhibition of the p38 MAPK and JNK signal transduction pathways. In addition, compound 18b displayed neuroprotective effects in a microglial-conditioned medium/neuron coculture and an experimental focal ischemic mouse model.

Multicomponent access to indolo[3,3a-c]isoquinolin-3,6-diones: formal synthesis of (±)-plicamine.

The complete tetracyclic core structure of plicamine, a novel Amaryllidaceae-type alkaloid, was expeditously prepared by a Ugi four-component condensation reaction, followed by a one-pot sequential phenolic oxidation and intramolecular coupling process. The employment of this strategy resulted in a rapid, formal synthesis of (±)-plicamine.

Fluorescent microspheres of poly(ethylene glycol)–poly(lactic acid)–fluorescein copolymers synthesized by Ugi four‐component condensation

ABSTRACTMicroparticles formed by poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) diblock copolymers containing fluorescein grafted to the polymer chain were synthesized by a Ugi four‐component condensation (UFCC) reaction. To synthesize these copolymers, lactide was first polymerized by a ring‐opening polymerization with alcohol initiators containing functional groups to give carboxyl‐ and aldehyde‐end‐functionalized PLA. Two different fluorescent block copolymers (FCPs) of PEG–PLA conjugated to fluorescein (FCP 1 and FCP 2) were then synthesized by UFCC; they gave yields in the range 65–75%. These copolymers were characterized well according their chemical structures and thermal properties, and we prepared fluorescent microspheres (FMSs) from them with the single emulsion–solvent evaporation method (FMS 1 and FMS 2). A new application of UFCC in the preparation of biomasked drug‐delivery systems is proposed. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 42994.

Efficient Construction of Azaspiro[4.5]trienone Libraries via Tandem Ugi 4CC/Electrophilic ipso-Iodocyclization in One-Pot.

A solution-phase parallel synthesis of pharmaceutically important azaspiro[4.5]trienones has been developed by performing tandem Ugi four-component condensation (U4CC), involving substituted p-anisidines, aldehydes, 3-alkyl/aryl-propiolic acids, and isocyanides, and iodine-mediated ipso-iodocyclization in one-pot. This highly atom economical process produced functionalized azaspiro[4.5]trienones in good to excellent overall yields and products were easily isolated by precipitation followed by crystallization. These vinyl-iodide bearing azaspiro[4.5]trienones were utilized for further modifications through Suzuki coupling and deiodination reaction to demonstrate the suitability of these products for various palladium catalyzed modifications. The present method provides an easy access to highly functionalized azaspiro[4.5]trienones that can be useful in drug discovery research.

ChemInform Abstract: Highly Stereoselective One‐Pot Construction of Trisubstituted Tetrahydro‐β‐carboline‐Fused Diketopiperazines: A Synthetic Route Towards Cialis Analogues.

AbstractThe one‐pot multi‐step reaction proceeds with excellent diastereoselectivity and applies the Ugi four‐component condensation, Boc‐deprotection, Pictet—Spengler reaction, and final lactamization.

ChemInform Abstract: One‐Pot Synthesis of New 1,5‐Disubstituted Tetrazoles Bearing 2,2‐Bis(trimethylsilyl)ethenyl Groups via the Ugi Four‐Component Condensation Reaction Catalyzed by MgBr2·2Et2O.

A simple one-pot Ugi four-component condensation reaction has been developed for the synthesis of tetrazoles bearing 2,2-bis(trimethylsilyl)ethenyl groups from the synthesized 4-[2,2-bis(trimethylsilyl) ethenyl]benzaldehyde (1), various amines, isocyanides, and trimethylsilylazide at room temperature, without solvent, and in the presence of catalytic amounts of MgBr2·2Et2O as catalyst.

Participation of ethyl 3-formylindole-2-carboxylate with the Ugi four-component condensation reaction

Multicomponent condensation of ethyl 3-formylindole 2-carboxylate, amines, isocyanide and (S)-N-boc-alanine or (S)-N-boc-serine is described. This Ugi four-component condensation (Ugi-4CC) reaction yielded a series of novel dipeptides containing an indolyl moiety. These compounds exhibit potential biological activity.