Ugi Four-component Reaction Research Articles

Access to Polycyclic Azepino[5,4,3-cd]indoles via a Gold-Catalyzed Post-Ugi Dearomatization Cascade.

The development of a rapid and diverse access to complex natural product-like 3,4-fused indole scaffolds has always attracted considerable attention from synthetic and medicinal communities. We herein disclose a modular and straightforward protocol to prepare the densely substituted polycyclic azepino[5,4,3-cd]indole scaffolds. This synthetic process involves an Ugi four-component reaction from easily available starting materials and a gold-catalyzed post-Ugi domino dearomatization/Michael addition sequence, enabling facile access to the highly functionalized azepino[5,4,3-cd]indole core with excellent chemo-, regio-, and diastereoselectivity.

Synthesis of the new tri-amide derivatives as novel α-glucosidase inhibitors by Ugi four-component reaction

In this study, new tri-amides 5a-l have been synthesized via a one-pot four-component Ugi reaction between repaglinide, aniline derivatives, aldehyde derivatives, and cyclohexyl isocyanide in good yields. These compounds were evaluated against yeast α-glucosidase. Obtained in vitro α-glucosidase results demonstrated that all the synthesized compounds 5a-l were more potent than standard inhibitor acarbose. Among them, the most potent compounds were compounds 5j, 5k, and 5h. The kinetic analysis of the most potent compound 5j revealed that this compound is a competitive inhibitor for α-glucosidase (Ki = 24 µM). Furthermore, docking study of the most potent compounds was also performed in the α-glucosidase active site to find interaction modes and binding energies of these compounds.

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics.

Hemiasterlin is an antimitotic marine natural product with reported sub‐nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four‐component Ugi reaction (Ugi‐4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI‐286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub‐nanomolar cytotoxicity against HER2‐expressing cancer cells, while showing no activity against antigen‐negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics.

New multimodal stationary phases prepared by Ugi multicomponent approach.

Eight different stationary phases based on two aminopropyl silicas of different brands suitable for multimodal chromatography applications have been prepared by a four-component Ugi reaction. The intention was to synthesize stationary phases significantly differing in their properties hereby demonstrating flexibility of the Ugi synthetic protocol. Diverse functional groups including a nonpolar long aliphatic chain, phenyl moiety, cholic acid scaffold, phenylboronic and monosaccharide units, charged betaine, and arginine moieties were immobilized on a silica surface. The novel sorbents were extensively characterized by elemental analysis, Raman spectroscopy, and chromatography. Considering the anchored chemical structures covalently bonded to the silica surface, reversed-phase, hydrophilic, and ion-exchange separation modes were expected. The chromatographic evaluation was performed directed to map the potential of the individual columns specifically in the mentioned chromatographic modes. The Ugi synthetic protocol has proven to be a simple, feasible, and versatile tool for the synthesis of sorbents of variable properties. The newly prepared stationary phases differed considerably in hydrophobicity and ion-exchange ability. A significant influence of the supporting aminopropyl silica on the final chromatographic behavior was observed. Finally, one practical example confirming applicability of the newly prepared sorbents was demonstrated in separation of cytarabine.

Protein-Templated Hit Identification through an Ugi Four-Component Reaction*.

Kinetic target‐guided synthesis represents an efficient hit‐identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β‐sliding clamp DnaN, respectively. Highly sensitive mass‐spectrometry methods enabled monitoring of the protein‐templated reaction of four complementary reaction partners, which occurred in a background‐free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN. The Ugi products we identified show low micromolar activity on endothiapepsin or moderate affinity for the β‐sliding clamp. We succeeded in expanding the portfolio of chemical reactions and biological targets and demonstrated the efficiency and sensitivity of this approach, which can find application on any drug target.

Synthesis of Fused Six-Membered Lactams to Isoxazole and Isoxazoline by Sequential Ugi Four-Component Reaction and Intramolecular Nitrile Oxide Cyclization

The advanced organic chemistry experiments describe the preparation of fused six-membered lactams to isoxazole and isoxazoline by employing Ugi four-component reaction (U-4CR) and intramolecular ni...

Fabrication of claviform fluorescent polymeric nanomaterials containing disulfide bond through an efficient and facile four-component Ugi reaction.

Multicomponent reactions (MCRs) have attracted broad interest for preparation of functional nanomaterials especially for the synthesis of functional polymers. Herein, we utilized an "old" MCR, the four-component Ugi reaction, to synthesize disulfide bond containing poly(PEG-TPE-DTDPA) amphiphilic copolymers with aggregation-induced emission (AIE) feature. This four-component Ugi reaction was carried out under rather mild reaction conditions, such as room temperature, no gas protection and absent of catalysts. The amphiphilic poly(PEG-TPE-DTDPA) copolymers with high number-average molecular weight (up to 86,440Da) can self-assemble into claviform fluorescent polymeric nanoparticles (FPNs) in aqueous solution, and these water-dispersed nanoparticles exhibited strong emission, large Stokes shift (142nm), low toxicity and remarkable ability in cellular imaging. Moreover, owing to the introduction of 3,3'-dithiodipropionic acid with disulfide bond, the resultant AIE-active poly(PEG-TPE-DTDPA) could display reduction-responsiveness and be utilized for synthesis of photothermal agents in-situ. Therefore, the AIE-active poly(PEG-TPE-DTDPA) could be promising for controlled intracellular delivery of biological activity molecules and fabrication of multifunctional AIE-active materials. Therefore, these novel AIE-active polymeric nanoparticles could be of great potential for various biomedical applications, such as biological imaging, stimuli-responsive drug delivery and theranostic applications.

Microwave-Induced Ugi-Four Component Reactions: Synthesis of New Hetero- Steroid-Amino Acid Conjugates.

Aza-steroids are an important class of compounds because of their numerous biological activities. The hetero steroids have different hydrogen bonding ability and hydrophobicity in comparison to steroids. Microwave-induced synthesis of a novel type of hybrid hetero-steroid amine conjugates, following Ugi-four component reactions of steroidal amines with alanine and valine methyl esters as amino acid residues is described. Specifically, hetero-steroid-amino acid conjugate based on D-ring fused hetero steroidal amine, hetero-steroid-amino acid conjugate based on A-ring hetero steroidal amine, and hetero-steroidamino acid conjugate based on B-ring hetero steroidal amine are synthesized. The yield of the products under microwave-induced process was considerably higher than that obtained by the conventional method. In contrast to the conventional method for the synthesis of these molecules, microwave-induced method has several advantages. These include rapid reaction, a superior yield of the product, minimum side reaction, and economical microwave-induced process.

Expanding the Scope of Ugi Multicomponent Bioconjugation to Produce Pneumococcal Multivalent Glycoconjugates as Vaccine Candidates.

Conjugate vaccines against encapsulated pathogens like Streptococcus pneumoniae face many challenges, including the existence of multiple serotypes with a diverse global distribution that constantly requires new formulations and higher coverage. Multivalency is usually achieved by combining capsular polysaccharide-protein conjugates from invasive serotypes, and for S. pneumoniae, this has evolved from 7- up to 20-valent vaccines. These glycoconjugate formulations often contain high concentrations of carrier proteins, which may negatively affect glycoconjugate immune response. This work broadens the scope of an efficient multicomponent strategy, leading to multivalent pneumococcal glycoconjugates assembled in a single synthetic operation. The bioconjugation method, based on the Ugi four-component reaction, enables the one-pot incorporation of two different polysaccharide antigens to a tetanus toxoid carrier, thus representing the fastest approach to achieve multivalency. The reported glycoconjugates incorporate three combinations of capsular polysaccharides 1, 6B, 14, and 18C from S. pneumoniae. The glycoconjugates were able to elicit functional specific antibodies against pneumococcal strains comparable to those shown by mixtures of the two monovalent glycoconjugates.

Bin Tan.

"My biggest motivation is to make a creative and significant contribution in several research fields … My favorite saying is to try our best without regret " Find out more about Bin Tan in his Author Profile.

TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics.

DNA‐encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA‐encoded combinatorial peptoid library was designed based on the Ugi four‐component reaction by employing tryptophan‐mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide‐alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor‐relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD‐YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.

Cyclic Imines in Ugi and Ugi-Type Reactions.

Ugi four-component reactions (U-4CRs) are widely recognized as being highly efficient for the synthesis of pseudopeptides. However, the products of these reactions are not so interesting as drug candidates because they are not conformationally restricted enough for a potent interaction with biological targets. One possible way to overcome this problem is to replace amine and oxo components in the U-4CRs with cyclic imines in so-called Joullié-Ugi three-component reactions (JU-3CRs). This approach provides a robust single-step route to peptide moieties connected to N-heterocyclic motifs that are found as core skeletons in many natural products and pharmaceutical compounds. JU-3CRs also provide much better diastereoselectivity than their four-component analogues. We survey here the redesign of many synthetic routes for the efficient preparation of a wide variety of three-, five-, six-, and seven-membered heterocyclic compounds connected to the peptide backbone. Additionally, in the Ugi reactions based on the cyclic imines, α-acidic isocyanides, or azides can be replaced with normal isocyanides or acids, respectively, leading to the synthesis of N-heterocycles attached to oxazoles or tetrazoles, which are of great pharmaceutical significance. This Review includes all research articles related to Ugi reactions based on the cyclic imines to the year 2020 and will be useful to chemists in designing novel synthetic routes for the synthesis of individual and combinatorial libraries of natural products and drug-like compounds.

Precise construction of polymer brush on a nanosilica surface via the combination of anionic polymerization and Ugi-4CR

In this paper, a novel process was presented to synthesize monomodal and bimodal polymer brushes by optimizing living anionic polymerization (LAP) and Ugi four-component reaction (Ugi-4CR). As a remarkable tool, LAP provides an efficient entrance to synthesize the di-endcapped polymer chains. Consequently, the α-terminal silicon oxide group enables polymer chains to be anchored on the surface of nanosilica particles, while the ω-terminal amino group enables Ugi-4CR to be used in the preparation of the multimodal brushes. Through the regulation of the graft density during the “grafting onto” process, the concentration of the amino groups on the nanoparticles involved in the Ugi reaction can be adjusted, and by changing the feeding ratio of aldehyde-terminated polystyrene, the efficiency of the Ugi reaction can be controlled, thereby achieving the synthesis of monomodal and bimodal polymer brushes. After precisely characterizing those polymer brushes, a flexible approach may be preliminarily raised for tuning the topological structure of the polymer chains on the nanoparticle surfaces.

N-Alkylated C-Glycosyl Amino Acid Derivatives: Synthesis by a One-Pot Four-Component Ugi Reaction.

C-glycosides represent an important group of naturally occurring glycosylation derivatives but are also efficient mimetics of native O-glycosides. Here, a one-pot four-component methodology is described toward a library of N-alkylated C-glycosyl amino acid derivatives comprising seven different isopropylidene-protected carbohydrate units. The applied methodology tolerates different amines and isocyanides and provides access to Ugi products in yields up to 85 %. X-ray analysis of selected products bearing three different carbohydrate motifs and comparison of their crystal structures with similar ones deposited in Cambridge Crystallographic Database revealed that four structures adopt different conformations, mostly not typical for peptide structures. This property opens the possibility to exploit here described N-alkylated C-glycosyl amino acid derivatives as templates to access different biotic and abiotic secondary structures.

N-benzyl 4,4-disubstituted piperidines as a potent class of influenza H1N1 virus inhibitors showing a novel mechanism of hemagglutinin fusion peptide interaction

The influenza virus hemagglutinin (HA) is an attractive target for antiviral therapy due to its essential role in mediating virus entry into the host cell. We here report the identification of a class of N-benzyl-4,4,-disubstituted piperidines as influenza A virus fusion inhibitors with specific activity against the H1N1 subtype. Using the highly efficient one-step Ugi four-component reaction, diverse library of piperidine-based analogues was synthesized and evaluated to explore the structure-activity relationships (SAR). Mechanistic studies, including resistance selection with the most active compound (2) demonstrated that it acts as an inhibitor of the low pH-induced HA-mediated membrane fusion process. Computational studies identified an as yet unrecognized fusion inhibitor binding site, which is located at the bottom of the HA2 stem in close proximity to the fusion peptide. A direct π-stacking interaction between the N-benzylpiperidine moiety of 2 and F9HA2 of the fusion peptide, reinforced with an additional π-stacking interaction with Y119HA2, and a salt bridge of the protonated piperidine nitrogen with E120HA2, were identified as important interactions to mediate ligand binding. This site rationalized the observed SAR and provided a structural explanation for the H1N1-specific activity of our inhibitors. Furthermore, the HA1-S326V mutation resulting in resistance to 2 is close to the proposed new binding pocket. Our findings point to the N-benzyl-4,4,-disubstituted piperidines as an interesting class of influenza virus inhibitors, representing the first example of fusion peptide binders with great potential for anti-influenza drug development.

Ultrasound-Activated Atom-Economical Approach to the Synthesis of Highly Substituted Pyrrolidin-2-ones through a Four-Component Ugi/5-endo-trig Intramolecular Radical Cyclization Reaction

An efficient and diversity-oriented access to functionalized pyrrolidin-2-ones through an Ugi reaction of readily available starting materials with a subsequent transformation is described. A two-step reaction sequence of a four-component Ugi reaction and an intramolecular radical-cyclization reaction leads to the chemo- and regioselective formation of a single product with high atom economy and good to high yields. The radicalization of the pseudopeptides generated from the first step by a cavitational mechanism produces the key intermediate for the ultrasound-activated formation of γ-lactams as the final products by β-Michael addition. Among the advantages of this approach are its use of cavitation bubble implosion as an exclusive path to radicalization of the polyfunctional Ugi adduct, its high selectivity, and its short reaction times.

Trimesic acid is a suitable building block in triple four-component Ugi reaction: access to unique trivalent compounds

A triple four-component Ugi reaction of isocyanide, amine, aldehyde, and trimesic acid as the acid component with three acidic functional groups in MeOH at 65 °C has been disclosed. The process employs readily available and low-cost reagents, a convenient synthetic procedure, and mild reaction conditions for the synthesis of pharmacologically significant and structurally interesting compounds with several peptide groups, suitable for dendrimers and self-assembling. Substituents could be independently varied at three different positions. The structural assignments are supported by 1H and 13C NMR data.

Multicomponent molecular memory

Multicomponent reactions enable the synthesis of large molecular libraries from relatively few inputs. This scalability has led to the broad adoption of these reactions by the pharmaceutical industry. Here, we employ the four-component Ugi reaction to demonstrate that multicomponent reactions can provide a basis for large-scale molecular data storage. Using this combinatorial chemistry we encode more than 1.8 million bits of art historical images, including a Cubist drawing by Picasso. Digital data is written using robotically synthesized libraries of Ugi products, and the files are read back using mass spectrometry. We combine sparse mixture mapping with supervised learning to achieve bit error rates as low as 0.11% for single reads, without library purification. In addition to improved scaling of non-biological molecular data storage, these demonstrations offer an information-centric perspective on the high-throughput synthesis and screening of small-molecule libraries.

Nanomolar Synthesis in Droplet Microarrays with UV-Triggered On-Chip Cell Screening.

Miniaturization and parallelization of combinatorial organic synthesis is important to accelerate the process of drug discovery while reducing the consumption of reagents and solvents. This work presents a miniaturized platform for on-chip solid-phase combinatorial library synthesis with UV-triggered on-chip cell screening. The platform is based on a nanoporous polymer coating on a glass slide, which is modified via photolithography to yield arrays of hydrophilic (HL) spots surrounded by superhydrophobic (SH) surface. The combination of HL spots and SH background enables confinement of nanoliter droplets, functioning as miniaturized reactors for the solid-phase synthesis. The polymer serves as support for nanomolar solid-phase synthesis, while a photocleavable linker enables the release of the synthesized compounds into the droplets containing live cells. A 588 compound library of bisamides is synthesized via a four-component Ugi reaction on the chip and products are detected via stamping of the droplet array onto a conductive substrate and subsequent matrix-assisted laser desorption ionization mass spectrometry. The light-induced cleavage shows high flexibility in screening conditions by spatial, temporal, and quantitative control.

Review on the Ugi Multicomponent Reaction Mechanism and the Use of Fluorescent Derivatives as Functional Chromophores.

In the present mini-review we discuss the findings, controversies, and gaps observed for the Ugi four-component reaction. The Ugi multicomponent reaction, performed by mixing an aldehyde, an amine, a carboxylic acid, and an isocyanide, is among the most important isocyanide-based multicomponent reactions (MCRs), allowing multiple bond formations (C–C and C–N) in a single synthetic step. The possibility of two reaction pathways and the little understood solvent effect over this transformation renders this reaction as one of the hardest challenges to overcome. The little knowledge of the mechanism of the Ugi MCR hinders the development of new and efficient chiral catalytic systems to further the application of the derivatives obtained by enantioselective versions. The asymmetric transformation is in this context a bigger challenge, and little is known about the mechanism of these few available versions. The new trend of functional chromophore synthesis by MCRs is also highlighted, and the few examples already disclosed in the literature exemplify the huge opportunity for investigation and creative ideas using the Ugi four-component reaction.