Cyclic Reagents Research Articles

Oxidative cyclization reagents reveal tryptophan cation-π interactions.

Methods for selective covalent modification of amino acids on proteins can enable a diverse array of applications, spanning probes and modulators of protein function to proteomics1-3. Owing to their high nucleophilicity, cysteine and lysine residues are the most common points of attachment for protein bioconjugation chemistry through acid-base reactivity3,4. Here we report a redox-based strategy for bioconjugation of tryptophan, the rarest amino acid, using oxaziridine reagents that mimic oxidative cyclization reactions in indole-based alkaloid biosynthetic pathways to achieve highly efficient and specific tryptophan labelling. We establish the broad use of this method, termed tryptophan chemical ligation by cyclization (Trp-CLiC), for selectively appending payloads to tryptophan residues on peptides and proteins with reaction rates that rival traditional click reactions and enabling global profiling of hyper-reactive tryptophan sites across whole proteomes. Notably, these reagents reveal a systematic map of tryptophan residues thatparticipate in cation-π interactions, including functional sites that can regulate protein-mediated phase-separation processes.

Exploring Protein Bioconjugation: A Redox-Based Strategy for Tryptophan Targeting.

Amino acid bioconjugation technology has emerged as a pivotal tool for linking small-molecule fragments with proteins, antibodies, and even cells. The study in Nature by Chang and Toste introduces a redox-based strategy for tryptophan bioconjugation, employing N-sulfonyloxaziridines as oxidative cyclization reagents, demonstrating high efficiency comparable to traditional click reactions. Meanwhile, this tool provides feasible methods for investigating the mechanisms underlying functional tryptophan-related biochemical processes, paving the way for protein function exploration, activity-based proteomics for functional amino acid identification and characterization, and even the design of covalent inhibitors.

Asymmetric Synthesis of Tetraphenylethylene Helicates and Their Full-Color CPL Emission with High glum and High Fluorescence Quantum Yield.

Tetraphenylethylene (TPE) helicates with single helical handedness not only owe high fluorescence quantum yield but also possess good helical chirality, showing an excellent circularly polarized luminescence active material. In this work, a new method for directly obtaining single-handed TPE helicates has been developed. By using chiral p-phenylenediamine derivatives as an intramolecular cyclization reagent of TPE, the single-handed propeller-like conformation and stable helical chirality of the TPE unit were obtained, avoiding complicated and expensive HPLC chiral column separation. The as-prepared chiral TPE helicates displayed strong emission with an almost quantitative fluorescence quantum yield (Φf) and strong circularly polarized luminescence (CPL). In addition, the chirality and CPL signals of the TPE helicates could be significantly magnified by the helical arrangement together with 4'-pentyl-4-biphenylcarbonitrile (5CB) liquid crystal molecules. Moreover, full-color CPL emissions with both a high absolute CPL dissymmetrical factor up to 0.43 and high Φf were afforded.

Reactions of α-Phenylglyoxylic Acids with ortho-Functionalized Anilines in Deep Eutectic Solvents: Selective Syntheses of 3-Aryl-2H-benzo[b][1,4]oxazin-2-ones, 2-Arylbenzothiazoles, and 3-Arylquinoxalin-2(1H)-ones

Abstractα-Phenylglyoxylic acid is a novel cyclization reagent. In this study, three cyclization products were synthesized by the reaction of α-phenylglyoxylic acids with ortho-functionalized anilines in deep eutectic solvents (DES). The five-membered-ring-formation products, the 2-arylbenzothiazoles, with a highest yield of 88%, were obtained by the reaction between 0.30 mmol of an o-aminothiophenol and 0.30 mmol of an α-phenylglyoxylic acid in choline chloride (ChCl)/d-(–)-tartaric acid DES at 60 °C for 0.5 h. The six-membered-ring-formation products, 3-aryl-2H-benzo[b][1,4]oxazin-2-one derivatives, were obtained in yields up to 99% by the reaction between 0.30 mmol of an o-aminophenol and 0.60 mmol of an α-phenylglyoxylic acid in ChCl/urea DES at 80 °C for 2.0 h. In the reaction between 0.30 mmol of o-phenylenediamine and 0.45 mmol of an α-phenylglyoxylic acid in ChCl/anhydrous tin(II) chloride DES at 70 °C for 1.5 h, the six-membered-ring-formation products, 3-arylquinoxalin-2(1H)-one derivatives, were synthesized, with a highest yield of 96%. This cyclization reaction occurred without the addition of other catalysts, and the title compounds were obtained with good yields under mild conditions.

Ru(III)-catalyzed construction of variously substituted quinolines from 2-aminoaromatic aldehydes (ketones) and isoxazoles: Isoxazoles as cyclization reagent and cyano sources

A Ru(Ⅲ)-catalyzed annulation reaction of 2-aminoaromatic aldehydes (ketones) and isoxazoles to afford diverse 3-cyanoquinolines has been developed. Notably, isoxazole acted as a cyclization reagent and nontoxic cyano source via N-O bond cleavage and fragmentation. Variously substituted (especially 6- or 7-substituted) quinolines could be easily afforded. This procedure features wide functional group compatibility, efficiency and avoiding toxic cyano source. Meanwhile, this protocol could be successfully applied to scale-up synthesis. Further chemical transformations of 3-cyanoquinoline could give some valuable skeletons, demonstrating its potential in synthetic application

Visible‐Light‐Induced Photocatalyst‐Free Oxidative Cyclization of Primary Alcohols by Selectfluor via HAT Process: Synthesis of Quinazolinones and Benzothiadiazines

AbstractA mild and convenient method for oxidative cyclization of primary alcohols with o‐aminobenzamides and o‐aminobenzenesulfonamides to achieve quinazolinones and benzothiadiazines by selectfluor under visible‐light irradiation was reported. Selectfluor is used as hydrogen atom transfer reagent for oxidative cyclization under visible light irradiation. This photochemical approach offers broad substrate scope of quinazolinones and benzothiadiazines under mild reaction conditions.

Construction of new framework of 1,3,4-oxadiazole energetic compounds using 1,1-dichloro-2-nitroethylene: design of high-performance molten-cast explosives

The design of low melting point energetic compounds has always been a difficult point. Two strategies are usually adopted one of them: (1) the construction of a suitable energetic skeleton; (2) the introduction of substituents that regulates the melting point. In this study, a spontaneous cyclization strategy for 1,1-dichloro-2-nitroethylene was adopted to introduce substituents for regulating the melting point while constructing a suitable energetic framework. All the compounds were characterized, and the structures of some compounds were characterized by X-ray diffraction. The thermal and detonation properties of all the compounds were studied; 2-nitromethyl-5-(2,4,6-trinitrophenyl)-1,3,4-oxadiazole, 2-nitromethyl-5-(5-nitroamino-1,2,4-triazol-3-yl)-1,3,4-oxadiazole hydroxylamine salt, 2-nitromethyl-5-(5-nitroamino-1,2,4-triazol-3-yl)-1,3,4-oxadiazole-3-amino-1,2,4-triazole salt, and 2-nitromethyl-5-(5-nitroamino-1,2,4-triazol-3-yl)-1,3,4-oxadiazole-4-amino-1,2,4-triazole salt had melting points equivalent to that of TNT (100.4, 94.2, 93.9 and 82.9 °C, respectively). They corresponding detonation velocities were 7587, 9033, 8290, and 8442 m/s, indicating the potential use of these compounds as molten-cast explosive carriers. Therefore, 2-nitromethyl-1,3,4-oxadiazole energetic compounds provide a new choice for the development of high-energy explosives and molten-cast explosives. Moreover, this synthetic method prevents the use of highly toxic cyclization reagents and simultaneously incorporates two strategies for lowering the melting point. Thus, this study lays a foundation for the expansion of engineering applications.

Kinetic Study of the Pyridine-Catalyzed Selenolactonization of 4-Pentenoic Acid

The kinetics and mechanism of the pyridine-catalyzed cyclofunctionalization of 4-pentenoic acid by means of PhSeX (X = Cl, Br) have been investigated spectrophotometrically, under pseudo-first order reaction conditions. The influence of the reaction temperature, the type of cyclization reagent and used catalyst on the reaction rate and mechanism was examined. The obtained data have showed that rate constants go on increasing as the temperatures go up and with use of PhSeCl as reagent. Also, the reaction rate is directly depended on the type of the catalyst used—stronger bases with higher tendency for hydrogen bond formation (DN) are promoting reaction in more efficient way.

Synthesis, Structures and DFT Computational Studies of [3.1.1]Metacyclophanes Containing Benzofuran Rings

Abstract[3.1.1]Metacyclophane ([3.1.1]MCP) 6 a containing two benzofuran rings was obtained by treatment of [3.3.3]MCP‐dione 5 with trimethylsilyl iodide. The precursor 5 was synthesized using (p‐tolylsulfonyl)methyl isocyanide (TosMIC) as the cyclization reagent. The 1H‐NMR spectrum of 6 a at room temperature reveals that it undergoes very fast conformational changes relative to the NMR time scale and that the phenolic hydrogen forms weak intramolecular hydrogen bonding with the oxygen of one of the benzofurans. O‐Methylation of 6 a afforded the calixarene analogue, macrocyclic [3.1.1]MCP 7 a whose 1H‐NMR spectrum reveals that it adopts a cone‐likeconformation in solution at room temperature and the alkoxy group is pointing above and away from the macrocyclic cavity.

Comparative Study on Conventional and Ultrasound Irradiation Promoted Synthesis of 2,3-Disubstitutedquinoxaline Derivatives

A series of ten chalcone-substituted quinoxalines (4a-e), (3a-e) starting from 1-(phenylquinoxalin-2-yl)ethanone and 1-(3-methylquinoxalin-2-yl)ethanone have been synthesized using conventional heating and ultrasound-assisted methods. Furthermore, novel of five quinoxaline derivatives including pyrazoline, isoxazole, pyrimidin-2-one, N-acylpyrazoline and pyridin-2-one moieties were also prepared from the reaction of chalcone compound 4a with different cyclization reagents using the same strategy. The structures of all synthesized compounds were established on the basis of FT-IR, 1H-NMR and 13C-NMR. The ultrasonic irradiation method provide several advantages over conventional heating method, including shorter reaction times (30-90 min.) and good percentage yields (65% - 88%), comparing with conventional protocol (5 to 20 hrs. with 30% to 55% reaction yields).

An introduction to the kinetics of the triethylamine-mediated selenocyclofunctionalization of 4-pentenoic acid

The aim of this work is exploration of kinetic, thermodynamic and mechanistic aspects of triethylamine-mediated selenocyclofunctionalization of 4-pentenoic acid by means of phenylselenyl halides (PhSeCl and PhSeBr). The kinetics and mechanism for these reactions have been investigated by the UV–Vis spectrophotometry. The rate constants, as well as thermodynamic parameters (ΔH≠, ΔS≠) have been determined using UV–Vis method at three different temperatures (288, 298 and 308 K) in THF as a solvent. All studied reactions gave negative values for entropy of activation, which is in agreement with the SN2 mechanism of substitution. In addition, obtained values for the rate constants have indicated the higher reactivity of PhSeCl as reagent for cyclization.

Iron-Mediated Synthesis of Isoxazoles from Alkynes: Using Iron(III) Nitrate as a Nitration and Cyclization Reagent.

A simple and direct method for the iron(III) nitrate-mediated synthesis of isoxazoles from alkynes has been developed; both self-coupling and cross-coupling products could be successfully prepared from alkynes. Meanwhile, for the cross-coupling and cyclizing of two different alkynes examined, the iron-mediated system shows a good chemoselectivity for the synthesis of corresponding isoxazoles. In our method, cheap and eco-friendly iron(III) nitrate is used as the nitration and cyclization reagent, and KI is used as the additive; they both play a positive role in this transformation. Furthermore, a different mechanism for the formation of isoxazoles from alkynes has been proposed.

Synthesis and conformational studies of chiral macrocyclic [1.1.1]metacyclophanes containing benzofuran rings.

Macrocyclic [1.1.1]metacyclophanes (MCPs) containing benzene and benzofuran rings linked by methylene bridges and which can be viewed as calixarene analogues, have been synthesized by demethylation of [3.3.1]MCP-diones with trimethylsilyl iodide (TMSI) in MeCN. The [3.3.1]MCP-diones are synthesized by using (p-tolylsulfonyl)methyl isocyanide (TosMIC) as the cyclization reagent in N,N-dimethylformamide (DMF) with an excess of sodium hydride. (1)H NMR spectroscopy revealed that the remaining hydroxyl group on the phenyl ring is involved in intramolecular hydrogen bonding with the oxygen of one of the benzofuran rings. O-Methylation at the lower rim of monohydroxy[1.1.1]MCP in the presence of K2CO3 in acetone afforded a novel and inherently chiral calixarene analogue, namely the macrocyclic [1.1.1]MCP, possessing C1 symmetry. The inherent chirality of the two conformers was characterized by (1)H NMR spectroscopy by addition of an excess of Pirkle's chiral shift reagent, which caused a splitting of the corresponding methylene protons to AB patterns. Single crystal X-ray analysis revealed the adoptation of a hemisphere-shaped cone isomer. DFT calculations were carried out to investigate the energy-minimized structures and the hydrogen bonds of the synthesized MCPs.

O-Iodoxy Benzoic Acid–Mediated Synthesis of 3,5-Diarylisoxazoles and Isoxazole-3-carboxylic Acids

A new, convenient, ecofriendly synthesis of 3,5-diarylisoxazoles is reported from α,β-unsaturated ketoximes. Similarly, a novel synthesis of isoxazole carboxylic acids is also reported. Both the methods use efficient, environmentally friendly, and nontoxic iodoxybenzoic acid (IBX) as an oxidative cyclizing reagent. Easy procedure, environmentally benign reaction conditions, and nontoxicity are advantages to the methodology.

Synthesizing 4′,4″(5″) Di‐tert‐butyldibenzo 18‐crown‐6 Monitored by Online FTIR

4′,4″(5″) Di‐tert‐butyldibenzo 18‐crown‐6 (DTBB18C6) was successfully synthesized by SN2 nucleophilic substitution with 4‐tert‐butyl catechol as starting material. Effects of cyclization reagents, solvents, and templates were investigated. Reaction process was monitored by the real‐time online FTIR to study the actual reaction route. The highest DTBB18C6 yield (above 33%) was obtained by using Cs2CO3 as the template, 2,2′‐diethylene glycol ditosylate as the cyclization reagent, and THF as the solvent. From the result of FTIR, four different reaction stages of DTBB18C6 synthesis process were proposed.

Optimization of Synthetic Strategy of 4′4″(5″)-Di-tert-butyldibenzo-18-crown-6 Using Response Surface Methodology

4′,4″(5″)-Di-tert-butyldibenzo-18-crown-6 (DTBB18C6) was synthesized using 4-tert-butyl catechol (TBC) as starting material, 2,2′-diethylene glycol di(p-touenesulfonate) as cyclization reagent, Cs2CO3 as template, and tetrahydrofuran (THF) as solvent. The reaction was carried out in a sealed environment with nitrogen, and Cs2CO3 was supplemented in three steps. Response surface methodology (RSM) was used to investigate the effects of reaction temperature (X1), initial concentration of TBC (X2), reaction time (X3), and Cs2CO3/TBC molar ratio (X4); the experiment method was compared with published methods. From the result of RSM, the operation conditions for maximum yield, such as reaction temperature, reaction time, initial concentration of TBC, and Cs2CO3/TBC molar ratio were found to be 49.15 °C, 72 h, 0.06 mol/L and 3.22, respectively. Under these optimum conditions, DTBB18C6 yield (Y) reached 43.38%.

Grabbing for the Ring: Macrocycles Tweak the Conventions of Drug Making

Newcomer Encycle Therapeutics was founded last January with $1 million in seed funding. The company is developing cradle-shaped macrocyclic peptides, dubbed nacellins, meant to penetrate cells. Encycle makes its nacellins using proprietary amphoteric cyclization reagents. Though the technology can be used to cyclize peptides or nonpeptidic molecules, Yudin said he plans to focus on smaller ring structures of 9–18 atoms. Aside from being a chemist, Yudin is also an artist, and draws whenever he can.According to Yudin, one of the biggest challenges is to find the ideal molecular size, producing medium-sized molecules just above the 500 Da, the size of small molecules that will be cell permeable, bioavailable, and have a conformational space rivaling that of a larger molecule. “One of the key ways to address this challenge is to make molecules that are as much as possible drug-like,” says Yudin. “But medium-sized macrocycles are difficult to make biologically, thus it is important to identify synthetic methods to produce them.” According to Yudin, although companies have innovative platforms geared toward diversity, the tendency is to produce big, very specific molecules that will have very high affinity to their targets; the risk is they won’t be at all drug-like. Potentially, they could stimulate the immune system, may not be absorbed in the digestive tract, or won’t penetrate cells. “So that is really where the problem is,” says Yudin. “We are trying to hit the middle spot.”It takes a good eye to spot the possibilities; the artistry is synthesizing them into existence.

A New Method for the Oxazolidinone Key Intermediate of Linezolid and its Formal Synthesis

In recent years, the incidence of increase in bacterial resistance to a number of available antimicrobial agent, such as β-lactam (penicillin) antibiotics, macrolides, quinolones and vancomycin, has become a critical issue. For instance, vancomycin, an antibiotic generally considered as the ultimate solution against serious gram-positive infections, has been found ineffective on the vancomycin-resistant enterococci (VRE). Therefore, there has been an increased need for totally new agents for effective therapy of grampositive infections by antimicrobial-resistant species. In the search for a new antimicrobial agent, several kinds of synthetic organic compounds have been focused. Among these new compounds, an oxazolidinone was first suggested as a candidate for use as a new antimicrobial agent by Du Pont scientists in 1978. With several biological assay tests, it was claimed that oxazolidinone compounds represent a new class of antimicrobial agents having a unique structure and activity against gram-positive pathogenic bacteria. After early discoveries of the new oxazolidinone antibacterial compounds demonstrated weak in vitro antimicrobial activity, further studies have been encouraged to develop the lead compound DuP-721 (Figure 1) as a drug candidate. Even though DuP-721 showed promising activity, advanced clinical testing was discontinued due to its toxicity. As a result, instead of the early lead compound, two new oxazolidinone compounds, eperezolid and linezolid (Figure 1), have been developed, both of which are active in vitro and in vivo against methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumonise and vancomycin-resistant Enterococcus faecium. A New Drug Application has been filed with the Food and Drug Administration (FDA, USA) for linezolid, presently being sold in the US under the brand name of “Zyvox”. It is known that the mechanism of action of this oxazolidinone antimicrobial agent is based on the inhibition of bacterial protein synthesis. Since the first synthesis of the oxazolidinone antimicrobial agent DuP-721 was reported in the 1980’s, numerous new oxazolidinone compounds have been synthesized and several new synthetic methods have been reported. Several synthetic methods have been studied and developed; however, in response to increasing concern about its antimicrobial activity, comparatively fewer studies on the development of the new synthetic method to provide the oxazolidinone compound have been performed. Hence, there is a clear need for the development of a new synthetic method for an oxazolidinone; in order to study this method of oxazolidinone antimicrobial agents, especially linezolid, we have utilized the epoxide intermediate, which has been developed in our research group. In this paper, a new pathway to the key intermediate oxazolidinone antibiotics is described, and the formal synthesis of linezolid is demonstrated. From a review of the previous syntheses it was determined that most methods for preparing an oxazolidinone ring were closely related to the intermolecular reaction. During the study of epoxide chemistry, it was discovered that an acidmediated epoxide ring opening of an epoxy carbamate yielded the oxazolidinone compound through an intramolecular reaction. Our synthetic strategy for linezolid, including the formation of the oxazolidinone ring, is outlined briefly in Scheme 1. According to Baldwin’s Rule, the formation of the smaller ring over the larger ring from this intramolecular cyclization could be properly explained. One of the detailed mechanisms of this reaction could be proposed in Scheme 2. First, CF3COOH, that is the best reagent for an intramolecular cyclization of an epoxy carbamate compound, might act as a Lewis acid liberating a proton to be coordinated on the epoxide oxygen atom. Now it is probable that the protoncoordinated epoxide could be easily attacked by a neighboring group, another oxygen atom of the carbamate group.

Clean and Convenient One-Pot Synthesis of 4-Hydroxycoumarin and 4-Hydroxy-2-quinolinone Derivatives

A simple, efficient, and environmentally friendly procedure has been developed for the reaction of Meldrum's acid with phenol, substituted phenols, aniline, or substituted anilines with Eaton's reagent (phosphoric anhydride + methylsulfonic acid) as cyclization reagent. 4-Hydroxycoumarins and 4-hydroxy-2-quinolinones were synthesized in moderate yields by carrying out the reaction in solvent-free, convenient, and clean one-pot preparation.

ChemInform Abstract: PhIO as a Powerful Cyclizing Reagent: Regiospecific [3 + 2]‐Tandem Oxidative Cyclization of Imine Toward Cofacially Self‐Aggregated Low Molecular Mass Organic Materials.

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