Unique Cyclization Research Articles

Phosphorescent iridium (III) complex with covalent organic frameworks as scaffolds for highly selective and sensitive detection of homocysteine.

Introduction: Developing a convenient and cost-effective platform for detecting homocysteine (Hcy) is of great interest as Hcy has been found to be a biomarker for Alzheimer's disease, gastric cancer, and other diseases. Methods: In this study, we synthesized five phosphorescent Ir(C∧N)2(N∧N)+ compounds (Irn, n = 1-5) with various substituents (-CHO or -CHO/-NH2), which were then doped into a covalent organic framework (COF) host via covalent bonding. Results and Discussion: The resulting optimal composites (denoted as Ir4/5@EBCOF) with -CHO/-NH2 substituents not only overcame the self-quenching issue of the bare Ir4/5 complexes but also showed rapid, highly selective, and sensitive detection of Hcy, with a limit of detection (LOD) of 0.23μM and reaction time of 88s. The sensing mechanism was revealed as the unique cyclization reaction between Ir(III) and Hcy that forms a six-membered ring. During the process, the color changes in the composites can be observed visually. It is expected that these phosphorescent Iridium (III) complexes with COFs will have the potential to serve as promising platforms for detecting thiols.

“On–off” fluorescence detection of exposed phosgene via pyrazine ring formation on a triphenyl amine backbone supplemented with a theoretical approach and practical environmental applications

A fluorescent probe ADM has been developed for the selective detection of phosgene through a unique cyclization pathway producing a substituted pyrazine derivative attached to a triphenyl amine backbone.

Photoluminescent and electrochemiluminescent detection of homocysteine based on bifunctional cyclometalated iridium(III) complex

A photoluminescent (PL) and electrochemiluminescent (ECL) chemodosimeter for homocysteine (Hcy) determination was developed based on a bifunctional cyclometalated iridium(III) complex (pba)2Ir(dcbpy). (pba)2Ir(dcbpy) was prepared by using 4′-(2-pyridyl)-benzaldehyde (pba) as main ligand and 2,2′-bipyridyl-4,4′-dicarboxylic acid (dcbpy) as ancillary ligand. The existence of aldehyde group on the main ligand and dicarboxylic acid groups on the ancillary ligand endows (pba)2Ir(dcbpy) good water solubility. Importantly, the aldehyde group on the main ligand also furnishes the chemodosimetric active site, which could react with Hcy highly in neutral buffer solution based on a unique cyclization reaction with aminoalkylthiol group to produce a binding adduct, enhancing both PL and ECL signal. The photophysical and ECL properties of (pba)2Ir(dcbpy) in the absence and presence of Hcy were investigated and the response mechanism of the luminescence enhancement was confirmed by mass spectrum. Both PL and ECL measurements exhibited good linear relationships to the Hcy with the detection of limit at micro-molar level. More significantly, (pba)2Ir(dcbpy) possessed a relatively high discriminating ability to differentiate Hcy from structurally related molecule (cysteine) under neutral buffer conditions. The PL and ECL chemodosimeter based on cyclometalated iridium(III) complex with specific active site is universal to the analysis of other targets, thus opening a new avenue for the application of cyclometalated iridium(III) complex in PL and ECL field.

Bicyclostreptins are radical SAM enzyme-modified peptides with unique cyclization motifs.

Microbial natural products comprise diverse architectures that are generated by equally diverse biosynthetic strategies. In peptide natural products, amino acid sidechains are frequently used as sites of modification to generate macrocyclic motifs. Backbone amide groups, among the most stable of biological moieties, are rarely used for this purpose. Here we report the discovery and biosynthesis of bicyclostreptins-peptide natural products from Streptococcus spp. with an unprecedented structural motif consisting of a macrocyclic β-ether and a heterocyclic sp3-sp3 linkage between a backbone amide nitrogen and an adjacent α-carbon. Both reactions are installed, in that order, by two radical S-adenosylmethionine (RaS) metalloenzymes. Bicyclostreptins are produced at nM concentrations and are potent growth regulation agents in Streptococcus thermophilus. Our results add a distinct and unusual chemotype to the growing family of ribosomal peptide natural products, expand the already impressive catalytic scope of RaS enzymes, and provide avenues for further biological studies in human-associated streptococci.

Palladium‐Catalyzed Novel C(formyl)‐C(aryl)/C(aryl)‐N(amine) Coupling Sequence Between 2‐(Methylamino)nicotinaldehyde and 3‐Bromo‐2‐chlorothiophene: An Efficient Construction of 4‐Pyridone Fused Hybrid Scaffolds

AbstractAn unique cyclization reaction between very simple starting materials such as 2‐ (methylamino)nicotinaldehyde and 3‐bromo‐2‐chlorothiophene has been reported. This strategy offers a facile access to a plethora of thieno[2,3‐b][1,8]naphthyridin‐4(9H)‐one derivatives, which are highly anticipating in pharmaceutical science as potential biologically active candidates.

Construction of N-Heterocyclic Systems Containing a Fully Substituted Allylic Carbon by Palladium/Phosphine Catalysis.

The unique cyclization of benzamide derivatives that contain an alkyne by a Pd(0)/dialkyl(biaryl)phosphine catalytic system is reported. The reaction efficiently provides a variety of six-membered N-heterocyclic compounds that contain a fully substituted carbon center without the need for a stoichiometric additive. Mechanistic studies suggest that this unprecedented cyclization starts with the cleavage of a propargylic C-O bond, and a 1,3-diene has been identified as a relevant intermediate.

Mechanistic Investigations of Lysine-Tryptophan Cross-Link Formation Catalyzed by Streptococcal Radical S-Adenosylmethionine Enzymes.

Streptide is a ribosomally synthesized and post-translationally modified peptide with a unique cyclization motif consisting of an intramolecular lysine-tryptophan cross-link. Three radical S-adenosylmethionine enzymes, StrB, AgaB, and SuiB from different species of Streptococcus, have been shown to install this modification onto their respective precursor peptides in a leader-dependent fashion. Herein, we conduct detailed investigations to differentiate among several plausible mechanistic proposals, specifically addressing radical versus electrophilic addition to the indole during cross-link formation, the role of substrate side chains in binding in the enzyme active site, and the identity of the catalytic base in the reaction cycle. Our results are consistent with a radical electrophilic aromatic substitution mechanism for the key carbon-carbon bond-forming step. They also elaborate on other mechanistic features that underpin this unique and synthetically challenging post-translational modification.

The Thioesterase Domain in Glycopeptide Antibiotic Biosynthesis Is Selective for Cross-Linked Aglycones.

The biosynthesis of the glycopeptide antibiotics (GPAs)-which include teicoplanin and vancomycin-is a complex enzymatic process relying on the interplay of nonribosomal peptide synthesis and a cytochrome P450-mediated cyclization cascade. This unique cyclization cascade generates the highly cross-linked state of these nonribosomal peptides, which is crucial for their antimicrobial activity. Given that these essential oxidative transformations occur while the peptide remains bound to the terminal module of the nonribosomal peptide synthetase (NRPS) machinery, it is important to assess the selectivity of the terminal thioesterase (TE) domain and how this domain contributes to the maintenance of an efficient biosynthetic pathway while at the same time ensuring GPA maturation is completed. In this study, we report the in vitro characterization of the thioesterase domain from teicoplanin biosynthesis, the first GPA thioesterase to be characterized. Our results show that the activity of this TE domain relies on the presence of an unusual extended N-terminal linker region that appears to be unique to the NRPS machineries found in GPA biosynthesis. In addition, we show that the activity of this domain against carrier protein bound substrates is dramatically enhanced for mature GPA aglycones as opposed to linear peptides and partially cyclized intermediates. These results demonstrate how the interplay between NRPS and P450s during late stage GPA biosynthesis is not only maintained but also leads to the efficient production of mature GPA aglycones. Thus, GPA TE domains represent another impressive example of the ability of TE domains to act as logic gates during NRPS biosynthesis, ensuring that essential late-stage peptide modifications are completed before catalyzing the release of the mature, bioactive peptide product.

Palladium-Catalyzed Cyclization of Alkynoic Acids To Form Vinyl Dioxanones Bearing a Quaternary Allylic Carbon.

A palladium-catalyzed intramolecular reaction of carboxylic acids and alkynes in a novel cyclization manner was developed. This unique cyclization efficiently provided a wide range of complex ring systems-vinyl dioxanones bearing a quaternary allylic carbon. Mechanistic studies suggest an allenyl carboxylate as an intermediate.

Rhenium‐Catalyzed Construction of Polycyclic Hydrocarbon Frameworks by a Unique Cyclization of 1,n‐Diynes Initiated by 1,1‐Difunctionalization with Carbon Nucleophiles

AbstractA regioselective cyclization of 1,n‐diynes under rhenium catalysis was developed on the basis of a rare type of 1,1‐difunctionalization of terminal alkynes with carbon nucleophiles, followed by sequential addition reactions of the resulting alkenylrhenium species. The reaction provides an efficient approach to the synthesis of complex cyclopentane‐fused bi‐ and tricycles and spirocycles, which are useful building blocks for the construction of essential frameworks of biologically active compounds as well as functional materials, from simple starting materials by the formation of up to six new carbon–carbon bonds in a single step. The reaction proceeds under neutral conditions and does not require external ligands or additives. The key to this reactivity is the unique activation mode of the rhenium carbonyl complex, which prefers to interact with heteroatoms in polar carbon–heteroatom bonds as well as nonpolar carbon–carbon unsaturated π bonds.

Rhenium‐Catalyzed Construction of Polycyclic Hydrocarbon Frameworks by a Unique Cyclization of 1,n‐Diynes Initiated by 1,1‐Difunctionalization with Carbon Nucleophiles

A regioselective cyclization of 1,n-diynes under rhenium catalysis was developed on the basis of a rare type of 1,1-difunctionalization of terminal alkynes with carbon nucleophiles, followed by sequential addition reactions of the resulting alkenylrhenium species. The reaction provides an efficient approach to the synthesis of complex cyclopentane-fused bi- and tricycles and spirocycles, which are useful building blocks for the construction of essential frameworks of biologically active compounds as well as functional materials, from simple starting materials by the formation of up to six new carbon-carbon bonds in a single step. The reaction proceeds under neutral conditions and does not require external ligands or additives. The key to this reactivity is the unique activation mode of the rhenium carbonyl complex, which prefers to interact with heteroatoms in polar carbon-heteroatom bonds as well as nonpolar carbon-carbon unsaturated π bonds.

ChemInform Abstract: Recent Progress on Nazarov Cyclizations: The Use of Iron Salts as Catalysts in Ionic Liquid Solvent Systems

AbstractReview: [60 refs.

Recent Progress on Nazarov Cyclizations: The Use of Iron Salts as Catalysts in Ionic Liquid Solvent Systems.

Nazarov cyclization is an important and versatile method for the synthesis of five-membered carbocycles, and extensive studies have been conducted to optimize the reaction. Among recent studies, several trends are recognized. One is the combination of different reactions with Nazarov cyclization in a one-pot reaction system which enables the preparation of unique cyclization products. The second is the use of a transition-metal catalyst, though Lewis or Brønsted acids have generally been used for the reaction. The third is the realization of the asymmetric Nazarov cyclization. The fourth is the base-catalyzed Nazarov cyclization. Furthermore, several useful protocols for realizing Nazarov cyclization have also been developed. The recent progress on Nazarov cyclizations is summarized in Section 2. Section 3 is our chronicle in this field. We focused on the use of iron as the catalyst in Nazarov cyclizations and ionic liquids as solvents: Nazarov cyclization of thiophene derivatives using FeCl3 as the catalyst was accomplished and we succeeded in demonstrating the first example of an iron-catalyzed asymmetric Nazarov reaction. We next established Nazarov cyclization of pyrrole or indole derivatives using Fe(ClO4 )3 ·Al2 O3 as the catalyst with high trans selectivities in excellent yields. Since the cyclized product was reacted with a vinyl ketone in the presence of the same iron salt, the system allowed realization of the sequential type of Nazarov/Michael reaction of pyrrole derivatives. Furthermore, we demonstrated the recyclable use of the iron catalyst and obtained the desired Nazarov/Michael reaction products in good yields for five repetitions of the reactions without any addition of the catalyst using an ionic liquid, [bmim][NTf2 ], as the solvent. We expect that the iron-catalyzed Nazarov cyclization, in particular, in an ionic liquid solvent might become a useful method to synthesize functional molecules that include cycloalkene moieties.

Conversion of Substrate Analogs Suggests a Michael Cyclization in Iridoid Biosynthesis

SummaryThe core structure of the iridoid monoterpenes is formed by a unique cyclization reaction. The enzyme that catalyzes this reaction, iridoid synthase, is mechanistically distinct from other terpene cyclases. Here we describe the synthesis of two substrate analogs to probe the mechanism of iridoid synthase. Enzymatic assay of these substrate analogs along with clues from the product profile of the native substrate strongly suggest that iridoid synthase utilizes a Michael reaction to achieve cyclization. This improved mechanistic understanding will facilitate the exploitation of the potential of iridoid synthase to synthesize new cyclic compounds from nonnatural substrates.

A triphenylamine based multi-analyte chemosensor for Hg2+ and Cu2+ ions in MeCN/H2O

A novel triphenylamine based oxidative chemosensor TOC was synthesized. The chromogenic and fluorogenic behaviors of TOC towards Hg2+ and Cu2+ ions in a binary mixture of MeCN/H2O (9/1) were dramatically different. TOC displays colorimetric ‘naked eye’ recognition of Hg2+ and fluorogenic ‘turn on’ response towards Cu2+ via a unique cyclization reaction using two different detection modes. Moreover, TOCAZOL obtained from the oxidative cyclization reaction of TOC with Cu(ClO4)2 can be used as a selective fluorescent sensor toward Hg2+ ion.

ヨウ素および（ポリ）ヨウ化水素を用いた多重結合活性化による環構造構築反応

Molecular iodine and hydrogen iodide are known to promote cationic species by addition to multiple bonds. The cationic species can form C-C, C-O, and C-N bonds. The development of new reactions using iodine and hydrogen iodide is playing an important role in synthetic organic chemistry. Herein we report our investigation of the carbon-carbon bond formation of conjugated compounds with iodine and hydrogen (poly)iodide using activation of the multiple bonds. Various cyclic compounds such as naphthalenes, iodobenzenes, quinolines, and dihydroquinolines were formed from aryldienes, dienynes, and enamines under thermal and photochemical conditions. We also found a unique cyclization reaction including a 1,2-sulfonyl migration using hydrogen polyiodide. The reactions specifically proceeded by the characteristic nature of the iodine element and the oxidative and reductive properties of iodine and hydrogen iodide, which were also used efficiently to yield various compounds in combination with the sulfur moiety attached to reaction materials.

Superelectrophilic intermediates in nitrogen-directed aromatic borylation.

The first examples of borylation under conditions of borenium ion generation from hydrogen-bridged boron cations are described. The observable H-bridged cations are generated by hydride abstraction from N,N-dimethylamine boranes Ar(CH(2))(n)NMe(2)BH(3) using Ph(3)C(+) (C(6)F(5))(4)B(-) (TrTPFPB) as the hydride acceptor. In the presence of excess TrTPFPB, the hydrogen-bridged cations undergo internal borylation to afford cyclic amine borane derivatives with n = 1-3. The products are formed as the corresponding cyclic borenium ions according to reductive quenching experiments and (11)B and (1)H NMR spectroscopy in the case with Ar = C(6)H(5) and n = 1. The same cyclic borenium cation is also formed from the substrate with Ar = o-C(6)H(4)SiMe(3) via desilylation, but the analogous system with Ar = o-C(6)H(4)CMe(3) affords a unique cyclization product that retains the tert-butyl substituent. An ortho-deuterated substrate undergoes cyclization with a product-determining isotope effect of k(H)/k(D) 2.8. Potential cationic intermediates have been evaluated using B3LYP/6-31G* methods. The computations indicate that internal borylation from 14a occurs via a C-H insertion transition state that is accessible from either the borenium pi complex or from a Wheland intermediate having nearly identical energy. The Ar = o-C(6)H(4)SiMe(3) example strongly favors formation of the Wheland intermediate, and desilylation occurs via internal SiMe(3) migration from carbon to one of the hydrides attached to boron.

The synthetic potential of pyridinium salt photochemistry

The discovery in the 1970s by Kaplan, Wilzbach and Pavlik that pyridinium salts undergo a unique cyclization reaction to produce bicyclic-aziridines was virtually unrecognized for nearly three decades. It was only comparatively recently that the process was explored in more detail and its synthetic potential exploited. In this Perspective, photocyclization reactions of pyridinium salts will be discussed, starting with the initial discovery, covering related processes of pyrylium salts, and extending to applications to the synthesis of natural and non-natural products of biomedical interest.

Functional evidence for the involvement of Arabidopsis IspF homolog in the nonmevalonate pathway of plastid isoprenoid biosynthesis

There are two independent pathways, the cytosolic mevalonate (MVA) pathway and the plastid nonmevalonate (nonMVA) pathway, to synthesize isopentenyl diphosphate and dimethylallyl diphosphate in plants. Carotenoids and the phytyl side chain of chlorophylls are isoprenoids derived from the plastid nonMVA pathway. All enzymes involved in the nonMVA pathway have been identified in Escherichia coli. The E. coli IspF protein catalyzes a unique cyclization reaction to convert 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate into 2-C-methyl-D-erythritol 2,4-cyclodiphosphate in the nonMVA pathway. We have characterized an Arabidopsis T-DNA insertion mutant, ispF-1, which has a null mutation in the IspF gene. Homozygous ispF-1 mutants are albino lethal and the IspF transcripts are undetectable in these plants. Moreover, the ispF-1 mutant chloroplasts are filled with vesicles instead of thylakoids. Amino acid sequence alignment reveals that the IspF proteins are highly conserved between plants and bacteria. Interestingly, expression of the Arabidopsis IspF protein can rescue the lethal phenotype of an E. coli ispF mutant. These results indicate that the Arabidopsis IspF may share similar enzymatic mechanisms with the E. coli protein.

Managing and manipulating carbocations in biology: terpenoid cyclase structure and mechanism

Terpenoid cyclases catalyze remarkably complex cyclization cascades that are initiated by the formation of a highly reactive carbocation in a polyisoprene substrate. Recent crystal structures of terpenoid cyclases show how these enzymes provide a template for binding and stabilizing the flexible substrate in the precise orientation required for catalysis, trigger carbocation formation, chaperone the conformations of the reactive carbocation intermediates through a unique cyclization sequence, and sequester and stabilize carbocations from premature quenching. Notably, terpenoid cyclases and catalytic antibodies have converged to similar chemical and structural strategies for managing highly reactive carbocations in polyisoprene cyclization cascades.