Mechanism Of Cyclization Research Articles

Distinct roles of Ag(I) and Cu(II) as cocatalysts in the intramolecular cyclization of N-methyl-N-phenylanthranilic acid: A theoretical investigation

• The selectivity is controlled by the additive employed in this reaction. • The silver oxide promotes C(sp 3 )−H activation and C−O cyclization to provide 1,2-dihydro-(4H)−3,1-benzoxazin-4-one. • The copper acetate contributes to C(sp 2 )−H activation and decarboxylative arylation to afford carbazole. • The origins of the selectivity could be attributed to the cation-π interaction between Ag and the substrate arene ring. The mechanisms of the intramolecular cyclization of N-methyl-N-phenylanthranilic acid catalyzed by Pd(OAc) 2 were investigated by employing the density functional theory (DFT) calculations. The selectivity is controlled by the additive employed in this reaction. Silver oxide promotes C(sp 3 )−H activation and C−O cyclization to provide 1,2-dihydro-(4H)-3,1-benzoxazin-4-one, while copper acetate contributes to C(sp 2 )−H activation and decarboxylative arylation to afford carbazole. The origins of the selectivity could be attributed to the cation-π interaction between Ag and the substrate arene ring, which significantly lowers the activation energy for C(sp 3 )−H deprotonation. The distinct roles of Ag(I) and Cu(II) as cocatalysts were clarified through our calculations.

Carbocation-Mediated Cyclization of Trienes in Acid Zeolites.

The mechanism by which acid zeolites catalyze the formation of aromatic species is not fully understood and is important in an array of industrial processes such as the methanol to gasoline reaction. The so-called "carbon pool" mechanism is generally agreed to be the main channel for the formation of hydrocarbons from methanol. There is, however, no agreed sequence of elementary steps that explains how linear intermediates transform to cyclic intermediates, let alone aromatic rings. Recent work suggests the formation of conjugated trienes during zeolite-catalyzed aromatization, but mechanisms involving triene-derived carbocations have never been investigated using modern computational tools. In this work, we propose a new mechanism for cyclization of hexatriene over the Brønsted acid site of faujasite zeolite. Microkinetic models (MKM) using the results of Density Functional Theory (DFT) calculations predict selectivity for neutral 5-membered-ring intermediates over 6-membered-ring intermediates, as suggested by infrared and UV-vis spectroscopic results reported by others. Given that the products of aromatization are 6-membered rings, this result suggests that triene cyclization can only explain how linear hydrocarbons become cyclic intermediates but not the mechanisms that ultimately lead to the aromatic rings seen in industrial zeolite-catalyzed hydrocarbon processes.

Advances in the Synthesis of Ring-Fused Benzimidazoles and Imidazobenzimidazoles.

This review article provides a perspective on the synthesis of alicyclic and heterocyclic ring-fused benzimidazoles, imidazo[4,5-f]benzimidazoles, and imidazo[5,4-f]benzimidazoles. These heterocycles have a plethora of biological activities with the iminoquinone and quinone derivatives displaying potent bioreductive antitumor activity. Synthesis is categorized according to the cyclization reaction and mechanisms are detailed. Nitrobenzene reduction, cyclization of aryl amidines, lactams and isothiocyanates are described. Protocols include condensation, cross-dehydrogenative coupling with transition metal catalysis, annulation onto benzimidazole, often using CuI-catalysis, and radical cyclization with homolytic aromatic substitution. Many oxidative transformations are under metal-free conditions, including using thermal, photochemical, and electrochemical methods. Syntheses of diazole analogues of mitomycin C derivatives are described. Traditional oxidations of o-(cycloamino)anilines using peroxides in acid via the t-amino effect remain popular.

Biosynthetic Cyclization Catalysts for the Assembly of Peptide and Polyketide Natural Products.

Many biologically active natural products are synthesized by nonribosomal peptide synthetases (NRPSs), polyketide synthases (PKSs) and their hybrids. These megasynthetases contain modules possessing distinct catalytic domains that allow for substrate initiation, chain extension, processing and termination. At the end of a module, a terminal domain, usually a thioesterase (TE), is responsible for catalyzing the release of the NRPS or PKS as a linear or cyclized product. In this review, we address the general cyclization mechanism of the TE domain, including oligomerization and the fungal C-C bond forming Claisen-like cyclases (CLCs). Additionally, we include examples of cyclization catalysts acting within or at the end of a module. Furthermore, condensation-like (CT) domains, terminal reductase (R) domains, reductase-like domains that catalyze Dieckmann condensation (RD), thioesterase-like Dieckmann cyclases, trans-acting TEs from the penicillin binding protein (PBP) enzyme family, product template (PT) domains and others will also be reviewed. The studies summarized here highlight the remarkable diversity of NRPS and PKS cyclization catalysts for the production of biologically relevant, complex cyclic natural products and related compounds.

Inside Cover Picture

By means of the simple chemistry of one‐pot synthesis, spiro[fluorene‐9,9'‐xanthene] derivatives (SFXs) become the next‐generation molecular building blocks of the sterically hindered groups in the organic semiconductors after spirobifluorenes (SBFs) that often afford the features of thermal ultrastability, molecular glassy states and other functionalities in attractor‐repulsor molecules. In the recent advances, the history and progress in one‐pot synthesis of spirofluorenes have been highlighted, involving their different mechanisms of cyclization, advantages and limitations.. More details are discussed in the article by Xie et al. on page 701—709. image

1,10/1,11-Cyclization catalyzed by diverged plant sesquiterpene synthases is dependent on a single residue.

The exquisite chemodiversity of terpenoids is the product of the large diverse terpene synthase (TPS) superfamily. Here, by using structural and phylogenetic analyses and site-directed mutagenesis, we identified a residue (Cys440 in Nicotiana tabacum 5-epi-aristolochene synthase) proximal to an ion-binding motif common to all TPSs and named the preNSE/DTE residue, which determines the product specificity of sesquiterpene synthases from different plant species. In sesquiterpene synthases catalyzing 1,10-cyclization (1,10-cyclases) of farnesyl diphosphate, mutation of the residue in both specific and promiscuous 1,10-cyclases from different lineages leads to the accumulation of monocyclic germacrene A-11-ol, which is "short-circuited" from complex cyclization cascades, suggesting a key role of this residue in generating the first common intermediate of 1,10-cyclization. Altering this residue in a specific 1,11-cyclase results in alternative 1,10-cyclization products. Moreover, the preNSE/DTE residue can be harnessed to engineer highly specific sesquiterpene synthases for an improved proportion of high-value terpenoids, such as patchoulol, a main constituent of several traditional Chinese medicines that could treat SARS-CoV-2.

Computational studies on the sterol-like cyclization of a monodomain class II terpene cyclase.

Recently the first example of a class II terpene cyclase comprised of only a single domain was reported. Class II synthases are a diverse group of enzymes that catalyze exceptionally complex reactions, including the remarkable cyclization of steroids. This discovery of a single-domain enzyme being able to catalyze a steroid-like product contradicted the long-held tenet that complex class II cyclizations required double-domain enzymes. The proposed mechanism for the sterol-like cyclization of a monodomain class II terpene cyclase was studied computationally by using density functional theory (DFT). The complete pathway for the conversion of 5-geranyl-3,4-dihydroxybenzoate to the steroid-like pentacyclic product merosterolic acid A was elucidated. The formation of a tricyclic carbocation intermediate with three cyclohexane rings was found to be a concerted, but asynchronous, cyclization. The formation of the fourth ring proceeds with a low energy activation Friedel-Crafts reaction. Subsequent deprotonation of this pentacyclic system gave as the final product merosterolic acid. The overall conversion was found to be highly exothermic due to the conversion of three C-C double bonds to C-C single bonds.

Efficient synthesis of isoindolones by intramolecular cyclisation of pyridinylbenzoic acids.

A straightforward one-pot method for the synthesis of unreported pyrido-[2,1-a]isoindolones in excellent yield is described. Two novel isoindolones were synthesized and fully characterized. The alkyl substituents on the pyridine play an important role in the outcome of the reaction. The mechanism, investigated through DFT calculations, features an unprecendented intramolecular cyclization reaction involving a carboxylic acid activated by tosyl chloride and an electron-poor pyridinic nitrogen. This protocol completes the known strategies to obtain functionalized isoindolones.

Easy wide scope access to luminescent fluorophosphoranes.

The almost quantitative synthesis of homologous luminescent fluorophosphoranes, by SNAr cyclization of (2'-F,2-(PR2)biaryl) phosphines made from easily accessible reagents, is reported and the DFT cyclization mechanism and alternative pathways to complete this isomerization are studied and discussed.

Applications of transition state calculations in the key cyclization of small molecule natural product synthesis

The diversification of the conformation and configuration of the carbocyclic skeleton of natural products is an important reason for the diversity and complexity of the structure of natural products. The corresponding cyclization synthesis has attracted much attention. Computational chemistry approaches have the advantages of non-toxic, harmless and relatively low cost, and they are increasingly used to model and understand molecular phenomena. The reaction mechanism and thermodynamic parameters determine the feasibility of the cyclization and the enantioselectivity of the cyclization products. The transition state calculations can provide these thermodynamic parameters, which helps to elucidate the cyclization mechanism, calculate the reaction rationality, predict the performance of the new synthesis method and provide a basis for the comprehensive synthesis design.

Synthesis of dithienofurans via cascade copper catalysed dual C-S coupling and ring closure reactions under mild conditions.

We have developed a mild catalytic approach for the synthesis of new dithienofuran derivatives via cascade copper catalysed dual C–S coupling and subsequent ring closure reactions. Sonogashira coupling between perbromofuran and terminal alkynes produced 3,4-dibromo-2,5-dialkynylfuran (1) in good yields. Next, copper catalysed C–S coupling between 1 and Na2S·9H2O and a subsequent ring-closure reaction afforded dithienofuran compounds (2) under mild conditions. We found that this strategy shows broad substrate scope and can be used to prepare not only aryl and heteroaryl but also alkyl substituted dithienofuran derivatives in up to 70% yields. Furthermore, we proposed a mechanism including two catalytic cycles: a typical Cu(i)/Cu(iii) catalytic cycle and a subsequent Cu(ii) induced cyclization mechanism.

Site-directed mutagenesis and substrate compatibility to reveal the structure-function relationships of plant oxidosqualene cyclases.

Covering: up to May 2020Oxidosqualene cyclases (OSCs) catalyze one of the most complex polycyclization reactions in nature, using the linear 2,3-oxidosqualene to generate an array of triterpene skeletons in plants. Despite the structural diversity of the products, the protein sequences of plant OSCs are highly conserved, where a few key amino acids could govern the product selectivity. Due to the absence of crystal structures, site-directed mutagenesis and substrate structural modification become key approaches to understand the cyclization mechanism. In this review, 98 mutation sites in 25 plant OSCs have been summarized, and the conserved key residues have been identified by sequence alignment. Structure-function relationships are further discussed. Meanwhile, the substrate selectivity has been summarized to probe the active site cavity of plant OSCs. A total of 77 references are included.

Cyclization mechanism and kinetics of poly(acrylonitrile-co-2-acrylamido-2-methylpropane sulfonic acid) copolymer investigated by FTIR spectroscopy

Cyclization reaction of poly(acrylonitrile-co-2-acrylamido-2-methylpropane sulfonic acid) [P(AN-co-AMPS)] copolymer during thermal oxidative stabilization (TOS) process was investigated by FTIR and two dimensional (2D) correlation analysis technique. The results showed the mechanism of cyclization reaction at different temperatures were varying. At 200 °C, the cyclization reactions generated by autocatalytic cyclization mechanism. While at higher temperatures, the cyclization reactions took place through ionic cyclization mechanism and free radical cyclization mechanism. The AMPS comonomer could reduce the heat release of cyclization reactions and improve the stability at 200 and 230 °C. At higher temperatures, the cyclization reactions were facilitated rapidly. However, the oxidation and degradation reactions were also intense, which will cause the molecular chain to break and defects in the final carbon fibers (CFs). This research has theoretical guiding significance for the optimization of heat treatment conditions for PAN copolymers used as CFs.

Revision of the Cyclisation Mechanism for the Diterpene Spiroviolene and Investigations of Its Mass Spectrometric Fragmentation.

The diterpene spiroviolene, its diterpene synthase from Streptomyces violens and the experimentally determined terpene cyclisation mechanism were reported in 2017. Recently, the structure of spiroviolene was revised based on a total synthesis, with consequences for the cyclisation mechanism. Herein, a reinvestigation of the terpene cyclisation to spiroviolene and the mass spectrometric fragmentation mechanism investigated by 13C‐labelling experiments are presented.

Theoretical study on a kind of cyclization mechanism of boron trichloride and hexamethyldisilazane to form the borazine ring for SiBCN ceramics precursor

Borazine rings act as a pivotal part in siliconboroncarbonitride ceramics (SiBCN) for high-temperature stability and great resistance to crystallization. A detailed investigation of the ring formation mechanism will guide the design and synthesis of SiBCN to meet application requirements under extreme conditions. Boron trichloride (BCl3) and hexamethyldisilazane (HN(SiMe3)2) are common raw materials for the synthesis of precursors for SiBCN. In this paper, quantum chemical calculation was used to study the cyclization reaction mechanism between BCl3 and HN(SiMe3)2 to form trichloroborazine (TCBZ) at the MP2/6-31G (d,p) level of theory. We discussed the structure properties, reaction pathways, energy barriers, reaction rates, and other aspects in detail. The results show that BCl3 and HN(SiMe3)2 alternately participate in the reaction process, accompanied by the release of trimethylchlorosilane (TMCS), and that the entire reaction shows an absolute advantage in terms of energy. In the Step by step reaction, lower reaction barriers are formed due to the introduction of BCl3 with more heat released compared to that for the introduction of HN(SiMe3)2. The final single-molecule cyclization and TMCS elimination steps are found to be faster compared to all previous bimolecular reactions.

Gold‐catalyzed Cyclization of Non‐conjugated Ynone‐oxime Derivatives: Incorporation of Solvent Molecule

AbstractAuııı‐promoted cyclization reaction of ynone‐oxime derivatives furnished 4H‐1,2‐oxazine ring under mild reaction conditions. When an alcohol is present in the reaction media, it was attached to the oxazine ring by the second activation of cyclic intermediate with a gold catalyst. Cholesterol, propargyl alcohol, phenol, and some of the different alcohol derivatives with alkyl chain were bonded to the oxazine ring in good yields. While amine derivatives did not attach to the ring under optimized reaction conditions, the molecule with the thiol group deactivated the gold catalyst under the same reaction conditions and did not give any cyclic products. With the obtained cyclization protocol, 11 unknown oxazine derivatives were synthesized and characterized. The proposed cyclization mechanism was drawn according to the two independent control experiments, DFT optimization, and NBO charges.

The mechanism of carboxylative cyclization of propargylamine by N-heterocyclic carbene complexes of Au(I)

The complex [Au(IPr)(2-oxazolidinone)] (1 = IKa) was prepared from reaction of [Au(IPr)Cl] (2), K2CO3, and propargyl amine (PPA). Kinetic studies have been performed for acid cleavage of 1 to yield the oxazolidinone product and an [Au(IPr)(X)] adduct. The fastest rates of cleavage were found to occur for the hydrogen chloride salt of PPA (PPA-HCl) and for the CO2 adduct of PPA, PPA-CO2 = the carbamic acid (CA). This transformation was studied as a function of [CA], pressure of CO2 as well as temperature. Detailed computational studies support the formation of a key intermediate and are also in agreement with a rapid carbonylation/decarbonylation reaction. The computed reactions mechanisms for addition of PPA-HCl and CA are also presented as well as the crystal structure of 1.

Biosynthesis Gene Cluster and Oxazole Ring Formation Enzyme for Inthomycins in Streptomyces sp. Strain SYP-A7193.

Inthomycins belong to a growing family of oxazole-containing polyketides and exhibit a broad spectrum of anti-oomycete and herbicidal activities. In this study, we purified inthomycins A and B from the metabolites of Streptomyces sp. strain SYP-A7193 and determined their chemical structures. Genome sequencing, comparative genomic analysis, and gene disruption of Streptomyces sp. SYP-A7193 showed that the inthomycin biosynthetic gene cluster (itm) belonged to the hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) system. Functional domain comparison and disruption/complementation experiments of itm12 resulted in the complete loss of inthomycins A and B and the subsequent restoration of their production, confirming that itm12 encodes a discrete acyltransferase (AT), and hence, itm was considered to belong to the trans-AT type I PKS system. Moreover, the disruption/complementation experiments of itm15 also resulted in the loss and restoration of inthomycin A and B formation. Further gene cloning, expression, purification, and activity verification of itm15 revealed that Itm15 is a cyclodehydratase that catalyzes a straight-chain dehydration reaction to form an oxazole ring for the biosynthesis of inthomycins A and B. Thus, we discovered a novel enzyme that catalyzes oxazole ring formation and elucidated the complete biosynthetic pathway of inthomycins.IMPORTANCEStreptomyces species produce numerous secondary metabolites with diverse structures and pharmacological activities that are beneficial for human health and have several applications in agriculture. In this study, hybrid nonribosomal peptide synthetase/polyketide synthase metabolites inthomycins A and B were isolated from after fermenting Streptomyces sp. SYP-A7193. Genome sequencing, gene disruption, gene complementation, heterologous expression, and activity assay revealed that the biosynthesis gene assembly line of inthomycins A and B was a 95.3-kb trans-AT type I PKS system in the strain SYP-A7193. More importantly, Itm15, a cyclodehydratase, was identified to be an oxazole ring formation enzyme required for the biosynthesis of inthomycins A and B; it is significant to discover this catalyzation reaction in the PKS/NRPS system in the field of microbiology. Our findings could provide further insights into the diversity of trans-AT type I PKS systems and the mechanism of oxazole cyclization involved in the biosynthesis of natural products.

A DFT Study on the Cyclization-Mechanism during Process of Thermal Vacuum Degradation for Poly(dimethylsiloxanes)

A DFT investigation was performed on the cyclization mechanism during the process of thermal degradation in vacuum for trimethylsilyl-terminated polydimethylsiloxane, methylsiloxane-α,ω-diol and methylsiloxane-1-ol. The formation of an intramolecular, four-centre cyclic transition state results from the flexibility of a main chain and the ability to rearrange siloxane bonds. The energy barrier of the reaction depends mostly on the four-centre cyclic structure, independent of molecular weight, the position of nucleophilic attacking, and products. The replacement of trimethylsilyl by hydroxyl leads to a great decrease of activation energy of degradation reaction, because the energy barrier of the Si-O bond interchange is much higher than that of hydrogen abstraction. The large cyclosiloxane tend to higher degree of cyclization degradation than linear siloxane with the same number Si atoms. From energetic viewpoint, cyclosiloxane products of various sizes have almost equal chance to form. Due to the continuous degradation of large ring, the D3 accounts for the predominating proportion, and steadily decreasing amounts of D4 and D5.

Biosynthetic Gene Cluster for Asperterpenols A and B and the Cyclization Mechanism of Asperterpenol A Synthase.

The biosynthetic gene cluster for the sesterterpenoids asperterpenols A and B from Aspergillus calidoustus CBS121601 is described. The cluster contains two genes, acldAS for a chimeric sesterterpene synthase and acldA-P450 for a cytochrome P450 monooxygenase. The cyclization mechanism of the asperterpenol A synthase, catalyzing the formation of a unique sesterterpene with a 6/6/8/5 tetracyclic ring system, was studied using isotopically labeled terpene precursors.