Secondary Cyclization Research Articles

Deciphering Biosynthesis Mechanism and Solution Properties of Cyclic Amylopectin

A novel cyclic amylopectin (CA) was synthesized from waxy corn starch (WCS) using Bacillus stearothermophilus branching enzyme (BstBE), providing insights into its biosynthesis mechanism and solution properties. During the first 4 h, BstBE partially cyclized WCS, producing 68.20% CA with a significantly reduced molecular weight (MW), from 8.98 × 10⁶ to 3.19 × 10⁴ g/mol and a lower polymer dispersity index (PDI), decreasing from 1.97 to 1.12. This resulted in a uniform CA structure with shorter chain lengths, particularly increasing DP 3–13, especially DP 7–9. Over the subsequent 4–12 h, the PDI slightly increased to 1.18 as the CA content decreased to 50.48%, with an increase in small ring structures (DP 6–12) of CA, suggesting both ring-opening and ring-downsizing due to continued enzyme catalysis. These results propose a two-stage reaction model: initial cyclization followed bybranching and secondary cyclization. CA exhibited excellent solution properties, with BE-4 and BE-12 samples demonstrating high solubility (≥65 g/100 mL), low viscosity (<0.01 Pa·s), and over 90% light transmittance after 14 days at 4 °C, highlighting its broad application potential.

ОСОБЕННОСТИ МЕТАЦИКЛИЗАЦИИ В РОК-ПОЭЗИИ: НА ПРИМЕРЕ ТВОРЧЕСТВА ГРУППЫ "ДДТ"

The phenomenon of metacyclization is based on a complex system of relationships that form the lyrical cycle of works and makes it possible to realize the creative ideas of the author, potentially unresolved in poetry in other ways. The article is about the features of metacyclization in modern rock poetry on the example of the works of Y. Shevchuk, the soloist of the group “DDT”. The essence and specifics of the phenomenon in lyrics are briefly defined and the main types of its implementation are listed. The article, using specific examples from Y. Shevchuk’s poetry, considers various forms of the existence of metacycles as secondary author’s cycles and as larger-scale lyrical cycles united by theme, chronotype, etc. The means and tools used by the author to create a single composition of the cycle, the implementation of the author’s intention are characterized. The paper states that in rock poetry the compositions, the most popular or subjectively significant for the author, as a rule, are subject to secondary cyclization. It was revealed by specific examples that the context of the metacycle not only enriches the works of rock poetry with new meanings, but sometimes also transforms their text in accordance with the current author’s position one whole concept of the lyrical cycle. Numerous references to the work of Russian writers and poets, to the compositions of colleagues confirm the unity and interconnection of Yu. Shevchuk’s poetry not only with modern Russian rock, but also with Russian literature in general.

Lewis Base Catalyzed, Sulfenium Ion Initiated Enantioselective, Spiroketalization Cascade.

A Lewis base catalyzed, enantioselective sulfenocyclization of alkenes to afford [6,6]spiroketals has been developed. The method uses a chiral Lewis base catalyst with an electrophilic sulfur source to generate enantioenriched thiiranium ion with alkenes. Upon formation, the thiiranium ion is subsequently captured in a cascade-type reaction, wherein a ketone oxygen serves as the nucleophile to open the thiiranium ion and an alcohol provides the secondary cyclization to form biorelevant spiroketals. A variety of electron-rich and electron-neutral E-substituted styrenes form the desired spiroketals in good yields with excellent enantio- and diastereoselectivities. Alkyl-substituted and terminal alkenes participate in the cascade reaction, but with a limited scope compared to the styrenyl substrates. This method allows for rapid formation of highly substituted spiroketals in good yield and excellent enantioselectivity.

Anti-Inflammatory, Antioxidant, and Anti-Nonalcoholic Steatohepatitis Acylphloroglucinol Meroterpenoids from Hypericum bellum Flowers.

In this work, 26 methylated acylphloroglucinol meroterpenoids with diverse skeletons, including 18 new ones (bellumones A-R, 1-18), were identified from the flowers of Hypericum bellum. Their structures including absolute configurations were elucidated by detailed spectroscopic data, calculated electronic circular dichroism (ECD), and X-ray diffraction (XRD). Through methylation at C-5, prenylation with different chain lengths of the acylphloroglucinol-derived core, along with different types of secondary cyclization, type A bicyclic polyprenylated acylphloroglucinols (BPAPs) (1-5 and 19-24) and dearomatized isoprenylated acylphloroglucinols (DIAPs) (6-18 and 25-26) were obtained. The significant results of anti-inflammatory, antioxidant, and anti-nonalcoholic steatohepatitis (anti-NASH) activities suggest its usefulness in daily health care.

The Double-Bond Configuration of Corynanthean Alkaloids and Its Impact on Monoterpenoid Indole Alkaloid Biosynthesis.

Experimental evidence is provided for the coherence of the double-bond geometry and the occurrence of "secondary cyclizations" in the biosynthesis of monoterpenoid indole alkaloids. Biosynthetically, akuammiline, C-mavacurine, and Strychnos alkaloids are proposed to be derived from the corynanthean alkaloid geissoschizine, a key intermediate in the biosynthetic pathway of these monoterpenoid indole alkaloids. This process occurs by so-called "secondary cyclizations" from geissoschizine or its derivatives. Although corynanthean alkaloids like geissoschizine incorporate E or Z double bonds located at C19-C20, the alkaloids downstream in the biosynthesis exclusively exhibit the E double bond. This study shows that secondary cyclizations preferentially occur with the E isomer of geissoschizine or its derivatives. This is attributed to the flexibility of the quinolizidine system of the corynanthean alkaloids, which can adopt a cis or trans conformation. For the secondary cyclization to take place, the cis-quinolizidine conformation is required. Experimental evidence supports the hypothesis that the E double bond of geissoschizine induces the cis conformation, whereas the Z double bond induces the trans conformation, which prohibits secondary cyclization of the Z compounds.

Secondary Amine-Mediated Cyclization of Methyl Propiolate with Imines

A facile method for the synthesis of tetrahydropyrimidines is described. Diethylamine was treated with methyl propiolate to provide Michael adduct (β-amino acrylate). In the presence of organic acid, the cyclization between imines with β-aminoacrylateoccurred at room temperature and completed within several minutes to give tetrahydropyrimidines with liberation of ammonium salt. Formaldimines show good toleration to the reaction.

Plasticity residues involved in secondary cyclization of terpene synthesis in Taiwania cryptomerioides

Terpenoids have many biological functions and a comprehensive range of applications. Here, we cloned two monoterpene synthase genes, Tc-αpin/teo and Tc-teo, from Taiwania cryptomerioides. The enzymes encoded by these genes shared 97 % amino acid sequences similarity but had different terpene product profiles. Using structural modeling and site-directed mutagenesis, we successfully identified three plasticity residues around the active site of Tc-αPIN/TEO, namely Y327, Y429 and Y575 that are involved in secondary cyclization. The mutants in which the phenolic residues were replaced with phenylalanines seemed to lose their preference for α-pinene synthesis, indicating that the tyrosine hydroxyl groups at these sites were necessary for the formation of bicyclic terpene products.

Microspheres of carbon xerogel: An alternative Pt-support for the selective hydrogenation of citral

A new carbon xerogel (A8) was obtained in powder by polymerization of resorcinol-formaldehyde using a stirred batch reactor, microwave drying and carbonization in inert atmosphere. The ability of this material as Pt-support regarding SiO2, TiO2 and Al2O3 to develop selective catalysts for the citral hydrogenation was analyzed on the basis of their morphologic, textural and acid characteristics. Inorganic supports are crystalline and mesoporous materials while the carbon xerogel is exclusively microporous and is formed by spherical nanoparticles of around 250nm in diameter of amorphous carbon. The supports acidity (pHpzc) vary in the sense Al2O3>TiO2> SiO2>A8. The Pt-dispersion depends on the support nature and pretreatment conditions used; in general, an increase of Pt-particle size favors the selectivity to unsaturated alcohols but the catalytic activity decrease. The conversion also strongly depends on the acidity of supports, but selectivity is more specifically influenced by the strength of the acid sites and pore size distribution. Cracking reactions are favored by Brönsted acid sites present in Al2O3 and the high mesopore volume of SiO2 induces mainly secondary cyclization and hydrogenation reactions. Pt-supported on carbon xerogel (Pt/A8) provided selectivity values to unsaturated alcohols of around 80%, a very high value for monometallic Pt-catalyst and only comparable with those obtained with Pt/TiO2 pretreated in H2-flow.

A New Insight into the Formation of Polymer Networks: A Kinetic Monte Carlo Simulation of the Cross-Linking Polymerization of S/DVB

The kinetic Monte Carlo simulation was used to predict the characteristics of the polymer network formation during pre- and postgelation regimes of free-radical cross-linking copolymerization. The simulation naturally considers the presence of multiradicals, primary and secondary cyclization with no preassumptions. The simulation was first validated in the pregel regime by comparing the microstructure with that given by a mean-field model. The Monte Carlo simulation was then used to predict the kinetics and development of the polymer microstructure of the sol and gel fractions up to full conversion, including the complete molecular weight distribution, cross-linking and pendant double bond densities, primary and secondary cyclization and the molecular weight distribution between cross-linking points. The simulation also allows studying the presence and evolution of multiradicals along the polymerization.

Bifunctional cis-Abienol Synthase from Abies balsamea Discovered by Transcriptome Sequencing and Its Implications for Diterpenoid Fragrance Production

The labdanoid diterpene alcohol cis-abienol is a major component of the aromatic oleoresin of balsam fir (Abies balsamea) and serves as a valuable bioproduct material for the fragrance industry. Using high-throughput 454 transcriptome sequencing and metabolite profiling of balsam fir bark tissue, we identified candidate diterpene synthase sequences for full-length cDNA cloning and functional characterization. We discovered a bifunctional class I/II cis-abienol synthase (AbCAS), along with the paralogous levopimaradiene/abietadiene synthase and isopimaradiene synthase, all of which are members of the gymnosperm-specific TPS-d subfamily. The AbCAS-catalyzed formation of cis-abienol proceeds via cyclization and hydroxylation at carbon C-8 of a postulated carbocation intermediate in the class II active site, followed by cleavage of the diphosphate group and termination of the reaction sequence without further cyclization in the class I active site. This reaction mechanism is distinct from that of synthases of the isopimaradiene- or levopimaradiene/abietadiene synthase type, which employ deprotonation reactions in the class II active site and secondary cyclizations in the class I active site, leading to tricyclic diterpenes. Comparative homology modeling suggested the active site residues Asp-348, Leu-617, Phe-696, and Gly-723 as potentially important for the specificity of AbCAS. As a class I/II bifunctional enzyme, AbCAS is a promising target for metabolic engineering of cis-abienol production.

Two Approaches to Diverting the Course of a Free-Radical Cyclization: Application of Cyclopropylcarbinyl Radical Fragmentations and Allenes as Radical Acceptors

Free radical cyclization of 4 and 7 gave the expected cyclization-reduction products (5 and 8) along with considerable amounts of products derived from a cyclization-atom transfer-secondary cyclization process (6 and 9). Two approaches to avoiding these unexpected products were explored. Use of a cyclopropylcarbinyl fragmentation avoided the secondary cyclization reaction (25 or 43 --> 26 or 44), whereas use of an allene as a radical acceptor avoided the atom-transfer reaction altogether (49 --> 52).

Chapter 3 Chemical and Biological Aspects of Narcissus Alkaloids

Publisher SummaryThis chapter discusses the chemical and biological aspects of Narcissus alkaloids. Numerous alkaloids have been isolated from Narcissus speciesasaresult of the continuing search for novel alkaloids with pharmacological activity in the Amaryllidaceae family. The alkaloids isolated from this genus, classified in relation to the different skeleton types. The different Narcissus wild species and intersectional hybrids, grouped into subgenera and sections, with their corresponding alkaloids, arranged according to their ring system are listed. The biosynthetic pathways of Narcissus alkaloids includes: (1) enzymatic preparation of the precursors, (2) primary cyclization mechanisms, (3) enzymatic preparation of intermediates, (4) secondary cyclization, diversification, and restructuring. The chapter discusses proton nuclear magnetic resonance (1H NMR), carbon nuclear magnetic resonance (13C NMR), and mass spectrometry (MS) for Narcissus alkaloids. A list of the different Narcissus alkaloids, their spectroscopic properties, and literature with the most recent spectroscopic data is given. Several Narcissus extracts shows the following activities: antiviral, prophage induction, antibacterial, antifungal, antimalarial, insecticidal, cytotoxic, antitumor, antimitotic, antiplatelet, hypotensive, emetic, acetylcholine esterase inhibitory, antifertility, antinociceptive, chronotropic, pheromone, plant growth inhibitor, and allelopathic.

Two pockets in the active site of maize sesquiterpene synthase TPS4 carry out sequential parts of the reaction scheme resulting in multiple products

One of the most interesting features of terpene synthases is their ability to form multiple products with different carbon skeletons from a single prenyl diphosphate substrate. The maize sesquiterpene synthase TPS4, for example, produces a mixture of 14 different olefinic sesquiterpenes. To understand the complex TPS4 reaction mechanism, we modeled the active site cavity and conducted docking simulations with the substrate farnesyl diphosphate, several predicted carbocation intermediates, and the final reaction products. The model suggests that discrete steps of the reaction sequence are controlled by two different active site pockets, with the conformational change of the bisabolyl cation intermediate causing a shift from one pocket to the other. Site-directed mutagenesis and measurements of mutant activity in the presence of ( E, E)- and ( Z, E)-farnesyl diphosphate as substrates were employed to test this model. Amino acid alterations in pocket I indicated that early steps of the catalytic process up to the formation of the monocyclic bisabolyl cation are probably localized in this compartment. Mutations in pocket II primarily inhibited the formation of bicylic compounds, suggesting that secondary cyclizations of the bisabolyl cation are catalyzed in pocket II.

Monitoring OH-Initiated Oxidation Kinetics of Isoprene and Its Products Using Online Mass Spectrometry

A novel technique has been developed to simultaneously monitor the kinetics of the OH radical-initiated oxidation of isoprene and formation and oxidation of its products (methyl vinyl ketone, methacrolein, 3-methylfuran, and formaldehyde) using online mass spectrometry. The kinetics of isoprene and its products were investigated at 323 K and at 1 atm total pressure. The responses of 30 representative ions for isoprene and its products were monitored during the reaction, and their concentration profiles were calculated by linear algebraic equations, which resolve the measured mass spectra of representative ions into the responses of individual target organics, and by calibrations, which converted the responses to individual target concentrations. Using this method, yields of methyl vinyl ketone, methacrolein, and 3-methylfuran at 323 K were measured to be 14.4+/-0.1%, 19.0+/-0.2%, and 2.9+/-0.2%, respectively, in excellent agreement with previously reported yields under NOx-free conditions. The reaction kinetics of isoprene and its oxidation products measured by the experimental procedure developed in this study were compared with those estimated by a kinetic model of isoprene oxidation. The observed methacrolein concentrations as a function of time were reproduced reasonably well by this model, while the observed methyl vinyl ketone concentration could be reproduced by including secondary reactions of some of the hydroperoxide products of isoprene oxidation. The observed 3-methylfuran concentrations could be reproduced using secondary cyclization reactions of some of the 1,4-hydroxycarbonyl products of isoprene oxidation. These results suggest that under low NOx conditions reactions of some of the hydroperoxides and hydroxycarbonyls produced from the OH-initiated oxidation of isoprene may be a significant source of methyl vinyl ketone and 3-methylfuran in the atmosphere.

Are acylphloroglucinols lead structures for the treatment of degenerative diseases?

In recent years a widespread interest in the antidepressant activity of Hypericum perforatum L. has attracted much activity in investigating metabolites from the Guttiferae, many of which are biologically active compounds with an acylphloroglucinol moiety. A common background in the traditional uses of plants belonging to Guttiferae family is their wound healing properties which has been connected to the established antimicrobial activities of the phloroglucinols present. These metabolites share a common acylated 1,3,5-trihydroxy-benzene core of polyketide origin which undergoes alkylation processes. Polycyclic polyprenylated acylphloroglucinols feature a highly oxygenated and densely substituted bicyclo[3.3.1]nonane-1,3,5-trione core appended with prenyl or geranyl side chains. Secondary cyclizations involve the β-diketone and pendant olefinic groups affording adamantanes, homoadamantanes, dihydrofurano- or pyrano- fused structures. These products are claimed to possess antioxidative, antiviral and antimitotic properties. Increasing interest is related to their function in the CNS as modulators of neurotransmitters associated with neuronal damage and depression.

Heterologous Expression and Characterization of a “Pseudomature” Form of Taxadiene Synthase Involved in Paclitaxel (Taxol) Biosynthesis and Evaluation of a Potential Intermediate and Inhibitors of the Multistep Diterpene Cyclization Reaction

The diterpene cyclase taxadiene synthase from yew (Taxus) species transforms geranylgeranyl diphosphate to taxa-4(5),11(12)-diene as the first committed step in the biosynthesis of the anti-cancer drug Taxol. Taxadiene synthase is translated as a preprotein bearing an N-terminal targeting sequence for localization to and processing in the plastids. Overexpression of the full-length preprotein in Escherichia coli and purification are compromised by host codon usage, inclusion body formation, and association with host chaperones, and the preprotein is catalytically impaired. Since the transit peptide-mature enzyme cleavage site could not be determined directly, a series of N-terminally truncated enzymes was created by expression of the corresponding cDNAs from a suitable vector, and each was purified and kinetically evaluated. Deletion of up to 79 residues yielded functional protein; however, deletion of 93 or more amino acids resulted in complete elimination of activity, implying a structural or catalytic role for the amino terminus. The pseudomature form of taxadiene synthase having 60 amino acids deleted from the preprotein was found to be superior with respect to level of expression, ease of purification, solubility, stability, and catalytic activity with kinetics comparable to the native enzyme. In addition to the major product, taxa-4(5),11(12)-diene (94%), this enzyme produces a small amount of the isomeric taxa-4(20),11(12)-diene (∼5%), and a product tentatively identified as verticillene (∼1%). Isotopically sensitive branching experiments utilizing (4R)-[4-2H1]geranylgeranyl diphosphate confirmed that the two taxadiene isomers, and a third (taxa-3(4),11(12)-diene), are derived from the same intermediate taxenyl C4-carbocation. These results, along with the failure of the enzyme to utilize 2,7-cyclogeranylgeranyl diphosphate as an alternate substrate, indicate that the reaction proceeds by initial ionization of the diphosphate ester and macrocyclization to the verticillyl intermediate, followed by a secondary cyclization to the taxenyl cation and deprotonation (i.e., formation of the A-ring prior to B/C-ring closure). Two potential mechanism-based inhibitors were tested with recombinant taxadiene synthase but neither provided time-dependent inactivation nor afforded more than modest competitive inhibition.

Synthesis of N,N-Dialkylaniline-2′-deoxyuridine Conjugates for DNA-Mediated Electron Transfer Studies

Syntheses of two analogs of deoxyuridine with N,N-dialkylaniline chromophores are reported. 5-[3-(N-methylphenylamino)propanoyl]-2′-deoxyuridine (1) and 5-[2-(4-N,N-dimethylaminophenyl)ethyl)]-2′-deoxyuridine (2) are prepared by palladium-mediated coupling. Preparation of 2 was facilitated by in situ transient O4-trimethylsilyl protection during alkynylation which suppressed secondary cyclization of the coupling adduct.

Low-Temperature Route to 1, 2-Benzoylenebenzimidazole Ladder Structure

Low-temperature catalytic conversion of N-( o-aminophenyl)phthalamic acid (I) was studied as a model reaction for the synthesis of ladder poly(aroylenebenzimidazole)s. The treatment of I with acetic anhydride/pyridine or trifluoroacetic anhydride resulted in the selective and quantitative cyclodehydration to yield either imide or isoimide structures respectively. The imidization was accompanied by acylation of the ortho amino group to form lateral acetamide or trifluoroacetamide substitutes. Thermodynamically unstable N-( o-trifluoroacetamidophenyl)phthalisoimide (III) underwent secondary cyclization to yield ladder 1, 2-benzoylenebenzimidazole (V) between 130 and 150 °C. The conversion of this reaction did not exceed 35% because it competed with the thermal isomerization of III to the stable N-( o-trifluoroacetamido-phenyl)phthalimide (IV). The cyclization of N-( o-trifluoroacetamidophenyl)phthalisoimide (III) was found to be possible even at room temperature. The formation of 30–35% of the ladder 1, 2-benzoylene-benzimidazole (V) was observed after III was dissolved in DMF and stored at room temperature for 4–10 h. This also was accompanied by the catalytic isoimide-to-imide isomerization. The obtained data may be useful for the further development of novel low-temperature approaches to the synthesis of ladder poly(aroylenebenzimidazole)s. Synthesis of aromatic polyimides and polyisoimides with lateral alkylamide or trifluoroalkylamide from available aromatic dianhydrides and tetraamines may also be of practical interest.

Spontaneous cyclodehydration ofN-(o-aminophenyl) amic acids

The model reaction between phthalic anhydride and 1,2-diaminobenzene was studied under conditions analogous to those of the low-temperature polycondensation of aromatic dianhydrides with bis(o-diamines) in amide solvents followed by thermal cyclodehydration in condensed state to form ladder polyimidazopyrrolones (polypyrrones). The intermediate N-(o-aminophenyl)phthalamic acid was found to undergo spontaneous cyclodehydration to give N-(o-aminophenyl)phthalimide and 2-(o-carboxy-phenyl)benzimidazole. The reaction occurred at ambient temperature in the presence of water or alcohol without using a dehydration agent. The yield of imide-amine and/or carboxy-benzimidazole depended on the temperature of the condensation reaction. Temperatures below 0°C appeared to favor the formation of the carboxy-benzimidazole. Thermal cyclization of N-(o-aminophenyl)phthalamic acid passed through the same intermediates: imide-amine and carboxy-benzimidazole. The former converted to corresponding pyrrone above 200°C, while the secondary cyclization of the latter started above 250°C. Spontaneous cyclodehydration was also observed for polyamide acid-amine precursors obtained by low-temperature polycondensation of pyromellitic dianhydride with 3,3′-diaminobenzidine. The prepolymer solutions in DMF diluted with water at room temperature turned to a gel after 48–72 h. A spectroscopic study of the resulting polymers indicated the presence of significant amounts of imide cycles. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 67: 609–619, 1998

Spontaneous cyclodehydration of N-(o-aminophenyl) amic acids

The model reaction between phthalic anhydride and 1,2-diaminobenzene was studied under conditions analogous to those of the low-temperature polycondensation of aromatic dianhydrides with bis(o-diamines) in amide solvents followed by thermal cyclodehydration in condensed state to form ladder polyimidazopyrrolones (polypyrrones). The intermediate N-(o-aminophenyl)phthalamic acid was found to undergo spontaneous cyclodehydration to give N-(o-aminophenyl)phthalimide and 2-(o-carboxy-phenyl)benzimidazole. The reaction occurred at ambient temperature in the presence of water or alcohol without using a dehydration agent. The yield of imide-amine and/or carboxy-benzimidazole depended on the temperature of the condensation reaction. Temperatures below 0°C appeared to favor the formation of the carboxy-benzimidazole. Thermal cyclization of N-(o-aminophenyl)phthalamic acid passed through the same intermediates: imide-amine and carboxy-benzimidazole. The former converted to corresponding pyrrone above 200°C, while the secondary cyclization of the latter started above 250°C. Spontaneous cyclodehydration was also observed for polyamide acid-amine precursors obtained by low-temperature polycondensation of pyromellitic dianhydride with 3,3′-diaminobenzidine. The prepolymer solutions in DMF diluted with water at room temperature turned to a gel after 48–72 h. A spectroscopic study of the resulting polymers indicated the presence of significant amounts of imide cycles. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 67: 609–619, 1998