Catalytic Dendrophanes as Enzyme Mimics: Synthesis,Binding Properties,Micropolarity Effect,and Catalytic Activity of Dendritic Thiazolio-cyclophanes

Catalytic dendrophanes 9 and 10 were prepared as functional mimics of the thiamine-diphosphate-dependent enzyme pyruvate oxidase, and studied as catalysts in the oxidation of naphthalene-2-carbaldehyde ( 4 ) to methyl naphthalene-2-carboxylate ( 8 ) (Scheme 1). They are composed of a thiazolio-cyclophane initiator core with four generation 2 (G-2) poly(etheramide) dendrons attached. The two dendrophanes were synthesized by a convergent growth strategy by coupling dendrons 11 and 12 , respectively (Scheme 2) with (chloromethyl)-cyclophane 42 (Scheme 5) and subsequent conversion with 4-methylthiazole (Scheme 7). The X-ray crystal structures of cyclophane precursors 30 (Scheme 3), 37 , and 38 (Scheme 5) on the way to dendrophanes were determined (Fig. 1). The crystal-structure analysis of the benzene clathrate of 37 revealed the formation of channel-like stacks by the cyclophane which incorporate its morpholinomethyl side chain and the enclathrated benzene molecule (Fig. 2). The interactions of the enclathrated benzene molecule with the phenyl rings of the two adjacent cyclophane molecules in the stack closely resemble those between neighboring benzene molecules in crystalline benzene (Fig. 3). The characterization by MALDI-TOF-MS (Fig. 4), and ¹H- and ¹³C-NMR spectroscopy (Fig. 5) proved the monodispersity of the G-2 dendrophanes 9 and 10 with molecular weights up to 11500 Da (for 10 ). ¹H-NMR and fluorescence binding titrations in H₂O and aqueous MeOH showed that 9 and 10 form stable 1 : 1 complexes with naphthalene-2-carbaldehyde ( 4 ) and 6-(p-toluidino)naphthalene-2-sulfonate ( 48 , TNS) (Tables 1 and 2). The evaluation of the fluorescence emission maxima of bound TNS revealed that the dendritic branching creates a microenvironment of distinctly reduced polarity at the cyclophane core by limiting its exposure to bulk solvent. Initial rate studies for the oxidation of naphthalene-2-carbaldehyde to methyl naphthalene-2-carboxylate in basic aqueous MeOH in the presence of flavin derivative 6 revealed only a weak catalytic activity of dendrophanes 9 and 10 (Table 3), despite the favorable micropolarity at the cyclophane active site. The low catalytic activity in the interior of the macromolecules was explained by steric hindrance of reaction transition states by the dendritic branches.     

On the oxidation of N-methyl and N-benzylpyrimidin-2- and -4-ones by rabbit liver aldehyde oxidase

The presence of a methyl or benzyl group at N-1 or N-3 of 2- and 4-pyrimidone does not affect the site of oxidation by rabbit liver aldehyde oxidase. From all substrates studies only one product viz. the corresponding N-1 or N-3 substituted uracil has been obtained. The maximum rates of oxidation by free enzyme show an optimum in the pH range 6.5–7.8, which is little influenced by the site and the size of the N-substituent. Application of immobilized enzyme in small scale synthesis gives 1- or 3-R-uracils (R = methyl, benzyl) in 43–78% yield.     

Catalytic Cyclophanes. Part IX. A Thiazolio-cyclophane as Model for Pyruvate Oxidase and One-Pot Synthesis of Aromatic Esters by Electrochemical Oxidation of Aldehydes Mediated by Bis(coenzyme) Catalysis

Macrocycle 3 with a hydrophobic cavity and an appended thiazolium ring is prepared following a novel synthetic sequence to monofunctionalized cyclophanes. Although the thiazolium ring of 3 prefers to be located in the cyclophane cavity, it could be displaced with low energetic costs by benzene and naphthalene guests which form stable 1:1 inclusion complexes with 3 in protic solvents. Initial rate studies show that 3 is a pyruvate-oxidase mimic and catalyzes the oxidation of aromatic aldehydes to carboxylic acids in aqueous solution. Cyclophane 3 also catalyzes the conversion of aromatic aldehydes to the corresponding esters in alcoholic solvents. The supramolecular catalyst 3 exhibits enzyme-like saturation kinetics, large turnover numbers, as well as high reaction and substrate selectivity, and it is far superior to the non-macrocyclic catalysts 4 and 5 which lack a substrate binding site. Following cyclic voltammetric investigations of the redox behavior and stability of thiazolium ions, a new one-pot electrochemical synthesis of aromatic esters is developed: Aromatic esters are prepared efficiently by indirect electrochemical oxidation of the corresponding aldehydes in alcoholic solvents, mediated by two coenzymes, the thiazolium ions 3 or 5 and flavin 21 . At the extraordinarily low working electrode potential of ?300 mV (vs. Ag/AgCl), high yields of the esters are obtained with high current efficiencies and high turnovers of the catalysts which are stable under the reaction conditions. The origin of the substrate and reaction selectivity, which is particularly pronounced in the supramolecular reactions catalyzed by 3 , is analyzed.     

Synthesis of methyl derivatives of uronic acids. I. Synthesis of methyl (methylα-D-galactopyranosid)uronate and its 2-, 3-, and 4-O-methyl ethers

Alternative unidirectional methods for synthesizing methyl (methyl α-D-galactopyranosid)uronate and its mono-O-methyl ethers by the oxidation (with CrO₃-H₂SO₄-acetone) of the corresponding methyl O-benzyl-O-methyl-α-D-galactopyranosides having unsubstituted 6-OH groups to the corresponding methyl O-benzyl-O-methyl-α-D-galactouronic acids followed by esterification with CH₂N₂ and the catalytic hydrogenolysis of the benzyl groups are proposed.     

Flavinyl peptides. I. Synthesis of flavinyl-aromatic amino acids

The syntheses of flavinyl peptides, in which L-tryptophan, L-tyrosine, or L-phenylalanine are attached via peptide linkage to the isoalloxazine system with ω-carboxyalkyl groups in position 3 or 10, are described. Lumiflavin was carboxymethylated by known methods to yield N-3-carboxymethyllumiflavin. Oxidation of 10-ω-hydroxyhexyl-, 10-ω-hydroxypentyl-, 10-ω-hydroxybutyl-, and 10-formylmethylflavins gave the corresponding 10-ω-carboxyalkylflavins. The 10-ω-carboxyethylflavin was obtained by condensation of 2-amino-4,5-dimethyl-N-ω-carboxyethylaniline with alloxan. Activations of the carboxyl group of the flavins were achieved with N,N′-carbonyldiimidazole and p-nitrophenyltrifluoroacetate to form the corresponding acyl imidazoles and p-nitrophenyl esters. 10-Carboxymethylflavin was hydrogenated to form 10-carboxymethyldihydroflavin and activated by carbodiimide. Reaction of the carboxy-activated flavins with the appropriate amino acid methyl esters, followed by air oxidation in the case of dihydroflavin, gave the corresponding flavinyl peptides. Interaction of the flavin with aromatic amino acids results in a broadening of the visible flavin absorption towards the green, without the appearance of discrete new maxima, and in quenching of the flavin fluorescence. The fluorescence efficiency increases with increasing numbers of methylene groups in the flavin side chain. The nonlinear dependency of fluorescence quenching versus number of methylene groups indicates that different types of intramolecular interactions are involved.     

Modification of Cyclodextrins for Use as Artificial Enzymes

The magical powers of enzymes have been attributed to their ability to bind specific substrates and catalyze reactions of the bound substrate. Artificial enzymes synthetically mimic the binding and the catalytic site to produce molecules that are not only smaller in size but also potentially have similar activity to the real enzymes. The main objective of our research is to create artificial redox enzymes by using cyclodextrins as binding sites and attaching flavin derivatives as the catalytic site. We have developed a strategy to attach a catalytic site to cyclodextrin exclusively at the 2-, 3- or the 6-position. The evaluation of the artificial enzyme in which flavin is attached to the 2-position gives a 647-fold acceleration factor. Although this is modest compared to those of real enzymes (which can have acceleration factors of a trillion), the artificial enzymes allow us to understand the elements that contribute to the incredible catalytic power of enzymes.     

BLUE AND ULTRAVIOLET-B LIGHT PHOTORECEPTORS IN PARSLEY CELLS

Abstract— Ultraviolet-B (UV-B) and blue light photoreceptors have been shown to regulate chalcone synthase and flavonoid synthesis in parsley cell cultures. These photoreceptors have not yet been identified. In the present work, we studied UV-B photoreception with physiological experiments involving temperature shifts and examined the possible role of flavin in blue and UV-B light photoreception. Cells irradiated with UV-B light (0.5–15 min) at 2°C have the same fluence requirement for chalcone synthase and flavonoid induction as controls irradiated at 25°C. This is indicative of a purely photochemical reaction. Cells fed with riboflavin and irradiated with 6 h of UV-containing white light synthesize higher levels of chalcone synthase and flavonoid than unfed controls. This effect did not occur with blue light. These results indicate that flavin-sensitization requires excitation of flavin and the UV-B light photoreceptor. The in vivo kinetics of flavin uptake and bleaching indicate that the added flavin may act at the surface of the plasma membrane. In view of the likely role of membrane-associated flavin in photoreception, we measured in vitro flavin binding to microsomal membranes. At least one microsomal flavin binding site was solubilized by resuspension of a microsomal pellet in buffer with high KPi and NaCl concentrations and centrifugation at 38000 g. The 38000 g insoluble fraction had much greater flavin binding and contained a receptor with an apparent K_D of about 3.6 μM and an estimated in vivo concentration of at least 6.7 × 10–⁸M. Flavin mononucleotide, roseoflavin, and flavin adenine dinucleotide can compete with riboflavin for this binding site(s), although each has lower affinity than riboflavin. Most microsomal protein was solubilized by resuspension of the microsomal pellet in non-denaturing detergents and centrifugation at 38 000 g ; however, this inhibited flavin binding, presumably because of disruption of the environment of the flavin receptor. The parsley microsomal flavin binding receptor(s) have a possible role in physiological photoreception.     

Selective aerobic oxidation of alcohols catalyzed by iron chloride hexahydrate/TEMPO in the presence of silica gel

An environmentally friendly and efficient process whereby FeCl₃?6H₂O/2,2,6,6‐tetramethylpiperidine N‐oxyl (TEMPO)‐catalyzed oxidation of alcohols to the corresponding aldehydes and ketones is accomplished in the presence of silica gel using molecular oxygen or air as the terminal oxidant. The electron‐deficient benzyl alcohol was smoothly oxidized to the corresponding aldehydes with up to 99% isolated yield. It was found that silica gel not only could enhance the catalytic reaction rate but also increase the selectivity for the product. The high performance of FeCl₃?6H₂O/TEMPO catalyst system in the presence of silica gel might be attributed to the surface silanol groups. UV–visible spectra analysis showed that the Fe (III)–TEMPO complex could serve as the active intermediate species in the present catalytic system. A plausible mechanism of the catalytic system is proposed. Copyright © 2012 John Wiley & Sons, Ltd.     

A versatile synthesis of 4,5‐dihydropyrrolo[1,2‐a]quinoxalines

The reaction of 1‐(2‐aminophenyl)pyrrole with aromatic or heteroaromatic aldehydes in ethanol and catalytic amounts of acetic acid leads to 4,5‐dihydropyrrolo[1,2‐a]quinoxalines in high yields. When aliphatic aldehydes were used under the same conditions, a slow oxidation to the corresponding pyrrolo[1,2‐a]quinoxalines can occur; the oxidation can be avoided by preparing in situ the 5‐acetyl derivatives of the 4,5‐dihydropyrrolo[1,2‐a]quinoxalines.     

Direct Oxidation of β‐Aryl Substituted Aldehydes to α,β‐Unsaturated Aldehydes Promoted by an o‐Anisidine–Pd(OAc)2 Co‐catalyst

An o‐anisidine‐Pd(OAc)₂ catalytic system for the direct co‐catalytic Saegusa oxidation of β‐aryl substituted aldehydes to α,β‐unsaturated aldehydes has been developed. The use of o‐anisidine in place of (S)‐diphenylprolinol made the process more simply and cost‐effective. The process not only features the use of unmodified aldehydes rather than enol silyl ethers, but also gives moderate to good yields (44–72 %).     

Pronounced Catalytic Activity of Manganese(III)–Schiff Base Complexes in the Oxidation of Alcohols by Tetrabutylammonium Peroxomonosulfate

A novel and practical catalytic method for efficient and highly selective oxidation of a wide range of benzylic, allylic, aliphatic, primary, and secondary alcohols to the corresponding aldehydes and ketones using tetrabutylammonium peroxomonosulfate catalyzed by tetradentate Schiff base–Mn^III complexes has been developed. Electron‐deficient and hindered alcohols required longer reaction times for oxidation in this catalytic system. The electron‐poor and hindered salicylidene ring of the ligand enhanced the catalytic activity and stability of Mn catalysts. The desired turnover numbers obtained in the oxidation reactions indicated the high efficiency and relative stability of these simple Schiff base complexes in this catalytic system.     

Coordination Booster‐Catalyst Assembly: Remote Osmium Outperforming Ruthenium in Boosting Catalytic Activity

Presented herein is a set of bimetallic and trimetallic “coordination booster‐catalyst” assemblies in which the coordination complexes [Ru^II(terpy)₂] and [Os^II(terpy)₂] acted as boosters for enhancement of the catalytic activity of [Ru^II(NHC)(para‐cymene)]‐based catalytic site. The boosters accelerated the oxidative loss of para‐cymene from the catalytic site to generate the active catalyst during the oxidation of alkenes and alkynes into corresponding aldehydes, ketones and diketones. It was found that the boosting efficiency of the [Os^II(terpy)₂] units was considerably higher than its congener [Ru^II(terpy)₂] unit in these assemblies. Mechanistic studies were conducted to understand this unique improvement.     

Catalytic photooxidation of 4-methoxybenzyl alcohol with a flavin-zinc(II)-cyclen complex

Flavin-zinc(II)-cyclen 10 contains a covalently linked substrate binding site (zinc(II)-cyclen) and a chromophore unit (flavin). Upon irradiation, compound 10 effectively oxidizes 4-methoxybenzyl alcohol (11-OCH3) to the corresponding benzaldehyde both in water and in acetonitrile. In the presence of air, the reduced flavin 10-H2 is reoxidized, and so catalytic amounts of 10 are sufficient for alcohol conversion. The mechanism of oxidation is based on photoinduced electron transfer from the coordinated benzyl alcohol to the flavin chromophore. This intramolecular process provides a much higher photooxidation efficiency, with quantum yields 30 times those of the comparable intermolecular process with a flavin chromophore without a binding site. For the reaction in buffered aqueous solution a quantum yield of Phi = 0.4 is observed. The turnover number in acetonitrile is increased (up to 20) by high benzyl alcohol concentrations. The results show that the covalent combination of a chromophore and a suitable binding site may lead to photomediators more efficient than classical sensitizer molecules.     

Synthesis of novel thiophene‐based chiral ligands and their application in asymmetric Henry reaction

Novel chiral thiolated amino alcohols were synthesized from norephedrine and thiophene carbaldehydes (methyl‐ or ethyl‐substituted) and applied to the catalytic asymmetric Henry reaction of various aldehydes with nitromethane to provide β‐hydroxy nitroalkanols in high conversion (92%). The reaction was optimized in terms of the metal, solvent, temperature and amount of chiral ligand. The corresponding catalyst with Cu(OTf)₂ and 2‐propanol as the solvent provided the best enantioselectivities (up to 96% ee) of the corresponding nitroalcohols for aliphatic aldehydes. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of methyl derivatives of uronic acids II. Synthesis of the 2,3-, 2,4-, and 2,4-di- and 2,3,4-tri-O-methyl ethers of methyl (methylα-D-galactopyranosid) uronate

Unidirectional methods are proposed for the synthesis of the 2,3-, 2,4-, and 3,4-di-, and 2,3,4-tri-O-methyl ethers of methyl (methyl α-D-galactopyranosid) uronate by the oxidation (CrO₃-H₂SO₄-acetone) of the corresponding methyl O-benzyl-O-methyl-α-D-galactopyranosides having unsubstituted 6-OH groups to the corresponding (methyl O-benzyl-O-methyl-α-D-galactosid) uronic acids followed by esterification with CH₂N₂ and catalytic hydrogenolysis of the benzyl groups.     

An organoantimony nitrate complex with azastibocine framework as water tolerant Lewis acid catalyst for the synthesis of 1,2-disubstitued benzimidazoles

A novel organoantimony complex of 6-cyclohexyl-6,7-dihydrodibenzo[c,f] [1,5]azastibocin-12(5H)-yl nitrate ( 2 ) was synthesized and systematically characterized by techniques such as NMR spectra, TG-DSC, and X-ray diffraction. It was found that the complex 2 exhibits relatively strong Lewis acidity (3.3 < Ho ≤ 4.8) and could be employed as a water tolerant Lewis acid catalyst for the synthesis of synthetically valuable benzimidazole derivatives starting from aldehydes and arylenediamines. This catalytic system shows excellent tolerance toward a wide variety of functional groups, such as methyl, methoxyl, fluoro, chloro, bromo, nitro, cyan, trifluoromethyl, 1-naphthaldehyde, furfural and n-butyl, together with facile reusability in 5 times scale enlarged synthesis.     

Zur Kenntnis der Reaktionsfähigkeit des Thiomorpholins und alkylsubstituierter Thiomorpholine, 4. Mitt.

Thiomorpholine as well as alkyl substituted thiomorpholines and their Sdioxides, respectively, are transformed into the corresponding N-Aminothiomorpholines by nitrosation (1–5) followed by the reduction with zinc in acetic acid/acetic acid anhydride under simultaneous formation of the corresponding N-acetyl derivates, and hydrolysis by hydrochloric acid (6–9). Examples of this method are described. 4-Aminothiomorpholines and their Sdioxides react with aldehydes or ketones to give azomethines (10–31). Acylation with mono-and dicarbonic acid chlorides leads to the N-acyl derivatives32–44.Mannich condensation is also possible. By oxidation with yellow mercury oxide tetracenes are formed (46–47).

Teil der DissertationM. Schmitz, Techn. Hochschule Aachen, 1975.     

离子液体-水介质中离子液体负载TEMPO催化选择氧化合成脂肪醇羟基芳香醛和酮

由于脂肪醇羟基和苄醇羟基具有相同的氧化反应活性,所以当分子内同时含有脂肪醇羟基和苄醇羟基时,很难选择氧化苄醇羟基合成含脂肪醇羟基的芳香醛或酮。本文报道了在离子液体-水介质中,NCS/NaBr/IL-TEMPO（离子液体负载TEMPO）催化氧化合成含有脂肪醇羟基的芳香醛、酮的方法,反应条件温和,选择性好,收率高,且离子液体和催化剂可以循环使用。     

Chemosensors based on <Emphasis Type="Italic">N</Emphasis><Superscript>2</Superscript>-(anthracen-9-ylmethyl)-naphthalene-2,3-diamine

Condensation of N ²-(anthracen-9-ylmethyl)naphthalene-2,3-diamine with aromatic and heterocyclic aldehydes gave a series of the corresponding Schiff bases and N-(anthracen-9-ylmethyl)-substituted naphtho-[2,3-d]imidazoles. Study on the luminescence spectra and complexing ability of the condensation products revealed their sensor properties toward some heavy metal cations.     

Flavin-mediated photoreactions in artificial systems: a possible model for the blue-light photoreceptor pigment in living systems.

Abstract— The photoreduction of cytochrome c and the photostimulation of oxygen uptake were studied in solutions of flavin and cytochrome as a possible model system for similar photoreactions which have been observed in vivo. Light causes the photoreduction of the flavin. Under aerobic conditions the photoreduced flavin reacts with oxygen to form the superoxide anion which in turn can reduce cytochrome c. Dismutation of the superoxide anions forms hydrogen peroxide which mediates the dark oxidation of the photoreduced cytochrome. Superoxide formation and dismutation also account for the light-induced oxygen uptake. Action spectra confirm the role of flavin in the photoreduction of cytochrome c and the photostimulation of oxygen uptake. Under anaerobic conditions the photoreduced flavin reduces cytochrome c directly. In the presence of an electron donor only catalytic amounts of flavin are required. In the absence of an added electron donor flavin itself can act as the electron donor if substrate amounts are present. Azide inhibits all of these flavin-mediated photoresponses. Azide also inhibits the photoreduction of cytochrome b which occurs in the mycelium of Newospora.