Ring-closing Step Research Articles

Synthesis of 14-Membered Ring Jaspamide Derivatives

Two synthetic approaches of simpler jaspamide derivatives were investigated. The ring closure step was attempted either by RCM or by macrolactonisation. 14-Membered ring derivatives 15-16 were prepared by final macrolactonisation using Yamaguchi reagent.

Improved Synthesis of Functional CTVs and Cryptophanes Using Sc(OTf)3 as Catalyst

Functional cyclotriveratrylene (CTV) and cryptophane derivatives are synthesized in the presence of scandium triflate [Sc(OTf)3]. This route allows the preparation of new derivatives that could not be prepared or easily obtained by using the previously reported experimental procedures. With a catalytic amount of scandium triflate (1% mol), CTVs were obtained with yields similar to or higher than those reported previously in reactions run under strong acidic conditions. Cryptophanes were also synthesized in fairly good yields by performing the ring-closure step in the presence of a stoichiometric amount of Sc(OTf)3. Interestingly, this novel approach strongly reduces the formation of side products and gives rise to novel functionalized molecules for the construction of supramolecular host-guest systems.

Dibenzotetraaza Crown Ethers: A New Family of Crown Ethers Based on o-Phenylenediamine

Dibenzotetraaza (DBTA) crown ethers possess two o-phenylenediamine moieties. They are homologues of dibenzo crown ether phase-transfer catalysts and were prepared from the condensation of benzimidazoles with oligo(ethyleneglycol) dichlorides and oligo(ethyleneglycol) ditosylates. Compounds with ring sizes ranging from 18-crown-6 to 42-crown-14 were prepared. In addition, various altered benzimidizoles were used to produce DBTA crown ethers with modified substituents and ether bridges, as well as benzimidazolidine crown ethers. The synthetic approach presented here proved to be a convenient route to a new family of crown ethers with overall yields of up to 48% based on the benzimidazole. Yields for the ring-closing step were generally high, ranging from 51% to 94%, without the need for high-dilution conditions. Reaction of the DBTA crown ethers with alkyl and benzyl halides was found to be a facile way to obtain the corresponding tetra(N-organyl) compounds. Picrate extraction studies were carried out to determine phase-transfer catalytic capabilities. Extraction efficiencies for alkali-metal ions were lower than those for dibenzo-18-crown-6. Efficiencies were higher for other metal ions, with some selectivity for Pb(2+). Tetra(N-methyl) DBTA-18-crown-6 generally exhibited higher extraction efficiencies than its N-H analogue, but the selectivity was lower.

Advantages of the Ns group in the reactions of N1-SO 2R inosines with benzylamine and with 15NH 3

The reactivity of N 1-alkylsulfonyl- and N 1-arylsulfonyl-2′,3′,5′-tri- O-acetylinosine with benzylamine and with 15NH 3, regarding the attack on C2, has been shown to be in the order CF 3SO 2 (Tf) > 2,4-(NO 2) 2C 6H 3SO 2 (DNs) ⩾ 4-NO 2C 6H 4SO 2 ( pNs) ≈ C 6F 5SO 2 (PFBs) > 2-NO 2C 6H 4SO 2 (Ns) ≫ CH 3SO 2 (Ms) > 4-CH 3C 6H 4SO 2 (Ts) > 2,4,6-(CH 3) 3C 6H 2SO 2 (Mts). In spite of its intermediate reactivity, the Ns group is the most appropriate, since in this case the formation of by-products is minimised during the ring-opening and ring-closing steps of the process. Another advantage of the Ns group is thus disclosed.

Exploring Two-State Reactivity Pathways in the Cycloaddition Reactions of Triplet Methylene

Spin forbidden 1,2-cycloadditions of triplet methylene to alkenes have been theoretically studied as an example of the two-state reactivity paradigm in organic chemistry. The cycloadditions of triplet methylene to ethylene and the (E)- and (Z)-2-butene isomers show spin inversion after the transition state and therefore with no effect on the reaction rate. A local analysis shows that while triplet methylene addition to alkenes leading to the formation of a biradical intermediate is driven by spin polarization, the ring closure step to yield cyclopropane is a pericyclic process. We have found that at the regions in the potential energy surface where the spin crossover is likely to occur, the spin potential in the direction of increasing spin multiplicity, mu(+)(s), tends to equalize the one in the direction of decreasing spin multiplicity, mu(-)(s). This equalization facilitates the spin transfer process driven by changes in the spin density of the system.

Carboxylate-stabilised sulfur ylides (thetin salts) in asymmetric epoxidation for the synthesis of glycidic acids. Mechanism and implications

The reaction of carboxylate-stabilised sulfur ylides (thetin salts) with aldehydes and ketones has been investigated. Using both achiral and chiral sulfur ylides, good yields were obtained with dimsylsodium or LHMDS as bases in DMSO or THF-DMSO mixtures. However, the enantioselectivities observed with a camphor-based sulfide were only moderate (up to 67%). The reaction was studied mechanistically by independent generation of the betaine (via the hydroxyl sulfonium salt) in the presence of a more reactive aldehyde, which resulted in incorporation of the more reactive aldehyde and showed that betaine formation was reversible. Thus, the moderate enantiomeric excess observed is a consequence of the enantiodifferentiating step being the ring closure step rather than the betaine forming step. We had expected betaine formation might be non-reversible because a carboxylate-stabilised ylide has only slightly higher stability than a phenyl-stabilised ylide, which does largely react non-reversibly with aldehydes. Evidently, a carboxylate-stabilised ylide is significantly more stable than a phenyl-stabilised ylide and as such reacts reversibly with aldehydes.

Molecular dynamics studies of ground state and intermediate of the hyperthermophilic indole-3-glycerol phosphate synthase.

Indole-3-glycerol phosphate synthase catalyzes the terminal ring closure step in tryptophan biosynthesis. In this paper, we compare the results from molecular dynamics (MD) simulations of enzyme-bound substrate at 298, 333, 363, and 385 K and the enzyme-bound intermediate at 385 K, solvated in TIP3P water box with a CHARMM force field. Results from MD simulations agree with experimental studies supporting the observation that Lys-110 is the general acid. Based on its location in the active site during the MD simulations, Glu-210 warrants classification as the general base instead of the previously proposed Glu-159. We find that the relative population of the reactive enzyme-substrate Michaelis conformers [near attack conformers (NACs)] with temperature correlates well (correlation coefficient of 0.96) with the relative activity of this thermophilic enzyme. At higher temperature, the enzyme-substrate electrostatic interaction favors the binding of the substrate in NAC conformation, whereas, at lower temperature, the substrate is distorted and bound in a nonreactive conformation. This change is reflected in the approximately 1,100-fold increase in population of NACs at 385 K relative to 298 K. The easily determined population of NACs at given temperature tells much about the thermophilic property of the enzyme. Thus, the hyperthermophilic enzyme has evolved to have optimum activity at high temperatures, and, with lowering of the temperature, the electrostatic interaction at the active site is enhanced and the structure is deformed. This model can be regarded as a general explanation for the activity of hyperthermophilic enzymes.

Synthesis and characterization of multiply fused dehydrobenzoannulenoannulene topologies.

[reaction: see text] From a common precursor, two unusual dehydrobenzoannulene topologies have been synthesized utilizing either Pd-catalyzed or Cu-mediated oxidative homocoupling as the ring-closure step.

Crystallization and preliminary crystallographic data of SnoaL, a polyketide cyclase in nogalamycin biosynthesis.

Nogalonic acid methyl ester cyclase (SnoaL) catalyzes the last ring-closure step in the biosynthesis of the polyketide antibiotic nogalamycin. Crystals of a complex of SnoaL with the substrate nogalonic acid methyl ester have been obtained using PEG 4000 as precipitant. The crystals are orthorhombic, space group I222, with unit-cell parameters a = 69.1, b = 72.0, c = 65.4 angstroms. They diffract to 1.35 angstroms resolution using synchrotron radiation. A Matthews coefficient of 2.0 angstroms3 Da(-1) suggests one subunit in the asymmetric unit. Diffraction data for an isomorphous uranium derivative were collected and a difference Patterson map showed strong peaks which allowed determination of the position of the uranium ions.

Easy access to 4-nitrothiochroman S, S-dioxides via ring-enlargement from 3-nitrobenzo[ b]thiophene

The ( E)-2-aryl-1-[2-(methylthio)phenyl]-1-nitroethylenes 5 can easily be oxidized to the relevant sulfones 6 and effectively subjected to cyclization via an intramolecular Michael addition after metallation with lithium bis(trimethylsilyl)amide in THF. After quenching with ammonium chloride the 3-aryl-4-nitrothiochroman S, S-dioxides 2 are obtained as diastereomeric mixtures in good to excellent yields. Both yields and stereochemistry of the ring-closure step appear to be influenced by steric effects of the 3-aryl moiety. As sulfides 5 derive from an initial ring opening of 3-nitrobenzo[ b]thiophene ( 1 ), the overall 1 to 2 process can be considered as an effective 5 to 6 ring enlargement of the sulfur heterocycle. A conformational 1H NMR and molecular-mechanics investigation on the isolated diastereomeric 2 has also been accomplished.

Computational Study of the Ground State of Thermophilic Indole Glycerol Phosphate Synthase: Structural Alterations at the Active Site with Temperature

Hyperthermophlic indole-3-glycerol phosphate synthase (IGPS) catalyzes the terminal ring-closure step in tryptophan biosynthesis. In this paper, we compare the results from the molecular dynamics (MD) simulation of enzyme-bound substrate at 298 K (E.S298) and 385 K (E.S385) solvated in the TIP3P water box using the CHARMM force field to address the question of the structural change of the Enzyme. Substrate complex with temperature. The population of the reactive Enzyme. Substrate conformers (near attack conformers or NACs) increases by approximately 1100-fold in going from room temperature (E.S298) to high temperature (E.S385). This increased population of NAC conformers in the Michaelis complex correlates well with the increase in rate in going from 298 to 385 K. The positioning of the two active site residues Lys53 and Lys110 controls binding of the substrate in the favorable orientation for general acid-catalyzed intramolecular ring formation reaction. It can be concluded that the NAC formation allowing general acid catalysis has much to do with the temperature dependence of the free energy of reaction.

Influence of substitution on kinetics and mechanism of ring transformation of substituted S-[1-phenylpyrrolidin-2-on-3-yl]isothiuronium salts.

Twelve new substituted S-(1-phenylpyrrolidin-2-on-3-yl)isothiuronium bromides and twelve corresponding 2-imino-5-(2-phenylaminoethyl)thiazolidin-4-ones have been prepared and characterised. Kinetics and mechanism of transformation reaction of S-[1-(4-methoxyphenyl)pyrrolidin-2-on-3-yl]isothiuronium bromide and its N,N-dimethyl derivative 5a into corresponding substituted thiazolidin-4-ones 2a and 6a have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and sodium hydroxide solutions (0.005-0.5 mol l(-1)) at 25 degrees C and at I= 1 mol l(-1) under pseudo-first-order reaction conditions. The kinetics observed show that the transformation reaction is subject to general acid-base, and hydroxide ion catalyses. Acid catalysis does not operate in the transformation of 1a; the rate-limiting step of the base-catalysed transformation is the decomposition of bicyclic tetrahedral intermediate In(+/-) and the Brønsted dependence is non-linear (pK(a) approximately 9.8). In the case of derivative 5a both base and acid catalyses make themselves felt. In the base catalysis, the rate-limiting step consists of the decomposition of bicyclic intermediate In, and the Brønsted dependence is linear (beta = 0.9; pK(a) > 11.5). The acid-catalysed transformation of 5a also proceeds via the intermediate In, and the reaction is controlled by diffusion (alpha approximately equal to 0). With compound 5a in triethylamine and butylamine buffers, the general base catalysis changes into specific base catalysis. The effect of substitution in aromatic moiety of compounds 1a-h and 3a-h on the course of the transformation reaction has been studied in solutions of sodium hydroxide (0.005-0.5 mol l(-1)) at 25 degrees C by the stopped-flow method. The electron-acceptor substituents 4-NO(2) and 4-CN do not obey the Hammett correlation, which is due to a suppression of cross-conjugation in the ring-closure step of the transformation reaction.

Total Synthesis of an Atropdiastereomer of RP‐66453 and Determination of Its Absolute Configuration.

A convergent synthesis of all S-configurated diastereoisomer of RP-66453 (aS,S,S,S,S,S), a peptide secondary metabolite, has been developed. The synthesis is notable for its brevity, partly because functionalized amino acids can be used directly. By combination of chem. evidence and NMR data, the abs. configuration of RP-66453 was detd. to be (aR,S,S,S,S,S). It is interesting to note that nature created RP-66453 with a thermodynamically less stable atropisomer, while lab. synthesis using intramol. Suzuki-Miyarura coupling as the last ring-closure step produced the thermodynamically more stable isomer. [on SciFinder (R)]

Total synthesis of an atropdiastereomer of RP-66453 and determination of its absolute configuration.

A convergent synthesis of all S-configurated diastereoisomer of RP-66453 (aS,S,S,S,S,S), a peptide secondary metabolite, has been developed. The synthesis is notable for its brevity, partly because functionalized amino acids can be used directly. By combination of chem. evidence and NMR data, the abs. configuration of RP-66453 was detd. to be (aR,S,S,S,S,S). It is interesting to note that nature created RP-66453 with a thermodynamically less stable atropisomer, while lab. synthesis using intramol. Suzuki-Miyarura coupling as the last ring-closure step produced the thermodynamically more stable isomer. [on SciFinder (R)]

Synthesis of 1,3‐Difunctionalized Cyclopentenes and 1,3,5‐Trifunctionalized Cyclohexanes by Silicon‐Induced Domino Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Quantitative formation of [2]catenanes using copper(I) and palladium(II) as templating and assembling centers: the entwining route and the threading approach.

Transition metal-mediated templating and self-assembly have shown powerful potentials for the synthesis of interlocked molecules. These two strategies were combined in designing and preparing a new type of coordination catenanes incorporating Cu(I) and Pd(II) metal centers. The ligand designed here contains a phenanthroline core and pyridine sidearms (compound 1). Using this phenanthroline-pyridine conjugated ligand, two approaches were examined, which were shown to be surprisingly efficient for the catenane synthesis: the entwining route (entwining of two ligands around Cu(I) followed by Pd(II) clipping) and the threading approach (Cu(I)-templated threading of a cyclic ligand on an acyclic ligand followed by the Pd(II) clipping of the second ring). In the former method, stepwise treatment of 1 with Cu(CH(3)CN)(4)PF(6) (templating center) and enPd(NO(3))(2) (assembling center) gives rise to the quantitative formation of CuPd(2) catenane 18. In the latter method, Cu(I) templates the threading of phenanthroline-containing macrocycle 2 on ligand 1, which is followed by Pd(II) clipping to give hetero catenane 20. In both approaches, the formation of catenanes is convincing thanks to the strong templating effect of Cu(I), while the ring closure steps are efficiently furnished by Pd(II)-directed self-assembly.

A theoretical study of the mechanisms and regiochemistry of the reactions of 5-alkoxyoxazole with thioaldehydes, nitroso compounds, and aldehydes.

A theoretical study based on B3LYP/6-31G calculations has been applied to the mechanisms and regiochemistry of reactions of 5-alkoxyoxazole with thioaldehydes, nitroso compounds, and aldehydes. All three reactions adopt similar mechanisms, which start with Diels-Alder (DA) reactions, followed by either a novel, concerted ring-opening-ring-closing (RORC) step to transfer the DA adduct to 2-alkoxycarbonyl-3-thiazoline and 2-alkoxycarbonyl-3-oxazoline for thioaldehydes and aldehydes, respectively, or stepwise ring-opening and ring-closing steps to generate 1,2,4-oxadiazoline for nitroso compounds. The reactions of 5-alkoxyoxazole with thioaldehydes and nitroso compounds can be conducted under thermal reaction conditions due to the 10 kcal/mol activation barriers for their rate-determining DA reactions. By contrast, the reaction of 5-alkoxyoxazole with aldehydes cannot take place under thermal conditions, since this bimolecular reaction has the rate-determining RORC transition state higher than the reactants by 30.5 kcal/mol.

Interaction of [RuIII(edta)(H2O)]– with amino acids in aqueous solution. Equilibrium, kinetic and protease inhibition studiesElectronic supplementary information (ESI) available: kinetic plots and a scheme showing the reaction between [RuIII(edta)(H2O)]– and cysteine. See http://www.rsc.org/suppdata/dt/b2/b208495n/

The interaction of [RuIII(edta)(H2O)]− (edta = ethylenediaminetetraacetate) with amino acids, viz. glycine, L-cysteine and S-methylcysteine, was investigated potentiometrically and kinetically. The concentration distribution of various complex species was evaluated as a function of pH. Kinetic data obtained as a function of [amino acid], temperature (5.0 to 45.0 °C) and pressure at a fixed pH of 6.0, reveal that the formation of [RuIII(edta)(Am)]− (Am = amino acid) occurs via a rapid amino acid concentration dependent complex-formation reaction of [RuIII(edta)(H2O)]−, followed by a slow amino acid concentration independent ring-closure step. The kinetic data and activation parameters are interpreted in terms of an associative interchange mechanism and discussed in reference to data reported for closely related systems in the literature. Enzyme inhibition studies revealed that [RuIII(edta)(H2O)]− effectively inhibits the cysteine protease activity in papain and bromalein enzymes.

A Chemoenzymatic Synthesis of the Styryllactone (+)‐Goniodiol from Naphthalene.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Metathesis of Olefin-Substituted Pyridines: The Metalated NCN-Pincer Complex in a Dual Role as Protecting Group and Scaffold Part of this work was presented at the 14th International Symposium on Olefin Metathesis, Boston, August 2001

Pincer-palladium(II) and -platinum(II) cat- ions, YCY-M (YCY (2,6-(YCH2)2C6H3) ;Y NMe2, SPh; M Pd II ,P t II ), bound to diolefin-substituted pyridines (3,5- or 2,6-substitution) were successfully synthesized, and subsequently used in olefin meta- thesis (RCM) as a model study for template-directed synthesis of macrocycles. Especially a 3,5-disubstitut- ed pyridine bound to a NCN-Pt II -center (5a) gave a fast metathesis reaction, while the same reaction with the Pd II analogue (4a) was much slower and less selective (isomerization products were formed). Fur- thermore, it was found that 2,6-diolefin-substituted pyridines (4b, 5b, 5c) gave slow metathesis reactions, which is mainly ascribed tosteric hindrance during the ring-closing step. In all cases where prolonged reaction times were required an isomerization pro- cess, most likely assisted by cationic pincer-M II species, was observed as a competing reaction. 1 HN MR spectroscopy experiments revealed that pyridines are stronger bound to a cationic NCN-Pt II -center than toits Pd II -analogue. This aspect is of crucial importance when these pincer-pyridine complexes are applied in metathesis, since free pyridine in solution deactivates the Ru-metathesis catalyst. For the tem- plated construction of macrocycles, a strong M-N(py) bond is also important since it determines the selectivity for the desired product. In addition, these results open a new research field in which organo- metallic (pincer) complexes are used as protecting groups for strong Lewis-basic groups in catalysis. From failed attempts to prepare macrocycles using hexakis(SCS-Pd II -(1a)) complex 14, and from the results obtained with the monometallic pincer com- plexes in RCM, it can be concluded that the most suitable candidate for constructing macrocycles should comprise 2,6-diolefin-substituted pyridines bound to a multi-(NCN-Pt II )-template. In such a system, intrapyridine metathesis (steric hindrance) as well as isomerization reactions (strong M-N(py) bond) are suppressed.