Multi-functionalized chiral crown ethers as enzyme models for the synthesis of peptides. Multiple chiral recognition in the enzyme model

A novel approach to the enzyme model for the synthesis of peptides has been established by using multi-functionalized chiral crown ethers as hosts. The new strategy consists of three key steps as follows. (1) Guest assembly: the host having one free thiol and one thioester withN-protected-amino acid or peptide proceeds via rapid intra-complex thiolysis of-amino acid ester salts to form the dithioester, and assembles two guests. (2) Amide formation: the intramolecular aminolysis occurs between the bound guests to form the amide bond. (3) Peptide chain elongation: as the thiol reactive group is regenerated, the above two reactions are repeated to elongate the peptide chain. In the present paper, we describe the multiple chiral recognition that could be achieved by the chiral crown ether in both the intra-complex thiolysis and the intramolecular aminolysis. For explanation of the chiral recognition, we propose a likely structure for the intermediate of the aminolysis.     

Biomimetic studies using artificial systems. IV. Biomimetic peptide synthesis by using multifunctionalized crown ethers as a novel enzyme model. A new concept in mimicking of enzyme-catalyzed bond-forming reactions

A novel approach to the mimicking of enzyme-catalyzed bond-forming reactions has been examined using multifunctionalized chiral crown ethers. In addition to the 18-crown-6 moiety as a binding site, the host have one thiol and one thio ester with an N-protected alpha-amino acid or a peptide, and have successfully achieved peptide synthesis in an enzyme-mimetic reaction mode. This new method involves the following three key reactions. (1) Intra-complex thiolysis: the host carries out the rapid intra-complex thiolysis of alpha-amino acid ester salts to form the dithioester, corresponding to the assembly of two guests by the host. (2) Amide formation: intramolecular aminolysis occurs between the bound guests to form the amide bond. (3) Peptide chain elongation: as the thiol reactive group is regenerated, the above two reactions are repeated to elongate the peptide chain. Formal turnover of the enzyme model has been demonstrated by the synthesis of a tetrapeptide derivative by the repetition of the above processes.     

Ion–molecule reactions between organometallic ions and crown ethers in the gas phase

Ion–molecule reactions of the metal-containing ions LM⁺ (L = (acac)₂, acac, C₆H₆, C₅H₅; M = In, Ga, Co, Fe, Ni, Cr, Mn, Pd, Rh, Tl, La, Pr, Yb, Nd) with crown ethers in the gas phase were studied. Two major reactions were observed: adduct formation and substitution of a metal atom ligand by a crown ether. The relative abundances of the two reactions depends on the ease with which the metal atom may be reduced. Ligand substitution can involve hydrogen rearrangements with loss of acetylacetone or cyclopentadiene for crown ethers having mobile H atom(s). The use of ion–molecule reactions in the structural characterization of crown ethers and transition metalcontaining ions is discussed.     

Regioselective SNAr reactions of substituted difluorobenzene derivatives: practical synthesis of fluoroaryl ethers and substituted resorcinols

In this Letter, we describe a practical and highly selective method for the preparation of fluoroaryl ethers and differentially substituted resorcinol derivatives. This synthetic strategy relies on a selective S_NAr of substituted difluorobenzene derivatives with various alcohols.     

1,3-Dipolar cycloaddition reactions. Regioselective synthesis of heterocycles and theoretical studies

We report a 1,3-dipolar cycloaddition reaction between a oxazolium 5-oxide derivative with chloroacrylonitrile or ethyl propiolate as dipolarophiles, in order to obtain substituted pyrrolizidines. Experimentally we found that the reaction is regiospecific with chloroacrylonitrile and regioselective with ethyl propiolate. The secondary attractive orbital interactions from the Frontier Molecular Orbital Theory, the differences in stability of the possible biradical intermediaries postulated for the reaction and some hindrance effects, explain the regioselectivity observed experimentally.     

Anilinopyrylium salts. Their synthesis and conversion to other heterocyclic systems

Two methods for the preparation of anilinopyrylium salts are described. The conversion of these salts to pyrans, pyridines, and nitrobenzenes is discussed. Azepines, benzimidazoles, and benxotriazoles are readily obtained from the o-aminoanilinopyrylium salts.     

Spectroscopic studies of the interaction between crown ethers and organic nitriles

The interaction of 18-crown-6 (18C6), diaza-18-crown-6 (DA18C6), and dithia-18-crown-6 (DT18C6) with acetonitrile and malononitrile was investigated using infrared spectroscopy, 1H and 13C NMR spectroscopy, and molecular modeling. The interaction between 18C6 and the nitriles involves hydrogen bonding between the CH3/CH2 protons of the nitriles and the ether oxygens of the crown. In contrast, the interaction between the organic nitriles and DA18C6 involves the nitrogen of the nitrile group and the N-H groups of the crown. Due to the bulkiness of the sulfur atoms of DT18C6, no interaction was observed to occur between acetonitrile and the crown.     

Complexation and transport of amino acid esters and their salts with synthesised chiral novel aza crown ether derivatives

The syntheses of four aza-15-crown-5 ethers bearing phenyl and phenoxymethyl moieties attached to a stereogenic centre on the crown ring were achieved. Macrocycles have exhibited strong binding ability (K_a = 5364–12,969 M^? 1) and modest enantiomeric discrimination towards the enantiomers of amino acid methyl ester salts by UV titration method in CHCl₃ at 25°C. Computer modelling results supported experimental data providing a detailed understanding of the molecular recognition mode between hosts and guests and the likely binding sites involved. Macrocycles were used for chiral discrimination of amino acids in their zwitterionic forms or as potassium and sodium salts in transport experiments across a bulk chloroform membrane with satisfactory selectivity.     

Desorption electrospray ionization reactions between host crown ethers and the influenza neuraminidase inhibitor oseltamivir for the rapid screening of Tamiflu

Competitive host-guest chemistry on a desorption electrospray ionization mass spectrometry (DESI MS) platform is presented here as the basis for a rapid and quantitative screening method for assessing the quality of Tamiflu capsules with minimal sample preparation. Oseltamivir, the active ingredient in Tamiflu, is an orally active neuraminidase inhibitor antiviral. The high cost and demand for this drug has made it a target for counterfeiters, and reports of counterfeit Tamiflu capsules have already appeared. This urges the development of rapid and sensitive tools for Tamiflu authentication. The method presented here is based on the selective recognition of oseltamivir by crown ethers added to the DESI spray solvent. Crown ethers with various ring sizes were evaluated, all being observed to form stable host-guest complexes with protonated oseltamivir. The relative gas phase stability of each of the host-guest complexes was assessed and the results compared with dispersion-corrected density functional theory. Competive experiments with various pairs of crown ethers were used to assess the relative binding selectivities for oseltamivir. The abundance ratio of the formed complexes was observed to be dependent on the amount of analyte present on the surface of the sample, and independent of DESI geometric factors. These competitive reactions were then successfully tested as a means for the rapid quantitation of oseltamivir by reactive DESI MS without the need for an internal standard.     

Aminopentadiene imines from zincke salts of 3-alkylpyridines. Application to a synthesis of pyridinium salts from amino acids

The reaction of Zincke salts with primary amines to give pyridinium salts generally requires rather elevated temperature to go to completion (50-100 degrees C). It is shown that the addition of 1 equiv of a secondary amine allows formation, at ambient temperature, of intermediate aminopentadiene imine salts which can be isolated and were found to cyclize in acidic medium to give pyridinium salts at temperatures which do not exceed 50 degrees C. If this process has a tendency to give lower yields of pyridinium salt than the standard Zincke procedure, it can be advantageous in some cases, as illustrated by the synthesis of pyridinium salts from amino acids, a challenging reaction which does not work starting from Zincke salt in the absence of diethylamine. More generally, the reaction can be extended to primary amines featuring polar functions, as exemplified by a pyridinium salt synthesis (75 degrees C) in 55% yield from l-carnosine.     

Design and synthesis of novel water-soluble amino acid derivatives of chlorin p6 ethers as photosensitizer

Eight new water-soluble amino acid derivatives of chlorin p₆ ethers 6a-h were designed and synthesized using purpurin-18 (2) as key intermediate. All target compounds exhibited better phototoxicity than talaporfin and the most phototoxic compound 6d showed IC₅₀ values of 0.20 μmol/L against A549 cell and 0.41 μmol/L against B16-F10 cell, which represented 31- and 24-fold increase of PDT antitumor efficacy compared to talaporfin.     

Umpolung reactivity of difluoroenol silyl ethers with amines and amino alcohols. application to the synthesis of enantiopure alpha-difluoromethyl amines and amino acids

Difluoroenol silyl ethers, produced in situ from acylsilanes and CF3TMS, react as electrophiles with amines to give difluoroimines, via the corresponding hemiaminal adduct, as evidenced by 19F NMR spectroscopy. Reaction with (R)-phenylglycinol led to 2-difluoromethyloxazolidines. After separation of the diastereomers, reduction with LAH and Strecker-type synthesis gave enantiopure alpha-difluoromethylamines and alpha-difluoromethyl-alpha-amino acids, respectively.     

Sterically crowded azulene-based dication salts as novel guests: synthesis and complexation studies with crown ethers and calixarenes in solution and in the gas phase

The 1,4-bis(3-guaiazulenylmethylium)benzene and 1,4-bis[1-(4,6,8-trimethylazulenylmethylium)]benzene dication salts were synthesized via an acid-catalyzed condensation/dehydration protocol with guaiazulene-terephthalaldehyde (2 : 1 ratio), and 4,6,8-trimethylazulene-terephthalaldehyde (2 : 1 ratio) respectively in one-pot processes. A similar condensation reaction with the parent azulene led to an insoluble oligomer that was shown by MALDI-TOF-MS to contain 1,4-bis[(diazulenyl)methylium]benzene as a repeating unit. Dication salts and were fully characterized by 2D NMR and NOE techniques and by electrospray-MS (ES-MS) and MALDI-TOF-MS. NMR studies confirm that the dications are best represented as bis-tropylium species. A delicate balance of electronic (inductive stabilization) and steric influence of the alkyl groups on the seven-membered ring seems to influence the chemo-/regioselectivity of the co-condensation process. NMR titration and T(1) measurements established that, despite its highly crowded structure, dication forms host-guest HG complexes with dibenzo-30-crown-10 (DB30C10) and dibenzo-24-crown-8 (DB24C8) in solution, but fails to complex with the smaller dibenzo-18-crown-6 (DB18C6). The corresponding HG cation-molecule cluster ions were also detected in the gas phase by ES-MS, showing the formation of both dication-crown 1 : 1 and 1 : 2 complexes. Similar complexation of dication salt with DB30C10 was observed via NMR titration and T(1) measurements in solution and by ES-MS in the gas phase. Although solution complexation studies (NMR titration) did not indicate stable complex formation between and p-tert-butyl-methoxycalix[8]arene, their [HG](2+) and [H(2)G](2+) clusters were detectable by ES-MS. Solution decomplexation experiments (HG(2+) --> H + G(2+)) were performed on -crown complex by addition of DMSO, acetone, silver tosylate, and tropylium cation salt. Complexation of with DB30C10 was also studied by microcalorimetric titration.     

Electrical conductivity of liquid and film polymer composites filled with anion-radical salts in the presence of crown ethers

In the example of alkali metal tetracyanoquinodimethanides (M⁺TCQDM), a study has been made of the influence of resonance charge exchange on the conductivity () of polymer composites filled with anion-radical salts. When neutral molecules TCQDM⁰ are introduced into such systems, this leads to an increase in as a result of the lower activation energy of jumps between states TCQDM and TCQDM⁰. The addition of molecules of crown ethers has an analogous effect: They favor the appearance in the polymer matrix (the same as in solution) of TCQDM molecules in different charge states (TCQDM⁰, TCQDM) with migration of the cation within the limits of ternary associates (CE...M⁺...A) that are formed in systems for which the ratio of the crown ether cavity diameter to the cation diameter 1.4. Symbaticity has been found in the dependences of the electrical conductivity of films and the limiting mobility of solutions with the same composition on the parameter .Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 25, No. 4, pp. 446–452, July–August, 1989.