Symmetrical Anhydrides Research Articles

Synthesis of fully protected peptides on a tetraethyleneglycol diacrylate (TTEGDA)-crosslinked polystyrene support with a photolytically detachable 2-nitrobenzyl anchoring group

1-Chloromethyl-2-nitro tetraethyleneglycol diacrylate (TTEGDA)-crosslinked polystyrene resin was prepared by nitration of chloromethyl (4%) TTEGDA-crosslinked polystyrene resin and used as a photosensitive solid support for the preparation of fully protected peptides. C-protected amino acid esters were attached to resin (1) using large excess of amino acid ester and equivalent amount of triethylamine (TEA). After estimation of first amino acid attachment, the stepwise synthesis of the peptides was carried out using the symmetric anhydride procedure. The fully protected peptides were cleaved from the support by photolysis. The crude product was purified on a silica gel column and characterised by amino acid analysis and tlc.

ChemInform Abstract: Nickel Boride Reduction of Symmetric and Mixed Anhydrides of Carboxylic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Preparation of 2-alkoxy-4-alkyl-5(4H)-oxazolones from mixed anhydrides of N-alkoxycarbonylamino acids.

A general procedure for the preparation of 2-alkoxy-4-alkyl-5(4H)-oxazolones (AlkOx's) from N-tert-butoxy-, N-benzyloxy- and N-(9-fluorenylmethoxy)-carbonylamino acids has been devised. Purified mixed anhydrides are prepared from the parent acid and isopropenyl chloroformate and left in chloroform (Boc) for 24 h or dimethylformamide (Z, Fmoc) for 0.5-2 h. Symmetrical anhydride that may originate from disproportionation or reaction of AlkOx with hydrolyzed product is partially removed by extracting the AlkOx into petroleum ether. The products contain 0.5-30% of symmetrical anhydride.

Orientation and bonding of benzoic acid, phthalic anhydride and pyromellitic dianhydride on Cu(110)

The interaction of the polyimide precursor pyromellitic dianhydride (PMDA), and the related compounds benzoic acid and phthalic anhydride, with Cu(110) has been studied by high resolution electron energy loss spectroscopy (HREELS). For benzoic acid, deprotonation of the carboxylic acid group occurs on adsorption leading to the formation of a surface benzoate species (C 6H 5COO-). Bonding to the surface occurs through a carboxylate linkage via two equivalent oxygen atoms. The HREEL spectrum is characterised by an intense dipole active band, the symmetric OCO stretching vibration, at ∼ 1420 cm −1. The plane of the carboxylate group is aligned perpendicular to the surface as is the plane of the benzene ring. A similar species is found following exposure of Cu(110) to phthalic anhydride. The carboxylate linkage results from disruption of the anhydride ring with loss of the CO character (C 6H 4COO-). In the case of the dianhydride species PMDA, only one of the anhydride units is used in bonding to the surface; the second unit points away from the surface and is characterised by the symmetric anhydride stretch at 1255 cm −1 and weak OO stretching vibrations at ∼ 1850 cm −1. In both cases, changes in the intensity of some of the bands compared with benzoic acid suggest that the carboxylate group is tilted away from the surface normal due to an interaction between one of the carbons of the aromatic ring and the copper surface. This implies that the plane of the aromatic ring is now twisted out of the plane of the carboxylate group and, although still perpendicular to the surface, the axis is tilted to allow one of the β-carbon atoms to interact with the surface. In all cases, off-specular measurements at a primary electron energy of ∼ 8 eV are dominated by the intense CH stretching vibration. Measurements of the intensity of this mode, in the surface benzoate species, as a function of incident electron energy suggest that excitation of this mode occurs via a resonance scattering mechanism.

Patent Evaluation : W0930121 I-: Peptide Technology Ltd: Peptides which abrogate TNF and/or LPS toxicity

Novelty: Novel peptides are disclosed which have the ability to abrogate TNF toxicity and/or LPS toxicity resulting from septicaemic shock induced by Gram-negative bacteria. The peptides are based primarily on residues 1 to 26 of human TNF. Compositions are claimed for the treatment of a large range of conditions associated with inflammation including viral and parasitic diseases, toxic shock, autoimmune disease, diabetes, etc.Biology: In a range of in vivo tests in mice the specified peptide (and analogues) prevented death in acute models of TNF lethality, inhibited both TNF and LPS-induced respiratory burst of human neutrophils and also inhibited the TNF-induced decrease in blood glucose levels. It did not however inhibit the desirable tumour regression effects showed by TNF.Chemistry: The peptides were synthesized by either standard FMOC solid-phase techniques, with coupling via either pentafluorophenyl or hydroxybenzotriazole esters, or by a BOC strategy using HOB+ or symmetrical anhydride coupling. Crude peptides were purified by reverse phase HPLC in a C4 or C18 column. Forty-seven sequences are given, the most active being Val-Arg-Ser-Ser-Ser-Arg-Thr-Pro-Ser-Asp-Lys-Pro-Val-Ala-His-Val-Val-Ala which corresponds to residues 1–18 of human TNF.

Efficient solid phase assembly of peptides bearing contiguous highly hindered Aib residues via Fmoc Aib fluoride

Fmoc-Aib-F shows superior efficiency for the introduction of Aib (α-aminoisobutyric acid) residues into a model peptide containing four adjacent Aib units in comparison with symmetrical anhydrides, UNCA's and activation by PyBroP. The Aib-rich sequence alamethicin acid has also been synthesized via Fmoc amino acid fluorides.

Solid-phase synthesis of [Ala1,3,11,15]-endothelin-1 by a modified double-coupling procedure.

[Ala1,3,11,15]-Endothelin-1, a linear analogue of endothelin-1 in which alanines replace the cystine residues, has been prepared by solid-phase synthesis in approximately 17% yield. Fmoc amino acids were coupled using an economical modified double-coupling (symmetrical anhydride followed by O-benzotriazolyl ester) procedure under fully automated conditions. Conditions for synthesis and purification were closely monitored and should be applicable to other endothelin analogues.

Studies on the disproportionation of mixed anhydrides of N-alkoxycarbonylamino acids.

Mixed anhydrides from Z-valine and ethyl, isobutyl, isopropyl and isopropenyl chloroformate, and from N-tert-butoxycarbonyl- (Boc) and N-benzyloxycarbonyl- (Z) leucine and phenylalanine and Boc- and N-9-fluorenylmethoxycarbonyl-valine and ethyl chloroformate were purified and left in dichloromethane at 23 degrees C. The symmetrical anhydride (SyAn) generated after 24 h was determined by normal phase high-performance chromatography. No SyAn was produced from the anhydrides of Z- and Boc-valine; SyAn was produced from the other anhydrides. Anhydrides examined without isolation generally produced more SyAn than the pure compounds. More SyAn was generated in dimethylformamide and tetrahydrofuran than in dichloromethane, or in the presence of an excess of N-methylmorpholine or triethylamine. The anhydride from isobutyl chloroformate was much more stable than the anhydride from ethyl chloroformate. It is suggested that disproportionation of pure mixed carboxylic acid--carbonic acid anhydrides occurs by a bimolecular mechanism.

A highly catalytic and selective conversion of carboxylic acids to 1-alkenes of one less carbon atom

An equimolar mixture of a carboxylic acid and acetic anhydride produces a reagent combination that undergoes a highly efficient decarbonylation/dehydration at 250[degrees]C using either Pd- or Rh-based catalyst systems, affording excellent yields of the corresponding 1-alkenes and one less carbon atom. The stoichiometric and catalytic decarbonylation of aliphatic aldehydes and acid chlorides to alkanes and alkenes, respectively, by transition-metal complexes are well-known and synthetically useful transformations. Relatively little, however, has been reported concerning the analogous decarbonylation/dehydration of aliphatic carboxylic acids to olefins, with generally poor results achieved in terms of catalyst efficiency and selectivity toward terminal olefin formation in the product. For example, the decarbonylation/dehydration of stearic acid to heptadecane using a Rh-based catalyst was reported to proceed with a maximum catalyst turnover number (TON; moles of olefin product formed per mole of catalyst used) of ca. 250, with selectivities toward 1-heptadecene formation typically below 50%. Interestingly, results were presented in this work which suggested that the decarbonylation of stearic acid proceeded via intermediate formation of stearic anhydride. Use of a preformed, symmetrical anhydride is not desirable from an economic or synthetic viewpoint, particularly since its decarbonylation should result in the formation of equal amounts of olefin and carboxylic acidmore » coproducts. The authors now report here that the use of a carboxylic acid substrate as an equimolar mixture with acetic anhydride (Ac[sub 2]O) produces a mixed anhydride system which undergoes an extremely facile decarbonylation reaction to provide a general and highly selective route to the corresponding 1-alkenes of one less carbon atom. 19 refs., 1 tab.« less

Carboxylic sulfonic mixed anhydrides: General utility and application to the synthesis of ceftazidime

A high-yielding acylation process which utilizes a mixed anhydride of the type RCO 2SO 2CH 3 for the synthesis of the cephalosporin ceftazidime is detailed. The mixed anhydride is conveniently prepared by addition of methanesulfonyl chloride to the triethylammonium salt of the acid 2a. Although known for some time, these anhydrides have not been used often in acylations. This lack of general utility is explained by side reactions, especially formation of the carboxylic symmetric anhydride in sterically unhindered systems.

Sequence Dependent Cyclization-Cleavage of Dipeptides from the Oxime Resin and Its Prevention

Abstract The rates of cyclization-cleavage of dipeptides with various sequences assembled on the Kaiser’s oxime resin were determined. cyclo(–Ala–Ala–) was liberated from the H–Ala–Ala–oxime resin with the apparent first-order rate constant, kapp, 1.8 × 10−1 min−1 under basic conditions. While cyclo(–Ala–Pro–) was much more rapidly formed (kapp = 1.5 min−1) from the H–Ala–Pro–resin, cyclo(–Ala–Val–) was produced with kapp, 2.2 × 10−2 and 5.5 × 10−2 min−1 from H–Ala–Val–resin and H–Val–Ala–resin, respectively. During the coupling reaction for tripeptides by the dicyclohexylcarbodiimide/1-hydroxybenzotriazole or the symmetrical anhydride method was observed significant loss of dipeptides by cyclization, which was successfully prevented by the [(benzotriazol-1-yl)oxy]tris(dimethylamino)phosphonium hexafluorophosphate (BOP) method except in the case of H–Ala–Pro–resin. In consequence of elucidating the defect and describing the method for the prevention, the reliability of the oxime resin was increased to be widely used in the practical synthesis of protected peptides.

Automated solid-phase peptide synthesis: Use of 2-(1 H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate for coupling of ert- butyloxycarbonyl amino acids

2-(1 H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) has been adapted for use as a coupling reagent for tert-butyloxycarbonyl (Boc) amino acids in automated solid-phase peptide synthesis. When compared to the existing preformed symmetrical anhydride procedure employing dicyclohexyl-carbodiimide (DCC), the use of TBTU in the presence of 1-hydroxybenzotriazol (HOBt) provides a more efficient coupling procedure for Boc-amino acid derivatives. Overall cycle times using TBTU HOBt coupling reagents (30 min) compare favorably to those of the DCC-mediated procedure (approx 65 min). Dimethyl-formamide can be used as the sole solvent for both activation and coupling reactions. Implementation of TBTU HOBt coupling conditions does not require replumbing of any lines of the Applied Biosystems Model 430 A instrument and necessitates changes to only three reagent bottle positions. The variable coupling efficiencies of Boc-asparagine following activation with TBTU HOBt (as low as 89%) can be overcome by protection of the amide function of Boc-asparagine with the 9-xanthyl group. Examples of the synthesis and characterization of a number of peptides ranging in length from 13 to 29 residues are given.

Prediction of liquid-liquid equilibria and of enthalpies of mixing in alkanoic acid anhydride + n-alkane mixtures using DISQUAC

Abstract Kehiaian, H.V., Gonzalez, J.A., Garcia, I., Escarda, R., Cobos, J.C. and Casanova, C, 1991. Prediction of liquid-liquid equilibria and of enthalpies of mixing in alkanoic acid anhydride + n -alkane mixtures using DISQUAC. Fluid Phase Equilibria, 69: 91-98. The liquid-liquid equilibrium (LLE) data from the literature on acetic anhydride + heptane and our molar excess enthalpies measured previously, H E , of butyric or heptanoic anhydrides + n -alkanes (hexane through tetradecane) are examined on the basis of the DISQUAC group-contribution model. These experimental data, along with structure-property relationships derived from the properties of related classes of carbonylic compounds, were used to estimate the interaction parameters for symmetrical or asymmetrical carboxylic acid anhydride [CH 3 (CH 2 ) u -1 -CO-O-CO-(CH 2 )[ v -1 CH 3 ] + alkane [CH 3 (CH 2 ) m -2 CH 3 ] mixtures. The anhydride (CO-O-CO group)/alkane (CH 3 or CH 2 groups) interaction parameters are the same for the anhydrides of all the carboxylic acids ( u, v > 1), except for acetic acid anhydride ( u, v = 1). The model describes consistently H E , LLE and the vapor-liquid equilibrium diagram of acetic anhydride + cyclohexane.

Synthesis of 1,3-diacylaminopropan-2-ols and corresponding 2-acyl derivatives as amide isosteres of natural lipids

N, N′-diacyl-1,3-diaminopropan-2-ols as amide isosteres of 1,3-diacylglycerols are obtained in 50–79% yields by treatment of 1,3-diaminopropan-2-ol with acid chlorides either in ether or THF in the presence of triethylamine and catalytic amounts of 4-dimethyl-aminopyridine. Subsequent acylation of the secondary alcohol function with a variety of carboxylic acids (e.g. fatty acids, N-protected amino acids, drug compounds) can be effected by various techniques (i.e. acid chlorides, symmetrical anhydrides, isopropenyl chloroformate) with yields ranging from 56% to 76%.

Reaction of thioxophosphorane sulfenyl bromides with ethyl vinyl ether: Mechanistic and synthetic aspects

The mechanistic and synthetic aspects of the addition reaction of thioxophosphorane sulfenyl bromide with ethyl vinyl ether were studied in detail by NMR techniques. It has been found that the regiospecific, primary product of the reaction, 1-bromo-1-ethoxy-2S(dialkoxythiophosphoryl)ethane I, is unstable and undergoes slow decomposition to give four compounds. The formation of thiophosphoryl derivatives, vinyl ethers II and III, aldehyde IV, and the symmetrical hemiacetal anhydride V, has been considered in terms of a carbocation intermediate. By choice of the appropriate reaction conditions, the aldehyde IV can be obtained in very high yield.

Lithium‐Salt Effects in Peptide Synthesis. Part I. Conditions for the Use of Lithium‐Salts in Coupling Reactions

AbstractThe influence of Li‐salts on the course of peptide‐coupling reactions was investigated. As a model for segment couplings, Ac‐Phe‐OH was coupled to HCl·H‐Ala‐OMe using the mixed anhydride, DCC1, DCCl/HOBt, BOP‐Castro and TBTU‐Knorr methods. As a model for stepwise synthesis Z‐Phe‐OH was coupled with HCl·Ala‐O(t‐Bu), using symmetrical anhydrides and active esters. The effects of salt additives such as LiCl, LiBr, LiC104, and ZnCl2 on yields, side‐product formation, racemisation, and reaction rates are reported.

Reaction rates for the production of selected hormones by solid-phase synthesis.

Reaction rates have been measured for the production of selected bradykinins, angiotensins, and endorphins by solid-phase synthesis. Reactor liquid concentrations are monitored by using a UV detector and flow cell. Experimentation has been limited to low excesses of the t-Boc amino symmetrical anhydride. More than 500 attachments have been monitored. Most data obtained from resins with 1% cross-linking show second-order behavior with reaction rate constants between 0.5 and 8 L/(mol.s). The reaction rate is affected by chemical structures of both the attached amino symmetrical anhydride and the anchored amino terminus on the peptide fragment. Increasing reaction temperature and initial solution concentrations promotes reaction rate. The structure of the polymer support affects not only the reaction rate but also the observed reaction kinetics.

Synthesis of glycosylated tuftsins and tuftsin‐containing IgG fragment undecapeptide

Syntheses are described of two new tuftsin derivatives containing a 2-acetamido-2-deoxy-D-galactopyranosyl unit alpha- or beta-glycosidically linked to the threonine's hydroxy side chain function and of the glycosylated undecapeptide corresponding to the tuftsin region of the heavy chain of IgG (amino acid sequence 289-299). The glycosylated tuftsins were synthesized by the solution procedure. Fmoc-[Gal NAc(Ac)3 alpha]Thr-OH and Fmoc-[GalNAc(Ac)3 beta]Thr-OH were allowed to react with H-Lys(Z)-Pro-Arg(NO2)-OBzl by the mixed anhydride procedure and the resulting glycosylated tetrapeptides were fully deblocked by catalytic hydrogenation followed by treatment with potassium cyanide, purified by ion exchange chromatography and characterized by analytical HPLC, elemental and amino acid analyses, optical rotation, and proton NMR spectroscopy. Synthesis of the glycosylated undecapeptide was achieved by the continuous flow solid phase procedure on 4-hydroxymethylphenoxyacetyl-norleucyl derivatized Kieselguhr-supported resin. Fmoc-amino acid symmetrical anhydrides or pentafluorophenyl esters, in the presence of N-hydroxybenzotriazole, were used as the acylating agents. To mimic the native sequence of the tuftsin region at the Fc-domain of immunoglobulin G a 2-acetamido-2-deoxy-beta-D-glucopyranosyl unit was N-glycosidically linked to the amide side chain of Asn 297. The glycosylated asparagine residue was introduced as N2-fluorenylmethyloxycarbonyl-N4-(2-acetamido-3,4,6-tri-O-acetyl-2 -deoxy-beta-D - glucopyranosyl)-asparagine pentafluorophenyl ester. After cleavage from the resin the glycopeptide was deprotected, purified by ion exchange chromatography, and characterized by analytical HPLC, amino acid analysis, high voltage electrophoresis, and proton NMR. The conformational features of the glyco-undecapeptide were determined by circular dichroism measurements both in water and in 98% trifluoroethanol. Results of biological assays will be published elsewhere.

Crystal structure of m-nitrobenzoic anhydride

The title compound (C14H8N2O7,M r =306.2) crystallizes in the orthorhombic space group Pbca witha=6.962(1).b=24.688(1), andc=15.890(1)A,V=2731.0 A3,D x =1.489 g·cm−3 forZ=8,μ=0.98 mm−1,F(000)=1296,T=293 K. FinalR=0.053 for 1873 observed reflections. The structure was solved by direct methods. Approximately planar molecules lie perpendicular to the [100] direction and show partial stacking. The structure is the first example of a symmetric anhydride which does not retain the symmetry in the crystal state. The two independent nitro groups twist out of the ring planes by 10.5 and 14.8°, respectively.

Folate analogs. 33. Synthesis of folate and antifolate poly-.gamma.-glutamates by [(9-fluorenylmethoxy)oxy]carbonyl chemistry and biological evaluation of certain methotrexate polyglutamate polylysine conjugates as inhibitors of the growth of H35 hepatoma cells

Representative examples of folate and antifolate poly-gamma-glutamyl metabolites were synthesized via the [(9-fluorenylmethoxy)oxy]carbonyl (Fmoc) chemistry using the KH polyamide resin. Polyglutamate yields were consistently better in all cases compared to the previous Merrifield method, and the crude products were obtained in greater than 85% purity. The symmetrical anhydride (7) derived from alpha-tert-butyl N-Fmoc-L-glutamate (6) was used for the initial coupling of the first glutamate residue to the KH resin and also for subsequent chain elongation. The alpha-tert-butyl protective groups were not labile under the conditions used for the cleavage of the finished peptide from the resin. A series of poly-gamma-glutamyl metabolites of methotrexate (MTX) with a chain length ranging from two to five glutamyl residues were synthesized and coupled with poly(L-lysine) having an average molecular weight of 27,000 and 52,000. Each conjugate was tested for its ability to inhibit the growth of wild type (H35) and MTX transport resistant (H35R) strains of hepatoma cells in culture, the latter having a 100-fold reduced sensitivity to MTX. 4-Amino-4-deoxy-N10-methylpteroylglutamyl-gamma-glutamylpoly (L-lysine) conjugate [MTX(G2)-poly-L-Lys-52000] and MTX(G4)-poly-L-Lys-52000 were among the most active (I50 = 8.0 and 10 nM against H35 cells) MTX-polylysines synthesized to date, and they were somewhat more inhibitory to the transport resistant cells. MTX(G5)-poly-L-Lys-52000 was approximately 1000 times more effective than MTX(G5)-poly-D-Lys-52000 in inhibiting the growth of H35R hepatoma cells in culture, indicating that internal cleavage of the gamma-glutamate chain of the conjugate with subsequent release of MTX or shorter chain polyglutamates of MTX is unlikely to be an important determinant of MTX-polyglutamate polylysine cytotoxicity. The results indicate that MTX-polyglutamate poly(L-lysine) conjugates are taken up by the cells independently of MTX and probably via endocytosis.