Symmetrical Anhydrides Research Articles

Sterically hindered C(alpha, alpha)-disubstituted alpha-amino acids: synthesis from alpha-nitroacetate and incorporation into peptides.

The preparation of sterically hindered and polyfunctional C(alpha,alpha)-disubstituted alpha-amino acids (alpha alpha AAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine (DIEA) in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gives the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic acid or hydrogen over Raney Ni gives the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The first synthesis of an orthogonally protected, tetrafunctional C(alpha,alpha)-disubstituted analogue of aspartic acid, 2,2-bis(tert-butylcarboxymethyl)glycine (Bcmg), is described. Also, the sterically demanding C(alpha,alpha)-dibenzylglycine (Dbg) has been incorporated into a peptide using solid-phase synthesis. It was found that once sterically congested Dbg is at the peptide N-terminus, further chain extension becomes very difficult using uronium or phosphonium salts (PyAOP, PyAOP/HOAt, HATU). However, preformed amino acid symmetrical anhydride couples to N-terminal Dbg in almost quantitative yield in nonpolar solvent (dichloroethane-DMF, 9:1).

ChemInform Abstract: A Convenient Method for Synthesis of Symmetrical Acid Anhydrides from Carboxylic Acids with Trichloroacetonitrile and Triphenylphosphine.

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.

The effect of microwave irradiation on carbodiimide-mediated esterifications on solid support

The esterification of a polymer-supported alcohol (PS Wang resin) with benzoic acid was investigated using microwave irradiation. Activation of the carboxylic acid was carried out using diisopropylcarbodiimide, either via the O-acylisourea or symmetrical anhydride protocols. In the microwave-assisted solid-phase coupling using the O-acylisourea method the main product of the reaction was 1-benzoyl-1,3-diisopropylurea, formed by rearrangement of the thermolabile isourea intermediate. On the other hand, significant rate enhancements were observed for the coupling of benzoic anhydride to Wang resin using microwave flash heating in 1-methyl-2-pyrrolidone as solvent. Reaction times were reduced from 2 to 3 days using conventional conditions, to 10 min by microwave dielectric heating.

A Convenient One-Pot Synthesis of Thiol Esters from Disulfides using a Zn/AlCl3 system

A novel synthetic procedure for the direct preparation of thiol esters from various disulfides and symmetrical anhydrides using a Zn/AlCl3 system is described.

Fatty acid terminated polyanhydrides

A systematic study on the synthesis, characterization, degradation, and drug release of fatty acid terminated poly(sebacic acid) (PSA) is reported. Fatty acid terminated sebacic acid polymers were synthesized by melt condensation of acetate anhydrides of linear fatty acids (C8–C18) and sebacic anhydride oligomers to yield waxy off-white materials. Polymers with molecular weights (Mw) in the range of 9,000 and 5,000 were obtained for the 10% and 30% (weight ratio) containing fatty terminals, respectively. Up to about 30% of fatty acid terminals, the final product is mainly fatty terminated polymer with up to about 5% w/w of the symmetric fatty anhydride. Increasing amounts of fatty acid acetate anhydride in the polymerization mixture had little effect on the polymer molecular weight up to a ratio of 40 : 60 (fatty acid acetate : sebacic acid oligomer) which remains in the range of 5,000–8,000. Above this ratio the molecular weight dropped to a level of 2,000–3,000 and the percent of the symmetric anhydride increased to 10–40%. The fatty terminals had little effect on PSA melting point and crystallinity. However, the fatty terminals had a significant effect on the polymer degradation and drug release rate. PSA with 30% w/w of C14–C18 terminals degraded and released the incorporated drug for more than 4 weeks as compared with 10 days for the acetate-terminated PSA. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 3337–3344, 1999

Amino acid derivatives of 2-R-7-hydroxy-3′,4′-ethylenedioxyisoflavones

A number of 7-O-aminoacyl derivatives of isoflavones have been obtained by the interaction of 2-R-7-hydroxy-3′,4′-ethylenedioxyisoflavones with the symmetrical anhydrides of N-protected amino acids.

Coupling difficulty following replacement of Tyr with HOTic during synthesis of an analog of an EGF B-loop fragment.

During Fmoc synthesis of an analog, [Abu HOTic]hEGF(20-31), of a fragment, Cys-Met-Tyr-Ile-Glu-Ala-Leu-Asp-Lys-Tyr-Ala-Cys, of the B-loop of human EGF, conductivity measurements showed that increased time was necessary for coupling and complete deprotection of the residues Met and Abu which followed the HOTic. Use of different active esterforming reagents, including HOBt and BOP, did not increase the yield. Use of symmetrical anhydride with extended coupling time increased the yield but did not complete the coupling. It appears that inclusion of HOTic in place of Tyr to introduce conformational constrain to peptide analogs can cause or augment a tendency towards conformations with increasing occlusion of N-terminal amino groups and result in the need for altered coupling strategies for completion of analog synthesis.

Esterification of 9-fluorenylmethoxycarbonyl-glycosylated serine and cysteine derivatives with an hydroxymethyl resin.

Esterification of glycosylated serine and cysteine derivatives with a 4-alkoxybenzyl alcohol (Wang) resin is described. The classical methods of ester bond formation (symmetrical anhydride, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate [TBTU]/4-dimethylaminopyridine [DMAP] with or without 1-hydroxybenzotriazole [HOBT], pentafluorophenyl [Pfp] esters gave high percentages of racemization of the glycosylated serine or cysteine residues. To reduce the D-amino acid content, we found that the best results were obtained with the highly efficient MSNT reagent (2,4,6-mesitylenesulfonyl-3-nitro-1,2,4-triazolide), which gave a high yield of substitution of the resin and the lowest percentage of racemization. A difference in behavior was observed between the two amino acids. The glycosylated cysteine derivative always gave lower racemization than the analogous glycosylated serine.

Polymeric adsorbents with peptide pendants as artificial receptors for β-lactam antibiotics by mimicking the binding sites of β-lactamases

A series of polymeric adsorbents with peptide pendants were designed as the artificial receptors of β-lactam antibiotics by mimicking the structures of binding site in β-lactamases. Crosslinked poly(N, N-dimethyl acrylamide) gel as a carrier was prepared by suspension copolymerization of N, N-dimethyl acrylamide and N. Ń-bisacryl-diaminoethane and then functionalized with ethylenediamine after partial hydrolysis. Using solid-phase peptide synthesis with symmetrical anhydride of protected amino acid step by step, various peptide pendants were respectively anchored onto the functionalized carrier. The adsorption properties of these peptide-containing adsorbents for β-lactam antibiotics such as ampicillin and cefotaxime were then studied. The results showed that only those adsorbents in which peptide chains contained more than one lysine residues could obviously adsorb both β-lactams and that static interaction as well as hydrogen bond played an important role during the adsorption.

Solid‐Phase Total Synthesis of Cyclosporine Analogues

AbstractSyntheses of cyclosporine analogues are reported wherein the peptide couplings were achieved in solid phase. The Wang resin was used as the solid support, and the peptide couplings commenced with the residue 11 of the cyclosporine skeleton. The couplings proceeded in a stepwide manner up to the residue MeBmt1, using symmetric anhydrides. The peptides were then cleaved off the resin, and the cyclization was achieved in solution using Castro's reagent. The solid‐phase synthesis described herein offers a very efficient method for the rapid synthesis of structurally diverse cyclosporine analogues in small quantities. The biological activities of the synthetic cyclosporine analogues were evaluated in two in vitro assays, including the IL‐2 reporter gene assay and the cyclophilin binding assay. The structure‐activity relationship is discussed.

Refractive index change in photochromic diarylethene derivatives and its application to optical switching devices

The refractive index change of photochromic diarylethene derivatives in solid polymer was studied with a view to fabricating an optical switching device. The reaction time required for a symmetric diarylethene photochromic compound in a copolymer of fluoroethyl methacrylate and methyl methacrylate (film thickness: 10 μm) was 20–30 s when exposed to UV light (intensity: 5.3 mW cm −2 at 350 nm) to form a closed ring and about 10 s with visible light (intensity: 3.7 mW cm −2 at 500 nm) to form an open ring. The refractive index change at 1.30 μm, measured with a prism coupler, was 0.0005 per 10 wt.% of diarylethene photochromic compound. The iteration number of the photochromic reactions in the polymer film decreased in the following order: symmetric, asymmetric diarylethene and acid anhydride. We propose a new type of self-holding optical switch combining a heat stable photochromic material with silica planar lightwave circuits.

Evaluation of Carbodiimides Using a Competition Method

A competitive reaction of activated Boc-Ala-OH and Boc-Phe-OH with H-Leu-resin has been developed for assessing the relative efficiencies of different carbodiimides. This allowed a comparison of the efficiency of the carbodiimides N,N;′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide, N-tert-butyl-N′-methylcarbodiimide and N-tert-butyl-N′-ethylcarbodiimide. Comparable results were obtained when these reagents were used for the preformation of symmetrical anhydrides or of 1-hydroxybenzotriazole esters in situ. Differential incorporation was observed when asymmetrical carbodiimides were used for peptide bond formation by the direct carbodiimide procedure. © 1997 European Peptide Society and John Wiley & Sons, Ltd.

Evaluation of Carbodiimides Using a Competition Method

A competitive reaction of activated Boc-Ala-OH and Boc-Phe-OH with H-Leu-resin has been developed for assessing the relative efficiencies of different carbodiimides. This allowed a comparison of the efficiency of the carbodiimides N,N;′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide, N-tert-butyl-N′-methylcarbodiimide and N-tert-butyl-N′-ethylcarbodiimide. Comparable results were obtained when these reagents were used for the preformation of symmetrical anhydrides or of 1-hydroxybenzotriazole esters in situ. Differential incorporation was observed when asymmetrical carbodiimides were used for peptide bond formation by the direct carbodiimide procedure. © 1997 European Peptide Society and John Wiley & Sons, Ltd.

Evaluation of carbodiimides using a competition method.

A competitive reaction of activated Boc-Ala-OH and Boc-Phe-OH with H-Leu-resin has been developed for assessing the relative efficiencies of different carbodiimides. This allowed a comparison of the efficiency of the carbodiimides N,N'-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide, N-tert-butyl-N'-methylcarbodiimide and N-tert-butyl-N'-ethylcarbodiimide. Comparable results were obtained when these reagents were used for the preformation of symmetrical anhydrides or of 1-hydroxybenzotriazole esters in situ. Differential incorporation was observed when asymmetrical carbodiimides were used for peptide bond formation by the direct carbodiimide procedure.

Synthesis of some 5?-O-amino acid derivatives of uridine as potential inhibitors ofUDP-glucuronosyltransferase

In an attempt to develop potential inhibitors ofUDP-glucuronosyltransferase, some 5′-O-amino acid derivatives of uridine were synthesized. N-protectedL-amino acids were coupled at the 5′-O-position of 2′,3′-O-isopropylideneuridine by esterification employing the method of symmetrical anhydrides in presence of 4-dimethylaminopyridine, 5′-O-(N-benzyloxycarbonyl-O-tert.butyl-L-threonl)-2′3′-O-isopropylideneuridine (1), 5′-O-(N-tert.butyloxycarbonyl-O-benzyl-L-seryl)-2′,3′-O-isopropylideneuridine and (2), 5′-O-(N-tert.butyloxycarbonyl-L-valyl)-2′,3′-O-isopropylideneuridine (3), and 5′-O-(N-tert.butyloxycarbonyl-L-valyl)-2′,3′-O-isopropylideneuridine (4) were obtained in good yield after column chromatography on silica gel. The treatment of2 withTFA/CH2Cl2 (6:1) at room temperature for 30 min led to a selective removal of theBoc group without deblocking of the 2′,3′-O-isopropylidene group of uridine. Treatment of2 withTFA/H2O (5:1) at room temperature for 1 h, however, released bothBoc and 2′,3′-isopropylidene groups. TheZ group of1 was deprotected by catalytic hydrogenolysis over 10% Pd/C/ammonium formate.

A new colorimetric protecting group allowing deprotection under neutral conditions

A 4,4′-dimethoxytrityl derivative of the levulinyl group has been developed for protection of nucleophilic functionalities such as hydroxyl groups by reaction of its symmetrical anhydride. It can rapidly be removed under mild conditions using a hydrazine-pyridinium acetate based buffer at near neutral pH. This protecting group can be detected with high sensitivity at 513 nm ( ε = 78,600).

Synthesis of alpha-factor analogues containing photoactivatable and labeling groups.

Analogues of alpha-factor, Saccharomyces cerevisiae tridecapeptide mating pheromone (H-Trp-His-Trp-Leu-Gln-Leu-Lys-Pro-Gly-Gln-Pro-Met-Tyr-OH), containing both p-benzoyl phenylalanine (Bpa), a photoactivatable group, and 3-(mono- or di-iodo-4-hydroxyphenyl)propanoic acid (iodinated HPP) or biotin as a tag, were synthesized using solid-phase methodologies on a [phenylacetamido]-methyl (PAM) resin. Bpa was introduced into the peptides using Bpa-hydroxybenzotriazole active ester during peptide chain assembly. Biotinylated alpha-factor analogues were prepared by assembling the desired peptide on the resin, and then reacting a specific amino group either with the symmetrical anhydride of biotin or with biotin using BOP as the activating agent prior to anhydrous hydrogen fluoride cleavage. Iodinated HPP was incorporated by acylating free peptides with Bolton-Hunter reagent (3-[diiodo-4-hydroxyphenyl]propanoic acid hydroxysuccinimide ester) in N,N-dimethylformamide and borate buffer (pH 8.0) solutions. Purification of all peptides to 98% or greater homogeneity was accomplished by high-performance liquid chromatography on a reversed-phase mu-Bondapak C18 column with acetonitrile/water/trifluoroacetic acid as the mobile phase. All products were characterized by amino acid analysis and fast atom bombardment mass spectrometry. Two analogues, alpha-(diiodotyrosine)-His-Bpa-Leu-Gln-Leu-Arg-Pro-Gly-Gln-Pro-Nle-Tyr-O H, and epsilon-(diiodo-HPP)-Lys-His-Bpa-Leu-Gln-Leu-Arg-Pro-Gly-Gln-Pro-Nle-Tyr -OH, were one twentieth to one-fortieth as active as a alpha-factor, and exhibited approximately one order of magnitude lower affinity to the alpha-factor receptor. The results suggest that these two analogues are alpha-factor agonists and that they can be used as probes of the alpha-factor receptor.

Synthesis of Iodo-aryl-azido Adenosine Analogs as Affinity Ligands for Adenylyl Cyclase

Abstract Potential affinity probes for adenylyl cyclase were synthesized that take advantage of the enzyme's sensitivity to “P”-site-mediated inhibition by 2′,5′-dideoxyadenosine analogs and its tolerance for large 3′-ribose substitutions. We report the synthesis of a series of 3′-substituted 2′,5′-dideoxyadenosine analogs. The syntheses involved the intermediate formation of symmetric anhydrides that were then coupled to 2′,5′-dideoxyadenosine by base-catalyzed esterification at the 3′-ribose position.

Quantitative analysis of mixtures of symmetric and mixed anhydrides

HPLC and GC methods were developed for the determination of symmetrical and mixed anhydrides. Both symmetrical and mixed anhydrides and their respective acids were determined in a single reversed-phase HPLC run using acetonitrile-water as the mobile phase. GC was useful for the quantitative analysis of a mixture of mixed anhydrides symmetric anhydrides. Similar results were obtained from the HPLC and GC analyses of mixtures containing mixed anhydrides of fatty acids with benzoic acid and their corresponding symmetrical anhydrides and acids. These methods are useful in the investigation of anhydride chemistry, the routine analysis of raw materials and the quality control and purity determination of polymers and other compounds containing anhydrides.

Coupling N-Methylated Amino Acids Using PyBroP and PyCloP Halogenophosphonium Salts: Mechanism and Fields of Application

PyBroP (1) and PyCloP (2), two halotripyrrolidinophosphonium hexafluorophosphates, are peptide-coupling reagents highly efficient for coupling N-methylated amino esters, in contrast with PyBOP (3), the hydroxybenzotriazolyl analogue. These halogenophosphonium salts 1 and 2 are convenient (one-pot reactions) stable solids soluble in conventional solvents. Use of them gave an excellent peptide yield with essentially no epimerization. Activation with these reagents probably involves the formation of an (acyloxy)phosphonium, as shown in the case of 2,4,6-trimethylbenzoic acid activation. In the case of reagents 1 and 2, oxazolone and/or a symmetrical anhydride were intermediates which were rapidly aminolyzed. In contrast, the benzotriazolyl ester intermediate which was formed with PyBOP (3) was poorly reactive with N-methylated amino esters. PyBroP (1) and PyCloP (2) were less efficient in the coupling of some Boc-amino acids because of N-carboxyanhydride formation; this was particulary the case when Boc-Val-OH or Boc-MeVal-OH was coupled with MeVal-OMe