Ester Substitution Research Articles

Synthesis of mesoionic 1,2,4-triazolo[4,3-a]pyrimidin-5-ones and subsituted formamidines from diethyl (5-1-r-1h-1,2,4-triazol -3-yl)aminomethylenemalonates

Hetaryl-substituted aminomethylenemalonates obtained by the condensation of aminoazoles with 2-alkoxymethylenemalonates are commonly used for the synthesis of biologically active azolopyrimidines [1, 2]. However, cyclization of hetaryl-substituted aminomethylenemalonates to give azolopyrimidines often proceeds only at high temperature or under upon microwave activation [1] or by using special reagents [2]. In the present work, we found that brief heating of diethyl aminomethylenemalonates 1a and 1b in ethanol in the presence of sodium ethylate leads to the formation of mesoionic 1,2,4-triazolo[4,3-a]pyrimidin-5-ones 2a or 2b in high yield. This reaction does not occur upon heating aminomethylenemalonates 1a or 1b with tertiary aliphatic amines in ethanol at reflux. However, heating esters 1 with primary or secondary amines in ethanol or acetonitrile at reflux leads to nucleophilic substitution of the malonate ester and formation of amidines 3a-c in high yield.

Expedient, accurate methods for the determination of the degree of substitution of cellulose carboxylic esters: Application of UV–vis spectroscopy (dye solvatochromism) and FTIR

Two techniques, namely UV–vis- and FTIR spectroscopy, have been employed in order to calculate the degree of substitution (DS) of cellulose carboxylic esters, including acetates, CAs, butyrates, CBs, and hexanoates, CHs. Regarding UV–vis spectroscopy, we have employed a novel approach, based on measuring the dependence of λ max of the intra-molecular charge-transfer bands of polarity probes adsorbed on DS of the ester films (solvatochromism). Additionally, we have revisited the use of FTIR for DS determination. Several methods have been used in order to plot Beer's law graph, namely: Absorption of KBr pellets, pre-coated with CA; reflectance (DRIFTS) of CAs-KBr solid–solid mixtures with, or without the use of 1,4-dicyanobenzene as an internal reference; reflectance of KBr powder pre-coated with CA. The methods indicated are simple, fast, and accurate, requiring much less ester than the titration method. The probe method is independent of the experimental variables examined.

ChemInform Abstract: A Novel Class of Apical Sodium Co-Dependent Bile Acid Transporter Inhibitors: The 2,3-Disubstituted-4-phenylquinolines.

A series of 2,3-disubstituted-4-phenylquinolines were prepared and were found to inhibit the apical sodium co-dependent bile acid transporter (ASBT). Alkyl and ester substitution at the 3-position showed comparable activities while substitution at the 2-position was much more sensitive to the nature of the substituent. The synthesis and in vitro potency data are presented for this novel class of compounds.

Dynamic kinetic resolution of (S)-mandelate-derived α-bromo esters in nucleophilic substitution and asymmetric syntheses of 3-substituted morpholin-2-ones

Dynamic kinetic resolution of (S)-mandelate-derived α-bromo esters in nucleophilic substitution reaction has been investigated. Substitutions with various alkyl amine nucleophiles in the presence of TBAI and DIEA can provide various α-amino esters up to 81% yield and 97:3 dr. Also, the substitution of α-bromo esters with N-substituted 2-aminoethanol nucleophiles and following spontaneous cyclization provides a practical protocol for asymmetric syntheses of 3substituted morpholin-2-ones up to 95:5 er.

Light-Induced Functionalization of Amphiphilic Block Copolymers: Application to Nanoparticles for Drug Targeting

Photografting of bifunctional photolinker on biocompatible amphiphilic copolymers, such as PCL-b-PEGs and PLGA-b-PEGs, has been developed as a practical and versatile strategy for the materials functionalisation. Depending on the copolymer nature (block length, % of crystallinity) and the experimental conditions we could selectively direct the grafting on the hydrophilic PEG segments. The resulting copolymers were further derivatized with molecules of interest (RGD-peptides, LDV-peptides, “home-made”peptidomimetics, mannose derivatives,…) by substitution of the O-succinimidyl ester of the photolinker. The derivatization rates were controlled by radiolabelling, colorimetric assay and XPS spectroscopy. The functionalized copolymers were used in the formulation of nanoparticles displaying the ligands on their outer-shell. This nanoparticulate system was successfully employed for the oral vectorisation of antigen and for the targeted delivery of an anticancer drug.

A new method for rapid degree of substitution and purity determination of chloroform-soluble cellulose esters, using 31P NMR

Chloroform-soluble palmitic and decanoic acid esters of cellulose were synthesized from the reaction of MCC with acid chlorides in LiCl/DMA and the ionic liquid [amim]Cl, as novel cellulose solvents. A process of derivatization of the remaining hydroxyl groups, as phosphite esters and subsequent 31P NMR analysis, allowed for simultaneous degree of substitution (DS) determination and quantification of the aqueous-quench acid by-product impurity, after the appropriate calculation. The full mathematical treatment for DS determination is presented, including scripts for the Python and Java programming languages for rapid interpretation of results. This method for DS determination was validated against traditional analyses of the palmitoyl cellulose and the fully substituted p-nitrobenzoyl palmitoyl diester product, from additional reaction with p-nitrobenzoyl chloride. DOSY NMR and SCORE analyses were also employed to demonstrate the utility of this rapid 31P derivatization and analytical process over traditional 1D NMR analyses.

Formation of Chiral C(sp3)−C(sp) Bond by Allylic Substitution of Secondary Allylic Picolinates and Alkynyl Copper Reagents

To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents, allylic esters bearing the (2-pyridine)CO2-, (2-pyrazine)CO2-, (EtO)2PO2-, C6F5CO2-, o-(Ph2P)C6H4CO2-, MeOCO2-, or AcO- group were examined. First, picolinate (R1 = Me, R2 = CH2OPMB) was subjected to reaction with (TMS-C[triple bond]C)2CuLi.LiBr at 0degreesC. Although no substitution took place, MgBr2 (3 equiv) was found to promote the reaction to produce the anti SN2' product in 93% yield with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with the copper reagent in the presence of MgBr2 were less reactive ((2-pyrazine)CO2-) or marginally reactive (other cases). Generality of the substitution using picolinates was established with five picolinates (R1 = Me, Ph(CH2)2, PMBO(CH2)3; R2 = Me, CH2OPMB, CH2OTBS, C5H11, c-C6H11) and seven alkynyl copper reagents (R3 = TMS, Ph, p-TBSOC6H4, p- and o-MeOC6H4, p-MeC6H4, p-FC6H4), furnishing anti SN2' products in 61-93% yields with high regioselectivity (usually >90%) and high chirality transfer (usually >95%). In addition, transformation of the products was briefly studied.

Fabrication of Size-Controlled Starch-Based Nanospheres by Nanoprecipitation

Nanometric and monodisperse starch acetate nanospheres can be prepared through a simple procedure of nanoprecipitation, by the dropwise addition of water to an acetone solution of starch acetate, without any stabilizing agent. This is the first report of the preparation of starch-based nanospheres by this method. The size of the nanospheres obtained can be easily controlled by a number of simple and efficient modifications, i.e., through regulation of the polymer concentration in acetone, the proportions of the water and organic phases, and the molecular weight and degree of substitution of the starch esters. A number of reasons are suggested to explain the observed transitions in the particle size. Fluorescence spectroscopic studies proved that these types of nanospheres could be potentially used for the encapsulation of hydrophobic drugs.

Synthesis and antinociceptive activity of capsinoid derivatives

According to the data of structural identification, six capsinoids or their derivatives were successfully synthesized to test for their analgesic activity. Three of them were capsinoids with different acyl chain compared with capsaicin after substitution of ester for amide at C 1 position. The other three could be described as capsinoid derivatives with different alkoxy chain, compared with capsaicin after substitution of ester for amide at C 1 position and alkoxy for hydroxy at C 4 position and synthesis of them was reported first. Compared with capsaicin, experiment results about pungency showed that capsinoids and their derivatives synthesized were all no or only slight pungent; that is, capsinoid derivates synthesized still have the same advantage of nonpungency with capsinoid. Relation between analgesic activity and molecular structure of compounds synthesized was also reported first, which would facilitate finding capsinoid derivatives owning excellent analgesic activity. The experiment results about analgesic activity showed that capsinoids displayed moderate analgesia effect and their antinociceptive activity decreased with the elongation of acyl chain at C 1 position; that antinociceptive activities of capsinoid derivatives synthesized were much stronger not only than those of indomethacin but also than those of their precursor (vanillyl decanoate), which increased with elongation of alkoxyl chain at C 4 position. Especially 4-hexyloxyl-3-methoxybenzyl decanoate showed the best antinociceptive activity in synthesized compounds, which was 9-fold higher than its precursor (vanillyl decanoate) and 6-fold higher than that of indomethacin.

Accurate determination of the degree of substitution of long chain cellulose esters

The determination of the degree of substitution (DS) of fatty acid cellulose esters with alkyl chain lengths from C8 to C18 was performed by direct transesterification with trimethylsulphonium hydroxide (TMSH) using tert-butyl methyl ether (MTBE) as a solvent. Transesterification was demonstrated to be quantitative at 75 °C in 60 min. The quantification of the formed fatty acid methyl esters was performed by gas chromatography (GC). After the optimization of the method, long chain cellulose esters (LCCE) could be analyzed in a wide range of DS. The obtained values were compared to those given by other existing protocols. LCCE with DS-values in a range of 5 × 10−5 to 3 were analyzed with high accuracy. Reproducibility is weakened for high DS values if the sample has a compact aspect limiting the accessibility of TMSH to the ester functions. This method can also be suitable for the analysis of mixed cellulose esters.

Synthesis of Novel β-Lactone Inhibitors of Fatty Acid Synthase

Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.

Supramolecular catalytic systems based on calix[4]resorcinarene for nucleophilic substitution in phosphorous acid esters

The aggregation and catalytic effect in the reaction of hydrolytic decomposition of phosphorous acid esters are studied for series of systems such as calixarene (CA)-sodium dodecyl sulfate (SDS), CA-poly(ethylene imine) (PEI), SDS-PEI, and CA-SDS-PEI. Using dynamic light scattering, sizes of aggregates are determined, cloud point is estimated, and catalytic effect is studied. Data obtained are consistent with the assumption of the joint aggregation in systems studied. The possibility of the passage from 20-fold inhibiting effect to the catalysis (higher than the order of magnitude) of studied reaction by the immobilization of anionic nanoaggregates (nanoreactors) on a catalytically active polymer matrix is demonstrated. The possibility of the passage from microheterogeneous to heterogeneous system and the separation of catalyst from the products are established.

Ultrafast Excited State Dynamics of Pt(II) Chromophores Bearing Multiple Infrared Absorbers

The paper reports the synthesis, structural characterization, electrochemistry, ultrafast time-resolved infrared (TRIR) and transient absorption (TA) spectroscopy associated with two independent d (8) square planar Pt(II) diimine chromophores, Pt(dnpebpy)Cl 2 ( 1) and Pt(dnpebpy)(C[triple bond]Cnaph) 2 ( 2), where dnpebpy = 4,4'-(CO 2CH 2- (t) Bu) 2-2,2'-bipyridine and CCnaph = naphthylacetylide. The neopentyl ester substitutions provided markedly improved complex solubility relative to the corresponding ethyl ester which facilitates synthetic elaboration as well as spectroscopic investigations. Following 400 nm pulsed laser excitation in CH 2Cl 2, the 23 cm (-1) red shift in the nu C=O vibrations in 1 are representative of a complex displaying a lowest charge-transfer-to-diimine (CT) excited state. The decay kinetics in 1 are composed of two time constants assigned to vibrational cooling of the (3)CT excited-state concomitant with its decay to the ground state (tau = 2.2 +/- 0.4 ps), and to cooling of the formed vibrationally hot ground electronic state (tau = 15.5 +/- 4.0 ps); we note that an assignment of the latter to a ligand field state cannot be excluded. Ultrafast TA data quantitatively support these assignments yielding an excited-state lifetime of 2.7 +/- 0.4 ps for the (3)CT excited-state of 1 and could not detect any longer-lived species. The primary intention of this study was to develop a Pt (II) complex ( 2) bearing dual infrared spectroscopic tags (C[triple bond]C attached to the metal and CO (ester) attached to the diimine ligand) to independently track the movement of charge density in different segments of the molecule following pulsed light excitation. Femtosecond laser excitation of 2 in CH 2Cl 2 at 400 nm simultaneously induces a red-shift in both the nu C=O (-30 cm (-1)) and the nu C[triple bond]C (-61 cm (-1)) vibrations. The TRIR data in 2 are consistent with a charge transfer assignment, and the significant decrease of the energy of the nu C[triple bond]C vibration suggests a considerable contribution from the acetylide ligands in the highest occupied molecular orbital. Therefore, we assign the lowest energy optical transitions in 2 as a combination of metal-to-ligand and ligand-to-ligand charge transfers. The excited-state of 2 is emissive at RT, with an emission maximum at 715 nm, quantum yield of 0.0012, and lifetime of 23 ns.

Aggregation and supramolecular chirality of achiral amphiphilic metalloporphyrins

Metalloporphyrin derivatives with three hydrophobic dodecyl chains and a hydrophilic ester or carboxylic acid substituent were designed in order to clarify the effect of the central metal ions on the aggregation as well as the supramolecular chirality in the Langmuir–Schaefer films. All the metalloporphyrins showed good spreading behavior on water surface and can be transferred onto solid substrates. The transferred films were characterized by a variety of methods including UV–visible spectroscopy, circular dichroism (CD) spectroscopy, FTIR spectroscopy, atomic force microscopy (AFM) and scanning electron microscope (SEM) measurements. It has been found that the copper derivative forms J-aggregates as well as H-aggregates in the film. Moreover, the film showed strong CD signals. Change from the ester substitution to carboxylic acid caused the decrease of the supramolecular chirality. On the contrary, the zinc derivative showed only a negligible CD signal although the corresponding free base could assemble into a chiral assembly. A possible mechanism for the subtle relationship between supramolecular chirality and molecular structures has been proposed.

π-Allylic Sulfonylation in Water with Amphiphilic Resin-Supported Palladium-Phosphine Complexes

π-Allylic substitution of allyl esters with sodium arylsulfinate was performed with an amphiphilic polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported phosphine-palladium complex in water as a single reaction medium under heterogeneous conditions to give allyl sulfones in good to high yields. Catalytic asymmetric allylic substitution of cycloalkenyl esters also took place in water using a PS-PEG resin-supported chiral imidazo­indolephosphine-palladium complex to give cycloalkenyl sulfones with up to 81% ee.

Structural Characterization and Solution Properties of a Galacturonate Polysaccharide Derived from Aloe vera Capable of in Situ Gelation

A series of highly purified galacturonate polysaccharides have been extracted from the Aloe vera plant and analyzed in terms of chemical composition and molecular weight. This Aloe vera polysaccharide (AvP) has been found to exist as a high molecular weight species and possess a unique chemical composition, including a high galacturonic acid (GalA) content and low degree of methyl ester substitution. These factors facilitate gel formation upon exposure to low concentrations of calcium ions, leading to potential application in formulations designed for in situ nasal or subcutaneous protein delivery. Thorough examination of classic dilute solution properties, the [eta]-M(w), and R(g)-M(w) relationships, persistence length (L(p)), and inherent chain stiffness (B parameter), indicate an expanded random coil in aqueous salt solutions. The critical concentration for transition from dilute to concentrated solution, C(e), was determined by measuring both the zero shear viscosity (eta(o)) and fluorescence emission of the probe molecule 1,8-anilino-1-naphthalene sulfonic acid (1,8-ANS) as a function of polymer concentration. Examination of zeta potential and C(e) as a function of ionic strength indicates that the shift in C(e) from 0.60 to 0.30 wt % is related to an increased occurrence of intermolecular interactions at high salt concentrations. Additionally, dynamic rheology data are presented highlighting the ability of AvP to form gels at low polymer and calcium ion concentrations, exemplifying the technological potential of this polysaccharide for in situ drug delivery.

Oxytocin analogues with amide groups substituted by tetrazole groups in position 4, 5 or 9.

Eleven oxytocin analogues substituted in position 4, 5 or 9 by tetrazole analogues of amino acids were prepared using solid-phase peptide synthesis method and tested for rat uterotonic in vitro and pressor activities, as well as for their affinity to human oxytocin receptor. The tetrazolic group has been used as a bioisosteric substitution of carboxylic, ester or amide groups in structure-activity relationship studies of biologically active compounds. Replacement of the amide groups of Gln(4) and Asn(5) in oxytocin by tetrazole analogues of aspartic, glutamic and alpha-aminoadipic acids containing the tetrazole moiety in the side chains leads to analogues with decreased biological activities. Oxytocin analogues in which the glycine amide residue in position 9 was substituted by tetrazole analogues of glycine had diminished activities as well. The analysis of differences in rat uterotonic activity and in the affinity to human oxytocin receptors of analogues containing either an acidic 5-substituted tetrazolic group or a neutral 1,5- or 2,5-tetrazole nucleus makes it possible to draw some new conclusions concerning the role of the amide group of amino acids in positions 4, 5 and 9 of oxytocin for its activity. The data suggest that the interaction of the side chain of Gln(4) with the oxytocin receptor is influenced mainly by electronic effects and the hydrogen bonding capacity of the amide group. Steric effects of the side chain are minor. Substitution of Asn(5) by its tetrazole derivative gave an analogue of very low activity. The result suggests that in the interaction between the amide group of Asn(5) and the binding sites of oxytocic receptor hydrogen bonds are of less importance than the spatial requirements for this group.

Synthesis of (+)-Microcladallene

(+)-Microcladallene was isolated from Laurencia microcladia, a red alga. A salient feature of the synthesis is the installation of a secondary bromoalkane function by nucleophilic substitution of a sulfonate ester (E to F) with retention of configuration using a nucleophile-assisting leaving group.

Use of acetate as a leaving group in palladium-catalyzed nucleophilic substitution of benzylic esters

The palladium complex prepared in situ from [Pd(η 3-C 3H 5)(cod)]BF 4 and bidentate phosphine DPPF was a good catalyst for the nucleophilic substitution of benzyl acetate. Significant acceleration of the palladium-catalyzed substitution was observed when an alcohol was employed as a reaction solvent. The palladium catalyst was effective for the benzylation of various stabilized carbanions, amines, and benzenesulfinate with benzylic acetates.

Micellization properties and the catalytic effect of the aqueous cetyltrimethylammonium bromide-Triton X-100 binary system in nucleophilic substitution in esters of phosphorus acids

The aggregation properties and catalytic effect of the cetyltrimethylammonium bromide-Triton X-100 binary system in nucleophilic substitution in esters of phosphorus acids are studied in the region of normal micelles and oil/water microemulsions. In the presence of phenol, the dissociation of O-alkyl-O-para-nitrophenyl chloromethyl phosphonates is up to 200 times more rapid than the same reaction in water. The efficiency of catalysis depends on the molar ratio of the surfactants and is determined by several factors: concentration, changes in the microenvironment of the reactants, and the shift of the pK a of phenol.