Ester Substitution Research Articles

Palladium-catalyzed substitution of esters of naphthylmethanols, 1-naphthylethanols, and analogues by sodium dimethyl malonate. Stereoselective synthesis from enantiomerically pure substrates

The palladium-catalyzed substitution of carbonates of the titled alcohols was performed at lower temperature than the previously reported reaction of the corresponding acetates. The use of enantiomerically pure carbonates gave substitution products with overall retention of the configuration (up to 97%).

Enantioselective hydrolysis of ethyl 2-hydroxyalkanoates by an extracellular esterase from a Bacillus sphaericus strain

An assay regimen for the detection of enantioselective esterase activity in bacteria and yeasts is described. This program was used to screen 167 culture collection strains and soil isolates for activity toward 2-substituted esters and yielded a Bacillus sphaericus strain that selectively hydrolyzes the R ester of ethyl mandelate, ethyl 2-hydroxypentanoate, and ethyl 2-hydroxyhexanoate. The latter substrate was resolved to the S ester in >99% enantiomeric excess after 56% hydrolysis.

Amphiphilic graft copolymers with poly(oxyethylene) side chains: Synthesis via activated ester intermediates—properties

AbstractAmphiphilic graft copolymers were synthesized via activated ester substitution of derivatives of fumaric acid with amino‐functionalized methoxypoly (oxyethylene)s (MPEO‐NH2) of different molecular weights. The monomeric activated esters, isopropyl pentachlorophenyl fumarate (PCPFA) and isopropyl succinimido fumarate (SIFA), were copolymerized with styrene (St) or N‐vinyl pyrrolidone (VP) at equimolar ratio. The polymeric‐activated esters proved to be good precursors for grafting of definite amounts of MPEO‐NH2. The aminolysis of the succinimide esters and VP‐containing copolymers proceeded with gel formation due to extensive hydrogen bonding. The hydrodynamic behavior, the emulsifying ability, the thermal properties, and crystallinity of the graft copolymers were studied as a function of their molecular characteristics. The length of the PEO grafts and the degree of grafting are the factors which affect the melting parameters and the crystallinity of the side chains. © 1994 John Wiley & Sons, Inc.

Tetrahydropyran Esters as New Attractants for Cockroaches

Twenty four tetrahydropyran esters were synthesised and tested as attractants toward Blattella germanica and Supella longipalpa in the laboratory by using the choice-chamber method. In general, carboxylates were superior to propionates and acetates. Among the 2-, 3-, or 4-substituted esters, substitution at the 4-position was better than at the other two positions. These results are explained in terms of the receptor model proposed earlier by others.

Convenient Synthesis of Biphenyl-2-carboxylic Acids via the Nucleophilic Aromatic Substitution Reaction of 2-Methoxybenzoates by Aryl Grignard Reagents

Abstract Nucleophilic aromatic substitution (SNAr) of 2-methoxybenzoic esters derived from 2,6-dialkylphenols by aryl Grignard reagents affords 1,1′-biphenyl-2-carboxylates in excellent yields by proper choice of the bulk of the 2,6-dialkyl-substituents. The phenoxyl protecting groups can be easily removed from the resulting biphenyl-2-carboxylates to the free acids by treatment with potassium hydroxide in aqueous ethanol (2,4,6-trimethylphenyl and 2,6-diisopropylphenyl esters) or sodium methoxide in toluene–hexamethylphosphoric triamide (2,6-di-t-butyl-4-methylphenyl esters). The regioselective biphenyl coupling reaction via the SNAr process is utilized for the key-step construction of the biphenyl skeleton in a formal synthesis of cannabinol.

Substitution and Michael reactions of bicyclic tetronic, tetramic and thiotetronic esters

The 1,4-addition of several heteroatom and carbon nucleophiles to the bicyclic structures 1, 2, 3 and 13 are reported along with the conversion of the resultant adducts to substituted tetronic, tetramic, thiotetronic acids and butenolides; a novel reaction mechanism has been observed for the iodotrimethylsilane (TMSI) or acetic anhydride/magnesium bromide-mediated furan ring-opening reactions of the bicyclic tetronate 1.

New strategies in using macromolecular catalysts in organic synthesis

The use of soluble triphenylphosphine ligands to activate Pd(0) catalysts for allylic substitution of allyl esters or ethers by amines and stabilized carbanion nucleophiles and carboalkoxylation of aryl iodides and decar☐ylation of allylic β-keto esters is described. Pd(0) catalysts studied included Pd/C and dispersions of Pd(0) in an insoluble divinylbenzene crosslinked polystyrene resin. The effects of added triphenylphosphine on each reaction were seen in several ways. Small amounts of added phosphine increased the reaction rate 10-fold or more in most cases. Experiments to detect the nature of the active catalyst species and to differentiate between catalysis by a homogeneous species and catalysis by a heterogeneous species were performed. These experiments uniformly failed to demonstrate the presence of a homogeneous catalyst.

Formation and substitution of remote ester functionalized organocopper reagents

Formation and substitution of remote ester functionalized organocopper reagents

Palladium-catalyzed nucleophilic substitution of napht hylmethyl and 1-naphthylethyl esters

Sodium dimethyl malonate reacted with naphthylmethyl and 1-naphthylethyl alcohol derivatives in DMF at 20–80°C, under palladium(o) / phosphine catalysis, to give the substitution products dimethyl naphthylmethyl- and 1-naphthylethylmalonates, respectively, in good (75–83%) yield.

Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgesics

In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

ChemInform Abstract: A Short Large Scale Synthesis of (.+-.)-Sarkomycin Esters.

Abstract : (k) Sarkomycin ethyl ester has been prepared in four steps from ethyl actylate. We have previously described the substitution of a-functionnal acrylic esters by Grignard reagents in the presence of a catalytic amount of copper (I) (1). This reaction can be applied to lithium enolates (ester or ketone). It gives then rise to new a-substituted functional actylates which are of great interest for the synthesis of biological active compounds (a-methylene &valerolactone, (+)-sarkomycin). CH,OAc flc”” =(COOEt FOOEt v 2.5% Cu(l), -7O”C, THF-Et20 - CH20Ac + COOEt Li-CH,-COOt-Bu THF-Et20, -80°C -CH2 Yield 83% COOEt ===c CH,-CH,-COO,-BU 1 Yield 66% A recent publication (2) on the synthesis of (+) sarkomycin including the same phosphonate 3 as a key intermediate prompts us to describe here our results. Many other preparations of (k) sarkomycm (or its esters) have been reported by mutli step syntheses (2, 3) with low overall yields. We report here a very short, large scale and improved synthesls of two (&) sarkomycin esters using low cost products and methodology. a-Methylene glutaric acid diester 1 can be included in a very short

Synthesis of stereospecifically labeled 3,6-dideoxyhexoses

Preparations of ascarylose (3,6-dideoxy- l- arabino-hexose), abequose (3,6-dideoxy- d- xylo-hexose), and paratose (3,6-dideoxy- d- ribo-hexose) with stereospecific deuterium labeling at C-3 are discussed. The methods used to synthesize these sugars, such as the hydrogenation of olefins, the displacement of halides, the reduction of epoxides, and the substitution of tosyl esters, illustrate a variety of strategies leading to stereospecific deuterium incorporation. Many of the techniques described here should be of general utility for the synthesis of other deuterium-labeled sugars.

A study of the low temperature nitration of cellulose in mixed acids

AbstractThe low temperature surface and bulk nitration of cellulose has been investigated by electron spectroscopy for chemical analysis (ESCA), 13C‐NMR and X‐ray diffraction. Acid mix composition has been probed at room temperature and at low temperatures (0–20°C) by Raman spectroscopy. This multitechnique approach has been employed to elucidate the behavior of surface degree of substitution (DOS) with acid mix composition over a 40°C temperature range. The data obtained have prompted a reinterpretation of previously reported work. Surface “equilibrium DOS” is shown to be established within 1 s at all temperatures investigated. but, at lower temperatures (> 5°C) the surface DOS as monitored by ESCA is observed to “dip” after immersion times of t < 5 s. This change in DOS is correlated with major structural changes in the fiber as observed by SEM. At low temperatures, e.g., −15°C, nitration is shown to be complete throughout the cellulose fiber after 10 h nitration. Solution state 13C‐NMR is used to compare the nitrate ester substitution distribution in cellulose nitrates prepared from acid mixes of the same composition at different temperatures.

Kinetic resolution of 2-substituted esters catalyzed by a lipase ex. Pseudomonas fluorescens

Enantioselective hydrolyses of a variety of 2-substituted racemic esters catalyzed by a bacterial lipase have been effected in high enantiomeric excess. These enzyme-catalyzed kinetic resolutions constitute an economical method of preparing enantiomerically pure 2-substituted esters and acids on a large scale. Several of the resolved enantiomers are important intermediates in the synthesis of bioactive compounds in the areas of prostanoids, angiotensin-converting enzyme inhibitors, and leukotriene antagonists

Interleukin‐1 release by rat synovial cells is dependent on sequential treatment with γ‐interferon and lipopolysaccharide

To determine the potential regulatory mechanisms involved in synovial cell interleukin-1 (IL-1) release, the ability of gamma-interferon (gamma-IFN) to influence IL-1 release was assessed. Rat synovial cells cultured in the presence of a variety of stimuli, including lipopolysaccharide (LPS), failed to release IL-1. However, pretreatment of synovial cells with gamma-IFN, followed by LPS stimulation, resulted in increased levels of intracellular IL-1 as well as release of IL-1 from the cell. The level of IL-1 release was dependent on the concentration of both gamma-IFN and LPS, and on length of exposure to the gamma-IFN. The kinetic and dose requirements for gamma-IFN-dependent IL-1 release were similar to those for Ia antigen expression, but LPS was necessary for IL-1 messenger RNA induction, intracellular IL-1 accumulation, and IL-1 release. In addition, sequential treatment, i.e., gamma-IFN followed by LPS, was essential for IL-1 induction. Substitution of phorbol ester or calcium ionophore for gamma-IFN did not result in similar IL-1 release. In addition, induction of IL-1 messenger RNA by another stimulus was not sufficient to result in IL-1 release following LPS treatment. These results suggest that release of IL-1 by rat synovial cells requires the production of a regulatory signal, which is inducible by gamma-IFN.

Protease-Catalyzed Peptide Formation under High Pressure

Abstract The effect of high pressure on peptide formation by the catalysis of carboxypeptidase Y (substitution of ester or peptide by amino acid derivative) or by thermolysin (condensation of N-acylamino acid and amino acid amide) was studied. The carboxypeptidase Y-catalyzed substitution reaction of N-[3-(2-furyl)acryloyl]phenylalanine ethyl ester with glycinamide or phenylalaninamide showed a six-fold higher total peptide yield at 200 MPa than at atmospheric pressure. In the case of the reaction of N-acyldipeptide and amino acid amide, both the peptide yield and substitution efficiency were improved at elevated pressure and the wasteful hydrolysis of the substrate was highly depressed by increasing pressure. The pressure was also effective to get rid of the substrate inhibition by the amino acid ester in the reaction between the N-acylamino acid ester and the amino acid ester and to yield much dipeptide ester at high pressure. An improvement of the peptide yield by pressure for the reaction of thermolysin was observed in a combination of less specific substrates, N-benzyloxycarbonyl-l-aspartic acid and phenylalanine methyl ester, since the high catalytic activity of this enzyme under elevated pressure was significant only in the case that the peptide yield was kinetic-controlled.

Kinetic study of thermal degradation of guar gum esters

The guar gum esters were synthesized by reacting guar gum with various anhydrides. The degree of substitution of guar gum esters was estimated. The thermal degradation of guar gum and its esters in the presence of air was examined by thermogravimetry to ascertain their relative thermal stabilities on the basis of various temperature parameters. The experiments were carried out at a heating rate of 10 °C min −1 in the range 25–550 °C.

Reproductive effects of four phthalic acid esters in the mouse

These studies compared the reproductive toxicity of four phthalates by a continuous breeding protocol. Mice were given diets with diethyl phthalate (DEP) (0.0, 0.25, 1.25, or 2.5%), di- n-butyl phthalate (DBP) (0.0, 0.03, 0.3, or 1.0%), di- n-hexyl phthalate (DHP) (0.0, 0.3, 0.6, or 1.2%), or di(2-ethylhexyl) phthalate (DEHP) (0.0, 0.01, or 0.3%). Both male and female CD-1 mice were dosed for 7 days prior to and during a 98-day cohabitation period. Reproductive function was evaluated during the cohabitation period by measuring the numbers of litters per pair and of live pups per litter, pup weight, and offspring survival. There was no apparent effect on reproductive function in the animals exposed to DEP, despite significant effects on body weight gain and liver weight. DBP exposure resulted in a reduction in the numbers of litters per pair and of live pups per litter and in the proportion of pups born alive at the 1.0% amount, but not at lower dose levels. A crossover mating trial demonstrated that female mice, but not males, were affected by DBP, as shown by significant decreases in the percentage of fertile pairs, the number of live pups per litter, the proportion of pups born alive, and live pup weight. DHP in the diet resulted in dose-related adverse effects on the numbers of litters per pair and of live pups per litter and proportion of pups born alive at 0.3, 0.6, and 1.2% DHP in the diet. A crossover mating study demonstrated that both sexes were affected. DEHP (at 0.1 and 0.3%) caused dose-dependent decreases in fertility and in the number and the proportion of pups born alive. A crossover mating trial showed that both sexes were affected by exposure to DEHP. These data demonstrate the ability of the continuous breeding protocol to discriminate the qualitative and quantitative reproductive effects of the more and less active congeners as well as the large differences in reproductive toxicity attributable to subtle changes in the alkyl substitution of phthalate esters.

Destruction of Leishmania mexicana amazonensis amastigotes within macrophages by lysosomotropic amino acid esters.

Leishmania amastigotes parasitize almost exclusively the mononuclear phagocytes of mammals. The organisms survive and multiply within acidified vacuoles (parasitophorous vacuoles; p.v.) akin to phagolysosomes. Certain amino acid esters are known to accumulate in and disrupt lysosomes. We postulated that, since Leishmania possess lysosome-like organelles, they may be susceptible to the potentially high ester concentrations attained in the p.v. We report here that L-amino acid esters can rapidly destroy intracellular Leishmania at concentrations that do not appear to damage the host cells. L-leu-OMe, which cured greater than or equal to 90% of infected macrophages at 0.8 mM concentrations, was used in most of the experiments. L-leu-OMe was only active after infection, implying inefficient transfer from secondary lysosomes to the p.v. Parasite destruction had several features in common with lysosomal and leukocyte damage induced by the esters, i.e., inactivity of D-amino acid esters, a marked pH dependence and increased killing after ester pulses at lower temperatures. Killing depended on the amino acid and on the ester substitution. The most active of the methyl esters assayed was that of leucine, followed by those of tryptophan, glutamic acid, methionine, phenylalanine, and tyrosine. Methyl esters of seven other amino acids were inactive when tested at up to 10 mM concentrations. Among leucine esters studied, benzyl ester was sixfold more active than the methyl homolog. The dipeptide L-leu-leu-OMe produced 90% cure at 0.08 mM concentrations. Leishmanicidal activity could be related to penetration of the parasites by the esters or to toxic ester hydrolysis products released in the p.v. The first hypothesis is supported by the pH-dependent destruction of isolated amastigotes by the esters. Furthermore, relatively high concentrations of L-leucine, methanol, or benzyl alcohol were not demonstrably toxic to the amastigotes. We postulate that ester concentrations sufficient to damage the intracellular amastigotes may be obtained within the p.v. after exposure of infected macrophages to the esters. Esters preferentially hydrolyzed by parasite enzymes may be expected to be leishmanicidal, but less damaging to the host.

Stereoelectronic control in transition metal-catalysed substitution and rearrangement of allylic esters and alcohols

In competitive experiments with cis- and trans-5-t-butyl-2-methylenecyclohexanols and their acetates, stereocontrol in the Pd- and Ni-catalysed alkylation of allylic derivatives and the Mo-catalysed isomerisation of allylic alcohols is observed.