Acid Lactone Research Articles

ChemInform Abstract: Umpolung Pd‐Catalyzed α‐Arylation Reactions in Natural Product Synthesis: Syntheses of (+)‐Xestodecalactone A, (‐)‐Curvularin, (+)‐12‐Oxocurvularin and (‐)‐Citreofuran.

AbstractTotal and formal syntheses of the title phenylacetic acid lactones are accomplished by utilizing a unified strategy of an umpolung Pd‐catalyzed α‐arylation of complex α‐bromo esters and boronic acids under mild reaction conditions.

Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates through desymmetrisation methodology. Enantioselective synthesis of (+) and (−) nor-mevalonic lactones

Solvent-free desymmetrisation of a meso-dialdehyde with chiral alcohols, led to preparation of 4-silyloxy-6-alkyloxytetrahydro-2H-pyran-2-one derivatives with a 96% de. This methodology, which yields the corresponding methyl nor-mevaldates with 99% ee, has been applied to the enantioselective synthesis of the (−)-(R) and (+)-(S) nor-mevalonic acid lactones.

Bioactive compounds in the stem bark of <i>Albizia coriaria</i> (Welw. ex Oliver)

Albizia coriaria was investigated for the bioactive compounds present in its stem bark. The plant was selected on the basis of its widespread use in traditional herbal medicine. Extraction of the plant material was done with ethyl acetate, methanol and water and the bioactivity of each extract was tested against Pseudomonas aeruginosa and Escherichia coli. Separation and purification of the compounds in the most active (ethyl acetate) extract was done using a combination of chromatographic techniques. The compounds were identified by 1D and 2D - 1 H and 13 C NMR techniques as well as Mass spectrometry (MS). Six compounds, namely: Lupeol (1), Lupenone (2), Betulinic acid (3), Acacic acid lactone (4), (+) – Catechin (5) and Benzyl alcohol (6) were identified and characterized from the ethyl acetate extract. The results of the bioactivity tests carried out in this study indicated that A. coriaria has potential antimicrobial activity. Four of the characterized compounds (1, 2, 3 & 5) have a wide range of biological activity reported in literature. This justifies the use of this plant in traditional medicine and indicates a promising potential for the development of medicinal agents from A. coriaria stem bark. Keywords : Biological activity, Lupeol, Lupenone, Betulinic acid, Acacic acid lactone, (+) – Catechin.

Unusual microbial lactonization and hydroxylation of asiatic acid by Umbelopsis isabellina

Asiatic acid (1) is a natural triterpenoid isolated from Centella asiatica. This paper reports the microbial transformation of asiatic acid by an endophytic fungus Umbelopsis isabellina to obtain derivatives potentially useful for further studies. Incubation of asiatic acid with U. isabellina afforded two derivatives 2α,3β,7β, 23-tetrahydroxyurs-12-ene-28-oic acid (2) and 2α,3β,7β,23-tetrahydroxyurs-11-ene-28,13-lactone (3). The structures of these compounds were elucidated by spectral data. Compound 3 has formed an unusual lactone. These two products are new compounds. The possible transformation passway was also discussed.

Synthesis and Antifeedant Activity of Racemic and Optically Active Hydroxy Lactones with the p-Menthane System.

Two racemic and two enantiomeric pairs of new δ-hydroxy-γ-lactones based on the p-menthane system were prepared from racemic and optically active cis- and trans-piperitols. The Johnson-Claisen rearrangement of the piperitols, epoxidation of the γδ-unsaturated esters, and acidic lactonization of the epoxy esters were described. The structures of the compounds were confirmed spectroscopically. The antifeedant activities of the hydroxy lactones and racemic piperitone were evaluated against three insect pests: lesser mealworm, Alphitobius diaperinus (Panzer); Colorado potato beetle, Leptinotarsa decemlineata (Say); and peach-potato aphid, Myzus persicae (Sulz.). The chemical transformation of piperitone by the introduction of a lactone moiety and a hydroxy group changed its antifeedant properties. Behavioral bioassays showed that the feeding deterrent activity depended on the insect species and the structure of the compounds. All hydroxy lactones deterred the settling of M. persicae. Among chewing insects, the highest sensitivity showed A. diaperinus adults.

Physiologically based pharmacokinetic modeling of disposition and drug–drug interactions for atorvastatin and its metabolites

Atorvastatin is the most commonly used of all statins to lower cholesterol. Atorvastatin is extensively metabolized in both gut and liver to produce several active metabolites. The purpose of the present study is to develop a physiologically based pharmacokinetic (PBPK) model for atorvastatin and its two primary metabolites, 2-hydroxy-atorvastatin acid and atorvastatin lactone, using in vitro and in vivo data. The model was used to predict the pharmacokinetic profiles and drug–drug interaction (DDI) effect for atorvastatin and its metabolites in different DDI scenarios. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministration of atorvastatin with different medications such as itraconazole, clarithromycin, cimetidine, rifampin and phenytoin. This population based PBPK model was able to describe the concentration–time profiles of atorvastatin and its two metabolites reasonably well in the absence or presence of those drugs at different dose regimens. The predicted maximum concentration (Cmax), area under the concentration–time curve (AUC) values and between-phase ratios were in good agreement with clinically observed data. The model has also revealed the importance of different metabolic pathways on the disposition of atorvastatin metabolites. This PBPK model can be utilized to assess the safety and efficacy of atorvastatin in the clinic. This study demonstrated the feasibility of applying PBPK approach to predict the DDI potential of drugs undergoing complex metabolism.

Crystal structure of (1R,4R)-tert-butyl 3-oxo-2-oxa-5-aza-bicyclo-[2.2.2]octane-5-carboxyl-ate.

In the title compound, C11H17NO4, commonly known as N-tert-but­oxy­carbonyl-5-hy­droxy-d-pipecolic acid lactone, the absolute configuration is (1R,4R) due to the enantiomeric purity of the starting material which remains unchanged during the course of the reaction. In the crystal there no inter­molecular hydrogen bonds.

Indole-3-acetic acid UDP-glucosyltransferase from immature seeds of pea is involved in modification of glycoproteins

The glycosylation of auxin is one of mechanisms contributing to hormonal homeostasis. The enzyme UDPG: indole-3-ylacetyl-β-d-glucosyltransferase (IAA glucosyltransferase, IAGlc synthase) catalyzes the reversible reaction: IAA+UDPG↔1-O-IA-glucose+UDP, which is the first step in the biosynthesis of IAA-ester conjugates in monocotyledonous plants. In this study, we report IAA-glucosyltransferase isolated using a biochemical approach from immature seed of pea (Pisum sativum). The enzyme was purified by PEG fractionation, DEAE-Sephacel anion-exchange chromatography and preparative PAGE. LC–MS/MS analysis of tryptic peptides of the enzyme revealed the high identity with maize IAGlc synthase, but lack of homology with other IAA-glucosyltransferases from dicots. Biochemical characterization showed that of several acyl acceptors tested, the enzyme had the highest activity on IAA as the glucosyl acceptor (Km=0.52mM, Vmax=161nmolmin−1, kcat/Km=4.36mMs−1) and lower activity on indole-3-propionic acid and 1-naphthalene acetic acid. Whereas indole-3-butyric acid and indole-3-propionic acid were competitive inhibitors of IAGlc synthase, d-gluconic acid lactone, an inhibitor of β-glucosidase activity, potentiated the enzyme activity at the optimal concentration of 0.3mM. Moreover, we demonstrated that the 1-O-IA-glucose synthesized by IAGlc synthase is the substrate for IAA labeling of glycoproteins from pea seeds indicating a possible role of this enzyme in the covalent modification of a class of proteins by a plant hormone.

ChemInform Abstract: Mn(OAc)3‐Mediated Phosphonation—Lactonization of Alkenoic Acids: Synthesis of Phosphono‐γ‐butyrolactones.

AbstractThe reaction proceeds through Mn(OAc)3‐mediated radical oxidative phosphonation and lactonization of alkenoic acids with H‐phosphonates and H‐phosphine oxide.

A Carbohydrate Approach for the First Total Synthesis of Cochliomycin C: Stereoselective Total Synthesis of Paecilomycin E, Paecilomycin F and 6′‐epi‐Cochliomycin C

AbstractThe first total synthesis of the chlorinated resorcylic acid lactone cochliomycin C is achieved starting from the readily available sugar D‐lyxose. The strategy has also lead to the total synthesis of natural resorcylic acid lactones paecilomycin E, paecilomycin F and a synthetic analogue 6‐epi‐cochliomycin C. The key reactions include Ohira–Bestmann alkynylation, ring closing metathesis and regioselective methylation under Mitsunobu conditions.

Triacetic acid lactone production in industrial Saccharomyces yeast strains.

Triacetic acid lactone (TAL) is a potential platform chemical that can be produced in yeast. To evaluate the potential for industrial yeast strains to produce TAL, the g2ps1 gene encoding 2-pyrone synthase was transformed into 13 industrial yeast strains of varied genetic background. TAL production varied 63-fold between strains when compared in batch culture with glucose. Ethanol, acetate, and glycerol were also tested as potential carbon sources. Batch cultures with ethanol medium produced the highest titers. Therefore, fed-batch cultivation with ethanol feed was assayed for TAL production in bioreactors, producing our highest TAL titer, 5.2g/L. Higher feed rates resulted in a loss of TAL and subsequent production of additional TAL side products. Finally, TAL efflux was measured and TAL is actively exported from S. cerevisiae cells. Percent yield for all strains was low, indicating that further metabolic engineering of the strains is required.

Cinatrins D and E, and virgaricin B, three novel compounds produced by a fungus, Virgaria boninensis FKI-4958.

Two new hydroxycitric acid lactone derivatives named cinatrins D (1) and E (2), and a new γ-lactam, virgaricin B (3), along with a known similar compound, virgaricin (4), were isolated from a fermentation broth of the fungus Virgaria boninensis FKI-4958. The absolute stereo structures of the new compounds were established by a combination of spectroscopic methods and chemical modifications. All three newly discovered compounds possessed weak antibacterial activity.

Umpolung Pd‐Catalyzed α‐Arylation Reactions in Natural Product Synthesis: Syntheses of (+)‐Xestodecalactone A, (–)‐Curvularin, (+)‐12‐Oxocurvularin and (–)‐Citreofuran

AbstractThe syntheses (total and formal) of four phenylacetic acid lactone (PAL) natural products have been accomplished by utilizing a unified strategy of an umpolung Pd‐catalyzed α‐arylation of complex α‐bromo esters and boronic acids under mild reaction conditions. As part of the synthetic approaches to these natural products, it was observed that the mild coupling reaction conditions readily tolerated terminal alkenes, other labile ester functionalities, an α,β‐unsaturated ester moiety, and a protected allylic alcohol, while chemoselectively engaging the α‐bromo ester. The completion of (+)‐xestodecalactone A and (–)‐curvularin coupled with the formal syntheses of (+)‐12‐oxocurvularin and (–)‐citreofuran highlight the umpolung Pd‐catalyzed α‐arylation strategy as a key convergent tactic in complex natural product synthesis.

Total syntheses of the resorcylic acid lactone neocosmosin A and its enantiomer.

A total synthesis of the structure, 1, assigned to the recently reported resorcylic acid lactone (RAL) neocosmosin A has been established. Olefin-cross metathesis, ring-closing metathesis, palladium-catalyzed Meinwald rearrangement, and Mitsunobu esterification reactions were used as key steps. A late-stage and simple modification to the reaction sequence also provided compound ent-1 that, in fact, represents the true structure of the natural product.

4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone is a Biologically Active Precursor for the Generation of 2-(ω-Carboxyethyl)pyrrole (CEP) Derivatives of Proteins and Ethanolamine Phospholipids.

2-(ω-Carboxyethyl)pyrrole (CEP) derivatives of proteins were previously shown to have significant pathological and physiological relevance to age-related macular degeneration, cancer and wound healing. Previously, we showed that CEPs are generated in the reaction of ε-amino groups of protein lysyl residues with 1-palmityl-2-(4-hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphatidylcholine (HOHA-PC), a lipid oxidation product uniquely generated by oxidative truncation of docosahexanenate-containing phosphatidylcholine. More recently, we found that HOHA-PC rapidly releases HOHA-lactone and 2-lyso-PC (t1/2 = 30 min at 37 °C) by nonenzymatic transesterification/deacylation. Now we report that HOHA-lactone reacts with Ac-Gly-Lys-OMe or human serum albumin to form CEP derivatives in vitro. Incubation of human red blood cell ghosts with HOHA-lactone generates CEP derivatives of membrane proteins and ethanolamine phospholipids. Quantitative analysis of the products generated in the reaction HOHA-PC with Ac-Gly-Lys-OMe showed that HOHA-PC mainly forms CEP-dipeptide that is not esterified to 2-lysophosphatidycholine. Thus, the HOHA-lactone pathway predominates over the direct reaction of HOHA-PC to produce the CEP-PC-dipeptide derivative. Myleoperoxidase/H2O2/NO2(-) promoted in vitro oxidation of either 1-palmityl-2-docosahexaneoyl-sn-glycero-3-phosphatidylcholine (DHA-PC) or docosahexaenoic acid (DHA) generates HOHA-lactone in yields of 0.45% and 0.78%, respectively. Lipid oxidation in human red blood cell ghosts also releases HOHA-lactone. Oxidative injury of ARPE-19 human retinal pigmented epithelial cells by exposure to H2O2 generated CEP derivatives. Treatment of ARPE-19 cells with HOHA-lactone generated CEP-modified proteins. Low (submicromolar), but not high, concentrations of HOHA-lactone promote increased vascular endothelial growth factor (VEGF) secretion by ARPE-19 cells. Therefore, HOHA-lactone not only serves as an intermediate for the generation of CEPs but also is a biologically active oxidative truncation product from docosahexaenoate lipids.

Stereoselective Total Synthesis of Paecilomycins E and F

The stereoselective total synthesis of two bioactive resorcylic acid lactones, paecilomycins E and F has been accomplished thorough a general pathway using cis-butene-1,4-diol as the starting material. The pivotal steps of the synthesis include Sharpless asymmetric epoxidation, Bestmann–Ohira alkynation, Jacobsen kinetic resolution, and Heck coupling reaction.

Bacillusin A, an Antibacterial Macrodiolide from Bacillus amyloliquefaciens AP183.

Bioassay-guided fractionation of the organic extracts of a Bacillus amyloliquefaciens strain (AP183) led to the discovery of a new macrocyclic polyene antibiotic, bacillusin A (1). Its structure was assigned by interpretation of NMR and MS spectroscopic data as a novel macrodiolide composed of dimeric 4-hydroxy-2-methoxy-6-alkenylbenzoic acid lactones with conjugated pentaene-hexahydroxy polyketide chains. Compound 1 showed potent antibacterial activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium with minimum inhibitory concentrations in a range of 0.6 to 1.2 μg/mL. The biosynthetic significance of this unique class of antibiotic compounds is briefly discussed.

New synthesis method for sultone derivatives: synthesis, crystal structure and biological evaluation of S-CA.

There has been no remarkable progress in the synthesis of sultones in recent years. To facilitate more detailed studies of this functional group, we found a new method to synthesize the sulfonic acid lactone derivatives and finish its ring-closing reaction. A new sultone derivative, (E)-ethyl 4-oxo-6-styryl-3,4-dihydro-1,2-oxathiine-5-carboxylate 2,2-dioxide (S-CA), was synthesized and structurally identified by 1H-NMR, 13C-NMR, HMQC and X-ray single crystal diffraction analysis. The new rapid synthesis extended the method of ring-closing reaction of sulfonic acid lactone derivatives. The angiogenesis activities of S-CA were evaluated by the chick chorioallantoic membrane (CAM) model. It could selectively suppress small angiogenesis in CAM, without influencing either middle and large angiogenesis. In addition, anticancer efficacy of S-CA was evaluated in vivo using a murine sarcoma S180 model. Reduction of the tumor weight and tumor HE staining regions demonstrated that S-CA (10 mg/kg, intraperitoneal injection) had potent inhibition effects and a 44.71% inhibitory rate in S180 mice. Moreover, an acute toxicity test showed that the LD50 value of S-CA via intraperitoneal injection was 25.624 mg/kg.

Adsorptive denitrogenation and desulfurization of diesel using activated carbons oxidized by (NH4)2S2O8 under mild conditions

(NH4)2S2O8 solutions were applied to oxidize a wood‐based activated carbon (AC) under different conditions. Oxidation decreases the specific surface area of AC samples but increases the oxygen functional groups. Carboxylic acid groups and ketone groups may facilitate the adsorption of nitrogen (N) and sulfur (S) compounds in light cycled oil (LCO). An appropriate adsorbent was determined as the oxidized carbon which shows high N removal from LCO. The resultant adsorbent, AC‐(NH4)2S2O8‐15%‐1.5, exhibits higher adsorption capacities for N and S compounds than the original carbon in dynamic adsorption of a model diesel fuel. Carboxylic acid groups and lactone groups might favour quinoline adsorption. Carboxylic anhydride groups and phenolic groups are likely to improve the adsorption of indole, carbazole and dibenzothiophene (DBT). The thermodynamic and kinetic behaviours of AC‐(NH4)2S2O8‐15%‐1.5 were investigated. The adsorption of carbazole on AC‐(NH4)2S2O8‐15%‐1.5 follows the Langmuir model, while that of quinoline, indole and DBT follows the Freundlich model. All the adsorption processes are spontaneous, with the nature of adsorption for indole and carbazole endothermic, and that for quinoline and DBT exothermic. The adsorption of the N and S compounds in this study follows a pseudo second‐order model. Intra‐particle diffusion is one of the rate‐controlled steps for N compounds.

Oxidative lactonization of oleanane and ursane acids by treating with ozone

Features of process of oxidative lactonization of 3-oxooleanolic and 3-oxoursolic acids under treatment with ozone were established. The similarity of the processes consists in generation of 3-oxooleanolic or 3-oxoursolic 13β,28-lactones with 12-oxo or 12-hydroxy group. In the case of ursane derivative the generation exclusively of compounds with β-oriented 12-hydroxy group was observed, in the case of oleanane lactones prevailingly compounds with α-oriented 12-hydroxy group were obtained. The processes differ by the generation of the product of allylic oxidation, 3,11-dioxoursolic acid, or the isolation of the product of the lactone cycle opening with participation of the solvent, 3,12-dioxoolean-28-olic acid.