Isomeric Lactones Research Articles

ChemInform Abstract: A Stereocontrolled Synthesis of Hagen′s Gland Lactones via Iterative Proline Catalyzed α‐Aminoxylation and Oxa‐Michael Addition Reactions.

A simple and efficient synthesis of Hagen's gland lactones was achieved using a sequential α-aminoxylation/oxa-Michael approach in a highly diastereoselective manner with assignment of relative configurations. This method was found to be applicable to the synthesis of various other isomers of Hagen's gland lactones.

Relationship between Menthiafolic Acid and Wine Lactone in Wine.

Menthiafolic acid (6-hydroxy-2,6-dimethylocta-2,7-dienoic acid, 2a) was quantified by GC-MS in 28 white wines, 4 Shiraz wines, and for the first time in 6 white grape juice samples. Menthiafolic acid was detected in all but one of the wine samples at concentrations ranging from 26 to 342 μg/L and in the juice samples from 16 to 236 μg/L. Various model fermentation experiments showed that some menthiafolic acid in wine could be generated from the grape-derived menthiafolic acid glucose ester (2b) during alcoholic and malolactic fermentation. Samples containing high concentrations of menthiafolic acid were also analyzed by enantioselective GC-MS and were shown to contain this compound in predominantly the (S)-configuration. Enantioselective analysis of wine lactone (1) in one of these samples, a four-year-old Chardonnay wine showed, for the first time, the presence of the 3R,3aR,7aS isomer of wine lactone (1b), which is the enantiomer of the form previously reported as the sole isomer present in young wine samples. The weakly odorous 3R,3aR,7aS 1b form comprised 69% of the total wine lactone in the sample. On the basis of the enantioselectivity of the hydrolytic conversion of menthiafolic acid to wine lactone at pH 3.0 determined previously and the relative proportions of (R)- and (S)-menthiafolic acid in the Chardonnay wine, the predicted ratio of wine lactone enantiomers that would be formed from hydrolysis at ambient temperature of the menthiafolic acid present in this wine was close to the ratio measured, which was consistent with menthiafolic acid being the major or sole precursor to wine lactone in this sample.

Hydroxy lactones with the gem-dimethylcyclohexane system – Synthesis and antimicrobial activity

Two new lactones comprising the gem-dimethylcyclohexane ring: 2-chloro-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one and 2-bromo-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one as well as the already known 2-iodo-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, were obtained from (6,6-dimethylcyclohex-2-en-1-yl)acetic acid. These lactones were used as substrates for the screening of biotransformation by whole cells of nine fungal strains (Fusarium species, Syncephalastrum racemosum and Cunninghamella japonica). Some of these microorganisms (mainly Fusarium species) transformed all three lactones during the hydrolytic dehalogenation into 2-hydroxy-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one. It is worth noting that two microorganisms (Fusarium culmorum and Fusarium scirpi) converted iodolactone with very high enantioselectivity (75.1% and 91.6%, respectively). The (+) isomer of hydroxy lactone was preferred. At the last step the hydroxy lactone obtained during biotransformation was examined for its biological activity against bacteria, yeasts and fungi. It was found that this compound inhibits growth of some tested microorganisms.

Lactones 42. Stereoselective enzymatic/microbial synthesis of optically active isomers of whisky lactone

Two different methods, enzyme-mediated reactions and biotrasformations with microorganisms, were applied to obtain optically pure cis- and trans-isomers of whisky lactone 4a and 4b. In the first method, eight alcohol dehydrogenases were investigated as biocatalysts to enantioselective oxidation of racemic erythro- and threo-3-methyloctane-1,4-diols (1a and 1b). Oxidation processes with three of them, alcohol dehydrogenases isolated from horse liver (HLADH) as well as recombinant from Escherichia coli and primary alcohol dehydrogenase (PADH I), were characterized by the highest degree of conversion with moderate enantioselectivity (ee=27–82%) of the reaction. In all enzymatic reactions enantiomerically enriched not naturally occurring isomers of trans-(−)-(4R,5S)-4b or cis-(+)-(4R,5R)-4a were formed preferentially. In the second strategy, based on microbial lactonization of γ-oxoacids, naturally occurring opposite isomers of whisky lactones were obtained. Trans-(+)-(4S,5R)-isomer (ee=99%) of whisky lactone 4b was stereoselectively formed as the only product of biotransformations of 3-methyl-4-oxooctanoic acid (5) catalyzed by Didimospheria igniaria KCH6651, Laetiporus sulphurens AM525, Chaetomium sp.1 KCH6670 and Saccharomyces cerevisiae AM464. Biotransformation of γ-oxoacid 5, in the culture of Beauveria bassiana AM278 and Pycnidiella resinae KCH50 afforded a mixtures of trans-(+)-(4S,5R)-4b with enantiomeric excess ee=99% and cis-(−)-(4S,5S)-4a with enantiomeric excesses ee=77% and ee=45% respectively.

Conformational Analysis of Antistaphylococcal Sesquiterpene Lactones from Inula helenium Essential Oil

Isomeric eudesmane-type sesquiterpene lactones: alantolactone (1), isoalantolactone (2) and diplophyllin (3), the main constituents of Inula helenium L. root essential oil, are strong antistaphylococcal agents. Energetically favorable conformations of these were calculated (MM+ and MMFF94 molecular mechanics and AM1 and PM3 semi-empirical methods) and mutually compared. The compounds were additionally described in terms of selected 2D and 3D molecular descriptors. Alantolactone and isoalantolactone mainly adopt "U"-shaped conformations (>99%, calculated at 298 K; "closed" geometries), with the carbonyl moiety being rather sterically hindered by the axial methyl group. In contrast, the cyclohexene and lactone rings of diplophyllin are mutually oriented in such a way to give the overall "S"-shape to the molecule ("open" geometry). These conformational differences, inherently influencing the optimal interaction of lactones 1-3 with the binding region of target biomolecules, could be, at least partially, responsible for the higher observed antistaphylococcal activity of diplophyllin in comparison with the other two isomeric lactones.

1,3-Dipolar addition of diazocyclopropane to eudesmane-type methylidene lactones and thermolysis of the resulting spiro-fused pyrazolines

Reactions of alanto-, isoalanto-, and alloalantolactones, which are unsaturated eudesmane-type lactones, with diazocyclopropane generated in situ from N-cyclopropyl-N-nitrosourea under the action of sodium methoxide proceed alike, are highly regio- and stereoselective, and always give spiro-fused pyrazolines via cycloaddition to the exocyclic double bond of the methylidene group of the lactone ring. Their thermolysis at 195–210 °C results in elimination of molecular nitrogen, mainly yielding spiropentane-containing lactones. Minor thermolysis products (10–12%) are isomeric 13-cyclopropyl lactones.

Fluorinated ɛ-caprolactone: Synthesis and ring-opening polymerization of new α-fluoro-ɛ-caprolactone monomer

Fluorinated polyester was synthesized from a novel α-fluoro-ɛ-caprolactone monomer (α-FCL). The monomer was synthesized from commercially available cyclohexene oxide in three steps. Baeyer–Villiger reaction using 3-chloroperoxybenzoic acid of the corresponding 2-fluorocyclohexanone resulted in formation of two isomeric lactones α-and-ɛ-fluoro-ɛ-caprolactones in 1:1.2 molar ratio, respectively. Poly(α-fluoro-ɛ-caprolactone) was synthesized by bulk ring-opening polymerization of α-fluoro-ɛ-caprolactone monomer (α-FCL) catalyzed by stannous octanoate, Sn(Oct) 2 at 120 °C for 6 h. Relationships between reaction time, polymer yield, and molecular weight were established. The ring-opening polymerization of ɛ-fluoro-ɛ-caprolactone (ɛ-FCL) produce geminal fluorohydrin, which is not stable and it is subsequently dehydrofluorinated to give the corresponding aldehyde. Copolymerization of α-FCL with ɛ-caprolactone (ɛ-CL) in various feed ratios was also investigated. Detail microstructure analyses of the copolymers were accomplished from 1H, 13C and 2-D NMR data. Presence of fluorine atoms is expected to regulate the chemical and physical properties of the polyester.

Evidence for a Volatile Pheromone inAgrilus planipennisFairmaire (Coleoptera: Buprestidae) That Increases Attraction to a Host Foliar Volatile

Analysis by gas chromatography/mass spectrometry (GC/MS) of volatiles from virgin female emerald ash borer, Agrilus planipennis Fairmaire confirmed the emission of (3Z)-lactone [(3Z)-dodecen-12-olide] but not its geometric isomer, (3E)-lactone [(3E)-dodecen-12-olide]. Gas chromatographic/electroantennographic (GC/EAD) analysis of synthetic (3Z)-lactone, which contained 10% (3E)-lactone, showed a strong response of male and female antennae to both isomers. EAG analysis with 0.01- to 100-μg dosages showed a positive dose response, with females giving significantly higher responses than males. In field experiments with sticky purple prism traps, neither lactone isomer affected catches when combined with ash foliar or cortical volatiles (green leaf volatiles or Phoebe oil, respectively). However, on green prism traps, the (3Z)-lactone significantly increased capture of male A. planipennis when traps were deployed in the canopy. Captures of males on traps with both (3E)-lactone and (3Z)-hexenol or with (3Z)-lactone and (3Z)-hexenol were increased by 45-100%, respectively, compared with traps baited with just (3Z)-hexenol. In olfactometer bioassays, males were significantly attracted to (3E)-lactone, but not the (3Z)-lactone or a 60:40 (3E):(3Z) blend. The combination of either (3E)- or (3Z)-lactone with Phoebe oil was not significantly attractive to males. Males were highly attracted to (3Z)-hexenol and the (3Z)-lactone + (3Z)-hexenol combination, providing support for the field trapping results. These data are the first to demonstrate increased attraction with a combination of a pheromone and a green leaf volatile in a Buprestid species.

ChemInform Abstract: The Photosensitized Oxygenation of Furanoeremophilanes. Part 3. The Transformations to the Skeletally Isomeric Lactones from Furanofukinol.

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Stereoisomerization of β-Hydroxy-α-sulfenyl-γ-butyrolactones Controlled by Two Concomitant 1,4-Type Nonbonded Sulfur−Oxygen Interactions As Analyzed by X-ray Crystallography

We have synthesized nine beta-hydroxy-alpha-sulfenyl-gamma-butyrolactones having different substituents. The syn-anti or syn-syn lactones (or any mixture of both) invariably isomerized into syn-anti/syn-syn lactones in a ratio of approximately 6/4. The other two possible isomeric lactones (anti-syn or anti-anti) were never observed. The crystal structures of syn-syn lactones have been determined. We found sulfur-oxygen distances to be less than the sum of the van der Waals radii (3.3 A), with the angle formed among the hydroxylic oxygen, sulfur, and quaternary aromatic carbon being close to 180 degrees. In addition, carbonylic oxygen-sulfur is directed <40 degrees from the perpendicular to the C-S-C. Theoretical calculations were performed which emphasize the directionality of the sulfur-oxygen interaction. The X-ray and theoretical studies demonstrate that two concomitant, attractive 1,4 intramolecular interactions of divalent sulfur with both carbonyl and hydroxyl oxygens are the driving force for the aforementioned stereochemical preference. Then nonbonded sulfur-oxygen interactions would control the stereoselectivity of the reaction. The same features are observed in the X-ray structure of a beta-hydroxy-alpha-sulfinyl-gamma-butyrolactone.

Towards synthesis of kavalactone derivatives

Kavalactone derivatives were synthesized using a Heck reaction of the 4-methoxy-6-vinyl-5,6-dihydropyran-2-one with aryl iodides. The Suzuki–Miyaura reaction of an aryl boronic acid and ( Z)-4-methoxy-6-(2-iodovinyl)-5,6-dihydropyran-2-one has also been successfully used to produce both Z and E isomers of lactones.

Mechanism of Wine Lactone Formation: Demonstration of Stereoselective Cyclization and 1,3-Hydride Shift

The cyclization mechanism of (E)-2,6-dimethyl-6-hydroxyocta-2,7-dienoic acid to wine lactone under acidic aqueous conditions was investigated using the two stereoselectively deuterium-labeled precursors (2E,6R,7Z)-[8-2H]-2,6-dimethyl-6-hydroxyocta-2,7-dienoic acid and (2E,7E)-(+/-)-[8-2H]-2,6-dimethyl-6-hydroxyocta-2,7-dienoic acid. A detailed analysis of the generated wine lactone isomers by enantioselective multidimensional gas chromatography (MDGC)/ion trap tandem mass spectrometry demonstrates that the formation of wine lactone proceeds via a nonenzymatic stereoselective cationic cyclization cascade that includes a 1,3-hydride shift. Usually, such mechanisms are features of cyclization reactions that are catalyzed by terpene cyclases. This nonenzymatic conversion of an acyclic precursor to a bicyclic monoterpene under relevant cationic cyclization conditions has rarely been observed and confirms recent suggestions that the precursor itself can provide the chemical functionality required for specific steps in the cyclization cascade.

High-performance CE: An effective method to study lactonization of α2,8-linked oligosialic acid

A sensitive and efficient method using high-performance CE (HPCE) and neuraminidase hydrolysis was developed to study the lactonization and hydrolysis of alpha2,8-pentasialic acid. Eleven lactone species of pentasialic acid formed in glacial acetic acid were detected and classified into three groups based on the number of carboxylic acids: monolactones with four carboxylic acids, dilactones with three carboxylic acids, and trilactones with two carboxylic acids. These lactones eluted between the original pentamer (with five carboxylic acids) and the fully lactonized species (with one carboxylic acid) in HPCE. Eight of the isomers were identified by hydrolysis with neuraminodase. Results obtained from previous reports and from this study together reveal a general rule for predicting the subtle difference in the acidity of each carboxylic acid in oligosialic acids: the closer the carboxylic acid is to the nonreducing end, the more acidic it is. Therefore, the elution order of lactone isomers having the same number of carboxylic groups can be predicted from the position of the free carboxylic groups in pentasialic acid. We used this principle and the results of hydrolysis with neuraminidase to identify hexamer lactone isomers separated by HPCE.

Cruentaren, a New Antifungal Salicylate-Type Macrolide from Byssovorax cruenta (Myxobacteria) with Inhibitory Effect on Mitochondrial ATPase Activity

The novel macrolide cruentaren A was produced at levels up to 3.2 mg/liter by cultures of the myxobacterium Byssovorax cruenta. The new compound strongly inhibited the growth of yeasts and filamentous fungi and showed high cytotoxicity against L929 mouse fibroblast cells. A minor co-metabolite of cruentaren A, named cruentaren B, and identified as a six-membered lactone isomer of cruentaren A, showed only marginal cytotoxicity and no antifungal activity. Cruentaren A inhibited F0F1 mitochondrial ATP-hydrolysis in submitochondrial particles of yeasts and beef heart.

Bioresponse-guided decomposition of roast coffee beverage and identification of key bitter taste compounds

Sensory-guided fractionation of a roasted coffee brew by means of sequential solvent extraction, ultrafiltration, and RP-HPLC demonstrated a group of ethyl acetate soluble compounds formed from O-hydroxycinnamoyl quinic acid derivatives upon coffee roasting as the key compounds contributing to the bitter taste of roasted coffee beverages. LC-MS/MS studies, 1D- and 2D-NMR spectroscopy, syntheses, and model roast experiments with 5-O-caffeoyl- and 5-O-feruloylquinic acid led to the unequivocal identification of 3-O-caffeoyl-γ-quinide (2a), 4-O-caffeoyl-γ-quinide (3a), 5-O-caffeoyl-epi-δ-quinide (4a), 4-O-caffeoyl-muco-γ-quinide (5a), 5-O-caffeoyl-muco-γ-quinide (6a), 3-O-feruloyl-γ-quinide (2b), and 4-O-feruloyl-γ-quinide (3b) as intense coffee bitter tastants. Besides these individual bitter compounds, a highly complex and intensely bitter HPLC fraction was isolated from the ethyl acetate extractables of coffee brew. Application of COSY spectroscopy and alkaline hydrolytic degradation gave strong evidence that the bitter taste of that fraction is due to a multiplicity of rather complex quinic acid lactone isomers multiply esterified with p-coumaric acid, caffeic acid, ferulic acid, 3,4-dimethoxycinnamic acid, and quinic acid, respectively. As representatives of this fraction, 3,4-O-dicaffeoyl-γ-quinide (10), 3,5-O-dicaffeoyl-epi-δ-quinide (11), and 4,5-O-dicaffeoyl-muco-γ-quinide (12) have been isolated, purified, and identified as strongly bitter-tasting compounds in roasted coffee. For the first time, bitter taste recognition thresholds were determined for the individual compounds showing that, strongly depending on their chemical structure, the bitter threshold levels ranged between 9.8 and 180 μmol/l (water).

Volatile composition and sensory characteristics of Chardonnay wines treated with American and Hungarian oak chips

Toasted or non-toasted chips of oak woods of different geographical provenances were macerated in Chardonnay wines (4 g/l) during a period of 25 days. Oak lactones were detected in significant quantities in wines treated with American oak. Only trace amounts of oak lactones were detected in the wines treated with Hungarian oak. Toasting of the oaks increased the quantities of the compounds derived from the thermal degradation of lignin: vanillin, eugenol, guaiacol and its derivatives and the pyrolysis of cellulose and hemicellulose: furfural and 5-methyl furfural, and decreased the concentrations of the two isomers of oak lactones. The concentrations of the majority of the volatile compounds did not present statistically significant differences between 15 and 25 days. However, the wines preferred by the tasters and with maximum intensity of the sensory attributes acquired were those treated with oak chips for 25 days. Chemical and sensorial analyses of wines revealed that the effect of the toasting of oak chips on wine characteristics was greater than the type of oak used. All wines studied were positively evaluated by the panellists.

Erratum to: Analysis and design of a dye-doped polymer optical fiber amplifier

A rhodamine-B-doped polymer optical fiber amplifier (RBDPOFA) has been successfully fabricated and tested. In this paper, all parameters affecting the gain of the RBDPOFA are recognized. The time-dependent and time-independent rate equations are solved. By using Runge–Kutta and finite-element methods, different conditions are described and fluctuations of the fiber laser are analyzed. From the time-dependent rate equations, the gain and level-density variations with time can be predicted. These fiber amplifiers have unstable conditions. In experiments, the decay of dye dopants in the high pump power regime has been observed. For example, in a high pump power rhodamine-B is converted from the zwitterion isomer to the colorless lactone isomer [1]. Therefore, for complete coincidence of theoretical and experimental results, this effect must be included in the analysis, which is however beyond the scope of this paper and will be discussed in the near future.

Erratum to: Analysis and design of a dye-doped polymer optical fiber amplifier

A rhodamine-B-doped polymer optical fiber amplifier (RBDPOFA) has been successfully fabricated and tested. In this paper, all parameters affecting the gain of the RBDPOFA are recognized. The time-dependent and time-independent rate equations are solved. By using Runge-Kutta and finite-element methods, different conditions are described and fluctuations of the fiber laser are analyzed. From the time-dependent rate equations, the gain and level-density variations with time can be predicted. These fiber amplifiers have unstable conditions. In experiments, the decay of dye dopants in the high pump power regime has been observed. For example, in a high pump power rhodamine-B is converted from the zwitterion isomer to the colorless lactone isomer [1]. Therefore, for complete coincidence of theoretical and experimental results, this effect must be included in the analysis, which is however beyond the scope of this paper and will be discussed in the near future.

Comparison of anti‐feedant and insecticidal activity of nimbin and salannin photo‐oxidation products with neem (Azadirachta indica) limonoids

Photo-oxidation of the neem limonoids nimbin and salannin with UV light in the presence of oxygen gives two isomeric lactone products per limonoid, nimbinolide and isonimbinolide, and salanninolide and isosalanninolide, respectively. When compared in insect tests with the important limonoids of neem seeds, azadirachtin, nimbin and salannin, isonimbinolide and isosalanninolide show activity greater than that of nimbin or salannin and in some respects show activity approaching that of azadirachtin. The photo-oxidation products were tested for anti-feedant activity and toxicity against larvae of three species of Lepidoptera, Spodoptera littoralis (Boisd), Spodoptera frugiperda (FE Smith) and Helicoverpa armigera (Hübner) and nymphs of the locusts Schistocerca gregaria (Forskål) and Locusta migratoria (L).

Metabolism of Deuterated Isomeric 6,7‐Dihydroxydodecanoic Acids in Saccharomyces cerevisiae – Diastereo‐ and Enantioselective Formation and Characterization of 5‐Hydroxydecano‐4‐lactone (=4,5‐Dihydro‐5‐(1‐hydroxyhexyl)furan‐2(3H)‐one) Isomers

AbstractThe chemical synthesis of deuterated isomeric 6,7‐dihydroxydodecanoic acid methyl esters 1 and the subsequent metabolism of esters 1 and the corresponding acids 1a in liquid cultures of the yeast Saccharomyces cerevisiae was investigated. Incubation experiments with (6R,7R)‐ or (6S,7S)‐6,7‐dihydroxy(6,7‐2H2)dodecanoic acid methyl ester ((6R,7R)‐ or (6S,7S)‐(6,7‐2H2)‐1, resp.) and (±)‐threo‐ or (±)‐erythro‐6,7‐dihydroxy(6,7‐2H2)dodecanoic acid ((±)‐threo‐ or (±)‐erythro‐(6,7‐2H2)‐1a, resp.) elucidated their metabolic pathway in yeast (Tables 1–3). The main products were isomeric 2H‐labeled 5‐hydroxydecano‐4‐lactones 2. The absolute configuration of the four isomeric lactones 2 was assigned by chemical synthesis via Sharpless asymmetric dihydroxylation and chiral gas chromatography (Lipodex ® E). The enantiomers of threo‐2 were separated without derivatization on Lipodex ® E; in contrast, the enantiomers of erythro‐2 could be separated only after transformation to their 5‐O‐(trifluoroacetyl) derivatives. Biotransformation of the methyl ester (6R,7R)‐(6,7‐2H2)‐1 led to (4R,5R)‐ and (4S,5R)‐(2,5‐2H2)‐2 (ratio ca. 4 : 1; Table 2). Estimation of the label content and position of (4S,5R)‐(2,5‐2H2)‐2 showed 95% label at C(5), 68% label at C(2), and no 2H at C(4) (Table 2). Therefore, oxidation and subsequent reduction with inversion at C(4) of 4,5‐dihydroxydecanoic acid and transfer of 2H from C(4) to C(2) is postulated. The 5‐hydroxydecano‐4‐lactones 2 are of biochemical importance: during the fermentation of Streptomyces griseus, (4S,5R)‐2, known as L‐factor, occurs temporarily before the antibiotic production, and (−)‐muricatacin (=(4R,5R)‐5‐hydroxy‐heptadecano‐4‐lactone), a homologue of (4R,5R)‐2, is an anticancer agent.