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PubMed2001

Stereoselective synthesis of delta-lactones from 5-oxoalkanals via one-pot sequential acetalization, Tishchenko reaction, and lactonization by cooperative catalysis of samarium Ion and mercaptan.

By the synergistic catalysis of samarium ion and mercaptan, a series of 5-oxoalkanals was converted to (substituted) delta-lactones in efficient and stereoselective manners. This one-pot procedure comprises a sequence of acetalization, Tishchenko reaction and lactonization. The deliberative use of mercaptan, by comparison with alcohol, is advantageous to facilitate the catalytic cycle. The reaction mechanism and stereochemistry are proposed and supported by some experimental evidence. Such samarium ion/mercaptan cocatalyzed reactions show the feature of remote control, which is applicable to the asymmetric synthesis of optically active delta-lactones. This study also demonstrates the synthesis of two insect pheromones, (2S,5R)-2-methylhexanolide and (R)-hexadecanolide, as examples of a new protocol for asymmetric reduction of long-chain aliphatic ketones.

Acetylation↗
PubMed2004

Conformationally constrained analogues of diacylglycerol. 24. Asymmetric synthesis of a chiral (R)-DAG-lactone template as a versatile precursor for highly functionalized DAG-lactones.

[structure: see text] Commercially available 2-methylenepropane-1,3-diol was converted to chiral epoxide (R)-2 via Sharpless asymmetric epoxidation in >96% ee. Regiospecific epoxide ring opening and reduction of the intermediate alkyne set the stage for a one-pot lactonization to give (R)-6, a convenient precursor for all functionalized chiral DAG-lactones used as potent PK-C ligands. The synthesis of the most potent DAG-lactones known to date, (Z)-10 and (E)-10, served to confirm PK-C's exclusive preference for the (R)-stereochemistry in this class of compounds.

Binding Sites↗
PubMed1999

Beta-lactones as a new class of cysteine proteinase inhibitors: inhibition of hepatitis A virus 3C proteinase by N-Cbz-serine beta-lactone.

[reaction: see text] N-Benzyloxycarbonyl-L-serine beta-lactone (1) is shown to irreversibly inactivate the 3C cysteine proteinase of hepatitis A virus (HAV) with k(inact) = 0.70 min(-1), K(I) = 1.84 x 10(-4) M and k(inact)/K(I) = 3800 M(-1) min(-1) at an enzyme concentration of 0.1 microM. Mass spectrometric and HMQC NMR studies using 13C-labeled 1 show that the active site cysteine (Cys-172) thiol of the HAV 3C proteinase attacks the beta-position (i.e. C-4) of the oxetanone ring, thereby leading to ring opening and alkylation of the sulfur. In contrast, the enantiomer of this beta-lactone, 2, is a reversible competitive inhibitor (Ki = 1.50 x 10(-6) M) at similar enzyme concentrations. The beta-lactone motif represents a new class of inhibitors of cysteine proteinases.

3C Viral Proteases↗
PubMed1975

Sesquiterpene lactones. XVI. In vitro studies on cytotoxic properties of sesquiterpene lactones in tissue cultures of human and animal malignant cells.

Cytoxicity of 18 new sesquiterpene lactones and related compounds was studied by tissue culture method using human malignant KB and HeLa cells, normal RK 13 animal cells, and by the modified plate test of Miyamura. On the basis of criteria of CCNSC HIH, USA, seven compounds with ED50 activities between 0-41 and 3-5 mug/ml were qualified for further investigation in vivo. Cytotoxic activity of sesquiterpene lactones was dependent on presence of an unsaturated lactone ring, (see article). As a rule activity of germacranolids was higher than that of guaianolides.

Animals↗
PubMed2002

Lactone enol cation-radicals: gas-phase generation, structure, energetics, and reactivity of the ionized enol of butane-4-lactone.

The cation-radical of 2-hydroxyoxol-2-ene (1(+*)) represents the first lactone enol ion whose structure and gas-phase ion chemistry have been studied by experiment and theory. Ion 1(+*) was generated by the McLafferty rearrangement in ionized 2-acetylbutane-4-lactone and characterized by accurate mass measurements, isotope labeling, metastable ion and collisionally activated dissociation (CAD) spectra. Metastable 1(+*) undergoes competitive losses of H-4 and CO that show interesting deuterium and (13)C isotope effects. The elimination of CO from metastable 1(+*) shows a bimodal distribution of kinetic energy release and produces (*)CH(2)CH(2)CHdbond;OH(+) (14(+*)) and CH(3)CHdbond;CHOH(+*) (15(+*)) in ratios which are subject to deuterium isotope effects. Ab initio calculations at the G2(MP2) level of theory show that 1(+*) is 105 kJ mol(-1) more stable than its oxo form, [butane-4-lactone](+*)(2(+*)). The elimination of CO from 1(+*) involves multiple isomerizations by hydrogen migrations and proceeds through ion-molecule complexes of CO with 14(+*) and 15(+*). In addition, CO is calculated to catalyze an exothermic isomerization 14(+*) --> 15(+*) in the ion-molecule complexes. Multiple consecutive hydrogen migrations in metastable 1(+*), as modeled by RRKM calculations on the G2(MP2) potential energy surface, explain the unusual deuterium kinetic isotope effects on the CO elimination.

Journal Article↗
PubMed2004

Bacterial populations in the rhizosphere of tobacco plants producing the quorum-sensing signals hexanoyl-homoserine lactone and 3-oxo-hexanoyl-homoserine lactone.

A tobacco line genetically modified to produce two N-acyl homoserine lactones and its non-transformed parental line were grown in non-sterile soil. Microbial populations inhabiting the bulk soil, and those colonizing the root system of the two tobacco lines, were analyzed using cultivation-independent (phospholipid fatty acid and denaturing gradient gel electrophoresis) and cultivation-based assays. The cell density of total cultivable bacteria, fluorescent pseudomonads, sporulated, and thermotolerant bacteria was also determined in a time-course experiment (15 weeks). A possible "rhizosphere effect" related to the development of the plant was seen. However, no dissimilarities in cell population densities or population ratios of the microbial groups were detected in the rhizosphere of the two plant lines. Similarly, bacterial communities that either produced N-acyl homoserine lactone or degraded the signal hexanoyl homoserine lactone were enumerated from the two plant lines. No noticeable differences were evidenced from one plant genotype to the other. Whilst the transgenic plants released detectable amounts of the quorum-sensing signal molecules and efficiently cross-talked with the surrounding microbial populations, the bias generated by these signals in the reported experimental conditions therefore appears to remain weak, if not non-existent.

4-Butyrolactone↗
PubMed1993

Conformationally constrained analogues of diacylglycerol (DAG)--II. Differential interaction of delta-lactones and gamma-lactones with protein kinase C (PK-C).

Starting with L- or D-tri-O-acetylglucal, the corresponding L- and D-isomers of 4-O-tetradecanoyl-2,3-dideoxyglucono-1,5-lactone (2a and 2b) were synthesized as rigid diacylglycerol (DAG) analogues. Consistent with results obtained previously with the equivalent L- and D-1,4-lactones (1a and 1b), the L-isomer (2a) was more potent in activating protein kinase C (PK-C) and inhibiting the binding of [3H]phorbol-12,13-dibutyrate to the enzyme's regulatory domain. In these experiments the difference in potency observed between the optical antipodes of the gluconolactones (2a and 2b) was greatly increased relative to the corresponding ribonolactones (1a and 1b). These results indicate that PK-C is more able to discriminate between optical antipodes, in favor of the L-isomer, as the lactone ring increases from five to six.

Binding Sites↗
PubMed2002

Conformation-dependent reaction thermochemistry: study of lactones and lactone enolates in the gas phase.

Gas-phase acidities (Delta H degrees (acid)) of lactones with ring sizes from four to seven have been measured on a Fourier transform ion cyclotron resonance mass spectrometer. Electron affinities (EAs) of the corresponding lactone enolate radicals were measured on a continuous-wave ion cyclotron resonance mass spectrometer, and the bond dissociation energies (BDEs) of the alpha C-H bonds were derived. In order of increasing ring size, Delta H degrees (acid) = 368.7 +/- 2., 369.4 +/- 2.2, 367.3 +/- 2.2, and 368.3 +/- 2.2 kcal/mol and BDE = 99.4 +/- 2.3, 94.8 +/- 2.3, 89.2 +/- 2.3, and 92.8 +/- 2.4 kcal/mol for beta-propiolactone, gamma-butyrolactone, delta-valerolactone, and epsilon-caprolactone, respectively. For their corresponding enolate radicals, EA = 44.1 +/- 0.3, 38.8 +/- 0.3, 35.3 +/- 0.3, and 37.9 +/- 0.6 kcal/mol. All of these lactones are considerably more acidic than methyl acetate, consistent with a dipole repulsion model. Both BDEs and EAs show a strong dependence on ring size, whereas Delta H degrees (acid) does not. These findings are discussed, taking into account differential electronic effects and differential strain between the reactant and product species in each reaction.

Journal Article↗
PubMed1999

Guaianolides as immunomodulators. Synthesis and biological activities of dehydrocostus lactone, mokko lactone, eremanthin, and their derivatives.

The naturally occurring guaianolides, namely mokko lactone (1), dehydrocostus lactone (2), eremanthin (3), and related guaianolides, 16, 17, 21, 22, 28-31, 33, 36, 37, and 39, have been synthesized starting from l-alpha-santonin in an effort to examine their structure-activity relationship as inhibitors of the killing function of cytotoxic T lymphocytes (CTL) and the induction of intercellular adhesion molecule-1 (ICAM-1). It was observed during the present study that the guaianolides possessing an alpha-methylene gamma-lactone moiety, i.e., 2, 3, 30, 33, 37, and 39, exhibited significant inhibitory activity toward the killing function of CTL and the induction of ICAM-1.

Adjuvants, Immunologic↗
PubMed1994

Selective inhibition of gastrointestinal beta-glucuronidase by poly(vinylbenzyl D-glucaro(1,4)lactonate). Part 2. Poly(vinylbenzyl D-glucaro(1,4) lactonate) in vitro inhibition studies.

In vitro inhibition studies with beta-glucuronidase from purified E. coli and mouse intestinal contents indicated that the polymer, poly(vinylbenzyl D-glucaro(1,4)lactonate, is an effective beta-glucuronidase inhibitor. Purified E. coli beta-glucuronidase was inhibited by 99.6% with 177 mM D-glucaro(1,4)lactone using the polymer-inhibitor. Similarly, 95% inhibition of beta-glucuronidase activity of mouse intestinal contents was obtained with 177 mM and 50% inhibition was obtained with 31.5 mM D-glucaro(1,4)lactone based on the modified polymer. The structural requirements of an effective beta-glucuronidase inhibitor based on the structure of the polymer-inhibitor are also discussed.

Animals↗
PubMed2004

Stereoselective synthesis of (+)-nephrosteranic acid, (+)-trans-cognac lactone, and (+)-trans-whisky lactone using a chiral cyclohexadienyl Ti compound.

We present the stereoselective transfer of cyclohexadienyl from 3-metalated 1,4-cyclohexadienes to various aldehydes. Lewis-acid-mediated "allylation" of aldehydes by treatment with 3-silylated and 3-stannylated 1,4-cyclohexadienes could not be achieved with high diastereoselectivity. In contrast, cyclohexadienyl titanium compounds reacted with both aliphatic and aromatic aldehydes with good-to-excellent diastereoselectivities. Reaction of a chiral TADDOL-derived (TADDOL, 2,2-dimethyl-alpha,alpha,alpha',alpha'-tetraphenyl-1,3-dioxolandimethanol) cyclohexadienyl Ti derivative with various aldehydes led to the corresponding homoallylic alcohols with excellent diastereo- and enantioselectivities. Lower selectivities were obtained with chiral B-cyclohexadienyldiisopinocampheylborane. The 1,3-cyclohexadienes are very useful building blocks for the preparation of biologically important gamma-butyrolactones. Short efficient syntheses of (+)-nephrosteranic acid, (+)-trans-whisky lactone, and (+)-trans-cognac lactone by desymmetrization of 1,4-cyclohexadiene are described.

Aldehydes↗
PubMed2001

Lactones: Part 11. Feeding-deterrent activity of some bi- and tricyclic terpenoid lactones.

The feeding-deterrent activities of thirteen synthetic terpenoid lactones, including isomeric bicyclic gamma-spirolactones with the limonene system and tricyclic gamma-lactones with the pinane system, were determined towards three storage pest insects: the adults of Sitophilus granarius, the adults and larvae of Tribolium confusum and the larvae of Trogoderma granarium. The configuration of chiral centres, as well as the presence of additional functional groups (double bond, iodine and hydroxy group) are important for antifeeding activity.

Animals↗
PubMed2002

A beta-lactone route to chiral gamma-substituted alpha-amino acids: application to the concise synthesis of (S)-alpha-azidobutyro lactone and a natural amino acid.

[reaction: see text] Beta-lactones are useful synthetic intermediates allowing access to a number of functional arrays. In this report, enantiomerically pure 4-trichloromethyl-2-oxetanone is shown to be a versatile amino acid synthon leading to a variety of gamma-substituted alpha-amino acid precursors. The utility of this methodology was demonstrated by the concise synthesis of a protected homoserine equivalent, alpha-azidobutyro lactone, and a naturally occurring alpha-amino acid from the seeds of Blighia unijugata.

4-Butyrolactone↗
PubMed1974

Microbial reduction of ketopantoyl lactone to pantoyl lactone.

The results of a microbial survey study have shown that the ability to reduce added ketopantoic acid (or ketopantoyl lactone) and accumulate pantoic acid (or pantoyl lactone) in the growth medium is widespread among diverse fungi. The reductions generally proceeded with less than full stereoselectivity. However, specific strains of the ascomycete Byssochlamys fulva were found to form D[-]-pantoic acid in unusually high yields and optical purity.

4-Butyrolactone↗
PubMed1999

The absolute configuration of belactin A, a beta-lactone-containing serine carboxypeptidase inhibitor: importance of the beta-lactone structure for serine carboxypeptidase inhibition.

The absolute configuration of belactin A, a beta-lactone-containing serine carboxypeptidase inhibitor was studied by a crystal X-ray diffraction analysis and its absolute structure was determined to be (2R,3S)-2-¿(3S)-3-[(2-amino-5-chlorophenyl)carboxamido]-1,1-dimethyl-2-o xobutyl¿-3-methyl-4-oxooxetane. The importance of the beta-lactone structure for inhibitory activity was found by preparing several derivatives of belactin A.

Benzamides↗
PubMed1988

Direct effects of 3,4-dihydroxybutanoic acid gamma-lactone and 2,4,5-trihydroxypentanoic acid gamma-lactone on lateral and ventromedial hypothalamic neurons.

The mechanism of central actions of endogenous sugar acids, 3,4-dihydroxybutanoic acid gamma-lactone (3,4-DB) and 2,4,5-trihydroxypentanoic acid gamma-lactone (2,4,5-TP) which have been newly identified as satiety and hunger substances respectively, was investigated. Intracellular recordings were made from neurons in the lateral hypothalamic area (LHA) of rats and ventromedial hypothalamic nucleus (VMH) of guinea pigs, brain areas referred to as feeding and satiety centers, respectively. The LHA neurons hyperpolarized by 3,4-DB show no change in membrane input resistance while the depolarized VMH neurons are associated with an increase in membrane resistance. The mechanisms related to the action of 3,4-DB on these hypothalamic neurons are similar to those in case of glucose on the glucose-sensitive neuron in the LHA and the glucoreceptor neuron in the VMH. 2,4,5-TP depolarized LHA neurons but hyperpolarized VMH neurons with a decrease in the membrane resistance. Our findings indicate that 3,4-DB and 2,4,5-TP have reciprocal effects on each LHA and VMH neurons, with regard to neuronal excitability.

Action Potentials↗