Lactone Products Research Articles

The molecular basis of Celmer's rules: the stereochemistry of the condensation step in chain extension on the erythromycin polyketide synthase.

Modular polyketide synthases (PKSs), for example, the 6-deoxyerythronolide B synthase (DEBS) responsible for synthesis of the aglycone core of the macrolide antibiotic erythromycin, generate an impressive diversity of asymmetric centers in their polyketide products. However, as noted by Celmer, macrolides have the same absolute configuration at all comparable stereocenters. Understanding how the stereochemistry of chain extension in controlled is therefore crucial to determining the common mechanism of action of these enzymes. We aimed to elucidate the molecular basis of Celmer's rules through in vitro studies with DEBS 1-TE, a bimodular derivative of DEBS from Saccharopolyspora erythraea, which uses (2S)-methylmalonyl-coenzyme. A to produce both D- and L-methyl centers in its triketide lactone product. We show here that condensation of (2S)-methylmalonyl-CoA in module 2 proceeds with decarboxylative inversion without cleavage of the C-H bond adjacent to the methyl group; in contrast, in module 1 the chain extension process involves loss of the hydrogen attached to C-2 of the methylmalonyl-CoA precursor. The production of the D-methyl center in module 2 without loss of hydrogen from the asymmetric center of the (2S)-methylmalonyl-CoA establishes that condensation takes place with inversion of configuration as in fatty acid biosynthesis. The loss of the key hydrogen from the (2S)-methylmalonyl-CoA to produce the L-methyl center generated in module 1 implies that an additional obligatory epimerization step takes place in that module. The nature and timing of the epimerization remain to be established.

A much improved synthesis of the siderophore enterobactin

Enterobactin, the cyclic trimer of N-(2,3-dihydroxybenzoyl)-L-serine has been efficiently prepared. A simple and high yield procedure has been developed for construction of N-protected serine trilactone as the key intermediate: methyl N-trityl-L-serinate and 2,2-dibutyl-1,3,2-dioxastannolane were refluxed in xylene to produce the triolide as the only lactone product in 85% yield.

Enantioselective oxidations by the diketocamphane monooxygenase isozymes from Psevdomonas putida

2,5-Diketocamphane 1,2-monooxygenase and 3,6-diketocamphane 1,6-monooxygenase isolated from (±)-camphor grown Pseudomonas putida NCIMB 10007 catalysed two different types of Baeyer-Villiger oxidations. The former isozyme biotransformed various bicyclic [3.2.0] ketones and aryl alkyl sulfides with consistently greater regio- and/or enantioselectivity, yielding lactone and sulfoxide products with enantiomeric excesses > 55%.

Synthesis of oxaspirolactones by manganic acetate promoted additions to exocyclic enol lactones

Oxidation of diverse β-diketones and β-ketoesters with manganic acetate generates intermediates which add to exocyclic enol lactones to afford spirocyclic lactone products. In the presence of added copper acetate the reaction pathway can be diverted to give unsaturated ketoesters.

Enantioselective whole cell and isolated enzyme catalysed Baever-Villiger oxidation of bicyclo[3.2.0]hept-2-en-6-one

Bicyclo[3.2.0]hept-2-en-6-one (Fig. 1, 1) was subjected to Baeyer-Villiger type oxidation using whole cells of Acinetobacter NCIMB 9871, Acinetobacter junii, Pseudomonas putida, Rhodococcus coprophilus, Rhodococcus fascians and cyclohexanone monooxygenase which had been purified 20-fold from Acinetobacter NCIMB 9871. In all cases, when the racemic ketone was oxidased, equal quantities of the regioisomeric lactones (−) 1( S),5( R) 2-oxabicyclo[3.3.0]oct-6-en-3-one (Fig.1, 3) and (−)-1 ( R), 5( S) 3-oxabicyclo[3.3.0]oct-6-en-2-one (Fig. 1, 4) were formed in high enantiomeric excess. The results were compared with peracid and alkaline peroxide mediated oxidations which showed no enantioselectivity towards the racemic ketone substrate and yielded only low amounts of 3-oxabicyclo[3.3.0]oct-6-en-2-one. Further investigation using purified cyclohexanone monooxygenase showed that the (+)-enantiomer was oxidised to 2-oxabicyclo[3.3.0]oct-6-en-3-one (Fig. 1, 3) whilst the (−)-enantiomer was oxidised to 3- oxabicyclo[3.3.0]oct-6-en-2-one (Fig. 1, 4). Both lactone products have potential applications as chirons for the synthesis of compounds containing cyclopentane and cyclohexane rings. The development of a chiral gas chromatography method allowed the rapid and accurate determination of the enantiomeric purity of bicyclic ketones and lactones.

The enzymatic Baeyer–Villiger oxidation of a series of bicyclo[2.2.1]hept-2-en-7-ones

The enzymatic Baeyer–Villiger oxidation of a series of bicyclo[2.2.1]hept-2-en-7-ones utilizing the enzyme cyclohexanone oxygenase (E.C. 1.14.13.-), isolated from the bacteria Acinetobacter NCIB 9871 provides lactone products with high enantiomeric excesses.

Synthesis of Lignan Aryldihydronaphthalene Lactones by Cyclization of Cinnamyl Arylpropiolate Esters: Revised Structure of β-Apopolygamatin

Unlike arylpropargyl arylpropiolates (e.g., 3) which yield, on heating in xylene, arylnaphthalene type I and type II lactones (4 and 5, respectively) in 1:1 ratio, cinnamyl arylpropiolates (e.g., 7) on heating in DMF gave the aryldihydronaphthalene-2-carboxylic acid lactones (e.g., 8) in excellent yield and regioselectivity. It is suggested that the aryldihydronaphthalene lactone product isolated from the tumor-inhibiting extract of Polygala polygama and previously named beta-apopolygamatin [17] has in fact the structure 1-(3',4'-methylene-dioxyphenyl)-3-hydroxymethyl-7,8-dimethoxy-3,4- dihydro-2- naphthoic acid lactone [18].

Ivermectin: A Long-Acting Microfilaricidal Agent

Ivermectin is a macrocyclic lactone (fermentation) product and actinomycete (Streptomyces avermitilis) that possesses an unusually broad spectrum of potent activity against several species of nematodes, arachnids, and insects that parasitize domestic animals. From clinical trials in humans it has been found to be microfilaricidal, killing microfilariae of Onchocerca volvulus (the parasite causing onchocerciasis), and interrupting its transmission by the black fly vector. Dermal microfilariae density in patients are reduced to near zero levels for 6-12 months after a single oral dose of ivermectin 0.15-0.2 mg/kg. Its precise mechanism of action is unknown. It has a time to maximum concentration of 2.7-4.3 h, and an elimination half-life of 28 +/- 10 h. When compared with an oral solution the tablet dosage form has a relative bioavailability of approximately 60 percent. Not much is known about its metabolism in humans, and the unchanged drug is not detected in the urine. Controlled clinical trials have shown ivermectin to be associated with milder side effects than diethylcarbamazine, the current drug of choice for onchocerciasis therapy. It does not cause the severe Mazzoti-type (anaphylactoid) reactions that are associated with diethylcarbamazine use. Ivermectin is effective, safer, and more tolerable than diethylcarbamazine. It should, therefore, replace diethylcarbamazine as the drug of choice for onchocerciasis therapy.

Acid-catalyzed rearrangement of pyran derivatives. An approach to the stereoselective synthesis of 1,3-diol derivatives

Peracid oxidation and HF-catalyzed treatment of furfuryl alcohol derivatives affords lactone products arising from a highly stereoselective rearrangement process. The lactones serve as precursors of highly functionalized anti-1,3-diol derivatives.

The kinetics and mechanism of the pyrolysis elimination of methyl 4‐bromocrotonate

AbstractThe pyrolysis of methyl 4‐bromocrotonate in the temperature range 300–340°C and pressure range 74–170 torr has been shown to be homogeneous, unimolecular, and to follow a first‐order rate law. The reaction was carried out in a static system, seasoned with allyl bromide, and in the presence of the radical chain exhibitor toluene. The rate coefficients are represented by the Arrhenius expression: log k1(s−1) = (13.30 ± 0.66) − (185.2 ± 7.5) kJ mol−1 (2.303RT)−1. The carbomethoxy group appears to provide anchimeric assistance in the process of dehydrobromination and lactone products formation. The partial rates for the parallel reaction have been estimated, reported, and discussed. The pyrolysis elimination is explained in terms of an intimate ion pair‐type of mechanism.

Enzymes in organic synthesis-29 : Preparations of enantiomerically pure cis -2,3- and 2,4-dimethyl lactones via horse liver alcohol dehydrogenase-catalyzed oxidations

Further examples of the broad applicability of horse liver alcohol dehydrogenase-catalyzed oxidations of meso-diols as a route to chiral lactones of asymmetric synthetic value are described. The acyclic meso substrates, cis-2,3-dimethyl- and -diethylbutane-l,4-diols, and cis-2,4-dimethylpentane-l,5diol, are stereospecifically oxidized in good yields to the corresponding enantiomerically pure γ- and δ-lactones. The oxidation of cis-3,4-bis(hydroxymethyl)thiacyclopentane is similarly stereospecific. For each meso-diol the oxidation takes place with a net stereospecificity for the hydroxymethyl groups attached to the S-enters, with the initially formed hydroxyaldehydes undergoing further enzymecatalyzed oxidations via their hemiacetal forms to produce lactone products directly.

Catalyzed reactions of organic molecules at clay surfaces: Ester breakdown, dimerizations, and lactonizations

The use of montmorillonites as Brønsted acid catalysts has been investigated for a range of reactions: (i) decomposition of cyclohexyl esters, (ii) dimerization of propenylbenzenes, and (iii) the lactonization of cyclooctene-5-carboxylic acid. The ester cracking can be accomplished with a wide range of ion-exchanged clays, with conversions of up to 98% after 7 hr at 140 °C (Al 3+-montmorillonite). Although the cracking rate is dependent upon the interlayer cations in the clay, at least some of the activity is due to sites on the external surfaces of the clay particles. The dimerization of anethole (1-(4-methoxybenzene)-prop-1-ene) is efficient when using either di- or trivalent cation-exchanged montmorillonites, e.g., 44% recoverable yield of metanethole is attainable in 1 hr at 126 °C compared with literature procedures giving 24% yields in 7 hr. For a second propenylbenzene, isohomogenol (1-(3,4-dimethoxybenzene)-prop-1-ene), dimerization could only be effected using the very acidic trivalent ion-exchanged montmorillonites. Yields were typically 60% after 5 hr at 69 °C. It is not apparent why there are large differences in reactivity between anethole and isohomogenol, which are closely related structurally. Cation-exchanged montmorillonites can also catalyze the conversion of cyclooctene-5-carboxylic acid initially to 4-cyclooctane carbolactone and then to a variety of other lactone products. The rate of consumption of the acid is similar with a variety of ion-exchanged clays, but the subsequent rate of isomerization is cation dependent. For the lactonizations the clay acid catalysts proved no better than liquid phase catalysts in producing a high percentage of one particular lactone.

Resolution of conflicting migratory reports in ring expansion of 3-keto steroids to oxygen and nitrogen

The migration of C-2 and/or C-4 to O or N in the Beckmann, Schmidt, and Baeyer–Villiger reactions of 3-keto steroids has been studied with the aid of 13Cmr spectroscopy. Authentic specimens of the eight possible lactone and lactam products from both 5α- and 5β-cholestan-3-one have been prepared; their physical properties and 13Cmr assignments are given. Seven ring expansion reactions reported to give only one product have been found to give both possible migration products. The much studied reactions of 5α-cholestane-3,6-dioneand its derivatives have been reexamined. The results emphasize again the necessity of using 13C spectra both as an analytical tool and as the best criterion of purity in work with these molecules.

ChemInform Abstract: BIPHASE AND TRIPHASE CATALYSIS. ARSONATED POLYSTYRENES AS CATALYSTS IN THE BAEYER‐VILLIGER OXIDATION OF KETONES BY AQUEOUS HYDROGEN PEROXIDE

AbstractMit 1% p‐Divinylbenzol vernetztes Polystyrol ergibt durch Bromierung, Lithiierung bei ‐78°C unter Ar, Umsetzung mit Triethylarsenit und Oxidation mit H2O2 modifizierte Polystyrole vom Typ (I).

Reactions de chlorhydrines acetyleniques avec des anions complexes du molybdene et du manganese: formation D'α-methylene lactones η 3-liees

Resume η3-Bonded α-methylene γ- or δ-lactone complexes are formed by intramolecular reactions fo hydroxy-σ-alkynyl-manganese and -molybdenum compounds. A cationic allenol complex gives a similar neutral lactone product and must be considered as a probable intermediate in the reaction.

Destruction of enteric bacteria in liquid egg with beta-propiolactone.

Liquid whole egg or egg white, inoculated with Escherichia coli 1485, Salmonella senftenberg ATCC 8400, or Salmonella typhimurium 84-I, was treated with concentrations of beta-propiolactone ranging from 0.05 to 0.3%. Egg white containing 1 x 10(3) to 1 x 10(6) cells of E. coli 1485 per ml was sterilized in 1 hr at 27 C by lactone concentrations of 0.2 and 0.3%. Egg white containing 1 x 10(5) cells of S. senftenberg ATCC 8400 per ml was sterilized in 12 hr at 10 C by 0.1% lactone and in 2 to 3 hr by 0.3% lactone at the same temperature. Liquid whole egg inoculated with 1 x 10(5) cells of either species of Salmonella was sterilized in 4 to 5 hr at 10 C with 0.2% lactone or in 2 to 3 hr by 0.3% lactone at this temperature. A mild heat treatment of either 15 min at 37 C or 1 min at 55 C markedly shortened the exposure times required for sterilization by beta-propiolactone at 10 C. After disinfection was complete, the lactone-treated liquid whole egg was reinoculated with low cell numbers of either species of Salmonella to determine the presence of residual lactone or toxic products. Liquid whole egg treated with 0.2% lactone would support the growth of salmonellae after 13 to 14 hr at 10 C. A heat treatment of 45 min at 37 C or 10 min at 55 C immediately after addition of 0.2% lactone allowed growth of the salmonellae in the lactone-treated liquid whole egg. No evidence of residual toxicity from the lactone treatment was found. The amount of lactone needed to prevent the outgrowth of low cell numbers of either strain of Salmonella in liquid whole egg was quantitated. Liquid whole egg containing 0.06 to 0.07% lactone would not support salmonellae growth from inocula of 1 to 10 cells per ml of egg. Lactone concentrations above 0.08% prevented outgrowth of salmonellae inocula of 10 to 200 cells per ml of liquid whole egg.

Destruction of Enteric Bacteria in Liquid Egg with β-Propiolactone

Liquid whole egg or egg white, inoculated with Escherichia coli 1485, Salmonella senftenberg ATCC 8400, or Salmonella typhimurium 84-I, was treated with concentrations of beta-propiolactone ranging from 0.05 to 0.3%. Egg white containing 1 x 10(3) to 1 x 10(6) cells of E. coli 1485 per ml was sterilized in 1 hr at 27 C by lactone concentrations of 0.2 and 0.3%. Egg white containing 1 x 10(5) cells of S. senftenberg ATCC 8400 per ml was sterilized in 12 hr at 10 C by 0.1% lactone and in 2 to 3 hr by 0.3% lactone at the same temperature. Liquid whole egg inoculated with 1 x 10(5) cells of either species of Salmonella was sterilized in 4 to 5 hr at 10 C with 0.2% lactone or in 2 to 3 hr by 0.3% lactone at this temperature. A mild heat treatment of either 15 min at 37 C or 1 min at 55 C markedly shortened the exposure times required for sterilization by beta-propiolactone at 10 C. After disinfection was complete, the lactone-treated liquid whole egg was reinoculated with low cell numbers of either species of Salmonella to determine the presence of residual lactone or toxic products. Liquid whole egg treated with 0.2% lactone would support the growth of salmonellae after 13 to 14 hr at 10 C. A heat treatment of 45 min at 37 C or 10 min at 55 C immediately after addition of 0.2% lactone allowed growth of the salmonellae in the lactone-treated liquid whole egg. No evidence of residual toxicity from the lactone treatment was found. The amount of lactone needed to prevent the outgrowth of low cell numbers of either strain of Salmonella in liquid whole egg was quantitated. Liquid whole egg containing 0.06 to 0.07% lactone would not support salmonellae growth from inocula of 1 to 10 cells per ml of egg. Lactone concentrations above 0.08% prevented outgrowth of salmonellae inocula of 10 to 200 cells per ml of liquid whole egg.