Hydroxymethylphenylnaphthoie acid lactones

Reduction of 1-phenylnaphthalene-2,3-dicarboxylic anhydride (I) with zinc and acetic acid or lithium aluminium hydride yields a mixture of 1-phenyl-3-hydroxymethyl-2-naphthoie acid lactone (II) and 1-phonyl-2-hydroxymethyl-3-naphthoie acid lactone (III). Catalytic hydrogenation of (I) gave the tetrahydronaphthalene dicarboxylic anhydride (IV). Oxidation of the phenyldihydronaphthofuran (X), prepared by base-catalyzed cyclization of the ether (IX), also yielded lactones (II) and (III). The phenyltetrahydronaphthofuran (XII) was similarly prepared by cyclization of the phenylpropargyl cinnamyl ether (XI).     

Mass spectral analysis of Schiff bases derived from 1,1,1-trifluoro-2,4-pentanedione and Bis(3,3′-aminopropyl)amine and bis(3,3′-aminopropyl)methylamine and their copper(II) and nickel(II) complexes

Mass spectra have been obtained for bis(5,5,5-trifluoro-4-oxopentan-2-N-propylene)amine, bis(5,5,5-trifluoro-4-oxopentan-2-N-propylene)methylamine, bis(5,5,5-trifluoro-4-oxopentan-2-N-propylene)aminocopper(II), bis(5,5,5-trifluoro-4-oxopentan-2-N-propylene)aminonickel(II), bis(5,5,5-trifluoro-4-oxopentan-2-N-propylene)methylaminocopper(II) and bis(5,5,5-trifluoro-4-oxopentan-2-N-propylene)methylaminonickel(II) using a Varian-MAT CH5 mass spectrometer. The first two compounds are seen to fragment primarily in the trimethylene chain γ to the middle nitrogen although fragmentation is seen at a variety of other sites as well. Lower molecular weight ions form a significantly larger fraction of the total ion intensity for the methylated middle nitrogen compound than for its non-methylated analog. In the metal complexes of these Schiff bases, the metal exerts its influence in two ways. The primary cleavage site inthe trimethylene bridge is β, rather than γ, to the middle nitrogen, and other fragments are produced which are ascribable to ligand to metal electron transfer.     

A sesquiterpene lactone fromAcroptilon repens

A new sesquiterpene lactone has been isolated from the epigeal part ofAcroptilon repens, with the composition C₁₉H₂₂O₆, mp 199–201°C, M⁺ 346, and it has been called acroptin (I). The treatment of (I) with acetic anhydride in pyridine gave a diacetate (II). The structure of (I) has been confirmed by the NMR spectra of (I) and (II). Details of the IR and NMR spectra of (I) and (II) are presented.     

2-Carbomethoxycyclopentenone as a synthon. synthesis of sarkomycin

The first regiospecific synthesis of sarkomycin (II), a compound active against ascites-type tumors, is reported. Treatment of 2-carbomythoxycyclopentenone (I) with Et₂AlCN generated the carbon skeleton; aelective functional group manipulations then gave the keto lactone X and the protected hydroxy acid XI; and mild acid treatment of these led to sarkomycin.     

Hydrogenations of triacetic acid lactone. A new synthesis of the carpenter bee (Xylocopahirsutissima) sex pheromone

under a variety of catalytic conditions, triacetic acid lactone, I, has been hydrogenated to differently oxidized lactones (II, III and V). C-Methylation of one of them, (II) is the key step for a convenient preparation of the carpenter bee sex pheromone.     

Stereoselective synthesis and structure of butalactin and lactone II isolated from Streptomyces species

Butalactin (1a) and lactone II (2a) have been synthesized starting from (S)-malic acid and sorbic acid by a straightforward route. The absolute stereochemistry of 1a and 2a was unambiguously established by this synthesis.     

Synthesis of certain metabolites and analogs of vitamin B6 and their ring-chain tautomerism

Pyridoxol and pyridoxal on benzylation with dimethylphenylbenzylammonium hydroxide (“leucotrope”) gave 3-O-benzylpyridoxol (IV) and 3-O-benzylpyridoxal (V), respectively. As a possible mechanism of this reaction an ion pair intermediate has been postulated. Oxidation of IV and V with chromic oxide-pyridine-acetic acid complex gave 3-O-benzyl-4-pyridoxic acid lactone (VI), which could also be obtained by benzylation of 4-pyridoxic acid. Treatment of VI with dimethylamine gave 2-methyl-3-benzyloxy-5-hydroxymethylpyridine-4-N,N-dimethylcarbox-amide (X) which oxidized to form the 5-formyl derivative (XI). The latter on hydrolysis yielded the metabolite, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylic acid (I). When reacted with liquid ammonia, VI gave 3-O-benzyl-4-pyridoxamide (VII) which was then oxidized to give 2-methyl-3-benzyloxypyridine-4,5-dicarboxylic acid cyclicimide(IX). Acid hydrolysis of IX gave another metabolite, 2-methyl-3-hydroxypyridine-4,5-dicarboxylic acid (XIII), which could also be obtained by oxidizing XI with potassium permanganate in water to yield 2-methyl-3-benzyloxy-5-carboxypyridine-4-N,N-dimethylcarboxamide (XII) and subsequent hydrolysis with hydrochloric acid. A positional isomer of I, 2-methyl-3-hydroxy-4-formylpyridine-5-carboxylic acid (XVII) was synthesized starting from 3-O-benzyl-5-pyridoxic acid lactone (XIV) following similar reaction sequences used for the preparation of I. Ring-chain tautomerism has been studied in I, XVII, opianic acid (XVIII), phthalaldehydic acid (XIX) and (2-carboxy-4,5-dimethoxy)-phenylacetaldehyde (XX) in different solvents by nmr and in the solid state by ir spectroscopy. A direct and reliable differentiation between the open form (aldehyde proton in low field) and the ring form (lactol proton in the intermediate field) has been obtained by nmr spectroscopy. In sodium deuteroxide and pyridine-d₅ the open chain form existed exclusively (except for homolog (XX) which is in cyclic form in pyridine-d₅), whereas in 18% hydrogen chloride in deuterium oxide all the compounds are completely in the cyclic form. In hexafluoroacetone hydrate-d₂, XVIII, XIX, and XX exist in the cyclic form whereas I is in the open form. In DMS0-d₆ both cyclic and open-chain forms have been observed in XVIII, XIX and XX. Definite peak assignment for the two forms could not be made in I due to broadening or superimposition with C₆-H. The metabolite I, isometabolite (XVII) and opianic acid (XVIII) form cyclic acetyl derivatives which give a sharp lactol peak. In the solid state XVIII, XIX are in the cyclic form and I and XX in the open-chain form as observed by ir spectroscopy.     

Evaluation of the Efficiency of the Macrolactonization Using MNBA in the Synthesis of Erythromycin A Aglycon

Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin A, are prepared from the corresponding seco‐acids using 2‐methyl‐6‐nitrobenzoic anhydride (MNBA) in the presence of 4‐(dimethylamino)pyridine (DMAP) with or without triethylamine. The efficiency of the MNBA lactonization is assessed by studying this method and comparing the results with those of the other established macrocyclization protocols. It has been finally concluded that (i) the conformationally appropriate substrate for the monomeric cyclization gave the desired lactone in excellent yield under mild reaction conditions in the presence of MNBA and DMAP, (ii) the highly‐strained substrate for the cyclization also afforded the monomeric lactone in relatively good yield at 100°C in toluene, and (iii) the seco‐acid having stable linear conformation, which preferred dimerizing more than forming the monomeric lactone, provided the corresponding diolide in high yield with the constant ratio of the monomer to dimeric lactone (approximately 1/5). © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 305–320; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900017     

1,2-Oxopalladation versus pi-allyl palladium route. A regioconvergent approach to a key intermediate for cyclopentanoids synthesis. New insights into the Pd(II)-catalyzed lactonization reaction

Regioconvergent synthesis of the key lactone 1 from an equimolar mixture of the two olefins 4 and 5 was achieved by unique Pd(II) chemistry. The synthetic versatility of lactone 1 has been demonstrated in the synthesis of iridoids and of the endo-Corey lactone 2, which is a key intermediate for the F(2)-isoprostane synthesis. Upon exposure of the sodium salts of 4 and 5 to a catalytic amount of Pd(OAc)(2) under oxygen, in the presence of AcOH, an isomeric lactone 12 was obtained in addition to the title compound 1. The Pd(II) lactonization was optimized by fine-tuning all the factors participating in the catalytic cycle: solvent, oxidant, co-oxidant, and Pd(II) source. The Hosokawa's heterobimetallic couple emerged as the catalyst of choice. With a Cu(II)-Pd(II) couple, the redox process was transferred to copper, and the formal oxidation state of palladium remained constant during the reaction. By virtue of this new methodology, lactone 1 was obtained in a rewarding 60% yield, along with isomeric lactone 12 in 30% yield. A detailed mechanistic study was carried out in order to elucidate the formation of lactones 1 and 12. Lactone 1 was formed from either olefin 8 or olefin 10; on the other hand, lactone 12 was formed exclusively from olefin 10. An intramolecular 1,2-acyloxypalladiation was invoked for the transformation of 8 into 1, whereas the pi-allyl complexes 13 and 11 were involved in the transformation of olefin 10 into 12 and 1, respectively.     

The McLafferty rearrangement in aliphatic aldehydes and ketones—a previously unconsidered mechanistic pathway

The possibility of a mass spectrometric counterpart to the cyclobutanol formation which is encountered in the photolysis of carbonyl compounds has been investigated by preparing 5,5,5-[²H₃]-2-methylpentanal (II) and 6,6,6-[₂H₃]-3-methylhexan-2-one (III) and examining their mass spectra at high and low voltage.     

Structure investigation of Maltacine D1a, D1b and D1c-cyclic peptide lactones of the Maltacine complex from Bacillus subtilis

A new complex of cyclic peptide lactone antibiotics from Bacillus subtilis, which we named Maltacines has recently been described. The structure elucidation of three of them is reported in this paper. The amino acid sequences and structures of the peptides were found by MS(n) of the ring-opened linear peptides that gave uninterrupted sequences of Bn and Y'n ions. The identities of four unknown residues in the sequences were solved by a combination of derivatisation with phenylisothiocyanate (PITC), high-resolution mass spectrometry and H/D exchange. The nature and position of the cyclic structure was disclosed by a chemo-selective ring opening with Na18OH and was found to be a lactone formed between a hydroxyl of residue number 4 and the C-terminal amino acid number 12. For verification of the structure of the B2 + ion, peptides with different combinations of P/Q and P/K at the N-terminus were synthesized. The structures of the four peptides is tentatively suggested to be: D1a: cyclo(4,12)-P-Q-Y-Adip-A-E-T-Y-Orn-HGly-Y-I-OH, D1b: cyclo(4,12)-P-Q-Y-Adip-A-E-T-Y-Orn-S-Y-I-OH and D1c: cyclo(4,12)-P-Q-Y-Adip-A-E-T-Y-K-S-Y-I-OH. Adip = aminodihydroxy pentanoic acid and HGly = hydroxyglycine.     

Synthese von 3-(2,4,5-Trihydroxyphenyl)-DL-alanin

Condensation of 2.4.5-trimethoxybenzaldehyde with hydantoin followed by catalytic hydrogenation gave 5-(2.4.5-trimethoxybenzyl)-hydantoin, which was converted to 3-amino-3.4-dihydro-6.7-dihydroxycoumarin by treatment with hydrobromic acid. Hydrolysis of the lactone led to 3-(2.4.5-trihydroxyphenyl)-DL -alanine.     

Structure investigation of Maltacine C1a, C1b, C2a and C2b-cyclic peptide lactones of the Maltacine complex from Bacillus subtilis

A new complex of cyclic peptide lactone antibiotics from Bacillus subtilis, which we named Maltacines, has recently been described. The structure elucidation of four of them is reported in this paper. The amino acid sequences and structures of the peptides were found by MS(n) of the ring-opened linear peptides, which gave uninterrupted sequences of Bn and Y'n ions. The identities of three unknown residues in the sequences were solved by a combination of derivatisation with phenylisothiocyanate (PITC), high-resolution mass spectrometry and H/D exchange. The nature and position of the cyclic structure was disclosed by a chemo-selective ring opening with Na18OH and was found to be a lactone formed between a hydroxyl of residue number 4 and the C-terminal amino acid number 12. For verification of the structure of the B2+ ion, peptides with different combinations of P/Q and P/K at the N-terminus were synthesised. The structure of the four peptides were found to be: C1a and C2a: cyclo-4,12(P-Q-Y-Adip-V-E-T-Y-Orn-103-Y-I-OH) and C1b/C2b: cyclo-4,12(P-Q-Y-Adip-V-E-T-Y-K-103-Y-I-OH). Adip = aminodihydroxy pentanoic acid.     

Synthese des (±)-Lasiodiplodins

Synthesis of (±)-Lasiodiplodin The synthesis of the plant growth inhibitor (±)-lasiodiplodin (VII), a 12 membered lactone of a substituted resorcylic acid is described. Condensation of methyl acetoacetate and methyl 11-hydroxy-2-undecenoate followed by treatment of the product with benzyl alcohol lead to the benzyl ether II which was aromatized via the benzeneselenenyl derivative. Methylation of the phenolic hydroxyl in III and conversion of the primary alcohol in the side chain into the secondary alcohol provided the hydroxy ester IV. The corresponding hydroxy acid V was transformed into the S-(2-pyridyl) carbothioate which cyclized under the influence of silver ions to yield 68% of 4-benzyl-lasiodiplodin (VI). Removal of the benzyl group by catalytic hydrogenation gave (±)-lasiodiplodin (VII).     

The tricarbonylchromium template for stereocontrol in radical reactions of arenes

Chromium tricarbonyl complexed aryl aldeyhydes and ketones underwent Sm(II)-promoted radical lactone formation in the presence of alpha,beta-unsaturated esters to produce diastereomerically pure lactones in good yields. The completely diastereoselective lactone formation involves capture of the benzylic ketyl radical by the ester anti to the chromium tricarbonyl moiety. The relative stereochemistry of the lactone and chromium tricarbonyl moieties was proven by X-ray crystallography and supports the proposed mechanism. Enantiopure chromium tricarbonyl complexed arenes afforded single enantiomers when subjected to Sm(II)-promoted radical lactone formation condiditions. The enantio- and diastereomerically pure chromium tricarbonyl complexed lactones were subsequently treated with BF3.OEt2 to generate a mixture of diastereomers via Lewis acid promoted chromium tricabonyl directed cationic rearrangement. The diastereomers were separated and individually decomplexed with I2 to afford both of the corresponding chromium-free enantiomerically pure lactones starting from a single enantiomerically pure chromium tricarbonyl complex.     

A novel type of formation of zwitterionic compounds,containing two phosphorus atoms of opposite charge and different coordination number

The oxidation of bis[bis(dialkylamino)phosphinyl]methane 1 with 5,5,5-trifluoro-4-(trifluoromethyl)penta-3-en-2-one 2 unexpectedly gave zwitterionic compound 7 which according to X-ray analysis contains two phosphorus atoms of opposite charge and different coordination number (lambda 4P(+); lambda 6P(-)) with a direct P-H bond at the hexacordinated phosphorus.     

Synthesis of branched carbasugars via photooxygenation and manganese(III) acetate free radical cyclization

Transformation of cyclohexa-1,3- and 1,4-dienes to carbasugars is described. Photooxygenation of dienes gave bicyclic endoperoxides, which were reduced with thiourea to the corresponding 1,4-diols with cis-configuration. Lactonization of the remaining double bond by oxidative addition of acetic acid to the double bond in the presence of Mn(OAc)₃ followed by lactone ring-opening reaction gave the target branched carbasugars.     

Formation of lactones from sialylated MUC1 glycopeptides

The tumor-associated carbohydrate antigens TN, T, sialyl TN and sialyl T are expressed on mucins in several epithelial cancers. This has stimulated studies directed towards development of glycopeptide-based anticancer vaccines. Formation of intramolecular lactones involving sialic acid residues and suitably positioned hydroxyl groups in neighboring saccharide moieties is known to occur for glycolipids such as gangliosides. It has been suggested that these lactones are more immunogenic and tumor-specific than their native counterparts and that they might find use as cancer vaccines. We have now investigated if lactonization also occurs for the sialyl TN and T antigens of mucins. It was found that the model compound sialyl T benzyl glycoside , and the glycopeptide Ala-Pro-Asp-Thr-Arg-Pro-Ala from the tandem repeat of the mucin MUC1, in which Thr stands for the 2,3-sialyl-T antigen, lactonized during treatment with glacial acetic acid. Compound gave the 1'--> 2' lactone as the major product and the corresponding 1'--> 4' lactone as the minor product. For glycopeptide the 1'--> 4' lactone constitued the major product, whereas the 1'--> 2' lactone was the minor one. When lactonized was dissolved in water the 1'--> 4' lactone underwent slow hydrolysis, whereas the 1'--> 2' remained stable even after a 30 days incubation. In contrast the corresponding 2,6-sialyl-TN glycopeptide did not lactonize in glacial acetic acid.     

The need for chromatographic and mass resolution in liquid chromatography/tandem mass spectrometric methods used for quantitation of lactones and corresponding hydroxy acids in biological samples

Because of the potential in-source conversion between a lactone and the corresponding hydroxy acid, it has been recognized that a liquid chromatography/tandem mass spectrometric (LC/MS/MS) method developed for quantitation of a lactone drug in the presence of its hydroxy acid metabolite (or vice versa) must incorporate chromatographic separation between the two compounds, unless in-source conversion between the two compounds has been eliminated by the appropriate selection of the LC/MS/MS parameters. We now report that chromatographic separation between a lactone and its hydroxy acid will be required under certain LC/MS/MS conditions used even in the absence of in-source conversion. This is due to the fact that the 18-mass-unit difference between a lactone and its hydroxy acid is, by coincidence, different by only one mass unit from the 17-mass-unit difference between the [M + H](+) and [M + NH(4)](+) ions of the lactone or the hydroxy acid. Thus, the [M + H](+) ion of a hydroxy acid is higher than the [M + NH(4)](+) ion of its lactone by only one mass unit. Therefore, in a method developed for quantitation of a hydroxy acid drug utilizing a selected-ion-monitoring (SRM) scheme that incorporates its [M + H](+) ion as the precursor ion, the quantitation would be inaccurate due to the interference by the contribution of the A + 1 isotope response from the [M + NH(4)](+) ion of the lactone metabolite present in the sample, unless there is a chromatographic separation between the two compounds. This is true even if Q1 is operated under a unit-mass resolution. The implication of this type of interference, arising from the presence of both the [M + H](+) and [M + NH(4)](+) ions of a drug and its metabolite, to the selection of LC and MS conditions (including mass resolution) will be discussed using the data obtained with a model lactone drug and its hydroxy acid metabolite.     

Synthesis and absolute configuration of lactone II isolated from Streptomyces sp. Go 40/10

All four possible stereoisomers of lactone II isolated from Streptomyces sp. Go 40/10, an autoregulator, have been efficiently synthesized in a stereoselective manner starting from (S)-malic acid and sorbic acid, and the absolute configuration was determined to be 2S, 3S, 9R, 10S.