Synthesis of fulgidic acid and the two possible stereoisomers of chaenomic acid D.

We synthesized fulgidic acid and the proposed structure for chaenomic acid D. The core part of the two natural products was constructed stereoselectively by the addition of acetic acid to the α,ß-unsaturated epoxy alcohol in the presence of a palladium catalyst. Subsequently, the two natural products were synthesized from the intermediate in a few steps. The data for the synthesized fulgidic acid were in good agreement with the reported data. Chaenomic acid was in good agreement with the natural product in the 1H and 13C NMR data, but not in the optical rotation. The 15R-isomer of chaenomic acid was also synthesized, but the 1H and 13C NMR data did not agree with the natural product.

Synthesis, Odour Characteristics, and Antimicrobial Activity of Optically Active (Z)-7-Decen-4-olide and Its Derivatives.

Six optically active (Z)-7-decen-4-olide derivatives (1a-1f) were synthesized in 99% enantiomeric excess using diastereomeric resolution. The odour properties of the racemic and optically active 1a-1f were evaluated in terms of their orthonasal aromas. All of the stereoisomers had different odour characteristics and thresholds. Decen-4-olides (1a-1c) had a strong fruity note, whereas undecen-4-olide (1d and 1e) and dodecen-4-olide (1f) had a strong green note. For 7-alken-4-olides (1a, 1d, and 1f), the (R)-enantiomer had a lower odour threshold than the (S)-enantiomer. In contrast, no difference in the odour threshold was observed for the enantiomers of the 8-alken-4-olides (1b and 1e). Furthermore, the antimicrobial activity against Escherichia coli (E. coli; ATCC 25922) and Staphylococcus aureus (S. aureus; ATCC 29213) were investigated. Although the no differences in the antimicrobial activity of the stereoisomers was observed, 1d and 1e showed slight antimicrobial activity against E. coli, whereas only 1f showed antimicrobial activity against S. aureus. No antimicrobial activity was exhibited by (R)-1f, whereas (S)-1f exhibited strong antimicrobial activity.

Total Synthesis of Clostrienose.

This paper considers the total synthesis of a cellular differentiation regulator of Clostridium acetobutylicum, clostrienose, which is a unique fatty-acid glycosyl ester consisting of clostrienoic acid, (3R,5E,8E,10E)-3-hydroxy-tetradeca-5,8,10-trienoic acid and α-d-galactofuranosyl-(1 → 2)-α-l-rhamnose. The key features of our synthesis include stereoselective construction of a skipped-triene system in clostrienoic acid and its esterification with a disaccharide residue. The partially protected clostrienoic acid employed for the coupling also served for the preparation of l-rhamnosyl clostrienoate, thus leading to confirmation of the proposed structure unambiguously.

Synthesis and herbicidal activity of optically active cinmethylin, its enantiomer, and C3-substituted cinmethylin analogs.

We investigated the synthesis and herbicidal activity of optically active cinmethylin, its enantiomer, and C3-substituted cinmethylin analogs. Optically active cinmethylin could be obtained in seven steps with the Sharpless asymmetric dihydroxylation of α-terpinene. The synthesized cinmethylin and its enantiomer showed similar herbicidal activity, which was independent of the stereochemistry. Next, we synthesized cinmethylin analogs with various substituents at the C3 position. We found that analogs with methylene, oxime, ketone, or methyl groups at the C3 position show excellent herbicidal activity.

Identification and characterization of bioactive metabolites of 12-hydroxyheptadecatrienoic acid, a ligand for leukotriene B4 receptor 2.

12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together, 12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity.

Total synthesis of resolvin D3.

Resolvin D3 was synthesized by the Suzuki-Miyaura cross-coupling reaction of C1-C8 borane with C9-C22 iodoolefin as the key reaction. The latter intermediate was obtained by the sequential Wittig reactions of C9-C13 phosphonium salt with C14-C19 aldehyde and then C9-C19 aldehyde with propyltriphenylphosphonium bromide. The stereogenic centers at C4, C11, and C17 were constructed by the ruthenium-catalyzed asymmetric transfer hydrogenation with high stereoselectivity.

Isoflurane attenuates sepsis-associated lung injury.

Acute lung injury is one of major complications associated with sepsis, responsible for morbidity and mortality. Patients who suffer from acute lung injury often require respiratory support under sedations, and it would be important to know the role of sedatives in lung injury. We examined volatile anesthetic isoflurane, which is commonly used in surgical setting, but also used as an alternative sedative in intensive care settings in European countries and Canada. We found that isoflurane exposure attenuated neutrophil recruitment to the lungs in mice suffering from experimental polymicrobial abdominal sepsis. We found that isoflurane attenuated one of major neutrophil chemoattractants LTB4 mediated response via its receptor BLT1 in neutrophils. Furthermore, we have shown that isoflurane directly bound to BLT1 by a competition assay using newly developed labeled BLT1 antagonist, suggesting that isoflurane would be a BLT1 antagonist.

Synthesis of a TNF inhibitor, flurbiprofen and an i-Pr analogue in enantioenriched forms by copper-catalyzed propargylic substitution with Grignard reagents.

The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCCCH(OH)CH2CH2OTBDPS with 3-c-C5H9-4-MeOC6H3MgBr, followed by several transformations, afforded a tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from phenylacetylene phosphate PhCCCH(OP(O)(OEt)2)CH2CH2OTBDPS. Furthermore, the substitution of phosphates derived from TMSCCCH(OH)CH3 and TMSCCCH(OH)-i-Pr with 3-F-4-PhC6H3MgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its i-Pr analogue, respectively. The copper-catalyzed substitutions in these syntheses proceeded in a regio- and stereoselective manner.

Synthesis and herbicidal activity of 3-substituted toxoflavin analogs.

We investigated the synthesis and herbicidal activity of 23 toxoflavin analogs, 1a-w, in which aromatic rings (R) were introduced into the C-3 position. In paddy field conditions, 1k (R=2-CF3-C6H4) and 1w (R=2-thienyl) showed excellent herbicidal activity. Under upland field conditions, we found that toxoflavin analogs 1a (R=C6H5), 1n (R=2-CH3O-C6H4), and 1p (R=4-CH3O-C6H4) exhibited wide herbicidal spectrum against Echinochloa crus-galli (L) var. crus-galli (ECHCG), Chenopodium album, and Amaranthus viridis (AMAVI). The analog with the 2-fluoro group on benzene ring 1b also showed high herbicidal activity against both ECHCG and AMAVI.

Chemical State Analysis of Heavy Metals and Radioactive Cesium in Municipal Solid Waste Incineration Fly Ash Contaminated with Radioactive Cesium Released by the FDNPP Accident.

The chemical states of heavy metals and radioactive Cs were estimated in fly ash sampled at Fukushima prefecture, Japan. Estimating the speciation of incinerator fly ash is important to ensure an appropriate and efficient management of fly ash generated from disaster-related waste. In this study, fly ash collected at a waste incineration facility in Fukushima prefecture was treated using a sequential extraction test. The test results indicated that the solubility behavior of radioactive Cs was similar to that of NaCl and KCl, and approximately 60% of radioactive Cs was included as water-soluble chloride compounds in the fly ash sample. Most heavy metals eluted in three fractions, in the extraction steps for carbonate-bound, free oxide, and bound to organic matter species. The chemical states of elements in the three non-water-soluble fractions and residue showed minimal elution into the environment. Therefore, most heavy metals in the fly ash exhibited minimal elution into the environment.

Water repellents for the leaching control of heavy metals in municipal solid waste incineration fly ash.

Suppression of heavy metal elution from municipal solid waste incineration (MSWI) fly ash by cement or geopolymer solidification was studied. When these approaches are implemented, however, the volume of the solidified body increases as a consequence of the solidifying agent addition. Considering that residual landfill disposal capacity is decreasing in the long term, a novel method to suppress the elution of heavy metals from MSWI fly ash without decreasing the disposal capacity is needed. We studied four different water repellents and the results indicated that heavy metal elution can easily be suppressed by impregnating the incineration fly ash with commercially available silane oligomers, alkyl alkoxysilane compounds, and water repellents like fatty acids.

α- and γ-Regiocontrol and Enantiospecificity in the Copper-Catalyzed Substitution Reaction of Propargylic Phosphates with Grignard Reagents.

The regioselectivity (r.s.) and enantiospecificity (e.s.) of the substitution reactions of secondary propargylic alcohol derivatives using reagents derived from ArMgBr and Cu salts were studied. First, the picolinate, 3-methylpicolinate, and diethylphosphonate derivatives of Ph(CH2 )2 CH(OH)C≡CTMS were reacted with PhMgBr/CuCN in ratios of 2.5:2.7-2.5:0.25. The use of 2.5:0.25 ratio in THF/DME (6:1) at 0 °C for 1 h afforded the α-substitution product from the phosphate with ≥98 % r.s. and 99 % e.s. CuBr⋅Me2 S gave similar selectivity. The reaction system was then applied to phosphates derived from R1 CH(OH)C≡CR2 and ArMgBr to obtain synthetically sufficient r.s. and e.s. values with R2 =TMS, Ph, whereas iPr was borderline in terms of size as an R1 substituent. The presence of a substituent at the o-position of Ar marginally affected the selectivity. We also found that the use of PhMgBr/Cu(acac)2 in a 2:1 ratio in THF produced the γ-substitution products (allenes) with high r.s. and e.s.

Biomimetic systems involving sequential redox reactions in glycolysis - the sulfur effect.

Magnesium hemithioacetates were used as model cysteine compounds to mimic natural hemithioacetals, and their biomimetic oxidation reactions using a model NAD+ compound were investigated. Cyclic hemithioacetate was found to be the best substrate for the reaction with the model NAD+ compound, which gave the corresponding NADH analog in excellent yield.

Total Synthesis of the Proposed Structure for Chaunopyran A and Its Absolute Configuration.

This paper describes a seven-step synthesis of the proposed structure for chaunopyran A produced by cocultivation of a Chaunopycnis sp. and Trichoderma hamatum. This synthesis included a coupling of a diene sulfone and a tetrahydropyranyl aldehyde as a key step. The sign of the specific rotation value of the synthetic sample was opposite that of the natural product, suggesting that the absolute configuration of the natural product should be revised.

Synthesis of Two Stereoisomers of Potentially Bioactive 13,19,20-Trihydroxy Derivative of Docosahexaenoic Acid.

The C16-C22 fragment with the acetylene terminus was constructed through the asymmetric dihydroxylation of the corresponding olefin, while the 15-iodo-olefin corresponding to the C11-C15 part was prepared via the asymmetric transfer hydrogenation of the corresponding acetylene ketone followed by hydrozirconation/iodination. Both pieces were joined by a Sonogashira coupling, and the product was further converted into the title compound via a Wittig reaction with the remaining C1-C10 segment and Boland reduction using Zn with TMSCl.

Use of the 2-Pyridinesulfonyloxy Leaving Group for the Fast Copper-Catalyzed Coupling Reaction at Secondary Alkyl Carbons with Grignard Reagents.

Investigation of the copper-catalyzed coupling reaction of 2-pyridinesulfonates with Grignard reagents revealed that reactions with catalytic Cu(OTf)2 were completed in <40 min. The results differed from those of the previous CuI-catalyzed reactions of tosylates in the presence of additives (LiOMe and TMEDA) for 12-24 h. It was shown that the preferred coordination of the leaving group to the reagents accelerated the reaction. Successful reagents were MeMgCl and other RMgX. Complete inversion was established.

Elucidation of Racemization Process of Azaspirene Skeleton in Neutral Aqueous Media.

Azaspirene and related congeners, which possess various biological activities, have a unique spirocyclic core structure. However, there are few studies on the chemical properties of (-)-azaspirene, despite the fact that it may provide important insights into unveiling the biosynthetic pathway. Here, we report a nine-step chemical synthesis of an azaspirene analogue with a new finding that the natural (-)-azaspirene skeleton easily racemizes in neutral aqueous media.

Resolvin E1 attenuates murine psoriatic dermatitis.

The potential of omega-3 poly-unsaturated fatty acids (PUFAs) as a therapeutic target for psoriasis, a chronic inflammatory skin disease of IL-23/IL-17 axis, is a long-disputed question, since various epidemiological studies have suggested the association between high-intake of omega-3 PUFAs and the reduced frequency and severity of psoriasis. However, their actual significance and the molecular mechanisms remain largely unknown. To address these issues, we focused on resolvin E1 (RvE1), an omega-3 PUFAs-derived metabolite, and examined its effects on psoriatic dermatitis, using an imiquimod-induced mouse psoriasis model. RvE1 potently suppressed the inflammatory cell infiltration and epidermal hyperplasia in the psoriatic skin. RvE1 decreased the mRNA expression of IL-23 in the skin. Consistently, RvE1 inhibited IL-23 production by dendritic cells (DCs) in vitro. Furthermore, RvE1 exerted inhibitory effects on migration of cutaneous DCs and γδ T cells, a major IL-17-producing cell population in mouse, both in vivo and in vitro. These suppressive effects of RvE1 were mediated by its antagonistic function on BLT1, a receptor of leukotriene B4, and were also observed in human DCs, Th17 and Tc17 cells. Our results indicate a novel mechanism of omega-3 PUFA-mediated amelioration of psoriasis, and suggest a potential of RvE1 as a therapeutic target for psoriasis.

Total Synthesis of Resolvin D5.

Resolvin D5 (RvD5) is a metabolite of docosahexanoic acid with anti-inflammatory activity that has not yet been thoroughly investigated because of its low biological availability. A synthetic route to optically active RvD5 was developed by assembling the C1-C10 aldehyde, C11-C13 phosphonium salt, and C14-C22 aldehyde building blocks. The aldehyde fragments were prepared by Sharpless asymmetric epoxidation of corresponding racemic (E)-1-TMS-1-alken-3-ols followed by reaction of the TBS ethers of the resulting epoxy alcohols with Et2AlCN and DIBAL reduction of the (E)-1-cyano-1-alken-3-ol derivatives. The C14-C22 aldehyde was connected with the C11-C13 fragment, i.e., [TBSO(CH2)3PPh3]+ Br-, by Wittig reaction. The resulting C11-C22 intermediate was converted to the phosphonium salt, which was attached to the C1-C10 aldehyde by Wittig reaction to yield the structure of RvD5.

Asymmetric synthesis of 12-hydroxyheptadecatrienoic acid and its 5,6-dihydro- and 14,15-dehydro-derivatives.

Natural 12-hydroxyheptadecatrienoic acid (12-HHT) with an S configuration was synthesised by a Suzuki-Miyaura coupling of C10-C17 iodo alcohol with C1-C9 vinylborane. The iodo alcohol was synthesised by utilising Sharpless asymmetric epoxidation of the corresponding trimethylsilyl alcohol. The method yielded more than 100 mg of 12-HHT. Similarly, syntheses of 5,6-dihydro- and 14,15-dehydro derivatives of 12-HHT, known as HHD and HHTE, respectively, were completed in a stereoselective manner.