著者

北村 雅人 塚本 眞幸 別所 祐紀

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天然有機化合物討論会

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no.44, pp.533-538, 2002-09-01

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Asymmetric hydrogenation of -(acylamino)acrylic acid derivatives was first established by Kagan in 1971. A cationic (R,R)-DIOP-Rh complex smoothly hydrogenates an enamide substrate to give (S)- and (R)-phenylalanine derivatives in 7:93 ratio. This finding paved the way to asymmetric hydrogenation world as well as the synthesis of optically active natural and unnatural amino acids. A perfect enantioselection in the Kagan reaction was achieved by use of BINAP ligand (BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) in 1980 although the Rh complex suffered from the high substrate specificity. A breakthrough has been made by the discovery of BINAP-Ru complexes, which serve as excellent catalyst precursors for highly enantioselective hydrogenation of a variety of functionalized prochiral olefins and ketones including enamides, ,-and ,-unsaturated carboxylic acids, allylic and homoallylic alcohols. keto esters, hydroxy ketones, and amino ketones. Interestingly, the sense of asymmetric induction in the (S)-BINAP-Ru(II)-catalyzed Kagan reaction is opposite to that observed with (S)-BINAP-Rh(I) catalysts. In this paper, we would like to focus on the mechanism of the BINAP-Rh- and -Ru-catalyzed Kagan reaction that is the origin of highly enantioselective hydrogenation. Combination of isotope labeling experiments and kinetics has revealed that the reaction proceeds via a monohydride-unsaturate mechanism involving the initial RuH formation followed by a reaction with an olefinic substrate. The major S and minor R enantiomers are produced via the same mechanism. The detail rate law analysis made it possible to determine the energy diagram of the catalytic species, which has also been experimentally substantiated by the ^<12>C/^<13>C and ^1H/^2H isotope effect measurements. The Ru monohydride species B is first generated from the diacetate A and H_2, and then forms a short-lived enamide complex C which delivers the hydride to the C(3) position. The addition of the RuH species to the olefinic bond is endergonic and reversible. The overall rate is limited by the Ru-C hydrogenolysis step of the resulting Ru-alkyl species D. The enantioselection is made during this irreversible step but actually is controlled by the relative free energies of the diastereomeric RuH/olefin complexes. Structural information was obtained by NMR studies as well as X-ray crystallographic analysis. Crystalline mono-methanol coordinated diacetate complex and the derivative of the Ru monohydride species were isolated and characterized by X-ray study. The molecular structures are consistent with those in solution estimated from NMR experiments. The reaction monitoring by NMR using ^<13>C-labeled substrates revealed that the observed Ru-enamide complex is nonproductive and that the mode of enamide coordination corresponds with that in the reactive RhH_2 intermediate in the related Rh-catalyzed hydrogenation which occurs via a unsaturate-dihydride mechanism. All of the observation strongly support the enantioface selection based on the stereo-complementary models of the enamide/metal chelate complexes.

著者

今井 直子 オニヤンゴ エヴァンス 鶴本 穣治 高橋 圭介 石原 淳 畑山 範

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天然有機化合物討論会

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no.48, pp.181-186, 2006-09-15

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Oxazolomycin and neooxazolomycin are structurally closely related antibiotics isolated from Streptomyces sp. by Uemura et al. The former is the parent member of a class of polyene bicyclic antibiotics, other members being oxazolomycin B and C, 16-methyloxazolomycin, and curromycin A and B. The oxazolomycins were found to exhibit wide ranging and potent antibiotic activity, including inhibitory activity against Gram-positive bacteria, antiviral activity against vaccina, herpes simplex type I and influenza A, as well as in vivo antitumor activity. The intriguing molecular architectures and the biological activities make these compounds attractive targets for synthesis. However, the total synthesis is limited to Kende's synthesis of neooxazolomycin. We report here a novel approach to neooxazolomycin, which can be also applicable to the synthesis of oxazolomycin. Our synthesis of right hand core 22 started with methyl (S)-hydroxyisobutyrate and proceeded through three major transformations involving regio- and stereoselective iodination via intramolecular Pt-catalyzed hydrosilylation, Pd-catalyzed enolate alkenylation, and stereoselective dihydroxylation accompanied by concomitant lactonization. Nozaki-Hiyama-Kishi coupling of aldehyde 23 obtained from 22 with N-Fmoc-iododienamine 24 gave 7S-isomer 25 and 7R-isomer 26 as a 1: 1 epimeric mixture. It was gratifyingly found that Dess-Martin oxidation of this epimeric mixture followed by L-Selectride reduction of the resulting ketone produced the desired 7R-isomer 26 in excellent stereoselectivity (94% de). Removal of the silyl protecting group allowed us to obtain the Kende's intermediate 27, the synthesis of which constitutes a formal synthesis of neooxazolomycin.

著者

河岸 洋和 畠山 美奈 何 普明 杉山 公男

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天然有機化合物討論会

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no.42, pp.517-522, 2000-10-01

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In the course of screening for liver injury preventing activity of 22 fruits, we found strong activity of avocado. We describe the isolation, structure determination, and biological activity of the liver injury preventing substances from the fruit Lyophilized materials were extracted with hexane. The hexane extract was chromatographed on a silica gel column followed by HPLC using an ODS column, giving five compounds 1-5. FAB-MS (positive) of 1 showed the [M+H]^+ ion at m/z 351. Its ^<13>C-NMR and DEPT experiment exhibited the presence of a carbonyl group (δ189.2), 4 double bonds (δ126.3, 127.8, 128.3, 129.2, 129.8, 130.3, 144.8, 148.7), 11 methylene groups, and a methyl one (δ14.09). Finally, the structure of the compound was determined by the interpretation of HMBC spectrum and its EI-MS fragmentation. Compounds 2 and 3 have been already isolated as an antifungal substance and/or radical scavengers. Elucidation of the structures of compounds 4 and 5 is now in progress. In vivo assay was done as follows. After direct administration of each compound (100mg/kg weight) into rats' stomachs by using catheters, liver injury was induced by treatment of the rats with D-GalN. All the compounds suppressed the increase of ALT and AST activity in the serum of the rats.

著者

大船 泰史

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天然有機化合物討論会

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no.24, pp.560-567, 1981-09-10

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I. (-)-Domoic acid (2) isolated from Rhodophyceae (Chondria armata Okamura), possessing strong neuroexciting activity, has been synthesized in optically pure form. The reported structure was (2S,3R,4S) 1 with undefined stereochemistry at C-5' carbon atom. Including determination of C-5' configuration, we planned to synthesize 1 as a target molecule. Comparison of both synthetic epimers 21a and 21b with natural domoic acid derivative showed uncorrectness of the structure 1. So, X-ray crystallographic analysis was examined by Takemoto et al. As a result, structure 1 was revised to 2 with C-2', C-3' Z double bond and C-5' R configuration. The synthesis to 1 and then, 2 are in the following. 1) C-3 and C-4 side chain of the pyrollidine ring were introduced by means of Diels-Alder reaction (6 and 4-methyl-2-trimethylsilyloxy-trans-1,3-butadiene). 2) Chemoselective reduction of C-5 amide function in the presence of N-t-Boc protecting group was achieved using BH_3-DMS (9→10) 3) C-4 side chain (13→20a,20b) was constructed in four steps via hydroxyselenenylation and selenoxide elimination, followed by Wittig reaction with 18a (C-5'R) and 18b (C-5'S). Wittig reaction of 18a and 16b afforded 22, which was converted in three steps to (-)-domoic acid (2). II. 2'-Deoxymugineic acid (25) isolated from wheat root (Triticum aestivum L.) and avenic acid A (26) isolated from oat root (Avena sativa L.) were synthesized in the stereospecific manner employing N-alkylation procedure of three optically active unit.

著者

鈴木 輝明 武田 聡 鈴木 稔 黒沢 悦朗

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天然有機化合物討論会

雑誌

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no.29, pp.576-583, 1987-07-25

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In our continuing work on the neutral extract of Laurencia obtusa (magiresozo in Japanese), which exhibited the remarkably cytotoxic properties, we previously reported the isolation and structure determination of strongly active squalene-derived polyethers. Further investigation of this extract has led to the isolation of five cytotoxic diterpenes (1)-(5), which are structurally related to parguerol or isoparguerol, along with inactive sesquiterpenes (6)-(9). The structures of these compounds were characterized by chemical and spectral methods.

著者

小口 剛正 渡邉 一弘 阿部 秀樹 加藤 正

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天然有機化合物討論会

雑誌

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no.49, pp.521-526, 2007-08-24

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(-)-Nalanthalide (1), isolated from the culture of Nalanthamala sp., was found to be a novel blocker of the voltage-gated potassium channel Kv 1.3 by Merck research group. In human T cell, to block Kv1.3 channels cause to prevent membrane depolarization, which attenuates intarcellular Ca^<2+> levels for T cell activation and proliferation. Therefore, (-)-1 is expected to be a promising new lead for the immunosuppressant. A closely related diterpenoid α-pyrone (+)-sesquicillin (2), wherein the γ-pyrone ring of (-)-1 is replaced with an α-pyrone ring, was previously isolated from Acremonium sp. It was reported that (+)-2 shows a variety of biological properties such as glucocorticoid antagonist. anti-inflammatory, anticancer, and G1 phase arrest activities. We envisioned that (+)-(2) would be elaborated through conversion from the γ-pyrone ring of (-)-1 to the corresponding a-pyrone ring. And (-)-(1) would be available through a coupling of 4 with 3. The intermediate 5 would be available through the strategic [2,3]-Wittig rearrangement of 6. The synthesis began with the preparation of intermediate 6, the substrate for the key [2,3]-Wing rearrangement, starting from 8. After conversion of 8 to 6, we carried out the [2,3]-Wittig rearrangement under several reaction conditions. Finally, we found that the designed [2,3]-Wittig rearrangement of 6 proceeded smoothly and cleanly by treatment with n-butyllithium in n-hexane at-50℃→room temperature. In this reaction, the use of n-hexane as the solvent was crucial. After conversion of 5 into 4, the coupling of 4 with 3-Iithio-γ-pyrone was achieved an initial bromine/lithium exchange on 3. The coupling product was converted to the key intermediate 19. Acetylation of 19 furnished (-)-(1). Next, we attempted direct conversion of (-)-(1) to (+)-(2) under several basic conditions; however, undesired deacetylation of the C3 acetyl group in (-)-1 occurred. Consequently, conversion of the γ-pyrone ring in 19 to the α-pyrone ring under basic conditions was conducted; the desired diacetate 20 was obtained upon acetylation of the product. Finally, selective deacetylation of the α-pyrone moiety in 20 under mild basic conditions furnished (+)-(2).

著者

廣田 洋 棚橋 善昭 高橋 武美

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天然有機化合物討論会

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巻号頁・発行日

no.19, pp.54-61, 1975-10-01

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Structure elucidation of LB, one of the volatile components of "San-shion" (Ligularia species), was accomplished in the following way. LB, C_<15>H_<26>O, was assumed to be a saturated guaiane-type sesquiterpene ether from its spectra and the dehydrogenation reaction. INDOR experiments on LB and 1-epiguaioxide(13) showed that LB is one of the eight stereoisomers of guaioxide(10). As six compounds of them are already known, the structure of LB must be represented by either 14 or 16. The reaction of LB with NBS in CCl_4 gave 4-bromo-LB(22) in 8〜18% yield. The compound(22) was dehydrobrominated into 23, which reacted with diborane to give 27. The oxidation of 27 with Jones' reagent gave the ketone(29), which then isomerized to 26. The structure of 22, 23, 26, 27, and 29 were confirmed by their spectral data, obtained by double resonance and lanthanide-induced shift techniques in PMR. The absolute structure of 29 was determined by the ORD and CD experiments. The hydrogenation of 23 gave 4-epi-LB. The compound(14) obtained by tosylation of 27 followed by reduction with LiAlH_4, was identical with 4-epi-LB. Therefore, the structure of LB was determined to be 16, including the absolute configuration.

著者

紺野 勝弘 白浜 晴久 松本 毅

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天然有機化合物討論会

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no.25, pp.421-428, 1982-09-10

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Clitocybe acromelalga is a poisonous mushroom distributed in Japan only. It exhibits unique toxicity. If one takes it accidentaly, one will have intolerable pain in fingers and toes after some days and the pain continues for about a month. We were interested in these remarkable physiological activities. It was difficult to reproduce the above described symptoms in experimental animals, however. So we fractionated various constituents of the mushroom testing the lethal effect on mice. Clitidine was a weakly toxic, a new nucleoside. Clithioneine, an unusual betaine, was nontoxic. From the most toxic fraction, acromelic acid A (ca. 110μg) and acromelic acid B (ca. 40μg) were isolated. We suggest formula 1 and 2 for A and B respectively on the basis of ^1H NMR and UV data.

著者

石井 永 石川 勉 小林 純一 関 宏子

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天然有機化合物討論会

雑誌

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no.34, pp.518-525, 1992-09-10

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Toddacoumalone (4) and toddacoumaquinone (5), isolated from Toddalia asiatica (L.) Lam. (T. aculeata Pers.) (Rutaceae), were established to be novel unique mixed dimers based on a coumarin by spectroscopic means mainly 2D-NMR. Toddacoumalone (4), C_<31>H_<31>NO_6, was isolated as colorless prisms, mp 202-204℃ (AcOEt), in a racemic form. Its IR, UV, and NMR (Table 1) spectra including the COLOC experiment based on three bond correlations (Table 2) indicated the presence of a 8-substituted 5, 7-dimethoxycoumarin like 6 and an N-methyl-2-quinolone like 7 in 4. A monoterpene bridge of CH=CHC(Me)CH_2CHCH=CMe_2 with cis arrangement between the two vinyl groups was interposed between the coumarin and the quinolone units. Though lack of coupling between the conjugated olefinic protons gave us no clue to the geometry, an E geometry for the double bond could be deduced by appearance of conjugated (E)-olefinic protons in toddalenol (12) as a 2H singlet and coexistence of toddasin (13) in the same plant. Connection of the C_<10> unit to the coumarin and the quinolone systems resulted in drawing the structure of 4 for toddacoumalone. Toddacoumaquinone (5), C_<23>H_<18>O_7, was isolated as orange prisms, mp 278-281℃ (AcOEt). The same 8-substituted 5, 7-dimethoxycoumarin moiety was also found to be in 5. In this case presence of an 8-substituted 2-methoxy-6-methyl-p-naphthoquinone system was reasonably deduced by spectral data. Thus, toddacoumaquinone should be a biaryl compound consisting of a coumarin and a naphthoquinone, the structure of which could be depicted as 5. Both the dimers would be synthesized in a plant body through Diels-Alder type cycloaddition reaction. The synthetic works based on this biogenetic consideration are now in progress.

著者

入江 一浩 増田 裕一 村上 一馬 上村 諭子 大東 肇 原 英之 大橋 竜太郎 中西 梓 竹腰 清乃理

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天然有機化合物討論会

雑誌

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no.49, pp.61-66, 2007-08-24

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Aggregation of the 42-mer amyloid β (Aβ42) plays a central role in the pathogenesis of Alzheimer's disease. Our recent research on the systematic replacement of Aβ42 with proline suggested that the formation of a turn structure at Glu-22 and Asp-23 could be essential to the potent aggregative ability and neurotoxicity of Aβ42. We verified the existence of this turn structure in the minor conformer of wild-type Aβ42 and E22K-Aβ42 (Italian mutation), by solid-state NMR using dipolar assisted rotational resonance (DARR). In E22K-Aβ42, the ionic interaction between Lys-22 and Asp-23 might promote the turn formation at this site. In order to identify the toxic conformation of Aβ42, we synthesized Aβ42-lactam(22K-23E) as a conformationally restricted analogue of the minor conformer, whose side chains of Lys-22 and Glu-23 are linked with an amide bond. Aβ42-lactam(22K-23E) showed much stronger aggregative ability and neurotoxicity than E22K-Aβ42. This implies that the minor conformer with a turn at Glu-22 and Asp-23 of Aβ42 should be considered as a toxic form. Neurotoxicity of Aβ42 is closely related to the radicalization at both Tyr-10 and Met-35. Our previous study reminds us that the S-oxidized radical cation at position 35, the ultimate toxic radical species, would be produced effectively through oxidation by the phenoxy radical at position 10 in the toxic conformer. Electron spin resonance (ESR) spectrometry using spin-labeling with MTSSL revealed that these residues are close to each other in Aβ42. This finding clearly accounts for the reason why the toxic conformer is more pathogenic than the physiological one.

著者

西沢 麦夫 山田 英俊 林 雄二

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天然有機化合物討論会

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no.28, pp.370-376, 1986-09-09

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A sweet principle of Phlomis betonicoides, baiyunoside (1a) reported by Tanaka, is a glycoside of 3-substituted furanoditerpene with labdane skeleton. During the series of our investigation dealing with a biomimetic olefin cyclization using mercury(III) triflate/N,N-dimethylaniline complex (2), we have examined the cyclization of some acyclic furano terpenoid, and observed that the cyclization of ambliofuran (3a) is mainly initiated from an internal double bond (Δ^<10>) to give 4 and 5, whereas the corresponding sulfone 3b affords terminal cyclization products 16, 17, and 18. The latter product 18 is a mixture of three isomeric olefins (Δ^<7,8>:Δ^<8,9>:Δ^<8,17>=9:4:3). Thus, the cyclization control of ambliofuran analog not only the initiation point but also the termination mode is essential in order to promote the selective total synthesis of (±)-baiyunol (1b), an aglycon of a sweet substance 1a. A furano ketone 3d is the best substrate to our purpose which gives Δ^<8,9> bicyclic product 28 in high yield. The resulting organomercuric ketone 28 is efficiently transformed to 1b, and which is identified with (+)-baiyunol derived from natural sweet glycoside. Glycosidation of (±)-baiyunol is currently undertaken.

著者

山田 英俊 西沢 麦夫

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天然有機化合物討論会

雑誌

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no.29, pp.349-355, 1987-07-25

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Sweet taste is one of the fascinating field of organic chemistry on the basis of social requirements to find low calorie and high quality taste. Baiyunoside (1) has been characterized as a sweet taste principle of chinese drug, Bai-Yun-Shen (Phlomis betonicoides), by Tanaka and co-workers along with the minor sweet glycoside named phlomisoside I (2). We have designed a general approach to this class of sweet glycosides in order to develop high quality artificial sweeteners. We have already reported an efficient total synthesis of (±)-baiyunol (4), the aglycon of 1 and 2 by means of selective olefin cyclization using mercury(II) triflate/N,N-dimethylaniline complex. We disclose herein the first total synthesis of baiyunoside (1) from (±)-baiyunol (4) via a novel 2' discriminated glycosidation using 2' free glycosyl halide. This novel glycosidation does not accompanied any oligosaccharide formation and this result suggests that very severe steric bulk exist at the newly formed 2' hydroxyl moiety of 6a. As is the case, 6a was entirely inert against a variety of Koenigs-Knorr type glycosidation in order to introduce the xylose moiety. However, Noyori's glycosidation based on a strong affinity between silicon and fluorine was efficiently applied to our purpose. When trimethylsilyl ether 16 was treated with fluorosugar 15 in toluene in the presence of catalytic amount of trimethylsilyl triflate afforded disaccharide 17 and 18 in 38: 62 ratio and in 58% yield. Deprotection of the latter afforded baiyunoside (1) and identified with natural product in every respects. Therefore, we have established a general way to prepare a wide variety of baiyunoside analogs in order to evaluate the taste.

著者

中村 誠宏 森川 敏生 加藤 泰世 李 寧 長友 暁史 池 桂花 大串 輝樹 浅尾 恭伸 松田 久司 吉川 雅之

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天然有機化合物討論会

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no.48, pp.535-540, 2006-09-15

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During the course of our characterization studies on bioactive saponins, the saponin fraction from the flowers, seeds of Camellia sinensis and C. japonica were found to show biological activities (gastroprotective, inhibitory effect on serum triglyceride (TG) elevation, and platelet aggregating effects, and so on). Therefore, we tried to isolate various bioactive saponin constituents from Camellia sinensis and C. japonica. 1. Camellia sinensis We have isolated nine new compounds [floratheasaponins A-I] from the flowers, twenty-three new compounds [theasaponins A_1-A_5, C_1, E_3-E_<13>, F_1-F_3, G_1, G_2 and H_1] from the seeds, and six new compounds [foliatheasaponins I-VI] from the leaves of C. sinensis. Floratheasaponins from the flowers were found to inhibit serum TG elevation in olive oilloaded mice. Theasaponins A_2 and E_2 showed inhibitory effects on ethanol-induced gastric mucosal lesions in rat, and their effects were stronger than that of reference compound, cetraxate hydrocholoride. 2. Camellia. Japonica We have isolated nine new compounds [camelliosides A-D, sanchasaponins A-D] from the flowers and six new compounds [camelliasaponins A_1, A_2, B_1, B_2, C_1, and C_2,] of C. japonica. Camelliosides, A and B showed gastroprotective and platelet aggregating effects. In addition, camelliasaponins B_1, B_2, C_1, and C_2 were found to exhibit inhibitory activity on ethanol absorption.

著者

眞岡 孝至 秋元 直茂 藤原 靖弘 橋本 圭二

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天然有機化合物討論会

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天然有機化合物討論会講演要旨集

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no.45, pp.611-616, 2003-09-01

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The ripe fruits of paprika (Capsicum annuum L.) is a good source of carotenoids and is used widely as a vegetable and food colorant. The red carotenoids are mainly capsanthin and capsorbin, possessing 3-hydroxy-6-oxo-κ-end group. In the course of the carotenoids studies of paprika, two new carotenoids 1 and 2 were isolated as minor components. The MeOH extract of ripe fruits of paprika (4kg) was saponified with 5% KOH/MeOH, and unsaponifiable matter was chromotographed on silica gel using an increasing percentage of acetone in hexane. The fraction eluted with acetone-hexane (1:9) was subjected to a series of HPLC on ODS with CHCl_3-acetonitrile (1:9) and on silica gel with acetone-hexane (2:8) to yield 1 (2mg) and 2 (0.5mg). The molecular formula of 1 was determined to be C_<40>H_<56>O_2 by HR FAB MS. The positive ion FAB MS/MS spectrum of the molecular ion (M^+) of 1 is shown in Fig 1a. Characteristic product ions of M-111 and M-139 which attributed to cleavage between C-5' and C-6' and between C-6' and C-7', respectively suggested the presence of 6-oxo-κ-end group in 1. The structure of 1 was determined to be 3-hydroxy-β,κ-caroten-6'-one by ^1H- and ^<13>C-NMR, COSY, TOCSY, NOESY, HSQC and HMBC data and named 3'-deoxycapsanthin. The structure of 2 was determined to be 3,4-didehydro-β,κ-caroten-6'-one by HR FAB MS, FAB MS/MS, UV-Vis and ^1H-NMR data. From the CD spectral data and biosynthetic consideration 3R, 5'R and 5'R chiralities were proposed for 1 and 2, respectively. They are the first example of carotenoids possessing 6-oxo-κ-end group.

著者

相見 則郎 高山 廣光 北島 満里子 内田 直喜 須田 真也 大矢 菜穂子 坂井 進一郎 POLZ Leo STOCKIGT Joachim MENDONZA Luis A.

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天然有機化合物討論会

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no.33, pp.480-487, 1991-09-07

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The technology of plant cell suspension cultures to generate useful secondary metabolites was emploied for two medicinal plants originally producing the indole alkaloids. I. Biotransformation of Ajmaline in Plant Cell Cultures of Rauwolfia Serpentina Benth. From the methanol extracts of the plant cell suspension cultures of R. serpentina, which have been cultivated in the alkaloid-production medium after feeding of ajmaline (1), three new indole alkaloids, raumacline (2), N_b-methylraumacline (3), and 19(S)-hydroxy-N_b-methylraumacline (4), were isolated. These structures first elucidated by spectroscopic analysis were unambiguously determined by the chemical synthesis from ajmaline (1). These new compounds are the first examples of the macroline-type indole alkaloids having the trans relationship between C15 and C16 positions. II. Isolation of Novel Indole Alkaloids from Cell Cultures of Aspidosperma Quebracho Blanco Schlecht. From the cell suspension cultures of A. quebracho blanco, two novel monoterpenoid indole alkaloids, aspidochibine (19) and 3-oxo-14,15-dehydrorhazinilam (21), were isolated, though the production amounts of them were very low at this stage. The structure elucidation and the stereochemical analysis were made by mainly 2D NMR technique. Aspidochibine (19), which has a characteristic ten-membered lactone, is a completely new structural class of the quebrachamine series.

著者

山口 潤一郎 掛谷 秀昭 庄司 満 長田 裕之 林 雄二郎

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天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.47, pp.25-30, 2005-09-15

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Lucilactaene (1), a cell-cycle inhibitor in p53-Transfected cancer, is a synthetically challenging molecule because of its rare hexahydro-3a-hydroxy-5-oxo-2H-furo [3,2-b]pyrrol-6-yl ring system and its substituted and conjugated E,E,E,E,E pentaene moiety, which is unstable to acid, base, and light. Lucilactaene (1), which readily undergoes racemization, has been synthesized for the first time in optically pure form via a biomimetic pathway. The conditions under which racemization occurs were elucidated during this total synthesis. The careful isolation of lucilactaene (1) from both the broth and the mycelia under neutral, nonracemizing conditions demonstrated that the isolable natural product is in fact itself racemic. This total synthesis, which enabled verification of the absolute configuration of lucilactaene (1), has several noteworthy features: All the reactions from NG-391 (2) are mild enough not to affect the labile E,E,E,E,E pentaene moiety; ether formation from 2 to 25 and 28 and the intramolecular Michael reaction from 26 to 27 or from 30 to 31 are both highly stereoselective; the reductive removal of the epoxide with Sml_2 without effecting demethoxylation, andthe deprotection of a hemiaminal under neutral, oxidative conditions via vinyl ether 33 by using a newly developed phenylselenylethyl protecting group, are also useful transformations.

著者

森田 桂 小林 栄

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.10, pp.111-117, 1966-09-15

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Lenthionine, a highly sulfur-containing odorous substance, has been isolated from Lentinus edodes (Berk.) Sing [Shiitake Mushroom]. The compound represents the characteristic odor of the mushroom and the structure was established to be 1,2,3,5,6-pentathiepane (1) by physico-chemical measurements. 1,2,4,6-Tetrathiepane (II) and 1,2,3,4,5,6-hexathiepane (III) were also separated from the mushroom in minor quantities. All these cyclic methylene polysulfides from natural source were synthesized from simple starting materials. A precursor of lenthionine was isolated in a crystalline form. The compound was not stable and gradually decomposed into lenthionine and its analogs after being left standing at room temperature. The structure of this precursor (IV) is proposed on the basis of the conventional and high resolution mass spectral studies. Finally, the mechanisms of formation of lenthionine and its analogs from the precursor is discussed.

著者

岡野 健太郎 徳山 英利 福山 透

出版者

天然有機化合物討論会

雑誌

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巻号頁・発行日

no.48, pp.175-180, 2006-09-15

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(+)-Yatakemycin (1), which was isolated from a culture broth of Streptomyces sp. TP-A0356, is an antitumor antibiotic that has a characteristic dienone cyclopropane ring found in duocarmycins and CC-1065. Among them, 1 has been shown to exhibit the most potent activity, and therefore has attracted a great deal of attention. The first total synthesis along with the revision of its structure and determination of the absolute configuration has recently been reported by Boger and co-workers. Herein, we describe an efficient total synthesis of 1 utilizing our copper-mediated amination for the construction of all five aryl-nitrogen bonds, allowing us to conduct a sub-gram-scale preparation of 1 in 16% overall yield over 17 steps (longest linear steps from the known starting compound 6). Synthesis of the left segment 3 commenced with dibromination of 6. Removal of the TFA group, and subsequent oxidation provided dihydroisoquinoline 7, which was readily converted to the cyclization precursor 9. The first amination reaction of 9 afforded indoline 10 with retention of the other bromo group. After conversion to the dehydroamino ester 12, the second amination was performed to provide dihydropyrroloindole 13. The Ns group and benzyl ester in 13 were then converted to Fmoc group and a methanethiol ester, respectively. Finally, an Fmoc-directed, regioselective demethylation was performed with BCl_3 to furnish the left segment 3. Our amination also proved to be highly effective for the construction of the middle segment 4. Cleavage of (S)-epichlorohydrin (18) with 2,6-dibromophenyllithium species 17 provided chlorohydrin 19, which was then converted to amination precursor 21. The crucial aryl amination took place smoothly to give tetrahydroquinoline 22. After Mizoroki-Heck reaction with a dehydroalanine derivative 23 and removal of the nosyl group, bromo group was introduced regioselectively. The second amination reaction at the sterically hindered position was achieved by using a stoichiometric amount of CuI to furnish the middle segment 4. The right-hand segment 5 was also prepared in a straightforward manner by using the aryl amination strategy. Three segments thus obtained were assembled to complete the total synthesis. After coupling of the middle segment 4 with the right segment 5, TBS ether 32 was converted into the mesylate 33. Subsequent hydrolysis provided 34, which was subjected to the condensation conditions with 3 without isolation. Two benzyl groups were then removed with BCl_3, in the presence of excess pentamethylbenzene as a scavenger of benzyl cation. Finally, spirocyclopropanation was carried out according to Boger's conditions to furnish (+)-1, which was identical in all respects to the natural product.

著者

下川 賢一郎 岩瀬 賢明 三輪 亮佳 池田 麻理子 大野 修 山田 薫 宮本 憲二 上村 大輔

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.50, pp.487-492, 2008-09-01

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(-)-Ternatin (1) is a highly N-methylated cyclic heptapeptide that was isolated from the mushroom Coriolus versicolor during our continuing search for potential anti-obesity agents from natural resources such as mushrooms. In our previous presentation (2006), we reported the isolation, structure elucidation and synthesis of 1, which potently inhibited fat accumulation against 3T3-L1 murine adipocytes. To clarify the detailed mode of action of (-)-ternatin (1) with regard to fat-accumulation inhibition in adipocytes, we started bioorganic studies of 1 and its analogues. We achieved the solution-phase synthesis of 1 and then evaluated its in vivo biological activity. Treatment with 1 at 5mg/kg/day was found to suppress the increase in body weight and fat accumulation in diet-induced obese mice. Due to the course, a structure-activity relationship (SAR) study of 1 was first investigated aimed at the recognition of the importance of side chain functionalities as well as a suitable site for advanced functionalization in its structure, e.g., biotinylation and introduction of a fluorescent unit.

著者

深井 俊夫 黒田 潤 小西 正隆 野村 太郎 宇野 潤 赤尾 三太郎 来栖 恵二

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.40, pp.461-466, 1998-08-31

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Bacillus polymyxa L-1129 produced a new peptide antibiotic complex, named LI-Fs, composed of more than ten components. In this reports we will describes the isolation, structure elucidation and biological activity of each components, LI-F03a, LI-F03b, LI-F04a, Li-F04b, LI-F05a, LI-F05b, LI-F06a, LI-F06b, LI-F07a, LIF07b, LIF08a and LIF08b. These antibiotics were active against gram positive bacteria, mycobacteria and wide range of fungi and yeast, but not for gram negative bacteria. The antibiotic complex LI-Fs (400mg) was isolated from 10 liters fermentation broth using several kind of column chromatography. HPLC analysis showed that the complex was composed of at least 12 components. The components were isolated by HPLC, and the structures of each components were determined by 1D and 2D NMR and MS spectra coupled with amino acid analyses to be hexadepsipeptide containing 15-guanidino-3-hydroxypentadecanoic acid as side chain. The structure of LI-F05a was identified to be a cyclohexadepsipeptide [L-thr(1)-D-val(2)-L-Ile(3)-D-allo Thr(4)-D-Asn(5)-D-Ala(6)] and LI-F05b was identified as an isomer of LI-F05a that was replaced the Asn residue in LI-F05b with Gln, similar pairs were also found in other components, (LI-F06a-LI-F06b, LI-F07a-LI-F07b, LI-F08a-LI-F08b) (Fig. 4). Four amino acids; L-Thr(1); D-Ala(6); D-Asn(5) or D-Gln(5); D-allo Thr(4) and one side chain were commonly found in the LI-Fs antibiotics. Thus, these moieties seems to be fundamental for biological activity of LI-Fs antibiotics.