天然有機化合物討論会講演要旨集
Online ISSN : 2433-1856
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選択された号の論文の119件中51~100を表示しています
  • 森 裕二, 浅井 基也, 古川 宏
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    セッションID: 45
    発行日: 1994/09/20
    公開日: 2017/08/18
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    The total synthesis of the polyene macrolide antibiotic roxaticin (1) is reported. Roxaticin is an oxo pentaene macrolide isolated from an unidentified streptomycete strain similar to Streptomycetes ruber and shows antifungal activity. The stereostructure was determined by X-ray crystal analysis, which revealed the presence of an alternating polyol chain containing both syn and anti-1,3-diol units. The polyol fragment was prepared by a three-fold convergent route. The optically pure building blocks 10 and (R)-and (S)-11 were prepared from (S)-malic acid and (S)-and (R)-glycidol, respectively. These chiral building blocks were assembled efficiently in a reiterative manner which included dithiane-epoxide coupling and 1,3-asymmetric reduction to give the protected polyol 28. Selective manipulation of the terminal 1,2-diol unit protected with diphenylmethylene ketal yielded the aldehyde 3. The small fragment 2 was prepared by the Evans' asymmetric aldol reaction. The Julia coupling reaction of 2 with 3 gave the polyol fragment 37, which was transformed into hydroxy aldehyde 39. The Wittig-Horner reaction of tetraene ester 4 and 39 provided the protected seco-ester 40. The macrocyclic ring was closed by lactonization using the Yamaguchi-Yonemitsu method, and acid-catalyzed deprotection completed the synthesis of roxaticin.
  • 池田 大四郎, 黄 世平, 西塚 俊雄, 近藤 信一
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    セッションID: 46
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Benanomicin A, isolated from the culture broth of Actinomadura spadix MH193-16F4, exhibits excellent therapeutic effects against systemic fungal infection in mice and inhibits the infection of T-cell with HIV and the syncytium formation by the virus. This antibiotic consists of a benzo[a]naphthacenedione, D-alanine and 3-O-(D-xylopyranosyl)-D-fucopyranose. The unique structure and activities of benanomicin A prompted us to start a program directed toward the construction of the substituted benzo[a]naphthacenedione skeleton, i.e. benanomi-cinone and analogs. The retrosynthetic analysis of the 5,6-dihydrobenzo[a]naphthacenedione derivative is shown in Scheme 1 which involves Diels-Alder reaction of a tetralone, A-B ring with a naphthoquinone, D-E ring. The synthesis of non-substituted 5,6-dihydrobenzo[a]naphthacenedione (6) was accomplished as shown in Scheme 2. α-Tetralone (1) was converted to methoxy-diene (5) which was easily cyclized with naphthoquinone to give 6 in a good yield. The ester (8) derived from 5 was treated with LDA and TMSCl and chloronaphthoquinone (10) to give 9,14-dihydroxy-11-methoxy-5,6-dihydrobenzo[a]naphthacenedione (11) via ketene acetal (9) .The tri-substitued α-tetralone derivative (18), a key intermediate to benanomicinone, was synthesized from 14 in a low yield. The yield of 18 was improved by the decarboxylation of 21 via 24. Compound 18 was coupled with 10 to give penta-substituted 5,6-dihydrobenzotainaphthaceneciione (26) by a similar method to 6. The synthesis of 14-hydroxy derivative (28 ) is now in progress. The introduction of hydroxy groups at C-5 and -6 positions of 5,6-dihydrobenzo[a]-naphthacenedione will be also discussed.
  • 藤原 憲秀, 天野 世治, 林 宣之, 美根 高明, 村井 章夫
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    セッションID: 47
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Polycavemoside A (1) has been isolated as one of the sources of human intoxication from the red alga Polycavernosa tsudai by Yasumoto et al. in 1993. They have proposed the planar structure of 1, which is a novel macrolide disaccharide, on the basis of ^1H and ^<13>C NMR spectra. However, although the respective relative configurations of the tetrahydrofuran ring, the tetrahydropyran ring, and the sugar moieties have been clarified, the absolute configuration of the whole molecule has not been established yet. We have started the total synthesis of this compound, because of its unusual molecular structure, the significant toxic activity, and the lack of a satisfactory natural source. We describe herein the construction of tetrahydrofuran ring segment 5, tetrahydropyran ring segment 6, and model compound 41 corresponding to the disaccharide segment 4. The synthesis of 5 was accomplished using Sharpless epoxidation reaction and Evans alkylation reaction as key steps. The stereoselective construction of tetrahydropyran ring of 6 was achieved by the intramolecular Michael reaction of (Z-α, β-unsaturated ester diol 32 which was synthesized from (S)-glycidol as starting material. Disaccharide 41 was conveniently synthesized from L-fucose and D-xylose. Further studies toward the total synthesis of 1 are now in progress.
  • 山田 晴夫, 原田 武雄, 宮崎 浩, 塚本 裕一, 加藤 哲也, 高橋 孝志
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    セッションID: 48
    発行日: 1994/09/20
    公開日: 2017/08/18
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    The elicitor-active hexa-P-D-glucopyranosyl-D-glucitol (1), isolated from mycelial walls of Phytophthora megasperma f. sp. glycinea, induces antibiotic phytoalexin accumulation in soybeans. Biological assays of several oligoglucosides revealed that hexa-β-glucoside 2 is the minimum structural element required for high elicitor activity. Synthesis of the oligosaccharides has made considerable progress as a result of the development of glycosidation procedures. However, only a few methodologies directed to the synthesis of oligosaccharide has been developed. Herein we describe an application of a new one-pot glycosidation methodology to the synthesis of an elicitoractive hexaglucoside 2. At first, two types of one-pot glycosidation, linear one-pot glycosidation and branched one-pot glycosidation, are examined. Both one-pot glycosidations provide a new method to construct several glycosidic bonds in one pot reaction, which enables the rapid and efficient synthesis of oligosaccharides. These one-pot glycosidations are based on the ability to control the reactivities of the glycosyl donors 3 and 8 for the linear one-pot glycosidation (Figure-2) and 30 and 38 for the branched one-pot glycosidation (Figure-4) by selecting appropriate activators. Namely, the glycosyl donors X1 in 3 and 30 are selectively activated in the presence of activator A1 to give disaccharides 9 and 37, respectively. Successive activations of X2 in 9 and 38 in the presence of A2, followed by coupling with the glycosyl acceptors 10 and 37 provide the linear trisaccharide 11 and the branched trisaccharide 35, respectively. The results of linear and branched one-pot glycosidations are shown in Table-1 and Figure-5, respectively. Synthesis of the elicitor-active hexaglucoside 2 by the linear one-pot glycosidation was carried out as follows. Initial coupling of glycosyl trichloroimidate 46 with thioglycoside 47 in the presence of a catalytic amount of TMSOTf gave the tetraglucoside. While the phenylthio groups in 47 and the tetraglucoside are stable to TMSOTf activation, addition of a second activators, NIS/TfOH and glycosyl acceptor 48 to the reaction mixture promoted the selective activation of the phenylthio group in the tetraglucoside to give hexaglucoside 49 in 50% yield. Base treatment of hexaglucoside 49, followed by hydrogenation provided the desired hexaglucoside 2 in 94% overall yield. Our studies on the conformation of hexaglucoside 2 in solution based on AMBER force field and GB/SA solvation model revealed that the β-(1-6) linked backbone residue shows a helical structure to which the two branched β-(1-3) glucoses are attached toward outside of the helix. (Figure-8)
  • 小林 昭雄, 秋山 康紀, 田井 章博, 河津 一儀
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    セッションID: 49
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Elicitor-active oligosaccharides have been produced from natural polysaccharides by the two approaches, 1) partial hydrolysis of the polysaccharides, 2) enzymatic synthesis utilizing glycosidase-catalyzed transglycosylation reaction. Natural polysaccharides were examined for their activity as elicitors in alfalfa cotyledons. Laminaran, which had a marked elicitor activity, was partially hydrolyzed and then purified by charcoal and gel filtration columns. Introduction of the pyridylamino group into the elicitor-active oligosaccharides was attempted in order to facilitate isolation. Their HPLC analysis showed three main peaks. The individual peaks (LN-1, 2, 3) were collected and subjected to the alfalfa cotyledon assay. LN-3 showed the highest activity (MEC; 650 nM). Based on the analyses of glycosyl-linkage and fragments by acetolysis, LN-3 is a linear pyridylaminated hepta-β-glucoside which consists of a PA-laminaribiose unit at the reducing end, a glucose and two laminaribiose units with three β-(1→6)-linkages. The glycosyl-sequence analysis only allows us to depict the structure as shown in Fig. 1-4.. Chitooligosaccharides and partially N-acetylchitooligosaccharides were synthesized by lysozyme-catalyzed transglycosylation reaction using N-acetylchitotriose and N-monochloroacetylchitotriose as substrates. The signals due to the H-1 protons of the GlcN units at δ4.85-4.95 and those of the GlcNAc units at δ4.55-4.65 in the ^1H NMR spectra indicated that glycosidic bond formation occurred in a regio- and stereoselective manner to afford oligosaccharides having β-(1→4) -linkage. The MALDI TOF MS analysis revealed that the range of the maximum molecular weight is 1700-2600 (d.p. 10-14). The chitooligosaccharide and partially N-acetylchitooligosaccharide (d.a. 36%) synthesized in an ammonium sulfate-containing buffer exhibited strong activity for phytoalexin (+)-pisatin induction in pea epicotyl elicitor assay. The transglycosylation of N-monochloroacetylated sugars followed by N-dechloroacetylation could be one of the most effective methods for producing chitooligosaccharides and partially N-acetylchitooligosaccharides, which could possess a variety of biological activities.
  • 李 波, 田中 圭, 冨士 薫, 横井 利夫, 新宮 徹朗, 多賀 徹, 孫 漢董
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    セッションID: P-1
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Taxol, a diterpenoid first isolated from Taxus brevifolia in 1971, invokes a great deal of interest amongst anticancer drugs from plant source due to its promising anticancer activity and unique action mechanism. Extensive chemical and biological investigations on this and related diterpenoids have been carried out worldwide for the purpose of ample and efficient material supply. Search for new taxoids from different kinds of Taxus species might not only lead to a solution of the problem but to a refinement of anticancer activity and formulation. As a part of our program to investigate new axanes of antitumor activity, we have isolated fourteen new diterpenoids from Chinese Taxaceae, Taxus chinensis, together with thirteen known compounds. Their structures were elucidated by spectral means, especially NMR technique. Among fourteen new diterpenoids, ten compounds possess a novel tricyclo 5/7/6-membered ring system, which was unambiguously confirmed by an X-ray analysis. The variable temperature NMR experiments indicated that some of new diterpenoids of this skeleton are more flexible in solution than their taxane counterpart, and exist as a mixture of two conformers at an ambient temperature.
  • 関谷 紀子, 吉原 和雄
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    セッションID: P-2
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Retinochrome is one of retinal proteins in squid retina, which has photoisomerase activity of all-trans-retinal to the 11-cis-isomer. In the protein the chromophore is linked to an amino group of lysin residue through the protonated Schiff base. To investigate protein environment surrounding the chromophore, which is considered to controll such a specific photoisomerization, 14-fluoro, 14-chloro, and 14-methyiretinals were incorporated into the protein. Highly electronegative fluorine substitution at 14-position of the chromophore exhibited mostly unprotonation of the Schiff base and less electronegative chlorine substituent gave less unprotonation than fluorine, whereas non-electronegative and bulky methyl substituent gave only a pigment having the protonated Schiff base same as natural retinochrome. Those results indicate that electrostatic effect of the 14-substituents causes of the unprotonation. PKa decreases of the Schiff bases due to 14-fluorination of retinal model Schiff bases, as such, were too small to cause the unprotonation in retinochrome, suggesting that, besides that effect, through space/medium electrostatic effect to protein moiety contributes to the unprotonation. Fully protonation of the Schiff base in the 14-Me-analog protein excluded another possibility of the steric effect for the unprotonation. The Schiff base counterion is most likely candidate for the protein moiety having the fluorine effect because both groups should be located in the vicinity of the Schiff base. It suggests 14,15-s-trans-C=N-anti conformation of the all-trans-chromophore in retinochrome.
  • 田崎 弘之, 鍋田 憲助, 奥山 寛, J. Zapp, H. Becker
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    セッションID: P-3
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Liverworts have oil bodies in their cells which contain a large variety of terpenes. Twelve new diterpenoids, including jamesoniellide D-G, and three new labdane-type diterpenoids have been isolated from the in vitro cultures of the liverwort Jamesoniella autumnalis (DC) Steph. (Jungermanniaceae). J. autumnalis was collected in December 1988 near Orscholz Saar (Germany). An axenic culture of J. autumnalis was induced from the surface-sterilized gametophyte of field material. The cultures were grown in flasks with modified B5 (pH 6.0) medium, containing 20gl^<-1> sucrose. The flasks were kept under constant illumination (2000 lux) at 22℃. A combination of column chromatography on silica gel and Sephadex LH-20 of an Et2O extract of J. autumnalis has resulted in the isolation of twelve new diterpenoids 4 to 15 together with five known compounds. The structures were established by spectroscopic methods. The terpenoids in the in vitro cultures are almost identical to those in the field collected materials.
  • 根本 英雄, 種部 哲朗, 福本 圭一郎
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    セッションID: P-4
    発行日: 1994/09/20
    公開日: 2017/08/18
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    A novel approach to chiral cyclobutanones has been developed by using asymmetric dihydroxylation(method A) and epoxydation(method B) of cyclopropylidene derivatives followed by concerted ring expansion of the resulted chiral diols and epoxides, respectively, as a key step. Although the former method A showed poor enantioselectivity, it was found that 1-hydroxymethylcyclobutanones(9) was obtained in high enantiomeric excess via the method B. Thus,a highly enantioselective total syntheses of (-)-mesembrine and (-)-ngaione, (+)-ipomeamarone and their epimers were achived through method B as a key step. The enantioselectivity in a synthesis of 1-aryl-1-hydroxymethylcyclo-butanone(27) through method B was also improved by examining the substituent effect of aryl part.
  • 小林 優, V. Anjaneyulu
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    セッションID: P-5
    発行日: 1994/09/20
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    It was assumed that the additivity relationships of the δ_c val-ues in the carbon-13 nuclear magnetic resonance spectra of polyhydroxy 5α,14α-steroids could be equated with the sum total of those of individual 1,2-and 1,3-glycol types involved in the molecule. The differences in the δ_c values (Δδg), reported for various types of glycols from those derived by addition of monohydroxy substituent effects, were converted to dihydroxy steroid parameters (Table 1). Several supplementary data for 8β-hydroxy steroids are derived. The dihydroxy steroid parameters were applied to 14 different types of known polyhydroxy steroids (6-19, Chart 3) and the calculated δ_c values were derived (Table 3). The results indicate that within reasonable deviations this method generally gives the predicted δ_c values of polyhydroxy steroids, except for those having an excessively severe steric hindrance, such as found in 4β, 6β,8β, 15β-tetrahy-droxylated steroid 19.
  • 井原 正隆, 谷口 孝彦, 徳永 雄次, 鈴木 秋一, 福本 圭一郎
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    セッションID: P-6
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Development of new methodology for synthesis of small ring compounds is an intriguing subject because of important biological activities of derivatives and their inherent chemical properties. Recently, we have elaborated several tools based on cascade reactions, which are useful for the synthesis of natural products. (A) Tandem Intramolecular Michael-Aldol Reaction Treatments of symmetrical (8) and α'-protected ketones (11 and 14) with TBSOTf in the presence of Et_3N provided four membered polycyclic compounds (9), (12) and (15), respectively, whereas (16) and (20) bearing two kinds of hydrogens adjacent to the ketocarbonyl group were transformed to (19) and (21) by the tandem reaction conducted under TMSI in the presence of (TMS)_2NH. It is noteworthy that the two reaction conditions were complementary. (B) Rearrangement of Cyclobutanes to Cyclopropanes A novel rearrangement of cyclobutanes (31) and (35) leading to cyclopropanes (32), (33) and (36) was achieved under three different conditions, using BF_3・OEt_2 or POCl_3-pyridine or Raney Ni (W-2). (C) Cleavage of Cyclopropyl Ketone Accompanied by Tandem Intramolecular Michael-Aldol Reaction A novel cascade reaction of α, β-unsaturated esters (44) and (47) possessing a cyclopropyl ketone moiety affording polycyclic cyclobutane (45) and (48) has been performed by the treatment with TMSI in the presence of (TMS)_2NH. (D) Total Synthesis of (±)-Anthoplalone and (±)-Lepidozene A synthesis of (±)-anthoplalone (49) and a formal synthesis of (±)-lepidozene (50) were achieved via the bicyclic compound (36), obtained by the tandem intramolecular Michael-aldol reaction and the rearrangement. (E) Synthetic Study of (±)-Filifolone The cascade reaction of the cyclopropyl aldehyde (56) produced the bicyclic iodide (57), which was converted into the potential intermediate (60) of filifolone (7).
  • 箭田 浩士, 佐藤 博二, 市原 耿民
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    セッションID: P-7
    発行日: 1994/09/20
    公開日: 2017/08/18
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    The resinous stem canker of Chamaecyparis obtusa Sieb. et Zucc., which has long been well-known among Japanese foresters but whose cause was unknown, and recently Kobayashi et. al. reported that Cryptosporiopsis abietina causes this disease. We isolated some sterols which indicate the abscisic activity against C. obtusa leaves, from the n-hexane extract of acetone soluble fraction of cultured C. abietina mycelium. We report here, the structure elucidation of abscisterol A-F (1-6) and 21-oic acid type sterol (7) by a series of 1D and 2D NMR experiments and an advanced Mosher method. The major component 1 has novel 21-nor-Δ^<17(20)>-double bond and 4β,19-ether bond. 2,4,5 also have 21-nor-Δ^<17(20)>-double bond. Only 7 has 21-carbon in abscisterol family as carboxyl group. Though a few naturally occurring Δ^<17(20)>-unsaturated sterols have been described, all of them possess 21-carbon. It is assumed that 21-nor-Δ^<17(20)>-double bond of abscisterols is formed from 21-oic acid precursor with decarboxylation. It is the first report of nor-21-Δ^<17(20)>-sterols from nature.
  • 榊原 和征, 内田 亜希
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    セッションID: P-8
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Endogenous digitalis-like substances(EDLS) or factors(EDLF) are putative substances which have been thought to be pathogens to hypertention and to possess cardiotonic activity through inhibiting of Na/K ATPase. Some of them seem to regulate natriuresis in kidney and those or the others of them seem to possess an unknown function in eyes, though recognized so far only as pathogens to cataract A lot of compounds have been reported as a substance of EDLF so far. Recently, a conclusion that EDLF was ouabain itself was reported by Hamlyn et al. However, it is still controversial if their ouabain is really endogenous, because it has been known that the digitalis activity derived from foods, especially vegitables, may accumulate in adrenal wherefrom it may be released into blood. Several years ago, Inagami et al reported their EDLF isolated from bovine adrenals possessed the molecular weight of 336. This fact, as well as several information by Grave et al, Bricker et al, and Goto et al, prompted us to deduce a structure for Inagami-Tamura's EDLF and thus lead us to a possible structure, (1). In order to reveal the structure more, we attempted to isolate a lot of amount of the EDLF from 92 kg of bovine adrenals. However, that work ended unsuccessfully. Thus, we decided to elucidate its structure through the repetetion of designing of a target molecule, synthesis, and biological evaluation. Target molecules, (26) and (29), synthesized through 17 steps from estradiol (2), showed the contractile activity on an isolated rat aorta and an isolated Guinea pig atrium. However, they were less potent than less oxygenated compounds, (30) and (31). (See Fig. 3,4,5,and 6.) These results suggest the structure (1) is substancially probable but a further study for a true character of the EDLF should be continued.
  • 森田 博史, 長島 伸治, 竹谷 孝一, 糸川 秀治, 飯高 洋一
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    セッションID: P-9
    発行日: 1994/09/20
    公開日: 2017/08/18
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    During the survey of novel antitumor compounds from medicinal plants, n-butanol extract from Aster tataricus showed potent antitumor activity. A. tataricus (Compositae) is known as a Chinese medicine containing several terpenoids and saponins and is also popular as a garden flower. Efforts at chromatographic purification of the n-butanol extract guided by antitumnor activity led to the isolation of nine cyclic pentapeptides and one acyclic peptide, named as astins A-J (1-10). The structures of a series of astins, containing one or two chlorine atoms, were elucidated by spectroscopic evidence, chemical degradation and chemical transformation. Conformational analysis of astin series was studied by spectro-scopic (NMR and X-ray analysis) and computational chemical methods (molecular dynamics and molecular mechanics calculation). These results indicated that the conformation in the solution state was, on the whole, homologous to that observed in the solid state. The difference between astin B. showing a cis configuration in a proline amide bond, and cyclochlorotine from penicillium islandicum, showing all trans amide configurations, was also discussed. To analyze the relationship between their structures and antitumor activities, various derivatives at Pro^1 and a thioamide derivative were synthesized. The presence of 3,4-dichloroproline was considered to play an important part to show antitumor activities. Further, the presence of an intramolecular hydrogen bond between Thr^2-OH and Ser^3-NH was necessitated to maintain the typical confor-mation appeared in astin B and was considered to relate the activity.
  • 岡村 浩昭, 山内 圭子, 神里 早月, 岩川 哲夫, 中谷 宗弘
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    セッションID: P-10
    発行日: 1994/09/20
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    Since the first limonoid, limonin, was elucidated in 1960, over 300 limonoids have been characterized (Fig. 1). Most of these compounds show various biological activities, e. g., insect antifeeding, cytotoxic, antitumor, and other activities. Their structure-activity relationship is very interested but it is little clarified due to their complex structures. On the other hand, a series of compounds known as degraded limonoids are biogenetically related to limonoids and have rather simple structures (Fig. 2). But their biological activities are almost unknown and only a few syntheses have been reported. Now we would like to report here the synthesis of fraxinellonone (3a) and related compounds including their stereoisomers (1a,b, 2a,b, and 3b), and their biological activity. The synthesis of these compounds were accomplished from common key intermediates (10) as shown in Scheme 2 and 3. Their ichtyotoxicity was examined and the resulting data was listed in Table 2. Compounds 1, 2, and 13 showed particularly strong toxicity. Their antifeedant test is now in progress.
  • 林 英雄, 麻生 佳秀, 村尾 澤夫, 荒井 基夫
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    セッションID: P-11
    発行日: 1994/09/20
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    During the course of searching for insecticidal compounds of microbial origin, we isolated Penicillium simplicissimum ATCC 90288 (formerly AK-40), which produced indole alkaloids, okaramines A (1) and B (2), as active principles. We also obtained okaramine C (3) from P. simplicissimum AHU 8402. Since okaramines have unique structures, we had an interest in the structure-activity relationships among okaramines and biogenesis of okaramines. We investigated minor metabolites in the fermentation products of okara (insoluble residue of whole soybean) with ATCC 90288, affoding three new congeners, 4, 5 and 6.4, named okaramine D, was revealed to be 12-hydroxyokaramine B. The structures of okaramine E (5) and okaramine F (6) were determined by spectroscopic methods. The LD_<50> value of 4 was 20μg/g diet. On the other hand, 5 and 6 showed no activity againt the larvae of silkworm, indicating that azetidine and pyrrolidine rings are very important for this activity. It is not revealed, however, which play more of an essential role in reducing activity, formation of the azetidine ring or hydroxylation at C-12.
  • 入江 統, 大和 敏宏, 大塚 正史, 宍戸 宏造
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    セッションID: P-12
    発行日: 1994/09/20
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    During the course of our program directed towards the total synthesis of diterpenoid quinones with interleukin-1 inhibitory activities, we found the novel and fascinating free-radical mediated cyclization reactions which led to the formation of tricyclic spiro compounds or bicyclo[5.4.0]undecanones. 1. Development of Radical Cascade Reaction Treatment of 7a,b with tri-n-butyltinhydride in the presence of AIBN in refluxing toluene provided the spiro ketones 8a,b in 57% and 51% yield, respectively. The mechanism of formation was speculated by deuterium incorporation experiments and calculations. 2. Free-Radical Mediated Ring Expansion Reaction In contrast to 7a,b, the radical reaction of the bicyclic keto thiocarbonate 17 afforded the bicyclo[5.4.0]undecanone 21, which would be produced via cyclopropyloxy radical 23 or acyl radical 24 intermediate, in 59% yield. 3. Formal Total Synthesis of (+)-Confertin Employing the Ring Expansion Reaction Exposure of 36, derived from the chiral enone 32, to the same conditions as before gave the bicyclo[5.3.0]decanone 37, which was converted to the hydroxy ketone 38. The spectral properties of 38 were identical to those of the authentic material reported in the total synthesis of racemic confertin by Heathcock. 4. Alternative Ring Expansion Reaction and Synthesis of (+)-O-Methylpodocarpic Acid The radical reaction of 50 having the different substitution pattern on the phenyl ring afforded unexpectedly the ring expanded ketone 52 as the major product along with spiro compound 51. This results was rationalized by calculations of the energy difference between the chair and the boat conformation of the intermediary radicals. Additionally, the chiral alcohol 44, a synthetic intermediate of 50, was successfully converted to the O-methylpodocarpinol 47, which had been led to (+)-O-methylpodocarpic acid 48 by Snider. Furthermore, the radical reaction of 54 involving the epimeric quaternary carboncenter appeared to give exclusively the ring expanded product 55.
  • 原田 健一, 藤井 清永, 島田 隆介, 鈴木 真言, 佐野 浩, 足立 恭子, Wayne W. Carmichael
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    セッションID: P-13
    発行日: 1994/09/20
    公開日: 2017/08/18
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    It is well known that cyanobacteria produce several toxic compounds. Microcystins, nodularin and cylindrospermopsin are known as the lethal hepatotoxins and the neurotoxins, anatoxin-a, anatoxin-a(s) and aphantoxins (saxitoxins) are also produced by some species of cyanobacteria. One strain of Anabaena flos-aquae called NRC 525-17 is a unique cyanobacterium that can simultaneously produce anatoxin-a(s) and microcystins. In a previous report we found that two unidentified peaks were detected by LC/MS along with those of microcystins in the toxic fraction from the cyanobacterium. The two compounds were purified by repeated silica gel and TOYOPEARL HW-40F chromatographies and designated as anabaenopeptins A (1) and B (2). Usual acid hydrolysis of 1 and 2 gave four amino acids, Val, Phe, Hty and MeAla having the L configuration, as determined by Marfey's method combimned with Frit-FAB or ESI LS/MS and confirmed by direct comparison with authentic samples. Application of the technique composed of Marfey's method and ESI LC/MS provided an additional advantage that it can sensibly detect trace amounts of the remaning constituent amino acids, Lys and Tyr for 1 and Lys and Arg for 2 in the hydrolysates. Further, the technique indicated clearly that 1 possesses L-Tyr and D-Lys and 2 possesses L-Arg and D-Lys. The common cyclic pentapeptide moiety, cyclo-(Lys-Val-Hty-MeAla-Phe), for 1 and 2 was deduced by 2D NMR techniques such as ^1H H^1COSY, HSQC, HMBC and NOESY. The results of the HMBC correlations and NOE correlations suggested that Arg is bound with α-NH of Lys through an ureido linkage in 2 and that 1 also has an ureido linkage between Lys and Tyr (Fig. I). Both 1 and 2 at 10-400μg/ml produced concentration-dependent relaxations (2-57% of norepinephrine-induced contraction) in rat aortic preparations with endothelium precontracted with norepinephrine. Recently, Kobayashi et al. reported the isolation and structural determination of keramamide A and konbamide from Okinawan marine sponges and the proposed structures for 1 and 2 have a resemblance to those for these two compounds. Since they also suggested that these cyclic peptides are produced by symbiotic microorganisms, the present case provides additional evidence that marine natural products are also produced by terrestrial microorganisms.
  • 佐川 勝一, 長岡 博人, 宮岡 宏明, 山田 泰司
    原稿種別: 本文
    セッションID: P-14
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Grayanotoxin is a toxic diterpenoid isolated from the leaves of Leucothoe grayana and has an interesting structure characterized by 5-7-6-5 ring system (grayanane skeleton). This diterpenoid shows potent biological activity increase in the membrane permeability to sodium ion. Herein, we wish to describe synthetic studies toward the total synthesis of grayanotoxin I using the sequential Michael-substitution reaction and fragmentation reaction in combination as key reactions. Sequential Michael-substitution reaction of ethyl α-bromoacrylate with the lithium enolate of cyclohexenone derivative (-)-16, which was obtained from the lipase-catalyzed enantioselective esterification of (±)-16, gave tricyclic compound 21 and 22. Both compounds 21 and 22 were converted to ester 27 via 23.. Reaction of the enolate of 27 with cyclopentenone 4, which was effectively synthesized starting from (-)-pantolactone (1) via 3, and from meso-diol 6, afforded 28 after deprotection of the silyl group. When 29 was treated with HClO_4 in CH_3CN, deprotection of the methoxymethyl group followed by fragmentation reaction occurred to give lactone 30 as a major product. Lactone 30 was converted to olefin 34 via 32 and 33. Synthesis of GTX-I from 34 is now in progress.
  • 村上 昌弘, 石田 啓史, 沖野 龍文, 沖田 裕司, 松田 久, 山口 勝己
    原稿種別: 本文
    セッションID: P-15
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Recently, Microcystis aeruginosa has been demonstrated to be a valuable source of unique biologically active peptides. In the course of our studies of protease inhibitors from microalgae, freshwater blue-green alga M aeruginosa (NIES-98) showed potent serine protease inhibitory activities. Here we report the isolation and structure elucidation of aeruginosin 98-A(1), B(2) and C(3) which inhibit trypsin, and aeruginoguanidine 98-A(4), B(5) and C(6) which shows weak cytotoxic activities. Microcystis aeruginosa (NIES-98) was obtained from the NIES-collection (Microbial Culture Collection, the National Institute for Environmental Studies, Japan). The 80% methanol extract of freeze-dried alga was partitioned between water and diethyl ether. The aqueous layer that showed potent trypsin inhibitory activity was further extracted with n-butanol and subjected to ODS column chromatography, followed by ODS HPLC to yield 1-6. Molecular formula of 1 was decided as C_<29>H_<45>N_6O_9ClS from HRFABMS and NMR data. Amino acid analysis of the acid hydrolyzate gave allo-Ile and an unknown imino acid. ^1H-^1H COSY, HMQC and HMBC data showed the presence of Chloro Hpla (3-chloro-4-hydroxyphenyllactic acid), allo-Ile, Choi sulfate (2-carboxy-6-hydroxyoctahydroindole sulfate) and agmatin. Interpretation of HMBC spectra revealed the structure of 1. The stereochemistry of allo-Ile was determined to be D-form by the chiral GC analysis. The relative stereochemistry of Choi sulfate was elucidated by NOESY spectra. The structures of 2 and 3 only differ from 1 in the substitution of the benzene ring of Chloro Hpla. The IC_<50> of 1, 2 and 3 against trypsin was 0.55, 0.6 and 3.93μg/mL, respectively. Molecular formula of 5 was decided as C_<34>H_<59>N_9O_<14>S_3 from HRFABMS and NMR data. ^1H-^1H COSY, HOHAHA, HMQC and HMBC data showed the presence of Hphpa trisulfate (1-(4-hydroxy-3-hydroxymethyl)phenyl-1 -hyciroxy-2-propylamine 4',3', 1-tri- O-sulfate), N-MeArg and NmgArg (Na^α-methyl-N^ω-geranylarginine). Interpretation of HMBC and NOESY spectra revealed the structure of 5. The structures of 4 and 6 were elucidated as analogs of 5, having the different side chains of N-MeArg. These compounds showed weak cytotoxity against P388 leukemia cells.
  • 一柳 幸生, 西村 邦彦, 生田 弘史, 竹谷 孝一, 糸川 秀治
    原稿種別: 本文
    セッションID: P-16
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Sinococuline (1) is a morphinane alkaloid isolated from the plant Cocculus trilobus native to Japan. 1 shows promising antitumor activity against animal tumor models. However, contents of 1 in the plant are inconstant, and its high polar and noncrystallizable property makes isolation/purification difficult. These hampered further preclinical studies for an anticancer agent. To develop an alternative supply route for 1, we have undertaken a program to synthesize 1 from sinomenine 2. It was envisaged that 2 would provide a suitable precursor for 1 since 2 possess a morphinane skeleton with the same substituents on ring A and is readily available in quantity from the roots of Sinomenium acuturn. C-4 phenolic hydroxyl group of 2 was protected as benzyl ether 3. 3 was subjected to N-demethylation, and the resultant amine was protected by benzyloxycarbonyl (Z) group to give 7 in 98% yield from 3. 4 was reduced stereospecifically with L-Selectride in THF to give C-6β-alcohol 10 b in 91% yield. 10b was converted to C-6α-seleno derivative 11b in 96% yield. Hydrogen peroxide oxidation of 11b gave C-81α-hydroxyl derivative 12 in 89% yield. 12 was subjected to Swern oxidation to provide diosphenol 16 (89% yield), which on treatment with methyl p-toluenesulfonate and potassium carbonate to give methyl ether 17 in 97% yield. Catalytic hydrogenation of 17 using (Ph_3)_3RhCl in benzene effected selective reduction of C-5-C-6 olefin to afford enone 5 in 97% yield. Potassium enolate of 5 was treated with (-)-(2S, 8aR)-(camphorsulfonyl)oxaziridine 22 to give C-6β-alcohol 4a and 4b in 50% and 17% yields, respectively, and 23% of 5 was recovered. 4a was protected as TBDMS ether 24 and was reduced with Super-Hydride to afford C-7β-alcohol 25a stereoselectively (25:1). 13 was deprotected to give diol 26 in 70% yield from 4a. 4a was treated with Pearlman's catalyst in refluxing cyclohexene-EtOH (1:1) to give 1 in 95% yield. The product thus obtained was found to be identical in all respects with 1 isolated from the plant. This work constitutes the first synthesis of 1 since (+)-sinomenine has been converted from thebaine.
  • 津田 正史, 川崎 直子, 小林 淳一
    原稿種別: 本文
    セッションID: P-17
    発行日: 1994/09/20
    公開日: 2017/08/18
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    The manzamine alkaloids from some genera of marine sponges are a series of β-carboline compounds having unique heterocyclic systems. In our search for biogenetic precursors of the manzamines, five novel alkaloids, keramaphidins B (6) and C (9), ircinols A (7) and B (8), and keramamine C (10), together with known manzamines have been isolated from an Okinawan marine sponge Amphimedon sp. The strucutures have been elucidated on the basis of NMR data and X-ray analysis. Interestingly ircinols A (7) and B (8) possessed opposite absolute configurations to those of ircinals A (4) and B (5), respectively, while a small amount of crystals of keramaphidin B (6) employed for X-ray analysis was revealed to be racemic. We propose a plausible biogenetic path of manzamines A〜C (1〜3) on the basis of the structures and the ratios of all the manzamine-related alkaloids isolated from this sponge and describe some differences from the biogenetic path proposed by Baldwin and Whitehead as follows; i) the presence of (-)-keramaphidin B ((-)-6) and ircinols A (7) and B (8) corresponding to antipodes of the manzamines, suggesting an incomplete stereoselectivity in intramolecular Diels-Alder type [4+2] cycloaddition of the bis-3-alkyldihydropyridine (a) to afford (+)-6 and (-)-6 as a major and a minor products, respectively. ii) 2,3-iminium form of major (+)-6 may be hydrolyzed to generate (+)-ircinals A (4) or B (5), which are probably converted into manzamines A (1) and B (2), respectively, through Pictet-Spengler cyclization with tryptamine, although Baldwin and Whitehead have proposed that manzamine A (1) could be derived from manzamine B (2). iii) on the other hand, minor (-)-6 may be converted into ircinols A (7) and B (8).
  • 前崎 直容, 福山 秀宣, 田中 徹明, 岩田 宙造, 八木 卓, 正垣 武志, 戸谷 治雅
    原稿種別: 本文
    セッションID: P-18
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Histrionicotoxin (HTX,1) was isolated from skin extracts of the Colombian poison dart frogs, Dendrobates histrionicus. The alkaloid and the fully hydrogenated congener, perhydr ohistrioniocotoxin (PHTX,4) have become attractive synthetic targets owing to their unusual spiropiperidine structures (Fig. 1), the scarcity of natural sources, and their interesting pharmacological properties. Although four asymmetric syntheses of PHTX have been reported, the stereocontrol at the three contiguous asymmetric carbon centres was poor (low selectivity or step-wise elaboration). Our pivotal synthetic strategy is the stereocontrolled construction of three contiguous asymmetric carbon centers via a carbonyl ene reaction or a palladium-catalyzed carbonyl allylation based on the chirality at the quaternary carbon center constructed by the Pummerer-type reaction of the chiral vinylic sulfoxide(6). We describe here two types of stereocontrol in the formation of spiro skeletons via a carbonyl ene reaction and a palladium-catalyzed carbonyl allylation. An asymmetric formal synthesis of (+)-PHTX is also reported via a product obtained from the latter reaction.
  • 土居 由貴子, 石橋 正己, 小林 淳一
    原稿種別: 本文
    セッションID: P-19
    発行日: 1994/09/20
    公開日: 2017/08/18
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    During our studies on bioactive substances from Okinawan marine organisms, we recently examined extracts of the compound tunicate Aplidium multiplicatum, and succeeded in isolating seven novel nucleoside derivatives, shimofuridins A (1)〜G (7), possessing an acylfucopyranoside moiety by careful studies on the HPLC separation of closely related analogs. Shimofuridin A (1), C_<34>H_<44>O_<12>N_4, was a nucleoside consisting of a purine base, two sugar units, and two unsaturated fatty acids, deduced from extensive analysis of the spectral data including several types of 2D NMR spectra (^1H-^1H COSY, HSQC, HMBC, NOESY, and ROESY). The structure of 1 including the stereochemistry of all chiral centers was established by degradation experiments and chiral HPLC and GC analyses. Shimofuridins B (2)〜E (5) were stereoisomers of double bonds of 1, while shimofuridins F (6) and G (7) were homologs of 1 with 2 more carbon units in the second acyl chain. The NMR chemical shift data of unsaturated acyl chain moiety studied in detail here may be helpful to investigate the stereochemistry of these types of unsaturated chain molecules. Shimofuridin A (1) exhibited cytotoxicity against murine lymphoma L1210 cells in vitro (IC_<50>, 9.5μg/mL), and also showed inhibitory activity against protein kinase C (IC_<50>, 20μg/mL).
  • 成瀬 政一, 青柳 榮, 宍戸 祐二, 樹林 千尋
    原稿種別: 本文
    セッションID: P-20
    発行日: 1994/09/20
    公開日: 2017/08/18
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    In an aqueous media, intramolecular hetero Diels-Alder cycloadditions of the chiral acylnitroso compounds 15a-d and 19a, b, generated from the chiral hydroxamic acids 14a-d and 18a, b, respectively, by in situ periodate oxidation, shows a pronounced enhancement (1.3-1.9:1 to 4.1-5.0:1) of the trans selectivity (with respect to C-4a and C-5) leading to the trans- 1,2-oxazinolactams 16a-d and 20a, b, compared with the results obtained by employing nonaqueous conditions. The trans stereoselectivity enhancement observed in these aqueous intramolecular cycloadditions would be explained by considering the hydrophobic packing effect which may have served to stabilize the more compact boat-like conformer 22A, leading to the trans adducts 16a-d and 20a, b, rather than the chair-like conformer 22B leading to the cis adducts 17a-d and 21a, b. The trans-1,2-oxazinolactams 16a, b and 20a thus obtained via these reactions were utilized as chiral precursors to synthesize optically active natural alkaloids including (-)-indolizidines [205A (7), 207A (8), 209 B (9), and 235B (10)] and (-)-pumiliotoxin C (11) both as poison-dart alkaloids, (-)-nupharamine (12), and (-)-swainsonine (13) in enantiocontrolled manner.
  • 高山 廣光, Sanan SUBHADHIRASAKUL, Niwat KEAWPRADUB, 水木 純子, 大森 修, 北島 満里子, 相 ...
    原稿種別: 本文
    セッションID: P-21
    発行日: 1994/09/20
    公開日: 2017/08/18
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    For the purpose of contributing to the development of medicinal material, we have continuously studied on the phytochemical investigation of Thai medicinal plants, mainly counting indole alkaloids. In the present study, the alkaloidal constituents of the three Apocynaceae plants, native to the south part of Thailand, were exhaustively investigated. I: Alkaloids from the leaves of Rauwoifia sumatrana Jack. Three new indole alkaloids, rausutrine (1), rausutranine (2), and 11-methoxystrictamine (5), were found from the ethanol extracts of the leaves of this plant, along with ten known bases. Rausutrine and rausutranine are novel bis-indole alkaloids composed of an akuammilane unit and a vincorane unit, the latter of which has a unique iminoquinone function. II: Alkaloids from Hunteria zeylanica (Retz.) Gardn. ex Thw. II-1. Glycosidic alkaloids Two novel glycosidic indole alkaloids, hunterioside (8) and hunterioside B (9), together with strictosidinic acid (6), were isolated from the n-BuOH fraction of the ethanol extracts of the stem bark of this plant, and their structures were respectively found to be 6'-α-glucoside and 3'-α-glucoside of strictosidinic acid. This isolation is the first finding of a biosidic congener of monoterpenoid indole alkaloid glucosides. II-2. A new class of dimeric indole alkaloids and the corymine-related alkaloids Two novel dimeric indole alkaloids, coryzeylamine (14) and deformylcoryzeylamine (15), which are composed of sarpagine-type and echitamine-type monoterpenoid indole alkaloids, were isolated from the leaves of Hunteria zeylanica. Furthermore, the major alkaloidal constituent, corymine (10), and three minor corymine derivatives (11-13), were obtained. III: Alkaloids from Alstonia glaucescens Mona. The first phytochemical investigation of this plant has resulted in the isolation of three new indole alkaloids (17-19) along with five known bases.
  • 陳 政宇, 南雲 紳史, 梅澤 勲, 尾能 満智子, 秋田 弘幸
    原稿種別: 本文
    セッションID: P-22
    発行日: 1994/09/20
    公開日: 2017/08/18
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    One of the most efficient method to synthesize optically pure natural products is to start off with chiral synthon. We synthesized three new chiral synthons (2R,3R)-4, (4R,5S)-27, and (S)-(-)-34 on the basis of the following two concepts; (1) to utilize the highly stereoselective chemical method to establish the relative configuration, (2) to carry out the kinetic resolution of racemates by ester-cleaving enzymes (lipase) at the next step. The Zn(BH_4)_2 reduction of β-keto ester (±)-3 afforded the alcohol (±)-syn-1 in high diastereoselectivity. The saponification of the corresponding acetate (±)-4 using the lipase "Amano A" proceeded enantioselectively to give acetate (2R,3R)-4 (48% yield, >99%ee) and alcohol (2S,3S)-1 (51% yield, 94%ee). The epoxidation of methyl sorbate followed by addition of thiophenol provided (±)-22 stereospecifically. The enantioselective esterification of (±)-22 using the lipase "PL266" in the presence of isopropenyl acetate gave alcohol (4R,5S)-22 (49.7%, >99%ee) and acetate (4S,5R)-23 (50.2%, 98%ee). The successful conversion of C-S into C-O bond at C_4 chiral center in stereo retentive manner was carried out to give (4S,5S)-21 which was converted into ketal (4R,5S)-27 via three steps. The coupling reaction of methyl 4,5-epoxy-(2E)-pentenoate 33 and m-methoxy toluene in the presence of lewis acid provided two alcohols 34 (23%) and 35 (49%). The enantioselective hydrolysis of acetate (±)-36 derived from 34 using the lipase "MY-30" gave alcohol (S)-(-)-34 (85%ee). The enzymatic esterification of this chiral compound using same lipase achieved the enrichment of optical purity. In result, we obtained (S)-(-)-36 (94%ee). These chiral compound were applicable to the syntheses of (-)-Oudemansins A, B and X, L-Acosamine, and (S)-(+)-Curcudiol.
  • 平本 昌志, 宮田 祐, 柴崎 充至, 斎田 裕治
    原稿種別: 本文
    セッションID: P-23
    発行日: 1994/09/20
    公開日: 2017/08/18
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    In the course of our screening program for cholecystokinin type-B (CCK-B) receptor antagonist, we isolated Q20547-A (1) from the cultured broth of Aspergillussp. Q20547. 1 inhibited CCK-8 binding to CCK-B receptors with an IC_<50> of 80nM. Structure of 1 was elucidated to a synmetrical dimer biosynthetically constructed from two molecules of L-Trp and L-Phe, and found to be identical with WIN64821, recently reported as a NK-1 antagonist. For the study of structure-activitiy relationship, we obtained many analogs of 1 by the biological mannar rather than complicated synthesis. First, weisolated six minor compounds analogous to 1 from the original cultured broth. Their structures were classified into two groups; one group consists of analogs with replacement one L-Phe unit of 1 to other amino acid (L-Leu, L-Val and L-Tyr), and the other group consists of stereoisomers or incorrectly biosynthesized isomers of 1. Second, we tried feeding experiments, various amino acids and non-amino acid substrates were added in the medium to obtain analogs of 1 biosynthetically. Many analogs of L-Trp and L-Phe were converted into the corresopnding analogs of 1, and a few amino acids (L-Leu, L-Val, L-met and L-thienylalanine) were substituted for L-Phe unit of 1. Furthermore, Trp-Xaa diketopiperaziznes were synthesized and fed to the culture. As expected from the biosynthetic passway, Trp-Xaa diketopiperazines were much better substrate than simple Xaa amino acids. Gly and L-Ala were incorporated instead of L-Phe by this method. Over 30 analogs of 1 obtained in these experiments were bioassayed. 23 and 25 (obtaind from feeding experiment of o-Cl-Phe and o-CF_3-Phe, respectively) were over 10-times more potent than 1. For the potent activity, comformation of four benzene ring seems to be important. Especially one phenylalanyl side chain is important to the binding, and the other phenylalanyl side chain is exchangeable for alkyl group of suitable size to show potent activity.
  • 三水 清寛, 小笠原 國郎
    原稿種別: 本文
    セッションID: P-24
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Heck reaction of 4,5-dihydro-1.3-dioxepins with aryl and alkenyl iodides furnished 5-substituted-4,5-dihydro-1,3-dioxepin derivatives in satisfactory yields. We found that the 5-aryl substituted 4,5-dihydro-1,3-dioxepins thus obtained afforded the corresponding 3-arylbutanals in good yields on Birch reduction. On the other hand, both of the 5-aryl and 5-alkenyl substituted 4.5-dihydro-1,3-dioxepins afforded the corresponding 2.3,4-trisubstituted tetrahydro-3-furfuryl alcohols in one step on exposure to diisobutylaluminum hydride by concurrent ring-contraction and reduction. Based on these two unprecedented reactions, we have developed a new synthetic route to the aromatic bisabolane sesquiterpenes and a diastereocontrolled route to the Furofuran lignans. Thus. 5-(4-methylphenyl)-4,5-dihydro-1,3-dioxepin gave 3-(4-methylphenyl)butanal in an excellent yield from which six aromatic Bisabolane sesquiterpenes could be obtained by conventional transformations. However, the present procedure was found to be unsuitable for the chiral synthesis, because complete racemization took place in the key reductive cleavage reaction in which chirality at the benzylic center was lost. While in the reductive ring-contracting reaction, it was found that the stereochemistry of the three substituents on the tetrahydrofuran could be controlled depending on the Lewis acids used. Thus, starting from the 5-alkenyl-2-aryl-4,5-dihydro-1,3-dioxepin, racemic synthesis of three Furofuran lignans having the same stereochemistry and the first synthesis of racemic asarinin having different stereochemistry have been accomplished by using appropriate Lewis acids. The latter compound has been synthesized for the first time. This procedure could also be modified chirotopically to produce these Furofuran lignans in optically active forms using the alkenyl iodide bearing a chirality controlling group in the molecule.
  • 中村 英士, 浅利 徹, 藤牧 一広, 佐藤 邦章, 村井 章夫, 菅 由紀子
    原稿種別: 本文
    セッションID: P-25
    発行日: 1994/09/20
    公開日: 2017/08/18
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    During the course of our survey for vasoconstrictive substances from symbiotic marine microorganisms, we found that a symbiotic alga Symbiodinium sp. (so called zooxanthella) associated with a flatworm produced water soluble vasoconstrictors, named zooxanthellatoxins (ZT). ZT-A isolated as one of the active principles has been determined to be a 62-membered lactone with several characteristic functionalities including a bisepoxide, a sulfate ester, an amide, two conjugated diene, and many allylic alcohols on the basis of its spectral data and chemical degradation experiments. Alkaline hydrolysis of ZT-A afforded a seco-acid and further degraded to give an acid, which was also found in a congener, ZT-B.
  • 戸嶋 浩明, 後藤 孝史, 市原 耿民
    原稿種別: 本文
    セッションID: P-26
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Oscillatoxin D (1) and 30-methyloscillatoxin D (2) are natural products derived from β-polyketides. They occur with aplysiatoxins, potent tumor promoters, in the marine blue-green algae belonging to the Oscillatoriaceae. Oscillatoxin D displays antileukemic activity against the L 1210 cell line. Aplysiatoxins and oscillatoxins have received much attention as attractive synthetic targets and several synthetic studies have recently been reported. In connection with a series of our synthetic studies on aplysiatoxins, we have succeeded to construct the unique spiroether of 1 and 2 which is absent in the structures of aplysiatoxins. Further, the first total synthesis of 2 has been completed. In retrosynthetic analysis, we adopted a possible biomimetic pathway for the cyclization of the spiroether ring and divided 1 and 2 into three main segments (A, B, C). The segment A (C_8-C_<23>) has been synthesized from D-glucose and acetophenon derivative. The segment B (C_1-C_7, C_<24>, C_<25>, C_<26>) has been synthesized from methyl (S)-3-hydroxy-2-methyl- propionate. The segment C1 (C_<27>-C_<30>) and the segment C2 (C_<27>-C_<31>) are known compounds. The acyclic compound (15), obtained by coupling of segment A and segment B, has been converted into the C_1-C_<26> spiroether (19) possessing the same stereogenic centers of oscillatoxin D. The stereochemistry of 19 was elucidated through detailed analysis of their NOE difference spectrum. The construction of the spiroether has been achieved by intramolecular aldol condensation and Michael-type addition as key steps. The cyclohexenone derivative (25) esterified with the segment C2 has been converted into the desired spiroether (26) under the acidic condition. The final deprotection of benzyl ether by hydrogenolysis with Raney-Ni (W-2) provided 30-methyloscillatoxin D (2). The ^1H-NMR spectrum of the synthetic 2 was completely identical with that of natural one.
  • 白 莉, 加藤 友子, 田上 けい子, 山木 正枝, 高木 修造, 山縣 ゆり子, 冨田 研一
    原稿種別: 本文
    セッションID: P-27
    発行日: 1994/09/20
    公開日: 2017/08/18
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    The tubers of Bletilla striata have been used in traditional medicine to treat pulmonary tuberculosis and branchiecta as hemostatic agent, but no detailed chemical study on them has been reported. In the course of our investigation on the constituents of B. striata, nine known compounds, two new glucoxybenzyl alcohols and thirty five new stilbenoids, six biphenanthrenes, four bis(phenanthrene)ethers, three dihydrophenanthropyrans, one phenanrenylspirolactone, ten phenanthrenes, four phenanthrene glucosides, seven bibenzyls were isolated. The structures were elucidated on the basis of spectroscopic and chemical transformation. Of them the dihydrophenanthropyrans and phenanrenylspirolactone have unique skeletons respectively. Two known compounds, batatasin(38) and 3'-O-methylbatatasin(39) exhibited 88.7% and 71.4% activities to branchiectasis at a concentra-tion of 10μM. Furthermore the 3'-O-methylbatatasin(39) also inhibited 75.4% edema calidum at 50mg/kg to suggest with antiinflammation. Above the phamacological activities were the 5first report and supported the traditional utilities.
  • 嶋垣 正之, 松本 一嗣, 宗嶋 寛明, 久保田 匡英, 佐藤 寛晃, 中田 忠, 大石 武
    原稿種別: 本文
    セッションID: P-28
    発行日: 1994/09/20
    公開日: 2017/08/18
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    The reaction of 2-hyroxyaldehyde derivatives 6,7,9,12,14 and 15 having R -configuration and dihydroxyacetone phosphate (DHAP) 5 gave stereoselective aldol equivalents of cyclic compound 19 and 21 via linear aldols or linear aldols 22,23 and 24 in the presence of FDP aldolase followed by acid phosphatase treatment. Contrary, the reaction of 2-hydroxyaldehyde derivatives having S-configuration 16 and 17 and 5 gave an epimeric mixture of aldols 25 and 26 via epimerization of the aldehydes in the same conditions. This fact expects that a diastereo-facial selective reaction to the aldehydes having R-configuration took place. Reductive removal of the primary hydroxy group from 27a, 27b derived from 19, and 30 derived from 23 by Barton reaction (radical reaction) and by LiAlH_4 reduction (S_N2 reaction), respectively, gave dehydrated compounds. These compounds gave pentamycin C-11-C-16 and C-9-C-16 fragments 29 and 31 with right stereochemistry. Based on the above expectation of diastereo-facial selective reactions, we tried aldehydes with sulfer or chlorine at 2-position 34a-34j. Although the former 34a-34h gave nothing of the aldols, the latter 34i and 34j gave the corresponding aldols 35i (24% yield) and 35j (27% yield) with diastero-facial selection. This means that we can obtain optically active non-carbohydrate key intermediates by controlling three carbon units with chlorine by differentiating from hydroxy groups starting from optically inactive RS-aldehydes and 5 in the presence of aldolase. Now, we are intending to determine the configuration of the chlorine of 35i and 35j. We explore a new method by controlling stereochemistry with an enzyme and followed by appropriate chemical transformations to non-carbohydrate key intermediates by carbon-carbon bond formation.
  • 塚本 佐知子, 廣田 洋, 加藤 治子, 伏谷 伸宏
    原稿種別: 本文
    セッションID: P-29
    発行日: 1994/09/20
    公開日: 2017/08/18
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    In the course of our studies on inducers of larval settlement and metamorphosis we have isolated urochordamines A and B from two ascidians Ciona savignyi and Botrylloides sp., and phlorotannins and sulfoquinovosyl diacylglycerols from the brown alga Sargassum thunbergii, which promoted larval metamorphosis in two ascidians Halocynthia roretzi and C. savignyi. Subsequently, we found a similar activity in the MeOH extract of a marine sponge, Jaspis sp. collected off the Izu Peninsula. Bioassay-guided isolation afforded two active metabolites, (E)-and (Z)-narains (1, 2) along with several related compounds. The structures of 1 and 2 were elucidated by spectroscopic methods to be new N,N-dimethylguanidinium styryl sulfates. Compounds 3-5 were obtained as racemates. Since compound 8 was obtained when extracted with MeOH, whereas the acetone extract afforded 9, it is strongly suggested that 3-5, 8, and 9 were derived from a catechol derivative with C_2-unit during extraction. (Z)-Narain (2) as well as the anion alone induced larval metamorphosis in H. roretzi at a concentration of 5μM, while no larvae in the control group underwent metamorphosis. This suggested that 2 was ten times more active than urochordamine A. However, (E)-narain 1 and the related compounds were less active than 2. No abnormal effects on larvae was observed when exposed to 2, indicating that 2 will be a good tool to study the metamorphosis mechanism of ascidian larvae.
  • 中村 精一, 清水 聡, 中田 雅久, 柴崎 正勝
    原稿種別: 本文
    セッションID: P-30
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Tautomycin (1), isolated from a culture of Streptomyces spiroverticillatus, is an antifungal antibiotic. It also inhibits protein phosphatases, which are specifically inhibited by a famous tumor promoter, okadaic acid. We took notice of this interesting biological activity and its unique structure, and hence started synthetic studies on tautomycin. We herein describe our synthetic studies. 1) Synthesis of the C_1〜C_<16> subunit (6); We already reported synthesis of the C_1〜C_<16> subunit (6) at the 35th Symposium. Since then, yields of Julia olefination of 7 and 8 and subsequent reduction of 9 have been improved. 2) Synthesis of the C_<17>〜C_<26> subunit (5); The C_<17>〜C_<26> subunit was synthesized from the 2-deoxyglucose derivative (11). The key features of the transformation to 5 are summarized below. a) Selective mono-alkylation by the stannylene ketal, b) Synthesis of the terminal isopropyl group by formation of the cyclopropane ring and subsequent ring opening, c) Transformation to the acyclic intermediate, the dithiane (15) under the optimized conditions, d) Construction of the C_<19> and C_<20> asymmetric centers by Evans's aldol reaction. 3) Coupling of the C_1〜C_<16> subunit and the C_<17>〜C_<26> subunit; Reaction of the dianion of methylketone (5) and aldehyde (6) afforded the aldol adduct 23. It was acetylated and treated with DBU to afford 3. 4) Synthesis of C1'〜C7' subunit; The C1'〜C7' subunit was synthesized from itaconic acid (24). Synthesis of 27 was carried out by asymmetric reduction of the β-keto ester (25). Synthesis of 2 from 27 is now under investigation, and the total synthesis of tautomycin is now undergoing completion.
  • 数馬 恒平, 白井 江利子, 奥野 智旦, 梅尾 和寛, 松本 毅
    原稿種別: 本文
    セッションID: P-31
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Precarthamin is known as a precursor of carthamin, a red pigment from Carthamus tinctorius L. (Safflower) and its existance in the petals have been proved since 1953. However, the structure determination has not been accomplished because of the difficulty of purification and the high sensitivity to autooxidation. Now we succeeded in the isolation of precarthamin by combination of several separation methods including HPLC (ODS column). The aqueous solution of the isolated precarthamin was quantitatively converted into carthamin by exposure to the air or treatment with dilute permanganate solution in the nutral condition. The ^1H and ^<13>C NMR (^1H, ^<13>C, DEPT, HH-COSY, CH-COSY, HMBC), UV, IR, and positive FAB-MS (m/z=979 as sodium salt) spectra were measured.The NMR spectra were analysed mainly by comparing with those of carthamin. As a result, the presence of a disubstituted acetic acid moiety instead of a methenyl moiety in carthamin was disclosed. Consequantly, the structure of precarthamin was determined to be the formula 1.
  • 杉山 長美, 野下 俊朗, 平舘 彰, 北住 賢治, 山下 恭平, 折谷 隆之
    原稿種別: 本文
    セッションID: P-32
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Aryl O-Δ^2-glycosides are considered to be 1-protected Δ^2-sugars as well as carbohydrate derivatives of aromatic compounds including aromatic antibiotics. The latter cases are expected to improve the solubility of less soluble compounds. Ferrier reaction is known to produce alkyl O-Δ^2-glycosides from acyl glycals and alcohols. Substitution of alcohols by phenols, however, resulted in poor yields of aryl O-Δ^2-glycosides. Reinvesti-gation of this reaction revealed that the condition using toluene as a solvent and a small amount (〜5mol%) of Lewis acid (BF_3・Et_2O) as a catalyst enabled to provide aryl O-Δ^2-glycosides in good yields. p-Methoxyphenol gave the best result among the phenols tested. This fact showed the great possibility of using the compound for a protection of 1-hydroxy group of Δ^2-sugars because p-methoxyphenyl group can be oxidatively cleaved to yield deprotected sugars. With a larger amount of catalyst and an elevated reaction temperature, O-Δ^2-glycosides rearranged to aryl C-Δ^2-glycosides. Next question to be solved was the method of removing the p-methoxyphenyl protective group from the anomeric center of Δ^2-sugars. Although CAN is complehensively used for such a purpose, it works in the strongly acidic medium and sometimes causes unfavorable side reactions. Silver(II) bis-(hydrogen dipicolinate) [Ag(DPAH)_2]was found to be a suitable agent working under weakly acidic condition and it oxidatively cleaved p-methoxyphenyl group to recover in high yields deprotected sugars without any side reaction. Using the above two methods, an introduction of p-methoxyphenyl group as a protective group for anomeric center of Δ^2-sugars and a mild oxidative deprotection, biologically active dihydropyranones such as osmundalactone (5), phomopsolide B (6), altholactone (7), aspyrone (8), and their stereoisomers were synthesized from carbohydrates.
  • 大山 雅義, 田中 稔幸, 飯沼 宗和
    原稿種別: 本文
    セッションID: P-33
    発行日: 1994/09/20
    公開日: 2017/08/18
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    In our continuous studies on the chemosystematics of the genus Sophora (Leguminosae), we have investigated the phenolic constituents in the roots of S. alopecuroides and S. leachiana in addition to those in S. exigua, S. fraseri and S. koreensis (=Echinosophora koreensis). The roots of S. alopecuroides, collected at Xinjiang, China, were extracted with acetone, and the extract was subjected to column chromatography on silica gel. Further purification by Sephadex LH-20 c.c. and VLC resulted in the isolation of alopecurones A (1)-F (6), leachianols A (11), F (16), G (17), ε-viniferin (19) and pallidol (20). Their structural elucidation were carried out by 2D NMR evidence. The roots of S. leachiana, collected at Oregon, were pulverized and extracted with acetone, and the extract was poured into water and partitioned with benzene, EtOAc and n-BuOH, successively. By use of Si c.c., Sephadex LH-20 c.c. and VLC, two flavonostilbenes, leachianone C (9) and sophoraflavanone I (7), were isolated from the benzene extract, whereas, two flavonostilbenes, leachianone I (10) and sophoraflavanone H (8), and eight oligostilbenes, leachianols A (11)-G(17), hopeaphenol (18), ε-viniferin (19) and pallidol (20), were from the EtOAc extract. All these structures were also established by means of 2D NMR experiments. Up to now, the occurrence of flavonostilbenes which are condensed a resveratrol with a flavanone through the B-ring of a flavanone skeleton to form a dihydrofuran ring has been reported in the roots of S. leachiana and S. moorcroftiana. On the other hand, flavonostilbenes in S. alopecuroides condensed a resveratrol with a flavanone through the A-ring are different from the above flavonostilbenes. The significant differences between S. leachiana and S. moorcroftiana were summarized by the oligostilbene structures, that is, the oligostilbenes in S. leachiana are characterized as a product oligomerized through a pallidol, in contrast, the oligostilbenes in S. moorcroftiana are through an ε-viniferin. The occurrence of resveratrol oligomers in S. alopecuroides indicated close similarity to S. leachiana from the standpoint of oligostilbene production, but two species have different pathways for the biosynthesis of flavonostilbenes.
  • 福田 保路, 志賀 太, 古田 浩祐, 大森 康男, 寺島 孜郎
    原稿種別: 本文
    セッションID: P-34
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Duocarmycins (1-6) isolated from Streptomyces sp. are novel antitumor antibiotics which are effective against various types of murine cancers. Synthesis of optically active (+)-1, (-)-1, and their C2-epimers (2-epiduocarmycin A) [(+)-7 and (-)-7] was examined to explore the relationships between absolute configuration and cytotoxicity. These studies let us develop novel duocarmycin congeners showing prominent antitumor activity. Thus, the optical resolution of tricyclic alcohols (dl-15 and dl-16) was achieved by separating their (S)-O-acetylmandelic esters by HPLC. After removal of the (S)-P-acetylmandelic acid moiety, the optically active alcohols (15^* and 16^*) were elaborated to optically active (+)-1, (-)-1, (+)-7 and (-)-7, respectively, in the same manner as employed for the synthesis of racemates. The absolute configurations of synthetic (+)-1 and (-)-1 were established by comparing their optical rotation values with that of natural (+)-1. Determination of the absolute configurations of unnatural (+)-7 and (-)-7 was next attempted by the optical resolution of the isatin derivative (dl-12) carrying a single asymmetric center. After experimentation, we found that the diastereomeric esters (19/ and 19m) prepared from dl-12 and the novel resolving agent, (S)-N-cinnnamoylproline, can be readily separated by column chromatography. The less polar ester (19/)was derived to the mandelates (17/ and 18/), by way of 15^* and 16^*. Based on these experiments correlating (+)-1 and (+)-7, the absolute configurations of (+)-7 and (-)-7 were definitely determined. With (+)-1, (-)-1, (+)-7 and (-)-7 in hand, their in vitro cytotoxicity against P388 murine leukemia was next studied. It was found that the level of cytotoxicity highly depends upon the absolute configuration of cyclopropane moiety and not upon that at the C2-position. In order to improve efficiency for producing (+)-1, (+)-7, and their congeners, we next examined the optical resolution of racemic bicyclic intermediate (dl-21) at the early synthetic stage. After numerous attempts, it was found that the diastereomeric (S)-N-cinnamoylprolyl esters (22/ and 22m) derived from dl-21 can be cleanly separated by a single recrystallization, affording less polar 22/ as crystals. This was elaborated to optically active key intermediate [(+)-11] with high optical purity. The more polar isomer (22m) was readily recycled to dl-21 by way of exomethylene derivative (25). Next, with an aim to prepare more effective anticancer agents, an efficient synthetic method was sought which can construct a novel pyrroloindole ring system such as those involved in dl-26. After experimentation, we found that pyrroloindole derivatives (dl-28) can be effectively produced from enamino esters (dl-28) by oxidative cyclization using palladium acetate. Subsequent chemical operations including condensation with various carboxylic acids furnished duocarmycin congeners (dl-27). These congeners were subjected to in vitro cytotoxicity and in vivo antitumor activity assay against P388 murine leukemia. Among dl-27 tested, those carrying a trifluoromethyl group (dl-27b) were found to exhibit promising in vitro and in vivo activity. Some of optically active duocarmycin congeners (27b^*) were similarly prepared by employing readily available (+)-11.
  • 廣瀬 裕子, 藤田 智之, 谷森 紳治, 林 英雄, 中山 充, 千田 直人
    原稿種別: 本文
    セッションID: P-35
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Quercetin is one of the most common flavonoids in plants, and has been already known to have several physiological functions in plants such as a protecting against sunlight damage and a resistance to microbial pathogens, and a naturally occurring antioxidant in food and living cells. However, there are few reports about an antioxidative function in living cells of plants. In this study, we have investigated the constituents of onion containing an amount of quercetin and its derivatives. The five components of onion were isolated by chromatographic methods and their structures were elucidated by IR, UV, NMR and MS spectra. Compound 2 was 2,5,7,3',4'-pentahydroxyflavan-3,4-dione which has been already reported as one of the oxidaiton products of quercetin. Compound 4 was quercetin and 3 was its glucoside derivative. Compound 6a and 6b were each structural isomers of bisflavonols which were the oxidation dimers of quercetin. One of the isomers, 6a was produced from quercetin by the lipid peroxidation and the radical-scavenging reaction. It can be presumed that quercetin in the outer scales of the bulbs of onion act to protect plants against the oxidative damage by inhibiting or quenching free radicals and reactive oxygen species.
  • 飯田 恭一郎, 石井 孝明, 佐藤 格, 赤堀 百合, 平間 正博
    原稿種別: 本文
    セッションID: P-36
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Very recently, a chromophore (1) of potent antitumor chromoprotein antibiotic, C-1027, as well as kedarcidin (2), has been disclosed to possess a highly strained bicyclo[7.3.0]dodecadiyne core structure. A strategy masking the 3-ene-1,5-diyne system 1 as 1,5-diyne 3 is a fascinating approach from the viewpoints of total synthesis and design of related DNA-cleaving molecules. We developed a general and efficient route for the 9-membered cyclic diyne system through an intramolecular acetylide addition mediated by Li(TMS)_2/CeCl_3, from a precursor such as 8 possessing a conformationally not rigid C4-C5 single bond. Futhermore, we found that the cyclic 1,5-diyne system such as bicyclo[7.3.0]dodeca-2,6-diyn-11-ene 11 undergoes an unprecedentedly facile Cope rearrangement below room temperature, although its isomeric bicyclo[7.3.0]dodeca-2,6-diyn-12- enes 21 and 23 do not. Thus, the delicate supression of Cope rearrangement of 9-membered cyclic 1,5-diyne system has been attained by a subtle remote structural change. In addition, we report stereocontrolled synthesis and the abusolute configuration of the sugar moiety.
  • 熊澤 敏弘, 金成 大輔, 國松 彰, 天野 義一, 佐藤 慎吾, 松葉 滋, 小原 平太郎, 小野寺 準一, 鈴木 政信, 佐藤 真弥
    原稿種別: 本文
    セッションID: P-37
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Carthmin,the red coloring matter of the flowers of Carthamus tinctorius L.(Safflower), is one of the representative old Japanese natural dyestuff with shikonin and indigo. The existence of yellow carthamin precursor in the extracts of the florets of safflower has hitherto been known, however, the structure has not been elucidated yet by reason of its instability. The yellow precursor was isolated from the fresh florets of Safflower, as micro needles through many purifying method, mainly column chromato-graphy. This pigment was unstable and immediately changed to red carthamin on spraying peroxidase-H_2O_2 solution. The ^1H- and ^<13>C-NMR spectra of this compound exhibited the existence of>CH-COOH moiety instead of-CH=moiety on carthamin. From these results along with mass spectral data, we propose the structure (1) for the precursor of carthamin. Further, the chemical and the spectral evidences of synthetic modet compound (3) were similar to those of precursor.
  • Dulce M. GARCIA, 山田 英俊, 畑山 範, 西沢 麦夫
    原稿種別: 本文
    セッションID: P-38
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Although a large number of glycosylation procedures have been reported, leaving groups at anomeric centers are usually activated by a stoichiometric amount of reagent. We found that the common glycosylation donor, glycosyl chloride, is effectively activated by a catalytic amount of zinc salt. Thus we describe herein zinc salt catalyzed rhamnosylation, glucosylation and galactosylation of a variety of alcohols. For example the reaction of cholesterol (2) and L-rhamnosyl chloride 1 in the presence of 0.1 equiv of Zn(acac)_2 in dichloromethane at room temperature for 3h afforded α-rhamnoside 3 in 95% yield with complete stereoselectivity. The new catalytic glycosylation was applied for the total synthesis of a unique cyclic glycolipid, arthrobacilin A (4), isolated from Arthrobactor sp. NR2967. The chiral β-hydroxyester 13 was prepared by Noyori's BINAP-Ru catalyzed asymmetric hydrogenation of β-ketoester. Glycosylation of 13 with galactosyl chloride 14 in the presence of 0.1 equiv of zinc p-tert-butylbenzoate (15) and 22 equiv of acid scavenger, 2-methyl-2-butene, provide β-galactoside in 73% yield selectively. Condensation/cyclization of ω-hydroxylic acid 16 was examined by using DCC/DMAP・HCl and the desired cyclic trimer was obtained in 38% yield. Deprotection by catalytic hydrogenation provided arthrobacilin A, and it was identified with natural product. Cytotoxicity of arthrobacilin A as well as synthetic arthrobacilin analogs against Hela as well as HL-60 were examined, and synthetic trimer showed same toxicity with natural product, and synthetic cyclic tetramer showed higher activity then natural product against Hela.
  • 土田 外志夫, 澤 竜一, 飯沼 寛信, 中村 光, 澤 力, 竹内 富雄
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    セッションID: P-39
    発行日: 1994/09/20
    公開日: 2017/08/18
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    In the course of our screening program for novel antimicrobial antibiotics against Pasteurella piscicida, we have isolated new antibiotics, tetrodecamycin (1) and weakly active dihydrotetrodecamycin (2) from a culture broth of a streptomycete. The MICs of 1 were 6.25-12.5μg/ml and 1.56-6.25μg/ml against Gram-positive bacteria and two strains of P.piscicida, respectively. The molecular formula of 1 was determined to be C_<18>H_<22>_O_6 by HRFAB-MS and ^<13>C-NMR spectral data of 1 and acetyl derivative (3). The planar structure of 1 was elucidated by various NMR spectral analyses of 1 and 3, except for an acyl tetronic acid alkyl ether moiety. This moiety was established by comparison of its ^<13>C chemical shifts with those of gregatin B. The IR and UV spectral data of 1 also suggested the presence of the acyl tetronic acid moiety. The structure of 2 was elucidated by comparison with the spectral data of 1. The relative stereochemistry of 2 was determined by X-ray crystallography. The stereochemistry of 1 was as same as 2, because 1 was converted into 2 by catalytic reduction. The absolute stereochemistry was determined by modified Mosher's method applied to secondary alcohol of 1. The structure-activity relationships of the ester derivatives of 1 were also described.
  • 金井 一夫, 星 道康, 佐野 信子, 津吹 政可, 本多 利雄
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    セッションID: P-40
    発行日: 1994/09/20
    公開日: 2017/08/18
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    The Sharpless asymmetric oxidation has been recognized as a versatile and useful synthetic method. We have already developed the method for preparation of chiral 2-furylmethanols by kinetic resolution of the racemates under the Sharpless reaction condition. As an application of this procedure to the synthesis of physiologically active natural products, an enantioselective synthesis of indolizidine alkaloid, swainsonine 4, a potent inhibitor of lysosomal α-mannosidase from Swainsona canescens, has been accomplished. The key feature ofthis synthesis was based on stereoselective construction of cis-fused oxabicyclononane 41 employing an intramolecular radical cyclization reaction, and a ring transformation into indolizidine skeleton by the Beckmann rearrangement. Furthermore, it has been realized that regio- and diastereo-selective oxidation of (E)-1-(2-furyl)but-2-en-1-ol 57 under the Sharpless reaction condition could be achieved depending on the chirality of DEPT used in the reaction. The procedure developed above was successfully appliedto the enantioselective synthesis of asperlin 66, isolated from Aspergillus nidulans, as a crystaline metabolite with antitumor and antibacterial activities.
  • 河村 直人, 澤 竜一, 高橋 良和, 一色 邦夫, 長縄 博, 竹内 富雄
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    セッションID: P-41
    発行日: 1994/09/20
    公開日: 2017/08/18
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    In the course of our screening program for novel antimicrobial or antitumor antibiotics, we found that a strain of Actinomadura sp. isolated from a soil sample collected on the premises of Institute of Microbial Chemistry, Tokyo, Japan, produced new antitumor antibiotics, pyralomicins (Fig. 1 1-7). The fermentation was carried out with a medium consisting of starch, corn steep liquor, yeast extract and some inorganic salts. Pyralomicins were purified by BuOAc extraction, silicagel column chromatography and HPLC. The structures of pyralomicins were determined as shown in Fig.1 by various NMR spectral analyses including ^1H-^<15>N HMBC and ^<13>C{^1H} NOE experiments. The ^1H and ^<13>C NMR data of pyralomicins are shown in Table 2 and Table 3. Pyralomicins were determined to be new type of antibiotics which have a benzopyranopyrrole ring as a chromophore. Pyralomicins 1a-1d (1-4) have a cyclohexene ring connected to the chromophore through a nitrogen atom. Another series of pyralomicins, 2a-2c (5-7) have a tetrahydropyran ring in place of the cyclohexene ring. The relative stereochemistry of pyralomicins were determined by NOE experiments using the acetyl derivatives of pyralomicin 1b (2) and 2a (5). Pyralomicins inhibited the growth of Micrococcus luteus at the concentration of 0.2-25mg/ml by agar dilution method. Pyralomicin 2a(5) showed antitumor activity against IMC carcinoma in mice when it was administered intraperitoneally. Pyralomicin 1a (1) did not show any acute toxicity in mice at a dose of 100mg/kg intraperitoneally.
  • 佐々木 誠, 野々村 太郎, 松森 信明, 村田 道雄, 橘 和夫, 佐竹 真幸, 石田 周, 安元 健
    原稿種別: 本文
    セッションID: P-42
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Maitotoxin (MTX, 1) has been isolated as one of the responsible toxins for ciguatera, which is a form of food poisoning caused by ingestion of coral reef fish. Consequently, the toxin was found to originate from a dinoflagellate Gambierdiscus toxicus. While the planar structure with partial stereochemical assignments for MTX has been reported recently, the stereostructures of acyclic parts, C1-C14, C36-C38, C64-C67, and C135-C142, remains unknown. In this study, we report a synthesis of the tetracyclic fragment corresponding to C56-C75 of MTX and elucidation of the stereochemistry at C64 and C66, which could not be assigned by spectroscopic methods. Preliminary investigations by NOE, ^3JH,H data, and MM2-type calculations (Discover/InsightII) implied that the two hydroxy-bearing carbons had (64S^*, 66S^*) relative stereochemistry. Thus, we first aimed at the synthesis of this stereoisomer. Key steps in our synthesis involved acid-catalyzed 6-endo selective cyclization of epoxy alcohol to construct cis-fused 1,6-dioxadecalin system, and chelation-controlled Aldol condensation of the L/M and N/O ring fragments followed by 1,3-anti reduction of the resulting β-hydroxy ketone, to provide the tetracyclic fragment with (64S, 66S) stereochemistry. Its NMR data agreed extremely well with those of the corresponding part of MTX.
  • 三原 知浩, 飯田 彰, 秋元 直茂, 藤多 哲朗, 高石 喜久, 井上 謙一郎, 久志本 理
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    セッションID: P-43
    発行日: 1994/09/20
    公開日: 2017/08/18
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    Antibiotic trichopolyns (TP)-I and II are 10-residue peptides obtained from the fungus Trichoderma polysporum (TMI 60146) and belong to the class of peptaibols. TPs are characterized by the presence of 2-methyldecanoyl group at the N-terminus and the C-terminal residue protected by trichodiaminol. Three new analogues, TP-III-V, have been isolated together with highly purified TPs-I and II. Their structures have been determined by the combined use of NMR, MS and MS/MS. TPs-III and IV differ from TPs-I and II in the replacement of Aib^9 by Ala, respectively. On the other hand, TP-V has the same amino acid sequence as TP-I, but the N-terminal acyl group is substituted by 3-hydroxy-2-methyldecanoic acid from 2-methyldecanoic acid. Conformational analysis for TPs was carried out by using CD and NMR. Their CD spectra in methanol exhibited two negative Cotton effects at 208 and 222nm, which are typical of a right-handed helical structure. Inter-residual NOE connectivities supported the CD data and, in addition, showed that the helices continue from the N-terminal residue to the C-terminal amino alcohol, trichodiaminol. TP-I exhibited immunosuppressive activity in mouse allogeneic mixed lymphocytic reaction. The activity was stronger than that of cyclosporin A.
  • 水口 栄作, 鈴木 哲子, 阿知波 一雄
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    セッションID: P-44
    発行日: 1994/09/20
    公開日: 2017/08/18
    会議録・要旨集 フリー
    Recently, many tocopherol analogs have been examined as antioxidants to find several effective hydrophilic scavengers of super oxide series such as trolox and MDL-73404. Particularly, MDL-73404 has cardioprotective properties and is under development for the reduction of myocardial infarct size. We now wish to report the asymmetric synthesis of (S)-MDL-73404 by lipase-catalyzed resolution of racemic chromanethanol, which could be led to the other tocopherol analogs. The transesterification of vinyl acetate by using lipaseB (Pseudomonas sp.) gave enantiomerically pure (>99%ee) (S)-chromanethanol, that was then converted to (S)-(-)-MDL-73404. The (R)-chromanethanol as by-product of lipase-catalyzed resolution was inverted to the (S)-isomer in four steps.
  • ハナフイ ムハマド, 柴田 耕造, 柏田 優, 植木 雅志, 谷口 誠
    原稿種別: 本文
    セッションID: P-45
    発行日: 1994/09/20
    公開日: 2017/08/18
    会議録・要旨集 フリー
    The mycelial cake was extracted with acetone, and filtered. The filtrate was concentrated to give aqueous solution, which was extracted with chloroform. Organic layer was concentrated to yield an oily material, followed by purification on silica gel column chromatography to give crude UK-1 and UK-2. Finally, the recrystallization of each fractions from MeOH, afforded UK-1 and UK-2. UK-1 (1), a novel metabolite, demonstrated potent cytotoxic activity against B16, Hela and P388 cells, and UK-2, novel complex of antibiotics, exhibited strong antifungal activity. The molecular formula of UK-1 was determined as C_<22>H_<14>N_2O_5 by HREI-MS data (M^+: m/z 386.0913). Methylation of UK-1 by CH_3I and anhydrous K_2CO_3 in dry acetone gave monomethyl ether derivative, Me-UK-1 (2). Alkaline hydrolysis of UK-1 afforded carboxylic acid derivative, DeMe-UK-1 (3). Partial structures, A, B, and C were elucidated by COSY, and COLOC experiments. Based on these results, the structure of UK-1 was deduced to be formula 1, the novel benzoxazole dimmer derivative. UK-2, novel metabolite containing complex of antibiotics, exhibited strong antifungal activity was purified by reverse phase HPLC, to give UK-2A, B, C and D. The molecular formulas C_<26>H_<31>N_2O_9 (M^+: 515.2030) for UK-2A, C_<27>H_<30>N_2O_9 (M^++H: 527.2030) for UK-2B and C_<27>H_<32>N_2O_9 (Mt^+: 528.2114) for UK-2C and D were established by EIRFAB-MS and HREI-MS, respectively. Partial structures, (3-hydroxy-4-methoxypicolinyl)-serine (E), 2-benzyl-3,4-dihydroxypentanoic acid (F), and carboxylic acids (G) were indicated by COSY, and COLOC spectra. Chemical degradation of UK-2 by 5% NaOH solution afforded (3-hydroxy-4-methoxypicolinyl)-serine (4) and mixture ester of 2-benzyl-3-hydroxy-4-methyl-4-butanolide (6). Based on these results, the structures of UK-2A, B, C and D were elucidated as nine membered dilactone derivatives, distinguished by acyl group at C-3. From NMR and mass spectral data, the structures of UK-2A, B, C and D were established as isobutyrate, tiglate, isovalerate, and 2-methylbutyrate of nine membered dilactone skeletone, respectively. Based on the result of synthesis of hydrolysis products (6 and 8), the absolute configuration of UK-2 was identified as shown in formula UK-2 [2(R), 3(R), 4(S)].
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