Talatisamine (1), isolated from an Aconitum species, is a C19-diterpenoid alkaloid that selectively inhibits K⁺ channel and exhibits an antiarrhythmic effect. The structure of 1 is quite unique, consisting of the intricately fused 6/7/5/6/6/5-membered hexacyclic ring system with five oxygen functionalities and twelve contiguous stereocenters. Both the intriguing structure and biological activities have attracted the attention of organic chemists. In this short review, recent total syntheses of 1 by Inoue and Reisman groups are discussed with focusing on synthetic strategy.

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A satisfactory method for quantitative determination of a series of diterpene alkaloids in Japnaese aconite roots was developed, using the combination of dual wave length thinlayer chromatography scan and gas chromatography. As an application of this method, change of each diterpene alkaloid content in some Japanese Aconitum species was examined in various seasons.

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The genus of Tripterygium has been used as traditional Chinese drugs for the treatment of cancer and as an insecticide for hundreds of years. Recently, the extracts (the so-called total multi-glycoside or T_<11>), derived from an water/chloroform extract of the roots of T. wilfordii Hook f. have been used in clinical treatment of rheumatoid arthritis, skin disorders, in male-fertility control and other inflammatory and autoimmune diseases. The precise mechanism of the therapeutic effect of T_<11>, however, has not been completely delineated. In order to search bioactive constituents of this genus, we started work on the isolation of the immunosuppressive and anti-HIV active principles of T. hypoglaucum and the extracts (T_<11>) of T wilfordii. Repeated column chromatography of the ethyl acetate soluble fraction from the methanol extract of the root barks of Tripterygium hypoglaucum (Levi.) Hutch and the extracts of T. wilfordii Hook f. yielded five novel sesquiterpene derivatives (1-5) from T. hypoglaucum and eleven new sesquiterpene alkaloids (16-26), three new diterpenoids (38-40) from the extracts (T_<11>) of T. wilfordii. Compound 1 was a sesquiterpene pyridine alkaloid derived from dihydroagarofuran polyol esters, contained evoninic acid and a monoterpene moiety by the analysis of 2D NMR spectral data, and finally determined by X-ray analysis. Compound 1 had a monoterpene structure bonded to the sesquiterpene molecule by ester linkage, are unique sesquiterpenoids first found in a natural source. In our bioactive screening experiment for above compounds, we examined inhibitory effect on cytokine production and anti-HIV activity. As a result in this study, compounds 53 and 54 showed significant inhibitory effect on cytokine production from lipopolysaccharide-stimulated human peripheral mononuclear cells compared with the reference compound (prednisolone), and compound 2 inhibited HIV replication in H9 lymphocytes with an EC_<50> value of <0.10mg/ml and it inhibited uninfected H9 cell growth with an IC_<50> value of>100mg/ml, calculated therapeutic index value of>1000. In general, TI>5.0 is considered to be significant activity; compounds 2, 7, 12 and 34 showed extremely potent anti-HIV activity with a TI value of>1000, that is uncommon in bioactive compounds from a natural source.

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The whole plant of Incarvillea sinensis has been used as anti-rheumatic and analgesic medicine in China. We have examined the constituents of this crude drug in order to reveal active principle(s), and obtained a number of novel alkaloids, which were classified into two groups: monoterpene alkaloid derivatives (1-10) and spermine related compounds (12-17), whose chemical structures have been clarified by the mass measurements, various NMR techniques and X-ray analyses. In parallel with this chemical investigation, the anti-inflammatory and analgesic activities of several fractions derived from the methanolic extract have been examined by formalin test in mice. This test has revealed that incarvillateine (8) has strong analgesic and sedative activities: Compound 8 (10mg/kg, i.p.) gradually inhibited both the first (neurogenic) and second (inflammatory) phases of formalin-induced pain and reduce the spontaneous motor activity. In this experiment, it has been suggested that anti-inflammatory and analgesic activity of 8 might be induced by its sedative action. However, 8 has showed the analgesic action for this test even in the range of 1-5mg/kg, i.p., in which 8 didn't show the effect toward the spontaneous motor activity in mice. Therefore, it has become clear that 8 could be accounted for the analgesic and sedative substance, whose actions are related to influence on the central nervous system.

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(+)-シトロネラール〔1〕から(-)-シトロネロニトリル〔3〕に導いた。〔3〕の光増感酸素化反応で得られるホトベルオキシドの混合物〔4〕を亜硫酸塩で還元してモノアルコール体の混合物〔5〕および〔6〕に導いた。〔5〕は酸処理または加熱によって脱水してジエン化合物〔7〕を与えることから〔6〕と〔7〕をそれぞれ単離した。〔7〕を高温(500°C)熱処理するとアクチニジン構造異性体〔9〕を与えた。

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Screening of new insecticidal and acaricidal antibiotics was carried out with reference to anti-brine shrimp activity from actinomycete strains. As a result, one actinomycete isolates identified as Streptomyces sioyaensis SA-1758 was found to produce a new substance, altemicidin. Altemicidin was purified by activated charcoal, Diaion CHP-20P and Sephadex LH-20 column chromatographies. The molecular formula was determined as C_<13>H_<20>N_4O_7S by elemental analysis, mass spectra and ^<13>C NMR spectrum. The structure was determined to be (1R,2S,3aR,7aS)-4-carbamoy1-2-hydroxy-6-methyl-1-(sulfamoylacetamido)-2,3,3a,6,7,7a-hexahydro-6-azaindene-1-carboxylic acid by the spectroscopic analysis and X-ray crystallographic analysis of its derivatives. Altemicidin belongs to the monoterpene alkaloid. Altemicidin showed not only acaricidal activity but also antitumor activity. And the compound showed no antimicrobial activity.

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The chemical constituents of Aconitum yesoense var. macroyesoense and Aconitum japonicum were examined using high-resolution spectral analysis. Twelve novel alkaloids were isolated from A. yesoense var. macroyesoense together with 20 known alkaloids. Eight novel alkaloids were isolated from A. japonicum together with 15 known alkaloids. An HPLC-atmospheric pressure chemical ionization-mass spectrometry (HPLC-APCI-MS) method was useful for the simultaneous determination of 21 Aconitum alkaloids found in A. yesoense var. macroyesoense and A. japonicum. These compounds were fairly stable under the conditions used, and the protonated molecules or fragment ions characteristic of the molecule appeared as base peaks in the mass spectra and were used for selected ion monitoring. HPLC-APCI-MS is a very promising approach for structural investigations of positional isomers and stereoisomers. This method was applied successfully to stereoisomeric Aconitum alkaloids differing in configuration at C-1, -6, or -12. Comparison of the APCI spectra showed that the abundance of fragment ions was significantly higher for the C-1, -6, or -12 β-form alkaloid than for C-1, -6, or -12 α-form alkaloid. The main alkaloid constituents in the root of A. yesoense var. macroyesoense, Aconitum alkaloids of the C₂₀-diterpenoid type, kobusine and pseudokobusine, and their acyl derivatives were examined for their peripheral vasoactivities by measuring laser-flowmetrically the cutaneous blood flow in the hind foot of mice after intravenous administration. It is thought that the hydroxyl groups of alkaloids, especially a free OH group of pseudokobusine at C-6, were important for action on the peripheral vasculature leading to dilatation, and the results indicated that esterification of the hydroxyl group at C-15 with either anisoate, veratroate, or p-nitrobenzoate may contribute to enhancement of the activity of the parent alkaloids.

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本論文は,著者らの開発した新しいヒドロシアン化反応の天然物,とくに多環式構造を有するステロイド,ジテルペン,あるいはそれらのアルカロイドの合成に対する有用性について述べている。新ヒドロシアン化法によって,多環式構造を有する共役ケトン体から目的に応じ立体的に有利に核間位にシアン化されたケトン体をえることができる。核間位シアン基は,他の種々の炭素置換基に変換されるし,またそれによって天然物に多く含まれる橋状環系の合成も容易に行なわれうる。したがって新ヒドロシアン化反応は一般に困難と考えられている核間位に炭素置換基を導入したり,また橋頭炭素の一つを核間位に有する橋状環の組み立てめ問題に一つの有力な手段を提供している。新ヒドロシアン化反応は,アルキルアルミニウム (R₃Al) とシアン化水素の組み合わせ (A法) ,あるいはシアン化ジアルキルアルミニウム (R₂AlCN) (B法) によって行なわれ,そのヒドロシアン化の効率は高い。核間位シアン化の場合の立体経路は用いる共役ケトンの構造に左右されるが,trans-または,cis-シアソケトンのいずれが優先的に生成するかは,多くの例からえられた経験則,あるいは理論的考察からある程度予知することができる。つぎに核間シアソ基の他の炭素置換基,たとえばカルボキシル基,イミノメチル基,アミノメチル基,ホルミル基,メチル基,ヒドロキシメチル基への適切な変換法が確立された。またシアンケトンから他の橋状環,たとえばピロリジン,ピペリジン,ピシクロ [3.2.1] ,あるいは [22.2]オクタン環系の組み立て法も研究された。この結果を応用して種々の天然物,たとえば二三のプレグナン系ステロイド,またはそのアルカロイドであるラチホリン,ジであるアチシン,ガリン,ビーチンなどが合成された。

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In the course of the investigation of biologically active substances from the rare plants, we isolated seven novel sesquiterpenoids, named euonymusins A〜G (1〜7) from the fruilts of the rare plant Euonymus chibae. Their absolute stereostructures were established by a combination of Mass, IR, 2D-NMR and CD spectra, and chemical reactions such as alkaline hydrolysis. The cytotoxic activities of compounds 1〜7 against three cancer cell lines (RERF-LC-KJ: lung cancer; HeLa:cervical cancer; and HSC-2:oral cancer) were examined. Compounds 5 and 6 selectively showed the strong cytotoxic activities against RERF-LC-KJ. A large amount of pigment (8) was isolated from the leaves of E. chibae. Compound 8 was identified as methyl phaeophoride a by FAB-Mass, IR, UV, and NMR spectra. It was possible to assign all carbon signals of compound 8 by measurement of 2D-INADEQUATE in pyridine-d_5.

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It was clarified that a new alkaloid (I), C₁₅H₂₃ON, isolated from the root of Nuphar japonicum DC. was the same as anhydronupharamine (IV) derived from the known alkaloid, nupharamine (III). I was kept standing in dilute hydrochloric acid and gave III. As the absolute configuration of III had already been defined, the formula IV would be presented as the structure and the absolute configuration of I.

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※本記事に抄録はありません。

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Aconite root (Bushi in Japanese) from Aconitum japonicum THUMB. has long been used as one of the most important herbs as a heart stimulant, diuretic agent ; and anodyne in Chinese medichine. Isolation and identification of the cardiac principle predicted by Yakazu are described. In the isolation process, the Yagi-Hartung method using frog heart was found to be useful for pharmacological measurement of cardiac activity of the material. The material was water soluble and was fairly unstable, especilly in a basic medium, and was tightly adsorbed on charcoal, alumina, silica gel, and cellulose powder, indicating that these agents are not useful for the separation. Isolation of the material was finally achieved by the limited combination of gel filtration through Sephadex LH-20 and counter current distribution, and colorless plates, mp 260°, were obtained as HCl salt. This principle stimulates frog heart even 1 : 10^-9 dilution, and it was designated as Higenamine. Higenamine was identified as dl-demethylcoclaurine (II) from the spectral data and by comparison with synthesized authentic sample.

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　アルテミシジン（1）は放線菌Streptomyces sioyaensisSA-1758から単離されたモノ

であり、抗腫瘍活性を示すことが知られている^１）。1はヘキサヒドロ–6–アザインデン骨格上にβ–ヒドロキシ–α,α–二置換アミノ酸およびスルホンアミド側鎖を含む複雑かつユニークな構造を有し、多くの合成化学者の興味を集めてきたが^２）、その全合成例は1995年のKendeらによる報告のみである^３）。今回我々は、分子内溝呂木−Heck反応による含窒素四置換炭素構築と、置換ピリジン誘導体の立体選択的部分還元を鍵反応として用い、斬新かつ効率的なアルテミシジンの全合成を達成したので報告する。

1. 合成計画

　アルテミシジン（1）の鍵中間体としてヘキサヒドロアザインデン骨格を有するエナミン2を設定し、このものをN−メチルピリジニウム塩3の立体選択的部分還元により合成することとした。3の前駆体となる置換ピリジン4は、ハロピリジン5の分子内溝呂木−Heck反応により誘導することとし、5は3−ブロモ−5−ヨード−4−メチルピリジン（7）から調製したアニオンを文献既知のα,β–不飽和アルデヒド6^４）に作用させれば合成可能と考えた。

2. ジヒドロ−6−アザインデン骨格と含窒素四置換炭素の構築

　市販のジブロモピコリン8をブロモヨードピコリン7に変換後、LDAを作用させてアニオンを調製し、不飽和アルデヒド6との1,2−付加反応を行った。生じた二級アルコール9をシリルエーテル10とした後、分子内溝呂木−Heck反応による5員環形成を詳細に検討した結果、以下の最適条件を見出した。すなわち、パラジウムの配位子としてP(2-furyl)₃を使用し、ヘキサフルオロイソプロパノール（HFIP）共存下、マイクロウェーブ反応装置を用いることで反応は円滑に進行し、83%の高収率で目的物の合成に成功した。環化体は、互いに分離困難な立体異性体11αと11βの混合物（3：1）として得られ、両者の立体化学はNOE測定により決定した。

環化体のTES基を除去した後、シリカゲルカラムクロマトグラフィー精製を行い、アルコール12および13を単離した。5員環上の窒素原子と水酸基に注目すると、主生成物12は天然物1と逆の相対立体配置を有するが、この問題については以下の解決法を見出した。すなわち、12をトリフラート化の条件に付すとBoc基の隣接基関与を経て立体反転が起こり、カルバマート14を与えた。一方、12のジアステレオマー13は、単に塩基処理を行うことで同一のカルバマート14に変換可能である。このように、分子内溝呂木−Heck反応における立体制御は困難なものの、環化体においてアルコールの立体配置を整える手法を確立することができた。そこで次に、臭化物14をニトリル15へ変換するべく、様々な触媒とシアノ化剤を組み合わせてカップリング反応を試みたが、目的物は全く得られなかった。この結果から、シアノ基の導入を合成の初期段階で行う新たな戦略を立案した。

ジブロモピコリン8を2工程でニトリル17に誘導後、先と同様な変換を経て

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Altemicidin (1) was the first 6-azaindene monoterpene alkaloid isolated as a metabolite of microorganisms by Takeuchi and coworkers in 1989. In addition to its potent acaricidal activity, Altemicidin has been shown to strongly inhibit the growth of tumor cells. The first total synthesis of Altemicidin was achieved by A. S. Kende et al in 1995. The unique β-hydroxyl α-disubstituted-α-amino acid structure was an attractive feature of this molecule and prompted synthetic studies in our laboratories. Our synthetic strategy was based on the idea that key intermediate 2, with Altemicidin's azabicyclo[4.3.0.]skelton, could be constructed from amide 4 via lactam 3 by the ring expansion. In turn amide 4 could be synthesized from β-ketoester 5 wherein the tetrasubstituted carbon and the neighboring secondary alcohol could be stereoselectively installed early on in the synthesis(Scheme 1). The synthesis initiated from the treatment of α-diazo-β-ketoester 6 with rhodium acetate to afforded bicyclo[3.3.0] β-ketoester 7 in excellent yield(Scheme 2). The bicyclo[3.3.0] framework provided excellent stereochemistry for the hydroxymethylation and carbonyl reduction to furnish diol 8. Amide 9 was quickly obtained after hydroxy group protections and an ester to amide transformation. Amide 9 was converted into lactam 11 by oxidative cleavage of double bond and subsequent hemiaminal reduction. Then the activation of lactam by nosyl group and opening of lactam followed by cyclization gave cyclic enamide 13. Cyclic enamide 13 which has Altemicidin's azabicyclo[4.3.0]skelton was successfully synthesized in 13 steps from bicyclic β-ketoester 7. After the introduction of the formyl group by Vilsmeier type reaction and the removal of nosyl group, the methylation smoothly occurred(Scheme 3). Deprotections followed by Curtius rearrangement gave oxazolidinone 16. Alcohol 17, oxazolidinone opening product, was obtained from the Boc imide under hydrolysis conditions. Like this, we succeeded in the introduction of the nitrogen into the tetrasubstituted carbon and formylation after the construction of the basic skelton. Final transformations toward the natural product are currently under investigation. Importantly, the synthesis of optically active Altemicidin has also been examined. In our laboratories, it was found out that the combination of chiral rhodium catalyst and chiral auxiliary derived from lactic acid gives high diastereoselectivity for C-H insertion reactions(Scheme 4). Applying this method to α-diazo β-ketoester 6, the C-H insertion reaction proceeded to give β-ketoester 21 with good diastereoselectivity. The determination of the absolute configulation and the application to total syntesis of Altemicidin is now under investigation.

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