Canadensolide is a mould metabolite produced by Penicillium canadense which shows antigerminative activity against fungi. Its structure and stereochemistry have been determined as (1a) by McCorkindale and vicinal coupling between 5-H and 6-H (4.5 Hz) in the nmr spectrum has been ascribed to the trans-disposition of these hydrogens. Compound (1a) and its C-5 epimer (1b) were synthesized stereoselectively in following pathways. Treatment of (4a) with Milas reagent led to bis-γ-lactone (13) directly, which was then converted to (1a) by acid-hydrolysis followed by Mannich reaction. On the other hand, treatment of (4a) with performic acid followed by hydrolysis with acid and subsequent introduction of the exomethylene group of the resulting γ-lactone mixture gave (1b). Comparison of the spectra of these synthetic products with those of the natural counterpart demonstrated that the stereochemistry (1a) previously assigned to canadensolide was incorrect and should be revised to (1b). It was found that treatment of some olefinic diacylhypoiodites in DMSO with silver acetate yields the corresponding bis-γ-lactone derivatives in one step. Employing this method, dicarboxylic acids (17), (19), (20), (21) and (22) were converted to (18), (25), (26), (14) and (16), respectively, in good yields. Application of this reaction to compound (30) and (31) leading to (1a) and (1b), respectively, is now under investigation.

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In vivo, acyclic terpenes having no asymmetric center are generally converted to cyclic terpenes carrying several asymmetric carbons by the enzymic cyclization reaction. In order to achive the same kinds of transformations as those obeserved in vivo by chemical means, we, at first, developed a new acid-catalyzed biogenetic-type cyclization of the citral pyrrolidine enamine (VII)a, which was found to give α-cyclocitral (V) in at most 41% yield with concomitant formation of the trace amount of β-cyclocitral (VI). When this novel reaction was applied to optically active enamines (VII)b〜f prepared from citral and several kinds of optically active pyrrolidines (X)b〜f, easily prepared from commercially available L-proline, optically active α-cyclocitral was obtained in at most 33.3% optical yield. Studies on the reaction mechanism for this novel cyclization reaction clearly demonstrated that the asymmetric induction had occurred at the stage of the cyclization of the imminium salt (VIII) which was, in situ, prepared from the enamine (VII). Optically active α-cyclocitral thus prepared was successfully used for the synthesis of the famous perfume, trans-α-damascone (XIV). Other possible method for the preparation of the optically active α-cyclocitral and approaches for the synthesis of optically active abscisic acid (XVIII) were also discussed.

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Synthetic methods have long been used to solve stereochemical problems in natural products chemistry. Herein are described recent two examples. Absolute Configuration of (-)-14-methylhexadec-8-cis-en-l-ol (I) and methyl (-)-14-methylhexadec-8-cis-enoate (II). These were isolated from a female dermestid beetle (Trogoderma inclusum) as the components of the sex attractant. The (S)-pheromones (I, II) have been synthesized from (S)-(-)-2-methylbutan-l-ol and shown to be dextrorotatory. Therefore the natural and levorotatory pheromones possess the 14R stereochemistry. Absolute configuration of (+)-abscisic acid (XIV). Our startegy to attack this problem was to secure an optically active ketone (XV) as a common intermediate from which both the natural grasshopper ketone (XVI) and dehydrovomifoliol (XVII) could be synthesized employing reactions with known steric courses. Since the absolute configuration of the grasshopper ketone had been established by X-ray analysis, this would enable us to assign the absolute stereochemistry of (+)-dehydrovomifoliol (XVII) which had been converted by others to (+)-abscisic acid (XIV). The present synthesis yielded (+)- and (-)-dehydrovomifoliols and (-)-trans-epoxy ketone (XXXIIIa). The last compound was indistinguishable from an sample derived from violaxanthin. Thus the stereochemistries of (+)-abscisic acid and related carotenoids were supported by synthesis.

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In connection with previous papers on isolation and structural determination of bazzanene, bazzanenol and δ-cuparenol, we have now isolated two additional novel sesquiterpene hydrocarbons from a liverwort, B. pompeana. These compounds were named α- and β-pompene, and their structures were respectively determined as 2,2,3,10-tetramethyl-tricyclo[5.3.1.0^<3,7>]undec-9-ene (I) and 2,2,3-trimethyl-10-methylene-tricyclo[5.3.1.0^<3,7>]undecane (XIII) on the basis of chemical and spectroscopic evidences.

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Starting from the previously described intermediate 19, methyl ester of a fungal sesquiterpenoid hirsutic acid has been stereoselectively synthesized in four steps(chart 8). A new route for 19 from 12(charts 4 and 5) has also described.

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As a continuation of our study on the biogenetic-type transformation leading to the natural terpenoids, the conversion of the eudesmane-type sesquiterpenoids aiming at the eremophilane-type sesquiterpenoids has been undertaken and the object has been accomplished. After several attempts, treatment of 5α,6α-epoxy-dihydroalan-tolactone(7), an eudesmanolide epoxide, with HCOOH-acetone at reflux has been found to afford six products: product A(10%), B(34%), C(2.2%), D(2.0%), E(0.5%), and F(3.4%). Among them, two major products(A and B) have been elucidated to be the desired eremophilanolides(10 and 11) on the basis of physico-chemical evidences, while product C has been assigned 13. The structures of other minor products D, E, and F have been also suggested to be 16, 17, and 18, respectively. In order to correlate product B(11) to the known natural eremophilane-type derivatives, some chemical conversions have been attempted.

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A Japanese cultivar of Gaillardia pulchella Foug. (Tenningiku) contained, in addition to the pseudoguaianolides, pulchellin(1) and neopulchellin(2), the guaianolide, gaillardin(4) apparently accompanied by its new epimer neogaillardin(5) and a new bromine-containing base Compound I(9),C_6H_<11>O_2N_2Br, entirely different from novel sesquiterpene alkaloids, pulchellidine(6) and neopulchellidine(7) found in a Florida collection. The structure of a minor new constituent, pulchellon(8), C_<12>H_<18>O_3, isolated also from the Florida collection, has been proposed, and that of another unique principle(9) mentioned above has been completely elucidated by chemical reactions and X-ray analysis. A possible biogenetic scheme for all the sesquiterpene lactones so far isolated from Gaillardia pulchella, including the eudesmanolides, pulchellin B, C, E and F(3a,b,c,d) found in a Texas race, is proposed in Fig. 2. Fig. 1 shows that especially for pulchellon(8) originating from pulchellin(1) and/or neopulchellin(2).

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Photosensitized oxygenation of acyclic 1,3-dienes was found to afford 3,6-dihydro-1,2-dioxins in good yields. Substituted furans can be prepared from the 1,2-dioxins by successive treatment with base and acid. Some furanoid terpenes, i. e., perillene, dendrolasin, neotorreyol, and torreyal were synthesized from β-myrcene based on the above-mentioned new reactions.

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We have previously shown the metabolic transformation of (±)-epoxy-farnesol by Helminthosporium sativum yielded optically active diol-metabolites (Fig. 1). Interestingly, these compounds were derived from both enantiomers of the substrate through stereoselective hydration of the racemic epoxide. We wish now to report our further advances on this subject in four parts. (1) The stereoselective hydration mechanism of the racemic epoxide was investigated by metabolizing three isotope-labbeled substrates,i.e. (±)-, (-)-(^<18>O)-, and (±)-(10-D)-10,11-epoxyfarnesols. The scheme shown in Fig.2 has been proposed. The optical purity of (-)-diol-metabolites was determined by nmr method using chiral shift reagents(Eu-csr). (-)-Methyl 10,11-dihydroxyfarnesoate (-)-5b, (α)_D-14.1°, was determined to consist of 86.5% of S-(-)- and 13.5% of R-(+)-enantiomers. (2) Metabolic transformation of racemic 10,11-epoxyhomofarnesol by H.sativum was carried out. Seven optically minus compounds were characterized. Among them, (-)-C_<17>-juvenile hormone, (α)_D-12.8°, was obtained. Its (+)-enantiomer, (α)_D+11.7°, was chemically derived from (-)-10b. The metabolic pathway was shown in Fig.3. (3) In our searching a fungus which can convert the racemic epoxide into (+)-diol, we noticed Collectotrichum nicotianae. By metabolizing (±)-methyl 10,11 -epoxyfarnesoate, we have succeeded in obtaining its (+)-dihydroxy-derivative as expected. (4) During the study for fungal transformation with H. sativum, we found that t,t-epoxyfarnesol was partly isomerized to its c,t-isomer. Mechanism of the trans-to-cis isomerization was investigated. When (1-D_2)-t,t-epoxyfarnesol was isomerized with the fungus, the obtained c,t-isomer lost almost one atom of D as shown in Table 2. Thus, the mechanism via an aldehydic intermediate has been presented as shown in Fig.5. This finding seems to offer a useful method to know a direct precursor in biosynthesis of prehelminthosporol, a normal product of the fungus, by differentiating t,t-farnesol from its c,t-isomer. A preliminary examination using (1-D_2, 2-^<14>C)-t,t-farnesol has been tried.

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The antifungal metabolite (I) obtained from Acrostalagmus NRRL-3481 has a similar structure to those of plant growth inhivitors, inumakilactones and nagilactones, of Podocarpus genus. It was made clear that (I) had, in fact, the same extent of activity as those. Although compound (I) has a nobel C-16 carbon skeleton, this was considered as terpenoid origin from the inspection of the structural feature. This study was done for the purpose of elucidation of biosynthetic pathway of (I). From the culture of Acrostalagmus, three new metabolites were isolated, and these structures were determined as (IV), (VIII), and (IX) by spectral studies and direct comparison with an authentic sample. In order to elucidate whether the precursor of (I) is a sesquiterpenoid or a diterpenoid, the incorporation experiments of [2-^<13>C]acetate and [2-^<14>C, 5-^3H_2]mevalonate were carried out, and the compound (I) was revealed to arise from a diterpenoid precursor such as labdadienol.

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The recent advances of the instruments and techniques made it possible to apply the ^<13>C NMR to the naturally occurring substances. In our attempts to use the method not only for the structural determination but also for the biosynthetic study of gibberellins, we analysed ^<13>C NMR spectra of several C_<19> gibberellins or their methyl esters. Spectra were obtained by using PFT technique with JNM PS 100 in deuteroacetone and/or deuteropyridine solution with TMS as an internal standard. The assignment was performed by analysing the proton off-resonance decoupled spectra and by compairing the spectra of gibberellin homologues which have similar structures but differ in substitution patterns. And ^<13>C NMR was applied to the structural determination of gibberellin A_<40>(GA_<40>). The comparison of the ^<13>C NMR spectrum of GA_<40>-Me with those of GA_4-Me and GA_9-Me, suggested that GA_<40> is an isomer of GA_4, and has a hydroxyl group on 2-C. The configuration of the hydroxyl was decided to be α (axial) from its PMR spectrum.

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In our studies on chemical conversion of pine tree (main component, l-abietic acid (1)) to biogenetically active compounds, the substitution to A-ring is regarded as one of the basic problems. An investigation of benzonilidene compound (2) derived from (1), gave a clue for the solution. Under an acidic condition (Ac_2-H_2SO_4), (2) underwent rearrangement to enol acetate (4) accompanied with migration of C-10 methyl group to the C-5 position. Treatment (conc. H_2SO_4) of (4) and its hydrolized compound (5) easily gave the original compound (2). In the rearrangement, the electrophilic reagent is used instead of the proton, selective substitution at C-1 should proceed. In fact, the two reactions (Ac_2O- and NBS-BF_3.Et_2O) of (2) and (5) succeed to give the compounds having substituted A-ring (17) and (24), respectively. Especially, the latter (24) is a potential intermediate for the above purpose. As an example of the synthesis, natural diterpene, teideadiol (3) was accomplished to synthesize from (24). Also, (24) was converted to (40), which is considered to be suitable for the synthesis of salviol (41) and hinokione (42).

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It was found recently that settling of swimming larvae to a specific marine plant was induced by adding a drop of sap of Sargassum tortile L., a marine plant to which the swimming larvae settle specifically. This finding prompted us to search the active substance in the plant. From the plant, we have obtained an active portion which consisted of at least six substances (Table 2). The compound B was proved to be identical with δ-tocotrienol (1) on the basis of NMR and mass spectra. The physical data of other materials are alike to B excepting some details and lead to postulation that A might have structure (2). On the meanwhile, J. D. Martin and his coworkers reported recently the structure of taondiol (3), isolated from a marine plant, Taonia atomaria. The synthesis of these three compounds were carried out, the results of which were shown in the figures.

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Toxic constituents of the title plant were examined, and a crystalline compound, named kansuinine A (1), amorphous kansuinine B (2), an ingenol derivative (30), and hydroxy ingenol derivatives (31)(32) were obtained. Kansuinines A and B were polyesters of the highly oxygenated diterpene alcohols, C_<20>H_<32>O_9 and C_<20>H_<30>O_<10>, respectively. The structure of kansuinine A was elucidated as (1) by spectral data and chemical reactions, especially the transannular reformation of ether linkage of (1) with p-TsOH and the formation of the large lactone ring by retro-aldol reaction with NaH of kansuinine A.

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Jasminin is the bitter principle isolated from Jasminum primulium Hemsel. We have proposed the structure 1 for jasminin. Being interested in the unusual reactions and the structure of jasminin, we have continued the synthetic study. At first, the synthesis of the methyl ester hexaacetate 25, which was obtained by mild alkaline hydrolysis of jasminin, was considered. The key intermediate 7 was synthesized from (+)-carvone epoxide by Favorskii rearrangement. The acid 7 was then converted by a six-step reaction into the desired monool diacetates 19 and 20. Since the formal synthesis of the seco-iridoid moiety 4 was already repoted by Inouye, we obtained 4 from jasminin by mild alkaline hydrolysis. Treatment of the tosylate 30 with the sodium salt 31 in DMF afforded 25, which was identical with the authentic sample. Thus the structure of jasminin was established as in 1. The conversion of 25 into jasminin is now in progress.

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Two novel norditerpenoids, teucvin and teucvidin, were isolated from the neutral fraction of Teucrium viscidum Bl. var. Miquelianum (Maxim.) Hara (Labiatae). A partial structure A of teucvin was clarified by chemical means. The X-ray analysis of its heavy atom derivative 10 and subsequent chemical reactions led to assignment of the structure and absolute configuration 1 to teucvin. Comparison between several spectroscopic data of teucvidin with those of teucvin led to presumption that both compounds must be diastereomeric. Detailed NMR investigation of teucvidin using INDOR and NOE techniques resulted in assignment of its relative stereochemistry except C-12. Subsequently, the X-ray analysis of teucvidin itself by direct method elucidated its molecular structure. On the basis of these results, teucvidin was proved to have structure of 28 or its antipode. Finally, biogenesis of teucvin (1) is discussed.

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From the rhizome(and the leaves) of Marginaria niponica and M. formosana (Polypodiaceae), triterpenoid hydrocarbons of hopane (migrated hopane) series [hop-22(29)-ene(1), hop-21-ene(2), neohop-13(18)-ene(3), fern-7-ene(4) and ferna-7,9(11)-diene(5)], and oleanane (migrated oleanane) series [olean-18-ene(11), olean-12-ene(12), taraxer-14-ene(13), multiflor-7-ene(14), multiflor-8-ene(15), multiflor-9(11)-ene(16), friedel-3-ene(17), ψ-taraxastene(18) and oleana-11,13(18)-diene(19)], triterpenoid alcohol and others of hopane series [22-hydroxyhopane(6), dryocrassol(30-hydroxyhopane(22S))(7), dryocrassy acetate(8), 17β,21β-epoxyhopane(9) and 17αH-trisnorhopan-21-one(10)] and oleanane series [germanicyl acetate(20), β-amyrin acetate(21), multiflorenyl acetate(22), 16-oxo-taraxer-14-ene(23) and 7α-hydroxytaraxer-14-ene(24)], triterpenoid acetates of lanostane series [25, 26, 27, 28 and 29], methylsteryl acetates [30 and 31], and sterols have been isolated and characterized.

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Fatsia japonica D. et P. has been used for a medicinal plant, but it is well known that the plant contains hemolytic constituents. We now examined the isolation and structural elucidation of chemical constituents of the leaves, the flowers, and the black seeds of Fatsia japonica in order to compare the constituents among parts of the plant. 1. Hederagenin-3-α-L-arabinoside (Saponin A), hederagenin-3-β-D-glucopyranoside (Saponin B), hederagenin-3-[β-D-glucopyranosyl (1→4)]-α-L-arabinoside (Saponin C), and Saponin D were elucidated as constituents of the acetone extract of the black seeds. Saponin D was composed of hederagenin and D-glucose, but its structure now remained unproved. Stigmasterol, palmityl triglyceride, and fatty acids (mainly C_<16> and C_<18>) were also identified. 2. From the acetone extract of the flowers, Saponin A, C, and E were isolated in addition to stigmasterol, methyl palmitate, methyl linoleate, and the fatty acids. The hydrolysis of Saponin E afforded oleanolic acid and D-glucose, but its structure is still unproved. 3. Together with stigmasterol and n-paraffins (nC_<16>〜nC_<31>), phytyl palmitate and phytyl linoleate, new naturally occurring esters, were isolated from the acetone extract of the leaves to elucidate their structure. Other constituents of the extract were Saponin A, B, C, and E.

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The INDOR method in NMR spectroscopy was first described by Baker, and its usefulness in the structure analyses of complex organic molecules has recently been demonstrated by several groups. We applied this technique to the assignments of methyl resonances and the structure elucidation of several triterpenes. (1) INDOR experiments with 16β- and 16α-acetoxyfriedelanes revealed that this method is very effective not only for the determination of signal positions of hidden protons which are mutually spin-coupled, but also for the qualitative detection of conventional nuclear Overhauser effect (NOE). (2) The structure of an acid-induced rearrangement product (product-B) of 16-keto-friedel-3-ene was investigated and assigned to the formula IV on the basis of chemical and spectroscopic analyses, especially of the application of INDOR technique. (3) NOE's between methyl groups were examined using β-amyrin type triterpenes as model compounds and it was found that the INDOR technique combined with the pseudo-contact shift is powerful for the qualitative detection of NOE between methyl groups located in close proximity.

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Friedelin(I) was oxidized with oxygen in the presence of potassium t-butoxide. After neutralization and methylation of the reaction mixture, five compounds, (II), (III), (IV), (V) and (XI) were isolated and characterized. Several potential intermediates of the oxidation, (XXVIII), (XXIX), (XXX) and (XXXI) were also subjected to the oxidation on the same reaction condition and the reaction products, (II), (III), (V), (VI), (VII), (IX) and (X) were separated and characterized. Some of the interesting aspects of the reaction were discussed. It is noteworthy that friedelan-2,3-dione,(XXVIII) is not formed during the oxidation of (I), and that formations of (II) and (V) include fission-recyclization process.

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Two new sterols, asterosterol(VII) and amuresterol(IX) have been isolated from the sterol fraction of the asteroid, Asterias amurensis. The structure of asterosterol was identified as 22-trans-24-nor-5α-cholesta-7,22-dien-3β-ol from the spectral data and partial synthesis from ergosterol. Amuresterol, a geometrical isomer of cholesta-7,22-dien-3β-ol(VI), was characterized by spectral data and by synthesis as 22-trans-27-nor-(24R)-24-methylcholesta-7,22-dien-3β-ol(IX), a sterol with biogenetically unprecedented side chain. Occurrence of a migrated cholestane type sterol and, particularly the configuration at C-24 of amuresterol, suggests that the C_<26> sterols ubiquitous in many marine invertebrates may have been formed from demethylation of brassicasterol. Other components characterized by spectral data and combined GLC-mass spectrometry are summarized in Fig. 2.

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Hydroboration of cholesta-1,5-diene-3-one followed by alkaline-peroxide oxidation resulted in the formation of 1α-and 2α-hydroxy derivatives of cholesterol in nearly equal-amounts. 1α-Hydroxycholesterol was then transformed to 1α-hydroxyvitamin D_3, via 1α-hydroxycholesta-5,7-diene-3β-ol (1α-hydroxyprovitamin D_3). 1α-Hydroxyvitamin D_3 was as active as 25-hydroxyvitamin D_3 in the stimulation of intestinal calcium transport and bone calcium mobilization in intact rats and moreover was able to produce both responses in anephric rats similar to 1α,25-dihydroxyvitamin D_3, the active metabolite of vitamin D_3, as reported originally by DeLuca's group.

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Fucosterol 6 is abundant and the almost sole sterol in brown algae, irrespective of species. Recently we have found that fucosterol-24,28-epoxide 7 is converted to desmosterol 8 by a brief treatment with BF_3-etherate. Thus, 8 is now readily available as the starting compound for the synthesis of the active forms of vitamin D_3. Oxymercuration-demercuration of desmosterol acetate 10 gave 25-hydroxycholesterol 3-acetate 14 in 85% yield. Dehydration of 14 yielded a mixture of Δ^<24>- and Δ^<25>-olefine(10 and 15), from which 24,25-glycol 16 and 25,26-glycol 17 were obtained by treatment with OsO_4 in high yields. 1α,25-Dihydroxycholesterol 31 was synthesized by two methods. In the first synthesis of 31 from 14, Δ^5-double bond was protected by hydroboration to give 6α-ol 22, which was inverted to 6β-ol 23 in order to assure the selective dehydration to recover Δ^5-double bond. Introduction of 1α-ol function rest on epoxydation with H_2O_2 -NaOH of 3-oxo-1-ene system 25. The second synthesis of 31 was based on the recently reported Barton's procedure. Thus, 14 was dehydrogenated with DDQ, followed by epoxidation to give 38, whose reduction with Li in liq. NH_3 afforded 31(over-all yield from 6; 6%). These hydroxycholesterol derivatives were transformed into the active forms of vitamin D by the established method.

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The hydrolysis of esters, amides, nitriles and proteins by ion exchange resins as a catalyst has been reported in several recent publications. The new procedure of hydrolysis on ion exchange resins and its application to the synthesis of γ-amino-β-hydroxybutanoic acid will be discussed. The new technique was developed on the basis of the thought that the compounds absorbed on ion exchange resin should be easily hydrolyzed. Because the hydrolyzing functional groups of the compound on the resin are inevitably quite closed to the catalytic function of the resin. Therefore, this kind of the reaction could be a crude model of enzymatic hydrolysis. γ-Aminobutanoic acid amides (2, 11, 12) were hydrolyzed on cation exchange resin Amberlite IR-12OB to the mother amino acid (7). Not only succinic acid mono-methyl ester (13) and succinic acid amides (14, 15) but also N-acetyl-γ-aminobutanoic acid (17) were hydrolyzed on anion exchange resin Amberlite IRA-400. γ-Amino-β-hydroxybutyronitrile (19) and its N-trimethyl derivative (20) were also hydrolyzed on Amberlite 252. As a application of this technique, γ-amino-β-hydroxybutanoic acid (GABOB) (22) was simply synthesized from γ-chloro-β-hydroxybutyronitrile (30) by three steps (the over-all yield: 65 %). Especially, the synthesis was characterized by using the same resin in order to purify and hydrolyze the intermediate amine-amide (24) at the only one process.

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A rule about the n-π* Cotton effect of seven-membered lactam ring (lactam rule) was investigated from ORD and CD spectra of A-azatetrahydro-α-santonins and A-azasteroids derived from their oximes by the Beckmann Rearrangement. From this rule, the seven-membered lactam was classified into two types A and B. Type A should have the negative and type B should have the positive Cotton effect. Further applications of the lactam rule to four-membered lactam, azetidinones, and five-membered lactam, camphorolactams and pyrrolidones are discussed. This rule was applied to simple seven-membered lactams, (-)-menthone lactam, N-methyl-(-)-menthone lactam, and N-methyl-A-azatetrahydro-α-santonins. Conformational equilibrium of these compound was discussed on the basis of the lactam rule.

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Two different sequence hexapeptide for the synthesis of ferrichrome were prepared using N^δ-tosyl-N^δ-benzyloxy-L-ornithine by means of N-hydr oxysuccinimide-N,N-dicyclohexylcarbodiimide or Woodward reagent K method. The linear hexapeptides (XII HCl and XIX HCl) were cyclized by excess N,N-dicyclohexylcarbodiimide to give cyclo-triglycyl-tri-N^δ-tosyl-N^δ-benzyloxy-L-ornithyl (XX). Detosylation, acetylation and successive reductive debenzylation of XX afforded deferri-ferrichrome (XXIV). Addition of ferric ion to XXIV gave ferrichrome, which was identical with naturally occurring ferrichrome.

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An alternative double labeling method which utilizes ^<13>C-^<13>C coupling in structural and biosynthetic studies was applied to the structural elucidation of dihydrolatumcidin. The cmr spectrum of the double labeled and mixed labeled metabolites showing strong ^<13>C-^<13>C coupling gave enough information on carbon sequences and made it possible to determine the total structure of the metabolite. Direct evidence was obtained that acetic acid was incorporated into dihydrolatumcidin without cleavage of the C-C bond of the acetic acid molecule. The detail mechanism of biosynthesis of polyketides, terpenes and steroid can be studied by utilizing ^<13>C-^<13>C coupling.

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Isomerization of methyl 2-thio-hexopyranoside derivatives in methanol to furanoside configurations by acid-catalyzed reaction was applied to the synthesis of daunosamine(3-amino-2,3,6-trideoxy-L-lyxo-hexose)(1) which is a component of the antibiotic Dauno-mycin. Methyl 3-azido-2-s-benzyl-3-deoxy-2-thio-α-D-altropyranoside(3) in methanol was transformed into the corresponding furanoside; methyl 3-azido-2-s-benzyl-3-deoxy-2-thio-α(andβ)-D-altrofuranoside (4a) by catalytic reaction of Amberlite CG120(H^+). Partial benzoy-lation of 4a gave 6-O-benzoyl derivatives(4b), the 5-O-p-toluene sulfonyl derivative of which was led to methyl 5,6-anhydro-3-azido-2-s-benzyl-3-deoxy-2-thio-α(andβ)-L-galactofuranoside(7) by epoxy-dation with methanolic sodium methoxide. Further, the 3-amino-3,6-dideoxy sugar(8a) was obtained from the reduction of 7 with LiAlH_4. Treatment of 8a with Raney Ni gave methyl 3-amino-2,3,6-trideoxy-α(andβ)-L-lyxo-furanoside(9) which was finally hydrolyzed to give 1 as the hydrochloride salt.

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Althiomycin (I, C_<16>H_<17>O_6N_5S_2) is an interesting antibiotic isolated from the culture filtrate of Streptomyces althioticus in 1957 and inhibits growth of both Gram-positive and -negative bacteria. The structural study of althiomycin was carried out in the following way. The hydrolysis of I with 6N-HCl afforded DL-cysteic acid (II), DL-serine (III), glycine, thiazole-4-carboxylic acid (IV) and ammonia. The hydrolysis with 2N-NaOH afforded 2-(hydroxyinimomethyl)-thiazole-4-carboxylic acid (V) as a key degradation product. The simple methanolysis gave 4-methoxy-3-pyrroline-2-one (VIII) and a methyl ester composed of C_<12>H_<12>O_4N_4S_2. Based on the chemical degradations and spectroscopic evidence of each compound, Ia or Ib was considered to be most reasonable structure for althiomycin. On the other hand, X-ray crystal analysis of didehydroalthiomycin (XV) unambig-uously demonstrated that the structure of I contains the thiazoline system of Ia rather than eight-membered ring system of Ib. Thus, the structure of althiomycin has been shown to be N-[2-hydroxy-1-[4-[(4-methoxy-2-oxo-3-pyrrolin-1-yl)carbonyl]-2-thiazoline-2-yl]ethyl]2-(hydroxyiminomethyl)-4-thiazolicarboxamide.

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Streptolidine (roseonine, geamine) is a component amino acid of a number of antibiotics of Streptothricin group. The structure of this guanidino amino acid was determined recently by X-ray analysis. We attempted, in this report, to synthesize it through stereospecific route starting from D-ribose. Most promising synthetic scheme was involved in guanidino ring formation from 2,3,5-triamino-4-hydroxy pentanoic acid lactam which was obtained by oxydation of 2,3,5-tribenzamido-2,3,5-trideoxy-D-arabinofuranose prepared from D-ribose through several synthetic steps. Thus, D-ribose could be converted to methyl 5-benzamido-2,3-benzoylepimino-2,3,5-trideoxy-β-D-lyxofuranoside by tosylation followed by action of sodium azide. The epimino ring in this compound was opened to 3-azido-2-benzamido derivative which was then changed to tribenzamido compound mentioned above. Reaction of crude 2,3,5-triamino-4-hydroxy pentanoic acid lactam with cyanogen bromide gave a spot of streptolidine on paperelectrophoresis, although the final step of this synthesis requires a prudent reinvestigation.

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We have been studied the relationship between the structures and the biological activities on 16-membered lactone ring macrolide antibiotics. The aglycone moiety from 16-membered macrolides has not been reported, but in the present series of work, we have chemically obtained the aglycone from leucomycin A_3 (LM A_3) (I). Treatment of (I) with m-chloroperbenzoic acid in CHCl_3 gave the N-oxide (II), which was refluxed with Ac_2O in CHCl_3 to obtaine aglycone, leuconolide-A_3 5,18-hemiacetal (III). In the above reaction, a neutral macrolide, 2'-acetyl 3'-desdimethylamino 3'-oxo LM A_3 (X) which 3'-dimethylamino group on mycaminose moiety was converted to ketone carbonyl was isolated from the same reaction product. Furthermore, (I) was reacted with Al-isopropoxide to give 9-dehydro 18-dihydro leucomycin A_3 (V). (V) was oxidized with m-chloroperbenzoic acid to N-oxide (VII), and(VII)was then treated with Ac_2O in CHCl_3 to obtain 9-dehydro 18-dihydro leuconolide-A_3 (VIII). In order to clarify the correlation between the structure and biological activity of mycaminose moiety, various derivatives were synthesized. The antimicrobial activities of the both glycone, (III) and (VIII) completly disappeared, and it was found that the decreasing of electro-density on dimethylamino group on mycaminose moiety resulted in the decrease of the activity.

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The epidithiodiketopiperazine structure is a common functionality in the natural products of the gliotoxin-sporidesmin class. Although a few simple epidithiodiketopiperazine derivatives have been synthesized, a general method of the synthesis is lacking. We will report a method (i.e. the sequence 1a & b→2→4→8 and the sequence 1a & b→2→4→9→10), which is expected to be generally useful for the synthesis of this functionality. Based on this new method, the first total synthesis (i.e. the sequence 11→13→14a→15→17a 14b→16→17b→18) of dehydrogliotoxin 18, the metabolite of Penicillium terlikowskii, and the formal stereospecific total synthesis (i.e. the sequence 19→20→21 22→23→24→25→26→27→28) of sporidesmin A 28, the major metabolite of Pithomyces chartarum, will be discussed.

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In the course of investigations on structure-activity relationships of viomycin(VM), a tuberculoststic antibiotic, chemical modifications of its reactive functional groups tuberactidine residue and its chromophoric 3-ureidodehydroalanine residue were studied. Thus, alkali treatment or reaction with bromine resulted abnormal reaction products AnVM or BroxoVM respectively those of which were characterised by chemical and physical analysis. Antimicrobial activities of oxidations products of VM showed nullified potencies, the results of which were agreeable from the predictions that D-form or dehydro derivative of amino acid residue are important factor for their potencies of original antibiotics while, 4HVM, a hydrogenated product of the chromophore group to alanine moiety still possessed one forth of original potencies. Chemical modifications on hydroxyl function of tuberactidine residue did not resulted significant inactivations except AnVM. The reason for the inactivation of AnVM could be attributed for conformational changes of 16 membered cyclic peptide ring.

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Pb(OAc)_4 oxidation of 7-hydroxy-6-methoxy-2-methyltetrahydro-isoquinolines possessing electron-donating group at C-3' position in the benzene nucleus of 1-benzyl or 1-phenethyl group, gave the corresponding p-quinol acetates. By the treatment of the p-quinol acetate with various acids, we succeeded in the syntheses of some aporphine, homoaporphine and homomorphinandienone type alkaloids. This cyclization reaction is new, and supplies the useful method for syntheses of some isoquinoline alkaloids.

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To the solution of 1,2,3,4-tetrahydrophenanthrene-9-ol (I) in 10% NaOH, CHBr_3 was added to give the enone (II). Two isomers of the bromocyclopropane derivatives (III and III') were obtained by the reduction of II with Fe-AcOH-EtOH. Reaction of these isomers (III and III') with CN^- gave a sole product (IV). Reduction of IV with NaBH_4 or catalytic reduction over Pd-C afforded A/B cis and trans fused alcohols (V and VI). These alcohols were reduced over Raney Ni to aminocompounds and then dehydrated to corresponding unsaturated aminocompounds (XIII and XIV). Cyclization of the compounds (XIII and XIV) to morphinan structures were accomplished treating with NCS and dichlorocompounds (XV and XVI) were obtained. Catalytic reduction of the dichlorocompounds (XV and XVI) gave morphinan and B/C trans-fused morphinan.

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Clivonine and clividine, isolated from Clivia miniata Regel (Amaryllidaceae), are the alkaloids of group characterized by benzo-pyrano[3,4-g]indole structure. The synthesis of the alkaloids of the group has not been reported so far. Cycloaddition of fumaric acid and 3,4-methylenedioxyphenyl allyl carbinol in acetic anhydride for 4 hr. gave two stereo-isomeric anhydrides (13) and (14). Hydrolysis of them gave the corresponding acids. Re-cyclization of the acids with acetic an-hydride under reflux furnished stereospecifically the same trans-cis-anhydride (12). Confirmation of the stereo-structure of the anhydrides was provided from the synthesis of α-, β-, and δ-lycoranes. Treatment of (12) with methanol gave the half-esters (19) and (20). Treatment of the former with thionyl chloride followed by sodium azide gave the azide (22) which was converted to the urethane (32). The diazoketone (34) derived from the acid (33) was subjected to the Wolff rearrangement in methanol to afford the ester (35). Hydrolysis of (35) gave the acid (36) which was easily cyclised to the oxoindole (37). Treatment of (37) with chloromethyl methyl ether followed by silver acetate furnished the acetate (38). Reduction of the acetate with lithium amuminum hydride gave the amine (40). Osmium tetroxide oxidation of the amine resulted in the formation of the stereoisomeric triols (41) and (42). Oxidation of the former with manganese dioxide gave (±)-clividine (2). The latter gave (±)-clivonine (1) on oxidation with the same reagent.

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Enamide photocyclization has been shown to be a new useful tool for the synthesis of various nitrogen containing heterocyclic systems. Particularly, the stereoselective photocyclization of the enamide derived from cyclohexanone to trans-fused phenanthridone offered wide applications to the alkaloids of this type of structure, which are abundant in nature, e.g. crinine, lycorine, some benzo(c)phenan-thridine, protcberberine, and yohimbine-type alkaloids. Irradiation of the enamides derived from the 2-substituted cyclo-hexanones afforded the corresponding phenanthridones which were converted into crinan, the basic structure of crinine, and a key intermediate for the total synthesis of tazettine and haemanthidine. Photocyclization of the enamides derived from the 1-tetralones afforded the B/C-trans benzo(c)phenanthridones which were readily converted into the alkaloids, e.g. nitidine and avicine. N-Acylation of 1-alkyl-3,4-dihydroisoquinolines yielded the corresponding N-acylates which underwent similar photocyclization to the berbine derivatives, thus enabling total syntheses of proto-berberine alkaloids, e.g. xylopinine, sinactine and cavidine. Further, the N-acylates of harmalane were similarly photocyclized to the yohimbine-type derivatives, which furnished the first and one-step total synthesis of angustidine, a new type of hetero-yohimbine alkaloid.

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In general, the indole alkaloids are interesting not only from the point of their complex structure, but also because of their pharmacologic activity. Therefore, we investigated the syntheses of several types of indole alkaloids and related compounds by means of the following reactions; synthesis via a nitrene intermediate, phenol oxidation, photolysis, thermolysis, and Grignard reaction. Thus, we synthesized harmane, (±)-dasycarpidone, (±)-epidasycarpidone, (±)-N-nordasycarpidone, (±)-maritidine, (±)-epicrinine and others.

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Fischer indolization of ethyl pyruvate 2-methoxyphenylhydrazone (1) gave unpredictable ethyl 6-chloroindole-2-carboxylate (2) as a main product instead of the expected ethyl 7-methoxyindole-2-carboxylate (4) in Fischer sence. On the other hand, treatment of the same hydrazone (1) with ZnCl_2 afforded another unexpected ethyl 5-chloroindole-2-carboxylate (9). These formations of abnormal indole products can be rationalized by the mechanism shown in Scheme 4. As an expanded application, we succeeded in developing these unexpected results to a synthetic method for indole derivatives having a unique carbon side chain at C_6. Treatment of 1 with TsOH in the presence of an excess amount of ethyl acetoacetate gave the indole product (13) possessing ethyl acetoacetate residue at C_6. We aimed at and succeeded in synthesizing the naturally occurring 6-(3-methylbuta-1,3-dienyl)indole (19) and 6-(3-methyl-2-butenyl)indole (27) from the above 13 through the synthetic routes in Scheme 6 and 7, respectively.

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Recent progress of electro-oxidation method in organic chemistry has been provided a new possibility for the synthesis of complex organic compounds. We were investigated an application of this method for the synthesis of complicated natural alkaloids and able to synthesize the titled compounds in excellent yield via anodic oxidation. Syntheses of crinine type alkaloids (±)-Oxocrinine, (±)-oxomaritidine, and related crinine type Amaryllidaceae alkaloids were synthesized from norbelladines 3 via cross conjugated dienone 4 by anodic oxidation. Syntheses of morphinandienone alkaloids (±)-Flavinanthine, (±)-pallidine, and (±)-amurine 10 were synthesized by electro-oxidation of 1-benzylisoquinolines 9 in high yield followed by hydrolysis. Syntheses of phenanthroquinolizidine alkaloids (±)-Cryptopleurine 19 was synthesized through electro-oxidation of substituted hexahydroquinolizinone 14.

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Formosanine(uncarine-B) and isoformosanine(uncarine-A) were isolated from Uncaria kawakamii and Ourouparia formosana, and mitraphylline and isomitraphylline are the alkaloids of Mitragina species. The structures of these alkaloids are delineated in Fig. I, in which their relationship as stereoisomers is shown by their ready interconversion and equilibration with acid or base. The total synthesis of formosanine and isoformosanine has been achieved by Winterfeldt by an oxidative conversion of the indole to the oxindole at the final step. The new synthesis of the entitled alkaloids through ten steps starting from the condensation of 2-hydroxytryptamine with the aldehyde(3) is reported with an interest in the proposal on the biosynthesis of indole alkaloids made by Scott. The first condensation product(5) was submitted to the Michael addition with methyl vinyl ketone, followed by acid treatment to give the α,β-unsaturated ketones as two stereoisomers(8a,b). The isomer(8a) was condensed with methyl malonate with sodium methoxide(0.5 mol.eq.) to yield the ester(11a), which was hydrogenated with Adams' catalyst to 12a. The compound(12a) was treated with dil. sulfuric acid to give the lactones(13a,b) as two spiro-isomers, an isomer(13b) of which in turn, was heated with the aminal ester in DMF for 2 hrs, then stirred with 5% MeOH-HCl overnight, refluxed with aqueous dioxane for 20 hrs, and heated with PPA at 70°for 2 hrs to afford dl-isoformosanine(1a) in 19% yield and dl-formosanine(1b) in 35% yield from 13b. Similarly, the isomer(15b) which was obtained from 11a by reduction with NaBH_4 and hydrolysis with acid, gave dl-isomitraphylline(2a) and dl-mitraphylline(2b) in 16% and 27% yields, respectively. The synthetic racemic alkaloids were identified with the natural products by direct comparisons of their i.r. spectra in chloroform solutions in addition to the other spectral data.

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Formerly we reported the isolation and characterization of gardmultine (I), a bisindole alkaloid of Gardneria multiflora Makino (Loganiaceae), under a tentative name of alkaloid E. Further chemical and spectroscopic study has led us to the conclusion that its monomeric components should be gardnera-mine (II) and chitosenine (IV), and that the structure of gardmultine is best expressed by the formula (I) shown in the text. The proposed structure (I) was supported by the following observations; Treatment of I with acetic acid or dilute hydrochloric acid gave rise to the respective dimeric oxindoles (III) and (VI), thus revealing the unique amide acetal system (B) in I. Introduction of acetate or chloride residue into the product can be explained by the mechanism shown in chart 4. A closely similar reaction had been found by us in our structural work on gardneramine(II)(chart 3). A methanesulfonate (IX) which was prepared from diol (VIII) by usual mesylation gave the starting base, gardmultine (I), on treatment with KOtBu in tBuOH (chart 5). Inspection of the stereostructure (I) using a stereo model reveals shielding effect of the aromatic ring (A) on the C_<18>,-olefinic methyl group whose NM R signal is observed atδ 0.88. Biogenetic type synthesis of I using gardneramine (II) and an appropriately functionalized derivative of chitosenine (IV) is now under progress. (chart 6).

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Cyclocoupling reaction of α,α,α',α'-tetrabromoacetone and N-carbomethoxypyrrole with the aid of diiron nonacarbonyl gives N-carbomethoxy-2,4-dibromo-8-azabicyclo[3.2.1]oct-6-en-3-ones (stereoisomers). Treatment of the adducts with zinc-copper couple in methanol affords the dehalogenation product, N-carbo-methoxy-8-azabicyclo[3.2.1]oct-6-en-3-one, which upon diisobutyl-aluminum hydride reduction is converted selectively to N-methyl-8-azabicyclo[3.2.1]oct-6-en-3α-ol (6-dehydrotropine). Since the unsaturated alcohol can be transformed to all naturally occurring tropane derivatives, the present procedure marks the realization of a new, general synthesis of the alkaloid family.

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The polyketide origin of fungal anthraquinones has been firmly established by the isotopic tracer studies with acetate and malonate as the precursors. On our experiments, it has been found that ^<14>C-emodin and ^<14>C-emodin-anthrone were efficiently incorporated into the anthraquinonoids of P. brun-neum and P. islandicum, and that ^3H-(-)flavoskyrin into skyrin, (-)rugulosin and (-)rubroskyrin. On the contrary, the metabolites other than emodin were recovered unchanged and the incorporations into the metabolites other than themselves were insignificant. The efficient incorporation of aromatic precursors reveals that the second-ary alcoholic group of the modified anthraquinones must be formed by the hydrogenation of aromatic ring and the incorporation of (-)flavoskyrin into the dimeric compounds suggests that the mechanism of the dimerization to afford modified anthraquinones involves (π2s+π4s) cycloaddition of Diels-Alder type and not phenol oxidative coupling. From these results, the biosynthetic pathway of anthraquinonoids of Penicillium species is proposed as Fig.3.

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Three new types of biflavone are reported: robustaflavone, 6-C-methylamentoflavone and ochnaflavone besides hitherto known four types, amentoflavone (1a), cupressuflavone (2a), agathisflavone (3a) and hinoki-flavone (4a). Robustaflavone was found in the leaves of Agathis robusta and the structure was established in a form of its hexamethyl ether (10), m.p. 305-308°.6-C-methyl-7-O-methylamentoflavone (13) was isolated from the leaves of Cephalotaxus harringtonia as the first example of C-methyl biflavones. Ochnaflavone (OSI, 15), and its mono- (OSII, 16) and di-(OSIII, 17) methyl ethers were isolated from the leaves of Ochna squarrosa (Ochnaceae) as three members of a new type biflavone which has a lingkage between side phenyls (Tab. 4). The structures of these new biflavones were easily elucidated mainly by using a shift reagent, Eu(FOD)_3 in the NMR spectra of their methyl ethers because H-6 showed much larger S-values than those of H-8 (Tab. 1 and 2). The synthesis of two compounds 14 and 20 starting from 18 and 19 respectively confirmed the structure 15 for ochnaflavone. It was also found that the shift reagent is similarly useful in the structure elucidation of isoflavone and xanthone derivatives.

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