Recently isolation of unique highly functionalized cyclohexenoid natural products designated pericosines A-E 1-5 as metabolites of Periconia byssoides OUPS-N133 originally separated from the sea hare, Aplysia kurodai, was reported. Among them pericosine A 1 showed remarkable inhibitory activity against the protein kinase EGFR and topoisomerase II in addition to in vivo antitumor activity against P388 cells. And the absolute stereostructure of pericosines A-C 1-3 had been elucidated by their total syntheses. However our successful first synthesis of pericosine A 1 was not satisfactory in the total yield. Here we disclose more effective second synthesis of (+)-1 via stereoselective ring opening of β-epoxide 11 derived from (-)-quinic acid 6. Syntheisi of (+)-pericosine C 3 from the same intermediate was also examined. On the other hand undefined absolute configuration of pericosine D 4 was elucidated by the short total synthesis via stereoselective ring opening of β-epoxide 15 assigned as methyl (3R,4R,5S,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate. Using the same strategy, synthesis of (-)-pericosine B 2 was also accomplished.

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TNF-α is a potent multifunctional cytokine that mediates a variety of biological actions with a central role in the pathogenesis of many inflammatory diseases. Thus, inhibitors of TNF-α production in the activated mast cells and basophils are promising candidates for a new type of anti-allergic agent. In our search for bioactive compounds from edible Chinese mushrooms, we isolated a new potent antioxidant, vialinin A (1) along with atromentin, a mixture of ganbajunins D, and E from the dry fruiting bodies of Thelephora vialis. Recently, we found that 1 strongly inhibited TNF-α production in rat basophilic leukemia (RBL-2H3) cells: the IC_<50> was 90pM when the clinical immunosuppressant FK-506 was used in the same run as a positive standard (IC_<50>=0.25nM). In order to clarify the target molecule of 1 and develop a new anti-allergic drug, we have started synthetic studies on bioactive p-terphenyl derivatives. In this symposium, we present total synthesis of 1 and its related compounds. Vialinin A (1) was synthesized from sesamol in 11 steps with 28% overall yield. The key reactions include a double Suzuki coupling of electron-rich aryl triflate with phenylboronic acid, and an oxidative deprotection of bis-MOM ether. A similar strategy enabled us to prepare atromentin, ganbajunins D and E from bromanilic acid. Furthermore total synthesis of the proposed structure for ganbajunin C suggested the necessity for structural revision of this natural product.

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Tubulysins (1a-e), a family of antimitotic agents isolated from the myxobacterial strains Archangium gephyra and Angiococous disciformis, possess potent cell growth inhibitor activity exceeding that of vinblastine. Therefore, tubulysins have attracted considerable attention as leads for the development of new anticancer agents. We report herein efficient methods for the synthesis of tubulysins that would provide convenient access to synthetic analogues. Tubulysin D (1b) is composed of four amino acid fragments, N-methyl-D pipecolic acid (D-Mep), L-isoleucine (L-Ile), tubuvaline (Tuv), and tubuphenylalanine (Tup) (Fig. 2). We especially focused on stereoselective synthesis of Tuv and Tup. The highly stereoselective synthesis of Tuv-methyl ester was accomplished by 1,3-dipolar cycloaddition of nitron 6 and acrylic acid derivatives 7 as a key step (Scheme 2-4). Synthesis of Tup involved an aldol reaction of boron enolate of (S)-4-isopropyl-3-propionyl-2-oxazolidinone with aldehyde 12, readily prepared from phenylalanine, follwed by Barton deoxygenation under radical conditions. With the Tuv and Tup in hand, we have accomplished a synthesis of tubulysin D (1b) by employing Ellman's sequence. We have succeeded in exploring a novel synthetic route to Tuv and Tup. These syntheses may be applied to other analogues required for investigation of the structure-activity relationship. Novel tubulysins analogues unavailable from natural resources are expected to be found in future.

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1,4-Cycloheptadiene skeletone can be seen in many natural products. Although various approaches have been reported, most of them require multi steps. Davies et al. have reported that rhodium-catalyzed reaction of 1,3-dienes and α-alkenyl-α-diazoacetates gives 1,4-cycloheptadiene derivatives in a highly enantioselective manner via cyclopropanation and subsequent Cope rearrangement. Although this is a straightforward approach, the yields of some reactions are unsatisfactory, due to instability of the diazo compound. Recently, Doyle and co-workers reported that cyclopropanation of 1,3-dienes using vinyldiazolactone 1, an equivalent of α-alkenyl-α-diazoacetates, gave alkenyl-α-spirocyclopropyl lactones, which could be converted into 1,4-cycloheptadiene derivatives, in good yields with moderate E- and enantio-selectivity. We have reported that iridium-salen complex 2 is an efficient catalyst for asymmetric cyclopropanation using α-diazoacetate. Thus, we examined the cyclopropanation of 1,3-dienes using 1 in the presence of 2 and found that the reactions gave alkenyl-α-spirocyclopropyl lactones with excellent E- and enantio-selectivity in good yields, irrespective of the substitution pattern of the alkenyl moiety.

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The diaryl ether is the common key structure for a variety of isodityrosine-class natural products, such as vancomycin, K-13, and OF-4949. These natural products exhibit a wide range of biological activity. Therefore, synthetic studies of natural products carrying the diaryl ether moieties have been reported by many synthetic chemists around the world. Our laboratory has studied application of oxidative phenolic coupling reaction to biomimetic synthesis of a wide range of natural products, such as simple isodityrosines and complicated cyclic peptides. Anodic oxidation and thallium (III) salt oxidation have been investigated in particular. Anodic oxidation is an extremely mild and safety method, since it is usually performed at ambient temperature under neutral conditions, without use of toxic metal oxidants. On the other hand, thallium (III) oxidation is a useful one in the synthesis of highly strained cyclic diaryl ether compounds. In this presentation, related to the two methods mentioned above, applications of electro-organic synthesis for wide range of conversions including direct/indirect anodic oxidation and indirect cathodic reduction, as well as basic study of electrochemical activation of thallium ion in catalytic system, will be discussed.

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Flavonoids are phenolic compounds widely present in plants and foods of plant origin. (+)-Catechin, (-)-epicatechin, Querucetin,, and taxifolin are type of flavons, daidzein and genistein are type of isoflavons and then resveratrol is type of stilbene. Taxiforin is included in Larix sibirica. Chrysin and querucetin are included in peel of citrous. Daidzein and genistein exist in soy beens. Resveratrol is included in red wine. These compounds are known to have the biological activities including an antioxidant property, anti-inflammatory and carcinogenic depression effects. These compounds are used as agents and food ingredients. Irrespective of such biological activities, the use of these compounds has been limited, because of their low solubility. Higher plants accumulate a wide range of glycosides as secondary metabolites, and are capable of conjugating sugar residues not only to endogenous metabolic intermediates but also to xenobiotics. To enhance the water-solubility of their flavonoids, we investigated the glycosylation using Eucalyptus perriniana. Eucalyptus perriniana plant cultured cells were tested for the glycosylation toward there compounds. As a result, (-)-epicatechin, daidzein and genistein were glycosylated at C7-position of hydroxyl group in the substrate molecules. (+)-Catechin was glycosylated at C7, C3'-position of hydroxyl group. Querucetin was glycosylated at C3-position of hydroxyl group. Taxifolin was glycosylated at C7 and C4'-position of hydroxyl group. Also, resveratrol was glycosylated at C3-position of hydroxyl group.

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9Z-Retinoic acid 1 and its synthetic analogues bind to RXRs (Retinoid X receptors) and regulate various biological functions such as cell differentiation, proliferation, and control of embryonic development. Therefore, the development of an efficient synthetic route of 1 and its synthetic analogues is desirable. In this presentation, we will demonstrate an efficient, rapid synthesis of 1 that includes Stille coupling reaction of stannanyl ester 4, having an electron-withdrawing group. as a key reaction. Advantages of our method are as follows; 1) Stannanyl ester 4 can be prepared from commercially available alcohol 6 in only three steps with in a large scale procedure. 2) The isomerization of the Z-double bond does not occur in the reaction. 3) Our originally developed stannanyl ester 4 can serve as a practical building block in convergent syntheses leading to useful analogues. Although Stille coupling reaction using organostannane with electron-withdrawing group has usually suffered from its unreactivity and homo-coupling, the use of cesium fluoride (CsF) as an additive caused not only the enhancement of the reaction rate but also the avoidance of the isomerization of Z-double bond. This Stille coupling reaction enabled us to accomplish the total synthesis of 1 in three steps from the aldehyde 2 in 63.0% overall yield or in five steps from the alcohol 6 in 62.7% overall yield. In conclusion, we developed a rapid synthesis of 9Z-retinoic acid 1, and a highly efficient, convergent synthetic route of its analogues by cesium fluoride promoted Stille coupling reaction using common stannyl ester 4.

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Platensimycin (1) was isolated from Streptomyces platensis by the Merck group as a potent inhibitor against MRSA and VRE. Platensimycin has a unique structural feature especially complicated tetracyclic core and it brought interest to synthetic organic chemists as an extremely challenging synthetic target. The syntheses of platensimycin have been recently reported by Nicolaou et al. and other groups. Corey et al. also reported the formal synthesis of platensimycin through a key intermediate 2 in 2007. We have independently studied the synthesis of platensimycin (1) and now report the synthesis of a key intermediate 2. Our synthetic plan is shown in Scheme 1. A key intermediate 2 could be prepared from 4 through the stereoselective iodoetherification followed by the intramolecular S_N2 reaction. Compound 4 could be prepared by the dehydration of the tert-hydroxyl group and the stereoselective reduction of the ketone of compound 5. The known compound 6 could be easily converted to 5 through the Friedel-Crafts acylation. Compound 6 was prepared from p-anisaldehyde with dimethyl succinate through the Stobbe condensation followed by the reduction of carbon-carbon double bond (Scheme 3). After conversion of 6 to 7 through the intramolecular Friedel-Crafts acylation in poly-phosphoric acid, the tert-alcohol moiety was constructed to obtain compound 5 as shown in Scheme 6. After cleavage of the methyl ether of 5, the dehydration of the tert-alcohol was achieved by treating of 16 with SOCl_2 in the presence of pyridine (Scheme 8). The ketone moiety of 18 was reduced diastereoselectively to obtain compound 4. The formal synthesis was achieved as shown in Scheme 9. The diastereoselective iodoetherification of 4 by the use of NIS and the construction of the tetracyclic core by treating of 3 with t-BuOK in refluxing t-BuOH gave the key intermediate 2. The spectroscopic data of synthetic 2 were identical with those of reported data.

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Haouamines, a family of marine alkaloids, were isolated from a tunicate, Aplidium haouarianum, in the southern coast of Spain by Zubia and co-workers. Among them, haouamine A (1) exhibits highly specific and strong cytotoxicity against HT-29 human colon carcinoma cell line (IC_<50>=200nM). Additionally, haouamines has the unique structural features such as cis-fused indeno-tetrahydropyridine and highly strained 3-aza-[7]-paracyclophane contained bent aromatic ring. Despite of its significant biological activity and unique structure, only one total synthesis has been reported because of its highly strained structure. According to the Baran's approach, we set the pentacyclic indeno-tetrahydropyridine 3 as a key intermediate, which would be obtained by intramolecular Friedel-Crafts reaction. We have prepared alcohol 16, the precursor of key intramolecular Friedel-Crafts reaction, starting from the known β-lactam 11. Staudinger ketene-imine cycloaddtion using ene-imine 10 and acid chloride 7 gave 11, which was then converted to 16 by a seven-step sequence including introductions of the two aryl groups. The crucial intramolecular Friedel-Crafts cyclization proceeded smoothly to furnish the unprecedented pentacyclic structure 19. The successful cyclization required exchanging of the phenolic protecting group from MOM ether to mesylate, activation of the tertiary hydroxy group, and the use of MeCN as aprotic polar solvent. After demesylation of 19, we examined oxidative deprotection of aryl group on the β-lactam nitrogen under several conditions. Finally, we found that the desired unprotected β-lactam 21 was obtained in high yield by treatment with iodebenzenediacetate in 1,4-dioxane-THF-water. In this reaction, choice of solvent was quite important. Then, β-lactam 21 was activated by installation of Boc group on the nitrogen and the ring opening reaction was investigated using a variety of organometallic reagents. While the β-lactam possessed a poor reactivity due to the steric hindrance, only benzonitrile anion cleanly added to furnish nitrile 23 in quantitative yield. Construction of the indeno-tetrahydropyridine skeleton is currently under investigation.

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Pd-catalyzed stereoselective cyclization of alkenylalcohol and alkenylamine is very important reaction for the stereoselective construction of oxygen and nitrogen heterocyclic compounds. In this symposium, we wish to present Pd-catalyzed diastereoselective O-and N-alkylation and their application of natural products. 1. Synthesis of pyranicin (1) Total synthesis of pyranicin (1) was achieved using Pd (II)-catalyzed diastereoselective cyclization of the allylic ester as the key step. The inhibitory activity of this compound for mitochondrial complex I was slightly poorer than that of mono-THF acetogenins. 2. Synthetic studies on spectamine A (2) Recently, a novel piperidine alkaloid from African legume, Cassia spectabilis, was isolated. The structure was elucidated as O-benzoyl derivative of (+)-iso-6-cassine. Herein we wish to present the progress toward synthesis of 2 using Pd-catalyzedd stereoselective cyclization to give 2,6-tans-piperidine ring 14t. Total synthesis of 2 is currently underway.

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Plukenetione A is a natural product isolated from Clusia plukenetii. The structural feature is a highly oxygenated and densely substituted adamantane core. We have found a method for the construction of the poly-functionalized bicyclo [3.3.1]nonenes by successive Michael reactions of 2-cyclohexenones with methacrylates. We also found that the adamantanes could be constructed via successive Michael reactions, followed by a Dieckmann condensation when ethyl 2,4-dioxocyclohexanecarboxylate was used as a Michael donor. In this report, synthesis of the adamantnae core 1 of plukenetione A via the successive Michael reactions is described. The bicyclo[3.3.1]nonene 3 was obtained by the successive Michael reactions of cyclohexenone 5 with methacrylate 4. Introduction of the C10-gem-dimethyl group was carried out after the reduction of the C9-carbonyl group. The C4-carbonyl group was introduced by the allylic oxidation of 8. The C9-carbonyl group was restructured by the oxidation of 9. The C3-benzoylated product 2 was obtained from 11 via the vinyl anion. When 2 was treated with TfOH in CH_2Cl_2, the adamantane core 1 was obtained. In order to apply the developed strategy to the asymmetric construction of the adamantane core, the organocatalytic asymmetric Michael reactions of 12 and 15 with 13 were investigated. When the leaving groups with low leaving ability were used for 13, the stereoselectivity in the Michael reaction was enhanced. The reaction temperature also affected the stereoselectivity. Attempts to improve the reaction yield are now in progress.

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Recent advances in the field of organocatalytic asymmetric synthesis have provided several new methods for preparing chiral compounds in an environmentally benign manner. Most attention has been focused on the use of proline due to its ready availability in either L- or D-form and the highly versatile nature of its reactivity. Recently, we found that aldehydes bearing 1,3-dithiane moiety at the β-position could serve as a useful synthon of straight-chain aliphatic aldehydes. Based on this strategy, enantioselective total synthesis of the following natural products have been performed. 1. (+)-Boronolide (1), isolated from the bark and branches of Tetradenia fruticose. 2. Pachastrissamine (2), isolated from the Okinawan marine sponge Pachastrissa sp. 3. (+)-Prosophylline (3), isolated from the African mimosa Prosopis africana Taub. The details of these works will be presented.

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Sphingofungins (A-F) are a family of antifungal metabolites produced by microorganisms, and have been shown to be potent and specific inhibitors of serine palmitoyl transferase, an essential enzyme for the biosynthesis of sphingolipids. These compounds have a lipid tail and a polyhydroxy-amino acid head moiety with four contiguous chiral centers and a trans-olefinic function. Due to their biological activity and structural complexity, the sphingofungins have inspired a number of synthetic efforts. We report here a novel synthetic approach to sphingofungins using D-gluconolactone as a chiral source of the head moiety. Gluconolactone 1 was converted to 2-azido-mannonate derivative 3, from which C5-aldehyde derivative 4 was readily prepared. The hydrophobic portion containing (R)-hydroxy group was prepared via asymmetric transfer hydrogenation of pentadec-8-yn-7-one 13. The resulting pentadec-1-yn-9(R)-ol derivative 15 was converted to pentadec-1(E)-enyl-zinc derivative 17, which was reacted with the C5-aldehyde 4 to give separable diastereomeric adducts (7:1). The major adduct was deduced to be natural C5-(S)-alcohol 18, a key intermediate for the synthesis of sphingofungins A-D. Acidic hydrolysis of 18 gave the azide-lactone 19, and the azide was reduced with zinc in acetic acid to give the amine 20. When the reduction was carried out in the presence of acetic anhydride, the acetamide 21 was obtained. Mild basic hydrolysis of 20 and 21 afforded sphingofungins B and D, respectively.

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Phoslactomycin B is a member of the phoslactomycin family of phosphate ester antibiotics (PLM) that display potent antitumor activity against a broad range of cancerous cell lines in vitro. Such antitumor activity is attributed to highly potent and selective inhibition of protein phosphatase 2A (PP2A). Their interesting molecular architectures and the potential as a lead compound for developing antitumor drugs make PLM attractive targets for synthesis. We describe here an efficient asymmetric synthesis of (+)-phoslactomycin B, which enables us to secure various analogues required for biological testing as well. Based on the methodology we have developed in the total synthesis of fostriecin, a congener of PLM, (+)-phoslactomycin B was synthesized by a highly enantio- and stereoselective approach involving asymmetric pentenylation for the introduction of C4 and C5 chiral centers, Suzuki-Miyaura coupling for the attachment of the characteristic C8 aminoethyl substituent, ring-closing metathesis for the construction of the δ-lactone moiety, Sharpless asymmetric dihydroxylation for the assembly of C8 and C9 hydroxy groups, and Stille coupling. The synthetic method developed enables us to synthesize three other isomers concerning the C11-OH and Δ^<12>-double bond.

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Maremycins 1-6 are diketopiperazines obtained from the culture broths of marine Streptomyces species. The stereochemistries of maremycins were tentatively proposed on the basis of molecular mechanics calculations and spectroscopic data of compounds 1 and 2. The fact that structurally related diketopiperazine FR900452 (7) is a potent and specific inhibitor of platelet-activating factor (PAF) also interests us in bioactivities of compounds 1-6. We present here the first synthesis of maremycins A (1) and D_1 (5) by using cycloaddition of 3-ethylideneindolin-2-one 10 with cyclic nitrone 11, and confirmed stereostructures of maremycins. When a mixture of 3-ethylidene-1-methylindolin-2-one (10) and nitrone 11 in toluene was heated at 60℃ for 48h, smooth cycloaddition occurred to afford a 22:78 mixture of cycloadducts 12 and its regioisomer 13 in 94% yield. Unfortunately, the desired cycloadduct 12 was the minor isomer, so we further examined the reaction conditions such as Lewis acids, temperatures, and solvents. After experimentation, we found that use of hexane or THF as a solvent afforded a 1:1 mixture of 12 and 13, although Lewis acids did not work. It was also found that undesired adduct 13 could be transformed to desired adduct 12 via cycloreversion-recycloaddition. Since cycloadduct 12 has the correct stereochemistry for maremycins A (1) and D_1 (5), synthesis of 1 and 5 was readily achieved by elaboration including hydrogenolysis, condensation with Boc-S-Me-L-Cys (16), diketopiperazine formation and oxidative desulfurization.

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Piperidine alkaloids are expected to be lead compounds for new medicines because of their various biological activities. In order to establish the efficient synthetic methods for a variety of functionalized piperidine alkaloids, we have developed Michael addition reaction between silyl ketene acetals and 2-pyridinone derivatives in the presence of Lewis acid. Recently we have examined the reactivity of substrates having a methoxycarbonyl group at the C3 or the C5-position on the 2-pyridinone ring for control of the regioselectivity. As a result, when the reaction was applied to the substrate having the C3-methoxycarbonyl group, C4-substituted product was selectively obtained in the presence of a catalytic amount of Lewis acid. On the other hand, the reaction of the substrate having the C5-methoxycarbonyl group provided C6-substituted product in the presence of a catalytic amount of Lewis acid and azabicyclic compound with 2 equivalents of Me_3Al. On the examination of the reaction mechanism, it was found that the active Lewis acid was not Me_3Al, but the complex produced from Me_3Al and silyl ketene acetal. These reactions were applied to the syntheses of natural products. The enantioselective synthesis of the DE ring system of camptothecin, anti-tumor natural product, was accomplished in six steps. Next, we have studied the synthesis of awajanomycin, which is a new anti-tumor natural product isolated from marine-derived fungus in 2006. Since its absolute configuration has not been determined yet, we planned the stereoselective synthesis of awajanomycin as an optically active form. To construct its azabicyclic part, we have examined introduction of functional groups to the Michael adduct.

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Brevenal is a pentacyclic polyether natural product isolated from the red tide dinoflagellate Karenia brevis. This natural product competitively displaces tritiated dihydrobrevetoxin-B ([^3H]-PbTx3) from voltage-sensitive sodium channels in a dose dependent manner, whereas it showed no toxicity in a fish bioassay. Moreover, brevenal increased tracheal mucus velocity in picomolar concentrations in an animal model of asthma. Thus, brevenal represents a potential lead for the development of novel therapeutic agents for treatment of mucociliary dysfunction associated with cystic fibrosis and other lung disorders. Toward elucidation of the biological mode of action at the molecular level and establishment of the structure-activity relationships, it is essential to develop an efficient, scalable, and flexible synthetic route to brevenal; however, our first-generation total synthesis involved lengthy fragment syntheses and tedious and capricious manipulations unsuitable for scale-up. Herein, we describe a highly convergent and efficient synthesis of the pentacyclic polyether core 2, which is a key intermediate in the previous synthesis. The present synthesis features i) highly efficient and scalable synthesis of the AB- and DE-ring fragments and ii) two-fold use of our Suzuki-Miyaura coupling/mixed thioacetalization-based convergent strategy for the synthesis of polycyclic ether frameworks. Our second-generation synthesis (total number of steps: 59; longest linear sequence: 32) is considerably more efficient than the original one (total number of steps: 73; longest linear sequence: 50).

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The xanthanolides were isolated primarily from the Xanthium (family Compositate). Recently, xanthanolides have been found to exhibit interesting biological profiles such as antimalarial and antitumor activity, inhibition of farnesylation of the human lamin-B as well as allelopathic activity. Due to their limited availability, there have been few investigations on xanthanolides as allelochemicals. Herein, we report the synthesis of sundiversifolide (4), isolated from the exudate of germinating sunflower (Helianthus annuus L.) as an allelopathic compound, along with its allelopathic activities and determination of the absolute configuration. We also report the synthesis of xanthanolides such as xanthatin (1), 8-epi-xanthatin (2), dihydroxanthatin (3) and diversifolide (5). Synthesis of sundiversifolide (4) is as follow: The key seven-membered ring construction was achieved by an intramolecular acylation of an organolithium species, and then the γ-lactone moiety was formed from a butenolide, prepared by the one-pot condensation of a α-hydroxyhemiacetal with Ph_3P=CMe(CO_2R). The absolute configuration of natural sundiversifolide (4) was determined by HPLC analysis using a chiral column and allelopathy assay. 8-epi-Xanthatin (2) was synthesized from the sundiversifolide precursor 22 by α-methylenation of the lactone, followed by cross metathesis with methyl vinyl ketone. Xanthatin (1), dihydroxanthatin (3) and diversifolide (5) were synthesized by the inversion of C-8 stereochemistry, which was carried out by the oxidation-reduction method. The ^1H and ^<13>C NMR spectra of synthetic 5 did not match those of the natural material reported by Kuo. We concluded that the correct structure of diversofolide is 11-epi-sundiversifolide (32).

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7,20-Diisocyanoadociane is a marine diterpenoid isocyanide isolated from the marine sponge of the genus Adocia collected in Australia, on the Great Barrier Reef. 7,20-Diisocyanoadociane has a unique all-trans-perhydropyrene ring system. 7,20-Diisocyanoadociane strongly inhibits proliferation of the malaria parasite Plasmodium falciparum. The biological activity and unique structural feature prompted the authors to undertake its synthesis. The authors established a formal synthesis of 7,20-diisocyanoadociane using a sequential isomerization-intramolecular Diels-Alder reaction as a key step. The synthesis of 7,20-diisocyanoadociane was conducted starting from known optically active lactone 2 (Scheme 1). Lactone 2 was converted to allylic alcohol 6 by introduction of diene and dienophile moieties. Oxidation of allylic alcohol 6 with IBX resulted, via an intramolecular Diels-Alder reaction, in the spontaneous formation of cis-decalin 8 as the sole product. cis-Decalin 8 was converted to triene 12 by introduction of a diene moiety through a Horner-Wadsworth-Emmons reaction. A solution of triene 12 in mesitylene was heated at 220℃ in the presence of DBU and BHT to facilitate a sequential isomerization-intramolecular Diels-Alder reaction to give a mixture of exo- and endo-cycloadducts 13 (Scheme 2). Following deprotection of the Tr group in 13, the mixture of exo/endo cycloadducts was separated to give alcohols 14a and 14b. Alcohol 14a was converted to diketone 1 via deformylation, reduction of the olefin and isomerization at C-11 and C-15. Diketone 1 was used as Corey's intermediate for the synthesis of 7,20-diisocyanoadociane.

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The optical resolution of racemic albicanol (rac-1) and racemic ketal (rac-2) were performed based on the lipase-catalyzed transesterification. The enzymetic resolution of rac-1 by using lipase QL and vinyl myristate as acyl donor afforded (-)-1 (99% ee) in 43% yield and (+)-1 (99% ee) in 37%, respectvely. The enzymetic resolution of rac-2 by using lipase QL and vinyl acetate afforded (-)-2 (99% ee) in 43% yield and (+)-2 (99% ee) in 37%, respectively. As the purpose of synthetic application of obtained optically active 1 and 2, several natural terpens were synthesized. (+)-Austrochaparol ((+)-3), (+)-cornarin E ((+)-4), (+)-cornarin A ((+)-5) and (+)-albaconol ((+)-6) were synthesized from (+)-1. The absolute configurations of (+)-3 and (+)-6 were determined to be 8aS by the comparison of their specific rotation between natural product and synthetic product. (-)-Copalic acid ((-)-7) possessing antimicrobial activity and (-)-copalol ((-)-8) were synthesized from (-)-1. (+)-Totarol ((+)-12) possessing antimicrobial activity against MRSA, (+)-podototarin ((+)-13), and (+)-sempervirol ((+)-14) were synthesized from (+)-2 based on Michael addition of β-ketoesters to α,β-unsaturated ketone ((8aS-17). The first total synthesis of (+)-jolkinolide D ((+)-15) that were known to induce apoptosis in tumor cells and (+)-jolkinolide E ((+)-16) were achieved from (-)-2.

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2,6-Diaminopimelic acid (DAP) is a naturally occurring amino acid found in both bacteria and higher plants. meso-DAP and (S,S)-DAP serve as the precursors in the biosynthesis of L-lysine in both bacteria and higher plants. meso-DAP is also an essential component of the peptidoglycan of most pathogenic bacteria. A number of peptidoglycan fragments featuring the DAP residue exhibit various biological activites such as antitumor, immunostimulant and sleep-inducing activities. FK-565 (1), DAP-containing structure, enhances host defense ability against microbial infections and exhibits strong antiviral activity and remarkable antitumor potency. iE-DAP is a peptidoglycan (PGN)-specific dipeptide and stimulates Nodl, which is a member of family of intracellular proteins that mediate host recognition of bacterial peptidoglycan. N-Acyl iE-DAP 2 and 3 exhibit higher ability to stimulate Nodl than the original iE-DAP. We describe a convenient synthesis of orthogonally protected meso-DAP and 1 using cis-1,4-diacetoxycyclohept-2-ene (4). We developed the new method to synthesize protected meso-DAP 20 using Grubbs' cross metathesis between vinyl 16 and allylglycine derivative 17. This strategy has been applied to total synthesis of 2 and 3.

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Lamellarin-class natural products have attracted considerable attention due to their unique structure and highly useful biological activities. For example, lamellarin D (1) exhibits potent cytotoxicity on P-glycoprotein-mediated multidrug-resistant (MDR) cancer cells. In 1997, we have reported the first total synthesis of 1 using N-ylide-mediated cyclization of a benzylisoquinoline derivative as the key ring-construction procedure. By using this strategy, we have synthesized ten lamellarin D analogues and carried out a structure-activity relationship (SAR) study. In this study, we revealed that the hydroxyl group at C-8 and C-20 positions are essential for cytotoxic activity. Recently, Bailly et al. have reported 1 is a potent inhibitor of DNA topoisomerase I and presented a theoretical model of 1-DNA-topoisomerase I ternary complex. The model is in perfect agreement with our SAR study. Based on these previous studies, we designed 1-dearyllamellarin D (2) and its C-1 substituted derivatives 3 as novel antitumor compounds. The synthesis of 2 has been achieved by combinational use of regioselective lithiation, Suzuki-Miyaura coupling, Mitsunobu type reaction, and intramolecular Heck reaction as key reactions. Electrophilic substitution of 22 proceeded at 1-position selectively to afford 23. In addition, bromide 23c could be converted into C-1 arylated or methylated 24 by using Pd-catalyzed Suzuki-Miyaura coupling reaction. These reactions allowed to produce a number of C-1 substituted 3.

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Salinosporamide A (1, NPI-0052) was isolated from a marine bacterium of the new genus Salinospora (strain CNB-392) by W. Fenical et al. in 2003. This compound displays remarkable in vitro cytotoxicity towards many tumour cell lines (IC_<50> of approximately 10nM), and its activity appears to be directed to the inhibition of the 20S proteasome. Owing to the potent biological activity and the fascinating inhibitory mechanism, as well as this complex chemical structure, 1 has been an attractive target for the synthetic chemist, and several total synthesis of the metabolite have now been published. Encouraged by the recent SAR studies showing that the chloroethyl moiety of 1 is responsible to the enhanced biological activities compared with omuralide (2), we have continued our studies to develop a convergent route to 1, featuring the intermolecular aldolization to connect the C2-C3 juncture. In the beginning, we started the model studies on the synthesis of 7,8-dihydrosalinosporamide A. The oxazoline 14 was synthesized from commercially available aldehyde 9 via azide 11, on treatment under various aldolization conditions, 14 brought about retro-Dieckmann decomposition. To avoid this pitfall, we converted keto ester 14' to ketone 17, which was subjected to Reformatsky reaction developed by Honda et al. to give 18a and 18b as a 1:1 stereoisomeric mixture. DBU-induced epimerization at C2 position afforded 18b from 18a in excellent yield After leading 18b to 21 in 5 steps, the treatment of diol 21 with 1-MeAZADO/PhI(OAc)_2 system provided β-lactone in one step, thereby confirming the feasibility of our strategy. Chiral azide 28 was synthesized from (S)-methyl lactate via 13 steps sequence (total 16 steps) involving Ireland-Claisen reaction, RCM using the 1st Grubbs catalyst We also developed more efficient route: oxazoline 35 was elaborated from (R)-Garner aldehyde via 10 steps. The details of the synthesis and progress toward the total synthesis of salinosporamide A will be discussed.

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Isomigrastatin (1) was isolated from Streptomyces platensis. NRRL18993 and has a 12-membered macrolactone, a glutarimide side chain and four adjacent stereogenic centers including adjacent hydroxyl group and methoxy group (C8 and C9). Interestingly, Shen and co-workers demonstrated that Migrastatin (2), Dorrigocin A (3) and Dorrigocin B (4) are shunt metabolites of 1. 2 inhibits human tumor cell migration and 3, 4 reverse the Morphology of Ras-transformed NIH3T3 Fibroblasts. These interesting chemical structures and biological activities have attracted considerable attention to us, because we have developed that regio- and diastereoselective construction of acyclic stereochemistry using palladium-catalyzed hydrogenolysis and nucleophilic addition of methoxide to alkenyloxiranes, which is efficiently applicable to construction of C8-C9 stereogenic centers of 1 and 4. We have planned to synthesize 1 and 2 by coupling of the phosphoric ester 5 with the readily available glutalimide 6 and the sulfone 7, using Horner-Wadsworth-Emmons reaction or Julia-Kocienski reaction. In this symposium we would like to describe the synthesis of the key intermediate 5 carried out starting with 8 in 21 steps, using palladium-catalyzed methodologies for the acyclic stereoselections as key reactions.

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Saxitoxin (STX) (1) and its derivatives are known to be neurotoxins that block the voltage-gated sodium channels, which are critical for depolarization and conduction in most excitable cells. STX (1) also binds to other receptor proteins, such as calcium and potassium channels, and appears to be of considerable biological importance. We have recently achieved an enantioselective total synthesis of (-)-doSTX (2). Herein, we described an enantioselective total synthesis of (+)-STX (1) with an improved synthetic method. Our synthesis of (-)-doSTX (2) features direct oxidation with o-iodoxybenzoic acid (IBX) at the α-position of the β-amino-substituted ketone, which was synthesized based upon the 1,3-dipolar cycloaddition reaction between methyl crotonate (6) and the chiral nitrone 5. In this synthetic study, we used the nitro-olefin 12 as a dipolarophile instead of the corresponding α,β-unsaturated ester to simplify the introduction of C5-nitrogene group. The 1,3-dipolar cycloaddition reaction of chiral nitrone ent-5 and nitro-olefin 17 gave 5-nitro-isoxazolidine 18 quantitatively. The chemoselective reduction of NO_2 group to NH-OH at C5 in the presence of N-O bond in the isoxazolidine ring was succeeded by treatment with Zn-AcOH condition. The nitrogen atom in NH-OH group of 21 was then protected with Cbz group, followed by reduction of two N-O bonds using TiCl_3 and Zn gave 2,3-diamino-1-alcohol 26. After several conversions, 13-carbamoyl-guanidinealcohol 37 was in hand. The completion of a formal total synthesis of (+)-STX (1) was achieved by treatment of 37 with B(OCOCF_3)_3 and gave β-saxitoxinol (38) in total 14 steps 4.5% yield.

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Copper catalyzed enantioselective conjugate addition of enones in the presence of chiral phosphorus ligand is a current topic in organic chemistry. Various mono- and multidentate chiral phosphorus ligands have been extensively studied as the chiral auxiliary for the reactions. As the results, it has been reported that many phosphorus ligands can be successfully applied to the reactions of cyclic enones, while a relatively small number of chiral ligands are effective for the reactions of acyclic enones. We expected that a P,O-ligand such as 1, which can seize both the copper and zinc species, could serve as an effective chiral auxiliary for copper-mediated asymmetric conjugate addition of alkylzinc to enones. We first examined the addition of ethyl group to acyclic enones using diethylzinc in the presence of copper complex of 1. Among these ligands, 1c having n-butyl group showed the best enantioselectivity. Interestingly, high enantioselectivities were observed in the reactions in polar solvents and, in particular, the reaction in N,N-dimethylformamide (DMF) showed excellent enantioselectivity of >99% ee together with good yield. Next we examined the addition of methyl group to acyclic enones using trimethylaluminium as nucleophile. Although poor enantioselectivity was obtained by using 1c, high enantioselectivity up to 98% ee was obtained by using the modified ligand 2 bearing o-methoxyphenyl group as the C3' substituent. Asymmetric syntheses of bisabolane terpenoid were achieved by using newly developed asymmetric conjugate addition of trimethylaluminium to enone 3 as a key reaction. These results will be discussed in more detail.

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Stereoselective construction of cyclic ethers is one of the major problems in the synthesis of fused-polycyclic ether marine toxins. We have explored a new method for the synthesis of vinyl-substituted tetrahydropyrans by metal-mediated cyclization of hydroxy allenes. Hydroxy allenes 6, 7, 13, and 14 were synthesized by reactions of aldehyde 1 with chromium reagents prepared from 3-trimethylsilylpropargyl bromide or 1-bromo-2-butyne and chromium (II) chloride. Treatment of δ-hydroxy allenes having an oxygenated substituent at the α-position with silver and mercuric salts produced vinyl-substituted tetrahydropyran derivatives in fairly good yields. Yield and stereochemistry of the products were highly dependent on both metal salt employed and the stereogenic center at the α-position. Silver perchlorate induced the cyclization of 6 to give 8 as a single isomer, whereas cyclization of its diastereomer 7 provided a mixture of products 9 and 10. This silver-mediated cyclizaion was further applied to the synthesis of methyl and vinyl-substituted tetrahydropyrans. Cyclizations of hydroxy methyl-substituted allenes 13 and 14 by silver salts were less effective. The best results were obtained by using mercuric triflate to give 15 from 13 as a single isomer and a mixture of 17 and 18 from 14. Iterative application of this silver-mediated cylization to 8 enabled the synthesis of trans-fused tricyclic ring system 23. Moreover, the 6-membered E ring of gambierol, a neurotoxin isolated from culture cells of Gambierdiscus toxicus, was constructed by silver-mediated cyclization of hydroxy allene 27.

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(1) Stereoselective Synthesis of Conjugated Dienes by Cross Coupling Reaction The regio- and stereoselective synthesis of trisubstituted alkenes remains one of the more troublesome problems in organic synthesis. One very attractive approach to stereodefined trisubstituted alkenes is the stepwise double substitution of readily available 1,1-dihaloalkenes by organometallic reagents in the presence of a transition-metal catalyst. Recently, Negishi and co-workers reported that palladium complex, such as Pd (PPh_3)_4 successfully catalyzed various disubstitutions of 1,1-dihaloalkenes. Stereoselective arylation/alkylation and alkynylation/alkylation sequences were accomplished with organozincs in the presence of the foregoing catalyst. and the desired compounds were obtained in good to excellent yield. This group also reported that steteroinverted alkylations might occur in the second step when utilizing certain dihalogenated compounds. Herein, the successful results of these studies are reported. wherein a stereoselective methylation with dienylbromide 8 has been developed Pd catalysts without isomerization. The reaction of dienylbromide 8 with 2 eq of Me_3Al in the presence of 5mol% Pd_2(dba)_3CHCl_3 and 20mol% tricyclohexylphosphine produced in high yields methylated compounds 9, that were >95% E,E. (2) Synthetic study of Spirofungin A using Pd catalyst Spirofungin A is a polypropionate-type antibiotic isolated from Streptomyces violaceusniger Tu 4113. Retrosynthetic fragmentation of spirofungin A affords three segments. We have already synthesized the segment A and B. Segment C was synthesized from (Z)-2-butene-1,4-diol in 9 steps. Finally, dibromoolefin 18 was coupled with the segment C by Suzuki-Miyaura coupling to afford the desired (Z,E)-diene 19. And the methylation of the diene 19 using Me_3Al and Pd(PPh_3)_4 catalyst was obtained desired (E,E)-diene 20 without alkene stereoisomerizaion.

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Zaragozic acids (squalestatins), a family of structurally related fungal metabolites isolated from different organisms by three independent groups in 1992, have been found to be potent inhibitor of squalene synthase and farnesyl-protein transferase. These compounds share a common highly oxygenated hydrophilic core and differ in two lipophilic side chains (e.g., zaragozic acid A (1)). A number of reports for synthesis of them was reflected their unique structures and biological activities. The most characteristic feature of them is the 2,8-dioxabicyclo[3.2.1]-octane core bearing six contiguous chiral carbon atoms. Total syntheses of zaragozic acids have been reported, however, various synthetic approaches are investigated continuously. Here we would like to report a new synthetic route for construction of the core moiety of zaragozic acids from furan derivative. This synthesis involves two crucial steps of regio- and stereoselective introduction of oxygen functionalities into C(3), C(4), C(6) and C(7) position on 7-oxabicyclo[2.2.1]hepta-2,5-diene derivative 5 (Scheme 1) and one-pot Grob fragmentation-reduction-iodo acetalization reaction of 7-oxabicyclo[2.2.1]heptane 20 to give 2,8-dioxabicyclo[3.2.1]-octane ring system 23 (Scheme 3). Enantioselective syntheses of the important intermediate (-)-8 by use of hydrolysis of symmetrical diester 6 with pig liver esterase (PLE) to give 26 and of side chain moiety 34 were also achieved as shown in Scheme 4 and Scheme 5, respectively.

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13-Oxyingenol (1) and ingenol (2) are diterpenoids isolated from the plants of Euphorbia sp. They and their analogs have interesting bioactivities. Particularly, 13-oxyingenol derivatives such as RD4-2138 have a strong anti-HIV activity. The structural features of ingenol and 13-oxyingenol are a high degree of oxygenation and a highly strained inside-outside bicylcic ring system. The molecular complexity of ingenol derivatives, in conjunction with their potent biological activities, has made them attractive synthetic targets. We planed the synthesis of 13-oxyingenol (1) by using ring-closing olein metathesis strategy. The starting point for this work was the construction of the β-ketoester 3 from 2-(4-hydroxyphenyl)ethanol. We stereoselectively introduced the methyl group to C-11 by using diastereoselective hydrogenation, to give β-ketoester 3 with desired stereochemistry. Then, we achieved the construction of the full carbon framework of 13-oxyingenol by using intramolecular spirocyclization and ring closing olefin metathesis as key steps. Further approach to 13-oxyingenol is currently underway in our group and will be reported in the symposium.

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Anthocyanins are resposible for most flower colors, from red through purple to blue. Nowadays, anthocyanins are attracting attention not only as a food colorant, but also for nutritional and medicinal usages. Furthermore, the pigments are expected as solar-cell devices. In spite of numerous chemical and biological researches for anthocyanin, only a few of synthetic methods have been reported until now. One is a Robinson's aldol condensation method in the early period of the 20^<th> century. However, the yield was sometimes low because of the drastic reaction condition at the final step. Thus, this method may be not applicable for synthesis of acylated anthocyanin. The other is the metal-reduction of flavonol glucoside. Though several reduction from rutin to the corresponding anthocyanin were attempted, the yield and reproducibility were low. To expand the possibility of anthocyanin science, we have been studied on synthesis of anthocyanin by development of the new methodologies. Our methodologies are two; the first is metal reduction on basis of new concept, the second is a biomimetic oxidative synthesis via flavenol glucoside as a key intermediate. By the first method, using a newly synthesized kaempferol 3-O-6"-O-acetyl-β-D-glucoside derived from phloroglycinol, a first total synthesis of pelargonidin 3-O-6"-O-acetyl-β-D-glucoside, an acylated anthocyanin of magenta-colored Verbena flowers, was succeded. By the second method, cyanidin and delphinidin glycosides have been synthesized via the corresponding flavenol glucosides in good yield.

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Salinosporamide A (1), a potent 20S proteasome inhibitor, was first isolated from marine actinomycete Salinospora tropicana by Fenical and colleagues in 2003. The β-lactone-γ-lactam bicycle structure is very similar to that of omuralide (2), a well-known potent 20S proteasome inhibitor derived from lactacystin (3) and first discovered by us in 1991 as a result of microbial screening for nerve growth factor-like activity. The proteasome inhibitory activity of 1 is approximately 35 times greater than 2; thus indicating that it is a strong candidate for development of new anticancer drugs. Indeed, related compounds are currently in clinical trials for the treatment of cancer. This biological profile and its structural complexity have prompted substantial efforts for the total synthesis of salinosporamide A (1). Herein, we report the total synthesis of salinosporamide A (1). The outstanding feature of our synthetic route is the stereoselective construction of the cyclohexene ring by controlling the C5 and C6 stereogenic centers through a chelation-controlled aldol reaction as a crucial reaction in an early stage of the total synthesis. This strategy differs from total syntheses previously reported. Other important features of our total synthesis include enzymatic desymmetrization, intramolecular aldol reaction, and intermolecular Reformatsky-type reaction followed by 1,4-reduction.

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1. Total Synthesis of Stemonamides Stemonamide (1), stemonamine (2), isostemonamide (3), and isostemonamine (4) were isolated from the roots of Stemona japonica, which have been used as Chinese and Japanese folk medicine. Herein, the total synthesis of stemonamide and related alkaloids based on the radical cascade as a key step is described. Radical precursor 6 was readily prepared from 1,2-cyclopentanedione 5. Treatment of 6 with Bu_3SnH/ACN (1,1-azobiscyclohexanecarbonitrile) caused radical cascade involving 7-endo-trig/5-endo-trig cyclization to afford the mixture of tricyclic compounds 7 and 8 (1:1). The mixture of tricyclic compounds 7 and 8 was converted to α,β-nusaturated ketones 9 as the by aldol condensation with benzaldehyde. Addition of lithium ethyl propiolate to α,β-nusaturated ketones 9 afforded compounds 10 and 11 in 50% and 48% yields, respectively. Synthesis of stemonamide (1) and isostemonamide (3) was accomplished by elaboration of compounds 10 and 11 including construction of methyl tetronate moiety, oxidative cleavage of olefin, and introductions of the methyl group and double bond, respectively. Stemonamine (2) and isostemonamine (4) were synthesized from stemonamide (1) and isostemonamide (3) by selective reduction of lactam via thioamidation. 2. Total Synthesis of (-)-Cephalotaxine Cephalotaxine (20), which was isolated from Cephalotaxus harringtonia, has attracted much attention from many chemists due to a combination of its fascinating pentacyclic structure and the antileukemic activity of its ester derivatives such as harringtonine (21) and homoharringtonine (22). Herein, a very short synthesis of (-)-cephalotaxine using the same radical cascade strategy is described. Radical Precursor 30 was readily prepared form known compounds 28 and 29. Treatment of 30 with Bu_3SnH/ACN caused radical cascade involving 7-endo-trig/5-endo-trig cyclization to afford a pentacyclic compound 31. After the removal of silyl groups of compound 31, the resulted diol 32 was oxidized to afford diketone 33. Synthesis of (-)-cephalotaxine 20 was accomplished by selective O-methylation of diketone 33 followed by reduction of two carbonyl groups.

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We reported a variety of natural steroidal glycosides originated from Solanum plants, and the steroidal glycosides containing a chacotriose (α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranose) at the oligosaccharide moiety exhibit most potent anti-cancer and anti-herpes activities. In order to investigate the structure-activity relationships of the aglycone parts of chacotriosides, we planed to develop a synthesis method for chacotriosyl glycosides having various aglycones. At first, the protected chacotrioside 4 was synthesized from D-glucose and L-rhamnose in 5 steps 19% yield. Next, some chacotriosyl donors were synthesized from 4, and were glycosylated to some aglycone moieties (diosgenin, cholesterol, cholestanol, glycyrrhetic acid, digitoxigenin) to afford corresponding α- and β-chacotriosyl glycosides (12α-15β). In the process, it was revealed that β-glycosides could be afforded predominatly by using phosphite donor 5, while α-glycosides were obtained mainly by using a trichloroacetimidate donor 6. In addition, allyl chacotrioside 16 was simply converted to various types of double-chain neoglycolipids that mimicked glycosyl ceramides in 3 steps. In cytotoxicity tests using A549, HepG2, RAW and LLC-PK1 cell lines, chacotriosyl glycosides containing cholesterol and cholestanol at the aglycone part exhibited potent activities as same as dioscin 7 and 5-FU. Compared with the form of glycosidic bond (α/β) possessing the same aglycone, the β-glycoside tended to show more potent effect rather than α-glycoside. Furthermore, only chacotriose moiety and aglycone parts did not exhibit activity. Among these obtained chacotriosyl glycolipids, only glycolipid 24 exhibited the potent activity as same as dioscin.

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(-)-Talaumidin (1), a 2,5-diaryl-3,4-dimethyltetrahydrofuran lignan, isolated from Brazilian Aristolochia arcuata Masters, showed significant neurite outgrowth promoting and neuroprotective activates in the primary cultured rat cortical neurons and NGF-mediated PC12 cells. Among a number of lignans, recently, 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans have attracted considerable attention from synthetic chemists and biochemists due to their structural diversity and biological activity. While talaumidin (1) possesses the four continuous stereogenic centers existing on a tetrahydrofuran ring, there are the possible eight diastereoisomers for 1. From a synthetic point of view, it is attractive not only to stereoselectively construct the four consecutive chiral centers, but also to prepare stereoisomer libraries which would provide useful information on the structure-activity relationship of 1. In this symposium, we report our independent synthetic studies on (-)-talumidin (1) and its stereoisomers 1a-1g and their neurotrophic activities in rat primary cultured cortical neurons and PC12 cells. Asymmetric synthesis of (2S,3S,4S,5S)-1 was established by the three key steps; the anti-selective Evans aldol reaction, the diastereoselective hydroboration, and the stereoselective Friedel-Crafts reaction. The stereoisomers 1a, 1b and 1c were also synthesized from commom intermediate 14. (2S,3S,4S,5R)-1a was derived from dihydrofuran 15 by the catalytic regioselective dehydrogenation. Reduction of hemi-acetal 16 with NaBH_3CN and BF_3-OEt_2 gave rise to (2S,3S,4R,5S)-1b. Furthermore, (2S,3S,4R,5R)-1c was synthesized from diol 17 by the Mitsunobu reaction with unusual stereochemistry. On the other hand, synthesis of (2S,3R,4S,5R)-1e bearing 2S, 3R configuration on the tetrahydrofuran ring was accomplished by using the syn-selective Evans aldol reaction as the first step, followed by the catalytic regioselective dehydrogenation as the final step. The neurotrophic activity of the prepared stereoisomers was evaluated for neurite-outgrowth of NGF-mediated PC12 cells. As results, it was found that 1 and 1a showed comparative neurotrophic activity. Interestingly, 1e having all cis substituents exhibits more potent activity than 1.

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In modern organic synthesis, the Suzuki-Miyaura coupling has been extensively utilized in the synthesis of structurally complex natural products and pharmaceuticals due to the powerful C-C bond forming ability, mild reaction conditions, and compatibility with virtually all functional groups. Although aryl and alkenyl halides and their triflate counterparts are generally used as an electrophilic component in the Suzuki-Miyaura coupling, α-heteroatom substituted alkenyl halides and triflates, potentially useful precursors for the synthesis of heterocycles, are difficult to prepare and handle because of their inherent instability. During the course of our synthetic studies on marine polycyclic ether natural products, we found that lactone-derived enol phosphates are stable enough for isolation/purification and are sufficiently reactive under the Suzuki-Miyaura conditions to yield cross-coupled products in high yields. Our continuous efforts to broaden the scope of the alkenyl phosphate-based palladium chemistry have culminated in the development of several efficient methods for the synthesis of heterocycles such as dihydropyrans and indoles. Here we report the total synthesis of cytotoxic marine metabolites, attenols A and B and (+)-neopeltolide, exploiting our recently developed strategy for the synthesis of dihydropyrans based on a sequential Suzuki-Miyaura coupling/ring-closing metathesis.

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When ether 1 and a catalytic amount of Rh_2(tfa)_4 (tfa=CF_3CO_2-) were heated in toluene, dihydropyran 2 was produced in good yield. The ring closure proceeded in a highly regioselective manner, and the isomeric five-membered product 3 was not detected at all. This reaction most likely involves the cleavage of benzylic C-H bond in the substrate and the subsequent ring closure between the resulting benzylic cation and vinyl-Rh species, which was supported by an experiment with D-labled substrate 4 (Scheme 1). Table 1 shows more examples of this transformation. Benzyl ethers having an electron-rich aromatic ring appear to gain better product yields (entries 1-5). Sulfonylacetylenes having a Ms or Tf group entered the reaction as well, to give the desired products (entries 6 and 7). Another synthetically useful aspect of this cyclization is that highly diastereoselective ring closure is viable as can be seen in entries 8-12. The above stereoselective synthesis of substituted dihydropyrans was readily applied to that of (±)-centrolobine (11), a fundamental member of naturally occurring cis-2,6-disubstituted tetrahydropyrans, as shown in Scheme 2. The synthesis started with aldehyde 5, which was propargylated with a titanium reagent and then p-methoxybenzylated under acidic conditions to give 7. The sulfonylation of 7 was carried out by a two-step sequence to give 8, the Rh-catalyzed cyclization of which afforded the desired product 9 in good yield and with high diastereoselectivity. After the sulfone moiety in 9 was removed, the reduction of the olefin and hydrogenolysis of the benzyl ether at the same time completed the synthesis of (±)-centrolobine (11).

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Chemo-enzymatic routes for naturally occurring bioactive products as well as chiral derivatizing reagents were developed in three examples. Firstly, (R)-3-hydroxy-3-methyl-5-hexanoic acid p-methoxybenzyl ester was prepared by carbon-chain elongation on the both termini of the starting material, (R)-3-benzyloxy-2-methylpropane-1,2-diol, which was prepared by an overexpressed Bacillus subtilis epoxide hydrolase-catalyzed enantioselective hydrolysis of the racemic 1-benzyloxymethyl-1-methyloxirane. One of the key steps of the requisite transformation was the Rhodococcus rhodochrous-mediated hydrolysis of cyano to carboxyl group under neutral conditions, to exclude any racemization of the intermediate and/or product. The enantiomerically pure form of (R)-hydroxy ester was applied to a new formal total synthesis of taurospongin A. Secondly, while the first total synthesis of modiolide A, a ten-membered ring lactone with a marine-origin was achieved, an important chiral building block for constructing the chirality at C-4, (S)-6-[(4-methoxybenzyl)oxy]-1-trimethylsilyl-1-hexyn-3-ol was obtained in as high as 96.1% ee. Asymmetric reduction of the corresponding silylated propargyl ketone mediated by whole-cell of Pichia minuta was established. The ee of the resulting alcohol was further enhanced by applying Pseudomonas cepacia lipase-catalyzed resolution. Thirdly, the synthesis of TBMB carboxylic acid, a chiral derivatizing agent with a characteristic quaternary acetal chiral center, based on enzyme-catalyzed asymmetric reduction of an aromatic trifluoromethyl ketone is presented. Among the possible four diastereomers of key intermediate, cultured cells of a fungus, Geotrichum candidum provided only two enantiomers, in the reduction of the substrate. Furthermore, Candida antarctica lipase B discriminated the remote chiral center on the occasion of the hydrolysis of corresponding acetates. The resulted stereochemically pure alcohol was derived to (S)-TBMB carboxylic acid.

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Epimerization of green tea catechins at C-2 position during the sterilization step has been studied. It was reported that these catechin epimers have more biological activities than the original catechins. Until now degradation and polymerization of catechins by oxidation couldn't be avoided in epimerization condition. Therefore we started to develop novel efficient method (s) to prepare the catechin epimers. Although it reported that catechin epimers was hardly obtained in pH 7 condition, we succeeded in epimerization of catechins to give catechin epimers in 55% yield respectively by introducing N_2 gas into the catechins buffer solution (pH 7) at 80℃ in. Furthermore, we also succeeded in isomerization of catechins in strong acidic condition in 1% H_2SO_4/ROH in which protonation at oxygen in ether ring promote the epimerization catechins. Such acidic isomerization with H_2SO_4 were especially useful for gallate-type catechins such as EGCg or ECg in 70% yield. Each theaflavins, one of the major black tea pigments, also gave only one corresponding epimers in weak alkaline condition (pH 8, 100℃). The structure was determined to be (10) by preparations of possible four isomers from catechins.

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10-Isocyano-4-cadinene (1), a marine sesquiterpene isolated from nudibranchs of the family Phyllidiidae by Okino et al., exhibits potent antifouling activity against the larvae of the barnacle Balanus amphitrite (EC_<50> 0.14μg/mL). 10-Isocyano-4-cadinene (1) is expected to be new nontoxic antifouling agents. Furthermore, the absolute stereochemistry of 1 has not been determined. To access these issues, we started the enantioselective total synthesis toward 1. The synthesis toward 1 was commenced with known imide 6, which was converted into dieneacetate 5c in 9 steps. The Diels-Alder reaction between 5c and methyl acrylate with MeAlCl_2 afforded cyclohexene 11c as a mixture of four diasereomers. This mixture was epimerized to two isomers, desired carboxylic acid 12 as a major product and ester 13, by the treatment of NaOMe followed by selective hydrolysis with 1N HCl in one-pot. Carboxylic acid 12 was transformed into aldehyde 14, which was cyclized by SmI_2-induced Barbier-type reaction to give alcohol 15. To introduce the functional groups at C10, homologation of 15 with TosMIC afforded aldehyde 16, which was treated with t-BuOK and 21 to give MPM ether 22 in stereoselective fashion. Wolff-Kishner reaction followed by Curtis rearrangement of 24 gave isocyanate 25, C10 was fully functionalized. Total synthesis was completed by reduction of isocyano group with NaBH_4 and dehydration with POCl_3. The absolute configuration of 1 was determined as (1R, 6R, 7S, 10R) by the comparison with the optical rotation between natural and synthetic samples.

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Prorocentin, isolated from dinoflagellate Prorocentrum lima by Lu et al., exhibits inhibitory activity against some human cancer cell lines [IC_<50>: 16.7μg/mL (DLD-1); 83.6μg/mL (RPMI7951)] and possesses an unique polyether structure, featured by a [6,6]-spirocyclic acetal fused with an oxane ring (BCD-ring), an epoxide (A-ring), a five membered ether (E-ring), and a side chain including a conjugated triene group. Although the absolute configuration of prorocentin has not yet been determined, its biological and structural features make it an attractive synthetic target. Thus, a project toward the total synthesis of prorocentin aiming at determination of the absolute stereochemistry has been commenced. The partial relative stereochemistry of prorocentin was proposed by Lu et al. from their intensive NMR experiments, and a possible stereostructure was also shown as 1 in their report. Therefore, we first elucidated a synthetic plan for prorocentin based on the stereochemistry of 1. At the final stage in the synthesis, assembly of 1 from dienyl boran 2 and iodoalkene 3 via a Suzuki-Miyaura coupling followed by removal of TBS group and the simultaneous epoxide formation is intended. Iodoalkene 3 would be derived from C8-C35 segment 4 in a few steps including Takai olefination and protective group manipulation. So far, we have synthesized segments 2 and 4, and examined the above transformation processes (4→3 and 3+2→1) in a model system. Details of the synthesis of 4, based on 6-endo Utimoto cyclization to create the B-ring and intramolecular double conjugate addition to produce the CD-ring, and the model experiments will be described in the poster session.

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The polyketide derived marine natural product thiomarinols, isolated from the bacterium Alteromonas rava sp. nov. SANK 73390, were found to exhibit potent antimicrobial activity. We report here the total synthesis of thiomarinol A (1), which had been successfully converted to thiomarinol B (2) by Sankyo group. Diastereoselective construction of the tetrahydropyran moiety, a common structural unit of the thiomarinols, with four contiguous stereogenic centers was achieved efficiently employing the oxy-Michael reaction under both anionic and high-pressure conditions. After assembling the 4-hydroxymonic acid segment, it was condensed with the pyrrothin chromophore and the 7-hydroxyoctanoic acid moiety to provide the protected thiomarinol A (1), which was treated with hydrochloric acid to give thiomarinol A (1). Spectral properties of the synthetic thiomarinol A were identical with those for the natural product.

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Bromomethylthioindoles MC 5-8 are isolated from Laurecia brongniartii as the most potent anti-MRSA substances in red algae. We are interested in the total synthesis of these compounds from the viewpoints of synthetic structural elucidation for the natural products and the structure-activity relationship. Preceding the total synthesis, we developed the introduction methods for 2, 3-disubstituents of the natural products (MC 5-8). The C^3-selective introduction of a methylthio group to unprotected indoles are developed via the C^3-dimethylsulfonium salt of indoles using a DMSO・TFAA complex. The sulfonium salts were easily de-methylated to 3-SMe indoles by refluxing in dipropylamine. It is a new synthetic method for 3-SMe indoles without using stinky thiols in excellent yields. The C^2-selective introduction of dimethylsulfonium or bromo group to 5-NO_2 or 1-Ts 3-SMe indoles are achieved, although 3-SMe indole itself caused dimerization. On the basis of the above findings, we succeeded the first total synthesis of MC 7 and MC 8 as follows. 1) Regio-selective synthesis of C^4-C^6 poly-brominated indoles 21. 2) Introduction of methylthio group into C^3-position of indoles without using stinky thiols. 3) Electrophilic substitution at C^2-position of 3-methylthioindoles 23. The synthesized MC 7, MC 8, and some synthetic intermediates showed potent anti-microbial activities against MRSA. Furthermore, we founded these compounds has potent anti-VRE activities.

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NKT cell is categorized as the fourth class of immunocytes, which has both NK and T cell receptors (TCR). CD1d is one of the surface proteins of antigen presenting cells. When NKT cell is activated by recognizing the complex of α-glycosylceramide-CD1d with its TCR, NKT cell can produce both Th1 (immunostimulatory) and Th2 (immunosuppressant) type cytokines in large quantities. In 1995, researchers at Kirin Brewery Co. developed KRN7000 (2), which is an analogue of agelasphins (main component is agelasphin-9b, 1) as the anticancer drug candidate. However, KRN7000 induces both Th1 and Th2 cytokines at the same time by single injection. Th1 and Th2 type cytokines can antagonize each other's biological function, and therefore use of KRN7000 for clinical therapy is limited. To circumvent this problem, we developed a new analogue, RCAI-61 (25c), which is a 6-O-methylated α-galactopyranosyl analogue of KRN7000. RCAI-61 could be easily synthesized by galactosylation of ceramide (23) with 6-O-methylated galactopyranoside intermediate (22c), which could be synthesized from commercially available methyl α-D-galactopyranoside (9). According to bioassay (mouse, in vivo), RCAI-61 was found to be a potent inducer of Th1 type cytokine production such as IFN-γ.

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Botcinolide (1) was isolated from culture broth of Botrytis cinerea as a significant phytotoxic metabolite in 1993 by Cutler et al. The relative configuration of 1 was suggested based on the spectroscopic analysis by the same group. In 1996, Collado et al. isolated other metabolites from B. cinerea (strain UCA 992) related to 1 named 4-O-methylbotcinolide (2), 3-O-acetyl-5-O-methylbotocinolide (3), 2-epibotcinolide (5), and 3-O-acetyl-2-epibotcinolide (6). In the same year, homobotcinolide (4) was also isolated from B. cinerea by Cutler. After one decade, Nakajima et al. obtained metabolites botcinic acid (7), botcinin E (11), and botcinin A (12) from the culture filtrate of a different strain of B. cinerea (strain AEM 211) and some of them showed antifungal activity against Magnaporthe grisea, a pathogen of the rice blast disease. Nakajima first assigned their forms and later reported that the structure of botcinolide (1) should be revised to that of 7, the structure of 4-O-methylbotcinolide (2) should be revised to that of botcinic acid methyl ester (8), and the structure of 3-O-acetyl-2-epibotcinolide (6) should be revised to that of 12. They also expected that the structures of 3-O-acetyl-5-O-methylbotcinolide (3), homobotcinolide (4) and 2-epibotcinolide (5) should be revised to those of 3-O-acetylbotcinic acid methyl ester (9), botcineric acid (10), and 11, respectively, based on the studies of the chemical conversion of the botcinic acid derivatives and comparison of their spectroscopic data. Recently, we have established methods for the syntheses of botcinins C (13), D (14), and F (15), and the proposed structure of 2-epibotcinolide (5) by the stereoselective aldol reactions and a rapid lactonization using MNBA. We concluded that the reported nine-membered ring structures of 2-epibotcinolide (5) and other related compounds are extremely doubtful based on the detailed comparison of the ^1H NMR spectrum of the synthetic intermediates with natural products. In this presentation, we will show the first total synthesis of the botcinic acid analogues (7-10) and botcinin E (11) which have updated the proposed structures of botcinolides (1-5) in order to show the true forms of these natural products.

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Although microwave irradiation has been used in chemical reactions as an efficient heating tool since 1986, we have found that microwave also contribute other factors while studying carbohydrate-related syntheses. 1) With microwave irradiation under Lewis acid conditions, methyl glycosides could behave as glycosyl donors. 2) In a case of synthesis Lewis X, microwave irradiation even at low temperatures was very effective as reducing byproducts and side-reactions. Especially, galactosylation for 4-OH in a fucosyl glucosamine acceptor has proceeded in high yield without producing byproducts, e.g., cleavage of the fucosyl bond or nucleophilic rearrangement of methylthio group. 3) Based on a preliminary study of microwave effect for coupling Fmoc-threonine having acetylated-Core2 to alanine onto supported resin, we successfully synthesized oligopeptide which consisted of twenty of amino acid residues with five of trisaccharides, a partial structure of MUC1 glycoprotein, in shorter time and higher yields. In addition, we also revealed that benzyl protection of glutamic acid was not suitable for basic microwave condition. 4) Microwave could activate azido groups and resulted to accelerate reductions by PPh_3 and Staudinger Ligations.

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Ozone is one of the simplest, economical, clean and efficient oxidation agents thereby widely utilized in various fields. Also in the field of organic synthesis, ozone is quite important agent, especially for the oxidative cleavage of carbon-carbon double bond which is well recognized as a "textbook reaction". On the other hand, addition-type oxidation of alkene is also important transformation in organic synthesis, however utilization of ozone for this purpose has been severely limited. To this end, we recently found that ozone oxidation of alkenylsilane 4 provides α-silylperoxy aldehyde or ketone 5 via addition-type oxidation. Thus obtained silylperoxides 5 can serves as a versatile precursor for polyol derivatives and acyloin compounds. For example, the silylperoxy moiety of 5 can be converted to silyl ether or carbonyl group by treatment with reducing agent or base, respectively. On the other hand, nucleophilic addition reaction of carbonyl group on 5 proceeds with the preservation of peroxide moiety in good to excellent diastereoselectivity. Detailed mechanism of the oxidation, its scope and limitation together with further synthetic elaboration of silylperoxides 5 will be presented.

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Overman rearrangement is a [3,3] sigmatropic rearrangement of an allylic trichloroacetimidate, readily prepared from an allylic alcohol, and is a powerful method for the construction of a tetra-substituted carbon with nitrogen and a 1,2-diamine structure in a stereo-controlled manner. Meanwhile, sugars and tartrates are useful starting materials for the natural product synthesis as they are inexpensive, readily available and have several chiral centers. We herein report the syntheses of salinosporamide A starting from D-glucose, and A-315675 from D-tartrate utilizing the Overman rearrangement as the key transformations. Salinosporamide A (1) was isolated from marine bacterium, shows potent proteasome inhibitory activity. Overman rearrangement of 11, derived from D-glucose, afforded amide 12 in good yield with moderate stereoselectivity. This was transformed into 13. Oxidation of 13, followed by protection, afforded γ-lactam 16, which was treated with cyclohexenyl zinc reagent to afford 17. Removal of the Bn, Cbz, and TMS protecting groups gave Corey's intermediate 18, representing the formal synthesis of 1. A-315675 (2) is a neuraminidase inhibitor developed by the Abbott laboratories. The characteristic 1,2-diamine moiety in 2 was stereo selectively constructed in one-step reaction by the cascade Overman rearrangement of vicinal allylic diol 24, derived from D-tartrate. Johnson-Claisen rearrangement of 24, followed by the lactam formation provided 29. Ozonolysis and subsequent epimerization afforded aldehyde 30 as a single isomer, whose Wittig reaction gave Z-propenyl compound 31. A-315675 (2) was totally synthesized via Hanessian's intermediate 32.

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