Danicalipin A (1), a major component of chlorosulfolipids (CSLs) from Ochromonas danica, was first isolated more than four decades ago along wigh its congeners 2-6. Although the planar structure of 1 was reorted in 1973, the absolute and relative stereochemistries of 1 have not been determined until 2009; total synthesis by Vanderwal and NMR analysis of natural sample by Okino. Due to the unprecedent structure of CSLs, CSLs have attracted much attention of synthetic chemists and total syntheses of 1, 7, and 8 were achieved by three groups. In this presentation, asymmetric total synthesis of Danicalipin A (1) will be described. The synthesis commenced with the known optically active epoxide 14, derived via Sharpless-Katsuki asymmetric epoxidation, which was transformed into the α,β-unsaturated ester 15. (Scheme 2) At this stage, the enantiomeric excess of 15 was enhanced from 85% ee to >99% ee by recrystallization. Four transformations involving regioselective epoxy opening reaction gave the aldehyde 13. After diastereoselective α-chlorination of 13 with 19, the aldehyde 10 was synthesized in 2 steps. Wittig reaction between 10 and the phosphonium salt 11, derived from the known aldehyde 12, afforded the alkene 24. E-olefin for the trans-dichloride at C15 and 16 was installed by Wiitg olefination, furnishing the α,β-unsaturated ester 26. After introduction of n-hexyl group from ester, trans addition of chlorine equivalent into E-olefin at 80℃ gave the adduct 29, which was successfully converted to Danicalipin A.

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Natural chlorosulfolipids that possess an unusual polychlorinated linear hydrocarbon motif have gained considerable attention due to their toxicological propertied (Figure 1). In quest for deeper knowledge of their risks and effects on human health, we initiated a research program that would allow us to chemically produce the lipids in sufficient quantities to facilitate biological investigations. In this presentation, we will disclose the asymmetric total synthesis of (+)-bexachlorosulfolipid (1), a toxic substance isolated from the Adriatic mussesl Mytilus galloprovincialis. 1. Stereospecific Multiple Chlorination of Epoxides Our initial effort was to establish a means for preparing chiral polychlorinated hydrocarbon motifs by nuclephilic chlorinaton reactions of readily available epoxides with N-chlorosuccinimide (NCS)/organophosphine reagents. The investigation led to the discovery that NCS/Ph_3P was best suited for this transformation and was applicable to various epoxides having eleborate structures to furnixh chiral polychlorides. 2. Asymmetric Total Synthesis of (+)-Hexachlorosulfolipid Our approach to (+)-hexachlorosulfolipid (1) features the use of the NCS/Ph_3P-mediated dichlorinations of epoxides. Installation of the vicinal dichloro functionality into chiral epoxide 7 (>98% ee) was successfully achieved using NCS/Ph_3P in toluene at 90℃ to afford dichloride 8 in 85% yield as a single isomer. Removal of the pivalic group of 8 followed by oxidation with Dess-Martin periodinane under buffered conditions delivered dichloroaldehyde 1, which was immediately reacted with allyltrimethylsilane in the presence of BF_3・OEt_2 to afford anti-chlorohydrin 9. Contrary to our expectations, all the efforts to make the desired all-syn chloro triad 11 from this alcohol by simple chlorination of the hydroxyl group were unfruitful due to the concomitant occurrence of elimination reactions. However, the epoxide-dichlorination method was again found to be suitable tor this process. Thus, dichloroalcohol 9 was first transformed into trans-epoxide 10 which, in turn, was subjected to dichlorination under Ph_3P/NCS conditions to furnish trichloride 11 in 70% yield. The stereoselective allylic hydreoxylation followed by olefin metathesis with 2-butene efficiently produced (E)-alkene 13 (E:Z = ca. 17:1). The Marko-Maguire dichlorination (KMnO_4/BnEt_3NCl/TMSCl) of this alcohol furnished desired (2R,3S)-pentachloride 18 as the majou product possessing all the requisite stereocenters relevant to the natural compound. Further simple transformations of peptachloride 18 eventually furnished (+)-hexachlorosulfolipid (1). The spectroscopic and analytical data of the synthetic compound were in good agreement wigh those recorded in the literature. The optical rotation of our material 1 was [α]^<24>_D+49 (c 0.59, MeOH)[lit. [α]^<25>_D +20.4 (c 0.0015, MeOH)], indicating that the absolute configuration of natural sulfolipid was as proposed by Ciminiello and Fattorusso.

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We have previously developed a highly stereoselective vinylogous Mukaiyama aldol reaction (VMAR) usin gvinylketene silyl N,O-acetal 1, which provides a unique and remarkable entry to a remote asymmetric induction. From a synthetic point of view, this method can directly afford th anti-δ-hydroxy-α,γ-dimethol-α,β-unsaturated carbonyl unit, which is seen in many naturally occurring products. In fact, VMAR has successfully been utilized in the total syntheses of various biologically active compounds by many groups including us. Se envisioned that the VMAR would be an efficient and powerful methodology for the synthesis of (+)-TMC-151C (2). This compound was isolated from Gliocladium sp. by the research group of Tanabe Seiyaku in 1999, and it shows the cytotoxicity to wide-rangingg tumor cell lines, such as HCT-116, B16 and HeLa. The structural significance as well as the biological property has stimulated the synthesis of TMC-151C (2). Herein, we report the first total synthesis of (+)-TMC-151C (2) using VMAR and Ring-Closing Metathesis (RCM) via a highly convergent synthetic route. Characteristic features of the present synthesis include: 1) the construction of C_1-C_5 segmetn and C_9-C_<13> segment was successfully achieved by VMAR, and 2) the stereoselective formation of C_6-C_7 double bond was accomplished by developing a unique E-olefin forming 8-membered RCM of silicon-tethered diene. Moreover, we observed a unique E-olefin forming 8-memberes ring RCM of silylene acetals, and proposed a plausible transition state as well as the structural requirement for E-olefin forming RCM. Although the E-olefin was produced only in a limited case, this methodology was quite useful for the total synthesis of TMC-151C (2).

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Aplyronine A (1) exhibits potent antitumor activity and actin-depolymerizing activity. In our previous studies, we investigated the structure-activity relationships of aplyronine A (1): the combination of a macrolactone and a side chain moiety is essential for the potent cytotoxicity of aplyronine (1). In addition, we determined the crystal structure of aplyronine A (1)-actin complex via X-ray analysis and obtained chemical evidence for the direct interactoion between actin and the side chain portio of aplyronine A (1) by photoaffinity labeling experiments. Mycalolide B (2) also interacts with actin in the same manner as aplyronine A (1). The actin-depolymerizing activity is stronger than that of aplyroine A (1). Because mycalolide B (2) possesses a similar side chain to that of aplyronine A (1), we expected a hybrid compound 3 consisting of the macrolactone part in aplyronine A (1) and the side chain part in mycalolide B (2) migt possess more potent actin-depolymerizing activity and cytotoxicity than aplyronine A (1). Herein we reort the synthesis and biological evaluation of a hybrid compound 3 of aplyronnine A (1) and mcalolide B (2). The C1-C19 segment 5 and the C20-C34 segment 6 were synthesized from segments 7 and 8, 9 and 10, respectively, by an asymmetric NHK reaction as a key step. Esterification reation between 5 and 6 under Yamaguchi conditions afforded compound 37, which was converted into a hybrid compound 3 by and intramolecular NHK reaction followed by the introduction of enamide, O,O-dimethyl-glyceric acid, and N,N,O-trimethylserine. A hybrid compound 3 showed more potent actin-depolymerizing activity than that of aplyronine A (1). However, the cytotoxicity of 3 against Hela S_3 cells was about 1000-fold weaker than aplyronine A (1).

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New labeling probes of fluorescenced and ^<68>Ga-DOTA, as the positron emission nucleus for PET, througn rapid 6π-azaelectrocyclization were designed and synthesized, (E)-ester aldehydes 1. The high reactivity of these probes enabled the labeling of lysine residues in peptides, proteins, and even the amino groups on the cell surfaced at very low concentration (-10^<-8>M) within a short recation time (-10min) to result in "selective" and "non-destructive" labeling of the more accessible amines. The first microPET of glycoproteins, ^<68>Ga-DOTA-orosomucoid and asialoorosomucoid successfully visualized the differences in the circulatory residence of glycoproteins, in the presence or absence of the sialic acids. New N-glycan clusters with MW of 50KDa were also developed and their in vivo dynamics, being affected significantly by their glycan structures, could be visualized through the present amine-labeling & PET and/or noninvasive fluorescence imaging. The azaelectrocyclization-based biocojugation is also applicable to the engineering of the proteins and/or the cell surfaces by the oligosacchrides; the chemically engineered lymphocytes by N-glycan sussessfully traget the tumor tissue implanted in the BALB/c nude mice, based on the noninvasive fluorescence imaging.

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TRAIL (Tumor ecrosis factor (TNF)-related apoptosis-inducing ligand) has emerged as an attrtactive anticaner molecule, because it can cause tomor-selective apoptosis. TRAIL is known to bind to death receptors, such as DR5 (death receptor 5), resulting in the activation of TRAIL signaling and leadint to tumor-selective apoptosis. However, it has become a problem that a number of cancer cells are resistant to TRAIL. Therefore, the activation of TRAIL pathway is very importan in drug discovery. In our search of bioactive antural products, we screened plant extracts collected in Thailand and Bangladesh by DR5 promoter activity assay and TRAIL overcoming activity assay for TRAiL signaling activators. DR5 promoter activity-guided fractionation of the extracts of Combretum quadrangulare (leaf) and Euphorbia neriifolia (lear) led to the isolation of sixteen new cycloartane triterpenes (1-9, 11-17) and a new ingol diterpene (18). Especially, 16 and 18 (2.2μM) enhanced DR5 expression 7.5 and 4.1-fold, respectively. TRAIL-resistance overcoming activity-quided fractionation of the extracts of Sida acuta (whole plants) and Amoora cucullata (leaf) led to the isolation of four new compound (21, 24-26) and several known compounds. Among them, 22 showed the most potent activity (IC_<50> with 100 ng/mL of TRAIL: 1.3 nM, IC_<50> without TRAIL: 18.8 nM). Compound 22 enhanced TRAIL-induced apoptosis through the activation of caspase-3/7, augmenting the expression of DR4 and DR5 in AGS cells.

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Amphotericin B (AmB, 1) is a polyene antibiotic that has been used for treatment of systemic fungal infections. It is generally accepted that an ion-permeable channel formed across cell membrane is responsible for the pharmacological activity of AmB, and higher affinity of AmB to ergosterol over cholesterol accounts for selective toxicity to fungi. A "barrel-stave" model has been most frequently discussed as its channel complex. Although many investigations on the channel structure have been carried out details of the structures are not fully understood. First we prepared ^<19>F-AmB (5) and ^<13>C-ergosterol (6) by chemical synthetic or biosynthetic methods. Then these labeled compounds were mixed with POPC and subjected to solid-state NMR measurements. ^<13>C{^<19>F}REDOR experiments successfully provided the evidence for direct molecular interactions between AmB and ergosterol. The experiments further indicated the presence of not only "head-to-head" but also "head-to-tail" interaction between AmB and Ergosterol. Especially, the latter interaction is the unexpected new finding. ^<13>C-ergosterol (6), however, gave some overlapping signals, which make it difficult to calculate the interatomic distance. Therefore, to estimate accurate distances between AmB and ergosterol in "head-to-head" and "head-to-tail" interactions, site specifically ^<13>C labeled ergosterols, 4-^<13>C ergosterol (9) and 26, 27-^<13>C_2 ergosterol (13), were prepared by chemical synthetic methods. Solid-state NMR experiments using these labeled ergosterols are now in progress, which will be also discussed.

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Since its discovery in 1950s, vancomycin has been used for the treatment of infections caused by Gram-positive bacteria including MRSA. Thus, the emergence of vancomycin-resistant bacteria (VREs and VRSAs) is the most concern today. In 1999 at this symposium, we reportetd preparation and activity evaluation of vancomycin polymer with antibacterial activity against VREs. This time, the novel vancomycin derivatives that exhibit potent antibacterial activities are described. Especially preparation of cyclic dimers, whose molecular conformation was restricted by installing another linker to the dimers, resulted in the important information to disclose "active conformation" of dimers. Biological assays were also conducted to clarify the mode of action of these compounds. In vitro semi-quantitative assay was established, giving new insight into the mechanism of vancomycin dimers. On the other hand, novel methodology of selective modification using Suzuki-Miyaura cross coupling reaction was developed. This discovery will contribute to the progress of vancomycin medicinal chemistry. To overcome infectious disease of vancomycin-resistant microorganisms, we think these results will lead to development of new drug candidates and discovery of new drug targets.

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Allosamidin 1, a secondary metabolite of Streptomyces, inhibits family 18 chitinases which are widely present in nature. Allosamidin has been used to study the physiological role of chitinases in a variety of organisms. With respect to its biological activity toward mammals, 1 attenuates asthmatic responses in asthma models of mouse. On the other hand, 1 dramatically promotes chitinase production and growth of its producing microorganism. 1 was released from the mycelia of allosamidin-producing Streptomyces by responding to chitin and strongly activated transcription of a gene encoding the main chitinase secreted to the culture broth through a two-component regulatory system in the presence of N,N'-diacetylchitobiose. This shows that 1 acts as a key signal molecule for chitinase production in its producing strains, which may be useful for their growth in chitin-rich environment. Effects of 1 and demethylallosamidin 2 on the activity of acidic mammalian chitinase (AMCase) and asthmatic inflammation were examined. 2 inhibited recombinant AMCase as strongly as allosamidin. In the mouse in vivo model of IL-13-induced asthma, both 1 and 2 decreased chitinase activity and eosinophils in BAL (bronchoalveolar lavage) fluid. Only 2, however, showed suppressive activity on airway hyperresponsiveness, suggessting that 2 may suppress IL-13-induced asthma more effectively than 1.

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4-Coumareate:coenzyme A ligase (4CL) plays a key role in phenylpropanoid metabilism, providing precursors for a variety of plant secondary metabolites such as flavonoids and lignin. The enzyme catalyzes formation of 4-coumaroyl-CoA by initial activation of 4-coumaric acid with ATP to form an acyl-AMP intermediate, which is followed by thioester bond formation with CoASH and the concomitant release of AMP. The activation of the carboxylate substrate with ATP to form the acyl-AMP intermediate is a common mechanism for other adenylate-forming enzymes, including fatty acyl-CoA synthetase, the adenylation domains of the modular non-ribosomal peptide synthetase, and firefly luciferase (the ANL superfamily enzymes). Here we report that 4CL from Arabiaopsis thaliana (At4CL2) shows remarkable substrate promiscuity and novel catalytic functions. First, it was demonstrated that, in the absence of CoASH, the enzyme catalyzed amide bond forming reactions by condensation of 4-coumaric acid and the amino group fo D- and L- amino acids. Second, the enzyme generated a variety of biologically active amides including homoserine lactones and capsaicin by coupling the corresponding acids and amines. Finally, unexpectedly, structure-based 4CL site-directed mutants, Y253F and Q345A, catalyzed formation of dipeptides from a series of amino acids in the presence of ATP. Thus, the CoA ligase was functionally converted to dipeptide synthetase by the single amino acid substitutions in the substrate binding pocket.

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Functional investigation of the proposed dehydratase(DH) domain of ATX, a 6-methiylsalicylic acid (6-MSA) synthase from Aspergillus terreus, revealed that the domain is not involved in dehydration of the β-hydroxy triketide intermediate tethered onthe acyl carrier proten (ACP) but catalyzes thioester hydrolysis to release the product from the ACP. Thus, we renamed this domain the thioester hydrolase (TH) domain. The intermediate bound to the TH domain of mutant H972A formed in the presence of NADPH was relased as 6-MSA by both the intact ATX and by THID (a 541 aa region containing TH domain and its downstream) protein, in trans. Furthermore, THID showed a caalytic activity to hydrolyze a model substrate, 6MSA-N-acetylcysteamine. The TH domain is the first example of a ptoduct releasing domain that is located in the middle of a multi-domain iterative type I polyketide synthase (iPKS). Moreover, it is functionally defferent from serine protease-type thioesterase domains of iPKSs.

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Fungal polyketide, known with structural deversity and various biological properties, are synthesized by iteractive type I polyketide synthase (PKS). We focused on the PKS which synthesizes emotion, ATEG_08451 in a filamentous fungi, Aspergillus terreus, here named "atrochrysone carboxylic acid synthase (ACAS)", is a non-reducing iterative type I PKS (NR-PKS) that does not contain Claisen cyclase/thioesterase domain (CLC/TE) domain. Because a CLC/TE domain is responsible for product release from NR-PKS, ACAS was predicted to have novel mechanism for product release. In vitro, reactions of ACAS wigh malonyl-CoA yielded a polyketide intermediate, probably attached to its acyl carrier protein (ACP). The addition of ATEG_08450, here named "Atrochrysone carboxyl ACP thioesterase" (ACTE), to the reaction resulted in the release of products derived from atrochrysone carboxylic acid, such as atrochrysone, endocrocin anthrone, endocrocin, emodin anthrone and emodin. Atrochrysone carboxyliic acid decarboxylates to yield atrochrysone, and dehydrates to yield indocrocin anthrone. Atrochrysone dehydrates to yield emodin anthrone. Endocrocin anthrone and emodin anthrone auto-oxidize to form endocrocin and emodin. ACTE, belonging to the β-Lactamase superfamily, thus appears to be a novel type of thioesterase responsible for product release in polyketide biosynthesis. These findings show that ACAS synthesizes the scaffold of atrochrysone carboxylic acid from malonyl-CoA and that ACTE hydrolyzes the thioester bond between the ACP of ACAS and the intermediate to release atrochrysone carboxylic acid as the reaction product.

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FD-891 is a 16-membered antibiotic macrolide, which is especially active against human leukemia such as HL-60 and Jurkat cells. In the present study, we found that FD-891 triggers caspase-8-dependent mitochondrial release of cytochrome c and subsequent qpoptosis in Jurkat cells. Also, the molecular target of FD-891 was found to be actin to inhibit the binding with actin-binding proteins on cell membrane causing aggregation of actin. We further identified the FD-891 biosynthetic (gfs) gene cluster from the producer Streptomyces graminofaciens A-8890 to prepare FD-891 analogs with biosynthetic technology. The identified gfs gene cluster contains five modular type I PKS genes (gfsA, B, C, D and E), a cytochrome P450 gene (gfsF) and a methyltransferase gene (gfsG). The gene organization of PKS agreed well with the basic polyketide skeleton of FD-891 indicating its involvement in the FD-891 boisynthesis. The gfsF and gfsG gene inactivation resulted in the loss of FD-891 production; instead, the gfsF gene disrupted mutant accumulated a novel FD-891 analog 25-O-methyl FD-892, which lacked an epoxide and a hydroxyl group of FD-891, and the gfsG gene disrupted mutant accumulated another analog 25-O-demethyl FD-891. Biochemical studies of the newly created FD-891 analogs will be also discussed.

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Nonribosomal peptide synthetases (NRPSs) are large multidomain enzymes that catalyze the condensation of amino acids by forming amide linkages with various modifications. The replacement of amide carbonyl groups with sp3 carbon centers in the common pentacyclic skeleton shared by the potent antitumor agents saframycin and ecteinascidin makes it difficult to speculate on the mechanism of the unique NRPS reaction. We found that the single enzyme (NRPS) SfmC catalyzes a seven-step transformation from readily synthesized dipeptidyl substrates with long acyl chains into a pentacyclic tetrahydroisoquinoline scaffold. Based on the results of deletion mutant analyses, we proposed the detailed mechanism involving the reduction of various peptidyl thioesters by an identical R-domain followed by C-domain-mediated Pictet-Spengler reactions in an iterative manner. Chemoenzymatic synthesis with SfmC may allow direct and stereoselective access to the common pentacyclic scaffold of therapeutically important anticancer agents.

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Ionotropic glutamate receptors (iGluRs) are involved in higher brain functions such as memory and learning, nociception, and a number of brain disorders. Here, we report the synthesis of twelve artificial glutamate analogs whose core structure was inspired by two marine-derived excitatory amino acids, dysiherbaine and kainia acid. Four 7-oxznorbornenes, 2a-2d, were prepared in two steps, starting from and Ugi four component coupling reaction followed by spontaneous Diels-Alder reaction between 2-furfural, 3-iodoacrylic acid, 4-methoxybenzylamine, and benzyl isocyanide. An unprecedented domino metathesis reaction with less reactive vinyl acetate as a cross metathesis substrate was then performed with the Hoveyda-Grubbs second-generation catalyst, to successfully deliver four heterotricycles 3a-3d in good yiels. After functional group transformations followed by diversification at the C-ring, twelve artificial glutamate analogs 6a-6d, 7a-7d, 8a-8d were synthesized in total 7.2-25.8% yield for 13-15 steps. Mice in vivo assays indicated that all analogs are biologically active; namely, 6b, 7a, 7b, and 8b produce hyperactivity in injected i.c.v., whereas other analogs induce hypoactiity in the animals. In vitro electrophysiological assays showed that some hypoactive analogs inhibit spontaneous excitatory synaptic currents in hippocampal neurons and glutamate-evoked currents from recombinant AMPA receptors. With these pharmacological profiles, synthesis of other analogs werer further performed, and pyrrolidone dicarboxylic acid analog IKM-159 was discovered as a more potent, AMPA receptor-selective antagonist.

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Kainic acid, isolated from the marine alga Digenea simplex by Takemoto et al. in 1953, was a parent memter of kainoids family of natural products that display potent anthelmintic properties and neuroexcitatory activities in the mammalian central nervous system. Kainic acid has attracted much attention as a synthetic target due to the above mentioned biological activity as well as the unique structural feature possessing three contiguous chiral centers on the pyrrolidine ring. More than thirty total syntheses including three large scale syntheses have been reported. In this report, we describe an efficient total synthesis of kainic acid which is highlighted by stereoselective construction of the trans-pyrroline via the copper-catalyzed Michael additon-cyclization reacton of chiral isocyanoacetamide 2 with α,β-unsaturated ketone 3. Treatment of isocyanoacetamide 2 with α,β-unsaturated ketone 3 in the presence of bis(N-tert-butylsalycylideneiminato)copper afforded pyrroline 4 in a single operation as a sole diasteromer in 54% yield. Removal of the chiral auxiliary followed by protection of the enamine nitrogen with a Boc group gave ester 8. The conversion to protected kainic acid methyl ketone 13 was achieved in a highly diastereoselective manner (dr=25:1) by the following sequence of transformations; (1) hydrolysis of the methyl ester to carboxylic acid 11, (2) reduction using excess L-Selectride, (3) treatment with aqueous HCl, and (4) esterification with CH_2N_2. The total synthesis of (-)-kainic acid from 13 was accomplished by the chemoselective olefination of the ketone, hydrolysis of the methyl ester, and removal of the N-Boc and t-Bu ester groups under acidic condition. The synthesis involved of 9 steps sequence (16.8% overall yield) of reaction from 2.

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Combinatorial chemistry greatly facilitates the systematical syntheses of small molecules that involve a common core structure. An effective application of combinatorial chemistry is the synthesis of combinatorial libraries based on the unique structures of natural products with biological activities. The libraries serve as attractive drug candidates and biochemical probes. In this pater, we report on the solid-phase synthesis of a combinatorial methylated (±)-epigallocatin gallate (EGCG) library and its biological evaluation. Epigallocatechin gallate (EGCG) and its methylated derivatives, which are members of the catechin family, exibit various anti-cancer effects. The solid-phase synthesis of methylated EGCG involved preparation of the a-acyloxyketone by coupling of a solid-supported aldehyde with a ketone and an acid. The subsequent release and reductive etherification reaction of the solid-supported a-acyloxyketone provided a protected EGCG in good total yields. Deprotection of the protected EGCG was achieved by utilizing a continuous-flow hydrogenation reactor(H-Cube[○!R]). Using the method described above, 64 methylated EGCGs were successfully prepared. The growth-inhibitory effects of the methylated EGCG library were examined. Although methylation of EGCG generally caused reduced growth inhibition, the growth-inhibitory effect of 7-OMe EGCGs was comparable to that of EGCG. The 7-OMe EGCGs are attractive drug candidates because of their enhanced bioavailability.

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Polygalolide A and B (Figure 1) were isolated from a Chinese medicinal plant, Polygala fallax, by Wei and co-workers in 2003. These structures indlude an oxabicyclo[3.2.1]ocate, a five-membered lactone, s six membered ether, an aromatic ring and contiguous quaternary stereo centers at the C-2 and C-8 positions. Total synthesis was reported by Hashimoto in 2006 and Snider in 2007. Although details of the biological activity have not been reported yet, polygalolides are attractive target for tatal synthesis because of the novel structure. In order to construct the congiguous quaternary stereo centers, the core structure of polygalolides, we have developed a new synthetic methodology through intramolecular C-glycocylation; siloxyfuran 4 underwent cyclization upon treatment of TiCl_4 or BF_3・OEt_2 to give the desired oxabicyclo compounds 5-A and 5-B (Table 1). Based on the above results, siloxyfuran 11 including acetylene at the C-8 position was synthesized from D-glucal in 13 steps. Treatment of 11 with TiCl_4 or BF_3・OEt_2 gave a byproduct 13 instead of a disired product 12. Further investigations led us to find that reaction of 11 with Et_3N and TBSOTf in CH_2Cl_2 afforded an oxabicyclo compound 12 as a single diasereomer in 63% yield. Reduction of unsaturated lactone of 12 was followed by radical deoxygenation at the C-3 position via xanthate 16 and then destannylation to give olefin 18. Deprotection of benzyl group, followed by oxidation gave enone 19. Further investigation toward the total synthesis of polygalolides is now in progress.

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Chiral cyclic ethers with tetrasubstitued carbon, especially benzofurans and chromans, are important frameworks found in numerous natural products and bioactive compounds. We have developed a method for enantioselective construction of amino acid derivatives with tetrasubstituted carbon. The asymmetric reactions proceed via chiral enolate A with a C-N axis (eq. 1). We applied this concept to the construction of chiral benzofurans and chromans with tetrasubstituted carbon via C-O axially chiral enolates. It is assumed that the expected enolate intermediate B has shorter half-life of racemization than that of enolate A because the rotational barriers of C-O bond shoud be much lower than that of C-N bond (eq. 2). To achieve the asymmetric induction via short-lived chiral enolate B, the effects of substituents on the aromatic ring, bases and solvents on cyclizations were thoroughly investigated. Precursors of cyclization were prepared from readily available ethyl lactate and the corresponding phenols by Mitsunobu etherification. In the five-membered cyclization, the bulkiness of substituent R at C(6) was found to critically affect the efficiency of asymmetric induction. Treatment of 10a (R=H) with NaHMDS gave 11a as a recemate, while that of 10c (R=^iPr) gave 11e in 82%, 99% ee (Table 2, entries 1 vs. 3). The absolute configuration of 11c was determined to be S. This indicates that five-membered cyclization proceeds with retention of configuration. In the six-membered cyclization, not only substituents at C(6) but also at C(3) were important for asymmetric induction. Cyclization of 13d with TMS('Bu)NLi gave 14d in 66%, 85% ee (Table 3, entry 8). The cyclization proceeds with inversion of configuration. In Michael addition reactions, the asymmetric induction was observed in the reaction of substrates with C(6)-H. This indicates that Michael reactions proceed faster than the corresponding alkylations. The rotational barrier of the C-O bond of 24 was estimeted to be 11.5kcal/mol by variable-temperature NMR of the corresponding ketene silyl acetal 26. This indicates that the half-life of racemization of the intermediary C-O axially chiral enolate is shorter than 1 sec at -78℃. Thus, we have developed a method for assymetric synthesis via short-lived C-O axially chiral enolates for the first time.

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Serakakinone A (1), an antifungal and antibacterial compound, was produced by an unidentified marine fungus symbiotic to rhodophyta Ceratodictyon spongiosum collected at Seragaki beach, Okinawa. The intriguing structure of 1 features a densely oxygenated pentacyclic structure with angular prenylation, as determined by extensive spectroscopic studies and single-crystal X-ray analysis, although the absolute configuration remained unassigned. Three major challenges in planning a symthetic route are: (1) the construction of the pentacyclic framework, (2) the stereoselective introduction of a prenyl unit into the sterically hindered angular position, and (3) the regio- and stereo-controlled installation of multiple oxygen functionalities. In this talk, we will present the first asymmetric total synthesis of (-)-seragakinone A. Noteworthy features of the synthesis include: (1) the benzoin-forming reactions worked well at two cyclization stages, including one catalytic enantioselective reaction, (2) the pinacol-type rearrangement was effective for installing tghe angular prenyl substituent. The synthetic material was identical in all respects to the natural sample, except for the sign of optical rotation, thereby allowing the assignment of the synthetic material as the antipode of the natural product.

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Jadomycins A (1) and B (2) are unique 8H-benzo[b]oxazolo[3,2-f]phenanthridine polyketide antibiotics containing isoleucine unit in the oxazolidinone ring, isolated from Streptomyces venezuelae. It was reported that jadomycin B (2) and the biosynthetic analogs with different amino acid units from isoleucine show cytotoxic activity against several cell lines; however, the jadomycin skeleton with five ring systems has never been synthesized until now. We present here the synthesis of dimethyljadomycin A (25) by the 1^<st> generation synthetic approach through spirolactone-diketone 6 as a key intermediate and jadomycin A (1) itselt by the 2^<nd> generation approach through automatical formation of the B-E ring by simultaneous attack of the carboxylic acid partof isoleucine unit to immonium function formed by condensation of aldehyde and secondary amine functions. Coupling reaction of 2-bromo-3-methoxy-5-methylbenzoate 9 and 4-methoxytetralone 10 afforded tetracyclic lactone 8, which was converted to spoirolactone-diketone 6 by successive reactions of OsO_4 oxidation, bromination, displacement with OH group, and IBX oxidartion. After introduction of isoleucinate unit to 6 by oxidative Michael reaction after treatment with base, reduction of c arboxylic acid function of the adduct 19 to benzyl alcohol one with BH_3・THF, hydrolysis of the isoleucinate unit, and oxidation of benzyl alcohol with MnO_2 provided dimethyljadomycin A (25). However, trials for demethylation of 25 toward jadomycin A (1) were unsuccessful. In the 2^<nd> generation approach, benzoxaborole 29 and MOM group were selected as a masked benzyl alcohol and phenol protection, respectively. Coupling reaction of 34 with bromojuglone 38 was catalyzed with Pd(P(^tBu)_3)_2 to afford quinone-alcohol 39 in good yield. A sequence of intfoduction of isoleucine unit, Dess-Martin oxidation, and acid treatment, as expected, smoothly produced jadomycine A (1) itself. In conclusion, jadomycin A (1) was successfully synthesized. This synthetic method could be widely applicable to the preparation of alternative jadomycin aglycons containing a different amino acid residue. Our next synthetic target is sugar-containing jadomycin B (2) and the related analogs such as jadomycins S (43) and DM (44).

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Anisatin (1), isolated as a toxic component of Japanese Star Anise, is a sesquiterpene characterized by eight contifuous stereogenic centers, oxabicyclo[3.3.1] skeleton, and spiro β-lactone. Its challenging structure, as well as the stron bioactivity as a GABA antagonist, has attracted many synthetic organic chemists. Despite numerous synthetic studies reported to date, only one total synthesis has been achieved. Inspired by its challenging structure, we also initiated our own research program directed toward a total synthesis of thi sinteresting molecule. Our synthesis commenced with the synthesis of phenol 7 from the known mono-protected catechol in seven steps. Oxidation of 7 with iodobenzene diacetate yielded orthoquinone monoketal, which upon heating underwent intramolecular Diels-Alder reaction to privide tetracyclic compound 14. After a three-step conversion, the resulting ether 16 was treated with methyllithium in the presence of HMPA, which induced diastereoselective [2,3]-sigmatropic rearrangement. Thus, the quaternary carbon was constructed with complete stereoselectivity. Selective cleavage of the trisubstituted souble bond of 17 by careful ozonolysis, followed by treatment with potassium carbonate provided 19. After a six-step conversion, iodide 22 was subjected to halogen-lithium exchange, which caused intramolecular addition to ketone to provide bicylco[4.3.0] skeleton. The enol ether moiety of 23 was oxidized to α-hydroxylactone, and the allyl alcohol moiety was converted to epoxide to provide 27. Upon ammonolysis of the lactone moiety, intramolecular S_N2 reaction to epoxide took place to give, after acid treatment, the desired lactone 29. Removal of the primary hydroxy group and protection of the resultin g tertiary alcohol afforded 31. The vinyl group of 31 was converted to carboxylic acid, followed by deprotection of the primary hydroxy group. Crucial lactonization was performed with MNBA to yield desired β-lactone successfully. A three-step sequence involving dihydroxylation of the trisubstituted olefin afforded 1. Having achieved total synthesis of racemic anisatin, we turned our attention to asymmetric synthesis. Phenol 35 and epoxyalcohol 36 were condensed by Mitsunobu reaction. Resulting ether 37 was subjected to halogen-lithium exchange. Bis(diethylaluminium)sulfate facilitated intramolecular S_N2 reaction to afford 38. HPLC analysis revealed that 38 was enantiomerically pure. Further synthetic studies toward asymmetric synthesis are currently under way.

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Ryanodine (1) is a potent modulator of the intracellular calcium channels (ryanodine receptors). The highly fused architecture of 1 decorated by the eight tetrasubstituted carbon centers poses a considerable synthetic challenge. In this paper we report an efficient stereoselective synthesis of the pentacyclic ryanodine skeleton. To simplify the synthetic route, we exploited a structural symmetry of the core framework of 1. Thus, the C_2-symmetric core structure 5 was synthesize through the pairwise symmetric functionalizations. Firsrt, C_2-symmetric core structure 5 was synthesized through the pairwise symmetric functionalizations. First, C_2-symmetric bicyclo[2.2.2]octene ring 2, obtained by the dearomatizing Diels-Alder reaction of 2,5-dimethylhydroquinone 8 and maleic anhydride 9, was converted to eight-membered-ring 3 via the two directional ring expansion. Then, the tricyclo[3.3.2.0^<2.6>]decene system was successfully constructed by the newly developed transannular aldol reaction of 14, leading to the key intermediate 5. After desymmetrization of 5 through dihydroxylation, the stereospecific alkylation at sterically hindered C11 position was accomplished by using the highly reactive bridgehead radical generated from thiocarbonate 24, resulting in formation of 25. Regio- and stereoselective C6-allylation from 25, followed by the fing-closing metathesis, provided C-ring of 1. Finally, installation of the C2-isopropenyl group and stereoselective reduction of the C3-ketone afforded 32, which has the pentacycle of ryanodine (1) along with the seven congiguous tetrasubstituted carbon centers.

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Solanoeclepin A (1), isolated from a large quantity of potatoes as the most active hatching agent of potato cyst nematodes in 1986, possesses a unique heptacyclic structure containing all ring sizes from three to seven with various oxygen functional groups. The first asymmetric total synthesis of Solanoeclepin A was achieved on the basis of (1) the intramolucular Diels-Alder reaction of a 3-methoxyfuran derivative, and (2) an intramolecular cyclization reaction of an epoxy nitrile. Epoxy nitrile 6 was synthesized from optically active nitrile 7 through semi-pinacol rearrangement of epoxy alcohol 12 mediated by TMSOTf. Treatment of epoxy nitrile 6 with LDA followed by TBSCl and HMPA afforded the cyclization product 10 having a the tricyclo[5.2.1.0^<1.6>]decane skeleton in high yield. Elaboration of the cyclopropane side chain was effected by using the enantioselective cyclopropanation reaction reported by Charette. A methoxyfuran moiety and an enone side chain was introduced to the right-hand segment 22, and the product 26 was subjected to the crucial intramolecular Diels-Alder reaction promoted by Me_2AlCl. The product having the heptacyclic skeleton of Solanoeclepin A was obtained in 62% yield. Oxidation of the 7-membered ring and elaboration of other functional groups gave rise to synthetic Solanoeclepin A (total 52 steps, 0.11% overall yield).

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To discover new antitumor natural products, we carried out investigation of the alkdloids in Gelsemium elegans and G. rankinii (Loganiaceae), resulting in teh isolation and structure elucidation of twenty one new alkaloids. Ten new gelsedine-type alkaloids (1-10) were isolated from G. elegans. Gelsevanillidine (1) is the first example of a monoterpenoid indole alkaloid having a vanillin residue on the side chain. Gelsoeoxazolidinine (7) consists of a hexacyclic skelton with an unprecedented oxazoliding ring. To confirm their unique structures, the chemical transformation of a known humantenine-type alkaloid 7 was performed. Ten new humantenine-type alkaloids were isolated from G. elegans and G. rankinii. Rankiniridine (24) and humantenrirdine (21) are new type of alkaloids having a nitrogen-carbon linkage between a humantenine-type monoterpenoid indole alkaloid and a monoterpene unit having an iridoid skeleton. 6-Hydroxyhumantenine (25) is the first example of a Gelsemium alkaloid with an oxygen function at C-6 position. From a biogenetic point of view, 25 seems to be a plausible biogenetic precursor of gelsemine-type alkaloids which is characterized by the ring closure between C-6 and C-20. One new koumine-type alkaloid, kounaminal (32) was isolated from G. elegans. Kounaminal (32) has and acetamide residue at C-21, and is the first instance of a koumine-type alkaloid that has a residue at C-21. This kind of natural product having an aminal moiety in its molecule is quite unusual.

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Species of the Apocynaceae family has long been known as a rich source of polycyclic indole alkaloids. Hunteria zeylanica Gardner and Leuconotis griffithii Hk.f are members of the Apocynaceae family found in Malaysia, especially in the Peninsular Malaysia and Indonesia. Traditionally and biolenetically interesting alkaloids from tropical plants found in Malaysia, three new bisindole alkaloids bisnicalaterine A, having a vobasine-vobasine type of skeleton, bisnicalaterines B and C, possessing an eburnane-corynanthe type of skeleton, were isolated from the leaves and bark of H. zeylanica. While, bisleuconothine A, a strychnan-strychnan bisindole alkaloids, were isolated from the bark and leaves extracts of L. griffithii, respectively. The relative structures of bisnicalaterines A-C, bisleuconothine A, and bisleucocurine A were determined by 1D & 2D-NMR data (^1H-^1H COSY, HSQC, HMBC, NOESY) and the absolute structures were assigned by CD spectra and X-ray crystallography. Bisnicalaterine A showed cytotoxicity against various cancer cell lines, while bisnicalaterines B and C showed no cytotoxicity up to 50μM of concentration. Bisnicalaterines B and C showed a vasorelaxation effect, and the vasorelaxation mechanism of bisnicalaterine B was endothelium independent and was partially related to the activation of TEA-sensitive K^+ channels. Bisnicalaterines B and C also showed antimalarial activity, and potency of bisnicalaterine C is 20 times higher than that of bisnicalaterine B. Bisleuconothine A and bisleucocurine A showed a cell growth inhibitory activity, and for HCT-116 cell line bisleuconothine A induced a G1 phase arrest in a dose-dependent manner. Bisleuconothine A and bisleucocurine A also showed potent antimalarial activity.

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Leishmaniasis is endemic in tropical regions, and currently affects 12 million people in 88 countries. This disease is transmitted by small biting sandflies (Phlebotomus sp.). The first-line drugs for the treatment of leishmaniasis are pentavalent antimonials such as N-methylglucamine antimonate (Glucantime) and sodium stilbogluconate (Pentostam). However, these drugs are toxic and generally expensive. From these reasons, we have been searching for newe treatment from medicinal plant resources. Three new sesquiterpenoid lactones were isolated from Peruvian folk medicine, Elephantopus mollis (local name: Lingua de vaca) together with four known sesquiterpenoids. They exhibited potent in vitro leishmanicidal activities against Leishmania major. The α-methylene-γ-butyrolactone moiety was found to be essential to the potent leishmanicidal effect observed. Leishmanicidal activities of benzophenanthridine alkaloids isolated from fruits of Bocconia pearcei and their derivatives were examined. Seven benzophenanthridine compounds were isolated from the methanolic extracts of B. pearcei. Among them, chelerythrine showed the most potent leishmanicidal activity (IC_<50> value: <0.001μg/ml). To examine the structure-activity relationship of the benzophenanthridine skeleton, the leishmanicidal activities for 32 synthetic samples were examined. The existence of bulky groups at the C_7-C_8 position was found to enhance the activity. On the other hand, bulkiness at the C_2-C_3 position on the D-ring, a carbonyl group at C-6, substitution at C-6 and cleavage or saturation of the C_5-C_6 bond reduced activity. A methyl group on nitrogen of the C-ring was thought to be necessary for significant activity. A new furostan-type saponin was isolated from the methanolic extract of Brunfelsia grandiflora (local name: Chilicsanango) leaves, together with four known compounds. The chemical structure of an active sonstituent was determined by spectroscopic analysis and chemical reaction to be 26-O-β-D-glucopyranosyl 22ξ-methoxyfurost-3β,26-diol3-O-β-D-xylopyranosyl(1→3)- {β-D-glucopyranosyl(1→2)}-β-D-glucopyranosyl(1→4)- β-D-glucopyranoside. Two new compounds, millettilone A and millettilone B, were isolated from the methanol extract of Millettia pendula (local name: Thinwin), together with six known compounds. Among these, pendulone showed the most potent leishmanicidal activity. Millettilone B, was found to be a purple pigment in this heartwood. Clinical trial tests of Japanese Kampo Medicine Ointment "Shi-un-kou" against cutaneous leishmaniasis were examined in Peru. 53 patients with Leishmaniasis cutaneous, voluntary and with consent, were applied "Shin-un-kou" getting as result 46 patients had heal lesions, 3 no answer, 1 left treatment and 3 abandon treatment.

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The naturally occurring furanones represented by furaneol^[○!R] (1), mesifuran (2) and homofuraneol (4a or 4b) are major flavor coponents in numerous fruits such as pineapples and strawberries. They have also been found in a range of cooked foodstuff as pleasant odor components that are generated mainly by heating sugars. These furanones are known to play an important role in flavor because of their extrelemy low threshold values and their burnt sugar odor charactristics. Since the discovery of these important aroma chemicals, large quantities have been utilized as raw materials in the flavor and fragrance industry, with worldwide annual consumption of up to almost 100t. These flavor-related furanones are believed to be biosynthesized via a glycoside from 6-deoxy-L-mannose in plants. However, most of such franones were isolated as optically inactive compounds due to their unique keto-enol tautomeric structures causing racemization. Furthermore, the keto-enol tautomeric structure has obstructed their derivatization toward an X-ray crystallographic study and a standard Mosher method, which has made any attempts to elucidate the relationship between their absolute configurations and odor unsuccessful. We have applied the vibrational circular dichroism (VCD) technique to these furanones. VCD is an emerging technique for stereochemical analyses in the field of life sciences as well as material sciences. We report the determination of the absolute configurations of these unique molecules and their chirality-dependent odor characteristics, which have remained unclear for the past 40 years since their isolation.

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Lepidopteran Type II sex pheromones, which are biosyntehsized from dietary linoleic and linolenic acids, are mainly composed of 6,9-dienes, 3,6,9-trienes, and their epoxides and identified from the species in the former family includes many species called emerald moths with green wings; however, the pheromones from these species have not been identified. In order to understand Type II pheromones in depth, we collected male and females in several emerald moths using a light trap in the Iriomote Islands and could find novel Type II pheromones, (Z,Z,A)-6,9,12-octadecatriene from H. tritonaria and (Z,Z,Z,Z)-3,6,9,13-icosatetraene from T. immissaria. The triene was synthesized by a double Wittig reaction between hexanal and an ylide derived from (Z)-1,6-diiodo-3-hexene. The tetraene was synthesized by a coupling between (Z)-3-undecenal and an ylide derived from (Z,Z)-1-iodo-3,6-nonadiene. Furthermore, pheromone gland extracts of both species interestingly contained (E,E)-α-farnesene. A field evaluation of the synthetic compounds showed that the Type II components were essential for male attraction and (E,E)-α-farnesene acted as a synergist. This is the first mating communication system of lepidopteran species mediated by farnesene, a representative sesquiterpene. From a lichen moth in the family of Arctiidae also inhabiting in the Iriomote Islands, we identified other novel components, 6-methyl- and 14-methyl-2-octadecanones, which were not grouped into any known pheromone types. These compounds include chiral centers and a mixture of both (S)-isomers effectively attracted the male moths. While the chiral GC did not achieve the resolution of the methyl-branched compounds, a normal-phase chiral HPLC column interestingly succeeded in the enantiometric separation. The chiral HPLC analysis of the pheromone extract revealed that the females did not produce optically pure compounds but dominantly the (S)-isomers. This analysis is the first successful application of chiral HPLC to methyl-branched pheromones.

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The duck-billed platypus (Ornithorhynchus anatinus) is one of the few venomous Australian mammals. The adult male platypus carries a thorn on each hind leg, and uses this device to inject their competitors with poison. However, the structure and function of their active compounds remais unclear. We found that the crude platypus venom showed potent Ca^<2+> influx in human neuroblastoma (IMR-32) cells. Guided by this bioassay, we identified 11 novel peptides, including a heptapeptide 1, H-His-Asp-His-Pro-Asn-Pro-Arg-OH. Compounds 1-4 and 5-11 coincided with the 6-9 N-terminal residues of Ornithorhynchus venom C-type natriuretic peptide (OvCNP), and the 132-150 part of OvCNP precursor peptide, respectivel. Heptapeptide 1, which is one of he primary components of the venom fluid(-200ng/μL), induced a significant increase in [Ca^<2+>]_i in IMR-32 cells at 75μM. To the best of our knowledge, this is the first example of the isolation of the N-terminal linear fragments of CNPs in any mammal. Heptapeptide 1 also facilitated neurogenic twitch in guinea pig ileum speciments at 30μM (39% contraction relative to 1.7μM histamine response). We have also established that a proteinous venom fraction strongly hydrolyzed Pro-Phe-Arg-MCA and cleaved a human low-molucular-weight kininogen, as with porcine pancreas kallikrein. These results indicated that platypus venom contained tissue kallikrein-like protease(s), and its proteolytic activity might synergistically contribute to toxicity through the specific cleavage of venom constituents.

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(-)-Exiguolide was isolated from the sponge Geodia exigua collected off Amami-Oshima, Japn, by Ohta, Ikegami, and co-workers. The gross structure including the relative stereochemistry was established through extensive 2D NMR studies, conformational analysis on the basis of ^3J_<H,H> values and NOE correlations, and JBCA method. The molecular structure, characterized by the 20-membered macrolactone core embedded with a methylene bis(tetrahydropyran) substructure, is related to that of bryostains. (-)-Exiguolide inhibits fertilization of the sea urchin gametes but not embryogenesis of the fertilized egg. These structural and biological aspects led to an assumption that (-)-exiguolide may represent a simplified analogue of the bryostatins by Nature and render this natural product an intriguing target for organic chemists. Herein, we present the enantioselective total synthesis of (-)-exiguolide, the nturally occurring enantiomer, for the first time. The methylene bis(tetrahydropyran) substructure was efficiently constructed in a convergent fashion. Thus, the readily available C1-C7 and C8-C16 segments were assembled through olefin cross-metathesis, and two tetrahydreopyran rings were successively forged via intramolecular oxa-conjugate cyclization and reductive etherification. Stereoselective formation of the sterically encumbered C16-C17 double bond was achieved via Julia-Kocienski olefination. The 20-membered macrolactone framework was constructed in an excellent yield by means of Yamaguchi macrolactonization. An alternative approach toward the macrocycle based on ring-closing metathesis was less effecient than the macrolactonization approach. Finally, the (E,Z,E)-triene side chain was introduced in a stereoselective manner via Suzuki-Miyaura coupling under exceptionally mild conditions.

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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); 83.67μg/mL (RPM17951)] and possesses an unique polyether structure, characterized 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 structure 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 performed the total symthesis of 1. First, the C8-C20 segment (6) was synthesized from alkyne 7 and 8 via a process including Pd-catalyzed 6-endo cyclization. Aldehyde 6 was then connected with the C21-C35 segment(5), and the resulting alcohol was transformed to 27. The intramolecular double conjugate addition reaction of 27 produced the CD-ring spiroacetal (28), which was transformed to E-iodoalkene 4. The Suzuki-Miyaura coupling of 4 with dienylborane 3 followed by the removal of TBS groups and the concomitant epoxide fromation completed the total synthesis of 1. However, the ^1H and ^<13>C NMR spectra of 1 disagreed with those of natural prorocentin. Since the large deviations of chemical shifts between them were observed in the B-ring, we conferred with Lu on the deviations and deduced structure 2, having a hydroxy group at C17 of the B-ring, as a plausible structure of prorocentin. Thus, we next achieved the total synthesis of 2. The synthetic process was almost similar to that of 1, except the preparation of the B-ring (36), which was carried out by a process involving the aldol reaction of ketone 37 and 38. Finally, compound 2 showed the same spectral properties as natural prorocentin, except the opposite sign of optical rotation, thereby concluding that natural prorocentin is the enantiomer of 2.

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Symbiodinolide (1), a novel polyol compound, has been isolated from the marine dinoflagellate Symbiodinium sp., which exhibits a Ca^<2+> channel-opening activity and COX-1 inhibitory effect. The planar structure and partial stereochemistry of 1 were elucidated by spectroscopic analysis. In this symposium, we will report our synthetic efforts on symbiodinolide (1) aiming for the complete structural elucidation. The synthesis of the C1'-C25' fragment 2 was achieved via Kotsuki coupling and Julia-Kocienski olefination in the introduction of the side chains. The synthetic C1'-C25' fragment was identical to the degraded C1'-C25' fragment obtained from 1 in all aspects (^1H NMR, HRMS, and specific rotation) indicating that the absolute configuration of this fragment was that described in 2. With regard to the C14-C24 fragment, the diol 3 and its 18-epimer were syntrhesized and compared with the degraded C14-C24 fragment in the spectroscopic data, respectively, which has confirmed that the abslute stereocheistry of this fragment is that shown in 3. All four possible stereoisomers on the diepoxide moiety of the C23-C34 fragment were synthesized, which has established that the stereostructure of this fragment is that depicted in 4. The C33-C42 fragment diol 5 was synthesized stereoselectively, which has resulted in the structural determination of this fragment.

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A polycyclic ether bravisn (1) was isolated from the red tide dinoflagellate Karenia brevis, which produces a variety of policyclic ethers such as bervetoxins, brevenal, and a mono cyclic ether amide brevisamide. Its unique structure consists of two fused tricyclic ether ring assemblies bridged by a methylene carbon and a conjugated aldehyde side chain, which is similar to brevenal and breviasmide. Its separated polycyclic ether skeleton in the center of the molecule is unusual in the marine polycyclic ethers. Interestingly, even though its skeletal structure is divided into two tricyclic ether units by the methylene, brevisin inhibits the binding of tritiated 42-dihydrobrevetoxin B (PbTx-3) to the voltage sensitive sodium channels (VSSC). In order to confirm its aberrant chemical structure, elucidate its interation was essential. Here the total synthesis of brevisin based on highly convergent strategy using Suzuki-Miyaura cross coupling and aldol reaction as the key reactions was achieved in 29 steps (the longest linear sequence), and the datails will be reported in this presentation.

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Kunze et al. reported the isolation of (-)-apicularen A (1) from a variety of strains of the myxobacterial genus Chondromyces in 1998. Subsequently, the gross structure of 1 including the relative and absolute stereochemistry was determined. Biological studied revealed 1 to be highly cytostatic to a wide range of human cancer cell lines with IC_<50> values in the range of 0.23 to 0.68 nM. In addition, recent reports indicated that 1 exhibited antiangiogenesis properties, induced apoptosis produced nitric oxide, and acted as a noverl specific V-ATPase inhibitors. From structural point of view, 1 is characterized by a number of motifs such as a trans-tetrahydropyran ring embedded in a 12-membered salicylate macrolactone, and four stereogenic centers within the macrolactone core which bears a higyly unsaturated N-acylenamine side chain. Because of its fascinationg molecular architecture and potent biological activity, 1 has been targeted by a number of synthetic research groups. To date, four total syntehses of 1, have been achieved along with four formal total synrtheses. In this presentation, we wish to present a novel stereoselective approach for the synthesis of 1. The key features of this total synthesis included (i) assembling of (E)-iodoalkene and substituted heptanal by Nozaki-Hiyama-Kishi coupling; (ii) stereospecific synthesis of trans-2,6-disubstituted dihydropyran 6 by using Pd(II)-catalyzed 1,3-chirality transferred reaction from triol 7; (iii) Yamaguchi macrolactonization of the seco acid to construct 12-membered lactone ring with dihydropyran bridge; (iv) regio- and stereo-selective introduction of hydroxy group at C-11 position of 5 by oxymercuration and reductive demercuration; (v) stereospecific CuI-mediated coupling of 2 with (2Z,4Z)-heptadienemide 3 under the mild conditions.

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Nodulisporacid A was isolated from a marine-derived fungus, Nodulisporium sp. CRIF1, by Kittakoop and co-workers in 2008 as an antiplasmodial agent (Fig. 1). This compound was reported to exist as a 1:1 equilibration mixture of the (E)- and (Z)-isomers. However the stereochemistry at the three asymmetric centers of Nodulisporacid A remained unclear. We report a synthesis of four stereoisomers of Nodulisporacid A by the concise approach which includes the three-component reaction and one-pot construction of the whole framework. The ^1H NMR comparison of the derivatives (10-12) revealed the absolute configuration of natural Nodulisporacid A to be 4R,4'R,6'R. Urechitol A was isolated from the methanolic root extract of Pentalinon andrieuxii by Pena-Rodriguez and co-workers in 2009. The relative stereochemistry of Urechitol A has been elucidated unambiguously by X-ray crystallographic analysis (Fig. 4). This compound has a novel and very unique structure, incorporating a highly functionalized cycloheptane ring with two oxygen bridges. Although Urechitol A itself exhibited no biological activity, its unique tetracyclic structure prompted us to investige its syntheiss. Recently, we synthesized Urechitol A as a racemate using a [4+3] cycloaddition reaction (19+20→21) and a methanol assisted intramolecular epoxide opening (22→23) as key steps for the efficient construction of the core tricyclic framework. The overall yield was 2.3% over 12 steps.

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We have already developed the stereocontrolled one-pot asymmetric 6π-azaelectrocyclization protocol using three compounds of cis-aminoindanol a as a chiral nitroge source, vinyliodide such as 3 and vinylstannane such as 17. Toward completing this method as a ssynthetic strategy for the alkaloids composed of a polysubstituted piperidine nucleus, we now describe the stereocontrolled syntheses of (-)-hippodamine, an azaphenalene alkaloid, and (-)-guettardine, an indole alkaloid, in order to further demonstrate this one-pot protocol. Hippodamine, which is a component of defensive alkaloids released by ladybird beetles, possesses the 2,4,6-trisubstitued piperidine structural unit. The desired unit 7 was synthesized by the one-pot reaction from (+)-a, tri-substituted olefin 3 and alkylvinylstannane 4. The reduction at C4 followed by alkylation at C6 and then removal of the aminoindanol moiety afforded compound 10, which was transformed into the precursor of the intramolecular Mannich reaction. The Mannich reaction cleanly produced the desired azaphenalene compound 12. The removal of the oxygen function completed the total synthesis of (-)-hippodamine. Next is the stereocontrolled total synthesis of (-)-guettardine, which is an indole alkaloid composed of 2,4,5-trisubstituted-piperidine nucleus. The one-pot 6π-azaelectrocyclization using (-)-a, bulky tetra-substituted vinyl iodide 5 and very bulky 2-(3-alkyl-2-indolyl)-vinylstannane 6 successfully afforded the desired coupling product 19, which possesses the opposite stereochemistry at the C5 position of (-)-guettardine. After stereoselective hydrogenation, an acid treatment of the resulting saturated compound 23 completely isomerized at the C5 position and quantitatively afforded the piperdine derivative 24 that has the desired stereochemistry. After removing the indanol moiety, one carbon was elongated at the C4 position followed by hydroboration to produce (-)-guettardine. Thus, the first stereocontrolled asymmetric total syntheses of (-)-hippodamine and (-)-guettardine were achieved, and the asymmetric one-pot azaelectrocyclization protocol can be regardea as a new and effective synthetic strategy for alkaloid synthesis.

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Oxazolomycin A and neooxazolomycin, originally isolated from a strain of Streptmyces by Uemura et al. in 1985, constitute a family of structurally unique oxazole polyene lactam-lactone antibiotics together with seven other congeners identified to date. These oxazolomycins were found to exhibit wide ranging and potent antibacterial and antiviral activities as well as in vivo antitumor activity. On the other hand, inthomycins A, B, and C were also isolated from Streptomyces by Omura et al. in 1990 and Henkel et al. in 1991. The structures of inthomycins are featured by oxazole, triene, and β-hydroxy units, which are corresponding to the left hand segment of oxazolomycins. In this reason, the intriguing molecular architectures and biological activities make imthomycins and oxazolomycins attractive targets for synthesis. However, the total synthesis is limited to neooxazolomycin achieved by Kende's group and our group, and other oxaolomycins having a spiro γ-lactam-β-lactone core have not been synthesized yet. We report here an efficient enantioselective synthesisi of inthomycin A based on organocatalyzed [2+2] cyclocondensation and the first synthesis of oxazolomycin A diacetate. In the synthesis of Inthomycin A, our synthesis started from a three-step transformation of propargyl alcohol 13 to aldehyde 4. When aldehyde 4 was reacted with propionyl chloride in the presence of 14 (20mol%), LiClO_4 (2 equiv), and ^iPr_2NEt (2 equiv), asymmetric [2+2] cyclocondensation took place wigh exellent enantio and diastereoselectivity to give β-lactone 15 (98% ee, 99% de) in 92% yield. Subsequent methylation, methanolysis, and Stille coupling with 8 gave left hand segment 9, which was successfully converted to inthomycin A. On the other hand, meooxazolomycin core 2, derived from 21 via Conia-ene reaction, was feasible for the synthesis of right hand segment 11. Transformation of 2 to carboxylic acid 26 in 7 steps, followed by esterification with SEMCl afforded SEM ester 27. Subsequent silylation, reduction, and oxidation gave aldehyde 10. Aldehyde 10 was converted to 30 through Nozaki-Hiyama-Kishi coupling with iodide 29. Oxidation, followed by stereoselective reduction and acetylation gave right hand segment 11. After amidation of 9 with 11, removed of the SEM and silyl acetal groups and construction of the β-lactone using HATU and ^iPr_2NEt afforded oxazolomycin A diacetate in good yield.

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Petrosin (1), isolated as a racemate from the marine sponge Petrosia seriata by Braekman in 1982, by and Kitagawa and Kobayashi in 1989, independently, is known to possess anti-HIV activity by inhibitions of reverse transcriptase and giant cell formation. The first racemic total synthesis of 1 has been reported by Heathcock and co-workers in 1994, who also confirmed that all stereocenters of the quinolizidine rings easily epimerized via retro-Mannich and Mannich reaction. Since the anti-HIV activity of each enantiomer has not yet been investigated, we initiated synthetic studies on petrosin in optically active form to examine the bioactivity between each enantiomer. First, optically active hemiaminal 6, prepared via desymmetrization of prochiral 1,3-diol, was treated with ketene silyl acetal 7 in the presence of catalytic TBSOTf to provide the desired product 5. Vinyl iodide 19 was prepared from 5 via modification of the side chain. Union of the fully elaborated monomer segments 5 and 19 was conducted by Suzuki-Miyaura coupling to afford dimer 20 in 89% yield. Stereoselective constuction of the quinolizidine rings was then conducted by aza-Michael reaction. The crucial formation of the 16-membered ring was effectively executed by ring-closing metathesis with the 2^<nd> generation Grubbs catalyst. Based on the Grubb's modification, we added p-quinone to avoid isomerization of C-C double bond. Finally, the double bond was reduced under hydrogenation conditions to give (-)-petrosin (1). The optical purity of the synthetic petrosin (>99% ee) was confirmed by Mosher's method for a diol derived from 1 by reduction of two carbonyl groups, indicating that epimerization of optically active petrosin did not proceed. We also synthesized (+)-1 in the same manner from the other enantiomer of hemiaminal 6. We then evaluated inhibitoty activity against syncytium formation. While a significant difference was not observed between each enantiomer, the partial structure 13 exhibited no inhibitory activity against giant cell formation. The results indicated that the dimeric structure would be essential for the bioactivity.

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(+)-Chaetocin (1) is a complex epidithiodiketopiperazine (ETP) alkaloid produced by Chaetonium minutum, which was isolated in 1970. In addition to its antibactericl and cytostatic activity, 1 is known to be a potent inhibitor of lysine-specific histone methyltransferases (HMTs). Because histone methylation plays important roles in controlling gene expression patterns, synthetic study of 1 and its analogs would be helpful in developing biological tools for epigenetic research. We herein describe the first total synthesis (+)-1 and its analogues. We also examined the biological activity of these compounds towards H3K9 HMT G9a, which is a potential therapeutic target in human cancer. Keeping a proposed biosynthetic route in mind, we initially attempted the α-oxidation of dimeric compound 3 (route A). Since enolate chemistry seemed inappropriate, we selected radical bromination reaction. However, the octacyclic core was extremely unstable under radical conditions, resulting in complete decomposition. Therefore, we decided to test the early-stage oxidation of the diketopiperazine (DKP) unit (route B). DKP ent-9 was synthesized without epimerization in good yield (5 steps) starting from known N-Cbz-protected N-methyl-D-serine and D-Trp-OMe・HCl. The obtained DKP was subjected to the bromocyclization reaction with NBS to afford 13 in 88% yield. While standard radical bromination reaction using AIBN at high temperature led to decomposition of 13, the reaction at room temperature using V-70 as a radical initiator gave the desired tribromide 16 cleanly in a stereoselective manner. The obtained crude tribromide was treated with water to afford diol 17a in 47% yiels as a major stereoisomer, accompanied with other three minor diastereomers. To our delight, Movassaghi's reductive coupling reaction using Co(I) complex was applicable to our hemiaminal 17a, affording the desired octacyclic tetraol 20 as a single isomer in 55% yield. Finally, the substitution reaction of 20 with condensed H_2S was carrid out in the presence of BF_3・OEt_2. It is likely that the sulfur nucleophile was delivered to the putative iminium ions stereoselectively, and pure (+)-1 was isolated in 44% yield after the treatment with molecular iodine. It should be noted that deprotection of four Lewis acid-sensitive protecting groups (TBS and Boc groups) also occurred in the final step. Based on the established route, we synthesized the antipode of (+)-1 (ent-1) and the sulfur-deficient analogs 22 and ent-22, and the inhibitory activity of these compounds against G9a was examined using a known ELISA method. Interestingly, 1 and ent-1 inhibited G9a equally effectively. In contrast, sulfur-deficient analogs 22 and ent-22 were inactive. These results clearly indicate that the sulfur functionality is crucial for the biological activity, while G9a is not sensetive to the 3D structure of 1. Details of the total synthesis of 1 and further structure-activity relationship studies will be discussed.

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Vialinin B (1) is a highly oxygenated dibenzofuran bearing p-hydroxyphenyl and phenylacetoxy groups that was isolate by us from the dry fruiting bodies of an edible Chinese mushroom, Thelephora vialis, and shows an extremely potent inhibitory activity against tumor necrosis factor (TNF)-α production in rat basophilic leukemia (RBL-2H3) cells (IC_<50>=20pM vs 0.25nM for FK-506).TNF-α is a potent multifunctional cytokene that mediates a variety of biological actions with a central fole 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 ghis symposium, we present total synthesis of 1 and its related compuonds. The key reactions include a double Suzuki coupling of electron-rich aryl bromide with a couple of phenylboronic acids, a copper-mediated Ullmann reaction, an oxidative cleavage of methylene acetal, and a LHMDS-promoted phenylacetylation. This synthesis proceeded in 11 steps with 18% overall yield from a known sesamol derivative. Furthermore synthesis of the related natural products such as ganbajunin B and vialinin C is also discussed.

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Haouamines A (1) and B (2) were isolated from the marine ascidian Aplidium haouarianum collected off the coast of southern Spain. They belong to an unprecedented class of alkdaloids. A unique feature of haouamines is an eleven-membered 3-aza-[7]-paracyclophane moiety, which is so highly strained. The B ring of paracyclophane moiety is non planar and exists in a pseudo-boat conformation. Other features are a diaryl-substituted stereogenic quaternary center and an anti-Bredt double bond. In solution, each haouamine exists as an inseparable mixture of two interconverting isomers. Haouamine A exibits cytotoxic activity against the HT-29 human colon carcinoma cell, and haouamine B does against the MS-1 mice endothelial cells. The novel molecular architecture, the kinetic aspect in the molecule, and the biological activity of haouamines atract a lot of chemists. Therefore, haouamines are challenging synthetic targets. Baran and Burns reported the synthesis of (±)-haouamine A in 2006, and the asymmetric synthesis of (+)-haouamine A in 2008. Recently Baran and co-workers accomplished the synthesis of an atropisomer of haouamine A, and indicated that the inseparable mixture oftwo interconverting isomers in solution was no due to atropisomerism. Weinreb's, Furstner's, and Ishibashi's groups have achieved the formal total synthesis. In this symposium, we report synthetic studies on haouamine B (2) by our original approach. We envisioned that the stereogenic quaternary center could be construced via an intramolecular palladium-catalyzed α-C-arylation, and the anti-Bredt doule bond introduced from a vinylogous amide by TsNHNH_2. The C2-C3 bond formation should be carried out through Suzuki-Miyaura coupling. Construction of the piperidine segment 5 could be completed by the regioselective introductoin of aryl substituents to 4-methoxypyridine (6) usin 3-methoxyphenylboronic acid (7) and 3,5-dimethoxybenzylzinc chloride (8). We also report an introducton of the stereogenic center at C17 position by Comins method.

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Aspergillides A, B, and C (1-3) are novel 14-membered macrolides which have been isolated by Kusumi and co-workers from marine-derived fungus, Aspergillus osteanus strain 01F313. These polyketide-derived metabolites are found to exhibit significant cytotoxicity against mouse lymphocytic leukemica cells (L1210). Because of the intriguing structural features and the biological profile, aspergillides represent attractive targets for total synthesis. We report here our successful total syntheses of aspergillides A (1), B (2) and C (3) employing a transannular oxy-Michael and an intramolecular oxy-Michael strategies for the construction of the substituted pyran moieties as the key steps.

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