The antitumor antibiotic C-1027 is a 1:1 complex of a highly labile enediyne chromophore (1) and a carrier apoprotein. C-1027 exhibited the potent cytotoxicity toward various cancer cells. The p-benzyne biradical (2), which is in equilibrium with 1, abstracts hydrogens from DNA to exert its biological activity. The apoprotein functions as both the stabilizer and the drug delivery system of 1. Recently, we found that the biradical 2 slowly abstracts α-proton of Gly96 of the apoprotein, which caused the oxidative cleavage of the peptides and led to a self-degradation of C-1027. To create a more stable analog of antibiotic C-1027, we designed a Gly96-deuterated (D-Gly) apoprotein. The D-Gly apoprotein was expressed in Escherichia coli in the presence of glycine-d_5. The unstable chromophore 1, isolated from natural C-1027, was then incorporated into the D-Gly apoprotein using HPLC techniques to obtain the D-Gly C-1027. Stability tests revealed that the D-Gly C-1027 was 1.8 and 4.9 times as stable as the natural one under solid and solution states, respectively. Cytotoxicity test also reflected the stability of D-Gly C-1027. Thus, we achieved the creation of supranatural products by rational design utilizing kinetic isotope effect. The presented work demonstrated the novel design principle to create the supra-natural products by integrating the data of physicochemical property of the small molecule and the atomic-level 3D-structure of the protein, which will be applicable to other biologically important natural products and proteins.

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Tomatine, a steroidal alkaloid glycoside, is regarded to be no longer included in ripe tomato fruit. However, for the first time, we have isolated steroidal alkaloid glycosides from major kinds of the ripe tomamtos such as "Momotaro" and "Cherry tomato" belonging to pink type and Italian tomato being to reddish type. It is interesting that from Japanese "Momotaro" and "Cherry tomato", a spirosolane type glycoside, 3-O-β-lycotetraosyl (23S, 25S)-3β,23,27-trihydroxy-5α-22αN-spirosolane 27-O-β-D-glucopyranoside, named Esculeoside A, has been obtained. While, from Italian tomato, solanocapsine type glycosides, 3-O-β-lycotetraosyl 22,26-epimino-16β,23-epoxy-5α,25α H-cholestane-3β,23,27-triol 27-O-β-D-glucopyranosides, named Esculeosides B-1 and B-2, have been isolated. Cytotoxities of Esculeoside A and Tomatine against MCF-7 cells were evaluated to be 24.5 and 15μM, respectively, in IC_<50>. Other various bio-activities of them are now investigated.

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In the course of our search for new antimitotic antitumor agents from microbial source, the fungus Cladorrhinum sp. KY4922 strain was found to produce a series of new compounds. Eight new compounds, MPC1001 (1), and MPC1001B (2)〜MPC1001H (8) were isolated from the culture broth by column chromatographies with various separation modes. The molecular formula of 1 was determined to be C_<28>H_<24>N_2O_<10>S_2 by HR-FAB MS and ^<13>C-NMR spectra. Interpretations of 1D and 2D NMR spectra along with physico-chemical data, 1 was revealed to be a new methyl derivative of emestrin, 15-membered antifungal macrolide possessing a unique epidithiodioxopiperazine moiety. The relative configuration of 1 elucidated by proton coupling constants and NOE experiments and the absolute structure via CD spectrum were the same as emestrin. 2 and 3 were deoxy, and 4 was trisulfide analogs of 1. Moreover, 5〜8 were retro-aldol type seco-aldehydes. 1 had an ability to arrest HCT 116 human colon cancer cells at M phase and exhibited an antiproliferative activity with the IC_<50> value 3.3nM. Other analogs possessing the polysulfide bridge also exerted potent antiproliferative activities against human prostate cancer cell line DU145.

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The analysis of bulk tissue samples gives the informations about solute and metabolite concentrations of all compartments and different cell types, and this do not reflect the fine scale patterns between adjacent cells or provide information about processes, that are regulated on the single cell level. To understand the physiology of a whole organism, it is necessary to understand the behavior of a single cell as its fundamental unit. Such investigations essentially require single cell or even subcellular analysis. Along with the progress of plant physiology, the reliable method for single cell sampling is sought-after to investigate the precise metabolic profiling of different cell types. Research on single cells of higher plants is relatively difficult, mainly because of their small size and rigid cell walls. Single cell sampling of plant cell is usually performed by a fine oil-filled glass microcapillary, mounted on a micromanipulator. However, this method is time consuming and rather needs high skill due to the hard and thick cell wall barrier. We developed a unique method of laser-assisted single cell sampling and applied this to metabolite analysis at the resolution of the individual cell. Some pico-litter cell content of GFP expressed transgenic torenia (Torenia hybrida.) were picked up from a single cell (epidermal and petal cell) using this method. The trans gene (GFP) mRNA was detected by RT-PCR, and the petal pigments i.e. peonidin-3,5-diglucoside and malvidin-3-glucoside-5-(p-coumaroyl)-glucoside were also identified by using nano flow LC-ESI MS/MS and MALDI TOF MS. This method would be one of the most powerful tools for studying metabolic profiling of individual plant cells.

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During the course of seeking for novel gluconeogenesis inhibitors, FR225659 and its four congeners were isolated from the fermentation broth of Helicomyces sp. No.19353. Series of NMR analysis allowed elucidation of their planar structures. The planar structure of FR225659 includes a novel acyl moiety, an unprecedented amino acid residue, 3-chloro-4-hydroxyarginine, and two unique amino acid residues, a 3-hydroxy-3-methylproline and a dehydrovaline. As all efforts to obtain crystals of 1 suitable for X-ray crystallography turned out to be in vain, a combination of chemical modification and spectroscopic methods was applied to elucidate the stereochemistry of 1. Acid hydrolysis followed by derivatization with chiral phthalic acid allowed X-ray crystallographic analysis of the proline analogue, which determined its stereochemistry to be (2S, 3R). Conformational analysis of 9 using ^<2,3>J_<CH> developed by Murata et. al. allowed assignment of the relative stereochemistry of the arginine analogue to be 2,3-erythro-3,4-threo. Then, the modified Mosher's method suggested that the absolute configuration of 4'-C is R, which was supported by NOE analysis of 1. The CD spectrum of 1 showed positive Cotton effect at 236nm, indicating an optical activity around the biphenyl axis between the quinoline and the phenol of 1. As the CD spectrum lacking clear Davydov split does not appear to be easy to translate, further elucidation of the axial chirality is now in progress. FR225659 family exerted potent inhibitory activities against glucagon-induced gluconeogenesis of rat primary liver cells, while they showed ten or more times less potent cytotoxicities against EL-4 cell line. As they do not suppress gluconeogenesis independent of glucagon, they should stop a signal pathway from glucagon. Diabetes patients are reported to produce more hepatic glucose than normal, and this leads to complications unless properly treated. Thus, FR225659 family can be drug candidates for diabetes to down-regulate the high blood glucose level of those patients. It is noteworthy that the hydroxyl group at position 3" plays important roles in both biological activities and solubility in various solvents.

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Small-molecule microarray has been developed as a new technology to investigate ligand-protein interactions en masse. To construct the microarrays, synthetic small-molecule library has been prepared by solid-phase split pool synthesis and diversity-oriented synthetic methodology, and immobilized on solid surfaces by using selective coupling reactions. Although this is well suitable method for immobilizing library of synthetic small molecules that have a certain functional group, it is expected to be difficult to immobilize structurally diverse small molecules including natural products library by using this method. Even though the small molecules could be introduced on the solid surfaces, a certain area of the small molecule faces toward the solid surface, and therefore some of the immobilized compounds will not come into contact with the relevant binding proteins. As it is difficult to predict the binding domain of small molecules that interact with unknown proteins, this poses a major drawback to such studies, especially when the goal is to discover new target proteins for small molecules using microarray technology. To address the problem, we developed conceptually new immobilization method, namely, functional group independent immobilization using photoaffinity reaction. In the present method, photoreactive aryl diazirines are first immobilized on glass slide via polyethylene glycol linker, and small molecules were printed on the diazirine-coated glass slide. Photoreactive aryl diazirines should be promoted upon irradiation to highly reactive species, which in turn bind or insert irreversibly to the small molecules printed on the glass slide. To demonstrate our concept, structurally diverse organic molecules were immobilized on the diazirine-coated glass slide. Specific interactions between the small molecules and labeled proteins were successfully detected on the slides. The results of these studies will be presented.

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Peroxisome proliferator-activated receptor γ (PPAR-γ), which belongs to the nuclear receptor superfamily, is expressed at high levels in the adipose tissue and functions as a master regulator of adipocyte differentiation. PPAR-γ is the predominant molecular target for the insulin-sensitizing thiazolodinedione drugs such as troglitazone and pioglitazone, which improve insulin resistance. In order to discover a novel natural PPAR-γ ligand, we have evaluated extracts of 70 spices and herbs for their PPAR-γ ligand-binding activity and found that the EtOAc extract of licorice (Glycyrrhiza uralensis roots) had higher activity than other materials tested. Bioassay-guided fractionation of the extract using a GAL4-PPAR-γ chimera assay method has resulted in the isolation of a total of 24 phenolic compounds, among which dehydroglyasperin D (1), dehydroglyasperin C (2), glyasperin D (3), glycycoumarine (4), glycyrin (5), and glyasperin B (13) exhibited significant PPAR-γ ligand-binding activity and mainly contribute to the activity of the licorice EtOAc extract. From a study of the structure-activity relationships, the isoprenyl group at C-6 and the ortho-hydroxy group at the aromatic ring-B part in the isoflavan or arylcoumarin skeleton were found to be the structural requirements for the activity. Grycyrin (5), one of the main PPAR-γ ligands of licorice, significantly decreased blood glucose levels of genetically diabetic KK-A^y mice. In addition, the licorice EtOH extract decreased blood glucose and serum insulin levels in diabetic KK-A^y mice, reduced weights of intra-abdominal adipose tissues in diet-induced obese mice, and suppressed increase in blood pressure in spontaneous hypertension rats.

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Enzymatic oxidation of epigallocatechin 3-O-gallate yielded dehydrotheasinensin A along with 2,3,5,7-tetrahydroxychroman-3-O-gallate and a known dimer of the quinone of epigallocatechin gallate. Dehydrotheasinensin A possesses a hydrated cyclohexentrione ring and is chemically equivalent to a quinone of theasinensin A, which was shown to be accumulated at initial stage of black tea manufacturing. Reduction of dehydrotheasinensin A with ascorbic acid or thiol compounds gave theasinensin A, a major phenolic constituent of black tea, in which two molecules of epigallocatechin gallate were connected by R-biphenyl bond between two B-rings. On the other hand, when the aqueous solution was heated, dehydrotheasinensin A was converted to theasinensin D, an S-atropisomer of theasinensin A, along with galloyl oolongtheanin. Furthermore, in phosphate buffer at pH6.8 at room temperature, dehydrotheasinensin A was converted to theasinensins A and D, galloyl oolongtheanin and an oxidation product which suffered an oxidative cleavage of the cyclohexenone ring. The results substantiated an assumption that epigallocatechin dimers in black tea were produced by dismutation of the corresponding theasinensin o-quinones. Furthermore, it was confirmed that dehydrotheasinensin A was produced by autoxidation of epigallocatechin-3-O-gallate in neutral aqueous solution.

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Stilbene and its oligomers including their glucosides are occurring in the particular families such as Dipterocarpaceae, Vitaceae, Cyperaceae, Leguminosae and Gnetaceae. Resveratrol (tran-3,5,4'-trihydroxystilbene), one of the stilbenes, has recently been drawn to attentions because of its various biological properties such as anti-oxidative, antimutagenic, and an inducer of phase II drug-metabolizing enzymes. The further wide-ranged biological activities like antifungal, cytotoxicic, anti-inflammatory, antivirus and antibacterial have been still more examined. Dipterocarpaceaeous plants are well known to rich resource of various resveratrol oligomers. A genus Vatica comprising 65 species belongs to the largest subfamily Dipterocarpoideae in Dipterocarpaceae, most of which distributes in Southeast Asia. Although some phytochemicals in a few families were disclosed, the systematical phenolic compositions have not been discussed yet. The structural elucidation of resveratrol oligomers in some Dipterocarpaceous plants [Vateria, Hopea, Vatica, and Shorea] and some biological properties of the characterized oligomers were discussed in our previous papers. The different oxidative condensation of resveratrol admitted the oligomers to a variety of frameworks in the family like dihydrobenzofuran ring, benzocyclopentane ring, dibenzo[2.1]octadiene, dibenzobicyclo[3.2.1]octadiene, dibenzobicyclo[3.3.0]octadiene and tribenzobicyclo[3.3.2]octatriene system. The unusual spectroscopic properties have been observed in the complex stereo structures of some stilbene oligomers caused by anisotropy and fixation of phenyl group and so on. The phytochemical and biological interest in resveratrol oligomers in the family led us the current study of Vatica pauciflora (Korth.). The present research deals with the isolation and structure elucidation of new resveratrol oligomers [pauciflorols A-C (1-3), and isovaticanols B (6) and C (8)] and the glucosides [pauciflorosides A (11), B (13) and C (14)] along with 17 known resveratrol cognates (4,5,7,9,10,12 and 15-25) and bergenin (26). Some unusual spectroscopic properties observed in isovaticanol B (6), vaticanol B (7) and isovaticanol C (8) in NMR spectrum are also comprehensively discussed.

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Avermectin (1), milbemycin (2) and nemadectin (1) are a series of 16-membered macrocyclic lactones produced by Streptomyces strains and they have potent antiparasitic and broad-spectrum activity against nematode and arthropod parasites. Milbemycin (2) and nemadectin (3) are structurally related to avermectin (1) but former two compounds lack the disaccharide at C13. In many cases, the sugar moiety of complex polyketide compounds is important for the biological activities. Since removal of both sugars of avermectin reduces the antiparasitic activity, introducing the sugar moiety to milbemycin or nemadectin will be useful for the improvement of their biological activities. Although avermectin has a substituent (hydroxyl residue; the residue is glycosylated at the later stage of biosynthesis) at C13, there are no substituents at C13 of nemadectin. These differences depend on the composition of catalytic domains in the polyketide synthases (PKSs). The genetic alternation of the PKS gene(s) by gene manipulation will be able to introduce the rational modification of polyketide structure. Two approaches were done for the production of C13-O-glycosylated nemadectin. Two genes for nemadectin PKSs (nemA3 and nemA4) were inactivated by the insertion mutation in the chromosome of S. cyaneogriseus and the mutants produced C13-hydroxylnemadectin (4) by introducing complementary PKS genes, aveA3 and aveA4, of S. avermitilis. Ultimately, the recombinant strains carrying genes involving L-oleandrose biosynthesis and the glycosylation produced the novel C13-O-L-oleandrosyl-L-oleandrosylnemadectin (5). The biologocal activity of the novel compound (5) was 180-fold higher than that of nemadectin (3) or C13-hydroxynemadectin (4).

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Determination of molecular structure by heteronuclear long-range C-H correlation methods such as HMBC and COLOC has a substantial problem in which a carbon bearing no proton within three bond cannot be detected. The structure elucidation of highly hydrogen deficient compounds might thus be problematic since the carbon network of those molecules could not be completely followed by information from indirect ^<2,3>J_<CH>. For the structure elucidation of such molecules, utilization of long-range ^<13>C-^<13>C coupling is necessarry to detect the super long-range H/C correlations via four bonds, ^1H-^<13>C-X-X-^<13>C. Large unwanted signals arising from single ^<13>C isotopomers were supressed by utilization of BIRD pulse or zz gradient-enhanced X-filter. The X-filter dose not contain any parameter to be optimized such as BIRD delay and was more efficiently supress those unwanted signals than the BIRD-included sequence. Accurate values of long-range ^<13>C-^<13>C coupling constants obtained from 1D X-filtered DEPT C-C relay were applied to determine discrimination of stereochemistry in sp^3 carbon systems. A two-dimensional version of the above method was constructed by an insertion of t_1 in place of the DEPT or long-range C-C evolution. The former gave the spectrum in F_1=^1H, F_2=^<13>C and the latter, F_1=F_2=^<13>C. Although the F_1=^1H spectrum showed direct connectivity between ^1H-^<13>C-X-X-^<13>C, its sensitivity was lower than that of the F_1=F_2=^<13>C spectrum probably due to long t_1 evolution time. The F_1=F_2=^<13>C spectrum gave correlation peaks between ^1H-^<13>C-X-X-^<13>C. This spectrum successfully assigned the acyl residues of phenol esters at natural ^<13>C abundance, which could not be determined by conventional HMBC. Spectral editing was also applied for the 2D version to obtain each CH-, CH_2-, and CH_3- subspectrum, in which the correlation peaks close to each other could be discriminated.

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α-Glucosidases not only process protein glycosylation, but also control oligosaccharide metabolism. Thus, inhibitors of α-glucosidases are potential therapeutics for the treatment of such diseases as viral diseases, cancer, and diabetes. In the course of our continuing search for potential drug leads from Japanese marine invertebrates, we found a potent α-glucosidase-inhibitory activity in the hydrophilic extract of the marine sponge Penares schulzei, whose bioassay-guided fractionation afforded three new tetrahydroisoquinoline alkaloids named schulzeines A-C. The structure of schulzeine A was elucidated by spectral analysis and chemical degradations to be the isoquinoline alkaloids, encompassing two amino acids and a C_<28> trisulfated fatty acid. The absolute stereochemistry of schulzeine A was determined by application of the advanced Mosher analysis to fragments obtained by chemical degradation. Schulzeine B was a desmethyl derivative of schulzeine A, with a stereogenic center in the tricyclic portion being epimerised. Schulzeine C was an epimer of schulzeine B. NMR data of the tricyclic part in schulzeine C was superimposable on that of schulzeine A, while the fatty acid portion was identical with that of schulzeine B. Schulzeines A-C inhibit α-glucosidase with IC_<50> values of 48-170nM. It should be noted that desulfated schulzeines also inhibited the enzyme albeit with diminished activity, thereby indicating that the activity of schulzeines was not thoroughly due to the presence of the three sulfate groups.

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Our ongoing search for the bioactive oligoglycosides from solanaceous plants has so far resulted in the isolation of cytotoxic compounds against several tumor cell lines, antifeeding substances and the key intermediates on the biosynthesis of steroidal alkaloids. In the present study, we have investigated the constituents in the respective organs of the leaves, stems and fruits of Solanum aethiopicum to provide three novel steroidal glycosides, named aethiosides A-C (1-3). 1 was acid-hydrolyzed to afford a sapogenol, named aethiogenin a (4), C_<29>H_<42>O_2, of which structure was determined to be a homo-cholestane derivative with an aromatized ring E by spectroscopic means. 1 was characterized as 3-O-β-chacotriosyl aethiogenin a 26-O-β-D-glucopyranoside. The production of 1 was plausibly deduced as shown in Chart 2, that is, starting from the conjugation of polyhydroxycholesterol and acetyl CoA resulting in the formation of a benzene ring at E-ring. The structures of 2 and 3 were also analogously determined. In case of 3, a malonyl CoA was deduced to be impregnated into the cholesterol molecule to give a carboxyl benzene ring. These three glycosides were for the first time isolated as the steroids with a novel skeleton carrying a benzene ring at E-ring by conjugation of cholesterol derivative and acetyl CoA or malonyl CoA.

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The yeast Malassezia furfur, present in the normal microflora on human skin, has been known to cause several skin diseases: tinea versicolor, Malassezia folliculitis, seborrheic dermatitis, psoriasis. Recently it has received much attention that M. furfur was reported to be closely related to atopic dermatitis (AD), because it has been observed in patients with head and neck AD and nine allergens have been found from it. On the other hand, in China, Korea and Japan the indigo plant, Polygonum tinctorium, has been used in traditional folk medicine for detoxicatipn, antipyrexia, anti-nociception, anti-inflammation and especially dermatopathy. Interesting in this plant correlated with the effect in dermatopathy, we have searched an antibacterial compound against M. furfur. Finally the high active compound has been isolated and identified as Tryptanthrin.

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The surface of the sea in tropical and subtropical region is a severe environment for the growth of organisms, because active oxygen and free radicals are generated by intense irradiation with strong sunlight. Recently, it has been reported that the marine microorganisms Agrobacterium aurantiacum produced astaxanthin, which has one of the strongest ^1O_2 quenching activities. Then, focusing on fungal type marine microorganisms, we screened ocean fungus for production of excellent carotenoid with antioxidative activity. Here we report on the structural determination and cultural characteristic of a new carotenoid from marine microorganisms. Strain T-1 producing orange pigment was isolated from the surface of sea water at Tanegashima, Kagoshima Prefecture in Japan in August 1999 and identified as a Fusarium sp. The microorganism was cultured in a 10-liter scale at 25℃ for 7 days on a reciprocal shaker, using a modified marine broth medium. The cultured cells were concentrated by centrifugation, then extracted with acetone. After separation and purification by column chromatography on silica gel and HPLC, successively, structures of the carotenoids were analyzed using UV-VIS, MS, ^1H- and ^<13>C-NMR spectrometry. Neurosporaxanthin β-D-glucopyranoside was identified as a new carotenoid from the strain. A yield of carotenoid in 1g freeze-dried fungus body was found to be 0.25mg. Main carotenoids of the strain were neurosporaxanthin (45% out of the all carotenoids), γ-carotene (32%) and the new carotenoid neurosporaxanthin β-D-glucopyranoside (11%). β-Carotene (5%) and torulene (3%) were minor constituents.

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The Okinawan soft coral Clavularia virids is recognized as a rich source of structurally unique antitumor prostanoids such as clavulones and chlorovulones, while other species belonging to the genus Clavularia inhabiting in the Okinawan coral reef contain a number of sesquiterpenoids and diterpenoids instead of prostanoids (Figure 1). Our continuous investigation on chemical constituents of the soft coral belonging to the genus Clavularia resulted in the isolation of a new terpenoid-related compound with a unique skeleton, stolonilactone (1), along with four new sesquiterpenoids (2,3,4 and 5) and two new diterpenoids (6 and 7) from Clavularia koellikeri. From the ethyl acetate soluble portion of the methanol extract of the soft coral, compounds 1-7 as well as (-)-trans-cembranolide and neodollabelenol were isolated by normal phase LCC, and normal and reverse phase HPLC. The plane structure of 1 possessing a fourteen-membered carbocyclic ring with a γ-lactone, bicyclo[2.2.1]heptene, and a cycloheptadiene (Figure 2), was elucidated by the analysis of 1D and 2D NMR spectral data (Table 1, Figure 3). The stereochemistry of three double bonds and the relative configuration of six chiral centers in 1 were assigned based on the NOESY spectral analysis (Figure 4). A possible biogenetic pathway for the unique structure of 1 was proposed: the [4+2] cycloaddition reaction between the clavukerin-type sesquiterpenoid diene and the exomethylene of the cembrane-type diterpenoid may proceed to yield the bicyclo[2.2.1]heptene (Figure 5). The absolute stereochemistry of 1 was thus suggested as shown in Figure 2, because absolute stereochemistries of (-)-trans-cembranolide and clavukerin were previously established.

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Three new diterpenes, tricholomalides A-C (1-3), were isolated from the methanol extract of the fruiting body of Tricholoma sp. Their structures were elucidated on the basis of their spectral data. The absolute stereochemistry of 1 was determined by applying the octant rule to the positive Cotton effect observed at 302nm (Δε=+0.31) due to the cyclopentanone in 1. Compound 2 was converted to 1 during storage at 4℃ in DMSO. Thereby, the absolute configuration of 2 was established as 2S, 7S, 8S, 1OR and 14R. The CD spectra of 2 and 3 revealed the Cotton effects with the same signs for the respective peaks; 234 (Δε-0.22) and 344nm (Δε+0.16) for 3 and 250 (Δε-0.57) and 336nm (Δε+0.53) for 2, which were closely associated with the same conformational and substitutional effects on cisoid α,β-unsaturated ketones in 2 and 3. Consequently, the structure of 3 was determined including the absolute stereochemistry. Tricholomalides 1-3 significantly induced neurite outgrowth in rat pheochromocytoma cells (PC-12) at concentration of 100μM.

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Peperomia duclouxii (Piperaceae) mainly grows in Yunnan, Guangxi, Guangdong and Fujian Provinces of China and is used as anti-cancer agent. There has been no report on its chemical constituents. In order to establish the bioactive compounds, we investigated the constituents of P. duclouxii. Ten new lignans (including 5 dibenzylbutyrolactones, 2 dibenzylbutanediols, 1 diaryltetrahydrofuran and 2 furofuran lignans) were obtained from the ethyl acetate extract and their structures were elucidated by extensive NMR and MS spectra and the absolute configurations were established by optical rotations and CD spectra. The CNS (central nervous system) activities of 1, 3, 5 and 6 are in progress. These isolated lignans indicated that the similar biosynthetic pathway with that in Forsythia maybe exists in P. duclouxii: furofuran lignans (4 or 7) →→ dibenzylbutanediol lignans (2 or 6)→dibenzylbutyrolactone lignans (1 or 5). But the absolute configuration of the starting point (-)-4 and/or (-)-7 was opposite that of (+)-pinoresinol, and the absolute configurations of the reduction and oxidation products (+)-2, (+)-6, (+)-1, (+)-5 were also opposite those of (-)-secoisolariciresinol, (-)-matairsinol, so maybe some other specific enzymes act on this procedure. It will also need more investigation whether the intermediate diaryltetrahydrofuran lignan exist in this procedure, because only (+)-3 was obtained whereas the intermediate should be (-)-3 according to our proposed biosynthetic procedure. Whatever, these results showed that the stereoselectivities of the biosynthesis procedure in P. duclouxii are different with those in Forsythia and most of other plants, and the mechanisms are worth researching. Compounds 8, 9 and 10 were the oxidation products of 5.

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A remarkably diverse array of biologically active alkaloids, for example, blockers of neuromuscular-type, ganglionic-type, and nicotinic receptor channels, occurs in amphibian skin, and over 500 alkaloids have been isolated to date. The structural diversity and pharmacological activity associated with these alkaloids have stimulated research in numerous synthetic groups. Among them, we achieved the first synthesis of the alkaloids 223A has been accomplished, the proposed structure has been revised, and the relative stereostructure of natural 223A was determined. We have demonstrated the first enantioselective total synthesis of the antipode of structurally unique alkaloid 205B, and the absolute stereochemistry of natural 205B has been determined to be 2aR, 5aR, 6S, 8S, 8aR. Furthermore, we achieved the chiral synthesis of quinolizidine 207I and its absolute stereochemistry was determined to be 1S, 4S, 10S by the GC-coinjection analysis of racemic compound and natural product. Finally, we also achieved the synthesis of both stereoisomers for the alkaloid 223I, and the determination of the ralative stereochemistry of natural 223I using GC-coinjection analysis of these isomers and natural product is now under investigations.

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Fostriecin (1, CI-920) is a structurally interesting novel metabolite of Streptomyces pulveraceus that was first isolated in 1983 by a research group at Warner Lambert-Parke Davis. It displays antitumor activity against a broad range of cancerous cell lines in vitro that is suggested to be intimately related to the potent and highly selective inhibitory activity against serine/threonine phosphatase PP2A. Therefore, fostriecin is a novel lead compound for anticancer drugs, as well as an important biological tool. We report herein our formal total synthesis of fostriecin 1. Common intermediates (2 and 24) were synthesized using a unique method that combines four catalytic asymmetric reactions. First, we constructed the chiral tertiary alcohol at C-8 with 85% ee through the catalytic enantioselective cyanosilylation of ketone 9, using titanium-based Lewis acid-Lewis base bifunctinal asymmetric catalyst 14. This reaction could be performed in a 50-g scale. After converting to 17, enantiomerically pure compound was obtained through recrystallization. The second chiral center at the α,β-unsaturated latone was constructed through H. Yamamoto's AgF-(R)-tol-BINAP catalyzed asymmetric allylation of aldehyde 8 (d.r.=28:1). The third chiral center at C-9 was next constructed through the novel direct catalytic asymmetric aldol reaction with aldehyde 6, using acetylene ketone 7 as a donor and Lewis acid-Bronsted base bifunctinal complex (S)-LLB as an asymmetric catalyst (d.r.=3.6:1). Finally, the fourth chiral center was constructed through Noyori reduction (d.r.=>97:3). Combined these four catalytic asymmetric reactions, we achieved the formal catalytic asymmetric synthesis of fostriecin. This methodology may have advantages for synthesizing stereoisomers of fostriecin.

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The Annonaceous acetogenins, those are endemic to certain plants of Annonaceae, are of much interest due to their unique structural features and their significant cytotoxic, antitumor, pesticidal, antiinfective, and antifeedant activities. More than 350 compounds belonging to this family have been isolated to date, and most of them posses one or more THF rings, together with a terminal α,β-unsaturated γ-lactone unit on C-35 or C-37 long carbon chain. In addition to this major group of acetogenins, there are several congeners bearing THP rings in place of the THF ring. Herein, we wish to report synthesis studies of two mono-THF acetogenins and THP containing acetogenin. 1. A total synthesis of cis-solamin (1a) A convergent total synthesis of cis-solamin (1a) and its diastereomer (1b) was accomplished using VO(acac)_2-catalyzed diastereoselective epoxidation followed by cyclization of bis-homoallylic alcohol (2a) as the key step. By comparison of the optical rotation of two possible diastereomers, it is suggested that the absolute configuration of natural cis-solamin is 1a. 2. Synthetic studies on reticulatain-1 (7) Synthetic studies on two possible diatereomers of reticulatain-1, 7a and 7b is described. The THF ring moiety was constructed using Sharpless asymmetric epoxidation, dihydroxilation, and Mitsunobu inversion as the key steps. Sonogashira cross coupling reaction of THF ring moiety with γ-lactone part afforded enyne. Studies directing toward total synthesis is underway. 3. Synthetic studies THP ring moiety of mucocin (16) Synthetic studies on THP part of mucocin (16) is described. The THP ring moiety was constructed using alkoxy palladation as the key step. Further studies is now in progress to examine diastereoselective THP ring formation.

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A short prenyl chain elongating enzyme, farnesyl diphosphate (FPP, C_<15>) synthase (FPS) catalyzes the sequential head-to-tail condensation of isopentenyl diphosphate (IPP, C_5) with an allylic primer substrate, dimethylallyl- (DMAPP) or geranyl diphosphate (GPP) to form FPP [1]. The genes encoding for the enzyme FPS have been cloned and sequenced from a wide variety of organisms [2]. The enzymes have several conserved regions in their amino acid sequences, which include two aspartate-rich motifs. It has been reported that the fifth amino acid before the first aspartate-rich motif (FARM) regulates the ultimate prenyl chain length of the product [3,5-7]. We constructed several kind of mutated FPSs of Bacillus stearothermophilus, in which tyrosine (Y)-81 was substituted with arginine (Y81R), with aspartate (Y81D), or with serine (Y81S). In order to study on the substrate specificity of these mutant enzymes with respect to the artificial allylic substrate homologs that have a hydrophilic group at ω-position, we examined the reactivity as allylic substrates of methoxy- or propoxygeranyl diphosphate (or 3-methylpent-2-en-4-ynyl diphosphate) with IPP for wild and mutated FPSs. The enzymatic reaction of methoxy- or propoxyGPP with IPP by use of wild-type B. stearothermophilus FPS gave methoxy- or propoxyFPP. On the other hand, the reaction of methoxy- or propoxyGPP with IPP by use of the mutated FPS, Y81R (Y81D or Y81S) gave methoxy- or propoxygeranylgeraniol as the major product, which could be given only a trace amount when the wild-type enzyme was employed. From a viewpoint of synthetic application of enzymatic reaction, these enzymatic reactions are interesting for the syntheses of biologically active substances.

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Lysergic acid, which possesses the common core skeleton of various ergot alkaloids, was isolated in 1934 and its structure was determined in 1954. Because of its interesting biological activities and its application to clinical purposes, lysergic acid and the related compounds have drawn much attention of synthetic chemist for a long time. Since the first total synthesis by Woodward, many synthetic routes to racemic lysergic acid have been developed. However, total synthesis of optically active lysergic acid has not yet been reported. In this paper, we describe a route for the synthesis of methyl lysergate featuring (1) conjugated addition of 2,6-dibromoaryllithium to optically active nitroolefin, and (2) Pd-mediated double cyclization, i.e. intramolecular amination and Heck reaction. First, synthesis of optically active nitroolefin was investigated. Easily accessible 1,3-diol was desymmetrized using lipase PS to give monoacetate (6). A nitrogen function was introduced by means of Mitsunobu reaction to give 8, whose enantiomeric excess was determined to be 88% by HPLC analysis. The terminal olefin was cleaved and the resulting aminoaldehyde was transformed to tetrahyrdropyridine derivative (12). Next, diastereoselective allylation to the acyliminium ion generated from 12 was investigated. Excellent selectivity was observed when acetyl or pivaloyl group was used for the protection of the hydroxy group. The high selectivity implies steric bias due to a neighboring group participation of the acyl groups to the iminium ion moiety (Table 1 and Figure 1). After cleavage of the terminal olefin, condensation of the resultant aldehyde with nitromethane gave nitroolefin (15). Coupling reaction of 2,6-dibromophenyllithium and the nitroolefin proceeded smoothly to give the adduct (16), which was transformed to the double cyclization precursor (17). After extensive investigation of the crucial double cyclization, the desired 4-membered skeleton (18) was formed in good yield. Having successfully constructed the desired framework, the requisite functional group manipulations were executed to furnish methyl paspalate (21), a structural isomer of methyl lysergate. Finally, heating of 21 with silica gel, isomerization of the olefin occurred to give methyl lysergate (22). Since transformation of methyl lysergate to lysergic acid has already been reported by Woodward, we have achieved a formal total synthesis of lysergic acid. Currently, we are undertaking further optimization of the established route.

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Ferrier's carbocyclization reaction is a most powerful method for construction of chiral cyclohexenols from carbohydrates. If one can transfer the C-O chirality in cyclohexenols derived from carbohydrates into stereogenic C-C bond formation, versatile chiral building blocks which are useful for synthesis of structurally complicated natural products, would be readily prepared. Herein we report the total synthesis of an Amaryllidaceae alkaloid (+)-vittatine (1), and a sesquiterpene, (-)-fumagillol (3), both starting from D-glucose based on the strategy described above. 1. Total synthesis of (+)-vittatine (1) A cyclohexane unit in (1) was prepared by Ferrier's carbocyclization reaction in an optically active form. Addition of a catechol moiety by Grignard reaction followed by allylic oxidation gave (12), whose stereoselective reduction gave (13). Claisen rearrangement of (13) successfully constructed the quaternary carbon of vittatine. Introduction of a nitrogen function followed by intramolecular aminomercuration generated the perhydroindole skeleton (17). Finally, Pictet-Spengler reaction of (18) completed the total synthesis of (+)-vittatine (1). 2. Total synthesis of (-)-furnagillol (3) The chiral cyclohexenol (22) was prepared stereoselectively from D-glucose by the combination of Ferrier's carbocyclization reaction and reduction. Stereoselective introduction of a carbon side-chain was accomplished by Claisen rearrangement via chirality transfer. Subsequent saponification of ester (25) afford cis-lactone (26) with the desired cis-diol moiety. Elongation of the side-chain by Wittig reaction and Stille coupling, followed by Corey-Chaykovsky epoxide formation and vanadium-catalyzed epoxidation of homoallyl alcohol furnished the (-)-fumagillol (3).

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Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa Korth., and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of structure-activity relationship, and surveys of intrinsic activities and potencies on opioid receptors were studied, as follows. Initially, a variety of mitragynine derivatives were prepared, which included the modification of the substituent at C9 and of the indole nucleus. During this study, we found unusual dimerization reactions of indole alkaloid at C7, when phenyliodine (III) bis (trifluoroacetate) (PIFA) or Pb(OAc)_4, was used. This finding led us to develop a concise total synthesis of meso- and rac- chimonanthines (25 and 26). An indole alkaloid, mitragynaline, was first isolated from the young leaves of Malaysian Mitragyna speciosa Korth. and its chemical structure was proposed in 1991. In the present study, we concluded the structure of mitragynaline to be formula 28 by exhaustive NMR analysis at low temperature, by partial synthesis from mitragynine (1), and finally by X-ray analysis. Opioid agonistic activities of mitragynine-related compounds were evaluated by their ability to inhibit the electrically-induced twitch contraction with guinea-pig ileum preparation. Their affinities for μ,δ, and κ-receptors were determined in a receptor-binding assay. As the result, the essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were clarified. It was found that the methoxy group on the indole ring at the C9 position is essential structural function for opioid agonistic activity. Interestingly, with altering the functional group at the C9 position, i.e., OMe→OH→H, of mitragynine, the activities of compounds dramatically shifted from that of full agonists through partial agonists to that of antagonists on opioid receptors. Mitragynaline (28) was found to exhibit a potent antagonist for opioid receptors. The oxidative derivatives of mitragynine, i.e., 7-hydroxymitragynine (5) and mitragynine pseudoindoxyl (19), were found as opioid agonists with higher potency than morphine in experiment with guinea pig ileum. In addition, 5 induced a potent analgesic activity in the tail flick test in mice. Especially, this compound showed remarkable antinociceptive activity at oral administration in mice. In conclusion, we could find a promising lead-molecule for the development of new type of analgesics, which were structurally different from morphine.

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Macrolactin A, which was isolated from a deep sea marine bacterium in 1989, exhibits a broad spectrum of activity with significant antiviral and cancer cell cytotoxic properties, for example controlling human HIV replication and inhibiting Herpes simplex types I and II. Because of its unique structural architecture and broad therapeutic application, Macrolactin A has been an attractive target for total synthesis and has further led to the development of novel synthetic methodology. However, it would be difficult to apply Macrolactin A for clinical use due to its structural instability. Therefore, we designed new structural analogues of Macrolactin A by replacing the (8E,10Z)-dienic system to a more rigid aromatic ring. We report herein the asymmetric synthesis of Macrolactin A analogue. Our initial strategy involved the asymmetric addition of conjugated dienylanion species derived from Fragment A to the aldehyde (Fragment B). The C23 stereocenter of Fragment A was introduced by asymmetric methylation with (+)-TADDOL as a chiral ligand, and the C7 and C13 stereocenters of Fragment B were constructed by asymmetric propargylation according to Yamamoto's procedure and asymmetric aldol addition with (S)-4-isopropyl-1,3-thiazolidine-2-thione, respectively. The absolute configurations of these stereocenters (C7, C13) were determined by modified Mosher's method. Unfortunately, the reaction of dienylzinc species prepared from Fragment A with Fragment B afforded no addition products, while the desired product 14 could be obtained by the Cr(II)-mediated cross-coupling in moderate yield with no stereoselectivity. To improve the stereoselectivity of C15 stereogenic center, we developed a new synthetic strategy involving isomerization of ynone 23 to E,E-conjugated dienone followed by diastereoselective reduction of β-hydroxyketone 24. Subsequent CuTC [copper(1) 2-thiophenecarboxylate]-mediated coupling with methyl (Z)-3-iodopropenoate gave the macrocyclization precursor 26 in much higher yield than the palladium-catalyzed Stille cross-coupling. Macrolactonization using a Yamaguchi protocol followed by deprotection of the protected macrocycle 28 gave the desired Macrolactin A analogue 1.

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Enantiocontrolled syntheses of γ-substituted butenolides (1), bearing with alkyl, alkenyl and aryl substituents, were established from a chiral tricyclic lactone (3) via continuous diastereoselective nucleophilic addition, followed by retro-Diels-Alder reaction as key steps. Both enantiomers of lactone (3) were prepared from known chiral alcohol (4) in large scale. Continuous nuceleophilic addition to lactone (3) proceeded diastereoselectively to construct chiral secondary and tertiary alcohol moieties and to furnish diol (10). Some of the newly generated asymmetric centers were controlled by the order in which the nucleophilic reagents were added. After oxidation of 10 to lactone (13), a retro-Diels-Alder reaction of 13 in refluxing diphenyl ether yielded corresponding γ-substituted butenolides (1). The synthetic butenolides (1) were utilized for the formal and total syntheses of natural products, such as (+)- and (-)-trans-quercus lactones (14), (-)-ngainone [(-)-16], (+)-ipomeamarone [(+)-16], and a constituent in lavender (Lavandura vera D. C.) oil (1e). During this research, we also found a new type of retro-Diels-Alder-ene (RDAE) reaction of lactone (17), bearing with homoprenyl and homocrotyl substituents at their γ-position, to yield bicyclic lactone (19). In the case of homocrotyl substituent, RDAE reaction afforded a single lactone (19b) with the corresponding butenolide (18b, 18c) in spite of their geometry of the alkene moiety. This result showed that RDAE reaction proceeded through the exo transition state in the case of (Z)-alkene and through the endo one in the case of (E)-alkene. The RDAE reaction was strongly accelerated by the introduction of trimethylsilyl (TMS) group on a crotyl unit to yield a single lactone (19c) without the butenolide (18c). The lactone (19c) was transformed to known bicyclic lactone (22) via oxidation of vinyl silane and following acidic ring opening of the epoxide as key steps. From 22, total synthesis of (+)-methyl jasmonate (24), which was isolated from jasmine and was an important compound in plant growth regulation, was achieved in 7 steps via 6-epi-cucurbate (23). In conclusion, we established new enatiocontrolled, partially enantiodivergent, syntheses of γ-substituted butenolides, bearing with versatile γ-substituents, from a chiral tricyclic lactone (3). We also achieved total synthesis of some natural products utilizing the synthetic γ-substituted butenolides (1) as key intermediates.

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Polyhydroxylated nitrogen heterocycles azasugars may be considered to be mimics of sugars in which the ring oxygen has been substituted for a nitrogen atom. The often potent inhibitory activity of many of these compounds toward carbohydrate-processing enzymes has suggested their use in a wide range of potential therapeutic strategies including the treatment of viral infections, cancer, diabetes, tuberculosis, lysosomal storage diseases, and parasitic protozoa. Recently three fagomine 3-epi-fagomine, and 3,4-di-epi-fagomine were found from Xanthocercis zambesiaca occurring in southern Africa in dry forest and three 3,4,5-trihydroxypiperidines were also isolated from Eupatorium fortunei Turz. Some of them have been shown to have some activity against mammalian α-glucosidase and β-galactosidase. We describe herein a new entriy to the synthesis of all stereoisomers of fagomine including 4-epi-fagomine by the preparation of chiral building block: 2-silyloxymethyl 3-piperidene in a traightforward and stereoselective manner using the Garner aldehyde and catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring. In addition, their inhibition of glycosidase activites were examined. Next, the stereoselective synthesis of all 3,4,5-trihydroxypiperidines using 4-piperiden-3-ol as building block obtained by the reaction of vinyl epoxide with allylamine followed by RCM is disclosed.

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Synthesis of Amphidenolide T1 (1) was studied using palladium-catalyzed hydrogenolysis of alkenyloxiranes as key reactions for constructing vicinal stereogenic centers of synthetic segments 2 and 3. Starting with the allylic alcohol 8, Sharpless asymmetric epoxidation of 8, followed by oxidation of the alcohol to the corresponding aldehyde and Horner-Emmons reaction gave the optically active (E)-alkenyloxirane 10. The reductive opening reaction of the oxirane was carried out selectively with retension of stereochemistry to give the alcohol 11 in 93% yield. After protection of the alcohol as TBS ether, ester was reduced with DIBAH followed by stereoselective epoxidation afforded epoxy alcohol 12. Then 12 was converted to 14 via regioselective opening of epoxide and cyclization. Coupling with 6, reduction of the double boond and deprotection of the Piv group formed desired synthetic intermediate 2. Using similar procedures, the allylic alcohol 16 was converted the vinylsulfonyloxiran 18. The reductive opening reaction of the vinyl sulfonyl oxirane was carried out selectively to give the alcohol 19 in 88% yield. Protection of the alcohol as MOM ether and reduction of the double bond with NaBH_4 gave sulfone 20. And coupling reaction of 20 with 7 by using of n-BuLi and BF_3・Et_2O afforded 21. Julia methylenation of 21 gave 22, subsequent deprotection and oxidation furnished the other synthetic intermediate 3. Total synthesis of 1 from the synthetic segments 2 and 3 is under way.

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Dihydrocuscohygrine, C_2-asymmetrical pyrroridine alkaloid, was isolated from Erythroxylon Coca leaves by Turner in 1981. We show here synthetic studies on dihydrocuscohygrine using 6 as a starting material. Our labolatory have been developed that C_2-asymmetrical bisxazolidine obtained easily from 6 and dialdehyde was reacted with Grignard reagent to afford diamine with high diastereoselectivity. First, we tried the synthesis of (-)-deoxycuscohygrine which bisxazolidine(7) could be prepared more simply. A key reaction, addition reaction to bisxazolidine with 1,3-dioxanylethylmagnesium bromide as Grignard reagent proceeded to afford 13 preferentially. Acidic cyclization of 13 provided the desired product(14), which was transformed to 1 via hydrolysis with Raney Ni in methanol. Asymmetrical synthesis of (-)-deoxycuscohygrine was accomplished from bisoxazolidine(7) in 4 steps. Similarly, asymmetrical synthesis of (-)-dihydrocuscohygrine carried out using addition reaction of Grignard reagent to bisoxazolidine(19) prepared from 15 gave diamine(20) with high diastereoselectivity. The absolute configuration at stereogenic center was established as R,R by X-ray analysis of a single crystal of 21. C_2-Asymmetrical synthesis of (-)-dihydrocuscohygrine was also accomplished from 15 in 10 steps and 9% overall yield.

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Kinamycin antibiotics and prekinamycin, produced by Streptomyces murayamaensis, were firstly proposed to be composed of N-cyanobenzo[b]carbazoloquinone skeletons. After that, the ring systems were revised to be benzo[b]fluorene skeletons with diazoalkane moiety based on synthetic studies and re-examination of their spectral data. However, the revised structure of prekinamycin was not identical with natural product, instead, an isomeric benzo[a]fluorene skeleton was proposed for the natural product, which was newly named as isoprekinamycin. We have started to synthesize the revised structure 2a of kinamycins for due to these structural confusions. Our synthetic strategy is as follows: synthesis of benz[f]indenone 5 and the Diels-Alder reaction with diene 6 followed by the elaboration of a highly oxygenated D ring. We tried the elaboration of D ring using a model indenone 7. Diels-Alder reaction of 7 and diene 6 followed by acid hydrolysis and oxygenation gave hydroxyketone 11. Hydroxylation and then stereoselective reduction gave tetraol 13. Dihydroxylation of TBS ether of 13 gave triol 17 with desired configurations on D ring. Dehydration followed by introduction of diazo moiety led to the successful synthesis of 9-diazofluorene 24. We next turned to the synthesis of 2a. Benz[f]indenone 5 was prepared by cyclization of 28, derived from bromonaphthalene 25, followed by oxidation with IBX. Successive reactions of Diels-Alder reaction with 5 and 6, acid hydrolysis and oxygenation afforded hydroxyketone 30. syn-Selective dihydroxylation of 30 followed by hydroxylation gave tetraol 34a, which was reduced with Me_4NBH(OAc)_3 to yield the expected pentaol 36.

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Quinazolinone-type alkaloids, febrifugine (1) and isofebrifugine (2), isolated from Dichroa febrifuga roots, show powerful antimalarial activity against Plasmodium falciparum. Unfortunately, their emetic effect and other undesirable side effects have precluded their clinical use in malaria. Due to their antimalarial potency, analogues were searched for, with the goal of preserving the strong antimalarial activity, while dramatically reducing side effects. We expected that compounds useful in drug development would exist in metabolites derived from 1 and Df-1 (3), the condensation product of 1 with acetone, by mouse liver S9. Feb-A and B (5 and 6) were isolated as the major metabolites of 1. In addition to 5 and 6, feb-C and D (7 and 8) were also purified from the metabolic mixture of 3.5 and 6 were compounds oxidized at C-6 and C-2 of the quinazolinone ring of 1, respectively. Compounds 7 and 8, derived from 3, also bear febrifugine-type structures in which 1 were oxidized at C-4" and C-6", respectively. In vitro antimalarial and cytotoxic tests using synthetically obtained racemic 5-7 and enantiomerically pure 8 demonstrated that 5 and 7 had antimalarial activity against P. falciparum, of similar potency to that of 1, with high selectivity. Antimalarial activity of 6 and 8, however, was dramatically decreased in the test. The results suggest that basicity of both the 1 and 1"-nitrogen atoms of 1 is crucial in conferring powerful antimalarial activity. Racemic 5 and 7 exhibited powerful in vivo antimalarial activity against mouse malaria P. berghei, and especially no serious side effects were observed with 5 and 7. Thus, the metabolites 5 and 7 appear to be promising lead compounds for development of new types of antimalarial drugs.

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Lycopene has aroused public interest owing to its role in preventing oxidative damage, cancer and aging, etc. These activities are considered to be due to its high ability of scavenging active oxygen species. In the present work, we have examined the products formed by the photosensitized oxygenation, hydrogen peroxide oxidation, m-chloroperbenzoic acid (mCPBA) oxidation and peroxinitrite oxidation of lycopene. We also isolated two oxygenated lycopenes with a novel five-membered ring end-group from tomato puree. In photosensitized oxygenation (singlet oxygen oxidation), we isolated apo-6'-lycopenal and 6-methyl-5-hepten-2-one. The reaction is supposed to proceed via 1,2 addition of singlet oxygen to 5,6 double bond of lycopene. In hydrogen peroxide and m CPBA oxidation, we isolated oxygenated lycopenes with a novel five-membered ring end-group (2,6-cyclolycopene-1,5-diol, 2,6-cyclolycopene-1,5-epoxide, 1,16-didehydro-2,6-cyclolycopene-5-ol and 1-methoxy-2,6-cyclolycopene-5-ol). It is proposed that the formation for these compounds occurs by rearrangement of lycopene 5,6-epoxide. In peroxinirite oxidation, we could classify the products into three types, 1) oxidative cleavage products, 2) non-cleavage oxidative products that have C40 carbon skeleton, and 3) Z-isomers of lycopene. The reaction pathways to form these compounds will be discussed.

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Nowadays, allelopathic agents have received a considerable amount of attention due to the agricultural potential of these compounds as environmentally benign herbicides. In 2000, F. A. Macias and his co-workers isolated breviones A〜E (1〜5) from Penicillium brevicompactum Dierckx as allelopathic agents. These compounds are structurally unique natural products consisting of diterpene and polyketide subunits. Especially, the spiro-fused CDE ring portion of breviones A〜D (1〜4) is characteristic and unusual. The useful biological activities and the unique structures of breviones attracted our attention and prompted us to undertake a project to synthesize them. A crucial point in the synthesis of breviones should be the construction of the characteristic spiro-fused CDE ring framework, and our plan for construction of the CDE ring system was based on the direct coupling of 14 and 7. Initially we examined the reaction of 6 and 7, and found that palladium(0)-mediated double S_N2'-type tandem reaction was efficient for the synthesis of the model compound (8). The next stage of our project was the total synthesis of brevione B (2). The known hydroxy ketone 10 was converted into enone 12 by 6 steps. The construction of the vinyl epoxide moiety of 14 was accomplished by the three steps from enone 12: treatment with methyl lithium, epoxidation with mCPBA, and dehydration with SO_2Cl_2. Although our attempts to obtain 18 by palladium(0)-mediated tandem reaction met with failure, after further detailed examination of this key reaction, we eventually found that the desired coupling reaction proceeded smoothly to give 18 without any catalyst. Finally, the protecting group of 18 was removed by treatment with acetic acid to furnish (±)-brevione B (2). Thus the first synthesis of (±)-brevione B (2) was accomplished by employing the double S_N2'-type tandem reaction as a key step. The enantioselective synthesis of breviones is now in progress.

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Many alkaloids possessing 1-substituted tetrahydroisoquinoline skeleton show unique pharmacological activity. Thus, construction of this class of compounds in optically active forms has drawn much attention of synthetic organic chemists. Although many efficient methodologies have been reported, most of them use stoichiometric asymmetric reaction for introducing the chirality at C1. A few highly enantioselective syntheses using catalytic asymmetric reactions have also been reported but, in these syntheses, the chirality introduction and the hetero-cyclization have been carried out in separate steps. We expected that the more efficient synthesis would be realized, if chirality introduction and the hetero-cyclization can be carried out in a single step. Intramolecular allylic amination was considered to be a highly potent method from this point of view. Furthermore, the resulting chiral tetrahydroisoquinoline bears 1-vinyl group that is amenable to further functionalization. We have already demonstrated that chiral 2-(phosphinophenyl)pyridine ligands bearing 7-substituted dihydropyrindine unit are efficient chiral auxiliaries for palladium-catalyzed allylic alkylation of both acyclic and cyclic alkenyl substrates. Thus, we examined palladium-catalyzed asymmetric intramolecular allylic amination of 1 using 2-(phosphinophenyl)pyridine as the chiral auxiliary. The key intermediate allylic acetate 1a and pivalate 1b was prepared from commercial 3,4-dimethoxy-β-phenethyl amine in a conventional manner. The allylic pivalate 1b was found to undergo the desired intramolecular allylic amination using Pd(0) complex of 2-(phosphinophenyl)pyridine 2 as the catalyst in the presence of potassium carbonate to give the desired 1-vinyltetrahydroisoquinoline 6 of 88% ee. The compound 6 was converted into (R)-carnegine in six steps. Thus, we were able to demonstrate the newly developed asymmetric intramolecular allylic amination using Pd(0) complex of 2-(phosphinophenyl)pyridine 2 as the catalyst was a useful tool for asymmetric synthesis of isoquinoline alkaloids.

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The proanthocyanidins are known as condensed tannins and/or oligomeric flavonoids, in which flavan-3-ol units are linked together by carbon-carbon bonds from the 4-position of one unit to the 8-position of the next unit. Many biological activities, powerful antioxidant activity, free-radical-scavenging activity and an anti-tumor-promoting effect, have been reported for flavonoids and their investigation is now increasingly important. Proanthocyanidins have been obtained from many kinds of plants, but because they are usually obtained as a complex mixture of structurally related compounds, it is very difficult to isolate them in a pure form. Consequently, we planned to develop efficient synthetic methods leading to procyanidins with a high level of purity and stereoselectivity. We previously described TMSOTf-catalyzed intermolecular condensation achieved high levels of 3,4-trans condensation in excellent isolation yields to synthesize procyanidin dimers. We report here in detail TMSOTf-catalyzed intramolecular dimer synthesis. Although intramolecular condensation of catechin-catechin units afforded 3,4-cis dimers selectively, condensation of catechin-epicatechin, epicatechin-catechin and epicatechin-epicatechin gave 3,4-trans dimers. The trimer synthesis with intramolecular condensation methdod is now underway. And we also report stereoselective synthetic studies of eight trimers with intermolecular condensation method. Monomer electrophiles reacted with dimer nucleophiles in the presence of TMSOTf and afforded the corresponding trimers. Catechin trimer and epicatechin-epicatechin-catechin trimer were synthesized in good yields with this method. However, when catechin-epicatechin dimer was used as a nucleophile, the TMSOTf-catalyzed condensation with catechin or epicatechin electrophile did not proceed at all. The inhibitory activity of Maillard reaction was tested using catechin 1, epicatechin 2, synthesized procyanidin oligomers, their methylated and acetylated compounds. As a result, phenolic and their acetylated compounds inhibited the Maillard reaction strongly, but methylated compounds had no inhibitory activity.

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A plant hormone, abscisic acid (ABA, 1) regulates physiological adaptation to environmental stress such as water deficiency, embryonic development, and so on. ABA has electrophilicity derived from the conjugated dienecarboxyl group in the side chain. Terem and Utley reported that ABA methyl ester (1-Me) gave a bicyclic compound (3) by cathodic reduction in electrolysis. An electron from a cathode could localize at C-2 of ABA, and C-2 may attack C-2' to give compound 3. The electrophilicity of ABA may be important for binding to a receptor, and anion radical of ABA could be used to label receptor proteins. We have studied the electrochemical property of ABA by analysis of its cathodic reaction. First, we chased the experiment of Terem and Utley with 100% CH_3CN solution of ABA methyl ester. However, no significant product formed under their condition. When the solvent was changed to an aqueous CH_3CN solution without pH control, a major product, 3-methyl-5-(1,3,3-trimethyl-2,5-dioxo-cyclohexyl)-pent-3-enoic cid (4), formed. The spectral data of its methyl ester (4-Me) was almost coincident with those of 3. ABA methyl ester in buffer solutions was reduced at a cathode at pH 3, 7, and 10. Cyclic voltammetry showed irreversible reduction with a peak potential at -1.6V. At pH 3 and 7, the ester gave 4-(1-hydroxy-2,2,6-trimethyl-4-oxo-bicyclo[4.1.0]hept-7-yl)-3-methyl-but-3-enoic acid methyl ester (5-Me) as a major product, and, at pH 10, 4-Me formed in addition to compound 5-Me. Compound 4-Me, an isomer of 5-Me, formed by isomerization under an alkaline condition. This finding showed that an electron localizes not at C-2 but at C-5, and C-5 attacks C-2'. Non-empirical calculation proved that Muliken negative charge and spin density at C-5 is the highest in anion radical of ABA methyl ester. Compound 3 was not detected under these conditions, suggesting that Terem and Utley incorrectly identified compound 4-Me as compound 3. Cyclic voltammetry of ABA was similar to its methyl ester. Cathodic reduction of ABA at pH 3 and 7 gave compound 5 as a major product. At pH 10, compounds 5 and 4 were not formed, and 1-deoxy-ABA (6), a dimer (7) with epoxy group and other compounds formed. The difference of the product at pH 10 between ABA and its methyl ester would be caused by dissociation of the carboxyl group. Cathodic reduction of phaseic acid (2), a metabolite of ABA, gave compound 8, showing that C-5 directly attacks C-4'. New compounds 4, 5, 7, and 8 were inactive in rice seedling test and lettuce seed germination test. This result suggests that the electrophilic side chain of ABA at C-1' is important for the biological activity.

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Many marine imidazole alkaloids such as clathridine 1, Naamidines (2-4), pyronaamidine 5 and isonaamidines (6, 7) have (1-methyl-2,5-dioxo-1,2,5H-imidazolin-4-yl) amino (MDA) moiety, which seems to be important for their antitumor and antifungal activities. We examined the dehydrative condensation of parabanic acid derivative with primary amines, and found an efficient and regioselective method for introduction of MDA by using 1-methyl-3-trimethylsilylimidazolidinetrione (9). The condensing agent 9 could be prepared from 1-methylparabanic acid 8 in 58% isolated yield by treatment with TMS_2NH. The reagent 9 gave regioselectively the desired condensation products 10 in 58-98% yields by only stirring with various primary amines in refluxing CHCl_3. Total syntheses of 1, 5, 6 and 7 were successfully achieved by applying the present method to the corresponding 2-aminoimidazole derivatives, prechlathridine A (12), naamine C (23), 33 and isonaamine A (34). Several synthesized compounds containing the MDA group were evaluated their antitumor activity, and some of them showed significant cytotoxicity against a wide variety of human tumor cells.

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A yeast strain, Torulaspora delbrueckii IFO10921 catalyzes the enantiotopic group-selective, and enantioface-selective reduction of 2-methyl-2-(3-oxoalkyl)cycloalkane-1,3-diones to give stereochemically pure forms of bicyclic hemiacetals. These yeast-mediated reduction products are the equivalents of hydroxyketones, and the subsequent chemical transformation to bicyclic compounds warranted their stereochemistries and stereochemical purities. Next, we achieved a novel approach to the enantiomerically pure forms of 2-alkenyl-3-hydroxy-2-methylcycloalkanones such as 14. Hemiacetals 5 and 9 served as the unique precursors, which underwent β-fragmentation of the corresponding alkoxy radicals to give eventually β-acetoxyketones 15 and 16 with 2-alkenyl substituent. This transformation was realized under the reflux condition of conbined use of PhI(OAc)_2, Cu(OAc)_2 and 2,6-lutidine in benzene in 39-65% yield. Through this fragmentation reaction, part of the original hemiacetal skeleton was converted to the protecting group of the newly liberated hydroxy group as the form of acetate. To demonstrate the synthetic potential of above β-acetoxyketones 15 and 16, we have developed straightforward routes to highly functionalized cyclohexanones and cyclopentanones, towards the syntheses of natural products. Carbonyl group of 15 was protected as 1,3-dioxolane and the subsequent ozonolysis and the reductive workup yielded a 2-alkoxymethyl-3-hydroxy-2-methylcyclohexanone equivalent 18. Hydroxyl groups of 18 could be protected with TBS and benzyl groups, and the subsequent methylation to give 20 and 22, which would be useful for synthesis of diterpenoid, such as triptocallol. On the other hand, a sterically congested cyclopentenone 27, possessing three functional groups directly attached to a quaternary chiral center, was efficiently obtained from 16. The introduction of two independent side chains was successful to provide 30, a key intermediate to madindoline.

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The importance of domino reaction, a consecutive bond forming reaction as a result of previous reaction, has been increasing in view of efficiency in organic syntheses. One of the fundamental nucleophilic domino reactions is the double Michael reaction of the kinetic enolate of cyclohexenone 1 with acrylate 4 leading to endo-bicyclo[2.2.2]octane derivatives 5, which required a stoichiometric amount of amide base 2 in aprotic media. We found for the first time two catalytic processes based on oxophorone derivatives 1 and cyclohexenone derivatives 11, respectively. By employing 0.1 equiv of LDA, reaction of oxophorones 1 with acrylates 4 provided bicyclo[2.2.2]octane-2,4-dione derivatives 7 in high yield. By employing a catalytic amount of bicyclic enolate 9', the reaction afforded bicyclic compound 7 in comparable yield. Based on this finding, autocatalytic cycle is proposed, in which bicyclic enolate 9' generated after second Michael reaction drives the catalytic cycle. The reaction was general with various oxophorone derivatives, acrylates and amide bases. Especially, complete diastereoselection was observed by employing 8-phenylmenthyl acrylate 10. In addition, recylcle use of amine for amide base was realized up to 5 times by using solid amine grafted on silica (NMAP). While, by employing 0.2 equiv of NMAP-Li, domino Michael reaction of trimethylsilylenol ether of cyclohexenone 11 with acrylate furnished bicyclo [2.2.2]octane derivative 5. In this reaction also NMAP was recycled up to 2 times. The reaction is proposed to proceed by Lewis base catalysis via hypervalent silyl intermediates. Utility of this protocol was exemplified by total synthesis of a new sesquiterpenoid, valeriananoid A 22 having a unique tricyclic carbon framework same as that of patchouli alcohol. This compound 22 was isolated by De Quan Yu et al. in 1997 from Valeriana jatamansii Jones which widely distributes in south-western China and the roots of this plant have been utilized as a Chinese folk medicine. Synthesis has started from bicyclo[2.2.2]octane-2,4-dione derivative 7 obtained by autocatalytic domino Michael reaction of oxophorone 1. Conventional ketalization allowed selective protection of the less hindered ketone to provide ketal 16. Treatment of the ketoester 16 with sodium ethoxide in ethanol resulted in complete isomerization of the ester group into the same side as the carbonyl group in 96% yield. Reduction of the ketoester 17 provided diol 18 in 95% yield. Oxidation of the diol 18 followed by addition of MeLi provided alcohol 19 in 72% overall yield (2 steps). PDC oxidation of alcohol 19 provided methylketone in 93% yield. Addition of vinylmagnesium bromide provided allylalcohol 20 as a separable mixture of diastereomers in 99% combined yield. Protection of the tertiary allylalcohol 20 as a MOM ether was successful in 75% yield by employing excess t-BuOK. The 6-endo-Trig-cyclization by single electron transfer process employing sodium provided tricyclic compound 21 in 44% yield. Catalytic hydrogenation of olefin 21 followed by hydrolysis of ketal moiety completed total synthesis of valeriananoid A 22.

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The photodynamic pigment stentorin (1), isolated from the protozoan Stentor coeruleus, is one of the longest known natural products having a perylenequinone skeleton. As a related family of this pigment, hypericin (2) and blepharismins (3) are also known. Due to their characteristic structure and interesting biological activity including anti-HIV activity, these compounds have attracted a considerable attention from organic as well as synthetic chemists. In our own efforts directed toward the total synthesis of stentorin, we have developed new synthetic methods: 1. A new practical method for the regioselective nucleophilic aromatic alkylation of p-methoxy-substituted benzoic esters with Grignard reagents, 2. An efficient construction of an anthraquinone key intermediate based on the coupling between 5 and 6, followed by intramolecular Friedel-Crafts acylation and oxidation, and 3. Construction of perylene derivative 19 via the oxidative coupling of anthracene 18 using FeCl_3. The final step for the conversion of 19 to 1 is now underway.

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Callipeltin A (1) is a cyclodepsipeptide from water sponge collected at New Caledonia. This compound shows anti-HIV and cytotoxic activities against KB and P388 cells and contains three new amino acid residues. β-methoxytyrosine (β-MeOTyr) (4), (2R,3R,4S)-4-amino-7-guanidino-2,-3-dihydroxyheptanoic acid (AGDHE) (5), (3S,4R)-3,4-dimethyl-L-glutamine (diMeGln) (6). In addition, two new truncated open-chain derivatives of Callipeltin A (1), named Callipeltin D (2) and E (3) were isolated. The unique structure and intriguing biological activities of this compound led us to explore total synthesis of Callipeltin A (1) and to elucidate stereochemistry of β-MeOTyr (4). We started to synthesize Callipeltin E (3) which contains β-MeOTyr (4). In order to synthesize four stereoisomer of β-MeOTyr (4), we attempted Evans anti or syn-Aldol reaction as a key step. Evans direct anti-aldol reaction with chiral benzyloxazolidinones (8) and p-hydroxy benzaldehyde (9) promoted by catalytic amounts of MgCl_2 in the presence of triethylamine and chlorotrimethylsilane. This proceder provide 3:1 diastereoselelctivity and 70% yield of isolated anti-aldol product (10). And Enolizalion of isocyanate oxazolidinone (13) with di-n-butylboryl trifrate and diisopropylethylamine followed by treatment with aldehyde 8 afford syn-aldol product 14 affording 88% yield and 1:5 anti: sin diastereomeric ratio. On the other hand, we tried Sharpless Asymmetric dihydroxylation (AD) and Aminohydroxylation (AA) to give all four stereoisomers of β-MeOTyr. Treatment of olefin (18) with AD-mix α provided diol (19) and the α position alcohol of 19 was converted to sulfone regioselectively followed by azidation and treatment of 20 with PPh_3 to afford aziridine (21). Addition of aziridine (21) and BF_3・Et_2O in methanol produced α-amino β-methoxy adduct (22). AA reaction protocol with t-butylcarbamate was successfully applied to afford desired 22 in single step. Now we construct Callipeltin E to determine absolute stereochemistry of β-MeOTyr (4). In addition, we report the synthesis of diMeGln (6) and (2R,3R,4S)-3-hydroxy-2-4-6-trimethyl hepanoic acid (7).

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Macrosphelides A-L are a family of 16-membered macrolides whose characteristic structure and potent cell-cell adhesion inhibitory activity have attracted a number of chemists and biologists. These natural products were isolated from Macrosphaeropsis sp. FO-5050 and Periconia byssoides, and reported to inhibit adhesion of human leukemia HL-60 cells to human-umbilical-vein endothelial cells with a high selectivity. As part of our ongoing study on the structure-activity relationships of macrosphelides, we planned to develop novel strategies for the synthesis of the macrosphelide family and its analogues, which include various oxidative derivatization of Macrosphelide Core (1) and a new synthetic route for macrosphelides A and B based on ring-closing metathesis. The synthesis of our initial target compound, Macrosphelide Core (1), was accomplished starting from methyl (S)-3-hydroxybutyrate (2) in 11 steps with a 37.2% overall yield (Scheme 2). This core compound could be converted into functionalized macrosphelides, including macrosphelide A, C, and several epoxy derivatives, as shown in Scheme 3. In addition, to achieve effective synthesis of macrosphelides A and B via a common synthetic process, we selected the macrocycle 35 as their precursor, which contains distinguishable protecting groups. For the construction of the macrocyclic system, ring-closing metathesis of 34 was our choice. On the basis of this strategy, we established the total synthesis of macrosphelides A and B from two commercially available chiral materials, methyl (S)-(+)-3-hydroxybutyrate (2) and methyl (S)-(-)-lactate (19) with high efficiency. In this meeting, details of these results will be discussed.

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Tobacco wildfire disease, caused by infection of tobacco wildfire disease fungus Pseudomonas tabaci, has been the most serious pest for tobacco, and tabtoxin (1) was isolated from the fungus as a phytopathogenic toxin. 1 is converted by host plant peptidases to tabtoxinine-β-lactam (2), which inactivates glutamine synthetase irreversibly. 1 can be a selective pesticide when crops resistant to 1 are developed. We began the synthetic studies of 2 to supply samples to its biological tests and to develop an efficient synthetic route. Zinc mediated coupling of iodide 4b with ester 6 and silyl ether 9 gave 10b and 13b, respectively. Sharpless asymmetric dihydroxylation of the double bonds of each compound afforded 19b (20-30%de) and 21b (81-91%de), respectively. The primary hydroxy group of the diol 19b was converted to amino group, and magnesium mediated β-lactam formation and deprotection gave 2. However, the diastereomeric selectivity of the dihydroxylation of 19b had not improved. So, we tried the conversion of 21b. Oxidation of the primary hydroxy group of 21b gave acid 32b. The corresponding benzyloxy amide 33b was converted to mesylate 35b. The key β-lactam formation using NaH afforded 36b. The last deprotection steps are now in progress.

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Antifungal substances, cystothiazoles and melithiazoles, were isolated from different strains of myxobacterium Cystobacter fuscus and Melittangium lichenicola, respectively. They are related to the oudemansins and myxothiazole which are naturally occurring congeners of β-methoxyacrylic acid. These antibiotics possessing a bis-thiazole skeleton as well as a β-methoxyacrylate moiety have indicated potent antifungal activity against the phytopathogenic fungus, and have shown activity against a broad range of additional fungi with no effect on bacterial growth. The fungicidal activity of these β-methoxyacrylate (MOA) inhibitors has been shown to be due to their ability to inhibit mitochondrial respiration by blocking electron transfer between cytochrome b and cytochrome c. We describe total synthesis of (+)-cystothiazoles A, B, F and (4R,5S)-melithiazoles B, F, H, I based on a catalytic synthesis of the β-methoxyacrylate moiety including the adjacent chiral centers. Retrosynthetically, the synthesis of cystothiazoles and melithiazoles can be achieved by Wittig condensation of the left-half aldehyde 1 and the right-half phosphonium iodide 2. Palladium-catalyzed cyclization-methoxycarbonylation of (2R,3S)-3-methylpenta-4-yne-1,2-diol 3 derived from (2R,3S)-epoxy butanoate 4 followed by methylation gave the tetrahydro-2-furylidene acetate 7, which was converted to the left-half aldehyde 1. A Wittig reaction between 1 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 2 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazoles A,B,F and (4R,5S)-melithiazoles B,F,H,I.

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A manzamine alkaloid nakadomarin A (1) was isolated from Okinawan Marine sponge Amphimedon sp. by Kobayashi and co-workers in 1997. Although some interesting biological activities of 1 have been reported, its limited availability has prevented a complete survey of its biological activity. Recently, we accomplished the first total synthesis of rac- and ent-1. However, an optical resolution of the key carboxylic acid gave only undesired isomer efficiently. Therefore, we have developed a new synthetic route to natural form of 1. Since the stereocenters of nakadomarin A are as same as those of ircinal A, we planed a new synthetic route using the same intermediate 7 which was developed for our previous synthetic study of ircinal A. The key intermediate 7, which was obtained by Diels-Alder reaction of 8 and 9, gave the tricyclic intermediate 10 via allylic cation intermediate (S_N' reaction) under the acidic conditions. Ozonolysis of 11, followed by aldol condensation with TAMA gave ring contracted intermediate 12, ABD rings. The furan ring (C ring) was constructed from endoperoxide 20 which was prepared by oxidation of 1,3-diene 19 with singlet oxygen. A presence of alkynyl side chain is essential to prevent isomerization of a terminal unsaturated bond under strong acidic conditions. We have observed that a dicobalt hexacarbonyl complex was useful as the protection of alkyne under RCM conditions. E ring was constructed using second-generation Grubbs catalyst. F ring was constructed by reduction of a dicobalt hexacarbonyl complex into an olefin, followed by the second RCM. Finally reduction of bislactum has accomplished the first asymmetric total synthesis of natural (-)-1.

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Since manzamine B (1) have been isolated from Okinawan marine sponge Haliclona sp. By Higa and co-workers in 1987, its pentacyclic structure involving large membered rings have been attractive as a synthetic target. While its interesting biological activities, such as cytotoxicity against P388 mouse leukaemia cells (IC_<50> 6μg/mL) and antitumor activity, have been reported, complete survey and further investigation have been prevented due to its limited availability. Herein, we report our synthetic approach of 1. Initially, we set the compound 7 as a key intermediate. In order to obtain 7 as an optically active form, asymmetric Diels-Alder reaction between 8 and aminodiene (9) using chiral-Cr-Salen complex was studied. After screening to reaction conditions, we have realized that 7a was obtained in 30% yield with up to 88% ee using carbamate-type aminodiene (9a). Amide-type aminodiene (9d) gave 7d in 37% with up to 81% ee, respectively. Next, construction of C-ring was investigated. Alkylation of formyl group of 7d, readily available by deprotection of N-allyl group with Pd (0), proceeded by Peterson reaction in 80% yield. After conversion of silyl enol ether to the corresponding ketal (23d), removal of N-chloroacetyl group was accomplished in pyridine under reflux conditions. Further transformation is currently under investigation.

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Phomopsidin was isolated from Phompsis sp. TUF95F47 by Namikoshi and co-workers in 1997, and its absolute structure and biological activity have been reported. Phomopsidin and its geometrical isomer (MK8383) showed potent inhibitory activity against assembly of microtubule proteins, exhibiting strong antitumor activity. It has been proposed that phomopsidin could be generated via the IMDA reaction of 1. Therefore, the potent antitumor activity and this biosynthetic background draw our attention to the synthesis of phomopsidin. We planned to synthesize the cis-decalin core 2 of phomopsidin first, and the side chain in the last stage of the synthesis because we anticipated that the IMDA reaction of 1 would hardly proceed as the (E,Z,E)-triene must take the energetically disfavored s-cis conformation in the IMDA reaction. The compound 2 was surmised to be constructed via the IMDA reaction of the open-chain triene 4, which would be synthesized by one-pot Suzuki-Miyaura coupling of alkyne 5 with iodoalkene 6. The synthesis of triene 4 was started from commercially available chiral alcohol 8. Conversion of 8 to trienes 14 and 15 proceeded in high yield. However, the IMDA reaction of the open-chain triene 14 afforded no cycloadduct, and that of 15 afforded an undesired cycloadduct. Hence, next we planned to synthesize the compound 2 via the TADA reaction of macrolactone 19. Commercially available alcohol 23 was successfully converted to macrolactone 29 in 17 steps. Heating macrolactone 29 in toluene for 24h provided the desired cycloadduct 30 selectively (2:1). The structure of 30 was confirmed by NOE experiment. In summery, we have succeeded in an asymmetric, stereoselective synthesis of the cis-decalin core of phomopsidin via the TADA reaction of 29. The last stage of the total synthesis of phomopsidin, that is, constructing the side-chain moieties, is now in progress.

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Annonaceous acetogenins are a class of plant metabolites featuring a long aliphatic chain bearing one, two, or three THF ring(s) with diverse stereochemistry at the middle and an α, β-unsaturated γ-lactone at the end. Considerable attention has been paid to these compounds due to their potent antitumor activity. The antitumor activity and a spectrum of effective tumor cell lines vary depending on the structure of the THF moiety. Therefore, it is very important for development of promising antitumor compounds to construct the THF ring segment with high stereoselectivity and excellent stereodivergency. We have developed a new synthetic method based on Carreira's asymmetric alkynylation using 3-butyne-1,2-diol derivative as a C_4-chiron and stereodivergent THF ring formation. We found that 3-butyne-1,2-diol benzylideneacetal 6 underwent highly stereoselective alkynylation with an α-oxyaldehyde 5, giving both syn- and anti-adducts (7a-b) in good yields and with high optical purities. Furthermore, the adducts 7a-b could be efficiently converted into all four stereoisomers 10a-d of the THF cores by stereodivergent THF ring formation. Next, we planned the asymmetric synthesis of murisolin 13, which was isolated from the seed of annona muricata. It shows potent cytotoxic activity against the human tumor cell lines, A-549, HT-29, and A-498, with potency 10^6 times that of adriamycin. Asymmetric alkynylation of α-tetrahydrofuranic aldehyde 10a, which was prepared by our systematic synthesis, with 1,6-heptadiyne using (1R,2S)-N-methylephedrine as the chiral ligand smoothly proceeded to give the THF ring segment 21 with threo/tarns/threo stereochemistry. γ-Lactone segment 22 was prepared by the coupling reaction of the triflate 18 with the lactone 19 followed by oxidation of sulfide and thermal elimination. Sonogashira coupling of the THF segment 21 and 22 afforded endiyne 23 in good yield. Reduction of 23 with Wilkinson catalyst provided bis-TBS ether 24. Finally, desilylation of 24 gave murisolin 13, whose spectral data were nicely consistent with the reported data of natural product.

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