Palladium(II) catalyzed intramolecular oxy-carbonylation of terminal acetylenes is considered to be a useful method for the conversion of an acetylene unit to a β-ketoester unit utilizing neighboring group participation. Compared with the impressive development of Pd^<II> catalyzed oxidative asymmetric reactons of alkenes, those of alkynes have received scant attention. We previously reported the first examples of asymmetric cyclization-carbonylation of meso-2-alkyl-2-propargylcyclohexzne-1,3-diols 1 and 2-methyl-2-propargylcyclohexane-1,3-diones 2 catalyzed by paladium(II) with chiral bisoxzzoline (box) ligands. Herein, we report a mechanistic insight of the latter reaction, and a parallel kinetic resolution of propargyl ketols 13. In the case of 2, hemiacetal formation step plays in important role in the asymmetric induction. However, in the case of 13, enantio selectivity of the reaction depends on trhe cyclication step. The products containing quaternary carbon were converted to optically active hydrindanes, and the chiral total synthesis of (+)-bakkenolide-A was achieved.

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In order to create useful substances, we examined oxidation-reduction reactions of acetophenone, 1-phenylethanol and their analogs by fungi, (Botrytis cinerea) or cultured cells of apple (Malus pumila 'Jonagold'). We found out that B. cinerea cells were not active for the oxidation of (rac)-1-phenlethanol into acetophenone, but active for the reduction of acetophenone into 1-phenylethanol. The biotransformed 1-phenylethanol was analyzed to be mixture of (S)- 1-phenylethanol (94% ee) and (R)-1-phenylethanol in a relative ratio of 97:3. On the other hand, we found out that apple tissue cultured cells were active for the oxidation of (rac)-1-phenylethanol into acetohenone but not active for the reduction of acetophenone into 1-phenlethanol. These results indicate that it is possible to control the oxidaton -reduction for a comound by selecting one-type of cell among various cells such as callus or fungi containing oxido-reductase activity, which is very interesting from a viewpoint of synthetic application.

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Enantioenriched epoxides are a useful chiral building block in asymmetric transformatons, and they are also an important morif sometimes found in natural products. Catalytic asymmetric epoxidation of olefins is the most direct and effective route to the optically active epoxides. Herein, we present the development of three chiral titanium catalysts, di-μ-oxo titanium(salan 3) complex, for asymmetric epoxidation of olefins with a green oxidant, aqueous hydrogen peroxide (Figure 1). Di-μ-oxo titanium complex 1 showed high caalytic performance in the epoxidation of terminal, cis-disubstituted and trisubstituted conjugate olefins (Scheme 1). In the epoxidation of 1,2-dihydronaphthalene, the desired epoxide was obtained in 92% yield with >99% ee in the presence of only 0.02 mol% of the catalyst. Aliphatic olefins, which are a challenging substrate in asymmetric epoxidation, were also converted to the epoxides with good to high enantioselectivity. High reactivity of titanium(salalen) 1 rendered asymmetric epoxidation of cis-alkenylsilanes possible, where the epoxysilanes were obtaine with complete enantioselectivity (Scheme 2). We proposed a peroxotitanium complex, which is activated by hydrogen bonding with amino proton, as active species (Figure 2). On the basis of the putative mechanism of the epoxidation with complex 1, we developed more-easily available titanium(salan) complexes which were prepared in situ from Ti(OiPr)_4 and the corresponding salan ligands (scheme 3). In particular, salan ligand 2 bearing ortho-methoxyphenyl groups at the C3 and C3' positions displayed high enantioselectivity in the epoxidation of conjugate olefins (scheme 4). The method could be applied to a gram-scale synthesis without eroding the enantioselectivity. For example, 50.0g of indene was transformed to indene oxide in 75% isolate yield with 98% ee (Scheme 5). Optically active styrene oxide derivatives are an important class of epoxides. However, there were no general and highly enantioselective (more than 95% ee) catalysts for asymmetric epoxidation of styrenes. Even with titanium(salalen) 1 which has two chiral axes and two chiral centers, the ee value observed in the epoxidation of styrene was 93% ee. Thus, we designed novel C_1-symmetric salan ligand 3 derived from naturally occuring α-amino acid proline for the epoxidation (Scheme 6). The in-situ prepared titanium(salan 3) catalyst exhibited high enantioselectivity ranging from 96 to 98% ee in the epoxidation of styrenes with electron-donating and -withdrawing groups (Scheme 7).

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Recent advances in organic chemistry enabled organic reactions in aqueous media with high yield under mild condition. This chemical evolution has promoted chemical modification of proteins, which contributes to protein engineering and chemical biology research. Here we demonstrate N-terminal glycine specific labeling of proteins by Pictet-Spengler reaction in combination with transamination reaction using pyridoxal-5-phosphate (PLP) under physiological condition. Horse heart myoglobin, a 153 amino acid residue heme-binding protein containing N-terminal glycine residue was oxidized by PLP, and the resultant aldehyde was coupled with tryptophan analogues in phosphate buffer (pH 6.5) at 37℃ to give corresponding 1,2,3,4-tetrahydro-β-carboline derivatives. Achromobacter protease I (Lys-C) liberated peptides were purified by ODS-HPLC to give N-terminal peptide (K1-peptide; the region from residue 1 to K16), which was analyzed by MALDI postsource decay (PSD) fragmentation. The ion peaks observed in the MALDI-PSD spectrum were assigned along the K1-peptide containing β-carboline skeleton, not 1,2,3,4-tetrahydro-β-carboline skeleton. A possible reason for this phenomenon is that the 1,2,3,4-tetrahydro-β-carboline skeleton might be spontaneously dehydrated during HPLC purification and laser desorption ionization. The circular dichroism (CD) spectral profiles of he modified myoglobin and the wild-type myoglobin were superimposable, which result showed that the tertiary structure of myoglobin was not altered during the reaction. Furthermore, modification of myoglobin was confirmed by SDS-PAGE and Western blot with no sign of decomposition.

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Methods for regioselective functionalization of one of the multiple hydroxy groups of carbohydrates have been poorly developed. Synthesis of complex glycoconjugates has usually been achieved by multi-step protection/deprotection procedures, which results in the long synthetic steps and low atom economy. For the progress of glycoscience, development of the methods for direct and regioselective functionalization of one of the multiple hydroxy groups is highly desired. We have developed catalysts for direct and regioselective functionalizations of carbohydrates. The acylation reaction of D-glucose derivatives with four hydroxy groups proceeded smoothly in the presence of catalyst 1 with perfect regioselectivity to give the 4-O-acylate exclusively. Investigation of mechanistic aspects for the regioselective acylation by 1 is expected to be benefickal to further development of catalysts for direct and regioselective functionalization of various carbohydrates. Choice of solvent is of critical importance for the regioselectivity. In polar solvents such as DMF and THF, the selectivity for the acylation of C(4)-OH of D-glucose derivatives was significantly diminished. On the other hand, in less polar solvents such as CHCl_3 and toluene, the C(4)-OH of glucose derivatives were preferentially acylated even in the presence of other sugar substrates. The lower temperature associated with high regioselectivity. All of these information indicate that multiple hydrogen bonding interactons between the catalyst and substrate are critical for the regioselective acylation with catalyst 1. The regioselective acylations is expected to proceed in an accelerative manner through the stabilization of transition state structure by these hydrogen bonding interactions. Improtantly, the accelerative acylation in the presence of catalyst 1 was observed specifically in D-glucose derivatives. In the poster session, we also would like to discuss further mechanistic details based on the structural analysis of the reactive intermediates.

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1. Synthesis of procyanidin B1-B4(1-4). Stereoselective synthesis of catechin and epocatechin under intermolecular condensation of equimolar amount of catechin derivatives catalyzed by Yb(OTf)_3. The coupled products were successfully converted to procyanidin B1 (1), B2 (2), B3 (3), and B4 (4), respectively. 2. synthetic of (-)-epicatechin 3-(3"-O-methylgallate) (13) and (+)-catechin 3-(3"-O-methylgallate) (14) A concise synthesis of (-)-epicatechin 3-(3"-O-methylgallate)(13, ECG3"Me), which is a minor constituent of tea, and (+)-catechin 3-(3"-O-methylgallate)(14, CG3"Me) via condensation of equimolar amount of catechin and gallate derivatives has been achieved. The anti-inflammatory effect of the synthetic compounds on TPA-induced inflammation of mouse ears was examined. Compounds 13 and 14 suppressed the TPA-induced inflammation of mouse ears by 50% and 43%, respectively, at a dose of 200μg. 3. Short step synthesis of resveratrol derivative. An efficient synthesis of trimethoxylated resveratrol (20) is presented using advanced Heck reaction promoted by Pd(dba)_2 in the presence of P(t-Bu)_3.

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It is well known that plants are the source of valuable product and some useful basic materials including cellulose, wood, and rubber. In addition, secondary metabolites such as terpenoids, cardenolide, coumarins, anthraquinines, flavonoids, glucosinolates and alkaloids are also produced by plant biosynthesis and are used as drug, pigments (food ingredients), and agrochemicals. Hitherto some secondar metabolites bave been produced using the plant cultured cells. Furthermore, many syudies have recently focused on the ability of the plant cultured cells to transform foreign substrate (biotransformation). In this study, to clarity the conversion ability of plant cultured cell, the biotransformation of bioactive compounds such as (-)-catechin, (+)-epicatechin, resveratrol, genistein, capsaicin, and curcumin is inestigated using the plant cultured cells Eucalyptus perriniana. These compounds are known to have the biological activities including an antioxidant property, anti-inflammatory and carcinogenic depression effects. These compounds are used as cosmetics and food ingredients. As these compounds are the low solubility in water, the use of these compounds has been libited. So, we investigate the glycosylation using Eucalyptus perriniana to enhance the water-solubility of their compounds. As a result, it was found that: (-)-Catechin was glycosylated at C7, C5-position of hydroxyl groups in the substrate molecules. (+)-Epicatechin and genistein were glycosylated at C7-position of hydroxyl groups. Resveratrol was glycosylated at C3-position of hydroxyl groups. Capsaicin was glycosylated at C4-position of hydroxyl groups. Curcumin was glycosylated at C4'-position of hydroxyl groups. Glucoside of resveratrol has antioxidant and tyrosinase activity. Also Glucoside of capsaicin has anti-obese activity.

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Epigallocatechin gallate (EGCG: 1), which exhibits various biological activities, including cancer prevention, antiviral, or antimicrobrial activities, is a major component of catechin deriatives derived from tea. The therapeutic potential of 1 and safe feature as food ingredient have attracted a great deal attention in recent years. Considering the development of 1 toward drug lead, further investigation on the mechanism of action and pharmacokinetics should be required. We therefore started the chemical modification of 1 in order to convert it into probe molecule. Initially, we prepared the synthetic derivative lacking two phenol hydroxyl groups on A ring, which were the intrinsic functional groups for 1 due to biosynthetic route. Interstingly, it was found that inhibitory activity of dideoxy-EGCG (2) aginst influenza virus infection was comparable to that exhibited by 1. These results suggested that two hydroxyl groups on A ring were not essential for anti-influenza virus activity, but B and D rings were essential. We therefore designed the catechin probe molecule having aminopentyl side chain of A ring. We had already reported the stereoselective construction of dihydropyran ring of catechin skeleton by 6-endo-cyclization of trans-epoxide. However, the mechanism of this ring closing process highly depended on the substrates. The employment of cis-epoxide or diol allowed formation of quinone methide intermidiate, which competed with S_N2 pathway. Our development of the synthesis into a more stereoselective process began with the investigation of the conditions required to bring about the neighboring group participation in formation of quinone methide. Wee accomplished this goal by the use of gallate unit as neighboring group during the stereoselective construction of cis- and trans-dihydropyran ring. Our work along these lines has demonstrated that the substrate having alkyl side chain also can be cyclized stereoselectively. Consequently, both aminopentyl-dideoxy-GCG (35) and -EGCG were successfully obtained. Taking advantage of the tethered amino group to DOEGCG, installations of various functional groups became possible such as the conjugation with carrier protein for antigen, immobilization to sensor chip for Biacore and introduction of fluorescent probe. Furthermore, introduction of triple bond enable aminopentyl-dideoxy-EGCG to be applicable to crick chemistry. According to this strategy, PET probe using ^<18>F can be alst introduced.

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DNA polymerases have important roles for DNA replication, recomgination, and repair in eukaryotes. Because not all functions of eukaryotic DNA polymerases have been fully elucidated, selective inhibitors to each DNA polymerase will be useful tools to distinguish DNA polymerases and to clarify their biological functions. In the screening of selective inhibitors of eukaryotic DNA polymerases, dehydroaltenusin from the fungus Acremonium sp. was found to be a specific inhibitor of DNA polymerase α(IC_<50>=0.68μM). Dehydroaltenusin did not influence the activities of other replicative DNA polymerases, and also showed no effect on the DNA polymerase α derived from vertebrate (fish) or plant species. The inhibitory effect of dehydroaltenusin is more selective and potent than that of aphidicolin (IC_<50>=20μM), whici is widely known as selective inhibitor of DNA polymerase α. We have newly synthesized nine dehydroaltenusin derivatives modified at the side chains or benzoquinone moiety. Among all synthesized derivatives, desmethoxydehydroaltenusin was the most selective inhibitor of DNA polymerase α. The O-hydroxy-p-benzoquinone (2-hydroxycyclohexa-2,5-dienone) moiety is essential for inhibition of DNA polymerase activities. Substitution at the 5-position of dehydroaltenusin is important for selective inhibition of DNA polymerase α activity. To determine the mechanism of dehydroaltenusin's inhibition, dehydroaltenusin is treated with N-acetylcysteine methyl ester, to give thioether. This result showed that one or more cysteine residues of DNA polymerae α may act as a targeto for this compound.

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Synthesis of the proposed structure of tyroscherin, a growth inhibitor of IGF-1-dependent tumor cells, was succeeded. However, spectroscopic data of synthetic compound were not identical to those of natural tyroscherin. The stereochemistry of tyroscherin was revised to 2S,3R,8R,10R by synthesis of several stereoisomers. The first total synthesis of tyroscherin was achieved by using one-pot Julia coupling. Over all yield was 18.7% in thirteen steps from L-tyrosine. Synthetic tyroscherin exhibited the most selective and strongest activity among stereoisomers and synthetic analogs, against IGF-1-dependent tomor cells.

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Amphidinolide T1 (1), a 19-membered macrolide isolated from the marine dinoflagellates Amphidinium sp., has shown potent activity against murine lymphoma L1210 and human epidermoid carcinoma KB coll lines. Synthesis of 1 was studied using palladium catalyzed hydrogenolysis of sulfonyloxirance as a key reaction to construct vicinal stereogenic centers. We have planned to synthesize 1 by coupling of tetrahydrofuran segment 4 and sulfone 5 via Julia-Kocienski reaction, followed by alkylation with TBS-enol segment 3, and macrolactonization of 2. The hydrogemolysis of sulfonyloxirane 6, which was synthesized from known alcohol 8, was carried out using palladium-HCO_2H and gave alcohol 11 with high stereoselectivity. After protection and reduction of the double bond, 12 was coupled with optically active epoxide 13 using n-BuLi and BF_3OEt_2. Protection of alcohol and Julia methylenation gave 15. Using similar procedures, sulfonyloxirane 7, enantiomer of 6, was synthesized. Hydrogenolysis of 7 with plladium-HCO_2H gave alcohol 17, followed by reduction and protection. Treating 18 with t-BuLi and HCO_2Et, deprotecton and introduction of azide gave 21. We could construct tetrahydrofuran moiety by treating 21 with BF_3OEt_2 and formed desired intermediate 4. Segment 5 was synthesized from (S)-4-Benzyl-2-oxazolidinone by stereoselective methylaton and introduction of phenyl tetrazole sulfone. Total synthesis of 1 using the synthetic segments 3, 4, 5 is under way.

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Cortistatins are the marine alkaloids which were isolated form the marine sponge Corticium aimplex by Kobayashi et al in 2006. Cortistatins have highly selective anti-proliferative activity against HUVECs. Moreover, these compounds possess unique abeo-9(10-19)-androstane type steroidal skeleton as well as isoquinoline moiety. Owing to potent biological activities and unique structures attract synthetic chemists. Herein, total synthesis of cortistatin A and J are described. Our strategy features a construction of common core structure of cortistatins using Knoevenagel condensation, electocyclic reaction and radical cyclization followed by stereoselective installation of isoquinoline moiety and functionalization of A-ring. First, CD-ring fragment 7 was synthesized in 10 steps from readily available (+)-Hajos-Parrish ketone 8. Treatment of 7 with cyclohexane-1,3-dione 6 in the presence of piperidine afforded the tetracyclic structure 12 via Knoevenagel condensation and electrocyclic reaction. After conversion of 12 into iodide 4, radical cyclization furnished the core structure 3. With the key intermediate 3 in hand, isoquinoline was installed. Ce-mediated nuclephilic attack of lithiated isoquinoline 14 afforded 15. After formation of thiocarbamate, one-pot removal of the thiocarbamate and chloride realized the constructon of isoquinoline moiety with desired stereochemistry. Finally, total synthesis of cortistatin A (1) and J (2) were accomplished by modification of A-ring. Treatment of enone 18 with dimethylamine furnished the 1,4-addition product. Reduction followed by elimination of the corresponding ketone afforded cortistatin J (2). Total synthesis of cortistatin A (1) was achieved following Nicolau/Chen's protocols in 3 steps from 18. In conclusion, we hae developed a highly efficient synthetic route to cortistatin A (1) and J (2).

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Kalkitoxin (1) was isolated from cyanobacterium Lyngbya majuscule in the Caribbean Sea. It is reported that 1 posssesses some intersting biological activities. For example, 1 shows a strong ichtyotoxic activity toward the common gold fish and brine shrimp. Also, kalkitoxin has a strong neurotoxicity (LC_<50>=3.86nM) in cerebellar granule neouron (CGN) as an inhibitor N-methyl-D-aspartate (NMDA) receptor antagonists and is a highly potent blocker of the voltage-depending sodium channel in mouse neuro-2a cells (EC_<50>=1nM). We have been attracted by the structure-activity relationship of kalkitoxins. In present paper, we describe the synthesis of kalkitoxin and its analogues (epimer and demethylated kalkitoxins (nor form) and their biological activity with brine shrimp. The synthesis was started from 15, which was converted to α,β-unsaturaed imide 14 with phosphonate 17. 1,4-Addition reaction to 14 with methyl curprate gave imide 18 as 10 : 1 mixture of diastereomers. The imide 18 was transformed into second 1,4-addition precursor 11 in 9 steps. The conjugate addition reaction of 11 proceeded smoothly to give imide 26 as a single diastereomer, which was derived to 1 via condensation with amine 10, synthesize without racemization by novel method, and highly efficient thiazoline formation with TiCl_4. Kalkitoxin analogues 2-7 were synthesized in the similar manner by simply changing the chiral auxiliary or chiral building block. Finally, the biological activity with 1-7 was evaluated as LC_<50> toward brine shrimp.

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Amphidinolides B, G, and H were isolated from the Cultured marine dinofragellate, Amphidinium sp. by Kobayashi and co-workers. These compounds share the 26 or 27-membered lactone with the S-cis diene and allyl eposice moieties, and exhibit potent cytotosic activity against L1210 murine leukemia cells and KB human epidermoid carcinoma cells. The unique structure and promising bioactivity of amphidinolides have attracted us to study the syntheses of amphidinolides. According to our retrosynthetic analysis, 1 was disconnected into the four fragments which were combined by esterification, aldol reaction, acetylide coupling, and ring closing metathesis, respectively (Scheme 1). In addition, the syntheses of 2 and 3 were performed by the same synthetic strategy. The fragment A was prepared from (2S,4S)-pentanediol featuring asymmetric dihydroxylation. The fragment B was synthesized from 3-methyl-3-butene-1-ol by using asymmetric dihydroxylation and Corey-Fuchs alkyne syntheiss. Synthesis of the fragment C was achieved by means of Evans alkylation between 15 and 16. The fragment D was synthesized from 4-pentene-1-ol in 3 steps. Acetylide coupling of the fragment B and C, followed by TPAP oxidation proceeded smoothly to afford the coupling product 21. After construction of the S-cis diene by means of Michael addition and Wittig reaction, TES deprotection and Dess-Martin oxidation provided 22. Then we explored the diastereoselectivility of aldol coupling (Table 1). The LHMDS-mediated reaction of the fragment A with the aldehyde 22 at -40℃ proceeded with poor diastereoselectivility favoring the 18S stereochemistry (d.r. 1.3:1). After introducing allyl epoxide moiety to 24, the 26-membered lactone was constructed by the Shiina esterification protocol and ring closing metathesis.

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The isonitrile analogue of diterpenoid geranyllinalool was isolated by Scheuer during a screening program for bioactive constituents from marine sponges Halichondria sp. as an active compound against Staphylococcus aureus. This molecule possesses a unique isonitrile-containing quaternay carbon at C-3. The nitrogen-substituted quaternary stereocenter was planned to constuct by [3.3] sigmatropic rearrangement of allyl cyanate. Starting with D-lactic acid methyl ester, allyl alcohol was prepared and then was transformed into allyl carbamate, dehydration of which was carrid out by using the modified Appel's conditions (PPh_3, CBr_4, Et_3N, CH_2Cl_2, -10℃) to generate allyl cyanate, which immediately underwent [3.3] sigmatropic rearrangement at -10℃ to afford allyl isocyanate. After careful work-up, the isolated isocyanate was treated with lithium tert-butoxide in THF. Further transformation of the resultant Boc-carbamate and synthesis of opticallyl active geranyllinalool isocyanide will be presented. Manzacidins A and C were isolated and its structure was determined by Kobayashi. The first synthesis of manzacidins A and C were reported by Ohfune, who established the stereochemistry by total synthesis. The most critical problem in the synthesis of manzacidins is the construction of quaternary stereogenic center attached nitrogen. Retrosynthetic analysis showed that dehydration of carbamate would generate the allyl cyanate, which will undergo [3,3] sigmatropic rearrangement to construct the quaternary stereogenic center attaced nitrogen. The isocyanate could be transformed to the Boc-carbamate by the reaction with tert-butanol. Further details of our synthetic studies of manzacidins will be reported.

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Armatol F (1), isolated from the red alga Chondria armata by Ciavatta et al., is an unusual triterpene compound characterized by the presence of an oxepane (A-ring), a 6/7/7 fusea-tricyclic ether (BCD-ring), six quaternary carbons, and two bromine atoms in its structure. It is also notable that 1 has a cis ring-fusion between C- and D-rings, which is a rare mode of ring-fusion in polycyclic ether natural procudts. The absolte configuraton of the A-ring and relative stereostructure of the BCD-ring have been elucidated by NMR and degradation studies, but the full absolute stereochemistry of 1 remains unclear. Although the bioactivity of 1 has not been reported, it is strongly expected that 1 would have some biological properties because of its striking structural similarity to bioactive thyrsiferol and the congeners. Since we have been interested in the structural complexity and the potential bioactivity of 1, we have been engaged in studies toward the total synthesis of 1 and the determination of its full absolute configuration. As a part of the studies, the model syntheses of the A and BCD-ring skeletons were performed. In the synthesis of A-ring model 16, a chirality transferring Ireland-Claisen rearrangement and a ring-closing olefin metathesis (RCM) were employed as key reactions for the construction of the oxepane skeleton, and the final bromination at C3 is now under investigation. BCD-ring model 18 was designed to be constructed from B-ring model 36 via a chirality transferring Ireland-Claisen rearrangement, an RCM, and Morimoto's intramolecular bromoetherification. At present, BC-ring 50, possessing a carbon chain corresponding to the D-ring, has been synthesized. The details of the model syntheses will be presented in the poster session.

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Ciguatoxin (1) is a principal toxin of ciguatera which is one of the most wide spread seafood poisonings. Our concept for the total synthesis toward Ciguatoxin (1) is based on acetylene dicobalthexacarbonyl complex-mediated ether-cyclizations. The reacton proceeds via a dicobalthexacarbonyl complex-stabilized cationic intermediate, which called Nicholas effect, subsequently undergoes endo cyclization to give a syn product thermodynamically. We have explored various decomplexation methods of the endo-acetylene cobalt complex. The retrosynthetic analysis toward ciguatoxin is revealed that the A, F, and G ring would be cyclized at the latest stage after the coupling between acetylene of left segment and aldehyde of right segment. Segment coupling between left segment 12 and right segment 13 afforded the acyclic acetylene 14. F-ring cyclization was successfully accomplished through intramolecular Nicholas reaction. The cyclic cobalt complex 16 was converted into corresponding ketone 17 via ligand exchange with dppm. Reductive etherification of the hydroxyketone provided BCDEFGHIJKLM-ring 19 in moderate yield. B-ring side chain was converted into acetylene in several steps. Sonogashira coupling with vinyliodide 25 to furnish the corresponding product enyne 37. Treatment of the acetylene cobalt complex of 37 with excess TMSOTf at -20℃ generated stable propargyl cation in dichloromethane solvent. Addition of THF solvent into this reaction mixture at -20℃ made a big progress by scavenging the excess Lewis acid in the reaction mixture to promote the equilibrium toward the cyclization product 38. Reductive decomplexation of the endo-cobalt complex 38 was accomplished under excess sodium hypophosphite to provide a cis olefin. Final deprotection of the four acyl groups with K_2CO_3 in a mixture of methanol and THF solvent afforded ciguatoxin (CTXIB, 1)

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Gambieric acids (GAs) are marine polycyclic ether natural products, isolated from the ciguatera causative dinoflagellate Gambierdiscus toxicus by Nagai, Yasumoto, and co-workers. The molecular architecture of GAs is composed of a nonacyclic polyether core and a side chain including a tetrahydrofuran. GAs show minimal toxocity against mammalians but display extraordinary potent antifungal activity against Aspergillus niger. The highly complicated structures coupled with the interesting biological activity make GAs attractive synthetic targets. We have previously reported the synthesis of the B-J-ring polycyclic ether core of gambieric acid A (GAA). Herein we report our efforts toward the total synthesis of GAA, which culminated in the stereochemical reassignment of the nonacyclic polyether core and the synthesis of the A/B-, DEFG-, and GHJI-ring fragments. The synthesis and NMR analysis of the A/BC-ring fragment of gambieric acid B confirmed that the absolute configuration of the polycyclic ether core of GAs is opposite to that of the originally proposed structure. Accordingly, we synthesized the A/B-ring fragment of GAA wigh the correct stereochemistry, wherein the A-ring was constructed via a Suzuki-Miyaura coupling and a diastereoselective iodoetherification. We devised a new strategy for the stereocontrolled synthesis of the DEFG-ring fragment of GAs, wherein a Suzuki-Miyaura coupling was implemented as the fragment assembly process and a seven-membered cyclic ether was utilized as a template for controlling the C25 stereogenic center. We also completed the synthesis of the GHIJ-ring fragment of GAs in a convergent manner. The G- and J-rings were assembled through an aldol coupling and the H- and I-rings were constructed by cyclodehydration and reductive etherification, respectively.

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A red tide dinoflagellate Karenia brevis is known to produce polycyclic ethers such as the bravetoxins and brevenal. During isolation of these toxins, a new cyclic ether alkaloid named brevisamide (1) was isolated from laboratory cultured of K. brevis. The molecular formula of 1 was deduced to be C_<18>H_<29>NO_4 by HRMS and NMR spectral data. Based on 2D NMR analyses, brevisamide was found to possess a 3,4-dimethyl-2,4-heptadienal side-chain and an acetylated terminal amine. 1 is the first nitrogen-containing mono-cyclic ether from K. brevis and may provide important biogenetic clues to the origin and biosynthetic assembly of polyethers. Here we report the synthesis of 1 and its plausible biosynthetic precursors 2 and 3 supplying additional biological testing material for elucidation of biosynthetic mechanism of marine ladder-shaped polyethers.

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Detoxification processes via molucular transformation of toxic materials into non-toxic compounds are highly desirable in a new eco-friendly and safe remedial approach replacing conventional treatmen, simply the removal and storage of pollutants from contaminated wastes, soils and waters. The efficient biomimetic catalysts that simulate the functions of natural enzymes with high activity and selectivity under mild conditions may play an important role i realising a low-energy-consumption and safe detoxificaton process. In particular, the detoxification of acutely toxic inorganic arsenic is realised by conerting arsenic trioxide, As_2O_3 [iAs(III)], into essentially non-toxic arsenobetaine (AB), which occurs naturally in many types of seafood. Here, it is demonstrated that methycobalamin (CH_3B_<12>), seving as a methyl group doner, conerting arsenic trioxide into TMAO as the main product in the presence of glutathione reduced (GSH), which followed by subsequent treatment of TMAO with iodoacetic acid and GSH to give AB with a high yield. Since vitamin B_<12> (CH_3B_<12>) and GSH are biomaterials and reactions proceed in water as an aqueous medium under mild conditions, a safe and environmentally-friendly process, conveting toxic inoganic arsenicals into non-toxic arsenibetaine, is successfully confirmed.

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Platensimycin was isolated from a strain of Streptomyces platensis by a Merck research group as a novel broad spectrum Gram-positive antibiotic. It inhibits bacterial grouwht by selectively inhibiting condensing enzyme FabF in the fatty acid synthesis pathway. Because of its unique mode of action, platensimycin showa no cross-ersistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-resistant enterococci. Platensimycin consists of an unusual 3-amino-2,4-dihydroxybenzoic acid polar domain linked through an amide bond to a relatively lipophilic, compact, tetra-cyclic core. Its attractive biological activity and intriguing structure prompted us to embark on the synthesis of platensimycin. Starting from a known carboxilic acid (9), Diels-Alder precursor 7 was prepared in 5 steps via iodolactonization, epoxidation, regioselective epocide opening with Et_2/AlCN/DME and elimination. Although the Diels-Alder reaction of 7 with Danishefsky's diene was unsuccessful, the reacton of 7 with Rawal's diene 10 proceeded smoothly under mild conditions (CH_2Cl_2, 40℃), giving 6 as a single diastereomer. After protection of the enone carbonyl group of 6 by Noyori's protocol, the resulting acetal 11 was converted into TBS-protected Weinreb's amide intermediate 12, which was then exposed to MeMgCl to afford ketone 5 in excellnt overall yield. The Wittig olefination of 5 and subsequent reduction of the nitrile group of the resultind product 13 gave olefinic aldehyde 14, the methylenation of which furnished RCM precursor 4. Treatment of 4 with the Grubb's second generation catalyst gave cyclization product 15. Finally, exposure of 15 to aqueous acidic conditions brought about deprotection of the two protecting groups as well as the cyclization to afford the targeted tetacyclic core structure (2) of platensimycin. Although we have completed the synthesis of 2, some of the steps, including the RCM reaction, need improvement in chemical yield. At present, we are also trying other synthetic routes involving several types of radical cyclization reactions.

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There are many bioactive macrolides containing Z-α,β-unsaturated lactone moiety such as macrolactin A, disctyostatin, phorboxazoles, and laulimalide. Although the intramolecular HWE reaction is one of the most reliable macroclization procedure, the reactions generaly give E-α,β-unsaturated olefines with high selectivity. Therefore, we decided to apply our Z-selective HWE reagents (ArO)_2P(O)CH_2CO_2R for the intramolecular HWE reaction and define the satisfactory reaction conditions. The substrates were prepared by the esterification of (ArO)_2P(O)CH_2CO_2H with the mono-THP protected diols, followed by deprotection and oxidation reaction. When the substrates having (o-t-BuPhO)_2P(O) moiety was added to a THF solution containing 3 eq. of NaH or NaI-DBU by using a syring pump, the intramolecular HWE reaction proceeded efficiently to give macrolactones in 94-99% Z selectivity with 60-99% yields. On the other hand, the substrate having (EtO)_2P(O) moiety was added to d CH_3CN solution containg 3 eq. of LiCl-DBU, the reaction give macrolactones in 89-100% E selectivity with 60-84% yields. [chemical formula]

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Oxazolomycin A and neooxazolomycin originally isolated from a strain of Streptomyces 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 al in vivo antitumor activity. The intriguing molecular architectures and biological activities make these compounds attractive targets for synthesis. However, the total synthesis is limited to neooxazolomycin achieved by Kende's group and our group, and other oxazolomycins having a spiro γ-lactam-β-lactone core have not been synthesized yet. We report here the highly stereoselective synthesis of the oxazolomycin core 3 based on In(OTf)_3-catalyzed Conia-ene type cyclization. Our synthesis of 3 started from a seven-step transformation of known propargyl alcohol 7 to amide 13. By taking advantage of In(OTf)_3-catalyze cyclization, which we have recently developed, 13. By taking advantage of In(OTf)_3-catalyzed cyclization, which we have recently developed, 13 was then converted to lactam 11 in good yield. Stereoselective dihydroxylation accompanied by lactonization and chemoselective reduction of the methyl ester converted 14 to bicyclic lactone 2. Successive methoxymethylation, LiBH_4 reduction, and silylation gave diol 20. We gratifyingly found that methylation of 20 with Me_3O^+BF_4^- in the presence of proton sponge afforded 5 in good yield. After conversion of 5 to carboxylic acid 6, Mitsunobu reaction afforded β-lactone 3. Now, the fully functionalized left hand core of the oxazolomycins was successfully synthesized for the first time.

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Previously, our group has developed a stereoselective construction of heterocyclic compounds using the Pd(II) catalyzed cyclization. We described here the applicaton of this methodology to synthesis of D-ribose, L-lyxose and spiro C-arylated glycoribosides (16). 1. Synthesis of D-ribose and L-lyxose The aldehyde 5 was prepared from cis-2-butene-1,4-diol (8) in 13 steps. By the reaction of hemiacetal derived from the aldehyde 5 and MeOH in the presence of 5 mol% of PdCl_2(PhCN)_2 in THF, the cyclized product 4 was obtained in 65% yield as diastereomer mixtures. D-ribose and L-lyxose were synthesized from the cyclized product 4A and 4B in 5 steps, respectively. 2. Synthesis of spiro C-arylated glycoriboside Spiro C-arylated glycopyranosides such as papulacandins 15 show many excellent activities. But there has been no report on the bioactivities of the spirocyclic ribose analogues. Thus we tried to synthesize the spiro C-arylated glycoriboside analogues 16 using Pd(II) catalyzed cyclization. The cyclized precursor 20 was prepared from the alcohol 12 in 3 steps. The key cyclization of 20 was achieved successfully by treatment with 20 mol% of PdCl_2(PhCN)_2 in THF to give the spiro compound 17. Finally, the glycoriboside analogue 16 was syntehsized from 17 in 5 steps.

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(-)-Kaitocephalin (1), isolated from a filamentous fungus Eupenicillium shearii PF1191 by Seto and Shin-ya et al., has attracted much attention due to its potent antagonist activity to ionotropic glutamate receptors. The structure of 1 is characterized by its 2,2,4-trisubstituted pyrroridine core assembled by N-acylalanine and threonine moieties connected with a carbon-carbon bond. In this presentation, we describe the efficient total synthesis of 1 from the known pyrroridine 8 in 12 steps. Neurobiological evaluation of its diastereomers, enantiomer, and functional froup removed analogs are also disclosed. The key to the total synthesis relied on the stereoselective construction of the five stereocenters including three chiral α-amino acid moieties. The three contiguous stereocenters of the right side chain were stereoselectively constructed by the aldol reaction of 6 with the known serinal ortho ester 7 and subsequent inversion of the C3 stereocenter of the resulting (3R)-9 to (3S)-11 via mild oxidation and reduction conditions. Conversion of the ortho ester to the methyl ester followed by the oxidation of the siloxymethyl side chain to the aldehyde gave 4. The alanine moiety was installed by Horner-Wadsworth-Emmons(HWE) olefination and stereoselective hydrogenation reactions. The use of the E-isomer of 3 was essential for the stereoselective preparation of the (9S)-14. To this end, E-selective dehydroamino acid synthesis using HWE reagent 5b was developed. All the protecting groups of (9S)-14 were removed at once by using AlCl_3-Me_2S to give kaitocephalin (1). Each step (12 steps) was reproducible and carried out in a gram quantity. Thus, stereoselective and short synthetic route to (-)-kaitocephalin 1 was established. Radio ligand binding assay of 1 and its analogs to iGluRs using rat brain synaptic membrane suggested that the C3 hydroxyl and C9 carboxyl groups are important for binding. In addition, the acyl amide moiet may be involved in the poteng binding. It is interesting to note that the enantiomer of 1 (ent-1) was a selective ligand of the NMDARs. Further biological evaluation is currently under investigation.

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(-)-Funebrine (1) is a novel pyrrole alkaloid isolated from fragrant flowers of Quararibea funebris at near Oaxaca, Mexico in 1984. The flowers have been used as a folk medicine for treating various diseases, and have also been used as an additive to chochlate drinds since pre-Columbian times. The structure of 1 was characterized by a 2,5-substituted pyrrole and two aminolactones poseessing three contiguous stereo centers. The datailed biological aactivity of 1 has not been unidentified probably due to insufficient supply of natural product. Only one report on an asymmetric synthesis of (-)-1 has been reported. Our synthetic plan toward the total synthesis of 1 was the use of α-amino γ-butyrolactone 4 as the key inermediate, which could be prepared via the enolate Claisen rearranement of the propargylsilane 5 followed by the novel Au-catalyzed regioselective γ-lactonization of the resulting allenylsilane 6. The Claisen rearrangement of optically active 5 gave desired allenylsilane 6. After screening of Au and other catalysts, [(Ph_3PAu)_3O]BF_4 was found to effectively catalyze the regiospecific γ-lactonizaton of 6 to give vinylsilane-containing γ-butyrolactone 7a. Since subsequent conversion of 7a to 4 was accompanied by a troublesome epimerization at C3, dimethylphenylsilane derivative 11 instead of 6a was employed as the starting material. Both the Claisen rearrangement and Au-catalyzed γ-lactonization proceeded smoothly to furnish the γ-butyrolactone 12 in a highly efficient manner, which, upon 4 step sequence of reactions, gave 4. Condensation of 4 with 1,4-diketone 3a produce the pyrrole-coupled 15. Finally, total synthesis of (-)-funebrine (1) was accomplished by the treatment of 2 with 4 upon heating.

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The tubulysind (1a-d), tetrapeptide derivatives, were first isolated from the myxobacterial strains Archangium gephyra and Angiococous disciformis. They are composed of four amino acid fragments, N-methyl-D-pipecolic acid (D-Mep), L-isoleucine (L-Ile), tubuvaline (Tuv), and tubuphenylalanine (Tup) / tubutyrosine (Tut)(Fig. 1), and exhibit strong antitumor activity by inhibiting tubulin polymerization. Owing to the remarkable biological activity and existence of unusual amino acids such as Tuv and Tup, tubulysins have attracted considerable attention as synthetic target molecules as well as leads for the development of new anticancer agents. We have now developed an efficient method for the stereoselective synthesis of Tuv-Me (2-Me) featuring the 1,3-dipolar cycloaddition of a nitrone D-3 with alkene 6 (Table 1 and Scheme 4), as well as a method for stereoselective synthesis of Tup (17-HCl) using na aldol reaction of 12 with aldehyde 13 followed by the Barton deoxygenation (Scheme 5). Using these methodologies, we have accomplished an efficient total synthesis of tubulysin U (1c) and V (1d), in which isoxazoline ring played an important role as a protecting group for the amine and the hydroxyl groups (Scheme 6). We have also synthesized tubulysin D (1b) and ent-tubulysin D (ent-1b) from 2-Me and 17-HCl, and ent-2-Me and ent-17-HCl by employing Ellman's sequence (Scheme 7). Antiproliferative activities of the synthetic tubulysins 1b, ent-1b, 1c, and 1d were evaluated in cancer cell lines.

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Lapidilectine B (1), isolated by Awang and co-workers from the leaves of Kopsia lapidilecta, is a hexacyclic monoterpene indole alkaloid calssified into the Aspidosperma type and possesses an indole ring fused a five membered lactone ring. Although its biological activities have not reported, related dimeric alkaloids tenuisine B (2) and tenuiphylline (3) exhibit cytotoxic activities against adriamycin against P388 and HL-60 respectively. Additionally the absolute configuration of 1 is unknown. So, we started the investigation of asymmetric synthesis of lapidilectine B (1) based on the azaspirocyclizatoin methodology. Although the reaction of 2-hydroxy-3,3-ethylenedioxyindoline derivative 18 derived from 2,3-indolinedione (15) with formic acid gave an octahydroacridine compound 23 as a single diastereomer in a preliminary study of spirocyclization, that of 2-substituted indole derivative 32 prepared from L-malic acid (24) with CF_3CO_2H in CH_2Cl_2 afforded the spirocompounds 34 and 35 in 73% at 1.9:1 ratio as an inseparable mixture. After several steps including separation, 34 and 35 were lead to the secondary alcohol 39 and its enantiomer 41 respectively. This result indicates that both enantiomers of lapidilectine B (1) will be synthsesized in this methodology. The secondary alcohol 39 was transformed to the ketone 43 through oxidation of hydroxy group and at the benzylic C3 position on the indoline ring of 39, followed by selective protection at C1' position of two carbonyl groups. Stereoselective allylaton of 43 with Grignard reagent occurred from the opposite to the siloxymethyl group to produce the teritiary alcohol 44 as a single diastereomer. The diol 45 was obtained by oxidative cleavage of the olefin, followed by reduction of the resulted aldehyde in a high yield from 44 for 3 steps. Mstunobu reaction of 45 with N-(2-(tert0butyldimethylsilyloxy)ethyl)-2-nitrobenzenesulfoneamide furnished the key intermediate 46 for the synthesis of 1 in 76% yield. Further investigation toward the total synthesis of 1 is now in progress.

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Lycopodium alkaloids have unique skeletal characteristics and a variety of biological activities, such as acetylcholine esterase (AChE) inhibiton. These have inspires many groups to research on total syntheses of the Lycopodium alkaloids. Recently, we have investigated the alkaloidal constituents in Lycopodium serratum and have found several novel alkaloids including lycoposerramine-C (1), -X (3) and -Z (4). Herein, we report the first asymmetric total syntheses of these alkaloids. 1. Total synthesis of lycoposerramine-C (1) Lycoposerramine-C (1) idolated from L. serratum is a new fawcettimine-type Lycopodium alkaloid possessing a double bond at the C6-C7 positons in fawcettimine (2). In order to deelop an efficient synthetic route of 1, to exacute direct confirmation of its absolute configuration, and to supply it for the study of biological activity, we planned asymmetric total synthesis of 1. The successful synthesis involved a Co-mediated Pauson-Khand reaction, stereoselective reduction, and subsequent vinyl Claisen rearrangement as key steps. 2. Total syntheseses of lycoposerramine-X (3) and -Z (4) From spectroscopic analyses, new alkaloids, lycoposerramine-X (3) and -Z (4), were found to be diastereomeric isomers at C13 position of phlegmarine-type alkaloids, which consist of a piperidine ring with a novel nitron residue and an octahydroquinoline ring with four chiral centers. Starting from (R)-3-methylcyclohexanone, the first asymmetric total syntheses of these alkaloids were accomplihde, which involved Johnson-Claisen rearrangement, Mitsunobu reaction, and cyclic nitron formation. The syntheses enabled us to established the absolute configuration of 3 and 4.

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We have recently investigated chemical components of embryo of the lotus, Nelumbo nucifera Gaertner, to isolate a new alkaloid (4) along with known alkaloids such as Neferine. We have also investigated inhibitory activity of some alkaloids of Nelumbo nucifera on locomotor activity. In this symposium we will present an asymmetric synthesis of the new alkaloid 4 and related compounds. New alkaloid 4 and streoisomers of Neferine (17-19) were synthesized by using Gawley asymmetric alkylation and Ullmann coupling as key reactions. Asymmetric alkylation of tetrahydroisoquinoline 11, bearing an oxazoline as chiral auxiliary, with chloride 10 in THF at -98℃ gave 12 in 99% of diastereoselectivity. Ullmann coupling of 14 and 15 which was synthesized by the same alkylation procedure was achieved by using cuprous bromide-dimethyl sulfide and cesium carbonate in refluxing pyridine to give bisbenzylisoquinoline 16. Deprotection of 16 gave the new alkaloid 4. By the same methodology, three streoisomers of Neferine (17-19) were also synthesized. In order to synthesize O-methylneferine (5), we have developed new diastereoselective Pictet-Spengler cycliztion reaction of urea 24 bearing 1-(1-naphthyl)ethyl group as chiral auxiliary. Reaction of 24 with aldehyde 25 in the presence of trifluoroacetic acid in dichloromethane proceeded at -20℃ to give, after silica gel column chromatography, tetrahydroisoquinoline 26 in 65% isolated yield along with 34% yield of the diastereomer. O-Methylneferine was also synthesized by Ullmann coupling of 27 with corresponding bromide which wasl alst synthesized by this Pctet-Spengler reaction. Pharmacological activity of these alkaloids was evaluated to show inhibition of locomotor activity in mice.

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Synthetically useful asymmetric nitrogen-carbon bond fromations that are otherwise difficult to accomplish have been achieved through conjugate addition reactions of both chiral and achiral lithium amides to enoates. Since the resulting lithium enolate intermediate is a powerful nucleophile, subsequent in situ alkylation is quite promising. Thus, potentially, usefl one-pot transformations to produce adjacent asymmetric carbon centers with concomitant installation of vicinal N-C and C-C bonds could be achieved. Of particular interest is the asymmetric construction of quaternary carbons in tandem fashin. Given our success in the development of chiral diether-mediated asymmetric conjugate additions of lithium arylmethyl- and allyl-trialkylsilylamides, we envisioned a tandem asymmetric conjugate addition-alkylation strategy for the construction of a quaternary carbon center. Herein, we describe a highly efficient enantioselective construction of a quaternaty carbon center with up to 97% ee and over 98% de and the use of the product in the asymmetric total synthesis of (-)-aspidospermidine (1). We began our studies with ethylation of the lithium enolate intermediate generated by conjugate addition of lithium N-mesitylmethyl-N-TMS-amide 4 to t-butyl cyclopentenecarboxylate 5 in the presence of C_2 symmetric chiral diether 2 in toluene. The conjugate additon was performed for 1.5h at -78℃ and additional stirring for 1.5h at -60℃. After that, the generated lithium enolate was alkylated by ethyl iodide in the presence of THF and HMPA to give desired addition-alkylation product 7d in 94% yield with 95% ee as a single diastereomer. The asymmetric total synthesis of aspidospermidine (1) has been considered to be a touchstone of the methodology for the asymmetric construction of quaternary carbons. The utility of the quaternary carbon product 7d was demonstrated by the asymmetric total synthesis of (-)-1. The ee of the ethylation product 7d (95% ee) was increased to>99% ee in 85% recovery by recrystallization of its hydrochloride from ethyl acetate. Successive methylation of the hydrochloride salt of 7d, N-oxidation with mCPBA, and Cope elimination with Al_2O_3 in t-butanol gave olefin 8 in 65% yield along with 13 (11%) and 14 (11%). Lithium aluminium hydride reduction of ester 8 to alchol 15, TRAP oxidation to the aldehyde, Wittig olefination for one-carbon elongation, hydrolysis to the aldehyde, and sodium borohydride reduction gave alcohol 19 in 79% yield (5 steps from 8). These steps shoud be carefully carried out because the products all have low boiling points and can easily be distilled off. Oxidative cleavage of olefin 19 with osmium tetroxide and sodium metaperiodate yields a lactol 22, which was then oxidized to δ-lactone 9, bearing three differently oxidized oxygen functionalities in 85% yield. Amide formation with lactone 9 and tryptamine in n-butanol at reflux gave 10 in 75% yield. The remaining transformations were a modification of the Harley-Mason's protocol. Sulfuric acid treatment of 10 induced Pictet-Spengler cyclization. Simultaneous rearrangement occurred at reflux for 2.5h. Lithium aluminium hydride reduction in THF at reflux for 1.5h conpleted the synthesis of (-)-aspidospermidine 1 in 37% yield.

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Fusicoccin (FC) and cotylenin (CN), fusicoccane diterpene glycosides, have been known to exhibit strong plant hormone-like activities through activation of H^+-ATPase in plant cells. FC forms a stable ternary complex with membrane-boudary H^+-ATPase and cytoplasmic 14-3-3 protein, and maintains the activated stage of the H^+-ATPase. Recently, we found that CN induces differentiation of human myeloid leukemia cells and, additionally, induces apoptosis against several solid cancer cell lines in combination use with interferon α (IFNα). However, natural FCs were less efficient in both activities. There are several differences in chemical structures of FC and CN. The SAR studies lead the conclusion that the removal of 12-OH is essential for differentiation induction. However, 12-deoxy-FC derivative 1 with IFNα, showed less efficiency on apoptosis induction. Aiming to create compounds, which exhibit identical anti-cancer activities with those of CN, we introduced a 3α-OH group, one of characterstic structural features of CN, onto the diterpenic core of 12-deoxy-FCs. Through stereoselective dihydoxylation on the 1,3(16)-diene moiety, 3 was successfully devived from FC-H. 3 induced potently differentiation on U937 cells and apoptosis on A549 cells in combination use with IFNα. Moreover, 3+IFNα treatment was effective not only in vitro but also in vivo, and efficiently inhibited the tumor growth of pancreatic cancer Miapaca-2 in nude mice as xenografts. Studies on the mode of action of apoptosis induction disclosed the inolvement of human 14-3-3ζ, down-regulation of p53 and up-regulation of DR5, which is one of the transcriptional targets of p53.

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Lipid rafts are membrane microdomains rich in sphingomyelin (SM) and cholesterol (Chol), and their physical properties are grossly different from surrounding lipid bilayers. Although lipid rafts are assumed to play essential roles in biological processes such as intercellular signal transduction, molecular interactions in lipid rafts are hardly understood because lipid molecules in rafts undergo a rapid association and dissociation equilibrium. In this study we attempted to prepare molecular probes for observing the interaction between SM and Chol in rafts. The ^<13>C{^<15>N}REDOR spectra of the membrane composed of 2-^<15>N-SM 6 and 4-^<13>C-Chol did not show any interaction between SM and Chol; the lifetime of their complex was too short to observe the intermolecular interaction due to thier rapid diffusion in the membrane. Then, for stabilizing the interaction, we synthesized SM-Chol conjugate 14 possessing hydroxylamine (-O-NH-) in the linker. Rafts formation by the conjugate 14 was assessed by several experiments, which consequently indicated that microdomains consisting of 14 were similar to those of SM/Chol. In order to examinc whether the conjuage reproduces hydrogen bond as seen for SM/Chol, we ran molecular dynamic simulation of the membrane comprised of the conjugate 14 or of SM/Chol=1/1. The resulte showed that the hydrogen bond was generated between the amide oxygen of SM part and -O-NH- hydrogen of Chol part in conjugate 14 to a comparable extent with SM/Chol=1:1. In summary, conjugate 14 was shown to reproduce the SM/Chol system, and therefore serve a molecular probe for studies of intermolecular interaction in lipid rafts.

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The natural phytotoxin coronatine, which is composed of two individual parts, coronafacic acid and coronamic acid, exhibits various promising biological activities similar to jasmonic acid, which is noe of the phytohormones. Interstingly, coronatine induces stomatal opening involving the swelling of guard cells in which jasmonic acid is not involved as an endogenous regulator. In order to apply the enantiodifferential approach for the identification of its target protein, we established syntheses of four stereoisomers of coronatine employing the exo-selectie Diels-Alder reaction as a key step. It will be advantageous to go through versatile intermediate for the preparation of various derivatives. Remarkable differences in a stomatal opening activity were observed between enantiomers of coronatine. This result strongly suggests that the stereostructure of coronatine is so important for its stomatal opening activity. In addition, structure-activity relationship studies suggested that coronatine operates as a molecular mimic of jasmonyl-L-isoleucine in plant guard celld. We also synthesized coronatine azide according to our synthetic strategy of coronatine, which possessed potent stomatal opening activity.

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We have designed dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin isolated from Amycolatopsis. In the course of our further screening of NF-kappa B inhibitors, we isolated 9-methystreptimidone from Streptomyces. We then prepared the derivatives having rather simple structures. We looded for the compounds that inhibit LPS-induced NO production in a mouse macrophage cell line RAW264.7. As a result, we found that DTCM0glutarimide, a novel derivative of 9-methylstreptimidone, inhibited the LPS-induced NO production. Then, we looked into the mechanism of inhibition. It inhibited LPS-induced expression of iNOS and COX-2. However, it did not inhibit NF-kappa B activation. Instead, we found that DTCM-glutarimide inhibited nuclear translocations of AP-1 consisting of c-Jun and c-Fos. In the present research, we further looked into the mechanism of AP-1 inhibition. It also inhibited the phosphorylation of c-Jun and c-Fos in cultured macrophage cells. Using recombinant JNK and c-Jun, DTCM-glutarimide inhibited the in vitro phosphorylation of c-Jun by JNK. In one hand, DTCM-glutarimide inhibited RANCL-induced osteoclast differentiation in mouse bone marrow-deried primary culture macrophages. It alst inhibited the invasion of mouse melanoma B16 cells in Mtrigel chamber assay. Thus, a novel piperidine compound, DTCM-glutarimide, was found to be a new AP-1 inhibitor that can be used for the cellular experiments. As a mechanism of inhibition, it is likely to inhibit phosphorylation of AP-1 components.

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Interactions between cell and extracellular matrix are pivotal survival of adherent cells both in vivo and in vitro. In vitro maintenance of adherent cells can be promoted by coating culture plates with artifical substrates, including native extracellular matrix molecules derived from either human/animal tissues or recombinant bacteria. However, many of these native molecules are not chemically defined and have the risk of contamination. Chemically defined synthetic polycationic peptides, such as poly(L/D-lysine), are also widely used for coating cell culture dises. Such nonspecific adhesive coatings, however, may cause abnormal cell-spreading, leading to cytotoxoc or physiologically irrelevant outcome. S synthetic molecule that promotes physiological cell adhesion would serve as a convenient reagent for a reproducible, safe, and biocompatible cell culture. In this paper, we report the discovery of the first non-peptidic organic molecule whose simple addition induces apparently normal cell adhesion to culture plates. Chemical and cell biological experiments suggest that adhesamine is most likely to exert its cell-adhesion activity by interacting with selective sulfated glysosaminoglycans (GAGs) to modulate cell surfate properties and intercellular signaling pathways. It is unllikely that adhesamine simply alters physical properties of cell surface through electrostatic interactions. Unlike poly-L-lysine, adhesamine induces apparently normal cell adhesion accompanied with organized actin structures, focal adhesion, activation of focal adhesion kinase/ERK kinases. Non-peptidic, completely organic molecules that promote normal cell adhesion and growth have never been reported, to our knowledge. Adhesamine may provide an additional framework to complement existing naturally derived or peptidic materials.

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Intra-specific diversity in L. kanaizensis, L. hodgsonil, and L. cyathieps was studied by chemical and genetic approaches. From the studies, as well as our previous results, we could obtain a hypothesis that the producton of furanoeremophilanes has conferred an ecological advantage. Fifteen L. kanaitzensis samples were collected in northwestern Yunna Province, China. The plant was found to be diverse with respect to its sesquiterpenodl composition and DNA sequence. Twenty-six eremophilane-type sesquiterpenoids, incluging six new compounds, were isolated from the species. From furanoeremophilane-producing samples, 4 and 5 were isolated as major components, while eremophilan-8-one derivatives 6 and 7 were obtained from the other samples. From the Japanese and the Chinese L. hodgsonii samples, 11 and 13a were isolated as the major component, respectively. In contrast to the large genetic difference, chemical diversity was limited to the positions of oxygen functionalities on the furanoeremophilane skeleton, supporting the above hypothesis. The chemical and genetic diversity in L. cyathiceps samples was found to be limited. Cacalol (14) and 6-acyloxyfuranoeremophilan-9-ones (15a,b) were isolated as major components in all the samples. Three new compounds 15c, 16, 17 were isolated. This observation and literature imply that the production of cacalol by L. cyathiceps and L. tsangchanensis may have a common origin.

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β-Isocryptoxanthin (BICX2), which is naturally occurring carotenoid, was isolated from sea urchins as a racemate. In the present study we analyzed the CD spectra observed for (4R)- and (4S)-BICX2 (BICX2R and BICX2S, respectively) and the corresponding benzoates (BICX3R and BICX3S, respectively) by time-dependent density functional theory (TD-DFT). The separation of the two enantiomers of β-isocryptoxanthin from the racemate was achieved by HPLC on a Chiralcel OD column after conversion to the corresponding monobenzoates. Saponification of each separated monobenzoate gave optically pure BICX2R and BICX2S. First, CD spectra of BICX2 and BICX3 were measured. Next the simulation of CD spectra for BICX2R based on TD-DFT calculations was performed by considering the following three types of conformers: 1) rotational isomers around R1 and R2 caused by steric hindrance between the methyl and methine groups, 2) stereoisomers based on rotation (R3) of thd hydroxy group, 3) conformational isomers of the cyclohexane rings base on puckerin near P1 and P2. The following points were clarified by TD-DFT calculations: 1) the effect of conformation of CD spectrum of BICX2R decreases in the order of R1, R2≫P1, P2>R3, 2) the contrast between the observed CD bands of BICX2R and BICX3R reflects a populaton of each conformer in equilibrium, 3) the intense positive CD band at around 230 nm is insensitive to the conformational changes, indicating that the absolute configuration of compounds similar to β-isocryptoxanthin can be suitably determined by using this CD band.

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Neurotrophin is recognized as an important regulatory substance in nervous system. However, it cannot cross brain-blood barrier because of the properties of its high molucular weight. To address this issue, considerable efforts have been made to find small molecules that mimic neurotrophic properties. As past of our continuing studies on neurotrophic-like active compounds in Illicium species, we investigated the chemical constituents of the pericarps of I. jiadifengpi, resulting in the isolation of two seco-prezizaane-type sesquiterpenoids 1 and 2 named jiadifenolide and 3,10-epoxymajucin. In this symposium, we present the structure elucidation and neurotrophic activit of new compounds. The structures of 1 and 2 were elucidated by analysis of spectroscopic data and comparison of their NMR data with those of majucin (4). It is surprised that the Dess-Martin oxidation of known sesquiterpene, neomajucin (3), gave rise to 1 in a straightforward fashin. This means that the absolute configuration of 1 can be assigned as the same of 3. To the best of our knowledge, jiadifenolide is the first example of a unique seco-prizizaane-type sesquiterpenoid with a γ-lactone formed between C-11 keto and C-4 hydroxyl groups. Compounds 1 and 2 significantly enhance neurite outgrowth in the primary cell cultures of fetal rat cortical neurons at 0.01μmolL^<-1> and 10μmolL^<-1>, respectively. It is worthy of note that compound 1 has a potential to significantly promote differentiation of multipotent neural stem cell line MEB5 cells into neurons at 1μmolL^<-1> and 0.1μmolL^<-1>.

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The Chinease quince, Chaenomeles sinensis is a species of Maloideae that bears an edible juicy fruit called 'Karin' in Japan. WE investigated the bioactive function of extracts of Karin leaf to achieve a more effective use of resources. In the present study, we found that the extract of Karin leaf showed anti-hyperglycemic activity in mice. It may thus be useful for preventing the postprandial absorption of carbohydrates used as drugs to treat diabetic patients and as functional food for people who need to control their own blood glucose level. The ethanol extract of Karin leaf suppressed the postprandial blood glucose level after an oral administration of soluble starch, maltose, sucrose and glucose in mice. The mechanism of action is proposed to be due to the separate components, the carbohydrate digestie enzyme-inhibiting activity and the glucose absorption-inhibiting activity in intestine, based on the results of in vitro and in vivo experiments. To clarify the mechanism of inhibitory activity on postprandial blood glucose elevation, the inhibitory effect of fractionated components from the crude extract on the glucose absorption in mouse intestine. Bioassay fractionation gave a carbohydrate, 1,5-anhydroglucitol (1-deoxyglucose) idenfied by spectral analysis. This compound is known as a non-metabolizable glucose analogue found in plasma due to ingest dietary intake. In this study, we found that Karin leaf suppressed the postprandial bolld glucose eleation in mice. The mechanism of action is thought to have involved the inhibition of glucose absorption in intestime by 1,5-anhydroglucitol in the extract. The Karin leaf may be a new resource for preventing metabolic disorders such as diabetes and to contribute to maintenance for people's health in the near future.

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Onion blend mixed with honey and vinegar is sometimes used as an antidiabetic agent and to control blood pressure. Moreover, it is known to exibit anticarcinogenic activities via enzymatic inhibition, enzymatic induction, and apoptosis. In addition, it possesses the following properties: antiinflammatory, antioxidant, antimicrobial, antifungal, and antiparasitic properties. Further, it plays a role in the prevention of cardiovascular diseases. Wagner et al. isolated thiosulphinates and α-sulphinyldisulphides from the chloroform extract of onion. However, these were not genuine constituents and were volatile and unstable. They also obtained novel biologically active 2,3-dimethyl-5,6- tithiabicyclo[2.1.1] hexane 5-oxide. In order to develop natural healthy foods that can prevent and combat the above diseases, we tried to isolate a stable substance from the acetone extract of onion. Onions were roughly chopped and soaked in acetone for 3 days at room temperature. The filtrate was evaporated at 40℃ in vacuo to yield a residue, which was subjected to Diaion HP-20 and then repeatedly dhromatographed on silica gel to give a small amount of a new compound named onionin A (1). The positive HR-FAB-MS of 1 showed peaks due to [M+Na]^+ and [C_6H_<11>OS]^+ at m/z 243.0489 (Calcd for C_9H_<16>O_2S_2Na, 243.0489), 70%, and at m/z 131.0525 [Calcd for C_6H_<11>OS, 131.0531], base peak, respectiely. The ^1H- and ^<13>C-NMR spectra and various 2D-NMR techniques revealed the structure of 1 as shown in Fig. 4. It is known that inhibition of M2 macrophage polarization suppresses tumor cell proliferation. We then examined the inhibitoy effect of 1, a new compound isolated from onion, on CD163 expression, M2 macrophage marker, by a Cell noncompetitive enzyme-linked immunosorbent assay (Cell-ELISA). As a result, 1 significantly inhibited CD13 expression. This result suggests that onionin A (1) has a potential to suppress tumor cell proliferation by inhibition of M2 macrophage polarization.

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Some phenolic compounds in nature have received much attention as powerful antioxidants to protect against oxidative deterioration of biomolecules. Phenolic acids including ferulic, caffeic and sinapic acids, are widely distibuts in edible and medicinal plants. These phenolic acids occur as ester forms with various polar and non polar compounds in plants. These esters in plants show potent antioxidant actiity with the phenolic acid part as actie site. The main mechanism for a phenolic antioxidant is the trapping and stabilizing of radical species, such as the lipid peroxyl radical. The antioxidation process of the phenolic compound is thought to be divided into two stages; radical trapping and termination stages. Although the first stage is a reversible process, the second stage is irreversible and must produce stable radical termination products. Structural information about these termination products would afford important contributions to the antioxodation mechanism studies. In this study, isolation and structure determination of the termination products from the phenolic acids were carried out and the results revealed that they are a dimer, a quinone, and several peroxides having tricyclic structures which consisted of ethyl linoleate, phenolic ester and molecular oxygen. Based on the formation pathway of the peroxide products, an antioxidation mechanism was proposed, including that radical scavenging reaction, which was occurred at the 3'-position of phenoic aced with peroxyl radicals of ethyl linoleate and a subsequent intramolecular Diels-Alder reaction.

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A phytochemical investigation of Tamarix nilotica (Ehrenb.) Bunge (collected in Egypt) led to the isolation of 15 new ellagitannins, along with 15 known ones. New tannins 9-14 were assigned as a series of monomeric tannins. Among these monomers, 14 includes a hellinoyl (m-GO-m-GOG) moiety. Structure 9 possesses both m-GOG and p-GOG moieties, and each of structures 10, 11, and 13 has a p-GOG unit. Structure 12 is the first methylated ellagitannin isolated from the family Tamaricaceae. The structures of the new dimers were grouped according to the type of linking unit and their connection mode: m-GOGand p-GOG linear dimers (15-19), m-GOG and p-GOG macrocyclic dimers (20 and 21), and m-GO-m-GOG dimers (23 and 24). Replacement of the HHDP group at O-4/O-6 with a galloyl group at the O-6 of glucose-2 in 23 is another structural feature. These findings reflect the ability of Tamarix plants to produce ellagitannins with various structures and provide valuable new information for elucidating the structure of higher oligomeric compounds.

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About 5,000 strains of actinomyctes were isolated from near coast. It was found that 2,600 strains have independent sequence. Additionally, 386 strains showed less than 98% homology with BLAST Search. Througn the search of rare actinomycete strains, less than 98% homology, six novel tricyclic acids of a new structure class, indoxamycins A-F 1-6), and two aromatic acids, lorneic acid A-B (7-8), were isolated from a saline culture medium of these strains. The chemical structures of these compounds were assigned by combine spectral and chemical methods. Indoxamycins A-F (1-6) were isolated from the culture medium of NPS643 (96% sequence homology). Growth inhibition activities (HT-29) of indoxamycins were identified as indoxamycin A (1) (IC_<50> 0.59μM), indoxamycin F (6) (IC_<50> 0.33μM). On the other hand, hydroxyl methyl analogs of 1, indoxamycin B-E (2-5), showed no activity at 3μM. Feeding experiment of ^<13>C-propionic acid revealed that tricyclic ring system was build from 6 propionate units. Lorneic acid A-B (7-8) were isolated from the culture medium of NPS554 (98% sequence homology). These acids showed very week growth inhibition activities against TF-1 cell (7: 98%, 8: 81%, 500μM). However, according to the enzyme inhibition activities against 150 targets, lorneic acid A (7) showed specific inhibition against pepsin (inhibition ratio: 88%, 10μM) and phosphodiesterase 5 (inhibition ratio: 50%, 10μM). Evaluation of their biological activities and detailed analysis of biosynthetic mechanisms are currently under infestigation.

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A procedure was developed for quantitative determination of chafuroside A1, a flavone C-glycoside with potent anti-inflammatory activity, and its regioisomer chafuroside B2, as well as isovitexin and vitexin, by selected reaction monitoring liquid chromatography-tandem mass spectrometry analysis. This method was successfully applied to commercial leaves of green tea, houji tea, oolong tea and black tea. High levels of chafuroside A and chafutoside B were found in oolong tea leaves that had been heated at over 140℃. Next, their precursors, prechafuroside A and prechafuroside B, were isolated frommethanol extract of oolong tea leaves prepared from Shizu 7132, Camellia sinensis (L.) O. Kuntze, by partiton with n-butanol and H_2O and chromatography on Diaion SP-825, Sephadex LH-20, and ODS C-18, guided by assay of chafuroside formation. Prechafuroside A and prechafutoside B gave chafuroside A and Chafuroside B, respectively, in good yields when heated at 160℃ for 0.5h. Hydrolysis of prechafuroside A and prechafuroside B with pyridine and dioxane quantitatively afforded isovitexin and vitexin, respectively. Based on these results and physicochemical data (MS, UV and NMR), prechafuroside A and prechafuroside B were concluded to be new flavone C-glycoside sulfates, isovitexin-2"-sulfate 5 and vitexin-2"-sulfate 6, respectively.

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Propolis is a natural resinous product collected by honeybees from certain plants. It has gained popularity as a food and alternative medicine. However, the propolis from Okinawa, Japan, contains some prenylflavonoids not seen in other regions such as Europe and Brazil, suggesting that the plant origin of Okinawan propolis is a particular plant that grows in Okinawa. To identify the plant origin of Okinawan propolis, we obsereved the behavior of honeybees as they collected material from plants and caulked it inside the hive. Honeybees scraped resinous material from the surface of plant fruits of Macaranga tanarius and brought it back to their hive to use it as propolis. The chemical constituents and biological activity of the ethanol extracts of the plant did not differ from those of propolis. This indicates directly that the plant origin of Okinawan propolis is M. tanarius. We carried out the quantitative analysis of prenylflavonoids in various parts of M. tanarius such as leaf, petiol, atem, leaflet, flower, and fruit. Fruits were further separated into seed, pericarp, and glandular trichome, the surface of the fruits of M. tanarius. Large amounts of prenylflavonoids were present in glandular trichome. Next we observed the glandular trichome by a low vacuum scanning electron microscepe. It had the unique structure with a large cabity which is expected to produce prenylflavonoids. We prepared the ethanol extracts of M. tanarius and evaluated its antimicrobial and antiangiogenic activities. The extracts had significant antimicrobial activity against Gram-positive bacteria and also indicated the potent antiangiogenesis effects. Thus M. tanarius was proved to be an intersting plant with unique biological activities.

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Actinomycetes have provided a diverse array of bioactive secondary metabolites. In particular, those belonging to the genus Streptomyces have been the most promising source of chemically diverse secondary metabolites. Their high capacity of secondary metabolite biosyntheis is largely attributable to the diversity of polyketide synthase (PKS) genes. In our continuing search for novel bioactive secondary metabolited from Streptomyces, we found a novel macrocyclic polyketide with an unprecedented framework from the culture extract of Streptomyces isolated from a leaf of chive Allium sp. For the production of the new compounds, the strain was fermented under a specific co-culturing condition with a bacterium Tsukamurella pulmonis. The 1-butanol extract of whole culture broth was separated by normal- and reversed-phase column chromatographies and HPLC to yield alchivemycins A (1) and B (2). Elucidation of the relative configurations of the alchivemycins was accomplished by a combination of NMR analysis and X-ray crystallography. Here we report the isolation and structure determination of the new compounds. This represents the first example of natural products containing a unique tetronic acid-tetramic acid hybrid substructure. Conpounds 1 and 2 inhibited tumor cell invasion without showing cytotoxic effects.

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Catechins included in the certain species of plants such as tea (Camellia sinensis, Camelliaceae) show various physiologically modulating effects such as anti-oxidative, anti-carcinogenic and anti-hypercholesterolemic. Interstingly, it is known that catechins form complexes with caffeine, especially in black tea and coffee. Such complexation is not only and interesting chemical phenomenon, but also may show intersting unique biological activities. Then various studies on the complexes of catechins and caffeine in solution state have been performed. In this study, the crystal structure of the complex of (-)-gallocatechin gallate (GCg) and caffeine was determined fully, and the interaction between GCg and caffeine moieties in the complex was also investigated. A suspension of GCg and caffeine in water afforded two kinds of complex, the 1:2 and 2:2 complexes of GCf and caffeine. The crystal structures of the two complexes were determined by X-ray crystallography. A remarkable difference in the layer structure between the crystal structures of the 1:2 and 2:2 complexes and GCg alone was observed (Figure 7). The units of the 1:2 complex piled up in the same direction almost vertically against the b-c plane, as shown in Figure 7a. The driving force for the formation of the 1:2 complex was thought to be mainly π-π interactions between the A, B' rings of GCg and the six-membered rings of caffeines. GCg molecules in the 2:2 complex piled up as shown in Figure 7b, and A and C rings of GCgs faced each other. The π-π interactions between the B ring of GCg and caffeine, the B' ring of GCg and caffeine, and the A rings of GCgs were formed in the 2:2 comples, whereas GCg molecules in the layer of GCg alone piled up in the same direction as shown in Figure 7c, and no π-π interaction was observed.

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Innate immunity is the first line of defense against infectious microorganisms, and the basic mechanisms of this process, including pathogen recognition and immune response activation, are evolutionarily conserved. In mammals, the innate immunity has an instructive role in the adaptive immune response specific to antigen by inducing co-stimulatory molecules and cytokines, indicating that a concerted and interactive innate and adaptive immune reaction is key for the regulated immune response. Therefore, from a pharmaceutical point of view, innate immunity is a good target for the development of immune regulators to suppress unwanted immune responses, such as septic shock, inflammatory diseases and autoimmunity, and to stimulate protective immune responses to some of the disease that largely elude the immune system, such as infectious diseases and cancer. To screen pharmaceuticals that target innate immunity, we established an ex vivo culture system based on the innate immune response of Drosophila, which is highly useful for idintifying immune regulators that act on human innate immunity. We used this system to search for natural substances that regulate innate immunity, and identified celastramycin A (1) and TP-554 (2) as a potent suppressor and an activator, respectively. The previously reported structure 3 for celastramycin A was corrected to 1 by synthesizing both compounds. In addition, we synthesized some derivatives of celastramycin A (1) to evaluate structure-activity relationship of these compounds.

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Stilbenoids such as resveratro have drawn much attention due to their roles in foods and beverages, and their diverse biological activities. These compounds, either in their glycosylated or non-glycosylated form, are typically found as oligomers in few plant families, such as Dipterocarpaceae, Vitaceae, Cyperaceae, and Gnetaceae. The rich structural variation and multifunctional bioactivity make stilbenoid oligomers interesting targets for detailed phytochemical investigations. Dipterocarpaeaeous plants are known to contain resveratrol oligomers, and their occurrences in Vatica, Vateria, Shorea, and Hopea genera have been discussed in our previous works. Vatica, a genus comprising 65 species, belongs to the largest subfamily of Dipterocarpoideae in the Dipterocarpaceae, most of which are native to Southeast Asia. The genus Vatica is well known for its abundance of resveratrol oligomers. In our current phytochemical studies of Dipterocarpaceae, the chemical constituents of V. albiramis were exzmined, and 14 new resveratrol oligomers (1, 2, 6-15, 19, and 24) were isolated, together with 15 known resveratrol derivatives. To the best our knowledge, 1 is the first resveratrol hexamer posseseing 9-Oxa-bicyclo[3,3,1] nonadiene ring system with dimer unit and one aromatic ring (E_1) rearranged like a 1, 2-aryl migration. Furthermore, Some unusual spectroscopic properties observed in new compounds in NMR spectrum are also comprehensiely discussed.

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