Eudistomidin B, a tetrahydro-ß-carboline alkaloid isolated from the Okinawan tunicate Eudistoma glaucus, shows potent cytotoxicity against murine leukemia cell and activates rabbit heart muscle actomyosin ATPase. Here in, we disclose the stereocontrolled total synthesis of Eudistomidin B, featuring application of asymmetric intramolecular Pictet-Spengler reaction via acyliminium intermediate as the key step. Hemiaminal 8 was synthesized from p-tolualdehyde in 12 steps. Upon treatment of 8 with TMSCl, stereoselective cyclization proceeded smoothly to provide cyclic carbamate 9 in 91% yield (d.r.= 12:1). From this compound, the total synthesis of Eudistomidin B was accomplished in 5 steps. However, the spectral data including 1H-, 13C-NMR and optical rotation of the synthetic Eudistomidin B were inconsistent with those in the literature, which posed a question about the proposed structure for Eustomidin B.

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Oteromycin is a HIV integrase inhibitor isolated from fungi MF5810 and MF5811, and has attracted a lot of attention for it's constructive features, decalin skeleton and alpha,beta-unsaturated-alpha-acyl-gamma-hydroxylactam moiety. In the initial stage of the total synthesis, the novel synthetic method of alpha,beta-unsaturated-alpha-acyl-gamma-hydroxylactam moiety was developed utilizing the catalytic acid-mediated dehydrogenation of alpha-acyl-gamma-hydroxylactam by DDQ. We succeeded in establishing the novel synthetic method, lanched synthesis of the decalin skeleton of Oteromycin. As a key step for the construction of the decalin skeleton, an intramolecular Diels-Alder (IMDA) reaction was adopted. The synthesis of the decalin equipped with all stereogenic centers has been achieved, starting from commercially available (+)-citronellal.

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Myxothiazos A (1) and Z (2) possessing a bithiazole skeleton as well as a beta-methoxyacrylate moiety were isolated from the myxobacterium Myxococcus fulvus strain Mxf161 and Myxococcus fulvus, respectively. Myxothiazos A (1) is active against many filamentous fungi and completely inhibits growth of Mucor hiemalis The fungicidal activity of the beta-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. Myxothiazos Z (2) was reported to exhibit potent cytotoxicity against human tumor cell. Convergent synthesis of (+)-myxothiazol A (1) and Z (2) was achieved based on Julia-Kocienski coupling between (3,5R)-dimethoxy-(4R)-methyl 6-oxo-(2E)-hexenamide (2), corresponding to left-side of the final molecule, and E-4-2'-(1S,6-dimethylheptadiene)-(2,4'-bis-thiazole)-4-methybenzothiazole sulfone (4) corresponding to right-side.

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Various novel 10-alkyl-2-deoxo-2-methylthio-5-deazaflavins have been synthesized by reaction of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones with Vilsmeier reagent. The similar 2-(N-substituted amino) derivatives were prepared by nucleophilic replacement reaction of the 2-methylthio moiety by appropriate amines. The 2-oxo derivatives (i.e., 5-deazaflavins) were obtained by acidic hydrolysis of the 2-methylthio derivatives. The antitumor activities against CCRF-HSB-2 and KB cells and the antiviral activities against HSV-1 and HSV-2 have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK has been done for lead optimization of these compounds as potential PTK inhibitors. Whereas, the designed 2-deoxo-5-deazaflavins connected with amino acids at the 2-position exhibited the good binding affinities into PTK with more hydrogen bonds.

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The increasing attention has been focused on new methodologies to control gene expression. We have previously developed 2-amino-6-vinylpurine (AVP) derivatives as cytidine selective cross-linking agents. The oligonucleotides containing these reactive derivatives have exhibited antisense effects with greater potency and selectivity than the corresponding unreactive oligonucleotides.
To extend the target nucleobase of our methodology, we report here design and synthesis of new reactive 2-vinyl-4-amino-6-oxopyrimidine (VAOP) derivatives targeted for guanine. The reactive nucleobase was synthesized from ethyl cyanoacetate and cyanamide. The vinyl group of VAOP was introduced by Stille reaction using tributyl(vinyl)tin. Then, the vinyl group was protected by octanethiol for DNA oligomer synthesis. Now, we are investigating coupling reaction between the reactive base and sugar parts. In this presentation, we would like to discuss these results in detail.

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We report an identification of trimannoside-recognizing peptide sequences from a T7 phage display screen using a quartz-crystal microbalance (QCM) device. A trimannoside derivative that can form self-assembled monolayer (SAM) on a gold surface was synthesized and used for immobilization on the gold electrode surface of QCM sensor chip. As a result of six sets of one-cycle affinity selection on this environment, T7 phage particles displaying PSVGLFTH (8-mer) and SVGLGLGFSTVNCF (14-mer) were found to be enriched at a rate of 17/44, 9/44, respectively, suggesting that these peptides specifically recognize trimannoside. Binding checks using respective single T7 phage also confirmed the specific binding of these sequences to the trimannoside-SAM. Subsequent similarity search showed that these sequences correspond to the part of primary peptide sequence in many of mannose- or other hexose-related proteins.

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Genome-targeting molecules would have broad applications as probes in genomic study, and therefore, have gained considerable attention. But the molecules which recognize abnormally long base sequences, such as triplet repeats, have not yet been reported.
In this study, we have attempted to establish a new binding mode, in which small molecular bisligands consisting of two DNA binding units and a linker may assemble on the DNA template by multidentate coordination with the metal cation. For realizing such binding system, we designed bisligands based on peri-hydroxy aromatic derivatives developed by us that show DNA binding ability in the presence of Mg²⁺.
At first, the binding property of the monoligand was evaluated, and it was shown that monoligand form 3:1-4:1 ligand-Mg²⁺ and binds to DNA. This paper reports the synthesis of bisligand and the DNA-binding properties of bisligand.

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We previously reported a new chemical strategy for determining the role of acid-base catalysis in a ribozyme function using an C4-linked imidzaole phosphoramidite (C0-PA), in which a direct role of A756 of natural VS ribozyme was powerfully supported.
In this study, a novel key building block, imidazole C2-ribonucleoside PA (C2-PA), which had a two carbon linker between the imidazole and ribose moieties and so was better structural mimic of a purine nucleobase, was designed and efficiently synthesized from commercially available tribenzyl D-ribose in 13 steps and 23 % overall yield. The key feature of the synthesis is the use of the cyanoethyl group as an efficient protecting group at 2'-OH.
Using the C2-PA, C2-imidazole was incorporated into G638 of VS ribozyme (G638C2Imz). It catalyzed the almost complete cleavage of a substrate and the pH dependence of the cleavage rate showed a bell-shaped profile based on the imidazole-substituted ribozyme.

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Protein kinase family transfers a phosphate group of adenosinetriphosphate (ATP), which functions as a coenzyme, to substrate protein and converts the hydroxyl group of the substrate to phosphoester group. The protein phosphorylation is crucial in the regulation of intracellular signal transduction pathways. Since these pathways are complicated, it is signified to identify each kinase-substrate pair. We developed a chemical method to detect correct kinase-substrate pair by fluorescent spectroscopy. In this system, the functional ATP analogue bearing ortho-dialdehyde moiety is expected to exhibit the characteristic fluorescence, only when it reacts with both the conserved lysine residue of kinase family and the thiol group of a mutated substrate, in which the serine or threonine residue that is phosphorylated was replaced with cysteine residue. Several ATP derivatives bearing ortho-dialdehyde moiety were synthesized, and their functions and fluorescent properties were examined.

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A combinatorial library consisting of 1000 peptidocalixarenes was screened to discover substrate-specific catalysts for hydrolysis of a tyrosine phenol ester. Phosphoric phenol ester of tyrosine was synthesized as a transition state analogue for this reaction. Several peptidocalixarenes with sequences of X-Arg-His in the library were found to bind the analogue. In the presence of the peptidocalixarenes as the catalysts, the rate for the hydrolysis of the tyrosine phenol ester was enhanced up to 40-fold over the uncatalyzed hydrolysis. The substrate specificity of the catalysts was also examined.

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Liver X receptors (LXRs) are members of the nuclear receptor superfamily and are involved in the regulation of cholesterol, lipid, and glucose metabolism. In macrophage, liver, and intestine, activation of LXRs induces the expression of genes involved in lipid metabolism and reverse cholesterol transport, but several LXR agonists activate triglyceride synthesis in the liver by the activation of sterol regulatory element binding protein 1c (SREBP-1c) and fatty acid synthase (FAS), and this limits the utility of these synthetic LXR agonists. Therefore, novel, specific LXR ligands are needed. We designed and synthesized conformationally restricted heterocyclic analogs of carba-T0901317. In vitro transactivation assay revealed that the structural modification altered the nature of the activity from LXR-agonistic to LXR-antagonistic.

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Highly-ordered DNA structures are involved in gene expression. Therefore it is expected that molecules which recognize such DNA structures would play an important role for the clarification of structural role. In this study, we report a new strategy to develop recognition molecules by Click Chemistry, in which a specific recognition molecule is selectively synthesized using the target DNA as a template. Porphyrin derivatives are used as DNA binding units. First, we synthesized the porphyrin dimer using Click Chemistry in the absent of DNA. It was suggested that the porphyrin dimer binds to double-strand DNA in an external binding mode.

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We have developed a reduction-triggered fluorescence probe with a new fluorogenic compound derivatized from rhodamine 110 for sensing oligonucleotides. The chemistry to activate the compound involves the reaction between the azide group of rhodamine derivatives and reducing reagents, with the fluorescence signal appearing after reduction of the azide group. The signal/background ratio of this fluorogenic compound reached 2100-fold enhancement in fluorescence intensity. Dithio-1,4-threitol or triphenylphosphine as reducing reagents were successfully utilized for this chemistry to be introduced into the DNA probe. The genetic detection requires that two strands of DNA bind onto target oligonucleotides, one probe carrying a reducible fluorogenic compound while the other carries the reducing reagents. The reaction proceeds automatically without any enzymes or reagents under biological conditions to produce a fluorescence signal within 10 min in the presence of target DNA or RNA.

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In recent years, calculations of electronic structures in the excited states have been very intriguing and actively studied. But the prediction of fluorescent emission energies (i.e., wavelengths of fluorescence) of even well established fluorescent molecules is still challenging. So, we compared the absorption / emission energies calculated by the recently established methods, which can be applicable to molecules of practical size and interest. We selected three chromophores of different structures and ranges of emission wavelengths, indoles (300~350 nm) and benzofurazanes (400~500 nm) and coumarins (380~430 nm). Finally we found a combination of calculation methods useful for theoretical evaluation of the excitation and emission energies of molecules frequently used in experiments.

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We have focused on optically active oligo(2,3-dioxyfunctionalized)naphthalenes, which are connected at their 1,4-positions in CuCl2/amine promoted oxidative homo coupling reactions. The pathway for the induction of axial chirality in the dimerization reaction is controlled by the kind of side chain on naphthalene, which seemingly does not influence chiral induction. In this poster, we report our last endeavor in the synthesis of oligonaphthalenes with n-butoxy side chains where axial chirality is induced under thermodynamic control, and the high solubilities and stabilities are attributed to the side chains. After suffering many difficulties, we could construct all-(S)-32mers! The chirality of the newly formed axis in the 32mers, which were the upper limit due to technical isolation or separation problems, could be unambiguously determined by the CD exciton chirality method.

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Polyglycerols are oligomers of glycerol. Their fatty acid esters are generally dispersible in water and soluble in oil. These polyglycerols are readily available in bulk quantities by industrial manufactures, and are widely used for food additives, cosmetic materials as surfactants, and pharmaceuticals. However, the commercially available materials are mixture of some structural isomer with same hydroxyl value. We have studied on the synthesis of polyglycerols as an authentic standard. In the racemic synthesis of cyclic triglycerol, separable two isomers are obtained. Their structures are expected to the Cs and C₃ form, respectively. The stereochemistry is confirmed by the stereocontrolled synthesis of both diastereomers.

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Dramatic conformational change is sometimes obtained in small molecules by introducing simple substituents. Typical examples are seen in benzanilide and N,N'-diphenylurea derivatives by introducing methyl group on the nitrogens. Considering these examples, the following requirements are come up in mind: The molecules have (1) plural aromatic rings (s) connected with plural sp² atoms, those consist planar functional group. When we look at structure of N-benzoyl-N'-phenylhydrazines, the order of carbonyl group and sp² nitrogen is changed by comparison with N,N'-diphenylurea, and therefore, planarity of tethered functional group is lost because of electronic repulsion between two lone-pair electrons on each nitrogen. We found that some of N-benzoyl-N'-phenylhydrazines changed their conformation dramatically by introducing methyl and acetyl groups on the N-position.

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Fluorous synthesis has become increasingly popular in modern organic synthesis, where fluorous tagged molecules are easily separated from non-fluorous molecules using fluorous technologies such as fluorous solid-phase extraction (F-SPE).
However, multi-step synthesis using fluorous protecting group is limited because of the lack of fluorous tags that are stable for strong acid and base. We recently developed perfluoroalkylated arylsulfonyl tag for the protection of indole ring nitrogen, and here we wish to report applicable scope of m-Rf8PhSO2 tag. We investigated fluorous synthesis of Yuehchukene as a model multi-step synthesis. In this case, m-Rf8PhSO2 tag was resist to acid, base, oxidation and reduction condition, thus this tag is suitable for multi-step synthesis.
Moreover, we developed fluorous nosyl tag as a new fluorous protecting group. Using this fluorous nosyl tag, synthesis of secondary amines was accomplished efficiently.

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Compounds that reversibly changes structures between double-helix and random-coil have attracted much interest. We previously reported that an optical active ethynylhelicene oligomer exhibited such property in solution by changing temperature, concentration, and solvent. In order to develop new double-helix compounds, we decided to examine its derivatives, and, in this study, three oligomers were synthesized. When the decyloxycarbonyl side chain of the original oligomer was changed to perfluorooctyl group, the new derivative formed double-helix with the reverse sense of helicity. When the acetylene moiety was change to amide, the oligomers again formed double-helix by hydrogen bond. p-Phenylene ethynylene oligomers possessing helicene side chain, a structural isomer of the original oligomer, also formed double-helix. It is shown that various derivatives of the ethynylhelicene oligomer form double-helix.

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Inositol 1,4,5-triphosphate (IP₃) is one of the important second messengers in intracellular signal transduction. Selective receptors or sensors for IP₃) are highly required to examine its concentration and location in living cells and sample solutions. We previously reported a supramolecular IP₃) sensor, Ru(Zn₂L¹)₃, as the first luminescent sensor that directly responds to IP₃ and its model compound, cis,cis-1,3,5-cyclohexanetriol triphosphate (CTP₃) in aqueous solution (J. Am. Chem. Soc., 2005). In this work, we have designed and synthesized a new IP₃ sensor, Ir(ZnL²)₃, that has a cyclometalated Ir complex and three Zn²⁺-cyclen complexes. In this presentation, we will describe synthesis of Ir(ZnL²)₃ via regioselective substitution reactions of Ir(ppy)₃ complex and its luminescent response to IP₃.

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Chiral derivatizing agents (CDAs) are currently used for the NMR assignments of the absolute configurations of chiral secondary alcohols. The validity of the assignments strongly depends on whether the correlation model of each CDA method is the same as the actual preferred conformation of the chiral derivatives in solutions. Here we present a novel CDA method using alpha-cyano-alpha-fluoro-p-tolylacetic acid (CFTA). The method involves a direct confirmation of the preferred conformation of the CFTA esters in solution by observing the C=O stretching absorption in IR spectra. Therefore, it must be quite reliable. We also discuss about the origin of conformational preference in CFTA esters by using methyl ester of alpha-cyano-alpha-fluorophenylacetic acid (CFPA) as a model system.

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Our longstanding interest in mild and powerful Ti- (or Zr-) crossed-Claisen condensations, and relevant aldol and Mannich reactions, led us to extend it toward the asymmetric Ti-Claisen condensation. The present method utilized readily available chiral template, 1,4-dioxolane-2,5-diones, which underwent a crossed Ti-Claisen condensation to give the acylated product with high diastereoselectivity (>95% de). With this result in hand, we achieved efficient asymmetric total syntheses of a couple of biologically active natural products, optically active alternaric acid and (-)-azaspirene, which have contiguous acyclic and cyclic stereogenic centers, respectively.

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Diversifolin is a highly oxygenated germacrane-type sesquiterpene, and inhibits the activation of the transcription factor NF-kB. The most characteristic structural feature of diversifoline is a strained 10-membered carbocyclic germacrane skeleton including 5-membered cyclic hemiketal. We were able to accomplish the first total synthesis of diversifolin. The synthetic features involve formal 1,3-asymmetric induction, unusual ring closing metathesis constructing 10-membered carbocycle system, and unique lactone transposition.

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(+)-Negamycin, a dipeptidic antibiotics, was isolated in 1970 from Streptomyces purpeofuscus and exhibited antimicrobial activity against multiple drug resistant Gram-negative bacteria. This activity was derived from genetic miscoding on bacterial ribosomal systems, thereby leading to a inhibition of protein biosynthesis. Because this miscoding causes read-through of termination signals in protein translation, considerable attention has been focused on negamycin as a potential therapeutic agent for genetic diseases, such as Duchenne muscular dystrophy (DMD). Herein, for the future development of anti-DMD drugs, we describe a new efficient strategy for the total synthesis of (+)-negamycin using achiral N-Boc-2-aminoacetaldehyde as a starting material with 42% overall yield over only eight steps including the asymmetric allylboration and Michael reaction with chiral methoxybornyl-10-benzylamine.

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A development of new method for a catalytic cyano-functionalization of alkynes using Pd(II), TMSCN and molecular oxygen has been studied. This novel reaction enables to introduce two cyano groups directly via cyanopalladation, which is a new mechanism in palladium chemistry, and the selectivity is strongly dependent on substrates (with up to Z:E = >25:1). Internal alkynes are usable in the presence of TMSOTf and tosyl group dramatically enhanced the reaction rate. Olefins, which are inert under these conditions, can be cyanated via cyclization of enynes to construct 5- and 6-membered rings. In case of methacrylamides, 6-endo cyclization followed by the formation of oxo-pi allyl complexes gave the corresponding lactams in sterepselective fashion. Both procedures include three sequential C-C bond formations through one operation to construct highly functionalized nitrogen heterocycles.

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Intermolecular [4 + 2] cycloaddition between 3-alkoxycyclobutanones and compounds bearing a C=X bond (X = O, C, N) by the activation with Lewis acid is reported. Aldehydes or ketones reacted with 6-alkyl-2-oxabicyclo[4.2.0]octan-7-ones by the catalysis of boron trifluoride etherate to afford 1-alkyl-5,7-dioxabicyclo[4.4.0]decan-2-one derivatives regioselectively (> 99 : 1) and diastereoselectively. Also, the reaction of 3-ethoxy-2,2-dialkylcyclobutanones at low temperature gave 3,3-dialkyl-6-ethoxy-2,3,5,6-tetrahydro-4H-pyran-4-one derivatives with high regioselectivities, while the reaction at room temperature gave tri- or tetrasubstituted dihydro-g-pyrones in a one-pot manner. In addition to aldehydes and ketones, 3-alkoxycyclobutanones reacted readily with N-Ts imines, allylsilanes, and silyl enol ethers to give the corresponding [4 + 2] cycloadducts.

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A convenient and straightforward access to various 2-arylbenzoxazoles is provided by a copper-catalyzed intramolecular oxidative C–O coupling of benzanilides. A wide variety of functionalized 2-arylbenzoxazoles are prepared in up to 93% yield with high functional group tolerance and regioselectivity. The catalytic cycle was achieved by use of molecular oxygen as terminal oxidant without adding any additives.

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Instantaneous C-C bond forming reactions were achieved by using a microchannel reactor bearing catalytic membrane inside the channel. Thus, the catalytic membrane PA-TAP-Pd was constructed inside the microchannel in a "ship-in-a-bottle" fashion via molecular convolution of an non-crosslinked polymeric phosphine ligand and (NH4)2PdCl4 at 25 C for 10 min at the interface between EtOAc and aqueous phases flowing laminarly, where an non-crosslinked polymer-bound phosphine and (NH4)2PdCl4 dissolved, respectively. The palladium-catalyzed Suzuki-Miyaura reaction of aryl halides in EtOAc/i-C3H7OH and arylboronic acids in aqueous Na2CO3 at 50 C was performed using the microreaction device to afford the corresponding biaryl compounds in 96-99% yield within 4 sec of retention time in the defined channel region. The microdevice system was also successfully applied to arylation of allylic esters to give allylarenes with retention time of 1 sec.

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We describe facile catalytic syntheses of allylamine derivatives by direct substitution of allylic alcohols with nitrogen nucleophiles. The direct amination of primary allylic alcohols with aryl and alkyl amines was achieved using platinum catalyst. The use of a large bite-angle bidentate diphosphine ligand DPEphos or Xantphos was essential for obtaining high catalyst activity and high monoallylation selectivity of primary amines. We demonstrated the synthetic utility of this catalysis by the one-step synthesis of the antifungal drug naftifine. Furthermore, the direct substitution with electron-deficient nucleophiles, such as nitroaniline, sulfonamide and carbamate was also achieved using gold catalyst to give the corresponding allylamine derivatives in high yield. Under the optimized conditions, the reaction with various tert-butyl carbamates proceeded smoothly to afford synthetically more useful Boc-protected allylamines.

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