Catalytic asymmetric alkynylation of carbonyl compounds is one of the most efficient routes for the synthesis of optically active propargylic alcohols. Although several efficient catalytic asymmetric alkynylations of aldehydes have been developed, the development of catalytic asymmetric alkynylation of ketones has had limited success.
Here, we report catalytic asymmetric alkynylation of alfa-keto ester with various aryl and alkyl substituted terminal alkynes catalyzed by as little as 3 mol% of C₁-symmetric Rh-Phebox complexes to afford the corresponding propargylic alcohols with greater than 99% ee. Because acetate ligand on the Rh complex acted as an internal base, the reactions proceeded at rt without any additives. In most cases, the C₁-symmetric complex gave better results than the C₂-symmetric complex. This Rh complex had unique chemoselectivity; it selectively reacted with alfa-keto ester over aldehyde.

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C-S/C-P bond formation is an essential process for the synthesis of organosulfur and organophosphorus compounds. Recently, we found single-bond metathesis reactions to be useful for such synthesis, and a variety of reactions involving cleavage of heteroatom bonds were developed. Single bond metathesis reactions were often reversible, and therefore the development of the method to control equilibrium turned to be important.
We developed an equilibrium control method using co-substrates. Rhodium-catalyzed method can be used for acyl transfer equilibrium between acid fluorides, acylphosphine sulfides, thioesters, and aryl esters. Appropriate co-substrates changed the relative thermodynamic stabilities of substrates and products, and efficiently provided desired products. This method using the combination of a transition metal catalyst and heteroatom acceptors can be generally used for the synthesis of organoheteroatom compounds.

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The oxidative cleavage of vic-diols is one of the most useful method for the C-C bond scission. Criegee reaction and Malaprade reaction are the representatives for this transformation, which normally produce aldehydes and ketones. We have recently developed highly efficient alcohol oxidation catalysts, AZADOs (2-azaadamantane N-oxyls). On the way of exploring the further utilities of AZADOs, we found two novel oxidative cleavage conditions (1-Me-AZADO(cat.)/NaOCl (cat.)/NaClO₂, AZADO(cat.)/PhI(OAc)₂/H₂O) which directry produce corresponding carboxylic acids. The former condition allows one-pot conversion of terminal vic-diols to carboxylic acids. On the other hand, the latter condition allows one-pot conversion of terminal and internal vic-diols to carboxylic acids. In this presentation, we report its scope and mechanistic details.

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We have developed a concise and efficient synthetic method of planar chiral pseudo-ortho-substituted aryl[2.2]paracyclophane molecules possessing C-H bond donors and/or nucleophilic functional groups through the stepwise successive palladium-catalyzed coupling of 12-bromo[2.2]cyclophan-4-yl triflate. Buchwald-Hartwig amination and subsequent Suzuki-Miyaura coupling, followed by the functional group transformation afforded aryl[2.2]cyclophanyl thiourea derivatives. The combination of Suzuki-Miyaura coupling and phosphinylation delivered arylcyclophanyl phosphines. The catalytic activities of the newly synthesized chiral cyclophanyl-thioureas and -phosphines were evaluated based on the aza-Morita-Baylis-Hillman reaction of N-tosylaldimine and methyl vinyl ketone.

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Furanones are well known as basic components of natural products, some of which display a wide range of characteristic physiological properties. Transition-metal catalyzed transformations of propargyl compounds have been widely used for the construction of a variety of carbo- and heterocycles. Tamaru et al. reported the cyclization of O-propargyl carbamates afforded oxazolidinones. Herein, we report a one-step synthesis of 5-alkoxy-3(2H)-furanones 2 via a novel box-Pd(II) catalyzed carbonylative cascade reaction of propargyl carbamates 1. The reaction of 1 in the presence of [PhboxPd(tfa)₂] (5 mol %) and p-benzoquinone (1.5 equiv.) in methanol under CO atmosphere (balloon) afforded 2 in 56-99 % yield. The first asymmetric version of this transformation is also discussed.

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In the course of our research into novel and powerful transformation catalyzed by organic bases, we recently focused on the onium amides generated from well soluble organofluoride and dialkylaminosilanes for deprotonative reactions. These studies have not been well investigated in spite of their potential capability to react as a strong base. Here we report the development of the 1,2-addition of phenylacetylene promoted by tetrabutylammonium fluoride catalyst and trimethylsilyl dimethylamine. For deprotonation of heteroaromatics, the combination of phosphazenium fluoride (P5F) catalyst developed by Schwesinger and TMSNMe₂ was found to be effective, furnishing the corresponding adducts in good yields. Further optimization of the reaction conditions and investigation on the scope and limitation are underway.

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Englerin A is a sesquiterpene isolated from stem bark of P. engleri. in east Africa. This natural product exhibits potent growth inhibitory activity against several renal cancer cell lines (GI₅₀ 1-87 nM) and is considered to be a promising lead compound for developing new anticancer drugs. Such biological activities as well as its intriguing structure attract much attention from a synthetic community and many synthetic studies including 6 total synthesis have been reported to date. In this symposium, we will report a formal synthesis of englerin A. Key features of this study include (i) Stereoselective construction of the cyclopentane ring system by cyclization of the epoxy nitrile. (ii) Stereoselective In-mediated Barbier coupling with 2-(bromomethyl)-3-methylbut-1-ene, (iii) RCM leading to the key intermediate in the total synthesis reported by Christmann

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Agelastatin A is an unusual tetracyclic alkaloid isolated by Pietra's group in 1993. The highly complex structure, coupled with its remarkable biological activities, has made agelastatin A an attractive target for total synthesis. In this symposium, we will report a highly efficient formal total synthesis of agelastatin A. In this study we have discovered the asymmetric aziridination of cyclic enones catalyzed by primary-secondary chiral diamines, which can be simply prepared from commercially available 1,2-diphenylethylenediamine. The chiral keto aziridine 2 derived from 2-cyclopenten-1-one could efficiently convert to the Ichikawa's chiral intermediate 1 by 6 steps, including a DBU catalyzed one-pot silylation-selenylation procedure, and a regioselective aziridine-opening by an azide anion as key steps.

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Spirotryprostatin A was isolated in 1996 from Aspergillus fumigatus by Osada and coworkers. Structurally intriguing features of this cytostatic natural product include spiro[pyrrolidine-3,3'-indolinone] core, annulated diketopiperazine and isopropylidene side chain. The key steps of our synthesis involve the intramolecular Heck reaction of aryl bromide and ethylidene moiety to construct the quarternary C3 stereocenter, as well as the installation of the nitrogen atom of the indolinone part, which was conducted by Beckmann rearrangement. Following cleavage of lactam, ozonolysis of the vinyl group and amide formation led to the convergent formation of spiroindolinone core. Highly stereoselective synthesis of spirotryprostatin A along this route will be presented.

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The selective detection of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA without chemical or enzymatic treatment is an attractive tool for genomic research. We designed and synthesized the non-natural nucleoside analog, the adenosine-1,3-diazaphenoxazine derivative (Adap), for selective recognition of 8-oxo-dG in DNA. This study has clearly shown that Adap has a highly selective stabilizing effect of the duplex having the Adap-8-oxodG base pair. Furthermore, the fluorescent property of Adap has been shown to be useful for the selective detection of 8-oxodG in the duplex DNA. To the best of our knowledge, this is the first successful demonstration of the non-natural nucleoside with a high selectivity for 8-oxo-dG in DNA.

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Development of an efficient methodology to identify and mimic the bioactive conformation of a GPCR-binding peptide ligand is described. We designed the cyclopropane-based peptidomimetics that are composed of eight stereoisomers and can mimic various three-dimensional structures of tetrapeptide. The peptidomimetic strategy was applied to design melanocortin receptor (MCR) ligands based on the active residues of the endogenous MCR ligands, i.e. His-Phe-Arg-Trp. The mimetics were synthesized from chiral epichlorohydrin via the diastereoselective Grignard reaction on sulfinylimine as the key step. From the structure-activity relationship study of the eight stereoisomers, mimetic ent-1 was found to mimic the bioactive conformation of the active tetrapeptide moiety. Using ent-1 as a lead, a more potent MC4R ligand ent-1-C₄Ph was developed.

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Affinity labeling is one of the powerful techniques for identification of the target proteins of drugs. Recently, we have developed a novel modular methodology for affinity labeling named MoAL. In this method, the three essential elements (ligand, labeling site, reactive site) of affinity probes are separated into individual module molecules: ligand module, labeling module, and reactive module. So, the method facilitates the design and synthesis of ligand module molecules with thus simplified structures.
Herein, we report a labeling study of cyclooxygenase (COX) by MoAL using ligand modules derived from anti-inflammatory drugs, which bind to COX to inhibit the production of prostaglandins. We successfully achieved the selective labeling of COX and the detection of endogenous COX from vesicular gland fraction.

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Oxidation is a most important transformation in organic synthesis; however, these reactions essentially involve the use of large quantities of heavy metals and complex organic compounds, which generate large amount of waste, and are not at all environmentally benign. Molecular oxygen has received much attention as an ultimate oxidant, since it is photosynthesized by plants, produces little waste, is inexpensive and of large atom efficiency than that of other oxidants. With this perspectives, we have found that methyl aromatics effectively oxidized to benzoic aicd by photooxidation with molecular oxygen as terminal oxidant in the presence of 2-chloroanthraquinone under irradiation of a fluorescent lamp. Furthermore, methyl aromatics were found to be oxidized to the corresponding methyl benzoate by one step with molecular oxygen as terminal oxidant in the presence of anthraquinone-2,3-dicarboxylic acid under irradiation of a 500 W xenon lamp.

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We will present a Cu(I)-catalyzed migratory oxidative coupling between nitrones and heterocycles or a methylamine as a new entry of Cross-dehydrogenative coupling (CDC) reaction. The mild conditions allow for broad substrate scope with excellent functional group tolerance and chemoselectivity compared with any previously reported CDCs. Several conversions of the products afforded valuable and densely functionalized unnatural α-amino acid surrogates, which are common in bioactive molecules and important for medicinal chemistry. Radical clock studies suggest that the nucleophilic addition of nitrones to an oxidatively generated carbocation is a key step.

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Benzynes have been used in organic synthesis in cycloaddition reactions to synthesize polycyclic aromatic compounds. But the regioselectivities of the reactions are generally quite low. Recently, we have reported the regioselective Diels-Alder reactions of benzynes substituted by a boryl or a silyl group at the 3-position with substituted furans. We have observed some different selectivities in the Diels-Alder reactions between silylbenzynes and borylbenzynes. On the other hand, we have just developed the regioselective [3+2] cycloadditions of silylbenzynes and borylbenzynes and these benzynes complement each other in these reactions.
In this conference, we are going to present results of the theoretical studies of regioselectivities in the cycloaddition reactions of boryl- and silylbenzynes. Transition states of the cycloaddition reactions optimized by B3LYP/6-31G(d) successfully explain the regioselectivities of the cycloaddition products.

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Synthesis and structure of hypervalent pentacoordinate carbon and boron compounds bearing a rigid anthracene skeleton and a relatively flexible van Koten skeleton, and synthesis of a novel tridentate ligand bearing a benzene ring condensed with two seven membered rings and its application for the synthesis of pentacoordinate carbon compounds will be discussed. Hypervalent hexacoordinate carbon compounds have never been reported except for the observation of CLi₆ in Knudsen-effusion mass spectrometry. Although calculation and synthesis of eight valence electron compounds such as CH₆²⁺ and (Ph₃PAu)₆C²⁺ has been reported, these are not classified as electron rich 12 electron hypervalent compounds. Here we discuss recently synthesized hypervalent hexacoordinate carbon compounds based on the X-ray structure.

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Arylpiperazines are important core structure for CNS drug substances and hence, many synthetic endeavors have been made for efficient entry into the requisite molecular alignment including Buchwald/Hartwig amination, Wynberg amination and other catalytic methods, whereby a variety of new options have been developed and to be noted for medicinal chemistry research. In this presentation some utility of Wynberg amination is emphasized where Buchwald-Hartwig amination reaction failed. For the conversion of poly-halogenated benzenes, Wynberg amination is quite effective starting with readily available anisol derivatives. Furthermore, interesting fragmentation-ring closure was observed to afford acridine skeleton via presumed benzyne intermediacy as shown below.

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We have developed symmetrically branched oligoglycerols (BGL) such as dimer (BGL002) and trimer (BGL003) as G2, hexamer (BGL006) and heptamers (BGL007) as G3, and dodecamer (BGL012) and tetradecamer (BGL014) as G4 dendrons. BGL family possess 2ⁿ (n = 1—3) of primary hydroxides at terminal region for water-solubilizing and⁄or water-affinity, and OH, NH, NH₂, or N₃ group and further linkered structures at apex region for the covalent bond formation of various molecules (BGLation) such as poorly water-soluble medicines or molecules with poorly water-affinity. We report chemistry of BGLations and the property of the resulting BGLated derivatives such as fibrates, paclitaxel, p-borophenylalanine, piceatannnol, artificial protein drug and liposome.

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We have demonstrated a new approach to synthesizing calothrixins A and B through the palladium-catalyzed tandem cyclization/cross-coupling reaction of indolylborate by taking advantage of the one-pot generation of the hexatrienes as a key intermediate for constructing indolophenanthridine. In addition, the unprecedented use of CuOTf for 6π-electrocyclization of hexatriene was developed. In another key transformation, indolophenanthridine quinone core of calothrixins was prepared from the indolophenanthridine aldehyde via one-pot Dakin oxidation sequence catalyzed by diphenyldiselenide.

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Cyclopentyl methyl ether (CPME) is a novel high performance ether used in many manufacturing process (such as reaction, extraction and crystallization) originated from Japan and has seven unique physical properties which other ethers do not have. We will report herein some contribution of CPME to green chemistry and process innovation. Physical properties of CPME and their manufacturing process are applied under eight items of The Twelve principles of Green Chemistry and so CPME would give high contribution to that. In improved synthesis of amine by Dr. Ellman, solvent unification by CPME is useful for process innovation such as the reduction of wastes and telescoping. The toxicological assessment (PDE values provided by the GLP animal studies) and solvent selection guide in a pharmaceutical company will be also reported.

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We have developed Ni-catalyzed cross-coupling reaction of functionalized alkyl (pseudo)halides with alkyl Grignard reagents in the presence of 1,3-butadiene as an additive. Under the optimized conditions, various functionalities such as esters, amides, nitriles, etc. were remained intact. In addition, carboxylic acid moieties, which have electrophilic carbonyl group as well as acidic proton, were also tolerated by the use of t-BuMgCl as an auxiliary base. Because bis(π-allyl)Ni generated by the reaction of NiCl₂ with 2 equivalents of allyl Grignard reagent works well as the catalyst for the cross-coupling reaction under low temperature, it is another suitable catalyst for the functionalized substrates. For example, methyl esters and ketones were remained intact under the optimized cross-coupling conditions.

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Palladium-catalyzed decarboxylative allylation of allyl β-keto esters can be carried out under extremely mild conditions, a variety of applications have been reported. In contrast to the extensive studies on the reactions of allyl β-ketoesters, no examples have been reported on the reactivity of propargyl β-keto esters with palladium. We report the palladium-catalyzed reaction of propargyl β-keto esters. This process produces tetra-substituted furans having a variety of substituents via a decarboxylative [3+2] cyclization pathway. Since many biological active natural products and industrially useful compounds having a furan component have been reported, our methodology would provide a new protocol for the synthesis of these compounds with high efficienct.

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The structure of sequosemperivirin A, isolated from Sequoia sempervirens (Taxodiaceae), was determined to be (4R)-4-(4-hydroxybenzyl)spiro[4,5]dec-1-en-8-ol on the basis of spectroscopic data including its X-ray analysis.
We were able to establish a novel synthetic path to construct a spiro[4.5]decane ring skeleton by using a samarium diiodide-promoted intramolecular Barbier-type reaction of 4-(3-iodopropyl-1-trimethylsilyloxy)-2- oxabicyclo[2.2.2]octan-3-one as the key step. By application of this strategy, we succeeded in a concise stereocontrolled synthesis of (-)-sequosempervirin A starting from the known cyclohexanone derivative in 20 steps in 26.6% overall yield. Based on this asymmetric synthesis, the absolute configuration of the natural compound was revised to (4S)-4-(4-hydroxybenzyl)spiro[4.5]dec-1-en-8-ol.

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A variety of approaches to controlling the conformations of peptides have been investigated, and the incorporation of α,α–disubstituted α–amino acids (dAAs) and cross–linked side chains into peptide sequences is of vital importance for constructing stable helical structures. Thus, we speculated that stable helical structures could be constructed using a combination of dAAs and a covalent cross–linking system. Here, we have designed and synthesized four L–leucine (L–Leu) based heptapeptides containing an aα–aminoisobutyric acid at the 4th position as a helical promoter and L/D–(homo)serine derivatives at the 3rd and 7th positions to produce a cross–linked subunit. N–terminal free peptides were used for enantioselective epoxidation of α,β–unsaturated ketones, which is known as the Julià–Colonna asymmetric reaction.

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We first developed the synthesis of di- and trisubstituted isoxazole through transition metal-catalyzed cyclization of alkynyl oxime ethers. When O-allyl alkynyl oxime ether was treated with AuCl₃, gold-catalyzed cyclization and [3,3]-sigmatropic rearrangement reaction proceeded to afford 3,4,5-trisubstituted isoxazole. In addition, treatment of O-benzyl alkynyl oxime ether with AgBF₄ and phenol in THF gave 3,5-disubstituted isoxazole in high yield via cyclization and protonation.A regioselective intramolecular cyclization/halogenation reaction of N-alkoxy-o-alkynylbenzamides with CuCl₂/NCS was also developed. The corresponding 3-(chloromethylene)isobenzofuran-1-ones were exclusively obtained via 5-exo-dig cyclization in moderate to excellent yields.

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Iodocyclization has been attracted methodology for constructing cyclic architecture along with C-I bond in the same molecules which can convert C-C bond by cross-coupling reactions. Recently, we developed new strategy for iodocyclization that took advantage of the dual nature of iodine as both an iodinating and an oxidizing agent. Namely, controlling of the oxidative aromatization by the reaction conditions enabled 'product switch' and enhanced the flexibility of the synthetic route for various heterocycles. We here report an application of this methodology toward the iodocyclization of α-propargylglycines 1. The use of IPy₂PF₆ produced 2,3-dihydropyrroles (2,3-dehydroprolines) 2 as a single product, on the other hand, that of I(coll)₂PF₆ afforded pyrroles 3 in good to excellent yields. Controlling the oxidative aromatization by ligand effect of iodonium species is reported for the first time.

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Two diastereoisomeric six-membered ring amino acids (1R,3R)-Ac₆c^M and (1S,3R)-Ac₆c^M were synthesized starting from (R)-3-methylcyclohexanone. Use of Bucherer-Bergs reaction stereoselectively gave (1R,3R)- Ac₆c^M, and that of Strecker reaction exclusively afforded (1S,3R)-Ac₆c^M. Homo-chiral homopeptides, up to hexapeptides, composed of (1R,3R)-Ac₆c^M or (1S,3R)-Ac₆c^M were prepared by solution-phase methods. Preferred secondary structures of two series of homo-chiral homopeptides were studied both in solution and in the crystal state.

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Aspartic protease (AP) plays an essential role in serious diseases, and thus, is thought to be a suitable target to design therapeutic inhibitors. In the present study, we focused on Beta-site Amyloid precursor protein Cleaving Enzyme-1 (BACE1), an aspartic protease involved in the production of amyloid β peptide (Aβ) in Alzheimer's disease.
The hydroxyethylamine scaffold was constructed from Z-Leu-OH using a Mannich-type reaction as a key reaction. Completion of the synthesis of hydroxyethylamine derivatives was accomplished by the coupling reaction of the hydroxyethylamine scaffold and a peptide sequence followed by deprotection and HPLC-purification. The inhibitory activity of the synthesized compound was evaluated using a recombinant BACE1 (rBACE1).

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o-iodoxybenzoic acid (IBX) as a hypervalent iodine compound has a great deal of attention in organic synthesis because IBX is a mild selective, metal-free, and non-toxic oxidation reagent. However, 2-iodosobenzoic acid (IBA), a waste product from oxidations of IBX, often makes it difficult to separate the desired products from the reaction mixture. To solve the problem we have attempted the development of a novel hypervalent iodine organocatalyst with a fluorous tag, fluorous IBX. Oxidation of alcohols in the presence of a catalytic amount of fluorous IBX and Oxone as a co-oxidant resulted in the corresponding carbonyl compounds in good to high yields. The fluorous IBX is readily recovered as insoluble fluorous IBA from the reaction mixture by simple filtration, and can be reused without significant loss of the catalytic activity.

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Abstract: A novel fluorination reagent, IF₅-pyridine-HF. IF₅-pyridine-HF, was prepared from IF₅ and pyridine-HF, which is a pale yellow solid and air stable. When a sulfur compound was added to slurry of IF₅-pyridine-HF in CH₂Cl₂, the colour of the mixture changed to dark red and fluorination of the substrate took place. Oxidative fluorination of sulphide, desulfurizing-difluorination of benzyl sulphide, and desulfurizing-fluorination of thioacetal were successfully performed by IF₅-pyridine-HF, and 1-3 fluorine atoms were introduced to the substrate.

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Arginine-rich CPPs have been gathering considerable research interest due to their ability to bring exogenous molecules into cells. The ability of arginine-rich CPPs to induce macropinocytosis is one of the explanations stimulating their cellular uptake. However, no substantive receptor has previously been identified that activates macropinocytosis, or even other forms of endocytosis, specifically responsible for the cellular uptake of arginine-rich CPPs. With the hope of identifying the membrane-associated molecules responsible for the cellular uptake of oligoarginines, we synthesized dodeca-arginine (R12) bearing the phenyl-trifluoromethyl diazirine moiety as a photo-crosslinker, and found that CXCR4 is a receptor that stimulates cellular uptake of the R12 peptide.

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Recentry, we have developed the palladium-catalyzed oxidative cyclization of olefinic keto and lactone esters (2^nd generation palladium-catalyzed cycloalkenylation) as an alternative method of the original palladium-catalyzed cycloalkenylation of silyl enol ethers developed by us. Additionally, we have succeeded in the application of this process to olefinic lactam esters for the construction of bicyclic lactams.
In this presentation, we will describe the details of the development of 2^nd generation palladium-catalyzed cycloalkenylation and its application to the synthesis of bioactive natural products, such as cis- and trans-195A, scholareins, and α-skytanthine.

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Jadomycins A and B are unique 8<i >H-benzo[b]oxazolo[3,2-f]phenanthridine polyketide antibiotics containing isoleucine unit in the 1,3-oxazolidin-5-one ring, isolated from Streptomyces venezuelae. It has been reported that jadomycin B and its analogs with other amino acid units show anti-MRSA, DNA cleaving and cytotoxic activities. Herein, we report the syntheses of jadomycin A and its analogs.
Suzuki-Miyaura coupling of benzoxaborole with bromojuglone gave 2-arylnaphthoquinone as a key intermediate. Introduction of L-isoleucine to this compound, Dess-Martin oxidation, and deprotection of the MOM group produced jadomycine A. Jadomycin M and W aglycons were also synthesized from the same intermediate. In trials for the synthesis of jadomycin S aglycon, reconstruction of an oxazolidine ring to oxazoline one was observed, allowing us to propose the possible structural revision of jadomycins S.

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Vinylogy, is a well-known concept of the retention of the chemical properties, such as reactivity, through the double bond. The vinylogous amide has been studied for a long time, however, the compounds with the amide bond intervented by the aromatic group has been rarely studied. In this presentation, we will report the synthesis and chemical properties of "aromatic vinylogous" amide compounds.
First, we synthesized the aromatic amide compounds by the Buchwald-Hartwig cross coupling. The structures of these compounds were studied by the X-ray crystallography to compare the bond length to estimate the effect of the resonance. The ortho and para substituted compounds showed the effect of resonance compared to the meta substituted analogue. In addition, carbonyl group of ortho and meta substituted compounds was less reactive toward the reduction by sodium borohydride compared to the meta substituted compound.

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Native chemical ligation, featuring chemoselective reactions between thioester and N-terminal cysteinyl peptides, has served as the most promising coupling methodology for protein synthesis. One limitation of the NCL is that the ligation site requires the cysteinyl residue, which has prompted one to establish a ligation protocol accomplished at non-cysteine sites. Here, we report a coupling method at proline site using 4-mercaptoproline (HSPro) via a sequence of two chemoselective reactions including NCL-like reaction between HSPro and thioester peptides, followed by desulfurization. A dual kinetically-controlled NCL strategy using HSPro combined with N -sulfanylethylanilide (SEAlide) peptide is also described. And this newly developed kinetic reaction allowed three peptide fragments simultaneously presented to be ligated in correct order.

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The biologically active carbazole alkaloids, carquinostatin A were isolated from Streptomyces chromo fuscus by Seto and co-workers in 1993. This compound was shown to be a potent neuronal cell protecting substance which exhibits a free radical scavenging activity. We report the asymmetric synthesis of the highly substituted carbazole alkaloid, carquinostatin A. The key step is a construction of the appropriate carbazole framework based on an allene-mediated electrocyclic reaction of the 6Π-electron system involving the indole 2,3-bond followed by lipase QLM catalyzed enantioselective acetylation of the racemic alcohol that the (-)-acetate and (+)-alcohol was obtained with high enantioselectivity, respectively.

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Phosphorylation of proteins serves as posttranslational modifications that are critical for intracellular signal transduction. Recently, a new posttransitional modification, in which adenosine was connected to a side chain of tyrosine or threonine by phosphodiester bond, is reported. This modification, called AMPylation, is presumed to control intracellular signal transduction in a manner similar to phosphorylation; however, its exact role remains unclear. To uncover the physiological role of AMPylation, AMPylated amino acid derivatives including naturally occurring amino acids and their nonhydrolyzable counterparts were synthesized. In terms of the nonhydrolyzable analogues, substitution of CF2 for oxygen atom of the phosphodiester linkage was used. Incorporation of these analogues in model peptides will be also discussed.

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The tandem reaction of cyanoacetanilides with triflic anhydride in DMF proceeded at room temperature to afford 3-formyl-4-hydroxyquinolin-2(1H)-ones in good to high yields. A detailed mechanistic study revealed that the tandem reaction proceeded via α-dimethylaminomethylenation, which promoted the subsequent Houben—Hoesch-type cyclization. Both α-functionalization and the cyclization steps were optimized, and a multi-gram scale synthesis of 3-formyl-4-hydroxyquinolin-2(1H)-one was achieved.

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Palladium-catalyzed reactions of propargylic compounds with nucleophiles have been extensively studied due to their versatile and specific reactivity. In this reaction, a substrate having two nucleophilic moieties within the molecule reacted sequentially with the π-propargylpalladium complex, resulting from propargylic compounds and palladium catalysts, to afford the cyclized product. In planning our investigation of this reaction, we focused on the nucleophilic activity of 2-oxocyclohex-3-enecarboxylates. We report the palladium-catalyzed reaction of propargylic acetates with 2-oxocyclohex-3-enecarboxylates, in which functionalized bicyclo[3.2.1]octenones have been constructed in a highly stereoselective manner.

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As part of our research for new metabolites through the isolation and characterization of biological active compound, we describe a 23-step synthesis of (+/-)-cribrostatin 4 from readily available 2,4,5-trimethoxy-3-methylbenzaldehyde. The synthesis features the concise construction of pentacyclic framework including a B-ring formation by Pictet-Spengler type cyclization and a D-ring formation along with dehydrogenation through a partial reduction and acid activation sequence, followed by the base-catalyzed epimerization of the C-1 stereo center of aldehyde.

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Ortho-selective α-hydroxyalkylation was one of versatile C-C bond forming reactions and its aromatic version is the most useful method for the preparation of 2-(α-hydroxyalkyl)phenols. Although the low regioselective insertion of carbon unit is usually encountered by phenol derivatives used as the substrates, 5-hydroxyindole derivatives exhibit high selectivity at C-4 position on the indole. Therefore, we attempted to synthesize decursivine analogues, including decursivine, serotobenine, moschaminindolol and flavumindole, from 5-hydroxyindole. Although serotobenine and decursivine have already been synthesized, total synthesis of moschaminindolol and flavumindole have not been achieved. We succeeded in inserting benzylaldehyde at C-4 position on 5-hydroxyindole by α-hydroxyalkylation. At present, modification of C-3 on indole and construction of eight-membered ring are under consideration.

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We have developed the transition metal-catalyzed intramolecular reactions of alkynyl compounds for novel and concise syntheses of heterocyclic compounds. From the progress of our study on the synthesis of heterocycles, we have recently demonstrated the metal-free formation of heterocyclic compounds through oxidative cycloisomerization of the alkynyl compounds using hypervalent iodine (III). Thus, phenyliodine(III) diacetate (PIDA) efficiently mediates the formation of 2,5-disubstituted oxazoles incorporated with acetoxy group through the oxidative cycloisomerization of propargylamide derivatives. The oxidative cycloisomerization of 2-propargyl 1,3-dicarbonyl compounds mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) or iodosobenzene leads to the selective synthesis of 4,5-disubstituted furfuryl alcohols or furfurals.

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We had reported that the reaction of disulfides with 2.5 equivalents of selectfluor (an electrophilic fluorinating reagent) efficiently produced the corresponding thiosulfonates in high yields accompanied with small amounts of sulfonyl fluorides. We also had found that sulfonyl fluorides could be effectively obtained from the reaction of disulfides with 6.5 equivalents of selectfluor. This time, the reactions of sulfides with electrophilic haloginating reagents, such as N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS), were examined to synthesize thiosulfonates or sulfonyl halides. Unfortunately, thiosulfonates could not selectively be obtained. The desired sulfonyl halides were effectively afforded from the reaction of disulfides with 6.0 equivalents of NCS or NBS in aqueous acetonitrile.

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The oxidative cleavage of carbon-carbon bonds in 1,2-diols (glycols) is a very important reaction which has frequently been utilized in organic syntheses. Representative oxidants include periodates and lead tetraacetate. Although periodates effectively react with glycols in many cases, the reaction dose not proceed for cyclic trans-glycols and ditertiary glycols. Lead tetraacetate can react with these reactants; and therefore, it has been widely used as a convenient oxidant for glycol cleavage in organic synthesis. However, it is highly toxic, and no less than a stoichiometric amount of reagent is required for the reaction. We found that the reaction of ditertiary glycols in the presence of a catalytic amount of vanadium oxytrichloride under an oxygen atmosphere caused cleavage of carbon-carbon bonds in glycols. This reaction must be an environmentally benign oxidative cleavage of ditertiary glycols.

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Constructions of monofluorocyclopropanes usually require freons as the starting materials or the reagents. The utilization of freons is nowadays restricted, because freons destruct the ozone layer of the earth. Therefore, it is almost impossible to synthesize monofluorocyclopropanes in these days. We would like to report that the reaction of chloromethyl phenyl sulfide with selectfluor provides chlorofluoromethyl phenyl sulfide. Chlorofluoromethyl phenyl sulfide has been used as the reagent for the constructing of mopnofluorocyclopropanes and has been prepared from dichlorofluoromethane (one of the freons). We also found that the reaction of carbanions derived from cyclopropanes containing a sulfonyl group with N-fluorobenzensulfonimide provided the fluorinated cyclopropanes. The successive desulfonization using magnesium afforded the monofluorocyclopropanes.

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Photolysis provides a powerful means for cleaving sp³C-H bonds adjacent to heteroatom such as nitrogen or oxygen but its application to complex organic synthesis is still relatively unexplored. Here, a new approach to kainic acid is reported, the key process of which is a novel photochemical sp³C-H bond carbamoylation of tertiary amine. The nitrogen-substituted sp³C-H bond of a cis-fused azabicyclo[4.3.0]nonane derivative was directly carbamoylated with phenyl isocyanate under UV irradiation to yield the proline motif of kainic acid. With the highly functionalized motif in possession, further chemical transformations that include silicon-directed regioselective Baeyer-Villiger oxidation were operated to successfully access the neuroexcitatory alkaloid.

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Previously we have explored a new function of silylated alkynes conjugated with a carbonyl group and reported a carbon-carbon bond forming reaction via a consecutive activation step of conjugated alkynes involving an intramolecular migration of the silyl group.
Herein we report a novel reaction of silylated conjugate olefin and aldehyde mediated by tri-n-butylphosphine to afford silyl dienol ether via 1,4-Brook rearrangement reaction. We suppose the mechanism of the above reactions involves 1,4-addition of tri-n-butylphosphine followed by 1,4-Brook rearrangement, and subsequent Wittig reaction of resulting phosphonium ylides with aldehydes. We will present further studies of this reaction, including various substrates and aldehydes, and stereochemical control of the product.

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Fluorescence responsible biaryl-type homooxacalix[3]arenes 1-4, which have deep cavities and three binding sites (COOH) on peripheral aromatic rings, were synthesized though Suzuki-Miyaura coupling. Fluorescence response with Host 1 having free hydroxy groups on lower rim and 2-benzoic acids on upper rim against triethylamine or hexamethylenetetramine were investigated. When triethylamine was added to the solution of host 1, the fluorescence from host 1 was completely quenched by PET mechanism. On the contrary, fluorescence was increasing by adding hexamethylenetetramine. This spectral behavior could be ascribed to the formation of 1:1 complex through three point interaction between COOH on host 1 and amino groups of guest and increasing the rigidity of host 1. Other properties such as the formation of the molecular capsules of hosts 2-4 and piperazine will be reported.

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In the field of chemical biology and/or supramolecular chemistry, fluorescein (1) had made great contributions as a mother skeleton of useful and sensitive fluorescent probe. However, naphtofluorescein, in which each one unit of benzene ring is expanded to the both sides of fluorescein, has received little attention. Only naphthofluorescein 2 is the single known example. Against such background, we constructed the novel naphthofluoresceins including linear derivative 3. The fluorescence spectra of 1-3 in basic aqueous medium were measured. Fluorescein (1) and 2 exhibited peaks at 513 nm and 670 nm, respectively. On the other hand, 3 showed emission in near-infrared region at 790 nm.

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Opioid analgesics, like a morphine, are widely used for severe pain of cancer. Recently, treatment with high concentration of buprenorphine and loperamide, which are opioid analogs, has been reported to induce apoptosis of human carcinoma, such as human lung cancer derived A549 cells. Both the molecular mechanisms and the required chemical structures of opioids for antitumor activity have been still unclear. Loperamide consists of two moieties, the 4-arylpiperidine unit and the N-substituent unit on piperidine. In this work, loperamide analogs, in which the N-substituents on piperidine are converted to the phenylalkyl groups, have been synthesized and tested the antitumor activities against human colon tumor derived HCT-116 cells. The N-phenylnonyl analog showed most potent inhibition of the tumor cells viability.

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