We have recently developed the polymer incarcerated (PI) method to immobilize Pd catalysts onto polymer supports. Herein, we report immobilization of platinum catalysts by using the PI method. PI Pt catalysts thus prepared showed high catalytic activity in hydrosilylation and hydrogenation, and recovery and reuse of the catalyst were attained without loss of the activity. Furthermore, we have developed a new and practical immobilization method of palladium catalysts using a polystyrene-based copolymer, by reduction of less expensive Pd(II) salts and alkali metal salts as additives. A remarkable effect of alkali metal salts on the loading level of the catalysts and a key factor for the success of immobilization of Pd nanoparticles were revealed. PI Pd catalysts thus prepared showed high catalytic activity in Mizoroki-Heck reaction and Suzuki-Miyaura coupling of various kinds of substrates including aryl chlorides.

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A peptidocalix[4]arene library consisting of 1000 members was synthesized, which was suitable for peptide recognition in aqueous media. Some peptidocalix[4]arenes, which selectively bind the peptides were found in the library. Ionic interaction between the hosts and the guests plays most important role for binding in aqueous media. In the course of this study, novel on-bead screening system in water was also developed. The system contains color reaction utilizing oxidative coupling of aniline-labeled guests and 4-Aminoantipyrine using H2O2 and HRP (horseradish peroxidase), which is great advantageous because the screening is free from specific interaction between labeles on the guests and peptide chains on the hosts in water.

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Optically active acyclic ethynylhelicene oligomers were synthesized by the Sonogashira coupling and deprotection. CD studies indicated that oligomers with more than six helicenes form helical structures, while those with less than seven helicenes form random coil structures in chloroform. The helical heptamer gradually unfolded to a random coil structure in various aromatic solvents, and the unfolding rates determined by the time dependences of the Cotton effect at 370 nm were found to be highly dependent on the type of aromatic substituent. The rate constant k differed by seven orders of magnitude between iodobenzene and trifluoromethylbenzene. The logk values exhibited good correlation with the absolute hardness η of the arenes, and higher unfolding rates were obtained in the soft arenes.

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In the course of our studies on the stereochemistry of aromatic amides, we found that the treatment of m-(methylamino)benzoic acid with Ph3PCl2 afforded a cyclic triamide 1 in good yield. The triamide 1 has a unique bowl-shape structure (syn conformation) in the crystal. The syn structure has molecular chirality based on the direction of the amide bonds at meta positions. In solution, the triamide 1 exists in an equiliburium between two conformers, syn and anti with one phenyl ring turning in the other direction. Here, we designed and synthesized novel cyclic triamides in which the conformational alteration from syn to anti conformations were restricted by introduction of the aromatic substituents ortho to the amide bonds.

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We have developed the chain-growth polycondensation of phenyl p-(alkylamino)benzoate which afforded poly(p-benzamide)s with controlled molecular weights and narrow polydispersities. In this study, various-sized poly(p-benzamide)s bearing a chiral side chain on the nitrogen atom were synthesized by this methodology, and their dynamic helical structures in several organic solvents were determined by the characteristic CD spectra. The CD signals were dependent on the temperature and molecular weight of the polyamides but independent of the solvent. The helical structure is also supported by X-ray crystallographic analysis of 4-(methylamino)benzoic acid oligomers. The molecular exciton model and the Rosenfeld equation indicated that poly(p-benzamide)s having an N-(S)-(methoxyethoxyethoxy)propyl group formed a right-handed helical structure ((P)-helix).

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Conformational studies of acetamide derivatives bearing N-phenyl-N-hydroquinonyl and N-phenyl-N-quinonyl groups has been conducted. 1H-NMR and crystallographic investigation showed that electron donating groups on the aromatic ring increased the cis conformer ratio, whereas electron-poor quinone group preffered trans conformer. Since these types of aromatic amides can be converted each other by the chemical or electrochemical reaction, redox reaction can be used as a tool for conformational switching of aromatic amides.

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We designed spin-labeled nucleosides in which a spin source is directly attached to nucleobase and synthesized 2-N-tert-butylaminoxylinosine(1a), 2-N-tert-butylaminoxyladenosine(2a) and oligodeoxynucleotides (ODNs) bearing them. Lithiation at the 2-position of 8-TIPS-6-chloropurine derivatives and the following reaction with 2-methyl-2-nitrosopropane afforded 2-N-tert-butylhydroxylamino-6-chloropurine, which was converted to 1a and 2a. The ODN bearing 1a and 2a were also synthesized successfully and EPR studies were carried out. Spectra of single strand showed broad three lines in phosphate buffer. Upon duplex formation, the upfield line disappeared completely at 0 °C and EPR spectra of single strand and duplex were distinguishable visually. Detailed analysis of spectra is in progress.

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The icosahedral carboranes (C₂B₁₀H₁₂) are cluster of high boron content, remarkable and chemical stability, topologically spherical geometry and hydrophobic character. The C-H protons of o-carborane are acidic ( pKa = 22.0 ), and have the potential for CH-O interaction. In the preparation of 3-(methoxyphenyl)-o-carboranes, we found an unusual dealkylation reaction. Reaction of 3-iodo-o-carborane with 2-methoxyphenylmagnesium bromide in the presence of palladium catalyst afforded demethylated 3-(2-hydroxyphenyl)-o-carborane. We deduced the mechanism including o-carborane CH-O interaction or exchange of the hydrogen to magnesium.

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As an extension of our study on the stereoselective synthesis of retinoids, we investigated a synthesis of 11Z-3,4-dehydroretinal, which is used as a chromophore of visual pigment rhodopsin in several fishes. The Horner-Emmons reaction of 3,4-Dehydro-β-ionylideneacetaldehyde, derived from-β-ionone, with 4-(diphenoxyphosphoryl)-3-methyl-2-butenenitrile using KN(TMS)₂ and 18-crown-6 as a base afforded the retinonitrile as a mixture of all-E- and 11Z-isomer (1:2). After separation of 11Z-isomer by column chromatography, the nitrile was converted into the retinal by DIBAL-H reduction in the dark without isomerization of the double bonds.

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The introduction of anti-cancer agents paclitaxel (Taxol) and docetaxel (Taxotere) has revolutionized the treatment of cancer. More recently, other taxoids, have been developed, with improved antitumor efficiency. However, despite the hope and promise that these agents have engendered, their poor water-solubility is a serious problem in intravenous administration. To overcome this problem, we have developed a new water-soluble prodrug strategy. For the first time the successful application of O-N intramolecular "acyloxy" migration in the prodrug design wass demonstrated. O-N Intramolecular acyloxy migration can be provided under aqueous conditions and without side products formation such as previously reported oxazolidone or product of carbonate hydrolysis. This migration also occurred as a common reaction of hydroxyamino acids, namely carbonate protective groups migrate to produce amino-protected carbamate derivatives of hydroxyamino acids with high efficiency and purity.

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Natural antifungal and antitumor β-substituted-type β-Methoxyacrylates (MOAs) such as Cystothiazoles and Melithiazols have two chiral centers on their γ-and β-positions. For the efficient construction of these chiral centers, an asymmetric version of the Lewis Acid-mediated vinylogous aldol reactions of silyl dienol ether with aldehydes was studied. Several chiral acyloxyborane (CAB) complexes prepared from D-(-)-tartaric acid and phenylboronic acid were examined as a promoter for the asymmetric reaction. The desired chiral β-substituted-type MOA was successfully obtained from trans-cinnamaldehyde in good yield with high enantioselectivity.

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Sialic acid is one of the most important compound on carbohydrate chemistry.2-Deoxy-N-acetylneuramic acid (Neu5Ac2en) consisting with glycal structure is a very chemically stable compound compared with glucal. However, reduction of carboxyl group of Neu5Ac2en1ol change the compound to a very high reactive one.We reported on the chemical property of the Neu5Ac2en1ol and its derivatives.

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Standishinal and its related compounds are promising candidates of anti-tumor agents. However, the practical asymmetric synthesis of their skeleton, abeo-abietane, was not reported so far. Therefore, we embarked on the establishment of a novel strategy to prepare the abeo-abietane by using asymmetric intramolecular Heck reaction. During the present study, we found the substrate of the Heck reaction existing as a mixture of racemic atropisomers was capable of being converted to one enantiomer. The phenomenum was explained by forming the distorted-boat conformation in a transition state, which allowed free rotation of the axis of the atropisomers. The total synthesis of standishinal and other naturally occurring compounds is in progress.

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γ-Amino-β-acyloxyphosphonic acid derivatives were prepared as phosphonic acid analogues of acylcarnitine in an optically active form expecting for CPT I inhibitory activities. The synthetic methodology was based on catalytic asymmetric dihydroxylation (AD) of β,γ-unsaturated phosphonates and subsequent regioselective amination via the cyclic sulfates. AD reactions of olefins having dibenzylphosphonyl group provided diols with improved enantioselectivity in comparison to those of the corresponding diethylphosphonyl group. Diols derived from dibenzylphosphonates could be obtained in an optically pure form through one recrystallization from AcOEt. Treatment of cyclic sulfates derived from diols with NaN₃ gave γ-azides with high regioselectivity. γ-Azides were converted into phosphonic acid analogues of acylcarnitine in 9 steps.

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We describe an access to meso-diaminopimelic acid (DAP), L,L-DAP, and D,D-DAP, starting from cis-1,4-diacetoxycyclohept-2-ene (1). RuCl3-catalyzed cleavage of 1 followed by methyl esterification gave meso-2,6-diacetoxydimethylester, which was converted with further manipulation into meso-DAP. Dissymmetrization of 1 with Novozyme 435 provided optical active monoacetate (98%ee), which was transformed in an enantiodivergent synthesis into D,D-DAP and L,L-DAP. in the similar manner, 6-benzyloxy-1,4-diacetoxycyclohept-2-ene was converted to meso-4-keto-DAP derivative, which is expected as an building block for interesting DAP homologues.

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Tokaramide A and miraziridine A are linear peptides containing unusual amino acids isolated from the marine sponge Theonella aff. mirabilis by Fusetani et. al. These natural peptides are reported to inhibit the action of catepsin B with an IC50 value of 29 ng/mL (for tokaramide A) and 1.4 mg/mL (for miraziridine A), respectively. In the course of our recent research regarding the cysteine protease inhibitors, we conducted the synthetic studies on these natural peptides, since the peptide aldehyde and aziridine structures seem to be efficient reactive groups for thiol functional group of cysteine protease. In the present study, tokaramide A was synthesized by the reduction of the corresponding peptide amide in conventional solution-phase as well as on solid-support. For the synthesis of miraziridine A, four Boc-protected unusual amino acids were prepared in parallel, and were coupled successively to construct the peptide backbone.

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We wish to report the synthesis of novel α-amino squaric acid analogs (α-ASqA) and their incorporation into Leu-Enkephalin. Two synthetic methods using a dianion enolates (method A) or an aminomalonate equivalent (method B) were developed to this objective. Method A involves an efficient generation of a dianion enolate from an N-Boc amino acid tert-butyl ester and its condensation with squaric acid diisopropyl ester. The resulting coupling products were transformed to the corresponding α-ASqAs by decarboxylation reaction. Alternatively, a sq-group containing amino malonate equivalent was used for the key carbon-carbon bond forming reaction to access to α-ASqAs (method B). The synthetic α-ASqA was incorporated into Gly2 of Leu-enkephalin.

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The structural features of the C-mannosylated tryptophan as well as the importance of a new posttranslational modification led us to the synthesis of C-D-mannosyl-L-tryptophan and its related C-glycosyl amino acids. Our synthetic strategy of C-glycosyl amino acids is based on the palladium -catalyzed coupling reaction between halogenated amino acids and glucal derivatives. The coupling of halogenated amino acid, 2-iodo-Trp derivative, 4-iodo-Phe derivative and 3-iodo-Tyr derivative, with 3-deoxy glucal derivative under the Heck reaction condition was achieved in moderate yield. Stille coupling reaction was also a useful method for the formation of C-glycosidic linkage between amino acid and sugar moiety.

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In the present study, we disclose that tertiary nitrogen-containing molecules, such as amides, ureas, and amines, undergo direct intermolecular addition to aldehydes under the Et₃B/air conditions, thereby providing a unique and simple means for the radical sp3 C-H transformation of nitrogen compounds. The present C-H transformation features the direct generation of α-aminoalkyl radicals from C-H substrates, which may potentially serve as an alternative to the homolysis of C-X (X=SR, SeR) bonds, the radical translocation, and the single electron transfer (SET) processes. This radical transformation enables the rapid construction of contiguous stereocenters functionalized with heteroatoms, which is not readily achieved by other C-H functionalization methods.

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We have developed efficient methods for the stereoselective synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles and 3-alkylidenebenzofuran-2-ones by two metnods. One is the method using tandem Indium mediated carbometallation and ligandless Pd-catalyzed coupling reaction and the other is using palladium-catalyzed Heck-Suzuki-Miyaura, Heck-Heck, and Heck-carbonylation-Suzuki-Miyaura domino reaction.

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Encouraged with our recent work on the indium(0)-mediated radical reactions in water which provide new carbon-carbon bond-forming methods, we have studied the carbon-carbon bond-forming reactions using indium(I) halide as a radical initiator. The reaction of glyoxylic oxime ether with isopropyl iodide in the presence of indium(I) chloride proceeded smoothly to give the 63% yield of desired product in aqueous media. Interestingly, when the indium(I) chloride-mediated reaction was carried out in the presence of CuCl, the chemical yield was dramatically improved to 97%. In addition, Michael-type radical reactions and tandem radical reactions of oxime ethers and related allylation reactions of aldehyde and sulfonylimine were also investigated. Not only metallic indium(0) but also indium(I) chloride are found to be efficient single electron-transfer radical initiator in aqueous media.

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Nucleophilic addition reactions to imines have often served as a straightforward method for the synthesis of amines. However, activations of the C=N bond, which is generally poor in reactivity, is necessary to obtain satisfactory efficiencies of these nucleophilic addition reactions. Typical MAC reagents (R=SiMe2tBu or OCHMeOEt) has been shown to be effective in promoting addition reactions to activated imines such as N-sulfonylated imines and sulfinimides. These reagents, however, did not exhibit similar effectiveness towards ordinary N-alkylated imines, even in the presence of a Lewis or Bronsted acid. We have developed a highly efficient nucleophilic addition to N-methylimines by using acylated MAC reagent without activations.

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(1,3-Dioxa-2-yl)ethylsulfonyl chloride and 4-nitrophenyl 3,3-dimethoxypropylsulfonate were synthesized and used as new versatile sulfonating agents for amines. Primary and secondary amines were sulfonated very easily in excellent yields with the agents at 0 °C to give the corresponding sulfonamides. The N-nonsubstituted and N-monosubstituted sulfonylamides were alkylated satisfactorily under the new Mitsunobu conditions utilizing (cyanomethylene)tributylphosphorane (CMBP). The sulfonyl groups were very stable under basic and reductive conditions and removed by heating in a hot aqueous solution of trifluoroacetic acid. As an application of the method, epilachnene, the defensive droplets from the Mexican bean beetle, Epilachna varivestis, was synthesized in short steps.

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Recently, we realized the rapid 6π-azaelectrocyclization resulting from the significant substitutent effect of the C4 carbonyl and the C6 olefin functions in the (E)-4-carbonyl-1-azatriene compounds. Then, we developed the highly stereoserective asymmetric azaelectrocyclization of liner 1-azatrienes which were obtained by the reaction of (E)-3-carbonyl-2,4,6-trienals and the novel chiral 7-alkyl substituted cis-aminoindanol derivatives, to produce chiral tetracyclic piperidine derivatives. We are applying this polysubstituted piperidine synthesis to the indole alkaloids synthesis. In this conference, we shall present the stereoselectivity of the asymmetric 6π-Azaelectrocyclization in the substituted indole compounds. These are regarded as basic studies directing toward the development of the new synthetic strategy for indole alkaloids.

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Reported here for the first time are the synthesis, isolation, and characterization of hypervalent β-haloalkenyl-λ³-bromanes. Exposure of terminal alkynes to p-trifluoromethylphenyl(difluoro)-λ³-bromane activated by BF₃-i-Pr₂O resulted in fluoro-λ³-bromanation of the triple bonds in a Markovnikov fashion yielding (E)-β-fluoroalkenyl-λ³-bromanes stereoselectively in good yields. 5-Chloro-1-pentynes undergo domino λ³-bromanation-chlorine shift-fluorination or λ³-bromanation-chlorine shift-alkyl shift-fluorination reaction depending on the substituents and afford (E)-β-chloroalkenyl-λ³-bromanes stereoselectively in high yields. The β-chloroalkenyl-λ³-bromanes contain three kinds of halogen atoms F, Cl, and Br in the molecule.

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In the course of our study regarding the photo-oxidation of methyl group at aromatic nucleus with molecular oxygen in the presence of stoichiometric amount of NBS, we found this oxidation reaction proceed smoothly even in the presence of catalytic NBS. Furthermore, we have also found that alcohols could be oxidized to the corresponding carboxylic acids. We now report our study on the generality of the photo-oxidation of alcohols and methyl group at aromatic nucleus with molecular oxygen as terminal oxidant in the presence of cat. NBS.

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The TBS (tert-butyldimethylsilyl) group is one of the most popular and reliable silyl protective group in organic syntheses. We have developed an efficient, practical, and chemoselective method for the deprotection of TBS groups using economical and available TiCl₄ - Lewis base complexes. The method using AcOEt or CH₃NO₂ as Lewis base involves smooth deprotections not only of aliphatic TBS ethers but also of relatively less reactive phenolic TBS ethers, in short periods under mild conditions. As an extension, we demonstrated the present desilylation method for the synthesis of 1β-methylcarbapenems, that is, TiCl₄ - CH₃NO₂ complex successfully applied to the final stage of its synthesis.

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We have investigated a new mild deprotective method for various O-allylphenols to give the corresponding phenols. The reaction of O-allylphenols bearing electron-withdrawing and weak electron-donating groups on the benzene ring proceeded smoothly, whereas the reaction of O-allylphenols having strong electron-donating groups gave phenols in nil to moderate yields. Mono-deprotection of O,O'-diallylcatechols was proceeded successfully to afford the corresponding O-allyloxyphenols. Moreover, we revealed that the present reaction proceeded via the SET process. Because 10% Pd/C is a heterogeneous catalyst, the deprotected phenol was obtained in essentially pure form by simple filtration and extraction procedure.

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The enantioselective Diels-Alder reactions of 1-phenoxycarbonyl-1,2-dihydropylidine with 1-alkylated acryloyl-pyrazolidin-3-ones using chiral cationic Palladium-phosphinooxazolidine (Pd-POZ) catalyst afforded chiral isoquinuclidines in excellent enantioselectivity (up to 97% ee).

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The Diels-Alder reaction and Friedel-Crafts reaction of 2-methyl-5,5-diphenyl-buta-2,3,4-trienal (1), stable [3]cumulene derivative, have been investigated. Upon treatment of 1 and cyclopentadiene with SnCl₄, the Diels-Alder (DA) reaction proceeded smoothly to give the allene derivatives in exo selectivity. The DA reaction with Danishefsky's diene and successive treatment of the cycloadduct with H+ or TBAF afforded the trisubstituted benzene derivative. These DA reactions selectively occurred on the C2-C3 double bond. On the other hand, with electron-rich heteroaromatics such as furan, pyrrole and indole derivatives, the Friedel-Crafts reaction proceeded to afford the tetrasubstituted alkene derivatives. Furthermore, the analogous nucleophilic addition of PhSH proceeded smoothly to give the corresponding diene.

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Treatment of 1-methoxy-Nb-methoxycarbonyltryptamine with iodine-morpholine in an appropriate alcohol as a solvent was established to be a simple synthetic method for 1,2,3,3a,8,8a-hexahydro-8-methoxy-1-methoxycarbonylpyrrolo-[2,3-b]indoles having an alkoxy group at the 3a position. The reaction was successfully applied to N-acetyl-1-methoxy- L-tryptophan methyl ester (A). As a result, optically active methyl 3a-alkoxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylates became readily available. Treatment of A with either NBS or NCS in MeCN afforded optically active methyl 3a-bromo- and 3a-chloro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylates (B). Optically active methyl 1,2,3,3a,8,8a-hexahydro-3a-hydroxypyrrolo[2,3-b]indole-2-carboxylate was prepared from B by the reac-tion with AgCN in MeCN-H2O.

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By using the C3-selective cyclization of C2-substituent of indole which we found, we succeeded in the total syntheses of natural 4-methoxy-β-carboline alkaloids. Recently, we also succeeded in the synthesis of 4-methoxy-β-carbolines using Fischer indolization, followed by oxidative acetalization-aromatization procedure, accompanied by reductive elimination of Nb-sulfonamide of 4-oxo-1,2,3,4-tetrahydro-β-carboline. We report here the subsequent progress. 1) The desired C3-cyclization product is formed thermodynamically from kinetic N1-cyclization product. 2) The oxidative acetalization-aromatization process for 4-methoxy-β-carboline occurred by reductive elimination of Nb-sulfonamide as sulfinic acid in aromatization of 4-oxo-1,2,3,4-tetrahydro-β-carboline. 3) The improvements of the synthetic method for 4-methoxy-β-carbolines are applicable to large scale synthesis.

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Recently we have reported the concise method for synthesis of a variety of 3-allyl-3-hydroxyindolin-2-ones using enolization-Claisen rearrangement of 2-allyloxyindolin-3-ones and synthesized 3-hydroxyindolin-2-one alkaloids, (±)-donaxaridine and (±)-convolutamydines. We now wish to describe the preparation of optical active 3-(2-nonen-1-yl)-3-hydroxyindolin-2-one through asymmetric Claisen rearrangement triggered by silyl-enolization of 2-(1-nonen-3-yl)oxyindolin-3-one and the synthesis of 3a-hydroxypyrrolo[2,3-b]indole alkaloid, alline.

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In our continuing study on the synthetic application of indolylborate, we previously reported the predominant formation of 3-pyridylindole from the reaction of indolylborate with pyridinium chloride. This possibly involved the intervention of indolylcopper intermediate arising from the transmetallation between boron and copper in situ. We will report our recent results of the reaction of indolylcyanocuprate with electrophiles, in which the reaction outcome was highly depended on the nature of electrophile used.. While treatment of indolylcyanocuprates with allyl bromide produced 2-allylindoles, indolylcyanocuprates reacted with pyridinium chloride to afford 3-pyridylindoles.

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We have developed the novel asymmetric aziridine formation from chiral guanidinium salts and aromatic aldehydes. Atom-economical synthesis of (+)-Lysergic acid by the effective use of constitutional atoms in the aziridine is designed. In this presentation, we report the C-ring construction of lysergic acid using model compounds through cyclization from the 4-position's side chain to the 3-position of indole ring. At first, we attempted the alkylation of the 3-position of indole by intramolecular Pummerer reaction, but only cyclization was occurred at the 5-position. Next, we examined acylation using intramolecular Vilsmeier reaction, in which the cyclization was, as expected, occurred at the 3-position. Thus, the desired products were obtained in 74% yield from simple amide and in 34% yield from amino acid derivative, respectively.

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We have found that the treatment of various 1-Boc-3-alkenyl-1H-indoles with excess of TFA gave the seven-membered ring cyclodimers, cyclohepta[1,2-b:4,5-b']diindoles in good to moderate yield, and the same reaction of 2'-(4-oxgenated phenyl)ethenyl derivative provided a mixture of seven-membered ring cyclodimers and the 2,3,4-trans substituted six-membered ring cyclodimers, tetrahydrocarbazoles. On the other hand, the reaction of 1-alkylated or unsubstituted 3-alkenyl-1H-indoles with 1 equivalent of TFA smoothly proceeded to give the 1,3-trans substituted five-membered ring cyclodimers, cyclopent[b]indoles in good yield.

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Benzocarbolines and benzocarbolinones, indoloquinoline alkaloids, have much attention due to their potential effectiveness in medical treatment. Beckmann rearrangement and Schmidt rearrangement are a good method for synthesis of amides from ketones. Albini reported that Beckmann rearrangement of 3-benzoylindole oxime in hot acetic acid gave 3-(benzoylamino)indole as a sole product. However, they did not show the influence of substituents on indole nitrogen and benzene ring about Beckmann rearrangement. Here, we show Beckmann rearrangement of 3-(4-methoxybenzoyl)indole oximes and 5H-indeno[3,2-b]indol-10-one oximes and its application of a synthesis of benzo-β-carbolinones and benzo-γ-carbolinones. In Schmidt rearrangement of 5H-indeno[3,2-b]indol-10-one, 6H-isoindolino[2,1-a]indol-6-one was obtained.

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A convenient synthesis of heterocycles fused with 5-oxo-5,6-dihydro[1,2,4]triazolo[1,5-c]pyrimidine as a new class of potential xanthine oxidase inhibitors is reported. Thus pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones were prepared by condesation of 4-hydrazinopyrrolo[2,3-d]pyrimidin-2(1H)-one with an appropriate triethyl orthoester or by oxidative cyclization of 4-benzylidenehydrazinopyrrolo[2,3-d]pyrimidin-2(1H)-one with chloranil, followed by the nimble rearrangement reaction via pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-ones. The thieno[3,2-e]- and thieno[2,3-e]-[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones were also synthesized in a similar manner as above. Herein, their inhibitory activities against bovine milk xanthine oxidase in vitro and their auto-ligand-docking scores against xanthine oxidase using BioMed CAChe Active Site 6.1 (Fujitsu Ltd.) were obtained.

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We have developed an efficient method for the preparation of 3-substituted indazoles using palladium catalyzed intramolecular amination reaction of 2-bromophenylketone hydrazone derivatives. Namely, when the reaction was conducted in the presence of Pd(OAc)2/bidentate phosphine ligand catalyst system in dioxane, the cyclization proceeded smoothly under mild reaction conditions, and various 3-substituted indazoles were obtained in good to excellent yields with good functional group compatibility. The choice of base such as Cs2CO3 and NaOtBu was crucial for this reaction. It was also found that the same catalyst system could be applied to the synthesis of 3-phenylbenzoisoxazole from corresponding 2-bromobenzophenone oximes. In addition, total synthesis of nigellicine was achieved using above method as a key step.

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Chiral N-heterocyclic carbenes (NHC) were used as enanthioselective acylation catalysts for kinetic resolution of secondary alcohols and desymmetrization of meso-diols. C2-Symmetric imidazolium salts, precursors of chiral NHCs, were prepared from chiral amines, glyoxal, and chloromethylethyl ether. N-Heterocyclic carbenes were generated by the treatment of imidazolium salts with t-BuOK and were used in situ. Using 1,3-bis-[(R)-1-(1-naphthyl)ethyl]imidazolium salts as catalysts and vinyl propionate as an acyl donor, the acylation of 1-(1-naphthyl)ethanol at 0°C for 1 day afforded the propionate in 68% ee with s factor 6.1. The use of various chiral NHCs and acyl donors for asymmetric acylation will be reported.

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We have disclosed the highly enantioselective desymmetrization of prochiral σ-symmetric compounds in the presence of a catalytic amount of chiral sulfonamide catalyst. The asymmetric thiolysis of several prochiral cyclic dicarboxylic anhydrides with benzylmercaptane (BnSH) in the presence of 5 mol% of chiral bifunctional sulfonamide proceeded at room temperature to give the corresponding S-benzyl thioesters in 87-100% yields with 83-98% ee. Furthermore, the asymmetric acetylation of meso-2-functionalized-1,3-diols in the presence of 5 mol% of new chiral sulfonamide-Zn complex at 0 °C afforded chiral mono-acetylation products in up to 92% yield with up to 88% ee. The optically active mono-aceylation products can be applied to the synthesis of α-substituted serines.

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The development of the lipase-catalyzed dynamic kinetic resolution (DKR) has been gaining increased attention, because it can overcome the inherent limitation of the ordinary kinetic resolution; viz., the maximum of 50% yields of the products. We present here a new DKR protocol of racemic allylic alcohols by the first combination of lipases with VO(OSiPh3)3, in which the vanadium complex catalyzes the racemization of the allyl alcohols through the 1,3-transposition. The advantages of this method include 1) the production of allyl esters with high optical (91-99% ee) and chemical yields (88-95%), 2) not requiring special apparatus and an easy experimental procedure, and 3) the novel preparation of optically active esters of secondary alcohols starting from readily available tertiary allyl alcohols.

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Spirofungins A and B are polyketide-type antibiotics isolated from Streptomyces violaceusniger Tu 4113 as a 4:1 mixture and show various antifungal activities, particularly against yeasts. The stereocontrolled total synthesis of (-)-spirofungin A and (+)-spirofungin B has been achieved with the Weinreb amide, the alkyne and the alkenylboronate readily available from the common intermediate employing Horner-Emmons reaction and Suzuki coupling reaction for the construction of the both side chains. It was determined that the absolute configuration of natural spirofungin A is 4S,5S,11R,12S,15S,18S,19R. The first synthesis proceeded with a longest linear sequence of 31 steps, affording (-)-spirofungin A and (+)-spirofungin B in 7.9% and 5.2% overall yields, respectiely.

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A highly stereoselective method for constructing a (2E)-methoxymethylidene-1,6-dioxaspiro[4,5]decane skeleton has been developed on the basis of the palladium (II)-catalyzed ring-closing reaction of the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one derivatives as a crucial step. The newly developed procedures could be successfully applied to the first total synthesis of five spiroacetal enol ether natural products starting from commercially available (R,R)- or (S,S)-diethyl tartrate.

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The enantioselective [2,3]-Wittig rearrangement of 1-allyloxy-1-(naphthlen-2-yl)-4-siloxy-2,4-pentadienyl anion, derived from optically enriched 4,5-epoxy-1-(naphthalen-2-yl)-5-silyl-2-pentenyl allyl ether via a base-induced ring opening of the epoxide followed by Brook rearrangement, has been studied. The chirality of the epoxide was transferred to the alcohols in up to 97%ee, depending on solvent. The best result was obtained in 1,4-dioxane at temperature above room temperature, which was in sharp contrast to the results obtained in THF where almost complete racemization occurred. The fact that a carbanion between an aryl group and a double bond has a sufficient configurational stability to be trapped by [2,3]-Wittig rearrangement in 1,4-dioxane was also observed with [2,3]-Wittig rearrangement of (1S)-1,3-diphenyl-2-propenyl allyl ether.

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Reaction of an aryllithium with ethyl perfluoroalkanoate resulted in the reduction of the intermediate ketones. The mechanism of this abnormal reduction was established to be caused by lithium ethoxide. Lithium isopoprxide was found to be more effective for this reduction. On the reduction of trifluoromethyl ketone with this alkoxide, a considerable amount of the aldol adduct of the ketone with acetone was formed, while larger perfluoroalkyl ketones were reduced to the corresponding alcohols without formation of these aldol adducts. When chiral lithium 1-phenylethoxide was used, chiral perfluoroalkyl alcohols were formed in fairly good enantiomeric excesses. This reduction is useful for those perfluoroalkyl ketones for which asymmetric reduction with the conventional CBS reduction gives asymmetric alcohols in low enantiomeric excesses.

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We have developed the first highly stereoselective synthesis of tetrasubstituted, functionalized (E)-enol ethers via olefination of esters with ynolates, which are generated from α,α-dibromo esters. Lithium ynolates easily react with esters at room temperature to give β-alkoxy- α,β-unsaturated carboxylates with good to excellent (E)-selectivity and in good yield. The E/Z selectivity is controlled by the torquoselectivity in the ring-opening of β-lactone enolate intermediates. In contrast to esters, thiol esters were found to provide β-keto thiol esters via the reaction with ynolates. This homologation can be regarded as the C-S insertion of ynolates. The α-keto ketene intermediates, which would be generated by elimination of the thiolates from the initial adducts, would be attacked by the thiolates to afford β-keto thiol esters.

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We have successfully verified that dehydrocondensation is ideally suited for micellar reaction. A bimolecular dehydrocondensation between amphiphilic carboxylate anions and amines was highly accelerated (2,000-fold) in a micellar system when a 1,3,5-triazine-type amphiphilic dehydrocondensing agent was used. Such an unusual rate enhancement of dehydrocondensation can be attributed to increased local concentration of substrates and a preorientational effect of the micelles on the amphiphilic dehydrocondensing reagent, the carboxylate, and the amine. It should be noted that the catalytic dehydrocondensation involving the activation of carboxylic acids takes place at the interface between water and the micelles, not in the hydrophobic interior of the micelles.

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