The direct coupling reactions of organoboronic acids with propargylic and allenic alcohols have been achieved using palladium catalyst. The reaction of the propargylic alcohol with arylboronic acid in the presence of palladium catalyst affords the coupled allenic and propargylic compound. The ratio of both products can be controlled by changing substituents on the substrate, and variety of aryl-substituted allenes and propargylic compounds can be rationally synthesized. The reaction can also be applied to allenic alcohols. When the allenic alcohol was subjected to the reaction with arylboronic acid in the presence of catalytic amount of palladium complex, the reaction is completed within 1 h to afford a coupled diene. Various aryl-substituted dienes can be directly synthesized from the corresponding allenic alcohols with arylboronic acids in high yields.

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Direct construction of polycyclic heterocycles from readily available compounds is one of the most important research areas in organic synthesis. Based on our recent findings, we investigated two types of tandem reactions. First, we studied tandem cyclization of bromoallenes, which can act as allylic dication equivalents, and found that the reaction of bromoallenes having a sulfamide moiety with NaOMe in MeOH in the presence of a palladium catalyst yields bicyclic compounds involving five- to eight-membered rings. In some cases, the tandem cyclization proceeds in the absence of a palladium catalyst. Second, we investigated the palladium(0)-catalyzed tandem cyclization of allenenes with various aryl halides and found that the reaction of allenenes with heteroaryl halides affords tri- or tetracyclic heteroarylic compounds in good yields.

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We present that the reactions of o-alkoxymethylstyrene derivatives with a stoichiometric amount of zirconocene-butene complex (“Cp₂Zr”, Negishi reagent, Cp=cyclopentadienyl) gave o-styrylmethylzirconocene intermediates in good yields under mild conditions. Reaction of o-alkoxymethylstyrene, which is substituted with dimethyl groups at the benzylic position, however, gave a dimeric product in a good yield. The dimerization reaction was efficiently carried out by using a catalytic amount of “Cp₂Zr” as well. In the presence of an excess amount of styrene, the reaction of the dimethylsubstituted styrene derivative with a stoichimetric and/or catalytic amount of “Cp₂Zr” gave intermolecularly coupled products as a single stereoisomer in good yields. Synthetic applications of the present zirconocene-mediated or -catalyzed chemistry are also presented.

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Scyphostatin, which was isolated from Dasyscyphus mollissimus SANK-13892 in 1997, is a lead compound for the treatment of inflammation and autoimmune desease for its potent activity inhibiting a neutral sphingomyelinase. But it is very unstable compound, which consists of highly substituted cyclohexane core with aminoalcohol unit and unsatuated fatty acid. We report herein regio and stereoselective asymmetric synthesis of scyphostatin from the chiral cyclohexane acetal obtained by an intramoleucular bromoetherification of σ-symmetric cyclohexadiene acetal, prepared from chiral hydrobenzoin.

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(–)-Laulimalide is a potent cell growth inhibitor with low nanomolar IC50 values that was isolated from Cacospongia mycofijiensis, Hyattella sp. and Fasciospongia rimosa. Laulimalide stimulates tubulin polymerization by a mechanism similar to that of paclitaxel, but unlike paclitaxel, inhibits proliferation of SKVLB-1, a multidrug-resistant cell line. The structure of laulimalide has two substituted dihydropyran rings inside and outside of the 20 membered macro lactone ring. These two specific dihydropyran rings have been constructed by Pd⁰ and Pd^II catalyzed ring formation reaction of allyl carbonate and allyl alcohol stereospecifically. Two fragments having allylsilane unit and unsaturated aldehyde unit have been assembled by Sakurai–Hosomi reaction and additional 5 steps have afforded the seco-acid, which was reported as a precursor of (–)-laulimalide.

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The asymmetric total syntheses of (+)-mycoepoxydiene and (–)-1893A have been completed. The present synthetic strategy features the use of one-pot ring-opening/cross metathesis (ROM/CM) followed by a ring-closing metathesis (RCM) reaction, allowing the concise construction of the 9-oxabicyclo[4.2.1]nona-2,4-diene framework from a 7-oxabicyclo[2.2.1]hept-2-ene derivative and 1,3-butadiene. The sequential metathesis product was converted into (+)-mycoepoxydiene through the oxidative rearrangement of a furfuryl alcohol to a pyranone, thereby establishing its absolute stereochemistry. From the common intermediate, a structurally related natural product (–)-1893A was also synthesized via the vinylogous aldol reaction.

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The reactions of (phenylsulfinyl)-furans, -thiophenes, -benzofurans, and -indoles with carbon nucleophiles in the presence of trifluoroacetic anhydride allowed the nucleophilic installation of carbon functional groups on these π-sufficient heteroaromatic nuclei. These reactions were initiated by their aromatic Pummerer-type reactions to generate highly electrophilic sulfonium intermediates, to which nucleophilic addition of carbon nucleophiles proceeded to give the products. The complete regioselectivity was attained in every case depending on the position of the sulfinyl group of the substrates, and the sulfur functional groups remaining on the products were utilized for the installation of the second carbon substituents at their ipso-position. These features make the developed method unique among a variety of existing carbon–carbon bond forming reactions of these π-sufficient heteroatomatics.

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A highly stereoselective aza-Claisen rearrangement reaction using N-methylformenamide derivatives, which were easily prepared from the corresponding 1-iodo-1-alkenes, was developed. Treatment of an N-methylformenamide derivative with a 1-alkenyllithium gave a lithium alkoxide intermediate that in turn underwent an aza-Claisen rearrangement reaction to afford a 1,5-dialdehyde derivative. The reaction proceeds through a chair-like six-membered transition state, and both diastereomers of the product are stereospecifically synthesized from a suitable combination of the geometrical isomers of an N-formenamide derivative and a 1-alkenyllithium. Stereoselective construction of contiguous quaternary chiral centers was also achieved by the reaction of a tri-substituted formenamide derivative and (2-methyl-1-hexenyl)lithium.

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A novel consecutive α- and β-activation of conjugated alkynes and its utility for new C–C bond forming reaction of propiolates are presented. This new concept is based on the 1,4-addition of a tertiary amine to the conjugated alkynes, the aldol-type addition to aldehydes, and subsequent intramolecular silyl migration. This sequential process is generally applicable for 3-trimethylsilylpropiolates. Combination of methyl 3-trimethylsilylpropiolate, DABCO, and aromatic aldehydes brought about a domino-type C–C bond formation to afford highly functionalized olefins as a major product. On the other hand, aliphatic aldehydes gave alkyne derivatives as a sole product, presumably via the reaction pathway common to the former cases. The intramolecular version of the reaction was successfully applied for the cyclization of trimethylsilylpropiolic esters derived from salicylaldehydes, leading to a new formylcoumarin synthesis.

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The removal of hydroxyl groups from aromatic rings is among the most fundamental subjects in organic synthetic chemistry, although phenolic hydroxyl groups are quite stable under various reaction conditions. We have recently established that a Pd/C–Et₂NH system efficiently catalyzed the hydrogenolysis of aromatic mesylates. We are now in a position to disclose that the Pd/C–Mg–MeOH system is efficient for elimination of the aromatic triflates without a hydrogen gas. The mechanism of this reaction is very attractive. In addition, we also found that the addition of catalytic amounts of ammonium acetate dramatically accelerated the reaction rate, expanded the application of this method and improved the yields.

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The reaction of cyclopropanol silyl ethers with diethylaminosulfur trifluoride in dichloromethane usually causes ring opening to produce allylic fluorides. However, cyclopropyl silyl ethers bearing a strong electron-donating substituent at C1 or an electron-withdrawing substituent at C2 do not afford allylic fluorides but fluorocyclopropanes. It has also been proved that an electron-donating substituent at C2 of the cyclopropanol silyl ethers promotes ring opening in the reaction with diethylaminosulfur trifluoride. These reactions proceed through allyl cations or cyclopropyl cations derived from cyclopropyl silyl ethers. In the cases of the reaction of cyclopropanol silyl ethers with diethylaminosulfur trifluoride in electron rich aromatic compounds, the carbocations derived from cyclopropyl silyl ethers mainly reacted with aromatic compounds.

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The synthesis of 3,4-dihydro-1H-isoindoles (isoindolines) was achieved via modified Pictet–Spengler reaction of arylmethylamines and aryl- or cycloalkylaldehyde. The condensation of arylmethylamine and aldehyde followed by formylation with acetic-formic anhydride of resulting imines gave effective intermediate acyliminium ions. Treatment of acyliminium ion with trifluoroacetic acid, after removal of the acylating reagent, yielded the 1-substituted isoindolines in excellent yields. The cyclization is able to proceed via the 5-exo-trig process of enamines produced from the isomerization of acyliminium ion under acidic condition, not the 5-endo-trig process of acyliminium ion. This Pictet–Spengler type cyclization was carried out under one pot procedure, providing an effective method for preparing 1-substituted isoindolines.

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An intramolecular 1,2-alkyl migration from boron to carbon in trialkylalkenylborate has been well defined as a useful protocol for carbon–carbon bond formation. We have embarked upon extending the scope of this migration process in indolylborates to an intramolecular cyclization enabling the one-pot construction of [a]- and [b]-annelated indole derivatives from the corresponding indoles. During these studies, it was found that the alkyl migration reaction in 1-methoxymethylindolylborates led to 1-methyl-2-alkylindoles, in which the intermediary formation of alkylboranes through a novel cascade of alkyl-boryl migration steps was taken as the key reaction feature.

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A simple and novel synthetic method of 1,2,3,3a,8,8a-hexahydro-8-methoxy-1-methoxycarbonylpyrrolo[2,3-b]indoles (A), having such alkoxy group as methoxy, ethoxy, allyloxy, benzyloxy, and 2-hydroxyethoxy, at the 3a position, is developed by treating 1-methoxy-Nb-methoxycarbonyltryptamine (B) with iodine–morphorine in an appropriate alcohol as a solvent. The reaction of B with either NBS or NCS in MeOH or EtOH was also found to be another good method. In the reaction with NCS, stable 3a-chloro-1,2,3,3a,8,8a-hexahydro-8-methoxy-1-methoxycarbonylpyrrolo[2,3-b]indole (C) was formed. Treatment of C with an appropriate alcohol in the presence of silica gel produced the corresponding A. An attempt to improve the yields of A and an application of C as a building block for natural product synthesis are in progress.

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We found a novel de-acylation reaction of 3-acetyl-4-bromoindole-2-carboxylate catalyzed by BF₃•OEt₂ at rt. This reaction proceeded with various 4-substituted 3-acetylindole-2-carboxylates, but for the 4-unsubstituted one, the 3-acetyl group was not removed under any condition. So we examined various acyl groups for the 4-unsubstituted indole-2-carboxylates. We found that a pivaloyl group is de-acylated by BF₃•OEt₂ at rt. Next, we examined various electrophilic substitutions of ethyl 3-pivaloylindole-2-carboxylate in order to develop a new protecting group for the 3-position of indoles. Expectedly, in bromination and nitration, the benzene-part substituted products were obtained in good yield. The products are de-acylated to give the benzene-part substituted indole-2-carboxylates by BF₃•OEt₂ at rt. This result shows that the pivaloyl group could be applied as a new protecting group for the C³-position of the indoles.

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Two different types of catalysts for the cyclization reactions of 2-ethynylanilines to indole derivatives were investigated. The Cu(OAc)₂ has been proved to be the catalyst for the sulfonamides, which have both electron-withdrawing and electron-donating groups on the aromatic ring and C2 position of indole. These catalytic systems can be applied to the primary and the secondary aniline derivatives. The sequential cyclization reaction to afford the tricyclic indole derivatives and synthetic studies of some natural products using these reactions will be also reported. During above investigation, the new catalytic systems derived from Pd(PPh₃)₄, methyl propiolate, and ⁱPr₂NEt, were found for the sequential coupling and cyclization reactions of 2-iodoaniline derivatives. The total synthesis of duocarmycin SA and synthetic studies of pyrroloquinoline quinone using this methodology will be reported.

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Caulersin, isolated in 1997 from the alga Caulerpa serrulata, is a member of bisindole alkaloids and has an extra seven-membered cyclic ring between the two indole rings incorporated directly with carbonyl group. Caulersin was synthesized by Molina, our group, and Bergman and the structure of the synthesized caulersin by Bergman was confirmed by X-ray diffraction study. However, ¹³C-NMR spectrum of the synthesized caulersin by Bergman is different from that of natural caulersin. We consider that the structure of caulersin is not correct and think out three isomers A–C of caulersin to decide the real structure. Three isomers A–C were synthesized by reaction of indole-2,3-dicarboxylic anhydride with methyl indole-2-acetate or methyl indole-3-acetate. Spectral data of the isomers A–C are not same as those of natural caulersin and the structure of caulersin is yet unclear.

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The efficient large-scale synthesis of 1-azabicyclo[1.1.0]butane (ABB) by treatment of 2,3-dibromopropylamine hydrobromide with n-BuLi was successfully established by our research group. In the consecutive cyclization of 2,3-dibromopropylamine with n-BuLi, a possible reaction mechanism generating initially 2-bromomethylaziridine and then ABB has been revealed by utilizing some model experiments, in which an intramolecular S_N2-type N–C bond formation involving the Br...Li coordination must be plausible. ABB has been exploited for expeditious syntheses of a number of useful azetidine derivatives. Several compounds of them have been employed for the syntheses of a new oral 1β-methylcarbapenem antibiotic L-084 and new quinolone antibiotics.

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Divalent positively charged nitrogen species (nitrenium ions) which are stabilized by the neighboring groups have been greatly applied in the field of synthetic organic chemistry. Previously, we reported that nitrenium ions (I) can be generated from the corresponding N-methoxy- or N-allyloxy-N-chloroamides by the action of silver or zinc ions or by direct oxidation of the corresponding amides with phenyliodine(III) bis(trifluoroacetate) (PIFA). Later, we also reported that nitrenium ions (II), generated from N-acylaminophthalimide with PIFA, react with arenes to give nitrogen heterocycles. In an extension of this work, we have investigated the reaction of II with olefins to give hydrazide derivatives having a trifluoroacetoxy group on the adjacent carbon in good yields. The procedure is operationally simple and the reaction is extremely regioselective.

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Oxazolidinones are the important precursors of amino alcohols and amino acids. We found a simple and convenient synthetic method of oxazolidinones. The reaction of primary amines and halomethyloxiranes with carbonates, such as K₂CO₃, in the presence of base (TEA, DBU) gave oxazolidinones in a high yield. When CO₂ was used instead of carbonates, oxazinones were first obtained predominantly and then converted to oxazolidinones. This conversion to oxazolidinones was confirmed by the use of oxazinones as starting materials in the presence of primary amines, halomethyloxiranes and K₂CO₃. Therefore, we confirmed that oxazinones formed in the reaction process were converted to oxazolidinones. The reaction conditions to improve yields and the use of various amines (e.g. Naltrexamine) were examined.

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Optically active (4S,αR)- and (4R,αR)-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinones (2 and 3, respectively) were synthesized from 2-(α-methylbenzyl)amino-1,3-propanediol (1) using CDI and Et₃N or DBU in CH₂Cl₂ or THF at room temperature in 17–87% yields and in 4–90% de. The intermediates of the reaction were a diastereomixture of monoimidazolylcarbonyl compounds 4/5 (67:33), and (R)-5-(α-methyl)benzylamino-1,3-dioxan-2-one (6) was also formed as a precursor of 2/3 from 4/5. Cyclic carbonate 6 were converted into 2 in >96% yields and in 94–92% de by treatment of DBU in CDCl₃ and THF-d₈ at room temperature; however, little amount of 2 was formed from 6 by treatment of Et₃N in CD₂Cl₂. Thus, the yields and diastereoselectivities of the reaction using CDI form 1 to 2/3 depended on the ratios of the reaction paths from 4/5 directly to 2/3 or from 4/5 to 2/3 via 6.

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Highly stereoselective synthesis of 1,4-bifunctional compounds was accomplished via Carreira's asymmetric alkynylation to α-oxyaldehyde followed by regio- and stereoselective Pd-catalyzed allylic substitution reaction. The stereogenic center at the protected chiral secondary alcohol not only works as a stereocontroller in the first step but also controls the regiochemistry in this reaction. Upon treatment with 10 mol % of Pd(PPh₃)₄ and two equivalents of nucleophile (Nu = NaCH(CO₂Me)₂, BnNH₂), both E- and Z-allylic trifluoroacetates underwent stereospecific chirality transfer to the distal position, giving anti- and syn-1,4-bifunctional compounds, respectively, in good yield and with very high diastereoselectivity (>97:3 dr).

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We examined the reactions of an electron-deficient alkylidenecyclopropane with alkynes in the presence of nickel catalysts and discovered a new [3+2+2] cycloaddition reaction. This reaction proceeded selectively and cycloheptadiene derivatives were isolated in good yields. Especially, highly regioselectivity was observed in the reaction of bulky terminal alkynes such as (trimethylsilyl)acetylene, 3,3-dimethyl-1-butyne and phenylacetylenes. The high reactivity of the electron-deficient alkylidenecyclopropane plays an important role for the progress of the reaction. The nickelacyclooctadiene intermediate formed by the reaction of two alkynes and an alkylidenecyclopropane was assumed as the key intermediate of this reaction. The structure of cycloheptadiene derivatives was confirmed by an X-ray crystal structure analysis.

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Cycloaddition of aziridines with phenyl isocyanate proceeded smoothly in the presence of nickel catalysts and five-membered heterocycles were isolated in good yields. The best result was obtained when the reaction was carried out in the presence of NiI₂. The selective formation of iminooxazolidine derivatives was observed in the reaction of N-benzylaziridine with phenyl isocyanate. On the other hand, the reaction of N-tosylaziridine with phenyl isocyanate proceeded smoothly in the presence of Ni(PPh₃)₂I₂ and an imidazolidinone derivative was isolated. The mechanism of the reaction was also proposed.

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Rh-Catalyzed intermolecular hydroacylation between salicylaldehyde and alkenylnitriles proceeded at room temperature to give a mixture of iso- and normal-hydroacylated products; preferentially the normal-products were obtained. Addition of CH₃CN and NaOAc is capable of accelerating the Rh-catalyzed hydroacylation of monoolefins to produce the normal-hydroacylated products under mild reaction conditions.

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Highly chemo- and regioselective deprotonative alumination of functionalized aromatic and heteroaromatic compounds was realized using a newly designed aluminum ate complex. Direct alumination followed by electrophilic trapping proved to be a powerful tool for the preparation of 1,2- or 1,2,3-multisubstituted aromatic compounds. In addition, the functionalized aromatic aluminate intermediate was found to undergo transition metal-catalyzed C–C bond-forming reactions and oxidation with high regio- and chemoselectivities. A structural study of ⁱBu₃Al(TMP)Li and a mechanistic investigation of this novel deprotonation reaction strongly suggested that an unique coordinative and electronic environment of the lithium/aluminum-hetero-bimetallic ate complex allows the facile and selective deprotonation reaction.

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We succeeded in the development of a new synthetic method of optically active vicinal diamine derivatives through enantioselective N-monoallylation with a chiral π-allyl-Pd catalyst. N-Monoallylation of meso-vicinal diamine bistrisylamides with (R,R)-Trost-ligand–Pd catalyst and allyl acetate proceeded with high enantioselectivity (up to 90% ee) to give desymmetrization products in good yields. The product was converted to known σ-receptor agonist in short steps. In addition, the present catalytic asymmetric N-allylation was applied to kinetic resolution of racemic-diamide.

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We present an efficient synthesis of a novel class of alicyclic chiral diamine DHPP and DMPP from L-proline, and their application to the asymmetric acylation of meso-1,2-diols catalyzed by chiral diamine–cupric chloride. One pot esterification of L-proline followed by dimerization gave corresponding diketopiperazine. Monomethylation of diketopiperazine was performed by Romo's procedure using KHMDS–iodomethane, and second methylation was conducted by lithium diethylamide–iodomethane to give cis-dimethyldiketopiperazine as sole diastereomer. Finally, diketopiperazine and dimethyldiketopiperazine were reduced by lithium aluminum hydride to give DHPP and DMPP. Asymmetric benzoylation of all meso-1,2-diols investigated was achieved in high enantioselectivity with CuCl₂–DMPP complex, while use of CuCl₂–bisoxazoline complex exhibited relatively low optical yield.

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Chiral aminoalcohols are promising catalysts in the enantioselective nucleophilic addition reaction of organozinc reagents to carbonyl compounds. In fact, many chiral 1,2-aminoalcohol-type ligands were known to give optical active 1-phenylpropan-1-ol over 98% ee in the reaction of diethylzinc with benzaldehyde. However, investigations on 1,3- or 1,4-aminoalcohol-type ligands would be still lacking. Thus, we designed and synthesized several new 1,3-aminoalcohol-type ligands, (1S,2R)-10-(dialkylamino)isoborneols. Initially, the reaction of diethylzinc to benzaldehyde with 5 mol % of ligands was examined. Of all, the ligand bearing granatanine as a dialkylamine moiety gave the best results (99 % yield, 94 % ee for R-isomer). The ligand also gave good enantioselectivity in the reaction using other aldehydes.

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Allylation and propargylation reactions of imine derivatives in the presence of a catalytic amount of palladium complex and indium(I) iodide were studied. The reversibility of allylation was observed in the reaction of glyoxylic oxime ether having camphorsultam. Excellent diastereoselectivity in allylation of glyoxylic oxime ether with allyl acetate was achieved in the presence of water, although low diastereoselectivity was observed in the absence of water. In the presence of water, the γ-adducts were kinetically formed from monosubstituted allylic reagents. In contrast, the selective formation of thermodynamically stable α-adducts was observed in anhydrous THF. Propargylation of glyoxylic oxime ether proceeded with good diastereoselectivities in the presence of Pd(dppf)Cl₂ and LiCl.

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Asymmetric oxidative lactonization of meso-diols using acetone as a cooxidant is described herein. The reaction was found to be catalyzed by 0.5 mol % of a chiral Ir complex prepared from [Cp*IrCl₂]₂, chiral amino alcohol and t-C₄H₉OK at 30 °C, giving corresponding lactones in up to 81% ee and excellent yield. A gram scale reaction was also performed without special techniques. Furthermore, an enantiomerically pure lactone was obtained by recrystallization. The reaction was successfully applied to the synthesis of various useful synthetic intermediates.

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Phase-transfer catalysis is one of the most efficient and practical processes due to its advantages such as environmental benighn, mild condition and simple operation. We have developed a new PTC derived from tartrate which can be easily prepared in large scale and has a highly symmetric structure (D₂-symmetry). The rigid structure around nitrogen and various side chains on each oxygen moieties in the catalyst could enable to show wide substrate-generality in various asymmetric transformations. For example, Michael reaction of glycine Schiff-base and acrylates with catalytic amount of newly-prepared ammonium salt gave the desired product in excellent yield and ee (up to 91% ee). The reaction rate was strongly dependent on the substitutions and high acceleration was observed (OR = 2-CF₃BnO).

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Trialkoxysilyl compounds have attracted a lot of attentions because they possess unique reactivities that their related compounds, trimethylsilyl derivatives, do not. We found that lithium dibromobinaphtholate is an effective catalyst activating trialkoxysilyl enol ethers in the aldol reaction with aldehydes. The aldol reaction of 1-trimethoxysilyloxy-3H-indene and cyclohexanecarbaldehyde catalyzed by lithium binaphtholate prepared from (R)-3,3'-dibromo-2,2'-binaphthol and n-BuLi afforded the corresponding syn-adduct predominantly with high enantioselectivity. The present reaction provides the first example of base-catalyzed enantioselective aldol reaction of trialkoxysilyl enol ethers with carbonyl compounds.

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Asymmetric reactions catalyzed by metal-free organic compounds have been widely focused on because of their stability and environmentally benign nature. Although phosphine oxides possess a notable electron-pair donor property to form complexes with a variety of compounds, less attention has been paid to chiral phosphine oxides in the field of asymmetric catalysis. We have developed the first enantioselective reactions of trichlorosilyl compounds catalyzed by a chiral phosphine oxide. Enantioselective allylations of aldehydes with allyltrichlorosilanes in the presence of BINAPO as a catalyst afforded the corresponding homoallyl alcohols of up to 71% ee. BINAPO also catalyzed the enantioselective ring opening of meso-epoxide with tetrachlorosilane to afford the correspounding chlorohydrin in 90% ee.

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Combinatorial approaches toward the exploration of novel asymmetric catalysts require a convenient high-throughput screening (HTS) for analyzing both of catalyst activity (i.e. chemical yield) and enantiomeric excess. A new HTS system was developed by coupling a circular dichroism (CD) detection and solid phase reactions. In the asymmetric solid catalysts, as far as the asymmetric induction is not produced by the catalysts, no significant CD-signal should be detected in the analysis of solution phase. Based on this principle, the newly developed HTS has been demonstrated in the model reaction of oxidative coupling of β-naphthol. After carrying out the asymmetric reaction, the reaction mixture of solution phase was directly introduced to the CD detector without use of chromatographic separation. The HTS system allowed the wide range analysis of relative efficiency of the catalyst activity and asymmetric induction.

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Thermodynamically controlled deracemization was developed as a new method to prepare optically active α-monosubstituted cyclohexanones. Therefore, we applied the method to acyclic ketones this time. Use of (R,R)-(–)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[5.4]decane (TADDOL) (1.0 equiv.) with alkaline in aqueous MeOH converted racemic 3-benzyl-5-hexen-2-one to the S-isomer of 48% ee in 98% yield. In the case of 3-benzyl-2-hexanone, deracemization using TADDOL (1.0 equiv.) afforded excellent (96% ee) optical purity.

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Ciguatoxins are the major causative toxins of ciguatera seafood poisoning. Limited availability of ciguatoxins has hampered the development of a reliable and specific immunoassay for detecting these toxins in contaminated fish. Monoclonal antibodies (mAbs) specific against both ends of ciguatoxin CTX3C were prepared by immunization of mice with protein conjugates of rationally designed synthetic haptens, 1 and 2, in place of the natural toxin. Haptenic groups that possess a surface area larger than 400 Ų were required to produce mAbs that can bind strongly to CTX3C itself. A direct sandwich enzyme-linked immunosorbent assay (ELISA) using these mAbs was established to detect CTX3C at the ppb level with no cross-reactivity against other related marine toxins, including brevetoxin A, brevetoxin B, okadaic acid, or maitotoxin.

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We designed a chiral bicyclic α,α-disubstituted α-amino acid {(1R,6R)-8-aminobicyclo[4.3.0] non-3-ene-8-carboxylic acid; (R,R)-Ab_5,6=c}, in which the α-carbon atom is not a chiral center but the asymmetric centers exist at the side-chain bicyclic skeleton. The amino acid (R,R)-Ab_5,6=c has efficiently been synthesized starting from (S,S)-cyclohexa-4-en-1,2-dicarboxylic acid. The modification of olefin function in the side-chain by ozonolysis afforded several amino acid and peptide analogs, before and after the preparation of the peptides. The conformation of homopeptides composed of (R,R)-Ab_5,6=c was studied by using X-ray crystallographic analysis, ¹H NMR, IR, and CD spectra.

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Development of quinoline based new ratiometric fluorescent chemosensors, which can be easily prepared from commercially available materials, was achieved. In toluene, these chemosensors showed maximum excitation and emission at 372 nm and 420 nm, respectively. Coordination of fluorescent chemosensors to zinc ion gave new emission peak at 503 nm. Other chemosensors having both quinoline and pyridine moieties showed a ratiometric response even in a protic solvent such as methanol under the presence of zinc ion.

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Photoaffinity beads containing aryl diazirine as a photoreactive group at the termini of the TentaGel resin were designed and prepared for affinity capture of proteins. The immobilization of compounds on the resin was easily achieved by UV irradiation. The DNA polymerase β inhibitors were immobilized on the photoaffinity beads by photoreaction. DNA polymerase β was successfully bound by the immobilized DNA polymerase β inhibitors.

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Homo coupling reactions of optically active binaphthalenes possessing several kinds of side chains under classical copper–amine conditions were investigated. The newly formed axis of the chirality was controlled under three different pathways as follows; for 1a, mechanism could be explained by epimerization of the axis along with diastereoselective crystallization (second order asymmetric transformation), for 1b, the axis chirality of 2b was directly induced in the coupling step (kinetic control) and in the case of 1d, the axis chirality should be controlled with the difference of thermodynamic stabilities of diastereomeric reaction intermediates. The second order asymmetric transformation was applicable to 8 mer to afford (S,S,S,S,S,S,S,S,S,S,S,S,S,S,S)-16 mer in 79% de and 78% yield.

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Two protocols to determine the absolute configuration of axial chirality of oligonaphthalene derivatives connected with 1,4-positions based on a modified circular dichroic (CD) exciton chirality method have been developed. (1) Two 4-(2-pyreneyl)-butyric acids were condensed to the scaffolding hydroxy groups as exciton part. Positive or negative sense at around 350 nm on CD spectrum, which was originated from π-π* transition of the pyrene moiety, was reflected the absolute configuration of the target axis bond. (2) Split cotton effects (CE) at ca. 425 nm between two porphyrin derivatives attached with both terminals of rigid-rod oligonaphthalenes were also reflected the absolute configuration of the oligonaphthalenes: CD absorptions of (S,S,S)-tetranaphthalene derivatives presented negative CE at longer wavelength, in contrast, those of (S,R,S)-derivatives presented positive effect.

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For the purpose of cleavage of integral membrane proteins, the artificial phospholipid, possessing saturated alkyl chains as a membrane anchor and protein recognition site as well as an Fe(III)–EDTA moiety as a protein cleavable polar head group, was designed and synthesized by the use of phosphoramidite method. The cleavage activity with the artificial phospholipid toward influenza virus membrane protein, hemagglutinin (HA), was observed in a selective manner. It has been shown that the lipophilic hydrocarbon chains of the synthesized phospholipid are essential structural elements for cleavage of HA.

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A new traceless aniline linker was developed to synthesize the azomethines, benzoxazoles, benzothiazoles and benzimidazoles on a solid support. The loading of the substrates on the solid support and the cleavage from the solid support were performed by an imine synthesis and by imine-exchanged process under the mild conditions, respectively. Utilizing the linker we have prepared 28 azomethine compounds as candidates for new liquid crystals though three-step combinatorial solid-phase parallel synthesis. Products with a thioester group exhibited liquid crystalline properties with the higher transition temperatures than the others. 6 Kinds of benzoxazoles, benzothiazoles and benzimidazoles have been also synthesized by imine-exchange reaction with concomitant air oxidation of the substates.

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Starting with 2-chloro-5-nitropyrimidine, readily prepared from 5-nitrouracil, seemed to potentially obviate our concerns, and applicability of the Suzuki–Miyaura coupling was examined in details. Competitive hydrolysis considerably occurred simultaneously with the desired reaction under aqueous conditions, typically employed in the Suzuki–Miyaura protocol. The optimal condition was obtained in an excellent yield when 1,1'-bis(di-tert-butylphosphino)ferrocene (D-t-BPF) was used as the ligand under an anhydrous condition. The tolerability with various arylboronic acids was also found out. Subsequent reduction of the coupling adduct with H₂/Pd-C gave diamines, which was further condensed with activated acid derivatives to afford a wide variety of the 2-arylpurine derivatives in excellent yields.

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6-Substituted purine analogs have a variety of biological activity such as anti-virus effects. A number of studies has been reported on a development of the efficient synthesis of these nucleoside analogs. We have demonstrated that the oligonucleotides containing 2-amino-6-vinylpurine (1) react with cytosine at the target site very selectively. For the synthesis of 2-amino-6-vinylpurine (1), we developed Pd(0)-catalyzed cross-coupling reaction using 2-amino-6-O-tosylate and vinyltributylstannane. In this study, we investigate to achieve the cross-coupling reaction by using the tosylate precursor and organometalic reagents with lower-toxicity than organotin reagents.

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A direct method for the construction of 2-acetamido-2-deoxy-β-D-glycosidic linkages has been developed. The 3,4,6-tri-O-benzyl- or 3,4,6-tri-O-acetyl-protected 2-acetamido-2-deoxy-α-D-glucosyl and galactosyl diethyl phosphites each reacted with a range of acceptor alcohols in the presence of a stoichiometric amount of bis(trifluoromethanesulfon)imide in CH₂Cl₂ at –78 °C to afford 1,2-trans-β-linked disaccharides in good to high yields. It is worthy of note that the alcohols bearing acid-sensitive acetal or epoxy groups were safely glycosylated under these conditions. Mechanistic investigations suggest that this protocol represents the first successful example of the direct glycosidation using 2-acetamido-2-deoxyglycosyl donors that does not proceed via an oxazolinium ion intermediate. A plausible reaction mechanism is proposed.

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Sialic acid is one of the most important compounds on carbohydrate chemistry. Our recent research interest has focused on the chemical property elucidation of the double bond in 2-deoxy-N-acetylneuramic acid (Neu5Ac2en). Neu5Ac2en consisting with glycal structure is chemically a very stable compound compared with glucal. However, reduction compound of carboxyl group on Neu5Ac1Me, 5-acetamido-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto-non-2-enitol (3), change into the compound with a very high reactivity. When treating under an acid condition in methanol, 3 gave a lot of products as shown in scheme 3. It was shown that the chemistry of double bond of 3 looks like similarly glucal.

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N-Acetylneuraminic acid (Neu5Ac), sialic acid and its various analogs play essential roles in a variety of biochemical and biological processes. The development of an efficient method of O-sialylation has been a challenging task in the field of sialic acid chemistry. The reaction of 2-thiosialic acids with alcohols was activated by silver triflate or cupric triflate as promoters to give the corresponding O-glycosides in moderate yields. Herein, we report a novel procedure for the synthesis of thiazolyl, pyridinyl, pyrimidinyl, benzothiazolyl and benzoxazoyl 2-thiosialic acids having substituted imidoyl groups as glycosyl donors and their application to the glycosylation reaction.

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As an extension of our study on the stereoselective synthesis of retinoic acid analogs, we developed a novel synthesis of analogs having the different substituted moiety on the cyclohexene ring in retinoic acid. Enol nonaflates derived from various cylohexene-1-yl-acetaldehyde are smoothly reacted with E- and Z-3-tributylstannyl-2-butenols in the presence of the palladium catalyst to afford the corresponding coupling products in good to excellent yields. After oxidation with MnO₂, the resulting aldehydes were converted into the retinoic acid analogs via Emmons–Horner reaction of C5 phosphonate and subsequent basic hydrolysis.

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