A new concept in the design of a unique device for green oxidation was demonstrated by using a temperature responsive polymer support. Novel polymer-bound ruthenium catalysts were designed utilizing poly(N-isopropylacrylamide) (PNIPAAm)-based polymers. Application of the intelligence of PNIPAAm-Ru catalysts to provide a catalytic oxidation system brought a remarkable acceleration of the reactivity and an ease of catalyst recovering in the oxidation with oxygen gas or t-butylhydroperoxide (TBHP). In addition, the recovered catalyst could also be used for consecutive reactions without any significant loss of catalytic efficacy.

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We have recently developed a novel palladium-catalyzed reaction of propargylic carbonates with phenols to form cyclic carbonates via the "CO₂ recycling process". In this work, the applicability of the "CO₂ recycling process" to allylic carbonate system was extensively explored. As a result, we have successfully demonstrated that the a variety of allylic carbonates bearing hydroxymethyl or aminomethyl group are amenable to the "CO₂ recycling process" and the corresponding cyclic carbonates or oxazolidinones were obtained, respectively. In these reactions, a palladium–catalyst promotes decarboxylation of allylic carbonates to generate a &pi-allylpalladium complex, which is followed by fixation of the liberated CO₂ and subsequent cyclization to furnish the corresponding cyclic carbonates or oxazolidinones.

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Palladium-catalyzed intramolecular cyanoamidation of 1,1-disubstituted alkenyl cyanoformamides proceed in 68-100% yield to afford oxindoles bearing a quaternary carbon center, which are key intermediates for the synthesis of alkaloids such as physostigmine. Practically, esermethol was synthesized via the reductive cyclization of the product in 22% yield in 6 steps. The reaction was also applied to alkynyl cyanoformamides to give the five- to seven-membered lactams having tetrasubstituted alkenes in high yield. The application of the products to the synthesis of benzoazepine alkaloids are under investigation.

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The oxidative phenol coupling process has been demonstrated to be the useful methodology to construct a spiro-cyclohexadiene moiety which is present in a wide range of natural products. Among the various oxidants, PIDA (phenyliodine diacetate), a representative hypervalent iodine reagent, is undoubtedly cheap, mild and selective oxidant for phenolic substrates. However, the oxidative phenol coupling reaction with enamide by PIDA has been unexplored. Herein, we report an unprecedented oxidative enamide-phenol coupling reaction, which led to an efficient synthesis of two isoquinoline alkaloids, stepharine, a representative proaporphine alkaloid, and annosqualine, a new type spiro-isoquinoline alkaloid.
In the course of the synthetic study of annosqualine, the crucial effect of phenoxide formation by the addition of base was also discussed.

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β-Isocupreidine (β-ICD)-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes and 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) takes place without racemization and exhibits the match-mismatch relationship between the substrate and the catalyst. In the case of acyclic amino aldehydes, L-substrates show excellent syn selectivity and high reactivity in contrast to D-substrates. On the other hand, in the case of cyclic amino aldehydes, D-substrates rather than L-substrates show excellent anti selectivity and high reactivity. A mechanistic proposal governed by hydrogen bonding is presented. The synthetic utility of this methodology is demonstrated by the synthesis of the highly functionalized pyrrolidones.

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Reaction of aryllithiums with tetrachlorosilane gave monoaryltrichlorosilanes, which were treated with other aryllithiums to afford diaryldichlorosilanes. After halogen exchange reaction using cupric fluoride, treatment of the resulting diaryldifluorosilanes with alkynyllithium followed by the similar reaction with other alkynyllithiums furnished the corresponding different kinds of alkynyl-substituted dialkynyldiarylsilanes. Treatment of the different kinds of alkynyl-substituted dialkynyldiarylsilanes with zirconocene-ethylene complex followed by acidification with 3N HCl gave regio- and stereoselectively the corresponding silacyclobutenes in good yields. Desilylation of the silacyclobutenes with tetrabutylammonium fluoride afforded stereoselectively unsymmetrical conjugated (1E,3E)-dienes and -trienes in excellent yields.

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A nickel(0)-catalyzed cyclization of ω-formyl-1,3-dienes using N-heterocyclic carbenes (NHC) as a ligand was investigated. When a substrate having a terminal diene moiety was treated with a catalytic amount of Ni(NHC) complex in the presence of silane, the cyclized product having a terminal olefin in the side chain was obtained, which would be produced via a five-membered nickelacycle intermediate. On the other hand, the reaction of a substrate having a phenyl, a silyl, or a vinyl group on the terminus of the diene moiety gave the cyclized product having an internal Z-olefin in a highly stereoselective manner, respectively, which would be formed via a seven-membered nickelacycle intermediate. These results indicate that the substituent on the 1,3-diene moiety in the substrate strongly would affect the stability of nickelacycle intermediates, which resulted in altering the stereoselectivity of the products.

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Mild Ni(0)-catalyzed transformation a ring opening process of cyclopropyl compounds having an unsaturated bond, such as vinylcyclopropanes (VCPs), has attracted considerable attention. We investigated the reaction of the Ni-catalyzed coupling of alkyne-tethered vinylcyclopropane and allyl chloride. The reaction would undergo a beta-carbon eliminations of cyclopropylcarbinylnickel intermediate, which is caused by the addition of allylnickel species to an alkyne moiety and the subsequent incorporation of the intramolecular VCP moiety, to afford coupling product.
As a result of investigating reaction condition, the reaction of yne-vinylcyclopropane with allyl chloride was carried out in the presence of 10 mol % Ni(cod)₂, 20 mol % PPh₃ and 200 mol % Zn powder in MeCN at room temperature, to give the corresponding product in 55% yield.

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N-Heterocyclic carbenes (NHCs) have attracted an attention as alternatives to phosphine ligands in transition metal-catalyzed reactions and highly active catalyst systems have been realized utilizing them. Recently, we reported that a novel NHC-derived pincer-type nickel(II) complex 1, readily prepared and air- and moisture-stable, could efficiently catalyze the Heck reaction. In order to examine the reactivity of nickel complex 1 in detail, we also investigated the Suzuki and Kumada coupling reactions. As a result, various aryl bromides, chlorides, and fluorides reacted smoothly with phenylboronic acid or Grignard reagents and the coupled products were obtained in high yields. Further studies, involving the expansion of the scope of substrates and the applications of nickel complex 1 toward various coupling reactions, are underway.

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Indenols can be synthesized by aryl, alkenyl, and alkylative cyclization of 2-ethynylbenzaldehydes with organoboronic reagents via palladium(0)-catalyzed 'anti-Wacker'- type oxidation addition. This method is suitable for their combitatorial synthesis due to not only facile preparation of 2-ethynylbenzaldehydes from 2-halobenzaldehydes and terminal alkynes by the Sonogashira reaction but also availability of the boronic reagents. The trans-addition of intramolecur electrophilic carbonyls and boronic reagents to the alkyne is enhanced by aryl and alkenyl substitutions at the terminal alkyne carbon. In comparison with other transition-metal catalyzed preparation of indenols from 2-halobenzaldehydes or 2-formylphenylboronic acids with internal alkynes, our procedure enables to introduce sterically and electronically similar two substituents at 2- and 3- positions in regioselective manner.

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In connection with our project to elucidate trialkyl(2-indolyl)borate as a potential synthetic intermediate, we have previously disclosed that indolylborate is highly effective, though nevertheless an ate complex, in the palladium-catalyzed cross-coupling process. By taking advantage of the attractive features of indolylborate in the cross-coupling reaction, we have interested in whether indolylborate might also be valid as a transfer agent in the palladium-catalyzed tandem cyclization-cross-coupling process, and herein, investigation of the palladium-catalyzed tandem cyclization-cross-coupling reaction using indolylborate as a transfer agent has been carried out. Furthemore, the cross-coupling reaction performed under carbon monoxide led to the generation of indolyl ketones.

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A palladium-catalyzed method for cyclizations of electron-deficient alkenes with tethered unsaturation in the presence of organoboron reagents was developed. Considerable flexibility in the structure of each reactive component was observed. Enals, enones, alkylidene malonates, and nitroalkenes participated as the electron-deficient alkene; alkynes and 1,2-dienes participated as the tethered unsaturation; and a variety of sp2 and sp3-hybridized organoboron reagents, including those that possess beta-hydrogens, participated as the nucleophilic component. Substrate structure, organoboron structure, ligand structure, and reaction solvent all played a significant role in the cyclization efficiency. Of particular synthetic significance was the opportunity to prepare either E or Z tri- or tetrasubstituted alkenes from a common alkyne. A discussion of probable mechanisms is provided.

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Organoantimony compounds [(Ph₃SbX₂), X=Null, Cl, OAc] have been studied as pseudo-halides in Suzuki-type cross-coupling reaction. It has been found that pentavalent triphenylantimony diacetae with arylboronic acid in the presence of Pd(PPh₃)₄ (5 mol%) in 1,4-dioxane resulted in cross-coupling reaction to give biaryl derivative in good yield (98 %) without any base which is usually used to activate boronic acid in Suzuki-Miyaura coupling with organic halides. This coupling reaction has wide generality and can be applied to a variety of boronic acids, including which bearing a base-sensitive functional group. Various triarylantimony diacetates can also react effectively and gave corresponding biaryls in modest to good yields (69~98 %). The results imply that the acetoxy moiety on antimony plays an important role in accelerating transmetallation of boronic acid in the present reaction.

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A recent study from our laboratory has shown that Rh₂(S-TCPTTL)₄, characterized by substitution of chlorine atoms for four hydrogen atoms on the phthalimido group in the parent Rh(II) complex, is well suited for enantioselective C–H amidation reation with [(4-nitrophenyl)sulfonylimino]phenyliodinane. As a logical extension of our study in this area, we addressed the enantioselective amidation of silyl enol ethers catalyzed by chiral Rh(II) carboxylates. The Rh(II)-catalyzed aziridination of acyclic silyl enol ethers with [(2-nitrophenyl)sulfonylimino]phenyliodinane followed by treatment with aq. TFA afforded optically active α-amino ketones. The fluorinated catalyst, Rh₂(S-TFPTTL)₄, proved to be the catalyst of choice for this process, exhibiting the highest enantioselectivity of 95% ee. The effectiveness of the present catalytic method has been demonstrated by the enantioselective synthesis of (–)-metazocine.

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We already reported that the reaction of CF₃I (1) and α,β-unsaturated ketones (2) in the presence of a rhodium catalyst as the development of new synthesis methods of organofluorine compounds. This reaction could selectively introduce a CF₃ group at the α-position of 2, and the application breaks down the difficulty of the synthesis of α-trifluoromethylated ketones (3). The oxidative addition and the reductive elimination to/from a rhodium enolate that generated in situ would concern to the reaction mechanism.
In this time, we would like to report a new reaction to give 1,3-diketones (5) which introduced an acyl group at the α-position of 2 when acid chlorides (4) were applied to this reaction instead of CF₃I.

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p-Allylmolybdenum complex (C₃H₅)Mo(CO)₂(MeCN)₂Br, which was made by reaction of molybdenum hexacarbonyl with allyl bromide in refluxing acetonitrile, catalyzed allyl substitution of allenyl ethers and esters in the presence of stoichiometric amount of propargyl bromide to produce 2-bromo-1,3-butadiene derivatives in good yields. Since the reaction did not undergo in the presence of ally bromide, propargyl bromide might act as mediator for production of an intermediary p-allylmolybdenum complex and as source of nucleophilic bromide anion.

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The treatment of the 2-benzotelluropyrylium salts was with 1,3-diene gave the telluroniaphenanthrene salts, tricyclic Diels-Alder adducts having a tellurium element at the bridgehead in 85 % yield. The tricyclic adducts were similarly synthesized from the pyrylium salts and the corresponding dienes in high yields. This reaction is the first example of the [4+2⁺] polar cycloaddition of Te⁺ = C with 1,3-dienes, while the hetero Diels-Alder reactions of the carbon-tellurium double bond were reported. As expected, the tricyclic adducts reacted with a primary and secondary alcohol, a primary and secondary amine, Me₂CuLi, LiAlH₄ and H₂O to give the 1-but-2-enyl-1H-isotellurochromenes under mild conditions in almost good to high yields, respectively. Contrary to our expectation, the treatment of the adducts with Grignard reagents resulted in a Te-C(8) bond fission, followed by the self-coupling reaction.

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Tetrahydroisoquinoline alkaloids are often selected as synthetic targets due to their various physiological activities and structural properties. In the process, it was thought that the introduction of an electrophilic carbon unit at C-1 position would be of immense use due to its applicability as a reaction site of nucleophiles. Thus, we studied catalytic addition of a carbon unit at C-1 of 6,7-dimethoxy-3,4-dihydroisoquinoline, and Jacobsen's thiourea-containing organocatalyst was found to be efficient for asymmetric Strecker reaction. The reaction was accomplished in high yield and high enantiomeric excess to give a 1-cyanoisoquinoline. The 1-cyanoisoquinoline thus obtained was readily transformed to natural products. Applications of nucleophilic addition of an isoquinolinecarbaldehyde, which was converted from the 1-cyanoisoquinoline, to synthesis of other alkaloids were examined, and (+)-laudanosine was synthesized via Grignard reaction.

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The Pictet-Spengler reaction is one of the most useful methods for synthesizing tetrahydroisoquinoline. This reaction is a kind of Friedel-Crafts reaction. We found that an intramolecular Friedel-Crafts reaction of the iminium cation afforded eight- and nine-membered cyclic amines fused with a benzene ring in high yield. Treatment of sulfonamide derivatives with an aromatic ring possessing one or two methyl groups with TMSOTf gave 1,2,3,4,5,6-hexahydrobenzo[c]azocine derivatives in high yields. Moreover, when sulfonamide derivatives having an acetylene cobalt complex moiety were subjected to the same conditions, not only eight-membered cyclic amine but also nine-membered cyclic amine was obtained in high yield.

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Marine polycyclic ethers have attracted the attention of synthetic organic chemists by the complex structures and potent bioactivities. We now report a useful method for the construction of cyclic ether based on SmI₂-induced reductive cyclization. Reaction of (E)- and (Z)-beta-alkoxyvinyl sulfones having an aldehyde with SmI₂ in the presence of MeOH in THF stereoselectively gave 2,6-syn-5,6-trans- and 2,6-syn-2,3-cis-tetrahydropyrans, respectively, which have a sulfonylmethyl group as the side chain. Transformation of the sulfonylmethyl group to a methyl group was performed by reduction with Raney-Ni in refluxing EtOH. The present method was successfully applied to the synthesis of the KLMN-ring system of gymnocin-A, a marine polycyclic ether.

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We have already reported that Sb-ethynyl- and Sb-aryl-1,5-azastibocines were good transmetallating agents in Pd-catalyzed cross-coupling with organic halides. Although our continuing attempt on Pd-catalyzed alkylation of organic halides with 1 was failed, we unexpectedly found the reduction of nitro function to form azoxyarenes (4). The reduction of various nitroarenes (3) with a stoichiometric amount of 1 proceeded smoothly to afford 4 in high yields, accompanied by Sb-oxide (2). Further studies revealed that 2 was reverted to 1 by use of benzoin (5) which was oxidized to benzil (6) by the Sb-oxide (2). This result made it possible to minimize the use of 1,5-azastibocine (1) to a catalytic amount in the reduction of nitroarenes (3). The catalytic reaction was quite general and detailed mechanism is also presented.

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We recently reported the design and synthesis of 1-methyl-2-azaadamantan-N-oxyl (1-Me-AZADO), which exhibits superb catalytic activity for oxidation of primary and secondary alcohols compared to TEMPO under standard conditions. We are interested in the use of polymer-supported catalyst to expand synthetic applicability of 1-Me-AZADO. Polymer-supported 1-Me-AZADO was synthesized from 1-adamantylamine in 6% yield by employing a 13-step sequence. Following typical protocol using NaOCl as a bulk oxidant, polymer-supported 1-Me-AZADO catalyzed rapid oxidation of various secondly alcohols to give ketones in good yields. The catalytic activity of the polymer-supported 1-Me-AZADO persisted after 5 times recycling.

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Novel polymer incarcerated gold nano-cluster catalysts (PI-Au catalysts) were synthesized by microencapsulation of gold nano-clusters and cross-linking using a co-polymer based on polystyrene. Transmission electron microscopy analysis revealed that this catalyst contained gold clusters whose size was nano order. This catalyst could be used in aerobic oxidation of various alcohols to aldehydes and ketones under atmospheric conditions at room temperature. In the oxidation of sec-phenethyl alcohol at 160 degree, turnover number frequency of the catalyst exceeded 20,000 /h. The oxidation reactions using PI-Au catalysts are excellent in terms of atom economy because only molecular oxygen is consumed and water is generated as the sole co-product.

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Phenyl sulfides are often used as precursors of alkenes. Alkenes are generally prepared from phenyl sulfides by pyrolysis of the corresponding sulfoxides at high temperature (100-150^oC). It is expected that the synthetic utility of the elimination would be enhanced if the elimination proceeded under milder conditions such as room temperature.
We have been developing new synthetic methodologies utilizing characteristic reactivity in a sulfur-nitrogen bond. We found that alkenes were prepared from phenyl sulfides in a one-pot manner at room temperature by treating phenyl sulfides with O-mesitylenesulfonylhydroxylamine(MSH) and potassium carbonate. Alkenes were formed stereoselectively by cis-elimination of in situ generated phenyl sulfilimines.

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Phenanthroindolizidine skeleton bearing angular methyl group 5 was constructed by treatment of bromo alkene 3 with Bu₃SnH in the presence of ACN (azobiscyclohexanecarbonitrile) in boiling toluene. This process involved continuous 6-endo-trig cyclization of aryl radical and 5-endo-trig cyclization of the resulting &alpha-amidoyl radical. Compound 7 which was reported as hypoestestatin 1 was obtained by reduction of 5 with lithium aluminum hydride. However, spectral data of 7 were not in accord with those of hypoestestatin 1. Then, we assumed that the real structure of hypoestestatin 1 was 8, and we synthesized 8 by the radical cascade reaction of 4 giving 6, followed by reduction of 6. Unfortunately, spectral data of compound 8 were not again in accord with those reported for hypoestestatin 1.

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Our laboratory is interested in developing the effective cascade reactions based on radical chemistry. Recently, we have reported the stereocontrol strategy that takes advantage of the hydroxamates. The control of the rotamer population would be crucial for achieving high enantioselectivity in radical cyclization. In cascade radical cyclization, hydroxamate acted as a coordination site with Lewis acid, and a high degree of stereocontrol was achieved probably due to the predominant formation of single reactive rotamer. In the case of substrate having acrylate moiety, the reaction with an isopropyl radical proceeded smoothly in the presence of box ligand and zinc Lewis acid to give the cyclic product with 92% ee. Excellent enantioselectivities were also observed in the reaction of other substrates.

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We found that thiols can be oxidized into disulfides by 1.0 eq. of 30% hydrogen peroxide in the presence of 1 mol% iodide ion in ethyl acetate at room temperature. This method gives the desired products in high yields with short reaction times (0.5 h) without producing any undesirable wastes. The reaction of sulfides with 20 eq. of 30% aqueous hydrogen peroxide in acetonitrile in the presence of 0.1 eq. of tantalum(V) chloride selectively provides the corresponding sulfoxides in high yields. On the other hand, the reaction of sulfides with 20 eq. of 30% aqueous hydrogen peroxide in methanol in the presence of 0.1 eq. of tantalum(V) chloride provides the corresponding sulfones in high yields.

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We previously reported that benzanilide exists in trans form, whereas N-methylbenzanilide exists in cis form, in the crystal and in various solvents. In this study, we found that N-hydroxylated benzanilide, that is, N-phenylbenzohydroxamic acid, showed solvent-dependent conformational alteration. Thus, the compound exists predominantly in cis form in methylene chloride, whereas the trans conformer was major in acetone. Two unique crystal structures of N-phenylbenzohydroxamic acid were obtained depending on the recrystallization solvents, and each crystal corresponded in structure to the major conformer in the solvent. These two crystals were distinguished by IR spectroscopy and DSC analysis. The results could be applied to design and development of solvent- or external-stimuli-responsive molecular machines.

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Benzocyclobutenes, having a beta-silicon atom on the cyclobutene ring, were prepared and subjected to thermal electrocyclic ring-opening reaction in the presence of maleic anhydride. Various reaction conditions (temperature and time) were applied for the reaction and the yields of addition products were compared with those of corresponding alkylated benzocyclobutenes. These examinations revealed that the beta-silicon atom significantly accelerated formation of o-quinodimethane intermediates, which could be reasonably explained by sigma-donating effect of the C-Si bond toward LUMO of the cloven C-C bond in the transition state. Much more strongly electron-donating group, oxy-anion, can enforce the ring fission at lower temperature. Utilizing these advantages, a novel successive 4pi-8pi electrocyclic reaction involving diazo group was developed to produce 2,3-benzodiazepines under extremely mild reaction conditions.

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We have previously reported that a new intermolecular [3+2+2]cycloaddition reaction of ethyl cyclopropylideneacetate with alkynes proceeded in the presence of a Ni(0)/PPh₃ catalyst, and cycloheptadiene derivatives were obtained. However, in the reaction of 1-cyclopropylidene-2-propanone with alkynes, a cycloheptatriene derivative was obtained instead of the cycloheptadiene derivative. It was anticipated that the isomerization of the cycloheptadiene derivative led to the formation of the cycloheptatriene derivative. In this study, we examined the isomerization of cycloheptadiene derivatives under acidic, basic and thermal conditions, and the progress of the isomerization was observed.

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Hajos-Parrish-Eder-Sauer-Wiechert reaction has been well-kwown as a successful intramolecular asymmetric aldol reaction mediated by an amino acid to synthesize Wieland-Miescher ketone derivatives. However, there have been few reports to apply this reaction to construct a medium ring in an enantioselective fashion. We report here a detailed study to assess the enantioselectivity of the amino acid-mediated intramolecular asymmetric aldol reaction of a 1,3-cycloheptanedione derivative to construct a new chiral building block. The cyclizations were mediated by a series of L-amino acids in the presence of an acid co-catalyst. Strikingly, the process was characterized by an inversion of enantioselectivity when compared to a similar reaction involving the 1,3-cyclohexanedione counterpart.

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Stereoselective C-C bond-forming reaction assembling quaternary carbon centers are of particular importance for synthesis of bioactive compounds. The challenge is exacerbated further when all-carbon quaternary stereocenters are adjacent. For construction of complex indole alkaloids, we now report that the efficient domino reactions (olefination, isomerization and high diastereoselective Claisen rearrangement) of (Z)- and (E)-2-(3',3'-disubstituted allyloxy)indolin-3-ones proceeded under mild conditions (-78ºC to rt) via preferential boat transition state to give (3R^*,3'R^*)- and (3R^*,3'S^*)-3-cyanomethyl-3-allylindolin-2-ones containing adjacent all-carbon quaternary stereocenters in high yields, respectively.

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We have recently reported the catalytic asymmetric allylation of a cyclic imine by allyltrimethoxysilane and catalytic amounts of (S)-tol-binap and CuCl. The reaction was examined to improve the yield and selectivity using a 3,4-dihydroisoquinoline as a substrate. A chiral 1-allyl derivative was obtained in 97% yield and 82%ee by use of 9 mol% DTBM-SEGPHOS and 6 mol% CuF2. The adduct thus obtained was applied to the total synthesis of schulzeine A. Schulzeine A is an alfa-glucosidase inhibitor, and consists of two fragments of an isoquinoline nucleus and C28 fatty acid. The allyl adduct was oxidized to an aldehyde, which was further transformed to an alkene by HWE reaction. The alkene was reduced using the H2-Rh-MONOPHOS catalyst to give correct stereocenters of the isoquinoline moiety.

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We have reported the Darzens reaction via ammonium ylides to afford 2,3-diaryl epoxides in trans selective manner when electron deficient p-substituted benzylammonium chlorides were used. With the aim of advancing useful methodology based on the new ammonium mediated Darzens reaction, we report the first example of trans selective asymmetric Darzens reaction via chira ammonium ylides to afford enantiomerically enriched 2, 3-diaryl epoxides. The reaction was carried out using amines shown in Chart 1. (Chart 1) The reaction via brucine-p-trifluoromethylbenzyl ammonium ylide afford the corresponding 2, 3-diaryl epoxide in high (98%) yield with moderate diastereo selectivity (17 / 83), and ee (65 %). Enantio and diastereo selectivity were both improved when the reaction were carried out at -20 and -40 degree. (Scheme 1) Next attention was focused on the reaction of a series of substituted benzaldehyde and chiral ammonium ylides. (Scheme 2)

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We developed novel chiral ligands based on concept of conformation control.
At first, we developed an N-heterocyclic carbene ligand 1. The substituent R on the N atom in the carbene ligand 1 may be conformationally flexible, but if the complexation of 1 and metal is reflected by the asymmetric center in 1, a more stable complex 2a, in which orientation of the substituent R on the N atom is fixed, is expected to be selectively formed (figure 1).
Next, we developed a hemilabile P-P=O ligand 3 with both soft and hard coordinated center within one molecule. Figure 2 shows the possible design of 3 such that the soft Ar₂P group coordinates with a soft metal and the hard Ar₂P=O group coordinates with a hard metal. These two coordinations allow a fixed conformation of the complex between the hemilabile ligand 3 and metals (soft and hard), leading to the creation of a favorable asymmetric environment.

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Tubelactomicins are tricyclic macrolide antibiotics, isolated from the culture broth of Nocardia sp., consisting of an octahydronaphthalene substructure with six contiguous stereogenic centers, and a 16-memberd lactone. We have explored the total synthesis of tubelactomicins by utilizing a biosynthesis-based transannular Diels-Alder (TADA) reaction as a key step.
The substrate for the macrocyclization reaction was synthesized by a multi-step sequence, including Horner-Wadsworth-Emmons reaction. The intramolecular Sonogashira coupling of this substrate proceeded at room temprature to give two TADA adducts, which might be produced after the Sonogashira reaction proceeded. Furthermore, this TADA reaction provided each an endo- and an exo-cycloadduct with excellent π-facial selectivity.

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Recently, we have synthesized (+)-hamacanthin A and B, and (–)-antipode of cis-dihydrohamacanthin B (1) from azide (S,R)-2 via (S)-indolylgrycinol 3. Now, we report the first asymmetric total synthesis of natural cis-(+)-dihydrohamacanthin B (1) via (R)-3. The reduction of (R,R)-4 with Cy₃P-H₂O followed by treatment with (Boc)₂O produced (R,R)-5 in moderate yield. But several attempts to effect reductive elimination of the oxazolidinone moiety of (R,R)-5 to (R)-3 were unsuccessful. On the other hand, azide (R,S)-2 was smoothly reduced followed by protected with Boc₂O to give (R,S)-6 in good yield. The reductive removal of the oxazolidinone moiety (R,S)-6 afforded (R)- 3 in good yield.

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Xestenone and secoxestenone, isolated from the northeastern Pacific sponge Xestospongia vanilla by Andersen et al., are norditerpenoids. Proposed structures for these compounds are based on spectroscopic analysis and chemical conversion. Secoxestenone is presumed to be a biogenetic precursor of xestenone. The authors reported one-pot synthesis of cycloalkane derivatives using allyl phenyl sulfone and epoxymesylate. This one-pot synthesis was applied to the construction of cyclopentane moiety of secoxestenone and xestenone. The total synthesis of xestenone and secoxestenone is now being carried out by coupling reaction cyclopentane moiety and side chain segment.

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(+)-Conagenin (1) was isolated from the fermentation broths of Streptomyces roseosporus, by Ishizuka and co-workers in 1991. It is a low molecular weight immunomodulator and stimulates activated T cells. We report here the setereoselective synthesis of (+)-1 and its analogues. Amine moiety of 1 was prepared from commercially available optically active methyl (R)-3-hydroxy-2-methylpropanoate [(R)-2] in 4 steps using dirhodium(II)-catalyzed C-H amination as a key step. On the other hand, carboxylic acid moiety was synthesized from (S)-2 by means of stepwise stereoselective chelation-controlled reductions using Zn(BH₄)₂ as key steps. Finally, amide formation of thus prepared subunits followed by deprotection was achieved to afford (+)-conagenin. And demethyl analogues of conagenin were synthesized by the similar procedures.

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Candelalides A-C (1-3), isolated from the culture broth of Sesquicillium candelabrum by the Merck research group in 2001, are novel blockers of the Kv1.3 and are promising candidates for the treatment of T-cell mediated autoimmune diseases such as rheumatoid arthritis and insulin-dependent diabetes. We wish to present the first total synthesis of candelalides A (1) and C (3) and the synthetic efforts towards candelalide B (2). The key steps of the syntheses are (i) stereocontrolled [2,3]-Wittig rearrangement of the stannylmethyl ether 4 (4~5), (ii) coupling reaction of the trans-decalin aldehyde 6 with the 3-lithio-γ-pyrone 7 and subsequent deoxygenation (6+7~8), and (iii) efficient construction of the functionalized pyran ring (A ring) (8~1 or 3). Further investigation towards the total synthesis of candelalide B (2) is now progress.

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A reliable and efficient procedure for constructing five- to eight-membered oxacycles has been developed. Treatment of allenes possessing sulfonyl group and a suitable hydroxyalkyl side chain at the C₁-position with potassium tert-butoxide in tert-butanol effected an endo mode ring-closing reaction at the sp-hybridized carbon center of allenyl moiety. On the basis of this developed endo mode ring-closing reaction, synthesis of 1,8-disubstituted oxocane and its highly oxygenated derivative were accomplished. Studies on the total synthesis of laurencin and related natural products isolated from red algae are now in progress.

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Dictyomedins were isolated from Dictyostelium by Oshima et al. Not only some attractive biological activities but also the structural uniqueness as novel dibenzofuran structure have been found and more attractive ones are under investigation. We recently reported an organic super-base catalyzed substitution of fluorobenzenes with silylaryl ethers, which provide diary ethers, excellent precursors for dibenzofuran synthesis. Here, we investigated direct coupling of fluorobenzenes and non-protected phenols using silylating reagents as additives. After various optimizations, TMSNEt₂ was found to be effective for this S_NAr reaction and various phenols reacted with various fluorobenzenes with a variety of EWG. We applied this reaction to the syntheses of Dictyomedins and the desired halodiaryl ether was successfully synthesized. Then, Suzuki coupling of the precursor followed by Pd catalyzed cyclization accomplished the first synthesis of Dictyomedin A.

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We have reported the first total synthesis of manzamine alkaloids, nakadomarin A, by two different synthetic strategies. Recently the total synthesis of rac-manzamine A have been achieved by using the same spirolactam intermediate in the total synthesis of ent-nakadomarin A. For the synthesis of natural manzamine A and nakadomarin A in a large quantity, an establishment of the practical synthetic route for the key intermediate in an optically active form is required. The quaternary stereogenic center was constructed with 81% ee by Pd-catalyzed asymmetric allylation of methyl 4-hydroxy-1-(phenylsulfonyl)-1,2,5,6-tetrahydro-3-piridinecarboxylate. Intramolecular Michael reaction of the B-TIPS-oxy substrate proceeded with high diastereoselectivity (>20:1) to give the desired isomer. This improved route required only single column chromatography and would be applied for large scale synthesis of chiral manzamine alkaloids.

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Cyclopentyl methyl ether (CPME) has become available in a commercial quantity since Nov. 2005 from Zeon Corporation. High boiling point as well as preferable characters (low formation of peroxides, relative stability under acidic or basic conditions, formation of azeotropes with water, a low affinity for water and small evaporation energy compared to other ethers coupled with narrow explosion range) make CPME as an affordable and alternative solvent with future prosperity. It is useful for general organometallic reactions including Grignard reactions, enolate formation, Claisen condensation, reductions and Pd-based transformations such as Buchwald-Hartwig amination. Consequently, it is safe to conclude that CPME is emerging as a potential alternative for THF, dioxane and DME. Due to these unique properties and applications, CPME possesses particular advantages and renders some conventional reaction sequences in one pot or easier process as a result of solvent unification.

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N-Heterocyclic carbenes (NHCs) prepared from imidazolium salts and bases have strong σ-donating properties, so we expected that the carbon-silicon bond in trimethylsilylcyanide (TMSCN) would be activated by a nucleophilic NHC as a Lewis base catalyst, which would promote cyanation reaction. Cyanosilylation reactions of not only aldehydes and aldimines but also ketones and ketimines with TMSCN in the presence of NHC were performed (Scheme 1). This provides a new synthetic strategy for the construction of tri- and tetra-substituted carbon by organocatalyst under the mild condtions. Hemilabile-type ligands display peculiar catalytic behavior which is different from C₂symmetrically homofunctional bidentate ligands due to the presence of two donors of diverse donating properties. Asymmetric allylic substitution reactions (Scheme 2) by several hemilabile ferrocene type ligands gave the corresponding products in up to 99% yield, 90%ee at rt in a short time.

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We prepared fluorous-FMOC (f-FMOC) reagents bearing C4F9 and C6F13 tag, for peptide synthesis with Fluorous Mixture Synthesis (FMS). The protection of amino acid, and the condensation reaction proceeded in good yields in a similar manner as regular FMOC reagent. The resulting f-FMOC dipeptides were separated from the non-fluorous by-products effectively utilizing Fluorous Solid Phase Extraction (FSPE). In addition, we conducted fluorous-HPLC analysis of the various f-FMOC-dipeptides bearing different fluorous tag. As the result, the remarkable difference was observed among these fluorous dipeptides. The resulting remarkable differences in the retention times of the dipeptides with different fluorous tags indicate that using f-FMOC as a tagging strategy in FMS of polypeptides is a viable strategy.

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Temporal and spatial control of function of peptides and proteins by external stimuli has been receiving increasing attention due to its potential utility in a wide variety of field such as chemical biology and drug delivery. We designed the external stimulus responsive model peptide which can release a functional peptide after external stimulus-induced removal of a phenolic protective group, followed by self-processing reaction. In the present study, we choose a photo-removable o-nitrobenyzl group for the protection of the phenolic hydroxyl group to afford the photo-responsive model peptide. Details of synthesis and photo-responsiveness of photo-responsive model peptides will be discussed.

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We designed chiral cyclic alpha,alpha-disubstituted alpha-amino acids; (1S,3S) and (1R,3S)-1-amino-3-methoxycyclopentanecarboxylic acids {(1S,3S) and (1R,3S)-Ac(5)c(OM)}, which have two different chiral centers at the side-chain cyclopentane ring and on the peptide backbone alpha-carbon. The diastereomeric amino acids (1S,3S)-Ac(5)c(OM) and (1R,3S)-Ac(5)c(OM) were synthesized starting from L-(-)-malic acid. That is to say, the malic acid was converted to a diiodide by esterification, methylation of alcohol, reduction of ester, and substitution with iodide. Then, bisalkylation of dimethyl malonate with the diiodide gave a cyclic diester. Monohydrolysis of diester, and subsequent Curtius rearrangement afforded a separable mixture of (1S,3S)-Ac(5)c(OM) and (1R,3S)-Ac(5)c(OM). The preferred conformation of diastereomeric homopeptides composed of (1S,3S)-Ac(5)c(OM) and (1R,3S)-Ac(5)c(OM) was studied by using X-ray crystallographic analysis, 1H NMR, IR, and CD spectra, respectively.

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Photolysis of a dansylamide moiety of N-dansylcyclen (L5) in the presence of zinc(II) ion in aqueous solution is reported (cyclen = 1,4,7,10-tetraazzacyclododecane). By potentiometric pH titrations, the complexation constant for the 1:1 complex of L5 and zinc(II), log K_s(ZnL5), in aqueous solution at 25 ^oC with I = 0.1 (NaNO3) was determined to be 6.5 +0.1. Upon complexation with zinc(II) at pH 7.4, fluorescent emission of L5 at 555 nm decreased (excitation at 308 nm). However, we accidentally found the considerable enhancement in fluorescence emission of ZnL5 upon UV irradiation, while UV and emission spectra of the metal-free L5 exhibited negligible change upon photoirradiation. We have revealed that photoinduced hydrolysis (by UV irradiation at 338 nm) of a sulfonylamide bond of ZnL5 promoted by Zn²⁺-bound HO^- in the excited states afforded Zn²⁺-cyclen and dansyl acid, whose emission is stronger than that of ZnL5.

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We have developed new fluorescent amino acids which were easily synthesized by condensation of the fluorescent molecule and protected amino acids, which were ornithine and serine. Fluorescent molecule was prepared from oxalacetic acid diethyl ester and N,N-dimethylphenylenediamine by 3 steps. Protected amino acids were prepared by 2 and 5 steps from commercially available ornithine and serine derivatives, respectively. With the increase of solvent polarity, the emission spectra of both fluorescent amino acids clearly shifted from 430 nm to 500 nm. Both of Fmoc-protected fluorescent amino acids could be converted to fluorescent peptides by solid-phase synthesis.

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