Many naturally occurring derivatives of monodehydro-2,5-Diketopiperazine (monodehydroDKP) possessing varied biological activity have been discovered. To develop a new synthetic method of these products, we focused on Gladiali et al.'s report that the reaction of a-ketoester and Boc-NH2 in the presence of a catalytic amount of p-TsOH, resulted in the formation of dehydroamino acid. It was thought that, if this reaction were applied to an intramolecular reaction, monodehydroDKPs would be formed with no racemization. According to this idea, a series of a-ketoacyl-Phe-NH2 was refluxed in toluene in the presence of acid catalysts resulted in the formation of corresponding monodehydroDKPs in high chemical yields with no racemization in case of b-aliphatic-a-keto acyl derivatives, while N-phenylpyruvoyl derivative showed low reactivity. This new method could be useful for the synthesis of natural monodehydroDKPs.

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A method for the construction of 1,2-cis-&alpha-glycosidic linkage has been developed. We found that a commercially available 0.1 M solution of HClO₄ in dioxane can be employed for the activation of glycosyl diphenyl phosphates in the presence of a wide variety of acceptor alcohols in dioxane/Et₂O (1:1) to give glycosides in high yields with high &alpha-selectivities. Alcohols bearing acid-sensitive acetal or epoxy groups were safety glycosylated under these conditions. This is the first example of direct catalytic glycosidation of glycosyl phosphates with alcohols. The synthetic utility of this glycosidation method was demonstrated by a stereoselective synthesis of the &alpha-galactosylceramide KRN7000, an activator of natural killer T cells through CD1d molecules.

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During the course of our studies on the developments of new methods for the synthesis of heterocyclic compounds, we have already reported for a new synthetic method of pyrroles from homopropargyl azide derivatives utilizing a catalytic amount of PtCl₄ in ethanol.
To apply this reaction to the synthesis of the other heterocycles, 2-phenylethynylcyclohexanol was selected as substrates. As a result, regioselectively hydrated compound, 2-(2-hydroxycyclohexyl)-1-phenylethanone, was obtained as a sole product in good yield. Presumably, it was produced through the Pt-catalyzed cyclization reaction followed by hydrolysis.
The reactions of the 7-phenyl-4-heptyn-1-ol or its acetate under the same condition gave the mixtures of the regioisomers. However, the reaction of the corresponding tosylamide derivatives afforded 4-methyl-N-(4-oxo-7-phenylheptyl)benzenesulfonamide, which would be formed via 5-exo-dig cyclization with high regioselectivity.

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Treatment of magnesium alkylidene carbenoids, which were generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagnesium chloride at low temperture in toluene or THF, with 2-lithio thiophenes and 2-lithio furans gave 2-alkenylated thiophenes and furans in good to high yields. When 2-lithio-5-methoxy furan was used as a nucleophile, allene was obtained with opening the furan ring. The intermediate of this reaction was found to be an alkenylmagnesium, which could be trapped with iodoalkanes and ethyl chloroformate. This procedure offers a novel and efficient one-pot synthesis of thiophenes and furans having a disubstituted or a trisubstituted olefin at the 2-position from thiophenes and furans in good yields.

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The regioselective tandem 5-exo-mode intramolecular ring closure reaction of dibenzylthiol (1a) and selenol (1b) into a triple bond gave the trans-biisobenzothiophene (2a) and selenophene (2b) as sole the product in good yields. In contrast, similar cyclization of dibenzyltellurol (1c) proceeded in both tandem 5-exo and 6-endo-mode to afford the trans-biisobenzotellurophene (1c) and ditellurachrysene (3).

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An efficient one-pot procedure which converts 5,15-disubstituted porphyrins into their corresponding meso acyl-, alkoxycarbonyl-, and carbamoyl-substituted meso-formylporphyrins has been developed. The procedure involves a sequential S_NAr reaction of porphyrins with PyMe₂SiCH₂Li, whose PyMe₂SiCH₂ group works as a formyl surrogate, followed by acylation or related reactions and oxidation. The method is compatible with the synthesis of a variety of 5,15-disubstituted free-base porphyrins, and affords the desired asymmetric free bases with two different carbonyl groups in good yields.

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Phase-transfer catalytic reactions have attracted much attention because of its simple operation, mild reaction conditions, and environmentally benign nature. We have recently reported a catalytic asymmetric alkylation of cyanoacetates using a chiral phase-transfer catalyst (CPTC), the catalyst is expensive and many steps are required for its synthesis. In the present study, chiral pyrrolidinium salts having substituents at the alpha, alpha-prime positions were synthesized to develop a new CPTC which have more simplified structures. The enantioselectivity of these synthesized catalysts was evaluated using asymmetric benzylation of N-(diphenylmethylene)glycine t-butyl ester, and alpha, alpha-prime disubstituded pyrrolidinium salts, which have a beta-hydroxyl group at a chiral center, were found to have moderate enantioselectivity.

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Biginelli-type condensation reaction, which is one of the multicomponent reactions, is a very useful reaction for preparing 3,4-dihydropyrimidin-2(1H)-ones (DHPMs). Traditionally, Biginelli reactions were carried out under strongly acidic conditions with heating, and the yields were only low to moderate. Recently, several DHPMs have been revealed to have interesting pharmaceutical properties. Thus, in the past ten years, Biginelli reactions have attracted much attention, and many improved methods have been exploited. Recently, secondary amine-based organocatalysts that promote the reactions via enamine formation have been extensively studied; however, for Biginelli reactions, only a few examples using (S)-proline or chiral secondary amines as organocatalysts have been reported. Here we report that pyrazolidine dihydrochloride is a more effective organocatalyst than the widely used modified pyrolidine derivatives for Biginelli reactions.

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Abstract:We have already discovered that tertiary amines were oxidized with OsO₄ to afford amideketones and amidealcohols. In the course of the investigation, we attempted asymmetric dihydroxylation of stilbene with OsO₄in the presence of naltrexone derivative. Contrary to our expectations, diketone 2 was obtained as a main product. To the best of our knowledge, direct conversion of olefins into diketones with OsO₄ is reported only as the side reaction of dihydroxylation of olefines.
Next, we examined the oxidation in the presence of various base. Although naltrexone derivatives were effective to the conversion of stilbene into diketone 2, the other examined bases were ineffective. Surprisingly, when there is no amine base (only the K₂CO₃ exited as a base), diketone 2 was obtained as a main product.
Here, we present the novel oxidative reaction of olefins into 1, 2-diketones in detail.

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In general, cyclopropane ring is rather stable to reductive cleavage reaction and ring opening reaction of the cyclopropane ring, which has no conjugated substituent and is not activated, requires harsh reaction conditions such as high temperature and/or high pressure.
We have already reported that naltrexone derivatives, which had nonactivated cyclopropylmethyl group as the N-substituent, were converted to N-isobutyl derivatives under mild reaction conditions (H₂(1atm), PtO₂(cat), HBr/MeOH, rt).
Under the same reaction conditions, reductive cleavage reaction of N-cyclopropylalkyl piperidine derivatives also proceeded. But N-cyclobutylmethyl derivative did not react at all.
Here, we present the scope of the reductive cleavage reaction of cyclopropane ring with PtO₂ and the mechanism of the reaction.

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Artificial enzymes have been developed focusing on the area of supramolecular chemistry and organic synthesis. We have already developed artificial acyl transferases using a combination of a tertiary amine catalyst and 2-chloro-4,6-dimethoxy-1,3,5-triazine. The enzynmes catalyze dehydrocondesation in a substrate-selective manner based on hydrogen bonding or hydrophobic effect. We herein focused on π-π interactions which could work as an attractive molecular recognition in a polar solvent like water and methanol. Among them, dialkoxynaphthalene (DAN) and naphthalenediimide (NDI), the pair of which was known to form an aromatic electron donor/acceptor complex, was introduced as a molecular recognizing site to the tertiary amine catalyst and a carboxylic acid, respectively. Competitive reactions between carboxylic acids showed that the DAN attached catalyst selectively catalyzed the amidation of the carboxylic acid possessing NDI.

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Development of chemoselective transformations is one of the most important tasks in synthetic chemistry because of chemoselective reaction requires no protection-deprotection processes during synthetic processes. The acylation of alcohols in the presence of amines is difficult task due to higher nucleophilicity of amines. We tackled to this task with well-designed multi metallic catalyst. As a result, we succeeded in developing a highly chemoselective acylation of hydroxyl groups of aminoalcohols catalyzed tetranuclear zinc cluster. This methodology is useful as an environmentally-friendly acylation, and it provides a useful tool for modern organic synthesis, as a protecting-group free reaction.

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3,3-Dimethoxypropylsulfonyl chloride (Dimps chloride) were synthesized and used as a new versatile sulfonating agent for amines and alcohols. 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)trimethylphosphorane (CMMP). The sulfonyl group was very stable under basic and reductive conditions and removed by heating in a hot aqueous solution of trifluoroacetic acid. Primary and secondary alcohols were also sulfonated very easily. The resulting sulfonate could be used as alkylating agents. Furthermore, the sulfonyl group was removed by acidic treatment at 0 C followed by the retro-Michael reaction induced by K2CO3.

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Addition reaction of "hydroxymethyl" equivalent to imine was developed by using acyloxymethyl radical as the equivalent. The reaction of iodomethyl pivalate with benzaldehyde N-tosylimine under portionwise addition of dimethylzinc over 10 h in dichloromethane at room temperature for 21 h gave a pivaloyloxymethylated tosylamide in 66% yield. The use of triethylborane, in place of dimethylzinc, dramatically improved the yield of the adduct to 96%. The pivaloyloxymethylated tosylamide was readily hydrolyzed with potassium hydroxide in aq methanol at room temperature to give hydroxymethylated tosylamide in 95% yield.

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Bromination of 1-substituted indole-2,3-dicarboxylate derivatives was investigated. Treatment of dimethyl 1-substituted indole-2,3-dicarboxylate with N-bromosuccinimide or bromine in the presence of Lewis acid gave dimethyl 5-bromoindole-2,3-dicarboxylate, dimethyl 6-bromoindole-2,3-dicarboxylate, and dimethyl 5,6-dibromoindole-2,3-dicarboxylate. The selectivity of the each product was controlled by the combination of the reagent and the substituent on indole ring. On the other hand, treatment of 1-substituted indole-2,3-dicarboxylic acid with oxone and LiBr afforded 3-bromoindole-2-carboxylic acid, 2,3-dibromoindole, and 3,3-dibromoindoline-2-one.

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Oxidation is a most important transformation in organic synthesis; however, these reactions essentially involve the use of large quantities of heavy metals and complex organic compounds, which generate large amount of waste, and are not at all environmentally benign. Molecular oxygen has received much attention as an ultimate oxidant, since it is photosynthesized by plants, produces little waste, is inexpensive and of large atom efficiency than that of other oxidants. With this background in mind, we examined a new oxidation method with the catalysis of a halogen source and molecular oxygen, and, in the course of our study of photo-oxidation, we have found that alkylbenzenes effectively produced phenacyl bromides by one step with molecular oxygen as terminal oxidant in the presence of HBr under VIS irradiation.

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Cross-coupling reactions are the established avenue for organic syntheses. Enol triflates are generally used, however, they are instable and high cost. The alternation for enol tosylates is considered to be one of the significant goals.
We have developed a general, robust, and cost-effective method for the (E) - or (Z) - stereocomplementary enol tosylation of b-keto esters using TsCl - N-methylimidazole (NMI) - base. b-Keto esters underwent (E)-selective tosylation using Et₃N, whereas (Z)-selective tosylation using LiOH as base (total 23 examples; 60-99% yield).
Stereocomplementary cross-couplings with enol tosylates proceeded smoothly to give the corresponding trisubstituted a,b-unsaturated esters with nearly complete stereoretention. As an extension of the aforementioned method, we are trying to develop an alternative route for the synthesis of anti-MRSA active 2-aryl-1-b-methyl carbapenems utilizing enol tosylates.

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The asymmetric direct aldol reaction is one of the most efficient methods for constructing asymmetric carbon centers during the carbon-carbon bond formation.
We have developed the direct asymmetric aldol reaction between ketones and aldehydes or between two aldehydes using a chiral phosphine oxide, BINAPO as a Lewis base catalyst. The silicon tetrachloride-mediated aldol reactions of cyclic ketones and conjugate aldehydes in propionitrile were catalyzed by BINAPO to afford the corresponding anti-aldol adducts with good enantioselectivity and high diastereoselectivity.
Then, we applied this method to the reactions between two aldeydes, which generally suffer from side reactions such as a self-condensation. The reaction of isobutyraldehyde and aromatic aldehyde afforded the aldol adduct in high yield with good enantioselectivity. No self-condensation adduct was observed. This method provides a new type of asymmetric direct aldol reactions using chiral Lewis bases

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Palladium-catalyzed hydrogenation and halogen-metal exchange reaction are well known and as the dehalogenation (reduction) of haloheteroaromatics. However, because there are the problems that these reactions are lacked in safety, simpleness, and easiness. Thus, development of simple and easy reduction is expected. When 7-chloro-4-iodoquinoline (1) and triphenylphosphine were heated at 110 °C for 1 h, heteroaryltriphenylphosphonium halide (2) was obtained in 85 % yield. Next, reaction of 2 with ethanol and triethylamine was heated under reflux for 1 h to give 7-chloroquinoline (3) in 87 % yield. In addition, when I performed a one-pot reaction without isolating 2, the dehalogenated product 3 was obtained in 90% yield. The one-pot reaction provided with simpleness and easiness of the operation.

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Highly chemoselective deprotection of acetal-type protecting groups of hydroxyl functions has been studied in detail. Treatment of alcohol derivatives protected by acetal-type protecting groups, THP-ethers, THF-ethers, and Methoxyethyl-ethers, with TESOTf-2,4,6-collidine followed by H₂O-treatment gave the corresponding hydroxyl compounds in good to exellent yields. The reaction proceeded via selectively formed cationic collidinium salt intermediates. The characteristic features of the method were very mild and chemoselective, so acid-labile functional groups such as Tr-ethers and TBS-ethers could co-exist in the molecule. TESOTf-other aromatic amine conditions could be applied to the deprotection of methylene acetals and acetonides which are acetal-type protecting groups of diols, whereas TESOTf-2,4,6-collidine conditions did not work well for these protecting groups.

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Since 1983, we have developed a wide range of Hg(OTf)2-catalyzed reactions. When the cycloisomerization of 2-(4-pentynyl)furan was examined, we found out that Hg(OAc)(OTf) prepared from mixing Hg(OAc)2 and Sc(OTf)3 showed highly efficient catalytic activity for cycloisomerization. This result suggested that a single -OTf was enough for the catalytic cycle. Thrilled by such finding, we successfully designed PhHgOTf as an efficient catalyst for cyclization. However, an organic mercury compound such as MeHgCl and Me2Hg is a deadly poison, therefore the development of reusable and recoverable catalyst is a challenging subject to stop the mercury contamination. Now we prepared solid supported mercury catalyst, which could be reused over 20 times in flow reaction system.

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Axially chiral biaryl compounds are classified as important building blocks present in various biologically active natural products. They have also been employed as effective chiral ligands for various enantioselective syntheses. The atropo-enantioselective borohydride reduction with dynamic kinetic resolution of biaryl lactones was catalyzed by the optically active b-ketoiminatocobalt(II) complex to afford the optically active biaryl compounds. The HPLC analysis of the starting biaryl lactones was carried out at various temperatures to determine the suitable reaction conditions for the dynamic kinetic resolution. Various types of axially chiral biaryl compounds were obtained with a high enantioselectivity. The absolute configuration of the axially chiral biaryl product corresponding to the (S,S)-cobalt(II) complex catalyst was revealed to be M by measuring its CD spectrum.

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Recently, we have demonstrated that a novel N-heterocyclic carbene (NHC)-derived pincer-type nickel(II) complex, which is readily prepared and is stable to air and moisture, serves as an effective catalyst in the Heck reaction, Suzuki-Miyaura coupling reaction, and Kumada-Tamao-Corriu coupling reaction. To further evaluate the catalytic activities of the nickel-pincer complexes having different stereo- and electrochemical properties, we synthesized various nickel(II) complexes and investigated their application to the Suzuki-Miyaura coupling reaction. As a result, it was found that a range of aryl bromides, chlorides, tosylates, and mesylates were smoothly coupled with both aryl- and alkenylboronic acids in the presence of a catalytic amount of the nickel-pincer complexes. Further studies to evaluate the catalytic activities of the nickel-pincer complexes in various coupling processes are underway.

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Ethyl glyoxylate O-tert-butyldimethylsilyloxime (1), on treatment with 2.2 equiv. of BF₃•OEt₂, generated N-boranonitrone A, which underwent intermolecular cycloaddition with alkenes 2 to afford isoxazolidines 3 in moderate to high yields. The cycloaddition of N-boranonitrone A with most of the alkenes gave 3,5-trans isoxazolidines 3 as the major isomers. This is the first example of intermolecular cycloaddition of oxime derivatives that can react with various alkenes. This cycloaddition of N-boranonitrone A with terminal alkenes is very useful for synthesis of 1,3-anti aminoalcohol 4 by reductive cleavage of an N-O bond.

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Development of efficient methods for construction of tetrasubstituted carbon is one of the most important tasks in organic chemistry. We have reported a new methodology named "Memory of Chirality" and prepared amino acids with tetrasubstituted carbon. In these reactions, the asymmetric reaction proceed without external chiral sources via axially chiral enolate intermediate with dynamic nature. We envisioned to apply this concept to the synthesis of chiral cyclic ethers with tetrasubstituted carbon. Since the enolate intermediate which is generated from ethyl lactate derivative would have planar chirality regulated by the C-O bond rotation, asymmetric induction via planar chiral enolates would be much more difficult than that via C-N axially chiral enolate intermediates. To realize the asymmetric induction with planar chiral enolate intermediates, we examined bases, solvents, and substituents on the aromatic ring.

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Since gem-difluoromethylene group performs as bioisosteric structure for hydroxymethylene group or ethereal oxygen, this functionality is widely found in the structure of biologically active molecules. It is also known that alpha,alpha-difluoroketone structure performs as a transition state mimic against several peptidases. To synthesize these compounds, we examined the reaction of trifluoroacetaldehyde N,O-acetals and 2 molar equivalents of alkyllithium reagents. In this reaction system, beta-elimination of fluoride followed by alkylation at beta-carbon of fluoro groups smoothly proceeded to give difluoromethylketone N,O-acetal products in excellent yield. As a further extension of this reaction, an effective and convergent synthetic method for beta-hydroxy-alpha,alpha-difluoroketones through this defluorinative alkylation of N,O-acetals and the subsequent aldol type reaction with carbonyl compounds was also developed.

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The unique reactivity of allenes which derives from the existence of two orthogonal -bonds makes them important compounds in organic and synthetic organic chemistry. As a result, the reactions of allenes have been the object of extensive examination. During the course of our studies on transition metal-catalyzed reactions of allenes, we found that similar reactions occurred using a hydroxopalladium complex [Pd₂(OH)₂(PPh₃)₄][BF₄]₂ under aqueous basic conditions. Furthermore, it was revealed that using the hydroxoplatinum complex [Pt₂(OH)₂(PPh₃)₄][BF₄]₂ was key to selectively producing one regioisomer. Against endo-olefinic products were selectively obtained in the reactions using hydroxopalladium complex, predominant production of exo-olefinic products was observed by the reaction with hydroxoplatinum complex.

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Efficient transformations of benzocyclobutenones into 2,3-benzodiazepines by a formal insertion of diazomethylene compounds are presented. This sequential process includes nucleophilic addition of diazomethylene anion, oxy-anion accelerated o-quinodimethane formation by an electrocyclic ring-opening reaction, and 8pi-electrocyclization in one-pot under remarkably mild conditions. Intermediary oxy-anion plays an important role for the efficient transformations. In addition, these reactions were successfully applied for the synthesis of 3,4-diazabenzo[b]tropone derivatives. These compounds were highly electron deficient, and easily formed amine-adduct at ambient temperature. Furthermore, gentle heating resulted in quantitative nitrogen extrusion to produce indenone derivatives. Thus, novel amine-catalyzed nitrogen extrusion reaction was found as a characteristic of new diazabenzotropone compounds.

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Organoboronic acids have received much attention as carbon nucleophiles due to its stability relative to other organometalic reagents. Asymmetric catalytic addition reactions of organoboronic acids have been achieved by using the organometallic compounds such as Rh. On the other hand, there were quite few reports on non-metallic version. Here we presente iminothiourea-catalyzed asymmetric conjugate addition of organoboronic acids to -hydroxy enones. Hydroxy groups of substrates play an important role in this reaction. In addition, the Michael adducts of this reaction can be converted into several unique cyclic compounds via the intramolecular nucleophilic addition reactions by using the hydroxy groups as a nucleophilic part or a leaving group.

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Aziridines have been used as starting materials or key intermediates for the synthesis of biologically active products. However, few methods for the palladium catalyzed ring-opening reaction of alkenyl aziridine via carbon-carbon bond formation have been reported until now. We report the reaction of MAC reagents and substituted N-mesitylenesulfonylated alkenyl aziridines. The desired compounds were obtained by using a palladium catalyst with high regio- and stereo-selectivity in excellent chemical yields at ambient temperature. The most effective solvent for this reaction was THF. Trimethylolpropane phosphite gave the largest chemical yields and highest regio- and stereoselectivity as a ligand for the palladium catalyst. This reaction yields a synthetic precursor of 2,5-disubstituted (3E)-5-amino-pent-3-enoic acid derivative, which is well known as a peptide isoster having hydrolysis-resistance of peptide bonds.

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We examined the possibility that the extent of chirality transfer in [2,3]-Wittig rearrangement employing a chiral β-substituted allyl benzyl carbanion is useful as a tool for evaluation of the effect of substituents on the configurational stability of a chiral carbanion through a double bond. As a group X we selected methyl, phenyl, cyano, benzenesulfonyl, diethoxyphosphoryl, diphenylphosphinoyl and trimethylsilyl groups. The noteworthy points are as follows: (1) when X is an anion-unstabilizing group such as a methyl group, little racemization was observed regardless of the solvent used (2) in the case of conjugating groups, phenyl and cyano groups, racemization occurs depending on the extent of their electron-withdrawing nature, and the phenyl group is very sensitive to changes in solvent, and (3) α-carbanion-stabilizing heteroatom substituents other than the silyl group cause considerable racemization.

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Lignans are natural products widely distributed in vascular plant. The natural products possess a variety of frameworks with diverse stereochemistry and also interesting biological activities such as cytotoxic, antiviral, antifungal, immunosuppressive, antiasthmatic, and antioxidant activities. We have developed a highly diastereoselective route to construct THF-lignan skeleton, wherein the keys of the stereocontrolled synthesis are a Michael addition to gamma-oxyenone intermediate and a subsequent alpha-alkylation to the resulting ketone. We also investigated an enantioselective [2,3]-Wittig rearrangement of functionalized allyl benzyl ethers to aim at an asymmetric synthesis of the lignans. As a result, we found that the reaction proceeded with excellent diastereo- and enantioselectivity using a chiral di-tert-butyl bis(oxazoline) ligand.

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Tandem enyne metathesis utilizing Ru-carbene catalyst is a useful synthetic reaction, which constructs bicyclic systems from diene-yne substrates in single reaction step. Because diene-yne function has multiple reaction sites for Ru-carbene catalyst, some reaction modes exist in this reaction. Thus the reaction often has selectivity problems. To promote selective tandem enyne metathesis, controlling the reactivities of those reaction sites is important. In this study, we have developed a new method for controlling the reactivities of olefins utilizing substituent effects. An allylic hydroxy group increases reactivity of olefin and tandem enyne metathesis predominantly proceeded from the olefin with an allylic hydroxy group. On the other hand, protection of the allylic hydroxy group decreases reactivity of olefin and in this case tandem enyne metathesis proceeded from the olefin without a protected allylic hydroxy group.

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A catalytic cascade reaction is a powerful and practical methods that minimize the reagents, solvents, cost, and time. It has been well documented that carbopalladation of allenes with an aryl- or alkenylpalladium halide easily occurs to afford allylpalladium intermediates, which undergo inter- or intramolecular nucleophilic substitution with various nucleophiles. We investigated novel domino reaction with allenic haloalkenes in the presence of palladium(0) catalyst. Treatment of allenic bromoalkenes bearing a nucleophilic moiety with a catalytic amount of palladium(0) in the presence of TBAF in MeCN affords bicyclic heterocycles in good to high yields. This reaction is widely applicable to cyclizations using nitrogen, oxygen, and carbon nucleophiles as well as construction of fused medium-sized heterocycles and benzoazepine framework.

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Total synthesis of jadomycins, bioactive penta-cyclic isoquinoline alkaloids, was examined. Methyl 2-bromo-3-methoxy-5-methylbenzoate and 5-methoxy-1-tetralone was subjected to Pd coupling reaction followed by oxidation with osmium tetroxide to give a spirolactone as a key intermediate. Model reaction using methylamine after introduction of additional carbonyl function to effectively yield an 8H-benzo[b]phenanthridine skeleton through an aminonaphthoquinone. The use of methyl isoleucinate in place of methylamine as an amine source gave the corresponding aminonaphthoquinone in moderate yield.

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Vancomycin is considered to be among the last line of defense antibiotics clinically used against Staphylococcus and other gram-positive bacteria which are notoriously methicillin-resistant. In order to address the constant need to develop effective antibiotics in the vancomycin series, tremendous effort has been dedicated to the design of new synthetic methods en route to the various subsections of vancomycin aglycon. A highly stereoselective route to the AB ring system of this natural product has been uncovered that relies on a newly designed nonracemic ligand tethered to the B ring. The targeted biaryl unit can be realized using a Suzuki-Miyaura coupling under mild, kinetic conditions, affording both a good yield (74%) and an excellent de (95%).

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(+)-Upial, isolated from the Kaneohe Bay, Oahu sponge Dysidea fragilis, was found to be a nonisoprenoid sesquiterpene aldehyde lactone containing the rare bicyclo[3.3.l]nonane skeleton. Due to its architecturally intriguing structural feature, upial and related analogues have received considerable attention from synthetic chemists over the years. The crucial step for the synthesis of upial lies in the stereocontrolled construction of a bicyclo[3.3.1]nonane ring system with five asymmetric carbon centers as well as facile introduction of the exo-methylene unit. To achieve this crucial step, we planned to exploit an intramolecular carbonyl-ene reaction of a corresponding allylsilane derivative, and we could establish a concise total synthesis of (+)-upial. This synthesis afforded the target compound in 10.2% overall yield in 15 steps from the readily accessible known starting material. Application of the strategy to the synthesis of trifarienols A and B was also investigated.

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We previously reported a new chiral thiourea catalyst for an asymmetric acyl-Strecker reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline with pyruvonitrile. The thiourea catalyst had a phenolic hydroxyl group connected to a thiourea through a chiral scaffold, and both functional groups played cooperative roles in the asymmetric induction of the acyl-Strecker reaction.
In this work, we examined an asymmetric reaction promoted by organocatalysts including a sulfonamide as a surrogate of the thiourea as a hydrogen bond donor. There are few reports that present asymmetric reaction using a Brønsted acid catalyst including sulfonamide. In the present investigation, the chiral sulfonamide catalysts were synthesized from a chiral amine known as Betti base, which is easily prepared from naphthol and benzaldehyde. The synthesized catalysts were applied to asymmetric Friedel-Crafts reaction with indoles and ethyl glyoxylate.

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Vibralactone which has an unusual fused beta-lactone moiety was recently isolated from cultures of the Basidiomycete Boreostereum vibrans by Liu and co-workers. Vibralactone inhibits pancreatic lipase, and the inhibition of the enzyme is clinically important for the treatment of obesity. This prompted us to undertake the synthesis of vibralactone, and in the present work, an efficient asymmetric synthesis of vibralactone using Meldrum's acid as a starting material was reported. Our synthetic strategy involves Knoevenagel condensation of t-butyl methyl malonate, enantioselective prenylation, and ring closing metathesis reaction. The enantioselective prenylation as a key step was investigated using phase transfer catalysts. We have accomplished the metathesis reaction using Hoveyda-Grubbs catalyst for five-membered ring of the target molecule. Further steps for synthesis of vibralactone are in progress.

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An improved synthesis of leustroducsin B was performed by using a Nozaki-Hiyama-Kishi (NHK) reaction. Leustroducsin B, a metabolite of Streptomyces platensis SANK 60191, exhibits induction of a colony-stimulating factor and thrombopoiesis. We have already reported a total synthesis of leustroducsin B via a convergent route. However, a key coupling reaction, Julia olefination, caused a low yield due to a significant side reaction. To fix this problem, we tried several coupling reactions, and found that an alternative coupling strategy using a NHK reaction led to a good yield and improved the previous synthesis. In this symposium, we will show this improved synthesis of leustroducsin B.

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Riccardin C, a nuclear receptor LXRa agonist, is a highly strained macrocyclic bis(bibenzyles) isolated from the liverwort Blasia pusilla. We have accomplished a total synthesis of riccardin C. The synthetic sequence highlights intramolecular Suzuki-Miyaura coupling to form 18-membered biaryl linkage. To investigate structure-activity relationship, seven riccardin C analogues, which consist of possible methyl ethers of three hydorxy groups existing in riccardin C, have been also synthesized.

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We have already succeeded in developing a new method to construct the asymmetric quaternary carbon center based on a desymmetrization reaction. Namely, the chiral secondary alcohol on C2-side chain in 2,2-disubstituted 1,3-cyclohexadione derivative, distinguishes one of the two carbonyl groups depending on its absolute configuration to form an acetal as a single diastereomer. The key features of the isolated compound are (1) most thermodynamically stable isomer among possible four diastereomers, (2) C-O bond formation was controlled by stereo-electronic effect, and (3) stabilized by an intramolecular hydrogen bonding.
We applied this reaction to the synthetic studies of lycopladine A, which is a natural product isolated in 2006. Lycopladine A is a tricyclic compound having a pyridine ring and a quaternary asymmetric carbon center at the angular position. We succeeded in the construction of the bicyclic intermediate utilizing the desymmetrization as a key reaction.

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We are interested in a diverse compounds library based on natural products and searching for useful small molecules. Heterocyclic-substituted chromones and flavonoids would be expected to have important bioactivity related with some disease. 4'-Benzyloxy-2'-hydroxyacetophenone reacted with various pyridinecarboxaldehydes or benzaldehydes to give intermediate chalcone derivatives, which underwent intramolecular cyclization followed by aldol reaction with another aldehyde to give various heterocyclic substituted chromones or flavonoids. On solid-phase synthesis, we can achieve these reactions under similar conditions of liquid-phase. For more diversity, Suzuki-Miyaura cross coupling progressed on both aromatic units. Some of synthesized compounds showed the inhibition of GLI-mediated transcription, cytotoxicity against some cancer cells and promoted differentiation of neural stem cell.

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Clavubicyclone was isolated from Okinawan soft coral, Clavularia viridis, by our group as a novel prostanoid-related compound. The absolute stereochemistry and biological activity of clavubicyclone have not yet been examined due to small quantities of isolated samples. We recently achieved the total synthesis of clavubicyclone as a racemic form through Cope rearrangement as a key step. However, there are several problems on our previous synthetic route; improvement of the yield of Cope rearrangement and shortening of the relatively longer sequence. To overcome these problems and to achieve an enantioselective synthesis, we examined further synthetic research. Cope rearrangement was proceeded smoothly by changing the stereochemistry of the substrate. We also achieved to obtain an intermediate as an optically active form by using enantioselective Mukaiyama aldol reaction. Introduction of side chains to an optically active bicyclo[3.2.1]octane skeleton is now underway.

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Ginkgolide C was first isolated from the root bark of Ginkgo biloba in 1932 from Furukawa. For approximately 5000 years, extracts of G. biloba have been used as herbal medicines to treat a variety of ailments, including coughs, asthma, and circulatory disorders. Recent clinical studies have attested to the potential benefits of ginkgolides in the delay of the onset of dementia. Because of its portentous molecular architecture, ginkgolide C is an intimidating challenge for chemical synthesis. Now, we describe the synthesis of the BCD tricyclic core of ginkgolide C.
As a result, we found a novel Pd(II)-promoted oxidative cyclization of the lactone ester constructs 6-oxatricyclo[6.3.0.0^1,5]undecane ring system, which is the tricyclic core of ginkgolide C.

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Merrilactone A, isolated from Illicium merrillianum, consists of a highly oxygenated pentacyclic skeleton with seven successive stereogenic centers and exhibits a neurite-outgrowth promoting activity in the primary cultures of rat cortical neurons. We have continued synthetic studies on this interesting molecule by employing our independent synthetic strategy. The right lactone ring was prepared from the Diels-Alder adduct by regioselective reduction of the anhydride, whereas the central cyclopentane ring was constructed by applying successive Heck and Stille reactions toward 1,1-dibromo-1-alkene. Furthermore, a route to the left lactone and cyclopentane rings were developed by using a model compound. As results, Tsuji-Trost reaction and Miyashita protocol was proved to be effective in the formation of the lactone and the cyclopentane ring, respectively. These methods have been applied to a synthesis of merrilactone A.

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The enantiopure (R)-(+)-Cibenzoline was synthesized in 2 steps from (R)- (+)-2,2-diphenylcyclopropylmethanol (98% ee), which was oxidized by Swern oxidation, followed by treatment with ethylenediamine in the presence of I2 and K2CO3 in tBuOH. The enantiopure (R)- (+)-2,2-diphenylcyclopropylmethanol was prepared by cyclopropanation of 3,3-diphenyl-2-propen-1-ols 1 with Et2Zn and CH2I2 in the presence of a catalytic amount of (S)-2-(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane, followed by esterification with 3,5-dinitorobenzoyl chloride, recrystallization, and hydrolysis.

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a-Acyl-g-Hydroxylactam is found in the structure of natural products. Their attractive molecular architectures and their diverse biological activities prompted several research groups to embark on the total synthesis of these compounds. These compounds have different substituted groups at its a-position and its g-position, it is expected that the difference of these two partial structures has a big influence on the appearance of its biological activity. Therefore, the author started with a project toward a development of a novel convergent method for the synthesis ofa-Acyl-g-Hydroxylactams. In the result, using the g-lactam as a key intermediate, a novel convergent method for the synthesis of a-Acyl-g-Hydroxylactams was developed. Now the author embarked on the total synthesis of PI-090 and PI-091 as an application of this method.

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2(5H)-Furanones comprise an important heterocycle incorporated in natural products and serve as useful synthetic building blocks for lactones and furans. r-Alkylidene-2(5H)-furanones, derivatives of 2(5H)-furanone, also occur widely in nature and possess interesting biologically activities. We present a straightforward synthetic method for di- or trisubstituted r-alkylidene-2(5H)-furanones using direct and regioselective Ti-crossed aldol addition between ketones and methyl pyruvate. As an application of the present method, total synthesis of 3-methyl-2H-furo[2,3-c]pyran-2-ones, a unique and remarkable seed germination stimulant (7 steps; 12% overall yield), and its analogue (2 steps; 34% overall yield) was performed utilizing Ti-crossed aldol addition as the key step.

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Hinckdentine A (1) was isolated from the bryozoans Hincksinoflustra denticulate living in the eastern coast of Tasmania. Its structure and absolute configulation were determined by single-crystal X-ray analysis. Hinckdentine A (1) has a unique architecture containing of seven -membered lactam ring fused to the tribromoindolo[1,2-c]quinazoline with a quaternary carbon center. The framework of 1 consists of biologically important dihydrotryptamine and dihydropyrimidine units together with cataleptically active indolo[1,2-c]quinazoline core, though the biological activity of 1 has not appeared in the literature.
We have accomplished the first total synthesis of (+/-)-hinckdentine A (1). The key steps are m-CPBA oxidation of 2-arylindole followed by acid-mediated Mannich-type C-C bond formation of 2-hydroxyindolin-3-one, seven-membered ring closure and regioselective tribromination.

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