We investigated Michael addition of a chiral amine derived from (+)-ketopinic acid as a part of our studies on the asymmetric Michael addition. After scrutinizing the reaction condition using tert-butyl cinnamate as a Michael acceptor, it was found that solvents and additives crucially affected both chemical yields and stereoselectivities. Namely, the reaction attained in THF afforded the ester of (S)-β-amino acid (1) in good yield and with satisfied d.e. while adding lithium triflate into the reaction medium increased in the yield and the diastereoselectivity. Surprisingly, the reaction conducted in Et₂O gave the ester of (R)-β-amino acid (2). It was noteworthy that the sole isomer of 2 was obtained by adding lithium trifluoroacetate in the reaction. Further studies revealed that the Michael addition is applicable to a variety of α,β-unsaturated esters to give esters of β-amino acids in 73-90% yield within 87-99% d.e.

View full abstract

Since an allyl group can be transformed into various functional groups, the development of effective methods to construct an allyl substituted asymmetric quaternary center will be useful for the organic synthesis. Thus, we started to examine the possibility of "desymmetrization of 2,2-disubstituted cyclohexane-1,3-dione by intramolecular acetalization reaction". It was discovered that the carbonyl group was discriminated by the hydroxyl group derived from 2,2-diallylcyclohexane-1,3-dione by mono-dihydroxylation reaction of the olefin and produced two diastereomers in 6:1 ratio. The major product was successfully transformed to decalone derivative having an allyl group on the angular position. The good optical purity was observed by the asymmetric dihydroxylation reaction for the substrate having 2,2-bis-trans-2-butene unit. The application of this methodology to the natural product synthesis will be also reported.

View full abstract

Since an allyl group can be transformed into various functional groups, the development of effective methods to construct an allyl substituted asymmetric quaternary center will be useful for the organic synthesis. Thus, we started to examine the possibility of "desymmetrization of 2,2-disubstituted cyclohexane-1,3-dione by intramolecular acetalization reaction". It was discovered that the carbonyl group was discriminated by the hydroxyl group derived from 2,2-diallylcyclohexane-1,3-dione by mono-dihydroxylation reaction of the olefin and produced two diastereomers in 6:1 ratio. The major product was successfully transformed to decalone derivative having an allyl group on the angular position. The good optical purity was observed by the asymmetric dihydroxylation reaction for the substrate having 2,2-bis-trans-2-butene unit. The application of this methodology to the natural product synthesis will be also reported.

View full abstract

Organosilicon compounds can be handled as stable molecules, while the carbanions generated of via C-Si bonds cleavage by fluoride anion undergo nucleophilic addition. Thus, organosilicon compounds has been regarded as powerful anion precursor in synthetic organic chemistry. Phosphazene base (t-Bu-P4 base) can be employed to activate carbon-silicon bonds in aryl- and heteroaryltrimethylsilane, generating in situ carbanion that coupled with various electrophiles including aldehydes and ketones. Addition of a variety of aryl- and heteroaryltrimethylsilane with trimethylacetaldehyde efficiently proceeded in the presence of catalytic amount of t-Bu-P4 base under mild conditions. The scope and limitation of these transformations were investigated.

View full abstract

The catalytic activation of C-Si and O-Si bond by t-Bu-P4 base has been investigated and the present study focused on the activation of C-Si bond of ethyl trimethylsilylacetate. The reaction with benzophenone in the presence of catalytic amount of t-Bu-P4 base proceeded at -78°Cto give the unsaturated carboxylate in excellent yield. This Peterson type olefination was applied for the synthesis of enaminoesters using N-alkylformanilide as substrates. The scope and limitation of these transformations were investigated.

View full abstract

Phosphazene bases have been applied in a variety of organic reactions because of their strong basicity. We have developed a new and efficient catalytic reaction using phosphazene bases. In the present study phosphazene base (t-Bu-P4 base) was found as activator of dialkylzinc. By treatment with Et2Zn and 30mol% t-Bu-P4 base in THF ethyl 4-iodobenzoate undergo a smooth iodine-zinc exchange reaction. The yield of the reaction is dramatically influenced by the solvent used. When DMF was used as a reaction solvent, only 5 mol% t-Bu-P4 base was sufficient to perform zincation. The reaction of the arylzinc with trans-chalcone selectively provided the 1,4-addition product in high yield.

View full abstract

We have already revealed new methods for aziridination of olefins with Chloramine-T as a nitrogen source. In order to clarify a potential utility of aziridines, their catalytic ring opening reactions are investigated by using the combination of trimethylsilyl cyanide and commercially available Lewis bases. Among these, a tertiary amine such as tetramethylethylenediamine (TMEDA) was found to be a good catalyst to afford regioselective ring opening products. The amine-catalyzed ring opening of aziridines with TMSCN is applicable to other silylated nucleophiles, TMSN3, and TMSX (X = Br, I) . A variety of aziridines were efficiently opened with silylated nucleophiles in the presence of TMEDA catalyst.

View full abstract

This study investigated the effect of oxgen substituents in benzoyl part of N-(2-iodophenyl)benzamide on the coupling position in its Pd-assisted biaryl coupling reaction. Benzamide with methylenedioxy, acetoxy, benzoyloxy and monochloroacetoxy groups yielded the ortho-product formed predominantly by connection to more hindered carbon.By contrast, methoxycarbonyl group provided the para-product selectively. The reaction of benzanilides possessing methoxy, dimethoxy and hydroxy groups, even a bulky tert-butoxy group, gave ortho-products and para-products in almost equal amounts. And, the general decrease in ortho-products from coupling reaction at the sterically hindered position indicates that ligand bulkiness influences regioselectivity. The reaction mechanism for the regioselectivity of coupling reaction is now under investigation.

View full abstract

Microwave irradiation provided unique chemical processes with special attributes as enhanced reaction rates, higher yields, greater selectivity. We are developing in the synthesis of fused pyridine ring by means of the thermal electrocyclic reaction of aza 6π-electron system incorporating one double bond of the aromatic or heteroaromatic moiety. We here describe the construction of isoquinoline framework based on the microwave assisted thermal electrocyclic reaction of 1-azahexatriene system involving the benzene 1,2-bond, and its applications to the synthesis of trispheridine (phenanthridine alkaloid) and 6-deoxybostrycoidin (azaanthraquinone alkaloid).

View full abstract

We found that intramolecular [2+2] cycloaddition of simple allenenes and allenynes proceeded under thermal conditions to give strained bicyclic compounds bearing a cyclobutane framework. N-[(1S)-1-Alkyl-2,3-butadienyl]-2,4,6-trimethyl-N-[(E)-3-phenylprop-2-enyl]phenylsulfonamides and other related substrates regio- and stereoselectively undergo intramolecular [2+2] cycloaddition at the distal double bond of allene moiety in DMF at 150°C to produce (1R,4S,8S)-4-alkyl-3-aza-8-phenyl-3-(2,4,6-trimethylphenylsulfonyl)bicyclo[4.2.0]oct-5-enes in high yields as the sole isolable isomer. This simple and environmentally-benign process would extend the potential application of fused bicyclic cyclobutanes in synthetic and medicinal chemistry.

View full abstract

We have developed a new fluorescent molecule which has the quinoline ring containing a pyrrolidine group to increase the intensity of fluorescence and an acryloyl moiety for the conjugation with thiol group of cysteine residue of the peptide. This fluorescent molecule can be prepared from oxalacetic acid diethyl ester and p-bromoaniline by 6 steps. The intensity of fluorescence of the molecule strongly depended on an environment around the molecule. The fluorescent molecule was conjugated with peptide, which is a substrate for phosphorylation by PKA (protein kinase A) and the resulting fluorescent peptide exhibited a remarkable response during phosphorylation in the presence of PKA.

View full abstract

Optically active (4S,αR)- and (4R,αR)-4-hydroxymethyl-4-phenyl-3-(α-methylbenzyl)-2-oxazolidinones (7a and 7b, respectively) were synthesized via a two-step synthesis. The first reaction was Petasis reaction using dihydroxyacetone, (R)-α-methylbenzylamine, and phenylboronic acid to afford (R)-2-(α-methylbenzyl)amino-2-phenyl-1,3-propanediol (4), and the second reaction was asymmetric desymmetrization of 4 using 2-chloroethyl chloroformate, Et₃N, DMAP in CH₂Cl₂ and then DBU gave 7a and 7b in 49 and 24 % yields, respectively. Synthetic application of 7a was also investigated. After removal of the α-methylbenzyl group of 7a by TfOH and anisole in MeCN in 50 °C, hydroxylmethyl group of the product was converted smoothly into other functional groups. Thus, 7a would be a useful synthetic intermediate for optically active compounds possessing quaternary asymmetric centers.

View full abstract

Microwave-assisted halogenation of hydroxyheteroaromatics and dehydration of primary amides were accomplished using phosphonium salt prepared by reaction of triphenylphosphine and N-chloro compounds. N-Chlorosuccinimide (NCS) and trichloroisocyanuric acid (TCICA) were used as a N-chloro compound. Both halogenation of hydroxyheteroaromatics and dehydration of primary amides under microwave-assisted condition proceeded without solvent in a short reaction time, whereas completion of the same reaction under thermal condition required solvent and longer time.

View full abstract

The conversion of the message site of the skeleton of naltrexone was carried out to improve the selectivity for opioid κ,δ, ε receptors and their subtypes. The naltrexone derivatives without 4,5-epoxy ring reacted with a sulfur ylide to afford a novel 6,14-epoxymorphynann having five membered ring ether. We will also report syntheses of various derivatives with this novel skeleton for obtaining opioid receptor subtype selective ligand.

View full abstract

To change the structure of message moiety of opioid ligand, a convenient method to convert N-substituted cyclopropylmethyl group of opioid antagonist (naltrexone) into isobutyl group was developed by the hydrogenolysis with PtO2 in 1 N HCl-MeOH at room temperature and under atmospheric pressure in a good yield. The effects of catalyst metals, solvent ratio and mole ratio of PtO2 to substrate were examined. The use of 10% Pd-C instead of PtO2 was not effective to the present ring-opening reaction. This kind of new opioid ligands are expected to have more interesting pharmacological activity.

View full abstract

A nickel-mediated intramolecular cyclization of allenes with a tethered aldehyde moiety was developed. When terminal allenes having an aldehyde moiety in the tether were treated with a stoichiometric amount of zero-valent nickel complex under an atmosphere of carbon dioxide, cyclic alcohols having a 1-carboxyvinyl moiety were obtained in a stereoselective manner. The reaction proceeded through a nickel-mediated carboxylation of the central allene carbon and an intramolecular nucleophilic addition of the resulting allylic nickellacycle intermediate to the aldehyde moiety. This novel carboxylation/cyclization cascade reaction could be applicable to the synthesis of five- to seven-membered ring compounds, which could be readily converted to bicyclic alpha-methylene-gamma-lactones under acidic conditions.

View full abstract

In the presence of (Ph₃P)₂NiCl₂catalyst, acylzirconocene chloride complex as an acyl group donor reacts with 1,6-ynal compounds to give cyclopentanol derivatives having (Z)-α,β-enone function. The reaction is considered to be brought about through (i) formation of metalacycle, (ii) transmetalation of acyl zirconium species to nickel, and (iii) reductive elimination of vinyl acyl nickel(II) intermediate. The Ni-catalyzed reactions of 1,6-enynes also proceed under the similar condition to give bicyclo[3.1.0]hexanes. The formation of bicyclo[3.1.0]hexanes would be derived from (i) formation of metalacycle, (ii) transmetalation of acyl zirconium species to nickel, and (iii) reductive elimination of vinyl acyl nickel(II) intermediate, and (iv) the intramolecular 1,4-addtion of alkyl zirconium species to α,β-enone function.

View full abstract

Two and three-component [3 + 2 + 2] cycloaddition reactions of ethyl cyclopropylideneacetate (1) and alkynes proceeded in the presence of Ni(0)-PPh3 catalyst. In this one-pot reaction, highly chemo- and regioselective reaction proceeded and the cycloheptadiene derivatives were isolated as single isomers. The formation of bicyclic compounds was observed when diynes were used as the substrates. The [3 + 4] cycloaddition of 1 with conjugated dienes also proceeded, and cycloheptenes were isolated. The scope and limitation, as well as the mechanism of these reactions, will also be discussed.

View full abstract

Haplophytine is the major alkaloid isolated from the dried leaves of the Mexican plant Haplophyton cimicidum, and exhibits an insecticidal activity. In spite of its unique and interesting structure that would attract strong interest of synthetic chemists, no total synthesis of haplophytine has been reported even after five decades from its isolation. We report herein the model studies for the construction of the left-hand segment of haplophytine, containing the unique bicyclo[3.3.1]skeleton, by biomimetic skeletal rearrangement. Furthermore, we have synthesized the optically active tetrahydro-β-carboline derivative, a key intermediate for the synthesis of the left hand segment, utilizing tin-mediated indole synthesis developed in our laboratory.

View full abstract

Total syntheses of serofendic acids A (1a) and B (1b) are described. The key strategic element of the approach involves the novel tin-free homoallyl-homoallyl radical rearrangement of 5 for the construction of bicyclo[2.2.2]octane ring system 4. In addition, the conversion of methyl atisirenoate 2 to serofendic acids A (1a) and B (1b) was achieved on the basis of the Michael reaction of sodium thiomethoxide. The methodology developed here should also provide access to synthetic analogs of serofendic acids (1).

View full abstract

We have developed a stereoselective synthesis of spirocylic frameworks, such as spiro[4.5]decanes or spirocyclic oxindoles, based on Claisen rearrangement in alkenyldihydropyran systems. The present Claisen rearrangement of bicyclic or tricyclic dihydropyrans, derived from easily available alcohols, is shown to afford the corresponding spirocyclic compounds in excellent yields and extremely high diastereoselectivities in all cases.

View full abstract

Recently, we have described that Hg(OTf)₂ and it's tetramethylurea (TMU) complex show highly efficient catalytic activity for the hydration of terminal alkynes to give methylketones, hydroxylative 1,6-enyne cyclization leading to exomethylene five-membered ring products, and arylalkyne cyclization leading dihydronaphthalene derivatives in excellent yield. We would like to discribe herein our recent observation dealing with Hg(OTf)₂-catalyzed cyclization of yne-ene-aryl substrate to give tricarbocyclic product. This is the first example of metal salt-catalyzed biomimetic tandem cyclization. We also disclose Hg(OTf)₂-catalyzed furan systhesis, cyclic enolether synthesis, ω-methylene-ω-lactone synthesis, novel glycosyration reaction, indol sysnthesis, hydroxylative enone synthsis from propargyl acetates, and inter molecular condensation of alkyne with carbon nucleophiles.

View full abstract

A pure ruthenium hydride complex with N-heterocyclic carbene (NHC) ligand was efficiently generated from the reaction of a 2nd-generation Grubbs ruthenium catalyst with vinyloxytrimethylsilane and unambiguously characterized. This ruthenium hydride complex showed high catalytic activity for the selective isomerization of terminal olefin and for the cycloisomerization of 1,6-dienes. These reactions of N-allyl-o-vinylaniline lead to novel synthetic methods for heterocycles such as indoles and 3-methylene-2,3-dihydroindoles, which are useful synthons for bioactive natural products. These procedures address an important issue in diversity-oriented synthesis.

View full abstract

We have succeeded in the development of a new and efficient synthetic method for optically acitive atropisomeric anilides using Pd-catalyzed enantioselective N-arylation. In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 catalyst, the N-arylation of achiral ortho-tert-butyl NH-anilides with p-nitroiodobenzene proceeded with high enantioselectivity (88-96% ee) to give optically active atropisomeric anilides having N-C chiral axis in good yield. The present catalytic asymmetric reaction can be applied to various substrates derived from carboxylic acids having alkenyl, alkynyl and acetal funcitional group.

View full abstract

We report here the first trans-selective alkylative cyclization of alkynals and alkynones under palladium catalysis, in which not only sp2- but also sp3-hybridized organoboronic reagents could be introduced. High functional group compatibility, ready availability, stability and non-toxicity of the organoboronic reagents and no need of additives render the described procedure facile and practical. The unusual reaction mechanism involving oxidative addition without oxametallacycle formation should be quite different from the corresponding Ni-catalyzed reaction. The obtained six-membered allylic alcohols with an endo tri- or tetra-substituted olefin and five-membered ones with an exo olefin could be useful for syntheses of various carbo- and hetero-cycles observed in natural- and pharmaceutical products because they have active reaction cites and allow functional transformation.

View full abstract

Although helical supramolecular polymers play important roles in biological systems, such as virus, microtubules, and microfilaments, there are few helical synthetic supramolecular polymers formed by host-guest systems. Now we found that 3-4-t-Boc-cinnamoylamino-α-cyclodextrin (3-4BocCiNH-α-CD) formed a supramolecular polymer in an aqueous solution. The supramolecular polymer was found to take a helical structure. This is the first example of the formation of a helical supramolecular polymer formed by host-guest interactions. In addition, we found that an α-CD derivative and a β-CD derivative formed alternating copolymers in aqueous solutions.

View full abstract

The regioselectivity of radical cyclization of enamides can be controlled by the difference in the position of the carbonyl group of amide. In this study, we found that 6-endo-trig selective cyclization of alkyl and acyl radical onto enamides gave perhydroquinoline deriveratives. This reaction was applied to the concise synthesis of cylindricine skeleton by using radical cascade involving 5-endo-trig cyclization. We also found that 7-endo-trig selective cyclization of aryl radical onto enamides gave benzazepine deriveratives. This reaction was applied to the synthesis of lennoxamine by using radical cascade involving homolytic aromatic substitution under non-reductive radical conditions. Three-step synthesis of lennoxamine was achieved in 22% overall yield.

View full abstract

Organonitroxyl radicals, such as 2,2,6,6-tetramethylpiperidin-N-oxyl (TEMPO), play an indispensable role as oxidation catalyst for eco-friendly conversion of alcohols to the corresponding carbonyl compounds. In the last symposium, we 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 report herein another synthetic utility of these organonitroxyl radicals and their derivatives serving (i) one-pot oxidation of primary alcohols to carboxylic acids, and (ii) oxidative rearrangement of tertiary allylic alcohols to α,β-unsaturated carbonyl compounds.

View full abstract

We have developed a new tin-free method for the generation of primary alkyl radicals from iodoalkanes using dimethylzinc-air as an initiator. The addition of the generated primary alkyl radicals to N-tosylimines was accelerated by the action of boron trifluoride-diethyl etherate and copper(II) triflate to give the corresponding adducts in good yields after 2-3 h. Air oxygen was essential for the reaction to proceed, showing involvement of a radical process in the reaction.

View full abstract

Utility of N-acylpyrroles as activated monodentate ester surrogates is demonstrated in several catalytic asymmetric reactions. In the direct Mannich-type reaction, the N-acylpyrrole was used as a donor, and an In(O-i-Pr)₃/linked-BINOL complex efficiently promoted the Mannich-type reaction to produce β-amino-α-hydroxy carboxylic acid derivatives in high yield and ee (up to 96% ee). α,β-Unsaturated N-acylpyrroles were useful as activated ester equivalent acceptors. In the asymmetric epoxidation reaction using a Sm(O-i-Pr)₃/H₈-BINOL complex, high catalyst turnover number (up to 4720), high turnover frequency (up to >3000 h^-1) and high ee (up to >99% ee)were realized. α,β-Unsaturated N-acylpyrroles were also effective substrates for asymmetric aza-Michael reaction. Heterobimetallic YLi₃tris(binaphthoxide) complex promoted the aza-Michael reaction in high enantioselectivity (up to 94% ee).

View full abstract

Although ammonia is a readily available and atom-economical nitrogen source, its introduction into organic molecules with high yields and selectivities has been little investigated. In the course of our investigations to address this issue, we have already reported three-component reactions of aldehydes, ammonia, and allylboronates which provide homoallylic primary amines efficiently. Herein, we report further studies on methods using easy-to-handle aqueous ammonia, stereoselective allylation of hydroxyglycine, 2-aza-Cope rearrangement of allylglycine derivatives, and platinum-catalyzed aminoallylation using allyltins.

View full abstract

Organic cations are usually relatively unstable and transient species. But the "cation pool" method enables the easy accumulation of organic cations in conventional reaction media such as dichloromethane. In the "cation pool method" cations are generated by low temperature electrochemical oxidation and accumulated in a solution. The applicability of the "cation pool" method depends upon the stability of the cation that is accumulated. This problem can be overcome by the "cation flow" method. In the "cation flow" method, cations are generated in a microflow electrochemical system. Based on the "cation pool" method, flash chemistry for conducting extremely fast reactions in microreactors has been developed.

View full abstract

Nucleophilic addition of the cyclic nitrone 1 derived from L-xylose with sp, sp2, and sp3-hybridized carbon-nucleophiles was examined. Nucleophilic addition of the lithium acetylide, Li-C≡C-TMS, was found to give the best yield of adduct with excellent stereoselectivity. With this result in hand, concise formal synthesis of (+)-hyacinthacine A2 was achieved by using nucleophilic addition of the nitrone 1 with Li-C≡C-CO₂Et. Next, synthetic study towards (+)-casuarine was made. Nucleophilic addition of the nitrone 2 with Li-C≡C-CH₂OTBDPS afforded the corresponding adduct in high yield. The adduct was converted to the precursor of (+)-casuarine by way of desilylation, half-reduction of the propargyl alcohol moiety by LiAlH₄, reductive cleavage of N-O bond, and dihydroxylation of (E)-double bond of the resulting allyl alcohol.

View full abstract

GKK1032s and pyrrocidines are novel antimicrobial and antitumor antibiotics, which consist of a decahydrofluorene (ABC ring) substructure with nine stereogenic centers and a fused 13-membered macrocycles containing a phenyl and a pyrrolidinone moiety. We have involved in the total syntheses of GKK1032s and pyrrocidines. As a key step for the construction of the decahydrofluorene units, an intramolecular Diels-Alder (IMDA) approach was adopted. The synthesis of the fully functionalized decahydrofluorene part has been accomplished, starting from the Diels-Alder adduct of trans-2-methyl-1,3-pentadiene and maleic anhydride.

View full abstract

We were succeeded in the total synthesis of 5, 8-disubstituted indolizidine type of poison frog alkaloids 193E, 203A, 205A, 219F, 221I, 231C, 233D, and 235B'' using highly stereoselective Michael type conjugate addition reaction to enaminoester to afford the trisubstituted piperidine ring system as the key step. As the result, the absolute stereochemistry of 203A and 233D has been determined, and relative stereochemistry of 219F and 221I has also been determined by these total syntheses. The pharmacological effects of these synthetic alkaloids on the neuronal nicotinic acetylcholine receptors will be discussed here.

View full abstract

Pseudodistomin A and B, isolated from the Okinawan tunicate Pseudodistoma kanoko, are isomeric piperidine alkaloids and shown to possess in vitro antitumor activity against L1210 and L5178 leukemia cells and to inhibit calmodulin-activated brain phosphodiesterase. We previously reported a formal synthesis of Pseudodistomin C utilizing an intramolecular transamidation with a catalytic hydrogenation. Encouraged by the result, we planned to synthesize Pseudodistomin A and B via a (3S,4R,6R)-3-amino-4-hydroxy-6-hydroxypropylpiperidine derivative as a common key intermediate. Here, we describe synthetic study of above described compound by using the intramolecular transamidation of 5-azidomethyl-4-hydroxypyrrolidin-2-one derivative and trans-selective allylation of N-acyliminium ion.

View full abstract

A large scale preparation of an advanced pentacyclic core of antitumor natural marine product, renieramycin M that was isolated from the Thai sponge, Xestospongia sp. pretreated KCN in phosphate buffer is described. Furthermore, successful conversion of natural renieramycin M into jorunnamycins C via jorunnamycins A was also presented. Jorunnamycins A and C have recently discovered as metabolite of Thai nudibranch, Jorunna funebris.

View full abstract

We developed the new S,O- and N,N-acetal type chiral ligands. Moreover we demonstrated both the catalytic asymmetric synthesis of (-)-CP-99,994 and (-)-L-733,061 using Pd-catalyzed asymmetric allylic amination as a key step.

View full abstract

Organic molecules bearing small fluorous tags (C6F13,C8F17) are called light fluorous molecules. Light fluorous reagents, scavengers and catalysts are especially convenient since they typically induce reactions of organic substrates under the same conditions as their non-fluorous relatives, but are reliably removed from crude reaction products by fluorous solid phase extraction. Herein we report light fluorous versions of the first- and second-generation Grubbs-Hoveyda metathesis catalysts. These exhibit the expected reactivity profile, are readily recovered from reaction mixtures by fluorous solid phase extraction, and can be routinely reused five or more times. The catalysts can be used in a standalone fashion, or supported on fluorous silica gel.

View full abstract

A highly enantio- and diastereoselective intramolecular C-H insertion reaction of α-diazoesters has been achieved with the use of dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate] as a catalyst, providing exclusively cis-2-arylcyclopentane-1-carboxylates in up to 95% ee with no evidence of alkene formation. As expected from the robust nature and high reactivity, 0.05 mol % of Rh₂(S-PTTL)₄ was found to catalyze the reaction of methyl 2-diazo-6-phenylhexanoate without compromising either the yield or enantioselectivity. Rh₂(S-PTTL)₄ was also found to catalyze the C-H insertion reaction of α-diazoester containing a benzene ring on the tether to give methyl cis-2,3-dihydro-1-phenyl-1H-indene-2-carboxylate in 92% ee. The present catalytic protocol provides attractive and powerful access to optically active cyclopentane building brocks.

View full abstract

Halogenated active methylene compounds are important synthetic intermediates owing to their high reactivity for the nucleophilic substitution. A number of methods have previously been described in the literature for the haloganation of active methylene compounds, however, most of them have serious disadvantage. We now report the novel chemoselective bromination of active methylene compounds using potassium bromide, hydrogen peroxide and hydrochloric acid. The monobrominated active methylene compounds were quantitatively obtained from the reaction of the active methylene compounds with potassium bromide and hydrogen peroxide in toluene and hydrochloric acid. Ester bonds, amide bonds and aromatic rings were not affected at all under the reaction conditions.

View full abstract

Previously we have reported the first chiral spiro bis(isoxazoline) ligands (SPRIXs) bearing a chiral spiro skeleton and two isoxazoline rings, and demonstrated the first example of Pd-catalyzed enantioselective aminocarbonylation of alkenylamide. In order to achieve the highly catalytic enantioselective aminocarbonylation, the effects of substituents on the isoxazoline rings of SPRIX and anions for Pd salts on the reaction were investigated. Among the combination we examined, the Pd-complex prepared from [Pd(CH3CN)4](BF4)2 and (M,S,S)-i-Pr-SPRIX in the ratio of 1 to 2 showed highest catalytic activity. In particular the reaction of alkenylurea afforded nitrogen-containing bicyclic product in good chemical yield with up to 86% ee. The X-ray crystallographic analysis of the Pd-SPRIX complex indicated the structure composed of one Pd metal, two molecular of (M,S,S)-i-Pr-SPRIX and two BF4 anions.

View full abstract

Novel reactions of propargylic epoxides with various reagents have been achieved using palladium catalyst. The reaction of propargylic epoxides with arylboronic acid in the presence of palladium catalyst afforded the coupled 4-aryl-2,3-allenols with high anti-diastereoselectivity. The palladium-catalyzed reaction with alkynes also produced the corresponding alkynyl-substituted allenols in good yields. These methodologies provide a new protocol for the synthesis of highly-substituted allenes in a diastereoselective manner. When the propargylic epoxide was subjected to the reaction with phenols, regio- and stereoselective addition of phenols to alkyne occurred to yield the phenoxy-substituted allylic epoxide. The reaction mechanism would be explained via the formation of π-propargylpalladium complex followed by addition of phenols.

View full abstract

We report here the solid-phase synthesis of Mappicine ketone library, as an antiviral lead compound with selective activity against herpes viruses (HSV-1 and HSV-2) and human cytomegaloviruses, based on three chemoselective palladium(0)-catalyzed reactions involving intramolecular Heck reaction at C-2, functionalization including Suzuki-Miyaura cross-coupling reaction, amination and thioetherification at C-7 and cleavage of benzenesulfonate linker at C-10. We have developed the palladium-catalyzed reductive cleavage of the sulfonate linker to release the parent arene including electron-donating groups, which was difficult so far. Furthermore, cleavage of the sulfonate linker with functionalization could also be achieved by the palladium- or nickel-catalyzed reaction.

View full abstract

Ring expansion reactions of four-membered ring compounds catalyzed by transition metal catalyst, triggered by release in the strain of them, are known to serve as useful methodology to afford various substituted cyclopentanones. We have developed palladium- or ruthenium-catalyzed novel and efficient carbon-carbon bond formation/ring expansion reactions of cyclobutanol derivatives. Palladium(0)-catalyzed transformations of allenylcyclobutanols and dienylcyclobutanols produced α-(β-styryl) and α-arylpropenyl cyclopentanones via π-allylpalladium intermediate, respectively. Acetylenylcyclobutanols also gave cyclopentanone derivatives having alkylidene substituents in the presence of ruthenium(II) complex. These reactions proceeded in a stereoselective manner and the mechanism caused the selectivity was investigated.

View full abstract

We have developed chiral palladium(II) complex catalyzed asymmetric cyclization-carbonylation of alkynyl diol and diketone. The cyclization-carbonylation of alkynyl diol 1 in the presence of chiral box-ligand 3 / palladium(II) / p-benzoquinone in methanol at -30--50°C under carbon monoxide atmosphere (balloon) afforded (E)-bicyclic-β-alkoxyacrylates 2 in 71-100% yield with 86-95%ee. In the case of alkynyl diketone, electronic effect of phenyl substituent on the box ligand was observed. The use of box ligand bearing dimethoxy phenyl groups gave the best result, the product was obtained in 74% yield with 76%ee.

View full abstract

Hypervalent organoantimony compounds (Stibanes) {[2-(XCH2C6H4)(Aryl)2Sb]: 1: X=NMe2, 2: OMe, 3: SMe}, have been conveniently prepared and the function of them in carbon-carbon bond-forming reactions has been studied. The results showed that, (1) two Ar moiety on the stibanes can couple with acid chlorides (RCOCl) to afford the corresponding ketones (RCOAr) along with homo-coupling products (Ar-Ar), especially 1 bearing strong Sb---N coordination gave RCOAr in good yield, (2) Pd catalyst having no phosphorous ligand [Pd(dba)2, Pd(OAc)2] is superior to phosphorous-ligated one [PdCl2(PPh3)2, Pd(PPh3)4] in terms of yields of the coupling products and reaction time, (3) This coupling reaction has wide generality and can be applied to a variety of acid chlorides and stibanes (Ar=Ph, p-Tol, 1-naphthyl).

View full abstract

We have developed simple and efficient devices for hydrogenation using microchannel reactors. Hydrogenation using Pd-immobilized microchannel reactors was conducted, and the reactions proceeded smoothly to afford the desired products quantitatively within 2 minutes for a variety of substrates. Here we could achieve an effective interaction between hydrogen, substrates, and a palladium catalyst utilizing large interfacial areas and the short path required for molecular diffusion in the very narrow channel space. Furthermore we used scCO2 as a reaction medium and found that the reactions proceeded more rapidly (within 1 second!) because of the high miscibility of scCO2 with hydrogen as well as liquid phase. We also demonstrated suitability of a device for a large scale synthesis utilizing capillary column reactors and realized noticeable space-time yields.

View full abstract

A novel synthetic method for oligoarenes through cross-coupling of hydroxyphenylboronic acids and triflation sequence has been developed. First, we investigated the reaction of 2-hydroxyphenylboronic anhydride with p-tolyl triflate using Pd(OAc)2 as a catalyst and KF as an additive. As a result, it was found that the reaction with PCy3 in DMF/H2O (4/1) and the reaction with X-PHOS or S-PHOS in THF/H2O (4/1) proceeded rapidly and quantitatively at room temperature. By using such conditions in the key cross-coupling step, an unfunctionalized ortho-connected pentamer and a meta-connected pentamer were obtained in high total yields. Furthermore, effective synthesis of a branched-type oligoarene was realized by using a mono-protected dihydroxyphenylboronic acid. The reaction conditions developed in this study is so mild that they will be applicable to the synthesis of various functionalized oligoarenes.

View full abstract

Two types of poly(N-isopropylacrylamide) (PNIPAAm) supported perruthenate, PEG-PINIPAAm-Ru and cross-linked-PNIPAAm-Ru, have been prepared. PEG-PINIPAAm-Ru showed highly activity in the oxidation of alcohol to carbonyl compounds with molecular oxygen, while cross-linked-PNIPAAm-Ru was effective for the oxidative biaryl coupling reaction of naphtols and substituted phenols with molecular oxygen. In addition, the recovered catalyst could also be used for consecutive reactions without any significant loss of catalytic efficacy in both cases.

View full abstract