荒井 孝義

Electrophilic indoles having two electron-withdrawing groups undergo nucleophilic attack at C2 and electrophilic functionalization at C3. This is the first enantioselective formal [3+2] cycloaddition using electrophilic indoles. The PyBidine/Cu catalyst smoothly promoted highly enantio-and exo'selective [3+2] cycloaddition using imino esters and 3-nitroindoles. This reaction provides a method for the preparation of diverse and complex chiral pyrroloindoline compounds.

A 3,3'-bis(aminoimino)BINOL ligand was newly designed and synthesized for the formation of a trinuclear Zn complex upon reaction with Zn(0Ac)2. Using the harmony of the tri-zinc atoms, 1 mol% Zn3(0Ac)4-3,3'-bis(aminoimino)binaphthoxide catalyzed asymmetric iodolactonization in up to 99.9% ee.

Switching enantioface selection of imines in the metal-catalyzed nitro-Mannich reaction was accomplished with the same enantiomer of diamine-derived bis(imidazolidine)pyridine (PyBidine) ligand. The (S,S)-PyBidine-CoCl2 complex catalyzed the nitro-Mannich reaction of N-Ts imines to give S-enriched adducts, while the Ni(OAc)(2) complex using the same ligand catalyzed the nitro-Mannich reaction of N-Boc imines in an R-stereoselective manner.

An (S,S)-diphenyldiamine-derived bis(imidazolidine)-pyridine (PyBidine)-NiCl2 complex catalyzed the nitro-Mannich reaction of isatin-derived N-Boc ketimines to construct a chiral quaternary aminocarbon center at the C3 position of oxindoles in yields of up to 99% with 95% ee.

The (S,S)-diphenylethylenediamine-derived imidazoline-aminophenol-Ni complex catalyzed tandem asymmetric Michael/Henry reaction of 2-mercaptobenzaldehydes with beta-nitrostyrenes to give the corresponding (2S,3R,4R)-2-aryl-3-nitrothiochroman-4-ols in up to 99% diastereoselectivity with 95% ee was demonstrated in diversity-oriented asymmetric catalysis. Reduction of the nitro group of the chiral thiochromanes gave a new series of (2S,3R,4R)-3-amino-2-arylthiochroman-4-ols with retention of the strereoselectiyity.

Catalytic asymmetric Friedel-Crafts reaction of indoles with nitroalkenes was catalyzed by the stereochemically tunable bis(oxazolidine)pyridine (PyBodine)-Cu(OTf)(2) complex. Using the PyBodine(Val)-Cu(OTf)(2) catalyst gave the Friedel-Crafts adducts with highly enantioselective manner. For the 1,4-bis[(E)-2-nitrovinyl]benzene, the reaction proceeded in a meso-trick manner to give the chiral double Friedel-Crafts adduct with 97% enantiomeric excess.

The structure of a nickel complex of imidazoline-aminophenol (IAP) prepared from IAP with Ni(OAc)(2) was elucidated as cis-bis(imidazolineaminophenoxide) [Ni(IAP)(2)]. The [Ni(IAP)(2)] complex smoothly promoted catalytic asymmetric 1,4-addition of 3-indolyl-3-oxindole to nitroethylene to provide chiral mixed 3,3-bisindoles with high enantioselectivities. Mechanistic studies using ESI-MS analyses suggest that one IAP ligand dissociated from [Ni(IAP)(2)] to generate the Ni-enolate of 3-indolyl-3-oxindole. From the optically active 3,3-mixed indole adduct, biologically important 3-indolyl-3-pyrrolidinoindoline was successfully synthesized in a three-step reaction sequence.

Indoles are composed of a common core structure, the indole ring, and are widely used as pharmaceuticals and their precursors. In this study, a newly composed relatively small indole compound, AWT-489 was examined to find a novel specific antagonist for DP receptors; the cognate receptors for prostaglandin D-2 (PGD(2)), to prevent colon cancer malignancy. Here we showed that AWT-489 antagonized DP receptor-mediated cyclic AMP formation, and expression of CD55, an inhibitor of the complement system that correlates with poor survival in patients with colorectal cancer, in LS174T human colon cancer cells. Interestingly, unlike a popular indole compound, indomethacin, AWT-489 did not act on the cyclooxygenases as a non-steroidal anti-inflammatory drug. Moreover, AWT-489 exhibited a better inhibitory effect than that of the well-used DP receptor antagonist, BWA868C when a dose close to the physiological concentration of PGD(2) was used. These results suggest that AWT-489 can act as a novel human DP receptor antagonist to reduce the expression of CD55 in LS174T human colon cancer cells. We believe that AWT-489 has potential as a lead compound for designing a new DP receptor antagonist that may help improve PGD(2)-related diseases, especially colon cancer in the near future. (C) 2013 Elsevier Inc. All rights reserved.

The combination of a PyBidine-Ni(OAc)(2) complex with a catalytic amount of iodine efficiently catalyzed asymmetric iodolactonization to generate chiral iodolactones with up to 89% enantiomeric excess. The formation of an intermediate Ni-carboxylate species from the alkenyl carboxylic acid is a key role in promoting the iodolactonization.

Highly functionalized complex molecules are key tools for promoting biochemical research and developing pharmaceuticals, because the network of chiralities, positions of heteroatoms, and direction of lone-pairs in the molecules are strictly linked to their biological activities. Catalytic asymmetric synthesis is the basis and core technology to supply these complex compounds in a stereoselective manner. Here, the catalytic asymmetric [3+2)-cycloaddition of iminoesters and nitroalkenes has been intensively investigated for giving chiral pyrrolidine structures which are observed abundantly in natural products and pharmaceuticals. Although the endo- or exo-selective [3+2]-cycloaddition has been widely examined using chiral Cu-catalysts, there is no report on the catalytic asymmetric synthesis of exo'-adduct. We accomplished the first catalytic asymmetric exo' selective [3+2]-cycloaddition of azomethine imines and nitroalkenes using imidazoline-aminophenol (IAP)-Ni(OAc)(2) complex to give the exo'-adduct in up to 99% ee. The first catalytic asymmetric exo'-selective [3+2]-cycloaddition of methyleneindolinones with iminoesters was also achieved by the IAP-Ni(OAc)(2) complex for the construction of a novel diastereomer of biologically important spiro[pyrrolidin-3,3'-oxindole]. Moreover, a novel C2-symmetric bis(imidazolidine)pyridine ligand (PyBidine) was easily synthesized in a single condensation of 2,6-pyridyl aldehyde and optically active (S,S)-diphenylethylene diamine. The newly developed PyBidine-Cu(OTI)(2) complex enabled the highly endo-selective [3+2]-cycloaddition of iminoesters with nitroalkenes.

A series of bis(oxazolidine)pyridine ligands (the PyBodines) were newly designed and synthesized for the development of a highly efficient, tailor-made catalyst for the [3+2] cycloaddition of azomethine imines with propiolates. The PyBodine(L-Ala)-Cu(OAc)(2) catalyst was selected on the basis of solid-phase catalysis/CD-HTS and exhibited high efficiency, producing the (R)-adducts with excellent enantioselectivity.

The first catalytic asymmetric cyclopropanation using styrene and diazooxindole was achieved with Rh-2(S-PTTL)(4). The reaction proceeded smoothly with 1 mol% catalyst loading to provide a good yield of the biologically important spiro-cyclopropyloxindole product with moderate to good enantioselectivity and excellent diastereoselectivity.

An air-stable Cu-carboxylate MOF complex can catalyze the cross-coupling reaction of phenylacetylene with 2-oxazolidone and Henry reaction. The Cu-carboxylate MOF encapsulated magnetic beads (MOF-MB II) was also prepared. The MOF-MB II was successfully reused in the Henry reaction by a simple magnetic separation.

[3+2] Cycloaddition of azomethine imines with electron-deficient terminal alkynes was smoothly catalyzed by a chiral bis(imidazolidine) pyridine-CuOAc complex to give bicyclic pyrazolo[1,2-a] pyrazolone derivatives with up to 74% ee.

Chiral, self-supported, polytopic imidazolinepyridine ligands were designed and synthesized for use in Cu catalysis. The tripodal imidazolinepyridine L6-Cu(BF4)2 complex catalyzed the asymmetric p-(tert-butyl)benzoylation of meso-hydrobenzoin to give the adduct in up to 85?%?ee. After completion of the asymmetric benzoylation reaction, the self-supported tripodal imidazolinepyridineCu catalyst could be easily recovered as a precipitate by adding hexane, and the recovered catalyst could be reused several times while maintaining the catalyst activity and selectivity.

The catalytic asymmetric Friedel-Crafts/protonation of indoles and pyrroles with a-substituted nitroalkenes to give the corresponding adducts in a highly anti-selective manner was achieved by an imidazoline aminophenol (L2)-Cu complex. The anti-adducts could be successfully transformed to biochemically important alpha-substituted beta-heteroarylalkylamines.

A four-step synthetic route to fully substituted chiral tetrahydro-beta-carbolines (THBCs) is described. Starting from the (R,S,S)-Friedel-Crafts/Henry adduct obtained from three-component coupling of an indole, nitroalkene, and aldehyde catalyzed by imidazoline-aminophenol-CuOTf, the (1S,3S,4R)-THBCs were readily synthesized in a three-step operation including reduction of the nitro-functionality and Pictet-Spengler cyclization.

Conjugate addition of Me(3)SiCN to ynones is smoothly catalyzed by Ni(cod)(2) to give beta-cyano-silyloxyallenes quantitatively. Subsequent treatment of the silyloxyallenes with N-bromo succinimide (NBS) provides the tetrasubstituted alpha-bromo-beta-cyanoenones in high yields (up to 95 %) with excellent Z-selectivity (E/Z = up to >1/99). X-ray crystallographic analysis shows a bent structure of the alpha-bromo-beta-cyanoenone due to deconjugation of the pi-bond and the carbonyl group. Furthermore, three-component coupling reactions of ynones, dialkylzinc, and aldehydes are catalyzed by Ni(cod)(2) to provide tetrasubstituted olefins.

The novel C-2-symmetric bis(imidazolidine)pyridine (PyBidine) ligand was easily synthesized in a single condensation of 2,6-pyridyl aldehyde and optically active (S,S)diphenylethylenediamine. In the C-2-symmetric PyBidine-Cu(OTf)(2) complex, imidazolidine rings act as "chiral fences" to shield the first and third quadrants. Use of the PyBidine-Cu(OTf)(2) complex as a catalyst enabled the highly endo-selective reaction of imino esters and nitroalkenes to give the adducts in up to 99% ee.

The catalytic synthesis of chiral molecules is of crucial importance in fine chemistry in order to ensure the supply of useful and valuable organic compounds. The importance of this research topic has stimulated chemists worldwide to develop numerous methods of asymmetric catalysis, although the process of developing new catalysts involves tedious effort even when modern methods are used. One way to overcome the time-consuming aspect of the process would be to use the technology of combinatorial chemistry for the discovery and optimization of catalysts. For efficient exploration of novel asymmetric catalysts using the combinatorial approach, a convenient technology of high-throughput screening (HTS) is required for analyzing both catalytic activity (chemical yield) and enantiomeric excess. With the aim of investigating novel asymmetric catalysts using a library of chiral ligands, we have developed a new high-throughput screening (HTS) by coupling a circular dichroism (CD) detection with a reaction on solid-phase catalysts. Using the "solid-phase catalysis/CD-HTS", several kinds of new asymmetric catalysts were discovered including an imidazoline-aminophenol-Cu catalyst. A novel catalytic asymmetric Friedel-Crafts/Henry reaction was successfully developed by the imidazoline-aminophenol-Cu catalyst to construct three contiguous acyclic stereocenters.

A diastereoselective Henry reaction of chiral aldehydes with nitroalkanes was developed using a chiral sulfonyldiamine (L1)-CuCl complex. The reaction of (R)-2-phenylpropanal and nitromethane was smoothly catalyzed by the (S,S,S)-L1-CuCl complex to give the adduct with 99/1 syn/anti selectivity in 99% ee. In the reaction of (S)-2-phenylpropanal and nitroethane, the (R,R,R)-L1-CuCl catalyst yielded the expected three contiguous stereogenic centers in a highly syn-selective Henry reaction.

Condensation of chiral diamines and aldehydes gave a series of chiral imidazolidine-pyridine compounds with high diastereoselectivities. The ability of these compounds to act as chiral ligands was examined in the catalytic Henry reaction.

Dibutyltin dibromide efficiently catalyzes addition of trimethylsilyl cyanide to aldehydes and aldimines. Various trimethylsilylated cyanohydrins and alpha-aminonitriles are obtained in moderate to high yield by this method.

Several methodologies for the immobilization of multicomponent asymmetric catalysts (MACs), which consist of two molecules of 1,1'-bi(2-naphthol) (BINOL) and two metals, have been developed. In the first place, Al-Li-bis(binaphthoxide) (ALB) and/or Ga-Na-bis(binaphthoxide) (GaSB) catalysts were introduced to the dendrimers and soluble polymers containing dendron units. Since these dendritic molecules require multi-step synthesis, efficient syntheses of the spherical particles that function like dendrimer-supported catalysts were realized by use of a micelle-derived polymer (MDP) and a monolayer-protected metal cluster (MPC). Secondly, a novel approach based on the use of "catalyst analogue" is found to be effective to position the ligands suitably on the polymer backbone. Thirdly, utilizing metal-bridged polymers, a simple and efficient method for immobilization without the need for a polymer support has also been realized. Heterogeneous ALB, GaSB and,mu-oxodititanium complexes thus obtained have been used as catalysts for the asymmetric Michael addition and the asymmetric carbonyl-ene reactions, respectively. The catalysts displayed high activity, affording the corresponding products with high enantiomeric excesses. These catalysts could be recovered and reused.

Conjugate addition of Me3SiCN to ynones is smoothly catalyzed by Ni(cod)(2) to give the beta-cyanosilyloxyallene quantitatively. Further reaction of the silyloxyallenes with NBS provides the tetrasubstituted alpha-bromo-beta-cyano enones in high yields (up to 95%) with excellent Z-selectivity (E/Z = up to >1/99). X-ray crystallographic analysis showed a bent structure of the alpha-bromo-beta-cyano enone due to a deconjugation of the pi-bond and carbonyl group.

Catalytic asymmetric Friedel-Crafts reaction of pyrrole with nitroalkenes was smoothly catalyzed by newly synthesized nitro-substituted imidazoline-aminophenol (1b)-Cu complex to give the adduct with up to 92% ee.

Nitrogen-tethered bisimidazoline (Nb-imidazoline) ligand was utilized in the Cu(I)-catalyzed benzoylation of 1,2-diols. With the assistance of i-Pr(2)NEt, the reaction of rac-1,2-diols with o-methylbenzoyl chloride was smoothly catalyzed by Nb-imidazoline-CuCl in CH(2)Cl(2) to give the corresponding o-methylbenzoylated secondary alcohols in tip to 79% ee.

The Michael addition of alkenyl trichloroacetates to p-benzoquinone was achieved using dibutyltin dimethoxide as a catalyst in a mixed solvent consisting of THF and MeOH. Various monoalkylated benzoquinone derivatives were obtained from cyclic and acyclic trichloroacetates in moderate yield. trans-beta-Nitrostyrene was also a favorable electrophile in this catalytic process, which gave an expected Michael adduct.

A catalytic asymmetric Henry reaction has been developed with use of a sulfonyldiamine-CuCl complex as a catalyst. A series of new binaphthyl-containing sulfonyldiamine ligands (2a-h) were readily synthesized in two steps starting from commercially available chiral 1,2-diamines. The (R,R)-diamine-(R)-binaphthyl ligand (2d)-CuCl complex smoothly catalyzed the enantioselective Henry reaction with the assistance of pyridine to give the corresponding adduct with high enantiomeric excess (up to 93%). Moreover, the 2d-CuCl-pyridine system promotes the diastereoselective Henry reaction in syn-selective manner to give the adduct in up to 99% yield with 92:8 syn/anti selectivity. The enantiomeric excess of the syn-adduct was 84% ee.

Since the first report of silver(I)-catalyzed asymmetric aldol-type reaction of activated isocyanides with aldehydes using a chiral ferrocenylphosphine as a chiral phosphine ligand has been appeared in 1990, various chiral phosphine-silver(i) catalysts have been utilized in asymmetric transformations. This feature articles describes recent examples of chiral phosphine-silver(i) complex-catalyzed asymmetric reactions such as allylation, aldol reaction, Mannich-type reaction, hetero-Diels-Alder reaction, 1,3-dipolar cycloaddition and nitroso aldol reaction.

A Barbier-type regioselective propargylation of aldehydes and ketones with (3-bromobut-1-ynyl)trimethylsilane has been achieved using reactive barium as a low-valent metal in THE Especially in the case of ketones, the corresponding homopropargylic alcohols form almost exclusively. In the reaction of cc,p-unsaturated carbonyl compounds, only 1,2-adducts have been observed. This method is also applicable to propargylation of imines, and the corresponding homopropargylic amines are obtained regiospecifically in good yields with diastereomeric ratios of up to 87:13.

A new strategy for the encapsulation of magnetic nanobeads was developed by using the in situ self-assembly of an organic-inorganic hybrid polymer. The hybrid polymer of {[Cu(bpy)(BF(4))(2)(H(2)O)(2)](bpy)}(n) (bpy=4,4'-bipyridine) was constructed on the surface of amino-functionalized magnetic beads and the resulting hybrid-polymer-encapsulated beads were utilized as catalysts for the oxidation of silyl enolates to provide the corresponding a-hydroxy carbonyl compounds in high yield. After the completion of the reaction, the catalyst was readily recovered by magnetic separation and the recovered catalyst could be reused several times. Because the current method did not require complicated procedures for incorporating the catalyst onto the magnetic beads, the preparation and the application of various other types of organic-inorganic hybrid-polymer-coated magnetic beads could be possible.

A library of imidazoline-aminophenol ligands was synthesized on solid supports. After immobilization of chiral chloromethylimidazolines 1 and 2 onto the polystyrylsulfonyl chloride, nucleophilic substitution with (R)or (S)-phenylethylamine (3 and 4) provided four combinations of polymer-supported imidazoline-amine ligands. Further reductive alkylation using salicylaldehydes 7-10 provided a series of imidazoline-aminophenol ligands (L9-L24). Analysis by solid-phase catalysis/circular dichroism high-throughput screening of a copper-catalyzed Henry reaction revealed that ligand L25, comprising a (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenyle-thylamine, and dibromophenol, was highly efficient, thus providing the adduct of nitromethane and benzaldehyde in 95% ee. The combination of stereogenic centers was crucial in promoting the highly stereoselective reactions. The unique reaction sphere of L25 was also examined in a FriedelCrafts alkylation of indole and nitroalkene to give the adduct in up to 83% ee.

The chiral diamine ligand 3 was designed and synthesized from (R,R)-1,2-diphenylethylenediamine, (S)-2,2'-dibromomethyl-1,1'-binaphthalene, and o-xylylene dibromide. The resulting 3-Cu(OAc)(2) complex was a highly efficient catalyst for the Henry reaction, giving the various nitroaldols with over 90% ee (up to > 99%). The reaction was performed in n-propyl alcohol at room temperature, and the Henry adducts were produced in high yield with excellent enantiomeric excess; these attributes are desirable in a catalyst for practical use.

A tandem cross-coupling reaction of aryl methyl ketones with aromatic aldehydes has been accomplished employing barium isopropoxide as a catalyst, in which barium enolates are generated and then three consecutive reactions (aldol reaction/beta-elimination/conjugate addition) occur; this one- pot procedure is a convenient method to obtain symmetrical 1,5-diketones in good yields. In some cases, addition of iso- propanol is effective in improving the chemical yield. (c) 2007 Elsevier Ltd. All rights reserved.

The design and synthesis of novel 15-membered 11-azalides and 16-membered 11,12-diazalide starting from 16-membered macrolides are reported. A mobile linear dialdehyde was isolated via a cyclic tetraol which was prepared by osmium oxidation of a conjugated diene. One-pot macrocyclization of this dialdehyde with an amine or a diamine afforded corresponding 15-membered azalides or 11,12-diazalide. Fundamental SAR studies of 15-membered 11-azalides disclosed their potentiality as a lead molecule for further chemical modifications. For environmental preservation, sustainable chemistry for synthesis of these azalides is also discussed.

Catalytic asymmetric benzoylation of 1,2-diols has been developed using a solid-phase asymmetric catalyst. The reaction conditions were optimized by the screening of different metal salts, solvents, bases, and temperatures. High-throughput screening was performed using circular dichroism detection, and the results revealed that Nb-imidazoline-copper(I) in combination with diisopropylethylamine was able to catalyze with high enantioselectivity, giving the monobenzoylated products in high yields and excellent enantiomeric excesses of up to 95% ee.

A family of chiral salicylhydrazones was designed and synthesized for application in asymmetric catalysis. The ability of newly prepared binaphthyl-containing salicylhydrazones as the chiral ligand was examined in the addition of diethylzinc to aldehyde, with the desired product obtained in up to 80% ee. (c) 2007 Elsevier Ltd. All rights reserved.