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Nonoyama A.,Institute of Microbial Chemistry BIKAKEN Tokyo | Kumagai N.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Institute of Microbial Chemistry BIKAKEN Tokyo
Tetrahedron | Year: 2017

An anti-selective catalytic asymmetric nitroaldol reaction was implemented in a continuous-flow reaction platform for the synthesis of a key intermediate of a drug candidate. The requisite solid-phase catalyst was readily prepared by mixing an amide-based chiral ligand and inexpensive inorganic salts, NdCl3•6H2O and NaOtBu, without covalent bond linkages. The flow system was operated with 2-Me-THF as the eluent for ca. 400 h to provide a crude nitroaldol adduct in a highly stereoselective manner with no work-up procedure, reaching turnover number over 1600. Facile reduction of the nitro group of the product afforded a key intermediate of AZD7594, a therapeutic candidate for asthma and chronic obstructive pulmonary disease. © 2017 Elsevier Ltd


Abe H.,Institute of Microbial Chemistry BIKAKEN Tokyo | Kawada M.,Institute of Microbial Chemistry BIKAKEN | Inoue H.,Institute of Microbial Chemistry BIKAKEN | Ohba S.-I.,Institute of Microbial Chemistry BIKAKEN | And 3 more authors.
Organic Letters | Year: 2013

Synthesis of intervenolin, a natural quinolone discovered by screening for selective growth inhibitors of cancer cells cocultured with stromal cells over monocultured cells, was achieved. The synthesis utilized a thiocyanate- isothiocyanate rearrangement and Suzuki-Miyaura coupling to furnish the characteristic substituents, the iminodithiocarbonate moiety, and the geranyl side chain, respectively. In vivo studies showed that intervenolin inhibited tumor tissue growth in model mice. © 2013 American Chemical Society.


Tamura K.,Institute of Microbial Chemistry BIKAKEN Tokyo | Kumagai N.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Japan Science and Technology Agency
European Journal of Organic Chemistry | Year: 2015

A direct catalytic asymmetric Mannich-type reaction of benzyl isocyanide using a CuI catalyst and N-(diphenylthiophosphinoyl)imines was developed. The simultaneous activation strategy by soft-soft interaction was the key to promote the reaction using a weakly acidic pronucleophile, benzyl isocyanide. The spontaneous cyclization of the Mannich adduct afforded the corresponding enantioenriched imidazolines, which could be precursors for a variety of 1,2-diarylethylenediamines. Enantioenriched 4,5-diarylimidazolines were directly accessed by catalytic asymmetric C-C bond-forming reaction of benzyl isocyanide and N-(thiophosphinoyl)aldimines. The imidazolines were readily transformed into enantioenriched 1,2-diarylethylenediamines. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Hashimoto K.,Institute of Microbial Chemistry BIKAKEN Tokyo | Kumagai N.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Japan Science and Technology Agency
Chemistry - A European Journal | Year: 2015

A readily recyclable asymmetric catalyst has been developed based on the self-assembly of a homogeneous catalyst in a fibrous network of multiwalled carbon nanotubes (MWNTs). Dimerization of an amide-based chiral ligand with a suitable spacer allows for the efficient formation of a heterogeneous catalyst by self-assembly on addition of Er(OiPr)3. The self-assembly proceeds in the MWNT fibrous network and small clusters of assembled catalyst are confined in the MWNTs, producing an easily handled solid-phase catalyst. The resulting MWNT-confined catalyst exhibits a good catalytic performance in a catalytic asymmetric Mannich-type reaction, which can be conducted in a repeated batch system and in a continuous-flow platform. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA.


Hashimoto K.,Institute of Microbial Chemistry BIKAKEN Tokyo | Kumagai N.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Institute of Microbial Chemistry BIKAKEN Tokyo
Chemistry (Weinheim an der Bergstrasse, Germany) | Year: 2015

A readily recyclable asymmetric catalyst has been developed based on the self-assembly of a homogeneous catalyst in a fibrous network of multiwalled carbon nanotubes (MWNTs). Dimerization of an amide-based chiral ligand with a suitable spacer allows for the efficient formation of a heterogeneous catalyst by self-assembly on addition of Er(OiPr)3. The self-assembly proceeds in the MWNT fibrous network and small clusters of assembled catalyst are confined in the MWNTs, producing an easily handled solid-phase catalyst. The resulting MWNT-confined catalyst exhibits a good catalytic performance in a catalytic asymmetric Mannich-type reaction, which can be conducted in a repeated batch system and in a continuous-flow platform. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Nishio M.,CHPI Institute | Umezawa Y.,Institute of Microbial Chemistry BIKAKEN Tokyo | Fantini J.,Aix - Marseille University | Weiss M.S.,Helmholtz Center Berlin | Chakrabarti P.,Bose Institute of India
Physical Chemistry Chemical Physics | Year: 2014

This is a sequel to the previous Perspective "The CH-π hydrogen bond in chemistry. Conformation, supramolecules, optical resolution and interactions involving carbohydrates", which featured in a PCCP themed issue on "Weak Hydrogen Bonds-Strong Effects?": Phys. Chem. Chem. Phys., 2011, 13, 13873-13900. Evidence that weak hydrogen bonds play an enormously important role in chemistry and biochemistry has now accumulated to an extent that the rigid classical concept of hydrogen bonds formulated by Pauling needs to be seriously revised and extended. The concept of a more generalized hydrogen bond definition is indispensable for understanding the folding mechanisms of proteins. The CH-π hydrogen bond, a weak molecular force occurring between a soft acid CH and a soft base π-electron system, among all is one of the most important and plays a functional role in defining the conformation and stability of 3D structures as well as in many molecular recognition events. This concept is also valuable in structure-based drug design efforts. Despite their frequent occurrence in organic molecules and bio-molecules, the importance of CH-π hydrogen bonds is still largely unknown to many chemists and biochemists. Here we present a review that deals with the evidence, nature, characteristics and consequences of the CH-π hydrogen bond in biological macromolecules (proteins, nucleic acids, lipids and polysaccharides). It is hoped that the present Perspective will show the importance of CH-π hydrogen bonds and stimulate interest in the interactions of biological macromolecules, one of the most fascinating fields in bioorganic chemistry. Implication of this concept is enormous and valuable in the scientific community. This journal is © the Partner Organisations 2014.


Weidner K.,Institute of Microbial Chemistry BIKAKEN Tokyo | Sun Z.,Institute of Microbial Chemistry BIKAKEN Tokyo | Kumagai N.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Institute of Microbial Chemistry BIKAKEN Tokyo | Shibasaki M.,Japan Science and Technology Agency
Angewandte Chemie - International Edition | Year: 2015

A direct aldol reaction of an α-azido 7-azaindolinylamide, promoted by a Cu-based cooperative catalyst, is documented. Aromatic aldehydes bearing an ortho substituent exhibited diastereodivergency depending on the nature of the chiral ligands used. Smooth reactions with ynals highlighted the broad substrate scope. A vicinal azido alcohol unit in the product allowed direct access to the corresponding aziridine and facile hydrolysis of the 7-azaindolinylamide moiety furnished enantioenriched β-hydroxy-α-azido carboxylic acid derivatives. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Umezawa Y.,Institute of Microbial Chemistry BIKAKEN Tokyo | Nishio M.,CHPI Institute
Supramolecular Chemistry | Year: 2013

A crystallographic database study was carried out to investigate the potentiality of guanidinium group acting as an effective CH acceptor (π-donor) of the CH/π hydrogen bond; it has been demonstrated that this group is a good receptor of CH in crystals of arginine and its derivatives. Implication of the present finding to protein biochemistry and rational drug design is suggested. © 2013 © 2013 Taylor & Francis.


PubMed | Institute of Microbial Chemistry BIKAKEN Tokyo
Type: Journal Article | Journal: Angewandte Chemie (International ed. in English) | Year: 2015

A direct aldol reaction of an -azido 7-azaindolinylamide, promoted by a Cu-based cooperative catalyst, is documented. Aromatic aldehydes bearing an ortho substituent exhibited diastereodivergency depending on the nature of the chiral ligands used. Smooth reactions with ynals highlighted the broad substrate scope. A vicinal azido alcohol unit in the product allowed direct access to the corresponding aziridine and facile hydrolysis of the 7-azaindolinylamide moiety furnished enantioenriched -hydroxy--azido carboxylic acid derivatives.


PubMed | Institute of Microbial Chemistry BIKAKEN Tokyo
Type: Journal Article | Journal: Organic letters | Year: 2013

Synthesis of intervenolin, a natural quinolone discovered by screening for selective growth inhibitors of cancer cells cocultured with stromal cells over monocultured cells, was achieved. The synthesis utilized a thiocyanate-isothiocyanate rearrangement and Suzuki-Miyaura coupling to furnish the characteristic substituents, the iminodithiocarbonate moiety, and the geranyl side chain, respectively. In vivo studies showed that intervenolin inhibited tumor tissue growth in model mice.

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