Updated on 2023/12/23

写真a

 
SAWADA Daisuke
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
External link

Degree

  • (BLANK) ( The University of Tokyo )

Research Interests

  • 機能性分子

  • 有機金属化学

  • 医薬化学

  • 全合成

  • Organic Chemisty

  • 有機化学

Research Areas

  • Life Science / Bioorganic chemistry

  • Life Science / Pharmaceutical chemistry and drug development sciences

  • Nanotechnology/Materials / Structural organic chemistry and physical organic chemistry

Research History

  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences   Professor

    2013.10

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  • Teikyo University   Faculty of Pharma-Science   Associate Professor

    2010.4 - 2013.9

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  • Teikyo University   Faculty of Pharma-Science   Lecturer

    2006.6 - 2010.3

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  • Teikyo University   Faculty of Pharma-Science   Research Assistant

    2001.4 - 2006.5

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  • The University of Tokyo   Graduate School of Pharmaceutical Sciences

    2000 - 2001

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Professional Memberships

 

Papers

  • Nucleophile-Triggered π-Topological Transformation: a New Synthetic Approach to Near-Infrared-Emissive Rhodamines. International journal

    Mei Harada, Misa Kutsuna, Taichi Kitamura, Yusuke Usui, Masayoshi Ujiki, Yuka Nakamura, Tohru Obata, Masaru Tanioka, Masanobu Uchiyama, Daisuke Sawada, Shinichiro Kamino

    Chemistry (Weinheim an der Bergstrasse, Germany)   e202301969   2023.7

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    We describe a π-topological transformation-based synthetic method for the preparation of a new type of near-infrared (NIR)-emissive rhodamine dye called Polymethine-embedded Rhodamine Fluorophore (PeR Fluor). In contrast to conventional NIR-emissive dyes that require tedious synthetic steps and/or a high cost, linear fully π-conjugated PeR Fluor can be regioselectively prepared in one step by mixing different nucleophiles with ABPXs, a family of rhodamines with a cross-conjugated structure. PeR Fluor exhibits bright NIR fluorescence emission and high photostability owing to the cooperative π-electron system of rhodamines and polymethine scaffolds. Large bathochromic shifts of the absorption and fluorescence emission maxima can be achieved by modifying the N-substituted group to obtain NIR-absorbing/emitting PeR Fluor. We also demonstrate the stimulus-responsive functionality of PeR Fluor through the addition of chemicals (acid/base), which shows switchable NIR and visible fluorescence response. Our π-topological transformation-based synthetic method is a promising approach to produce new functionalized rhodamine dyes.

    DOI: 10.1002/chem.202301969

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  • First Total Synthesis of Reassigned Echinosulfonic Acid D Reviewed

    Takumi Abe, Ren Nakajima, Toshiki Yamashiro, Daisuke Sawada

    Journal of Natural Products   2022.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Chemical Society ({ACS})  

    DOI: 10.1021/acs.jnatprod.2c00559

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  • Indole Editing Enabled by HFIP‐Mediated Ring‐Switch Reactions of 3‐Amino‐2‐Hydroxyindolines Reviewed

    Takumi Abe, Toshiki Yamashiro, Kaho Shimizu, Daisuke Sawada

    Chemistry – A European Journal   2022.5

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1002/chem.202201113

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  • Chemo- and Site-Selective Replacement of N-Terminal Carbamates in Peptides Reviewed

    Miho Ibara, Takumi Abe, Daisuke Sawada

    Organic Letters   142nd   2022.3

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    DOI: 10.1021/acs.orglett.2c00370

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  • Synthesis of 2-monosubstituted indolin-3-ones by cine-substitution of 3-azido-2-methoxyindolines

    Toshiki Yamashiro, Takumi Abe, Daisuke Sawada

    Organic Chemistry Frontiers   2022

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    Publishing type:Research paper (scientific journal)   Publisher:Royal Society of Chemistry (RSC)  

    We have developed an efficient reaction of 3-azido-2-methoxyindolines with <italic>O</italic>-nucleophiles in the presence of a Lewis acid, affording 2-monoacyloxy or alkoxy indolin-3-ones.

    DOI: 10.1039/d2qo00048b

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  • Synthesis of α-substituted indolylacetamide using acetonitriles as acetamide enolate equivalents through O-transfer reactions. International journal

    Takumi Abe, Kenta Noda, Daisuke Sawada

    Chemical communications (Cambridge, England)   57 ( 61 )   7493 - 7496   2021.7

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    We introduce readily available ammonium hemiaminals as O-transfer reagents and commercially available acetonitriles as a primary amide enolate precursor. The combination serves as an amide enolate equivalent, thereby providing one-pot access to α-substituted indolylacetamides. A broad substrate scope and good functional group tolerance as well as gram-scale synthesis make this protocol highly attractive. Mechanistic experiments suggest that the cyano group is trapped by a hydroxy group of hemiaminals en route to the desired primary amides under metal-free conditions.

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  • Cis-3-Azido-2-Methoxyindolines as Safe and Stable Precursors to Overcome the Instability of Fleeting 3-Azidoindoles

    Toshiki Yamashiro, Takumi Abe, Masaru Tanioka, Shinichiro Kamino, Daisuke Sawada

    Chemical Communications   2021

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    Publishing type:Research paper (scientific journal)   Publisher:Royal Society of Chemistry (RSC)  

    Use of 3-azidoindoles in organic synthesis remains difficult task owing to their instabilities. Herein, we report a general and concise approach for tackling this problem by using 3-azidoindole surrogates. The...

    DOI: 10.1039/d1cc06033c

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  • Morpholine-Substituted Rhodamine Analog with Multi-Configurational Switches for Optical Sensing of pH Gradient under Extreme Acidic Environments. International journal

    Natsumi Koga, Masaru Tanioka, Shinichiro Kamino, Daisuke Sawada

    Chemistry (Weinheim an der Bergstrasse, Germany)   27 ( 11 )   3761 - 3765   2020.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-V C H VERLAG GMBH  

    Superior pH-responsive molecules are required for the development of functional materials applicable to advanced molecular technologies. Despite having been widely developed, many rhodamine-based pH-responsive molecules exhibit a single configurational switch for "turn-on." Herein, we report a new type of rhodamine-based pH-responsive molecule with multi-configurational switches displaying stable two-step structural and color conversion in response to pH. This rhodamine analog could be successfully applied to optical sensing of pH gradient under extreme acidic environments both in solution and on hydrogel through high-contrast color change. We demonstrated that this multi-responsive character enabled optical memory of different pH information.

    DOI: 10.1002/chem.202004254

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  • Stepwise structural and fluorescent colour conversion in rhodamine analogues based on light and acid stimulations

    Masaru Tanioka, Shinichiro Kamino, Natsumi Koga, Daisuke Sawada

    JOURNAL OF MATERIALS CHEMISTRY C   8 ( 2 )   543 - 549   2020.1

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ROYAL SOC CHEMISTRY  

    The research and development of multi-stimuli, multi-responsive molecules have attracted considerable attention in chemistry, biology, and material science. Herein, we propose a multi-stimuli-responsive multi-fluorescence system in a single molecule. This system is based on the isomerization that involves ring-opening/closing reactions of spirolactones of rhodamine analogues (ABPXs), developed by our group, which can be independently controlled by light and chemical stimuli. UV light irradiation opens one of the spirolactones to give thermally stable coloured isomer (Z) in solution. Detailed synthetic and theoretical investigations reveal that the ring-opening reaction of ABPXs proceeds via the formation of a photo-induced charge separated state, followed by the recombination of the biradicals. Furthermore, we explore the structure-kinetic relationships and demonstrate that the introduction of electron-donating substituents into the xanthene ring can tune the lifetime of the photo-generated isomer. Chemical stimulation by an acid further promotes the ring-opening reaction to give a red-shifted isomer (D). These light and chemical input signals can be converted into output signals of distinct colour and fluorescence. The multi-stimuli-responsive multi-colour fluorescence could be distinctively expressed through the combinatorial logic gate.

    DOI: 10.1039/c9tc05054j

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  • Efficient and practical synthesis of N-acetyl enamides from ketoximes by unique iron catalytic system

    Takahiro Kunishige, Daisuke Sawada

    TETRAHEDRON LETTERS   60 ( 24 )   1562 - 1565   2019.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    A new procedure for the iron-catalyzed synthesis of enamides from ketoximes was developed, and its mechanism was proposed. A unique reduction system, with the concerted use of KI and Na2S2O4, was involved. The reaction exhibited a wide substrate scope and gave good yields in a short reaction time. The procedure is operationally simple and also applicable for the large-scale synthesis. (C) 2019 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2019.05.006

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  • Syntheses and acid-stimulus responsiveness of aminobenzopyranoxanthene spiroethers

    Ryosuke Hosoda, Shinichiro Kamino, Masashi Ueda, Daisuke Sawada

    Heterocycles   99 ( 2 )   820 - 824   2019

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    Novel aminobenzopyranoxanthene spiroethers (ABPX-SEs) based on the spirocyclization of the hydroxymethyl group were synthesized from ABPX spirolactones (ABPX-SLs). The addition of an acid induces a ring-opening reaction to yield two colored monocationic and dicationic spiro-ring species of ABPX. The acid-stimulus responsiveness of the ABPX-SEs is lower than that of ABPX-SLs in polar organic solvents. In addition, the ABPX-SEs exhibit stepwise structural changes of the three equilibrium species at acidic pH, although rapid conversion from the spirolactone to dicationic species occurs in the case of ABPX-SLs.

    DOI: 10.3987/COM-18-S(F)66

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  • Synthesis of a tetracyclic aminobenzimidazole derivative via tandem cyclization of triphenylguanidine

    Yuki Akamatsu, Shinichiro Kamino, Daisuke Sawada

    Heterocycles   99 ( 2 )   815 - 819   2019

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    We developed a new reaction for the one-pot synthesis of a fused cyclic compound from triphenylguanidine, which was thought to be tandem cyclization, with a moderate yield. In this reaction, conditions such as the metal reagent, oxidant, solvent, and ligand affected whether single or tandem cyclization was preferred.

    DOI: 10.3987/COM-18-S(F)61

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  • Stable Thiele's Hydrocarbon Derivatives Exhibiting Near-Infrared Absorption/Emission and Two-Step Electrochromism. International journal

    Yuta Okamoto, Masaru Tanioka, Atsuya Muranaka, Kazunori Miyamoto, Tetsuya Aoyama, Xingmei Ouyang, Shinichiro Kamino, Daisuke Sawada, Masanobu Uchiyama

    Journal of the American Chemical Society   140 ( 51 )   17857 - 17861   2018.12

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    We report synthesis and characterization of near-infrared (NIR)-absorbing/emitting Thiele's hydrocarbon derivatives, in which four aryl groups are bridged to a quinodimethane skeleton. The quinoid structure of the bridged-tetra-aryl- p-quinodimethanes (BTAQs) was confirmed by spectroscopic, X-ray crystallographic, and computational methods. Although quinodimethane derivatives with a small HOMO-LUMO energy gap often exhibit biradical character, BTAQs showed no biradical character. Instead, they exhibited two-step near-infrared electrochromism. The donor/acceptor properties of the aryl groups were found to play a key role in the unique properties of BTAQs.

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  • Effects of 2-substitution on 14-epi-19-nortachysterol-mediated biological events: Based on synthesis and X-ray co-crystallographic analysis with human vitamin D receptor Reviewed

    Daisuke Sawada, Shinji Kakuda, Akiko Takeuchi, Fumihiro Kawagoe, Midori Takimoto-Kamimura, Atsushi Kittaka

    ORGANIC & BIOMOLECULAR CHEMISTRY   16 ( 14 )   2448 - 2455   2018.3

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    Both 2- and 2-hydroxypropyl substituted 14-epi-1,25-dihydroxy-19-nortachysterols were synthesized to study the human vitamin D receptor (hVDR) binding affinity, binding configurations, and interactions with amino acid residues in the ligand binding domain of hVDR by X-ray co-crystallographic analysis. In conjunction with our previous results on 14-epi-19-nortachysterol, 2-methylidene-, 2-methyl-, 2-methyl, and 2-hydroxypropoxy-14-epi-19-nortachysterol, we propose a variety of effects of substitution at the C2 position in the 14-epi-19-nortachysterol skeleton on biological activities.

    DOI: 10.1039/c8ob00158h

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  • Synthesis of Aminobenzopyranoxanthenes with Nitrogen-Containing Fused Rings Reviewed

    Natsumi Fukino, Shinichiro Kamino, Minami Takahashi, Daisuke Sawada

    JOURNAL OF ORGANIC CHEMISTRY   82 ( 24 )   13626 - 13631   2017.12

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    An efficient and practical method for the synthesis of a variety of aminobenzopyranoxanthenes (ABPXs) with different nitrogen containing fused rings was developed. On the basis of the mechanistic studies of the formation of the xanthene framework, the presented methodology was developed to facilitate access to previously inaccessible asymmetric ABPXs.

    DOI: 10.1021/acs.joc.7b02290

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  • Synthesis of 2 alpha- and 2 beta-(3-hydroxypropyl)-7,8-cis-14-epi-1 alpha,25-dihydroxy-19-norvitamin D-3 and their biological activity Reviewed

    Daisuke Sawada, Eiji Ochiai, Akiko Takeuchi, Shinji Kakuda, Midori Kamimura-Takimoto, Fumihiro Kawagoe, Atsushi Kittaka

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   173   79 - 82   2017.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    According to the binding mode of 14-epi-1 alpha,25-dihydroxy-19-nortachysterol in the ligand binding domain of human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration that was shown by X-ray co-crystallographic analysis, 7,8-cis-locked 1 alpha,25(OH)(2)D-3 analogs were synthesized. In this paper, the synthesis and biological activity of 2 alpha- and 2 beta-(3-hydroxypropyl)-7,8-cis-14-epi-1 alpha,25-dihydroxy-19-norvitamin D-3 are reported. The A-ring and CD-ring precursors for the Julia-Kociensky coupling reaction to create a diene system of the target molecules were prepared using our original methods. hVDR binding affinity and osteocalcin promoter transactivation activity of the new 7,8-cis-14-epi-vitamin D-3 analogs were evaluated. Interestingly, the 2 beta-substituted 7,8-cis-analog was a better binder for hVDR than the 2 alpha-isomeric counterpart. (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2016.09.007

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  • Direct C-H substitution reaction of anilides using hypervalent iodine and their regioselective issues Reviewed

    Kohki Yamamoto, Shinichiro Kamino, Daisuke Sawada

    TETRAHEDRON LETTERS   58 ( 41 )   3936 - 3938   2017.10

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    The direct C-H substitution reactions of anilides using hypervalent iodine proceeded to afford azide, chloro, bromo, and fluoro derivatives, and their regioselectivity were described. In the specific reaction conditions, the unique regioisomers were obtained. (C) 2017 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2017.08.079

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  • Novel screening system for high-affinity ligand of heredity vitamin D-resistant rickets-associated vitamin D receptor mutant R274L using bioluminescent sensor Reviewed

    Hiroki Mano, Miyu Nishikawa, Kaori Yasuda, Shinichi Ikushiro, Nozomi Saito, Daisuke Sawada, Shinobu Honzawa, Masashi Takano, Atsushi Kittaka, Toshiyuki Sakaki

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   167   61 - 66   2017.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    Hereditary vitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor (VDR) gene. Arg274 located in the ligand binding domain (LBD) of VDR is responsible for anchoring 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)(2)D-3) by forming a hydrogen bond with the 1 alpha-hydroxyl group of 1 alpha,25(OH)(2)D-3. The Arg274Leu (R274L) mutation identified in patients with HVDRR causes a 1000-fold decrease in the affinity for 1 alpha,25(OH)(2)D-3, and dramatically reduces vitamin D-related gene expression. Recently, we successfully constructed fusion proteins consisting of split-luciferase and LBD of the VDR. The chimeric protein LucC-LBD-LucN, which displays the C-terminal domain of luciferase (LucC) at its N-terminus, can detect and discriminate between VDR agonists and antagonists. The LucC-LBD (R274L)LucN was constructed to screen high-affinity ligands for the mutant VDR (R274L). Of the 33 vitamin D analogs, 5 showed much higher affinities for the mutant VDR (R274L) than la,25(OH)2D3, and 2 alpha-[2-(tetrazol-2-ypethy1]-1 alpha,25-(OH)(2)D-3 showed the highest affinity. These compounds might be potential therapeutics for HVDRR caused by the mutant VDR (R274L). (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2016.11.008

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  • SYNTHESES AND PHOTOPHYSICAL PROPERTIES OF AMINOBENZOPYRANOXANTHENE DYES CONTAINING VARIOUS ALKYL CHAINS AT AMINE MOIETIES Reviewed

    Shinichiro Kamino, Masaru Tanioka, Daisuke Sawada, Shuichi Enomoto

    HETEROCYCLES   95 ( 2 )   1167 - 1176   2017.1

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    Aminobenzopyranoxanthene (ABPX) dyes containing linear n-alkyl chains at amino groups were synthesized, and their cis and trans stereoisomers were isolated. Detailed spectrophotometric studies revealed that all the ABPX derivatives exhibited fluorescence emission in the far-red and near-infrared wavelength regions, and their fluorescence quantum efficiency increased with increasing n-alkyl chain length. Almost no differences in photophysical properties were observed between the cis and trans stereoisomers.

    DOI: 10.3987/COM-16-S(S)65

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  • Water-tunable solvatochromic and nanoaggregate fluorescence: dual colour visualisation and quantification of trace water in tetrahydrofuran Reviewed

    Masaru Tanioka, Shinichiro Kamino, Atsuya Muranaka, Yoshinao Shirasaki, Yousuke Ooyama, Masashi Ueda, Masanobu Uchiyama, Shuichi Enomoto, Daisuke Sawada

    PHYSICAL CHEMISTRY CHEMICAL PHYSICS   19 ( 2 )   1209 - 1216   2017.1

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ROYAL SOC CHEMISTRY  

    While investigating the unique optical properties of aminobenzopyranoxanthenes (ABPXs), organic fluorescent dyes with the fusion of two rhodamines, we have found that the spirolactone form of ABPXs exhibited solvatochromic fluorescence in organic solvents. Detailed spectrophotometric and theoretical analyses showed that the solvatochromic fluorescence of ABPXs originated from the photo-excited charge separation in solvents of different dipolarities. Further studies revealed that fluorescent nano-aggregates were also formed in highly concentrated solution. The intriguing dual fluorescence properties of ABPXs were tunable in response to the water content, and served as a new detection principle for naked-eye visualisation (above 0.5 wt%) and quantification (0.010-0.125 wt%) of water in tetrahydrofuran.

    DOI: 10.1039/c6cp06808a

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  • Fused-Fluoran Leuco Dyes with Large Color-Change Derived from Two-Step Equilibrium: iso-Aminobenzopyranoxanthenes Reviewed

    Yoshinao Shirasaki, Yuta Okamoto, Atsuya Muranaka, Shinichiro Kamino, Daisuke Sawada, Daisuke Hashizume, Masanobu Uchiyama

    JOURNAL OF ORGANIC CHEMISTRY   81 ( 23 )   12046 - 12051   2016.12

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    Fluorans are popular leuco dyes that are used in various applications, such as carbonless-copy papers and thermal papers. Here, we describe unique leuco dyes in which two fluoran units are fused into a C-2h structure (iso-aminobenzopyranoxanthenes; iso-ABPXs). iso-ABPXs exhibited a large two-step color change (colorless/pink and pink/blue-green) due to opening closing of two spirolactone rings. The two-step equilibrium among the colorless, pink, and blue-green forms could be well controlled by adjusting acid concentration, solvent, and/or temperature.

    DOI: 10.1021/acs.joc.6b02403

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  • Revisiting the 7,8-cis-vitamin D3 derivatives: synthesis, evaluating the biological activity, and study of the binding configuration Reviewed

    Daisuke Sawada, Shinji Kakuda, Midori Kamimura-Takimoto, Akiko Takeuchi, Yotaro Matsumoto, Atsushi Kittaka

    Tetrahedron   72 ( 22 )   2838 - 2848   2016.4

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    Four 7,8-cis-1 alpha,25-dihydroxyvitamin D-3 derivatives, 7,8-cis- and 7,8-cts-14-epi-1 alpha,25-dihydroxy-19-norvitamin D-3 as well as 7,8-cis- and 7,8-cis-14-epi-1 alpha,25-dihydroxyvitamin D3 were synthesized, and their chemical stability was characterized. In our previous work, we disclosed that 14-epi-19-nortachysterol showed the unprecedented binding configuration in human vitamin D receptor (hVDR), that is, 5,6- and 7,8-s-trans configuration. However, this configuration is variable because of the rotation at the single bond between C7 and C8. For the precise discussion of the 7,8-s-trans configuration, we designed and synthesized the 7,8-cis-locked skeleton of vitamin D-3 derivatives. Among four analogs, the 19-nor derivatives were stable at ambient temperature, and their hVDR binding affinity and co-crystallographic analysis of their hVDR complexes were studied. The other derivatives with the triene system were isomerized to corresponding previtamin D-3 and vitamin D-3. (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2016.03.081

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  • Reversible Near-Infrared/Blue Mechanofluorochromism of Aminobenzopyranoxanthene Reviewed

    Masaru Tanioka, Shinichiro Kamino, Atsuya Muranaka, Yousuke Ooyama, Hiromi Ota, Yoshinao Shirasaki, Jun Horigome, Masashi Ueda, Masanobu Uchiyama, Daisuke Sawada, Shuichi Enomoto

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   137 ( 20 )   6436 - 6439   2015.5

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    Mechanochromic organic molecules (MOMs) that exhibit a large difference of fluorescence wavelength between two states have important potential applications, but few such compounds are known. Here, we report a new MOM, cis-ABPX01(0), which shows switchable near-IR and blue fluorescence responses. Detailed spectrophotometric and single-crystal X-ray analyses revealed that the near-IR fluorescence is attributable to fluorescence from slip-stacked dimeric structures in crystals, while the blue fluorescence is attributable to fluorescence from the monomer. Switching between the two is achieved by dynamic structural interconversion between the two molecular packing arrangements in response to mechanical grinding and solvent vapor-fuming.

    DOI: 10.1021/jacs.5b00877

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  • Synthesis and metabolic studies of 1 alpha,2 alpha,25-, 1 alpha,4 alpha,25-and 1 alpha,4 beta,25-trihydroxyvitamin D-3 Reviewed

    Masashi Takano, Daisuke Sawada, Kaori Yasuda, Miyu Nishikawa, Akiko Takeuchi, Ken-ichiro Takagi, Kyohei Horie, G. Satyanarayana Reddy, Tai C. Chen, Toshiyuki Sakaki, Atsushi Kittaka

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   148   34 - 37   2015.4

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    Three different A-ring perhydroxylated trihydroxyvitamin D-3 metabolites were synthesized from their appropriate A-ring precursors and CD-ring for their potential therapeutic applications. We first chemically synthesized 1 alpha,2 alpha,25-trihydroxyvitamin D-3 [1 alpha,2 alpha,25(OH)(3)D-3] to study its VDR binding affinity because this metabolite is a product of recombinant human CYP3A4 catalysis when 2 alpha-(3-hydroxypropoxy)-1 alpha,25-dihydroxyvitamin D-3 (O2C3), a more potent vitamin D receptor (VDR) binder than 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3], is used as the substrate. We found that this metabolite retained 27.3% of the VDR binding affinity compared to 1 alpha,25(OH)(2)D-3. The k(cat)/K-m value of CYP24A1 for 1 alpha,2 alpha,25(OH)(3)D-3 is 60% of that for 1 alpha,25(OH)(2)D-3. Since the biological activity and the metabolic fate of a naturally occurring C4-hydroxylated vitamin D-2 metabolite found in the serum of rats treated with pharmacological doses of vitamin D-2 have never been described, we next synthesized 1 alpha,4 alpha,25-trihydroxyvitamin D-3 and its diastereoisomer, 1 alpha,4 beta,25-trihydroxyvitamin D-3, to study their metabolism and biological activities. Both 4-hydroxylated isomers showed weaker VDR binding affinity than 1 alpha,25(OH)(2)D-3. Although either 4-hydroxylated isomer can be metabolized by CYP24A1 almost at the same level as 1 alpha,25(OH)(2)D-3, their metabolic patterns catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) are different; only the 4 alpha-hydroxylated analog can be metabolized by UGT to produce a glucuronate conjugate. The results provide important information for the synthesis of new novel chemotherapeutic vitamin D analogs which would be less subjective to degradation and therefore more bioavailable than 1 alpha,25(OH)(2)D-3.This article is part of a Special Issue entitled '17th Vitamin D Workshop'. (C) 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2014.09.021

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  • ビタミンD受容体リガンドの創製 Invited

    橘高敦史, 澤田大介

    ファルマシア   51 ( 3 )   196 - 200   2015.3

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  • SYNTHESIS AND PRELIMINARY BIOLOGICAL EVALUATION OF 2-[3-(TETRAZOLYL)PROPYL]-1 alpha,25-DIHYDROXY-19-NORVITAMIN D-3 Invited Reviewed

    Masashi Takano, Erika Higuchi, Kazunari Higashi, Keisuke Hirano, Akiko Takeuchi, Daisuke Sawada, Atsushi Kittaka

    HETEROCYCLES   90 ( 2 )   1274 - 1287   2015.1

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    Four new 19-norvitamin D-3 analogs, 2 alpha-[3-(tetrazol-1-yl)propyl]-, 2 beta-[3-(tetrazol-1-yl)propyl]-, 2 alpha-[3-(tetrazol-2-yl)propyl]-, and 2 beta-[3-(tetrazol-2-yl)propyl]-1 alpha,25-dihydroxy-19-norvitamin D-3 were synthesized. Among them, 2 alpha-[3-(tetrazol-1-yl)propyl] -1 alpha,25-dihydroxy-19-norvitamin D-3 showed weak binding affinity for vitamin D receptor (VDR) (2.6% of 1 alpha,25-dihydroxyvitamin D-3: ca. 15% of 1 alpha,25-dihydroxy-19-norvitamin D-3) and weak VDR transactivation activity in human osteosarcoma cells, which was determined by luciferase assays (EC50 7.3 nM, when 1 alpha,25-dihydroxyvitamin D-3 0.23 nM). Although the other three compounds could not act as VDR binders by evaluation of the competition assays, 2 alpha[3-(tetrazol-2-yl)propyl] analog showed weak transactivation activity (EC50 12.5 nM).

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  • Synthesis and Properties of 14-epi-1 alpha,25-Dihydroxy-19-Nortachysterol and its 2-Substituted Derivatives Invited Reviewed

    Daisuke Sawada, Atsushi Kittaka

    CURRENT TOPICS IN MEDICINAL CHEMISTRY   14 ( 21 )   2454 - 2459   2014.12

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    As the first stable tachysterol analogs, 14-epi-19-nortachysterol and its 2-substituted derivatives were synthesized using the Stille coupling reaction between the A-ring precursor (three vinylstannanes) and the CD-ring vinyl trifrate. Among them, the 2-methylidene group was hydrogenated with Wilkinson's catalyst regioselectively to obtain 2 alpha -and 2 beta-methyl analogs after separation; therefore, five new 14-epi-19-nortachysterols were constructed. All 14-epi-19-nortachysterols showed moderate to strong human vitamin D receptor (hVDR) binding affinity except the 2 alpha-(3-hydroxypropoxy) substituted analog. X-ray cocrystallographic analysis of the [truncated hVDR]-[2-methyl-14-epi-19-nortachysterol] complex exhibited an unusual binding structure that has not been observed previously.

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  • Design and synthesis of 2α-(tetrazolylethyl)-1α,25-dihydroxyvitamin D3 as a high affinity ligand for vitamin D receptor. Reviewed

    Matsuo M, Hasegawa A, Takano M, Saito H, Kakuda S, Takagi K, Ochiai E, Horie K, Takimoto-Kamimura M, Takenouchi K, Sawada D, Kittaka A

    The Journal of steroid biochemistry and molecular biology   144PA ( PART A )   201 - 203   2014.10

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    X-ray cocrystallographic studies of the human vitamin D receptor (hVDR)-[2 alpha-(3-hydroxypropyl)-1 alpha,25-dihydroxyvitamin D-3 (01C3)] complex showed that the terminal hydroxy group of the 2 alpha-functional group of 01C3 formed a hydrogen bond with Arg274 in the ligand binding domain (LBD) of hVDR to stabilize the complex; therefore, 01C3 showed 3-times greater binding affinity for VDR than the natural hormone. Here, the effects of a heteroaromatic ring on binding to hVDR instead of the terminal OH group of 01C3 and also on preliminary biological activities were studied. We synthesized 2 alpha-[2-(tetrazol-2-yl)ethyl]-1 alpha,25(OH)(2)D-3 (1a) and its regioisomer 2 alpha-[2-(tetrazol-1-yl)ethyl]-1 alpha,25(OH)(2)D-3 (1b), in which 1a showed much higher hVDR binding affinity and greater osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells than those of 1b. X-ray cocrystallographic analysis of the hVDR-1a complex showed new hydrogen bond formation between one of the nitrogen atoms of the tetrazole ring and Arg274. (C) 2013 Elsevier Ltd. All rights reserved.

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  • Synthesis and biological activity of 1α,2α,25-trihydroxyvitamin D3: active metabolite of 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP3A4. Reviewed

    Takano M, Ohya S, Yasuda K, Nishikawa M, Takeuchi A, Sawada D, Sakaki T, Kittaka A

    Chemical & pharmaceutical bulletin   62 ( 2 )   182 - 184   2014

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    Our previous studies revealed that recombinant human CYP3A4 converted 2 alpha-(3-hydroxypropoxy)-1 alpha,25-dihydroxyvitamin D-3 (O2C3), which was a more potent binder to vitamin D receptor (VDR) than the natural hormone, 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D3, 1), to 1 alpha,2 alpha,25-trihydroxyvitamin D-3 (2). Here, we synthesized 2 using the Trost Pd-mediated coupling reaction between an A-ring precursor and a CD-ring bromoolefin and evaluated its preliminary biological activity. We found that metabolite 2 from O2C3 was still active as a VDR ligand while maintaining human VDR binding affinity (27.3% of 1 alpha,25(OH)(2)D-3) and HL-60 cell differentiation activity (62% of 1 alpha,25(OH)(2)D-3).

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  • Synthesis of 2α-heteroarylalkyl active vitamin d3 with therapeutic effect on enhancing bone mineral density in vivo. Reviewed

    Matsuo M, Hasegawa A, Takano M, Saito H, Kakuda S, Chida T, Takagi K, Ochiai E, Horie K, Harada Y, Takimoto-Kamimura M, Takenouchi K, Sawada D, Kittaka A

    ACS medicinal chemistry letters   4 ( 7 )   671 - 674   2013.7

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    2 alpha-Heteroarylethyl-1 alpha,25-dihydroxyvitamin D-3 analogues, which were designed to form a hydrogen bond between Arg274 of human vitamin D receptor (hVDR) and a nitrogen atom of the heteroaromatic ring at the 2 alpha-position, were synthesized. Among them, 2 alpha-[2-(tetrazol-2-yl)ethyl]-1 alpha,25-dihydroxyvitamin D-3 showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats, osteoporosis model animals, on enhancing bone Mineral density than those of active vitamin D-3. X-ray cocrystallographic analysis of the hVDR-ligand complex confirms that the new hydrogen bond formation stabilized the complex.

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  • Synthesis of 14-epi-2α-hydroxypropoxy-1α,25-dihydroxy-19-nortachysterol and its hVDR binding. Reviewed

    Sawada D, Tsukuda Y, Saito H, Takagi K, Kakuda S, Takimoto-Kamimura M, Ochiai E, Takenouchi K, Kittaka A

    The Journal of steroid biochemistry and molecular biology   136 ( 1 )   27 - 29   2013.7

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    Recently, we evaluated a novel skeleton in the vitamin D family, 14-epi-1 alpha,25(OH)(2)-19-nortachysterol, and discovered its unique binding configuration in the human vitamin D receptor (VDR) with the C5,6- and C7,8-s-trans triene configuration. Because of its unprecedented form, this skeleton has a promising characteristic profile for clinical use, and also the synthesis of its derivatives should be versatile. Therefore, we synthesized the novel analog, 2 alpha-hydroxypropoxy substituted 14-epi-1 alpha,25(OH)(2)-19-nortachysterol, and evaluated its human VDR binding affinity. Although this substitution is one of the promising modification of vitamin D-3 such as eldecalcitol (ED-71), it had negative effects on the binding affinity, and the compound showed lower affinity than 1 alpha,25(OH)(2)D-3 and its parent compound, 14-epi-1 alpha,25(OH)(2)-19-nortachysterol. It was thought that the unprecedented binding configuration of this skeleton should not allow the terminal hydroxyl group of the 2 alpha-substituent to construct effective hydrogen bond networks around the amino acid residues in the binding pocket.This article is part of a Special Issue entitled 'Vitamin D Workshop'. (c) 2012 Elsevier Ltd. All rights reserved.

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  • Potent 19-norvitamin D analogs for prostate and liver cancer therapy. Reviewed

    Kittaka A, Yoshida A, Chiang KC, Takano M, Sawada D, Sakaki T, Chen TC

    Future medicinal chemistry   4 ( 16 )   2049 - 2065   2012.10

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    The active form of vitamin D-3, 1 alpha,25(OH)(2)D-3 or calcitriol, is known to inhibit the proliferation and invasiveness of many types of cancer cells, including prostate and liver cancer cells. These findings support the use of 1 alpha,25(OH)(2)D-3 for prostate and liver cancer therapy. However, 1 alpha,25(OH)(2)D-3 can cause hypercalcemia, thus, analogs of 1 alpha,25(OH)(2)D-3 that are less calcemic but exhibit potent antiproliferative activity would be attractive as therapeutic agents. We have developed 2 alpha-functional group substituted 19-norvitamin D-3 analogs with and without 14-epimerization. Among them, 2 alpha- and 2 beta-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitamin D-3 (MART-10 and -11, respectively) and 14-epi-2 alpha- and 14-epi-2 beta-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitam in D-3 (14-epi-MART-10 and 14-epi-MART-11, respectively) were found to be the most promising. In this review, we discuss the synthesis of this unique class of vitamin D analogs, the molecular mechanism of anticancer actions of vitamin D, and the biological evaluation of these analogs for potential application to the prevention and treatment of prostate and liver cancer.

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  • C15-functionalized 16-ene-1α,25-dihydroxyvitamin D3 is a new vitamin D analog with unique biological properties. Reviewed

    Kumagai G, Takano M, Shindo K, Sawada D, Saito N, Saito H, Kakuda S, Takagi K, Takimoto-Kamimura M, Takenouchi K, Chen TC, Kittaka A

    Anticancer research   32 ( 1 )   311 - 317   2012.1

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    The Delta(16) structure as a vitamin D analog enhanced vitamin D receptor (VDR) binding affinity and induced significant cell differentiation, whereas its relative calcemic activity was reduced compared to 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3). Methodologies available to introduce a double bond at C16-C17 of the D-ring on the seco-steroidal skeleton were limited; therefore, a new synthetic strategy was developed to obtain not only the Delta(16) structure, but also a new C15 functional group. Since C15-functionalization was unprecedented in vitamin D analog studies, the hybrid structure of Delta(16) and the C15-OH group at the D-ring may provide important information on the structure-activity relationship with vitamin D analogs. The synthesized 16-ene-2 alpha-methyl-1 alpha,15 alpha,25-trihydroxyvitamin D-3 showed almost 3-times higher VDR binding affinity and an equipotent level of osteocalcin promoter transactivation activity in human osteosarcoma cells as compared to 1 alpha,25(OH)(2)D-3.

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  • The difference between 14-epi-previtamin D3 and 14-epi-19-norprevitamin D3: their synthesis and binding affinity for human VDR. Reviewed

    Sawada D, Katayama T, Tsukuda Y, Saito N, Saito H, Kakuda S, Takimoto-Kamimura M, Takenouchi K, Kittaka A

    Anticancer research   32 ( 1 )   319 - 326   2012.1

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    The synthesis of 14-epi-1 alpha,25(OH)(2)previtamin D-3, 14-epi-19-nor-1 alpha,25(OH)(2)previtamin D-3, and their 2-substituted analogs is described. The vitamin D receptor (VDR) binding affinity was further evaluated and 2 alpha-methyl substituted 14-epi-1 alpha,25(OH)(2)previtamin D-3 had 17-fold more potent affinity than 14-epi-1 alpha,25(OH)(2)previtamin D-3. In the comparison of these compounds, the effects of thermal equilibrium, with or without 19-carbon at the A-ring, and their CD-ring structures are discussed.

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  • Synthesis and biological activities of 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D(3) and their metabolism by human CYP24A1 and UDP-glucuronosyltransferase. Reviewed

    Sawada D, Tsukuda Y, Yasuda K, Sakaki T, Saito H, Takagi K, Takenouchi K, Chen TC, Reddy GS, Kittaka A

    Chemical & pharmaceutical bulletin   60 ( 10 )   1343 - 1346   2012

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    A previous report has demonstrated the existence of a C4-hydroxylated vitamin D-2 metabolite in serum of rats treated with pharmacological doses of vitamin D-2. However, the biological significance and metabolic fate of this metabolite have not been described. To explore its potential biological activities, we therefore synthesized 1 alpha,4 alpha,25-trihydroxyvitamin D-3 and its diastereoisomer, 1 alpha,4 beta,25-trihydroxyvitamin D-3, using Trost Pd-mediated coupling reaction, and studied their vitamin D receptor (VDR) binding affinity, osteocalcin promoter transactivation activity, and their further metabolism by human CVP24A1 as well as by human liver microsomal fraction based on CVP- and UDP-glucuronosyltransferases (UGTs)-reactions.

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  • A Multivalent Probe for AI-2 Quorum-Sensing Receptors Reviewed

    Amanda L. Garner, Junguk Park, Joseph S. Zakhari, Colin A. Lowery, Anjali Kumari Struss, Daisuke Sawada, Gunnar F. Kaufmann, Kim D. Janda

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   133 ( 40 )   15934 - 15937   2011.10

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    Multivalency is a common principle in the recognition of cellular receptors, and multivalent agonists and antagonists have played a major role in understanding mammalian cell receptor biology. The study of bacterial cell receptors using similar approaches, however, has lagged behind. Herein we describe our efforts toward the development of a dendrimer-based multivalent probe for studying AI-2 quorum-sensing receptors. From these studies, we have discovered a chemical probe specific for Lsr-type AI-2 quorum-sensing receptors with the potential for enabling the identification of new bacterial species that utilize AI-2 as a quorum-sensing signaling molecule.

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  • New C15-substituted active vitamin D3. Reviewed

    Shindo K, Kumagai G, Takano M, Sawada D, Saito N, Saito H, Kakuda S, Takagi K, Ochiai E, Horie K, Takimoto-Kamimura M, Ishizuka S, Takenouchi K, Kittaka A

    Organic letters   13 ( 11 )   2852 - 2855   2011.6

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    C15-Substituted 1 alpha,25-dihydroxyvitamin D-3 analogs were synthesized for the first time to investigate the effects of the modified CD-ring on biological activity concerning the agonistic positioning of helix-3 and helix-12 of the vitamin D receptor (VDR). X-ray cocrystallographic analysis proved that 0.6 angstrom shifts of the CD-ring and shrinking of the side chain were necessary to maintain the position of the 25-hydroxy group for proper interaction with helix-12. The 15-hydroxy-16-ene derivative showed higher binding affinity for hVDR than the natural hormone.

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  • Development of 14-epi-19-Nortachysterol and Its Unprecedented Binding Configuration for the Human Vitamin D Receptor Reviewed

    Daisuke Sawada, Yuya Tsukuda, Hiroshi Saito, Shinji Kakuda, Midori Takimoto-Kamimura, Eiji Ochiai, Kazuya Takenouchi, Atsushi Kittaka

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   133 ( 18 )   7215 - 7221   2011.5

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    In the study of the synthesis of 14-epi-19-norprevitamin D-3, we found 14-epi-19-nortachysterol derivatives through C6,7-cis/trans isomerization. We also succeeded in their chemical synthesis and revealed their marked stability and potent VDR binding affinity. To the best of our knowledge, this is the first isolation of stable tachysterol analogues. Surprisingly, 14-epi-19-nortachysterol derivatives exhibited an unprecedented binding configurations for the ligand binding pocket in hVDR, C5,6-s-trans and C7,8-s-trans triene configurations, which were opposite the natural C7,8-ene-configuration of 1 alpha,25(OH)(2)D-3.

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  • Medicinal Chemistry as a Conduit for the Modulation of Quorum Sensing Reviewed

    Colin A. Lowery, Nicholas T. Salzameda, Daisuke Sawada, Gunnar F. Kaufmann, Kim D. Janda

    JOURNAL OF MEDICINAL CHEMISTRY   53 ( 21 )   7467 - 7489   2010.11

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  • Studies on the Synthesis and Metabolism of 14-epi-2-(3-Hydroxypropyl)-19-norvitamin D3 and Its 2-Isomer

    Atsushi Kittaka, Hideki Hara, Kaori Yasuda, Masashi Takano, Midori A. Arai, Daisuke Sawada, Hiroshi Saito, Kazuya Takenouchi, Tai C. Chen, Toshiyuki Sakaki

    Heterocycles   82 ( 1 )   649 - 661   2010

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    Two derivatives of 14-epi-1 alpha,25-Dihydroxy-19-norvitamin D-3, 14-epi-2 alpha-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitamin D-3 (14-epi-MART-10) and its 2-epimeric analog (14-epi-MART-11), were synthesized using Julia coupling reaction to connect between the C5 position (steroidal numbering) of an A-ring precursor ketone derived from (-)-quinic acid and the C6 position of a protected 14-epi-CD-ring benzothiazole sulfone. The coupling and deprotection reactions generated a mixture of 14-epi-MART-10 and 14-epi-MART-11 in a moderate yield. The C2-isomers were then separated as their pivalate forms. The C2-stereochemistry of 2 alpha- and 2 beta-isomers was determined by H-1 NMR studies including NOE experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11. The metabolism of these two new analogs was further studied in a reconstituted cell-free human CYP24A1 system to elucidate the potential mechanism of their super agonistic action on vitamin D receptor. Our results indicate that epimerization at C14 makes the analogs less susceptible to CYP24A1 degradation and therefore more bio-available, leading to enhanced biological activities.

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  • Synthesis of 2- and 2-Substituted-14-epi-previtamin D3 and Their Genomic Activity

    Daisuke Sawada, Tomoyuki Katayama, Yuya Tsukuda, Nozomi Saito, Hiroshi Saito, Ken-ichiro Takagi, Eiji Ochiai, Seiichi Ishizuka, Kazuya Takenouchi, Atsushi Kittaka

    Tetrahedron   66 ( 29 )   5407 - 5423   2010

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    2 alpha- and 2 beta-Substituted analogs of 14-epi-previtamin D-3 were synthesized and isolated after thermal isomerization of 14-epi-vitamin D-3 triene at 80 degrees C. The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were tested, and the 2 alpha-methyl-substituted analog was found to have greater genomic activity than 14-epi-previtamin D-3. We found that modification at the C2 position of the seco-steroidal skeleton afforded interesting effects for biological genomic activity for the previtamin D form as well as the natural vitamin D form. (C) 2010 Elsevier Ltd. All rights reserved.

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  • Synthesis of 2-Substituted-14-epi-previtamin D3 and Testing of Its Genomic Activity

    Daisuke Sawada, Yuya Tsukuda, Hiroshi Saito, Ken-ichiro Takagi, Eiji Ochiai, Seiichi Ishizuka, Kazuya Takenouchi, Atsushi Kittaka

    J. Steroid Biochem. Mol. Biol.   121 ( 1-2 )   20 - 24   2010

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    2 beta-Substituted analogs of 14-epi-previtamin D-3 were synthesized for the first time by the thermal isomerization of the corresponding 14-epi-vitamin D-3 that were available using coupling reaction between the A-ring phosphine oxide derived from a chiral epoxide and CD-ring cis-hydrindanone. The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were evaluated, and the new analogs were found to be less active, 0.01-0.18% of VDR binding affinity compared with the natural hormone and EC50 1.0-9.1 nM for transactivation activity, than 14-epi-previtamin D3 with 0.5% (VDR) and EC50 0.46 nM, respectively. (C) 2010 Elsevier Ltd. All rights reserved.

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  • Revisiting AI-2 Quorum Sensing Inhibitors: Direct Comparison of Alkyl-DPD Analogues and a Natural Product Fimbrolide Reviewed

    Colin A. Lowery, Takumi Abe, Junguk Park, Lisa M. Eubanks, Daisuke Sawada, Gunnar F. Kaufmann, Kim D. Janda

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   131 ( 43 )   15584 - +   2009.11

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    Quorum sensing (QS) systems have been discovered in a wide variety of bacteria, and mediate both intra- and interspecies communication. The AI-2-based QS system represents the most studied of these proposed interspecies systems and has been shown to regulate diverse functions such as bioluminescence, expression of virulence factors, and biofilm formation. As such, the development of modulatory compounds, both agonists and antagonists, is of great interest for the study of unknown AI-2-based QS systems and the potential treatment of bacterial infections. The fimbrolide class of natural products has exhibited excellent inhibitory activity against AI-2-based QS and as such may be considered the "gold standard" of AI-2 inhibitors. Thus, we sought to include a fimbrolide as a control compound for our recently developed alkyl-DPD panel of AI-2 modulators. Herein, we present a revised synthesis of a commonly studied fimbrolide as well as a direct comparison between the fimbrolide and alkyl-DPD analogues. We demonstrate that our alkyl-DPD analogues are more potent inhibitors of QS in both Vibrio harveyi and Salmonella typhimurium, the two organisms with defined AI-2 QS systems, and in doing so call into question the widely accepted use of fimbrolide-derived compounds as the "gold standard" of AI-2 inhibition.

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  • Synthesis of 2alpha-substituted-14-epi-previtamin D3 and its genomic activity. Reviewed

    Sawada D, Katayama T, Tsukuda Y, Saito N, Takano M, Saito H, Takagi K, Ochiai E, Ishizuka S, Takenouchi K, Kittaka A

    Bioorganic & medicinal chemistry letters   19 ( 18 )   5397 - 5400   2009.9

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    We synthesized and isolated 2 alpha-substituted analogs of 14-epi-previtamin D-3 after thermal isomerization at 80 degrees C for the first time. The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were evaluated, and the 2 alpha-methyl-substituted analog was found to have greater genomic activity than 14-epi-previtamin D-3. (C) 2009 Elsevier Ltd. All rights reserved.

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  • Synthesis and biological activities of 14-epi-MART-10 and 14-epi-MART-11: implications for cancer and osteoporosis treatment. Reviewed

    Kittaka A, Hara H, Takano M, Sawada D, Arai MA, Takagi K, Chida T, Harada Y, Saito H, Takenouchi K, Ishizuka S, Hayashi K, Ikushiro S, Sakaki T, Sugiura T, Chen TC

    Anticancer research   29 ( 9 )   3563 - 3569   2009.9

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    The 14-epimer of MART-10, namely 14-epi-MART-10 (14-epi-2 alpha-(3-hydroxypropyl)-1 alpha,25-dihydroxy-19-norvitamin D-3) and its 2-epimeric analog (14-epi-MART-11) were efficiently synthesized using the Julia coupling reaction to connect between the C5 and C6 positions (steroid numbering). An A-ring precursor was prepared from (-)-quinic acid as shown in the previous MART-10 synthesis. The novel 14-epi-CD-ring coupling partner with an elongated two carbon unit as a sulfone was synthesized from 14-epi-25-hydroxy Grundmann's ketone in good yield. The subsequent coupling reaction followed by a deprotection step afforded a mixture of 14-epi-MART-10 and 14-epi-MART-11 in 40% yield. To separate 14-epi-MART-10 and 14-epi-MART-11, each primary hydroxyl group was esterified with a pivaloyl group and the resulting pivalates 2 alpha and 2 beta were separated by high performance liquid chromatography. After the separation, the C2-stereochemistry of each (2 alpha or 2 beta) was determined by H-1 NMR (nuclear magnetic resonance) studies including NOE (nuclear Overhauser effect) experiments. The pivaloyl group was removed under basic conditions to obtain the target molecules of 14-epi-MART-10 and 14-epi-MART-11, respectively. The VDR (vitamin D receptor)-binding affinity, HL-60 (human promyelocytic leukemia) cell differentiation activity, antiproliferative activity in PZ-HPV-7 (immortalized normal prostate) cells and transactivation activity of the osteocalcin promoter in HOS (human osteoblast cell line) cells (serum-free conditions) were investigated. In addition, the effects on bone mineral density (BMD) and the blood and urine calcium concentrations of ovariectomized (OVX) rats were examined. 14-epi-MART-10 has much greater antiproliferative and cell differentiation activities compared to 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3).

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  • Synthesis and Biological Evaluation of 4-Substituted Vitamin D and 14-Epi-Previtamin D Analogs

    Daisuke Sawada, Yuya Tsukuda, Hiroshi Saito, Ken-ichiro Takagi, Kyouhei Horie, Eiji Ochiai, Kazuya Takenouchi, Atsushi Kittaka

    Chem. Pharm. Bull.   57 ( 12 )   1431 - 1433   2009

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    We synthesized the 4-hydroxy and 4-methoxy analogs of active vitamin D, (1 alpha,25(OH)(2)D-3, 1) and its C-14-epimer with the previtamin D-3 form of 14-epi-1 alpha,25(OH)(2)preD(3) (14-epi-pre1). Their vitamin D receptor (VDR) binding affinity and osteocalcin promoter transactivation activity in HOS cells were evaluated, and had lower activity than the natural hormone (1) and 14-epi-pre1, respectively.

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  • Novel synthesis of oligosaccharides linked with carbamate and urea bonds utilizing modified Curtius rearrangement Reviewed

    Daisuke Sawada, Shinya Sasayama, Hideyo Takahashi, Shiro Ikegami

    TETRAHEDRON   64 ( 37 )   8780 - 8788   2008.9

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    We describe a novel synthesis of various carbamate- and urea-linked disaccharides stereospecifically using sugar carboxylic acids and sugar alcohols or sugar amines by the modified Curtius rearrangement. In this reaction, the reactivity of each hydroxyl group in glucose as an acceptor has been disclosed. Furthermore. we applied this method to the synthesis of carbamate-linked oligosaccharides including a dendritic molecule. (C) 2008 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2008.06.089

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  • Novel synthesis of carbamate-linked oligosaccharides by a modified curtius rearrangement Reviewed

    Daisuke Sawada, Shinya Sasayama, Hideyo Takahashi, Shiro Ikegami

    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY   2007 ( 7 )   1064 - 1068   2007.2

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    We describe a novel stereospecific synthesis of various carbamate-linked disaccharides using sugar carboxylic acids and sugar alcohols by a modified Curtius rearrangement. Furthermore, we applied this method to the synthesis of carbamate-linked oligosaccharides including a dendritic molecule. (C) Wiley-VCH Verlag GmbH & Co.

    DOI: 10.1002/ejoc.200600993

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  • Short-step synthesis of 5-thio-l-hexopyranoses from d-glyconothio-O-lactones Reviewed

    Daisuke Sawada, Shinya Sasayama, Hideyo Takahashi, Shiro Ikegami

    Heterocycles   66 ( 1 )   441 - 451   2005.12

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    We developed a synthetic method for 5-thio-l-hexopyranose from d-glyconothio-O-lactone using the initial ring-opening reaction and subsequent recyclization under Mitsunobu conditions. Using this method, only a three-step transformation is required from d-glyconothio-O-lactone to 5-thio-l-glyconolactone. © 2005 The Japan Institute of Heterocyclic Chemistry.

    DOI: 10.3987/COM-05-S(K)52

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  • Synthesis of N-protected azaoligosaccharides and their cyclic derivatives Reviewed

    Daisuke Sawada, Hideyo Takahashi, Moto Shiro, Shiro Ikegami

    Tetrahedron Letters   46 ( 14 )   2399 - 2403   2005.4

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    Azaoligosaccharides are prepared through the glycosylation of nojirimycin derivatives with catalytic amounts of TMSOTf. Also, the 1-6′, 1′-6-cyclic azadisaccharides are successfully synthesized, and their one-pot syntheses are demonstrated. © 2005 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2005.02.057

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  • Efficient synthesis of 1-deoxy-azasugars as useful synthetic tools Reviewed

    Daisuke Sawada, Hideyo Takahashi, Shiro Ikegami

    Tetrahedron Letters   44 ( 15 )   3085 - 3088   2003.4

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    1-Deoxy-azasugars are efficiently prepared from sugar-lactones using a stereoinversion process and they are applied to the synthesis of a natural product. © 2003 Elsevier Science Ltd. All rights reserved.

    DOI: 10.1016/S0040-4039(03)00512-4

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  • A new method for formacetal linkage formation: Protection of alcohols, phenols and carboxylic acids

    Daisuke Sawada, Yukishige Ito

    Tetrahedron Letters   42 ( 13 )   2501 - 2504   2001.3

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    A new formacetal linkage (ROCH2OR′) forming reaction was developed, which exploited a combination of sulfide (R′OCH2SR″) and CuBr2-Bu4NBr. This reaction proceeded to give high yields under neutral conditions and was applied to the protection of alcohols, phenols and carboxylic acids by several types of α-oxymethyl groups. © 2001 Elsevier Science Ltd.

    DOI: 10.1016/S0040-4039(01)00212-X

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  • Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis Reviewed

    D Sawada, M Kanai, M Shibasaki

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   122 ( 43 )   10521 - 10532   2000.11

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    An enantioselective total synthesis of epothilones A (1) and B (2) using multifunctional asymmetric catalysis such as a cyanosilylation of an aldehyde, an aldol reaction of an unmodified ketone with an aldehyde, and a protonation in the conjugate addition of a thiol to an alpha,beta -unsaturated thioester has been achieved. We divided 1 and 2 into fragment A, fragment B, and fragment C. A catalytic asymmetric synthesis of fragments A and B was accomplished using a catalytic asymmetric cyanosilylation as a key step. An enantiocontrolled synthesis of fragment C was achieved in two ways. One is the use of a direct catalytic asymmetric aldol reaction of an unmodified ketone with an aldehyde as a key step, and the other utilizes a catalytic asymmetric protonation in the conjugate addition of a thiol to an alpha,beta -unsaturated thioester as a key step. Suzuki cross-coupling of fragment A with fragment C followed by Yamaguchi lactonization as key steps led to an enantiocontrolled synthesis of epothilone A (1). On the other hand, Suzuki cross-coupling of fragment B with fragment C followed by Yamaguchi lactonization accomplished an enantiocontrolled synthesis of epothilone B (2).

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  • Enantioselective total synthesis of epothilone A using multifunctional asymmetric catalyses Reviewed

    D Sawada, M Shibasaki

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   39 ( 1 )   209 - +   2000

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    A catalytic version has now been developed for the enantioselective total synthesis of epothilone A (1). The key is the use of multifunctional asymmetric catalySes for a direct aldol reaction and cyanosilylation. This successful approach demonstrated the usefulness of these reactions for the catalytic asymmetric synthesis of complex molecules.

    DOI: 10.1002/(SICI)1521-3773(20000103)39:1<209::AID-ANIE209>3.0.CO;2-F

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  • A new bifunctional asymmetric catalysis: An efficient catalytic asymmetric cyanosilylation of aldehydes Reviewed

    Y Hamashima, D Sawada, M Kanai, M Shibasaki

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   121 ( 11 )   2641 - 2642   1999.3

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  • Novel phorbol analogs which bind to protein kinase C (PKC) without activation

    K. Sugita, D. Sawada, M. Sodeoka, H. Sasai, M. Shibasaki

    Chemical and Pharmaceutical Bulletin   44 ( 2 )   463 - 465   1996

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    13-Deacetoxy-11-demethyl-phorbol derivatives with acyl groups of various lengths (from hexanoyl to tetradecanoyl) at the C-12 position were synthesized in an optically active form. Although considerable binding affinities to PKC were observed by analogs 3-7, no activation of PKC was seen even at 10 μM.

    DOI: 10.1248/cpb.44.463

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  • 4 SYNTHESIS TOWAED ADVANCED ANALOG OF PMA AND EVALUATION OF ITS BIOLOGICAL ACTIVITY

    SUGITA Kazuyuki, SAWADA Daisuke, SODEOKA Mikiko, SASAI Hiroaki, SHIBASAKI Masakatsu

    Symposium on the Chemistry of Natural Products, symposium papers   ( 37 )   19 - 24   1995.9

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    The enzyme protein kinase C (PKC) is thought to play a major role in cellular signal transduction and has been shown to exist as several isoforms. PKC is activated in cells by diacylglycerol and other diverse tumor promotors such as phorbol 12-myristate-13-acetate (1; PMA). Computer modeling studies on PMA have suggested that carbonyl group at C-3, hydroxyl groups at C-4, C-9, and C-20, and a long-chain hydrophobic portion at C-12 would be important to bind with PKC. However these structural hypotheses have not been confirmed by determining the actual PKC binding affinity or activity relationships of such substituted phorbols. We report here the entire stereospecific syntheses of phorbol analogs with the proposed necessary structural features in PKC activation. In particular, these include the syntheses of the analogs 7 and 10 having long-chain hydrophobic moieties at C-12 of their phorbol C-rings. The key intermediate 18 for the synthesis of these analogs is prepared from (+)-3-carene in a stereocontrolled manner. For the synthesis of 10, treatment of 18 with the phosphonate carbanion generated from 19 resulted in stereospecific formation of the E-stereoisomer of 20. DIBAH reduction of 20 and protection of the resulting primary alcohol, as its tert-butyldiphenylsilyl ether, yielded 21. A three-step series of reactions involving tosylation, iodide substitution, and nitration gave 22. The next crucial step was intramolecular cyclization of 22 to the corresponding isoxazolin 23, which was subsequently hydrogenated to the hydroxy ketone 24 in 85% yield (2 steps). Internal cerium alkoxide assisted propynylation of 24 was then followed by oxidation and conversion of the resulting intermediate into the ethyl-ketone 26. Intramolecular aldol cyclization of 26 and dehydration of the resulting aldol mixture in one-pot, followed by deprotection of the silyl ethers, gave the analog 9. Its allylic alcohol functionality was protected as its trityl ether, and the long-chain myristate group was then introduced at C-12. Selective deprotection of the trityl group of the resulting intermediate afforded the phorbol analog 10. The remaining hydrophobic analog 7 was obtained from 18 using similar methods to those used in the conversion of 18 to 10. The in vitro binding affinity of the phorbol analogs 7 and 10, relative to that of PMA (1), was then evaluated. The analog 7 proved to be very weak with respect to its affinity to bind to PKC, and an approximate 100 fold concentration of 10 was required. These results suggested that either the additional methyl and/or the acetoxyl groups at C-11 and C-13 respectively of 1 are also responsible for its high binding affinity to PKC. They may also be attributed to the presence of too much hydrophobic character due to the long chain at C-12 of the deacetoxy analog 10 resulting in a different hydrophobic interaction with phosphatidyl serine or PKC. In fact, an analog which has octanoyl group at C-12 shows higher binding affinity than that of 10.

    DOI: 10.24496/tennenyuki.37.0_19

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  • Synthesis of 2-arylindoles by the dehydrative skeletal rearrangement and its application

    清水香帆, 阿部匠, 谷岡卓, 神野伸一郎, 澤田大介

    日本薬学会年会要旨集(Web)   142nd   2022

  • Development and application of indolyl azide equivalents based on the stabilization by O-Nβ bonding

    山城寿樹, 阿部匠, 谷岡卓, 神野伸一郎, 澤田大介

    日本薬学会年会要旨集(Web)   142nd   2022

  • アジドインドリンの開発とその応用

    山城寿樹, 阿部匠, 谷岡卓, 神野伸一郎, 澤田大介

    反応と合成の進歩シンポジウム講演要旨集   48th   2022

  • Synthesis of Indolyacetamides by Alkylation・Cyclization・O-Transfer Reactions

    阿部匠, 野田健太, 澤田大介

    日本薬学会年会要旨集(Web)   141st   2021

  • Synthesis of benzothiazole-linked polycyclic compounds via intramolecular C-H bond activation - cyclization and application to macrocyclic compounds

    和久夢, 阿部匠, 澤田大介

    日本薬学会年会要旨集(Web)   141st   2021

  • 二重極性転換型インドール試薬の開発と芳香族求核置換反応への応用

    平尾誠弥, 阿部匠, 澤田大介

    反応と合成の進歩シンポジウム講演要旨集   47th   2021

  • ベンゾチアゾール連結型大環状化合物の合成研究

    和久夢, 木全桃子, 阿部匠, 澤田大介

    反応と合成の進歩シンポジウム講演要旨集   47th   2021

  • チオアミドを用いたペプチドN末端カルバメート保護基変換反応の開発

    茨実穂, 阿部匠, 澤田大介

    反応と合成の進歩シンポジウム講演要旨集   47th   2021

  • Development of chromic molecule that can change color and absorption/fluorescence wavelengths largely in response to external stimuli

    Shinichiro Kamino, Masaru Tanioka, Daisuke Sawada

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry   76 ( 10 )   1066 - 1075   2018

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    Aminobenzopyranoxanthene (ABPX) dye, developed by our group, exhibits two-step color change in solution through a spiro-ring opening/closing process in response to chemical stimuli such as acids, metal ions and phenols. Using this unique characteristic, we have developed ABPX-based colorimetric sensor that change color depending on Cu2+ concentration, enabling visualization by spectrophotometry and the naked eye. Furthermore, an efficient and practical method to prepare ABPX with various nitrogen-containing fused rings was developed. Using a simple acid-catalyzed reaction consisting of 1,3-diisopropoxybenzene and CH 3SO 3H, a variety of benzophenones gave ABPX directly in excellent yields. We discovered that ABPX is a new type of mechanochromic organic molecule with a large wavelength difference of fluorescence (near-IR/blue). Detailed spectrophotometric and single-crystal X-ray analyses revealed that the near-IR fluorescence is attributable to fluorescence from slip-stacked dimeric structures in crystals, while the blue fluorescence is attributable to fluorescence from the monomer. Switching between the two is achieved by dynamic structural interconversion in response to mechanical grinding and exposure to the vapor of solvents.

    DOI: 10.5059/yukigoseikyokaishi.76.1066

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  • 2. 7,8-cis-19-Norvitamin D_3の合成とVDR結合および7,8-cis-vitamin D_3の化学的性質(研究発表,第348回会議研究発表要旨,脂溶性ビタミン総合研究委員会)

    澤田 大介, 松本 洋太郎, 川越 文裕, 竹内 明子, 角田 真二, 上村 みどり, 橘高 敦史

    ビタミン   90 ( 2 )   84 - 85   2016.2

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  • 8,9‐ジヒドロ‐19‐ノルタキステロール誘導体の合成と生物活性評価

    松本洋太郎, 澤田大介, 竹内明子, 橘高敦史

    反応と合成の進歩シンポジウム講演要旨集   40th   27   2014.10

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  • 8,9‐ジヒドロ‐19‐ノルタキステロールの合成研究

    松本洋太郎, 山田徹, 森幸樹, 澤田大介, 橘高敦史

    日本薬学会関東支部大会講演要旨集   58th   189   2014.9

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  • 2-II-19 2α位にテトラゾールプロピル基を有する19-ノル型ビタミンD_3の合成と生物活性評価(一般演題要旨,第66回大会講演要旨)

    高野 真史, 樋口 恵理香, 竹内 明子, 澤田 大介, 橘高 敦史

    ビタミン   88 ( 4 )   244 - 244   2014.4

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  • 14‐エピ‐8,9‐ジヒドロ‐1α,25‐ジヒドロキシ‐19‐ノルタキステロールの合成

    澤田大介, 松本洋太郎, 竹内明子, 橘高敦史

    日本薬学会年会要旨集(CD-ROM)   134th   ROMBUNNO.29AMS-054   2014

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  • 2. 2α-アゾールエチル基を有する1α, 25-ジヒドロキシビタミンD_3の合成と生物活性評価(研究発表,第340回会議研究発表要旨,脂溶性ビタミン総合研究委員会)

    橘高 敦史, 堀江 恭平, 上村 みどり, 竹之内 一弥, 松尾 実紀, 長谷川 麻美, 高野 真史, 澤田 大介, 齋藤 博, 角田 真二, 高木 健一郎, 落合 鋭士

    ビタミン   87 ( 11 )   652 - 652   2013

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    DOI: 10.20632/vso.87.11_652

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  • 2-III-6 14-エピタキステロール類の合成とVDR結合様式の解明(一般演題要旨,第65回大会講演要旨)

    澤田 大介, 堀江 恭平, 落合 鋭士, 竹内 明子, 角田 真二, 上村 みどり, 橘高 敦史

    ビタミン   87 ( 4 )   220 - 220   2013

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  • 2alpha-(3-ヒドロキシプロピル)-lalpha,25-ジヒドロキシ-19-ノルビタミンD_3(MART-10)とその類縁体の合成と抗がん活性等(研究発表,第336回会議研究発表要旨,脂溶性ビタミン総合研究委員会)

    高野 真史, 澤田 大介, 橘高 敦史, 高木 健一郎, 千田 貴之, 原田 善文, 齋藤 博, 山本 恵子, 榊 利之, Chiang Kun-Chun, Zheng Shasha, Flanagan John N, Chen Tai C

    ビタミン   86 ( 12 )   694 - 696   2012.12

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    DOI: 10.20632/vso.86.12_694

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  • ヒト由来CYP24A1抵抗性ビタミンD誘導体合成とATRA耐性APL細胞分化誘導(一般演題要旨,日本ビタミン学会第64回大会講演要旨)

    高野 真史, 松本 直樹, 林 恵子, 生城 真一, 榊 利之, 角田 真二, 高木 健一郎, 落合 鋭士, 堀江 恭平, 上村 みどり, 澤田 大介, 野尻 久雄, 橘高 敦史

    ビタミン   86 ( 4 )   243 - 243   2012.4

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  • 14-エピ-19-ノルタキステロールの合成とVDRリガンド骨格としての可能性(第332回会議研究発表要旨,脂溶性ビタミン総合研究委員会)

    澤田 大介, 佃 勇也, 橘高 敦史, 齋藤 博, 角田 真二, 上村 みどり, 竹之内 一弥

    ビタミン   86 ( 3 )   181 - 182   2012.3

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  • EVALUATION AND CHARACTERIZATION OF 14-EPI-19-NORTACHYSTEROL ANALOGS FROM 14-EPI-19-NORPREVITAMIN D-3

    D. Sawada, Y. Tsukuda, H. Saito, K. Takagi, S. Kakuda, M. T. Kamimura, K. Takenouchi, A. Kittaka

    ANTICANCER RESEARCH   31 ( 4 )   1501 - 1501   2011.4

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  • SYNTHESIS OF C15-MODIFIED 16-ENE-ACTIVE VITAMIN D-3 ANALOGS FOR THE RECEPTOR-LIGAND INTERACTION STUDIES

    A. Kittaka, G. Kumagai, M. Takano, D. Sawada, H. Saito, S. Kakuda, K. Takagi, E. Ochiai, K. Horie, K. Takenouchi, M. T. Kamimura, T. C. Chen

    ANTICANCER RESEARCH   31 ( 4 )   1500 - 1501   2011.4

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  • 変異VDR(Arg274Leu)に対するセコステロイドリガンドの設計と合成(第329回会議研究発表要旨,脂溶性ビタミン総合研究委員会)

    本澤 忍, 高橋 尚志, 山本 康弘, 荒井 緑, 高野 真史, 澤田 大介, 山下 純, 杉浦 隆之, 橘高 敦史, 角田 真二, 齋藤 博, 高木 健一郎, 上村 みどり, 石塚 誠一, 竹之内 一弥, 榊 利之, 加藤 茂明, 栗原 正明

    ビタミン   85 ( 3 )   166 - 167   2011.3

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    DOI: 10.20632/vso.85.3_166_2

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  • 2-II-20 2α位にアゾール環側鎖を有する活性型ビタミンD_3の合成と生物活性評価(一般演題要旨,日本ビタミン学会第63回大会講演要旨)

    高野 真史, 上村 みどり, 竹之 内一弥, 澤田 大介, 橘高 敦史, 松尾 実紀, 長谷川 麻美, 中村 優子, 齋藤 博, 角田 真二, 高木 健一郎, 落合 鋭士, 堀江 恭平

    ビタミン   85 ( 4 )   236 - 236   2011

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  • 1-I-6 新規15位置換活性型ビタミンD_3の合成研究(一般演題,日本ビタミン学会第62回大会発表要旨)

    熊谷 剛, 上村 みどり, 竹之内 一弥, 橘高 敦史, 澤田 大介, 新藤 香菜子, 高野 真史, 角田 真二, 齋藤 博, 高木 健一郎, 落合 鋭士, 堀江 恭平

    ビタミン   84 ( 4 )   2010

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  • 1-I-5 14-epi-19-norprevitamin D_3から14-epi-19-nortachysterolへの展開(一般演題,日本ビタミン学会第62回大会発表要旨)

    澤田 大介, 佃 勇也, 堀江 恭平, 落合 鋭士, 齋藤 博, 角田 真二, 上村 みどり, 竹之内 一弥, 橘高 敦史

    ビタミン   84 ( 4 )   157 - 157   2010

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  • 1-I-7 2α位に2-(1H-テトラゾール-1-イル)エチル基及び 2-(2H-テトラゾール-2-イル)エチル基を有する活性型ビタミンD_3の合成と生物活性評価(一般演題,日本ビタミン学会第62回大会発表要旨)

    松尾 実紀, 上村 みどり, 竹之内 一弥, 澤田 大介, 橘高 敦史, 長谷川 麻美, 高野 真史, 中村 優子, 齋藤 博, 角田 真二, 高木 健一郎, 落合 鋭士, 堀江 恭平

    ビタミン   84 ( 4 )   158 - 158   2010

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  • 新規15位置換活性型ビタミンD3の合成とビタミンD受容体との相互作用および生物活性(第324回脂溶性ビタミン総合研究委員会研究発表要旨)

    新藤 香菜子, 高野 真史, 齋藤 望, 澤田 大介, 橘高 敦史, 角田 真二, 齋藤 博, 高木 健一郎, 上村 みどり, 石塚 誠一, 竹之内 一弥

    ビタミン   83 ( 10 )   593 - 593   2009.10

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    DOI: 10.20632/vso.83.10_593_1

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  • 活性型ビタミンD3の2α位の構造修飾とVDRリガンド結合領域に存在する水分子(water channel)との相互作用と生物活性(第321回会議研究発表要旨,脂溶性ビタミン総合研究委員会)

    高野 真史, 澤田 大介, 橘高 敦史, 杉浦 隆之, 高木 健一郎, 石塚 誠一, 竹之内 一弥, 角田 真二, 上村 みどり, 林 恵子, 生城 真一, 榊 利之

    ビタミン   83 ( 5 )   328 - 329   2009.6

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    DOI: 10.20632/vso.83.5-6_328

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  • 活性型ビタミンD3誘導体における核内受容体Water Channelの維持と生物活性(一般研究発表,日本ビタミン学会第61回大会研究発表要旨)

    高野 真史, 澤田 大介, 林 恵子, 生城 真一, 榊 利之, 角田 真二, 高木 健一郎, 堀江 恭平, 上村 みどり, 竹之内 一弥, 杉浦 隆之, 野尻 久雄, 橘高 敦史

    ビタミン   83 ( 4 )   206 - 206   2009.4

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  • MEDI 428-New vitamin D3 analogs: 2alpha-(2,3-Dihydroxypropoxy)- and 2alpha-(2-hydroxypropoxy)- active vitamin D3 with highly potent VDR agonism

    Masashi Takano, Daisuke Sawada, Keiko Hayashi, Shin-ichi Ikushiro, Toshiyuki Sakaki, Ken-ichiro Takagi, Seiichi Ishizuka, Midori Takimoto-Kamimura, Maiko Gokoh, Takayuki Sugiura, Atsushi Kittaka

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   236   2008.8

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  • MEDI 87-Synthesis and biological evaluation of novel 2-substituted 14-epi-previtamin D3 analogs

    Daisuke Sawada, Yuya Tsukuda, Nozomi Saito, Tomoyuki Katayama, Hiroshi Saito, Ken-ichiro Takagi, Kazuya Takenouchi, Seiichi Ishizuka, Midori Takimoto-Kamimura, Masashi Takano, Atsushi Kittaka

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   236   2008.8

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  • 2位置換14-エピプレビタミンD3誘導体の合成と活性評価(一般研究発表,新世紀ビタミン学の展望と先進的展開を目指して,日本ビタミン学会第60回大会発表要旨)

    澤田 大介, 佃 勇也, 片山 智之, 齋藤 望, 齋藤 博, 竹之内 一弥, 高木 健一郎, 滑川 淳一, 石塚 誠一, 橘高 敦史

    ビタミン   82 ( 4 )   272 - 272   2008.4

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  • 14-エピプレビタミンD3への4位置換基の導入(一般研究発表,新世紀ビタミン学の展望と先進的展開を目指して,日本ビタミン学会第60回大会発表要旨)

    佃 勇也, 澤田 大介, 高木 健一郎, 石塚 誠一, 橘高 敦史

    ビタミン   82 ( 4 )   272 - 272   2008.4

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  • 2α-(2-Hydroxypropoxy)-1α,25-dihydroxyvitamin D_3の合成と生物活性評価(一般研究発表,新世紀ビタミン学の展望と先進的展開を目指して,日本ビタミン学会第60回大会発表要旨)

    高野 真史, 澤田 大介, 林 恵子, 生城 真一, 榊 利之, 高木 健一郎, 石塚 誠一, 杉浦 隆之, 橘高 敦史

    ビタミン   82 ( 4 )   271 - 271   2008.4

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  • Vitamin D hormone: Structural refinement of the seco-steroidal skeleton and the nuclear receptor mediated biological activity

    Atsushi Kittaka, Daisuke Sawada, Masashi Takano, Nozomi Saito, Tomoyuki Katayama, Kanako Shindo, Yuya Tsukuda, Shinobu Honzawa, Midori A. Arai, Hiroshi Saito, Ken-ichiro Takagi, Kazuya Takenouchi, Seiichi Ishizuka, Toshiyuki Sakaki, Tai C. Chen

    ANTICANCER RESEARCH   28 ( 3A )   1618 - 1619   2008

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  • A環修飾14-epi-ビタミンD3と14-epi-19-ノルビタミンD3誘導体の合成と生物活性(第316回脂溶性ビタミン総合研究委員会発表要旨)

    澤田 大介, 齋藤 望, 片山 智之, 佃 勇也, 原 英己, 高野 真史, 橘高 敦史, 齋藤 博, 高木 健一郎, 千田 貴之, 原田 善史, 竹之内 一弥, 上村 みどり, 石塚 誠一, Chen Tai C

    ビタミン   81 ( 11 )   582 - 583   2007.11

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    DOI: 10.20632/vso.81.11_582

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  • 2α-(2, 3-Dihydroxypropoxy)-1α,25-dihydroxyvitamin D3の合成と生物活性評価(ビタミン学の原点・栄養学への21世紀的回帰, 日本ビタミン学会第59回大会)

    高野 真史, 澤田 大介, 林 恵子, 生城 真一, 榊 利之, 高木 健一郎, 石塚 誠一, 岸本 成史, 杉浦 隆之, 橘高 敦史

    ビタミン   81 ( 4 )   151 - 151   2007.4

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  • A new and facile synthesis of carbamate- and urea-linked glycoconjugate using modified Curtius rearrangement

    Daisuke Sawada, Shinya Sasayama, Hideyo Takahashi, Shiro Ikegami

    TETRAHEDRON LETTERS   47 ( 40 )   7219 - 7223   2006.10

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    We describe a facile synthetic method of carbamate- and urea-linked glycoconjugates using sugar carboxylic acids by the modified Curtius rearrangement. This reaction is a simple one-pot procedure, and various nucleophiles including tertiary alcohols can be utilized to afford desired compounds in moderate to high yields. And the stereospecific synthesis of the anomeric isomers is achieved using the corresponding two stereoisomers of glycosyl carboxylic acid. (c) 2006 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2006.07.139

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  • A new and facile synthesis of carbamate- and urea-linked glycoconjugate using modified Curtius rearrangement

    Daisuke Sawada, Shinya Sasayama, Hideyo Takahashi, Shiro Ikegami

    TETRAHEDRON LETTERS   47 ( 40 )   7219 - 7223   2006.10

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    We describe a facile synthetic method of carbamate- and urea-linked glycoconjugates using sugar carboxylic acids by the modified Curtius rearrangement. This reaction is a simple one-pot procedure, and various nucleophiles including tertiary alcohols can be utilized to afford desired compounds in moderate to high yields. And the stereospecific synthesis of the anomeric isomers is achieved using the corresponding two stereoisomers of glycosyl carboxylic acid. (c) 2006 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2006.07.139

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  • Divergent synthesis of (L)-sugars and (L)-iminosugars from D-sugars

    Hideyo Takahashi, Tomomi Shida, Yuko Hitomi, Yoshinori Iwai, Namisa Miyama, Kazusa Nishiyama, Daisuke Sawada, Shiro Ikegami

    CHEMISTRY-A EUROPEAN JOURNAL   12 ( 22 )   5868 - 5877   2006.7

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    An efficient divergent synthesis Of L-sugars and L-iminosugars from D-sugars is described. The important intermediate, delta-hydroxyalkoxamate, prepared from D-glucono-/galactono-1,5-lactone, was cyclized under Mitsunobu conditions to give the O-cyclized oxime compound and the N-cyclized lactam compound as mixtures. A more detailed investigation revealed that the appropriate protecting groups and solvents controlled the specificity for the O-/N-cyclization of the delta-hydroxyalkoxamate. Suitable protection at the delta-position of 6-hydroxyalkoxamate, derived from D-glucono-1,5-lactone, afforded the corresponding delta-alkylation product alone. Thus we succeeded in applying this to the total synthesis of L-iduronic acid. In contrast, with both TBDMS as the protecting group and RCN as the solvent the efficient conversion of D-glucono/galactono-1,5-lactone into the corresponding L-iminosugars (L-idonolactam and L-altronolactam) was achieved.

    DOI: 10.1002/chem.200600268

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  • Divergent synthesis of (L)-sugars and (L)-iminosugars from D-sugars

    Hideyo Takahashi, Tomomi Shida, Yuko Hitomi, Yoshinori Iwai, Namisa Miyama, Kazusa Nishiyama, Daisuke Sawada, Shiro Ikegami

    CHEMISTRY-A EUROPEAN JOURNAL   12 ( 22 )   5868 - 5877   2006.7

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    An efficient divergent synthesis Of L-sugars and L-iminosugars from D-sugars is described. The important intermediate, delta-hydroxyalkoxamate, prepared from D-glucono-/galactono-1,5-lactone, was cyclized under Mitsunobu conditions to give the O-cyclized oxime compound and the N-cyclized lactam compound as mixtures. A more detailed investigation revealed that the appropriate protecting groups and solvents controlled the specificity for the O-/N-cyclization of the delta-hydroxyalkoxamate. Suitable protection at the delta-position of 6-hydroxyalkoxamate, derived from D-glucono-1,5-lactone, afforded the corresponding delta-alkylation product alone. Thus we succeeded in applying this to the total synthesis of L-iduronic acid. In contrast, with both TBDMS as the protecting group and RCN as the solvent the efficient conversion of D-glucono/galactono-1,5-lactone into the corresponding L-iminosugars (L-idonolactam and L-altronolactam) was achieved.

    DOI: 10.1002/chem.200600268

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  • Highly enantioselective cyanosilylation of aldehydes catalyzed by a Lewis acid-Lewis base bifunctional catalyst

    Yoshitaka Hamashima, Daisuke Sawada, Hiroyuki Nogami, Motomu Kanai, Masakatsu Shibasaki

    Tetrahedron   57 ( 5 )   805 - 814   2001.1

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    A new bifunctional asymmetric catalyst containing a Lewis acid and a Lewis base (1) was developed and applied to the catalytic asymmetric cyanosilylation of aldehydes. The products were obtained generally with excellent enantiomeric excess. The experiments using the control catalyst (5) and the catalyst containing more electron-rich phosphine oxide (6) suggest that the catalyst 1 should promote the reaction via a dual activation of the aldehyde by the aluminum and TMSCN by the phosphine oxide. This reaction is practical and was applied to the catalytic asymmetric total synthesis of epothilone A. © 2001 Elsevier Science Ltd.

    DOI: 10.1016/S0040-4020(00)01039-5

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