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有機合成化学協会中国四国支部  

第 69 回パネル討論会  プラス  

Seminar on Green Sustainable Chemistry in Tottori (2013-1)

 

日時：2013年6月13日（木）   13：30〜17：00  

場所：鳥取大学大学院工学研究科大講義室  

鳥取市湖山町南4-101  

主催   有機合成化学協会中国四国支部  

共催   鳥取大学グリーン・サスティナブル・ケミストリー(GSC)研究

センター  

 

 

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プログラム  

 

開会挨拶   センター長   伊藤  敏幸  

 

13:30-14:  30:  座長   松浦  和則  

藤井   郁雄   （大阪府立大学大学院理学系研究科教授，生命環境科学

域  自然科学類・学類長）  

「Molecular  Basis  for  Transition-state  Stabilization  in  

Catalytic  Antibodies」  

 

14:30-15:30：座長   斎本  博之    

宇梶   裕（金沢大学理工研究域物質化学系教授）  

Development   of   novel   synthetic   methods   for  

heterocycles  utilizing  1,3-dipoles」  

 

15:30-16:30：座長   南条  真佐人  

三好   徳和（徳島大学大学院教授・ソシオアーツ＆サイエンス研究部）  

「Development  and  Application  for  Unexpected  

Sr-mediated  Reactions」  

 

16:30-17:00：パネルディスカッション   司会：伊藤  敏幸  

 

閉会  

 

 

   

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Ikuo Fujii. Ikuo Fujii was born in Ube, Yamaguchi, Japan, in 1956. He earned his Ph.D. on pharmaceutical science under the direction of Professor Ken Kanematsu at Kyushu University (Fukuoka) in 1986, and then he was an assistant professor at Kyushu University. He was a postdoctoral associate in the laboratory of Professor Emil T. Kaiser at the Rockefeller University (New York) from 1988-1989. He was moved to The Scripps Research Institute (San Diego) to work with Professor Richard A. Lerner in 1989. In 1991, he was appointed to a senior research scientist to direct the antibody-engineering group in Protein Engineering Research Institute (Osaka). He was moved to Biomolecuar Engineering Research Institute (Osaka) and promoted to a research director in Department of Bioorganic Chemistry in 1996. In 2003, he was appointed to a professor in Osaka Prefecture University. At present, He is a professor of Department of Biological Science in Osaka Prefecture University, and the dean of School of Science. In 1996, he received The Pharmaceutical Society of Japan Award for Young Scientists for his contribution in the field on catalytic antibodies. His current research interests include directed evolution of a novel class of biofunctional molecules, (i) artificial enzymes (catalytic antibodies) and (ii) molecular-targeting peptides (antibody-like peptides).

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Molecular Basis for Transition-state Stabilization in Catalytic Antibodies

Ikuo Fujii Department of Biological Science, Graduate School of Science, Osaka Prefecture

University, 1-2 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8570, Japan. E-mail: fujii@b.s.osakafu-u.ac.jp, URL: http://www.b.s.osakafu-u.ac.jp/~fujii/

Abstract Both antibodies and enzymes play an important role in biological systems. Although enzymes can accelerate biological reactions, antibodies generally cannot. Pauling was the first to note that the difference between the two is that enzymes have evolved to selectively bind the transition state in the chemical transformations and are selected based on catalytic efficiency, whereas antibodies have evolved to maximize affinity for molecules in the ground state. In 1969, Jencks predicted that stable molecules resembling the transition state of a reaction might be used as haptens to generate antibodies with tailored catalytic activities and selectivities. Implementation of this idea was made possible by the development of monoclonal antibody techniques and in 1986 Lerner and Schultz independently reported antibody catalysis for the hydrolysis of aryl esters and carbonates, respectively. These antibodies were generated by immunization with putative transition-state analog (TSA), with the expectation that the induced antigen-combining site could be both geometrically and electronically complementary to the transition-state (Fig 1). Since the mammalian immune system is characterized by an almost limitless potential for providing receptor-like molecules for virtually any chemical structure, catalytic antibodies can provide “tailor-made” catalysts for any chemical transformation, including reactions for which no natural counterparts exists. Fig. 1. Generation of esterolytic catalytic

antibodies by immunization of a phosphonate transition-state analog (2).

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We were interested in the molecular mechanism of transition-state stabilization that is one outstanding characteristic of enzymes, and then have studied the biochemical properties within a panel of six hydrolytic catalytic antibodies elicited against a phosphonate transition-state analog 5 (Fig. 2).1 Six antibodies catalyzed the prodrug activation of chloramphenicol monoester 3 to provide the original drug 4. The transition-state analyses (kcat/kuncat versus Km/Ki) displayed a linear relationship with five antibodies, 6D9, 8D11, 4D5, 3G6, and 9C10, which have homologous primary amino acid sequences, while antibody 7C8 deviates from the linear relationship.2 These results suggest that the five antibodies catalyze the hydrolysis by the same reaction mechanism of transition-state stabilization and that catalytic factors other than transition-state stabilization are involved for antibody 7C8. The structure of 6D9 Fab with the transition-state analog (TSA) has been solved, showing that 6D9 binds the phosphonate of TSA by forming one hydrogen bond with His.3 The kinetic, structural, and thermodynamic analyses of 6D9 indicate that this antibody provides an efficient catalyst by transition-state stabilization through the hydrogen bond with His and the destabilization of the substrate. These analyses allow us to visualize the mechanisms of transition-state stabilization as well as substrate destabilization. Although catalytic antibodies are still much inferior to natural enzymes in their catalytic efficiency, several aspects including the mechanism of enzyme catalysts can be faithfully mimicked. Therefore, the molecular mechanism of catalytic antibodies might provide useful insights to understanding the catalysis in enzymes. 1. H. Miyashita, Y. Karaki, M. Kikuchi, I. Fujii, Proc. Natl. Acad. Sci. USA 1993, 90, 5337.

(b) N. Takahashi, H. Kakinuma, L. Liu, Y. Nishi, I. Fujii, Nature Biotechnology 2001, 19, 563.

2. H. Miyashita, T. Hara, R. Tanimura, F. Tanaka, M. Kikuchi, I. Fujii, Proc. Natl. Acad. Sci. USA 1994, 91, 6045.I. (b) Fujii, F. Tanaka, H. Miyashita, R. Tanimura, K. Kinoshita, J. Am. Chem. Soc. 1995, 117, 6199. (c) H. Miyashita, T. Hara, R. Tanimura, S.

Fig. 2. Prodrug activation via antibody- catalyzed reaction

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Fukuyama, C. Cagnon, A. Kohara, I. Fujii, J. Mol. Biol. 1997, 267, 1247. 3. O. Kristensen, D. G. Vassylyev, F. Tanaka, K. Morikawa, I. Fujii, J. Mol. Biol. 1998,

281, 501. (b) B. Gigant, T. Tsumuraya, I. Fujii, M. Knossow, Structure 1999, 7, 1385. 4. M. Oda, N. Ito, T. Tsumuraya, K. Suzuki, M. Sakakura, I. Fujii, J. Mol. Biol. 2007, 369,

198. (b) M. Sakakura, H. Takahashi, N. Shimba, I. Fujii, I. Shimada, J. Mol. Biol. 2007, 367, 133.

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Yutaka Ukaji Yutaka Ukaji was born in Fuji, Shizuoka, Japan, in 1960. He received his B. Sc. in 1982 and Dr. Sc. in 1987 from the University of Tokyo under the direction of the Professor T. Mukaiyama. In 1987, he was appointed as Assistant in Professor T. Fujisawa’s group at Mie University. In 1991, he moved to Professor K. Inomata’s group at Kanazawa University, where he is currently Full Professor. He joined Professor R. L. Danheiser’s group at MIT in 1995. He also joined Professor C. P. Casey’s group at University of Wisconsin-Madison as a visiting Associate Professor in 2002–2003. He was a recipient of Progress Award in Synthetic Organic Chemistry, Japan (1998) and the BCSJ Awards (2004 and 2010). His research interest is in the area of asymmetric synthesis, heterocycles, organometallic chemistry, “syn-effect,” and chemistry of phytochrome.

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Development of novel synthetic methods for heterocycles utilizing 1,3-dipoles

Yutaka Ukaji Division of Material Sciences ���Graduate School of Natural Science and Technology,

Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan E-mail: ukaji@staff.kanazawa-u.ac.jp

URL: http://chem.s.kanazawa-u.ac.jp/org/index.html Abstract

1,3-Dipoles are important chemical species containing heteroatoms, which could produce various kinds of heterocycles via concerted 1,3-dipolar cycloaddition. In order to develop a practical method for the construction of optically active heterocycles, we have designed a novel chiral reaction system possessing multi-metal centers utilizing tartaric acid ester as a chiral auxiliary.1 Based on this concept, we have developed an asymmetric 1,3-dipolar cycloaddition reaction of azomethine imines.2

Toward the preparation of heterocycles using 1,3-dipoles, a strategy consisted of a stepwise addition to 1,3-dipoles, such as nitrones, followed by cyclizaion could be an alternative and regiocontrolled pathway. We have been also interested in nucleophilic addition reactions to nitrones. In pursuing them, synthesis of heterocycles based on a new strategy of stepwise nucleophilic addition–cyclization and related transformations consisted of [1,3]-sigmatropic rearrangement were developed.3

1) Y. Ukaji, K. Inomata, Chem. Rec. 2010, 10, 173–187. 2) K. Tanaka, T. Kato, S. Fujinami, Y. Ukaji, K. Inomata, Chem. Lett. 2010, 39, 1036–1038. 3) Y. Miyamoto, N. Wada, T. Soeta, S. Fujinami, K. Inomata, Y. Ukaji, Chem. –Asian J. 2013, 8, 824–831.

OHR2

n

HO

HO

O

O

R''MgX

MeCN or EtCN, 80 °C

OiPrOiPr

O

OMg

MgO

OiPr

OO O

X

iPr

R1

NN

H OR2

nn

up to 99% ee

N N

R1

O

OH

R1

NN O

R2

(n = 1 or 2)

X2Mg

R1

N

R2

OHBn

BnN O

R2R1

AgBF4 – CuCl

NBn

N

HHO O

BnN

R1 R2

O

AgBF4

AgBF4 – CuClheat

BnR2

OR1

maleimide

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Norikazu Miyoshi Norikazu Miyoshi was born in Tokyo, Japan, in 1961. He studied the methodology in organic synthesis under Professor Teruaki Mukaiyama at Department of Chemistry, Faculty of Science, The University of Tokyoto, and completed the Bachelor's and Master's program. Successively, he studied Doctor’s program under Professor Kohichi Narasaka at the Graduate School of Science, The University of Tokyo. He accepted Assistant under Prof. Yoshiaki Ohgo, at Niigata Pharmaceutical College in 1989. He obtained Ph. D. from the Graduate School of Science, The University of Tokyo in 1993. The title of his Ph.D. thesis is “Studies on the regio- and stereoselecive carbon-carbon formation reaction catalyzed by samarium diiodide.” In 1994, he accepted the position of Lecturer at Faculty of Integrated Arts and Sciences, The University of Tokushima, and was promoted to Associate Professor at the same University in 1996. From June, 2000 to March 2001, he got a chance to research under Prof. Antony G. M. Barrett, at Imperial College, UK. In 2005, he was promoted to the position of Professor at Faculty of Integrated Arts and Sciences, The University of Tokushima. He’s research interests lie in the environmental benign and new synthetic methods mediated by metallic strontium.

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Development and Application for Unexpected Sr-mediated Reactions

Norikazu Miyoshi Department of Chemistry, Faculty of Integrated Arts and Sciences, The University of

Tokushima, 1-1 Minamijousanjima, Tokushima, 770-8502, Japan E-mail: miyoshi@ias.tokushima-u. ac.jp

Abstract Organometallic compounds are some of the most versatile reagents in organic synthesis

and among them there are organometallic compounds of alkaline-earth elements. Especially, numerous reports have been published on the so-called Grignard reagents using magnesium. However, few studies on the preparation and reactivity of organostrontium compounds were found in the literature outside our study.1)

We have been investigating synthetic reactions using strontium compounds and have reported that the alkylation of carbonyl compounds with alkyl iodides proceeded smoothly using metallic strontium to afford the corresponding adducts in good yields. In addition, to investigate the addition reaction of carboxylic acids, we found that carboxylic acids reacted with alkyl iodides to give mono-alkylated ketones in moderate to good yields preferentially, and the new alkylation method at the p-position of the aromatic ring of benzoic acid was demonstrated. When we recently extended our investigation to include the dialkylation of esters, we have recently reported the esterification of bulky tertiary alcohols, because it is found that the strontium alkoxide has powerful nucleophilicity for acid chlorides or acid anhydrides.

It is the nature of the Grignard procedure that side reactions often occurs using bulky substrates or bulky Grignard reagents. On the other hand, in strontium-mediated reaction, bulky alkylation to bulky substrates can also proceed in good yields. Moreover, unexpected reaction takes place using strontium. In these points, it seems that strontium procedures are superior methods than Grignard procedures.

Strontium is low toxic, rich deposit and not expensive. Furthermore, the handling of strontium is easy. Thus, the method using strontium has several advantages from these viewpoints. Therefore, we have every confidence that strontium method will contribute in green chemistry. 1) N. Miyoshi et al., J. Synth. Org. Chem., Jpn., 64, 845–852 (2006); 67, 1274-1281 (2009).

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鳥取大学GSCセミナーの歴史    

○第1回（Seminar  on  Green  and  Sustainable  Chemistry  in  Tottori），日本化学会・グ

リーンケミストリー研究会（17th  Green  Chemistry  Forum）と共催，平成20年12月10

日，とりぎん文化会館（鳥取県民文化会館）小ホール,  講師3名，出席者187名  

講師：上村明男（山口大学大学院医学系研究科  教授），「プラスチックの化学リサイクルに向

けた新しい方法」  

講師：丹羽   幹（鳥取大学大学院工学研究科  教授），「Y ゼオライトのブレーンステッド酸性

質発現と触媒活性」  

講師：萩原久大（新潟大学大学院自然科学研究科  教授）「イオン液体固定化触媒（SILC）とグ

リーンケミストリー」  

講師：  Professor  TECK  PENG  LOH（Nanyang  Technological  University,（Singapore））

“Ionic  Liquids  as  Green  Solvents  &  Catalysts  for  Organic  Synthesis”  

 

○第2回（Seminar  on  Green  and  Sustainable  Chemistry  in  Tottori  2009  (1)）（科研

費，特定領域研究「イオン液体の科学」，触媒学会，石油学会と共催），Ｈ21年11月14日，

工学研究科大講義室，講師13名，出席者167名  

講師：Professor  Douglas  MacFarlane(  Monash  Univ.,  Australia)”  Ionic  Liquids  and  

Global  Sustainability”  

講師：Dr.  Asako  Narita  (Kyoto  University,  Japan)  “Ionic  Liquid-modified  Inorganic  

Nanoparticles  and  their  Biomedical  Applications”  

講師：Dr.  Hideo  Midorikawa  (Asahi  Kasei  Chemicals  Corp.,  Japan),  “Environmental  

Friendly   Process   for   Producing   Cyclohexanol   from   Benzene   by   Using  

Heterogeneous  Catalysts”  

講師：Dr.   Kazu   Okumura   (Tottori   Univ.,   Japan),   “In   situ   X-ray   Absorption  

Spectroscopic  Study  of  Highly  Dispersed  Pd  Species  Active  in  the  Suzuki-Miyaura  

Reactions”  

講師：Professor  Toshiyuki  Itoh  (Tottori  Univ.,  Japan),  “Iron  Salt-catalyzed  One-Pot  

Nazarov  Cyclization  /  Michael  Reaction  of  Pyrrole  Derivatives  

講師：Professor  Bohari  M.  Yamin   (Univ.  Kebangsaan,  Malaysia),  “Structural   and  

Complexation  Studies  of  Fluorophenylthioureas”  

講師：Dr.  Hyunjoo  Lee  (KIST,  Korea),”  Alkyl  Polyfluoroalkyl  Imidazolium  Ionic  liquids:  

Synthesis  and  Characterization”  

講師：Dr.   Hisashi   Shimakoshi   (Kyushu   Univ.,   Japan),   “Bio-related   Tetrapyrrole  

Catalyst  with  Ionic  Liquid”  

講 師 ： Professor   Kenji   Takahashi,   (Kanazawa   Univ.,   Japan),”   ormation   of  

Anhydrosugars  from  Cellobiose  in  Ionic  Liquids”  

講師：Dr.  Mayumi  Nishida  (Koei  Chemical  Co.  Ltd.,  Japan),  ”  The  Development  of  

Koei’s  Ionic  Liquids”  

講師：Professor   Seiji   Suga,   (Okayama   Univ.,   Japan),   ”   Electroorganic   Synthesis  

Using  Micro  Reaction  Systems”  

講師：Professor  Toshio  Fuchigami  (Tokyo  Institute  of  Technology,  Japan),”  Highly  

Selective  Fluorination  of  Organic  Molecules  and  Macromolecules  in  Ionic  Liquids”  

講 師 ： Professor   Junko   N.   Kondo   (Tokyo   Institute   of   Technology,   Japan),  

“Crystalline  Mesoporous  Ta2O5  Photocatalyst  for  Overall  Water  Splitting”  

 

 

12

○第3回（Seminar  on  Green  and  Sustainable  Chemistry  in  Tottori  2009  (2)）Ｈ21

年12月1日，工学研究科代講義室,  講師2名，出席者154名  

講師：Professor  Pedro  Lozano  (University  of  Murcia,  Spain),  “Enzymatic  Catalysis  in  

Ionic  Liquids  and  sc-CO2  Biphasic  Systems”  

講師：Professor  Joe  Chappell University  of  Kentucky,  USA),“Evolving  the  Catalytic    (

Specificity  of  Terpene  Biosynthetic  Enzymes  and  the  Development  of  Sustainable,  

Robust  Production  Platforms  in  Yeast  and  Plants”  

 

○第4回（2010年度GSC  in  Tottori（1））（日本化学会，第53回中国四国産学連携化学

フォーラムと共同開催）Ｈ22年9月20日，工学研究科大講義室，講師5名，出席者177    

特別講演：  J-E.  Bäckvall（ストックホルム大学教授）” A  Biomimetic  Approach  to  Green  Organic  Transformations”  

特別講演：  B.  K.  Mihovilovic（ウイーン工業大学教授）“Bioorganic  Chemistry  in  

Sustainable  Synthesis”  

講師：國信洋一郎（岡山大学大学院自然科学研究科  助教）「不活性結合の切断を鍵とする新規

有機合成反応の開発」  

講師：米山公啓（広島大学大学院工学研究科  助教）「安全・安価な金属触媒を活用した有機合

成反応」  

講師：依馬  正（岡山大学大学院自然科学研究科  准教授）「多重水素結合部位を有するキラル

大環状化合物の不斉識別機能」  

 

○第5回（2010年度GSC  in  Tottori  (2)）(日本化学会，触媒学会，石油学会，化学工学会

と共催)，H22年11月13日工学研究科大講義室，講師4名，出席者188名  

講師：Suk  Bong  HONG  (Pohang  University  of  Science  and  Technology,  Korea)  

“Zeolite  Syntheses  via  a  CDM  Approach”  

講師：Shinji  INAGAKI  (Toyota  Central  R&D  Labs,  Inc.,  Japan)      

“Synthesis   of   Optically   Active   Periodic   Mesoporous   Organosilicas   toward   the  

Construction  of  Artificial  Photosynthesis”  

講師：  Akira  MIYAMOTO  (Tohoku  University,  Japan)  

“Multi-level   Computational   Chemistry   Methods   for   Green   and   Sustainable  

Chemistry”  

講師：  German  SASTRE  (Instituto  de  Tecnologia  Quimica  UPV-CSIC,  Spain)  

“Synthesis  of  Octahedral  Metal  Oxides  with  Pore  Structures”  

 

○第6回（2010年度GSC  in  Tottori(3)），（第1回イオン液体討論会（イオン液体研究会）

と共催）  

平成23年1月17日,18日，とりぎん文化会館，参加者186名  

特別講演：R.  Rogers（アラバマ大学  教授，米国）“Ionic  Liquid  Solvents  for  the  Grand  

Challenge  Inherent  in  a  Biorefinery:  Extraction  and  Separation  of  Lignin,  Cellulose,  

and  Hemicellulose” 特別講演：M-J.  KOO（インハ大学  教授，韓国，韓国生物工学会会長）“Application  of  

Ionic  Liquids  in  Bioconversion  Process”  

 

○第7回（2011  Green  Sustainable  Chemistry  Seminar  in  Tottori  (1)）  

2011年12月15日（木），共通教育棟A20講義室，出席者93名，講師3名  

講師：久枝良雄   （九州大学大学院工学研究院   教授）「Bio-inspired   Catalysts   for  

Degradation  of  Environmental  Pollutants:  Lessons  from  Metalloenzyme（バイオイン

スパイアード触媒の創製と環境浄化への応用）」  

13

講師：稲永純二  （九州大学先導物質化学研究所  教授）「Green  Asymmetric  Catalysis  with  

Diionic   Chiral   Sc-Complex   in   Ionic   Liquid:   An   Organic   Solvent-Free   Catalytic  

Asymmetric  Reaction  Process（有機溶媒フリーの不斉反応プロセスの構築）」  

講師：Suojiang  Zhang  （中国科学院(北京)教授，プロセス工学研究所長）「Hydrogen  Bonds:  

A  New  Insight  Into  Ionic  Liquids」  

 

○第8回（2011  Green  Sustainable  Chemistry  Seminar  in  Tottori  (2)）  

2012年2月14日（火曜），工学研究科大講義室，出席者193名，講師3名  

講師：小川   順（京都大学大学院農学研究科   教授）「Valuable   microbial   functions  

pioneering   bio-based   industry-   development   of   bio-lipid   platform   and  

biotransformation  」  

講師：酒井貴志（岡山大学大学院自然科学研究科  教授）「New  and  Efficient  Catalysts  for  

Activation  of  Carbon  Dioxide  and  Epoxide  to  Produce  Cyclic  Carbonate」  

講師：Xin-Hui  Xing（中国，清華大学  教授）「Microbial  Evolution  Engineering  for  Microbial  

Strain  Improvement」  

 

○第9回（2012  Green  Sustainable  Chemistry  Seminar  in  Tottori  (1)）  

GSC研究センター設置記念講演会  

2012年10月14日（火曜），共通教育棟A20講義室，出席者152名，講師3名  

講師：奥村   和（鳥取大学大学院工学研究科  准教授）  

「Structure  and  catalysis  of  layered  NbW  oxide  catalysts  constructed  by  the  

self-assembly  of  nanofibers」  

講師：Dae  Yoon  Chi（韓国  Sogang大学  教授）  

「New   Concept   Nucleophilic   Fluorination   Assisted   by   1H-1,2,3-Triazol-3-ium  

Triflates」  

講師：吉田  潤一（京都大学大学院工学研究科  教授）  

「空間で時間を制御する合成化学」  

 

○第10回（2012  Green  Sustainable  Chemistry  Seminar  in  Tottori  (2)）  

2012年12月3日（月曜），工学研究科大講義室，出席者156名，講師3名  

講師：Franz  Hollmann  (オランダ，Delft  工科大学  准教授)「Oxidoreductases  for  a  

greener  organic  synthesis  –  scope  and  challenges」  

講師：伊藤   伸哉（富山県立大学教授，生物工学研究センター所長）  

「Development  of  novel  biocatalysts  for  producing  chiral  compounds」  

講師：溝端   知宏（鳥取大学大学院工学研究科  准教授）  

「Elucidating  the  molecular  mechanism  of  chaperonin-  facilitated  protein  folding」  

 

延べ参加者1653名，講師41名