2007 Fiscal Year Final Research Report Summary
Development of synthetic methodogies for organofluorine compounds in medicinal chemistry
| Project/Area Number |
17590015
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
TAGUCHI Takeo Tokyo University of Pharmacy and Life Science, School of Pharmacy, Professor (00016180)
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| Co-Investigator(Kenkyū-buntansha) |
KITAGAWA Osamu Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Associate Professor (30214787)
YANAI Hikaru Tokyo University of Pharmacy and Life Sciences, School of Pharmacy, Research Associate (10408685)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Fluorinated olefin / Peptidemimetics / Chromium chloride / Glutamate receptor / Trifluoroacetaldehyde / Diels-Alder reaction / Fluoroacrylate / Atoropisomeric amide |
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| Research Abstract |
As our continuous studies on development of new synthetic methodologies for organofluorine compounds toward to the preparation of fluoro analogs of biologically important substances or to introduction of fluorine or fluoroalkyl substituent into newly designed molecules based on the characteristic features of fluorine related to biological responses, we have investigated the following research projects during these three years with the financial support in part from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Our achievements are summarized as follows.
(1) Concerning the development of efficient synthetic method for fluorine-substituted functionalized olefins related to the chemical modification of amide bond in biologically active peptides, we have established a completely stereo-controlled method, which involves defluorinative allylic alkylation reaction. This reaction has been applied to the preparation of fluoroolefin analog of pepstatin, aspartyl prote
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ase inhibitory active naturally occurring peptide. As an alternative new synthetic method for fluoroolefinic compounds, we have found that reaction of dibromofluoroalkylated substrates with low valent chromium provides the corresponding fluoroolefinic compounds in stereoselective and functional group selective manner. An efficient preparation of fluoroalkenyl ester compounds has been achieved by this reaction.
(2) For the synthesis of conformationally restricted glutamate analogs to find out selective agonist or antagonist for group II mGluR, we have applied radical addition reaction offluoroiodoacetate to olefin leading to fluorocyclopropane carboxylate, which was developed by us before.
(3) Trifluoromethyl group is widely recognized as an important substituent in drug design, and thus development of new and efficient methods for heterocyclic compounds having trifluoromethyl group using easily available building blocks is of great importance. We have achieved that a variety of quinoline and related derivatives having trifluoromethyl group at 2 position can be prepared by the reaction of 2-aminostyrene derivatives with trifluoroacetaldehyde hemiacetal.
(4) We have developed several bidentate Lewis acids, which can promote the intramolecular cycloaddition reactions of ester tethered substrates, in particular the Diels- Alder reaction of 1,7,9-decatrienoale derivatives involving 2-fluoroacrylate derivatives.
(5) Although application to the fluorine containing substrates will be a future subject, we have successfully developed a highly effective method for the preparation of atropisomeric amide compounds via enantioselective catalytic aromatic amination reaction. Some asymmetric syntheses using these chiral molecules have been also explored. Less
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Research Products
(28 results)
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[Journal Article] Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen- 9-y1)-ethyl]-1-fluorocyclopropane carboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist2008
Author(s)
Sakagami, K., Yasuhara, A., Chaki, S., Yoshikawa, R., Kawasaki, Y., Saito, A., Taguchi, T., Nakazato, A
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Journal Title
Bioorg. Med. Chem 16
Pages: 4359-4366
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Convenient synthesis of fluorinated quinoline, 1,2-dihydroquinoline and 1,2,3,4-tetrahydroquinoline Derivatives2007
Author(s)
Yanai, H., Mimura, H., Kawada, K., Taguchi, T
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Journal Title
Tetrahedron 63
Pages: 2153-2160
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] An efficient synthetic method for Z-fluoroalkene dipeptide isosteres : Application to the synthesis of the dipeptide isostere of Sta-Ala.2006
Author(s)
Nakamura, Y.,Okada, M., Koura, M., Tojo, M., Saito, A., Sato, A
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Journal Title
J. Fluorine Chem 127
Pages: 627-636
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Intramolecular [3+2] cycloaddition reaction of α,β-enoate derivatives having allylsilane parts : 1,1'-biphenyl-2,2'-di(triflypamide (BIPAM) + 2Me2A1C1 as a Novel Lewis acid2006
Author(s)
Saito, A., Sakamoto, W., Yanai, H., Taguchi, T
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Journal Title
Tetrahedron Lett 47
Pages: 4181-4185
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Highly Enantioselective Synthesis of Atropisomeric Anilide Derivatives through Catalytic Asymmetric N-Arylation : Conformational Analysis and Application to Asymmetric Enolate Chemistry2006
Author(s)
Kitagawa, O., Yoshikawa, M., Tanabe, H., Morita, T., Takahashi, M., Dobashi, Y., Taguchi, T
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Journal Title
J. Am. Chem. Soc 128
Pages: 12923-12931
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Stereoselective synthesis of (Z)-fluoroalkenes directed to peptide isosteres : copper mediated reaction of trialkylaluminum with 4,4-difluoro-5-hydroxyallylic alcohol derivatives2005
Author(s)
Nakamura, Y., Okada, M., Sato, A., Horikawa, H., Koura, M., Saito, A., Taguchi, T
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Journal Title
Tetrahedron 61
Pages: 5741-5753
Description
「研究成果報告書概要(欧文)」より
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