2003 Fiscal Year Final Research Report Summary
Research of development and application of the synthesis of fluoroolefins for dipeptide isosteres
| Project/Area Number |
14572010
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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 Women's Medical University |
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Principal Investigator |
OKADA Midori Tokyo Women's Medical University, School of Medicine, Lecturer, 医学部, 講師 (20147391)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Azusa Tokyo Women's Medical University, School of Medicine, Research Assistant, 医学部, 助手 (10338965)
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| Project Period (FY) |
2002 – 2003
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| Keywords | peptide isostere / fluoroolefin / alkylaluminum -copper(I) / S_N2'-type reaction / imine / allylzirconium species / carbocyclization reaction / difluoroalkenyl methine |
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| Research Abstract |
Fluoroolefins (-CF=CH-) are considered to be ideal mimics for amide bonds (-CO-NH-) owing to the close similarity of the steric and electric properties. Therefore we researched the synthesis of (Z)-fluoroolefins which attract much attention as nonhydrolyzable and/or conformationally restricted dipeptide or depsipeptide isosteres.
Reaction of (E)-γ,γ-difluoro-α,β-enoates having a δ-hydroxyl group with trialkyl-aluminum (R_3Al) in the presence of CuI・2LiCl proceeded in SN2'-type manner to give α-alkylated (Z)-γ-fluoro-β,γ-enoates, while reductive defluorination with Me_2CuLi followed by reaction with alkyl halides provided the same products. Although both reactions proceed with complete Z-selectivity, low diastereoselectivity on chiral centers (2-and 5-positions) of each reaction is a problem to he solved. Then we examined Cu(I)-mediated alkyl-transfer reaction of R_3Al with (E)-or (Z)-4,4-difluoro-5-hydroxyallylic alcohols, which proceeded in similar manner mentioned above to give the co
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rresponding 2-alkylated (Z)-4-fluoro-5-hydroxyhomoallylic alcohols with 2,5-syn or 2,5-anti selectivity, respectively. As the reaction with R_3Al-Cu(I) of the substrates lacking of hydroxyl group on 5-position didn't proceed, 5-hydroxyl group seemed to be essential for Cu(I)-mediated alkyl-transfer reaction. It is likely that formation of a five-membered complex involving fluorine-aluminum coordination should be the first step in the present reaction. Oxidation of the primary hydroxyl group of the product to carboxylic acid was achieved without epimerization on the chiral centers and 5-hydroxyl group was converted to amino group via sulfonylation, followed by azidation in one-pot manner. We also found the preparation of 4-fluorohomoallylic alcohols via regioselective hydride reduction of 4,4-difluoroallylic alcohols. These reactions provide the stereoselective synthesis or depsipeptide and peptide isosteres.
Furthermore, we examined carbocyclization reaction of the terminally difluorinated alkenyl active methine compounds.
In addition, copper-catalyzed reactions of γ,γ-dialkoxyallylic zirconium species with imines proceeded at γ-position of zirconium species to give homoallylic amines. This result provides the possibility of the preparation of peptide isosteres using zirconium species. Less
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Research Products
(8 results)
