2006 Fiscal Year Final Research Report Summary
Development of synthesis and applications of fluoroolefins directed to peptide mimetics.
| Project/Area Number |
16590014
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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, Associate Professor, 医学部, 准教授 (20147391)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Azusa Tokyo Women's Medical University, School of Medicine, Assistant Professor, 医学部, 助教 (10338965)
NAKAMURA Yuko Tokyo Women's Medical University, School of Medicine, Assistant Professor, 医学部, 助教 (00161216)
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| Project Period (FY) |
2004 – 2006
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| Keywords | peptide isostere / fluoroalkenes / organofluorine compounds / copper(I) mediated reaction / γ,γ-dialkoxyallylic zirconium species / carbon-carbon bond forming reaction |
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| Research Abstract |
(Z)-fluoroolefins attracts much attention as a no hydrolysable dipeptide isostere. For the construction of fluorinated dipeptide isosteres, stereocontrol of the fluoroolefin part and relative stereochemistry of two chiral centers at C2 and C5 should be major issues to be solved. We developed reductive defluorination of γ,γ-difluoro-α,β-enoates with lithiocuprate followed by reaction with alkyl halides to give the corresponding (Z)-a-alkylated products in high yields. This reaction was applied to the preparation of dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of aspartate proteases. Optically pure γ,γ-difluoro-α,β-enoate derived from N-Boc leucinol was converted to the desired α-methylated product in excellent yield in moderate Z selectivity (Z/E=6.4:1), but without diasteroselectivity. Fortunately, separation of the product mixture could be carried out to give N-Boc-Sta-Ψ[CF=CH]-Ala ethyl ester. This reaction was
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also applicable to construction of fluorinated Bestatin analogues which is a protease inhibitor and has been used as an anticancer drug.
As a new strategy, defluorinative allylic alkylation of 4,4-difluoro-3-hydroxy-5-alkenol derivatives were achieved using Grignard reagent and a catalytic amount of CuI (20 mol%) to afford 6-alkylated 4-fluoro-3-hydroxy-4-alkenols 1. Then, 1 was converted to 5-amino-4-fluoro-3-alkenol derivatives through Overman reaction or one-pot mesylation-azidation reaction in 2,5-syn or 2,5-anti selectivity, respectively. These reactions are useful methods for the diastereoselective construction of fluorinated peptide isosteres.
We have developed carbon-carbon bond-forming reaction using γ,γ-dialkoxyallylic zirconium species 2. Without an additive, 2 reacts with carbonyl compounds at the γ-position of 2. Under Lewis acid prompted conditions, 2 reacts with carbonyl compounds at the β-position followed by the cyclopropanation or cyclobutanation reaction.
In the presence of CuCN, reaction of 2 with imines proceeded at the γ-position to give gem-dialkoxyhomoallylic amines in high yield. The product could be changed to the vinyl ketones. Less
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Research Products
(12 results)
