2004 Fiscal Year Final Research Report Summary
Development of Stereoselective Synthetic Methods for Fluoroolefin Amide Isosteres
| Project/Area Number |
15590009
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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 | The University of Tokushima |
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Principal Investigator |
SANO Shigeki The University of Tokushima, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・ヘルスバイオサイエンス研究部, 助教授 (20226038)
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| Project Period (FY) |
2003 – 2004
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| Keywords | amide isosteres / fluorine and compounds / olefination / isomannide / isosorbide / axis of chirality / α-fluoro-α,β-unsaturated carboxylic acids / α-fluoro-α,β-unsaturated esters |
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| Research Abstract |
In the course of studies on "Development of Stereoselective Synthetic Methods for Fluoroolefin Amide Isosteres", we have developed several new reactions. Conformationally fixed (Z)-fluoroolefins were recently suggested to be equivalent to (s-Z)-amide from the standpoint of a mimic of the electronic features and the steric demands. Thus, we investigated the stereoselective Horner-Wadsworth-Emmons (HWE) and related reactions for the Stereoselective synthesis of (Z)-fluoroolefins.
We have developed the stereoselective HWE reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid utilizing i-PrMgBr for the synthesis of (Z)-α-fluoro-α,β-unsaturated carboxylic acids as the major products (up to 100% diastereomeric excess). In addition, a tandem stereoselective reduction-olefination reaction of ethyl 2-acyl-2-fluoro-2-diethylphosphonoacetate employing NaBH4 in EtOH was developed. The one-pot reaction gave α-fluoro-α,β-unsaturated esters with excellent (Z)-selectivity (up to 100% diastereomeric excess). A plausible mechanism involving a diastereoselective reduction predicted by the Felkin-Anh model, followed by olefination similar to the HWE reaction, has been proposed. This one-pot reaction may be expanded to provide wide application for convenient syntheses of fluoroolefin peptide isosteres.
On the other hand, the diastereoselective HWE reaction of chiral phosphonoacetates with σ-symmetric 4-tertbutylcyclohexanone and 4-phenylcyclohexanone was investigated by employing isomannide and isosorbide derivatives as chiral auxiliaries. α-Fluoro-α,β-unsaturated esters with an axis of chirality were obtained in diastereomer ratio up to 14:86 (aR:aS). This novel HWE reaction may find application in the organic synthesis of fluoroolefin amide isosteres possessing an axis of chirariy.
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