1997 Fiscal Year Final Research Report Summary
Synthesis and Utilization of Fluorine-containing Chiral Building Blocks for Development of the New Type of Drugs
| Project/Area Number |
07557304
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
医薬分子機能学
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| Research Institution | TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
TAKEUCHI Yoshio Toyama Med.Pharm.Univ., Fac.Pharm.Sci., Professer, 薬学部, 教授 (20111750)
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| Co-Investigator(Kenkyū-buntansha) |
TACHIBANA Shinro Eisai Pharm.Co., Reseach Head, 嘱託
KOMETANI Tadashi Toyama Nat.Col.Tech., DEept.Mat.Sci., Professer, 物理学科, 教授 (60042842)
HIRAI Yoshiro Toyama Univ., Dept.Sci., Professer, 理学部, 教授 (70111747)
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| Project Period (FY) |
1995 – 1997
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| Keywords | alpha-Fluoro-alpha-amino Acid / N-Fluoroproline / Fluorine-containing Peptides / Isostere / Asymmetric Fluorination / Fluorotetralone / Fluoroindanone / Five-membered Sultam |
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| Research Abstract |
1.2-(1-Fluoroethenyl) pyrrolidine, designed as a potential isostere of proline amide, was successfully prepared from proline ester by manipulation of the ester moiety. The alpha-fluoroproline derivative was also prepared by suitable protection of both C- and N-terminals.
2. The synthesis of conformationally constrained oligopeptides containing the hydantoin structure was achieved. A new route to the suitably protected alpha-amino acid amides was developed during the synthetic studies of alpha-fluoroglycine-containing oligopeptides.
3. Although the synthesis of alpha-fluoromaloni diesters was successful, all attempts to achieve the enzymatic hydrolysis of the diesters to get optically active mono-esters were unsuccessful.
4. The five-membered sultam derivatives were successfully resolved by converting them to the diastereomeric menthoxyacetyl derivatives followed by hydrolysis. The sultams were readily fluorinated to give the N-fluoro derivatives, which were expected to be potent agents for stereoselective fluorination. These agents were used for asymmetric fluorination of some indanones and tetralones. The best results were obtained when the N-fluorosultam, having both methyl and cyclohexyl groups on the chiral center, was used for fluorination of 2-methyl-1-tetralone. This gave 2-fluoro-2-methyl-1-tetralone in 80% yield with ee of 80%.
5. The synthesis of six-membered sultams was also achieved starting with N-acyl-o-toluenesulfonamides by treatment with BuLi followed by hydrogenation. The corresponding N-fluoro derivatives were prepared and they have been shown to posses enough reactivity for electrophilic fluorination.
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Research Products
(12 results)
