| Project/Area Number |
63850176
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Synthetic chemistry
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| Research Institution | TOKYO INSTITUTE OF TECHNOLOGY |
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Principal Investigator |
NAKAI Takeshi TOKYO INSTITUTE OF TECHNOLOGY, DEPT. CHEMICAL TECHNOLOGY, PROFESSOR, 工学部, 教授 (90016717)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAYA Takao FUJISAWA PHARMACEUTICAL CO., NEW DRUG RESEARCH LABORATORY, DIRECTOR, 新薬研究所, 所長
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| Project Period (FY) |
1988 – 1989
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| Project Status |
Completed (Fiscal Year 1989)
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| Budget Amount *help |
¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1989: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1988: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Keywords | Carbapenem / Antibiotic / Asymmetric synthesis / 1beta-Methylcarbapenem / beta-Lactam / Aldol reaction / beta-Hydroxybutyrates / Double-Asymmetric Synthesis / カルバペネム系抗性物質 / 1βーメチルカルバペネム / βーラクタム / βーヒドロキシ酪酸 / βーヒドロキシイソ酪酸 / カルバペネム中間体 / アルドール反応 / βーヒドロキシ酪酸メチル |
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| Research Abstract |
Recently much attention has been focused on 1beta-methylcarbapenem antibiotics as the most promising candidates for the next generation of beta-lactam antibiotics. The main purpose of this project is to develop practical methods for asymmetric synthesis of the,1beta-methylcarbapenem key precursor.
1. A highly stereocontrolled method has been developed for the asymmetric synthesis of the 1beta-methylcarbapenem key precursor from commercially available (R)-methyl beta-hydroxybutyrate. The key step is the aldol-type reaction of an achiral ketone Sn(II)-enolate with the chiral beta-acetoxy-beta-lactam intermediate which is easily accessible from the (R)-hydroxybutyrate via our previously-developed method.
2. A new synthetic route to the 1beta-methylcarbapenem key precursor from easily available (S)-methyl beta-hydroxyisobutyrate has been developed which involves as a key step the chelation-controlled aldol reaction of (S)-3-benzyloxy-2-methylpropanal with the ketone silyl acetal of ethyl (trimethylsilyl)acetate.
3. A novel, highly efficient approach to the 1beta-methylcarbapenem key precursor has been developed which employs the (R)-hydroxybutyrate and the (S)-hydroxyisobutyrate as the starting materials. The key steps are the chelation-controlled double-asymmetric aldol reaction and the N-C_4 cyclization of the stereochemically pure aldol product.
4. A variety of 1beta-methylcarbapenem derivatives have been synthesized and their antibiotic activities have been evaluated.
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