1992 Fiscal Year Final Research Report Summary
Efficient Asymmetric Syntheses of 1- or 6- Fluorocarbapenem Derivatives
| Project/Area Number |
03557093
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
FUKUMOTO Keiichiro Tohoku University, Pharmaceutical Department, Professor, 薬学部, 教授 (50004586)
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| Co-Investigator(Kenkyū-buntansha) |
IHARA Masataka Tohoku University, Pharmaceutical Department, Associate Professor, 薬学部, 助教授 (00006339)
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| Project Period (FY) |
1991 – 1992
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| Keywords | Antibiotics / Fluorocarbapenem / Chiral Building Blocks / Thienamycin Derivatives / Fluoromalonate / beta-Lactam / Quaternary Asymmetric Center / Asymmetric Synthesis |
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| Research Abstract |
Thienamycin and related naturally occurring carbapenems possess potent and broad-spectrum antibacterial properties, but they suffer serious disadvantages in that they are chemically unstable and readily metabolized by renal dehydropeptidase-I. The discovery that substitution of a beta-methyl group at the 1-position of carbapenems results in high stability without loss of antibiotic activity led us to investigate the effects of other groups on the carbapenem skeleton. It has shown that fluorinated analogues of naturally occurring biologically active compounds often exhibit unique physiological activities. Therefore, we studied (A) the development of a general method for the construction of quaternary stereogenic centers possessing a fluorine atom and (B) the synthesis of fluorocarbapenems.
(A) Diastereoselective construction of quaternary stereogenic center was achieved by two approaches, fluorination of chiral alkylmalonates with 1-fluoro-2,4,6-trimethylpyridinium triflate in the presence of lithium bases and alkylation of a chiral fluoromalonate in the presence of lithium bases. Thus, a number of potential chiral building blocks of 1-fluorocarbapenems were enantioselectively prepared.
(B) The displacement reaction of the 4-acetoxyazetidin-2-one with dimethyl fluoromalonate was easily performed in the presence of lithium bases. The product was converted into two synthetic intermediates of 1-fluorocarbapenems.
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