Studies on Efficient Syntheses of Tetronomycin and Tetronasin
| Project/Area Number |
03453155
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| Research Category |
Grant-in-Aid for General 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 | Toyama Medical and Pharmaceutical University |
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Principal Investigator |
YOSHII Eiichi Fac Pharm Sci, Professor, 薬学部, 教授 (50019105)
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| Co-Investigator(Kenkyū-buntansha) |
HORI Kozo Fac Pharm Sci, Assistant, 薬学部, 助手 (50173612)
NOMURA Keiichi Fac Pharm Sci, Professor, 薬学部, 教授 (30019111)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1992: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1991: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Ionophore / Antibiotic / Tetronomycin / Tetronasin / Synthesis / Tetronic acid / 天然物 / 全合成 |
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| Research Abstract |
Tetronomycin (1) and tetronasin (2) are the only member of tetronic acid polyether ionophore antibiotics, reported in the early 1980s by ICI (UK) and Sandoz (Swiss), respectively, and their novel structures have recently attracted considerable attention to synthetic chemists for the total syntheses. This investigation focuses on not only total syntheses but more importantly on finding structurally simplified ionophores of this class that are more active than the natural products. As the first goal, we have achieved the first (the only to this date) total syntheses of both natural products.
1. Synthesis of the Polyether AB Ring System: The tetrahydrofuran (THP) fragments of 1 and 2 (enantiomeric at the common 3 chiral centers) were prepared by starting with L- rhamnal. The tetrahydropyran (THP)fragments were obtained using commercially available (R)- or (S)-methyl 3-hydroxy-2-methylpropionate as the starting materials. Coupling of the THF and THP fragments was accomplished by means of employing silane chemistry (for 1), or Julia coupling technology (for 2).
2. Synthesis of the Cyclohexane C Ring: We have introduced a new annulation methodology for the construction of the functionallized C ring possessing 4 contiguous stereogenic centers. Treatment of 2,4-dimethyl-2,7-nonadienoic acid diester with L- Selectride produces stereospecifically trans/trans 1,2,3-trisubstituted cyclohexane derivative, which could be transformed to the desired C ring fragment.
3. Total Synthesis: The ABC ring system of tetronomycin was obtained by an aldol reactin between the AB-ring ester and the C-ring aldehyde, then it was coupled with gamma- methylene-beta-tetronate to lead to natural tetronomycin sodium salt. For the tetronasin synthesis, its ABC-ring aldehyde was subjected to a Lewis acid catalyzed reaction with methyl (diazoacetoxy) acetate to afford a beta-ketoester, which upon an internal cyclization provided tetronasin.
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Report
(3 results)
Research Products
(7 results)
