2002 Fiscal Year Final Research Report Summary
Synthetic Studies on Endistonins, Which Potent Anti-virel Activity.
| Project/Area Number |
13672208
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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 Tokyo |
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Principal Investigator |
TOKUYAMA Hidetoshi The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学系研究科, 助教授 (00282608)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Eudistomins / Indde Alkaloids / Anti-viral Agent / Oxathiazepin / Tetrahydroisogvinoline / Anti-tumor Agent / Pictet-Spenglar reaction / Heck reaction |
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| Research Abstract |
The aim of this research is to establish an efficient and practical synthetic route to eudistomins, which have proved to possess potent anti-viral and anti-tumor activity. After fundamental explorations of the synthetic route, we thoroughly investigated a strategy utilizing our indole synthesis by radical cyclization of o-alkenylthioanilides. The stereoselective formation of the 7-membered oxathioazepin ring was successfully achieved via β-lactam fused system. Although the desired indole formation precursor could be obtained, the expected indole formation reaction did not take place at all in spite of extensive investigation on the reaction conditions. In the course of investigation, however, we have developed a novel transformation of primary amines to N-alkylhydroxylamines.
We then turned our attention to develop a novel formation of oxathiazepin by intramolecular alleviation of thiol. Finally, we achieved a total synthesis of (-)-eudistomin C featuring highly diastereoselective Picte
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d-Spenglar reaction catalyzed by dichloroacetic acid, and a novel protocol for the formation of oxathiazepin. The requisite indole segment was prepared by Macor's procedure exploiting intramolecular Heck reaction. After conversion to hydroxylamine derivative protectin with methyl thiomethyl (MTM) group by Mitsunobu reaction, the compound was subjected to Picted-Spengler reaction conditions with the Garner's aldehyde. In the presence of dichloroacetic acid, the desired diastereomer was obtained in high selectivity. The crucial oxathiazepin formation was started by conversion of MTM protected compound to thioacetate by treatment with sulfuly1 chloride and thioacetice acid in the presence of base After functional group manipulation, the obtained cyclization precursor bearing mesylate and thioacete functionalities was treated with potassium carbonate in methanol to furnish the oxathiazepin ring in high yield. Finally, total synthesis of (-)-eudistomin C was completed by deprotection of Boc and methoxu group with BBr_3. Less
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