2003 Fiscal Year Final Research Report Summary
Development of Efficient Synthetic Method of Antitamor Annonaceous Acetogenins and Investigation of Highly Potent Derivatives
| Project/Area Number |
14572006
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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 | Osaka University |
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Principal Investigator |
MAEZAKI Naoyoshi Osaka University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (00229296)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Tetsuaki Osaka University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (40116059)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Annonaceous Acetogenin / Asymmetric Synthesis / Antitumor Natural Product / Asymmetric Alkynylation / Reiterative Synthesis / Stereodivergent Synthesis / Systematic Synthesis / Annonaceous Plant |
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| Research Abstract |
Annonaceous acetogenins are class of natural product which exhibit potent cyctotoxicity against human antitumor cell lines. Development of efficient synthetic method of these compounds is required for finding of highly potent derivatives, structure determination of the natural acetogenins, and research of the mode of action. We investigated a novel systematic synthesis of THF cores of acetogenins based on reiterative process, which will be a powerful tool to synthesize various congeners. As a result of the research, we obtained results as follows.
1)Asymmetric Alkynylation of α-Oxyaldehydes with a C_4-unit
Investigation for an appropriate C_4-unit to realize high yield and excellent diastereoselectivity revealed that 3-butyne-1,2-diol benzylideneacetal was the best C_4-unit among those we tested. Diastereoselectivity was completely controlled by changing a chiral ligand of alkynylating reagent.
2)Stereodivergent Synthesis of THF Ring Segment
Four kinds of diastereomers of mono-THF segment are stereodivergently synthesized by changing the method of THF ring closure.
3)Highly Stereocontrolled Synthesis of Poly-THF Ring Segment by Reiterative Process
Synthesis of poly-THF segment based on reiterative strategy was examined. Eight kinds of bis-THF cores were synthesized in good yield with excellent diastereoselectivity.
4)Synthesis of Acetogenin by Assembly with γ-Lactone Segment
To confirm that our method can be applied to a synthesis of acetogenins, murisolin (mono-THF acetogenin) was synthesized by employing asymmetric alkynylation with diyne as a key step. Thus, the methodology for synthesis of annonaceous acetogenins was established.
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