2007 Fiscal Year Final Research Report Summary
Synthetic Study of HIF-1α Inhibitor, Manassantin B
| Project/Area Number |
18590097
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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 |
Drug development chemistry
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| Research Institution | Otani Womens University |
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Principal Investigator |
MAEZAKI Naoyoshi Otani Womens University, Faculty of Pharmacy, Professor (00229296)
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| Co-Investigator(Kenkyū-buntansha) |
KITAMURA Maria Osaka Ohtani University, Faculty of Pharmacy, Assistant Professor (00434811)
HIROKAWA Yoshimi Osaka Ohtani University, Faculty of Pharmacy, Associate Professor (40454582)
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| Project Period (FY) |
2006 – 2007
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| Keywords | cancer / biological activity / organic chemistry |
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| Research Abstract |
This project aimed to develop a novel synthetic strategy of manassantin B and the derivatives having potent inhibitory activity against HI-α, which is considered as an intermediate of cancer, cerebral infarction, and cardiac infarction.
1) Synthesis of tetrasubstituted 2,5-diayl THF skeleton
To establish a synthetic method of 2,5-daryl THF skeleton, we have investigated a diastereoselective Michael addition to γ-oxy-α,β-unsaturated ketone. As a result, we found that the reaction proceeded in good yield and with excellent diastereoselectivity to give the anti-isomer by using Gilman reagent (71%, 30:1 dr) or Gilman reagent and BF_3・ether (72%, 33:1 dr). Subsequent α-methylation of the ketone also underwent in almost quantitatively with 14:1 dr when KHMDS was employed as a base in the presence of HMPA. Finally, re1-(7S,8S,7'R,8'S)-7,.7'-epoxylignan skeleton was constructed via THF ring formation.
2) Synthetic research of chiral tetrasubstituted 2,5-diayl THF skeleton
To construct two of four stereogenic centers enantioselectively, asymmetric [2,3]-Wittig rearrangement of functionalized allyl benzyl ethers was examined as a key reaction. Using a chiral di-tert-butyl bis(oxazoline) ligand, the reaction proceeded with excellent diastereo- and enantioselectivity when no methoxy substituent was present at the ortho-position on the benzyl group. On the other hand, the enantioselectivity was drastically decreased in the presence of an ortho-methoxy group. Scope and limitation of the reaction were investigated for application to the target molecules.
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