2007 Fiscal Year Final Research Report Summary
Studies on the total synthesis and SAR of natural products that bind to tublin
| Project/Area Number |
17590020
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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 | Waseda University |
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Principal Investigator |
NAKADA Masahisa Waseda University, Faculty of Science and Engineering, Professor (50198131)
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| Project Period (FY) |
2005 – 2007
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| Keywords | tubluin / natural products / asymmetric total synthesis / chiral building blocks / intramolecular Diels-Alder reaction / intramolecular hetero Diels-Alder reaction / S_N2' reduction / intramolecular Heck reaction |
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| Research Abstract |
Natural products that bind to tublin are classified to two groups, the compounds inhibit polymerization of tublin and the ones inhibit de-polymerization. These compounds resultantly inhibit mitosis to exhibit cytotoxicity. Vinblastine and taxol derivatives have been clinically used as antitumor drugs and epothilone derivatives have been conceived to be promising antitumor drugs. Thus, natural products that bind to tublin are the potential lead compounds for antitumor drugs. Hence, in this project we aimed at developing the improved synthetic route to(+)-phomopsidin, which shows tubulin polymerization inhibitory activity, as well as aimed at developing the asymmetric synthetic route of FR182876 and taxol for their SAR studies. In the studies of the efficient synthesis of (+)-phomopsidin, we successfully established the improved synthetic method through the highly stereoselective TADA reaction of the 13-membered macrocyclic lactone possessing the inverted C11 stereogenic center with the TIPS protected hydroxyl group. In the studies on the asymmetric total synthesis of FR182876, we have developed the stereoselective construction of the ABCD rings of FR182876 by the IMDA reaction and the HIMDA reaction, and we have succeeded in constructing the highly strained seven-membered ring moiety by the intramolecular Heck reaction to accomplish the asymmetric total synthesis of FR182877, which is a precursor of FR182876. In the studies on the asymmetric total synthesis of taxol, we have developed the general synthetic method for 2-benzyloxymethyl-2-methylcycloalkane-1, 3-diones and found that both their baker's yeast reduction and their CBS reduction proceeded with high diastereo-and enantioselectivity. Moreover, we have accomplished the highly stereoselective construction of the taxol C3 stereogenic center by the S_N2' reduction of the allylic phosphonium salt or the conjugate addition of a cyanide to the enone possessing the taxol A-ring and, C-ring moieties.
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