| Budget Amount *help |
¥4,170,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥570,000)
Fiscal Year 2007: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Purpose of this research is to synthesize tetrodotoxin derivatives labeled with stable-isotope, which is indispensable for elucidation of the food chain mechanism and its biosynthetic study. We have synthesized 5-deoxytetrodotoxin and 5,6,11-trideoxytetrodotoxin, the most plausible precursors of tetrodotoxin, as shown below.
We have successfully developed a practical synthetic route of a new common synthetic intermediate bearing a hydroxyl group at the C-11 position, which actually allowed preparing 100 g scale of the intermediate. The synthesis of 5-deoxytetrodotoxin started from the new common intermediate. Hydroxylation at the C-8 position was carried out by neighboring group participation of trichloroacetamide, and then the configuration was inverted by oxidation-reduction of the resulting hydroxyl group. Cyclic olefin was selectively epoxidized with MCPBA, the vinyl group was ozonized to an aldehyde. Addition of acetylene, a carboxylic acid equivalent, was best carried out by lithium acetylide to give a propargyl alcohol in a highly stereoselective manner. After protective group manipulation, the alkyne moiety was cleavaged with RuO4 to generate an a-hydroxyl carboxylic acid, which spontaneously opened the epoxide to furnish lactone product.
The remaining task is installation of guanidinin group and cleavage of 1,2-glycol of the lactone intermediate. We will accomplish the synthesis of 5-deoxytetrodotoxin and then 5,6,11-trideoxytetrodotoxin labeled with stable isotope such as ^15N and ^13C atoms
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