18 (-)-デカルバモイルオキシサキシトキシンの全合成(口頭発表の部)

抄録

Saxitoxin (STX) (1) and its derivatives are known to be neurotoxins that block the voltage-gated sodium channels, which are critical for depolarization and conduction in most excitable cells. STX (1) also binds to other receptor proteins, such as calcium and potassium channels, and appears to be of considerable biological importance. In this paper, we described an enantioselective total synthesis of (-)-decarbamoyloxysaxitoxin (doSTX) (7), which has the same skeleton as STX and its natural analogues. Our synthesis of doSTX features direct oxidation with o-iodoxybenzoic acid (IBX) at the α-position of the β-amino-substituted ketone, which was synthesized based upon the 1,3-dipolar cycloaddition reaction between methyl crotonate (13) and the chiral nitrone 12. Oxidation of the ketone derived from alcohol 22 at C4 selectively took place with IBX (1.1 equiv.) in DMSO, and gave the aminal 23 in 51% yield. Treatment of 23 with sodium borohydride at 0℃ diastereoselectively gave the alcohol, whose Boc group was deprotected with TFA, and a Cbz-protected guanidine group was installed to give 26. The structure of 26 was confirmed unequivocally by X-ray crystallographic analysis. The synthesis of 7 was completed with the following three steps from 26. Deprotection of the four Cbz groups with hydrogen in the presence of Pd(OH)_2, followed by treatment with TFA, gave the decarbamoyloxysaxitoxinol 27 in 60% overall yield. Finally, oxidation of the alcohol with dimethylsulfoxide and diisopropylcarbodiimide afforded (-)-doSTX (7) in 60% yield. All the spectroscopic data of the synthetic material were consistent with the reported data for the natural product. The optical rotation value of 7 was -23.3°(c 0.7, MeOH).