P-50 (+)-サキシトキシンの全合成およびその誘導体のナトリウムチャネル阻害活性評価(ポスター発表の部)

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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. We have recently achieved an enantioselective total synthesis of (-)-doSTX (2). Herein, we described an enantioselective total synthesis of (+)-STX (1) with an improved synthetic method. Our synthesis of (-)-doSTX (2) 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 (6) and the chiral nitrone 5. In this synthetic study, we used the nitro-olefin 12 as a dipolarophile instead of the corresponding α,β-unsaturated ester to simplify the introduction of C5-nitrogene group. The 1,3-dipolar cycloaddition reaction of chiral nitrone ent-5 and nitro-olefin 17 gave 5-nitro-isoxazolidine 18 quantitatively. The chemoselective reduction of NO_2 group to NH-OH at C5 in the presence of N-O bond in the isoxazolidine ring was succeeded by treatment with Zn-AcOH condition. The nitrogen atom in NH-OH group of 21 was then protected with Cbz group, followed by reduction of two N-O bonds using TiCl_3 and Zn gave 2,3-diamino-1-alcohol 26. After several conversions, 13-carbamoyl-guanidinealcohol 37 was in hand. The completion of a formal total synthesis of (+)-STX (1) was achieved by treatment of 37 with B(OCOCF_3)_3 and gave β-saxitoxinol (38) in total 14 steps 4.5% yield.
2008-09-01

P-50 (+)-サキシトキシンの全合成およびその誘導体のナトリウムチャネル阻害活性評価(ポスター発表の部)

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