118(P58) 新規海洋産アミノ酸神経毒(-)-Dysiherbaineの全合成研究(ポスター発表の部)

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(-)-Dysiherbaine was isolated from a Micronesian sponge Dysidea herbacea after screening for substances that exhibit potent neurotoxic activity. This amino acid was found to be a selective agonist of non-NMDA type glutamate receptors in CNS. The relative structure was determined spectroscopically to be a novel di-amino di-carboxylic acid consisting of a cis fused-hexahydrofuro[3,2-b]pyran ring substituted with a 3-[2-aminopropanoic acid] side chain. However, its absolute structure has not been determined yet. The combination of its unique molecular architecture and potent biological activity prompted us to commence the synthetic investigation on (-)-dysiherbaine. Retrosynthetic analysis of dysiherbaine led to tricyclic lactone 3 as a key intermediate. The strategy we have employed to construct the cis fused-hexahydrofuro[3,2-b]pyran core of 3 relies on the versatility of chiral epoxy alcohol 4 which is available from the Katsuki-Sharpless asymmetric epoxidation of σ-symmetrical divinyl carbinol 5. Thus, tricyclic lactone 3 was synthesized through the following major transformations (i, inversion of the hydroxy group of 4 giving 6; ii, stereo- and regioselective introduction of nitrogen atom giving 11 by the reaction of 6 with benzoyl isocyanate followed by base-treatment; iii, conversion of 11 to butenolide 14 via (Z)-α,β-unsaturated ester 13; iv, BCl_3 promoted debenzylation followed by intramolecular Michael addition of the deprotected hydroxy group to the butenolide ring). We could synthesized an advanced intermediate 19 from 3 via nitrile 2 by a four-step sequence involving DIBAL reduction, acetylation, cyanation, and alkylation of 2 with allyl bromide in the presence of (TMS)_2NNa. Although the stereochemistry of the newly formed C-4 asymmetric center is unknown, the remaining task is the construction of the 2-aminopropanoic acid moiety, for example, by ozonolysis, Strecker reaction, and hydrolysis. Furthermore, another advanced intermediate 22 having 2-amino-2-cyanopropyl side chain was also prepared from 3 by a six step sequence involving formation of Weinreb amide 20, Grignard reaction with allylmagnesium chloride followed by intramolecular ketalization giving 21, ozonolysis, Strecker reaction, and acetylation. Lewis acid catalyzed cyanation of 22 is now under investigation to achieve a total synthesis of dysiherbaine from 22.
天然有機化合物討論会の論文
1998-08-31

118(P58) 新規海洋産アミノ酸神経毒(-)-Dysiherbaineの全合成研究(ポスター発表の部)

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