P-72 ダイシハーベインおよび類縁体の全合成と生物活性(ポスター発表の部)

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Dysiherbaine (DH, 1) and its congener neodysiherbaine A (2), isolated from the Micronesian marine sponge, Dysidea herbacea, are remarkable excitatory amino acids with potent convulsant activity. DH activates the AMPA and kainate classes of ionotropic glutamate receptors, with a higher affinity for the latter. Furthermore, it has been revealed that DH had extremely high affinity for GluR5 and GluR6 kainate receptor subunits. Due to these intriguing pharmacological properties to kainite receptors, DH and its designed analogues are anticipated to serve as useful tools for understanding the complex functions of glutamate receptors in the central nervous system. In this presentation, we describe an efficient total synthesis of dysiherbaine. In addition, we report preparation and preliminary biological evaluation of several DH analogues to elucidate the detailed structure-activity relationship profile. A key intermediate 15 was synthesized by two approaches. The first synthetic route utilized compound 6 as the starting point, and the cis-oriented amino alcohol functionality on the tetrahydropyran ring was installed by using an S_N2 cyclization of N-Boc protected amino alcohol 12. An alternative and even more efficient synthetic approach to 15 featured stereoselective introduction of an amino group at C8 by iodoaminocyclization prior to constructing the bicyclic ether skeleton. The amino acid appendage was efficiently constructed by a catalytic asymmetric hydrogenation of enamide ester 24. The synthetic route developed here provided access to several DH analogues, including 9-epi-dysiherbaine (26a), 9-deoxydysiherbaine (26b), 9-O-methyldysiherbaine (26c), and N-ethyldysiherbaine (26d). The preliminary biological evaluation of these variants will be presented.
天然有機化合物討論会の論文
2007-08-24

P-72 ダイシハーベインおよび類縁体の全合成と生物活性(ポスター発表の部)

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