P-70 2,5-ビアリール-3,4-ジメチルテトラヒドロフラン型リグナン(-)-タラウミジンおよびその立体異性体の不斉合成と神経栄養因子様活性(ポスター発表の部)

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(-)-Talaumidin (1), a 2,5-diaryl-3,4-dimethyltetrahydrofuran lignan, isolated from Brazilian Aristolochia arcuata Masters, showed significant neurite outgrowth promoting and neuroprotective activates in the primary cultured rat cortical neurons and NGF-mediated PC12 cells. Among a number of lignans, recently, 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans have attracted considerable attention from synthetic chemists and biochemists due to their structural diversity and biological activity. While talaumidin (1) possesses the four continuous stereogenic centers existing on a tetrahydrofuran ring, there are the possible eight diastereoisomers for 1. From a synthetic point of view, it is attractive not only to stereoselectively construct the four consecutive chiral centers, but also to prepare stereoisomer libraries which would provide useful information on the structure-activity relationship of 1. In this symposium, we report our independent synthetic studies on (-)-talumidin (1) and its stereoisomers 1a-1g and their neurotrophic activities in rat primary cultured cortical neurons and PC12 cells. Asymmetric synthesis of (2S,3S,4S,5S)-1 was established by the three key steps; the anti-selective Evans aldol reaction, the diastereoselective hydroboration, and the stereoselective Friedel-Crafts reaction. The stereoisomers 1a, 1b and 1c were also synthesized from commom intermediate 14. (2S,3S,4S,5R)-1a was derived from dihydrofuran 15 by the catalytic regioselective dehydrogenation. Reduction of hemi-acetal 16 with NaBH_3CN and BF_3-OEt_2 gave rise to (2S,3S,4R,5S)-1b. Furthermore, (2S,3S,4R,5R)-1c was synthesized from diol 17 by the Mitsunobu reaction with unusual stereochemistry. On the other hand, synthesis of (2S,3R,4S,5R)-1e bearing 2S, 3R configuration on the tetrahydrofuran ring was accomplished by using the syn-selective Evans aldol reaction as the first step, followed by the catalytic regioselective dehydrogenation as the final step. The neurotrophic activity of the prepared stereoisomers was evaluated for neurite-outgrowth of NGF-mediated PC12 cells. As results, it was found that 1 and 1a showed comparative neurotrophic activity. Interestingly, 1e having all cis substituents exhibits more potent activity than 1.
天然有機化合物討論会の論文
2008-09-01

P-70 2,5-ビアリール-3,4-ジメチルテトラヒドロフラン型リグナン(-)-タラウミジンおよびその立体異性体の不斉合成と神経栄養因子様活性(ポスター発表の部)

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