16 不斉ニトロオレフィン化反応を鍵反応とする光学活性フィゾスチグミンの合成(口頭発表の部)

概要

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(-)-Physostigmine (1), a principal alkaloid of the Calabar bean, has been used clinically for glaucoma and myasthenia gravis. Recently, selected analogues of 1 have shown promise as Alzheimer's disease therapeutic agents. Here we report chiral total syntheses of 1 via asymmetric nitroolefination. 1. Synthesis starting with the lactone 4. Reaction of zinc-enolate 3 with chiral nitroenamine 2 afforded the nitroolefin 4 of 86% ee (99% yield). Diels-Alder reaction of 4 with Danishefsky diene furnished the adduct 6, which was then converted into (-)-eserethole (15) in ten steps. Transformation of 15 to 1 has already been known. 2. Synthesis starting with the lactam 18. Asymmetric nitroolefination of 17 was achieved with chiral nitroolefin 16, where chiral sulfoxide functions as a leaving group. Thus, 18 was obtained in 84% ee and 91% yield, which was converted into (-)-esermethole (24) in seven steps. Transformation of 24 to 1 has already been known. 3. Synthesis starting with the oxindole 26. To develop the most straightforward synthetic route to 1, 25 was selected as a starting material. Asymmetric nitroolefination of 25 with 2 afforded 26 of only 38% ee. On the other hand, use of the novel chiral nitroenamine 28 furnished 26 of 95% ee (83% yield). Transformation of 26 into 24 was achieved in four steps.
天然有機化合物討論会の論文
1991-09-07