Syntheses of Alkaloids Using Palladium-Catalyzed Asymmetric Synthesis

以(S)-BINAPO为手性配体，钯催化实现了2-芳基环己烯碳酸甲酯的不对称合成。利用该方法，通过钯催化酰胺化和锆促进环化相结合，成功地合成了(-)-膜膜和(-)-膜膜。由于其广泛的生物活性，苋菜科生物碱已成为人们感兴趣的合成靶点。从Amaryllidaceae中分离出的生物碱超过100种，其中大部分可分为8个骨骼均匀的亚群。首次完成了碱类生物碱(+)-碱胺、(-)-海曼啶和(+)-pretazettine的不对称全合成。采用钯催化不对称胺化法制备起始环己烯胺，收率为80%，ee为74%。产物由甲醇重结晶。有趣的是，从母液中得到了ee含量99%的(-)-环己烯胺衍生物。分子内羰基烯反应以高度立体选择性的方式进行，得到六氢吲哚衍生物作为唯一产物。在Lewis酸催化羰基-烯反应中，分离到一个有趣的高收率重排产物。以该产物为原料，在很短的时间内合成了(+)-红胺、(-)-海曼啶和(+)-pretazettine。用x射线晶体学证实了中间钯配合物的结构。

Palladium-catalyzed asymmetric synthesis of methyl 2-arylcyciohexenyl carbonate was realized using (S)-BINAPO as a chiral ligand. Using this method, we succeeded in the total syntheses of (-)-mesembrane and (-)-mesembrine by combination of palladium-catalyzed amidation followed by zirconium-promoted cyclization. The Amaryllidaceae alkaloids have been of interest as synthetic targets due to their wide range of biological activities. Over 100 alkaloids have been isolated from memberes of the Amaryllidaceae, and most of these may be classified into eight skeletally homogeneous subgroups. We accomplished the first asymmetric total syntheses of the crinane-type alkaloids, (+)-crinamine, (-)-haemanthidine, and (+)-pretazettine. The starting cyclohexenyl amine was obtained by palladium-catalyzed asymmetric amination in 80% yield and with 74% ee. The product was recrystalyzed from MeOH. Interestingly, (-)-cyclohexenyl amine derivative with 99% ee was obtained from the mother liquor. Intramolecular carbonyl-ene reaction proceeds in a highly stereoselective manner to give hexahydroindole derivative as the sole product. In the Lewis acid-catalyzed carbonyl-ene reaction, an interesting rearrangement product was isolated in high yield. From this product, the above alkaloids, (+)-crinamine, (-)-haemanthidine, and (+)-pretazettine, were synthesized in very few steps. The structure of intermediary palladium complex was confirmed by X-ray crystallography.