Syntheses of Alkaloids Using Palladium-Catalyzed Asymmetric Synthesis

以(S)-联苯二胺为手性配体，实现了钯催化不对称合成2-芳基环己烯基碳酸酯甲酯。用这种方法，我们成功地合成了钯催化的酰胺化和锆促的环化相结合的(-)-介膜和(-)-介膜。石蒜科生物碱因其广泛的生物活性而成为人们感兴趣的合成靶标。从石蒜科植物中已分离出100多种生物碱，其中大部分可分为8个骨架均一的亚类。我们首次完成了景天烷型生物碱、(+)-景天胺、(-)-山茶碱和(+)-pretazettin的不对称全合成。通过钯催化的不对称胺化反应合成了环己烯胺，产率为80%，ee为74%。产物以甲醇为原料重结晶。有趣的是，从母液中得到了(-)-环己烯胺衍生物，其ee为99%。分子内的羰基-烯反应以高度立体选择性的方式进行，得到作为唯一产物的六氢吲哚衍生物。在Lewis酸催化的羰基-烯反应中，高产率地分离出了有趣的重排产物。以该产物为原料，用很少的步骤合成了上述生物碱，即(+)-金雀花胺、(-)-山毛碱和(+)-pretazettin。用X-射线单晶衍射法确证了中间体钯配合物的结构。

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.