Total Synthesis of Alkaloids usingAsymmetric Catalysts

我们研究了在异喹啉和β-卡宾的C-1位引入手性中心的新方法。在异喹啉为底物的情况下，具有双膦配体的烯丙基铜试剂具有中等的对映体选择性来合成1-几乎1-1-1，2，3，4-四氢异喹酚Ne衍生物。这是在手性催化剂存在下，环亚胺的加成反应以不对称方式进行的快速例子。将得到的产物作为不对称全合成埃米汀的起始原料，并将该反应体系应用于具有较高α-葡萄糖苷酶抑制活性的天然产物α-Schulzeine的全合成。通过使用DTBM-SEGFOS作为双齿配体，实现了烯丙基铜与原料的关键的不对称加成反应，实现了高的对映选择性。这样得到的烯丙基加合物在立体选择性…中转化为Schulzeine的核心结构更多的风度。为了在3，4-二氢异喹啉的氯位引入缺电子的氯单元，将雅克布森硫脲催化剂应用于3，4-二氢异喹啉，得到了高对映选择性的1-氰基-1，2，3，4-四氢异喹啉。将所得产物应用于3，4-二氢β-3-甲苯基衍生物的合成，得到了1-取代手性1，2，3，4-四氢-β-Carbol-Ne衍生物，产率高，对映体选择性高。在反应条件的优化过程中，发现反应体系中少量的水是获得高立体选择性的关键。这是在Pro的有机催化化学中，水对立体化学的贡献的最快例子。以反应产物为原料，不对称全合成二氢香豆醇和育亨宾。

We have investigated new methods for the introduction of a chiral center at C-1 position of isoquinolines and β-carbolines. In the case of isoquinolines as substrates, allylcopper reagents which have diphosphine ligands afforded moderate enantioselectivity to give 1-aIly1-1, 2, 3, 4-tetrahydroisoquinol ne derivatives. This is the fast example that the addition reaction to cyclic imines proceeded in an enantioselective manner in the presence of a chiral catalyst. The product thus obtained was used as a starting material for the enantioselective total synthesis of emetine.The reaction system was further applied to the total synthesis of α-schulzeine, which is a natural product having a high α-glucosidase inhibitory activity. By using DTBM-segphos as a bidentate ligand, a high enantioselectivity was accomplished for the crucial asymmetric addition of allylcopper to the starting material. The allyl adduct thus obtained was transformed to the core structure of schulzeine in a stereoselectiv … More e manner. In addition, inhibition of a-glucosidase activity was planned to measure using bioassay.In order to introduce an electron-deficient Cl unit at Cl position of isoquinoline derivative in an enantioselective manner, Jacobsen thiourea catalyst was applied to 3, 4-dihydroisoquinoline, and 1-cyano-1, 2, 3, 4-tetrahydroisoquinoline derivatives were abtained in a highly enantioselective manner. The product thus obtained was applied to the synthesis of several isoquinoline alkaloids such as trolline and crispine.In the cases of 3, 4-dihydro β3-carboline derivatives, proline-catalyzed Mannich reaction proceeded to give chiral 1-substituted 1, 2, 3, 4-tetrahydro-β-carbol ne derivatives in good yields and a high enantioselectivity. In the process of the optimization of reaction conditions, it was revealed that the small amount of water in the reaction system was crucial for obtaining the high stereoselectivity. This is the fast example that the contribution of water to the stereochemistry was suggested in organocatalytic chemistry of proline. The reaction products were used as a starling material for theasymmetric total synthesis of dihydrocorynantheol and yohimbine Less