Development of a method for the asymmetric construction of substituted citric acid structures and synthesis of natural products as leading compounds for drug discovery

柠檬酸烷基酯家族的天然产物如绿菌素和粗枝酸由于其对生物学上重要的酶（如丝氨酸-棕榈酰转移酶、磷脂酶A2、乙酰肝素酶、角鲨烯合酶）的有效抑制活性以及合成上有趣的结构而吸引了如此多的关注。然而，尚未开发用于构建含有季中心的高度官能化的柠檬酸结构的一般方法。本论文以柠檬酸烷基酯为目标化合物，以β-异铜脒（β-ICD）为催化剂，建立了一种高效的不对称Baylis-Hillman反应体系，并在此基础上进行了柠檬酸烷基酯的全合成研究。此外，我们还成功地以奎宁为起始原料合成了两种β-ICD的对映体互补催化剂。结果表明，β-ICD催化的γ-（对甲氧基苄基）氧基-α-酮丁酸酯的Baylis-Hillman反应具有较高的对映选择性和较好的产率。我们还考察了γ-（对甲氧基苄基）氧基-α-酮丁酸酯与S-叔丁基-4-烯硫代酸酯衍生的酮基硅醚在几种BOX-Cu催化剂上的不对称Mukaiyama aldol反应，但没有得到令人鼓舞的结果，在后一研究中，我们首次实现了基于Nozaki-Hiyama-Kishi反应的（+）-粗枝酸和（±）-粗枝酸的全合成，并测定了其绝对结构。此外，我们采用烯烃交叉复分解作为关键步骤完成了（-）-virifiofungin A的第一个全合成。

Alkylcitrate family of natural products such as viridiofungin and trachyspic acid have attracted so much attention due to their potent inhibitory activities against biologically important enzymes (e.g. serine-palmitoyl transferase, phospholipase A2, heparanase, squalene synthase) as well as synthetically intriguing structures. However, a general method for the construction of highly functionalized citric acid structures containing a quaternary center has not been developed yet. In this research, we focused on developing a general and efficient method for the asymmetric synthesis of such citric acid structures, and aimed to achieve total syntheses of alkylcitrate family of natural products.In the former research, we developed a highly efficient asymmetric Baylis-Hillman reaction using dried β-isocupreidine (β-ICD). In addition, we succeeded in synthesizing two enantio-complementary catalysts to β-ICD starting from quinine. We found that β-ICD-catalyzed Baylis-Hillman reaction of γ-(p-methoxybenzyl)oxy-α-ketobutanoate proceeded with high enantioselectivity in good yield. We also examined asymmetric Mukaiyama aldol reaction of γ-(p-methoxybenzyl)oxy-α-ketobutanoate with the ketne silyl ether drived from S-tert-butyl pent-4-enethioate using several BOX-Cu catalysts but the encouraging results were not obtained.In the latter research, we achieved the first total synthesis of (+)-trachyspic acid as well as (±)-trachyspic acid based on Nozaki-Hiyama-Kishi reaction, therby determining its absolute structure. Furthermore, we accomplished the first total synthesis of (-)-virifiofungin A employing olefin cross metathesis as a key step.