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

开发取代柠檬酸结构的不对称构建方法以及合成天然产物作为药物发现的主要化合物

• 批准号: 15390008
• 负责人: HATAKEYAMA Susumi
• 金额: $ 9.79万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390008/
• 关键词: alkylcitrate natural product; Baylis-Hillman reaction; Mukaiyama aldol reaction; asymmetric reaction; trachyspic acid; virifiofungin; total synthesis; 不斉Bayis-Hillman反応; 不斉向山アルドール反応; 不斉Baylis-Hillman反応

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.

烷基柠檬酸酯类天然产物如病毒菌素和粗胞酸，因其对重要的生物酶(如丝氨酸-棕榈酰转移酶、磷脂酶A2、乙酰肝素酶、角鲨烯合成酶)的有效抑制活性以及合成上有趣的结构而备受关注。然而，构建含有四元中心的高功能化柠檬酸结构的通用方法还没有开发出来。在本研究中，我们致力于开发一种通用而有效的方法来不对称合成这类柠檬酸结构，旨在实现烷基柠檬酸系列天然产物的全合成。在前期的研究中，我们利用干燥的β-异铜啶开发了高效的不对称贝利-希尔曼反应(β-IC)。此外，我们还成功地合成了两种以奎宁为原料合成β-ICD的对映体互补催化剂。我们发现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，且产率较高。我们还研究了γ-(对甲氧基苄基)氧基-α-酮丁酸酯与S-叔丁基-4-硫代戊酸酯酮硅基醚的不对称Mukaiyama-Aldol反应，但没有得到令人鼓舞的结果。在后者的研究中，我们首次实现了基于Nozaki-Hiyama-Kishi反应的(+)-粗草酸和(±)-粗草酸的全合成。此外，我们还完成了首次以烯烃交叉复分解为关键步骤的(-)-病毒菌素A的全合成。

项目成果

Synthesis of a pseudoenantiomer of β-isocupreidine(β-ICD), a chiral amine catalyst for asymmetric Baylis-Hillman reactions

β-异铜啶 (β-ICD) 假对映体的合成，一种用于不对称 Baylis-Hillman 反应的手性胺催化剂

• 发表时间: 2005
• 期刊: Heterocycles 66・1
• 作者: 中野 綾子;Ayako Nakano;中野綾子;諸熊 賢治;中野 綾子;中野 綾子
• 通讯作者: 中野 綾子

β-isocupreidine-hexafluoroisopropyl acrylate method for asymmetric Baylis-Hillman reactions

• DOI: 10.1016/j.tet.2005.09.072
• 发表时间: 2006-01-09
• 期刊: TETRAHEDRON
• 影响因子: 2.1
• 作者: Nakano, A;Kawahara, S;Hatakeyama, S
• 通讯作者: Hatakeyama, S

Total Synthesis of (±)-Trachyspic Acid and Determination of the Relative Configuration

(±)-粗锥酸的全合成及相对构型的测定

• 发表时间: 2003
• 期刊: Organic letters 5・6
• 作者: 中野 綾子;Ayako Nakano;中野綾子;諸熊 賢治;中野 綾子;中野 綾子;Kenji Morokuma;Ayako Nakano;Ayako Nakano;中野綾子;中野綾子;諸熊賢治;畑山 範;Susumi Hatakeyama;畑山 範;平井 加奈子
• 通讯作者: 平井 加奈子

Total synthesis of viridiofungin A

• DOI: 10.1039/b500660k
• 发表时间: 2005-01-01
• 期刊: CHEMICAL COMMUNICATIONS
• 影响因子: 4.9
• 作者: Morokuma, K;Takahashi, K;Hatakeyama, S
• 通讯作者: Hatakeyama, S

不斉求核触媒-シンコナアルカロイドを中心にした化学

不对称亲核催化剂 - 以金鸡纳生物碱为中心的化学

• 发表时间: 2004
• 期刊: 化学と工業 577
• 作者: 中村葉子;宮武良至;猪俣 翔;清田洋正;上田 実;上田 実;Mumen F.A. Amer;中野綾子;畑山 範;中野綾子;中野綾子;中野綾子;諸熊賢治;畑山 範
• 通讯作者: 畑山 範