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天然产物Robustanoids A/B的全合成及手性亚胺酯的α-硫官能化反应研究
Thesis Advisor卢崇道、徐燕军
Degree Grantor中国科学院大学
Place of Conferral北京
Degree Name硕士
Degree Discipline有机化学
KeywordRobustanoids A/b 全合成 金属催化c—n键形成 N-叔丁基亚磺酰亚胺酯 不对称硫官能化

Robustanoids A和Robustanoids B是从咖啡豆中分离出来的两种天然产物,具有特征的吡咯并[2,3-b]吲哚骨架。Robustanoids B具有对阳性阿卡波糖相当的α-葡萄糖苷酶抑制活性。通过逆合成分析,将上述分子分割为两个主要片段。第一个主要片段是合成相应的吡咯并[2,3-b]吲哚骨架,具体做法为以L-色氨酸作为初始底物,通过5步(收率73%)合成出其结构。第二个主要片段是通过Knoevenagel缩合反应制备的α-溴代不饱和酰氯结构。两个分子片段经过高选择性的缩合、分子内金属催化碳氮键的形成,以及保护基团的选择性脱除,实现了天然产物Robustanoids A和 Robustanoids B的全合成。有机硫化合物在化学合成及其天然产物化学中扮演着非常重要的角色,也存在于一些活性药物分子和天然产物中,因此C-S键的构建是有机合成化学中不可或缺的一部分。N-叔丁基亚磺酰亚胺酯α位的氢在碱性的条件下去除,得到碳负离子(或其aza-enolate)中间体,随后被亲电硫基化试剂捕捉,以高收率和优异的立体选择性实现N-叔丁基亚磺酰亚胺酯的不对称α-硫官能化。以该反应作为关键合成步骤,实现了抗菌药物硫康唑(sulconazole)的不对称合成。另外,通过该反应方法学快速构建了一种潜在治疗动脉粥样硬化和高脂血症的抑制剂(S)-Eflucimibe的关键合成中间体。

Other Abstract

Robustanoids A and B, isolated from Coffea canephora beans, are two natural products with the featured pyrrolo[2,3-b]indole skeleton, of which the latter showed α-glucosidase inhibitory activity comparable to that of the positive control, acarbose.Initially, we envisioned a retrosynthetic disconnection of the above molecules in two fragments: the corresponding pyrrolo[2,3-b]indole and α-bromo- -α,β-unsaturated acyl chloride. The first segment was obtained in 73% overall yield (over 5 steps) using L-tryptophan as starting material, while another fragment was synthesized by Knoevenagel condensation. The final assembly of the individual fragments commenced with coupling of two segments through highly selective condensation, followed by metal-catalyzed intramolecular C?N bond-forming reaction and selective removal of protecting groups.Organosulfur compounds play a significant role in chemical synthesis and natural product chemistry, as well as existed in some active drug molecules and natural products. Therefore, construction of C-S bond is indispensable in synthetic organic chemistry. After deprotonation α-hydrogen of N-tert-butanesulfinyl imidates under basic conditions, the formed carbaions (or aza-enolates) can be captured by electrophilic sulfuration reagents to afford α-thiofunctionalization imidates with general high yield and diastereoselectivity. Then, asymmetric synthesis of sulconazole was successfully realized using the above reaction as the key step. Besides, the crucial intermediate of (S)-Eflucimibe, an inhibitor potentially for the treatment of atherosclerosis and hyperlipidemia, was also constructed by means of this method.

Document Type学位论文
Recommended Citation
GB/T 7714
牛盛童. 天然产物Robustanoids A/B的全合成及手性亚胺酯的α-硫官能化反应研究[D]. 北京. 中国科学院大学,2018.
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