Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China.
Chemistry. 2020 Aug 17;26(46):10439-10443. doi: 10.1002/chem.202002404. Epub 2020 Jul 20.
The Eburnamine-Vincamine alkaloids have been studied intensively over the past six decades for their outstandingly potent vasorelaxation activity. Stereocontrolled assembly of the C20/C21 adjacent chiral centers has been a formidable challenge in the synthesis of this family. Herein, we report a concise stereoselective total synthesis of two trans-ring-fused non-natural analogues, (-)-20-epi-Vincamine and (-)-20-epi-Eburnamonine, that features the following key steps: a) a continuous-flow oxidation/lactam alcoholysis cascade producing the symmetrical dihydro-β-carboline diester precursors, and b) a highly stereoselective Ir/f-Binaphane-catalyzed hydrogenation/lactamization cascade leading to the privileged trans-(20R, 21S) lactam ester scaffold with high-level enantio- and diastereocontrol.
过去六十年中，埃伯胺-长春胺生物碱因其出色的血管舒张活性而受到了深入研究。在该类化合物的合成中，立体控制 C20/C21 相邻手性中心的构建一直是一个艰巨的挑战。在此，我们报道了两种反式稠合非天然类似物（-）-20-表-长春胺和（-）-20-表-埃伯胺的简洁立体选择性全合成，其特征在于以下关键步骤：a）连续流氧化/内酰胺醇解级联反应生成对称的二氢-β-咔啉二酯前体，和 b）高立体选择性的 Ir/f-Binaphane 催化氢化/内酰胺化级联反应，生成具有高对映和非对映选择性的优势反式（20R,21S）内酰胺酯骨架。
