Shiomi Shinya, Misaka Remi, Kaneko Mayu, Ishikawa Hayato
Department of Chemistry , Graduate School of Science and Technology , Kumamoto University , 2-39-1, Kurokami, Chuo-ku , Kumamoto 860-8555 , Japan . Email:
Faculty of Advanced Science and Technology , Kumamoto University , 2-39-1, Kurokami, Chuo-ku , Kumamoto 860-8555 , Japan.
Chem Sci. 2019 Sep 27;10(41):9433-9437. doi: 10.1039/c9sc03879e. eCollection 2019 Nov 7.
A practical enantioselective total synthesis of the unnatural (+)-quinine and (-)-9--quinine enantiomers, which are important organocatalysts, is reported. The key transformation is a successive organocatalytic formal aza [3 + 3] cycloaddition/Strecker-type cyanation reaction to form an optically active tetrasubstituted piperidine derivative. This organocatalytic reaction proceeded in high yield and gave excellent enantiomeric excess with only 0.5 mol% catalyst loading. In addition, an imidate group, derived from a cyano group, was incorporated in the strategy for site-selective modification of the C4-alkyl chiral piperidine ring of quinine. Furthermore, an efficient coupling between the quinuclidine precursor and dihydroquinoline unit was achieved on a gram scale. The 15-step (LLS) synthetic protocol provided both (+)-quinine and (-)-9--quinine, each with 16% overall yield.
报道了一种实用的对映选择性全合成方法，用于合成重要的有机催化剂——非天然（+）-奎宁和（-）-9-表奎宁对映体。关键转化步骤是连续进行有机催化的形式氮杂[3 + 3]环加成/施特雷克型氰化反应，以形成光学活性的四取代哌啶衍生物。该有机催化反应产率高，仅使用0.5 mol%的催化剂负载量就能获得优异的对映体过量。此外，在奎宁的C4-烷基手性哌啶环的位点选择性修饰策略中引入了一个由氰基衍生的亚胺酸酯基团。此外，在克级规模上实现了奎宁环前体与二氢喹啉单元之间的有效偶联。这个15步（最长线性序列）的合成方案得到了（+）-奎宁和（-）-9-表奎宁，各自的总产率为16%。
