Shiomi Shinya, Sugahara Erika, Ishikawa Hayato
Department of Chemistry, Graduate School of Science and Technology , Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555 (Japan), Fax: (+81) 96-342-3397 http://www.sci.kumamoto-u.ac.jp/∼ishikawa/ishikawa-lab/Top.html.
Chemistry. 2015 Oct 12;21(42):14758-63. doi: 10.1002/chem.201503117. Epub 2015 Sep 3.
Chiral piperidines which contain an alkyl group at C4 positions are one of the important architectures because it is appeared in several natural products. An efficient protocol for the preparation of C4-alkyl substituted chiral piperidines using secondary amine catalyzed formal aza [3+3] cycloaddition reaction with aliphatic α,β-unsaturated aldehydes and thiomalonamate derivatives is reported. In our reaction system, thiomalonamate is an excellent nucleophile and the addition of suitable acid and its amount is an important factor for the acceleration effect in organocatalytic reaction. Furthermore, water and MeOH also have an acceleration effect. These efforts lead to only 0.1 mol % catalyst loading in multigram scale synthesis for suitable reaction time. In addition, the efficient enantioselective total synthesis of (+)-α-skytanthine by using our developed reaction as key step was achieved in total 15 % yield. All carbon and nitrogen units were introduced by one step with high enantioselectivity.
在C4位含有烷基的手性哌啶是重要的结构之一，因为它存在于多种天然产物中。本文报道了一种利用仲胺催化脂肪族α,β-不饱和醛与硫代丙二酸酯衍生物进行正式的氮杂[3+3]环加成反应来制备C4-烷基取代手性哌啶的有效方法。在我们的反应体系中，硫代丙二酸酯是一种优异的亲核试剂，合适酸的添加及其用量是有机催化反应中加速效应的重要因素。此外，水和甲醇也有加速作用。这些努力使得在多克规模合成中，合适的反应时间下催化剂负载量仅为0.1 mol%。此外，以我们开发的反应为关键步骤，实现了(+)-α-天芥菜碱的高效对映选择性全合成，总收率为15%。所有的碳和氮单元通过一步反应以高对映选择性引入。
