Lindsay Karl B, Skrydstrup Troels
Center for Insoluble Protein Structures, Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark.
J Org Chem. 2006 Jun 23;71(13):4766-77. doi: 10.1021/jo060296c.
A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based class of protease inhibitors. The thioester derivative of the amino acid representing the C5-C9 fragment of the aliskiren carbon skeleton underwent a carbon chain extension via a SmI2-promoted radical addition to n-butyl acrylate. Introduction of the C3-isopropyl group with the correct relative configuration was accomplished via stereoselective reduction of the obtained ketone with concomitant lactonization, followed by an aldol reaction with acetone. Further functional group and protecting group manipulation culminated in a formal total synthesis of aliskiren in 10 steps from the corresponding fully protected non-natural amino acid.
公开了一种有效的肾素抑制剂阿利吉仑的形式全合成方法，该方法利用了本实验室最近开发的一种替代偶联策略，用于制备基于羟乙烯等排体类的蛋白酶抑制剂。代表阿利吉仑碳骨架C5-C9片段的氨基酸硫酯衍生物通过SmI2促进的自由基加成到丙烯酸正丁酯上进行碳链延长。通过将所得酮立体选择性还原并伴随内酯化，然后与丙酮进行羟醛反应，实现了具有正确相对构型的C3-异丙基的引入。进一步的官能团和保护基操作最终以相应的完全保护的非天然氨基酸为原料，经过10步反应实现了阿利吉仑的形式全合成。
