Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
J Org Chem. 2011 Aug 19;76(16):6931-6. doi: 10.1021/jo2010846. Epub 2011 Jul 26.
A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.
本文描述了一种强效胆固醇抑制剂依泽替米贝 1 的全合成。该合成的关键步骤基于 Cu(I)介导的 Kinugasa 环加成/重排级联反应，其中末端炔烃来自 L-甘油醛的缩酮，与合适的 C，N-二芳基硝酮反应。以高立体选择性得到的具有 (3R,4S) 构型的氮杂环丁酮加合物，随后进行二醇侧链的脱保护，接着进行甘醇裂解，以及在 C3 碳原子上进行碱诱导的异构化，得到 (3S,4S) 醛，该醛已被先灵葆雅集团转化为依泽替米贝。
