Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
J Org Chem. 2013 Jul 19;78(14):7048-57. doi: 10.1021/jo400807c. Epub 2013 Jun 27.
Ezetimibe (1), a strong β-lactamic cholesterol absorption inhibitor, was synthesized from (R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with C-(4-benzyloxyphenyl)-N-(4-fluorophenyl)-nitrone (8), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N-O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc(OTf)3-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule 1.
依泽替米贝（1），一种强效的β-内酰胺胆固醇吸收抑制剂，可由（R）-6-（4-氟苯基）-5,6-二氢-2H-吡喃-2-酮 7 合成。为了选择最佳的合成途径，我们分析了独立的路径，其中涉及到 1,3-偶极环加成反应与 C-(4-苯氧苯基）-N-(4-氟苯基）-亚硝基（8），内酯的苄位的分子内亲核取代，N-O 键的断裂，水分子的消除，双键的氢化，六元内酯环的重排为β-内酰胺部分，以及最后酚羟基的脱保护。高度立体选择性的 Sc(OTf)3 催化的 1,3-偶极环加成反应是合成中最关键的步骤。由于环加成的刚性过渡态，起始内酯的绝对构型控制了最终分子 1 中其他手性中心的形成。
