Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR China.
J Org Chem. 2013 Mar 1;78(5):1790-801. doi: 10.1021/jo301277n. Epub 2012 Aug 14.
We report, for the first time, the synthesis of 8-aza-analogues of PGE2. The SmI2-mediated cross coupling reactions of γ-lactam-hemiaminal 9, lactam 2-pyridyl sulfide 17, and lactam 2-pyridyl sulfone 18 with activated alkenes/alkyne were first developed, giving the corresponding γ-lactams in 49-78%, 45-75%, and 75-90%, respectively. The reactions of lactam 2-pyridyl sulfide and 2-pyridyl sulfone proceeded with ≥12:1 trans-diastereoselectivities. This represents the first intermolecular coupling reaction of the γ-lactam N-α-alkyl radicals of types B, B1, and B2 with activated alkenes. Two radical-based mechanisms were suggested. The asymmetric synthesis of the 11-hydroxylated analogue of the highly selective EP4 receptor agonist PF-04475270 (30), the 11-hydroxylated analogue of ocular hypotensive CP-734432 (31), compounds 35 and 36 have been achieved on the basis of this method.
我们首次报道了 PGE2 的 8-氮杂类似物的合成。首次开发了 SmI2 介导的γ-内酰胺-半亚胺 9、内酰胺 2-吡啶基硫化物 17 和内酰胺 2-吡啶基砜 18 与活化烯烃/炔烃的交叉偶联反应，分别以 49-78%、45-75%和 75-90%的产率得到相应的γ-内酰胺。内酰胺 2-吡啶基硫化物和 2-吡啶基砜的反应以≥12:1 的 trans-非对映选择性进行。这代表了 B、B1 和 B2 型γ-内酰胺 N-α-烷基自由基与活化烯烃的首次分子间偶联反应。提出了两种基于自由基的机制。在此方法的基础上，实现了高度选择性 EP4 受体激动剂 PF-04475270（30）的 11-羟化物类似物和眼压低 CP-734432（31）的 11-羟化物类似物、化合物 35 和 36 的不对称合成。
