报道了一例Brønsted酸催化的炔酰胺分子内氢烷氧化/Claisen重排反应合成八元环内酰胺化合物的方法. 首先, 炔酰胺在Brønsted酸活化条件下形成烯酮亚胺鎓中间体, 并通过氢键及离子对的方式与分子内的羟基作用, 进而发生氢烷氧化/Claisen重排串联反应生成八元环内酰胺化合物. 此外, 利用手性Brønsted酸催化的动力学拆分策略对该不对称反应进行了初步探究, 并成功合成了几类手性八元环内酰胺产物. 该无金属催化的方法不仅操作简单、反应条件温和, 还具有良好的官能团兼容性. 这项研究为合成具有重要生物活性的八元环内酰胺骨架提供了实用的新方法.

A Brønsted acid-catalyzed intramolecular hydroalkoxylation/Claisen rearrangement of ynamides for the synthesis of eight-membered lactams is presented. Firstly, the keteniminium intermediate was generated from the activation of ynamide by Brønsted acid, which could interact with intramolecular hydroxy group through hydrogen bonding and ion pairing effects. Then, the tandem hydroalkoxylation/Claisen rearrangement took place and produced eight-membered lactams. Meanwhile, preliminary studies were conducted into the chiral Brønsted acid-catalyzed kinetic resolution, and several chiral eight-membered lactams were successfully synthesized. Other notable features of this metal-free method include the simple procedure, mild reaction conditions and good functional group compatibility. This research provides a practical method for the synthesis of biologically important eight-membered lactam skeletons. Accordingly, MsOH (5 mol%, 0.005 mmol, 0.32 μL) was added to the solution of ynamide (1 equiv., 0.1 mmol) in dry PhCl (4 mL) at room temperature. The reaction mixture was then stirred at 60 ℃ and the progress of the reaction was monitored by thin layer chromatography (TLC). Upon completion, the reaction was quenched with Et₃N (0.005 mmol, 0.7 μL), concentrated and purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, V∶V=5∶1), to afford the desired eight-membered lactam. Under this condition, a series of ynamides with different substituents worked smoothly to provide the corresponding eight-membered lactams efficiently. Furthermore, chiral Brønsted acid (10 mol%, 0.005 mmol, 3.5 mg) and H₂O (0.05 mmol, 0.9 μL) were added to the solution of ynamide (1 equiv., 0.05 mmol) in PhCl (2 mL) at –20 ℃ and the progress of the reaction was monitored by TLC. Upon completion, the reaction was quenched with Et₃N (0.005 mmol, 0.75 μL), concentrated and purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, V∶V=5∶1), to afford the chiral eight-membered lactam and chiral substrate. Also, a plausible mechanism involving the hydrogen bonding and ion pairing effects is proposed based on experimental results.