关键词: 不对称反应, 铜催化, Kinugasa反应, aldol反应, retro-aldol/aldol过程

β-Lactams and spiro β-lactams represent privileged structural motifs that are prevalent in numerous natural products and pharmacologically active compounds. Due to their profound biological significance and versatile applications in medicinal chemistry, considerable research efforts have been devoted to developing efficient synthetic methodologies for these important scaffolds. Among various synthetic approaches, the copper(I)-catalyzed [3＋2] cycloaddition between terminal alkynes and nitrones, commonly referred to as the Kinugasa reaction, has emerged as one of the most straightforward and efficient strategies for constructing the β-lactam core structure. By combining the Kinugasa reaction with subsequent transformations, researchers have established various cascade or one-pot processes that enable the synthesis of multisubstituted β-lactams and spiro β-lactam derivatives. In our previous investigations, we successfully developed an asymmetric copper(I)-catalyzed Kinugasa/aldol cascade reaction utilizing N-(2-acylaryl)propiolamides and nitrones as substrates. This methodology provided efficient access to chiral 1',4'-dihydro-2'H-spiro[azetidine-3,3'-quinoline]-2,2'-diones with excellent stereocontrol. The high diastereoselectivity observed in these reactions was attributed to a base-mediated retro-aldol/aldol epimerization process, which effectively converted the minor diastereomer into the thermodynamically favored major product, thereby enhancing the overall stereoselectivity of the transformation. To expand the substrate scope of this methodology, the current study focused on examining the reactivity of linear alkyl ketone-tethered propiolamides with nitrones. Initial experiments conducted in PhCF₃ as solvent revealed that the retro-aldol/aldol process was significantly less efficient for alkyl alcohol products under standard reaction conditions, resulting in poor diastereoselectivity for the cascade reaction. To overcome this limitation, we implemented a strategic modification by introducing the polar aprotic solvent N,N-dimethyl- formamide (DMF) after the initial reaction phase. This solvent switch proved crucial in promoting the retro-aldol/aldol epimerization process, ultimately leading to the desired products with substantially improved diastereoselectivity. The optimized reaction protocol involves several key steps: First, the alkyl ketone-tethered propiolamides, nitrones, Cu(OTf)₂ catalyst, and chiral ligand are combined in PhCF₃ solvent at 0 ℃ in the presence of ^tBuOLi as base, with stirring maintained for 12 h to allow complete conversion. Following this initial phase, the solvent is carefully removed under reduced pressure, and DMF is introduced as the secondary solvent. The reaction mixture is then stirred for an additional 5 h at ambient temperature to facilitate the epimerization process, during which the minor diastereomer is converted to the major product. This carefully opti-

mized two-step procedure enables the synthesis of target compounds in moderate yields while achieving high diastereoselectivity, thereby significantly expanding the synthetic utility of this methodology for the preparation of structurally diverse β-lactam derivatives.

Key words: asymmetric reaction, copper-catalyzed, Kinugasa reaction, aldol reaction, retro-aldol/aldol process