Phosphine-catalyzed Asymmetric (4+2) Cyclization Of Propargyl Carboxylates With O-Quinone Methides

4H-chromene is an important six-membered oxygen-containing heterocyclic skeleton with various biological activities such as antioxidant,anti-HIV,anti-tumor,and antibacterial effects.In recent years,research on the synthesis and related pharmacological activities of 4H-chromene has achieved significant progress,and its synthesis methods mainly focus on the tandem cyclization of ortho-Quinone Methides(o-QMs)with different nucleophilic reagents.Therefore,searching for suitable C2 synthon is crucial for constructing the 4H-chromene skeleton.As an important four-atom synthon,o-QMs have been widely used in(4+n)cyclization reactions in recent years,constructing a series of bioactive oxygen-containing heterocyclic compounds.As a simple and readily available raw materials,propargyl carboxylates can form nucleophilic amphiphilic ion salts under the catalysis of phosphine,selectively forming 2C synthons This paper investigated the chiral phosphine-catalyzed asymmetric(4+2)cycloaddition of propargyl carboxylates with o-QMs,and developed a method for constructing a series of chiral 4H-chromene derivatives with good yields(65-89%)and excellent enantioselectivity(88-96% ee)by screening factors such as chiral catalysts,bases,solvents,and temperatures.The method has a wide range of applicable substrates and high functional group tolerance.The absolute configuration of desired products were determined by X-ray crystallographic analysis.Furthermore,the probable mechanism was proposed.The scaled-up reaction obtained the desired product with yield and enantioselectivity close to the template reaction condition,providing a reliable method for the large-scale synthesis of chiral4H-chromene compounds.