Enantioselective Synthesis Of Polycyclic Tropanes Via Dearomative [3+2] Cycloaddition Reactions Of 2-nitrobenzofurans

The tropane framework（8-azabicyclo[3,2,1]octane）is widely found in natural products and drug molecules with important physiological functions.Many tropane alkaloids play pivotal roles in the clinical treatment of immune,neurological,psychiatric diseases,etc.In particular,fused polycyclic tropane compounds exhibited excellent biological activities including NMDA receptor antagonist,antiarrhythmia,anticancer,deaddiction,antiepileptic,and antiinflammatory activities.Guan-fu base A has been approved as an antiarrhythmia drug.Synthetic methods to build up enantiomerically pure tropane scaffolds have been used for some time,but most of them need to start from the chiral raw material and often generate structurally simple tropane compounds.At present,the direct catalytic asymmetic construction of the structurally complex tropane compounds remains challenging.We used 2-nitrobenzofuran and cyclic azomethine ylides as the reaction substrates for enantioselective synthesis polycyclic tropane via dearomative cycloaddition reactions.After a series of optimization of reaction conditions,the optimum reaction conditions were determined.In the presence of 1 mol%metal and ligand,the reaction was carried out at 0°C for 10 h in nitrogen atmosphere with K₂CO₃ as base and tert-butyl methyl ether as solvent.Under these conditions,a series of functionalized polycyclic tropane derivatives were obtained in high yields（up to 91%）with excellent enantioselectivity（up to 98%ee）,and the absolute configuration of the product was determined by single crystal diffraction analysis.The reaction substrate has a wide range and the model reaction can carry out a large number of experiments to achieve gram-scale synthesis.At the same time,the addition amount of catalyst can be further reduced to 0.5 mol%.The derived experiments showed that the enantioselectivity of the products were well maintained,and the polycyclic tropane compounds with more abundant functional groups could be successfully synthesized.In summary,a new synthetic route of enantioselective synthesis of polycyclic tropane through a dearomative[3+2]cycloaddition process was successfully developed.The polycyclic tropane compounds were synthesized by using cheap and stable divalent copper as metal catalyst with low amount of catalyst.The synthetic products are more complex and diverse,and this method provided a new idea for the enantioselective synthesis of polycyclic tropane.At the same time,we also tried the asymmetric dearomative cycloaddition reaction of other nitro-heteroarenes with cyclic azomethine ylides.Through a series of reaction conditions screening,we did not get satisfactory experimental results.