Organocatalytic Asymmetric Construction of 2,6‐Diazabicyclo[2.2.2]octanes by Harnessing the Potential of an 3‐Oxindolium Ion Intermediate

Due to its structural complexity and intrinsic sensitivity of bridged aminal junction, 2,6‐diazabicyclo[2.2.2]octane (2,6‐DABCO) has remained a highly desirable target in synthetic chemistry. However, the asymmetric access to this unit is still insufficient and hampered by the need for meticulously created functionalities for intricate double aza‐cyclizations. Herein, we have developed a novel enantio‐ and diastereoselective protocol to access polycyclic chiral 2,6‐DABCOs under metal‐free conditions. This domino process involves the amine‐catalyzed [4+2] annulation between glutaraldehyde and 2‐arylindol‐3‐ones, followed by an acid‐mediated Pictet‐Spengler reaction/intramolecular aza‐cyclization cascade sequence with tryptamine by trapping of in situ generated 3‐oxindolium ion intermediate for the first time. Overall, 2,6‐DABCOs fused with medicinally relevant scaffolds were isolated with good yield and excellent stereoselectivity by constructing five new bonds and four stereocenters in a one‐pot operation.