Organocatalytic asymmetric construction of 2,6-diazabicyclo-[2.2.2]Octanes by harnessing the potential of an 3-oxindolium ion intermediate

Abstract

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.