Asymmetric Catalytic Construction of 1,1-Diheteroquaternary Tetrahydro-β-carbolines Enables Collective Syntheses of Polycyclic Alkaloids

1,1-Disubstituted THβCs with a C1 diheteroatom-bearing quaternary center represent a prevalent skeleton in natural products and pharmaceutical molecules. However, the catalytic asymmetric approach for this skeleton remains elusive. Herein, we developed an asymmetric catalytic annulation between dihydro-β-carbolines and enals for constructing chiral diheteroquaternary THβCs. With this method, we accomplished the gram-scale total synthesis of (+)-naucleamide E, which is the first case of synthesizing a THβC natural product with the C1 diheteroquaternary center by directly constructing the C1 chiral center in an asymmetric catalytic manner. This approach also enabled concise collective syntheses of tetracyclic alkaloids (-)-dihydrocorynantheol, (-)-dihydrocorynantheal, (-)-arboricine, and pentacyclic alkaloid (-)-yohimbane. Additionally, the obtained THβCs show excellent anti-IAV effects both <i>in vitro</i> and <i>in vivo</i> through targeting the virus NS1 protein. This work not only implicates the high potential of THβCs as overlooked compounds in the anti-influenza virus research field but also provides a promising strategy for next-generation anti-influenza drug discovery.