Asymmetric Entry into 10-aza-Analogues of Alkaloids Reveals a Pronounced Electronic Effect on Antiviral Activity.

Development of a chiral pool-based synthesis of 10-aza-analogues of biologically active alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.