Terminal Alkynes as One‐Carbon Donors in [5+1] Heteroannulation: Synthesis of Pyridines via Ynimine Intermediates and Application in the Total Synthesis of Anibamine B

Abstract

AbstractTransition‐metal‐catalyzed [4+2] heteroannulation of α,β‐unsaturated oximes and their derivatives with alkynes has been developed into a powerful strategy for the synthesis of pyridines. It nevertheless lacks regioselectivity when unsymmetrically substituted alkynes are used. We report herein the unprecedented synthesis of polysubstituted pyridines by a formal [5+1] heteroannulation of two readily accessible building blocks. A copper‐catalyzed aza‐Sonogashira cross‐coupling between β,γ‐unsaturated oxime esters and terminal alkynes affords ynimines, which, without isolation, undergo an acid‐catalyzed domino reaction involving ketenimine formation, 6π‐electrocyclization and aromatization to afford pyridines. Terminal alkynes served as a one‐carbon donor to the pyridine core in this transformation. Di‐ through pentasubstituted pyridines are accessible with complete regioselectivity and excellent functional‐group compatibility. The first total synthesis of anibamine B, an indolizinium alkaloid with potent antiplasmodial activity, was accomplished featuring this reaction as a key step.