Terminating E-ring cyclizations for caged indole alkaloids: The secret to success?

Abstract

Achieving the synthesis of densely-functionalized, cage-like alkaloids has long proven quite challenging, with the success of individual events often being acutely sensitive to minute differences in the geometry and strain of the substrate, particularly as each successive ring is constructed. As such, consideration of what ring to form last has proven to be of particular design significance. In this review, we analyze seminal examples where the E-ring of various structurally related caged indole alkaloids has been targeted as the site of terminal ring closure. As these examples demonstrate, a terminating E-ring approach can enable highly efficient syntheses, but often bespoke solutions are required, given the near-consistent failure of conventional cyclization strategies to forge such rings.