Facile Diels−Alder Reactions with Pyridines Promoted by Tungsten

The isoquinuclidine (2-azabicyclo[2.2.2]octane) core is found in numerous molecules of biological
and medicinal importance, including the widely investigated Iboga alkaloids and their related bisindole
Cantharanthus alkaloids (Sundberg, R. J.; Smith, S. Q. Alkaloids (San Diego, CA, United States) 2002,
59, 281−386). A diverse range of synthetic methods for the stereoselective construction of this architecture
is required for the efficient development of related pharmaceuticals. Here, we report a fundamentally new
methodology that constructs the isoquinuclidine core directly from pyridines, using a π-basic tungsten
complex to disrupt the aromatic stabilization of these otherwise inert heterocycles. By this approach, common
pyridines are found to undergo stereoselective Diels−Alder reactions with electron-deficient alkenes under
mild reaction conditions, thus providing access to a broad range of functionalized isoquinuclidines. Further,
by using the common terpene α-pinene, a single enantiomer of the tungsten fragment can be isolated and
used to provide access to enantio-enriched isoquinuclidines from pyridines.