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 pi-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 alpha-pinene, a single enantiomer of the tungsten fragment can be isolated and used to provide access to enantio-enriched isoquinuclidines from pyridines.
Graham
Peter M
PM
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319, USA.
Delafuente
David A
DA
Liu
Weijun
W
Myers
William H
WH
Sabat
Michal
M
Harman
W D
WD
D000475:Alkenes / Q000737:chemistry; D018360:Crystallography, X-Ray; D011725:Pyridines / Q000737:chemistry*; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry; D014414:Tungsten / Q000737:chemistry*
D000475:Alkenes; D011725:Pyridines; D011812:Quinuclidines; D014414:Tungsten