Catalytic Enantioselective Hetero-[6+4] and -[6+2] Cycloadditions for the Construction of Condensed Polycyclic Pyrroles, Imidazoles, and Pyrazoles

The
development of the first chemo-, regio-, and stereoselective
hetero-[6+4] and -[6+2] cycloadditions of heteroaromatic compounds
via amino aza- and diazafulvenes is presented. Pyrroles, imidazoles,
and pyrazoles substituted with a formyl group react with an aminocatalyst
to generate an electron-rich hetero-6π-component that reacts
in a chemo-, regio-, and stereoselective manner with electron-deficient
dienes and olefins. For the hetero-[6+4] cycloaddition of the pyrrole
system with dienes, a wide variation of both reaction partners is
possible, providing attractive pyrrolo-azepine products in high yields
and excellent enantioselectivities (99% ee). The hetero-[6+4] cycloaddition
reaction concept is extended to include imidazoles and pyrazoles,
giving imidazolo- and pyrazolo-azepines. The same activation concept
is successfully employed to include hetero-[6+2] cycloadditions of
the pyrrole system with nitroolefins, giving important pyrrolizidine-alkaloid
scaffolds. Experimental NMR and mechanistic studies allowed for the
identification of two different types of intermediates in the reaction.
The first intermediate is the result of a rapid formation of an iminium
ion, which generates a hetero-6π aminofulvene intermediate as
a mixture of two isomers. Density functional theory calculations were
used to determine the mechanism and sources of asymmetric induction
in the hetero-[6+4] and -[6+2] cycloadditions. After formation of
the reactive hetero-6π-components, a stepwise addition occurs
with the diene or olefin, leading to a zwitterionic intermediate that
undergoes cyclization to afford the cycloadduct, followed by eliminative
catalyst release. The stereoselectivity is controlled by the second
step, and computations elaborate on the various substrate and catalyst
effects that alter the experimentally observed enantioselectivities.
The computational studies provided a basis for improving the enantioselectivity
of the hetero-[6+2] cycloaddition.