A Photochemical Strategy for the Conversion of Nitroarenes into Rigidified Pyrrolidine Analogues

Bicyclic
amines are important motifs for the preparation
of bioactive
materials. These species have well-defined exit vectors that enable
accurate disposition of substituents toward specific areas of chemical
space. Of all possible skeletons, the 2-azabicyclo[3.2.0]heptane framework
is virtually absent from MedChem libraries due to a paucity of synthetic
methods for its preparation. Here, we report a modular synthetic strategy
that utilizes nitroarenes as flat and easy-to-functionalize feedstocks
for the assembly of these sp3-rich materials. Mechanistically,
this approach exploits two concomitant photochemical processes that
sequentially ring-expand the nitroarene into an azepine and then fold
it into a rigid bicycle pyrroline by means of singlet nitrene-mediated
nitrogen insertion and excited-state-4π electrocyclization.
A following hydrogenolysis provides, with full diastereocontrol, the
desired bicyclic amine derivatives whereby the aromatic substitution
pattern has been translated into the one of the three-dimensional
heterocycle.
These molecules can be considered rigid pyrrolidine analogues with
a well-defined orientation of their substituents. Furthermore, unsupervised
clustering of an expansive virtual database of saturated N-heterocycles
revealed these derivatives as effective isosteres of rigidified piperidines.
Overall, this platform enables the conversion of nitroarene feedstocks
into complex sp3-rich heterocycles of potential interest
to drug development.