posted on 2023-12-07, 16:20authored byEsteban Matador, Michael J. Tilby, Iakovos Saridakis, Manuel Pedrón, Dawid Tomczak, Josep Llaveria, Iuliana Atodiresei, Pedro Merino, Alessandro Ruffoni, Daniele Leonori
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.