TY - JOUR
T1 - A Photochemical Strategy for the Conversion of Nitroarenes into Rigidified Pyrrolidine Analogues
AU - Matador, Esteban
AU - Tilby, Michael J.
AU - Saridakis, Iakovos
AU - Pedrón, Manuel
AU - Tomczak, Dawid
AU - Llaveria, Josep
AU - Atodiresei, Iuliana
AU - Merino, Pedro
AU - Ruffoni, Alessandro
AU - Leonori, Daniele
N1 - Publisher Copyright:
© 2023 American Chemical Society
PY - 2023/12/20
Y1 - 2023/12/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85180072014&partnerID=8YFLogxK
U2 - 10.1021/jacs.3c10863
DO - 10.1021/jacs.3c10863
M3 - Article (Academic Journal)
C2 - 38059920
AN - SCOPUS:85180072014
SN - 0002-7863
VL - 145
SP - 27810
EP - 27820
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 50
ER -