Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity

We describe the synthesis through
visible-light photocatalysis
of novel functionalized tetracyclic scaffolds that incorporate a fused
azabicyclo[3.2.0]­heptan-2-one motif, which are structurally interesting
cores with potential in natural product synthesis and drug discovery.
The synthetic approach involves an intramolecular [2 + 2] cycloaddition
with concomitant dearomatization of the heterocycle via an energy
transfer process promoted by an iridium-based photosensitizer, to
build a complex molecular architecture with at least three stereogenic
centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]­heptan-2-one-based
tetracycles were obtained in high yield (generally >99%) and with
excellent diastereoselectivity (>99:1). The late-stage derivatization
of a bromine-substituted, tetracyclic indoline derivative with alkyl
groups, employing a mild Negishi C–C bond forming protocol
as a means of increasing structural diversity, provides additional
modularity that will enable the delivery of valuable building blocks
for medicinal chemistry. Density functional theory calculations were
used to compute the T1–S0 free energy
gap of the olefin-tethered precursors and also to predict their reactivities
based on triplet state energy transfer and transition state energy
feasibility.