Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity.
Martins S OderindeEdna MaoAntonio RamirezJoseph PawluczykChristine JorgeLyndon A M CorneliusJames KempsonVetrichelvan MuthalaguManivel PitchaiAnuradha GuptaArun Kumar GuptaNicholas A MeanwellArvind MathurT G Murali DharPublished in: Journal of the American Chemical Society (2020)
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.
Keyphrases
- visible light
- energy transfer
- density functional theory
- drug discovery
- quantum dots
- molecular dynamics
- randomized controlled trial
- tissue engineering
- photodynamic therapy
- single molecule
- ms ms
- liquid chromatography tandem mass spectrometry
- molecular dynamics simulations
- high performance liquid chromatography
- molecular docking
- risk assessment
- simultaneous determination
- tandem mass spectrometry
- ultra high performance liquid chromatography