1. Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity
- Author
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Joseph Pawluczyk, Nicholas A. Meanwell, Muthalagu Vetrichelvan, Arvind Mathur, T. G. Murali Dhar, Manivel Pitchai, James Kempson, Cornelius Lyndon A M, Martins S. Oderinde, Arun Kumar Gupta, Antonio Ramirez, Edna Mao, Christine Jorge, and Anuradha Gupta
- Subjects
chemistry.chemical_classification ,Negishi coupling ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Catalysis ,Cycloaddition ,0104 chemical sciences ,Stereocenter ,Cyclobutane ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,Intramolecular force ,Indoline ,Triplet state ,Alkyl - Abstract
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.
- Published
- 2020
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