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

• Published in: Journal of the American Chemical Society Vol. 142; no. 6; pp. 3094 - 3103
• Main Authors: Oderinde, Martins S, Mao, Edna, Ramirez, Antonio, Pawluczyk, Joseph, Jorge, Christine, Cornelius, Lyndon A. M, Kempson, James, Vetrichelvan, Muthalagu, Pitchai, Manivel, Gupta, Anuradha, Gupta, Arun Kumar, Meanwell, Nicholas A, Mathur, Arvind, Dhar, T. G. Murali
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.02.2020; Amer Chemical Soc
• Subjects: chemical bonding; Chemistry; Chemistry, Multidisciplinary; cycloaddition reactions; density functional theory; derivatization; diastereoselectivity; energy transfer; Gibbs free energy; light; moieties; photocatalysis; photosensitizing agents; Physical Sciences; Science & Technology; CYCLOADDITION; CATALYSIS; ARYL; 2+2 PHOTOCYCLOADDITION; PHOTOCHEMICAL-REACTIONS
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.9b12129

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.