Electrochemical and Photoredox Catalysis for Constructing 5,5‐Spirocycles via Reductive Activation of N‐alkoxyphthalimides for the Total Synthesis of (−)‐Cephalosporolide F

The electrosynthetic (ES) approach employing rapid alternating polarity electrolysis and blue LED photoredox catalysis (PRC) is revised and compared in the synthesis of [5,5]-spiroketals through a tandem reductive activation of N-alkoxyphthalimides to alkoxy radical, followed by hydrogen atom transfer, and spirocyclization sequence. The role of leaving group and redox conditions is explored in the electrochemical transformation, revealing that diphenylphosphate-derived substrates exhibit superior performance. Both methodologies enable the stereoselective synthesis of (-)-Cephalosporolide F from the chiral pool, with a slightly higher yield for the PRC involving an iridium catalyst. This study showcases the potential use of electrochemical and photochemical green redox methodologies for radical-mediated transformations and late-stage synthesis of natural products, avoiding toxic stannyl reagents and bypassing expensive metal-based catalysts. These findings support the development of more sustainable synthetic strategies for complex natural products while acknowledging the use of CH2Cl2 and tetrabutylammonium salts in the ES procedure.