Synthesis of (±)‐Physovenine through Electrochemical C−O Bond Formation

• Published in: European journal of organic chemistry 2022-12, Vol.2022 (47), p.n/a
• Main Authors: Wang, Feijun, Frankowski, Kevin J.
• Format: Article
• Language: English
• Subjects: alkaloids; Aluminum hydrides; Aromatic compounds; Bonding; Chemical synthesis; cyclization; electrochemistry; Enantiomers; Lithium aluminum hydrides; Metal hydrides; Natural products; Nucleophiles; Reagents; Stereoselectivity; Substitution reactions; Substrates; total synthesis
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202201153

We investigated an electrochemical C−O bond formation approach to (±)‐physovenine. The reaction conditions are mild compared to canonical routes, which typically utilize strong hydride reagents such as lithium aluminum hydride. This enabled extension of the electrochemical cyclization to a substrate bearing the fully functionalized phenyl ring of the natural product. The electrochemical cyclization is diastereoselective and starting from enantiopure substrate would provide a single enantiomer of physovenine. In the course of an initial formal synthesis, we identified conditions to afford modest enantioselective substrate synthesis that demonstrate the feasibility of an enantioselective synthesis. Among the substrates investigated, acetyl‐, tosyl‐ or Boc‐nitrogen substitution led to an alternative electrochemical C−O bond formation pathway where the hydroxyl nucleophile cyclized onto the aromatic ring vs. the 2‐position of the indoline. This work expands the utility of electrochemical C−O bond formation and provides a foundation for further applications to functionalized cyclic ether construction. The total synthesis of the alkaloid physovenine demonstrates the utility of a late‐stage electrochemical C−O bond formation method. Among the substrates surveyed, a correlation between the nature of nitrogen substitution and an alternative electrochemical C−O bond formation pathway was identified where the hydroxyl nucleophile cyclized onto the aromatic ring vs. the 2‐position of the indoline.