Total Synthesis of Dragocins A−C through Electrochemical Cyclization

• Published in: Angewandte Chemie International Edition 2024-05, Vol.63 (19), p.e202401107-n/a
• Main Authors: Smith, Brendyn P., Truax, Nathanyal J., Pollatos, Alexandros S., Meanwell, Michael, Bedekar, Pranali, Garrido‐Castro, Alberto F., Baran, Phil S.
• Format: Article
• Language: English
• Subjects: alkaloids; Electrochemical oxidation; Electrochemistry; Natural products; Oxidation; Pyrrolidine; Ribose; Stereoselectivity; Synthesis; total synthesis
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202401107

The first total synthesis of dragocins A−C, remarkable natural products containing an unusual C4’ oxidized ribose architecture bridged by a polyhydroxylated pyrrolidine, is presented through a route featuring a number of uncommon maneuvers. Several generations towards the target molecules are presented, including the spectacular failure of a key C−H oxidation on a late‐stage intermediate. The final route features rapid, stereocontrolled access to a densely functionalized pyrrolidine and an unprecedented diastereoselective oxidative electrochemical cyclization to forge the hallmark 9‐membered ring. Preliminary studies suggest this electrochemical oxidation protocol is generally useful. An electrochemical cyclization is leveraged to forge the central 9‐membered ring in the hybrid metabolites dragocins A−C. The route features several stereocontrolled reactions to address the stereotetrad of the pyrrolidine fragment and a penultimate decarboxylative chlorination and global deprotection to furnish both dragocins B and C. Dragocin A was prepared through simple methanolysis of dragocin C.