Generation of the Camptothecin Scaffold by a Flavin-Catalyzed Photooxidative Skeletal Reorganization

The plant alkaloid camptothecin is a high-value precursor for the semisynthesis of multiple anticancer drugs. The key transformation during its biosynthetic pathway is a yet enigmatic skeletal reorganization from a 6/5/6 tetrahydro-β-carboline ring system to the 6/6/5 pyrroloquinoline scaffold that is characteristic of camptothecin-related alkaloids. Here, we show that this scaffold transition can be efficiently catalyzed by flavin cofactors such as flavin mononucleotide in a photooxidative process. As part of this complex transformation, we verified the existence of a previously postulated macrocyclic ketolactam intermediate. Based on the mild conditions - oxygen, light, and flavins - we show that this conversion can also take place in leaves of Nicotiana benthamiana, a plant which does not normally produce camptothecin or related alkaloids. Our optimized biomimetic photochemical reaction conditions enable a short, mild, and efficient semisynthesis of the alkaloids (3S)-pumiloside, (3R)-pumiloside and vincosamide ketolactam, also known as turpiniside, without any protecting groups. Thus, our work improves our understanding of this key skeletal reorganization step forming the camptothecin scaffold in nature and provides streamlined photocatalytic access to camptothecin-related alkaloids.