Nonenzymatic skeletal rearrangement of 6/5/6 to 6/6/5 ring system in the biosynthesis of camptothecin.

The 6/5/6 to 6/6/5 ring system rearrangement from indole alkaloids strictosidine (1) and strictosamide (2) to quinoline alkaloid pumiloside (3) is an essential but unelucidated process in the biosynthesis of camptothecin, especially, the intermediates involved in the process have not been identified. Herein, the nonenzymatic conversions including spontaneous reaction from 1 to 2, and light- or flavin-catalyzed skeletal rearrangement from 2 to 3 have been discovered. Particularly, the crucial biosynthetic intermediate strictosamide ketolactam (2a) with dicarbonyl nine-membered ring involved in the conversion from 2 to 3 is obtained and structurally characterized. Moreover, the successive conversion from 1 to 3 is achieved in Nicotiana benthamiana. These findings not only provide a new insight into and better understanding for the biosynthesis of camptothecin with rare nonenzymatic reactions, also lay the foundation for further elucidation of the biosynthetic pathway of camptothecin.