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.