Progress toward the total synthesis of acutumine

ORGN 744

Alexandre Côté, acote@princeton.edu, Robert J. Moreau, rmoreau@princeton.edu, and Erik J. Sorensen, ejs@princeton.edu. Department of Chemistry, Princeton University, Princeton, NJ 08544
Acutumine was isolated from the plant Menispermum dauricum DC in 1929, and its unprecedented chlorine-containing, tetracyclic alkaloid structure (including its absolute stereochemistry) was elucidated in 1967 through the application of chemical degradation and X-ray crystallographic methods. In addition to its unique architecture, acutumine has also shown various promising biological activities including: in vivo inhibition of human T cell growth and memory-enhancing properties on animal models. Starting from the parent pyrrolidine ring of acutumine, a rapid and efficient synthesis is proposed to access the framework of this complex natural molecule. Our strategy mainly relies on three classical reactions: elimination/Michael addition cascade, Wagner-Meerwein rearrangement and Dieckmann condensation. Exceptional behaviors of carbonyl groups, which have been observed in the course of our work, will also be briefly highlighted.