Progress toward the total synthesis of acutumine

ORGN 744

Alexandre Côté,, Robert J. Moreau,, and Erik J. Sorensen, 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.