Total Syntheses of Giraldine I and Heterophyllisine.

Abstract

Aconitine and related norditerpenoid alkaloids are chemically and biologically significant natural products that represent a formidable synthetic challenge. Here, we report the first total syntheses of aconitine-type alkaloid giraldine I and lactone-type alkaloid heterophyllisine. Key strategies include (1) early stage installation of the C4 all-carbon quaternary stereocenter and nitrogen atom via allene hydrocyanation, (2) skeletal editing through hydrodealkenylative fragmentation/Mannich cyclization to build the A/B/E/F tetracyclic scaffold, (3) a Claisen rearrangement/ring-closing metathesis (RCM) sequence followed by transannular pinacol coupling to form the characteristic C/D rings of aconitines, and (4) a bioinspired and regioselective Baeyer-Villiger oxidation to access the lactone-type alkaloid.