Total Synthesis of (±)-Giraldine I

Keywords

(±)-giraldine I - aconitine-type norditerpenoid alkaloids - oxidative dearomatization - Diels–Alder cycloaddition - hydroalkenylative fragmentation - Mannich reaction - Claisen rearrangement - olefin metathesis - pinacol coupling

Significance

Liu, Qin, and co-workers report a total synthesis of (±)-giraldine I, an aconitine-type norditerpenoid alkaloid. The natural product exhibits a highly caged hexacyclic framework, representing a challenging target for synthetic efforts. Additionally, numerous members of the class of norditerpenoid alkaloids show promising bioactivity, ranging from analgesic to anticancer effects. This further reinforces the need for synthetic strategies toward these natural products.

Comment

The synthesis commences with oxidative dearomatization of phenol A, which enables Diels–Alder cycloaddition to give tricyclic ketone B. After a series of functional group interconversions, hydrodealkenylative fragmentation, followed by Mannich reaction and one-carbon ring expansion, yields tetracyclic amide E. This sets the stage for a Claisen rearrangement/olefin metathesis sequence to access pentacyclic aldehyde J. SmI₂-mediated pinacol coupling completes the full carbon skeleton of (±)-giraldine I.