Tandem Decarboxylative Cyclization/Alkenylation Strategy for Total Syntheses of (+)-Longirabdiol, (−)-Longirabdolactone, and (−)-Effusin

Structurally
complex and bioactive ent-kaurane
diterpenoids have well-characterized biological functions and have
drawn widespread attention from chemists for many decades. However,
construction of highly oxidized forms of such diterpenoids still
presents considerable challenges to synthetic chemists. Herein, we
report the first total syntheses of C19 oxygenated spiro-lactone ent-kauranoids, including longirabdiol, longirabdolactone,
and effusin. A concise synthesis of the common intermediate used for
all three syntheses was enabled via three free-radical-based reactions:
(1) a newly devised tandem decarboxylative cyclization/alkenylation
sequence that forges the cis-19, 6-lactone concomitantly
with vicinal alkenylation, (2) a Ni-catalyzed decarboxylative Giese
reaction that constructs C10 quaternary center stereoselectively,
and (3) a vinyl radical cyclization that generates a rigid bicyclo[3.2.1]­octane.
A series of late-stage oxidations from the common intermediate then
provided each of the natural products in turn. Further biological
evaluation of these synthetic natural products reveals broad anticancer
activities.