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

Abstract

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.

Transition Metal‐Mediated C−C Single Bond Cleavage: Making the Cut in Total Synthesis

“…Here,wediscuss the first syntheses of these natural products by Li and co-workers,who made use of decarboxylative tactics for the formation of key C À C bonds. [58] Specifically,L ia nd co-workers envisioned that the bicyclo[3. Li and co-workers began their synthesis with ak nown five-step sequence,i nw hich commercially available ethyl 2cyclohexanonecarboxylate was converted enantioselectively into carboxylic acid 196;i na na dditional three steps, Nacyloxyphthalimide 197 was synthesized, which serves as ap recursor for the key tandem decarboxylative cyclization/ alkenylation sequence (Scheme 24 B).…”

Zn-Mediated Hydrodeoxygenation of Tertiary Alkyl Oxalates

“…16 By contrast, copper salts were incompetent (entry 10). 17 Replacement of PBI with other pyridine-containing additives did not improve the results (entries 11-13). While other independent hydrogen sources such as H 2 , BH 3 , and H 2 O, were not suitable (entries 14-16 and Supporting Information, Table S2).…”

Recent Progress in Radical Decarboxylative Functionalizations Enabled by Transition-Metal (Ni, Cu, Fe, Co or Cr) Catalysis

“…to make the key intermediate 42.1 using decarboxylative radical cross-coupling in a sequential radical cyclization/alkenylation cascade (Scheme 42). 33 After extensive exploration of catalysts, ligands, additives as well as reaction conditions, compound 42.1 was obtained in good yield through a sequential Cu-catalyzed decarboxylative cyclization/alkenylation. Encouraged by this success, Li and coworkers further explored the generality of the reaction by using a broad range of substrates and vinyl bromide part-ners (Scheme 42).…”

“…Encouraged by this success, Li and coworkers further explored the generality of the reaction by using a broad range of substrates and vinyl bromide part-ners (Scheme 42). 33 It was demonstrated that this robust process could deliver a variety of structurally diverse lactone ring systems, including those bearing quaternary centers. This synthetic strategy offered a streamlined approach to access sterically congested terpenoid systems, as exemplified by the synthesis of three natural products.…”