Total Synthesis of Atisane-Type Diterpenoids: Application of Diels–Alder Cycloadditions of Podocarpane-Type Unmasked ortho-Benzoquinones

Abstract

Few examples of [4 + 2] cycloaddition with unmasked ortho-benzoquinones (UMOBs) as carbodiene have been reported in complex molecule synthesis. Herein we report that this cycloaddition with podocarpane-type UMOB was developed and applied to construct fully functionalized bicyclo[2.2.2]octanes. Based on this methodology, divergent total syntheses of atisane-type diterpenoids, including (±)-crotobarin, crotogoudin, atisane-3β,16α-diol, and 16S,17-dihydroxy-atisan-3-one, were accomplished in 14, 14, 12, and 16 steps, respectively. Key elements in these total syntheses include: (1) FeCl3-catalyzed cationic cascade cyclization to construct podocarpane-type skeleton; (2) Mn(III)/Co(II)-catalyzed radical hydroxylation of alkene with high regio-, diastereo-, and chemoselectivities; (3) and a ketal-deprotection/lactone-opening/deprotonation/lactonization cascade. Additionally, the synthetic utility of the fully functionalized bicyclo[2.2.2]octane framework was further elucidated by applying ring distortion strategy to afford different skeleton-rearranged natural product-like compounds.

Recent Advances and Prospects in the Chemistry of o‐Benzoquinones

“…A new protocol was developed by the same group in the synthesis of atisane‐type diterpenoids by converting the differently substituted bicyclo[2.2.2]octanes formed by the [4+2] Diels‐Alder reaction of complex unmasked ortho ‐benzoquinones . Here, the first step involves the synthesis of podocarpane‐type ortho‐ benzoquinone using FeCl 3 as the catalyst via a cascade ring formation.…”

Diterpenoids of terrestrial origin

“…The total synthesis of atisane diterpenoids has been reported. 169 The biological activity of scopadulciol has been examined. 170…”

Divergent Total Synthesis of Atisane‐Type Diterpenoids

“…In 2015, our group accomplished the divergent total syntheses of atisane‐type diterpenoids, including (±)‐crotobarin, (±)‐crotogoudin, (±)‐atisane‐3β,16α‐diol, and (±)‐16 S ,17‐dihydroxyatisan‐3‐one (Schemes –) . Crotobarin ( 51 ) and crotogoudin ( 54 ), isolated from Croton barorum and Croton goudotii , belong to the rare ent ‐3,4‐seco‐atisane family of diterpenoids and possess a unique tetracyclic framework with five stereocenters including three contiguous quaternary carbon centers.…”