Total synthesis of (−)-kopsinine and ent-(+)-kopsinine

Abstract

The total synthesis of (−)-kopsinine and its unnatural enantiomer is detailed, enlisting a late-stage SmI2-mediated transannular free radical conjugate addition reaction for construction of the core bicyclo[2.2.2]octane ring system with strategic C21–C2 bond formation. Key to the approach is assemblage of the underlying skeleton by an intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the precursor C21 functionalized pentacyclic ring system 1 in a single step in which the C3 methyl ester found in the natural product served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels–Alder reaction and stabilizing the intermediate 1,3-dipole.

Inverse Electron Demand Diels–Alder Reactions of Heterocyclic Azadienes, 1-Aza-1,3-Butadienes, Cyclopropenone Ketals, and Related Systems. A Retrospective

“…Kopsinine was accessed in eight steps from cycloadduct 188 . Key to the synthesis was a late-stage C2–C21 bond formation mediated by SmI 2 in 10:1 THF–HMPA, proceeding through a radical-mediated conjugate addition cyclization and subsequent protonation of the further reduced ester enolate from the less hindered convex face to provide the product in excellent yield (75%) and as a single diastereomer (Scheme ).…”

Diastereoselective Methylation at the Congested β-Position of a Butenolide Ring: Studies toward the Synthesis of seco-Prezizaane-Type Sesquiterpenes

“…We next examined the installation of the methyl group through silicon-tethered cyclization (Scheme ). Because the introduction of the bromomethylsilyl group onto the C4 tertiary hydroxy group did not proceed efficiently (vide infra), bromomethylsilyl ether 16 was initially prepared and subjected to the radical cyclization involving n Bu 3 SnH and AIBN . Unfortunately, undesired cyclization was promoted to afford the five-membered silyl ether 17 in 28% yield.…”

Samarium(ii) iodide-mediated reactions applied to natural product total synthesis

“…Later in 2015, Boger and colleague 87 developed the asymmetric total synthesis of (−)-kopsinine 165 and its unnatural enantiomer from the common Aspidosperma -like pentacyclic intermediate 161. The key steps contain a tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles to provide the stereochemically rich C21-functionalized pentacyclic core precursor 161 of the natural product, and the C21–C2 bond formation via a late-stage SmI 2 -promoted transannular free radical conjugate addition reaction constructing the bicyclo[2.2.2]octane core.…”