Asymmetric Total Synthesis of Naturally Occurring (<i>R</i>)-2′-Methoxydihydroartemidin, (<i>R</i>)-(<i>E</i>)-3′-Hydroxyartemidin, and Its Structural Congeners: Method Optimization and Mechanistic Analysis

Asymmetric total synthesis of naturally occurring 3-substituted isocoumarins, 2'-methoxydihydroartemidin, (<i>E</i>)-3'-hydroxyartemidin, and two structural congeners is reported in this article. Enantiopure 3-alkylisocoumarin core present in those target molecules was accessed through an atom-economical and regiodefined 6-<i>endo</i>-<i>dig</i> cyclization from properly substituted 2-halobenzoic acids and chiral terminal alkynes through ligand-free Cu(I) catalysis. A detailed mechanistic investigation was carried out through control experiments, and density functional theory (DFT) analysis reveals that solvent directed a non-Sonogashira pathway through direct insertion of alkyne through a regiodefined way is operating. The synthesized 3-alkylisocoumarins are synthetically manipulated into various small molecular entities.