Asymmetric Total Synthesis of Naturally Occurring ()-2'-Methoxydihydroartemidin, ()-()-3'-Hydroxyartemidin, and Its Structural Congeners: Method Optimization and Mechanistic Analysis.

Asymmetric total synthesis of naturally occurring 3-substituted isocoumarins, 2'-methoxydihydroartemidin, ()-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-- 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.