Asymmetric Total\nSynthesis of Naturally Occurring\n(<i>R</i>)‑2′-Methoxydihydroartemidin, (<i>R</i>)‑(<i>E</i>)‑3′-Hydroxyartemidin,\nand Its Structural Congeners: Method Optimization and Mechanistic\nAnalysis

Asymmetric total synthesis of naturally occurring 3-substituted\nisocoumarins, 2′-methoxydihydroartemidin, (<i>E</i>)-3′-hydroxyartemidin, and two structural congeners is reported\nin this article. Enantiopure 3-alkylisocoumarin core present in those\ntarget molecules was accessed through an atom-economical and regiodefined\n6-<i>endo</i>-<i>dig</i> cyclization from properly\nsubstituted 2-halobenzoic acids and chiral terminal alkynes through\nligand-free Cu(I) catalysis. A detailed mechanistic investigation\nwas carried out through control experiments, and density functional\ntheory (DFT) analysis reveals that solvent directed a non-Sonogashira\npathway through direct insertion of alkyne through a regiodefined\nway is operating. The synthesized 3-alkylisocoumarins are synthetically\nmanipulated into various small molecular entities.