Total Synthesisof aFew Naturally Occurring Isocoumarinsand Dihydroisocoumarins: Successful Exploration of the Ag(I)-Mediated6-<i>Endo</i>-<i>Dig</i> Cyclization and AsymmetricHydrogenation Strategy

We disclose the total synthesis of naturally occurring isocoumarins: (<i>S</i>)-fusarimarin B, (<i>S</i>)-diaporthin, (10<i>S</i>)-8-methoxydiaporthin, (<i>S</i>)-orthosporin, (<i>S</i>)-monarubin B, (<i>S</i>)-lunatinin, and isochromans aspergillumarin A, aspergillumarin B, and penicimarin B. The synthetic strategy highlights an efficient Ag­(I)-mediated 6-<i>endo</i>-<i>dig</i> cyclization of properly substituted 2-alkynylated benzoates to yield the corresponding isocoumarins in excellent yields. The obtained isocoumarins, upon asymmetric hydrogenation with the Ru-BINAP catalyst, provided the corresponding isochromans with excellent yields and enantioselectivity. A Sonogashira cross-coupling reaction of properly functionalized terminal alkynes and substituted aryl bromides was employed to access 2-alkynylated benzoates. This report constitutes the first asymmetric synthesis of three naturally occurring isocoumarins: (<i>S</i>)-fusarimarin B, and (<i>S</i>)-monarubin B.