Hyperimonates A and B, a pair of unprecedented polyprenylated acylphloroglucinols from Hypericum monogynum: Structural elucidation, total synthesis, and lipid-lowering activity

Hyperimonates A (<b>1</b>) and B (<b>2</b>), two minor polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented hexahydro-1<i>H</i>-cyclopenta[<i>c</i>]furan-1-one and 2-oxabicyclo[2.2.1]heptane ring system were isolated from <i>Hypericum monogynum</i>. To obtain adequate materials for biological research, the asymmetric total syntheses of <b>1</b> and <b>2</b> were completed from commercially available geraniol <i>via</i> a bioinspired strategy that features an Au(I)-catalyzed carbometallic cascade cyclization and a Mn(III)/Cu(II) mediated oxidative radical cyclization as vital steps. Biological study implied that compound <b>1</b> showed excellent lipid-lowering activity <i>in vitro via</i> inhibiting two signaling pathways, Notch and PPAR, further verified by non-alcoholic fatty liver disease (NAFLD) zebrafish model. These findings provide a new structural template for the treatment of NAFLD and asymmetric synthetic approaches could also facilitate further evaluation for drug development.