Total Synthesis of Lugdunomycin via Sequential Photoinduced Spiroketalization and Isobenzofuran Diels–Alder Reactions

The presence of sterically rigid contiguous quaternary stereocenters in natural products imposes conformational constraints with significant effects on their biological activities. However, achieving the direct synthesis of multiple contiguous quaternary stereocenters in a single step remains a formidable challenge. Here, we present the total synthesis of the antibacterial metabolite lugdunomycin (1) in thirteen steps via a sequence of photochemical transformations. A photoenolization, keto-enol tautomerization, and spiroketalization sequence was developed to generate the spiroketal 4 from actinaphthoran B (3). Subsequently, a photoinduced isobenzofuran Diels-Alder reaction between elmonin (4) and iso-maleimycin (5) was developed to construct the polycyclic benzaza[4,3,3]propellane framework bearing three contiguous quaternary stereocenters in the compact C-ring along with a distal hydroxyl group at C19. The mechanism of these photochemical reactions was investigated using synthetic and computational approaches.