Divergent asymmetric synthesis of (–)-ganocins A–C and (+)-cochlearol B via a non-biomimetic strategy

Natural products are of substantial value in drug discovery screening campaigns. Their three-dimensional structures exhibit high complementarity with target proteins, via a multimodal combination of hydrogen bonds, hydrophobic contacts, electrostatic interactions, and van der Waals interactions. Skeletal diversity directly determines the three-dimensional shape diversity of compound libraries. Therefore, the rapid access to distinct molecular skeletons significantly increases the odds of drug discovery. Ganocins A–C and cochlearol B, Ganoderma meroterpenoids, feature distinct skeletons and diverse bioactivities. Despite tremendous efforts by synthetic chemists, a unified asymmetric synthetic strategy towards all four members has remained elusive. Here, we report the unified, asymmetric total synthesis of (–)-ganocins A–C and (+)-cochlearol B via a non-biomimetic strategy, featuring diastereoselective oxa-Michael addition, acid-controlled divergent cascade aldol/etherification cyclization or aldol/dehydration, and SmI 2 -mediated 4- exo -trig reductive cross-coupling. This meticulously designed synthetic strategy establishes a general solution to a problem previously deemed intractable by biomimetic approaches.