Synthesis of Chiral Cyclophanes via Pd(II)-Catalyzed Atroposelective C–H Macrocyclization: Total Synthesis of Isoplagiochin D

Chiral cyclophanes are structurally intriguing macrocycles found in natural products and pharmaceuticals with promising biological activities. The development of efficient asymmetric macrocyclization strategies is therefore of great importance, yet remains a formidable challenge due to the entropic penalty and stereochemical complexities inherent to macrocyclization. Here, we report a palladium-catalyzed atroposelective C–H macrocyclization using l - tert -leucine as a chiral transient directing group. This method enables the efficient construction of a broad range of chiral cyclophanes with varied ring sizes in good yields (up to 88%) and excellent enantioselectivities (up to 99% ee) and further allows the dynamic kinetic resolution of prochiral macrocycles via intermolecular C–H olefination. The synthetic utility of this strategy is demonstrated by the asymmetric total synthesis of isoplagiochin D, which was completed in 10 linear steps with 16.8% overall yield and 97% ee.