Total synthesis of (−)-cylindrocyclophane A facilitated by C−H functionalization

(−)-Cylindrocyclophane A is a 22-membered C 2 -symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (−)-cylindrocyclophane A that uses 10 C−H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C–H functionalization of primary and secondary positions, which was complemented by palladium-catalyzed C(sp 2 )–C(sp 2 ) cross-couplings, resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. The use of a late-stage palladium-catalyzed fourfold C(sp 2 )–H acetoxylation installed the bis-resorcinol moieties. This research exemplifies how multilaboratory collaborations can produce substantial modernizations of complex total synthesis endeavors.