Total synthesis of (−)-cylindrocyclophane A facilitated by C−H functionalization
Aaron T. Bosse, Lorraine Hunt, Camila A. Suarez, Tyler D. Casselman, Elizabeth L. Goldstein, Austin C. Wright, Hojoon Park, Scott C. Virgil, Jin‐Quan Yu, Brian M. Stoltz, Huw M. L. Davies
Abstract
(−)-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.