Enantioselective Synthesis of Planar Chiral Macrocyclic Metacyclophanes by Pd-Catalyzed C–O Cross-Coupling

Abstract

Despite the presence of planar chiral elements in natural products and in ligands for asymmetric catalysis, catalytic enantioselective methods for installing planar chirality remain underdeveloped relative to methods for installing central and axial chirality. Here, we report an enantioselective Pd-catalyzed C–O bond-forming macrocyclization to access enantioenriched planar chiral macrocyclic metacyclophanes incorporating 2,3,4-trisubstituted pyridines. A variety of bridging chains and substituents can be incorporated in the metacyclophanes under the same reaction conditions (14 examples, 59–85% yields, 79–92% ee) to generate enantioenriched meta-, metaortho-, and metapara- cyclophanes. The syn-/anti-conformational preferences of metacyclophanes were elucidated by the X-ray structures, 1H NMR analyses, and computational studies. We also found that the two enantiomers of the metacyclophane can be obtained using the same enantiomer of the chiral ligand by starting from two regioisomeric linear precursors. This work provides an entry into the design of enantioselective cross-coupling macrocyclizations to access planar chiral structures for applications in medicinal chemistry and catalysis.