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.

Enantioselective Synthesis of Planar‐Chiral Sulfur‐Containing Cyclophanes by Chiral Sulfide Catalyzed Electrophilic Sulfenylation of Arenes

“…[10] In early studies, chiral auxiliary-enabled resolution was used to obtain planar-chiral cyclophanes. [11] Recently, some elegant catalytic asymmetric methods have been disclosed for the enantioselective synthesis of planar-chiral cyclophanes, e.g., the rhodium-catalyzed asymmetric [2 + 2 + 2] cycloaddition developed by Tanaka's group, [12] the Candida antarctica lipase B (CALB)-catalyzed macrolactonizations between diacids and diols achieved by Collins and co-workers, [13a] the N-heterocyclic carbene (NHC)-catalyzed macrolactonizations for the construction of planar-chiral indoles documented by Wang group, [13b] palladium-catalyzed CÀ O crosscoupling reactions for the synthesis of planar-chiral macrocyclic metacyclophanes reported by Li group, [14] and the late-stage asymmetric functionalizations of prochiral cyclophanes developed by Shibata, [15] Yang, [16] and Zhao. [17] Inspired by these successful approaches, and in combination with our research interest in chiral organosulfur chemistry, [5] we decided to explore the use of catalytic asymmetric electrophilic sulfenylation of prochiral cyclophanes to synthesize planar-chiral sulfur-containing cyclophanes.…”

Catalytic asymmetric synthesis of planar-chiral dianthranilides via (Dynamic) kinetic resolution

“…Metallocenes 8 – 13 , cyclophanes 14 – 21 , and some rigid cycloalkenes 22 – 28 are typical planar-chiral structures. With recognition of the importance of planar chirality, particularly in chiral ligand/catalyst discovery 29 – 33 , several catalytic enantioselective synthesis methods have been developed 34 – 39 . This is the case for assembling planar-chiral ferrocenes via enantioselective C−H activation by You, Zhou, and others 40 – 45 .…”

Kinetic Resolution of a Planar–Chiral [2.2]Paracyclophane via Michael Addition to Nitroolefins Catalyzed by N‐Terminal Guanidinylated Helical Peptide

“…[15][16][17][18][19][20][21] Although several new synthetic methods for planar-chiral cyclophanes appeared in the past three years, they are constrained by the structural characteristics of the substrates involved. [22][23][24][25][26][27] To this end, kinetic resolution of racemic substrates stands out as a promising approach. [16,28] Concerning this, our group has reported the peptide catalyzed kinetic resolution of disubstituted metallocenes and that of a monosubstituted [2.2]paracyclophane (22PC).…”