Enantioselective Synthesis of Planar/Multiple Chiral [n]Cyclophanes through Asymmetric Allylation

Abstract

Planar-chiral cyclophanes with carbon-centered chirality are important targets in natural products and pharmaceuticals. However, synthesizing such planar chiral cyclophanes with two stereogenic elements via a one-step asymmetric reaction remains a formidable challenge. Herein, we present an efficient kinetic resolution method for synthesizing planar-chiral [n]cyclophanes with carbon-centered chirality. This is achieved through the enantioselective allylation of racemic aldehyde [n]cyclophanes catalyzed by Bi(OAc)₃ and chiral phosphoric acid. The reaction delivers planar-chiral [n]cyclophanes and multiple chiral [n]cyclophanes with high yields and excellent enantioselectivities, showcasing remarkable kinetic resolution efficiency (s factor up to 292). The broad substrate scope, scalability, and potential for derivatization highlight the value of this methodology. DFT calculations have also been performed to provide insights into the origin of the experimentally observed diastereo- and enantioselectivity for this reaction.