Catalytic Asymmetric Reductive Amination for Planar Chiral [2,2]Paracyclophanes via Desymmetrization and/or Kinetic Resolution

Abstract

Despite the significant potential of planar chiral [2.2]paracyclophane (PCP) derivatives in medicinal chemistry, asymmetric catalysis, and material science, their efficient synthesis remains a great challenge. The organocatalytic asymmetric reductive amination (ARA) represents a cornerstone methodology in the production of optically active amines. However, the application of ARA for the control of planar chirality in [2.2]PCPs has yet to be explored. To fill this gap, we describe herein an unprecedented chiral phosphoric acid (CPA)-promoted ARA of center-symmetrical pseudo-para-diformyl [2.2]PCP with aromatic amines in the presence of Hantzsch ester, which involves a desymmetrization/kinetic resolution (KR) sequence. The CPA serves as a competent bifunctional catalyst to facilitate differentiation of enantiotopic faces, allowing for access to a wealth of benzylamine-containing 4,16-disubstituted planar chiral [2.2]PCPs with good yields and high to perfect enantioselectivities (up to 89% yield, >99% ee). The ARA-KR of racemic formyl [2.2]PCPs also proceeds smoothly with moderate to good selectivity factors. The diverse late-stage functionalization further highlights the value of current chemistry.

Keywords

Planar chirality / [2,2]Paracyclophanes / Desymmetrization / Kinetic resolution / Chiral phosphoric acid / Asymmetric catalysis / Reductive amination / Aldehydes

RIGHTS & PERMISSIONS

2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH