Unified Organocatalytic Enantioselective Approach to Axially Chiral Spiranes and Alkylidenecycloalkanes

Axially chiral alkylidenecycloalkanes and spiranes represent two intriguing classes of axially chiral cycloalkane-type molecules that have received considerably less research attention compared to axially chiral atropisomers and allenes. In principle, the asymmetric formation of a stereocenter could enable a unified synthesis of these two types of axially chiral scaffolds. However, due to the significant challenges associated with remote stereocontrol, enzymatic reduction remains the only method reported to date. In this work, we present a unified organocatalytic asymmetric reductive amination protocol for the synthesis of axially chiral spiranes and alkylidenecycloalkanes. By fine-tuning the extended ortho-aryl substituents on chiral phosphoric acid (CPA) catalysts, the reductive amination of prochiral spirane ketones or alkylidene cycloalkanones with aromatic amines and Hantzsch esters afforded both classes of axially chiral products in high yields and with excellent enantioselectivities. Detailed computational studies were conducted to elucidate the origin of the precise remote stereocontrol, highlighting the critical role of multiple noncovalent interactions (NCIs) between the catalyst’s extended ortho-aryl groups and the substrates. The operational simplicity, broad substrate scope, ease of scale-up, and straightforward access to both enantiomers underscore the significant value of this methodology.