Reversal of enantioselectivity by tuning the ring size of ProPhenol

Abstract

Enantiodivergent synthesis to prepare both enantiomers of a chiral molecule using a single chiral source has aroused widespread interest. Great achievements have been made by tuning non-chiral parameters such as solvents, additives, metal cations, anions, temperature and even reaction time. However, reversal of enantioselectivity by variation of the achiral subunits of a chiral ligand while keeping the stereogenic components unchanged has met with less success. Herein, we report a ligand-ring-size controlled enantiodivergent aza-Friedel–Crafts alkylation reaction of 3-aminophenols with imines. Under the same conditions, the Trost ligand afforded the (R)-products, while its azetidine analogue delivered the opposite (S)-enantiomers. By using this protocol, the two enantiomers of products were readily prepared in good yields with excellent enantioselectivities. Control experiments and DFT calculations were performed to shed light on the origin of enantiodivergence. The space and size of the ligand ring, which have been identified as essential factors impacting the non-covalent interaction between the substrate and the catalyst ligand, are found to determine the configuration of the products.