Enantioselective Synthesis of Axially Chiral Diaryl Ethers through Chiral Phosphoric Acid-Catalyzed Desymmetric Acylation with Azlactones

Abstract

C–O axially chiral diaryl ethers play important roles in natural products and bioactive molecules, but because of the low rotational barrier and strict steric hindrance requirements, the catalytic asymmetric construction of axially chiral diaryl ethers still remains a challenge. Herein, we devised a strategy employing achiral azlactone for the desymmetrization of prochiral diamines under the catalysis of chiral phosphoric acid. The targeted C–O axially chiral diaryl ethers were obtained in very good yields (up to 98%) and high enantioselectivities (up to >99.5:0.5 er). The synthetic utility was demonstrated through large-scale reaction and transformations of the products. Moreover, DFT calculations were conducted to probe the origins of enantioselectivity.

Enantioselective Synthesis of Heteroatom‐Linked Non‐Biaryl Atropisomers

“…From related prochiral 1,3-benzenediamines 54, Zheng and Li described an atroposelective acylation reaction using azlactones 55 as acylating reagents catalyzed by chiral phosphoric acid ent-C4 (Scheme 15). [39] Benzamide atropisomers 56 were obtained in moderate to excellent yields and high enantioselectivities. Kinetic of racemization experi-ments have allowed to determine barriers to enantiomerization of three benzamides ranging between 127.1 and 133.8 kJ.mol À 1 , depending on the nature of the ortho substituent on the phenyl moiety.…”