NHC-catalyzed atropoenantioselective synthesis of axially chiral biaryl amino alcohols via a cooperative strategy

Abstract

Axially chiral biaryl amino-alcohols play a pivotal role in organic synthesis and drug discovery. However, only a very few enantioselective methods have been reported to synthesize chiral biaryl amino-alcohols. Therefore, the rapid enantioselective construction of optically active biaryl amino-alcohols still remains a formidable challenge. Here we report an N-heterocyclic carbene (NHC)-catalyzed atropoenantioselective acylation of biphenols triggered by a cooperative strategy consisting of desymmetrization followed by kinetic resolution. This protocol features broad substrate scope and good functional group tolerance, and allows for a rapid construction of axially chiral biaryl amino-alcohols in good to high yields and with excellent enantioselectivities. Furthermore, the structurally diverse axially chiral biaryl amino-alcohol derivatives provide multiple possibilities for chemists to develop catalysts or ligands for different chemical transformations.

Fig. 1

Representative molecules and synthetic protocols. a Two representative axially chiral molecules. b Asymmetric kinetic resolution of achiral biaryl amino alcohols. c Our synthetic proposal via a NHC-catalyzed atroposelective synthesis of axially chiral biaryl amino-alcohols via a cascade strategy of desymmetrization followed by kinetic resolution

Fig. 2

Scope of aldehydes. Reaction conditions: a mixture of 1a (0.10 mmol), 2 (0.15 mmol), K₂CO₃ (0.12 mmol), and DQ (0.12 mmol) in CH₂Cl₂ (1.0 mL) was stirred at room temperature under N₂ for 12–24 h

Fig. 3

Scope of biaryl biphenols. Reaction conditions: a mixture of 4a–4o (0.10 mmol), 2a (0.15 mmol), K₂CO₃ (0.12 mmol), and DQ (0.12 mmol) in CH₂Cl₂ (1.0 mL) was stirred at room temperature under N₂ for 12–24 h. ^bent-cat. C5 was used

Fig. 4

Postulated mechanistic pathways. a The control experiments (Eqs. (1) and (2)) show that the desymmetrization process is the main contributor to the observed ee of the product and the second acylation is a effective KR process that could improve the ee of (−)-3a. b The postulated mechanistic pathway to generate product (−)-3a

Fig. 5

Synthetic transformations. Reaction conditions: (1) 4n, TMSCHN₂, CHCl₃:MeOH/5:1, r.t., 24 h. (2) NaOMe, MeOH, r.t., 1.0 h. (3) Pd/C, H₂, MeOH, r.t., 3.0 h

Fig. 6

Synthetic applications. a Use of 7 as a chiral catalyst. b Utility of 15–17 as chiral ligands

Fig. 7

Gram-scale synthesis. Reaction conditions: a mixture of 1a (3.4 mmol, 1.19 g), 2a (5.1 mmol, 0.55 mL), in CH₂Cl₂ (34.0 mL) was stirred at room temperature for 15 h