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

Gongming Yang,Donghui Guo,Di Meng,Jian Wang

doi:10.1038/s41467-019-10878-7

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.

Highlights

Chiral biaryl amino-alcohols play a pivotal role in organic synthesis and drug discovery
Kinetic resolution is recognized as an impresive technology to produce such biaryl structures
We have successfully reported the N-heterocyclic carbene-catalyzed atropoenantioselective [3 + 3] annulation and kinetic resolution of anilides, affording valuable chiral α-pyrone-aryls and isoindolinones, respectively[32,33]

Summary

Results

We commenced our study by using biphenols (1a–c) as the model prochiral substrates, aldehyde (2a) as acylation reagent[54,55,56,57,58,59,60,61,62] and DQ as oxidant[63,64]. Building upon the indanol-derived triazolium scaffold, precatalysts with. N-2,4,6-(Cl)3C6H265, or N-C6F566, substituents (Table 1, C2 and C3), derived from α-amino acids, were tested but exhibited low conversions and enantioselectivities (Table 1, entries 4 and 5). Precatalyst C1 with N-2,4,6-(Me)3C6H2 (N-Mes)[67] substituent provided 3a in 63% with 85% ee (Table 1, entry 1). If substrate 1b or 1c replaced 1a (R = NO2 or NH2; More information about changing R groups, see Supplementary Table 2),

C1 C1 C2 C3 C4 C5 C5 C5 C5 C5 C5 C5 C5 C5 C5

Discussion

Methods