Dynamic kinetic resolution of biaryl atropisomers via peptide-catalyzed asymmetric bromination

Abstract

Despite the widespread use of axially chiral, or atropisomeric, biaryl ligands in modern synthesis and the occurrence of numerous natural products exhibiting axial chirality, few catalytic methods have emerged for the direct asymmetric preparation of this compound class. Here, we present a tripeptide-derived small-molecule catalyst for the dynamic kinetic resolution of racemic biaryl substrates. The reaction proceeds via an atropisomer-selective electrophilic aromatic substitution reaction using simple bromination reagents. The result is an enantioselective synthesis that delivers chiral nonracemic biaryl compounds with excellent optical purity and good isolated chemical yields (in most cases a >95:5 enantiomer ratio and isolated yields of 65 to 87%). A mechanistic model is advanced that accounts for the basis of selectivity observed.

Figure 1

(a) Biaryl atropisomers are isolable if the barrier to rotation about the single bond linking the rings is high. The enantiomers interconvert via racemization if the barrier is low. (b) sp³-Hybridized carbon atoms with four different substituents form generally stable enantiomers. (c) Vancomycin is a natural product that exists as a single atropisomer. (d) BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) is a widely used chiral ligand.

Figure 2

Assessment of the catalytic efficiency of simple functional groups.

Figure 3

X-ray structure of the major enantiomer of 3d, and a possible docking model explaining selectivity. Structure shown is an ORTEP diagram (ellipsoids shown at the 30% probability level).