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, general catalytic methods for the direct asymmetric preparation of this compound class have proven elusive. 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 employing simple bromination reagents. The result is an enantioselective synthesis that delivers chiral non-racemic biaryl compounds with excellent optical purity and good isolated chemical yields (in most cases >95:5 enantiomer ratio and isolated yields 65 to 87%). A mechanistic model is advanced that explains the basis of selectivity observed.

Current Methods for Asymmetric Halogenation of Olefins

“…A simple tripeptide-catalyst promotes atropisomerselective bromination of rapidly racemizing biaryl compounds in the presence of NBS. [57] In the absence of catalyst, bromination is sluggish, and 104 is converted to 106 in only 15 % yield after 18 h (Scheme 28). Several experiments with potentially catalytic moieties point to amide catalysis, perhaps via a type of [O-Br]-cationic species.…”

Trifunctional Organocatalysts: Catalytic Proficiency by Cooperative Activation

“…[41] Reactions proceeded with exellent yields (65-85 %) and high enantioselectivity (74-94 %) at room temperature over 18 h with low catalyst loading (10 mol-%). Catalyst 106 is highly functionalised with many chemical motifs: three amides (Brønsted acid, Lewis base, Brønsted acid) and a tertiary amine (Brønsted base).…”

Atroposelective Organocatalysis

“…[8a,b] In recent years those in the field of organocatalysis have explored new approaches for the control of issues related to absolute or relative stereochemical configurations; however, addressing the problem of selectivity in a dynamic mixture of freely rotating atropoisomers still constitutes a formidable challenge. Recently, this challenge was undertaken by Miller and co-workers [9] who have described a dynamic kinetic resolution of biaryl atropoisomers by peptide catalysis (Scheme 2). Peptides were effective catalysts [12] for the derivatization of aromatic compounds, and Miller and coworkers have reported a peptide catalyst that is capable of mediating an electrophilic aromatic substitution that takes place at the ortho position of a biaryl molecule, thus forming stereoisomers with high atroposelectivity.…”