Enantioselective Synthesis of Pyrrolopyrimidine Scaffolds through Cation-Directed Nucleophilic Aromatic Substitution

Abstract

The catalytic enantioselective synthesis of 3-aryl-substituted pyrrolopyrimidines (PPYs), a common motif in drug discovery, is achieved through a kinetic resolution via quaternary ammonium salt-catalyzed nucleophilic aromatic substitution (S_NAr). Both enantioenriched products and starting materials can be functionalized with no observed racemization to give enantiodivergent access to diverse chiral analogues of an important class of kinase inhibitor. One of the compounds was found to be a potent and selective inhibitor of breast tumor kinase.

Figure 1

Overview of the potential of atroposelective S_NAr in drug discovery. Atropisomeric axes are designated with curly arrows.

Figure 2

Evaluation of enantioenriched PPYs across Src and Brk kinases. IC₅₀ values were determined using Promega’s ATP Glo Kinase Inhibition Assay in duplicate. See the SI for more details.

Scheme 1

Overview of Atroposelective S_NAr Methodology

Scheme 2. Substrate Scope of PPYs

^aReactions were performed on a 25 mg scale of 1. ^bReported er was determined for one trial of the S_NAr of each substrate and its product. ^cConversions and s-factors were determined using HPLC. ^dResults are reported as an average of at least three trials. ^eThe er and s-factor were determined from the aminated substrate. See the SI for more details.

Scheme 3

Transformation of Enantioenriched (eq 1) Starting Materials and (eq 2) Products into C-4-Aminated Kinase Inhibitors and (eq 3) Modification of C-2 (See the SI for More Details)