Atropisomerism, or axial chirality, is ubiquitous in drug discovery. Notably, 80% of FDA approved kinase inhibitors possess at least one atropisomeric axis. The vast majority of biologically relevant atropisomers are stereochemically unstable, and thus exist as rapidly racemizing compounds. However, these compounds bind to the target active site in a single atropisomeric conformation with the non-relevant atropisomer contributing little to the desired activity. By rigidifying the atropisomeric axis and then isolating each atropisomer, we could decouple the promiscuous activities to specific atropisomer conformations. However, the lack of synthetic methodologies to obtain ‘large-scale’ quantities of atropisomerically pure drug scaffolds represents a major synthetic challenge. We are currently developing an ‘organocatalytic’ nucleophilic aromatic substitution with other heterocyclic biaryls such as pyridines and quinolines (common moieties found in many FDA-approved drugs). We have tested a few substrates with our current nucleophilic conditions, and our preliminary results suggest we are close to the optimized reaction (yields of 70%, with enantiomeric ratios up to 10:90). We are currently synthesizing a plethora of different biaryl quinolines and pyridines that we hope to soon enantiomerically enrich via our nucleophilic substitution chemistry. We envision that these studies will serve as a springboard to implement other atroposelective methodologies towards other pharmaceutically relevant atropisomeric scaffolds.

Enantioselective synthesis of biaryl pyridines and quinolines via cinchona alkaloid-catalyzed nucleophilic aromatic substitution

2019 Spring National Meeting

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