Atropisomerism is becoming increasingly important in synthesizing more potent and selective pharmaceuticals. One long-standing challenge is the reliance on semi-preparative HPLC on chiral stationary phase. Though appropriate for early-stage medicinal chemistry, it becomes inefficient as it is time consuming, limits the scalability, and is resource/cost-intensive. Herein we report a general atroposelective strategy to obtain pharmaceutically relevant pyrrolopyrimidines (a common kinase-inhibiting scaffold), pyridines and quinolines (which are among the most common moieties in FDA-approved drugs). Through enantioselective nucleophilic aromatic substitution with thiophenol, we can synthesize a diverse range of heterocyclic, pharmaceutically relevant scaffolds in high atroposelectivity. We show the resulting enantioenriched sulfide products can be converted to a sulfone and subjected to a second nucleophilic aromatic substitution with any nucleophile (with no observed racemization). Importantly, we are able to expand our atroposelective nucleophilic aromatic substitution strategy to access enantioenriched small-molecules with known biological activities. We have observed higher relative selectivity and potency through implementing our synthetic strategy of designing more stable atropisomeric compounds.

Developing atroposelective syntheses to access diverse pharmaceutically relevant scaffolds

2019 Spring National Meeting

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