One-Pot Bioisosteric Replacement of Alkyl Carboxylic Acids via Organic Photoredox Catalysis.

Drug development is often hindered by the pharmacokinetic and physicochemical limitations of lead compounds. Bioisosteric replacement is commonly employed to bolster drug viability; however, methods for accessing drug analogs are often synthetically inefficient. To address this challenge, we disclose strategies to access carboxylic acid bioisosteres via organic photoredox catalysis. A one-pot method enables the direct conversion of carboxylic acids to their most common bioisostere, tetrazoles. Additional functionalization to an amidoxime intermediate affords access to three other bioisosteres: oxathiadiazolones, oxadiazolones, and oxadiazole thiones. HPLC lipophilicity measurements of carboxylic acids and bioisostere derivatives illustrate the synthetic value of these methods for improving lead compound viability.