1,3-Dipolar Cycloaddition of Nitroalkanes as a Tool of DOS/LOS-like Strategy for the Synthesis of Isoxazoles and Isoxazolines

An efficient and common strategy for the generation of pharmaceutically relevant functionalized molecules based on the diversity- and lead-oriented synthesis (DOS/LOS)-like concepts is presented. The approach is implemented for the case of functionalized sp3-enriched derivatives of isoxazole and isoxazoline. The key chemical transformation used was regioselective [3+2] cycloaddition of functionalized alkenes or alkynes and nitrile oxides, which were generated from nitroalkanes upon treatment with Boc2O and DMAP under mild conditions. Further functional group transformations provided a library of building blocks (amines, carboxylic acids, alcohols, amino acids, etc.) with good scaffold and appendage diversity that met LOS physicochemical parameter constraints. The proposed method was used for the successful preparation and further biological validation of isoxazole analogs of the clinically relevant JAK inhibitors Baricitinib and Ruxolitinib, thus demonstrating potential applications in medicinal chemistry.