Fast MacMillan’s Imidazolidinone-Catalyzed Enantioselective Synthesis of Polyfunctionalized 4-Isoxazoline Scaffolds

Abstract

The enantioselective 1,3-dipolar cycloaddition of nitrones and arylpropionaldehydes to generate highly functionalized scaffolds for application in drug discovery was herein investigated. The use of a second-generation MacMillan catalyst as hydrochloride salt consistently accelerated the reaction speed, allowing a decrease in the reaction time up to >100 times, still affording 4-isoxazolines with good to excellent enantiomeric ratios at room temperature. As a proof of concept, further functionalization of the isoxazoline core through Pd-catalyzed cross-coupling was performed, generating differently functionalized chemical architectures in high yield.

Facile synthesis of (polyfluoro)alkanesulfinyl 4-isoxazolines: a stepwise solvent- and catalyst-free approach or a one-pot process in water

“…[3][4][5][6][7] 1,3-Dipolar cycloadditions between nitrones and alkynes or allenes are the most common strategy to synthesize 4-isoxazolines. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Regioisomers are often obtained in cycloaddition reactions between nitrones and asymmetrically substituted alkynes or allenes. 8,9 However, with some monosubstituted or electrondeficient alkynes, 4-isoxazolines can be achieved with good regioselectivity, which has been explained by FMO analysis.…”