Efficient green synthesis of the targeted proteolysis system component

This study presents an efficient, scalable, and green synthetic route for cereblon ligase modulator used in proteolysis-targeting chimera (PROTAC) technology. The one-pot Heck–Matsuda reaction of the special diazonium salt with tert-butyl acrylate is accompanied by the elimination of the tert-butyl ester group and affords (2E)-3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acrylic acid in high yield and high stereoselectivity. The resulting alkyl-linked ligand demonstrates applicability in PROTAC design, offering a safe, cost-effective, and industrially adaptable pathway for producing key PROTAC component.