2,5-dioxopyrrolidin-1-yl 1-(bicyclo[6.1.0]non-4-yn-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oate

This PROTAC linker is designed to connect a warhead to an E3-ligase ligand through a stable, amide-containing scaffold that supports productive ternary complex formation. Its rigid bicyclic alkyne handle and heteroatom-rich spacer help tune conformational behavior and solubility, which are commonly important for targeted protein degradation workflows. The sections below describe its structure and the practical chemistry used to incorporate it into PROTAC architectures in detail.

Structure: The linker contains a lactam-derived dioxopyrrolidine carbonyl motif and a central heteroatom-rich, oxygen- and nitrogen-containing chain that provides polarity and flexibility. It includes an alkynyl substituent for conjugation and multiple carbonyl groups, with an ester linkage and amide functionality.

Reactivity: Use the reactive ester/lactam-derived carbonyl functionality for acylation or nucleophilic substitution steps that install the linker onto complementary PROTAC fragments. The alkynyl handle enables copper-catalyzed or strain-promoted azide–alkyne coupling, depending on the partner functionality. Typical conditions employ polar aprotic solvents, mild base for ester activation steps, and standard coupling catalysts appropriate to the chosen conjugation strategy.