Abstract
<jats:p>Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy based on the selective degradation of disease-relevant proteins through Proteolysis Targeting Chimeras (PROTAC). The synthesis of PROTAC precursors commonly requires the functionalization of E3 ligase recruiters using polar aprotic solvents such as DMF or DMSO, which present environmental and safety concerns. In this work, we investigated the bio-based solvent Cyrene (dihydrolevoglucosenone) as an alternative for the functionalization of the widely used E3 ligase recruiters lenalidomide and VH032-Me by amidation reactions. Reaction conditions were optimized using different coupling systems and activation methods, including ultrasound irradiation, providing efficient access to a library of 22 derivatives bearing diverse linker functionalities. The optimized protocols afforded the desired products in moderate to high yields, with significantly shorter reaction times compared to conventional conditions, and simplified purification procedures based on aqueous workups, avoiding chromatographic purification. The scalability of the method was demonstrated at the gram scale, and partial solvent recovery allowed reuse of Cyrene in successive reaction cycles without significant loss of efficiency.</jats:p>