Exploring the use of Cyrene TM for the amidation of E3 ligase recruiters: efficient access to PROTAC precursors
Abstract
Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy based on the selective degradation of disease-relevant proteins through proteolysis targeting chimeras (PROTACs). 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 TM (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 work-up, 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.
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BibTeX
@article{galli2026exploring,
title = {{Exploring the use of Cyrene TM for the amidation of E3 ligase recruiters: efficient access to PROTAC precursors}},
author = {Michela Galli and Andrea Citarella and Valerio Fasano and Daniele Passarella and Alessandra Silvani},
journal = {Beilstein Journal of Organic Chemistry},
year = {2026},
month = oct,
doi = {10.3762/bjoc.22.118},
url = {https://www.beilstein-journals.org/bjoc/articles/22/118},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exploring the use of Cyrene TM for the amidation of E3 ligase recruiters: efficient access to PROTAC precursors
AU - Michela Galli
AU - Andrea Citarella
AU - Valerio Fasano
AU - Daniele Passarella
AU - Alessandra Silvani
PY - 2026
DA - 2026/10/20
JO - Beilstein Journal of Organic Chemistry
DO - 10.3762/bjoc.22.118
UR - https://www.beilstein-journals.org/bjoc/articles/22/118
AB - Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy based on the selective degradation of disease-relevant proteins through proteolysis targeting chimeras (PROTACs). 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 TM (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 work-up, 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.
SN - 1860-5397
ER -