Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation
2023 | journal article. A publication with affiliation to the University of Göttingen.
Jump to: Cite & Linked | Documents & Media | Details | Version history
Cite this publication
Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation
Antermite, D.; Friis, S. D.; Johansson, J. R.; Putra, O. D.; Ackermann, L. & Johansson, M. J. (2023)
Nature Communications, 14(1). DOI: https://doi.org/10.1038/s41467-023-43789-9
Documents & Media
Details
- Authors
- Antermite, Daniele; Friis, Stig D.; Johansson, Johan R.; Putra, Okky Dwichandra; Ackermann, Lutz; Johansson, Magnus J.
- Abstract
- Abstract PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules emerging as a powerful modality in drug discovery, with the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these derivatives are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to access fully elaborated heterobifunctional compounds. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C–H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of both CRBN and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.
- Issue Date
- 2023
- Journal
- Nature Communications
- eISSN
- 2041-1723
- Language
- English