Ruthenium-catalysed C‒H amidation for the late-stage synthesis of PROTACs

27 March 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

PROteolysis TArgeting Chimeras (PROTACs) are a powerful modality in drug discovery, offering 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 compounds are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to provide modular access to both fully elaborated PROTACs and drug conjugates. 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 PROTAC and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.

Keywords

PROTACs
late-stage functionalization
C-H activation
ruthenium
catalysis
dioxazolones

Supplementary materials

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Supporting Information
Description
Supporting information includes extended optimization data (S6-S12); Full details on LSF informer library screen (S13-S17); Crystallographic data for compound 8r (S18-S19); Experimental details and characterization data (S20-S68); and NMR data for novel compounds (S69-S136).
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