Fig. 1: Developing a late-stage C‒H functionalisation platform applicable to the synthesis of heterobifunctional compounds. | Nature Communications

Fig. 1: Developing a late-stage C‒H functionalisation platform applicable to the synthesis of heterobifunctional compounds.

From: Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation

Fig. 1

a PROTACs consists of 3 different structural components: a POI-ligand, an E3-ligand, and a linker. As representative examples, the chemical structures of ARV-110 and ARV-471, the first 2 PROTACs to enter clinical trials, are shown. Multistep and labour-intensive synthetic sequences are required in PROTAC discovery, typically relying on the de novo synthesis of pre-functionalised POI-ligand precursors. b Ruthenium-catalysed late-stage C‒H amidation with readily available dioxazolone reagents. Streamlined access to PROTAC-like molecules and other drug conjugates is provided through direct C‒H functionalisation of advanced POI-ligands, either in a stepwise (i.e. installation of functional handles for subsequent conjugation, path 1, or single-step approach, path 2). POI protein of interest, CRBN cereblon E3 ligase, AR androgen receptor, ER estrogen receptor, FG functional handle (for conjugation), X linker attachment.

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