Fig. 6: Application of ruthenium-catalysed C‒H amidation to the single-step synthesis of heterobifunctional derivatives as PROTACs and chemical biology tools. | Nature Communications

Fig. 6: Application of ruthenium-catalysed C‒H amidation to the single-step synthesis of heterobifunctional derivatives as PROTACs and chemical biology tools.

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

Fig. 6

a Direct access to fully elaborated CRBN and biotin conjugates via late-stage C‒H amidation. Yields refer to the isolated product. Conditions A: substrate 7 (0.1–0.25 mmol), dioxazolone 13 (1.0 equiv), [Ru(p-cymene)Cl2]2 (5 mol%), AgPF6 (20 mol%), PivOH (30 mol%), TFE (0.1 M), 60 °C, 16 h. Conditions B: substrate 7 (0.1–0.25 mmol), dioxazolone 13 (1.0 equiv), [Ru(p-cymene)Cl2]2 (5 mol%), AgSbF6 (20 mol%), (PhO)2PO2H (30 mol%), DME (0.1 M), 60 °C, 16 h. a De novo synthesis: number of steps to prepare the depicted product via a traditional lengthy synthesis as opposed to this LSF approach. The number of steps is based on a proposed synthetic route as the compounds are unknown (see the Supplementary Information, Section 8 for more details). b Pivalic acid (PivOH) was used in place of (PhO)2PO2H. b Human CRBN binding and physicochemical profile of products 14a–14e (n ≥ 3). FG directing functional group, TFE 2,2,2-trifluoroethanol, DME 1,2-dimethoxyethane, CRBN cereblon E3 ligase, MW molecular weight, chrom LogD chromatographic LogD, ePSA exposed polar surface area, Clint intrinsic clearance in rat hepatocytes.

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