Fig. 5: Ruthenium-catalysed C‒H amidation with bifunctional dioxazolones for late-stage linker installation.
a Late-stage installation of linkers offering orthogonal functional handles for subsequent derivatisation. Yields refer to the isolated product (0.1–0.25 mmol scale). a Partial Boc deprotection observed: 10d was isolated as the free amine, after one-pot treatment with trifluoroacetic acid (TFA). bPartial Boc deprotection observed: 10e was isolated after one-pot treatment with di-tert-butyl dicarbonate. c Pivalic acid (PivOH) used instead of (PhO)2PO2H. d In situ tert-butyl ester deprotection observed: 10g was isolated as the free acid. e Conversion of substrate to 10h after C‒H amidation, as determined by LC-MS. f Carboxylate 10i was isolated after telescoped saponification with NaOH. See the Supplementary Information, Section 9.4 for substrate specific details. b Examples of derivatisation following late-stage C‒H amidation: fluorescent tag labelling (11) and synthesis of VHL derivative 12. g Reaction conditions: BDP-FL NHS ester (0.02 mmol), 10d (1.2 equiv), DIPEA (1.2 equiv), MeCN, rt, 1 h. h Reaction conditions: 10i (0.03 mmol), VHL ligand (1.1 equiv), HATU (1.2 equiv), DIPEA (3.0 equiv), DMF, rt, 2 h. CDI 1,1’-carbonyldiimidazole, FG directing functional group, TFE 2,2,2-trifluoroethanol, DME 1,2-dimethoxyethane, Fmoc fluorenylmethoxycarbonyl, Cbz benzyloxycarbonyl, Boc tert-butyloxycarbonyl, BODIPY boron-dipyrromethene, VHL von Hippel-Lindau E3 ligase.
