Scheme 13
From: Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs
Chemical synthesis of alkyl-connected lenalidomide-based PROTACs. Reagents and conditions: a Pd(PPh3)2Cl2, Copper (I) Iodide, triethylamine, DMF, 80 °C, 3 h to overnight (time varies depending on the type of linker); b1 Palladium on Carbon (Pd/C), H2, methanol/DMF, rt, 12 h (depending on the type of linker); b2 Palladium on Carbon (Pd/C), H2, ethanol, rt, 2 h (depending on the type of linker); c t-BuONO, bis(pinacolato)diboron, dibenzoyl peroxide, acetonitrile, rt, 4 h; d i. Sodium periodate, THF, water, rt, 2 h; ii. 1 M HCl, rt, 18 h; e i. tert-butyl bromoacetate, Pd(PPh3)4, cesium fluoride, dimethoxyethane, dichloromethane, reflux, 18 h; ii. Trifluoroacetic acid, dichloromethano, rt, 2 h, quant.; f HATU, DIPEA, DMF, rt, overnight (depending on the type of linker).
