Scheme 1.

Synthesis of KEAP1-targeting PROTAC.

Reagent and conditions: (a) BnBr, K₂CO₃, EtOH, 70 °C, 81%; (b) Br₂, AcONa, AcOH, r.t, 96%; (c) MeI, NaH, DMF, 0 °C to r.t, 79%; (d) Zn dust, AcOH, 0 °C–45 °C, 59%; (e) NaNO₂, 10% H₂SO₄ (aq.), 87%; (f) tert-Butyl acrylate, Pd(PPh₃)₄, P(O-Tol)₃, DMF, 95 °C, 79%; (g) 13, [RhCl(Cod)]₂, Et₃N, Dioxane/H₂O (2:1), 95 °C, 53%; (h) 16, DIAD, PPh₃, anhydrous THF, r.t, 75%; (i) H₂, Pd/C, MeOH, r.t, 98%; (j) 20a-c, K₂CO₃, DMF, 90 °C, 21–39%; (k) 4 N HCl/Dioxane, r.t, 53–88%.