Synthesis of designed Smac mimetics.
Reagents and conditions: (a) 4 N HCl in 1,4-dioxane, methanol, rt, overnight, 95%; (b) i. formaldehyde (37% in water), NaBH3CN, HOAc, methanol, rt, overnight; ii. 4 N HCl in 1,4-dioxane, methanol, rt, overnight, 71% over two steps; (c) i. BnBr, NaHCO3, 1,4-dioxane, rt, overnight; ii. 4 N HCl in 1,4-dioxane, methanol, rt, overnight, 77% over two steps; (d) i. Ac2O or BnCOCl, N,N-diisopropylethylamine, CH2Cl2, rt, overnight; ii. 4 N HCl in 1,4-dioxane, methanol, rt, overnight; 85% for 5 and 87% for 6 over two steps.