Scheme 2.
Reagents and conditions: (a) paraformaldehyde, p-TsOH·H2O, toluene, reflux, 2 h, 98%; (b) HNR1R2, HOBt, EDC·HCl, DMF, 0 °C–rt, overnight, 80–98%; (c) CsF, CF3Si(CH3)3, THF, sonication, rt, 3 h then MeOH, rt, 30 min then NaBH4, rt, overnight, 48–61%; (d) H2, Pd/C (10%), MeOH, rt, overnight, 100%; (e) Cbz-AA-OH, HOBt, EDC·HCl, DMF, 0 °C–rt, overnight; (f) Dess–Martin periodinane, CH2Cl2, rt, 16 h, EtOAc then filtration through Celite followed by HPLC purification.
