Scheme 1. General Synthesis of N-Substituted Pyroglutamic Acid Intermediates.

Reagents and conditions: (a) NaH, THF or DMF, rt; (b) LiOH, THF:MeOH:H₂O (3:1:1), rt, 32-69% for 2 steps; (c) NaOH, H₂O, 50 °C; (d) concentrated HCl, acetone, reflux, 60% for 2 steps; (e) TBDMS-Cl, Et₃N, imidazole, THF-DMF, rt, quantitative yield; (f) RuO₂·H₂O, NaIO₄, EtOAc-H₂O, rt, 89-98%; (g) TFA, DCM, 0 °C - rt, quantitative yield; (h) Cs₂CO₃, CH₃I, 50 °C, 37%; (i) NaH, CH₃I, DMF, 50 °C, 26%; (j) DAST, DCM, 0 °C to rt, 34%; (k) 4M HCl in dioxane, DCM, rt, 63%.