Scheme 3.

Solid-phase synthesis of 15 by Silverman and coworkers.

Reagents and conditions: (a) LiOH, THF/H₂O (7:1), rt, 16 h; (b) HBTU, DIPEA, NMP, 16 h; (c) 2% thioanisole and 50% TFA in CH₂Cl₂, 15 min; (d) Fmoc-Leu-OH, HBTU, DIPEA, NMP, 6 h; (e) 20% piperidine in DMF 40 min; (f) Fmoc-Val-OH, HBTU, DIPEA, NMP, 6 h; (g) CHCl₃/AcOH/NMM, Pd(PPh₃)₄, 3 h; (h) HBTU, DIPEA, NMP, 16 h; (i) 2% thioanisole and 50% TFA in CH₂Cl₂, 36 h; (j) allyl bromide, K₂CO₃, acetone, 48 h (95%); (k) Boc-Leu-OH, DMAP (cat.), DCC, CH₂Cl₂, 48 h (63%); (l) 50% TFA in CH₂Cl₂, 5 min; (m) O-allyl-Leu, HBTU, DIPEA, NMP, 16 h; (n) Fmoc-Leu-OH, HBTU, DIPEA, NMP, 6 h; (o) MSNT (1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole), NMI (1-methylimidazole), CH₂Cl₂, 16 h.