Scheme 2. Synthesis of CyHQ Linker 1b^a.

Reagents and conditions: (a) MEMCl, iPr₂NEt, CH₂Cl₂, 3 h; (b) SeO₂, t-Bu-OOH, 1,4-dioxane, 45 °C, 3 h; (c) allyl bromide, indium, sat. NH₄Cl(aq), THF, sonication, 55 °C, 90 min; (d) K₂OsO₄, 2,6-lutidine, NaIO₄, 1:1 THF/H₂O, 12 h; (e) methylamine (2.0 M in MeOH), AcOH, NaBH(OAc)₃, THF, 12 h; (f) methyl adipoyl chloride, CH₂Cl₂, DIEA, 0 °C to rt, 6 h; (g) carbonyl diimidazole, CH₂Cl₂, 10 min; (h) N,N′-dimethylethylenediamine, CH₂Cl₂, 0 °C, 10 min; (i) chloroacetyl chloride, DIEA, 0 °C, 4 h; (j) trifluoroacetic acid/water (1:1), 40 °C, 12 h; (k) disuccinimidyl carbonate, pyridine, CH₃CN, 12 h.