Scheme 6.

Synthesis of 18-membered analogs by S_NAr macroetherification

Key: (a) i. Boc₂O, CH₃CN, rt, 12 h; ii. Na₂CO₃, MeOH, H₂O (4:1), rt, 76%; (b) TIPSCl, DMF, rt, 24 h, 95%; (c) i. TFA, CH₂Cl₂, (1:1), rt, 1h; ii. NaHCO₃ (aq), 95%; (d) i. N-Boc-β-alanine, EDCI, HOBt, CH₂Cl_2, rt, 12 h; ii. 0.5 N HCl, 92%; (e) i. TFA, CH₂Cl₂, (1:1), rt, 1 h; ii. NaHCO₃ (aq), 97%; (f) i. 17, EDCI, HOBt, CH₂Cl₂, rt, 12 h; ii. 0.5 N HCl; 93%; (g) CsF, DMSO (2mM), 4 Å sieves, rt, 20 h, 84%; (h) BBr₃, CH₂Cl₂, rt, 8h, 82%; (i) CrCl₂, DMF, rt, 12h, 55%; (j) BBr₃, CH₂Cl₂, rt, 8h, 54%; (k) i. AcOH/H₂O, 9:1, NaNO₂ 0 °C; ii. NaN₃, 0 °C, 69%; (l) i. CuBr₂ (0.8 equiv), ^tBuONO, CH₃CN, 0 °C, 1h; ii. 40 in portions, 0 °C, 2h then warmed to rt; iii. 1N HCl, 25%; (m) BBr₃, CH₂Cl₂, rt, 8h, 94%; (l) i. CuBr₂ (3.0 equiv), ^tBuONO, CH₃CN, 0 °C, 1h; ii. 40 in portions, 0 °C, 2h then warmed to rt; iii. 1N HCl, 29%; (m) BBr₃, CH₂Cl₂, rt, 8h, 72%.