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General Procedure for the Synthesis of 6a and 6b: Amino acid-bound Rink amide MBHA resin 1 (200 mg) was mixed with NTFBA (5.0 equiv) in DMF (5 mL). After shaking for 3 h at r.t. the resin was filtered and washed with DMF (3 ¥ 5 mL), CH2Cl2 (3 ¥ 5 mL) and MeOH (3 ¥ 5 mL). The resin was treated with a large excess of primary aliphatic amine (10.0 equiv) in DMF (5 mL) overnight at r.t. followed by washing with DMF (3 ¥ 5 mL), CH2Cl2 (3 ¥ 5 mL) and MeOH (3 ¥ 5 mL). The diamines 3a and 3b were reduced with 2 M SnCl2⟨2H2O/2 M NMM in DMF (5 mL) overnight at r.t. under an argon atmosphere. After quick washing with DMF (6 ¥ 5 mL), CH2Cl2 (3 ¥ 5 mL) and MeOH (3 ¥ 5 mL), the triamines 4a and 4b were treated with 10.0 equiv aldehyde in HOAc-DMF (4:96, 5 mL). After shaking for 72 h at r.t. the resin was washed with DMF (4 ¥ 5 mL), CH2Cl2 (4 ¥ 5 mL) and MeOH (4 ¥ 5 mL). The washed resin was cleaved with TFA-H2O (95:5, 5 mL) for 50 min at r.t. and then the remaining resin was rinsed with CH2Cl2 (3 ¥ 3 mL) and MeOH (3 ¥ 3 mL). The combined solvents were evaporated under vacuum and the residue was refluxed in MeOH (8 mL) for 10 h to give the final products 6a and 6b. The target compounds were easily separated with reverse-phase column chromatography with a gradient elution from MeCN-H2O (9:1) to MeCN-H2O (1:9) in 10% alternation.
11 Selected spectroscopic data for 6a-I: yellow oil. 1H NMR (500 MHz, CDCl3): δ = 1.11 [d, J = 7.0 Hz, 6 H, CH(CH
3)2], 2.39 [m, 1 H, CH(CH3)2], 3.08 (t, J = 6.5 Hz, 2 H, PhCH
2CH2N), 3.65 (t, J = 6.5 Hz, 2 H, PhCH2CH
2N), 3.79 (d, J = 4.0 Hz, 1 H, NHCHCHCONH2), 3.89 [s, 6 H,
Ar-(OCH
3)2], 3.93 (s, 3 H, Ar-OCH
3), 4.78 (br s, 1 H, NH), 5.75 (s, 1 H, CONHH), 6.41 (s, 1 H, CONHH), 6.67 (s, 2 H, Ar-H
2), 6.71 (d, J = 7.5 Hz, 2 H, o-Ar-H
2
), 7.15 (dd, J = 7.5 Hz, J = 7.0 Hz, 2 H, m-Ar-H
2
), 7.20 (d, J = 7.0 Hz, 1 H,
p-Ar-H), 7.69 (d, J
H-F = 10.0 Hz, 1 H, Ar-H). ESI-MS: m/z = 539.2 [M + H+]. HRMS-FAB: m/z [M + H]+ calcd for C28H33F2N4O4, 539.2470; found, 539.2823. For 6b-I: white solid; mp 179.3 °C. 1H NMR (500 MHz, CDCl3): δ = 1.35 [d, J = 7.0 Hz, 6 H, CH(CH
3)2], 2.90 (t, J = 6.5 Hz, 2 H, PhCH
2CH2), 3.61 [sep, J = 7.0 Hz, 1 H, CH(CH3)2], 3.64 (t, J = 6.5 Hz, 1 H, PhCH2CH
2N), 6.81 (d, J
F-H = 11.0 Hz, 1 H, Ar-H), 7.20 (d, J = 7.5 Hz, 2 H, o-Ar-H
2
), 7.23 (d, J = 7.0 Hz, 1 H, p-Ar-H), 7.32 (dd, J = 7.5 Hz, J = 7.0 Hz, 2 H,
m-Ar-H
2
), NH and OH were not observed. ESI-MS: m/z = 344.1 [M + H+]. HRMS-FAB: m/z [M + H]+ calcd for C19H20F2N3O, 344.1574; found, 344.1809.