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7 HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate; TBTU: N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium-tetrafluoroborate; PyBop: benzotriazole-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate.
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10 Preparation of 1a: The HCl salt 5a (440 mg, 0.94 mmol) was dissolved in anhyd DMF (17 mL) and added within 1 h via syringe pump to a stirred solution of HATU (1.07 g, 2.81 mmol) and Hünig’s base (1.44 mL, 8.43 mmol) in anhyd DMF (90 mL). The reaction mixture was stirred for an additional hour before removal of all volatiles at reduced pressure. The remaining oil was extracted with CH2Cl2 (100 mL) and 2 M HCl (50 mL). The aqueous layers were extracted with CH2Cl2 (2 × 50 mL), the organic layers were washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent at reduced pressure followed by flash chromatography on silica gel (EtOAc) yielded the cyclotripeptide 1a (285 mg, 0.69 mmol, 73%) as a white solid. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 5.07 (dd, J = 8.1 Hz, 2.1 Hz, 3 H; Hα), 4.52 (dd, J = 12.5 Hz, 8.1 Hz, 3 H; Hδ), 4.04 (dtd, J = 9.9 Hz, 8.1 Hz, 5.3 Hz, 3 H; Hγ), 3.14 (dd, J = 12.5 Hz, 8.2 Hz, 3 H; Hδ), 2.64 (ddd, J = 13.9 Hz, 5.2 Hz, 2.1 Hz, 3 H; Hβ), 2.54 (ddd, J = 13.8 Hz, 10.0 Hz, 8.2 Hz, 3 H; Hβ). 13C NMR (125 MHz, CDCl3, 25 °C): δ = 165.9, 56.3, 55.7, 49.3, 34.1. FT-IR (NaCl): 2108, 1646, 1441, 1362, 1263, 1211 cm-1. ESI-MS: m/z Calcd for C15H18N12O3 [M + Na]+ 437. Found: 437 (100%). Elemental analysis calcd for C15H18N12O3 (414.16): C, 43.48; H, 4.38; N, 40.56. Found: C, 43.41; H, 4.34; N, 40.50.
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17 The distance of 7-8 Å has proven to be an ideal distance between the attachment sites of the recognition elements of two-armed receptors, see ref 3.
