Glycotriazolophane Synthesis via Click Chemistry

Abstract

A glycotriazolophane (carbohydrate-triazole-cyclophane hybrid) has been synthesized from a sugar amino acid via copper-catalysed azide-alkyne cycloaddition.

Key words

cyclophane - carbohydrates - macrocycle - 1,2,3-tri­azole - azide-alkyne cycloaddition

References and Notes

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14

Preparation of 3 and 5
To ice-cold 1 (0.95 g, 2.75 mmol) in CH₂Cl₂ (anhyd, 20 mL) was added oxalyl chloride (0.25 mL, 3.03 mmol), followed by DMF (0.005 mL) under N₂ and the mixture stirred for 0.5 h. p-Xylenediamine (0.169 mg, 1.24 mmol) and DIPEA (0.48 mL, 2.75 mmol) were stirred together in the presence of 4 Å MS in CH₂Cl₂ (anhyd, 10 mL) until complete dissolution of the amine. The solution containing the acid chloride was added, and the mixture was stirred for a further 2 h at 0 ˚C. The mixture was extracted with CH₂Cl₂ (20 mL), washed with NaHCO₃ (2 × 15 mL), HCl (2 × 15 mL), brine (2 × 15 mL), H₂O (2 × 15 mL), dried (Na₂SO₄), filtered, and the solvent removed to give a pale brown foam. Silica gel chromatography (EtOAc-Cy, gradient elution, 1:1 to 2:1) gave the protected diamide as a white foam (0.359 g, 37%). This diamide (74.9 mg, 0.095 mmol) was dissolved in MeOH-CH₂Cl₂ (3.5 mL, 6:1) to which was added NaOMe in MeOH (0.1 mL of 1.09 M) and the mixture left to stir for 3 h at r.t. The solvent was removed and the residue dissolved in H₂O. Lyophilization gave 3 as an off-white powder (51 mg, quant.); [α]_D -30.81 (c 0.37 g, H₂O). ^¹H NMR (500 MHz, D₂O): δ = 7.24 (s, 4 H, ArH), 4.73 (d, J = 8.8 Hz, 2 H, H-1), 4.37 (s, 4 H, PhCH₂), 3.93 (d, J = 9.3 Hz, 2 H, H-5), 3.55-3.46 (m, 4 H, overlapping of H-3, H-4), 3.25 (m, 2 H, H-2). ^¹³C NMR (125 MHz, CDCl₃): δ = 170.2 (CONH), 136.9 (ArC), 127.7 (CH), 90.4, 77.1, 75.6, 72.6, 71.3 (each CH), 42.7 (NHCH₂Ph). LRMS: m/z found: 561.1 [M + Na]⁺, 537.2 [M - H]^-. HRMS (ES): m/z calcd for C₂₀H₂₇O₁₀N₈: 539.1850; found: 539.1865 [M + H]⁺.
The bisazide 3 (60 mg, 0.111 mmol) was dissolved in a solution of MeCN-H₂O (1:1, 4.5 mL) to which was added alkyne 4 (20 mg, 0.111 mmol) and the reactants stirred before the addition of sodium ascorbate (2 mg, 0.011 mmol) followed by CuSO₄˙5H₂O (0.55 mL of a 0.01 M solution, 0.0055 mmol) and then stirred for a further 13 h. The resulting precipitate was 5 (45 mg, 56%). ^¹H NMR (300 MHz, DMSO-HOD, 9:1): δ = 8.38 (s, 2 H, C=CHN), 7.13 (s, 4 H, ArH), 6.95 (s, 4 H, ArH), 5.58 (d, J = 9.3 Hz, 2 H, H-1), 5.04 (s, 4 H, PhOCH₂), 4.20 (s, 4 H, PhCH₂), 3.92 (d, J = 9.7 Hz, 2 H, H-5), 3.85 (dd, J = 9.9, 8.1 Hz, 2 H, H-2), 3.55-3.51 (m, 2 H, H-4), 3.41 (dd, J = 9.5, 8.7 Hz, 2 H, H-2). LRMS: m/z found: 747.1 [M + Na]⁺, 723.2 [M - H]^-. HRMS (ES): m/z calcd for C₃₂H₃₇O₁₂N₈: 725.2531; found: 725.2549 [M + H]⁺.