Molecules 2017, 22, 1682
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by silica gel column chromatography (CH2Cl2:MeOH, 5%) to afford 13 (642 mg, 96%) as a white
1
solid. Rf (CH2Cl2–MeOH, 5%) = 0.66. H-NMR (CDCl3):
δ 9.99 (br s, 1H), 7.73 (d, J = 7.4 Hz, 2H),
7.56 (d, J = 7.0 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 2H), 5.99 (d, J = 7.8 Hz, 1H), 5.27 (s, 2H),
4.95 (br s, 1H), 4.54–4.26 (m, 3H), 4.18 (t, J = 7.0 Hz, 1H), 3.88 (t, J = 10.0 Hz, 1H), 3.52 (d, J = 11.1 Hz,
1H), 2.69 (br s, 2H), 2.10–2.02 (m, 1H), 1.85–1.70 (m, 2H), 1.63–1.42 (m, 3H).
N-(1-Oxo-1-(((tetrahydro-2H-pyran-2-yl)oxy)amino)pent-4-yn-2-yl)-[1,1
'
-biphenyl]-4-carboxamide
(14).
Compound 13 (759 mg, 1.◦75 mmol) was dissolved in anhydrous CH2Cl2 (3.5 mL) under Ar and the
solution was cooled to 0 C. Piperidine (20% in DMF, 2 mL) was added dropwise to the solution.
After the reaction was complete, as determined by TLC, the reaction mixture was concentrated under
pressure. Immediately following the deprotection reaction, the crude product, biphenyl-4-carboxylic
acid (285 mg, 1.44 mmol), EDC HCl (409 mg, 2.13 mmol), and HOBt (303 mg, 1.98 mmol) were
·
dissolved in anhydrous CH2Cl2 (15 mL) under Ar gas at 0 ◦C. Next, DIPEA (1 mL, 5.74 mmol) was
added to the reaction mixture at 0 ◦C. The reaction ran for 1 h at 0 ◦C and then warmed to r.t. to run
for 18 h. After stopping the reaction, the reaction mixture was diluted with CH2Cl2 (15 mL) and
washed with 1.6 M citric acid (pH ~3, 30 mL), saturated NaHCO3 solution (30 mL), and brine (30
mL). The organic layer was dried with Na2SO4, filtered, and concentrated under reduce pressure.
The crude product was then purified via silica gel column chromatography (CH2Cl2:MeOH, 5%,
1
Hex:EtOAc, 1:1) to produce 14 (240 mg, 35%) as a white solid. Rf (1:1 Hex–EtOAc) = 0.44. H-NMR
(CDCl3):
δ 7.88 (m, 2H), 7.67–7.51 (m, 4H), 7.48–7.30 (m, 4H), 5.09–4.98 (m, 1H), 4.92 (t, J = 6.7 Hz,
1H), 4.16–4.05 (m, 1H), 3.96 (t, J = 9.0 Hz, 1H), 3.67–3.50 (m, 1H), 2.96–2.77 (m, 2H), 2.22–2.15 (m, 1H),
2.11 (td, J = 2.6, 5.4 Hz, 1H), 2.05–2.00 (m, 2H), 1.95–1.71 (m, 4H), 1.71–1.60 (m, 2H), 1.60–1.46 (m, 3H),
1.27–1.20 (m, 2H), 1.15–1.03 (m, 1H).
tert-Butyl ((2S)-3-(1-(((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-oxo-1-(((tetrahydro-2H-pyran-2-yl)oxy)-
amino)propan-2-yl)carbamate (15). Azide 11 (155 mg, 0.501 mmol) was dissolved in CH3CN (3.4 mL) and
added to alkyne 12 (149 mg, 0.477 mmol). DI water (0.6 mL) and Cu powder (13 mg, 0.21 mmol) were
added. The reaction was sonicated for 10 min before stirring at 35 ◦C overnight. At 21 h, the reaction
was concentrated under reduced pressure. The green crude product was purified by silica gel column
chromatography (CH2Cl2:MeOH 6%) to afford the desired product 15 (225 mg, 76%) as an off-white
1
solid. Rf (CH2Cl2–MeOH, 6%) = 0.44. H-NMR (CDCl3):
δ 1.30 (s, 3H) 1.37 (s, 8H) 1.50 (s, 6H) 1.72
(s, 3H) 3.12 (s, 1H) 3.54 (s, 1H) 3.91 (m, 1H) 4.41 (s, 1H) 4.67 (s, 1H) 4.86 (s, 1H) 5.02 (s, 1H) 5.54
(d, J = 10.2 Hz, 1H) 5.71 (s, 1H) 5.82 (s, 1H) 7.16 (s, 1H) 7.43–7.66 (m, 1H) 10.24–10.47 (m, 1H).
N-(3-(1-(((3aR,4R,6R,6aR)-6-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-oxo-1-(((tetrahydro-2H-pyran-2-yl)oxy)amino)propan-2-yl)-
[1,1
'-biphenyl]-4-carboxamide (16). Azide 11 (179 mg, 0.58 mmol) was first dissolved in CH3CN (1.25 mL),
and the solution was transferred to a flask containing 14 (240 mg, 0.61 mmol). Upon dissolution of 14
,
Cu powder (13 mg, 0.20 mmol) and DI H2O (1.0 mL) were added to the reaction mixture. The reaction
◦
mixture was then subjected to sonication for 15 min, and then stirred for 21 h at 35 C. The crude
reaction mixture was concentrated under reduced pressure and purified via silica gel column
chromatography (CH2Cl2:MeOH, 5%) to yield 16 (231 mg, 57%) as a white solid. Rf (CH2Cl2–MeOH,
5%) = 0.32. 1H-NMR (CDCl3):
δ 7.87 (d, J = 8.2 Hz, 2H), 7.64–7.52 (m, 5H), 7.46–7.39 (m, 2H),
7.36 (d, J = 7.4 Hz, 1H), 7.11 (dd, J = 3.3, 8.0 Hz, 1H), 5.70 (d, J = 7.8 Hz, 1H), 5.47 (d, J = 3.9 Hz, 1H),
5.29 (s, 3H), 5.01 (t, J = 5.3 Hz, 1H), 4.98–4.89 (m, 2H), 4.87–4.79 (m, 1H), 4.66 (d, J = 5.1 Hz, 2H),
4.45–4.36 (m, 1H), 3.93 (br s, 1H), 3.55 (br s, 1H), 3.37 (d, J = 6.7 Hz, 1H), 3.24 (br s, 1H), 1.74 (br s, 2H),
1.49 (s, 3H), 1.26 (s, 3H).
(S)-2-Amino-3-(1-(((2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydro-
furan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-hydroxypropanamide (
H2O) was added to 15 (187 mg, 0.30 mmol) dissolved in CH2Cl2 (1 mL) at 0 C. After 14.5 h,
3
). Trifluoroacetic acid (3 mL, 90% in
◦