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R. Orth et al.
PAPER
1,2,3,4,6-Penta-O-acetyl-b-D-glucopyranose (4)
1H NMR (400 MHz, DMSO): d = 8.08 (s, 1 H, triazole), 7.85 (d, J =
7.5 Hz, 2 H, fluorenyl), 7.67 (dd, J = 5.1, 12.2 Hz, 2 H, fluorenyl),
7.38 (t, J = 7.4 Hz, 2 H, fluorenyl), 7.29 (t, J = 7.5 Hz, 2 H, fluore-
nyl), 6.28 (d, J1,2 = 9.0 Hz, 1 H, H-1, Glc), 5.55 (dd, J1,2 = 9.5 Hz,
J2,3 = 9.5 Hz, 1 H, H-2, Glc), 5.48 (dd J2,3 = 9.5 Hz, J3,4 = 9.5 Hz,
1 H, H-3, Glc), 5.23–5.06 (m, 1 H, H-4, Glc), 4.31 (ddd, J5,6b = 2.2
D-Glucose (10.0 g, 55.5 mmol) was dissolved in pyridine–Ac2O
(3:2, 12.5 mL) at 4 °C. The reaction mixture was stirred at r.t. for 16
h. Then, the mixture was concentrated to half of its original volume
and codistilled with toluene to remove the AcOH. After dilution
with CH2Cl2 (10 mL), the organic layer was extracted with H2O (15
mL), 1 M aq HCl (15 mL) and H2O (15 mL). The organic layer was
dried (MgSO4) and concentrated. The product 4 (14.1 g, 36.1 mmol,
65%) was obtained as an ochre syrup.
Hz, J5,6 = 5.2 Hz, J4,5 = 10.0 Hz, 1 H, H-5, Glc), 4.25–4.14 (m, 4 H,
a
CH-NH-, fluorenyl-CH-CH2, fluorenyl-CH-CH2), 4.11 (dd, J6a,6b
=
12.6 Hz, J5,6a = 5.4 Hz, 1 H, H-6a, Glc), 4.00 (dd, J6a,6b = 12.5 Hz,
J5,6b = 2.1 Hz, 1 H, H-6b, Glc), 3.10 (dd, J = 5.0, 15.0, 1 H, CH2-
CNH), 2.97 (dd, J = 9.1, 15.0, 1 H, CH2-CNH), 1.99 (s, 3 H, OAc),
1.94 (s, 3 H, OAc), 1.91 (s, 3 H, OAc), 1.71 (s, 3 H, OAc).
13C NMR (100 MHz, DMSO): d = 173.26 (COOH), 170.41, 169.98,
169.75, 168.78 (C=O, Ac), 156.37 (C=ONH), 144.24, 144.19,
144.15, 141.11 (fluorenyl C, triazole), 128.06, 127.50, 125.67,
122.49, 120.53 (fluorenyl C), 84.07 (C1 Glc), 73.71 (C5 Glc), 72.69
(C3 Glc), 70.43 (C2 Glc), 67.97 (C4 Glc), 66.15 (CH2-CH), 62.15
(C6 Glc), 54.17 (C-CONH), 47.02 (CH-CH2), 27.62 (CH2-CNH),
20.90, 20.80, 20.68, 20.25 (OCOCH3).
1H NMR (400 MHz, CDCl3): d = 6.33 (d, J1,2 = 3.69 Hz, 1 H, H-1,
Glc), 5.40 (dd, J2,3 = 10.29 Hz, J3,4 = 9.94 Hz, 1 H, H-3, Glc), 5.13
(dd, J3,4 = 9.81 Hz, J4,5 = 9.81 Hz, 1 H, H-4, Glc), 5.10 (dd,
J1,2 = 3.71 Hz, J2,3 = 10.29 Hz, 1 H, H-2, Glc), 4.27 (dd,
J5,6a = 12.39 Hz, J6a,6b = 3.98 Hz, 1 H, H-6a, Glc), 4.13–4.10 (m, 2
H, H-5, H-6b, Glc), 2.17, 2.09, 2.03, 2.02, 2.01 (s, 15 H, OAc).
13C NMR (100 MHz, CDCl3): d = 170.59, 170.19, 169.61, 169.35,
168.71 (C=O, Ac), 89.04 (C-1, Glc), 69.80 (C-3, Glc), 69.79 (C-5,
Glc), 69.16 (C-2, Glc), 67.86 (C-4, Glc), 61.42 (C-6, Glc), 20.86,
20.68, 20.64, 20.55, 20.43 (OCOCH3).
HRMS (ESI): m/z calcd for C34H37N4O13 [M + H]+: 709.235; found:
709.236.
HRMS (ESI): m/z calcd for C34H35N4O13 [M – H]–: 707.220; found:
HRMS (ESI): m/z calcd for C16H22NaO11 [M + Na]+: 413.105;
found: 413.105.
2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl Bromide (5)
707.219.
1,2,3,4,6-Penta-O-acetyl-b-D-glucopyranose (4; 0.4 g, 1.025 mmol)
was added carefully to a soln of 33% (v/v) HBr in glacial AcOH (5.7
mL) at 0 °C. The solution was stirred at r.t. for 1 h. The reaction
mixture was extracted with ice water (3 × 35 mL), dried (MgSO4)
and concentrated. The bromide 5 (424.7 mg, 1.033 mmol, quant)
was obtained by silica gel chromatography (CH2Cl2–MeOH, 10:1);
Rf = 0.86. This product was unstable; therefore, proper analysis was
not possible and the material was used directly for further synthesis.
1,2,3,4,6-Penta-O-acetyl-b-D-galactopyranose (8)
Acetylated galactopyranose 8 was prepared from D-galactose (1.0 g,
5.55 mmol) using the procedure as described above for the prepara-
tion of glucopyranose 4. The product 8 (0.9692 g, 2.48 mmol, 45%)
was obtained as an ochre oil.
1H NMR (400 MHz, CDCl3): d = 6.33 (dd, J1,2 = 1.82 Hz,
J1,5 = 1.22 Hz, 1 H, H-1, Gal), 5.46 (dd, J2,3 = 1.16 Hz, J3,4 = 2.52
Hz, 1 H, H-3, Gal), 5.30–5.29 (m, 2 H, H-4, H-2, Gal), 4.34–4.29
(m, 1 H, H-6a, Gal), 4.08–4.04 (m, 2 H, H-5, H-6b, Gal), 2.12, 2.12,
2.00, 1.98, 1.96 (s, 15 H, OAc).
13C NMR (100 MHz, CDCl3): d = 170.30, 170.09, 170.07, 169.82,
168.88 (C=O, Ac), 89.63 (C-1, Gal), 69.69 (C-3, Gal), 67.35 (C-5,
Gal), 67.29 (C-2, Gal), 66.37 (C-4, Gal), 61.19 (C-6, Gal), 20.84,
20.62, 20.60, 20.56, 20.50 (OCOCH3).
2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl Azide (6)
A mixture of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide
(5; 443.0 mg, 1.08 mmol) and NaN3 (109 mg, 1.67 mmol) in anhyd
DMF (4 mL) was heated at 130 °C for 18 h. The NaN3 did not dis-
solve initially. The cooled mixture was diluted with CHCl3 (4 mL)
and filtered. The solution was then washed with H2O (10 mL), dried
(MgSO4) and concentrated to a syrup. The azide 6 (116.7 mg, 312
mmol, 29%) was obtained by silica gel chromatography (CH2Cl2–
MeOH, 30:1); Rf = 0.22.
HRMS (ESI): m/z calcd for C16H22NaO11 [M + Na]+: 413.105;
found: 413.105.
1H NMR (400 MHz, CDCl3): d = 5.21 (dd, J2,3 = 9.48 Hz,
J3,4 = 9.48 Hz, 1 H, H-3, Glc), 5.10 (dd, J3,4 = 10.0 Hz, J4,5 = 9.47
Hz, 1 H, H-4, Glc), 4.95 (dd, J1,2 = 8.88 Hz, J2,3 = 9.54 Hz, 1 H, H-
2, Glc), 4.65 (d, J1,2 = 8.86 Hz, 1 H, H-1, Glc), 4.28 (dd, J5,6a = 4.7
Hz, J6a,6b = 12.49 Hz, 1 H, H-6a, Glc), 4.17 (dd, J5,6b = 2.31 Hz,
J6a,6b = 12.49 Hz, 1 H, H-6b, Glc), 3.81–3.76 (m, 1 H, H-5, Glc),
2.10, 2.07, 2.02, 2.00 (s, 12 H, OAc).
13C NMR (100 MHz, CDCl3): d = 170.60, 170.11, 169.28, 169.19
(C=O, Ac), 87.89 (C-1, Glc), 73.98 (C-5, Glc), 72.55 (C-3, Glc),
70.58 (C-2, Glc), 67.81 (C-4, Glc), 61.33 (C-6, Glc), 20.70, 20.57,
20.57, 20.54 (OCOCH3).
2,3,4,6-Tetra-O-acetyl-a-D-galactopyranosyl Bromide (9)
Bromide 9 was prepared from 1,2,3,4,6-penta-O-acetyl-b-D-galac-
topyranose (8; 0.3 g, 769 mmol) using the procedure as described
above for the preparation of bromide 5. The bromide 9 (322.6 mg,
784 mmol, quant) was obtained by silica gel chromatography
(CH2Cl2–MeOH, 10:1); Rf = 0.86. This product was unstable; there-
fore, proper analysis was not possible and the material was used di-
rectly for further synthesis.
2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl Azide (10)
Azide 10 was prepared from 2,3,4,6-tetra-O-acetyl-a-D-galactopyr-
anosyl bromide (9; 443.0 mg, 1.08 mmol) using the procedure as
described above for the preparation of azide 6. The azide 10 (118.3
mg, 316 mmol, 29%) was obtained by silica gel chromatography
(CH2Cl2–MeOH, 30:1); Rf = 0.22.
1H NMR (400 MHz, CDCl3): d = 5.41 (dd, J3,4 = 3.36 Hz,
J4,5 = 1.13 Hz, 1 H, H-4, Gal), 5.15 (dd, J1,2 = 8.75 Hz, J2,3 = 10.40
Hz, 1 H, H-2, Gal), 5.03 (dd, J2,3 = 10.37 Hz, J3,4 = 3.36 Hz, 1 H, H-
3, Gal), 4.60 (d, J1,2 = 8.73 Hz, 1 H, H-1, Gal), 4.15 (m, 2 H, H-6a,
H-6b, Gal), 4.00 (ddd, J4,5 = 6.83 Hz, J5,6a = 6.57 Hz, J5,6b = 1.17
Hz, 1 H, H-5, Gal), 2.16, 2.08, 2.05, 1.97 (s, 12 H, OAc).
HRMS (ESI): m/z calcd for C14H23N4O9 [M + NH4]+: 391.146;
found: 391.146.
Na-(9-Fluorenylmethoxycarbonyl)-N7-(2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl)-6-azahistidine (7)
Azide 6 (50.0 mg, 134 mmol) and L-N-Fmoc-propargylglycine (54.0
mg, 161 mmol, 1.19 equiv) were dissolved in anhyd DMF (1.5 mL).
Anhyd DIPEA (46 mL, 270 mmol, 2 equiv) and CuI (6.15 mg, 32.3
mmol, 0.24 equiv) were added. The reaction mixture was stirred at
r.t. for 2 h, then diluted with CH2Cl2 (20 mL) prior to extraction with
0.5 M aq HCl (10 mL). The triazole 7 (60.2 mg, 84.95 mmol, 63%)
was obtained by silica gel chromatography (CH2Cl2–MeOH, 20:1);
Rf = 0.33.
13C NMR (100 MHz, CDCl3): d = 170.36, 170.10, 169.98, 169.36
(C=O, Ac), 88.27 (C-1, Gal), 72.82 (C-5, Gal), 70.68 (C-3, Gal),
Synthesis 2010, No. 13, 2201–2206 © Thieme Stuttgart · New York