Q.-H. Fan et al. / Bioorg. Med. Chem. 24 (2016) 661–671
669
1H), 4.82 (s, 1H), 4.72 (dd, 12.3, 21.8, 2H), 4.59 (dd, 11.8, 15.3, 2H),
4.30 (d, 8.3, 1H), 4.13–4.07 (m, 1H), 3.92 (dd, 2.3, 8.3, 1H), 3.90–
3.84 (m, 1H), 3.82–3.70 (m, 2H), 3.53 (s, 3H); dC (acetone-d6)
202.7, 139.8, 139.5, 139.1, 129.2, 129.1, 129.1, 128.9, 128.6,
128.5, 128.5, 128.3, 128.3, 82.5, 80.6, 76.0, 75.4, 73.8, 73.0, 69.5,
60.6, 58.1; HRMS (ESI) calcd for C28H32NO4S [M+H]+: 478.2052;
found: 478.2048.
ent temperature. After 19 h, the solution was concentrated under
reduced pressure. The obtained residue was purified by column
chromatography over silica gel (cyclohexane/ethyl acetate = 1/0,
10/1–1/1, 0/1–1/2, v/v) and filtered over deactivated basic alumina
using ethyl acetate yielding compound 17c as a colorless oil
(0.12 g, 0.212 mmol, 10%); Rf 0.73 (hexane/ethyl acetate, 1/1 (v/v)
containing 1% (v/v) triethylamine); dH (acetone-d6) 7.49–7.23 (m,
15H), 7.11 (dd, 8.0, 28.1, 4H), 5.48 (br s, 1H), 4.88 (dd, 2.3, 11.5,
2H), 4.69 (dd, 11.4, 13.7, 2H), 4.59 (dd, 12.0, 17.8, 2H), 4.43 (dd,
1.3, 9.5, 1H), 4.33 (d, 14.6, 1H), 4.23 (d, 14.6, 1H), 4.08 (t, 1.9,
1H), 4.01 (dd, 1.9, 9.4, 1H), 3.72–3.63 (m, 2H), 3.62–3.57 (m, 1H),
3.57 (s, 3H), 2.28 (s, 3H); 156.2, 140.1, 139.7, 139.6, 138.4, 136.7,
129.6, 129.2, 129.2, 129.1, 128.8, 128.7, 128.5, 128.4, 128.4,
128.2, 82.9, 76.6, 76.5, 74.1, 73.6, 72.2, 71.5, 61.0, 60.1, 44.8,
21.2; HRMS (ESI) calcd for C36H41N2O4 [M+H]+: 565.3066, found:
565.3067.
4.7. Synthesis of glyconoamidines
4.7.1. N-p-Methylbenzyl-3,4,6-tri-O-benzyl-2-deoxy-D-lyxo-
hexonoamidine (17a)
Meerwein’s salt (0.17 g, 0.899 mmol, 1.5 equiv) was added to a
solution of 16a (0.27 g, 0.604 mmol) in 6 mL of dry dichloro-
methane at 0 °C under nitrogen atmosphere. After 2 h, freshly dis-
tilled p-methylbenzylamine (0.15 g, 1.240 mmol, 2.0 equiv) was
added at 0 °C, and the solution was allowed to warm to ambient
temperature. After 72 h, the solution was concentrated under
reduced pressure. The obtained residue was purified by column
chromatography over silica gel (cyclohexane/ethyl acetate = 2/1–
1/2, v/v) yielding compound 17a as a colorless foam (0.25 g,
0.468 mmol, 75%); Rf 0.30 (SiO2, cyclohexane/ethyl acetate = 1/2,
v/v); the compound exists as a mixture of two resonance isomers
in a 1 to 1.4 molar ratio; dH (CD2Cl2) 8.50 (t, 5.0, 1H), 8.32 (t, 5.0,
1H), 8.02 (s, 1H), 7.52–6.98 (m, 30H), 6.67 (s, 1H), 4.86 (dd, 11.3,
14.1, 2H), 4.72–4.49 (m, 7H), 4.48–4.29 (m, 7H), 4.11 (s, 1H), 4.00
(br s, 1H), 3.88 (dddd, 1.5, 6.0, 10.5, 16.7, 2H), 3.76–3.64 (m, 2H),
3.61 (d, 7.0, 2H), 3.55–3.44 (m, 2H), 3.24 (dd, 5.8, 17.8, 1H), 3.12
(dd, 10.5, 17.6, 1H), 2.91 (dd, 6.3, 17.6, 1H), 2.80 (dd, 10.3, 17.6,
1H); dC (CD2Cl2) 165.6, 163.3, 139.3, 138.9, 138.1, 138.1, 138.0,
137.9, 137.9, 137.7, 132.1, 130.5, 130.3, 130.3, 129.1, 129.0,
128.9, 128.9, 128.8, 128.7, 128.6, 128.6, 128.6, 128.5, 128.5,
128.5, 128.4, 128.2, 128.2, 128.1, 127.7, 74.9, 74.8, 74.1, 74.1,
74.0, 73.5, 72.0, 71.7, 71.1, 70.7, 68.9, 57.0, 57.0, 47.2, 46.5, 29.5,
27.8, 21.4; HRMS (ESI) calcd for C35H39N2O3 [M+H]+: 535.2961,
found: 535.2957.
4.8. Synthesis of glyconoamidines
4.8.1. N-p-Methylbenzyl-2-deoxy-D-lyxo-hexonoamidine (1a)
The synthesis of 1a was achieved after modifying our previous
synthetic strategy toward galactonoamidines by lowering the cat-
alyst amount compared to perbenzylated amidine from 2/1 to 1/1
(w/w) and reducing the trifluoroacetic acid amount compared to
ethanol from 1/5 to 1/10 or 1/50 (v/v).7,10 A mixture of compound
17a (0.12 g, 0.225 mmol) and Pd/C (0.12 g, 10% Pd on C) in 0.5 mL
trifluoroacetic acid and 5 mL ethanol were stirred under hydrogen
atmosphere at ambient temperature. After 24 h, the mixture was
filtered through a pad of celite, and the celite was washed three
times with ethanol 2 mL each. The combined filtrates were concen-
trated yielding a residue that was lyophilized to give 1a as a pale
22.0
white foam (0.08 g, 0.225 mmol, quantitative); [
a]
D = +42.3 (c
0.0756, H2O); Rf 0.12 (SiO2, ethyl acetate/methanol, 3/1, v/v); the
compound is a mixture of two resonance isomers in a 1 to 5.4
molar ratio; dH (D2O) 7.38–7.06 (m, 5H), 4.52–4.48 (m, 1H), 4.44
(s, 2H), 4.23–3.99 (m, 2H), 3.79 (dd, 9.3, 14.3, 1H), 3.73–3.59 (m,
1H), 2.90 (dd, 5.8, 17.8, 1H), 2.75 (dd, 10.3, 17.6, 1H), 2.29 (s,
3H); dC (D2O + CD3OD) 163.2, 139.8, 131.7, 130.6, 130.6, 128.8,
128.4, 66.7, 65.7, 61.1, 58.3, 46.3, 30.4, 21.1; MS (HR-ESI) calcd
for C14H21N2O3 [M+H]+: 265.1552, found: 265.1546.
4.7.2. N-p-Methylbenzyl-3,4,6-tri-O-benzyl-2-O-methyl-D-
galactonoamidine (17b)
Meerwein’s salt (0.60 g, 3.145 mmol, 1.5 equiv) was added to a
solution of 16b (1.00 g, 2.096 mmol) in 10 mL dry dichloromethane
at 0 °C under nitrogen atmosphere. After 2 h, freshly distilled 4-
methyl benzylamine (0.51 g, 4.19 mmol, 2.0 equiv) was added at
0 °C, and the resulting solution was allowed to warm to ambient
temperature while stirring for additional 13 h. The solution was
then concentrated under reduced pressure yielding a residue that
was purified by column chromatography over silica gel dried at
80 °C using freshly distilled solvents (cyclohexane/ethyl acet-
ate = 1/1–0/1, v/v) as eluents to afford 17b as a colorless oil
(0.90 g, 1.596 mmol, 76%); Rf 0.24 (SiO2, ethyl acetate); dH (CD2Cl2)
7.23–7.49 (m, 15H), 7.15 (dd, 31.4, 7.8, 4H), 4.88 (d, 11.3, 1H), 4.77
(d, 11.5, 1H), 4.69 (d, 11.5, 1H), 4.39–4.62 (m, 6H), 4.19–4.24 (m,
1H), 3.99 (dd, 9.8, 1.8, 1H), 3.82–3.90 (m, 1H), 3.69 (s, 3H), 3.50–
3.67 (m, 3H), 2.30 (s, 3H); dC (CD2Cl2) 162.6, 139.3, 138.0, 137.8,
131.0, 130.4, 129.1, 129.0, 129.0, 128.7, 128.6, 128.5, 128.5,
128.4, 79.6, 75.7, 75.6, 74.0, 72.9, 72.1, 68.8, 62.0, 57.2, 46.5,
21.4; HRMS (ESI) calcd for C36H41N2O3 [M+H]+: 565.3066, found:
565.3059.
4.8.2. N-p-Methylbenzyl-2-O-methyl-D-galactonoamidine (1b)
The suspension of compound 17b (0.10 g, 0.17 mmol), Pd/C
(0.06 g, 30% Pd on charcoal) and 0.06 mL trifluoroacetic acid in
6 mL ethanol was stirred under hydrogen atmosphere at ambient
temperature. After 14 h, the mixture was filtered, and the filtrate
was concentrated under reduced pressure to give a residue that
was lyophilized yielding 1b as
a colorless foam (0.05m
0.170 mmol, 96%); Rf 0.20 (SiO2, ethyl acetate/methanol = 16/1, v/
22.0
v); [
a]
D = +51.9 (c 0.0964, H2O); dH (D2O) 7.23 (dd, 12.8, 8.3,
4H), 4.49–4.62 (m, 3H), 4.25 (t, 2.3, 1H), 4.19 (dd, 10.0, 2.5, 1H),
3.62–3.78 (m, 4H), 3.54 (s, 3H), 2.29 (s, 3H); dC (D2O + CD3OD)
163.4, 139.8, 131.6, 130.7, 128.4, 75.8, 69.8, 68.3, 60.9, 59.5, 58.3,
46.0, 21.1; MS (HR-ESI) calcd for C15H23N2O4 [M+H]+: 295.1658,
found: 295.1651.
4.8.3. N-p-Methylbenzyl-4-O-methyl-D-galactonoamidine (1c)
The suspension of compound 17c (0.07 g, 0.124 mmol), Pd/C
(0.07 g, 30% Pd on charcoal) and 0.06 mL trifluoroacetic acid in
6 mL ethanol was stirred under hydrogen atmosphere at ambient
temperature. After 12 h, the mixture was filtered, the filtrate con-
centrated under reduced pressure, and the resulting residue lyo-
4.7.3. N-p-Methylbenzyl-3,4,6-tri-O-benzyl-4-O-methyl-D-
galactonoamidine (17c)
Meerwein’s salt (0.62 g, 3.26 mmol, 1.5 equiv) was added to a
solution of 16c (1.01 g, 2.11 mmol) in 20 mL of dry dichloro-
methane at 0 °C under nitrogen atmosphere. After 2.5 h, freshly
distilled 4-methylbenzylamine (0.60 mL, 4.65 mmol, 2.2 equiv)
was added at 0 °C, and the solution was allowed to warm to ambi-
philized to yield 1c as colorless foam (0.03 g, 0.102 mmol, 83%);
22.0
Rf 0.18 (ethyl acetate/methanol = 20/1, v/v); [
a
]
D = +64.6 (c
0.0758, H2O); dH (D2O) 7.22 (dd, 14.8, 8.5, 4H), 4.59 (d, 10.0, 1H),
4.54 (d, 2.0, 2H), 4.01 (dd, 10.0, 2.5, 1H), 3.97 (t, 2.4, 1H), 3.73–