4814
V. Parmenopoulou et al. / Bioorg. Med. Chem. 22 (2014) 4810–4825
All reactions sensitive to oxygen or moisture were carried out
under nitrogen atmosphere using oven-dried glassware. DMF and
MeOH were stored over 3E molecular sieves. 2,3,4,6-Tetra-O-
acetyl-b-D-glucopyranosyl azide (AcGlc-N3) was prepared accord-
2H, J = 8.7 Hz, ArH), 5.36–5.25 (2pseudo t, 2H, J = 9.5, 9.2 Hz, H-1,
H-3), 5.10 (t, 1H, J = 9.7 Hz, H-4), 5.03 (t, 1H, J = 9.6 Hz, H-2),
4.58, 4.45 (q, AB-system, 2H, J = 15.2 Hz, CH2), 4.35 (dd, 1H,
J = 4.1, 12.6 Hz, H-6a), 4.10 (dd, 1H, J = 1.5, 12.6 Hz, H-6b), 3.86
(ddd, 1H, J = 1.8, 3.7, 10.0 Hz, H-5), 2.08, 2.03, 2.02, 1.88 (4s, 12H,
4OAc); 13C NMR (125 MHz, CDCl3) d 170.6, 170.5, 169.9, 169.5,
169.2 (CO), 156.4, 140.2, 135.3, 128.8, 128.4, 127.0, 126.7, 114.9
(Ar-C), 77.9, 73.6, 72.5, 70.0, 68.0, 67.1, 61.5 (CH2 and C-1–C-6),
20.7, 20.5, 20.3 (OCOCH3); MS (ESI, m/z) calcd for C28H32NO11
ing to the procedures described in literature and its chemical and
physical properties were in agreement with previous data.44
2.2.1. General procedure for preparation of the 2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosylamine (AcGlc-NH2)
After two vacuum/H2 cycles to remove air from the reaction
tube, the stirred mixture of azide AcGlc-N3 (5.00 g, 13.4 mmol)
and 10% Pd/C (0.95 g) in ethyl acetate (EtOAc, 184.6 mL) was
hydrogenated at ambient pressure (balloon) and temperature (ca.
20 °C) for 24 h. The reaction mixture was filtered and the filtrate
was concentrated in vacuum. The residue was purified by flash col-
umn chromatography using EtOAc. The spectroscopic properties of
amine AcGlc-NH2 were in agreement with previous data.45
558.20, found 558.43 (MH)+. Anal. Calcd for C28H31NO11
60.32; H, 5.60; N, 2.51; Found: C, 60.72; H, 5.26; N, 2.40.
: C,
2.2.2.4.
N-(E)-3-(4-Isopropylphenyl)acryloyl-(2,3,4,6-tetra-O-
acetyl-b-
D
-glucopyranosyl)-amine (AcS6).
White foam, 66%
+10 (c 0.20, CHCl3);
22
yield; Rf = 0.53 (n-hexane/EtOAc 1:1); [
a]
D
1H NMR (500 MHz, CDCl3): d 7.63 (d, 1H, J = 15.7 Hz, CH@CH),
7.44 (d, 2H, J = 8.2 Hz, ArH cumenyl), 7.25 (d, 2H, J = 8.4 Hz, ArH
cumenyl), 6.34–6.26 (m, 2H, NH, CH@CH), 5.42–5.32 (2pseudo t,
2H, J = 9.4, 9.5 Hz, H-1, H-3), 5.09 (t, 1H, J = 9.4 Hz, H-4), 4.99 (t,
1H, J = 9.6 Hz, H-2), 4.33 (dd, 1H, J = 4.4, 12.5 Hz, H-6a), 4.10 (dd,
1H, J = 1.7, 12.5 Hz, H-6b), 3.88 (ddd, 1H, J = 2.0, 4.1, 10.0 Hz, H-
5), 2.98–2.88 (m, 1H, CH3–CH–CH3), 2.08, 2.04, 2.03 (3s, 12H,
4OAc), 1.28 (d, 6H, J = 6.8 Hz, CH3–CH–CH3); 13C NMR (125 MHz,
CDCl3) d 171.3, 170.6, 169.9, 169.6, 166.0 (CO), 151.6, 143.3,
131.8, 128.2, 127.0, 118.2 (CH@CH and Ar-C), 78.5, 73.5, 72.7,
70.7, 68.2, 61.6 (C-1–C-6), 34.1, 23.8 (CH3–CH–CH3), 20.8, 20.7,
20.6 (OCOCH3); MS (ESI, m/z) calcd for C26H34NO10 520.22, found
520.58 (MH)+. Anal. Calcd for C26H33NO10: C, 60.11; H, 6.40; N,
2.70; Found: C, 60.51; H, 6.15; N, 2.31.
2.2.2. General procedure for preparation of the N-acyl-2,3,4,6-
tetra-O-acetyl-b-D-glucopyranosylamines (AcS)
To a stirred mixture of AcGlc-NH2 (1.44 mmol) in 3 ml anhy-
drous DMF and Et3N (0.96 mmol) the corresponding acylating
agent RCOCl (1, 2, 3, 6, 20, 21) (0.96 mmol) was added in one por-
tion. The reaction mixture was left for 1 h at room temperature,
then concentrated and the residue was purified by flash chroma-
tography to give the desired analogues AcS as foams.
2.2.2.1. N-(E)-3-(Biphenyl-4-yl)acryloyl-(2,3,4,6-tetra-O-acetyl-
b-D
-glucopyranosyl)-amine (AcS1).
White foam, 68% yield;
22
Rf = 0.30 (n-hexane/EtOAc 1:1); [
a
]
D
+6 (c 0.20, CHCl3); 1H NMR
(500 MHz, CDCl3): d 7.69 (d, 1H, J = 15.7 Hz, CH@CH), 7.64–7.37
(m, 9H, ArH), 6.42 (d, 1H, J = 9.4 Hz, NH), 6.36 (d, 1H, CH@CH),
5.44–5.33 (2pseudo t, 2H, J = 9.4, 9.5 Hz, H-1, H-3), 5.11 (t, 1H,
J = 9.8 Hz, H-4), 5.01 (t, 1H, J = 9.6 Hz, H-2), 4.35 (dd, 1H, J = 4.3,
12.6 Hz, H-6a), 4.11 (dd, 1H, J = 1.9, 12.6 Hz, H-6b), 3.89 (ddd, 1H,
J = 2.0, 4.1, 10.2 Hz, H-5), 2.09, 2.06, 2.05, 2.04 (4s, 12H, 4OAc);
13C NMR (125 MHz, CDCl3) d 171.3, 170.6, 169.9, 169.6, 165.8
(CO), 143.1, 142.9, 140.1, 133.1, 128.9, 128.6, 127.9, 127.5, 127.0,
119.0 (CH@CH and Ar-C), 78.5, 73.6, 72.7, 70.7, 68.1, 61.6 (C-1–C-
6), 20.8, 20.7, 20.6 (OCOCH3); MS (ESI, m/z) calcd for C29H32NO10
2.2.2.5.
acetyl-b-
N-(R)-3-(4-Ethylphenyl)butanoyl-(2,3,4,6-tetra-O-
D-glucopyranosyl)-amine (AcS20). Yellow foam,
22
62% yield; Rf = 0.42 (n-hexane/EtOAc 3:2); [
a]
ꢁ2 (c 0.20,
D
CHCl3); 1H NMR (500 MHz, CDCl3): d 7.14–7.11 (m, 4H, ArH),
6.23 (d, 1H, J = 9.2 Hz, NH), 5.33-5.17 (2pseudo t, 2H, J = 9.4,
9.5 Hz, H-1, H-3), 5.04 (pseudo t, 1H, J = 9.8 Hz, H-4), 4.87 (pseudo
t, 1H, J = 9.6 Hz, H-2), 4.32 (dd, 1H, J = 4.3, 12.5 Hz, H-6a), 4.06 (dd,
1H, J = 2.0, 12.5 Hz, H-6b), 3.80 (ddd, 1H, J = 1.9, 4.0, 10.1 Hz, H-5),
3.29–3.18 (m, 1H, CH), 2.65-2.41 (m, 4H, CH2, CH2CH3), 2.08–2.00
(m, 12H, 4OAc), 1.31–1.19 (m, 6H, CH3, CH2CH3); 13C NMR
(125 MHz, CDCl3) d 176.6, 172.0, 171.0, 170.6, 169.6 (CO), 142.7,
142.2, 128.0, 126.6 (Ar-C), 78.0, 73.5, 72.6, 70.4, 68.0, 61.6 (C-1–
C-6), 45.3, 42.4, 35.8 (CH and 2CH2), 28.3, 21.8, 20.7, 20.6, 15.5
(OCOCH3, CHCH3, CH2CH3); MS (ESI, m/z) calcd for C26H36NO10
554.20, found 554.21 (MH)+. Anal. Calcd for C29H31NO10
62.92; H, 5.64; N, 2.53; Found: C, 63.10; H, 5.52; N, 2.74.
: C,
2.2.2.2.
(2,3,4,6-tetra-O-acetyl-b-
N-4-(5,6,7,8-Tetrahydronaphthalen-2-yl)butanoyl-
-glucopyranosyl)-amine
D
522.23, found 522.62 (MH)+. Anal. Calcd for C26H35NO10
59.87; H, 6.76; N, 2.69; Found: C, 60.24; H, 6.48; N, 2.98.
: C,
(AcS2).
Yellow foam, 63% yield; Rf = 0.6 (n-hexane/EtOAc 1:1);
22
[a]
ꢁ8 (c 0.20, CHCl3); 1H NMR (500 MHz, CDCl3): d 6.99–6.86 (m,
D
3H, ArH), 6.16 (d, 1H, J = 9.3 Hz, NH), 5.34–5.24 (2pseudo t, 2H,
J = 9.6, 9.5 Hz, H-1, H-3), 5.06 (t, 1H, J = 9.9 Hz, H-4), 4.91 (t, 1H,
J = 9.6 Hz, H-2), 4.32 (dd, 1H, J = 4.3, 12.6 Hz, H-6a), 4.07 (dd, 1H,
J = 1.9, 12.6 Hz, H-6b), 3.82 (ddd, 1H, J = 2.0, 4.1, 10.1 Hz, H-5), 2.73
(m, 4H, tetrahydronaphthalene moiety), 2.53 (t, 2H, J = 7.4 Hz,
CH2), 2.22-2.15 (m, 2H, CH2), 2.07, 2.03, 2.02, 2.01 (4s, 12H, 4OAc),
1.94-1.87 (m, 2H, CH2), 1.80–1.76 (m, 4H, tetrahydronaphthalene
moiety); 13C NMR (125 MHz, CDCl3) d 173.1, 171.1, 170.6, 169.9,
169.6 (CO), 138.1, 137.1, 134.8, 129.2, 129.0, 125.5 (Ar-C), 78.0,
73.5, 72.6, 70.5, 68.0, 61.6 (C-1–C-6), 35.8, 34.5, 29.3, 29.0, 26.6,
23.2, 23.1 (3CH2 and 4CH2 of tetrahydronaphthalene moiety), 20.7,
20.6, 20.5 (OCOCH3); MS (ESI, m/z) calcd for C28H38NO10 548.25,
found 548.63 (MH)+. Anal. Calcd for C28H37NO10: C, 61.41; H, 6.81;
N, 2.56; Found: C, 61.75; H, 7.14; N, 2.30.
2.2.2.6.
(2,3,4,6-tetra-O-acetyl-b-
(AcS21).
N-(S)-3-(4-Isopropylphenyl)-2-methylpropanoyl-
-glucopyranosyl)-amine
D
Yellow foam, 63% yield; Rf = 0.47 (n-hexane/EtOAc
]
22 +2 (c 0.20, CHCl3); The 1H NMR spectrum showed hin-
D
1:1); [
a
dered rotation around the amide bond. 1H NMR (500 MHz, CDCl3):
d 7.13–7.04 (m, 4H, ArH cumenyl), 6.23 (2d, 1H, J = 9.3 Hz, NH),
5.33–5.20 (2pseudo t, 2H, J = 9.3, 9.5 Hz, H-1, H-3), 5.05 (pseudo
t, 1H, J = 9.5 Hz, H-4), 4.88 (t, 1H, J = 9.6 Hz, H-2), 4.33 (dd, 1H,
J = 3.6, 12.5 Hz, H-6a), 4.06 (dd, 1H, J = 2.0, 12.5 Hz, H-6b), 3.81
(ddd, 1H, J = 1.9, 4.9, 9.8 Hz, H-5), 3.02-2.81 (m, 2H, CH2), 2.57–
2.40 (m, 2H, CH, CH3–CH–CH3), 2.08, 2.02, 2.01, 1.99 (4s, 12H,
4OAc), 1.22, 1.20 (2d, 6H, J = 6.9 Hz, CH3-CH-CH3), 1.12, 1.06 (2d,
3H, J = 6.7 Hz, CH3); 13C NMR (125 MHz, CDCl3) d 176.3, 170.9,
170.6, 169.9, 169.6 (CO), 146.8, 136.3, 128.9, 126.4 (Ar-C), 78.1,
73.5, 72.5, 70.4, 68.1, 61.6 (C-1–C-6), 43.1, 38.9, 33.6 (2CH and
CH2), 24.0, 20.7, 20.6, 20.5, 17.1 (CH3–CH–CH3, OCOCH3, CHCH3);
MS (ESI, m/z) calcd for C27H38NO10 536.25, found 536.38 (MH)+.
Anal. Calcd for C27H37NO10: C, 60.55; H, 6.96; N, 2.62; Found: C,
60.67; H, 6.72; N, 2.84.
2.2.2.3. N-2-(Biphenyl-4-yloxy)acetyl-(2,3,4,6-tetra-O-acetyl-b-
D
-glucopyranosyl)-amine (AcS3).
Yellow foam, 83% yield;
22
Rf = 0.33 (n-hexane/EtOAc 1:1); [
NMR (500 MHz, CDCl3): d 7.56–7.32 (m, 8H, ArH, NH), 6.98 (d,
a]
D
ꢁ6 (c 0.20, CHCl3); 1H