Glucosyltransferase Inhibitors
FULL PAPER
with preparative TLC (CHCl3/MeOH 25:1) to afford 10 (50.2 mg,
3.2 Hz), 4.00–3.30 (m, 44H), 2.83 (dd, 2H, 3J
(H,H)=9.3, 2J
ACHRTUNEG ACHTREUNG(H,H)=
0.03945 mmol, 85%). [a]D23
=
ꢁ40 (c=1.13 in chloroform); 1H NMR
13.9 Hz), 2.37 (t, 4H, 3J
ACHTREUNG
(400 MHz, CDCl3): d=7.45 (d, 2H, 3J
A
1.31 (m, 16H); 13C NMR (100 MHz, D2O, 40 8C): d=174.3, 171.7, 97.5,
96.9, 94.4, 73.8, 73.3, 72.3, 70.9, 70.7, 68.3, 68.1, 67.4, 67.34, 67.27, 67.1,
64.6, 64.1, 58.2, 52.8, 46.4, 38.9, 31.3, 26.3, 26.0–25.7, 22.7, 21.9, 20.1; HR
ESI-MS: m/z: calcd for C60H104N2O34S2Na: 1483.5810, found 1483.5834
[M+Na]+.
28H), 5.85 (br, 1H), 4.99 (d, 1H, 2J
(m, 3H), 4.83 (d, 1H, 3J(H,H)=8.3 Hz), 4.73 (d, 2H, 2J
PhCH), 4.66 (d, 1H, 2J
(H,H)=11.7 Hz; PhCH), 4.52–4.39 (m, 6H), 4.34
(s, 1H), 4.22 (m, 1H), 4.01 (m, 1H), 3.96–3.85 (4H), 3.71–3.56 (11H),
3.54–3.44 (m, 4H), 3.37 (m, 1H), 3.31 (m, 1H), 2.29 (t, 2H, 3J
(H,H)=
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
AHCTREUNG
tert-Butyldimethylsilyl 3,4,6-tri-O-acetyl-2-(benzyloxycarbonyl)amino-2-
deoxy-b-d-glucopyranoside (15): Hydrazine acetate (916 mg, 9.95 mmol)
was added at 48C to a solution of 14 (4.53 g, 9.41 mmol) in THF
(120 mL). After stirring for 24 h at room temperature, ice-water was
added and the mixture was extracted with CHCl3 (3). The combined or-
ganiclayers were washed with brine (2), dried over Na 2SO4, filtered,
and concentrated. Separation by silica gel chromatography (toluene/
EtOAc5:1 ! 1:1) gave hemiacetal (3.86 g, 8.79 mmol, 93%).
7.6 Hz), 1.86 (s, 3H), 1.61 (m, 4H), 1.31 (m, 8H); 13C NMR (100 MHz,
CDCl3): d=174.0, 171.1, 138.2–137.4, 128.3–127.3, 101.8, 99.4, 98.3, 82.5,
80.0, 76.1, 75.1, 74.9, 74.9, 74.2, 73.7, 73.6, 73.43, 73.38, 73.0, 72.9, 72.5,
71.4, 71.2, 70.3, 69.8, 66.5, 65.5, 62.0, 56.2, 51.5, 34.1, 29.7, 29.34, 29.32,
29.2, 26.2, 25.0, 23.6; HR ESI-MS: m/z: calcd for C72H89NO18Na:
1278.5978; found 1278.5973 [M+Na]+.
8-Methoxycarbonyloctyl 2-acetamido-3,6-di-O-benzyl-4-O-chloroacetyl-2-
deoxy-b-d-glucopyranosyl-(1!2)-3-O-benzyl-6-O-tosyl-a-d-mannopyra-
A solution of the hemiacetal (3.85 g, 8.76 mmol) in DMF were added
TBSCl (2.00 g, 13.3 mmol) and imidazole (1.79 g, 26.3 mmol) at 48C.
After stirring for 11 h at room temperature, the mixture was quenched
with 10% aqueous citric acid. Aqueous phase was extracted with CHCl3
(3). The combined organic layers were washed with brine (2), dried
over Na2SO4, filtered, and concentrated. Purification by silica gel chro-
matography (toluene/EtOAc15:1 ! 4:1) gave 15 (4.61 g, 8.33 mmol,
95%). [a]2D2 = +9.9 (c=1.15 in chloroform); 1H NMR (400 MHz, C6D6,
nosyl-(1!6)-2,3,4-tri-O-benzyl-b-d-mannopyranoside
(11):
DMAP
(3.5 mg, 0.029 mmol) and TsCl (4.2 mg, 0.022 mmol) were added at 48C
to a solution of triol 10 (26.0 mg, 0.021 mmol) in CH2Cl2. After stirring
for 10 h at room temperature under Ar atmosphere, the second portions
of DMAP (3.0 mg, 0.025 mmol) and TsCl (3.2 mg, 0.017 mmol) were
added. After the additional stirring for 13 h, the mixture was diluted with
CHCl3 and washed with 0.5m HCl. The aqueous phase was extracted
with CHCl3 (2), and the combined organic layers were washed with
brine (2), dried over Na2SO4, filtered, and concentrated. Purification
with preparative TLC (CHCl3/MeOH 20:1) produced 11 (17.6 mg,
708C): d=7.25–7.00 (m, 5H), 5.28 (t, 1H, 3J
(t, 1H, 3J(H,H)=9.6 Hz; H-4), 5.04 (s, 2H), 4.57 (d, 1H, 3J
7.6 Hz; NH), 4.33 (br, 1H, H-1), 4.17 (dd, 1H, 3J(H,H)=5.6, 2J
12.0 Hz; H-6a), 4.11 (dd, 1H, 3J(H,H)=2.8, 2J
(H,H)=12.0 Hz; H-6b),
ACHTREUNG
R
ACHTREUNG
A
ACHTREUNG
0.0125 mmol, 60%). [a]D23
=
ꢁ41 (c=0.69 in chloroform); 1H NMR
A
ACHTREUNG
(400 MHz, CDCl3): d=7.71 (d, 2H, 3J
(H,H)=8.5 Hz), 7.45–7.14 (m,
3.58 (m, 1H, H-2), 3.40 (m, 1H, H-5), 1.74–1.68 (9H), 0.96 (s, 9H), 0.16
(s, 3H), 0.11 (s, 3H); 13C NMR (100 MHz, C6D6, 608C): d=170.1, 169.7,
169.0, 155.8, 137.3, 128.6–127.8, 96.7, 72.8, 72.4, 69.9, 67.0, 62.6, 58.9, 26.0,
20.31, 20.26, 18.3, ꢁ3.9, ꢁ4.8; elemental analysis calcd (%) for
C26H39NO10Si: C 56.40, H 7.10, N 2.53; found: C 56.39, H 7.11, N 2.46.
3
3
32H), 6.08 (d, 1H, J
A
A
(d, 1H, 2J
ACHTREUNG ACHTRENUG
(H,H)=12.7 Hz; PhCH), 4.89 (d, 1H, 2J
PhCH), 4.87 (d, 1H, 2J
T
ACHTREUNG
AHCTREUNG
tert-Butyldimethylsilyl 3,4,6-tri-O-acetyl-2-bromoacetamido-2-deoxy-b-d-
glucopyranoside (16): 10% Pd/C (96 mg) was added to a solution of 15
(536.0 mg, 0.968 mmol) in EtOAc, and the mixture was stirred under H2
atmosphere for 2.5 h. After additional stirring for 15 min under N2 atmos-
phere, the catalyst was filtered off through Celite, and the filtrate was
concentrated, and exposed to high-vacuum for 2 h. The resulting solid
was dissolved in CH2Cl2 (10 mL), and treated with bromoacetic anhy-
dride (336 mg, 1.29 mmol) and pyridine (100 mL, 1.24 mmol) at 48C.
After stirring for 30 min at 48C, the mixture was neutralized with 10%
aqueous citric acid. The aqueous phase was extracted with CH2Cl2 (2).
The combined organic layers were washed with brine (2), dried over
Na2SO4, filtered, and concentrated. Purification by silica gel chromatog-
ACHTREUNG
ACHTREUNG
13C NMR (100 MHz, CDCl3): d=174.0, 171.9, 144.5, 138.6–137.4, 133.1,
129.7–127.3, 102.0, 98.4, 97.4, 82.5, 79.2, 77.2, 75.7, 74.8, 74.5, 74.2, 73.7,
73.6, 73.5, 73.2, 71.9, 71.3, 71.2, 70.3, 70.1, 69.7, 68.8, 67.2, 65.0, 58.6, 51.5,
34.2, 29.8, 29.39, 29.36, 29.2, 26.2, 25.1, 23.8, 21.7; HR ESI-MS: m/z:
calcd for C79H95NO20SNa: 1432.6066, found 1432.6059 [M+Na]+.
8-Methoxycarbonyloctyl 2-acetamido-2-deoxy-b-d-glucopyranosyl-(1!2)-
6-O-tosyl-a-d-mannopyranosyl-(1!6)-b-d-mannopyranoside (12): A sol-
ution of tosylate 11 (286.7 mg, 0.191 mmol) in MeOH (20 mL) containing
AcOH (0.5 mL) was hydrogenated over Pd(OH)2/C (20%, 253 mg)
under vigorous stirring for 12 h. After additional stirring under an N2 at-
mosphere for 30 min, the catalyst was filtered off through Celite, and the
filtrate was concentrated. Purification by silica gel chromatography
(CHCl3/MeOH 10:1 to CHCl3/MeOH/H2O 6:2:0.2) gave 12 (147.0 mg,
raphy (toluene/EtOAc15:1
98%). [a]2D4 +2.5 (c=0.97 in chloroform); 1H NMR (400 MHz,
CDCl3): d=6.33 (d, 1H, 3J(H,H)=8.8 Hz; NH), 5.19 (dd, 1H, 3J
(H,H)=
9.6, 10.8 Hz; H-3), 4.92 (t, 1H, 3J
(H,H)=9.6 Hz; H-4), 4.79 (d, 1H,
3J(H,H)=8.0 Hz; H-1), 4.08 (dd, 1H, 3J(H,H)=6.0, 2J
(H,H)=12.4 Hz;
H-6a), 4.01 (dd, 1H, 3J(H,H)=2.8, 2J
(H,H)=12.4 Hz; H-6b), 3.73 (m,
!
4:1) gave 16 (513.2 mg, 0.950 mmol,
=
A
ACHTREUNG
AHCTREUNG
0.169 mmol, 88%). [a]D22
=
ꢁ12 (c=1.12 in methanol); 1H NMR
A
N
ACHTREUNG
(400 MHz, CD3OD): d=7.79 (d, 2H, 3J
ACHTRE(UNG H,H)=8.3 Hz), 7.43 (d, 2H,
A
ACHTREUNG
3J
H-1GN), 4.46 (s, 1H, H-1bMan), 4.27 (dd, 1H, 3J
(dd, 1H, 3J(H,H)=7.3, 10.4 Hz), 4.01 (dd, 1H, 3J
3.89–3.27 (m, 20H), 2.45 (s, 3H), 2.30 (t, 2H, 3J
(H,H)=7.6 Hz), 1.92 (s,
T
ACHTRE(UNG H,H)=8.3 Hz;
1H, H-2), 3.69 (s, 2H), 3.61 (m, 1H, H-5), 1.96–1.91 (9H), 0.86 (s, 9H),
0.11 (m, 6H); 13C NMR (100 MHz, CDCl3): d=170.3, 170.2, 169.0, 165.1,
95.4, 77.2, 71.7, 70.2, 68.7, 62.3, 57.1, 28.6, 25.5, 20.67, 20.65, 20.60, 17.8,
ꢁ4.2, ꢁ5.3; elemental analysis calcd (%) for C20H34BrNO9Si: C 44.44, H
6.34, N 2.59; found: C 44.37, H 6.27, N 2.53.
AHCTREUNG
N
ACHTREUNG
AHCTREUNG
3H), 1.58 (m, 4H), 1.31 (8H); 13C NMR (100 MHz, CD3OD): d=175.9,
174.1, 146.3, 134.2, 131.0, 129.0, 101.8, 100.8, 98.5, 77.8, 77.6, 76.9, 75.3,
75.2, 72.4, 72.0, 71.6, 70.7, 68.4, 67.8, 62.6, 57.1, 52.0, 49.3, 34.8, 30.7, 30.4,
30.3, 30.1, 27.0, 26.0, 23.4, 21.6; HR ESI-MS: m/z: calcd for
C37H59NO20SNa: 892.3249, found 892.3289 [M+Na]+.
3,4,6-Tri-O-acetyl-2-bromoacetamido-2-deoxy-a-d-glucopyranosyl phos-
phate diallyl ester (18): A solution of 16 (394.5 mg, 0.7299 mmol) in
CH3CN (5.0 mL) was added 47% aq. HF (750 mL), and stirred for 11 h at
room temperature. The mixture was neutralized with aq. NaHCO3, and
the aqueous phase was extracted with CHCl3 (3). The combined organ-
iclayers were washed with brine (2), dried over Na 2SO4, filtered, and
concentrated. Purification by silica gel chromatography (toluene/EtOAc
5:1 ! 1:1) gave the hemiacetal (290.3 mg, 0.6811 mmol, 93%). 1H NMR
Compound 13a: A solution of tosylate 12 (22.3 mg, 0.0256 mmol) in
DMF (1.5 mL) was added AcSK (9.2 mg, 0.081 mmol), and stirred for 9 h
at 658C under N2 atmosphere. The mixture was cooled to room tempera-
ture, to which were added MeOH/H2O 7:3 (3 mL) and Et3N (0.3 mL).
After stirring for 15 h at room temperature, the mixture was concentrat-
ed. Purification by size-exclusion chromatography (Sephadex LH-20,
CHCl3/MeOH 1:4) gave 13a (13.4 mg, 9.2 mmol, 72%). [a]2D2 = +31 (c=
0.71 in methanol); 1H NMR (400 MHz, D2O, 40 8C): d=4.93 (2H), 4.59–
(400 MHz, CDCl3): d=6.65 (1H, 3J
A
A
3J
3J
ACHTREUNG
AHCTREUNG
2H), 3.19 (d, 1H, 3J
A
4.57 (m, 4H, overlapped with HOD), 4.11 (dd, 2H, 3J
A
(100 MHz, CDCl3): d=170.7, 170.3, 168.9, 165.5, 91.2, 77.2, 70.3, 67.9,
Chem. Eur. J. 2006, 12, 3449 – 3462
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3457