8636 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 24
Klein et al.
and 13C NMR spectra was achieved using 2D methods (COSY,
HSQC, TOCSY). Chemical shifts are expressed in ppm using
residual CHCl3, CHD2OD, and HDO as references. Optical
rotations were measured using Perkin-Elmer polarimeter 341.
Electron spray ionization mass spectra (ESI-MS) were obtained
on a Waters micromass ZQ. HRMS analysis were carried out
using a Bruker Daltonics micrOTOF spectrometer equipped
with a TOF hexapole detector. Microanalyses were performed
at the Department of Chemistry, University of Basel, Switzerland.
Microwave-assisted reactions were carried out with a CEM Dis-
cover and Explorer. Reactions were monitored by TLC using
glass plates coated with silica gel 60 F254 (Merck) and visualized
by using UV light and/or by heating to 140 °C for 5 min with a
molybdate solution (a 0.02 M solution of ammonium cerium
sulfate dihydrate and ammonium molybdate tetrahydrate in
aqueous 10% H2SO4). Column chromatography was performed
on a CombiFlash Companion (Teledyne-ISCO, Inc.) using
RediSep normal phase disposable flash columns (silica gel). Re-
versed phase chromatography was performed on LiChro-
prepRP-18 (Merck, 40-63 μm). Commercially available
reagents were purchased from Fluka, Aldrich, Merck, AKSci, ASDI,
or Alfa Aesar. Methanol (MeOH) was dried by refluxing with
sodium methoxide and distilled immediately before use. Toluene
was dried by filtration over Al2O3 (Fluka, type 5016 A basic).
Dioxane was dried by distillation from sodium/benzophenone.
4-Bromophenyl 2,3,4,6-Tetra-O-acetyl-r-D-mannopyranoside
(14a). To a stirred solution of 12 (1.17 g, 3.00 mmol) and
4-bromophenol (13a, 623 mg, 3.60 mmol) in toluene (12 mL),
TMSOTf (65 μL, 0.36 mmol) was added dropwise under
argon. The mixture was stirred at rt for 5 h and then diluted
with toluene (15 mL) and washed with satd aqNaHCO3. The
organic layer was separated, and the aqueous layer was
extracted three times with toluene. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by flash chromatography on silica
(petroleum ether/EtOAc, 19:1 to 1.5:1) to yield 14a (1.17 g,
74%) as a white solid.
repeated once, and then freshly degassed dioxane (5 mL) was
added under a stream of argon. The reaction tube was quickly
sealed and the contents were stirred at 80 °C overnight. The
reaction mixture was cooled to rt, diluted with EtOAc (10 mL),
washed with satd aq NaHCO3 (5 mL) and brine (5 mL), and
dried over Na2SO4. The solvents were removed in vacuo, and the
residue was purified by flash chromatography on silica
(petroleum ether/EtOAc, 3:1 to 3:2) to give 15a (474 mg, 85%)
as a white solid.
1
[R]D þ80.8 (c 1.00, CHCl3). H NMR (500 MHz, CDCl3):
δ 2.02, 2.03, 2.04, 2.19 (4s, 12H, COCH3), 3.91 (s, 3H, OCH3),
4.08 (m, 2H, H-6a, H-5), 4.27 (dd, J=5.2, 12.2 Hz, 1H, H-6b),
5.37 (t, J=10.1 Hz, 1H, H-4), 5.45 (dd, J=1.8, 3.4 Hz, 1H, H-2),
5.56 (m, 2H, H-1, H-3), 7.16 (AA0 of AA0BB0, J=8.7 Hz, 2H,
C6H4), 7.57 (m, 4H, C6H4), 8.07 (BB0 of AA0BB0, J=8.4 Hz, 2H,
C6H4). 13C NMR (125 MHz, CDCl3): δ 20.74, 20.75, 20.77, 21.0
(4 COCH3), 52.2 (OCH3), 62.1 (C-6), 65.9 (C-4), 68.9 (C-3), 69.3,
69.4 (C-2, C-5), 95.8 (C-1), 116.9, 126.7, 128.5, 128.7, 130.2, 134.8,
144.8, 155.7 (12C, 2 C6H4), 167.0, 169.8, 170.0, 170.1, 170.6 (5 CO).
ESI-MS calcd for C28H30NaO12 [M þ Na]þ 581.2; found 581.0.
Methyl 40-(2,3,4,6-Tetra-O-acetyl-r-D-mannopyranosyloxy)-
30-chlorobiphenyl-4-carboxylate (15b). A microwave tube was
charged with bromide 14b (720 mg, 1.34 mmol), 4-methoxy-
carbonylphenylboronic acid (289 mg, 1.61 mmol), cesium
carbonate (1.31 g, 4.02 mmol), and Pd(PPh3)4 (77.4 mg,
0.067 mmol). The tube was sealed with a Teflon septum,
evacuated through a needle, and flushed with argon. Degassed
dioxane (1.5 mL) was added and the closed tube was degassed
in an ultrasonic bath for 15 min, flushed again with argon for
20 min, and exposed to microwave irradiation at 120 °C for
500 min. The solvent was evaporated in vacuo. The residue was
dissolved in DCM (10 mL), washed with brine (2 ꢀ 10 mL),
dried over Na2SO4, and concentrated in vacuo. The residue
was purified by flash chromatography on silica (petroleum
ether/EtOAc, 5:1 to 0.5:1) to yield 15b (333 mg, 42%) as a
white foam.
[R]D þ66.3 (c 1.06, CHCl3). 1H NMR (500 MHz, CDCl3): δ
2.03, 2.06, 2.20 (3s, 12H, COCH3), 3.92 (s, 3H, OCH3), 4.08 (dd,
J=2.4, 12.3 Hz, 1H, H-6a), 4.17 (m, 1H, H-5), 4.28 (dd, J=5.4,
12.3 Hz, 1H, H-6b), 5.39 (t, J=10.6 Hz, 1H, H-4), 5.54 (dd, J=
1.9, 3.4 Hz, 1H, H-2), 5.59 (d, J=1.8 Hz, 1H, H-1), 5.62 (dd, J=
3.5, 10.1 Hz, 1H, H-3), 7.24 (s, 1H, C6H3), 7.44 (dd, J=2.2,
8.5 Hz, 1H, C6H3), 7.57 (AA0 of AA0BB0, J=8.5 Hz, 2H, C6H4),
7.65 (d, J=2.2 Hz, 1H, C6H3), 8.08 (BB0 of AA0BB0, J=8.5 Hz,
2H, C6H4). 13C NMR (125 MHz, CDCl3): δ 20.9, 21.0, 21.1 (4C,
4 COCH3), 52.5 (OCH3), 62.3 (C-6), 66.0 (C-4), 69.0 (C-3), 69.5
(C-2), 70.0 (C-5), 96.8 (C-1), 117.4, 126.7, 126.9, 129.5, 130.5,
136.4, 143.6, 151.3 (12C, C6H3, C6H4), 167.0, 169.9, 170.0,
170.2, 170.7 (5 CO). ESI-MS calcd for C28H29ClNaO12 [M þ
Na]þ 615.1; found 615.2. Anal. Calcd for C28H29ClO12: C 56.71,
H 4.93. Found: C 56.79, H 4.92.
Methyl 40-(r-D-Mannopyranosyloxy)-biphenyl-4-carboxylate
(16a).17d To a solution of 15a (170 mg, 0.304 mmol) in MeOH
(3 mL) was added freshly prepared 1 M NaOMe in MeOH
(100 μL) under argon. The mixture was stirred at rt until the
reaction was complete (monitored by TLC), then neutralized
with Amberlyst-15 (Hþ) ion-exchange resin, filtered, and con-
centrated in vacuo. The residue was purified by reversed-phase
chromatography (RP-18, H2O/MeOH, 1:0-1:1) to give 16a
(90 mg, 76%) as white solid.
1H NMR (500 MHz, CDCl3): δ 2.06 (s, 9H, 3 COCH3), 2.19
(s, 3H, COCH3), 4.06 (m, 2H, H-5, H-6a), 4.27 (dd, J=5.6, 12.4
Hz, 1H, H-6b), 5.36 (t, J = 10.2 Hz, 1H, H-4), 5.43 (dd, J =
1.8, 3.5 Hz, 1H, H-2), 5.48 (d, J=1.7 Hz, 1H, H-1), 5.53 (dd, J=
3.5, 10.1 Hz, 1H, H-3), 6.98, 7.41 (AA0, BB0 of AA0BB0, J =
9.0 Hz, 4H, C6H4). 13C NMR (125 MHz, CDCl3): δ 20.71, 20.73,
20.74, 20.9 (4 COCH3), 62.1 (C-6), 65.9 (C-4), 68.8 (C-3), 69.2
(C-2), 69.3 (C-5), 95.9 (C-1), 115.6, 118.3, 132.6, 154.7 (6C,
C6H4), 170.0 (4C, 4 CO).
4-Bromo-2-chlorophenyl 2,3,4,6-tetra-O-acetyl-r-D-mannopyran-
oside (14b). According to the procedure described for 14a,
compound 12 (2.38 g, 4.84 mmol) and 4-bromo-2-chloro-
phenol (13b, 1.20 g, 5.80 mmol) were treated with TMSOTf
(107 mg, 0.484 mmol) to yield 14b (1.54 g, 59%) as a white solid.
1
[R]D þ60.6 (c 0.40, CHCl3). H NMR (500 MHz, CDCl3):
δ 2.02, 2.04, 2.18 (3s, 12H, 4 COCH3), 4.05 (dd, J=2.3, 12.2 Hz,
1H, H-6a), 4.10 (ddd, J=2.7, 5.3, 9.6 Hz, 1H, H-5), 4.24 (dd, J=
5.4, 12.2 Hz, 1H, H-6b), 5.35 (t, J=10.1 Hz, 1H, H-4), 5.48 (m,
2H, H-1, H-2), 5.56 (dd, J=3.2, 10.1 Hz, 1H, H-3), 7.03 (d, J=
8.8 Hz, 1H, C6H3), 7.30 (dd, J=2.4, 8.8 Hz, 1H, C6H3), 7.53 (d,
J=2.4 Hz, 1H, C6H3). 13C NMR (125 MHz, CDCl3): δ 20.9,
21.1 (4C, 4 COCH3), 62.3 (C-6), 65.9 (C-4), 68.9 (C-3), 69.4
(C-2), 70.1 (C-5), 96.9 (C-1), 115.9, 118.4, 125.7, 130.8, 133.3,
150.6 (C6H3), 169.9, 170.0, 170.1, 170.7 (4 CO). ESI-MS calcd for
C20H22BrClNaO10 [M þ Na]þ 559.0; found 559.0; Anal. Calcd
for C20H22BrClO10: C 44.67, H 4.12.Found: C 45.08, H 4.14.
Methyl 40-(2,3,4,6-Tetra-O-acetyl-r-D-mannopyranosyloxy)-
biphenyl-4-carboxylate (15a). A Schlenk tube was charged with
14a (503 mg, 1.00 mmol), 4-methoxycarbonylphenylboronic
acid (224 mg, 1.24 mmol), S-Phos (20.5 mg, 0.05 mmol), cesium
carbonate (1.17 g, 3.6 mmol), Pd2(dba)3 (10.4 mg, 0.01 mmol),
and a stirring bar. The tube was closed with a rubber septum and
was evacuated and flushed with argon. This procedure was
[R]D þ82.8 (c 0.2, MeOH). 1H NMR (500 MHz, CD3OD): δ
3.62 (m, 1H, H-5), 3.72 (m, 3H, H-4, H-6a, H-6b), 3.92 (m, 4H,
H-3, OCH3), 4.03 (s, 1H, H-2), 5.55 (s, 1H, H-1), 7.24 (AA0 of
AA0BB0, J = 8.0 Hz, 2H, C6H4), 7.64 (AA0 of AA0BB0, J = 7.5
Hz, 2H, C6H4), 7.71 (BB0 of AA0BB0, J = 8.0 Hz, 2H, C6H4),
8.07 (BB0 of AA0BB0, J = 7.5 Hz, 2H, C6H4). 13C NMR (125
MHz, CD3OD): δ 52.6 (OCH3), 62.7 (C-6), 68.3 (C-4), 72.0 (C-2),
72.4 (C-3), 75.5 (C-5), 100.1 (C-1), 118.2, 127.7, 131.1, 135.1,
146.6, 158.2, 160.3 (12C, 2 C6H4), 166.1 (CO). HR-MS calcd for
C20H22NaO8 [M þ Na]þ 413.1212; found 413.1218.