Y. Fu, S. Laurent, R. N. Muller
FULL PAPER
ring H), 5.2Ϫ5.4 (m, 3 H, sugar ring H), 5.5 (d, J ϭ 1.2 Hz, 1 H, The residue was dissolved in CHCl3 (100 mL), and washed with
sugar C-1 H), 7.1Ϫ7.5 (m, 8 H, aromatic H) ppm. 13C NMR cold saline (2 ϫ 15 mL). The organic layer was dried with MgSO4.
(CDCl3): δ ϭ 20.9 (CH3CO), 41.2 (CH2Ar), 52.2 (OCH3), 65.9, After evaporation of the solvent, a crude product was obtained as
68.5, 68.9, 69.6 62.2 (mannose C-2 to C-6), 96.8 (mannose C-1), a slightly yellow syrup. Further purification was carried out by sil-
116.4, 123.9, 128.4, 128.8, 129.0, 130.6, 131.3, 132.3, 134.3, 138.0
ica gel chromatography with PE/EtOAc (3:2) as eluent. The frac-
(aromatic C), 152.7 (C-O, aromatic C), 169.8, 169.9, 170.2, 170.8 tions with Rf ϭ 0.17 (PE/EtOAc, 3:2) were collected to give 1.22 g
(CϭO of Ac groups), 172.4 (CO2CH3) ppm.
Methyl {3-[5-(3-Bromopropionyl)-2-(2,3,4,6-tetra-O-acetyl-α-
(54%) of 8 as a syrup. IR (film): ν˜ ϭ 2100 cmϪ1. 1H NMR (CDCl3):
δ ϭ 1.3 (m, 2 H, CH2CH2N3), 1.9Ϫ2.2 (4 s, 12 H, 1:1:1:1, acetyl
groups), 3.1 (m, 2 H, ArCH2CH2), 3.4 (t, J ϭ 5 Hz, 2 H, CH2N3),
3.6 (s, 3 H, OCH3), 3.7 (s, 2 H, CH2CO2), 3.8Ϫ4.2 (m, 3 H, sugar
ring H), 5.1 (m, 3 H, sugar ring H), 5.3 (d, J ϭ 1.2 Hz, 1 H, sugar
C-1 H), 6.8Ϫ7.4 (m, 7 H, aromatic H) ppm. 13C NMR (CDCl3):
δ ϭ 20.9, 26.1, 32.1, 40.3, 44.8, 52.3, 61.9, 68.3, 71.0, 71.6, 72.5,
97.1, 117.4, 122.0, 126.3, 126.4, 126.7, 129.6, 130.7, 134.8, 136.3,
141.1, 141.5, 156.1, 169.9, 170.1, 170.5, 171.1,171.9 ppm.
D-
mannopyranosyloxy)phenyl]phenyl}acetate (6): Bromopropionyl
chloride (3.43 g, 20 mmol) and 5 (8.27 mmol), contaminated with
α--mannose pentaacetate, were dissolved in CH2Cl2 (150 mL) and
then cooled to Ϫ78 °C. Anhydrous AlCl3 (16.6 g) was added and
the mixture was stirred in an ice/water bath for 1 h. The reaction
was quenched by ice-cold water (50 mL). The mixture was stirred
until the aluminum chloride was completely hydrolyzed (30 min)
and then extracted with dichloromethane (50 mL). The organic
phase was dried and concentrated to give 7.15 g of a clear syrup
containing 7.68 mmol (93%) of 6. This compound could be used
in the next step without further purification although it still con-
tained α--mannose pentaacetate. TLC (PE/EtOAc, 3:2) showed
that the starting compound 5 (Rf ϭ 0.48) was entirely consumed
(product Rf ϭ 0.33). Pure 6 could be easily separated from the
crude product through silica gel chromatography (PE/EtOAc, 3:2)
Methyl {3-[5-(3-Aminopropyl)-2-(2,3,4,6-tetra-O-acetyl-α-D-manno-
pyranosyloxy)phenyl]phenyl}acetate (9): The Pd/C catalyst (10%,
0.68 g) was suspended in a mixture of formic acid and methanol
(30 and 60 mL) and hydrogen was bubbled into the solution. This
activation process lasted 0.5Ϫ1 h. The azide derivative 8 (1.75 g,
2.67 mmol) in methanol (30 mL) was added to the suspension. The
reaction was continued for 5 h under H2 at room temperature. TLC
(EtOAc/CH3OH, 8:1) showed that the azide (Rf ϭ 0.94) was gradu-
ally consumed and the amine (as formate, Rf ϭ 0.18) was produced
during this period. After this reaction, the solvents were removed
and the residue was purified on the silica gel column eluting first
with a EtOAc/CH3OH (3:1) mixture, then with CH3OH alone.
Fractions with Rf ϭ 0.18 (ninhydrin-positive) were collected and
1
at a 93% yield. H NMR (CDCl3): δ ϭ 1.9Ϫ2.2 (4 s, 12 H, 1:1:1:1,
acetyl groups), 3.0 (t, J ϭ 7.4 Hz, 2 H, OϭCCH2CH2Br), 3.6 (t,
J ϭ 7.4 Hz, 2 H, CH2Br), 3.7 (s, 3 H, OCH3), 3.8 (s, 2 H, O2CCH2),
3.9Ϫ4.4 (m, 3 H, sugar ring H), 5.2Ϫ5.5 (m, 3 H, sugar ring H),
5.6 (d, J ϭ 1.4 Hz, 1 H, sugar C-1 H), 7.2Ϫ7.6 (m, 5 H, aromatic
H), 7.9Ϫ8.1 (m, 2 H, aromatic H) ppm. 13C NMR (CDCl3): δ ϭ
21.3, 25.9, 37.9, 41.6, 52.7, 62.5, 66.1, 69.1, 69.6, 70.3, 96.6, 115.8,
124.2, 128.7, 129.4, 130.6, 130.9, 132.0, 133.2, 134.9, 137.2, 139.4,
156.9, 170.3, 171.2, 172.0, 172.8, 173.9, 196.1 ppm.
1
gave 1.14 g (63%) of the amine. H NMR (CDCl3): δ ϭ 1.3 (m, 2
H, CH2CH2N), 1.9Ϫ2.2 (4 s, 12 H, 1:1:1:1, acetyl groups), 3.1 (m,
2 H, ArCH2CH2,), 3.6 (s, 3 H, OCH3), 3.7 (t, 2 H, CH2CO2), 3.8
(t, 2 H, CH2N), 3.9Ϫ4.3 (m, 3 H), 5.1Ϫ5.4 (m, 3 H), 5.5 (d, J ϭ
1.4 Hz, 1 H, sugar C-1 H), 6.1Ϫ6.7 (br, 3 H, RNH3ϩ, exchangeable
with D2O), 7.0Ϫ7.7 (m, 7 H, aromatic H), 8.3 (s, 1 H, HCO- of
formate ion) ppm. 13C NMR (CDCl3): δ ϭ 20.8, 30.1, 30.6, 40.4,
41.6, 52.2, 61.9, 68.2, 70.9, 71.6, 72.7, 97.0, 117.6, 121.9, 126.5,
129.7, 129.8, 130.2, 131.1, 134.9, 136.3, 140.9, 142.2, 157.1, 169.8,
169.9, 170.2, 171.1, 171.7 ppm.
Methyl {3-[5-(3-Bromopropyl)-2-(2,3,4,6-tetra-O-acetyl-α-D-manno-
pyranosyloxy)phenyl]phenyl}acetate (7): Under nitrogen, BH3·THF
reagent (1.0 , 15 mL) was added in portions to the FriedelϪCrafts
reaction residue (containing 7.68 mmol of 6 with 4.41 mmol of
mannose pentaacetate), dissolved in anhydrous THF (150 mL).
Under anhydrous conditions, this reaction lasted 3 h at room tem-
perature. After adding methanol (15 mL) to destroy the excess bor-
ane, the mixture was concentrated under reduced pressure to afford
a clear syrup. The crude product was purified by silica gel chroma-
tography using PE/EtOAc (3:2) as eluent. 3.68 g (5.31 mmol) of
pure 7 (Rf ϭ 0.19; PE/EtOAc, 3:2) was obtained. The overall yield
of the last two steps was 64% and this reduction step gave a yield
of 69% (in several preparations this yield ranged from 69Ϫ74%). To
monitor the reaction progress, samples obtained from the reaction
{3-[5-(3-Aminopropyl)-2-(α-D-mannopyranosyloxy)phenyl]-
phenyl}acetic Acid (10): A 12.5% NaOH solution (4 mL) was added
to 6 mL of a solution of compound 9 (682 mg, 1.01 mmol) in meth-
anol. The mixture was stirred at room temperature for 24 h, and
then concentrated after adjustment of the pH to neutrality with
HCl. Hot methanol (30 mL) was added to the residue. The insol-
uble salt was filtered and the filtrate was concentarted. This crude
residue was dissolved in distilled water (5 mL) and the pH was
adjusted to ca. 3 with HCl. The purification was conducted by
preparative reversed-phase HPLC monitored at 254 nm. The frac-
tions containing the eluted product 10 were concentrated and lyo-
philized to give 483 mg of a yellowish solid which consisted of HCl
salt of 10 and a small amount of salt. From the contents of Naϩ
and ClϪ determined by ion-selective electrode and classical ClϪ
quantification,[19] it could be calculated that this mixture was com-
posed of 0.79 mmol of 10 as HCl salt (382 mg) and 101 mg of
NaCl. The NaCl was subsequently removed by chromatography
on Sephadex G-15. The yield was 78%. Analytical reversed-phase
HPLC: retention time 6.20 min. UV: λmax ϭ 209, 249, and 280 nm
(in H2O). L-SIMS: m/z ϭ 483 [Mϩ], 505 [M Ϫ H ϩ Na]ϩ for
1
mixture were analyzed by TLC. H NMR (CDCl3): δ ϭ 1.8 (m, 2
H, CH2CH2Br), 1.9Ϫ2.2 (4 s, 12 H, 1:1:1:1, acetyl groups), 3.4 (m,
2 H, ArCH2CH2), 3.5 (t, J ϭ 6.4 Hz, 2 H, CH2Br); 3.7 (s, 3 H,
OCH3), 3.8 (s, 2 H, CH2CO2), 3.9Ϫ4.2 (m, 3 H, sugar ring H),
5.2Ϫ5.4 (m, 3 H, sugar ring H), 5.5 (d, J ϭ 1.0 Hz, 1 H, sugar C-
1 H), 7.1Ϫ7.5 (m, 7 H, aromatic H) ppm. 13C NMR (CDCl3): δ ϭ
20.5, 32.9, 34.1, 34.7, 40.4, 52.2, 61.9, 68.8, 70.9, 71.5, 72.5, 97.1,
118.2, 122.0, 126.7, 128.4, 129.6, 130.7, 131.0, 134.8, 135.4, 139.9,
141.2, 157.1, 169.8, 169.9, 170.8, 171.1, 171.9 ppm.
Methyl {3-[5-(3-Azidopropyl)-2-(2,3,4,6-tetra-O-acetyl-α-D-manno-
pyranosyloxy)phenyl]phenyl}acetate (8): The bromide 7 (2.37 g,
3.42 mmol) was dissolved in DMF (40 mL) and heated to 50 °C.
Sodium azide (1.11 g, 17.1 mmol) was added. The light yellow solu-
tion immediately turned orange. The reaction mixture was kept at
50 °C for 24 h. The insoluble salts were filtered off and the filtrate
was concentrated by solvent evaporation under reduced pressure.
1
C23H30ClNO8. H NMR (D2O): δ ϭ 1.3 (m, 2 H, CH2CH2N), 2.9
(m, 2 H, ArCH2CH2), 3.3 (t, J ϭ 8.3 Hz, 2 H, CH2N), 3.6 (s, 2 H,
CH2CO2), 3.6Ϫ4.1 (m, 6 H, sugar ring H), 5.4 (d, J ϭ 1.2 Hz, 1
H, sugar C-1 H), 7.1Ϫ7.5 (m, 7 H, aromatic H) ppm. L-SIMS:
3972
Eur. J. Org. Chem. 2002, 3966Ϫ3973