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Y. Li et al. / Carbohydrate Research 346 (2011) 1714–1720
3.3. 2-Azido-2-deoxy-
a
-D
-glucopyranosyl phosphate (2)
3.5. Ethyl 2-azido-4,6-O-benzylidene-2-deoxy-1-thio-b-
D-
allopyranoside (16)
Crystalline phosphoric acid (1.1 g, 10.7 mmol) was dried in va-
cuo over phosphorus pentoxide for 12 h. 1,3,4,6-tetra-O-acetyl-2-
A mixture of 15 (4.7 g, 10 mmol), sodium nitrite (6.9 g,
azido-2-deoxy-
a
/b-
D
-glucopyranose (8)14 (500 mg, 1.34 mmol)
100 mmol), 15-crown-5 (2.2 mL, 11 mmol), and hexamethylphos-
phoramide (50 mL) was stirred at room temperature under nitro-
gen for 12 h. The reaction solution was filtered through Celite,
the filtrate was diluted with EtOAc (100 mL), and the mixture
was sequentially washed by water (4 ꢂ 30 mL) and brine. The
organic layer was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. Purification of this residue via flash column
chromatography on silica gel (5:1 petroleum ether–EtOAc,
Rf = 0.2) yielded 16 (2.5 g, 75%) as a white solid. Spectral data are
was added and the mixture was heated at 60 °C in vacuo. The for-
mation of a melt and the evolution of CH3COOH vapors were ob-
served. After 2 h, heating was ceased and the resulting dark black
mixture was dissolved in anhydrous THF (20 mL). The solution
was cooled to 0 °C and concentrated ammonium hydroxide
(2 mL) was added. The precipitate of ammonium phosphate was
filtered off and washed with THF (50 mL). The combined filtrate
and washings were evaporated to give a syrupy residue that was
used in the next step without further purification. This crude mate-
rial was dissolved in MeOH (50 mL) and cooled to 0 °C, and then
diethylamine (5 mL, 48 mmol) was slowly added dropwise. The
reaction mixture was slowly warmed to room temperature and
was stirred for two days. The solvent was removed in vacuo at
30 °C to give a brown oil, which was purified twice over Bio-gel
P2 (2 ꢂ 100 cm column) with 0.25 M NH4HCO3 as eluent, followed
by desalting on Bio-gel P2 with water; this yielded compound 2
(111 mg, 29%) as a yellow solid. The product was lyophilized. Spec-
as follows: mp = 137–138 °C. ½a D22
ꢃ
= ꢀ20.14 (c 0.45, MeOH). 1H
NMR (CDCl3, 400 MHz): d 7.50–7.48 (m, 2H, ArH), 7.40–7.38 (m,
3H, ArH), 5.58 (s, 1H, PhCH), 5.00–4.97 (d, J1,2 = 10.4 Hz, 1H, H-1),
4.45 (d, J3,2 = J3,4 = 2.4 Hz, 1H, H-3), 4.41–4.37 (dd, J5,6eq = 5.2 Hz,
J6eq,6ax = 12.4 Hz, 1H, H-6eq), 4.08–4.02 (ddd, J5,4 = 9.6 Hz,
J5,6eq = 5.2 Hz, J5,6ax = 2.6 Hz, 1H, H-5), 3.78–3.72 (dd, J
=
6ax,6eq
12.4 Hz, J5,6ax = 2.6 Hz, 1H, H-6ax), 3.61–3.58 (dd, J4,5 = 9.6 Hz,
J4,3 = 2.4 Hz, 1H, H-4), 3.33–3.30 (dd, J1,2 = 10.4 Hz, J2,3 = 2.4 Hz,
1H, H-2), 2.85–2.75 (q, 2H, –SCH2–), 2.5 (s, 1H, 3-OH), and 1.38–
1.34 (t, J = 7.6 Hz, 3H, –CH3); 13C NMR (CDCl3, 100 MHz): d 136.8
(1C), 129.4 (1C), 128.4 (2C), 126.1 (2C), 101.9 (1C, PhCH), 81.5
(1C, C-1), 78.5 (1C, C-4), 68.9 (1C, C-3), 68.7 (1C, C-6), 65.9 (1C,
C-5), 62 (1C, C-2), 24.9 (1C, –SCH2–), 15.1 (1C, –CH3). ESI-HRMS:
tral data are as follows: mp = 160 °C. ½a D22
ꢃ
= +42.17 (c 0.45, MeOH).
IR (KBr):
m
2117 cmꢀ1 (N3). 1H NMR (D2O, 400 MHz): d 5.52 (dd,
J1,2 = 3.2 Hz, J1,P = 8.0 Hz, 1H, H-1), 3.99 (dd, J6eq,6ax = 12.4 Hz,
J5,6eq = 2.6 Hz, 1H, H-6eq), 3.97 (t, J2,3 = J3,4 = 9.6 Hz, 1H, H-3), 3.92
(dd, J6eq,6ax = 12.4 Hz, H5,6ax = 5.2 Hz, 1H, H-6ax), 3.81 (ddd,
J4,5 = 9.6 Hz, J5,6ax = 5.2 Hz, J5,6eq = 2.6 Hz, 1H, H-5), 3.52 (t,
J3,4 = J4,5 = 9.6 Hz, 1H, H-4), 3.33 (dd, J1,2 = 3.2 Hz, J2,3 = 9.6 Hz, 1H,
H-2); 13C NMR (D2O, 100 MHz): d 96.05 (d, 1C, JC,P = 5.3 Hz, C-1),
75.09 (1C, C-5), 73.69 (1C, C-4), 72.81 (1C, C-3), 66.16 (1C, C-6),
and 63.45 (1C, C-2). 31P NMR (D2O): d ꢀ0.05.
calcd for
360.0985.
C
15H19N3O4SNa [M+Na]+ m/z 360.1001; found m/z
3.6. Ethyl 2-azido-4,6-O-benzylidene-2,3-dideoxy-3-fluoro-1-
thio-b- -glucopyranoside (17)
D
DAST (1.2 g, 7.56 mmol) was added to a solution of allopyrano-
side 16 (850 mg, 2.52 mmol) in CH2Cl2 (20 mL) at ꢀ40 °C. The mix-
ture was allowed to slowly warm to room temperature and was
stirred for 2 h. The mixture was again cooled to ꢀ10 °C and MeOH
(8 mL) was added. Purification of the concentrated mixture by flash
column chromatography (10:1 petroleum ether–EtOAc, Rf = 0.2)
afforded 17 (470 mg, 55%) as a white solid. Spectral data are as fol-
3.4. Ethyl 2-azido-4,6-O-benzylidene-2-deoxy-3-O-
trifluoromethanesulfonyl-1-thio-b-D-glu-copyranoside (15)
A mixture of compound 14 (3.76 g, 11.2 mmol) was dissolved in
dichloromethane (100 mL) under nitrogen; the reaction flask was
immersed in an ice bath. Pyridine (14 mL) was added and trifluoro-
methanesulfonic anhydride (0.65 mL, 13.4 mmol) was injected into
the solution. The mixture was gradually warmed to room temper-
ature, and the solution was stirred continuously for 4 h. MeOH
(20 mL) was added to quench the reaction, the mixture was stirred
for another 30 min, and the resulting solution was evaporated un-
der reduced pressure. Water (100 mL) was added to the residue,
the mixture was extracted with EtOAc (3 ꢂ 30 mL), and the com-
bined organic layers were consecutively washed with 2 N HCl
(aq), saturated NaHCO3 (aq), water, and brine. The organic phase
was dried over MgSO4, filtered, and concentrated in vacuo to pro-
vide a residue, which was purified by flash column chromatogra-
phy (10:1 petroleum ether–EtOAc, Rf = 0.3) to afford 3-OTf-1-SEt
(15; 5.2 g, 99%) as a white solid. Spectral data are as follows:
lows: mp = 117–118 °C. ½a D22
ꢃ
= ꢀ80.01 (c 0.45, MeOH). 1H NMR
(CDCl3, 400 MHz): d 7.50–7.26 (m, 5H, Ar), 5.56 (s, 1H, PhCH),
4.47–4.65 (dt, J3,2 = J3,4 = 8.8 Hz, J3,F = 52.4 Hz, 1H, H-3), 4.41 (d,
J1,2 = 10.4 Hz, 1H, H-1), 4.35–4.39 (dd, J4,5 = 9.2 Hz, J5,6b = 5.2 Hz,
1H, H-5), 3.84 (dd, J3,4 = 8.8 Hz, J4,5 = 9.2 Hz, 1H, H-4), 3.77 (dd,
J5,6eq = 5.2 Hz, J6eq,6ax = 12.4 Hz, 1H, H-6eq), 3.56–3.64 (dd,
J1,2 = 10.4 Hz, J2,3 = 8.8 Hz, 1H, H-2), 3.40–3.46 (dd, J5,6ax = 2.6 Hz,
J6eq,6ax = 12.4 Hz, 1H, H-6ax), 2.74–2.82 (q, J = 7.2 Hz, 2H, –SCH2–),
1.34 (t, J = 7.2 Hz, 3H, –CH3). 13C NMR (CDCl3, 100 MHz): d 136.5
(1C, Ar), 129.3 (2C, Ar), 128.3 (2C, Ar), 126.1 (1C, Ar), 101.6 (1C,
PhCH), 93.2–91.3 (1C, d, JC,F = 191 Hz, C-3), 84.7 (1C, d, JC,S = 6.8 Hz,
C-1), 78.4 (1C, d, JC,F = 16.7 Hz, C-4), 69.5 (1C, d, JC,F = 8 Hz, C-5),
68.2 (1C, s, C-6), 64.8 (1C, d, JC,F = 17.9 Hz, C-2), 25.2 (1C, –SCH2–),
15.0 (1C, –CH3). 19F NMR (CDCl3): d ꢀ82.7. ESI-HRMS: calcd for
mp = 120–121 °C. ½a D22
ꢃ
= ꢀ55.3 (c 0.45, MeOH). 1H NMR (CDCl3,
C
15H18FN3O3SNa [M+Na]+ m/z 362.0871; found m/z 362.0863.
400 MHz): d 7.48–7.36 (m, 5H, ArH), 5.58 (s, 1H, PhCH), 4.80–
4.75 (t, J2,3 = J4,3 = 9.6 Hz, 1H, H-3), 4.49 (d, J1,2 = 10 Hz, 1H, H-1),
4.42–4.38 (dd, J5,6eq = 4.8 Hz, J6ax,6eq = 12.4 Hz, 1H, H-6eq), 3.83–
3.77 (m, 2H, H-4, H-6ax), 3.65–3.60 (dd, J1,2 = 10 Hz, J2,3 = 9.6 Hz,
1H, H-2), 3.48–3.46 (m, 1H, H-5), 2.85–2.76 (q, J = 7.2 Hz, 2H,
SCH2–), 1.38–1.34 (t, J = 7.2 Hz, 3H, –CH3); 13C NMR (CDCl3,
100 MHz): d 136.04 (1C), 129.2 (1C), 128.3 (2C), 125.8 (2C), 101.4
(1C, PhCH), 86 (1C, C-1), 85.2 (1C, C-3), 77.4 (1C, C-4), 70.3 (1C,
C-5), 68.1 (1C, C-6), 64.3 (1C, C-2), 25.5 (1C, –SCH2–), 15 (1C, –
CH3). ESI-HRMS: calcd for C16H19F3N3 O6S2 [M+H]+ m/z 470.0665;
found m/z 470.0657. calcd for C16H18F3N3O6S2Na [M+Na]+ m/z
492.0473; found, m/z 492.04767.
3.7. Ethyl 2-azido-4,6-di-O-benzyl-2,3-dideoxy-3-fluoro-1-thio-
b-D
-glucopyranoside (18)
Compound 17 (100 mg, 0.29 mmol) was suspended in 5 mL
MeOH and catalytic p-TsOH (5 mg, 0.03 mmol) was added. The
reaction mixture was stirred until TLC indicated complete conver-
sion of the starting material into a lower running spot. The reaction
mixture was neutralized by the addition of 0.5 mL NEt3 and con-
centrated under reduced pressure to give the crude product, which
was dried in vacuo and used in the next step without further puri-
fication. The crude product was dissolved in 2 mL of dried DMF,