22
H. Mikula et al. / Carbohydrate Research 370 (2013) 19–23
t
0.84 (s, 9H, SiC(CH3)3), 0.16 (s, 3H, Si(CH3)2 Bu), 0.13 (s, 3H,
were added under vigorous stirring at room temperature. After 1 h
the reaction mixture was quenched by addition of Na2S2O3 solu-
tion (100 mL, 10% in H2O) and extracted with EtOAc
(2 ꢂ 100 mL). The organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
dissolved in dry DMF (70 mL) and treated with KHCO3 (6.0 g,
60 mmol) and R-X (methyl iodide or benzyl bromide, 30 mmol).
After stirring for 10 h, the reaction mixture was poured onto water
(250 mL) and extracted with EtOAc (3 ꢂ 150 mL). The combined
organic layer was washed with brine, dried over Na2SO4, and con-
centrated in vacuo. Column chromatography (90 g SiO2, 60 mL/
min, hexanes/EtOAc = 10:1 to 3:1 gradient elution) afforded the
pure glucuronals.
t
t
Si(CH3)2 Bu), 0.10 (s, 3H, Si(CH3)2 Bu), 0.08 (s, 9H, Si(CH3)3), 0.05
(s, 3H, Si(CH3)2 Bu); 13C NMR (acetone-d6): d 169.2 (s, 1C, C-6),
t
145.5 (d, 1C, C-1), 101.8 (d, 1C, C-2), 73.6 (d, 1C, C-4), 71.7 (d, 1C,
C-5), 65.3 (d, 1C, C-3), 63.7 (t, 1C, OCH2), 26.2 (q, 3C, SiC(CH3)3),
26.0 (q, 3C, SiC(CH3)3), 18.51 (s, 1C, SiC(CH3)3), 18.48 (s, 1C,
SiC(CH3)3), 17.7 (t, 1C, CH2TMS), ꢀ1.4 (q, 3C, Si(CH3)3), ꢀ3.9 (q,
t
t
t
1C, Si(CH3)2 Bu), ꢀ4.3 (q, 1C, Si(CH3)2 Bu), ꢀ4.4 (q, 1C, Si(CH3)2 Bu),
ꢀ4.8 (q, 1C, Si(CH3)2 Bu); ESI-MS: m/z 511.6 [M+Na]+; HRMS
t
(MALDI): m/z Calcd for C23H49O5Si3 [M+H]+: 489.2888. Found:
489.2871.
1.7. Improved large-scale preparation of 3,4-di-O-benzyl-
D-glucal (13)
1.9. Methyl 3,4-di-O-benzyl-D-glucal (15)
K2CO3 (1.52 g, 11.0 mmol) was added to a solution of 9 (19.98 g,
Starting from 3,4-di-O-benzyl-
D
-glucal (13, 3.3 g, 10 mmol) and
73.4 mmol) in dry MeOH (140 mL) and the resulting solution was
stirred at room temperature for 3 h, until TLC indicated complete
conversion (9: Rf 0.83, 10: Rf 0.20, CH2Cl2/MeOH = 10:1). After con-
centration under reduced pressure, the residue was dissolved in
dry DMF (110 mL), cooled to 0 °C, and treated with imidazole
(15.0 g, 220.2 mmol) and TIPS-Cl (18.39 g, 95.4 mmol). After stir-
ring over-night at room temperature, TLC showed complete con-
sumption of the starting material and formation of the desired
product 11 (Rf 0.50, CH2Cl2/MeOH = 10:1). The reaction mixture
was quenched and diluted with water (400 mL). After extraction
with Et2O (5 ꢂ 200 mL), the organic layer was washed with satd
NH4Cl (2 ꢂ 250 mL), dried over Na2SO4 and evaporated under re-
following the general procedure described above, compound 15
(2.95 g, 83%) was obtained as colorless syrup: Rf 0.31 (hexanes/
EtOAc = 5:1); ½a 2D5
ꢃ
ꢀ26.2 (c 1.0, CHCl3); 1H and 13C NMR spectral
data matched that reported;20 ESI-MS: m/z 377.7 [M+Na]+; HRMS
(MALDI): m/z Calcd for
C
21H25O4 [M+H]+: 355.1545. Found:
355.1546; Anal. Calcd for C21H22O5: C, 71.17; H, 6.26; O, 22.57.
Found: C, 71.01; H, 6.10.
1.10. Benzyl 3,4-di-O-benzyl-D-glucal (16)
Starting from 3,4-di-O-benzyl-
D
-glucal (13, 3.3 g, 10 mmol) and
following the general procedure described above, compound 16
(2.71 g, 88%) was obtained as white solid: mp 50–52 °C, Rf 0.40
duced pressure to afford crude 6-O-(triisopropylsilyl)-D-glucal
(11). This compound was dissolved in dry DMF (180 mL) and trea-
ted slowly with NaH (7.0 g, 294 mmol; 60% dispersion in mineral
oil was washed with dry hexane and used immediately) at 0 °C.
After warming to room temperature within 1 h, the reaction mix-
ture was cooled again to 0 °C, treated dropwise with benzyl bro-
mide (44.0 g, 257 mmol), and stirring was continued over-night.
The reaction mixture was quenched and diluted with water
(500 mL) and extracted with Et2O (4 ꢂ 250 mL). The organic layer
was washed with satd. NH4Cl (2 ꢂ 250 mL), dried over Na2SO4,
and evaporated in vacuo to yield crude 3,4-di-O-benzyl-6-O-
(hexanes/EtOAc = 5:1); ½a D25
ꢃ
ꢀ36.1 (c 1.0, CHCl3); 1H NMR (CDCl3):
d 7.3–7.1 (m, 15H, Ar-H), 6.56 (d, 1H, J1,2 6.3 Hz, H-1), 4.98 (d, 1H,
Jgem 12.3 Hz, PhCH2-O-C6), 4.94 (ddd, 1H, J2,3 5.7, J2,4 1.4 Hz, H-2),
4.79 (d, 1H, PhCH2-O-C6), 4.74 (dd, J4,5 4.2, J3,5 0.9 Hz, H-5), 4.61
(d, 1H, Jgem 12.1 Hz, PhCH2-O-C4), 4.55 (d, 1H, PhCH2-O-C4), 4.34
(d, 1H, Jgem 11.6 Hz, PhCH2-O-C3), 4.25 (d, 1H, PhCH2-O-C3), 4.13
(ddd, 1H, J3,4 2.9 Hz, H-4), 3.77 (ddd, 1H, H-3); 13C NMR (CDCl3):
d 168.2 (s, 1C, C-6), 145.2 (d, 1C, C-1), 138.1 (s, 1C, Ar), 137.5 (s,
1C, Ar), 135.4 (s, 1C, Ar), 128.6 (d, 2C, Ar), 128.5 (d, 2C, Ar),
128.41 (d, 2C, Ar), 128.40 (d, 2C, Ar), 128.3 (d, 1C, Ar), 128.1 (d,
1C, Ar), 128.0 (d, 4C, Ar), 127.8 (d, 1C, Ar), 98.7 (d, 1C, C-2), 73.4
(d, 1C, C-4), 72.9 (d, 1C, C-5), 72.1 (t, 1C, PhCH2O-C4), 69.5 (t, 1C,
PhCH2O-C3), 67.8 (d, 1C, C-3), 67.1 (t, 1C, PhCH2O-C6); ESI-MS: m/z
453.8 [M+Na]+; HRMS (MALDI): m/z Calcd for C27H27O5 [M+H]+:
431.1858. Found: 431.1860; Anal. Calcd for C27H26O5: C, 75.33;
H, 6.09; O, 18.58. Found: C, 75.50; H, 6.20.
(triisopropyl)-D-glucal (12, Rf 0.18, hexanes/CH2Cl2 = 2:1). Column
chromatography (980 g SiO2, 200 mL/min, hexanes/CH2Cl2 = 9:1
to 2:1 gradient elution) may be performed at this stage to remove
excess of benzyl bromide and side-products (dibenzyl ether, ben-
zyl alcohol) of the benzylation step, but we did not observe signif-
icantly higher yields for the following de-silylation.
Tetrabutylammonium fluoride (TBAF, 100 mL, 100 mmol, 1 M in
THF) was dropwise added to a solution of crude 12 in dry THF
(150 mL) at 0 °C. After stirring for 4 h at room temperature, the
solution was diluted with Et2O (500 mL) and washed with water
(2 ꢂ 300 mL), which was re-extracted twice. The combined organic
layer was dried over Na2SO4 and concentrated under reduced pres-
sure. The resulting residue was purified by column chromatogra-
phy (980 g SiO2, 200 mL/min, hexanes/EtOAc = 5:1 to 3:1 gradient
elution) to afford the desired product 13 (15.1 g, 63% over 4 steps)
Acknowledgement
The Theodor Körner fund (Vienna, Austria) is gratefully
acknowledged for financial support.
Supplementary data
as colorless syrup: Rf 0.36 (hexanes/EtOAc = 3:1); ½a D25
ꢀ99.8 (c 1.0,
ꢃ
Supplementary data associated with this article can be found, in
CHCl3), lit.38 ꢀ102.0 (c 1, CHCl3); 1H and 13C NMR spectral data
matched that reported;35,38 ESI-MS: m/z 349.3 [M+Na]+; HRMS
(MALDI): m/z Calcd for
C
20H23O4 [M+H]+: 327.1596. Found:
References
327.1603; Anal. Calcd for C20H22O4: C, 73.60; H, 6.79; O, 19.61.
Found: C, 73.51; H, 6.81.
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1.8. General procedure for oxidation of glycals and subsequent
esterification of D-glucuronals
To a solution of 6-OH-glycal (10 mmol) in CH2Cl2 (30 mL) and
water (15 mL), TEMPO (0.31 g, 2 mmol) and BAIB (8.1 g, 25 mmol)