Page 11 of 15
The Journal of Organic Chemistry
71.6 (C3), 71.5 (C4), 65.4 (C6). HRMS ESI+ Q-TOF (m/z): [M+Na]+
calcd for C15H13Cl9O10: 690.7603; found, 690.7638.
M HCl solution and extracted 3 times with 50 mL of ethyl acetate.
The combined organic extracts were washed again with 1 M HCl, a
saturated solution of NaHCO3, brine, dried over sodium sulfate, and
evaporated to yield the crude product. The crude product was purified
by silica column chromatography (3:1 hexanes:ethyl acetate) and
fractions were concentrated and evaporated to yield the title com-
1
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3
4
5
6
7
8
3,4,6-tri-O-methoxymethyl-D-glucal (8)
3,4,6-tri-O-methoxymethyl-D-glucal was prepared as previously
described. D-glucal (400 mg, 2.74 mmol) was dissolved to between
0.2 and 0.3 M in DMF (~10 mL), and cooled to 0 oC followed by the
addition of 3.6 eq of NaH (95% dry, 200 mg, 8.21 mmol). The reac-
tion was allowed to warm to room temperature over 30 minutes fol-
D
pound as a clear oil. (yield 467 mg, 73%). [α]25 = -3 (0.2, CH3OH).
1H NMR (500 MHz, CDCl3) δ 6.46 (d, J = 6.1 Hz, 1H, H1), 5.33-5.26
(m, 2H, H3 + H4), 4.78 (ddd, J = 6.2, 2.4, 1.2 Hz, 1H, H2), 4.12 (qt, J
= 5.1, 2.6 Hz, 1H, H5), 3.89 (d, J = 4.8 Hz, 2H), 2.05 (s, 3H, COCH3),
2.03 (s, 3H, COCH3), 1.05 (m, 21H, Si(i-Pr)3). 13C{1H} NMR (126
MHz, CDCl3) δ 170.5 (COCH3), 169.4 (COCH3), 146.0 (C1), 98.1
(C2), 76.8 (C5), 67.6 (C3), 67.3 (C4), 61.4 (C6), 21.1 (COCH3), 20.9
(COCH3), 17.9 (SiCH(CH3)2), 11.9 (SiCH(CH3)2). HRMS ESI+ Q-
TOF (m/z): [M+Na]+ calcd for C19H34O6Si: 409.2022; found
409.2024.
o
lowed by cooling to 0 C. 3.3 eq of MOM-Cl (700 µL, 9.04 mmol)
was added dropwise and the reaction was allowed to warm to room
temperature overnight. The reaction was quenched with methanol,
poured into 200 mL of a 0.1 M HCl solution, and extracted 3 times
with 50 mL of ether. The combined organic extracts were washed
with brine, dried over sodium sulfate, and evaporated to yield the
crude product. The crude product was purified by silica column
chromatography (3:1 hexanes:ethyl acetate) and fractions were con-
centrated and evaporated to yield the title compound as a clear oil.
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25
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32
33
34
35
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3,4-di-O-(p-methoxybenzyl)-6-O-triisopropylsilyl-D-
glucal (11)
D
1
(yield 591 mg, 77%). [α]25 = +19 (0.50, CH3OH). H NMR (500
MHz, CDCl3) δ 6.40 (dd, J = 6.3, 1.2 Hz, 1H, H1), 4.89-4.84 (m, 1H,
H2, OCH2O), 4.84-4.78 (m, 1H, OCH2O), 4.76-4.72 (m, 1H,
OCH2O), 4.71-4.64 (m, 3H, OCH2O), 4.17 (dddd, J = 9.3, 5.9, 3.1,
1.9 Hz, 1H, H5), 4.11 (ddt, J = 4.8, 2.3, 1.3 Hz, 1H, H3), 3.88-3.82
(m, 1H, H4), 3.82-3.77 (m, 2H, H6), 3.41-3.35 (m, 9H, OCH3).
13C{1H}NMR (126 MHz, CDCl3) δ 144.2 (C1), 100.0 (C2), 96.7-95.4
(OCH2O), 76.2 (C5), 73.0 (C4), 71.7 (C3), 65.9 (C6), 56.0-55.5
(OCH3). HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd for C12H22O7:
301.1263; found, 301.1257.
3,4-di-O-(p-methoxybenzyl)-6-O-triisopropylsilyl-D-glucal
was
prepared as previously described. 6-O-triisopropylsilyl-D-glucal (400
o
mg, 1.32 mmol) was dissolved in 10 mL of DMF and cooled to 0 C
followed by the addition of 2.4 eq of NaH (95% dry, 76 mg, 3.17
mmol). The reaction was allowed to warm to room temperature over
o
30 minutes followed by cooling to 0 C. 2.2 eq of PMB-Cl (400 µL,
2.90 mmol) was added dropwise and the reaction was allowed to
warm to room temperature overnight. The reaction was quenched
with methanol, poured into 200 mL of a 0.1 M HCl solution, and
extracted 3 times with 50 mL of ether. The combined organic extracts
were washed with brine, dried over sodium sulfate, and evaporated to
yield the crude product. The crude product was purified by silica
column chromatography (5:1 hexanes:ethyl acetate) and fractions
were concentrated and evaporated to yield the title compound as a
clear to pale oil. (yield 572 mg, 79%). [α]25D = -0.8 (0.3, CH3OH). 1H
NMR (500 MHz, CDCl3) δ 7.28 (ddd, J = 9.5, 4.5, 2.6 Hz, 4H, ArH),
6.92 – 6.84 (m, 4H, ArH), 6.39 (dd, J = 6.1, 1.4 Hz, 1H, H1), 4.82
(dd, J = 6.2, 2.7 Hz, 1H, H2), 4.75 (bq, 2H, ArCH2), 4.56 (q, 2H,
ArCH2), 4.18 (ddt, J = 4.3, 2.6, 1.5 Hz, 1H, H3), 4.05 – 3.97 (m, 2H,
H6), 3.90 (m, 2H, H4 + H5), 3.81 (s, 6H, ArOCH3), 1.22 – 1.01 (m,
Benzyl 3,4-di-O-benzyl-D-glucuronal (9)
Benzyl 3,4-di-O-benzyl-D-glucuronal was synthesized as previous-
ly described. 3,4-di-O-benzyl-D-glucal (400 mg, 1.22 mmol) and 1.1
eq of diacetoxyiodobenzene (434 mg, 1.35 mmol) were dissolved in 5
mL of DCM and 5 mL of H2O. The reaction mixture was cooled to 0
oC followed by the addition of 0.2 eq of TEMPO (38.1 mg, 0.24
mmol) and vigorous stirring with monitoring by TLC (permanganate,
UV, and bromocresol green). After 4 h, the starting material was
found to be consumed and a new spot with a double bond, UV ab-
sorbance, pH < 7, and lower Rf (0.1 in 2:1 hexanes:ethyl acetate)
appeared. The reaction was poured into 200 mL of 0.1 M HCl and
extracted 4 times with 50 mL of ethyl acetate. The combined organic
extracts were dried over magnesium sulfate, followed by sodium
sulfate, and the solvent was evaporated. The crude residue was then
dissolved in 20 mL of DMF, followed by the addition of KHCO3 (3 g,
30 mmol). After stirring at room temperature for 1 h, the solution was
21H, Si(i-Pr)3). 13C{1H} NMR (126 MHz, CDCl3)
δ 159.3
(ArCOCH3), 159.2 (ArCOCH3), 144.7 (C1), 130.7-129.4 (Ar), 113.8-
113.8 (Ar), 99.7 (C2), 78.2 (C5), 75.5 (C3), 73.7 (C4), 73.5 (ArCH2),
70.4 (ArCH2), 62.0 (ArCH2), 55.3 (OCH3), 18.0 (SiCH2CH3), 12.1-
12.0 (SiCH2CH3). HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd for
C31H46O6Si: 565.2961; found 565.2970.
o
cooled to 0 C and benzyl bromide was added to the solution drop-
3,4-di-O-benzyl-6-O-acetyl-D-glucal (13)
wise (3.42 mL, 28.8 mmol). The reaction was allowed to warm to
room temperature overnight and was poured into 250 mL of a 0.1 M
HCl solution followed by extraction 4 times with 50 mL of ether. The
combined organic extracts were further washed with a saturated Na-
HCO3 solution, brine, and dried over sodium sulfate. The crude prod-
uct was purified by silica column chromatography (gradient 10:1 to
6:1 hexanes:ethyl acetate) and fractions were concentrated and evapo-
rated to yield the title compound as a clear oil. (Yield 165 mg, 32%
over 2 steps). 1H NMR (500 MHz, CDCl3) δ 7.40-7.17 (m, 15H,
ArH), 6.66 (d, J = 6.3 Hz, 1H, H1), 5.06 (d, J = 12.3 Hz, 1H, ArCH2),
5.03 (ddd, J = 6.5, 5.0, 1.5 Hz, 1H, H2), 4.88 (d, J = 12.3 Hz, 1H,
ArCH2), 4.83 (dd, J = 3.1, 1.3 Hz, 1H, H5), 4.72-4.62 (m, 2H,
ArCH2), 4.43 (d, J = 11.6 Hz, 1H, ArCH2), 4.34 (d, J = 11.6, 1H,
ArCH2), 4.22 (td, J = 2.9, 1.5 Hz, 1H, H4), 3.86 (ddd, J = 4.6, 2.7, 1.2
Hz, 1H, H3). 13C{1H} NMR (126 MHz, CDCl3) δ 168.1 (COOBn),
145.1 (C1), 128.7-127.7 (Ar), 98.6 (C2), 73.3 (C4), 72.8 (C5), 72.0
3,4-di-O-benzyl-6-O-acetyl-D-glucal was prepared as previously
described. 3,4-di-O-benzyl- D-glucal (400 mg, 1.22 mmol) was dis-
o
solved in 8 mL of pyridine and cooled to 0 C. 2 mL of acetic anhy-
dride (21.1 mmol, 17 eq) was added dropwise and the reaction was
allowed to warm to room temperature over 3 h while monitoring by
TLC. Upon completion, the reaction was poured into 200 mL of a 1
M HCl solution and extracted 3 times with 50 mL of ethyl acetate.
The combined organic extracts were washed again with 1 M HCl, a
saturated solution of NaHCO3, brine, dried over sodium sulfate, and
evaporated to yield the crude product. The crude product was purified
by silica column chromatography (4:1 hexanes:ethyl acetate) and
fractions were concentrated and evaporated to yield the title com-
D
pound as a clear oil. (yield 380 mg, 84%). [α]25 = +3 (0.1, CH3OH).
1H NMR (500 MHz, CDCl3) δ 7.45 – 7.27 (m, 10H, ArH), 6.44 (dd, J
= 6.2, 1.3 Hz, 1H, H1), 4.96 (dd, J = 6.2, 2.7 Hz, 1H, H2), 4.90 (d, J =
11.4 Hz, 1H, ArCH2), 4.75 – 4.67 (m, 2H, ArCH2), 4.60 (d, J = 11.6
Hz, 1H, ArCH2), 4.43 (qd, J = 12.1, 4.1 Hz, 2H, H6), 4.27 (ddd, J =
6.0, 2.7, 1.3 Hz, 1H, H3), 4.14 (ddd, J = 8.3, 5.3, 2.7 Hz, 1H, H5),
3.83 (dd, J = 8.6, 6.0 Hz, 1H, H4), 2.08 (s, 3H, COCH3). 13C{1H}
NMR (126 MHz, CDCl3) δ 170.7 (COCH3), 144.4 (C1), 138.2-137.9
(Ar), 128.7,-127.8 (Ar), 100.1 (C2), 75.5 (C3), 75.1 (C5), 73.9 (C4),
73.9-70.5 (ArCH2), 62.8 (C6), 20.9 (COCH3). HRMS ESI+ Q-TOF
(m/z): [M+Na]+ calcd for C22H24O5: 391.1521; found 391.1508.
1
(ArCH2), 69.4 (ArCH2), 67.7 (C3), 67.0 (ArCH2). H and 13C spec-
troscopy data matched those previously reported79.
3,4-di-O-acetyl-6-O-triisopropylsilyl-D-glucal (10)
6-O-triisopropylsilyl-D-glucal (400 mg, 1.32 mmol) was dissolved
o
in 10 mL of pyridine and cooled to 0 C. 5 eq of acetic anhydride
(1.25 mL, 13.2 mmol) was added dropwise and the reaction was al-
lowed to warm to room temperature over 3 h while monitoring by
TLC. Upon completion, the reaction was poured into 200 mL of a 1
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