A R T I C L E S
Demchenko et al.
5 (100 mg, 0.117 mmol) in n-butanol (10 mL), ethylenediamine (2
mL, 30 mmol) was added and stirred for 20 h at 90 °C. The reaction
mixture was concentrated in vacuo to dryness and coevaporated with
toluene (2 times, 10 mL). The residue was purified by silica gel column
chromatography (2% gradient methanol in DCM) to afford phenyl 6-O-
(2-amino-4,6-O-benzylidene-2-deoxy-â-D-glucopyranosyl)-2-azido-4-
O-benzyl-2-deoxy-1-thio-R-D-glucopyranoside as a colorless syrup (67.4
mg, 91%): Rf ) 0.55 (methanol/DCM, 1/9, v/v). Dicyclohexylcarbo-
diimide (DCC) (87 mg, 0.42 mmol) was added to a solution of 6 (190.5
mg, 0.281 mmol) in DCM (5 mL) and stirred for 10 min, followed by
the addition of the previously mentioned amino derivative (178.7 mg,
0.281 mmol) in DCM (3 mL). The reaction mixture was stirred for 16
h at room temperature, the solids were filtered off, and the residue
was washed with DCM (2 times, 10 mL). The combined filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (4% gradient diethyl ether in DCM) to afford 7 as a
white solid (340 mg, 93%): Rf ) 0.35 (diethyl ether/DCM, 3/17, v/v).
1H NMR (300 MHz, CDCl3): δ ) 7.26-7.52 (m, 15H, aromatic), 5.75
(d, 1H, JNH,2′ ) 6.3 Hz, NH), 5.55 (d, 1H, J1,2 ) 5.3 Hz, H-1), 5.50 (s,
1H, >CHPh), 4.96 (m, 1H, H-3L), 4.76 (dd, 2H, J2 ) 11.2 Hz, CH2-
Ph), 4.66 (d, 1H, J1′,2′ ) 8.3 Hz, H-1′), 4.34-4.38 (m, 1H, H-5), 4.28
(dd, 1H, J5′,6′a ) 4.9 Hz, J6′a,6′b ) 10.3 Hz, H-6′a), 3.92-4.11 (m, 3H,
H-3,3′,6a), 3.70-3.82 (m, 3H, H-2,6b,6b′), 3.39-3.53 (m, 4H,
solution of 7 (755 mg, 0.583 mmol) and 1,3-propanedithiol (1.2 mL,
11.65 mmol) in pyridine (41 mL) and H2O (5.8 mL). The reaction
mixture was stirred for 16 h at room temperature and then evaporated
in vacuo to dryness and coevaporated with toluene (2 times, 10 mL)
and ethanol (2 times, 10 mL). The residue was purified by silica gel
column chromatography (2% gradient methanol in DCM) to afford
phenyl 2-amino-4-O-benzyl-6-O-{4,6-O-benzylidene-2-deoxy-2-[(R)-
3-octacosanoyloxy-hexadecan]amido-â-D-glucopyranosyl}-2-deoxy-1-
thio-R-D-glucopyranoside as a colorless syrup (693 mg, 94%): Rf )
1
0.45 (methanol/DCM, 1/9, v/v). H NMR (300 MHz, CDCl3): δ )
7.22-7.58 (m, 15H, aromatic), 5.80 (d, 1H, JNH,2 ) 5.8 Hz, NH), 5.52
(s, 1H, >CHPh), 5.47 (d, 1H, J1,2 ) 5.4 Hz, H-1), 5.02 (m, 1H, H-3L),
4.82 (dd, 2H, J2 ) 11.2 Hz, CH2Ph), 4.73 (d, 1H, J1′,2′ ) 8.3 Hz, H-1′),
4.34-4.40 (m, 1H, H-5), 4.32 (dd, 1H, J5′,6′a ) 4.9 Hz, J6′a,6′b ) 10.2
Hz, H-6′a), 4.15 (dd, 1H, J5,6a ) 2.0 Hz, J6a,6b ) 11.2 Hz, H-6a), 4.11
(dd, 1H, J3′,4′ ) 9.3 Hz, H-3′), 3.84 (dd, 1H, J5,6b ) 5.0 Hz, H-6b),
3.75 (dd, 1H, J5′,6′b ) 10.2 Hz, H-6′b), 3.40-3.62 (m, 5H, H-2′,3,4,4,5′),
3.04 (dd, 1H, J2,3 ) 10.3 Hz, H-2), 2.27 (dd, 1H, J2L′,3L′ ) 7.8 H, H-2L′),
a
a
b
a
2.22 (dd, 1H, J2L ,3L ) 7.8 Hz, J2L ,2L ) 14.7 Hz, H-2L ), 2.11 (dd, 1H,
b
b
J2L ,3L ) 4.4 Hz, H-2L ), 1.00-1.75 [m, 74H, H-(4L-15L), (3L′-27L′)],
0.83 (m, 6H, Hz-16L,28L′). 13C NMR (75 MHz, CDCl3): δ ) 125.00-
132.00 (aromatic), 101.71 (>CHPh), 100.96 (C-1′), 91.88 (C-1), 80.96
(C-4′)*, 77.50 (C-4)*, 74.31 (C-3), 73.81 (CH2Ph), 71.03 (C-5,3L), 70.49
(C-3′), 68.28 (C-6), 69.19 (C-6′), 66.11 (C-5′), 56.56 (C-2), 49.02 (C-
2′), 42.11 (C-2L), 34.20 (C-2L′), 25.12-26.00, 29.64 [C-(4L-15L), (3L′-
27L′)], 23.16 (CL-16L,28L′). DCC (43 mg, 0.21 mmol) and DMAP (4.3
mg, 0.035 mmol) were added to a stirred solution of 8 (51 mg, 0.14
mmol) in DCM (3 mL) and stirred for 10 min, followed by addition of
the previously mentioned amino derivative (45 mg, 0.035 mmol) in
DCM (1.5 mL). The reaction mixture was stirred for 16 h at room
temperature, the solids were filtered off, and the residue was washed
with DCM (2 times, 10 mL). The combined filtrate was concentrated
in vacuo. The residue was purified by silica gel column chromatography
(3% gradient ethyl acetate in DCM) to afford 9 as a white solid (51.2
mg, 63%): Rf ) 0.40 (ethyl acetate/DCM, 1/9, v/v); [R]26D +14.9° (c
a
H-2′,4,4′,5′), 2.26 (dd, 2H, J2L′,3L′ ) 7.3 Hz, H-2L′), 2.23 (dd, 1H, J2L ,3L
a
b
a
b
) 3.3 Hz, J2L ,2L ) 14.5 Hz, H-2L ), 2.13 (dd, 1H, J2L ,3L ) 4.9 Hz,
b
H-2L ), 1.10-1.60 [m, 74H, H-(4L-15L), (3L′-27L′)], 0.83 (m, 6H,
H-16L,28L′). 13C NMR (75 MHz, CDCl3): δ ) 127.0-133.0 (aromatic),
102.6 (>CHPh), 101.5 (C-1′), 87.8 (C-1), 82.0 (C-4′), 79.1 (C-4), 75.4
(CH2Ph), 74.9 (C-3), 72.0 (C-3L), 71.1 (C-5,3′), 69.2 (C-6a), 68.8 (C-
6′), 67.1 (C-5′), 64.7 (C-2), 59.3 (C-2′), 42.8 (C-2L), 35.0 (C-2L′), 31.0
[C-(5L-15L), (4L′-27L′)], 25.2 (C-4L,3L′), 25.9 (C-16L, 28L′). HR MS
(m/z) for C76H120N4O11SNa: calcd, 1319.8572; found, 1319.8512. (NMR
data given graphically in the Supporting Information.)
Synthesis of (R)-3-Octacosanoyloxy-hexadecanoic Acid (8). Tri-
fluoromethanesulfonic acid (TfOH) (8.5 µL, 0.10 mmol) was added to
a stirred solution of 2-(4-bromophenyl)-2-oxoethyl (R)-3-hydroxyhexa-
decanoate (300 mg, 0.64 mmol) and benzyl trichloroacetimidate (178
µL, 0.96 mmol) in DCM (3.5 mL) at 0 °C. The reaction mixture was
stirred for 22 h and then diluted with DCM (35 mL) and washed with
saturated aqueous NaHCO3 (2 times, 20 mL) and water (2 times, 20
mL). The organic phase was dried (MgSO4) and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by silica gel
column chromatography (2% gradient ethyl acetate in toluene), followed
by crystallization from diethyl ether to afford 2-(4-bromophenyl)-2-
oxoethyl (R)-3-benzyloxyhexadecanoate as white crystals (315 mg,
88%): Rf ) 0.65 (ethyl acetate/toluene, 1/9, v/v). 1H NMR (300 MHz,
CDCl3): δ ) 7.20-7.80 (m, 9H, aromatic), 5.26 (ps, 2H, CH2), 4.56
(dd, 2H, J2 ) 11.4 Hz, CH2Ph), 3.94 (m, 1H, H-3), 2.79 (dd, 1H, J2a,3
) 7.1 Hz, J2a,2b ) 15.3 Hz, H-2a), 2.65 (dd, 1H, J2b,3 ) 5.5 Hz, H-2b),
1.55-1.72 (m, 1H, H-4), 1.35-1.45 (m, 2H, H-5,15), 1.30 [bs, 18H,
H-(6-14)], 0.88 (pt, 3H, H-16). The previously described synthesized
benzyloxy-hexadecanoate (295 mg, 0.523 mmol) was subjected to
treatment with Zn/AcOH, as described for the synthesis of 6, and
purification by silica gel column chromatography (5% gradient ethyl
acetate in toluene) to afford 8 as a colorless syrup (165 mg, 87%): Rf
1
1.4, CHCl3). H NMR (300 MHz, CDCl3): δ ) 7.00-7.41 (m, 30H,
aromatic), 6.46 (d, 1H, JNH,2 ) 8.3 Hz, 2-NH), 5.70 (d, 1H, J1,2 ) 5.3
Hz, H-1), 5.59 (d, 1H, JNH,2′ ) 8.3 Hz, 2′-NH), 5.37 (s, 1H, >CHPh),
5.37 (dd, 1H, J3′,4′ ) 9.3 Hz, H-3′), 5.24 (dd, 1H, J3,4 ) 8.8 Hz, H-3),
4.95 (m, 1H, H-3L), 4.80 (d, 1H, J1′,2′ ) 8.3 Hz, H-1′), 4.37-4.61 (m,
9H, H-2, 4 × CH2Ph), 4.33 (m, 1H, H-5), 4.29 (dd, 1H, J5,6′a ) 5.5
Hz, J6′a,6′b ) 11.0 Hz, H-6′a), 3.64-4.00 (m, 8H, H-2′,4,6a,6b,6′b, 3
× H-3S), 3.60 (dd, 1H, J4′,5′ ) 9.3 Hz, H-4′), 3.48 (m, 1H, H-5′), 1.90-
a
b
a
b
2.64 [m, 10H, H-2L ,2L ,2L′ ,2L′ , 3 × H-2Sa,2Sb], 1.05-1.63 (m, 146H,
H-(4L-15L), (3L′-27L′), 3 × H-(4S-15S)], 0.85 (m, 15H, H-16L,28L′,
3 × H-16S). 13C NMR (75 MHz, CDCl3): δ ) 125.0-131.5 (aromatic),
101.2 (>CHPh), 100.9 (C-1′), 87.0 (C-1), 78.0 (C-4′), 75.9 (C-4, 2 ×
C-3S), 75.2 (CS-3), 74.5 (CH2Ph), 73.0 (C-3), 71.2 (C-5), 70.9 (C-3′),
70.4-70.6 (3 × CH2Ph), 70.3 (C-3L), 68.2 (C-6′), 67.4 (C-6), 66.0
(C-5′), 55.5 (C-2′), 52.6 (C-2), 32.0-42.2 (C-2L,2L′, 3 × C-2S), 29.9
[C-(4L-15L), (3L′-27L′), 3 × H-(4S-15S)], 14.3 (C-16L,28L′, 3 × C-16S).
HR MS (m/z) for C145H230N2O17SNa: calcd, 2326.6847; found,
2326.7550. (NMR data given graphically in the Supporting Informa-
tion.)
Synthesis of 4-O-Benzyl-6-O-{4,6-O-benzylidene-3-O-[(R)-3-ben-
zyloxy-hexadecanoyl]-2-deoxy-2-[(R)-3-octacosanoyloxy-hexadecan]-
amido-â-D-glucopyranosyl}-2-[(R)-3-benzyloxy-hexadecan]amido-
3-O-[(R)-3-benzyloxy-hexadecanoyl]-2-deoxy-r-D-glucopyranose (10).
N-Iodosuccinimide (95 mg, 0.42 mmol) and TfOH (3.5 µL, 0.04 mmol)
were added to a stirred solution of 9 (312 mg, 0.135 mmol) in DCM/
H2O (10 mL, 100:1) at 0 °C. The reaction mixture was vigorously stirred
for 30 min at 0 °C until TLC analysis indicated that the reaction had
gone to completion. The reaction mixture was diluted with DCM (20
mL) and washed with aqueous Na2S2O3 (20%, 20 mL) and water (3
times, 20 mL). The organic phase was dried (MgSO4) and filtered, and
the filtrate was concentrated in vacuo. The residue was purified by
) 0.40 (ethyl acetate/toluene, 1/3, v/v); [R]26 -8.2° (c 1.0, CHCl3).
D
1H NMR (300 MHz, CDCl3): δ ) 7.30-7.40 (m, 5H, aromatic), 4.58
(ps, 2H, CH2Ph), 3.95 (m, 1H, H-3), 2.58 (m, 2H, H-2a, 2b), 1.30-
1.71 (m, 3H, H-4,5,15), 1.28 [bs, 18H, H-(6-14)] 0.85 (pt, 3H, H-16).
HR MS (m/z) for C23H38O3: calcd, 362.2821; found, 362.2842. (NMR
data given graphically in the Supporting Information.)
Synthesis of Phenyl 4-O-Benzyl-6-O-{4,6-O-benzylidene-3-O-[(R)-
3-benzyloxy-hexadecanoyl]-2-deoxy-2-[(R)-3-octacosanoyloxy-hexa-
decan]amido-â-D-glucopyranosyl}-2-[(R)-3-benzyloxy-hexadecan]-
amido-3-O-[(R)-3-benzyloxy-hexadecanoyl]-2-deoxy-1-thio-r-D-
glucopyranoside (9). Triethylamine (∼1.25 mL) was added to a stirred
9
6110 J. AM. CHEM. SOC. VOL. 125, NO. 20, 2003