10.1002/cmdc.202000417
ChemMedChem
FULL PAPER
A basic) and stored over activated molecular sieves (3Å, 4Å). Pyridine
was distilled over KOH under argon atmosphere and stored over KOH
pellets. Dry DMF was purchased from Acros Organics. Molecular sieves
(3Å, 4Å) were activated under vacuum at 500 °C for 0.5 h immediately
before use.
Methyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-
glycero-α-D-galacto-2-nonulopyranosylonate)-(2→3)-2,4-di-O-
benzoyl-β-D-galactopyranoside (7). To a solution of 6 (485 mg, 0.44
mmol) in pyridine (10 mL) in a Teflon container was added HF·pyr (3.0
mL) dropwise and the reaction mixture was stirred at rt for 2.5 h. The
reaction was neutralized with satd aq. NaHCO3 and the aqueous phase
was extracted with DCM. The crude product was purified by flash
chromatography (DCM/MeOH, 1:0 to 19:1) to afford 7 (360 mg, 93%) as
a white solid. [α]D20 = +58.2 (c = 0.8, MeOH); 1H NMR (500 MHz, CDCl3):
δ = 8.24-8.15 (m, 2H, Ar-H), 8.14-8.04 (m, 2H, Ar-H), 7.63-7.56 (m, 2H,
Ar-H), 7.50-7.47 (m, 4H, Ar-H), 5.65 (m, 1H, H-8’), 5.47 (dd, J = 8.0. 10.1
Hz, 1H, H-2), 5.21 (dd, J = 2.6, 9.6 Hz, 1H, H-7’), 5.13 (d, J = 3.3 Hz, 1H,
H-4), 4.90 (d, J = 10.1 Hz, 1H, NH), 4.82-4.66 (m, 3H, H-1, H-3, H-4’),
4.33 (dd, J = 2.4, 12.4 Hz, 1H, H-9’a), 3.98 (dd, J = 5.8, 12.4 Hz, 1H, H-
9’b), 3.88 (m, 1H, H-5), 3.84 (m, 1H, H-5’), 3.80 (s, 3H, COOMe), 3.76-
3.70 (m, 2H, H-6a, H-6’), 3.53 (s, 3H, OMe), 3.52 (m, 1H, H-6b), 2.77 (dd,
J = 6.5, 8.4 Hz, 1H, OH-6), 2.45 (dd, J = 4.5, 12.7, 1H, H-3’e), 2.24, 2.09,
1.91, 1.79 (4 s, 12H, 4 OAc), 1.72 (t, 1H, J = 12.5 Hz, H-3’a), 1.51 ppm (s,
3H, NHAc); 13C NMR (126 MHz, CDCl3): δ = 170.72, 170.70, 170.6,
170.2, 170.0, 168.3, 167.7, 165.4 (8 C=O), 133.7, 133.0, 130.21, 130.18,
130.1, 128.8, 128.6, 128.4 (12C, Ar-C), 102.4 (C-1), 96.8 (C-2’), 73.2 (C-
5’), 72.0 (C-6’), 71.4 (C-3), 71.0 (C-2), 69.1 (2C, C-4, C-4’), 69.1 (C-8’),
67.5 (C-7’), 62.4 (C-9’), 60.3 (C-6), 57.2 (OMe), 53.2 (COOMe), 48.8 (C-
5’), 37.5 (C-3’), 23.1 (NHAc), 21.5, 20.8, 20.7, 20.3 ppm (4 OAc); MS
(ESI): m/z calcd for C41H49NO20: 898.3 [M+Na]+; found: 898.5.
Methyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-
glycero-α-D-galacto-2-nonulopyranosylonate)-(2→3)-6-O-tert-
butyldiphenylsilyl-β-D-galactopyranoside (5). To a suspension of 3[42]
(3.65 g, 6.10 mmol), 4[41] (1.20 g, 2.77 mmol) and 3Å molecular sieves in
MeCN/DCM (5:3, 70 mL) at -40 °C, was added N-iodosuccinimide (2.74
g, 12.1 mmol), followed by dropwise addition of TfOH (98 µL, 1.1 mmol).
The reaction mixture was stirred at -40 °C for 16 h under argon and then
was neutralized with NEt3. The suspension was warmed up to rt, filtered
over celite and the solvents were evaporated. The residue was dissolved
in DCM (60 mL), washed with 1 M Na2S2O3 (30 mL) and H2O (3 × 30 mL),
dried over Na2SO4, filtered and evaporated. The crude product was
purified by flash column chromatography (toluene/acetone, 1:0 to 1:1) to
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afford 5 (853 mg, 34%). [α]D = –11.8 (c = 1.0, CHCl3); 1H NMR (500
MHz, CDCl3): δ = 7.79-7.75 (m, 4H, Ar-H), 7.53-7.44 (m, 6H, Ar-H), 5.45
(ddd, J = 2.7, 4.9, 9.3 Hz, 1H, H-8’), 5.43 (dd, J = 2.0, 9.2 Hz, 1H, H-7’),
5.30 (d, J = 9.8 Hz, 1H, NH), 5.04 (ddd, J = 4.6, 10.2, 12.2 Hz, 1H, H-4’),
4.44 (d, J = 7.7 Hz, 1H, H-1), 4.36 (dd, J = 2.8, 12.6 Hz, 1H, H-9’a), 4.22-
4.16 (m, 3H, H-3, H-6’, H-9’b), 4.08 (q, J = 10.2 Hz, 1H, H-5’), 4.03 (dd, J
= 7.1, 10.1 Hz, 1H, H-6a), 3.91 (dd, J = 5.0, 10.2 Hz, 1H, H-6b), 3.88 (d,
J = 3.6 Hz, 1H, H-4), 3.85 (s, 3H, COOMe), 3.78 (ddd, J = 1.1, 7.7, 9.2
Hz, 1H, H-2), 3.68 (m, 1H, H-5), 3.63 (s, 3H, OMe), 2.89 (s, 1H, OH-4),
2.86 (dd, J = 4.6, 12.9 Hz, 1H, H-3’e), 2.59 (d, J = 4.0 Hz, 1H, OH-2),
2.24, 2.20, 2.13 (3 s, 9H, 3 OAc), 2.13 (m, 1H, H-3’a), 2.12 (s, 3H, OAc),
1.98 (s, 3H, NHAc), 1.13 ppm (s, 9H, C(CH3)3); 13C NMR (126 MHz,
CDCl3): δ = 171.0, 170.7, 170.4, 170.2, 168.4 (6C, 6 C=O), 135.73,
135.67, 133.2, 133.1, 129.99, 129.95, 127.92, 127.88 (12C, Ar-C), 104.0
(C-1), 97.4 (C-2’), 77.4 (C-3), 73.7 (C-5), 72.7 (C-6’), 69.5 (C-2), 68.6 (C-
4’), 68.0 (C-8’), 67.9 (C-4), 66.9 (C-7’), 62.6 (C-6), 62.4 (C-9’), 56.8
(OMe), 53.2 (COOMe), 49.8 (C-5’), 38.2 (C-3’), 26.9 (3C, C(CH3)3), 23.3
(NHAc), 21.4, 21.0, 20.91, 20.90 (4 OAc), 19.4 ppm (C(CH3)3); MS (ESI):
m/z calcd for C43H59NO18Si: 928.4 [M+Na]+; found: 928.4.
Methyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-
glycero-α-D-galacto-2-nonulopyranosylonate)-(2→3)-2,4-di-O-
benzoyl-6-O-sulfonato-β-D-galactopyranoside (8). To a solution of 7
(280 mg, 0.32 mmol) in dry DMF (7 mL) was added SO3·pyr (508 mg,
3.20 mmol) at 0 °C under argon atmosphere. The reaction mixture was
warmed up to rt and stirred for 2.5 h. Then, powdered NaHCO3 was
added and the suspension was stirred for 2 h. The suspension was
filtered over celite, and the solvent removed by co-evaporation with
xylenes. The crude product was purified by flash column chromatography
(DCM/MeOH, 1:0 to 8:2) to afford 8 (290 mg, 93%) as a white solid.
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[α]D = +48.2 (c = 1.1, MeOH); 1H NMR (500 MHz, CD3OD): δ = 8.21-
8.15 (m, 2H, Ar-H), 8.14-8.05 (m, 2H, Ar-H), 7.65 (m, 2H, Ar-H), 7.57-
7.51 (m, 4H, Ar-H), 5.66 (ddd, J = 2.5, 5.9, 9.7 Hz, 1H, H-8’), 5.40 (m, 1H,
H-4), 5.32 (dd, J = 7.9, 10.1 Hz, 1H, H-2), 5.19 (dd, 1H, J = 2.7, 9.7 Hz,
H-7’), 4.93 (dd, J = 3.3, 10.1 Hz, 1H, H-3), 4.85-4.79 (m, 2H, H-1, H-4’),
4.34 (dd, J = 2.5, 12.4 Hz, 1H, H-9’a), 4.21 (m, 1H, H-5), 4.06-4.05 (m,
2H, H-6), 3.95 (s, 3H, COOMe), 3.94 (m, 1H, H-9’b), 3.74 (dd, J = 2.6,
10.7 Hz, 1H, H-6’), 3.67 (m, 1H, H-5’), 3.55 (s, 3H, OMe), 2.42 (dd, J =
4.7, 12.5 Hz, 1H, H-3’e), 2.24, 2.05, 1.88, 1.73 (4 s, 12H, 4 OAc), 1.48 (m,
1H, H-3’a), 1.45 ppm (s, 3H, NHAc); 13C NMR (126 MHz, CD3OD): δ =
172.42, 173.38, 171.7, 171.4, 169.4, 167.2, 167.0 (8C, 8 C=O), 131.5,
131.2, 130.9, 129.8, 129.7, 124.6 (12C, Ar-C), 103.4 (C-1), 98.3 (C-2’),
73.1 (C-5), 72.8 (2C, C-6’, C-3), 72.7 (C-2), 71.0 (C-4’), 70.5 (C-4), 68.8
(C-8’), 68.7 (C-7’), 67.3 (C-6), 63.6 (C-9’), 57.5 (OMe), 53.9 (COOMe),
49.3 (C-5’), 38.4 (C-3’), 22.7 (NHAc), 21.7, 20.7, 20.6 ppm (4C, 4 OAc);
MS (ESI): m/z calcd for C41H48NNaO23S: 1000.2 [M+Na]+; found: 1000.3.
Methyl (methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-
glycero-α-D-galacto-2-nonulopyranosylonate)-(2→3)-2,4-di-O-
benzoyl-6-O-tert-butyldiphenylsilyl-β-D-galactopyranoside (6). To a
solution of 5 (974 mg, 1.08 mmol) in pyridine (30 mL) was added DMAP
(47 mg, 0.38 mmol) followed by portion-wise addition of Bz2O (3.18 g,
14.0 mmol) at 0 °C. The mixture was warmed up to rt and stirred for 16 h.
Then, the solvent was removed by co-evaporation with toluene. The
residue was dissolved in EtOAc (30 mL), washed with H2O (3 × 10 mL),
satd aq. CuSO4 (3 × 10 mL), H2O (10 mL) and brine (10 mL), dried over
Na2SO4, filtered and evaporated. The crude product was purified by flash
column chromatography (petroleum ether/acetone, 1:0 to 1:1) to afford 6
(1.10 g, 92%) as a brown vitreous solid. [α]D20 = +61.7 (c = 1.00, CHCl3);
1H NMR (500 MHz, CDCl3): δ = 8.23-8.14 (m, 2H, Ar-H), 8.13-8.02 (m,
2H, Ar-H), 7.70-7.62 (m, 6H, Ar-H), 7.62-7.52 (m, 2H, Ar-H), 7.52-7.34 (m,
4H, Ar-H), 7.29-7.24 (m, 3H, Ar-H), 7.12 (t, J = 7.6 Hz, 1H, Ar-H), 5.66
(ddd, J = 2.4, 5.4, 9.5 Hz, 1H, H-8’), 5.62 (d, J = 3.2 Hz, 1H, H-4), 5.36
(dd, J = 7.9, 10.1 Hz, 1H, H-2), 5.25 (dd, J = 2.8, 9.7 Hz, 1H, H-7), 5.00
(d, J = 10.2 Hz, 1H, NH), 4.96-4.86 (m, 2H, H-3, H-4'), 4.73 (d, J = 7.9 Hz,
1H, H-1), 4.36 (dd, J = 2.3, 12.5 Hz, 1H, H-9’a), 3.97 (s, 3H, COOMe),
4.02-3.93 (m, 2H, H-5, H-9’b), 3.81 (q, J = 10.4 Hz, 1H, H-5’), 3.74-3.64
(m, 2H, H-6), 3.58 (dd, J = 2.8, 10.7 Hz, 1H, H-6’), 3.47 (s, 3H, OMe),
2.51 (dd, J = 4.7, 12.6 Hz, 1H, H-3’e), 2.24, 2.10, 1.93, 1.79 (4 s, 12H, 4
OAc), 1.67 (t, J = 12.4 Hz, 1H, H-3’a), 1.46 (s, 3H, NHAc), 1.03 ppm (s,
9H, C(CH3)3); 13C NMR (126 MHz, CDCl3): δ = 170.8, 170.7, 170.6,
170.2, 170.1, 168.1, 165.5, 165.4 (8 C=O), 135.6, 135.4, 132.91, 132.89,
130.4, 130.2, 130.0, 129.9, 129.7, 129.6, 128.3, 127.7, 127.5 (24C, Ar-C),
102.4 (C-1), 96.9 (C-2’), 73.2 (C-5), 71.9 (C-3), 71.6 (C-6’), 71.4 (C-2),
69.6 (C-4’), 67.9 (C-4), 67.5 (C-8’), 66.4 (C-7’), 62.3 (C-9’), 60.9 (C-6),
57.1 (OMe), 53.2 (COOMe), 48.9 (C-5’), 37.3 (C-3’), 26.6 (3C, C(CH3)3),
23.1 (NHAc), 21.5, 20.8, 20.7, 20.3 (4 OAc), 19.0 ppm (C(CH3)3); MS
(ESI): m/z calcd for C57H67NO20Si: 1136.4 [M+Na]+; found: 1136.4.
Methyl (sodium 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-
nonulopyranosylonate)-(2→3)-6-O-sulfonato-β-D-galactopyranoside
(2). To a solution of 8 (70 mg, 0.07 mmol) in dry MeOH (2 mL) was
added a freshly prepared solution of MeONa in MeOH (1.5 M, to pH 10).
The reaction mixture was stirred for 5 h at 50 °C and then neutralized
with Dowex50X8 (H+ form) to pH 5. The suspension was filtered,
concentrated and the crude product dissolved in 0.1 M NaOH. The
reaction mixture was stirred for 1 h, then neutralized and concentrated.
The crude product was purified by reversed-phase column
chromatography
(RP-18,
H2O)
and
size-exclusion
column
chromatography (P-2 gel, H2O) to afford 2 (40 mg, 84%) as a white solid.
[α]D20 = +5.8 (c = 0.7, H2O); 1H NMR (500 MHz, D2O): δ = 4.44 (d, J = 8.0
Hz, 1H, H-1), 4.22-4.20 (m, 2H, H-6), 4.13 (dd, J = 3.2, 9.8 Hz, 1H, H-3),
4.02 (m, 1H, H-4), 3.95 (m, 1H, H-5), 3.91-3.85 (m, 3H, H-5’, H-8’, H-9’a),
3.74-3.64 (m, 3H, H-4’, H-6’, H-9’b), 3.62 (dd, J = 1.8, 8.9 Hz, 1H, H-7’),
3.60 (s, 3H, OMe), 3.57 (dd, J = 8.0, 9.8 Hz, 1H, H-2), 2.78 (dd, J = 4.6,
8
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