The Journal of Organic Chemistry
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739, 697 cm−1. [α]D25 = +123.0° (c 1.0, CH2Cl2). HRESI-MS: m/z
calcd for C26H32NO5S [M + NH4]+, 470.1996; found, 470.2016.
Thiophenyl 2,3-Di-O-benzyl-4-deoxy-α-pent-4-enopyrano-
side (5). Diol 4 (200 mg, 0.442 mmol) was dissolved in 2:1
CH2Cl2/H2O at rt. TEMPO (13.8 mg, 0.088 mmol) and BAIB (427
mg, 1.326 mmol) were added sequentially, and the reaction was stirred
for 3 h, quenched with saturated aqueous Na2S2O3, extracted with
EtOAc (3 × 250 mL), and concentrated. The residue was purified by
silica gel chromatography using a 33−66% EtOAc in hexanes gradient
with 1% AcOH to afford 182 mg of the corresponding carboxylic acid.
The carboxylic acid (162 mg, 0.348 mmol) was dissolved in DMF
(4 mL) in a sealed microwave tube. DMFDNA (484 μL, 1.738 mmol)
was added, and the reaction mixture was heated under microwave
conditions at 225 °C for 2.5 min. The reaction was concentrated under
vacuum, and the residue was purified via silica gel chromatography to
10.5 Hz, 1H), 3.16 (ddd, J = 2.0, 4.4, 9.7 Hz, 1H), 1.76 (s, 3H), 1.26
(s, 9H). 13C NMR (100 MHz, C6D6): δ 169.2, 144.3, 142.8, 138.7,
138.5, 135.9, 135.7, 134.0, 133.5, 129.6, 129.6, 128.9, 128.2, 128.1,
127.8, 127.2, 126.9, 108.6, 101.3, 100.6, 99.4, 86.8, 76.0, 75.3, 75.1,
74.1, 73.4, 72.4, 70.2, 68.6, 64.4, 62.9, 62.5, 29.8, 26.6, 20.3, 19.3. IR:
3062, 2919, 2851, 2111, 1753, 1643, 1221, 1112, 1051, 700 cm−1.
[α]D25 = +29.5° (c 1.0, CH2Cl2). HRESI-MS: m/z calcd for
C64H67N3O10SiNa [M + Na]+, 1088.4488; found, 1088.4505.
Methyl (Methyl 2-O-acetyl-4-O-(2′,3′-di-O-benzyl-4′-deoxy-
α-pent-4′-enopyranosyl)-α-D-glucopyranosiduronate (11). Thi-
ophenyl 4-DP donor 2 (33 mg, 0.08 mmol) was coupled with acceptor
1026 (25 mg, 0.11 mmol) using BSP/Tf2O conditions (see the general
procedure). After work up, the product was treated with MeOH (1
mL) to produce the desired GlcA methyl ester, which was purified by
silica gel chromatography using a 5−10% EtOAc in hexanes gradient
with 1% Et3N to yield 4′-DP disaccharide 11 (28 mg, 62% over 2
steps). 1H NMR (400 MHz, C6D6): δ 7.35−7.01 (m, 10H), 5.98 (d, J
= 6.3 Hz, 1H), 5.21−5.10 (m, 2H), 5.03 (d, J = 3.6 Hz, 1H), 4.83 (dd,
J = 2.2, 6.5 Hz, 1H), 4.66−4.53 (m, 2H), 4.53−4.37 (m, 4H), 4.10 (t, J
= 9.4 Hz, 1H), 3.96 (s, 1H), 3.81 (dd, J = 2.8, 8.1 Hz, 1H), 3.50 (s,
3H), 2.98 (s, 3H), 2.13 (s, 1H), 1.69 (s, 3H). 13C NMR (100 MHz,
C6D6): δ 169.8, 168.4, 140.2, 138.8, 137.6, 128.4, 128.2, 128.1, 108.6,
101.8, 100.5, 97.6, 82.6, 77.4, 73.9, 73.3, 72.6, 71.0, 70.9, 70.3, 54.8,
51.5, 20.0. IR: 3472, 2937, 1748, 1650, 1497, 1454, 1372, 1234, 1197,
1136, 1100, 1049, 928, 741, 699 cm−1. [α]D25 = +114.2° (c 0.5,
CH2Cl2). HRESI-MS: m/z calcd for C29H34O11Na [M + Na]+,
581.1993; found, 581.2022.
Thiotolyl 3-O-Acetyl-2-azido-4-O-(2′,3′-di-O-benzyl-4′-
deoxy-α-pent-4′-enopyranosyl)-6-O-tert-butyldiphenylsilyl-2-
deoxy-β-D-glucopyranoside (13). Thiophenyl 4-DP donor 2 (28
mg, 0.069 mmol) was coupled with acceptor 1246 (94 mg, 0.139
mmol) using BSP/Tf2O conditions (see the general procedure). After
work up, the product was purified by silica gel chromatography using
5% EtOAc in hexanes with 1% Et3N to yield 4′-DP disaccharide 13
(36 mg, 60%). 1H NMR (500 MHz, C6D6): δ 8.01 (t, J = 8.3 Hz, 4H),
7.67 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 7.4 Hz, 2H), 7.33−7.29 (m, 4H),
7.25 (t, J = 7.2 Hz, 2H), 7.22−7.12 (m, 6H), 7.11−7.05 (m, 2H), 6.86
(d, J = 8.0 Hz, 2H) 6.06 (d, J = 5.9 Hz, 1H), 5.31 (t, J = 9.6 Hz, 1H),
5.09 (d, J = 1.7 Hz, 1H), 4.78−4.71 (m, 2H), 4.62 (d, J = 12.0 Hz,
1H), 4.33 (d, J = 11.6 Hz, 1H), 4.25 (d, J = 11.7 Hz, 1H), 4.16 (d, J =
10.1 Hz, 1H), 4.06 (d, J = 2.9 Hz, 2H), 3.97 (d, J = 5.4 Hz, 1H), 3.82
(t, J = 9.5 Hz, 1H), 3.76 (dt, J = 1.1, 4.9 Hz, 1H), 3.16 (t, J = 10.0 Hz,
1H), 2.98 (dt, J = 9.7, 3.5 Hz, 1H), 1.99 (s, 3H), 1.64 (s, 3H), 1.24 (s,
9H). 13C NMR (100 MHz, C6D6): δ 169.1, 142.8, 138.7, 138.4, 138.2,
135.9, 135.8, 133.9, 133.7, 133.5, 129.73, 129.65, 128.2, 108.6, 100.4,
99.3, 85.8, 79.4, 76.0, 75.8, 74.5, 73.4, 72.4, 70.1, 63.0, 62.5, 29.8, 26.7,
20.6, 20.2, 19.2. IR: 3068, 2928, 2857, 2110, 1755, 1643, 1216, 1112,
1051, 809, 701 cm−1. [α]D25 = +31.8° (c 1.0, CH2Cl2). HRESI-MS: m/z
calcd for C50H59N4O8SSi [M + NH4]+, 903.3817; found, 903.3809.
Thiophenyl 2-O-Benzoyl-3-O-benzyl-4-deoxy-β-pent-4-eno-
pyranoside (14). 4,6-Anisylidene-protected glucopyranoside 2046
(85 mg, 0.14 mmol) was dissolved in 8:1:1 AcOH/THF/H2O (5 mL)
and heated at 70 °C in an oil bath for 3 h. After cooling to rt, the
solution was concentrated, azeotroped with toluene to remove residual
AcOH, redissolved in EtOAc, washed with brine, dried over Na2SO4,
and concentrated to a white solid. The residue was purified by silica gel
chromatography using a 20−100% EtOAc in hexanes gradient to
afford the corresponding 4,6-diol as a white crystalline solid (66 mg,
96%). The diol was subjected to TEMPO/BAIB oxidation and workup
conditions described in the synthesis of compound 2 and was purified
by silica gel chromatography using 5% EtOAc in hexanes with 1%
Et3N to yield thiophenyl 4-DP 14 as white solid; mp 92−95 °C (28
mg, 47% over 2 steps). 1H NMR (400 MHz, C6D6): δ 8.09 (d, J = 8.0
Hz, 2H), 7.53 (d, J = 7.5 Hz, 2H), 7.25−6.90 (m, 11H), 6.32 (d, J =
6.4 Hz, 1H), 5.90 (d, J = 1.6 Hz, 1H), 5.76 (d, J = 1.2 Hz, 1H), 4.98 (t,
J = 12 Hz, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.58 (d, J = 12.0 Hz, 1H),
3.87 (m, 1H). 13C NMR (100 MHz, C6D6): δ 165.0, 142.9, 138.59,
138.58, 136.3, 133.1, 131.5, 129.9, 129.0, 128.4, 128.1, 127.82, 127.75,
127.6, 127.3, 100.9, 83.4, 70.2, 68.3. IR: 3072, 2886, 1722, 1649, 1265,
1
afford 4-DP 5 as an oil (107 mg, 69% over 2 steps). H NMR (400
MHz, C6D6): δ 7.59 (d, J = 6.8 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H), 7.28
(d, J = 7.3 Hz, 2H), 7.24−7.09 (m, 7H), 7.07−6.95 (m, 2H), 6.30 (d, J
= 6.1 Hz, 1H), 5.70 (d, J = 2.3 Hz, 1H), 4.94−4.85 (m, 1H), 4.51 (d, J
= 2.2 Hz, 1H), 4.51 (s, 2H), 4.42 (dd, J = 8.1, 12.0 Hz, 2H), 4.11 (d, J
= 2.6 Hz, 2H). 13C NMR (100 MHz, C6D6): δ 144.0, 138.7, 138.1,
135.1, 131.4, 128.9, 128.2, 127.6, 127.0, 100.6, 85.0, 77.2, 72.4, 70.6,
70.3. IR: 3063, 3029, 2869, 1644, 1454, 1231, 1092, 1055, 1026, 737,
697 cm−1. [α]D25 = +167.3° (c 1.0, CH2Cl2). HRESI-MS: m/z calcd for
C25H25O3S [M + H]+, 405.1519; found, 405.1501.
Isopropyl 3-O-Acetyl-4-O-(2′,3′-di-O-benzyl-4′-deoxy-α-
pent-4′-enopyranosyl)-6-O-tert-butyldiphenylsilyl-2-deoxy-2-
phthalimido-β-D-glucopyranoside (7). Thiophenyl 4-DP donor 2
(50 mg, 0.12 mmol) was coupled with acceptor 646 (145 mg, 0.23
mmol) under BSP/Tf2O conditions (see above). BSP (34 mg, 0.16
mmol), TTBP (49 mg, 0.20 mmol), and 4 Å mol sieves (100 mg) were
dispersed in CH2Cl2 (0.8 mL), cooled to −78 °C, treated with Tf2O
(34 μL, 0.20 mmol), and stirred for 45 min prior to treatment with a
solution of 6 in CH2Cl2 (0.4 mL, cooled to −78 °C). The reaction
mixture was stirred at −78 °C for 12 h, warmed slowly to 0 °C over a
period of 4 h, and quenched with workup according to the general
procedure. The product was purified by silica gel chromatography
using a 5−10% EtOAc in hexanes gradient with 1% Et3N to yield 4′-
DP disaccharide 7 as a yellow oil (84 mg, 75%). 1H NMR (500 MHz,
C6D6): δ 7.93 (dd, J = 1.6, 8.0 Hz, 2H), 7.85 (dd, J = 2.0, 7.4 Hz, 2H),
7.56 (m, 1H), 7.48 (m, 1H), 7.45−7.41 (m, 2H), 7.38−7.33 (m, 2H),
7.31−7.06 (m, 12H), 6.85−6.78 (m, 2H), 6.25 (dd, J = 9.0, 10.7 Hz,
1H), 6.04 (dd, J = 1.2, 6.2 Hz, 1H), 5.68 (d, J = 8.4 Hz, 1H), 5.39 (br
s, 1H), 4.75 (dd, J = 8.5, 10.7 Hz, 1H), 4.69 (dd, J = 4.0, 6.2 Hz, 1H),
4.59 (d, J = 11.7 Hz, 1H), 4.56−4.48 (m, 3H), 4.30 (t, J = 9.4 Hz, 1H),
4.09 (d, J = 11.0 Hz, 1H), 4.03 (dd, J = 1.6, 10.8 Hz, 1H), 3.98 (t, J =
4.6 Hz, 1H), 3.90 (sep, J = 6.2 Hz, 1H), 3.59 (m, 1H), 3.36 (ddd, J =
1.7, 3.4, 9.9 Hz, 1H), 1.68 (s, 3H), 1.18 (s, 9H), 1.15 (d, J = 6.2 Hz,
3H), 0.93 (d, J = 6.1 Hz, 3H). 13C NMR (125 MHz, C6D6): δ 169.5,
167.8, 167.4, 142.1, 139.4, 138.4, 135.9, 135.5, 134.0, 133.4, 133.1,
133.1, 131.9, 131.6, 129.5, 128.7, 128.1, 128.0, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 127.0, 122.8, 122.8, 100.5, 96.4, 75.7, 75.2, 71.9,
70.8, 70.1, 62.3, 55.9, 26.6, 23.1, 21.2, 20.2, 19.1. IR: 3069, 2931, 2858,
1750, 1738, 1387, 1225, 1113, 1038, 702 cm−1. [α]D25 = +68.5° (c 1.0,
CH2Cl2). HRESI-MS: m/z calcd for C54H63N2O11Si [M + NH4]+,
943.4196; found, 943.4172.
2-Ethoxytrityl 3-O-Acetyl-2-azido-4-O-(2′,3′-di-O-benzyl-4′-
deoxy-α-pent-4′-enopyranosyl)-6-O-tert-butyldiphenylsilyl-2-
deoxy-β-D-glucopyranoside (9). Thiophenyl 4-DP donor 2 (20 mg,
0.05 mmol) was coupled with acceptor 8 (76 mg, 0.099 mmol) using
BSP/Tf2O conditions (see the general procedure). After work up, the
product was purified by silica gel chromatography using a 5−10%
EtOAc in hexanes gradient with 1% Et3N to yield 4′-DP disaccharide 9
1
(33 mg, 57%). H NMR (400 MHz, C6D6): δ 7.99 (ddd, J = 1.5, 3.1,
6.5 Hz, 4H), 7.70 (d, J = 8.5 Hz, 6H), 7.45 (d, J = 6.8 Hz, 2H), 7.37−
7.17 (m, 23H), 6.17 (d, J = 6.1 Hz, 1H), 5.40 (dd, J = 9.2, 10.5 Hz,
1H), 5.24 (s, 1H), 4.97−4.76 (m, 2H), 4.69 (d, J = 12.0 Hz, 1H), 4.41
(d, J = 11.6 Hz, 1H), 4.33 (d, J = 11.5 Hz, 1H), 4.18 (dd, J = 3.4, 7.3
Hz, 2H), 4.14−4.04 (m, 3H), 4.00 (t, J = 9.5 Hz, 1H), 3.93−3.80 (m,
1H), 3.61−3.50 (m, 1H), 3.44 (t, J = 4.9 Hz, 2H), 3.39 (dd, J = 8.0,
4885
dx.doi.org/10.1021/jo500449h | J. Org. Chem. 2014, 79, 4878−4891