10.1002/cbic.201600694
ChemBioChem
FULL PAPER
triethylamine and filtered through a pad of Celite and poured into
saturated aq. NaHCO3 and 10% aq. Na2S2O3. The aqueous layer was
extracted with two portions of ethtyl acetate. The combined extract was
washed with brine, dried over MgSO4, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel with 99:1
chloroform/methanol to give 6 (1.27 g, 1.96 mmol, 89%, α:β = >95: 5) as
a colorless neat. The α:β ratio was determined by 1H NMR analysis.
11: To a stirred solution of 4-hydroxybenzoic acid (5.00 g, 36.2 mmol) in
methanol (100 mL) was added H2SO4 (0.500 mL) at room temperature.
After being stirred at reflux for 24 h, the reaction mixture was
concentrated in vacuo. The residue was poured into water and Et2O. The
aqueous layer was extracted with two portions of Et2O. The combined
extract was washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was used for the next reaction
without further purification. To a stirred solution of the above residue in
DMF (50.0 mL) was added K2CO3 (7.30 g, 53.2 mmol) and 2-(2-
azidoethoxy)ethyl tosylate (12.1 g, 53.2 mmol) at room temperature. After
being stirred at 50 oC for 12 h, the residue was poured into 1 M HCl and
ethyl acetate. The aqueous layer was extracted with two portions of ethyl
acetate. The combined extract was washed with brine, dried over MgSO4,
filtered and concentrated in vacuo. The residue was used for the next
reaction without further purification. To a stirred solution of the above
residue in 1,4-dioxane (25.0 mL) and H2O (25.0 mL) was added a
catalytic amount of LiOH•H2O at room temperature. After being stirred at
60 oC for 12 h, the residue was poured into aq. NH4Cl and ethyl acetate.
The aqueous layer was extracted with two portions of ethyl acetate. The
combined extract was washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was used for the next reaction
without further purification. To a stirred solution of the above residue in
CH2Cl2 (25.0 mL) was added DCC (8.97 g, 43.5 mmol) and N-
hydroxysuccinimide (5.38 g, 39.8 mmol) at room temperature. After being
stirred at the same temperature for 2 h, the reaction mixture was
concentrated in vacuo. The residue was chromatographed on silica gel
with 50:50 ethyl acetate/hexane to give 11 (6.31 g, 19.9 mmol, 4 steps
55%) as a colorless neat. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, 2H, J =
9.2 Hz), 6.93 (d, 2H, J = 8.7 Hz), 4.14 (t, 2H, J = 4.8 Hz), 3.80 (t, 2H, J =
4.8 Hz), 3.66 (t, 2H, J = 5.3 Hz), 3.33 (t, 2H, J = 5.3 Hz), 2.80 (s, 4H);
13C NMR (100 MHz, CDCl3) δ 169.4, 163.8, 161.2, 132.5, 117.0, 114.6,
69.9, 69.0, 67.5, 50.3, 25.4; IR (neat); 3526, 2936, 2107, 1739, 1605,
1511, 1257, 993, 925, 846, 765 cm-1; HRMS (ESI-TOF) [M+H]+ calcd.
349.1148, found 349.1150.
33
[α]D = -6.89 (c = 0.980, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.98-7.24
(m, 5H), 5.50 (dt, 1H, J = 2.4, 10.1 Hz), 5.43-5.39 (m, 2H), 4.61 (d, 1H, J
= 12.1 Hz), 4.37 (d, 1H, J = 15.0 Hz), 4.36 (d, 1H, J = 12.1 Hz), 4.26 (dd,
1H, J = 1.9, 10.1 Hz), 4.18 (d, 1H, J = 15.5 Hz), 3.99 (d, 1H, J = 14.5 Hz),
3.95-3.60 (m, 8H), 3.79 (s, 3H), 3.43-3.35 (m, 4H), 3.09 (t, 1H, J = 9.7
Hz), 2.88 (dd, 1H, J = 3.4, 12.1 Hz), 2.08 (dd, 1H, J = 12.1, 12.6 Hz); 13
C
NMR (100 MHz, CDCl3) δ 168.6, 167.8, 166.5, 159.1, 137.0, 128.9, 128.5,
128.1, 128.0, 125.2, 100.0, 76.6, 73.5, 73.2, 72.3, 70.3, 70.0, 69.9, 69.8,
69.1, 66.9, 64.9, 61.7, 57.4, 53.0, 50.6, 50.5, 41.2, 40.2, 37.2; IR (neat);
3408, 2956, 2112, 1767, 1304, 1076, 1014, 756 cm-1; HRMS (ESI-TOF)
[M+H]+ calcd. 663.1472, found 663.1468.
7: To a stirred solution of 6 (1.18 g, 1.82 mmol) in DMF (9.00 mL) was
added thiourea (832 mg, 10.9 mmol) and 2,6-lutidine (503 µL, 4.37
mmol) at room temperature. After being stirred at 80 oC for 6 h, the
reaction mixture was poured into 1 M HCl. The aqueous layer was
extracted with two portions of ethtyl acetate. The combined extract was
washed with 1 M HCl, saturated aq. NaHCO3, brine, dried over MgSO4,
filtered and concentrated in vacuo. The residue was chromatographed on
silica gel with 98:2 chloroform/methanol to give 7 (434 mg, 0.877 mmol,
33
48%) as a colorless neat. [α]D = -23.7 (c = 1.42, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.33-7.27 (m, 5H), 6.18 (br-s, 1H), 4.58 (s, 2H), 4.00-3.83
(m, 3H), 3.82 (s, 3H), 3.80-3.72 (m, 4H), 3.70-3.58 (m, 5H), 3.49 (dd, 1H,
J = 9.7, 11.1 Hz), 3.40-3.33 (m, 4H), 2.97 (dd, 1H, J = 3.9, 12.1 Hz), 2.12
(dd, 1H, J = 12.1, 13.0 Hz); 13C NMR (100MHz, CDCl3) δ 168.7, 160.1,
137.7, 128.4, 127.78, 127.74, 100.7, 77.4, 73.5, 71.5, 71.3, 70.0, 69.9,
69.8, 64.4, 57.4, 53.3, 50.5, 36.8; IR (neat); 3391, 2927, 2109, 1769,
1454, 1280, 1075, 942, 756 cm-1; HRMS (ESI-TOF) [M+H]+ calcd.
511.2040, found 511.2040.
3b: To a stirred solution of 6 (76.4 mg, 0.118 mmol) in 1,4-dioxane (2.00
mL) and H2O (2.00 mL) was added LiOH•H2O (90.0 mg) at room
temperature. After being stirred at 80 oC for 40 h, the reaction mixture
was concentrated in vacuo. The residue was purified by reverse-phase
column chromatography (Bond Elut-C18). The residue was used for the
next reaction. To a stirred solution of the above residue in H2O (4.00 mL)
was added NaHCO3 (100 mg) and acetic anhydride (120 µL) at room
temperature. After being stirred at the same temperature for 1 h, the
reaction mixture was concentrated in vacuo. The residue was used for
the next reaction without further purification. To a stirred solution of the
above residue in methanol (4.00 mL) was added NaOMe (100 mg) at
room temperature. After being stirred at the same temperature for 1 h,
the reaction mixture was concentrated in vacuo. The residue was purified
by reverse-phase column chromatography (Bond Elut-C18). The residue
was used for the next reaction. To a stirred solution of the above residue
in THF (2.00 mL) was added a large amount of liq.NH3 and Na at -78 oC.
After being stirred at same temperature for 1 h, the reaction mixture was
quenched by methanol and purified by gel filtration. The residue was
used for the next reaction. To a stirred solution of the above residue in
1,4-dioxane (1.00 mL) and H2O (1.00 mL) was added 11 (41.0 mg, 0.118
mmol) and NaHCO3 (50.0 mg) at room temperature. After being stirred at
room temperature for 4 h, the reaction mixture was concentrated in
vacuo. The residue was purified by reverse-phase column
chromatography (Bond Elut-C18) to 3b (40.8 mg, 0.0649 mmol, 5 steps
55%) as a white solid. [α]D33 = -14.2 (c = 0.890, D2O); 1H NMR (400 MHz,
D2O) δ 7.74 (δ, 2H, J = 9.2 Hz), 7.05 (d, 2H, J = 9.2 Hz), 4.24 (m, 2H),
3.92-3.54 (m, 19H), 3.47 (t, 2H, J = 4.8 Hz), 2.68 (dd, 1H, J = 4.3, 12.1
Hz), 2.01 (s, 3H), 1.59 (t, 1H, J = 12.1 Hz); 13C NMR (100MHz, D2O,
Acetone-d6) δ 216.4, 175.8, 174.2, 170.7, 161.9, 130.0, 127.0, 115.4,
8: To a stirred solution of 5 (826 mg, 1.28 mmol) in CH2Cl2 (8.50 mL) was
added 7 (434 mg, 0.850 mmol) and pulverized activated MS3A (850 mg).
After being stirred at room temperature for 30 min under argon to remove
a trace amount of water, the reaction mixture was cooled to -78 oC. After
10 min, N-iodosuccinimide (459 mg, 2.04 mmol) and a catalytic amount
of trifluoromethanesulfonic acid (44.7 µL, 0.51 mmol) was added to the
reaction mixture at the same temperature. After being stirred for 3 h, the
reaction mixture was neutralized with triethylamine and filtered through a
pad of Celite and poured into saturated aq. NaHCO3 and 10% aq.
Na2S2O3. The aqueous layer was extracted with two portions of ethtyl
acetate. The combined extract was washed with brine, dried over MgSO4,
filtered and concentrated in vacuo. The residue was chromatographed on
silica gel with 99:1 chloroform/methanol to give 8 (691 mg, 0.663 mmol,
78%, α:β = 92:8) as a colorless neat. The α:β ratio was determined by 1H
33
NMR analysis. [α]D = -19.9 (c = 1.69, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.39-7.24 (m, 10H), 5.96 (br-s, 1H), 5.44-5.30 (m, 3H), 4.61-
4.52 (m, 3H), 4.38-4.33 (m, 2H), 4.22-4.15 (m, 2H), 4.06-4.00 (m, 3H),
3.95-3.75 (m, 13H), 3.65-3.40 (m, 7H), 3.34 (t, 2H, J = 6.8 Hz), 3.08 (dd,
1H, J = 10.1, 10.6 Hz), 2.92-2.86 (m, 2H), 2.20-2.00 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.7, 168.0, 167.7, 166.9, 159.7, 159.1, 137.8,
136.9, 128.5, 128.4, 128.2, 128.1, 127.7, 127.5, 100.8, 100.0, 77.1, 76.8,
76.5, 76.2, 73.8, 73.4, 73.3, 72.1, 70.4, 70.1, 70.0, 70.0, 69.8, 69.4, 66.8,
64.4, 57.7, 57.4, 53.4, 52.9, 50.5, 41.2, 40.2, 37.1, 36.8; IR (neat); 3403,
2955, 2108, 1712, 1295, 1233, 1153, 1014, 754 cm-1; HRMS (ESI-TOF)
[M+H]+ calcd. 1042.2739, found 1042.2732.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.