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(56 mL). The suspension was evacuated to the point that bumping
commenced, then let down to nitrogen, and this process was re-
peated four times. After a final evacuation, the nitrogen line was
replaced with a hydrogen balloon, and the flask was let down to
hydrogen gas. The suspension was stirred vigorously overnight
and the following day the hydrogen was evacuated, flushing the
flask liberally with nitrogen. The solution was filtered through
Celite S filtre-aid, using a Pasteur pipette containing a wad of
cotton wool, and the charcoal rinsed with water/MeOH (1:9, 5 mL);
see caution above. The filtrate was evaporated, then re-evaporated
CH2O), 61.46 (OCH2CH2OH), 37.04 (CH2N); m/z (MALDI-TOF+) [M+
Na]+: 2637.0; calcd for C120H229NNaO58+: 2636.49.
w-Azido hexapentaconta(ethylene glycol) (32): w-Toluenesulfonyl
hexapentaconta(ethylene glycol) (28, 52 mg, 19.7 mmol), NaHCO3
(14 mg, 0.17 mmol, 8.5 equiv) and NaN3 (20 mg, 0.31 mmol,
16 equiv) were dissolved in DMF (0.5 mL) to which was added
water (85 mL). The reaction was stirred overnight at 708C, and the
next day the solvent was evaporated in vacuo (oil pump), re-evap-
orating the residue from MeCN (3ꢂ5 mL). The residue was parti-
tioned between half sat. NaHCO3 and CHCl3. The aqueous layer
was back-extracted with further CHCl3 (4ꢂ), the combined organic
layers dried over Na2SO4, and the solvent was stripped off under
reduced pressure. The crude material (50 mg) was fractionated
through a column of flash silica, eluting with a gradient of MeOH-
CHCl3 (containing a trace of Et3N) to afford the title compound as
a waxy solid (41 mg, 85%). Rf (MeOH-CHCl3 1:9+trace Et3N)=0.30;
1H NMR (400 MHz, CDCl3): d=3.71–3.59 (m, 222H), 3.37 (t, J=
5.0 Hz, 2H); 13C NMR (101 MHz, CDCl3): d=72.55 (OCH2CH2OH),
70.53 (107C), 70.28, 70.00 (109ꢂCH2O), 61.65 (OCH2CH2OH), 50.64
(CH2N3); m/z (MALDI-TOF+) [M+K]+: 2550.2; calcd for
C112H225KN3O56+: 2548.45.
1
from MeCN (3ꢂ) to give a waxy solid (32 mg), but H NMR revealed
that the reaction was incomplete. The hydrogenation was repeat-
ed, exactly as before, this time affording a waxy solid (29 mg), ex-
1
hibiting no singlets around 4.6 ppm in the H NMR spectrum corre-
sponding benzylic methylene protons. The crude material was frac-
tionated through a column of flash silica, eluting with a gradient of
MeOH/CHCl3 (containing a trace of Et3N), to afford a mixed fraction
containing higher Rf contaminants as well as the main product
(12 mg), and the main product (9 mg) apparently pure by TLC. Rf
(MeOH/CHCl3 3:17+trace Et3N)=0.24; 1H NMR (400 MHz, CDCl3):
d=3.75–3.55 (m, ca. 222H, CH2O), 2.52 (t, J=5.8 Hz, 2H, CH2N);
13C NMR (101 MHz, CDCl3): d=72.56 (OCH2CH2OH), 70.51 (105C),
w-(tert-Butyl acetoxy)hexapentaconta(ethylene glycol)-a-tolu-
enesulfonate (33): w-(tert-Butyl acetoxy)hexapentaconta(ethylene
glycol) (26, 117 mg, 45.0 mmol) was evaporated from MeCN (3ꢂ
2 mL) and re-dissolved in CH2Cl2 (0.4 mL). To the solution were
added Et3N (25 mL, 0.18 mmol, 4.0 equiv), N-methylimidazole
(7.1 mL, 89 mmol, 2.0 equiv) and toluene sulfonyl chloride (16.9 mg,
89 mmol, 2.0 equiv), and the reaction was stirred overnight. The
next day the reaction was diluted with CH2Cl2 and extracted with
half sat. brine. Once the first partition was complete, water was
added portion-wise, with vigorous shaking in between, until an
emulsion at the interface had dispersed. The aqueous layer was
back-extracted with further CH2Cl2 (4ꢂ), the combined organic
layers dried over Na2SO4, a few drops of Et3N were added, and the
solution was concentrated under reduced pressure (but not to dry-
ness). The crude concentrate was fractionated through a column
of flash silica, eluting with a gradient of MeOH-CHCl3 (containing
a trace of Et3N) to afford the title compound as a waxy solid
(79 mg, 64%); weaker fractions on either side of the main band
(total of 23 mg) appeared to be product by 1H NMR, but also
seemed to contain faint contaminants by TLC. Rf (MeOH/CHCl3
1:9+trace Et3N)=0.39; 1H NMR (400 MHz, CDCl3): d=7.73 (d, J=
8.3 Hz, 2H, Ts CH), 7.29 (d, J=7.8 Hz, 2H, Ts CH), 4.09 (m, 2H,
CH2OTs), 3.96 (s, 2H, OCH2CO2), 3.66–3.55 (m, 218H, CH2O), 3.52 (s,
4H, OCH2CH2O), 2.39 (s, 3H, Ts CH3), 1.41 [s, 9H, C(CH3)3]; 13C NMR
(101 MHz, CDCl3): d=169.45 (CO2), 144.57 (Ts CSO3), 132.81 (Ts
CMe), 129.63 (2C, Ts CH), 127.77 (2C, Ts CH), 81.28 (CO2CMe3),
70.53, 70.51 (108C), 70.36, 69.06, 68.83, 68.46 (112ꢂCH2O +
OCH2CO2), 27.92 [C(CH3)3], 21.46 (Ts CH3); m/z (ESI+) [M+2Na]+:
1399.27; calcd for C125H242Na2O61S2+: 1399.269.
70.24, 70.19, 65.71 (106ꢂCH2O), 61.65 (OCH2CH2OH), 56.99, 43.76;
m/z (MALDI-TOF+) [M+H]+: 2512.8; calcd for C112H228N3O56
2512.51; (ESI+) [M+H+NH4]2+: 1265.268; calcd for C112H232N4O56
: 1265.2726.
:
+
2+
w-Amino hexapentaconta(ethylene glycol) (30): w-Phthalimido
hexapentaconta(ethylene glycol) (31, 38 mg, 14.54 mmol) was dis-
solved in MeOH (0.45 mL) to which was added hydrazine hydrate
(50 mL). The following day acetone (0.5 mL) was added, and after
30 min the solvent was stripped off. The residue was then parti-
tioned between CHCl3 and 5% sat. brine, the aqueous layer was
back-extracted with further CHCl3 (4ꢂ), the combined organic
layers dried over Na2SO4, and the solvent was stripped off under
reduced pressure. The residue (40 mg) was fractionated through
a column of flash silica, eluting with a gradient of MeOH/CHCl3
(containing a trace of Et3N), to afford the title compound as a waxy
solid (24 mg, 66%). Rf (MeOH/CHCl3 1:4 + trace Et3N)=0.43;
1H NMR (400 MHz, CDCl3): d=3.92 (brs, 2H, CH2O), 3.77–3.74 (m,
2H, CH2O), 3.73–3.59 (m, 218H, CH2O), 3.18 (brs, 2H, CH2NH2);
13C NMR (101 MHz, CDCl3): d=72.52 (OCH2CH2OH), 70.47 (99C),
70.36, 70.30, 70.20, 70.07, 70.03, 69.97, 69.86, 69.81, 69.66, 66.72
(109ꢂCH2O), 61.58 (OCH2CH2OH), 40.42 (CH2NH2); m/z (MALDI-
TOF+) [M+K]+: 2523.1; calcd for C112H227KNO56+: 2522.46.
w-Phthalimido hexapentaconta(ethylene glycol) (31): w-Toluene-
sulfonyl hexapentaconta(ethylene glycol) (28, 67 mg, 25.4 mmol)
was evaporated from MeCN (4 mL), then potassium phthalimide
(47 mg, 0.25 mmol, 10 equiv) was added, and the evaporation
from MeCN repeated (2ꢂ4 mL). The residue was dissolved in DMF
(2.0 mL) and stirred overnight at 658C. The following day the sol-
vent was stripped off and the residue re-evaporated from MeCN
(2ꢂ5 mL). The residue was then partitioned between CHCl3 and
10% sat. brine, the aqueous layer was back-extracted with further
CHCl3 (4ꢂ), the combined organic layers dried over Na2SO4, and
the solvent was stripped off under reduced pressure. The residue
(80 mg) was fractionated through a column of flash silica, eluting
with a gradient of MeOH-CHCl3 (containing a trace of Et3N), to
afford the title compound as a waxy solid (44 mg, 65%). Rf (MeOH-
CHCl3 1:9+trace Et3N)=0.32; 1H NMR (400 MHz, CDCl3): d=7.84–
7.79 (m, 2H), 7.72–7.67 (m, 2H), 3.86 (t, J=5.8 Hz, 2H), 3.72–3.68
(m, 4H), 3.66–3.55 (m, 218H); 13C NMR (101 MHz, CDCl3): d=168.02
(2C, ArCON), 133.75 (2C, Ar CH), 131.91(2C, Ar C), 123.02 (2C, Ar
CH), 72.40 (OCH2CH2OH), 70.35 (106C), 70.09, 69.86, 67.69 (109ꢂ
w-Azido hexapentaconta(ethylene glycol)oxyacetate tert-butyl
ester (34): Compound 33 (70 mg, 26.9 mmol), NaHCO3 (19 mg,
0.23 mmol, 8.4 equiv) and NaN3 (27 mg, 0.42 mmol, 15 equiv) were
dissolved in DMF (0.7 mL) to which was added water (120 mL). The
reaction was stirred for 22 h at 708C, and the next day the solvent
was evaporated in vacuo (oil pump), re-evaporating the residue
from MeCN (3ꢂ5 mL). The residue was partitioned between half
sat. NaHCO3 and CH2Cl2. The aqueous layer was back-extracted
with further CH2Cl2 (4ꢂ), the combined organic layers dried over
Na2SO4, and the solvent was stripped off under reduced pressure.
The crude material (67 mg) was fractionated through a column of
flash silica, eluting with a gradient of MeOH-CHCl3 (containing
a trace of Et3N) to afford the title compound as a waxy solid
Chem. Eur. J. 2014, 20, 10038 – 10051
10050
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim