Dendronized Polymers
FULL PAPER
under H2 (3 bar) at room temperature for 4 h. The solution was then fil-
tered through celite and the solvent evaporated at room temperature to
yield 2a as a viscous oil (1.10 g, 97%). The product was used for the next
step without further purification and structural analysis.
1H NMR (CDCl3): d=1.42 (s, 9H; CCH3), 1.75 (m, 8H; CH2), 1.88 (m,
4H; CH2), 2.57 (m, 8H; CH2Ph), 2.70 (m, 4H; CH2Ph), 3.07 (t, J=
3.3 Hz, 2H; CH2NH), 3.14 (q, J=5.1 Hz, 6H; CH2NH), 3.34 (t, J=
5.1 Hz, 4H; CH2NH), 5.01 (s, 6H; OCH2Ph), 5.15 (brs, 2H; NH), 6.83 (s,
1H; ArH), 7.04 (s, 2H; ArH), 7.27 (m, 19H; ArH), 7.73 ppm (s, 2H;
ArH); 13C NMR (CDCl3): d=28.39, 31.23, 31.29, 32.58, 33.16, 39.72,
40.14, 66.79, 125.03, 127.79, 128,15, 128.24, 128.65, 131.84, 134.55, 135.59,
136.64, 141.93, 142.96, 156.87, 175.80 ppm; ESI-MS: m/z: 1198 [M+Na]+.
Ethyl-3-{3,5-bis[3-(benzyloxycarbonylamino)propyl]benzoylamino}-5-[3-
(tert-butyloxycarbonylamino)propyl] benzoate (4): N-hydroxybenzotria-
zole (HOBt; 0.30 g, 2.28 mmol) was added to a solution of 3 (1.10 g,
2.18 mmol) in CH2Cl2 (60 mL). After 10 min at À308C, N-(3-dimethyla-
minopropyl)-N’-ethylcarbodiimide
hydrochloride
(EDC;
0.46 g,
3-(3-{3,5-Bis-[3-(benzyloxycarbonylamino)propyl]benzoylamino}propyl)-
5-(3-{3-[3-(benzyloxycarbonylamino)propyl]-5-[3-(tert-butyloxycarbonyl-
amino)propyl]benzoylamino}propyl)benzoic acid 2,5-dioxopyrrolidin-1-yl
ester (7b): N-Hydroxysuccinimide (HOSu; 46 mg, 0.39 mmol) was added
to a solution of 7a (0.33 g, 0.27 mmol) in dry CH2Cl2 (10 mL) at room
temperature. After 15 min, dicyclohexylcarbodiimide (DCC; 85 mg,
0.41 mmol) was added at À208C. The resulting mixture was warmed to
room temperature and stirred overnight. The precipitate was isolated by
filtration and the solvent was evaporated at room temperature. Chroma-
tographic separation (silica gel, CH2Cl2/MeOH 4:1) yielded 7b (0.29 g,
83%) as a white foam. 1H NMR (CDCl3): d=1.37 (s, 9H; CCH3), 1.73
(m, 8H; CH2), 1.92 (m, 4H; CH2), 2.58 (m, 8H; CH2Ph), 2.69 (m, 4H;
CH2Ph), 2.85 (s, 4H; CH2), 3.00 (t, J=6.3 Hz, 2H; CH2NH), 3.08 (q, J=
8.1 Hz, 6H; CH2NH), 3.35 (t, J=6.6 Hz, 4H; CH2NH), 5.01 (s, 6H;
OCH2Ph), 7.07 (s, 2H; ArH), 7.27 (m, 15H; ArH), 7.35 (s, 3H; ArH),
7.37 (s, 2H; ArH), 7.75 ppm (s, 2H; ArH); 13C NMR (CDCl3): d=28.35,
30.66, 31.18, 32.47, 32.93, 39.49, 40.01, 66.57, 79.24, 124.90, 125.17, 127.88,
128.08, 128.51, 131.84, 134.55, 135.59, 141.93, 142.95, 157.11, 162.23,
168.77, 169.99 ppm; ESI-MS: m/z: 1295 [M+Na]+; elemental analysis
calcd (%) for C72H85N7O14 (1272.62): C 67.96, H 6.73, N 7.71; found: C
67.53, H 7.05, N 7.56.
2.38 mmol) was added. The mixture was stirred until the hydrochloride
had dissolved (ꢀ3 h), then a solution of 2 (0.59 g, 1.83 mmol) and Et3N
(1.03 mL, 7.33 mmol) in MeOH/CH2Cl2 (10 mL, 1:1) was added dropwise
at À208C. The mixture was warmed to room temperature and stirred
overnight. It was then washed with saturated NaHCO3 (50 mL) and brine
(50 mL), and dried over MgSO4. Chromatographic separation (silica gel,
1
EtOAc/hexane 2:1) yielded 4 (1.56 g, 63%) as a colorless foam. H NMR
(CDCl3): d=1.38 (t, J=7.2 Hz, 3H; CH3), 1.44 (s, 9H; CCH3), 1.86 (m,
6H; CH2), 2.00 (m, 2H; CH2), 2.64 (m, 6H; CH2Ph), 2.74 (t, J=7.8 Hz,
2H; CH2Ph), 3.13 (m, 6H; CH2NH), 3.45 (q, J=6.0 Hz, 2H; CH2NH),
4.38 (q, J=6.9 Hz, 2H; OCH2), 4.75 (brs, 1H; NH), 5.06 (s, 4H;
OCH2Ph), 5.12 (brs, 2H; NH), 6.89 (brs, 1H; NH), 7.09 (s, 1H; ArH),
7.22 (s, 1H; ArH), 7.30 (m, 10H; ArH), 7.41 (s, 2H; ArH), 7.68 (s, 1H;
ArH), 7.73 ppm (s, 1H; ArH); 13C NMR (CDCl3): d=14.36, 28.43, 31.04,
31.14, 31.59, 32.38, 32.77, 33.20, 39.75, 40.06, 60.96, 66.63, 79.22, 124.87,
127.17, 127.18, 127.99, 128.09, 128.51, 131.65, 133.20, 134.93, 136.56,
141.68, 142.04, 142.07, 156.06, 156.58, 1.66.81, 167.91 ppm; ESI-MS: m/z:
873 [M+Na]+; elemental analysis calcd (%) for C49H62N4O9 (851.04): C
69.15, H 7.34, N 6.58; found: C 69.24, H 7.49, N 6.56.
Ethyl-3-{3,5-bis[3-(benzyloxycarbonylamino)propyl]benzoylamino}-5-(3-
amino)propyl benzoate (5): Aqueous 25% HCl (0.75 mL, 5 equiv) in
THF (3 mL) was added slowly to a solution of 4 (0.98 g, 1.15 mmol) in
THF (25 mL) at 08C. The mixture was stirred for 3 h. The solvent was
evaporated at room temperature to yield 5 as viscous oil (0.87 g, 96%).
The product was used for the next step without further purification and
structural analysis.
3,5-Bis(3-tert-butyloxycarbonylaminopropyl)benzyl phthalimide (9a):
Mesyl chloride (1.77 mL, 22.8 mmol) in CH2Cl2 (5 mL) was added to a
solution of 8 (8.4 g, 19.9 mmol) and Et3N (8.5 mL, 59.7 mmol) in CH2Cl2
(150 mL) at À308C. The mixture was stirred at À208C for 2 h and regu-
larly checked by TLC (EtOAc/hexane 1:1) until 8 had disappeared. The
reaction was then quenched with MeOH and the solution washed four
times with cold water and brine. The organic phase was dried over
MgSO4, the solvent was evaporated at room temperature, and the prod-
uct was dried under vacuum. The residue was then dissolved in DMF
(100 mL), potassium phthalimide (4.05 g, 21.8 mmol) was added at room
temperature, and the mixture was stirred overnight at 1008C. The DMF
was evaporated and the residue was dissolved in CH2Cl2 (70 mL), washed
with 0.5m NaOH, saturated brine, and saturated NaHCO3, and finally
dried over MgSO4. Chromatographic separation (silica gel, EtOAc/
hexane 1:1) yielded 9a (10 g, 91%) as a pale gray solid. 1H NMR
(CDCl3): d=1.44 (s, 18H; CH3), 1.78 (m, 4H; CH2), 2.58 (t, J=7.8 Hz,
4H; ArCH2), 3.14 (m, 4H; NHCH2), 4.66 (brs, 2H; NH), 4.79 (s, 2H;
CH2), 6.92 (s, 1H; ArH), 7.08 (s, 2H; ArH), 7.72 (m, 2H; ArH),
7.85 ppm (m, 2H; ArH); 13C NMR (CDCl3): d=28.43, 31.64, 32.88, 40.13,
41.57, 79.04, 94.71, 123.36, 126.38, 128.06, 132.14, 133.96, 136.54, 142.21,
156.00, 168.06 ppm; ESI-MS: m/z: 574 [M+Na]+; elemental analysis
calcd (%) for C47H60N4O8 (551.67): C 67.49, H 7.49, N 7.62; found: C
67.54, H 7.50, N 7.57.
Ethyl-3-(3-{3,5-bis[3-(benzyloxycarbonylamino)propyl]benzoylamino}-
propyl)-5-(3-{3-[3-(benzyloxycarbonylamino)propyl]-5-[3-(tert-butyloxy-
carbonylamino)propyl]benzoylamino}propyl) benzoate (6): HOBt
(90 mg, 0.66 mmol) was added to a solution of 1b (0.30 g, 0.63 mmol) in
CH2Cl2 (20 mL) at room temperature. After 10 min at À308C, EDC
(0.13 g, 0.68 mmol) was added and the mixture stirred for 3 h. Then a sol-
ution of 5 (0.40 g, 0.51 mmol) and Et3N (0.57 mL, 4.1 mmol) in MeOH/
CH2Cl2 (15 mL, 1:1) was added dropwise at À208C. The resulting mixture
was warmed to room temperature and stirred for 14 h. It was then
washed with brine (40 mL) and saturated NaHCO3 (40 mL). The organic
phase was dried over MgSO4 and the solvent removed in vacuum. Chro-
matographic separation (silica gel, EtOAc/hexane 3:1) yielded 6 (0.48 g,
78%) as a colorless foam. 1H NMR (CDCl3): d=1.37 (t, J=6.9 Hz, 3H;
CH3), 1.43 (s, 9H; CCH3), 1.75 (m, 8H; CH2), 1.97 (m, 4H; CH2), 2.58
(m, 8H; CH2Ph), 2.69 (m, 4H; CH2Ph), 3.08 (q, J=6.9 Hz, 2H;
CH2NH), 3.13 (q, J=6.1 Hz, 6H; CH2NH), 3.42 (t, J=5.8 Hz, 4H;
CH2NH), 4.33 (q, J=7.2 Hz,2H; CH2), 5.05 (s, 6H; OCH2Ph), 6.85 (brs,
2H; NH), 7.05 (s, 2H; ArH), 7.25 (s, 2H; ArH), 7.30 (m, 15H; ArH),
7.38 (s, 3H; ArH), 7.70 ppm (s, 2H; ArH); 13C NMR (CDCl3): d=14.73,
28.43, 30.66, 31.01, 32.35, 32.95, 39.42, 40.05, 66.64, 79.24, 124.86, 125.17,
127.88, 128,04, 128.11, 128.52, 136.56, 141.65, 141.99, 156.55, 162.23,
168.77 ppm; ESI-MS: m/z: 1226 [M+Na]+; elemental analysis calcd (%)
for C47H60N4O8 (1203.46): C 69.86, H 7.20, N 6.98; found: C 69.66, H
7.12, N 7.02.
3,5-Bis(3-tert-butyloxycarbonylaminopropyl)benzylamine (9b): Hydra-
zine hydrate (2.64 mL, 54.3 mmol) was added to a solution of 9a (10 g,
18.1 mmol) in THF/EtOH (80 mL, 1:1) and the mixture was stirred at
608C for 6 h. After the reaction was finished (TLC), the solvent was
evaporated. The precipitate was then dissolved in CH2Cl2 and washed
with 0.5m NaOH and saturated brine. Chromatographic separation (silica
gel, CH2Cl2/MeOH/Et3N 100:10:1) yielded 9b (6.66 g, 87%) as a yellow-
ish oil. 1H NMR (CDCl3): d=1.45 (s, 18H; CH3), 1.77 (m, 4H; CH2),
2.60 (t, J=7.5 Hz, 4H; ArCH2), 3.14 (q, J=6.6 Hz, 4H; NHCH2), 3.89 (s,
2H; CH2NH), 4.79 (brs, 2H; NH), 6.92 (s, 1H; ArH), 6.98 ppm (s, 2H;
ArH); 13C NMR (CDCl3): d=28.44, 31.67, 31.89, 32.96, 40.13, 46.41,
79.05, 124.83, 127.00, 141.96, 143.53, 156.00 ppm; ESI-MS: m/z: 422
[M+Na]+.
3-(3-{3,5-Bis[3-(benzyloxycarbonylamino)propyl]benzoylamino}propyl)-5-
(3-{3-[3-(benzyloxycarbonylamino)propyl]-5-[3-(tert-butyloxycarbonyl-
amino)propyl]benzoylamino}propyl)benzoic acid (7a): Compound
6
(0.39 g, 0.32 mmol) was heated with KOH pellets (0.07 g, 1.24 mmol) in
THF/MeOH/H2O (24 mL, 2:3:1) at 558C for 6 h. After the reaction was
finished (TLC), water (3 mL) and then acetic acid were added until pH 5
was reached. The solvent was evaporated and the G2 acid 7a extracted
with CH2Cl2. The organic phase was dried over MgSO4. After evapora-
tion of the solvent, acid 7a (0.33 g, 87%) was obtained as a white solid.
3,5-Bis(3-tert-butyloxycarbonylaminopropyl)benzylmethacrylamide (10):
Methacryloyl chloride (2.05 mL, 21.2 mmol) in CH2Cl2 (4 mL) was added
dropwise to a solution of 9b (7.45 g, 17.7 mmol) and Et3N (3.72 mL,
Chem. Eur. J. 2006, 12, 6542 – 6551
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6549