G. R. Newkome et al.
Synthesis of acrylamide 15: Acryloyl chloride (60 mg, 650 mmol) was
added to a stirred solution of amine 14 (1 g, 650 mmol) and Et3N (184 mL,
1.3 mmol) in dry THF at 08C. After 5 h at 258C, the reaction mixture
was washed with water, then saturated brine. The organic solution was
dried (MgSO4), filtered, and concentrated in vacuo to give a crude solid,
which was subjected to chromatography (SiO2) eluting with a 30%
EtOAc in CHCl3 mixture to afford amide 15 as a white solid. Yield:
990 mg (96%); 1H NMR: d=1.44 (s, 81H; CH3), 1.79 (t, J=5.1 Hz, 2H;
CH2CO), 1.98 (brm, 36H; CH2CH2CO, CH2CO), 2.21 (t, J=4.5 Hz, 2H;
CH2CH2CO), 2.27 (m, 12H; CH2CH2CONH, CH2CONH), 3.25 (t, J=
4.8 Hz, 2H; NHCH2), 5.58 (brm, 1H; CH2=CH), 6.12 (brm, 1H; CH2=
CH), 6.21 (brm, 1H; CH2=CH), 6.41 (s, 2H; NH), 6.51 (s, 2H; NH), 6.41
(s, 1H; NHCH2), 7.35 ppm (s, 2H; NH2); 13C NMR: d=25.7 (CH2CO),
28.0 (CH3), 29.5 (CH2CH2CO2), 29.7 (CH2CO2), 30.9 (CH2CH2CO), 31.6
(CH2CH2CONH), 31.9 (CH2CO2), 33.1 (CH2CH2CONH), 34.3
(CH2CONH), 35.3 (HNCH2CH2), 38.8 (HNCH2), 57.3, 57.9 (3HNC),
80.3, 80.4 (2CMe3), 125.5 (CH2=CH), 132.1 (CH2=CH), 165.5, 172.1,
172.6, 172.7 (4CONH), 172.9, 173.7 ppm (2CO2); IR: n˜ =3350 (NH),
1730 (C=O), 1720 (C=O), 1620 (C=C), 1670 cmꢀ1 (C=O); ESI-MS: m/z
calcd: 1602.4 [M+Na]+; found: 1602.1.
13C NMR: d=23.8 (CH3), 24.1 (CH2CO), 26.2 (CH2CH2), 28.5 (CH3),
29.8, 31.0, 31.3, 32.1, 33.9, 34.4, 34.9 (CH2CH2CO, CH2CH2CONH), 38.8
(HNCH2), 55.5, 55.6, 57.3, 57.4 (4HNC), 80.4, 80.5, 80.6 (3CMe3), 93.4
(O2NC), 171.0, 171.8, 172.2, 172.4, 172.7, 172.8, 172.9 (7CONH), 173.0,
173.1, 173.7 ppm (3CO2); IR: n˜ =3350 (NH), 1730 (C=O), 1720 (C=O),
1550 cmꢀ1 (NO2); MALDI-TOF MS: m/z calcd: 3824.9 [M+Na]+; found:
3825.5.
Synthesis of amine 19: Asuspension of 18 (1 g, 263 mmol) and T-1
Raney-Ni (3 g) in absolute EtOH (50 mL) was hydrogenated at 60 psi at
508C for 48 h. The solution was cautiously filtered (pyrophoric) through
Celite, after which the solvent was concentrated in vacuo to afford of
amine 19 as a white solid. Yield: 770 mg (78%); 1H NMR: d=1.24 (s,
6H; CH3), 1.43 (s, 189H; CH3), 1.91 (brs, 84H; CH2CH2CO2), 2.20 (brs,
48H; CH2CH2CONH), 3.20 (brs, 2H; HNCH2), 4.18 (brs, 2H; HNCH2),
6.15 (s, 6H; NH), 6.52 (s, 3H; NH), 6.55 ppm (s, 4H; NH, H2N);
13C NMR: d=24.1 (CH3), 24.5 (CH2CO), 26.4 (CH2CH2), 28.3 (CH3),
29.7, 31.0, 31.5, 32.3, 33.9, 34.4, 34.9 (CH2CH2CO, CH2CH2CONH), 38.8
(NHC), 53.2 (H2NC), 55.6, 57.3, 57.4, (3HNC), 80.4, 80.5, 80.6 (3CMe3),
171.3, 172.4, 173.5 (3CONH), 173.9 ppm (CO2); IR: n˜ =3400–3000
(NH2), 1730 (C=O), 1720 cmꢀ1 (C=O); MALDI-TOF MS: m/z calcd:
3794.9 [M+Na]+; found: 3794.6.
Synthesis of extended nitroamide 16: TMG (250 mL) was added to a stir-
red solution of acryl amide 15 (1 g, 630 mmol) in a MeNO2/CHCl3 mix-
ture (1:1; 50 mL), and the resulting solution was maintained at 508C for
15 h. The mixture was then concentrated in vacuo to give a crude solid,
which was dissolved in CHCl3 and then sequentially washed with dilute
aqueous HCl, water, and saturated brine. The organic solution was dried
(Na2SO4), filtered, and concentrated in vacuo to give a crude oil, which
was subjected to column chromatography (SiO2) eluting with 40%
EtOAc in CHCl3 to give amide 16 as a white solid. Yield: 900 mg (87%);
1H NMR: d=1.44 (s, 81H; CH3), 1.79 (t, J=5.1 Hz, 2H; CH2CO), 1.96
(brm, 36H; CH2CH2CO, CH2CH2CO), 2.15 (brs, 2H; CH2CO), 2.21
(quint, J=4.5 Hz, 2H; CH2CH2CH2CO), 2.27 (m, 12H; CH2CH2CONH,
CH2CONH), 2.30 (m, 4H; CH2CH2), 3.27 (t, J=4.8 Hz, 2H; NHCH2),
4.51 (t, J=4.8 Hz, 2H; O2NCH2), 6.09 (s, 2H; NH), 6.25 (s, 2H; NH),
6.43 ppm (t, J=3.9 Hz, 1H; NHCH2); 13C NMR: d=22.8 (CH2CO), 25.7
Synthesis of isocyanate dendron 20: Triphosgene (23 mg, 79 mmol) in
THF (10 mL) was added to a stirred solution of amine 19 (500 mg,
132 mmol), Et3N (26 mL, 264 mmol) in dry THF (25 mL) at 08C. The solu-
tion was stirred for 12 h, was filtered, and concentrated in vacuo to
afford crude solid. This solid was subjected to column chromatography
(SiO2) eluting with EtOAc to afford isocyanate 20 as a solid. Yield:
1
380 mg (75%); H NMR: d=1.25 (s, 6H; CH3), 1.44 (s, 189H; CH3), 1.95
(brs, 84H; CH2CH2CO2), 2.20 (brs, 48H; CH2CH2CONH), 3.24 (brs,
HNCH2), 3.52 (brs, HNCH2), 6.10 (s, NH), 6.52 (s, NH), 6.55 ppm (s,
NH); 13C NMR: d=23.8 (CH3), 24.1 (CH2CO), 26.2 (CH2CH2), 28.5
(CH3), 29.8, 31.0, 31.3, 32.1, 33.9, 34.4, 34.9, 38.8 (CH2CH2CO,
CH2CH2CONH), 55.6, 57.3, 57.4 (3HNC), 62.3 (OCNC), 80.4, 80.5, 80.6
(3CMe3), 123.2 (OCN), 171.2, 172.4, 172.7 (3CONH), 172.8 ppm (CO2);
IR: n˜ =3300 (NH), 2210 (OCN), 1730 (C=O), 1720 cmꢀ1 (C=O);
MALDI-TOF MS: m/z calcd: 3820.91 [M+Na]+; found: 3822.87.
(CH2CO),
27.9
(CH3),
29.6
(CH2CH2CO2,
CH2CO),
31.3
(CH2CH2CONH), 31.4 (CH2CONH), 32.6 (O2NCH2CH2), 34.3
(HNCH2CH2), 34.7 (CH2CONH), 38.8 (HNCH2), 57.2, 57.7 (4HNC),
74.9 (O2NCH2), 80.3, 80.4 (2CMe3), 170.8, 172.0, 172.5, 172.7 (4CONH),
172.7, 173.5 ppm (2CO2); IR: n˜ =3350 (NH), 1735 (C=O), 1720 (C=O),
1550 cmꢀ1 (NO2); ESI-MS: m/z calcd: 1663.08 [M+Na]+; found: 1662.90.
Synthesis of amide 23: DCC (2.3 g, 11 mmol) and 1-HOBT (1.5 g, 11
mol) were added to a stirred solution of adamantane acid 21 (2 g,
11 mmol) in dry DMF (50 mL) at 258C; after 2 h, aminopentanol 22
(1.15 g, 11 mmol) was added. The mixture was stirred for 5 h, after which
the white precipitate was filtered. The filtrate was concentrated in vacuo
to give a crude oil, which was subjected to column chromatography
(SiO2) eluting with 20% EtOAc in hexane to afford the amide 23 as a
white solid. Yield: 2.5 g (87%); m.p. 103–1048C; 1H NMR: d=1.37–1.51
(brm, 6H; CH2CH2CH2), 1.72–1.85 (brm, 15H; adamantane), 2.01 (s,
1H; OH), 3.25 (t, J=6.9 Hz, 2H; HNCH2), 3.65 (t, J=6.3 Hz, 2H;
HOCH2), 5.60 ppm (s, 1H; NH); 13C NMR: d=23.0 (CH2), 28.1 (CH of
adamantane), 29.4 (CH2), 32.2 (CH2CH2NH), 36.5 (CH2 of adamantane),
36.7 (CH2CH2OH), 39.1 (C48 of adamantane), 39.2 (CH2 of adamantane),
40.5 (HNCH2), 62.2 (HOCH2), 178.2 ppm (CONH); IR: n˜ =3450–3000
(OH), 1720 cmꢀ1 (C=O); ESI-MS: m/z calcd: 288.39 [M+Na]+; found:
288.0.
Synthesis of aminoamide 17: Asolution of predendron 16 (1 g, 610 mmol)
in absolute EtOH (150 mL) with T-1 Raney Ni (3 g) was hydrogenated
(60 psi) at 508C for 24 h. The solution was cautiously filtered, as in the
above procedure, through Celite, then concentrated in vacuo to give the
amino ester 17. Yield: 930 mg (95%); 1H NMR: d=1.44 (s, 81H; CH3),
1.79 (t, J=5.1 Hz, 2H; CH2CO), 1.96 (brm, 36H; CH2CH2CO,
CH2CH2CO), 2.15 (brs, 2H; CH2CO), 2.21 (brm, 2H; CH2CH2CO), 2.27
(m, 12H; CH2CH2CONH, CH2CONH), 2.30 (m, 4H; CH2CH2), 2.80 (t,
J=4.8 Hz, 2H; NHCH2), 3.25 (m, 2H; H2NCH2), 6.09 (s, 2H; NH), 6.25
(s, 2H; NH), 6.96 ppm (t, J=3.9 Hz, 1H; NHCH2); 13C NMR: d=23.1
(CH2CO), 26.0 (CH2CO), 28.0 (CH3), 29.7 (CH2CH2CO2, CH2CO2), 30.7
(CH2CH2CONH), 31.0 (CH2CONH), 31.2 (CH2CH2CONH), 31.3
(CH2CONH), 33.9 (HNCH2CH2), 34.3 (H2NCH2CH2), 38.4 (HNCH2),
39.9 (H2NCH2), 57.3, 57.4, 57.7 (4HNC), 80.3, 80.4 (2CMe3), 172.7, 172.8,
172.9, 173.0 (4CONH), 173.3, 173.9 ppm (2CO2); IR: n˜ =3400–3000
(NH2), 1735 (C=O), 1720 cmꢀ1 (C=O); ESI-MS: m/z calcd: 1633.10
[M+Na]+; found: 1633.0.
Synthesis of mesylate 24: Mesyl chloride (431 mg, 3.7 mmol) in THF
(20 mL) was added to a stirred solution of 23 (1 g, 3.7 mmol), Et3N
(570 mL, 5.6 mmol) in dry THF (50 mL) at 08C. The solution was stirred
for 3 h at 258C. After filtration, the solvent was removed in vacuo to give
a residue, which was dissolved in CHCl3 (100 mL) and washed with water
(100 mL, 2) and then saturated brine. The organic phase was dried
(MgSO4) and concentrated in vacuo to give a solid that was subjected to
column chromatography (SiO2) eluting with 20% EtOAc in hexane to
give 24 as a white solid. Yield: 1.15 g (90%); m.p. 108–1098C; 1H NMR:
d=1.44–1.67 (brm, 6H; CH2CH2CH2), 1.72–1.85 (brm, 15H; adaman-
tane), 3.01 (s, 3H; O2SCH3), 3.25 (t, J=6.6 Hz, 2H; NHCH2), 4.24 (t, J=
6.3 Hz, 2H; OCH2), 5.62 ppm (s, 1H; NH); 13C NMR: d=22.7, 28.1 (CH
of adamantane), 28.7 (CH2), 29.0 (CH2), 36.5 (CH2 of adamantane), 37.3
(O2SCH3), 38.8 (C48 of adamantane), 39.3 (CH2 of adamantane), 40.5
(HNCH2), 69.9 (OCH2), 178.0 ppm (CONH); IR: n˜ =3300 (NH),
1720 cmꢀ1 (C=O); ESI-MS: m/z calcd: 366.48 [M+Na]+; found: 366.0.
Synthesis of predendron 18: DCC (93 mg, 450 mmol) and 1-HOBT
(61 mg, 450 mmol) were added at 258C to a stirred solution of acid 9 (1 g,
450 mmol) in dry DMF (30 mL); after 2 h, extended amine 17 (930 mg,
450 mmol) was added. The mixture was stirred for 24 h, after which the
white precipitate was filtered. The filtrate was concentrated in vacuo to
give a crude oil, which was subjected to column chromatography (SiO2)
eluting with EtOAc to afford predendron 18 as a white solid. Yield: 1.1 g
(65%); 1H NMR: d=1.23 (s, 6H; CH3), 1.44 (s, 189H; CH3), 1.95 (brm,
84H; CH2CH2CO2), 2.20 (brm, 48H; CH2CH2CONH), 3.24 (brm, 4H;
HNCH2), 6.10 (s, 6H; NH), 6.52 (s, 3H; NH), 6.55 ppm (s, 2H; NH);
3732
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 3726 – 3734