2094 J. Am. Chem. Soc., Vol. 119, No. 9, 1997
Zanini and Roy
was stirred vigorously for 3 h at 25 °C. The solution was concentrated
and dried under vacuum overnight. The trifluoroacetate salt of 4 was
recovered as a yellow resin in 96% yield (2.14 g, 3.75 mmol) and used
without further purification.
The trifluoroacetate salt of 7 was isolated as above from ester 6 to
provide 7 as a yellow resin in quantitative yield.
Compounds 9, 16, 21, and 26 were prepared in a similar fashion
from hexamethylenediamine (8) or tris(2-(aminoethyl)amine 15 and
from di- or tetravalent acids 4 and 7. Reaction times required for
complete coupling as measured Via ninhydrin testing were each 20 h.
After chromatography, isolated yields were 86% for 9, 88% for 16,
79% for 21, and 72% for 26.
1
Data for 4: 1H-NMR (CDCl3) δ 1.78 (m, 4H, â-CH2), 3.11 (m, 8H,
R-CH2, γ-CH2), 3.79 (s, 2H, NCH2C(O)), 4.99 (s, 4H, Cbz-CH2), 5.81
(br s, 2H, Cbz-NH), 7.24-7.28 (m, 10H, Cbz-Ph), 10.6-11.2 (br s,
CO2H); 13C-NMR (CDCl3) δ 27.8 (â-C), 37.6 (γ-C), 53.0 (R-C), 53.4
(NCH2C(O)), 66.9 (Cbz-CH2), 114.9 and 117.2 (trifluoroacetate salt),
127.9, 128.2, and 128.4 (Cbz-Ph, ortho, meta, para), 136.3 (Cbz-Ph,
C-1), 157.4 (acid CdO), 161.0 and 161.3 (Cbz CdO’s), 167.9
(trifluoracetate salt CdO); FAB-MS (pos) calcd for C24H31N3O6 457.22,
found 458.2 (M+ + 1, 17.2% base peak).
Data for 6: H-NMR (CDCl3) δ 1.40 (s, 9H, tBu), 1.52-1.59 (m,
12H, â-CH2), 2.47-2.57 (m, 12H, R-CH2), 3.02-3.27 (m, 18H, γ-CH2,
NCH2C(O)), 5.04 (s, 8H, Cbz-CH2), 5.52 (br s, 4H, Cbz-NH), 7.24-
7.36 (m, 20H, Cbz-Ph), 7.58 (br s, 2H, amide NH); 13C-NMR (CDCl3)
δ 27.2 (â-C), 28.1 (CH3), 37.3 and 38.9 (γ-C), 52.0 and 52.4 (R-C),
55.8 and 57.8 (NCH2C(O)), 57.8 (Cbz-CH2), 81.4 (OCMe3), 128.0 and
128.5 (Cbz-Ph, ortho, meta, para), 136.7 (Cbz-Ph, C-1), 165.8-171.0
(CdO); FAB-MS (pos) calcd for C60H85N9O12 1123.63, found 1125.1
(M+ + 1, 14.5% base peak).
Data for 9: 1H-NMR (CDCl3) δ 1.24 (m, 4H, a-CH2), 1.43 (m, 4H,
b-CH2), 1.55 (m, 8H, â-CH2), 1.89 (m, 8H, R-CH2), 2.94 (br s, 4H,
NCH2C(O)), 3.14 (m, 12H, γ-CH2, c-CH2), 5.02 (s, 8H, Cbz-CH2),
5.52 (br s, 4H, Cbz-NH), 7.23-7.30 (m, 20H, Cbz-Ph), 7.58 (br s, 2H,
NH amide); 13C-NMR (CDCl3) δ 26.1 (a-C), 27.4 (â-C), 29.3 (b-C),
38.6 (c-C), 38.9 (γ-C), 52.5 (R-C), 58.4 (NCH2C(O)), 66.5 (Cbz-CH2),
127.8, 128.0, 128.3 (Cbz-Ph, ortho, meta, para), 136.7 (Cbz-Ph, C-1),
156.6-171.2 (CdO); FAB-MS (pos) calcd for C54H74N8O10 994.55,
found 995.5 (M+ + 1, 75.6% base peak).
1
Data for 7: H-NMR (CDCl3) δ 1.83 (m, 12H, â-CH2), 3.15 (m,
24H, R-CH2, γ-CH2), 3.92 (m, 6H, NCH2C(O)), 5.15 (br s, 8H, Cbz-
CH2), 5.81 (br s, 4H, Cbz-NH), 7.21-7.40 (m, 20H, Cbz-Ph).
Preparation of Di- (5), Tetra- (10), Hexa- (17), Octa- (22), and
Dodeca- (27) Amines. Typical Procedure. To compound 3 (400 mg,
0.78 mmol) was added MeOH (10 mL) containing 10% Pd/C (40 mg).
H2 was bubbled through the solution and the mixture stirred for 30
min at 25 °C. The mixture was then filtered and the Pd/C washed
twice with MeOH. All filtrates were combined and dried down, giving
compound 5 in 90% yield (264 mg, 0.70 mmol). Yellow resin 5 was
used as is.
1
Data for 16: H-NMR (CDCl3) δ 1.55 (m, 12H, â-CH2), 2.41 (m,
12H, R-CH2), 2.53 (m, 6H, a-CH2), 3.12-3.23 (m, 24H, γ-CH2, b-CH2,
NCH2C(O)), 5.02 (s, 12H, Cbz-CH2), 5.65 (br s, 6H, Cbz-NH), 7.23-
7.30 (m, 30H, Cbz-Ph), 7.54 (br s, 3H, NH amide); 13C-NMR (CDCl3)
δ 27.3 (â-C), 37.4 (b-C), 38.9 (γ-C), 52.5 (R-C), 54.1 (a-C), 58.0
(NCH2C(O)), 66.5 (Cbz-CH2), 127.8, 128.0, 128.5 (Cbz-Ph, ortho, meta,
para), 136.7 (Cbz-Ph, C-1), 156.7-171.6 (CdO); FAB-MS (pos) calcd
for C78H105N13O15 1464.77, found 1466.4 (M+ + 1, base peak).
Data for 21: 1H-NMR (CDCl3) δ 1.21-1.25 (m, 4H, a-CH2), 1.38-
1.44 (m, 4H, b-CH2), 1.54 (m, 24H, â-CH2), 2.38 (m, 24H, R-CH2),
2.90-3.34 (2m, 50H, γ-CH2, c-CH2, NCH2C(O)), 5.01 (s, 16H, Cbz-
CH2), 5.64, 5.74 (2br s, 4H, NH amide), 5.84, 5.94 (2br s, 8H, Cbz-
NH), 7.23-7.29 (m, 40H, Cbz-Ph), 7.39-7.41 (br s, 2H, NH amide);
13C-NMR (CDCl3) δ 26.4 (a-C), 27.3 (â-C), 29.3 (b-C), 36.6 (c-C),
38.8 (γ-C), 52.3 (R-C), 58.3 (NCH2C(O)), 66.4 (Cbz-CH2), 127.9,
128.0, 128.4 (Cbz-Ph, ortho, meta, para), 136.6 (Cbz-Ph, C-1), 156.6-
172.9 (CdO); FAB-MS (pos) calcd for C118H166N20O22 2216.74, found
2218 (M+ + 1, 3.2% base peak).
Amines 10, 17, 22, and 27 were obtained in a similar manner as
white solids in yields of 95, 93, 100, and 61%, respectively. Reaction
times were 20 h.
1
Data for 5: H-NMR (CDCl3) δ 1.34 (s, 9H, tBu), 1.49 (m, 4H,
â-CH2), 1.75 (br s, 4H, NH2), 2.49 (t, 4H, JR,â ) 7.0 Hz, R-CH2), 2.64
(t, 4H, Jâ,γ ) 6.7 Hz, γ-CH2), 3.07 (s, 2H, NCH2C(O)); 13C-NMR
(CDCl3) δ 28.1 (CH3’s), 30.9 (â-C), 40.3 (γ-C), 52.0 (R-C), 56.0
(NCH2C(O)), 170.9 (CdO); mass spectrum (CI) (rel intens) m/z 246.1
(M+, 51.6%).
1
Data for 10: H-NMR (CDCl3) δ 1.23 (m, 4H, a-CH2), 1.48 (m,
12H, b-CH2, NH2), 1.59 (m, 8H, â-CH2), 2.49 (m, 8H, R-CH2), 2.72
(m, 8H, γ-CH2), 3.02 (s, 4H, NCH2C(O)), 3.21 (m, 4H, c-CH2), 7.56
(s, 2H, NH amide); 13C-NMR (CDCl3) δ 26.6 (a-C), 29.7 (b-C), 30.9
(â-C), 38.8 (c-C), 40.3 (γ-C), 51.9 (R-C), 58.7 (NCH2C(O)), 171.5
(CdO); mass spectrum (CI) (rel intens) m/z 458.9 (M+, base peak).
Data for 17: 1H-NMR (CDCl3) δ 1.52-1.75 (m, 24H, â-CH2, NH2),
2.47-2.92 (m, 30H, R-CH2, γ-CH2, a-CH2), 3.02 (s, 6H, NCH2C(O)),
3.43 (m, 6H, b-CH2); 13C-NMR (CDCl3) δ 30.5, 30.6 (â-C), 36.9 (b-
C), 38.7 (γ-C), 52.7 (R-C), 53.7 (a-C), 58.8 (NCH2C(O)), 170.9 (CdO);
FAB-MS (pos) calcd for C30H69N13O3 659.56, found 660.5 (M+ + 1,
3.1% base peak).
1
Data for 26: H-NMR (CDCl3) δ 1.56 (m, 36H, â-CH2), 2.39 (m,
42H, R-CH2, a-CH2), 2.89-3.35 (2m, 60H, γ-CH2, b-CH2, NCH2C-
(O)), 5.01 (s, 24H, Cbz-CH2), 5.68-5.82 (m, 12H, Cbz-NH), 7.24-
7.30 (m, 60H, Cbz-Ph); 13C-NMR (CDCl3) δ 27.4 (â-C), 37.4 (b-C),
38.9 (γ-C), 52.4 (R-C), 58.3 (NCH2C(O)), 66.4 (Cbz-CH2), 127.8,
128.0, 128.4 (Cbz-Ph, ortho, meta, para), 136.7 (Cbz-Ph, C-1), 156.7-
172.9 (CdO).
Preparation of N-Chloroacetylated Dendrimers 11, 18, 23, and
28. Typical Procedure. To a solution of amine 10 (38 mg, 0.086
mmol) in DMSO (2 mL) was added chloroacetic anhydride (1.2 equiv
per amine functionality, 70 mg, 0.41 mmol). The solution was stirred
for 2 h at 25 °C. The reaction was judged to be complete by the
ninhydrin test. The solvent was removed in Vacuo and the residue
was subjected to basic alumina chromatography using 20% H2O in CH3-
CN as eluent in order to remove the chloroacetate anion of 11.
Compound 11 was isolated in 81% yield as a yellow resin (52 mg,
0.069 mmol).
Data for 22: 1H-NMR (DMSO-d6) δ 1.22 (m, 4H, a-CH2), 1.52 (m,
4H, b-CH2), 1.65 (m, 24H, â-CH2), 2.36-2.49 (2m, 24H, R-CH2), 2.75
(m, 12H, NCH2C(O)), 2.99-3.26 (m, 28H, γ-CH2, c-CH2), 4.91 (br s,
NH2); 13C-NMR (DMSO-d6) δ 25.5 (â-C), 26.6 (a-C), 29.1 (b-C), 37.8
(c-C), 38.4 (γ-C), 51.7, 52.0 (R-C), 57.0 (NCH2C(O)), 170.4-173.6
(CdO).
1
Data for 24: H-NMR (DMSO-d6) δ 1.53-1.65 (m, 24H, â-CH2),
2.39-2.51 (m, 24H, R-CH2), 2.74 (m, 12H, NCH2C(O)), 2.93-3.27
(m, 36H, γ-CH2, a-CH2, b-CH2), 5.00 (br s, NH2); 13C-NMR (DMSO-
d6) δ 25.3, 26.6 (â-C), 36.7 (b-C), 37.6, 37.8 (γ-C), 51.7, 52.0 (R-C),
57.0, 57.5 (NCH2C(O)), 170.8-173.3 (CdO).
N-Chloroacetylated dendrimers 18, 23, and 29 were isolated in 86,
64, and 78% yields, respectively.
Synthesis of Cbz-Protected Dendrimers 9, 16, 21, and 26. Typical
Procedure. To a solution of amine 5 (170 mg, 0.45 mmol) in CH3CN
(15 mL) was added acid 4 (1.2 equiv per amine group, 617 mg, 1.08
mmol) already dissolved in CH2Cl2 (2 mL) and neutralized with DIPEA.
To the stirred solution were added diisopropylcarbodiimide (DIC, 136
mg, 1.08 mmol) and hydroxybenzotriazole (HOBt, 146 mg, 1.08 mmol),
and the mixture was stirred at 25 °C. The pH was kept at 9 by the
addition of DIPEA. Completion of the reaction was monitored by the
ninhydrin test. After 3 h, the solution was treated with HOj resin for
15 min in order to remove excess acid and HOBt. The solution was
concentrated and the residue subjected to column chromatography using
a slow gradient of CH3CN to 20% water in CH3CN. Tetravalent 6
was isolated as a yellow resin in 82% yield (448 mg, 0.40 mmol).
Data for 11: 1H-NMR (CDCl3) δ 1.33 (m, 4H, a-CH2), 1.51 (m, 4H,
b-CH2), 1.69 (m, 8H, â-CH2), 2.50 (m, 8H, R-CH2), 3.02 (br s, 4H,
NCH2C(O)), 3.24 (m, 4H, c-CH2), 3.34 (m, 8H, γ-CH2), 4.02 (s, 8H,
ClCH2); 13C-NMR (CDCl3) δ 26.1 (a-C), 26.9 (â-C), 29.3 (b-C), 38.1
(γ-C), 38.7 (c-C), 42.7 (ClCH2), 52.5 (R-C), 58.4 (NCH2C(O)), 166.3,
171.1 (CdO); FAB-MS (pos) calcd for C30H54N8O6Cl4 762.29, found
763.3 (M+ + 1, 61.9% base peak).
1
Data for 18: H-NMR (DMSO-d6) δ 1.75 (m, 12H, â-CH2), 2.47-
2.50 (m, 12H, R-CH2), 3.12 (m, 30H, γ-CH2, a-CH2, b-CH2, NCH2C-
(O)), 4.03 (s, 12H, ClCH2); 13C-NMR (DMSO-d6) δ 26.1 (â-C), 36.7
(b-C), 37.0 (γ-C), 42.6 (ClCH2), 51.9 (R-C), 53.1 (a-C), 60.2 (NCH2C-