Convergent Synthesis and Diversity of Amino Acid Based Dendrimers
FULL PAPER
ϫ CЈЈЈЈH2NЈЈЈЈH), 3.65 (br. s, 60 H, 2 ϫ CH2NH, 4 ϫ CЈH2NЈH, according to the procedure described in 22, using hydrochloride
8 ϫ CЈЈH2NЈЈH, 16 ϫ CЈЈЈH2NЈЈЈH), 3.87 (br. s, 124 H, 2 ϫ OCH2, salt 27 (232 mg; 0.50 mmol), (Boc)9-[G2]-CO2H (3.32 g;
4 ϫ OCЈH2, 8 ϫ OCЈЈH2, 16 ϫ OCЈЈЈH2, 32 ϫ OCЈЈЈЈH2), 5.41
1.50 mmol), BOP (828 mg; 1.88 mmol), acetonitrile (5 mL) and Di-
(br. s, 32 H, 32 ϫ NЈЈЈЈH), 6.32, 6.40 (2br. s., 31 H, Ph-C4-H, 2 ϫ PEA (0.85 ml; 4.88 mmol). Column chromatography (MeOH/
Ph-C4Ј-H, 4 ϫ Ph-C4ЈЈ-H, 8 ϫ Ph-C4ЈЈЈ-H, 16 ϫ Ph-C4ЈЈЈЈ-H), 6.81, DCM, 4:96) afforded the third generation dendrimer 29 as a white
6.89 (2br. s., 62 H, Ph-C2,6-H, 2 ϫ Ph-C2Ј,6Ј-H, 4 ϫ Ph-C2ЈЈ,6ЈЈ-H, solid (2.29 g, 66%). Ϫ Rf ϭ 0.57 (MeOH/DCM, 1:9). Ϫ H NMR
1
8 ϫ Ph-C2ЈЈЈ,6ЈЈЈ-H, 16 ϫ Ph-C2ЈЈЈЈ,6ЈЈЈЈ-H), 7.68 (br. s, 30 H, 2 ϫ
NH, 4 ϫ NЈH, 8 ϫ NЈЈH, 16 ϫ NHЈЈЈ); 13C NMR (CDCl3): δ ϭ
(CDCl3): δ ϭ 1.40, 1.42, 1.43 [3 s, 243 H, 27 ϫ C(CH3)3], 1.79Ϫ2.11
(m, 78 H, 3 ϫ OCH2CH2, 9 ϫ OCЈH2CЈH2, 27 ϫ OCЈЈH2CЈЈH2),
27.9 [C(CH3)3], 40.0 (CH2NH, CЈH2NЈH, CЈЈH2NЈЈH, 3.17Ϫ3.60 (m, 78 H, 3 ϫ NHCH2, 9 ϫ NЈHCЈH2, 27 ϫ
CЈЈЈH2NЈЈЈH, CЈЈЈЈH2NЈЈЈЈH), 52.0 (OCH3), 66.7, 67.3 (OCЈH2, NЈЈHCЈЈH2), 3.80, 4.00Ϫ4.10 (2 m, 78 H, 3 ϫ OCH2, 9 ϫ OCЈH2,
OCH2, OCЈЈH2, OCЈЈЈH2, OCЈЈЈЈH2), 79.3 [C(CH3)3], 104.9, 106.3
27 ϫ OCЈЈH2), 3.86 (s, 3 H, OCH3), 5.40 (br. s, 27 H, 27 ϫ NЈЈH),
(Ph-C4,4Ј,4ЈЈ,4ЈЈЈ,4ЈЈЈЈ, Ph-C2,6,2Ј,6Ј,2ЈЈ,6ЈЈ,2ЈЈЈ,6ЈЈЈ,2ЈЈЈЈ,6ЈЈЈЈ), 132.0 (Ph-C1), 7.00, 7.13, 7.27 (3 br. s., 26 H, Ph-C2,6-H, 3 ϫ Ph-C2Ј,6Ј-H, 9 ϫ Ph-
136.4 (Ph-C1Ј,1ЈЈ,1ЈЈЈ,1ЈЈЈЈ), 157.3 [CϭO (Boc)], 160.2 (Ph- C2ЈЈ,6ЈЈ-H), 7.78, 7.93, 8.03 (3 br. s., 12 H, 3 ϫ NH, 9 ϫ NЈH). Ϫ 13C
C3,5,3Ј,5Ј,3ЈЈ,5ЈЈ,3ЈЈЈ,5ЈЈЈ,3ЈЈЈЈ,5ЈЈЈЈ), 167.1 (CO2CH3), 168.8 (CЈϭO, CЈЈϭ
NMR (CDCl3): δ ϭ 28.2 [C(CH3)3], 29.0, 29.4, 29.9 (OCH2CH2,
O, CЈЈЈϭO, CЈЈЈЈϭO). Ϫ MS (ESI): m/z ϭ 2026 [M ϩ 5 H]5ϩ, 2030 OCЈH2CЈH2, OCЈЈH2CЈЈH2), 37.2, 37.8, 38.1, 38.7 (NHCH2,
[M ϩ 4 H ϩ Na]5ϩ, 2035 [M ϩ 3 H ϩ 2 Na]5ϩ, 2039 [M ϩ 2 H
NЈHCЈH2, NЈЈHCЈЈH2), 52.0 (OCH3), 66.8, 71.3, 72.5 (OCH2,
ϩ 3 Na]5ϩ, 2047 [M ϩ 1 H ϩ 4 Na]5ϩ, 2048 [M ϩ 5 Na]5ϩ. Ϫ OCЈH2, OCЈЈH2), 78.7 [C(CH3)3], 105.6 (Ph-C2Ј,6Ј, Ph-C2ЈЈ,6ЈЈ),
C502H694N262O158: calcd. C 59.55, H 6.91, N 8.58; found C 59.43,
H 7.01, N 8.46.
107.5 (Ph-C2,6), 125.0 (Ph-C1), 129.3, 129.4, 129.5, 130.0, 130.2
(Ph-C1Ј, Ph-C1ЈЈ), 139.6, 139.7, 139.9 (Ph-C4Ј, Ph-C4ЈЈ), 141.4 (Ph-
C4), 152.0, 152.2 (Ph-C3,5, Ph-C3Ј,5Ј, Ph-C3ЈЈ,5ЈЈ), 155.9 [CϭO
(Boc)], 166.3 (CO2CH3), 167.0, 167.1, 167.1, 167.3 (NЈHCЈϭO,
NЈЈHCЈЈϭO). Ϫ MS (ESI): m/z ϭ 1389 [M ϩ 5 H]5ϩ, 1736 [M ϩ
4 H]4ϩ, 2336 [M ϩ H ϩ 2 Na]3ϩ. Ϫ C344H545N39O107: calcd. C
59.54, H 7.92, N 7.87; found C 59.68, H 7.88, N 7.91.
Hydrochloride Salt 27: Boc deprotection of monomer 15 (7.87 g;
12.0 mmol), was performed using the procedure described for 18,
affording a white solid (5.70 g) in a quantitative yield. Ϫ Rf ϭ 0.22
1
(CHCl3/MeOH/25% NH4OH, 60:45:20). Ϫ H NMR (D2O): δ ϭ
2.14 (m, 2 H, Ph-C4-OCH2CH2), 2.26 (m, 4 H, Ph-C3,5-OCH2CH2),
3.26 (m, 6 H, 3 ϫ NHCH2), 3.95 (s, 3 H, OCH3), 4.27 (m, 6 H, 3
ϫ OCH2), 7.44 (s, 2 H, Ph-C2,6-H). Ϫ 13C NMR (D2O): δ ϭ 25.9
(Ph-C3,5-OCH2CH2), 26.6 (Ph-C4-OCH2CH2), 36.5, 37.0
(NHCH2), 52.1 (OCH3), 65.6, 70.7 (OCH2), 107.5 (Ph-C2,6), 124.7
(Ph-C1), 139.5 (Ph-C4), 150.7 (Ph-C3,5), 167.3 (CO2CH3).
(Boc)81-[G4]-CO2Me (30): (Boc)27-[G3]-CO2Me (29) (2.30 g;
0.33 mmol) was saponified following the same procedure as de-
scribed in the synthesis of 20, using slightly modified Tesser’s base
(2.5 mL). After stirring overnight at 40 °C, (Boc)27-[G3]-CO2H
(1.55 g; 68%) was obtained as a white solid. The coupling step was
performed similar to the procedure described in 22, using hydro-
chloride salt 27 (30 mg; 0.064 mmol), (Boc)27-[G3]-CO2H (1.32 g;
0.19 mmol), BOP (105 mg; 0.24 mmol), acetonitrile (0.85 mL) and
DiPEA (0.11 ml; 0.62 mmol). Column chromatography (MeOH/
DCM, 6:94) afforded the fourth generation dendrimer 30 as a white
solid (922 mg, 69%). Ϫ Rf ϭ 0.55 (MeOH/DCM, 1:9). Ϫ 1H NMR
(CDCl3): δ ϭ 1.39, 1.41 [2 br. s, 729 H, C(CH3)3], 1.88 (br. s, 240
H, OCH2CH2, OCЈH2CЈH2, OCЈЈH2CЈЈH2, OCЈЈЈH2CЈЈЈH2),
3.20Ϫ3.59 (m, 240 H, CH2NH, CЈH2NЈH, CЈЈH2NЈЈH,
CЈЈЈH2NЈЈЈH), 3.78, 3.92Ϫ4.00 (2 m, 240 H, OCH2, OCЈH2,
OCЈЈH2, OCЈЈЈH2), 3.82 (s, 3 H, OCH3), 5.46 (br. s, 81 H, NЈЈЈH),
6.99, 7.13, 7.26 (3br. s., 80 H, Ph-C2,6-H, Ph-C2Ј,6Ј-H, Ph-C2ЈЈ,6ЈЈ-H,
Ph-C2ЈЈЈ,6ЈЈЈ-H), 7.83, 8.08, 8.14 (3br. s., 39 H, NH, NЈH, NЈЈH). Ϫ
13C NMR (CDCl3): δ ϭ 28.4 [C(CH3)3], 29.6, 30.1 (OCH2CH2,
OCЈH2CЈH2, OCЈЈH2CЈЈH2, OCЈЈЈH2CЈЈЈH2), 37.5, 38.0, 38.2
(CH2NH, CЈH2NЈH, CЈЈH2NЈЈH, CЈЈЈH2NЈЈЈH), 67.0, 71.5,
72.3(OCH2, OCЈH2, OCЈЈH2, OCЈЈЈH2), 78.9 [C(CH3)3], 105.8 (Ph-
C2Ј,6Ј, Ph-C2ЈЈ,6ЈЈ, Ph-C2ЈЈЈ,6ЈЈЈ), 129.5, 129.6, 129.7, 130.1 (Ph-C1Ј,
Ph-C1ЈЈ, Ph-C1ЈЈЈ), 140.0 (Ph-C4Ј, Ph-C4ЈЈ, Ph-C4ЈЈЈ), 152.3, 152.4
(Ph-C3,5, Ph-C3Ј,5Ј, Ph-C3ЈЈ,5ЈЈ, Ph-C3ЈЈЈ,5ЈЈЈ), 156.1 (CϭO Boc),
167.3, 167.3, 167.4, 167.5 (CЈϭO, CЈЈϭO, CЈЈЈϭO). The signals of
Ph-C1, Ph-C4 and CO2CH3 are not visible. Ϫ MS (ESI): m/z ϭ
(Boc)9-[G2]-CO2Me (28): (Boc)3-[G1]-CO2Me (15) (9.8 g;
15.0 mmol) was saponified following the same procedure as de-
scribed in the synthesis of 20, using slightly modified Tesser’s base
(170 mL). After stirring overnight, acid 26 (9.0 g, 94%) was ob-
tained as a white foam. The coupling step was performed according
to the procedure described for 20, using acid 26 (8.7 g; 13.5 mmol),
hydrochloride salt 27 (2.1 g; 4.5 mmol) and BOP (7.4 g;
16.9 mmol), dichloromethane (60 mL) and DiPEA (7.6 mL;
43.9 mmol). The mixture was stirred for 4 h. Column chromato-
graphy (MeOH/DCM, 4:96) afforded the second generation den-
drimer 28 as a white solid (9.0 g, 90%). Ϫ Rf ϭ 0.67 (MeOH/DCM,
1:9). Ϫ 1H NMR (CDCl3): δ ϭ 1.42, 1.42, 1.44 [3s, 81 H, 9 ϫ
C(CH3)3], 1.88Ϫ1.99 (m, 18 H, 9 ϫ OCЈH2CЈH2), 2.10 (m, 6 H, 3
ϫ OCH2CH2), 3.19Ϫ3.39 (m, 18 H, 9 ϫ NЈHCЈH2), 3.64 (m, 6 H,
3 ϫ NHCH2), 3.82, 4.06 (2 m, 18 H, 9 ϫ OCЈH2), 3.89 (s, 3 H,
OCH3), 4.13 (m, 6 H, 3 ϫ OCH2), 5.21, 5.36 (2br. s., 9 H, 9 ϫ
NЈH), 6.98 [s, 2 H, Ph(B)-C2Ј,6Ј-H], 7.11 [s, 4 H, Ph(AA)-C2Ј,6Ј-H],
7.28 (s,
OCH2CH2CH2NH), 7.54 (br. s, 1 H, Ph-C4-OCH2CH2CH2NH).
13C NMR (CDCl3): δ ϭ 28.4, 28.4 [C(CH3)3], 29.2, 29.6, 30.0
2
H, Ph-C2,6-H), 7.30 (br. s,
2
H, Ph-C3,5
-
Ϫ
(OCH2CH2, OCЈH2CЈH2), 37.6, 38.0, 38.3, 38.7 (NHCH2,
NЈH2CЈH2), 52.2 (OCH3), 66.9, 67.1, 71.5, 72.8 (OCH2, OCЈH2),
79.0 [C(CH3)3], 105.7, 105.9 (Ph-C2Ј,6Ј), 107.9 (Ph-C2,6), 125.5 (Ph-
C1), 129.8 (Ph-C1Ј), 140.1 (Ph-C4Ј), 141.4 (Ph-C4), 152.3, 152.3,
152.3 (Ph-C3,5, Ph-C3Ј,5Ј), 156.1 [CϭO (Boc)], 166.3 (CO2CH3),
167.1, 167.4 (NЈHCЈϭO). Ϫ MS (FAB): m/z ϭ 2249.6 (average
mass) [M ϩ Na]ϩ . Ϫ C110H176N12O35: calcd. C 59.34, H 7.97, N
7.55; found C 59.26, H 7.92, N 7.48.
2343.8 [M ϩ 9 H]9ϩ, 2636.4 [M ϩ 8 H]8ϩ. Ϫ C1046H1652N120O323
:
calcd. C 59.61, H 7.90, N 7.97; found C 59.79, H 7.85, N 7.87.
Thioacetate 32: 12-Aminododecanoic acid (31) was esterified, Boc-
protected, reduced and mesylated following the procedures de-
scribed in the synthesis of 9 and 10, to afford Boc(H)N(CH2)12OMs
as a white solid (87%, 4 steps). A suspension of Boc(H)(CH2)12-
OMs (174 mg, 0.5 mmol), potassium thioacetate (63 mg,
0.55 mmol) and a catalytic amount of 18-crown-6 in THF (1 mL)
was stirred at room temp. overnight. The mixture was concentrated
(Boc)27-[G3]-CO2Me (29): (Boc)9-[G2]-CO2Me (28) (4.45 g;
2.00 mmol) was saponified following the same procedure as de-
scribed in the synthesis of 20, using slightly modified Tesser’s base
(15 mL). After stirring overnight, (Boc)9-[G2]-CO2H (4.34 g, 98%) and dissolved in ethyl acetate and water. The organic layer was
was obtained as a white solid. The coupling step was performed
washed with 5% NaHCO3, water and brine, dried (Na2SO4) and
1913
Eur. J. Org. Chem. 2001, 1903Ϫ1915