Convergent synthesis of 1 → 3 C-branched polyamide dendrons

Article abstract of DOI:10.1055/s-1998-1945

A convergent synthesis of 1 → 3 C-branched polyamide dendrons was developed providing a facile access to defined monodisperse dendritic building blocks.

Full text of DOI:10.1055/s-1998-1945

1
396
LETTERS
SYNLETT
Convergent Synthesis of 1 → 3 C-Branched Polyamide Dendrons
Michael Brettreich and Andreas Hirsch*
Institut für Organische Chemie der Universität Erlangen-Nürnberg, Henkestr. 42, D-91054 Erlangen, Germany
Fax: +49 9131 8526864; e-mail: hirsch@organik.uni-erlangen.de
Received 27 August 1998
Abstract: A convergent synthesis of 1 → 3 C-branched polyamide
Acknowledgments
dendrons was developed providing
monodisperse dendritic building blocks.
a facile access to defined
We thank the Fonds der Chemischen Industrie for financial support.
References and Footnotes
Dendrons are increasingly used as versatile building blocks in organic
chemistry in order to design stereochemically defined macromolecules
with attractive solubility-, polarity-, amphiphilic-, molecular
aggregation-, biological activity-, reactivity-, catalytical- and
(
1) Newkome, G. R.; Moorefield, C. N.; Vögtle, F. Dendritic
Molecules, VCH, New York, 1996.
(
2) a.) Newkome, G. R.; Behera, R. K.; Moorefield, C. N.; Baker, G.
R. J. Org. Chem. 1991, 56, 7162; b.) Newkome, G. R.; Nayak, A.;
Behera, R. K.; Moorefield, C. N.; Baker, G. R. J. Org. Chem.
1
photochemical properties . Among the various types of dendritic
building blocks 1 → 3 C-branched polyamide dendrimers, developed by
1
992, 57, 358.
3) Newkome, G. R.; Weis, C. D., Moorefield, C. N. Macromolecules
997, 30, 2300.
2
Newkome et al. are of interest due to their high branching multiplicity
(
and bulkiness as well as the hydrophilicity of their corresponding
unprotected polyacids. So far, only divergent syntheses involving the
1
3
problem of incomplete transformation of the multiple termini have
(4) Newkome, G. R.; Narayanan, V. V.; Echegoyen, L.; Peréz-
2
been applied for these dendrimers bearing cores like adamantane ,
Cordero, E.; Luftmann, H. Macromolecules 1997, 30, 5187.
4
5
anthraquinone derivatives , metal complexes , porphyrines and
cyclophanes .
(
5) Newkome, G. R.; Güther, R.; Moorefield, C. N.; Cardullo, F.;
Echegoyen, L.; Peréz-Cordero, E.; Luftmann, H. Angew. Chem.
Int. Ed. Engl. 1995, 34, 2023.
6
In a project aimed at the synthesis of dendrimers involving C as a very
6
0
7
,8
versatile structure determining core
we became interested in the
(6) Dandliker, P. J.; Diederich, F.; Zingg, A.; Gisselbrecht, J.-P.;
Gross, M.; Louati, A.; Sanford, E. Helv. Chim. Acta 1997, 80,
1773; Mattei, S.; Seiler, P.; Diederich, F.; Gramlich, V. Helv.
Chim. Acta 1995, 78, 1904; Wallimann, P.; Seiler, P.; Diederich, F.
Helv. Chim. Acta 1996, 79, 779.
development of water soluble and superamphiphilic dendrimers
containing Newkome type 1 → 3 C-branched polyamide dendrons as
hydrophilic moieties. For this purpose it is desirable to have a series of
defined dendrons in hand and to elaborate a convergent synthesis of
dendrons like 1 which can easily be attached to the fullerene core either
after the introduction of a functional group allowing for a direct
coupling with C60 or via coupling to suitable precursor adducts.
(7) Camps, X.; Schönberger, H.; Hirsch, A. Chem. Eur. J. 1997, 3,
5
61.
(8) Brettreich, M.; Hirsch, A. Tetrahedron Lett. 1998, 39, 2731.
The convergent synthesis of 1 (Scheme 1) is based on the use of the
nitro tricarboxylic acid 2 and the amino tricarboxylate 3 as starting
(9) Newkome, G. R.; Weis, C. D. Org. Prep. Proced. Int. 1996, 28,
4
85; Newkome, G. R.; Behera, R. K.; Baker, G. R. Acta
2
,9
materials . At the same time 2 was employed as the trifunctional
coupling component in each branching step. For the synthesis of the
second generation dendrons 4 and 5 the two components were subjected
to a standard amide formation procedure using 1-hydroxy-benzotriazole
Crystallogr. 1994, C50, 120.
(10) 9-Cascade:nitromethane[3]:(2-aza-3-oxopentylidyne):propionic-
acid-tert-butylester 4: A solution of 160 mg (0.58 mmol)
4
4
-nitro-4-[2-(carboxyethyl)]heptanediacid 2, 800 mg (1.93 mmol)
-amino-4-[2-(tert-butoxycarbonyl)ethyl)]-heptanedioate 3, 234
[
HOBT] and dicyclohexylcarbodiimide [DCC] in DMF as condensing
agents. Triscarboxamide 4 was isolated in 71 % yield after flash
chromatography on silica gel. The reduction of the nitro group in 4 was
achieved with hydrogenation using Raney-nickel as catalyst affording
mg (1.73 mmol) HOBT and 357 mg (1.73 mmol) DCC in 15 ml
DMF was stirred for 48 hours at room temperature. The white
precipitate was filtered and DMF was removed in vacuum. The
residue was disolved in 25 ml ethyl acetate and this solution was
washed with 10% HCl, water, saturated aqueous NaHCO3 and
brine solutions. After drying the organic phase over MgSO4 and
concentration in vacuum the product was purified by flash
chromatography on silica gel (cyclohexane:ethyl acetate 2:1) to
nd
the 2 generation amine 5 in 90 % yield. After a second cycle using the
rd
same procedures for the coupling reaction the 3 generation nitro
compound 6 was obtained in 21 % yield after flash chromatography on
rd
silica gel. Finally, hydrogenation of 6 afforded the dendritic 3
generation amine 1 in 75 % yield.
1
0
With the development of the 2nd and 3rd generation amines 1 and 6 we
provided building blocks susceptible to a variety of subsequent coupling
reactions. The attachment to various central cores should be
straightforward for example if they contain carboxylic acid
functionalities (e.g. via peptide-coupling) or any other functionality that
readily reacts with primary amines. We have already published a
give 605 mg (71 %) of 4. 1H-NMR (400 MHz, CDCl , 25 °C):
3
δ[ppm] = 1.44 (s, H-10, 81 H), 1.95 (m, H-6, 18 H), 2.11 (m, H-2
and H-3, 12 H), 2.20 (m, H-7, 18 H), 6.23 (s, NH, 3 H); 13C-NMR
(
100 MHz, CDCl , 25 °C): δ[ppm] = 28.10 (C-10), 29.82, 29.93,
3
3
9
1.32 and 31.35 (C-2, C-3, C-6, C-7), 57.64 (C-5), 80.72 (C-9),
2.56 (C-1), 170.57 (C-4), 172.82 (C-8); FAB-MS: m/z = 1470
nd
successful coupling of the 2 generation amine to C60 as a core
+
13 12
-1
(
M ; calc. for
C C75H132N O : 1470); IR(KBr): ν (cm ) =
4 23
8
molecule (see ref. ).
3
1
367, 2979, 2936, 1731, 1683, 1665, 1538, 1456, 1368, 1317,
255, 1155, 953, 848, 757. Anal. calc. for C76H132N O23.0.5
The newly synthesized compounds were fully characterized by IR- and
NMR-spectroscopy, by FAB-mass spectrometry as well as by elemental
analysis (experimental datails and spectroscopic data are given in
4
C6H12 (1512.0): C 62.76, H 9.20, N 3.71; found: C 62.39, H 9.60,
N 3.61.
1
0
ref. ).
9-Cascade:aminomethane[3]:(2-aza-3-oxopentylidyne):pro-
panoicacid-tert-butylester 5: To a solution of 163 mg ( 0.11 mmol)

December 1998
SYNLETT
1397
O
O
O
O
O
O
O
O
O
O
O
O
NH
HN
O
OH
OH
O
O
1
3
H2N
R
O2N
+
O
O
DCC, HOBT, DMF
3
O
O
O
O
OH
2
4
NH
O
O
O
O
5
6
7
O
8
2
3
O
O
O
O
9
10
R = NO2
R = NH2
4
5
O
O
O
O
O
O
H2, Raney-nickel
O
O
O
O
O O
O
O
O
HN
O
HN
NH
O
O
O
O
O
O
O
O
O
O
O
O
NH
O
O
NH
HN
O
O
H
1
N
O
O
R
O
2, DCC, HOBT, THF
3
O
NH
2
O
O
4
O
O
O
NH
5
O
O
O
O
6
8
O
O
O
7
NH
O
O
O
O
O
HN
HN
9
1
0
O
1
O
O
O
1
4
2
11
O
O
1
3
O
O
O
O
O
O
R = NO2
6
1
O
H2, Raney-Nickel
R = NH2
Scheme 1
4
in 15 ml dry ethanol 150 mg Raney-nickel [Aldrich] were added
(100 MHz, CDCl , 25 °C) [ppm]: δ = 27.98 (C-10), 29.70, 29.79,
3
and hydrogenated under normal pressure and room temperature
for 24 hours. After filtering the solution on celite and removing
the solvent the product was purified by flash chromatography on
silica gel using first cyclohexane:ethyl acetate 1:2 and then
31.45 and 35.02 (C-2, C-3, C-6, C-7), 52.68 (C-5), 57.29 (C-1),
80.45 (C-9), 172.35 (C-4), 172.64 (C-8); FAB-MS: m/z = 1440
+
13 12
-1
(M ; calc. for
C C75H134N O : 1440); IR(KBr): ν (cm ) =
4 21
3359, 2978, 2935, 1731, 1680. 1655, 1542, 1457, 1420, 1392,
1368, 1317, 1255, 1154, 1102, 1037, 954, 848, 758, 590; Anal.
cyclohexane:ethyl acetate: methanol 1:2:1 as eluent to give 143
1
mg (90 %) of 5. H-NMR (400 MHz, CDCl , 25 °C) [ppm]: δ =
calc. for C76H134N O21.EtOH (1486.0): C 63.05, H 9.50, N 3.77;
3
4
1
.43 (s, H-10, 81 H), 1.61 (m, H-1, 6 H), 1.95 (m, H-6, 18 H), 2.17
found: C 63.11, H 9.87, N 3.71.
1
3
(m, H-3, 6 H), 2.21 (m, H-7, 18 H), 6.04 (s, NH, 3 H); C-NMR

1
398
LETTERS
SYNLETT
2
2
2
7-Cascade:nitromethane[3]:(2-aza-3-oxopentylidyne) :pro-
panoicacid-tert-butylester 6: The third generation nitro compound
was prepared in yield 21 % using the same procedure applied for
27-Cascade:aminomethane[3]:(2-aza-3-oxopentylidyne) :pro-
panoicacid-tert-butylester 1: The third generation dendron 1 was
synthesized in 75 % yield analoguously to 6 by reduction with
hydrogen. H-NMR (400 MHz, CDCl , 25 °C) [ppm]: δ = 1.43 (s,
6
1
the synthesis of 4. However, instead of DMF, THF was used as
3
solvent. The purification was achieved by flash chromatography
H-14, 81 H), 1.59 (m, H-2, 6 H), 1.94 (m, C-6, C-10, 72 H), 2.14
(m, H-3, 6 H), 2.19 (m, H-7, H-11, 72 H), 6.24 (s, NH, 9H), 6.91
1
(silica gel; cyclohexane:ethyl acetate = 3:2.). H-NMR (400 MHz,
CDCl , 25 °C) [ppm]: δ = 1.43 (s, H-14, 243 H), 1.95 (m, H-6, H-
(s, NH, 3 H); 13C-NMR (100 MHz, CDCl , 25 °C) [ppm]: δ =
3
3
1
0, 72 H), 2.15 (m, H-2, H-3, 12 H), 2.19 (m, H-7, H-11, 72 H),
28.01 (C-14), 29.72, 31.22, 31.47, 35.24 (C-2, C-3, C-6, C-7, C10,
C-11), 52.98 (C-1), 57.29 (C-9), 57.71 (C-5), 80.31 (C-13),
172.64 (C-8, C-12), 173.25 (C-4); FAB-MS: m/z = 4513 (M ;
1
3
6.35 (s, NH, 9 H), 7.04 (s. NH, 3 H); C-NMR (100 MHz,
+
CDCl , 25 °C) [ppm]: δ = 28.14 (C-14), 29.80, 31.11, 31.22 (C-2,
C-3, C-6, C-7, C-10, C11), 57.38 (C-9), 57.97 (C-5), 80.42 (C-13),
3
1
3
12
+
calc. for
C2 C236H413N13O66: 4512), 4535 ([M+Na] );
-
1
92.97 (C-1), 171.06 (C-4), 172.65 (C-12), 172.69 (C-8); FAB-MS:
IR(KBr): ν (cm ) =3437, 3378, 3327, 2979, 2935, 1736, 1681,
1652, 1540, 1457, 1421, 1392, 1368, 1316, 1255, 1215, 1155,
1103, 1035, 955, 921, 848, 758, 592, 758, 592, 465, 433; Anal.
calc. for C238H413N13O66.2 EtOH (4605.1): C 63.12, H 9.30, N
3.95; found: C 62.95, H 9.64, N 3.82.
+
13 12
m/z = 4674 ([M+Cs] ; calc. for C2 C236H411N13 O68Cs:
-1
4
1
8
6
675); IR(KBr): ν (cm ) = 3376, 2980, 2934, 1735, 1681, 1656,
539, 1457, 1393, 1368, 1319, 1256, 1213, 1166, 1147, 1102, 956,
48, 758; Anal. calc. for C238H411N13O68.C H (4627.1): C
6
12
3.34, H 9.21, N 3.94; found: C 62.95, H 9.64, N 3.82.