Synthesis of a novel class of chiral polyaromatic amide dendrimers bearing an amino acid derived C3-symmetric core

Article abstract of DOI:10.1016/S0040-4039(02)02518-2

Chiral polyaromatic amide dendrimers incorporating a C₃-core have been prepared as potential catalysts for asymmetric reactions.

Full text of DOI:10.1016/S0040-4039(02)02518-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 37–40
Synthesis of a novel class of chiral polyaromatic amide
dendrimers bearing an amino acid derived C3-symmetric core
Barbara Romagnoli, Laurence M. Harwood and Wayne Hayes*
School of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
Received 10 September 2002; revised 28 October 2002; accepted 8 November 2002
Abstract—Chiral polyaromatic amide dendrimers incorporating a C3-core have been prepared as potential catalysts for
asymmetric reactions. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
(TREN) ligand.9 The first, second and third generation
polyaromatic amide dendrons have been synthesized
via a convergent approach10 using 1,3-diamino-2-
hydroxypropane and 4-carboxybenzaldehyde as the
building blocks. The multifunctional C3-symmetric core
system has been prepared via reductive alkylation of
ammonia with the so-called Garner aldehyde.
Dendrimers represent a novel class of polymers1 that
possess regular highly branched and well-defined struc-
tures. The primary interest of early dendrimer research;
the preparation and characterization of new hyper-
branched polymers that possess minimal structural
defects, has now led to detailed investigations of the
chemical and physical properties of this class of macro-
molecules. The modulation of these properties via min-
imal structural modifications has resulted in numerous
applications of these functionalized dendrimers includ-
ing drug delivery systems,2 artificial antennae,3 sensors,4
unimolecular micelles5 and catalysts.6 Indeed, one of
the most promising developments of dendrimer
research is the preparation of novel and efficient cata-
lytically active hyperbranched macromolecules.7 Den-
drimers combine the main advantages of both
homogeneous and heterogeneous catalysts, i.e. excellent
solubility in common organic solvents (an advantage of
homogeneous catalysts) and ease of removal from the
reaction media by membrane and ultrafiltration tech-
niques as a direct result of their large size in compari-
son to the products (an advantage of heterogeneous
catalysts).8
2. Results and discussion
A convergent approach11 was chosen in order to avoid
formation of structural defects during dendrimer con-
struction. Commercially available 1,3-diamino-2-
hydroxypropane was selected as the AB2 type
monomer, and 4-carboxybenzaldehyde has been used as
the rigid ‘linker’ between the branched points. After
initial protection of the amino groups (with Boc moi-
eties) of the branching unit to form the peripheral
surface of the resultant dendrimers, coupling with 4-
carboxybenzaldehyde using dicyclohexylcarbodiimide
(DCC) as the coupling agent afforded the first genera-
tion dendron featuring an aldehyde focal point. Subse-
quent oxidation of the aldehyde functionality with
KMnO4 yielded the corresponding first generation den-
dron with a carboxylic acid at the focal point 1 (Fig. 1).
Selective coupling with the amino functionalities of a
further equivalent of 1,3-diamino-2-hydroxypropane
led to the formation of the second generation dendron
that featured a hydroxyl group at the focal point.
Repetition of the esterification, oxidation and amide
formation steps led to the second and third generation
dendrons 2 and 3, respectively (Fig. 1). Optimum con-
ditions for selective amide bond formation involved use
of either diphenylphosphorylazide (DPPA) or 1-benzo-
triazolyloxy-tris-(dimethylamino)-phosphonium hexa-
As part of a programme directed towards the prepara-
tion of dendritic catalysts for use in metal catalyzed
asymmetric transformations, we hereby report the syn-
thesis of a novel class of polyaromatic amide den-
drimers that incorporate a chiral C3-symmetric core
unit that is analogous to the tris(2-ethylamino)amine
Keywords: chiral dendrimers; Garner aldehyde; asymmetric catalysis.
* Corresponding author. Fax: +44 (0) 118 931 6331; e-mail:
w.c.hayes@rdg.ac.uk
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02518-2

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B. Romagnoli et al. / Tetrahedron Letters 44 (2003) 37–40
Figure 1. The first, second and third generation polyaromatic amide dendrons featuring carboxylic acid focal points.
fluorophosphane (BOP). The second and third genera-
tion dendrons were thus constructed in yields of 83 and
65%, respectively.11
from the trialkylated system 6). The enantiomeric chiral
core system has also been prepared from the -Garner
-serine) in
D
aldehyde derivative (in turn obtained from
D
an equally efficient manner.
In a parallel study to the work of Raymond et al.,12 we
have prepared the chiral C3-symmetric core unit 4 in an
The final coupling step between the dendrons 1, 2 and
3 with the chiral core system 4 was performed using DCC
as the coupling agent to afford the corresponding den-
drimers (see 7 in Fig. 2).15,16 All of the dendritic systems
have been characterized via 1H NMR, 13C NMR and IR
spectroscopy, optical rotation, MALDI-TOF mass spec-
trometry and GPC analyses.15
efficient manner (Scheme 1) from the so-called L-Garner
aldehyde 5.
L
-Garner aldehyde 5 was synthesized from
L
-serine using an efficient four step route described by
Taylor and co-workers.13 Reductive alkylation of ammo-
nium acetate with the Garner aldehyde in the presence
of NaBH(OAc)3 led to the formation of the trialkylated
system 6 in 90% yield. This intermediate was then
exposed to HCl (6N) to effect complete deprotection of
the oxazolidine and Boc groups to afford the correspond-
ing triamino-triol. Selective Boc protection14 of the three
amino functionalities then afforded the desired optically
pure C3-symmetric core system 4 (>90% overall yield
The binding efficacy of these chiral dendritic ligands for
a range of transition metals is being assessed at present
and the use of these complexes in metal catalyzed
asymmetric transformations will be reported in due
course.
Scheme 1. Synthesis of the chiral C3-symmetric core unit derived from
(6N), >99%; (iii) (Boc)2O, THF/water, >90%.
L-serine. (i) NaBH(OAc)3, CH3OH, 4 h, rt, 90%; (ii) HCl

B. Romagnoli et al. / Tetrahedron Letters 44 (2003) 37–40
39
Figure 2. The second generation chiral polyaromatic amide dendrimer 7 (RRR-enantiomer shown above—both enantiomers have
been synthesized).
Acknowledgements
Leeuwen, P. W. N. M. Angew. Chem., Int. Ed. Engl.
2001, 40, 1828–1849; (b) Kreiter, R.; Kleij, A. W.; Klein
Gebbink, R. J. M.; van Koten, G. Top. Curr. Chem.
2001, 217, 163–199.
We gratefully acknowledge the University of Reading
Research Endowment Trust Fund (B.R.) for their
financial support of this work. The authors would also
like to thank EPSRC (GR/M91884) and SAI Ltd for
the funding provided for the MALDI-TOF MS facili-
ties at the University of Reading.
9. (a) Raposo, C.; Almaraz, M.; Martin, M.; Mussons, M.
L.; Alcaraz, V.; Caballero, M. C.; Moran, J. R. Chem.
Lett. 1995, 759–760; (b) Hammes, B. S.; Young, V. G.;
Borovik, A. S. Angew. Chem., Int. Ed. Engl. 1999, 38,
666–669.
10. Hawker, C. J.; Fre´chet, J. M. J. J. Chem. Soc., Chem.
Commun. 1990, 1010–1013.
11. (a) Romagnoli, B.; Harwood, L. M.; Hayes, W. Polym.
Mater. Sci. Eng. 2001, 84, 778–779; (b) Hayes, W.;
Romagnoli, B.; Harwood, L. M.; Philp, D.; Price, D. W.;
Smith, M. Tetrahedron, submitted for publication.
12. Karpishin, T. B.; Stack, T. D. P.; Raymond, K. N. J.
Am. Chem. Soc. 1993, 115, 6115–6125.
References
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K.; Frey, H.; Weener, J. W.; Meijer, E. W.; Paulus, W.;
Duncan, R. J. Control. Release 2000, 65, 133–148.
3. Gilat, S. L.; Adronov, A.; Fre´chet, J. M. J. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1422–1427.
13. Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K.
Synthesis 1998, 1707–1708.
14. To a solution of the fully deprotected core (0.15 g, 0.43
mmol) and triethylamine (0.546 mL, 3.92 mmol) in THF/
water (10 mL, 9:1), di-tert-butyl-dicarbonate (0.72 g, 3.25
mmol) dissolved in THF (4 mL) was added dropwise.
After 4 h of stirring at room temperature the solvent was
evaporated to afford the crude product as a yellowish oil
that was purified by column chromatography
(CHCl3:EtOH, 90:10) (0.21 g, 92%).
4. James, T. D.; Shinmori, H.; Takeuchi, M.; Shinkai, S. J.
Chem. Soc., Chem. Commun. 1996, 705–706.
5. Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J. J. Chem.
Soc., Perkin Trans. 1 1993, 1287–1297.
6. (a) Chow, H.-F.; Mong, T. K.-K.; Nongrum, M. F.;
Wan, C.-W. Tetrahedron 1998, 54, 8543–8660; (b) Fis-
cher, M.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1999,
38, 885–905; (c) Vo¨gtle, F.; Gestermann, S.; Hesse, R.;
Schwierz, H.; Windish, B. Prog. Polym. Sci. 2000, 25,
987–1041; (d) Inoue, K. Prog. Polym. Sci. 2000, 25,
453–571.
Mp 119–121°C, [h]D20 −44.6 (c 1.0, CHCl3). TLC Rf=0.7
(CHCl3:EtOH, 85:15). 1H NMR (250 MHz, d6-DMSO)
l, ppm 1.44 (27H, s, (CH3)C-); 2.26 (3H, m, -CH2NH-);
2.65 (3H, m, -CH2NH-); 3.45–3.48 (3H, bm,
-NHCHCH2-, 3H, m, -CH2OH); 4.49 (3H, m, -CH2OH);
6.39 (3H, d, J=6.6, -NH-); 13C NMR (62.5 MHz,
d6-DMSO) l, ppm 28.6 (CH3)3C; 50.9, -NHCHCH2-;
56.4, -CH2N-; 61.9, -CH2OH; 79.6, (CH3)3C-; 155.5,
7. Romagnoli, B.; Hayes, W. J. Mater. Chem. 2002, 12,
767–800.
8. (a) Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; van

40
B. Romagnoli et al. / Tetrahedron Letters 44 (2003) 37–40
-OCONH-. Accurate mass MS (CI) m/z 537.3517 (M+1).
Elemental analysis, required 53.71% C, 9.01% H, 10.43%
(24H, bm, H-ArOCO-); 8.80 (6H, bm, -NHCO-). 13C
NMR (100.1 MHz, d6-DMSO) l, ppm 27.9, 28.1
(CH3)3C-; 40.6 -(CH2)2CH; 47.8 -CH2CHNH; 56.0
-(CH2)3N-; 65.2 -CHCH2OCO-; 73.0, 73.2 -CH(CH2)2-;
77.8, 79.2 (CH3)3C; 127.1, 129.5, 130.1, H-Ar; 132.4,
133.4, 133.6, 138.1 -OC-Ar; 155.3 -NHOCO-; 155.7
-NHOCO-; 164.8 -OCO-; 166.0 -OCO-. MALDI-TOF
N, found 53.29% C, 9.14% H, 10.32% N, IR wmax 3388,
3340, 2977, 1716, 1677, 1536, 1367 cm−1
.
15. A solution of 2 (0.36 g, 0.34 mmol), the chiral core 4
(0.03 g, 0.056 mmol) and a catalytic amount of dimethyl-
aminopyridine (DMAP) in dry CH2Cl2 (5 mL) was
cooled to 0°C under nitrogen. DCC (0.07 g, 0.34 mmol)
in dry CH2Cl2 (3 mL) was then added dropwise to the
stirred solution. The mixture was stirred for 12 h and
then filtered to isolate the white solid containing dicyclo-
hexylurea and the product 7. Purification by size exclu-
sion chromatography (THF) afforded the pure product in
55% yield (0.11 g).
MS: calculated for
found: 3756.3 (M+K)+. IR wmax 3355, 2976, 1711, 1530,
1503, 1268, 1168, 1107, 871 cm−1
C183H252O60N22 (M+Na)+3740.9,
.
16. The first and second generation dendrimers were isolated
in 75 and 55% yield, respectively. In contrast to the
smaller dendrimers, isolation of the third generation den-
drimer proved difficult (despite extensive chromato-
graphic separation attempts) and therefore an
approximate yield (30%) is reported. Problematic purifi-
cations involving structurally related polyamide den-
drimers have also been documented in the literature by
several other research groups (see Appelhans, D.;
Komber, H.; Vogt, D.; Ha¨ussler, L.; Voit, B. I. Macro-
molecules 2000, 33, 9494–9503; Ishida, Y.; Jikei, M.;
Kakimoto, M.-A. Macromolecules 2000, 33, 3202.)
[h]2D0 −10.1 (c 1.1, CHCl3); 1H NMR (400 MHz, d6-
DMSO) l, ppm 1.30 (135H, s, (CH3)3C); 2.45 (3H, bm,
-(CH2)2N-); 2.80 (3H, bm, -(CH2)2N-); 3.20 (24H, bm,
-CONHCH2-); 3.75 (12H, bm, -CONHCH2-); 3.92 (3H,
bm, -CH2CHNH-); 4.19 (3H, bm, -CHCH2O-); 4.40 (3H,
bm, -CHCH2O-); 4.90 (6H, bm, -CH(CH2)2); 5.40 (3H,
bm, -CH(CH2)2); 6.95 (12H, bm, -OCONH-); 7.10 (3H,
bm, -OCONH-); 7.90 (12H, bm, H-ArCONH-); 7.99