Multi-tier dendrimers with an aromatic core

Article abstract of DOI:10.1002/ejoc.200801150

We report various multi-tier designer dendritic molecules that incorporate an aromatic core and heterocyclic and peptide units. The 5-(azidomethyl)benzene- 1,3-dicarbonyl unit was chosen as the scaffold as this unit allows two identical units and a reacti

Full text of DOI:10.1002/ejoc.200801150

FULL PAPER
DOI: 10.1002/ejoc.200801150
Multi-Tier Dendrimers with an Aromatic Core
V. Haridas,*[a] Yogesh K. Sharma,[a] and Sarala Naik[a]
Dedicated to the memory of Dr. Darshan Ranganathan
Keywords: Dendrimers / Click reactions / Heterocycles / Amino acids
We report various multi-tier designer dendritic molecules
that incorporate an aromatic core and heterocyclic and pep-
tide units. The 5-(azidomethyl)benzene-1,3-dicarbonyl unit
was chosen as the scaffold as this unit allows two identical
units and a reactive end to be incorporated, thus generating
a dendron suitable for dendrimer synthesis. The design and
synthesis of dendrimers with multi-tier architectures will be
useful for generating dendritic structures with various func-
tions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
proaches to the synthesis of dendrimers: convergent and di-
vergent approaches.[11] In the convergent approach, den-
drons are synthesized separately and then linked together
in a modular fashion, converging to form a dendrimer.[12]
In the divergent approach, the dendrimer is built stepwise
and diverges outward.[13]
We herein report various dendritic molecules that incor-
porate an aromatic core and heterocyclic and peptide units.
As biological molecules, peptides are an attractive choice
for incorporation into dendritic structures.
Introduction
Dendrimers are molecules with a tree-like architecture,
having a central core, branching units and surface function-
alities. Owing to their multivalent nature, dendrimers can
increase binding to receptors, thus enhancing biological ef-
fects.[1] Dendritic molecules with multiple functionalities
can act as matrix structures for many biological applica-
tions, including multiple antigen peptides (MAP),[2] carrier
molecules,[3,4] vaccine developments,[5] artificial enzymes[6]
and globular protein mimetics.[7] Biocompatible dendri-
mers[8] are much sought after for biological applications be-
cause the success of dendrimers as carriers or biomaterials
is dependent upon their biocompatibility, that is, the ability
of compounds to exist or perform in a biological environ-
ment without any undesired toxic effects. In general, toxic-
ity is related mostly to the size, charge and surface function-
ality of the dendrimers.
The various beneficial attributes of dendrimers create a
strong impetus for the design and synthesis of these tree-
like macromolecules.[9,10] An ideal dendrimer synthesis is
one that provides the opportunity to incorporate a variety
of functional groups into the dendrimer by design and has
a robust synthetic strategy, a simple purification procedure
and a good yield. However, many accounts of dendrimer
synthesis reported in the literature do not meet all the above
criteria and the development of a versatile dendrimer syn-
thesis is therefore highly warranted. There are two key ap-
Results and Discussion
Lysine, with Nα and Nε amino groups as its reactive ends,
is a suitable amino acid for forming a branching unit by
sequential propagation of lysines. The Nα and Nε amino
groups can be functionalized with lysine units to double the
number of terminal amino groups. The sequential addition
of Lys units will generate a dendron with a large number
of Lys units with a single C-terminal moiety. Reaction with
propargylamine and BocLys(Boc)-OH in the presence of N-
hydroxysuccinimide and DCC produced propargyl amide,
which on deprotection and coupling with BocLys(Boc)-OH
produced Lys-dendron 2 with a C-terminal alkyne moiety
(Scheme 1).
In order to have carboxylate groups on the surface of the
dendrimer we chose aspartic acid as the monomer unit. The
Cα and Cβ carboxylic acid groups are able to act as
branching units by the sequential addition of Asp units
(Scheme 2). Boc-Asp on reaction with Asp.diOMe in the
presence of N-hydroxysuccinimide and DCC produced Asp-
(Asp.diOMe)Asp.diOMe. Sequential addition of Asp units
can generate an Asp-based dendron ideal for dendrimers
with peripheral methoxycarbonyl groups.
[a] Department of Chemistry and School of Biological Sciences,
Indian Institute of Technology (IIT)
New Delhi 110016, India
E-mail: haridasv@chemistry.iitd.ac.in
h_haridas@hotmail.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Multi-Tier Dendrimers with an Aromatic Core
Scheme 1. Synthesis of the Lys-based dendron.
Scheme 3. Synthesis of aryl-anchored dendrons 13a, 13b and 13c.
Reagents and conditions: (a) MeOH/H2SO4; (b) 1 equiv. of NaOH;
(c) BH3·Me2S; (d) SOCl2, reflux; (e) NaN3; (f) 2  NaOH; (g)
SOCl2, reflux; (h) i. Asp.diOMe HCl, NEt3; ii. Asp(Asp.diOMe)-
Asp.diOMe, NEt3; iii. Asp(Leu.OMe)Leu.OMe, NEt3.
The advantage of the CuI-catalysed azide–alkyne coup-
ling reaction (click reaction)[15,16] is that it can link the un-
protected peptide fragments to the central core. This is
demonstrated by the synthesis of 21 and 24 in 51 and 72%
yields, respectively. The CuI-catalysed click reaction exclu-
Scheme 2. Synthesis of Asp-based dendron.
The 5-(azidomethyl)benzene-1,3-dicarbonyl unit was sively yielded the triazole-1,4-diyl product.[17] Owing to its
chosen as the scaffold because this unit allows us to incor- high chemoselectivity, this highly atom-economic and ef-
porate two identical units and a reactive end, thus generat- ficient coupling reaction is a powerful tool for the effective
ing a dendron suitable for dendrimer synthesis. The 1,3,5- construction of complex dendrimers.[18]
benzenetricarboxylic acid was converted into 5-(azido-
To synthesize various dendrimers, the azide-truncated
methyl)benzene-1,3-dicarbonyl dichloride in seven steps dendrons 13a and 13b were treated with various trialkynes
by a literature method (Scheme 3).[14] In a typical pro- to provide a host of dendrimers. The trialkyne unit 14 was
cedure, 1,3,5-benzenetricarboxylic acid (5) was converted synthesized in 62% yield from 1,3,5-tris(chlorocarbonyl)-
into trimethyl ester 6 in the presence of a small amount of benzene and propargylamine (Scheme 5). This trialkyne 14
acid. The triester 6 was selectively hydrolysed to mono acid was treated with azide dendrons 13a and 13b to provide
7, which on reduction with BH3·Me2S furnished mono 40 and 43% yields of dendrimers 18 and 19, respectively
alcohol 8. The alcohol 8 thus generated was converted into (Scheme 4).
the azide 10 by treatment with thionyl chloride followed by
The dendrimer 18 has a central benzene core, a second
reaction with sodium azide. The mono azide 10 was con- tier of heterocyclic triazole units, a third tier of benzene
verted into the diacid 11 by base hydrolysis and further con- units and peripheral peptide units. To illustrate the versatil-
verted into the acid chloride by reaction with thionyl chlo- ity of this approach, we decided to synthesize dendrimers
ride under reflux. The reaction of H2N-Asp.diOMe, H2N- that incorporate various structurally distinct units on mov-
Asp(Asp.diOMe)-Asp.diOMe or H2N-Asp(Leu.OMe)-Leu- ing from the central core to the periphery. With this in mind
.OMe with 5-(azidomethyl)benzene-1,3-dicarbonyl dichlo- the hexaalkyne 15 was designed and synthesized from Boc-
ride (12) afforded the azido-substituted dendrons 13a, 13b Asp. Propargyl alcohol was treated with Boc-Asp in the
and 13c, respectively (Scheme 3).
presence of N-hydroxysuccinimide and DCC to produce
The mono azide 13b was allowed to react, in the presence propargyl-functionalized aspartic acid, which on deprotec-
of cuprous iodide (CuI), with Lys-dendron 17 containing a tion using 25% TFA and further reaction with 1,3,5-tris-
C-terminal alkyne unit, which provided unsymmetrical den- (chlorocarbonyl)benzene afforded hexaalkyne 15. The azide
drimer 22 in 55% yield (Scheme 4). The fully protected den- dendron 13a was treated with hexaalkyne 15 to generate a
dron 17 was deprotected by using 25% TFA in CH2Cl2, hybrid dendrimer 20 with a central aromatic ring, a second
affording cationic dendron 16, which on reaction with 13a tier of Asp units, a third tier of triazole units, a fourth tier
provided the cationic dendrimer 21. Dendrimer 21 can also of benzene rings and a fifth tier of peptide units. All the
be synthesized from the fully protected dendrimer by treat- compounds were characterized and the structures were in
ing it with 50% TFA in dry CH2Cl2.
accordance with the spectroscopic data.
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V. Haridas, Y. K. Sharma, S. Naik
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Scheme 4. Synthesis of symmetrical and unsymmetrical dendrimers using click reaction.
This synthesis allows us to incorporate a wide variety of (Scheme 6). To synthesize an all-amide symmetric den-
amino acids into the dendrimer skeleton. The versatility of drimer, AspdiOMe was treated with 1,3,5-tris(chlorocar-
the design is illustrated by the incorporation of the hydro- bonyl)benzene to yield 65% of the first-generation den-
phobic leucine as peripheral units. Z-Asp (Z = benzyloxy- drimer 30. To synthesize higher-generation dendrimers, the
carbonyl) was treated with Leu.OMe under N-hydroxysuc- Asp-dendron 13a was reduced with Pd/C in methanol to
cinimide/DCC coupling conditions to generate Z-Asp- produce amine 29, which on reaction with 1,3,5-tris(chloro-
(Leu.OMe)Leu.OMe in 94% yield. Deprotection of the carbonyl)benzene yielded 83% of the all-amide dendrimer
benzyloxycarbonyl group with H2 in the presence of Pd/C 31. Dendrimer 31 has a central benzene core, a second tier
and reaction with acid chloride 12 afforded dendron 13c, of benzene units and surface peptide units. The second tier
which on click reaction with Lys-dendrons provided unsym- of benzene rings act as branching units.
metrical dendrimers.
The dendrimers were characterized by HPLC, NMR and
The additional advantage of dendrons 13a and 13b with mass spectrometry. The purity of all the dendrimers synthe-
an azide unit is that it is not only suitable for click chemis- sized was checked by reversed-phase analytical HPLC (RP-
try, but may also be reduced to generate amine-truncated HPLC) using a C-18 column and a binary gradient with
dendrons. The amine-truncated dendrons 28 and 29 were the mobile phase solvents [solvent A: 0.1% trifluoroacetic
used for the synthesis of all-amide dendrimers[19] 30 and 31 acid (TFA) in water; solvent B: 0.1% TFA in acetonitrile
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Multi-Tier Dendrimers with an Aromatic Core
Scheme 5. Synthesis of tri- and hexaalkyne cores.
Scheme 6. Synthesis of all-amide dendrimers.
(see the Supporting Information)]. HPLC traces showed an
increase in retention time with increasing generation of den-
drimers. For example, 18 and 20 showed a retention time of
Conclusions
The synthetic strategy and design of dendrimers with
24.2 and 39.3 min in a binary gradient with the acetonitrile/ multi-tier architecture will be useful for generating dendritic
water/TFA system. The NMR spectrum of dendrimer 18 structures with the capability of trapping substrates in dif-
indicated a very symmetrical structure with 18 α-COOMe ferent tier regions, which could thus act as reaction vessels.
and 18 β-COOMe units resonating at δ = 3.62 and These dendrimers could be designed to trap biologically im-
3.60 ppm, respectively. The five-tier dendrimer 20 showed a portant molecules for site-specific delivery in cells. The two
single peak for each of the 36 α-COOMe and 36 β-COOMe synthetic approaches demonstrated herein will be useful for
units. The molecular integrity was shown by mass spec- the future generation of dendrimers with functional proper-
trometry; the mass spectrometric analysis showed a strong ties. The orthogonality and fidelity of the click reaction will
molecular-ion peak for all dendrimers synthesized. For ex- facilitate the conjugation of important chemical entities in
ample, dendrimer 20 showed a mass of 3849.1419 in the presence of numerous other unprotected functionalities.
HRMS, compared with the theoretical molecular weight of
The synthesis reported herein is particularly attractive
3849.1418 calculated for C165H183N33NaO75.
because it has the potential to produce dendrimers with en-
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V. Haridas, Y. K. Sharma, S. Naik
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94%; m.p. 143–144 °C. [α]D = –40.4 (c = 0.5, MeOH). 1H NMR
(CDCl3, 300 MHz): δ = 0.90 (m, 12 H), 1.57 (m, 6 H), 2.63 (dd, J
= 15.3, 7.0 Hz, 1 H), 2.87 (br. d, 1 H), 3.70 (s, 3 H), 3.71 (s, 3 H),
4.55 (m, 3 H), 5.11 (s, 2 H), 6.40 (d, J = 7.2 Hz, 1 H), 6.71 (d, J =
7.5 Hz, 1 H), 7.31 (m, 6 H) ppm. 13CNMR (75 MHz, CDCl3): δ =
21.6, 21.7, 22.6, 22.7, 24.7, 33.8, 38.0, 40.7, 41.0, 50.9, 51.0, 51.4,
52.1, 52.2, 67.0, 127.9, 128.0, 128.4, 136.1, 156.0, 170.6, 170.8,
hanced biocompatibility and biodistribution. These are de-
sirable properties for dendrimers to find applications in bio-
logy. The dendrimers reported herein can be easily modified
at their surfaces to obtain desired biological properties.
Experimental Section
173.2, 173.5 ppm. IR (KBr): ν = 3298, 3076, 2956, 2878, 1740,
˜
1702, 1653, 1542, 1441, 1362, 1257, 1141 cm–1. HRMS: calcd. for
C26H39N3NaO8 544.2635; found 544.2636.
Synthesis of Aryl-Anchored Dendrons
Preparation of 13a: Dry triethylamine (NEt3; 0.76 mL, 5.5 mmol)
was added to an ice-cooled solution of Asp.diOMe.HCl (28;
0.493 g, 2.5 mmol) in dry CH2Cl2 (20 mL) and the mixture was
stirred for 20 min. 5-(Azidomethyl)benzene-1,3-dicarbonyl dichlo-
ride (12; 0.258 g, 1 mmol) dissolved in dry CH2Cl2 (50 mL) was
added dropwise for 15 min and left to stir for 24 h. The reaction
mixture was mixed with distilled CH2Cl2 (30 mL) and washed with
aqueous 2  H2SO4 followed by water and aqueous NaHCO3 solu-
tion. The organic layer was dried with Na2SO4 and evaporated to
yield 0.370 g of the crude product. Chromatographic purification
of the crude product yielded 0.300 g of 13a. Yield 59%; viscous
liquid. [α]D = +0.171 (c = 0.270, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 3.00 (dd, J = 17.1, 4.3 Hz, 2 H), 3.16 (dd, J = 17.1,
4.3 Hz, 2 H), 3.72 (s, 6 H), 3.81 (s, 6 H), 4.47 (s, 2 H), 5.08 (m, 2
H), 7.41 (d, J = 7.8 Hz, 2 H), 7.92 (s, 2 H), 8.20 (s, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 29.6, 35.9, 49.1, 52.1, 52.9, 53.8,
Preparation of NH2-Asp.(Leu.OMe)Leu.OMe: An ice-cooled solu-
tion of Z-Asp.(Leu.OMe).Leu.OMe (0.650 g, 1.24 mmol) in dry
MeOH (10 mL) was mixed with 10% Pd/C (peptide/catalyst 1:0.25,
w/w) and H2 was bubbled through the reaction mixture for 1.5 h.
After completion of the reaction (TLC), the solution was filtered
and the filtrate was evaporated to yield 0.442 g of the product.
Yield 92%. H NMR (CDCl3, 300 MHz): δ = 0.95 (m, 12 H), 1.58
(m, 6 H), 1.91 (m, 2 H), 2.51 (dd, J = 14.7, 7.5 Hz, 1 H), 2.75 (dd,
J = 14.5, 4.4 Hz, 1 H), 3.73 (s, 6 H), 4.53 (m, 2 H), 4.58 (m, 1 H)
1
6.99 (br. d, 1 H), 7.84 (d, J = 8.4 Hz, 1 H) ppm. IR (KBr): ν =
˜
3324, 3188, 3077, 2960, 1752, 1679, 1525, 1443, 1375, 1313, 1242,
1204, 1164 cm–1. HRMS: calcd. for C18H33KN3O6 426.2006; found
426.2007.
Preparation of the Azide: Et3N (0.26 g, 2.6 mmol) was added to
an ice-cooled solution of NH2-Asp.(Leu.OMe).Leu.OMe (0.442 g,
1.14 mmol) in dry CH2Cl2 (30 mL) and the mixture was stirred for
125.4, 129.9, 134.6, 137.0, 165.6, 171.0, 171.5 ppm. IR (KBr): ν =
˜
3390, 2955, 2102, 1740, 1655, 1532, 1442, 1219 cm–1. HRMS: calcd.
for C21H25N5NaO10 530.1499; found 530.1499.
20 min.
5-(Azidomethyl)benzene-1,3-dicarbonyl
dichloride
(0.134 g, 0.52 mmol) dissolved in dry CH2Cl2 (40 mL) was added
dropwise over 25 min and left to stir overnight. The reaction mix-
ture was mixed with distilled CH2Cl2 (20 mL) and washed with
aqueous 2  H2SO4 and aqueous NaHCO3 solution. The organic
layer was dried with Na2SO4 and evaporated to yield 0.5 g of the
crude product. Chromatographic purification of the crude product
yielded 0.480 g of 13c. Yield 96%. [α]D = –34.0 (c = 0.2, MeOH).
1H NMR (CDCl3, 300 MHz): δ = 0.81 (m, 12 H), 0.92 (m, 12 H),
1.67 (m, 12 H), 2.74 (dd, J = 14.8, 6.1 Hz, 2 H), 2.98 (dd, J = 12.1,
5.1 Hz, 2 H), 3.63 (s, 6 H), 3.69 (s, 6 H), 4.37 (s, 2 H), 4.62 (m, 4
H), 5.13 (m, 2 H), 6.98 (br. d, 2 H), 7.75 (s, 2 H), 7.90 (br. d, 2 H),
8.11 (s, 1 H), 8.41 (br. d, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.4, 21.6, 22.7, 22.8, 24.7, 29.6, 37.9, 40.1, 40.8, 50.8, 51.5,
52.2, 53.7, 126.0, 129.3, 134.1, 136.5, 165.2, 170.7, 172.1,
Preparation of 13b: Et3N (0.5 mL, 3.52 mmol) was added to an
ice-cooled solution of H2N-Asp(Asp.diOMe)Asp.diOMe (0.591 g,
1.41 mmol) in dry CH2Cl2 (10 mL) and the mixture was stirred
for 20 min. 5-(Azidomethyl)benzene-1,3-dicarbonyl dichloride (12;
0.182 g, 0.705 mmol) dissolved in dry CH2Cl2 (40 mL) was added
dropwise for 15 min and left to stir for 24 h. The reaction mixture
was mixed with distilled CH2Cl2 (20 mL) and washed with aqueous
2  H2SO4 and aqueous NaHCO3 solution. The organic layer was
dried with Na2SO4 and evaporated to yield 0.535 g of the crude
product. This was dissolved in CHCl3 and precipitated with the
addition of hexane to yield 0.495 g of 13b. Yield 69%; m.p. 194–
195 °C. [α]D = +0.769 (c = 0.130, MeOH). 1H NMR (CDCl3,
300 MHz): δ = 2.83–3.07 (br. m, 12 H), 3.49 (s, 6 H), 3.66 (s, 6 H),
3.75 (s, 12 H), 4.39 (s, 2 H), 4.90 (m, 4 H), 5.07 (m, 2 H), 7.37 (d,
J = 7.8 Hz, 2 H), 7.76 (d, J = 8.4 Hz, 2 H), 7.87 (s, 2 H), 8.08 (s,
1 H), 8.27 (d, J = 6.9 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 35.7, 35.9, 37.5, 48.9, 49.0, 50.8, 52.1, 52.8, 52.9, 53.8, 125.2,
130.4, 133.9, 136.9, 165.9, 170.2, 170.9, 171.1, 171.2, 171.6,
173.6 ppm. IR (KBr): ν = 3288, 3066, 2984, 2096, 1743, 1646, 1536,
˜
1441, 1376, 1243 cm–1. HRMS: calcd. for C45H69N9NaO14
982.4862; found 982.4862.
Preparation of Symmetrical Dendrimers 18–20
171.8 ppm. IR (KBr): ν = 3296, 3070, 2955, 2103, 1741, 1649, 1536,
˜
1440, 1220, 1000 cm–1. HRMS: calcd. for C41H53N9NaO22
1046.3203; found 1046.3204.
Preparation of Trialkyne Core 14: Dry NEt3 (0.7 mL, 5 mmol) was
added to an ice-cooled solution of propargylamine (26; 0.2 mL,
3 mmol) in dry CH2Cl2 (25 mL) and the mixture was stirred for
20 min. 1,3,5-Tris(chlorocarbonyl)benzene (25; 0.265 g, 1 mmol)
dissolved in dry CH2Cl2 (50 mL) was added dropwise over a period
of 15 min and the mixture was stirred for 24 h. The solvent was
evaporated and the residue obtained was dissolved in distilled ethyl
acetate (50 mL) and washed with aqueous 2  H2SO4 followed by
Preparation of Dendron 13c
Preparation of Z-Asp.(Leu.OMe)Leu.OMe: A solution of NH2-
Leu.OMe (2.20 g, 15.06 mmol) containing triethylamine (1.51 g,
15.00 mmol) was added to a well-stirred and ice-cooled solution of
Z-aspartic acid (1.6 g, 5.99 mmol), N-hydroxysuccinimide (1.72 g,
14.99 mmol) and DCC (3.09 g, 14.97 mmol) in dry CH2Cl2 water and saturated aqueous NaHCO3 solution. The organic layer
(20 mL). After stirring for 24 h at room temperature, the reaction
mixture was filtered. The residue was washed with CH2Cl2
(4ϫ20 mL) and the combined filtrates were washed sequentially
with 2  H2SO4, H2O and 5% aqueous NaHCO3. The organic layer
was dried with Na2SO4, evaporated in vacuo and the crude product
was purified by chromatography on a column of silica gel using
EtOAc/hexane as eluent to afford 2.950 g of the peptide. Yield
was dried with Na2SO4 and the solvent evaporated to yield 0.200 g
of 14. Yield 62%; m.p. Ͼ300 °C. 1H NMR ([D6]DMSO, 300 MHz):
δ = 3.16 (s, 3 H), 4.08 (d, J = 2.6 Hz, 6 H), 8.44 (s, 3 H), 9.18 (br.
d, 3 H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 29.2, 73.6, 81.5,
129.4, 134.9, 165.6 ppm. IR (KBr): ν = 3282, 3243, 3059, 2930,
˜
1639, 1551, 1292, 1417, 1292 cm–1. HRMS: calcd. for C18H16N3O3
322.1192; found 322.1192.
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Multi-Tier Dendrimers with an Aromatic Core
Synthesis of Hexaalkyne Core 15: TFA (3 mL) was added to an ice-
cooled solution of Boc-Asp-dipropargyl ester (0.825 g, 2.67 mmol)
in dry CH2Cl2 (6 mL). The solution was left to stir for 2 h and
completion of the reaction was monitored by TLC. The reaction
mixture was subjected to a high vacuum to yield 0.558 g of the
amine 27, which was used as such without further purification.
Yield 100%. H NMR (D2O, 300 MHz): δ = 2.83 (t, J = 2.4 Hz, 1
H), 2.86 (t, J = 2.4 Hz, 1 H), 3.06 (dd, J = 18.1, 4.6 Hz, 1 H), 3.17
(dd, J = 18.3, 5.7 Hz, 1 H), 4.44 (m, 1 H), 4.67 (d, J = 2.4 Hz, 2
DIEA (0.05 mL, 0.273 mmol) was added followed by the azide 13b
(0.256 g, 0.25 mmol) and CuI (0.008 g, 0.042 mmol). The reaction
mixture was stirred under N2 for 24 h. The reaction mixture was
evaporated and subjected to high vacuum. The solid obtained was
washed several times in ethyl acetate to remove unreacted starting
materials. The ethyl acetate insoluble part was obtained in 0.132 g
yield and was confirmed to be the product 19. Yield 43%; m.p.
Ͼ250 °C. 1H NMR ([D6]DMSO, 300 MHz): δ = 2.68 (m, 36 H),
3.50 (s, 18 H), 3.56 (s, 36 H), 3.60 (s, 18 H), 4.61 (br. s, 18 H), 4.80
(br. s, 6 H), 5.67 (br. s, 6 H), 7.98 (br. s, 6 H), 8.16 (br. s, 3 H),
8.28 (br. s, 3 H), 8.45 (br. s, 15 H), 8.68 (br. s, 6 H), 9.21 (br. s, 3
1
H), 4.76 (dd, J = 3.3, 2.4 Hz, 2 H) ppm. IR (KBr): ν = 3419, 3298,
˜
2931, 2873, 2132, 1752, 1675, 1527, 1435, 1397, 1196 cm–1. HRMS:
calcd. for C10H12NO4 210.0766; found 210.0766.
H) ppm. IR (KBr): ν = 3288, 2954, 1737, 1653, 1533, 1438, 1372,
˜
1285, 1224 cm–1. HRMS: calcd. for C141H174KN30O69 3430.0666;
found 3430.0694.
Dry NEt3 (0.3 mL, 1.98 mmol) was added to an ice-cooled solution
of 27 (0.140 g, 0.67 mmol) in 10 mL of dry CH2Cl2 and the mixture
was stirred for 20 min. 1,3,5-Benzenetricarbonyl trichloride (25;
0.058 g, 0.22 mmol) dissolved in dry CH2Cl2 (20 mL) was added
dropwise over a period of 10 min and stirred for 24 h. The reaction
mixture was mixed with distilled CH2Cl2 (30 mL) and washed with
Preparation of 20: The propargyl derivative 15 (0.040 g,
0.051 mmol) was dissolved in dry CH3CN (10 mL). N2 was bubbled
through the solution for 30 min and after that DIEA (0.026 mL,
0.153 mmol) was added followed by the azide 13a (0.155 g,
aqueous 2  H2SO4 followed by water and aqueous NaHCO3 solu- 0.306 mmol) and CuI (0.008 g, 0.042 mmol). N2 bubbling was con-
tion. The organic layer was dried with Na2SO4 and the solvent
tinued for an additional 2–3 h and then the reaction mixture was
evaporated to yield 0.120 g of 15. Yield 71%; m.p. 150–151 °C.
[α]D = –12.00 (c = 0.100, MeOH). H NMR (CDCl3, 300 MHz): δ subjected to high vacuum. The solid thus obtained was washed
stirred under N2 for 24 h. The reaction mixture was evaporated and
1
= 2.55 (m, 6 H), 3.12 (dd, J = 17.4, 4.6 Hz, 3 H), 3.22 (dd, J =
several times in ethyl acetate to remove the unreacted starting mate-
17.4, 5.7 Hz, 3 H), 4.76 (d, J = 2.4 Hz, 6 H), 4.82 (d, J = 2.1 Hz, rials. The ethyl acetate insoluble part was dissolved in CHCl3,
6 H), 5.16 (m, 3 H), 7.55 (d, J = 7.8 Hz, 3 H), 8.29 (s, 3 H) ppm. washed with an aqueous NH4Cl/NH4OH (9:1) solution followed
13C NMR (CDCl3, 75 MHz): δ = 35.8, 49.4, 52.7, 53.5, 75.5, 75.8,
by 0.5  H2SO4. The organic layer was dried with Na2SO4 and
evaporated to yield 0.147 g of 20. Yield 75%. [α]D = –0.006 (c =
0.130, CHCl3). H NMR (CDCl3, 300 MHz): δ = 3.04 (m, 30 H),
3.68 (s, 36 H), 3.77 (s, 36 H), 4.95–5.51 (m, 39 H), 7.60–8.45 (m,
42 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 29.7, 35.8, 49.4, 52.1,
52.9, 57.9, 58.9, 125.1, 125.7, 128.5, 129.7, 130.0, 134.4, 135.8,
128.9, 134.2, 165.5, 169.9 ppm. IR (KBr): ν = 3292, 3070, 2944,
˜
2131, 1746, 1647, 1560, 1436, 1383, 1272, 1168 cm–1. HRMS: calcd.
for C39H33KN3O15 822.1549; found 822.1547.
1
Preparation of 16: TFA (10 mL, 130 mmol) was added to an ice-
cooled solution of 17 (0.252 g, 0.30 mmol) in dry CH2Cl2 (4 mL)
and the mixture was stirred at room temp. for 3 h. The reaction
mixture was then subjected to a vacuum to remove CH2Cl2 and
TFA to afford 0.132 g of 16. Yield 100%. 1H NMR (D2O,
142.6, 165.8, 170.5, 171.3 ppm. IR (KBr): ν = 3428, 2927, 1735,
˜
1650, 1534, 1446, 1347, 1220 cm–1. HRMS: calcd. for
C165H183N33NaO75 3849.1418; found 3849.1419.
300 MHz): δ = 1.20–1.90 (m, 18 H), 2.52 (m, 1 H), 2.90 (m, 4 H), Preparation of Unsymmetrical Dendrimers 21–24
3.13 (m, 2 H), 3.82–3.93 (m, 4 H), 4.16 (t, J = 7.0 Hz, 1 H) ppm.
Preparation of 21: The propargyl derivative 16 (0.132 g, 0.30 mmol)
IR (KBr): ν = 3425, 3277, 3083, 2922, 2833, 1772, 1675, 1548,
˜
was dissolved in dry CH3CN (20 mL). N2 was bubbled through the
reaction mixture for 30 min and after that DIEA (0.3 mL,
1.8 mmol) was added followed by the azide 13a (0.150 g, 0.3 mmol)
and CuI (0.012 g, 0.063 mmol). N2 bubbling was continued for an
additional 2–3 h and then the reaction mixture was stirred under
N2 for 24 h. The CH3CN was evaporated and subjected to high
vacuum. It was washed several times with a 1:1 mixture of EtOAc/
hexane to remove all other impurities. The product 21 was obtained
1434, 1196 cm–1. HRMS: calcd. for C21H42N7O3 440.3349; found
440.3352.
Preparation of 18: The propargyl derivative 14 (0.041 g,
0.129 mmol) was dissolved in dry CH3CN by heating. N2 was
bubbled through the homogeneous solution for 30 min and after
that DIEA (0.07 mL, 0.386 mmol) was added followed by the azide
13a (0.196 g, 0.386 mmol) and CuI (0.008 g, 0.042 mmol). The reac-
tion mixture was stirred under N2 for 24 h. The solvent was evapo-
rated and subjected to a high vacuum. The solid obtained was
washed several times in ethyl acetate to remove unreacted starting
materials. The ethyl acetate insoluble part was dissolved in CHCl3
(30 mL) and washed with an aqueous NH4Cl/NH4OH (9:1) solu-
tion followed by 0.5  H2SO4. The organic layer was dried with
Na2SO4 and evaporated to yield 0.095 g of the pure product 18.
Yield 40%; m.p. 160–161 °C. [α]D = –4.667 (c = 0.150, MeOH). 1H
NMR ([D6]DMSO, 300 MHz): δ = 2.85 (dd, J = 16.5, 7.8 Hz, 6
1
in 0.143 g yield. Yield 51%. [α]D = +1.33 (c = 0.300, CHCl3). H
NMR (D2O, 300 MHz): δ = 0.90–1.85 (br. m, 18 H), 2.65–3.10 (br.
m, 10 H), 3.56 (s, 6 H), 3.63 (s, 6 H), 3.80 (m, 3 H), 4.06 (m, 2 H),
4.88 (s, 2 H), 5.59 (s, 2 H), 7.74 (s, 2 H), 7.86 (s, 1 H), 7.96 (s, 1
H) ppm. 13C NMR (D2O, 75 MHz): δ = 22.2, 26.3, 27.7, 30.4, 35.3,
39.0, 49.8, 52.6, 53.3, 126.4, 130.5, 134.3, 136.4, 161.3, 162.0, 162.5,
162.9, 168.7, 169.4, 172.4, 172.9, 173.2 ppm. IR (KBr): ν = 3435
˜
(br), 3272 (br), 3077 (br), 2954 (br), 1739, 1677, 1547, 1437, 1202,
1133, 1004 cm–1. HRMS: calcd. for C42H67N12O13 947.4951; found
H), 2.97 (dd, J = 16.5, 5.8 Hz, 6 H), 3.61 (s, 18 H), 3.64 (s, 18 H), 947.4951.
4.54 (br. s, 6 H), 4.85 (m, 6 H), 5.69 (s, 6 H), 7.99 (s, 6 H), 8.12 (s,
Preparation of 22: The propargyl derivative 17 (0.084 g, 0.1 mmol)
3 H), 8.29 (s, 3 H), 8.46 (s, 3 H), 9.17 (br. d, J = 7.5 Hz, 9 H) ppm.
was dissolved in dry CH3CN (30 mL) and N2 was bubbled through
the liquid for 30 min and after that DIEA (0.05 mL, 0.3 mmol)
was added followed by the azide 13b (0.102 g, 0.1 mmol) and CuI
(0.008 g, 0.042 mmol). N2 bubbling was continued for an additional
2–3 h and then the reaction mixture was stirred under N2 for 24 h.
The reaction mixture was evaporated and subjected to high vac-
uum. The solid thus obtained was washed several times with ethyl
13C NMR ([D6]DMSO, 75 MHz): δ = 34.7, 48.9, 51.3, 51.8, 122.9,
129.9, 134.1, 136.2, 164.8, 164.9, 170.0, 170.6 ppm. IR (KBr): ν =
˜
3426, 2955, 1739, 1656, 1538, 1439, 1286, 1222 cm–1. HRMS: calcd.
for C81H90N18NaO33 1865.5815; found 1865.5812.
Preparation of 19: The propargyl derivative 14 (0.029 g,
0.090 mmol) was dissolved in dry CH3CN (10 mL) by heating.
Eur. J. Org. Chem. 2009, 1570–1577
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1575

V. Haridas, Y. K. Sharma, S. Naik
FULL PAPER
acetate to remove unreacted starting materials. The ethyl acetate
insoluble part was obtained in 0.169 g yield and was confirmed to
be the product 22. Yield 90%. H NMR ([D6]DMSO, 300 MHz):
dry CH2Cl2 (20 mL) and the mixture was stirred for 20 min at 0 °C.
The acid chloride 25 (0.265 g, 1 mmol) dissolved in 15 mL of dry
CH2Cl2was added dropwise over a period of 30 min. The reaction
1
δ = 0.95–1.70 (s + m, 54 H), 2.59–2.95 (m, 18 H), 3.45 (s, 12H mixture was left to stir for 24 h. The reaction mixture was mixed
merged with solvent residual peak), 3.51 (s, 12 H), 3.75–4.85 (br. with CH2Cl2 (50 mL) and washed with aqueous 2  H2SO4 fol-
m, 11 H), 5.63 (br. s, 2 H), 6.68 (br. m, 3 H), 6.84 (br. m, 1 H), lowed by aqueous NaHCO3 solution and water. The organic layer
7.68 (br. m, 2 H), 7.92 (br. m, 2 H), 8.23 (br. m, 2 H), 8.39 (br. m, was dried with anhydrous Na2SO4 and evaporated to give 0.350 g
5 H), 8.63 (br. m, 2 H) ppm. IR (KBr): ν = 3138, 1739, 1650, 1532, of 30. Yield 55%; m.p. 205–206 °C. [α]D = +59.25 (c = 0.400,
˜
1
1401, 1279, 1171 cm–1. HRMS: calcd. for C82H126N16NaO33
1885.8571; found 1885.8588.
CHCl3). H NMR (CDCl3, 300 MHz): δ = 3.09 (m, 6 H), 3.74 (s,
9 H), 3.82 (s, 9 H), 5.13 (m, 3 H), 7.68 (d, J = 7.8 Hz, 3 H), 8.26
(s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 35.8, 49.4, 52.1,
Preparation of Dendrimer 23: DIEA (0.022 mL, 0.13 mmol), 13c
(0.115 g, 0.12 mmol) and CuI (0.003 g, 0.015 mmol) were added to
an ice-cooled solution of 17 (0.100 g, 0.12 mmol) in dry acetonitrile
(25 mL) under nitrogen. The reaction mixture was stirred under N2
for 16 h. The reaction mixture was evaporated and the residue was
washed sequentially with EtOAc (3ϫ15 mL) and chloroform
(3ϫ15 mL). The combined filtrates were evaporated, dissolved in
EtOAc (60 mL) and washed sequentially with 0.2  H2SO4, water,
5% aqueous NaHCO3 solution, aqueous NH4CI/NH4OH (9:1)
solution and finally with water. The organic layer was dried with
anhydrous Na2SO4, filtered and evaporated to yield 0.180 g of den-
52.9, 128.9, 134.5, 165.4, 171.3 ppm. IR (KBr): ν = 3249, 3065,
˜
2958, 2854, 1746, 1645, 1555, 1440, 1364, 1310, 1227, 1169 cm–1.
HRMS: calcd. for C27H33N3NaO15 662.1809; found 662.1810.
Preparation of 31: Dry NEt3 (0.2 mL, 1.36 mmol) was added to an
ice-cooled solution of 29 (0.246 g, 0.51 mmol) in dry CH2Cl2
(50 mL) and the mixture was stirred for 20 min. Compound 25
(0.045 g, 0.17 mmol) dissolved in dry CH2Cl2 (20 mL) was added
dropwise to this solution over a period of 20 min. The reaction
mixture was left to stir for 24 h. The reaction mixture was mixed
with distilled CH2Cl2 (20 mL) and treated with aqueous 2  H2SO4
followed by aqueous NaHCO3 solution and water. The organic ex-
tract was dried with anhydrous Na2SO4 and evaporated to provide
1
drimer 23. Yield 83%. [α]D = –20.4 (c = 0.25, MeOH). H NMR
(CDCl3, 300 MHz): δ = 0.81 (m, 12 H), 0.97 (m, 12 H), 1.25–1.55
(s + m, 48 H), 1.55–1.85 (m, 18 H), 2.40 (m, 6 H), 2.83 (m, 2 H),
3.09 (m, 2 H), 3.72 (s, 12 H), 4.15 (m, 2 H), 4.57 (m, 7 H), 5.20
(m, 6 H), 5.90 (m, 2 H), 7.15 (br. m, 3 H), 7.70 (br. m, 4 H), 8.10
(br. m, 4 H), 8.85 (br. d, 2 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 17.64, 21.75, 22.53, 22.72, 22.80, 24.73, 24.88, 28.34, 28.41,
28.45, 29.36, 29.48, 29.56, 29.65, 30.65, 38.65, 39.78, 40.05, 40.23,
40.76, 49.42, 50.78, 51.11, 51.81, 52.21, 52.34, 54.24, 78.83, 79.67,
122.89, 126.16, 129.65, 133.79, 135.73, 145.00, 156.23, 165.23,
1
0.225 g of 31. Yield 83%. [α]D = –10.833 (c = 0.120, MeOH). H
NMR ([D6]DMSO, 300 MHz): δ = 2.79–3.05 (m, 12 H), 3.61 (s, 18
H), 3.64 (s, 18 H), 4.59 (br. s, 6 H), 4.85 (m, 6 H), 7.99 (s, 6 H),
8.22 (s, 3 H), 8.58 (s, 3 H), 9.15 (d, J = 7.2 Hz, 6 H), 9.46 (s, 3
H) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 35.3, 42.8, 49.4,
51.8, 52.3, 125.2, 129.1, 129.7, 133.9, 134.7, 140.1, 165.5, 165.8,
170.6, 171.2 ppm. IR (KBr): ν = 3421 (br), 2958, 1738, 1657, 1540,
˜
1439, 1270, 1222 cm–1. HRMS: calcd. for C72H81N9NaO33
1622.4834; found 1622.4834.
170.44, 172.13, 172.69, 173.57, 175.09 ppm. IR (KBr): ν = 3314,
˜
3075, 2959, 2870, 1741, 1657, 1533, 1446, 1368, 1248, 1169 cm–1.
HRMS: calcd. for C86H142N16NaO25 1822.0230; found 1822.0225.
Supporting Information (see also the footnote on the first page of
this article): The 1H and 13C NMR and mass spectra of all new
compounds. The HPLC chromatograms of compounds 18, 20 and
30.
Preparation of Dendrimer 24: DIEA (0.061 mL, 0.36 mmol), 13c
(0.115 g, 0.12 mmol) and CuI (0.003 g, 0.015 mmol) were added to
an ice-cooled solution of 16 (0.052 g, 0.12 mmol) in dry acetonitrile
(25 mL) under nitrogen. The reaction mixture was stirred under N2
for 16 h. The reaction mixture was evaporated and the residue was
washed with ethyl acetate and dichloromethane to remove all impu-
rities. The dendrimer 24 was obtained in 0.120 g yield (72%). 1H
NMR (D2O, 300 MHz): δ = 0.46 (br. m, 12 H), 0.77 (br. m, 12 H),
1.10–1.90 (m, 30 H), 2.85 (m, 4 H), 2.93 (m, 4 H), 3.08 (m, 2 H),
3.63 (s, 6 H), 3.69 (s, 6 H), 3.88 (m, 1 H), 3.96 (m, 1 H), 4.20 (m,
1 H), 4.35 (m, 6 H), 4.95 (s, 2 H), 5.69 (s, 2 H), 7.97 (m, 3 H), 8.20
Acknowledgments
Financial assistance from the Council of Scientific and Industrial
Research (CSIR), New Delhi and from the Department of Science
and Technology (DST), New Delhi is acknowledged.
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1576
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: November 19, 2008
Published Online: February 18, 2009
Eur. J. Org. Chem. 2009, 1570–1577
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