Efficient synthesis of immolative carbamate dendrimer with olefinic periphery

Article abstract of DOI:10.1016/j.tetlet.2007.05.034

An efficient synthetic strategy for immolative carbamate dendrons and dendrimers is described that requires no protection/deprotection in the convergent growth step. 1,3-Diamino-2-propanol was used as AB₂ building block and 4-nitrophenyl chloro

Full text of DOI:10.1016/j.tetlet.2007.05.034

Tetrahedron Letters 48 (2007) 4919–4923
Efficient synthesis of immolative carbamate dendrimer with
olefinic periphery
Jeong-Kyu Lee, Young-Woong Suh, Mayfair C. Kung, Christopher M. Downingà
and Harold H. Kung*
Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA
Received 8 November 2006; revised 8 May 2007; accepted 9 May 2007
Available online 16 May 2007
Abstract—An efficient synthetic strategy for immolative carbamate dendrons and dendrimers is described that requires no protec-
tion/deprotection in the convergent growth step. 1,3-Diamino-2-propanol was used as AB2 building block and 4-nitrophenyl chlo-
roformate as carbamate forming reagent. The method was demonstrated with a G3-dendron. A combination of convergent and
divergent growth method was used to couple G2-dendrons to a G2-core or G3-dendrons to a tetrahedral G1-core with amine func-
tional groups to form a spherical carbamate dendrimer (G4) possessing an olefinic periphery.
Ó 2007 Elsevier Ltd. All rights reserved.
Because of their highly regulated topology (mostly
spherical or disk shaped) and high densities of interior
functional groups and end groups, dendrimers have
been explored for many applications such as artificial
enzymes and drug-delivery agents,1 catalysts,2 scaffold
for metal catalysts,3 liquid crystals and organic light-
emitting diodes,4 sensors,5 and magnetic resonance
imaging (MRI) contrast agents.6 The structures and
compositions of the dendrimers are designed for specific
applications.7 Thus, preservation of the structural fea-
tures during use is important. However, there are exam-
ples where destruction of the dendrimer is desirable. For
example, molecular imprinting inside a dendrimer is
achieved by cleavage of the template core from the
cross-linked shell,8 and self-immolative dendrons are
attractive candidates for drug-delivery.9 Such examples
suggest that a nano-scale dendrimer (2–10 nm), which
has properties that include immolative linkages of build-
ing blocks, possibilities for shell cross-linking, easily tun-
able peripheral end groups, and a functional core, offers
possible new applications including temporary scaffold
or transfer agent. However, most common dendrimers
are designed for high structural stability, including
´
Frechet’s polyether and Tomalia’s poly(amidoamine).
The carbamate linkage (R1–NHCOO–R2) is ideal for
immolative dendrimers as it can be readily cleaved by
a selective chemical treatment10 or thermolysis,11 but is
stable under common synthesis conditions. There are
reports of dendron or dendrimer synthesis using carba-
mate linkages formed by reaction between alcohols
and isocyanates12 or diphenylphosphorylazide coupling
with carboxylic acids at elevated temperatures.13 Here,
we report a convenient synthetic strategy for a spherical
carbamate dendrimer of 4th generation (G4) in which 4-
nitrophenyl (PNP) chloroformate was used as the carba-
mate-forming reagent and 1,3-diamino-2-propanol as
the AB2 branching unit. The hydroxyl group of the
AB2 branching unit reacts with PNP chloroformate to
form a carbonate intermediate, which reacts selectively
with the amine groups of 1,3-diamino-2-propanol. Thus,
in the convergent growth sequence, hydroxyl protection
is unnecessary. Although PNP chloroformate9b,c,14 or
carbonyl diimidazole15 can be used to form carbamate
linkages and both can be handled without special pre-
cautions, we opted to use the former reagent because
of its higher reactivity. An olefinic periphery was de-
signed to permit easy modification of surface properties.
Keywords: Immolative dendrimer; Carbamate dendron; 1,3-Diamino-
2-propanol; 4-Nitrophenyl chloroformate.
*
Corresponding author. E-mail: hkung@northwestern.edu
Present address: Clean Technology Research Center, Korea Institute
of Science and Technology, 39-1 Hawolgok-dong, Seongbuk-gu,
Seoul 136-791, South Korea.
As an illustration to synthesize a symmetrical, spherical
dendrimer, we used a tetrahedral core prepared by
esterification between pentaerythritol and Boc-Glycine
à Department of Chemistry.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.034

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J.-K. Lee et al. / Tetrahedron Letters 48 (2007) 4919–4923
(Boc-Gly-OH). A convergent approach was employed
for dendron growth up to 3rd generation (G3). A full
G4-dendrimer was formed by reacting G3-dendrons
with a G1-core, or G2-dendrons with a G2-core, that
is, by using a combination of divergent and convergent
methods. Because of steric crowding, the yield from
G3-dendrons coupling to a G1-core was lower than that
from G2-dendrons to a G2-core.
the G4-carbamate dendrimers were successfully pre-
pared by using the same reaction steps as growing carba-
mate dendrons (Scheme 3). The hydroxyl group of a
dendron was activated with PNP chloroformate to give
PNPC-dendron (PNPC-G2D or PNPC-G3D), which
was then coupled to the core amines after Boc-deprotec-
tion with TFA. We found that coupling of PNPC-G2D
(8) to Core-G2D-Boc (7) (G2-dendrons to G2-core) gave
a higher yield (72%) than coupling of PNPC-G3D to
Core-Boc (5) (G3-dendrons to G1-core). Reaction (c)
in Scheme 3, between 7 and 8, was found to be complete
in 4 days at room temperature, much slower than the
same reaction between small molecules due to steric hin-
drance, as is usually the case for coupling large dendrons
to small cores.8 The pure G4-dendrimer (9) was ob-
tained after two series of flash chromatography using
large-pore (15 nm) silica gel. Excess PNPC-G2D was re-
moved in the first series, and the complete dendrimer (8/
8 product) was separated from small amounts of incom-
plete dendrimers (mainly 7/8 and 6/8) in the second ser-
ies (see Supplementary data, Fig. S3). The complete
dendrimer was synthesized in gram scale.
Scheme 1 shows the convergent synthetic route for car-
bamate dendrons up to G3. 2-Methyl-3-buten-2-ol was
condensed with PNP chloroformate to generate 1 in
95% yield. Subsequent reaction between 1 and 1,3-di-
amino-2-propanol (2:1 molar ratio) gave G1-dendron
(G1D, 2, 93% yield). The selective reaction of 2-nitro-
phenyl carbonate intermediate with amines was advan-
tageous for multi-generation growth by eliminating the
need for protection of the alcohol functionality in the
AB2 branching unit. Activating the hydroxyl group of
G1D with PNP chloroformate followed by reaction with
the linker (1,3-diamino-2-propanol) produced the G2
carbamate dendron (G2D, 3, 85% yield). Repeating the
same reactions yielded G3 carbamate dendron (G3D,
4) in 75% yield. These results suggest that extending
the growth to higher generation dendrons can be readily
accomplished.
All the dendrons and dendrimers were white solids read-
ily soluble in a variety of solvents such as dichlorometh-
ane, chloroform, alcohols, ethyl acetate, and toluene.
1
Their chemical structures were confirmed with H, 13C
To synthesize a G4-dendrimer by coupling G3-dendrons
to a G1-core, we designed a tetrahedral core, Core-Boc
(5, Scheme 2). Pentaerythritol was coupled to Boc-
Gly-OH by esterification, using N-(3-dimethylamino-
propyl)-N0-ethylcarbodiimide (EDC) and 4-di(methyl-
amino)pyridine (DMAP) as coupling agents16 to afford
5 (95%) as a white solid. For the alternative method of
coupling G2-dendrons to a G2-core, a Core-G2D-Boc
(7) was synthesized by coupling 4 equiv of PNP-acti-
vated, Boc-protected linker PNPC-LK-Boc (6) (Scheme
2) to 1 equiv of Boc-deprotected Core-Boc (5). Finally,
NMR, and MALDI-TOF mass spectroscopy. As ex-
pected, the H NMR spectra of the G1–G3-dendrons
1
and the G4-dendrimer (Fig. 1) are quite similar, except
that the peaks broaden for higher generations, especially
for the dendrimer. Therefore, careful integration of each
peak was required to differentiate the generations. For
example, the integral ratio of –CH2– (at 3.2–3.5 ppm)
to ACH@CH2 peaks (at 5.0–5.2 ppm) increased from
1.0 to 1.5 to 1.75 for G1, G2, and G3-dendrons, respec-
tively. The chemical shifts of the 13C carboxyl peaks
A(C@O)A of the carbamate groups at 156–157 ppm
Scheme 1. Synthesis of carbamate dendrons. Reagents and conditions: (a) CH2Cl2, DMAP, pyridine, rt, 3–5 h; (b) CH2Cl2, DMF, Et3N, rt,
overnight.

J.-K. Lee et al. / Tetrahedron Letters 48 (2007) 4919–4923
4921
Scheme 2. Synthesis of cores and intermediates. Reagents and conditions: (a) DMF, CH2Cl2, DMAP, EDC, rt, overnight; (b) CH2Cl2, TFA, rt, 2 h;
(c) DMF, DIPEA, CH2Cl2, TEA, rt, 5 h; (d) t-BuOH/MeOH, rt, overnight; (e) CH2Cl2, DMAP, pyridine, rt, 3 h; (f) CH2Cl2, DMAP, pyridine, rt,
5 h.
Scheme 3. Synthesis of G4-carbamate dendrimer. Reagents and conditions: CH2Cl2/TFA, DMF, DIPEA, rt, 3–4 days.
(Fig. S2, Supplementary data) were slightly different for
the different generations, resulting in one (d 157.1), two
(d 156.7 and 156.3), and three (d 156.8, 156.6, and 156.4)
peaks for G1D, G2D and G3D, respectively. The chem-
ical shifts for the carbons at CH2–(CO–)–CH2 (d G1D
71.1, G2D 72.7 and 69.5, G3D 72.7, 72.0, and 69.6)
and CH2–(CO–)–CH2 (d G1D 43.7, G2D 44.1 and
40.5, G3D 44.3, 40.9, and 40.7) also varied among the
generations (Fig. S1, Supplementary data). The 1H
NMR peaks of G4-dendrimer were broad, but all the
protons could be detected and the peaks could be
assigned. However, in its 13C NMR spectrum, the
carbon atoms with small populations near the core were
beyond detection.
Additional structural confirmation was obtained with
MALDI-TOF mass spectroscopy. The mass spectrum
of a purified G4-dendrimer (Fig. 2) exhibited a peak at
[(M+Na)+ = 7222.7], close to the theoretical mass of
7226.7. In addition, there were other intense peaks at

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J.-K. Lee et al. / Tetrahedron Letters 48 (2007) 4919–4923
linkages with high yields without employing protection
and deprotection. The dendrons so obtained were cou-
pled to an amine core to form a dendrimer. The tertiary
alkyl allyl end groups of the dendrons and dendrimer
can be functionalized to generate surface functional
groups or be subjected to metathesis or hydrosilylation
with alkoxysilanes or chlorosilanes for shell cross-link-
ing if desired. This versatile dendrimer and its synthetic
scheme should find applications in many areas.
G4 Dendrimer
G3D
G2D
Acknowledgement
G1D
This work was supported by the US Department of
Energy, Office of Science, Basic Energy Sciences, Grant
No. DE-FG02-01ER15184.
8.0
7.0
6.0
5.0
4.0
PPM
3.0
2.0
1.0
0.0
Figure 1. 1H NMR spectra of carbamate dendrons and dendrimer.
Supplementary data
7155 and 7087, which could be assigned to G4-dendri-
mers lacking one and two surface tertiary alkyl allyl
groups (mass of C5H8 = 68.0), respectively, consequence
of fragmentation during analysis. The FTIR spectrum
of a G4-dendrimer showed intense characteristic bands
for A(C@O)A (m 1701), A(NAH)A (m 3343), and
A(CH@CH2) (m 2981, 1519) (Supplementary data,
Fig. S4). The approximate size of G4-dendrimer was
measured by dynamic light scattering (DLS) to be
4.3 nm in diameter, consistent with the simulated mole-
cular structure (highly symmetrical and spherical shape,
inset, Fig. 2) obtained by semi-empirical equilibrium
geometry calculation (AM1).
Detailed experimental procedures for the synthesis of
carbamate dendrons and dendrimers, and the related
analysis methods and results are available online. Sup-
plementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet
2007.05.034.
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