Polyester-based carborane-containing dendrons

Article abstract of DOI:10.1021/ic060866r

New carborane-containing dendrons based on a 2,2-bis(hydroxymethyl) propanoic acid scaffold have been prepared for applications in boron neutron capture therapy. A generation-2 carborane-containing dendron carrying 40 boron atoms was the highest generation synthetically available due to the steric crowding. The structure of this dendron has been simulated by molecular dynamics. A 10-carbon linker carrying a carboxylic group has been installed at the focal point of the dendron to distance the attachment point from the sterically hindered core.

Full text of DOI:10.1021/ic060866r

Inorg. Chem. 2006, 45, 7815−7820
Polyester-Based Carborane-Containing Dendrons
Kristin M. Galie, Alexis Mollard, and Ilya Zharov*
Department of Chemistry, UniVersity of Utah, Salt Lake City, Utah 84112
Received May 18, 2006
New carborane-containing dendrons based on a 2,2-bis(hydroxymethyl)propanoic acid scaffold have been prepared
for applications in boron neutron capture therapy. A generation-2 carborane-containing dendron carrying 40 boron
atoms was the highest generation synthetically available due to the steric crowding. The structure of this dendron
has been simulated by molecular dynamics. A 10-carbon linker carrying a carboxylic group has been installed at
the focal point of the dendron to distance the attachment point from the sterically hindered core.
Chart 1
Introduction
Boron neutron capture therapy (BNCT) is a binary form
of cancer treatment in which two nontoxic species, a boron-
containing compound and thermal neutrons, interact to cause
a cytotoxic event in or near cancer cells. Boron-10 nuclides
capture slow-moving neutrons and undergo a fission reaction,
producing lethal high linear energy transfer 4He2+ and 7Li3+
particles1-4 with a penetration range of approximately the
diameter of one cell (9-10 µm).5 Several factors define the
choice of agents suitable for BNCT. Bringing a sufficient
number of boron atoms to cancer cells (g109 10B atoms/cell
≈ 20-35 µg 10B/cell) is critical.6,7 In this respect, carboranyl
clusters, such as o-, m-, and p-carborane (Chart 1) have
received much attention6-19 due to their high kinetic stability,
high boron content, and ease of derivitization.7,20 Among the
carboranyl clusters shown in Chart 1, o-carborane is par-
ticularly attractive due to its ease of preparation from
decaborane.21
Carboranyl clusters have been incorporated into biologi-
cally relevant molecules such as nucleic acid bases, epidermal
growth factor, liposomes, intercalators, and antibodies for
use in BNCT.7 In addition, carbon nanotubes have been
functionalized with carboranes for BNCT applications.22
Several strategies have been used to increase the boron
content of BNCT agents, such as attachment of multiple
carboranes to a porphyrin framework7,23 and incorporation
of carboranes into macromolecules. The use of macromol-
* To whom all correspondence should be addressed. E-mail:
zharov@chem.utah.edu.
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10.1021/ic060866r CCC: $33.50
Published on Web 08/25/2006
© 2006 American Chemical Society
Inorganic Chemistry, Vol. 45, No. 19, 2006 7815

Galie et al.
ecules in drug delivery24-27 has been shown to enhance the
targeting and efficiency of the treatment.28-30 Dendrimers,
albeit harder to prepare than linear polymers, are character-
ized by a low polydispersity index (∼1.0) and thus show
very reproducible pharmacokinetic behavior,31-33 making
them ideal candidates for model studies. Dendritic polymers
allow control of solubility, molecular weight, and most
importantly, multiplicity of therapeutic agents via modifica-
tion of their periphery.34 Previously, dendrimers carrying
multiple carboranes have been prepared for use in BNCT35-42
but demonstrated low water solubility and cytotoxicity.43
More recently, biocompatible polyester dendrimers have been
elegantly prepared with as many as 16 p-carboranes in their
interior, and water solubility has been achieved by modifica-
tion of their periphery, making them good candidates for
use in BNCT.44
One drawback when using dendrimers for drug delivery
is their uniform exterior functionality. Although the outer
shell of dendrimers can be used to control their solubility
and targeted delivery, introducing a combination of different
functional groups at the periphery of a given dendrimer
remains challenging. Thus, we decided to explore the
possibility of synthesizing functional dendrons (i.e., dendritic
wedges) for use in BNCT, in which carborane moieties
would be attached to the exterior of the dendron, while a
targeting functionality would be found at the focal point.
Alternatively, the focal point could be used to combine a
carborane-containing dendron with other dendrons carrying
Figure 1. Representative structures of BCD-2A obtained by MD simula-
tions (boron atoms, pink; carbon atoms, gray; hydrogen atoms, white;
oxygen atoms, red). Carboxyl groups are marked with white arrows.
targeting moieties and/or solubilizing groups, thus producing
a modular macromolecular BNCT agent. Herein, we describe
the synthesis and properties of o-carborane-containing den-
drons.
Experimental Section
General. All reagent-grade solvents were used without further
purification except for dichloromethane and toluene, which were
dried over calcium hydride. Decaborane and 1-n-butyl-3-meth-
ylimidazolium chloride were purchased from Alfa Aesar. 4-Pen-
tynoic acid (98%) and dicyclohexylcarbodiimide (99%) were
purchased from Lancaster Synthesis, Inc. Zinc dust was purchased
from Fisher Scientific. 2,2,2-Trichloroethanol and 10-hydroxyde-
canoic acid were purchased from Aldrich. 1-(3-Dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (EDC) was purchased
from Advanced ChemTech. 4-Dimethylaminopyridinium 4-tolu-
enesulfonate was prepared as previously reported.45
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123/124, 457-85.
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Biocompatibility, II; Williams, D. F., Ed.; CRC Press: Boca Raton,
FL, 1981; pp 159-180.
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Biopharm. 2000, 50, 61-81.
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J.; Ulbrich, K.; Duncan, R. Eur. J. Cancer 1995, 31A, 766-770.
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ecules: Concepts, Synthesis, PerspectiVes; VCH: Weinheim, Ger-
many, 1996.
TLC: Merck silica gel 60 F254 plates (Al support, 0.2 mm
thickness); detection of carborane compounds by KMnO4 stain. IR
spectra: Perkin-Elmer-FT-1600-IR spectrometer; in cm-1. NMR
Spectra: Varian VXL-300 or Varian Unity-300 at 300 MHz for
1H, 160 MHz for 11B, and 75 MHz for 13C; Bruker DRX at 600
1
MHz for H and 150 MHz for 13C. Mass spectra were obtained
using Finnigan MAT95, ThermoFinnigan LCQ and Micromass
Quattro II. Molecular dynamics simulations were performed using
Cerius2, v4.5 (Accelrys, Inc.). For simulated annealing, a Dreiding
force field was used. Each structure shown in Figure 1 has been
obtained after five annealing cycles from 300 to 500 K in a total
of 220 ps and by choosing the lowest-energy structure of each cycle.
Synthesis of 2,2,2-Trichloroethyl-4-pentynoate (3). 4-Pentynoic
acid (2, 4.35 g, 44.31 mmol) and 2,2,2-trichloroethanol (5.0 mL,
52.00 mmol) were dissolved in dry dichloromethane (83 mL).
4-(Dimethylamino)pyridiunium p-toluenesulfonate (DPTS, 2.71 g,
9.21 mmol) was added followed by DCC (10.22 g, 49.53 mmol).
The reaction mixture was stirred at room temperature under nitrogen
overnight. The DCU was then filtered off and the filtrate was
evaporated. The byproducts were precipitated in cold hexanes and
filtered through a glass funnel. The filtrate was concentrated and
purified by flash chromatography on silica gel, eluting with hexanes
and gradually increasing the polarity to 70:30 hexanes/EtOAc to
give 3 as a yellow oil (9.60 g, 93%). TLC (silica) Rf ) 0.82
(34) Gillies, E. R.; Frechet, J.-M. J. J. Am. Chem. Soc. 2002, 124, 14137-
14146.
(35) Nemoto, H.; Cai, J. P.; Yamamoto, Y. J. Chem. Soc., Chem. Commun.
1994, 5, 577-578.
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Chem. 1995, 60, 1478-1478.
(37) Barth, R. F.; Adas, D. M.; Soloway, A. H.; Alam, F.; Darby, M. V.
Bioconjugate Chem. 1994, 5, 58-66.
(38) Yao, H. J.; Grimes, R. N.; Corsini, M.; Zanello, P. Organometallics
2003, 22, 4381-4383.
(39) Nunez, R.; Gonzalex, A.; Vinas, C.; Teixidor, F.; Sillanpaa, R.;
Kivekas, R. Org. Lett. 2005, 7, 231-233.
(40) Qualmann, B.; Kessels, M. M.; Musiol, H. J.; Sierralta, W. D.;
Jungblut, P. W.; Moroder, L. Angew. Chem., Int. Ed. Engl. 1996, 35,
909-911.
(41) Armspach, D.; Cattalini, M.; Constable, E. C.; Housecroft, C. E.;
Phillips, D. Chem. Commun. 1996, 15, 1823-1824.
(42) Thomas, J.; Hawthorne, M. F. Chem Commun. 2001, 18, 1884-1885.
(43) Malik, N.; Wiwattanapatapee, R.; Klopsch, R.; Lorenz, K.; Frey, H.;
Weener, J. W.; Meijer, E. W.; Paulus, W.; Duncan, R. J. Controlled
Release 2000, 68, 299-302.
(44) Parrott, M. C.; Marchington, E. B.; Valliant, J. F.; Adronov, A. J.
Am. Chem. Soc. 2005, 127, 12081-12089.
(45) Moore, J.; Stupp, S. Macromolecules 1990, 23, 65-70.
7816 Inorganic Chemistry, Vol. 45, No. 19, 2006

Polyester-Based Carborane-Containing Dendrons
(hexanes/EtOAc: 70:30). IR (neat, cm-1): 3298, 2994, 2945, 2918,
2120, 1756, 1433, 1143. H NMR (CDCl3): δ 4.77 (s, 2H, CH2-
CCl3), 2.73 (td, J ) 7.2, 1.4 Hz, 2H, CH2), 2.58 (tdd, J ) 7.2, 2.7,
0.9 Hz, 2H, CH2), 2.01 (t, J ) 2.7 Hz, 1H, CH). 13C NMR
(CDCl3): δ 170.38, 94.94, 82.03, 74.26, 69.68, 33.28, 14.46. MS
(CI): m/z 229 [M + H]+.
128.78, 128.46, 73.90, 67.18, 66.02, 61.76, 46.37, 33.21, 32.54,
17.99. 11B NMR (CDCl3): δ -2.83, -6.26, -10.11, -12.54,
-13.27. MS (CI): m/z 622 [M + H]+.
1
Synthesis of Generation-2 Boron-Containing Dendron (BCD-
2). The acid 1 (235 mg, 1.090 mmol), gen-2 dendron (985 mg,
0.216 mmol) and EDC (248 mg, 1.300 mmol) were dissolved in
dry dichloromethane (4 mL). DMAP (8.5 mg, 0.070 mmol) was
then added to the reaction flask. The reaction mixture was stirred
under nitrogen for 48 h. Upon completion, dichloromethane was
added (25 mL). Using a separatory funnel, the organic layer was
washed with water (3 × 20 mL), 10% sodium bicarbonate (3 × 20
mL), and brine (3 × 20 mL) then dried over sodium sulfate. The
solvent was removed in vacuo, giving a white foam that was
purified by liquid chromatography on silica gel, eluting with hexanes
and gradually increasing the polarity to 70:30 hexanes/ethyl acetate
to give BCD-2 as a white solid (203 mg, 75%). TLC (silica) Rf )
0.53 (hexanes/EtOAc, 60:40). IR (neat): υ 3056, 2954, 2582, 1733,
Synthesis of Trichloroethyl 3-(1′,2′-Dicarbo-closo-dodecabo-
rane-1′-yl)propanoate (4). 2,2,2-Trichloroethyl-4-pentynoate (3,
9.40 g, 41.22 mmol) and decaborane (7.62 g, 62.21 mmol) were
dissolved in a biphasic system of toluene (153 mL) and 1-butyl-
3-methylimidazolium chloride (6.18 g, 35.36 mmol). The reaction
mixture was vigorously stirred to form an emulsion and heated to
120 °C under nitrogen. After 1 h, the reaction mixture was cooled
to room temperature, diluted with toluene (100 mL), and transferred
to a separatory funnel. The organic layer was washed with 1 M
NaOH (3 × 100 mL) and brine (3 × 100 mL), dried over sodium
sulfate, and filtered, and the solvent was removed in vacuo to give
a yellow oil. This crude material was purified by liquid chroma-
tography on silica gel, eluting with hexanes and gradually increasing
the polarity to 60:40 hexanes/ethyl acetate, affording 4 as a white
solid (6.60 g, 46%). TLC (silica) Rf ) 0.76 (hexanes/EtOAc, 70:
30). IR (neat, cm-1): 3070, 3000, 2951, 2921, 2581, 1742, 1172.
1H NMR (CDCl3): δ 4.77 (s, 2H, CH2CCl3), 3.73 (bs, 1H, CH),
2.69 (m, 4H, CH2CH2). 13C NMR (CDCl3): δ 170.19, 94.13, 83.50,
74.53, 61.75, 33.33, 32.58. 11B NMR (CDCl3): δ -2.74, -6.18,
-10.03. -12.46, -13.55. MS (CI): m/z 348 [M + H]+.
1
1167, 1134. H NMR (CDCl3): δ 7.37 (m, 5H, Ar), 5.17 (s, 2H,
CH2Ar), 4.25 (q, J ) 12.6 Hz, 4H, CH2O), 4.16 (m, 8H, CH2),
3.74 (bs, 4H, CH), 2.56 (bs, 16H, CH2), 1.31 (s, 3H, CH3), 1.19 (s,
6H, CH3). 13C NMR (CDCl3): δ 174.75, 171.84, 171.12, 135.39,
129.01, 128.93, 128.53,73.65, 66.55, 65.81, 61.79, 46.94, 33.30,
32.63, 17.96. 11B NMR (CDCl3): δ -2.74, -6.01, -10.03, -12.46.
MS (CI): m/z 1248 [M + H]+.
Synthesis of Generation-2 Boron containing dendron acid
(BCD-2A). The dendron BCD-2 (183 mg, 0.147 mmol) was
dissolved in methanol (60 mL). Palladium (10% on carbon, 210
mg) was then added under nitrogen to the Parr hydrogenation bomb.
The reaction mixture was stirred at room temperature under 45 psi
of H2 atmosphere for 19 h. The bomb was then depressurized; the
reaction mixture was filtered over a pad of Celite and washed with
methanol (2 × 30 mL). The solvent was removed in vacuo, giving
the off-white solid BCD-2A (143 mg, 84%). TLC (silica) Rf )
0.88 (EtOAc/MeOH, 80:20). IR (neat, cm-1): 3359, 3057, 2577,
1734, 1234, 1167, 1132. 1H NMR (CDCl3): δ 4.24 (m, 12H, CH2),
3.76 (bs, 4H, CH), 2.58 (bs, 16H, CH2), 1.32 (s, 3H, CH3), 1.28 (s,
6H, CH3). 13C NMR (CDCl3): δ 180.55, 172.00, 171.20, 73.22,
68.73, 65.93, 61.85, 46.83, 33.36, 32.63, 18.06. 11B NMR
(CDCl3): δ -2.57, -5.84, -9.78, -12.46. MS (ESI+): m/z 1178
[M + Na]+.
Synthesis of 3-(1′,2′-Dicarbo-closo-dodecaborane-1′yl)pro-
panoic Acid (1). Carborane trichlorester 4 (5.0 g, 12.37 mmol)
was dissolved in 90% acetic acid (113 mL), followed by the addition
of zinc dust (11.1 g, 169.77 mmol). The reaction mixture was stirred
at room temperature under nitrogen for 3 h, after which TLC
revealed the disappearance of the starting material,. The zinc was
filtered off and washed with deionized water (2 × 70 mL) then
dichloromethane (2 × 70 mL). Using a separatory funnel, the
aqueous phase was washed with dichloromethane (2 × 70 mL).
The organic layers were combined, washed with water (3 × 50
mL) and brine (3 × 50 mL), and then dried over sodium sulfate.
The solvent was removed in vacuo, giving 1 as a white solid (2.8
1
g, 90%). H NMR (CDCl3): δ 3.67 (bs, 1H, CH), 2.65-2.54 (m,
4H, CH2CH2). 13C NMR (CDCl3): δ 171.1, 73.7, 61.7, 33.3, 32.5.
11B NMR (CDCl3): δ -2.51, -5.96, -11.93, -12.57, -13.31, in
agreement with published data.46
Synthesis of Acetonide Generation-2 Dendron with Benzyl
10-Hydroxydecanoic Acid Linker (AGen-2L). The acetonide-
protected gen-2 acid dendron (147 mg, 0.329 mmol), benzyl-10-
hydroxydecanoate (57 mg, 0.205 mmol), and EDC (58 mg, 0.302
mmol) were dissolved in dry dichloromethane (3 mL). DMAP (10.8
mg, 0.088 mmol) was then added to the reaction flask. The reaction
mixture was stirred under nitrogen for 48 h. Upon completion,
dichloromethane was added (20 mL). Using a separatory funnel,
the organic layer was washed with water (3 × 20 mL), 10% sodium
bicarbonate (3 × 20 mL), and brine (3 × 20 mL) then dried over
sodium sulfate. The solvent was removed in vacuo, giving a white
foam that was purified by liquid chromatography on silica gel,
eluting with 90:10 hexanes/ethyl acetate and gradually increasing
the polarity to 70:30 hexanes/ethyl acetate to give AGen-2L as a
colorless oil (27 mg, 18%). TLC (silica) Rf ) 0.55 (hexanes/EtOAc,
Synthesis of Generation-1 Boron-Containing Dendron (BCD-
1). The acid 1 (186 mg, 0.852 mmol), gen-1 dendron (75.4 mg,
0.337 mmol), and EDC (197 mg, 1.030 mmol) were dissolved in
dry dichloromethane (3 mL). 4-Dimethylaminopyridine (DMAP,
14.4 mg, 0.118 mmol) was then added to the reaction flask. The
reaction mixture was stirred under nitrogen for 24 h. Upon
completion, dichloromethane was added (25 mL). Using a sepa-
ratory funnel, the organic layer was washed with water (3 × 20
mL), 10% sodium bicarbonate (3 × 20 mL), and brine (3 × 20
mL) then dried over sodium sulfate. The solvent was removed in
vacuo, giving a white foam that was purified by liquid chroma-
tography on silica gel, eluting with hexanes and gradually increasing
the polarity to 70:30 hexanes/ethyl acetate to give BCD-1 as a white
solid (179 mg, 86%). TLC (silica) Rf ) 0.83 (hexanes/EtOAc, 60:
40). IR (neat, cm-1): 3062, 2938, 2577, 1737, 1164, 1132. 1H NMR
(CDCl3): δ 7.36 (m, 5H, Ar), 5.18 (s, 2H, CH2Ar), 4.24 (q, J )
12, 6 Hz, 4H, CH2O), 3.68 (bs, 2H, CH), 2.48 (m, 8H, CH2), 1.28
(s, 3H, CH3). 13C NMR (CDCl3): δ 172.28, 171.04, 135.54, 128.84,
1
60:40). IR (neat, cm-1): 2921, 2851, 1738, 1218, 1154, 1082. H
NMR (CDCl3): δ 7.36 (m, 5H, Ar), 5.12 (s, 2H, CH2Ar), 4.33 (s,
4H, CH2), 4.15 (d, J ) 12 Hz, 4H, CH2), 4.11 (t, J ) 12 Hz, 2H,
CH2), 3.62 (d, J ) 12 Hz, 4H, CH2), 2.36 (t, J ) 12 Hz, 2H, CH2),
1.63 (m, 4H, CH2), 1.42 (s, 6H, CH3), 1.37 (s, 6H, CH3), 1.29 (bs,
10H, CH2), 1.26 (s, 3H, CH3), 1.68 (s, 6H, CH3). 13C NMR
(CDCl3): δ 173.62, 173.52, 172.60, 135.90, 128.53, 128.15, 66.05,
65.94, 65.43, 61.79, 46.71, 42.02, 34.29, 29.27, 29.16, 29.14, 29.07,
(46) Valliant, J. F.; Morel, P.; Schaffer, P.; Kaldis, J. H. Inorg. Chem. 2002,
41, 628-630.
Inorganic Chemistry, Vol. 45, No. 19, 2006 7817

Galie et al.
Scheme 1
Scheme 2
the dendrons, we selected a polyester backbone47,48 based
on 2,2-bis(hydroxymethyl)propanoic acid (bis-MPA) that has
been shown to be biodegradable, nonimmunogenic, water-
soluble, and nontoxic to cells in vivo.49 The polyester bis-
MPA-based dendrons were synthesized using the reported47,48
divergent approach shown in Scheme 1.
28.50, 25.84, 24.91, 24.80, 22.42, 20.63, 18.60, 17.71. MS (CI):
m/z 707 [M + H]+.
Synthesis of Generation-2 (OH)4 Dendron with Benzyl-10-
hydroxydecanoic Acid Linker (Gen-2L). AGen-2L (26 mg,
0.0367 mmol) was dissolved in methanol (3 mL). Dowex H+ (72
mg) was then added to the reaction flask under nitrogen. The
reaction mixture was stirred at room temperature for 3 h, after which
the resin was then filtered off and washed with methanol (2 × 10
mL). The solvent was removed in vacuo, giving the colorless solid
Gen-2L (23 mg, 99%). TLC (silica) Rf ) 0.58 (EtOAc/Acetone,
80:20). IR (neat, cm-1): 3245, 2931, 2855, 1728, 1461, 1219, 1135,
Esterification suggested itself as the preferred method to
attach a carboranyl moiety to the polyhydroxyl outer shell
of the dendrons. However, we and others44 have found that
the esterification of carboranyl acids in which the carboxylic
group is directly attached to the boron cluster is impaired
by the steric bulk of the boron cluster. Thus, direct attachment
of such acids to bis-MPA proved impossible, and it became
apparent that a spacer, such as a propanoic acid derivative,46
was necessary to reduce the steric hindrance around the
carboxylic group. To avoid the deprotonation/protection/
deprotection sequence required for the preparation of bi-
functional p-carboranes,44 we relied on the hydroboration
reaction of alkynes with decaborane which yields o-carbor-
anyl derivatives.10,50-52 The synthesis of o-carboranyl acid
1 is shown in Scheme 2. 4-Pentynoic acid 2 was first
protected as the trichloroester 3 since acids (and alcohols)
are known to degrade the polyhedral borane cage (B10H14)
involved in the insertion reaction.10,50-52 Previously, o-
carboranes have been synthesized via a base-promoted two-
step process.10,50-52 This reaction involves formation of an
activated B10H12L2 adduct (where L is typically acetonitrile)
followed by alkyne insertion to yield the o-carborane product.
Applied to the preparation of 1, this procedure required 4
days with yields of ca. 50%. Thus, a more efficient route
was sought. The use of ionic liquids (IL) in the hydrobora-
tion of alkenes and alkynes has been recently reported.21
This reaction involves a refluxing biphasic system of toluene
and an ionic liquid (1-butyl-3-methylimidazolium chloride,
1
1042. H NMR (CDCl3): δ 7.35 (m, 5H, Ar), 5.11 (s, 2H, CH2-
Ar), 4.43 (d, J ) 10.9 Hz, 2H, CH2), 4.24 (d, J ) 10.9 Hz, 2H,
CH2), 4.21 (t, J ) 6 Hz, 2H, CH2), 3.68 (m, 8H, CH2), 2.35 (t, J
) 6 Hz, 2H, CH2), 1.63 (m, 4H, CH2), 1.09 (s, 3H, CH3), 1.06 (s,
6H, CH3). 13C NMR (CDCl3): δ 178.29, 175.24, 173.24, 131.80,
128.71, 128.34, 126.31, 67.45 66.29, 65.01, 62.69, 49.90, 46.46,
34.46, 29.26, 28.63, 25.96, 25.05, 18.35, 17.30. MS (CI): m/z 627
[M + H]+.
Synthesis of Generation-2 Boron-Containing Dendron with
Benzyl-10-hydroxydecanoic Acid Linker (BCD-2L). Gen-2L (22
mg, 0.352 mmol), carborane acid 1 (39 mg, 0.181 mmol) and EDC
(50 mg, 0.262 mmol) were dissolved in dry dichloromethane (2
mL). DMAP (3.1 mg, 0.0254 mmol) was then added to the reaction
flask. The reaction mixture was stirred under nitrogen for 48 h.
Upon completion, dichloromethane was added (20 mL). Using a
separatory funnel, the organic layer was washed with water (3 ×
20 mL), 10% sodium bicarbonate (3 × 20 mL), and brine (3 × 20
mL) then dried over sodium sulfate. The solvent was removed in
vacuo, giving a white foam that was purified by liquid chroma-
tography on silica gel, eluting with 70:30 hexanes/ethyl acetate and
gradually increasing the polarity to 100% ethyl acetate to give BCD-
2L as a white solid (6.5 mg, 13%). TLC (silica) Rf ) 0.77 (hexanes/
EtOAc, 60:40). IR (neat, cm-1): 3061, 2920, 2850, 2591, 1738,
1730, 1241, 1169. 1H NMR (CDCl3): δ 7.36 (m, 5H, Ar), 5.12 (s,
2H, CH2Ar), 4.23 (m, 12H, CH2), 4.12 (t, J ) 6 Hz, 2H, CH2),
3.76 (bs, 4H, CH), 2.58 (bs, 16H, CH2), 2.36 (t, J ) 6 Hz, H2H,
CH2), 1.66 (m, 2H, CH2), 1.31 (s, 3H, CH3), 1.29 (s, 6H, CH3),
1.26 (bs, 10H, CH2). 13C NMR (CDCl3): δ 173.57, 171.96, 171.70,
170.83, 136.08, 128.52, 128.16, 128.12, 73.22, 69.36, 66.81, 65.62,
61.60, 55.57, 41.88, 46.50, 34.29, 32.50, 29.72, 29.30, 29.17, 29.09,
28.90, 28.54, 26.20, 24.91, 17.87, 17.73, 17.07. 11B NMR
(CDCl3): δ -2.35, -3.81, -3.96, -9.52, -11.16, -13.20. MS
(CI): m/z 1420 [M + H]+.
(47) Ihre, H.; Hult, A. Macromolecules 1998, 31, 406-4068.
(48) Malkoch, M.; Malmstro¨m, E.; Hult, A. Macromolecules 2002, 35,
8307-8314.
(49) Padilla De Jesu´s, O. L.; Ihre, H. R.; Fre´chet, J. M. J.; Szoka, F. L., Jr.
Bioconjugate Chem. 2002, 13, 453-461.
(50) Heying, T. L.; Ager, J. W., Jr.; Clark, S. L.; Mangold, D. J.; Goldstein,
H. L.; Hillman, M.; Polak, R. J.; Szymanski, J. W. Inorg. Chem. 1963,
2, 1089-1092.
(51) Fein, M. M.; Bobinski, J.; Mayes, N.; Schwartz, N.; Cohen, M. S.
Inorg. Chem. 1963, 2, 1111-1115.
Results and Discussion
(52) Fein, M. M.; Grafstein, D.; Paustian, J. E.; Bobinski, J.; Lichstein, B.
M.; Mayes, N.; Schwartz, N. N.; Cohen, M. S. Inorg. Chem. 1963, 2,
1115-1119.
Our choice of the dendritic scaffold was dictated by
general requirements for BNCT agents.20 Thus, to construct
7818 Inorganic Chemistry, Vol. 45, No. 19, 2006

Polyester-Based Carborane-Containing Dendrons
Scheme 3
Scheme 4
(bmim)Cl) that allows the hydroboration to proceed in a
matter of hours. Indeed, when this procedure was applied to
the preparation of 3 (Scheme 2), the reaction time was
reduced from 4 days to 1 hour. The yield remained reason-
ably high, and the ionic liquid could be easily removed by
flash chromatography. The trichloroester 3 was then cleaved53
to yield the o-carboranyl acid 1.
In the consequent step, 1 was coupled to the benzyl ester
of bis-MPA using conditions similar to those reported
earlier,44 providing generation-1 boron-containing dendron
BCD-1 (Scheme 3). However, further coupling of BCD-1
to the benzyl ester of bis-MPA to prepare a higher-generation
boron-containing dendron in a convergent fashion could not
be achieved (Scheme 3). Using a divergent approach, we
were able to couple o-carboranyl acid 1 to generation-2 bis-
MPA-based dendron (Scheme 3) to obtain generation-2
carborane-containing dendron BCD-2 (with four boron
clusters). Unfortunately, this procedure failed to provide the
next-generation dendron BCD-3 (with eight boron clusters)
upon coupling of 1 to the generation-3 bis-MPA-based
dendron (Scheme 3). Equally unsuccessful were our attempts
to synthesize BCD-3 through the coupling of BCD-2 to the
benzyl ester of bis-MPA (Scheme 3). In an attempt to
alleviate the steric strain associated with the 1,3-diol of bis-
MPA, we investigated the benzyl ester of 4,4-bis-(4-hydroxy-
phenyl)pentanoic acid.54 However, the increased spatial
separation between the hydroxyl groups of this new core did
not improve the reactivity, and higher-generation boron-
containing dendrons could not be accessed.
On the basis of the above observations, it appears that,
with four carborane cages, the BCD-2 dendron is extremely
(53) Windholz, T. B.; Johnston, D. B. R. Tetrahedron Lett. 1967, 27, 2555-
2557.
(54) Al-Azemi, T. F.; Bisht, K. S. Polymer 2002, 43, 2161-2167.
Inorganic Chemistry, Vol. 45, No. 19, 2006 7819

Galie et al.
sterically hindered. This was confirmed by molecular dy-
namics simulations of its three-dimensional structure (rep-
resentative structures are shown in Figure 1). The calculated
dendron possesses a globular structure with a hindered
carboxylic focal point. This explains its lack of reactivity
toward the benzyl ester of bis-MPA and suggests that higher-
generation boron-containing dendrons are unattainable through
coupling of 1 to higher generations of bis-MPA-based
dendrons.
To further explore the reactivity of the carboxylic group at
the focal point and to enable the attachment of BCD-2 to
other moieties, we first considered adding a 10-carbon alkyl
linker to the focal point of BCD-2 using 10-hydroxybenzyl-
decanate,55 easily prepared from the corresponding acid.56
However, the esterification at the focal point of BCD-2 with
this primary alcohol failed (Scheme 4), presumably for the
same steric reasons. An alternative route was chosen to install
the linker, and it proved to be successful. The acetonide-pro-
tected generation-2 dendritic acid (AGen-2A, Scheme 4) was
prepared by hydrogenation of its benzyl ester as previously
reported;47,48 the linker was attached to the focal point first
followed by the attachment of the carboranyl acid 1 to yield
BCD-2L (Scheme 4). Installing this linker shifts the carbox-
ylic group outside the sterically hindered dendron and should
allow its incorporation into BNCT macromolecular agents.
Conclusions
We prepared new carborane-containing dendrons based
on a 2,2-bis(hydroxymethyl)propanoic acid (bis-MPA) scaf-
fold and showed that they are highly sterically congested. A
generation-2 carborane-containing dendron carrying 40 boron
atoms was the highest generation synthetically available. The
structure of this dendron has been simulated by molecular
dynamics. A 10-carbon linker carrying a carboxylic group
has been installed at the focal point of the dendron to distance
the attachment point from the sterically hindered core. We
are presently working on the attachment of these dendrons
to targeting moieties for use in BNCT.
Acknowledgment. This work has been funded in part
by the NIH Training Grant Fellowship for K. M. G. and by
University of Utah Funding Incentive Seed Grant. We are
grateful to Prof. Bogdan Olenyuk (University of Arizona)
for fruitful collaboration. We thank Dr. Valeria Molinero
(California Institute of Technology) for assistance with
molecular dynamics simulations.
(55) Holt, D. A.; Luengo, J. I.; Yamashita, D. S.; Oh, H.-J.; Konialian, A.
L.; Yen, H. K.; Rozamus, L. W.; Brandt, M.; Bossard, M. J.; Levy,
M. A.; Eggleston, D. S.; Liang, J.; Schultz, L. W.; Stout, T. J.; Clardy,
J. J. Am. Chem. Soc. 1993, 115, 9925-9938.
(56) We consistently obtained yields higher (e.g., 81% vs 54%) than
previously reported.
IC060866R
7820 Inorganic Chemistry, Vol. 45, No. 19, 2006