Synthesis of a water soluble boron neutron capture therapy agent: 1-amino-3-[2-(7-{3-[2-(2-hydroxymethyl-ethoxy)-1-(2-hydroxy-1-hydroxymethyl- ethoxymethyl)ethoxy]propyl}-1,7-di-carba-closo-dodecaboran-1-yl)ethyl] cyclobutanecarboxylic acid

Article abstract of DOI:10.1016/S0022-328X(00)00630-6

A water soluble boronated amino acid containing a cascade polyol, 1-amino-3-[2-(7-{3-[2-(2-hydroxymethyl-ethoxy)-1-(2-hydroxy-1-hydroxymethyl- ethoxymethyl)ethoxy]propyl}-1,7-di-carba-closo-dodecaboran-1-yl)ethyl] cyclobutanecarboxylic acid, has been deve

Full text of DOI:10.1016/S0022-328X(00)00630-6

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 614–615 (2000) 255–261
Synthesis of a water soluble boron neutron capture therapy agent:
1-amino-3-[2-(7-{3-[2-(2-hydroxymethyl-ethoxy)-1-(2-hydroxy-1-
hydroxymethyl-ethoxymethyl)ethoxy]propyl}-1,7-di-
carba-closo-dodecaboran-1-yl)ethyl]cyclobutanecarboxylic acid
Bhaskar C. Das, George W. Kabalka *, Rajiv R. Srivastava, Weiliang Bao,
Sasmita Das, Guisheng Li
Departments of Chemistry and Radiology, Uni6ersity of Tennessee Knox6ille, TN 37996-1600, USA
Received 5 May 2000
Dedicated to Professor Sheldon Shore on the occasion of his 70th birthday.
Abstract
A water soluble boronated amino acid containing a cascade polyol, 1-amino-3-[2-(7-{3-[2-(2-hydroxymethyl-ethoxy)-1-(2-hy-
droxy-1-hydroxymethyl-ethoxymethyl)ethoxy]propyl}-1,7-di-carba-closo-dodecaboran-1-yl)ethyl]cyclobutanecarboxylic acid, has
been developed. The key step in the synthesis is the alkylation of 3-[2-(1,7-dicarba-closo-dodecarboran-1-yl)ethyl]cyclobutanone
hemithioketal with toluene-4-sulfonic acid 3-[2-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-1-(2-benzyloxy-1-benzyloxymethyl-
ethoxymethyl)ethoxy]propyl ester which gave the required precursor ketone which was then converted to the title amino acid via
a Bu¨cherer–Strecker synthesis followed by hydrogenolysis to remove the benzyl protecting groups. © 2000 Elsevier Science B.V.
All rights reserved.
Keywords: BNCT; Polyol; Amino acid; Carborane
BNCT is a binary therapy which is dependent on the
selective deposition of boron-10 in the tumor prior to
1. Introduction
irradiation by slow (thermal) neutrons [5]. The interac-
Boron neutron capture therapy (BNCT) was first
tion of a boron-10 atom with a thermal neutron pro-
proposed as a potential cancer therapy in 1936 [1] but
duces an a-particle and a high energy lithium-7 ion.
the successful application of BNCT to the treatment of
The linear energy transfer (LET) of these heavy
cancer still presents a challenge in modern medical
7
charged particles (4He and Li) has a range of approxi-
research. Early attempts to cure cancer using BNCT
mately one cell diameter and thus they are lethal to the
were unsuccessful, due to vascular damage caused by
cells in which they are generated. To minimize damage
the nonselective uptake of the boronated agents [2,3].
to normal tissues, the quantity of boron in the tumor
Encouraging results obtained in Japan [4] using sodium
mercaptoundecahydrodecaborate (Na2B12H11SH, BSH)
(ꢀ30 mg of 10B g−1 of tumor) must exceed that in the
surrounding normal tissues by at least a factor of three
and 4-dihydroxyborylphenylalanine (BPA) has led to a
[6,7]. A variety of carrier molecules have been used to
resurgence of interest in BNCT. Current clinical trials
deliver boron to the tumor cells. These include carbohy-
suggest that BNCT can play an important role in
drates [8–10], amino acids [11–14], nucleosides [15,16],
cancer therapy.
antisense agents [17], porphyrins [18], antibodies
[19,20], and liposomes [21].
Boron-containing amino acid derivatives have been
examined as potential agents for BNCT [22–24]. It is
believed that amino acids are preferentially taken up by
* Corresponding author. Tel.: +1-865-9743260; fax: +1-865-
9742997.
E-mail address: kabalka@utk.edu (G.W. Kabalka).
0022-328X/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00630-6

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B.C. Das et al. / Journal of Organometallic Chemistry 614–615 (2000) 255–261
growing tumor cells. In fact, the only drug (BPA)
currently in clinical trials in the US is an amino acid
[25]. Carboranyl analogues of phenylalanine [15,16]
have also been synthesized and are currently being
evaluated as potential BNCT agents.
Relatively large cellular concentrations of boron are
required for successful BNCT which makes it impera-
tive that the carrier molecules be non-toxic. For this
reason, we have focused our efforts on a cyclic a-amino
acid, 1-aminocyclobutanecarboxylic acid (ACBC), as a
boron carrier. This unnatural amino acid is non-toxic
and is preferentially retained in intracerebral tumors. In
fact, carbon-11 labeled ACBC is used for imaging brain
tumors at the University of Tennessee Medical Center
[26,27].
2. Results and discussion
Recently we reported the syntheses of a meta-carbo-
rane-containing ACBC derivative and a less lipophilic
nido-analogue [28,29]. The nido derivative provided
good water-solubility but the ionic character of the cage
has always been problematic in in vivo studies because
it leads to non-specific protein binding [30,31]. How-
ever, closo-meta-carboranyl-ACBC and its less lipo-
philic analogue, the hydroxyethyl derivative, are ex-
tremely hydrophobic and therefore their in vivo uses
are limited. In order to increase the water solubility of
meta-carboranyl-ACBC, we decided to introduce
polyol substituents. We wish to report the syntheses of
a water soluble polyol (of the cascade type) containing
a meta-carboranyl-ACBC derivative, 1-amino-3-[2-(7-
{3-[2-(2-hydroxymethyl-ethoxy)-1-(2-hydroxy-1-hy-
droxymethyl - ethoxymethyl) - ethoxy]propyl} - 1,7 - di-
carba - closo - dodecaboran - 1 - yl)ethyl]cyclobutanecar-
boxylic acid (1).
The key synthetic step in the formation of the title
compound is the preparation of the benzyl protected
meta-carboranylcyclobutanone 5 (Scheme 1). Ketone 5
was prepared by coupling the lithium salt of the meta-
carboranyl-cyclobutanone hemithiol ketal 3 with the
polyol tosylate 11. Hemithiol ketal 3 was obtained by
refluxing the meta-carboranyl-cyclobutanone 2 with
mercaptoethanol in the presence of a catalytic amount
of p-toluenesulfonic acid. Tosylate 11 was prepared
from cascade polyol 8 in three steps (Scheme 2). The
benzyl protected polyol 8 was allylated at the secondary
hydroxyl position. Alkene 9, thus obtained, was sub-
jected to hydroboration followed by oxidation to ob-
tain primary alcohol 10 which was then converted to
the desired tosylate 11 by the action of p-toluenesul-
fonic acid in pyridine. In the next step, the hemithiol
ketal group in 4 was removed by the action of mercuric
chloride in tetrahydrofuran containing aqueous sodium
Scheme 1. Synthesis of cascade polyl-containing meta-carbonyl ACBC: Reaction condition: (a) HO(CH)2SH, TsOH, C6H6; (b) BuLi, THF, 11;
(c) HgCl2, 0.1 N NaOH, THF; (d) KCN, (NH4)2CO3, aqueous EtOH (50% solution in H2O); (e) 2 N NaOH; (f) H2, PdꢀC, MeOH.

B.C. Das et al. / Journal of Organometallic Chemistry 614–615 (2000) 255–261
257
Scheme 2. Synthesis of p-toluene sulfonate derivative of cascade polyol. Reaction condition: (a) allyl bromide, NaH, DMF; (b) (i) (c-C6H11)2BH,
THF (ii) p-TsCl, pyridine.
Column chromatography was performed using silica
hydroxide to generate ketone 5 which was reacted
with ammonium carbonate and potassium cyanide in a
pressure tube. Hydantoin 6 was formed in good yield.
The hydantoin was then hydrolyzed with sodium hy-
droxide at 160°C (oil bath) to generate amino acid 7.
Removal of the benzyl groups from 7 was achieved by
hydrogenolysis in the presence of palladium on
activated carbon to afford the desired product,
1-amino-3-[2-(7-{3-[-(2-hydroxymethyl-ethoxymethyl)-
1-(2-hydroxy-1-hydroxymethyl-ethoxymethyl)ethoxyl]-
propyl}-1,7-di-carba-closo-dodecaboran-1-yl)ethyl]-
cyclobutanecarboxylic acid (1), which was found to
readily dissolve in water (\60 g l−1).
,
gel (60 A, 230–400 mesh, Baxter Co., McGaw Park,
IL). Reverse-phase column chromatography was per-
formed utilizing octadecyl functionalized silica gel
(Aldrich Chemical Co., Milwaukee, WI). Analytical
thin layer chromatography was performed on 250 mi-
cron silica (Analtech Inc., Newark, DE) and were visu-
alized by phosphomolybdic acid, palladium chloride,
and silver nitrate solutions.
Melting points are uncorrected. Infrared (Bio-Rad
FTS-7) spectra were obtained either neat or as Nujol
1
mulls. H- and 13C-NMR spectra were recorded on a
Bruker AC250 at 250.13 and 62.89 MHz, respectively.
In cases where more than one isomer was formed, we
report the 13C-NMR of the major isomer. 11B-NMR
(1H-decoupled) spectra were obtained on a Bruker
3. Conclusions
1
AMS-400 at 128.38 MHz. Chemical shifts for H- and
13C-NMR spectra were determined using the residual
protons in the deuterated solvents and referenced to
Si(CH3)4. Microanalysis were performed by Galbraith
Laboratories Inc, Knoxville, TN. HR-FABMS [M+1]
were obtained in a glycerol matrix using a ZAB-EQ
mass spectrometer. Positive ion electrospray mass spec-
tra (ES+) were obtained in instances where satisfactory
elemental analyses were obtained for compounds con-
taining carbon and hydrogen but where boron values
exceeded acceptable limits (not uncommon for boron
cages).
A water soluble, boron containing amino acid, 1-
amino-3-[2-(7-{3-[2-(2-hydroxymethyl-methylethoxy)-1-
(2-hydroxy-1-hydroxymethyl-ethoxymethyl)ethoxy]pro-
pyl}-1,7-dicarba-closo-dodecaboran-1-yl)ethyl]cyclo-
butanecarboxylic acid was prepared. A cascade polyol
was attached to the carboranyl portion of the amino
acid to impart water solubility. This agent is being
evaluated as a potential BNCT agent.
4. Experimental
4.2. Synthesis of 3-[2-(2-benzyloxy-1-benzyloxymethyl-
ethoxy)-1-(2-benzyloxy-1-benzyloxymethyl-ethoxy-
methyl)ethoxy]propene (9)
4.1. General methods
All solvents were reagent grade. Tetrahydofuran and
diethyl ether were distilled from sodium benzophenone
ketyl; benzene was distilled from calcium hydride; all
were stored under nitrogen. All other chemicals
(Aldrich Chemical Co., Milwaukee, WI) were used as
received.
A solution of 2-[2-allyloxy(1,3-dibenzyloxy-2-propy-
loxy)-2-propanol (8) [32] (4.80 g, 6.73 mmol) in anhy-
drous DMF (15 ml) was allowed to react with sodium
hydride (1.08 g, 60% in mineral oil, 26.9 mmol). After
the mixture was stirred at room temperature (r.t.) for

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B.C. Das et al. / Journal of Organometallic Chemistry 614–615 (2000) 255–261
0.5 h, allyl bromide (2.83 ml, 32.3 mmol) was added and
solution stirred overnight at r.t. The reaction mixture was
then diluted with ether (100 ml), washed successively with
water (3×10 ml), brine (10 ml) and dried over anhydrous
magnesium sulfate. The solvent was removed under
reduced pressure and the residue dried under vacuum (0.1
mmHg) for 1 h to yield 9 as a yellow oil (4.60 g), which
was used in the next step without further purification;
Rf=0.65 (30% ethyl acetate in hexane). 1H-NMR
(CDCl3): l 7.29 (m, 20H), 5.87 (m, 1H), 5.21 (dt, 1H,
J=17.5, 6.4), 5.08 (dt, 1H, J=12.5, 6.4), 4.50 (s, 8H),
4.11 (d, 2H, J=6.4), 3.80–3.50 (m, 15H). 13C-NMR
(CDCl3): l 138.29, 135.32, 128.26, 127.47, 116.42, 78.64,
77.61, 73,29, 71.21, 70.36, 70.10; IR (neat) 3063, 3029,
2906, 2863, 1495, 1453, 1365, 1306, 1257, 1205, 1101, 1027,
997, 921,738, cm −1. Anal. Calc. for C40H48O7: C, 74.97;
H, 7.55. Found: C, 74.92; H, 7.68%.
alcohol 10 (1.56 g, 2.37 mmol), pyridine (5 ml) and cooled
to 0°C (ice bath), p-toluenesulfonyl chloride (0.679 g, 3.56
mmol) was added and the solution stirred for 6 h while
maintaining the bath temperature at 0°C. TLC indicated
the disappearance of the starting alcohol. The reaction
mixture was poured into a mixture of Et2O (150 ml), ice
(20 g) and HCl (5.3 ml). The ether solution was separated,
washed with ice water (3×20 ml) and dried over
anhydrous magnesium sulfate. Solvents were removed
under reduced pressure and residue was purified by
chromatography (30% EtOAc in hexane) to give 11 as
a colorless oil (1.57 g, 82% yield); Rf=0.30 (35% EtOAc
1
in hexane). H-NMR (CDCl3): l 7.74 (d, 2H, J=8.2),
7.37–7.08 (m, 22H), 4.49 (s, 8H), 4.08 (t, 2H, J=6.3),
3.74–3.39 (m, 17H), 2.38 (s, 3H), 1.80 (m, 2H). 13C-NMR
(CDCl3): l 144.50, 138.26, 133.22, 129.73, 128.28, 127.79,
127.52, 78.46, 73.27, 70.24, 70.08, 69.91, 65.70, 29.58,
21.53. The tosylate was used without further purification.
4.3. Synthesis of 3-[2-(2-benzyloxy-1-benzyloxymethyl-
ethoxy)-1-(2-benzyloxy-1-benzyloxymethyl-ethoxy-
methyl)ethoxy]propan-1-ol (10)
4.5. Synthesis of 3-[2-(1,7-di-carba-dodecaboran-1-yl)-
ethyl]cyclobutanone hemithiol ketal (3)
A 50 ml round-bottomed flask equipped with an Ar
filled balloon was charged with BH3·THF (11.1 ml, 10.1
mmol). While keeping the flask at 0°C (ice bath),
cyclohexene (2.10 ml, 20.2 mmol) was added via a syringe
over a period of 10 min. The solution was stirred for an
additional 1 h. Alkene 9 (3.20 g, 5.00 mmol) was added
to the flask and the resulting mixture was stirred under
an argon atmosphere for 12 h at r.t. The reaction mixture
was cooled in an ice-bath and then the organoborane
carefully oxidized using a mixture of water (10 ml) and
sodium perborate tetrahydrate (4.60 g, 30.0 mmol).
Volatiles were removed under reduced pressure and the
residue extracted with ether (3×40 ml), the ether solu-
tions washed with brine, dried over anhydrous magne-
sium sulfate and the solvent removed under reduced
pressure to obtain a faint yellow oil. The product was
purified by column chromatography using silica gel
(30–50% ethyl acetate in hexane) to obtain 10 as a
colorless oil (3.42 g, 79% yield based on 9); Rf=0.186
(30% ethyl acetate in hexane). 1H-NMR (CDCl3): l 7.29
(m, 20H), 4.50 (s, 8H), 3.85–3.45 (m, 19H), 2.95 (brs, 1H),
1.74 (m, 2H). 13C-NMR (CDCl3) l 138.22, 128.31, 127.58,
78.62, 73.32, 70.30, 70.14, 69.06, 61.24, 31.40; IR (neat)
3477, 3087, 3063, 3030, 2914, 2867, 1584, 1495, 1452, 1366,
1273, 1205, 1100, 1027, 911, 740, 713 cm −1. Anal. Calc.
for C40H50O8: C, 72.92; H, 7.65. Found: C, 72.10; H,
7.58%.
A 250 ml three-necked, round-bottomed flask equipped
with a Dean–Stark apparatus and reflux condenser was
charged with closo-3-[2-(1,7-di-carba-dodecaboran-1-
yl)ethyl]cyclobutanone (2) (0.488 g, 2.03 mmol), mercap-
toethanol (0.170 ml, 2.44 mmol), and p-toluenesulfonic
acid monohydrate (0.020 g, 0.10 mmol) in benzene (100
ml). The reaction mixture was refluxed for 4 h and the
reaction was monitored by thin layer chromatography
(TLC). After 4 h, the contents of the flask were cooled
to r.t. and neutralized with aqueous 0.1 N NaOH. The
mixture was transferred to a separatory funnel, washed
with water (3×20 ml), brine (1×20 ml), dried over
anhydrous magnesium sulfate and concentrated under
reduced pressure to yield a colorless oil. The crude
material was purified using a silica gel column to obtain
3 as a white solid (0.576 g, 94% yield): m.p. 48–50°C;
Rf=0.52 (30% EtOAc in hexane). 1H-NMR (CDCl3): l
4.01 (m, 2H), 3.06 (m, 2H), 2.90 (s, 1H), 2.53 (m, 2H),
2.20–1.75 (m, 5H), 1.52 (m, 2H); 13C-NMR (CDCl3): l
89.92, 75.99, 69.42, 54.81, 44.58, 36.39, 34.79, 33.66,
25.97;IR(Nujol)2926, 2860, 2601, 1458, 1916, 1375, 1271,
1253, 1139, 1057, 1008, 940, 830, 727 cm−1. Anal. Calc.
for C10H24B10OS: C, 39.97; H, 8.05. Found: C, 40.02; H,
8.14%.
4.6. Synthesis of 3-[2-(7-{3-[2-(2-benzyloxy-1-
benzyloxymethyl-ethoxy)-1-(2-benzyloxy-1-
benzyloxymethyl-ethoxymethyl)ethoxy]propyl}-1,7-di-
carba-closo-dodecaboran-1-yl)ethyl]cyclobutanone
hemithiol ketal (4)
4.4. Synthesis of toluene-4-sulfonic acid 3-[2-(2-
benyloxy-1-benzyloxymethyl-ethoxy)-1-(2-benzyloxy-
1-benzyloxymethyl-ethoxymethyl)ethoxy]propyl ester
(11)
A 100 ml three-necked, round-bottomed flask, fitted
with an argon filled balloon, was charged with 3-[2-(1,7-
di-carba-closo-dodecaboran-1-yl)ethyl]cyclobutanone
A 25 ml round-bottomed flask was charged with

B.C. Das et al. / Journal of Organometallic Chemistry 614–615 (2000) 255–261
259
hemithiol ketal (3) (0.568 g, 1.89 mmol) in THF (10
ml). The flask was cooled to 0°C in an ice bath.
Butyllithium (2.08 mmol, 1.30 ml of 1.60 M solution in
hexane) was added dropwise via a syringe. The resul-
tant solution was stirred at 0°C for 30 min and then at
r.t. for 1 h. The solution was cooled to 0°C and then a
solution of toluene-4-sulfonic acid 3-[2-(2-benzyloxy-1-
benzyloxymethyl-ethoxy)-1-(2-benzyloxy-1-benzyloxy-
methyl-ethoxymethyl)ethoxy]propyl ester (11) (1.57 g)
in THF (2 ml) was added dropwise via a syringe. The
reaction mixture was allowed to stir overnight (during
which time the bath temperature was allowed to come
to r.t.) and then it was refluxed for 1 h. The reaction
was quenched with saturated aqueous ammonium chlo-
ride solution and then transferred to a separatory fun-
nel. The product was extracted into ether (100 ml) and
the organic layer was washed sequentially with water
(2×20 ml), brine (2×20 ml), dried over anhydrous
magnesium sulfate and concentrated under reduced
pressure to obtain a thick oil (1.40 g). The product was
purified by column chromatography using silica gel
(25% EtOAc in hexane) to obtain 4 as a semi-solid (1.12
g, 83% yield) along with the recovery of unreacted
hemithiol ketal 3 (0.19 g, 33% yield); Rf=0.476 (20%
0.256 (30% EtOAc in hexane). 1H-NMR (CDCl3): l
7.29 (m, 20H), 4.50 (s, 8H), 3.79–3.47 (m, 15H), 3.43 (t,
2H, J=6.1), 3.10 (m, 2H), 2.57 (m, 2H), 2.19 (m, 1H),
1.93 (m, 4H), 1.57 (m, 4H). 13C-NMR (CDCl3): l
206.67, 138.17, 128.22, 127.46, 78.54, 78.32, 75.79,
74.78, 73.21, 70.20, 70.23, 69.05, 52.24, 36.12, 35.48,
33.62, 30.38, 23.26; IR (neat) 3207, 3040, 2949, 2850,
2597, 1761, 1455, 1350, 1250, 1170, 1020, 778, 727, 643
cm−1. Anal. Calc. for C48H68B10O8: C, 65.43; H, 7.78.
Found, 64.63; H, 7.72%.
4.8. Synthesis of the hydantoin of 3-[2-(7-{3-[2-(2-
benzyloxy-1-benzyloxymethyl-ethoxy)-1-(2-benzyloxy-
1-benzyloxymethyl-ethoxymethyl)ethoxy]propyl}-1,7-
di-carba-closo-dodecaboran-1-yl)ethy]cyclobutanone (6)
A 35 ml Ace pressure tube was charged with 3-[2-(7-
{3-[2-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-1-(2-
benzyloxy - 1 - benzyloxymethyl - ethoxymethyl)ethoxy]-
propyl}-1,7-di-carba-closo-dodecaboran-1-yl)ethyl]-
cyclobutanone (5, 0.720 g, 0.817 mmol), potassium
cyanide (0.106 g, 1.63 mmol), ammonium carbonate
(0.314 g, 3.27 mmol), EtOH (4 ml), water (4 ml) and a
stirring bar. The reaction vessel was sealed and heated
at 80°C (oil bath) for 16 h. The reaction vial was then
cooled to r.t. and carefully opened in a fume hood. The
mixture was acidified using dilute aqueous hydrochloric
acid and extracted with ether (150 ml). The ether layer
was washed with brine (2×20 ml), dried over anhy-
drous magnesium sulfate, and concentrated under re-
duced pressure to obtain an oil. The product was
obtained by column chromatography using silica gel
(10% methanol in methylene chloride) to obtain hydan-
toin 6 as a colorless oil (0.585 g, 73% yield); Rf=0.56
1
EtOAc in hexane). H-NMR (CDCl3): l 7.30 (m, 20H),
4.50 (s, 8H), 4.00 (dt, 2H, J=2.5, 6.1), 3.76–3.47 (m,
15H), 3.43 (dt, 2H, J=12.3, 6.1), 2.52 (m, 2H), 2.20–
1.68 (m, 5H), 1.55 (m, 4H). 13C-NMR (CDCl3): l
138.27, 128.31, 127.53, 90.80, 78.62, 78.42, 75.72, 75.38,
70.36, 70.14, 69.39, 69.20, 44.57, 36.33, 34.80, 33.72,
33.64, 30.46, 26.97; IR (neat) 3062, 3030, 2922, 2863,
2595, 1783, 1739, 1495, 1453, 1369, 1254, 1176, 1101,
1028, 737, 698 cm−1. Anal. Calc. for C50H12B10O8S: C,
63.80; H, 7.71. Found: C, 64.06; H, 7.56%.
1
(10% methanol in CH2Cl2). H-NMR (CDCl3): l 8.40
4.7. Synthesis of 3-[2-(7-{3-[2-(2-benzyloxy-1-
benzyloxymethyl-ethoxy)-1-(2-benzyloxy-1-
benzyloxymethyl-ethoxymethyl)ethoxy]propyl}-1,7-
dicarba-closo-dodecaboran-1-yl)ethyl]cyclobutanone (5)
(brs, 1H), 7.30 (m, 20H), 6.33 (brs, 1H), 4.50 (s, 8H),
3.75–3.48 (m, 15H), 3.43 (t, 2H), J=6.1), 260 (m, 2H),
2.27 (m, 1H), 195–1.70 (m, 6H), 1.65–1.40 (m, 4H).
13C-NMR (CDCl3): l 177.28, 155.98, 138.26, 128.34,
127.58, 78.64, 78.44, 75.82, 75.05, 73.33, 70.36, 70.14,
69.18, 58.74, 38.94, 37.09, 34.19, 33.72, 30.48, 26.36; IR
(neat) 3225, 3032, 2925, 2863, 2759, 2592, 1760, 1726,
1495, 1452, 1305, 1279, 1099, 738, 698 cm−1. Anal.
Calc. for C50H70B10N2O9; C, 63.13; H, 7.41; N, 2.94.
Found: C, 62.53; H, 7.45; N, 2.84%.
To a vigorously stirred solution of 3-[2-(7-{3-[2-(2-
benzyloxy-1-benzyloxymethyl-ethoxy)-1-(2-benzyloxy-
1 - benzyloxymethyl - ethoxymethyl)ethoxy]propyl} - 1,7-
dicarba - closo - dodecaboran - 1 - yl)ethyl]cyclobutanone
hemithiol ketal (4) (0.912 g, 0.970 mmol) and HgCl2
(0.276 g, 1.02 mmol) in THF (80 ml) was added
aqueous 0.1 N NaOH (10 ml) via a syringe over a
period of 30 min and the reaction monitored by TLC.
After the reaction was complete, the THF was removed
under reduced pressure and the residue extracted into
Et2O (3×30 ml). The ether solution was washed with
brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to obtain an oil.
The product was purified by column chromatography
using silica gel (10% MeOH in methylene chloride) to
obtain 5 as a colorless oil (0.774 g, 91% yield); Rf=
4.9. Synthesis of 1-amino-3-[2-(7-{3-[-(2-benzyloxy-1-
benzyloxymethyl-ethoxy)-1-(2-benzyloxy-1-
benzyloxymethyl-ethoxymethyl)ethoxy]propyl}-1,7-di-
carba-closo-dodecaboran-1-yl)ethyl]cyclobutane-
carboxylic acid (7)
The hydantoin of 3-[2-(7-{3-[2-(2-benzyloxy-1-benzy-
loxymethyl-ethoxy)-1-(2-benzyloxy-1-benzyloxymethyl-
ethoxymethyl)ethoxy]propyl}-1,7-di-carba-closo-dode-

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B.C. Das et al. / Journal of Organometallic Chemistry 614–615 (2000) 255–261
caboran-1-yl)ethyl]cyclobutanone (6), (0.310 g, 0.326
mmol) was placed in a 15 ml Ace pressure tube along
with a solution of sodium hydroxide (4 ml of 2 N
NaOH). The tube was sealed and then heated at 160°C
(oil bath) for 3 h. It was then cooled to r.t. and
carefully opened. The contents of the flask were washed
with Et2O (2×1 ml) and the aqueous suspension was
neutralized with aqueous 0.5 N HCl. The solids ob-
tained were dissolved in CH2Cl2 (100 ml) and washed
with distilled water (3×10 ml). The solvent was re-
moved under reduced pressure to obtain 1-amino-3-[2-
(7-{3-[2-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-1-(2-
benzyloxy - 1 - benzyloxymethyl - ethoxymethyl)ethoxy]-
propyl}-1,7-di-carba-closo-dodecaboran-1-yl)ethyl]-
cyclobutane carboxylic acid (7) (0.252 g, 83%) as a
semi-solid; Rf=0.62 (isopropanol:water:AcOH in
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10:10:0.5). H-NMR (CDCl3): l 7.26 (brs, 20H), 4.67
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(7)
(0.062 g), and 10% palladium on activated carbon
(0.050 g) in MeOH (3 ml) were vigorously stirred under
1 atmosphere of hydrogen for 2 days in a 100 ml
round-bottomed flask. The mixture was filtered through
a pad of Celite® and washed with MeOH (3×10 ml).
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semi-solid (0.33 g, 87% yield); Rf=0.49 (iso-
propanol:water:AcOH
in
10:10:0.5).
1H-NMR
(CD3OD): l 3.85–3.45 (m, 17H), 2.50–1.38 (m, 13H).
13C-NMR (CD3OD): l 89.67, 81.90, 81.27, 78.08, 75.84,
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Acknowledgements
We wish to thank the US Department of Energy and
the Robert H. Cole Foundation for financial support of
this study.

B.C. Das et al. / Journal of Organometallic Chemistry 614–615 (2000) 255–261
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