Alpha (α-) and beta (β-carboranyl-C-deoxyribosides: Syntheses, structures and biological evaluation

Article abstract of DOI:10.1016/j.ejmech.2014.06.005

The syntheses of the unprotected neutral closo-carboranyl-C-deoxyriboses, starting from anomeric mixture of 1-ethynyldeoxyriboses, and their corresponding open-cage nido-derivatives have been described. The structures of both the α- and β-anomers were con

Full text of DOI:10.1016/j.ejmech.2014.06.005

European Journal of Medicinal Chemistry 83 (2014) 389e397
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Alpha (
a-) and beta (b-carboranyl-C-deoxyribosides: Syntheses,
structures and biological evaluation
a
b
c
ꢁ d
ꢀ
ꢀ
ꢀ
ꢀ
Ivan Snajdr , Zbynek Janousek , Masao Takagaki , Ivana Císarova ,
Narayan S. Hosmane e **, Martin Kotora a
a Department of Organic Chemistry, Charles University in Prague, Hlavova 8, 153 00 Praha 2, Czech Republic
,
, b, *
b
ꢁ
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2, 166 10 Praha 6, Czech Republic
c Graduate School of Human & Environmental Studies, Kyoto University, Nihonmatsu, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
d Department of Inorganic Chemistry, Charles University in Prague, Hlavova 8, 153 00 Praha 2, Czech Republic
e Department of Chemistry & Biochemistry, Northern Illinois University, DeKalb, IL 60115-2862, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The syntheses of the unprotected neutral closo-carboranyl-C-deoxyriboses, starting from anomeric
mixture of 1-ethynyldeoxyriboses, and their corresponding open-cage nido-derivatives have been
Received 1 August 2013
Received in revised form
27 November 2013
Accepted 3 June 2014
Available online 19 June 2014
described. The structures of both the
a- and b-anomers were confirmed by single-crystal X-ray
diffraction. While limited water solubility of the neutral closo-anomers led to high cytotoxicity, their
cesium salts (nido-species) exhibited higher water solubility leading to lower cytotoxicity. However,
in vitro boron neutron capture therapy (BNCT) investigation using the murine squamous cell carcinoma
(SCCVII) cell lines showed that there are no significant differences between the survival fractions of the
two species.
Keywords:
Alkynes
Carboranes
© 2014 Elsevier Masson SAS. All rights reserved.
Boron neutron capture therapy
Antitumor agents
Drug research
1. Introduction
to be useful as pharmacophores [6]. However, these boron de-
rivatives cannot be transported to tumor cells by themselves and,
Sugars are known to be the main source of metabolic energy in
living cells. Among them, glucose uptake is the rate-limiting step
indicating the importance of GLUT (solute carrier family 2 with the
gene name SLC2A) transporters in metabolism. Evidently, cancer
cells display an increased consumption of glucose [1] which is
metabolized primarily through the fermentative pathway leading
to lactic acid production [2]. On the other hand, boron possessess
unique structural properties that make them exceptionally stable
allowing their exploitation in many areas of human activity [3]. In
this regard, it is significant that one of the isotopes of boron, 10B, has
been exploited in medicinal applications, including boron neutron
capture therapy for cancer (BNCT). Other applications of boron
compounds, in general, have been in radionuclide diagnostics and
therapy and other related fields [4]. In addition, while some car-
borane derivatives exhibited antiviral activity [5], the others found
therefore, a suitable transporter molecules need to be incorporated
in the first place and then make them water soluble in order to be
the effective transporters. It was in this context, a number of sac-
charideecarborane conjugates with the CeO-glycosidic bond such
as those with glucose [7], glucuronic acid [8], galactose [7a,7e]
mannose [7c,7e], glucose, fructose, lactose [7c,7d], maltose [7c],
disaccharides [9], cyclodextrins [10], or glycophosphonates [11]
have been synthesized [12], and, surprisingly, only one report to
date has dealt with the preparation of 1-carboranyl-C-saccharide
derivatives (with glucose) without the glycosidic bond [13]. Since
the glycosidic bond can easily undergo enzymatic cleavage, the
BNCT evaluations of the saccharideecarborane conjugates have not
been explored further. To the best of our knowledge, there have
been no reports on the syntheses, structures and biological evalu-
ations of the carboranyl derivatives possessing the deoxyribose
moiety. The fact that the carborane cages in these neutral species
can be opened to form the corresponding water soluble salts, we
embarked on a research project involving both
(cage)-linked carboranyldeoxyribose derivatives in order meet the
two essential demands e a good transporter metabolite into tumor
a and b anomers of
* Corresponding author. Department of Organic Chemistry, Charles University in
Prague, Hlavova 8, 153 00 Praha 2, Czech Republic.
** Corresponding author.
C
E-mail address: kotora@natur.cuni.cz (M. Kotora).
http://dx.doi.org/10.1016/j.ejmech.2014.06.005
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

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with a reasonable water solubility and abundant 10B nuclei for
BNCT to destroy the tumor. Here, we report the results of this
investigation.
2. Results and discussion
2.1. Synthesis of alkynyldeoxyriboside precursors
The anomeric mixture of ethynyldeoxyribosides 1a (2/1 1a
a/
1a
b) was prepared from the corresponding halogenose and ethy-
nylmagnesium chloride. [14] The Sonogashira coupling reaction of
this mixture 1a afforded the corresponding anomeric species 1b (2/
1 1b
a/1bb) in 43% isolated yield (Scheme 1) [14e]. In an analogous
Scheme 2. Synthesis of carboranyl-C-deoxyribosides.
reaction involving 1a with 1-iodo-4-(2-phenylethynyl)benzene, the
bisalkynyl derivatives 1c (2/1 mixture of 1ca and 1cb) were isolated
in 31% yield.
2.2. Synthesis of carboranyldeoxyriboses
It has been well established that alkynes readily react with 6,9-
(ligand)2-arachno-B10H12 to give the corresponding ortho-carbor-
anes [15]. We envisioned that the same procedure could also be
used for reaction with the above described alkynyldeoxyribosides.
In general, refluxing 6,9-(Me2S)2-arachno-B10H12 [16] with
anomeric mixtures of the alkynyldeoxyribosides 1
toluene for 16 h gave the corresponding anomeric mixtures of
carboranyl-C-deoxyribosides 2 and 2 (Scheme 2). However, it
a and 1b in
a
b
should be emphasized that despite the use of anomeric mixtures of
alkynyldeoxyribosides, the corresponding mixture of products of
carboranyl-C-deoxyribosides could be readily separated into the
stereochemically pure substances by chromatography using silica
gel columns. Table 1 describes the details of the products and their
corresponding yields.
Treatment of 2/1 anomeric mixture 1a/1b with 6,9-(Me2S)2-
arachno-B10H12 produced the corresponding closo-dodecaborane
derivatives which were then subjected to column chromatography
Scheme 3. Deprotection of 2a and 2b to 3a and 3b.
the formation of anomeric mixtures of the corresponding carbor-
anyl-C-deoxyribosides is synthetic disadvantage, the opposite is
rather true, because in a single reaction sequence can obtained both
anomers that are easily separated into individual stereoisomers.
In subsequent synthetic steps, deprotection of the OH groups of
2a
and 2
b
b led to yield the desired carboranyl-C-deoxyriboses 3a
and 3 . Given the sensitivity of the carborane cages to basic con-
to isolate 2a
isolated yield 64%), respectively. On the other hand, the reaction of
phenylethynyl derivatives 1b and 1b (2/1) proceeded with lower
efficiency yielding the corresponding 2b and 2b in 31 and 15%
isolated yields (combined isolated yield 46%). Finally, the reaction
with the di-ne derivatives 1c and 1c (2/1) proceeded, as ex-
pected, giving rise to biscarboranyl products 2c (14%) and 2c (7%)
a and 2ab in 42% and 22% isolated yields (combined
ditions, that are suitable for the removal of toluoyl groups, it was
assumed that the transesterification of the toluoyl groups with
MeOH under acidic conditions (10% of p-TSA) could result in simple
deprotection. However, the reaction was unsuccessful and the
starting materials were recovered unchanged. The first successful
approach involved reductive conditions that removed the ester
a
b
a
b
a
b
a
b
(combined isolated yield 21%). Considering lower reactivity of both
the triple bonds due to steric hindrance, as well as separation
problems from the unreacted starting material and numerous un-
defined side-products (as it could be judged from TLC analysis), it is
not at all surprising that the isolated yields are rather low. It should
be emphasized that the monocarboranyl derivatives were neither
isolated nor detected in the reaction mixture. Attempts to improve
groups in 2aa upon treatment with LiAlH4 in THF producing 3aa
(30% yield after isolation) in a mixture of a side-products with the
degraded carborane cage (ca. 10%). Further improvement was
achieved by using a milder reductant such as DIBAL-H yielding
analytically pure 3aa in 65%. Finally, it was found that the treat-
ment of the protected carboranyl-C-deoxyribosides with K2CO3 in
9/1 mixture of MeOH/H2O could bring about the deprotection un-
der mild conditions furnishing the corresponding carboranyl-C-
the yields by using a direct reaction of the alkynyldeoxyribosides 1
a
and 1 with B10H14 in an ionic liquid [17] were unsuccessful and led
b
deoxyribosides 3
a and 3b in isolated yields over 82%. Thus,
to intractable reaction mixtures. Although, it may seem that the use
of the anomeric mixtures of the alkynyldeoxyribosides resulting in
deprotection of 2a
deoxyribosides 3a
(Scheme 3).
a
e2c
e3c
a
yielded the corresponding carboranyl-C-
in 88, 85, and 82% yields, respectively
a
a
Analogously, deprotection of 2a
sponding carboranyl-C-deoxyribosides 3a
yields, respectively. The structures of 3a
be2cb provided the corre-
be3cb
in 89, 84, and 83%
and 3b were
b
, 3aa
b
confirmed by a single crystal X-ray analyses (Figs. 1e3).
Because of low solubility of 3a and 3a (0.5 mg/mL), these
compounds were allowed to react with CsF in ethanol to form the
cesium salts of the open-cage species, 4 and 4 , in 94 and 92%
a
b
a
b
isolated yields, respectively (Scheme 4) [18]. These cesium salts are
highly soluble in water with over 60 mg/mL.
Scheme 1. Alkynyldeoxyribosides 1a and 1b.

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391
Table 1
Precursors and the products of the reaction of alkynyldeoxyribosides with 6,9-(Me2S)2-arachno-B10H12 and the corresponding yields.
Entry
Starting alkynyldeoxyribosidea
Products
Yield (%)b
1
42 þ 22
1a
2aa
þ 2ab
2
31 þ 15
1b
2ba
þ 2b
b
3
14 þ 7
1c
2ca
þ 2cb
a
2/1 1
Isolated yields.
a b.
/1
b
2.3. Cytotoxicity studies
Proliferation Assay. The SCCVII cells were incubated in a 96 well
plate for 3 days in MEM containing various concentrations of 3a
a,
The murine squamous cell carcinoma (SCCVII) cell lines were
incubated at subconfluent conditions in standard medium of MEM
(Nissui, Tokyo, Japan), that was supplemented with 10% fetal cow
serum at 36 ꢀC under 5% carbon dioxide atmosphere overnight. The
IC50 (mol/L), that is the concentration that inhibited the growth of
SCCVII cells by 50% after 3 day of continuous exposure with agents,
was determined via CellTiter 96® Aqueous One Solution Cell
3a , 4 , 4
b
a
b
and 10BSH (Table 2). There was no significant difference
Fig. 1. PLATON plot of 3a
b
showing the atom labeling scheme and displacement el-
Fig. 2. PLATON plot of 3aa showing the atom labeling scheme and displacement el-
lipsoids at the 30% probability level.
lipsoids at the 30% probability level.

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Table 2
Cytotoxicity IC50 of 3, 4, and its comparison with BSH.
Carboranyl compound
3a /3a
IC50 (M)
Relative IC5
a
b
5.8 ꢁ 10ꢂ5
1.0 ꢁ 10ꢂ4
2.8 ꢁ 10ꢂ2
2.1 ꢁ 10ꢂ3
3.6 ꢁ 10ꢂ3
1
4a/4b
10BSHa
a
Sodium mercaptoundecahydrododecaborate.
with the value of 1.0 ꢁ 10ꢂ1 mM, but they failed to accumulate
significantly into tumor cells in order to be a good candidate for
in vivo BNCT. Fig. 4 shows the in vitro BNCT surviving fractions of the
two anomeric salts that were not significantly different from each
other.
2.4. Statistics
Fig. 3. PLATON plot of 3bb showing the atom labeling scheme and displacement el-
lipsoids at the 30% probability level.
Triplicate study of the cytotoxicity and in vitro BNCT were car-
ried out. Values were expressed as mean SE (standard errors).
Significant differences in the survival study were assessed by the
student t-test. The statistical analysis was performed using Prism®
5 of GraphPad Software Inc., CA, USA.
between the IC50 data of the anomers, 3a
a/3a
b
and 4aa/4ab, as
experimentally determined.
For in-vitro BNCT study, aliquots of 3a
a
, 3a , 4
b
a, 4b
and 10BPA
3. Conclusions
were added for 3 h into the Petri dishes, respectively, for uptaking
of tumor cells in dose-dependent manner (0.43 and 1.29 ppm 10B/
The reaction of 6,9-(Me2S)2-arachno-B10H12 with 1-
alkynyldeoxyribosides constitutes a simple approach for the syn-
thesis of the corresponding 1,2-closo-carboran-1-yl-C-deoxyribo-
sides in reasonable isolated yields. Conveniently, anomeric
mixtures the 1-alkynyldeoxyribosides could be used, because
anomeric mixtures of the corresponding 1,2-closo-carboran-1-yl-C-
deoxyribosides could be separated by a simple column chroma-
tography. In addition, deprotection of hydroxyl groups was easily
achieved under basic conditions (K2CO3/MeOH) without degrada-
tion of the carborane cage. Water soluble nido-derivatives were
formed by the reaction with CsF. The selected compound was tested
for cytotoxicity and accumulation in cancer cells. The mechanism of
highly toxic character of 3aa, 3ab is very intriguing, despite the
presence of deoxyribose units linked to the carborane cage without
utilizing the glycosidic bonds. The ineffectiveness of the corre-
sponding cesium salts, 4a and 4b, in the in vitro BNCT application is
more puzzling, despite the fact that these anomeric salts are
3a
time-dependent manners. The 10B concentrations in media were
confirmed by prompt -ray spectroscopy. The tumor cells were
a/3ab a/4b
, 6 and 20 ppm 10B/4 , and 20 ppm 10B/10BPA) and/or
g
washed twice after boron loading. Aliquots containing 5 ꢁ103 cells/
mL were pipetted into cylindrical Teflon tubes of 1 cm in diameter
and 3 cm high that did not generate any secondary radiation when
subjected to thermal neutrons. The inability of cells to adhere to
Teflon allows precise quantitative manipulation of cells without
trypsinization. The thermal neutron fluence was determined by
averaging the activity of two gold films symmetrically attached to
the Teflon tube surface along the thermal neutron axis. The ther-
mal/epithermal neutron fluence ranged from 0 to 3.4 ꢁ 1012
/
6.1 ꢁ1011 n/cm2 (absorbed equivalent dose <1.4 Gy). The
g-ray dose
was monitored by thermoluminescent dosimeters (TLDs) attached
to the tubes and ranged from 0 to 0.6 Gy. Immediately after irra-
diation, 500 cells were seeded in 6-cm Petri dishes (Corning, NY)
and incubated for 10 days in a humidified 36 ꢀC atmosphere of 98%
air/5% carbon dioxide to allow colony formation. The colonies were
fixed and stained with a 10% formaldehyde/1% toluidine blue so-
lution and then counted microscopically.
reasonably soluble in aqueous media and that they are significantly
less toxic than their precursors. Water soluble Cs-salts of 3a
(¼4 /4 ) showed the positive BNCT effect (see Fig. 4) in a dose-
dependent manner as for 4 /4 . However, 4 /4 are not strong
a/3ab
a
b
a
b
a b
Compounds 3aa and 3ab were found to be sparingly soluble in
water and/or MEM. However, there was no significant difference
was observed in toxicity between the two anomers. As expected,
candidates as BNCT agents due to their high toxicity. Nonetheless,
the deoxyribose itself could prove to be a better carborane-binding
sugar than the glucopyranose whose biological properties need to
be explored further [19].
the cytotoxicity of the cesium salts (4
a
and 4
b) slightly improved
Therefore, further investigation is warranted before their in vivo
BNCT can be explored.
4. Experimental section
4.1. General
All solvents were used as obtained unless otherwise noted. THF
was distilled from sodium and benzophenone. Toluene was
distilled from calcium hydride and dried over sodium. Decabor-
aneedimethylsulfide adduct was prepared according to previously
reported procedure [16]. All other reagents were obtained from
commercial sources. All Sonogashira reactions and formations of
carboranyl cage were carried out under an argon atmosphere using
Schlenk-tube technique. The NMR spectra were measured on
Scheme 4. Synthesis of 4
a
and 4
b.

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393
Fig. 4. Surviving fraction of 4a (left) and 4b (right).
Varian Mercury 300, Varian Mercury 400 and Bruker AVANCE 600
1b
b
: Rf ¼ 0.60 (Hex/EtOAc 4:1); m.p. 90e92 ꢀC; [
a
]
¼ ꢂ62.7ꢀ
D
instruments (1H at 300 or 600 MHz; 13C at 75 or 151 MHz, and 11
B
(c ¼ 0.00453 g/mL, CHCl3); 1H NMR (300 MHz, CDCl3, 20 ꢀC, TMS)
NMR at 128 MHz) as solutions in CDCl3 at 20 ꢀC unless otherwise
noted. Chemical shifts are given in
-scale (1H NMR spectra were
referenced toTMS as an internal standard, 13C NMR spectra to CDCl3
at
77.0 and 11B NMR to BF3. Et2O as an internal standard), coupling
d 8.03e7.89 (m, 4H; H-o-Tol), 7.46e7.38 (m, 2H; HeAr), 7.35e7.22
d
(m, 5H; 4H-Tol, 1HeAr), 7.18 (d, J ¼ 8.0 Hz, 2H; HeAr), 5.59 (td,
J ¼ 4.4, 4.0, 2.2 Hz, 1H; H-4), 5.13 (t, J ¼ 7.8 Hz, 1H; H-1), 4.59 (d,
J ¼ 4.4 Hz, 2H; H-5), 4.47 (td, J ¼ 4.5, 2.3 Hz, 1H; H-3), 2.61e2.52 (m,
2H; H-2), 2.43 (s, 3H; CH3-Tol), 2.39 (s, 3H; CH3-Tol); 13C NMR
d
constants J are given in Hz. Melting points (uncorrected) were
determined using a Kofler apparatus. Infrared spectra were recor-
ded as CHCl3 solutions or as KBr tablets and are reported in wave
numbers (cmꢂ1). Fluka 60 silica gel was used for flash chroma-
(75 MHz, CDCl3, 20 ꢀC)
d 166.34 (C]O), 165.97 (C]O), 144.20 (C-
Tol), 143.73 (C-Tol), 131.83 (C-Tol), 129.79 (C-Tol), 129.73 (C-Tol),
129.20 (C-Tol), 129.10 (C-Tol), 128.57 (CeAr), 128.21 (CeAr), 127.10
(C-Tol), 126.81 (C-Tol), 122.29 (CeAr), 86.86 (C^C), 85.96 (C^C),
82.63 (C-4), 68.92 (C-3), 64.50 (C-5), 40.07 (C-2), 21.72 (CH3-Tol); IR
tography. TLC was performed on silica gel 60
aluminum.
F254-coated
(KBr) n
1718,1611,1488,1280,1175,1110, 766 cmꢂ1; MS (EI): m/z (%):
454.2 (10), 335.1 (15), 277.1 (25), 199.1 (20), 182.1 (40), 119.0 (100),
91.0 (50); HRMS (EI): m/z calcd. for C29H26O5: 454.1780, found
454.1791.
4.2. (2S,3S,5S)-5-phenylethynyl-2-(toluoyloxymethyl)-3-
toluoyloxytetrahydrofuran (1ba) and (2S,3S,5R)-5-phenylethynyl-
2-(toluoyloxymethyl)-3-toluoyloxytetrahydrofuran (1b
b)
Into a solution of 1a (0.75 g, 1.98 mmol) in dry THF (8 mL) and
dry Et3N (3 mL) under argon was added iodobenzene (0.4 g,
1.98 mmol), Pd(PPh4)3 (7 mg, 0.5 mol %) and CuI (18 mg, 0.5 mol %).
The formed reaction mixture was then stirred at room temperature
for 6 h, and then reduced to 1/3 of its volume in vacuo. Ethyl acetate
(30 mL) was added and the solution was washed with 10% NH4Cl
(aq) (10 mL) and dried over MgSO4. Removal of volatiles in vacuo
and column chromatography of the residue on silica gel (6:1 hex-
4.3. (2S,3S,5S)-5-[(4-phenylethynyl)phenylethynyl]-2-
(toluoyloxymethyl)-3-toluoyloxytetra-hydrofuran (1c
(2S,3S,5R)-5-[(4-phenylethynyl)phenylethynyl]/2-(toluoyl-
oxymethyl)-3-toluoyloxytetrahydrofuran (1c
a) and
b
)
Into a solution of 1a (0.28 g, 0.74 mmol) in dry THF (3 mL) and
dry Et3N (1 mL) under argon was added 1-iodo-4-(2-
phenylethynyl)-benzene (0.25 g, 0.81 mmol), Pd(PPh4)3 (1.5 mg,
0.5 mol %) and CuI (6 mg, 0.5 mol %). The formed reaction mixture
was then stirred at room temperature for 6 h, and then reduced to
1/3 of its volume in vacuo. Ethyl acetate (30 mL) was added and the
solution was washed with 10% NH4Cl (aq) (10 mL) and dried over
MgSO4. Removal of volatiles in vacuo and column chromatography
of the residue on silica gel (6:1 hexane/EtOAc) afforded 0.13 g (31%)
ane/EtOAc) afforded 0.39 g (43%) of the anomeric mixture of 1b
a
and 1b
1b
b
as a colorless oil.
a: Rf ¼ 0.61 (Hex/EtOAc 4:1); [
a]
¼ 42.5ꢀ (c ¼ 0.00416 g/mL,
D
CHCl3); 1H NMR (300 MHz, CDCl3, 20 ꢀC, TMS)
d 7.96e7.85 (m, 4H;
H-o-Tol), 7.36 (dt, J ¼ 7.7, 1.5 Hz, 2H; HeAr), 7.30e7.14 (m, 5H; 4H-
Tol, 1HeAr), 7.07 (d, J ¼ 7.9 Hz, 2H; HeAr), 5.52 (dd, J ¼ 6.8, 2.2 Hz,
1H; H-4), 5.19 (dd, J ¼ 7.9, 2.9 Hz, 1H; H-1), 4.63 (dt, J ¼ 5.8, 4.7 Hz,
1H; H-3), 4.58e4.43 (m, 2H; H-5), 2.69 (dt, J ¼ 14.2, 7.3 Hz, 1H; H-
of the anomeric mixture of 1c
substance.
a and 1cb as a colorless solid
2a), 2.44 (dt, J ¼ 13.9, 2.6 Hz, 1H; H-2b), 2.36 (s, 3H; CH3-Tol), 2.33
1ca
: Rf ¼ 0.50 (Hex/EtOAc 4:1); m.p. 126e128 ꢀC; [
a
]
¼ 33.9ꢀ
D
13
(s, 3H, CH3-Tol); C NMR (75 MHz, CDCl3, 20 ꢀC)
d
166.29 (C]O),
(c ¼ 0.00884 g/mL, CHCl3); 1H NMR (300 MHz, CDCl3, 20 ꢀC, TMS)
166.23 (C]O), 144.00 (C-Tol), 143.86 (C-Tol), 131.78 (CeAr), 129.88
(C-Tol), 129.73 (C-Tol), 129.15 (C-Tol), 129.07 (C-Tol), 128.46 (CeAr),
128.23 (CeAr), 127.04 (C-Tol), 126.95 (C-Tol), 122.55 (CeAr), 88.32
(C^C), 85.65 (C^C), 82.28 (C-4), 75.87 (C-3), 68.97 (C-5), 64.40 (C-
d 8.00e7.90 (m, 4H; H-o-Tol), 7.58e7.50 (m, 2H; HeAr), 7.46 (dd,
J ¼ 8.4, 3.1 Hz, 2H; HeAr), 7.42e7.31 (m, 5H, 4H-Tol; 1HeAr),
7.30e7.19 (m, 2H; HeAr), 7.15 (dd, J ¼ 8.3, 2.7 Hz, 2H; HeAr),
5.64e5.56 (m,1H; H-4), 5.25 (dd, J ¼ 7.8, 3.1 Hz,1H; H-1), 4.73e4.66
(m, 1H; H-3), 4.64e4.49 (m, 2H; H-5), 2.75 (dtd, J ¼ 14.2, 7.4, 2.9 Hz,
1H; H-2a), 2.49 (dt, J ¼ 13.8, 2.7 Hz, 1H; H-2b), 2.41 (s, 3H; CH3-Tol),
1), 39.81 (C-2), 21.70 (CH3-Tol); IR (KBr)
n 1718, 1611, 1271, 1175,
1107, 752 cmꢂ1; MS (EI) m/z (%): 454.2 (10), 335.1 (15), 277.1 (25),
199.1 (40), 182.1 (80), 119.0 (100), 91.0 (80); HRMS (EI) m/z calcd. for
2.40 (s, 3H; CH3-Tol); 13C NMR (75 MHz, CDCl3, 20 ꢀC)
d 166.28 (C]
C
29H26O5: 454.1780, found 454.1783.
O), 166.21 (C]O), 144.12 (C-Tol), 143.89 (C-Tol), 131.69 (CeAr),

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131.62 (CeAr), 131.41 (CeAr), 129.85 (C-Tol), 129.73 (C-Tol), 129.16
(C-Tol), 129.10 (C-Tol), 128.53 (CeAr), 128.41 (CeAr), 127.02 (C-Tol),
126.90 (C-Tol), 123.38 (CeAr), 122.94 (CeAr), 122.34 (CeAr), 91.28
(C^C), 90.16 (C^C), 88.92 (C^C), 85.29 (C^C), 82.36 (C-4), 75.88
(C-3), 68.95 (C-5), 64.37 (C-1), 39.74 (C-2), 21.73 (CH3-Tol), 21.71
5.2 Hz, 1H; H-2a), 2.44 (s, 3H; CH3-Tol), 2.43 (s, 3H; CH3-Tol), 2.21
(ddd, J ¼ 13.9, 10.8, 6.2 Hz, 1H; H-2b); 13C NMR (151 MHz, CDCl3,
20 ꢀC)
d 166.19 (C]O), 165.91 (C]O), 144.52 (C-Tol), 144.26 (C-Tol),
129.71 (C-Tol), 129.65 (C-Tol), 129.32 (C-Tol), 129.26 (C-Tol), 126.67
(C-Tol), 126.36 (C-Tol), 84.04 (C-4), 78.41 (C-1), 75.89 (C-3), 63.46
(C-5), 59.53 (C-carborane), 39.62 (C-2), 21.71(CH3-Tol); 11B NMR
(CH3-Tol); IR (KBr)
n 1718, 1611, 1506, 1270, 1175, 1108, 1018, 836,
752, 690 cmꢂ1; MS (EI): m/z (%): 554.2 (10), 418.2 (10), 277.1 (25),
299.1 (50), 282.1 (100), 254.1 (50), 229.1 (50); HRMS (EI): m/z calcd.
for C37H30O5: 554.2093, found 554.2090.
(128 MHz, acetone d-6, 20 ꢀC)
d
ꢂ3.58 (bs,1B; B-9), ꢂ4.84 (bs,1B; B-
12), ꢂ9.50 (bs, 2B; B-8,10), ꢂ12.07 (bs, 3B; B-4,7,11), ꢂ13.57 (bs, 3B;
B-3,5,6); IR (KBr)
1718, 1268, 1177, 1102, 1020, 751 cmꢂ1; MS (EI):
n
1cb
: Rf ¼ 0.55 (Hex/EtOAc 4:1); m.p. 113e115 ꢀC; [
a]
¼ ꢂ67.0ꢀ
m/z (%): 496.3 (8), 377.3 (12), 347.3 (8), 224.2 (10), 119.7 (100), 91.0
(45), 65.0 (10); HRMS (ESI): m/z calcd. for C23H32B10O5Na: 521.3073,
found 521.3075.
D
(c ¼ 0.00446 g/mL, CHCl3); 1H NMR (300 MHz, CDCl3, 20 ꢀC, TMS)
d
8.02e7.88 (m, 4H; H-o-Tol), 7.55e7.48 (m, 2H; HeAr), 7.49e7.42
(m, 2H; HeAr), 7.42e7.30 (m, 5H; 4H-Tol, 1HeAr), 7.30e7.15 (m,
4H; HeAr), 5.63e5.50 (m, 1H; H-4), 5.13 (t, J ¼ 7.7 Hz, 1H; H-1), 4.59
(d, J ¼ 3.8 Hz, 2H; H-5), 4.50e4.42 (m, 1H; H-3), 2.66e2.52 (m, 2H;
H-2), 2.42 (s, 3H; CH3-Tol), 2.39 (s, 3H; CH3-Tol); 13C NMR (75 MHz,
4.5. (2S,3S,5S)-2-(toluoyloxymethyl)-3-toluoyloxy-5-(2-phenyl-
dicarba-closo-dodecaboran-1-yl)tetrahydrofuran (2b
(2S,3S,5R)-2-(toluoyloxymethyl)-3-toluoyloxy-5-(2-phenyl-
dicarba-closo-dodecaboran-1-yl)tetrahydrofuran (2b
a) and
CDCl3, 20 ꢀC)
d 166.32 (C]O), 165.98 (C]O), 144.23 (C-Tol), 143.79
(C-Tol), 131.76 (CeAr), 131.64 (CeAr), 131.40 (CeAr), 129.80 (C-Tol),
129.74 (C-Tol), 129.22 (C-Tol), 129.13 (C-Tol), 128.52 (CeAr), 128.40
(CeAr), 127.09 (C-Tol), 126.79 (C-Tol), 123.52 (CeAr), 122.97 (CeAr),
122.08 (CeAr), 91.31 (C^C), 88.93 (C^C), 88.70 (C^C), 85.59
(C^C), 82.71 (C-4), 76.53 (C-3), 68.91 (C-5), 64.46 (C-1), 40.02 (C-2),
b)
Into a solution of an anomeric mixture of 1b (0.42 g, 0.92 mmol)
in dry toluene (10 mL) was added bis(dimethylsulfide)decaborane
complex (0.34 g, 1.4 mmol) under argon. The formed reaction
mixture was then refluxed at 120 ꢀC for 16 h. MeOH (5 mL) was
added to the solution and after 30 min were volatiles removed in
vacuo and column chromatography of the residue on silica gel (12:1
21.73 (CH3-Tol), 21.70 (CH3-Tol); IR (KBr)
n 1710, 1611, 1508, 1270,
1176, 1110, 1078, 1018, 833, 750, 690 cmꢂ1; MS (EI): m/z (%): 554.2
(10), 418.2 (15), 308.0 (20), 299.1 (20), 282.1 (65), 254.1 (100), 229.1
(50); HRMS (EI): m/z calcd. for
C
37H30O5: 554.2093, found
hexane/EtOAc) afforded 0.16 g (31%) of 2ba and 0.08 g (15%) of 2bb
554.2095.
as a colorless oil.
2b
a
: Rf ¼ 0.63 (Hex/EtOAc 4:1); [
a
]
¼ 48.8ꢀ (c ¼ 0.00164 g/mL,
D
4.4. (2S,3S,5S)-2-(toluoyloxymethyl)-3-toluoyloxy-5-(dicarba-
closo-dodecaboran-1-yl)tetra-hydrofuran (2a ) and (2S,3S,5R)-2-
(toluoyloxymethyl)-3-toluoyloxy-5-(dicarba-closo-dodecaboran-1-
yl)tetrahydrofuran (2a
CHCl3); 1H NMR (300 MHz, CDCl3, 20 ꢀC, TMS)
d 7.94e7.87 (m, 2H;
a
H-o-Tol), 7.72e7.57 (m, 4H; HeAr), 7.30e7.13 (m, 7H; 6H-Tol,
1HeAr), 5.31 (ddd, J ¼ 7.2, 6.1, 4.5 Hz, 1H; H-3), 4.47 (dt, J ¼ 5.8,
4.7 Hz, 1H; H-4), 4.33e4.19 (m, 2H; H-5), 3.88 (dd, J ¼ 8.3, 6.9 Hz,
1H; H-1), 2.69 (dt, J ¼ 14.2, 7.2 Hz, 1H; H-2a), 2.42 (bs, 6H; CH3-Tol),
2.34 (ddd, J ¼ 14.0, 8.5, 5.9 Hz,1H; H-2b); 13C NMR (151 MHz, CDCl3,
b
)
Into a solution of an anomeric mixture of 1a (2.68 g, 7.09 mmol)
in dry toluene (50 mL) was added bis(dimethylsulfide)decaborane
complex (2.6 g, 2.97 mmol) under argon. The formed reaction
mixture was then refluxed at 120 ꢀC for 16 h. MeOH (10 mL) was
added to the solution and after 30 min were volatiles removed in
vacuo and column chromatography of the residue on silica gel (12:1
20 ꢀC)
d 166.14 (C]O), 165.77 (C]O), 144.34 (C-Tol), 143.86 (C-Tol),
131.02 (CeAr), 130.68 (C-Tol), 129.75 (C-Tol), 129.48 (CeAr), 129.20
(CeAr), 129.08 (CeAr), 128.52 (CeAr), 126.70 (C-Tol), 126.30 (C-Tol),
83.53 (C-carborane), 81.65 (C-4), 77.18 (C-carborane), 76.36 (C-1),
74.51 (C-3), 64.22 (C-5), 38.90 (C-2), 21.69 (CH3-Tol), 21.67 (CH3-
hexane/EtOAc) afforded 1.11 g (42%) of 2a
as a colorless oil.
a
and 0.55 g (22%) of 2a
b
Tol); 11B NMR (128 MHz, CDCl3, 20 ꢀC)
d
ꢂ1.72 (bs, 1B; B-9), ꢂ3.50
(bs, 1B; B-12), ꢂ9.57 (bs, 2B; B-8,10), ꢂ10.44 (bs, 3B; B-
2aa
: Rf ¼ 0.62 (Hex/EtOAc 4:1); [
a
]
¼ ꢂ80.8ꢀ (c ¼ 0.0099 g/mL,
4,7,11), ꢂ11.71 (bs, 3B; B-3,5,6); IR (KBr)
n 1707, 1437, 1160, 1120,
D
CHCl3); 1H NMR (600 MHz, CDCl3, 20 ꢀC, TMS)
d
7.92 (d, J ¼ 8.2 Hz,
1088, 1047, 757, 691 cmꢂ1; MS (EI): m/z (%): 572.4 (10), 436.3 (15),
2H; H-o-Tol), 7.88 (d, J ¼ 8.2 Hz, 2H; H-o-Tol), 7.30e7.22 (m, 4H; H-
m-Tol), 5.47 (ddd, J ¼ 7.3, 4.8, 3.5 Hz,1H; H-3), 4.66 (t, J ¼ 7.3 Hz,1H;
H-1), 4.54 (dt, J ¼ 4.1, 3.9 Hz, 1H; H-4), 4.49 (dd, J ¼ 11.8, 4.9 Hz, 1H;
H-5a), 4.43 (dd, J ¼ 12.0, 3.8 Hz, 1H; H-5b), 4.06 (bs, 1H; H-car-
borane)2.84 (dt, J ¼ 14.5, 7.4 Hz, 1H; H-2a), 2.43 (s, 3H; CH3-Tol),
300.2 (20), 137.1 (20), 119.0 (100), 91.0 (90); HRMS (EI): m/z calcd.
10
for C
H
B121B8O5: 572.3566, found 572.3564.
29 36
2b
b
: Rf ¼ 0.60 (Hex/EtOAc 4:1); [
a
]
¼ 5.5ꢀ (c ¼ 0.00181 g/mL,
D
CHCl3); 1H NMR (600 MHz, CDCl3, 20 ꢀC, TMS)
d
7.94 (d, J ¼ 8.0 Hz,
2H; H-o-Tol), 7.69 (d, J ¼ 7.9 Hz, 24H; 2HeAr), 7.65 (d, J ¼ 7.9 Hz, 2H;
H-Tol), 7.45 (t, J ¼ 7.4 Hz, 1H; HeAr), 7.36 (t, J ¼ 7.7 Hz, 2H; HeAr),
7.26 (d, J ¼ 8.7 Hz, 2H; H-Tol), 7.17 (d, J ¼ 7.9 Hz, 2H; H-Tol), 5.38 (d,
J ¼ 5.9 Hz, 1H; H-3), 4.47e4.38 (m, 2H; H-5), 4.11 (td, J ¼ 4.4, 1.8 Hz,
1H; H-4), 3.84 (dd, J ¼ 10.8, 5.0 Hz, 1H; H-1), 2.42 (s, 3H; CH3-Tol),
2.40 (s, 3H; CH3-Tol), 2.37e2.29 (m, 1H; H-2a), 2.18 (dd, J ¼ 13.8,
2.42 (s, 3H; CH3-Tol), 2.35 (ddd, J ¼ 14.2, 7.2, 4.8 Hz, 1H; H-2b); 13
C
NMR (151 MHz, CDCl3, 20 ꢀC)
d 166.09 (C]O), 144.50 (C-Tol), 144.17
(C-Tol), 129.75 (C-Tol), 129.60 (C-Tol), 129.29 (C-Tol), 129.27 (C-Tol),
126.68 (C-Tol), 126.26 (C-Tol), 82.96 (C-4), 79.00 (C-1), 74.99 (C-3),
63.73 (C-5), 59.20 (C-carborane), 38.49 (C-2), 21.71 (CH3-Tol), 21.68
(CH3-Tol); 11B NMR (128 MHz, acetone d-6, 20 ꢀC)
d
ꢂ3.39 (bs,1B, B-
5.0 Hz, 1H; H-2b); 13C NMR (151 MHz, CDCl3, 20 ꢀC)
d 166.11 (C]O),
9), ꢂ4.58 (bs, 1B, B-12), ꢂ9.43 (bs, 2B, B-8,10), ꢂ11.97 (bs, 3B, B-
165.52 (C]O), 144.22 (C-Tol), 143.95 (C-Tol), 131.24 (CeAr), 130.58
(CeAr), 130.20 (CeAr), 129.67 (C-Tol), 129.51 (C-Tol), 129.16 (C-Tol),
129.06 (C-Tol), 128.64 (CeAr), 126.82 (C-Tol), 126.44 (C-Tol), 83.10
(C-4), 83.02 (C-carborane), 81.78 (C-carborane), 76.53 (C-1), 75.55
(C-3), 63.70 (C-5), 39.33 (C-2), 21.66 (CH3-Tol); 11B NMR (128 MHz,
4,7,12), ꢂ13.28 (bs, 3B, B-3,5,6); IR (KBr)
n 1717, 1271, 1178, 1105,
1020 cmꢂ1; MS (EI): m/z (%): 496.3 (8), 360.3 (10), 347.3 (20), 224.2
(20), 119.7 (100), 91.0 (95), 65.0 (20); HRMS (ESI): m/z calcd. for
C
23H32B10O5: 496.3253, found 496.3251.
2a
: Rf ¼ 0.60 (Hex/EtOAc 4:1); [
b
a
]
¼ ꢂ3.3ꢀ (c ¼ 0.0272 g/mL,
CDCl3, 20 ꢀC)
d
ꢂ1.88 (bs, 1B; B-9), ꢂ3.58 (bs, 1B; B-12), ꢂ9.82 (bs,
D
CHCl3); 1H NMR (600 MHz, CDCl3, 20 ꢀC, TMS)
d
7.92 (dd, J ¼ 13.2,
2B; B-8,10), ꢂ10.52 (bs, 6B; B-3,4,5,6,7,11); IR (KBr)
n 1720, 1610,
8.2 Hz, 4H; H-o-Tol), 7.32e7.21 (m, 6H; H-Tol), 5.51 (d, J ¼ 6.4 Hz,
1H; H-3), 4.62 (dd, J ¼ 12.0, 3.7 Hz, 1H; H-5a), 4.58 (dd, J ¼ 10.7,
4.9 Hz, 1H; H-1), 4.48 (dd, J ¼ 12.0, 3.8 Hz, 1H; H-5b), 4.36 (td,
J ¼ 3.7, 1.9 Hz, 1H; H-4), 4.10 (s, 2H; H-carborane), 2.40 (dd, J ¼ 14.2,
1447, 1269, 1176, 1102, 1019, 751, 690 cmꢂ1; MS (EI): m/z (%): 572.4
(10), 436.3 (15), 300.2 (30), 189.1 (15), 137.1 (20), 119.0 (100), 91.0
(95); HRMS (EI): m/z calcd. for C
572.3561.
10
H
29 36
B121B8O5: 572.3566, found

ꢀ
I. Snajdr et al. / European Journal of Medicinal Chemistry 83 (2014) 389e397
395
4.6. (2S,3S,5S)-2-(toluoyloxymethyl)-3-toluoyloxy-5-[2-(2-phenyl-
dicarba-closo-dodecabo-ran-1-yl)-dicarba-closo-dodecaboran-1-
yl]tetrahydrofuran (2c ) and (2S,3S,5R)-2-(toluoyloxymethyl)-3-
toluoyloxy-5-[2-(2-phenyl-dicarba-closo-dodecaboran-1-yl)-dicar-
ba-closo-dodecaboran-1-yl]tetrahydrofuran (2c
(Hex/EtOAc 1:1); m.p. 141e143 ꢀC; [
a
]
¼ ꢂ29.76ꢀ (c ¼ 0.0107 g/mL,
D
MeOH); 1H NMR (600 MHz, MeOD, 20 ꢀC, TMS)
d 4.67 (s, 1H; H-
a
carborane), 4.47 (dd, J ¼ 9.0, 6.6 Hz, 1H; H-1), 4.20 (dt, J ¼ 7.8,
6.8 Hz, 1H; H-3), 3.77 (ddd, J ¼ 6.5, 5.0, 2.9 Hz, 1H; H-4), 3.67 (dd,
J ¼ 12.0, 3.0 Hz, 1H; H-5a), 3.52 (dd, J ¼ 12.0, 5.0 Hz, 1H; H-5b), 2.49
(dt, J ¼ 13.0, 6.7 Hz, 1H; H-2a), 1.97 (dt, J ¼ 12.6, 8.5 Hz, 1H; H-2b);
b
)
Into a solution of an anomeric mixture of 1c (0.51 g, 0.92 mmol)
in dry toluene (10 mL) was added bis(dimethylsulfide)decaborane
complex (0.67 g, 2.76 mmol) under argon. The formed reaction
mixture was then refluxed at 120 ꢀC for 16 h. MeOH (5 mL) was
added to the solution and after 30 min were volatiles removed in
vacuo and column chromatography of the residue on silica gel (15:1
13C NMR (151 MHz, MeOD, 20 ꢀC)
d 87.65 (C-4), 79.78 (C-carborane),
79.19 (C-1), 72.12 (C-3), 62.73 (C-5), 61.74 (C-carborane), 42.45 (C-
11
2); B NMR (128 MHz, MeOD, 20 ꢀC)
(bs, 1B; B-12), ꢂ9.28 (bs, 2B; B-8,10), ꢂ11.73 (bs, 3B; B-
d
ꢂ3.27 (bs, 1B; B-9), ꢂ4.27
4,7,11), ꢂ13.05 (bs, 3B; B-3,5,6); IR (KBr)
n
1366, 1174, 1084, 1046,
725 cmꢂ1; MS (EI): m/z (%): 283.2 (10), 259.2 (10), 242.2 (10), 229.2
(100), 211.2 (80), 168.2 (80), 74.0 (60); HRMS (ESI): m/z calcd. for
C7H20B10O3Na: 285.2235, found 285.2232.
hexane/EtOAc) afforded 0.101 g (14%) of 2ca and 0.050 g (7%) of 2cb
as a colorless oil.
2ca
: Rf ¼ 0.50 (Hex/EtOAc 4:1); [
a
]
¼ ꢂ5.4ꢀ (c ¼ 0.00205 g/mL,
D
CHCl3); 1H NMR (300 MHz, CDCl3, 20 ꢀC, TMS)
d
7.90 (d, J ¼ 8.2 Hz,
2H; H-o-Tol), 7.84 (d, J ¼ 8.0 Hz, 2H; H-o-Tol), 7.40 (d, J ¼ 8.4 Hz, 2H;
H-Tol), 7.33 (dd, J ¼ 24.5, 8.1 Hz, 4H; HeAr), 7.29e7.22 (m, 5H; 2H-
Tol, 3HeAr), 7.13 (t, J ¼ 7.6 Hz, 2H; HeAr), 5.19 (dt, J ¼ 6.9, 5.7 Hz,
1H; H-3), 4.42 (dt, J ¼ 4.5, 4.4 Hz, 1H; H-4), 4.27e4.13 (m, 2H; H-5),
3.59 (t, J ¼ 7.6 Hz, 1H; H-1), 2.53 (dt, J ¼ 14.3, 7.4 Hz, 1H; H-2a), 2.44
(s, 3H; CH3-Tol), 2.42 (s, 3H; CH3-Tol), 2.27 (dt, J ¼ 13.8, 7.0 Hz, 1H;
4.8. (2S,3S,5R)-2-(hydroxymethyl)-5-(dicarba-closo-dodecaboran-
1-yl)tetrahydrofuran-3-ol (3a
b)
Into a solution of 2a (2.57 g, 5.17 mmol) in the 9:1 mixture of
b
methanol/water (50 mL) was added potassium carbonate (2.0 g,
14.47 mmol). The formed reaction mixture was then stirred at room
temperature for 16 h. Removal of volatiles in vacuo and column
chromatography of the residue on silica gel (1:2 hexane/EtOAc)
H-2b); 13C NMR (75 MHz, CDCl3, 20 ꢀC)
d 166.04 (C]O), 165.87 (C]
O), 144.46 (C-Tol), 144.24 (C-Tol), 133.20 (CeAr), 132.02 (CeAr),
130.78 (CeAr), 130.73 (CeAr), 130.58 (CeAr), 130.33 (CeAr), 130.20
(CeAr), 129.76 (C-Tol), 129.57 (C-Tol), 129.28 (C-Tol), 129.23 (C-Tol),
128.31 (CeAr), 126.60 (C-Tol), 126.17 (C-Tol), 85.13 (C-carborane),
83.80 (C-carborane), 83.03 (C-carborane), 81.60 (C-carborane),
81.31 (C-4), 76.12 (C-1), 74.17 (C-3), 63.63 (C-5), 38.50 (C-2), 21.70
afforded 1.20 g (89%) of 3a
b
as a colorless solid substance: Rf ¼ 0.15
(Hex/EtOAc 1:1); m.p. 153e155 ꢀC; [
a
]
¼ 9.35ꢀ (c ¼ 0.0096 g/mL,
D
1
MeOH); H NMR (600 MHz, MeOD, 20 ꢀC, TMS)
d 4.73 (bs, 1H; H-
carborane), 4.54 (dd, J ¼ 10.0, 5.4 Hz, 1H; H-1), 4.23 (d, J ¼ 5.3 Hz,
1H; H-3), 3.83 (td, J ¼ 5.1, 1.9 Hz, 1H; H-4), 3.52 (d, J ¼ 5.1 Hz, 2H; H-
(CH3-Tol); 11B NMR (128 MHz, CDCl3, 20 ꢀC)
d
ꢂ1.50 (bs, 6B), ꢂ9.27
5), 2.06 (dd, J ¼ 13.2, 5.4 Hz,1H; H-2a), 2.02e1.95 (m, 1H; H-2b); 13
C
(bs, 14B); IR (KBr)
n
1717, 1609, 1510, 1447, 1270, 1176, 1099, 1018,
NMR (151 MHz, MeOD, 20 ꢀC)
d 89.82 (C-4), 79.57 (C-1), 78.07 (C-
848, 754, 692 cmꢂ1; MS (EI): m/z (%): 790.6 (10), 654.5 (15), 519.5
carborane), 73.43 (C-3), 63.42 (C-5), 61.76 (C-carborane), 42.77 (C-
11
(50), 189.1 (10), 137.1 (30), 119.0 (100), 91.0 (80); HRMS (EI): m/z
2); B NMR (128 MHz, MeOD, 20 ꢀC)
(bs, 1B; B-12), ꢂ8.94 (bs, 2B; B-8,10), ꢂ11.58 (bs, 3B; B-
d
ꢂ3.35 (bs, 1B; B-9), ꢂ4.21
10
calcd. for C
H
37 50
B141B16O5: 790.5665, found 790.5651.
2cb
: Rf ¼ 0.55 (Hex/EtOAc 4:1); [
a
]
D
¼ ꢂ40.4ꢀ (c ¼ 0.00371 g/mL,
4,7,11), ꢂ12.98 (bs, 3B; B-3,5,6); IR (KBr)
n
1354, 1182, 1097, 1057,
CHCl3); 1H NMR (300 MHz, CDCl3, 20 ꢀC, TMS)
d
7.94 (d, J ¼ 8.0 Hz,
729 cmꢂ1; MS (EI): m/z (%): 286.2 (10), 259.2 (10), 242.2 (10), 229.2
(100), 211.2 (70), 199.2 (60), 168.2 (80), 57.0 (20); HRMS (ESI): m/z
calcd. for C7H20B10O3: 260.2343, found 260.2343.
2H; H-o-Tol), 7.76 (d, J ¼ 8.0 Hz, 2H; H-o-Tol), 7.44 (d, J ¼ 8.5 Hz, 2H;
HeAr), 7.38e7.21 (m, 8H; 4H-Tol, 4HeAr), 7.07 (t, J ¼ 7.4 Hz, 1H;
HeAr), 6.98 (t, J ¼ 7.7 Hz, 2H; HeAr), 5.30 (dd, J ¼ 6.3, 2.0 Hz, 1H; H-
3), 4.40 (d, J ¼ 4.4 Hz, 2H; H-5), 3.80 (dt, J ¼ 4.1, 3.8 Hz, 1H; H-4),
3.61 (dd, J ¼ 10.6, 5.2 Hz, 1H; H-1), 2.44 (s, 3H; CH3-Tol), 2.42 (s, 3H;
CH3-Tol), 2.26 (ddd, J ¼ 13.9, 10.5, 6.4 Hz, 1H; H-2a), 2.18 (dd,
4.9. (2S,3S,5S)-2-(hydroxymethyl)-5-(2-phenyl-dicarba-closo-
dodecaboran-1-yl)tetrahydro-furan-3-ol (3b
a)
J ¼ 13.9, 5.2 Hz, 1H; H-2b); 13C NMR (75 MHz, CDCl3, 20 ꢀC)
d 166.04
(C]O), 165.77 (C]O), 144.67 (C-Tol), 144.16 (C-Tol), 133.04 (CeAr),
132.15 (CeAr), 131.02 (CeAr), 130.54 (CeAr), 130.51 (CeAr), 130.26
(CeAr), 130.20 (CeAr), 129.66 (C-Tol), 129.48 (C-Tol), 129.34 (C-Tol),
129.27 (C-Tol), 128.27 (CeAr), 126.81 (C-Tol), 126.28 (C-Tol), 85.15
(C-carborane), 83.39 (C-4), 83.15 (C-carborane), 81.81 (C-carbor-
ane), 80.71 (C-carborane), 76.55 (C-1), 75.33 (C-3), 63.52 (C-5),
39.54 (C-2), 21.72 (CH3-Tol); 11B NMR (128 MHz, CDCl3, 20 ꢀC)
Into a solution of 2b (0.11 mmol, 0.07 g) in the 9:1 mixture of
a
methanol/water (2.2 mL) was added potassium carbonate
(0.27 mmol, 0.04 g). The formed reaction mixture was then stirred
at room temperature for 16 h. Removal of volatiles in vacuo and
column chromatography of the residue on silica gel (1:1 hexane/
EtOAc) afforded 0.03 g (85%) of 3b
a as a white solid substance:
Rf ¼ 0.12 (Hex/EtOAc 1:1); m.p. 112e114 ꢀC; [
a
]
D
¼ þ40.7ꢀ
d
ꢂ2.16 (bs, 6B), ꢂ10.01 (bs, 14B); IR (KBr)
n
1720, 1610, 1507, 1446,
(c ¼ 0.00638 g/mL, CHCl3); 1H NMR (300 MHz, MeOD, 20 ꢀC, TMS)
1271, 1179, 1106, 1020, 847, 751, 689 cmꢂ1; MS (EI): m/z (%): 790.6
d 7.76e7.67 (m, 2H; HeAr), 7.52e7.35 (m, 3H; HeAr), 3.97 (dt,
(5), 654.5 (10), 519.5 (50), 189.1 (10), 137.1 (70), 119.0 (100), 91.0
J ¼ 14.9, 7.5 Hz, 1H; H-3), 3.76e3.60 (m, 2H, H-1; H-4), 3.52 (dd,
J ¼ 11.9, 3.1 Hz, 1H; H-5a), 3.35 (dd, overlapped J ¼ 5.2 Hz, 1H; H-
5b), 2.29 (dt, J ¼ 12.9, 6.7 Hz,1H; H-2a), 2.01 (dt, J ¼ 12.4, 9.2 Hz,1H;
10
(95); HRMS (EI): m/z calcd. for C
H
37 50
B141B16O5: 790.5665, found
790.5672.
H-2b); 13C NMR (75 MHz, MeOD, 20 ꢀC)
d 131.07 (CeAr), 130.54
4.7. (2S,3S,5S)-2-(hydroxymethyl)-5-(dicarba-closo-dodecaboran-
1-yl)tetrahydrofuran-3-ol (3a
(CeAr), 130.17 (CeAr), 128.65 (CeAr), 128.48 (CeAr), 85.44 (C-4),
a)
84.99 (C-carborane), 83.38 (C-carborane), 75.14 (C-3), 70.58 (C-1),
11
61.13 (C-5), 41.27 (C-2); B NMR (128 MHz, MeOD, 20 ꢀC)
d
ꢂ2.69
Into a solution of 2a
a
(0.79 g, 1.59 mmol) in the 9:1 mixture of
(bs, 1B; B-9), ꢂ4.27 (bs, 1B; B-12), ꢂ9.98 (bs, 4B; B-4,5,8,10), ꢂ10.98
methanol/water (30 mL) was added potassium carbonate (0.61 g,
4.45 mmol). The formed reaction mixture was then stirred at room
temperature for 16 h. Removal of volatiles in vacuo and column
chromatography of the residue on silica gel (1:2 hexane/EtOAc)
(bs, 4B; B-3,6,7,11); IR (KBr) n 1493, 1437, 1363, 1159, 1121, 1088,
1002, 723, 691 cmꢂ1; MS (EI): m/z (%): 336.3 (10), 318.3 (20), 305.3
(30), 287.2 (60), 277.3 (40), 258.2 (60), 244.2 (80), 230.2 (70), 74.0
10
(100), 57.0 (40); HRMS (ESI): m/z calcd. for
C
H
B121B8O3:
13 24
afforded 0.47 g (88%) of 3a
a
as a colorless solid substance: Rf ¼ 0.15
336.2729, found 336.2730.

ꢀ
396
I. Snajdr et al. / European Journal of Medicinal Chemistry 83 (2014) 389e397
4.10. (2S,3S,5R)-2-(hydroxymethyl)-5-(2-phenyl-dicarba-closo-
dodecaboran-1-yl)tetrahydro-furan-3-ol (3b
mL, CHCl3); 1H NMR (600 MHz, MeOD, 20 ꢀC, TMS)
d 7.58e7.52 (m,
b)
4H; HeAr), 7.46 (dd, J ¼ 7.7, 1.7 Hz, 2H; HeAr), 7.32e7.28 (m, 1H;
HeAr), 7.24e7.19 (m, 2H; HeAr), 4.13 (dt, J ¼ 5.7, 1.7 Hz, 1H; H-3),
3.62 (dd, J ¼ 10.4, 5.4 Hz, 1H; H-1), 3.51 (td, J ¼ 5.7, 1.7 Hz, 1H; H-4),
3.46 (dd, J ¼ 11.4, 5.2 Hz, 1H; H-5a), 3.35 (dd, J ¼ 11.5, 6.1 Hz, 1H; H-
Into a solution of 2bb (0.11 mmol, 0.07 g) in the 9:1 mixture of
methanol/water (2.2 mL) was added potassium carbonate
(0.27 mmol, 0.04 g). The formed reaction mixture was then stirred
at room temperature for 16 h. Removal of volatiles in vacuo and
column chromatography of the residue on silica gel (1:1 hexane/
5b), 1.95 (ddd, J ¼ 13.2, 10.4, 5.5 Hz, 1H; H-2a), 1.85 (ddd, J ¼ 13.2,
13
5.3, 1.5 Hz, 1H; H-2b); C NMR (151 MHz, MeOD, 20 ꢀC)
d 134.26
(CeAr), 133.71 (CeAr), 132.41 (CeAr), 132.19 (CeAr), 131.82 (CeAr),
131.72 (CeAr), 131.26 (CeAr), 129.68 (CeAr), 89.77 (C-4), 86.84 (C-
carborane), 85.33 (C-carborane), 84.96 (C-carborane), 82.66 (C-
carborane), 77.47 (C-1), 73.27 (C-3), 63.55 (C-5), 42.86 (C-2); 11B
EtOAc) afforded 0.03 g (84%) of 3bb as a white solid substance:
Rf ¼ 0.14 (Hex/EtOAc 1:1); m.p. 142e144 ꢀC; [
a]
¼ ꢂ26.7ꢀ
D
1
(c ¼ 0.0071 g/mL, CHCl3); H NMR (300 MHz, MeOD, 20 ꢀC, TMS)
d
7.73 (dd, J ¼ 7.4, 1.9 Hz, 2H; HeAr), 7.53e7.34 (m, 3H; HeAr), 4.15
NMR (128 MHz, MeOD, 20 ꢀC)
(KBr)
d
ꢂ2.58 (bs, 6B), ꢂ10.35 (bs, 14B); IR
(d, J ¼ 5.2 Hz, 1H; H-3), 3.85 (dd, J ¼ 10.4, 5.4 Hz, 1H; H-1),
3.65e3.54 (m, 1H; H-4), 3.49 (dd, J ¼ 11.4, 5.1 Hz, 1H; H-5a), 3.36
(dd, J ¼ 11.5, 6.5 Hz, 1H; H-5b), 2.01 (ddd, J ¼ 13.2, 10.4, 5.2 Hz, 1H;
H-2a), 1.89 (ddd, J ¼ 13.1, 5.4, 1.4 Hz, 1H; H-2b); 13C NMR (75 MHz,
n
1333, 1282, 1084, 1053, 988, 886, 731, 579 cmꢂ1; MS (EI): m/z
(%): 554.5 (10), 536.5 (30), 505.4 (30), 495.5 (40), 463.4 (90), 81.0
(10), 74.0 (100), 61.0 (20), 57.0 (20); HRMS (EI): m/z calcd. for
10
C
H
B141B16O5: 554.4827, found 554.4805.
37 50
MeOD, 20 ꢀC)
d 131.08 (CeAr), 130.54 (CeAr), 128.46 (CeAr), 88.28
(C-3), 83.86 (C-carborane), 83.26 (C-carborane), 76.09 (C-1), 72.12
4.13. Cesium (2S,3S,5S)-7-{2-[(hydroxymethyl)-3-hydroxy-
(C-4), 62.29 (C-5), 41.34 (C-2); 11B NMR (128 MHz, acetone-d6,
tetrahydrofuran-5-yl]}-7,8-dicarba-nido-undecaborate(ꢂ) (4
a)
20 ꢀC)
d
ꢂ2.65 (bs, 1B; B-9), ꢂ4.08 (bs, 1B; B-12), ꢂ10.09 (bs, 4B;
B-4,5,8,10), ꢂ11.19 (bs, 4B; B-3,6,7,11); IR (KBr)
n 1471, 1095, 1061,
Into a solution of 3aa (0.52 g, 2.0 mmol) in absolute ethanol
1032, 997, 732, 692 cmꢂ1; MS (EI): m/z (%): 336.3 (10), 318.3 (25),
(50 mL) was added cesium fluoride (0.91 g, 6.0 mmol) under argon
atmosphere. The formed reaction mixture was then refluxed at
90 ꢀC for 16 h. After removal of the solvent in vacuo ethyl acetate
(50 mL) was added, the solution was washed with distilled water
(10 mL) and then dried over MgSO4. Volatiles were removed in
vacuo and column chromatography of the residue on silica gel (10:1
287.2 (80), 277.3 (60), 258.2 (50), 244.2 (95), 230.2 (70), 168.2 (40),
10
74.0 (100), 57.0 (40); HRMS (ESI): m/z calcd. for C
H
B121B8O3:
13 24
336.2729, found 336.2731.
4.11. (2S,3S,5S)-2-(hydroxymethyl)-5-[2-(2-phenyl-dicarba-closo-
dodecaboran-1-yl)-dicarba-closo-dodecaboran-1-yl]
EtOAc/MeOH) afforded 0.72 g (94%) of 4a as a colorless solid sub-
tetrahydrofuran-3-ol (3c
a)
stance: Rf ¼ 0.26 (EtOAc/MeOH 8:1); m.p. 248e250 ꢀC; [
a]
¼ 34.6ꢀ
D
1
(c ¼ 0.0081 g/mL, MeOH); H NMR (300 MHz, MeOD, 20 ꢀC, TMS)
Into a solution of 2c
a
(0.05 mmol, 0.04 g) in the 9:1 mixture of
d
4.06e4.00 (m, 2H; H-1, H-3), 3.67e3.62 (m, 2H; H-4, H-5a), 3.50
methanol/water (2.2 mL) was added potassium carbonate
(0.13 mmol, 0.02 g). The formed reaction mixture was then stirred
at room temperature for 16 h. Removal of volatiles in vacuo and
column chromatography of the residue on silica gel (2:1 hexane/
(dd, J ¼ 12.0, 5.6 Hz, 1H; H-5b), 3.36 (s, 1H; H-carborane), 2.09 (dt,
J ¼ 12.3, 6.1 Hz, 1H; H-2a), 1.68 (dt, J ¼ 12.3, 10.0 Hz, 1H; H-2b); 13
C
NMR (75 MHz, MeOD, 20 ꢀC)
d 84.19 (C-4), 81.42 (C-1), 71.29 (C-3),
61.80 (C-5), 48.10 (C-carborane), 41.31 (C-2); 11B NMR (128 MHz,
MeOD, 20 ꢀC)
ꢂ11.20 (s, 1B; B-9), ꢂ12.78 (s, 1B; B-11), ꢂ15.47 (s,
1B; B-3), ꢂ17.20 (s, 2B; B-5, B-6), ꢂ20.08 (s, 1B; B-2), ꢂ22.55 (s, 1B;
EtOAc) afforded 0.02 g (82%) of 3ca as a colorless solid substance:
d
Rf ¼ 0.54 (Hex/EtOAc 1:1); m.p. 181e183 ꢀC; [
a
]
¼ 48.6ꢀ
D
(c ¼ 0.00473 g/mL, CHCl3); 1H NMR (600 MHz, MeOD, 20 ꢀC, TMS)
B-4), ꢂ33.61 (s, 1B; B-10), ꢂ37.68 (s, 1B; B-1); IR (KBr)
n 2519, 1374,
d
7.58e7.53 (m, 4H; HeAr), 7.50 (d, J ¼ 7.9 Hz, 2H; HeAr), 7.31 (t,
1278,1083,1028, 910 cmꢂ1; MS (ESI): m/z (%): 250.2 (100),186.9 (5),
113.1 (5); HRMS (ESI): m/z calcd. for C7H20B9O3: 251.2255, found
251.2255.
J ¼ 7.4 Hz, 1H; HeAr), 7.21 (t, J ¼ 7.9 Hz, 2H; HeAr), 3.92 (dt, J ¼ 8.6,
7.2 Hz, 1H; H-3), 3.62 (ddd, J ¼ 7.7, 5.2, 3.0 Hz, 1H; H-4), 3.51 (dd,
J ¼ 12.1, 3.0 Hz,1H; H-5a), 3.35e3.31 (m,1H; H-1), 3.28 (dd, J ¼ 12.0,
5.2 Hz, 1H; H-5b), 2.11 (dt, J ¼ 13.0, 6.7 Hz, 1H; H-2a), 1.92 (dt,
J ¼ 12.3, 9.4 Hz, 1H; H-2b); 13C NMR (151 MHz, MeOD, 20 ꢀC)
4.14. Cesium (2S,3S,5R)-7-{2-[(hydroxymethyl)-3-hydroxy-
d
134.28 (CeAr), 133.67 (CeAr), 132.35 (CeAr), 132.33 (CeAr),
tetrahydrofuran-5-yl]}-7,8-dicarba -nido-undecaborate(ꢂ) (4
b)
131.92 (CeAr), 131.67 (CeAr), 131.44 (CeAr), 129.57 (CeAr), 86.86
(C-carborane), 86.78 (C-4), 86.25 (C-carborane), 85.06 (C-carbor-
ane), 82.80 (C-carborane), 76.32 (C-1), 71.86 (C-3), 62.42 (C-5),
Into a solution of 3a
b (0.5 g, 1.9 mmol) in absolute ethanol
(45 mL) was added cesium fluoride (0.88 g, 5.8 mmol) under argon
atmosphere. The formed reaction mixture was then refluxed at
90 ꢀC for 16 h. After removal of the solvent in vacuo ethyl acetate
(50 mL) was added, the solution was washed with distilled water
(10 mL) and then dried over MgSO4. Volatiles were removed in
vacuo and column chromatography of the residue on silica gel (10:1
42.51 (C-2); 11B NMR (128 MHz, MeOD, 20 ꢀC)
d
ꢂ2.69 (bs,
6B), ꢂ10.42 (bs, 14B); IR (KBr)
n 1407, 1363, 1083, 1033, 848, 729,
691, 583 cmꢂ1; MS (EI): m/z (%): 554.5 (10), 536.5 (30), 505.4 (30),
495.5 (40), 463.4 (80), 81.0 (10), 74.0 (100), 57.0 (20); HRMS (EI): m/
10
z calcd. for C
H
B141B16O5: 554.4827, found 554.4816.
37 50
EtOAc/MeOH) afforded 0.67 g (92%) of 4b as a colorless solid sub-
4.12. (2S,3S,5S)-2-(hydroxymethyl)-5-[2-(2-phenyl-dicarba-closo-
dodecaboran-1-yl)-dicarba-closo-dodecaboran-1-yl]
stance: Rf
¼
0.26 (EtOAc/MeOH 8:1); m.p. 258e260 ꢀC;
[a
]
¼ ꢂ10.0ꢀ (c ¼ 0.0102 g/mL, MeOH); 1H NMR (300 MHz, MeOD,
D
tetrahydrofuran-3-ol (3c
b)
20 ꢀC, TMS)
d
4.17 (dd, J ¼ 10.0, 5.8 Hz, 1H; H-1), 4.09 (dt, J ¼ 5.2,
2.4 Hz, 1H; H-3), 3.67 (td, J ¼ 5.6, 2.5 Hz, 1H; H-4), 3.52 (dd, J ¼ 11.5,
5.4 Hz,1H; H-5a), 3.45 (dd, J ¼ 11.5, 5.8 Hz,1H; H-5b), 3.38 (s,1H; H-
carborane), 1.74e1.67 (m, 2H; H-2); 13C NMR (75 MHz, MeOD,
Into a solution of 2c
b
(0.02 g, 0.025 mmol) in the 9:1 mixture of
methanol/water (1.2 mL) was added potassium carbonate (0.01 g,
0.07 mmol). The formed reaction mixture was then stirred at room
temperature for 16 h. Removal of volatiles in vacuo and column
chromatography of the residue on silica gel (2:1 hexane/EtOAc)
20 ꢀC)
d
86.51 (C-4), 82.49 (C-1), 72.73 (C-3), 62.79 (C-5), 48.15 (C-
carborane) 39.52 (C-2); 11B NMR (128 MHz, MeOD, 20 ꢀC)
d
ꢂ10.51
(s, 1B; B-9), ꢂ11.92 (s, 1B; B-11), ꢂ14.50 (s, 1B; B-3), ꢂ17.43 (s, 2B, B-
5, B-6), ꢂ21.32 (s, 1B; B-2), ꢂ23.37 (s, 1B; B-4), ꢂ33.56 (s, 1B, B-
afforded 0.01 g (83%) of 3c
b
as a colorless solid substance: Rf ¼ 0.55
(Hex/EtOAc 1:1); m.p. 178e180 ꢀC; [
a
]
D
¼ ꢂ22.4ꢀ (c ¼ 0.00402 g/
10), ꢂ37.64 (s, 1B, B-11); IR (KBr)
n ;
2531, 1353, 1278, 1027, 917 cmꢂ1

ꢀ
I. Snajdr et al. / European Journal of Medicinal Chemistry 83 (2014) 389e397
397
(c) L.F. Tietze, U. Bothe, Ortho-carboranyl glycosides of glucose, mannose,
maltose and lactose for cancer treatment by boron neutron-capture therapy,
Chem. Eur. J. 4 (1998) 1179e1183;
MS (ESI): m/z (%): 250.3 (100); HRMS (ESI): m/z calcd. for
C7H20B9O3: 251.2255, found 251.2255.
(d) G.B. Giovenzana, L. Lay, D. Monti, G. Palmisano, L. Panza, Synthesis of
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Acknowledgments
(e) L.F. Tietze, U. Bothe, U. Griesbach, M. Nakaichi, T. Hasegawa, H. Nakamura,
Y. Yamamoto, Carboranyl bisglycosides for the treatment of cancer by boron
neutron capture therapy, ChemBioChem. 2 (2001) 326e334.
[8] S. Ronchi, D. Prosperi, C. Thimon, C. Morin, L. Panza, Synthesis of mono- and
bisglucuronylated carboranes, Tetrahedron Asym. 16 (2005) 39e44.
[9] F. Campo, M. Mossotti, L. Panya, Synthesis of complex glycosylated carboranes
for BNCT, Synlett (2012) 120e122.
Financial supports from the Ministry of Education, Youth and
Sports of the Czech Republic (project nos. LC06070, 1M0508, P207/
13/159155 and MSM0021620857), National Science Foundation
(CHE-0906179 to NSH), and Kishwaukee Community Hospital
Foundation are gratefully acknowledged.
ꢀ
ꢀ
ꢀ
[10] I. Snajdr, Z. Janousek, J. Jindrich, M. Kotora, Cross-metathesis of allylcarbor-
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€
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Supplementary data related to this article can be found at http://
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