Chemical ligation : A versatile method for nucleoside modification with boron clusters

Article abstract of DOI:10.1002/chem.200801053

A general approach to the synthesis of nucleoside conjugates containing carborane and metallocarborane complexes, based on Huisgen 1,3-dipolar cycloaddition ( chemical ligation ), is described. Boron-clusterdonors bearing terminal azide or ethynyl groups were prepared in the ringopening reaction of dioxane-boron-cluster adducts and an azide anion or suitable alkynol-derived alcoholate nucleophile. Analogous derivatives bearing terminal sulfhydryl groups were also prepared. Nucleosides with various spacers containing terminal azide or ethynyl groups, located within nucleobases or sugar residues, were used as boron-cluster acceptors. The proposed methodology provides a convenient way to synthesize libraries of boron-cluster-modified nucleosides for various applications.

Full text of DOI:10.1002/chem.200801053

FULL PAPER
DOI: 10.1002/chem.200801053
“Chemical Ligation”: A Versatile Method for Nucleoside Modification with
Boron Clusters
Błazej A. Wojtczak,[a] Agnieszka Andrysiak,[a] Bohumꢀr Grꢁner,[b] and
Zbigniew J. Lesnikowski*[a]
Abstract: A general approach to the
synthesis of nucleoside conjugates con-
taining carborane and metallocarbor-
ane complexes, based on Huisgen 1,3-
dipolar cycloaddition (“chemical liga-
tion”), is described. Boron-cluster-
donors bearing terminal azide or eth-
ynyl groups were prepared in the ring-
opening reaction of dioxane-boron-
cluster adducts and an azide anion or
suitable alkynol-derived alcoholate nu-
cleophile. Analogous derivatives bear-
ing terminal sulfhydryl groups were
also prepared. Nucleosides with various
spacers containing terminal azide or
ethynyl groups, located within nucleo-
bases or sugar residues, were used as
boron-cluster acceptors. The proposed
methodology provides
a convenient
way to synthesize libraries of boron-
cluster-modified nucleosides for various
applications.
Keywords: alkynes · azides · chemi-
cal ligation · nucleosides · thiols
Introduction
semimetal-containing compounds have properties that are
gained through the inclusion of nearly 100 additional ele-
ments. Macromolecules containing metal and metal-like ele-
ments are widespread in nature; metalloenzymes supplying
a number of essential physiological functions are one the
best known examples. The variety of molecules containing
metal and metal-like components is extremely large, not
only because of the larger number of metallic and metalloid
elements, but also because of the diversity of available oxi-
dation states, the use of combinations of different metals,
and the ability to include a plethora of organic moieties or-
ganized in the form of low-molecular compounds or macro-
molecular structures.[1] One of the most useful platforms for
such new materials is nucleic acids. Nucleic acid constructs
used for technological applications consist usually of two
clearly different domains; the nucleic acid itself in the role
of an information-bearing platform, and a second, function-
providing modification, in this case a metal or metal-carry-
ing complex.[2] Modified nucleosides are indispensable build-
ing blocks needed for the synthesis of modified nucleic
acids. This paper describes the modification, metalloid units,
in the form of boron clusters or its complex with metal.
Recently, we described several methods for the incorpora-
tion of boron clusters and their metal complexes (metallo-
carboranes) into nucleosides and nucleotides—nucleoside
conjugates with a broad range of potential applications and
modified building blocks for the synthesis of boron and
metal-bearing nucleic acids.[2–4]
Contemporary technologies take advantage of the knowl-
edge of different fields of science. The crossroads of biologi-
cal and inorganic chemistry, and further, biology and materi-
als engineering is a fruitful field yielding new technologies
such as nanobiotechnology, bioelectronics, biocomputing,
and biosensing. Progress in these fields depends heavily
upon the accessibility of new materials, not yet available,
possessing novel physical, chemical, or biological properties
that differ significantly from those accessible in solely bioor-
ganic- or inorganic-based compounds. New properties can
be often achieved through new compositions or new molec-
ular structures.
Most traditional molecules deal with fewer than ten ele-
ments (mainly C, H, N, O, S, P, Cl, Fe), whereas metal and
[a] B. A. Wojtczak, A. Andrysiak, Prof. Z. J. Lesnikowski
Institute of Medical Biology
Laboratory of Molecular Virology and Biological Chemistry
Polish Academy of Sciences, 106 Lodowa St.
93-232 Lodz (Poland)
Fax (+48)42-272-3630
E-mail: zlesnikowski@cbm.pan.pl
[b] Dr. B. Grꢀner
Institute of Inorganic Chemistry of the Academy of Sciences, v.v.i.
ˇ
ˇ
Husinec-Rez 1001
ˇ
ˇ
250 68 Rez (Czech Republic)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801053.
Chem. Eur. J. 2008, 14, 10675 – 10682
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10675

Practical applications of boron clusters/nucleoside conju-
gates range beyond use for the modification of DNA. Due
to the crucial role of nucleosides in many metabolic path-
ways and interactions with other biomolecules, the nucleo-
sides, their derivatives, and analogues are widely used as
chemotherapeutics, mainly as antiviral or anticancer agents.
Boron clusters are used as lipophilic pharmacophors and
modulators of the nucleosidesꢂ physicochemical, biological,
and pharmacological properties. They are also extensively
studied as boron carriers for boron neutron capture therapy
(BNCT) of tumors.
azide and alkyne fusion. The 1,2,3-triazole functions as a
rigid linking unit that can mimic the atom placement and
electronic properties of a peptide bond without the same
susceptibility to hydrolytic cleavage, even enough the extra
atom in the triazole backbone leads to an increase in dis-
tance between N1–C4 substituents relative to the typical
amide bond. Due to the high dipole moment (actually
higher than an amide bond), the 1,2,3-triazole linker can
participate in hydrogen-bond formation as both a hydrogen-
bond donor and acceptor, which helps the 1,2,3-triazole unit
to fit well into the diverse environments of biological mole-
cules.
The advantageous properties of Huisgen cycloaddition,
together with the most useful modular nature of the click
chemistry approach, make it well suited for use in the syn-
thesis of new molecules, especially conjugates composed of
two quite different subunits. Examples are bioorganic/inor-
ganic conjugates such as the nucleosides and boron clusters
presented here.
In our approach, two types of building blocks were con-
structed: one is the boron-cluster donor equipped with a ter-
minal azido or ethynyl function, the second is the nucleo-
side–boron-cluster acceptor, similarly furnished with a ter-
minal alkyne or azido group. The combination of all four
possibilities, two types of boron-cluster donors and two
types of boron-cluster acceptors, provides high versatility for
the proposed methodology.
Syntheses of the boron-cluster donors are shown in
Scheme 1. These were prepared in two variants: one con-
tained a 7,8-dicarba-nido-undecaborate anion (C2B9H12)À
and the second, a [3-metal bis(1,2-dicarbollide) (-1)]ate
Herein, we propose a new and versatile approach based
on Huisgen 1,3-dipolar cycloaddition of azides and terminal
alkynes for the modification of pyrimidine as well as purine
nucleosides.
The CuI-catalyzed 1,3-dipolar cycloaddition of azide and
alkyne to form a triazole, termed “click chemistry” or
“chemical ligation” reaction, was established recently as an
important tool for the chemical and biological modification
of biomolecules.[5,6] The reactants, azide and alkyne, are con-
venient to introduce independently, are stable, and do not
react with common organic reagents or functional groups in
biomolecules (are orthogonal). The triazole formation is ir-
reversible and usually proceeds with high yield. In addition,
this reaction benefits from an extremely mild and regiose-
lective copper(I) catalyst system that is surprisingly indiffer-
ent to solvent and pH. All these factors allow the applica-
tion of “click chemistry” approaches to be envisaged not
only in general organic synthesis or its offshoots, such as
synthesis on solid supports or combinatorial chemistry, but
also in the emerging field of “organic chemistry in vivo”.[7]
Results and Discussion
In the “chemical ligation”
strategy based on the “click
chemistry” approach, reactive
molecular building blocks are
designed to “click” together
selectively and covalently. Al-
though there are several reac-
tions that fulfill in general the
requirements of the “click”
process,[5,7] the Huisgen dipolar
cycloaddition of azides and al-
kynes[8,9] to give triazoles is the
most useful, reliable, and
broadly applied member of
this family.
In addition to the advantag-
es of the Huisgen-type cycload-
Scheme 1. Synthesis of boron-cluster donors: 10-(5-azido-3-oxa-pentoxy)-7,8-dicarba-nido-undecaborane (2),
8-(5-azido-3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide) (5), 8-(5-azido-3-oxa-pentoxy)-3-iron bis(1,2-dicarbol-
lide) (6), 8-(5-propargyl-3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide) (7), 8-[5-(4-pentyn-1-yl)-3-oxa-pentoxy]-
3-cobalt bis(1,2-dicarbollide) (8), 8-[(5-thia-(3-thiolo-propan-1-yl)-3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)
dition mentioned above, fur-
ther interest in this reaction
stems from the attractive prop-
erties of the 1,2,3-triazole
linker formed as a result of
(9). i) NaN3, DMF, RT; ii) HOCH2CCH or HOCAHTUNGTREN(NGU CH2)3CCH, NaH, toluene, RT; iii) HSCAHTUNGTREN(NUGN CH2)3SH, NaH, tolu-
ene/DMF, RT.
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Chem. Eur. J. 2008, 14, 10675 – 10682

Chemical Ligation
FULL PAPER
Table 1. Characteristics of boron-cluster azides 2, 5, 6 and alkynes 7, 8.
modification, derivatives 2 and
3–9, respectively. As a metal
component of the metallocar-
borane complex, cobalt or iron
was used. All compounds 2–9
were synthesized through diox-
ane ring-opening in cyclic oxo-
nium derivatives of the 7,8-di-
Compound
Molecular formula
MS[a]
UV[b] [nm]
lmax
IR [cmÀ1
]
nN3
TLC[e]
Rf
lmin
nBÀ
H
2
5
C6H19B9N3O2
C8H29B18CoN3O2
263.3[h]
453.2[i]
–
–
2513.4[c]
2553.2
2119.1[c]
2122.2
0.42
0.22
236.31
351.56
350.30
293.30
237.56
232.55
232.55
313.31
375.39
372.16
311.82
282.44
312.57
312.29
6
C8H29B18FeN3O2
450.5[h]
2564.8
2554.8
2123.9
0.22
7
8
C11H32B18CoO3
C13H36B18CoO3
467.0[h]
494.5[h]
2565.0
2565.0
0.50
0.53
carba-nido-undecaborate
or
[3-metal bis(1,2-dicarbollide)
(-1)]ate ion by azide anion or
2-propyn-1-ol, 4-pentyn-1-ol,
1,3-propanedithiol derived al-
coholate or thiolate nucleo-
philes.
[a] MS (FAB, -ve), glycerine was used as a matrix. Typically, the most intense signal in the plot corresponds to
the relative abundance 100% in the spectrum. Mass of this peak corresponds to the average isotopic mass dis-
tribution and is usually close to the MW. [b] In 95% C2H5OH. [c] In Nujol. [d] In KBr. [e] TLC precoated silica
gel 60 F254 plates. [f] Eluting solvent system: CH2Cl2/CH3OH 9:1. [g] [M+H]À. [h] [M]À.
The derivative 2, with a ter-
minal azido group, was prepared from adduct 1 in the reac-
tion with sodium azide in dimethylformamide. The reaction
was completed after 1 h and provided 2 in high yield. The
alkoxide and thiolate anions were generated in situ by addi-
tion of sodium hydride to a solution of adduct 3 or 4 and
the corresponding alcohol or thiol in anhydrous toluene, fol-
lowed by stirring at room temperature for 5–18 h. The reac-
tion progress was monitored by TLC. In some cases, a mix-
ture of toluene and dimethyl formamide was used as the re-
action medium.
Following Hawthorneꢂs seminal works on ligand deriva-
tives of the 7,8-dicarba-nido-undecaborate anion,[10] Plesekꢂs
original concept of the ring-opening reaction in cyclic ethers
and polyhedral boron hydride adducts with various nucleo-
philes[11–13] has been established over last two decades as a
very useful methodology for the attachment of functional
groups to boron-cluster derivatives.[14–18] In 2006 we demon-
strated that the azide anion can serve as a nucleophile in the
ring-opening reaction of the 10-dioxane-7,8-dicarba-nido-un-
decaborane (1) adduct.[19] An analogous approach, but using
ethyl alcohol instead of dimethylformamide as a reaction
medium, was published recently by other authors.[20] Table 1
summarizes the characteristics of compounds 2–6, 7, and 8.
Herein, we demonstrate that this original approach may
be successfully extended for [8-dioxane-3-cobalt bis(dicar-
bollide)]0 and [8-dioxane-3-iron bis(dicarbollide)]0 zwitter-
ions with no interference from the quite reactive metallo-
borane B(8’) site, as no acid catalysis is required to attach
the functional group to the cage boron atom. We show also
that alcoholate or thiolate nucleophiles derived from alkyne
alcohols or thiols, such as 2-propyn-1-ol, 4-pentyn-1-ol, or
1,3-propanedithiol, can cleanly
It may be expected that the greater accessibility to two
kinds of metalloborane building blocks bearing either termi-
nal azide groups or terminal triple bonds will further en-
hance the usability of the “click chemistry” approach in the
design of molecular constructions based on various boron
clusters. A broad range of applications can be expected in
the emerging field of the bioorganic chemistry of boron
compounds as pharmacophors.
The application of a 1,3-propanedithiol derived thiolate
nucleophile for the synthesis of 9 is also noteworthy. The
ring-opening reactions of cyclic oxonium derivatives of poly-
hedral boron hydrides with a sulfur donor atom are quite
rare. A single example, published in the simple borane
series, is represented by cleavage of the tetrahydrofurane
ring attached to the closo-dodecaborate or closo-decaborate
cluster by the hydrosulfide ion.[18]
The synthesis of boron-cluster acceptors, the nucleosides
equipped with terminal azido or ethynyl functions, is shown
in Scheme 2. Synthesis of 3N-(4-pentyn-1-yl)thymidine (12)
was performed similarly to that described for 3-(2-propyn-1-
yl)thymidine, with the exception that in the present synthe-
sis suitable tosylate was applied,[25] instead of alkyne bro-
mide as used previously.[24]
Substitution of the good leaving tosyl group in (14), the
already described compound,[25] by sodium azide in dry di-
methylformamide provided 15 in high yield. The target nu-
cleoside–boron-cluster conjugates were obtained in a simple,
one-step procedure shown in Scheme 3. The reaction was
performed under the standard “click chemistry” version of
Huisgen azide–alkyne cycloaddition.[26] A suitable nucleo-
side acceptor with a spacer of different type (alkyl, ether)
cleave the onium rings of 3
and 4 with no side reaction.
Considering utilization of the
azide and alkynoxy nucleo-
philes for oxonium ring-open-
ing, an additional known ex-
ample is cleavage of the
Scheme 2. Synthesis of nucleoside boron-cluster acceptors 3N-[(5-azido-3-oxa-pentoxy)]thymidine (15) and
3N-(4-pentyn-1-yl)thymidine (12): i) TsOACTHUNGNERTN(UNG CH2)3CCH (11), K2CO3, DMF; ii) TsOAHCTUNREGT(NGNUN CH2)2OACTHNUGTRENN(UNG CH2)2OTs (13),
K2CO3, DMF; iii) NaN3, DMF.
[B12H12]2À
tetrahydrofurane
adduct.[21–23]
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10677

Z. J. Lesnikowski et al.
fication to the sugar residue of the nucleoside. Two other
nucleosides, 3N-(4-pentyn-1-yl)thymidine (12) and 3N-[5-
azido-3-oxa-pentoxy)]thymidine (15), contained a spacer at-
tached to the N3 of thymine base, terminated with an ethyn-
yl or azido group, respectively. These substrates allowed at-
tachment of the modification to the nucleobase part of the
nucleoside. Boron clusters used as modifying units represent
two important classes of the boron-cage derivatives carbor-
ane and metallocarborane. Table 2 compiles some pertinent
characteristics of the obtained metallocarborane/nucleoside
conjugates.
The general “click chemistry” methodology for the syn-
thesis of boron cluster/nucleoside conjugate presented
herein is an extension of our original approach used for the
synthesis of 8-{[5-(7,8-dicarba-nido-undecaborane-10-yl)-3-
oxa-pentoxy]-1N-1,2,3-triazole-4-yl}-2’-O-deoxyadenosine
from 8-ethynyl-2’-deoxyadenosine and boron-cluster donor
2,[19] and shows its applicability for the synthesis of both
purine and pyrimidine nucleosides modified with boron
AHCTUNGTRENNUNG
of closo-dodecaborate [B12H12]2À anion derivatives utilizing
reactions of compounds with terminal ethynyl or azido
groups attached to the cluster through ether spacers with
various organic azides and terminal alkynes[22,23] shows the
further potential of Huisgen 1,3-dipolar cycloaddition in the
synthesis of nucleoside/boron-cluster conjugates.
Compounds 17–24, together with other nucleoside/boron-
cluster conjugates synthesized in our laboratory are current-
ly the subject of biological evaluation. Their cytotoxicity and
susceptibility to phosphorylation by nucleoside kinases and
immunomodulatory properties are being studied. Selected
conjugates are transformed into 5’-O-dimethoxytrityldeoxy-
Scheme 3. Synthesis of nucleoside boron-cluster conjugates through
“chemical ligation” using nucleoside boron-cluster acceptors and boron-
cluster donors: 17–24. i) 2, 5, or 6, CuSO4·5H2O/potassium ascorbate,
tert-butanol/water 1:1; ii) 7 or 8, CuSO4·5H2O/potassium ascorbate, tert-
butanol/water 1:1.
and length (1–4 carbon atoms) was dissolved in a mixture of
tert-butanol and water, together with an equimolar amount
of a boron-cluster donor equipped with a 3-oxa-pentoxy
spacer terminated with an
nucleoside
3’-O-(N,N-diisopropyl-b-cyanoethyl)phosphor-
azido, a 2-propyn-1-oxy, or 4-
pentyn-1-oxy substituent.
Catalytic amounts of CuSO4
and potassium ascorbate solu-
tions were added to the solu-
tion obtained. Reactions were
performed at room tempera-
ture over 8–50 h (usually 24 h)
with TLC control. After reac-
tion completion, the solvents
were evaporated and the crude
products were purified by
column chromatography on
silica gel. The yields of purified
products usually ranged from
30 to 65%.
Table 2. Characteristics of carborane- and metallocarborane/nucleoside conjugates 17–24.
Compound
Molecular formula
MS
UV[c] [nm]
IR [cmÀ1
]
TLC
Rf
0.30[f]
0.47[f]
lmin
lmax
nBÀ
H
17
18
C18H31B9N5O8
C20H43B18CoN5O8
545.4[a,h]
735.5[a,i]
236.31
235.68
288.92
348.43
235.68
294.56
243.20
240.06
291.42
240.06
295.19
238.19
290.80
240.06
291.42
262.45
267.36
313.41
373.74
270.54
312.61
267.91
271.31
313.10
274.04
310.10
271.45
312.57
271.20
312.57
2521.5[d]
2562.0[e]
19
C20H43B18FeN5O8
732.6[a,i]
2542.7[d]
0.36[f]
20
21
C21H38B9N5O7
C23H49B18CoN5O7
572.0[b,j]
762.0[b,k]
2530.0[d]
2562.0[d]
0.29[f]
0.35[f]
22
23
24
C23H49B18FeN5O7
C25H53B18CoN5O9
C27H57B18CoN5O9
759.0[b,k]
822.0[b,k]
850.0[b,k]
2560.0[d]
2561.0[d]
2561.0[d]
0.35[f]
0.21[g]
0.18[g]
Several
boron-cluster-
donor/-acceptor combinations
were tested. First, 2’-O-propar-
giluridine (16) was used as a
boron-cluster acceptor. This al-
lowed attachment of the modi-
[a] MS (FAB, Gly, -ve). [b] MS (ESI, 80 eV). [c] Typically, the most intense signal in the plot corresponds to
the relative abundance 100% in the spectrum. Mass of this peak corresponds to the average isotopic mass dis-
tribution and is usually close to the MW. [d] In 95% C2H5OH. [e] In KBr. [f] In Nujol. [g] Eluting solvent
system: CH2Cl2/CH3OH 8:2. [h] Eluting solvent system: CH2Cl2/CH3OH 9:1. [i] [M+3H]À. [j] [M]À.
[k] [M+2H]À. [l] [M+H]À.
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Chem. Eur. J. 2008, 14, 10675 – 10682

Chemical Ligation
FULL PAPER
using a linear gradient of methanol in methylene chloride as an eluting
solvent system.
amidites or H-phosphonates, the monomers suitable for auto-
mated DNA synthesis. Results will be published elsewhere.
Yield 2: 113 mg, 80%; TLC (CH2Cl2/CH3OH 9:1): Rf =0.42; UV/Vis
(96% EtOH): no absorption in the range 220–320 nm was detected;
FTIR (Nujol): nmax =2513.4 (BH), 2119.1 (N3), 2870.7, 2923.6, 2945.8 cmÀ1
(CH2); 1H {11B BB} NMR (250.131 MHz, CD3COCD3, 258C, TMS): d=
À0.49 (s, BH bridge), 0.45 (s, 1H; H3), 1.16 (s, 2H; H5,6), 1.37 (s, 2H;
H2,4), 2.15 (s, 2H; H9,11), 3.46–3.71 ppm (m, 8H; CH2); 11B NMR
Experimental Section
Materials: Most chemicals were obtained from Aldrich and used without
further purification, unless stated. Thymidine and uridine were purchased
from Pharma–Waldhof GmbH (Dꢀsseldorf, Germany). Sodium hydride
(60% suspension in mineral oil) was purchased from Lancaster (More-
cambe, England). Flash chromatography was performed using silica gel
60 (230–400 mesh, ASTM, Aldrich). Rf values refer to analytical TLC
performed using precoated silica gel 60 F254 plates purchased from
Sigma–Aldrich (Steinheim, Germany) and developed in the solvent
system indicated. Compounds were visualized by use of UV light
(254 nm) or 0.5% acidic solution of [PdCl2] in HCl/methanol for boron-
containing derivatives. The yields are not optimized.
(80.25 MHz, CD3COCD3, 258C, BF /
N
8-(5-Azido-3-oxa-pentoxy)-3-cobalt
(CH2CH2O)2-1,2-C2B9H10)(1’,2’-C2B9H11-3,3’-Co)]Na (5) and 8-(5-azido-3-
oxa-pentoxy)-3-iron bis(1,2-dicarbollide) [(8-N3-(CH2CH2O)2-1,2-
C2B9H10)(1’,2’-C2B9H11-3,3’-Fe)]Na (6): The 8-dioxane-3-cobalt bis(dicar-
bollide) (3; 150 mg, 0.362 mmol) or 8-dioxane-3-iron bis(dicarbollide) (4,
150 mg, 0.364 mmol) and sodium azide (28 mg, 0.43 mmol) were dis-
solved in dry dimethylformamide (3 mL). The mixture was stirred at RT
until TLC monitoring (CH2Cl2/CH3OH 9:1) showed complete conversion
of the starting material (ca. 4 h). Then, the solvent was evaporated to
dryness under vacuum yielding crude product 5 (280 mg) or 6 (300 mg),
which was purified by silica gel column chromatography (230–400 mesh)
using a linear gradient of methanol in methylene chloride as an eluting
solvent system.
NMR spectroscopy: 1H, 13C, and 11B NMR spectra were recorded by
using a Bruker Avance DPX 250-MHz spectrometer equipped with BB
inverse probe-head, the spectra for 1H, 13C and 11B nuclei were recorded
at 250.13, 62.90, and 80.25 MHz, respectively. Tetramethylsilane and
1
BF /
N
tively. All chemical shifts are reported in ppm (d) relative to external
standards. The following abbreviations explain the multiplicities: s=sin-
glet, d=doublet, dd=double doublet, t=triplet, dt=double triplet, q=
quartet, quin=quintet, bs=broad singlet, m=multiplet. Coupling con-
stants are reported in Hertz.
Yield 5: 144 mg, 87%; TLC (CH2Cl2/CH3OH 9:1): Rf =0.22; UV/Vis
(96% EtOH): lmin =351.56, 236.31, lmax =375.39, 313.31 nm; FTIR
(Nujol): nmax =2553.2 (BH), 2122.2 (N3), 2874.4, 2929.3, 3038.3 cmÀ1
(CH2); 1H {11B BB} NMR (250.131 MHz, CD3COCD3, 258C, TMS): d=
1.42 (s, 1H; H6), 1.56 (s, 2H; H5,11), 1.66 (s, 2H; H5’,11’), 1.78 (s, 1H;
H6’), 1.99 (s, 2H; H9,12), 2.45 (s, 2H; H9’,12’), 2.70 (s, 1H; H10’), 2.91 (s,
2H; H4,7), 3.13 (s, 1H; H8’), 3.54–3.69 (m, 8H; CH2), 4.26 ppm (s, 4H;
CHcarborane); 11B {1H BB} NMR (80.25 MHz, CD3COCD3, 258C,
Mass spectrometry: Fast atom bombardment (FAB, Gly) mass spectra
were recorded by using a Finnigan MAT (Bremen, Germany). Electro-
spray ionization (ESI trihydroxyacetophenone/ammonium citrate) spec-
tra in negative mode were recorded by using an AMD Intectra mass
AMD 402 spectrometer. The m/z values were measured in negative
mode. Calculation of the theoretical molecular mass was performed using
the “Show Analysis Window” option in the ChemDraw8.0 program. Typ-
ically, the most intense signal in the plot corresponds to 100% relative
abundance in the spectrum is provided. The mass of this peak corre-
sponds to the average isotopic mass (average mass) and is usually close
to the MW. The Supporting Information shows data regarding the molecu-
lar ions and compares this with calculated values based on the isotopic
distribution (exact mass).
BF /
(C2H5)2O): d=22.933 (s, B8), 4.02 (s, B8’), 0.41 (s, B10’), À2.45 (s,
B10), À4.16 (s, B4’,7’), À7.40 (s, B9’,12’), À8.20 (s, B9,12), À17.22 (s,
B5’,11’), À20.35 (s, B5,11), À28.47 ppm (s, B6); 11B NMR (80.25 MHz,
CD3COCD3, 258C, BF3/ACTHNUGTRNEUNG(C2H5)2O): d=22.93 (s, B8), 4.02 (d, B8’, J=
128.48 Hz), 0.41 (d, B10’, 2JBH =148.38 Hz), À2.45 (d, B10, JBH
139.8 Hz), À4.16 (d, B4’,7’, 2JBH =139.8 Hz), À7.40 (d, B9’,12’, JBH
155.28 Hz), À8.20 (d B9,12, 2JBH =135.14 Hz), À17.22 (d, B5’,11’, JBH
159.45 Hz), À20.35 (d, B5,11, 2JBH =156.00 Hz), À28.47 ppm (d, B6,
2JBH =153.84 Hz); MS (Gly, FAB, -ve): m/z (%): calcd for
C8H29B18CoN3O2: 452.87 [M]À; found: 453.2 (100) [M]À.
UV spectroscopy: UV measurements were performed by using a GBC
Cintra10e UV/Vis spectrometer (Dandenong, Australia). Samples for UV
experiments, approximately 0.5 A260 ODU of each compound, were dis-
solved in 95% C2H5OH. Measurements were performed at ambient tem-
perature.
Yield 6: 132 mg, 80%; TLC (CH2Cl2/CH3OH 9:1): Rf =0.22; UV/Vis
(96% EtOH): lmin =350.30, 293.30, 237.56, lmax =372.16, 311.82,
282.44 nm; FTIR (KBr): nmax =2564.8, 2554.8 (BH), 2123.9 (N3), 2872.8,
2925.4, 3029.7 cmÀ1 (CH2); 11B {1H BB} NMR (80.25 MHz, CD3COCD3,
IR spectroscopy: Infrared absorption spectra were recorded by using a
Fourier-transform, infrared spectrophotometer Nexus (Thermo-Nicolet)
or an ATI Mattson Infinity series MI-60, equipped with a silicon carbide
(SiC) air-cooled source for the IR range, cesium iodide beam splitter,
and DTGS (deuterated triglycine sulfate) detectors. Samples were pre-
pared by diluting compounds with potassium bromide (70–140 mg of KBr
per sample) and then pressing in the stainless-steel die to form discs of
0.8 cm diameter. Alternatively, the spectra were taken in Nujol mulls.
Methods: Synthesis of pentynyl tosylate (11),[27] (diethylene glycol)di-
para-tosylate (13),[28] and 2’-O-propargiluridine (16)[29] was performed ac-
cording to literature procedures. 10-Dioxane-7,8-dicarba-nido-undecabor-
ane (1),[30] [8-dioxane-3-cobalt bis(dicarbollide)]0 (3),[31] and [8-dioxane-3-
iron bis(dicarbollide)]0 (4)[32] were obtained as described.
258C, BF3/ACHTNUGRTENUNG(C2H5)2O): d=117.12, 100.80 (s, B6,6’), 52.24, 41.14, 30.44,
À1.23, À6.05, À40.73 (B5,5’,9,9’,10,10’,11,11’,12,12’), À70.05 ppm (B10,
B10’); MS (Gly, FAB, -ve): m/z (%): calcd for C8H29B18FeN3O2: 449.78
[M+H]À; found: 450.5 (100).
8-(5-Propargyl-3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide) [(8-C3H3O-
(CH2CH2O)2-1,2-C2B9H10)(1’,2’-C2B9H11–3,3’-Co]Na (7): NaH (10 mg,
0.42 mmol) (60% suspension in mineral oil) was added at RT to a stirred
solution of [8-dioxane-3-cobalt bis(dicarbollide)]0 (3) (100 mg,
0.24 mmol) and propargyl alcohol (14 mg, 0.24 mmol) in dry toluene
(3 mL). The progress of the reaction was monitored by TLC chromatog-
raphy using CH2Cl2/CH3OH (9:1) as developing solvent system. After
18 h the solvent was evaporated to dryness under vacuum yielding crude
product (7), which was purified by silica gel column chromatography
(230–400 mesh) using a linear gradient of methanol in methylene chlo-
ride as an eluting solvent system.
10-(5-Azido-3-oxa-pentoxy)-7,8-dicarba-nido-undecaborane
[(10-N3-
(CH2CH2O)2-7,8-C2B9H11)]Na (2): The 10-dioxane-7,8-dicarba-nido-unde-
caborane (1; 120 mg, 0.54 mmol) and sodium azide (39 mg, 0.59 mmol)
were dissolved in dry dimethylformamide (3 mL). The mixture was
stirred at RT until TLC monitoring (CH2Cl2/CH3OH 9:1) showed com-
plete conversion of the starting material (ca. 1 h). Then, the solvent was
evaporated to dryness under vacuum yielding crude product 2 (250 mg),
which was purified by silica gel column chromatography (230–400 mesh)
Yield 7: 100 mg, 85%; TLC (CH2Cl2/CH3OH 9:1): Rf =0.50; UV/Vis
(96% EtOH), lmin =232.55, lmax =312.57 nm; FTIR (KBr): nmax =2565
(BH), 2871, 2923, 3040 (CH2), 3290 cmÀ1 (CH); 1H NMR (250.131 MHz,
CD3OH, 258C, TMS): d=2.82 (t, 1H; C CH, 4JHH =2.50 Hz), 3.63–3.70
(m, 8H; 2ꢃCH2CH2), 4.14 (brs, 4H; CHcarborane), 4.19 ppm (2H; CH2C=
Chem. Eur. J. 2008, 14, 10675 – 10682
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10679

Z. J. Lesnikowski et al.
CH, 4JHH =2.50 Hz); 1H {11B BB} NMR (250.131 MHz, CD3OH, 258C,
TMS): d=1.44 (s, 1H; H6), 1.51 (s, 2H; H5,11), 1.59 (s, 2H; H5’,11’),
1.70 (s, 2H; H9,12), 1.94 (s, 2H; H9’,12’), 2.49 (s, 1H; H10), 2.65 (s, 1H;
À28.38 ppm (s, B6); 11B NMR (80.25 MHz, CD3COCD3, 258C,
BF3/ACHTNUGRTNEUNG
(C2H5)2O): d=22.67 (s, B8), 3.61 (d, B8’, 2JBH =134.28 Hz), 0.54 (d,
2
B10’, JBH =140.38 Hz), À2.41 (d, B10, 2JBH =137.33 Hz), À4.13 (d, B4’,7’,
2JBH =143.43 Hz), À7.40 (d, B9’,12’, 2JBH =128.18 Hz), À8.35 (d,
ꢀ
H10’), 2.81 (s, 1H; C CH), 2.86 (s, 1H; H8’), 3.52–3.57 (m, 4H;
2
2
CH2CH2), 3.62–3.69 (m, 4H; CH2CH2), 4.14 (s, 4H; CHcarborane), 4.19 ppm
B9,12,4,17, JBH =131.22 Hz), À17.25 (d, B5’,11’, JBH =152.58 Hz), À20.41
(d, B5,11, 2JBH =158.69 Hz), À21.74 (B6’, overlap), À28.34 ppm (B6,
2JBH =164.79 Hz); MS (Gly, FAB, -ve): m/z (%): calcd for
C11H36B18CoO2S2: 518.06 [M]À; found: 518.1 (100).
(d, 2H; CH2C CH, 4JHH =0.75 Hz); 11B NMR (80.25 MHz, CD3COCD3,
ꢀ
258C, BF /
N
0.44 (d, B10’, 2JBH =143.43 Hz), À2.42 (d, B10, 2JBH =140.38 Hz), À4.29
(d, B4’,7’, 2JBH =146.48 Hz), À7.33 (d, B9’, 12’, 2JBH =125.13 Hz), À8.16
(d, B9,12,4,7, 2JBH =128.17 Hz), À17.27 (d, B5’,11’, 2JBH =155.64 Hz),
À20.44 (d, B5,11, 2JBH =158.69 Hz), À21.98 (B6’, overlap), À28.42 ppm
(d, B6, 2JBH =167.84 Hz); 11B {1H BB} NMR (80.25 MHz, CH3OD, 258C,
3N-(4-Pentyn-1-yl)thymidine (12): A solution of pentynyl tosylate (11)
(0.98 g, 4.12 mmol) in dry dimethylformamide (2 mL) was added at RT
to a stirred solution of thymidine (10) (1.00 g, 4.12 mmol) and potassium
carbonate (1.82 g, 13.18 mmol) in the same solvent (8 mL). The progress
of the reaction was monitored by TLC using CH2Cl2/CH3OH (92:8) as a
solvent system. After 18 h the solvent was evaporated to dryness under
vacuum yielding crude product (12) (0.96 g), which was purified by silica
gel column chromatography (230–400 mesh) using a linear gradient of
methanol in methylene chloride as an eluting solvent system.
BF /
G
B10’), À4.25 (s, B4’,7’), À7.39 (s, B9’,12’), À8.16 (s, B9,12,4,7), À17.27 (s,
B5’,B11’), À20.44 (s, B5,B11), À21.90 (s, B6’), À28.43 ppm (s, B6); MS
(ESÀ): m/z (%): calcd for C11H32B18CoO3: 465.90 [M+H]À; found: 467.0
(100).
8-[5-(4-Pentyn-1-yl)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide) [(8-
C5H7O-(CH2CH2O)2-1,2-C2B9H10)(1’,2’-C2B9H11-3,3’-Co]Na (8): NaH
(5 mg, 0.21 mmol, 60% suspension in mineral oil) was added at RT to a
stirred solution of [8-dioxane-3-cobalt bis(dicarbollide)]0 (3) (50 mg,
0.12 mmol) and 4-pentyn-1-ol (10 mg, 0.12 mmol) in dry toluene (3 mL).
The reaction progress was monitored by TLC chromatography using
CH2Cl2/CH3OH (9:1) as eluting solvent system. After 18 h the solvent
was evaporated to dryness under vacuum yielding crude product (8),
which was purified by silica gel column chromatography (230–400 mesh)
using a linear gradient of methanol in methylene chloride as an eluting
solvent system.
Yield 12: 956 mg, 74%; TLC (CH2Cl2/CH3OH 92:8): Rf =0.39; UV/Vis
(96% EtOH): lmin =237.56, lmax =268.03 nm; FTIR (KBr): nmax =3423
(OH), 2929, 3080 (CH2), 1629 cmÀ1 (C=O); 1H NMR (250.131 MHz,
ꢀ
CH3OD, 258C, TMS): d=1.77–1.88 (quin, 2H; CH2CH2C CH), 1.89 (d,
3H; CH3, 4JHH =1.16 Hz), 2.19–2.27 (m, 5H; CH2-C CH, C CH, H-2’),
3.73–3.79 (m, 2H; 5’a,5’b-H, 3JHH =3.07, 12.04, 8.55 Hz), 3.89–3.90 (m,
ꢀ
ꢀ
4
3
1H; H-4’), 3.98–4.04 (dt, 2H; CH2N, JHH =1.13 Hz, JHH =7.19 Hz), 4.37–
4.39 (m, 1H; H-3’), 6.28 (t, 1H; H-1’, 3JHH =6.94 Hz), 7.82 ppm (d, 1H;
H-6, 4JHH =1.18 Hz); 13C NMR (62.90 MHz, CD3OH, 258C, TMS): 13.37
(CH3), 16.93 (CH2), 27.43 (CH2), 41.31 (CH2N), 41.71 (C-2’), 62.70 (C-5’),
ꢀ
ꢀ
69.78 (C CH), 72.00 (C-3’), 84.06 (C CH), 87.12 (C-1’), 88.79 (C-4’),
110.88 (C-5), 136.48 (C-6), 152.36 (C-2), 165.48 ppm (H-4); MS (ESÀ): m/
z (%): calcd for C15H20N2O5: 308.33 [M+Na]À; found: 331.0 (100).
Yield 8: 44 mg, 73%; TLC (CH2Cl2/CH3OH 9:1): Rf =0.53; UV/Vis
(96% EtOH): lmin =232.55, lmax =312.29 nm; FTIR (KBr): nmax =2565
(BH), 2873, 2924, 3037 (CH2), 3293, 3275 cmÀ1 (CH); 1H NMR (25
0.131 MHz, CD3OH, 258C, TMS): d=1.75 (quin, 2H; CH2CH2CH2,
3JHH =7.06 Hz), 2.17 (t, 1H; CCH, 4JHH =2.79 Hz), 2.24 (dt, 2H;
3N-[1-(para-Toluensulfonyl)-3-oxa-pentoxy)]thymidine (14): A solution
of diethylene glycol di(p-toluenesulfonate)(13) (0.65 g, 1.57 mmol) in dry
dimethylformamide (3 mL) was added at RT to a stirred solution of thy-
midine (10) (0.127 g, 0.52 mmol) and potassium carbonate (0.216 g,
1.57 mmol) in the same solvent (4 mL). The progress of the reaction was
monitored by TLC using CH2Cl2/CH3OH (8:2) as a solvent system. After
18 h the solvent was evaporated to dryness under vacuum yielding crude
product, which was purified by silica gel column chromatography (230–
400 mesh) using a linear gradient of methanol in methylene chloride as
an eluting solvent system.
3
4
CH2CCH, JHH =7.06 Hz, JHH =2.68 Hz), 3.50–3.61 (m, 8H; 2ꢃCH2CH2),
4.15 ppm (brs, 4H; CHcarborane); 11B {1H BB} NMR (80.25 MHz,
CD3COCD3, 258C, BF3/ACHTUNGTRENNUNG(C2H5)2O): d=22.94 (s, B8), 3.91 (s, B8’), 0.44 (s,
B10’), À2.41 (s, B10), À4.24 (s, B4’,7’), À7.35 (s, B9’,12’), À8.16 (s,
B9,12,4,7), À17.27 (s, B5’,11’), À20.44 (s, B5,11), À21.91 (s, B6’),
À28.40 ppm (s, B6); 11B NMR (80.25 MHz, CD3COCD3, 258C,
BF3/ACHTUNGTRENNUNG
(C2H5)2O): d=22.90 (s, B8), 3.91 (d, B8’, 2JBH =137.32 Hz), 0.55 (d,
B10’, 2JBH =143.43 Hz), À2.41 (B10, 2JBH =137.33 Hz), À4.23 (B4’,7’,
Yield 14: 225 mg, 89%; TLC (CH2Cl2/CH3OH 8:2): Rf =0.42; UV/Vis
(96% EtOH): lmin =242.00, lmax =267.76 nm; FTIR (Nujol): nmax =3409
(OH), 2875, 2928, 3067 cmÀ1 (CH2), 1652, 1705 (C=O); 1H NMR
(250.131 MHz, CDCl3), 258C, TMS): d=1.92 (s, 3H; CH3), 2.33–2.49 (m,
2H; H-2’), 3.63–3.68 (m, 4H; OCH2CH2O), 3.81–3.95 (part AB of ABX
spin system, 2H; Ha,b-5’, 3JHH =3.04, 3.28 Hz, 2JHH =11.45 Hz), 3.98–4.01
(part X of ABX spin system, 1H; H-4’, 3JHH =3.16, 3.41 Hz), 4.08–4.15
(m, 4H; NCH2CH2,), 4.58 (dt, 1H; H-3’, 3JHH =3.97, 6.64 Hz), 6.17 (t,
1H; H-1’, 3JHH =6.64 Hz), 7.41 (d, 1H; H-6, 4JHH =1.13 Hz), 7.56 ppm
(4H; dd, Ar, 3JHH =8.27, 8.58 Hz); MS (ESI): m/z (%): calcd for
C21H28N2O9S: 484.52 [M+H]À; found: 485.0 (10).
2JBH =146.48 Hz), À7.28 (B9’,12’, 2JBH =125.12 Hz), À8.23 (B9,12,4,7, J=
2
125.12 Hz), À17.26 (B5’,11’, 2JBH =155.64 Hz), À20.45 (B5,11, JBH
=
158.69 Hz), À21.80 (B6’, overlap), À28.40 ppm (B6, 2JBH =170.89 Hz);
MS (Gly, FAB, -ve): m/z (%): calcd for C13H36B18CoO3: 493.95 [M+H]À;
found: 494.5 (100).
8-[(5-Thia-(3-thiolo-propan-1-yl)-3-oxa-pentoxy)-3-cobalt
bis(1,2-dicar-
bollide) [(8-HS(CH2)3S-(CH2CH2O)2-1,2-C2B9H10)(1’,2’-C2B9H11-3,3’-
ACHTUNGTRENNUNG
Co)]Na (9): [8-Dioxane-3-cobalt bis(dicarbollide)]0 (3, 50 mg, 0.12 mmol)
was dissolved in a mixture of dry toluene and DMF (6:1 v/v, 600 mL).
The resultant solution was added dropwise over 30 min to the mixture of
suspension of sodium hydride (60% suspension in mineral oil) and 1,3-
propanedithiol in dry toluene (500 mL). The reaction was monitored by
TLC (MeOH/CH2Cl2 1:9) After reaction completion (approximately 4–
5 h) the solvents were evaporated under vacuum. The crude product was
purified by silica gel chromatography using a linear gradient of methanol
in CH2Cl2.
3N-[5-Azido-3-oxa-pentoxy)]thymidine (15): Thymidine 14 (430 mg
(0.89 mmol) and sodium azide (145 mg, 2.25 mmol) were dissolved in dry
dimethylformamide (7 mL). The mixture was stirred at RT until TLC
monitoring (CH2Cl2/CH3OH 92:8) showed complete conversion of the
starting material (ca. 18 h). Then, the solvent was evaporated to dryness
under vacuum yielding crude product 15 (259 mg), which was purified by
silica gel column chromatography (230–400 mesh) using a linear gradient
of methanol in methylene chloride as an eluting solvent system.
Yield 9: 20 mg, 31%; TLC (CHCl3/CH3OH 8:2): Rf =0.35; UV/Vis (96%
MeOH): lmax =312.32, 363.87 nm, lmin =234.42, 397.37 nm; FTIR (KBr):
nmax =2563.0 (BH), overlapped with 2553 (SH), 2870.0, 2924.0,
Yield 15: 259 mg, 82%; TLC (CH2Cl2/CH3OH 92:8): Rf =0.37; UV/Vis
(96% EtOH): lmin =236.20, lmax =268.03 nm; FTIR (Nujol): nmax =3431
3039.0 cmÀ1 (CH2); 1H NMR (250.131 MHz, MeOD, 258C, TMS): d=
3
1.87 (quin, 2H; CH2CH2CH2, 3JHH =7.11 Hz), 2.61 (t, 2H; SCH2, JHH
=
(OH), 2872, 2927, 3076 (CH2), 2108 (N3), 1698 cmÀ1 (C=O); 1H NMR
3
6.93 Hz), 2.68 (t, 2H; CH2SH, 3JHH =6.83 Hz), 2.69 (t, 2H; CH2S, JHH
=
4
(250.131 MHz, CD3OH, 258C, TMS): d=1.89 (d, 3H; CH3, JHH
=
5.84 Hz), 3.25–3.29 (m, 2H; 2ꢃOCH2), 4.17 (brs, 4H; CHcarborane), 4.87–
4.96 ppm (m, 2H; 2ꢃOCH2); 11B {1H BB} NMR (80.25 MHz,
1.18 Hz), 2.20–2.26 (m, 2H; H-2’), 3.63–3.65 (m, 4H; OCH2CH2N), 3.66
(t, 2H; CH2CH2O, 3JHH =5.93 Hz), 3.63–3.76 (part AB of ABX spin
system, 2H; Ha,b-5’,3JHH =3.16, 8.71, 3.77 Hz), 3.77–3.88 (part X of ABX
CD3COCD3, 258C, BF3/ACHTUNGTRENNUNG(C2H5)2O): d=22.68 (s, B8), 3.63 (s, B8’), 0.44 (s,
3
B10’), À2.41 (s, B10), À4.17 (s, B4’,7’), À7.45 (s, B9’,12’), À8.31 (s,
spin system, 1H; H-4’, 3JHH =3.37, 3.41 Hz), 4.14 (t, 2H; CH2N, JHH
=
B9,12,4,17), À17.27 (s, B5’,11’), À20.44 (s, B5,11), À21.88 (s, B6’, overlap),
5.85 Hz), 4.37 (m, 1H; H-3’), 6.28 (t, 1H; H-1’, 3JHH =6.76 Hz), 7.82 ppm
10680
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10675 – 10682

Chemical Ligation
FULL PAPER
(d, 1H; H-6, 4JHH =1.06 Hz); MS (ESI): m/z (%): calcd for C14H21N5O6:
355.35 [M+Na]À; found: 378.0 (100).
-ve,): m/z (%): calcd for C20H43B18FeN5O8: 732.03 [M]À; found: 732.6
(100).
3N-{[5-(7,8-dikarba-nido-undekaborane-10-yl)-3-oxa-pentoxy]-1N-1,2,3-
triazole-4-yl}(4-propan-1-yl)thymidine (20): Yield 20: 23 mg, 40%; TLC
(CH2Cl2/CH3OH 8:2): Rf =0.29; UV/Vis: (96% EtOH): lmin =243.20,
lmax =267.91 nm; FTIR (KBr): nmax =2530.0 (BH), 2873, 2930, 2972
(CH2), 1697, 1667, 1632 cmÀ1 (CO); 1H NMR (250.131 MHz, DMSO,
258C, TMS): d=2.10 (quin, 2H; CH2CH2CH2, 3JHH =7.01 Hz), 2.26–2.29
(m, 2H; H-2’), 3.30 (t, 2H; CH2CH2CH2, 3JHH =7.70 Hz), 3.56–3.90 (m,
10H; 4CH2O, H-5’), 4.02 (t, 2H; H-3’, J=6.65 Hz), 4.30–4.40 (m, 1H; H-
4’), 4.55 (t, 2H; NCH2, 3JHH =5.13 Hz), 6.29 (t, 1H; H-1, 3JHH =7.50 Hz),
7.80 (s, 1H; H-6), 7.94 ppm (s, 1H; Htriazole); 11B {1H BB} NMR
General procedure for the synthesis of compounds 17–24: The boron-
clusters acceptor furnished with terminal alkyne (16, 17) or azido group
(15) (0.04–0.14 mmol, typically 0.05 mmol) and an equimolar amount or
slight excess (ca. 5%) of boron-cluster donor equipped with terminal
azido (5, 6) or ethynyl function (7, 8)) (0.04–0.14 mmol, typically
0.05 mmol) were dissolved in 0.6–2.1 mL of a mixture of tert-butanol and
water (1:1). To the obtained solution, a solution of CuSO4·5H2O (0.002–
0.007 mmol, 5% mol, 20–70 mL of 100-mm solution) was added, followed
by addition of a twofold molar excess of potassium ascorbate solution
(0.004–0.017 mmol, 40–170 mL of 100-mm solution) generated in situ from
solutions of potassium hydroxide and ascorbic acid (an equimolar
amount of potassium ascorbate can be used with only slight yield de-
crease). The mixture was stirred at RT until TLC monitoring (CH2Cl2/
CH3OH 8:2 for 17, 19, 21, 22 or CH2Cl2/CH3OH 9:1 for 18, 20, 23, 24)
showed complete conversion of the nucleoside starting material (8–50 h,
typically 24 h). Then, the solvent was evaporated to dryness under
vacuum and the crude product was purified by silica gel column chroma-
tography (230–400 mesh) using a linear gradient of methanol in dichloro-
methane as an eluting solvent system. Pure product was lyophilized from
a mixture of benzene/methanol (9:1).
(80.25 MHz, CD3COCD3, 258C, BF /
G
À25.36 (s, B3), 24.00 (s, B2,4), À17.32 (s, B5,6), À12.26 (B9,11),
À9.21 ppm (s, B10); 11B NMR (80.25 MHz, CD3COCD3, 258C,
BF3/ACHTGNUTRENNUNG
(C2H5)2O): d=À40.46 (d, B1, 2JBH =134.28 Hz), À25.23 (d, B3 over-
lap), À24.01 (d, B2,4, 2JBH =149.53 Hz), À17.31 (d, B5,6, JBH
134.27 Hz), À12.34 (d, B9,11, 2JBH =134.28 Hz), À9.33 ppm (s, B10); MS
(ESÀ): m/z (%): calcd for C21H38B9N5O7: 569.85 [M+2H]À; found: 572.0
(100).
3N-{{5-[3-cobalt bis(1,2-dicarbollide)-8-yl]-3-oxa-pentoxy}-1N-1,2,3-tria-
zole-4-yl}(4-propan-1-yl)thymidine (21): Yield 21: 19 mg, 33%; TLC
(CH2Cl2/CH3OH 8:2): Rf =0.35; UV/Vis: (96% EtOH): lmin =240.06,
291.42, lmax =271.31, 313.10 nm; FTIR (KBr): nmax =2562 (BH), 2872,
2926 (CH2), 1695, 1667, 1632 cmÀ1 (CO); 1H NMR (250.131 MHz,
CD3OH, 258C, TMS): d=0.5–3.0 (brs, 18H; BHcarborane), 1.90 (s, 3H;
2’-O-{[5-(7,8-Dicarba-nido-undecaborane-10-yl)-3-oxa-pentoxy]-1N-1,2,3-
triazole-4-yl}methyluridine (17): Yield 17: 32 mg, 65%; TLC (CH2Cl2/
CH3OH 8:2): Rf =0.30; UV/Vis (96% EtOH): lmin =236.31, lmax
=
262.45 nm; FTIR (Nujol): nmax =2521.5 (BH), 2925.8, 2874.6 (CH2),
1690.8 cmÀ1 (C=O); 1H NMR (250.131 MHz, CD3OH, 258C, TMS): d=
0.85–3.0 (bm, 11H; CHcarborane), 3.51–3.65 (m, 6H; CH2OCH2CH2O),
3
CH3), 1.99 (t, 2H; CH2CH2CH2, JHH =7.47 Hz), 2.21–2.33 (m, 2H; H-2’),
2.76 (quin, 2H; CH2CH2CH2, 3JHH =7.68 Hz), 3.52–3.62 (m, 6H; 3ꢃ
3
CH2O), 3.74–3.90 (m, 3H; H-4’,H-5’), 4.00 (t, 2H; NCH2, JHH =7.88 Hz),
3.67–3.90 (m, 4H; H-5’, OCH2), 4.10–4.15 (m, 1H; H-4’), 4.20–4.25 (m,
4.08 (brs, 4H; CHcarborane), 4.25–4.30 (m, 1H; H-3’), 4.50–4.55 (m, 2H;
3
1H; H-3’), 4.54–4.58 (m, 3H; NCH2CH2), 5.64 (d, 1H; H-5, JHH
=
3
NCH2CH2), 6.29 (t, 1H; H-1, JHH =7.50 Hz), 7.80 (s, 1H; H-6), 7.88 ppm
3
8.54 Hz), 5.79 (d, 1H; H-1’, 3JHH =3.78 Hz), 7.98 (d, 1H; H-6, JHH
=
(s, 1H; Htriazole); 13C NMR (62.90 MHz, CDCl3, 258C, TMS): d=13.30
(CH3), 23.96 (CH2CH2CH2), 28.08 (CH2CH2CH2), 41.30 (C-2’), 41.88
8.53 Hz), 8.05 ppm (s, 1H; 1-Htriazole); 11B NMR (80.25 MHz, CD3COCD3,
2
258C, BF /
(C2H5)2O): d=À9.50 (s, B10), À11.96 (d, B9,11, JBH
=
(NCH2CH2CH2), 47.98 (2ꢃCHcarborane), 50.62 (2ꢃCHcarborane
)
51.37
2
152.59 Hz), À16.80 (d, B5,6, 2JBH =125.12 Hz), À23.25 (d, B2,4, JBH
=
(NCH2), 62.74 (CH2–5’), 69.84 (CH2O), 70.31 (CH2O), 72.00 (CH-3’),
72.96 (CH2O), 87.12 (CH-1’), 88.70 (CH-4’), 110.74 (C-5), 124.40
(CHtriazole), 136.38 (CH-6), 152.25 (C-2), 165.39 ppm (C-4); 11B {1H
149.54 Hz, B3 overlap), À40.18 ppm (d, B1, 2JBH =140.38 Hz); 11B {1H
BB} NMR (80.25 MHz, CD3COCD3, 258C, BF /
(C2H5)2O): d=À9.51 (s,
B10), À11.95 (d, B9,11), À16.81 (s, B5,6), À23.25 (s, B2,4, B3 overlap),
À40.19 ppm (s, B1); MS (FAB, Gly, -ve): m/z (%): calcd for
C18H31B9N5O8: 542.77 [M+3H]À; found: 545.4 (100).
BB} NMR (80.25 MHz, CD3OD, 258C, BF3/ACHTUNTGRNNEUG(C2H5)2O): d=23.71ACHTUNGTRENNUNG(s, B8),
5.49 (s, B8’), 1.14 (s, B10’), À1.71 (s, B10), À4.11(s, 4’,7’), À6.82 (s,
G
B9’,12’,9,12,4,7), À16.64 (s, B5’,11’), À19.80 (s, B5,11), À21.87 (s, B6),
À27.75 ppm (s, B6); 11B NMR (80.25 MHz, CD3OD, 258C,
2’-O-{{5-[3-cobalt bis(1,2-dicarbollide)-8-yl]-3-oxa-pentoxy}-1N-1,2,3-tria-
zole-4-yl} methyluridine (18): Yield 18: 17 mg, 32%; TLC (CH2Cl2/
CH3OH 9:1): Rf =0.47; UV/Vis: (96% EtOH): lmin =235.68, 288.92,
348.43, lmax =267.36, 313.41, 373.74 nm; FTIR (Nujol): nmax =2562.0
(BH), 2869.2, 2924.1, 3050.3 (CH2), 1699.6 cmÀ1 (C=O); 1H NMR
(250.131 MHz, CD3OH, 258C, TMS): d=0.5–3.0 (brs, 18H; BHcarborane),
2
BF /
G
2JBH =143.43 Hz), À1.73 (d, B10, 2JBH =146.48 Hz), À4.01 (d, B4’,7’,
2JBH =146.48 Hz), À6.10–(À8.9) (m, B9’, 12’,9,12,4,7), À16.70 (d, B5,11’,
2JBH =155.64 Hz), À19. ppm (d, B5,11, 2JBH =164.8 Hz); MS (ESIÀ): m/z
(%): calcd for C23H49B18CoN5O7: 761.20 [M+H]À; found: 762.0 (100).
3.54–3.88 (m, 8H; 3OCH2), 3.96–4.25 (m, 7H; H-3’, H-4’, H-5’,
3N-{{5-[3-iron
bis(1,2-dicarbollide)-8-yl]-3-oxa-pentoxy}-1N-1,2,3-tria-
3
4CHcarborane), 4.52–4.56 (m, 3H; NCH2, H-2’), 5.63 (d, 1H; H-5, JHH
=
zole-4-yl}(4-propan-1-yl)thymidine (22): Yield 22: 23 mg, 40%; TLC
(CH2Cl2/CH3OH 8:2): Rf =0.35; UV/Vis: (96% EtOH): lmin =240.06,
295.19, lmax =274.04, 310.10 nm; FTIR (KBr): nmax =2560 (BH), 2872,
2927, 2967, 3040 (CH2), 1695, 1667, 1633 cmÀ1 (C=O); 11B {1H BB} NMR
3
8.04 Hz), 5.95 (d, 1H; H-1’, 3JHH =4.2 Hz), 7.94 (d, 1H; H-6, JHH
=
8.0 Hz), 8.10 ppm (s, 1H; Htriazole); 11B NMR (80.25 MHz, CD3COCD3,
258C, BF3/ACHTUNGTRENNUNG
(C2H5)2O): d=23.31 (s, B8), 4.63 (d, B8’, 2JBH =131.23 Hz),
0.56 (d, B10’, 2JBH =143.43 Hz), À2.51 (d, B10 overlap), À4.33 (d, B4’,7’,
2JBH =143.44 Hz), À7.16 (d, B9’,12’, 2JBH =128.17 Hz), À8.12 (d, B9,12,
2JBH =115.97 Hz), À17.26 (d, B5’11’, 2JBH =155.64 Hz), À20.33 (d, B5,11,
2JBH =137.33 Hz), À22.09 (d, B6’ overlap), À28.61 ppm (d, B6); 11B {1H
(80.25 MHz, CD3COCD3, 258C, BF /
(C2H5)2O): d=À480.97 (s, B8’),
À441.40 (s, B8), À374.76, À370.25 (s, B4,7,4’,7’), À40.60, À5.50, À1.03,
30.83, 40.29 (s, B5,5’,11,11’,9,9’,12,12’), 103.03, 120.15 ppm (s, B6,6’); MS
(ESIÀ): m/z (%): calcd for C23H49B18FeN5O7: 758.11 [M+H]À; found:
759.0 (100).
BB} NMR (80.25 MHz, CD3COCD3, 258C, BF3/ACHTUNTRGNEUNG(C2H5)2O): d=23.32 (s,
B8), 4.55 (s, B8’), 0.35 (s, B10’), À2.51 (s, B10 overlap), À4.48 (s, B4’,7’),
À7.26 (s, B9’,12’), À8.12 (s, B9,12), À17.34 (s, B5’,11’), À20.39 (s, B5,11),
À22.10 (s, B6’ overlap), À28.62 ppm (s, B6); MS (FAB, Gly, -ve,): m/z
(%): calcd for C20H43B18CoN5O8: 735.11 [M]À; found: 735.5 (36).
3N-{{5-[3-cobalt bis(1,2-dicarbollide)-8-yl]-3-oxa-pentoxy}methyl-(4-1,2,3-
triazole-1N-yl}} (1-ethoxyethan-4-yl)thymidine (23): Yield 23: 42 mg,
90%; TLC (CH2Cl2/CH3OH 9:1): Rf =0.21; UV/Vis: (96% EtOH): lmin
=
238.19, 290.80, lmax =312.57, 271.45 nm; FTIR (KBr): nmax =2561 (BH),
2873, 2926, 3036 (CH2), 1636, 1664, 1699 cmÀ1 (C=O); 1H NMR
(250.131 MHz, CD3OH, 258C, TMS): d=0.5–3.0 (bm, 18H; BHcarborane),
1.89 (d, 3H; CH3, 4JHH =1.15 Hz), 2.22–2.27 (m, 2H; H-2’), 3.61–3.68 (m,
8H; 4ꢃCH2O), 3.75–3.83 (m, 5H; H-4’, H-5’, NCH2), 4.10–4.14 (m, 7H;
2ꢃCH2O, 4 ꢃ CHcarborane), 4.32–4.42 (m, 1H; H-3’), 4.53 (t, 2H; NCH2,
3JHH =5.0 Hz), 4.63 (s, 2H; CH2), 6.26 (t, 1H; H-1’, 3JHH =6.78 Hz), 7.81
(t, 1H; H-1’, 4JHH =1.21 Hz), 7.94 ppm (s, 1H; Htriazole); 11B {1H
2’-O-{{5-[3-iron bis(1,2-dicarbollide)-8-yl]-3-oxa-pentoxy}-1N-1,2,3-tria-
zole-4-yl}methyluridine (19): Yield 19: 20 mg, 65%; TLC (CH2Cl2/
CH3OH 8:2): Rf =0.36; UV/Vis: (96% EtOH): lmin =235.68, 294.56,
lmax =270.54, 312.61 nm; FTIR (KBr): nmax =2542.7 (BH), 2861.4, 2924.5,
2955.6 (CH2), 1698.6 cmÀ1 (C=O); 11B {1H BB} NMR (80.25 MHz,
CD3COCD3, 258C, BF /
À377.14, À371.68 (s, B4,7,4’,7’), À40.27, À5.41, À1.03, 30.31, 39.15 (s,
B5,5’,11,11’,9,9’,12,12’), 102.98, 120.06 ppm (s, B6,6’); MS (FAB, Gly,
G
BB} NMR (80.25 MHz, CD3COCD3, 258C, BF3/ACHTUNTRGNEUNG(C2H5)2O): d=22.91 (s,
Chem. Eur. J. 2008, 14, 10675 – 10682
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10681

Z. J. Lesnikowski et al.
B8), 4.00 (s, B8’), 0.44 (s, B10’), À2.44 (s, B10), À4.24 (s, B4’,7’), À7.38 (s,
B9’,12’), À8.19 (s, B9,12,4,7 overlap), À17.30 (s, B5’,11’), À20.41 (s,
B5,11), À21.88 (s, B6’, overlap), À28.38 ppm (s, B6); 11B NMR
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Padwa), Wiley, New York, 1984, pp. 1–176.
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2006, 51–68.
(80.25 MHz, CD3COCD3, 258C, BF /
(C2H5)2O): d=22.80 (s, B8), 3.91 (d,
B8’, 2JBH =134.27 Hz), 0.47 (d, B10’, 2JBH =134.27 Hz), À2.44 (d, B10,
2JBH =113.38 Hz), À4.19 (d, B4’,7’, 2JBH =152.58 Hz), À7.29 (d, B9’,12’,
2JBH =128.17 Hz), À8.25 (d, B9,12,4,7 overlap, 2JBH =122.07 Hz), À17.26
(d, B5’,11’, 2JBH =152.58 Hz), À20.45 (d, B5,11, 2JBH =152.59 Hz), À21.88
(d, B6’, overlap), À28.39 ppm (s, B6, 2JBH =119.02 Hz); MS (ESIÀ): m/z
(%): calcd for C25H53B18CoN5O9: 821.25 [M+H]À; found: 822 (90) 429.0
(100) [MÀ(metallocarborane group and linker]).
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[13] J. Plesek, B. Grꢀner, S. Hermꢄnek, J. Bꢄca, V. Marecek, J. Jꢅnche-
3N-{{5-[3-cobalt bis(1,2-dicarbollide)-8-yl]-3-oxa-pentoxy}propyl-(4–1,2,3-
triazole-1N-yl}} (1-ethoxyethan-4-yl)thymidine (24): Yield 24: 23 mg,
´
´
ˇ
novꢄ, A. Lhotsky, K. Holub, P. Selucky, J. Rais, L. Cꢆsarovꢄ, J.
ˇ
´
Cꢄslavsky, Polyhedron 2002, 21, 975–986.
24%; TLC (CH2Cl2/CH3OH 9:1): Rf =0.18; UV/Vis: (96% EtOH): lmin
=
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240.06, 291.42, lmax =312.57, 271.20 nm; FTIR (KBr): nmax =2561 (BH),
2872, 2926, 3036 (CH2), 1636, 1664, 1698 cmÀ1 (C=O); 1H NMR
(250.131 MHz, CD3OH, 258C, TMS): d=0.5–3.0 (bm, 18H; BHcarborane),
1.89–1.93 (m, 3H; CH2CH2CH2O), 1.92 (d, 3H; CH3, 4JHH =1.11 Hz),
2.20–2.25 (m, 2H; H-2’), 2.76 (t, 2H; H, CH2CH2CH2O, 3JHH =7.49 Hz),
3.51–3.65 (m, 10H; 5ꢃCH2O), 3.73–3.83 (m, 5H; H-4’, H-5’, NCH2),
4.12–4.20 (m, 5H; 4ꢃCHcarborane, CH2O), 4.36–4.42 (m, 1H; H-3’), 4.50 (t,
2H; NCH2, 3JHH =5.36 Hz), 6.27 (t, 1H; H-1’, 3JHH =6.61 Hz), 7.70 (s,
1H; Htriazole), 7.82 ppm (d, 1H; H-6, 4JHH =1.20 Hz); 11B {1H BB} NMR
ˇ
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Acids 2007, 26, 1611–1613.
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Bragin, P. V. Petrovskii, V. N. Tsupreva, O. V. Sorokina, V. I. Bre-
gadze, Collect. Czech. Chem. Commun. 2007, 72, 1676–1688.
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(80.25 MHz, CD3COCD3, 258C, BF3/ACHTNUGRTNEUNG(C2H5)2O): d=22.82 (s, B8), 3.77 (s,
B8’), 0.44 (s, B10’), À2.39 (s, B10), À4.15 (s, B4’,7’), À7.43 (s, B9’,12’),
À8.24 (s, B9,12,4,7), À17.27 (s, B5’,11’), À20.39 (s, B5,11), À21.93 (s, B6’),
À28.21 ppm (s, B6); 11B NMR (80.25 MHz, CD3COCD3, 258C,
BF3/ACHTUNGTRENNUNG
(C2H5)2O): d=22.80 (s, B8), 3.76 (d, B8’, 2JBH =140.38 Hz), 0.49 (d,
2
B10’, JBH =140.38 Hz), À2.39 (d, B10, 2JBH =137.33 Hz), À4.18 (d, B4’,7’,
2
2JBH =140.38 Hz), À7.36 (d, B9’,12’, JBH =128.18 Hz), À8.33 (d, B9,12,4,7,
2JBH =125.13 Hz), À17.31 (d, B5’,11’, 2JBH =158.69 Hz), À20.45 (d, B5,11,
2JBH =155.64 Hz), À21.93 (B6’, overlap), À28.21 ppm (B6); MS (ESIÀ):
m/z (%): calcd for C27H57B18CoN5O9: 849.30 [M+H]À; found: 850.0 (100).
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Acknowledgements
This work was supported in part by the Polish Ministry of Science and
Higher Education (Grant No. N405 051 32/3592 and K152/H03/2007/10)
and the Ministry of Education (MSMT) of the Czech Republic within
programme LC523 and Research Plan AV0Z40320502 from AS CR.
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Received: May 30, 2008
Published online: October 22, 2008
10682
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10675 – 10682