Modular synthesis of 5-substituted thiophen-2-yl C-2′- deoxyribonucleosides

Article abstract of DOI:10.1021/jo800177y

(Chemical Equation Presented) A new modular methodology of preparation of 5-substituted thiophene-2-yl C-nucleosides was developed. A Friedel-Crafts-type of C-glycosidation of 2-bromothiophene with toluoyl-protected methylglycoside 2 gave the desired protected 1β-(5-bromothiophen-2-yl)-1,2- dideoxyribofuranose 4a in 60%. The key intermediate 4a was then subjected to a series of palladium-catalyzed cross-coupling reactions. The cross-coupling reactions with alkyl organometallics gave β-(5-alkylthiophen-2-yl)-2- deoxyribonucleosides 4 and 7 in moderate yields accompanied by side-products of reduction. On the other hand, cross-couplings with arylstannanes proceeded smoothly to give a series of β-(5-arylthiophen-2-yl)-2-deoxyribonucleosides 4 in good yields. Deprotection of toluoylated nucleosides by NaOMe in MeOH and silylated nucleosides by Et₃N·3HF gave a series of free C-nucleosides 6. Alternatively, other types of 5-arylthiophene C-nucleosides 6 were prepared in one step by the aqueous-phase cross-coupling reactions of unprotected 1β-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose with boronic acids. Title 5-arylthiophene C-nucleosides 6 exhibit interesting fluorescent properties with emission maxima varying from 339 to 396 nm depending on the aryl group attached.

Full text of DOI:10.1021/jo800177y

Modular Synthesis of 5-Substituted Thiophen-2-yl
C-2′-Deoxyribonucleosides
Jan Ba´rta,† Radek Pohl,† Blanka Klepeta´rˇova´,† Nikolaus P. Ernsting,‡ and Michal Hocek*,†,§
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead
Sciences & IOCB Research Center, CZ-16610, Prague 6, Czech Republic, and Institut fu¨r Chemie,
Humboldt UniVersita¨t zu Berlin, Brook-Taylor-Str. 2, D-12489 Berlin, Germany
hocek@uochb.cas.cz
ReceiVed January 23, 2008
A new modular methodology of preparation of 5-substituted thiophene-2-yl C-nucleosides was developed.
A Friedel-Crafts-type of C-glycosidation of 2-bromothiophene with toluoyl-protected methylglycoside
2 gave the desired protected 1ꢀ-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose 4a in 60%. The key
intermediate 4a was then subjected to a series of palladium-catalyzed cross-coupling reactions. The cross-
coupling reactions with alkyl organometallics gave ꢀ-(5-alkylthiophen-2-yl)-2-deoxyribonucleosides 4
and 7 in moderate yields accompanied by side-products of reduction. On the other hand, cross-couplings
with arylstannanes proceeded smoothly to give a series of ꢀ-(5-arylthiophen-2-yl)-2-deoxyribonucleosides
4 in good yields. Deprotection of toluoylated nucleosides by NaOMe in MeOH and silylated nucleosides
by Et3N · 3HF gave a series of free C-nucleosides 6. Alternatively, other types of 5-arylthiophene
C-nucleosides 6 were prepared in one step by the aqueous-phase cross-coupling reactions of unprotected
1ꢀ-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose with boronic acids. Title 5-arylthiophene C-nucleo-
sides 6 exhibit interesting fluorescent properties with emission maxima varying from 339 to 396 nm
depending on the aryl group attached.
Introduction
Triphosphates of some of the C-nucleosides are efficiently
incorporated to DNA by DNA polymerase.3
C-Nucleosides bearing hydrophobic aryl groups as nucleobase
surrogates attracted great attention due to their use in the
extension of the genetic alphabet.1 In oligonucleotide duplexes,
they selectively pair with the same of other hydrophobic
nucleobases due to increased stacking and favorable desolvation
energy as compared to canonical hydrophilic nucleobases.2
Biaryl C-nucleosides are of particular interest because of
largely extended stacking and formation of very stable du-
plexes.4 Both theoretical calculations5 and experimental (NMR
structure) results6 confirmed that they form a stacked pair within
the B-DNA duplex. On the other hand, incorporation of bulky
(2) (a) Ogawa, A. K.; Abou-Zied, O. K.; Tsui, V.; Jimenez, R.; Case, D. A.;
Romesberg, F. E. J. Am. Chem. Soc. 2000, 122, 9917–9920. (b) Wu, Y. Q.;
Ogawa, A. K.; Berger, M.; Mcminn, D. L.; Schultz, P. G.; Romesberg, F. E.
J. Am. Chem. Soc. 2000, 122, 7621–7632. (c) Guckian, K. M.; Krugh, T. R.;
Kool, E. T. J. Am. Chem. Soc. 2000, 122, 6841–6847. (d) Parsch, J.; Engels,
J. W. J. Am. Chem. Soc. 2002, 124, 5664–5672. (e) Lai, J. S.; Qu, J.; Kool,
E. T. Angew. Chem., Int. Ed. 2003, 42, 5973–5977. (f) Lai, J. S.; Kool, E. T.
J. Am. Chem. Soc. 2004, 126, 3040–3041.
† Academy of Sciences of the Czech Republic.
‡ Humboldt Universita¨t zu Berlin.
§ Phone: +420 220183324. Fax: +420 220183559.
(1) Reviews: (a) Wang, L.; Schultz, P. G. Chem. Commun. 2002, 1–11. (b)
Henry, A. A.; Romesberg, F. E. Curr. Opin. Chem. Biol. 2003, 7, 727–733. (c)
Kool, E. T.; Morales, J. C.; Guckian, K. M. Angew. Chem., Int. Ed. 2000, 39,
990–1009. (d) Kool, E. T. Acc. Chem. Res. 2002, 35, 936–943.
3798 J. Org. Chem. 2008, 73, 3798–3806
10.1021/jo800177y CCC: $40.75 2008 American Chemical Society
Published on Web 04/17/2008

Synthesis of Thiophen-2-yl C-2′-Deoxyribonucleosides
biaryl C-nucleoside into the duplex opposite to the purine or
pyrimidine nucleobase causes local disruption of the stacking.7
Very recently, donor- and acceptor-modified biphenyl C-
nucleoside-containing oligonucleotide was used8 for recognition
of another hydrophobic modification in the opposite strand or
even of a bulge position. Moreover, oligoaryl C-nucleosides
have been used by Kool et al.9for construction of fluorescent
oligonucleotide probes. Some related biaryl N-nucleosides have
been used as nucleoside fleximers10 and for major groove
recognition of the GC pair.11
sides,17 6-substituted pyridin-2-yl C-nucleosides,18 and 6-sub-
stituted pyridin-3-yl C-nucleosides19 by the preparation of a
general halogenated C-arylnucleoside intermediate followed by
displacement of the bromine for alkyl, aryl, or amino substituents
by cross-coupling reactions. Here, we wish to report on a
modular synthesis of diverse 5-substituted thiophen-2-yl C-
nucleosides. Thiophene as a sulfur heterocycle should not be a
good H-acceptor in the minor groove, and thus the nucleosides
could be used for further studies on the role of the H-bonding
for the fidelity of polymerases. Unsubstituted and 5-methylth-
iophene deoxyribonucleosides were prepared and incorporated
to oligonucleotides by Romesberg and found to form stable and
selective self-pairs.20 Moreover, oligoaryl thiophene nucleosides9
are fluorescent which makes the target aryl-substituted thiophene
nucleosides potential candidates for fluorescent labeling of
nucleic acids.
There are several synthetic approaches12 to C-nucleosides:
(i) additions of organometallics to ribono- or 2-deoxyribonolac-
tones,3,13 (ii) coupling of a halogenose with organometallics,14
(iii) electrophilic substitutions of electron-rich aromatics with
sugars under Lewis acid catalysis,15 or (iv) Heck-type coupling
of aryl iodides with glycals.16 However, none of them is truly
general, and many of them suffer from poor selectivity and low
yields. Therefore, the development of modular approaches to
the synthesis of these important compounds is of great interest.
We are currently involved in development of modular
methodologies based on larger scale syntheses of versatile
C-nucleoside intermediates and their further use for generation
of a series of diverse derivatives. We have already developed
modular syntheses of 3- and 4-substituted benzene C-nucleo-
Results and Discussion
The two known thiophene C-nucleosides were reported21,20
to be prepared by addition of lithiothiophene to lactol followed
by cyclization and deprotection. The first two steps are not
stereoselective, and the whole sequence gives ca. 15% overall
yields with two difficult separations of epimers. Our selected
approach of choice for the synthesis of a series of 5-substituted
thiophen-2-yl C-nucleosides was based on the synthesis of a
suitably protected 5-bromothiophen-2-yl C-nucleoside interme-
diate and on its further synthetic transformations (cross-coupling,
amination). To efficiently prepare this key intermediate, we have
tried several synthetic pathways based on analogy with some
known related nucleosides. After initial unsuccessful attempts
on additions of 2-bromo-5-lithiothiphene to protected 2-deox-
yribonolactone (in analogy to ref 22) followed by reduction by
Et3SiH in the presence of BF3 ·Et2O which unfortunately lead
only to products of elimination, we have focused on the
Friedel-Crafts-type C-glycosidation.15 2-Bromothiophene is an
electron-rich aromatic system which should be reactive enough
for this type of reaction. Applying conditions found in the
literature,15c either halogenose 1 or methyl glycoside 2 was used
as starting material. The reaction of chloro-sugar 1 with
2-bromothiophene 3 in the presence of BF3 ·Et2O gave the
desired ꢀ-(5-bromothiophen-2-yl) C-nucleoside 4a in 22% yield
and another 22% of undesired R-anomer 5a (Scheme 1). The
same reaction using AgBF4 as Lewis acid gave ꢀ-anomer 4a in
improved 54% yield and R-anomer 5a in 14% yield. The
Friedel-Crafts reactions of more stable and easily available
methyl glycoside 2 with 3 in the presence of SnCl4 and
AgOCOCF3 gave the desired ꢀ-C-nucleoside 4a in excellent
60% yield, while the R-anomer 5a was formed only in 25%
yield. The anomers 4a and 5a were reasonably well separable
by column chromatography using 2.5% ethyl acetate in hexane
to efficiently get pure ꢀ-anomeric key intermediate 4a in
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J. Org. Chem. Vol. 73, No. 10, 2008 3799

Ba´rta et al.
SCHEME 1. Preparation of the Key Intermediate by
C-Glycosidation of 2-Bromothiophenea
mides have been tried. However, in most cases, complex
unseparable mixture products of cross-coupling 4c-4e or 7c-7e
with products of reduction 4b or 7b were obtained (Table 1,
entries 3-11). For the methylation, the Suzuki-Miyaura
reaction of 4a and 7a with methylboronic acid has also been
tried. While the reaction of toluoyl-protected 4a gave the mixture
of 4c/4b in a ratio of 6:1, the reaction of TBS-protected 7a
gave the analogous mixture 7c/7b in 9:1 ratio in acceptable 73%
yield. The desired methyl derivatives 4c or 7c were not isolable
in pure form at this stage, and therefore the mixtures were
directly deprotected. Toluoylated nucleosides 4c/4b were cleaved
using NaOMe/MeOH, while the silylated 7c/7b were depro-
tected making use of Et3N·3HF.23 The resulting mixture of 6b
and 6c was separable on column chromatography to give the
desired 5-methylthienyl C-nucleoside 6c in 39% or 33% overall
yield from 4a or 7a, respectively. Our further efforts focused
on introduction of an ethyl group. However, the Suzuki coupling
reaction of 4a with ethylboronic acid under analogous conditions
to methylation gave only the product of reduction, 4b (entry
8). The Negishi coupling of 7a with EtZnCl gave an unseparable
mixture of desired 7d and reduced 7b in excellent yield and a
ratio of 4:1 (entry 9). Deprotection followed by separation of
the mixture gave the target free nucleoside 6d in 53% overall
yield from 7a. Finally, benzylation was attempted by reaction
of 4a with BnZnCl giving only the product of reduction in low
yield. Ni-catalyzed coupling of 7a with BnMgCl gave a complex
unseparable mixture which was directly deprotected using
Et3N·3HF. Careful column chromatography of the resulting
mixture of free nucleosides furnished the desired pure ben-
zylthiophene nucleoside 6e in acceptable 32% overall yield from
7a. Apparently, the introduction of alkyl substituents by cross-
coupling reactions of 4a or 7a is not very practical due to the
side-reaction (reduction); however, it is still possible to use it
for the synthesis of these compounds.
a Reagents and conditions: (a) BF3 ·Et2O, DCM, -10 °C, 100 min, 4a
(22%) and 5a (22%); (b) AgBF4, DCM, -10 °C, 10 min, 4a (54%) and 5a
(14%); (c) AgOCOCF3, SnCl4, DCM, -20 °C, 10 min, 4a (60%) and 5a
(25%); (d) TFA, BSA, DCM, 42 °C, 22 h, 4a (25%).
SCHEME 2. Protecting Group Manipulationsa
a Reagents and conditions: (a) methanol, MeONa, rt, 24 h, 93%; (b)
TBDMSCl, imidazole, rt, 24 h, 94%.
Then our attention turned to the introduction of aryl and
hetaryl groups. Toluoyl-protected ꢀ-C-deoxribonucleoside 4a
was used as a starting compound for the Stille cross-coupling
reactions with aryl stannanes in the presence of PdCl2dppf in
DMF (entries 12-15). In all cases, the reactions proceeded
smoothly to give the target protected biaryl ꢀ-C-nucleosides
4f-4i in good yields. In the case of 4f and 4i, even after repeated
column chromatography, the products were still impured by
stannanes. Therefore, the crude products after chromatography
were treated with Me3Al in toluene to destroy the stannane
impurities and rechromatographed to give pure products in ca.
65% yields. Deprotection using MeONa in MeOH gave the free
ꢀ-biaryl-C-deoxyribonucleosides 6f-6i in good yields.
multigram amounts. Nevertheless, we have also tried epimer-
ization of the R-anomeric side product 5a using a mixture of
benzenesulfonic acid (BSA) and trifluoroacetic acid (TFA) in
dichloromethane at 40 °C for 22 h to give a mixture containing
only 25% of ꢀ-anomer 4a. Apparently, the epimerization of 5a
is not an efficient way for preparation of an additional amount
of intermediate 4a.
Subsequent deprotection of intermediate 4a under Zemplen
conditions (NaOMe/MeOH) gave free ꢀ-C-nucleoside 6a in 93%
yield which was further silylated with TBDMSCl to give
persilylated intermediate 7a in 94% yield (Scheme 2).
Having the optimized multigram-scale procedures for the
synthesis of the protected 5-bromothiophen-2-yl C-nucleosides
4a and 7a in hand, we have studied further functional group
transformations (Scheme 3, Table 1). At first, we tried to convert
bromothiophene nucleoside 4a to unsubstituted thiophene 4b.
Thus, catalytical hydrogenation of bromothiophene nucleoside
4a using H2 under Pd/C in a mixture of EtOH, THF, and H2O
gave the desired thiophene nucleoside 4b in 95% yield (Table
1). Deprotection under Zemplen conditions afforded the free
thiophene nucleoside 6b in 81% yield.
Hartwig-Buchwald aminations24 were performed to intro-
duce N-substituents to thiophene.25 These reactions were
successfully used for amination of halopyridine C-nucleosides.18–19
Lithium bis(trimethylsilyl)amide (LiN(SiMe3)2) was used as an
ammonia equivalent for introduction of the amino group, but
reaction gave only products of degradation. It is not surprising
since aminothiophenes are known to be very unstable in
unprotected form.26 Therefore, we focused on the introduction
of a dimethylamino group. The reaction of 7a with dimethyl-
amine proceeded only when Pd2dba3 catalyst was used in
combination with bdtbp as a ligand (entry 18) to give a complex
Then we focused on the introduction of alkyl substituents
which were in benzene and pyridine series easily introduced
by cross-couplings with trialkylaluminum or alkylzinc halide
reagents. Several cross-coupling reactions of either toluoyl- (4a)
or TBS-protected (7a) bromothiophene nucleosides with tri-
alkylaluminums, alkylzinc chlorides, or alkylmagnesium bro-
(22) (a) Wichai, U.; Woski, S. A. Bioorg. Med. Chem. Lett. 1998, 8, 3465–
3468. (b) Wichai, U.; Woski, S. A. Org. Lett. 1999, 1, 1173–1175.
ˇ
(23) Capek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2005, 70, 8001–8008.
(24) Reviews: (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125–146. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 3, 805–818.
3800 J. Org. Chem. Vol. 73, No. 10, 2008

Synthesis of Thiophen-2-yl C-2′-Deoxyribonucleosides
SCHEME 3. Cross-Couplings, Aminations, and Deprotections of 5-Bromothiophene C-Nucleosides 4a and 7a
TABLE 1. Reagents, Conditions, and Yields of Reactions
start
compd
coupling
product
deprot.
product
yield
(%)
entry
reagent
catalyst, ligand (base)
Pd/C, Et3N
Pd/C, Et3N
Pd(PPh3)4
solvent
conditions
yield (%)
1
2
H2
H2
4a
7a
4a
4a
4a
7a
4a
4a
7a
4a
4a
4a
4a
4a
4a
7a
7a
7a
THF/EtOH/H2O
THF/EtOH/H2O
THF
rt, 101 kPa
rt, 101 kPa
12 h/105 °C
24 h/70 °C
43 h/115 °C
24 h/115 °C
2 h/rt
24 h/115 °C
48 h/85 °C
71 h/60 °C
14 h/85 °C
29 h/115 °C
16 h/110 °C
22 h/120 °C
22 h/100 °C
48 h/rt
4b
7b
95
98
6b
6b
81
78
3
Me3Al
4c/4ba
4c/4ba
4c/4ba
7c/7ba
4d/4ba
4bc
48 (1:1)
80 (2:1)
60 (6:1)
73 (9:1)
73 (1:2)
76
4
MeZnCl
Pd2dba3, bdtbpb
Pd(PPh3)4, K2CO3
Pd(PPh3)4, K2CO3
Pd2dba3, bdtbp
Pd(PPh3)4, K2CO3
Pd2dba3, bdtbp
Pd(PPh3)4
THF
5
6
7
MeB(OH)2
MeB(OH)2
EtZnCl
toluene
toluene
THF
toluene
THF
THF
THF
DMF
DMF
6c
6c
74
50
8
9
EtB(OH)2
EtZnCl
7d/7ba
4b
93 (4:1)
27
6d
73
10
11
12
13
14
15
16
17
18
BnZnBr
BnMgCl
NiCl2(dppp)
nid
6e
6f
6g
6h
6i
32e
95
93
94
65
2-Bu3Sn-Pyf
2-Bu3Sn-Thh
2-Bu3Sn-Fui
6-Bu3Sn-biPyj
LiN(SiMe3)2
Me2NH·HCl
Me2NH/THF
PdCl2, dppfg
4f
4g
4h
4i
66
90
89
64
PdCl2, dppf
PdCl2, dppf
PdCl2, dppf
Pd2dba3, P(t-Bu)3HBF4
Pd(OAc)2, Josiphosk, t-BuONa
Pd2dba3, bdtbp, t-BuONa
DMF
DMF
degrad.
nr
DME
toluene
72 h/65 °C
7 h/70 °C
7k
49l
a Unseparable mixture. b bdtbp ) (2-biphenyl)di-tert-butylphosphine. c Reaction gave only the product of reduction. d Not isolated. e Overall yield
after two steps. f 2-Bu3Sn-Py ) 2-tributylstannylpyridine. g dppf ) 1,1′-bis(diphenylphosphino)ferrocene. h 2-Bu3Sn-Th ) 2-tributylstannylthiophene.
i 2-Bu3Sn-Fu ) 2-tributylstannylfurane. j 6-Bu3Sn-biPy ) 6-(tributylstannyl)[2,2′]bipyridine, prepared in situ from 6-bromo-2,2′-bipyridine. k Josiphos )
(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine. l Product quickly decomposed.
SCHEME 4. Suzuki-Miyaura Reactiona
mixture out of which the desired (dimethylamino)thiophene 7k
was isolated in 49% yield. However, compound 7k was very
unstable, and any attempts to deprotect it led to complex
mixtures of decomposition products only. Therefore, it can be
concluded that Pd-catalyzed aminations are not suitable for
introduction of N-constituents in thiophene C-nucleosides.
Recently, we became interested in applications of aqueous-
phase cross-coupling reactions for direct and efficient function-
alizations of unprotected nucleosides.27 Therefore, we have
tested this approach in thiophene C-nucleosides. The unprotected
ꢀ-C-nucleoside6awasusedfortheaqueous-phaseSuzuki-Miyaura
cross-coupling reactions with a variety of arylboronic acids in
the presence of Pd(OAc)2, TPPTS (P(Ph-SO3Na)3) ligand, and
Cs2CO3 as a base (Scheme 4, Table 2). The reactions were
performed in a mixture of acetonitrile/water (2:1) for 2-4 h at
90-120 °C to give biaryl ꢀ-C-nucleosides 6l-6p in very good
yields (Table 2). This approach is the most efficient to attach
a Reagents and conditions: (a) R-B(OH)2, Cs2CO3, Pd(OAc)2, TPPTS,
H2O/MeCN (2:1), 2-5 h, 90-120 °C.
TABLE 2. Suzuki-Miyaura Reaction
entry
reagent
conditions
product
yield (%)
1
2
3
4
5
PhB(OH)2
4-F-PhB(OH)2
3-ThB(OH)2
3-FuB(OH)2
3 h/90 °C
4 h/120 °C
4 h/120 °C
2 h/90 °C
2 h/90 °C
6l
72
80
70
78
74
6m
6n
6o
6p
a
b
(25) Pd-catalyzed aminations of thiophenes: (a) Watanabe, M.; Yamamoto,
T.; Nishiyama, M. Chem. Commun. 2000, 13, 3–134. (b) Hooper, M. W.;
Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68, 2861–2873. (c) Begouin,
A.; Hesse, S.; Queiroz, M.-J. R. P.; Kirsch, G Eur. J. Org. Chem. 2007, 1678–
1682.
3-NO2-PhB(OH)2
a 3-ThB(OH)2 ) 3-thienylboronic acid. b 3-FuB(OH)2 ) 3-furylboronic
acid.
(26) (a) Eck, D. L.; Stacy, G. W. J. Heterocycl. Chem. 1969, 6, 147–151.
(b) Tarasova, O. A.; Klyba, L. V.; Vvedensky, V. Y.; Nedolya, N. A.; Trofimov,
B. A.; Brandsma, L.; Verkruijsse, H. D Eur. J. Org. Chem. 1998, 253–256.
(27) (a) Western, E. C.; Daft, J. R.; Johnson, E. M., II; Garnnett, P. M.;
an aryl or hetaryl group whenever the corresponding boronic
acid is available.
All compounds were fully characterized, and the crystal
structures of 6l and 6n were also determined by X-ray diffraction
ˇ
Shoughnessy, K. H. J. Org. Chem. 2003, 68, 6767–6774. (b) Capek, P.; Pohl,
R.; Hocek, M. Org. Biomol. Chem. 2006, 4, 2278–2284. (c) Vra´bel, M.; Pohl,
R.; Klepeta´rˇova´, B.; Votruba, I.; Hocek, M. Org. Biomol. Chem. 2007, 5, 2849–
2857.
J. Org. Chem. Vol. 73, No. 10, 2008 3801

Ba´rta et al.
FIGURE 1. ORTEP drawings of crystal structures of 6l (a) and 6n (b) with the atom numbering scheme. Thermal ellipsoids are drawn at the 50%
probability level.
(Figure 1). Both these C-nucleosides in the solid state occur in
the expected C2′-endo conformation. No inter- or intramolecular
hydrogen bonds were observed to the S10 sulfur atom which
confirms our assumption that the thiophene C-nucleosides should
not form minor-groove H-bonds in the active site of DNA
polymerase.
F(ν˜) are described by a log-normal function29 (see Supporting
Information, Table S1 and equation 1).
Conclusions
A new modular methodology for the synthesis of diverse
5-substituted thiophen-2-yl C-2′-deoxyribonucleosides has been
developed based on the Friedel-Crafts-type C-glycosidation of
2-bromothiophene followed by functional group transformations
of the bromine. It can be easily reduced off to efficiently give
unsubstituted thiophene nucleosides (6b was prepared in 46%
overal yield compared to 15% by the literature procedure21).
Cross-coupling reactions of protected bromothiophene inter-
mediates with alkylzinc, -magnesium, -aluminum, and/or -bo-
ronic acids proceeds usually with simultaneous dehalogenation,
and the isolation of the desired alkylthiophene nucleosides is
very problematic at the protected stage. However, the separation
is achievable after deprotection, so still the method can be
relatively efficiently used for the preparation of alkylthiophene
C-nucleosides (e.g., 6c was prepared in 22% overal yield
comparedto16%bytheliteratureprocedure20).Hartwig-Buchwald
reactions were not suitable for amination of the intermediates
due to instability of the aminothiophenes. On the other hand,
arylations proceeded very smoothly both using the Stille
coupling of protected intermediates with arylstannanes in DMF
and using the Suzuki reaction of free nucleoside with arylboronic
acids. Most of the 5-aryl- and 5-hetarylthiophene C-nucleosides
exhibit fluorescence with emission maxima strongly depending
on the nature of the aryl groups. Since the aryl group is attached
in the last step(s) via arylstannanes or arylboronic acids
(hundereds of diverse reagents of these types are commercially
available), the arylation is practical for fine-tuning of the
fluorescent properties of the nucleosides. We plan to apply some
of these or related nucleosides for incorporation to DNA and/
or for fluorescent DNA labeling.
Absorption and fluorescence spectra of the final C-nucleosides
have been studied. Spectral changes when 1ꢀ-(2-thienyl)-2-
deoxyribose is substituted at the 5-position of the thiophene
moiety by different aryl groups have been observed (Figure 2,
Table 3 and Table S1 in Supporting Information). When 1ꢀ-
(2-thienyl)-2-deoxyribose is substituted at the 5-position of the
thiophene moiety by aryl groups, electronic coupling of the two
chromophores produces ππ* absorption bands which peak in
the range 280-310 nm. Figure 2a shows the spectra of phenyl
and fluorophenyl derivatives 6l (red) and 6m (blue). Figure 2b
collects the optical spectra when the second moiety is furan,
while the analogous dithiophenes are shown in Figure 2c. The
conjugated electron system is longer when the extending moiety
is connected at its 2-position, which is why 6h and 6g have
their absorption maxima at λ > 300 and fluorescence at 360
and 374 nm, respectively, while the corresponding 3-linked
analogues 6n and 6o are blue-shifted both in absorption and
fluorescence (blue curves in Figure 2b,c). Pyridine- and bipy-
ridine-extension 6f and 6i leads to the significantly red-shifted
spectra in Figure 2d. We did not observe fluorescence from the
5-(3-nitrophenyl)-thiophene derivative 6p and the bromo-, alkyl-,
and amino-substituted derivatives 6a-d and 6k.
In general, the substitution of the 5-position in thiophene
C-nucleosides by diverse aryl groups can be used for fine-tuning
of the absorption and fluorescent spectral maxima. Compounds
6f-6i having absorption maxima at >300 nm may be good
candidates for selective excitation within DNA at these wave-
lengths. Stokes shifts between absorption and fluorescence peaks
are normal (≈5500 cm-1), and mirror symmetry between the
S1 r S0 and S1 f S0 bands is observed. The only exception to
mirror symmetry is given by 6i, indicating close-lying bright
singlet states. In applications, the exact form of the fluorescence
spectrum may be required, for example, when energy transfer
rates are to be calculated from the overlap with the acceptor
absorption spectrum.28 For this purpose the fluorescence spectra
Experimental
1ꢀ-(5-Bromothiophen-2-yl)-1,2-dideoxy-3,5-di-O-toluoyl-D-ribo-
furanose (4a) and 1r-(5-Bromothiophen-2-yl)-1,2-dideoxy-3,5-
di-O-toluoyl-D-ribofuranose (5a). To a dried flask containing a
(29) Lakowicz, J. R. Principles of Fluorescence Spectroscopy; Springer:
Berlin, 2006; Chapter 13.
(28) Siano, D. B.; Metzler, D. E. J. Chem. Phys. 1969, 51, 1856–1861.
3802 J. Org. Chem. Vol. 73, No. 10, 2008

Synthesis of Thiophen-2-yl C-2′-Deoxyribonucleosides
NaHCO3 (3 × 50 mL) and saturated NaCl (1 × 100 mL). Then
the collected organic layers were dried over MgSO4, and solvents
were evaporated under a vacuum. Products were isolated by flash
chromatography on silica gel in gradient hexane to hexane/EtOAc
(19.5/0.5) to give the desired product 4a (3.21 g, 60%) followed
by R-anomer 5a (1.34 g, 25%). Compound 4a was crystallized from
isopropanol/heptane to obtain white crystals (mp: 71-72 °C). MS
(FAB) m/z 515 (M + H). HRMS (FAB) for C25H24BrO5S [M +
H] calculated 515.0528, found 515.0516. 1H NMR (600 MHz,
CDCl3): 2.34 (ddd, 1H, Jgem ) 13.8, J2′b,1′ ) 10.7, J2′b,3′ ) 6.0,
H-2′b); 2.41 and 2.42 (2 × s, 2 × 3H, CH3-Tol); 2.56 (ddd, 1H,
Jgem ) 13.8, J2′a,1′ ) 5.1, J2′a,3′ ) 1.2, H-2′a); 4.49 (td, 1H, J4′,5′
)
4.0, J4′,3′ ) 2.0, H-4′); 4.59 (d, 2H, J5′,4′ ) 4.0, H-5′); 5.40 (ddt,
1H, J1′,2′ ) 10.7, 5.1, J1′,3 ) 0.8, J1′,3′ ) 0.5, H-1′); 5.59 (dddd,
1H, J3′,2′ ) 6.0, 1.2, J3′,4′ ) 2.0, J3′,1′ ) 0.5, H-3′); 6.79 (dd, 1H,
J3,4 ) 3.7, J3,1′ ) 0.8, H-3); 6.89 (d, 1H, J4,3 ) 3.7, H-4); 7.24 and
7.26 (2 × m, 2 × 2H, H-m-Tol); 7.95 (m, 4H, H-o-Tol). 13C NMR
(151 MHz, CDCl3): 21.64 and 21.67 (CH3-Tol); 41.6 (CH2-2′); 64.4
(CH2-5′); 76.8 (CH-3′); 76.9 (CH-1′); 83.0 (CH-4′); 112.1 (C-5);
125.0 (CH-3); 126.7 and 126.95 (C-i-Tol); 129.1 and 129.2 (CH-
m-Tol); 129.3 (CH-4); 129.67 and 129.69 (CH-o-Tol); 143.8 and
144.2 (C-p-Tol); 145.5 (C-2); 165.95 and 166.25 (CO). IR spectrum
(CCl4): 3095, 3065, 1726, 1631, 1448, 1377, 1310, 1298, 1268,
1248, 1209, 1178, 1119, 1102 cm-1. R20 +4.2 (c 2.64, CHCl3).
D
Anal. Calcd C25H23BrO5S (515.4): C, 58.26; H, 4.50. Found: C,
58.02; H, 4.47. Compound 5a: colorless oil. MS (FAB) m/z 515
(M + H). HRMS (FAB) for C25H24BrO5S: [M + H] calculated
515.0528, found 515.0523. 1H NMR (500 MHz, CDCl3): 2.40 (ddd,
1H, Jgem ) 14.0, J2′b,1′ ) 4.6, J2′b,3′ ) 3.0, H-2′b); 2.41 (s, 6H,
CH3-Tol); 2.91 (ddd, 1H, Jgem ) 14.0, J2′a,1′ ) 7.7, J2′a,3′ ) 6.8,
H-2′a); 4.52 (dd, 2H, Jgem ) 11.8, J5′b,4′ ) 4.7, H-5′b); 4.55 (dd,
2H, Jgem ) 11.8, J5′a,4′ ) 4.4, H-5′a); 4.64 (ddd, 1H, J4′,5′ ) 4.7,
4.4, J4′,3′ ) 2.7, H-4′); 5.40 (ddd, 1H, J1′,2′ ) 7.7, 4.6, J1′,3 ) 1.0,
H-1′); 5.58 (ddd, 1H, J3′,2′ ) 6.8, 3.0, J3′,4′ ) 2.7, H-3′); 6.74 (dd,
1H, J3,4 ) 3.7, J3,1′ ) 1.0, H-3); 6.91 (d, 1H, J4,3 ) 3.7, H-4); 7.22
and 7.24 (2 × m, 2 × 2H, H-m-Tol); 7.76 and 7.94 (2 × m, 2 ×
2H, H-o-Tol). 13C NMR (125.7 MHz, CDCl3): 21.7 (CH3-Tol); 40.3
(CH2-2′); 64.3 (CH2-5′); 76.0 (CH-3′); 76.8 (CH-1′); 82.2 (CH-
4′); 111.6 (C-5); 124.3 (CH-3); 126.7 and 126.95 (C-i-Tol); 129.1
and 129.15 (CH-m-Tol); 129.5 (CH-4); 129.7 (CH-o-Tol); 143.9
and 144.1 (C-p-Tol); 148.1 (C-2); 166.1 and 166.25 (CO).
1ꢀ-(5-Bromothiophen-2-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (7a). Imidazole (1.73 g, 25.4 mmol)
was added to a solution of 6a (1.77 g, 6.34 mmol) in dry DMF (30
mL). The mixture was stirred for 5 min, and then TBDMSCl (2.39
g, 15.9 mmol) was added in one portion. The resulting solution
was stirred for 15 h at rt. Then, the solvent was evaporated, and
the residue was chromatographed on a silica gel column in gradient
hexane to hexane/EtOAc (19.5/0.5) to give product 7a (3 g, 94%)
as a colorless oil. MS (FAB) m/z 507 (M + H). HRMS (FAB) for
C21H40BrO3SSi2: [M + H] calculated 507.1420, found 507.1415.
1H NMR (500 MHz, CDCl3): 0.08 and 0.09 (2 × s, 2 × 6H, CH3Si);
FIGURE 2. Optical spectra of substituted thiophene nucleosides in
acetonitrile. Solid lines: absorption. Dashed lines: fluorescence. Peak
wavelengths are given as insets.
TABLE 3. Absorption and Fluorescence Band Positions in
Acetonitrile
compound
absorption/nm
fluorescence/nm
6f
307
308
303
304
290
288
291
367
374
360
396
347
346
345
339
-
6g
6h
6i
0.908 and 0.909 (2 × s, 2 × 9H, (CH3)3C); 1.98 (ddd, 1H, Jgem
)
6l
12.7, J2′b,1′ ) 10.3, J2′b,3′ ) 5.2, H-2′b); 2.14 (ddd, 1H, Jgem ) 12.7,
6m
6n
6o
6p
J2′a,1′ ) 5.3, J2′a,3′ ) 1.6, H-2′a); 3.52 (dd, 1H, Jgem ) 10.8, J5′b,4′
)
6.4, H-5′b); 3.71 (dd, 1H, Jgem ) 10.8, J5′a,4′ ) 4.0, H-5′a); 3.92
(ddd, 1H, J4′,5′ ) 6.4, 4.0, J4′,3′ ) 1.8, H-4′); 4.42 (dddd, 1H, J3′,2′
279
277/295sha
) 5.2, 1.6, J3′,4′ ) 1.8, J3′,1′ ) 0.6, H-3′); 5.28 (dddd, 1H, J1′,2′
)
a sh ) shoulder.
10.3, 5.3, J1′,3 ) 0.8, J1′,3′ ) 0.6, H-1′); 6.73 (dd, 1H, J3,4 ) 3.8,
J3,1′ ) 0.8, H-3); 6.88 (d, 1H, J4,3 ) 3.8, H-4). 13C NMR (125.7
MHz, CDCl3): -5.5, -5.4, and -4.7 (CH3Si); 18.0 and 18.4
(C(CH3)3); 25.8 and 25.95 ((CH3)3C); 44.15 (CH2-2′); 63.8 (CH2-
5′); 74.3 (CH-3′); 76.2 (CH-1′); 88.2 (CH-4′); 111.4 (C-5); 124.45
(CH-3); 129.2 (CH-4); 147.7 (C-2). IR spectrum (CCl4): 2897, 1471,
1463, 1448, 1407, 1389, 1362, 1257, 1204, 1092, 1054, 971, 939
solution of the methyl glycoside 2 (4 g, 10.4 mmol) and 2-bro-
mothiophene 3 (3.02 mL, 31.2 mmol) in dry dichloromethane (64
mL) at -20 °C under argon was added AgOCOCF3 (3.45 g, 15.6
mmol) in one portion. After 5 min stirring, SnCl4 (730 µL,
6.24 mmol) was added by syringe, and the mixture was stirred at
-20 °C for 10 min. After quenching of the reaction by saturated
Na2CO3(250 mL), 2% aqueous NH3 solution (100 mL) was added
(for better solubility of Ag and Sn complexes). The mixture was
extracted with EtOAc (3 × 70 mL) and washed with saturated
cm-1. R20 +2.8 (c 4.49, CHCl3).
D
1ꢀ-(5-Methylthiophen-2-yl)-1,2-dideoxy-3,5-di-O-toluoyl-D-ri-
bofuranose (4c). Dry toluene (15 mL) was added to an argon-
purged flask containing 4a (500 mg, 0.97 mmol), K2CO3 (200 mg,
J. Org. Chem. Vol. 73, No. 10, 2008 3803

Ba´rta et al.
1.44 mmol), methylboronic acid (116 mg, 1.94 mmol), and
Pd(PPh3)4 (54 mg, 0.05 mmol), and the mixture was stirred under
Ar at 115 °C for 43 h. Afterwords, the mixture was cooled to rt
and filtered through cellite. Evaporation of the solvent, followed
by column chromatography on silica gel in gradient hexane to
hexane/toluene (9.7/0.3), afforded the mixture of products 4c/4b
(6:1) (260 mg, 60%) as a colorless oil. For characterization data,
see the Supporting Information.
1ꢀ-(5-Ethylthiophen-2-yl)-1,2-dideoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-D-ribofuranose (7d). A solution of ZnCl2 (5.7 mL,
0.5 M in THF, 2.84 mmol) was added dropwise to a stirred solution
of EtMgBr (2.4 mL, 1 M in THF, 2.36 mmol) in THF (3 mL)
during 5 min at 0 °C under Ar, and the stirring was continued for
25 min at 0 °C. This solution was transferred into a solution of 7a
(400 mg, 0.79 mmol), Pd2dba3 (36 mg, 0.04 mmol), and bdtbp (24
mg, 0.08 mmol) in THF (5 mL), and the resulting reaction mixture
was stirred at rt for 10 min and then at 85 °C for 23 h. The mixture
was cooled to rt, poured into saturated NH4Cl solution (20 mL),
and filtered through cellite, and the products were extracted with
EtOAc (3 × 20 mL). Evaporation of the organic phase followed
by column chromatography on silica gel in gradient hexane to
hexane/EtOAc (9.7/0.3) afforded the mixture of products 7d/7b
(4:1) (330 mg, 93%) as a colorless oil. For characterization data,
see the Supporting Information.
1ꢀ-(5-Benzylthiophen-2-yl)-1,2-dideoxy-D-ribofuranose (6e).
A solution of BnMgCl (780 µL, 2 M in THF, 1.55 mmol) was
added dropwise to a stirred solution of 4a (400 mg, 0.78 mmol)
and NiCl2(dppp) (42 mg, 0.08 mmol) in THF (4 mL) during 40
min at -20 °C under Ar. The stirring was continued for 10 min to
reach rt, and then the mixture was stirred at 85 °C for 14 h. The
mixture was cooled to rt and then filtered through cellite, extracted
to EtOAc (20 mL), and evaporated. The crude mixture was treated
with NaOMe (1 M solution) in MeOH at rt for 24 h, and the residue
after evaporation of the solvent was flash-chromatographed on silica
gel in gradient EtOAc to EtOAc/MeOH (8/2) to give 6e (72 mg,
32% after two steps) followed by 6b (26 mg, 17%) and 6a (36
mg, 17%) as yellow oils. For characterization data, see the
Supporting Information.
General Procedure for the Stille Cross-Coupling Reaction.
2-(Tributylstannyl)hetaryl (1.2-5 equiv) was added dropwise under
argon to a stirred solution of 4a (1 equiv) and PdCl2dppf (5 mol
%) in DMF (5.0 mL). The mixture was stirred at 100-120 °C for
16-22 h. The crude reaction mixture was diluted with EtOAc (15
mL), filtered through cellite, and washed with 2 M HCl and brine.
The water layers were extracted with EtOAc (3 × 20 mL). Then,
the collected organic layers were dried over MgSO4, and solvents
were evaporated under a vacuum. The crude product was chro-
matographed on silica gel in gradient hexane to hexane/EtOAc (9.7/
0.3).
1H, J3,4 ) 3.7, J3,1′ ) 0.7, H-3); 7.13 (ddd, 1H, J5,4 ) 7.4, J5,6 )
4.9, J5,3 ) 1.2, H-5-py); 7.22 and 7.27 (2 × m, 2 × 2H, H-m-Tol);
7.44 (d, 1H, J4,3 ) 3.7, H-4); 7.57 (ddd, 1H, J3,4 ) 8.0, J3,5 ) 1.2,
J3,6 ) 1.0, H-3-py); 7.66 (ddd, 1H, J4,3 ) 8.0, J4,5 ) 7.4, J4,6
)
1.8, H-4-py); 7.97 (m, 4H, H-o-Tol); 8.55 (ddd, 1H, J6,5 ) 4.9, J6,4
) 1.8, J6,3 ) 1.0, H-6-py). 13C NMR (125.7 MHz, CDCl3): 21.6
and 21.7 (CH3-Tol); 41.6 (CH2-2′); 64.6 (CH2-5′); 77.0 (CH-1′);
77.0 (CH-3′); 83.0 (CH-4′); 118.6 (CH-3-py); 121.9 (CH-5-py);
124.2 (CH-4); 125.7 (CH-3); 127.0 and 127.2 (C-i-Tol); 129.1 and
129.2 (CH-m-Tol); 129.75 and 129.8 (CH-o-Tol); 136.5 (CH-4-
py); 143.7 and 144.1 (C-p-Tol); 144.3 (C-5); 146.1 (C-2); 149.5
(CH-6-py); 152.5 (C-2-py); 166.0 and 166.4 (CO). IR spectrum
(KBr): 1716, 1612, 1584, 1565, 1550, 1487, 1454, 1432, 1375,
1271, 1209, 1153, 1105, 1040, 993, 776, 618 cm-1. R20D -60.8 (c
3.13, CHCl3).
General Procedure for the Suzuki Cross-Coupling. To an
argon-purged flask containing TTPTS (36 mg, 0.06 mmol) and
Pd(OAc)2 (5.6 mg, 0.025 mmol), a mixture of H2O/acetonitrile (2:
1) (2.5 mL) was added, and the mixture was sonicated for 2 min.
This solution was added into a mixture of 6a (140 mg, 0.5 mmol),
boronic acid (0.75 mmol), and Cs2CO3 (489 mg, 1.5 mmol) in H2O/
acetonitrile (2:1) (2 mL). The mixture was then stirred at 90 or
120 °C for 2-4 h. After evaporation, the crude product was purified
by flash chromatography on silica gel in gradient CHCl3 to CHCl3/
MeOH (9.5/0.5).
1ꢀ-(5-Phenylthiophen-2-yl)-1,2-dideoxy-D-ribofuranose (6l).
6l was prepared from 6a and phenylboronic acid (92 mg, 0.75
mmol) by the general procedure (90 °C, 3 h). 6l (100 mg, 72%)
was obtained as a colorless oil and crystallized from isopropanol/
heptane to give colorless crystals (mp 145-147 °C). MS (FAB)
m/z 277 (M + H). HRMS (FAB) for C15H17O3S: [M + H]
calculated 277.0898, found 277.0885. 1H NMR (500 MHz, DMSO-
d6): 1.96 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 10.1, J2′b,3′ ) 5.6, H-2′b);
2.14 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 5.5, J2′a,3′ ) 1.8, H-2′a); 3.38
(dt, 1H, Jgem ) 11.3, J5′b,4′ ) 6.0, J5′b,OH ) 5.9, H-5′b); 3.46 (dt,
1H, Jgem ) 11.3, J5′a,OH ) 5.3, J5′a,4′ ) 5.1, H-5′a); 3.77 (ddd, 1H,
J4′,5′ ) 6.0, 5.1, J4′,3′ ) 2.3, H-4′); 4.21 (m, 1H, J3′,2′ ) 5.6, 1.8,
J3′,OH ) 3.9, J3′,4′ ) 2.3, J3′,1′ ) 0.5, H-3′); 4.77 (t, 1H, JOH,5′
)
5.9, 5.3, OH-5′); 5.12 (d, 1H, JOH,3′ ) 3.9, OH-3′); 5.23 (ddt, 1H,
J1′,2′ ) 10.1, 5.5, J1′,3 ) 0.8, J1′,3′ ) 0.5, H-1′); 7.04 (dd, 1H, J3,4
3.6, J3,1′ ) 0.8, H-3); 7.29 (m, 1H, H-p-Ph); 7.34 (d, 1H, J4,3
)
)
3.6, H-4); 7.40 (m, 2H, H-m-Ph); 7.61 (m, 2H, H-o-Ph). 13C NMR
(125.7 MHz, DMSO-d6): 43.6 (CH2-2′); 62.7 (CH2-5′); 72.5 (CH-
3′); 75.4 (CH-1′); 88.0 (CH-4′); 123.2 (CH-4); 125.4 (CH-o-Ph);
125.9 (CH-3); 127.7 (CH-p-Ph); 129.3 (CH-m-Ph); 134.1 (C-i-Ph);
142.5 (C-5); 146.0 (C-2). IR spectrum (CHCl3): 3612, 3336, 3066,
1599, 1549, 1469, 1311, 1091, 1038, 957 cm-1. R20D +4.2 (c 2.36,
CHCl3). Anal. Calcd C15H16O3S (276.4): C, 65.19; H, 5.84. Found:
C, 64.82; H, 5.88.
General Procedure for the Zemplen Deprotection. A 1 M
NaOMe solution in MeOH (0.2.mL, 0.2 mmol) was added to a
solution of toluoyl-protected C-nucleosides 4a-4c and 4f-4i (0.1
mmol) in MeOH (100 mL), and the resulting solution was stirred
overnight at room temperature. Then the solvent was evaporated,
and products were isolated by flash chromatography on silica gel
in gradient chloroform to chloroform/methanol (19.5/0.5). Some
compounds (6c, 6f, 6i) were repurified by flash chromatography
on a reverse-phase C18 column (with linear gradient of H2O to
MeOH).
1ꢀ-[5-(Pyridin-2-yl)thiophen-2-yl]-1,2-dideoxy-3,5-di-O-tolu-
oyl-D-ribofuranose (4f). 4f was prepared from 4a (500 mg, 0.97
mmol) and 2-(tributylstannyl)pyridine (235 µL, 0.85 mmol), by the
general procedure (115 °C, 29 h). The crude product after
chromatography was further stirred with Me3Al (470 µL, 2 M in
toluene, 0.93 mmol) in toluene (13 mL) at rt for 24 h. The reaction
mixture was quenched by saturated Na2CO3 (30 mL), washed with
saturated NaHCO3 (1 × 50 mL), and extracted with EtOAc (3 ×
30 mL). Then, the collected organic layers were dried over MgSO4,
and solvents were evaporated under vacuum. Flash chromatography
on silica gel eluting hexane to hexane/EtOAc (19.8/0.2) gave pure
product 4f (261 mg, 66%) as a colorless oil. MS (FAB) m/z 514
(M + H). HRMS (FAB) for C30H28NO5S: [M + H] calculated
514.1688, found 514.1666. 1H NMR (500 MHz, CDCl3): 2.39 and
2.43 (2 × s, 2 × 3H, CH3-Tol); 2.45 (ddd, 1H, Jgem ) 13.8, J2′b,1′
1ꢀ-(5-Bromothiophen-2-yl)-1,2-dideoxy-D-ribofuranose (6a).
Compound 6a was prepared from 4a (3.52 g, 6.83 mmol) by the
general procedure. 6a (1.77 g, 93%) was obtained as a yellow oil.
Crystallization from isopropanol/heptane gave yellow crystals (mp
74-75 °C). MS (FAB) m/z 278 (M + H). HRMS (FAB) for
1
) 10.5, J2′b,3′ ) 6.0, H-2′b); 2.61 (ddd, 1H, Jgem ) 13.8, J2′a,1′
)
C9H12BrO3S: [M + H] calculated 278.9691, found 278.9684. H
5.2, J2′a,3′ ) 1.3, H-2′a); 4.53 (td, 1H, J4′,5′ ) 4.4, J4′,3′ ) 2.0, H-4′);
4.58 and 4.62 (2 × dd, 2H, Jgem ) 11.7, J5′,4′ ) 4.4, H-5′); 5.49
(dddd, 1H, J1′,2′ ) 10.5, 5.2, J1′,3 ) 0.7, J1′,3′ ) 0.5, H-1′); 5.63
(dddd, 1H, J3′,2′ ) 6.0, 1.3, J3′,4′ ) 2.0, J3′,1′ ) 0.5, H-3′); 7.05 (dd,
NMR (500 MHz, DMSO-d6): 1.88 (ddd, 1H, Jgem ) 12.8, J2′b,1′ )
10.1, J2′b,3′ ) 5.6, H-2′b); 2.11 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 5.6,
J2′a,3′ ) 1.8, H-2′a); 3.34 (bddd, 1H, Jgem ) 11.1, J5′b,4′ ) 6.0, J5′b,OH
) 5.4, H-5′b); 3.42 (bddd, 1H, Jgem ) 11.1, J5′a,OH ) 5.4, J5′a,4′
)
3804 J. Org. Chem. Vol. 73, No. 10, 2008

Synthesis of Thiophen-2-yl C-2′-Deoxyribonucleosides
4.9, H-5′a); 3.74 (ddd, 1H, J4′,5′ ) 6.0, 4.9, J4′,3′ ) 2.2, H-4′); 4.18
(bm, 1H, H-3′); 4.75 (bt, 1H, JOH,5′ ) 5.4, OH-5′); 5.11 (bd, 1H,
JOH,3′ ) 2.8, OH-3′); 5.19 (dddd, 1H, J1′,2′ ) 10.1, 5.6, J1′,3 ) 0.8,
J1′,3′ ) 0.6, H-1′); 6.88 (dd, 1H, J3,4 ) 3.7, J3,1′ ) 0.8, H-3); 7.05
(d, 1H, J4,3 ) 3.7, H-4).13C NMR (125.7 MHz, DMSO-d6): 43.6
(CH2-2′); 62.6 (CH2-5′); 72.5 (CH-3′); 75.5 (CH-1′); 88.0 (CH-
4′); 110.3 (C-5); 125.2 (CH-3); 129.95 (CH-4); 148.7 (C-2). IR
spectrum (KBr): 3402, 3292, 1632, 1103, 1054, 1444, 1366, 1203,
(CH2-5′); 72.6 (CH-3′); 75.55 (CH-1′); 88.0 (CH-4′); 118.55 (CH-
3-py); 122.4 (CH-5-py); 124.8 (CH-4); 125.6 (CH-3); 137.3 (CH-
4-py); 143.4 (C-5); 148.8 (C-2); 149.5 (CH-6-py); 152.1 (C-2-py).
IR spectrum (KBr): 3409, 2904, 1699, 1632, 1584, 1550, 1486,
1429, 1058, 1029, 995, 970 cm-1. R20D +4.4 (c 2.70, CHCl3). Anal.
Calcd C14H15NO3S (277.3): C, 60.63; H, 5.45; N, 5.05; S, 11.56.
Found: C, 60.25; H, 5.34; N, 4.71.
1ꢀ-(5-(Thiophen-2-yl)thiophen-2-yl)-1,2-dideoxy-D-ribofura-
nose (6g). Compound 6g was prepared from 4g (681 mg, 1.31
mmol) by the general procedure. 6g (345 mg, 93%) was obtained
as a colorless oil which was crystallized from isopropanol/heptane
to give colorless crystals (mp 84-85 °C). MS (FAB) m/z 283 (M
+ H). HRMS (FAB) for C13H15O3S2: [M + H] calculated 283.0463,
968, 1071 cm-1. R20 +21.9 (c 1.81, MeOH). Anal. Calcd
D
C9H11BrO3S (279.2): C, 38.72; H, 3.97; Br, 28.62. Found: C, 38.51;
H, 3.99; Br, 28.85.
1ꢀ-(5-Thiophen-2-yl)-1,2-dideoxy-D-ribofuranose (6b). Com-
pound 6b was prepared from 4b (385 mg, 0.88 mmol) by the
general procedure. 6b (143 mg, 81%) was obtained as a yellow
oil. Crystallization from isopropanol/heptane gave colorless crystals
(mp 74-75 °C). MS (FAB) m/z 223 (M + Na). HRMS (FAB) for
C9H13O3S: [M + H] calculated 201.0585, found 201.0582. 1H NMR
(500 MHz, DMSO-d6): 1.92 (ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 10.1,
J2′b,3′ ) 5.6, H-2′b); 2.11 (ddd, 1H, Jgem ) 12.8, J2′a,1′ ) 5.4, J2′a,3′
) 1.7, H-2′a); 3.34 and 3.42 (2 × bm, 2H, H-5′); 3.74 (ddd, 1H,
J4′,5′ ) 6.3, 5.2, J4′,3′ ) 2.3, H-4′); 4.19 (bddd, 1H, J3′,2′ ) 5.6, 1.7,
J3′,4′ ) 2.3, H-3′); 4.78 (bs, 1H, OH-5′); 5.13 (bs, 1H, OH-3′); 5.23
(ddt, 1H, J1′,2′ ) 10.1, 5.4, J1′,3 ) J1′,3′ ) 0.7, H-1′); 6.96 (dd, 1H,
J4,5 ) 5.0, J4,3 ) 3.5, H-4); 7.03 (ddd, 1H, J3,4 ) 3.5, J3,5 ) 1.3,
J3,1′ ) 0.7, H-3); 7.42 (dd, 1H, J5,4 ) 5.0, J5,3 ) 1.3, H-5). 13C
NMR (125.7 MHz, DMSO-d6): 43.8 (CH2-2′); 62.7 (CH2-5′); 72.5
(CH-3′); 75.3 (CH-1′); 88.0 (CH-4′); 124.65 (CH-3); 125.2 (CH-
5); 126.8 (CH-4); 146.2 (C-2). IR spectrum (KBr): 1540, 1442,
1
found 283.0454. H NMR (500 MHz, DMSO-d6): 1.93 (ddd, 1H,
Jgem ) 12.8, J2′b,1′ ) 10.2, J2′b,3′ ) 5.6, H-2′b); 2.13 (ddd, 1H, Jgem
) 12.8, J2′a,1′ ) 5.6, J2′a,3′ ) 1.8, H-2′a); 3.36 (ddd, 2H, Jgem
)
11.3, J5′b,4′ ) 6.1, J5′b,OH ) 6.0, H-5′b); 3.44 (ddd, 2H, Jgem ) 11.3,
J5′a,OH ) 5.1, J5′a,4′ ) 5.0, H-5′a); 3.76 (ddd, 1H, J4′,5′ ) 6.1, 5.0,
J4′,3′ ) 2.2, H-4′); 4.20 (m, 1H, J3′,2′ ) 5.6, 1.8, J3′,OH ) 3.9, J3′,4′
) 2.2, J3′,1′ ) 0.5, H-3′); 4.76 (dd, 1H, JOH,5′ ) 6.0, 5.1, OH-5′);
5.11 (d, 1H, JOH,3′ ) 3.9, OH-3′); 5.22 (dddd, 1H, J1′,2′ ) 10.2,
5.6, J1′,3 ) 0.8, J1′,3′ ) 0.5, H-1′); 6.99 (dd, 1H, J3,4 ) 3.6, J3,1′
)
0.9, H-3); 7.07 (dd, 1H, J4,5 ) 5.1, J4,3 ) 3.6, H-4-thienyl); 7.12
(d, 1H, J4,3 ) 3.6, H-4); 7.25 (dd, 1H, J3,4 ) 3.6, J3,5 ) 1.2, H-3-
thienyl); 7.48 (dd, 1H, J5,4 ) 5.1, J5,3 ) 1.2, H-5-thienyl). 13C NMR
(125.7 MHz, DMSO-d6): 43.65 (CH2-2′); 62.61 (CH2-5′); 72.5 (CH-
3′); 75.4 (CH-1′); 88.0 (CH-4′); 123.45 (CH-4); 123.9 (CH-3-
thienyl); 125.4 (CH-5-thienyl); 125.6 (CH-3); 128.5 (CH-4-thienyl);
135.7 (C-5); 136.85 (C-2-thienyl); 145.6 (C-2). IR spectrum (KBr):
1242, 1080, 1053, 1066, 1034, 966, 1322, 1424, 1632 cm-1. R20
D
1092, 1049, 1028, 1472, 1351, 1208, 970, 1427, 1081 cm-1. R20
+18.1 (c 2.16, MeOH). Anal. Calcd C9H12O3S (200.3): C, 53.98;
H, 6.04. Found: C, 53.92; H, 6.01.
D
+11.7 (c 2.77, MeOH). Anal. Calcd C13H14O3S2 (282.4): C, 55.29;
H, 5.00. Found: C, 54.91; H, 4.97.
1ꢀ-(5-Methylthiophen-2-yl)-1,2-dideoxy-D-ribofuranose (6c).
Compound 6c was prepared from a mixture of 4c/4b (254 mg, 0.57
mmol) by the general procedure. Chromatography gave 6c (89 mg,
74%) and 6b (10 mg, 9%) as yellow oils. Product 6c did not
crystallize. Lyophilization gave a yellow amorphous solid (mp
39-41 °C). MS (FAB) m/z 215 (M + H). HRMS (FAB) for
1ꢀ-[5-(Furan-2-yl)thiophen-2-yl]-1,2-dideoxy-D-ribofura-
nose (6h). Compound 6h was prepared from 4h (164 mg, 0.33
mmol) by the general procedure. 6h (82 mg, 94%) was obtained
as a yellow oil which was crystallized from isopropanol/heptane
to give yellow crystals (mp 105-107 °C). MS (FAB) m/z 267 (M
+ H). HRMS (FAB) for C13H15O4S: [M + H] calculated 267.0691,
found 267.0696. 1H NMR (500 MHz, CD3OD): 2.12 (ddd, 1H, Jgem
1
C10H15O3S: [M + H] calculated 215.0742, found 215.0750. H
NMR (500 MHz, CD3OD): 2.09 (ddd, 1H, Jgem ) 13.2, J2′b,1′
)
10.2, J2′b,3′ ) 5.7, H-2′b); 2.18 (ddd, 1H, Jgem ) 13.2, J2′a,1′ ) 5.5,
) 13.1, J2′b,1′ ) 10.0, J2′b,3′ ) 5.8, H-2′b); 2.25 (ddd, 1H, Jgem
)
J2′a,3′ ) 1.9, H-2′a); 2.43 (d, 3H, 4J ) 1.2, CH3); 3.56 (dd, 1H, Jgem
13.1, J2′a,1′ ) 5.6, J2′a,3′ ) 2.0, H-2′a); 3.60 (dd, 1H, Jgem ) 11.7,
J5′b,4′ ) 5.5, H-5′b); 3.64 (dd, 1H, Jgem ) 11.7, J5′a,4′ ) 5.3, H-5′a);
3.60 (ddd, 1H, J4′,5′ ) 5.5, 5.3, J4′,3′ ) 2.5, H-4′); 4.34 (dddd, 1H,
J3′,2′ ) 5.8, 2.0, J3′,4′ ) 2.5, J3′,1′ ) 0.6, H-3′); 5.34 (dddd, 1H, J1′,2′
) 10.0, 5.6, J1′,3 ) 0.8, J1′,3′ ) 0.6, H-1′); 6.47 (dd, 1H, J4,3 ) 3.4,
J4,5 ) 1.9, H-4-furyl); 6.53 (dd, 1H, J3,4 ) 3.4, J3,5 ) 0.8, H-3-
furyl); 6.97 (dd, 1H, J3,4 ) 3.7, J3,1′ ) 0.8, H-3); 7.11 (d, 1H, J4,3
) 3.7, H-4); 7.47 (dd, 1H, J5,4 ) 1.9, J5,3 ) 0.8, H-5-furyl). 13C
NMR (125.7 MHz, CD3OD): 44.8 (CH2-2′); 64.1 (CH2-5′); 74.3
(CH-3′); 77.4 (CH-1′); 89.2 (CH-4′); 105.9 (CH-3-furyl); 112.7
(CH-4-furyl); 123.0 (CH-4); 126.3 (CH-3); 134.4 (C-5); 143.0 (CH-
5-furyl); 145.7 (C-2); 150.8 (C-2-furyl). IR spectrum (KBr): 3148,
) 11.6, J5′b,4′ ) 5.6, H-5′b); 3.61 (dd, 1H, Jgem ) 11.6, J5′a,4′
)
5.3, H-5′a); 3.88 (ddd, 1H, J4′,5′ ) 5.6, 5.3, J4′,3′ ) 2.4, H-4′); 4.30
(dddd, 1H, J3′,2′ ) 5.7, 1.9, J3′,4′ ) 2.4, J3′,1′ ) 0.6, H-3′); 5.26 (dd,
4
1H, J1′,2′ ) 10.2, 5.5, H-1′); 6.60 (dq, 1H, J4,3 ) 3.4, J ) 1.2,
5
H-4); 6.81 (dq, 1H, J3,4 ) 3.4, J ) 0.4, H-3). 13C NMR (125.7
MHz, CD3OD): 15.25 (CH3); 44.6 (CH2-2′); 64.1 (CH2-5′); 74.3
(CH-3′); 77.55 (CH-1′); 89.0 (CH-4′); 125.6 (CH-4); 125.9 (CH-
3); 140.7 (C-5); 143.9 (C-2). IR spectrum (KBr): 1216, 1374, 1491,
1559, 3069, 3401 cm-1. R20D +20.4 (c 2.20, MeOH). Anal. Calcd
C10H14O3S (214.3): C, 56.05; H, 6.59. Found: C, 55.68; H, 6.52.
1ꢀ-[5-(Pyridin-2-yl)thiophen-2-yl]-1,2-dideoxy-D-ribofura-
nose (6f). Compound 6f was prepared from 4f (402 mg, 0.78 mmol)
by the general procedure. 6f (206 mg, 95%) was obtained as a
colorless oil which was crystallized from isopropanol/heptane to
give colorless crystals (mp 106-108 °C). MS (FAB) m/z 278 (M
+ H). HRMS (FAB) for C14H16NO3S: [M + H] calculated
3073, 2909, 1632, 1539, 1504, 1447, 1092, 1051, 1030, 969 cm-1
.
R20 +10.0 (c 1.81, MeOH). Anal. Calcd C13H14O4S (266.3): C,
D
58.63; H, 5.30. Found: C, 58.26; H, 5.53.
1ꢀ-[5-([2,2′]Bipyridin-6-yl)thiophen-2-yl]-1,2-dideoxy-D-ribo-
furanose (6i). Compound 6i was prepared from 4i (150 mg, 0.25
mmol) by the general procedure. 6i (59 mg, 65%) was obtained as
a colorless oil which was crystallized from isopropanol/heptane to
give colorless crystals (mp 152-154 °C). MS (FAB) m/z 355 (M
+ H). HRMS (FAB) for C19H19N2O3S: [M + H] calculated
1
278.0851, found 278.0842. H NMR (500 MHz, DMSO-d6): 1.95
(ddd, 1H, Jgem ) 12.8, J2′b,1′ ) 10.1, J2′b,3′ ) 5.3, H-2′b); 2.15 (ddd,
1H, Jgem ) 12.8, J2′a,1′ ) 5.5, J2′a,3′ ) 1.8, H-2′a); 3.37 (dd, 1H,
Jgem ) 11.1, J5′b,4′ ) 6.3, H-5′b); 3.46 (dd, 1H, Jgem ) 11.1, J5′a,4′
) 5.1, H-5′a); 3.78 (ddd, 1H, J4′,5′ ) 6.3, 5.1, J4′,3′ ) 2.2, H-4′);
4.22 (bm, 1H, H-3′); 4.77 (bs, 1H, OH-5′); 5.12 (bs, 1H, OH-3′);
5.24 (dd, 1H, J1′,2′ ) 10.1, 5.5, H-1′); 7.06 (dd, 1H, J3,4 ) 3.8, J3,1′
) 0.8, H-3); 7.25 (ddd, 1H, J5,4 ) 7.3, J5,6 ) 4.8, J5,3 ) 1.2, H-5-
1
355.1116, found 355.1122. H NMR (600 MHz, CD3OD): 2.18
(ddd, 1H, Jgem ) 13.2, J2′b,1′ ) 10.1, J2′b,3′ ) 5.8, H-2′b); 2.30 (ddd,
1H, Jgem ) 13.2, J2′a,1′ ) 5.6, J2′a,3′ ) 1.9, H-2′a); 3.65 and 3.69 (2
× dd, 2H, Jgem ) 11.6, J5′,4′ ) 5.3, H-5′); 3.96 (td, 1H, J4′,5′ ) 5.3,
J4′,3′ ) 2.5, H-4′); 4.37 (dddd, 1H, J3′,2′ ) 5.8, 1.9, J3′,4′ ) 2.5, J3′,1′
) 0.7, H-3′); 5.39 (ddt, 1H, J1′,2′ ) 10.1, 5.6, J1′,3 ) J1′,3′ ) 0.7,
H-1′); 7.08 (dd, 1H, J3,4 ) 3.7, J3,1′ ) 0.7, H-3); 7.44 (ddd, 1H,
py); 7.62 (d, 1H, J4,3 ) 3.8, H-4); 7.80 (ddd, 1H, J4,3 ) 8.0, J4,5
)
7.3, J4,6 ) 1.7, H-4-py); 7.86 (ddd, 1H, J3,4 ) 8.0, J3,5 ) 1.2, J3,6
) 0.9, H-3-py); 8.49 (ddd, 1H, J6,5 ) 4.8, J6,4 ) 1.7, J6,3 ) 0.9,
H-6-py). 13C NMR (125.7 MHz, DMSO-d6): 43.7 (CH2-2′); 62.7
J5′,4′ ) 7.5, J5′,6′ ) 4.8, J5′,3′ ) 1.2, H-5′-bipy); 7.60 (d, 1H, J4,3
)
J. Org. Chem. Vol. 73, No. 10, 2008 3805

Ba´rta et al.
3.7, H-4); 7.79 (dd, 1H, J5,4 ) 7.8, J5,3 ) 0.9, H-5-bipy); 7.88 (dd,
1H, J4,3 ) J4,5 ) 7.8, H-4-bipy); 7.96 (ddd, 1H, J4′,3′ ) 8.0, J4′,5′
0.0278, wR ) 0.0324, GoF ) 1.0293 for 2508 reflections with I >
2σ(I) and 174 parameters.
)
7.5, J4′,6′ ) 1.8, H-4′-bipy); 8.16 (dd, 1H, J3,4 ) 7.8, J3,5 ) 0.9,
H-3-bipy); 8.51 (ddd, 1H, J3′,4′ ) 8.0, J3′,5′ ) 1.2, J3′,6′ ) 1.0, H-3′-
bipy); 8.63 (ddd, 1H, J6′,5′ ) 4.8, J6′,4′ ) 1.8, J6′,3′ ) 1.0, H-6′-
bipy). 13C NMR (151 MHz, CD3OD): 44.9 (CH2-2′); 64.1 (CH2-
5′); 74.4 (CH-3′); 77.7 (CH-1′); 89.3 (CH-4′); 119.6 (CH-5-bipy);
119.9 (CH-3-bipy); 122.7 (CH-3′-bipy); 125.35 (CH-5′-bipy); 125.6
(CH-4); 126.7 (CH-3); 138.7 (CH-4′-bipy); 139.0 (CH-4-bipy);
145.5 (C-5); 149.3 (C-2); 150.0 (CH-6′-bipy); 153.5 (C-6-bipy);
156.4 (C-2-bipy); 157.1 (C-2′-bipy). IR spectrum (KBr): 3374,
3055, 1591, 1578, 1475, 1382, 1226, 1066, 1049, 1029, 997, 803
Crystal data for 6n: C13H14O3S2, monoclinic, space group P21,
a ) 5.1041(1) Å, b ) 8.2609(1) Å, c ) 15.5067(1) Å, ꢀ )
93.3987(8)°, V ) 652.68(2) Å3, Z ) 2, M ) 282.38, 9848 reflections
measured, 2589 independent reflections. Final R ) 0.0565, wR )
0.0678, GoF ) 0.9786 for 2211 reflections with I > 2σ(I) and 165
parameters.
CCDC 674694 (6l) and 674695 (6n) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
cm-1. R20 -5.5 (c 2.16, MeOH). Anal. Calcd C19H18N2O3S
D
(354.4): C, 64.39; H, 5.12; N, 7.90. Found: C, 64.04; H, 5.16; N,
7.51.
Acknowledgment. This work is a part of the research project
Z4 055 905. It was supported by the Centre of Biomolecules
and Complex Molecular Systems (LC 512) and by NIH, Fogarty
International Center (grant 1R03TW007372-01), and Gilead
Sciences Inc.
Single Crystal X-Ray Structure Analysis. The diffraction data
of single crystals of 6l (colorless, 0.07 × 0.37 × 0.50 mm) and 6n
(brownish, 0.09 × 0.30 × 0.77 mm) were collected on an Xcalibur
X-ray diffractometer with Cu KR (λ ) 1.54180 Å) at 150 K (6l)
and 295 K (6n). Both structures were solved by direct methods
with SIR9230 and refined by full-matrix, least-squares methods
based on F with CRYSTALS.31 The hydrogen atoms were located
in a difference map, but those attached to carbon atoms were
repositioned geometrically and then refined with riding constraints,
while all other atoms were refined anisotropically in both cases.
Crystal data for 6l: C15H16O3S1, monoclinic, space group P21, a
) 5.7250(2) Å, b ) 9.9297(3) Å, c ) 11.9718(4) Å, ꢀ )
100.190(3)°, V ) 669.83(4) Å3, Z ) 2, M ) 276.35, 10 484
reflections measured, 2655 independent reflections. Final R )
Supporting Information Available: General experimental,
alternative ways of preparation of 4a, detailed experimental
procedures, and characterization data for compounds 4b,c,g-i,
6b-e,m-p, 7b-d,k, experimental details of fluorescence
measurements and table of log-normal parameters, and copies
of all NMR spectra and cif files for 6l and 6n. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800177Y
(30) Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla,
M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435–435.
(31) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487–1487.
3806 J. Org. Chem. Vol. 73, No. 10, 2008