A rapid efficient microwave-assisted synthesis of a 3′,5′-pentathymidine by copper(I)-catalyzed [3+2] cycloaddition

Article abstract of DOI:10.1016/j.tet.2008.04.006

Starting from 5′-O-tosylthymidine, sequential azidation and Cu-catalyzed [3+2] azide-alkyne 1,3-dipolar cycloaddition led to the formation of a 3′,5′-pentathymidine in high yield. The whole process needed only work-up/precipitation steps and was completed

Full text of DOI:10.1016/j.tet.2008.04.006

Tetrahedron 64 (2008) 5467–5471
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Tetrahedron
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A rapid efficient microwave-assisted synthesis of a 30,50-pentathymidine
by copper(I)-catalyzed [3þ2] cycloaddition
,
a
a
b
Romain Lucas a, Rachida Zerrouki a , Robert Granet , Pierre Krausz , Yves Champavier
*
a Laboratoire de Chimie des Substances Naturelles EA1069, Faculte´ des Sciences et Techniques, 123 Avenue Albert Thomas, F-87060 Limoges, France
b Universite´ de Limoges, Service Commun de RMN, Faculte´ de Pharmacie, 2 rue du Dr Marcland, F-87025 Limoges, France
a r t i c l e i n f o
a b s t r a c t
Starting from 50-O-tosylthymidine, sequential azidation and Cu-catalyzed [3þ2] azide–alkyne 1,3-dipolar
cycloaddition led to the formation of a 30,50-pentathymidine in high yield. The whole process needed
only work-up/precipitation steps and was completed within just 18 min, thanks to microwave activation.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 29 January 2008
Received in revised form 31 March 2008
Accepted 2 April 2008
Available online 7 April 2008
Keywords:
Pentathymidine
Click chemistry
Microwave
1. Introduction
a new strategy beginning with the selective 50-O-tosylation of
thymidine.
Synthetic oligonucleotides play pivotal roles in the design of
molecular tools used in genomic research and biotechnology.1
Antisense and triple helix therapies are two major applications of
these oligomeric structures.2 Oligonucleotide analogues have thus
attracted a lot of interest and more especially those harboring
a non-phosphodiester backbone.3 However, nucleoside chemistry,
made extremely delicate because of numerous reactive sites, re-
quires appropriate and often cumbersome protection/deprotection
steps. Thus, reduction in their number constitutes an attractive
challenge. In this way, the Huisgen 1,3-dipolar cycloaddition4 be-
tween azides and alkynes, performed by the recently discovered
copper(I) catalysis5 appears as a promising way to generate oligo-
mers6 and particularly non-natural oligodeoxyribonucleotides,
which can resist chemical or enzymatic depolymerization. More-
over the 100% regioselective formation of 1,4-disubstituted-1,2,3-
triazole conserves the directional character of DNA strands. At last,
microwave activation, associated to Cu-catalyzed [3þ2] azide–al-
kyne cycloaddition, dramatically decreases reaction time.7
The tosyl group is a good compromise; it can be used as a
protective group and it can easily generate azido-functionalized
compounds. Thus, tosylated thymidine was transformed into
50-azidothymidine and, in a separate reaction, 30-hydroxyl was
alkylated by an alkynylbromide, then these two precursors were
conjugated using the [3þ2] cycloaddition reaction.
Selective tosylation of the primary hydroxyl group of thymidine
gave the already known product 1.9 Then azidation of 1 using
15 equiv of sodium azide in DMF produced in 91% yield precursor 2
after 1 min microwave activation (120 ꢀC, 300 W).10 Alkyne 3 was
obtained by regioselective 30-O-alkylation using Chattopadhyaya’s
two-step method11 under microwave irradiation. During the first
step compound 1 was activated (40 ꢀC, 200 W, 3 min) with
2.5 equiv of NaH in THF then in the second step 2.5 equiv of
propargyl bromide was added and the mixture was irradiated
3 min. The reaction produced compound 3 in 96% yield (Scheme 1).
Derivatives 2 and 3 were then coupled using copper(I)-catalyzed
cycloaddition in order to obtain 1,4 dithymidine-substituted-1,2,
3-triazole 4 (Scheme 2). Optimization of this reaction has been de-
scribed in a previous paper.8 Alkyne and azide precursors were sus-
pended in a 1:1 mixture of water and ethanol, together with catalyst
and sodium ascorbate. After 3 min of irradiation, treatment with THF
gave dimer 4 in excellent yield (92%). Despite of a TLC analysis, which
unveiled traces of remaining compound 3, the reaction mixture
containing dimer 4 was directly used in following steps.
2. Results and discussion
In conjunction with our efforts to generate rapidly and ef-
ficiently oligonucleosides,8 we were especially interested in
Tosyldithymidine (4) was then converted into ‘azido’ dimer 5 by
using the same conditions as for synthesis of compound 2. In this
* Corresponding author. Tel.: þ33 5 55 45 72 24; fax: þ33 5 55 45 72 02.
E-mail address: rachida.zerrouki@unilim.fr (R. Zerrouki).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.006

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R. Lucas et al. / Tetrahedron 64 (2008) 5467–5471
per million with Me4Si as an internal standard (
d
¼0). Data are
reported as follows: chemical shift, multiplicity (s, singlet; d, dou-
blet; t, triplet; q, quartet; m, multiplet, and br, broad), coupling
constants (Hz), and assignment. Melting points (mp) were de-
termined with an Electrothermal Digital Melting Point Apparatus
IA9000 series. IR spectra were recorded on a Perkin–Elmer 1310
grating spectrophotometer and are reported in wave number (cmꢁ1).
4.2. Synthesis
4.2.1. Synthesis of precursor 2
Compound 1 (100 mg, 0.38 mmol) was treated with 15 equiv of
sodium azide (372 mg, 5.7 mmol) in DMF (8 mL) and was activated
by microwave for 1 min (120 ꢀC, 300 W). Compound 2 gave intense
purple spots after spraying first PPh3/Et2O then ninhydrin and
heating. The mixture was evaporated and purified by flash chro-
matography with a CHCl3/MeOH elution gradient. Pure product was
obtained as a white solid in 91% yield; mp¼164–166 ꢀC; IR: nmax
(cmꢁ1)¼3366, 2104, 1690, 1645. 1H NMR (DMSO-d6) thymine: 11.32
(br s, 1H, N–H), 7.49 (s, 1H, H6), 1.79 (s, 3H, CH3); ose: 6.20 (t, 1H,
Scheme 1. Preparation of precursors 2 and 3. Reagents and conditions: (i) NaN3, DMF,
MW (120 ꢀC, 300 W, 1 min); (ii) (1) NaH, THF, MW (40 ꢀC, 200 W, 3 min), (2) propargyl
bromide, MW (40 ꢀC, 200 W, 3 min).
case 2 min (120 ꢀC, 300 W) of activation were necessary for the
total disappearance of the starting tosylated compound. Treatment
with THF led to the desired product in 94% yield.
0
0
J¼7 Hz, H1 ), 5.41 (d, 1H, J¼3.7 Hz, OH), 4.19 (m, 1H, H3 ), 3.85 (br dd,
0
0
1H, J¼5.2, 8.9 Hz, H4 ), 3.58 (dd,1H, J¼5.3,13.0 Hz, H5 a), 3.53 (dd,1H,
A click reaction between compounds 5 and 3 using the same
reagents and activation time as for dimer 4 gavedwithout purifi-
cationdtrimer 6 in quantitative yield. These two steps of azidation
and [3þ2] cycloaddition were repeated under identical conditions
and provided ‘azido’ trimer 7 (80%) and tetramer 8.12 Compound 8
precipitated during the reaction. After filtration and washing with
THF, pure tosyltetramer was isolated in 72% yield. Azidation of
compound 8 in DMF gave ‘azido’ tetramer 9 in 93% yield after
extraction with THF. Since tetramer is insoluble in H2O/EtOH, CuI/
DIPEA/DMF click system8,13 was used for [3þ2] cycloaddition and
gave pentamer 10 after 3 min of microwave activation (120 ꢀC,
300 W). After precipitation with water and filtration, pure penta-
thymidine was isolated in 99% yield.
0
0
J¼5.3, 13.0 Hz, H5 b), 2.25 (ddd, 1H, J¼6.5, 7, 13.6 Hz, H2 a), 2.09 (ddd,
1H, J¼3.7, 6.4, 13.5 Hz, H2 b). 13C NMR (DMSO-d6): 163.6 (C4), 150.5
0
(C2),136.0 (C6),109.7 (C5), 84.5 (C40), 83.8 (C10), 70.6 (C30), 51.6 (C50),
38.0 (C20), 12.0 (CH3); MS (IS) m/z¼268.1 (MþHþ), 290.1 (MþNaþ),
306.1 (MþKþ), 535.3 (MHþM), 557.2 (MNaþM), 824.3 (M3Naþ).
4.2.2. Synthesis of precursor 3
To a solution of compound 1 (1.011 g, 2.55 mmol) in dry THF
(15 mL) was added 2.5 equiv of NaH (60%, 255 mg, 6.38 mmol) and
the mixture was activated by microwave irradiation (40 ꢀC, 200 W,
3 min). Propargyl bromide of 2.5 equiv (80% in toluene, 690 mL,
6.38 mmol) was then added and the mixture was activated by
microwave irradiation (40 ꢀC, 200 W, 3 min). After work-up (NH4Cl/
H2O) and purification by chromatography (chloroform as eluent) 3
was recovered in 96% yield (1.107 g); mp¼40–41 ꢀC; IR: nmax
(cmꢁ1)¼3040, 2359, 1688, 1361. 1H NMR (DMSO-d6) thymine: 11.34
(br s, 1H, N–H), 7.41 (d, 1H, JH ; CH ¼ 0:8 Hz, H6), 1.77 (s, 3H, CH3);
Overall process combining the five steps from the first to the last
cycloaddition reaction totaled only 18 min; pure pentamer 10 was
synthesized in 46% overall yield from 2.
Structures of isolated products 3–10 were determined by 1H, 13C,
1H–1H COSY, 13C–1H HMQC, and 13C–1H HMBC measurements (after
purification of each product by preparative chromatography, except
for compounds 8–10).
6
3
0
ose: 6.08 (dd, 1H, J¼6.5, 7.7 Hz, H1 ), 4.27 (dd, 1H, J¼3.6, 10.9 Hz,
0
0
0
H
5 a), 4.25 (m, 1H, H3 ), 4.21 (dd, 1H, J¼5.5, 10.9 Hz, H5 b), 4.08 (m,
0
0
1H, H4 ), 2.29 (ddd, 1H, J¼6.3, 7.7, 14.2 Hz, H2 a), 2.22 (ddd, 1H, J¼6.3,
0
6.5, 14.2 Hz, H2 b); tosyl: 7.79 (d, 2H, J¼8.2 Hz, H2, H6), 7.48 (d, 2H,
3. Conclusion
J¼8.2 Hz, H3, H5), 2.40 (s, 3H, CH3); propargyl: 4.18 (d, 2H, J¼2.3 Hz,
CH2), 3.47 (t, 1H, J¼2.3 Hz, C–H). 13C NMR (DMSO-d6): 163.5 (C4),
0
0
0
In conclusion, a new, fast, and efficient procedure using alter-
nating azidation and click chemistry was developed for tetrathy-
midine analogue synthesis. Microwave activation was used
throughout and provided 10 in good yield. Continued advancement
of this strategy could find interesting applications in solid phase
synthesis to generate a new family of oligonucleotide analogues.
150.3 (C2), 135.7 (C6), 109.5 (C5), 84.3 (C1 ), 80.6 (C4 ), 77.8 (C3 ), 69.9
0
0
(C5 ), 35.3 (C2 ), 11.9 (CH3); tosyl: 145.1 (C4), 131.2 (C1), 130.1 (C3, C5),
127.5 (C2, C6), 21.0 (CH3); propargyl: 79.9 (C), 77.4 (CH), 56.2 (CH2);
MS (IS) m/z¼435.2 (MþHþ), 457.2 (MþNaþ), 891.3 (MNaþM).
4.3. General procedure for click chemistry
4. Experimental
Compound 2 (317 mg,1.19 mmol), 3 (490 mg,1.13 mmol), sodium
ascorbate (680 mL, 1 M, 0.6 equiv), and copper sulfate pentahydrate
4.1. General methods
(17 mg, 0.06 equiv) were suspended in a 1:1 mixture of water and
ethanol (4 mL each) in a 25 mL bicol (open reaction vessel). The
mixture was then irradiated for 3 min at 80 ꢀC, using an irradiation
power of 300 W. After work-up (THF), the crude residue was con-
centratedinvacuoandproduct4wasrecoveredasawhitesolid(92%).
All the solvents and chemicals were commercially available and,
unless otherwise stated, were used as received. Reactions were
monitored by thin layer chromatography (TLC) on precoated 0.2 mm
silica gel 60 F254 (Merck) plates and visualized in several ways: with
an ultraviolet light source at 254 nm, by spraying with sulfuric acid
(6 N), and heating to 200 ꢀC. Microwave irradiations were performed
by the means of an Ethos 1600 MicroSynth reactor from Milestone.
Temperature was measured with a fiber optic thermometer (ATC-
FO)/Ethos. 1H NMR spectra were recorded at 400.13 MHz with
4.4. Compounds 4–10
4.4.1. Compound 4
Isolation by preparative chromatography: CHCl3/EtOH (8:2). 1H
NMR (DMSO-d6) thymines: 11.33 (s, 1H, NH), 11.30 (s, 1H, NH), 7.40
(d, 1H, J¼0.8 Hz, H6B), 7.34 (d, 1H, J¼0.9 Hz, H6A), 1.79 (d, 3H,
a Bru¨ker DPX spectrometer. Chemical shifts (d) are expressed in parts

R. Lucas et al. / Tetrahedron 64 (2008) 5467–5471
5469
Scheme 2. Synthesis of pentathymidine 10. Reagents and conditions: (i) 3, CuSO4 (0.06 equiv), Na ascorbate (0.6 equiv), H2O/EtOH (1:1), MW (80 ꢀC, 300 W, 3 min); (ii) NaN3, DMF,
MW (120 ꢀC, 300 W, 2 min); (iii) 3, CuI (1 equiv), DIPEA (3 equiv), DMF, MW (120 ꢀC, 300 W, 3 min).
J¼0.5 Hz, 5ACH3), 1.77 (d, 3H, J¼0.5 Hz, 5BCH3); oses: 6.16 (br t,
or C2B), 136.1 (C6A), 135.8 (C6B), 109.8 (C5A, C5B), 12.1 (5ACH3 or
0 0 0
5BCH3), 12.0 (5ACH3 or 5BCH3); oses: 84.3 (C1 B), 84.0 (C1 A or C4 A),
0 0 0 0 0 0
83.9 (C1 A or C4 A), 80.8 (C4 B), 78.3 (C3 B), 70.7 (C3 A), 70.1 (C5 B), 51.2
0
0
1H, J¼7.0 Hz, H1 A), 6.09 (br t, 1H, J¼7.5 Hz, H1 B), 5.50 (d, 1H,
0
J¼4.4 Hz, OH), 4.71 (dd, 1H, J¼4.4, 14.2 Hz, H5 A), 4.61 (dd, 1H, J¼7.6,
0
0
0
0
0
0
14.2 Hz, H5 A), 4.28 (dd, 1H, J¼3.4, 10.7 Hz, H5 B), 4.28 (m, 1H, H3 A),
(C5 A), 37.9 (C2 A), 35.6 (C2 B); linker: 143.6 (Ctriazol), 124.7 (CHtriazol),
62.1 (CH2); tosyl: 145.2 (C4), 132.1 (C1), 130.2 (C3, C5), 127.6 (C2, C6),
21.1 (CH3); mp¼153–155 ꢀC; IR (cmꢁ1): nmax¼3651, 3550, 1691,
1363, 1176; MS (IS) m/z¼724.3 (MþNaþ).
0
4.22 (dd, 1H, J¼5.5, 10.9 Hz, H5 B), 4.17 (br ddd, 1H, J¼3.0, 5.7 Hz,
0
0
0
H
3 B), 4.09 (m, 1H, H4 B), 4.07 (br dd, 1H, J¼4.2, 7.6 Hz, H4 A), 2.23 (m,
0
0
2H, H2 B), 2.17 (br dd, 1H, J¼6.7, 13.7 Hz, H2 A), 2.10 (ddd, 1H, J¼3.9,
0
6.4, 13.5 Hz, H2 A); linker: 8.08 (s, 1H, Htriazol), 4.54 (d, 1H, J¼12.2 Hz,
CH2), 4.51 (d, 1H, J¼12.1 Hz, CH2); tosyl: 7.79 (d, 2H, J¼8.3 Hz, H2,
H6), 7.47 (d, 2H, J¼8.2 Hz, H3, H5), 2.40 (s, 3H, CH3). 13C NMR
(DMSO-d6) thymines: 163.6 (C4A, C4B), 150.4 (C2A or C2B), 150.3 (C2A
4.4.2. Compound 5
Isolation by preparative chromatography: CHCl3/EtOH (8:2). 1H
NMR (DMSO-d6) thymines: 11.30 (s, 2H, 2NH), 7.44 (br s, 1H, H6B),

5470
R. Lucas et al. / Tetrahedron 64 (2008) 5467–5471
0
7.29 (br s, 1H, H6A), 1.78 (br s, 6H, 5ACH3, 5BCH3); oses: 6.20 (br t, 1H,
C
2 C); linkers: 143.8 (Ctriazol), 143.6 (Ctriazol), 124.7 (2CHtriazol), 62.1
0
0
J¼7.3 Hz, H1 A), 6.18 (br t, 1H, J¼8.4 Hz, H1 B), 5.50 (d, 1H, J¼4.4 Hz,
(CH2), 62.0 (CH2); mp¼240–242 ꢀC; IR (cmꢁ1): nmax¼3360, 2103,
1686; MS (IS) m/z¼900.3 (MþNaþ).
0
OH), 4.71 (dd, 1H, J¼4.4, 14.3 Hz, H5 A), 4.61 (dd, 1H, J¼7.6, 14.4 Hz,
0
0
H
5 A), 4.28 (br ddd, J¼3.6, 6.6 Hz, H3 A), 4.15 (br ddd, 1H, J¼2.5,
0
0
0
5.3 Hz, H3 B), 4.07 (br dd, 1H, J¼4.0, 7.6 Hz, H4 A), 4.03 (m, 1H, H4 B),
4.4.5. Compound 8
Isolation by precipitation. 1H NMR (DMSO-d6) thymines: 11.34
(br s, 3H, 3NH),11.31 (br s,1H, NH), 7.41 (br s,1H, H6B), 7.40 (br s,1H,
0
0
3.60 (dd, 1H, J¼6.2, 13.1 Hz, H5 B), 3.55 (dd, 1H, J¼4.6, 13.2 Hz, H5 B),
0
0
2.22 (m, 2H, H2 B), 2.16 (br dd, 1H, J¼6.8, 13.7 Hz, H2 A), 2.07 (ddd,
0
1H, J¼3.8, 6.4, 13.4 Hz, H2 A); linker: 8.11 (s, 1H, Htriazol), 4.61 (d, 1H,
H6C or H6D), 7.39 (br s, 1H, H6C or H6D), 7.35 (br s, 1H, H6A), 1.79 (br s,
J¼11.9 Hz, CH2), 4.58 (d, 1H, J¼11.9 Hz, CH2). 13C NMR (DMSO-d6)
thymines: 163.6 (C4A, C4B), 150.3 (C2A, C2B), 135.7 (C6A), 135.5 (C6B),
109.8 (C5A, C5B), 12.5 (5ACH3 or 5BCH3), 12.4 (5ACH3 or 5BCH3); oses:
9H, 5ACH3, 5CCH3, 5DCH3), 1.77 (br s, 3H, 5BCH3); oses: 6.17 (br t, 1H,
0
0
0
0
J¼7.0 Hz, H1 A), 6.12 (br t, 1H, J¼6.0 Hz, H1 B or H1 C or H1 D), 6.11 (br
0
0
0
0
t, 1H, J¼7.1 Hz, H1 B or H1 C or H1 D), 6.09 (br t, 1H, J¼6.5 Hz, H1 B or
0
0
0
0
0
0
0
0
84.1 (C1 A or C1 B), 84.0 (C1 A or C1 B), 83.8 (C4 A), 81.9 (C4 B), 79.1
H
H
H
1 C or H1 D), 5.52 (d, 1H, J¼4.3 Hz, OH), 4.73 (dd, 1H, J¼4.6, 14.5 Hz,
0
0
0
0
0
0
0
0
0
0
(C3 B), 70.8 (C3 A), 52.0 (C5 B), 51.3 (C5 A), 38.0 (C2 A), 35.4 (C2 B);
linker: 143.7 (Ctriazol), 124.8 (CHtriazol), 62.1 (CH2); mp¼197–199 ꢀC;
IR (cmꢁ1): nmax¼3050, 2103, 1694; MS (IS) m/z¼595.3 (MþNaþ).
5 B or H5 C), 4.72 (dd, 1H, J¼4.2, 14.0 Hz, H5 A), 4.70 (m, 2H, H5 B or
0
0
0
5 C), 4.65 (dd, 1H, J¼7.4, 14.4 Hz, 1H, H5 B or H5 C), 4.62 (dd, 1H,
0
0
0
0
0
0
J¼6.6, 14.0 Hz, H5 A), 4.35–4.25 (m, 5H, H3 A, H3 B, H4 B, H3 C, H4 C),
0
0
4.26 (m, 1H, H5 D), 4.21 (dd, 1H, J¼5.5, 10.9 Hz, H5 D), 4.17 (m, 1H,
0
0
0
0
0
0
,
4.4.3. Compound 6
H
H
H
3 D), 4.11–4.06 (m, 2H, H4 A, H4 D), 2.35–2.15 (m, 8H, H2 A, H2 B, H2 C
Isolation by preparative chromatography: CHCl3/EtOH (7:3). 1H
NMR (DMSO-d6) thymines: 11.33 (br s, 2H, 2NH),11.30 (br s,1H, NH),
7.41 (br s, 1H, H6B), 7.39 (br s, 1H, H6C), 7.34 (br s, 1H, H6A), 1.79 (br s,
2 D); linkers: 8.12 (s, 1H, Htriazol), 8.11 (s, 1H, Htriazol), 8.10 (s, 1H,
triazol), 4.57 (m, 4H, A–BCH2, B–CCH2), 4.54 (d, 1H, J¼12.6 Hz,
0
C–DCH2), 4.51 (d, 1H, J¼12.6 Hz, C–DCH2); tosyl: 7.79 (d, 2H, J¼8.2 Hz,
H2, H6), 7.46 (d, 2H, J¼8.2 Hz, H3, H5), 2.39 (s, 3H, CH3). 13C NMR
(DMSO-d6) thymines: 163.6 (1C: C4A or C4B or C4C or C4D), 163.5 (3C:
0
9H, 3CH3); oses: 6.17 (br t, 1H, J¼7.0 Hz, H1 A), 6.11 (br t, 1H,
0
0
J¼6.8 Hz, H1 C), 6.09 (br t, 1H, J¼6.5 Hz, H1 B), 5.50 (d, 1H, J¼4.3 Hz,
0
0
OH), 4.72 (dd, 1H, J¼4.4, 14.3 Hz, H5 A or H5 B), 4.71 (dd, 1H, J¼4.2,
C4A or C4B or C4C or C4D), 150.3 (C2A, C2B, C2C, C2D), 135.9 (C6A, C6C
,
0
0
0
0
14.1 Hz, H5 A or H5 B), 4.64 (dd, 1H, J¼7.1, 14.6 Hz, H5 A or H5 B), 4.62
C6D), 135.7 (C6B), 109.8 (C5A, C5B, C5C, C5D), 12.0 (4CH3); oses: 84.3
0 0 0 0 0 0 0
(2C: C1 B or C1 C or C1 D), 84.2 (1C: C1 B or C1 C or C1 D), 83.9 (C1 A),
0 0 0 0 0 0 0
83.8 (C4 A), 81.4 (C4 B, C4 C), 80.8 (C4 D), 78.9 (C3 B, C3 C), 78.2 (C3 D),
0
0
0
0
(dd, 1H, J¼6.3, 14.1 Hz, H5 A or H5 B), 4.35–4.25 (m, 3H, H3 A, H3 B
,
0
0
0
H
4 B), 4.26 (m, 1H, H5 C), 4.20 (dd, 1H, J¼5.5, 10.9 Hz, H5 C), 4.17 (m,
0
0
0
0
0
0 0 0 0 0 0
70.6 (C3 A), 70.0 (C5 D), 51.2 (2C: C5 A or C5 B or C5 C), 51.1 (1C: C5 A or
1H, H3 C), 4.11–4.06 (m, 2H, H4 A, H4 C), 2.35–2.05 (m, 6H, H2 A, H2 B
,
0
0
0
0
0
0
0
H
2 C); linkers: 8.11 (s, 1H, Htriazol), 8.09 (s, 1H, Htriazol), 4.59 (d, 1H,
C5 B or C5 C), 37.8 (C2 A), 35.5 (C2 B), 35.0 (C2 C, C2 D); linkers: 143.6
(2C: Ctriazol), 143.5 (Ctriazol), 124.7 (CHtriazol), 124.6 (2C: CHtriazol),
62.0 (3CH2); tosyl: 145.1 (C4), 131.9 (C1), 130.1 (C3, C5), 127.5 (C2, C6),
20.7 (CH3); mp¼197–199 ꢀC; IR (cmꢁ1): nmax¼3056, 1698, 1369; MS
(IS) m/z¼1334 (MþNaþ).
J¼12.6 Hz, A–BCH2), 4.56 (d, 1H, J¼12.6 Hz, A–BCH2), 4.55 (d, 1H,
J¼12.6 Hz, B–CCH2), 4.52 (d, 1H, J¼12.6 Hz, B–CCH2); tosyl: 7.79 (d,
2H, J¼8.2 Hz, H2, H6), 7.46 (d, 2H, J¼8.2 Hz, H3, H5), 2.40 (s, 3H, CH3).
13C NMR (DMSO-d6) thymines: 163.6 (C4A, C4B, C4C),150.4 (2C: C2A or
C
2B or C2C),150.3 (1C: C2A or C2B or C2C),136.0 (2C: C6A or C6B or C6C),
135.8 (1C: C6A or C6B or C6C), 109.9 (1C: C5A or C5B or C5C), 109.8 (2C:
4.4.6. Compound 9
C
C
Isolation by work-up (THF/CHCl3/H2O). 1H NMR (DMSO-d6)
thymines: 11.32 (br s, 4H, 4NH), 7.52 (br s, 1H, H6B), 7.40 (br s, 2H,
0 0 0
5A or C5B or C5C), 12.1 (3CH3); oses: 84.4 (C1 B or C1 C), 84.3 (C1 B or
0
0
0
0
0
0
1 C), 84.0 (C1 A), 83.9 (C4 A), 81.5 (C4 B), 80.8 (C4 C), 79.0 (C3 B), 78.3
0
0
0
0
0
0
0
(C3 C), 70.7 (C3 A), 70.1 (C5 C), 51.3 (C5 A or C5 B), 51.2 (C5 A or C5 B),
H6C, H6D), 7.35 (br s, 1H, H6A), 1.80 (br s, 6H, 5CCH3, 5DCH3), 1.79 (br s,
0
0
0
0
37.9 (C2 A), 35.6 (C2 B), 35.1 (C2 C); linkers: 143.7 (Ctriazol), 143.6
(Ctriazol), 124.7 (CHtriazol), 124.6 (CHtriazol), 62.1 (2CH2); tosyl: 145.2
(C4), 132.1 (C1), 130.2 (C3, C5), 127.6 (C2, C6), 21.1 (CH3); mp¼170–
173 ꢀC; IR (cmꢁ1): nmax¼3055, 1686, 1364, 1176; MS (IS) m/z¼1007.4
(MþHþ), 1029.3 (MþNaþ), 1045.3 (MKþ).
6H, 5ACH3, 5BCH3); oses: 6.17 (br t, 1H, J¼7.0 Hz, H1 A), 6.15 (br t, 1H,
0
0
0
0
0
J¼7.9 Hz, H1 B or H1 C or H1 D), 6.12 (br t, 1H, J¼7.2 Hz, H1 B or H1 C or
0
0
0
0
H
1 D), 6.11 (br t,1H, J¼7.0 Hz, H1 B or H1 C or H1 D), 5.52 (br s,1H, OH),
0
0
0
4.75–4.65 (m, 5H, H5 A or H5 B or H5 C), 4.62 (dd, 1H, J¼7.6, 14.6 Hz,
0 0 0 0 0 0
5 A), 4.35–4.26 (m, 5H, H3 A, H3 B, H4 B, H3 C, H4 C), 4.17 (br dd, 1H,
H
0
0
J¼2.8, 5.6 Hz, H3 D), 4.09 (br dd, 1H, J¼4.2, 7.6 Hz, H4 A), 4.05 (br dd,
0
0
4.4.4. Compound 7
1H, J¼3.0, 6.3 Hz, H4 D), 3.59 (dd, 1H, J¼6.3, 13.0 Hz, H5 D), 3.55 (dd,
Isolation by preparative chromatography: CHCl3/EtOH (7:3). 1H
NMR (DMSO-d6) thymines: 11.31 (s, 3H, 3NH), 7.52 (d, 1H, J¼0.7 Hz,
1H, J¼4.6, 13.1 Hz, H5 D), 2.34–2.22 (m, 6H, H2 B, H2 C, H2 D), 2.19 (br
0
0
0
0
0
0
dd, 1H, J¼7.1, 13.3 Hz, H2 A), 2.11 (ddd, 1H, J¼4.0, 6.3, 13.4 Hz, H2 A);
linkers: 8.14 (s, 1H, Htriazol), 8.12 (s, 1H, Htriazol), 8.10 (s, 1H, Htriazol),
4.60 (d, 2H, J¼12.2 Hz, A–BCH2 or B–CCH2 or C–BCH2), 4.58 (d, 4H,
J¼12.2 Hz, A–BCH2 or B–CCH2 or C–BCH2). 13C NMR (DMSO-d6) thy-
mines: 163.6 (C4A, C4B, C4C, C4D), 150.5 (1C: C2A or C2B or C2C or C2D),
150.4 (3C: C2A or C2B or C2C or C2D), 136.1 (C6A, C6B, C6C, C6D), 109.9
H
6B), 7.41 (d, 1H, J¼0.6 Hz, H6C), 7.35 (d, 1H, J¼0.7 Hz, H6A), 1.80 (br
s, 3H, 5ACH3 or 5BCH3 or 5CCH3), 1.79 (br s, 6H, 5ACH3 or 5BCH3 or
0
0
5CCH3); oses: 6.16 (br t, 1H, J¼7.0 Hz, H1 A or H1 B), 6.14 (br t, 1H,
0
0
0
J¼6.7 Hz, H1 A or H1 B), 6.11 (br t, 1H, J¼6.7 Hz, H1 C), 5.51 (d, 1H,
0
0
,
J¼4.4 Hz, OH), 4.73 (dd, 1H, J¼4.2, 14.3 Hz, H5 B), 4.70 (m, 2H, H5 A
0
0
0
0
0
H
5 B), 4.62 (dd, 1H, J¼7.6, 14.6 Hz, H5 A), 4.32 (br ddd, J¼2.6, 5.2 Hz,
(C5A, C5B, C5C, C5D), 12.1 (4CH3); oses: 84.5 (2C: C1 B or C1 C or C1 D),
0
0
0
0 0 0 0 0 0
84.2 (1C: C1 B or C1 C or C1 D), 84.0 (C1 A), 83.9 (C4 A), 82.1 (C4 D), 81.6
0 0 0 0 0 0 0
(C4 B, C4 C), 79.0 (C3 B, C3 C), 78.9 (C3 D), 70.7 (C3 A), 51.9 (C5 D), 51.2
0 0 0 0 0 0 0
(2C: C5 A or C5 B or C5 C), 51.1 (1C: C5 A or C5 B or C5 C), 37.9 (C2 A), 35.2
H
4 B), 4.30 (m, 1H, H3 B), 4.29 (m, 1H, H3 A), 4.17 (br ddd, 1H, J¼2.7,
0
0
5.7 Hz, H3 C), 4.09 (br dd, 1H, J¼4.3, 7.7 Hz, H4 A), 4.05 (br dd, 1H,
0
0
J¼4.1, 6.8 Hz, H4 C), 3.59 (dd, 1H, J¼6.2, 13.1 Hz, H5 C), 3.55 (dd,
0
0
0
0
0
0
0
0
0
1H, J¼5.2, 13.1 Hz, H5 C), 2.35–2.23 (m, 4H, H2 B, H2 C), 2.19 (br dd,
(1C: C2 B or C2 C or C2 D), 35.1 (2C: C2 B or C2 C or C2 D); linkers: 143.8
(Ctriazol), 143.7 (Ctriazol), 143.6 (Ctriazol), 124.8 (CHtriazol), 124.7 (2C:
CHtriazol), 62.1 (2C: CH2), 62.0 (CH2); mp¼140 ꢀC; IR (cmꢁ1):
nmax¼2103; MS (IS) m/z¼1205.4 (MþNaþ).
0
0
1H, J¼6.8, 13.7 Hz, H2 A), 2.11 (ddd, 1H, J¼3.9, 6.3, 13.4 Hz, H2 A);
linkers: 8.14 (s, 1H, Htriazol), 8.10 (s, 1H, Htriazol), 4.61 (d, 1H,
J¼12.2 Hz, A–BCH2), 4.58 (d, 1H, J¼12.2 Hz, A–BCH2), 4.58 (d, 1H,
J¼12.2 Hz, B–CCH2), 4.55 (d, 1H, J¼12.2 Hz, B–CCH2). 13C NMR
(DMSO-d6) thymines: 163.6 (C4A, C4B, C4C), 150.5 (1C: C2A or C2B or
4.4.7. Compound 10
C
2C), 150.4 (2C: C2A or C2B or C2C), 136.0 (C6A, C6B, C6C), 109.9 (2C: C5A
or C5B or C5C), 109.8 (1C: C5A or C5B or C5C), 12.1 (3CH3); oses: 84.4
(C1 C), 84.2 (C1 B), 84.0 (C1 A), 83.9 (C4 A), 82.1 (C4 C), 81.5 (C4 B), 79.0
Isolation by precipitation using H2O. 1H NMR (DMSO-d6) thy-
mines: 11.33 (br s, 5H, 5NH), 7.47 (br s, 1H, H6A or H6B or H6C or H6D
or H6E), 7.38 (br s, 3H, H6A or H6B or H6C or H6D or H6E), 7.33 (br s,1H,
0
0
0
0
0
0
0
0
0
0
0
0
0
(C3 B or C3 C), 78.9 (C3 B or C3 C), 70.7 (C3 A), 51.9 (C5 C), 51.3 (C5 A or
H6A or H6B or H6C or H6D or H6E), 1.79 (br s, 15H, 5ACH3, 5BCH3, 5CCH3,
0
0
0
0
0
0
0
0
0
0
C
5 B), 51.2 (C5 A or C5 B), 37.9 (C2 A), 35.2 (C2 B or C2 C), 35.0 (C2 B or
5DCH3, 5ECH3); oses: 6.16 (br t, 2H, J¼7.0 Hz, H1 A or H1 B or H1 C or

R. Lucas et al. / Tetrahedron 64 (2008) 5467–5471
5471
C. K., Baker, D. C., Eds.; Plenum: New York, NY, 1993; pp 311–324; (c) Milligan, J.
F.; Matteuci, M. D.; Martin, J. C. J. Med. Chem. 1993, 36, 1923–1937; (d) Sanghvi,
Y. S.; Cook, P. D. Carbohydrate Modifications in Antisense Research. In Carbo-
hydrates; Sanghvi, Y. S., Cook, P. D., Eds.; American Chemical Society: Wash-
0
0
0
0
0
0
H1 D or H1 E), 6.10 (br t, 3H, J¼6.9 Hz, H1 A or H1 B or H1 C or H1 D or
0
0
0
0
,
H
1 E), 5.56 (br d,1H, J¼2.0 Hz, OH), 4.74–4.58 (m, 8H, H5 A, H5 B, H5 C
0
0
0
0
0
0
0
0
0
H
5 D), 4.38–4.20 (m, 9H, H3 A, H3 B, H4 B, H3 C, H4 C, H3 D, H4 D, H5 E),
0
0
0
¨
ington, DC, 1994; pp 1–23; (e) De Mesmaeker, A.; Haner, R.; Martin, P.; Moser,
H. E.; Heinz, E. Acc. Chem. Res. 1995, 28, 366–374.
4.17 (m, 1H, H3 E), 4.10–4.07 (m, 2H, H4 A, H4 E), 2.30–2.09 (m, 10H,
0
0
0
0
0
H
2 A, H2 B, H2 C, H2 D, H2 E); linkers: 8.12 (br s, 3H, Htriazol), 8.09 (s, 1H,
triazol), 4.58 (m, 8H, A–BCH2, B–CCH2, C–DCH2, D–ECH2); tosyl: 7.78 (d,
3. Among the latest: (a) Fairhurst, R. A.; Collingwood, S. P.; Lambert, D.; Taylor, R. J.
Synlett 2001, 467–472; (b) Reddy, P. M.; Bruice, T. C. Bioorg. Med. Chem. Lett.
2003, 13, 1281–1285; (c) Bouillon, C.; Meyer, A.; Vidal, S.; Jochum, A.; Chevelot,
Y.; Cloarec, J. P.; Praly, J. P.; Vasseur, J. J.; Morvan, F. J. Org. Chem. 2006, 71, 4700–
4702; (d) Hayakawa, Y.; Hirabayashi, Y.; Hyodo, M.; Yamashita, S.; Matsunami,
T.; Cui, D. M.; Kawai, R.; Kodama, H. Eur. J. Org. Chem. 2006, 17, 3834–3844;
Kumar, R. K.; Gusaev, A. P.; Rentel, C.; Ravikumar, V. T. Tetrahedron 2006, 62,
4528–4534; (e) Lietard, J.; Meyer, A.; Vasseur, J. J.; Morvan, F. Tetrahedron Lett.
2007, 48, 8795–8798.
H
2H, J¼8.0 Hz, H2, H6), 7.48 (d, 2H, J¼8.0 Hz, H3, H5), 2.39 (s, 3H, CH3).
13C NMR (DMSO-d6) thymines: 163.7 (C4A, C4B, C4C, C4D, C4E), 150.4
(C2A, C2B, C2C, C2D, C2E), 136.1 (C6A, C6B, C6C, C6D, C6E), 109.9 (C5A, C5B
5C, C5D, C5E), 12.1 (5CH3); oses: 84.5 (2C: C1 B or C1 C or C1 D), 84.4
(1C: C1 B or C1 C or C1 D), 84.1 (C1 A, C1 E), 83.9 (C4 A), 81.5 (C4 B, C4 C
0 0 0 0 0 0 0 0
4 D, C4 E), 79.1 (1C: C3 B or C3 C or C3 D or C3 E), 79.0 (3C: C3 B or C3 C
or C3 D or C3 E), 70.7 (C3 A), 67.0 (C5 E), 51.3 (3C: C5 A or C5 B or C5 C or
,
0
0
0
C
0
0
0
0
0
0
0
0
,
C
4. Huisgen, R.; Knorr, R.; Mobius, L.; Szeimies, G. Chem. Ber. 1965, 98, 4014–
4021.
0
0
0
0
0
0
0
5. (a) Tornoe, C. W.; Meldal, M. Peptidotriazoles: Copper(I)-Catalysed 1,3-Dipolar
Cycloadditions on Solid-phase. In Peptides: Proceedings of the American Peptide
Symposium; Lebl, M., Houghten, R. A., Eds.; American Peptide Society and
Kluwer Academic: San Diego, CA, 2001; pp 263–264; (b) Rostovtsev, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–
2599; (c) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–
3064; (d) Helms, B.; Mynar, J. L.; Hawker, C. J.; Frechet, J. M. J.; Sharpless, K. B.
J. Am. Chem. Soc. 2004, 126, 15020–15021; (e) Wu, P.; Feldman, A. K.; Nugent,
A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless,
K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2004, 43, 2938–2954.
6. Montagnat, O. D.; Lessene, G.; Hughes, A. B. Tetrahedron Lett. 2006, 47,
6971–6974.
0
0
0
0
0
0
0
0
C
C
5 D), 51.2 (1C: C5 A or C5 B or C5 C or C5 D), 37.9 (C2 A), 35.1 (C2 B, C2 C
,
0
0
2 D, C2 E); linkers: 143.7 (2C: Ctriazol), 143.6 (2C: Ctriazol), 124.8
(CHtriazol), 124.7 (3C: CHtriazol), 62.1 (3CH2), 61.7 (1CH2); tosyl: 145.2
(C4), 132.2 (C1), 130.2 (C3, C5), 127.6 (C2, C6), 20.8 (CH3); mp¼277 ꢀC;
IR (cmꢁ1): nmax¼3055, 1690, 1366; MS (IS) m/z¼1639 (MþNaþ).
Acknowledgements
´
Financial support from the ‘Conseil Regional du Limousin’ is
gratefully acknowledged. The authors thank Dr. Michel Guilloton
for his help in writing the manuscript.
7. (a) Appukkutan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E. Org. Lett. 2004,
6, 4223–4225; (b) Gru¨nefeld, P.; Richert, C. J. Org. Chem. 2004, 69, 7543–7551;
(c) Colombeau, L.; Zerrouki, R.; Krausz, P.; Champavier, Y. Lett. Org. Chem. 2005,
2, 613–615; (d) Roy, V.; Zerrouki, R.; Krausz, P. Nucleosides, Nucleotides Nucleic
Acids 2005, 24, 289–301; (e) Ge´ci, I.; Filichev, V. V.; Pedersen, E. B. Chem.dEur. J.
2007, 13, 6379–6386.
Supplementary data
8. Lucas, R.; Neto, V.; Hadj Bouazza, A.; Zerrouki, R.; Granet, R.; Krausz, P.;
Champavier, Y. Tetrahedron Lett. 2008, 49, 1004–1007.
Supplementary data (spectroscopic data) associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.04.006.
9. (a) Kochetkova, S. V.; Timofeev, E. N.; Korobeinikova, E. A.; Kolganova, N. A.;
Florentiev, V. L. Tetrahedron 2001, 57, 10287–10292; (b) Wang, H.; Cheng, C.;
Zheng, H.; Liu, X.; Fang, C.; Xu, S.; Zhao, Y. Chem. Lett. 2005, 34, 432–433.
10. Microwave irradiations were performed by the means of an Ethos 1600
MicroSynth reactor from Milestone. The temperature was measured with a
fiber optic thermometer ATC-FO/Ethos.
References and notes
11. Wu, J. C.; Xi, Z.; Gioeli, C.; Chattopadhyaya, J. Tetrahedron 1991, 47, 2237–2254.
12. Lu, G.; Lam, S.; Burgess, K. Chem. Commun. 2006, 1652–1654.
13. Hotha, S.; Kashyap, S. J. Org. Chem. 2006, 71, 364–367.
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