Synthesis of 6-aryl-2′-deoxyuridine nucleosides via a Liebeskind cross-coupling methodology

Article abstract of DOI:10.1016/j.tetlet.2011.11.036

Hitherto, the synthesis of 6-substituted 2′-deoxyuridine nucleoside analogues via Pd-catalyzed Suzuki cross-coupling reaction was hampered by the instability of the TIPDS-protected precursor 6-iodo-2′-deoxyuridine 1 in alkaline media due to cleavage of th

Full text of DOI:10.1016/j.tetlet.2011.11.036

Tetrahedron Letters 53 (2012) 253–255
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 6-aryl-20-deoxyuridine nucleosides via a Liebeskind
cross-coupling methodology
⇑
Martin Kögler, Steven De Jonghe, Piet Herdewijn
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Hitherto, the synthesis of 6-substituted 20-deoxyuridine nucleoside analogues via Pd-catalyzed Suzuki
cross-coupling reaction was hampered by the instability of the TIPDS-protected precursor 6-iodo-20-deox-
yuridine 1 in alkaline media due to cleavage of the glycosidic bond. Herein, the successful application of
the Liebeskind reaction under base-free conditions is reported. This method comprises of the stoichiom-
etric use of copper thiophene carboxylate (CuTC) as co-reagent at slightly elevated temperatures.
Fluoride-mediated desilylation and Yoshikawa-phosphorylation afforded the nucleotide analogues
4b–c, 4e, and 4i.
Article history:
Received 7 October 2011
Revised 3 November 2011
Accepted 8 November 2011
Available online 15 November 2011
Keywords:
6-Substituted 20-deoxyuridine nucleoside
analogues
Ó 2011 Elsevier Ltd. All rights reserved.
Liebeskind cross-coupling reaction
Copper thiophene carboxylate
Nucleoside analogues constitute an important class of organic
molecules with interesting biological profiles.1 In the past decades,
substitution at position 5 of the uracil moiety in 20-deoxyuridine
nucleosides has been proven a validated strategy for the develop-
ment of drugs used for the treatment of cancer and viral infec-
tions.2 Aryl and heteroaryl groups are usually introduced via a
Suzuki–Miyaura cross-coupling reaction3 using arylboronic acids
or via a Stille coupling using arylstannanes.4 The Suzuki–Miyaura
cross-coupling reaction has become the method of choice as a large
number of non-toxic, structurally diverse (hetero)arylboronic acids
is commercially available. It also allows carrying out the reaction in
the presence of H2O, which is favorable in terms of environmental
impact. On the other hand, position 6 of the uracil base in nucleo-
sides remained largely unexplored in medicinal chemistry pro-
grams and relatively few derivatives have been reported in the
literature. This might partly be due to the difficulties encountered
during the preparation of these compounds. Hitherto, gaining en-
try to these derivatives required multistep reaction sequences
and their further development was hampered by low overall yields
and the reduced chemical stability compared with their C-5 cong-
eners. Two recent papers elaborate on new synthetic methodolo-
gies for the preparation of 6-aryl-uridines. Shih and Chien
prepared a series of 6-aryl uridines using palladium(II)acetate as
catalyst, triphenylphosphine as ligand and sodium carbonate as a
base.5 On the other hand, Nencka et al. reported the synthesis of
6-aryl-50-O-TBDMS-20,30-O-isopropylideneuridine nucleosides un-
der standard, as well as ligand-free, Suzuki–Miyaura conditions.6
Recently, a number of cross-coupling reactions with protected
and unprotected uracil derivatives at position 6 have been reported
in the literature.7,8 In detail, Cernová et al. described the regioselec-
tive C–H arylation at C-6 of protected uracils in the presence of a
Pd-catalyst and CuI.8 However, the reported yields were frequently
low to moderate and mixtures of the two regioisomers (C-5 and
C-6-substituted products) were obtained. Furthermore, this
approach would require the inclusion of additional steps (depro-
tection, silylation, glycosylation) which makes it less attractive in
medicinal chemistry programs. To the best of our knowledge,
6-(hetero)aryl-20-deoxy-uridines are not known in the literature.
As part of an ongoing drug discovery program toward the identifi-
cation of novel mycobacterial thymidylate synthase inhibitors,9 we
were in need of an efficient process to get access to 6-aryl-20-
deoxy-uridines. In this letter, we describe their synthesis via a
base-free Liebeskind methodology.
ˇ
ˇ
In order to get access to 6-aryl-20-deoxyuridine derivatives,
6-iodo-20-deoxyuridine derivative 1 was considered as an ideal
key intermediate. It was prepared according to a literature protocol
from 20-deoxyuridine by protection of both hydroxyls as
a
1,1,3,3-tetraisopropoxydisiloxanylidene (TIPS) group, followed by
iodination at position 6.10 Classical Suzuki–Miyaura coupling of 1
with a number of substituted phenylboronic acids was envisioned.
However, for the synthesis of the corresponding 20-deoxyuridine
congeners, all attempts in which classical conditions (various Pd-
catalysts, such as Pd(PPh3)4, PdCl2(PPh3)2, or PdCl2(dppf), boronic
acids or their pinacol esters, and aqueous base) were employed,
failed. These results highlight a particular instability of compound
1 in alkaline media, which predominantly led to deglycosylation. It
is noteworthy that the attempted fluoride-mediated desilylation
⇑
Corresponding author. Tel.: +32 16 337387; fax: +32 16 337340.
E-mail address: Piet.Herdewijn@rega.kuleuven.be (P. Herdewijn).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.036

254
M. Kögler et al. / Tetrahedron Letters 53 (2012) 253–255
O
N
O
O
N
HN
HN
HN
O
R
O
N
R
O
R
O
HO
Na2O3PO
O
O
O
a
b
TIPDS
O
OH
3b R=4-F-Ph (90 %)
3c R=4-OMe-Ph (98 %)
3e R=3-CN-Ph (65 %)
3i R=styryl (89 %)
OH
4b R=4-F-Ph (18 %)
4c R=4-OMe-Ph (33 %)
4e R=3-CN-Ph (19 %)
2b R=4-F-Ph
2c R=4-OMe-Ph
2e R=3-CN-Ph
2i R=styryl
4i
R=styryl (24 %)
Scheme 1. Reagents and conditions: (a) TBAF, THF, rt; (b) POCl3, proton sponge, PO(OMe)3, 0 °C.
Table 1
Liebeskind cross-coupling reaction of 1 with various boronic acids or their esters
O
O
N
HN
HN
O
N
I
O
R
O
O
R-B(OH)2 (1.2 eq.), Pd(PPh3)4 (7 mol %)
CuTC (1.2 eq.), THF, 50 °C
O
O
TIPDS
TIPDS
O
O
2a-j
1
Entry
1
Compound
R
Yield (%)
79
2a
2
3
2b
2c
84
64
F
OMe
OMe
4
5
6
2d
2e
2f
72
66
0
CN
N
O
7
8
2g
2h
0
S
33a
9
2i
2j
76
0c
Ph
10b
a
b
c
An unseparable 5:1 mixture of 2h:1 was obtained.
Boronic acid pinacol ester used.
Complex reaction mixture.
of compound 1 (TBAF/THF or NH4F/MeOH) resulted in the formation
of 6-iodouracil along with other degradation products and that no
unprotected 6-iodo-20-deoxyuridine could be obtained. Conse-
quently, alternative Suzuki conditions were sought. Using a suspen-
sion of a base (e.g., K2CO3 or K3PO4) in an organic solvent, such as
toluene or DMF, was equally unsuccessful. Furthermore, tempera-
tures above 70 °C and long reaction times (>24 h) also appeared to
have a detrimental effect on the stability of 1.

M. Kögler et al. / Tetrahedron Letters 53 (2012) 253–255
255
This major stumbling block has been overcome by switching to
References and notes
an alternative base-free Suzuki coupling methodology developed
by Liebeskind and co-workers.11 This method comprises the stoi-
chiometric use of copper thiophene carboxylate (CuTC), acting as
a Cu(I)-cocatalyst, and allows to run reactions under nonbasic con-
ditions even at room temperature. Although the original Liebes-
kind methodology12 uses thioalkyl groups as leaving groups, we
applied the methodology on aryliodide 1 as substrate. Using stan-
dard Liesbeskind reaction conditions (1.2 equiv of boronic acid or
ester, 1.2 equiv of CuTC and 7 mol % of Pd(PPh3)4 in dry THF at
50 °C) the TIPDS-protected 6-substituted nucleoside derivatives
were obtained in moderate to good yields (60–80%).
This method works well with substituted phenylboronic acids
(compounds 2a–e), as well as with (E)-(2-phenylvinyl)-boronic
acid (compound 2i). Fluoride-mediated desilylation10 (TBAF/THF)
of compounds 2b–e and 2i furnished the desired nucleosides
3a–e and 3i (Scheme 1).13
1. (a) De Clercq, E. Nat. Rev. Drug Discovery 2002, 1, 13–25; (b) De Clercq, E. Med.
Res. Rev. 2003, 23, 253–274; (c) De Clercq, E. J. Clin. Virol. 2004, 30,
115–133.
2. (a) Lehman, N. L. Expert Opin. Investig. Drugs 2002, 11, 1775–1787; (b) Kumar, R.
Curr. Med. Chem. 2004, 11, 2749–2766.
3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
4. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992–4998; (b)
Wigerinck, P.; Kerremans, L.; Claes, P.; Snoeck, R.; Maudgal, P.; De Clerq, E.;
Herdewijn, P. J. Med. Chem. 1993, 36, 538–543.
5. Shih, Y.-C.; Chien, T.-C. Tetrahedron 2011, 67, 3915–3923.
6. Nencka, R.; Sinnaeve, D.; Karalic, I.; Martins, J. C.; Van Calenbergh, S. Org.
Biomol. Chem. 2010, 8, 5234–5246.
7. Bardagí, J. I.; Rossi, R. A. J. Org. Chem. 2008, 73, 4491–4495.
ˇ
ˇ
ˇ
ˇ
8. Cernová, M.; Cerna, I.; Pohl, R.; Hocek, M. J. Org. Chem. 2011, 76,
5309–5319.
9. Kögler, M.; Vanderhoydonck, B.; De Jonghe, S.; Rozenski, J.; Van Belle, K.;
Herman, J.; Louat, T.; Parchina, A.; Sibley, C.; Lescrinier, E.; Herdewijn, P. J. Med.
Chem. 2011, 54, 4847–4862.
10. Tanaka, H.; Hayakawa, H.; Iijima, S.; Haraguchi, K.; Miyasaka, T. Tetrahedron
1985, 41, 861–866.
This is the first time a series of 6-aryl-20-deoxy-nucleosides has
been prepared in an efficient way. In order to broaden the applica-
bility of this method, it was envisioned to introduce also a number
of heteroaryl groups at position 6 of the uracil base. It turned out,
however, that heterocyclic boronic acids are much less reactive un-
der these reaction conditions. In the case of 3-pyridylboronic acid
2f and 2-furylboronic acid 2g, no conversion was observed after
48 h at 50 °C. When 2-thiopheneboronic acid was employed, an
unseparable 5:1 mixture (as determined by 1H NMR) of the desired
2-thienyl derivative 2h and unreacted 1 was obtained after 24 h,
albeit in low yield. Prolonged reaction times (up to 3 days at
50 °C) had no measurable improvement on this ratio. Similarly,
performing the reaction with the pinacol ester of (E)-2-cyclo-
propylvinylboronic acid gave only a low yield of the desired deriv-
ative 2j containing substantial amounts of impurities. The results
are summarized in Table 1. These 6-aryl nucleoside analogues
were made as part of a project toward the identification of inhibi-
tors of a novel flavin-dependent thymidylate synthase from Myco-
bacterium tuberculosis, called ThyX. It has been shown that the
presence of a 50-phosphate moiety is required for ThyX-inhibition.9
Therefore, nucleosides 3b–c, 3e, and 3i have been selected for
phosphorylation of the primary hydroxyl group under standard
Yoshikawa-conditions14 (POCl3/proton sponge/PO(OMe)3/0 °C)
and evaluated in a biochemical assay as potential inhibitors of
11. Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149–2152.
12. Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91–93.
13. Representative example: Synthesis of 6-(4-fluorophenyl)-20-deoxyuridine 3b:
Compound
1 (419 mg, 0.7 mmol), Pd(PPh3)4 (49 mg, 0.042 mmol), CuTC
(147 mg, 0.77 mmol), and 4-fluorophenylboronic acid (118 mg, 0.84 mmol)
were flushed with Ar and subsequently suspended in dry THF (8 ml) under an
Ar atmosphere. The reaction mixture was stirred at 50 °C for 24 h and then
allowed to cool to room temperature. The solvent was evaporated, and the
residue was taken up in EtOAc (30 ml), and the organic layer was washed with
satd NaHCO3 (2 ꢀ 20 ml) and brine (1 ꢀ 20 ml), dried over MgSO4, and
evaporated. The residue was purified by silica gel column chromatography
(0.5% EtOH in CH2Cl2) to yield the TIPDS-protected intermediate 2b (332 mg,
84%). 1H NMR (300 MHz, CDCl3) d 8.56 (br s, 1H, NH), 7.43 (br s, 2H, ArH), 7.18
(t, 2H, J = 8.6 Hz, ArH), 5.55 (s, 1H, H-5), 5.51 (dd, 1H, J = 9.5, 3.1 Hz, H-10), 4.97
(m, 1H, H-30), 4.08–3.92 (m, 2H, H-50), 3.67 (m, 1H, H-40), 2.94–2.83 (m, 1H, H-
20), 2.24–2.10 (m, 1H, H-20), 1.15–0.96 (m, 28H, 4 ꢀ i-propyl). 13C NMR
(75 MHz, CDCl3) d 163.98 (d, JCF = 251 Hz), 162.19, 155.93, 149.76, 130.24 (d,
JCF = 8.3 Hz), 129.33 (d, JCF = 3.8 Hz), 116.47 (d, JCF = 22.5 Hz), 104.08, 86.50,
86.24, 73.76, 64.23, 39.79, (17.69, 17.57, 17.50, 17.47, 17.29, 17.12: 8 C), 13.42,
13.36, 12.83, 12.71. MS (ESI) calcd for C27H41FN2O6Si2 587.24 (M+Na+), 1151.49
(2 M+Na+); found 587.12, 1151.62.
To a solution of intermediate 2b (332 mg, 0.588 mmol) in dry THF (12 ml) was
added TBAF (1 M in THF, 1.18 ml, 1.18 mmol), and the reaction mixture was
stirred at room temperature for 45 min. The solvent was evaporated, and the
residue was purified by silica gel column chromatography (7–8% EtOH in
CH2Cl2), which yielded compound 3b (171 mg, 90%) as a white solid. 1H NMR
(300 MHz, CDCl3–MeOD = 5:2) d 7.48 (s, 2H, ArH), 7.22 (t, 2H, J = 8.1 Hz, ArH),
5.65 (t, 1H, J = 7.2 Hz, H-10), 5.60 (s, 1H, H-5), 4.57 (m, 1H, H-30), 3.87–3.70 (m,
3H, H-40 and H-50), 3.06–2.93 (m, 1H, H-20), 2.03–1.92 (m, 1H, H-20). 13C NMR
(75 MHz, CDCl3–MeOD = 5:2) d 163.77 (d, JCF = 252 Hz), 163.12, 155.95, 151.04,
129.81 (d, JCF = 9.1 Hz), 128.91 (d, JCF = 3.8 Hz), 116.20 (d, JCF = 21.9 Hz), 104.20,
88.23, 87.56, 70.99, 62.31, 37.59. MS (ESI) calcd for
(M+Na+), 667.18 (2 M+Na+); found 345.0, 666.85. HRMS (ESI) calcd for
15H15FN2O5 345.0857 (M+Na+); found 345.0867.
Synthesis of 6-(4-fluorophenyl)-20-deoxyuridine-50-monophosphate 4b: To
solution of compound 3b (127.6 mg, 0.396 mmol) and proton sponge
(132 mg, 0.61 mmol) in 2.1 ml of (MeO)3P@O was added POCl3 (56 l,
C15H15FN2O5 345.09
mycobacterial ThyX. At a concentration of 50 lM, none of the
tested nucleotides showed significant ThyX-inhibition.
C
a
Herein, the application of the base-free Liebeskind cross-cou-
pling methodology for the synthesis of 6-substituted 20-deoxyuri-
dine nucleosides is described. Position 6 of the uracil moiety has
been largely unexplored in medicinal chemistry programs and
6-aryl-20-deoxyuridine analogues are not known in the literature.
Therefore, the Liebeskind methodology, as presented here, shows
great promise to introduce structural variation at position 6 of dif-
ferent nucleosides and to study its effect on the biological activity.
This methodology works well with simple substituted phenylbo-
ronic acids. Unfortunately, the corresponding heteroaryl deriva-
tives could not be obtained and further optimization is required
in order to find a versatile method for the synthesis of this class
of organic molecules.
l
0.61 mmol) in one portion at 0 °C, and the reaction mixture was stirred at
0 °C for 3 h. The reaction mixture was poured into ice/H2O and brought to pH
8–9 with 1 M NaOH, then the volatiles were removed in vacuo. The residue was
purified by silica gel column chromatography (2-propanol/NH4OH/
H2O = 85:10:5?75:15:10) followed by RP-HPLC (30 mM aq TEAB/
CH3CN = 90:10?85:15, 16 ml/min). Next, the phosphates were subjected to
ion exchange (Dowex 50 WX-8, Na+) and lyophilized, yielding title compound
4b (32 mg, 18%) as a white solid. 1H NMR (500 MHz, D2O) d 7.52 (br s, 2H, ArH),
7.29 (m, 2H, ArH), 5.75 (dd, 1H, J = 8.8, 4.4 Hz, H-10), 5.74 (s, 1H, H-5), 4.53 (m,
1H, H-30), 4.01–3.95 (m, 1H, H-50), 3.92–3.86 (m, 1H, H-50), 3.85–3.78 (m, 1H,
H-40), 2.96–2.89 (m, 1H, H-20), 2.10–2.01 (m, 1H, H-20). 13C NMR (125 MHz,
D2O) d 165.17, 163.34 (d, 1C JCF = 247.5 Hz), 156.92, 151.13 129.93 (d, 2C,
JCF = 8.8 Hz), 128.19, 115.73 (d, 2C, JCF = 22.5 Hz), 103.36, 86.80, 84.87 (d, 1C,
JCP = 7.5 Hz), 70.65, 63.60 (d, 1C, JCP = 3.8 Hz), 35.99. 31P NMR (121 MHz, D2O) d
3.91. HRMS (ESI) calcd for C15H16FN2O8P 401.0555 (MꢁH+); found 401.0543.
14. Yoshikawa, M.; Kato, T.; Takenish, T. Bull. Chem. Soc. Jpn. 1969, 42, 3505–3508.
Acknowledgment
Martin Kögler is deeply indebted to the IWT Vlaanderen for pro-
viding a PhD-scholarship.