Synthesis and biological evaluation of prodrugs of 2-fluoro-2-deoxyribose- 1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate

Article abstract of DOI:10.1016/j.bmcl.2013.02.117

We report in this Letter the synthesis of prodrugs of 2-fluoro-2- deoxyarabinose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate. We demonstrate the difficulty of realising a phosphorylation step on the anomeric position of 2-deoxyribose, and we discover that introduction of fluorine atoms on the 2 position of 2-deoxyribose enables the phosphorylation step: in fact, the stability of the prodrugs increases with the degree of 2-fluorination. Stability studies of produgs of 2-fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate in acidic and neutral conditions were conducted to confirm our observation. Biological evaluation of prodrugs of 2,2-difluoro-2-deoxyribose-1-phosphate for antiviral and cytotoxic activity is reported.

Full text of DOI:10.1016/j.bmcl.2013.02.117

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of prodrugs of 2-
fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-
2-deoxyribose-1-phosphate
Nadege Hamon a, Maurizio Quintiliani a, Jan Balzarini b, Christopher McGuigan a,
⇑
a School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK
b Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
We report in this Letter the synthesis of prodrugs of 2-fluoro-2-deoxyarabinose-1-phosphate and
2,2-difluoro-2-deoxyribose-1-phosphate. We demonstrate the difficulty of realising a phosphorylation
step on the anomeric position of 2-deoxyribose, and we discover that introduction of fluorine atoms on
the 2 position of 2-deoxyribose enables the phosphorylation step: in fact, the stability of the prodrugs
increases with the degree of 2-fluorination. Stability studies of produgs of 2-fluoro-2-deoxyribose-1-phos-
phate and 2,2-difluoro-2-deoxyribose-1-phosphate in acidic and neutral conditions were conducted to
confirm our observation. Biological evaluation of prodrugs of 2,2-difluoro-2-deoxyribose-1-phosphate
for antiviral and cytotoxic activity is reported.
Received 16 January 2013
Revised 26 February 2013
Accepted 28 February 2013
Available online xxxx
Keywords:
Sugars
Deoxyribose
Phosphorylation
Prodrugs
Ó 2013 Published by Elsevier Ltd.
Fluorination
Glycosyl-1-phosphates are important compounds in many life
processes. They are essential constituents of larger biomolecules
and are key intermediates in the metabolism of sugars and their
transformation into nucleosides. Among them, 2-deoxy-
Many papers have reviewed the introduction of a phosphate
group at the anomeric position of a glycosyl unit.8 Three main
strategies are observed: (a) the sugar, activated at the anomeric
position, acts as an electrophilic compound and a nucleophilic
displacement reaction is performed thanks to a phosphate anion.
In this case, the electrophilic compounds are generally glycosyl
halides,9 glycosyl-trichloroacetimidates,10 glycosyl nitrates,11 or
glycosyl thioimidoyl derivatives;12 (b) the anomeric hydroxyl
group of the sugar acts as the nucleophilic component and attacks
an activating phosphate or phosphite in the presence of a base; (c)
another alternative strategy consists in synthesising P(III) interme-
diates: the most famous approaches are the phosphoramidite
methodology followed by oxidation of the intermediate phos-
phite;13 or the H-phosphonate approach which entails phosphity-
lation of the hydroxylic sugar followed by oxydation of the
resulting H-phosphonate.14 However, these strategies are mainly
applied to glycosyls in their pyranose form. In the case of the furan-
osyl family, the phosphorylation step has been successfully applied
in the case of the ribo or arabinofuranosyl analogues,15 but it is
hardly described in the case of 2-deoxyribose derivatives: due to
the absence of a 2-hydroxyl group, the anomeric phosphate is more
labile, so its synthesis is quite difficult. In fact, to the best of our
knowledge, only one strategy concerning the phosphorylation step
at the anomeric position of 2-deoxyribose was described:16 under
acidic conditions and with an excess of phosphoric acid, 2-deoxy-
ribose-1-chloride 1 was phosphorylated in good yield to give com-
pound 2 (Scheme 1).
a-D-ribose-1-phosphate is a catabolic product of thymidine phos-
phorylase (EC 2.4.2.4), an enzyme involved in the metabolism of
pyrimidine nucleosides and which may promote angiogenesis.1
Thymidine phosphorylase is also involved in the degradation of
antiviral agents such as BVDU.2 It is recognized that the therapeutic
potential of drugs bearing a phosphate, phosphinate or phospho-
nate moiety is considerably reduced due to their low membrane
permeation because each of these groups carry negative charges
at physiological pH.3 Several prodrug technologies have been
investigated to overcome this problem4 and, among them, the
phosphoramidate ProTide technology has been successfully applied
to various nucleoside analogues.5 Furthermore the phosphorami-
date technology has been recently applied to sugars (mainly
glucosamine)6 in order to improve their therapeutic potential. The
synthesis of phosphoroamidate prodrugs of 2-deoxy-a-D-ribose-l-
phosphate is of great interest, as they could act as inhibitors of
thymidine phosphorylase or regulators in associated metabolic
processes.7
⇑
Corresponding author. Tel./fax: +44 029 2087 4537.
E-mail address: mcguigan@cardiff.ac.uk (C. McGuigan).
0960-894X/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2013.02.117
Please cite this article in press as: Hamon, N.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.02.117

2
N. Hamon et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Scheme 1. Phosphorylation of 1-choro-3,5-di-para-chlorobenzoyl-2-deoxyribose.
We knew from our previous experience16b and from the
literature16a that a phosphorylation reaction was possible on the
1-chloro-3,5-di-para-chlorobenzoyl-2-deoxyribose. Encouraged by
this preliminary result, we decided to study the phosphorylation
of 3,5-di-benzyl-2-deoxyribose. Results are summarized in
Table 1 in the Supplementary data. The phosphorylation step was
first tried in classical conditions using POCl3, phenyldichlorophos-
phate19 or chlorodiphenyl phosphate20 in the presence of different
bases and activating agents such as PyBOP.21 We also investigated
the P(III) strategy: we tried to use the phosphoramidite,22 phospho-
radiamidite23 and H-phosphonate24 methodologies. We decided to
try the phosphorylation with charged phosphorylating agents such
as methyl pyridinium dichlorophosphate25 or of the dibarium salt
of 2-cyanoethylphosphate26 in order to stabilize the resulting phos-
phate. To finish our study, we decided to invert our strategy by plac-
ing the leaving group on the anomeric position of the sugar15a,b, 27
and to use the phosphate reagent as the attacking agent. But all
these attempts did not lead to the desired products, which lead to
the conclusion that final compounds are not stable under the reac-
tion conditions.
BnO
HO
a, b, c
O
O
OH
OH
BnO
HO
4
3
R1
O
BnO
O
R2
d
O
P
N
H
O
O
OAr
BnO
5
Ar = Ph, Naph
1 = CH3, CH(CH3)2
R2 = CH3, CH2 C(CH3)3, cyclohexyl
R
Scheme 2. Synthesis of prodrugs of 2-deoxyribose-1-phosphate. (a) CH3COCl,
MeOH, rt, 1 h, 100%, (b) BnCl, KOH, THF, reflux, 31 h, 74%, (c) AcOH/H2O 8:2, 36 h,
50 °C, 75% (d) appropriate phosphorochloridate, tBuMgCl or NMI, THF.
At this stage, we concluded that the problem in all these phos-
phorylation reactions came from the 2-deoxyribose sugar: the lack
of a group at the 2 position destabilizes the resulting phosphate.
This hypothesis is confirmed by the fact that the phosphorylation
reaction was described several times on ribose and 2-fluoro-2-
deoxyribose derivatives in the literature.15 Considering this
information and the fact that the fluorine atom is a good isostere
of the hydrogen atom, we decided to synthesize prodrugs of
2-fluoro-2-deoxyarabinose-1-phosphate. The synthesis started
However it is well-known that the presence of a fluorine
substituent adjacent to the anomeric centre stabilizes glycosyl
phosphates or nucleosides15 and excellent reviews on fluorinated
sugars describing their high potential and their broad field of
applications have been published.17 In this paper we describe our
attempts to phosphorylate the anomeric position of 3,5-dibenzyl-
2-deoxyribose and how the gem-difluorination of the sugar signif-
icantly stabilises the resulting phosphate. We were particularly
interested to prepare C1-phosphoramidates as prodrugs of the free
phosphate, following procedures we have widely reported for
nucleosides.5,18
The strategy used to synthesise prodrugs of 2-deoxyribose-1-
phosphate is shown in Scheme 2: the anomeric position of 2-deoxy-
ribose 3 was first quantitatively protected as a methyl glycoside in
standard conditions. Protection of the diol was accomplished in 74%
yield and removal of the methyl ether was realised under acidic
conditions. The next step was the coupling of compound 4 with dif-
ferent suitable phosphorochloridates in order to obtain the desired
phosphoramidates. We tried this reaction under different condi-
tions (À78 °C or rt) and with different bases (DMAP, NMI, tBuMgCl)
but unfortunately this coupling reaction did not work.
from commercially 1,3,5-tri-benzoyl-2-fluoro-2-deoxyribose
6
(Scheme 3): bromination of the anomeric position28 followed by
the alcohol formation in the presence of triethylamine, water and
dimethylformamide23 was realized in quantitative yield. Protection
of the resulting alcohol as a silyl ether29 yielded compound 9 in a
a/b
1:0.9 ratio. We then needed to change the benzoyl protecting
groups of the sugar since the basic conditions used to remove them
are not compatible with the presence of the future phosphorami-
date group. In a recent paper, Schinazi and co-workers30 explained
that a benzyloxycarbonyl protecting group was well-adapted with
synthesis of nucleoside aryloxy phosphoramidate prodrugs: this
protecting group is easy to introduce, and the neutral conditions
Table 1
Stability study of compound 14b and 25c
2-Fluoro-2-deoxyarabinose
2,2-Fluoro-2-deoxyribose family compound 25c
family compound 14b
Stability study at pH 2
Stability study at pH 5
Stability study at pH 7
Stability study at À20 °C
t1/2 = 64 min
—
t1/2 = 120 min
Purity after 1 h: 68%
Purity after 13 h: 30%
Purity after 20 h: 8%
—
No degradation observed over 2 days
No degradation observed over 2 days
No degradation observed after 4 months
Please cite this article in press as: Hamon, N.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.02.117

N. Hamon et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
BzO
BzO
BzO
BzO
O
O
O
O
OBz
a
Br
b
OH
c
OTIPS
BzO
F
BzO
F
BzO
F
BzO
F
6
7
8
9
HO
CbzO
CbzO
CbzO
O
P
O
O
O
O
g
e
OTIPS
OTIPS
OH
O
AA
d
f
OAr
HO
F
CbzO
F
CbzO
F
CbzO
F
10
11
12
13
14a: Ar = Ph, AA = L-Ala methyl ester
HO
O
P
OAr
14b: Ar = Ph, AA = L-Ala cyclohexyl ester
14c: Ar = Ph, AA = L-Val methyl ester
14d: Ar = Ph, AA = L-Ala neopentyl ester
14e: Ar = Naph, AA = L-Val methyl ester
14f: Ar = Naph, AA = L-Ala neopentyl ester
14g: Ar = Naph, AA = L-Ala methyl ester
14h: Ar = Naph, AA = L-Ala cyclohexyl ester
O
h
O
AA
HO
F
14
Scheme 3. Synthesis of 2-f luoro-2-deoxy-arabinose-1-phosphate prodrugs. (a) HBr, DCM, rt, 13 h, (b) Et3N, H2O, DMF, rt, 1.5 h, 100% over two-steps, (c) TIPS-OTf, 2,6-
lutidine, CH2Cl2, 0 °C, 2.5 h, 100%, (d) Et3N, H2O, MeOH, rt, 3 days, 86%, (e) CbzCl, DMAP, CH2Cl2, rt, 12 h, 95%, (f) HF-pyr, pyridine, rt, 44 h, 100%, (g) appropriated
phosphorochloridate, tBuMgCl, THF, rt, 15 h, (h) H2, Pd/C, EtOH, rt, 2 h.
used to remove it are compatible with the presence of the phosphor-
amidate group. So we decided to apply this group to our strategy of
synthesis. Compound 9 was deprotected under basic conditions and
the resulting diol was protected in the presence of benzyl chlorofor-
mate to yield quantitatively compound 11 in a a/b ratio 1:1. Depro-
tection of the anomeric position was tried in several conditions
(TBAF, NH4F, HCl, TFA) but the yields were low (0–20%) in all these
conditions. Thus, we finally decided to perform the deprotection in
the presence of HF-pyridine,29 and in this case the yield was quan-
titative and the
it was easy to discriminate the
a
/b ratio changed to 1:0.2. Thanks to the literature,31
a
from the b diastereoisomers: the a
anomers had J1,2 = 0 Hz, confirming that H1 and H2 were trans to
each other, so the NMR signal of H2 was a doublet with J2-F = 49-
50 Hz. In the case of the b anomer, J1-F = 0 Hz, which confirmed that
H1 and 2F were trans to each other, and the signal of H2 was in this
case
a ddd (with a general range of J1,2 = 4 Hz, J2-F = 50 Hz,
J2,3 = 6 Hz). Finally, coupling of compound 12 with the appropriate
aryloxy phosphorochloridates followed by deprotection of the
benzyloxy carbonyl protecting groups25 yielded the desired 2-flu-
oro-2-deoxyarabinose-1-phosphate prodrugs 14a–h. Their success-
ful isolation highlights the change in stability upon 2-fluorination.
Surprisingly, only the
a prodrugs were isolated. However,
during the purification of the final prodrugs, we experienced con-
siderable difficulty in isolating pure compound and we discovered
that a second purification, either by preparative TLC, column chro-
matography or preparative HPLC, led to a degradation of the pro-
drugs. Thus, we conducted
a preliminary stability study of
compound 14b. One hour after purification by column chromatog-
raphy the purity of compound 14b was 68%, after one night at
À20 °C, the purity of the compound decreased dramatically to
30%, and after 20 h it was only 8%. At pH 2, the half-life of com-
pound 14b was only 64 min, while at pH 7 it was 120 min (Fig. 1).
Since all our 2-fluoro-2-deoxyarabinose-1-phosphate prodrugs
were not stable, they could not be biologically evaluated but we
were encouraged by these results: indeed by adding one fluorine
atom on the 2 position of 2-deoxyribose, the phosphorylation
was possible on the anomeric position, even if the resulting pro-
drugs were not stable enough to be tested. So we decided to ex-
plore the 2,2-difluoro-2-deoxyribose family. We hypothesized
Figure 1. Stability studies of compound 14b. Blue experiment was done at pH 2.
Red experiment was done at pH 7. (a) Percentages of purity of compound 14b
according to the time at different pH values. (b) Calculation of t1/2 of compound 14b
at different pH values.
that the addition of a second fluorine atom at the 2 position would
further increase the stability of the resulting prodrugs.
The strategy used to synthesize prodrugs of 2,2-difluoro-2-
deoxyribose-1-phosphate was the same as the one previously used
in the case of the 2-fluoro-2-deoxyribose family (Scheme 4).
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4
N. Hamon et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
BzO
BzO
BzO
BzO
HO
O
O
O
O
O
O
b
a
OH
OTIPS
OTIPS
OTIPS
F
F
F
F
F
BzO
F
BzO
F
BzO
F
HO
F
BzO
F
17
15
16
18
19
HO
CbzO
CbzO
O
O
O
c
d
e
f
OTIPS
OTIPS
OH
F
F
F
HO
F
CbzO
F
CbzO
F
20
21
22
CbzO
O
P
HO
O
P
HO
O
P
O
O
O
g
O
AA
O
AA
O
AA
OAr
OAr
OAr
F
F
F
CbzO
F
HO
F
HO
F
24a: Ar = Ph, AA = L-Ala neopentyl ester
24b: Ar=Ph, AA = L-Ala methyl ester
24c: Ar = Ph, AA = L-Ala cyclohexyl ester
24d: Ar = Ph, AA = L-Val methyl ester
24e: Ar = Naph, AA = L-Val methyl ester
25a
25b
25c
23
25d
25e
25f
24f: Ar = Naph, AA = L-Ala neopentyl ester
24g: Ar = Naph, AA = L-Ala methyl ester
24h: Ar = Naph, AA = L-Ala cyclohexyl ester
25g
25h
Scheme 4. Synthesis of 2,2-difluoro-2-deoxyribose-1-phosphate prodrugs. (a) LiAl(OtBu)3H, THF/H2O 4:1, À78 °C, 2 h, (b) TIPS-OTf, 2,6-lutidine, CH2Cl2, 0 °C, 2 h, 67% over 2
steps, (c) Et3N, H2O, MeOH, rt, 4 days, 70%, (d) CbzCl, DMAP, CH2Cl2, rt, 12 h, 100%, (e) HF-pyr, pyridine, rt, 100%, (f) appropriate phosphorochloridate, tBuMgCl, THF, rt, 15 h,
(g) H2, Pd/C, EtOH, rt, 2 h.
Reduction of the lactone 15 was achieved in the presence of
LiAl(OtBu)3H and the resulting alcohol was protected as a silyl
ether with 46% yield. We were also able to isolate a mixture of
the monobenzoylated sugars 18 and 19 with 31% yield but this par-
tial deprotection was acceptable as the next step consisted in
removing all the benzoyl esters. Protection of the resulting 3 and
5 alcohols was achieved in the presence of benzyl chloroformate
and deprotection of the silyl ether at the anomeric position was
They had no antiviral activity and were not cytotoxic in HEL cell cul-
tures (herpes simplex virus-1 (KOS), herpes simplex virus-2 (G),
vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1
TKÀ KOS ACV, varicella-zoster virus (OKA, 07-1), cytomegalovirus
(AD-169, Davis), EC50 >20–100
no activity against feline corona virus (FIPV) and feline herpes virus
in CRFK cell cultures (EC50 >20–100 M, CC50 >100 M), nor anti
HIV-1 (IIIB) and HIV-2 (ROD) activity in human T-lymphocyte CEM
cell cultures (EC50 >50 M for the naphthyl series, EC50 >250 lM
lM, MCC P100 lM), and they had
l
l
done with HF-Pyridine and yielded compound 22 in a 1:0.6
a/b ra-
l
tio. The coupling reaction of the compound 22 with the appropriate
phosphorochloridates was done in the presence of tBuMgCl, and
the final step consisted in the hydrogenolysis of the benzyloxycar-
bonyl groups which led to the desired prodrugs of 2,2-difluoro-2-
deoxyribose-1-phosphate (with yields of between 24% and 68%
for the phenyl series). They were not significant inhibitors of the
proliferation of murine leukemia cells (L1210) and human T-lym-
phocyte cells (CEM) (IC50 from 30 to >250 lM).
As a conclusion, we have demonstrated that introducing a phos-
phate group on the anomeric position of 2-deoxyribose is difficult
due to the lack of a stabilizing group at the 2 position. However, by
introducing one or two fluorine atoms on the 2 position, we in-
creased the stability of the resulting prodrug: the higher the degree
of fluorination on the 2 position, the more stable is the prodrug.
We have confirmed this tendency by performing a pH stability
study of the 2,2-difluoro-2-deoxyribose-1-phosphate prodrug and
the 2-fluoro-2-deoxyarabinose-1-phosphate prodrug: the difluoro
prodrugs are stable for 2 days under acidic conditions whereas
the mono-fluorinated derivative had a half-life of 64 min. More-
over, the 2,2-difluoro prodrugs are stable at À20 °C for more than
4 months whereas the mono-fluorinated analogs were almost fully
degradated within 24 h. Unfortunately, biological evaluation of the
pro-drugs of the 2,2-difluoro-2-deoxyribose-1-phosphate showed
that they had no inhibitory activity against a variety of virus infec-
tions and cancer cell proliferation.
over the two last steps). For each compound,
a anomers 25 and b
anomers 24 were isolated as a mixture of PS and PR diastereoiso-
mers. In order to characterize the two anomers we performed dif-
ferent experiments. We first examined the NOE effects between
the H1 and H4 protons, without success. So we based our study
on the literature:32 in the b anomer the signal of the fluorines are
close to each other (À125 and À127 ppm in 19F NMR), whereas
in the
a
anomer, the two signals are much more separated (À110
and À126 ppm in 19F NMR).
As expected, the 2,2-difluoro-2-deoxyribose-1-phosphate pro-
drugs are much more stable than the 2-fluoro-2-deoxyribose-1-
phosphate prodrugs. Compound 25c showed no degradation at
all after 4 months at À20 °C whereas the corresponding mono-flu-
oro prodrug was almost completely degradated after only 24 h (Ta-
ble 1). Stability studies of compound 25c showed no degradation at
all after 2 days in acidic (pH 5) and neutral (pH 7) conditions. Thus,
difluorination of the sugar affords striking stabilization of the ano-
meric phosphate prodrugs.
Acknowledgments
2,2-Difluoro-2-deoxyribose-1-phosphate prodrugs were sub-
jected to biological evaluation because it could be expected that
such ribose phosphate analogues can interfere with several
enzymes of the purine and pyrimidine nucleoside metabolism.
Unfortunately, these compounds did not show biological activity.
We thank Helen Murphy for secretarial assistance and Leentje
Persoons, Frieda De Meyer, Lizette van Berckelaer and Leen Ingels
for excellent technical assistance. The biological evaluations were
supported by the KU Leuven (GOA no. 10/014).
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N. Hamon et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
5
15. (a) Joe, M.; Lowary, T. L. Carbohydr. Res. 2006, 341, 2723; (b) Smellie, I. A.;
Bhakta, S.; Sim, E.; Fairbanks, A. J. Org. Biomol. Chem. 2007, 5, 2257; (c) Zhang,
Q. B.; Liu, H. W. J. Am. Chem. Soc. 2001, 123, 6756; (d) Maryanoff, B. E.; Reitz, A.
B.; Nortey, S. O. Tetrahedron 1988, 44, 3093.
16. (a) Komatsu, H.; Awano, H. J. Org. Chem. 2002, 67, 5419; (b) Voorde, J. V.;
Quintiliani, M.; McGuigan, C.; Liekens, S.; Balzarini, J. Biochem. Pharmacol. 2012,
83, 1358.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.02.
117.
17. (a) Penglis, A. A. E. Adv. Carbohydr. Chem. Biochem. 1981, 38, 105; (b) Tsuchiya,
T. Adv. Carbohydr. Chem. Biochem. 1990, 48, 91.
18. Cahard, D.; McGuigan, C.; Balzarini, J. Mini-Rev. Med. Chem. 2004, 4, 371.
19. Sabesan, S.; Neira, S. Carbohydr. Res. 1992, 223, 169.
20. Lee, J. P., Gha Seung; Lee, Moonsub; Bang, Hyo-Jeong; Lee, Jae Chul; Kim, Cheol
Kyong; Choi, Chang-Ju; Kim, Han Kyong; Lee, Hoe Chul; Chang, Young-Kil et al.
From PCT Int. Appl. (2006), WO 2006071090 A1 20060706.
21. Zalcharova, V. M.; Serpi, M.; Krylov, I. S.; Peterson, L. W.; Breitenbach, J. M.;
Borysko, K. Z.; Drach, J. C.; Collins, M.; Hilfinger, J. M.; Kashemirov, B. A.;
McKenna, C. E. J. Med. Chem. 2011, 54, 5680.
22. Nikan, M.; Bare, G. A. L.; Sherman, J. C. Tetrahedron Lett. 2011, 52, 1791.
23. Yamada, K. M. N.; Hayakawa, H. Nucleosides Nucleotides Nucleic Acids 2009, 28,
1117.
24. Chang, A.-L. G. G.; Wagner, C. R. Nucleosides Nucleotides Nucleic Acids 2001, 20,
1571.
25. Jaworek, C. H.; Iacobucci, S.; Calias, P.; d’Alarcao, M. Carbohydr. Res. 2001, 331,
375.
26. Tener, G. M. J. Am. Chem. Soc. 1961, 83, 159.
27. Gao, M.; Chen, Y.; Tan, S.; Reibenspies, J. H.; Zingaro, R. A. Heteroat. Chem. 2008,
19, 199.
References and notes
1. Griffiths, L.; Stratford, I. J. Br. J. Cancer 1997, 76, 689.
2. De Clercq, E. Biochem. Pharmacol. 2004, 68, 2301.
3. He, G.-X.; Krise, J. P. Biotechnol. Pharm. Aspects 2007, 5, 923.
4. Carston, R.; Carston, R. Wagner; Vidhya, V. Iyer; McIntee, E. J. Med. Res. Rev.
2000, 20, 417.
5. Mehellou, Y.; Balzarini, J.; McGuigan, C. ChemMedChem 2009, 4, 1779.
6. Serpi, M.; Bibbo, R.; Rat, S.; Roberts, H.; Hughes, C.; Caterson, B.; Jose Alcaraz,
M.; Torrent Gibert, A.; Alaez Verson, C. R.; McGuigan, C. J. Med. Chem. 2012, 55,
4629.
7. Rubira, M. J.; Jimeno, M. L.; Balzarini, J.; Camarasa, M. J.; Perez-Perez, M. J.
Tetrahedron 1998, 54, 8223.
8. (a) Zamyatina, A. K. P. Carbohydr. Chem. 2009, 35, 71–98; (b) Nikolaev, A. V.;
Botvinko, I. V.; Ross, A. J. Carbohydr. Res. 2007, 342, 297; (c) Hansson, J.;
Oscarson, S. Curr. Org. Chem. 2000, 4, 535; (d) Nakamura, S.; Nambu, H. H. S. In
Handbook of Chemical Glycosylation; Demchenko, A., Ed.; Wiley-Vch: Weinheim,
Germany, 2008; p 223. ch 3.4.
9. (a) Binch, H.; Stangier, K.; Thiem, J. Carbohydr. Res. 1998, 306, 409; (b)
Timmons, S. C.; Jakeman, D. L. Carbohydr. Res. 2008, 343, 865; (c) Oberthur, M.;
Leimkuhler, C.; Kahne, D. Org. Lett. 2004, 6, 2873.
28. McGuigan, C.; Derudas, M.; Quintiliani, M.; Andrei, G.; Snoeck, R.; Henson, G.;
Balzarini, J. Bioorg. Med. Chem. Lett. 2009, 19, 6264.
29. Guzi, T. J. P., D. A.; Labroli, M. A.; Dwyer, M. P.; Paruch, K.; Rosner, K. E.; Shen,
R.; Popovici-Muller, J. PCT Int. Appl. WO 2009061781 A1 20090514, 2009.
30. Cho, J. H.; Amblard, F.; Coats, S. J.; Schinazi, R. F. Tetrahedron 2011, 67, 5487.
31. (a) Shortnacy-Fowler, A. T.; Tiwari, K. N.; Montgomery, J. A.; Secrist, J. A.
Nucleosides Nucleotides Nucleic Acids 2001, 20, 1583; (b) Pathak, A. K.; Pathak,
V.; Suling, W. J.; Riordan, J. R.; Gurcha, S. S.; Besra, G. S.; Reynolds, R. C. Bioorg.
Med. Chem. 2009, 17, 872; (c) Tiwan, K. N.; Shortnacy-Fowler, A. T.; Parker, W.
B.; Waud, W. R.; Secrist, J. A., III Nucleosides Nucleotides Nucleic Acids 2009, 28,
657; (d) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988,
53, 2406.
10. Bowers, S. G.; Mahmud, T.; Floss, H. G. Carbohydr. Res. 2002, 337, 297.
11. Illarionov, P. A.; Torgov, V. I.; Hancock, I. C.; Shibaev, V. N.; Illarionova, P. A.
Tetrahedron Lett. 1999, 40, 4247.
12. (a) Ferrieres, V.; Blanchard, S.; Fischer, D.; Plusquellec, D. Bioorg. Med. Chem.
Lett. 2002, 12, 3515; (b) Euzen, R.; Ferrieres, V.; Plusquellec, D. J. Org. Chem.
2005, 70, 847.
13. (a) Hitchcock, S. A.; Eid, C. N.; Aikins, J. A.; Zia-Ebrahimi, M.; Blaszczak, L. C. J.
Am. Chem. Soc. 1916, 1998, 120; (b) Men, H. B.; Park, P.; Ge, M.; Walker, S. J. Am.
Chem. Soc. 1998, 120, 2484; (c) Liu, H. T.; Sadamoto, R.; Sears, P. S.; Wong, C. H.
J. Am. Chem. Soc. 2001, 123, 9916; (d) VanNieuwenhze, M. S.; Mauldin, S. C.;
Zia-Ebrahimi, M.; Aikins, J. A.; Blaszczak, L. C. J. Am. Chem. Soc. 2001, 123, 6983.
14. Naundorf, A.; Natsch, S.; Klaffke, W. Tetrahedron Lett. 2000, 41, 189.
32. Wirth, D. Eur. Pat. Appl. EP 727433 A1 19960821, 1996.
Please cite this article in press as: Hamon, N.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.02.117