Deoxygenation of 5-O-benzoyl-1,2-isopropylidene-3-O-imidazolylthiocarbonyl-α-d-xylofuranose using dimethyl phosphite: an efficient alternate method towards a 3′-deoxynucleoside glycosyl donor

Article abstract of DOI:10.1016/j.tetlet.2008.03.079

An efficient radical deoxygenation reaction of thiocarbonylimidazolyl activated glycoside analogue using dimethyl phosphite as hydrogen source and radical chain carrier was performed as a key step in a multi step synthesis towards a common 3-deoxy glycosyl donor for 3′-deoxynucleosides. This method has safety and cost advantages compared to the generally used radical reduction reagents.

Full text of DOI:10.1016/j.tetlet.2008.03.079

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3288–3290
Deoxygenation of 5-O-benzoyl-1,2-isopropylidene-3-O-
imidazolylthiocarbonyl-a-D-xylofuranose using dimethyl
phosphite: an efficient alternate method towards a
0
3
-deoxynucleoside glycosyl donor
Ivan Zlatev, Jean-Jacques Vasseur, Franßcois Morvan *
Institut des Biomol e´ cules Max Mousseron (IBMM), UMR 5247 CNRS—Universit e´ Montpellier 1, Universit e´ Montpellier 2,
Place Eug e` ne Bataillon, CC1704, 34095 Montpellier Cedex 5, France
Received 23 January 2008; revised 4 March 2008; accepted 17 March 2008
Available online 21 March 2008
Abstract
An efficient radical deoxygenation reaction of thiocarbonylimidazolyl activated glycoside analogue using dimethyl phosphite as
hydrogen source and radical chain carrier was performed as a key step in a multi step synthesis towards a common 3-deoxy glycosyl
0
donor for 3 -deoxynucleosides. This method has safety and cost advantages compared to the generally used radical reduction reagents.
Ó 2008 Elsevier Ltd. All rights reserved.
0
Keywords: 3 -Deoxynucleosides; Barton–McCombie deoxygenation; Thiocarbonylimidazolyl; Dimethyl phosphite
0
The removal of the 3 -hydroxy group in nucleoside ana-
environment and produces tin byproducts that are difficult
to remove from the final product, considerable efforts were
done in the development of alternate radical reagents.
0
logues, leading to the corresponding 3 -deoxy compounds
is a well-known chemical modification, explored by several
research groups in the aim to improve the antiviral and/or
9
,10
Tributylgermanium hydride
and silanes, such as tri-
1
–5
6,7
11
antineoplastic,
or more recently the anti-SARS-CoV
ethylsilane or tris-trimethylsilylsilane, reveal to be as effi-
activities of modified nucleosides.
cient as n-Bu SnH. Furthermore, they are superior reagents
3
The chemical route of these compounds involves a deoxy-
genation reaction on the 3 position of the furanose moiety
of either a nucleoside or a glycoside precursor. Indeed, in
nucleoside and glycoside chemistry, deoxygenation is a
common transformation which is generally carried out
effectively by radical reduction. In the original Barton–
from ecological and practical points of view since they are
less or even non-toxic and work-up procedures are easier.
However, their cost is a serious drawback making their
use not a cheap alternative to tin hydride.
In the beginning of the 1990s, Barton et al. reported that
reagents containing a P–H bond such as dimethyl and
8
12
McCombie method, thionocarbonates or xanthates are
diethyl phosphites and hypophosphorous acid or its
1
3,14
efficiently reduced using tributyltin hydride (n-Bu SnH)
salts
are efficient hydrogen sources and chain carriers
3
which is the hydrogen atom source, and the corresponding
for radical reductions of various thionocarbonates and
xanthates. These reagents are commercially available,
cheap and far less toxic than organotin compounds, which
make them almost an ideal alternative.
Å
tin radical (n-Bu Sn ) is the radical chain carrier. However,
3
as this reagent is toxic, expensive and harmful for the
Since then, however not much attention was paid to the
general use or development of these reagents, as only few
*
Corresponding author.
E-mail address: morvan@univ-montp2.fr (F. Morvan).
1
5–17
reports resumed it.
Moreover, we would like to stress
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.079

I. Zlatev et al. / Tetrahedron Letters 49 (2008) 3288–3290
3289
on the fact that although deoxygenation reaction is very
common, particularly in nucleoside chemistry, these radical
reduction reagents remain widely unpopular or even some-
what unknown despite their numerous practical advanta-
oxidative cleavage of the corresponding diol, followed by
reduction of the resulting aldehyde, as previously reported
2
1
21
by Robins et al. The resulting xylofuranose 2 was selec-
2
2
tively benzoylated on the primary hydroxyl giving 3 and
after work-up the crude was directly treated with
1.2 M equiv of TCDI which reacted with the sole remain-
ing hydroxyl providing the desired 3-O-imidazolylthio-
carbonyl derivative 4 in good yield (58% from D-glucose)
1
8
ges and low cost.
We focused on the deoxygenation reaction using
0
dimethyl phosphite with a view to prepare some 3 -
deoxy-oligoribonucleotides. Hence, we needed a universal
glycosyl donor, namely, the a,b-1,2-di-O-acetyl-5-O-benz-
oyl-3-deoxyribofuranose 6. This compound can be readily
obtained after the radical reduction of the suitably
activated analogue of the 3-hydroxy-xylofuranose 3.
2
3
after silica gel chromatography. This compound was then
reacted with dimethyl phosphite and portion-added
benzoyl peroxide in boiling dioxane, following Barton’s
1
3
protocol. Reduction proceeded smoothly and the desired
1
2–14,16
12–16
22
Thionocarbonates
or xanthates
are the activa-
deoxy sugar 5 was obtained after evaporation, under
tors that are reported to be successfully used with the
P–H bond containing reducing reagents. However, we
wished to concentrate on the use of thiocarbonylimidazolyl
activated compounds, as they are more easily and effi-
ciently prepared from a simple reaction of the correspond-
vacuum, of the solvents and the dimethyl phosphite excess
2
4
and eventually chromatography purification. It is worth
noting that using only 10 M equiv of dimethyl phosphite
gave low yields, and best results were obtained when 30–
50 M equiv was used, as yields rose from good to excellent
(80–93%). Finally, a two-step ‘one-pot’ procedure of acidic
hydrolysis of the 1,2-O-isopropylidene protection followed
by 1,2-O-acetylation, provided the expected 3-deoxy
0
ing hydroxyl analogue with 1,1 -thiocarbonyldiimidazole
1
8–20
(
TCDI).
To our knowledge, only one case of a free
radical reduction of a thiocarbonylimidazolyl nucleoside
by a P–H bond containing reagent was ever reported using
2
5
glycosyl donor 6. As an example for glycosylation, we
1
7
4
4
1
0 M equiv of it and the reaction yield was rather low.
successfully coupled 6 with either N -benzoyl- or N -
26
Thus, we decided to investigate the free radical deoxygen-
ation of 5-O-benzoyl-1,2-isopropylidene-3-O-imidazolyl-
thiocarbonyl-a-D-xylofuranose 4 by dimethyl phosphite
as a key step reaction in a multi gram scale synthesis
acetyl-cytosine using Vorbr u¨ ggen’s conditions, providing
0
5,27
3 -deoxycytidine
tection (Scheme 2).
with a 90% yield after ammonia depro-
In conclusion, we report an efficient alternative for free
radical deoxygenation reaction of thiocarbonylimidazolyl
activated glycoside analogue using cheap and convenient
dimethyl phosphite as hydrogen source and radical chain
carrier. Reaction proceeds smoothly and with good yields.
The present method is useful for the preparation of a com-
0
towards the glycosyl precursor for 3 -deoxynucleosides 6
(
Scheme 1).
The 3-O-imidazolylthiocarbonyl derivative 4 was pre-
pared in four steps starting from D-glucose as depicted in
Scheme 1. First, hydroxyl groups 1, 2, 5 and 6 were pro-
tected as isopropylidene bridges, leading to di-acetone-D-
glucose 1. Efficient ‘dehomologation’ of the di-O-isopro-
pylidenehexofuranose was carried out by a sequential selec-
tive acid-catalyzed hydrolysis of the terminal acetal and
0
mon 3-deoxy glycosyl donor for 3 -deoxynucleosides. We
believe that good reaction yields and safety and cost advan-
tages of this method would make it more applicable on
laboratory or industrial scale.
O
O
HO
BzO
OH
OH
OH
O
O
O
i
ii, iii
iv
D-glucose
O
O
O
O
O
O
1
2
3
v
N
N
BzO
vii, viii
BzO
vi
BzO
S
O
O
O
O
OAc
O
O
O
O
OAc
6
5
4
Scheme 1. Reagents and conditions: (i) acetone, H
pyridine, 0 °C, 1 h 30; (v) TCDI, 1,2-dichloroethane, reflux, 2 h, 90%; (vi) dimethyl phosphite, (BzO)
reflux, 2 h, then Na CO neutr; (viii) Ac O, DMAP, pyridine, rt, overnight, 80%.
2
SO
4
, CuSO
4
, rt, 24 h, 80%; (ii) H
5
IO
6
, AcOEt, rt, 2 h; (iii) NaBH
4
, EtOH, rt, 1 h 30, 80%; (iv) BzCl,
2
, dioxane, reflux, 2 h 30, 93%; (vii) AcOH-80%,
2
3
2

3290
I. Zlatev et al. / Tetrahedron Letters 49 (2008) 3288–3290
NHR
NH2
N
N
BzO
BzO
HO
O
N
O
N
i
ii
O
O
O
OAc
OAc
OAc
OH
CN, reflux, 1 h, then TMSOTf, rt, 5 h; (ii) NH OH-28%, THF/MeOH
6
4
4
Scheme 2. Reagents and conditions: (i) N -acetyl or N -benzoyl-cytosine, BSA, CH
2:1 (v/v), 50 °C, 6 h, 90%.
3
4
–
Acknowledgments
15. Cho, D. H.; Jang, D. O. Tetrahedron Lett. 2005, 46, 1799–1802.
1
1
6. Jang, D. O.; Song, S. H. Tetrahedron Lett. 2000, 41, 247–249.
7. Takamatsu, S.; Katayama, S.; Hirose, N.; Naito, M.; Izawa, K.
Tetrahedron Lett. 2001, 42, 7605–7608.
This work was supported by grant from ANRS. IZ
thanks the ‘Minist e` re National de la Recherche et de la
Technologie’ for the award of a research studentship.
F.M. is from Inserm.
1
8. From Aldrich, Acros and Alfa Aesar: Dimethylphosphite is about 13
times and 386 times less expensive than triethylsilane and tris-
0
trimethylsilylsilane, respectively. 1,1 -Thiocarbonyldiimidazole is
about three times less expensive than phenyl chlorothionocarbonate
and reacts as efficiently. AIBN and benzoyl peroxide cost the same.
9. Chochrek, P.; Wicha, J. J. Org. Chem. 2007, 72, 5276–5284.
0. Goto, M.; Miyoshi, I.; Ishii, Y.; Ogasawara, Y.; Kakimoto, Y. I.;
Nagumo, S.; Nishida, A.; Kawahara, N.; Nishida, M. Tetrahedron
2002, 58, 2339–2350.
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23. NMR data for compound 4: H NMR: (CDCl
3
, 400 MHz) d 8.30 (1H,
3
4
s), 7.92 (2H, dd, J = 8.5 Hz, J = 1.4 Hz), 7.52 (1H, d, J = 1.3 Hz),
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J = 7.4 Hz), 7.00 (1H, d, J = 1.1 Hz), 5.98 (1H, d, J = 3.7 Hz), 5.93
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room temperature. It was diluted with ethyl acetate and the solvents
were evaporated on an oil pump (0.2 mbar, 80 °C). The crude reaction
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pure 5 as white crystals (1.46 g, 93%).
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1
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1