Selective deprotection of fully benzoylated nucleoside derivatives

Article abstract of DOI:10.1081/CAR-200030095

Selective deprotection of benzoylated hydroxyl groups is one of the crucial problems in the synthesis of nucleoside analogues as well as of other polyfunctional molecules. Copyright

Full text of DOI:10.1081/CAR-200030095

This article was downloaded by: [Moskow State Univ Bibliote]
On: 28 November 2013, At: 12:57
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Carbohydrate Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lcar20
Selective Deprotection of Fully
Benzoylated Nucleoside Derivatives
Rachida Zerrouki a , Vincent Roy a , Amel Hadj‐Bouazza a & Pierre
Krausz a
a Laboratoire de Chimie des Substances Naturelles, Faculté des
Sciences et Techniques , 123 Avenue Albert Thomas, F‐87060,
Limoges, France
Published online: 18 Aug 2006.
To cite this article: Rachida Zerrouki , Vincent Roy , Amel Hadj‐Bouazza & Pierre Krausz (2004)
Selective Deprotection of Fully Benzoylated Nucleoside Derivatives, Journal of Carbohydrate
Chemistry, 23:5, 299-303, DOI: 10.1081/CAR-200030095
To link to this article: http://dx.doi.org/10.1081/CAR-200030095
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 23, No. 5, pp. 299–303, 2004
Selective Deprotection of Fully Benzoylated
Nucleoside Derivatives
*
Rachida Zerrouki, Vincent Roy, Amel Hadj-Bouazza,
and Pierre Krausz
´
Laboratoire de Chimie des Substances Naturelles, Faculte des Sciences
et Techniques, Limoges, France
CONTENTS
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . 300
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
ABSTRACT
Selective deprotection of benzoylated hydroxyl groups is one of the crucial problems in
the synthesis of nucleoside analogues as well as of other polyfunctional molecules.
Key Words: Selective deprotection; Benzoylated groups; Nucleoside analogues.
*
´
Correspondence: Rachida Zerrouki, Laboratoire de Chimie des Substances Naturelles, Faculte des
Sciences et Techniques, 123 Avenue Albert Thomas, F-87060 Limoges, France; Fax: þ33(0) 5 55
45 72 02; E-mail: rachida.zerrouki@unilim.fr.
299
DOI: 10.1081/CAR-200030095
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

300
Zerrouki et al.
Scheme 1. Access to 20,30-dihydroxy nucleosides.
RESULTS AND DISCUSSION
So far, two methods have been reported for the preparation of 20,30-dihydroxy
nucleosides (Sch. 1).
The first method includes at least two steps (route 1). First, protecting acyl groups are
removed by treatment with a solution of sodium methoxide or ammonia in methanol at
rt.[1] Then the primary hydroxyl function at C-50 of the sugar residue is protected selec-
tively, for instance by silylation. This reaction is highly selective if bulky protecting
groups, such as tert-butyldiphenylsilyl (TBDPS) or tert-butyldimethylsilyl (TBDMS),
are used.[2,3] The other option is to deprotect selectively the 20 and 30 positions (route 2).
Only one method, reported by Nishino et al.,[4] has appeared in the literature. Benzoyl
groups protecting secondary hydroxyls are removed selectively in THF in the presence
of powdered sodium methoxide. The mixture has to be rigorously dried otherwise a
complete deprotection of the hydroxyl groups occurs.
During the course of our investigations on the synthesis of nucleoside analogues, we
became interested in the selective deprotection of benzoylated secondary hydroxyl
groups. As reported above, total deprotection is well described by using ammonia in
methanol. However, we have found that secondary hydroxyl groups can be efficiently
and selectively generated from their benzoylated form by controlling the amount of
NH3, reaction time and temperature (see Table 1). This method requires no particular
precaution and implies an easy workup (concentration of the reaction mixture) unlike
the method with sodium methoxide. The reaction is stopped by evaporation (under
reduced pressure) in an ice bath. The applicability of this selective deprotection reaction
to benzoylated nucleoside analogues was investigated using nucleoside derivatives 1–3
(see Fig. 1).
Table 1. Selective debenzoylation of compounds 1–4.
NH3
(eq)
Time
(hr)
Temperature
(8C)
Yield
(%)b
Entry
Substratea
Product
1
2
3
4
1
2
3
4
25c
25c
25c
1.5d
12
6
215
22
5
6
7
8
68
70
65
65
6
215
22
6
aConditions: substrate 0.5 mmol, solvent: MeOH (2 mL).
bYield after purification by PLC.
cEq per benzoyl protecting secondary hydroxy group, solution of ammonia (7 N).
dEq per acetyl group.

Benzoylated Nucleoside Derivatives
301

302
Zerrouki et al.
Scheme 2. Selective debenzoylation of compounds 9 and 10.
In every case, the reaction was checked by TLC and stopped as soon as the trihydroxyl
derivative appeared. After evaporation, the crude products were easily separated by
preparative thin layer chromatography (silica gel, CH2Cl2/EtOH) and the main producta
was isolated in good yield as shown in Table 1.
At rt, compound 2 yielded the partially deprotected nucleoside 6 in an acceptable
yield (70%). The selective debenzoylation of compounds 1 and 3 at rt always gave
the deprotected compounds 5 and 7 only in low yields also by varying the amounts
of ammonia. The best results were obtained at 2158C using 25 eq of ammonia
a 1H NMR data follow: 5 (400 MHz, CDCl3): d 1.45 (s, 9H, t-Bu), 1.68 (bs, 3H, CH3), 4.27 (dd,
J ¼ 4, 5 Hz, 1H, H-20), 4.33 (t, J ¼ 5 Hz, 1H, H-30), 4.42 (m, 1H, H-40), 4.53 (d, J ¼ 16.3 Hz, 1H,
CH2), 4.54 (dd, J ¼ 3.8, 12.5 Hz, 1H, H-50), 4.58 (d, J ¼ 16.3 Hz, 1H, CH2), 4.74 (dd, J ¼ 2.5,
12.5 Hz, 1H, H-50), 5.82 (d, J ¼ 4 Hz, 1H, H-10), 7.3 (bs, 1H, H-6), 7.6 (m, 5H, Har). 6
(400 MHz, CDCl3): d 1.53 (m, 2H, CH2), 1.68 (m, 2H, CH2),1.89 (s, 3H, CH3), 3.40 (dt, J ¼ 6.3,
9.6 Hz, 1H, CH2), 3.66 (t, J ¼ 7.7 Hz, 2H, CH2), 3.75 (dt, J ¼ 6.3, 9.6 Hz, 1H, CH2), 4.12
(d, J ¼ 4.7 Hz, 1H, H-20), 4.28 (dd, J ¼ 4.7, 6.6 Hz, 1H, H-30), 4.42 (m, 1H, H-40), 4.44 (dd,
J ¼ 5.7, 12 Hz, 1H, H-50), 4.58 (dd, J ¼ 3.5, 12 Hz, 1H, H-50), 5.0 (s, 1H, H-10), 6.95 (s, 1H,
H-6), 7.41 (t, J ¼ 7.7 Hz, 2H, Har), 7.54 (t, J ¼ 7.5 Hz, 1H, Har), 8.05 (t, J ¼ 7.5 Hz, 2H, Har),
9.79 (s, 1H, N-H). 7 (400 MHz, DMSO): d 2.56 (ddd. J ¼ 3.2, 6.4, 14.4 Hz, 1H, H-20); 2.64 (dd,
J ¼ 7.2, 14.4 Hz, 1H, H-200); 4.51 (m, 1H, H-40); 4.58 (dd, J ¼ 5.0, 11.6 Hz, 1H, H-50); 4.62 (dd,
J ¼ 4.8, 11.6, 1H, H-50); 5.5 (m, 1H, H-3); 5.7 (d, J ¼ 8.0 Hz, 1H, H-5); 6.28 (dd, J ¼ 6.8,
7.2 Hz, 1H, H-10); 7.72 (d, J ¼ 8.0 Hz, 1H, H-6); 7.8 (m, 5H, Har). 8 (400 MHz, CDCl3): d 1.61
(m, 2H, CH2), 1.73 (m, 2H, CH2), 1.86 (d, J ¼ 0.84 Hz 3H, CH3), 3.50 (dt, J ¼ 6.10, 9.64 Hz,
1H, CH2), 3.65 (m, 2H, CH2), 3.85 (dt, J ¼ 5.58, 9.64 Hz, 1H, CH2), 4.44 (bd, J ¼ 2.6 Hz, 1H,
H-20), 4.62 (dd, J ¼ 5.9, 12 Hz, 1H, H-50), 4.63 (dd, J ¼ 5.9, 12 Hz, 1H, H-50), 4.88 (q, J ¼ 6 Hz,
1H, H-40), 5.07 (d, J ¼ 1 Hz, 1H, H-10), 5.42 (dd, J ¼ 2.6, 6.2 Hz, 1H, H-30), 6.88 (d, J ¼ 0.84 Hz,
1H, H-6), 7.39 (m, 4H, Har), 7.54 (m, 2H, Har), 8.00 (m, 4H, Har), 8.99 (s, 1H, N-H). 11 (400 MHz,
CDCl3 þ CD3OD): d 3.4 (dd, 1H, J ¼ 1.0, 9.0 Hz, H-4), 3.42 (s, 3H, CH3O), 3.45 (dd, J ¼ 3.7,
9.2 Hz, 1H, H-2), 3.67 (t, J ¼ 9.2 Hz, 1H H-3), 3.86 (ddd, J ¼ 2.1, 6.0, 9.96 Hz, H-5), 4.45 (dd,
J ¼ 6.0, 11.8 Hz, 1H H-6a), 4.64 (dd, J ¼ 2.1, 11.8 Hz, 1H, H-6b), 4,69 (d, J ¼ 3.7 Hz, 1H, H-1),
7.47 (tt, J ¼ 1.5, 7.5 Hz, 2H, Har), 7.60 (tt, J ¼ 1.5, 7.5 Hz, 1H, Har), 8.04 (dd, J ¼ 1.5, 7.5 Hz,
Har). 12 (400 MHz, CDCl3 þ CD3OD): d 3.41 (s, 3H, CH3O), 3.78 (dd, J ¼ 3.1, 10.1 Hz, 1H,
H-3), 3.83 (dd, J ¼ 3.5, 10.1 Hz, 1H, H-2), 3.97 (dd, J ¼ 0.9, 3.1 Hz, 1H, H-4), 4.13 (ddd,
J ¼ 0.9, 4.9, 7.5 Hz, H-5), 4.48 (dd, J ¼ 4.9, 11.4 Hz, 1H, H-6a), 4.53 (dd, J ¼ 7.5, 11.4 Hz, 1H,
H-6b), 4,76 (d, J ¼ 3.5 Hz, 1H, H-1), 7.47 (tt, J ¼ 1.5, 7.5Hz, 2H, Har), 7.60 (tt, J ¼ 1.5, 7.5 Hz,
1H, Har), 8.04 (dd, J ¼ 1.5, 7.5 Hz, Har).

Benzoylated Nucleoside Derivatives
303
per benzoyl protected secondary hydroxyl group (Table 1, entries 1 and 3). The
composition of the final mixture was analyzed and the compound structures were deter-
mined by 400-MHz 1H NMR spectroscopy. In any case, about 10% of starting nucleosides
and 5% of the fully deprotected product remained. By comparison with the starting
1
nucleosides, H NMR data show an important shielding in low field (21.5 ppm) for
H-20 and H-30.
In order to investigate the effect of selective deprotection, acetylated nucleoside 4 was
used (Fig. 1). An excess of ammonia increased a ratio of the 20,30-deprotected nucleoside.
However, the use of 1.5 eq of ammonia in methanol at rt, yielded the selective deacetylated
nucleoside 8 in 65% yield (Table 1, entry 4). The IR spectrum displays the expected
1
hydroxyl band at 3400 cm21. H NMR indicates the disappearance of the acetyl proton
and the presence of two benzoyl groups.
This new method offers an easy access to 20,30 unprotected nucleosides in good yields.
Noteworthy, we equally succeeded in deprotecting acetylated secondary hydroxyl group at
C-20 without affecting the benzoyl group at C-30.
In order to evaluate to what extent this method can be generalized, we used it
for selectively deprotecting methyl 2,3,4,6-tetra-O-benzoyl-a-D-glucopyranoside (9)
and methyl 2,3,4,6-tetra-O-benzoyl-a-D-galactopyranoside (10). In agreement with
our results in the nucleoside series, using 25 eq of ammonia per benzoyl protected
secondary hydroxyl group at rt during 5 hr, we obtained compounds 11 and 12 in 65%
yield (Sch. 2).
In summary, these results indicate for the first time that the use of a well-define con-
centration of ammonia and a specific reaction temperature resulted in selective debenzoyl-
ation of secondary hydroxyl groups. The convenient method disclosed herein does not
need any specific treatment or precaution. As exemplified, the present strategy may be
easily used for other carbohydrate derivatives.
REFERENCES
1. Holy, A. Nucleic acid components and their analogs. Preparation of 20-deoxy-L-ribo-
nucleosides of the pyrimidine series. Collect. Czech. Chem. Comm. 1972, 37 (12),
4072–4087.
2. Hanessian, S.; Lavallee, P. Preparation and synthetic utility of tert-butyldiphenylsilyl
ethers. Can. J. Chem. 1975, 53 (19), 2975–2977.
3. Corey, E.J.; Venkateswarlu, A. Protection of hydroxyl groups as tert-butyldimethyl-
silyl derivatives. J. Am. Chem. Soc. 1972, 94 (17), 6190–6191.
4. Nishino, S.; Rahman, M.A.; Takamura, H.; Ishido, Y. Partial protection of carbo-
hydrate derivatives. Part 18. Simple preparative procedure for 50-O-acylribonucleo-
sides; highly regioselective O-deacylation at 20 and 30 positions of fully acylated
purine and pyrimidine ribonucleosides with the sodium methoxide-THF system. Tetra-
hedron 1985, 41 (23), 5503–5506.
Received October 23, 2003
Accepted December 12, 2003