Selective deacetylation using iodine-methanol reagent in fully acetylated nucleosides

Article abstract of DOI:10.1016/j.tetlet.2005.09.142

Selective deprotection of primary acetyl ester in nucleosides and carbohydrates using 1% iodine-methanol solution (w/v) was described and the mechanism was also discussed.

Full text of DOI:10.1016/j.tetlet.2005.09.142

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8083–8086
Selective deacetylation using iodine–methanol reagent
in fully acetylated nucleosides
Bo Ren, Li Cai, Liang-Ren Zhang, Zhen-Jun Yang and Li-He Zhang*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100083, PR China
Received 4 August 2005; revised 23 September 2005; accepted 23 September 2005
Available online 10 October 2005
Abstract—Selective deprotection of primary acetyl ester in nucleosides and carbohydrates using 1% iodine–methanol solution (w/v)
was described and the mechanism was also discussed.
Ó 2005 Elsevier Ltd. All rights reserved.
50-Hydroxyl of acetylated nucleosides or 6-hydroxyl of
acetylated carbohydrates are key intermediates in the
preparation of many biological active molecules.1–3 In
general, 50-hydroxyl of acetylated nucleosides were ob-
tained by selective protection of the 50-hydroxyl first
and followed by a multi-steps protection and deprotec-
tion (Scheme 1, method I). Regioselective deacetylation
of fully protected nucleosides or carbohydrates had been
investigated by several groups.4–8 Nudelman5 et al.
reported selective deacetylation of anomeric sugar ace-
tates with tin alkoxides, however, a mixture of 50-hydr-
oxyl and 30-hydroxyl nucleoside was obtained in poor
yield. Recently, Orita6 et al. reported the high selective
deacetylation of peracetylated carbohydrates with neu-
tral [tBu2SnOH(Cl)]2, and also 50-hydroxyl uridine and
cytidine could be obtained in 89% and 77% yields,
respectively (Scheme 1, method II). In addition, enzy-
matic methods had been used for selective deprotection
of acetyl ester in nucleosides and carbohydrates,9–11
even though the application is not yet widely available.
Herein, we reported a new method for the facile regio-
selective deacetylation of fully acetyl protected nucleosides
or carbohydrates in the presence of 1% (w/v) solution
of iodine in methanol to give 50-hydroxyl nucleosides
or 6-hydroxyl carbohydrates in good yields.
in carbohydrates.12 Ronald et al. reported that 50-trityl
group in nucleosides and carbohydrates could be
removed with a solution of iodine in methanol.13 We
found that this system could cleave the trityl ether in
the described condition. Furthermore, when the reaction
was carried out at a higher temperature and longer time,
this reagent could also remove the acetyl group at the
other position of carbohydrate. After optimization of
the reaction condition, peracetylated nucleosides I–IV
and 3,4,6-tri-O-acetyl carbohydrates VI–VIII were trea-
ted with this system to give 50-hydroxyl acetylated
nucleosides 1–4 and 6-hydroxyl of protected carbo-
hydrates 6–8 in reasonable yields (Table 1).
Fully acetyl protected nucleoside (0.100 g, 0.27 mmol)
was dissolved into a solution of I2 (200 mg, 0.79 mmol)
in methanol (20 mL). The solution was heated and TLC
(dichloromethane/methanol, 18:1) was used to monitor
the reaction. Upon completion, a small quantity of
sodium thiosulfate was added to quench the reaction.
The solvent was removed and the residue was purified
by column chromatography on silica gel (dichlorometh-
ane/methanol, 50:1) to give 50-hydroxy-20,30-di-O-
acetylnucleoside 1–4.14 The same procedure for the
selective deacetylation of compounds VI-VIII gave com-
pounds 6–8.14 All of the compounds (1–8) were identi-
1
The reaction system, iodine and methanol, was used to
open oxirane rings then the same group described the
application for the cleavage of acetals and dithioacetals
fied by HNMR and specific rotatory power compared
to the authentic compounds.
Interestingly, when N6-acetyl-20,30,50-tri-O-acetyl-cyti-
dine V was treated with 1% iodine in methanol at reflux
for 5 h, a high yield of 20,30,50-tri-O-acetyl cytidine 514
was obtained. The selective deacetylation was carried
*
Corresponding author. Tel.: +86 10 82801700; fax: +86 10
82802724; e-mail: zdszlh@mail.bjmu.edu.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.142

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
8084
B. Ren et al. / Tetrahedron Letters 46 (2005) 8083–8086
Base
Base
Base
Base
TritylO
HO
TritylO
HO
c
b
a
O
O
O
O
Method I
Method II
OAcOAc
OH OH
OH OH
OAcOAc
a: Trityl chloride; b: Ac2O/pyridine; c: I2/CH3OH
Base
Base
Base
HO
AcO
HO
e
O
O
d
O
OH OH
OAcOAc
OAcOAc
d: Ac2O/pyridine; e: selective deacetylation
Scheme 1.
Table 1. Selective deacetylation of protected nucleosides and carbohydrates
Compd
Substrate
Reaction temp. (°C)
Reaction time (h)
Product
Yielda (%)
O
N
O
NH
NH
O
I
68 °Cb
14.5
69
O
N
AcO
HO
O
O
OAc OAc
OAc OAc
1
NH2
N
NH2
N
N
N
75–80 °Cc
40
9.5
30
5
60.5
57.4
55.1
78
N
N
N
II
N
HO
AcO
O
O
OAc OAc
O
OAc OAc
O
2
NH
NH
78 °Cb
N
O
N
O
III
IV
V
AcO
HO
O
O
OAc
3
OAc
O
N
O
N
N
N
N
NH
NH
67 °Cc
N
O
NHAc
NHAc
AcO
HO
O
OAc OAc
4
OAc OAc
NH2
NHAc
N
N
Refluxb
N
O
N
O
AcO
AcO
AcO
AcO
O
O
OAc OAc
OAc OAc
5
OH
O
OAc
O
S
S
AcO
AcO
VI
70 °Cb
5.5
42.8
O
O
N
O
N
O
6

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
B. Ren et al. / Tetrahedron Letters 46 (2005) 8083–8086
8085
Table 1 (continued)
Compd
Substrate
Reaction temp. (°C)
70 °Cb
Reaction time (h)
5.5
Product
Yielda (%)
OH
OAc
O
O
VII
38
AcO
AcO
AcO
AcO
S
S
S
S
OAc
7
8
OAc
OH
OAc
O
70 °Cb
5.5
41
O
AcO
AcO
VIII
AcO
AcO
N3
N3
a Isolated yield.
b Open system.
c Closed system.
out at N6 position and a small amount of 5-iodo-20,30,50-
tri-O-acetyl-cytidine was afforded as side product.
2. Wu, T. F.; Ogilvie, K. K. J. Org. Chem. 1990, 55, 4717–
4724.
3. Lambert, R. W.; Martin, J. A.; Thomas, G. J.; Duncan,
I. B.; Hall, M. J.; Heimer, E. P. J. Med. Chem. 1989, 32,
367–374.
4. Levene, P. A.; Tipson, R. S. J. Biol. Chem. 1937, 121, 131–
153.
5. Nudelman, A.; Herzig, J.; Gottlieb, H. E.; Keinan, E.;
Sterling, J. Carbohydr. Res. 1987, 162, 145–152.
6. Orita, A.; Hamada, Y.; Nakano, T.; Toyoshima, S.; Otera,
J. J. Chem. Eur. 2001, 7, 3321–3327.
7. Zeng, Y.; Li, A.; Kong, F. Tetrahedron Lett. 2003, 44,
8325–8329.
8. Li, A.; Zeng, Y.; Kong, F. J. Carbohydr. Res. 2004, 339,
673–681.
9. Singh, H. K.; Cote, G. L.; Sikorski, R. S. Tetrahedron
Lett. 1993, 34, 5201–5204.
10. Ciuffreda, P.; Casati, S.; Santaniello, E. Tetrahedron 2000,
56, 3239–3243.
The mechanism of the reactions of acetal cleavage and
deprotection of trityl group in carbohydrates by io-
dine–methanol reagent was proposed to be electrophilic
attack of iodine on oxygen12 or acid-catalyzed cleav-
age.13 In our case, we found that the reaction can be car-
ried out in the presence of base, therefore, the reaction is
not an acid-catalyzed cleavage. We suggested that the
deacetylation by iodine–methanol presumably involved
initially a complexation of an iodine species with one
of the oxygen atoms of the primary acetate in nucleoside
and a subsequent nucleophilic attack with methanol
would lead to the free alcohols. The steric hindrance
of 2- and 3-O-acetyl- position may lead the selectivity
(Scheme 2). Proposed mechanism:
11. Zinni, A.; Schmidt, A.; Gallo, M.; Iglesias, L.; Iribarren,
A. Molecules 2000, 5, 533–534.
12. Zarek, W. A.; Zamojski, A.; Tiwari, K. N.; Ison, E. R.
Tetrahedron Lett. 1986, 27, 3827–3830.
I
O
I
Base
O
O
H
H
O
13. Wahlstrom, Jan L.; Ronald, Robert C. J. Org. Chem.
1998, 63, 6021–6022.
C
14. Compd 1: lit.9; Compd 2: Ciuffreda, P.; Casati, S.;
Santaniello, E. Tetrahedron 2000, 56, 3239–3243. Compd
3: Koole, Leo H.; van Genderen, Marcel H. P.; Buck,
Hendrik M. J. Am. Chem. Soc. 1987, 109, 3916–3921.
O
O
O
I
O
I
not easy to form complex
1
Compd 4: N2-acetyl-20,30-di-O-acetylguanosine H NMR
Scheme 2.
(DMSO-d6): d 12.08 (br s, 1H), 11.73 (br s, 1H), 8.30 (s,
1H), 6.06 (d, 1H, J = 7.0 Hz, 10-H), 5.75 (dd, 1H, J = 7.0,
5.5 Hz, 20-H), 5.46 (dd, 1H, J = 5.0, 2.0 Hz, 30-H), 5.39
(t, 1H, J = 5.0 Hz, –OH), 4.22 (d, 1H, J = 2 Hz, 40-H),
3.64–3.73 (m, 2H, 50-H), 2.19 (s, 3H), 2.13 (s, 3H), 1.99
(s, 3H).
In summary, we reported a selective deprotection of
primary acetyl ester in nucleosides and carbohydrates
using 1% iodine–methanol solution (w/v) in good yields.
An iodine–acetate complex may involve in the mecha-
nism of this reaction.
Compd 5: Saladino, R.; Mincione, E.; Crestini, C.;
Mezzetti, M. Tetrahedron 1996, 52, 6759–6780.
Compd. 6: p-methylphenyl 2-deoxy-2-phthalimido-3,4-di-
O-acetyl-6-hydroxy-1-thio-b-D-glycopyranoside. 1H NMR
(DMSO-d6): d 7.91–7.94 (m, 4H, arom.), 7.26 (d, 2H,
J = 8.1 Hz, arom.), 7.10 (d, 2H, J = 8.1 Hz, arom.), 5.68
(d, 1H, J = 10.5 Hz, 1-H), 5.63 (t, 1H, J=10.5Hz, 4-H),
4.94–5.03 (m, 2H, 3-H and –OH), 4.16 (t, 1H, J=10.5 Hz,
2-H), 3.57–3.60 (m, 1H, 5-H), 3.43–3.51 (m, 2H, 6-H), 2.26
(s, 3H), 2.00 (s, 3H), 1.77 (s, 3H). 13C NMR (CDCl3): d
170.1, 167.9, 138.9, 134.4, 134.3, 133.9, 131.2, 129.8, 126.8,
123.7, 83.0, 78.2, 71.5, 69.0, 61.6, 53.8, 21.2, 20.7, 20.4.
Anal. Calcd for C25H25NO8S: C, 60.11; H, 5.04; N, 2.80.
Found: C, 60.03; H, 5.11; N, 2.75.
Acknowledgements
This work was supported by the National Natural
Science Foundation of China (20132032 and 20272030).
References and notes
1. Vaghefi, M. M.; Bernacki, R. J.; Hennen, W. J.; Robins,
R. K. J. Med. Chem. 1987, 30, 1391–1399.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
8086
B. Ren et al. / Tetrahedron Letters 46 (2005) 8083–8086
Compd. 7: p-methylphenyl 2,3,4-tri-O-acetyl-1-thio-b-D-
glycopyranoside.1H NMR (DMSO-d6): d 7.37 (d, 2H,
J = 8.1 Hz, arom.), 7.16 (d, 2H, J = 8.1 Hz, arom.) 5.29 (t,
1H, J = 9.3 Hz, 3-H ), 5.14 (d, 1H, J = 9.9 Hz, 1-H), 4.85
(t, 1H, J = 9.6 Hz, 2-H), 4.82–4.88 (m, 1H, 6-OH), 4.75 (t,
1H, J = 9.6 Hz, 4-H), 3.74–3.81 (m, 1H, 5-H), 3.34–3.53
(m, 2H, 6-H), 2.30 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H), 1.91
(s, 3H).
Compd 8: p-methylphenyl 2-deoxy-2-azido-3,4-di-O-acet-
yl-1-thio-b-D-glycopyranoside.1H NMR (DMSO-d6): d
7.42 (d, 2H, J = 8.1 Hz, arom.), 7.18 (d, 2H, J = 8.1 Hz,
arom.), 5.74 (d, 1H, J = 6.0 Hz, 1-H), 5.08 (t, 1H,
J = 9.6 Hz, 3-H), 4.96 (t, 1H, J = 9.6 Hz, 4-H), 4.83–4.87
(m, 1H, 6-OH), 4.41 (dd, 1H, J = 10.2, 5.7 Hz, 2-H), 4.19–
4.22 (m, 1H, 5-H), 3.31–3.53 (m, 2H, 6-H), 2.30 (s, 3H),
2.04 (s, 3H), 2.00 (s, 3H).