A solid-supported acidic oxazolium perchlorate as an easy-handling catalyst for the synthesis of modified pyrimidine nucleosides via Vorbrüggen-type N-glycosylation

Article abstract of DOI:10.1016/j.tetlet.2017.03.046

A solid-supported acidic oxazolium perchlorate was investigated as a heterogeneous catalyst in N-glycosylation reactions using silylated modified pyrimidines and an acylated ribose or glucose to afford the corresponding pyrimidine nucleosides. This salt is a nonhygroscopic and stable powder whose activity is comparable to that of 2-methyl-5-phenylbenzoxazolium perchlorate. A reaction with this polymer catalyst can be conducted on a gram scale. Reusability of the solid-supported catalyst was also investigated.

Full text of DOI:10.1016/j.tetlet.2017.03.046

Accepted Manuscript
A solid-supported acidic oxazolium perchlorate as an easy-handling catalyst for
the synthesis of modified pyrimidine nucleosides via Vorbrüggen-type N-gly-
cosylation
Nabamita Basu, Kin-ichi Oyama, Masaki Tsukamoto
PII:
S0040-4039(17)30350-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.046
TETL 48747
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 September 2016
11 March 2017
16 March 2017
Please cite this article as: Basu, N., Oyama, K-i., Tsukamoto, M., A solid-supported acidic oxazolium perchlorate
as an easy-handling catalyst for the synthesis of modified pyrimidine nucleosides via Vorbrüggen-type N-
glycosylation, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.046
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A solid-supported acidic oxazolium perchlorate as
an easy-handling catalyst for the synthesis of
modified pyrimidine nucleosides via Vorbrüggen-
type N-glycosylation
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Nabamita Basu, Kin-ichi Oyama, and Masaki Tsukamoto*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A solid-supported acidic oxazolium perchlorate as an easy-handling catalyst for the
synthesis of modified pyrimidine nucleosides via Vorbrüggen-type N-glycosylation
Nabamita Basua, Kin-ichi Oyamab, and Masaki Tsukamotoa,∗
aGraduate School of Information Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
bChemical Instrumentation Facility, Research Center for Materials Science, Nagoya University, Nagoya 464-8602, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
A solid-supported acidic oxazolium perchlorate was investigated as a heterogeneous catalyst in
N-glycosylation reactions using silylated modified pyrimidines and an acylated ribose or glucose
to afford the corresponding pyrimidine nucleosides. This salt is a nonhygroscopic and stable
powder whose activity is comparable to that of 2-methyl-5-phenylbenzoxazolium perchlorate.
A reaction with this polymer catalyst can be conducted on a gram scale. Reusability of the
solid-supported catalyst was also investigated.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
N-Glycosylation
Pyrimidine nucleoside
Polyoxazole
Acidic oxazolium perchlorate
N-Glycosylation promoted by trimethylsilyl triflate (TMSOTf)
utilizing sugar acetates such as 1 and silylated pyrimidines 2 is a
standard method of synthesizing modified pyrimidine
nucleosides that are utilized for antiviral and anticancer agents as
well as for various applications in the life sciences (cf. Scheme
1).1–4 To complete the reaction, a stoichiometric amount of
TMSOTf is generally used due to its low reactivity. In addition,
this reagent’s hygroscopic nature requires extreme caution in
handling.1,2 To solve this problem, Jamison et al. proposed acidic
pyridinium salts as the first Brønsted acid catalysts.5 We
invented 2-methyl-5-phenylbenzoxazolium perchlorate (4) as a
nonhygroscopic and stable catalyst, which showed higher
reactivity than those of TMSOTf and 2,6-di-tert-butyl-4-
methylpyridinium triflate.6 The only drawback of this method is
the tedious purification procedure necessitated by the remaining
oxazole compound after workup. If the acidic oxazolium salt
derived from a polyoxazole were employed as a catalyst, it would
be easier to remove it from the reaction mixture. Although
various kinds of polymer-supported reagents have been
Scheme 1. Standard N-glycosylation reactions using 1-O-
acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (1) and silylated
5-substituted uracils 2.
developed,7–9 they have not been applied to the synthesis of
pyrimidine nucleosides. Because polyoxazoles such as poly(4,5-
diphenyl-2-vinyloxazole) (5) have been synthesized,10,11 we
prepared a solid-supported acidic oxazolium salt 6 from 5 and
investigated its potential as a catalyst for N-glycosylation.
First, we optimized the conditions for the preparation of 4,5-
diphenyl-2-vinyloxazole (9), which is the building block for
poly(4,5-diphenyl-2-vinyloxazole) (5). Kurusu et al. prepared
this monomer unit in 43% yield by reaction of benzoin (7) and
acrylonitrile (8) (1.1 equiv) in the presence of sulfuric acid
(Table 1, entry 1).10 On the basis of their method, we conducted
an experiment on a 1-gram scale to afford 9 in only 23% yield,
with unidentified by-products. Therefore, we modified this
———
∗ Corresponding author. Tel.: +81-52-789-4779; fax: +81-52-789-4779; e-mail: tsukamoto@is.nagoya-u.ac.jp (M. Tsukamoto)

2
Tetrahedron Letters
Table 1. Preparation of 4,5-diphenyl-2-vinyloxazole (9).
Entry
7, mmol
8, equiv
1.1
H2SO4, equiv
Tf2O, equiv
Temperature and time
Yield, %
1a
40
5
14
8
0
0 °C for 2 h
43
68
81
38
2
10
0
0 °C for 10 min, then rt for 1 h
0 °C for 10 min, then rt for 1 h
0 °C for 10 min, then rt for 1 h
3
5
10
5
0.5
0.5
4
14
10
5
aData from Ref 10.
procedure by using an excess amount of 8 as a solvent as well as
by decreasing the amount of sulfuric acid. With 10 equiv of 8
and 8 equiv of sulfuric acid, the desired product was obtained in
68% yield (entry 2). The amount of sulfuric acid was reduced to
5 equiv in the presence of trifluoromethanesulfonic anhydride
(0.5 equiv)12,13 to afford 9 in 81% yield (entry 3). Unfortunately,
scaling up to ca. 14 mmol of 7 decreased the yield to 38%.
Nevertheless, a sufficient amount of pure 9 for the subsequent
reaction was obtained by repeating the small-scale reaction.
glycosides. After the reaction was over, the polymer residue
derived from catalyst 6 was stuck to the wall of a reaction vessel
and was not soluble in ethyl acetate acetonitrile, which was used
for the workup. Therefore, it was easy to remove the polymer
from the reaction mixture.14 In the reaction with silylated 5-
nitrouracil 2f, the desired nucleoside 3f was not obtained (entry
6) along with the recovered starting materials (i.e., sugar acetate
1 and 5-nitrouracil). The reaction with silylated thymine 2g was
quite slow and could not be completed within 6 h. Thus, the
reaction temperature was increased. As a result, the reaction at
140 °C for 14 h afforded 3g in 95% yield (entry 7). This may
have been due to the electron-donating property of 2g, which
deactivates the catalytic activity. The same approach was applied
to the reaction of 1 (0.3 mmol) and silylated N6-benzoyladenine
to produce N6,2',3',5'-tetra-O-benzoyladenosine (11) in 88%
yield.15,16
The polymerization of 9 was conducted as reported by
Kurusu et al. by using 2,2'-azodiisobutyronitrile (AIBN) as an
initiator to give poly(4,5-diphenyl-2-vinyloxazole) (5),10 whose
number average molecular weight (Mn) and weight average
molecular weight (Mw) were estimated to be 1.19 x 104 and 12.5
x 104, respectively, by gel permeation chromatography (GPC)
measurement. 5 was then converted to nonhygroscopic poly(4,5-
diphenyl-2-vinyloxazolium perchlorate) (6) by treatment with
perchloric acid. The loading amount of acid on 6 was determined
to be 2.6–2.8 mmol/g. The elemental analysis of 6 indicated that
ca. 90% of the oxazole nitrogen was protonated.
Under the above-optimized conditions in either acetonitrile
or acetone, the reaction of sugar acetate 1 (0.1 mmol) and
silylated N6-benzoyladenine ended with the recovery of 1 and N6-
benzoyladenine, as in the case of catalyst 4.6
The catalytic activity of poly(oxazolium perchlorate) 6 was
evaluated in the reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-
ribofuranose (1) and silylated 5-fluorouracil 2a on a 0.1 mmol
scale as previously described (cf. Scheme 1).6 The catalyst
loading was set at 5 mol%. After refluxation for 2 h using a
stirring bar, the yield of the N-glycosylated product 3a was
determined by 1H NMR. The use of 6 in acetonitrile afforded a
77% yield of 3a, which was comparable to that obtained by our
conventional catalyst 4 (80% yield) and was superior to that with
TMSOTf (50% yield).6 In contrast to the reaction with 4, N1,N3-
bis-N-glycoside 10 was not detected. The polymer catalyst 6 also
showed similar activity in acetone to afford a 74% yield.
Therefore, we applied these conditions in acetonitrile for the
synthesis of various modified pyrimidine nucleosides.
Table 2. Synthesis of pyrimidine ribosides 3 from 1-O-
acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (1) and silylated
5-substituted uracils 2 by using solid-supported oxazolium
perchlorate 6a
Entry
Silylated base
Nucleoside
Isolated yield, %
1
2
3
4
5b
6
7
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
90
87
92
95
97
0c,d
2g
3g
15e (95)f
aUnless otherwise stated, reactions were conducted on a 0.3
mmol scale under the following conditions: [1] = 100 mM, [2] =
130 mM, 6 (5 mol %), MeCN, reflux, 6 h.
b[2e] = 120 mM.
cThe same result was obtained in acetone.
d1 and 5-nitrouracil were recovered.
eThe yield was determined by 1H NMR analysis. 1 (85%) and
To investigate the applicability of our polymer catalyst 6, we
conducted reactions of 1 with silylated pyrimidines 2 having
halogens, trifluoromethyl, and nitro groups on a 0.3 mmol scale
in acetonitrile (Scheme 1). As shown in Table 2, reactions with
the silylated pyrimidines 2a–2e were finished within 6 h, giving
the corresponding nucleosides 3a–3e in 87–97% yields without
the formation of a significant amount of unwanted N1,N3-bis-N-
thymine were also observed by TLC and 1H NMR analyses.
fThe reaction was conducted under the following conditions:
[1] = 100 mM, [2g] = 110 mM , 6 (5 mol %), MeCN, 140 °C, 14
h.

3
Table 4. Synthesis of pyrimidine glucosides 16 and
galactoside 17 from pentaacetyl-β-D-glucose (13) and
silylated 5-substituted uracils 2 by using solid-supported
oxazolium perchlorate 6a
Subsequently, we employed tetra-O-acetyl-β-D-ribofuranose
(12) as a glycosyl donor in acetonitrile. As shown in Table 3, the
tri-acetylated pyrimidine ribosides 13 were obtained in 89–98%
yields. For the synthesis of 13e, the reaction was easily scaled up
to the 1-gram level. The reaction was finished within 30 min, as
in the case of that using catalyst 4.6 Triacetyl 5-nitrouridine (13f)
was obtained in a reasonable yield (entry 6) in contrast to the
reaction using the glycosyl donor 1 (Table 2, entry 6).
Entry
Glycosyl
donor
Silylated
base
Nucleoside Time, h
Isolated
yield, %
Table 3. Synthesis of pyrimidine ribosides 13 from 1,2,3,5-
tetra-O-acetyl-β-D-ribofuranose (12) and silylated 5-
substituted uracils 2 by using solid-supported oxazolium
perchlorate 6a
1
14
14
14
14
14
14
15
2a
2b
2c
2d
2e
2f
16a
16b
16c
16d
16e
16f
24
24
24
24
2
93
92
91
98
98
98
98
2
3
4
5b
6
24
24
7c
2a
17a
aUnless otherwise stated, reactions were conducted on a 0.3
mmol scale under the following conditions: [14] or [15] = 100
mM, [2] = 130 mM.
Entry
Silylated base
Nucleoside
Time, h
Isolated yield,
%
b[2e] = 120 mM.
cPolyoxazole 5 was recovered in a ratio of 94%.
1
2a
2b
2c
2d
2e
2f
13a
13b
13c
13d
13e
13f
6
91
89
93
96
98
90
2
6
3
6
Table 5. Investigation of catalyst reusability in the reaction
of 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose (18) and
silylated 5-(trifluoromethyl)uracil 2e by using solid-supported
oxazolium perchlorate 6a
4
7
5b
6
0.5
6
aUnless otherwise stated, reactions were conducted on a 0.3
mmol scale under the following conditions: [12] = 100 mM, [2]
= 130 mM.
b[2e] = 120 mM.
We also conducted reactions of pentaacetyl-β-D-glucose (14)
and silylated 5-substituted uracils 2 in the presence of polymer
catalyst 6 as shown in Table 4.2,17,18 Because the glycosyl donor
14 had lower reactivity than ribofuranoses 1 and 11, catalyst
loading was set at 10 mol% in order to complete the reactions
within 24 h.6 The pyrimidine glucosides 16 were obtained in 91–
98% yields. In the case of 2e, the reaction was completed in 2 h
(entry 5). A mixture of penta-O-acetyl-β-D-galactopyranose
(15), 2a, and 6 (10 mol%) led to the formation of 17a17 in 98%
yield (entry 7).
Run Catalyst
Isolated
yield, %
1
6 (5 mol%)
Polymer recovered after Run 1
98
0b
2
3c
Polymer recovered after Run 2 was acidified and used as 97
catalyst
aReactions were conducted on a 1 mmol scale under the
following conditions: [18] = 100 mM, [2e] = 110 mM.
bDetermined by TLC and 1H NMR analyses.
Finally, catalyst reusability was investigated in the reaction of
1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose (18) and silylated 5-
(trifluoromethyl)uracil 2e (Table 5).19 With 5 mol% of 6, 2′,3′-
di-O-acetyl-5-(trifluoromethyl)-5′-deoxyuridine (19) was
obtained in 98% yield (Run 1). The recovered polymer,
cAfter Run 3 was conducted, polyoxazole 5 was recovered in a
ratio of 82% based on the amount of 6 used in Run 1, indicating
that 93–94% of the polymer was recovered for each Run.

4
Tetrahedron
6. Shirouzu, H.; Morita, H.; Tsukamoto, M. Tetrahedron 2014, 70,
3635–3639.
however, did not show any catalytic activity with the recovery
of the starting materials (Run 2). We assumed that 6 was
converted to the polyoxazole 5. Therefore, the recovered
7. Manecke, G.; Storck, W. Angew. Chem. Int. Ed. Engl. 1978, 17,
657–670.
polymer after Run 2 was acidified with perchloric acid and then
used for the N-glycosylation (Run 3). The catalytic activity of
the acidified polymer was returned to the original level,
supporting the above assumption.
8. Lu, J.; Toy, P. H. Chem. Rev. 2009, 109, 815–838.
9. Bradley, M.; Galaffu, N. In Encyclopedia of Polymer Science and
Technology, 4th edn.; Mark, H. F., Eds.; Wiley: Hoboken, NJ,
2014, Vol. 11, pp. 17–47.
10. Kurusu, Y.; Nishiyama, H.; Okawara, M. Kogyo Kagaku Zasshi
1968, 71, 1741–1744.
In summary, poly(4,5-diphenyl-2-vinyloxazolium
11. Hilborn, J. G.; Labadie, J. W.; Hedrick, J. L. Macromolecules
1990, 23, 2854–2861.
perchlorate), prepared by the reaction of poly(4,5-diphenyl-2-
vinyloxazole) and perchloric acid, was found to be effective as an
easy-handling catalyst for the synthesis of modified pyrimidine
nucleosides via N-glycosylation reaction. The catalytic activity
was comparable to that of 2-methyl-5-phenylbenzoxazolium
perchlorate. The reaction can be scaled up to the gram level.
Because the polymer residue derived from the catalyst can be
removed from the reaction mixture, the purification procedure is
simpler than that of 2-methyl-5-phenylbenzoxazolium
12. Martínez, A. G.; Alvarez, R. M.; Vilar, E. T.; Fraile, A. G.;
Hanack, M.; Subramanian, L. R. Tetrahedron Lett. 1989, 30, 581–
582.
13. Lai, P.-S.; Taylor, M. S. Synthesis 2010, 1449–1452.
14. The polymer residue after the N-glycosylation can be recovered by
an aqueous workup or by simply removing the reaction mixture
from the vessel. Quantitative analyses were made in the syntheses
of 17a (Table 4) and 19 (Table 5). The polymer can be included
in the crude material, but due to its high polarity, it is easily
removed by column chromatography.
perchlorate. The recovered polymer lost the catalytic activity;
however, treatment with perchloric acid activated the polymer
residue so that it could be used as a catalyst.
15. Vorbrüggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1251–1255.
16. Under the refluxing conditions in either acetonitrile or acetone, the
reaction of sugar acetate 1 (0.1 mmol) and silylated N6-
benzoyladenine ended with the recovery of 1 and N6-
benzoyladenine, as in the case of catalyst 4.6
Acknowledgments
17. Haeckel, R.; Weber, K.; Germann, C.; Haberkorn, U.; Zeisler, S.;
Eisenbarth, J.; Wiessler, M.; Oberdorfer, F. J. Label. Compds.
Radiopharm. 1996, 38, 1061–1070.
18. Kantsadi, A. L.; Hayes, J. M.; Manta, S.; Skamnaki, V. T.;
Kiritsis, C.; Psarra, A.-M. G.; Koutsogiannis, Z.; Dimopoulou, A.;
Theofanous, S.; Nikoleousakos, N.; Zoumpoulakis, P.; Kontou,
M.; Papadopoulos, G.; Zographos, S. E.; Komiotis, D.; Leonidas,
D. D. ChemMedChem 2012, 7, 722–732.
This work was supported by JSPS KAKENHI Grant Number
26410041. The authors are grateful to Messrs Hiroki Morita,
Hiroshi Shirouzu, and Atsuya Fukuhara for their preliminary
experiments.
References and notes
19. Shen, B.; Jamison, T. F. Org. Lett. 2012, 14, 3348–3351.
1. Vorbrüggen, H. Acc. Chem. Res. 1995, 28, 509–520.
2. Vorbrüggen, H.; Ruh-Pohlenz, C. Handbook of Nucleoside
Synthesis; Wiley: New York, NY, 2001.
Supplementary Material
3. Nucleosides and Nucleotides as Antitumor and Antiviral Agents;
Chu, C. K., Baker, D. C., Eds.; Plenum: New York, NY, 1993.
4. Ahmadian, M.; Bergstrom, D. E. In Modified Nucleosides: in
Biochemistry, Biotechnology and Medicine; Herdewijn, P., Ed.;
Wiley-VCH, Weinheim, Germany, 2008, Chap. 10, pp. 251–276.
5. Sniady, A.; Bedore, M. W.; Jamison, T. F. Angew. Chem. Int. Ed.
2011, 50, 2155–2158.
Supplementary material including the detailed experimental
procedures and spectral data related to this article can be found at
the journal’s homepage.

5
Polyvinyloxazolium perchlorate was prepared by
acidification of polyvinyloxazole.
Polyvinyloxazolium perchlorate catalyzes
Vorbrüggen-type N-glycosylations.
Polyvinyloxazolium perchlorate works as a
heterogeneous catalyst.