Synthesis of various substituted 5-methyluridines (xm5U) and 2-thiouridines (xm5s2U) via nucleophilic substitution of 5-pivaloyloxymethyluridine/2-thiouridine

Article abstract of DOI:10.1016/j.tetlet.2015.10.023

5-Pivaloyloxymethyluridine and its 2-thio analogue have been utilized as convenient substrates for the synthesis of various 5-methyluridines (xm⁵U) and 5-methyl-2-thiouridines (xm⁵s²U). The pivaloyloxy group (OPiv) located at the pseudobenzylic position was effectively substituted with a series of nucleophiles: ammonia, primary and secondary amines including secondary cyclic amines, tetrabutylammonium salts of amino acids, an alkoxide and a thiolate.

Full text of DOI:10.1016/j.tetlet.2015.10.023

Tetrahedron Letters 56 (2015) 6593–6597
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
5
Synthesis of various substituted 5-methyluridines (xm U)
5
2
and 2-thiouridines (xm s U) via nucleophilic substitution
of 5-pivaloyloxymethyluridine/2-thiouridine
⇑
Karolina Bartosik, Grazyna Leszczynska
Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Pivaloyloxymethyluridine and its 2-thio analogue have been utilized as convenient substrates for the
Received 2 September 2015
Revised 1 October 2015
Accepted 6 October 2015
Available online 8 October 2015
5
5 2
synthesis of various 5-methyluridines (xm U) and 5-methyl-2-thiouridines (xm s U). The pivaloyloxy
group (OPiv) located at the pseudobenzylic position was effectively substituted with a series of
nucleophiles: ammonia, primary and secondary amines including secondary cyclic amines, tetrabutylam-
monium salts of amino acids, an alkoxide and a thiolate.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Modified nucleosides
5
2
5
-Methyl(-2-thio)uridines (xm (s )U)
5
-Pivaloyloxymethyl(-2-thio)uridine
5
2
(
Pivom (s )U)
Pivaloyloxyl group
5
5 2
5
-Methyluridines (xm U) and their 2-thio analogues (xm s U)
2-thiouridine derivatives are an important element of those stud-
1
5
5 2
are a biologically important class of modified nucleosides. In
particular, 5-aminomethyluridine/2-thiouridine derivatives, for
example, 5-methylaminomethyl- (mnm U and mnm s U), 5-car-
boxymethylaminomethyl- (cmnm U and cmnm s U) and 5-tauri-
nomethyl-modified uridines (
ies. Moreover, native 5-methyluridines xm U/xm s U are fre-
quently used as authentic standards to identify individual
ribonucleosides in RNA hydrolyzates using liquid chromatogra-
5
5 2
5
5
2
8
phy–mass spectrometry analysis. Some of them are important
5
5 2
s
m U and
s
m s U), are present at
synthons for the preparation of more complex nucleosides, for
5
2
5 2
the first position of the anticodon (the wobble position) in several
example, mnm s U or cmnm s U can be considered as substrates
cytosolic and/or mitochondrial tRNAs that are responsible for pre-
for the synthesis of recently discovered 5-substituted S-gerany-
lated 2-thiouridines.
2,3
9
cise recognition of the purine-ending codons. In some cases, the
5
2
lack of xm s U wobble units totally inhibits the protein biosynthe-
Unnatural C5-modified pyrimidine nucleosides have been
4
,5
5
2
10
sis. For example, the absence of
s
m s U34 in the sequence of
screened for antiviral and antibacterial activities.
Various
Lys
human mitochondrial (mt) tRNA
gives a defect of UUA and
5-amine or 5-thiol containing pyrimidine nucleosides have found
application as useful units for duplex structure stabilization as well
UUG-rich genes translation that results in mitochondrial
4
encephalomyopathic disease MERRF. In DNA sequences, the
as for the introduction of additional RNA functionality such as
5
0
5
11
presence of xm -modified 2 -deoxyuridines (xm dU) is limited to
-hydroxymethyldU that is a well-characterized product of thy-
aptamers, biosensors or catalysts.
The protected forms of
5
5-hydroxymethyldU were applied in the transient chemical pro-
tection of DNA against cleavage by restriction endonucleases.12
The most frequently used method for the synthesis of the title
compounds involves nucleophilic substitution of 5-chloromethyl-
mine oxidation and was recently shown to be an epigenetic base
in mouse embryonic stem cells DNA.6
Site-specific incorporation of the native 5-methyluridines/
0
0
13–17
2
-thiouridines into oligoribonucleotide sequences offers a reliable
2 ,3 -O-isopropylideneuridine/2-thiouridine (1a/1b, Fig. 1).
The reactions of 1a/1b with nucleophiles proceed under mild
tool for model studies on the structural requirements of tRNA
interactions with partners in complex bioprocesses.3 Efficient
and simple approaches to the synthesis of 5-methyluridine and
,7
5
5 2
anhydrous conditions affording xm U/xm s U products (x = –CN,
–N , –NHCH , –NHCH COOH(R), –NHCH CH SO H(R)) in moderate
yields.
3
3
2
2
2
3
1
3–17
However, a significant decrease in yield has been
observed in the synthesis of 2-thiouridine analogues.1
Additionally, the susceptibility of the chloromethyl group of
1a/1b to hydrolysis renders some nucleophilic substitution
4–16
⇑
Corresponding author. Tel.: +48 42 631 31 50; fax: +48 42 636 55 30.
E-mail address: grazyna.leszczynska@p.lodz.pl (G. Leszczynska).
http://dx.doi.org/10.1016/j.tetlet.2015.10.023
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

6
594
K. Bartosik, G. Leszczynska / Tetrahedron Letters 56 (2015) 6593–6597
To prepare 5-pivaloyloxymethyluridine (8a) and its 2-thio
0
0
analogue 8b, 5-hydroxymethyl-2 ,3 -O-isopropylideneuridine/2-
2
3
thiouridine (4a/4b) was converted into 8a/8b by selective pival-
oylation of the 5-hydroxymethyl group followed by removal of the
0
0
2
,3 -isopropylidene protecting group (Scheme 1). Different reac-
0
tivities of the 5 -hydroxyl and 5-hydroxymethyl groups under
acidic conditions were previously reported by Sowers and
Beardsley for selective acetylation of 5-hydroxymethyl-2 -
0
2
4
deoxyuridine. Using a similar procedure, compound 4a was trea-
ted with pivalic acid (PivOH) in the presence of trifluoroacetic acid
at 120 °C for 10 h. Although the desired regioisomer 7a was
formed, the following isolation and purification proved difficult
for separation of the pure product from the pivalic acid side-
products. Multiple attempts to purify 7a resulted in a significant
decrease in yield (<30%). A more effective method of 5-hydrox-
ymethyl acylation involved a strategy previously reported for the
2
5
regioselective pivaloylation of carbohydrates.
Compounds
4
a/4b were treated with 1.1 equiv of pivaloyl chloride (PivCl) in
pyridine (Scheme 1) under mild conditions (0 °C, 7 h). Although
the low temperature significantly increased the selectivity of pival-
oylation, a mixture of unreacted substrate 4a/4b, 5-pivalate-7a/7b
5
Figure 1. Substrates utilized for the synthesis of 5-methyluridines xm U and
0
5
2
and 5,5 -bispivalate esters in a 1:2:1 ratio was obtained. To achieve
2
-thiouridines xm s U reported in the literature.
the complete conversion of substrates 4a/4b, an additional
0.9 equiv of PivCl was added and the reaction continued for 10 h.
Mono 5-pivalate component 7a/7b was separated by column chro-
matography and treated with 50% aq acetic acid for effective
reactions unsuccessful, for example, amination of 1a/1b with aque-
1
7
ous NH
ammonium salts 2a/2b, 3a (Fig. 1),
luridine/2-thiouridine 4a/4b,20 5-formyluridine/2-thiouridine
3
.
Alternative methods involve using N-methyl quaternary
17–19
5-hydroxymethy-
0
0
removal of the 2 ,3 -acetonide. After purification, 5-pivaloy-
1
5
21
5
5
a/5b or 5-aminomethyluridine/2-thiouridine 6a/6b deriva-
tives as substrates. The reactions involving compounds 2a/2b–
a/6b proceed with moderate to low yields and have been
loxymethyluridine (8a, Pivom U) and its 2-thio analogue (8b,
5
2
Pivom s U) were obtained in ca. 50% total yield in each case.
Nucleosides 8a/8b were then reacted with a wide range of
structurally diverse nucleophilic reagents: ammonia, primary and
secondary amines including cyclic amines (piperidine, morpho-
line), tetrabutylammonium salts of amino acids (glycine and tau-
rine), an alkoxide and a thiolate (ESI, pg. S6–S14). The reaction
conditions were optimized in terms of solvent (EtOH/MeOH, water,
DMF and neat conditions), reaction time and the excess of nucle-
ophilic reagent (Table 1). The products of nucleophilic substitution
9a–17a/9b–17b were purified by preparative RP HPLC and their
6
demonstrated only on a single target molecule. Notably, the treat-
ment of 2-thiouridines 2b or 4b with a nucleophile resulted in
2
2 16,20
partial desulfurization (s ? o ).
In this work, we present an effective and convenient approach
5
to the synthesis of various 5-methyluridines (xm U) and
5
2
2
-thiouridines (xm s U) utilizing the reaction of 5-pivaloy-
loxymethyluridine 8a and its 2-thio analogue 8b and a set of
different nucleophiles: ammonia, primary and secondary amines,
amino acid salts, an alkoxide and a thiolate. Previous studies
1
13
structures unambiguously confirmed by H and C NMR as well
as mass spectrometry (ESI, pg. S32–S49).
0
reported partial nucleophilic substitution of 5-acetoxymethyl-2 -
deoxyuridine/cytidine-modified DNAs with ammonia that
involved a substitution of the acetoxy group (OAc) located at the
pseudobenzylic position.22 However, ammonolysis of the acetate
ester was predominant and regeneration of the parent pseudoben-
zyl alcohol was observed.22 Contrary to other ester based alcohol
protecting groups, pivalate shows relative stability in the presence
of base; thus we assumed that its ammonolysis would be signifi-
cantly reduced or even eliminated under basic conditions.
Additionally, the formation of a pivalate ester at the pseudoben-
In general, these reactions were carried out at elevated temper-
ature (50–60 °C) except for the nucleophilic substitution with
methylamine (entry 4) which proceeded at room temperature.
Esters 8a/8b rapidly reacted with ammonia and methylamine
3
(1–4 h) under anhydrous conditions using 8 M NH /EtOH (entry
1) and 8 M MeNH /EtOH (entries 3 and 4) to give products 9a/9b
2
and 10a/10b, respectively, in good yields of 86–90%. Interestingly,
changing from anhydrous conditions to an aqueous solution of
ammonia or methylamine (entries 2 and 5) resulted in only a slight
decrease in yield which was attributed to aminolysis of the piva-
late ester and regeneration of 5-hydroxymethyluridine/2-thiouri-
zylic position could effectively promote an S
N
reaction, with
nucleophilic attack occurring at the pseudobenzylic carbon with
OPiv acting as a leaving group.
5
5 2
dine (hm U/hm s U). On the other hand, effective nucleophilic
Scheme 1. Synthetic route to 5-pivaloyloxymethyluridine/2-thiouridine (8a/8b). Reagents and conditions: (i) PivCl (1.1 ? 2 equiv), py, 17 h, 0 °C; (ii) 50% aq AcOH, 1.5 h,
5 °C.
8

K. Bartosik, G. Leszczynska / Tetrahedron Letters 56 (2015) 6593–6597
6595
Table 1
Nucleophilic substitution of 5-pivaloyloxymethyluridine (8a) and 5-pivaloyloxymethyl-2-thiouridine (8b)
Entry
–Nu
Nu system
8 M NH /EtOH
Time (h)
Product
Yieldb (%)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
–NH
–NH
–NHMe
–NHMe
–NHMe
2
2
3
4
2
1
2
1
20
20
20
20
20
20
1
9a
9a
87
80
90
89
85
70
84
85
80
77
75
72
70
9b
9b
86
80
90
87
84
70
80
80
75
75
75
70
70
30% aq NH
8 M MeNH
8 M MeNH
3
2
2
/EtOH
/EtOH
10a
10a
10a
11a
12a
13a
13a
14a
15a
16a
17a
10b
10b
10b
11b
12b
13b
13b
14b
15b
16b
17b
40% aq MeNH
Et NH/H O 4/1 v/v
Morpholine/H O 4/1 v/v
Piperidine/EtOH 1/1 v/v
2
–NEt
2
2
2
–NC
–NC
–NC
4
H
H
H
8
O
2
5
5
10
10
Piperidine/H
2
O 4/1 v/v
ꢀ
+
10
11
12
13
–NHCH
2
COOH
SO
0.8 M NH
0.8 M NH
0.1 M K CO
2 3
2
CH
(CH
/MeOH
0.5 M EtSNa/EtOH
2
COO NBu
4
/EtOH
/EtOH
ꢀ
+
–NH(CH
–OMe
–SEt
2
)
2
3
H
2
2
)
2
SO
3
NBu
4
1
a
rt for synthesis of 10a, 10b (entry 4), 50 °C for synthesis of 11a, 11b (entry 6).
Isolated yields.
b
0
Scheme 2. Synthetic route to 5 -O-pivaloyl-5-pivaloyloxymethyluridine/2-thiouridine (19a/19b). Reagents and conditions: (i) PivCl (3 equiv), py, 2 h, rt; (ii) 50% aq AcOH,
2
h, 85 °C.
substitution of 8a/8b with a secondary aliphatic amine and mor-
pholine (entries 6 and 7) required aqueous conditions for complete
substrate conversion. For piperidine, both anhydrous and aqueous
solutions provided products 13a/13b in good yield (entries 8 and
and 5-ethylthiomethyluridine/2-thiouridine (17a/17b), respec-
5
5 2
tively, along with small amounts of hm U/hm s U (<5%). For the
preparation of 16a/16b, 10% DBU/MeOH and 0.5 M MeONa/MeOH
were also tested, however methanolysis of the pivalate ester was
predominant.
9
). Contrary to ammonia and methylamine, the reactions of
8
a/8b with secondary amines required prolonged reaction times.
To investigate the potential of the new method, we carried out
the nucleophilic substitution of the 5-OPiv group in a moiety con-
taining an additional pivalate ester at the aliphatic 5 -hydroxyl posi-
Due to the use of aqueous conditions, the formation of minor
5
5
2
0
amounts of hm U/hm s U (1–5%) was also observed. Attempts to
substitute the 5-OPiv group of 8a/8b with amino acids were per-
formed with glycine and taurine which are the fragments of native,
wobble 5-substituted uridines and 2-thiouridines. Prior to the
reaction, both amino acids were converted into their correspond-
ing tetrabutylammonium salts, providing good solubility in EtOH
as well as enhanced nucleophilicity compared to their zwitterionic
forms. The reactions of 8a/8b with 0.8 M solutions of the tetrabuty-
lammonium salts of glycine or taurine in anhydrous EtOH (entries
tion. The conditions previously screened for 5-OPiv substitution
0
(Table 1) were used to investigate the reactivity of the 5 -pivaloyl
group. For the synthesis of bispivalate esters 19a/19b 5-hydrox-
0
0
ymethyl-2 ,3 -O-isopropylideneuridine/2-thiouridine (4a/4b)
were reacted with 3 equiv of PivCl (rt, 2 h) and the cis diol functional
group was selectively deprotected by treatment with 50% aq acetic
acid to give 19a/19b in 70% overall yield (Scheme 2) (ESI).
Compounds 19a/19b were reacted with the same series of
0
1
0 and 11) proceeded at 60 °C for 20 h to give 5-carboxymethy-
nucleophiles (Table 2). In general, the 5 -O-pivaloyl group proved
laminomethyluridine/2-thiouridine 14a/14b and 5-taurinomethy-
luridine/2-thiouridine 15a/15b, all in ca. 75% yields.
to be stable under the employed conditions, affording compounds
2 2
20a–25a/20b–25b. Exceptions included Et NH/H O (4/1 v/v), 0.1 M
In addition to nitrogen nucleophiles, alkoxide and thiolate
nucleophilic reagents were utilized for 5-OPiv substitution. The
K
2
CO /MeOH and 0.5 M EtSNa/EtOH solutions (entries 3, 8 and 9),
3
in which nucleophilic substitution at the pseudobenzylic carbon
was accompanied by deprotection of the 5 -hydroxyl functional
0
reactions of 8a/8b with 0.1 M K
2
CO
3
/MeOH (entry 12) and 0.5 M
EtSNa/EtOH (entry 13) proceeded rapidly under anhydrous condi-
tions yielding 5-methoxymethyluridine/2-thiouridine (16a/16b)
group of the sugar moiety. Products 11a/11b, 16a/16b and
17a/17b were afforded in 60–70% yields. In these cases, detectable

6
596
K. Bartosik, G. Leszczynska / Tetrahedron Letters 56 (2015) 6593–6597
Table 2
0
0
Nucleophilic substitution of 5 -O-pivaloyl-5-pivaloyloxymethyluridine (19a) and 5 -O-pivaloyl-5-pivaloyloxymethyl-2-thiouridine (19b)
Entry
–Nu
–NH
–NHMe
–NEt
Nu system
8 M NH /EtOH
8 M MeNH /EtOH
Et NH/H O 4/1 v/v
Morpholine/H O 4/1 v/v
Time (h)
Product
Yieldc (%)
80d
Product
Yieldc (%)
d
1
2
3
4
5
6
7
8
9
2
3
4
1
9a
9b
77
88
d
d
2
10a
11a
12a
13a
14a
15a
16a
17a
90
10b
11b
12b
13b
14b
15b
16b
17b
2
2
2
20
20
20
20
20
1
67
65
d
d
–NC
–NC
4
H
H
8
O
2
85
70
80
70
d
d
5
10
Piperidine/EtOH 1/1 v/v
ꢀ
+
d
d
–NHCH
2
COOH
SO
0.8 M NH
2
CH
(CH
/MeOH
0.5 M EtSNa/EtOH
2
COO NBu
4
/EtOH
75
85
72
75
ꢀ
+
d
d
–NH(CH
–OMe
–SEt
2
)
2
3
H
0.8 M NH
2
)
2 2
SO
3
NBu
4
/EtOH
0.1 M K
2
CO
3
70
70
60
70
1
a
The numbering of the intermediate compounds has been assigned as follows: 20a/20b (–NH
–NHCH COOH), 25a/25b (–NHCH CH SO H).
0 °C for the synthesis of 11a, 11b (entry 3).
Isolated yields.
Yield over 2 steps.
2
), 21a/21b (–NHMe), 22a/22b (–NC
4
H
8
O), 23a/23b (–NC
5
H10), 24a/24b
(
5
2
2
2
3
b
c
d
5
5 2
amounts of hm U/ hm s U (<5%) were also formed. The crude com-
References and notes
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0
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5
obtained were comparable with those for substitution of Pivom U/
5
2
Pivom s U 8a/8b (Table 1) and both methods can be used
interchangeably.
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Kurata, S.; Weixlbaumer, A.; Ohtsuki, T.; Shimazaki, T.; Wada, T.; Kirino, Y.;
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5
5 2
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5 2
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5 2
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1
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2
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of Chemistry, Technical University of Lodz (for K.W.), Poland.
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