One-Pot Synthesis of Nucleotides and Conjugates in Aqueous Medium

Article abstract of DOI:10.1002/ejoc.201601299

Herein, we describe a one-pot synthesis, in a mixture of water/acetonitrile, of nucleoside 5′-polyphosphates and some derivatives starting from their corresponding nucleoside 5′-monophosphates. Phosphorimidazolide intermediates are formed in the presence of imidazole and 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate. Under these mild conditions, nucleoside 5′-di- and 5′-triphosphates, dinucleoside 5′,5′-polyphosphates, as well as some nucleotide analogues modified either on the nucleoside or on the phosphate moieties are obtained in moderate to high yields.

Full text of DOI:10.1002/ejoc.201601299

A Journal of
Accepted Article
Title: One-pot synthesis of nucleotides and conjugates in aqueous
medium
Authors: Anaïs DEPAIX, Suzanne PEYROTTES, and Béatrice ROY
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601299
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601299
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601299
SHORT COMMUNICATION
One-pot synthesis of nucleotides and conjugates in aqueous
medium
[
a]
[a]
[a]
Anaïs Depaix, Suzanne Peyrottes, and Béatrice Roy*
Abstract: Herein, we describe a one-pot synthesis, in a mixture of
water-acetonitrile, of nucleoside 5’-polyphosphates and some
derivatives starting from their corresponding nucleoside 5’-
monophosphates. Phosphorimidazolide intermediates are formed in
the presence of imidazole and 2-chloro-1,3-dimethylimidazolinium
hexafluorophosphate. Under these mild conditions, nucleoside 5’-di-
and 5’-triphosphates, dinucleoside 5’,5’-polyphosphates as well as
some nucleotide analogues modified either on the nucleoside or on
the phosphate moieties, were obtained in moderate to high yields.
reaction of NMPs with 1,1’-carbonyldiimidazole (CDI). These
reactions are usually performed in anhydrous organic solvents,
thus requiring the preparation of tri- or tetra-alkyl ammonium salts
of both the NMP and the phosphate reagent. In 2012, Tanaka et
al. have made a breakthrough in the chemical synthesis of NDP-
sugars by performing the coupling of a sugar-1-phosphate with a
[
12]
nucleotide in D
2
O.
The key reagent for the synthesis is 2-
imidazolyl-1,3-dimethylimidazolinium chloride (ImIm), formed in
situ (Scheme 1), by mixing 2-chloro-1,3-dimethylimidazolinium
chloride (DMC) and imidazole (Im). ImIm can activate a NMP into
its corresponding phosphoroimidazolide (NMP-Im), which is then
converted to the desired sugar nucleotide by reaction with the
appropriate sugar-1-phosphate salt. Interestingly, phosphorylated
reagents are used as their commercially available and water-
soluble sodium and potassium salts. However, only 6–10 % of
NMP introduced in the reaction ends up in the final NDP-sugar
due to the use of 4 equiv. of NMP for 1 equiv. of sugar-1-
phosphate and low yields. Finally, this protocol allows to obtain
only a few milligrams of the desired compounds. In 2014, the
Fiedler research group reported a pyrophosphorylation method of
peptides in water by reacting a peptide monophosphate with O-
Introduction
Given the importance of nucleotides and their derivatives in
biological processes, numerous methods have been developed to
[
1]
access to these compounds and their structural analogues.
Their scope ranges from mechanistic probes to versatile chemical
tools for assay development and biomedical applications. As
example, nucleoside 5’-triphosphates are the cornerstone of
[
2]
genome analysis and medical diagnostics.
tetraphosphate (Up U, diquafosol) is an agonist of the P2Y2
purinergic receptor, used to treat dry eye disease. Dinucleotides
Di(uridine)-
4
[
13]
[
3]
benzylphosphorimidazolide in the presence of zinc chloride.
[
4]
also appear to be a promising new class of antiplatelet agents.
Moreover, a large number of nucleotide analogues and their
conjugates have been synthesized and studied as
[
5]
inhibitors/promoters of therapeutically relevant enzymes.
Methods for the chemical synthesis of these derivatives are
[
1]
based either on P(III) or P(V) chemistry. Phosphoramidates, in
general, and phosphorimidazolides in particular, have been
extensively used as intermediates for pyrophosphate bond
[
6]
formation in anhydrous organic solvents. This approach is based
on the nucleophilic substitution of nucleoside 5’-monophosphates
(
NMPs) activated as phosphoramidate monoesters, by suitable
inorganic phosphate salts. The products obtained are nucleoside
[
12]
[
7]
[8]
Scheme 1. Proposed activation mechanism of UMP to UMP-Im by ImIm.
5
’-diphosphates (NDPs), nucleoside 5’-triphosphates (NTPs),
[
9]
dinucleoside 5’,5’-polyphosphates (DNPs), and conjugates such
[
10]
[11]
as
NDP-sugars
and
CDP-choline.
Nucleoside
[
12]
Our main objectives were to improve Tanaka’s conditions
and to expand this approach to the synthesis of various families
of nucleotides, while using H O instead of D O. Consequently, our
phosphorimidazolide intermediates can be obtained by the
2
2
protocol is cheap and suitable for large scale synthesis.
[a]
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247
CNRS, Université de Montpellier, ENSCM, Université de
Montpellier, Campus Triolet, cc 1705, Place Eugène Bataillon,
3
4095 Montpellier cedex 5, France
Results and Discussion
E-mail: beatrice.roy@umontpellier.fr
https://ibmm.umontpellier.fr/
At the outset, activation of several NMPs (UMP, CMP, AMP) was
performed following the reported conditions (NMP/DMC/Im 1/2/4
Supporting information for this article is given via a link at the end of
the document.
[
12]
1
2
in D O at 40 °C). The reaction progress was monitored by H-
3
1
decoupled P NMR spectroscopy which gives two signals at
approximately 2 and –8 ppm corresponding to NMP and NMP-Im,
respectively. Activation was incomplete after 1 h and the
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European Journal of Organic Chemistry
10.1002/ejoc.201601299
SHORT COMMUNICATION
2
formation of symmetrical dinucleoside diphosphate Np N as a by-
product was observed (singlet at around –11 ppm, see
supplementary information). Indeed, the reported conversion of
UMP to UMP-Im in D
O. This difference may be attributed to the reduced
nucleophilicity of compared to in hydrolysis
2
O was 70 %, while it was only 40–50 % in
H
2
D
2
O
2
H O
[
12,14]
reaction.
As 2-chloro-1,3-dimethylimidazolinium chloride is highly
hygroscopic and therefore difficult to handle, we replaced it with
its hexafluorophosphate salt (DMP, Scheme 2). This last was
[
15]
obtained by treatment of DMC with KPF
6
in acetonitrile.
The
counter-ion exchange resulted in a lower solubility of the reagent
in water, which was overcome by the addition of an organic co-
3
solvent (CH CN or THF). In addition, we hypothesized that this
co-solvent would also reduce the extent of NMP-Im hydrolysis,
and therefore prevent dimer formation. Secondly, cost-effective
2 2
D O was replaced by H O thus allowing to increase the reaction
scale. Therefore, activation with UMP was optimized by varying
the solvent mixtures, temperature, as well as the relative ratio of
UMP/DMP/Im (Scheme 2 and supplementary information).
31
Figure 1. P NMR (121 MHz, D
2
O) after 1h of activation of UMP under the
2 3
optimized conditions (UMP/DMP/Im 1/3/6 in H O/CH CN 1/1).
O
O
Cl
-O
P
O-
O
N
N
P
O-
O
B
B
O
T °C
O
N+
PF6
Then, we extended this approach to the synthesis of a nucleotide
conjugate (CDP-choline) and various analogues modified either
on the nucleoside or the phosphate moieties (Scheme 3). Thus,
treatment of CDP-Im with choline phosphate (CholP) afforded
CDP-choline in 34% isolated yield (Table 1, entry 7). Concerning
analogues, two cases were considered: (i) synthesis of 5’-di- and
N
HN
N
Solvent
HO OH
NMP
HO OH
NMP-Im
DMP
Im
Scheme 2. Optimization settings of the activation conditions.
5
’-triphosphates starting from a sugar-modified nucleoside 5’-
monophosphate and (ii) synthesis of a b,g-methylene NTP starting
from a natural NMP.
The activation step was almost complete after 1h when using 1
equiv. of UMP, 3 equiv. of DMP and 6 equiv. of Im in H O/CH CN
1/1, v:v) at 40 °C. As shown in Figure 1, the P NMR spectrum
2
3
As regards the nucleoside analogues (NAs), phosphorylation in
3
1
[5]
(
cells is achieved by cellular or viral kinases. The mechanism of
of the crude reaction mixture shows a signal at –8 ppm (UMP-Im),
and no dimer is observed. Under the same experimental
conditions, the activation was also almost complete for CMP and
AMP (see supplementary information).
action of antiviral or anticancer NAs involves the interaction of
their 5’-phosphorylated derivatives with essential enzymes, such
[
5]
as DNA or RNA polymerases. For example, 3’-azido-2’,3’-
deoxythymidine 5’-triphosphate (AZTTP) interact with HIV
reverse transcriptase, leading to the inhibition of viral replication.
Therefore, the availability of nucleotide analogues is required for
biochemical and pharmacological studies. Using our optimized
conditions, AZTMP was converted into AZT 5’-diphosphate
(AZTDP) and 5’- triphosphate (AZTTP) in 49 % and 32 % yields,
respectively (Scheme 3 and Table 1, entries 8–9). Secondly, we
were interested in the synthesis of b,g-methylene NTPs. Indeed,
these non-hydrolysable compounds that are isosteric and
isoelectronic with NTPs, are used to probe the mechanism of
With these optimized reaction conditions in hand, we then
examined the scope of this reaction for the preparation of various
natural nucleotides (NDPs, NTPs). For this purpose, a 1–3 equiv.
of the suitable and commercially available phosphate salts were
added to the NMP-Im and allowed to react for 2 to 17 h (Scheme
3
). We found that 30 min activation was better than 1 h to minimize
the formation of by-products (symmetrical dinucleoside
diphosphates, NMP). Subsequently, addition of the phosphate
reagent was done after 30 min.
[
17]
phosphoryl transfer in enzyme-catalysed processes
and
Applying our procedure, UMP was
converted into uridine 5’-b,g-methylene triphosphate (UDPCH P)
products were purified by ion-exchange chromatography followed, in 48
yield using equiv. of tetrasodium methylene
in some cases, by a size exclusion chromatography to remove the
diphosphonate as a reagent (Table 1, entry 10).
HNEt .PF salts. Conversion ranged from 35 to 49 %, and the
compounds were isolated in 22–40 % yields (Table 1, entries 1–
[
18]
Nucleoside 5’-di- and 5’-triphosphates were obtained by using 1
receptors specificity.
equiv. of NaH
2
PO
4
and 3 equiv. of Na
4
P
2
O
6
, respectively. Crude
2
%
1
3
6
We also probed the ability of DMP/Im to activate inorganic
phosphate or pyrophosphate. Indeed, Yanachkov at al. have
1
2
6
). For NTP synthesis, we also replaced tetrasodium
reported the formation of P ,P -diimidazolyl derivatives of
[
16]
[19]
pyrophosphate by PPN pyrophosphate.
However, the latter
pyrophosphate by treatment of the latter with CDI in DMF.
was poorly soluble in the reaction medium, resulting in lower
yields (data not shown).
Under our optimized conditions (1 equiv. phosphate or
pyrophosphate, 3 equiv. DMP, 6 equiv. Im), only minor products
3
1
were observed by P NMR monitoring (data not shown).
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601299
SHORT COMMUNICATION
O
P
O-
O
P
O-
-O
O-
HO OH
O
O
O
-O
P
O-
O
P
O
B
O
m= 0,1
O
P
O
P
O-
O
n
B
O
O
O
B
O
O-
O-
UDP: B = Ura; R1 = R2 = OH; n = 1
UTP: B = Ura; R1 = R2 = OH; n = 2
CDP: B = Cyt; R1 = R2 = OH; n = 1
CTP: B = Cyt; R1 = R2 = OH; n = 2
ADP: B = Ade; R1 = R2 = OH; n = 1
ATP: B = Ade; R1 = R2 = OH; n = 2
R1 R2
Up2U: B = Ura; R1 = R2 = OH
Cp2C: B = Cyt; R1 = R2 = OH
Ap2A: B = Ade; R1 = R2 = OH
R1 R2
O
O
O
N+
Cl-
-O
O-
O
P
O-
O
P
O-
O-
O
P
O-
P
O-
O
P
O-
N+
Cl-
O
P
O-
O
O
N
O
O
O
B
N
O
B
-O
P
O-
O
P
O
B
O
O
m= 0,1
O
O-
n
R1 R2
R1 R2
R1 R2
CDP-Choline: B = Cyt; R1 = R2 = OH
O
P
O-
O
P
O-
AZTDP: B = Thy; R1 = N3; R2 = H; n = 1
-O
O-
AZTTP: B = Thy; R1 = N ; R2 = H; n = 2
3
O
P
O-
O
O
P
O-
-O
P
O-
O
O
B
O
R1 R2
UDPCH2P : B = Ura; R1 = R2 = OH
Scheme 3. Study of the scope of the reaction.
Finally, we took advantage of the formation of the dimers (Np
2
N)
Thus, our synthetic strategy provides a general and simple access
to nucleotides, their conjugates as well as some of their
analogues.
as by-products in the activation step to isolate these compounds.
Therefore, activation of several NMPs (UMP, CMP or AMP) was
performed in one-pot without adding any other reagent than DMP
3
1
and Im, until the P NMR signal of NMP-Im disappeared.
Conversion ranged from 31 to 70 % (Table 1, entries 11–13).
[a]
Entry
NMP
Phosphorus
reagent
Product
Yield [%]
Compared to the existing methods in anhydrous media based on
[
b]
[c]
[
1]
1
2
3
4
5
6
7
8
9
UMP
UMP
CMP
CMP
AMP
NaH
Na
NaH
Na
NaH PO4
2
PO
4
UDP
47 , 40
phosphorimidazolate intermediates, our protocol has several
advantages. While the first ones require technical expertise in
handling under an inert atmosphere, the second does not require
any particular skills to perform the chemical reactions and
phosphorus reagents are used in their commercially available
forms. Moreover, our protocol prevent carbonation of
[b]
[c]
4
P
2
O
7
UTP
43 ,25
[
b]
[c]
[c]
[c]
[c]
2
PO
4
CDP
42 , 24
[b]
4
P
2
O
7
CTP
49 , 24
[
7]
[b]
ribonucleotides usually observed with the use of CDI.
Our
ADP
35 , 27
2
procedure applied for NDPs and NTPs gives yields in the same
[
b]
[
1, 7–9, 20–21]
AMP
Na
CaCholP
NaH PO
Na
4
P
2
O
7
ATP
43 , 22
order of magnitude as anhydrous procedures
whereas
[
11]
better yields are reported in the literature for CDP-choline and
[c]
CMP
AZTMP
AZTMP
UMP
UMP
CMP
AMP
CDP-Choline
AZTDP
AZTTP
2
34
[
22]
2
UDPCH P. Last but not least, ~ 30–60 % of NMP introduced in
[
b]
the reaction ends up in the final product. This is a great advantage
when it comes to the synthesis of nucleotide analogues starting
from high-added value NMPs.
2
4
49
32
48
[b]
4
P
2
O
7
[
[
b]
b]
1
1
1
1
0
1
2
3
Na CH P O
4
2
2
6
UDPCH P
Conclusions
[c]
none
Up
Cp
2
U
C
A
70 , 68
The attractive features of this one-pot strategy include absence of
protecting groups on the starting material and convenient set-up
[b]
none
none
2
31
[
b]
[c]
Ap
2
50 , 39
(
i.e. use of water, non-dry solvent and reagents, commercially
available sodium or potassium salts). The experimental results
demonstrated the applicability of the reported method for the
synthesis of a variety of nucleotides. Finally, this protocol allows
to synthesize hundreds of milligrams of the desired product.
[
a] Used as their commercially available disodium salts. [b] Conversion rate
based on the corresponding NMP and calculated from signal integrations in
the H NMR or P spectrum of the crude reaction mixture. [c] Isolated yields.
1
31
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601299
SHORT COMMUNICATION
[
[
8]
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2
-chloro-1,3-dimethylimidazolinium hexafluorophosphate (DMP) was
[
15]
synthesized according to Kitamura.
General procedure for nucleotide
synthesis: NMP disodium salt (0.41 mmol) was placed in a small test tube
with a stir bar, and dissolved in H O/CH CN 1/1 (1080 µL). The solution
was heated to 40 °C and then DMP (1.23 mmol, 3 equiv.) and imidazole
2.45 mmol, 6 equiv.) were added. In the case of addition of a phosphorus
2
3
(
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from 2 to 17 h. When suitable, additional solvent was added for a better
solubility (supplementary information). At the end of the reaction, the crude
reaction mixture was freeze-dried and purified by ion exchange
chromatography on diethylaminoethyl (DEAE) Sephadex, using a gradient
of triethylammonium hydrogen carbonate buffer (TEAB) at pH = 7.5. For
some of them, the excess of hexafluorophosphate triethylammonium salts
[
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[
2
was removed by
a supplementary size exclusion chromatography,
performed on Bio-Gel P-2 Gel, fine (Bio-Rad laboratories) and using water
as eluent.
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Acknowledgements
We are thankful for the financial support provided by the
Université de Montpellier (PhD grant for Anaïs Depaix).
[
[
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Keywords: nucleotides • phosphorylation • water chemistry •
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European Journal of Organic Chemistry
10.1002/ejoc.201601299
SHORT COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Key Topic: Nucleotide Synthesis
Anaïs Depaix, Suzanne Peyrottes,
Béatrice Roy*
Page No. – Page No.
Title: One-pot synthesis of nucleotides
and conjugates in aqueous medium
Text for Table of Contents
A two-step reaction sequence for the preparation of nucleoside 5’-
polyphosphates in a mixture of water-acetonitrile was developed. This
method also provides access to nucleotides analogues, modified either
on the nucleoside or on the phosphate moieties.
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