Synthesis of nucleoside tetraphosphates and dinucleoside pentaphosphates from nucleoside phosphoropiperidates via the activation of P(V)N bond

Article abstract of DOI:10.1016/j.cclet.2014.09.015

A novel and efficient method for the preparation of nucleoside 5′-tetraphosphates has been developed by coupling nucleoside 5′-phosphoropiperidates with triphosphate reagent in the presence of 4,5-dicyanoimidazole (DCI) activator. Further coupling of the nucleoside 5′-tetraphosphates with nucleoside 5′-phosphoropiperidates via the P(V)N activation strategy provided a reliable synthetic method for both symmetrical and asymmetrical dinucleoside pentaphosphates.

Full text of DOI:10.1016/j.cclet.2014.09.015

Chinese Chemical Letters 26 (2015) 89–92
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of nucleoside tetraphosphates and dinucleoside
pentaphosphates from nucleoside phosphoropiperidates via the
activation of P(V)–N bond
Qi Sun *, Jian Sun, Shan-Shan Gong, Cheng-Jun Wang, Xing-Cong Wang
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, China
A R T I C L E I N F O
A B S T R A C T
0
Article history:
A novel and efficient method for the preparation of nucleoside 5 -tetraphosphates has been developed
Received 12 June 2014
0
by coupling nucleoside 5 -phosphoropiperidates with triphosphate reagent in the presence of 4,
Received in revised form 29 August 2014
Accepted 11 September 2014
Available online 19 September 2014
0
5
-dicyanoimidazole (DCI) activator. Further coupling of the nucleoside 5 -tetraphosphates with
0
nucleoside 5 -phosphoropiperidates via the P(V)–N activation strategy provided a reliable synthetic
method for both symmetrical and asymmetrical dinucleoside pentaphosphates.
ß 2014 Qi Sun. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of
Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
Keywords:
4
,5-Dicyanoimidazole
Phosphoropiperidate
Nucleoside tetraphosphate
Dinucleoside pentaphosphate
P(V)–N activation
0
1
. Introduction
triphosphate by using N,N -dicyclohexylcarbodiimide (DCC) or
0
N,N -carbonyldiimidazole (CDI) [5a,6–8]. But this method was
As strong agonists of the purinergic receptors, endogenous
dinucleoside pentaphosphates, including Ap A, Ap G, and Gp G,
are essential extracellular signaling molecules, and play important
roles in physiological and pathological processes in cardiovascular
typically low yielding (10%–20%) and time-consuming (1–3 days).
Though Jones et al. [9] and Taylor et al. [10] reported novel methods
for dinucleoside pentaphosphate synthesis, the protection of the
nucleosides and preparation of specific condensing reagents
limited their values in practical applications. On the basis of the
P(V)–N activation strategy we developed for the synthesis for
nucleoside polyphosphates [11], we report in this paper a general
5
5
5
and nervous systems [1]. Ap
vasoregulatory effect and proliferative effect on vascular smooth
muscle cells (VSMCs), and Gp G [3,4] only induces proliferation of
VSMCs. In biochemical research, the Ap
5 5
A [2] and Ap G [2b,3] exhibit both
5
2+
5
A-Zn complex has been
and facile approach for the synthesis of dinucleoside pentapho-
0
utilized as a probe to elucidate the configurational requirement for
adenylate kinase catalysis [5]. In addition, artificial dinucleoside
sphates (Np
5
N s) via the 4,5-dicyanoimidazole (DCI)-promoted
0
coupling of nucleoside 5 -phosphoropiperidates with nucleoside
0
pentaphosphates, such as Up
sized. While Up U showed selective agonist activity on P2Y
receptor [6], Ap T exhibited strong inhibitory effects on thymidine
5 5
U and Ap T, have also been synthe-
5 -tetraphosphates (Np
4
s). The P(V)–N activation method for the
s [12] is also described.
5
2
efficient synthesis of Np
4
5
kinase, thymidylate kinase, and ribonucleotide reductase [7].
Currently, the available synthetic methods for the preparation
of dinucleoside pentaphosphates are still limited compared to
those for dinucleoside di-, tri-, and tetraphosphates. The most
commonly employed strategy was the direct condensation of
nucleoside diphosphate with another molecule of nucleoside
2
. Experimental
All reactions were performed in anhydrous solvents under an
atmosphere of dry argon. The triethylammonium salts of nucleo-
side 5 -phosphoropiperidates were synthesized according to the
procedure described in a previous report [11b]. Tris(tetra-n-
butylammonium) dihydrogen triphosphate was prepared accord-
ing to a known method [12a]. Ion exchange chromatography
employed DEAE Sephadex A-25 exchanger. Preparative HPLC was
0
*
Corresponding author.
E-mail address: sunqi96@tsinghua.org.cn (Q. Sun).
equipped with a RP C18 column (19 mm ꢀ 250 mm, 10
mm). NMR
http://dx.doi.org/10.1016/j.cclet.2014.09.015
001-8417/ß 2014 Qi Sun. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
1

9
0
Q. Sun et al. / Chinese Chemical Letters 26 (2015) 89–92
1
3
spectra were obtained with a 400 MHz instrument with chemical
shifts reported in parts per million (ppm, ). IR spectra were
recorded on a FT-IR spectrometer. Low-resolution mass spectra
were obtained with an ion trap mass spectrometer and
reported as m/z.
2H); C NMR (100 MHz, D
2
O):
d
159.2, 154.1, 152.0, 138.0, 116.4,
86.7, 84.4, 73.7, 70.6, 65.6; P NMR (D O, 162 MHz):
ꢁ10.4 (d, 1P,
J = 19 Hz), ꢁ14.8 (d, 1P, J = 19 Hz), ꢁ25.6 (dd, 1P, J = J = 18 Hz),
max 3378, 2960, 2950,
3
1
d
2
d
1
2
ꢁ
1
ꢁ26.2 (d, 1P, J
1 2
= J = 18 Hz); IR (cm ): n
1712, 1673, 1543, 1403, 1255, 1065, 914, 812; LRMS (ESIꢁ): m/z
calcd. for C10
H
16
N
5
O
17
P
4
[MꢁH]ꢁ 601.9; found: 602.0.
2
5
.1. General procedure for the synthesis of nucleoside
0
0
-tetraphosphates (5–8)
2.2. General procedure for the synthesis of dinucleoside-5 ,
0
5
-pentaphosphates (9–11)
0
To a solution of nucleoside 5 -phosphoropiperidate (0.1 mmol)
0
in DMF (2 mL) were added tris(tri-n-butylammonium) dihydrogen
triphosphate (0.2 mmol) and 4,5-dicyanoimidazole (DCI,
To a solution of nucleoside 5 -phosphoropiperidate (0.1 mmol)
0
in N-methylpyrrolidone (2 mL) were added nucleoside 5 -tetra-
phosphate (tetra-n-butylammonium salt, 0.04 mmol) and DCI
(0.2 mmol). The reaction was stirred at 20 8C for 16–18 h. The
white precipitation was collected by centrifuge. The crude product
was dissolved in deionized H
Sephadex A-25 ion exchange column (1.6 cm ꢀ 25 cm). Elution
with NH HCO buffer (linear gradient 0.5 to 0.9 mol/L), combina-
tion of appropriate fractions, and lyophilization afforded dinucleo-
side pentaphosphate in ammonium salt form. To remove the small
amount of contaminated polyphosphate byproducts, the ammo-
nium salt was further purified by a preparative RP HPLC [flow
rate = 20 mL/min; linear gradient of 0–10% MeOH in TEAB buffer
(10 mmol/L, pH 8.0) over 15 min; UV detection at 254 nm].
Combination of appropriate fractions and lyophilization afforded
dinucleoside pentaphosphate in triethylammonium salt form.
0
.6 mmol). The reaction was stirred at 20 8C for 12 h and
concentrated in vacuo. The residue was dissolved in NaOAc
aqueous solution (3 mol/L, 1 mL) and EtOH (50 mL) was added.
The resulting white precipitate was collected by centrifuge. The
2
O (0.5 mL) and loaded on a DEAE
crude product was dissolved in deionized H
on a DEAE Sephadex A-25 ion exchange column (1.6 cm ꢀ 25 cm).
Elution with NH HCO buffer (linear gradient 0.3–0.6 mol/L),
combination of appropriate fractions, and lyophilization afforded
Np in ammonium salt form. For characterization, passage of the
solution of the ammonium salt in deionized H O through a bed of
2
O (1 mL) and loaded
4
3
4
3
4
2
+
Dowex 50W-X8 ion exchange resin (Na form) and lyophilization
0
afforded nucleoside 5 -tetraphosphate as pentasodium salt. For the
next step reaction, to the ammonium salt in deionized H
2
O was
added tetra-n-butylammonium hydroxide (3 equiv.), and the
solution was repeatedly evaporated with deionized
H
2
O
Passage of the solution of the triethylammonium salt in deionized
0
+
(
1 mL ꢀ 3) to afford nucleoside 5 -tetraphosphate as more soluble
2
H O through a bed of Dowex 50W-X8 ion exchange resin (Na
tris(tetra-n-butylammonium) salt.
form) and lyophilization afforded dinucleoside pentaphosphate as
pentasodium salt.
0
Uridine 5 -tetraphosphate, pentasodium salt (5): Starting from
1
1
5
0
0
1
(49 mg), 5 (45 mg, 67%) was obtained as a white solid. H NMR
P ,P -Diadenosine-5 ,5 -pentaphosphate, pentasodium salt (9):
(
4
400 MHz, D
2
O):
.40 (m, 2H), 4.35–4.30 (m, 1H), 4.30–4.23 (m, 2H); C NMR
O): 166.2, 152.0, 141.7, 102.8, 88.1, 83.6 (d,
P,C = 9.0 Hz), 73.7, 69.8, 65.2 (d, JP,C = 5.1 Hz); P NMR (D
d
7.99 (d, 1H, J = 8.0 Hz), 6.06–5.98 (m, 2H), 4.50–
Starting from 7 (52 mg), 9 (14 mg, 35%) was obtained as a white
13
1
solid. H NMR (400 MHz, D
2
O):
d
8.38 (s, 2H), 8.11 (d, 2H,
(100 MHz, D
2
d
J = 6.0 Hz), 6.06–5.98 (m, 2H), 4.75–4.68 (m, 2H), 4.60–4.51 (m,
31
13
J
2
O,
2H), 4.39–4.32 (m, 2H), 4.31–4.15 (m, 4H); C NMR (100 MHz,
1
62 MHz):
d
= J
ꢁ8.0 (d, 1P, J = 18 Hz), ꢁ11.1 (dd, 1P, J = 18 Hz), ꢁ22.3
D
2
31
O):
d
154.4, 151.8, 148.1, 138.9, 117.3, 85.7, 73.7, 69.4, 67.6, 64.3;
P NMR (D O, 162 MHz):
ꢁ11.5 (m, 2P), ꢁ22.9 (m, 3P); IR
ꢁ
(cm ): nmax 3324, 3149, 2975, 1714, 1492, 1404, 1260, 1087,
ꢁ
1
(dd, 1P, J
1
2
= 18 Hz), ꢁ22.5 (d, 1P, J
1
= J
2
= 18 Hz); IR (cm ):
2
d
1
n
max 3336, 2987, 2899, 1695, 1413, 1228, 1087, 924, 838; LRMS
(ESIꢁ): m/z calcd. for C
9
H
15
N
2
O
18
P
4
[MꢁH]ꢁ 562.9; found: 563.0.
1044, 967, 924; LRMS (ESIꢁ): m/z calcd. for C20
28 10 55 5
H N O P
0
ꢁ
5
Cytidine 5 -tetraphosphate, pentasodium salt (6): Starting from
(49 mg), 6 (41 mg, 61%) was obtained as a white solid. H NMR
[MꢁH] 915.0; found: 915.1.
1
1
0
0
2
P ,P -Diguanosine-5 ,5 -pentaphosphate, pentasodium salt
(
400 MHz, D
2
O):
d
7.96 (d, 1H, J = 7.2 Hz), 6.14 (d, 1H, J = 7.4 Hz),
(10): Starting from 8 (52 mg), 10 (14 mg, 34%) was obtained as
1
6
4
8
.01 (d, 1H, J = 4.4 Hz), 4.43–4.37 (m, 1H), 4.36–4.30 (m, 1H), 4.29–
a white solid. H NMR (400 MHz, D
4.60–4.44 (m, 4H), 4.35–4.15 (m, 6H); C NMR (100 MHz, D
2
O):
d
8.00 (s, 2H), 5.80 (s, 2H),
13
13
.20 (m, 3H); C NMR (100 MHz, D
9.0, 83.1 (d, JP,C = 8.7 Hz), 74.3, 69.6, 65.0 (d, JP,C = 5.6 Hz);
O, 162 MHz):
ꢁ9.4 (d, 1P, J = 18 Hz), ꢁ14.4 (d, 1P,
J = 18 Hz), ꢁ24.9 (dd, 1P, = J = 18 Hz), ꢁ25.7 (dd, 1P,
max 3370, 2985, 2894, 1693, 1537,
2
O):
d
166.3, 157.9, 141.7, 96.9,
2
O):
d
P
3
1
31
P
158.6, 153.5, 151.3, 137.4, 115.8, 86.4, 83.6, 73.1, 70.0, 65.0;
ꢁ11.0 (m, 2P), ꢁ22.4 (m, 3P); IR (cmꢁ ):
1
NMR (D
2
d
2
NMR (D O, 162 MHz): d
nmax 3388, 2964, 2922, 1673, 1543, 1413, 1250, 1065, 914, 816;
J
1
2
ꢁ
1
[MꢁH]ꢁ 947.0; found:
J
1
= J
2
= 18 Hz); IR (cm ):
n
LRMS (ESIꢁ): m/z calcd. for C20
H
28
N
10
O
24
P
5
1
418, 1235, 1079, 887; LRMS (ESIꢁ): m/z calcd. for C
9
H
16
N
3
O
17
P
4
947.1.
ꢁ
1
0
5
0
[
MꢁH] 561.9; found: 562.0.
P -Adenosine-5 -P -guanosine-5 -pentaphosphate,
pentaso-
0
Adenosine 5 -tetraphosphate, pentasodium salt (7): Starting
dium salt (11): Starting from 7 (52 mg), 11 (13 mg, 31%) was
1
1
from 3 (52 mg), 7 (45 mg, 65%) was obtained as a white solid. H
NMR (400 MHz, D O): 8.54 (s, 1H), 8.24 (d, 1H, J = 6.5 Hz), 6.14 (d,
H, J = 6.1 Hz), 4.72–4.70 (m, 1H), 4.64 (dd, 1H, J = J = 4.8 Hz),
.48–4.40 (m, 1H), 4.36–4.27 (m, 1H), 4.27–4.18 (m, 1H); C NMR
O): 155.6, 152.8, 149.2, 139.9, 118.6, 86.5, 84.3 (d,
P,C = 9.0 Hz), 74.2, 70.4, 65.4 (d, JP,C = 5.3 Hz); P NMR (D
2
obtained as a white solid. H NMR (400 MHz, D O): d 8.33 (s, 1H),
2
d
8.04 (s, 1H), 7.91 (s, 1H), 5.95 (d, 1H, J = 5.8 Hz), 5.70 (d, 1H,
1
4
1
2
J = 6.3 Hz), 4.63 (m, 2H), 4.45 (m, 2H), 4.25–4.20 (m, 2H), 4.13–4.10
13
13
2
(m, 4H); C NMR (100 MHz, D O): d 159.0, 155.6, 154.0, 153.0,
(100 MHz, D
2
d
151.8, 149.2, 140.1, 137.9, 118.6, 116.3, 86.8 (ꢀ2), 84.2 (ꢀ2), 74.4,
31
31
J
2
O,
ꢁ11.5 (d, 1P, J = 18 Hz), ꢁ14.8 (d, 1P, J = 18 Hz), ꢁ25.8
73.5, 70.5 (ꢀ2), 65.5 (ꢀ2); P NMR (162 MHz, D
2
O):
d
ꢁ11.0 (m, 2P),
ꢁ
1
1
(
n
9
62 MHz):
d
ꢁ22.8 (m, 3P); IR (cm ):
nmax 3783, 3455, 2950, 2673, 2480, 1722,
1706, 1618, 1442, 1380, 1243, 1122, 1060, 948, 800, 732; LRMS
ꢁ
1
dd, 1P, J
1
= J
2
= 18 Hz), ꢁ26.2 (dd, 1P, J
1
= J
2
= 18 Hz); IR (cm ):
max 3354, 3049, 2795, 1714, 1492, 1453, 1260, 1087, 1044, 967,
24; LRMS (ESIꢁ): m/z calcd. for C10
(ESIꢁ): m/z calcd. for C20
H
28
N O P
10 23 5
[MꢁH]ꢁ 931.0; found: 931.1.
H
16
N
5
O
16
P
4
[MꢁH]ꢁ 586.0;
found: 586.1.
3. Results and discussion
0
Guanosine 5 -tetraphosphate, pentasodium salt (8): Starting
1
0
from 4 (54 mg), 8 (46 mg, 64%) was obtained as a white solid. H
NMR (400 MHz, D
As shown in Scheme 1, nucleoside 5 -tetraphosphates (5–8)
0
2
O):
d
8.14 (s, 1H), 5.93 (d, 1H, J = 6.0 Hz), 4.75–
were efficiently synthesized by treating nucleoside 5 -phosphor-
4
.70 (m, 1H), 4.65–4.58 (m, 1H), 4.43–4.33 (m, 1H), 4.31–4.16 (m,
opiperidates (1–4) with 2.0 equiv. of tris(tetra-n-butylammonium)

Q. Sun et al. / Chinese Chemical Letters 26 (2015) 89–92
91
0
Scheme 1. The P(V)–N activation method for the synthesis of nucleoside 5 -tetraphosphates (5–8).
3
1
4
Fig. 1. The P NMR spectrum of crude reaction mixture of Up (5).
Table 1
The P(V)–N activation method for the synthesis of dinucleoside pentaphosphates (9–11).
.
0
Entry
Base
Base
Reaction time (h)
Product
Ap A (9)
Isolated yield (%)
1
2
3
A (3)
G (4)
G (4)
A (7)
G (8)
A (7)
16
18
18
5
35
34
31
Gp
Ap
5
G (10)
G (11)
5
triphosphate and 6.0 equiv. of DCI in anhydrous DMF at 20 8C for
2 h. The precipitated crude products were separated by filtration.
addition of acidic DCI (2.0 equiv.) promoted the reaction to
completion in 16 h. But when 3 disappeared, there was still
1
Ethanol precipitation of the sodium salts followed by ion exchange
significant amount of
7
(ꢂ20%) unreacted due to its low
chromatography afforded 5–8 in good isolated yields ranging from
nucleophilicity and the self-condensation of 3. Decrement of the
equivalent of 7 to 0.4 effectively promoted its consumption, and
31
6
1% to 67%. The P NMR spectrum of crude reaction mixture of 5
3
1
(
Fig. 1) showed that the conversion of 1–5 was smooth and clean.
5
the P NMR yield of Ap A (9) was improved to around 50%. But we
31
The calculated P NMR yield of 5 was close to 90%. Compared to
nucleoside5 -triphosphatesynthesis[11a], longerreactiontimewas
found that ion exchange chromatography alone was difficult to
completely separate the desired Np
0
0
5
N products from other closely
required, indicating that the nucleophilicity of triphosphate reagent
was lower than that of pyrophosphate. However, due to the highly
negatively charged nature, the isolated yields of 5–8 were slightly
lower than those of nucleoside di- and tri-phosphates. It was also
related long chain polyphosphate impurities. Therefore, RP-HPLC
was employed afterward to ensure the purity of these highly
negatively charged compounds. As shown in Table 1, three
0
naturally occurring Np
5
N s (9–11) were synthesized and isolated
4
noticed that Np s were less stable than their NTP counterparts.
in 31%–35% yields following this P(V)–N activation method.
When the aqueous solution of 7 was stored at ꢁ20 8C, about 10%
of 7 decomposed after 6 months.
4. Conclusion
0
In the following research, adenosine 5 -phosphoropiperidate
(
3) was coupled with Ap
4
(7) in 1:0.5 molar ratio [11d] in N-
In summary, we developed efficient P(V)–N activation methods
for the synthesis of both nucleoside 5 -tetraphosphates and
dinucleoside pentaphosphates. Compared to the known methods,
these new approaches feature easily accessible starting materials,
31
0
methylpyrrolidone at 20 8C with or without DCI. P NMR tracing
experiments showed that there was almost no reaction between
the reactants after 24 h without DCI. This result was in accordance
with the observed low reactivity of phosphoropiperidate toward
phosphate nucleophiles in our previous research. In contrast,
mild reaction conditions, and moderate to good isolated yields, and
0
provide facile and reliable access to Np
4
s and Np
5
N s.

9
2
Q. Sun et al. / Chinese Chemical Letters 26 (2015) 89–92
6] W. Pendergast, B.R. Yerxa, J.G. Douglass, et al., Synthesis and P2Y receptor activity
[
Acknowledgment
0
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2001) 157–160.
(
We thank the National Natural Science Foundation of China
Nos. 21002041 and 21262014), Key Project of Chinese Ministry of
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(
Education (No. 212092), Scientific Research Foundation of Chinese
Ministry of Human Resources and Social Security for Returned
Chinese Scholars (2011), and Research Funds (Nos. ky2012zy08
and 2013QNBJRC001) and Startup Funds for PhDs (2010) from
JXSTNU for financial support.
[
8] (a) P. Feldhau, T. Fr o¨ hlich, R.S. Goody, et al., Synthetic inhibitors of adenylate
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