Synthesis of novel deoxynucleoside S-methylphosphonic acids using S-(diisopropylphosphonomethyl)isothiouronium tosylate, a new equivalent of mercaptomethylphosphonate

Article abstract of DOI:10.1039/c0ob00738b

The synthesis of the novel nucleotide analogues 5′-deoxynucleoside- 5′-S-methylphosphonates, starting from 5′-deoxy-5′- haloribonucleosides, 5′-O-tosylribonucleosides, and 2′-O- triflylnucleosides, is described. The phosphonothiolation of these compounds

Full text of DOI:10.1039/c0ob00738b

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PAPER
Synthesis of novel deoxynucleoside S-methylphosphonic acids using
S-(diisopropylphosphonomethyl)isothiouronium tosylate, a new equivalent of
mercaptomethylphosphonate†
Ivana Ko´sˇiova´, Milosˇ Budeˇsˇ´ınsky´, Natalya Panova and Ivan Rosenberg*
Received 17th September 2010, Accepted 6th January 2011
DOI: 10.1039/c0ob00738b
The synthesis of the novel nucleotide analogues 5¢-deoxynucleoside-5¢-S-methylphosphonates, starting
from 5¢-deoxy-5¢-haloribonucleosides, 5¢-O-tosylribonucleosides, and 2¢-O-triflylnucleosides, is
described. The phosphonothiolation of these compounds was achieved using
S-(diisopropylphosphonomethyl)isothiouronium tosylate, a new, odourless, and efficient equivalent of
mercaptomethylphosphonate. The thiolate anion of mercaptomethylphosphonate was generated in situ
from the isothiouronium salt in both protic and aprotic solvents using two equivalents of sodium
iso-propoxide. The prepared nucleoside 5¢-S-methylphosphonates were deprotected, and the free
phosphonic acids were transformed into diphosphoryl derivatives (the NTP analogues). Both
mononucleotides and NTP analogues were studied as substrates/inhibitors of several enzymes that are
involved in the nucleoside/nucleotide metabolism.
RNase L.10 The fact that all these oligomers contain an ether–
ester type phosphonate linkage prompted us to extend the scope
of this research by elaborating a suitable method for the synthesis
of nucleotides containing the thioether–ester C5¢(2¢)–S–CH2–
Introduction
In various areas where relatively subtle chemical modifications are
needed to study biologically important systems and their functions
in vivo, the replacement of oxygen atoms with sulfur, a change fre-
quently employed in such investigations, is known to bring distinct
P(O)(OH)2 moiety instead of the C5¢(2¢)–O–CH2–P(O)(OH)2 one,
as reported earlier.10–13 We describe here the synthesis of S-
new properties into the organic molecule. In contrast to the oxygen
methylphosphonates and some of their diphosphoryl derivatives
atom, the sulfur atom is bulkier, more lipophilic, and considerably
(NTP analogues).
more nucleophilic. In the field of nucleic acid chemistry, the
To accomplish the key thiophosphonylations (see below), we
well-known oligonucleotide phosphorothioates1 may serve as an
considered the use of mercaptomethylphosphonates first. The syn-
example to document dramatic changes that are due to the oxygen–
thesis of mercaptomethylphosphonates using various precursors
sulfur replacement. These changes include increased lipophilicity
has been reported in the literature several times. The prepara-
and thus increased cellular uptake, increased nuclease stability,
and a strong, non-specific binding to proteins.
tion involves their in situ generation by the alkaline hydrolysis
of S-acetylthiomethyl phosphonate,14,15 the reduction of phos-
phonodithioformate with sodium borohydride in acetonitrile,16
and the reaction of lithium methylphosphonate carbanion with
elemental sulfur.17 Mercaptomethylphosphonates are useful inter-
mediates for the synthesis of many organic compounds,18–24 among
them are certain biologically active derivatives.15,25
In our laboratory, we have been continuously interested in
the synthesis of novel isopolar phosphonate-based analogues
of mono- and oligonucleotides and their biophysical and bio-
logical evaluation.2–7 Modified oligodeoxynucleotides containing
phosphodiester and phosphonate C3¢–O–P–CH2–O–C5¢¢ inter-
nucleotide linkages in an alternating mode are capable of elic-
iting RNase H activity8 and were found to hybridise with an
RNA target similar to the natural ones.9 In addition, several
modified 2¢,5¢-linked tetrameric oligoadenylates containing re-
gioisomeric phosphonate C2¢–O–CH2–P–O–C5¢¢ internucleotide
linkages were recognised as potent agonists and antagonists of
A
literature search revealed that the respective di-
alkylphosphonomethylisothiouronium salts, a possible equiv-
alent of mercaptomethylphosphonate, have not been synthe-
sised so far. It was, therefore, worth trying to prepare S-
diisopropylphosphonomethylisothiouronium tosylate, and prove
its usefulness for the task.
Results and discussion
Institute of Organic Chemistry and Biochemistry, Academy of Sciences v. v. i.,
Flemingovo 2, 166 10 Prague 6, Czech Republic. E-mail: ivan@uochb.cas.cz
The new compound for the intended transformations, S-
(diisopropylphosphonomethyl)isothio-uronium tosylate (2a), was
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c0ob00738b
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Table 1
smoothly prepared from diisopropyl tosyloxymethylphospho-
nate26 (1, Scheme 1) and thiourea by refluxing in ethanol.
Nucleoside
Base
Solvent
iPrOH
Time/h
Product
Yield (%)
3a
3b
3c
6
A
G
12
18
16
1
1
2
4a
62
4b
48
U
4c
64a
ABz
CBz
ABz
DMF
DMF
8 (4a)
9 (4d)
11
79 (72)b
85 (76)b
87
7
10
Scheme 1
a After removal of 2,3¢-O-isopropylidene group. b After removal of 2,3¢-O-
methoxymethylidene and N-benzoyl groups.
The precipitation with diethyl ether gave 2a as a white solid
in excellent yield. The product is odourless (an advantage over
mercaptomethylphosphonate and its S-acetyl derivative) and
stable at 4 ◦C.
The generation of the thiolate anion 2b in situ was achieved
by the alkaline hydrolysis of 2a with two equivalents of
sodium iso-propoxide in iso-propanol or DMF. The use of
iso-propoxide to hydrolyse 2a was chosen for its compatibility
with the phosphonate ester group (to prevent a possible base-
catalysed transesterification). The subsequent reaction with 5¢-
bromo-5¢-deoxyadenosine 3a27 (prepared by a modified reac-
tion of adenosine with triphenyl phosphine and carbon tetra-
bromide in pyridine in the presence of N-methylimidazole,
see Experimental), 5¢-deoxy-5¢-iodoguanosine28 3b, 5¢-deoxy-5¢-
iodo-2¢,3¢-O-isopropylideneuridine29 3c (Scheme 2), and 5¢-O-
tosylribonucleosides30,31 6, 7 (Scheme 3) afforded the desired 5¢-
deoxyribonucleoside 5¢-S-methylphosphonates 5.
In contrast to 5¢-haloribonucleosides, the use of fully protected
5¢-O-tosylribonucleosides provided better yields (Table 1) due to
the easier purification of the fully protected nucleoside phospho-
nates.
To prepare 2¢-deoxy-2¢-S-methylphosphonate 11, we checked
the reactivity of the protected 2¢-O-triflyladenosine32 10 with the
thiolate anion 2b generated from 2a (Scheme 4). Also, in this
case, the nucleophilic displacement of the triflyloxy group for the
thioate 2b proceeded smoothly and provided an excellent yield of
Scheme 4
the desired arabino S-methylphosphonate 11 after removal of the
disiloxanyl group (Table 1).
This compound was prepared as a building unit for the synthesis
of the modified 2¢-5¢ oligoadenylates. In our recent study10 on
the RNase L agonists/antagonists, the tetramer containing an
arabino-configured 2¢-O-methylphosphonate unit (similar to 11
but with the 2¢-oxygen instead of 2¢-sulfur atom) was recognised
as a potent nanomolar antagonist.
Nucleoside phosphonates 4a–d were deprotected by treatment
with bromotrimethylsilane and 2,6-lutidine in acetonitrile to
afford phosphonic acids 5a–d in good yields (Table 2).
The free phosphonic acids 5a–d were transformed into diphos-
phoryl derivatives 13a–d (the NTP analogues) by Lohrmann’s
procedure33 via phosphonoimidazolides 12a–d as intermediates.
Scheme 2
Scheme 3
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Scheme 5
Table 2
nucleosides 4d and 5d with the cytosine base, the N-type conformer
is more populated.
Diphosphoryl
Phosphonate Base Phosphonic acid Yield (%) derivative
To find a “physically correct” combination of the N- and S-
type conformers from the alternative ones obtained from the
PSEUROT calculations, we decided to explore the conformational
behaviour of the studied compounds by molecular modeling.
The uracil derivative 4c (without any substituents on the sulfur
atom) was chosen as the model compound. Twenty conformers,
defined by phase angle P in 18◦ steps and fmax = 38◦, were
constructed and their geometries were energetically optimised
with only restrained endocyclic torsion angles using the AMBER
version of the HYPERCHEM 8.0 program package.
Thus, the relation between conformer geometry and calculated
energy was obtained over the entire pseudorotation pathway (see
Fig. 1). The calculated fmax in the entire range of P adopted
realistic values between 34.5◦ and 39.5. There are two low-energy
minima with P ~ 36◦ and ~180◦, differing by approximately 0.22
kcal mol-1, and the third energy minimum with approximately 1
kcal higher energy content and therefore much less probability of
population. Therefore, only set A of the conformation parameters
from PSEUROT is in acceptable agreement with the calculated
energy in the pseudorotation pathway.
Yield (%)
4a
4b
4c
4d
A
G
U
C
5a
5b
5c
5d
64
48
84
80
13a
13b
13c
13d
46
69
55
72
The activation of 5 with triphenylphosphine and 2,2-dipyridyl
disulfide in the presence of imidazole afforded the corresponding
phosphonoimidazolides which were treated, after precipitation,
with a 0.5 M solution of bis(tributylammonium)pyrophosphate in
DMSO (Scheme 5). The NTP analogues 13a–d were obtained
in very good yields (Table 2) after purification on a POROS
50 HQ anion exchanger column in ammonium hydrogen carbo-
nate.
The prepared triphosphate analogues 13a–d exhibited very high
IC50 values (100–250 mM) in an HCV RNA-dependent RNA
polymerase competition assay.34,35 With regard to the study with 5¢-
nucleotidases and purine nucleoside phosphorylase, no inhibition
by the free phosphonic acids 5a–d was observed.
Conformational analysis of compounds 4a–d and 5a–d
The vicinal proton coupling constants and the program
PSEUROT,36 based on the concept of pseudorotation,37 were
used to obtain the information regarding the conformation of
the furanose ring in compounds 4a–d and 5a–d. The NMR con-
formational studies show that with nucleotides in solution, mostly
two preferred conformers of the furanose ring are present in a fast
equilibrium and can be fully described by five parameters (phase
angles for both conformers (P(N), P(S)), puckering amplitudes
(fm(N), fm(S)) and the molar concentration of one conformer
(X(N) or X(S)).
3
Because there are only three J(H,H) in the furanose ring of
4a–d and 5a–d, we started our PSEUROT calculation with the
assumption that fm(N) = fm(S) and changed their values in 2◦ steps
over the range of 30◦ to 46◦, calculating P(N), P(S) and X(N) to
3
obtain the best fit between the calculated and observed J(H,H)
values. The actual set of J values and a periodicity of the Karplus
relation gives two solutions, A and B, for each fm (two different
combinations of P(N) and P(S)). Table 3 shows the observed
3J(H,H) values and two ranges of calculated combinations of
P(N), P(S) and X(N) that give an excellent agreement between
the calculated and observed 3J(H,H) (rms ~ 0).
It can be seen from Table 3 that the calculated data are very
similar, except in populations X(N) and X(S). In compounds 4a–
c and 5a–c, the S-type conformer somewhat prevails, while in
Fig. 1 Conformation analysis of the furanose ring in the uracil derivative
4c (without any substituents on the sulfur atom) by molecular mechanics
(AMBER in HYPERCHEM 8.0).
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Table 3 Pseudorotation analysis of compounds 4a–d and 5a–d (The fmax(N) = fmax(S) approximation was used and its value changed with 2◦ steps in the
range of 30◦–46◦. Phase angles P(N), P(S) and populations X(N) and X(S) were optimised. Ranges of calculated parameters for set A and B are given
for rms £ 0.001. The given P(N) and P(S) values were rounded to the closest unit)
Comp.
4a
Solvent
DMSO
DMSO
DMSO
DMSO
D2O
J(1¢,2¢)
5.58
6.00
5.46
4.44
5.70
5.89
4.93
4.28
J(2¢,3¢)
5.17
4.80
5.46
5.47
5.46
5.40
5.16
5.34
J(3¢,4¢)
4.00
3.60
4.44
5.40
4.20
3.96
4.50
5.88
Set
Um(N) = Um(S)
P(N)
X(N)
P(S)
X(S)
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
34 to 44
34 to 40
36 to 44
36 to 44
36 to 42
34 to 44
36 to 40
38 to 42
34 to 42
34 to 42
34 to 44
34 to 42
34 to 40
34 to 40
36 to 38
36 to 42
42 to 68
-11 to -34
29 to 62
-4 to -40
60 to 70
-18 to -43
52 to 58
-29 to -37
58 to 74
-19 to -42
57 to 79
-18 to -42
37 to 53
-11 to -32
47 to 50
0.40 to 0.35
0.40 to 0.46
0.34 to 0.30
0.36 to 0.44
0.46 to 0.42
0.41 to 0.49
0.56 to 0.53
0.55 to 0.58
0.44 to 0.40
0.38 to 0.45
0.41 to 0.37
0.36 to 0.43
0.46 to 0.42
0.48 to 0.53
0.61 to 0.60
0.56 to 0.60
182 to 213
178 to 135
175 to 206
159 to 140
199 to 214.
134 to 121
204 to 214
119 to 113
189 to 214
136 to 125
187 to 216
139 to 128
186 to 208
146 to 132
196 to 204
123 to 111
0.60 to 0.65
0.60 to 0.54
0.66 to 0.70
0.64 to 0.56
0.54 to 0.58
0.59 to 0.51
0.44 to 0.47
0.46 to 0.42
0.56 to 0.60
0.62 to 0.55
0.59 to 0.63
0.64 to 0.57
0.54 to 0.58
0.52 to 0.47
0.39 to 0.40
0.44 to 0.40
4b
4c
4d
5a
5b
D2O
5c
D2O
5d
D2O
-14 to -32
Table 4 Pseudorotation analysis of compounds 4a–5d (The pseudorotation parameters Um(N), Um(S), P(N) and P(S) are fixed to calculated values from
the energy minimisation in Fig. 1, and only X(N) and X(S) were optimised)
Compound
X(N)
Um(N)
P(N)
X(S)
Um(S)
P(S)
rms
DJ(1¢,2¢)
DJ(2¢,3¢)
DJ(3¢,4¢)
4a
4b
4c
4d
5a
5b
5c
5d
0.39
0.34
0.44
0.55
0.40
0.37
0.46
0.59
0.61
0.66
0.56
0.45
0.60
0.63
0.54
0.41
0.245
0.051
0.382
0.369
0.392
0.366
0.292
0.262
-0.12
-0.06
0.03
-0.15
0.06
0.06
-0.28
-0.02
0.39
0.05
0.66
0.60
0.68
0.63
0.34
0.45
-0.11
-0.05
-0.02
-0.15
0.01
0.01
-0.24
-0.04
38
36 (4T3)
37
179 (3T2)
To check the consistency between the results of geometry
optimisation (calculated by energy minimisation; Fig. 1) and
those obtainable from NMR data, we applied PSEUROT using
fixed values of P(N), P(S), fmax(N) and fmax(S) (corresponding
to the lowest energy conformers in Fig. 1) and only the ratio of
X(N) : X(S) variable in the whole series of compounds 4a–d and
5a–d. The results are shown in Table 4. Although the rms values
are somewhat worse than in Table 3, we believe that they can give
a realistic picture of the conformational behaviour of the studied
compounds. It is not surprising that the structural similarity of
4a–d and 5a–d can result in the same type of the preferred N-
and S-conformers with a higher population of S-type 3T2 in 4a–c
and 5a–c (in accordance with its calculated lower energy; Fig. 1).
Fig. 2 The calculated N- and S-type conformers (4T3 and 3T2) shown on
the model of the uracil derivative 4c.
The reason for a preference for the N-type conformer T3 in the
4
cytidine derivatives 4d and 5d is not clear. The calculated N- and
S-type conformers are shown for 4c in Fig. 2.
inhibitors of cytosolic and mitochondrial 5¢-nucleotidases, and
purine nucleoside phosphorylase and the NTP compounds were
tested as the substrates/inhibitors of the HCV RNA-dependent
RNA polymerase. Although none of the prepared compounds
were recognised as inhibitors or substrates by the selected enzymes,
the phosphonomethylthio motif can be further exploited in
regard to its incorporation into the modified oligonucleotides,
in which the internucleotide linkages C3¢(2¢)–O–P–CH2–O–C5¢¢
and C3¢(2¢)–O–CH2–P–O–C5¢¢ that have already been evaluated
will be substituted with C3¢(2¢)–O–P–CH2–S–C5¢¢ or C3¢(2¢)–S–
CH2–P–O–C5. Further work on this topic is underway and will be
reported elsewhere.
In summary, the novel compounds 5¢-deoxy-5¢-phospho-
nomethylthioribonucleosides were synthesised by the reaction of
5¢-deoxy-5¢-haloribonucleoside derivatives with diisopropyl mer-
captomethylphosphonate generated in situ from its new synthetic
equivalent, the S-(diisopropylphosphonomethyl)isothiouronium
tosylate. The NMR conformational study of both protected and
unprotected nucleotides revealed a preference for the N-type
conformer in the case of the only cytidine derivatives (the reasons
are unclear). Novel modified 5¢-ribonucleotides and their diphos-
phoryl derivatives (the NTP analogues) were tested as potential
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14 G. K. Farrington, A. Kumar and F. C. Wedler, Org. Prep. Proced. Int.,
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Acknowledgements
15 J. L. Kelley, J. A. Linn, E. W. McLean and J. V. Tuttle, J. Med. Chem.,
1993, 36, 3455–3463.
Support by the Research centre KAN200520801 (Acad. Sci.
CR), grants 202/09/0193 and 203/09/0820 (Czech Science
Foundation), and Research centre and LC060061 (Ministry
of Education, CR), and under the Institute research project
Z40550506 is gratefully acknowledged. The authors are indebted
to Dr. Tomas Cihlar and Dr. Richard Mackman (Gilead Sci.,
Ltd., CA) for the evaluation of substrate/inhibition properties
of NTP analogues. The authors would also like to thank Dr.
Zdeneˇk Tocˇ´ık for the valuable discussions, and the staff of the
Mass Spectrometry Group and Infrared Spectroscopy Group of
IOCB for HR-MS spectra and the interpretation of IR spectra,
respectively.
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