Nucleoside H-phosphonates, XXII: Synthesis and properties of new nucleotide analogues - H-phosphonothiolate diesters

Article abstract of DOI:10.1055/s-2007-991072

Condensation of nucleoside 3′-H-phosphonate monoesters with various thiols, promoted by condensing agents, provides a convenient access to a new class of H-phosphonate analogues, H-phosphonothiolate diesters. Chemical properties, relevant to possible appl

Full text of DOI:10.1055/s-2007-991072

2748
LETTER
Nucleoside H-Phosphonates, XXII: Synthesis and Properties of New
Nucleotide Analogues – H-Phosphonothiolate Diesters
S
ynthesis of H-P
e
hosphonoth
n
iolates ata Hiresova,a Jacek Stawinski*a,b
a
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
E-mail: js@organ.su.se
b
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
Received 10 August 2007
As part of our program in developing synthetic methods
for biologically important phosphorus compounds based
on H-phosphonate methodology,5,19 we have embarked on
exploration a new class of synthetic intermediates, H-
Abstract: Condensation of nucleoside 3¢-H-phosphonate mono-
esters with various thiols, promoted by condensing agents, provides
a convenient access to a new class of H-phosphonate analogues, H-
phosphonothiolate diesters. Chemical properties, relevant to possi-
ble applications of these compounds as a new type of synthetic phosphonothiolates, that could provide a convenient ac-
intermediates in the preparation of nucleotide analogues bearing a
sulfur atom at the bridging position of a phosphate group, were
investigated.
cess to phosphorothiolates (the P–S–C functionality) and
their analogues. Although thiols are poor nucleophiles in
the SN2(P) reactions at P(V) centers,7 we previously
Key words: H-phosphonates, H-phosphonothiolates, phosphate
analogues, nucleotide analogues
observed that activated H-phosphonates reacted with
hydrogen sulfide20,21 to form H-phosphonothioate and H-
phosphonodithioates monoesters. Thus, as a viable
approach to H-phosphonothiolate diesters of type 2
Oligonucleotide analogues containing modified inter-
nucleotide linkages are of growing interest as potential
therapeutic agents1 and tools in molecular biology for
manipulation of RNA and DNA.2 Among these, oligo-
nucleoside phosphorothioates3 and phosphorodithioates4
are particularly attractive since they are isopolar and iso-
steric to their natural congeners.
(Scheme 1) we considered a condensation of H-phospho-
nate monoesters with thiols, promoted by a condensing
agent.
O
O
NH
NH
DMTO
DMTO
N
O
N
O
In contrast to the P=S functionality, which can be relative-
ly easy introduced into biologically important phosphates
via sulfurization of the corresponding H-phosphonate5 or
phosphite triesters6 precursors, the synthesis of analogues
bearing sulfur atom at the bridging position of a phosphate
group as in a P–S–C functionality, is usually a more
complicated task. Due to inherently low reactivity of S-
nucleophiles toward hard P(V) centers,7 such compounds
are usually prepared via alkylation of sulfur in phos-
phorothioate derivatives using suitable C-electrophiles,8–
O
O
RSH
O
P
condensing agent
O
P
S
O
H
O
H
O
R
2a–d
1
O
NH
O
N
O
10
by nucleophilic substitution at soft, tervalent P(III)
R:
OTBS
c
center,11 oxidation of the P(III) precursors with reactive
disulfides,12 or using dedicated thiophosphorylating
reagent bearing already the P–S–C bond system.13
a
b
d
O
O
DMT = 4,4'-dimethoxytrityl
PhO P OPh
Cl
condensing
agent:
Cl
PvCl
It is worth noting that due to different conformational
preferences and the increased lability conferred by the P–
S–C functionality, phosphorothiolates have distinct, from
those of phosphorothioates (P=S), chemical and biologi-
cal properties.13–15 In the middle of the 1950s, numerous
phosphorothiolate diesters were extensively investigated
as potential antiradiation drugs,9,16 and more recently, as
potential antisense/antigene agents,14 pronucleotides,17
and tools in mechanistic investigations of ribozymes.10,18
DPCP
Scheme 1
To assess reactivity of thiols towards activated H-phos-
phonate monoesters, we subjected nucleoside H-phospho-
nate 1 to the reaction with ethanethiol (2 equiv) in
pyridine, in the presence of pivaloyl chloride (PvCl, 3
equiv). 31P NMR spectroscopy revealed that the starting
1
material 1 (d = 2.80 ppm, JPH = 640 Hz) was consumed
within five minutes, but no product with a large 1JPH cou-
pling constant, indicative of the presence of the desired H-
phosphonothiolate 2a, could be detected. Instead, two
SYNLETT 2007, No. 17, pp 2748–2752
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991072; Art ID: G24907ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of H-Phosphonothiolates
2749
phosphorus species, resonating at d = 32.91 ppm phonate diesters, in a separate experiment 2a was
(3JPH = 9.2 Hz, m; ca 53%) and 159.0 ppm (3JPH = 10.7 generated as described above, and subjected to reactions
Hz, sext; ca 47%) were formed. On the basis of the chem- with various nucleophiles and electrophiles. It was found
ical shifts and the observed splitting pattern in the 1H-cou- (31P NMR spectroscopy experiments) that addition of
pled 31P NMR spectra, these signals were tentatively water to the reaction mixture (200 equiv) cause immediate
assigned to the P-acylphosphonate 3 (d = 32.91 ppm)22 hydrolysis of 2a producing the starting nucleoside H-
and dithiophosphite 4 (d = 159.0 ppm,23 Figure 1). Since phosphonate 1. As expected, primary amines, e.g. of n-bu-
both compounds contained the P–S–C bonds, we assumed tylamine (2 equiv) also rapidly reacted with H-phospho-
that apparently the desired H-phosphonothiolate 2a was nothiolate 2a affording within few minutes the
initially formed, but under the reaction conditions under- corresponding n-butyl nucleoside H-phosphonamidate 6
1
3
went subsequent reactions that ultimately led to the P-acy- (d = 13.6 and 13.8 ppm, JPH = 640 Hz, JPH = 10.3 Hz;
lated product 3 and the corresponding dithiophosphite 4.
dq; >90%).24 High susceptibility of this class of com-
pounds to nucleophilic substitution at the phosphorus cen-
ter was confirmed in the reaction of H-phosphonothioate
2a with two equivalents of ethanol that produced quanti-
tatively the corresponding nucleoside ethyl H-phospho-
nate 5 (d = 7.9 ppm, 1JPH = 704 Hz, 3JPH = 8.9 Hz; dq).25
O
P
H
O
P
C
O
P
H
SEt
SEt
RO
P
RO
NH-n-Bu
RO
SEt
RO
OEt
O
3
4
5
6
Since most relevant to possible applications of H-
phosphonothiolates of type 2 as synthetic intermediates
for the preparation of various nucleotide analogues were
oxidative transformations, we subjected compound 2a to
oxidation under different experimental conditions.
R = 5'-O-dimethoxytritylthymidin-3'-yl
Figure 1
To suppress such undesired reactions, the condensation
was carried out in less basic medium, namely in acetoni-
trile–pyridine mixture (4:1), and the amount of PvCl was
reduced to 1.5 equivalents. Under these new reaction
conditions, the condensation of H-phosphonate 1 with
ethanethiol was still rapid (<5 min) but produced as a ma-
jor product (>90%) a compound resonating at d = 33.8
and 34.1 ppm (1JPH = 658 Hz). Since the two signals of
equal intensity were indicative of a one-spin system of
phosphorus diastereomers, and their chemical shift values
and a large 1H–31P coupling constant were consistent with
the presence of a P–S–C and P–H functionalities, we as-
signed these signals to the expected H-phosphonothiolate
2a. Although acylphosphonate 3 (10%; d = 33.2 ppm)
was initially the only byproduct present in the reaction,
upon standing (ca 10 min), additional signals at 159.4
ppm (compound 4) and at 2.8 ppm (H-phosphonate 1)
started to emerge, and after few hours, H-phosphono-
thioate 2a was completely replaced by these two species
(ca 1:1 ratio; 31P NMR).
As expected, standard oxidation system for the transfor-
mation of H-phosphonate diesters into the corresponding
phosphates, consisting of iodine in 2% aqueous pyridine,
gave poor results affording with one equivalent of iodine
mainly the hydrolysis product (compound 1, ca. 30%),
dithiophosphite 4 (ca 50%), and only ca. 20% of the de-
sired phosphorothiolate 7a (d = 18.8 ppm, 3JPH = 11.1 Hz,
q). However, under the Atherton–Todd oxidation condi-
tions,26 using carbon tetrachloride as an oxidant in the
presence of triethylamine and water (Scheme 2), the oxi-
dation proceeded smoothly producing within few minutes
exclusively the desired product, phosphorothiolate 7a
(isolated in 82% yield). Also sulfurization with elemental
sulfur in the presence of triethylamine was uneventful and
afforded cleanly the corresponding phosphorodithioate 8a
3
(d = 74.2 and 75.3 ppm, JPH = 12.6 Hz, q; isolated in
67% yield).
Using the reaction conditions developed for 2a, other
representative H-phosphonothiolate diesters bearing a
longer alkyl chain (2b), a cholesteryl moiety (2d), or an-
other nucleosidic unit (2c), were efficiently generated
Since reactivity of H-phosphonothiolate 2a seemed to dif-
fer significantly from that of the corresponding H-phos-
O
O
O
NH
NH
NH
DMTO
DMTO
DMTO
N
O
N
O
N
O
O
O
O
[S]
[O]
O
P
S
O
P
S
O
P
S
O
O
O
S
O
H
R
R
R
8a–d
7a–d
2a–d
2a, 7a, 8a, R = Et
2b, 7b, 8b, R = n-Bu
2c, 7c, 8c, R = 3'-OTBS-thymidin-5'-yl
2d, 7d, 8d, R = cholesteryl
Scheme 2 Oxidation conditions: CCl4 (10 equiv), H2O (50 equiv), Et3N (2 equiv). Sulfurization conditions: S8 (3 equiv), Et3N (2 equiv).
Synlett 2007, No. 17, 2748–2752 © Thieme Stuttgart · New York

2750
R. Hiresova, J. Stawinski
LETTER
from nucleoside H-phosphonate 1 and the corresponding Probably, by changing a pyridine content in the reaction
thiols (Scheme 1). All these compounds showed similar to mixture, a compromise between coupling efficiency and
2a chemical properties, and were converted cleanly into extent of P-acylation, could be achieved, however, since
nucleotide analogues 7a–d and 8a–d.
formation of byproducts of type 3 was obviously related
to the condensing agent used, we investigated diphenyl
phosphorochloridate (DPCP) as possible condensing
agents. Indeed, this reagent turned out to be superior to
PvCl in terms of purity of the generated H-phosphono-
thiolates 2, and since the condensations were also rapid
(<5 min), this reagent was used in further preparative
runs.28
In light of the above, it was apparent that due to high
reactivity towards nucleophiles and electrophiles, H-
phosphonothiolate diesters, in most cases, probably could
not be isolated by chromatographic methods, but instead,
should be treated as reactive intermediates that have to be
in situ converted into various phosphate analogues bear-
ing single or multiple modifications at the phosphorus
center. In this context, purity of the generated H-phos- As to possible mechanisms of dithiophosphites of type 4
phonothiolates of type 2 might be a synthetically impor- formation, some additional observations were pertinent.
tant issue, and for this reason we decided to carry out Irrespective of the condensing agent used, the reactions in
some additional studies on factors that can promote neat pyridine afforded dithiophosphites 4 as major reac-
byproduct formation during synthesis of H-phosphonothi- tion products. When excess of DPCP and a thiol were add-
olate diesters.
ed to a reaction mixture containing H-phosphonothiolates
2 in pyridine, within a few minutes a complete conversion
of 2 into the corresponding dithiophosphite 4 was ob-
served. In less basic reaction media, e.g. in acetonitrile–
pyridine (4:1), this byproduct was usually formed after
10–15 minutes after completion of the condensation reac-
tion, and in the presence of a limiting amount of a con-
densing agent, the formation of dithiophosphite 4 was
accompanied by the appearance of the starting material,
nucleoside H-phosphonate 1. Finally, upon addition of a
triethylamine (10 equiv) to a reaction mixture containing
2, an immediate disappearance of the H-phosphono-
thiolate diester occurred, and formation of equimolar
amounts of the corresponding dithiophosphite 4 and
nucleoside H-phosphonate 1 was observed.
Since formation of P-acylated products is known to be
favored under basic conditions,5,27 to suppress or to elim-
inate formation of this type of byproducts (compounds of
type 3), we attempted to carry out synthesis of H-
phosphonothiolates 2 in acetonitrile containing 1% pyri-
dine. Indeed, under such reaction conditions we did not
observe (by 31P NMR) formation of a P-acylated product
of type 3 (due to a subsequent reaction of pivaloyl chlo-
ride with the produced H-phosphonothiolates 2), howev-
er, the condensation became less efficient. In the reaction
with ethanethiol (2 equiv), after five minutes the reaction
mixture consisted of almost equimolar amounts of the de-
sired H-phosphonothiolate 2a and the corresponding H-
phosphonic-pivalic mixed anhydride (d = 2.18 and 2.28
1
3
ppm, JPH = 747 Hz, JPH = 9.2 Hz), and the reaction As a possible explanation for the above observations, we
seemed to stop at this stage. With more ethanethiol (4 propose two mechanisms that can be involved in the for-
equiv), the reaction proceeded to ca. 70% completion, but mation of byproducts of type 4 during the investigated
still, the unreacted mixed anhydride was present in the re- condensations. These are depicted in Scheme 3 as path A
action mixture. Extending the reaction time (40 min) did and path B. The first mechanism (path A, Scheme 3) is
not provide any improvement in terms of yield of the pro- related to that of disproportionation of some aryl H-
duced H-phosphonothiolate 2a, and only decomposition phosphonates21,29 or phosphonic–carboxylic mixed an-
products of the mixed anhydride started to form.
hydrides,30 which under similar conditions afforded
OH
P
RO
SEt
SEt
OR
P
SEt
HO
O
P
H
O
O
OR
SEt
SEt
EtSH
RO
O P
RO
P
H
RO
P
H
1
O
PvCl
path A
2a
PvCl
path B
O
O
P
O
SEt
EtSH
RO
P
RO
P
O
+
RO
SEt
SEt
H
1
9
4
Scheme 3
Synlett 2007, No. 17, 2748–2752 © Thieme Stuttgart · New York

LETTER
Synthesis of H-Phosphonothiolates
2751
(12) (a) Garegg, P. J.; Regberg, T.; Stawinski, J.; Strömberg, R.
J. Chem. Soc., Perkin Trans. 1 1987, 1269. (b) Liu, X. H.;
Reese, C. B. Tetrahedron Lett. 1995, 36, 3413.
(c) Weinstein, L. B.; Earnshaw, D. J.; Cosstick, R.; Cech, T.
R. J. Am. Chem. Soc. 1996, 118, 10341.
(13) Cook, A. F. J. Am. Chem. Soc. 1970, 92, 190.
(14) Beevers, A. P. G.; Fettes, K. J.; O’Neil, I. A.; Roberts, S. M.;
Arnold, J. R. P.; Cosstick, R.; Fisher, J. Chem. Commun.
2002, 1458.
equimolar amounts of the corresponding tervalent and
tetracoordinate P(III) species. This mechanism is consis-
tent with the observed rapid transformation of H-
phosphonothiolates 2 into equimolar mixture of dithio-
phosphites 4 and the staring H-phosphonate monoester 1,
in the presence of added triethylamine.
To find out if an alternative reaction pathway (path B,
Scheme 3), i.e. activation of the produced H-phosphono-
thiolates 2 by a condensing agent, followed by the reac-
tion with a thiol, could contribute also to the formation of
dithiophosphites of type 4, we carried out the condensa-
tion of nucleoside H-phosphonate 1 with excess of both
ethanethiol (10 equiv) and PvCl (5 equiv) in acetonitrile–
pyridine (4:1). Since no detectable increase in the rate of
formation of dithiophosphite of type 4 compared to the re-
action with less thiol and the condensing agent (2 equiv of
both) was observed, we can tentatively conclude that this
type of byproducts was mainly formed via disproportion-
ation of H-phosphonothiolates 2.
(15) Cook, A. F.; Holman, M. J.; Nussbaum, A. L. J. Am. Chem.
Soc. 1969, 91, 6479.
(16) Åkerfeldt, S.; Fagerlind, L. J. Med. Chem. 1967, 10, 115.
(17) Padmanabhan, S.; Coughlin, J. E.; Zhang, G. R.; Kirk, C. J.;
Iyer, R. P. Bioorg. Med. Chem. Lett. 2006, 16, 1491.
(18) (a) Kuimelis, R. G.; Mclaughlin, L. W. J. Am. Chem. Soc.
1995, 117, 11019. (b) Kuimelis, R. G.; McLaughlin, L. W.
Nucleic Acids Res. 1995, 23, 4753. (c) Kuimelis, R. G.;
McLaughlin, L. W. Biochemistry 1996, 35, 5308.
(19) (a) Stawinski, J.; Kraszewski, A. Acc. Chem. Res. 2002, 35,
952. (b) Kraszewski, A.; Stawinski, J. Trends Org. Chem.
2003, 10, 1.
(20) (a) Stawinski, J.; Zain, R. Nucleosides Nucleotides 1995, 14,
711. (b) Cieslak, J.; Jankowska, J.; Sobkowski, M.; Kers, A.;
Kers, I.; Stawinski, J.; Kraszewski, A. Collect. Symp. Ser.
1999, 2, 63.
(21) Cieslak, J.; Jankowska, J.; Stawinski, J.; Kraszewski, A.
J. Org. Chem. 2000, 65, 7049.
(22) Compound 3 was obtained on independent way by reacting
H-phosphonothiolate 2a with pivaloyl chloride in MeCN–
pyridine (4:1). The signals of two P-diastereomers were not
resolved in the 31P NMR spectrum.
(23) Ethyl H-phosphonate reacted with ethanethiol analogously
to that of 1, producing compound of type 4 (R = Et) that
resonated at dP = 157.8 ppm (3JPH = 9.4 Hz, hept). This
compound was prepared independently by reacting ethyl
phosphorodichloridite with 2 equiv of ethanethiol in MeCN–
pyridine (4:1).
In conclusion, we developed an efficient protocol for
generation of H-phosphonothiolate diesters of type 2, con-
sisting of condensation of H-phosphonate monoesters
with various thiols, in the presence of a condensing agent.
The coupling reactions were clean, rapid, and the pro-
duced H-phosphonothiolate diesters could be converted
via oxidative transformations into various nucleotide ana-
logues bearing sulfur atom at the bridging position in the
phosphate group. The method is experimentally simple,
makes use of easily accessible H-phosphonate mono-
esters,31 and expands range of biologically important
phosphate analogues that can be prepared via H-phospho-
nate methodology.
(24) Comparison with original sample obtained by reaction of 1
with phenol in the presence of pivaloyl chloride, followed by
the addition of n-butylamine. See: Kers, A.; Stawinski, J.;
Kraszewski, A. Tetrahedron 1999, 55, 11579.
Acknowledgment
Financial support from the Swedish Research Council is gratefully
acknowledged.
(25) Comparison with original sample obtained by condensation
of 1 with ethanol in the presence of pivaloyl chloride. The
P-diastereomers were not resolved.
(26) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc.
1945, 660.
References and Notes
(27) Sekine, M.; Satoh, M.; Yamagata, H.; Hata, T. J. Org. Chem.
1980, 45, 4162.
(1) Wilson, C.; Keefe, A. D. Curr. Opin. Chem. Biol. 2006, 10,
607.
(28) General Procedure for Synthesis and Oxidative
Transformations of H-Phosphonothiolates 2a–d
Nucleoside H-phosphonate monoester 1 (0.15 mmol) was
rendered anhydrous by evaporation of added pyridine, and
the residue was dissolved in MeCN–pyridine (4:1; 2 mL) or
in CH2Cl2–pyridine (4:1; 2 mL, for thiols c and d). To this
solution, the appropriate thiol a–d (2 equiv) and a
condensing agent (diphenyl phosphorochloridate; 1 equiv)
were added. The reactions were complete within 5 min (31P
NMR analysis) producing the expected nucleoside H-
phosphonothiolates 2.
(2) (a) Tuschl, T.; Thomson, J. B.; Eckstein, F. Curr. Opin.
Struct. Biol. 1995, 5, 296. (b) Eckstein, F. Antisense Nucleic
Acid Drug Dev. 2000, 10, 117.
(3) Eckstein, F.; Gish, G. Trends Biochem. Sci. 1989, 14, 97.
(4) Beaton, G.; Brill, W. K.-D.; Grandas, A.; Ma, Y.-X.;
Nielsen, J.; Yau, E.; Caruthers, M. Tetrahedron 1991, 47,
2377.
(5) Stawinski, J. In Handbook of Organophosphorus Chemistry;
Engel, R., Ed.; Marcel Dekker: New York, 1992, 377.
(6) Beaucage, S. L.; Iyer, R. P. Tetrahedron 1993, 49, 10441.
(7) Horner, L. J. Prakt. Chem. 1992, 334, 645.
(8) Åkerfeldt, S. Acta Chem. Scand. 1959, 13, 1479.
(9) Åkerfeldt, S. Acta Chem. Scand. 1962, 16, 1897.
(10) Xu, Y.; Kool, E. T. Nucleic Acids Res. 1998, 26, 3159.
(11) (a) Cosstick, R.; Vyle, J. S. J. Chem. Soc., Chem. Commun.
1988, 992. (b) Cosstick, R.; Vyle, J. S. Nucleic Acids Res.
1990, 18, 829. (c) Mag, M.; Lüking, S.; Engels, J. W.
Nucleic Acids Res. 1991, 19, 1437.
31P NMR Data for Compounds 2
Compound 2a: d = 33.75 and 34.08 ppm (1JPH = 658.2 Hz,
3JPH = 11.1 Hz, dq); 2b: d = 33.96 and 34.23 ppm (1JPH
=
659.9 Hz, 3JPH = 10.7 Hz, dq); 2c: d = 32.66 and 32.79 ppm
(1JPH = 672.2 Hz, 3JPH = 10.7 Hz, dq); 2d: d = 33.01 and
33.37 ppm (1JPH = 652.0 Hz, 3JPH = 11.4 Hz, dt).
To the solution containing 2a–d, a mixture of CCl4 (10
equiv), H2O (50 equiv), and Et3N (2 equiv) was added. The
Synlett 2007, No. 17, 2748–2752 © Thieme Stuttgart · New York

2752
R. Hiresova, J. Stawinski
LETTER
reactions were complete within 5 min (31P NMR analyses),
producing quantitatively the corresponding
31P NMR Data for Compounds 8
Compound 8a (67%): d = 74.22 and 75.26 ppm (3JPH = 12.6
Hz, q); 8b (61%): d = 74.39 and 75.26 ppm (3JPH = 12.7 Hz,
q); 8c (65%): d = 73.85 and 74.17 ppm (3JPH = 12.6 Hz, q);
8d (59%): d = 74.54 and 76.35 ppm (3JPH = 12.9 Hz, t).
(29) (a) Gallagher, M. J.; Garbutt, R.; Liu, Y. H.; Gum, H. L.
Phosphorus, Sulfur Silicon Relat. Elem. 1993, 75, 201.
(b) Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.;
Kraszewski, A. Tetrahedron 1996, 52, 9931.
phosphorothiolates 7a–d, that were isolated by silica gel
column chromatography (purity >98%, 1H NMR).
31P NMR Data for Compounds 7
Compound 7a (82%): d = 18.76 ppm (3JPH = 11.1 Hz, q); 7b
(72%): d = 18.99 ppm (3JPH = 11.1 Hz, q); 7c (64%):
d = 16.64 ppm (3JPH = 10.2 Hz, q); 7d (56%): d = 19.86 ppm
(3JPH = 10.1 Hz, t).
Sulfurization of the in situ generated H-phosphonothiolates
2a–d was performed by the addition of elemental sulfur (3
equiv) and Et3N (2 equiv) to the corresponding reaction
mixtures. The reactions were complete within 5 min (31P
NMR analyses), affording quantitatively the corresponding
phosphorodithioates 8a–d, that were isolated by silica gel
column chromatography (purity >98%, 1H NMR).
(30) Cieslak, J.; Szymczak, M.; Wenska, M.; Stawinski, J.;
Kraszewski, A. J. Chem. Soc., Perkin Trans. 1 1999, 3327.
(31) (a) Stawinski, J.; Strömberg, R. In Current Protocols in
Nucleic Acid Chemistry; Beaucage, S. L.; Bergstrom, D. E.;
Glick, G. D.; Jones, R. A., Eds.; John Wiley and Sons, Inc.:
New York, 2001, Chap. 2.6.1. (b) Stawinski, J.; Strömberg,
R. In Oligonucleotide Synthesis: Methods and Applications,
Vol. 288; Herdewijn, P., Ed.; Humana Press: Totowa NJ,
2004, 81.
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