Nucleoside H-phosphonates XX. Efficient method for the preparation of nucleoside H-phosphonoselenoate monoesters

Article abstract of DOI:10.1055/s-2005-865300

The preparation of an H-phosphonoselenoyl group transferring reagent, 9-fluorenemethyl H-phosphonoselenoate, and its application to the synthesis of separate diastereomers of nucleoside 3′-H-phosphonoselenoate monoesters, are described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-865300

1668
PAPER
Nucleoside H-Phosphonates XX. Efficient Method for the Preparation of
Nucleoside H-Phosphonoselenoate Monoesters
Nucleoside
H
-Phospho
a
nates rtin Kullberg,a Jacek Stawinski*a,b
a
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
E-mail: js@organ.su.se
b
Received 20 January 2005
Results and Discussion
Abstract: The preparation of an H-phosphonoselenoyl group trans-
ferring reagent, 9-fluorenemethyl H-phosphonoselenoate, and its
application to the synthesis of separate diastereomers of nucleoside
3¢-H-phosphonoselenoate monoesters, are described.
Since nucleoside H-phosphonoselenoate monoesters are
chiral at the phosphorus centre, access to the separate RP
and SP diastereomers is required to exploit in full their
synthetic potential. Unfortunately, the presence of a neg-
ative charge in an H-phosphonoselenoate moiety usually
overshadows possible chromatographic differences be-
tween isomeric compounds and effectively prevents sepa-
ration of their P-diastereomers on silica gel.9 To overcome
this problem, we designed a dedicated H-phosphonosele-
noyl group transferring reagent, 9-fluorenemethyl H-
phosphonoselenoate 4 (Scheme 1), which upon reaction
with a hydroxylic component (e.g. a nucleoside) can pro-
duce uncharged H-phosphonoselenoate diesters of type 6
(Scheme 2). These are much more easy to separate into di-
astereomers and after the removal of the fluorenemethyl
group, RP and SP diastereomers of H-phosphonoselenoate
monoesters 7 can be obtained. The fluorenemethyl group
in H-phosphonoselenoate diesters 6 acts as a lipophilic
handle that facilitates separation of these compounds by a
silica gel column chromatography, and since it is remov-
able via a b-elimination mechanism, its deprotection does
not affect stereochemical integrity of the phosphorus cen-
ter. The added value of this approach is that, if separate
diastereomers of H-phosphonoselenoates 7 are not re-
quired the synthesis can be simplified by subjecting H-
phosphonoselenoate diesters 6 to deprotection directly af-
ter condensation to afford diastereomeric mixture of the
corresponding H-phosphonoselenoate monoesters.
Key words: nucleotides, phosphorylation, selenium, protecting
groups, elimination
Introduction
A close resemblance of selenium to biologically impor-
tant element sulfur, constitutes a strong rationale for in-
corporation of selenium into potential medicinal agents.
The toxic nature of most selenium compounds may pose
a serious obstacle in drug development but does not per se
rule out this type of modification for drug use.1 Kindled by
hopes of finding novel, useful properties, selenium has
been incorporated into various biologically important
compounds, e.g. carbohydrates,2 lipids,3,4 nucleosides,5
oligonucleotides.6,7
Selenophosphates are usually prepared via selenization of
suitable P(III) precursors, e.g. phosphite triesters,6,8 H-
phosphonate3,7 and H-phosphonothioate7 diesters, al-
though derivatives accessible by these routes are usually
limited to the corresponding selenophosphate di- and tri-
esters, and selenothiophosphate diesters. Recently, we
started to explore a new type of synthetic intermediates,
H-phosphonoselenoate monoesters9,10 that can provide
access to new selenophosphate derivatives with double
modifications at the phosphorus centre.
In this paper we report on the synthesis and application of
a dedicated H-phosphonoselenoyl group-transferring re-
agent, namely, 9-fluorenemethyl H-phosphonoselenoate,
that permits an easy preparation of nucleoside H-
phosphonoselenoate monoesters either as diastereomeric
mixtures or as separate P-diastereomers. This latter possi-
bility can be potentially exploited in a stereospecific syn-
thesis of P-chiral selenophosphate derivatives.
Synthesis of H-Phosphonoselenoyl Group Transfer-
ring Reagent 4
9-Fluorenemethyl H-phosphonoselenoate 410 was pre-
pared using standard phosphinate approach previously de-
veloped for the synthesis of H-phosphonothioate
monoesters.11 Thus treatment of 9-fluorenemethanol (1)
with triethylammonium phosphinate (2) (31P NMR:
d = 2.85, 1JP,H = 517 Hz, t) in pyridine in the presence of
pivaloyl chloride, followed by selenization of the pro-
duced phosphinate intermediate 3 (31P NMR: d = 14.22,
1JP,H = 572 Hz, 3JP,H = 9.8 Hz, tt) with elemental selenium
for two hours, produced 9-fluorenemethyl H-phospho-
noselenoate 4 as the major product (>90%, 31P NMR:
d = 50.41, 1JP,H = 570 Hz, 3JP,H = 9.1 Hz, dt; 1JP,Se = 685.2
Hz) (Scheme 1). Since reagent 4 in the form of triethylam-
SYNTHESIS 2005, No. 10, pp 1668–1674
x
x.
x
x
.
2
0
0
5
Advanced online publication: 07.04.2005
DOI: 10.1055/s-2005-865300; Art ID: P01005SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Nucleoside H-Phosphonates
1669
PvCl
Pyridine
O
Se
O
P
H
O
P
H
+
Se–
OH
O
P
H
-O
H
O
H
2
4
3
1
PvCl = pivaloyl chloride
Scheme 1
monium salt was a sticky oil and difficult to handle, it was Removal of a fluorenemethyl group from H-phospho-
converted into a S-(p-chlorobenzyl)isothiuronium salt noselenoates 6 to produce the corresponding H-phospho-
(88% overall yield). This solid salt was stable, non-hygro- noselenoate monoesters 7 was rather straightforward and
scopic and could be used directly for the condensations could be effected quantitatively by treatment of 6 in
without necessity of changing the cationic part.
dichloromethane with triethylamine (TEA) for 1 h.
Progress of this reaction can be conveniently monitored
by TLC analysis (decrease in mobility on a silica gel upon
conversion to 7) or by 31P NMR spectroscopy. In the latter
method, the removal of the fluorenemethyl group from 6
Synthesis of Nucleoside 3¢-H-Phosphonoselenoate
Monoesters 7
First, reaction conditions for condensation of H-phospho- is accompanied by a huge change in the chemical shift
noselenoate 4 with a hydroxylic component 5 to produce from that of ca. 70 ppm for compounds of type 6 to ca. 45
9-fluorenemethyl derivatives 6 were investigated. Among ppm for compounds 7. Other diagnostic parameters that
the condensing agents tried [pivaloyl chloride, 2-chloro- vary significantly with structure are one-bond phospho-
2-oxo-5,5-dimethyl-1,3,2-dioxaphosphinane, diphenyl rus–selenium (1JP,Se) and phosphorus–hydrogen (1JP,H
phosphorochloridate (DPCP)],12 the best in terms of coupling constants (see experimental section).
chemoselectivity, purity of the produced compounds and
)
If separated diastereomers of nucleoside H-phosphonose-
lenoate monoester 7 would be required, fluorenemethyl
derivatives 6 could be separated into RP and SP diastereo-
mers via silica gel chromatography prior to the deprotec-
tion step. As expected, the removal of the fluorenemethyl
group from 6 was completely stereospecific and occurred
most likely with retention of configuration.
the shortest reaction time, turned out to be DPCP. With
this reagent (2.5 equiv), a model reaction of nucleoside 5a
with H-phosphonoselenoate 4 (1.1 equiv) in acetonitrile
containing pyridine (5 equiv) was complete within 10
minutes affording the expected H-phosphonoselenoate 6a
as the sole nucleotidic material [31P NMR: d = 77.29
(1JP,Se = 870 Hz) and 76.43 (1JPSe = 871 Hz)]. These reac-
tion conditions worked well also for other nucleosides 5
investigated (Scheme 2).
Although the absolute configurations at the phosphorus
centre in compounds 6 and 7 are yet remain to be deter-
mined, there seems to be a relationship between the con-
figuration and the observed 31P NMR chemical shift or the
mobility on silica gel, as reported previously for other P-
chiral nucleotide analogues.13 For the compounds investi-
gated, chromatographically faster moving diastereomers
of 6 always resonated at higher field in the 31P NMR spec-
tra, while those of the lower chromatographic mobility,
gave signals at lower field. For H-phosphonoselenoate
monoesters 7, the diastereomers showed almost identical
mobility on silica gel, but they differed in the 31P NMR
shift values. Since P-diastereomers of 7 resonating at high
Due to some instability of nucleoside H-phosphonosele-
noate diesters 6 in aqueous basic media, the work-up of
the reaction mixtures after condensations was critical. Op-
timal conditions found consisted of quenching the reac-
tion mixtures with water containing pyridine, followed by
the dilution with toluene–ethyl acetate, and passing the
mixture through silica gel pad. This procedure provided
fluorenemethyl nucleoside H-phosphonate 6 of purity
>98% (1H NMR spectroscopy) and in consistently high
yields.
B
B
RO
-O
RO
O
O
O
B
RO
DPCP
TEA
O
O
O
P
H
O
+
O
Se–
P
H
Se
CH3CN/pyridine
P
H
Se
CH2Cl2
HO
5
4
6
7
5a, 6a, 7a, B = thymin-1-yl
R = 4,4'-dimethoxytrityl
DPCP = diphenyl chlorophosphate
TEA = triethylamine
5b, 6b, 7b B = N4-benzoylcytosin-1-yl
5c, 6c, 7c, B = N6-benzoyladenin-9-yl
5d, 6d, 7d, B = N2-isobutylguanin-9-yl
Scheme 2
Synthesis 2005, No. 10, 1668–1674 © Thieme Stuttgart · New York

1670
M. Kullberg, J. Stawinski
PAPER
(Na2SO4), filtered and then concentrated. The residue was co-evap-
orated with toluene (100 mL) to remove pyridine. The residue was
added on top of a silica gel column that had been equilibrated with
CH2Cl2 containing 1% MeOH and 0.2% Et3N, and the product was
eluted with CH2Cl2 containing 1% MeOH. This afforded fluorene-
methyl H-phosphonoselenoate 4 (1.32 g, triethylammonium salt) in
96% yield as a sticky, colorless oil. The residue was dissolved in
Et2O (100 mL), and H2O (100 mL) together with S-(4-chloroben-
zyl)isothiuronium chloride (1.1 equiv) was added. The H2O phase
was extracted with Et2O (2 × 100 mL). The organic layer was dried
(Na2SO4), filtered and concentrated to yield the fluorenemethyl H-
phosphonoselenoate S-(4-chlorobenzyl)isothiuronium salt as a
white foam in 88% overall yield (1.51 g). The foam can be dissolved
in minimal amount of CHCl3 and precipitated from pentane to give
the product as a white powder (1.32 g) in 77% overall yield; Rf 0.42
field were formed ‘high field’ (or ‘fast’) diastereomers of
6, while those at low field, were formed from ‘low field’
(or ‘slow’) 6, these established a configurational relation-
ship between diastereomeric compounds 6 and 7.
Conclusion
In conclusion, we have developed a dedicated reagent, 9-
fluorenemethyl H-phosphonoselenoate 4, for transferring
an H-phosphonoselenoate moiety into hydroxylic compo-
nents, and used it for a simple preparation in high yields
of the separate RP and SP diastereomers of nucleoside H-
phosphonoselenoate monoesters 7. The reagent is stable, (System A).
1H NMR (CDCl3): d = 8.53 (br, 4 H, NH), 8.49 (d, J = 570 Hz, PH),
7.68 (d, J = 7.32 Hz, 2 H, H-4 and H-5), 7.56 (dd, J = 7.32, 2.54, 2
H, H-1, H-8), 7.33 (t, J = 7.32 Hz, 2 H, H-3 and H-6), 7.21 (m, 2 H,
H-2 and H-7), 7.15–7.07 (q, 4 H, J = 8.42 Hz, ArH of chloroben-
zyl), 4.29–4.24 (m, 1 H, H-9), 4.17–4.14 (m, 4 H, 2 CH2).
13C NMR (CDCl3): d = 169.94 (C of thiourea), 144.10, 144.02,
141.44 and 141.36 (4 C of fluorenyl), 134.63 (ipso C of chloroben-
zyl), 131.31 (para C of chlorobenzyl), 130.50 and 129.38 (4 CH of
chlorobenzyl), 127.85 (C-3 and C-6), 127.26 and 127.20 (C-1 and
C-2), 125.36 and 125.31 (C-1 and C-8), 120.06 (C-4 and C-5),
67.41 (C-9), 48.20 (CH2 at C-9), 35.40 (CH2).
easy to prepare, and has a fluorenemethyl group as a lipo-
philic handle that facilitates separation into diastereomers
of the intermediate produced, 9-fluorenemethyl nucleo-
side H-phosphonoselenoate diesters 6. The fluorenemeth-
yl group can be removed via b-elimination to keeps the
integrity of the configuration at the phosphorus intact. In
addition, 9-fluorenemethyl nucleoside H-phosphonosele-
noates 6, which are accessible in diastereomerically pure
forms, can be considered as potentially useful intermedi-
ates on their own for the preparation of various P-chiral
phosphoroselenoate monoester analogues.
1
31P NMR (CDCl3): d = 44.64 (1JP,H = 570 Hz, JP,Se = 685.2 Hz,
3JP,H = 9.1 Hz).
1H and 31P NMR spectra were recorded on a Varian Unity 400 BB
VT spectrometer. The 31P NMR experiments were carried out at 25
°C in 5 mm tubes using 0.1 M concentrations of phosphorus-con-
taining compounds in appropriate solvents (0.6 mL), and the spectra
were referenced to 2% H3PO4 in D2O (external standard). TLC anal-
yses were carried out on Merck silica gel 60 F254 precoated plates
using the following solvent systems: (A) CHCl3–MeOH (9:1); (B)
toluene–EtOAc (1:1). Pyridine (LabScan Ltd.) and anhyd MeCN
(LabScan Ltd.) were stored over molecular sieves 4Å. The starting
materials for the synthesis, suitably protected nucleoside 5 were
prepared by modifications of published procedures.14 Anhyd trieth-
ylammonium phosphinate (2) was prepared by neutralization of
50% aq phosphinic acid with Et3N, followed by repeated evapora-
tion of added pyridine.
HRMS: m/z calcd for C22H23ClN2O2PSSe [M + H]+: 525.0072;
found: 525.0066.
Anal. Calcd for C22H22ClN2O2PSSe: C, 50.44; H, 4.23; N, 5.35.
Found: C, 50.14; H, 4.10; N, 5.42.
5¢-O-Dimethoxytritylnucleoside Fluorenemethyl 3¢-H-Phospho-
noselenoate Diesters 6; General Procedure
To a solution of 5¢-O-dimethoxytritylnucleoside 5 (272 mg, 0.5
mmol) and fluorenemethyl H-phosphonoselenoate S-(4-chloroben-
zyl)isothiuronium salt (4; 278 mg, 0.55 mmol, 1.1 equiv) in MeCN
(5 mL) containing pyridine (201 mL, 2.5 mmol, 5 equiv), was added
diphenyl chlorophosphate (DPCP, 259 mL, 1.25 mmol, 2.5 equiv).
After 10 min, the reaction mixture was quenched with H2O (2 mL)
and pyridine (806 mL, 20 equiv), stirred for 10 min and then diluted
with EtOAc (50 mL) and toluene (50 mL). The insoluble material
was removed and the organic layer was dried (Na2SO4). After con-
centration, the residue was passed through a silica gel pad (3 × 3
cm) and washed with toluene–EtOAc (1:1, 200 mL). This gave the
desired products 6 as a mixture of diastereoisomers of purity >98%
(1H NMR spectroscopy). Chromatography of the diastereomeric
mixture of 6 on a silica gel column using toluene–EtOAc (2:1) as an
eluent, afforded separate diastereomers of 6, designated as ‘fast’
and ‘slow’, according to their chromatographic mobility.
The assignments of signals in the 31P NMR spectra to particular
products or intermediates were done on the basis of their chemical
1
1
shifts, multiplicity of the signals in H-coupled and H-decoupled
spectra, by spiking the reaction mixtures with appropriate species
and, if possible, by isolation of a compound in question from reac-
tion mixtures. The assignment of proton and carbon resonances of
4, 6 and 7 was done on the basis of known or expected chemical
1
shifts in conjunction with H-1H, 1H-13C, and DEPT correlated
NMR spectroscopy.
Fluorenemethyl H-Phosphonoselenoate (S-Chlorobenzyl)iso-
thiuronium Salt (4)
5¢-O-Dimethoxytritylthymidine Fluorenemethyl 3¢-H-Phospho-
noselenoate Diester (6a)
Fluorenylmethanol (1.0 g, 5.1 mmol, 1.5 equiv) and triethylammo-
nium phosphinate (568 mg, 3.4 mmol, 1 equiv) were rendered an-
hydrous by coevaporation of added pyridine and then dissolved in
pyridine (15 mL). The solution was cooled to 0 °C, pivaloyl chlo-
ride (628 mL 5.1 mmol, 1.5 equiv), followed by elemental Se (805
mg, 10.2 mmol, 3 equiv) were added, and the reaction mixture was
allowed to attain r.t. After stirring for 3 h, the solution was filtered
through Celite onto H2O (200 mL), the filtrate was concentrated and
then dissolved in CHCl3 (100 mL). This solution was washed with
H2O (3 × 50 mL; to the last extraction 200 mL of Et3N was added to
improve the separation of layers), the organic phase was dried
White solid (1:1 mixture of diastereomers); yield: 357 mg (84%);
Rf 0.62 and 0.57 (System B).
HRMS: m/z calcd for C45H44N2O8PSe [M + H]+: 851.2000; found:
851.2010.
Fast Moving Diastereoisomer of 6a
Rf 0.62 (System B).
1H NMR (CDCl3): d = 9.19 (s, 1 H, NH), 8.20 (d, J = 650 Hz, 1 H,
PH), 7.76 (dd, J = 7.32, 3.66 Hz, 2 H, H-4 and H-5 of fluorenyl),
7.63 (dd, J = 7.01, 2.13 Hz, 2 H, H-1 and H-8 of fluorenyl), 7.45–
Synthesis 2005, No. 10, 1668–1674 © Thieme Stuttgart · New York

PAPER
Nucleoside H-Phosphonates
1671
7.20 (m, 13 H, ArH), 6.84 (d, J = 8.84 Hz, 4 H, ArH ortho to OMe)
6.38 (t, J = 7.62 Hz, 1 H, H-1¢), 5.36 (m, 1 H, H-3¢), 4.58–4.40 (m,
2 H, CH2), 4.25 (t, J = 6.40 Hz, 1 H, H-9 of fluorenyl), 4.14 (m, 1
H, H-4¢), 3.78 (s, 6 H, 2 CH3O), 3.41 (m, 2 H, H-5¢), 2.3–2.2 (m, 2
H, H-2¢), 1.47 (s, 3 H, CH3 at C-5).
13C NMR (CDCl3): d = 164.02 (C-4), 159.02 [2 C of dimethoxytrityl
(DMT)], 150.62 (C-2), 144.47 (2 C of DMT), 143,16 and 143.03 (2
C of fluorenyl), 135.49, 135.44 and 135.37 (2 C of DMT, C-6),
130.31, 128.39, 128.31, 127.55, 127.51 and 127.44 (13 ArCH),
125.26 (C-1 and C-8 of fluorenyl), 120.45 and 120.42 (C-4 and C-
5 of fluorenyl), 113.62 (4 C of DMT), 111.85 (C-5), 87.50 (C of
DMT), 85.12 (d, J = 5.44 Hz, C-4¢), 84.57 (C-1¢), 77.79 (C-3¢),
69.42 (d, J = 8.00 Hz, CH2 of fluorenyl), 63.29 (C-5¢), 55.51 (2
CH3O), 48.03 (d, J = 7.73 Hz, CH of fluorenyl), 39.25 (d, J = 4.00
Hz, C-2¢), 12.00 (CH3 at C-5).
Slow Moving Diastereoisomer of 6b
Rf 0.37 (System B).
1H NMR (CDCl3): d = 8.69 (br, 1 H, NH), 8.26 (d, J = 644 Hz, 1 H,
PH), 8.07 (d, J = 7.42 Hz, 1 H, ArH), 7.89 (d, J = 7.23 Hz, 2 H,
ArH), 7.69 (d, J = 7.62 Hz, 2 H, ArH), 7.55 (t, 2 H, J = 7.42 Hz, 2
H, ArH), 7.51–7.10 (m, 12 H, ArH, H-5 and H-6), 6.80–6.77 (m, 4
H, ortho to OMe), 6.26 (t, J = 6.44 Hz, 1 H, H-1¢), 5.90–5.32 (m, 1
H, H-3¢), 4.81–4.40 (m, 1 H, CH2 of fluorenyl), 4.22–4.12 (m, 3 H,
H-4¢, CH and CH2 of fluorenyl), 3.73 (s, 3 H, CH3O), 3.72 (CH3O),
3.36–3.31 (m, 2 H, H-5¢), 2.83–2.78 (m, 1 H, H-2¢), 2.25–2.17 (m,
1 H, H-2¢).
13C NMR (CDCl3): d = 162.39 (C=O of Bz, C-4 and C-2), 158.94 (2
C of DMT), 144.42 (ArC), 144.07 (2 C of DMT), 143.10 and 142.93
(2 C of fluorenyl), 141.55 (2 C of DMT), 135.31 and 135.12 (2 C of
DMT), 133.41 (ArCH), 130.36, 130.19, 129.26, 128.28, 127.75 and
127.46 (ArCH, C-5 and C-6), 125.35 and 125.14 (C-1 and C-8 of
fluorenyl), 120.33 (ArCH), 113.59 (4 C of DMT), 87.43 (C-1¢),
85.72 (C-4¢), 69.21 (CH2 of fluorenyl), 62.58 (C-5¢), 55.44 (2
CH3O), 47.91 (d, J = 7.67 Hz, CH of fluorenyl), 40.72 (C-2¢).
31P NMR (CDCl3): d = 70.89 (1JP,Se = 870.8 Hz, 1JP,H = 649.5 Hz).
Slow Moving Diastereoisomer of 6a
Rf 0.57 (System B).
1H NMR (CDCl3): d = 9.49 (s, 1 H, NH), 8.31 (d, J = 647 Hz, 1 H,
PH), 7.90–7.10 (m, 17 ArH and H-6), 6.85 (d, J = 8.84 Hz, 4-H,
ArH ortho to OMe), 6.47–6.42 (m, 1 H, H-1¢), 5.53–5.47 (m, 1 H,
H-3¢), 4.53–4.43 (m, 2 H, CH2 of fluorenyl), 4.27–4.15 (m, 1 H, CH
of fluorenyl), 4.04 (br, 1 H, H-4¢), 3.78 (s, 6 H, 2 CH3O), 3.40–3.30
(m, 2 H, H-5¢), 2.56–2.27 (m, 2 H, H-2¢), 1.50 (s, 3 H, CH3 at C-5).
13C NMR (CDCl3): d = 164.14 (C-4), 159.03 (2 C of DMT), 150.80
(C-2), 144.40 (2 C of DMT), 143.14 and 142.98 (2 C of fluorenyl),
141.63 and 141.58 (2 C of fluorenyl), 135.50, 135.41 and 135.34 (2
C of DMT and C-6), 130.29, 128.32 and 127.50 (13 ArCH), 125.37
and 125.16 (C-1 and C-8 of fluorenyl), 120.39 (C-4 and C-5 fluore-
nyl), 113.65 (4 C of DMT), 111.95 (C-5), 87.50 (C of DMT), 85.05
(C-4¢), 84.69 (C-1¢), 78.37 (C-3¢), 69.27 (d, J = 6.87 Hz, CH2 of flu-
orenyl), 63.19 (C-5¢), 55.51 (2 CH3O), 47.95 (d, J = 8.02 Hz, CH of
fluorenyl), 39.41 (d, J = 5.73, C-2¢), 12.06 (CH3 at C-5).
31P NMR (CDCl3): d = 75.137 (1JP,Se = 872.4 Hz, 1JP,H = 644 Hz).
5¢-O-Dimethoxytrityl-N6-benzoyladenosine Fluorenemethyl 3¢-
H-Phosphonoselenoate Diester (6c)
White solid (1:1 mixture of diastereomers); yield: 433 mg (90%);
Rf 0.43 and 0.38 (System B).
HRMS: m/z calcd for C52H47N5O7PSe [M + H]+: 964.2378; found:
964.2389.
Fast Moving Diastereoisomer of 6c
Rf 0.43 (System B).
1H NMR (CDCl3): d = 9.10 (s, 1 H, NH), 8.71 (s, 1 H, H-2), 8.28 (d,
J = 648 Hz, 1 H, PH), 8.11 (s, 1 H, H-8), 8.03 (d, J = 7.32 Hz, 2 H,
ArH), 7.71 (d, J = 6.71 Hz, 1 H, ArH), 7.67–7.48 (m, 5 H, ArH),
7.40–7.12 (m, 14 H, ArH), 6.79 (d, J = 8.84 Hz, 4 H, ortho to OMe),
6.32 (dd, J = 8.38, 5.64 Hz, 1 H, H-1¢), 5.40–5.33 (m, 1 H, H-3¢),
4.62–4.47 (m, 2 H, H-4' and CH of fluorenyl), 3.76 (s, 6 H, 2
CH3O), 3.39–3.37 (m, 2 H, H-5¢), 2.85–2.74 (m, 1 H, H-2¢), 2.33–
2.24 (m, 1 H, H-2¢).
13C NMR (CDCl3): d = 164.83 (C=O of Bz), 158.84 (2 C of DMT
and C-6), 152.87 (C-2), 151.81 (C-6), 149.78 (C-4), 144.56 (2 C of
DMT), 143.23 and 142.99 (2 C of fluorenyl), 141.72 (C-8), 141.57
(2 C of DMT), 135.69 and 135.64 (2 C of DMT), 133.87, 133.04,
130.28, 129.12, 128.34, 128.28, 128.18, 128.10, 127.51 and 127.23
(ArCH), 125.22 (C-1 and C-8 of fluorenyl), 120.41 and 120.34
(ArCH), 113.49 (4 C of DMT), 87.05 (C of DMT), 85.38 (d,
J = 6.58 Hz, C-4¢), 84.66 (C-1¢), 77.91 (d, J = 5.44 Hz, C-3¢), 69.20
(d, J = 6.30 Hz, CH2 of fluorenyl), 63.20 (C-5¢), 55.47 (2 CH3O),
48.06 (d, J = 7.73 Hz, CH of fluorenyl), 38.88 (C-2¢).
31P NMR (CDCl3): d = 71.66 (1JP,Se = 871.2 Hz, 1JP,H = 647.0 Hz).
5¢-O-Dimethoxytrityl-N4-benzoylcytidine Fluorenemethyl 3¢-H-
Phosphonoselenoate Diester (6b)
White solid (1:1 mixture of diastereomers); yield: 436 mg (90%);
Rf 0.45 and 0.37 (System B).
HRMS: m/z calcd for C51H47N3O8PSe [M + H]+: 940.2266; found:
940.2276.
Fast Moving Diastereoisomer of 6b
Rf 0.45 (System B).
1H NMR (CDCl3): d = 8.87 (br, 1 H, NH), 8.16 (d, J = 649 Hz, 1 H,
PH), 8.14 (d, J = 7.42 Hz, ArH), 7.89 (d, J = 7.42 Hz, 1 H, ArH),
7.73 (t, J = 7.42 Hz, 1 H, ArH), 7.61 (d, J = 7.42 Hz, 1 H, ArH),
7.58–7.11 (m, 12 H, ArH, H-5 and H-6), 6.84 (d, J = 8.79 Hz, 4 H,
ortho to OMe), 6.28–6.21 (m, 1 H, H-1¢), 5.27–5.21 (m, 1 H, H-3¢),
4.57–4.39 (m, 2 H, H-4¢ and CH of fluorenyl), 3.76 (s, 6 H, 2
CH3O), 3.43–3.41 (m, 2 H, H-5¢), 2.66–2.60 (m, 1 H, H-2¢), 2.19–
2.08 (m, 1 H, H-2¢).
13C NMR (CDCl3): d = 162.56 (C=O of Bz, C-4 and C-2), 158.99 (2
C of DMT), 144.57 (ArC), 144.21 and 144.19 (2 C of DMT), 143.15
and 143.00 (2 C of fluorenyl), 141.61 and 141.58 (2 C of fluorenyl),
135.39, 135.26 and 135.24 (2 C of DMT and ArC), 133.40 (ArCH),
130.36, 130.30, 129.29, 129.24, 128.33, 127.89 and 127.51 (ArCH,
C-6 and C-5), 125.44 and 125.25 (C-1 and C-8 of fluorenyl), 120.42
(ArCH), 113.64 (4 C of DMT), 87.49 (C-1¢), 85.78 (C-4¢), 69.43
(CH2 of fluorenyl), 62.64 (C-5¢), 55.49 (2 CH3O), 48.05 (d, J = 8.43
Hz, CH of fluorenyl), 40.73 (C-2¢).
31P NMR (CDCl3): d = 71.07 (1JP,Se = 872.5 Hz, 1JP,H = 648 Hz).
Slow Moving Diastereoisomer of 6c
Rf 0.38 (System B).
1H NMR (CDCl3): d = 9.07 (s, 1 H, NH), 8.70 (s, 1 H, H-2), 8.30 (d,
J = 644 Hz, 1 H, PH), 8.14 (s, 1 H, H-8), 8.02 (d, J = 7.01 Hz, 2 H,
ArH), 7.72 (dd, J = 7.32, 2.74 Hz, 2 H, ArH), 7.70–7.47 (m, 5 H,
ArH), 7.41–7.16 (m, 14 H, ArH), 6.76 (d, J = 8.84 Hz, 4 H, ortho to
OMe), 6.44 (dd, J = 8.38, 5.64 Hz, 1 H, H-1¢), 5.53–5.46 (m, 1 H,
H-3¢), 4.60–4.50 (m, 1 H, CH2 of fluorenyl), 4.33–4.15 (m, 3 H, H-
4¢, CH2 and CH of fluorenyl), 3.74 (s, 6 H, 2 CH3O), 3.41–3.30 (m,
2 H, H-5¢), 3.00–2.90 (m, 1 H, H-2¢), 2.68–2.60 (m, 1 H, H-2¢).
13C NMR (CDCl3): d = 164.81 (C=O), 158.84 (2 C of DMT), 152.87
(C-2), 151.78 (C-6), 149.79 (C-4), 144.48 (2 C of DMT), 143.23
and 143.02 (2 C of fluorenyl), 141.59 (2 C of DMT), 135.62 (2 C of
DMT), 133.86, 133.04, 130.23, 129.11, 128.33, 128.18, 128.09,
31P NMR: (CDCl3): d = 74.57 (1JP,Se = 872.44 Hz, 1JP,H = 648.9 Hz).
Synthesis 2005, No. 10, 1668–1674 © Thieme Stuttgart · New York

1672
M. Kullberg, J. Stawinski
PAPER
127.49 and 127.25 (ArCH), 125.34 and 125.13 (C-1 and C-8 of
fluorenyl), 120.37 (ArCH), 113.49 (4 C of DMT), 87.09 (C of
DMT), 85.42 (C-4¢), 84.83 (C-1¢), 78.50 (d, J = 6.01 Hz, C-3¢),
69.29 (d, J = 6.59 Hz, CH2 of fluorenyl), 63.07 (C-5¢), 55.46 (2
CH3O), 48.00 (d, J = 7.73 Hz, CH of fluorenyl), 38.96 (C-2¢).
equiv) for 1 h. Nucleoside 3¢-H-phophonoselenoate monoesters 7
were isolated by precipitation from pentane–Et2O (2:1) as white sol-
ids of purity >98% (1H NMR spectroscopy).
5¢-O-Dimethoxytritylthymidine 3¢-H-Phosphonoselenoate, Tri-
ethylammonium Salt (7a)
7a Fast
31P NMR (CDCl3): d = 71.05 (1JP,Se = 875.05 Hz, 1JP,H = 644.9 Hz).
From faster moving diastereoisomer of 6a; white solid; yield: 71 mg
(74%); Rf 0.30 (System A).
5¢-O-Dimethoxytrityl-N2-isobutyrylguanosine Fluorenemethyl
3¢-H-Phosphonoselenoate Diester (6d)
White solid (1:1 mixture of diastereomers); yield: 378 mg (80%);
Rf 0.09 and 0.08 (System B).
HRMS: m/z calcd for C49H49N5O8PSe [M + H]+: 946.2484; found:
1H NMR (CDCl3): d = 11.56 (br, 1 H, NH), 9.38 (s, 1 H, NH), 8.61
(d, J = 570.1 Hz, 1 H, PH), 7.59 (d, J = 0.92 Hz, 1 H, H-6), 7.42–
7.16 (m, 10 ArH), 6.83–6.79 (m, 4 ArH ortho to OMe), 6.44 (dd,
J = 8.84, 5.83 Hz, 1 H, H-1¢), 5.48–5.41 (m, 1 H, H-3¢), 4.25–4.24
(m, 1 H, H-4¢), 3.76 (s, 6 H, 2 CH3O), 3.46 (dd, J = 10.52, 2.59 Hz,
1 H, H-5¢), 3.36 (dd, J = 10.52, 2.59 Hz, 1 H, H-5¢), 3.16–3.06 (m,
6 H, 3 CH2 of Et3N), 2.70–2.34 (m, 2 H, H-2¢), 1.37–1.28 (m, 12 H,
3 CH3 of Et3N and CH3 at C-5).
13C NMR (CDCl3): d = 164.24 (C-4), 158.89 (2 C of DMT), 150.80
(C-2), 144.62 (2 C of DMT), 135.96, 135.75 and 135.57 (2 C of
DMT and C-6), 130.37, 128.42, 128.23 and 127.26 (8 C of DMT),
113.54 (4 C of DMT), 111.46 (C-5), 87.27 (C of DMT), 85.11 (C-
4¢), 84.86 (C-1¢), 76.23 (d, J = 4.87 Hz, C-3¢), 63.93 (C-5¢), 55.48 (2
CH3O), 45.95 (3 CH2 of Et3N), 40.12 (C-2¢), 11.86 (CH3 at C-5),
8.87 (3 CH3 of Et3N).
946.2475.
Fast Moving Diastereoisomer of 6d
Rf 0.09 (System B).
1H NMR (CDCl3): d = 11.94 (s, 1 H, NH), 8.21 (d, J = 650 Hz, 1 H,
PH), 7.99 (s, 1 H, H-8), 7.74–7.57 (m, 4 H, ArH), 7.42–7.12 (m, 13
H, ArH), 6.79–6.73 (m, 4 H, ortho to OMe), 5.96 (t, J = 6.56 Hz, 1
H, H-1¢), 5.66–5.57 (m, 1 H, H-3¢), 4.57–4.42 (m, 2 H, CH2 of fluo-
renyl), 4.14–4.10 (m, 1 H, H-4¢), 3.75 (s, 6 H, 2 CH3O), 3.35 (dd,
J = 10.82, 3.20 Hz, 1 H, H-5¢), 3.20 (dd, J = 10.67, 3.66 Hz, 1 H, H-
5¢), 2.86–2.76 (m, 1 H, H-2¢), 2.18–2.10 (m, 1 H, H-2¢), 2.08–1.97
[m, 1 H, CH of IBu (isobutylguanin)], 1.06 (d, J = 7.01 Hz, 3 H,
CH3 of Ibu), 0.93 (d, J = 7.01 Hz, 3 H, CH3 of Ibu).
13C NMR (CDCl3): d = 178.40 (C=O), 158.90 (2 C of DMT), 155.61
(C-6), 147.86 (C-3), 147.28 (C-4), 144.81 (2 C of DMT), 143.11
and 142.95 (2 C of fluorenyl), 141.70 (2 C of DMT), 138.45 (C-8),
135.95 and 135.68 (2 C of DMT), 130.22, 129.26, 128.28, 128.19,
127.47, 127.28 and 127.17 (ArCH), 120.43 and 120.37 (ArCH),
113.44 (4 C of DMT), 86.70 (C of DMT), 84.30 (C-1¢ and C-4¢), 69,
32 (CH2 of fluorenyl), 62.77 (C-5¢), 55.47 (2 CH2O), 48.00 (d,
J = 8.00 Hz, CH of fluorenyl), 38.04 (C-2¢), 36.57 (CH of Ibu),
19.98 and 18.89 (2 CH3 of Ibu).
31P NMR (CDCl3): d = 44.785 (dd, 1JP,Se = 714.8 Hz, 1JP,H = 570.3
Hz, 3JP,H = 12.57 Hz).
Anal. Calcd for C37H48N3O8PSe: C, 57.51; H, 6.26; N, 5.44. Found:
C, 57.33; H, 6.08; N, 5.51.
7a Slow
From slower moving diastereoisomer of 6a; white solid; yield: 80
mg (98%); Rf 0.30 (System A).
1H NMR (CDCl3): d = 11.57 (br, 1 H, NH), 9.28 (br, 1 H, NH), 8.69
(d, J = 564.7 Hz, 1 H, PH), 7.60 (br, 1 H, H-6), 7.42–7.14 (m, 10
ArH), 6.83–6.80 (m, 4 H, ortho to OMe), 6.47 (dd, J = 8.54, 5.49
Hz, 1 H, H-1¢), 5.41–5.35 (m, 1 H, H-3¢), 4.36 (br, 1 H, H-4¢), 3.76
(s, 6 H, 2 CH3O), 3.57–3.34 (m, 2 H, H-5¢), 3.12–3.05 (m, 6 H, 3
CH2 of Et3N), 2.60–2.31 (m, 2 H, H-2¢), 1.38–1.27 (m, 12 H, 3 CH3
of Et3N and CH3 at C-5).
13C NMR (CDCl3): d = 164.21 (C-4), 158.88 (2 C of DMT), 150.76
(C-2), 144.67 (2 C of DMT), 135.97, 135.80 and 135.61 (2 C of
DMT and C-6), 130.39, 128.55, 128.44, 128.23 and 127.26 (8 C of
DMT), 113.55 (4 C of DMT), 111.42 (C-5), 87.28 (C of DMT),
85.93 (d, J = 5.44 Hz, C-4¢), 84.94 (C-1¢), 63.76 (C-5¢), 55.49 (2
CH3O), 45.93 (3 CH2 of Et3N), 39.58 (d, J = 3.48 Hz, C-2¢), 11.82
(CH3 at C-5), 8.87 (3 CH3 of Et3N).
31P NMR (CDCl3): d = 71.59 (1JP,Se = 869.08 Hz, 1JP,H = 649.6 Hz).
Slow Moving Diastereoisomer of 6d
Rf 0.08 (System B).
1H NMR (CDCl3): d = 11.98 (s, 1 H, NH), 8.24 (d, J = 645 Hz, 1 H,
PH), 8.23 (s, 1 H, H-8), 7.75–7.13 (m, 17 H, ArH), 6.78–6.71 (m, 4
H, ortho to OMe), 6.09 (dd, J = 7.62, 5.79 Hz, 1 H, H-1¢), 5.61–5.53
(m, 1 H, H-3¢), 4.53–4.43 (m, 1 H, CH2 of fluorenyl), 4.25–4.09 (m,
3 H, H-4¢, CH2 and CH of fluorenyl), 3.72 (s, 3 H, OCH3), 3.71 (s,
3 H, OCH3), 3.34 (dd, J = 10.67, 3.05 Hz, 1 H, H-5¢), 3.18 (dd,
J = 10.52, 3.81 Hz, 1 H, H-5¢), 3.06–2.96 (m, 1 H, H-2¢), 2.53–2.44
(m, 1 H, H-2¢), 2.20–2.03 (m, 1 H, CH of Ibu), 1.06 (d, J = 6.71 Hz,
3 H, CH3 of Ibu), 0.94 (d, J = 6.71 Hz, 3 H, CH3 of Ibu).
13C NMR (CDCl3): d = 178.62 (C=O), 158.91 (2 C of DMT), 155.67
(C-6), 148.07 (C-3), 147.45 (C-4), 144.75 (2 C of DMT), 143.05
and 142.96 (2 C fluorenyl), 141.58 (2 C of DMT), 138.19 (C-8),
135.88 and 135.67 (2 C of DMT), 130.18, 129.27, 128.37, 128.32,
128.207, 127.46, 127.32, 127.28 and 125.04 (ArCH), 120.39
(ArCH), 113.48 (4 C of DMT), 86.74 (C of DMT), 84.77 (d,
J = 4.58 Hz, C-4¢), 84.57 (C-1¢), 69.25 (d, J = 6.30 Hz, CH2 of fluo-
renyl), 62.93 (C-5¢), 55.47 (2 CH3), 47.94 (d, J = 7.73 Hz, CH of
fluorenyl), 38.67 (C-2¢), 36.50 (CH of Ibu), 18.99 (CH3 of Ibu),
18.90 (CH3 of Ibu).
1
1
31P NMR (CDCl3): d = 45.69 (dd, JP,Se = 714.8 Hz, JP,H = 564.7
Hz, 3JP,H = 12.6 Hz).
Anal. Calcd for C37H48N3O8PSe: C, 57.51; H, 6.26; N, 5.44. Found:
C, 57.18; H, 6.15; N, 5.60.
5¢-O-Dimethoxytrityl-N4-benzoylcytidine 3¢-H-Phosphonosele-
noate, Triethylammonium Salt (7b)
7b Fast
From faster moving diastereoisomer of 6b; white solid; yield: 65
mg (92%); Rf 0.28 (System A).
1H NMR (CDCl3): d = 8.60 (d, J = 573 Hz, 1 H, PH), 8.21 (d,
J = 7.62 Hz, 1 H, ArH), 7.88 (d, J = 7.62 Hz, 2 H, ArH), 7.61–7.10
(m, 13 H, 11 ArH, H-5 and H-6), 6.87–6.83 (m, 4 H, ortho to OMe),
6.30 (t, J = 6.10 Hz, 1 H, H-1¢), 5.45–5.37 (m, 1 H, H-4¢), 3.78 (s, 6
H, 2 CH3O), 3.54–3.49 (m, 2 H, H-5¢), 3.10–3.02 (m, 6 H, 3 CH2 of
Et3N), 2.97–2.91 (m, 1 H, H-2¢), 2.41–2.29 (m, 1 H, H-2¢), 1.33–
1.25 (m, 9 H, 3 CH3 of Et3N).
31P NMR (CDCl3): d = 71.43 (1JP,Se = 871.64 Hz, 1JP,H = 645 Hz).
5¢-O-Dimethoxytritylnucleoside 3¢-H-Phosphonoselenoate, Tri-
ethylammonium Salts 7; General Procedure
Separated diastereomers of nucleoside fluorenemethyl 3¢-H-
phosphonoseleonate diesters 6 (425 mg, 0.5 mmol) were dissolved
in CH2Cl2 (15 mL) and treated with Et3N (695 mL, 5 mmol, 10
Synthesis 2005, No. 10, 1668–1674 © Thieme Stuttgart · New York

PAPER
Nucleoside H-Phosphonates
1673
13C NMR (CDCl3): d = 162.27 (C=O of Bz, C-2 and C-4), 158.85 (2
C of DMT), 144.96 and 144.40 (2 C of DMT), 135.71 and 135.50
(2 C of DMT), 133.29 (ArCH), 130.41, 130.34, 129.22, 128.46,
128.25, 127.79 and 127.26 (ArCH), 113.56 (4 C of DMT), 87.54
(C-1¢), 85.67 (C-4¢), 74.83 (C-3¢), 63.11 (C-5¢), 55.46 (2 CH3O),
45.89 (3 CH2 of Et3N), 41.58 (C-2¢), 8.92 (3 CH3 of Et3N).
1H NMR (CDCl3): d = 9.04 (s, 1 H, NH), 8.66 (s, 1 H, H-2), 8.66 (d,
J = 567 Hz, 1 H, PH), 8.14 (s, 1 H, H-8), 7.97–7.94 (m, 2 H, ArH),
7.53 (t, J = 7.32 Hz, 1 H, ArH), 7.45 (t, J = 7.41 Hz, 2 H, ArH), 7.36
(d, J = 7.81 Hz, 2 H, ArH), 7.27–7.10 (m, 7 H, ArH), 6.73 (d,
J = 8.79 Hz, 4 H, ortho to OMe), 6.56–6.52 (m, 1 H, H-1¢), 5.42–
5.35 (m, 1 H, H-3¢), 4.52–4.48 (m, 1 H, H-4¢), 3.70 (s, 6 H, 2 CH3O),
3.45 (dd, J = 10.25, 4.2 Hz, 1 H, H-5¢), 3.35 (dd, J = 10.25, 3.42 Hz,
1 H, H-5¢), 3.09–3.02 (m, 6 H, 3 CH2 of Et3N), 2.92–2.84 (m, 1 H,
H-2¢), 2.78–2.72 (m, 1 H, H-2¢), 1.29–1.19 (m, 9 H, 3 CH3 of Et3N).
13C NMR (CDCl3): d = 164.80 (C=O), 158.68 (2 C of DMT), 152.76
(C-2), 151.77 (C-6, 149.55 (C-4), 144.73 (2 C of DMT), 141.65 (2
C of DMT), 135.87 and 135.82 (2 C of DMT), 133.92, 132.92,
130.32 129.64 128.39, 128.05 and 127.04 (ArCH), 113.37 (4 C of
DMT), 86.79 (C of DMT), 86.29 (C-4¢), 84.98 (C-1¢), 76.49 (C-3¢),
63.71 (C-5¢), 55.41 (2 CH3O), 45.79 (3 CH2 of Et3N), 39.73 (C-2¢),
8.81 (3 CH3 of Et3N).
31P NMR (CDCl3): d = 44.76 (d, 1JP,Se = 713.5 Hz, 1JP,H = 573 Hz,
3JP,H = 11.93 Hz).
Anal. Calcd for C43H51N4O8PSe: C, 59.93; H, 5.96; N, 6.50. Found:
C, 59.71; H, 5.76; N, 6.81.
7b Slow
From slower moving diastereoisomer of 6b; white solid; yield: 44
mg (79%); Rf 0.28 (System A).
1H NMR (CDCl3): d = 8.75 (d, J = 562 Hz, 1 H, PH), 8.21 (d,
J = 7.32 Hz, 1 H, ArH), 7.88 (d, J = 7.01 Hz, 2 H, ArH), 7.62–7.17
(m, 13 H, 11 ArH, H-5 and H-6), 6.87–6.83 (m, 4 H, ortho to OMe),
6.31 (t, J = 6.10 Hz, 1 H, H-1¢), 5.28–5.20 (m, 1 H, H-3¢), 4.48–4.45
(m, 1 H, H-4¢), 3.78 (s, 6 H, 2 CH3O), 3.56–3.42 (m, 2 H, H-5¢),
3.11–3.02 (m, 6 H, 3 CH2 of Et3N), 2.92–2.84 (m, 1 H, H-2¢), 2.37–
2.27 (m, 1 H, H-2¢), 1.31–1.25 (m, 9 H, CH3 of Et3N).
13C NMR (CDCl3): d = 162.28 (C=O of Bz, C-2 and C-4), 158.85 (2
C of DMT), 144.95 and 144.41 (2 C of DMT), 135.72 and 135.50
(2 C of DMT), 133.30 (ArCH), 130.42, 130.34, 129.22, 128.46,
128.25, 127.81 and 127.26 (ArCH), 113.57 (4 C of DMT), 87.62
(C-1¢), 86.35 (d, J = 6.30 Hz, C-4¢), 75.88 (C-3¢), 62.92 (C-5¢),
55.47 (2 CH3O), 45.88 (3 CH2 of Et3N), 40.95 (C-2¢), 8.95 (3 CH3
of Et3N).
1
31P NMR (CDCl3): d = 48.66 (1JP,Se = 714.7 Hz, JP,H = 567 Hz,
3JP,H = 12.48 Hz).
Anal. Calcd for C44H51N6O7PSe: C, 59.66; H, 5.80; N, 9.49. Found:
C, 59.47; H, 5.55; N, 9.65.
5¢-O-Dimethoxytrityl-N2-isobutyrylguanosine H-Phosphonose-
lenoate, Triethylammonium Salt (7d)
7d Fast
From faster moving diastereoisomer of 6d; white solid; yield: 21
mg, (74%); Rf 0.35 (System A).
1H NMR (CDCl3): d = 11.98 (s, 1 H, NH), 8.54 (d, J = 572 Hz, 1 H,
PH), 7.77 (s, 1 H, H-8), 7.37–7.13 (m, 9 H, ArH), 6.75–6.71 (m, 4
H, ortho to OMe), 6.13 (dd, J = 7.01, 4.88 Hz, 1 H, H-1¢), 5.87–5.75
(m, 1 H, H-3¢), 4.23–4.18 (m, 1 H, H-4¢), 3.74 (s, 6 H, OCH3), 3.36
(dd, J = 10.67, 3.05 Hz, 1 H, H-5¢), 3.22 (dd, J = 10.67, 4.12 Hz, 1
H, H-5¢), 3.14–3.06 (m, 7 H, H-2¢ and 3 CH2 of Et3N), 2.69–2.59 (m,
1 H, H-2¢), 2.55–2.45 (m, 1 H, CH of Ibu), 1.31–1.27 (m, 9 H, 3 CH3
of Et3N), 1.14 (d, J = 7.01 Hz, 3 H, CH3 of Ibu), 1.08 (d, J = 6.71, 3
H, CH3 of Ibu).
13C NMR (CDCl3): d = 179.31 (C=O), 158.67 (2 C of DMT), 156.01
(C-6), 147.87 (C-3), 147.45 (C-4), 144.89 (2 C of DMT), 138.97 (C-
8), 136.10 and 135.98 (2 C of DMT), 130.26, 128.39, 127.97 and
127.00 (8 C of DMT), 113.27 (4 C of DMT), 86.44 (C of DMT),
84.39 (C-4¢), 74.31 (C-3¢), 62.99 (C-5¢), 55.44 (2 CH3O), 45.96 (3
CH2 of Et3N), 38.50 (C-2¢), 36.39 (CH of Ibu), 19.20 and 19.11
(CH3 of Ibu), 8.89 (3 CH3 of Et3N).
1
31P NMR (CDCl3): d = 45.99 (1JP,Se = 717.3 Hz, JP,H = 562 Hz,
3JP,H = 12.15 Hz).
Anal. Calcd for C43H51N4O8PSe: C, 59.93; H, 5.96; N, 6.50. Found:
C, 59.63; H, 5.70; N, 6.72.
5¢-O-Dimethoxytrityl-N6-benzoyladenosine H-Phosphonosele-
noate, Triethylammonium Salt (7c)
7c Fast
From faster moving diastereoisomer of 6c; white solid; yield: 82 mg
(88%); Rf 0.37 (System A).
1H NMR (CDCl3): d = 9.04 (br, 1 H, NH), 8.67 (s, 1 H, H-2), 8.62
(d, J = 568 Hz, 1 H, PH), 8.14 (s, 1 H, H-8), 7.96 (d, J = 7.62 Hz, 2
H, ArH), 7.54 (t, J = 7.32 Hz, 1 H, ArH), 7.45 (t, J = 7.52 Hz, 2 H,
ArH), 7.36 (d, J = 7.22 Hz, 2 H, ArH), 7.27–7.11 (m, 7 H, ArH),
6.73 (d, J = 8.79 Hz, 4 H, ortho to OMe), 6.56–6.51 (m, 1 H, H-1¢),
5.41–5.36 (m, 1 H, H-3¢), 4.39–4.38 (m, 1 H, H-4¢), 3.71 (s, 6 H, 2
CH3O), 3.40 (dd, J = 10.25, 4.39 Hz, 1 H, H-5¢), 3.34 (dd,
J = 10.25, 3.81 Hz, 1 H, H-5¢), 3.11–3.05 (m, 6 H, 3 CH2 of Et3N),
2.95–2.83 (m, 1 H, H-2¢), 1.30–1.26 (m, 9 H, 3 CH3 of Et3N).
13C NMR (CDCl3): d = 164.79 (C=O), 158.69 (2 C of DMT), 152.76
(C-2), 151.76 (C-6), 149.55 (C-4), 144.73 (2 C of DMT), 141.65 (2
C of DMT), 135.88 (2 C of DMT), 132.92, 132.92, 130.30, 129.04,
128.39, 128.06 and 127.04 (ArCH), 113.37 (4 C of DMT), 86.78 (C
of DMT), 85.64 (C-4¢), 84.63 (C-1¢), 75.99 (C-3¢), 63.78 (C-5¢),
55.42 (2 CH3O), 45.82 (3 CH2 of Et3N), 40.00 (C-2¢), 8.84 (3 CH3
of Et3N).
1
31P NMR (CDCl3): d = 45.50 (1JP,Se = 703.7 Hz, JP,H = 572 Hz,
3JP,H = 14.07 Hz).
Anal. Calcd for C41H53N6O8PSe: C, 56.74; H, 6.16; N, 9.68. Found:
C, 56.39; H, 6.03; N, 9.88.
7d Slow
From slower moving diastereoisomer of 6d; white solid; yield: 41
mg (76%); Rf 0.35 (System A).
1H NMR (CDCl3): d = 8.50 (d, J = 578 Hz, 1 H, PH), 7.78 (s, 1 H,
H-8), 7.40–7.13 (m, 9 H, ArH), 6.75–6.71 (m, 4 H, ortho to OMe),
6.18–6.13 (m, 1 H, H-1¢), 5.84–5.74 (m, 1 H, H-3¢), 4.36–4.31 (m,
1 H, H-4¢), 3.74 (s, 6 H, 2 CH3O), 3.51–3.35 (m, 2 H, H-5¢), 3.09–
3.00 (m, 7 H, H-2¢ and 3 CH2 of Et3N), 2.65–2.46 (m, 2 H, H-2¢ and
CH of Ibu), 1.34–1.19 (m, 9 H, 3 CH3 of Et3N), 0.90–0.84 (m, 6 H,
2 CH3 of Ibu).
13C NMR (CDCl3): d = 179.41 (C=O), 158.67 (2 C of DMT), 156.02
(C-6), 147.95 (C-3), 147.55 (C-4), 144.94 (2 C of DMT), 138.78 (C-
8), 136.08 (2 C of DMT), 130.36, 128.48, 127.94 and 126.95 (8 C
of DMT), 113.24 (4 C of DMT), 86.45 (C of DMT), 85.13 (C-4¢),
84.64 (C-1¢), 75.08 (C-3¢), 63.61 (C-5¢), 55.40 (2 CH3O), 45.95 (3
CH3 of Et3N), 38.22 (C-2¢), 36.34 (CH of Ibu), 19.21 and 19.07
(CH3 of Ibu), 8.99 (3 CH3 of Et3N).
31P NMR (CDCl3): d = 48.61 (d, 1JP,Se = 715.9 Hz, 1JP,H = 568 Hz,
3JP,H = 12.48 Hz).
Anal. Calcd for C44H51N6O7PSe: C, 59.66; H, 5.80; N, 9.49. Found:
C, 59.38; H, 5.48; N, 9.73.
7c Slow
From slower moving diastereoisomer of 6c; white solid; yield: 80
mg (96%); Rf 0.37 (System A).
Synthesis 2005, No. 10, 1668–1674 © Thieme Stuttgart · New York

1674
M. Kullberg, J. Stawinski
PAPER
(3) Lindh, I.; Stawinski, J. J. Org. Chem. 1989, 54, 1338.
31P NMR (CDCl3): d = 44.97 (1JP,Se = 707.1 Hz, JP,H = 578.4 Hz,
1
3JP,H = 12.57 Hz).
(4) Stamatov, S. D.; Gronowitz, S. Lipids 1993, 28, 351.
(5) (a) Adiwidjaja, G.; Schulze, O.; Voss, J.; Wirsching, J.
Carbohyd. Res. 2000, 325, 107. (b) Cosford, N. D. P.;
Schinazi, R. F. J. Org. Chem. 1991, 56, 2161.
(6) (a) Koziolkiewicz, M.; Uznanski, B.; Stec, W. J.; Zon, G.
Chem. Scr. 1986, 26, 251. (b) Mori, K.; Boiziau, C.;
Cazenave, C.; Matsukura, M.; Subasinghe, C.; Cohen, J. S.;
Broder, S.; Toulme, J. J.; Stein, C. A. Nucleic Acids Res.
1989, 17, 8207.
Anal. Calcd for C41H53N6O8PSe: C, 56.74; H, 6.16; N, 9.68. Found:
C, 56.48; H, 6.09; N, 9.77.
Acknowledgment
Financial support from the Swedish Research Council is gratefully
acknowledged.
(7) Stawinski, J.; Thelin, M. J. Org. Chem. 1994, 59, 130.
(8) Stec, W. J.; Zon, G.; Egan, W.; Stec, B. J. Am. Chem. Soc.
1984, 106, 6077.
References
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