Stereoselective synthesis of 4′-selenonucleosides using the Pummerer glycosylation reaction

Article abstract of DOI:10.1016/j.carres.2008.02.014

The syntheses of four selenonucleosides, namely 4′-β-selenoadenosine, -cytidine, -thymidine, and -uridine are described. Commercially available d-ribonolactone was converted to the key intermediate 1,4-anhydro-4-seleno-d-ribitol in seven steps in overall excellent yield. Oxidation of the seleno-d-ribitol with MCPBA gave a single diastereomeric selenoxide in excellent yield, which upon Pummerer reaction in the presence of silylated purine or pyrimidine bases gave stereoselectively the corresponding 4′-β-selenonucleosides. The stereochemistry at the anomeric center was determined by means of 1D-NOE experiments.

Full text of DOI:10.1016/j.carres.2008.02.014

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 1790–1800
0
Stereoselective synthesis of 4 -selenonucleosides
using the Pummerer glycosylation reaction
Kumarasamy Jayakanthan, Blair D. Johnston and B. Mario Pinto*
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6
Received 18 January 2008; received in revised form 11 February 2008; accepted 14 February 2008
Available online 21 February 2008
0
Abstract—The syntheses of four selenonucleosides, namely 4 -b-selenoadenosine, -cytidine, -thymidine, and -uridine are described.
Commercially available D-ribonolactone was converted to the key intermediate 1,4-anhydro-4-seleno-D-ribitol in seven steps in over-
all excellent yield. Oxidation of the seleno-D-ribitol with MCPBA gave a single diastereomeric selenoxide in excellent yield, which
0
upon Pummerer reaction in the presence of silylated purine or pyrimidine bases gave stereoselectively the corresponding 4 -b-seleno-
nucleosides. The stereochemistry at the anomeric center was determined by means of 1D-NOE experiments.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Selenonucleosides; Purine base; Pyrimidine bases; Pummerer reactions; Selenoxides
1. Introduction
dispersion (MAD) has led to the development of solid-
phase synthetic methods for the production of oligo-
0
The substitution of one or more oxygen atoms in nucleo-
sides by other heteroatoms, most notably by sulfur, has
been the subject of numerous synthetic studies. The
nucleotides containing 2 -SeCH nucleosides such as 2.
3
The preparation of oligonucleotides in which one or
more 2 -OH groups were replaced by 2 -SeCH groups
1
0
0
3
potent antiviral activity of some of the modified nucleo-
sides has given impetus to these studies and many thio-
gave compounds having similar crystallization behavior
and stereochemistry to the native RNA structures; how-
ever, X-ray structural studies were simplified through
more convenient phasing of the data using the heavy-
2
substituted derivatives have been prepared and tested.
0
More recently, 4 -thionucleotides were incorporated into
6
–8
short RNA oligonucleotides to stabilize some small inter-
fering RNA (siRNA) duplex constructs that are being
atom anomalous diffraction effect.
3
developed for therapeutic gene-silencing purposes.
H
N
0
Encouragingly, the incorporation of only a few 4 -thio-
N
O
O
F
O
0
0
nucleotides at either the 3 or the 5 end of the sense
and/or the antisense stands gave significant resistance
to nucleosidase degradation without adversely affecting
the gene-silencing activity. We have reported similar
studies using 2 -F-substituted-4 -thioarabinonucleoside
N
N
S
O
NH
NH2
HO
HO
HO
N
4
HO
HO
SeCH3
0
0
1
2
5
1
. Studies of selenium-modified nucleosides have been
much less numerous. The utility of heavy atoms in
X-ray structural studies of oligonucleotides with syn-
chrotron radiation using multi wavelength anomalous
H
N
H
N
O
O
NH2
O
O
N
O
N
Se
Se
HO
*
Corresponding author. Tel.: +1 778 782 4152; fax: +1 778 782
860; e-mail: bpinto@sfu.ca
3
4
4
0
008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.02.014

K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
1791
SeBn
OH
Ph P, Im
Se
?
Se
3
SeBn
B
TBSO
TBSO
HO
SeBn
I2
AcO
AcO
HO
B = Nucleoside base
Scheme 1.
5
Selenium has been incorporated in various other posi-
tions of synthetic nucleoside derivatives to give, for
nucleoside 1, certainly augurs well for interesting
0
biological applications of the corresponding 4 -
selenooligonucleotides.
0
5b
example, a 3 -Se analogue (3) of the anti-AIDS drug
9
3
TC and bicyclic nucleoside analogues such as com-
0
10
11
pound 4 having a 2 -Se-anhydro bridge. Huang has
applied for a patent covering the preparations of several
2. Results and discussion
nucleosides and nucleotide derivatives having SeCH
3
0
0
0
groups at the 2 or 5 positions as well as compounds
with selenium atoms substituting for various oxygen
atoms in the phosphate or nitrogenous base portions
of the molecules. Included in the patent disclosure was
a single example of a proposed strategy for the incorpo-
ration of selenium as the ring atom in 2-deoxyribose
nucleosides and nucleosides (Scheme 1).
However, it is our contention that the application of
the illustrated reagents to effect ring-closure of dibenzyl-
seleno acetal intermediates is likely, at least in some
Our approach to 4 -Se-ribonucleosides is based on pro-
0
cedures reported for the practical synthesis of 4 -S-ribo-
1
5
nucleosides.
By analogy with these methods, we
propose the use of a 2,3-O-isopropylidene-protected
1,4-anhydro-4-seleno-D-ribitol derivative (compound a,
Scheme 2). Oxidation to selenoxide (b) and Pummerer
glycosylation with silylated pyrimidine or purine bases,
as developed by Matsuda’s group for the synthesis of
4 -thio nucleosides should lead to the desired nucleoside
derivatives (c) with good selectivity for the desired b-
isomers.
The choice of a benzyl group for the protection of the
1
6
0
cases, to involve inversion rather than retention at the
0
4
2
2
-position, and could thus lead to the corresponding
-deoxy-L-lyxose derivatives rather than the claimed
-deoxy-D-ribose compounds. A similar reaction for a
0
5 -hydroxyl functional group, which has been developed
2
c
for the synthesis of thionucleosides, was considered.
However, this option would have required removal
either by hydrogenolysis using a Pd catalyst or by treat-
1
2
related dithioacetal was initially reported to proceed
with retention; however, this was later corrected by sub-
1
3
sequent investigators who proved that the true course
of such reactions yields products from inversion at C-4.
ment with BCl ; neither possibility was attractive based
3
on preliminary studies with other compounds contain-
ing selenium. The use of a protecting group that could
be removed under the mildly acidic conditions necessary
for simultaneous isopropylidene removal was therefore
given priority, and the 5-t-butyldimethylsilyl (TBS)
group was chosen as the candidate. The initial target
compound, 1,4-anhydro-5-t-butyldimethylsilyl-2,3-O-
isopropylidene-4-seleno-D-ribitol 14, was readily
prepared in quantity by the procedures outlined in
Schemes 3 and 4.
1
4
0
The very recently reported syntheses of 4 -selenouri-
0
dine and 4 -selenocytidine prompts us to report our
own findings on the synthesis of this class of molecules,
containing purine and pyrimidine bases.
0
We describe herein the synthesis of 4 -selenonucleos-
ides, based on the Pummerer rearrangement of a selen-
oxide, with trapping of reaction intermediates by the
silylated pyrimidine or purine bases. The selenonucleo-
sides could be incorporated into oligonucleotides for
gene-silencing applications. The recently reported
The starting compound, D-ribonolactone (6), is avail-
able commercially or can be advantageously prepared in
high yield by bromine oxidation of ribose 5. Protection
0
preference for the southern conformation of 4 -seleno-
1
4
17
uridine, and the reported northern conformation in
our previous work with 2 -F-substituted-4 -thioarabino-
0
0
as the 2,3-O-isopropylidene acetal (7) and activation of
O
Se
Se
Se
B
PO
PO
PO
O
O
O
O
O
O
a
c
b
B = Nucleoside base
P = Protecting group
Scheme 2.

1792
K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
O
O
O
HO
O
MsCl
py.
Br2
HO
DMP
H+
D-ribose
O
O
HO
OH
5
6
7
O
O
O
O
O
O
HO
O
OH
MsO
O
KOH
O
O
O
O
8
9
10
1
7
Scheme 3.
O
O
oxide 15 in the presence of trimethylsilylated thymine,
trimethylsilyl triflate (TMSOTf, 2 equiv), and diisopro-
pylethylamine (DIPEA, 2 equiv) gave selenonucleoside
O
TBSO
DMF
O
HO
O
NaBH4
THF / MeOH
TBSCl
O
O
O
imidazole
1
6 in very poor yield. We attempted to optimize the
yield by changing solvent, (acetonitrile or dichloro-
methane), temperature (between ꢀ30 °C and rt), and
the quantity of reagents (between 2 equiv and 9 equiv
of TMSOTf and DIPEA). Under optimized conditions,
the use of 6 equiv of each of TMSOTf and DIPEA at
0 °C, in dichloromethane resulted in an improvement
of the yield to 41%. Stereoselectivity for the formation
of the b-isomer at the anomeric center 16 was excellent,
1
0
11
TBSO
Se
OR
TBSO
OR
O
O
O
O
NaBH4 / Se / EtOH
14
1
2
3
R = H
R = Ms
MsCl / py.
9
2% from 10
with less than 1% contamination by the corresponding
1
1
a-isomer (according to
H NMR). Simultaneous
Scheme 4.
removal of the silyl and isopropylidene protecting groups
by treatment of compound 16 with aqueous acetic acid
gave the target nucleoside 17 as a crystalline solid
(Scheme 5). The configuration at C-1 was confirmed
as b by analysis of the 1D-NOE spectrum of 17. Clear,
0
the 5-position by mesylation gave the intermediate com-
1
8
pound 8. Treatment with base resulted in lactone
hydrolysis and the formation of an intermediate open-
chain epoxide (9), which immediately recyclized when
acidified to produce a c-lactone (10) with inversion at
positive NOE correlations were observed between the
0
0
thymine H-6 resonance and the ribose H-2 and H-3
0
resonances. The H-6/H-2 NOE was larger than the
H-6/H-1 NOE, as expected if the thymine moiety pref-
1
9
0
the 4-position. This route to compound 10 from D-
1
7
ribose was recently optimized for use on a large scale
and gives the L-lyxonolactone derivative 10 as an easily-
purified, crystalline compound in good yield. Protection
of the 5-hydroxyl group as the t-butyldimethylsilyl ether
gave the fully-protected compound 11. This was
reduced with sodium borohydride to 1,4-diol 12, which
was treated with excess methanesulfonyl chloride and
pyridine to give the dimesylate 13, that was treated
immediately with sodium selenide in EtOH/DMF to
afford the key intermediate 14 in excellent overall yield
erentially populates the anti-conformation around the
0
C-1 –N1 bond, as shown to be the case for the related
0
0
20
2 -deoxy-4 -thio system.
Under the optimized conditions, the treatment of
selenoxide 15 with trimethylsilylated uracil gave the
selenouridine derivative 18 in 56% yield, with complete
b-stereoselectivity (Scheme 6). The TBS and acetonide
protecting groups were removed in good yield by heat-
ing at reflux with 60% aqueous acetic acid for 30 min.
1
5
0
Once again, the stereochemistry at C-1 was confirmed
(
Scheme 4).
by means of 1D-NOE experiments.
Oxidation of the selenium center with m-chloroper-
Under similar conditions to those reported above,
selenoxide 15 reacted with trimethylsilylated cytosine
to give the selenocytidine derivative in very low yield
(ꢁ10%). Thus, we examined the use of the N-acetylcytos-
ine derivative in the Pummerer reaction. Accordingly, a
solution of selenoxide 15 and silylated N-acetylcytosine
oxybenzoic acid (MCPBA) yielded selenoxide 15 as a
single diastereomer. The configuration of the selenoxide
was tentatively assigned as the R-Se isomer based on
steric arguments. The compound was reacted immediately
after its formation. Pummerer rearrangement of selen-

K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
1793
O
Se
TBSO
Se
TMSOTf/ D IPEA/ CH Cl
M
CPBA
2
2
TBSO
O
O
>95%
OTMS
N
O
O
1
4
15
TMSO
N
H
N
H
N
O
O
O
O
N
N
Se
Se
HOAc / H O
2
TBSO
HO
O
O
HO
OH
1
6
41%
17 59%
Scheme 5.
O
OTMS
N
HMDS
TMSOTf, DIPEA
NH
N
1
5
N
H
O
TMSCl (cat)
TMSO
Uracil
H
N
H
N
O
O
O
O
N
HOAc / H O
2
Se
TBSO
N
Se
HO
O
O
HO
19
OH
80%
18
56%
Scheme 6.
in CH Cl were added to an excess of DIPEA and
made to identify these isomers as the mixture was found
to be unstable. However, when the reaction was carried
out at ꢀ30 °C, it yielded exclusively one regioisomer in
53% yield (Scheme 8). This regioisomer could be either
the N-3 or N-7-linked isomer. The configuration of 22
at the anomeric center was assigned as b on the basis
of 1D-NOE experiments. Thus, irradiation of the H-8
2
2
TMSOTf at 0 °C. The reaction proceeded immediately,
but the desired protected selenocytidine 20 was pro-
duced in low yield (35%). Although the stereoselectivity
of the resulting nucleoside was b as expected, the iso-
lated yield was not satisfactory. Thus, the reaction con-
ditions were modified: silylation of N-acetylcytosine
1
6
0
using Et N and TMSOTf in toluene, followed by the
resonance gave enhancements of the H-5 and TBS
3
0
addition of selenoxide 15 in CH Cl improved the yield
resonances. Moreover, the H-8/H-2 NOE was larger
2
2
0
to 47%. Hydrolysis of N-acetate in 20 using methanolic
ammonia at 0 °C, followed by removal of the TBS and
acetonide groups in acetic acid gave the desired nucleos-
ide 21 in 65% yield over two steps (Scheme 7).
We next turned our attention to purine-containing
nucleosides, and report here the synthesis of the first
candidate. Thus, the reaction of selenoxide 15 with
adenine gave a complex mixture, while the reaction with
than the H-8/H-1 NOE, as observed for the pyrimidine
nucleosides. Further, no enhancements were observed
0
between protons H-8 and H-4 .
Compound 22 was treated with 50% trifluoroacetic
acid at room temperature to remove the TBS and aceto-
nide protecting groups, followed by heating with
ethanolic ammonia at 100 °C to give the adenine
nucleoside 23 in 72% yield over two steps (Scheme 8).
1
6
-chloropurine at 0 °C gave the coupled product in 41%
The H NMR signals for compound 23 were observed
yield as a mixture of two regioisomers (Scheme 8) as
indicated by H NMR of the mixture. No attempt was
at d 8.62 and 8.11 (H-2 and H-8), and 6.04 ppm
1
0
(H-1 ). The absorption maximum appeared at 270 nm

1794
K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
NHAc
NHAc
NH
0 oC, CH Cl2
2
TMSOTf
Et N, toluene
N
15
3
TMSO
N
N
H
O
O
N
NHAc
N
NH2
O
N
Se
. NH , MeOH, 0 o
1
C
N
TBSO
3
Se
HO
O
O
2
. HOAC / H O, reflux
2
HO
OH
4
7%
65%
21
20
Scheme 7.
9
N
3
4
5
N
2
1
5'
Se
3'
B
8
TBSO
5'
TMSOTf / DIPEA / CH Cl
4
'
1'
1. 50% TFAA in H2O, rt,1 h
N
N
2
2
Se
2
'
6
HO
7
15
1'
2'
4
'
O
O
NH2
silylated 6-chloropurine
2. NH , EtOH, 100 oC, 24 h
3'
3
HO
OH
-
30 oC, 53%
2
3
2
2
Cl
Cl
6
6
7
7
N
N
5
N
5
1
N
1
N
B :
8
or
8
4
4
2
N
9
2
N
N
3
9
3
Scheme 8.
0
in H O. The regioisomer 23 was finally identified as
being the N-7 isomer, as discussed below.
4 -thio-adenosine derivative by Pummerer reaction
2
1
6
under similar conditions.
In view of the fact that the kinetic N-7 isomer was
expected to rearrange
Formation of the N-3 isomer of adenosine was
observed in the alkylation reaction of adenine with
1
6,23
into the N-9 isomer, the N-7
2
2a
glycosyl halides
or by blocking the N-7 and N-9
isomer 22 was heated at reflux in 60% aqueous acetic
acid for 15 min; however, the only isolated product
was the deprotected N-7 isomer. Therefore, heating at
reflux was continued for 4 h; interestingly, rearrange-
ment and deprotection of 22 to the desired 24 in 34%
yield was observed (Scheme 9). The product 24 has an
acetate group, resulting from the displacement of the
chlorine atom by acetic acid. The presence of the acetate
positions by substituting a bulky group at the N-8 posi-
2
2b
tion.
Otherwise, only the N-7 isomers were generally
preferred to form as intermediates during glycosylation
reactions of silylated adenine with anomeric acetates
1
6,23
and sulfoxides.
These N-7 linked intermediates were
converted into the thermodynamically more stable N-9
isomers by heating them in the presence of acids.
Recently, an interesting N-1 isomer was also identified
1
3
group was confirmed by the observed carbonyl C reso-
nance at d 171.2, and a H methyl resonance at d 2.12.
2
3a
1
by Boryski and co-workers
under silylation and
glycosylation of an N-6 protected adenine. These vari-
ous regioisomers were generally differentiated by UV
spectroscopy. Thus, kmax of N-3, N-7, and N-9 isomers
were observed at 274–280, ꢁ270 and ꢁ259 nm, respec-
Treatment of 24 with ethanolic ammonia at 100 °C gave
the desired selenoadenosine 25 in 65% yield (Scheme 9).
The UV spectrum of the N-9 isomer 25 in H O showed
2
an absorption maximum at 259 nm, characteristic of the
1
tively, at neutral pH. Because k
of 23 appears at
N-9-glycosyl adenosine. The H NMR signals for the
max
2
70 nm, we conclude that this compound is an N-7-
N-9 isomer (25) were observed at d 8.56 and 8.01 (H-2
and H-8), and 6.22 ppm (H-1 ), while those of the N-7
0
linked regioisomer, and by inference, that 22 is also
the N-7-linked regioisomer. It is noteworthy that a
similar result was observed in the formation of a
isomer 23 were observed further downfield at d 8.62
0
and 8.11 (H-2 and H-8), and 6.04 ppm (H-1 ), consistent

K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
1795
NH2
N
OAc
N
N
N
N
NH , EtOH
Se
N
6
0% AcOH
reflux, 4 h
4%
3
HO
Se
N
N
22
HO
o
24 h, 100 C
HO
OH
3
HO
OH
65%
2
5
24
Scheme 9.
with the literature precedent for the sulfur
congeners.
washed with satd aq NaHCO solution (80 mL). The
3
1
6,23d
organic phase was dried over anhyd MgSO , filtered,
4
and concentrated to give a waxy solid which changed
into a dry, crystalline solid when placed under high vac-
1
3. Conclusions
uum. The yield of crude product, which was pure by H
NMR except for a trace of imidazole, was 7.71 g
(ꢁ100%). This material could be purified if necessary
by flash chromatography (hexanes/ethyl acetate, 3:1),
In summary, we have developed a stereoselective route
to the synthesis of 4 -b-selenonucleosides. The starting
0
precursor, 1,4-anhydro-4-seleno-D-ribitol 14 was readily
prepared in a few steps, in multigram quantities from
the commercially available D-ribonolactone. Oxidation
of the 1,4-anhydro-4-seleno-D-ribitol using MCPBA
gave a single selenoxide diastereomer in excellent yield,
which upon treatment under Pummerer glycosylation
but was generally suitable for use without further purifi-
1
cation. H NMR (500 MHz, CDCl
): d 4.82–4.79 (2H,
3
m, H-2 and H-3), 4.52 (1H, m, H-4), 3.98 (1H, dd,
J
4,5a = 6.1, J5a,5b = 10.8 Hz, H-5a), 3.93 (1H, dd,
4,5b = 6.6 Hz, H-5b), 1.46 (3H, s, CH ), 1.39 (3H, s,
), 0.90 (9H, s, SiC(CH );
), 0.10 (6H, s, 2 ꢂ SiCH
C NMR (125 MHz, CDCl ); d 173.8 (C@O), 114.0
(C(CH ), 79.4 (C-2), 76.0 and 75.7 (C-3 and C-4),
60.9 (C-5), 26.8 and 25.9 (2 ꢂ CH ) 25.8 (SiC(CH ),
18.3 (SiC(CH ).
), ꢀ5.4 and ꢀ5.5 (2 ꢂ SiCH
J
3
CH
)
3
3
3
3
1
3
0
conditions, gave the 4 -seleno-thymidine, -cytidine,
3
-
adenosine, and -uridine derivatives with high b-stereo-
)
3 2
0
selectivity. Deprotection then offered the target 4 -
selenonucleosides.
3
)
3 3
)
3
3
3
4
. Experimental
.1. General experimental methods
Optical rotations were measured at 20 °C. H and
4.3. 5-O-t-Butyldimethylsilyl-2,3-di-O-isopropylidene-L-
lyxitol (12)
4
The previous crude silyl derivative 11 (7.71 g) was dis-
solved in a mixture of THF/MeOH (5:1, 80 mL) and
the solution was stirred at ambient temperature while
1
13
C
NMR spectra were recorded at 500 and 125 MHz,
respectively. All assignments were confirmed with the
aid of two-dimensional H, H (COSYDFTP) or H,
NaBH (1.1 g, 29 mmol) was added in portions over
4
1
1
1
20 min. The mixture was stirred for 1 h and then concen-
trated on a rotary evaporator. The residue was parti-
tioned between EtOAc (150 mL) and 20% aq tartaric
acid solution (50 mL). The organic phase was washed
with saturated 20% aq tartaric acid solution (20 mL),
1
3
C (INVBTP) experiments using standard pulse pro-
grams. Column chromatography was performed with
Silica Gel 60 (230–400 mesh). High resolution mass
spectra were obtained by the Fast Atom Bombardment
(
FAB) technique, using a JEOL AX505HA high resolu-
saturated aq NaHCO solution (20 mL), saturated aq
3
tion magnetic sector mass spectrometer.
NaCl solution (20 mL), and then dried over anhyd
MgSO , filtered, and concentrated to give diol 12 as a
4
4
.2. 5-O-t-Butyldimethylsilyl-2,3-di-O-isopropylidene-L-
colorless crystalline solid (7.49 g, 96% for two steps from
1
lyxono-c-lactone (11)
lactone 10). H NMR (500 MHz, CDCl ): d 4.26–4.21
3
(2H, m, H-2 and H-3), 3.84–3.74 (3H, m, H-4, H-1a,
A solution of 2,3-di-O-isopropylidene-L-lyxono-c-lac-
tone 10 (4.79 g, 25.5 mmol) in CH Cl (80 mL) contain-
ing imidazole (2.05 g, 30.1 mmol) was stirred at ambient
and H-1b), 3.72 (1H, dd, J4,5a = 6.3, J5a,5b = 9.8 Hz,
H-5a), 3.62 (1H, dd, J4,5b = 6.8 Hz, H-5b), 1.50 (3H, s,
CH ), 1.37 (3H, s, CH ), 0.89 (9H, s, SiC(CH ) ), 0.07
2
2
3
3
3
3 3
1
temperature while t-butyldimethylsilyl chloride (4.30 g,
(6H, s, 2 ꢂ SiCH ); C NMR (125 MHz, CDCl ): d
3
3
2
8.5 mmol) was added in small portions over 10 min.
The mixture was stirred under an inert atmosphere for
0 min and then diluted with CH Cl (150 mL) and
108.2 (C(CH ) ), 77.3 and 75.7 (C-2 and C-3), 69.2
3 2
(C-4), 64.5 (C-5), 62.7 (C-1), 27.1 and 25.0 (2 ꢂ CH ),
3
5
25.8 (SiC(CH ) ), 18.3 (SiC(CH ) ), ꢀ5.4 and ꢀ5.5
2
2
3 3
3 3

1796
K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
(
9
2 ꢂ SiCH ); Anal. Calcd for C H SiO : C, 54.87; H,
combined extracts were dried over MgSO , filtered,
3
14 30
5
4
.87. Found: C, 54.99; H, 10.03.
and concentrated to give the crude product as an oily
residue containing small amounts of pyridine and
DMF. This was purified by flash chromatography to
give the product 14 as a pale yellow oil (8.32 g, 92%
for 4 steps from isopropylidene lyxonolactone (10)).
4
1
.4. 5-O-t-Butyldimethylsilyl-2,3-di-O-isopropylidene-
,4-di-O-methanesulfonyl-L-lyxitol (13)
2
D
0
1
The previous diol 12 (7.49 g, 24.5 mmol) was dissolved
in CH Cl (20 mL) and the solution was added dropwise
½aꢃ +104.0 (c 0.5, CHCl3); H NMR (500 MHz,
CDCl ): d 4.94 (1H, ddd, H-2), 4.78 (1H, dd,
2
2
3
to a stirred mixture of MsCl (18.6 mL, 0.24 mol) and
pyridine (19.3 mL, 0.24 mol) with ice-bath cooling.
The cooling bath was removed and the mixture stirred
at ambient temperature for 2 h. The cooling bath was
replaced and the excess MsCl was hydrolyzed by the
addition of ice (ꢁ10 g). After 10 min, the reaction mix-
ture was poured into cold water (350 mL) and extracted
J2,3 = 1.7 Hz, H-3), 3.86 (1H, dd, J4,5a = 5.2,
J5a,5b = 10.6 Hz, H-5a), 3.69 (1H, dd, J4,5b = 6.9 Hz,
H-5b), 3.59 (1H, ddd, H-4), 3.24 (1H, dd, J1a,2 = 5.2,
J1a,1b = 11.1 Hz, H-1a), 2.95 (1H, dd, J1b,2 = 2.3 Hz,
H-1b), 1.53 (3H, s, CH ), 1.32 (3H, s, CH ), 0.90 (9H,
3
3
1
3
s, SiC(CH ) ), 0.07 (6H, s, 2 ꢂ SiCH ); C NMR
3
3
3
(125 MHz, CDCl ): d 110.2 (C(CH ) ), 87.6 and 85.3
3
3 2
with Et O (3 ꢂ 100 mL). The combined extracts were
(C-2 and C-3), 66.2 (C-5), 66.1 (C-1), 50.5 (C-4), 26.8
2
washed with satd 20% aq tartaric acid solution
and 24.6 (2 ꢂ CH ), 25.9 (SiC(CH ) ), 18.3 (SiC(CH ) ),
3
3 3
3 3
(
3 ꢂ 50 mL), satd aq NaHCO solution (50 mL), satd
ꢀ5.4 (2C, 2 ꢂ SiCH ); MALDI MS m/e 375.46
3
3
+ +
aq NaCl solution (50 mL), and then dried over anhyd
[M+Na] , 353.51 [M+H] ; Anal. Calcd for
C H SiO Se: C, 47.85; H, 8.03. Found: C, 47.58; H,
MgSO , filtered, and concentrated to give the dimesylate
4
14 28
3
1
3 as a pale yellow oil (12.4 g) that was used immedi-
8.21.
1
ately in the next reaction. H NMR (400 MHz, CDCl ):
3
d 4.74 (1H, ddd, H-4), 4.49–4.34 (4H, m, H-1a, H-1b,
4.6. 5-O-t-Butyldimethylsilyl-2,3-di-O-isopropylidene-
1,4-anhydro-4-seleno-D-ribitol selenoxide (15)
H-2, and H-3), 3.96 (1H, dd, J4,5a = 5.4, J5a,5b
=
1
3
0.9 Hz, H-5a), 3.82 (1H, dd, J4,5b = 6.2 Hz, H-5b),
.12 (3H, s, OSO CH ), 3.08 (3H, s, OSO CH ), 1.51
A solution of selenoether 14 (427 mg, 1.21 mmol) in
2
3
2
3
(
0
3H, s, CH ), 1.38 (3H, s, CH ), 0.90 (9H, s, SiC(CH ) ),
CH Cl (10 mL) was cooled in an ice-bath and stirred
3
3
3 3
2
2
1
3
.10 (3H, s, SiCH ), 0.097 (3H, s, SiCH ); C NMR
while 68% MCPBA (344 mg, 1.35 mmol) was added in
small portions over 15 min. After a further 10 min at
0 °C, the mixture was warmed to rt and diluted with
CH Cl (100 mL). The solution was washed with satd
3
3
(
100 MHz, CDCl ): d 109.6 (C(CH ) ), 78.9 (C-4), 75.4
3 3 2
and 74.5 (C-2 and C-3), 67.9 (C-1), 63.1 (C-5), 38.9
and 37.6 (2 ꢂ OSO CH ), 27.2 and 25.4 (2 ꢂ CH ), 25.8
2
3
3
2
2
(
SiC(CH ) ), 18.3 (SiC(CH ) ), ꢀ5.5 (2C, 2 ꢂ SiCH ).
aq NaHCO3 (30 mL), dried over MgSO , and con-
3
3
3 3
3
4
centrated to give selenoxide 15 in quantitative yield as
a colorless unstable crystalline solid. This material was
used immediately in subsequent reactions. Analysis by
4
1
.5. 5-O-t-Butyldimethylsilyl-2,3-di-O-isopropylidene-
,4-anhydro-4 seleno-D-ribitol (14)
1
H NMR indicated that the product was composed of
1
A solution of Na Se was first prepared by the method of
Krief et al.
a single selenoxide diastereomer. H NMR (500
2
2
1
Thus, dry gray selenium (2.20 g,
MHz, CDCl ): d 5.19 (1H, ddd, H-2), 5.02 (1H, dd,
3
2
7.9 mmol) and NaBH (2.11 g, 55.8 mmol) were mixed
J2,3 = 3.9 Hz, H-3), 4.14 (1H, dd, J4,5a = 3.8,
J5a,5b = 11.5 Hz, H-5a), 4.04 (1H, dd, J4,5b = 7.2 Hz,
H-5b), 3.59 (1H, ddd, H-4), 3.43 (1H, dd, J1a,2 = 2.5,
J1a,1b = 12.8 Hz, H-1a), 3.12 (1H, dd, J1b,2 = 6.1 Hz,
H-1b), 1.46 (3H, s, CH ), 1.31 (3H, s, CH ), 0.90 (9H,
4
and stirred in an ice-bath while anhyd EtOH (10 mL)
was slowly added. The cooling bath was removed and
the mixture was allowed to reach ambient temperature
over 15 min, giving a brown suspension of partially
reduced selenium. The cooling bath was replaced and
anhydrous DMF (35 mL) was added. This gave a
vigorous reaction, accompanied by H2 evolution, to
3
3
1
3
s, SiC(CH ) ), 0.12 (6H, s, 2 ꢂ SiCH ); C NMR
3
3
3
(100 MHz, CDCl ): d 111.0 (C(CH ) ), 83.6 and 81.5
3
3 2
(C-2 and C-3), 63.4 (C-5), 56.6 (C-4), 52.7 (C-1), 27.3
eventually produce a colorless solution of Na Se upon
and 24.4 (2 ꢂ CH ), 25.8 (SiC(CH ) ), 18.2 (SiC(CH ) ),
2
3
3 3
3 3
warming to room temperature. This Na Se solution
ꢀ5.4 and ꢀ5.6 (2 ꢂ SiCH ).
2
3
was then rapidly added to a pre-prepared solution of
the previous crude dimesylate 13 (12.4 g) in DMF
0
0
0
4.7. N-1-(5 -O-t-Butyldimethylsilyl-2 ,3 -di-O-isopropyl-
0
(
40 mL). The resulting mixture was placed under an
idene-4 -seleno-b-D-ribofuranosyl)-thymine (16)
N atmosphere and slowly warmed to 60 °C over 2 h,
2
and maintained at 60 °C for a further 1 h. The mixture
Thymine (1.24 g, 9.88 mmol) in acetonitrile (30 mL) was
heated at reflux with hexamethyldisilazane (8.0 mL) and
was cooled to ambient temperature, and poured into
water (800 mL), and extracted with 1:1 Et O/hexanes
trimethylsilyl chloride (0.5 mL) for 40 min under N . The
2
2
(
3 ꢂ 100 mL) and with ethyl acetate (3 ꢂ 100 mL). The
mixture was cooled to room temperature and

K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
1797
0
0
0
0
concentrated to give di-O-silylated thymine as a cloudy
syrup. Meanwhile, selenoether 14 (1.76 g, 5.02 mmol)
was oxidized to the selenoxide as described above. The
crude selenoxide 15 (1.81 g) was combined with silylated
thymine in CH Cl (80 mL) and the mixture was cooled
78.3 (C-2 ), 74.5 (C-3 ), 63.3 (C-5 ), 59.3 (C-1 ), 47.8
0
(C-4 ), 11.7 (5-CH3); MALDI MS m/e 345.46
+
+
[M+Na] , 323. 14 [M+H] ; Anal. Calcd for
C H N O Se: C, 37.40; H, 4.39; N, 8.72. Found: C,
1
0
14
2
5
37.67; H, 4.51; N, 8.95.
2
2
in an ice-bath. Diisopropylethylamine (5.2 mL, 30 mmol)
was added, followed by dropwise addition of TMSOTf
0
0
0
4.9. N-1-(5 -O-t-Butyldimethylsilyl-2 ,3 -di-O-isopropyl-
0
(
5.4 mL, 30 mmol). The mixture was stirred in the ice-
idene-4 -seleno-b-D-ribofuranosyl)-uracil (18)
bath for 30 min and then allowed to warm to room tem-
perature, and quenched by the addition of a satd aq
In the same manner as described for 16, selenoxide 15
(1.04 g, 2.84 mmol), when reacted with trimethylsilyl-
ated uracil (1.45 g, 5.68 mmol), gave 18 as a pale yellow
NaHCO (50 mL) and, after a further 10 min of rapid
3
stirring, the two-phase mixture was filtered through Cel-
ite with the aid of additional CH Cl . The filtrate was sep-
2
0
1
syrup (0.733 g, 56%); ½aꢃ ꢀ42.5 (c 1.6, CHCl ); H
2
2
D
3
arated and the organic phase was washed with water
80 mL) and dried over MgSO . Filtration and solvent
NMR (500 MHz, CDCl ): d 9.36 (1H, br s, NH), 7.72
3
(
(1H, d, J = 8.0 Hz, H-6), 6.30 (1H, d, J
0 0
¼ 3:0 Hz,
4
1 ;2
0
removal yielded the crude product as an orange semi-
solid mixture that was purified by column chromato-
graphy on silica gel (hexanes/ethyl acetate, 1:1) to give
selenonucleoside 16 as a pale yellow foam (1.11 g,
H-1 ), 5.70 (1H, d, J = 8.0 Hz, H-5), 4.64 (2H, m,
H-2 , H-3 ), 3.88 (3H, m, H-4 , H-5 a, H-5 b), 1.49
0
0
0
0
0
(3H, s, CH ), 1.20 (3H, s, CH ), 0.81 (9H, s, SiC(CH ) ),
3
3
3 3
1
3
0.01 (3H, s, SiCH ), 0.00 (3H, s, SiCH ); C NMR
3
3
2
D
0
1
4
6%); ½aꢃ ꢀ52.0 (c 1.0, CHCl ); H NMR (500 MHz,
(125 MHz, CDCl ): d 163.0 (C@O), 150.0 (C@O),
3
3
CDCl ): d 8.56 (1H, br s, NH), 7.37 (1H, q, J = 1.2 Hz,
H-6), 6.34 (1H, d, J1
142.3 (C-6), 111.9 (C(CH ) ), 103.2 (C-5), 90.6 and
3
3 2
0
0
0
0
0
0
0
¼ 4:6 Hz, H-1 ), 4.77 (1H, dd,
85.6 (C-2 and C-3 ), 65.5 (C-5 ), 59.9 (C-1 ), 50.2
;2
0
0
0
J2
4
(
1
0
0
¼ 5:6 Hz, H-2 ), 4.71(1H, dd, J
0
0
¼ 3:4 Hz, H-3 ),
(C-4 ), 27.9 and 25.4 (2 ꢂ CH ), 25.8 (SiC(CH ) ), 18.4
;3
3 ;4
3
3 3
0
.03 (1H, dd, J
0
0
¼ 5:0; J
0
0
¼ 9:7 Hz, H-5 a), 3.97
(SiC(CH ) ), ꢀ5.2 and ꢀ5.3 (2 ꢂ SiCH ); FAB HRMS
4
;5 a
5 a;5 b
3 3
3
0
0
1H, ddd, H-4 ), 3.89 (1H, dd, J
.94 (3H, d, J = 1.2 Hz, 5-CH ), 1.59 (3H, s, CH ), 1.30
0
0
¼ 6:1 Hz, H-5 b),
(m-nitrobenzoic acid (MNBA)) calcd for C H N O -
4
;5 b
18 30
2
5
+
SeSi, 463.1167 [M+H] ; found, 463.1170.
3
3
(
3H, s, CH ), 0.92 (9H, s, SiC(CH ) ), 0.10 (3H, s,
3 3 3
1
3
0
SiCH ), 0.096 (3H, s, SiCH ); C NMR (125 MHz,
4.10. N-1-(4 -Seleno-b-D-ribofuranosyl)-uracil (19)
3
3
CDCl ): d 163.2 (C@O), 150.0 (C@O), 137.5 (C-6),
3
0
1
(
12.7 and 111.9 (C-5 and C(CH ) ), 89.5 (C-2 ), 84.7
C-3 ), 65.2 (C-5 ), 59.0 (C-1 ), 49.9 (C-4 ), 27.9 and 25.4
Selenouridine 18 (0.50 g, 1.08 mmol) was deprotected,
using the procedure that was used to obtain 17 as a col-
3
2
0
0
0
0
2
D
0
(
(
4
2 ꢂ CH ), 25.8 (SiC(CH ) ), 18.4 (SiC(CH ) ), 12.6
orless solid (0.265 g, 80%). Mp 190–193 °C; ½aꢃ ꢀ90.0
3
3 3
3 3
1
5-CH3), ꢀ5.2 and ꢀ5.3 (2 ꢂ SiCH ); MALDI MS m/e
(c 0.4, H O); H NMR (500 MHz, D O): d 7.98 (1H,
3
2
2
+
+
0
99.34 [M+Na] , 477.21 [M+H] ; Anal. Calcd for
d, J = 8.0 Hz, H-6), 6.03 (1H, d, J1
0
0
¼ 7:5 Hz, H-1 ),
;2
C H N SiO Se: C, 47.99; H, 6.78; N, 5.89. Found: C,
4
5.79 (1H, d, J = 8.0 Hz, H-5), 4.31 (1H, dd, J
0 0
¼
1
9
32
2
5
2 ;3
0
0
8.08; H, 6.84; N, 6.08.
3:5 Hz, H-2 ), 4.17 (1H, dd, J
0
0
;4
¼ 3:0 Hz, H-3 ), 3.80
3
0
(
1H, dd, J4
0
0
¼ 6:5; J
0 0
¼ 12:0 Hz, H-5 a), 3.70
;5 a
5 a;5 b
0
0
0
4
.8. N-1-(4 -Seleno-b-D-ribofuranosyl)-thymine (17)
(1H, dd, J
0
0
¼ 6:0 Hz, H-5 b), 3.46 (1H, ddd, H-4 );
4
;5 b
1
3
C NMR (125 MHz, D O): d 166.2 (C@O), 152.3
2
0
The protected selenonucleoside 16 (1.02 g, 2.15 mmol)
was heated at reflux in 60% aqueous HOAc (50 mL)
for 0.5 h. The mixture was cooled and concentrated by
rotary evaporation under high vacuum. Water (30 mL)
was added and removed under reduced pressure to
remove the last of the HOAc. This crude product was
purified by a silica gel column, eluted with CH Cl /
(C@O), 143.9 (C-6), 102.7 (C-5), 78.4 (C-2 ), 74.6
0
0
0
0
(C-3 ), 63.4 (C-5 ), 59.6 (C-1 ), 47.8 (C-4 ); FAB HRMS
(MNBA) calcd for C H N O Se, 308.9990 [M+H] ;
+
9
12
2
5
found, 308.9994.
4
4.11. N -Acetyl-1-(5 -O-t-butyldimethylsilyl-2 ,3 -di-O-
isopropylidene-4 -seleno-b-D-ribofuranosyl)-cytosine (20)
0
0
0
0
2
2
MeOH (10:1) to give 17 as a pale tan-colored solid
2
D
0
(
0.604 g, 59%). Mp 150–153 °C; ½aꢃ ꢀ21.5 (c 0.7,
N-Acetylcytosine (0.869 g, 5.68 mmol) was silylated
1
H O); H NMR (400 MHz, D O); d 7.85 (1H, q,
using TMSOTf (3.1 mL, 17.04 mmol) and Et N
2
2
3
0
J = 1.2 Hz, H-6), 6.13 (1H, d, J1
4
J3
6
0
0
¼ 7:9 Hz, H-1 ),
(1.2 mL, 8.52 mmol) in toluene (10 mL) according to
;2
0
15
.40 (1H, dd, J2
0
0
¼ 3:5 Hz, H-2 ), 4.28 (1H, dd,
the procedure of Matsuda for the silylation of uracil.
;3
0
0
0
¼ 2:8 Hz, H-3 ), 3.90 (1H, dd,
J
0
0
4 ;5 a
¼
¼
A solution of selenoxide 15 (1.04 g, 2.84 mmol) in dry
;4
0
:7; J5
0
0
¼ 12:0 Hz, H-5 a), 3.80 (1H, dd, J
0
0
CH Cl (10 mL) was added dropwise to the solution of
a;5 b
4 ;5 b
2
2
0
0
5
:8 Hz, H-5 b), 3.54 (1H, ddd, H-4 ), 1.84 (3H, d,
the trimethylsilylated cytosine in toluene/CH Cl (2:1,
2 2
1
3
J = 1.2 Hz, 5-CH3); C NMR (125 MHz, D O): d
69.1 (C@O), 152.5 (C@O), 139.3 (C-6), 112.0 (C-5),
12 mL) at 0 °C. An additional amount of Et N
2
3
1
(1.2 mL, 8.52 mmol) in CH Cl (2 mL) was added
2
2

1798
K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
dropwise to the reaction mixture at the same tempera-
(4.0 mL) and trimethylsilyl chloride (0.25 mL) for
ture. After stirring for 15 min at 0 °C, the reaction was
60 min under N . The mixture was cooled to room tem-
2
quenched by the addition of satd aq NaHCO (25 mL),
perature and concentrated to give the silylated 6-chloro-
purine as a syrup. The crude selenoxide 15 (1.05 g,
2.84 mmol) was combined with the silylated 6-chloro-
purine in CH Cl (20 mL) and the mixture was cooled
3
and the reaction mixture was partitioned between
CH Cl (20 mL) and H O (10 mL). The organic layer
2
2
2
was dried over Na SO , and the resulting residue was
2
4
2
2
purified by silica gel column (hexanes/ethyl acetate,
:1) to give selenonucleoside 16 as a pale yellow oil
to ꢀ30 °C. Diisopropylethylamine (3.5 mL, 20 mmol)
was added followed by dropwise addition of TMSOTf
(3.6 mL, 20 mmol). The mixture was stirred at the same
temperature for 30 min and then quenched by the addi-
tion of satd NaHCO3 (25 mL) and, after a further
10 min of rapid stirring, the two-phase mixture was
filtered through Celite with the aid of additional
CH Cl . The filtrate was separated and the organic
4
2
0
1
(
(
0.67 g, 47%). ½aꢃ ꢀ36.5 (c 1.2, CHCl ); H NMR
D
3
500 MHz, CDCl ): d 9.82 (1H, br s, NH), 8.12 (1H, d,
3
J = 7.5 Hz, H-6), 7.36 (1H, d, J = 7.5 Hz, H-5), 6.28
0
0
0
(
3
1H, d, J1
0
0
¼ 1:5 Hz, H-1 ), 4.75 (2H, m, H-2 , H-3 ),
;2
0 0 0
.90 (3H, m, H-4 , H-5 a, H-5 b), 2.20 (3H, s, NAc),
1
.49 (3H, s, CH ), 1.21 (3H, s, CH ), 0.82 (9H, s,
3
3
2
2
SiC(CH ) ), 0.01 (3H, s, SiCH ), 0.00 (3H, s, SiCH );
phase was washed with water (50 mL) and dried over
3
3
3
3
1
3
C NMR (125 MHz, CDCl ): d 171.0 (C@O), 162.6
MgSO . Filtration and solvent removal yielded the
3
4
(
9
6
(
C@NH), 154.8 (C@O), 147.3 (C-6), 111.6 (C(CH ) ),
7.5 (C-5), 91.2 and 86.3 (C-2 and C-3 ), 65.5 (C-5 ),
crude product as a brown syrup that was purified by
column chromatography on silica gel (hexanes/
ethyl acetate, 1:1) to give selenonucleoside 22 as a
3
2
0
0
0
0
0
2.8 (C-1 ), 51.8 (C-4 ), 27.7 and 25.9 (2 ꢂ CH ), 25.8
3
2
0
SiC(CH ) ), 24.9 (C(O)CH ), 18.4 (SiC(CH ) ), ꢀ5.2
yellow syrup (0.758 g, 53%). ½aꢃ +20.0 (c 1.3, CHCl3);
3
3
3
3 3
D
1
and ꢀ5.3 (2 ꢂ SiCH ); FAB HRMS (MNBA) calcd for
H NMR (500 MHz, CDCl ): d 8.95 (1H, s, H-8), 8.77
3
3
+
0
C H N O SeSi, 504.1433 [M+H] ; found, 504.1437.
(1H, s, H-2), 6.70 (1H, d, J
0 0
¼ 3:0 Hz, H-1 ), 4.83
2
0
33
3
5
1 ;2
0
(1H, dd, J2
0
0
¼ 5:5 Hz, H-2 ), 4.77 (1H, dd,
;3
0
0
0
4
.12. N-1-(4 -Seleno-b-D-ribofuranosyl)-cytosine (21)
J3
0
0
0
¼ 3:0 Hz, H-3 ), 3.97 (1H, m, H-4 ), 3.90 (2H, m,
;4
0
H-5 a, H-5 b) 1.52 (3H, s, CH ), 1.22 (3H, s, CH ),
3
3
The protected selenocytidine 20 (100 mg, 0.20 mmol)
was dissolved in methanolic ammonia (saturated at
0.81 (9H, s, SiC(CH ) ), 0.03 (3H, s, SiCH ), 0.00
3 3 3
1
3
(3H, s, SiCH3); C NMR (125 MHz, CDCl ): d 162.3,
3
0
°C, 7 mL) and the reaction mixture was kept overnight
143.0, and 122.2 (C-4, C-5, and C-6), 152.6 (C-2),
0 0
148.9 (C-8), 112.2 (C(CH ) ), 92.3 (C-2 ) 86.2 (C-3 ),
3 2
at room temperature. The solvent was removed under
vacuum, the residue was dissolved in 60% AcOH
0
0
0
65.5 (C-5 ), 60.0 (C-1 ), 51.2 (C-4 ), 27.6 and 25.9
(
10 mL), and the reaction mixture was heated under re-
(2 ꢂ CH ), 25.2 (SiC(CH ) ), 18.5 (SiC(CH ) ), ꢀ5.2
3
3 3
3 3
flux for 1 h. The mixture was cooled and concentrated
by rotary evaporation under high vacuum. Water
and ꢀ5.3 (2 ꢂ SiCH ); FAB HRMS (MNBA) calcd
3
+
for C H ClN O SeSi, 505.0939 [M+H] ; found,
1
9
29
4
3
(
3 mL) was added and removed under reduced pressure
505.0940.
to remove the remaining HOAc. The crude product was
purified by silica gel column chromatography (CH Cl /
0
4.14. 7-(4 -Seleno-b-D-ribofuranosyl) adenine (23)
2
2
MeOH, 10:1) to give 21 as a colorless solid (40 mg, 65%,
2
D
0
over 2 steps). Mp 151–154 °C; ½aꢃ ꢀ155.5 (c 0.5, H O);
The protected selenonucleoside 22 (0.10 g, 0.2 mmol)
was dissolved in 50% aq trifluoroacetic acid and the
reaction mixture was stirred at room temperature for
1 h. The mixture was concentrated by rotary evapora-
tion under vacuum, water (1 mL) was added, and the
last traces of TFAA were removed. The crude product
was dissolved in ethanolic ammonia (5 mL) and heated
for 24 h at 100 °C in a steel container. The solvent was
removed in vacuo, and the residue was purified by silica
2
1
H NMR (500 MHz, D O): d 8.14 (1H, d, J = 8.0 Hz,
2
0
H-6), 6.28 (1H, d, J1
0
0
¼ 7:0 Hz, H-1 ), 5.79 (1H, d,
;2
0
J = 8.0 Hz, H-5), 4.33 (1H, dd, J2
0
0
¼ 3:5 Hz, H-2 ),
;3
0
4
.22 (1H, dd, J3
0
0
¼ 3:0 Hz, H-3 ), 3.90 (1H, dd,
;4
0
J4
J4
0
0
¼ 6:5; J
0 0
¼ 12:0 Hz, H-5 a), 3.80 (1H, dd,
;5 a
5 a;5 b
0
0
13
0
0
¼ 6:0 Hz, H-5 b), 3.59 (1H, ddd, H-4 );
C
;5 b
NMR (125 MHz, D O): d 166.1 (C@O), 157.7 (C@O),
2
0 0
43.3 (C-6), 95.4 (C-5), 79.1 (C-2 ), 75.1 (C-3 ), 63.9
1
(
0
0
0
C-5 ), 57.7 (C-1 ), 47.8 (C-4 ); FAB HRMS (MNBA)
calcd for C H N O Se, 308.0150 [M+H] ; found,
gel chromatography to give 23 as a colorless solid
+
20
D
(48 mg, 72% over two steps). Mp 185 °C (dec) ½aꢃ
9
13
3
4
1
3
08.0159.
+42.2 (c 0.9, H O); H NMR (500 MHz, D O): d 8.62
2
2
(
1H, s, H-8), 8.11 (1H, s, H-2), 6.04 (1H, d, J
0
0
¼
1
;2
0
0
0
0
0
4
.13. 6-Chloro-7-(5 -O-t-Butyldimethylsilyl-2 ,3 -di-O-
0
7:5 Hz, H-1 ), 4.53 (1H, dd, J
(1H, dd, J3
J4
J4
0
0
¼ 3:0 Hz, H-2 ), 4.32
2
;3
0
isopropylidene-4 -seleno-b-D-ribofuranosyl)-9H-purine
0
0
¼ 2:3 Hz, H-3 ), 3.98 (1H, dd,
;4
0
(
22)
0
0
¼ 7:0; J
0 0
¼ 12:0 Hz, H-5 a), 3.79 (1H, dd,
;5 a
5 a;5 b
0
0
13
0
0
¼ 7:0 Hz, H-5 b), 3.61 (1H, ddd, H-4 );
C
;5 b
6
-Chloropurine (0.88 g, 5.67 mmol) in acetonitrile
NMR (125 MHz, D O): d 158.2, 154.6, and 148.2
2
(
10 mL) was heated at reflux with hexamethyldisilazane
(C-4, C-5, and C-6), 154.4 (C-2), 152.1 (C-8), 80.3

K. Jayakanthan et al. / Carbohydrate Research 343 (2008) 1790–1800
1799
0
0
0
0
0
(
C-2 ), 74.8 (C-3 ), 63.2 (C-5 ), 57.4 (C-1 ), 48.8 (C-4 );
Supplementary data
FAB HRMS (MNBA) calcd for C H N O Se,
1
0
13
5
3
+
1
13
H and C NMR spectra of compounds 14 and 16–25.
3
32.0262 [M+H] ; found, 332.0263.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
0
4
(
.15. 6-Acetyl-9-(4 -seleno-b-D-ribofuranosyl)-9H-purine
24)
2008.02.014.
The protected selenonucleoside 22 (0.50 g, 1.0 mmol)
was heated at reflux in 60% aqueous HOAc (15 mL)
for 4 h. The mixture was cooled and concentrated by
rotary evaporation under high vacuum. Water (5 mL)
was added and removed under reduced pressure to
remove the last of the HOAc. The crude product was
purified by silica gel column chromatography
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14
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. H o¨ bartner, C.; Micura, R. J. Am. Chem. Soc. 2004, 126,
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1
141–1149.
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1
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2
2
(
J
2
J4
1H, s, H-8), 8.01 (1H, s, H-2), 6.22 (1H, d,
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;2
2 ;3
0
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3. Bellon, L.; Leydier, C.; Barascut, J. L.; Imbach, J. L.
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