Highly β-stereoselective nucleosidation from α-D-xylo- and α-D-ribo-furanose 1,2-thiocarbonates

Article abstract of DOI:10.1016/j.tetasy.2003.12.037

Cyclic 1,2-thiocarbonates of α-D-xylo- and α-D-ribo-furanoses were found to be excellent glycosyl donors in mild NIS-mediated nucleophilic substitution reactions, affording β-nucleosides with complete stereoselectivity and moderate to high yields after treatment with persilylated pyrimidinic bases. The nucleophile is believed to open the thiocarbonate ring at the anomeric position presumably via an S_N2 mechanism. Participation of the nucleobase silylating agent [N,O-bis(trimethylsilyl) acetamide] in the mechanism of the nucleosidation step was shown, where a large excess of it has been proven to be necessary in order to achieve high yields. Absolute configurations at C-1′ were ascertained by chemical correlation synthesizing the corresponding 2,2′-anhydro-nucleosides.

Full text of DOI:10.1016/j.tetasy.2003.12.037

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 831–838
Highly b-stereoselective nucleosidation from a- -xylo- and
D
a- -ribo-furanose 1,2-thiocarbonates
D
*
ꢀ
Rafael Robles, Concepcion Rodrıguez, Luis Alvarez de Cienfuegos and Antonio J. Mota
ꢀ
ꢀ
Departamento de Quꢀımica Orgꢀanica, Facultad de Ciencias, Universidad de Granada. Campus de Fuentenueva s/n,
18071 Granada, Spain
Received 3 December 2003; accepted 17 December 2003
Abstract—Cyclic 1,2-thiocarbonates of a-
D
-xylo- and a-D-ribo-furanoses were found to be excellent glycosyl donors in mild NIS-
mediated nucleophilic substitution reactions, affording b-nucleosides with complete stereoselectivity and moderate to high yields
after treatment with persilylated pyrimidinic bases. The nucleophile is believed to open the thiocarbonate ring at the anomeric
position presumably via an SN2 mechanism. Participation of the nucleobase silylating agent [N,O-bis(trimethylsilyl)acetamide] in the
mechanism of the nucleosidation step was shown, where a large excess of it has been proven to be necessary in order to achieve high
yields. Absolute configurations at C-10 were ascertained by chemical correlation synthesizing the corresponding 2,20-anhydro-
nucleosides.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and 2b as starting materials. The nucleobases employed
in each case were thymine, uracil and 5-fluorouracil,
which were used as their persilylated derivatives.
Cyclic 1,2-thiocarbonate sugars have been reported as
substrates in nucleophilic substitution reactions owing
to their properties: they are stable compounds, easily
prepared and handled, and susceptible to regioselective
nucleophilic openings under mild conditions. For
instance, they have been employed as glycosyl donors in
glycosidation reactions using a sulfur methylating agent
as a promoter.1 In the same manner, vic-diol cyclic
thiocarbonates gave very good yields and regioselectiv-
ities in nucleophilic reactions using different nitrogen,2
oxygen2a and sulfur nucleophiles.2a
2. Results and discussion
After the satisfactory results in the reaction of 1,2-
thiocarbonates 1a and 2a with sodium azide to afford
the corresponding glycosyl azides,4 it was envisioned
to carry out nucleosidation reactions under similar
conditions. Experiments conducted using thymine/NaH
or thymine/DBU in dimethylformamide afforded the
expected products in less than 10% yield. Also, the use
of persilylated thymine led to unsuccessful results owing
to their moderate nucleophilic character. Finally, the
reaction was performed with persilylated nucleobases
using NIS as promoter, which acts by oxidizing the
sulfur atom. A similar procedure has been reported for
the nucleosidation of phenylthio glycosides by means of
NBS.6
On the other hand, cyclic 1,2-sulfite sugars latter have
also been used as glycosyl donors in nucleoside synthesis
using persilylated pyrimidinic bases with good yields
and, in some cases, good stereoselectivities.3 We have
also previously reported the use of cyclic 1,2-thiocar-
bonate sugars as excellent starting materials for the
synthesis of glycosyl azides and nucleosides,4 the latter
being an NIS-mediated process. We now report an
extensive study on nucleoside synthesis using 3,5-di-
O-benzyl-1a1;4 and 3,5-di-O-benzoyl-a-
D-xylo-furanose
Early experiments, where dichloromethane was chosen
as the solvent, showed low yields, complex reaction
mixtures and longer reaction times than expected. In
addition, the reaction between 1b and persilylated thy-
mine afforded a minor fraction considered as the
1,2-thiocarbonates 1b5 as well as the ribo analogues 2a
1
a-nucleoside, as evidenced from H NMR data. This
fact could be explained based on neighbouring group
* Corresponding author. Tel.: +34-958-243846; fax: +34-958-243845;
e-mail: rrobles@ugr.es
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.037

832
R. Robles et al. / Tetrahedron: Asymmetry 15 (2004) 831–838
Ph
Ph
+
+
O
O
BzO
BzO
O
H
O
H
O
O
NIS
Nu:
O
1b
α-Nucleoside
CH2Cl2
O
I
O
O
S
S
I
Scheme 1. Possible mechanism for the obtention of the a-anomer in the nucleosidation essays in dichloromethane.
participation that cannot take place in the other deriv-
atives (Scheme 1).
demonstrated to be absolutely necessary in order to
obtain high yields in the nucleosidation products
(Scheme 2).4
On changing to acetonitrile as the solvent, yields were
improved up to 90% and the reaction times were
shortened to 10 min along with a complete consumption
of the starting material. Furthermore, only the b-ano-
mer was achieved independent of the sugar configura-
tion (xylo or ribo). This fact suggests a possible SN2
mechanism takes place on these compounds as sug-
gested by Mukaiyama.1a A participation of the silylating
agent was found in the reaction [persilylated nucleobases
was previously obtained using a large excess of N,O-
bis(trimethylsilyl)acetamide], performing the final step
of the nucleosidation process. This excess has been
In the case of 1b, a side reaction leads to the corre-
sponding 20-O deprotected compounds 5bT,7 5bU7 and
5bF8 to a considerable extent. It can be seen that better
results were afforded for thymine, when benzyl was the
sugar protecting group (compounds 3aT4 and 4aT), and
for uracil when benzoyl was (compounds 3bU+5bU and
4bU). Yields obtained are summarized in Table 1.
In order to remove the protecting group at C-20, the
obtained nucleosides can be treated under acidic
(CF3CO2H/H2O/dioxane) or basic (DABCO/dioxane or
+
B:
R3
R3
R3
B
R1
R2
R1
R2
R1
R2
O
O
O
NIS
CH3CN
O
I
O
O
O
I
O
O
S
S
S
1a R1 = R3 = OBn, R2 = H
1b R1 = R3 = OBz, R2 = H
2a R2 = R3 = OBn, R1 = H
2b R2 = R3 = OBz, R1 = H
1b
O
N
O
R
R
NH
NH
O
O
N
R3
BzO
R1
R2
OBz
O
O
O
O
S
H
OH
N
H
O
3aT R1 = R3 = OBn, R2 = H, R = Me
3aU R1 = R3 = OBn, R2 = H, R = H
3aF R1 = R3 = OBn, R2 = H, R = F
3bT R1 = R3 = OBz, R2 = H, R = Me
3bU R1 = R3 = OBz, R2 = H, R = H
3bF R1 = R3 = OBz, R2 = H, R = F
4aT R2 = R3 = OBn, R1 = H, R = Me
4aU R2 = R3 = OBn, R1 = H, R = H
4aF R2 = R3 = OBn, R1 = H, R = F
4bT R2 = R3 = OBz, R1 = H, R = Me
4bU R2 = R3 = OBz, R1 = H, R = H
4bF R2 = R3 = OBz, R1 = H, R = F
5bT R = Me
5bU R = H
5bF R = F
Scheme 2. Nucleosides afforded from thiocarbonates 1a, 1b, 2a and 2b.

R. Robles et al. / Tetrahedron: Asymmetry 15 (2004) 831–838
Table 1. Yields achieved in the nucleosidation process
833
Starting thiocarbonate
Persilylated nucleobase
Nucleosidea (yield %)
20-O deprotection (yield %)
xylo
1a
1b
Thymine
Uracil
5-Fluorouracil
3aT (90)
3aU (76)
3aF (71)
––
––
––
Thymine
Uracil
5-Fluorouracil
3bT (61)
3bU (65)
3bF (51)
5bT (32)
5bU (33)
5bF (22)
ribo
2a
2b
Thymine
Uracil
5-Fluorouracil
4aT (90)
4aU (74)
4aF (83)
––
––
––
Thymine
Uracil
5-Fluorouracil
4bT (60)
4bU (92)
4bF (68)
––
––
––
a Nemotecnic rules for numbering: (1) odd numbers: xylo sugars; even numbers: ribo sugars. (2) letter a: benzyl as O protecting group; letter b:
benzoyl. (3) T: Thymine; U: Uracil; F: 5-fluorouracil.
O
N
O
R
R
NH
NH
O
O
N
Acid or base
R3
R3
R1
R1
O
O
O
R2
R2
O
S
OH
N
H
O
3aT R1 = R3 = OBn, R2 = H, R = Me
3aU R1 = R3 = OBn, R2 = H, R = H
3aF R1 = R3 = OBn, R2 = H, R = F
3bT R1 = R3 = OBz, R2 = H, R = Me
3bU R1 = R3 = OBz, R2 = H, R = H
3bF R1 = R3 = OBz, R2 = H, R = F
4aT R2 = R3 = OBn, R1 = H, R = Me
4aU R2 = R3 = OBn, R1 = H, R = H
4aF R2 = R3 = OBn, R1 = H, R = F
4bT R2 = R3 = OBz, R1 = H, R = Me
4bU R2 = R3 = OBz, R1 = H, R = H
4bF R2 = R3 = OBz, R1 = H, R = F
5aT R1 = R3 = OBn, R2 = H, R = Me
5aU R1 = R3 = OBn, R2 = H, R = H
5aF R1 = R3 = OBn, R2 = H, R = F
5bT R1 = R3 = OBz, R2 = H, R = Me
5bU R1 = R3 = OBz, R2 = H, R = H
5bF R1 = R3 = OBz, R2 = H, R = F
6aT R2 = R3 = OBn, R1 = H, R = Me
6aU R2 = R3 = OBn, R1 = H, R = H
6aF R2 = R3 = OBn, R1 = H, R = F
Scheme 3. 20-O deprotection by means of acidic or basic conditions.
tion of the benzoyl protecting group affording insepa-
rable mixtures or full deprotection. Yields and
experimental conditions are reported on Table 2.
Table 2. Yields afforded in the deprotection reaction
Starting nucleoside 20-O
deprotection
(yield %)
Experimental
conditionsa
Even though some of these nucleosides have been pre-
viously reported, they were poorly characterized. Hence,
in order to demonstrate unequivocally the b-configura-
tion at the anomeric position, compounds 5aT,9 5bU
and 6aT10 were first treated with MsCl in pyridine
obtaining the corresponding 20-O-mesylated derivatives
7aT,11 7bU and 8aT. Then, basic conditions (DBU/
acetonitrile) initiated the expected intramolecular dis-
xylo
3aT
3aU
3aF
3bT
3bU
3bF
5aT (90)
5aU (88)
5aF (85)
5bT (86)
5bU (85)
5bF (90)
KOH/water
KOH/water
KOH/water
CF3CO2H/water/dioxane
DABCO/dioxane
DABCO/dioxane
ribo
4aT
4aU
4aF
6aT (93)
6aU (87)
6aF (90)
KOH/water
KOH/water
KOH/water
placement that led to the already described 2,20-anhydro-
nucleosides 9aT,4;12 9bU
and 10aT14 (Scheme 4).
12b;13
a See experimental for a detailed description.
In addition, compound 4bU was treated with KOH/
water in order to obtain the well known nucleoside
uridine 11 (Scheme 1). With the 1H NMR spectra, these
results demonstrate unequivocally the b-configuration
KOH/water) conditions to yield the corresponding
deprotected compounds (Scheme 3). Compounds 4bT,
4bU and 4bF suffered either partial 30-O fi 20-O migra-

834
R. Robles et al. / Tetrahedron: Asymmetry 15 (2004) 831–838
O
N
O
N
O
N
R
R
R
NH
NH
NH
O
O
R3
R3
R3
R1
R1
R1
O
O
O
O
MsCl
DBU
CH3CN
Py
R2 OH
R2 OMs
R2
R1 = R3 = OBn, R2 = H, R = Me
R1 = R3 = OBn, R2 = H, R = Me
R1 = R3 = OBz, R2 = H, R = H
R2 = R3 = OBn, R1 = H, R = Me
5aT
7aT
7bU
8aT
9aT
9bU
10aT
5bU R1 = R3 = OBz, R2 = H, R = H
6aT
R2 = R3 = OBn, R1 = H, R = Me
O
O
NH
NH
O
O
N
N
BzO
HO
KOH (1N in water)
50 ˚C
O
O
O
BzO
OH
OH
O
S
N
H
O
4bU
11
Scheme 4. Chemical correlation in order to ascertain the C-10 configuration.
Table 3. Yields afforded in the chemical correlation steps
rotations were performed in dichloromethane and con-
centrations were 1 g/100 mL (c 1), unless otherwise was
indicated, and measured on JASCO DIP-370 and Perkin
Elmer 141 polarimeters. IR spectra were recorded on
Perkin Elmer 782 and Mattson Satellite FTIR spec-
Starting nucleoside Mesylation Anhydriza- Full deprotec-
(yield %) tion (yield %) tion (yield %)
xylo
ribo
5aT
5bU
7aT (90)
7bU (85)
9aT (85)
9bU (85)
––
––
€
trometers. NMR spectra were obtained from Bruker
6aT
4bU
8aT (86)
––
10aT (85)
––
––
11 (89)
AM-300, AMX-300 and ARX-400 for solutions in
CDCl3 (Me4Si as internal reference) unless otherwise
was indicated. High-resolution mass spectra were mea-
sured on Fisons Mod. Platform II and VG Autospec-Q
spectrometers. Column chromatography was performed
on silica gel (Merck 7734) and thin layer chromatogra-
phy (TLC) on precoated silica gel 60 F254 aluminium
sheets. Usual workup means that the organic layer was
dried over magnesium sulfate, filtered and evaporated
under vacuum.
of all the afforded nucleosides. Yields are summarized in
Table 3.
3. Conclusions
In summary, we have reported a new method to prepare
nucleosides from 1,2-thiocarbonate sugars. Thus, cyclic
1,2-thiocarbonates from a-
D
-xylo-and a-D-ribo-fura-
4.1. General procedure for the synthesis of a- -ribo-
D
noses have been treated with different persilylated pyr-
imidinic bases along with NIS acting as promoter.
Solvent election has been shown to be crucial since the
reaction does not go in CH2Cl2 but it works very well in
CH3CN. Yields go from moderate to high, and reactions
were performed under very mild conditions to achieve
the expected nucleosides with complete b-stereoselec-
tivity. This fact was ascertained by chemical correlation.
It is expected that this new method of nucleosidation
could be applied on other different systems in order to
obtain a wide range of new products.
furanose 1,2-thiocarbonates 2a and 2b
1,10-thiocarbonyl-diimidazole (196 mg, 1.1 mmol) was
added to solutions of both the ribo-furanose 1,2-diol
derivatives 1a and 1b (1 mmol) in dry CH2Cl2 (5 mL),
stirring for 30 min at room temperature. Mixtures were
diluted with CH2Cl2 (25 mL), washed with aq 10% HCl,
water and brine. After usual workup, the residues were
chromatographed using mixtures of ether–hexane to
afford the corresponding 1,2-thiocarbonates 2a and 2b.
4.1.1. 3,5-Di-O-benzyl-1,2-O-thiocarbonyl-a- -ribo-fura-
D
23
D
4. Experimental
nose 2a. 279 mg (75%); mp 75–76 ꢁC; ½aꢀ ¼ þ200; mmax
(KBr) 1290 cmꢁ1
;
1H NMR (300 MHz) d 7.39–7.24
Melting points were determined with a Gallenkamp
Melting Point apparatus and were uncorrected. Optical
(10H, m), 6.25 (1H, d, J ¼ 4:8 Hz), 5.04 (1H, t,
J ¼ 4:6 Hz), 4.72, 4.54 (2H, 2d, J ¼ 11:7 Hz), 4.52, 4.47

R. Robles et al. / Tetrahedron: Asymmetry 15 (2004) 831–838
835
(2H, 2d, J ¼ 12:0 Hz), 4.15–4.07 (2H, m), 3.79 (1H, dd,
J ¼ 1:6, 11.4 Hz), 3.61 (1H, dd, J ¼ 2:9 Hz); 13C NMR
(75 MHz) d 190.5, 137.5, 136.6, 128.7, 128.6, 128.5,
128.3, 128.1, 127.9, 107.2, 81.7, 79.8, 75.9, 73.6, 73.0,
66.7; HRMS (LSIMS) 395.09289 [M+Na]þ, calcd for
C20H20O5SNa: 395.0929 (dev. 0.1 ppm).
128.5, 110.5, 93.1, 80.6, 80.0, 76.9, 61.7, 12.5; HRMS
(LSIMS) 489.12765 [M+Na]þ, calcd for C24H22N2O8Na:
489.12738 (dev.)0.6 ppm).
4.2.3. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-ben-
zoyl-b- -xylo-furanosyl)uracil 3bU. 370 mg (65%); mp
D
23
140–141 ꢁC; ½aꢀ ¼ þ147; mmax (KBr) 1722, 1694 cmꢁ1
;
D
4.1.2. 3,5-Di-O-benzoyl-1,2-O-thiocarbonyl-a-
D
23
D
-ribo-fura-
1H NMR (400 MHz, acetone-d6) d 10.13 (1H, s), 8.79
(1H, s), 8.06–8.03, 7.97–7.92, 7.67–7.60, 7.52–7.45 (10H,
4m), 7.93 (1H, d, J ¼ 8:2 Hz), 6.14 (1H, d, J ¼ 2:3 Hz),
5.88 (1H, br d), 5.80 (1H, br s), 5.66 (1H, dd,
J ¼ 2:0 Hz), 4.97 (1H, dt, J ¼ 3:8, 5.5 Hz), 4.80 (2H, d),
2.11 (3H, s); 13C NMR (100 MHz, acetone-d6) d 171.2,
170.0, 166.3, 165.4, 163.4, 151.1, 140.5, 134.6, 134.1,
130.6, 130.5, 130.3, 129.8, 129.5, 129.4, 103.0, 89.4, 83.1,
79.9, 75.9, 62.5, 22.8; HRMS (LSIMS) 592.10057
[M+Na]þ, calcd for C26H23N3O10SNa: 592.10018 (dev.
)0.7 ppm).
nose 2b. 300 mg (75%); mp 111–112 ꢁC; ½aꢀ ¼ þ170;
mmax (KBr) 1725, 1269 cmꢁ1
;
1H NMR (300 MHz) d
8.15–7.98, 7.64–7.52, 7.48–7.37 (10H, 3m), 6.43 (1H, d,
J ¼ 4:7 Hz), 5.59 (1H, t, J ¼ 5:1 Hz), 5.24 (1H, dd,
J ¼ 9:0 Hz), 4.78 (1H, dd, J ¼ 3:0, 12.2 Hz), 4.65–4.59
(1H, m), 4.55 (1H, dd, J ¼ 4:8 Hz); 13C NMR
(100 MHz) d 189.7, 165.9, 165.5, 134.2, 133.6, 130.2,
129.8, 129.2, 128.7, 128.6, 128.0, 106.6, 80.9, 77.0, 71.8,
61.7; HRMS (LSIMS) 423.05194 [M+Na]þ, calcd for
C20H16O7SNa: 423.05144 (dev. )1.2 ppm).
4.2. General procedure for the nucleosidation process
4.2.4. 1-(30,50-Di-O-benzoyl-b-
-xylo-furanosyl)uracil
23
D
5bU.7 149 mg (33%); mp 69–70 ꢁC; ½aꢀ ¼ þ56; mmax
D
1
N,O-Bis(trimethylsilyl)acetamide (1.5 mL, 6 mmol) was
added to a stirred suspension of the corresponding pir-
imidine (thymine, uracil, or 5-fluorouracil, 2 mmol) in
CH3CN (15 mL). Once the pirimidine was dissolved
(15 min), compounds 1a, 1b or 2a, 2b (1 mmol) and NIS
(450 mg, 2 mmol) were added. The solution was stirred
at room temperature until the starting material disap-
peared (10 min). The crude was evaporated, the residue
was dissolved in CH2Cl2 (25 mL), and the solution was
successively washed with NaHCO3 saturated aqueous
solution, water, 10% Na2S2O3 solution, and water. After
usual workup, the residue was purified by column
chromatography (CH2Cl2–MeOH 25:1) to achieve 3a,b
(T,U,F)–4a,b (T,U,F) and 5b (T,U,F). For a complete
description of compounds 3aT, 3aU and 3aF see Ref. 4.
(KBr) 3232, 1711 cmꢁ1; H NMR (300 MHz) d 10.43
(1H, s), 7.96, 7.86, 7.58, 7.41 (10H, 4m), 7.93 (1H, d,
J ¼ 8:3 Hz), 5.87 (1H, s), 5.72 (1H, d), 5.64 (1H, d,
J ¼ 3:2 Hz), 5.02 (1H, q), 4.86 (1H, dd, J ¼ 6:5,
12.3 Hz), 4.73 (1H, dd, J ¼ 4:2 Hz), 4.56 (1H, s); 13C
NMR (75 MHz) d 166.2, 165.1, 163.9, 151.0, 139.9,
134.0, 133.4, 129.8, 129.7, 129.3, 128.7, 128.5, 128.4,
101.9, 93.2, 80.9, 79.9, 77.0, 61.7; HRMS (LSIMS)
475.11195 [M+Na]þ, calcd for C23H20N2O8Na:
475.11173 (dev. )0.5 ppm).
4.2.5. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-ben-
zoyl-b-
D
-xylo-furanosyl)-5-fluorouracil
3bF.
300 mg
23
D
(51%); mp 154–155 ꢁC; ½aꢀ ¼ þ156; mmax (KBr) 1721,
1694 cmꢁ1
;
1H NMR (400 MHz, acetone-d6) d 10.58
(1H, s), 8.80 (1H, s), 8.08 (1H, d, J ¼ 6:7 Hz), 8.03 (2H,
d, J ¼ 7:4 Hz), 7.95 (2H, d, J ¼ 7:4 Hz), 7.64, 7.60 (2H,
d, J ¼ 7:4 Hz), 7.46, 7.44 (4H, 2t), 6.14 (1H, s), 5.86 (1H,
d, J ¼ 3:5 Hz), 5.82 (1H, s), 4.96–4.93 (1H, m), 4.87 (1H,
dd, J ¼ 6:0, 12.0 Hz), 4.81 (1H, dd, J ¼ 4:6 Hz), 2.09
(3H, s); 13C NMR (100 MHz, acetone-d6) d 171.3, 169.9,
166.4, 165.4, 157.5 (d, J ¼ 27:0 Hz), 149.6, 141.5 (d,
J ¼ 231:5 Hz), 134.6, 134.1, 130.6, 130.5, 130.2, 129.8,
129.5, 129.4, 124.8 (d, J ¼ 35:0 Hz) 89.4, 83.0, 80.1, 75.8,
62.5, 22.8; HRMS (LSIMS) 610.09146 [M+Na]þ, calcd
for C26H22N3O10FSNa: 610.09076 (dev. )1.1 ppm).
4.2.1.
1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-
D
benzoyl-b- -xylo-furanosyl)thymine 3bT. 355 mg (61%);
23
D
½aꢀ ¼ þ164; mmax (KBr) 1713, 1694 cmꢁ1
;
1H NMR
(400 MHz) d 10.25 (1H, s), 8.25 (1H, s), 7.97–7.91, 7.60–
7.51, 7.44–7.34 (10H, 3m), 7.42 (1H, s), 6.08 (1H, d,
J ¼ 2:2 Hz), 5.73 (1H, dd, J ¼ 1:2, 3.1 Hz), 5.48 (1H,
bs), 4.75–4.66 (3H, m), 2.14 (3H, s), 1.75 (3H, s); 13C
NMR (100 MHz)d 172.0, 169.7, 166.0, 164.5, 163.8,
150.9, 134.5, 134.2, 133.5, 129.8, 129.7, 129.1, 128.8,
128.5, 128.2, 111.8, 88.6, 82.7, 79.1, 74.8, 61.3, 23.0,
12.4; HRMS (LSIMS) 606.11619 [M+Na]þ, calcd for
C27H25N3O10SNa: 606.11583 (dev. )0.6 ppm).
4.2.6. 1-(30,50-Di-O-benzoyl-b-
-xylo-furanosyl)-5-fluoro-
23
D
uracil 5bF.8 103 mg (22%);½aꢀ ¼ þ96 (c 1, MeOH);
D
4.2.2. 1-(30,50-Di-O-benzoyl-b-
D
-xylo-furanosyl)thymine
mmax (KBr) 3429, 1711 cmꢁ1
;
1H NMR (300 MHz) d
23
D
5bT.7 149 mg (32%); mp 102–103 ꢁC; ½aꢀ ¼ þ52 (c 1,
10.29 (1H, s), 7.99 (1H, d, J ¼ 6:0 Hz), 7.97–7.79, 7.56–
7.50, 7.42–7.33 (10H, 3m), 7.93 (1H, d, J ¼ 8:3 Hz), 5.83
(1H, s), 5.59 (1H, d, J ¼ 3:2 Hz), 5.02 (1H, d,
J ¼ 3:5 Hz), 4.98–4.93 (1H, m), 4.87 (1H, dd, J ¼ 6:2,
12.2 Hz), 4.68 (1H, dd, J ¼ 4:1 Hz), 4.50 (1H, br s); 13C
NMR (75 MHz) d 166.3, 165.1, 157.1 (d, J ¼ 26:3 Hz),
149.3, 140.5 (d, J ¼ 236:7 Hz), 134.2, 133.5, 129.7, 129.6,
129.2, 129.0, 128.9, 128.6, 124.3 (d, J ¼ 34:9 Hz), 92.8,
MeOH); mmax (KBr) 3385, 1720, 1690 cmꢁ1; H NMR
1
(300 MHz) d 10.34 (1H, br s), 7.97, 7.86, 7.56, 7.38 (10H,
4m), 7.69 (1H, s), 5.87 (1H, s), 5.61 (1H, d, J ¼ 3:3 Hz),
5.56 (1H, br s), 5.02–4.97 (1H, m), 4.85 (1H, dd, J ¼ 6:2,
12.1 Hz), 4.69 (1H, dd, J ¼ 4:2 Hz), 4.50 (1H, s), 1.85
(3H, s); 13C NMR (80 MHz) d 166.3, 165.0, 164.4, 150.8,
135.6, 134.0, 133.4, 129.8, 129.6, 129.4, 128.8, 128.6,

836
R. Robles et al. / Tetrahedron: Asymmetry 15 (2004) 831–838
80.7, 80.0, 77.0, 61.6; HRMS (LSIMS) 493.10226
[M+Na]þ, calcd for C23H19N2O8FNa 493.10223 (dev.
+0.1 ppm).
[M+Na]þ, calcd for C27H25N3O10SNa: 606.11583 (dev.
)1.0 ppm).
4.2.11. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-
4.2.7. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-ben-
benzoyl-b- -ribo-furanosyl)uracil 4bU. 523 mg (92%);
D
23
D
23
mp 171–172 ꢁC; ½aꢀ ¼ ꢁ43; mmax (KBr) 1713,
zyl-b-
D
-ribo-furanosyl)thymine 4aT. 500 mg (90%); ½aꢀ
¼
D
1
1694 cmꢁ1; H NMR (300 MHz, acetone-d6) d 10.2 (1H,
þ67; mmax (KBr) 3238, 1692 cmꢁ1; 1H NMR (400 MHz) d
9.83 (1H, s), 7.88 (1H, s), 7.48 (1H, s), 7.34–7.19 (10H,
m), 6.10 (1H, d, J ¼ 4:3 Hz), 5.41 (1H, t, J ¼ 4:5 Hz),
4.70, 4.44 (2H, 2d, J ¼ 11:9 Hz), 4.51, 4.45 (2H, 2d,
J ¼ 11:7 Hz), 4.25–4.16 (2H, m), 3.79 (1H, d,
J ¼ 10:4 Hz), 3.49 (1H, d), 2.13 (3H, s), 1.51 (3H, s); 13C
NMR (100 MHz) d 171.8, 170.3, 164.1, 150.9, 137.2,
137.1, 135.6, 128.7, 128.6, 128.5, 128.2, 128.1, 127.7,
111.4, 87.3, 82.3, 78.0, 75.0, 73.6, 73.3, 68.6, 23.1, 12.1;
HRMS (LSIMS) 578.15630 [M+Na]þ, calcd for
C27H29N3O8SNa: 578.15730 (dev. +1.8 ppm).
s), 8.73 (1H, s), 8.09–7.99, 7.69–7.60, 7.56–7.46 (10H,
3m), 7.75 (1H, d, J ¼ 8:1 Hz), 6.08 (1H, d, J ¼ 3:4 Hz),
6.02–5.96 (2H, m), 5.59 (1H, d), 4.79–4.64 (3H, m), 2.04
(3H, s); 13C NMR (75 MHz, acetone-d6) d 170.4, 169.6,
165.7, 165.0, 162.6, 150.3, 141.4, 133.7, 133.3, 130.0,
129.9, 129.6, 129.1, 128.8, 128.6, 102.4, 90.0, 79.4, 76.5,
70.2, 63.3, 22.0; HRMS (LSMIS) 592.10064 [M+Na]þ,
calcd for C26H23N3O10SNa: 592.10018 (dev. )0.8 ppm).
4.2.12. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-
benzoyl-b- -ribo-furanosyl)-5-fluorouracil 4bF. 400 mg
D
23
D
(68%); mp 202–203 ꢁC; ½aꢀ ¼ ꢁ32; mmax (KBr)
4.2.8. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-ben-
1713 cmꢁ1
;
1H NMR (300 MHz, acetone-d6) d 10.68
23
zyl-b-
D
-ribo-furanosyl)uracil 4aU. 400 mg (74%); ½aꢀ ¼
D
(1H, s), 8.75 (1H, s), 8.08–8.06, 7.69–7.61, 7.56–7.45
(10H, 3m), 7.98 (1H, d, J ¼ 6:6 Hz), 6.11 (1H, d,
J ¼ 3:4 Hz), 6.00–5.91 (1H, m), 4.81–4.70 (3H, m), 2.04
(3H, s); 13C NMR (75 MHz, acetone-d6) d 170.4, 169.6,
165.7, 164.9, 156.7 (d, J ¼ 28:7 Hz), 149.0, 140.8 (d,
J ¼ 248:1 Hz), 133.7, 133.4, 130.0, 129.8, 129.6, 129.1,
128.8, 128.6, 125.2 (d, J ¼ 36:2 Hz), 89.4, 79.7, 76.5,
70.1, 63.3, 22.0; HRMS (LSIMS) 610.09071 [M+Na]þ,
calcd for C26H22N3O10FSNa: 610.09076 (dev.
+0.1 ppm).
þ92; mmax (KBr) 3215, 1692 cmꢁ1; 1H NMR (300 MHz) d
9.95 (1H, s), 7.92 (1H, s), 7.73 (1H, d, J ¼ 8:2 Hz), 7.38–
7.20 (10H, m), 6.07 (1H, d, J ¼ 3:8 Hz), 5.42 (1H, br s),
5.36 (1H, d), 4.70, 4.42 (2H, 2d, J ¼ 11:8 Hz), 4.43 (2H,
s), 4.22 (2H, br s), 3.80 (1H, d, J ¼ 10:6 Hz), 3.52 (1H,
d), 2.14 (3H, s); 13C NMR (75 MHz) d 171.8, 170.2,
163.6, 150.6, 140.0, 137.1, 137.0, 128.6, 128.5, 128.2,
128.2, 128.0, 127.9, 102.5, 87.6, 82.2, 77.7, 75.3, 73.6,
73.2, 68.3, 23.0; HRMS (LSIMS) 564.14125
[M+Na]þ, calcd for C26H27N3O8SNa: 564.14165 (dev.
+0.7 ppm).
4.3. General procedures in order to remove the 20-O-
acetamidomercaptocarbonyl group
4.2.9. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-ben-
zyl-b-
D
-ribo-furanosyl)-5-fluorouracil
4aF.
464 mg
1H
Method A: Nucleosides 3a(T,U,F)–4a(T,U,F) (0.5 mmol)
were added to an aqueous solution of KOH (1 N,
10 mL). The mixture was stirred and heated at 50 ꢁC
until consumption of the starting product was observed
(TLC, ether). The reaction mixture was diluted with
EtOH (25 mL) and neutralized with Amberlite IR 120.
The solvent was evaporated and the residue was purified
by column chromatography (CH2Cl2–MeOH 20:1) to
give nucleosides 5a(T,U,F)–6a (T,U,F).
23
(83%); ½aꢀ ¼ þ98; mmax (KBr) 3233, 1708 cmꢁ1
;
D
NMR (300 MHz)
d 9.90 (1H, s), 7.98 (1H, d,
J ¼ 6:2 Hz), 7.75 (1H, s), 7.38–7.24 (10H, m), 6.10 (1H,
d, J ¼ 3:5 Hz), 5.43 (1H, br s), 4.70, 4.43 (2H, 2d,
J ¼ 11:8 Hz), 4.52, 4.45 (2H, 2d, J ¼ 11:5 Hz), 4.23 (2H,
s), 3.80 (1H, d, J ¼ 10:8 Hz), 3.47 (d, 1H), 2.15 (3H, s);
13C NMR (100 MHz)
d 171.8, 170.3, 157.2 (d,
J ¼ 28:0 Hz), 149.4, 140.7 (d, J ¼ 252:0 Hz), 137.0,
136.6, 128.7, 128.6, 128.5, 128.3, 128.2, 128.1, 124.0 (d,
J ¼ 36:8 Hz), 87.5, 82.7, 77.7, 75.5, 73.8, 73.3, 68.1, 23.0;
HRMS (LSIMS) 582.13230 [M+Na]þ, calcd for
C26H26N3O8FSNa: 582.13223 (dev.)0.1 ppm).
Method B: Nucleosides 3bU and 3bF (0.5 mmol) were
deprotected with DABCO in dioxane under reflux. The
reaction mixture was finished after 12 h, the solvent was
removed, and the residue was partitioned into CH2Cl2–
H2O. The organic layer was successively washed with a
diluted solution of HCl and water. After usual workup,
the residue was purified by column chromatography
(CH2Cl2–MeOH 20:1) to afford the already described
pure 5bU (192 mg, 85%) and 5bF (212 mg, 90%).
4.2.10. 1-(20-O-Acetamidomercaptocarbonyl-30,50-di-O-
benzoyl-b- -ribo-furanosyl)thymine 4bT. 350 mg (60%);
D
23
D
½aꢀ ¼ ꢁ59; mmax (KBr) 3259, 1713, 1692 cmꢁ1; 1H NMR
(300 MHz) d 9.73 (1H, s), 8.04–8.02, 7.60–7.53, 7.48–
7.39 (10H, 3m), 7.74 (1H, s), 7.12 (1H, s), 6.14 (1H, d,
J ¼ 5:5 Hz), 5.78 (1H, dd, J ¼ 5:8, 3.9 Hz), 5.64 (1H, t),
4.81 (1H, dd, J ¼ 3:6, 13.2 Hz), 4.61–4.56 (2H, m), 2.06
(3H, s), 1.56 (3H, s); 13C NMR (75 MHz) d 171.6, 170.4,
166.1, 165.5, 163.8, 150.7, 135.0, 134.0, 133.8, 130.1,
129.7, 129.2, 128.9, 128.8, 128.4, 112.3, 87.8, 80.3, 76.3,
70.6, 63.5, 23.0, 12.2; HRMS (LSIMS) 606.11644
Method C: Nucleoside 3bT (122 mg, 0.21 mmol) was
treated with CF3CO2H (500 ll) in water–dioxane 2:1 (3
mL) at 60 ꢁC. After 12 h the mixture was neutralized
with a solution of NaHCO3. The solvent was evaporated
and the residue was partitioned into CH2Cl2–H2O. After
usual workup, the residue was chromatographed

R. Robles et al. / Tetrahedron: Asymmetry 15 (2004) 831–838
837
(CH2Cl2–MeOH 20:1) to afford the already described
nucleoside 5bT (84 mg, 86%).
4.3.5.
1-(30,50-Di-O-benzyl-b-
D
-ribo-furanosyl)uracil
23
D
6aU.15 184 mg (87%); mp 74–75 ꢁC; ½aꢀ ¼ þ30; mmax
(KBr) 3405, 3061, 1693 cmꢁ1; H NMR (300 MHz) d
1
9.65 (1H, s), 7.74 (1H, d, J ¼ 8:2 Hz), 7.39–7.22 (10H,
m), 5.94 (1H, d, J ¼ 4:1 Hz), 5.34 (1H, d), 4.69, 4.57
(2H, 2d, J ¼ 11:9 Hz), 4.47 (2H, s), 4.28–4.22 (2H, m),
4.08 (1H, t, J ¼ 5:0 Hz), 3.82 (1H, dd, J ¼ 2:4,
10.7 Hz), 3.76 (1H, br s), 3.56 (1H, dd, J ¼ 2:0 Hz);
13C NMR (75 MHz) d 163.5, 150.9, 140.3, 137.3,
137.1, 128.7, 128.4, 128.3, 128.1, 128.0, 127.9, 102.3,
90.1, 81.5, 76.7, 74.0, 73.7, 72.7, 69.1; HRMS
4.3.1. 1-(30,50-Di-O-benzyl-b-
-xylo-furanosyl)thymine
D
23
D
5aT.9 197 mg (90%); ½aꢀ ¼ ꢁ24; mmax (KBr) 3380, 3207,
1
1695 cmꢁ1; H NMR (300 MHz) d 10.58 (1H, s), 7.47
(1H, s), 7.40–7.30 (10H, m), 5.90 (1H, s), 5.48 (1H, br s),
4.68, 4.62 (2H, 2d, J ¼ 12:0 Hz), 4.69 (1H, m), 4.56, 4.47
(2H, 2d, J ¼ 11:3 Hz), 4.46 (1H, s), 4.06 (1H, d,
J ¼ 3:6 Hz), 3.93 (1H, dd, J ¼ 5:2, 10.9 Hz), 3.90 (1H,
dd, J ¼ 4:2 Hz), 1.68 (3H, s); 13C NMR (80 MHz) d
164.6, 151.2, 137.8, 137.1, 136.8, 128.5, 128.4, 128.0,
127.9, 127.8, 127.6, 109.8, 92.8, 82.5, 82.2, 78.3, 73.5,
72.0, 67.6, 12.3; HRMS (LSIMS) 461.16866 [M+Na]þ,
calcd for C24H26N2O6Na: 461.16885 (dev. +0.4 ppm).
(LSIMS)
C23H24N2O6Na: 447.15320 (dev. +1.4 ppm).
447.15260
[M+Na]þ,
calcd
for
4.3.6. 1-(30,50-Di-O-benzyl-b-
D
23
D
-ribo-furanosyl)-5-fluoro-
uracil 6aF. 200 mg (90%); ½aꢀ ¼ þ19; mmax (KBr) 3429,
1
3063, 1712 cmꢁ1; H NMR (300 MHz) d 9.97 (1H, s),
8.00 (1H, d, J ¼ 6:4 Hz), 7.38–7.24 (10H, m), 5.98 (1H,
dd, J ¼ 4:3, 1.3 Hz), 4.67, 4.57 (2H, 2d, J ¼ 11:8 Hz),
4.55, 4.47 (2H, 2d, J ¼ 11:6 Hz), 4.31–4.24 (2H, m), 4.09
(1H, t, J ¼ 4:9 Hz), 3.81 (1H, dd, J ¼ 2:3, 10.9 Hz), 3.50
(1H, dd, J ¼ 1:7 Hz); 13C NMR (75 MHz) d 157.1 (d,
J ¼ 28:2 Hz), 149.6, 140.6 (d, J ¼ 251:4 Hz), 137.1,
136.9, 128.8, 128.7, 128.6, 128.5, 128.3, 128.1, 124.5 (d,
J ¼ 37:0 Hz), 89.9, 81.7, 76.8, 74.1, 73.8, 72.7, 68.7;
HRMS (LSIMS) 465.14374 [M+Na]þ, calcd for
C23H23N2O6FNa 465.14378 (dev. +0.1 ppm).
4.3.2. 1-(30,50-Di-O-benzyl-b-
-xylo-furanosyl)uracil
23
D
5aU.3a 186 mg (88%); mp 80–81 ꢁC; ½aꢀ ¼ ꢁ4 (c 14,
D
1
CH2Cl2); mmax (KBr) 3573, 3177, 1694, 1682 cmꢁ1; H
NMR (300 MHz) d 10.74 (1H, s), 7.64 (1H, d,
J ¼ 8:1 Hz), 7.36-7.14 (10H, m), 5.85 (1H, s), 5.53 (1H,
d), 5.45 (1H, br s), 4.67 (1H, m), 4.64, 4.58 (2H, 2d,
J ¼ 12:1 Hz), 4.55, 4.44 (2H, 2d, J ¼ 11:5 Hz), 4.45 (1H,
s), 4.04 (1H, d, J ¼ 3:5 Hz), 3.87 (2H, d, J ¼ 5:7 Hz); 13C
NMR (75 MHz) d 164.3, 151.3, 141.0, 137.9, 137.2,
128.6, 128.5, 128.3, 128.2, 127.9, 127.8, 101.3, 93.2, 82.8,
82.0, 78.3, 73.6, 72.2, 67.7; HRMS (LSIMS) 447.15310
[M+Na]þ, calcd for C23H24N2O6Na: 447.15320 (dev.
+0.2 ppm).
4.4. Synthesis of the 20-O-mesyl derivatives 7aT,7bU and
8aT
Mesylation of 5aT, 5bU and 6aT (0.5 mmol) with mesyl
chloride (78 lL, 1 mmol) in dry pyridine (2 mL) was
worked up as usually. The crude was purified by column
chromatography (Cl2CH2–MeOH 25:1) to give 7aT,
7bU and 8aT, respectively.
4.3.3. 1-(30,50-Di-O-benzyl-b-
D
-xylo-furanosyl)-5-fluoro-
23
uracil 5aF. 188 mg (85%); mp 103–104 ꢁC; ½aꢀ ¼ ꢁ4 (c
D
6, CH2Cl2); mmax (KBr) 3417, 3184, 1713 cmꢁ1; 1H NMR
(300 MHz) d 10.70 (1H, s), 7.78 (1H, d, J ¼ 6:3 Hz),
7.36–7.17 (10H, m), 5.81 (1H, s), 5.04 (1H, br s), 4.64,
4.59 (2H, 2d, J ¼ 11:9 Hz), 4.61 (1H, m), 4.58, 4.50 (2H,
2d, J ¼ 11:6 Hz), 4.43 (1H, s), 4.05 (1H, d, J ¼ 3:6 Hz),
3.86 (2H, d, J ¼ 5:5 Hz); 13C NMR (75 MHz) d 157.6 (d,
J ¼ 26:0 Hz), 149.6, 140.0 (d, J ¼ 235:1 Hz), 137.6,
136.9, 128.6, 128.5, 128.2, 128.0, 127.9, 127.7, 125.5 (d,
J ¼ 35:0 Hz), 92.8, 82.8, 81.7, 78.4, 73.6, 72.3, 67.5;
HRMS (LSIMS) 465.14406 [M+Na]þ, calcd for
C23H23N2O6FNa 465.14378 (dev. )0.6 ppm).
4.4.1. 1-(30,50-Di-O-benzyl-20-O-mesyl-b-
D
-xylo-furano-
¼
23
D
syl)thymine 7aT.11 232 mg (90%); mp 127–128 ꢁC; ½aꢀ
þ8 (c 3.5, CH2Cl2); mmax (KBr) 3032, 1697 cmꢁ1
;
1H
NMR (300 MHz) d 9.39 (1H, br s), 7.38–7.20 (11H, m),
5.99 (1H, s), 5.06 (1H, s), 4.67, 4.61 (2H, 2d,
J ¼ 12:0 Hz), 4.64, 4.57 (2H, 2d, J ¼ 11:7 Hz), 4.54 (1H,
m), 4.26 (1H, d, J ¼ 3:3 Hz), 3.88 (2H, d, J ¼ 5:2,
5.7 Hz), 3.28 (3H, s), 1.74 (3H, s); 13C NMR (75 MHz) d
163.4, 150.7, 137.6, 136.5, 135.3, 128.7, 128.6, 128.5,
128.1, 128.0, 127.9, 110.6, 89.0, 84.1, 82.1, 80.5, 73.6,
72.6, 66.9, 38.8, 12.4; HRMS (LSIMS) 539.14676
[M+Na]þ, calcd for C25H28N2O8SNa 539.14640 (dev.
)0.7 ppm).
4.3.4. 1-(30,50-Di-O-benzyl-b-
-ribo-furanosyl)thymine
D
23
D
6aT.10 203 mg (93%); ½aꢀ ¼ þ8 (c 4, CH2Cl2); mmax
(KBr) 3405, 3188, 1693 cmꢁ1; H NMR (300 MHz) d
1
9.61 (1H, s), 7.50 (1H, s), 7.38–7.22 (10H, m), 5.98 (1H,
d, J ¼ 4:5 Hz), 4.72, 4.60 (2H, 2d, J ¼ 11:9 Hz), 4.54,
4.49 (2H, 2d, J ¼ 11:7 Hz), 4.30–4.26 (2H, m), 4.11 (1H,
t, J ¼ 4:9 Hz), 3.90 (1H, br s), 3.82 (1H, dd, J ¼ 2:4,
10.7 Hz), 3.55 (1H, dd, J ¼ 2:2 Hz), 1.54 (3H, s); 13C
NMR (75 MHz) d 163.3, 150.3, 136.6, 136.4, 135.1,
127.9, 127.8, 127.4, 127.1, 127.0, 126.9, 110.2, 88.9, 81.5,
76.9, 74.1, 73.6, 72.7, 68.5, 11.3; HRMS (LSIMS)
461.16822 [M+Na]þ, calcd for C24H26N2O6Na:
461.16885 (dev. +1.4 ppm).
4.4.2. 1-(30,50-Di-O-benzoyl-20-O-mesyl-b-
D
-xylo-furano-
23
D
syl)uracilo 7bU. 225 mg (85%); mp 63–64 ꢁC; ½aꢀ ¼ þ64
(c 1, acetone); mmax (KBr) 3196, 2967, 1723, 1692 cmꢁ1
;
1H NMR (300 MHz, acetone-d6) d 10.12 (1H, s),
8.04–7.95, 7.68–7.59, 7.50–7.44 (10H, 3m), 8.00 (1H, d),
6.16 (1H, d, J ¼ 1:7 Hz), 5.93 (1H, dd, J ¼ 1:4, 3.8 Hz),
5.65 (1H, d, J ¼ 8:2 Hz), 5.61 (1H, t), 5.02 (1H, dt), 4.88
(1H, dd, J ¼ 5:8, 12.1 Hz), 4.84 (1H, dd, J ¼ 5:2 Hz),

838
R. Robles et al. / Tetrahedron: Asymmetry 15 (2004) 831–838
3.38 (3H, s); 13C NMR (75 MHz, acetone-d6) d 165.6,
164.7, 162.7, 150.7, 139.6, 133.9, 133.4, 129.9, 129.8,
129.5, 128.9, 128.7, 128.6, 101.9, 89.6, 84.5, 79.7, 75.5,
61.7, 37.9; HRMS (LSIMS) 553.08989 [M+Na]þ, calcd
for C24H22N2O10SNa: 553.08928 (dev. )1.1 ppm).
Acknowledgements
We thank the Spanish Ministerio de Ciencia y Tecno-
ꢀ
logıa for the grant to L. Alvarez de Cienfuegos.
ꢀ
4.4.3. 1-(30,50-Di-O-benzyl-20-O-mesyl-b-
-ribo-furano-
D
23
D
syl)thymine 8aT. 222 mg (86%); ½aꢀ ¼ þ88; mmax (KBr)
References and notes
3063, 1693 cmꢁ1; H NMR (300 MHz) d 9.22 (1H, s),
1
7.65 (1H, s), 7.38–7.19 (10H, m), 6.02 (1H, d,
J ¼ 2:1 Hz), 5.22 (1H, t, J ¼ 2:2 Hz), 4.84, 4.46 (2H, 2d,
J ¼ 11:6 Hz), 4.50, 4.44 (2H, 2d, J ¼ 11:8 Hz), 4.27 (2H,
d), 3.94 (1H, d, J ¼ 11:0 Hz), 3.62 (1H, dd, J ¼ 2:2 Hz),
3.25 (3H, s), 1.45 (3H, s); 13C NMR (75 MHz) d 163.2,
150.0, 136.4, 136.2, 134.2, 128.7, 128.6, 128.4, 128.3,
128.3, 127.9, 110.5, 87.5, 81.3, 80.1, 73.8, 73.6, 73.0,
66.6, 38.4, 11.2; HRMS (LSIMS) 517.16393 [M+H]þ,
calcd for C25H29N2O8SNa: 517.16446 (dev. +1.0 ppm).
1. (a) Murakami, M.; Mukaiyama, T. Chem. Lett. 1983, 23,
1733–1736; (b) Patroni, J. J.; Stick, R. V.; Tilbrook, D. M.
G.; Skelton, B. W.; White, A. H. Aust. J. Chem. 1989, 42,
2127–2141.
2. (a) Ko, S. Y. J. Org. Chem. 1995, 60, 6250–6251; (b) He,
L.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2000, 65, 7627–
7633.
3. (a) Gagnieu, C. H.; Guiller, A.; Pacheco, H. Carbohydr.
Res. 1988, 180, 233–242; (b) Moon, H. R.; Kim, H. O.;
Chun, M. W.; Jeong, L. S. J. Org. Chem. 1999, 64, 4733–
4741.
ꢀ
ꢀ
4. Alvarez de Cienfuegos, L.; Rodrıguez, C.; Mota, A. J.;
Robles, R. Org. Lett. 2003, 5, 2743–2745.
4.5. Synthesis of the 2,20-anhydro-nucleosides 9aT,4;12
9bU,12b;13 10aT14
ꢀ
5. Robles, R.; Rodrıguez, C.; Izquierdo, I.; Plaza, M. T.
Carbohydr. Res. 1997, 300, 375–380.
DBU (34 lL, 0.23 mmol) was added to different solu-
tions of 7aT, 7bU and 8aT (0.2 mmol) in CH3CN (3 mL)
at room temperature. TLC (CH2Cl2–MeOH 25:1)
showed after 15 min the absence of the starting nucleo-
sides, and the presence of slower-running compounds
corresponding to the 2,20-anhydro derivatives. The
mixture was neutralized with acetic acid, concentrated
and purified by column chromatography (CH2Cl2–
MeOH 40:1) to give, respectively, the previously
reported compounds 9aT, 9bU and 10aT (85% in all
cases).
6. Sugimura, H.; Muramoto, I.; Nakamura, T.; Osumi,
K. Chem. Lett. 1993, 169–172.
7. Gosselin, G.; Bergogne, M. C.; Imbach, J. L. Nucleosides
and Nucleotides 1984, 3, 265–275.
8. Tolstikov, G. A.; Mustafin, A. G.; Gataullin, R. R.;
Spirikhin, L. V.; Sultanova, V. S.; Abdrakhmanov, I. B.
Izv. Akad. Nauk, Ser. Khim. 1993, 6, 1137–1141.
9. Benhaddou, R.; Czernecki, S.; Valery, J. M.; Bellosta,
V. Bull. Soc. Chim. Fr. 1991 (Jan.–Feb.), 108–111.
10. Ning, J.; Kong, F. Bioorg. Med. Chem. Lett. 1997, 7,
2941–2944.
11. Gurjar, M. K.; Lalitha, S. V. S.; Sharma, P. A.; Rao,
A. V. R. Tetrahedron Lett. 1992, 33, 7945–7948.
12. (a) Hrebabecky, H. and Holy, A. Czech. Patent CZXXA9
CS 274511, 1992; Chem. Abstr. 1994, 120:8932; (b)
4.6. Conversion of 4bU in uridine 11
ꢀ
Robles, R.; Rodrıguez, C.; Izquierdo, I.; Plaza, M. T.;
Mota, A.; Alvarez de Cienfuegos, L. Tetrahedron: Asym-
ꢀ
4bU (285 mg, 0.5 mmol) were added to an aqueous
solution of KOH (1 N,10 mL). The mixture was stirred
and heated at 50 ꢁC until consumption of the starting
product was observed (TLC, ether). The reaction mix-
ture was diluted with EtOH (25 mL) and neutralized
with Amberlite IR 120. The solvent was evaporated and
the residue was crystallized in ethanol affording uridine
(11, 109 mg, 89%).
metry 2000, 11, 3069–3077.
13. Yung, N. C.; Fox, J. J. J. Am. Chem. Soc. 1961, 83, 3060–
3066.
14. Ikeda, H.; Fernandez, R.; Wilk, A.; Barchi, J. J., Jr.;
ꢀ
Huang, X.; Marquez, V. E. Nucleic Acid Res. 1998, 26,
ꢀ
2237–2244.
15. Baker, J.; Jarman, M.; Stock, J. A. J. Chem. Soc., Perkin.
Trans. 1 1973, 7, 665–669.