Synthesis and conformational analysis of 1-[2,4-dideoxy-4-C-hydroxymethyl- α-L-lyxopyranosyl]thymine

Article abstract of DOI:10.1021/jo040130g

Previously different types of nucleosides with a six-membered carbohydrate moiety have been evaluated for their potential antiviral and antibiotic properties and as building blocks in nucleic acid synthesis. However, a pyranose nucleoside with a 1,4-subst

Full text of DOI:10.1021/jo040130g

Syn th esis a n d Con for m a tion a l An a lysis of
1-[2,4-Did eoxy-4-C-h yd r oxym eth yl-r-L-lyxop yr a n osyl]th ym in e
Veerle Vanheusden,† Roger Busson,‡ Piet Herdewijn,‡ and Serge Van Calenbergh*,†
Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, 9000 Gent, Belgium,
and Laboratory for Medicinal Chemistry, Rega Institute, Catholic University of Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
serge.vancalenbergh@ugent.be
Received February 9, 2004
Previously different types of nucleosides with a six-membered carbohydrate moiety have been
evaluated for their potential antiviral and antibiotic properties and as building blocks in nucleic
acid synthesis. However, a pyranose nucleoside with a 1,4-substitution pattern like 1-[2,4-dideoxy-
4-C-hydroxymethyl-R-L-lyxopyranosyl]thymine (4) has not been studied yet. Modeling suggested
4
that this nucleoside would show the C1 conformation in contrast to anhydrohexitol nucleosides (1)
1
whose most stable conformation is C4. The key to the synthesis of 4 involves the stereoselective
introduction of the hydroxymethyl group onto the C-4 carbon of the pyranose sugar. Attempts to
achieve this via hydroboration/oxidation of a C-4′-exocyclic vinylic intermediate selectively yielded
the undesired R-directed hydroxymethyl group. Therefore, we envisaged another approach in which
the C-4 substituent was introduced upon treatment of 2,3-O-isopropylidene-1-O-methyl-4-O-
phenoxythiocarbonyl-R-L-lyxopyranose with â-tributylstannyl styrene. This allowed stereoselective
â-directed introduction of a 2-phenylethenyl group at C-4, which was converted via oxidation/
reduction (OsO4, NaIO4/NaBH4) into the desired 4-hydroxymethyl group (20). The resulting 1-O-
methyl-2,3,6-tri-O-acetyl-protected sugar was coupled with silylated thymine, using SnCl2 as Lewis
acid (22). After suitable protection, Barton deoxygenation of the 2′-hydroxyl function of the obtained
ribo-nucleoside yielded the desired 2′-deoxynucleoside 4, indeed showing the expected equatorial
orientation of the thymine ring (4C1).
In tr od u ction
Nucleosides with a six-membered carbohydrate moiety
have been evaluated for their potential antiviral1-4 and
antibiotic5 properties and as building blocks in nucleic
acid synthesis.6,7 Antiviral activity1-3 has been found in
the hexitol series (1) (Figure 1). These molecules are
characterized by the presence of an axial base moiety in
the most stable conformation.1 When evaluated as ligand
* To whom correspondence should be addressed. Tel: +32 (0)9 264
81 24. Fax: +32 (0)9 264 81 46.
† Ghent University.
‡ Catholic University of Leuven.
(1) Verheggen, I.; Van Aerschot, A.; Toppet, S.; Snoeck, R.; J anssen,
G.; Balzarini, J .; De Clercq, E.; Herdewijn, P. J . Med. Chem. 1993, 36,
2033-2040.
(2) Verheggen, I.; Van Aerschot, A.; Van Meervelt, L.; Rozenski, J .;
Wiebe, L.; Snoeck, R.; Andrei, G.; Balzarini, J .; Claes, P.; De Clercq,
E.; Herdewijn, P. J . Med. Chem. 1995, 38, 826-835.
(3) Ostrowski, T.; Wroblowski, B.; Busson, R.; Rozenski, J .; De
Clercq, E.; Bennet, M. S.; Champness, J . N.; Summers, W. C.;
Sanderson, M. R.; Herdewijn, P. J . Med. Chem. 1998, 41, 4343-4353.
(4) Maurinsh, Y.; Schraml, J .; De Winter, H.; Blaton, N.; Peeters,
O.; Lescrinier, E.; Rozenski, J .; Van Aerschot, A.; De Clercq, E.; Busson,
R.; Herdewijn, P. J . Org. Chem. 1997, 62, 2861-2871.
(5) Haouz, A.; Vanheusden, V.; Munier-Lehmann, H.; Froeyen, M.;
Herdewijn, P.; Van Calenbergh, S.; Delarue, M. J . Biol. Chem. 2003,
278, 4963-4971.
F IGURE 1. Structures of compounds 1-5.
for HSV-1 TK, it was observed that the hexitol nucleoside
cocrystallizes with the enzyme in a conformation with
an equatorial base moiety (which is a high energy
conformation).3 This conformation, however, is the most
stable one for the carbocyclic congener (2).4 When incor-
porated in oligonucleotides, it is suggested that the
carbocyclic nucleoside undergoes a chair flip and that it
adopts the same conformation as found in HNA.8 These
observations clearly show the possibility of conforma-
tional adaptation of 1,4-substituted (when considering the
(6) Vastmans, K.; Pochet, S.; Peys, A.; Kerremans, L.; Van Aerschot,
A.; Hendrix, C.; Marliere, P. Herdewijn P. Biochemistry 2000, 39,
12757-12765.
(7) Vastmans, K.; Froeyen, M.; Kerremans, L.; Pochet, S.; Herdewijn,
P. Nucleic Acids Res. 2001, 29, 3154-3163.
10.1021/jo040130g CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004
4446
J . Org. Chem. 2004, 69, 4446-4453

1,4-Substituted Pyranose Nucleoside
SCHEME 1. Syn th esis of 14a
a
Reagents: (a) CF3COOH, H2O; (b) (Ac)2O, pyridine; (c) 5-methyl-2,4-bis[(trimethylsilyl)oxy]pyrimidine, CH3CN, SnCl2; (d) NH3, MeOH;
(e) 2,2-dimethoxypropane, acetone, p-toluenesulfonic acid; (f) (i) 9-BBN-H, THF, (ii) H2O2, NaOH; (g) (PhO)2CO, NaHCO3, DMF; (h) HOAc,
H2O.
base moiety and the hydroxymethyl substituent) nucleo-
sides dependent on their “biological” environment.
â-Pyranose nucleosides (3) have a base moiety in the
1′-position and an hydroxymethyl group in the 5′-posi-
tion.9 Both substituents are equatorially oriented. This
conformation is very stable, no chair flip has been
observed, and oligonucleotides built up out of the pyra-
nose nucleosides show only a very small helical twist.10
No biological activity has been determined for this type
of natural-like nucleosides. A pyranose nucleoside with
F IGURE 2. Image of the steric hindrance caused by the 2′,3′-
a 1,4-substitution pattern (4) has not been studied yet
O-isopropylidene in the 1C4 and 4C1 conformation.
because of its difficult synthetic availability. Sugar-base
condensation reaction of its appropriate 2′-deoxy sugar
of 4-deoxy-2,3-O-isopropylidene-1-O-methyl-4-C-methyl-
precursor is expected to give rise to the thermodynami-
ene-â-D-erythro-pentopyranose (6) with borane in THF,
cally most stable R-nucleoside.11 Therefore the synthetic
followed by oxidation with H2O2, yielded mainly the
scheme should involve the introduction of the base moiety
undesired 4-R-hydroxymethyl sugar, probably caused by
using anchimeric assistance of a 2′-acetoxy group in order
steric hindrance of the 2,3-O-isopropylidene protective
to be able to isolate the â-nucleoside. Pyranose nucleoside
group during borane addition.
4 is a structural analogue of an anhydrohexitol nucleoside
(1) as crystallized with the active site of HSV-1 TK and
an analogue of a carbocyclic nucleoside (2) in its most
In other studies, we observed that preferential attack
of borane on an exo double bond is not always predictable
and may be governed by complexation of the reagent and
stable conformation, which motivates the synthesis and
steric effects.13 By carrying out the hydroboration/oxida-
biological evaluation of this new type of six-membered
tion of the 4-methylene function after sugar-base coup-
nucleoside analogue.
ling, we postulated that the presence of the thymine
4
moiety would favor a C1 conformation of the pyranose,
Resu lts a n d Discu ssion
which reduces the steric hindrance caused by the isopro-
pylidene protective group (Figure 2). We hoped this would
influence the stereochemical outcome of this reaction
toward the formation of the 4-â-hydroxymethyl compound
(5).
Ch em istr y. Two strategies toward the synthesis of 5,
the ribo-precursor of the target nucleoside, were already
attempted.12 Both reaction schemes are not useful for the
synthesis of significant amounts of the target molecule
because of low yields and very difficult separation
problems at different stages. In one of these attempts
Doboszewski and Herdewijn12 experienced that treatment
Synthesis was started from 4-deoxy-2,3-O-isopropyl-
idene-1-O-methyl-4-C-methylene-â-D-erythro-pentopyranose
(6), obtained in four steps from L-lyxose (Scheme 1).12
Because acid-catalyzed exchange of the 1-O-methyl
group of 6 with an 1-O-acetyl group is known to cause
partial ring opening,12 it was decided to maintain the
methyl protective group at the 1-O-position. The 2,3-O-
isopropylidene protective group of 6 was selectively
removed upon short treatment with CF3COOH,12 and the
2- and 3-hydroxyl groups were reprotected by acetylation.
(8) Maurinsh, Y.; Rosemeyer, H.; Esnouf, R.; Medvedovici, A.; Wang,
J .; Ceulemans, G.; Lescrinier, E.; Hendrix, C.; Busson, R.; Sandra, P.;
Seela, F.; Van Aerschot, A.; Herdewijn, P. Chem. Eur. J . 1999, 5, 2139-
2150.
(9) Yamazaki, T.; Matsuda, K.; Sugiyama, H.; Seto, S.; Yamaoka,
N. J . Chem. Soc., Perkin Trans. 1 1977, 14, 1654-1659.
(10) Lescrinier, E.; Froeyen, M.; Herdewijn, P. Nucleic Acids Res.
2004, 32, 863-864.
(11) Augustyns, K.; Rozenski, J .; Van Aerschot, A.; Busson, R.; Claes,
P.; Herdewijn, P. Tetrahedron 1994, 50, 1189-1198.
(12) Doboszewski, B.; Herdewijn, P. A. M. Nucleosides Nucleotides
1996, 15, 1495-1518.
(13) Wang, J .; Busson, R.; Blaton, N.; Rozenski, J .; Herdewijn, P.
J . Org. Chem. 1998, 63, 3051-3058.
J . Org. Chem, Vol. 69, No. 13, 2004 4447

Vanheusden et al.
SCHEME 2. Syn th esis of 4a
a
Reagents: (a) PhOC(S)Cl, DMAP, CH3CN; (b) â-tributylstannyl styrene, AIBN, benzene; (c) NMMO, OsO4, dioxane; (d) NaIO4, H2O;
(e) NaBH4, EtOH, H2O; (f) CF3COOH, H2O; (g) (Ac)2O, pyridine; (h) 5-methyl-2,4-bis[(trimethylsilyl)oxy]pyrimidine, CH3CN, SnCl2; (i)
NH3, MeOH; (j) (iPr2SiCl)2O, DMF; (k) PhOC(S)Cl, DMAP, CH3CN; (l) Bu3SnH, AIBN, toluene; (m) Bu4NF, THF.
Coupling of the resulting sugar 8 with silylated thymine
in the presence of trimethylsilyl triflate or SnCl4 as
catalysts proceeded slowly and yielded an uncharacter-
ized side product with a similar polarity as 9, rendering
purification of the desired nucleoside difficult. This
problem could be overcome by performing the coupling
reaction under reflux conditions in CH3CN using SnCl2
as a Lewis acid, which selectively yielded the desired 1-â-
nucleoside in 48% yield.14 The remaining starting mater-
ial 8 could be recuperated (37%). To avoid possible side
reactions during hydroboration,15 the 2′- and 3′-hydroxyl
groups were deprotected and reprotected with an isopro-
pylidene protective group to yield 11. Reaction of 11 with
9-BBN-H exclusively yielded 12, the undesired epimer.
The selectivity of the formation of 12 was most unex-
pected. Analysis of its 1H NMR spectrum reveals an axial-
axial coupling between H-1′ and H-2′ and another one
between H-4′ and H-5′. The former is indicative for an
equatorial orientation of the thymine ring, while the
latter and the narrow H-3′ signal (half bandwidth of 7.8
most stable product (both the 4′-hydroxymethyl and the
base are oriented equatorially)11 govern the stereochem-
ical outcome of the hydroboration. Attempts to increase
the steric hindrance at the â-side of the sugar ring,
through the formation of a 2,2′-anhydronucleoside (15)
failed. Upon treatment of 10 with diphenyl carbonate and
NaHCO3, elimination of the base occurred, yielding an
uncharacterized highly volatile sugar analogue.
Because synthesis of 4 from 10 failed, it was decided
to exploit the steric space at the â-side of the sugar ring
through radical-mediated introduction of a carbon group
(Scheme 2).
Thus 2,3-O-isopropylidene-1-O-methyl-4-O-phenoxy-
thiocarbonyl-R-L-lyxopyranose (17), obtained through
reaction of 16 with phenyl chlorothionocarbonate,16 was
reacted with â-tributylstannylstyrene.17 This led to ster-
eoselective introduction of a 2-phenylethenyl group at the
â-side of the sugar ring (18) as indicated by its 1C4
conformation and the positive NOEDIF effect between
H-3′ and H-â of the styrene moiety (3.9% enhancement).18
Via oxidative cleavage of the double bond and in situ
reduction (OsO4, NaIO4/NaBH4), the phenylethenyl group
of 18 was converted into a 4-hydroxymethyl group in a
53% overall yield (20).18 A similar reaction sequence as
described for the synthesis of 10 was employed for the
conversion of 20 to ribo-analogue 5. The yield of the
sugar-base condensation reaction was only 38%. The
presence of the acetoxymethyl moiety in the 4′-position
4
Hz) suggest a C1 chair conformation with an R-directed
4′-hydroxymethyl. This assumption was supported by a
NOEDIF experiment showing a weak increase (0.53%)
of the H-2′ signal upon irradiation of the H-4′ signal.
After deprotection of 12 with acetic acid (to give 13), the
R-orientation of the 4′-CH2OH was confirmed via protec-
tion of the 6′- and 3′-hydroxyls with an isopropylidene
protective group (14), which would be formed less likely
for 5. Apparently, steric hindrance of the 2′,3′-O-isopro-
pylidene and the formation of the thermodynamically
(16) Lin, T. S.; Zhu, J .-L.; Dutschman, G. E.; Cheng, Y.-C.; Prusoff,
W. H. J . Med. Chem. 1993, 36, 353-362.
(17) Saihi, M. L.; Pereyre, M. Bull. Soc. Chim. Fr. 1977, 1251-1255.
(18) An, H. Y.; Wang, T. M.; Maier, M. A.; Manoharan, M.; Ross, B.
S.; Cook, P. D. J . Org. Chem. 2001, 66, 2789-2801.
(14) Martin, P. Helv. Chim. Acta 1996, 79, 1930-1938.
(15) Koga, M.; Schneller, S. W. J . Org. Chem. 1993, 58, 6471-6473.
4448 J . Org. Chem., Vol. 69, No. 13, 2004

1,4-Substituted Pyranose Nucleoside
TABLE 1. 1H NMR Ch em ica l Sh ifts (δ) a n d Cou p lin g Con sta n ts (J ) in Su ga r P a r ts of 4, 5, 13, 23, a n d 25a
13
5
23
25
4
proton
coupling
δ
J
δ
J
δ
J
δ
J
δ
J
1′
5.60
3.63
5.59
5.36
5.93
5.82
1′-2′A
1′-2′B
9.6
9.6
2.7
4.8
0
11.4
0
2′A
3.66
4.49
2.18
1.51
2′A-2′B
2′A-3′
2′A-2′OH
14.7
10.4
11.4
b
3.6
b
b
b
2.7
5.1
2′B
3′
2.54
4.26
1.96
4.02
2′B-3′
3.3
<1
3.95
1.91
3.97
1.77
3.99
2.22
3′-4′
3′-3′OH
b
b
b
b
10.2
10.4
b
2.7
4′
1.79
1.51
4′-5′A
4′-5′B
4′-6′A
4′-6′B
11.7
4.8
b
0
2.4
b
11.4
5.7
0
11.7
4.8
0
0
2.1
7.2
8.4
6.3
b
2.1
2.7
5′A
3.52
3.68
3.66
3.75
3.72
3.77
5′A-5′B
11.7
11.7
11.4
11.1
11.7
11.7
11.4
5′B
6′A
3.83
3.50
3.87
3.55
3.86
3.57
3.92
3.50
under H2O
6′A-6′B
6′A-6′OH
10.8
b
11.7
b
10.1
5.1
6′B
3.41
3.59
3.92
4.14
3.60
6′B-6′OH
b
b
5.1
a
Chemical shifts indicated in the first column are δ values relative to the residual solvent peak in DMSO-d6 (2.48 ppm) in the case of
4, 5, 13, and 23 and in CDCl3 (7.26 ppm) in the case of 25. Coupling constants between the protons indicated in the second column are
values in Hz. Protons are labeled by the number of the carbon atom to which they are bonded; if two protons are bonded to the same
b
carbon atom, the one resonating at a higher field is denoted by A and the other by B. Not determined.
(instead of the 5′-position in natural sugars) has an
important effect on the reaction. The 4′-acetoxymethyl
group would favor R-attack of the base moiety,11 while
the neighboring group effect of the 2′-acetoxygroup would
favor â-attack of the thymine base.11 To allow selective
deoxygenation of the 2′-hydroxyl of 5, we envisaged a
simultaneous protection of the 3′- and 6′-hydroxyl groups
with a 1,1,3,3-tetraisopropyldisiloxan-1,3-diyl (TIPDS)
F IGURE 3. Structure of 4 and 13.
group. At room temperature this reaction was unsuc-
cessful as a result of the axial position of the 4′-
hydroxylmethyl and 3′-hydroxyl functions. Heating to 30
°C allowed conformational change of the sugar moiety
analysis was difficult in the case of 5 and 13. Coupling
constants in the pentopyranosyl parts of 4 and 5 are
essentially the same; hence the conformational analysis
for compound 4 applies to compound 5 as well. This is
also the case for the 23-25 couple.
1
in order to adopt the C4 conformation, positioning both
groups equatorially and resulting in a successful protec-
tion.19 Esterification of the 2′-hydroxyl as a phenyl
thionocarbonate ester, followed by Barton deoxygenation
and removal of the TIPDS group with TBAF, yielded the
desired six-membered ring nucleoside 4. Upon removal
of the TIPDS protective group, the chair conformation
of the sugar ring was restored to the C1 conformation
(J 1′,2′ ) 11.4 Hz), indicating that the thymine ring of 4
indeed adopts an equatorial orientation.
According to the Karplus equation, the coupling be-
tween H-1′ and H-2′ (J 1′,2′ ) 9.6 Hz) in compound 13
indicates that the dihedral angle between these protons
is close to 180 °C, consistent with an axial-axial arrange-
ment of these bonds in a chair conformation. This points
to an equatorially oriented base. The J 4′,5′A (11.7 Hz) and
the small coupling for H-3′ indicate that H-4′ and H-5′A
are in axial and H-3′ in an equatorial arrangement, thus
leading to the chair conformation as shown in Figure 3.
Herein the 4′-hydroxymethyl is necessarily directed
equatorially.
In 4, proton H-1′ shows also a large coupling (11.4 Hz)
with H-2′A, indicating an axial position of both protons.
The 3′ proton is in an equatorial conformation because
its half bandwidth (ν1/2) is about 7.2 Hz for three
couplings. This cannot contain an axial-axial coupling.
Also the absence of a large coupling between H-4′-H-
5′A or H-4′-H-5′B points to an equatorial H-4′ proton
and further proves that 4 is in a chair conformation with
the base in an equatorial position and the 4′-hydroxy-
methyl axially oriented as depicted in Figure 3.
4
Con for m a t ion a l An a lysis. The conformations of
nucleosides 4, 5, 13, 23, and 25 were studied by NMR
spectroscopy. The data are given for each compound in
the Experimental Section. A standard numbering system
is used for carbon atoms as exemplified for 4 in Figure
3. All 13C resonances were consistently assigned by
1
gHMQC experiments. The H NMR results for 4, 5, 13,
23, and 25 are summarized in Table 1. Because of
1
occasional overlapping of H NMR spectra, full spectral
(19) Moyroud, E.; Biala, E.; Strazewski, P. Tetrahedron 2000, 56,
1475-1484.
J . Org. Chem, Vol. 69, No. 13, 2004 4449

Vanheusden et al.
water filtrates were evaporated, and the residue was thor-
oughly dried under high vacuum. The resulting 4-deoxy-1-O-
methyl-4-methylene-â-D-erythro-pentopyranose (7) was dis-
solved in pyridine. Ac2O was added, and the mixture was
stirred at room temperature for 2 h. Evaporation and coevapor-
ation with toluene yielded crude 8 (980 mg, 79%). 1H NMR
(300 MHz, CDCl3): δ 2.10 (6H, s, OCOCH3), 3.43 (3H, s,
OCH3), 4.09 (1H, d, J ) 12.3 Hz, H-5A), 4.34 (1H, ddd, J )
12.3, 1.5 and 0.6 Hz, H-5B), 4.72 (1H, d, J ) 2.4 Hz, H-1),
5.02 and 5.10 (2H, 2m, methylene), 5.14 (1H, m, H-2), 5.78
(1H, m, H-3). 13C NMR (75 MHz, CDCl3): δ 20.1 (OCOCH3),
21.0 (OCOCH3), 55.6 (OCH3), 64.2 (C-5), 68.8 (C-3), 70.7 (C-
2), 100.0 (C-1), 110.6 (C-6), 138.2 (C-4), 169.8 (CO), 170.4 (CO).
HRMS (ESI-MS) for C11H16O6 [M + Na]+: found, 267.0849;
calcd, 267.0844.
1-[2,3-Di-O-acetyl-4-deoxy-4-m eth ylen e-â-D-er yth r o-pen -
top yr a n osyl]th ym in e (9). Thymine (991 mg, 7.86 mmol) was
suspended in hexamethyldisilazane (87.8 mL, 416 mmol),
containing trimethylsilyl chloride (0.71 mL, 5.6 mmol) and
pyridine (7 mL). The mixture was heated to 125 °C and stirred
overnight. The reaction mixture was evaporated and coevapor-
ated with toluene. The resulting residue and 8 (980 mg, 4.01
mmol) were dissolved in CH3CN (27 mL), SnCl2 (anhydrous,
1.98 g, 10.5 mmol) was added, and the mixture was refluxed
under nitrogen during 39 h. After cooling, the mixture was
poured in 10% Na2CO3 and extracted with CH2Cl2. After drying
and evaporation of the organic layer, the obtained residue was
purified by column chromatography (CH2Cl2-MeOH, 100:0 f
98:2) yielding 9 (640 mg, 48%) as a white foam and recuperated
starting material 8 (355 mg, 37%). 1H NMR (300 MHz, DMSO-
d6): δ 1.73 (3 H, s, 5-CH3), 1.90 (3H, s, OCOCH3), 2.11 (3H, s,
OCOCH3), 4.28 (1H, d, J ) 12.6 Hz, H-5′A), 4.35 (1H, d, J )
12.1 Hz, H-5′B), 5.16 (1H, dd, J ) 3.3 and 9.9 Hz, H-2′), 5.34
and 5.36 (2H, 2s, methylene), 5.78 (1H, d, J ) 3.0 Hz, H-3′),
5.93 (1H, d, J ) 9.9 Hz, H-1′), 7.67 (1H, s, H-6). HRMS (ESI-
MS) for C15H18N2O7 [M + Na]+: found, 361.1011; calcd,
361.1011. UV 265 (9839).
F IGURE 4. Structure of 23.
In 23, a J 1′,2′ value of 2.7 Hz indicates an equatorial
orientation of both protons and thus an axially directed
thymine ring. From J 3′,4′ (10.2 Hz) and J 4′,5′A (11.4 Hz) it
can be concluded that H3′, H4′, and H5′A are all three
in an axial orientation, hereby confirming the flipping
of the chair conformation from C1 to 1C4 upon introduc-
4
tion of a TIPDS protective group on 5 (Figure 4).
Summarizing, the values of the vicinal H,H-coupling
constants lead to the conclusion that 13, 4, and 5 are in
chair conformations with the base in an equatorial
position, contrary to 23 and 25 where the base is in an
axial orientation.
The data for 4 and 5 indicate that the conformational
preference of 4-deoxy-4-C-hydroxymethyl-R-L-lyxopyra-
nosyl nucleosides is opposite to that of the anhydro-
hexitol nucleosides (Figure 1).1 When 4 is considered, an
axially oriented heterocycle would lead to an unfavorable
1,3-diaxial interaction between the nucleoside base and
the 3′- and 5′-postions. With an equatorially oriented
heterocycle, this unfavorable interaction is present be-
tween the 4′-hydroxymethyl function and the hydrogen
atom in the 2′-positon and also between the 3′-OH and
the H-5′ and H-1′. These latter interactions may be less
unfavorable than the ones with the thymine ring. Con-
sidering the anhydro-hexitol nucleosides, on the contrary,
only one sterically unfavorable 1,3-diaxial interaction is
present when the nucleoside base is oriented axially.
Apart from this, a hydrogen bond between the 6′-CH2-
OH and the ring oxygen may also stabilize the 4C1
conformation in 4 and 5.
1-[4-Deoxy-4-m eth ylen e-â-D-er yth r o-p en top yr a n osyl]-
th ym in e (10). A solution of 9 (30 mg, 0.089 mmol) in 7 N
methanolic ammonia solution (5 mL) was stirred for 2 h at
room temperature and was evaporated under reduced pres-
sure. The resulting residue was purified by column chroma-
tography (CH2Cl2-MeOH, 90:10) yielding 10 (20 mg, 89%) as
1
a white foam. H NMR (300 MHz, DMSO-d6): δ 1.75 (3 H, d,
J ) 1.2 Hz, 5-CH3), 3.68 (1H, m, H-2′), 4.02 and 4.28 (3H, d
and m, H-3′ and H-5′), 5.00 (1H, br s, methylene), 5.07 (1H, d,
J ) 1.8 Hz, methylene), 5.74 (1H, d, J ) 9.3 Hz, H-1′), 7.52
(1H, q, H-6). 13C NMR (75 MHz, DMSO-d6): δ 12.5 (5-CH3),
67.4, 69.9 and 73.0 (C-2′, C-3′ and C-5′), 80.3 (C-1′), 110.3 (C-
5), 114.5 (C-6′), 137.5 (C-6), 144.0 (C-4′), 151.7 (C-2), 164.6 (C-
4). HRMS (ESI-MS) for C11H14N2O5Na [M + Na]+: found,
277.0812; calcd, 277.0800. UV 265 (10830).
1-[4-Deoxy-2,3-O-isopr opyliden e-4-m eth ylen e-â-D-er yth -
r o-p en top yr a n osyl]th ym in e (11). To a stirred suspension
of 10 (129 mg, 0.51 mmol) in anhydrous acetone (3 mL) and
2,2-dimethoxypropane (0.31 mL, 2.52 mmol) was added p-
toluenesulfonic acid monohydrate (97 mg, 0.51 mmol). After
4 h the resulting solution was poured slowly into stirred
aqueous 0.5 M NaHCO3 (2 mL). The solution was concentrated
in vacuo to ca. 1.5 mL, diluted with water, and extracted with
CH2Cl2. The combined organic layers were dried, evaporated
under reduced pressure, and quickly sent over a silica gel
column (CH2Cl2-MeOH, 97:3) yielding 11 (124 mg, 83%) as a
white foam. HRMS (ESI-MS) for C14H18 N2O5Na [M + Na]+:
found, 317.1109; calcd, 317.1113.
Con clu sion s
We have successfully developed a stereoselective ap-
proach for the synthesis of 1-[2,4-dideoxy-4-C-hydroxy-
methyl-R-L-lyxopyranosyl]thymine (4) from 2,3-O-isopro-
pylidene-1-O-methyl-R-L-lyxopyranose (16) in 13 steps.
The key steps of this synthetic route involve the stereo-
selective introduction of the 6′-carbon on the â-side of the
sugar ring, via radical-mediated substitution of the 4′-
hydroxyl group by a phenylethenyl group (17 f 18)
followed by the introduction of the base via a SnCl2-
mediated coupling. Conformational analysis proves that
4
4 shows the expected C1 conformation with an equato-
rially oriented thymine ring. Biological evaluation of this
nucleoside will be published elsewhere.
Exp er im en ta l Section
See Supporting Information for general synthetic methods
and materials.
1-[4-Deoxy-4-(h yd r oxym eth yl)-2,3-O-isop r op ylid en e-â-
D-r ibop yr a n osyl]th ym in e (12). To an ice-cooled solution of
11 (102 mg, 0.40 mmol) in anhydrous THF (1 mL), under
nitrogen, was added dropwise 9-BBN-H (2.0 mL of a 0.5 M
solution in THF, 1.0 mmol). The mixture was slowly warmed
to room temperature and stirred for 24 h. The reaction mixture
was cooled to 0 °C and treated sequentially with EtOH (1.6
2,3-Di-O-a cet yl-4-d eoxy-1-O-m et h yl-4-m et h ylen e-â-D-
er yth r o-p en top yr a n ose (8). Compound 612 (1.02 g, 5.08
mmol) was treated with 90% trifluoroacetic acid (9 mL) during
5 min. After evaporation, water was added, followed by Dowex
1×2 (OH- form) to neutralize residual acid. The resin was
removed by filtration and washed with water. The combined
4450 J . Org. Chem., Vol. 69, No. 13, 2004

1,4-Substituted Pyranose Nucleoside
mL), a 2 N solution of NaOH (0.78 mL, 1.56 mmol), and 30%
aqueous H2O2 solution (0.78 mL, 6.8 mmol). The resulting
mixture was stirred for 24 h and then poured into a mixture
of EtOAc (10 mL) and water (10 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc
(three times). The combined organic layers were dried over
MgSO4 and evaporated under reduced pressure. The obtained
residue was purified by column chromatography (CH2Cl2-
MeOH, 95:5 f 98:2) yielding pure 12 (77 mg, 62%) as a white
foam. 1H NMR (300 MHz, DMSO-d6): δ 1.09 (3 H, s, C(CH3)2),
1.26 (3H, s, C(CH3)2), 1.76 (3H, s, 5-CH3), 2.23 (1H, m, H-4′),
3.20 (1H, dd, J ) 11.2 and 5.4 Hz, H-6′A), 3.37 (1H, dd, J )
8.31 and 10.8 Hz, H-5′A), 3.43 (1H, t, J ) 11.72, H-6′B), 3.53
(1H, dd, J ) 10.8 and 6.35 Hz, H-5′B), 4.33 (1H, m, H-2′), 4.42
(1H, m, H-3′), 4.71 (1H, t, 6′-OH), 5.41 (1H, d, J ) 9.0 Hz,
H-1′), 7.63 (1H, q, J ) 0.9 Hz, 6-H). 13C NMR (75 MHz, DMSO-
d6): δ 12.5 (5-CH3), 28.4 and 27.0 (C(CH3)2), under DMSO
signal (C-4′), 59.5 (C-6′), 66.6 (C-5′), 72.7 and 74.1 (C-2′ and
C-3′), 82.0 (C-1′), 110.1 (C-5), 110.8 C(CH3)2), 137.3 (C-6), 151.4
(C-2), 164.2 (C-4). HRMS (ESI-MS) for C14H20N2O6Na [M +
H]+: found, 335.1232; calcd, 335.1219. UV 265 (10640).
H-5B), 4.16 (1H, dd, J ) 5.4 and 3.2 Hz, H-2), 4.45 (1H, m,
H-3), 4.71 (1H, d, J ) 3.0 Hz, H-1), 5.49 (1H, m, H-4), 7.10-
7.44 (5H, m, arom H). 13C NMR (75 MHz, CDCl3): δ 26.5 and
28.1 (C(CH3)2), 56.1 (OCH3), 58.7 (C-5), 74.5 (C-3), 75.4 (C-2),
78.9 (C-4), 100.3 (C-1), 110.2 (C(CH3)2), 122.1 (arom Co), 126.9
(arom Cp), 129.8 (arom Cm), 153.6 (arom Ci), 194.7 (O(CS)O).
HRMS (ESI-MS) for C16H20O6S1Na [M + Na]+: found, 363.0865;
calcd, 363.0878.
2,3-O-Isopr opyliden e-1-O-m eth yl-4-C-(2-ph en yleth en yl)-
r-L-lyxop yr a n ose (18). To a solution of 17 (1.47 g, 4.3 mmol)
in benzene (34 mL) was added â-tributylstannylstyrene (4.02
g, 10.22 mmol). The resulted solution was degassed three times
with nitrogen at room temperature and 45 °C. After 2,2′-
azobisisobutyronitrile (AIBN) (230 mg, 1.4 mmol) was added,
the solution was refluxed for 2 h. Another part of AIBN (230
mg, 1.4 mmol) was added after cooling the reaction mixture
to 40 °C. The reaction mixture was then refluxed for 2 h. This
procedure was repeated until the starting material disap-
peared (six times). The solvent was evaporated, and the
residue was purified by column chromatography (CH2Cl2-
MeOH, 98:2) to give 18 (773 mg, 62%) as an oil. 1H NMR (300
MHz, CDCl3): δ 1.26 (3H, s, CCH3), 1.44 (3H, s, CCH3), 2.55
(1H, m, H-4), 3.46 (3H, s, OCH3), 3.50 (2H, app d, H-5), 3.92
(1H, dd, J ) 2.1 and 5.1 Hz, H-2), 4.11 (1H, dd, J ) 5.1 and
7.2 Hz, H-3), 4.78 (1H, d, J ) 2.1 Hz, H-1), 6.15 (1H, dd, J )
16.2 and 7.8 Hz, H-â styrene), 6.52 (1H, d, J ) 16 Hz, H-R
styrene), 7.11-7.40 (5H, m, arom H). 13C NMR (75 MHz,
CDCl3): δ 26.6 (CCH3), 28.5 (CCH3), 42.8 (C-4), 55.7 (OCH3),
61.3 (C-5), 73.9 (C-3), 76.1 (C-2), 99.9 (C-1), 109.3 (CCH3), 126.5
(arom Co), 127.2 and 127.7 (arom Cp and CR styryl), 128.7
(arom Cm), 132.8 (Câ styryl), 137.1 (arom Ci). HRMS (ESI-
MS) for C17H22O4Na [M + Na]+: found, 313.1412; calcd,
313.1415.
4-Deoxy-4-C-h yd r oxym eth yl-2,3-O-isop r op ylid en e-1-O-
m eth yl-r-L-lyxop yr a n ose (20). To a solution of styrene 18
(330 mg, 1.1 mmol) and N-methylmorpholine-N-oxide (NMMO)
(200 mg, 1.7 mmol) in dioxane (20 mL), was added a catalytic
amount of 4% osmium tetraoxide in H2O (0.3 mL, 0.04 mmol).
The flask was covered by aluminum foil, and the reaction
mixture was stirred at room temperature overnight. A solution
of NaIO4 (731 mg, 3.4 mmol) in water (1 mL) was added to
the stirred reaction mixture. It was stirred for 1 h at 0 °C and
2 h at room temperature, followed by addition of EtOAc (20
mL). The mixture was filtered through a Celite pad and
washed with EtOAc. The filtrate was washed three times with
10% aqueous Na2S2O3 solution until the color of the aqueous
phase disappeared. The organic phase was further washed
with water, dried (MgSO4), and concentrated. The obtained
aldehyde was dissolved in EtOH-H2O (4:1 v/v, 16 mL). NaBH4
(190 mg, 5.0 mmol) was added in portions at 0 °C. The
resulting reaction mixture was stirred at room temperature
for 2 h and then treated with ice water. The mixture was
extracted with EtOAc. The organic phase was washed with
water and brine, dried (MgSO4), and concentrated. The
obtained residue was purified by column chromatography
(CH2Cl2-MeOH, 9:1) to give 20 (127 mg, 53% over three steps)
as an oil. 1H NMR (300 MHz, DMSO-d6): δ 1.24 (3H, s, CCH3),
1.38 (3H, s, CCH3), 1.78 (1H, m, H-4), 3.28 (3H, s, OCH3),
3.30-3.55 (4H, m, H-5 and H-6), 3.79 (1H, dd, J ) 3.0 and 5.4
Hz, H-2), 4.03 (1H, dd, J ) 5.1 and 6.6 Hz, H-3), 4.60 (1H, d,
J ) 3.0 Hz, H-1), 4.66 (1H, t, J ) 5.7 Hz, 6-OH). 13C NMR (75
MHz, DMSO-d6): δ 26.9 (CCH3), 22.8 (CCH3), under DMSO
signal (C-4), 55.5 (OCH3), 59.9 and 60.1 (C-5 and C-6), 72.5
(C-3), 73.8 (C-2), 100.5 (C-1), 108.6 (CCH3). HRMS (ESI-MS)
for C10H18O5Na [M + Na]+: found, 241.1050; calcd, 241.1052.
1-[4-Deoxy-4-(h yd r oxym eth yl)-â-D-r ibop yr a n osyl]th y-
m in e (13). Compound12 (70 mg, 0.21 mmol) was refluxed for
3 h in a 1:1 mixture of HOAc-H2O (5 mL). The mixture was
evaporated under reduced pressure and coevaporated with
EtOH, and the resulting residue was purified by column
chromatography (CH2Cl2-MeOH, 95:5), yielding 13 (51 mg,
1
98%) as a white foam. H NMR (300 MHz, DMSO-d6): δ 1.76
(1H, d, J ) 0.9 Hz, 5-CH3), 1.91 (1H, m, H-4′), under H2O
signal (1H, H-6′A), 3.41 (1H, dd, J ) 6.3 and 10.8 Hz, H-6′B),
3.52 (1H, t, J ) 11.7 Hz, H-5′A), 3.63 (1H, dd, J ) 3.6 and 9.3
Hz, H-2′), 3.68 (1H, dd, J ) 4.8 and 10.8 Hz, H-5′B), 3.95 (1H,
br s, H-3′), 4.49 (1H, br s, 6′-OH), 4.92 (1H, br s, 3′-OH, 5.11
(1H, br s, 2′-OH), 5.60 (1H, d, J ) 9.6 Hz, H-1′), 7.57 (1H, q,
J ) 1.2 Hz, 6-H). 13C NMR (75 MHz, DMSO-d6): δ 12.7 (5-
CH3), 43.9 (C-4′), 59.8 (C-6′), 64.9 (C-5′), 68.8 and 69.4 (C-2′
and C-3′), 80.7 (C-1′), 109.9 (C-5), 137.7 (C-6), 151.8 (C-2), 164.5
(C-4). HRMS (ESI-MS) for C11H16N2 O6Na [M + Na]+: found,
295.9010; calcd, 295.0906. UV 265 (10320).
1-[4-Deoxy-4-(h yd r oxym eth yl)-3,6-O-isop r op ylid en e-â-
D-r ibop yr a n osyl]th ym in e (14). To a stirred suspension of
13 (13 mg, 0.048 mmol) in anhydrous acetone (0.1 mL) and
2,2-dimethoxypropane (0.03 mL, 0.24 mmol) was added p-
toluenesulfonic acid monohydrate (0.15 mg, 0.8 µmol). After 1
h the resulting solution was poured slowly into stirred aqueous
0.5 M NaHCO3 (2 mL). The solution was concentrated in vacuo,
diluted with water, and extracted with CH2Cl2. The combined
organic layers were dried, evaporated under reduced pressure,
and purified by column chromatography (CH2Cl2-MeOH, 98:2
f 97:3) yielding pure 14. 1H NMR (300 MHz, DMSO-d6): δ
1.33 (3 H, s, C(CH3)2), 1.41 (3H, s, C(CH3)2), 1.76 (4H, m, 5-CH3
and H-4′), 3.45-4.05 (5H, m, H-5′, H-6′ and H-2′), 4.38 (1H,
m, ν1/2 ) 6.6 Hz, H-3′), 5.09 (1H, br s, 2-OH), 5.59 (1H, d, J
) 9.9 Hz, H-1′), 7.58 (1H, s, 6-H). 13C NMR (75 MHz, DMSO-
d6): δ 12.6 (5-CH3), 19.3 and 30.3 (C(CH3)2), 34.0 (C-4′), 60.1
(C-6′), 64.8, 67.4 and 69.3 (C-2′, C-3′ and C-5′), 80.2 (C-1′), 99.2
(C(CH3)2), 110.1 (C-5), 137.4 (C-6), 151.7 (C-2), 164.4 (C-4).
HRMS (ESI-MS) for C14H20N2O6 [M + Na]+: found, 335.1207;
calcd, 335.1219. UV 265 (10625).
2,3-O-Isop r op ylid en e-1-O-m eth yl-4-O-p h en oxyth ioca r -
bon yl-r-L-lyxop yr a n ose (17). To an ice-cold solution of 16
(2.50 g, 12.2 mmol) and DMAP (3.00 g, 24.5 mmol) in CH3CN
(100 mL) was gradually added phenyl chlorothionocarbonate
(2.3 mL, 16.4 mmol). The mixture was stirred at 0 °C for 5 h.
The solvent was removed in vacuo, and the residue was
dissolved in CH2Cl2. The solution was washed with water,
dried over anhydrous MgSO4, filtered, and evaporated in
vacuo. The obtained residue was purified by column chroma-
tography (CH2Cl2-MeOH, 95:5) to give 17 (3.6 g, 87%) as a
syrup. 1H NMR (300 MHz, CDCl3): δ 1.39 (3H, s, C(CH3)2),
1.58 (3H, s, C(CH3)2), 3.46 (3H, s, OCH3), 3.83 (1H, dd, J )
7.5 and 12.0 Hz, H-5A), 3.92 (1H, dd, J ) 4.2 and 12.1 Hz,
2,3,6-Tr i-O-acetyl-4-deoxy-4-C-h ydr oxym eth yl-1-O-m eth -
yl-r-L-lyxop yr a n ose (21).12 A solution of 20 (72 mg, 0.3
mmol) in trifluoroacetic acid-H2O (9:1 v/v, 1 mL) was stirred
for 5 min. The solution was neutralized with Dowex 1×2
(OH-). The resin was removed by filtration and washed with
MeOH-H2O (3:1). The filtrate was evaporated under dimin-
ished pressure and purified by column chromatography (CH2-
J . Org. Chem, Vol. 69, No. 13, 2004 4451

Vanheusden et al.
Cl2-MeOH, 90:10), yielding 4-deoxy-4-C-hydroxymethyl-1-O-
dropwise. The mixture was stirred for 3 h at room temperature
and overnight at 30 °C. Water was added, and the mixture
was extracted with CH2Cl2. The organic layer was dried over
MgSO4 and evaporated under reduced pressure. The obtained
residue was purified by column chromatography (CH2Cl2-
MeOH, 99:1) to afford 23 (78 mg, 89%) as a white foam. 1H
NMR (300 MHz, DMSO-d6): δ 0.95 (28H, m, CH(CH3)2), 1.75
(3H, s, 5-CH3), 2.22 (1H, m, H-4′), 3.55 (1H, d, J ) 11.1 Hz,
H-6′A), 3.75 (1H, t, J ) 11.4 Hz, H-5′A), 3.87 (1H, dd, J ) 5.7
and 11.4 Hz, H-5′B), 3.92 (1H, dd, J ) 2.1 and 11.1 Hz, H-6′B),
3.99 (1H, dd, J ) 2.7 and 10.2 Hz, H-3′), 4.49 (1H, br, H-2′),
5.30 (1H, d, J ) 5.1 Hz, 2′-OH), 5.36 (1H, d, J ) 2.7 Hz, H-1′),
7.41 (1H, s, 6-H), 11.31 (1H, s, NH). 13C NMR (75 MHz, DMSO-
d6): δ 12.6, 12.7, 12.8, 13.4, 13.5 (CH(CH3)2 and 5-CH3), 17.1,
17.8, 17.8, 17.9, 17.9 (CH(CH3)2), 38.8 (C-4′), 59.4 (C-6′), 65.2
(C-5′), 66.5 (C-3′), 68.2 (C-2′), 88.5 (C-1′), 109.8 (C-5), 137.6
(C-6), 151.3 (C-2), 164.4 (C-4). HRMS (ESI-MS) for C23H43N2O7-
Si2 [M + H]+: found, 515.2619; calcd, 515.2608. UV 265
(10090).
1
methyl-R-L-lyxopyranose12 (45 mg, 77%) as a glassy solid. H
NMR (300 MHz, DMSO-d6): δ 1.91 (1H, m, H-4), 3.20 (3H, s,
OCH3), 3.30-3.61 (6H, m, H-6, H-2, H-3 and H-5), 4.35 (2H,
t, 6- and 3-OH), 4.45 (1H, d, J ) 4.5 Hz, H-1), 4.47 (1H, app d,
J ) 2.1 Hz, 2-OH). 13C NMR (75 MHz, DMSO-d6): δ under
DMSO signal (C-4), 54.9 (OCH3), 60.1, 61.8, 66.7 and 69.4 (C-
6, C-2, C-3 and C-5), 102.5 (C-1). HRMS (ESI-MS) for C7H14O5-
Na [M + Na]+: found, 201.0750; calcd, 201.0739. The above
mentionned glassy solid (40 mg, 0.2 mmol) was dissolved in
pyridine (2.5 mL) and acetic anhydride (2.5 mL) was added.
The solution was stirred at room temperature for 3 h. The
solvent was removed under vacuum, and the resulting residue
was purified by column chromatography (CH2Cl2-MeOH, 99:
1) to yield 21 (60 mg, 89%) as a foam. 1H NMR (300 MHz,
CD3OD): δ 1.97, 2.02 and 2.10 (OCOCH3), 2.47 (1H, m, H-4),
3.38 (3H, s, OMe), 3.70 (1H, t, J ) 11.4 Hz, H-5A), 3.77 (1H,
dd, J ) 11.4 and 5.4 Hz, H-5B), 4.01 (1H, dd, J ) 11.4 and 2.7
Hz, H-6A), 4.11 (1H, dd, J ) 6.0 and 11.7 Hz, H-6B), 4.65 (1H,
d, J ) 5.1 Hz, H-1), 5.09 (1H, dd, J ) 5.1 and 3.0 Hz, H-2),
5.13 (1H, dd, J ) 3.0 and 11.0 Hz, H-3). 13C NMR (75 MHz,
CD3OD): δ 19.3, 19.4 and 19.5 (OCOCH3), 35.7 (C-4), 54.0
(OCH3), 60.3 (C-5), 61.0 (C-6), 67.3 (C-3), 68.1 (C-2), 99.3 (C-
1), 170.6, 170.9 and 170.2 (OCOCH3). HRMS (ESI-MS) for
1-[4-Deoxy-4-C-h yd r oxym eth yl-3,6-O-(1,1,3,3,-tetr a iso-
p r op yld isiloxa n -1,3-d iyl)-2-O-p h en oxyth ioca r bon yl-r-L-
lyxop yr a n osyl]th ym in e (24). Compound 23 (126 mg, 0.24
mmol) was dissolved in anhydrous CH3CN (4 mL). DMAP (58
mg, 0.48 mmol) was added at 0 °C. The mixture was stirred
15 min at 0°C, then phenylchlorothionocarbonate (46 µL, 0.33
mmol) was added dropwise, and the resulting solution was
stirred overnight at room temperature. After adding 7%
NaHCO3 solution (7 mL), the mixture was evaporated to
dryness, and the obtained residue was dissolved in EtOAc,
washed with water, dried over MgSO4, evaporated under
reduced pressure, and purified by column chromatography
(CH2Cl2-MeOH, 99.5:0.5) to afford 24 (140 mg, 89%) as a
white foam. 1H NMR (300 MHz, CDCl3): δ 1.03 (28H, m,
CH(CH3)2), 1.94 (3H, s, 5-CH3), 2.25 (1H, m, H-4′), 3.60 (1H,
d, J ) 11.7 Hz, H-6′A), 3.82-3.99 (2H, m, H-5′A and H-5′B),
4.10 (1H, dd, J ) 11.7 and 2.4 Hz, H-6′B), 4.52 (1H, dd, J )
2.8 and 11.1 Hz, H-3′), 5.61 (1H, d, J ) 2.6 Hz, H-1′), 6.58
(1H, d, J ) 2.7 Hz, H-2′), 7.09-7.44 (5H, m, arom H), 8.06
(1H, s, 6-H). 13C NMR (75 MHz, CDCl3): δ 12.6 (5-CH3), 12.8,
13.0, 13.5, 13.7 (CH(CH3)2), 17.4, 17.5, 17.6, 17.7, 17.7 (CH-
(CH3)2), 39.7 (C-4′), 58.7 (C-6′), 65.0 and 65.0 (C-3′ and C-5′),
80.8 (C-2′), 85.8 (C-1′), 112.0 (C-5), 122.0 (arom Co), 126.9 (arom
Cp), 129.8 (arom Cm), 136.7 (C-6), 150.0 (arom Ci), 153.6 (C-2),
163.4 (C-4), 194.8 (OC(S)O). HRMS (ESI-MS) for C30H46N2O8-
SSi2Na [M + Na]+: found, 673.2409; calcd, 673.2411. UV 265
(10000).
C
13H20O8Na [M + Na]+: found, 327.1058; calcd, 327.1056.
1-[2,3,6-O-Tr i-a cet yl-4-d eoxy-4-C-h yd r oxym et h yl-r-L-
lyxop yr a n osyl]th ym in e (22).12 Thymine (615 mg, 4.9 mmol)
was suspended in hexamethyldisilazane (55 mL, 260 mmol)
containing trimethylsilyl chloride (0.48 mL, 3.8 mmol) and
pyridine (4 mL). The mixture was heated to 125 °C and stirred
overnight. The reaction mixture was evaporated and coevapo-
rated with toluene. The resulting residue and 21 (744 mg, 2.44
mmol) were dissolved in CH3CN (17 mL), SnCl2 (anhydrous,
1.23 g, 6.5 mmol) was added, and the mixture was refluxed
under nitrogen during 39 h. After cooling it was poured in 10%
Na2CO3 and extracted with CH2Cl2. After drying and evapora-
tion of the organic layer, the obtained residue was purified by
column chromatography (CH2Cl2-MeOH 99:1 f 97:3) yielding
pure 22 (367 mg, 38%) as a white foam and residual starting
1
product 21 (315 mg, 42%). H NMR (300 MHz, DMSO-d6): δ
1.75 (3H, s, 5-CH3), 1.88, 2.04 and 2.11 (OCOCH3), 2.18 (1H,
m, H-4′), 3.86 (1H, d, J ) 12.3 Hz, H-5′A), 3.97 (1H, d, J )
12.3 Hz, H-5′B), 4.36 (2H, m, H-6′A and H6′B), 5.30 (1H, dd,
J ) 2.7 and 9.9 Hz, H-2′), 5.45 (1H, br s, H-3′), 5.80 (1H, d, J
) 9.9 Hz, H-1′), 7.82 (1H, s, 6-H), 11.40 (1H, s, NH). 13C NMR
(75 MHz, DMSO-d6): δ 12.5 (5-CH3), 21.0, 21.3 and 21.5
(OCOCH3), 55.6 (C-4′), 62.5 and 64.9 (C-5′ and C-6′), 66.2 and
68.4 (C-2′ and C-3′), 79.2 (C-1′), 110.7 (C-5), 137.1 (C-6), 151.4
(C-2), 164.2 (C-4), 169.8, 170.3 and 170.9 (OCOCH3). HRMS
(ESI-MS) for C17H22N2O9Na [M + Na]+: found, 421.1253; calcd,
421.1223. UV 265 (8800).
1-[2,4-Did eoxy-4-C-h yd r oxym et h yl-3,6-O-(1,1,3,3,-t et -
r a isop r op yld isiloxa n -1,3-d iyl)-r-L-lyxop yr a n osyl]t h y-
m in e (25). Compound 24 (134 mg, 0.20 mmol) was coevapo-
rated three times with anhydrous toluene, dissolved in toluene
(32 mL), and degassed with nitrogen for 30 min. In a second
flask, AIBN (17 mg, 0.10 mmol) and Bu3SnH (166 µL, 0.62
mmol) in toluene (2 mL) were degassed with nitrogen for 30
min. The first flask was heated to 80 °C, and the second
solution was added dropwise via a syringe. The mixture was
heated to 90 °C for 2 h. After cooling to room temperature,
the mixture was evaporated, and the residue was purified by
column chromatography (CH2Cl2-MeOH, 99.5:0.5) to afford
25 (81 mg, 79%) as a white foam. 1H NMR (300 MHz, CDCl3):
δ 1.05 (28H, m, CH(CH3)2), 1.79 (1H, m, H-4′), 1.90 (3H, s,
5-CH3), 2.18 (1H, m, H-2′A), 2.54 (1H, dd, J ) 3.3 and 14.1
Hz, H-2′B), 3.57 (1H, d, J ) 11.7 Hz, H-6′A), 3.72 (1H, t, J )
11.7 Hz, H-5′A), 3.86 (1H, dd, J ) 4.8 and 11.7 Hz, H-5′B),
4.14 (1H, dd, J ) 2.7 and 12.0 Hz, H-6′B), 4.26 (1H, m, H-3′),
5.93 (1H, d, J ) 4.8 Hz, H-1′), 8.04 (1H, s, 6-H). 13C NMR (75
MHz, CDCl3): δ 12.7 (5-CH3), 12.8, 13.5, 13.8 (CH(CH3)2), 17.4,
17.4, 17.5, 17.5, 17.6, 17.6 (CH(CH3)2, 36.4 (C-2′), 45.7 (C-4′),
59.0 (C-6′), 64.8 and 63.3 (C-3′ and C-5′), 82.3 (C-1′), 110.5 (C-
5), 136.6 (C-6), 150.5 (C-2), 163.5 (C-4). HRMS (ESI-MS) for
1-[4-Deoxy-4-C-h yd r oxym eth yl-r-L-lyxop yr a n osyl]th y-
m in e (5).12 Compound 22 (410 mg, 1.03 mmol) was treated
with a 7 N methanolic ammonia solution (30 mL) at room
temperature for 7 h. Evaporation yielded a residue that was
purified by column chromatography (CH2Cl2-MeOH, 90:10)
to afford 5 (218 mg, 78%) as a white foam. 1H NMR (300 MHz,
DMSO-d6): δ 1.77 (4H, br s, 5-CH3 and H-4′), 3.50 (1H, m,
H-6′A), 3.59 (1H, m, H-6′B), 3.66 (2H, m, H-5′A and H-2′), 3.83
(1H, dd, J ) 2.4 and 11.1 Hz, H-5′B), 3.97 (1H, br s, H-3′),
4.65 (1H, t, J ) 5.1 Hz, 6′-OH), 4.97 (2H, br s, 2′-OH and 3′-
OH), 5.59 (1H, d, J ) 9.6 Hz, H-1′), 7.56 (1H, s, 6-H), 11.25
(1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δ 12.6 (5-CH3),
46.0 (C-4′), 60.0 (C-6′), 63.9 (C-2′) and 66.2 (C-5′), 68.8 (C-3′),
81.2 (C-1′), 109.9 (C-5), 137.7 (C-6), 151.7 (C-2), 164.4 (C-4).
HRMS (ESI-MS) for C11H16N2O6Na [M + Na]+: found, 295.0902;
calcd, 295.0906. UV 265 (10120).
1-[4-Deoxy-4-C-h yd r oxym eth yl-3,6-O-(1,1,3,3,-tetr a iso-
pr opyldisiloxan -1,3-diyl)-r-L-lyxopyr an osyl]th ym in e (23).
Compound 5 (46 mg, 0.17 mmol) and imidazole (60 mg, 0.88
mmol) were dissolved in DMF (1 mL) at 0 °C. 1,3-Dichloro-
1,1,3,3-tetraisopropyldisiloxane (58 µL, 0.19 mmol) was added
C
23H43N2O6Si2 [M + H]+: found, 499.2571; calcd, 499.2659. UV
265 (9900).
4452 J . Org. Chem., Vol. 69, No. 13, 2004

1,4-Substituted Pyranose Nucleoside
1-[2,4-Did eoxy-4-C-h yd r oxym eth yl-r-L-lyxop yr a n osyl]-
th ym in e (4). Compound 25 (76 mg, 0.15 mmol) was dissolved
in THF (8 mL), and Bu4NF (1 M in THF, 0.76 mL, 0.76 mmol)
was added. The mixture was stirred for 1 h at room temper-
ature, evaporated to dryness, and purified by column chro-
matography (CH2Cl2-MeOH, 93:7) to afford 4 (38 mg, 97%)
d6): δ 12.6 (5-CH3), 33.8 (C-2′), 43.4 (C-4′), 60.5 (C-6′), 64.7
(C-5′), 64.8 (C-3′), 78.1 (C-1′), 110.1 (C-5), 137.3 (C-6), 150.9
(C-2), 164.4 (C-4). HRMS (ESI-MS) for C11H16N2O5Na [M +
Na]+: found, 279.0952; calcd, 279.0957; UV 265 (10590).
Ack n ow led gm en t. V.V. is indebted to the “Fonds
voor Wetenschappelijk Onderzoek-Vlaanderen” for a
position as Aspirant.
1
as a white foam. H NMR (300 MHz, DMSO-d6): δ 1.51 (2H,
m, H-2′A and H-4′), 1.76 (3H, s, 5-CH3), 1.96 (1H, app t, J )
11.4 Hz, H-2′B), 3.50 (1H, m, J ) 8.4 and 10.2 Hz, H-6′A),
3.60 (1H, m, J ) 7.2 and 10.2 Hz, H-6′B), 3.77 (1H, d, J )
11.4 Hz, H-5′A), 3.92 (1H, dd, J ) 2.1 and 11.4 Hz, H-5′B),
4.02 (1H, m, H-3′), 4.58 (1H, t, J ) 5.1 Hz, 6′-OH), 4.98 (1H,
d, J ) 2.7 Hz, 3′-OH), 5.82 (1H, d, J ) 11.4 Hz, H-1′), 7.57
(1H, s, 6-H), 11.25 (1H, s, NH). 13C NMR (75 MHz, DMSO-
Su p p or t in g In for m a t ion Ava ila b le: 13C NMR spectra
and elemental analysis results. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O040130G
J . Org. Chem, Vol. 69, No. 13, 2004 4453