Synthesis and structural elucidation of 2′-deoxy-4′-thio-L-threo-pentofuranosylpyrimidine and -purine nucleosides

Article abstract of DOI:10.1002/1099-0690(200103)2001:6<1077::AID-EJOC1077>3.0.CO;2-0

Benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-L-threo-pentofuranoside (13) was used as glycosyl donor for the synthesis of 4′-thio-L-threo-pentofuranosyluracil derivatives 23-29. The corresponding cytidine analogue 33 was prepared from 13 via the triazolo der

Full text of DOI:10.1002/1099-0690(200103)2001:6<1077::AID-EJOC1077>3.0.CO;2-0

FULL PAPER
-threo-
Synthesis and Structural Elucidation of 2Ј-Deoxy-4Ј-thio-
L
pentofuranosylpyrimidine and -purine Nucleosides[‡]
Jörn Wirsching,[a] Jürgen Voss,*[a] Gunadi Adiwidjaja,[b] Anja Giesler,[c] and Jürgen Kopf[c]
Keywords: Carbohydrates / Nucleosides / Reaction mechanisms / 4-Thiofuranosides
Benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-
anoside (13) was used as glycosyl donor for the synthesis of
4Ј-thio- -threo-pentofuranosyluracil derivatives 23−29. The
corresponding cytidine analogue 33 was prepared from 13
via the triazolo derivative 31. Adenine and hypoxanthine did
not react with 13. Therefore, 13 was transformed into the 1-
L
-threo-pentofur-
O-acetate 15, which was a sufficiently reactive donor for the
purine bases, yielding 4Ј-thio- -threo-pentofuranosylpurines
36 and 37. In most cases it was possible to obtain pure ano-
mers of the deprotected nucleoside analogues, three of which
were suitable for X-ray structural analyses.
L
L
Introduction
4Ј-Thionucleosides have been prepared and investigated
since the 1960s[1,2] and 1970s.[3,4] Over the last 40 years, nu-
merous articles on this scientific topic have been pub-
lished.[5] In particular, bioorganic chemists’ attention has
been drawn to 4Ј-thionucleosides containing 2-deoxy-4-
thio--ribose[5] or 4-thio--ribose[6] as the sugar moiety,
since these compounds are the analogues of the natural
DNA and RNA building blocks. As important representat-
ives of this class of substances, 4Ј-S-AZT (1)[7] and 4Ј-S-
BVDU (2)[7] should be mentioned (Scheme 1). In 1995,
Leydier et al.[8] published the first results on the synthesis
of 4Ј-thio--ribo-oligonucleotides, the starting material for
4Ј-thio-RNA. Since the synthesis of 2Ј,3Ј-dideoxy-3Ј-thia-
cytidine (3-TC, 3), with its remarkable activity against the
AIDS virus,[9] 4Ј-thionucleosides of the unnatural  config-
uration have become compounds of increased scientific
interest.[10Ϫ12]
Scheme 1
tural elucidation of various 2Ј-deoxy-4-thio--threo-pento-
furanosylnucleosides [‘‘2Ј-deoxy-4Ј-thio--lyxo-furanosyl-
nucleosides’’], most of which are new compounds not yet
mentioned in the literature.
Results and Discussion
In 1997 we prepared benzyl 2-deoxy-3,5-di-O-methyl-1,4-
dithio--threo-pentofuranoside (10) from 2-deoxy--ribose,
in five steps.[16] Using NOE measurements on 10, we estab-
lished the inversion of the  configuration into the  form.
Analogously, we converted 2-deoxy--ribose into the di-
thioacetal 11 in two steps, following the synthetic proced-
ures reported by Dyson et al.[17] After mesylation of 11, the
mesylate 12 was cyclised in the presence of tetrabutylammo-
nium iodide and barium carbonate, in pyridine at reflux
In 1998, Satoh et al.[13] reported on the synthesis of the
4Ј-thio--arabino-nucleosides 4 and 6 and investigated their
antiviral activities (Scheme 2). Independently, we have syn-
thesised 4 and the corresponding uridine 5,[14] as well as the
analogous 5-halo derivatives 7Ϫ9.[15] In continuation of our
synthetic work we report here on the synthesis and struc-
temperature, to afford the 2-deoxy-1,4-dithio--threo-pento-
[‡]
[18]
Thiosugars, 7. Ϫ Part 6: O. Schulze, S. Bruns, J. Voss,
furanoside 13
(85% yield), as an anomeric mixture with
G. Adiwidjaja, Carbohydr. Res., 2000, 329, 781Ϫ790.
a ratio of α/β ϭ 2:1 (Scheme 3). The spectroscopic data of
13 are in agreement with those reported by Dyson et al.[17]
In 1993, Huang and Hui[19] described the formation of the
2-deoxy-1,4-dithio--ribofuranoside 14 from 12, with the
aid of triphenylphosphane/iodine/imidazole. However, our
spectroscopic data for 13 agree with those of Huang and
Hui’s compound 14, but not with those of the well-known
authentic 14.[17] Tiwari et al.[20] have already repeated Hu-
ang and Hui’s synthesis and obtained 13 instead of 14. This
means that double inversion Ϫ i.e., retention of configura-
[a]
Institut für Organische Chemie der Universität Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax (internat.) ϩ 49-(0)40/42838-5592
E-mail: voss@chemie.uni-hamburg.de
[b]
Mineralogisch-Petrographisches Institut der Universität
Hamburg,
Grindelallee 48, 20146 Hamburg, Germany
[c]
Institut für Anorganische und Angewandte Chemie der
Universität Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
Eur. J. Org. Chem. 2001, 1077Ϫ1087
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0306Ϫ1077 $ 17.50ϩ.50/0
1077

J. Wirsching, J. Voss, G. Adiwidjaja, A. Giesler, J. Kopf
FULL PAPER
Scheme 2
Scheme 3
tion at C-4 in the dithioacetal 12 Ϫ had not taken place. as well as that at C-4, were assigned by NOE measurements.
Rather, the cyclisation mechanism consists of a single intra- For the α anomers, significant NOE interactions were ob-
molecular SN2 displacement reaction.[14,16,20] As a con- served between H-6 of the nucleobase and one of the pro-
sequence, Huang and Hui’s thymidine, 5-fluoro- and 5- tons H-2Ј, as well as H-3Ј and H-4Ј. Moreover, we observed
iodouridine derivatives also do not exhibit the claimed  an NOE between H-2Ј and H-4Ј, which is only possible in
configuration, but the  form.
the  configuration, as well as an NOE between the other
Treatment of 1,4-dithiofuranoside 13 with mercuric H-2Ј proton and one of the H-5Ј protons. For the β ano-
acetate[21Ϫ23] gave the 1-O-acetyl-4-thiofuranose 15 as a mers, we observed an NOE between the H-6 proton of the
pure α anomer, with a yield of 64% (Scheme 3).
nucleobase and one of the H-2Ј protons, as well as an NOE
Treatment of 1,4-dithiofuranoside 13 with 2,4-bis-O-tri- between H-6 and one of the H-5Ј protons. The other H-2Ј
methylsilyluracil[24] and N-iodosuccinimide (NIS)[5,25,26] proton and H-3Ј showed interactions with H-4Ј, which
yielded the benzyl-protected 1-(4-thio--threo-pentofurano- again is only possible in the  configuration of the nucleos-
syl)uridine derivative 16 in 75% yield. The anomers were ides 16 and 17.
separated by column chromatography and obtained in an
Coupling of 13 with silylated 5-fluorouracil[27] yielded the
α/β ratio of 2:3. Analogously, the thymidine derivative 17 5-fluorouridine derivative 18, with an α/β ratio of 1:2 and
was obtained from 13 and 2,4-bis-O-trimethylsilylthym- in 68% yield. The 5-chlorouridine 19 was obtained in a yield
ine[24] as a 1:1 inseparable mixture of anomers, in a yield of of 67% as an anomeric mixture (α/β ϭ 1:3). Treatment of
55% (Scheme 4). The anomeric configurations of 16 and 17, 13 with silylated 5-bromouracil[27] gave the benzyl-protected
Scheme 4
1078
Eur. J. Org. Chem. 2001, 1077Ϫ1087

2Ј-Deoxy-4Ј-thio- -threo-pentofuranosylpyrimidine
L
FULL PAPER
5-bromouridine derivative 20, with an anomeric ration of
1:2 (α/β) and in a yield of 60%. The 5-iodouridine 21 was
obtained from 13 and silylated 5-iodouracil[27] in 72% yield.
Again, the α/β ratio was 1:2. Only for 21 was it possible to
separate the anomers by column chromatography. The 5-
nitrouridine derivative 22 was surprisingly obtained as a
pure β anomer, although in a low yield of 26% (Scheme 4).
For all 5-substituted uridine derivatives 18؊22, the anom-
eric configurations were assigned by comparison of their
NMR spectra with those of 16 and 17.
Cleavage of the benzyl groups of 16 and 17 was achieved
by treatment with boron tribromide at Ϫ80 °C.[18,28] After
quenching the excess boron tribromide, neutralisation of
the formed hydrobromic acid with silver carbonate[14] and
reversed-phase HPLC, the separated anomers α-23 and β-
23 were obtained in yields of 47% and 25%, respectively. It
was possible to crystallise α-23 from water and to determine
its structure by X-ray diffraction analysis (cf. Figure 1), cle-
Figure 2. ORTEP view of the X-ray diffraction structure of 5-
iodouridine derivative α-28; thermal ellipsoids are drawn at the
50% probability level
arly confirming the expected -threo configuration, in con- tion products, was recovered in either case. As well as this,
trast to Huang and Hui’s assumption[19] of a 2-deoxy--ribo a route to 32 via the 4-thionouracil derivative 30, described
configuration. The separated thymidine derivatives α-24 for similar cases by Leydier et al.,[6] was unsuccessful. While
and β-24 were obtained in yields of 27% and 12%, respect- the first step, thionation of 16 with Lawesson’s reagent,
ively.
worked well with a yield of 82%, no reaction of 30 took
place with methanolic ammonia. Eventually, Uenishi’s al-
ternative approach[29] to cytidine derivatives via 4-(1,2,4-tri-
azolo) derivatives proved applicable. To be successful, we
had to use a large excess of 1,2,4-triazole, phosphoryl chlor-
ide and triethylamine, obtaining a 72% yield of 31 (anom-
eric ratio α/β ϭ 3:2) (Scheme 5). The displacement of the
1,2,4-triazolyl substituent with ammonia resulted in the de-
sired benzyl-protected cytidine derivative 32 in 72% yield.
Again, the anomeric ratio was 3:2. Deprotection of 32 with
boron tribromide provided the cytidine derivative 33 as
mixture of anomers (Scheme 5). A proportion of the α an-
omer of 33 could be separated from the mixture by column
chromatography. The pure β anomer could not be obtained
because of intense tailing, even during reversed-phase
HPLC. The total yield of the cleavage reaction was 26%.
As shown in Scheme 6, purine nucleoside analogues de-
Figure 1. ORTEP view of the X-ray diffraction structure of uridine
derivative α-23; thermal ellipsoids are drawn at the 50% probabil-
ity level
Treatment of 18 with boron tribromide gave α-25 (37%)
and β-25 (11%). Cleavage of the benzyl groups in 5-chlorou- rived from 2-deoxy-4-thio--threo-pentofuranose are also
ridine 19 produced α-26 (49%) and β-26 (9%). The unpro- accessible. Coupling of the glycosyl donor 15 with adenine
tected 5-bromouridine derivatives α-27 and β-27 were isol- in the presence of TMSOTf[6] yielded adenosine derivative
ated in only 16% and 8% yields. Deprotection of 21 yielded 34 with an anomeric ratio of α/β ϭ 1:5 and in 60% yield.
α-28 (23%) and β-28 (8%). An X-ray structure analysis was Treatment of 15 with hypoxanthine under the same condi-
performed on a single crystal of α-28, unequivocally con- tions produced the inosine derivative 35, obtained as the
firming the α--threo configuration (cf. Figure 2), in con- pure β anomer in 68% yield. The pronounced preponder-
trast with Huang and Hui’s findings.[19] In all cases, the ance of the β anomers is surprising, as one would expect
cleavage reactions were carried out using the anomeric mix- steric hindrance to favour the formation of α anomers.
tures of the benzylated 5-halouridines 18؊21. The anomers Cleavage of the benzyl groups of 34 and 35 with boron tri-
of the deprotected products were then separated by re- bromide and separation of the anomers by reversed phase
versed-phase HPLC. This was not, however, necessary for HPLC yielded the adenosine analogues α-36 and β-36, to-
the 5-nitrouridine 29, which was obtained as the pure β an- gether with the inosine derivative 37. The deprotection steps
omer (9%) (Scheme 4).
gave low yields of only 12% of α-36, 13% of β-36 and 6%
Attempts to synthesise the benzyl-protected cytidine de- of 37, due to the strongly basic properties of the purine
rivative 32 by coupling thiosugar 13 with 2,4-bis-N,O-trime- moieties; these formed persistent hydrobromides and made
thylsilylcytosine[24] in the presence of NIS or trimethylsilyl workup difficult. However, β-36 could be crystallised from
trifluoromethanesulfonate (TMSOTf)[6,23] failed. Only the water as a monohydrate. A single crystal was suitable for
starting material, together with unidentifiable decomposi- X-ray structural analysis. As in the cases of the uridine de-
Eur. J. Org. Chem. 2001, 1077Ϫ1087
1079

J. Wirsching, J. Voss, G. Adiwidjaja, A. Giesler, J. Kopf
FULL PAPER
Scheme 5
Scheme 6
rivatives α-23 and α-28, the anomeric configuration was S24, C24 and C23 nearly form a plane, while the torsion
confirmed, together with the  configuration at the C-4 angle at the S24ϪC24 bond is Ϫ8.45°. The plane of the
atom of β-36 (cf. Figure 3). Like that of α-28 (cf. Figure 2), pyrimidine ring and the S24ϪC21ϪC22 triangle in α-23
the thiofuranose moiety of β-36 exhibits an envelope con- and α-28 are situated perpendicularly to each other. Be-
formation, with centres C24, S24, C21 and C22 arranged in cause of its steric requirements, the purine ring, i.e., the
nearly coplanar manner and a torsion angle of only Ϫ2.5° C14ϪN13 edge of β-36, exists in a staggered conformation
at the S24ϪC21 bond (α-28: Ϫ8.7°), whereas in α-23, C21, with respect to the S24ϪC21ϪH21 triangle (cf. Figure 3).
Experimental Section
General: IR: ATI Mattson Genesis spectrometer. Ϫ NMR: Bruker
AMX 400 and DRX 500. Chemical shifts (ppm) are relative to
Me4Si (1 H) and CDCl3 (13C, δ ϭ 77.05). Standard correlation tech-
niques were used for assignments. Ϫ Mass spectra: Varian CH 7
(EI) and VG Analytical 70Ϫ250 S (FAB, HRMS). Ϫ Melting
points: Electrothermal apparatus (values are corrected). Ϫ HPLC
(MerckϪHitachi equipment): Semipreparative HPLC was carried
out with a LiChroCART 250Ϫ10 column containing LiChrosher
100 RP-18 (10 µm), and analytical HPLC was performed with an
EcoCART 125-3 column containing LiChrosher 100 RP-18 end-
capped (5 µm). Solvents for HPLC were obtained from Merck
(MeCN, HPLC grade) and Riedel-de Hae¨n (water, HPLC grade).
Ϫ TLC was carried out on Merck PF254 foils (detection: UV light,
iodine vapour, or EtOH/H2SO4 spray/200 °C), and column chro-
matography on Merck Kieselgel 60 (70Ϫ230 mesh); Rf(A1) and
Rf(A2) correspondent to fast and slowly eluted fractions without
Figure 3. ORTEP view of the X-ray diffraction structure of adenos-
ine derivative β-36 with one molecule of crystal water; thermal
ellipsoids are drawn at the 50% probability level
1080
Eur. J. Org. Chem. 2001, 1077Ϫ1087

2Ј-Deoxy-4Ј-thio- -threo-pentofuranosylpyrimidine
L
FULL PAPER
assignment of the anomers. Solvents were purified and dried accor-
ding to standard laboratory procedures.[30] The pyrimidine bases,
adenine and hypoxanthine are commercially available.
When the reaction was complete, the pyridine was evaporated and
the residue dissolved in CH2Cl2 and extracted with 0.1  HCl,
water and saturated NaHCO3 solution to give the crude mesylate
12 (22.0 g). This was dissolved in pyridine (300 mL), tetrabutylam-
monium iodide (13.22 g, 35.79 mmol) and barium carbonate (7.12
g, 36.07 mmol) were added and the mixture was refluxed for 2.5 h.
Solid compounds were filtered off and the pyridine was removed
under reduced pressure. The residue was dissolved in CH2Cl2 and
extracted as described above. The crude product was purified by
column chromatography [silica gel, petroleum ether/EtOAc, 4:1,
Rf(α,β) ϭ 0.25] to give 13 (13.26 g, 85%) as an α/β ϭ 2:1 mixture
of anomers; pale yellow syrup. Ϫ C26H28O2S2 (436.6): calcd. C
71.52, H 6.46, S 14.69; found C 71.89, H 7.57,[33] S 14.91.
X-ray Structure Analysis: The crystal data and a summary of ex-
perimental details for the nucleosides α-23, α-28 and β-36 are given
in Table 1. For α-23 and β-36, data collection was performed with a
Kappa-CCD Nonius diffractometer with graphite-monochromated
˚
Mo-Kα radiation (0.71073 A) in the rotation Φ scan mode at a tem-
perature of 293 K. The data for α-28 were collected with an
EnrafϪNonius CAD4 diffractometer in the 2θ/ω scan mode with
˚
graphite-monochromated Cu-Kα radiation (1.54178 A) at a temper-
ature of 173 K. The structures were solved by direct methods using
the SIR-97[31] program, and refined by full-matrix-block least
squares on F2 using all data and the SHELXL-97[32] program.
Crystallographic data for the structures reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre
as supplementary publications no. CCDC-142899 (α-23), -144783
(α-28) and -142901 (β-36). Copies of the data can be obtained free
of charge on applicaton to CCDC, 12 Union Road, Cambridge
1-O-Acetyl-3,5-di-O-benzyl-2-deoxy-4-thio-α,L-threo-pentofuranose
(15): Thiosugar 13 (1.28 g, 2.93 mmol) and mercuric acetate (1.83
g, 5.74 mmol) were dissolved in glacial acetic acid (60 mL) and
stirred at room temperature for 2.5 h. After the reaction was com-
plete (TLC, petroleum ether/EtOAc, 4:1), the solvent was removed,
and the residue was diluted with CH2Cl2 and filtered through a
Celite pad. The crude product was purified by column chromato-
graphy [petroleum ether/EtOAc, 4:1, Rf(α,β) ϭ 0.22] to yield 15
(673 mg, 64%) as pure α anomer; colourless oil. Ϫ [α]2D0 ϭ Ϫ118.7
(c ϭ 0.9, CHCl3). Ϫ C21H24O3S (356.5): calcd. C 70.76, H 6.79, S
9.00; found C 70.21, H 6.55, S 9.13.
CB2 1EZ, UK [Fax: (internat.)
deposit@ccdc.cam.ac.uk].
ϩ 44-1223/336-033; E-mail:
3,5-Di-O-benzyl-2-deoxy-D-ribose Dibenzyl Dithioacetal (11): Com-
pound 11 was prepared from 2-deoxy--ribose according to stand-
ard procedures. Compound 11 is described in the literature[17,19,20]
but with poor spectroscopic data, which are therefore addressed in
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)uracil
the Supporting Information (see footnote on first page). Ϫ [α]2D0
ϭ
(16): NIS (431 mg, 1.92 mmol) was added to a solution of 13 (618
Ϫ45.1 (c ϭ 1.0, CHCl3), ref.[17] [α]2D0 ϭ Ϫ102 (c ϭ 2.0, EtOH). Ϫ
C33H36O3S2 (544.8) calcd. C 72.76, H 6.66, S 11.77; found C 72.05,
H 6.80, S 11.65.
mg, 1.42 mmol), 2,4-bis-O-trimethylsilyluracil[24] (474 mg,
˚
1.85 mmol) and 4-A molecular sieves (20 mg) in dry MeCN (15
mL), and the reaction mixture was stirred for 2 h at room temper-
ature. Then aq. sodium thiosulfate solution was added and stirring
Benzyl 3,5-Di-O-benzyl-2-deoxy-1,4-dithio-L-threo-pentofuranoside
(13):[19] A solution of mesyl chloride (5.20 mL, 7.64 g, 66.73 mmol) was continued for another 0.5 h. The solids were filtered off, and
in dry pyridine (150 mL) was added dropwise into an ice-cold solu-
tion of 11 (19.41 g, 35.63 mmol) in dry pyridine (150 mL). The
mixture was allowed to warm to room temp. and stirred for 24 h.
the filtrate was extracted with CHCl3. The organic phase was separ-
ated, dried with MgSO4 and concentrated. The resulting crude
product was purified by silica gel chromatography [petroleum ether/
Table 1. Crystal data and structure refinement for α-23, α-28 and β-36
α-23
α-28
β-36
Crystal system
Space group
tetragonal
P43212
7.2450(10)
7.2450(10)
40.1820(10)
triclinic
monoclinic
P21
4.9140(10)
8.7000(10)
15.1830(2)
P1
˚
a [A]
5.1453(17)
6.2338(10)
10.379(3)
α ϭ 71.345(18)
β ϭ 84.18(3)
γ ϭ 76.193(18)
0.70 ϫ 0.25 ϫ 0.20
2.007
˚
b [A]
˚
c [A]
α/β/γ [°]
β ϭ 95.300(10)
Crystal size [mm]
0.38 ϫ 0.31 ϫ 0.18
1.538
1024
0.308
0.31 ϫ 0.12 ϫ 0.09
ρcalcd. [g cmϪ3
]
1.466
F000
180
22.224
300
µ [mmϪ1
]
0.264
h/k/l limits
θ limits [°]
0,9/0,6/Ϫ50,51
3.98/27.49
11060
0,6/Ϫ7,7/Ϫ13,13
4.50/76.31
1447
0,6/Ϫ11,10/Ϫ19,19
2.69/27.40
5353
Number of reflections
Independent reflections
1987
1436
2745
Number of reflections with I Յ 2σ(I)
1660
1436
2494
w ϭ 1/[σ2(Fo ) ϩ (0.0522P)2
w ϭ 1/[σ2(Fo ) ϩ (0.0832P)2
w ϭ 1/[σ2(Fo )
2
2 2
2
2
2
Weighting scheme [Σw(Fo Ϫ Fc ) ]
ϩ 0.0343P]
ϩ 1.1778P]
ϩ (0.0410P)2 ϩ 0.1499P]
2
2
2
2
2
2
with P ϭ (Fo ϩ 2Fc )/3
with P ϭ (Fo ϩ 2Fc )/3
with P ϭ (Fo ϩ 2Fc )/3
Number of parameters
194
164
233
R
0.0366
0.0412
0.0345
Rw
0.0786
0.1090
0.0808
GoF
0.993
1.104
1.060
Largest difference peak and hole
0.165 and Ϫ0.223
2.538 and Ϫ2.313
0.147 and Ϫ0.153
Ϫ3
˚
[e A
]
Refinement of H atoms
difmap/geom
geom
difmap/geom
Eur. J. Org. Chem. 2001, 1077Ϫ1087
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J. Wirsching, J. Voss, G. Adiwidjaja, A. Giesler, J. Kopf
FULL PAPER
EtOAc 1:3, Rf(β) ϭ 0.60, Rf(α) ϭ 0.43] to give α-16 (228 mg, 29%)
Ϫ FAB HRMS (mNBA): calcd. 551.0502 [M ϩ H]ϩ; found
551.0423.
and β-16 (159 mg, 59%) as white amorphous solids. Ϫ α-16: [α]2D0
ϭ
Ϫ8.9 (c ϭ 1.0, CHCl3). Ϫ FAB MS (mNBA); m/z: 425 [M ϩ H]ϩ.
Ϫ FAB HRMS (mNBA): calcd. 425.1535 [M ϩ H]ϩ; found
425.1533. Ϫ C23H24N2O4S (424.5): calcd. C 65.08, H 5.70, N 6.60,
S 7.55; found C 65.18, H 5.97, N 6.36, S 7.64. Ϫ β-16: [α]2D5 ϭ 10.3
(c ϭ 1.0, CHCl3). Ϫ FAB MS (mNBA); m/z: 425 [M ϩ H]ϩ. Ϫ
FAB HRMS (mNBA): calcd. 425.1535 [M ϩ H]ϩ; found 425.1572.
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-β-L-threo-pentofuranosyl)-5-
nitrouracil (22): Compound 22 was prepared as described for 16;
from 13 (600 mg, 1.37 mmol), NIS (795 mg, 3.53 mmol), 5-nitro-
˚
2,4-bis-O-trimethylsilyluracil (1.62 g, 5.37 mmol), 4-A molecular
sieves (60 mg) and MeCN (15 mL). The crude product was recrys-
tallised from EtOAc to give β-22 (170 mg, 26%) as a white solid.
Ϫ M.p. 169Ϫ172 °C (decomp.). Ϫ [α]2D5 ϭ ϩ39.0 (c ϭ 1.0, CHCl3).
Ϫ FAB MS (mNBA); m/z: 470 [M ϩ H]ϩ. Ϫ FAB MS (mNBA);
m/z: 470 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd. 470.1386 [M
ϩ H]ϩ; found 470.1361. Ϫ C23H23N3O6S (469.5): calcd. C 58.84,
H 4.94, N 8.95, S 6.83; found C 58.68, H 5.09, N 8.69, S 6.66.
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)thymine
(17): Compound 17 was prepared as described for 16; from 13 (1.5
g, 3.44 mmol), NIS (982 mg, 4.36 mmol), 2,4-bis-O-trimethylsilyl-
thymine[24] (1.13 g, 4.18 mmol), 4-A molecular sieves (80 mg) and
˚
MeCN (30 mL). After chromatographic workup [silica gel, petro-
leum ether/EtOAc, 1:3, Rf(α,β) ϭ 0.39], 17 (823 mg, 55%) was ob-
tained as an amorphous white solid. The anomers were inseparable
(α/β ϭ 1:1). Ϫ FAB MS (mNBA); m/z: 439 [M ϩ H]ϩ. Ϫ FAB
HRMS (mNBA): calcd. 439.1692 [M ϩ H]ϩ; found 439.1679.
1-(2-Deoxy-4-thio-L
-threo-pentofuranosyl)uracil (23):[34] Boron tri-
bromide (1.0 mL, 2.64 g, 10.54 mmol) was added to dry CH2Cl2
(10.0 mL); the mixture was cooled to Ϫ90 °C. A solution of 16
(948 mg, 2.23 mmol, α/β ϭ 3:2) in CH2Cl2 (8.0 mL) was added
dropwise with vigorous stirring. The temperature was kept below
Ϫ80 °C. After complete addition, stirring was continued at Ϫ90 °C
for 1 h. Then the excess of boron tribromide was quenched at Ϫ90
°C by dropwise addition of a 1:1 mixture of CH2Cl2/MeOH (16
mL). After the solution had warmed to room temperature, silver
carbonate (10.21 g, 37.03 mmol) was added to neutralise the hydro-
bromic acid. After 0.5 h, the inorganic salts were filtered off, the
solution was concentrated to dryness and the remaining crude
product was purified by silica gel chromatography [CHCl3/MeOH
4:1, Rf(A1) ϭ 0.35, Rf(A2) ϭ 0.32], followed by reversed-phase
HPLC (MeCN/H2O, 5:95) to yield α-23 (51 mg, 16%) and β-23 (41
mg, 19%) as white solids. A portion of α-23 was used to grow single
crystals (colourless sheets), suitable for X-ray structural analysis,
from H2O. Ϫ α-23: M.p. 180 °C. Ϫ [α]2D0 ϭ Ϫ91.0 (c ϭ 1.0, MeOH).
Ϫ IR (KBr): ν˜ ϭ 3422, 3087, 3047, 2934, 2889, 2833, 1690, 1469,
1426, 1382, 1304, 1241, 1169, 1113, 1068, 1027, 981, 912, 823, 760,
707, 622, 557, 512, 417 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO):
δ ϭ 11.28 (ws, 1 H, NH), 7.49 (d, 1 H, H-6), 6.32 (dd, 1 H, H-1Ј),
5.68 (d, 1 H, H-5), 5.08 (d, 1 H, 3Ј-OH), 4.77 (dd, 1 H, 5Ј-OH),
4.39Ϫ4.42 (m, 1 H, H-3Ј), 3.93 (ddd, 1 H, H-4Ј), 3.74 (ddd, 1 H,
H-5Јb), 3.46 (ddd, 1 H, H-5Јa), 2.27 (ddd, 1 H, H-2Јb), 2.12 (ddd,
1 H, H-2Јa). J1Ј,2Јa ϭ 9.7, J1Ј,2Јb ϭ 6.6, J2Јa,3Ј ϭ 4.4, J2Јb,3Ј ϭ 2.2,
J2Јa,2Јb ϭ 13.1, J3Ј,4Ј ϭ 3.4, J3Ј,OH ϭ 4.4, J4Ј,5Јa ϭ 7.7, J4Ј,5Јb ϭ 6.2,
J5Јa,5Јb ϭ 10.8, J5Јa,OH ϭ 5.9, J5Јb,OH ϭ 4.8, J5,6 ϭ 8.1 Hz. Ϫ 13C
NMR (126 MHz, [D6]DMSO): δ ϭ 163.0 (4-CO), 150.9 (2-CO),
142.0 (C-6), 102.6 (C-5), 72.2 (C-3Ј), 61.2 (C-5Ј), 60.5 (C-1Ј), 57.5
(C-4Ј), 43.8 (C-2Ј). Ϫ FAB MS (mNBA); m/z: 245 [M ϩ H]ϩ. Ϫ
FAB HRMS (mNBA): calcd. 245.0596 [M ϩ H]ϩ; found 245.0623.
Ϫ β-23: M.p. 220 °C. Ϫ [α]2D0 ϭ Ϫ2.2 (c ϭ 1.0, MeOH). Ϫ IR
(KBr): ν˜ ϭ 3412, 3045, 2935, 2882, 2816, 1691, 1467, 1392, 1259,
1141, 1097, 1035, 910, 816, 752, 624, 556, 511, 420 cmϪ1. Ϫ 1H
NMR (500 MHz, [D6]DMSO): δ ϭ 11.21 (ws, 1 H, NH), 8.32 (d,
1 H, H-6), 6.10 (dd, 1 H, H-1Ј), 5.62 (d, 1 H, H-5), 5.35 (d, 1 H,
3Ј-OH), 4.86 (dd, 1 H, 5Ј-OH), 4.32Ϫ4.37 (m, 1 H, H-3Ј), 3.85
(ddd, 1 H, H-5Јb), 3.62 (ddd, 1 H, H-5Јa), 3.54 (ddd, 1 H, H-4Ј),
2.38 (ddd, 1 H, H-2Јb), 2.13 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.6, J1Ј,2Јb ϭ
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)-5-fluoro-
uracil (18): Compound 18 was prepared as described for 16; from
13 (240 mg, 0.55 mmol), NIS (182 mg, 0.81 mmol), 5-fluoro-2,4-
bis-O-trimethylsilyluracil[27] (320 mg, 1.17 mmol), 4-A molecular
˚
sieves (40 mg) and MeCN (12 mL). After chromatographic workup
[silica gel, petroleum ether/EtOAc 1:3, Rf(α,β) ϭ 0.58], 18 (166 mg,
68%) was obtained as an amorphous white solid. The anomers were
inseparable (α/β ϭ 1:2). Ϫ FAB MS (mNBA); m/z: 443 [M ϩ H]ϩ.
Ϫ FAB HRMS (mNBA): calcd. 443.1441 [M ϩ H]ϩ; found
443.1455. Ϫ C23H23FN2O4S (442.5): calcd. C 62.43, H 5.24, F 4.29,
N 6.33; found C 61.90, H 5.18, F 4.44, N 6.63.
5-Chloro-1-(3,5-di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)-
uracil (19): Compound 19 was prepared as described for 16; from
13 (400 mg, 0.92 mmol), NIS (307 mg, 1.36 mmol), 5-chloro-2,4-
bis-O-trimethylsilyluracil[27] (830 mg, 2.85 mmol), 4-A molecular
˚
sieves (50 mg) and MeCN (14 mL). After chromatographic workup
[silica gel, petroleum ether/EtOAc 1:3, Rf(α,β) ϭ 0.51], 19 (283 mg,
67%) was obtained as an amorphous white solid. The anomers were
inseparable (α/β ϭ 1:3). Ϫ FAB MS (mNBA); m/z: 459 [M ϩ H]ϩ.
Ϫ FAB HRMS (mNBA): calcd. 459.1145 [M ϩ H]ϩ; found
459.1189. Ϫ C23H23ClN2O4S (459.0): calcd. C 60.19, H 5.05, N
6.10; found C 60.67, H 5.21, N 6.26.
5-Bromo-1-(3,5-di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)-
uracil (20): Compound 20 was prepared as described for 16; from
13 (507 mg, 1.16 mmol), NIS (384 mg, 1.71 mmol), 5-bromo-2,4-
bis-O-trimethylsilyluracil[27] (780 mg, 2.32 mmol), 4-A molecular
˚
sieves (50 mg) and MeCN (12 mL). After chromatographic workup
[silica gel, petroleum ether/EtOAc 1:3, Rf(α,β) ϭ 0.61], 20 (352 mg,
60%) was obtained as an amorphous white solid. The anomers were
inseparable (α/β ϭ 1:2). Ϫ FAB MS (mNBA); m/z: 505 [M ϩ H,
for 81Br]ϩ, 503 [M ϩ H, for 79Br]ϩ. Ϫ C23H23BrN2O4S (503.4):
calcd. C 54.88, H 4.61, N 5.56, S 6.37; found C 53.83[33], H 4.47,
N 5.63, S 6.26.
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)-5-iodo-
uracil (21): Compound 21 was prepared as described for 16; from
13 (500 mg, 1.15 mmol), NIS (667 mg, 2.96 mmol), 5-iodo-2,4-bis-
8.2, J2Јa,3Ј ϭ 2.7, J2Јb,3Ј ϭ 4.1, J2Јa,2Јb ϭ 14.3, J3Ј,4Ј ϭ 4.2, J3Ј,OH
ϭ
3.7, J4Ј,5Јa ϭ 7.4, J4Ј,5Јb ϭ 5.4, J5Јa,5Јb ϭ 10.8, J5Јa,OH ϭ 5.8,
J5Јb,OH ϭ 5.0, J5,6 ϭ 8.2 Hz. Ϫ 13C NMR (126 MHz, [D6]DMSO):
δ ϭ 163.3 (4-CO), 151.1 (2-CO), 143.4 (C-6), 101.0 (C-5), 72.1 (C-
3Ј), 62.2 (C-1Ј), 60.9 (C-5Ј), 58.1 (C-4Ј), 44.3 (C-2Ј). Ϫ FAB MS
(mNBA); m/z: 245 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd.
245.0585 [M ϩ H]ϩ; found 245.0623.
O-trimethylsilyluracil[27] (880 mg, 2.30 mmol), 4-A molecular sieves
˚
(70 mg) and MeCN (15 mL). After chromatographic workup (silica
gel, petroleum ether/EtOAc 1:2, Rf,α ϭ 0.35, Rf,β ϭ 0.22), α-21 (156
mg, 25%) and β-21 (296 mg, 47%) were obtained as white solids.
Ϫ α-21: M.p. 82 °C. Ϫ[α]2D0 ϭ Ϫ6.1 (c ϭ 1.0, CHCl3). Ϫ FAB MS
(mNBA); m/z: 551 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd.
551.0502 [M ϩ H]ϩ; found 551.0309. Ϫ β-21: M.p. 68 °C. Ϫ [α]2D5
ϭ
1-(2-Deoxy-4-thio-L-threo-pentofuranosyl)thymine (24): Compound
24, which has also been obtained as a mixture of anomers by Ti-
ϩ27.4 (c ϭ 1.0, CHCl3). Ϫ FAB MS (mNBA); m/z: 551 [M ϩ H]ϩ.
1082
Eur. J. Org. Chem. 2001, 1077Ϫ1087

2Ј-Deoxy-4Ј-thio- -threo-pentofuranosylpyrimidine
L
FULL PAPER
wari et al.,[21] was prepared as described for 23; from 17 (522 mg,
1.19 mmol, α/β ϭ 1:1) in CH2Cl2 (4.0 mL), boron tribromide (0.53
mL, 1.40 g, 5.59 mmol) in CH2Cl2 (5.3 mL) and silver carbonate
(5.39 g, 19.55 mmol). After chromatographic workup [silica gel,
CHCl3/MeOH, 4:1, Rf(A1) ϭ 0.40, Rf(A2) ϭ 0.33] and reversed-
[C4H3FN2O2ϩ•], 115.0218 [C5H7OSϩ•]; found 262.0434, 133.0315,
130.0170, 115.0185. Ϫ β-25: M.p. 156Ϫ159 °C. Ϫ [α]2D5 ϭ ϩ2.2 (c ϭ
0.7, MeOH). Ϫ IR (KBr): ν˜ ϭ 3427, 3052, 2933, 2822, 1693, 1476,
1
1397, 1245, 1104, 1036, 971, 906, 829, 749, 682, 534 cmϪ1. Ϫ H
NMR (500 MHz, [D6]DMSO): δ ϭ 11.75 (ws, 1 H, NH), 8.60 (d,
phase HPLC (MeCN/H2O, 13:87), the separated anomers α-24 (41 1 H, H-6), 6.10 (ddd, 1 H, H-1Ј), 5.47 (d, 1 H, 3Ј-OH), 4.91 (ws, 1
mg, 27%) and β-24 (19 mg, 12%) were obtained as white solids. Ϫ
H, 5Ј-OH), 4.34Ϫ4.37 (m, 1 H, H-3Ј), 3.84 (dd, 1 H, H-5Јb), 3.64
(dd, 1 H, H-5Јa), 3.54 (ddd, 1 H, H-4Ј), 2.39 (ddd, 1 H, H-2Јb),
α-24: M.p. 180 °C. Ϫ [α]2D0 ϭ Ϫ79.2 (c ϭ 1.0, MeOH). Ϫ IR (KBr):
ν˜ ϭ 3416, 3198, 3052, 2930, 2824, 1683, 1470, 1388, 1306, 1245, 2.15 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.3, J1Ј,2Јb ϭ 8.3, J1Ј,F ϭ 2.0,
1222, 1170, 1125, 1071, 1045, 1020, 985, 958, 904, 797, 765, 692, J2Јa,3Ј ϭ 2.5, J2Јb,3Ј ϭ 4.0, J2Јa,2Јb ϭ 14.4, J3Ј,4Ј ϭ 4.0, J3Ј,OH ϭ 3.0,
635, 585, 534, 481, 416 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO): J4Ј,5Јa ϭ 7.3, J4Ј,5Јb ϭ 5.8, J5Јa,5Јb ϭ 10.8, J6,F ϭ 8.0 Hz. Ϫ 13C
δ ϭ 11.26 (ws, 1 H, NH), 7.79 (q, 1 H, H-6), 6.35 (dd, 1 H, H-1Ј), NMR (126 MHz, [D6]DMSO): δ ϭ 157.1 (d, 4-CO), 149.6 (2-CO),
5.06 (d, 1 H, 3Ј-OH), 4.77 (dd, 1 H, 5Ј-OH), 4.39Ϫ4.42 (m, 1 H, 139.2 (d, C-5), 127.7 (d, C-6), 72.0 (C-3Ј), 61.8 (C-1Ј), 60.8 (C-5Ј),
H-3Ј), 3.95 (ddd, 1 H, H-4Ј), 3.74 (ddd, 1 H, H-5Јb), 3.64 (ddd, 1 58.3 (C-4Ј), 44.3 (C-2Ј). J4,F ϭ 26.2, J5,F ϭ 228.3, J6,F ϭ 35.7 Hz.
H, H-5Јa), 2.24 (ddd, 1 H, H-2Јb), 2.15 (ddd, 1 H, H-2Јa), 1.80 (d,
Ϫ
19F NMR (471 MHz, [D6]DMSO): δ ϭ Ϫ168.10 (d, 1 F, F-5).
3 H, CH3). J1Ј,2Јa ϭ 9.8, J1Ј,2Јb ϭ 6.7, J2Јa,3Ј ϭ 3.4, J2Јb,3Ј ϭ 2.0, JF,6 ϭ 8.0 Hz. Ϫ FAB MS (mNBA); m/z: 263 [M ϩ H]ϩ. Ϫ MS
J2Јa,2Јb ϭ 13.0, J3Ј,4Ј ϭ 3.3, J3Ј,OH ϭ 4.4, J4Ј,5Јa ϭ 7.6, J4Ј,5Јb ϭ 6.2, (70 eV); m/z: 262 (6) [Mϩ•], 133 (56) [C5H9O2Sϩ•], 130 (36)
J5Јa,5Јb ϭ 10.8, J5Јa,OH ϭ 5.8, J5Јb,OH ϭ 4.9, J6,Me ϭ 1.1 Hz. Ϫ 13C [C4H3FN2O2ϩ•], 115 (29) [C5H7OSϩ•], 85 (100), 57 (21). Ϫ HRMS:
NMR (126 MHz, [D6]DMSO): δ ϭ 163.7 (4-CO), 150.9 (2-CO), calcd. 262.0424 [Mϩ•], 133.0323 [C5H9O2Sϩ•], 130.0179
137.3 (C-6), 110.4 (C-5), 72.2 (C-3Ј), 61.2 (C-5Ј), 60.2 (C-1Ј), 57.5 [C4H3FN2O2ϩ•], 115.0218 [C5H7OSϩ•]; found 262.0418, 133.0366,
(C-4Ј), 43.7 (C-2Ј), 12.3 (CH3). FAB MS (mNBA); m/z: 259 [M ϩ 130.0201, 115.0188.
H]ϩ. Ϫ FAB HRMS (mNBA); calcd. 259.0723 [M ϩ H]ϩ; found
5-Chloro-1-(2-deoxy-4-thio-
L
-threo-pentofuranosyl)uracil
(26):
259.0840. Ϫ β-24: M.p. 220 °C. Ϫ [α]2D5 ϭ ϩ28.3 (c ϭ 1.0, MeOH).
Ϫ IR (KBr): ν˜ ϭ 3422, 3065, 2931, 2823, 1687, 1474, 1397, 1278,
1224, 1109, 1081, 1039, 970, 900, 766, 632, 563, 486, 417 cmϪ1. Ϫ
1H NMR (500 MHz, [D6]DMSO): δ ϭ 11.22 (ws, 1 H, NH), 8.19
(q, 1 H, H-6), 6.12 (dd, 1 H, H-1Ј), 5.37 (d, 1 H, 3Ј-OH), 4.87 (dd,
1 H, 5Ј-OH), 4.34Ϫ4.37 (m, 1 H, H-3Ј), 3.85 (ddd, 1 H, H-5Јb),
3.65 (ddd, 1 H, H-5Јa), 3.52 (ddd, 1 H, H-4Ј), 2.38 (ddd, 1 H, H-
2Јb), 2.13 (ddd, 1 H, H-2Јa), 1.76 (d, 3 H, CH3). J1Ј,2Јa ϭ 3.4,
J1Ј,2Јb ϭ 8.4, J2Јa,3Ј ϭ 3.5, J2Јb,3Ј ϭ 4.2, J2Јa,2Јb ϭ 14.1, J3Ј,4Ј ϭ 4.6,
Compound 26 was prepared as described for 23; from 19 (283 mg,
0.62 mmol, α/β ϭ 1:3) in CH2Cl2 (3.0 mL), boron tribromide (0.28
mL, 739 mg, 2.95 mmol) in CH2Cl2 (2.8 mL) and silver carbonate
(2.93 g, 10.63 mmol). After chromatographic workup [silica gel,
CHCl3/MeOH, 4:1, Rf(A1) ϭ 0.38, Rf(A2) ϭ 0.30] and reversed-
phase HPLC (MeCN/H2O, 10:90), the separated anomers α-26 (21
mg, 49%) and β-26 (11 mg, 9%) were obtained as white solids. Ϫ
α-26: M.p. 200 °C. Ϫ [α]2D0 ϭ Ϫ61.9 (c ϭ 1.0, MeOH). Ϫ IR (KBr):
ν˜ ϭ 3444, 3168, 3019, 2926, 2839, 1708, 1665, 1468, 1439, 1376,
1345, 1302, 1246, 1197, 1151, 1054, 1024, 980, 899, 844, 746, 649,
628, 579, 521, 457, 417 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO):
δ ϭ 11.80 (ws, 1 H, NH), 8.33 (s, 1 H, H-6), 6.31 (dd, 1 H, H-1Ј),
5.07 (d, 1 H, 3Ј-OH), 4.78 (dd, 1 H, 5Ј-OH), 4.36Ϫ4.40 (m, 1 H,
H-3Ј), 4.01 (ddd, 1 H, H-4Ј), 3.74 (ddd, 1 H, H-5Јb), 3.46 (ddd, 1
J3Ј,OH ϭ 3.7, J4Ј,5Јa ϭ 7.2, J4Ј,5Јb ϭ 5.7, J5Јa,5Јb ϭ 10.9, J5Јa,OH
ϭ
5.8, J5Јb,OH ϭ 4.8, J6,Me ϭ 1.2 Hz. Ϫ 13C NMR (126 MHz,
[D6]DMSO): δ ϭ 163.8 (4-CO), 151.0 (2-CO), 138.9 (C-6), 108.5
(C-5), 72.1 (C-3Ј), 61.0 (C-5Ј), 60.2 (C-1Ј), 57.6 (C-4Ј), 43.8 (C-2Ј),
12.7 (CH3). Ϫ FAB HRMS (mNBA): calcd. 259.0723 [M ϩ H]ϩ;
found 245.0757.
H, H-5Јa), 2.27 (ddd, 1 H, H-2Јb), 2.20 (ddd, 1 H, H-2Јa). J1Ј,2Јa
9.7, J1Ј,2Јb ϭ 6.7, J2Јa,3Ј ϭ 3.3, J2Јb,3Ј ϭ 2.0, J2Јa,2Јb ϭ 13.0, J3Ј,4Ј
ϭ
ϭ
1-(2-Deoxy-4-thio-L-threo-pentofuranosyl)-5-fluorouracil (25): Com-
3.3, J3Ј,OH ϭ 4.3, J4Ј,5Јa ϭ 7.8, J4Ј,5Јb ϭ 6.1, J5Јa,5Јb ϭ 10.8, J5Јa,OH ϭ
5.8, J5Јb,OH ϭ 4.8 Hz. Ϫ 13C NMR (126 MHz, [D6]DMSO): δ ϭ
159.0 (4-CO), 150.0 (2-CO), 139.3 (C-6), 107.8 (C-5), 72.2 (C-3Ј),
61.3 (C-1Ј), 61.2 (C-5Ј), 57.6 (C-4Ј), 43.9 (C-2Ј). Ϫ FAB MS
(mNBA); m/z: 279 [M ϩ H]ϩ Ϫ FAB HRMS (mNBA): calcd.
279.0206 [M ϩ H]ϩ; found 279.0209. Ϫ β-26: M.p. 190 °C. Ϫ
[α]2D0 ϭ ϩ12.8 (c ϭ 1.0, MeOH). Ϫ IR (KBr): ν˜ ϭ 3434, 3057,
2932, 2826, 1693, 1459, 1386, 1257, 1131, 1078, 1037, 971, 904,
797, 754, 626, 525, 443 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO):
δ ϭ 11.76 (ws, 1 H, NH), 8.67 (s, 1 H, H-6), 6.08 (dd, 1 H, H-1Ј),
5.43 (d, 1 H, 3Ј-OH), 4.93 (dd, 1 H, 5Ј-OH), 4.36 (dddd, 1 H, H-
3Ј), 3.85 (ddd, 1 H, H-5Јb), 3.64 (ddd, 1 H, H-5Јa), 3.57 (ddd, 1 H,
H-4Ј), 2.38 (ddd, 1 H, H-2Јb), 2.18 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.0,
J1Ј,2Јb ϭ 8.2, J2Јa,3Ј ϭ 2.3, J2Јb,3Ј ϭ 3.8, J2Јa,2Јb ϭ 14.4, J3Ј,4Ј ϭ 3.8,
pound 25 was prepared as described for 23; from 18 (165 mg,
0.39 mmol, α/β ϭ 1:2) in CH2Cl2 (1.3 mL), boron tribromide (0.17
mL, 449 mg, 1.79 mmol) in CH2Cl2 (1.7 mL) and silver carbonate
(1.86 g, 6.75 mmol). After chromatographic workup [silica gel,
CHCl3/MeOH, 4:1, Rf(A1) ϭ 0.33, Rf(A2) ϭ 0.25] and reversed-
phase HPLC (MeCN/H2O, 9:91), the separated anomers α-25 (12
mg, 37%) and β-25 (7 mg, 11%) were obtained as white solids. Ϫ
α-25: M.p. 213 °C. Ϫ [α]2D0 ϭ Ϫ63.8 (c ϭ 1.0, MeOH). Ϫ IR (KBr):
ν˜ ϭ 3439, 3213, 3066, 2928, 2807, 1707, 1661, 1479, 1385, 1243,
1
1122, 1070, 1029, 925, 865, 771, 709, 583, 529 cmϪ1. Ϫ H NMR
(500 MHz, [D6]DMSO): δ ϭ 11.32 (ws, 1 H, NH), 8.32 (d, 1 H,
H-6), 6.34 (ddd, 1 H, H-1Ј), 5.09 (d, 1 H, 3Ј-OH), 4.80 (ws, 1 H,
5Ј-OH), 4.39Ϫ4.42 (m, 1 H, H-3Ј), 3.99 (ddd, 1 H, H-4Ј), 3.75 (dd,
1 H, H-5Јb), 3.47 (dd, 1 H, H-5Јa), 2.28 (ddd, 1 H, H-2Јb), 2.16
J3Ј,OH ϭ 3.4, J4Ј,5Јa ϭ 7.4, J4Ј,5Јb ϭ 5.6, J5Јa,5Јb ϭ 10.7, J5Јa,OH
ϭ
(ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 9.7, J1Ј,2Јb ϭ 6.7, J1Ј,F ϭ 1.9, J2Јa,3Ј
3.3, J2Јb,3Ј ϭ 2.0, J2Јa,2Јb ϭ 13.0, J3Ј,4Ј ϭ 3.1, J3Ј,OH ϭ 4.1, J4Ј,5Јa
ϭ
5.7, J5Јb,OH ϭ 4.9 Hz. Ϫ 13C NMR (126 MHz, [D6]DMSO): δ ϭ
159.2 (4-CO), 150.2 (2-CO), 140.9 (C-6), 105.9 (C-5), 72.1 (C-3Ј),
62.3 (C-1Ј), 60.8 (C-5Ј), 58.6 (C-4Ј), 44.5 (C-2Ј). Ϫ FAB MS
(mNBA); m/z: 279 [M ϩ H]ϩ Ϫ FAB HRMS (mNBA): calcd.
279.0206 [M ϩ H]ϩ; found 279.02.09.
ϭ
7.6, J4Ј,5Јb ϭ 6.2, J5Јa,5Јb ϭ 10.8, J6,F ϭ 7.3 Hz. Ϫ 13C NMR
(126 MHz, [D6]DMSO): δ ϭ 157.5 (d, 4-CO), 149.5 (2-CO), 141.2
(d, C-5), 126.3 (d, C-6), 72.1 (C-3Ј), 61.2 (C-1Ј, C-5Ј), 57.5 (C-4Ј),
43.7 (C-2Ј). J4,F ϭ 26.2, J5,F ϭ 231.2, J6,F ϭ 34.4 Hz. Ϫ 19F NMR
(471 MHz, [D6]DMSO): δ ϭ Ϫ166.03 (dd, 1 F, F-5). JF,6 ϭ 7.3, 5-Bromo-1-(2-deoxy-4-thio-L-threo-pentofuranosyl)uracil (27): Com-
JF,NH ϭ 1.5 Hz. Ϫ FAB MS (mNBA); m/z: 263 [M ϩ H]ϩ. Ϫ MS
(70 eV); m/z: 262 (8) [Mϩ•], 133 (54) [C5H9O2Sϩ•], 130 (39)
pound 27 was prepared as described for 23; from 20 (570 mg,
1.13 mmol, α/β ϭ 1:2) in CH2Cl2 (6.0 mL), boron tribromide (0.51
[C4H3FN2O2ϩ•], 115 (27) [C5H7OSϩ•], 85 (100), 57 (30). Ϫ HRMS: mL, 1.35 g, 5.35 mmol) in CH2Cl2 (5.1 mL) and silver carbonate
calcd. 262.0424 [Mϩ•], 133.0323 [C5H9O2Sϩ•], 130.0179 (5.19 g, 18.82 mmol). After chromatographic workup [silica gel,
Eur. J. Org. Chem. 2001, 1077Ϫ1087
1083

J. Wirsching, J. Voss, G. Adiwidjaja, A. Giesler, J. Kopf
FULL PAPER
CHCl3/MeOH, 4:1, Rf(A1) ϭ 0.37, Rf(A2) ϭ 0.30] and reversed-
(s, 1 H, H-6), 6.05 (dd, 1 H, H-1Ј), 5.40 (d, 1 H, 3Ј-OH), 4.93 (dd,
phase HPLC (MeCN/H2O, 11:89), the separated anomers α-27 (20 1 H, 5Ј-OH), 4.36 (dddd, 1 H, H-3Ј), 3.85 (ddd, 1 H, H-5Јb), 3.64
mg, 16%) and β-27 (19 mg, 8%) were obtained as white solids. Ϫ
(ddd, 1 H, H-5Јa), 3.57 (ddd, 1 H, H-4Ј), 2.36 (ddd, 1 H, H-2Јb),
2.16 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.0, J1Ј,2Јb ϭ 8.1, J2Јa,3Ј ϭ 2.1,
α-27: M.p. 215 °C. Ϫ [α]2D0 ϭ Ϫ54.7 (c ϭ 1.0, MeOH). Ϫ IR (KBr):
ν˜ ϭ 3437, 3179, 3050, 2931, 2825, 1694, 1448, 1240, 1038, 903, 751, J2Јb,3Ј ϭ 3.9, J2Јa,2Јb ϭ 14.4, J3Ј,4Ј ϭ 3.9, J3Ј,OH ϭ 3.5, J4Ј,5Јa ϭ 7.5,
619, 502, 426 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO): δ ϭ 11.76 4Ј,5Јb ϭ 5.5, J5Јa,5Јb ϭ 10.6, J5Јa,OH ϭ 5.7, J5Јb,OH ϭ 4.9 Hz. Ϫ 13C
J
(ws, 1 H, NH), 8.38 (s, 1 H, H-6), 6.31 (dd, 1 H, H-1Ј), 5.06 (d, 1 NMR (126 MHz, [D6]DMSO): δ ϭ 160.6 (4-CO), 150.8 (2-CO),
H, 3Ј-OH), 4.78 (dd, 1 H, 5Ј-OH), 4.36Ϫ4.39 (m, 1 H, H-3Ј), 4.02 148.4 (C-6), 72.1 (C-3Ј), 67.8 (C-5), 62.2 (C-1Ј), 60.90 (C-5Ј), 58.6
(ddd, 1 H, H-4Ј), 3.74 (ddd, 1 H, H-5Јb), 3.46 (ddd, 1 H, H-5Јa),
2.27 (ddd, 1 H, H-2Јb), 2.21 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 9.7, J1Ј,2Јb ϭ
(C-4Ј), 44.7 (C-2Ј). Ϫ FAB MS (mNBA); m/z: 371 [M ϩ H]ϩ. Ϫ
FAB HRMS (mNBA): calcd. 370.9563 [M ϩ H]ϩ; found 370.9540.
6.8, J2Јa,3Ј ϭ 2.2, J2Јb,3Ј ϭ 2.0, J2Јa,2Јb ϭ 13.0, J3Ј,4Ј ϭ 3.3, J3Ј,OH
ϭ
1-(2-Deoxy-4-thio-β-L-threo-pentofuranosyl)-5-nitrouracil
(29):
4.3, J4Ј,5Јa ϭ 7.8, J4Ј,5Јb ϭ 6.1, J5Јa,5Јb ϭ 10.8, J5Јa,OH ϭ 5.9,
J5Јb,OH ϭ 4.8 Hz. Ϫ 13C NMR (126 MHz, [D6]DMSO): δ ϭ 159.1
(4-CO), 150.2 (2-CO), 141.7 (C-6), 96.4 (C-5), 72.3 (C-3Ј), 61.3 (C-
1Ј), 61.2 (C-5Ј), 57.6 (C-4Ј), 43.9 (C-2Ј). Ϫ MS (70 eV); m/z: 324
(2) [Mϩ•, for 81Br], 322 (2) [Mϩ•, for 79Br], 306 (8) [Mϩ• ϪH2O,
for 81Br], 304 (8) [Mϩ• ϪH2O, for 79Br], 192 (7) [C4H381BrN2O2ϩ•],
190 (7) [C4H379BrN2O2ϩ•], 133 (35) [C5H9O2Sϩ•], 115 (30)
[C5H7OSϩ•], 85 (100), 59 (9), 45 (10). Ϫ HRMS: calcd. 323.9601
[Mϩ•, for 81Br], 321.9603 [Mϩ•, for 79Br], 305.9496 [Mϩ• ϪH2O, for
81Br], 303.9468 [Mϩ• ϪH2O, for 79Br]; found 323.9628, 321.9602,
305.9524, 303.9491. Ϫ β-27: M.p. 201Ϫ203 °C. Ϫ [α]2D5 ϭ ϩ9.2 (c ϭ
1.0, MeOH). Ϫ IR (KBr): ν˜ ϭ 3428, 3053, 2934, 2826, 1692, 1453,
Compound 29 was prepared as described for 23; from 22 (170 mg,
0.36 mmol) in CH2Cl2 (8.0 mL), boron tribromide (0.17 mL, 449
mg, 1. 97 mmol) in CH2Cl2 (1.7 mL) and silver carbonate (1.73
g, 6.27 mmol). After chromatographic workup (silica gel, CHCl3/
MeOH, 4:1, Rf ϭ 0.34) and recrystallisation from H2O, 29 (9 mg,
9%) was obtained as a white solid. Ϫ M.p. 186Ϫ188 °C. Ϫ [α]2D5
ϭ
ϩ11.4 (c ϭ 0.9, MeOH). Ϫ IR (KBr): ν˜ ϭ 3453, 3171, 3076, 2959,
2826, 1708, 1612, 1509, 1456, 1378, 1343, 1303, 1255, 1101, 1018,
989, 906, 818, 757, 698, 624, 604, 512, 486 cmϪ1. Ϫ 1H NMR
(500 MHz, [D6]DMSO): δ ϭ 12.00 (ws, 1 H, NH), 9.84 (s, 1 H, H-
6), 6.04 (dd, 1 H, H-1Ј), 5.29 (d, 1 H, 3Ј-OH), 4.98 (dd, 1 H, 5Ј-
OH), 4.40 (dddd, 1 H, H-3Ј), 3.87Ϫ3.91 (m, 1 H, H-5Јb), 3.63Ϫ3.69
(m, 2 H, H-4Ј, H-5Јa), 2.35 (ddd, 1 H, H-2Јb), 2.31 (ddd, 1 H, H-
1
1267, 1122, 1078, 1035, 970, 833, 755, 618, 522, 435 cmϪ1. Ϫ H
NMR (500 MHz, [D6]DMSO): δ ϭ 11.70 (ws, 1 H, NH), 8.75 (s,
1 H, H-6), 6.07 (dd, 1 H, H-1Ј), 5.42 (d, 1 H, 3Ј-OH), 5.42 (d, 1
H, 3Ј-OH), 4.93 (dd, 1 H, 5Ј-OH), 4.36 (dddd, 1 H, H-3Ј), 3.85
(ddd, 1 H, H-5Јb), 3.64 (ddd, 1 H, H-5Јa), 3.57 (ddd, 1 H, H-4Ј),
2.37 (ddd, 1 H, H-2Јb), 2.18 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.0, J1Ј,2Јb ϭ
2Јa). J1Ј,2Јa ϭ 1.8, J1Ј,2Јb ϭ 6.7, J2Јa,3Ј ϭ 1.8, J2Јb,3Ј ϭ 3.3, J2Јa,2Јb
ϭ
14.5, J3Ј,4Ј ϭ 3.0, J3Ј,OH ϭ 3.0, J5Јa,OH ϭ 5.1, J5Јb,OH ϭ 5.1 Hz. Ϫ
13C NMR (126 MHz, [D6]DMSO): δ ϭ 154.9 (4-CO), 149.5 (2-
CO), 149.3 (C-6), 124.1 (C-5), 72.3 (C-3Ј), 65.2 (C-1Ј), 61.1 (C-5Ј),
59.4 (C-4Ј), 44.7 (C-2Ј). Ϫ FAB MS (mNBA); m/z: 290 [M ϩ H]ϩ.
Ϫ FAB HRMS (mNBA): calcd. 290.0447 [M ϩ H]ϩ; found
290.0430.
8.0, J2Јa,3Ј ϭ 2.2, J2Јb,3Ј ϭ 3.8, J2Јa,2Јb ϭ 14.5, J3Ј,4Ј ϭ 3.8, J3Ј,OH
ϭ
3.4, J4Ј,5Јa ϭ 7.5, J4Ј,5Јb ϭ 5.7, J5Јa,5Јb ϭ 10.6, J5Јa,OH ϭ 5.7,
J5Јb,OH ϭ 4.8 Hz. Ϫ 13C NMR (126 MHz, [D6]DMSO): δ ϭ 159.3
(4-CO), 150.4 (2-CO), 143.5 (C-6), 94.3 (C-5), 72.1 (C-3Ј), 62.4 (C-
1Ј), 60.9 (C-5Ј), 58.7 (C-4Ј), 44.6 (C-2Ј). Ϫ FAB MS (mNBA); m/z:
325 [M ϩ H, for 81Br], 323 [M ϩ H, for 79Br]. Ϫ FAB HRMS
(mNBA): calcd. 322.9701 [M ϩ H, for 79Br]; found 322.9766.
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)-4-thio-
uracil (30): A solution of 16 (710 mg, 1.67 mmol, α/β ϭ 2:1) and
Lawesson’s reagent (388 mg, 0.96 mmol) in dry 1,2-dichloroethane
(30 mL) was heated for 2.5 h at 83 °C. After the solution had been
allowed to cool to room temperature, the solvent was evaporated,
the residue was dissolved in CHCl3 and extracted with water, and
1-(2-Deoxy-4-thio-L-threo-pentofuranosyl)-5-iodouracil (28): Com-
pound 28 was prepared as described for 23; from 21 (400 mg, the organic phase was separated, dried with MgSO4 and concen-
0.73 mmol, α/β ϭ 1:2) in CH2Cl2 (3.5 mL), boron tribromide (0.32
mL, 845 mg, 3.37 mmol) in CH2Cl2 (3.2 mL) and silver carbonate
(3.40 g, 12.33 mmol). After chromatographic workup [silica gel,
CHCl3/MeOH 4:1, Rf(A1) ϭ 0.39, Rf(A2) ϭ 0.34] and reversed-
trated. The crude product was purified by silica gel column chro-
matography [petroleum ether/EtOAc, 2:1, Rf(α) ϭ 0.29, Rf(β) ϭ
0.21] to yield α-30 (405 mg, 83%) and β-30 (199 mg, 81%) as yellow
solids. Ϫ α-30: M.p. 139Ϫ141 °C (decomp.). Ϫ [α]2D0 ϭ Ϫ6.8 (c ϭ
phase HPLC (MeCN/H2O, 12:88), the separated anomers α-28 (21 1.0, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3077, 3030, 2924, 2854, 1705, 1614,
mg, 23%) and β-28 (14 mg, 8%) were obtained as white solids. A 1454, 1365, 1252, 1136, 1075, 1029, 759, 699 cmϪ1. Ϫ 1H NMR
portion of α-28 was used to grow single crystals (colourless
needles), suitable for X-ray structural analysis, from H2O. Ϫ α-17:
M.p. 210 °C (decomp.). Ϫ [α]2D0 ϭ Ϫ37.2 (c ϭ 1.0, MeOH). Ϫ IR
(KBr): ν˜ ϭ 3427, 3047, 2928, 2816, 1690, 1443, 1240, 1086, 908,
(500 MHz, CDCl3): δ ϭ 9.56 (ws, 1 H, NH), 7.57 (d, 1 H, H-6),
7.28Ϫ7.38 (m, 10 H, ArH), 6.45 (dd, 1 H, H-5), 6.40 (dd, 1 H, H-
1Ј), 4.52, 4.56 (AB system, 2 H, CH2Ph, JAB ϭ 11.9 Hz), 4.49, 4.62
(AB system, 2 H, CH2Ph, JAB ϭ 11.9 Hz), 4.31 (ddd, 1 H, H-3Ј),
612, 519 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO): δ ϭ 11.67 4.03 (ddd, 1 H, H-4Ј), 3.86 (dd, 1 H, H-5Јb), 3.66 (dd, 1 H, H-5Јa),
(ws, 1 H, NH), 8.36 (s, 1 H, H-6), 6.32 (dd, 1 H, H-1Ј), 5.08 (d, 1 2.77 (ddd, 1 H, H-2Јb), 1.86 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 8.3, J1Ј,2Јb ϭ
H, 3Ј-OH), 4.80 (dd, 1 H, 5Ј-OH), 4.38Ϫ4.41 (m, 1 H, H-3Ј), 4.04 6.8, J2Јa,3Ј ϭ 3.7, J2Јb,3Ј ϭ 3.5, J2Јa,2Јb ϭ 13.6, J3Ј,4Ј ϭ 3.8, J4Ј,5Јa
ϭ
(ddd, 1 H, H-4Ј), 3.76 (ddd, 1 H, H-5Јb), 3.48 (ddd, 1 H, H-5Јa), 6.9, J4Ј,5Јb ϭ 6.4, J5Јa,5Јb ϭ 9.2, J5,6 ϭ 7.7, J5,NH ϭ 1.6 Hz. Ϫ 13C
2.27 (ddd, 1 H, H-2Јb), 2.23 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 9.7, J1Ј,2Јb ϭ NMR (125 MHz, CDCl3): δ ϭ 189.0 (4-CS), 148.1 (2-CO), 137.6
6.9, J2Јa,3Ј ϭ 3.3, J2Јb,3Ј ϭ 2.1, J2Јa,2Јb ϭ 13.0, J3Ј,4Ј ϭ 3.2, J3Ј,OH
ϭ
(Cq), 137.4, 135.3 (C-6), 128.53 (CArH), 128.47, 128.0, 127.9, 127.8,
4.3, J4Ј,5Јa ϭ 7.8, J4Ј,5Јb ϭ 6.0, J5Јa,5Јb ϭ 10.8, J5Јa,OH ϭ 5.9,
127.7, 114.1 (C-5), 79.9 (C-3Ј), 73.6 (CH2Ph), 71.8(CH2Ph), 69.2
J5Јb,OH ϭ 4.7 Hz. Ϫ 13C NMR (126 MHz, [D6]DMSO): δ ϭ 160.5 (C-5Ј), 61.8 (C-1Ј), 53.1 (C-4Ј), 41.5 (C-2Ј). Ϫ FAB MS (mNBA);
(4-CO), 150.6 (2-CO), 146.2 (C-6), 72.3 (C-3Ј), 70.2 (C-5), 61.3 (C-
5Ј), 61.0 (C-1Ј), 57.6 (C-4Ј), 43.9 (C-2Ј). Ϫ FAB MS (mNBA); m/z: ϩ9.3 (c ϭ1.0, CHCl3). Ϫ IR (KBr): ν˜ ϭ 3079, 3030, 2925, 2855,
m/z: 441 [M ϩ H]ϩ. Ϫ β-30: M.p. 155Ϫ157 °C (decomp.). Ϫ [α]2D5
ϭ
371 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd. 370.9563 [M ϩ
1998, 1615, 1495, 1454, 1368, 1255, 1211, 1178, 1135, 1030, 760,
700, 668 cmϪ1. Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 9.43 (ws, 1
H, NH), 8.01 (d, 1 H, H-6), 7.28Ϫ7.39 (m, 10 H, ArH), 6.18 (dd,
1 H, H-1Ј), 6.08 (wd, 1 H, H-5), 4.60, 4.57 (AB system, 2 H,
H]ϩ; found 370.9476. Ϫ β-28: M.p. 195 °C (decomp.). Ϫ [α]2D5
ϭ
ϩ30.4 (c ϭ 1.0, MeOH) Ϫ IR (KBr): ν˜ ϭ 3431, 3066, 2927, 2853,
1688, 1450, 1385, 1274, 1118, 1077, 1036, 938, 756, 611 cmϪ1. Ϫ
1H NMR (500 MHz, [D6]DMSO): δ ϭ 11.59 (ws, 1 H, NH), 8.78 CH2Ph, JAB ϭ 11.6 Hz), 4.44 (s, 2 H, CH2Ph), 4.27 (ddd, 1 H, H-
1084
Eur. J. Org. Chem. 2001, 1077Ϫ1087

2Ј-Deoxy-4Ј-thio-
L
-threo-pentofuranosylpyrimidine
FULL PAPER
3Ј), 3.93 (dd, 1 H, H-5Јb), 3.77Ϫ3.84 (m, 2 H, H-4Ј, H-5Јa), 2.45 gel; CHCl3/MeOH, 9:1, Rf(β) ϭ 0.23, Rf(α) ϭ 0.14] to yield the
(ddd, 1 H, H-2Јb), 2.34 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 7.4, J1Ј,2Јb
3.2, J2Јa,3Ј ϭ 4.0, J2Јb,3Ј ϭ 3.7, J2Јa,2Јb ϭ 14.4, J3Ј,4Ј ϭ 4.0, J4Ј,5Јb
ϭ
ϭ
cytidines α-32 (292 mg, 71%) and β-32 (203 mg, 74%) as white
solids. Ϫ α-32: M.p. 144 °C (decomp.). Ϫ [α]2D5 ϭ ϩ2.7 (c ϭ 1.0,
CHCl3). Ϫ FAB MS (mNBA); m/z: 424 [M ϩ H]ϩ. Ϫ FAB HRMS
6.0, J5Јa,5Јb ϭ 8.9, J5,6 ϭ 7.7, J5,NH Ͻ 0.5 Hz. Ϫ 13C NMR
(125 MHz, CDCl3): δ ϭ 189.2 (4-CS), 148.7 (2-CO), 137.8 (C-6), (mNBA): calcd. 424.1695 [M ϩ H]ϩ; found 424.1742. Ϫ β-32: M.p.
137.6, 136.9 (Cq), 128.54, 128.48, 128.1, 127.93, 127.87, 127.8
156Ϫ158 °C (decomp.). Ϫ [α]2D0 ϭ Ϫ58.1 (c ϭ 1.0, CHCl3). Ϫ FAB
424.1695 [M ϩ H]ϩ; found 424.1715.
1-(2-Deoxy-4-thio-
-threo-pentofuranosyl)cytosine (33):[34] Com-
(CArH), 112.5 (C-5), 79.8 (C-3Ј), 73.5 (CH2Ph), 71.3, (CH2Ph), 68.8 MS (mNBA); m/z: 424 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd.
(C-5Ј), 62.2 (C-1Ј), 53.6 (C-4Ј), 41.3 (C-2Ј). Ϫ FAB MS (mNBA);
m/z: 441 [M ϩ H]ϩ.
L
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)-4-(1,2,4-
pound 33 was prepared as described for 23; from 32 (487 mg,
1.15 mmol, α/β ϭ 3:2) in CH2Cl2 (4.0 mL), boron tribromide (0.51
mL, 1.35 g, 5.39 mmol) in CH2Cl2 (5.1 mL) and silver carbonate
(5.20 g, 18.86 mmol). After chromatographic workup [silica gel,
CHCl3/MeOH, 2:1, Rf(β) ϭ 0.31, Rf(α) ϭ 0.27], it was possible to
isolate a proportion of α-33 (27 mg, 16%) as the pure anomer
(white solid). β-33 was obtained as a 1:1 mixture with α-33 [total:
46 mg, β-33 (calcd. yield): 23 mg, 21%]. Ϫ α-33: M.p. 185 °C. Ϫ
[α]2D0 ϭ Ϫ61.5 (c ϭ 1.0, MeOH). Ϫ IR (KBr): ν˜ ϭ 3404, 3204,
3007, 2929, 1721, 1650, 1529, 1490, 1406, 1277, 1197, 1049, 956,
788, 703, 617, 564 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO): δ ϭ
8.09 (ws, 1 H, NHH), 8.02 (d, 1 H, H-6), 7.59 (ws, 1 H, NHH),
6.31 (dd, 1 H, H-1Ј), 5.87 (d, 1 H, H-5), 5.05 (ws, 1 H, 3Ј-OH),
4.74 (ws, 1 H, 5Ј-OH), 4.37Ϫ4.38 (m, 1 H, H-3Ј), 3.84 (ddd, 1 H,
H-4Ј), 3.70 (dd, 1 H, H-5Јb), 3.41 (dd, 1 H, H-5Јa), 2.24 (ddd, 1 H,
triazol-1-yl)pyrimidine-2(1H)-one (31): Phosphoryl chloride (3.0
mL, 5.04 g, 32.87 mmol) was added to a suspension of 1,2,4-tria-
zole (10.42 g, 151 mmol) in anhydrous MeCN (30.0 mL) at room
temperature, and the suspension was cooled in an ice bath to 0
°C. Triethylamine (20.0 mL, 14.6 g, 144 mmol) was added to the
suspension, the ice bath was removed, a solution of 16 (1.07 g,
2.52 mmol, α/β ϭ 3:2) in MeCN (10.0 mL) was added and the
mixture was stirred at room temperature for 2 h. After the reaction
was complete, triethylamine (13.8 mL) and water (3.6 mL) were
added and stirring was continued for 0.5 h. Solid components were
filtered off, the solvents were removed under reduced pressure, and
the residue was dissolved in CHCl3 and extracted with satd aq
NaHCO3 solution (100 mL) and water (100 mL). The organic
phase was dried with MgSO4 and concentrated, and the resulting
crude product was purified by silica gel column chromatography
[petroleum ether/EtOAc, 1:3, Rf(α,β) ϭ 0.14] to yield pure 31 (825
mg, 72%, α/β ϭ 3:2) as a colourless, resinous solid. The anomers
were inseparable. Ϫ IR (KBr): ν˜ ϭ 3116, 3062, 3030, 2924, 2860,
1674, 1626, 1547, 1507, 1465, 1416, 1379, 1364, 1283, 1241, 1178,
1088, 1027, 987, 928, 874, 783, 737, 698, 670, 629 cmϪ1. Ϫ α-31:
1H NMR (400 MHz, CDCl3): δ ϭ 9.26 (s, 1 H, Htriazole), 8.58 (d,
1 H, H-6), 8.12 (s, 1 H, Htriazole), 7.05Ϫ7.38 (m, 10 H, ArH), 7.08
(d, 1 H, H-5), 6.54 (d, 1 H, H-1Ј), 4.58, 4.54 (AB system, 2 H,
CH2Ph, JAB ϭ 11.9 Hz), 4.50, 4.65 (AB system, 2 H, CH2Ph, JAB ϭ
11.9 Hz), 4.31Ϫ4.33 (m, 1 H, H-3Ј), 4.07 (ddd, 1 H, H-4Ј),
3.87Ϫ3.93 (m, 1 H, H-5Јb), 3.70 (dd, 1 H, H-5Јa), 3.00 (ddd, 1 H,
H-2Јb), 2.00 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 9.4, J1Ј,2Јb ϭ 6.6, J2Јa,3Ј
3.6, J2Јb,3Ј ϭ 2.4, J3Ј,4Ј ϭ 3.5, J4Ј,5Јa ϭ 7.6, J4Ј,5Јb ϭ 6.3, J5Јa,5Јb
ϭ
ϭ
10.6, J5,6 ϭ 7.6 Hz. Ϫ 13C NMR (126 MHz, [D6]DMSO): δ ϭ 44.3
(C-2Ј), 57.3 (C-4Ј), 61.2 (C-5Ј), 61.2 (C-1Ј), 72.25 (C-3Ј), 95.0 (C-
5), 144.1 (C-6), 157.3, 163.4 (2-CO, C-4). Ϫ FAB MS (mNBA);
m/z: 244 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd. 244.0756 [M
ϩ H]ϩ; found 244.0746. Ϫ β-33: IR (KBr, 1:1 mixture with α-33):
ν˜ ϭ 3389, 2926, 2855, 1714, 1666, 1537, 1405, 1278, 1097, 1075,
1017, 919, 810, 758, 616 cmϪ1
. Ϫ
1H NMR (500 MHz,
[D6]DMSO): δ ϭ 8.88 (ws, 1 H, NHH), 8.55 (d, 1 H, H-6), 7.92
(ws, 1 H, NHH), 6.08 (dd, 1 H, H-1Ј), 6.03 (d, 1 H, H-5), 5.21 (ws,
1 H, 3Ј-OH), 4.91 (ws, 1 H, 5Ј-OH), 4.38Ϫ4.41 (m, 1 H, H-3Ј),
3.89 (dd, 1 H, H-5Јb), 3.65 (dd, 1 H, H-5Јa), 3.60 (ddd, 1 H, H-4Ј),
2.38 (ddd, 1 H, H-2Јb), 2.21 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.2, J1Ј,2Јb ϭ
H-2Јb), 1.92 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 7.2, J1Ј,2Јb ϭ 6.9, J2Јa,3Ј
3.8, J2Јb,3Ј ϭ 4.2, J2Јa,2Јb ϭ 13.8, J3Ј,4Ј ϭ 4.3, J4Ј,5Јa ϭ 7.5, J4Ј,5Јb
ϭ
ϭ
6.0, J5Јa,5Јb ϭ 9.4, J5,6 ϭ 7.3 Hz. Ϫ 13C NMR (101 MHz, CDCl3):
δ ϭ 158.9, 154.9 (2-CO, C-4), 154.0 (Ctriazole), 147.8 (C-6), 143.3
(Ctriazole), 137.7, 137.4 (Cq), 128.53, 128.47, 127.99, 127.90, 127.8,
127.7 (CArH), 95.2 (C-5), 78.0 (C-3Ј), 73.6 (CH2Ph), 71.8 (CH2Ph),
7.7, J2Јa,3Ј ϭ 2.3, J2Јb,3Ј ϭ 3.8, J3Ј,4Ј ϭ 3.5, J4Ј,5Јa ϭ 7.7, J4Ј,5Јb
ϭ
5.5, J5Јa,5Јb ϭ 10.6, J5,6 ϭ 7.8 Hz. Ϫ 13C NMR (126 MHz,
[D6]DMSO): δ ϭ 160.31, 158.9 (2-CO, 4-C), 147.6 (C-6), 93.2 (C-
5), 72.4 (C-3Ј), 63.9 (C-1Ј), 61.0 (C-5Ј), 57.7 (C-4Ј), 44.6 (C-2Ј).
1
69.4 (C-5Ј), 63.8 (C-1Ј), 52.9 (C-4Ј), 42.2 (C-2Ј). Ϫ β-31: H NMR
9-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)adenine
(400 MHz, CDCl3): δ ϭ 9.25 (s, 1 H, Htriazole), 8.11 (s, 1 H,
Htriazole), 8.08 (d, 1 H, H-6), 7.05Ϫ7.38 (m, 10 H, ArH), 6.61 (d, 1
H, H-5), 6.29 (d, 1 H, H-1Ј), 4.63, 4.59 (AB-system, 2 H, CH2Ph,
JAB ϭ 11.7 Hz), 4.31Ϫ4.33 (m, 1 H, H-3Ј), 4.28, 4.35 (AB system,
2 H, CH2Ph, JAB ϭ 11.3 Hz), 4.00 (dd, 1 H, H-5Јb), 3.87Ϫ3.93 (m,
1 H, H-4Ј), 3.85 (dd, 1 H, H-5Јa), 2.72 (ddd, 1 H, H-2Јb), 2.41 (ddd,
1 H, H-2Јa). J1Ј,2Јa ϭ 7.1, J1Ј,2Јb ϭ 2.1, J2Јa,3Ј ϭ 3.6, J2Јb,3Ј ϭ 2.6,
(34): A solution of 15 (1.05 g, 2.95 mmol), adenine (746 mg,
˚
5.52 mmol) and 4-A molecular sieves (100 mg) in dry MeCN (26
mL) was cooled to Ϫ18 °C and TMSOTf (1.94 mL, 2.39 g,
10.74 mmol) was added. The reaction mixture was stirred for 2 h
and the temperature was allowed to rise to room temperature. The
mixture was then quenched with an excess of saturated aq
NaHCO3 solution and stirred for another 0.5 h. The solids were
filtered off and the filtrate was extracted with CHCl3. The organic
phase was separated, dried with MgSO4 and concentrated. The re-
sulting crude product was purified by silica gel chromatography
[CHCl3/MeOH, 9:1, Rf(α,β) ϭ 0.34] to yield 34 (871 mg, 66%) as
an amorphous solid. The anomers were inseparable. FAB MS
(mNBA); m/z: 448 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd.
448.1807 [M ϩ H]ϩ; found 448.1849.
J2Јa,2Јb ϭ 14.7, J4Ј,5Јa ϭ 6.1, J4Ј,5Јb ϭ 6.0, J5Јa,5Јb ϭ 8.4, J5,6
ϭ
7.3 Hz. Ϫ 13C NMR (101 MHz, CDCl3): δ ϭ 158.8, 154.9 (2-CO,
C-4), 153.8 (Ctriazole), 150.5 (C-6), 143.2 (Ctriazole), 137.7, 136.8 (Cq),
128.6, 128.4, 128.1, 128.0, 127.9, 127.8 (CArH), 93.5 (C-5), 80.1 (C-
3Ј), 73.6 (CH2Ph), 71.5 (CH2Ph), 68.8 (C-5Ј), 65.6 (C-1Ј), 54.4 (C-
4Ј), 41.5 (C-2Ј). Ϫ FAB MS (mNBA); m/z: 476 [M ϩ H]ϩ.
1-(3,5-Di-O-benzyl-2-deoxy-4-thio-L-threo-pentofuranosyl)cytosine
(32): A solution of 31 (774 mg, 1.69 mmol, α/β ϭ 3:2) in 1,4-diox-
ane (20 mL) and ammonia (25% NH3 in H2O, 9.6 mL) was stirred
at room temperature for 24 h. The solvents were evaporated, the
residue was dissolved in CHCl3 and extracted with water, and the
organic phase was separated, dried with MgSO4 and concentrated.
The crude product was purified by column chromatography [silica
9-(3,5-Di-O-benzyl-2-deoxy-4-thio-β-L-threo-pentofuranosyl)inosine
(35): Compound 35 was prepared as described for 34; from 15 (375
˚
mg, 1.05 mmol), hypoxanthine (287 mg, 2.11 mmol), 4-A molecular
sieves (40 mg), TMSOTf (0.99 mL, 1.22 g, 5.48 mmol) and MeCN
(15 mL). After chromatographic workup (CHCl3/MeOH, 9:1, Rf ϭ
Eur. J. Org. Chem. 2001, 1077Ϫ1087
1085

J. Wirsching, J. Voss, G. Adiwidjaja, A. Giesler, J. Kopf
FULL PAPER
0.31), pure β-35 (322 mg, 68%) was obtained as a white solid. Ϫ
Supporting Information Available: 1H NMR, 13C NMR, IR and MS
M.p. 116Ϫ118 °C. Ϫ [α]2D0 ϭ Ϫ2.0 (c ϭ 1.0, CHCl3). Ϫ FAB MS data of 11, 13, 15؊22, 32, 34, 35 (see also footnote on the first
(mNBA); m/z ϭ 449 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd.
449.1647 [M ϩ H]ϩ; found 449.1694.
page of this article).
9-(2-Deoxy-4-thio-L-threo-pentofuranosyl)adenine (36): Compound
Acknowledgments
36 was prepared as described for 23; from 34 (500 mg, 1.12 mmol,
α/β ϭ 1:5) in CH2Cl2 (4.0 mL), boron tribromide (0.50 mL, 1.32
g, 5.27 mmol) in CH2Cl2 (5.0 mL) and silver carbonate (5.20 g,
18.86 mmol). After chromatographic workup [silica gel, CHCl3/
MeOH, 2:1, Rf(α,β) ϭ 0.26] and reversed-phase HPLC (MeCN/
H2O, 8:92), the separated anomers α-36 (6 mg, 12%) and β-36 (32
mg, 13%) were obtained as white solids. A portion of β-36 was
used to grow a single crystal (small, colourless needles), which was
suitable for X-ray structural analysis. Ϫ α-36: M.p. 183 °C. Ϫ
[α]2D0 ϭ Ϫ13.9 (c ϭ 0.3, MeOH). Ϫ IR (KBr): ν˜ ϭ 3440, 3188,
3030, 2956, 2860, 1665, 1603, 1474, 1421, 1372, 1310, 1265, 1180,
1112, 1050, 997, 915, 797, 699, 640, 595, 537, 476 cmϪ1. Ϫ 1H
NMR (500 MHz, [D6]DMSO): δ ϭ 2.47Ϫ2.51 (m, 1 H, H-2Јa; co-
vered by DMSO), 2.73 (ddd, 1 H, H-2Јb), 3.49 (ddd, 1 H, H-5Јa),
3.80 (ddd, 1 H, H-5Јb), 4.02 (ddd, 1 H, H-4Ј), 4.54Ϫ4.57 (m, 1 H,
H-3Ј), 4.78 (dd, 1 H, 5Ј-OH), 5.16 (d, 1 H, 3Ј-OH), 6.32 (dd, 1 H,
H-1Ј), 7.22 (br. s, 2 H, NH2), 8.13 (s, 1 H, Hade), 8.40 (s, 1 H, Hade).
J1Ј,2Јa ϭ 6.5, J1Ј,2Јb ϭ 9.3, J2Јb,3Ј ϭ 3.6, J2Јa,2Јb ϭ 12.9, J3Ј,4Ј ϭ 3.6,
The Deutsche Forschungsgemeinschaft and the Fonds der Chem-
ischen Industrie are gratefully acknowledged for their financial sup-
port. We would like to thank DegussaϪHüls AG for supporting
this work by supplying silver carbonate. We also thank Prof. Dr.
Chris Meier and Dipl.-Chem. Andreas Lomp, University of Ham-
burg, for making their HPLC equipment available to us.
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J3Ј,OH ϭ 4.0, J4Ј,5Јa ϭ 7.6, J4Ј,5Јb ϭ 6.1, J5Јa,5Јb ϭ 10.8, J5Јa,OH
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[7a] M. R. Dyson, P. L. Coe, R. T. Walker, J. Med. Chem. 1991,
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(Cade), 72.4 (C-3Ј), 61.2 (C-5Ј), 58.8 (C-1Ј), 57.6 (C-4Ј), 44.3 (C-2Ј).
Ϫ FAB MS (mNBA); m/z: 268 [M ϩ H]ϩ. Ϫ FAB HRMS (mNBA):
calcd. 268.0868; found 268.0890. Ϫ β-36: M.p. 206Ϫ208 °C (de-
comp.). Ϫ [α]2D5 ϭ ϩ15.0 (c ϭ 0.5, MeOH). Ϫ IR (KBr): ν˜ ϭ 3318,
3146, 2969, 2899, 1662, 1604, 1474, 1420, 1372, 1293, 1239, 1208,
1177, 1075, 998, 909, 815, 797, 699, 641, 596, 574, 539 cmϪ1. Ϫ 1H
NMR (500 MHz, [D6]DMSO): δ ϭ 8.47 (s, 1 H, Hade), 8.12 (s, 1
H, Hade), 7.21 (ws, 2 H, NH2), 6.19 (dd, 1 H, H-1Ј), 5.56 (ws, 1 H,
3Ј-OH), 4.88 (ws, 1 H, 5Ј-OH), 4.45Ϫ4.50 (m, 1 H, H-3Ј),
3.89Ϫ3.96 (m, 1 H, H-5Јb), 3.63Ϫ3.70 (m, 2 H, H-4Ј, H-5Јa), 2.56
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34, 2782Ϫ2786. Ϫ
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Dukhan, F. De Valette, R. Marquet, B. Ehresman, C. Ehres-
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(ddd, 1 H, H-2Јb), 2.46 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.6, J1Ј,2Јb
ϭ
[11] [11a]
L. S. Jeong, H. R. Moon, Y. J. Choi, M. W. Chun, H. O.
8.0, J2Јa,3Ј ϭ 2.9, J2Јb,3Ј ϭ 4.1, J2Јa,2Јb ϭ 14.2 Hz. Ϫ 13C NMR
(126 MHz, [D6]DMSO): δ ϭ 156.1 (Cade), 152.4 (CHade), 149.2
(Cade), 140.7 (CHade), 118.9 (Cade), 72.6 (C-3Ј), 61.1 (C-5Ј), 58.3
(C-4Ј), 58.2 (C-1Ј), 44.4 (C-2Ј). Ϫ FAB MS (mNBA); m/z: 268 [M
ϩ H]ϩ. Ϫ FAB HRMS (mNBA): calcd. 268.0868; found 268.0873.
[11b]
Kim, J. Org. Chem. 1998, 63, 4821Ϫ4825. Ϫ
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H. R. Moon, S. J. Yoo, S. N. Lee, M. W. Chun, Y.-H. Lim,
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9-(2-Deoxy-4-thio-β-L-threo-pentofuranosyl)inosine (37): Prepara-
[14]
[15]
tion of 37 was carried out as described for 23; using 35 (503 mg,
1.12 mmol) in CH2Cl2 (4.0 mL), boron tribromide (0.50 mL, 1.32
g, 5.27 mmol) in CH2Cl2 (5.0 mL) and silver carbonate (5.20 g,
18.86 mmol). After chromatographic workup (silica gel, CHCl3/
MeOH, 2:1, Rf ϭ 0.27) and reversed-phase HPLC (MeCN/H2O,
9:91), 37 (19 mg, 6%) was obtained as a white solid. Ϫ M.p. 205
°C. Ϫ [α]2D5 ϭ ϩ41.3 (c ϭ 1.0, MeOH). Ϫ IR (KBr): ν˜ ϭ 3422,
3052, 2923, 1697, 1588, 1545, 1415, 1373, 1201, 1093, 971, 906,
789, 648, 599 cmϪ1. Ϫ 1H NMR (500 MHz, [D6]DMSO): δ ϭ 12.27
(ws, 1 H, NH), 8.43 (s, 1 H, Hino), 8.03 (s, 1 H, Hino), 6.14 (dd, 1
H, H-1Ј), 5.38 (d, 1 H, 3Ј-OH), 4.86 (dd, 1 H, 5Ј-OH), 4.47Ϫ4.50
(m, 1 H, H-3Ј), 3.91 (ddd, 1 H, H-5Јb), 3.63Ϫ3.69 (m, 2 H, H-4Ј,
H-5Јa), 2.55 (ddd, 1 H, H-2Јb), 2.45 (ddd, 1 H, H-2Јa). J1Ј,2Јa ϭ 2.5,
[16]
[17]
[18]
[19]
[20]
[21]
[22]
D. Seebach, Synthesis 1969, 17Ϫ36.
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[23]
J1Ј,2Јb ϭ 7.9, J2Јa,3Ј ϭ 2.8, J2Јb,3Ј ϭ 4.0, J2Јa,2Јb ϭ 14.2, J3Ј,OH ϭ 3.9,
˚
J. Branalt, I. Kvarnström, G. Niklasson, S. C. T. Svensson, J.
J4Ј,5Јb ϭ 9.6, J5Јa5Јb ϭ 9.6, J5Јa,OH ϭ 5.7, J5Јb,OH ϭ 4.8 Hz. Ϫ 13C
NMR (126 MHz, [D6]DMSO): δ ϭ 156.7 (Cino), 148.1 (Cino), 145.7
(CHino), 140.1 (CHino), 124.0 (Cino), 72.5 (C-3Ј), 61.1 (C-5Ј), 58.7
(C-1Ј), 58.2 (C-4Ј), 44.5 (C-2Ј). Ϫ FAB MS (mNBA); 269 [M ϩ
H]ϩ. Ϫ FAB HRMS (mNBA): calcd. 269.0708 [M ϩ H]ϩ; found
269.0656.
Org. Chem. 1994, 59, 1783Ϫ1788.
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S. G. Rahim, N. Trivedi, M.V. Bogunovic-Batchelor, G. W.
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39, 789Ϫ795.
1086
Eur. J. Org. Chem. 2001, 1077Ϫ1087

2Ј-Deoxy-4Ј-thio- -threo-pentofuranosylpyrimidine
L
FULL PAPER
Direct Methods and Refinement, Bari, Perugia, Rome, Italy,
1997.
G. M. Sheldrick, SHELXL-97: Program for Crystal Structure
Refinement, University of Göttingen, Göttingen, Germany,
1997.
The elemental analyses of 13 and 20 deviate by approx. 1%
from the calcd. values due to impurities.
[26]
G. P. Otter, M. I. Elzagheid, G. D. Jones, A. C. MacCulloch,
R. T. Walker, M. Oivanen, K. D. Klika, J. Chem. Soc., Perkin
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H. Aoyama, Bull. Chem. Soc. Jpn. 1987, 60, 2073Ϫ2077.
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[34]
J. A. Secrist III, K. N. Tiwari, A. T. Shortnacy-Fowler, L. Mes-
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The structures of 23 and 33 have been erroneously reported
by J.-C. G. Graciet, R. F. Schinazi, ‘‘From - to -Nucleoside
Analogs as Antiviral Agents’’, in Advances in Antiviral Drug
Design (Ed.: E. De Clercq), JAI Press Inc., Stamford Con-
necticut, 1999, vol. 3, pp. 1Ϫ68, esp. p. 55. The cited com-
pounds belong, however, to the 2-deoxy--ribo rather than the
2-deoxy--threo series according to ref.[29]
[29]
[30]
[31]
J. Uenishi, K. Takahashi, M. Motoyama, H. Akashi, T. Sasaki,
Nucleosides Nucleotides 1994, 13, 1347Ϫ1361.
Autorenkollektiv, Organikum, 19th ed., Johann Ambrosius
Barth Verlag, Leipzig, 1993, pp. 659Ϫ681.
A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, A.
G. G. Moliterni, M. C. Burla, G. Polidori, M. Camalli, R.
Spagna, SIR97: A Package for Crystal Structure Solution by
Received July 20, 2000
[O00370]
Eur. J. Org. Chem. 2001, 1077Ϫ1087
1087