Stereocontrolled synthesis of ara-type cyclohexenyl nucleosides

Article abstract of DOI:10.1021/jo0300946

A highly stereocontrolled synthesis of a new class of carbocyclic nucleosides, ara-type cyclohexenyl nucleosides, was developed. The key intermediate (±)-9 was obtained after a series of transformations starting from easily available endo-bicyclo carboxyl

Full text of DOI:10.1021/jo0300946

Ster eocon tr olled Syn th esis of Ar a -Typ e Cycloh exen yl Nu cleosid es
J ing Wang, Dolores Vin˜a, Roger Busson, and Piet Herdewijn*
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
piet.herdewijn@rega.kuleuven.ac.be
Received March 18, 2003
A highly stereocontrolled synthesis of a new class of carbocyclic nucleosides, ara-type cyclohexenyl
nucleosides, was developed. The key intermediate (()-9 was obtained after a series of transforma-
tions starting from easily available endo-bicyclo carboxylic acid (()-3. The allylic hydroxyl group
of (()-9 was masked via oxidation with manganese dioxide and released, after protection of the
2′-hydroxyl group, via reduction with NaBH4 in the presence of CeCl3‚7H2O. The base moiety was
introduced with use of the Mitsunobu methodology.
In tr od u ction
Cyclohexenyl nucleosides are a newly emerging class
of carbocyclic nucleosides in which the sugar ring of a
natural nucleoside is replaced by a cyclohexene ring.1-7
Cyclohexenyl nucleosides possess the properties of car-
bocyclic nucleosides, which due to the absence of an
anomeric center are stable against chemical and enzy-
matic degradation. The presence of the double bond
induces flexibility in the ring, similar to the flexibility of
a furanose nucleoside. From a stereoelectronic point of
view, the carbon-carbon double bond may take the
function of the oxygen atom of a furanose. The resulting
πfσ*C1′-N interaction mimics the anomeric effect of a
natural nucleoside and considerably reduces the energy
difference among the different conformers of a cyclohex-
ene ring.2 These nucleosides are therefore conformation-
ally flexible and can be considered as the isosteres of
natural nucleosides.
F IGURE 1. Structure of representative examples of cyclo-
hexenyl nucleosides.
Previously, we have demonstrated that D-cyclohexenyl
guanine is an interesting antiviral agent.1 It shows
selective anti-herpesvirus activity. Its activity profile is
comparable to that of the known antiviral drug ganci-
clovir. This compound represents the most potent anti-
viral nucleoside with a six-membered carbohydrate moi-
ety that has been reported.
in an equilibrium between two-half-chair conformations
(3H2 and 2H3) and that the 3H2 conformation with the base
3
moiety in a pseudoaxial position predominates.4 The H2
and 2H3 conformations resemble the 3′-endo and 3′-exo
sugar conformations, respectively, of a natural nucleo-
side. It is generally accepted that conformational flex-
ibility is important for potent antiviral activity,8 because
metabolic activation of a nucleoside (by enzymes) may
require different conformations at the different phospho-
rylation steps. Therefore a rapid equilibrium between the
different conformers of a nucleoside may support potent
antiviral activity. Besides the remarkable antiviral activ-
ity of cyclohexenyl nucleosides, cyclohexenyl nucleic acids
hybridize with both DNA and RNA, further demonstrat-
ing their conformational flexibility. They hold the promise
as potential antisense candidates.5
Conformational analysis of these cyclohexenyl nucleo-
sides shows that at the single molecular level they exist
(1) Wang, J .; Froeyen, M.; Hendrix, C.; Andrei, G.; Snoeck, R.; De
Clercq, E.; Herdewijn, P. J . Med. Chem. 2000, 43(4), 736-745.
References for related six-membered carbocyclic nucleosides are cited
therein.
(2) Herdewijn, P.; De Clercq, E. Bioorg. Med. Chem. Lett. 2001, 11,
1591-1597.
(3) Wang, J .; Morral, J .; Hendrix, C.; Herdewijn, P. J . Org. Chem.
2001, 66, 8478-8482.
(4) Wang, J .; Herdewijn, P. J . Org. Chem. 1999, 64 (21), 7820-7827
(5) Wang, J .; Verbeure, B.; Luyten, I.; Froeyen, M.; Hendrix, C.;
Rosemeyer, H.; Seela, F.; Van Aerschot, A.; Herdewijn, P. J . Am. Chem.
Soc. 2000, 122 (36), 8595-8602.
(6) Wang, J .; Herdewijn, P. Perspectives in Nucleoside and Nucleic
Acid Chemistry; Verlag Helvetica Chimica Acta: Zu¨rich, Switzerland,
2000; pp 95-108.
(7) Wang, J .; Busson, R.; Blaton, N.; Rozenski, J .; Herdewijn, P. J .
Org. Chem. 1998, 63, 3051-3058.
In continuation of our study on cyclohexenyl nucleo-
sides and to further understand their structure-activity
relationship, we synthesized the ara-type cyclohexenyl
nucleosides 2a -d (Figure 1). The additional OH group
(8) Herdewijn, P. Drug Discovery Today 1997, 2, 235-242.
10.1021/jo0300946 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/07/2003
J . Org. Chem. 2003, 68, 4499-4505
4499

Wang et al.
SCHEME 1. Syn th esis of th e Nu cleosid e P r ecu r sor 9 Sta r tin g fr om
(()-en d o-7-Oxa bicyclo[2.2.1]h ep t-5-en e-2-ca r boxylic Acid (3)
at the C2′ position might influence the conformational
behavior of the cyclohexene ring and drive the confor-
mational equilibrium in the 3H2 direction (in this con-
formation the 2′-OH group is equatorially oriented).
Additionally, the extra hydroxyl group could increase the
hydration and influence the stability of the polymeric
structure once incorporated into the DNA skeleton. For
the sake of clarity, we will use the nucleoside numbering
system for compounds 2a -d as indicated in Figure 1.
by a OBz group, using LiBr/NaOBz in DMF at 130 °C
for 30 h, gave directly the cyclohexenyl tetraacetate 7 in
a moderate yield.11 All intermediates were purified by
crystallization without the use of chromatography.
Deprotection of 7 by using NaOMe in MeOH yielded
the free tetraol 8. Selective protection of 8 as benzylidene
acetal was carried out by using benzylidene dimethyl
acetal in the presence of PTSA at 60 °C under reduced
pressure (15-20 mmHg) for 4.5 h. Treatment of 9 with
2.5 equiv of tert-butyldimethylsilyl chloride in the pres-
ence of imidazole gave monosilylated 10 in 56% yield,
together with bis-silyl ethers 11 (14%) and 12 (7%)
(Scheme 2). The structural assignment of these three
compounds was carried out by NMR experiments. Acety-
lation of 10 with Ac2O in pyridine gave 13 in 96% yield.
Removal of the TBS protecting group (see Scheme 2) by
using TBAF was troublesome, giving rise to a 1.2:1:1.3
mixture of 14, 15, and 9, respectively. While selective
protection of one of the two hydroxyl groups of 9 proved
difficult, the allylic hydroxyl group of 9 was oxidized to
the corresponding enone 16 by using manganese dioxide
in CH2Cl2 (81% yield). The remaining hydroxyl group was
then protected as TBS ether under standard reaction
conditions and reduction of enone 17 with NaBH4 in the
Resu lts a n d Discu ssion
The synthesis of the ara-cyclohexenyl nucleosides is
outlined in Schemes 1-3. Diels-Alder reaction of furan
and acrylic acid in the presence of hydroquinone at room
temperature under an inert atmosphere for 75 days
provided the endo-bicyclo carboxylic acid 3 as the single
isomer after recrystallization from ethanol (Scheme 1).9
No attempts were made to reduce the initially described
reaction time. Lactonization of 3 with H2O2 and formic
acid, followed by reduction with LiAlH4 and acetylation
under standard conditions, gave rise to the triacetate 5.
Opening of the O-bridge was carried out with use of 15%
HBr in acetic acid in a sealed tube at 75 °C for 24 h,
generating dibromide 6.10 Elimination of the ring bromide
and simultaneous replacement of the primary bromide
(10) Ogawa, S.; Kasahara, I.; Suami, T. Bull. Chem. Soc. J pn. 1979,
52 (1), 118-123.
(11) Ogawa, S.; Miyamoto, Y.; Nose, T. J . Chem. Soc., Perkin Trans.
1 1988, 2675-2680.
(9) Suami, T.; Ogawa, S.; Nakamoto, K.; Kasahara, I. Carbohydr.
Res. 1977, 58, 240
4500 J . Org. Chem., Vol. 68, No. 11, 2003

“Arabino” Cyclohexenyl Nucleosides
SCHEME 2. Syn th etic Str a tegy for th e In tr od u ction of th e ter t-Bu tyld im eth ylsilyl P r otectin g Gr ou p
presence of CeCl3‚7H2O gave the R-alcohol 18 as the sole
isomer in 41% yield over two steps.
indicating the cis relationship between the guanine base
and the 2′-OH group.
Introduction of the base moiety onto the cyclohexenyl
ring was effected via a Mitsunobu reaction (Scheme 3).
Treatment of 18 with adenine in the presence of PPh3
and DEAD in dioxane at room temperature for 1 day gave
rise to 19 in 43% yield. Complete deprotection of 19 with
TFA/H2O (3:1) at room temperature overnight afforded
the adenine compound 2a in 70% yield. The ara-cyclo-
hexenyl guanine 2b was synthesized by treatment of 18
with 2-amino-6-chloropurine under Mitsunobu reaction
conditions and subsequent conversion of the purine-6-
chloro group to the guanine function with TFA/H2O (3:
1) at room temperature for 2 days. In the process
complete deprotection of the hydroxyl groups took place,
giving directly the desired compound 2b in 57% yield over
the two steps.
Synthesis of the uracil derivative 2c was carried out
as above with use of N3-benzoyluracil in the Mitsunobu
reaction. Deprotection of the base-protecting group with
a saturated ammonia solution in MeOH, followed by
removal of the OH-protecting groups on the cyclohexenyl
ring, generated 2c in 16% overall yield over the three
steps.
The cytosine compound 2d was obtained via conversion
of the uracil intermediate 22 into the cytosine derivative
23 upon treatment with POCl3 and 1,2,4-triazole followed
by ammonia gas. Deprotection of the OH groups gave rise
to the cytosine compound 2d .
The relative configuration of the ara-cyclohexenyl
guanine was determined by NMR techniques. All proton
and carbon signals were assigned with use of 1D and 2D
NMR experiments. The â-configuration of the base moiety
was established by a nOe experiment. Irradiation of H1′
of 2b gave rise to an 11% increase of the H2′ signal,
Con clu sion
A highly stereocontrolled approach toward the synthe-
sis of ara-type cyclohexenyl nucleosides was developed.
It consists of 12 steps and proved to be useful for the
synthesis of the pyridine as well as the purine nucleo-
sides. The relative configuration was confirmed by nOe
experiments. Only the guanine compound demonstrated
marginal antiviral activity against herpes simplex virus
type 1.12
Exp er im en ta l Section
Melting points were determined with a Bu¨chi-Tottoli ap-
paratus and are uncorrected. The 1H and 13C NMR spectra
were recorded with 200- and 500-MHz spectrometers. Chemi-
cal shifts are reported in δ (ppm) and are referred to TMS as
internal standard. Liquid secondary ion mass spectra (LSIMS)
were recorded with thioglycerol (THGLY) and 3-nitrobenzyl
alcohol (NBA) as the matrix. All air-sensitive reactions were
carried out under nitrogen. THF and Et2O were distilled from
sodium/benzophenone, 1,4-dioxane from CaH2, and CH2Cl2
from P2O5. Precoated Alugram SIL G/UV254 plates were used
for TLC and spots were examined with UV light and sulfuric
acid/anisaldehyde spray. Elemental analysis were done at the
University of Konstanz, Germany.
(()-(4a r,7r,8a â,8â)-2-P h en yl-4a ,7,8,8a -tetr a h yd r o-4H-
1,3-ben zod ioxin -7,8-d iol (9). To a mixture of 711 (2.56 mmol,
1 g) in methanol (15 mL) at 0 °C was added dropwise a solution
of 30% NaOMe in methanol (0.73 mL). The reaction was
(12) Compounds 2a -d were evaluated for their inhibitory effect on
the cytopathogenicity of herpes simplex virus type 1 (HSV-1), herpes
simplex virus type 2 (HSV-2), vaccinia virus, and vesicular stomatitis
virus. The guanine analogue 2b shows an EC50 value of 4 µg/mL
against HSV-1 and 30 µg/mL against HSV-2.
J . Org. Chem, Vol. 68, No. 11, 2003 4501

Wang et al.
SCHEME 3. In tr od u ction of Nu cleoba ses in th e Allylic P osition
stirred at 0 °C for 2 h and neutralized with Amberlite IR-120B
(H+) until pH <6. The clear solution was transferred and
evaporated to give crude 8 (450 mg) as yellow solids. The crude
8 (450 mg) was dissolved into dry DMF (10 mL). PhCH(OMe)2
(0.5 mL) and PTSA (6 mg) were added. The mixture was
immersed into a 60 °C preheated oil bath and stirred under
reduced pressure (15-20 mmHg) for 4.5 h. After the solution
was cooled to room temperature, solid NaHCO3 was added to
quench the reaction. The resulting mixture was concentrated
and the residue was chromatographed on silica gel (hexanes-
EtOAc 1:1 then pure EtOAc) to give 9 (446 mg, 70% over two
steps) as a white solid.
1:1) 249 (M + H)+; HRMS calcd for C14H17O4 (M + H)+
249.1126, found 249.1115.
(()-(4a r,7r,8a â,8â)-7-(ter t-Bu t yld im et h ylsilyloxy)-2-
ph en yl-4a,7,8,8a-tetr ah ydr o-4H-1,3 -ben zodioxin -8-ol (10),
(()-(4a r,7r,8a â,8â)-7,8-Bis(ter t-bu tyld im eth yl-silyloxy)-
2-p h en yl-4a ,7,8,8a -tetr a h yd r o-4H-ben zo-1,3-d ioxin e (11),
a n d
(()-(3râ,4â,7a r,7r)-4,7-Bis(ter t-b u t yl-d im et h yl-
silyloxy)-2-p h en yl-3a ,4,7,7a -tetr a h yd r o-ben zo-1,3-d ioxole
(12). To a solution of 9 (370 mg, 1.49 mmol) in DMF (10 mL)
at 0 °C was added imidazole (507 mg, 7.45 mmol, 5 equiv),
followed by TBSCl (564 mg, 3.74 mmol, 2.5 equiv) in portions.
The reaction was stirred at 0 °C for 0.5 h and at room
temperature overnight. Crashed ice was added to quench the
reaction and the resulting mixture was concentrated. The
residue was taken into EtOAc and washed with water and
brine, dried over Na2SO4, and concentrated. The resulting
light-yellow oil was chromatographed on silica gel (hexanes-
EtOAc 10:1) and further by HPLC (hexanes-EtOAc 7:1) to
afford 10 (300 mg, 56%) as colorless oil, 11 (100 mg, 14%) as
a colorless oil, and 12 (65 mg, 9%) as a colorless oil.
1H NMR (DMSO-d6) δ 2.44 (m, 1H), 3.49-3.59 (m, 3H), 4.00
(m, 1H), 4.19 (dd, 1H, J ) 10.4, 4.6 Hz), 5.07 (d, 1H, J ) 2.4
Hz, OH), 5.08 (d, 1H, J ) 3.4 Hz, OH), 5.31 (dt, 1H, J ) 9.7,
2.0 Hz), 5.57 (dt, 1H, J ) 9.7, 2.9 Hz), 5.59 (s, 1H), 7.35-7.39
(m, 3H), 7.47 (m, 2H). 13C NMR (CDCl3/DMSO-d6) δ 38.4 (d,
CH), 69.9 (t), 73.9 (d, CH), 75.4 (d, CH), 80.6 (d, CH), 102.0
(d, CH), 123.8 (d, CH), 126.3 (d, CH), 128.1 (d, CH), 128.9 (d,
CH), 130.8 (d, CH), 137.9 (s, C). ES (isopropyl alcohol/water
4502 J . Org. Chem., Vol. 68, No. 11, 2003

“Arabino” Cyclohexenyl Nucleosides
1
10: Rf 0.44 (hexanes-EtOAc 5:1). H NMR (CDCl3) δ 0.15
(s, 3H, CH3Si), 0.16 (s, 3H, CH3Si), 0.94 (s, 9H, (CH3)3C), 2.58
(d, 1H, J ) 1.8 Hz, OH), 2.67 (m, 1H), 3.59 (dd, 1H, J ) 10.6,
5.5 Hz), 3.64 (dd, 1H, J ) 10.2, 8.0 Hz), 3.92 (ddd, 1H, J )
10.2, 7.0, 1.8 Hz), 4.29 (dd, 1H, J ) 10.6, 4.6 Hz), 4.37 (m,
1H), 5.34 (dt, 1H, J ) 9.9, 1.8 Hz), 5.60 (s, 1H, PhCH(O)2),
5.56-5.64 (m, 1H), 7.38 (m), 7.50 (m). 13C NMR (CDCl3) δ -4.8
(q, CH3Si), -4.5 (4q, CH3Si), 18.1 (s, C), 25.8 (q, (CH3)3C), 38.1
(d, CH), 70.0 (t, CH2), 74.8 (d, CH), 75.6 (d, CH), 81.0 (d, CH),
102.1 (d, CH, PhCH), 123.4 (d, CH), 126.2 (d, CH), 128.3 (d,
CH), 129.1 (d, CH), 132.0 (d, CH), 137.9 (s, C). ES (isopropyl
alcohol/water 1:1) 363 (M + H)+; HRMS calcd for C20H31O4Si
(M + H)+ 363.1991, found 363.1992.
SO4, and concentrated. The residue was chromatographed on
silica gel (hexanes-EtOAc 1:2) to give a 1.2:1:1.3 ratio of 14
as a colorless residue, 15 as a colorless residue, and 9 as a
white solid.
14 (145 mg, 0.5 mmol, 32%): Rf 0.37 (hexanes-EtOAc 1:2).
1H NMR (CDCl3) δ 2.15 (s, 3H, CH3COO), 2.75 (m, 1H), 3.35
(br s, 1H, OH), 3.65 (t, 1H, J ) 11.0 Hz), 3.77 (t, 1H, J ) 10.6
Hz), 4.30 (dd, 1H, J ) 10.6, 4.6 Hz), 4.40 (m, 1H), 5.13 (dd,
1H, J ) 11.0, 7.0 Hz), 5.42 (dd, 1H, J ) 9.9, 1.4 Hz), 5.57 (s,
1H, PhCH(O)2), 5.75 (dm, 1H, J ) 9.9 Hz), 7.36 (m, 3H), 7.47
(m, 2H). 13C NMR (CDCl3) δ 21.0 (q, CH3CO), 38.0 (d, CH),
69.8 (t, CH2), 72.8 (d, CH), 78.2 (d, CH), 78.4 (d, CH), 101.6
(d, CH, PhCH), 124.6 (d, CH), 126.1 (d, CH), 128.2 (d, CH),
128.9 (d, CH), 130.1 (d, CH), 137.8 (s, C), 172.4 (s, CH3COO).
ES (isopropyl alcohol/water 1:1) 291 (M + H)+; HRMS calcd
for C16H18O5 (M + H)+ 291.1232, found 291.1227.
11: Rf 0.60 (hexanes-EtOAc 5:1). 1H NMR (500 MHz,
DMSO-d6) δ -0.10 (s, 3H, CH3Si), -0.01 (s, 3H, CH3Si), 0.09
(s, 3H, CH3Si), 0.10 (s, 3H, CH3Si), 0.77 (s, 9H, (CH3)3C), 0.89
(s, 9H, (CH3)3C), 2.52 (m, 1H), 3.56 (t, 1H, J ) 10.7 Hz), 3.57
(t, 1H, J ) 10.2 Hz), 3.81 (dd, 1H, J ) 10.2, 6.8 Hz), 4.19 (dd,
1H, J ) 10.7, 4.9 Hz), 4.28 (m, 1H), 5.39 (dt, 1H, J ) 10.0, 1.7
Hz), 5.56 (dt, 1H, J ) 10.0, 2.7 Hz), 5.57 (s, 1H, PhCH(O)2),
7.35 (m), 7.42 (m, 2H). 13C NMR (DMSO-d6) δ -4.2 to -3.9
(4q, 4CH3Si), 17.8 (s, C), 18.0 (s, C), 26.0 (two q, two (CH3)3C),
38.8 (d, CH), 69.2 (t, CH2), 75.8 (d, CH), 76.6 (d, CH), 80.7 (d,
CH), 101.8 (d, CH), 124.4 (d, CH), 126.6 (d, CH), 128.0 (d, CH),
128.9 (d, CH), 131.4 (d, CH), 138.4 (s, C). ES (isopropyl alcohol/
water 1:1) 477 (M + H)+; HRMS calcd for C26H45O4Si2 (M +
H)+ 477.2856, found 477.2847.
15 (119 mg, 0.4 mmol, 27%): Rf 0.50 (hexanes-EtOAc 1:2).
1H NMR (500 MHz, CDCl3) δ 2.13 (s, 3H, CH3COO), 2.66 (m,
1H), 2.93 (br s, 1H, OH), 3.64-3.70 (m, 2H), 4.10 (dd, 1H, J )
10.5, 7.2 Hz), 4.30 (dd, 1H, J ) 11.0, 4.4 Hz), 5.46 (m, 1H),
5.49 (dt, 1H, J ) 9.8, 1.7 Hz), 5.61 (s, 1H, PhCH(O)2), 5.67
(dt, 1H, J ) 9.8, 3.0 Hz), 7.38 (m, 3H), 7.51 (m, 2H). 13C NMR
(125 MHz, CDCl3) δ 21.1 (q, CH3CO), 37.8 (d, CH), 69.7 (t,
CH2), 72.7 (d, CH), 76.8 (d, CH), 80.9 (d, CH), 102.2 (d, CH,
PhCH), 126.2 (d, CH), 126.4 (d, CH), 127.0 (d, CH), 128.3 (d,
CH), 129.1 (d, CH), 137.6 (s, C), 171.0 (s, CH3COO). ES
(isopropyl alcohol/water 1:1) 291 (M + H)+; HRMS calcd for
C
16H18O5 (M + H)+ 291.1232, found 291.1222.
12: Rf 0.64 (hexanes-EtOAc 5:1). 1H NMR (500 MHz,
DMSO-d6) δ -0.03 (s, 3H, CH3Si), -0.01 (s, 3H, CH3Si), 0.10
(s, 3H, CH3Si), 0.11 (s, 3H, CH3Si), 0.82 (s, 9H, (CH3)3C), 0.88
(s, 9H, (CH3)3C), 2.57 (m, 1H), 3.47 (t, 1H, J ) 9.7 Hz), 3.56
(dd, 1H, J ) 10.2, 6.3 Hz), 3.64 (dd, 1H, J ) 9.7, 8.8 Hz), 3.77
(dd, 1H, J ) 10.2, 4.0 Hz), 4.56 (m, 1H), 5.52 (dt, 1H, J ) 8.2,
2.2 Hz), 5.64 (dt, 1H, J ) 8.2, 1.7 Hz), 6.07 (s, 1H, PhCH(O)2),
7.38 (m, 3H), 7.44 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ
-5.6, -5.4, -4.8, -4.6 (4q, 4CH3Si), 17.9 (s, C), 18.0 (s, C),
25.7 (two q, two (CH3)3C), 44.2 (d, CH), 63.0 (t, CH2), 71.1 (d,
CH), 74.3 (d, CH), 83.9 (d, CH), 103.9 (d, Ph-CH), 126.4 (d,
CH), 128.0 (d, CH), 128.3 (d, CH), 129.0 (d, CH), 131.3 (d, CH),
139.3 (s, C). ES (isopropyl alcohol/water 1:1) 477 (M + H)+;
9 (134 mg, 0.54 mmol, 35%): Rf 0.25 (hexanes-EtOAc 1:2).
(()-(4a r,8a â,8â)-8-Hyd r oxy-2-p h en yl-4,4a ,8,8a -tetr a h y-
d r o-ben zo-1,3-d ioxin -7-on e (16). A mixture of 9 (650 mg,
2.62 mmol) and MnO2 (2.28 g, 26.2 mmol, 10 equiv) in dry CH2-
Cl2 (40 mL) was stirred vigorously at room temperature
overnight. The reaction mixture was filtered through Celite
and washed with CH2Cl2. The filtrate was concentrated to give
16 (460 mg, 71%) as a red solid.
1H NMR (CDCl3) δ 3.01 (m, 1H), 3.83 (t, 1H, J ) 11.2 Hz),
3.92 (dd, 1H, J ) 11.2, 9.1 Hz), 4.38 (d, 1H, J ) 11.2 Hz), 4.45
(dd, 1H, J ) 11.2, 4.7 Hz), 5.64 (s, 1H, PhCH(O)2), 6.26 (dd,
1H, J ) 10.3, 3.4 Hz), 6.67 (dd, 1H, J ) 10.3, 2.0 Hz), 7.39 (m,
3H), 7.55 (m, 2H). 13C NMR (CDCl3) δ 39.1 (d, CH), 68.7 (t,
CH2), 76.4 (d, CH), 82.5 (d, CH), 101.8 (d, CH), 126.3 (d, CH),
128.3 (d, CH), 129.2 (d, CH), 129.3 (d, CH), 137.2 (s, C), 146.3
(d, CH), 197.6 (s, C, CO).
(()-(4a r,8a â,8â)-8-(ter t-Bu tyld im eth ylsilyloxy)-2-p h en -
yl-4,4a ,8,8a -tetr a h yd r o-ben zo-1,3-d ioxin -7-on e (17). To a
solution of 16 (200 mg, 0.81 mmol) in DMF (5 mL) at 0 °C
under N2 was added imidazole (276 mg, 2.05 mmol, 5 equiv),
followed by TBSCl (306 mg, 2.03 mmol, 2.5 equiv) in portions.
The reaction mixture was stirred at 0 °C for 0.5 h and at room
temperature for 3 h. Crushed ice was added to quench the
reaction and the resulting mixture was concentrated. The
residue was taken into EtOAc, washed with water and brine,
dried over Na2SO4, and concentrated. The residue was chro-
matographed on silica gel (hexanes-EtOAc 10:1, 5:1) to give
17 (150 mg, 51%) as a reddish oil.
1H NMR (CDCl3) δ 0.09 (s, 3H, CH3Si), 0.21 (s, 3H, CH3Si),
0.94 (s, 9H, (CH3)3C), 2.91 (m, 1H), 3.80 (t, 1H, J ) 11.2 Hz),
3.93 (dd, 1H, J ) 11.2, 9.2 Hz), 4.33 (d, 1H, J ) 11.2 Hz), 4.44
(dd, 1H, J ) 11.2, 4.6 Hz), 5.63 (s, 1H, PhCH(O)2), 6.15 (dd,
1H, J ) 10.0, 2.9 Hz), 6.52 (dd, 1H, J ) 10.0, 1.9 Hz), 7.38 (m,
3H), 7.53 (m, 2H). 13C NMR (CDCl3) δ -5.3 (q, CH3Si), -4.6
(q, CH3Si), 18.7 (s, C), 25.7 (q, (CH3)3C), 39.3 (d, CH), 68.9 (t,
CH2), 78.1 (d, CH), 82.5 (d, CH), 101.4 (d, CH), 126.1 (d, CH),
128.1 (d, CH), 128.8 (d, CH), 131.0 (d, CH), 137.6 (s, C), 143.7
(d, CH), 197.0 (s, CO).
(()-(4a r,8a â,8â)-8-(ter t-Bu tyld im eth ylsilyloxy)-2-p h en -
yl-4,4a ,8,8a -tetr a h yd r o-ben zo-1,3-d ioxin -7-ol (18). To a
solution of 17 (240 mg, 0.67 mmol) in MeOH (10 mL) was
added CeCl3‚7H2O (369 mg, 0.99 mmol, 1.5 equiv). The mixture
was stirred at room temperature for 0.5 h until a homogeneous
solution was obtained. NaBH4 (30 mg, 0.80 mmol, 1.2 equiv)
HRMS calcd for
477.2844.
C
26H45O4Si2 (M + H)+ 477.2856, found
(()-(4a r,7r,8a â,8â)-8-Acet oxy-7-(ter t-b u t yld im et h yl-
silyloxy)-2-p h en yl-4a ,7,8,8a -tetr a h yd r o-4H-ben zo-1,3-d i-
oxin e (13). Compound 10 (600 mg, 1.66 mmol) was treated
with pyridine (20 mL) and Ac2O (10 mL) at room temperature
overnight. The reaction mixture was concentrated and the
residue was chromatographed on silica gel (hexanes-EtOAc
10:1) to give 13 (640 mg, 96%) as a white solid.
1H NMR (CDCl3) δ 0.09 (s, 3H, CH3Si), 0.11 (s, 3H, CH3Si),
0.90 (s, 9H, (CH3)3C), 2.10 (s, 3H, CH3CO), 2.79 (m, 1H), 3.63
(t, 1H, J ) 11.0 Hz), 3.69 (t, 1H, J ) 11.0 Hz), 4.28 (dd, 1H, J
) 11.0, 4.5 Hz), 4.49 (m, 1H), 5.35 (dd, 1H, J ) 11.0, 7.7 Hz),
5.36 (dm, 1H, J ) 9.9 Hz), 5.54 (s, 1H, PhCH(O)2), 5.61 (dt,
1H, J ) 9.9, 2.6 Hz), 7.35 (m, 3H), 7.45 (m, 2H). 13C NMR
(CDCl3) δ -4.9 (q, CH3Si), -4.7 (q, CH3Si), 17.9 (s, C), 21.0 (q,
CH3CO), 25.5 (q, (CH3)3C), 38.7 (d, CH), 69.9 (t, CH2), 72.5 (d,
CH), 75.8 (d, CH), 78.8 (d, CH), 101.6 (d, CH, PhCH), 123.7
(d, CH), 126.0 (d, CH), 128.2 (d, CH), 128.8 (d, CH), 131.6 (d,
CH), 137.9 (s, C), 170.0 (s, CH3COO). ES (isopropyl alcohol/
water 1:1) 405 (M + H)+; HRMS calcd for C22H32O5Si (M +
H)+ 405.2097, found 405.2091.
(()- (4a r,7r,8a â,8â)-8-Acetoxy-2-p h en yl-4a ,7,8,8a -tet-
r a h yd r o-4H-ben zo-1,3-d ioxin -7-ol (14) a n d (()-(4a r,7r,-
8aâ,8â)-7-Acetoxy-2-ph en yl-4a,7,8,8a-tetr ah ydr o-4H-ben zo-
1,3-d ioxin -8-ol (15). To a solution of 13 (620 mg, 1.53 mmol)
in THF (15 mL) at 0 °C was added slowly a 1 M TBAF in THF
solution (4.59 mL, 4.59 mmol, 3 equiv). After remaining at 0
°C for 0.5 h, the reaction was brought to room temperature
and stirred for 1 h. TLC showed the completion of the reaction.
Ice was added to quench the reaction. The mixture was diluted
with EtOAc, washed with water and brine, dried over Na2-
J . Org. Chem, Vol. 68, No. 11, 2003 4503

Wang et al.
was added in portions. The reaction mixture was stirred at
room temperature for 3 h. Ice was added to the reaction
mixture and the mixture was concentrated. The residue was
taken into EtOAc, washed with water and brine, dried over
Na2SO4, and concentrated. The residue was chromatographed
on silica gel (hexanes-EtOAc 10:1, then 5:1) to afford 18 (210
mg, 87%) as a colorless oil.
1H NMR (CDCl3) δ 0.02 (s, 3H, CH3Si), 0.13 (s, 3H, CH3Si),
0.89 (s, 9H, (CH3)3C), 2.22 (d, 1H, J ) 4.4 Hz, OH), 2.66 (m,
1H), 3.60 (dd, 1H, J ) 10.6, 4.4 Hz), 3.65 (dd, 1H, J ) 10.2,
7.0 Hz), 3.90 (dd, 1H, J ) 10.2, 7.0 Hz), 4.24 (dd, 1H, J ) 10.6,
4.8 Hz), 4.32 (m, 1H), 5.37 (dt, 1H, J ) 9.9, 2.0 Hz), 5.57 (s,
1H, PhCH(O)2), 5.70 (dt, 1H, J ) 9.9, 2.8 Hz), 7.37 (m, 3H),
7.51 (m, 2H). 13C NMR (CDCl3) δ -4.9 (q, CH3Si), -4.3 (q, CH3-
Si), 18.2 (s, C), 25.8 (q, (CH3)3C), 39.1 (d, CH), 70.0 (t, CH2),
75.4 (d, CH), 77.0 (d, CH), 80.9 (d, CH), 102.3 (d, CH), 124.5
(d, CH), 126.3 (d, CH), 128.0 (d, CH), 128.8 (d, CH), 130.4 (d,
CH), 138.0 (s, C). ES (isopropyl alcohol/water 1:1) 363 (M +
H)+; HRMS calcd for C20H30O4Si (M + H)+ 363.1991, found
363.1982.
dioxane and filtered and the solid washed with CH2Cl2. The
filtrate and washings were concentrated and the residue was
chromatographed on silica gel (CH2Cl2-EtOAc 1:1) to give the
crude 20 (560 mg) asa yellow foam.
The crude 20 (560 mg) was treated with TFA/water (3:1, 10
mL) at room temperature for 2 days. The reaction mixture was
concentrated and coevaporated with toluene. The residue was
chromatographed on reverse HPLC (5% CH3CN in water
containing 0.1% TFA) to afford 2b (78 mg, 57% over two steps)
as a white foam.
1H NMR (500 MHz, D2O) δ 2.47 (m, 1H, H4′), 3.72 (dd, 1H,
J ) 9.8, 7.8 Hz, H3′), 3.85 (dd, 1H, J ) 10.2, 2.4 Hz, H7a′),
3.89 (dd, 1H, J ) 10.2, 3.4 Hz, H7b′), 4.14 (dd, 1H, J ) 10.3,
5.2 Hz, H2′), 5.47 (t-br, 1H, J ) 5.2 Hz, H1′), 5.87 (ddd, 1H, J
) 9.7, 5.2, 2.4 Hz, H6′), 6.19 (ddd, 1H, J ) 9.7, 2.4, 1.4 Hz,
H5′), 8.64 (s, 1H, H8). 13C NMR (125 MHz, D2O) δ 48.5 (CH,
C4′), 57.2 (CH, C1′), 63.6 (CH2, C7′), 69.3 (CH, C3′), 72.9 (CH,
C2′), 117.9 (C, C5), 124.1 (CH, C6′), 138.8 (CH, C5′), 139.9 (CH,
C8), 153.8 (C, C4), 157.8 (C, C2), 158.4 (C, C6). ES (isopropyl
alcohol/water 1:1) 294 (M + H)+; HRMS calcd for C12H16N5O4
(M + H)+ 294.1202, found 294.1207. Anal. Calcd for C12H15N5O3
(MW 293.112): C, 49.13; H, 5.16; N, 23.89. Found: C, 49.07;
H, 4.98; N, 23.57.
(()-2′-O-ter t-Bu t yld im et h ylsilyl-3′,7′-O-b en zylid en e-
a r a -cycloh exen yl-N1-ben zoylu r a cil (21). To a mixture of
18 (380 mg, 1.05 mmol), N3-benzoyluracil (283 mg, 1.3 mmol),
and Ph3P (330, 1.3 mmol) in dry dioxane (10 mL) was slowly
added a solution of DEAD (0.2 mL, 1.3 mmol) in dry dioxane
(1 mL). The mixture was stirred at room temperature over-
night and the solvent was evaporated. The residue was
chromatographed on silica gel (n-hexane/EtOAc, 9:1, 8:2, 7:3,
5:5). Evaporation afforded compound 21 (250 mg, 43%) as a
yellow foam.
(()-2′-O-ter t-Bu t yld im et h ylsilyl-3′,7′-O-b en zylid en e-
a r a -cycloh exen yl-a d en in e (19). To a mixture of 18 (140 mg,
0.39 mmol), adenine (111 mg, 0.78 mmol), and Ph3P (216 mg,
0.78 mmol) in dry dioxane (6 mL) under N2 at room temper-
ature was added a solution of DEAD (136 µL, 0.78 mmol) in
dry dioxane (2.5 mL) over a period of 30 min. The reaction
mixture was stirred at room temperature overnight and
concentrated. The resulting residue was chromatographed on
silica gel (CH2Cl2/MeOH, 98:2) to yield 19 (80 mg, 43%) as a
white solid.
1
Mp 225-227 °C. H NMR (CDCl3) δ -0.07 (s, 3H, CH3Si),
-0.08 (s, 3H, CH3Si), 0.49 (s, 9H, (CH3)3C), 2.71 (m, 1H, H4′),
3.86 (t, 1H, J ) 11.0 Hz, H7′a), 3.89 (t, 1H, J ) 9.8 Hz, H3′),
4.37 (dd, 1H, J ) 10.2, 6.8 Hz, H2′), 4.42 (dd, 1H, J ) 10.9,
4.5 Hz, H7′b), 5.58 (br, 2H, NH2), 5.59 (obs, 1H, H1′), 5.62 (s,
1H, PhCH(O)2), 5.77 (dt, 1H, J ) 9.5, 1.5 Hz, H5′), 5.86 (1H,
ddd, J ) 9.5, 4.0, 3.1 Hz, H6′), 7.36 (m, 3H), 7.49 (m, 2H),
7.87 (s, 1H, H8), 8.37 (s, 1H, H2). 13C NMR (CDCl3) δ -4.9
(CH3Si), -4.7 (CH3Si), 17.9 (C), 25.2 (CH3)3, 39.1 (CH, C4′),
53.8 (CH, C1′), 70.0 (CH2, C7′), 70.7 (CH, C2′), 79.6 (CH, C3′),
102.8 (PhCH(O)2), 119.5 (C5), 126.1 (CH, C6′), 126.4 (CHo),
128.1 (CHm), 128.5 (CH, C5′), 128.9 (CHp), 137.7 (C,Ci), 140.5
(CH, C8), 151.1 (C, C4), 152.8 (CH, C2), 155.3 (C, C6).
Assignments based on 2D COSY, GHSQC- and GHMBC-
spectra. HRMS calcd for C25H33N5O3Si (M + H)+ 480.2353,
found 480.2433.
1H NMR (CDCl3) δ 0.005 (s, 6H, (CH3)2Si), 0.77 (s, 9H,
(CH3)3C), 2.61 (m, 1H, H4′), 3.65 (t, 1H, J ) 9.9 Hz, H3′), 3.79
(t, 1H, J ) 11.0 Hz, H7′a), 4.30 (dd, 1H, J ) 9.9, 7.3 Hz, H2′),
4.39 (dd, 1H, J ) 11.0, 4.5 Hz, H7′b), 5.61 (s, 1H, PhCH(O)2),
5.67-5.79 (m, 3H, H1′, H5′, H6′), 5.86 (d, 1H, J ) 8.1 Hz, H5),
7.33-7.68 (3m, 10H 2 ar), 7.97 (d, 1H, J ) 8.1 Hz, H6). 13C
NMR (CDCl3) δ -6.3 (CH3Si), -6.1 (CH3Si), 16.7 (C), 24.2
(CH3)3C), 36.9 (CH, C4′), 53.0 (CH, C1′), 68.5 (CH2, C7′), 68.8
(CH, C2′), 78.2 (CH, 3′), 100.1 (CH, C5), 101.5 (Ph, CH(O)2),
125.1 (2(CH, C6′ + Pho)), 126.8 (CH), 127.7 (CH), 128.5 (CH,-
C5′), 129.3 (CH), 130.2 (C), 133.6 (CH), 136.2 (C), 141.4 (CH,
C6), 149.1 (CdO, C2), 161.0 (CdO, C4). HRMS calcd for
C
31H36N2O6Si (M + H)+ 561.2343, found 561.2435.
(()-a r a -Cycloh exen yl-a d en in e (2a ). 19 (150 mg, 0.31
mmol) was treated with TFA-H2O (3:1, 6 mL) at room
temperature overnight. The reaction mixture was concentrated
and coevaporated with toluene (3×). The residue was chro-
matographed on silica gel such as eluent CH2Cl2/MeOH (10:
0.5, 10:1, 10:2) to afford 2a (60 mg, 70%) as a white solid.
(()-2′-O-ter t-Bu t yld im et h ylsilyl-3′,7′-O-b en zylid en e-
a r a -cycloh exen yl-u r a cil (22). 21 (370 mg, 0.66 mmol) was
treated with NH3/MeOH (25 mL) at room temperature over-
night. Evaporation left an oil, which was purified on silica gel
(CH2Cl2/MeOH, 99:1) to afford 22 as a white solid (200 mg,
67%).
Mp 143-145 °C. 1H NMR (DMSO) (500 MHz) δ 2.22 (m,
1H, H4′), 3.69 (m, 3H, H7′a, H7′b, H3′), 3.78 (dt, 1H, J ) 8.3,
5.1 Hz, H2′), 4.87 (t, 1H, J ) 5.0 Hz, 7′-OH), 4.92 (d, 1H, J )
4.4 Hz, 3′-OH), 5.10 (d, 1H, J ) 5.1 Hz, 2′-OH), 5.32 (m, 1H,
H1′), 5.74 (ddd, 1H, J ) 10.0, 3.9, 2.4 Hz, H6′), 5.97 (dt, 1H, J
) 10.0, 2.2 Hz, H5′), 7.11 (br, 2H, NH2), 7.95 (s, 1H, H8), 8.12
(s, 1H, H2). 13C NMR (DMSO) (500 MHz) δ 46.4 (CH,C4′), 52.2
(CH, C1′), 61.4 (CH, C7′), 67.2 (CH, C3′), 70.2 (CH, C2′), 118.7
(C, C5), 123.2 (CH, C6′), 133.5 (CH, C5′), 140.4 (CH, C8), 150.3
(C, C4), 152.1 (CH, C2), 156.0 (C, C6). HRMS calcd for
1
Mp 200-202 °C. H NMR (CDCl3) δ -0.04 (s, 3H, CH3Si),
0.03 (d, 3H, CH3Si), 0.73 (s, 9H, (CH3)3C), 2.60 (m, 1H, H4′),
3.56 (t, 1H, J ) 9.8 Hz, H3′), 3.76 (t, 1H, J ) 11.0 Hz, H7′a),
4.25 (dd, 1H, J ) 10.2, 7.4 Hz, H2′), 4.39 (dd, 1H, J ) 11.0,
4.6 Hz, H7′b), 5.58 (s, 1H, PhCH(O)2), 5.64-5.81 (3m, 4H, H1′,
H5′, H6′, H5), 7.27 (m, 2H), 7.36 (m, 2H), 7.49 (m, 2H), 8.40
(s, 1H, NH). 13C NMR (CDCl3) δ -5.1 (CH3Si), -4.8 (CH3Si),
18.0 (C), 25.5 ((CH3)3C), 38.1 (CH, C4′), 53.7 (CH, C1′), 69.9
(CH2, C7′), 70.2 (CH, C2′), 79.5 (CH, C3′), 101.6 (CH, C5), 102.9
(CH, Ph CH(O)2), 126.4 (2CH, C6′ and CHO), 128.2 (CH, CHm),
129.1 (CH, C5′), 129.8 (CH, CHp), 137.5 (C, Ci), 142.6 (CH,
C6), 151.2 (CdO, C2), 162.9 (CdO, C4). HRMS calcd for
C
12H15N503 (M + H)+ 278.1175, found 278.1253. Anal. Calcd
for C12H15N5O3 (MW 277.1175): C, 51.96; H, 5.46; N, 25.27.
Found: C, 51.64; H, 5.84; N, 25.59.
C
24H32N2O5Si (M + H)+ 457.2081, found 457.2166.
(()-a r a -Cycloh exen yl-gu a n in e (2b). To a mixture of 18
(165 mg, 0.46 mmol), PPh3 (241 mg, 0.92 mmol, 2 equiv), and
2-amino-6-chloropurine (156 mg, 0.92 mmol, 2 equiv) in dry
dioxane (5 mL) under nitrogen at room temperature was added
a solution of DIAD (182 µL, 0.92 mmol, 2 equiv) in dioxane (3
mL) very slowly. The reaction mixture was stirred further at
room temperature overnight. The mixture was diluted with
(()-a r a -Cycloh exen yl-u r a cil (2c). 22 (100 mg, 0.22
mmol) was treated with TFA-H2O (3:1, 6 mL) at room
temperature for 24 h. The reaction mixture was concentrated
and coevaporated with toluene (3×). The residue was chro-
matographed on silica gel (CH2Cl2/MeOH 99:1) to afford 2c
(30 mg, 54%) as a white solid, which was crystallizated from
MeOH.
4504 J . Org. Chem., Vol. 68, No. 11, 2003

“Arabino” Cyclohexenyl Nucleosides
Mp 223 °C. 1H NMR (DMSO) (500 MHz) δ 2.15 (m, 1H, H4′),
3.54 (ddd, 1H, J ) 10.2, 5.6, 2.0 Hz, H7′a), 3.61 (m, 1H, H7′a),
3.64 (m, 1H, H3′), 3.70 (m, 1H, H2′), 4.80 (t, 1H, J ) 5.6 Hz,
7′OH), 4.99 (d, 1H, J ) 4.2 Hz, 3′OH), 5.23 (d, 1H, J ) 5.6 Hz,
2′OH), 5.26 (td, J ) 5.4, 2.7 Hz, H1′), 5.49 (d, 1H, J ) 8.1 Hz,
H5), 5.50 (m, 1H, H6′), 5.95 (dt, J ) 10.2, 2.7 Hz, H5′), 7.35
(d, 1H, J ) 8.1 Hz, H6), 11.16 (s, 1H, NH). 13C NMR (DMSO)
(500 MHz) δ 45.7 (CH, C4′), 52.5 (CH, C1′), 61.6 (CH2, C7′),
67.5 (CH, C3′), 68.8 (CH, C2′), 99.9 (CH, C5), 122.9 (CH, C6′),
133.7 (CH, C5′), 144.1 (CH, C6), 151.4 (CdO, C2), 163.6
(CdO, C4). Assignments based on 2D COSY, GHSQC- and
PhCH(O)2), 5.66 (s, 2H, H1′, H5′), 5.72 (d, 1H, J ) 7.3 Hz,
H5), 5.95 (dm, 1H, J ) 7.7 Hz, H6′), 7.26-7.52 (3m, 6H, H6,
5CH). 13C NMR (CDCl3) δ -5.2 (CH3Si), -4.9 (CH3Si), 18.0
(C), 25.4 ((CH3)3C), 37.8 (CH, C4′), 54.2 (CH, C1′), 70.0 (CH2,
C7′), 70.3 (CH, C2′), 79.9 (CH, C3′), 94.1 (CH, C5), 102.7 (CH,
Ph CH(O)2), 126.4 (CH, CHO), 127.6 (CH, C5′), 128.2 (CH,
CHm), 128.5 (CH, C6′), 129.1 (CH, CHp), 137.7 (C, Ci), 144.5
(CH, C6), 157.2 (CdO, C2), 165.0 (CdO, C4). HRMS calcd for
C
24H33N3O4Si (M + H)+ 456.2240, found 456.2317.
(()-a r a -Cycloh exen yl-cytosin e (2d ). 23 (100 mg, 0.22
mmol) was treated with TFA-H2O (3:1, 6 mL) at room
temperature overnight. The mixture was concentrated and
coevaporated with toluene (3×). The residue was chromato-
graphed on silica gel (CH2Cl2/MeOH, 96:4, 95:5, 93:7, 90:10,
5:2) to afford 2d as a white solid (40 mg, 72%).
GHMBC-spectra. HRMS calcd for
C
11H14N2O5 (M + H)+
255.0903, found 255.0972. Anal. Calcd for C11H14N2O5 (MW
254.093): C, 51.95; H, 5.55%, N, 11.02. Found: C, 52.16; H,
5.44; N, 11.21.
(()-2′-O-ter t-Bu tyld im eth ylsilyl-3′,7′-O-ben ylid en e-a r a -
cycloh exen yl-cytosin e (23). 22 (200 mg, 0.44 mmol) was
added to a premixed solution of 68 µL of phosphorus oxychlo-
ride and 1,2,4-triazole (205 mg, 2.96 mmol) in anhydrous
pyridine (15.35 mL). The reaction mixture was stirred for 24
h at room temperature. The reaction mixture was cooled to 0
°C and ammonia gas was bubbled through the mixture for 15
min. The reaction mixture was further stirred for 15 min at
room temperature, evaporated, and coevaporated with toluene.
The residue was suspensed in 100 mL of CH2Cl2/MeOH (1:1)
and filtered over a small layer of Celite to remove most of the
inorganic salts. The filtrate was evaporated, dissolved in CH2-
Cl2, and washed with water to remove 1,2,4-triazole. The
organic residue was evaporated and purified by column
chromatography (CH2Cl2/MeOH 97:3) to afford 23 (100 mg,
50%) as a yellow oil.
Mp 124-126 °C. 1H NMR (DMSO) δ 2.19 (m, 1H, H4′), 3.39
(br, 2′, 3′, 7′-OH and HOD), 3.52 (dd, 1H, J ) 10.2, 5.6 Hz,
H7′a), 3.62 (dd, 1H, J ) 10.2, 5.6 Hz, H7′b), 3.68 (dd, J ) 6.0,
3.7 Hz, H-3′), 3.75 (t, 1H, J ) 5.5 Hz, H2′), 5.30 (m, 1H, H1′),
5.49 (dm, 1H, J ) 10.3 Hz, H6′), 6.00 (m, 2H, H5′, H5), 7.66
(d, 1H, J ) 7.6 Hz, H6), 8.72 (s, 1H, NH2), 9.32 (s, 1H, NH2).
13C NMR (DMSO) δ 45.6 (CH, C4′), 54.0 (CH, C1′), 61.7 (CH2,
C7′), 67.4 (CH, C3′), 68.0 (CH, C2′), 92.6 (CH, C5), 121.9 (CH,
C6′), 134.1 (CH, C5′), 148.33 (CH, C6), 148.6 (CdO, C2), 159.7
(CdO, C4). HRMS calcd for C11H15N3O4 (M + H)+ 254.1063,
found 254.1136. Anal. Calcd for C11H15N3O4 (MW 253.106): C,
52.15; H, 5.97; N, 16.60. Found: C, 51.93; H, 6.28; N, 16.56.
Ack n ow led gm en t. This research was financially
supported by a grant from the Katholieke Universiteit
Leuven (GOA 97/11). The authors thank Dr. Erik De
Clercq for antiviral data.
1H NMR (CDCl3) δ 0.09 (d, 6H, 2 × CH3Si), 0.72 (s, 9H,
(CH3)2C), 2.58 (m, 1H, H4′), 3.58 (t, 1H, J ) 9.9 Hz, H3′), 3.74
(t, 1H, J ) 11.2 Hz, H7′a), 4.28 (dd, 1H, J ) 9.9 and 8.1 Hz,
H2′), 4.37 (dd, 1H, J ) 11.2 and 4.8 Hz, H7′b), 5.55 (s, 1H,
J O0300946
J . Org. Chem, Vol. 68, No. 11, 2003 4505