Synthesis and antiviral activity of the α-analogues of 1,5-anhydrohexitol nucleosides (1,5-anhydro-2,3-dideoxy-D-ribohexitol nucleosides)

Article abstract of DOI:10.1021/jo961982m

1,5-Anhydro-2,3-dideoxy-D-ribohexitol nucleosides were synthesized starting from 4,6-di-O-benzyl-1,5-di-O-pivaloyl-3-deoxy-D-glucitol using a ring closure procedure. The target nucleoside adopts a ⁴C₁ conformation as also demonstrated for the corresponding 1,5-anhydrohexitol nucleosides with β-configuration of the base-substituted carbon atom. The cytosine congener demonstrated a moderate but selective activity against Herpes simplex virus types 1 and 2.

Full text of DOI:10.1021/jo961982m

2442
J . Org. Chem. 1997, 62, 2442-2447
Syn th esis a n d An tivir a l Activity of th e r-An a logu es of
1,5-An h yd r oh exitol Nu cleosid es
(1,5-An h yd r o-2,3-d id eoxy-D-r iboh exitol Nu cleosid es)
Nafizal Hossain, J ef Rozenski, Erik De Clercq, and Piet Herdewijn*
Rega Institute for Medical Research, Laboratory of Medicinal Chemistry,
Minderbroedersstraat 10, B-3000 Leuven, Belgium
Received October 22, 1996X
1,5-Anhydro-2,3-dideoxy-D-ribohexitol nucleosides were synthesized starting from 4,6-di-O-benzyl-
1,5-di-O-pivaloyl-3-deoxy-D-glucitol using a ring closure procedure. The target nucleoside adopts
4
a C1 conformation as also demonstrated for the corresponding 1,5-anhydrohexitol nucleosides with
â-configuration of the base-substituted carbon atom. The cytosine congener demonstrated a
moderate but selective activity against Herpes simplex virus types 1 and 2.
Sch em e 1
In tr od u ction
The research on antiviral nucleosides with a six-
membered carbohydrate moiety has been far behind the
research on biological active nucleosides with modified
five-membered ring structures. This is due to the fact
that six-membered rings are conformationally less flex-
ible than five-membered rings, and conformational flex-
ibility of a nucleoside is important for the metabolic
activation and for the interaction with the target enzyme.
With nonflexible molecules, a perfect steric and electronic
fit is necessary between enzyme and substrate, and this
is difficult to obtain. Recently, however, a new series of
nucleosides with a six-membered carbohydrate moiety
has been discovered showing potent antiviral activity.1
This class of nucleosides also shows an increased RNA
duplex stability when used as building blocks for oligo-
nucleotides.2,3 These nucleosides have a 2,3-dideoxy-1,5-
anhydro-D-mannitol moiety with a heterocyclic base
situated in the 2â-position. A particular characteristic
of these nucleosides is an axial orientation of the base
moiety, which is due to the fact that nucleosides with a
six-membered carbohydrate moiety prefer a conformation
avoiding as much as possible unfavorable 1,3-diaxial
interactions. As part of the investigation on the struc-
tural requirements of anhydrohexitols for antiviral activ-
ity, we synthesized the R-analogues of the aforemen-
tioned 2,3-dideoxy-1,5-anhydro-D-mannitol nucleosides
starting from either 4,6-dibenzyl-2,3-dideoxy-2-D-man-
nitylthymine or 4,6-di-O-benzyl-1,5-di-O-pivaloyl-3-deoxy-
Resu lts a n d Discu ssion
Recently, we described4 the synthesis of a new series
of acyclic nucleoside analogues (1) starting from com-
mercially available 2-deoxy-D-ribose. These nucleoside
analogues can theoretically be used for the preparation
of the target compounds. Therefore, compound 1 (Scheme
1) was treated with p-toluenesulfonyl chloride in pyridine
at room temperature to afford intermediate 2, which upon
treatment with NaH in DMF at room temperature
smoothly cyclized to give 3 in 55% yield in two steps.
Benzyl groups were removed from 3 upon treatment5
with Pd(OH)2 on C to give 4 in 94% yield. The ring-
closure reaction with adenine or 6-chloro-2-aminopurine
as base, however, was unsuccessful, using either the
Mitsunobu reaction or simple nucleophilic displacement,
and resulted in a complex mixture.
4
D-glucitol. These nucleosides adopt a C1 conformation,
and the cytosine congener demonstrates activity against
Herpes simplex virus types 1 and 2.
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) (a) Verheggen, I.; Van Aerschot, A.; Toppet, S.; Snoeck, R.;
J anssen, G; Balzarini, J .; De Clercq, E.; Herdewijn, P. J . Med. Chem.
1993, 36, 2033-2040. (b) Verheggen, I.; Van Aerschot, A.; Van
Meervelt, L.; Rozenski, J .; Wiebe, L.; Snoeck, R.; Andrei, G.; Balzarini,
J .; Claes, P.; De Clercq, E.; Herdewijn, P. J . Med. Chem. 1995, 38,
826-835. (c) Tino, J . A.; Bisacchi, G. S.; Ahmad, S. U.S. Patents
5,314,893 and 5,414,000.
(2) Herdewijn, P.; De Winter, H.; Doboszewski, B.; Verheggen, I.;
Augustyns, K.; Hendrix, C.; Saison-Behmoaras, T.; De Ranter, C.; Van
Aerschot, A. Carbohydrate Modifications in Antisense Research; Ameri-
can Chemical Society Symposium Series No. 580; American Chemical
Society: Washington, DC, 1994; pp 80-99.
(3) Van Aerschot, A.; Verheggen, I.; Hendrix, C.; Herdewijn, P.
Angew. Chem. 1995, 34, 1338-1339.
It appears that this synthetic scheme is limited to the
synthesis of certain pyrimidine nucleoside derivatives.
To develop a more general scheme that can be used for
the synthesis of pyrimidine as well as purine analogues,
(4) Hossain, N.; Rozenski, J .; De Clercq, E.; Herdewijn, P. Tetrahe-
dron 1996 52, 13655-13670.
(5) Tippie, M. A.; Martin, J . C.; Smee, D. F.; Matthews, T. R.;
Verheyden, J . P. H. Nucleosides Nucleotides 1984, 3, 525-535.
S0022-3263(96)01982-2 CCC: $14.00 © 1997 American Chemical Society

R-Analogues of 1,5-Anhydrohexitol Nucleosides
J . Org. Chem., Vol. 62, No. 8, 1997 2443
Sch em e 2
Sch em e 3
it proved necessary to first transform the pentofuranose
sugar to an anhydrohexitol sugar derivative before
introducing the base moiety. Conditions for alkylation
of the nucleobases, however, are dependent on the base
considered.
Sch em e 4
The synthetic strategy is given in Scheme 2. A base-
stable protecting group for the 2-hydroxyl group of 5 is
needed during removal of the pivaloyl groups at positions
1 and 5 and also during the ring-closure reaction of 8 to
9. To this end, the tetrahydropyran-1-yl group6 could be
used. Treatment of 5 with dihydropyran in dichlo-
romethane in the presence of a catalytic amount of
p-toluenesulfonic acid at room temperature for 30 min
gave 6 in 94% yield. The pivaloyl groups of 6 were
removed with aqueous NaOH (N) and dioxane at 55 °C
for 30 h to give 7 in 95% yield. These pivaloyl groups
are surprisingly resistant to hydrolysis upon treatment
with aqueous NaOH (N) in dioxane at room temperature
and were insufficient for hydrolysis. Attempted ring-
closure reaction of 7 under Mitsunobu conditions was
unsuccessful, in contrast to a simple nucleophilic substi-
tution reaction. Compound 7 was treated with p-tolu-
enesulfonyl chloride in pyridine at room temperature to
afford 8, which was not isolated but used directly for the
next step after usual workup. Treatment of 8 with NaH
in DMF gave 9 in 62% yield. The yield of the acidic
hydrolysis of the tetrahydropyran-1-yl group in 9 using
aqueous acetic acid never exceeded 60%. When 9 was
treated with p-toluenesulfonic acid7 in methanol at room
temperature for 30 min, however, 10 was isolated in 90%
yield. Compound 10 can be used as a general starting
material for the synthesis of both pyrimidine and purine
nucleoside analogues.
with methanesulfonyl chloride in the presence of triethyl-
amine in dichloromethane to give 12 (100%) or with
p-toluenesulfonyl chloride in pyridine at room tempera-
ture to give 13 in 90% yield. Treatment of 12 or 13 with
cytosine and cesium carbonate10 in DMF at 120 °C gave
14 (11%) and 16 (40%). The use of 12 or 13 does not
make any difference in yield of 14 and 16. Unfortunately,
Mitsunobu reaction conditions9 in combination with
protected cytosine did not improve the yield. The benzyl
groups in 14 and 16 were removed to give 15 (96%) and
17 (91%), respectively.
An analogous procedure was used for the synthesis of
the purine derivatives (Scheme 4). The adenine analogue
may be obtained either from 10 using triphenylphos-
phine, adenine, and DEAD in dioxane (21% yield) or from
12 using adenine in the presence of NaH in DMF at 90
°C (18% yield). This low yield is due to steric hindrance,
Treatment of 10 with N3-benzoylthymine8 (Scheme 3),
triphenylphosphine, and diethylazodicarboxylate (DEAD)9
in dioxane gave 11, which was directly treated with
aqueous NaOH in dioxane to give 3 (precursor of 4) in
47% yield (two steps). Compound 10 was treated either
(6) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons, Inc.: New York, 1991; pp 31-
34.
(7) Corey, E. J .; Niwa, H.; Knolle, J . J . Am. Chem. Soc. 1978, 100,
1942-1943.
(10) (a) Vandendriessche, F.; Snoeck, R.; J anssen, G.; Hoogmartens,
J .; Van Aerschot, A.; De Clercq, E.; Herdewijn, P. J . Med. Chem. 1992,
35, 1458-1465. (b) Bronson, J . J .; Ghazzouli, I.; Hitchcock, M. J . M;
Webb, R. R.; Martin, J . C. J . Med. Chem. 1989, 32, 1457-1463.
(8) Cruickshank, K. A.; J iricny, J .; Reese, C. B. Tetrahedron Lett.
1984, 25, 681-684.
(9) Mitsunobu, O. Synthesis 1981, 1-28.

2444 J . Org. Chem., Vol. 62, No. 8, 1997
Hossain et al.
Sch em e 5
Ta ble 1. Cytotoxicity a n d An tivir a l Activity of th e
Cytosin e An a logu e 15 in E6SM Cell Cu ltu r es15,16 (ED50
Va lu es Ar e Given in µg/m L)
which is consistent with previously published work.11 The
benzyl groups in 18 were removed to give 19 in 91% yield.
Treatment of the triflate derivative 20 with the tetrabu-
tylammonium salt of 6-iodo-2-aminopurine12 in dichlo-
romethane at 0 °C and with aqueous CF3COOH13 at room
temperature gave 22 in 9% yield (three steps). Mainly
elimination reactions occurred. The benzyl groups from
22 were removed to give 23 in 90% yield.
minimum inhibitory
concentrationb
compd 15
acyclovir
cell morphologya
>400
7
400
0.02
0.07
>200
10
Herpes simplex virus-1 (KOS)
Herpes simplex virus-2 (G)
Vaccinia virus
20
20
10
4
To be able to unambiguously determine the configu-
ration of compounds 4, 15, 19, and 23, we repeated the
synthetic scheme for the thymine analogue using the C-2
epimeric starting material 27 (Scheme 5). In this way,
the anhydrohexitol nucleoside1 with a â-configuration at
position 2 was obtained. Previously, we have described4
the synthesis of 24-26 using AD-mix R. In order to
achieve better stereoselectivity in favor of 25, we have
tried AD-mix â, but the effort was unsuccessful. In case
of AD-mix â, we used the same procedure as described
before4 using 24, AD-mix â14 in 2-methyl-2-propanol, and
water to give 25 (46%) and 26 (46%) in a combined yield
of 92%. We have performed this reaction on a 7.6 mmol
scale using the same experimental conditions as de-
scribed previously.4 The spectroscopic properties of 25
and 26 were identical to those of earlier work.4 Com-
pound 274 was treated with N3-benzoylthymine, DEAD,
and Ph3P in dioxane to afford crude 28, which was
directly treated with aqueous NaOH (N) in dioxane to
give 29 in 45% yield (two steps). Compound 29 was
treated with p-toluenesulfonyl chloride in pyridine, and
after usual workup the residue was treated with NaH in
DMF solution to give the cyclized product 31 in 55% yield
(two steps). Finally, the benzyl groups in 31 were
removed to give 32 in 94% yield. The site of alkylation
of the nucleobase in 3, 4, 14-23, and 31-32 is deter-
mined on the basis of 13C-NMR spectra. In case of O2-
alkylated pyrimidine nucleoside derivatives the sugar C
attached to O2 of the nucleobase resonates at lower field
Herpes simplex virus-1 TK-(B2006)
Herpes simplex virus-1 (TK-/TK+)
(VMW 1837)
1
a
Minimum cytotoxic concentration or concentration required
to cause a microscopically detectable alteration of normal cell
b
morphology. Required to reduce virus-induced cytopathogenecity
by 50%.
F igu r e 1.
(60-70 ppm), whereas the C-atom attached to N1 of the
heterocyclic base resonates more upfield (45-55 ppm).
All of these data are in agreement with our earlier work.4
The configuration and conformation of 4, 15, 19, and
23 were determined on the basis of their 1H-NMR
spectra. This is described here using the thymine ana-
(11) Pe´rez-Pe´rez, M.-J .; Rozenski, J .; Busson, R.; Herdewijn, P. J .
Org. Chem. 1995, 60, 1531-1537.
1
loge 4 as a representative example (Figure 1). The H-
NMR spectrum of 4 shows large 3J HH coupling constants,
(12) Bisacchi, G. S.; Singh, J .; Godfrey, J . D., J r.; Kissick, T. P.; Mitt,
T.; Malley, M. F.; Di Marco, J . D.; Gougoutas, J . Z.; Mueller, R. H.;
Zahler, R. J . Org. Chem. 1995, 60, 2902-2905.
3
3J 2′,3′′ ) 11.2 Hz, 3J 3′′,4′ ) 9.8 Hz, 3J 4′,5′ ) 9.4 Hz, and J 1′′,2′
3
) 12.7 Hz. These large J HH coupling constants are
(13) J indrich, J .; Holy, A.; Dvorakova, H. Collect. Czech. Chem.
Commun. 1993, 58, 1645-1667.
expected for diaxial orientation of the respective protons
(14) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768-2771.
(15) De Clercq, E.; Descamps, J .; Verhelst, G.; Walker, R. T.; J ones,
A. S.; Torrence, P. F.; Shugar, D. J . Infect. Dis. 1980, 141, 563-574.
(16) De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini,
J .; Maudgal, P. C. A. Nature 1986, 323, 464-467.
3
(structure A). In structure B or D, the J 4′eq,5′eq should
be small, which was not observed in the 1H-NMR
3
3
spectrum of 4. In C, the J 1′′ax,2′eq and J 2′eq,3′′ax should
3
differ from our observed J HH coupling constants. From
these observations it is clear that the large J HH coupling
3

R-Analogues of 1,5-Anhydrohexitol Nucleosides
J . Org. Chem., Vol. 62, No. 8, 1997 2445
constants of 4 fit well with structure A. This together
with the independent synthesis of the C-2 epimer of 4
(i.e., 32) proves the configuration of the synthesized
compounds. Note that the precursors of 1 and 29 were
obtained as diastereomeric mixtures by Sharpless dihy-
droxylation of 24. The obtained results also confirmed
the previously determined configuration of both starting
materials.4
The antiviral activity of the synthesized compounds
was determined against herpes simplex virus type 1,
herpes simplex virus type 2, vaccinia virus, vesicular
stomatitis virus, Coxsackie virus type B4, respiratory
syncytial virus, parainfluenza-3 virus, reovirus-1, Sindbis
virus, and Punta Toro virus. Except for 15, none of the
compounds demonstrated any antiviral activity. The
antiviral activity and cytotoxicity data for 15 are pre-
sented in Table 1 in comparison with acyclovir. Although
the antiviral activity was moderate, the compound proved
selective in its antiviral action, as it showed no toxicity
to the host cells. Moreover, the compound was as active
against thymidine kinase positive (TK+) as against
thymidine kinase negative (TK-) herpesvirus strains
(Table 1). The observed activity is remarkable as it
proves that even the R-isomers of this anomalous class
of nucleosides are able to selectively interfere with viral
specific processes. Further studies are needed to unravel
the mode of action of this compound.
organic layer was washed with water, dried, filtered, and
concentrated. The residue was purified by silica gel
column chromatography (2.5-50% EtOAc in hexane) to
afford 3 (50 mg, 47% in two steps). 1H-NMR (CDCl3):
9.10 (br s, 1H); 7.41-7.15 (m, 10 H); 6.98 (s, 1H); 4.78-
4.38 (m, 5H); 4.05 (m, J ) 4.6, 10.6 Hz, 1H); 3.81-3.58
(m, 3H); 3.49-3.35 (m, 2H); 2.48 (m, 1H); 1.90 (s, 3H);
1.81 (m, 1H). 13C-NMR (CDCl3): 163.5, 150.8, 138.0,
137.7, 128.5, 128.0, 127.9, 111.3, 80.1, 73.7, 72.4, 71.5,
69.0, 68.7, 50.3, 34.2; 12.7. HRMS: calcd for C25H29N2O5
(M + H)+ 437.2076, found 437.2075.
1,5-An h yd r o-2,3-d id eoxy-2-(t h ym in -1-yl)-D-r ib o-
h exitol (4). Compound 3 (80 mg, 0.18 mmol) was
treated with Pd(OH)2 on C(20%) (80 mg) in methanol (10
mL) and cyclohexene (3 mL) at reflux temperature for
24 h. The reaction mixture was filtered and concentrated
to give a white solid, which was washed with hexane and
dichloromethane to afford pure 4 (44 mg, 94%). Mp:
220-222 °C. 1H-NMR (DMSO-d6): 11.91 (br s, 1H); 7.51
(s, 1H); 5.05 (d, J ) 5.0 Hz, 1H); 4.46 (t, J ) 5.8 Hz, 1H);
4.35 (m, J ) 12.7 Hz, 1H); 3.73 (ddd, J ) 4.5, 10.3, 1.8
Hz, 1H); 3.69 (ddd, J ) 2.0, 14.8, 5.8 Hz, 1H); 3.42 (m,
2H); 3.38 (m, 1H); 3.03 (ddd, J ) 6.2, 9.4, 2.0 Hz, 1H);
2.04 (m, J ) 4.3, 4.9, 11.8 Hz, 1H); 1.86 (m, J ) 11.2, 9.8
Hz, 1H); 1.75 (s, 3H). 13C-NMR (DMSO-d6): 164.8, 152.0,
138.9, 110.1, 83.9, 68.6, 66.3, 62.3, 51.0, 37.7, 13.1.
HRMS: calcd for C11H17N2O5 (M + H)+ 257.1137, found
257.1154. Anal. Calcd for C11H16N2O5‚0.3C6H14
: C,
54.50; H, 7.22; N, 9.93. Found: C, 54.37; H, 6.98; N, 9.68.
3-Deoxy-4,6-d i-O-ben zyl-1,5-d i-O-p iva loyl-2-O-(tet-
r a h yd r op yr a n -1-yl)-D-glu citol (6). Compound 5 (7.3
g, 14.2 mmol) was treated with dihydropyran (6.0 g) and
p-toluenesulfonic acid (24 mg) in dichloromethane (100
mL) for 30 min at room temperature. The reaction
mixture was diluted with dichloromethane (150 mL) and
washed successively with aqueous saturated NaHCO3 (10
mL) and water (5 mL). The organic layer was dried,
filtered, and concentrated. The residue was purified by
silica gel column chromatography (0-15% EtOAc in
hexane) to give 6 (8.0 g, 94%). Compound 6 is a mixture
of two diastereoisomers due to the chirality of the
tetrahydropyran-1-yl (THP) group. 1H-NMR (CDCl3):
7.41-7.19 (m, 10 H); 5.45 (m, 1H); 5.00-4.50 (m, 4H);
4.41-3.38 (m, 9H); 1.98-1.41 (m, 8H); 1.25 and 1.20 (2
× s, 18 H). HRMS: calcd for C35H50O8 (M + Na)
621.3403, found 621.3434.
3-Deoxy-4,6-d i-O-ben zyl-2-O-(tetr a h yd r op yr a n -1-
yl)-D-glu citol (7). A mixture of 6 (7.0 g, 11.7 mmol),
aqueous NaOH (N) (150 mL), and dioxane (150 mL) was
kept at 55 °C for 30 h. The reaction mixture was cooled
to 0 °C and adjusted to pH 7 by addition of dilute aqueous
HCl. The reaction mixture was reduced to one third of
its volume, and it was extracted with ethyl acetate (3 ×
200 mL). The organic layer was dried, filtered, and
concentrated. The residue was purified by silica gel
column chromatography (2.5-60% EtOAc in hexane) to
afford 7 (4.8 g, 95%), which is a mixture of two diaste-
reoisomers due to the chirality of THP group. 1H-NMR
(CDCl3 + D2O): 7.41-7.20 (m, 10 H); 4.58-4.48 (m, 5H);
4.18-3.38 (m, 9H); 1.99-1.38 (m, 8H). HRMS: calcd for
C25H35O6 (M + H)+ 431.2433, found 431.2447.
Exp er im en ta l Section
Analytical instruments used were described previ-
ously.4 All concentrations were done in a vacuum, and
organic layers were dried over anhydrous Na2SO4. Chemi-
cal shifts are reported in δ units.
1,5-An h ydr o-4,6-di-O-ben zyl-2,3-dideoxy-2-(th ym in -
1-yl)-D-r iboh exitol (3). A mixture of 14 (170 mg, 0.37
mmol) and p-toluenesulfonyl chloride (85 mg, 0.45 mmol)
in pyridine (3 mL) was kept at room temperature
overnight and then concentrated. After addition of water
(3 mL), the mixture was extracted with dichloromethane
(3 × 20 mL). The combined organic layer was concen-
trated and coevaporated with toluene (3 × 10 mL). The
residue was dissolved in dichloromethane (40 mL) and
washed successively with aqueous saturated NaHCO3 (3
× 5 mL) and water (5 mL). The organic layer was dried,
filtered, and concentrated. The residue was dissolved in
DMF (1 mL), added to a suspension of NaH (80%) (32
mg, 1.1 mmol) in DMF (4 mL), and kept at room
temperature overnight. The mixture was concentrated,
and after addition of aqueous saturated NaHCO3 (3 mL)
it was extracted with ethyl acetate (3 × 20 mL). The
combined organic layer was washed with water (3 mL),
dried, filtered, and concentrated. The residue was puri-
fied by silica gel column chromatography (2.5-50%
EtOAc an hexane) to give 3 (90 mg, 55%). Alter n a tive
Meth od . Compound 3 was also prepared by the Mit-
sunobu reaction. Thus, to a mixture of 10 (80 mg, 0.24
mmol), Ph3P (126 mg, 0.48 mmol), and N3-benzoylthy-
mine (109 mg, 0.48 mmol) in dioxane (5 mL) was added
DEAD (74 µL) in dioxane (10 mL) over a period of 60
min at room temperature, and the reaction mixture was
kept at room temperature overnight. The reaction
mixture was concentrated to give crude 11, which was
directly treated with aqueous NaOH (N) in dioxane at
room temperature for 4 h. The reaction mixture was
adjusted to pH 7.0 by addition of dilute aqueous HCl, and
the volume was reduced to 1/3 of its original volume and
extracted with ethyl acetate (2 × 20 mL). The combined
1,5-An h yd r o-3-d eoxy-4,6-d i-O-ben zyl-2-O-(tetr a h y-
d r op yr a n -1-yl)-D-a r a bin oh exitol (9). Compound 7
(4.7 g, 10.9 mmol) was treated with p-toluenesulfonyl
chloride (2.27 g, 11.9 mmol) in pyridine (100 mL) at room
temperature overnight, and an additional 400 mg of
p-toluenesulfonyl chloride was added and kept at room
temperature for another 5 h. After addition of methanol

2446 J . Org. Chem., Vol. 62, No. 8, 1997
Hossain et al.
(5 mL), the mixture was concentrated. The residue was
dissolved in ethyl acetate (200 mL) and washed with
water (20 mL). The combined organic layer was concen-
trated and coevaporated with toluene (3 × 20 mL) and
the residue redissolved in ethyl acetate (200 mL) and
washed successively with aqueous saturated NaHCO3 (3
× 20 mL) and water (10 mL). The organic layer was
dried, filtered, and concentrated. The residue was dis-
solved in DMF (5 mL) and added to a suspension of NaH
(80%) (650 mg, 21.7 mmol) in 75 mL of DMF. The
reaction mixture was kept at room temperature over-
night. After concentration, saturated aqueous NH4Cl (20
mL) was added, and the mixture was extracted with ethyl
acetate (3 × 60 mL). The combined organic layer was
washed with water (20 mL), dried, and concentrated. The
residue was purified by silica gel column chromatography
(2.5-40% EtOAc in hexane) to give 9 (2.8 g, 62%). This
compound is a mixture of two diastereoisomers due to
the chirality of the tetrahydropyran-1-yl group. 1H-NMR
(CDCl3): 7.41-7.18 (m, 10 H); 4.71-4.37 (m, 5H); 4.10-
3.38 (m, 9H); 2.55-2.30 (m, 1H); 1.91-1.39 (m, 7H).
1,5-An h yd r o-3-d eoxy-4,6-d i-O-b en zyl-d -a r a b in o-
h exitol (10). Compound 9 (2.8 g, 6.8 mmol) was treated
with p-toluenesulfonic acid (1.52 g, 8.0 mmol) in methanol
(60 mL) at room temperature for 30 min. After concen-
tration, the residue was dissolved in dichloromethane
(200 mL) and washed successively with aqueous satu-
rated NaHCO3 (3 × 25 mL) and water (20 mL). The
combined organic layer was dried, filtered, and concen-
trated. The residue was purified by silica gel column
chromatography (2.5-50% EtOAc in hexane) to give 10
(2.0 g, 90%). 1H-NMR (CDCl3): 7.41-7.18 (m, 10 H);
4.65-4.32 (m, 4H); 3.98 (m, 1H); 3.90-3.35 (m, 6H); 2.45
(m, J ) 4.3, 13.2 Hz, 1H); 2.22 (d, J ) 7.6 Hz, 1H); 1.55
(m, 1H). 13C-NMR (CDCl3): 138.0, 128.3, 128.0, 127.9,
127.6, 80.6, 73.5, 72.1, 71.0, 69.8, 69.5, 66.7 and 36.0.
HRMS: calcd for C20H25O4 (M + H)+ 329.1752, found
329.1768.
1,5-An h yd r o-3-d eoxy-4,6-d i-O-ben zyl-2-O-m esyl-D-
a r a bin oh exitol (12). Compound 10 (328 mg, 1.0 mmol)
was treated with methanesulfonyl chloride (116 µL, 1.5
mmol) in the presence of triethylamine (208 µL, 1.5
mmol) in dichloromethane (10 mL) at 0 °C for 2 h. After
addition of 2 mL of water the two layers were separated.
The organic layer was washed successively with aqueous
saturated NaHCO3 (2 × 3 mL) and water (3 mL). The
organic layer was dried, filtered, and concentrated to give
12 (406 mg, 100%), which was used in the next step
without further purification. 1H-NMR (CDCl3): 7.39-
7.18 (m, 10 H); 4.98 (m, 1H); 4.67-4.38 (m, 4H); 4.15 (dt,
J ) 2.3, 13.3 Hz, 1H); 3.83-3.57 (m, 4H); 3.45 (m, 1H);
3.02 (s, 3H); 2.65 (m, J ) 4.6, 14.1 Hz, 1H); 1.72 (m, 1H).
13C-NMR (CDCl3): 138.0, 137.8, 128.4, 127.8, 127.7, 80.4,
76.0, 73.6, 71.5, 69.3, 39.0 and 34.5.
2H); 7.40-7.11 (m, 12 H); 4.76 (m, 1H); 4.62-4.28 (m,
4H); 3.90 (br d, J ) 2.0, 12.9 Hz, 1H); 3.78-3.57 (m, 3H);
3.46 (br d, 1H); 3.38 (m, 1H); 2.48 (m, 1H); 2.42 (s, 3H);
1.60 (m, 1H). 13C-NMR (CDCl3): 144.8, 138.1, 137.8,
129.9, 128.3, 127.7, 80.2, 76.8, 73.5, 71.4, 69.6, 69.5, 69.0,
34.1, 21.6.
1,5-An h yd r o-2-(cytosin -1-yl)-2,3-d id eoxy-4,6-d i-O-
ben zyl-D-r iboh exitol (14) a n d 1,5-An h yd r o-2-(cy-
tosin -2-O-yl)-2,3-d id eoxy-4,6-O-d iben zyl-D-r iboh ex-
itol (16). Compound 13 (400 mg, 0.83 mmol) was treated
with cytosine (150 mg, 1.35 mmol) in the presence of
cesium carbonate (588 mg, 1.80 mmol) in DMF (10 mL)
at 120 °C for 14 h. The reaction mixture was cooled to
room temperature and concentrated. After addition of
dichloromethane (20 mL) and methanol (1 mL), the
mixture was filtered, concentrated, and purified by silica
gel column chromatography (0.5-6.0% MeOH in CH2Cl2)
to give 14 (40 mg, 11%) and 16 (140 mg, 40%). Com -
p ou n d 14. 1H-NMR (CDCl3): 7.40-7.18 (m, 11 H); 5.88
(d, J ) 7.1 Hz, 1H); 4.75 (m, 1H); 4.68-4.38 (m, 4H); 4.05
(m, J ) 4.2, 10.5 Hz, 1H); 3.81-3.55 (m, 3H); 3.46-3.28
(m, 2H); 2.48 (m, 1H), 1.85 (m, 1H). 13C-NMR (CDCl3):
165.1, 156.2, 141.5, 138.0, 137.9, 128.4, 127.9, 127.8,
127.7, 95.2, 80.1, 73.6, 72.6, 71.3, 69.3, 50.9, 34.4.
HRMS: calcd for C24H28N3O4 (M + H)+ 422.2079, found
422.2075. Com p ou n d 16. 1H-NMR (CDCl3): 8.00 (d,
J ) 5.6 Hz, 1H); 7.41-7.18 (m, 10 H); 6.09 (d, J ) 5.6
Hz, 1H); 5.07 (m, 1H); 4.89 (br s, 2H); 4.70-4.36 (m, 4H);
4.25 (m, J ) 5.1, 10.6 Hz, 1H); 3.82-3.55 (m, 3H); 3.48-
3.28 (m, 2H); 2.71 (m, 1H); 1.68 (m, 1H). 13C-NMR
(CDCl3): 164.7, 157.8, 138.2, 128.4, 127.9, 127.7, 127.6,
99.5, 80.0, 73.6, 72.2, 71.0, 69.4, 69.3, 68.7, 35.4.
HRMS: calcd for C24H28N3O4 (M + H)+ 422.2079, found
422.2079.
1,5-An h yd r o-2-(cyt osin -1-yl)-2,3-d id eoxy-D-r ib o-
h exitol (15). The reaction was performed as described
for 4 using 14 (40 mg, 0.095 mmol) and Pd(OH)2 on C
(20%) (40 mg) in methanol (10 mL) and cyclohexene (3
mL) to give pure 15 (22 mg, 96%). 1H-NMR (DMSO-d6):
7.67 (d, J ) 7.4 Hz, 1H), 7.18, 7.00 (2 × br s, 2H); 5.69
(d, J ) 7.4 Hz, 1H); 5.18 (d, J ) 4.9 Hz, 1H); 4.59 (t, J )
5.8 Hz, 1H); 4.45 (m, 1H); 3.69 (m, 2H); 3.49-3.13 (m,
3H, under DMSO peak); 3.01 (m, 1H); 2.01 (m, 1H); 1.78
(m, 1H). 13C-NMR (DMSO-d6): 165.3, 155.6, 142.5, 93.8,
82.9, 68.3, 65.2, 61.2, 50.5, 37.0. HRMS: calcd for
C10H16N3O4 (M + H)+ 242.1140, found 242.1124. Anal.
Calcd for C10H15N3O4‚0.5CH2Cl2‚2.0H2O: C, 39.44; H,
6.30; N, 13.14. Found: C, 39.98; H, 6.22; N, 13.17.
1,5-An h yd r o-2-(cytosin -2-O-yl)-2,3-d id eoxy-D-r ibo-
h exitol (17). The reaction was performed as described
for 4 using 16 (125 mg, 0.30 mmol), Pd(OH)2 on C (20%)
(125 mg) in cyclohexene (3 mL), and methanol (10 mL)
to give 17 (65 mg, 91%). 1H-NMR (DMSO-d6): 7.82 (d,
J ) 5.8 Hz, 1H); 7.01 (br s, 2H); 6.08 (d, J ) 5.8 Hz, 1H);
4.98 (d, J ) 3.5 Hz, 1H); 4.82 (m, 1H); 4.50 (br s, 1H);
4.04 (m, J ) 5.0, 10.0 Hz, 1H); 3.72-3.22 (m, 3H, under
DMSO peak); 3.15-2.93 (m, 2H), 2.38 (m, 1H, under
DMSO peak); 1.45 (m, 1H). 13C-NMR (DMSO-d6): 165.6,
163.5; 155.2; 99.6; 83.2; 68.4; 64.4; 61.2; 38.3. HRMS:
Calcd for C10H16N3O4 (M + H)+ 242.1140, found 242.1153.
Anal. Calcd for C10H15N3O4‚0.1CH3OH‚0.7H2O: C, 47.19;
H, 6.59; N, 16.35. Found: C, 47.46; H, 6.29; N, 16.01.
2-(Ad en in -9-yl)-1,5-a n h yd r o-4,6-d i-O-b en zyl-2,3-
d id eoxy-D-r iboh exitol (18). Diethyl azodicarboxylate
(129 µL) in dioxane (10 mL) was added to a mixture of
10 (140 mg, 0.43 mmol), Ph3P (220 mg, 0.84 mmol), and
adenine (113 mg, 0.84 mmol) in dioxane (10 mL) over a
period of 60 min at room temperature. After 20 h, the
1,5-An h yd r o-3-d eoxy-4,6-d i-O-ben zyl-2-O-tosyl-D-
a r a bin oh exitol (13). A mixture of 10 (656 mg, 2.0
mmol) and p-toluenesulfonyl chloride (572 mg, 3.0 mmol)
in 10 mL of pyridine was stirred at room temperature
for 24 h. After concentration, the residue was dissolved
in dichloromethane (30 mL) and washed with water (5
mL). The organic layer was concentrated and coevapo-
rated with toluene (3 × 10 mL). The residue was
dissolved in dichloromethane (30 mL) and washed suc-
cessively with aqueous saturated NaHCO3 (3 × 5 mL)
and water (5 mL). The organic layer was dried, filtered,
and concentrated. The residue was purified by silica gel
column chromatography (0-30% EtOAc in hexane) to
give pure 13 (870 mg, 90%). 1H-NMR (CDCl3): 7.79 (m,

R-Analogues of 1,5-Anhydrohexitol Nucleosides
J . Org. Chem., Vol. 62, No. 8, 1997 2447
reaction mixture was concentrated and the residue
purified by silica gel column chromatography (0.5-6.0%
MeOH in CH2Cl2) to give pure 18 (40 mg, 21%). This
compound was also prepared by a nucleophilic displace-
ment reaction as follows: a mixture of adenine (270 mg,
2.0 mmol) and NaH (80%) (60 mg, 2.0 mmol) in DMF
(10 mL) was kept at 90 °C for 60 min. To the sodium
salt of adenine was added 12 (406 mg, 1.0 mmol) in DMF
(1 mL) and the mixture left at 90 °C for 24 h. The
reaction mixture was cooled to room temperature. The
solvent was removed, and aqueous saturated NaHCO3
(10 mL) was added and extracted with ethyl acetate (3
× 30 mL). The combined organic layer was washed with
water (10 mL), dried, filtered, and concentrated. The
residue was purified by silica gel column chromatography
(0.5-6% MeOH in CH2Cl2) to give pure 18 (80 mg, 18%).
1H-NMR (CDCl3): 8.38 (s, 1H); 7.80 (s, 1H); 7.41-7.18
(m, 10 H); 5.76 (br s, 2H); 4.72 (m, 1H); 4.66-4.41 (m,
4H); 4.20 (ddd, J ) 1.9, 4.7, 10.7 Hz, 1H); 3.85-3.51 (m,
5H); 2.72 (m, 1H); 2.24 (m, 1H). 13C-NMR (CDCl3):
155.5, 153.0, 150.0, 138.4, 138.0, 137.7, 128.4, 127.9,
127.8, 119.9, 80.2, 73.6, 72.2, 71.5, 69.7, 69.0, 50.4, 35.3.
HRMS: calcd for C25H28N5O3 (M + H)+ 446.2192, found
446.2199.
64.8, 61.2, 49.4, 37.9. HRMS: calcd for C11H16N5O4 (M
+ H)+ 282.1202, found 282.1240.
1-(2,3-Did eoxy-4,6-d i-O-b en zyl-2-D-glu cit yl)t h y-
m in e (29). This reaction was performed as described for
11 (see alternative procedure for the preparation of 3)
using 274 (900 mg, 1.75 mmol), Ph3P (915 mg, 3.48 mmol),
N3-benzoylthymine (796 mg, 3.48 mmol), and DEAD (540
µL in 20 mL dioxane) in dioxane (20 mL) to give crude
28, which was directly treated, as described previously,4
with 20 mL of NaOH (N) and dioxane (20 mL) at room
temperature for 24 h to give 29 (360 mg, 45%). The
workup and purification is identical to the procedure
previously described.4 1H-NMR (CDCl3): 9.68 (br s, 1H);
7.41-7.18 (m, 10 H); 7.00 (s, 1H); 4.68 (m, 1H); 4.58-
4.30 (m, 4H); 3.95 (m, 1H), 3.80-3.53 (m, 4H); 3.42 (m,
1H); 2.08 (m, 1H); 1.85 (m, 1H); 1.69 (s, 3H). 13C-NMR
(CDCl3): 164.2, 151.9, 139.3, 137.6, 128.6, 128.0, 110.5,
77.0, 73.6, 72.6, 71.1, 70.8, 64.0, 56.6, 29.5, 12.5.
HRMS: calcd for C25H31N2O6 (M + H)+ 455.2181, found
455.2184.
1,5-An h ydr o-4,6-di-O-ben zyl-2,3-dideoxy-2-(th ym in -
1-yl)-D-a r a bin oh exitol (31). Compound 29 (227 mg, 0.5
mmol) was treated with p-toluenesulfonyl chloride (114
mg, 0.6 mmol) in pyridine (3 mL) at room temperature
overnight. After addition of water (3 mL), it was ex-
tracted with ethyl acetate (2 × 20 mL). The combined
organic layer was concentrated and coevaporated with
toluene (3 × 10 mL). The residue was dissolved in ethyl
acetate (20 mL) and washed successively with aqueous
saturated NaHCO3 (2 × 5 mL) and water (3 mL). The
organic layer was dried, filtered, and concentrated to give
crude 30. The residue was dissolved in DMF (2 mL) and
added to a suspension of NaH (80%, 45 mg, 1.5 mmol) in
DMF (5 mL). The reaction mixture was stirred at room
temperature overnight. The solvent was removed, and
the residue was dissolved in ethyl acetate (20 mL) and
washed successively with saturated aqueous NaHCO3 (2
× 5 mL) and water (5 mL). The organic layer was dried,
filtered, and concentrated. The residue was purified by
silica gel column chromatography (2.0-60% EtOAc in
hexane) to give pure 31 (120 mg, 55% in two steps). 1H-
NMR (CDCl3): 9.10 (br s, 1H); 7.92 (s, 1H); 7.42-7.18
(m, 10 H); 4.75 (m, 1H); 4.61-4.36 (m, 4H); 4.16 (m, 1H);
3.88 (dd, J ) 3.3, 13.5 Hz, 1H); 3.82-3.68 (m, 3H); 3.52
(m, 1H); 2.48 (m, 1H); 1.88 (m, 1H); 1.78 (s, 3H). 13C-
NMR (CDCl3): 163.8, 151.1, 138.9, 138.0, 137.6, 128.5,
127.9, 127.8, 127.7, 110.6, 79.9, 73.5, 71.4, 69.1, 68.5,
68.4, 50.6, 33.0, 12.5. HRMS: calcd for C25H29N2O5 (M
+ H)+ 437.2076, found 437.2050. Experimental proce-
dure for the preparation of 32 is analogous to 4. The
spectroscopic properties of 32 were identical with that
of the previously synthesized compound.1
2-(Ad en in -9-yl)-1,5-a n h yd r o-2,3-d id eoxy-D-r ib o-
h exitol (19). The reaction was performed as described
for 4 using 18 (70 mg, 0.16 mmol) and Pd(OH)2 on C
(20%) (70 mg) in methanol (10 mL) and cyclohexene (3
mL) to give 19 (38 mg, 91%). 1H-NMR (DMSO-d6): 8.28,
8.16 (2 × s, 2H); 7.31 (br s, 2H); 5.17 (br s, 1H); 4.53 (m,
2H); 3.98 (m, 1H); 3.71 (m, 2H); 3.58-3.28 (m, 2H, under
DMSO peak); 3.16 (m, 1H); 2.28 (m, 2H). 13C-NMR
(DMSO-d6): 155.8, 152.3, 149.4, 139.9, 119.0, 83.2, 68.7,
64.9, 61.3, 50.4, 37.9. HRMS: calcd for C11H16N5O3 (M
+ H)+ 266.1253, found 266.1256. Anal. Calcd for
C11H15N5O3‚0.8CH3OH‚H2O: C, 45.88; H, 6.59; N, 22.67.
Found: C, 45.92; H, 6.15; N, 22.46.
1,5-An h ydr o-4,6-di-O-ben zyl-2,3-dideoxy-2-(gu an in -
9-yl)-D-r iboh exitol (22). The reaction was performed
following a literature procedure12 using 10 (280 mg, 0.85
mmol), trifluoromethanesulfonic anhydride (214 µL in 3
mL of CH2Cl2), and pyridine (136 µL). After workup,12
the filtrate was dried over Na2SO4 at 0 °C and directly
filtered onto a solution of the tetrabutylammonium salt
of 6-iodo-2-aminopurine (502 mg, 1.0 mmol) in CH2Cl2
(2 mL) at 0 °C and stirred for 8 h. The residue was
concentrated and treated with 80% CF3COOH in water
(3 mL) at room temperature for 48 h. The solvent was
removed. The residue was treated with NH4OH (1 mL)
in methanol (3 mL). After concentration, the residue was
purified by silica gel column chromatography (0.5-7.0%
MeOH in CH2Cl2) to give 22 (35 mg, 9% in three steps).
1H-NMR (DMSO-d6): 8.95 (br s, 1H); 7.80 (s, 1H); 7.41-
7.20 (m, 10 H); 6.50 (br s, 2H); 4.68-4.37 (m, 4H); 4.30
(m, 1H); 3.90 (m, 1H); 3.80-3.40 (m, 4H); 3.09 (m, 1H);
2.60 (m, 1H); 2.15 (m, 1H). HRMS: calcd for C25H28N5O4
(M + H)+ 462.2141, found 462.2151.
1,5-An h yd r o-2-(gu a n in -9-yl)-2,3-d id eoxy-D-r ib o-
h exitol (23). The reaction was performed as described
for 4 using 22 (20 mg, 0.043 mmol), Pd(OH)2 on C (20%)
(20 mg) in methanol (6 mL), and cyclohexene (2 mL) to
give pure 23 (11 mg, 90%). 1H-NMR (DMSO-d6): 10.62
(br s, 1H); 7.80 (s, 1H); 6.58 (br s, 2H); 5.18 (d, J ) 4.8
Hz, 1H); 4.58 (t, J ) 5.5 Hz, 1H); 4.30 (m, 1H); 3.90 (m,
1H), 3.71 (m, 1H); 3.58-3.30 (m, 3H, under DMSO peak);
3.10 (m, 1H); 2.28 (m, 1H); 2.08 (m, 1H). 13C-NMR
(DMSO-d6): 156.9, 153.6, 150.9, 135.4, 116.7, 83.0, 68.7,
Ackn owledgm en t. The authors thank Mieke Vande-
kinderen for editorial help, Anita Van Lierde and Frieda
De Meyer for technical assistance, and Professor W.
Pfleiderer for elemental analysis. This work was sup-
ported by the grant GOA.97/11. We also thank referees
for constructive criticisms.
Su p p or t in g In for m a t ion Ava ila b le: Copies of 1H and
(or) 13C and (or) attached proton test (APT) NMR spectra for
compounds 3, 4, 6, 7, 9, 10, 12-19, 22, 23, 29, and 31 (36
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O961982M