Synthesis of [4,5-bis(hydroxymethyl)-1,3-dioxolan-2-yl]nucleosides as potential inhibitors of HIV

Article abstract of DOI:10.1021/jo960008k

The synthesis of 1,3-dioxolan-2-ylnucleosides and related chemistry is described. We have shown that 2-methoxy-1,3-dioxolane (6) reacts with silylated thymine and trimethylsilyl triflate to give the acyclic formate ester 1-[2-(formyloxy)ethyl]thymine (8) rather than 1-(1,3-dioxolan-2-yl)thymine (7). A tentative mechanism which could explain this result is discussed. On the other hand, 2-methoxy-1,3-dioxolane 13c reacts with silylated bases to give [4,5-bis(hydroxymethyl)-1,3-dioxolan-2-yl]nucleosides, thus representing the first examples of this novel class of compounds. The nature of the nucleobase and the hydroxyl protecting groups was found to have great influence on the reaction and on the stability of the nucleosides. Compounds 16 and 18 were found to be inactive when tested for anti HIV-1 activity in vitro.

Full text of DOI:10.1021/jo960008k

J . Org. Chem. 1996, 61, 3599-3603
3599
Syn th esis of [4,5-Bis(h yd r oxym eth yl)-1,3-d ioxola n -2-yl]n u cleosid es
a s P oten tia l In h ibitor s of HIV
J onas Brånalt and Ingemar Kvarnstro¨m
Department of Chemistry, Linko¨ping University, S-581 83 Linko¨ping, Sweden
Bjo¨rn Classon and Bertil Samuelsson*,†
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
S-106 91 Stockholm, Sweden
Received J anuary 2, 1996X
The synthesis of 1,3-dioxolan-2-ylnucleosides and related chemistry is described. We have shown
that 2-methoxy-1,3-dioxolane (6) reacts with silylated thymine and trimethylsilyl triflate to give
the acyclic formate ester 1-[2-(formyloxy)ethyl]thymine (8) rather than 1-(1,3-dioxolan-2-yl)thymine
(7). A tentative mechanism which could explain this result is discussed. On the other hand,
2-methoxy-1,3-dioxolane 13c reacts with silylated bases to give [4,5-bis(hydroxymethyl)-1,3-dioxolan-
2-yl]nucleosides, thus representing the first examples of this novel class of compounds. The nature
of the nucleobase and the hydroxyl protecting groups was found to have great influence on the
reaction and on the stability of the nucleosides. Compounds 16 and 18 were found to be inactive
when tested for anti HIV-1 activity in vitro.
In tr od u ction
yl)-1,3-dioxolan-4-yl]guanine (DG) (2) and (-)-(2R,4R)-
9-[2-(hydroxymethyl)-1,3-dioxolan-4-yl]-2,6-diaminopu-
rine (DAPD) (3) are undergoing preclinical evaluation as
anti-HIV and anti-HBV agents, respectively.10
There are today four nucleoside analogues approved
for the treatment of human immunodeficiency virus
(HIV), the causative agent of acquired immunodeficiency
syndrome (AIDS),1 AZT (Zidovudine),2 ddC (Zalcitabine),3
ddI (Didanosine),3 and d4T (Stavudine).4 A drawback
with these compounds is their unfavorable toxicity
profiles and that they are susceptible to the development
of resistant strains of HIV.1 In the search for therapeuti-
cally improved inhibitors of HIV, several novel classes
of nucleosides have been investigated. Developments in
this area have indicated that fundamental changes of the
carbohydrate moiety can be compatible with potent
antiviral activity.5 An interesting approach involves the
replacement of the 3′-carbon with oxygen or sulfur
forming dioxolanyl- or oxathiolanylnucleosides, respec-
tively. The first example of this class of compounds,
racemic dioxolane T (1), was independently reported in
1989 by Norbeck et al.6 and Belleau et al.7 and was found
to exhibit potent anti-HIV activity in vitro.8 Extensive
investigations of the structure-activity relationships for
dioxolanylnucleosides have since then been performed.9
Potent anti-HIV activity in vitro was found in both the
purine and pyrimidine series, and for several derivatives,
both enantiomers and some of the R-anomers were found
to be active. Currently, (-)-(2R,4R)-9-[2-(hydroxymeth-
We11 and others12 have previously reported on the
synthesis of 2′,3′-dideoxy-3′-C-(hydroxymethyl)cytidine
(9) (a) Kim, H. O.; Ahn, S. K.; Alves, A. J .; Beach, J . W.; J eong, L.
S.; Choi, B. G.; Van Roey, P.; Schinazi, R. F.; Chu, C. K. J . Med. Chem.
1992, 35, 1987. (b) Kim, H. O.; Schinazi, R. F.; Nampalli, S.; Shan-
muganathan, K.; Cannon, D. L.; Alves, A. J .; J eong, L. S.; Beach, J .
W.; Chu, C. K. J . Med. Chem. 1993, 36, 30. (c) Kim, H. O.; Schinazi,
R. F.; Shanmuganathan, K.; J eong, L. S.; Beach, J . W.; Nampalli, S.;
Cannon, D. L.; Chu, C. K. J . Med. Chem. 1993, 36, 519. (d) Belleau, B.
R.; Evans, C. A.; Tse, H. L. A.; J in, H.; Dixit, D. M.; Mansour, T. S.
Tetrahedron Lett. 1992, 33, 6949. (e) J in, H.; Tse, H. L. A.; Evans, C.
A.; Mansour, T. S. Tetrahedron: Asymmetry 1993, 4, 211. (f) Evans,
C. A.; Dixit, D. M.; Siddiqui, M. A.; J in, H.; Tse, H. L. A.; Cimpoia, A.;
Bednarski, K.; Breining, T.; Mansour, T. S. Tetrahedron: Asymmetry
1993, 4, 2319. (g) Siddiqui, M. A.; Brown, W. L.; Nguyen-Ba, N.; Dixit,
D. M.; Mansour, T. S. Bioorg. Med. Chem. Lett. 1993, 3, 1543.
(10) Xiang, Y.; Teng, Q.; Chu, C. K. Tetrahedron Lett. 1995, 36, 3781.
(11) Svansson, L.; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J .
Org. Chem. 1991, 56, 2993.
(12) (a) Sterzycki, R. Z.; Martin, J . C.; Wittman, M.; Brankovan,
V.; Yang, H.; Hitchcock, M. J .; Mansuri, M. M. Nucleosides Nucleotides
1991, 10, 291. (b) Bamford, M. J .; Coe, P. L.; Walker, R. T. J . Med.
Chem. 1990, 33, 2494. (c) Tseng, C. K.-H.; Marquez, V. E.; Milne, G.
W. A.; Wysocki, R. J .; Mitsuya, H.; Shirasaki, T.; Driscoll, J . S. J . Med.
Chem. 1991, 34, 343. (d) Mann, J .; Weymouth-Wilsson, A. C. J . Chem.
Soc., Perkin Trans. 1 1994, 3141.
† Additional address: Astra Ha¨ssle AB, S-431 83 Mo¨lndal, Sweden.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) For a recent review, see: De Clercq, E. J . Med. Chem. 1995, 38,
2491.
(2) Mitsuya, H.; Weinhold, K. J .; Furman, P. A.; St. Clair, M. H.;
Nusinoff Lehrman, S.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.; Broder,
S. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 7096.
(3) Mitsuya, H.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83,
1911.
(4) Balzarini, J .; Kang, G.-J .; Dalal, M.; Herdewijn, P.; De Clercq,
E.; Broder, S.; J ohns, D. G. Mol. Pharmacol. 1987, 32, 162.
(5) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(6) Norbeck, D. W.; Spanton, S.; Broder, S.; Mitsuya, H. Tetrahedron
Lett. 1989, 30, 6263.
(7) Belleau, B.; Dixit, D. M.; Nguyen-Ba, N.; Kraus, J . L. Abstracts
of Papers, Fifth International Conference on AIDS, Montreal, Canada,
1989, Abstract T.C.O.1.
(8) Choi, W.-B.; Wilson, L. J .; Yeola, S.; Liotta, D. C.; Schinazi, R.
F. J . Am. Chem. Soc. 1991, 113, 9377.
S0022-3263(96)00008-4 CCC: $12.00 © 1996 American Chemical Society

3600 J . Org. Chem., Vol. 61, No. 11, 1996
Bra˚nalt et al.
Sch em e 1
Sch em e 2
et al. also reported that the compound proposed to be 7
is unstable toward base and converts into 1-(2-hydroxy-
ethyl)thymine (9) by a rearrangement reaction for which
they have also proposed a mechanism.16 When we
treated 8 with base, hydrolysis of the formate ester
occurred and we obtained 9 in all aspects identical with
that reported.16 To further confirm our assignment, we
treated 9 with formic acid21 at 70 °C and obtained the
formate ester 8 in 79% yield. This compound was in all
aspects identical to that obtained from the glycosylation
reaction (vide supra). Further evidence for the assign-
ment of compound 8 was obtained by reacting thymine
with a large excess of ethylene oxide to give 9, followed
by treatment with formic acid. Compound 8 was ob-
tained in 12% yield by separation from unreacted thym-
ine and 1-(2-hydroxyethyl)thymine (9) and shown to be
identical with that obtained above. We have proposed a
tentative mechanism for the reaction of 6 with silylated
bases under Vorbru¨ggen conditions,17 which is based on
the reported reactivity of 1,3-dioxolan-2-ylium ions22
(Scheme 2). Generally, cyclic orthoesters react with
Lewis acids in anhydrous media predominantly by loss
of the exocyclic group over dioxolane ring cleavage with
in situ formation of the corresponding 1,3-dioxolan-2-
ylium ions.23 This is also true for the formation of the
(4), a potent inhibitor of HIV activity in vitro, considered
as a new interesting lead compound.13 As a part of our
program to prepare analogues14 of 4, we became inter-
ested in applying the successful concept of substituting
a methylene group in the pentofuranosyl moiety with an
oxygen atom. Replacing C-2′ of 4 with an oxygen gives
the nucleoside derivative 5. To our knowledge, com-
pounds of this novel type which basically can be viewed
as cyclic orthoester derivatives, have not been previously
reported.15 In the present paper we describe the syn-
thesis of some [4,5-bis(hydroxymethyl)-1,3-dioxolan-2-yl]-
nucleosides and related chemistry.
Resu lts a n d Discu ssion
During the preparation of this paper Chu et al.16
reported that 2-methoxy-1,3-dioxolane (6) reacts with
silylated thymine and trimethylsilyl triflate (TMSOTf)
under Vorbru¨ggen conditions17 to give 1-(1,3-dioxolan-2-
yl)thymine (7) (Scheme 1). We have repeated their
experiment and obtained a single product with analytical
1
data identical with that reported16 (mp and H NMR).18
However, on the basis of NMR data, we have assigned
the product as 1-[2-(formyloxy)ethyl]thymine (8).19 Con-
sequently, we believe that the open chain formate ester
8 is formed rather than the dioxolanylnucleoside 7.20 Chu
(19) Because of the symmetry of structure 7, C-4 and C-5 in the
dioxolanyl moiety are identical. However, in the 13C NMR spectra of
the compound obtained, two peaks corresponding to these carbons are
found, indicating an asymmetric structure. Furthermore, one would
expect C-2 in the dioxolanyl moiety of 7 to appear at ca. 90-115 ppm.
For the compound obtained, the only peak present in this region is
C-5 of thymine at 108.3 ppm. Compared to compound 9, an additional
signal at 161.7 ppm is found, which is in excellent agreement with a
formate ester. This is also true for the proton singlet at 8.22 ppm. We
have measured the C,H coupling constant for the carbon at 161.7 ppm
in 8 to be 233 Hz. Formate esters usually have C,H coupling constants
near 230 Hz, whereas the corresponding value for an orthoester
derivative is expected to be below 200 Hz. The structure of 8 was
further confirmed by H,C-COSY experiments, optimized for long-range
C,H coupling constants of 3.5-5 Hz.
(20) Chu et al. (ref 16) also report the preparation of the fluorouracil
and cytosine analogue of 7 and some [4-(hydroxymethyl)-1,3-dioxolan-
2-yl]nucleosides. Since these compounds have the same spectral
characteristics (NMR) as compound 8, we believe that the open chain
formate esters are formed in these cases as well.
(21) Primary and secondary alcohols react with formic acid without
catalyst to give the corresponding formate ester: (a) Ringold, H. J .;
Lo¨ken, B.; Rosenkranz, G.; Sondheimer, F. J . Am. Chem. Soc. 1956,
78, 816. (b) Werner, W. J . Chem. Res. 1980, 196.
(13) Herdewijn, P. A. M. M. Antiviral. Res. 1992, 19, 1.
(14) (a) Brånalt, J .; Kvarnstro¨m, I.; Niklasson, G.; Svensson, S. C.
T.; Classon, B.; Samuelsson, B. J . Org. Chem. 1994, 59, 1783. (b)
Brånalt, J .; Kvarnstro¨m, I.; Svensson, S. C. T.; Classon, B.; Samuels-
son, B. J . Org. Chem. 1994, 59, 4430. (c) J ansson, M.; Svansson, L.;
Svensson, S. C. T.; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B.
Nucleosides Nucleotides 1992, 11, 1793. (d) Rosenquist, Å.; Kvarnstro¨m,
I.; Svensson, S. C. T.; Classon, B.; Samuelsson, B. J . Org. Chem. 1994,
59, 1779.
(15) Compounds similar to 5 containing an additional methylene
group inserted between the base and the dioxolane moiety have been
prepared and evaluated as potential antiviral agents: (a) Efimtseva,
E. V.; Mikhailov, S. N.; Meshkov, S. V.; Lo¨nnberg, H. Acta Chem.
Scand. 1992, 46, 1122. (b) Mikhailov, S. N.; Efimtseva, E. V.; Meshkov,
S. V.; Kern, E. R. Nucleosides Nucleotides 1994, 13, 615.
(16) Liang, C.; Lee, D. W.; Newton, G.; Chu, C. K. J . Org. Chem.
1995, 60, 1546.
(17) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234.
(18) The 13C NMR spectrum is also identical with that reported
except for the thymine C-5 methyl group which is not reported in ref
16. 1H and 13C NMR spectra are available as supporting information.
See the Experimental Section for more details.
(22) For reviews, see: (a) Pittman, C. U.; McManus, S. P.; Larsen,
J . W. Chem. Rev. 1972, 72, 357. (b) Hu¨nig, S. Angew. Chem., Int. Ed.
Engl. 1964, 3, 548. (c) Pindur, U.; Mu¨ller, J .; Flo, C.; Witzel. Chem.
Soc. Rev. 1987, 16, 75.

1,3-Dioxolan-2-ylnucleosides as Potential Inhibitors of HIV
J . Org. Chem., Vol. 61, No. 11, 1996 3601
Sch em e 3
Sch em e 4
used. In contrast, the dibenzyl derivative 14b was
isolated in a small but reproducible yield. A considerably
higher yield of the desired nucleoside was obtained using
the bulky tert-butyldimethylsilyl group. The thymine
derivative 14c was isolated in 63% yield as a stable solid
which could be stored for months (Scheme 4). Desilyla-
tion of 14c using tetrabutylammonium fluoride in tet-
rahydrofuran gave the thymine derivative 16 in 95%
yield. This compound was surprisingly stable and could
be purified by standard silica gel chromatography with-
out detectable hydrolysis. The corresponding uracil
derivatives 17 and 18 were obtained in a similar way in
53% and 97% yields, respectively. Condensation of 13c
with silylated 6-chloropurine under normal Vorbru¨ggen
conditions17 was not successful. However, if the reaction
was quenched with pyridine after addition of 0.3 equiv
of trimethylsilyl triflate, 19 could be isolated in 49% yield.
Unfortunately, compound 19 was not stable enough for
full characterization and spontaneously hydrolyzed into
formate ester 15c and 6-chloropurine. All attempts to
condense 13c with silylated cytosine or N4-benzoylcy-
tosine were unsuccessful, giving the formate ester 15c
as the main product. Neither was it possible to convert
the uracil derivative 17 into cytosine using 1,2,4-triazole
and p-chlorophenyl phosphodichloridate.26
1,3-dioxolan-2-ylium ion (10).23 Ions of this type are
ambidentate cations which can react with nucleophiles
in two ways depending on the reaction conditions. Under
kinetic control the nucleophile is expected to react at C-2,
the atom of greatest electron deficiency (path a). Attack
at C-4, in a thermodynamically controlled reaction,
proceeds with alkylation of the nucleophile to give the
carboxylic ester (path b). The preferred route and thus
the product distribution depend mainly on the nature of
the nucleophile, the stability of the ambident cation, the
reaction temperature, and the reaction time. If the
kinetic product is stable enough, dissociation back to the
cation may be avoided and the kinetic product can be
isolated. Although some exceptions have been reported,
products from the kinetically controlled reaction can
usually only be isolated when strongly nucleophilic or
basic reagents are used.22 We believe that the C-2
substituted product 11 might be formed initially but
under the reaction conditions used this compound should
be in equilibrium with ion 10, allowing the reaction to
proceed to the thermodynamic product 8.
For the synthesis of [4,5-bis(hydroxymethyl)-1,3-diox-
olan-2-yl]nucleosides, the 1,4-diprotected derivatives of
D-threitol (12a -c) were used as starting materials
(Scheme 3). The corresponding 2-methoxy-1,3-dioxolanes
13a -c were prepared in almost quantitative yields by
treatment with trimethyl orthoformate in the presence
of camphorsulfonic acid (CSA). Condensations of these
compounds with silylated thymine in the presence of
trimethylsilyl triflate gave mixtures of the desired nu-
cleosides 14a -c24 and the formate esters 15a -c.25 For-
mation of products arising from attack at C-4 could not
in any case be detected, probably due to the steric
hindrance exerted by the hydroxymethyl groups. We
found that the product distribution was highly dependent
on the hydroxyl protecting groups used. We were not
able to isolate any detectable amounts of the dibenzoyl
derivative 14a although several reaction conditions were
Compounds 16 and 18 were tested for inhibition of HIV
multiplication in a XTT assay in M4 cells.27 Both
compounds were found to be inactive in the assay.28
Exp er im en ta l Section
Concentrations were performed under diminished pressure
(1-2 kPa) at a bath temperature not exceeding 40 °C. 1H
NMR and 13C NMR spectra were measured at 250 and 62.9
MHz, respectively, using CDCl3, MeOH-d4, or DMSO-d6 solu-
tions with TMS as internal standard. The shifts are reported
in ppm (δ scale). TLC was performed on precoated silica gel
plates. Spots were visualized by UV light and/or charring with
ethanol/sulfuric acid/p-anisaldehyde/acetic acid (90:4:4:2). Col-
umn chromatography was performed using silica gel (0.040-
0.063 mm). Organic phases were dried over anhydrous
magnesium sulfate.
(23) (a) Chiang, Y.; Kresge, A. J .; Salomaa, P.; Young, C. I. J . Am.
Chem. Soc. 1974, 96, 4494. (b) Burt, R. A.; Chambers, C. A.; Chiang,
Y.; Hillock, C. S.; Kresge, A. J .; Larsen, J . W. J . Org. Chem. 1984, 49,
2622.
(24) Because of the C-2 symmetry of the intermediate 1,3-dioxolan-
2-ylium ion, only one diastereomer is formed in the glycosylation
reaction.
(26) Sung, W. L. J . Chem. Soc., Chem. Commun. 1981, 1089.
(27) Vial, J . M.; J ohansson, N. G.; Wrang, L.; Chattopadhyaya, J .
Antiviral Chem. Chemother. 1990, 1, 183.
(28) Compounds 16 and 18 are expected to be very sensitive to acid-
catalyzed hydrolysis. Although stable for at least 24 h in a neutral
methanol solution, it cannot be ruled out that these compounds might
hydrolyze during the biological evaluation.
(25) The formate esters 15a -c were also formed from dioxolanes
13a -c when stored without exclusion of moisture.

3602 J . Org. Chem., Vol. 61, No. 11, 1996
Bra˚nalt et al.
1
Gen er a l P r oced u r e for Silyla tion of Nu cleosid e Ba ses.
A suspension of thymine, uracil, cytosine, N4-benzoylcytosine,
or 6-chloropurine (10 mmol) and a small crystal of ammonium
sulfate in a mixture of hexamethyldisilazane (20 mL) and
trimethylchlorosilane (2 mL) was refluxed until a clear solution
was obtained. Volatile matters were evaporated off, the
residue was coevaporated with toluene and dissolved in
dichloromethane (10 mL) to give stock solutions (1.0 M) of
silylated bases for direct use in the coupling reactions.
1-[2-(F or m yloxy)eth yl]th ym in e (8). 2-Methoxy-1,3-di-
oxolane (6)29 was condensed with silylated thymine using 1.1
equiv of trimethylsilyl triflate as described by Chu et al.16 to
give 8 as a white solid. 1H NMR was in agreement with that
reported. 8: mp 169-170 °C (lit.16 mp 168-170 °C); 1H NMR
(250 MHz, DMSO-d6) δ 1.77 (d, J ) 1.1 Hz, 3H), 3.92 (t, J )
5.2 Hz, 2H), 4.31 (t, J ) 5.2 Hz, 2H), 7.52 (d, J ) 1.1 Hz, 1H),
8.22 (s, 1H), 11.1 (bs, 1H); 13C NMR (62.9 MHz, DMSO-d6) δ
11.8, 46.2, 60.7, 108.3, 141.4, 150.8, 161.7, 164.1.
+16.5° (c 1.3, CHCl3); H NMR (250 MHz, CDCl3) δ 3.36 (s,
3H), 4.4-4.65 (m, 6H), 5.88 (s, 1H), 7.4-7.6 (m, 6H), 8.0-8.1
(m, 4H); 13C NMR (62.9 MHz, CDCl3) δ 52.0, 63.9, 64.9, 75.7,
76.0, 116.8, 128.5, 129.7, 133.2, 133.2, 166.1. Anal. Calcd for
C
20H20O7: C, 64.51; H, 5.41. Found: C, 64.29; H, 5.34.
(4R,5R)-2-Met h oxy-4,5-b is[(ben zyloxy)m et h yl]-1,3-d i-
oxola n e (13b). Compound 13b was prepared from 1,4-di-O-
benzyl-D-threitol (12b) (300 mg, 0.99 mmol) using the same
methodology as described for the preparation of compound 13a .
Compound 13b (348 mg, 100%) was obtained as a colorless
oil which was used in the following steps without further
purification. 13b: [R]22 -10° (c 1.2, CHCl3); H NMR (250
1
D
MHz, CDCl3) δ 3.31 (s, 3H), 3.60 (dd, J ) 11.5, 5.0 Hz, 1H),
3.65-3.70 (m, 2H), 3.73 (dd, J ) 10.0, 5.8 Hz, 1H), 4.1-4.3
(m, 2H), 4.55, 4.56 (2s, 4H), 5.79 (s, 1H), 7.2-7.4 (m, 10 H);
13C NMR (62.9 MHz, CDCl3) δ 51.6, 70.0, 71.4, 73.5, 77.3,
116.4, 127.6, 128.4, 137.9, 138.0. Anal. Calcd for C20H24O5:
C, 69.75; H, 7.02. Found: C, 69.48; H, 6.98.
1-(2-Hyd r oxyeth yl)th ym in e (9). Compound 8 (35 mg,
0.177 mmol) was treated with methanolic ammonia (3 mL,
saturated) for 5 h. The solvent was evaporated, and the
residue purified by column chromatography (ethyl acetate/
methanol 4:1) to give 9 (28 mg, 94%) as a white solid. 1H NMR
was in agreement with that reported. 9: mp 179-180 °C (lit.16
mp 180-181 °C); 1H NMR (250 MHz, DMSO-d6) δ 1.76 (s, 3H),
3.57 (q, J ) 5.2 Hz, 2H), 3.69 (t, J ) 5.2 Hz, 2H), 4.91 (t, J )
5.4 Hz, 1H), 7.44 (s, 1H), 11.2 (bs, 1H); 13C NMR (62.9 MHz,
DMSO-d6) δ 11.8, 49.8, 58.5, 107.5, 142.3, 150.8, 164.3.
P r ep a r a tion of 8 fr om 9. A solution of compound 9 (18
mg, 0.106 mmol) in formic acid (85%, 2 mL) was heated at 70
°C for 2 h. The solvent was evaporated and coevaporated with
toluene. The solid residue was purified by column chroma-
tography (ethyl acetate) to give 8 (16.5 mg, 79%) as a white
solid, identical to that obtained above.
P r ep a r a tion of Com p ou n d 8 fr om Th ym in e a n d Eth -
ylen e Oxid e.30 To a suspension of thymine (1.00 g, 7.93
mmol) and potassium carbonate (40 mg) in dimethylformamide
(10 mL) was added ethylene oxide (6.0 g, 150 mmol). The
mixture was refluxed at 60 °C overnight. Excess ethylene
oxide and residual solvents were evaporated, and the solid
residue was dissolved in formic acid (85%, 5 mL) and heated
at 70 °C for 2 h. After evaporation of the solvent and
coevaporation with toluene, the crude product was purified by
column chromatography (ethyl acetate) to give 8 (188 mg, 12%)
as a white solid identical to that described above. Further
elution with ethyl acetate/methanol (4:1) gave a mixture of 8,
9, and thymine.
1,4-Bis-O-(ter t-bu tyld im eth ylsilyl)-D-th r eitol (12c). To
a stirred solution of D-threitol (1.55 g, 12.7 mmol) in dimeth-
ylformamide (30 mL) were added imidazole (1.73 g, 25.4 mmol)
and tert-butyldimethylsilyl chloride (3.84 g, 25.4 mmol). The
resulting mixture was stirred overnight at room temperature.
The solution was diluted with toluene and washed with
saturated aqueous sodium hydrogen carbonate. The organic
phase was dried, filtered, concentrated, and purified by column
chromatography (toluene/ethyl acetate 9:1) to give 12c (3.25
g, 73%) as a colorless oil which solidified on standing. 12c:
[R]22D -4.4° (c 1.2, CHCl3); 1H NMR (250 MHz, CDCl3) δ 0.082
(s, 12H), 0.90 (s, 18H), 2.8 (m, 2H), 3.75 (m, 6H); 13C NMR
(62.9 MHz, CDCl3) δ -5.47, 18.2, 25.8, 65.0, 71.4. Anal. Calcd
for C16H38O4Si2: C, 54.81; H, 10.92. Found: C, 54.67; H,
10.73.
(4R,5R)-2-Met h oxy-4,5-b is[[(ter t-b u t yld im et h ylsilyl)-
oxy]m eth yl]-1,3-d ioxola n e (13c). Compound 13c was pre-
pared from 12c (3.25 g, 9.29 mmol) using the same method-
ology as described for the preparation of compound 13a .
Compound 13c (3.62 g, 99%) was obtained as a colorless oil
which was used in the following steps without further puri-
fication. 13c: [R]22D +4.8° (c 2.0, CHCl3); 1H NMR (250 MHz,
CDCl3) δ 0.066 (s, 12H), 0.89 (s, 18H), 3.31 (s, 3H), 3.65-3.8
(m, 3H), 3.83 (dd, J ) 10.2, 5.2 Hz, 1H), 4.01 (dt, J ) 5.2, 6.3
Hz, 1H), 4.09 (dt, J ) 4.2, 6.3 Hz, 1H), 5.75 (s, 1H); 13C NMR
(62.9 MHz, CDCl3) δ -5.42, 18.3, 25.8, 51.2, 63.6, 64.6, 78.1,
78.8, 116.2. Anal. Calcd for C18H40O5Si2: C, 55.06; H, 10.27.
Found: C, 54.82; H, 10.13.
Isolation of 1,4-Di-O-ben zoyl-2-O-for m yl-D-th r eitol (15a)
d u r in g th e Attem p ted P r ep a r a tion of 14a . To a stirred
solution of 13a (500 mg, 1.27 mmol) in dichloromethane (10
mL) were added silylated thymine (4 mL of a 1.0 M solution
in dichloromethane) and trimethylsilyl triflate (0.26 mL, 1.40
mmol). The resulting solution was stirred at room for 5 min.
The reaction mixture was neutralized by the addition of
pyridine, poured onto a silica gel column, and eluted with
toluene/ethyl acetate (5:1). Further purification by column
chromatography (toluene/ethyl acetate 3:1) gave 15a (290 mg,
64%) as a colorless solid. 15a : [R]22D -8.1° (c 0.6, CHCl3); mp
152.4-152.8 °C (EtOAc/hexane); 1H NMR (250 MHz, DMSO-
d6) δ 4.2 (bs, 1H), 4.28 (dd, J ) 11.1, 5.2 Hz, 1H), 4.33 (dd, J
) 11.1, 6.5 Hz, 1H), 4.49 (dd, J ) 11.9, 7.8 Hz, 1H), 4.62 (dd,
J ) 11.9, 3.4 Hz, 1H), 5.42 (m, 1H), 5.73 (bs, 1H), 7.5-7.8 (m,
6H), 7.9-8.05 (m, 4H), 8.40 (s, 1H); 13C NMR (62.9 MHz,
DMSO-d6) δ 63.6, 64.8, 66.8, 71.2, 128.7, 128.8, 129.2, 129.3,
129.6, 133.5, 133.6, 161.9, 165.5, 165.6. Anal. Calcd for C19
H18O7: C, 63.68; H, 5.06. Found: C 63.61; H, 5.11.
(4R,5R)-1-[4,5-Bis[(ben zyloxy)m eth yl]-1,3-d ioxola n -2-
yl]th ym in e (14b) a n d 1,4-Di-O-ben zyl-2-O-for m yl-D-th r ei-
tol (15b). To a stirred solution of 13b (200 mg, 0.58 mmol)
in dichloromethane (10 mL) were added silylated thymine (4
mL of a 1.0 M solution in dichloromethane) and trimethylsilyl
triflate (0.12 mL, 0.64 mmol). The resulting solution was
stirred at room temperature for 5 min. The reaction mixture
was neutralized by the addition of pyridine, poured onto a
silica gel column, and eluted with toluene/ethyl acetate (5:1).
Further purification by column chromatography (toluene/ethyl
acetate 3:1) gave 15b (72 mg, 38%) and 14b (22 mg, 9%) as
colorless syrups. 14b: [R]22 -5.2° (c 0.4, CHCl3); 1H NMR
(4R,5R)-2-Meth oxy-4,5-bis[(ben zoyloxy)m eth yl]-1,3-d i-
oxola n e (13a ). To a solution of 1,4-di-O-benzoyl-D-threitol
(12a ) (3.00 g, 9.09 mmol) in trimethyl orthoformate/dichlo-
romethane (40 mL, 1:1) was added camphorsulfonic acid (45
mg, 0.18 mmol). After being stirred at room temperature for
1 h, the reaction mixture was diluted with dichloromethane
and washed with saturated aqueous sodium hydrogen carbon-
ate. The organic phase was dried, filtered, and concentrated
to give 13a (3.28 g, 97%) as a colorless oil which was used in
D
(250 MHz, CDCl3) δ 1.67, (d, J ) 1.1 Hz, 3H), 3.55-3.70 (m,
2H), 3.99 (dd, J ) 11.0, 2.9 Hz, 1H), 4.30 (dt, J ) 3.0 Hz, 1H),
4.45-4.60 (m, 2H), 4.59 (s, 4H), 6.99 (s, 1H), 7.3-7.4 (m, 10
H), 7.52 (d, J ) 1.1 Hz, 1H), 8.2 (bs, 1H); 13C NMR (62.9 MHz,
CDCl3) δ 12.1, 68.7, 69.8, 73.7, 76.1, 78.3, 102.1, 111.1, 127.6-
128.6, 134.8, 137.3, 137.4, 150.2, 163.4. Anal. Calcd for
C24H26O6N2: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.89; H,
5.92; N, 6.19. 15b: [R]22D -11.3° (c 0.7, CHCl3); 1H NMR (250
MHz, CDCl3) δ 2.74 (d, J ) 5.1 Hz, 1H), 3.49 (dd, J ) 9.7, 6.0
Hz, 1H), 3.54 (dd, J ) 9.7, 4.9 Hz, 1H), 3.67 (dd, J ) 10.6, 5.3
Hz, 1H), 3.72 (dd, J ) 10.6, 4.4 Hz, 1H), 4.07 (dt, J ) 5.0 Hz,
1H), 4.45-4.60 (m, 4H), 5.25 (m, 1H), 7.25-7.40 (m, 10 H),
8.11 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ 69.0, 69.7, 70.6,
the following steps without further purification. 13a : [R]22
D
(29) Baganz, H.; Domaschke, L. Chem. Ber. 1958, 91, 650.
(30) Ca u tion ! All handling with ethylene oxide was performed in
a well-ventilated fume hood.

1,3-Dioxolan-2-ylnucleosides as Potential Inhibitors of HIV
J . Org. Chem., Vol. 61, No. 11, 1996 3603
1
72.2, 73.5, 73.6, 127.7, 127.9, 128.2, 128.5, 137.5, 137.6, 160.6.
Anal. Calcd for C19H22O5: C, 69.07; H, 6.71. Found: C, 69.22;
H, 6.80.
CHCl3); H NMR (250 MHz, CDCl3) δ 0.085, 0.099 (2s, 12H),
0.91, 0.92 (2s, 18H), 3.73 (dd, J ) 11.0, 3.6 Hz, 1H), 3.77 (dd,
J ) 11.5, 2.6 Hz, 1H), 3.82 (dd, J ) 11.0, 4.6 Hz, 1H), 4.00
(dd, J ) 11.5, 2.9 Hz, 1H), 4.23 (dt, J ) 6.2, 2.6 Hz, 1H), 4.33
(ddd, J ) 6.2, 4.6, 3.6 Hz, 1H), 5.70 (d, J ) 8.4 Hz, 1H), 6.98
(s, 1H), 7.81 (d, J ) 8.4 Hz, 1H), 9.75 (bs, 1H); 13C NMR (62.9
MHz, CDCl3) δ -5.55, -5.45, 18.2, 18.3, 21.4, 25.8, 62.2, 63.3,
76.9, 79.5, 102.0, 102.7, 139.4, 150.5, 163.5. Anal. Calcd for
C21H40O6N2Si2: C, 53.36; H, 8.53; N, 5.93. Found: C, 53.19;
H, 8.34; N, 6.01.
(4R,5R)-1-[4,5-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]-
1,3-d ioxola n -2-yl]th ym in e (14c) a n d 1,4-Di-O-(ter t-bu -
tyld im eth ylsilyl)-2-O-for m yl-D-th r eitol (15c). Compound
14c was prepared from 13c (500 mg, 1.27 mmol) using the
same methodology as described for the preparation of com-
pound 14b. Compound 15c (67 mg, 14%) was obtained as a
colorless syrup, and compound 14c (0.381 g, 63%) as a colorless
syrup which solidified on standing. 14c: [R]22 -3.5° (c 1.0,
(4R,5R)-1-[4,5-Bis(h yd r oxym eth yl)-1,3-d ioxola n -2-yl]-
u r a cil (18). Compound 17 (53 mg, 0.112 mmol) was dissolved
in tetrahydrofuran (4 mL), tetrabutylammonium fluoride (1.12
mL of a 0.5 M solution in tetrahydrofuran) was added, and
the resulting solution was stirred for 1 h at room temperature.
The solvent was evaporated and the crude product purified
by column chromatography (ethyl acetate/methanol 4:1) to give
D
1
CHCl3); H NMR (250 MHz, CDCl3) δ 0.081, 0.10 (2s, 12H),
0.91, 0.92 (2s, 18H), 1.92 (d, J ) 1.1 Hz, 3H), 3.72 (dd, J )
11.0, 3.4 Hz, 1H), 3.78, (dd, J ) 11.4, 2.3 Hz, 1H), 3.84 (dd, J
) 11.0, 4.4 Hz, 1H), 3.98 (dd, J ) 11.4, 3.4 Hz, 1H), 4.21 (dt,
J ) 6.4, 3.1 Hz, 1H), 4.30 (ddd, J ) 6.4, 4.4, 3.4 Hz, 1H), 6.93
(s, 1H), 7.37 (d, J ) 1.1 Hz, 1H) 9.05 (bs, 1H); 13C NMR (62.9
MHz, CDCl3) δ -5.54, -5.42, -5.35, 18.2, 18.4, 25.8, 25.9, 62.2,
63.3, 77.2, 78.9, 101.7, 111.2, 134.4, 150.3, 163.8. Anal. Calcd
18 (26.5 mg, 97%) as a white solid. 18: [R]22 +17° (c 0.4,
D
1
MeOH); H NMR (250 MHz, MeOH-d4) δ 3.64 (dd, J ) 12.3,
for C22H42O6N2Si2: C, 54.29; H, 8.70; N, 5.76. Found: C, 54.41;
4.0 Hz, 1H), 3.72 (dd, J ) 12.4, 3.6 Hz, 1H), 3.80 (dd, J ) 12.3,
3.4 Hz, 1H), 3.89 (dd, J ) 12.4, 3.1 Hz, 1H), 4.20 (dt, J ) 6.9,
3.4 Hz, 1H), 4.32 (dt, J ) 6.9, 3.8 Hz, 1H), 5.71 (d, J ) 8.0 Hz,
1H), 6.93 (s, 1H), 7.94 (d, J ) 8.0 Hz, 1H); 13C NMR (62.9 MHz,
MeOH-d4) δ 61.7, 62.6, 79.6, 80.6, 103.1, 103.5, 141.3, 152.2,
166.0. Anal. Calcd for C9H12O6N2: C, 44.27; H, 4.95; N, 11.47.
Found: C, 44.06; H, 5.01; N, 11.24.
1
H, 8.41; N, 5.82. 15c: [R]22 -15.5° (c 1.2, CHCl3); H NMR
D
(250 MHz, CDCl3) δ 0.056, 0.063 (2s, 12H), 0.88 (s, 18H), 2.90
(d, J ) 4.9 Hz, 1H), 3.6-3.7 (m, 2H), 3.82 (dd, J ) 11.1, 5.1
Hz, 1H), 3.91 (dd, J ) 11.1, 4.5 Hz, 1H), 3.9-4.0 (m, 1H), 5.07
(q, J ) 4.5 Hz, 1H), 8.14 (s, 1H); 13C NMR (62.9 MHz, CDCl3)
δ -5.54, 18.1, 18.2, 25.7, 25.8, 62.5, 63.4, 70.9, 73.3, 160.6.
Anal. Calcd for C17H38O5Si2: C, 53.92; H, 10.12. Found: C,
54.06; H, 10.00.
(4R,5R)-9-[4,5-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]-
1,3-d ioxola n -2-yl]-6-ch lor op u r in e (19). To a stirred solu-
tion of 13c (250 mg, 0.637 mmol) in dichloromethane (4 mL)
were added silylated 6-chloropurine (1.0 mL of a 1.0 M solution
in dichloromethane) and trimethylsilyl triflate (0.035 mL, 0.19
mmol). The resulting solution was stirred at room tempera-
ture for 15 min, neutralized by the addition of pyridine, poured
onto a silica gel column, and eluted with toluene/ethyl acetate
(9:1) containing 2% pyridine. Further purification by column
chromatography (toluene/ethyl acetate 9:1 + 2% pyridine) gave
19 (160 mg, 49%) as a colorless syrup. 19: 1H NMR (250 MHz,
CDCl3) δ 0.05 (s, 12 H), 0.84, 0.86 (2s, 18 H), 3.5-4.5 (m, 6H),
7.12 (s, 1H), 8.54 (s, 1H), 8.66 (s, 1H); 13C NMR (62.9 MHz,
CDCl3) δ -5.62, -5.51, 18.0, 18.2, 25.6, 25.7, 61.9, 62.5, 77.3,
80.1, 101.8, 131.5, 142.4, 150.3, 151.7, 152.0. Compound 19
was too unstable for further characterization.
(4R,5R)-1-[4,5-Bis(h yd r oxym eth yl)-1,3-d ioxola n -2-yl]-
th ym in e (16). Compound 14c (27 mg, 0.057 mmol) was
dissolved in tetrahydrofuran (2 mL), tetrabutylammonium
fluoride (0.57 mL of a 0.5 M solution in tetrahydrofuran) was
added, and the resulting solution was stirred for 1 h at room
temperature. The solvent was evaporated and the crude
product purified by column chromatography (ethyl acetate/
methanol 4:1) to give 16 (14 mg, 95%) as a white solid. 16:
[R]22 +15° (c 0.4, MeOH); 1H NMR (250 MHz, MeOH-d4) δ
D
1.88 (d, J ) 1.1 Hz, 3H), 3.64 (dd, J ) 12.3, 4.1 Hz, 1H), 3.73
(dd, J ) 12.5, 3.6 Hz, 1H), 3.79 (dd, J ) 12.3, 3.5 Hz, 1H),
3.91 (dd, J ) 12.5, 3.1 Hz, 1H), 4.19 (dt, J ) 7.0, 3.3 Hz, 1H),
4.33 (dt, J ) 7.0, 3.9 Hz, 1H), 6.93, (s, 1H), 7.77 (d, J ) 1.1
Hz, 1H); 13C NMR (62.9 MHz, MeOH-d4) δ 12.4, 61.7, 62.6,
79.4, 80.5, 103.4, 111.8, 136.8, 152.4, 166.3. Anal. Calcd for
C10H14O6N2: C, 46.51; H, 5.46; N, 10.85. Found: C, 46.24; H,
5.34; N, 10.68.
Ack n ow led gm en t. We thank the National Swedish
Board for Technical Development, Medivir AB, and
Stipendium Berzelianum for financial support and
Medivir AB for the biological testings.
(4R,5R)-1-[4,5-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]-
1,3-d ioxola n -2-yl]u r a cil (17). To a stirred solution of 13c
(500 mg, 1.27 mmol) in dichloromethane (10 mL) were added
silylated uracil (4.0 mL of a 1 M solution in dichloromethane)
and trimethylsilyl triflate (0.26 mL, 1.40 mmol). The resulting
solution was stirred at room temperature for 5 min. The
reaction mixture was neutralized by the addition of pyridine,
poured onto a silica gel column, and eluted with toluene/ethyl
acetate (5:1). Further purification by column chromatography
(toluene/ethyl acetate 3:1) gave 17 (318 mg, 53%) as a colorless
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compound 8 (2 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.
syrup which solidified on standing. 17: [R]22 +7.5° (c 2.1,
J O960008K
D