Synthesis of [4,5-bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides as potential inhibitors of HIV via stereospecific base-induced rearrangement of a 2,3-epoxy thioacetate

Article abstract of DOI:10.1021/jo960009c

The synthesis of [4,5-bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides is described. 2,3-Epoxy alcohol 10 was converted in one pot into thioacetate 11. Treatment of 11 under mild alkaline conditions gave thiirane 12 with inversion of configuration at C-2. We also found that thioacetate 11 rearranges into thiirane 14 under mild acidic conditions. This rearrangement reaction was shown by independent synthesis to proceed with net retention of configuration at C-2. We have proposed a tentative mechanism which may explain the results obtained. Opening of thiiranes 12 and 14 followed by deprotection gave (2R,3R)-2-thiothreitol (23) and (2S,3R)-2-thioerythritol (25), respectively. Regioselective silylation of the primary hydroxyl groups of 23 followed by treatment with trimethyl orthoformate gave 2-methoxy-1,3-oxathiolanes 26 and 27. Condensation with silylated bases followed by deprotection and separation of the anomers gave the oxathiolanyl nucleosides. Compounds 29-31, 34, and 35 were found to be inactive when tested for inhibition of HIV-1 activity in vitro.

Full text of DOI:10.1021/jo960009c

3604
J . Org. Chem. 1996, 61, 3604-3610
Syn th esis of
[4,5-Bis(h yd r oxym eth yl)-1,3-oxa th iola n -2-yl]n u cleosid es a s
P oten tia l In h ibitor s of HIV via Ster eosp ecific Ba se-In d u ced
Rea r r a n gem en t of a 2,3-Ep oxy Th ioa ceta te1
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 [4,5-bis(hydroxymethyl)-1,3-oxathiolan-2-yl]nucleosides is described. 2,3-Epoxy
alcohol 10 was converted in one pot into thioacetate 11. Treatment of 11 under mild alkaline
conditions gave thiirane 12 with inversion of configuration at C-2. We also found that thioacetate
11 rearranges into thiirane 14 under mild acidic conditions. This rearrangement reaction was
shown by independent synthesis to proceed with net retention of configuration at C-2. We have
proposed a tentative mechanism which may explain the results obtained. Opening of thiiranes 12
and 14 followed by deprotection gave (2R,3R)-2-thiothreitol (23) and (2S,3R)-2-thioerythritol (25),
respectively. Regioselective silylation of the primary hydroxyl groups of 23 followed by treatment
with trimethyl orthoformate gave 2-methoxy-1,3-oxathiolanes 26 and 27. Condensation with
silylated bases followed by deprotection and separation of the anomers gave the oxathiolanyl-
nucleosides. Compounds 29-31, 34, and 35 were found to be inactive when tested for inhibition
of HIV-1 activity in vitro.
In tr od u ction
In 1989, the first example of a new class of nucleosides
was reported, in which the 3′-carbon atom was replaced
by sulfur giving compounds with potent anti-HIV activity
in vitro.2 Further synthesis work3 has resulted in the
discovery of (-)-3TC (Lamivudine) (1), which currently
is in advanced clinical trials for AIDS and HBV infec-
tions,4 and its 5-fluoro analogue (-)-FTC (2).5 Lamivu-
dine and (-)-FTC are unusual in that they constitute the
first examples of nucleosides where the L-configuration
is more potent than the corresponding D-form. In addi-
tion, the L-nucleosides in these series were also generally
found to be less toxic than their D-forms. Further
investigations of this class of compounds have led to the
structurally similar compounds 3-6 which have in vitro
antiviral activity.6
As a part of our program7 to prepare bioisosteres of 7,
a potent inhibitor of HIV activity in vitro,8 we report the
synthesis of oxathiolanylnucleosides 8 and 9. In analogy
with the corresponding 1,3-dioxolan-2-ylnucleosides,9
compounds of this type have not been previously re-
ported. Retrosynthetic analysis of 8 and 9 shows (2R,3R)-
2-thiothreitol to be a common precursor, which to our
knowledge has not been prepared previously in nonra-
cemic form.10 The principal methods for preparing chiral
thiosugars with the sulfur atom attached to a secondary
carbon involves displacement of a leaving group with a
† Additional address: Astra Ha¨ssle AB, S-431 83 Mo¨lndal, Sweden.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) For part 1 in this series, see ref 9.
(2) 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.
(3) (a) J eong, L. S.; Schinazi, R. F.; Beach, J . W.; Kim, H. O.;
Nampalli, S.; Shanmuganathan, K.; Alves, A. J .; McMillan, A.; Chu,
C. K.; Mathis, R. J . Med. Chem. 1993, 36, 181. (b) J eong, L. S.; Schinazi,
R. F.; Beach, J . W.; Kim, H. O.; Shanmuganathan, K.; Nampalli, S.;
Chun,W.-K.; Choi, B. G.; Chu, C. K. J . Med. Chem. 1993, 36, 2627. (c)
Warren Beach. J .; J eong, L. S.; Alves, A. J .; Pohl, D.; Kim, H. O.;
Chang, C.-N.; Doong, S.-L.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K.
J . Org. Chem. 1992, 57, 2217.
(4) J in, H.; Siddiqui, M. A.; Evans, C. A.; Tse, H. L. A.; Mansour, T.
S.; Goodyear, M. D.; Ravenscroft, P.; Beels, C. D. J . Org. Chem. 1995,
60, 2621 and references cited therein.
(5) Frick, L. W.; St. J ohn, L.; Taylor, L. C.; Painter, G. R.; Furman,
P. A.; Liotta, D. C.; Furfine, E. S.; Nelson, D. J . Antimicrob. Agents
Chemother. 1993, 37, 2285.
(6) (a) Mansour, T. S.; J in, H.; Wang, W.; Hooker, E. U.; Ashman,
C.; Cammack, N.; Salomon, H.; Belmonte, A. R.; Wainberg, M. A. J .
Med. Chem. 1995, 38, 1. (b) Wang, W.; J in, H.; Mansour, T. S.
Tetrahedron Lett. 1994, 35, 4739. (c) Belleau, B.; Brasili, L.; Chan, L.;
DiMarco, M. P.; Zacharie, B.; Nguyen-Ba, N.; J enkinson, H. J .; Coates,
J . A. V.; Cameron, J . M. Bioorganic Med. Chem. Lett. 1993, 3, 1723.
(7) (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.
S0022-3263(96)00009-6 CCC: $12.00 © 1996 American Chemical Society

1,3-Oxathiolan-2-ylnucleosides as Potential Inhibitors of HIV
J . Org. Chem., Vol. 61, No. 11, 1996 3605
Sch em e 1
sulfur-containing nucleophile including opening of a
terminal thiirane.11 Indeed, the scope of these methods
relies on naturally occurring carbohydrates as the source
of chirality. The renewed interest in this area has
resulted in de novo thiosugar synthesis using readily
available chiral 2,3-epoxy alcohols as precursors.12 How-
ever, opening of secondary 2,3-epoxy alcohols with sulfur
nucleophiles usually proceed with low to moderate regio-
selectivity,13 although high selectivity has been observed
in the presence of titanium tetraisopropoxide14 or by
using triisopropoxytitanium thiobenzoate.15 Highly re-
gioselective openings of 2,3-epoxy alcohols with a sulfur
nucleophile can be obtained using the C-1 hydroxyl group
for intramolecular transfer of the sulfur nucleophile. This
strategy has recently been successfully employed by
Uenishi et al.16 in the formation of a cyclic xanthate and
by Gill et al.17 with in situ formation and opening of a
terminal thiiranium ion. During the preparation of this
paper, Ko18 reported on a new method for preparing
chiral 2-thio 1,3-diols by rearrangement and subsequent
reduction of cyclic thionocarbonates of 2,3-dihydroxy
esters. We now report on a modified Payne-type rear-
rangement19,20 involving a thiol group, as a new method
for the regio- and stereospecifically introduction of sulfur
into the 2-position of a 2,3-epoxy alcohol.
Ta ble 1. Con ver sion of 2,3-Ep oxy th ioa ceta te 11 in to
Th iir a n e 12 u n d er Alk a lin e Con d ition s
conditionsa
time, h
yieldb of 12, %
0.5 M NaOH/THF 1:1
< 0.5
< 0.5
1c
0
0
42
49
89
1 equiv of LiOH in THF/H2O 3:1
1 equiv of K2CO3 in MeOH
methanolic ammonia (sat.)
methanolic ammonia (sat.)/
MeOH 1:10
1c
3c
a
The concentration of 11 was 50 mM. All reactions were carried
out at 0 °C. Referres to isolated yield. c The reaction was stopped
b
when TLC showed complete disappearance of starting material
11.
Sch em e 2
Resu lts a n d Discu ssion
The hydroxyl group of chiral epoxy alcohol 1021 was
substituted by thioacetate in a one-pot reaction using
triphenylphosphine (PPh3), diisopropyl azodicarboxylate
(DIAD), and thioacetic acid in tetrahydrofuran to give
11 in 96% yield (Scheme 1) using a modified Mitsunobu
procedure,22 developed by Volante.23 Treatment of 11
with sodium hydroxide (0.5 M) using standard conditions
for the Payne rearrangement20 failed to produce 12, likely
due to extensive polymerization of the terminal thiirane
(8) (a) Svansson, L.; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J .
Org. Chem. 1991, 56, 2993. (b) Sterzycki, R. Z.; Martin, J . C.; Wittman,
M.; Brankovan, V.; Yang, H.; Hitchcock, M. J .; Mansuri, M. M.
Nucleosides Nucleotides 1991, 10, 291. (c) Bamford, M. J .; Coe, P. L.;
Walker, R. T. J . Med. Chem. 1990, 33, 2494. (d) 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. (e) Mann, J .; Weymouth-
Wilsson, A. C. J . Chem. Soc., Perkin Trans. 1 1994, 3141.
(9) Brånalt, J .; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J . Org.
Chem. 1996, 61, 3599-3603.
in the alkaline media.24 Notably, high yields of 12 (89%)
could be obtained using dilute solutions of ammonia in
methanol (Table 1). No detectable amounts of starting
material 11 or of the corresponding 2,3-epoxy thiol were
observed. Compound 12 was unstable upon prolonged
storage and was therefore used up immediately or
acetylated to 13 for complete characterization. Surpris-
ingly, we noted that 11, during silica gel chromatography,
slowly rearranged into thiirane 14 with net retention of
configuration at C-2 (Scheme 2). This silica gel promoted
rearrangement25 of 11 was found to be a very clean
reaction which could be optimized to give quantitative
yield, either by stirring 11 in a slurry of silica gel in
toluene or by adding compound 11 onto a column of silica
gel in toluene and then allowing the solution to stand
for 48 h after which the product (14) was eluted.
Performing the rearrangement reaction under nonanhy-
drous conditions, i.e., stirring 11 in a slurry of silica gel
in toluene without exclusion of moisture, gave a lower
yield of 14 due to formation of a 1:1 mixture of two
compounds, tentatively assigned as 15 and 16, which
(10) For a racemic synthesis of 1,4-di-O-benzyl-2-thiothreitol and
1,4-di-O-benzyl-2-thioerythritol, see: Forster, R. C.; Owen, L. N. J .
Chem. Soc., Perkin Trans. 1 1978, 822.
(11) For a review, see: Horton, D.; Hutson, D. H. Adv. Carbohyd.
Chem. 1963, 18, 123.
(12) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 5976.
(13) Behrens C. H.; Sharpless, K. B. J . Org. Chem. 1985, 50, 5696.
(14) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1560.
(15) (a) Raifeld, Y. E.; Nikitenko, A. A.; Arshava, B. M. Tetrahe-
dron: Asymmetry 1991, 2, 1083. (b) Raifeld, Y. E.; Nikitenko, A. A.;
Arshava, B. M.; Mikerin, I. E.; Zilberg, L. L.; Vid, G. Y.; Lang, S. A.;
Lee, V. J . Tetrahedron 1994, 50, 8603.
(16) (a) Uenishi, J .; Motoyama, M.; Nishiyama, Y.; Wakabayashi,
S. J . Chem. Soc., Chem. Commun. 1991, 1421. (b) Uenishi, J .;
Motoyama, M.; Takahashi, K. Tetrahedron: Asymmetry 1994, 5, 101.
(17) Gill, D. M.; Pegg, N. A.; Rayner, C. M. J . Chem. Soc., Perkin
Trans. 1 1993, 1371.
(18) Ko, S. Y. J . Org. Chem. 1995, 60, 6250.
(19) Recently, a method for converting 2,3-epoxy amines into 3-hy-
droxy-1,2-aziridines was reported utilizing an aza-Payne type
rearrangement: (a) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.;
Otaka, A.; Tamamura, H.; Fujii, N.; Nimura, N.; Miwa, Y.; Taga, T.;
Chounan, Y.; Yamamoto, Y. J . Org. Chem. 1995, 60, 2044. (b) Nakai,
K.; Ibuka, T.; Otaka, A.; Tamamura, H.; Fujii, N.; Yamamoto, Y.
Tetrahedron Lett. 1995, 36, 6247.
(20) Payne, G. B. J . Org. Chem. 1962, 27, 3819.
(21) Chong, J . M.; Wong, S. J . Org. Chem. 1987, 52, 2596.
(22) Mitsunobu, O. Synthesis 1981, 1.
(24) See, for example: Hall, L. D.; Hough, L.; Pritchard, R. A. J .
Chem. Soc. 1961, 1537.
(25) For a recent report on silica gel promoted reactions, see: Kropp,
P. J .; Breton, G. W.; Craig, S. L.; Crawford, S. D.; Durland, W. F., J r.;
J ones, J . E., III; Raleigh, J . S. J . Org. Chem. 1995, 60, 4146. For a
report on the rearrangement of oxiranes into aldehydes using silica
gel, see: Lemini, C.; Ordonez M.; Perez-Flores, J .; Cruz-Almanza, R.
Synth. Commun. 1995, 25, 2695.
(23) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119.

3606 J . Org. Chem., Vol. 61, No. 11, 1996
Bra˚nalt et al.
Sch em e 3
Sch em e 5
Sch em e 4
Sch em e 6
after acetylation gave 17 as a single diastereomer. The
rearrangement of 11 could alternatively also be per-
formed in glacial acetic acid-acetic anhydride (1:1) at 60
°C for 2 h to give 14 in an almost quantitative yield. A
possible mechanism for the conversion of 11 into 14 under
acidic conditions is depicted in Scheme 3. Opening of the
activated epoxide 18 at C-2 by the thioacetate carbonyl
oxygen gives 1,3-oxathiolan-2-ylium ion 19, which rear-
ranges into the more stable 1,3-dioxolan-2-ylium ion 20.26
A second inversion at C-2 is effected by nucleophilic
substitution involving the thiol group at C-1 to give 14
with net retention of configuration at C-2. As in the case
of the base-promoted rearrangement, the driving force
of this rearrangement is likely due to the higher stability
of thiiranes as compared to oxiranes.27 Under nonanhy-
drous conditions, intermediate 20 will trap water and
give a 1:1 mixture of 15 and 16. The stereochemistry
and optical purity of thiirane 14 was determined by
independent synthesis (Scheme 4). Thus, Payne rear-
rangement20 of 10 using sodium hydroxide (0.5 M) in
tetrahydrofuran-water gave a 3:2 equilibrium mixture
of 10 and 21 from which compound 21 was isolated by
column chromatography. Acetylation of the hydroxyl
group followed by conversion of the oxirane into the
corresponding thiirane using thiourea28 with inversion
of configuration at C-2 gave 14 in 75% yield from 21, in
all aspects identical to the product obtained by the silica
gel promoted rearrangement (vide supra).
Opening of thiirane 12 with sodium acetate in glacial
acetic acid-acetic anhydride (1:1) gave 22 in 85% yield
(Scheme 5). Deblocking of the p-bromobenzyl group of
22 using boron tribromide at -80 °C followed by deacety-
lation under acidic conditions to avoid thiirane formation
and polymerization24,29 gave (2R,3R)-2-thiothreitol (23)
in 74% yield from 22. Using the same methodology, the
erythro derivative 24 was obtained from thiirane 14 in
79% yield. Deprotection gave (2S,3R)-2-thioerythritol
(25) in 70% yield. Interestingly, starting from 2,3-epoxy
thioacetate 11, the rearrangement-opening procedure
via thiirane 14 to 24 could be performed in situ as a one-
pot reaction giving the same yield. Regioselective sily-
Sch em e 7
lation of the primary hydroxyl groups of (2R,3R)-2-
thiothreitol (23) using tert-butyldimethylsilyl chloride
and imidazole in dimethylformamide, followed by treat-
ment with trimethyl orthoformate and a catalytic amount
of camphorsulfonic acid, gave a separable mixture of
2-methoxy-1,3-oxathiolanes 26 and 2730 in 86% total yield
(Scheme 6).
For the synthesis of 1,3-oxathiolan-2-ylnucleosides,
2-methoxy-1,3-oxathiolane (28) was used as a model
compound (Scheme 7). Condensation of 28 with silylated
thymine and trimethylsilyl triflate under Vorbru¨ggen
conditions31 gave racemic 29 in 38% yield. No product
arising from opening of the oxathiolane ring at C-4 or
C-5 was detected. This reactivity is in sharp contrast to
the corresponding dioxolanylnucleoside series.9 Conden-
sation of the diastereomeric mixture 26 and 27 with
silylated thymine and trimethylsilyl triflate under Vor-
bru¨ggen conditions gave mainly dimeric products.32 In
dilute solutions, dimers were still formed, but the desired
oxathiolanylnucleosides could be isolated in moderate
yields. Desilylation followed by separation of the ano-
(29) Goodman, L.; Benitez, A.; Baker, B. R. J . Am. Chem. Soc. 1958,
80, 1537.
(30) Assignments of the 2(S,R) configuration of compounds 26 and
27 were based on 1H NOE difference spectroscopy. In both 26 and 27,
H-4 and H-5 were easily distinguished by a large difference in chemical
shift (0.6-0.7 ppm). Because of the higher electronegativity of oxygen
compared to sulfur, it is assumed that H-5 appears at a higher chemical
shift than H-4. Irradiation of H-5 in 26 gave enhancement of H-2 (1.3%)
whereas irradiation of H-5 in 27 gave enhancement of the methoxy
group (1.5%).
(31) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234.
(32) For the acid-catalyzed formation of dimers from 2-methoxy-1,3-
oxathiolane, see: Tanimoto, S.; Miyake, T.; Okano, M. Bull. Inst. Chem.
Res., Kyoto Univ. 1977, 55, 276.
(26) For a review on heterocyclic cations, see: Pittman, C. U.;
McManus, S. P.; Larsen, J . W. Chem. Rev. 1972, 72, 357.
(27) Fokin, A. V.; Kolomiets, A. F. Russ. Chem. Rev. 1975, 44, 306
and references cited therein.
(28) Culvenor, C. C. J .; Davies, W.; Pausacker, K. H. J . Chem. Soc.
1946, 1050.

1,3-Oxathiolan-2-ylnucleosides as Potential Inhibitors of HIV
J . Org. Chem., Vol. 61, No. 11, 1996 3607
Sch em e 8
F igu r e 1.
from 34 and 35, respectively, by p-nitrobenzoylation of
the hydroxyl groups (Figure 1). In both 40 and 41, H-4′
and H-5′ were well resolved and easily distinguished by
a large difference in chemical shift. It is well-known that
protons syn to the base are more deshielded than those
which are anti.34 The H-5′ proton of 40 appeared at a
considerably higher field than that of 41. A smaller
reverse effect was observed for the H-4′ proton. These
Sch em e 9
1
characteristic H NMR features, which were also found
in compounds 32-35, were used to assign the 2(S,R)
configuration of thymine derivatives 30 and 31. Anomer
30 which had a downfield shift for H-5′ was assigned as
(2S) and 31 assigned as (2R).
Exp er im en ta l Section
General methods were the same as those previously de-
scribed.9
(2R,3R)-1-S-Acetyl-4-[(p-br om oben zyl)oxy]-2,3-ep oxy-
1-bu ta n eth iol (11). Diisopropyl azodicarboxylate (DIAD)
(13.3 g, 65.8 mmol) was added to an efficiently stirred solution
of triphenylphosphine (21.6 g, 82.4 mmol) in tetrahydrofuran
(180 mL) at 0 °C. After the solution was stirred at 0 °C for 30
min, a white precipitate formed. Compound 1021 (9.00 g, 32.9
mmol) and thioacetic acid (5.00 g, 65.8 mmol) in tetrahydro-
furan (75 mL) were slowly added over 10 min, and the mixture
was stirred for an additional 2 h at 0 °C. During this time
the precipitate was dissolved and a clear yellow solution was
obtained. The solvent was evaporated, and the solid residue
was dissolved in hot toluene and set in a freezer overnight to
precipitate most of the triphenylphosphine oxide formed. The
solids were filtered off and washed with cold toluene. The
solvent was evaporated, and the crude product was purified
by flash column chromatography (toluene/ethyl acetate 20:1)
to give 11 (10.4 g, 96%) as a colorless oil. It was important to
make sure that the product was eluted as rapidly as possible
mers by fractional crystallization gave 30 and 31 in 14%
and 13% yields, respectively (Scheme 8). The uracil
derivatives 32 and 33 were prepared from silylated uracil
in a similar way in 13% and 11.5% yields, respectively,
after separation by column chromatography. Desilyla-
tion gave 34 and 35 in 88% and 87% yields, respectively.
Condensation of the oxathiolanes 26 and 27 with sily-
lated N4-benzoylcytosine gave formate ester 37 in 36%
yield but no detectable amounts of the desired nucleo-
sides (Scheme 9). Interestingly, compound 37 was not
formed during synthesis of the thymine or uracil deriva-
tives, nor was it formed by treatment of 26 or 27 with
trimethylsilyl triflate. It is likely that nucleoside 36 is
formed in the coupling reaction but hydrolyzes spontane-
ously into formate ester 37 during quenching of the
reaction. Condensation of the diastereomeric mixture 26
and 27 with silylated 6-chloropurine gave an unseparable
mixture (1:1) of 38 and 39 in 31% total yield, which
hydrolyzed upon desilylation.
to minimize the exposure to silica gel. 11: [R]22 +8.5° (c 2.0,
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ 2.37 (s, 3H), 3.07 (2d, J
) 5.5 and 6.9 Hz, 2H), 3.13 (ddd, J ) 6.9, 5.5, 4.1 Hz, 1H),
3.25 (dt, J ) 6.2, 4.1 Hz, 1H), 3.58 (dd, J ) 11.3, 6.2 Hz, 1H),
3.76 (dd, J ) 11.3, 4.1 Hz, 1H), 4.54 (2d, J ) 12.0 Hz, 2H),
7.2-7.5 (m, 4H); 13C NMR (62.9 MHz, CDCl3) δ 27.6, 30.5, 54.4,
56.0, 68.0, 72.5, 121.7, 129.4, 131.6, 136.8, 194.6. Anal. Calcd
for C13H15O3SBr: C, 47.14; H, 4.56; S, 9.68. Found: C, 47.05;
H, 4.62; S, 9.46.
Compounds 29-31, 34, and 35 were tested for inhibi-
tion of HIV-multiplication in a XTT assay in M4 cells.33
All compounds were found to be inactive in the assay.
(2R,3S)-2-O-Acetyl-1-[(p-br om oben zyl)oxy]-3,4-ep ith io-
2-bu ta n ol (13). To a solution of 11 (4.60 g, 13.9 mmol) in
methanol (120 mL) was added methanolic ammonia (12 mL,
Str u ctu r e Assign m en ts
(33) Vial, J . M.; J ohansson, N. G.; Wrang, L. Chattopadhyaya, J .
Antiviral Chem. Chemother. 1990, 1, 183.
(34) See, for example: Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro,
L. J .; Coffen, D. L. J . Org. Chem. 1988, 53, 4780.
Assignments of the 2(S,R) configuration of uracil
derivatives 32-35 were based on 1H NOE difference
spectroscopy which was performed on 40 and 41, obtained

3608 J . Org. Chem., Vol. 61, No. 11, 1996
Bra˚nalt et al.
saturated) at 0 °C, and the solution was stirred at this
temperature for 3 h. The mixture was diluted with dichlo-
romethane, washed with water, dried, filtered, and evaporated.
The residue was purified by column chromatography (toluene/
ethyl acetate 9:1) to give (2R,3S)-1-[(p-bromobenzyl)oxy]-3,4-
epithio-2-butanol 12 (3.57 g, 89%) as a colorless oil. 12: 1H
NMR (250 MHz, CDCl3) δ 2.20 (d, J ) 8.0 Hz, 1H), 2.40 (dd,
J ) 5.6, 0.8 Hz, 1H), 2.44 (dd, J ) 6.5, 0.8 Hz, 1H), 3.26 (ddd,
J ) 6.5, 5.6, 4.0 Hz, 1H), 3.53 (dd, J ) 9.5, 5.8 Hz, 1H), 3.61
(dd, J ) 9.5, 5.6 Hz, 1H), 3.85 (ddd, J ) 8.0, 5.7, 4.0 Hz, 1H),
4.57 (s, 2H), 7.2-7.5 (m, 4H); 13C NMR (62.9 MHz, CDCl3) δ
21.2, 38.1, 69.6, 72.8, 74.1, 121.7, 129.3, 131.6, 136.9. Com-
pound 12 polymerized easily, which precluded further char-
acterization, and was consequently used immediately in the
next reactions. A small sample of 12 (18 mg, 0.0623 mmol)
was treated with acetic anhydride (0.5 mL) in pyridine (1 mL)
at room temperature for 30 min. The solvent was evaporated
and coevaporated with added toluene, and the residue was
purified by column chromatography (toluene/ethyl acetate 20:
1) to give 13 (20 mg, 97%) as a colorless syrup. 13: [R]22D -3.5°
(c 2.2, CHCl3); 1H NMR (250 MHz, CDCl3) δ 2.10 (s, 3H), 2.30
(dd, J ) 5.4, 1.3 Hz, 1H), 2.52 (dd, J ) 6.5, 1.3 Hz, 1H), 3.18
(ddd, J ) 7.2, 6.5, 5.4 Hz, 1H), 3.65 (d, J ) 5.1 Hz, 2H), 4.50
(2d, J ) 12.3 Hz, 2H), 4.81 (dt, J ) 7.2, 5.1 Hz, 1H), 7.15-7.5
(m, 4H); 13C NMR (62.9 MHz, CDCl3) δ 21.0, 22.2, 33.9, 70.9,
72.6, 74.9, 121.7, 129.2, 131.6, 136.8, 170.0. Anal. Calcd for
C13H15O3SBr: C, 47.14; H, 4.56; S, 9.68. Found: C, 47.01; H,
4.53; S, 9.50.
Calcd for C17H21O6SBr: C, 47.12; H, 4.88; S, 7.40. Found: C,
47.05; H, 4.85; S, 7.23.
(2R,3R)-1-[(p -Br om ob en zyl)oxy]-3,4-ep oxy-2-b u t a n ol
(21). To a solution of 10 (250 mg, 0.916 mmol) in tetrahydro-
furan (5 mL) was added sodium hydroxide (5 mL, 0.5 M), and
the resulting mixture was stirred at room temperature for 3
h. Ammonium sulfate was added, and the mixture was
extracted with diethyl ether. The organic phase was dried,
filtered, and concentrated to give a mixture of starting material
10 and 21 (3:2) which was separated by column chromatog-
raphy (toluene/ethyl acetate 1:1) to give 21 (96 mg, 38%) as a
colorless oil. 21: [R]22 -9.7° (c 0.7, CHCl3); 1H NMR (250
D
MHz, CDCl3) δ 2.30 (d, J ) 6.2 Hz, 1H), 2.78 (dd, J ) 5.0, 2.9
Hz, 1H), 2.81 (t, J ) 5.0 Hz, 1H), 3.13 (dt, J ) 2.9, 3.9 Hz,
1H), 3.59 (dd, J ) 9.6, 6.1 Hz, 1H), 3.63 (dd, J ) 9.6, 4.8 Hz,
1H), 3.79 (m, 1H), 4.53 (s, 2H), 7.15-7.55 (m, 4H); 13C NMR
(62.9 MHz, CDCl3) δ 44.0, 52.7, 69.6, 71.9, 72.7, 121.7, 129.3,
131.6, 136.8. Anal. Calcd for C11H13O3Br: C, 48.37; H, 4.80.
Found: C, 48.12; H, 4.80.
P r ep a r a tion of (2R,3R)-2-O-Acetyl-1-[(p-br om oben zyl)-
oxy]-3,4-ep ith io-2-bu ta n ol (14) fr om (2R,3R)-1-[(p-Br o-
m oben zyl)oxy]-3,4-ep oxy-2-bu ta n ol (21). To a solution of
compound 21 (43 mg, 0.157 mmol) in pyridine (1 mL) was
added acetic anhydride (1 mL). After 30 min at room tem-
perature, the solvent was evaporated and coevaporated with
added toluene. The residue was dissolved in dichloromethane,
washed with hydrogen chloride (1 M) and saturated aqueous
sodium hydrogen carbonate, dried, filtered, and concentrated.
The crude product was dissolved in methanol, thiourea was
added, and the mixture was stirred at room temperature for
3 h. The solvent was evaporated, and the residue was
suspended in dichloromethane and washed with water. The
organic phase was dried, filtered, concentrated, and purified
by column chromatography (toluene/ethyl acetate 20:1) to give
14 (39 mg, 75%), in all aspects identical with that obtained
above.
(2R,3R)-2-O-Acetyl-1-[(p-br om oben zyl)oxy]-3,4-ep ith io-
2-bu ta n ol (14). Compound 11 (792 mg, 2.39 mmol) in toluene
was allowed to stand in a column of silica gel for several days,
after which it was eluted (toluene/ethyl acetate 9:1). Evapora-
tion of the solvent gave a colorless oil of 14 (788 mg, 100%) as
a single diastereomer. Alternatively, compound 11 (92 mg,
0.278 mmol) in glacial acetic acid/acetic anhydride (1:1, 2 mL)
was stirred at 60 °C for 2 h. The solvent was evaporated and
coevaporated with added toluene, and the residue was purified
by column chromatography (toluene/ethyl acetate 20:1) to give
(2R,3R)-1,3-O,2-S-Tr ia cetyl-4-(p-br om oben zyl)-2-th io-
th r eitol (22). To a solution of 12 (4.70 g, 16.3 mmol) in acetic
acid (25 mL) and acetic anhydride (25 mL) was added sodium
acetate (6.70 g, 81.3 mmol), and the reaction mixture was
heated at 60 °C for 1 h to give the acetylated compound 13.
The reaction was further heated at 130 °C for 48 h and allowed
to attain room temperature. Toluene was added, the solids
were filtered off, and the filtrate was evaporated. The residue
was purified by column chromatography (toluene/ethyl acetate
14 (90 mg, 98%) in all aspects identical with that obtained
1
above. 14: [R]22 +39.6° (c 0.7, CHCl3); H NMR (250 MHz,
D
CDCl3) δ 2.11 (s, 3H), 2.43 (dd, J ) 5.2, 1.1 Hz, 1H), 2.50 (dd,
J ) 6.2, 1.1 Hz, 1H), 3.12 (ddd, J ) 8.2, 6.2, 5.2 Hz, 1H), 3.75
(2d, J ) 3.8 and 4.7 Hz, 2H), 4.53 (2d, J ) 12.3 Hz, 2H), 4.62
(dt, J ) 8.2, 4.1 Hz, 1H), 7.2-7.5 (m, 4H); 13C NMR (62.9 MHz,
CDCl3) δ 21.1, 23.8, 32.1, 71.1, 72.5, 76.3, 121.6, 129.2, 131.6,
136.9, 170.2. Anal. Calcd for C13H15O3SBr: C, 47.14; H, 4.56;
S, 9.68. Found: C, 47.25; H, 4.49; S, 9.44.
9:1) to give 22 (6.04 g, 85%) as a colorless syrup. 22: [R]22
D
-4.4° (c 0.85, CHCl3); 1H NMR (250 MHz, CDCl3) δ 2.05, 2.06
(2s, 6H), 2.36 (s, 3H), 3.51 (dd, J ) 10.0, 6.0 Hz, 1H), 3.59 (dd,
J ) 10.0, 6.1 Hz, 1H), 4.06 (dd, J ) 9.4, 4.3 Hz, 1H), 4.18 (ddd,
J ) 7.6, 4.3, 2.8 Hz, 1H), 4.24 (dd, J ) 9.4, 7.6 Hz, 1H), 4.46
(s, 2H), 5.45 (dt, J ) 2.8, 6.0 Hz, 1H), 7.1-7.5 (m, 4H); 13C
NMR (62.9 MHz, CDCl3) δ 20.8, 30.6, 43.3, 63.2, 66.9, 69.8,
72.5, 121.7, 129.4, 131.6, 136.7, 169.9, 170.5, 193.5. Anal.
Calcd for C17H21O6SBr: C, 47.12; H, 4.88; S, 7.40. Found: C,
47.21; H, 4.85; S, 7.26.
(2S,3R)-1-S,2,3-O-Tr ia cet yl-4-(p -b r om ob en zyl)-1-t h io-
th r eitol (17). Compound 11 (363 mg, 1.10 mmol) in a slurry
of silica gel in wet toluene was stirred at room temperature
for 5 days without exclusion of moisture. The silica gel was
filtered off, and the solvent was evaporated. The residue was
purified by column chromatography (toluene/ethyl acetate 5:1)
to give compound 14 and a mixture (1:1) of 15 and 16 (264
mg, 69%) that could not be separated by column chromatog-
raphy. 15 and 16: 1H NMR (250 MHz, CDCl3) δ 1.46 (t, J )
8.8 Hz, 1H), 1.55 (t, J ) 8.7 Hz, 1H), 2. 05, 2.09 (2s, 6H),
2.50-2.95 (m, 6H), 3.46 (dd, J ) 9.6, 6.1 Hz, 1H), 3.50 (dd, J
) 9.6, 4.7 Hz, 1H), 3.63 (dd, J ) 10.5, 5.3 Hz, 1H), 3.69 (dd, J
) 10.5, 5.5 Hz, 1H), 3.87 (m, 1H), 4.11 (m, 1H), 4.45 (m, 4H),
4.94 (dt, J ) 3.1, 6.6 Hz, 1H), 5.13 (dt, J ) 3.6, 5.1 Hz, 1H),
7.1-7.5 (m, 8H); 13C NMR (62.9 MHz, CDCl3) δ 21.0, 21.9, 24.5,
27.9, 69.3, 71.4, 72.2, 72.5, 72.6, 72.8, 74.9, 121.8, 129.3, 129.4,
131.6, 136.5, 136.6, 170.6. A small sample of the mixture of
15 and 16 (45 mg, 0.129 mmol) was treated with acetic
anhydride (1 mL) in pyridine (1 mL) for 3 h. The solvent was
evaporated, and the residue was purified by column chroma-
tography (toluene/ethyl acetate 9:1) to give syrupy 17 (53 mg,
95%) as a single diastereomer. 17: [R]22D +19° (c 0.5, CHCl3);
1H NMR (250 MHz, CDCl3) δ 2.03, 2.10 (2s, 6H), 2.33 (s, 3H),
2.90 (dd, J ) 14.0, 6.8 Hz, 1H), 3.31 (dd, J ) 14.0, 5.2 Hz,
1H), 3.50 (dd, J ) 10.3, 5.0 Hz, 1H), 3.56 (dd, J ) 10.3, 5.3
Hz, 1H), 4.44 (s, 2H), 5.1-5.2 (m, 2H), 7.1-7.5 (m, 4H); 13C
NMR (62.9 MHz, CDCl3) δ 20.7, 20.9, 29.2, 30.4, 68.1, 70.2,
71.0, 72.5, 121.7, 129.3, 131.6, 136.6, 169.9, 170.2, 194.3. Anal.
(2R,3R)-2-Th ioth r eitol (23). To a solution of 22 (490 mg,
1.13 mmol) in dichloromethane (10 mL) was added BBr3 (0.13
mL, 1.36 mmol) at -80 °C. The mixture was slowly allowed
to warm to -20 °C (2 h) and stirred at this temperature for
30 min. The mixture was again cooled to -80 °C and quenched
by the dropwise addition of methanol/pyridine (1:1, 8 mL). The
mixture was allowed to attain room temperature, and the
solvent was evaporated. The residue was suspended in
toluene, and the solids were filtered off and were thoroughly
washed with toluene. Evaporation of the solvent gave an oily
residue which was applied onto a short column of silica gel
and eluted with toluene/ethyl acetate (1:1). The appropriate
fractions were combined, evaporated, and treated with 5%
hydrogen chloride in methanol for 14 h. Evaporation of the
solvent, coevaporation with added toluene, and purification of
the residue by column chromatography (ethyl acetate/metha-
nol 5:1) gave 23 (115 mg, 74%) as a colorless oil. 23: [R]22
D
-38.7° (c 2.7, MeOH); 1H NMR (250 MHz, MeOH-d4) δ 2.95-
3.05 (m, 1H), 3.60-3.80 (m, 4H), 3.98 (dt, J ) 2.5, 6.3 Hz, 1H);
13C NMR (62.9 MHz, MeOH-d4) δ 45.1, 64.8, 66.1, 71.4. Anal.

1,3-Oxathiolan-2-ylnucleosides as Potential Inhibitors of HIV
J . Org. Chem., Vol. 61, No. 11, 1996 3609
Calcd for C4H10O3S: C, 34.77; H, 7.29; S, 23.20. Found: C,
34.90; H, 7.33; S, 22.96.
for C8H10O3SN2: C, 44.85; H, 4.71; S, 14.91; N, 13.08. Found:
C, 44.78; H, 4.58; S, 14.91; N, 12.99.
(2S,3R)-1,3-O,2-S-Tr ia cet yl-4-(p -b r om ob en zyl)-2-t h io-
er yth r itol (24). To a solution of 14 (2.05 g, 6.19 mmol) in
acetic acid (10 mL) and acetic anhydride (10 mL) was added
sodium acetate (2.50 g, 30.5 mmol), and the reaction mixture
was heated at 130 °C for 48 h and then allowed to attain room
temperature. Toluene was added, the solids were filtered off,
and the filtrate was evaporated. The residue was purified by
column chromatography (toluene/ethyl acetate 9:1) to give 24
1-[(4R,5R)-4,5-Bis(h yd r oxym et h yl)-1,3-oxa t h iola n -2-
yl]th ym in es (30 a n d 31). To a stirred solution of compounds
26 and 27 (240 mg, 0.588 mmol) in dichloromethane (40 mL)
were added silylated thymine (0.35 mL of a 1.0 M solution in
dichloromethane) and trimethylsilyl triflate (0.12 mL, 0.647
mmol). The resulting solution was stirred at room tempera-
ture overnight, neutralized by the addition of pyridine, poured
onto a column of silica gel, and eluted with ethyl acetate to
give an anomeric mixture (1:1) of protected 30 and 31 which
could not be separated by column chromatography: 1H NMR
(250 MHz, CDCl3) δ 0.054, 0.067 (2s, 24 H), 0.90 (s, 36 H),
1.94, 1.97 (2d, J ) 0.9 Hz, 6H), 3.65-4.05 (m, 11H), 4.53 (dt,
J ) 2.4, 5.1 Hz, 1H), 7.31, 7.34 (2s, 2H), 7.46, 7.49 (2d, J )
0.9 Hz, 2H). The anomeric mixture was dissolved in tetrahy-
drofuran (5 mL), tetrabutylammonium fluoride (1.0 mL of a
0.5 M solution in tetrahydrofuran) was added, and the result-
ing solution was stirred at room temperature for 1 h. The
solvent was evaporated, and the crude product was filtered
through a short column of silica gel to give a 1:1 mixture of
30 and 31. Fractional crystallization from methanol gave 30
(22.5 mg, 14%) as white crystals and 31 (21 mg, 13%) as a
colorless syrup. 30: [R]22D +8.3° (c 0.3, MeOH); 1H NMR (250
MHz, MeOH-d4) δ 1.92 (d, J ) 0.9 Hz, 3H), 3.7-3.85 (m, 3H),
3.90-3.95 (m, 2H), 4.02 (ddd, J ) 8.0, 4.3, 3.1 Hz, 1H), 7.3 (s,
1H), 7.77 (d, J ) 0.9 Hz, 1H); 13C NMR (62.9 MHz, MeOH-d4)
δ 12.4, 52.8, 62.4, 63.9, 87.1, 89.8, 112.5, 137.4, 151.8, 166.1.
Anal. Calcd for C10 H14 O5 S N2: C, 43.79; H, 5.15; N, 10.22;
(2.13 g, 79%) as a colorless syrup. 24: [R]22 +19° (c 1.3,
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ 2.02, 2.05 (2s, 6H), 2.33
(s, 3H), 3.62 (d, J ) 4.9 Hz, 2H), 4.1-4.35 (m, 3H), 4.40 (d, J
) 12.2 Hz, 1H), 4.50 (d, J ) 12.2 Hz, 1H), 5.26 (q, J ) 5.0 Hz,
1H), 7.1-7.5 (m, 4H); 13C NMR (62.9 MHz, CDCl3) δ 20.7, 20.9,
30.6, 42.9, 63.0, 69.1, 70.9, 72.5, 121.7, 129.3, 131.5, 136.6,
169.9, 170.5, 193.4. Anal. Calcd for C17H21O6SBr: C, 47.12;
H, 4.88; S, 7.40. Found: C, 47.00; H, 4.83; S, 7.30.
(2S,3R)-2-Th ioer yth r itol (25). Compound 25 was pre-
pared from 24 (77 mg, 0.177 mmol) following the same
methodology as described for the preparation of 2-thiothreitol
(23) to give 25 (17 mg, 70%) as a colorless oil. 25: [R]22D +5.9°
1
(c 1.7, MeOH); H NMR (250 MHz, MeOH-d4) δ 2.96 (q, J )
5.5 Hz, 1H), 3.60-3.90 (m, 5H); 13C NMR (62.9 MHz, MeOH-
d4) δ 44.8, 65.1, 65.4, 75.6. Anal. Calcd for C4H10O3S: C,
34.77; H, 7.29; S, 23.20. Found: C, 34.86; H, 7.15; S, 23.12.
(2R,4R,5R)- a n d (2S,4R,5R)-2-Meth oxy-4,5-bis[[(ter t-
bu tyld im eth ylsilyl)oxy]m eth yl]-1,3-oxa th iola n es (26 a n d
27). A solution of 23 (192 mg, 1.39 mmol), tert-butyldimeth-
ylsilyl chloride (460 mg, 3.06 mmol), and imidazole (245 mg,
3.61 mmol) in dimethyl formamide (2 mL) was stirred at room
temperature for 24 h. The reaction mixture was diluted with
toluene and washed with saturated sodium hydrogen carbon-
ate. The organic phase was dried, filtered, and concentrated.
The residue was dissolved in dichloromethane/trimethyl ortho-
formate (1:1, 20 mL), and camphorsulfonic acid (30 mg) was
added. After being stirred at room temperature for 1 h, the
mixture was diluted with dichloromethane and washed with
saturated sodium hydrogen carbonate. The organic phase was
dried, filtered, and concentrated to give a mixture of 26 and
27 which was separated by column chromatography (toluene/
S, 11.67. Found: C, 43.60; H, 4.91; N, 9.93; S, 11.36. 31:
1
[R]22 -5.0° (c 0.2, MeOH); H NMR (250 MHz, MeOH-d4) δ
D
1.91 (d, J ) 0.9 Hz, 3H), 3.65-3.85 (m, 5H), 4.54 (dt, J ) 4.2,
5.2 Hz, 1H), 7.26 (s, 1H), 8.01 (d, J ) 0.9 Hz, 1H); 13C NMR
(62.9 MHz, MeOH-d4) δ 12.5, 53.2, 62.9, 64.3, 86.8, 91.4, 111.9,
137.2, 152.2, 166.2. Anal. Calcd for C10 H14 O5 S N2: C, 43.79;
H, 5.15; N, 10.22; S, 11.67. Found: C, 43.80; H, 5.17; N, 9.81;
S, 11.52.
1-[(4R,5R)-4,5-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]-
1,3-oxa th iola n -2-yl]u r a cils (32 a n d 33). To a stirred solu-
tion of compounds 26 and 27 (290 mg, 0.711 mmol) in
dichloromethane (50 mL) were added silylated uracil (1.4 mL
of a 0.6 M solution in dichloromethane) and trimethylsilyl
triflate (0.14 mL, 0.782 mmol). The resulting solution was
stirred at room temperature overnight, neutralized by the
addition of pyridine, poured onto a column of silica gel, and
eluted with toluene/ethyl acetate (1:1). Further purification
by column chromatography (toluene/ethyl acetate 3:1) gave 32
ethyl acetate 50:1) to give 26 and 27 (488 mg, 86%) in a ratio
1
of 1:1.4 as colorless oils. 26: [R]22 +10.5° (c 2.0, CHCl3); H
D
NMR (250 MHz, CDCl3) δ 0.053, 0.070 (2s, 12 H), 0.88, 0.89
(2s, 18H), 3.37 (s, 3H), 3.5-3.6 (2d, J ) 8.1 and 6.0 Hz, 2H),
3.67 (ddd, J ) 8.5, 5.7, 2.8 Hz, 1H), 3.72 (dd, J ) 10.1, 5.3 Hz,
1H), 3.85 (dd, J ) 10.1, 7.6 Hz, 1H), 4.33 (ddd, J ) 7.6, 5.3,
2.8 Hz, 1H), 6.16 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ -5.3,
18.2, 25.8, 52.1, 54.6, 63.7, 65.2, 85.2, 110.9. Anal. Calcd for
C18H40O4SSi2: C, 58,89; H, 9.86; S, 13.74. Found: C, 59.01;
(45 mg, 13%) and 33 (40 mg, 11.5%). 32: [R]22 +38° (c 0.3,
D
CHCl3); 1H NMR (250 MHz, CDCl3) δ 0.078 (s, 12H), 0.90, 0.91
(s, 18H), 3.75-4.05 (m, 6H), 5.79 (d, J ) 8.0 Hz, 1H), 7.29 (s,
1H), 7.77 (d, J ) 8.0 Hz, 1H), 8.95 (bs, 1H); 13C NMR (62.9
MHz, CDCl3) δ -5.45, 18.3, 25.8, 50.9, 62.7, 64.6, 86.1, 89.0,
103.2, 139.9, 149.8, 162.8. Anal. Calcd for C21H40O5SN2Si2:
C, 51.62; H, 8.26; S, 6.54; N, 5.74. Found: C, 51.39; H, 8.10;
H, 9.97; S, 13.46. 27: [R]22 -0.7° (c 2.7, CHCl3); 1H NMR
D
(250 MHz, CDCl3) δ 0.052, 0.063 (2s, 12 H), 0.88, 0.90 (2s,
18H), 3.36 (s, 3H), 3.54 (dt, J ) 8.2, 6.3 Hz, 1H), 3.7-3.9 (m,
4H), 4.25 (dt, J ) 6.3, 5.1 Hz, 1H), 6.11 (s, 1H); 13C NMR (62.9
MHz, CDCl3) δ -5.3, 18.3, 25.9, 51.2, 54.4, 63.8, 66.0, 84.9,
110.4. Anal. Calcd for C18H40O4SSi2: C, 58,89; H, 9.86; S,
13.74. Found: C, 58.96; H, 10.07; S, 13.52.
S, 6.73; N, 5.88. 33: [R]22 -27° (c 0.3, CHCl3); 1H NMR (250
D
MHz, CDCl3) δ 0.082, 0.092 (2s, 12H), 0.91 (s, 18H), 3.65-
3.85 (m, 5H), 4.50 (dt, J ) 3.2, 5.0 Hz, 1H), 5.79 (d, J ) 8.0
Hz, 1H), 7.28 (s, 1H), 7.85 (d, J ) 8.0 Hz, 1H), 8.2 (bs, 1H);
13C NMR (62.9 MHz, CDCl3) δ -5.45, -5.35, 18.2, 18.3, 25.8,
52.1, 63.5, 64.7, 84.5, 90.5, 102.9, 139.7, 149.9, 162.7. Anal.
Calcd for C21H40O5SN2Si2: C, 51.62; H, 8.26; S, 6.54; N, 5.74.
Found: C, 51.37; H, 8.11; S, 6.62; N, 5.75.
Gen er a l P r oced u r e for th e Silyla tion of Nu cleosid e
Ba ses. Stock solutions of silylated bases (1.0 M in dichlo-
romethane) were prepared as described previously.9
r a c-1-(1,3-Oxa th iola n -2-yl)th ym in e (29). To a stirred
solution of racemic 2-methoxy-1,3-oxathiolane 2832 (166 mg,
1.38 mmol) in dichloromethane (90 mL) were added silylated
thymine (1.7 mL of a 1.0 M solution in dichloromethane) and
trimethylsilyl triflate (0.28 mL, 1.52 mmol). The resulting
solution was stirred at room temperature overnight. The
reaction was neutralized by the addition of pyridine, poured
onto a column of silica gel, and eluted with dichloromethane/
ethyl acetate (1:1). Further purification by column chroma-
tography (toluene/ethyl acetate 1:1) gave racemic 29 (113 mg,
38%) as a colorless solid. 29: 1H NMR (250 MHz, CDCl3) δ
1.95 (d, J ) 0.8 Hz, 3H), 3.18 (ddd, J ) 10.3, 5.6, 3.1 Hz, 1H),
3.32 (ddd, J ) 10.3, 9.0, 5.7 Hz, 1H), 3.99 (dt, J ) 5.6, 9.2 Hz,
1H), 4.52 (ddd, J ) 9.3, 5.7, 3.1 Hz, 1H), 7.31 (s, 1H), 7.34 (d,
J ) 0.8 Hz, 1H), 8.9 (bs, 1H); 13C NMR (62.9 MHz, CDCl3) δ
12.6, 33.1, 71.5, 90.4, 111.9, 135.0, 150.4, 163.7. Anal. Calcd
1-[(2R,4R,5R)-4,5-Bis(h yd r oxym eth yl)-1,3-oxa th iola n -
2-yl]u r a cil (34). To a solution of 32 (30 mg, 0.0614 mmol) in
tetrahydrofuran (3 mL) was added tetrabutylammonium
fluoride (0.60 mL of a 0.5 M solution in tetrahydrofuran). The
resulting solution was stirred at room temperature for 1 h.
The solvent was evaporated, and the residue was purified by
column chromatography (ethyl acetate/methanol 5:1) to give
34 (14 mg, 88%) as an amorphous solid. 34: [R]22 +89° (c
D
0.7, MeOH); 1H NMR (250 MHz, MeOH-d4) δ 3.71 (dd, J )
11.2, 6.1 Hz, 1H), 3.75-3.95 (m, 4H), 4.03 (ddd, J ) 8.1, 4.5,
3.2 Hz, 1H), 5.77 (d, J ) 8.0 Hz, 1H), 7.29 (s, 1H), 7.96 (d, J
) 8.0 Hz, 1H); 13C NMR (62.9 MHz, MeOH-d4) δ 52.9, 62.5,
63.9, 87.4, 90.1, 103.7, 141.9, 151.7, 165.8. Anal. Calcd for

3610 J . Org. Chem., Vol. 61, No. 11, 1996
Bra˚nalt et al.
C9H12O5N2S: C, 41.53; H, 4.65; N, 10.76; S, 12.32. Found: C,
41.86; H, 4.69; N, 10.44; S, 12.07.
1-[(4R,5R)-4,5-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]-
1,3-oxa th iola n -2-yl]-6-ch lor op u r in es (38 a n d 39). To a
stirred solution of compounds 26 and 27 (114 mg, 0.279 mmol)
in dichloromethane (20 mL) were added silylated 6-chloropu-
rine (0.35 mL of a 1.0 M solution in dichloromethane) and
trimethylsilyl triflate (0.057 mL, 0.307 mmol). The resulting
solution was stirred at room temperature overnight, neutral-
ized by the addition of pyridine, poured onto a column of silica
gel, and eluted with toluene/ethyl acetate (1:1). Further
purification by column chromatography (toluene/ethyl acetate
9:1) gave a 1:1 mixture of 38 and 39 (46 mg, 31%) which could
not be separated by column chromatography. 38 and 39: 1H
NMR (250 MHz, CDCl3) δ 0.050-0.124 (7s, 24 H), 0.88-0.92
(4s, 36H), 3.75-4.0 (m, 9H), 4.07 (q, J ) 6.3 Hz, 1H), 4.26 (dt,
J ) 6.6, 4.3 Hz, 1H), 4.43 (q, J ) 5.0 Hz, 1H), 7.46 (2s,
overlapping, 2H), 8.60, 8.73, 8.76, 8.77 (4s, 4H); 13C NMR (62.9
MHz, CDCl3) δ -5.4, 18.3, 18.4, 25.8, 52.2, 53.4, 62.9, 63.0,
63.7, 64.3, 84.3, 86.7, 87.8, 88.1, 132.2, 132.4, 143.5, 143.9,
151.2, 151.3, 151.5, 152.3, 152.4. Anal. Calcd for a mixture
of 38 and 39 (C22H39O3N4SClSi2): C, 49.74; H, 7.40; N, 10.54;
S, 6.04. Found: C, 49.83; H, 7.66; N, 10.22; S, 5.88.
1-[(2S,4R,5R)-4,5-Bis(h yd r oxym eth yl)-1,3-oxa th iola n -
2-yl]u r a cil (35). Compound 33 (26 mg, 0.0532 mmol) was
deprotected using the same method as described for compound
34, to give 35 (12 mg, 87%) as an amorphous solid. 35: [R]22
D
1
-63° (c 0.6, MeOH); H NMR (250 MHz, MeOH-d4) δ 3.65-
3.80 (m, 5H), 4.54 (dt, J ) 4.2, 5.2 Hz, 1H), 5.75 (d, J ) 8.1
Hz, 1H), 7.24 (s, 1H), 8.07 (d, J ) 8.1 Hz, 1H); 13C NMR (62.9
MHz, MeOH-d4) δ 53.1, 62.9, 64.4, 87.1, 91.7, 103.0, 141.6,
152.0, 165.9. Anal. Calcd for C9H12O5N2S: C, 41.53; H, 4.65;
N, 10.76; S, 12.32. Found: C, 41.64; H, 4.72; N, 10.56; S, 12.18.
Isola tion of (2R,3R)-1,4-Bis-O-(ter t-bu tyld im eth ylsilyl)-
3-O-for m yl-2-t h iot h r eit ol (37) d u r in g t h e At t em p t ed
P r ep a r a tion of Com p ou n d 36. To a solution of compounds
26 and 27 (120 mg, 0.294 mmol) in dichloromethane (20 mL)
were added silylated N4-benzoylcytosine (0.30 mL of a 1.0 M
solution in dichloromethane) and trimethylsilyl triflate (0.060
mL, 0.323 mmol). The resulting solution was stirred at room
temperature overnight. The reaction mixture was neutralized
by the addition of pyridine, poured onto a silica gel column,
and eluted with toluene/ethyl acetate (3:1). Further purifica-
tion of by column chromatography (toluene/ethyl acetate 20:
1) gave 37 (42 mg, 36%) as a colorless syrup. 37: [R]22D -10.5°
1
Ack n ow led gm en t. We thank the National Swedish
Board of Technical Development, Medivir AB, and
Stipendium Berzelianum for financial support, and
Medivir AB for the biological testings.
(c 0.4, CHCl3); H NMR (250 MHz, CDCl3) δ 0.052, 0.069 (2s,
12 H), 0.88, 0.89 (2s, 18H), 1.60 (d, J ) 10.6 Hz, 1H), 3.16
(dddd, J ) 10.6, 8.1, 4.8, 3.4 Hz, 1H), 3.58 (dd, J ) 10.2, 8.1
Hz, 1H), 3.75-3.9 (m, 3H), 5.27 (dt, J ) 3.4, 6.0 Hz, 1H), 8.10
(s, 1H); 13C NMR (62.9 MHz, CDCl3) δ -5.45, 18.2, 25.8, 41.5,
61.7, 65.0, 73.2, 160.4. Anal. Calcd for C17H38O4SSi2: C, 51.73;
H, 9.70; S, 8.12. Found: C, 51.62; H, 9.49; S, 7.95.
J O960009C