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

Article abstract of DOI:10.1021/jo952228o

The synthesis of [4,5-bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides is described. (2S,3S)-1,2:3,4-Diepoxybutane (13) was reacted with potassium thiocyanate to give (2R,3R)-1,2:3,4-diepithiobutane (14). Thiiranering opening with acetate followed by deacetylation gave (2R,3R)-2,3-dithiothreitol (19) which was silylated and treated with trimethyl orthoformate to give the 2-methoxy-1,3-dithiolane 20. Condensation of 20 with silylated thymine, uracil, N⁴-benzoylcytosine and 6-chloropurine using a modified Vorbruggen procedure, followed by deprotection, gave the nucleoside analogues. Compounds 26, 28, and 30 were found to be inactive when tested for anti-HIV activity in vitro.

Full text of DOI:10.1021/jo952228o

J . Org. Chem. 1996, 61, 3611-3615
3611
Syn th esis of [4,5-Bis(h yd r oxym eth yl)-1,3-d ith iola n -2-yl]n u cleosid es
a s P oten tia l In h ibitor s of HIV1
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 December 19, 1995X
The synthesis of [4,5-bis(hydroxymethyl)-1,3-dithiolan-2-yl]nucleosides is described. (2S,3S)-1,2:
3,4-Diepoxybutane (13) was reacted with potassium thiocyanate to give (2R,3R)-1,2:3,4-diepithio-
butane (14). Thiiranering opening with acetate followed by deacetylation gave (2R,3R)-2,3-
dithiothreitol (19) which was silylated and treated with trimethyl orthoformate to give the
2-methoxy-1,3-dithiolane 20. Condensation of 20 with silylated thymine, uracil, N4-benzoylcytosine
and 6-chloropurine using a modified Vorbru¨ggen procedure, followed by deprotection, gave the
nucleoside analogues. Compounds 26, 28, and 30 were found to be inactive when tested for anti-
HIV activity in vitro.
In tr od u ction
nucleosides 7 (X ) Y ) S) as potential inhibitors of HIV.
Although extensive synthetic work and structure-activ-
ity relationship investigations have been performed in
the dioxolanyl7 and oxathiolanyl nucleoside series,8 to the
best of our knowledge, the synthesis of nucleosides with
two sulfur atoms in the carbohydrate moiety have previ-
ously not been reported.
We2 and others3 have reported 2′,3′-dideoxy-3′-C-(hy-
droxymethyl)cytidine (1) to be a potent inhibitor of HIV-1
activity in vitro and thus considered it to be a new
interesting lead compound.4 On the basis of the antiviral
activities of several carbocyclic,5 4′-thio,6 dioxolanyl7 and
oxathiolanyl nucleosides,8 we have initiated a program
to synthesize analogues of 1. Previously, the syntheses
of hydroxymethyl-substituted carbocyclic (2)9 and 4′-thio
nucleosides (3)10 have been reported by us and other
groups, and in the previous papers in this series, the
synthesis of dioxolanyl (4)11 and oxathiolanyl nucleosides
(5 and 6)12 is described. In the present paper, we report
the synthesis of the corresponding 1,3-dithiolan-2-yl-
† Additional address: Astra Ha¨ssle AB, S-431 83 Mo¨lndal, Sweden.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) For parts 1 and 2 in this series, see refs 11 and 12, respectively.
(2) Svansson, L.; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J . Org.
Chem. 1991, 56, 2993.
(3) (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.
For the synthesis of the dithiolanyl moiety of 7,
(2R,3R)-2,3-dithiothreitol was envisaged as a pivotal
intermediate. Although several low molecular weight
dithiol compounds are known, (2R,3R)-2,3-dithiothreitol
and its enantiomer have, to our knowledge, not been
prepared previously in isomerically pure form.13 Com-
pounds of this type are of potential interest as antidotes
for heavy metal poisoning due to their metal-chelating
properties,14 and recently, 2,3-dithioerythritol prepared
by reduction of meso-dimercaptosuccinic acid, was re-
ported as a new potential arsenic antidote.14 Further-
more, the 1,4-dithiol derivatives of threitol and erythritol
(Clelands reagent) are commercially available and used
(4) Herdewijn, P. A. M. M. Antiviral Res. 1992, 19, 1.
(5) For
a recent review, see: Borthwick, A. D.; Biggadike, K.
Tetrahedron 1992, 48, 571.
(6) For a recent review, see: Wnuk, S. F. Tetrahedron 1993, 49,
9877.
(7) See, for example: (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.; Shanmuganathan, 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.
(8) See, for example: (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) Beach, J . W.; 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.
(10) (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.; Samuel-
sson, B. J . Org. Chem. 1994, 59, 4430. (c) Mann, J .; Tench, A. J .;
Weymouth-Wilson, C.; Shaw-Ponter, S.; Young, R. J . J . Chem. Soc.,
Perkin Trans. 1 1995, 677.
(11) Brånalt, J .; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J . Org.
Chem. 1996, 61, 3599-3603.
(12) Brånalt, J .; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J . Org.
Chem. 1996, 61, 3604-3610.
(9) (a) Boumchita, H.; Legraverend, M.; Bisagni, E. Heterocycles
1991, 32, 1785. (b) J ansson, M.; Svansson, L.; Svensson, S. C. T.;
Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. Nucleosides Nucleotides
1992, 11, 1793. (c) Buenger, G. S.; Marquez, V. E. Tetrahedron Lett.
1992, 33, 3707.
(13) For the synthesis of a mixture of racemic 2,3-dithiothreitol and
2,3-dithioerythritol, see: Fitt, P. S.; Owen, L. N. J . Chem. Soc. 1957,
2240.
(14) Boyd, V. L.; Harbell, J . W.; O’Connor, R. J .; McGown, E. L.
Chem. Res. Toxicol. 1989, 2, 301 and references cited therein.
S0022-3263(95)02228-6 CCC: $12.00 © 1996 American Chemical Society

3612 J . Org. Chem., Vol. 61, No. 11, 1996
Bra˚nalt et al.
Sch em e 1
Sch em e 2
for the cleavage of disulfide bonds in proteins.15 In
principle, protected (2R,3R)-2,3-dithiothreitol (10) could
be prepared from (2S,3S)-1,4-diprotected-2,3-ditosyl-
threitol 8 by disubstitution of the secondary tosylates
with a sulfur-containing nucleophile via the monosub-
stituted intermediate 9 (Scheme 1). This methodology
has previously successfully been used for the preparation
of 2,3-diazido- and 2,3-diaminothreitol.16 However, with
sulfur as nucleophile, the stereochemical integrity might
not be preserved when a second sulfur substituent is
introduced.17 Notably, in the preparation of 2,3-butane-
dithiol from 2,3-butanediol using this reaction sequence,
partial epimerization occurred to at least 20% with the
thiocyanate ion.18 To circumvent this problem, we have
developed a route to (2R,3R)-2,3-dithiothreitol (19) start-
ing from (S,S)-diepoxybutane which involves the stereo-
specific introduction of sulfur with inversion of configu-
ration at both chiral centers.
to suppress polymerization24 by dilution, cooling, neu-
tralization with acid, or use of different solvents were
not successful. Interestingly, substituting potassium
thiocyanate for thiourea gave an increased rate of poly-
merization. However, one product could be isolated in
25% yield and identified as 3,6-dithiabicyclo[3.1.0]hexane
(15).25 Opening of diepithiobutane 14 with sodium
acetate in acetic acid-acetic anhydride (1:1) at 120 °C
gave tetraacetylated 2,3-dithiothreitol 16 in 51% yield.
Compounds 17 and 18 were also formed in 25% and 8%
yields, respectively.26 Deprotection of 16 under acidic
conditions to avoid thiirane formation and polymeriza-
tion27 gave white crystals of (2R,3R)-2,3-dithiothreitol
(19) as a single diastereomer in 91% yield.28 Selective
protection of the hydroxyl groups of 2,3-dithiothreitol 19
as tert-butyldimethylsilyl ethers, followed by treatment
with trimethyl orthoformate in the presence of camphor-
sulfonic acid (CSA) gave 2-methoxy-1,3-dithiolane 20 in
80% yield.
Resu lts a n d Discu ssion
As starting material diepoxybutane was used, which
is a versatile chiral building block,19 readily available in
both enantiomeric forms from diethyl D- or L-tartrate in
five steps.20,21 (S,S)-Diepoxybutane (13) was converted
to the corresponding (R,R)-diepithio compound 14 with
inversion of configuration at both chiral centers by
treatment with potassium thiocyanate22 in water, as
described by Feit,23 in 56% yield (Scheme 2). Compound
14 was obtained as a single diastereomer, indicating that
no epimerization had occurred in this reaction. As
reported,23 diepithiobutane is prone to polymerization,
due to the basicity of the reaction medium, and attempts
Initially, we used 2-methoxy-1,3-dithiolane (21)29 as a
simplified model system for the condensation of 2-meth-
oxy-1,3-dithiolanes with silylated bases (Scheme 3).
Condensation of 21 with silylated thymine under Vor-
bru¨ggen conditions30 did not give the expected 1,3-
dithiolan-2-ylnucleoside 22, although dilute12 conditions
were used. Instead, 1,2-bis(1,3-dithiolan-2-yl)dithio-
(15) (a) Carmack, M.; Kelley, C. J . J . Org. Chem. 1968, 33, 2171.
(b) Zahler, W. L.; Cleland, W. W. J . Biol. Chem. 1968, 243, 716.
(16) (a) Lohray, B. B.; Ahuja, J . R. J . Chem. Soc., Chem. Commun.
1991, 95. (b) Haines, A. H.; Morley, C.; Murrer, B. A. J . Med. Chem.
1989, 32, 742.
(17) The ease of sulfur to form intermediate episulfonium ions by
anchimeric assistance is a well-known process. See, for example:
Sander, M. Chem. Rev. 1966, 66, 297.
(24) (a) Bordwell, F. G.; Andersen, H. M. J . Am. Chem. Soc. 1953,
75, 4959. (b) Hall, L. D.; Hough, L.; Pritchard, R. A. J . Chem. Soc.
1961, 1537.
(25) Lautenschlaeger, F.; Schwartz, N. V. J . Org. Chem. 1969, 34,
3991.
(26) The absolute and relative configurations of compounds 17 and
18 were only tentatively assigned, based on the possible mechanisms
of their formation.
(27) Goodman, L.; Benitez, A.; Baker, B. R. J . Am. Chem. Soc. 1958,
80, 1680.
(18) Corey, E. J .; Mitra, R. B. J . Am. Chem. Soc. 1962, 84, 2938.
(19) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483 and references cited therein.
(20) Feit, P. W. J . Med. Chem. 1964, 7, 14.
(28) (2S,3S)-2,3-Dithiothreitol should be equally available using the
same methodology as described above starting from (R,R)-diepoxy-
butane.
(29) (a) Stutz, P.; Stadler, P. A. Helv. Chim. Acta 1972, 55, 75. (b)
Tanimoto, S.; Miyake, T.; Okano, M. Bull. Inst. Chem. Res., Kyoto Univ.
1977, 55, 276.
(21) Recently, a simple two-step procedure to (R,R)-diepoxybutane
from trans-1,4-dichloro-2-butene via asymmetric dihydroxylation was
reported. Vanhessche, K. P. M.; Wang, Z-M.; Sharpless, K. B. Tetra-
hedron Lett. 1994, 35, 3469.
(22) For a recent review, see: Chew, W.; Harpp, D. N. Sulfur Rep.
1993, 15, 1.
(30) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981,
114, 1234.
(23) Feit, P. W. J . Med. Chem. 1969, 12, 556.

1,3-Dithiolan-2-ylnucleosides as Potential Inhibitors of HIV
J . Org. Chem., Vol. 61, No. 11, 1996 3613
Sch em e 3
yield. The uracil derivatives 27 and 28 were obtained
using the same methodology in 39% and 95% yields,
respectively. In contrast to the corresponding 1,3-diox-
olan-2-yl11 and 1,3-oxathiolan-2-yl12 series it was possible
to condense 20 with silylated N4-benzoylcytosine to give
the protected cytosine derivative 29 in 27% yield. Depro-
tection of the silyl protecting groups followed by treat-
ment with methanolic ammonia gave the cytosine de-
rivative 30 in 87% yield. The 6-chloropurine derivative
31 was prepared from 20 and silylated 6-chloropurine
using the methodology described above in 39% yield.
However, we were not able to remove the silyl protecting
groups of 31 under conditions that did not result in total
decomposition.
Sch em e 4
Compounds 26, 28, and 30 were tested for inhibition
of HIV multiplication in a XTT assay in M4 cells.32 All
compounds were found to be inactive in the assay.
Exp er im en ta l Section
General methods were the same as those previously de-
scribed.11
(2R,3R)-1,2:3,4-Diep ith iobu ta n e (14). Compound 14 was
prepared from (2S,3S)-1,2:3,4-diepoxybutane (13)20,33 (1.20 g,
13.9 mmol) according to the method of Feit23 and purified by
column chromatography (hexane/chloroform 1:1) to give 14
(918 mg, 56%) as a white solid. Mp and [R]22 were in
D
agreement with those reported.23 14: 1H NMR (250 MHz,
CDCl3) δ 2.2-2.3 (m, 2H), 2.45-2.55 (m, 2H), 3.15-3.25 (m,
2H); 13C NMR (62.9 MHz, CDCl3) δ 23.8, 36.9.
3,6-Dith ia bicyclo[3.1.0]h exa n e (15). To a solution of
(2S,3S)-1,2:3,4-diepoxybutane (13)20,33 (294 mg, 3.42 mmol) in
methanol (10 mL) was added thiourea (1.56 g, 20.5 mmol) at
0 °C. After 5 h at 0 °C, water was added and the mixture was
extracted with dichloromethane. The organic phase was dried,
filtered, and evaporated to give 15 (101 mg, 25%) as a colorless
oil: bp 108-111 °C (10 mmHg), lit. 45 °C (0.1 mmHg).25 15:
1H NMR (250 MHz, CDCl3) δ 3.17 (d, J ) 12.6 Hz, 2H), 3.28
(dd, J ) 12.6, 2.0 Hz, 2H), 3.47 (d, J ) 2.0 Hz, 2H); 13C NMR
(62.9 MHz, CDCl3) δ 34.8, 42.0.
(2R,3R)-1,4-O,2,3-S-Tetr a a cetyl-2,3-d ith ioth r eitol (16).
A mixture of 14 (500 mg, 4.24 mmol), acetic anhydride (5 mL),
acetic acid (5 mL), and sodium acetate (3.0 g, 42.4 mmol) was
heated at 120 °C for 20 h. After the solution was cooled to
room temperature, toluene was added and the solids were
filtered off and washed with toluene. The solvent was
evaporated, and the residue was purified by column chroma-
tography (toluene/ethyl acetate 20:1) to give 17 (233 mg, 25%)
and 18 (56 mg, 6%) as colorless oils. Further elution with
toluene/ethyl acetate (9:1) gave 16 (696 mg, 51%) as a colorless
oil which solidified on standing. 16: [R]22D -3.4° (c 1.0, CHCl3);
1H NMR (250 MHz, CDCl3) δ 2.07 (s, 6H), 2.36 (s, 6H), 4.04
(dd, J ) 15.0, 9.7 Hz, 2H), 4.2-4.3 (m, 4H); 13C NMR (62.9
MHz, CDCl3) δ 20.7, 30.6, 43.0, 63.7, 170.4, 193.0. Anal. Calcd
for C12H18O6S2: C, 44.71; H, 5.63; S, 19.89. Found: C, 44.61;
ethane (23)31 was formed in 92% yield. Condensation of
20 with silylated thymine in the presence of trimethyl-
silyl triflate using dilute conditions gave the expected
nucleoside 25 in yields of less than 10%. The yield of 25
was improved by preforming a dilute solution of the 1,3-
dithiolan-2-ylium ion 24 by reacting 20 with trimethyl-
silyl triflate in dichloromethane at -80 °C. Adding this
solution to an excess of silylated thymine in dichloro-
methane at -60 °C gave thymine derivative 25 in 45%
yield (Scheme 4). Standard deprotection of the silyl
protecting groups using tetrabutylammonium fluoride in
tetrahydrofuran gave dithiolanylnucleoside 26 in 96%
o
1
H, 5.50; S, 19.95. 17: [R]22 + 30 (c 0.5, CHCl3); H NMR
D
(250 MHz, CDCl3) δ 2.11 (s, 3H), 2.37 (s, 3H), 3.0 (dd, J )
13.8, 7.9 Hz, 1H), 3.15-3.3 (m, 2H), 3.45 (dd, J ) 13.8, 5.0
Hz, 1H), 4.15 (dd, J ) 12.1, 7.4 Hz, 1H), 4.45 (dd, J ) 12.1,
5.7 Hz, 1H); 13C NMR (62.9 MHz, CDCl3) δ 20.8, 30.1, 30.4,
36.4, 37.9, 63.8, 170.4, 194.6. Anal. Calcd for C8H12O3S2: C,
43.61; H, 5.49; S, 29.11. Found: C, 43.55; H, 5.51; S, 28.93.
1
18: [R]22 -95° (c 1.0, CHCl3); H NMR (250 MHz, CDCl3) δ
D
2.06 (s, 3H), 2.33 (s, 3H), 3.35 (ddd, J ) 9.1, 8.2, 0.8 Hz, 1H),
3.42 (d, J ) 7.3 Hz, 1H), 3.45 (d, J ) 7.9 Hz, 1H), 3.5 (t, J )
8.7 Hz, 1H), 3.75 (dq, J ) 0.8, 7.5 Hz, 1H), 5.8 (q, J ) 8.0 Hz,
1H); 13C NMR (62.9 MHz, CDCl3) δ 20.7, 30.5, 30.8, 32.6, 48.0,
(31) The instability of 2-methoxy-1,3-dithiolane (21) to form 1,2-bis-
(1,3-dithiolan-2-yl)dithioethane (23), especially under acidic conditions,
has been well-documented, see: Coffen, D. L.; Chambers, J . Q.;
Williams, D. R.; Garrett, P. E.; Canfield, N. D. J . Am. Chem. Soc. 1971,
93, 2258 and ref 29.
(32) Vial, J . M.; J ohansson, N. G.; Wrang, L.; Chattopadhyaya, J .
Antiviral Chem. Chemother. 1990, 1, 183.
(33) Ca u tion ! Diepoxybutane is highly mutagenic. Diepithiobutane
might have similar properties. All handling with these compounds was
performed in a well-ventilated fume hood.

3614 J . Org. Chem., Vol. 61, No. 11, 1996
Bra˚nalt et al.
67.6, 169.4, 194.9. Anal. Calcd for C8H12O3S2: C, 43.61; H,
5.49; S, 29.11. Found: C, 43.80; H, 5.56; S, 28.72.
fluoride (0.80 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 was purified by column chromatography (ethyl acetate/
methanol 4:1) to give 26 (22 mg, 96%) as a white solid. 26:
(2R,3R)-2,3-Dith ioth r eitol (19). A solution of 16 (638 mg,
1.98 mmol) in methanol (10 mL) containing hydrogen chloride
(5%, w/w) was stirred at room temperature for 24 h. The
solvent was evaporated, and residual solvents were coevapo-
rated with added toluene. The solid residue was recrystallized
[R]22 +55° (c 0.4, MeOH); 1H NMR (250 MHz, MeOH-d4) δ
D
1.92 (s, 3H), 3.6-4.1 (m, 6H), 7.20 (s, 1H), 7.98 (s, 1H); 13C
NMR (62.9 MHz, MeOH-d4) δ 12.6, 59.6, 59.8, 64.6, 64.8, 67.0,
112.5, 137.8, 152.3, 166.0. Anal. Calcd for C10H14O4N2S2: C,
41.37; H, 4.86; N, 9.65; S, 22.09. Found: C, 41.09; H, 4.67; N,
9.85; S, 22.01.
from chloroform to give 19 (277 mg, 91%) as white crystals.
1
19: mp 114.8-115.3 °C; [R]22 -6.3° (c 2.0, EtOH); H NMR
D
(250 MHz, CDCl3) δ 1.60 (d, J ) 9.5 Hz, 2H), 2.22 (dd, J )
7.8, 4.6 Hz, 2H), 3.3-3.4 (m, 2H), 3.75 (ddd, J ) 11.3, 7.8, 6.8
Hz, 2H), 3.85 (dt, J ) 11.3, 5.0 Hz, 2H); 13C NMR (62.9 MHz,
MeOH-d4) δ 43.9, 66.3. Anal. Calcd for C4H10O2S2: C, 31.15;
H, 6.53; S, 41.57. Found: C, 31.09; H, 6.38; S, 41.71.
(4R,5R)-1-[4,5-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]-
1,3-d ioth iola n -2-yl]u r a cil (27). A solution of 20 (112 mg,
0.264 mmol) in dichloromethane (20 mL) was cooled to -80
°C, and trimethylsilyl triflate (0.053 mL, 0.290 mmol) was
added dropwise. The resulting solution was slowly added to
silylated uracil (1,0 mL of a 1.0 M solution in dichloromethane)
in dichloromethane (2 mL) at -60 °C, and the solution was
stirred for 30 min. Pyridine was added, and the mixture was
filtered through a short column of silica gel. The solvent was
evaporated, and the residue was purified by column chroma-
tography (toluene/ethyl acetate 3:1) to give 27 (52 mg, 39%)
(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 ith iola n e (20). A solution of 19 (340 mg,
2.21 mmol), tert-butyldimethylsilyl chloride (733 mg, 4.86
mmol), and imidazole (450 mg, 6.62 mmol) in dimethylform-
amide (3 mL) was stirred at room temperature for 24 h. The
reaction mixture was diluted with toluene and washed with
saturated aqueous sodium hydrogen carbonate. The organic
phase was dried, filtered, and concentrated. The oily residue
was dissolved in dichloromethane/trimethyl orthoformate (1:
1, 20 mL) followed by the addition of camphorsulfonic acid (30
mg). After being stirred at room temperature for 1 h, the
mixture was diluted with dichloromethane and washed with
saturated aqueous sodium hydrogen carbonate. The organic
phase was dried, filtered, and concentrated. The residue was
purified by flash column chromatography (hexane/toluene 1:1)
as a colorless syrup. 27: [R]22
+54° (c 0.4, CHCl3); 1H NMR
D
(250 MHz, CDCl3) δ 0.08, 0.10 (2s, 12 H), 0.90, 0.91 (2s, 18
H), 3.69 (dd, J ) 10.1, 5.7 Hz, 1H), 3.74 (dd, J ) 9.6, 8.1 Hz,
1H), 3.78 (dd, J ) 9.6, 5.5 Hz, 1H), 3.83 (dd, J ) 10.1, 7.9 Hz,
1H), 3.95 (ddd, J ) 8.1, 5.5, 2.8 Hz, 1H), 4.00 (ddd, J ) 7.9,
5.7, 2.8 Hz, 1H), 5.84 (dd, J ) 8.0, 0.5 Hz, 1H), 7.22 (s, 1H),
7.96 (d, J ) 8.0 Hz, 1H), 9.0 (bs, 1H); 13C NMR (62.9 MHz,
CDCl3) δ -5.41, -5.32, -5.27, 18.2, 25.8, 57.9, 58.0, 64.7, 64.9,
66.5, 103.5, 140.4, 150.3, 162.6. Anal. Calcd for C21H40O4-
to give 20 (750 mg, 80%) as a colorless oil. 20: [R]22 +34° (c
D
0.4, CHCl3); 1H NMR (250 MHz, CDCl3) δ 0.052, 0.068 (2s, 12
H), 0.89 and 0.90 (2s, 18 H), 3.31 (s, 3H), 3.52 (dd, J ) 10.1,
5.6 Hz, 1H), 3.60-3.75 (m, 2H), 3.80-3.95 (m, 2H), 4.15 (dd,
J ) 9.6, 5.6 Hz, 1H), 6.01 (s, 1H); 13C NMR (62.9 MHz, CDCl3)
δ -5.33, -5.26, 18.2, 25.9, 56.0, 56.8, 57.8, 65.0, 94.9. Anal.
Calcd for C18H40O3S2Si2: C, 50.89; H, 9.49; S, 15.10. Found:
C, 50.64; H, 9.29; S, 14.87.
N2
S2Si2: C, 49.96; H, 7.99; N, 5.55; S, 12.70. Found: C, 50.11;
H, 8.23; N, 5.50; S, 12.59.
(4R,5R)-1-[4,5-Bis(h yd r oxym eth yl)-1,3-d ioth iola n -2-yl]-
u r a cil (28). Compound 27 (34 mg, 0.067 mmol) was dissolved
in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.68
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 was
purified by column chromatography (ethyl acetate/methanol
Gen er a l P r oced u r e for Silyla tion of Nu cleosid e Ba ses.
Stock solutions of silylated bases in dichloromethane (1.0 M)
were prepared as described previously.11
4:1) to give 28 (18 mg, 95%) as a white solid. 28: [R]22 +69°
Isola tion of 1,2-Bis(1,3-d ith iola n -2-yl)d ith ioeth a n e (23)
d u r in g th e Attem p ted P r ep a r a tion of Com p ou n d 22. To
a solution of 2-methoxy-1,3-dithiolane (21)29 (500 mg, 3.68
mmol) in dichloromethane (250 mL) were added silylated
thymine (5.5 mL of a 1.0 M solution in dichloromethane) and
trimethylsilyl triflate (0.74 mL, 4.04 mmol). After 12 h at room
temperature, the reaction mixture was neutralized with pyri-
dine, applied to a column of silica gel, and eluted with toluene/
ethyl acetate (9:1) to give 23 (340 mg, 92%) as a white solid.
Mp and 1H NMR were in agreement with those reported.29,31
23: 13C NMR (62.9 MHz, CDCl3) δ 34.1, 38.4, 58.0.
D
(c 1.0, MeOH); 1H NMR (250 MHz, MeOH-d4) δ 3.67 (dd, J )
11.3, 6.1 Hz, 1H), 3.73 (dd, J ) 11.0, 6.3 Hz, 1H), 3.79 (dd, J
) 11.0, 7.6 Hz, 1H), 3.85 (dd, J ) 11.3, 7.2 Hz, 1H), 3.94 (ddd,
J ) 7.2, 6.1, 3.4 Hz, 1H), 4.03 (ddd, J ) 7.6, 6.3, 3.4 Hz, 1H),
5.80 (d, J ) 8.0 Hz, 1H), 7.29 (s, 1H), 8.21 (d, J ) 8.0 Hz, 1H);
13C NMR (62.9 MHz, MeOH-d4) δ 59.8, 64.6, 64.9, 67.5, 103.5,
142.4, 152.2, 165.7. Anal. Calcd for C9H12O4N2S2: C, 39.12;
H, 4.38; N, 10.14; S, 23.21. Found: C, 39.04; H, 4.44; N, 10.35;
S, 22.98.
(4R ,5R )-N
4-Be n zoyl-1-[4,5-b is[[(t er t -b u t yld im e t h yl-
silyl)oxy]m eth yl]-1,3-d ioth iola n -2-yl]cytosin e (29). A so-
lution of 20 (25 mg, 0.295 mmol) in dichloromethane (20 mL)
was cooled to -80 °C, and trimethylsilyl triflate (0.059 mL,
0.324 mmol) was added dropwise. The resulting solution was
slowly added to silylated N4-benzoylcytosine (1.0 mL of a 1.0
M solution in dichloromethane) in dichloromethane (2 mL) at
-60 °C, and the solution was stirred for 30 min. Pyridine was
added, and the mixture was filtered through a short column
of silica gel. The solvent was evaporated, and the residue was
purified by column chromatography (toluene/ethyl acetate 1:1)
(4R,5R)-1-[4,5-Bis[[(ter t-bu tyldim eth ylsilyl)oxy]m eth yl]-
1,3-d ioth iola n -2-yl]th ym in e (25). A solution of 20 (120 mg,
0.283 mmol) in dichloromethane (20 mL) was cooled to -80
°C, and trimethylsilyl triflate (0.056 mL, 0.311 mmol) was
added dropwise. The resulting solution was slowly added to
silylated thymine (1.0 mL of a 1.0 M solution in dichloro-
methane) in dichloromethane (2 mL) at -60 °C, and the
solution was stirred for 30 min. Pyridine was added, and the
mixture was filtered through a short column of silica gel. The
solvent was evaporated, and the residue was purified by
column chromatography (toluene/ethyl acetate 3:1) to give 25
to give 29 (48 mg, 27%) as a white solid. 29: [R]22 +64° (c
D
0.3, CHCl3); 1H NMR (250 MHz, CDCl3) δ 0.09 (s, 12 H), 0.91,
0.92 (2s, 18 H), 3.70 (dd, J ) 9.8, 5.4 Hz, 1H), 3.75 (dd, J )
9.0, 5.8 Hz, 1H), 3.80 (dd, J ) 9.0, 5.4 Hz, 1H), 3.86 (dd, J )
9.8, 4.8 Hz, 1H), 3.95-4.05 (m, 2H), 6.33 (d, J ) 7.7 Hz, 1H),
7.26 (s, 1H), 7.45-7.55 (m, 3H), 8.00-8.05 (m, 2H), 8.27 (d, J
) 7.7 Hz, 1H), 9.45 (bs, 1H); 13C NMR (62.9 MHz, CDCl3) δ
-5.39, -5.27, 18.2, 25.8, 57.6, 57.9, 64.7, 64.8, 68.3, 106.5,
127.6, 128.7, 131.8, 135.6, 140.9, 156.3, 165.3, 172.7. Anal.
Calcd for C28H45O4N3S2Si2: C, 55.32; H, 7.46; N, 6.91; S, 10.55.
Found: C, 55.34; H, 7.28; N, 6.77; S, 10.29.
(66 mg, 45%) as a colorless syrup which solidified on standing.
1
25: [R]22 +48° (c 0.6, CHCl3); H NMR (250 MHz, CDCl3) δ
D
0.08, 0.10 (2s, 12 H), 0.90, 0.92 (2s, 18 H), 1.97 (d, J ) 0.8 Hz,
3H), 3.69 (dd, J ) 9.6, 5.9 Hz, 1H), 3.77 (t, J ) 9.0 Hz, 1H),
3.80 (dd, J ) 9.0, 5.3 Hz, 1H), 3.86 (t, J ) 9.6 Hz, 1H), 3.94
(ddd, J ) 9.6, 5.3, 2.3 Hz, 1H), 4.02 (ddd, J ) 9.0, 5.8, 2.3 Hz,
1H), 7.25 (s, 1H), 7.63 (d, J ) 0.8 Hz, 1H), 8.34 (bs, 1H); 13C
NMR (62.9 MHz, CDCl3) δ -5.34, -5.22, 12.8, 18.2, 25.8, 57.6,
58.1, 64.8, 65.1, 66.2, 112.0, 135.8, 150.2, 162.9. Anal. Calcd
for C22H42O4N2S2Si2: C, 50.92; H, 8.16; N, 5.40; S, 12.36.
Found: C, 50.74; H, 8.22; N, 5.47; S, 12.09.
(4R,5R)-1-[4,5-Bis(h yd r oxym eth yl)-1,3-d ioth iola n -2-yl]-
cytosin e (30). Compound 29 (30 mg, 0.049 mmol) was
dissolved in tetrahydrofuran (2 mL), tetrabutylammonium
fluoride (0.50 mL of a 0.5 M solution in tetrahydrofuran) was
(4R,5R)-1-[4,5-Bis(h yd r oxym eth yl)-1,3-d ioth iola n -2-yl]-
th ym in e (26). Compound 25 (40 mg, 0.079 mmol) was
dissolved in tetrahydrofuran (3 mL), tetrabutylammonium

1,3-Dithiolan-2-ylnucleosides as Potential Inhibitors of HIV
J . Org. Chem., Vol. 61, No. 11, 1996 3615
added, and the resulting solution was stirred for 1 h at room
temperature. The solvent was evaporated, and the crude
product was purified by column chromatography (ethyl acetate/
methanol 4:1). The appropriate fractions were combined,
evaporated and treated with methanolic ammonia (saturated,
4 mL), and the solution was stirred at room temperature for
24 h. The solvent was evaporated, and the residue was
purified by column chromatography (chloroform/methanol 3:1)
to silylated 6-chloropurine (1,0 mL of a 1.0 M solution in
dichloromethane) in dichloromethane (2 mL) at -60 °C, and
the solution was stirred for 30 min. Pyridine was added, and
the mixture was filtered through a short column of silica gel.
The solvent was evaporated, and the residue was purified by
column chromatography (toluene/ethyl acetate 9:1) to give 31
(63 mg, 39%) as a white solid. 31: [R]22 +39° (c 0.6, CHCl3);
D
1H NMR (250 MHz, CDCl3) δ 0.10 (s, 12H), 0.92 (s, 18H), 3.73
(dd, J ) 10.2, 5.6 Hz, 1H), 3.78 (dd, J ) 10.3, 5.7 Hz, 1H),
3.84 (dd, J ) 10.3, 8.9 Hz, 1H), 3.91 (dd, J ) 10.2, 8.6 Hz,
1H), 4.09 (ddd, J ) 8.9, 5.7, 2.8 Hz, 1H), 4.21 (ddd, J ) 8.6,
5.6, 2.8 Hz, 1H), 7.21 (s, 1H), 8.69 (s, 1H), 8.77 (s, 1H); 13C
NMR (62.9 MHz, CDCl3) δ -5.31, 18.2, 25.8, 58.1, 58.8, 64.0,
64.4, 64.6, 132.3, 143.5, 151.2, 151.4, 152.1. Anal. Calcd for
C22H39O2N4S2Si2Cl: C, 48.28; H, 7.18; N, 10.24; S, 11.72.
Found: C, 48.13; H, 7.05; N, 10.07; S, 11.48.
to give 30 (12 mg, 87%) as a foam. 30: [R]22 +36° (c 0.6,
D
1
MeOH); H NMR (250 MHz, MeOH-d4) δ 3.63 (dd, J ) 11.2,
6.1 Hz, 1H), 3.69 (dd, J ) 10.9, 5.8 Hz, 1H), 3.76 (dd, J ) 11.2,
7.8 Hz, 1H), 3.83 (dd, J ) 10.9, 7.4 Hz, 1H), 3.91 (ddd, J )
7.4, 5.8, 3.2 Hz, 1H), 3.99 (ddd, J ) 7.8, 6.1, 3.2 Hz, 1H), 6.00
(d, J ) 7.7 Hz, 1H), 7.20 (s, 1H), 8.25 (d, J ) 7.7 Hz, 1H); 13
C
NMR (62.9 MHz, MeOH-d4) δ 59.6, 59.7, 64.7, 65.0, 68.4, 97.0,
142.9, 158.3, 167.4. Anal. Calcd for C9H11O3N3S2: C, 39.55;
H, 4.06; N, 15.37; S, 23.46. Found: C, 40.04; H, 4.36; N, 15.22;
S, 23.13.
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 ioth iola n -2-yl]-6-ch lor op u r in e (31). A solution of 20
(125 mg, 0.295 mmol) in dichloromethane (20 mL) was cooled
to -80 °C, and trimethylsilyl triflate (0.059 mL, 0.324 mmol)
was added dropwise. The resulting solution was slowly added
J O952228O