Synthesis and anti-HIV activity of D- and L-thietanose nucleosides

Article abstract of DOI:10.1021/jm050912h

Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic

Full text of DOI:10.1021/jm050912h

J. Med. Chem. 2006, 49, 1635-1647
1635
Synthesis and Anti-HIV Activity of D- and L-Thietanose Nucleosides
Hyunah Choo,† Xin Chen,† Vikas Yadav,† Jianing Wang,† Raymond F. Schinazi,‡ and Chung K. Chu*,†
College of Pharmacy, The UniVersity of Georgia, Athens, Georgia 30602, and Emory UniVersity School of Medicine/Veterans Affairs Medical
Center, Decatur, Georgia 30033
ReceiVed September 14, 2005
Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane
ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions.
Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford
various nucleoside derivatives. Among the synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-
fluorocytidine (25), and L-cytidine (52) analogues showed moderate anti-HIV activity, with EC50 ) 6.9,
1.3, 5.8, and 14.1 µM, respectively. However, these four nucleoside analogues are cytotoxic in peripheral
blood mononuclear and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, the
oxetanocin A analogue 33 was not active. Comparison of the minimized reverse transcriptases (RTs)
complexed with the corresponding triphosphates of the cytidine analogue 24 and the adenosine analogue 33
by molecular modeling studies showed that there is no difference in the binding mode of the triphosphate
of the cytidine analogue 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosine
analogue 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kinase showed
that the catalytic efficiency of phosphorylation through a nucleophilic attack of the 4′-hydroxyl group of
thietanose on the γ-phosphate of ATP is diminished in the case of L-cytidine analogue (52) due to the
increased distance between the 4′-hydroxyl group and the γ-phosphate.
Introduction
Nucleoside analogues have been well established as one of
the richest sources of antiviral agents despite their toxicity1 and
drug resistance.2 Various nucleosides have been reported as
potent inhibitors against viruses such as human immunodefi-
ciency virus (HIV),3 herpes simplex virus (HSV),4 hepatitis B
virus (HBV),5 varicella zoster virus (VZV),6 and human
Figure 1. Oxetanocin A, T, and G and carbocyclic analogues
oxetanocin A and G.
cytomegalovirus (HCMV).7 In the search for new antiviral
nucleosides with favorable antiviral and toxicological profiles,
numerous modifications have been conducted on naturally
occurring nucleosides. A natural nucleoside, oxetanocin A,
which has a four-membered oxetane ring instead of a five-
membered ribose ring, showed antiviral and antitumor activity
(Figure 1).8 The unique structure as well as the interesting
biological activity of oxetanocin A has prompted nucleoside
chemists to explore the antiviral and antitumor activities of the
nucleosides with four-membered-ring sugar-like moieties.9 The
study of structure-activity relationships (SARs) of oxetanocin
A resulted in several bioactive analogues.9 Oxetanocin T, in
which the heterocyclic base is thymine, showed activity against
VZV, HSV-1, and HSV-2,10 and oxetanocin G, with guanine
as the heterocyclic base, inhibited HBV replication in cell culture
with an EC50 of 1.5 µM.11 The carbocyclic analogue of
oxetanocin A was also found to be active against HBV and
HSV,12 and the carbocyclic oxetanocin G was also active against
HBV and HSV.12 Additionally, thietanose nucleosides which
have a four-membered thietane ring are of interest because the
replacement of oxygen in the sugar ring with a sulfur usually
increases the nucleoside’s stability toward acidic hydrolysis as
well as against phosphorylases which cleave the glycosyl bond,
thus resulting in the inactivation of nucleosides.13 However, only
two synthetic methodologies for the synthesis of thietanose
nucleosides have been reported in the literature, presumably due
to the synthetic difficulties.14 Formulation of the thietane ring
as well as the condensation reaction with heterocyclic bases
occurred in poor to moderate yield, which was not sufficient to
conduct SAR studies of thietanose nucleosides. For the synthesis
of various thietanose nucleosides, an efficient method of
synthesis of a common intermediate is required, from which
various analogues can be prepared for the study of the SARs
of the thietanose nucleosides. Herein, we report the synthesis
and anti-HIV activity of various D- and L-thietanose nucleosides,
including D- and L-3′-thio analogues of oxetanocin A.
Results and Discussion
Chemistry. â-3-Hydroxythietanes, such as compound 7, can
serve as the key intermediate for the synthesis of various 2′-
substituted thietanose nucleosides. The â-3-hydroxy group of
7 in the thietane ring can be derivatized to other desired moieties,
such as methylene 9 or hydroxymethyl group 10, under mild
reaction conditions. To synthesize the key intermediate com-
pound 7, the substitution reaction of 1-thioacetyl-3-mesylate 4,
reported by several groups,15 was adapted with some modifica-
tions. To synthesize the D-3′-thio analogues with various
heterocyclic bases (22-27, 33-35), D-xylose 1 was converted
to the diol 2 in five steps by using the reported method (Scheme
1).16 The diol 2 was mesylated with MsCl, TEA, and DMAP
to give the 1,3-dimesylate 3 in 90% yield, which was selectively
converted to the mono-thioacetate 4 by treatment with KSAc
* Corresponding author. Tel.: (706) 542-5379. Fax: (706) 542-5381.
E-mail: dchu@rx.uga.edu.
† The University of Georgia.
‡ Emory University School of Medicine/Veterans Affairs Medical Center.
10.1021/jm050912h CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/08/2006

1636 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Scheme 1. Synthesis of the Key Intermediate 12a
Choo et al.
a Reagents and conditions: (a) MsCl, pyr, DMAP, CH2Cl2; (b) KSAc, DMF; (c) NaHCO3, EtOH/H2O, reflux; (d) 4% TFA, OH- resin; (e) NaIO4,
NaBH4, MeOH; (f) TBDPSCl, TEA, DMAP, CH2Cl2; (g) i. Ac2O, DMSO, ii. Petasis reagent, THF/Et2O (1:1), reflux; (h) BH3SME2, THF, H2O2, 1 N
NaOH; (i) Swern oxidation, NaOMe, MeOH, NaBH4; (j) TBDPSCl, imidazole, CH2Cl2.
in DMF at room temperature in 80% yield. By employing a
substitution reaction similar to one previously reported,15
the correct configuration at the 2′-position, the major product
10 was oxidized to an aldehyde and equilibrated under basic
conditions. Thus, Swern oxidation of compound 10, followed
by epimerization with NaOMe and reduction with NaBH4, gave
the desired product 11 in 47% overall yield in three steps.
Compound 11 was protected by treatment with TBDPSCl and
imidazole to give compound 12 in 90% yield.
a
solution of the mono-thioacetate 4 and NaHCO3 in deoxygenated
95% aqueous EtOH was refluxed under nitrogen atmosphere
for 6 h to give compound 5 in 92% yield. The compound 5
was deprotected by treatment with 4% TFA, followed by
neutralization with Amberlite(OH-) resin, to give the triol 6 in
90% yield. The compound 6 was oxidatively cleaved to give
the key intermediate 7 in 70% yield, from which various 2′-
substituted thietanose nucleosides were synthesized. For opti-
mum yield of the 1,2-diol cleavage, several reaction conditions,
such as the amount of NaIO4 (1.2 equiv), vigorous stirring,
reaction time (1 h), and temperature (0 °C), turned out to be
critical.
The selective protection of the primary alcohol in compound
7 with TBDPSCl was explored with a few base catalysts, from
which 2,4,6-collidine was found to give the highest selectivity
between the primary and secondary hydroxyl groups. Thus,
treatment of 7 with triethylamine and a catalytic amount of 2,4,6-
collidine in CH2Cl2 gave the monoprotected compound 8 in 85%
yield with no diprotected compound. Compound 8 was then
oxidized under Moffatt-type conditions using DMSO and acetic
anhydride to give a ketone as the intermediate, which was
converted to the methylene derivative with Petasis reagent (Cp2-
TiMe2) to give compound 9 in 40% yield. Compound 9
underwent hydroboration upon treatment with BH3‚SMe2,
followed by oxidation with 3% H2O2 and 1 N NaOH to give
the undesired 2′-â-hydroxymethyl derivative 10 as the major
product in 70% yield, along with the desired 2′-R-hydroxy-
methyl compound 11 in 12% yield. The sterically hindered
nature of the â-side of compound 9, caused by the bulky silyl
protecting group, was probably unfavorable for the approach
of BH3 from the â-side, resulting in the formation of the
undesired â-configuration of the 2′-hydroxymethyl group. This
hypothesis is supported by the similar result obtained for the
synthesis of (-)-cyclobut-A.17 To obtain the intermediate with
Condensation of the thietanose derivative 12 with heterocyclic
bases was conducted by the Pummerer-type rearrangement after
formation of a sulfoxide with mCPBA (Scheme 2).18 Silylated
heterocyclic bases, such as thymine, uracil, 5-fluorouracil,
5-chlorouracil, 5-bromouracil, 6-chloropurine, and 6-chloro-2-
fluoropurine, were obtained under reflux conditions using
HMDS and acetonitrile, which were condensed with the
corresponding sulfoxide of 12 in the presence of TMSOTf,
triethylamine, and a catalytic amount of ZnI2 to provide the
protected nucleoside derivatives (13, 14, 16, 17, 18, 28, and
29) as R/â mixtures in 28-46% yield. For the pyrimidine
nucleosides, R and â anomers cannot be separated from each
other, while for the purine derivatives, it was possible to separate
the desired â anomers from their R anomers by using silica gel
column chromatography.
Condensation of compound 12 with thymine, uracil, 5-fluo-
rouracil, 5-chlorouracil, and 5-bromouracil gave anomeric
mixtures of protected nucleosides 13, 14, 16, 17, and 18 with
â/R ratio of 2:1 in 46%, 40%, 37%, 32%, and 28% yield,
respectively. The uracil, 5-fluorouracil, 5-chlorouracil, and
5-bromouracil derivatives 14, 16, 17, and 18 were aminated by
treatment with 2,4,6-triisopropylbenzenesulfonyl chloride, tri-
ethylamine, and DMAP in acetonitrile, followed by aqueous
ammonia solution, to give the cytosine, 5-fluorocytosine,
5-chlorocytosine, and 5-bromocytosine derivatives 15, 19, 20,
and 21, respectively. The nucleoside analogues 13-15, 19-21
were treated with TBAF in THF at room temperature to afford
pyrimidine thietanose nucleosides 22-27.

D- and L-Thietanose Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1637
Scheme 2. Synthesis of D-Thietanose Nucleosidesa
a Reagents and conditions: (a) mCPMA, CH2Cl2; (b) pyrimidine or purine, HMDS, CH3CN, TMSOTf, TEA, ZnI2, toluene; (c) 2,4,6-triisopropylben-
zenesulfonyl chloride, TEA, DMAP, CH3CN, NH4OH; (d) TBAF, THF; (e) i. NaN3, DMF, ii. H2, Pd(0), MeOH; (f) NaOMe, 2-mercaptoethanol, MeOH;
(g) i. NaOMe, 2-mercaptoethanol, MeOH, ii. NH3, EtOH, 60 °C.
Scheme 3. Synthesis of L-3′-Thio Analogues of Oxetanocin Aa
a Reagents and conditions: (a) MsCl, pyr, DMAP, CH2Cl2; (b) KSAc, DMF; (c) NaHCO3, EtOH/H2O, reflux; (d) 4% TFA, OH- resin; (e) NaIO4,
NaBH4, MeOH; (f) TBDPSCl, TEA, 2,4,6-collidine, CH2Cl2; (g) Ac2O, DMSO; (h) Petasis reagent, (i) BH3SMe2, THF; (j) (COCl)2, DMSO, NaOMe,
MeOH; (k) NaBH4, MeOH; (l) TBDPSCl, imidazole, CH2Cl2.
Compound 12 was condensed with 6-chloropurine and
6-chloro-2-fluoropurine to give compounds 28 and 29 as well
as their R-isomers in 40-45% yield with a â/R ratio of 5:4
(Scheme 2). Compound 28 was converted to the adenine
derivative 30 in 72% yield by using NaN3 in DMF, followed
by hydrogenation with 10% Pd(0) on carbon in methanol.
Compound 28 was also converted to the inosine derivative 31
in 85% yield by treatment with NaOMe and 2-mercaptoethanol
in methanol. On the other hand, the guanosine analogue 32 was
obtained in 74% yield by treatment of 29 with NaOMe and
2-mercaptoethanol in methanol, followed by amination in
ethanolic ammonia at 60 °C. Deprotection of compounds 30-
32 by TBAF gave the purine thietanose nucleosides 33-35 in
89-94% yield.
The L-3′-thio analogues of oxetanocin A were also synthe-
sized under similar reaction conditions starting from the opposite
enantiomer, L-xylose (Scheme 3). L-Xylose was converted to
the key intermediate 46, the enantiomer of compound 12, which
was obtained through the thietane diol 41, the enantiomer of
compound 7. After coupling of 46 with the appropriate silylated
pyrimidine and purine bases, the L-3′-thio analogues (50-52,
58-60) of oxetanocin A were obtained by using the same
procedures employed for the synthesis of the D-isomers (Scheme
4).

1638 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Scheme 4. Synthesis of L-Thietanose Nucleosidesa
Choo et al.
a Reagents and conditions: (a) mCPBA, CH2Cl2; (b) pyrimidine or purine, HMDS, CH3CN, TMSOTf, TEA, ZnI2, toluene; (c) 2,4,6-triisopropylben-
zenesulfonyl chloride, TEA, DMAP, CH3CN, NH4OH; (d) TBAF, THF; (e) i. NaN3, DMF, ii. H2, Pd(0), MeOH; (f) NaOMe, 2-mercaptoethanol, MeOH;
(g) i. NaOMe, 2-mercaptoethanol, MeOH, ii. NH3, EtOH, 60 °C.
Table 1. Anti-HIV Activity of D- and L-3′-Thio Thietanose Nucleoside Analogues
HIV (PBM)
toxicity (IC50, µM)
compd
config
base
thymine
uracil
cytosine
5-fluorocytosine
5-chlorocytosine
5-bromocytosine
adenine
hypoxanthine
guanine
thymine
uracil
cytosine
adenine
hypoxanthine
guanine
EC50 (µM)
>100
6.9
1.3
5.8
>100
11.5
>100
EC90 (µM)
PBM
CEM
Vero
22
23
24
25
26
27
33
34
35
50
51
52
58
59
60
AZT
D
D
D
D
D
D
D
D
D
L
>100
23.1
>100
>100
4.9
>100
>100
8.5
5.3
13.9
e1.0
<1.0
>100
4.3
19.0
54.8
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
41.9
>100
>100
>100
>100
>100
>100
1.8
>100
>100
>100
>100
>100
47.6
>100
>100
>100
0.01
>100
>100
>100
>100
>100
45.6
>100
>100
>100
14.3
>100
>100
>100
>100
L
L
14.1
13.1
L
>100
>100
>100
>100
>100
>100
>100
L
L
0.004
29.0
Anti-HIV Activity. The antiviral activity of the synthesized
D- and L-thietanose nucleosides (22-27, 33-35, 50-52, 58-
60) was evaluated against HIV-1 in human peripheral blood
mononuclear (PBM) cells in vitro using AZT as a positive
control, and the results are summarized in Table 1. Among the
synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-
fluorocytidine (25), and L-cytidine (52) analogues show moder-
ate anti-HIV activity, with EC50 ) 6.9, 1.3, 5.8, and 14.1 µM,
respectively. However, these four nucleoside analogues are also
cytotoxic in PBM and CEM cells.
We synthesized the D-cytidine analogue in the early stages
of this project, when some antiviral activity for the D-cytidine
analogue (24, Table 1) was observed, and then we decided to
explore the SAR at the 5-position of the pyrimidine ring. The
addition of a halogen atom at the 5-position of the pyrimidine
ring has been found to alter the kinetic parameters as well as
the antiviral potency of the corresponding nucleoside ana-
logues.19 It is well known that modification of the 5-position
of the cytosine ring with fluorine may result in reduced toxicity
and in some cases increase the antiviral potency.20 However,
introduction of different halogens at the 5-position in this
thietanose series (25-27) resulted in a decrease in antiviral
potency (Table 1). The complete inactivity of 26 was un-
expected. The other nucleosides showed neither anti-HIV
activity nor cytotoxicity up to 100 µM. It is well known that
nucleosides/nucleotides analogues can inhibit human DNA
polymerases, which may cause side effects such as cytotoxicity,
mitochondrial toxicity, etc.21 Consequently, if compounds 24,
25-27, and 52 can be phosphorylated to triphosphates, the low
selectivity of these nucleotides between the HIV reverse
transcriptase (RT) and cellular polymerase may explain the
observed antiviral activity as well as the cytotoxicity. Viral
inhibition may also be due to the deleterious effect of the
nucleosides on the cellular viability, caused by their metabolites
to cellular machineries other than polymerase (e.g., ribonucleo-
tide reductase, CTP synthase, etc.22). To confirm the hypothesis,
however, more detailed experiments have to be conducted. As
all the purine analogues, including the 3′-thio-oxetanocin A
analogue 33, showed no detectable anti-HIV activity while the
compound 33 was found to have binding characteristics similar
to those of the HIV RT by molecular modeling studies (vide
infra), the purine thietanose nucleosides might have a low level

D- and L-Thietanose Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1639
nicely accommodated at the 3′-OH pocket, which would
favorably contribute to their binding affinity to RT.
While the D-cytidine analogue 24 is moderately active against
HIV, which has the same sugar conformation as D-adenosine
analogue 33 based on the Monte Carlo conformational search,
the D-adenosine analogue 33 does not show any anti-HIV
activity. To understand the difference in anti-HIV activity
between the cytidine analogue 24 and the adenosine analogue
33, molecular modeling studies using the crystal structure of
HIV-1 RT (PDB code 1RTD) were conducted, replacing TTP
with the corresponding triphosphates of the nucleoside analogues
24 and 33.23 Each triphosphate was docked to the active site of
HIV-1 RT, and the resulting complex was minimized using the
Kollman all-atom force field. In the minimized structures, both
nucleoside triphosphates are nicely accommodated at the active
site of HIV-1 RT without any steric hindrance by amino acid
residues from the active site of RT. As expected, each hydroxy
moiety of the 2′-hydoxymethyl group (-CH2OH) of the two
thietanose nucleoside triphosphates is hydrogen-bonded to Tyr
115 of the 3′-hydroxy pocket in the active site of HIV RT as
well as their own â-phosphate (Figure 3). From the molecular
modeling studies, it is suggested that there would be no
difference in the ability of both of the nucleoside triphosphates
to bind to the active site of HIV RT. Thus, the lack of anti-
HIV activity of the adenosine analogue 33 might have originated
from the lack of phosphorylation by the initial kinase.
Figure 2. Superimposed structures of adenosine analogue 33, oxe-
tanocin A, and TTP, where the C3′-C4′ bond in adenosine analogue
33 is in blue, the C3′-C4′ bond in oxetanocin A is in red, and the
C4′-C5′ bond in TTP is in orange.
of phosphorylation from the initial nucleoside kinase, which
probably results in a low, if any, level of the triphosphate.
Molecular Modeling Studies. Molecular modeling studies
on the synthesized thietanose adenosine derivative 33 as well
as oxetanocin A were conducted to compare the conformations
of these two nucleosides with that of thymidine triphosphate in
the crystal structure of HIV-1 RT (PDB code 1RTD).23 The
most stable conformation of thietanose adenosine derivative 33
was obtained by a Monte Carlo conformational search using
the molecular graphics and simulation program, MacroModel
version 7.0 (Schro¨dinger, Inc.).24 The crystal structure of
oxetanocin A was obtained from the Cambridge Structural
Database. The three conformations of thietanose adenosine
derivative 33, oxetanocin A, and TTP, were superimposed using
Sybyl 6.7 (Figure 2). The C3′-C4′ bond (in blue) in thietanose
adenosine derivative 33 is displaced by 0.6 Å from the C4′-
C5′ bond (in orange) in TTP, and the 3′-sulfur atom in thietanose
adenosine derivative 33 extrudes the 3′-oxygen in oxetanocin
A and the 4′-oxygen in TTP. Another noticeable feature is that
the 2′-hydroxymethyl groups of thietanose adenosine derivative
33 and oxetanocin A are completely overlapped with the 3′-
hydroxy group of TTP. It is well known that the 3′-hydroxy
pocket, composed of Asp113, Ala114, Tyr115, and Gln151,
strengthens the binding of natural substrates to the active site
of HIV-1 RT through hydrogen bonding, particularly with Tyr
115.21 This 3′-hydroxy pocket also plays an important role in
binding of AZTTP to HIV RT, which was demonstrated in our
previous molecular modeling studies.25 Thus, the 2′-hydroxy-
methyl groups of thietanose adenosine derivative 33 could be
To investigate this possibility, we conducted molecular
modeling studies of D- and L-thietanose cytidine analogues (24,
52) with deoxycytidine kinase (dCK, PDB code 1P60).26
Detailed analysis of the reported crystal structure (1P60.pdb)
revealed that Glu53 and Arg128 are the acid-base pair which
abstracts the proton and initiates the catalysis (Figure 4).26 The
distance between the nucleoside 5′-OH and Glu53 is critical
for the phosphorylation. The 3′-OH is critical for activity; thus,
if 3-OH is missing, the catalytic efficiency decreases.27 The final
minimized structures of 24 and 52 revealed that there is
considerable preference for the D-thietanose analogue (24) over
the L-thietanose analogue (52). The catalytic efficiency of
phosphorylation through a nucleophilic attack of the 4′-hydroxyl
group of thietanose on the γ-phosphate of ATP is diminished
in the case of compound 52 due to the increased distance
between the 4′-hydroxyl group and the γ-phosphate. Slight steric
clashes are also observed between Leu82 and the 2′-hydroxy-
Figure 3. Minimized structures of HIV reverse transcriptase complexed with (a) the triphosphate of cytidine analogue 24 and (b) the triphosphate
of adenosine analogue 33, showing that both triphosphates are bound to the active site of HIV RT, interacting with Tyr115 and their own â-phosphate
through hydrogen bonding.

1640 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Choo et al.
Figure 4. Minimized structures of deoxycytidine kinase (dCK) complexed with (a) the D-cytidine analogue (24) and (b) the L-cytidine analogue
(52), revealing the increased distance (1.2 Å) between the 4′-hydroxyl group and the γ-phosphate in the case of compound 52, which may be
responsible for the lower catalytic efficiency of phosphorylation through the nucleophilic attack.
Figure 5. Steric clashes are observed between compound 52 and Leu82 but are absent in the case of compound 24.
Chemical shifts (δ) are reported as s (singlet), d (doublet), t (triplet),
q (quartet), quin. (quintet), m (multiplet), or br s (broad singlet).
UV spectra were recorded on a Beckman DU-650 spectrophotom-
eter. Optical rotations were measured on a Jasco DIP-370 digital
polarimeter. Mass spectra were recorded on a Micromass Autospec
high-resolution mass spectrometer. TLC was performed on Uni-
plates (silica gel) purchased from Analtech Co. Column chroma-
tography was performed using either silica gel-60 (220-440 mesh)
for flash chromatography or silica gel G (TLC grade, >440 mesh)
for vacuum flash column chromatography. Elemental analyses were
performed by Atlantic Microlab Inc., Norcross, GA.
methyl group of 52 (Figure 5), which is due to the distinct
binding mode of L-thietanose analogues. Thus, it can be
concluded from the studies that the increased distance for
nucleophilic attack on the γ-phosphate, coupled with the steric
clashes observed for compound 52, makes it less likely for 52
to be phosphorylated as efficiently as compound 24, which may
partially explain its lower anti-HIV activity.
In summary, various thietanose nucleosides, such as D- and
L-3′-thio analogues of oxetanocin A and 2′-R- and 2′-â-
hydroxythietanose nucleosides, were efficiently synthesized from
D- and L-xylose. Among the synthesized nucleosides, D-uridine
(23), D-cytidine (24), D-5-fluorocytidine (25), and L-cytidine (52)
analogues show moderate anti-HIV activity as well as cytotox-
icity. Molecular modeling studies show that the triphosphates
of D-cytidine analogue 24 and adenosine analogue 33 are nicely
accommodated at the active site of HIV RT through hydrogen-
bonding interactions, but the initial kinase (dCK) may not
efficiently phosphorylate compound 33, resulting in a low level
of its triphosphate, which in turn provides no anti-HIV activity.
1,2-O-Isopropylidene-3,5-di-O-mesyl-R-D-ribofuranoside (3).
A solution of compound 2 (33.2 g, 175 mmol) and pyridine (56.6
mL, 700 mmol) in CH2Cl2 (500 mL) was treated with MsCl (33.8
mL, 437 mmol) and DMAP (4.3 g, 35 mmol) at 0 °C for 18 h. The
reaction mixture was diluted with CH2Cl2 (500 mL), washed with
1 N HCl, aqueous NaHCO3, and brine, and dried over MgSO4.
The filtrate was concentrated and crystallized with a 1:10 mixture
of CH2Cl2 and hexanes to give the product 3 (29.3 g, 0.0816 mol,
90%) as a white solid: mp 115-116 °C; [R]22 77.8° (c 0.43,
D
CHCl3); 1H NMR (CDCl3) δ 5.84 (d, J ) 3.4 Hz, 1H), 4.82-4.74
(m, 2H), 4.55 (dd, J ) 11.8, 1.9 Hz, 1H), 4.41-4.30 (m, 2H), 3.16
(s, 3H), 3.08 (s, 3H), 1.58 (s, 3H), 1.38 (s, 3H). Anal. (C10H18O9S2)
C, H.
Experimental Section
Melting points were determined on a Mel-temp II apparatus and
are uncorrected. Nuclear magnetic resonance spectra were recorded
5-S-Acetyl-1,2-O-isopropylidene-3-O-mesyl-r-D-ribofurano-
side (4). A solution of compound 3 (81.5 g, 235 mol) in DMF
1
on a Varian Inova 500 spectrometer at 500 MHz for H NMR.

D- and L-Thietanose Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1641
(400 mL) was treated with KSAc (29.5 g, 258 mmol) at room
temperature. After 16 h, the reaction mixture was diluted with
EtOAc, washed with water (2 × 1 L), and dried over MgSO4. The
filtrate was concentrated and purified with 20% EtOAc in hexanes
by silica gel column chromatography to give product 4 (61.4 g,
A mixture of titanocene dichloride (38.7 g, 115 mmol) in Et2O
(1 L) was treated with 1.6 M MeLi solution (214 mL) in Et2O at
room temperature for 2 h. The reaction mixture was quenched with
ice and extracted with Et2O. The organic layer was dried over
anhydrous Na2SO4 and concentrated to dryness. This reagent
(Petasis reagent) was dissolved in THF (80 mL). A solution of the
intermediate ketone (10.0 g, 28.1 mmol) in Et2O (50 mL) was
treated with the freshly prepared Petasis reagent solution. The
resulting mixture was refluxed at 60 °C bath temperature. After 48
h, the reaction mixture was cooled to room temperature, diluted
with hexanes, and filtered through the silica gel pad. The filtrate
was concentrated and purified with 2% EtOAc in hexanes by silica
188 mmol, 80%) as a brownish solid: mp 112-113 °C; [R]23
D
1
68.5° (c 0.35, CHCl3); H NMR (CDCl3) δ 5.77 (d, J ) 3.7 Hz,
1H), 4.75 (t, J ) 4.2 Hz, 1H), 4.48 (dd, J ) 8.8, 4.6 Hz, 1H),
4.31-4.25 (m, 1H), 3.35 (dd, J ) 14.5, 4.1 Hz, 1H), 3.23 (J )
14.5, 5.1 Hz, 1H), 3.16 (s, 3H), 2.36 (s, 3H), 1.55 (s, 3H), 1.34 (s,
3H). Anal. (C11H18O7S2) C, H, S.
3,5-Thioanhydro-1,2-O-isopropylidene-r-D-xylofuranoside (5).
A mixture of EtOH (100 mL) and water (5 mL) was refluxed under
Ar for 2 h and cooled. Compound 4 (2.12 g, 6.50 mmol) and solid
NaHCO3 (1.09 g, 13.0 mmol) were added to the solvent, and the
resulting mixture was refluxed for 8 h. The reaction mixture was
cooled, diluted with Et2O, filtered, and purified with 5% Et2O in
hexanes by silica gel column chromatography to give the product
5 (1.12 g, 5.98 mmol, 92%) as an oil: [R]22D 78.7° (c 2.1, CHCl3);
1H NMR (CDCl3) δ 6.41 (d, J ) 3.4 Hz, 1H), 5.26 (t, J ) 5.3 Hz,
1H), 4.71 (d, J ) 3.4 Hz, 1H), 4.08 (d, J ) 5.3 Hz, 1H), 3.49 (dd,
J ) 10.6, 5.4 Hz, 1H), 2.84 (d, J ) 10.6 Hz, 1H), 1.43 (s, 3H),
1.36 (s, 3H). Anal. (C8H12O3S) C, H, S.
3,5-Thioanhydro-r-D-xylofuranose (6). Compound 5 (1.10 g,
5.84 mmol) was treated with 4% solution of TFA in water at room
temperature for 8 h, and then the reaction mixture was neutralized
with Amberlite(OH) resin, which was prewashed with water (2 ×
100 mL). After filtration, the filtrate was concentrated and purified
with 50% EtOAc in hexanes by silica gel column chromatography
to give the product 6 (0.75 g, 5.06 mmol, 87%): 1H NMR (CDCl3)
for major δ 6.11 (d, J ) 2.3 Hz, 1H), 5.16-5.12 (m, 1H), 4.17 (d,
J ) 2.5 Hz, 1H), 3.95 (d, J ) 5.9 Hz, 1H), 3.50 (dd, J ) 10.9, 6.3
Hz, 1H), 3.00 (d, J ) 10.9 Hz, 1H), for minor δ 5.56 (s, 1H),
5.29-5.24 (m, 1H), 4.37 (s, 1H), 3.95 (d, J ) 5.9 Hz, 1H), 3.64
(dd, J ) 10.9, 6.1 Hz, 1H), 3.12 (d, J ) 10.9 Hz, 1H). Anal.
(C5H8O3S) C, H, S.
gel column chromatography to give the product 9 (4.12 g, 11.6
1
mmol, 41%) as an oil: [R]22 73.6° (c 0.80, CH2Cl2); H NMR
D
(CDCl3) δ 7.72-7.65 (m, 4H), 7.47-7.37 (m, 6H), 4.86 (d, J )
2.1 Hz, 1H), 4.71 (d, J ) 2.1 Hz, 1H), 4.44-4.37 (m, 1H), 4.00
(dd, J ) 10.3, 6.8 Hz, 1H), 3.87 (dd, J ) 10.3, 6.8 Hz, 1H), 3.84-
3.74 (m, 2H), 1.06 (s, 9H). Anal. (C21H26OSSi) C, H, S.
[(2S,3R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-thietan-3-
yl]-methanol (10). A solution of compound 9 (4.12 g, 11.6 mmol)
in THF (200 mL) was treated with 2 M BH3SMe2 solution (11.5
mL) in THF at 0 °C for 30 min. The reaction mixture was warmed
to room temperature and stirred for 2 h. The reaction mixture was
quenched with 3% H2O2 (26 mL) and 1 N NaOH (23 mL). After
2 h, the reaction mixture was treated with saturated Na2S2O3 and
extracted with EtOAc. The organic layer was washed with brine
and dried over Na2SO4. The filtrate was concentrated and purified
with 10% EtOAc in hexanes by silica gel column chromatography
to give the product 10 (3.35 g, 8.13 mmol, 70% yield) as well as
compound 11 (0.51 g, 1.37 mmol, 12% yield): [R]22D 43.4° (c 1.18,
1
CHCl3); H NMR (CDCl3) δ 7.78-7.32 (m, 10H), 4.28 (t, J )
10.1 Hz, 1H), 4.01 (t, J ) 9.9 Hz, 1H), 3.80-3.42 (m, 5H), 3.02-
2.83 (m, 2H), 1.07 (s, 9H). Anal. (C21H28O2SSi) C, H, S.
[(2R,3S)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-thietan-3-
yl]-methanol (11). Oxalyl chloride (1.56 mL, 17.9 mmol) was
added dropwise to a solution of DMSO (1.90 mL, 26.8 mmol) in
CH2Cl2 (30 mL) at -78 °C. After 10 min, a solution of compound
10 (3.33 g, 8.94 mmol) in CH2Cl2 (20 mL) was added to the reaction
mixture at -78 °C. After 20 min, TEA (5.0 mL, 36 mmol) was
added at -78 °C. After 10 min, the reaction mixture was warmed
to room temperature for 1 h. The resulting mixture was diluted
with CH2Cl2 and washed with water. The organic layer was dried
over anhydrous Na2SO4 and concentrated to dryness. The aldehyde
was dissolved in MeOH (30 mL) and treated with NaOMe (1.45
g, 26.8 mmol) for 16 h. The resulting mixture was treated with
NaBH4 (1.01 g, 26.7 mmol) for 2 h. The reaction mixture was
neutralized with 1 N HCl, concentrated to a tenth volume of the
solution, and extracted with CH2Cl2. The organic layer was dried
over anhydrous Na2SO4, concentrated, filtered, and purified by silica
gel column chromatography with 10% EtOAc in hexanes to give
(2R,3S)-2-Hydroxymethyl-thietan-3-ol (7). A solution of com-
pound 6 (1.92 g, 12.9 mmol) in MeOH (50 mL) was treated with
an aqueous solution of NaIO4 (3.04 g, 14.2 mmol) in water (25
mL) dropwise at 0 °C for 10 min with vigorous stirring. After 20
min, well-ground NaBH4 was added portionwise to the reaction
mixture at 0 °C. After 30 min, the resulting mixture was filtered,
and the filtrate was neutralized with 1 N HCl and concentrated.
The residue was dissolved in a mixture of CH2Cl2 and MeOH (1:
1), and the white solid was filtered off. The filtrate was concentrated
and purified with 3-5% MeOH in CH2Cl2 by silica gel column
chromatography to give the products 7 (1.08 g, 9.0 mmol, 70%):
1
[R]24 166.2° (c 0.63, MeOH); H NMR (CDCl3) δ 5.00 (quin., J
D
) 8.1 Hz, 1H), 4.09-3.98 (m, 2H), 3.85 (d, J ) 8.9 Hz, 1H), 3.76-
3.71 (m, 1H), 3.37-3.24 (m, 3H). Anal. (C4H8O2S‚0.35H2O) C,
H, S.
the product 11 (1.58 g, 4.24 mmol, 47% yield): [R]24 40.7° (c
D
1
0.81, CH2Cl2); H NMR (CDCl3) δ 7.70-7.36 (m, 10H), 3.82-
3.58 (m, 5H), 3.22-3.10 (m, 1H), 3.01-2.93 (m, 2H), 1.06 (s,
9H). Anal. (C21H28O2SSi) C, H, S.
(2R,3S)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-thietan-3-
ol (8). A solution of compound 7 (5.00 g, 41.6 mmol), triethylamine
(11.6 mL, 83.2 mmol), and 2,4,6-collidine (0.46 mL, 4.2 mmol) in
CH2Cl2 was treated with TBDPSCl (11.45 mL, 43.7 mmol) at 0
°C for 2 h. The resulting mixture was concentrated and purified
with 5% EtOAc in hexanes by silica gel column chromatography
(2R,3S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-thie-
tane (12). A solution of compound 11 (2.00 g, 5.37 mmol) and
imidazole (0.77 g, 11 mmol) in CH2Cl2 was treated with TBDPSCl
(1.54 mL, 5.92 mmol) at room temperature for 3 h. The reaction
mixture was concentrated and purified with 2% EtOAc in hexanes
to give the product 8 (11.9 g, 33.2 mmol, 82%) as an oil: [R]20
D
1
74.1° (c 0.91, CHCl3); H NMR (CDCl3) δ 7.84-7.38 (m, 10H),
5.06 (quin., J ) 8.1 Hz, 1H), 4.19-4.10 (m, 2H), 3.88 (d, J ) 9.7
Hz, 1H), 3.73-3.67 (m, 1H), 3.54 (t, J ) 8.3 Hz, 1H), 3.33 (t, J
) 8.3 Hz, 1H), 1.12 (s, 9H). Anal. (C20H26O2SSi) C, H, S.
tert-Butyl-[(2S)-3-methylene-thietan-2-ylmethoxy]-diphenyl-
silane (9). Compound 8 (10.9 g, 30.4 mmol) was treated with
DMSO (45 mL) and Ac2O (30 mL) at room temperature overnight.
The reaction mixture was quenched with ice, diluted with Et2O
(500 mL), and washed with water. The organic layer was dried
over anhydrous Na2SO4 and concentrated. The residue was purified
with 3% EtOAc in hexanes by silica gel column chromatography
to give the intermediate ketone (10.0 g, 28.1 mmol, 92%) as an
oil.
to give the product 12 (2.95 g, 4.83 mmol, 90%) as an oil: [R]22
D
45.0° (c 0.38, CH2Cl2); 1H NMR (CDCl3) δ 7.70-7.33 (m, 20H),
3.90 (dd, J ) 9.7, 6.1 Hz, 1H), 3.77 (dd, J ) 10.2, 6.6 Hz, 1H),
3.73-3.65 (m, 3H), 3.16-2.95 (m, 3H), 1.05 (s, 9H), 1.04 (s, 9H).
Anal. (C37H46O2SSi2) C, H, S.
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-thymine (13). A solution of compound 12 (0.250 g,
0.409 mmol) in CH2Cl2 was treated with a solution of 77% mCPBA
(0.092 g, 0.411 mmol) in CH2Cl2 dropwise at -78 °C. The mixture
was stirred at -78 °C for 30 min. The reaction was quenched with
aqueous Na2S2O3, diluted with CH2Cl2, washed with aqueous
Na2S2O3, aqueous NaHCO3, and brine, and dried over MgSO4. The

1642 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Choo et al.
1
filtrate was concentrated to dryness. The crude sulfoxide was used
for the next reaction without further purification. A mixture of
thymine (0.155 g, 1.23 mmol) in acetonitrile (10 mL) and HMDS
(10 mL) was refluxed for 3 h until the solution became clear. After
evaporation, the residue was treated successively with a solution
of the crude sulfoxide in toluene (10 mL), triethylamine (0.11 mL,
0.79 mmol), TMSOTf (0.16 mL, 0.88 mmol), and ZnI2 (0.039 g,
0.12 mmol) at 0 °C. After 24 h, the reaction was quenched with
water at 0 °C, and the reaction mixture was diluted with CH2Cl2.
The organic layer was dried over NaSO4, filtered, concentrated,
and purified with 30% EtOAc in hexane by preparative TLC to
give the product 13 (0.138 g, 0.188 mmol, 46%) as an R/â mixture
(1:3): UV (CH2Cl2) λmax 270.0 nm; 1H NMR (CDCl3) δ 9.03, 8.99
(2br s, 1H), 7.98, 7.80 (2s, 1H), 7.72-7.30 (m, 20H), 6.30 (d, J )
6.8 Hz, 0.75H), 6.20 (d, J ) 7.7 Hz, 0.25H), 3.88 (dd, J ) 9.8, 5.9
Hz, 0.25H), 3.81-3.45 (m, 5H), 3.26-3.19 (m, 0.75H), 1.87, 1.83
(2s, 3H), 1.07, 1.044, 1.036, 0.98 (4s, 18H). Anal. (C42H50N2O4-
SSi2) C, H, N, S.
Cl2) λmax 278.0 nm; H NMR (CDCl3) δ 8.58, 8.53 (2br s, 1H),
8.19 (d, J ) 7.8 Hz, 0.3H), 8.16 (d, J ) 7.8 Hz, 0.7H), 7.70-7.33
(m, 20H), 6.24 (d, J ) 6.8 Hz, 0.7H), 6.20 (d, J ) 7.8 Hz, 0.3H),
5.69 (d, J ) 8.8 Hz, 0.3H), 5.60 (d, J ) 7.8 Hz, 0.7H), 3.85 (dd,
J ) 10.7, 5.8 Hz, 0.3H), 3.77-3.46 (m, 5H), 3.26-3.20 (m, 0.7H),
1.07, 1.05, 1.03, 0.98 (4s, 18H); HRMS (ESI, Mona+) calcd for
C41H47BrN2O4SSi2Na 821.1876, found 821.1867.
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-5-fluorocytosine (19). See the procedure for com-
pound 14 for the amination reaction with the uridine analogue. The
title compound 19 was obtained on a 0.284-mmol scale in 73%
1
yield: UV (CH2Cl2) λmax 285 nm; H NMR (CDCl3) δ 8.31 (d, J
) 7.8 Hz, 0.3H), 8.25 (d, J ) 7.8 Hz, 0.7H), 7.69-7.28 (m, 20H),
6.26 (d, J ) 6.8 Hz, 0.7H), 6.24 (d, J ) 7.8 Hz, 0.3H), 5.62 (d, J
) 6.8 Hz, 0.3H), 5.58 (d, J ) 6.8 Hz, 0.7H), 3.92 (dd, J ) 10.7,
5.8 Hz, 0.3H), 3.83-3.46 (m, 5H), 3.18-3.11 (m, 0.7H), 1.07, 1.03,
1.00 (3s, 18H); HRMS (ESI, M + Na+) calcd for C41H48FN3O3-
SSi2Na 760.2837, found 760.2845.
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-uracil (14). See the procedure for compound 13 for
the condensation reaction with thymine. The title compound 14
was obtained on a 0.301-mmol scale in 40% yield: UV (CH2Cl2)
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-5-chlorocytosine (20). See the procedure for com-
pound 14 for the amination reaction with the uridine analogue. The
title compound 20 was obtained on a 0.318-mmol scale in 68%
max 265.0 nm; 1H NMR (CDCl3) δ 8.58, 8.53 (2br s, 1H), 8.19 (d,
1
λ
yield: UV (CH2Cl2) λmax 277 nm; H NMR (CDCl3) δ 8.31 (d, J
J ) 7.8 Hz, 0.3H), 8.16 (d, J ) 7.8 Hz, 0.7H), 7.70-7.33 (m,
20H), 6.24 (d, J ) 6.8 Hz, 0.7H), 6.20 (d, J ) 7.8 Hz, 0.3H), 5.69
(d, J ) 8.8 Hz, 0.3H), 5.60 (d, J ) 7.8 Hz, 0.7H), 3.85 (dd, J )
10.7, 5.8 Hz, 0.3H), 3.77-3.46 (m, 5H), 3.26-3.20 (m, 0.7H), 1.07,
1.05, 1.03, 0.98 (4s, 18H). Anal. (C41H48N2O4SSi2) C, H, N, S.
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-cytosine (15). A solution of compound 14 (0.120 g,
0.166 mmol) in acetonitrile was treated with triethylamine (0.07
mL, 0.50 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (0.151
g, 0.499 mmol), and DMAP (0.061 g, 0.50 mmol) at room
temperature. After 16 h, ammonia water was added to the resulting
mixture. After 3 h, the mixture was diluted with CH2Cl2 (50 mL),
and the organic layer was washed with brine, dried over Na2SO4,
concentrated, and purified by column chromatography with 5%
MeOH in CH2Cl2 to give an R/â mixture of compound 15 (0.090
g, 0.125 mmol, 75% yield): UV (CH2Cl2) λmax 285.5 nm; 1H NMR
(CDCl3) δ 8.31 (d, J ) 7.8 Hz, 0.3H), 8.25 (d, J ) 7.8 Hz, 0.7H),
7.69-7.28 (m, 20H), 6.26 (d, J ) 6.8 Hz, 0.7H), 6.24 (d, J ) 7.8
Hz, 0.3H), 5.62 (d, J ) 6.8 Hz, 0.3H), 5.58 (d, J ) 6.8 Hz, 0.7H),
3.92 (dd, J ) 10.7, 5.8 Hz, 0.3H), 3.83-3.46 (m, 5H), 3.18-3.11
(m, 0.7H), 1.07, 1.03, 1.00 (3s, 18H). Anal. (C41H49N3O3SSi2) C,
H, N, S.
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-5-fluorouracil (16). See the procedure for compound
13 for the condensation reaction with thymine. The title compound
16 was obtained on a 0.389-mmol scale in 37% yield: UV (CH2-
Cl2) λmax 271 nm; 1H NMR (CDCl3) δ 8.58, 8.53 (2br s, 1H), 8.19
(d, J ) 7.8 Hz, 0.3H), 8.16 (d, J ) 7.8 Hz, 0.7H), 7.70-7.33 (m,
20H), 6.24 (d, J ) 6.8 Hz, 0.7H), 6.20 (d, J ) 7.8 Hz, 0.3H), 5.69
(d, J ) 8.8 Hz, 0.3H), 5.60 (d, J ) 7.8 Hz, 0.7H), 3.85 (dd, J )
10.7, 5.8 Hz, 0.3H), 3.77-3.46 (m, 5H), 3.26-3.20 (m, 0.7H), 1.07,
1.05, 1.03, 0.98 (4s, 18H); HRMS (ESI, M + Na+) calcd for C41H47-
FN2O4SSi2Na 761.2677, found 761.2671.
) 7.8 Hz, 0.3H), 8.25 (d, J ) 7.8 Hz, 0.7H), 7.69-7.28 (m, 20H),
6.26 (d, J ) 6.8 Hz, 0.7H), 6.24 (d, J ) 7.8 Hz, 0.3H), 5.62 (d, J
) 6.8 Hz, 0.3H), 5.58 (d, J ) 6.8 Hz, 0.7H), 3.92 (dd, J ) 10.7,
5.8 Hz, 0.3H), 3.83-3.46 (m, 5H), 3.18-3.11 (m, 0.7H), 1.07, 1.03,
1.00 (3s, 18H); HRMS (ESI, M + Na+) calcd for C41H48FN3O3-
SSi2Na 776.2541, found 776.2533.
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-5-bromocytosine (21). See the procedure for com-
pound 14 for the amination reaction with the uridine analogue. The
title compound 21 was obtained on a 0.338-mmol scale in 63%
1
yield: UV (CH2Cl2) λmax 292 nm; H NMR (CDCl3) δ 8.31 (d, J
) 7.8 Hz, 0.3H), 8.25 (d, J ) 7.8 Hz, 0.7H), 7.69-7.28 (m, 20H),
6.26 (d, J ) 6.8 Hz, 0.7H), 6.24 (d, J ) 7.8 Hz, 0.3H), 5.62 (d, J
) 6.8 Hz, 0.3H), 5.58 (d, J ) 6.8 Hz, 0.7H), 3.92 (dd, J ) 10.7,
5.8 Hz, 0.3H), 3.83-3.46 (m, 5H), 3.18-3.11 (m, 0.7H), 1.07, 1.03,
1.00 (3s, 18H); HRMS (ESI, M + Na+) calcd for C41H48BrN3O3-
SSi2Na 820.2036, found 820.2027.
1-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-thymine (22).
A solution of compound 13 (0.130 g, 0.177 mmol) in THF (10
mL) was treated with 0.35 mL of 1 M TBAF solution in acetonitrile
at 0 °C. After 3 h, the reaction mixture was concentrated and
purified by preparative TLC with 7% MeOH in CH2Cl2 to give
compound 22 (0.029 g, 0,112 mmol, 63% yield) and the R-isomer
(0.011 g, 0.043 mmol, 24% yield): mp > 200 °C (dec); [R]26
D
-86.8 ° (c 0.075, DMSO); UV (H2O) λmax 264.0 nm (ꢀ 9400, pH
2), 262.0 nm (ꢀ 9900, pH 7), 265.5 nm (ꢀ 7100, pH 11); 1H NMR
(MeOH) δ 8.30 (s, 1H), 6.08 (d, J ) 6.8 Hz, 1H), 3.76 (dd, J )
11.7, 3.9 Hz, 1H), 3.72 (dd, J ) 11.7, 4.9 Hz, 1H), 3.58 (d, J )
3.9 Hz, 2H), 3.54-3.49 (m, 1H), 3.32-3.26 (m, 1H), 1.95 (s, 3H).
Anal. (C10H14N2O4S) C, H, N, S.
1-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-uracil (23).
See the procedure for compound 22 for the deprotection reaction
with 1 M TBAF solution. The title compound 23 was obtained on
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-5-chlorouracil (17). See the procedure for compound
13 for the condensation reaction with thymine. The title compound
17 was obtained on a 0.291-mmol scale in 32% yield: UV (CH2-
a 0.083-mmol scale in 59% yield: mp > 200 °C (dec); [R]22
D
-35.4° (c 0.17, MeOH); UV (H2O) λmax 265.5 nm (ꢀ 9200, pH 2),
1
265.5 nm (ꢀ 8500, pH 7), 265.5 nm (ꢀ 6900, pH 11); H NMR
(MeOH) δ 8.46 (d, J ) 7.8 Hz, 1H), 6.07 (d, J ) 6.8 Hz, 1H),
5.81 (d, J ) 7.8 Hz, 1H), 3.76 (dd, J ) Hz, 1H), 3.71 (dd, J ) Hz,
1H), 3.60 (d, J ) Hz, 2H), 3.54-3.49 (m, 1H), 3.28-3.21 (m,
1H). Anal. (C9H12N2O4S) C, H, N, S.
1-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-cytosine (24).
See the procedure for compound 22 for the deprotection reaction
with 1 M TBAF solution. The title compound 24 was obtained on
a 0.118-mmol scale in 59% yield: mp 125-126 °C; [R]23D -59.2°
(c 0.14, MeOH); UV (H2O) λmax 282.5 nm (ꢀ 12 500, pH 2), 274.5
nm (ꢀ 9700, pH 7), 275.5 nm (ꢀ 9600, pH 11); 1H NMR (MeOH)
δ 8.43 (d, J ) 6.8 Hz, 1H), 6.04 (s, J ) 6.8 Hz, 1H), 6.00 (d, J )
7.8 Hz, 1H), 3.75 (dd, J ) 11.7, 4.9 Hz, 1H), 3.69 (dd, J ) 11.7,
1
Cl2) λmax 273.0 nm; H NMR (CDCl3) δ 8.58, 8.53 (2br s, 1H),
8.19 (d, J ) 7.8 Hz, 0.3H), 8.16 (d, J ) 7.8 Hz, 0.7H), 7.70-7.33
(m, 20H), 6.24 (d, J ) 6.8 Hz, 0.7H), 6.20 (d, J ) 7.8 Hz, 0.3H),
5.69 (d, J ) 8.8 Hz, 0.3H), 5.60 (d, J ) 7.8 Hz, 0.7H), 3.85 (dd,
J ) 10.7, 5.8 Hz, 0.3H), 3.77-3.46 (m, 5H), 3.26-3.20 (m, 0.7H),
1.07, 1.05, 1.03, 0.98 (4s, 18H); HRMS (ESI, M + Na+) calcd for
C41H47ClN2O4SSi2Na 777.2382, found 777.2378.
1-[(2R,3S,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-5-bromouracil (18). See the procedure for compound
13 for the condensation reaction with thymine. The title compound
18 was obtained on a 0.375-mmol scale in 28% yield: UV (CH2-

D- and L-Thietanose Nucleosides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1643
5.6 Hz, 1H), 3.66-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.14 (quin.,
J ) 6.8 Hz, 1H). Anal. (C9H12N2O4S) C, H, N, S.
85% yield): [R]24D 27.9° (c 0.21, CH2Cl2); UV (CH2Cl2) λmax 262.5
nm; 1H NMR (CDCl3) δ 8.45 (s, 1H), 7.72 (s, 1H), 7.68-7.12 (m,
20H), 6.56 (d, J ) 5.9 Hz, 1H), 3.89 (dd J ) 10.7, 5.9 Hz, 1H),
3.85-3.68 (m, 4H), 3.39-3.32 (m, 1H), 1.05 (s, 9H), 1.01 (s, 9H).
Anal. (C42H48N4O3SSi2) C, H, N, S.
1-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-5-fluorocy-
tosine (25). See the procedure for compound 22 for the deprotection
reaction with 1 M TBAF solution. The title compound 25 was
obtained on a 0.109-mmol scale in 51% yield: mp 125-126 °C;
9-[(2R,3S,4R)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-guanine (32). A solution of compound 29 (0.138 g,
0.177 mmol), 2-mercaptoethanol (0.049 mL, 0.70 mmol), and
NaOMe (0.019 g, 0.35 mmol) in MeOH was refluxed for 4 h. The
mixture was cooled to room temperature, neutralized with AcOH,
concentrated, and filtered through a silica gel pad. The filtrate was
concentrated to dryness. The residue was treated with ethanolic
ammonia at 60 °C for 6 h. The reaction mixture was concentrated
and purified by column chromatography with 2% MeOH in CH2-
[R]26 -53.3 ° (c 0.30, MeOH); UV (H2O) λmax 272 nm (ꢀ 9226,
D
1
pH 2), 288 nm (ꢀ 14 146, pH 7), 278 nm (ꢀ 12 588, pH 11); H
NMR (MeOH) δ 8.65 (d, J ) 6.8 Hz, 1H), 6.04 (dd, J ) 6.6, 2.2
Hz, 1H), 3.76 (dd, J ) 9.0, 4.4 Hz, 2H), 3.67 (dd, J ) 5.6, 3.9 Hz,
2H), 3.55-3.51 (m, 1H), 3.24-3.20 (m, 1H). Anal. (C9H12N2O4S)
C, H, N, S.
1-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-5-chlorocy-
tosine (26). See the procedure for compound 22 for the deprotection
reaction with 1 M TBAF solution. The title compound 26 was
obtained on a 0.112-mmol scale in 46% yield: mp 125-126 °C;
Cl2 to give the product 32 (0.115 g, 0.151 mmol, 74% yield): [R]24
D
1
17.8 ° (c 0.12, CHCl3); UV (CH2Cl2) λmax 264.0 nm; H NMR
[R]25 -43.4° (c 0.22, MeOH); UV (H2O) λmax 297 nm (ꢀ 5486,
(CDCl3) δ 8.36 (s, 1H), 7.75-7.24 (m, 20H), 6.36 (d, J ) 6.8 Hz,
1H), 3.95-3.63 (m, 5H), 3.37-3.30 (m, 1H), 1.04 (s, 9H), 0.99
(s, 9H). Anal. (C42H49N5O3SSi2) C, H, N, S.
D
pH 2), 291 nm (ꢀ 4567, pH 7), 291 nm (ꢀ 6903, pH 11); 1H NMR
(MeOH) δ 8.61 (s, 1H), 5.87 (d, J ) 6.3 Hz, 1H), 3.62 (dd, J )
8.5, 4.1 Hz, 2H), 3.55 (dd, J ) 5.6, 2.9 Hz, 1H), 3.42-3.38 (m,
1H), 3.13-3.07 (m, 1H). Anal. (C9H12N2O4S) C, H, N, S.
1-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-5-bromocy-
tosine (27). See the procedure for compound 22 for the deprotection
reaction with 1 M TBAF solution. The title compound 27 was
obtained on a 0.105-mmol scale in 37% yield: mp 125-126 °C;
9-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-adenine (33).
See the procedure for compound 22 for the deprotection reaction
with 1 M TBAF solution. The title compound 33 was obtained on
a 0.188-mmol scale in 94% yield: mp > 200 °C; [R]25 95.2° (c
D
0.057, MeOH); UV (H2O) λmax 272.5 nm (ꢀ 15 000, pH 2), 270.5
nm (ꢀ 10 000, pH 7), 271.5 nm (ꢀ 10 000, pH 11); 1H NMR
(MeOH) δ 8.84 (s, 1H), 8.24 (s, 1H), 6.17 (d, J ) 6.6 Hz, 1H),
3.80 (d, J ) 4.6 Hz, 2H), 3.73 (dd, J ) 11.7, 6.6 Hz, 1H), 3.69
(dd, J ) 11.7, 5.1 Hz, 1H), 3.62-3.56 (m, 1H), 3.55-3.48 (m,
1H). Anal. (C10H13N5O2S) C, H, N, S.
[R]23 -25.3 ° (c 0.14, MeOH); UV (H2O) λmax 302 nm (ꢀ 8311,
D
pH 2), 293 nm (ꢀ 6585, pH 7), 293 nm (ꢀ 7005, pH 11); 1H NMR
(MeOH) δ 8.83 (s, 1H), 6.00 (s, J ) 6.4 Hz, 1H), 3.74 (dd, J )
8.1, 4.1 Hz, 2H), 3.68 (dd, J ) 5.6, 3.2 Hz, 2H), 3.56-3.52 (m,
1H), 3.33-3.28 (m, 1H). Anal. (C9H12N2O4S) C, H, N, S.
9-[(2R,3S,4R)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-6-chloropurine (28). See the procedure for compound
13 for the condensation reaction with thymine. The title compound
28 as well as the R-isomer were obtained on a 0.622-mmol scale
9-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-hypoxan-
thine (34). See the procedure for compound 22 for the deprotection
reaction with 1 M TBAF solution. The title compound 34 was
obtained on a 0.150-mmol scale in 89% yield: mp 213-214 °C;
[R]26 22.0° (c 0.13, MeOH); UV (H2O) λmax 256.5 nm (ꢀ 7600,
D
1
pH 2), 258.0 nm (ꢀ 7200, pH 7), 263.0 nm (ꢀ 7600, pH 11); H
in 45% yield as a 5:4 mixture of compound 28 and the R-isomer:
1
[R]23 16.8 ° (c 0.65, CHCl3); UV (CH2Cl2) λmax 264.5 nm; H
NMR (MeOH-d4) δ 8.91 (s, 1H), 8.02 (s, 1H), 6.36 (d, J ) 5.9
Hz, 1H), 3.83 (dd, J ) 11.7, 4.9 Hz, 1H), 3.78 (dd, J ) 11.7, 4.9
Hz, 1H), 3.77-3.70 (m, 2H), 3.60 (q, J ) 4.9 Hz, 1H), 3.48 (quin.,
J ) 5.9 Hz, 1H). Anal. (C10H12N4O3S) C, H, N, S.
D
NMR (CDCl3) δ 8.87 (s, 1H), 8.86 (s, 1H), 7.66-7.27 (m, 20H),
6.56 (d, J ) 7.1 Hz, 1H), 3.82-3.62 (m, 5H), 3.39-3.31 (m, 1H),
1.06 (s, 9H), 1.02 (s, 9H). Anal. (C42H47ClN4O2SSi2) C, H, N, S.
9-[(2R,3S,4R)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-6-chloro2-fluoropurine (29). See the procedure for
compound 13 for the condensation reaction with thymine. The title
compound 29 as well as the R-isomer were obtained on a 0.797-
mmol scale in 40% yield as a 5:4 mixture of compound 29 and the
9-[(2R,3S,4R)-2,3-Dihydroxymethyl-thietan-4-yl]-guanine (35).
See the procedure for compound 22 for the deprotection reaction
with 1 M TBAF solution. The title compound 35 was obtained on
a 0.132-mmol scale in 91% yield: mp > 200 °C (dec); [R]23
D
-73.7° (c 0.11, DMSO); UV (H2O) λmax 251.5 nm (ꢀ 7300, pH 2),
1
R-isomer: [R]24 9.3 ° (c 0.21, CHCl3); UV (CH2Cl2) λmax 254.5
266.0 nm (ꢀ 6900, pH 7), 266.0 nm (ꢀ 7100, pH 11); H NMR
D
1
(DMSO-d6) δ 13.48 (br s, 1H), 8.79 (s, 1H), 6.23 (d, J ) 6.8 Hz,
1H), 5.07 (t, J ) 4.9 Hz, 1H), 4.99 (br s, 1H), 3.79-3.46 (m, 5H),
3.30-2.26 (m, 1H). Anal. (C10H13N5O3S) C, H, N, S.
nm; H NMR (CDCl3) δ 8.85 (s, 1H), 7.64-7.24 (m, 20H), 6.47
(d, J ) 6.8 Hz, 1H), 3.83-3.65 (m, 5H), 3.36-3.28 (m, 1H), 1.06
(s, 9H), 1.03 (s, 9H). Anal. (C42H46ClFN4O2SSi2) C, H, N, S.
9-[(2R,3S,4R)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-adenine (30). A solution of compound 28 (0.202 g,
0.265 mmol) in DMF (2 mL) was treated with NaN3 (0.172 g, 2.65
mol) at room temperature for 16 h. The resulting mixture was
directly filtered through a silica gel pad using as eluent a 1:1 mixture
of hexanes and EtOAc. The filtrate was concentrated to dryness.
A solution of the crude azide in MeOH (15 mL) was treated with
0.030 g of Pd(0)/C and H2 balloon for 48 h. The resulting mixture
was filtered through a Celite pad, and the filtrate was concentrated
and purified by column chromatography with 2% MeOH in CH2-
(-)-[2R,3R,4S,5S]-Methanesulfonic Acid 5-Methanesulfon-
yloxymethyl-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yl
Ester (37). Using the same procedure described for the preparation
of compound 3, the title compound was prepared on a 81.6-mmol
scale in 90% yield as a white solid: mp 115-116 °C; [R]22D -80.2°
1
(c 0.57, CHCl3); H NMR (CDCl3) δ 5.84 (d, J ) 3.4 Hz, 1H),
4.82-4.74 (m, 2H), 4.55 (dd, J ) 11.8, 1.9 Hz, 1H), 4.41-4.30
(m, 2H), 3.16 (s, 3H), 3.08 (s, 3H), 1.58 (s, 3H), 1.38 (s, 3H).
Anal. (C10H18O9S2) C, H.
(-)-[2R,3R,4S,5S]-Thioacetic acid S-(6-methanesulfonyloxy-
2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-ylmethyl) ester
(38) was prepared from compound 37 on a 14.0-mmol scale in
Cl2 to give the product 30 (0.143 g, 0.192 mmol, 72% yield): [R]23
D
1
41.5° (c 0.17, CH2Cl2); UV (CH2Cl2) λmax 272.0 nm; H NMR
(CDCl3) δ 8.44 (s, 1H), 7.85 (s, 1H), 7.66-7.30 (m, 20H), 6.06
(br s, 2H), 6.03 (d, J ) 8.6 Hz, 1H), 3.91-3.83 (m, 2H), 3.74-
3.54 (m, 3H), 3.43-3.34 (m, 1H), 1.09 (s, 9H), 1.05 (s, 9H). Anal.
(C42H49N5O2SSi2) C, H, N, S.
9-[(2R,3S,4R)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-hypoxanthine (31). A solution of compound 28
(0.134 g, 0.176 mmol), 2-mercaptoethanol (0.049 mL, 0.70 mmol),
and NaOMe (0.038 g, 0.70 mmol) in MeOH was refluxed for 6 h.
The mixture was cooled to room temperature, neutralized with
AcOH, concentrated, and purified by column chromatography with
2% MeOH in CH2Cl2 to give the product 31 (0.112 g, 0.150 mmol,
80% yield as a brownish solid by the same procedure described
1
for 4: mp 112-113 °C; [R]23 -70.0° (c 0.53, CHCl3); H NMR
D
(CDCl3) δ 5.77 (d, J ) 3.7 Hz, 1H), 4.75 (t, J ) 4.2 Hz, 1H), 4.48
(dd, J ) 8.8, 4.6 Hz, 1H), 4.31-4.25 (m, 1H), 3.35 (dd, J ) 14.5,
4.1 Hz, 1H), 3.23 (J ) 14.5, 5.1 Hz, 1H), 3.16 (s, 3H), 2.36 (s,
3H), 1.55 (s, 3H), 1.34 (s, 3H). Anal. (C11H18O7S2) C, H, S.
(-)-4,4-Dimethyl-tetrahydro-3,5,6-trioxa-2-thia-cyclobuta[a]-
pentalene (39) was prepared from compound 38 on a 30.85-mmol
scale in 95% yield as a yellowish oil by the same procedure
described for 5: [R]23D -89.4° (c 1.76, CH2Cl2); 1H NMR (CDCl3)
δ 6.41 (d, J ) 3.4 Hz, 1H), 5.26 (t, J ) 5.3 Hz, 1H), 4.71 (d, J )

1644 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
Choo et al.
3.4 Hz, 1H), 4.08 (d, J ) 5.3 Hz, 1H), 3.49 (dd, J ) 10.6, 5.4 Hz,
1H), 2.84 (d, J ) 10.6 Hz, 1H), 1.43 (s, 3H), 1.36 (s, 3H). Anal.
(C8H12O3S) C, H, S.
200 °C (dec); [R]26D 82.8° (c 0.13, DMSO); UV (H2O) λmax 264.0
nm (ꢀ 9400, pH 2), 262.0 nm (ꢀ 9900, pH 7), 265.5 nm (ꢀ 7100,
pH 11); H NMR (MeOH) δ 8.30 (s, 1H), 6.08 (d, J ) 6.8 Hz,
1
1H), 3.76 (dd, J ) 11.7, 3.9 Hz, 1H), 3.72 (dd, J ) 11.7, 4.9 Hz,
1H), 3.58 (d, J ) 3.9 Hz, 2H), 3.54-3.49 (m, 1H), 3.32-3.26 (m,
1H), 1.95 (s, 3H). Anal. (C10H14N2O4S) C, H, N, S.
(-)-2-Oxa-6-thia-bicyclo[3.2.0]heptane-3,4-diol (40) was pre-
pared from compound 39 on a 27.77-mmol scale in 90% yield as
a yellowish oil (anomeric mixture) by the same procedure described
for 6.
1-[(2S,3R,4S)-2,3-Dihydroxymethyl-thietan-4-yl]-uracil (51)
was prepared from compound 48 on a 0.043-mmol scale in 59%
yield as a white solid by the same procedure described for 23: mp
> 200 °C (dec); [R]24D 33.2° (c 0.23, MeOH); UV (H2O) λmax 265.5
nm (ꢀ 9200, pH 2), 265.5 nm (ꢀ 8500, pH 7), 265.5 nm (ꢀ 6900,
(-)-[2R,3S]-2-Hydroxymethyl-thietan-3-ol (41) was prepared
from compound 40 on a 10.11-mmol scale in 70% yield as a
yellowish oil by the same procedure described for 7: [R]24D -173.5°
(c 0.84, MeOH); 1H NMR (CDCl3) δ 5.00 (quin., J ) 8.1 Hz, 1H),
4.09-3.98 (m, 2H), 3.85 (d, J ) 8.9 Hz, 1H), 3.76-3.71 (m, 1H),
3.37-3.24 (m, 3H). Anal. (C4H8O2S‚0.35H2O) C, H, S.
(-)-[2R,3R]-2-(tert-Butyl-diphenyl-silanyloxymethyl)-thietan-
3-ol (42) was prepared from compound 41 on a 17.10-mmol scale
in 85% yield as a yellowish oil by the same procedure described
for 8: [R]22D -78.6° (c 0.68, CHCl3); 1H NMR (CDCl3) δ 7.84-
7.38 (m, 10H), 5.06 (quin., J ) 8.1 Hz, 1H), 4.19-4.10 (m, 2H),
3.88 (d, J ) 9.7 Hz, 1H), 3.73-3.67 (m, 1H), 3.54 (t, J ) 8.3 Hz,
1H), 3.33 (t, J ) 8.3 Hz, 1H), 1.12 (s, 9H). Anal. (C20H26O2SSi)
C, H, S.
1
pH 11); H NMR (MeOH) δ 8.46 (d, J ) 7.8 Hz, 1H), 6.07 (d, J
) 6.8 Hz, 1H), 5.81 (d, J ) 7.8 Hz, 1H), 3.76 (dd, J ) Hz, 1H),
3.71 (dd, J ) Hz, 1H), 3.60 (d, J ) Hz, 2H), 3.54-3.49 (m, 1H),
3.28-3.21 (m, 1H). Anal. (C9H12N2O4S) C, H, N, S.
1-[(2S,3R,4S)-2,3-dihydroxymethyl-thietan-4-yl]-cytosine (52)
was prepared from compound 49 on a 0.043-mmol scale in 56%
yield as a white solid by the same procedure described for 24: mp
126-127 °C; [R]25D 61.7° (c 0.11, MeOH); UV (H2O) λmax 282.5
nm (ꢀ 12 500, pH 2), 274.5 nm (ꢀ 9700, pH 7), 275.5 nm (ꢀ 9600,
1
pH 11); H NMR (MeOH) δ 8.43 (d, J ) 6.8 Hz, 1H), 6.04 (s, J
) 6.8 Hz, 1H), 6.00 (d, J ) 7.8 Hz, 1H), 3.75 (dd, J ) 11.7, 4.9
Hz, 1H), 3.69 (dd, J ) 11.7, 5.6 Hz, 1H), 3.66-3.58 (m, 1H),
3.51-3.47 (m, 1H), 3.14 (quin., J ) 6.8 Hz, 1H). Anal. (C9H12N2O4S)
C, H, N, S.
(-)-[2R]-tert-Butyl-(3-methylene-thietan-2-ylmethoxy)-diphenyl-
silane (43) was prepared from compound 42 on a 5.32-mmol scale
in 40% yield as a yellowish oil by the same procedure described
for 9: [R]23D -71.8° (c 1.60, CH2Cl2); 1H NMR (CDCl3) δ 7.72-
7.65 (m, 4H), 7.47-7.37 (m, 6H), 4.86 (d, J ) 2.1 Hz, 1H), 4.71
(d, J ) 2.1 Hz, 1H), 4.44-4.37 (m, 1H), 4.00 (dd, J ) 10.3, 6.8
Hz, 1H), 3.87 (dd, J ) 10.3, 6.8 Hz, 1H), 3.84-3.74 (m, 2H),
1.06 (s, 9H). Anal. (C21H26OSSi) C, H, S.
(-)-[2R,3R]-[2-(tert-Butyl-diphenyl-silanyloxymethyl)-thietan-
3-yl]-methanol (44) was prepared from compound 43 on a 4.43-
mmol scale in 64% yield as a yellowish oil by the same procedure
described for 10: [R]22D -32.1° (c 0.82, CHCl3); 1H NMR (CDCl3)
δ 7.78-7.32 (m, 10H), 4.28 (t, J ) 10.1 Hz, 1H), 4.01 (t, J ) 9.9
Hz, 1H), 3.80-3.42 (m, 5H), 3.02-2.83 (m, 2H), 1.07 (s, 9H).
Anal. (C21H28O2SSi) C, H, S.
(-)-[2R,3S]-[2-(tert-Butyl-diphenyl-silanyloxymethyl)-thietan-
3-yl]-methanol (45) was prepared from compound 44 on a 2.27-
mmol scale in 45% yield as a yellowish oil by the same procedure
described for 11: [R]22D -39.5° (c 0.91, CH2Cl2); 1H NMR (CDCl3)
δ 7.70-7.36 (m, 10H), 3.82-3.58 (m, 5H), 3.22-3.10 (m, 1H),
3.01-2.93 (m, 2H), 1.06 (s, 9H). Anal. (C21H28O2SSi) C, H, S.
(-)-[2R,3S]-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-thie-
tane (46) was prepared from compound 45 on a 2.16-mmol scale
in 92% yield as a yellowish oil by the same procedure described
for 12: [R]24D -44.7° (c 0.43, CH2Cl2); 1H NMR (CDCl3) δ 7.70-
7.33 (m, 20H), 3.90 (dd, J ) 9.7, 6.1 Hz, 1H), 3.77 (dd, J ) 10.2,
6.6 Hz, 1H), 3.73-3.65 (m, 3H), 3.16-2.95 (m, 3H), 1.05 (s, 9H),
1.04 (s, 9H). Anal. (C37H46O2SSi2) C, H, S.
1-[(2S,3R,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-thymine (47) was prepared from the coupling of
sulfoxide, which was obtained from the oxidation of compound 46
with silylated thymine, on a 0.18-mmol scale in 44% yield (R/â
mixture, R:â ) 1:3 as determined by NMR) by the same procedure
described for 13: UV (CH2Cl2) λmax 270.0 nm. Anal. (C42H50N2O4-
SSi2) C, H, N, S.
9-[(2S,3R,4S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-6-chloropurine (53). Using the same condensation
procedure as for the preparation of compound 28, the title compound
53 was obtained on a 0.370-mmol scale in 40% yield, together with
its R anomer (R:â ) 4:5): [R]22 -16.8° (c 0.58, CHCl3); UV
D
(CH2Cl2) λmax 264.5 nm; 1H NMR (CDCl3) δ 8.87 (s, 1H), 8.86 (s,
1H), 7.66-7.27 (m, 20H), 6.56 (d, J ) 7.1 Hz, 1H), 3.82-3.62
(m, 5H), 3.39-3.31 (m, 1H), 1.06 (s, 9H), 1.02 (s, 9H). Anal.
(C42H47ClN4O2SSi2) C, H, N, S.
9-[(2S,3R,4S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-6-chloro2-fluoropurine (54). Using the same con-
densation procedure as for compound 29, the title compound 54
was obtained on a 0.797-mmol scale in 23% yield, together with
its R anomer (R:â ) 4:5): [R]24 -10.1° (c 0.54, CHCl3); UV
D
1
(CH2Cl2) λmax 254 nm; H NMR (CDCl3) δ 8.85 (s, 1H), 7.64-
7.24 (m, 20H), 6.47 (d, J ) 6.8 Hz, 1H), 3.83-3.65 (m, 5H), 3.36-
3.28 (m, 1H), 1.06 (s, 9H), 1.03 (s, 9H). Anal. (C42H46ClFN4O2SSi2)
C, H, N, S.
9-[(2S,3R,4S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-adenine (55) was prepared from compound 53 on a
0.078-mmol scale in 74% yield as a white solid by the same
procedure described for 30: [R]23 -40.7° (c 0.15, CH2Cl2); UV
D
(CH2Cl2) λmax 272.0 nm; 1H NMR (CDCl3) δ 8.44 (s, 1H), 7.85 (s,
1H), 7.66-7.30 (m, 20H), 6.06 (br s, 2H), 6.03 (d, J ) 8.6 Hz,
1H),;3.91-3.83 (m, 2H), 3.74-3.54 (m, 3H), 3.43-3.34 (m, 1H),
1.09 (s, 9H), 1.05 (s, 9H). Anal. (C42H49N5O2SSi2) C, H, N, S.
9-[(2S,3R,4S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-hypoxanthine (56) was prepared from compound 53
on a 0.11-mmol scale in 84% yield as a white solid by the same
procedure described for 31: [R]24 26.9° (c 0.13, CH2Cl2); UV
D
(CH2Cl2) λmax 262.5 nm; 1H NMR (CDCl3) δ 8.45 (s, 1H), 7.72 (s,
1H), 7.68-7.12 (m, 20H), 6.56 (d, J ) 5.9 Hz, 1H), 3.89 (dd J )
10.7, 5.9 Hz, 1H), 3.85-3.68 (m, 4H), 3.39-3.32 (m, 1H), 1.05
(s, 9H), 1.01 (s, 9H). Anal. (C42H48N4O3SSi2) C, H, N, S.
1-[(2S,3R,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-uracil (48). Using a condensation procedure similar
to that for the preparation of compound 13, the title compound 48
was obtained on a 0.325-mmol scale in 40% yield as an R/â mixture
(R:â ) 1:2 as determined by NMR): UV (CH2Cl2) λmax 265.0 nm.
Anal. (C41H48N2O4SSi2) C, H, N, S.
1-[(2S,3R,4R/S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-cytosine (49). Using a condensation procedure similar
to that for the preparation of compound 15, the title compound 49
was obtained on a 0.16-mmol scale in 75% yield as an R/â
mixture: UV (CH2Cl2) λmax 285.5 nm. Anal. (C41H49N3O3SSi2) C,
H, N, S.
9-[(2S,3R,4S)-2,3-Bis(tert-butyl-diphenyl-silanyloxymethyl)-
thietan-4-yl]-guanine (57) was prepared from compound 54 on a
0.11-mmol scale in 84% yield as a white solid by the same
procedure described for 32: [R]22D 17.8° (c 0.29, CHCl3); UV (CH2-
1
Cl2) λmax 264.0 nm; H NMR (CDCl3) δ 8.36 (s, 1H), 7.75-7.24
(m, 20H), 6.36 (d, J ) 6.8 Hz, 1H), 3.95-3.63 (m, 5H), 3.37-
3.30 (m, 1H), 1.04 (s, 9H), 0.99 (s, 9H). Anal. (C42H49N5O3SSi2)
C, H, N, S.
9-[(2S,3R,4S)-2,3-Dihydroxymethyl-thietan-4-yl]-adenine (58).
Using the same procedure as for deprotection of compound 33,
the title compound 58 was obtained on a 0.094-mmol scale in 84%
1-[(2S,3R,4S)-2,3-Dihydroxymethyl-thietan-4-yl]-thymine (50)
was prepared from compound 47 on a 0.043-mmol scale in 63%
yield as white solid by the same procedure described for 22: mp >
yield: mp > 200 °C; [R]25 -93.3° (c 0.11, MeOH); UV (H2O)
D

D- and L-Thietanose Nucleosides
max 272.5 nm (ꢀ 15 000, pH 2), 270.5 nm (ꢀ 10 000, pH 7), 271.5
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1645
λ
Log phase Vero, CEM, and PHA-stimulated human PBM cells were
seeded at a density of 5 × 103, 2.5 × 103, and 5 × 104 cells/well,
respectively. All of the cells were plated in 96-well cell culture
plates containing 10-fold serial dilutions of the test drug. The
cultures were incubated for 3, 4, and 5 days for Vero, CEM, and
PBM cells, respectively, in humidified 5% CO2 air at 37 °C. At
the end of incubation, MTT tetrazolium dye solution (Cell titer 96,
Promega, Madison, WI) was added to each well and incubated
overnight. The reaction was stopped with stop-solubilization
solution (Promega, Madison, WI). The plates were incubated for 5
h to ensure that the formazan crystals were dissolved. The plates
were read at a wavelength of 570 nm using an ELISA plate reader
(Bio-tek instruments, Inc., Winooski, VT, model EL 312e). The
50% inhibition concentration (IC50) was determined from the
concentration-response curve using the median effect method.28
1
nm (ꢀ 10 000, pH 11); H NMR (MeOH) δ 8.84 (s, 1H), 8.24 (s,
1H), 6.17 (d, J ) 6.6 Hz, 1H), 3.80 (d, J ) 4.6 Hz, 2H), 3.73 (dd,
J ) 11.7, 6.6 Hz, 1H), 3.69 (dd, J ) 11.7, 5.1 Hz, 1H), 3.62-3.56
(m, 1H), 3.55-3.48 (m, 1H). Anal. (C10H13N5O2S) C, H, N, S.
9-[(2S,3R,4S)-2,3-Dihydroxymethyl-thietan-4-yl]-hypoxan-
thine (59). Using the same procedure as for the deprotection of
compound 33, the title compound 59 was obtained on a 0.145-
mmol scale in 86% yield: mp 213-214 °C; [R]27D -23.9° (c 0.15,
MeOH); UV (H2O) λmax 256.5 nm (ꢀ 7600, pH 2), 258.0 nm (ꢀ
1
7200, pH 7), 263.0 nm (ꢀ 7600, pH 11); H NMR (MeOH-d4) δ
8.91 (s, 1H), 8.02 (s, 1H), 6.36 (d, J ) 5.9 Hz, 1H), 3.83 (dd, J )
11.7, 4.9 Hz, 1H), 3.78 (dd, J ) 11.7, 4.9 Hz, 1H), 3.77-3.70 (m,
2H), 3.60 (q, J ) 4.9 Hz, 1H), 3.48 (quin., J ) 5.9 Hz, 1H). Anal.
(C10H12N4O3S) C, H, N, S.
9-[(2S,3R,4S)-2,3-Dihydroxymethyl-thietan-4-yl]-guanine (60).
Using the same procedure as for the deprotection of compound
25, the title compound 35 was obtained on a 0.124-mmol scale in
86% yield: mp > 200 °C (dec); [R]23D 70.7° (c 0.12, DMSO); UV
(H2O) λmax 251.5 nm (ꢀ 7300, pH 2), 266.0 nm (ꢀ 6900, pH 7),
Molecular Modeling Studies. (a) Conformational Analysis.
The initial conformations of D-cytidine analogue 24 and D-adenosine
analogue 33 were constructed and geometrically optimized through
a Monte Carlo conformational search using MMFF94s force field
in Macromodel, version 7.0 (Schro¨dinger, Inc.).
1
266.0 nm (ꢀ 7100, pH 11); H NMR (DMSO-d6) δ 13.48 (br s,
(b) Binding Affinity Study to HIV-1 Reverse Transcriptase.
All molecular modeling of the enzyme-substrate complexes was
carried out using Sybyl 6.7 (Tripos Associates, St. Louis, MO) on
a Silicon Graphics Octane2 workstation. The enzyme site of the
enzyme-ligand complex was constructed on the basis of the X-ray
structure of the covalently trapped catalytic complex of HIV-1 RT
with TTP and primer-template duplex (PDB code 1rtd). A model
of the NRTI binding site was constructed which consisted of
residues between Lys1 and Pro243 in the p66 subunit and a 7:4
(template-primer) duplex. The geometrically optimized structures
of each inhibitor, obtained from the geometry optimization study,
were used as the initial Cartesian coordinates. The heterocyclic
moiety of the (n + 1)-th nucleotide in template overhang was
modified to the base complementary to the incoming NRTIs. Thus,
the adenine moiety which was in the original X-ray structure (1rtd)
was modified to guanine. The inhibitor triphosphates were manually
docked to the active site of the enzyme by adjusting the torsional
angles to those found in the X-ray structure. Ga¨steiger-Hu¨ckel
charge was given to the enzyme-ligand complex with formal
charges (+2) to two Mg atoms in the active site. Then, Kollman
all-atom charges were loaded to the enzyme site from the biopoly-
mer module in Sybyl. To eliminate local strains resulting from
merging inhibitors and/or point mutations, residues less than 6 Å
from the merged inhibitors and mutated residues were annealed
until the energy change from one iteration to the next was less
than 0.05 kcal/mol. The annealed enzyme-inhibitor complexes
were minimized by using the Kollman all-atom force field until
the iteration number reached 5000.
1H), 8.79 (s, 1H), 6.23 (d, J ) 6.8 Hz, 1H), 5.07 (t, J ) 4.9 Hz,
1H), 4.99 (br s, 1H), 3.79-3.46 (m, 5H), 3.30-2.26 (m, 1H). Anal.
(C10H13N5O3S) C, H, N, S.
Antiviral Assay. Human PBM cells (obtained from Atlanta Red
Cross) were isolated by Ficoll-Hypaque discontinuous gradient
centrifugation from healthy seronegative donors. Cells were
stimulated with phytohemagglutinin A (Difco, Sparks, MD) for 2-3
days prior to use. HIV-1LAI, obtained from the Centers for Disease
Control and Prevention (Atlanta, GA), was used as the standard
reference virus for the antiviral assays. The molecular infectious
clones HIV-1xxBru were obtained from Dr. John Mellors (University
of Pittsburgh). Infections were done in bulk for 1 h, either with
100 TCID50/1 × 107 cells for a flask (T25) assay or with 200
TCID50/6 × 105 cells/well for a 24-well plate assay. Cells were
added to a plate or flask containing a 10-fold serial dilution of the
test compound. Assay medium was RPMI-1640, supplemented with
heat-inactivated 16% fetal bovine serum, 1.6 mM L-glutamine, 80
IU/mL penicillin, 80 µg/mL streptomycin, 0.0008% DEAE-Dextran,
0.045% sodium bicarbonate, and 26 IU/mL recombinant interleu-
kin-2 (Chiron Corp., Emeryville, CA). AZT was used as a positive
control for the assay. Untreated and uninfected PBM cells were
grown in parallel at equivalent cell concentrations as controls. The
cell cultures were maintained in humidified 5% CO2 air at 37 °C
for 5 days, and supernatants were collected for determination of
RT activity.
Supernatants were centrifuged at 12 000 rpm for 2 h to pellet
the virus. The pellet was solubilized with vortexing in 100 µL of
virus solubilization buffer (VSB) containing 0.5% Triton X-100,
0.8 M NaCl, 0.5 mM phenylmethylsulfonyl fluoride, 20% glycerol,
and 0.05 M Tris, pH 7.8. Ten-microliter portions of each sample
were added to 75 µL of RT reaction mixture (0.06 M Tris, pH 7.8,
0.012 M MgCl2, 0.006 M dithiothreitol, 0.006 mg/mL poly(rA)n
(c) Binding Affinity Study to Deoxycytidine Kinase (dCK).
All molecular modeling of the enzyme-substrate complexes was
carried out using Sybyl 6.7 (Tripos Associates, St. Louis, MO) on
a Silicon Graphics Octane2 workstation. The enzyme site of the
enzyme-ligand complex was constructed on the basis of the X-ray
structure of the catalytic complex of dCK with dC and adenosine
diphosphate (ADP) (PDB code 1P60).26 Terminal residues were
capped with acetyl and methyl groups, Mg2+ atom was added, and
γ-phosphate was added. Substrate coordinates of 24 and 52 were
constructed and geometrically optimized through a Monte Carlo
conformational search using MMFF94s force field in Macromodel,
version 7.0 (Schro¨dinger, Inc.). Substrates were docked into the
binding pocket on the basis of the coordinates of dC. Ga¨steiger-
Hu¨ckel charges and Kollman all-atom charge were loaded to the
ligands and dCK, respectively, with formal charges (+2) to Mg
atom in the active site. And the residues less than 6 Å (hot region,
6 Å; interesting region, 12 Å) from the substrate were annealed
until the energy change from one iteration to the next was less
than 0.05 kcal/mol. The annealed dCK-substrate complex was fully
minimized by using the Kollman all-atom force field for 5000
iterations.
3
oligo(dT)12-18, 96 µg/mL dATP, and 1 µM of 0.08 mCi/mL H-
thymidine triphosphate (Moravek Biochemicals, Brea, CA)) and
incubated at 37 °C for 2 h. The reaction was stopped by the addition
of 100 µL of 10% trichloroacetic acid containing 0.05% sodium
pyrophosphate. The acid-insoluble product was harvested onto filter
paper using a Packard harvester (Meriden, CT), and the RT activity
was read on a Packard direct beta counter (Meriden, CT). The RT
results were expressed in counts per minute (CPM) per milliliter.
The antiviral 50% effective concentration (EC50) and 90% effective
concentration (EC90) were determined from the concentration-
response curve using the median effect method.28
Cytotoxicity Assays. The compounds were evaluated for their
potential toxic effects on uninfected PHA-stimulated human PBM
cells, in CEM (T-lymphoblastoid cell line obtained from American
Type Culture Collection, Rockville, MD) and Vero (African green
monkey kidney) cells. PBM cells were obtained from whole blood
of healthy seronegative donors (HIV-1 and hepatitis B virus) by
single-step Ficoll-Hypaque discontinuous gradient centrifugation.

1646 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5
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Supporting Information Available: Elemental analyses data
of compounds 3-15, 22-60. This material is available free of
charge via the Internet at http://pubs.acs.org.
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