Synthesis of dioxane-based antiviral agents and evaluation of their biological activities as inhibitors of Sindbis virus replication

Article abstract of DOI:10.1016/j.bmc.2007.01.040

The crystal structure of the Sindbis virus capsid protein contains one or two solvent-derived dioxane molecules in the hydrophobic binding pocket. A bis-dioxane antiviral agent was designed by linking the two dioxane molecules with a three-carbon chain ha

Full text of DOI:10.1016/j.bmc.2007.01.040

Bioorganic & Medicinal Chemistry 15 (2007) 2667–2679
Synthesis of dioxane-based antiviral agents and evaluation
of their biological activities as inhibitors of Sindbis virus replication
Ha Young Kim,a Richard J. Kuhn,b Chinmay Patkar,b
Ranjit Warrierb and Mark Cushmana,*
aDepartment of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences,
The Purdue Cancer Center, West Lafayette, IN 47907, USA
bDepartment of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
Received 18 December 2006; accepted 19 January 2007
Available online 24 January 2007
Abstract—The crystal structure of the Sindbis virus capsid protein contains one or two solvent-derived dioxane molecules in the
hydrophobic binding pocket. A bis-dioxane antiviral agent was designed by linking the two dioxane molecules with a three-carbon
chain having R,R connecting stereochemistry, and a stereospecific synthesis was performed. This resulted in an effective antiviral
agent that inhibited Sindbis virus replication with an EC50 of 14 lM. The synthesis proceeded through an intermediate (R)-2-hy-
droxymethyl-[1,4]dioxane, which unexpectedly proved to be a more effecting antiviral agent than the target compound, as evidenced
by its EC50 of 3.4 lM as an inhibitor of Sindbis virus replication. Both compounds were not cytotoxic in uninfected BHK cells at
concentrations of 1 mM.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
that effort, including the synthesis and biological testing
of 24 dioxane derivatives in addition to the originally
reported four compounds. These additional compounds
include the enantiomer and meso diastereomer of the
initial target compound, as well as homologues of vari-
ous linker chain lengths. The results obtained from the
full set of compounds document the correctness of the
linker length and absolute configuration indicated by
the structure-based drug design approach reported in
the preliminary communication.5
The alphaviruses are a genus of approximately 27
arthropod-transmitted plus-strand RNA viruses found
in the Togaviridae family.1,2 The viruses found in this
group are responsible for a wide range of diseases and
many of them are important human and animal patho-
gens.3,4 Several examples of alphaviruses are Sindbis,
Semliki Forest, and Venezuelan equine encephalitis
viruses. Infection can result in fever, rash, arthralgia
or arthritis, lassitude, headache, and myalgia. The pro-
totypic alphavirus is Sindbis virus (SINV), which is
transmitted to humans through mosquito bites. At the
present time, there are no effective antiviral agents for
treatment of alphavirus infections.
Crystallographic evidence supports the hypothesis that
the intermolecular bonding of residues 108 and 110 in
the N-terminal arm of the SINV CP molecule to a hydro-
phobic pocket on an adjacent capsid protein molecule is
involved in capsid assembly.6 Furthermore, an apparent
structural analogy between residues L108 and L110 in
the N-terminal arm and residues Y400 and L402 in the
membrane E2 glycoprotein spikes suggests that the bond-
ing of these glycoprotein residues to the hydrophobic
pocket of the capsid protein is involved in the budding
of virus from the cell.6 The proposed role of the capsid res-
idues L108 and L110 in capsid assembly has been con-
firmed by mutational studies. Similarly, mutational
studies of the E2 glycoprotein have confirmed that resi-
dues Y400 and L402 play critical roles in the budding pro-
cess.6,7 These results indicate that small molecules that
We recently reported a preliminary account of an at-
tempt to obtain dioxane-based antiviral agents by cova-
lently linking two solvent-derived dioxane molecules
found in the crystal structure of a Sindbis virus capsid
protein (SINV CP) fragment.5 The present communica-
tion provides a detailed description of the outcome of
Keywords: Antiviral; Synthesis; Sindbis virus; Dioxane; Alphaviruses.
*
Corresponding author. Tel.: +1 765 494 1465; fax: +1 765 494
6790; e-mail addresses: cushman@pharmacy.purdue.edu; cushman@
sparky.pnhs.purdue.edu
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.01.040

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H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
could bind to the hydrophobic binding pocket of the
alphaviruses might effectively inhibit the viral replication
cycle by blocking capsid assembly as well as budding from
the cell. A SINV nucleocapsid protein fragment 114–264
having an ‘empty’ hydrophobic pocket has been crystal-
lized, and the resulting X-ray structure displayed a hydro-
phobic pocket occupied by one or two dioxane molecules
derived from the crystallization solvent.8 The two dioxane
molecules occupy the same space as the two leucine resi-
dues (L108 and L110) present when the hydrophobic
pocket is occupied by the N-terminal arm of an adjacent
protein molecule.
Figure 1. Molecular model on the binding of the dioxane dimer 8 in
the hydrophobic binding pocket of the Sindbis virus capsid protein.
The figure is programmed for wall-eyed (relaxed) viewing.
The crystallography results suggest that the linkage of
two dioxane molecules by a hydrocarbon linker chain
could result in a potential drug molecule that would
simultaneously occupy both dioxane-binding sites and
thus display increased affinity for the protein relative
to dioxane itself. A series of compounds that were pre-
dicted to bind in the hydrophobic pocket of the alphavi-
rus capsid protein were therefore designed and
synthesized. These ligands are expected to block the
interaction of the viral capsid protein with the N-termi-
nal arm of an adjacent capsid protein molecule, which
could inhibit capsid assembly. In addition, the occupa-
tion of the hydrophobic binding pocket could also be
expected to block the binding of the viral capsid protein
to the membrane-bound E2 glycoprotein spikes, thus
inhibiting viral budding.
and (S)-2-hydroxymethyl-[1,4]dioxane [(S)-4], which
were readily prepared by our previously reported asym-
metric synthesis (Scheme 1).5,9 Three-carbon linker
chain compounds 8–12 were synthesized from dithiane
intermediate 7, prepared as outlined in Scheme 2.
Hydrolysis10,11 of dithiane 7 with methyl iodide and
sodium carbonate in aqueous acetonitrile afforded the
ketone 9, and reduction of the carbonyl functional
group with LAH provided the alcohol 10. The carbonyl
compound 9 was also transformed into two oxime deriv-
atives 11 and 12 by reacting with hydroxylamine or
methoxylamine in methanol containing two equivalents
of pyridine.
In addition to the previously reported compound 14,5
the four-carbon linker chain compound 16 was synthe-
sized from intermediate 6 in order to experimentally
confirm that the optimal linker chain length was indeed
three carbon atoms long. As outlined in Scheme 3,
deprotonation of intermediate 6 with n-butyllithium in
a mixed solvent of THF and HMPA, followed by reac-
tion of the anion with iodide 29 (Scheme 6), provided
the dithiane 15. The desired product 16 was obtained
through desulfurization12 with Raney nickel in refluxing
ethanol and subsequent hydrogenation of the intermedi-
ate alkene with Pd/C. The ketone 17 was synthesized by
hydrolysis of the dithiane 15, and lithium aluminum
hydride reduction of the ketone afforded the diastereo-
meric mixture of alcohols 18.
2. Results and discussion
2.1. Design
The general approach described above requires connect-
ing two dioxane molecules by a linker chain. The length
of the linker chain and the stereochemistry of the attach-
ment are variables that must be considered carefully for
the strategy to be successful. Therefore, molecular mod-
eling was performed using the structure of the mutant
SINV capsid protein SCP(114–264) (1WYK) occupied
8
˚
by two dioxane molecules. Using a 10 A sphere sur-
rounding the two dioxane molecules as the starting tem-
plate, the two dioxane molecules were extracted, linked,
and docked back into the empty pocket. The energy of
the ligand was then minimized using Sybylꢁ 7.0 while
the protein structure was frozen. The investigation of
an array of bis-dioxane molecules containing linker
chains of various lengths and stereochemistries led to
the conclusion that a three-carbon linker would allow
the two dioxane moieties to occupy approximately the
same space as the two dioxanes in the starting crystal
structure. This encouraged the selection of the bis-diox-
ane 8 (Scheme 2) as the initial target compound. The
hypothetical model of the dioxane dimer 8 bound in
the hydrophobic binding pocket of the Sindbis virus
capsid protein is displayed in Figure 1.
In order to confirm that the stereochemistry of linker
attachment represented in the R,R-bis-dioxane 8 is in
Cl
a
b
*
*
Cl
Cl
O
O
OH
(S)-1
(R)-1
(S)-2
(R)-2
O
Cl
*
c
OH
*
O
O
O
(S)-3
(R)-3
(R)-4 from (S)-3
2.2. Chemistry
(S)-4 from (R)-3
Synthesis of the dioxane analogues began from key
intermediates (R)-2-hydroxymethyl-[1,4]dioxane [(R)-4]
Scheme 1. Reagents and conditions: (a) BF3ÆEt2O, 2-chloroethanol,
45 ꢂC, 1.5 h; (b) NaOH, H2O, rt, 2 h; (c) NaOH, H2O, 90 ꢂC, 2 h.

H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
2669
O
O
S
O
O
O
O
O
O
S
b
a
a
b
I
I
(R)-4
(S)-4
S
S
5
20
6
19
O
H
O
O
O
O
O
O
O
c
d
c
S
S
O
O
O
21
8
7
Scheme 4. Reagents and conditions: (a) imidazole, PPh3, I2, toluene–
THF, rt, 10 h; (b) 1,3-dithiane, n-BuLi, THF–HMPA, ꢀ78 ꢂC to rt; (c)
MeI, NaHCO3, CH3CN–H2O, 40 ꢂC, 15 h.
e
O
O
O
O
O
O
f
O
OH
O
O
O
O
O
O
O
O
O
O
a
c
b
d
9
10
20
20
S
S
S
S
g for 11
h for 12
22
24
23
25
O
O
O
O
O
O
O
O
O
O
O
N
OR
O
11 R = H
12 R = CH3
Scheme 5. Reagents and conditions: (a) n-BuLi, 5, THF–HMPA,
ꢀ78 ꢂC to rt; (b) Raney Ni, abs EtOH, reflux, 20 h; (c) n-BuLi, 19,
THF–HMPA, ꢀ78 ꢂC to rt; (d) Raney Ni, abs EtOH, reflux, 15 h.
Scheme 2. Reagents and conditions: (a) imidazole, PPh3, I2, toluene–
THF, rt, 3 h; (b) 1,3-dithiane, n-BuLi, THF–HMPA, ꢀ70 ꢂC to rt; (c)
n-BuLi, 5, THF–HMPA, ꢀ70 ꢂC to rt; (d) Raney Ni, absÆEtOH, reflux,
5 h; (e) MeI, NaHCO3, CH3CN-H2O, 40 ꢂC, 12 h; (f) LiAlH4, THF, rt,
1 h; (g) H2NOHÆHCl, pyridine, MeOH, 65 ꢂC, 40 h, sealed tube;
(h) H2NOMeÆHCl, pyridine, MeOH, 65 ꢂC, 40 h, sealed tube.
prepared as shown in Scheme 4. Intermediate (S)-4
was converted to 2-iodomethyl-[1,4]dioxane 1913,14 with
imidazole, triphenylphosphine, and iodine in a mixed
solvent of toluene and tetrahydrofuran at ambient tem-
perature in 84% yield.15 Displacement of iodide from
intermediate 1913,14 with the lithiated anion derived
from 1,3-dithiane afforded the product 20, which was
readily hydrolyzed to yield aldehyde 21 with excess
methyl iodide and sodium bicarbonate in acetonitrile
and water at 40 ꢂC.
O
O
O
O
a
c
b
d
6
6
S
S
S
13
14
O
O
O
O
By employing the same strategies used in the synthesis of
dioxane 8, the meso-dioxane analogue 23 and the chiral
dioxane analogue 25 were synthesized (Scheme 5). The
dithiane intermediates 22 and 24 were prepared by the
treatment of starting material 20 with n-butyllithium in
a mixed solvent of THF and HMPA, followed by reac-
tion of the anion with each iodide 5 or 19. The final
products 23 and 25 were obtained from each of dithiane
22 or 24 through desulfurization12 with Raney Nickel in
refluxing ethanol.
O
O
O
O
S
15
16
e
O
O
O
O
O
O
O
O
f
O
OH
17
The alcohol (R)-4 unexpectedly proved to be more potent
than bis-dioxane 8 as an inhibitor of viral replication.5
This result led us to synthesize the corresponding homol-
ogated alcohols 27 and 31 (Scheme 6) and to compare
their biological activities with those of (R)-4 and 8. The
hydrolysis10,11 of 6 with methyl iodide and sodium car-
bonate in a mixed solvent of acetonitrile–water provided
the aldehyde 26, and subsequent reduction with sodium
borohydride in methanol at ambient temperature affor-
ded the alcohol 27 in nearly quantitative yield in two steps.
The enantiomer 28 was obtained by sodium borohydride
18, diastereomeric mixture
Scheme 3. Reagents and conditions: (a) n-BuLi, (2-iodoethyl)benzene,
THF–HMPA, ꢀ70 ꢂC to rt; (b) Raney Ni, abs EtOH, reflux, 15 h; (c)
n-BuLi, 29, THF–HMPA, ꢀ70 ꢂC to rt; (d) i—Raney Ni, EtOH,
reflux, 12 h, ii—10% Pd/C, H2, EtOH, rt, 15 h; (e) MeI, NaHCO3,
CH3CN-H2O, 40 ꢂC, 15 h; (f) LiAlH4, THF, rt, 1 h.
fact ideal, the corresponding enantiomer 25 and the
meso compound 23 were synthesized as portrayed in
Schemes 4 and 5. A key intermediate, dithiane 20, was

2670
H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
O
O
H
O
O
OH
O
O
O
O
O
O
a
I
a
b
b
6
31
S
S
O
26
27
34
35
c
c
d
O
O
I
O
OH
O
O
O
O
O
b
21
O
O
28
O
O
O
29
36
37
Scheme 7. Reagents and conditions: (a) imidazole, PPh3, I2, toluene-
THF, rt, 15 h; (b) 6, n-BuLi, THF–HMPA, ꢀ78 ꢂC to rt; (c) Raney Ni,
EtOH, 80 ꢂC, 15 h; (d) MeI, NaHCO3, CH3CN–H2O, 40 ꢂC, 12 h.
S
O
O
e
OH
S
d
O
O
31
30
2.3. Biological results and discussion
Biological assays were focused on testing for inhibition
of SINV production and for cytotoxicity in uninfected
baby hamster kidney (BHK) cells. Virus production
using SIN-IRES-Luc was used to monitor antiviral
activity. SIN-IRES-Luc is Sindbis virus with a firefly
luciferase gene inserted at the 30-end of the genome,
which is expressed off of an Internal Ribosomal Entry
Site (IRES). The infectivity of the virus could be assayed
directly as a measure of the luciferase amounts produced
in infected cells over a period of time.
O
OH
CH3
O
O
O
g
H
f
(S)-4
O
32
33 (diastereomeric mixture)
Scheme 6. Reagents and conditions: (a) MeI, NaHCO3, CH3CN–H2O,
40 ꢂC, 12 h; (b) NaBH4, MeOH, rt, 0.5 h; (c) imidazole, PPh3, I2,
toluene-THF, rt, 12 h; (d) 1,3-dithiane, n-BuLi, THF–HMPA, ꢀ78 ꢂC
to rt; (e) i—MeI, NaHCO3, CH3CN–H2O, 40 ꢂC, 12 h, ii—NaBH4,
MeOH, rt, 1 h; (f) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢂC to rt, 5 h;
(g) MeMgBr, THF, rt, 2 h.
A cell viability assay was performed initially in order to
plot a cytotoxicity curve for the compounds. A standard
XTT-based colorimetric assay was employed using the
‘Quick Cell Proliferation Kit’ (BioVision, Inc.). This in-
volved treating BHK cells with various concentrations
of the compounds and then using an XTT-conjugated
substrate that formed an orange precipitate on reaction
with mitochondrial dehydrogenases to determine cell
viability. Spectrophotometric readings were taken at
450 nm and the intensity of the color was proportional
to the viability of the cells. The cytotoxic concentrations
for each of the compounds were established by compar-
ing the spectrophotometric readings for the treated and
untreated cells. In the assay for inhibition of Sindbis
virus production, BHK cells were grown to confluency
in 96-well plates. BHK cells were infected with SIN-
IRES-Luc virus at a multiplicity of infection (MOI) of
less than 1. Media containing the compounds at concen-
trations less than cytotoxic concentrations were added
onto the infected cells, and the cells were further incu-
bated at 37 ꢂC for 12 h. Cell extracts were taken and
luciferase assays were performed on the extracts using
the LmaxII 96-well plate luminometer (Molecular
Devices).17,18
reduction of 21. The alcohol compound 27 was iodin-
ated with iodine in the presence of imidazole and
triphenylphosphine in a mixed solvent of toluene and
tetrahydrofuran at ambient temperature to afford 29.
Coupling of iodide 29 with lithiated anion of 1,3-dithi-
ane yielded intermediate 30. The dithiane intermediate
30 was hydrolyzed with excess of methyl iodide and
sodium bicarbonate, and the intermediate aldehyde re-
duced in the presence of sodium borohydride to yield a
three-carbon extended alcohol product 31. The Swern
oxidation16 was employed for the synthesis of aldehyde
32, which was treated with methylmagnesium bromide
to provide a diastereomeric mixture of alcohols 33.
In order to further investigate the effect of linker chain
length on antiviral activity, the synthesis of two five-car-
bon linker chain compounds 36 and 37 was performed
as outlined in Scheme 7. The alcohol starting material
31 was converted to iodide 34 with iodine, imidazole,
and triphenylphosphine. The anion of 6, generated
in situ by deprotonation with n-butyllithium in a mixed
solvent of THF–HMPA at ꢀ78 ꢂC, was treated with io-
dide 34 to afford the alkylated product 35. Raney nickel
desulfurization of 35 eliminated the dithiane moiety to
provide a five-carbon linker chain compound 36 in
84% yield. Hydrolysis of the dithiane fragment of 35
with methyl iodide, followed by treatment with aqueous
acetonitrile, afforded the corresponding ketone 37 in
88% yield.
Our initial molecular modeling studies indicated that a
chiral bis-dioxane derivative having a three-carbon link-
er chain with R,R connecting stereochemistry would be
ideal for binding to the Sindbis virus capsid protein
(Fig. 1). The results provided in Table 1 show that, in-
deed, connecting two dioxane molecules with a three-
carbon linker does in fact provide an inhibitor of virus
replication with an EC50 value of 14 lM. The corre-

H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
Table 1. Antiviral activities and cytotoxicities of dioxane derivatives
2671
a
EC50 (M)
b
CC50 (M)
Compound
(R)-3
(S)-3
1.0 0.90 · 10ꢀ3
1.0 0.28 · 10ꢀ3
3.4 0.45 · 10ꢀ6
1.5 0.32 · 10ꢀ3
1.4 0.25 · 10ꢀ5
NAc
6.7 0.23 · 10ꢀ4
NA
NA
>1 · 10ꢀ3
>5 · 10ꢀ3
>1 · 10ꢀ3
>5 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>5 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
>1 · 10ꢀ3
ꢁ1 · 10ꢀ3
>1 · 10ꢀ3
(R)-4
(S)-4
8
9
10
11
12
Figure 2. Molecular model of the binding of the dioxane derivative
(R)-4 in the hydrophobic binding pocket of Sindbis virus capsid
protein. The figure is programmed for wall-eyed (relaxed) viewing.
14
15
NA
NA
16
17
1.5 0.17 · 10ꢀ3
NA
displayed in Figure 2. The hypothetical structure dis-
played in Figure 2 indicates that it would be possible
for the primary hydroxyl groups of two molecules of
(R)-4 to hydrogen bond to the Lys135 side chain and
the backbone carbonyl of Gly251. This model essentially
maintains the orientations of the two dioxane molecules
found in the crystal structure of SINV CP. There are
clearly other residues lining the binding pocket that
would be capable of hydrogen bonding to different ori-
entations of the ligand (R)-4, including Met132,
Glu133, Met137, and Thr253. Two bound molecules
of (R)-4 could also theoretically hydrogen bond to each
other.
18
20
NA
1.0 0.43 · 10ꢀ3
4.6 0.51 · 10ꢀ4
2.9 0.36 · 10ꢀ5
NA
21
22
23
24
NA
NA
25
27
1.4 0.15 · 10ꢀ3
NA
28
29
2.5 0.19 · 10ꢀ4
NA
30
31
NA
33
36
9.9 0.14 · 10ꢀ5
1.5 0.22 · 10ꢀ3
NA
The bis-dioxanes 9–12 constitute a set of compounds
having linker chains of the same length and connecting
stereochemistry as the most active bis-dioxane 8. The
ketone 9, as well as the corresponding oxime 11 and
methoxime 12, were all inactive, while the alcohol 10 re-
tained a low level of antiviral activity (EC50 670 lM).
The bis-dioxane system 8 evidently does not tolerate
functionalization at the central carbon atom.
37
Chlorpromazine
Verapamil
8.2 0.16 · 10ꢀ6
1 · 10ꢀ4
1.3 0.17 · 10ꢀ3
>1 · 10ꢀ3
a The EC50 is the concentration of the compound resulting in a 50%
reduction in virus production.
b The CC50 is the concentration of the compound causing a 50%
growth inhibition of uninfected BHK cells.
c No antiviral activity was observed up to
a concentration of
1.0 · 10ꢀ3 mM.
Several of the dithiane intermediates were also tested as
inhibitors of Sindbis virus replication. These included
the dithianes 15, 20, 22, and 24. Compounds 15 and
22 were inactive, while intermediate 20 displayed a low
level of antiviral activity (EC50 1000 lM). However,
the dithiane derivative 22 was much more active (EC50
20 lM) than the others.
sponding bis-dioxanes 16 and 36 with four-carbon and
five-carbon linkers proved to be much less active, with
EC50s of 1500 and 1000 lM, respectively. Moreover,
the enantiomer of 8 (bis-dioxane 25) and the corre-
sponding meso compound 23 were both inactive, so
the stereochemistry of the linker attachment is obviously
also important. These results demonstrate the validity of
the structure-based drug design approach used to con-
ceptually derive the active compound 8 from two inac-
tive dioxane molecules.
In addition to being tested antiviral activity, all of the
compounds in the series were examined for cytotoxicity
in uninfected BHK cells. All of the compounds were not
cytotoxic at concentrations of 1000 lM (Table 1). Three
of the compounds [(S)-3, 21, and (S)-4] were examined
at concentrations of 5000 lM without any apparent evi-
dence of cytotoxicity. The therapeutic index (EC50/CC50
ratio) of 8 was therefore greater than 71, while that of
(R)-4 was greater than 294.
The relatively high activity of the starting alcohol (R)-4
as an inhibitor of viral replication (EC50 3.4 lM) was a
welcome surprise and it encouraged the synthesis of the
homologated alcohols 27 and 31. The alcohol 27, which
is a one-carbon homologue of (R)-4, proved to have
greatly reduced antiviral activity, with an EC50 of
1400 lM, while the next higher homologue 31 was com-
pletely inactive. The methylated analogue 33 of (R)-4
displayed significantly reduced activity, inhibiting viral
replication with an EC50 of 99 lM.
3. Summary
In summary, prior crystallographic studies of the Sind-
bis virus capsid protein showed the presence of one or
two solvent-derived dioxane molecules in the hydropho-
bic binding pocket.8 This structure provided a template
for design of the dioxane-based antiviral agent 8. Com-
puter graphics molecular modeling indicated that two
The possible binding mode of (R)-4 to the capsid protein
was investigated by molecular modeling using the proce-
dure described for 8. This resulted in the model

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H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
solvent-derived dioxane molecules found the hydropho-
bic binding pocket during crystallography could theoret-
ically be linked by a three-carbon chain having R,R
connection stereochemistry without appreciable move-
ment of the two dioxane rings. A stereospecific route
to the synthesis was carried out, and the investigation
of the bis-dioxane 8 revealed that it in fact was an inhib-
itor of Sindbis virus replication, with an EC50 of 14 lM.
Lengthening the linker chain, changing the stereochem-
istry of the linker chain connection, or functionalization
of the linker chain all resulted in complete or substantial
loss of antiviral potency. Unexpectedly, the synthetic
intermediate (R)-4 proved to be the most active com-
pound in the series, having an EC50 of 3.4 lM. This
study has proven to be fruitful example of structure-
based drug design culminating in effective dioxane-based
antiviral agents against Sindbis virus, a prototype of the
alphavirus family. The dioxane-based antiviral agents
are novel, and they provide a template for further devel-
opment of antiviral agents targeted against alphaviruses.
uct was obtained as a light brown liquid (21.2 g, 96%):
IR (film) 3430, 2961, 2911, 2874, 1627, 1431, 1299,
1129 cmꢀ1 1H NMR (CDCl3) d 4.04–3.59 (m, 9H),
;
2.61 (br s, 1H); 13C NMR (CDCl3) d 71.7, 71.4, 70.1,
45.7, 42.8; EIMS m/z (rel intensity) 138 (M+ꢀHCl, 2),
136 (M+ꢀHCl, 6), 95 (CH2OCH2CH2Cl+, 34), 93
(CH2OCH2CH2Cl+, 100); CIMS m/z (rel intensity) 175
(MH+, 15), 173 (MH+, 23), 157 (MH+ꢀH2O, 61), 155
(MH+ꢀH2O, 100). Anal. Calcd for C5H10Cl2O2: C,
34.71; H, 5.82; Cl, 40.98. Found: C, 34.62; H, 5.80; Cl,
40.83.
4.3. (R)-3-(2-Chloroethoxy)-1,2-epoxypropane [(R)-3]
(R)-1-(2-Chloroethoxy)-3-chloro-propan-2-ol
[(R)-2]
(11 g, 64 mmol) was added dropwise to a stirred solution
of NaOH (6.36 g, 159 mmol) in water (7.60 mL) on an
ice-bath. The ice-bath was immediately removed after
addition of (R)-2. After stirring 2 h at an ambient tem-
perature, diethyl ether (150 mL) and water (50 mL) were
added. The organic layer was washed with water
(1 · 50 mL), dried over sodium sulfate, and concentrat-
ed to give a light brown liquid (R)-3 (7.0 g, 81%): IR
4. Experimental
(film) 2961, 2917, 2874, 1431, 1299, 1124 cmꢀ1 1H
;
Melting points were determined in capillary tubes and
are uncorrected. Except where noted, NMR spectra
were obtained at 300 MHz (1H) and 75 MHz (13C) using
CDCl3 as solvent and the solvent peak as internal
standard. Flash chromatography was performed with
230–400 mesh silica gel. TLC was carried out using Bak-
er-flex silica gel IB2-F plates of 250 lm thickness. Com-
pounds were visualized with short wavelength UV light.
Unless otherwise stated, chemicals and solvents were of
reagent grade and used as obtained from commercial
sources without further purification. Tetrahydrofuran
(THF) was freshly distilled from sodium/benzophenone
ketyl radical prior to use. Dichloromethane was freshly
distilled from calcium hydride prior to use. All yields
given refer to isolated yields of pure products.
NMR (CDCl3) d 3.83–3.39 (m, 6H), 3.14 (m, 1H),
2.79–2.59 (m, 2H); 13C NMR (CDCl3) d 71.8, 71.3,
50.7, 44.0, 42.7; EIMS m/z (rel intensity) 100 (M+ꢀHCl,
9), 57 (100); CIMS m/z (rel intensity) 139 (MH+, 5), 137
(MH+, 15), 101 (MH+ꢀHCl, 100). Anal. Calcd for
C5H9ClO2: C, 43.97; H, 6.64; Cl, 25.96. Found: C,
43.88; H, 6.62; Cl, 25.90.
4.4. (S)-3-(2-Chloroethoxy)-1,2-epoxypropane [(S)-3]
The procedure for the preparation of (R)-3 was used for
this compound. The product was obtained as a clear li-
quid (14 g, 84%): IR (film) 2961, 2917, 2874, 1431, 1299,
1125 cmꢀ1; 1H NMR (CDCl3) d 3.83–3.39 (m, 6H), 3.14
(m, 1H), 2.79–2.59 (m, 2H); 13C NMR (CDCl3) d 71.8,
71.3, 50.7, 44.0, 42.7; EIMS m/z (rel intensity) 100
(M+ꢀHCl, 12), 57 (100); CIMS m/z (rel intensity) 139
(MH+, 4), 137 (MH+, 16), 101 (MH+ꢀHCl, 100). Anal.
Calcd for C5H9ClO2: C, 43.97; H, 6.64; Cl, 25.96.
Found: C, 43.94; H, 6.63; Cl, 25.88.
4.1. (R)-1-(2-Chloroethoxy)-3-chloropropan-2-ol [(R)-2]
Epoxide (R)-1(5.0 mL, 64 mmol) was slowly added to a stir-
red solution of 2-chloroethanol (12.86 mL, 191.8 mmol)
and BF3ÆEt2O (0.45 mL, 3.2 mmol) at 45 ꢂC. The reaction
mixture was heated on an oil bath for 1.5 h at 45 ꢂC. Diethyl
ether (100 mL) was added to thissolution. The organic layer
was washed with water (1 · 80 mL), dried over magnesium
sulfate, and concentrated to yield a light brown liquid (R)-2
(11.07 g, quantitative): IR (film) 3430, 2961, 2911, 2874,
4.5. (S)-2-Hydroxymethyl-[1,4]dioxane [(S)-4]
(R)-3-(2-Chloroethoxy)-1,2-epoxypropane [(R)-3] (5.5 g,
41 mmol) was added to a solution of NaOH (4.09 g,
102 mmol) in water (40 mL) at room temperature. The
reaction mixture was heated on an oil bath for 2 h at
90 ꢂC. The resulting solution was extracted overnight
at 50 ꢂC through a high density continuous extractor
with dichloromethane (50 mL). The organic layer was
dried over sodium sulfate and concentrated under re-
duced pressure. The residue was purified by column
chromatography (EtOAc/hexane = 2:1–3:1) to give a
clear liquid (S)-4 (1.74 g, 36%): IR (film) 3436, 2959,
1
1627, 1431, 1299, 1129 cmꢀ1; H NMR (CDCl3) d 4.04–
3.59 (m, 9H), 2.61 (br s, 1H); 13C NMR (CDCl3) d 71.7,
71.4, 70.1, 45.7, 42.8; EIMS m/z (rel intensity) 138
(M+ꢀHCl, 1), 136 (M+ꢀHCl, 5), 95 (CH2OCH2CH2Cl+,
33), 93 (CH2OCH2CH2Cl+, 100); CIMS m/z (rel intensity)
175 (MH+, 17), 173 (MH+, 27), 157 (MH+ꢀH2O, 61), 155
(MH+ꢀH2O, 100). Anal. Calcd for C5H10Cl2O2: C, 34.71;
H, 5.82; Cl, 40.98. Found: C, 34.59; H, 5.81; Cl, 40.92.
2915, 2860, 1647, 1453, 1124, 1084, 1045 cmꢀ1 1H
;
4.2. (S)-1-(2-Chloroethoxy)-3-chloropropan-2-ol [(S)-2]
NMR (CDCl3) d 3.85–3.41 (m, 9H), 2.15 (br s, 1H);
13C NMR (CDCl3) 75.5, 67.7, 66.2, 66.0, 61.9;
[a]D = +3.0 (c 1, EtOH); EIMS m/z (rel intensity) 118
(M+, 5), 87 (M+ꢀCH2OH, 100); CIMS m/z (rel intensi-
The procedure for the preparation of (R)-2 was used for
this compound, starting from epoxide (S)-1. The prod-

H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
2673
ty) 119 (MH+, 79), 101 (MH+ꢀ H2O, 100). Anal. Calcd
for C5H10O3: C, 50.84; H, 8.53. Found: C, 50.64; H,
8.50.
(M+ꢀC5H9O2, 100); CIMS m/z (rel intensity) 221
(MH+, 100). Anal. Calcd for C9H16O2S2: C, 49.06; H,
7.32; S, 29.10. Found: C, 49.21; H, 7.34; S, 29.21.
4.6. (R)-2-Hydroxymethyl-[1,4]dioxane [(R)-4]
4.9. 1,3-Bis{(R)-[1,4]dioxan-2-yl}-2-([1,3]dithian-2-
yl)propane (7)
The procedure for the preparation of (S)-4 was used for
this compound, starting from (S)-3. The product was
obtained as a light yellow liquid (4.28 g, 36%): IR (film)
3436, 2959, 2915, 2859, 1645, 1453, 1124, 1084,
A 2.4 M solution of n-BuLi (0.22 mL, 0.52 mmol) in
hexane was added to a solution of 1,3-dithianate 6
(0.12 g, 0.54 mmol) in THF (2.5 mL) and HMPA
(0.5 mL) at ꢀ70 ꢂC. The solution was allowed to stir
for 1 h between ꢀ10 ꢂC and ꢀ20 ꢂC, and cooled to
ꢀ70 ꢂC. A solution of iodide 5 (0.10 g, 0.45 mmol) in
THF (2.0 mL) was added via cannula. The reaction mix-
ture was slowly warmed up to room temperature for 3 h,
quenched with water (10 mL) and brine (10 mL), and
extracted with ethyl acetate (3 · 15 mL). The combined
extracts were dried over sodium sulfate, and concentrat-
ed under reduced pressure. The residue was purified by
column chromatography (EtOAc/hexane = 1:7) to give
a light yellow oil 7 (0.11 g, 76%): IR (film) 2953, 2907,
1045 cmꢀ1 1H NMR (CDCl3) d 3.85–3.41 (m, 9H),
;
2.15 (br s, 1 H); 13C NMR (CDCl3) d 75.5, 67.7, 66.2,
20
66.0, 61.9; ½aꢂ ꢀ3.0 (c 1, EtOH); EIMS m/z (rel inten-
D
sity) 118 (M+, 5), 87 (M+ꢀCH2OH, 100); CIMS m/z
(rel intensity) 119 (MH+, 76), 101 (MH+ꢀH2O, 100).
Anal. (C5H10O3) C, H.
4.7. (S)-2-Iodomethyl-[1,4]dioxane (5)
Imidazole (0.24 g, 3.5 mmol), triphenylphosphine
(0.47 g, 1.8 mmol), and iodine (0.45 g, 1.8 mmol) were
successively added to a solution of alcohol (R)-4
(0.2 g, 1.69 mmol) in toluene (10 mL). After stirring
for 1 h at room temperature, THF (5 mL) was added
and the mixture was allowed to stir 2 h. The resulting
solution was quenched with saturated Na2S2O3 solution
(10 mL) and extracted with diethyl ether (3 · 20 mL).
The extracts were washed with brine (1 · 30 mL), dried
over sodium sulfate, and concentrated under reduced
pressure. The residue was extracted with ether–hexane
(3 mL/20 mL) to remove solid triphenylphosphine
oxide. The extract was concentrated and purified by col-
umn chromatography (EtOAc/hexane = 1:6) to give a
clear liquid 5 (0.36 g, 93%): IR (film) 2960, 2855, 1449,
2850, 1735, 1446, 1279, 1122, 1105 cmꢀ1 1H NMR
;
(CDCl3) d 3.97–3.55 (m, 12H), 3.32 (t, J = 10.5 Hz,
2H), 2.89–2.65 (m, 4H), 2.19–1.88 (m, 6H); 13C NMR
(CDCl3) d 72.8, 71.2, 66.4, 66.1, 50.6, 42.1, 26.3 24.þ5;
EIMS m/z (rel intensity) 320 (M+, 5), 87 (C4H7O2
,
100); CIMS m/z (rel intensity) 321 (MH+, 100). Anal.
Calcd for C14H24O4S2: C, 52.47; H, 7.55; S, 20.01.
Found: C, 52.61; H, 7.52; S, 19.99.
4.10. 1,3-Bis{(R)-[1,4]dioxan-2-yl}propane (8)
A solution of 7 (80 mg, 0.25 mmol) in absolute ethanol
(5.0 mL) was added to a suspension of Raney nickel
(0.5 g, pore size ca. 50 lm) in absolute ethanol (10 mL)
at room temperature. The mixture was heated at reflux
for 5 h, and the resulting solution was decanted. The
decanted solution was concentrated and purified by col-
umn chromatography (EtOAc/hexane = 1:1 to only
EtOAc) to give a clear liquid 8 (23.6 mg, 44%): IR (film)
2953, 2911, 2851, 1449, 1112 cmꢀ1; 1H NMR (CDCl3) d
3.80–3.48 (m, 12H), 3.26 (dd, J = 10.0 Hz, J = 10.0 Hz,
1107, 913, 879 cmꢀ1 1H NMR (CDCl3) d 3.91–3.49
;
(m, 6H), 3.28 (dd, J = 9.5 Hz, 9.5 Hz, 1H), 3.05 (d,
J = 6.0 Hz, 2H); 13C NMR (CDCl3) d 74.1, 70.4, 66.6,
66.0, 2.7; EIMS m/z (rel intensity) 228 (M+, 100), 101
(M+ꢀI, 66); CIMS m/z (rel intensity) 229 (MH+, 100).
Anal. Calcd for C5H9IO2: C, 26.34; H, 3.98; I, 55.65.
Found: C, 26.27; H, 3.98; I, 55.67.
4.8. (R)-2-([1,3]Dithian-2-ylmethyl)-[1,4]dioxane (6)
2H), 1.54–1.26 (m, 6H); 13C NMR (CDCl3) d 75.3,
23
71.3, 66.8, 66.5, 31.6, 20.9; ½aꢂ ꢀ0.2 (c 1, EtOH); EIMS
D
A 2.4 M solution of n-BuLi (0.73 mL, 1.8 mmol) in hex-
ane was added to a solution of 1,3-dithiane (0.25 g,
2.1 mmol) in THF (2.5 mL) and HMPA (0.5 mL) at
ꢀ70 ꢂC. The solution was allowed to stir for 1 h between
ꢀ10 ꢂC and ꢀ20 ꢂC, and cooled to ꢀ70 ꢂC. A solution
of iodide 5 (0.16 g, 0.70 mmol) in THF (2.0 mL) was
added via cannula. The reaction mixture was slowly
warmed up to room temperature overnight, quenched
with water (15 mL) and brine (10 mL), and extracted
with ethyl acetate (3 · 15 mL). The combined extracts
were dried over sodium sulfate, and concentrated under
reduced pressure. The residue was purified by column
chromatography (EtOAc/hexane = 1:7) to give a yellow
solid 6 (0.15 g, 98%): mp 63.5–64.5 ꢂC. IR (film) 2907,
m/z (rel intensity) 216 (M+, 14), 112 (C6H8O2þ, 100);
CIMS m/z (rel intensity) 217 (MH+, 100). Anal. Calcd
for C11H20O4: C, 61.09; H, 9.32. Found: C, 60.99; H,
9.30.
4.11. 1,3-Bis{(R)-[1,4]dioxan-2-yl}-2-propanone (9)
Methyl iodide (0.14 mL, 2.2 mmol) and sodium bicar-
bonate (92 mg, 1.1 mmol) in water (4.0 mL) were added
to a solution of the 1,3-dithiane 7 (70 mg, 0.22 mmol) in
acetonitrile (4.0 mL) at room temperature. The reaction
mixture was stirred 12 h at 40 ꢂC and cooled to room
temperature. The resulting solution was added to water
(15 mL) and extracted with ethyl acetate (3 · 15 mL).
The combined organic layer was dried over sodium sul-
fate and concentrated. The residue was purified by col-
umn chromatography (EtOAc/hexane = 3:2 to only
EtOAc) to give a clear liquid 9 (40 mg, 80%): IR (film)
1
2852, 1422, 1278, 1123 cmꢀ1; H NMR (CDCl3) d 4.22
(m, 1H), 3.91–3.55 (m, 6H), 3.29 (t, J = 9.9 Hz, 1H),
2.99–2.75 (m, 4H), 2.19–1.57 (m, 4H); 13C NMR
(CDCl3) d 71.5, 70.9, 66.6, 66.4, 42.7, 37.4, 30.4, 29.9,
25.8; EIMS m/z (rel intensity) 220 (M+, 49), 119
1
2959, 2906, 2854, 1718, 1124 cmꢀ1; H NMR (CDCl3)

2674
H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
d 4.06 (m, 2H), 3.80–3.55 (m, 10H), 3.29 (dd,
J = 10.0 Hz, J = 10.0 Hz, 2H), 2.63 (dd, J = 7.5 Hz,
J = 7.5 Hz, 2H), 2.41 (dd, J = 5.1 Hz, J = 5.1 Hz, 2H);
water (10 mL) were added to the residue. The mixture
was extracted with ethyl acetate (3 · 10 mL). The organ-
ic layer was washed with water (20 mL), dried over sodi-
um sulfate and concentrated to give the desired product
12 as a light yellow liquid (28.3 mg, 92%). IR (film)
13C NMR (CDCl3) d 205.4, 71.8, 71.0, 67.1, 66.7, 46.0;
23
½aꢂ ꢀ0.1 (c 1, EtOH); EIMS m/z (rel intensity) 230
D
(M+, 10), 87 (C4H7O2þ, 100); CIMS m/z (rel intensity)
231 (MH+, 100). Anal. Calcd for C11H18O5: C, 57.38;
H, 7.88. Found: C, 57.37; H, 7.90.
2958, 2906, 2853, 1448, 1362, 1123 cmꢀ1 1H NMR
;
(CDCl3) d 3.91–3.54 (m, 12H), 3.87 (s, 3H), 3.34–3.24
(m, 2H), 2.54–2.24 (m, 4H); 13C NMR d (CDCl3)
154.9, 73.6, 73.3, 73.2, 71.4, 67.2, 66.8, 61.8, 37.6, 37.4,
31.2, 30.9; ESIMS m/z 282 (100, MNa+). Anal. Calcd
for C12H21NO5: C, 55.58; H, 8.16; N, 5.40. Found: C,
55.56; H, 8.18; N, 5.38.
4.12. 1,3-Bis{(R)-[1,4]dioxan-2-yl}propan-2-ol (10)
A
solution of 1.0 M lithium aluminum hydride
(0.22 mL, 0.22 mmol) in diethyl ether was added to a
solution of the ketone 9 (51.1 mg, 0.222 mmol) in THF
(3.0 mL) at room temperature. The reaction mixture
was stirred 1 h at room temperature, and then quenched
with water (5 mL). The solution was extracted with ethyl
acetate (1 · 10 mL) and dichloromethane (3 · 10 mL).
The organic layer was dried over sodium sulfate and
concentrated to give a white solid 10 (46.5 mg, 90%):
mp 59.5–60 ꢂC. IR (film) 3460, 2954, 2912, 2853, 1448,
4.15. (R)-2-(2-Phenethyl-[1,3]dithian-2-ylmethyl)-[1,4]di-
oxane (13)
A 2.4 M solution of n-BuLi (0.28 mL, 0.67 mmol) in
hexane was added to a solution of 1,3-dithianate 6
(0.14 g, 0.64 mmol) in THF (2.5 mL) and HMPA
(0.5 mL) at ꢀ70 ꢂC. The solution was allowed to stir
for 1 h between ꢀ10 ꢂC and ꢀ20 ꢂC, and cooled to
ꢀ70 ꢂC. A solution of (2-iodoethyl)benzene (0.10 mL,
0.69 mmol) in THF (2.0 mL) was added via cannula.
The reaction mixture was slowly warmed up to room
temperature for 3 h, quenched with water (10 mL) and
brine (10 mL), and extracted with ethyl acetate
(3 · 15 mL). The combined extracts were dried over
sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by column chromatogra-
phy (EtOAc/hexane = 1:6) to provide as a mixture of the
desired product 13 (0.14 g, 70%) and the starting mate-
rial 6 (30%) as a light yellow oil. After characterization
of the mixture by 1H NMR, 13C NMR, and EI/CI mass
spectral data, the crude product was used directly in the
1124 cmꢀ1 1H NMR (CDCl3) d 4.05 (m, 1H), 3.85–
;
3.52 (m, 12H), 3.34–3.25 (m, 2H), 1.54–1.39 (m, 4H);
13C NMR (CDCl3) d 76.2, 74.7, 72.3, 71.4, 70.9, 67.2,
66.7, 66.4, 66.3, 39.0, 38.4; EIMS m/z (rel intensity)
214 (M+ꢀH2O, 1), 87 (C4H7O þ, 100); CIMS m/z (rel
2
intensity) 233 (MH+, 100), 215 (MH+ꢀH2O, 61). Anal.
Calcd for C11H20O5: C, 56.88; H, 8.68. Found: C,
55.75; H, 8.65.
4.13. 1,3-Bis{(R)-[1,4]dioxan-2-yl}-2-oximinopropane
(11)
Hydroxylamine hydrochloride (52.8 mg, 0.760 mmol)
and pyridine (0.123 mL, 1.52 mmol) were added to a
solution of the ketone 9 (35 mg, 0.15 mmol) in MeOH
(3.0 mL) in a sealed tube. The reaction mixture was
heated on an oil bath 40 h at 65 ꢂC and cooled to room
temperature. The methanol solvent was evaporated un-
der reduced pressure, and the residue was added ethyl
acetate (10 mL) and water (10 mL). The mixture was
extracted with ethyl acetate (3 · 10 mL). The organic
layer was washed with water (20 mL), dried over sodium
sulfate and concentrated to give the desired product 11
as a clear liquid (36.3 mg, 97%). IR (film) 3340, 2959,
1
next reaction. H NMR (CDCl3) d 7.34–7.18 (m, 5H),
3.85–3.55 (m, 7H), 2.97–2.70 (m, 6H), 2.31–1.81 (m,
6H); 13C NMR (CDCl3) d 141.9, 128.4, 128.3, 125.8,
72.6, 71.2, 66.4, 66.2, 51.8, 41.1, 40.0, 30.8, 26.0, 25.1;
EIMS m/z (rel intensity) 324 (M+, 20), 91 (C7H7þ, 83),
87 (C4H7O2þ, 100); CIMS m/z (rel intensity) 325
(MH+, 100).
4.16. (R)-2-(4-Phenylbutyl)-[1,4]dioxane (14)
A solution of the mixture of 70% of 13 (0.14 g,
0.44 mmol) and 30% of 6 in absolute ethanol (5.0 mL)
was added to a suspension of Raney nickel (0.5 g, pore
size ca. 50 l) in absolute ethanol (10 mL) at room tem-
perature. The mixture was heated at reflux for 15 h,
and the resulting solution was filtered through a Celite
layer. The filtrate was concentrated and diluted with
dichloromethane (30 mL) and washed with water
(1 · 30 mL). The organic layer was dried over sodium
sulfate and concentrated under the reduced pressure.
The residue was purified by column chromatography
(EtOAc/hexane = 1:1 to only EtOAc) to afford a clear li-
quid 14 (70 mg, 71%): IR (film) 3026, 2934, 2853, 1604,
2909, 2855, 1651, 1448, 1362, 1123 cmꢀ1 1H NMR
;
(CDCl3) d 6.06 (br s, 1H), 3.97–3.54 (m, 12H), 3.32
(m, 2H), 2.68–2.36 (m, 4H); 13C NMR (CDCl3) d
155.7, 73.0, 72.7, 71.0, 70.8, 66.8, 66.7, 66.3, 66.2, 37.1,
30.4; ESIMS m/z (relative intensity) 268 (MNa+, 100),
246 (MH+, 70). Anal. Calcd for C11H19NO5: C, 53.87;
H, 7.81; N, 5.71. Found: C, 53.77; H, 7.83; N, 5.70.
4.14. 1,3-Bis{(R)-[1,4]dioxane-2-yl}-2-(methyloximi-
no)propane (12)
Methoxylamine hydrochloride (49.5 mg, 0.593 mmol)
and pyridine (0.10 mL, 1.2 mmol) were added to a solu-
tion of the ketone 9 (27.3 mg, 0.119 mmol) in MeOH
(3.0 mL) in a sealed tube. The reaction mixture was
heated on an oil bath 40 h at 65 ꢂC and cooled to room
temperature. The methanol solvent was evaporated
under reduced pressure, and ethyl acetate (10 mL) and
1
1496, 1453, 1125 cmꢀ1; H NMR (CDCl3) d 7.57–7.40
(m, 5H), 4.05–3.74 (m, 6H), 3.52 (dd, J = 10.1 Hz,
J = 10.1 Hz, 1H), 2.88 (t, J = 7.7 Hz, 2H), 1.96–1.55
(m, 6H); 13C NMR (CDCl3) d 142.5, 128.4, 128.3,
125.7, 75.3, 71.4, 66.8, 66.5, 35.8, 31.6, 31.5, 24.8;
23
D
½aꢂ ꢀ1.4 (c 1, EtOH); EIMS m/z (rel intensity) 220

H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
2675
(M+, 3), 91 (C7H7þ, 100); CIMS m/z (rel intensity) 221
(MH+, 100). Anal. Calcd for C14H20O2: C, 76.33; H,
9.15. Found: C, 76.60; H, 9.17.
tion mixture was stirred overnight at 40 ꢂC and cooled
to room temperature. The resulting solution was added
to water (15 mL) and extracted with ethyl acetate
(3 · 15 mL). The combined organic layer was dried over
sodium sulfate and concentrated. The residue was puri-
fied by column chromatography (EtOAc/hexane = 1:1
to EtOAc only) to give a white solid 17 (14.1 mg,
27%): mp 61–62 ꢂC. IR (film) 2963, 2910, 2851, 1709,
4.17. 1,4-Bis{(R)-[1,4]dioxan-2-yl}-2-([1,3]dithian-2-
yl)butane (15)
A solution of 1.97 M n-BuLi (0.22 mL, 0.43 mmol) in
hexane was added to a solution of 6 (0.090 g,
0.41 mmol) in THF (2.0 mL) and HMPA (0.3 mL) at
ꢀ70 ꢂC. The solution was allowed to stir for 10 min be-
tween ꢀ70 ꢂC and ꢀ60 ꢂC, and cooled to ꢀ70 ꢂC. A
solution of iodide 29 (0.09 g, 0.3718 mmol) in THF
(1.0 mL) was added via cannula. The reaction mixture
was slowly warmed up to room temperature for 2 h,
quenched with water (10 mL), and extracted with ethyl
acetate (3 · 10 mL). The combined extracts were dried
over sodium sulfate and concentrated under reduced
pressure. The residue was purified by column chroma-
tography (EtOAc/hexane = 1:3 to 1:2) to yield a light
yellow oil 15 (0.12 g, 99%): IR (film) 2953, 2907, 2851,
1112 cmꢀ1 1H NMR (CDCl3) d 4.10–4.00 (m, 1H),
;
3.79–3.47 (m, 11H), 3.33–3.23 (m, 2H), 2.70–2.48 (m,
2H), 2.36 (dd, J = 5.0 Hz, J = 5.0 Hz, 1H), 1.76–1.53
(m, 3H); 13C NMR (CDCl3) d 207.3, 74.4, 71.6, 71.1,
70.7, 66.7, 66.4, 66.3, 44.7, 39.0, 25.0; EIMS m/z (rel
intensity) 244 (M+, 4), 87 (C4H7O2, 100); CIMS m/z
(rel intensity) 245 (MH+, 63), 183 (MH+ꢀ62, 100). Anal.
Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 59.23;
H, 8.23.
4.20. 1,4-Bis{(R)-[1,4]dioxan-2-yl}butan-2-ol (18)
A
solution of 1.0 M lithium aluminum hydride
1
1447, 1277, 1123 cmꢀ1; H NMR (CDCl3) d 3.93–3.46
(0.13 mL, 0.13 mmol) in diethyl ether was added to a
solution of the ketone starting material 17 (31.8 mg,
0.13 mmol) in THF (3.0 mL) at room temperature.
The reaction mixture was stirred for 1 h at room temper-
ature and then quenched with slow addition of water
(10 mL). The solution was extracted with ethyl acetate
(1 · 10 mL) and dichloromethane (3 · 10 mL). The
organic layer was dried over sodium sulfate and concen-
trated to give a white solid 18 (28 mg, 87%) containing a
2:1 mixture of diastereomers. IR (film) 3509, 3446, 2966,
(m, 12 H), 2.36–3.24 (m, 2H), 2.89–2.70 (m, 4H), 2.28–
1.53 (m, 8H); 13C NMR (CDCl3) d 75.4, 72.4, 71.2,
71.1, 66.7, 66.4, 66.2, 51.7, 40.5, 40.0, 34.3, 26.5, 26.0,
25.0; EIMS m/z (rel intensity) 334 (M+, 45), 87
(C4H7O2þ, 100). Anal. Calcd for C15H26O4S2: C,
53.86; H, 7.83; S, 19.17. Found: C, 53.84; H, 7.85; S
19.09.
4.18. 1,4-Bis{(R)-[1,4]dioxan-2-yl}butane (16)
2939, 2916, 2859, 1458, 1443, 1122 cmꢀ1 1H NMR
;
A solution of starting material 15 (53 mg, 0.16 mmol) in
absolute ethanol (2.0 mL) was added to a suspension of
Raney nickel (0.3 g, pore size ca. 50 lm) in absolute eth-
anol (5 mL) at room temperature. The mixture was
heated at reflux for 12 h, and the resulting solution
was decanted to remove the nickel catalyst. The decant-
ed solution was concentrated and purified by short-pass
column chromatography (EtOAc/hexane = 1:3 to only
EtOAc) to give an oily product. The oily product was
dissolved in ethanol (2.0 mL), and this solution was add-
ed to a suspension of Pd/C (10%, 0.3 g) in ethanol
(3.0 mL). The mixture was stirred 15 h under hydrogen,
and the resulting solution was decanted to remove the
palladium catalyst. The decanted solution was concen-
trated and purified by short-path column chromatogra-
phy (EtOAc/hexane = 1:3 to only EtOAc) to give a
white solid 16 (36 mg, 100%): mp 78.5–79.5 ꢂC. IR (film)
2927, 2904, 2855, 1458, 1127 cmꢀ1; 1H NMR (CDCl3) d
3.82–3.49 (m, 12H), 3.35–3.23 (m, 2H), 2.69–1.24 (m,
8H); 13C NMR (CDCl3) d 75.3, 71.3, 66.8, 66.5, 31.5,
25.1; EIMS m/z (rel intensity) 230 (M+, 9), 87
(C4H7Oþ2 , 100); CIMS m/z (rel intensity) 231 (MH+,
59), 169 (MH+ꢀ62, 100). Anal. Calcd for C12H22O4:
C, 62.58; H, 9.63. Found: C, 62.53; H, 9.60.
(CDCl3) d 3.88–3.50 (m, 13 H), 3.36–3.22 (m, 2 H),
1.65–1.37 (m, 6H); 13C NMR (CDCl3), major diastereo-
mer, d 76.2, 75.2, 73.0, 71.3, 71.0, 70.5, 67.8, 66.8, 66.4,
37.8, 32.9, 27.2; EIMS m/z (rel intensity) 228 (M+ꢀH2O,
(rel intensity) 247 (MH+, 32), 229 (MH+ꢀH2O, 100).
Anal. Calcd for C12H22O5: C, 58.52; H, 9.00. Found:
C, 58.66; H, 8.96.
2), 145 (M+ꢀC5H9O2, 6), 87 (C4H7O þ, 100); CIMS m/z
2
4.21. (R)-2-Iodomethyl-[1,4]dioxane (19)
Imidazole (0.59 g, 8.7 mmol), triphenylphosphine
(1.17 g, 4.44 mmol), and iodine (1.13 g, 4.44 mmol) were
successively added to a solution of alcohol (S)-4 (0.50 g,
4.2 mmol) in toluene (10 mL). After stirring for 10 min
at room temperature, THF (10 mL) was added, and
the reaction mixture was allowed to stir 10 h. The result-
ing solution was quenched with saturated Na2S2O3 solu-
tion (20 mL) and extracted with diethyl ether
(3 · 20 mL). The extracts were washed with brine
(1 · 30 mL), dried over sodium sulfate, and concentrat-
ed under reduced pressure. The residue was extracted
with ether–hexane (3 mL/20 mL) to remove solid triphe-
nylphosphine oxide. The extract was concentrated and
purified by column chromatography (EtOAc/hex-
ane = 1:6) to give a clear liquid 19 (0.81 g, 84%): IR
4.19. 1,4-Bis{(R)-[1,4]dioxan-2-yl}-2-butanone (17)
1
(film) 2960, 2855, 1449, 1107, 913, 879 cmꢀ1; H NMR
Methyl iodide (0.13 mL, 2.1 mmol) and sodium bicar-
bonate (89.8 mg, 1.07 mmol) in water (4.0 mL) were
added to a solution of dithiane 15 (71.5 mg, 0.214 mmol)
in acetonitrile (4.0 mL) at room temperature. The reac-
(CDCl3) d 3.91–3.49 (m, 6H), 3.28 (dd, J = 9.7 Hz,
9.7 Hz, 1H), 3.05 (d, J = 6.1 Hz, 2H); 13C NMR
(CDCl3) d 74.2, 70.5, 66.7, 66.1, 2.7; EIMS m/z (rel
intensity) 228 (M+, 26), 127 (I+, 100), 101 (M+ꢀI, 48);

2676
H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
CIMS m/z (rel intensity) 229 (MH+, 49), 185
(MH+ꢀC2H4O, 192), 101 (MH+ꢀHI, 100). Anal. Calcd
for C5H9IO2: C, 26.34; H, 3.98; I, 55.65. Found: C,
26.42; H, 3.97; I, 55.49.
between ꢀ78 ꢂC and ꢀ65 ꢂC, and cooled to ꢀ78 ꢂC. A
solution of iodide 5 (0.13 g, 0.59 mmol) in THF (1.5
mL) was added to the solution via cannula. The reaction
mixture was slowly warmed up to room temperature
over 3 h, quenched with water (5 mL) and brine
(10 mL), and extracted with ethyl acetate (3 · 15 mL).
The combined extracts were dried over sodium sulfate
and concentrated under reduced pressure. The residue
was purified by column chromatography (EtOAc/hex-
ane = 1:3) to give a light yellow solid 22 (0.16 g, 86%):
mp 99.5–100.5 ꢂC. IR (film) 2953, 2906, 2850, 1445,
4.22. (S)-2-([1,3]Dithian-2-ylmethyl)-[1,4]dioxane (20)
A 1.95 M solution of n-BuLi (0.73 mL, 1.4 mmol) in
hexane was added to a solution of 1,3-dithiane
(0.2056 g, 1.710 mmol) in THF (2.0 mL) and HMPA
(0.3 mL) at ꢀ78 ꢂC. The solution was allowed to stir
for 30 min between ꢀ78 ꢂC and ꢀ65 ꢂC, and cooled to
ꢀ78 ꢂC. A solution of iodide 19 (0.13 g, 0.57 mmol) in
THF (1.0 mL) was added to the solution via cannula.
The reaction mixture was slowly warmed up to room
temperature overnight, quenched with water (5 mL)
and brine (10 mL), and extracted with ethyl acetate
(3 · 15 mL). The combined extracts were dried over
sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by column chromatogra-
phy (EtOAc/hexane = 1:7) to give a yellow solid 20
(98 mg, 78%): mp 63–64 ꢂC. IR (film) 2953, 2903,
1
1278, 1124, 1104 cmꢀ1; H NMR (CDCl3) d 3.88–3.79
(m, 2H), 3.78–3.49 (m, 10H), 3.27 (t, J = 10.8 Hz, 2H),
2.73–2.62 (m, 4H), 2.06–1.83 (m, 6H); 13C NMR
(CDCl3) d 72.6, 70.9, 66.4, 66.2, 50.6, 40.5, 26.3, 26.1,
24.8; EIMS m/z (rel intensity) 320 (M+, 10), 219
(M+ꢀC5H9O2, 21), 87 (C4H7O þ, 100); CIMS m/z (rel
2
intensity) 321 (MH+, 25), 179 (100). Anal. Calcd for
C14H24O4S2: C, 52.47; H, 7.55; S, 20.01. Found: C,
52.68; H, 7.53; S, 19.95.
4.25. 1,3-Bis{(R,S)-[1,4]dioxan-2-yl}propane (23)
1
2853, 1423, 1276, 1124 cmꢀ1; H NMR (CDCl3) d 4.19
(qt, J = 4.5 Hz, 1H), 3.91–3.55 (m, 6H), 3.26 (dd,
J = 9.9 Hz, J = 9.9 Hz, 1 H), 2.99–2.75 (m, 4H), 2.19–
1.57 (m, 4H); 13C NMR (CDCl3) d 71.5, 71.0, 66.7,
66.4, 42.3, 37.3, 30.4, 30.0, 25.8; EIMS m/z (rel intensity)
220 (M+, 3), 119 (C4H7S2þ, 100); CIMS m/z (rel intensi-
ty) 221 (MH+, 92), 87 (C4H7O2þ, 100). Anal. Calcd for
C9H16O2S2: C, 49.06; H, 7.32; S, 29.10. Found: C, 48.92;
H, 7.34; S, 29.18.
A solution of 22 (35.5 mg, 0.111 mmol) in absolute eth-
anol (2.0 mL) was added to a suspension of Raney nick-
el (0.25 g, pore size ca. 50 l) in absolute ethanol
(3.0 mL) at room temperature. The mixture was heated
at reflux for 20 h, and the resulting solution was decant-
ed to remove the nickel catalyst. The decanted solution
was concentrated and purified by column chromatogra-
phy (EtOAc/hexane = 1:1) to give a clear liquid 23
(20.1 mg, 84%): IR (film) 2956, 2909, 2852, 1449,
4.23. (S)-[1,4]Dioxan-2-yl-acetaldehyde (21)
1119 cmꢀ1 1H NMR (CDCl3) d 3.81–3.46 (m, 12H),
;
3.35–3.22 (m, 2H), 2.26–1.22 (m, 6H); 13C NMR
(CDCl3) d 75.6, 71.3, 67.2, 66.9, 31.9, 21.0; EIMS m/z
(rel intensity) 216 (M+, 6), 112 (C6H8O2þ, 100); CIMS
m/z (rel intensity) 217 (MH+, 100). Anal. Calcd for
C11H20O4: C, 61.09; H, 9.32. Found: C, 61.00; H, 9.29.
Methyl iodide (1.13 mL, 18.2 mmol) and sodium bicar-
bonate (0.76 g, 9.1 mmol) in water (4.0 mL) were added
to a solution of the 1,4-dioxanyl 1,3-dithiane 20 (0.40 g,
1.8 mmol) in acetonitrile (12.0 mL) at room tempera-
ture. The reaction mixture was stirred 15 h at 45 ꢂC
and cooled to room temperature. The resulting solution
was added to water (15 mL) and the mixture extracted
with ethyl acetate (3 · 15 mL) and dichloromethane
(15 mL). The combined organic layer was dried over
sodium sulfate and concentrated. The residue was puri-
fied by column chromatography (EtOAc/hexane = 1:3
to 1:1) to give the desired product 21 as a clear liquid
(0.18 g, 78%): IR (film) 2962, 2910, 2855, 2738, 1728,
4.26. 1,3-Bis{(S)-[1,4]dioxan-2-yl}-2-([1,3]dithian-2-
yl)propane (24)
A 1.95 M solution of n-BuLi (0.17 mL, 0.33 mmol) in
hexane was added to a solution of dithiane 20
(76.2 mg, 0.346 mmol) in THF (2.0 mL) and HMPA
(0.3 mL) at ꢀ78 ꢂC. The solution was allowed to stir
for 30 min between ꢀ78 ꢂC and ꢀ65 ꢂC, and cooled to
ꢀ78 ꢂC. A solution of iodide 19 (68.6 mg, 0.301 mmol)
in THF (1.0 mL) was added to the above solution via
cannula. The reaction mixture was slowly warmed up
to room temperature over 3 h, quenched with water
(5 mL) and brine (10 mL), and extracted with ethyl ace-
tate (3 · 15 mL). The combined extracts were dried over
sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by column chromatogra-
phy (EtOAc/hexane = 1:3) to give a light yellow oil 24
(82.4 mg, 86%): IR (film) 2953, 2906, 2851, 1446, 1278,
1126, 1093 cmꢀ1 1H NMR (CDCl3) d 9.78 (s, 1 H),
;
4.12 (m, 1H), 3.57–3.72 (m, 5H), 3.35 (dd, J = 10.0 Hz,
J = 10.0 Hz, 1H), 2.37–2.61 (m, 2H); 13C NMR (CDCl3)
d 199.8, 70.5, 70.4, 66.7, 66.3, 45.4; EIMS m/z (rel inten-
sity) 130 (M+, 3), 101 (M+ꢀCHO, 45), 87 (C4H7O
,
þ
2
100); CIMS m/z (rel intensity) 131 (MH+, 100). Anal.
Calcd for C6H10O3: C, 55.37; H, 7.74. Found: C,
55.30; H, 7.72.
4.24. 1,3-Bis{(R,S)-[1,4]dioxan-2-yl}-2-([1,3]dithian-2-
yl)propane (22)
1123, 1105 cmꢀ1 1H NMR (CDCl3) d 3.89 (m, 2H),
;
3.78–3.51 (m, 10H), 3.29 (dd, J = 10.2 Hz, J = 10.2 Hz,
2H), 2.87–2.69 (m, 4H), 2.05–1.85 (m, 6H); 13C NMR
(CDCl3) d 72.9, 71.3, 66.5, 66.2, 50.7, 42.1, 26.3, 24.þ6;
A 1.95 M solution of n-BuLi (0.33 mL, 0.65 mmol) in
hexane was added to a solution of dithiane 20 (0.15 g,
0.68 mmol) in THF (2.5 mL) and HMPA (0.4 mL) at
ꢀ78 ꢂC. The solution was allowed to stir for 30 min
EIMS m/z (rel intensity) 320 (M+, 7), 87 (C4H7O2
,
100); CIMS m/z (rel intensity) 321 (MH+, 9), 87

H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
2677
(C4H7O2þ, 100). Anal. Calcd for C14H24O4S2: C, 52.47;
H, 7.55; S, 20.01. Found: C, 52.36; H, 7.53; S, 19.96.
(MH+, 100), 115 (MH+ꢀH2O, 80). Anal. Calcd for
C6H12O3: C, 54.53; H, 9.15. Found: C, 54.35; H, 9.18.
4.27. 1,3-Bis{(S)-[1,4]dioxan-2-yl}propane (25)
4.30. (S)-2-[1,4]Dioxan-2-yl-ethanol (28)
A solution of 24 (37.6 mg, 0.118 mmol) in absolute eth-
anol (2.0 mL) was added to a suspension of Raney nick-
el (0.25 g, pore size ca. 50 lm) in absolute ethanol
(3.0 mL) at room temperature. The mixture was heated
at reflux for 15 h, and the resulting solution was decant-
ed to remove the nickel catalyst. The decanted solution
was concentrated and purified by column chromatogra-
phy (EtOAc/hexane = 1:2 to 1:1) to give a clear liquid 25
(17 mg, 67%): IR (film) 2953, 2911, 2851, 1449,
Sodium borohydride (6.1 mg, 0.16 mmol) was added to
a solution of aldehyde 21 (7.0 mg, 0.054 mmol) in meth-
anol (3.0 mL) at room temperature. The reaction mix-
ture was stirred for 30 min at ambient conditions and
the solvent was evaporated under reduced pressure.
The residue was dissolved in water (10 mL) and extract-
ed using a high-density continuous extractor with
dichloromethane (30 mL). The organic layer was dried
over sodium sulfate and concentrated to give a clear
oil 28 (7.1 mg, quantitative): IR (film) 3413, 2958,
1113 cmꢀ1 1H NMR (CDCl3) d 3.80–3.48 (m, 12H),
;
3.24 (dd, J = 10.0 Hz, J = 10.0 Hz, 2H), 1.54–1.20 (m,
6H); 13C NMR (CDCl3) d 75.3, 71.3, 66.8, 66.5, 31.6,
20.9; EIMS m/z (rel intensity) 216 (M+, 10), 112
(C6H8O2þ, 100); CIMS m/z (rel intensity) 217 (MH+,
100). Anal. Calcd for C11H20O4: C, 61.09; H, 9.32.
Found: C, 61.17; H, 9.30.
2857, 1655, 1450, 1124 cmꢀ1 1H NMR (CDCl3) d
;
3.83–3.57 (m, 8H), 3.34 (dd, J = 10.2 Hz, J = 10.2 Hz,
1H), 2.28 (s, 1H), 1.72–1.54 (m, 2H); 13C NMR (CDCl3)
d 75.2, 71.0, 66.8, 66.4, 60.4, 33.5; EIMS m/z (rel inten-
sity) 132 (M+, 16), 87 (M+ꢀCH2OH, 100); CIMS m/z
(rel intensity) 133 (MH+, 100), 115 (MH+ꢀH2O, 80).
Anal. Calcd for C6H12O3: C, 54.53; H, 9.15. Found:
C, 54.45; H, 9.17.
4.28. (R)-[1,4]Dioxan-2-yl-acetaldehyde (26)
Methyl iodide (1.41 mL, 22.7 mmol) and sodium bicar-
bonate (0.95 g, 11 mmol) in water (4.0 mL) were added
to a solution of the 1,4-dioxanyl 1,3-dithiane 6 (0.50 g,
2.3 mmol) in acetonitrile (12.0 mL) at room tempera-
ture. The reaction mixture was stirred 12 h at 45 ꢂC
and cooled to room temperature. The resulting solution
was to added water (15 mL) and the mixture extracted
with ethyl acetate (3 · 15 mL) and dichloromethane
(15 mL). The combined organic layer was dried over
sodium sulfate and concentrated. The residue was puri-
fied by column chromatography (EtOAc/hexane = 1:3
to 1:1) to give the desired product 26 as a clear liquid
(0.29 g, 98%): IR (film) 2962, 2910, 2855, 2738, 1728,
4.31. (R)-2-(2-Iodoethyl)-[1,4]dioxane (29)
Imidazole (0.20 g, 2.9 mmol), triphenylphosphine
(0.40 g, 1.5 mmol), and iodine (0.38 g, 1.5 mmol) were
added to a solution of alcohol 27 (0.19 g, 1.4 mmol) in
toluene (5 mL). After stirring for 10 min at room
temperature, THF (5 mL) was added and the mixture al-
lowed to stir 12 h. The resulting solution was quenched
with a saturated Na2S2O3 solution (10 mL) and extract-
ed with diethyl ether (3 · 20 mL). The extracts were
washed with brine (1 · 30 mL), dried over sodium sul-
fate, and concentrated under reduced pressure. The res-
idue was extracted with ether–hexane (1 mL:10 mL) to
remove solid triphenylphosphine oxide. The extract
was concentrated and purified by column chromatogra-
phy (EtOAc/hexane = 1:5) to give a clear liquid 29
(0.29 g, 84%): IR (film) 2957, 2853, 1446, 1120, 931,
1126, 1093 cmꢀ1 1H NMR (CDCl3) d 9.78 (s, 1H),
;
4.12 (m, 1H), 3.57–3.72 (m, 5H), 3.35 (dd, J = 10.0 Hz,
J = 10.0 Hz, 1H), 2.37–2.61 (m, 2H); 13C NMR (CDCl3)
d 199.8, 70.5, 70.4, 66.7, 66.3, 45.4; EIMS m/z (rel inten-
sity) 130 (M+, 3), 101 (M+ꢀCHO, 45), 86 (C4H6O
,
968 cmꢀ1 1H NMR (CDCl3) d 3.80–3.56 (m, 6H),
;
þ
2
100); CIMS m/z (rel intensity) 131 (MH+, 100). Anal.
Calcd for C6H10O3: C, 55.37; H, 7.74. Found: C,
55.30; H, 7.72.
3.36–3.22 (m, 3H), 1.98–1.89 (m, 2H); 13C NMR
(CDCl3) d 74.9, 70.4, 66.7, 66.5, 35.3, 1.1; EIMS m/z
(rel intensity) 242 (M+, 11), 115 (M+ꢀI, 46), 87
(M+ꢀCH2OH, 100); CIMS m/z (rel intensity) 243
(MH+, 72), 199 (MH+ꢀC2H4O, 100). Anal. Calcd for
C6H11IO2: C, 29.77; H, 4.58; I, 54.53. Found: C,
29.68; H, 4.59; I, 54.29.
4.29. (R)-2-[1,4]Dioxan-2-yl-ethanol (27)
Sodium borohydride (0.25 g, 6.7 mmol) was added to a
solution of aldehyde 26 (0.29 g, 2.2 mmol) in methanol
(8.0 mL) at room temperature. The reaction mixture
was stirred for 30 min at ambient temperature and the sol-
vent was evaporated under reduced pressure. The residue
was dissolved in water (10 mL) and extracted with dichlo-
romethane (30 mL) using a high-density continuous
extractor. The organic layer was dried over sodium sulfate
and concentrated to give a clear oil 27 (0.29 g, quantita-
4.32. (R)-2-(2-[1,3]Dithian-2-yl-ethyl)-[1,4]dioxane (30)
A 1.95 M solution of n-BuLi (0.26 mL, 0.52 mmol) in
hexane was added to a solution of 1,3-dithiane
(74.5 mg, 0.620 mmol) in THF (3.5 mL) and HMPA
(0.5 mL) at ꢀ78 ꢂC. The solution was allowed to stir
for 30 min between ꢀ78 ꢂC and ꢀ60 ꢂC, and cooled to
ꢀ78 ꢂC. A solution of iodide 29 (50 mg, 0.21 mmol) in
THF (1.5 mL) was added to the above solution via can-
nula. The reaction mixture was slowly warmed up to
room temperature over 5 h, quenched with water
(5 mL) and brine (10 mL), and extracted with ethyl ace-
tate (3 · 10 mL). The combined extracts were dried over
tive): IR (film) 3413, 2958, 2857, 1655, 1450, 1124 cmꢀ1
;
1H NMR (CDCl3) d 3.83–3.57 (m, 8H), 3.34 (dd,
J = 10.2 Hz, J = 10.2 Hz, 1H), 2.28 (s, 1H), 1.72–1.54
(m, 2H); 13C NMR (CDCl3) d 75.2, 71.0, 66.8, 66.4,
60.4, 33.5; EIMS m/z (rel intensity) 132 (M+, 16), 87
(M+ꢀCH2OH, 100); CIMS m/z (rel intensity) 133

2678
H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by column chromatogra-
phy (EtOAc/hexane = 1:6) to give a yellow solid 30
(47.5 mg, 98%): mp 90–91 ꢂC. IR (film) 2950, 2902,
idue was purified by column chromatography (EtOAc/
hexane = 1:1–2:1) to give a clear liquid 32 (79.3 mg,
1
35%): IR (film) 2960, 2859, 1736, 1118 cmꢀ1; H NMR
(CDCl3) d 9.66 (s, 1H), 4.12–3.37 (m, 7H); 13C NMR
(CDCl3) d 200.0, 78.9, 74.1, 71.3, 68.2; EIMS m/z (rel
intensity) 116 (M+, 5), 87 (M+ꢀCHO, 100); CIMS m/z
(rel intensity) 117 (MH+, 73), 99 (MH+ꢀH2O, 34) 87
(MH+ꢀCHOH, 100). Anal. Calcd for C5H8O3: C,
51.72; H, 6.94. Found: C, 51.63; H, 6.93.
1
2851, 1448, 1422, 1276, 1125 cmꢀ1; H NMR (CDCl3)
d 4.04 (t, J = 6.9 Hz, 1H), 3.80–3.55 (m, 6H), 3.29 (dd,
J = 9.9 Hz, J = 9.9 Hz, 1H), 2.89–2.84 (m, 4H), 2.18–
1.1.74 (m, 4H), 1.64–1.54 (m, 2H); 13C NMR (CDCl3)
d 74.8, 71.1, 66.7, 66.5, 47.3, 31.0, 30.3, 28.5, 25.9; EIMS
m/z (rel intensity) 234 (M+, 33), 132 (M+ꢀC5H10O2,
100), 119 (M+ꢀ C6H11O2, 83); CIMS m/z (rel intensity)
235 (MH+, 100). Anal. Calcd for C10H18O2S2: C, 51.24;
H, 7.71; S, 27.36. Found: C, 51.44; H, 7.71; S, 27.38.
4.35. 1-{(R)-[1,4]Dioxane-2-yl}ethan-1-ol (33)
A
solution of 3.0 M methylmagnesium bromide
(0.26 mL, 0.78 mmol) in diethyl ether was added to a
solution of the aldehyde 32 (60 mg, 0.52 mmol) in
THF (3.0 mL) at room temperature. The reaction mix-
ture was stirred for 2 h at room temperature, quenched
with water (10 mL), and a solution of 4.0 N HCl (5 mL)
was added. The solution was extracted with ethyl acetate
(10 mL) and dichloromethane (3 · 10 mL). The organic
layer was dried over sodium sulfate and concentrated.
The residue was purified by silica gel column chroma-
tography (EtOAc/hexane = 1:1–2:1) to give a clear li-
quid 33 (28.1 mg, 41%): IR (film) 3458, 2964, 2913,
4.33. (R)-3-([1,4]Dioxan-2-yl)propan-1-ol (31)
Methyl iodide (0.69 mL, 11.04 mmol) and sodium bicar-
bonate (0.46 g, 5.52 mmol) in water (10.0 mL) were added
to a solution of the 1,3-dithiane 30 (0.26 g, 1.10 mmol) in
acetonitrile (8.0 mL) at room temperature. The reaction
mixture was stirred for 12 h at 40 ꢂC and cooled to room
temperature. Water (10 mL) was added to the resulting
solution and the mixture was extracted with ethyl acetate
(2 · 10 mL) and dichloromethane (2 · 10 mL). The com-
bined organic layer was dried over sodium sulfate and
concentrated. The residue was purified by silica gel flash
chromatography (EtOAc/hexane = 3:1–1:1) to give an
aldehyde intermediate as a clear liquid (0.13 g, 84%).
The aldehyde was immediately used in the next step. Sodi-
um borohydride (0.11 g, 2.79 mmol) was added to a solu-
tion of aldehyde (0.13 g, 0.93 mmol) in methanol (6.0 mL)
at room temperature. The reaction mixture was stirred for
1 h at ambient condition and the solvent was evaporated
under reduced pressure. The residue was dissolved in
water (10 mL) and extracted with dichloromethane
(3 · 10 mL). The organic layer was dried over sodium sul-
fate and concentrated to give a clear liquid 31 (0.12 g,
85%): IR (film) 3413, 2953, 2918, 2854, 1652, 1449,
1
2858, 1450, 1118 cmꢀ1; H NMR (CDCl3) d 3.87–3.35
(m, 8H), 2.07 (br s, 1H), 1.13 (dd, J = 6.6 Hz,
J = 6.4 Hz, 3H); 13C NMR (CDCl3), major diastereo-
mer, d 74.6, 71.9, 68.8, 68.3, 66.9, 18.7; EIMS m/z (rel
intensity) 132 (M+, 1), 87 (C4H7O2
, 100), 45
þ
(CH3CHOH+, 100); CIMS m/z (rel intensity) 133
(MH+, 3), 115 (MH+ꢀH2O, 100). Anal. Calcd for
C6H12O3: C, 54.53; H, 9.15. Found: C, 54.63; H, 9.17.
4.36. (R)-2-(3-Iodopropyl)-[1,4]dioxane (34)
Imidazole (0.11 g, 1.6 mmol), triphenylphosphine (0.22 g,
0.83 mmol), and iodine (0.21 g, 0.83 mmol) were added to
a solution of alcohol 31 (0.12 g, 0.79 mmol) in toluene
(5 mL). After stirring for 10 min at room temperature,
THF (5 mL) was added and the mixture allowed to stir
15 h. The resulting solution was quenched with saturated
Na2S2O3 solution (10 mL) and extracted with diethyl
ether (3 · 20 mL). The extracts were washed with brine
(1 · 30 mL), dried over sodium sulfate, and concentrated
under reduced pressure. The residue was extracted with
ether/hexane (1 mL:10 mL) to remove solid triphenyl-
phosphine oxide. The extract was concentrated and puri-
fied by silica gel flash chromatography (EtOAc/
hexane = 1:5) to give a clear liquid 34 (0.16 g, 77%): IR
1125 cmꢀ1 1H NMR (CDCl3) d 3.81–3.51 (m, 8 H),
;
3.27 (dd, J = 10.1 Hz, J = 10.1 Hz, 1H), 1.98 (br s, 1H),
1.71–1.62 (m, 2H), 1.52–1.39 (m, 2H); 13C NMR (CDCl3)
d 75.5, 71.2, 66.8, 66.4, 62.7, 28.8, 28.4; EIMS m/z (rel
intensity), 146 (M+, 1), 128 (M+ꢀH2O, 6), 87
(C4H7O2þ, 72), 59 [(CH2)3OH+, 100]; CIMS m/z (rel
intensity) 147 (MH+, 22), 129 (MH+ꢀH2O, 100). Anal.
Calcd for C7H14O3: C, 57.51; H, 9.65. Found: C, 57.64;
H, 9.62.
4.34. (R)-[1,4]Dioxane-2-carbaldehyde (32)
(film) 2955, 2909, 2851, 1447, 1121 cmꢀ1 1H NMR
;
A solution of 2.0 M oxalyl chloride (1.46 mL, 2.92 mmol)
in dichloromethane was diluted in dry dichloromethane
(6.0 mL). Dimethyl sulfoxide (0.28 mL, 3.9 mmol) was
added dropwise to this solution at ꢀ78 ꢂC. After
10 min, a solution of dioxane-alcohol starting material
(S)-4 (0.23 g, 2.0 mmol) in dichloromethane (4.0 mL)
was added dropwise over 5 min at ꢀ78 ꢂC, followed by
addition of triethylamine (1.36 mL, 9.74 mmol). The
reaction mixture was slowly warmed up to room temper-
ature over 5 h and quenched with water (10 mL). The
resulting solution was extracted with dichloromethane
(3 · 10 mL), and the organic layer was dried over sodium
sulfate and concentrated under reduced pressure. The res-
(CDCl3) d 3.76–3.49 (m, 6 H), 3.29–3.16 (m, 3H), 2.04–
1.78 (m, 2H), 1.50–1.42 (m, 2H); 13C NMR (CDCl3) d
74.4, 71.2, 66.8, 66.5, 32.3, 29.1, 6.68; EIMS m/z (rel inten-
sity) 256 (M+, 0.2), 129 (M+ꢀI, 100); CIMS m/z (rel inten-
sity) 257 (MH+, 17), 129 (MH+ – HI, 100). Anal. Calcd for
C7H13IO2: C, 32.83; H, 5.12; I, 49.56. Found: C, 32.90; H,
5.14; I, 49.46.
4.37. 1,5-Bis{(R)-[1,4]dioxan-2-yl}-2-{[1,3]dithian-2-
yl}pentane (35)
A 1.60 M solution of n-BuLi in hexane (0.44 mL,
0.71 mmol) was added to a solution of dithiane

H. Y. Kim et al. / Bioorg. Med. Chem. 15 (2007) 2667–2679
2679
(0.17 g, 0.77 mmol) in THF (3.0 mL) and HMPA
(0.5 mL) at ꢀ78 ꢂC. The solution was allowed to stir
for 30 min between ꢀ78 ꢂC and ꢀ40 ꢂC, and cooled to
ꢀ78 ꢂC. A solution of iodide 34 (0.14 g, 0.55 mmol) in
THF (2.0 mL) was added to the above solution via can-
nula. The reaction mixture was slowly warmed up to
room temperature over 3 h, quenched with water
(15 mL) and brine (10 mL), and extracted with ethyl ace-
tate (3 · 15 mL). The combined extracts were dried over
sodium sulfate and concentrated under reduced pres-
sure. The residue was purified by silica gel column chro-
matography (EtOAc/hexane = 1:3 to 1:2) to give a light
yellow oil 35 (92.1 mg, 48%): IR (film) 2952, 2908, 2851,
J = 7.6 Hz, 1H), 2.45 (t, J = 7.2 Hz, 2H), 2.30 (dd,
J = 5.1 Hz, J = 5.1 Hz, 1H), 1.77–1.52 (m, 2H), 1.42–
1.22 (m, 2H); 13C NMR (CDCl3) d 207.5, 75.1, 71.6,
22
D
71.2, 70.7, 66.7, 66.5, 66.3, 44.6, 43.4, 30.8, 19.1; ½aꢂ
+0.3 (c 0.268, CHCl3); EIMS m/z (rel intensity) 258
(M+, 4), 87 (C4H7O2þ, 100); CIMS m/z (rel intensity)
259 (MH+, 27), 197 (MH+ꢀ62, 89), 135 (MH+ꢀ124,
100). Anal. Calcd for C13H22O5: C, 60.45; H, 8.58.
Found: C, 60.37; H, 8.55.
Acknowledgment
1
1447, 1277, 1123 cmꢀ1; H NMR (CDCl3) d 3.90–3.79
This work was made possible by the National Institutes
of Health (NIH) through support with RCE Award U54
AI57153. This research was conducted in a facility con-
structed with support from Research Facilities Improve-
ment Program Grant Number C06-14499 from the
National Center for Research Resources of the National
Institutes of Health.
(m, 1 H), 3.79–3.49 (m, 10 H), 3.32–3.20 (m, 2H),
2.83–2.70 (m, 4H), 2.03–1.80 (m, 6H), 1.22–1.79 (m,
5H); 13C NMR (CDCl3) d 75.1, 72.9, 71.3, 66.9, 66.6,
66.3, 52.0, 40.1, 39.1, 31.7, 26.2, 25.2, 19.9; EIMS m/z
(rel intensity) 348 (M+, 72), 219 (M+ꢀC7H13O2, 56),
87 (C4H7O2þ, 100); CIMS m/z (rel intensity) 349
(MH+, 100). Anal. Calcd for C16H28O4S2: C, 55.14; H,
8.10; S, 18.40. Found: C, 55.22; H, 8.11; S, 18.35.
References and notes
4.38. 1,5-Bis{(R)-[1,4]dioxan-2-yl}pentane (36)
1. Strauss, J. H.; Strauss, E. G.; Hahn, C. S.; Hahn, Y. S.;
Galler, R.; Hardy, R. W.; Rice, C. M. In Positive Strand
RNA Viruses, UCLA Symposia on Molecular and Cellular
Biology; Brinton, M. A., Rueckert, R., Eds.; Alan R. Liss:
New York, 1987; pp 209–225.
2. Murphy, F. A. In The Togaviruses; Schlesinger, R. W.,
Ed.; Academic: New York, 1980; pp 241–316.
3. Burke, D. S.; Monath, T. P. In Fields Virology; Knipe, D.
M., Howley, P. M., Eds., 4th ed.; Lippencott Williams and
Wilkins: Philadelphia, 2001; pp 1043–1125.
4. Griffin, D. E. In Fields Virology; Knipe, D. M., Howley, P.
M., Eds., 4th ed.; Lippincott Williams and Wilkins:
Philadelphia, 2001; pp 917–962.
5. Kim, H. Y.; Patkar, C.; Warrier, R.; Kuhn, R.; Cushman,
M. Bioorg. Med. Chem. Lett. 2005, 15, 3207–3211.
6. Lee, S.; Owen, K. E.; Choi, H.-K.; Lee, H.; Lu, G.;
Wengler, G.; Brown, D. T.; Rossmann, M. G.; Kuhn, R.
J. Structure 1996, 4, 531–541.
A solution of dioxane–dithiane starting material 35
(55 mg, 0.16 mmol) in absolute ethanol (3.0 mL) was
added to a suspension of Raney nickel (0.3 g, pore size
ca. 50 lm) in absolute ethanol (3 mL) at room tempera-
ture. The mixture was heated at reflux for 15 h, and the
resulting solution was decanted to remove the nickel cat-
alyst. The decanted solution was concentrated and puri-
fied by short-pass column chromatography (EtOAc/
hexane = 1:3 to only EtOAc) to give a clear liquid 36
(32.4 mg, 84%): IR (film) 2933, 2853, 1449, 1115 cmꢀ1
;
1H NMR (CDCl3) d 3.77–3.64 (m, 8H), 3.51–3.45 (m,
4H), 3.23 (dd, J = 10.0 Hz, J = 10.0 Hz, 2H), 1.48–1.21
(m, 10H); 13C NMR (CDCl3) d 75.3, 71.4, 66.8, 66.5,
22
31.6, 29.6 24.9; ½aꢂ +2.1 (c 0.574, CHCl3); EIMS m/z
D
(rel intensity) 244 (M+, 4), 87 (C4H7O2þ, 100); CIMS
m/z (rel intensity) 245 (MH+, 100). Anal. Calcd for
C13H24O4: C, 63.91; H, 9.90. Found: C, 64.01; H, 9.91.
7. Owen, K. E.; Kuhn, R. J. Virology 1997, 230, 187–196.
8. Lee, S.; Kuhn, R. J.; Rossmann, M. G. Proteins 1998, 33,
311–317.
9. Pallavicini, M.; Valoti, E.; Villa, L. Enantiomer 2001, 6,
267–273.
4.39. 1,5-Bis{(R)-[1,4]dioxan-2-yl}pentan-2-one (37)
10. Nagumo, Y.; Oguri, H.; Shindo, Y.; Sasaki, S.; Oishi, T.;
Hirama, M.; Tomioka, Y.; Mizugaki, M.; Tsumuraya, T.
Bioorg. Med. Chem. Lett. 2001, 11, 2037–2040.
11. Solladie, G.; Zianicherif, C. J. Org. Chem. 1993, 58, 2181–
2185.
12. Mehta, G.; Murthy, A. N. J. Org. Chem. 1987, 52, 2875–
2881.
13. Werner, L. H.; Scholz, C. R. J. Am. Chem. Soc. 1954, 76,
2701–2705.
Methyl iodide (71 lL, 1.2 mmol) and sodium bicarbon-
ate (48.2 mg, 0.57 mmol) in water (5.0 mL) were added
to a solution of dithiane 35 (40 mg, 0.11 mmol) in aceto-
nitrile (5.0 mL) at room temperature. The reaction mix-
ture was stirred 12 h at 40 ꢂC and cooled to room
temperature. The resulting solution was added to water
(10 mL) and extracted with ethyl acetate (3 · 15 mL).
The combined organic layer was dried over sodium sul-
fate and concentrated. The residue was purified by col-
umn chromatography (EtOAc/hexane = 1:1 to only
EtOAc) to give a white solid 37 (26 mg, 88%): mp 47–
14. Evans, R. D.; Magee, J. W.; Schauble, J. H. Synthesis
1988, 862–868.
15. Hosokawa, S.; Isobe, M. J. Org. Chem. 1999, 64, 37–48.
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R. A. Antiviral Res. 1987, 8, 1–12.
47.5 ꢂC. IR (film) 2936, 2885, 2855, 1701, 1115 cmꢀ1
;
1H NMR (CDCl3) d 4.06–3.96 (m, 1H), 3.76–3.44 (m,
11H), 3.29–3.18 (m, 2H), 2.55 (dd, J = 7.6 Hz,