Sulfone and phosphinic acid analogs of decaprenolphosphoarabinose as potential anti-tuberculosis agents

Article abstract of DOI:10.1016/j.bmc.2004.08.014

Mycobacteria biosynthesize a cell wall structure that is rich in polysaccharides containing arabinofuranose residues. The source of these arabinofuranose residues is decaprenolphosphoarabinose (1), the donor substrate for mycobacterial arabinosyltransferases. We have previously demonstrated that an analog of 1, C-phosphonate 7, prevented the growth of mycobacteria and this compound is currently undergoing testing for efficacy in tuberculosis-infected mice. We describe here the synthesis and testing of additional analogs of 1 that contain either a sulfone (8-14) or phosphinic acid (15-19) moiety in place of the phosphodiester functionality. Screening of these compounds in vitro against Mycobacterium tuberculosis strain H₃₇Rv revealed that while some of these compounds possessed low to modest activity, none was as potent as 7.

Full text of DOI:10.1016/j.bmc.2004.08.014

Bioorganic & Medicinal Chemistry 12 (2004) 5495–5503
Sulfone and phosphinic acid analogs of
decaprenolphosphoarabinose as potential anti-tuberculosis agents
Charla A. Centrone and Todd L. Lowary*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA
Received 16 July 2004; revised 30 July 2004; accepted 12 August 2004
Available online 11 September 2004
Abstract—Mycobacteria biosynthesize a cell wall structure that is rich in polysaccharides containing arabinofuranose residues. The
source of these arabinofuranose residues is decaprenolphosphoarabinose (1), the donor substrate for mycobacterial arabinosyl-
transferases. We have previously demonstrated that an analog of 1, C-phosphonate 7, prevented the growth of mycobacteria
and this compound is currently undergoing testing for efficacy in tuberculosis-infected mice. We describe here the synthesis and test-
ing of additional analogs of 1 that contain either a sulfone (8–14) or phosphinic acid (15–19) moiety in place of the phosphodiester
functionality. Screening of these compounds in vitro against Mycobacterium tuberculosis strain H37Rv revealed that while some of
these compounds possessed low to modest activity, none was as potent as 7.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
O
P
HO
O
All mycobacteria, including the human pathogen Myco-
bacterium tuberculosis, produce a cell wall structure that
fulfills an important role in protecting these organisms
from their environment.1,2 Two polysaccharides, arabi-
nogalactan (AG) and lipoarabinomannan (LAM), are
major structural components of the cell wall in these
organisms. An unusual structural feature of these gly-
cans is that all of the arabinose and galactose residues
exist in the furanose ring form. The arabinan compo-
nent of AG and LAM is biosynthesized by a family of
arabinosyltransferases (AraTÕs) that use decaprenol-
phosphoarabinose (DPA, 1, Fig. 1) as the donor of the
arabinofuranose residues.3–6
HO
O
O
O
8
HO
1
Figure 1. Decaprenolphosphoarabinose, DPA.
furanose residues into AG and LAM. Polysaccharides
containing furanose residues are unknown in mammals
and the enzymes that are involved in the biosynthesis
of these glycans are therefore ideal targets for drug ac-
tion.9,10 The emergence of drug resistant strains of
mycobacteria11,12 and the resurgence of these diseases,
in particular in immunocompromised individuals,13
has prompted increasing interest in the identification
of new anti-mycobacterial drugs.
Mycobacteria require an intact cell wall for viability and
therefore compounds that inhibit the enzymes responsi-
ble for biosynthesizing this structure have potential as
anti-mycobacterial agents.7,8 Of particular note are the
enzymes that introduce the galactofuranose and arabino-
We have a long-standing interest in inhibitors of myco-
bacterial AraTÕs given their demonstrated suitability as
targets for drug action. Previous studies14–16 have shown
that ethambutol, a drug used in the treatment of tuber-
culosis, inhibits the AraTÕs that produce the arabinan
component of AG and LAM. In an earlier report,17
we described the synthesis of a panel of C-phospho-
nate-based DPA analogs (2–7, Chart 1) and their subse-
quent evaluation as anti-tuberculosis agents. It was
Keywords: Mycobacteria; Glycolipid analogs; Sulfones; Phosphinic
acids.
*
Corresponding author at present address: Alberta Ingenuity Centre
for Carbohydrate Science, Department of Chemistry, The University
of Alberta, Gunning–Lemieux Chemistry Centre, Edmonton, AB
T6G 2G2, Canada. Tel.: +78 0492 1861; fax: +78 0492 7705; e-mail:
tlowary@ualberta.ca
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.08.014

5496
C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
O
S
O
P
O
P
HO
O
OR
HO
HO
O
HO
R
HO
O
R
HO
O
O
O
O
HO
HO
HO
2, R = (CH2)6CH3
3, R = (CH2)7CH3
4, R = (CH2)8CH3
5, R = (CH2)9CH3
6, R = (CH2)11CH3
7, R = (CH2)15CH3
15, R = (CH2)7CH3
16, R = (CH2)9CH3
17, R = (CH2)11CH3
18, R = (CH2)15CH3
19, R = (CH2)19CH3
8, R = (CH2)8CH3
9, R = (CH2)9CH3
10, R = (CH2)11CH3
11, R = (CH2)15CH3
12, R = (CH2)19CH3
13, R = (CH2)10O(CH2)15CH3
14, R =
Chart 1.
expected that replacement of the glycosidic oxygen in 1
with a methylene group would provide compounds that
would be bound by mycobacterial AraTÕs, but that
could not turn over therefore blocking cell wall biosyn-
thesis and killing the organism. When tested against M.
tuberculosis strain H37Rv, only one of these C-phospho-
nates, 7, was shown to prevent the growth of the organ-
ism in vitro, with an MIC value of 3.13lg/mL. Further
studies18 revealed that 7 had an IC50 against Vero cells
of 36.4lg/mL and thus the selectivity index19 was 11.6.
Based on these results, C-phosphonate 7 is currently
being tested for efficacy in tuberculosis-infected mice.
Given this success, we chose to prepare additional
DPA analogs in which the phosphate group was
replaced with other isosteres. We describe here the syn-
thesis of a series of glycosyl sulfone20,21 DPA analogs
(8–14) and their evaluation as potential anti-tuberculosis
agents. We also describe the results of screening a panel
of phosphinic acid-containing DPA analogs (15–19)
against M. tuberculosis. The synthesis of these phosphi-
nic acids has been previously reported.22
2. Results and discussion
2.1. Synthesis of glycosyl sulfones
The synthesis of the glycosyl sulfones 8–11 (Scheme 1)
began with iodide 21, which was prepared in two steps
from commercially available 2,3,5-tri-O-benzyl-D-arab-
inofuranose, 20.23 Reaction of 21 with potassium thioac-
etate afforded 22 in 94% yield and conversion to thiol 23
was achieved with lithium aluminum hydride (97%). We
also attempted this deacylation under milder reaction
conditions (e.g., sodium borohydride, or sodium meth-
oxide), however the yields were lower due to the forma-
tion of significant amounts of a byproduct. The spectral
data for this byproduct was consistent with it being
disulfide 24. Alkylation of 23 with sodium hydride and
commercially available linear alkyl iodides (C9, C10,
C12, and C16) afforded sulfides 25–28 in 65–82% yield.
Attempts to directly synthesize these sulfides by reaction
of iodide 21 with various long-chain alkyl thiolate salts
gave lower yields of the product, and thus we view the
OBn
BnO
O
OH
BnO
20
2 steps
Ref 23
O
S
HO
O
BnO
O
HO
BnO
BnO
O
X
R
BnO
SR
d
BnO
O
BnO
S
O
HO
BnO
BnO
c
BnO
24
21, X = I
22, X = SAc
23, X = SH
a
b
2
25, R = (CH2)8CH3
26, R = (CH2)9CH3
27, R = (CH2)11CH3
28, R = (CH2)15CH3
8, R = (CH2)8CH3
9, R = (CH2)9CH3
10, R = (CH2)11CH3
11, R = (CH2)15CH3
Scheme 1. Reagents and conditions: (a) KSAc, DMF, rt, 94%; (b) LiAlH4, Et2O, rt, 97%; (c) for synthesis of 25: CH3(CH2)8I, NaH, DMF, rt, 72%;
for synthesis of 26: CH3(CH2)9I, n-BuLi, Et2O, 0ꢁC ! rt, 65%; for synthesis of 27: CH3(CH2)11I, NaH, DMF, rt, 82%; for synthesis of 28:
CH3(CH2)15I, NaH, DMF, rt, 74%; (d) m-CPBA, CH2Cl2, rt, followed by workupand then H 2, Pd/C, CH3OH, HOAc, rt, yields of: 8—79%, 9—
85%, 10—76%, and 11—49%.

C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
5497
form 1-hexadecene. Deprotection of the tetrahydropyr-
anyl ether was achieved by heating 34 in a mixture of
acetic acid, tetrahydrofuran, and water at 65ꢁC, yielding
35 in 84% yield. Conversion of 35 into the correspond-
ing tosylate, 36, required comparably vigorous
conditions (potassium hydride, 18-crown-6, p-toluene-
sulfonyl chloride) and provided the product in only
low (26%) yield. More conventional methods for prepa-
ration of this tosylate (p-toluenesulfonyl chloride, pyri-
dine) failed. With 36 in hand, it was coupled with 23
in the presence of potassium hydride and 18-crown-6
providing the thioether, 37, which could not be sepa-
rated from unreacted 36. Therefore, the crude mixture
of 36 and 37 was oxidized with m-chloroperoxybenzoic
acid to afford, after purification, sulfone 38 in 30% over-
all yield from 23. In an effort to improve the coupling
yield of 36 and 23, the use of n-BuLi in THF and
NaH in DMF was explored, but under these conditions
the major product was disulfide 24 (see Scheme 1).
Hydrogenolysis of 38 yielded 13 in 60% yield.
BnO
O
BnO
X
TsO(CH2)19CH3
29
BnO
23, X = SH
30, X = S(CH2)19CH3
31, X = SO2(CH2)19CH3
a
b
c
12
Scheme 2. Reagents and conditions: (a) 29, n-BuLi, THF, 0ꢁC ! rt;
(b) m-CPBA, CH2Cl2, rt, 30% from 23; (c) H2, Pd/C, CH3OH, HOAc,
rt, 80%.
indirect approach via 23 as superior. Oxidation of 25–28
with m-chloroperoxybenzoic acid yielded the corre-
sponding benzylated sulfones, which were then depro-
tected by hydrogenolysis yielding 8–11 in 49–85% yield
over the two steps.
The synthesis of sulfone 12 (Scheme 2) involved the cou-
pling of 23 with 1-p-toluenesulfonyloxyeicosane, 29,
which was prepared from 1-eicosanol and p-toluene-
sulfonyl chloride.22 The product sulfide, 30, was impos-
sible to separate from 29 and thus the crude product was
oxidized affording, after purification, sulfone 31 in 50%
yield from 23. Hydrogenolysis provided target 12 in 80%
yield.
The final target, 14, was synthesized as outlined in
Scheme 4 in a manner analogous to the other com-
pounds. Thiol 23 was alkylated with geranyl tosylate,
39, generated in situ from gerianol, to afford 40 in
76% yield. Oxidation of 40 provided 41 in 53% yield,
which was then deprotected yielding 14 in 64% yield.
We endeavored to prepare a sulfone with a longer
(>C20) alkyl group and therefore explored the prepara-
tion of a tosylate from 1-triacontanol (CH3(CH2)29OH).
However, the extreme insolubility of this C30 alcohol in
essentially all common organic solvents (e.g., hexanes,
THF, pyridine, glacial acetic acid, CHCl3, and mixtures
of these and other solvents), made this impractical. In-
stead, we opted to prepare a long-chain alkylating agent
containing an ether linkage, which we anticipated would
increase solubility in organic solvents. Because 7, which
is active against M. tuberculosis, has an oxygen atom in
the linear chain, we did not anticipate that the inclusion
of an ether moiety into a sulfone analog would abrogate
activity. Thus, commercially available 1,10-decanediol,
32, was reacted (Scheme 3) with 3,4-dihydropyran and
a catalytic amount of p-toluenesulfonic acid. The mono-
protected alcohol, 33, was obtained in 53% yield along
with the corresponding bis-tetrahdropyranyl acetal and
unreacted 32. Alcohol 33 was then alkylated with 1-
iodohexadecane to afford 34 in low (21%) yield. At-
tempts to improve the yield by increasing the reaction
temperature, led only to elimination of the iodide to
2.2. Screening of compounds as potential anti-mycobac-
terial agents
DPA analogs 8–20 were screened for their ability to pre-
vent the growth of M. tuberculosis strain H37Rv using
the fluorescence-based Alamar Blue microplate assay.24
This assay makes use of the Alamar Blue dye that
changes from blue (and non-fluorescent) to pink (and
fluorescent) in the presence of the growing bacteria.
Compounds that prevent the growth of the organism
thus result in a decrease in fluorescence, which is quant-
itated. The results obtained when compounds 8–20 were
tested in this assay are presented in Table 1. For pur-
poses of comparison, the data previously obtained for
7 is also included.
From the results presented in the table, it is clear that
none of the sulfone (8–14) or phosphinic acid (15–20)
DPA analogs were as potent inhibitors of mycobacterial
growth as C-phoshonate 7. Although some compounds
did show some activity, the amount of growth inhibition
is low to modest and not at a level that warrants further
b
e
BnO
O
BnO
X
X
O
X
7
HO
a
3
3
34, X = OTHP
35, X = OH
36, X = OTs
c
BnO
32, X = OH
33, X = OTHP
d
37, X = S(CH2)10O(CH2)15CH3
38, X = SO2(CH2)10O(CH2)15CH3
g
f
13
Scheme 3. Reagents and conditions: (a) 3,4-dihydropyran, p-TsOH, THF, rt, 53%; (b) CH3(CH2)15I, NaH, DMF, rt, 21%; (c) AcOH, THF, H2O,
65ꢁC, 84%; (d) p-TsCl, KH, 18-crown-6, THF, rt, 26%; (e) 23, KH, 18-crown-6, THF, rt; (f) m-CPBA, CH2Cl2, rt, 45% from 36; (g) H2, Pd/C,
CH3OH, AcOH, 60%.

5498
C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
BnO
O
BnO
SH
BnO
O
BnO
a
X
TsO
BnO
39
BnO
23
40, X = S
41, X = SO2
c
b
14
Scheme 4. Reagents and conditions: (a) 39, n-BuLi, THF À78ꢁC, 76%; (b) NaIO4, CH3OH, H2O, 70ꢁC, 53%; (c) H2, Pd/C, CH3OH, AcOH, 64%.
Table 1. Activity of 7–20 against M. tuberculosis strain H37Rva
mycobacterial agents. None of these compounds was
Compound
% Inhibition
shown to have appreciable activity. However, it is inter-
esting to note that the most active of these compounds,
azasugars 45 and 46, contain a C12 alkyl chain, as does
the most active of our sulfone and phosphinic acid ana-
logs (10 and 17, respectively). The significance of this
observation is unclear in view of the low anti-tuberculo-
sis activity of these compounds.
7b
8
92
0
9
21
45
0
10
11
12
13
14
15
16
17
18
19
4
0
20
0
The apparent failure of the phosphinic acid in the long-
chain analogs (e.g., 18 and 19) to serve as mimics of the
phosphate group in 1 is somewhat surprising and could
be due to the difference in pKa between the phosphate
and phosphinic acid protons. The proton of a phos-
phoric acid diester (e.g., 1) would be expected26 to be
more acidic than the proton in an analogous phosphinic
acid and thus the former should be significantly more
ionized at physiological pH. The degree of ionization
of this moiety would likely influence the binding of these
compounds to the enzyme and hence their inhibitory
and anti-tuberculosis potential. Consistent with this
hypothesis is the lack of activity of the sulfones, which
cannot be ionized.
0
17
0
0
a All compounds were screened at a concentration of 6.25lg/mL using
the Alamar Blue assay.24
b Taken from Ref. 17; 7 has a MIC of 3.13lg/mL.
screening of these compounds as potential anti-tubercu-
losis agents. Moreover, the results demonstrate that no
clear correlation exists between structure and biological
activity. For example, in our previous studies with C-
phosphonates 2–7, it was demonstrated that only the
analog with the longest alkyl chain was active. However,
the same trend is not observed with these sulfone and
phosphinic acid-containing compounds.
In summary, we have described the synthesis of analogs
of decaprenolphosphoarabinose (1), the mycobacterial
donor substrate of arabinofuranose residues. Screening
of these compounds for anti-tuberculosis activity
showed that although some compounds did inhibit the
growth of the organism, the effects were low to modest.
Therefore, more detailed study of these compounds,
either in additional assays or in investigations to deter-
mine their mode of action (perhaps as inhibitors of
To the best of our knowledge, no previous phosphinic-
acid containing DPA analogs have been synthesized or
tested for anti-mycobacterial activity. In contrast, a pre-
vious report,25 has described the preparation and testing
of five sulfone DPA analogs (42–46, Fig. 2) as anti-
O
O
HO
OH
HO
O
HO
S
S
HO
Ph
HO
H
O
S
Ph
O
O
N
Ph
O
HO
O
HO
HO
42
43
44
O
S
HO
OH
H
HO
N
HO
H
(CH2)11CH3
O
S
N
(CH2)11CH3
O
HO
O
HO
45
46
Figure 2. Previous sulfone-containing DPA analogs tested for anti-mycobacterial activity.

C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
5499
mycobacterial AraTÕs) is likely of only limited value in
the context of drug development.
added and the mixture stirred for 20min. Workupas de-
scribed for the oxidation of 25 yielded a crude sulfone
(251mg) that was, without further purification, dis-
solved in CH3OH (5mL) containing AcOH (10lL). Pal-
ladium on carbon (10%, 40mg) was added and the
mixture was stirred under H2 overnight. After filtering
the solid and evaporating the solvent, the residue was
purified by chromatography (EtOAc) to afford 9
(92mg, 85% over two steps) as a white solid: Rf 0.25
(EtOAc); mp88–89 ꢁC; [a]D +8.7 (c 1.0, CHCl3); 1H
NMR (400MHz, CDCl3) dH 0.85 (t, 3H, J = 6.8Hz),
1.34–1.18 (m, 12H), 1.43–1.35 (m, 2H), 1.83–1.73 (m,
2H), 3.15–3.03 (m, 2H), 3.32 (dd, 1H, J = 14.8,
4.6Hz), 3.41 (dd, 1H, J = 14.8, 8.4Hz), 3.79–3.68 (m,
2H), 3.92–3.87 (m, 1H), 4.07–3.99 (m, 2H), 4.17–4.13
(m, 1H), 4.27–4.22 (m, 1H), 4.51–4.45 (m, 1H), 4.71–
4.67 (m, 1H); 13C NMR (100MHz, CDCl3) dC 14.1,
21.7, 22.7, 28.5, 29.2, 29.3, 29.4, 29.5, 31.9, 52.8, 54.2,
62.1, 75.4, 78.0, 78.3, 86.1; HRMS calcd for C16H32O6S-
Na+: 375.1812. Found: 375.1804.
3. Experimental
3.1. General methods
Solvents were distilled from the appropriate drying
agents before use. Unless stated otherwise, all reactions
were carried out at room temperature under a positive
pressure of argon and were monitored by TLC on silica
gel 60 F254. Spots were detected under UV light or by
charring with 10% H2SO4 in ethanol. All hydrogenolysis
reactions were carried out at atmospheric pressure. Sol-
vents were evaporated under reduced pressure and below
40ꢁC (bath). Organic solutions of crude products were
dried over anhydrous Na2SO4. Column chromatography
was performed on silica gel 60 (40–60lM). The ratio be-
tween silica gel and crude product ranged from 100 to
50:1 (w/w). Optical rotations were measured at
21 2ꢁC. Melting points are uncorrected. 1H NMR
spectra were recorded at 250, 400, or 500MHz, and
chemical shifts are referenced to either TMS (0.0, CDCl3)
or CD3OH (4.78, CD3OD). 13C NMR spectra were re-
corded at 62.5, 100, or 125MHz and chemical shifts
are referenced to CDCl3 (77.00, CDCl3) or CD3OD
(49.00, CD3OD). Electrospray mass spectra were re-
corded on samples suspended in mixtures of THF and
CH3OH with added trifluoroacetic acid or NaCl.
3.4. 1-(Dodecyl)-2,5-anhydroglucityl sulfone (10)
Thioether 27 (140mg, 0.23mmol) was dissolved in
CH2Cl2 (5mL) and m-CPBA (167mg, 0.68mmol) was
added and the mixture stirred for 20min. Workupas de-
scribed for the oxidation of 25 yielded a crude sulfone
(181mg) that was, without further purification, dis-
solved in CH3OH (5mL) containing AcOH (10lL). Pal-
ladium on carbon (10%, 40mg) was added and the
reaction mixture was stirred under H2 overnight. After
filtering the solid and evaporating the solvent, the resi-
due was purified by chromatography (EtOAc) to afford
10 (65mg, 76% over two steps) as a white solid: Rf 0.26
3.2. 1-(Nonyl)-2,5-anhydroglucityl sulfone (8)
Thioether 25 (91mg, 0.16mmol) was dissolved in CH2Cl2
(5mL) and m-CPBA (117mg, 0.47mmol) was added and
the mixture stirred for 20min. The reaction mixture was
neutralized with a saturated aqueous solution of sodium
bicarbonate and diluted with CH2Cl2 (20mL). The or-
ganic layer was washed with H2O (2 · 10mL) and then
dried. The solvent was evaporated to afford the crude
sulfone as a white solid (200mg) that was, without fur-
ther purification, dissolved in CH3OH (5mL) containing
AcOH (10lL). Palladium on carbon (10%, 25mg) was
added and the reaction mixture was stirred under H2
overnight. After filtering the solid and evaporating the
solvent, the residue was purified by chromatography
(EtOAc) to afford 8 (42mg, 79% over two steps) as a
white solid: Rf 0.21 (EtOAc); mp101–103 ꢁC; [a]D +6.7
1
(EtOAc); mp94–95 ꢁC; [a]D +10.3 (c 0.8, CHCl3); H
NMR (500MHz, CDCl3) dH 0.86 (t, 3H, J = 6.8Hz),
1.34–1.18 (m, 16H), 1.46–1.35 (m, 2H), 1.90–1.77 (m,
2H), 2.68 (br s, 3H), 3.15–3.03 (m, 2H), 3.30 (dd, 1H,
J = 14.8, 3.8Hz), 3.41 (dd, 1H, J = 14.8, 8.4Hz), 3.87–
3.75 (m, 2H), 3.98–3.95 (m, 1H), 4.04–4.00 (m, 1H),
4.24 (s, 1H), 4.57–4.52 (m, 1H); 13C NMR (100MHz,
CDCl3) dC 14.1, 21.7, 22.7, 28.5, 29.2, 29.4, 29.4, 29.6,
29.7, 29.7, 31.9, 52.8, 54.2, 62.2, 75.5, 78.1, 78.3, 86.1;
HRMS calcd for C18H36O6SNa+: 403.2125. Found:
403.2152.
3.5. 1-(Hexadecyl)-2,5-anhydroglucityl sulfone (11)
1
(c 1.0, CHCl3); H NMR (400MHz, CDCl3) dH 0.86 (t,
Thioether 28 (140mg, 0.21mmol) was dissolved in
CH2Cl2 (5mL) and m-CPBA (153mg, 0.62mmol) was
added and the mixture stirred for 20min. Workupas de-
scribed for the oxidation of 25 yielded a crude sulfone
(210mg) that was, without further purification, dis-
solved in CH3OH (5mL) containing AcOH (10lL). Pal-
ladium on carbon (10%, 40mg) was added and the
mixture was stirred under H2 overnight. After filtering
the solid and evaporating the solvent, the residue was
purified by chromatography (EtOAc/hexane, 5:1) to af-
ford 11 (37mg, 49% over two steps) as a white solid: Rf
0.21 (5:1, EtOAc/hexane); mp180–181 ꢁC; [a]D +3.6 (c
3H, J = 6.9Hz), 1.33–1.19 (m, 10H), 1.45–1.35 (m, 2H),
1.83–1.75 (m, 2H), 3.16–3.03 (m, 2H), 3.32 (dd, 1H,
J = 14.6, 3.6Hz), 3.41 (dd, 1H, J = 14.8, 8.2Hz), 3.78–
3.68 (m, 2H), 3.91–3.87 (m, 1H), 4.06–4.01 (m, 1H),
4.17–4.10 (m, 2H), 4.36–4.32 (m, 1H), 4.51–4.45 (m,
1H), 4.74–4.69 (m, 1H); 13C NMR (100MHz, CDCl3)
dC 14.1, 21.6, 22.6, 28.5, 29.1, 29.2, 29.3, 31.8, 52.8,
54.2, 62.1, 75.4, 78.0, 78.2, 86.1; HRMS calcd for
C15H30O6SNa+: 361.1655. Found: 361.1654.
3.3. 1-(Decyl)-2,5-anhydroglucityl sulfone (9)
1
1.2, CH3OH); H NMR (400MHz, CD3OD) dH 0.82
Thioether 26 (133mg, 0.23mmol) was dissolved in
CH2Cl2 (5mL) and m-CPBA (172mg, 0.69mmol) was
(t, 3H, J = 6.9Hz), 1.31–1.17 (m, 24H), 1.41–1.33 (m,
2H), 1.78–1.68 (m, 2H), 3.25–3.02 (m, 3H), 3.35 (dd,

5500
C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
1H, J = 15.2, 9.2Hz), 3.65–3.55 (m, 2H), 3.79–3.75 (m,
1H), 3.89–3.87 (m, 1H), 3.94–3.90 (m, 1H), 4.39–4.34
(m, 1H); 13C NMR (100MHz, CD3OD) dC 14.4, 22.8,
23.7, 29.5, 30.2, 30.5, 30.7, 30.8, 30.8, 33.1, 54.4, 55.0,
63.4, 77.2, 79.4, 79.5, 88.1; HRMS calcd for C22H44O6S-
Na+: 459.2751. Found: 459.2764.
CDCl3) dC 20.0, 20.0, 23.4, 23.5, 26.1, 26.2, 29.5, 29.8,
29.9, 33.6, 33.7, 38.2, 38.3, 40.7, 53.6, 53.7, 54.7, 54.7,
57.2, 63.6, 63.8, 77.6, 77.6, 78.5, 79.8, 80.0, 82.2, 88.6;
HRMS calcd for C16H32O6SNa+: 375.1818. Found:
375.1823.
3.9. 3,4,6-Tri-O-benzyl-2,5-anhydroglucityl thioacetate
(22)
3.6. 1-(Eicosyl)-2,5-anhydroglucityl sulfone (12)
Sulfone 31 (120mg, 0.16mmol) was dissolved in
CH3OH (5mL) containing AcOH (10lL). Palladium
on carbon (10%, 50mg) was added and the mixture
was stirred under H2 overnight. After filtering the solid
and evaporating the solvent, the residue was purified by
chromatography (EtOAc/hexane, 5:1) to afford 12
(62mg, 80%) as a white solid. Rf 0.21 (5:1, EtOAc/hex-
ane); mp105–107 ꢁC; 1H NMR (400MHz, CD3OD)
dH 0.82 (t, 3H, J = 6.8Hz), 1.30–1.10 (m, 32H), 1.42–
1.32 (m, 2H), 1.79–1.68 (m, 2H), 3.19–3.01 (m, 2H),
3.35 (dd, 1H, J = 15.0, 9.1Hz), 3.65–3.51 (m, 2H),
3.77–3.73 (m, 1H), 3.84–3.78 (m, 1H), 3.89–3.86 (m,
1H), 3.92–3.90 (m, 1H), 4.39–4.34 (m, 1H); 13C NMR
(100MHz, CD3OD) dC 14.5, 22.9, 23.7, 29.5, 30.2,
30.5, 30.7, 30.8, 33.1, 54.4, 55.0, 63.4, 77.2, 79.4, 79.6,
88.1; HRMS calcd for C26H52O6SNa+: 515.3377.
Found: 515.3348.
Iodide 21 (4.70g, 8.63mmol) was dissolved in dry DMF
(30mL) and potassium thioacetate (1.48g, 12.9mmol)
was added and the reaction mixture stirred for 12h.
The solution was diluted with ether (250mL), washed
with H2O (3 · 100mL), dried, and concentrated. The
resulting residue was purified by chromatography (hex-
ane/EtOAc, 5:1) affording 22 (3.98g, 94%) as a pale yel-
low oil: Rf 0.23 (hexane/EtOAc, 6:1); [a]D +25.1 (c 1.1,
1
CHCl3); H NMR (250MHz, CDCl3) dH 2.31 (s, 3H),
3.20 (d, 2H, J = 6.9Hz), 3.50 (dd, 1H, J = 9.9, 6.8Hz),
3.60 (dd, 1H, J = 9.9, 5.6Hz), 3.93–3.89 (m, 2H), 3.98–
3.95 (m, 2H), 4.60–4.36 (m, 6H), 7.38–7.22 (m, 15H);
13C NMR (62.5MHz, CDCl3) dC 27.9, 30.4, 70.2, 71.4,
71.5, 73.2, 79.9, 82.9, 82.9, 83.2, 127.6, 127.6, 127.7,
127.7, 127.8, 127.8, 128.3, 128.4, 137.5, 137.6, 138.1,
195.4; HRMS calcd for C53H82O7SNa+: 515.1863.
Found: 515.1867.
3.7. 1-(Decyl-100-O-hexadecyl)-2,5-anhydroglucityl sulf-
one (13)
3.10. 3,4,6-Tri-O-benzyl-2,5-anhydroglucityl thiol (23)
Thioacetate 22 (170mg, 0.35mmol) was dissolved in
anhydrous Et2O (7mL) and lithium aluminum hydride
(13mg, 0.35mmol) was added and the mixture stirred
for 1h. The solution was diluted with ethyl acetate
(30mL), and the organic layer was washed with H2O
(10mL) and brine (10mL) before being dried and con-
centrated. The resulting residue was purified by chroma-
tography (hexane/EtOAc, 6:1) affording 23 (151mg,
97%) as a colorless oil: Rf 0.44 (hexane/EtOAc, 4:1);
Sulfone 38 (40mg, 0.048mmol) was dissolved in a 5:1
mixture of CH3OH and AcOH (2mL) and hydrogeno-
lyzed as described for the preparation of 12 using palla-
dium on carbon (10%, 20mg). Purification by
chromatography (EtOAc/hexane, 3:1) afforded 13
(17mg, 60%) as a white solid: Rf 0.12 (3:1, EtOAc/hex-
ane); 1H NMR (400MHz, CDCl3) dH 0.86 (t, 3H,
J = 6.8Hz), 1.35–1.18 (m, 36H), 1.45–1.36 (m, 2H),
1.59–1.49 (m, 4H), 1.86–1.77 (m, 2H), 3.17–3.01 (m,
2H), 3.43–3.25 (m, 9H), 3.82–3.72 (m, 2H), 4.03–3.92
(m, 2H), 4.21 (s, 1H), 4.56–4.48 (m, 1H); 13C NMR
(100MHz, CDCl3) dC 14.1, 21.8, 22.7, 26.1, 26.2, 28.4,
29.0, 29.1, 29.4, 29.4, 29.5, 29.6, 29.7, 29.7, 31.9, 52.7,
54.3, 62.3, 71.0, 71.0, 75.8, 77.2, 78.2, 78.6, 86.2; HRMS
calcd for C32H64O7SNa+: 615.4265. Found: 615.4259.
1
[a]D +44.3 (c 1.1, CHCl3); H NMR (250MHz, CDCl3)
d
H 1.39 (t, 1H, J = 8.8Hz), 2.76 (d, 1H, J = 7.2Hz), 2.80
(d, 1H, J = 7.2Hz), 3.49 (dd, 1H, J = 9.8, 6.7Hz), 3.59
(dd, 1H, J = 9.9, 5.9Hz), 3.96–3.93 (m, 1H), 4.01–3.98
(m, 1H), 4.18–4.05 (m, 2H), 4.39 (d, 1H, J = 11.8Hz),
4.60–4.47 (m, 5H), 7.38–7.21 (m, 15H); 13C NMR
(62.5MHz, CDCl3) dC 22.7, 70.4, 71.4, 73.3, 83.1, 83.1,
83.2, 83.2, 127.6, 127.7, 127.8, 127.8, 127.9, 128.3,
128.5, 137.6, 137.7, 138.1.
3.8. 1-(3,7-Dimethyloctyl)-2,5-anhydroglucityl sulfone
(14)
3.11. 1-(Nonyl)-3,4,6-tri-O-benzyl-2,5-anhydroglucityl
sulfide (25)
Sulfone 41 (66mg, 0.12mmol) was dissolved in CH3OH
(5mL) containing AcOH (10lL) and hydrogenolyzed as
described for the preparation of 12 using palladium on
carbon (10%, 30mg). Purification by chromatography
(EtOAc/hexane, 3:1) afforded 14 (24mg, 64%) as a pale
yellow oil that was a 3:1 mixture of diastereomers: Rf
0.13 (5:1, EtOAc/hexane); [a]D +13.7 (c 1.0, CHCl3); Se-
lected NMR data: 1H NMR (400MHz, CD3OD) dH
0.84 (s, 3H), 0.85 (s, 3H), 0.90–0.87 (m, 3H), 1.19–1.08
(m, 3H), 1.35–1.22 (m, 3H), 1.63–1.45 (m, 3H), 1.84–
1.73 (m, 1H), 3.28–3.04 (m, 3H), 3.39 (dd, 1H,
J = 15.0, 9.1Hz), 3.67–3.55 (m, 2H), 3.81–3.77 (m,
1H), 3.93–3.90 (m, 1H), 3.98–3.96 (m, 1H), 4.42–4.38
(m, 1H); Selected NMR data: 13C NMR (100MHz,
Sodium hydride (19mg, 0.80mmol) was added to a solu-
tion of thiol 23 (120mg, 0.27mmol) in dry DMF (5mL).
After 5 min, 1-iodononane (0.16mL, 0.80mmol) was
added and the mixture was stirred for 1h before CH3OH
(1mL) and then Et2O (20mL) were added. The organic
layer was washed with H2O (2 · 40mL), brine (15mL),
and then dried and concentrated. The resulting residue
was purified by chromatography (hexane/EtOAc, 10:1)
affording 25 (111mg, 72%) as a colorless oil: Rf 0.28
(hexane/EtOAc, 10:1); [a]D +41.0 (c 1.0, CHCl3); 1H
NMR (400MHz, CDCl3) dH 0.88 (t, 3H, J = 6.9Hz),
1.39–1.22 (m, 12H), 1.61–1.52 (m, 2H), 2.53 (t, 2H,

C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
5501
J = 7.4Hz), 2.91–2.73 (m, 2H), 3.50 (dd, 1H, J = 9.9,
6.8Hz), 3.61 (dd, 1H, J = 9.8, 5.8Hz), 3.92–3.90 (m,
1H), 3.98–3.96 (m, 1H), 4.30–4.02 (m, 2H), 4.59–4.40
(m, 6H), 7.37–7.22 (m, 15H); 13C NMR (100MHz,
CDCl3) dC 14.1, 22.6, 28.8, 29.2, 29.2, 29.5, 29.8, 30.1,
31.8, 32.9, 70.5, 71.4, 71.6, 73.3, 81.2, 82.5, 83.0, 83.6,
127.5, 127.6, 127.7, 127.7, 127.7, 127.8, 128.3, 128.3,
128.4, 137.8, 137.8, 138.2.
Workup as described for the preparation of 25 and puri-
fication by chromatography (hexane/EtOAc, 10:1) af-
forded 28 (167mg, 74%) as a colorless oil: Rf 0.56
(hexane/EtOAc, 9:1); [a]D +28.2 (c 1.1, CHCl3); 1H
NMR (250MHz, CDCl3) dH 0.88 (t, 3H, J = 6.6Hz),
1.39–1.20 (m, 26H), 1.62–1.50 (m, 2H), 2.53 (t, 2H,
J = 7.4Hz), 2.93–2.72 (m, 2H), 3.49 (dd, 1H, J = 9.9,
6.8Hz), 3.61 (dd, 1H, J = 9.9, 5.9Hz), 3.94–3.90 (m,
1H), 4.00–3.96 (m, 1H), 4.30–4.01 (m, 2H), 4.61–4.40
(m, 6H), 7.38–7.22 (m, 15H); 13C NMR (62.5MHz,
CDCl3) dC 14.1, 22.6, 28.8, 29.2, 29.3, 29.5, 29.6, 29.6,
29.6, 29.7, 30.0, 31.9, 70.5, 71.5, 71.6, 73.2, 81.2, 82.4,
83.0, 83.5, 127.5, 127.6, 127.6, 127.7, 127.7, 127.7,
128.3, 128.3, 128.4, 137.7, 137.7, 138.0.
3.12. 1-(Decyl)-3,4,6-tri-O-benzyl-2,5-anhydroglucityl
sulfide (26)
n-Butyl lithium (0.1mL, 0.16mmol) was added to a solu-
tion of thiol 23 (66mg, 0.15mmol) in anhydrous Et2O
(5mL) at 0ꢁC. After 5min, 1-iododecane (38lL,
0.18mmol) was added and the solution was stirred for
12h, while warming to room temperature. Workup as
described for the preparation of 25 and purification by
chromatography (hexane/EtOAc, 9:1) afforded 26
(56mg, 65%) as a colorless oil: Rf 10.35 (hexane/EtOAc,
10:1); [a]D +31.3 (c 1.0, CHCl3); H NMR (250MHz,
CDCl3) dH 0.88 (t, 3H, J = 6.6Hz), 1.40–1.19 (m,
14H), 1.62–1.50 (m, 2H), 2.53 (t, 2H, J = 7.4Hz),
2.92–2.72 (m, 2H), 3.49 (dd, 1H, J = 10.0, 6.8Hz), 3.61
(dd, 1H, J = 9.8, 6.0Hz), 3.94–3.90 (m, 1H), 3.99–3.95
(m, 1 H), 4.29–4.00 (m, 2H), 4.61–4.40 (m, 6H), 7.39–
7.18 (m, 15H); 13C NMR (62.5MHz, CDCl3) dC 14.1,
22.6, 28.9, 29.2, 29.3, 29.5, 29.5, 29.8, 30.1, 31.9, 32.9,
70.6, 71.4, 71.7, 73.3, 81.3, 82.6, 83.0, 83.6, 127.6,
127.6, 127.7, 127.7, 127.7, 127.8, 128.3, 128.3, 128.4,
137.8, 137.8, 138.2.
3.15. 1-(Decadecyl)-3,4,6-tri-O-benzyl-2,5-anhydrogluci-
tyl sulfone (31)
Thiol 23 (291mg, 0.65mmol) was dissolved in THF
(10mL) at 0ꢁC. n-Butyl lithium (0.44mL, 0.71mmol)
was added, followed by a solution of 2922 (400mg,
0.88mmol) in THF (15mL). The mixture was warmed
to rt and stirred for 4h and then neutralized with AcOH,
and diluted with EtOAc (40mL). The organic layer was
washed with H2O (15mL), brine (15mL), dried, and
concentrated to afford an inseparable mixture of 29
and 30 (466mg total). The crude mixture (413mg) was
dissolved in CH2Cl2 (10mL) and m-CPBA (418mg,
1.69mmol) was added and the mixture stirred for 2h.
Workupas described for the oxidation of 25 yielded a
crude product that was purified by chromatography
(hexane/EtOAc, 4:1) to afford 31 (164mg, 30% over
two steps) as an amorphous white solid: Rf 0.32 (hex-
3.13. 1-(Dodecyl)-3,4,6-tri-O-benzyl-2,5-anhydroglucityl
sulfide (27)
1
ane/EtOAc, 4:1); [a]D +5.2 (c 1.3, CHCl3); H NMR
(400MHz, CDCl3) dH 0.95 (t, 3H, J = 6.8Hz), 1.44–
1.26 (m, 34H), 1.92–1.82 (m, 2H), 3.20–3.07 (m, 3H),
3.67–3.48 (m, 3H), 4.06–4.01 (m, 2H), 4.21–4.18 (m,
1H), 4.43–4.39 (m, 1H), 4.65–4.52 (m, 6H), 7.44–7.26
(m, 15H); 13C NMR (100MHz, CDCl3) dC 14.1, 21.7,
22.6, 28.4, 29.0, 29.2, 29.3, 29.5, 29.6, 29.6, 29.6, 31.9,
53.2, 54.1, 70.1, 71.5, 71.6, 73.3, 75.5, 82.5, 83.1, 83.2,
127.6, 127.6, 127.7, 127.7, 127.8, 127.8, 127.9, 128.1,
128.3, 128.4, 128.5, 128.5, 137.1, 137.4, 137.9; HRMS
calcd for C47H70O6SNa+: 785.4785. Found: 785.4781.
Sodium hydride (40mg, 1.00mmol) was added to a solu-
tion of thiol 23 (150mg, 0.33mmol) in dry DMF (5mL).
After 5min, 1-iodododecane (0.25mL, 1.00mmol) was
added and the reaction mixture was stirred for 1h before
CH3OH (1mL) and then Et2O (20mL) were added.
Workupas described for the preparation of 25 and puri-
fication by chromatography (hexane/EtOAc, 10:1) af-
forded 27 (168mg, 82%) as a colorless oil: Rf 0.45
(hexane/EtOAc, 9:1); [a]D +28.9 (c 1.0, CHCl3); 1H
NMR (250MHz, CDCl3) dH 0.88 (t, 3H, J = 6.6Hz),
1.41–1.18 (m, 18H), 1.62–1.50 (m, 2H), 2.53 (t, 2H,
J = 7.4Hz), 2.92–2.72 (m, 2H), 3.49 (dd, 1H, J = 9.9,
6.8Hz), 3.61 (dd, 1H, J = 9.9, 5.9Hz), 3.94–3.90 (m,
1H), 4.00–3.96 (m, 1H), 4.30–4.01 (m, 2H), 4.61–4.40
(m, 6H), 7.39–7.20 (m, 15H); 13C NMR (62.5MHz,
CDCl3) dC 14.1, 22.7, 28.9, 29.2, 29.3, 29.5, 29.6, 29.6,
29.7, 30.0, 70.5, 71.4, 71.6, 73.3, 81.2, 82.4, 83.0, 83.5,
127.6, 127.7, 127.7, 127.7, 128.3, 128.3, 128.4, 137.7,
137.8, 138.1.
3.16. 10-Tetrahydropyranyloxy-1-decanol (33)
1,10-Decanediol, 32, (2.0g, 11.5mmol) was dissolved in
THF (50mL) and 3,4-dihydropyran (1.15mL,
12.6mmol) added, followed by p-TsOH (328mg,
1.73mmol). The mixture was stirred for 2h and then
pyridine (2mL) was added and the solvent evaporated.
Purification by chromatography (hexane/EtOAc, 4:1)
afforded 33 (1.56g, 53%) as a colorless oil: Rf 0.20
1
(4:1, hexane/EtOAc); H NMR (500MHz, CDCl3) dH
3.14. 1-(Hexadecyl)-3,4,6-tri-O-benzyl-2,5-anhydrogluci-
tyl sulfide (28)
1.33–1.20 (m, 12H), 1.58–1.43 (m, 8H), 1.69–1.63 (m,
1H), 1.82–1.74 (m, 2H), 3.33 (dt, 1H, J = 9.6, 6.7Hz),
3.47–3.42 (m, 1H), 3.57 (t, 2H, J = 6.7Hz), 3.67 (dt,
1H, J = 9.6, 6.9Hz), 3.85–3.79 (m, 1H), 4.53–4.51 (m,
1H); 13C NMR (125MHz, CDCl3) dC 19.6, 25.4, 25.7,
26.1, 29.3, 29.4, 29.4, 29.5, 29.7, 30.7, 32.7, 62.2, 62.8,
67.6, 98.8; HRMS calcd for C15H30O3Na+: 281.2087.
Found: 281.2087.
Sodium hydride (40mg, 1.00mmol) was added to a solu-
tion of thiol 23 (150mg, 0.33mmol) in dry DMF (5mL).
After 5min, 1-iodohexadecane (350mg, 1.00mmol) was
added and the reaction mixture stirred for 12h before
CH3OH (1mL) and then Et2O (20mL) were added.

5502
C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
3.17. 10-O-Hexadecyl-1-tetrahydropyranyloxydecane
(34)
3.20. 1-(Decyl-100-O-hexadecyl)-3,4,6-tri-O-benzyl-2,5-
anhydroglucityl sulfone (38)
Alcohol 33 (517mg, 2.00mmol) was dissolved in dry
DMF (10mL) and sodium hydride (160mg, 4.00mmol)
was added followed, after 10min, by 1-iodohexadecane
(1.06g, 3.01mmol) in DMF (5mL). The reaction mix-
ture was stirred for 12h and then CH3OH (5mL) and
Et2O (50mL) were added. The organic layer was washed
with H2O (2 · 30mL), brine (30mL) and then dried and
concentrated. Purification by chromatography (hexane/
EtOAc, 7:1) gave 34 (204mg, 21%) as a colorless oil:
Rf 0.58 (6:1, hexane/EtOAc); 1H NMR (500MHz,
CDCl3) dH 0.86 (t, 3H, J = 7.1Hz), 1.39–1.19 (m,
38H), 1.60–1.45 (m, 10H), 1.72–1.66 (m, 1H), 1.85–
1.76 (m, 1H), 3.38–3.33 (m, 5H), 3.50–3.45 (m, 1H),
3.70 (dt, 1H, J = 9.6, 6.9Hz), 3.87–3.82 (m, 1H), 4.56–
4.54 (m, 1H); 13C NMR (125MHz, CDCl3) dC 14.1,
19.7, 22.7, 25.5, 26.2, 26.2, 29.3, 29.5, 29.5, 29.5, 29.5,
29.6, 29.6, 29.7, 29.8, 29.8, 30.8, 31.9, 62.3, 67.7, 71.0,
71.0, 98.8; HRMS calcd for C31H62O3Na+: 505.4591.
Found: 505.4584.
Thiol 23 (117mg, 0.26mmol) was dissolved in THF
(5mL) and 18-crown-6 (95mg, 0.31mmol) was added,
followed by potassium hydride (12mg, 0.31mmol). A
solution of 36 (59mg, 0.11mmol) in THF (15mL) was
added dropwise and the reaction stirred for 45min.
The mixture was then neutralized with AcOH, diluted
with EtOAc (20mL), washed with H2O (10mL), brine
(10mL), and then dried. The solvent was evaporated
to give sulfide 37 that was inseparable from 36 (50mg
total). The crude mixture (46mg) was then dissolved in
CH2Cl2 (3mL) and m-CPBA (41mg, 0.17mmol) was
added and the reaction mixture stirred for 30min.
Workupas described for the oxidation of 25 yielded a
residue that was purified by chromatography (hexane/
EtOAc, 6:1) to afford 38 (41mg, 45% over two steps)
as an amorphous white solid: Rf 0.24 (hexane/EtOAc,
5:1); [a]D +4.9 (c 1.0, CHCl3); 1H NMR (400MHz,
CDCl3) dH 0.81 (t, 3H, J = 7.0Hz), 1.37–1.10 (m,
38H), 1.53–1.43 (m, 4H), 1.80–1.67 (m, 2H), 3.08–2.91
(m, 3H), 3.31 (overlapping t, 4H, J = 6.8Hz), 3.53–
3.35 (m, 3H), 3.91–3.88 (m, 2H), 4.08–4.03 (m, 1H),
4.27 (d, 1H, J = 11.7Hz), 4.53–4.38 (m, 6H), 7.30–7.11
(m, 15H); 13C NMR (100MHz, CDCl3) dC 14.1, 21.7,
22.7, 26.2, 26.2, 28.4, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6,
29.6, 29.7, 29.8, 31.9, 53.3, 54.2, 70.1, 70.9, 71.0, 71.6,
73.3, 75.5, 82.5, 83.2, 83.2, 127.7, 127.7, 127.7, 127.8,
127.8, 127.9, 128.1, 128.4, 128.5, 128.5, 128.6, 137.1,
137.5, 137.9; HRMS calcd for C53H82O7SNa+:
885.5673. Found: 885.5601.
3.18. 10-O-Hexadecyl-1-decanol (35)
10-O-hexadecyl-1-tetrahydropyranyloxydecane, 34 (200
mg, 0.41mmol), was dissolved in a 3:1:1 mixture of
AcOH/THF/H2O (10mL) and heated at 65ꢁC for 3h.
The mixture was diluted with CH2Cl2 (20mL) and the
organic layer was washed with H2O (2 · 10mL), brine
(10mL), and then dried. The solvent was evaporated
and the residue was purified by chromatography (hex-
ane/EtOAc, 7:1) to afford 35 (139mg, 84%) as a white
solid: Rf 0.25 (6:1, hexane/EtOAc); mp67–68 ꢁC; 1H
NMR (250MHz, CDCl3) dH 0.85 (t, 3H, J = 6.9Hz),
1.35–1.16 (m, 36H), 3.40–3.30 (m, 8H), 3.36 (t, 4H,
J = 6.7Hz), 3.60 (t, 2 H, J = 6.6Hz); 13C NMR
(62.5MHz, CDCl3) dC 14.1, 22.7, 25.7, 26.2, 29.4, 29.4,
29.5, 29.5, 29.6, 29.7, 29.8, 31.9, 32.8, 63.0, 70.9, 71.0;
HRMS calcd for C26H54O2Na+: 421.4016. Found:
421.4015.
3.21. 1-Geranyl-3,4,6-tri-O-benzyl-2,5-anhydroglucityl
sulfide (40)
n-Butyl lithium (0.8mL, 1.26mmol) was added dropwise
to a solution of 23 (515mg, 1.14mmol) dissolved in
THF (10mL) at À78ꢁC and geranyl tosylate (39) was
added. Tosylate 39 was prepared by the addition of n-
butyl lithium (3.9mL, 6.20mmol) to geraniol (870mg,
5.64mmol) in THF (15mL) at À78ꢁC, followed by the
addition of p-TsCl (1.40g, 7.33mmol); this solution
was added directly to the alkylation reaction. The mix-
ture was slowly warmed to rt over 2h and then H2O
(20mL) and Et2O (30mL) were added. The organic
layer was separated, washed with brine (10mL), dried,
and concentrated. The residual oil was purified by chro-
matography (hexane/EtOAc, 9:1) to afford 40 (509mg,
76%) as a colorless oil: Rf 0.42 (6:1, hexane/EtOAc);
3.19. 10-O-Hexadecyl-1-p-toluenesulfonyloxydecane (36)
Alcohol 35 (139mg, 0.35mmol) and 18-crown-6
(127mg, 0.42mmol) were dissolved in THF (10mL).
Potassium hydride (17mg, 0.42mmol) was added, and
after 5min, p-TsCl (200mg, 1.05mmol). The mixture
was stirred for 12h at rt and then CH3OH (1mL) and
EtOAc (10mL) were added. The organic layer was
washed with H2O (10mL), brine (10mL), and then dried
and concentrated. The resulting residue was purified by
chromatography (hexane/EtOAc, 9:1) to afford 36
(50mg, 26%) as a white solid: Rf 0.44 (6:1, hexane/
1
[a]D +22.4 (c 1.0, CHCl3); H NMR (400MHz, CDCl3)
d
H 1.58 (s, 3H), 1.62 (s, 3H), 1.67 (s, 3H), 2.10–1.97 (m,
4H), 2.85–2.75 (m, 2H), 3.26–3.11 (m, 2H), 3.49 (dd, 1H,
J = 9.8, 7.0Hz), 3.60 (dd, 1H, J = 9.8, 5.8Hz), 4.18–3.91
(m, 2H), 4.20–4.09 (m, 2H), 4.59–4.39 (m, 6H), 5.10–
5.03 (m, 1H), 5.27–5.20 (m, 1H), 7.35–7.20 (m, 15H);
13C NMR (100MHz, CDCl3) dC 16.0, 17.5, 25.5, 26.4,
29.0, 29.9, 39.5, 70.4, 71.2, 71.5, 73.1, 81.1, 82.5, 82.9,
83.4, 120.3, 123.8, 127.4, 127.5, 127.5, 127.5, 127.6,
127.7, 128.1, 128.2, 128.3, 129.6, 131.4, 137.7, 137.7,
138.1, 138.8; HRMS calcd for C37H46O4SNa+:
609.2919. Found: 609.2914.
1
EtOAc); mp71–72 ꢁC; H NMR (250MHz, CDCl3) dH
0.85 (t, 3H, J = 6.8Hz), 1.38–1.14 (m, 38H), 1.67–1.45
(m, 6H), 2.42 (s, 3H), 3.36 (t, 4H, J = 6.7Hz), 3.99 (t,
2H, J = 6.5Hz), 7.31 (d, 2H, J = 8.0Hz), 7.76 (d, 2H,
J = 8.3Hz); 13C NMR (62.5MHz, CDCl3) dC 14.1,
22.7, 25.7, 26.2, 26.2, 29.4, 29.4, 29.5, 29.5, 29.6, 29.7,
29.8, 31.9, 32.8, 63.0, 70.6, 70.9, 71.0, 127.8, 129.7,
133.3, 144.5; HRMS calcd for C33H60O4SNa+:
575.4104. Found: 575.4119.

C. A. Centrone, T. L. Lowary / Bioorg. Med. Chem. 12 (2004) 5495–5503
5503
3.22. 1-Geranyl-3,4,6-tri-O-benzyl-2,5-anhydroglucityl
sulfone (41)
References and notes
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Sulfide 40 (116mg, 0.23mmol) was dissolved in a mix-
ture of acetonitrile (8mL) and H2O (0.3mL). Sodium
periodate (145mg, 0.68mmol) was added and the reac-
tion mixture was heated at 70ꢁC. The reaction pro-
ceeded for 2d and, during this time, three more
portions of sodium periodate (145mg, 0.68mmol each)
were added. After cooling to rt and evaporating the sol-
vent, the crude mixture was purified by chromatography
(hexane/EtOAc, 4:1) to afford 41 (65mg, 53%) as a col-
orless oil: Rf 0.33 (3:1, hexane/EtOAc); [a]D +10.0 (c 1.1,
1
CHCl3); H NMR (250MHz, CDCl3) dH 1.58 (s, 3H),
1.67 (s, 6H), 2.08 (s, 4H), 2.86 (dd, 1H, J = 13.3,
3.4Hz), 3.05 (dd, 1H, J = 13.2, 9.3Hz), 3.66–3.44 (m,
4H), 3.94–3.91 (m, 1H), 4.01–3.97 (m, 1H), 4.17–4.07
(m, 1H), 4.36 (d, 1H, J = 11.8Hz), 4.60–4.45 (m, 6H),
5.10–5.00 (m, 1H), 5.35–5.24 (m, 1H), 7.40–7.19 (m,
15H); 13C NMR (62.5MHz, CDCl3) dC 16.9, 17.6,
25.6, 26.2, 39.7, 51.8, 52.4, 70.1, 71.4, 71.4, 73.2, 75.1,
82.9, 83.4, 83.6, 111.1, 123.5, 127.6, 127.7, 127.7,
127.7, 127.9, 128.3, 128.4, 128.4, 131.8, 137.4, 137.6,
138.0, 145.0; HRMS calcd for C37H46O6SNa+:
641.2907. Found: 641.2874.
13. De Jong, B. C.; Israelski, D. M.; Corbett, E. L.; Small,
P. M. Annu. Rev. Med. 2004, 55, 283–301.
´
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´
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get compounds was carried out as previously reported
using the fluorescence-based Alamar Blue microplate as-
say.24 All compounds were tested against Mycobacte-
rium tuberculosis strain H37Rv (ATCC 27294) at a
concentration 6.25lg/mL. The results of these assays,
expressed as a percent inhibition of growth of the bacte-
ria in provided in Table 1.
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´
Besra, G. S.; Mikusova, K.; Brennan, P. J.; Chatterjee, D.
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18. Centrone, C. A.; Lowary, T. L., unpublished data.
19. Selectivity index = IC50/MIC.
20. Richert, C.; Roughton, A. L.; Benner, S. A. J. Am. Chem.
Soc. 1996, 118, 4518–4531.
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The National Institutes of Health (AI44045-01) sup-
ported this work. C.A.C. was a recipient of a GAANN
fellowshipfrom the U.S. Deaprtment of Education.
Anti-mycobacterial data were provided by the Tubercu-
losis Anti-microbial Acquisition and Coordinating
Facility (TAACF) through a research and development
contract with the U.S. National Institute of Allergy and
Infectious Diseases. We thank Marc Meunier and Luke
Moisey for technical assistance.