A new class of antituberculosis agents

Article abstract of DOI:10.1021/jm000149l

Long-chain lipid envelopes are characteristic of mycobacteria such as those that cause tuberculosis and leprosy. Inhibition of fatty acid synthesis or elongation is a strategy demonstrated to be clinically effective against M. tuberculosis. A new class of

Full text of DOI:10.1021/jm000149l

3304
J . Med. Chem. 2000, 43, 3304-3314
A New Cla ss of An titu ber cu losis Agen ts
Paul B. J ones,† Nikki M. Parrish,‡ Todd A. Houston,†,# Anthony Stapon,† Niharika P. Bansal,†
J ames D. Dick,*,‡,§ and Craig A. Townsend*,†
Department of Chemistry, The J ohns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218,
Department of Pathology and Medicine, School of Medicine, The J ohns Hopkins University, Baltimore, Maryland 21205, and
Department of Molecular Microbiology and Immunology, School of Public Health, The J ohns Hopkins University,
Baltimore, Maryland 21205
Received April 3, 2000
Long-chain lipid envelopes are characteristic of mycobacteria such as those that cause
tuberculosis and leprosy. Inhibition of fatty acid synthesis or elongation is a strategy
demonstrated to be clinically effective against M. tuberculosis. A new class of compounds
designed to inhibit the â-ketoacyl synthase reaction of fatty acid synthesis has been developed.
Of >30 compounds described, the most active were acetamides containing alkylsulfonyl
substituents. Inhibitory activities were acutely sensitive to net charge, chain length, and degree
of unsaturation. The most active compound 5 (alkyl ) C10) contained a single methylene spacer
between the sulfone and carboxamide and exhibited an MIC of 0.75-1.5 µg/mL, comparable to
first-line antituberculosis drugs. These compounds are species-specific, exhibiting no significant
activity against bacterial species other than M. tuberculosis and closely related strains. The
synthesis, biological activity, and specificity of these compounds are described.
In tr od u ction
ethionamide.11-13 Thus, while the synthesis of fatty
acids occurs in all living organisms, mycobacteria pos-
sess accessory fatty acid synthase (FAS) enzymes with
specialized substrate and product specificities that are
attractive targets for drug development.
Tuberculosis (TB) is the leading cause of death from
a single infectious agent in the world. Approximately
one-third of the world’s population harbors latent TB,1
and 3 million will die from its effects this year. Despite
the fact that it is treatable and preventable, the disease
has been spreading at a steady rate over the past
decade.2 Two developments make the resurgence in TB
especially alarming. The first is pathogenic synergy with
HIV. The overall incidence of TB in HIV-positive
patients is 50 times that of the rate for HIV-negative
individuals.3 The second is the emergence of drug-
resistant and multi-drug-resistant TB (MDRTB). The
term MDRTB is used to describe strains that are
resistant to two or more of the five first-line anti-TB
drugs (isoniazid, rifampin, pyrizinamide, ethambutol,
and streptomycin).4-6 Little has changed in our arsenal
for TB treatment in more than 30 years when the last
anti-TB drug (rifampin) was introduced. There is a
pressing need for new chemotherapeutic agents to
combat the emergence of resistance and, ideally, shorten
the duration of therapy (currently g6 months).
Although the mechanism of fatty acid biosynthesis is
essentially the same in all organisms, FASs are orga-
nized into two types.3,14 In type I FAS the catalytic sites
are assembled into complexes of multidomain enzymes.
These large, polyfunctional type I synthases are most
commonly found in eukaryotes. In contrast, type II FASs
are comprised of smaller, monofunctional proteins that
carry out fatty acid synthesis in transient acyl carrier
protein (ACP)-dependent complexes. Type II systems
are found primarily in bacteria and plants. Mycobacteria
possess both type I and type II FASs, as well as
mycocerosic acid synthase, which synthesizes long-
chain, multi-methyl-branched fatty acids. These fatty
acids make up components of waxes and some acylated
trehaloses found in the outer cell wall of some slow-
growing mycobacteria.7,9
It has been shown in Mycobacterium smegmatis that
the type I FAS is located in the cytosolic protein fraction
and synthesizes C16-C18 and C24-C26 fatty acyl-CoA
chains in a bimodal distribution. The ACP-dependent
type II synthase functions primarily as an elongation
system, utilizing C16 fatty acid primers to produce C24-
Mycobacteria produce a wide array of complex fatty
acids, such as mycocerosic acid and mycolic acids, not
found in mammalian cells.7-9 These long-chain acids
form a thick hydrophobic outer barrier and constitute
30% dry weight of the cell.10 Significantly, mycolic acid
biosynthesis is essential for mycobacterial survival as
evidenced by the bactericidal properties of drugs that
inhibit mycolic acid synthesis such as isoniazid and
C
30 fatty acyl-ACPs. Although capable of producing fatty
acids with chain lengths of C30, neither of these cytosolic
systems is capable of producing fatty acids of sufficient
length required for mycolic acids. This observation
suggests the presence of additional FASs.15,16 While no
other FAS enzymes have been definitively identified,
several studies support their existence.17-19 Further-
more, examination of the Mycobacterium tuberculosis
genome reveals that there are approximately 5 times
as many FAS-related enzymes as in E. coli.19
* To whom correspondence should be addressed. C.A.T.: tel, (410)
516-7444; fax, (410) 261-1233; e-mail, townsend@jhunix.hcf.jhu.edu.
J .D.D.: tel, (410) 955-5077; fax, (410) 614-8087; e-mail, jdick@jhmi.edu.
† Department of Chemistry.
‡ Department of Pathology and Medicine.
§ Department of Molecular Microbiology and Immunology.
#
Present address: Department of Chemistry, Virginia Common-
wealth University, Richmond, VA 23284.
10.1021/jm000149l CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/24/2000

New Class of Antituberculosis Agents
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3305
Sch em e 1
was planned to mimic the acetyl enolate formed after
decarboxylation of malonyl-ACP. This component of the
reaction must, at some point, add to the thioester of the
extending fatty acyl chain to form a tetrahedral inter-
mediate via a one-atom spacer. Structural mimics of this
key reactive intermediate could be visualized in a
phosphinate, sulfone, or sulfoxide, among others. Bear-
ing in mind, however, that charged, small molecules are
generally excluded by the highly lipophilic mycobacte-
rial cell wall,8 neutral, albeit polar, analogues of the
tetrahedral and acetyl centers were sought in the design
of potential inhibitors. Using this structural model as
a guide, the family of compounds shown in Table 1 was
synthesized.
Syn th esis. Most of the compounds shown in Table 1
were prepared in a straightforward manner (Scheme 2).
Alkylation of the appropriate thiol 32 was carried out
with 2-bromoacetate derivatives 33, followed by oxida-
tion of the resulting thioether 34 and conversion to the
desired acyl derivative. If necessary, the thiol could be
prepared by Mitsunobu reaction of the corresponding
alcohol 35 with thiolacetic acid to give the thioacetate
36, which was readily hydrolyzed. Alternatively, alkyl
bromides 37 could be reacted using methyl thioglycolate
(38) to thioether 39, which could be oxidized to the
sulfone 40 and substituted at the acyl center as neces-
sary.
Synthesis of the R,â-unsaturated sulfones 10 and 11
was accomplished as shown in Scheme 3. Formation of
a thioacetal 42 from methyl thioglycolate 38 and nonyl
aldehyde 41 proceeded smoothly using boron trifluoride
as a catalyst. Oxidation of 42 to obtain the monosul-
foxide 43, as a mixture of diastereomers, was carried
out using m-CPBA in 61% yield. This sulfoxide could
be converted to the vinyl sulfide 44 in refluxing toluene
in the presence of sodium bicarbonate. The vinyl sulfide
44 was obtained as an inseparable mixture of E- and
Z-isomers in 75% yield. Ammonolysis of this ester
provided the primary amides 45E/Z, which could be
separated by preparative TLC. Oxidation to the sulfones
using m-CPBA was carried out in 87% and 91% yield
for the E- and Z-isomers 10 and 11, respectively.
The phosphinate 15 was prepared by the method of
Regan.27-29 Ammonium hypophosphonate was heated
under an inert atmosphere with a slight excess of
hexamethyldisilazane (HMDS) to give bis(trimethylsi-
lyl)phosphonite (46). Alkylation with 1-iododecane fol-
lowed by resilylation with HMDS and a second alkyla-
tion with methyl bromoacetate afforded ester 47 as the
ammonium salt in 30% overall yield. Ammonolysis of
the ester was readily achieved followed by conversion
to the potassium salt 15.
Ch em istr y
We chose to target â-ketoacyl synthase (KAS) for
inhibitor design. This domain catalyzes the most mecha-
nistically complex of the sequence of FAS reactions yet
is definable with respect to geometry and charge. In
addition, this reaction, unlike the others involved in
fatty acid synthesis, is found only in FAS and polyketide
synthase (PKS)-type enzymes. Cerulenin and thiolac-
tomycin, two naturally occurring inhibitors of this chain
extension reaction, are known.20-25 Cerulenin irrevers-
ibly inactivates both type I and type II FASs by
alkylating the strictly conserved active site cysteine thiol
of KAS. Thiolactomycin, on the other hand, while also
acting against KAS, reversibly inhibits only type II FAS.
Both thiolactomycin18 and cerulenin26 are active in vitro
against M. tuberculosis.
In the KAS-mediated step, malonyl-ACP homologates
an existing fatty acid by two carbons. Scheme 1 shows
how this is accomplished. Decarboxylation of malonyl-
ACP provides the enolate of acetyl-ACP, which is
positioned to undergo a Claisen reaction with the
cysteine-bound thioester of the growing fatty acyl chain.
This addition generates the classical tetrahedral inter-
mediate. The latter, in turn, collapses to give an
extended â-keto thioester and the resting state of KAS.
While loss of carbon dioxide drives this reaction ther-
modynamically, it is likely that the enzyme has evolved
an architecture that stabilizes formation of the tetra-
hedral intermediate. Our initial attempts to design an
inhibitor of mycobacterial growth were directed to
molecules that geometrically and electronically mimic
the presumed transition state of this reaction.
Synthesis of the sulfonamides 28-30 was carried out
in one step from commercially available octanesulfonyl
chloride and either urea, methanesulfonamide, or sulf-
amide.30 The anion was formed using sodium hydride
in DMF. These compounds were obtained in 70%, 82%,
and 69% yields, respectively.
Biologica l Resu lts a n d Discu ssion
Central to realization of this goal are the five boxed
atoms in the structures depicted in Scheme 1. A
generalized inhibitor structure is shown beside the
putative transition state of the thio Claisen reaction. A
carboxylic acid, ester, amide, sulfone, or sulfonamide
The compounds shown in Table 1 were tested for
activity against M. tuberculosis (H37Rv) using the
standard BACTEC radiometric growth assay.31 All but
a few of these compounds (1, 7, 15, and 27-31)

3306 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
Ta ble 1. Anti-TB (H37Rv) Activity
J ones et al.
displayed activity against M. tuberculosis. Minimum
inhibitory concentrations (MIC) ranged from less than
1 to 25 µg/mL for the active compounds. Compounds in
this family consist of four structural elements. These
are an acyl derivative, spacer, tetrahedral mimic, and
hydrophobic tail. The effects of each element on anti-
mycobacterial activity are discussed below.
Most of the compounds in Table 1 have a primary
amide as the acyl derivative. The exceptions are a
methyl ester (19, 20), benzyl ester (21, 22), carboxylic
acid (23), sulfone (29), or sulfamide (30). Both methyl
and benzyl esters were active against M. tuberculosis
but had decreased activity relative to the corresponding
amides. As the benzyl esters were slightly more active
than the corresponding methyl esters, it seems reason-
able to suggest that this segment of the molecule
occupies a large, flexible binding site or is protruding
into solution. The carboxylic acid 23, phosphinate 15,
and sulfonimide derivatives 28-30 are likely to be
ionized in the assay buffer (pH 7.2). As noted earlier, it
is likely these molecules are not able to enter the
mycobacterial cell.8
H37Rv. Thus, a methyl branch at this site, extension
to two methylenes, or replacement by a readily ionized
N-H is strongly unfavorable. This finding is consistent
with the original design as any spacing greater than
one atom would alter both the geometrical and elec-
tronic similarity between a potential inhibitor and the
putative KAS transition state depicted in Scheme 1.
With two exceptions the tetrahedral mimic employed
by compounds in Table 1 is a sulfone or a sulfoxide. In
general, a sulfone appears to give superior activity
relative to the corresponding sulfoxide. For example, the
MICs for 5 (sulfone) and 16 (sulfoxide) are 0.75 and 6.25
µg/mL, respectively. However, in the case of compounds
having an ester as the acyl derivative, a sulfoxide is
slightly more active than the corresponding sulfone.
Comparison of 21 and 22, with MICs of 6.25 and 12.5
µg/mL, respectively, demonstrates this behavior. There
is no explanation apparent for this difference between
the amide and ester. In the case of the sulfoxides,
activity was unaffected by the stereochemistry of the
sulfur. Both the R- and S-enantiomers of 17 and 18 were
prepared using the method of Naso.32 Each enantiomer
showed the same level of activity against H37Rv as the
racemate.
Most of the compounds shown in Table 1, and all
active compounds, have a single methylene spacer
between the tetrahedral mimic and acyl center. The
exceptions, 12, 13, and 28-30, are inactive against
It is not known whether these compounds undergo
oxidation to the sulfone under the conditions of the

New Class of Antituberculosis Agents
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3307
Sch em e 2a
a
(a) K2CO3, DMSO/acetone; (b) m-CPBA, CH2Cl2; (c) PPh3, DIAD, CH3COSH, THF; (d) K2CO3, MeOH, BrCH2CONH2; (e) aq NH3,
MeOH.
Sch em e 3a
Sch em e 4a
a
(a) 1. HMDS, C10H21I, THF, 2. HMDS, BrCH2CO2Me; (b) aq
NH3, i-PrOH.
anism of action of the compounds described in this
paper. That â-oxidation inhibition is not occurring was
also borne out in BACTEC assays of M. smegmatis,
which were still able to oxidize palmitate to carbon
dioxide (data not shown).
The most varied element in the set of compounds
studied was side chain length. The vast majority of the
compounds have a hydrocarbon tail, although one, 27,
has a glycol tail. This comparatively hydrophilic com-
pound, freely soluble in water, was completely inactive
against H37Rv. The most striking structural require-
ment for these compounds was the length of the side
chain. Compounds in Table 1 with a chain length
between 8 and 10 carbons were the most active. The
difference between a 7-carbon tail (2, MIC > 25 µg/mL)
and an 8-carbon tail (3, MIC ) 6.25 µg/mL) was
dramatic. A less abrupt loss of activity was observed in
the transition from a 10-carbon tail (5, MIC ) 0.75 µg/
mL) to a 12-carbon tail (6, MIC ) 12.5 µg/mL). However,
7 with a longer, 18-carbon tail was completely inactive
against H37Rv.
a
(a) BF3‚Et2O, CH2Cl2 0 °C; (b) 0.9 equiv m-CPBA, CH2Cl2; (c)
toluene, NaHCO3, 110 °C; (d) aq NH3, MeOH; (e) PTLC; (f)
m-CPBA, CH2Cl2.
assay. Possibly in keeping with this suggestion, the
simple thioether 14 displays low, but measurable,
activity against M. tuberculosis and may itself be
oxidized under the prolonged period of the assay. This
proposed background oxidation is supported by the
negative control that ether 31 displays extremely low
activity. The sharp decrease in activity for both 14 and
31, and for shorter- and longer-chain sulfones, argues
against inhibition of â-oxidation as one possible mech-

3308 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
J ones et al.
Regardless of additional substitution, the requirement
for an 8-10-carbon side chain appears to hold. Two
compounds having alkyl branches (8, MIC ) 1.5 µg/mL;
and 9, MIC ) 6.25 µg/mL) inhibited H37Rv growth.
Three compounds have a ω-phenyl substituent (24-26).
While none of these compounds was highly active
relative to the compounds lacking a phenyl group, the
most active of the three was 26, having a 10-carbon tail
(counting along the phenyl ring).
Two compounds were prepared that have an R,â-
unsaturated sulfone, 10 and 11. Surprisingly, these two
isomers (E and Z, respectively) were approximately
equal in their activity against H37Rv. Although an
NMR sample of 11 in 1:1 DMSO-d6:50 mM K2HPO4 (pH
8.0) did not show any isomerization in 5 days, the
addition of an equivalent of a thiol (38) led to loss of
the vinyl proton signals from the 1H NMR spectrum
within 30 min. This behavior suggests that, in vivo, an
addition-elimination reaction by nucleophiles in the cell
(such as glutathione, cysteine, etc.) could serve to
convert both 10 and 11 to the same equilibrium mixture,
which would then display similar MIC values. However,
these minimal experiments do not rule out the possibil-
ity that both 10 and 11 act as electrophiles and interfere
with some vital cell function with equivalent effective-
ness.
As the criteria for calculating MIC data using the
BACTEC assay system are rigid, compounds with equal
MICs may have different activity depending on the
conditions of the assay. For this reason, 14 compounds
(marked by asterisks, Table 1) were selected and as-
sayed against aliquots of a standard culture of H37Rv
at a concentration of 6.25 µg/mL. The results of these
assays are shown in Figure 1. With the exception of 20
and 22, all of these compounds effectively inhibited
mycobacterial growth for 10 days. However, for the most
active compounds even this assay did not adequately
distinguish which was the most active.
F igu r e 1. Activity of compounds as numbered in Table 1 at
6.25 µg/mL against M. tuberculosis strain H37Rv on day 10
posttreatment. Growth index in BACTEC units. Abbrevia-
tion: C, untreated control.
To make this distinction, four of the most active
compounds were tested against aliquots of a standard
H37Rv culture at a concentration of 3.0 µg/mL. The
growth curves generated in this assay are shown in
Figure 2. Compound 3, having an 8-carbon tail, was
clearly the least active of this group. The activity of 4
fell between 3 and the other two compounds. The two
remaining compounds, 5 and 8, were both highly active
against H37Rv, completely inhibiting mycobacterial
growth over 5 days.
The compounds marked with an asterisk in Table 1
were also tested against other bacterial strains includ-
ing Staphylococcus aureus (ATCC 29213), Enterococcus
faecalis (ATCC 29212), Escherichia coli (ATCC 25922),
and Pseudomonas aeruginosa (ATCC 27853). None
exhibited any activity against these bacteria at concen-
trations up to 50 µg/mL. In addition, 3 did not show
activity against M. smegmatis at concentrations as high
as 200 µg/mL.
Preliminary studies indicate that 3, but not cerulenin,
is active in the presence of serum.33 These studies also
demonstrated that 21 is a moderate inhibitor of myco-
bacterial type I FAS and that 3 inhibits the synthesis
of mycolic acids. The results of mechanistic and bio-
F igu r e 2. Seven-day BACTEC growth curves of M. tubercu-
losis strain H37Rv in the presence of 3.0 mg/mL of the four
most potent compounds listed in Table 1. Abbreviation: C,
untreated control.
chemical experiments conducted using the compounds
described in this paper will soon be reported else-
where.34
Con clu sion
A new class of readily synthesized compounds with
anti-TB activity has been prepared. The most active

New Class of Antituberculosis Agents
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3309
NMR (CDCl3, ppm) 171.97, 35.80, 33.10, 31.85, 29.50, 29.46,
29.26, 29.13, 29.08, 28.74, 22.65, 14.09. Anal. (C12H25NOS) C,
H, N, S.
members of this group are amide derivatives of 3-sul-
fonyl fatty acids with an alkyl tail of between 8 and 10
carbons in length. The MICs for these compounds are
comparable to those of the first-line anti-TB drugs. The
efficacy of these compounds is very sensitive to varia-
tions in alkyl tail length, charge and relative position
of the sulfone to the amide. Designed to be transition-
state mimics of the KAS step of fatty acid biosynthesis,
these compounds are highly species-specific, showing no
activity against other bacteria including strains of
nonpathogenic mycobacteria, such as M. smegmatis.
Met h yl 3-Th iot r id eca n oa t e (34f). Methyl thioglycolate
(2.43 mL, 27.1 mmol); 1-bromodecane (5.0 g, 22.6 mmol); the
residue was chromatographed over silica gel (10% EtOAc in
hexane) to give a white solid: 5.4 g, 22.1 mmol, 99%; 1H NMR
(CDCl3, ppm) 3.71 (s, 3H), 3.20 (s, 2H), 2.60 (t, J ) 7.4 Hz,
2H), 1.57 (m, 2H), 1.36 (m, 2H), 1.25 (m, 12H), 0.85 (t, J ) 6.8
Hz, 3H); 13C NMR (CDCl3, ppm) 171.03, 33.45, 32.72, 31.85,
29.51 (2 signals), 29.46, 29.27, 29.15, 28.94 (2 signals), 22.64,
14.07.
Meth yl 3-Th iop en ta d eca n oa te (39a ). Methyl thioglyco-
late (1.79 mL, 20.1 mmol); 1-bromododecane (5.0 g, 20.1 mmol);
the residue was chromatographed over silica gel (9% EtOAc/
hexane) to give a white solid that was used without further
purification: 5.0 g, 18.3 mmol, 91%; 1H NMR (CDCl3, ppm)
3.68 (s, 3H), 3.16 (s, 2H), 2.57 (t, J ) 7.4 Hz, 2H), 1.53 (m,
2H), 1.22 (m, 18H), 0.82 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3,
ppm) 170.88, 52.14, 33.31, 32.60, 31.80, 29.53, 29.51, 29.47,
29.39, 29.23, 29.07, 28.86, 28.63, 22.57, 13.98.
Exp er im en ta l Section
Melting points are uncorrected. Chemicals for which a
synthesis is not reported were purchased commercially. All
1H and 13C nuclear magnetic resonance (NMR) spectra were
recorded using a Varian Unity-400 spectrometer at 400 MHz
for 1H and 100 MHz for 13C, unless otherwise noted. Infrared
spectra were recorded using a Perkin-Elmer 1600 series FTIR
and a 0.1 mM NaCl solution cell or KBr disk. Elemental
analyses were performed by Atlantic Microlabs (Atlanta, GA).
Rep r esen ta tive Alk yla tion P r oced u r e: 3-Th ion on a n -
a m id e (34a ). To a suspension of potassium carbonate (4.00
g, 30 mmol) in acetone/DMSO (30 mL/10 mL) was added
bromoacetamide (1.38 g, 10 mmol) followed by hexanethiol (1.4
mL, 1.18 g, 10 mmol). The resulting mixture stirred at ambient
temperature for 24 h. The contents were then partitioned
between EtOAc (100 mL) and 1 N HCl (200 mL). The aqueous
layer was extracted twice more with EtOAc (30 mL each) and
the combined organic layers were washed with 1 N HCl (5 ×
50 mL), water (2 × 50 mL), brine (1 × 50 mL), and dried over
anhydrous MgSO4. Solvent was removed in vacuo to give a
white powder that was used without purification: 1H NMR
(CDCl3, ppm) 6.77 (bs, 1H), 6.46 (bs, 1H), 3.16 (s, 2H), 2.52 (t,
J ) 7.2 Hz, 2H), 1.57 (m, 2H), 1.25 (m, 6H), 0.84 (t, J ) 7.2
Hz, 3H); 13C NMR (CDCl3, ppm) 172.31, 35.76, 33.00, 31.23,
28.97, 28.33, 22.41, 13.91.
Meth yl 3-Th ioh en eicosa n oa te (39b). Methyl thioglyco-
late (1.59 g, 15.0 mmol); 1-bromooctadecane (5.0 g, 15.0 mmol);
the residue was chromatographed over silica gel (7.5% EtOAc/
hexane) to give a white, waxy solid: 4.85 g, 13.5 mmol, 90%;
mp 33-35 °C; 1H NMR (CDCl3, ppm) 3.70 (s, 3H), 3.19 (s, 2H),
2.59 (t, J ) 7.4 Hz, 2H), 1.56 (m, 2H), 1.34 (m, 2H), 1.22 (m,
28H), 0.85 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, ppm) 170.99,
52.25, 33.41, 32.69, 31.88, 29.66 (multiple signals), 29.55,
29.46, 29.32, 29.14, 28.93, 28.70, 22.65, 14.06.
Eth yl 4-Th iotetr a d eca n oa te (48). n-Decanethiol (2.1 mL,
1.74 g, 10.0 mmol); ethyl 3-bromopropionate (1.3 mL, 1.81 g,
10.0 mmol): 2.56 g (oil), 9.3 mmol, 93%; 1H NMR (CDCl3, ppm)
4.12 (q, J ) 7.2 Hz, 2H), 2.73 (t, J ) 7.2 Hz, 2H), 2.54 (t, J )
7.4 Hz, 2H), 2.48 (t, J ) 7.4 Hz, 2H), 1.52 (m, 2H), 1.28 (m,
17H), 0.83 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, ppm) 171.91,
60.50, 34.89, 32.08, 31.80, 29.49, 29.47, 29.44, 29.22, 29.14,
28.79, 26.90, 22.59, 14.12, 14.02.
Gen er a l Th ioa cetyla tion P r oced u r e: S-Acetyl 5-P h en -
ylp en ta n eth iol (36d ). To a solution of triphenylphosphine
(5.25 g, 20 mmol) in THF (50 mL) cooled to 0 °C was added a
solution of diisopropyl azodicarboxylate (4.17 g, 20 mmol) in
THF (15 mL) dropwise. The resulting solution stirred for 30
min during which time a yellow precipitate formed. Thiolacetic
acid (1.5 g, 20 mmol), 5-phenylpentanol (1.64 g, 10 mmol) in
THF (25 mL) were then added dropwise. The solution became
green. After stirring for 30 min at 0 °C, the solution was
allowed to warm to ambient temperature over the course of 1
h. The solution was transferred to a separatory funnel and
washed with 0.5 M NaOH (2 × 100 mL), water (1 × 100 mL),
brine (1 × 100 mL), dried over sodium sulfate, and concen-
trated in vacuo. The residue was chromatographed over silica
(7.5% EtOAc in hexane) to give a yellow oil: 1.84 g, 8.3 mmol,
3-Th iod eca n a m id e (34b). Bromoacetamide (1.38 g, 10
mmol); heptanethiol (1.53 mL, 1.32 g, 10 mmol): 1.85 g, 9.8
mmol, 98%; mp 73-74 °C; 1H NMR (CDCl3, ppm) 6.79 (bs,
1H), 5.80 (bs, 1H), 3.20 (s, 2H), 2.56 (t, J ) 7.2 Hz, 2H), 1.58
(m, 2H), 1.15 (m, 8H), 0.83 (t, J ) 7.2 Hz, 3H); 13C NMR
(CDCl3, ppm) 172.32, 35.76, 33.00, 31.59, 29.02, 28.73, 28.63,
22.49, 13.98. Anal. (C9H19NOS) C, H, N, S.
Meth yl 3-Th iou n d eca n oa te (34c). Octanethiol (2.50 mL,
14.4 mmol); methyl bromoacetate (1.36 mL, 14.4 mmol): 2.91
1
g, 13.3 mmol, 93%; H NMR (CDCl3, ppm) 3.69 (s, 3H), 3.18
(s, 2H), 2.58 (t, J ) 7.4 Hz, 2H), 1.56 (m, 2H), 1.33 (m, 2H),
1.25 (m, 8H), 0.84 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, ppm)
170.98, 52.24, 38.39, 32.66, 31.71, 29.08, 29.06, 28.90, 28.67,
22.56, 14.00.
3-Th iod od eca n a m id e (34d ). Bromoacetamide (860 mg,
6.23 mmol); nonanethiol (1.2 mL, 1 g, 6.23 mmol); used without
purification: 1H NMR (CDCl3, ppm) 6.78 (bs, 1H), 5.87 (bs,
1H), 3.20 (s, 2H), 2.56 (t, J ) 7.2 Hz, 2H), 1.59 (m, 2H), 1.27
(m, 12H), 0.87 (t, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, ppm)
173.03, 36.91, 34.20, 32.92, 30.53, 30.31, 30.24, 30.20, 29.85,
23.74, 15.19.
1
83%; H NMR (CDCl3, ppm) 7.28 (m, 2H), 7.18 (m, 3H), 2.87
(t, J ) 7.3 Hz, 2H), 2.61 (t, J ) 7.3 Hz, 2H), 2.32 (s, 3H), 1.63
(m, 4H). 1.42 (m, 2H); 13C NMR (CDCl3, ppm) 195.84, 142.34,
128.30, 128.19, 125.60, 35.67, 30.86, 30.55, 29.33, 29.95, 28.34.
S-Acetyl 8-Meth yln on a n eth iol (36a ). 8-Methylnonanol35
(1.24 g, 7.85 mmol); silica chromatography (0-5% EtOAc in
hexane) gave the product as a colorless oil: 1.50 g, 6.94 mmol,
1
88%; H NMR (CDCl3, ppm) 2.83 (t, J ) 7.5 Hz, 2H), 2.29 (s,
Meth yl 3-Th iod od eca n oa te (34e). Nonanethiol (15 g, 93.6
3H), 1.52 (m, 3H), 1.08-1.40 (bm, 10H), 0.83 (d, J ) 6.8 Hz,
6H); 13C NMR (CDCl3, ppm) 195.98, 38.93, 30.58, 29.68, 29.46,
29.11 (2 signals), 28.78, 27.90, 27.26, 22.60.
mmol); methyl bromoacetate (14.3 g, 93.6 mmol): 20.2 g, 89.4
mmol, 96%; H NMR (CDCl3, ppm) 3.72 (s, 3H), 3.21 (s, 2H),
1
2.61 (t, J ) 7.2 Hz, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 1.24 (m,
10H), 0.86 (t, J ) 8.0 Hz, 3H); 13C NMR (CDCl3, ppm) 171.06,
52.33, 33.46, 32.72, 31.84, 29.43, 29.23, 29.16, 28.95, 28.72,
22.64, 14.09.
3-Th iotr id eca n a m id e (14). Bromoacetamide (1.66 g, 12
mmol); n-decanethiol (1.74 g, 10 mmol); the product was
purified by recrystallization from hot hexane/EtOAc: 1.98 g,
9.12 mmol, 91%; mp 80-81 °C; 1H NMR (CDCl3, ppm) 6.76
(bs, 1H), 5.92 (bs, 1H), 3.19 (s, 2H), 2.54 (t, J ) 7.5 Hz, 2H),
1.57 (m, 2H), 1.1-1.3 (m, 14H), 0.86 (t, J ) 7.0 Hz, 3H); 13C
S-Acetyl 3,7-Dim eth ylocta n eth iol (36b). 3,7-Dimethyl-
octanol (1.58 g, 10 mmol); the product was isolated by
repetitive crystallization of the contaminant triphenylphos-
phine oxide; a yellow oil was obtained: 875 mg, 4.05 mmol,
41%; 1H NMR (CDCl3, ppm) 2.82 (complex multiplet, 2H), 2.29
(s, 3H), 1.51 (m, 3H), 1.38 (m, 1H), 1.23 (m, 4H), 1.09 (m, 4H),
0.87 (d, J ) 6.4 Hz, 3H), 0.84 (m, 6H); 13C NMR (CDCl3, ppm)
195.97, 39.17, 36.78, 36.51, 32.29, 30.58, 27.90, 27.06, 24.56,
22.65, 22.56, 19.21.

3310 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
J ones et al.
S-Acetyl 4-P h en ylbu ta n eth iol (36c). 4-Phenylbutanol
(1.50 g, 10 mmol); silica chromatography (5-10% EtOAc in
hexane) gave the product as a yellow oil: 2.05 g, 9.86 mmol,
(q, J ) 7.4 Hz, 2H), 3.22 (s, 2H), 2.75 (t, J ) 7.2 Hz, 2H), 1.17
(t, J ) 7.4 Hz, 3H); 13C NMR (ppm, CDCl3) 175.50, 72.02, 71.25,
70.84, 67.58, 36.20, 32.91, 15.42.
1
99%; H NMR (CDCl3, ppm) 7.27 (m, 2H), 7.18 (m, 3H), 2.90
Rep r esen ta tive Oxid a tion (Su lfon e) P r oced u r e: 3-Su l-
fon yln on a n a m id e (1). To a solution of 3-thiononamide (34a )
(1.69 g, 9.6 mmol) in 200 mL dichloromethane was added
m-CPBA (6.8 g, 40 mmol) slowly at ambient temperature. After
stirring for 12 h, the reaction mixture was concentrated in
vacuo. The white powdery residue was redissolved in EtOAc
(300 mL) and this solution washed with saturated potassium
carbonate (5 × 200 mL), water (1 × 100 mL), and brine (1 ×
100 mL). The organic layer was dried over anhydrous sodium
sulfate and concentrated in vacuo to give the sulfone as a white
solid which was recrystallized from hot hexane to give white
flakes: 964 mg, 4.7 mmol, 49%; mp 133-134 °C; 1H NMR (CD3-
OD, ppm) 3.96 (s, 2H), 3.28 (t, J ) 8.0 Hz, 2H), 1.80 (m, 2H),
1.48 (m, 2H), 1.33 (m, 4H), 0.90 (t, J ) 8.2 Hz, 3H); 13C NMR
(CD3OD, ppm) 166.80, 54.42, 49.80, 32.52, 29.26, 23.56, 22.88,
14.45. Anal. (C8H17NO3S) C, H, N, S.
(t, J ) 7.4 Hz, 2H), 2.63 (t, J ) 7.4 Hz, 2H), 2.32 (s, 3H), 1.65
(m, 4H); 13C NMR (CDCl3, ppm) 195.77, 141.93, 128.28, 128.22,
125.69, 35.27, 30.52, 30.40, 29.02, 28.81.
S-Acetyl 6-P h en ylh exa n eth iol (36e). 6-Phenylhexanol
(1.00 g, 5.62 mmol); silica chromatography (2% EtOAc in
hexane) gave the product as a yellow oil: 1.02 g, 4.31 mmol,
1
77%; H NMR (CDCl3, ppm) 7.27 (m, 2H), 7.18 (m, 3H), 2.85
(t, J ) 7.4 Hz, 2H), 2.60 (t, J ) 7.4 Hz, 2H), 2.31 (s, 3H), 1.60
(m, 4H). 1.36 (m, 4H); 13C NMR (CDCl3, ppm) 196.01, 142.60,
128.32, 128.19, 125.56, 35.80, 31.24, 30.59, 29.38, 29.06, 28.70,
28.60.
S-Acetyl 3,6-Dioxoocta n eth iol (36f). Ethylene glycol
ethyl ether (3.35 g, 25 mmol); silica chromatography (30%
EtOAc in hexane) gave the product as a yellow oil: 3.52 g,
18.3 mmol, 91%; 1H NMR (CDCl3, ppm) 3.52 (m, 8H), 3.04 (t,
J ) 6.4 Hz, 2H), 2.29 (s, 3H), 1.16 (t, J ) 7.0 Hz, 3H); 13C
NMR (CDCl3, ppm) 195.45, 72.21, 70.27, 69.67, 66.58, 30.47,
28.70, 15.06.
3-Su lfon yld eca n a m id e (2). 3-Thiodecanamide (34b) (500
mg, 2.64 mmol); a white solid was obtained which was
recrystallized from 100 mL boiling 3:1 EtOAc:hexane; white
needles were obtained: 490 mg, 2.21 mmol, 84%; mp 140-
Gen er a l in Situ Alk yla tion P r oced u r e: 8-Meth yl-3-
th iododecan am ide (34g). S-Acetyl-8-methylnonanethiol (36a)
(910 mg, 4.2 mmol) was dissolved in methanol (20 mL) and
the solution degassed by bubbling argon for 1 h. Potassium
carbonate (2.17 g, 16 mmol) was added in one portion. The
suspension stirred for 6 h at ambient temperature. Bromo-
acetamide (830 mg, 6 mmol) was added in one portion and
the resulting mixture stirred for 18 h. The pinkish mixture
was partitioned between ethyl acetate and water. The organic
layer was washed with 4 × 125 mL water, 1 × 125 mL aqueous
NH4Cl, 1 × 125 mL water, 1 × 125 mL brine, dried over
anhydrous MgSO4, and concentrated in vacuo to give a white
solid that was used without further purification: 1H NMR
(ppm, CDCl3) 6.80 (bs, 1H), 5.53 (bs, 1H), 3.28 (s, 2H), 2.46 (t,
J ) 7.2 Hz, 2H), 1.2-1.6 (m, 13H), 0.92 (d, J ) 7.8 Hz, 6H);
13C NMR (ppm, CDCl3) 171.89, 38.95, 35.79, 33.10, 29.71,
29.16, 29.09, 28.75, 27.93, 27.28, 22.62.
6,10-Dim eth yl-3-th iou n d eca n a m id e (34h ). S-Acetyl 3,7-
dimethyloctanethiol (36b) (875 mg, 4.05 mmol); silica chro-
matography (0-20% EtOH in CH2Cl2) afforded a viscous oil:
430 mg, 1.86 mmol, 46%; 1H NMR (ppm, CDCl3) 6.78 (bs, 1H),
6.10 (bs, 1H), 3.19 (s, 2H), 2.55 (m, 2H), 1.0-1.6 (m, 10H), 0.84
(m, 9H); 13C NMR (ppm, CDCl3) 172.09, 39.14, 36.83, 36.22,
35.83, 32.14, 30.95, 27.88, 24.58, 22.65, 22.55, 19.22.
7-P h en yl-3-th ioh ep ta m id e (34i). S-Acetyl 4-phenylbu-
tanethiol (36c) (1.08 g, 5.19 mmol); the product was isolated
crude and used without further purification: 747 mg, 3.35
mmol, 65%; 1H NMR (ppm, CDCl3) 7.29 (m, 2H), 7.16 (m, 3H),
6.70 (bs, 1H), 6.06 (bs, 1H), 3.17 (s, 2H), 2.59 (m, 4H), 1.67
(m, 4H); 13C NMR (ppm, CDCl3) 171.96, 141.87, 128.32, 128.30,
125.80, 38.91, 35.33, 32.87, 30.37, 28.53.
1
140.5 °C; H NMR (CDCl3, ppm) 6.51 (bs, 1H), 5.60 (bs, 1H),
3.86 (s, 2H), 3.14 (t, J ) 7.5 Hz, 2H), 1.88 (m, 2H), 1.35 (m,
8H), 0.88 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, ppm) 162.99,
58.50, 53.38, 31.38, 28.63, 28.25, 22.48, 21.88, 14.00. Anal.
(C9H19NO3S) C, H, N, S.
Meth yl 3-Su lfon ylu n d eca n oa te (20). Methyl 3-thioun-
decanoate (34c) (560 mg, 2.56 mmol): 626 mg (oil), 2.51 mmol,
98%; 1H NMR (CDCl3, ppm) 3.93 (s, 2H), 3.76 (s, 3H), 3.19 (t,
J ) 8.0 Hz, 2H), 1.80 (m, 2H), 1.41 (m, 2H), 1.25 (m, 8H), 0.82
(t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, ppm) 163.46, 56.98, 53.37,
53.18, 31.51, 28.80, 28.73, 28.15, 22.41, 21.65, 13.89. Anal.
(C11H22O4S) C, H, S.
3-Su lfon yld od eca n a m id e (4). 3-Thiododecanamide (34d )
(1.34 g, 6.18 mmol); a fluffy white solid was obtained after
recrystallization from hot hexane:EtOAc (150 mL, 2:1): 1.10
g, 4.64 mmol, 75%; mp 145-146 °C; 1H NMR (CDCl3, ppm)
6.50 (bs, 1H), 5.58 (bs, 1H), 3.84 (s, 2H), 3.12 (t, J ) 8.0 Hz,
2H), 1.85 (m, 2H), 1.42 (m, 2H), 1.25 (m, 10H), 0.86 (t, J ) 6.8
Hz, 3H); 13C NMR (CDCl3, ppm) 162.94, 58.49, 53.40, 31.76,
29.17, 29.12, 28.97, 28.30, 22.62, 21.89, 14.08. Anal. (C11H23
NO3S) C, H, N, S.
-
3-Su lfon yltr id eca n a m id e (5). 3-Thiotridecanamide (14)
(6.31 g, 27.3 mmol); a white solid was obtained which was
recrystallized from hot EtOAc to give shiny, white crystals:
4.37 g, 16.6 mmol, 61%; mp 141-142 °C; 1H NMR (DMSO-d6,
ppm) 7.70 (bs, 1H), 7.40 (bs, 1H), 3.95 (s, 2H), 3.19 (t, J ) 8.0
Hz, 2H), 1.64 (m, 2H), 1.33 (m, 2H), 1.22 (m, 12H), 0.83 (t,
J ) 7.0 Hz, 3H); 13C NMR (DMSO-d6, ppm) 163.84, 57.79,
52.54, 31.33, 28.96, 28.78, 28.72, 28.54, 27.73, 22.13, 21.08,
13.95. Anal. (C12H25NO3S) C, H, N, S.
8-P h en yl-3-th ioocta n a m id e (34j). S-Acetyl 5-phenylpen-
tanethiol (36d ) (588 mg, 2.61 mmol); the product was isolated
crude and used without further purification: 427 mg, 1.80
mmol, 69%; 1H NMR (ppm, CDCl3) 7.28 (m, 2H), 7.16 (m, 3H),
6.72 (bs, 1H), 6.30 (bs, 1H), 3.17 (s, 2H), 2.60 (t, J ) 7.6 Hz,
2H), 2.54 (t, J ) 7.6 Hz, 2H), 1.62 (m, 4H), 1.42 (m, 2H); 13C
NMR (ppm, CDCl3) 172.17, 142.25, 128.29, 128.20, 125.63,
38.87, 35.65, 32.87, 30.86, 28.87, 28.24.
9-P h en yl-3-th ion on a m id e (34k ). S-Acetyl 6-phenylpen-
tanethiol (36e) (464 mg, 1.85 mmol); the product was isolated
crude and used without further purification: 466 mg, 1.65
mmol, 89%; 1H NMR (ppm, CDCl3) 7.26 (m, 2H), 7.16 (m, 3H),
6.75 (bs, 1H), 6.40 (bs, 1H), 3.18 (s, 2H), 2.59 (t, J ) 7.7 Hz,
2H), 2.54 (t, J ) 7.3 Hz, 2H), 1.61 (m, 4H), 1.38 (m, 4H); 13C
NMR (ppm, CDCl3) 172.24, 142.47, 128.29, 128.16, 125.55,
35.72, 32.91, 29.00, 28.88, 28.64, 28.49, 28.24.
Meth yl 3-Su lfon yltr id eca n oa te (5a ). Methyl 3-thiotridec-
anoate (34f) (3.0 g, 12.2 mmol); a brown solid was obtained
that was recrystallized from hot hexane/EtOAc to give white,
shiny crystals: 2.66 g, 9.54 mmol, 78%; mp 45-47 °C; 1H NMR
(CDCl3, ppm) 3.94 (s, 2H), 3.80 (s, 3H), 3.22 (t, J ) 8.0 Hz,
2H), 1.82 (m, 2H), 1.42 (m, 2H), 1.25 (m, 12H), 0.85 (t, J ) 6.8
Hz, 3H); 13C NMR (CDCl3, ppm) 163.55, 57.09, 53.48, 53.27,
31.78, 29.37, 29.17, 28.94 (2 signals), 28.26, 22.59, 21.80, 14.03.
Meth yl 3-Su lfon ylp en ta d eca n oa te (40a ). Methyl 3-thio-
pentadecanoate (39a ) (4.82 g, 17.6 mmol); a brown solid was
obtained and recrystallized from hot hexane to give white,
shiny crystals: 3.99 g, 13.1 mmol, 74%; mp 58-60 °C; 1H NMR
(CDCl3, ppm) 3.94 (s, 2H), 3.81 (s, 3H), 3.23 (t, J ) 8.0 Hz,
2H), 1.84 (m, 2H), 1.44 (m, 2H), 1.23 (m, 16H), 0.86 (t, J ) 6.8
Hz, 3H); 13C NMR (CDCl3, ppm) 163.58, 57.12, 53.52, 53.32,
31.87, 29.55 (2 signals), 29.45, 29.29, 29.20, 28.98, 28.30, 22.65,
21.85, 14.09.
6,9-Oxo-3-th iou n d eca n a m id e (34l). S-Acetyl-3,6-dioxo-
octanethiol (36f) (2.23 g, 11.6 mmol); a clear oil was obtained,
which was a hydrate of the desired compound and used
without further purification: 1H NMR (ppm, CDCl3) 7.05 (bs,
1H), 5.77 (bs, 1H), 3.72 (t, 2H, J ) 7.2 Hz), 3.59 (m, 4H), 3.52
Meth yl 3-Su lfon ylh en eicosa n oa te (40b). Methyl 3-thio-
heneicosanoate (39b) (3.0 g, 8.4 mmol); a white solid was
obtained: 2.5 g, 6.4 mmol, 76%; mp 71-73 °C; 1H NMR (CDCl3,
ppm) 3.94 (s, 2H), 3.81 (s, 3H), 3.23 (t, J ) 8.0 Hz, 2H), 1.85

New Class of Antituberculosis Agents
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3311
(m, 2H), 1.44 (m, 2H), 1.26 (m, 28H), 0.86 (t, J ) 6.8 Hz, 3H);
13C NMR (CDCl3, ppm) 163.58, 57.14, 53.53, 31.91, 29.68
(multiple signals), 29.57, 29.47, 29.35, 29.22, 29.00, 28.32,
22.68, 21.87, 14.11.
8-Meth yl-3-su lfon yld od eca n a m id e (8). 8-Methyl-3-thio-
dodecanamide (34g) (0.960 g, 4.2 mmol); a white solid was
obtained which was recrystallized from hot EtOAc:hexane (1:
3) to give white crystals: 573 mg, 2.18 mmol, 52%; mp 136-
137 °C; 1H NMR (ppm, CDCl3) 6.56 (bs, 1H), 5.68 (bs, 1H),
3.85 (s, 2H), 3.13 (t, J ) 8.1 Hz, 2H), 1.84 (m, 2H), 1.2-1.6
(m, 9H), 0.83 (d, J ) 6.8 Hz, 6H); 13C NMR (ppm, CDCl3)
163.02, 58.49, 53.38, 38.88, 30.93, 29.46, 29.00, 28.30, 27.91,
27.20, 22.61. Anal. (C12H25NO3S) C, H, N, S.
Eth yl 4-Su lfon yltetr a d eca n oa te (51). Ethyl 4-thiotet-
radecanoate (48) (2.56 g, 9.3 mmol); a white solid was obtained
and used without further purification: 2.48 g, 8.10 mmol, 87%;
1H NMR (CDCl3, ppm) 4.15 (q, J ) 7.2 Hz, 2H), 3.26 (t, J )
7.4 Hz, 2H), 2.95 (t, J ) 7.8 Hz, 2H), 2.83 (t, J ) 7.4 Hz, 2H),
1.82 (m, 2H), 1.40 (m, 2H), 1.23 (m, 15H), 0.84 (t, J ) 7.2 Hz,
3H); 13C NMR (CDCl3, ppm) 170.40, 61.39, 53.39, 47.82, 31.75,
29.36, 29.15 (2 signals), 28.94, 28.36, 26.80, 22.56, 21.86, 14.04,
14.01.
allowed to stir at ambient temperature for a further 12 h. The
mixture was partitioned between EtOAc (50 mL) and water
(50 mL). The aqueous layer was extracted with additional
EtOAc (3 × 50 mL). The combined organic layers were washed
with water (3 × 50 mL), brine (100 mL), dried over sodium
sulfate, and concentrated in vacuo to give a white solid: 231
1
mg, 0.79 mmol, 79%; H NMR (CDCl3, ppm) 3.91 (q, J ) 7.0
Hz, 1H), 3.81 (s, 3H), 3.15 (m, 2H), 1.82 (m, 2H), 1.62 (d, J )
7.0 Hz, 3H), 1.41 (m, 2H), 1.21 (m, 12H), 0.86 (t, J ) 6.8 Hz,
3H); 13C NMR (CDCl3, ppm) 167.23, 62.62, 53.28, 51.08, 31.81,
29.41, 29.20 (2 signals), 29.02, 28.47, 22.62, 21.18, 14.06, 10.57.
Gen er a l Am m on olysis P r oced u r e: 3-Su lfon ylu n d ec-
a n a m id e (3). Methyl 3-sulfonylundecanoate (20) (40 mg, 0.16
mmol) was dissolved in methanol (1 mL) and concentrated
aqueous ammonia (0.3 mL) was added causing the reaction to
turn yellow. The reaction was stirred at ambient temperature
for 18 h during which time an off-white precipitate formed.
The mixture was diluted with EtOAc (15 mL) and water (10
mL). The layers were separated and the aqueous layer was
extracted with additional EtOAc (3 × 15 mL). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated to an off-white solid: 22 mg, 0.94 mmol, 59%;
mp 140-142 °C; 1H NMR (CDCl3, ppm) 6.56 (bs, 1H), 5.69 (bs,
1H), 3.87 (s, 2H), 3.15 (t, J ) 8.0 Hz, 2H), 1.87 (m, 2H), 1.46
(m, 2H), 1.35 (m, 8H), 0.88 (t, J ) 6.8 Hz, 3H); 13C NMR (CD3-
OD, ppm) 166.78, 54.40, 49.60, 33.05, 30.27, 30.10, 29.57,
23.82, 22.90, 14.55. Anal. (C10H21NO3S) C, H, N, S.
6,10-Dim et h yl-3-su lfon ylu n d eca n a m id e (9). 6,10-Di-
methyl-3-thioundecanamide (34h ) (430 mg, 1.86 mmol); the
product was purified by recrystallization from hot hexane
followed by recrystallization from water/MeOH (3:1): 341 mg,
1
1.3 mmol, 70%; mp 99.5-100 °C; H NMR (DMSO-d6, ppm)
7.73 (bs, 1H), 7.43 (bs, 1H), 3.99 (s, 2H), 3.25 (m, 2H), 1.70
(m, 2H), 1.51 (m, 2H), 1.22 (m, 3H), 1.18 (m, 3H), 0.85 (m,
9H); 13C NMR (DMSO-d6, ppm) 163.83, 57.71, 50.63, 38.64,
36.07, 31.28, 27.57, 27.37, 23.97, 22.56, 22.48, 19.08. Anal.
(C12H25NO3S) C, H, N, S.
7-P h en yl-3-su lfon ylh ep ta m id e (24). 7-Phenyl-3-thiohep-
tamide (34i) (747 mg, 3.35 mmol); the product was purified
by recrystallization from hot hexane: 399 mg, 1.56 mmol, 47%;
mp 112-113 °C; 1H NMR (ppm, CDCl3) 7.29 (m, 2H), 7.16 (m,
3H), 6.51 (bs, 1H), 5.70 (bs, 1H), 3.85 (s, 2H), 3.17 (t, J ) 8.2
Hz, 2H), 2.65 (t, J ) 7.5 Hz, 2H), 1.91 (m, 2H), 1.69 (m, 2H);
13C NMR (ppm, CDCl3) 163.05, 141.04, 128.49, 128.34, 126.12,
58.54, 53.18, 35.23, 29.98, 21.49. Anal. (C12H17NO3S) C, H, N,
S.
8-P h en yl-3-su lfon ylocta n a m id e (25). 8-Phenyl-3-thio-
octamide (34j) (160 mg, 0.68 mmol); the product was purified
by recrystallization from hot hexane: 92 mg, 0.34 mmol, 50%;
mp 134-135 °C; 1H NMR (ppm, CDCl3) 7.28 (m, 2H), 7.18 (m,
3H), 6.52 (bs, 1H), 5.78 (bs, 1H), 3.88 (s, 2H), 3.14 (t, J ) 8.2
Hz, 2H), 2.63 (t, J ) 7.5 Hz, 2H), 1.90 (m, 2H), 1.67 (m, 2H),
1.49 (m, 2H); 13C NMR (ppm, CDCl3) 163.00, 141.83, 128.36
(2 signals), 125.87, 58.52, 53.23, 35.43, 30.73, 27.82, 21.76.
Anal. (C13H19NO3S), C, H, N, S.
3-Su lfon ylp en ta d eca n a m id e (6). Methyl 3-sulfonylpen-
tadecanoate (40a ) (2.95 g, 9.67 mmol); a white solid was
obtained which was recrystallized from hot EtOAc (100 mL)
to give shiny, white crystals: 1.74 g, 6.0 mmol, 62%; mp 144-
145 °C; 1H NMR (DMSO-d6, ppm) 7.70 (bs, 1H), 7.40 (bs, 1H),
3.95 (s, 2H), 3.21 (t, J ) 8.0 Hz, 2H), 1.66 (m, 2H), 1.32 (m,
2H), 1.21 (m, 16H), 0.82 (t, J ) 7.2 Hz, 3H); 13C NMR (DMSO-
d6, ppm) 163.80, 57.75, 52.47, 31.30, 29.01 (2 signals), 28.96,
28.72 (2 signals), 28.50, 27.69, 22.10, 21.06, 13.96. Anal.
(C14H29NO3S) C, H, N, S.
3-Su lfon ylh en eicosa n a m id e (7). Methyl 3-sulfonylhene-
icosanoate (40b) (350 mg, 0.9 mmol); a white solid was
obtained which was recrystallized from hot EtOAc to give
shiny, white crystals: 236 mg, 0.63 mmol, 70%; mp 139-140
°C; 1H NMR (DMSO-d6, ppm) 7.73 (bs, 1H), 7.44 (bs, 1H), 3.98
(s, 2H), 3.26 (t, J ) 8.0 Hz, 2H), 1.68 (m, 2H), 1.38 (m, 2H),
1.24 (m, 28H), 0.85 (t, J ) 7.2 Hz, 3H). Anal. (C20H41NO3S) C,
H, N, S.
3-Su lfen yld od eca n a m id e (17). Methyl 3-sulfenyldodec-
anoate (18) (0.79 g, 2.86 mmol); a white solid was obtained
which was recrystallized from a hot hexane/EtOAc mixture:
1
336 mg, 1.44 mmol, 50%; mp 127-128 °C; H NMR (CDCl3,
ppm) 6.98 (bs, 1H), 5.72 (bs, 1H), 3.66 (d, J ) 14.4 Hz, 1H),
3.25 (d, J ) 14.4 Hz, 1H), 2.91 (m, 1H), 2.76 (m, 1H), 1.80 (m,
9-P h en yl-3-su lfon yln on a m id e (26). 9-Phenyl-3-thionon-
amide (34k ) (170 mg, 0.67 mmol); the product was purified
by recrystallization from hot hexane: 116 mg, 0.41 mmol, 61%;
mp 116-117 °C; 1H NMR (ppm, CDCl3) 7.26 (m, 2H), 7.14 (m,
3H), 6.52 (bs, 1H), 5.71 (bs, 1H), 3.86 (s, 2H), 3.12 (t, J ) 8.1
Hz, 2H), 2.60 (t, J ) 7.5 Hz, 2H), 1.87 (m, 2H), 1.62 (m, 2H),
1.49 (m, 2H), 1.44 (m, 2H); 13C NMR (ppm, CDCl3) 166.79,
143.92, 129.56, 129.43, 126.83, 54.38, 49.50, 36.88, 32.53,
29.84, 29.39, 22.90. Anal. (C14H21NO3S), C, H, N, S.
6,9-Oxo-3-su lfon ylu n d eca n a m id e (27). 6,9-Dioxo-3-thio-
undecanamide (34l) (143 mg, 0.69 mmol); the product was
purified by flash chromatography (silica gel, 5% MeOH in
2H), 1.44 (m, 2H), 1.23 (m, 10H), 0.86 (t, J ) 6.8 Hz, 3H); 13
C
NMR (CDCl3, ppm) 166.08, 53.06, 51.49, 31.76, 29.23, 29.13,
29.10, 28.67, 22.87, 22.60, 14.06. Anal. (C11H23NO3S) C, H, N,
S.
4-Su lfon yltetr a d eca n a m id e (13). Ethyl 4-sulfonyltet-
radecanoate (51) (2.4 g, 7.84 mmol); the product was purified
by recrystallization from water/MeOH to give a white pow-
der: 1.16 g, 4.23 mmol, 54%; mp 138-139 °C; 1H NMR
(DMSO-d6, ppm) 7.46 (bs, 1H), 6.98 (bs, 1H), 3.22 (t, J ) 8.0
Hz, 2H), 3.06 (t, J ) 8.0 Hz, 2H), 2.48 (t, J ) 8.0 Hz, 2H), 1.62
(m, 2H), 1.80 (m, 2H), 1.33 (m, 2H), 1.22 (m, 10H), 0.83 (t, J
) 6.8 Hz, 3H); 13C NMR (CDCl3, ppm) 170.89, 51.73, 47.79,
31.29, 28.91, 28.77, 28.67, 28.49, 27.73, 27.17, 22.10, 21.28,
13.96. Anal. (C13H27NO3S) C, H, N, S.
1
EtOAc) to give a clear oil: 61 mg, 0.26 mmol, 38%; H NMR
(ppm, CD3OD) 4.13 (s, 2H), 3.93 (t, J ) 5.0 Hz, 2H), 3.5-3.7
(m, 8H), 1.17 (t, J ) 7.0 Hz, 3H); 13C NMR (ppm, CD3OD)
166.73, 71.48, 70.71, 67.63, 65.91, 61.05, 54.67, 15.61. Anal.
(C8H17NO5S) H, N, S; calcd C, 40.16; found C, 39.38.
Meth yl 2-Meth yl-3-su lfon yltr id eca n oa te (49). Methyl
3-sulfonyltridecanoate (5a ) (278 mg, 1.0 mmol) was dissolved
in dry methanol (12 mL) and sodium (23 mg, 1 mmol) was
added. The solution stirred until homogeneous (approximately
one h) and the solution was yellow. Methyl iodide (142 mg, 62
µL, 1 mmol) was added via syringe. After 1 h a precipitate
had formed and the color had dissipated. The reaction was
2-Meth yl-3-su lfon yltr id eca n a m id e (12). Methyl 2-meth-
yl-3-sulfonyltridecanoate (49) (225 mg, 0.75 mmol); the product
was purified by recrystallization from hot hexane: 161 mg,
1
0.58 mmol, 77%; mp 115-116 °C; H NMR (DMSO-d6, ppm)
7.71 (bs, 1H), 7.42 (bs, 1H), 3.88 (q, J ) 7.0 Hz, 1H), 3.05 (m,
2H), 2.48 (t, J ) 8.0 Hz, 2H), 1.62 (m, 2H), 1.38 (d, J ) 7.0
Hz, 3H), 1.36 (m, 2H), 1.21 (m, 10H), 0.82 (t, J ) 6.8 Hz, 3H);
13C NMR (DMSO-d6, ppm) 167.26, 62.72, 48.96, 31.28, 28.90,

3312 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
J ones et al.
28.75, 28.67, 28.53, 27.80, 22.09, 20.33, 13.96, 11.64. Anal.
(C13H27NO3S) C, H, N, S.
164.85, 134.71, 128.56, 128.55, 128.41, 67.59, 55.74, 52.78,
31.58, 28.97, 28.86, 28.55, 22.48, 22.19, 13.96. Anal. (C17H26O3S)
C, H, S.
R ep r esen t a t ive Oxid a t ion (Su lfoxid e) P r oced u r e:
Meth yl 3-Su lfen ylu n d eca n a oa te (19). Methyl 3-thiounde-
canoate (34c) (5.37 g, 24.8 mmol) was dissolved in CH2Cl2 (150
mL) and cooled to 0 °C in an ice-water bath. m-CPBA (3.85
g, 0.9 equiv) was added slowly in several portions. The solution
stirred for 45 min and then the reaction was quenched by
addition of 0.5 N NaOH (200 mL). The layers were separated
and the organic layer was washed once more with 0.5 N NaOH,
once with brine (100 mL), dried over anhydrous MgSO4 and
concentrated in vacuo. The white residue was recrystallized
from boiling hexane to give white crystals: 2.76 g, 13.1 mmol,
Ben zyl 3-Su lfon ylu n d eca n oa te (22). 3-Sulfonylundec-
anoic acid (23) (236 mg, 1.0 mmol): 310 mg, 0.92 mmol, 92%;
mp 39-40 °C; 1H NMR (CDCl3, ppm) 7.36 (m, 5H), 5.21 (s,
2H), 3.96 (s, 2H), 3.17 (t, J ) 8.1 Hz, 2H), 1.79 (m, 2H), 1.2-
1.4 (m, 10H), 0.87 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, ppm)
162.88, 134.37, 128.77, 128.68, 128.51, 68.23, 57.28, 53.54,
31.61, 28.87, 28.83, 28.23, 22.53, 21.79, 14.01. Anal. (C17H26O4S)
C, H, S.
n -Decyl Acetoxym eth ylp h osp h in ic Acid (47). Dry am-
monium phosphinate (ammonium hypophosphonate; 1.64 g,
19.8 mmol) was heated to 100 °C for 20 h under argon with
hexamethyldisilazane (4.4 mL, 21 mmol). After cooling in an
ice-water bath, dichloromethane (20 mL) was added and the
reaction mixture was stirred for 10 min, at which time n-decyl
iodide (4.2 mL, 19.8 mmol) was added over 10 min and stirring
was continued for 2 days at ambient temperature. The reaction
was then cooled to 0 °C and additional hexamethyldisilazane
(4.4 mL, 19.8 mmol) was added. After 2 h at 0 °C, methyl
bromoacetate (1.87 mL, 19.8 mmol) was added slowly over 10
min. The reaction mixture was stirred for 2 h at 0 °C, brought
to room temperature and stirred for 2 days. The reaction was
quenched by the addition of methanol (2 mL), filtered through
Celite and concentrated in vacuo. The residue was purified
by silica gel chromatography (2:5:93 formic acid:methanol:
acetonitrile) to give a viscous white oil: 1.57 g 5.64 mmol, 29%;
1H NMR (CDCl3, ppm) 10.00 (bs, 1H), 3.74 (s, 3H), 2.96 (d,
J ) 16.8 Hz, 2H), 1.77 (m, 2H), 1.62 (m, 2H), 1.26 (m, 14H),
0.88 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, ppm) 167.84, 52.14,
37.13 (d, J ) 78.6 Hz), 31.87, 30.82 (d, J ) 16.8 Hz), 29.57,
29.46, 29.31, 29.28 (d, J ) 98.4 Hz), 29.17, 22.65, 21.68 (d,
J ) 3.1 Hz), 14.08.
1
53%; mp 43-44 °C; H NMR (ppm, CDCl3) 3.79 (s, 3H), 3.68
(s, 2H), 3.25 (ABq, J AB ) 15.4 Hz, 2H), 1.79 (m, 2H), 1.46 (m,
2H), 1.2-1.35 (m, 8H), 0.88 (t, J ) 6.7 Hz, 3H); 13C NMR (ppm,
CDCl3) 165.54, 55.64, 52.96, 52.85, 31.68, 29.10, 28.96, 28.69,
22.57, 22.36, 14.04. Anal. (C11H22O3S) C, H, S.
Meth yl 3-Su lfen yld od eca n oa te (18). Methyl 3-thiododec-
anaoate (34e) (20.0 g, 88.5 mmol): 11.3 g, 46.7 mmol, 56%;
mp 124-125 °C; 1H NMR (ppm, CDCl3) 3.79 (s, 3H), 3.67 (ABq,
J AB ) 14.2 Hz, 2H), 2.74 (dt, J ) 14.3, 2.8 Hz, 2H), 1.78 (m,
2H), 1.45 (m, 2H), 1.2-1.35 (m, 10H), 0.86 (t, J ) 6.7 Hz, 3H);
13C NMR (ppm, CDCl3) 165.57, 55.63, 52.94, 52.81, 31.73,
29.21, 29.10 (2 signals), 28.65, 22.57, 22.32, 14.03. Anal.
(C12H24O3S) C, H, S.
3-Su lfen yltr id eca n a m id e (16). 3-thiotridecanamide (14)
(250 mg, 1.1 mmol); the sulfoxide was recrystallized from hot
1
hexane/EtOAc: 197 mg, 0.8 mmol, 80%; mp 127-128 °C; H
NMR (CDCl3, ppm) 7.60 (bs, 1H), 7.26 (bs, 1H), 3.52 (ABq,
J AB ) 13.3 Hz, 2H), 2.76 (m, 2H), 1.61 (m, 2H), 1.38 (m, 2H),
1.24 (m, 12H), 0.83 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3, ppm)
166.33, 57.08, 51.16, 31.30, 28.94, 28.83, 28.70, 28.70, 28.10,
22.11, 21.85, 13.97. Anal. (C12H25NO2S) C, H, N, S.
n -Decyl Acetoa m id op h osp h on ic Acid (15). Methyl ester
47 (150 mg, 0.54 mmol) was dissolved in a 1:1 solution of
2-propanol and aqueous ammonia (3 mL) and sealed in a
pressure tube. After heating overnight at 75 °C, the solution
was transferred to a round-bottomed flask and cooled in an
ice-water bath. To this solution was added 0.5 N KOH (1.5
mL) and stirred for 2 h. After acidification to pH ) 1 with 0.5
N HCl and cooling for 4 h at 4 °C, the precipitated product
was collected by vacuum filtration as white crystals: 116 mg,
Gen er a l Hyd r olysis P r oced u r e: 3-Su lfen ylu n d eca n oic
Acid (50). Methyl 3-sulfenylundecanoate (19) (2.02 g, 8.70
mmol) was dissolved in 70 mL MeOH and 0.5 N NaOH(aq)
(100 mL) was added. The mixture was stirred at ambient
temperature for 2 h, extracted with ether (100 mL), acidified
(concentrated aqueous HCl), and extracted with EtOAc (3 ×
100 mL). The combined EtOAC extracts were washed with
water (5 × 100 mL), brine (1 × 100 mL), dried over anhydrous
MgSO4, and concentrated in vacuo to give the acid as a white
solid which was used without further purification: 1.74 g, 7.90
1
0.44 mmol, 82%; mp 150-153 °C; H NMR (D2O, ppm) 2.63
1
(d, J ) 16.3 Hz, 2H), 1.55 (m, 4H), 1.26 (m, 14H), 0.81 (t, J )
6.3 Hz, 3H); 13C NMR (D2O, ppm) 174.56, 40.44 (d, J ) 73.2
Hz), 31.33, 30.44 (d, J ) 16.0 Hz), 30.10 (d, J ) 96.1 Hz), 28.87,
28.75, 28.62, 28.41, 22.19, 21.94 (d, J ) 3.8 Hz), 13.56; exact
mass m/z 281.2001, C12H26O3NP requires 281.1994.
mmol, 91%; H NMR (CDCl3, ppm) 9.55 (bs, 1H), 3.62 (ABq,
J AB ) 14.6 Hz, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.78 (m, 2H),
1.46 (m, 2H), 1.2-1.4 (m, 8H), 0.88 (t, J ) 6.9 Hz, 3H); 13C
NMR (CDCl3, ppm) 166.83, 54.40, 51.65, 31.59, 28.98, 28.87,
28.48, 22.47, 22.36, 13.95.
P ota ssiu m n -Decyl Acetoa m id op h osp h on a te (15). The
amide above was dissolved in 1 mL deionized water and
potassium hydroxide (1.0 equiv) was added. After stirring for
30 min, lyophilization yielded the potassium salt in quantita-
tive yield.
3-Su lfon ylu n d eca n oic Acid (23). Methyl 3-sulfonylun-
decanoate (20) (3.75 g, 15 mmol); the acid was recrystallized
from hot hexane: 1.78 g, 7.6 mmol, 51%; mp 92-94 °C; 1H
NMR (CDCl3, ppm) 9.87 (bs, 1H), 4.01 (s, 2H), 3.27 (t, J ) 8.1
Hz, 2H), 1.87 (m, 2H), 1.46 (m, 2H), 1.2-1.4 (m, 8H), 0.88 (t,
J ) 6.9 Hz, 3H); 13C NMR (CDCl3, ppm) 166.93, 56.99, 53.79,
3-Oxotr id eca n a m id e (31). Sodium hydride (60% in min-
eral oil, 480 mg, 20 mmol) was suspended in dry DMF (15 mL).
Decyl alcohol (5 mL, 26.2 mmol) was added and the mixture
stirred at ambient temperature for 30 min as gas evolved. After
gas evolution ceased, chloroacetamide (2 g, 21.5 mmol) was
added in one portion. The reaction stirred at ambient temper-
ature for 12 h. The reaction mixture was then partitioned
between 0.1 N HCl (300 mL) and chloroform (100 mL). The
aqueous layer was extracted twice more with chloroform (100
mL each) and the combined organic layers were washed with
brine (150 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was dissolved in ether (20
mL) and toluene (20 mL) and cooled to -15 °C. White crystals
formed and were collected and dried in vacuo to give the
product: 3.96 g, 18.4 mmol, 92%; mp 83-84 °C; 1H NMR
(CDCl3, ppm) 6.52 (bs, 1H), 6.04 (bs, 1H), 3.90 (s, 2H), 3.48 (t,
J ) 7.2 Hz, 2H), 1.56 (m, 2H), 1.22 (m, 14H), 0.83 (t, J ) 7.4
Hz, 3H); 13C NMR (CDCl3, ppm) 173.03, 71.85, 69.97, 31.84,
29.52, 29.48, 29.36, 29.27, 26.00, 26.64, 22.64, 14.07. Anal.
(C12H25NO3) C, H, N.
31.64, 28.94, 28.86, 28.27, 22.56, 21.83, 14.04. Anal. (C10H20
SO4) C,H,S.
-
Gen er a l EDC Cou p lin g P r oced u r e: Ben zyl 3-Su lfen yl-
u n d eca oa te (21). To a stirring solution of 3-sulfenylundec-
anoic acid (50) (600 mg, 2.72 mmol) in chloroform (50 mL) were
added DMAP (33 mg, 0.27 mmol 10 mol %) and benzyl alcohol
(324 mg, 3 mmol). To this solution was added, in several
portions, EDC (574 mg, 3 mmol). The solution stirred at
ambient temperature for 18 h and then was diluted with
EtOAc (250 mL). The mixture was washed 3 × 100 mL
saturated aqueous sodium bicarbonate, 3 × 0.5 N aqueous HCl,
2 × 100 mL water, and 1 × 100 mL brine. The organic layer
was dried over anhydrous MgSO4 and was concentrated in
vacuo. The residue was chromatographed over silica gel (30-
100% EtOAc in hexane) to give a white powder that was
recrystallized from boiling hexane: 428 mg, 1.38 mmol, 51%;
mp 44-45 °C; 1H NMR (CDCl3, ppm) 7.34 (m, 5H), 5.18 (s,
2H), 3.68 (s, 2H), 2.75 (m, 2H), 1.73 (m, 2H), 1.39 (m, 2H),
1.26 (m, 8H), 0.85 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, ppm)

New Class of Antituberculosis Agents
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17 3313
Non yl Ald eh yd e Dim eth yla cetylth ioa ceta l (42). Nonyl
aldehyde (41) (0.85 mL, 5 mmol) was dissolved in chloroform
(10 mL) and cooled to 0 °C. Boron trifluoride etherate (5.5
mmol) was added and the mixture stirred for 5 min. Methyl
thioglycolate (0.9 mL, 10 mmol) was added neat to the yellow
solution. The solution stirred for 1 h at 0 °C. The reaction was
quenched by addition of ice and partitioned between water and
chloroform. The organic layer was washed with 2 × 50 mL
aqueous sodium bicarbonate, 2 × 50 mL aqueous ammonium
chloride, 2 × 50 mL water, 1 × 50 mL brine, dried over
anhydrous MgSO4, and concentrated in vacuo to give pure
thioacetal: 1.48 g, 4.75 mmol, 95%; 1H NMR (ppm, CDCl3) 4.06
(t, J ) 6.0 Hz, 1H), 3.68 (s, 6H), 3.35 (ABq, J AB ) 14.6 Hz,
4H), 1.75 (m, 2H), 1.47 (m, 2H), 1.23 (m, 10H), 0.84 (t, 3H,
J ) 6.6 Hz); 13C NMR (ppm, CDCl3) 170.87, 53.05, 52.46, 35.24,
31.85, 31.82, 29.36, 29.20, 29.00, 27.32, 22.64, 14.09.
m-CPBA (1.8 mmol, 310 mg). The mixture stirred at ambient
temperature for 24 h. The solution was diluted with chloroform
and washed 3 × 150 mL aqueous sodium bicarbonate, 1 × 50
mL water, 1 × 50 mL brine, dried over anhydrous MgSO4, and
concentrated in vacuo to give the desired sulfone as a white
solid: 134 mg, 0.54 mmol, 87%; mp 106-108 °C; 1H NMR
(ppm, CDCl3) 6.97 (dt, J ) 6.9, 15.1 Hz, 1H), 6.68 (bs, 1H),
6.37 (dt, J ) 1.4, 15.1 Hz, 1H), 5.96 (bs, 1H), 3.87 (s, 2H), 2.28
(m, 2H), 1.47 (m, 2H), 1.2-1.4 (m, 8H), 0.84 (t, J ) 7.3 Hz,
3H); 13C NMR (ppm, CDCl3) 162.90, 151.89, 126.76, 60.46,
31.71, 31.61, 28.96, 28.91, 27.44, 22.57, 14.04. Anal. (C11H21
NO3S) C, H, N, S.
-
(Z)-3-Su lfon yld od ec-4-en a m id e (11). Amide 45Z (134 mg,
0.54 mmol) was dissolved in CH2Cl2 (10 mL) and treated with
m-CPBA (1.8 mmol, 310 mg). The mixture stirred at ambient
temperature for 24 h. The solution was diluted with chloroform
and washed 3 × 150 mL aqueous sodium bicarbonate, 1 × 50
mL water, 1 × 50 mL brine, dried over anhydrous MgSO4, and
concentrated in vacuo to give the desired sulfone as a white
solid: 121 mg, 0.49 mmol, 91%; mp 99-100 °C; 1H NMR (ppm,
CDCl3) 6.58 (bs, 1H), 6.47 (dt, J ) 7.1, 10.9 Hz, 1H), 6.26 (dt,
J ) 1.6, 10.9 Hz, 1H), 5.60 (bs, 1H), 3.88 (s, 2H), 2.63 (qd, J )
1.6, 7.6 Hz, 2H), 1.47 (m, 2H), 1.2-1.4 (m, 8H), 0.85 (t, J )
7.3 Hz, 3H); 13C NMR (ppm, CDCl3) 162.85, 151.35, 126.51,
61.25, 31.65, 29.11, 28.94, 28.69, 28.12, 22.57, 14.08. Anal.
(C11H21NO3S) C, H, N, S.
N-Octa n esu lfon yl Meth a n esu lfon a m id e (29). Sodium
hydride (280 mg, 11.7 mmol) was suspended in dry DMF (10
mL). Methanesulfonamide (969 mg, 10.2 mmol, 4 equiv) was
added in one portion. Gas evolved and the gray solution turned
slightly yellow. After 90 min octanesulfonyl chloride was added
via syringe. Heat and gas were again generated. The reaction
stirred at ambient temperature for 20 h. The mixture was
diluted with water (10 mL) and concentrated HCl (10 drops)
was added. The mixture was poured into 1 N HCl and
extracted 3 × 50 mL EtOAc. The combined organic layers were
washed with 1 N HCl (3 × 50 mL), water (2 × 50 mL), brine
(1 × 50 mL), and dried over sodium sulfate. Solvent was
removed in vacuo to give a white solid which was recrystallized
from 50 mL boiling hexane: yield 570 mg, 2.10 mmol, 82%;
mp 80-81 °C; 1H NMR (CDCl3, ppm) 3.42 (t, J ) 8.0 Hz, 2H),
3.33 (s, 3H), 1.87 (m, 2H), 1.44 (m, 2H), 1.28 (m, 8H), 0.87 (t,
J ) 7.2 Hz, 3H); 13C NMR (CDCl3, ppm) 55.50, 43.53, 31.65,
28.89 (2 signals), 27.94, 23.15, 22.56, 14.04. Anal. (C9H21NO4S2)
C, H, N, S.
Meth yl 3-Su lfen yl-3-(ca r bom eth oxyth iom eth yl)d od ec-
a n oa te (43). Thioacetal 42 (320 mg, 1.03 mmol) was dissolved
in methylene chloride (8 mL) and treated with m-CPBA (172
mg, 1 mmol) at ambient temperature. The resulting solution
stirred for 18 h. It was then partitioned between aqueous
sodium bicarbonate and chloroform. The organic layer was
washed 4 × 50 mL aqueous sodium bicarbonate, 1 × 50 mL
water, 1 × 50 mL brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was chromatographed over
silica (10-25% MeCN-chloroform) to give the desired product
(a mixture of diastereomers) as a colorless oil: 199 mg, 0.62
1
mmol, 61%; H NMR (ppm, CDCl3, mixture of diastereomers
with the following signals) 4.14 (dd, J ) 3.6, 14.0 Hz, 0.5H),
4.01 (d, J ) 14.0 Hz, 0.5H), 3.94 (dd, J ) 7.2, 26.0 Hz, 0.5H),
3.85 (bs, 1.5H), 3.78 (s, 2H), 3.77 (s, 1H), 3.72 (s, 1H), 3.71 (s,
2H), 3.55-3.65 (m, 1H), 3.33 (dd, J ) 15.6, 18.0 Hz, 1H), 2.20
(m, 0.4H), 1.98 (m, 0.6H), 1.2-1.8 (bm, 13H), 0.82 (t, J ) 7.2
Hz, 3H).
(E,Z)-Meth yl 3-Th ia d od ec-4-en oa te (44). Monosulfoxide
43 (1.15 g, 3.5 mmol) was dissolved in toluene (120 mL) and
heated to reflux in the presence of sodium bicarbonate (1.4 g).
After 3.5 h, TLC indicated there was no starting material
remaining. The solution was washed 3 × 50 mL water, dried
over anhydrous MgSO4, and concentrated in vacuo to give an
oil. The oil was chromatographed over silica (4% ethyl acetate/
hexane) to give the desired olefin (1:1 mixture of geometric
isomers) as a clear, colorless oil: 600 mg, 2.61 mmol, 75%; 1H
NMR (ppm, CDCl3) 5.94 (m, 1H), 5.58-5.75 (m, 1H), 3.71 (2
singlets, 3H), 3.30 (s, 2H), 2.05 (m, 2H), 1.2-1.5 (m, 10H), 0.84
(t, J ) 7.2 Hz, 3H).
N-Octa n esu lfon ylsu lfa m id e (30). Sodium hydride (306
mg, 12.8 mmol) was suspended in dry DMF (10 mL). Sulfamide
(1.0 g, 10.4 mmol) was added in one portion. Gas evolved as
the reaction stirred at ambient temperature under an argon
atmosphere. After 45 min gas evolution had ceased and
octanesulfonyl chloride (0.5 mL, 2.55 mmol) was added via
syringe. Heat and gas were again evolved. After 2.5 h the
mixture was diluted with water (15 mL) and then 1 N HCl
(20 mL). The mixture was extracted with EtOAc (3 × 60 mL).
The combined organic layers were washed with 1 N HCl (6 ×
50 mL), water (2 × 40 mL), brine (3 × 50 mL), and dried over
sodium sulfate. Solvent was removed in vacuo to give a white
solid. This solid was recrystallized from 50 mL boiling hexane:
EtOAc (25:1) to give white flakes: 480 mg, 1.76 mmol, 69%;
mp 121-122 °C; 1H NMR (CDCl3, ppm) 5.40 (bs, 2H), 3.41 (t,
J ) 8.0 Hz, 2H), 1.86 (m, 2H), 1.45 (m, 2H), 1.28 (m, 8H), 0.88
(t, J ) 8.0 Hz, 3H); 13C NMR (CD3OD, ppm) 54.45, 32.84, 30.06,
30.03, 29.04, 24.32, 23.62, 14.39. Anal. (C8H20N2O4S2) C, H,
N, S.
Su scep tibility Testin g. Susceptibility testing and MIC
determination for M. tuberculosis (H37Rv) were carried out
at least in duplicate using the standard BACTEC radiometric
growth system (Becton Dickinson, Sparks, MD). Initial stock
solutions (1 mg/mL) and subsequent dilutions of test com-
pounds were prepared in DMSO (Sigma). Stock concentrations
(0.1 mL) were then added to individual 4.0-mL BACTEC
bottles resulting in the following final concentrations (µg/
mL): 50, 25, 12.5, 6.25, 3.0, 1.5. A 1.0 McFarland suspension
of M. tuberculosis (H37Rv) was prepared and 0.1 mL was
(E,Z)-3-Th ia d od ec-4-en a m id e (45). Methyl ester 44 (600
mg, 3.5 mmol) was dissolved in methanol (12 mL) and
ammonium hydroxide (5 mL) was added. The cloudy mixture
stirred at ambient temperature for 36 h. The mixture was
partitioned between ethyl acetate and water. The aqueous
layer was extracted 2 × 40 mL ethyl acetate and the combined
organic layers were washed 2 × aqueous sodium bicarbonate,
1 × 50 mL water, 1 × 50 mL brine, dried over anhydrous
MgSO4, and concentrated in vacuo to give a yellow-white solid,
which was the desired amide (487.4 mg, 2.27 mmol, 65%). The
geometric isomers were separated by preparative TLC (4 plates
of 200 µm thickness). The plates were eluted in the following
manner: 1 × 60% hexane/ether, 2 × 50% hexane/ether, 1 ×
40% hexane/ether, 1 × 30% hexane/ether, 2 × 25% hexane/
ether. The compound was visualized with UV and the two
bands were cleanly separated. The lead band had an Rf under
the above eluting conditions of 0.6 while the trailing band had
an Rf of 0.45.
(E)-3-Th iod od ec-4-en a m id e (45E). Leading band: 1H
NMR (ppm, CDCl3) 6.60 (bs, 1H), 5.96 (bs, 1H), 5.83 (d, J )
15.0 Hz, 1H), 5.71 (dt, J ) 6.9, 15.0 Hz, 1H), 3.30 (s, 2H), 2.02
(m, 2H), 1.2-1.4 (m, 10H), 0.83 (t, J ) 6.8 Hz, 3H).
(Z)-3-Th iod od ec-4-en a m id e (45Z). Trailing band: 1H
NMR (ppm, CDCl3) 6.52 (bs, 1H), 6.04 (bs, 1H), 5.80 (dt, J )
1.2, 9.3 Hz, 1H), 5.71 (dt, J ) 7.1, 9.3 Hz, 1H), 3.33 (s, 2H),
2.10 (m, 2H), 1.2-1.4 (m, 10H), 0.83 (t, J ) 6.8 Hz, 3H).
(E)-3-Su lfon yld od ec-4-en a m id e (10). Amide 45E (154 mg,
0.62 mmol) was dissolved in CH2Cl2 (10 mL) and treated with

3314 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 17
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Institute of Health (NIH AI43846) which funded this
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Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
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